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Part 3 / HEALTH HAZARDS

PART 3: HEALTH HAZARDS

3.1.   Acute toxicity

Acute toxicity

3.1.1.   Definitions

Definitions

▼M19 ▼M19

3.1.1.1. Acute toxicity means serious adverse health effects (i.e., lethality) occurring after a single or short-term oral, dermal or inhalation exposure to a substance or mixture.

3.1.1.1. Acute toxicity means serious adverse health effects (i.e., lethality) occurring after a single or short-term oral, dermal or inhalation exposure to a substance or mixture.  

▼B ▼B

3.1.1.2. The hazard class Acute Toxicity is differentiated into:

3.1.1.2. The hazard class Acute Toxicity is differentiated into:  

— 
Acute oral toxicity;
— 
— 
Acute oral toxicity;
Acute oral toxicity;
— 
Acute dermal toxicity;
— 
— 
Acute dermal toxicity;
Acute dermal toxicity;
— 
Acute inhalation toxicity.
— 
— 
Acute inhalation toxicity.
Acute inhalation toxicity.

3.1.2.   Criteria for classification of substances as acutely toxic

Criteria for classification of substances as acutely toxic

▼M19 ▼M19

3.1.2.1. Substances can be allocated to one of four hazard categories based on acute toxicity by the oral, dermal or inhalation route according to the numeric cut-off criteria as shown in the table below. Acute toxicity values are expressed as (approximate) LD50 (oral, dermal) or LC50 (inhalation) values or as acute toxicity estimates (ATE). While some in vivo methods determine LD50/LC50 values directly, other newer in vivo methods (e.g. using fewer animals) consider other indicators of acute toxicity, such as significant clinical signs of toxicity, which are used as a reference to assign the hazard category. Explanatory notes are shown following Table 3.1.1.

3.1.2.1. Substances can be allocated to one of four hazard categories based on acute toxicity by the oral, dermal or inhalation route according to the numeric cut-off criteria as shown in the table below. Acute toxicity values are expressed as (approximate) LD50 (oral, dermal) or LC50 (inhalation) values or as acute toxicity estimates (ATE). While some in vivo methods determine LD50/LC50 values directly, other newer in vivo methods (e.g. using fewer animals) consider other indicators of acute toxicity, such as significant clinical signs of toxicity, which are used as a reference to assign the hazard category. Explanatory notes are shown following Table 3.1.1.   50 50 in vivo 50 50 in vivo

Table 3.1.1

Acute toxicity estimate (ATE) values and criteria for acute toxicity hazard categories.

▼M2

Exposure route

Category 1

Category 2

Category 3

Category 4

Oral (mg/kg bodyweight)

ATE ≤ 5

5 < ATE ≤ 50

50 < ATE ≤ 300

300 < ATE ≤ 2 000

See:

Note (a)

Note (b)

Dermal (mg/kg bodyweight)

ATE ≤ 50

50 < ATE ≤ 200

200 < ATE ≤ 1 000

1 000 < ATE ≤ 2 000

See:

Note (a)

Note (b)

Gases (ppmV (1))

ATE ≤ 100

100 < ATE ≤ 500

500 < ATE ≤ 2 500

2 500 < ATE ≤ 20 000

see:

Note (a)

Note (b)

Note (c)

Vapours (mg/l)

ATE ≤ 0,5

0,5 < ATE ≤ 2,0

2,0 < ATE ≤ 10,0

10,0 < ATE ≤ 20,0

see:

Note (a)

Note (b)

Note (c)

Note (d)

Dusts and mists (mg/l)

ATE ≤ 0,05

0,05 < ATE ≤ 0,5

0,5 < ATE ≤ 1,0

1,0 < ATE ≤ 5,0

see:

Note (a)

Note (b)

Note (c)

(1)   

Gas concentrations are expressed in parts per million per volume (ppmV).

Table 3.1.1 Table 3.1.1

Acute toxicity estimate (ATE) values and criteria for acute toxicity hazard categories. Acute toxicity estimate (ATE) values and criteria for acute toxicity hazard categories.

▼M2 ▼M2

Exposure route

Category 1

Category 2

Category 3

Category 4

Oral (mg/kg bodyweight)

ATE ≤ 5

5 < ATE ≤ 50

50 < ATE ≤ 300

300 < ATE ≤ 2 000

See:

Note (a)

Note (b)

Dermal (mg/kg bodyweight)

ATE ≤ 50

50 < ATE ≤ 200

200 < ATE ≤ 1 000

1 000 < ATE ≤ 2 000

See:

Note (a)

Note (b)

Gases (ppmV (1))

ATE ≤ 100

100 < ATE ≤ 500

500 < ATE ≤ 2 500

2 500 < ATE ≤ 20 000

see:

Note (a)

Note (b)

Note (c)

Vapours (mg/l)

ATE ≤ 0,5

0,5 < ATE ≤ 2,0

2,0 < ATE ≤ 10,0

10,0 < ATE ≤ 20,0

see:

Note (a)

Note (b)

Note (c)

Note (d)

Dusts and mists (mg/l)

ATE ≤ 0,05

0,05 < ATE ≤ 0,5

0,5 < ATE ≤ 1,0

1,0 < ATE ≤ 5,0

see:

Note (a)

Note (b)

Note (c)

(1)   

Gas concentrations are expressed in parts per million per volume (ppmV).

Exposure route

Category 1

Category 2

Category 3

Category 4

Oral (mg/kg bodyweight)

ATE ≤ 5

5 < ATE ≤ 50

50 < ATE ≤ 300

300 < ATE ≤ 2 000

See:

Note (a)

Note (b)

Dermal (mg/kg bodyweight)

ATE ≤ 50

50 < ATE ≤ 200

200 < ATE ≤ 1 000

1 000 < ATE ≤ 2 000

See:

Note (a)

Note (b)

Gases (ppmV (1))

ATE ≤ 100

100 < ATE ≤ 500

500 < ATE ≤ 2 500

2 500 < ATE ≤ 20 000

see:

Note (a)

Note (b)

Note (c)

Vapours (mg/l)

ATE ≤ 0,5

0,5 < ATE ≤ 2,0

2,0 < ATE ≤ 10,0

10,0 < ATE ≤ 20,0

see:

Note (a)

Note (b)

Note (c)

Note (d)

Dusts and mists (mg/l)

ATE ≤ 0,05

0,05 < ATE ≤ 0,5

0,5 < ATE ≤ 1,0

1,0 < ATE ≤ 5,0

see:

Note (a)

Note (b)

Note (c)

(1)   

Gas concentrations are expressed in parts per million per volume (ppmV).

Exposure route

Category 1

Category 2

Category 3

Category 4

Exposure route

Exposure route

Category 1

Category 1

Category 2

Category 2

Category 3

Category 3

Category 4

Category 4

Oral (mg/kg bodyweight)

ATE ≤ 5

5 < ATE ≤ 50

50 < ATE ≤ 300

300 < ATE ≤ 2 000

Oral (mg/kg bodyweight)

Oral (mg/kg bodyweight)

ATE ≤ 5

ATE ≤ 5

5 < ATE ≤ 50

5 < ATE ≤ 50

50 < ATE ≤ 300

50 < ATE ≤ 300

300 < ATE ≤ 2 000

300 < ATE ≤ 2 000

See:

Note (a)

Note (b)

See:

See:

Note (a)

Note (b)

Note (a)

Note (b)

Dermal (mg/kg bodyweight)

ATE ≤ 50

50 < ATE ≤ 200

200 < ATE ≤ 1 000

1 000 < ATE ≤ 2 000

Dermal (mg/kg bodyweight)

Dermal (mg/kg bodyweight)

ATE ≤ 50

ATE ≤ 50

50 < ATE ≤ 200

50 < ATE ≤ 200

200 < ATE ≤ 1 000

200 < ATE ≤ 1 000

1 000 < ATE ≤ 2 000

1 000 < ATE ≤ 2 000

See:

Note (a)

Note (b)

See:

See:

Note (a)

Note (b)

Note (a)

Note (b)

Gases (ppmV (1))

ATE ≤ 100

100 < ATE ≤ 500

500 < ATE ≤ 2 500

2 500 < ATE ≤ 20 000

Gases (ppmV (1))

Gases (ppmV (1)) (1) 1

ATE ≤ 100

ATE ≤ 100

100 < ATE ≤ 500

100 < ATE ≤ 500

500 < ATE ≤ 2 500

500 < ATE ≤ 2 500

2 500 < ATE ≤ 20 000

2 500 < ATE ≤ 20 000

see:

Note (a)

Note (b)

Note (c)

see:

see:

Note (a)

Note (b)

Note (c)

Note (a)

Note (b)

Note (c)

Vapours (mg/l)

ATE ≤ 0,5

0,5 < ATE ≤ 2,0

2,0 < ATE ≤ 10,0

10,0 < ATE ≤ 20,0

Vapours (mg/l)

Vapours (mg/l)

ATE ≤ 0,5

ATE ≤ 0,5

0,5 < ATE ≤ 2,0

0,5 < ATE ≤ 2,0

2,0 < ATE ≤ 10,0

2,0 < ATE ≤ 10,0

10,0 < ATE ≤ 20,0

10,0 < ATE ≤ 20,0

see:

Note (a)

Note (b)

Note (c)

Note (d)

see:

see:

Note (a)

Note (b)

Note (c)

Note (d)

Note (a)

Note (b)

Note (c)

Note (d)

Dusts and mists (mg/l)

ATE ≤ 0,05

0,05 < ATE ≤ 0,5

0,5 < ATE ≤ 1,0

1,0 < ATE ≤ 5,0

Dusts and mists (mg/l)

Dusts and mists (mg/l)

ATE ≤ 0,05

ATE ≤ 0,05

0,05 < ATE ≤ 0,5

0,05 < ATE ≤ 0,5

0,5 < ATE ≤ 1,0

0,5 < ATE ≤ 1,0

1,0 < ATE ≤ 5,0

1,0 < ATE ≤ 5,0

see:

Note (a)

Note (b)

Note (c)

see:

see:

Note (a)

Note (b)

Note (c)

Note (a)

Note (b)

Note (c)

(1)   

Gas concentrations are expressed in parts per million per volume (ppmV).

(1)   

Gas concentrations are expressed in parts per million per volume (ppmV).

(1)   

Gas concentrations are expressed in parts per million per volume (ppmV).

(1)    1

Gas concentrations are expressed in parts per million per volume (ppmV).

Notes to Table 3.1.1: Notes to Table 3.1.1:

(a) 

The acute toxicity estimate (ATE) for the classification of a substance is derived using the LD50/LC50 where available.

(a) 
(a) 

The acute toxicity estimate (ATE) for the classification of a substance is derived using the LD50/LC50 where available.

The acute toxicity estimate (ATE) for the classification of a substance is derived using the LD50/LC50 where available. 50 50

(b) 

The acute toxicity estimate (ATE) for the classification of a substance in a mixture is derived using:

— 
the LD50/LC50 where available,
— 
the appropriate conversion value from Table 3.1.2 that relates to the results of a range test, or
— 
the appropriate conversion value from Table 3.1.2 that relates to a classification category.
(b) 
(b) 

The acute toxicity estimate (ATE) for the classification of a substance in a mixture is derived using:

— 
the LD50/LC50 where available,
— 
the appropriate conversion value from Table 3.1.2 that relates to the results of a range test, or
— 
the appropriate conversion value from Table 3.1.2 that relates to a classification category.

The acute toxicity estimate (ATE) for the classification of a substance in a mixture is derived using:

— 
the LD50/LC50 where available,
— 
— 
the LD50/LC50 where available,
the LD50/LC50 where available,
50 50
— 
the appropriate conversion value from Table 3.1.2 that relates to the results of a range test, or
— 
— 
the appropriate conversion value from Table 3.1.2 that relates to the results of a range test, or
the appropriate conversion value from Table 3.1.2 that relates to the results of a range test, or
— 
the appropriate conversion value from Table 3.1.2 that relates to a classification category.
— 
— 
the appropriate conversion value from Table 3.1.2 that relates to a classification category.
the appropriate conversion value from Table 3.1.2 that relates to a classification category.

▼M4 ▼M4

(c) 

The ranges of the acute toxicity estimates (ATE) for inhalation toxicity used in the Table are based on 4-hour testing exposures. Conversion of existing inhalation toxicity data which have been generated using a 1-hour exposure can be carried out by dividing by a factor of 2 for gases and vapours and 4 for dusts and mists.

(c) 
(c) 

The ranges of the acute toxicity estimates (ATE) for inhalation toxicity used in the Table are based on 4-hour testing exposures. Conversion of existing inhalation toxicity data which have been generated using a 1-hour exposure can be carried out by dividing by a factor of 2 for gases and vapours and 4 for dusts and mists.

The ranges of the acute toxicity estimates (ATE) for inhalation toxicity used in the Table are based on 4-hour testing exposures. Conversion of existing inhalation toxicity data which have been generated using a 1-hour exposure can be carried out by dividing by a factor of 2 for gases and vapours and 4 for dusts and mists.

▼M2 ▼M2

(d) 

For some substances the test atmosphere will not just be a vapour but will consist of a mixture of liquid and vapour phases. For other substances the test atmosphere may consist of a vapour which is near the gaseous phase. In these latter cases, classification shall be based on ppmV as follows: Category 1 (100 ppmV), Category 2 (500 ppmV), Category 3 (2 500 ppmV), Category 4 (20 000 ppmV).

The terms ‘dust’, ‘mist’ and ‘vapour’ are defined as follows:

— 
dust: solid particles of a substance or mixture suspended in a gas (usually air),
— 
mist: liquid droplets of a substance or mixture suspended in a gas (usually air),
— 
vapour: the gaseous form of a substance or mixture released from its liquid or solid state.

Dust is generally formed by mechanical processes. Mist is generally formed by condensation of supersaturated vapours or by physical shearing of liquids. Dusts and mists generally have sizes ranging from less than 1 to about 100 μm.

(d) 
(d) 

For some substances the test atmosphere will not just be a vapour but will consist of a mixture of liquid and vapour phases. For other substances the test atmosphere may consist of a vapour which is near the gaseous phase. In these latter cases, classification shall be based on ppmV as follows: Category 1 (100 ppmV), Category 2 (500 ppmV), Category 3 (2 500 ppmV), Category 4 (20 000 ppmV).

The terms ‘dust’, ‘mist’ and ‘vapour’ are defined as follows:

— 
dust: solid particles of a substance or mixture suspended in a gas (usually air),
— 
mist: liquid droplets of a substance or mixture suspended in a gas (usually air),
— 
vapour: the gaseous form of a substance or mixture released from its liquid or solid state.

Dust is generally formed by mechanical processes. Mist is generally formed by condensation of supersaturated vapours or by physical shearing of liquids. Dusts and mists generally have sizes ranging from less than 1 to about 100 μm.

For some substances the test atmosphere will not just be a vapour but will consist of a mixture of liquid and vapour phases. For other substances the test atmosphere may consist of a vapour which is near the gaseous phase. In these latter cases, classification shall be based on ppmV as follows: Category 1 (100 ppmV), Category 2 (500 ppmV), Category 3 (2 500 ppmV), Category 4 (20 000 ppmV).

The terms ‘dust’, ‘mist’ and ‘vapour’ are defined as follows:

— 
dust: solid particles of a substance or mixture suspended in a gas (usually air),
— 
— 
dust: solid particles of a substance or mixture suspended in a gas (usually air),
dust: solid particles of a substance or mixture suspended in a gas (usually air),
— 
mist: liquid droplets of a substance or mixture suspended in a gas (usually air),
— 
— 
mist: liquid droplets of a substance or mixture suspended in a gas (usually air),
mist: liquid droplets of a substance or mixture suspended in a gas (usually air),
— 
vapour: the gaseous form of a substance or mixture released from its liquid or solid state.
— 
— 
vapour: the gaseous form of a substance or mixture released from its liquid or solid state.
vapour: the gaseous form of a substance or mixture released from its liquid or solid state.

Dust is generally formed by mechanical processes. Mist is generally formed by condensation of supersaturated vapours or by physical shearing of liquids. Dusts and mists generally have sizes ranging from less than 1 to about 100 μm.

▼B ▼B

3.1.2.2.   Specific considerations for classification of substances as acutely toxic Specific considerations for classification of substances as acutely toxic

3.1.2.2.1. The preferred test species for evaluation of acute toxicity by the oral and inhalation routes is the rat, while the rat or rabbit are preferred for evaluation of acute dermal toxicity. When experimental data for acute toxicity are available in several animal species, scientific judgement shall be used in selecting the most appropriate LD50 value from among valid, well-performed tests.

3.1.2.2.1. The preferred test species for evaluation of acute toxicity by the oral and inhalation routes is the rat, while the rat or rabbit are preferred for evaluation of acute dermal toxicity. When experimental data for acute toxicity are available in several animal species, scientific judgement shall be used in selecting the most appropriate LD50 value from among valid, well-performed tests.   50

3.1.2.3.   Specific considerations for classification of substances as acutely toxic by the inhalation route Specific considerations for classification of substances as acutely toxic by the inhalation route

3.1.2.3.1. Units for inhalation toxicity are a function of the form of the inhaled material. Values for dusts and mists are expressed in mg/l. Values for gases are expressed in ppmV. Acknowledging the difficulties in testing vapours, some of which consist of mixtures of liquid and vapour phases, the table provides values in units of mg/l. However, for those vapours which are near the gaseous phase, classification shall be based on ppmV.

3.1.2.3.1. Units for inhalation toxicity are a function of the form of the inhaled material. Values for dusts and mists are expressed in mg/l. Values for gases are expressed in ppmV. Acknowledging the difficulties in testing vapours, some of which consist of mixtures of liquid and vapour phases, the table provides values in units of mg/l. However, for those vapours which are near the gaseous phase, classification shall be based on ppmV.  

3.1.2.3.2.  ►M12  Of particular importance in classifying for inhalation toxicity is the use of well articulated values in the highest hazard categories for dusts and mists. ◄ Inhaled particles between 1 and 4 microns mean mass aerodynamic diameter (MMAD) will deposit in all regions of the rat respiratory tract. This particle size range corresponds to a maximum dose of about 2 mg/l. In order to achieve applicability of animal experiments to human exposure, dusts and mists would ideally be tested in this range in rats.

3.1.2.3.2.  ►M12  Of particular importance in classifying for inhalation toxicity is the use of well articulated values in the highest hazard categories for dusts and mists. ◄ Inhaled particles between 1 and 4 microns mean mass aerodynamic diameter (MMAD) will deposit in all regions of the rat respiratory tract. This particle size range corresponds to a maximum dose of about 2 mg/l. In order to achieve applicability of animal experiments to human exposure, dusts and mists would ideally be tested in this range in rats.   ►M12 ►M12 ►M12  ◄

3.1.2.3.3. In addition to classification for inhalation toxicity, if data are available that indicates that the mechanism of toxicity was corrosivity, the substance or mixture shall also be labelled as ‘corrosive to the respiratory tract’ (see note 1 in 3.1.4.1). Corrosion of the respiratory tract is defined by destruction of the respiratory tract tissue after a single, limited period of exposure analogous to skin corrosion; this includes destruction of the mucosa. The corrosivity evaluation can be based on expert judgment using such evidence as: human and animal experience, existing (in vitro) data, pH values, information from similar substances or any other pertinent data.

3.1.2.3.3. In addition to classification for inhalation toxicity, if data are available that indicates that the mechanism of toxicity was corrosivity, the substance or mixture shall also be labelled as ‘corrosive to the respiratory tract’ (see note 1 in 3.1.4.1). Corrosion of the respiratory tract is defined by destruction of the respiratory tract tissue after a single, limited period of exposure analogous to skin corrosion; this includes destruction of the mucosa. The corrosivity evaluation can be based on expert judgment using such evidence as: human and animal experience, existing (in vitro) data, pH values, information from similar substances or any other pertinent data.  

3.1.3.   Criteria for classification of mixtures as acutely toxic

Criteria for classification of mixtures as acutely toxic

3.1.3.1. The criteria for classification of substances for acute toxicity as outlined in section 3.1.2 are based on lethal dose data (tested or derived). For mixtures, it is necessary to obtain or derive information that allows the criteria to be applied to the mixture for the purpose of classification. The approach to classification for acute toxicity is tiered, and is dependent upon the amount of information available for the mixture itself and for its ingredients. The flow chart of Figure 3.1.1 outlines the process to be followed.

3.1.3.1. The criteria for classification of substances for acute toxicity as outlined in section 3.1.2 are based on lethal dose data (tested or derived). For mixtures, it is necessary to obtain or derive information that allows the criteria to be applied to the mixture for the purpose of classification. The approach to classification for acute toxicity is tiered, and is dependent upon the amount of information available for the mixture itself and for its ingredients. The flow chart of Figure 3.1.1 outlines the process to be followed.  

▼M2 ▼M2

3.1.3.2. For acute toxicity each route of exposure shall be considered for the classification of mixtures, but only one route of exposure is needed as long as this route is followed (estimated or tested) for all components and there is no relevant evidence to suggest acute toxicity by multiple routes. When there is relevant evidence of toxicity by multiple routes of exposure, classification is to be conducted for all appropriate routes of exposure. All available information shall be considered. The pictogram and signal word used shall reflect the most severe hazard category and all relevant hazard statements shall be used.

3.1.3.2. For acute toxicity each route of exposure shall be considered for the classification of mixtures, but only one route of exposure is needed as long as this route is followed (estimated or tested) for all components and there is no relevant evidence to suggest acute toxicity by multiple routes. When there is relevant evidence of toxicity by multiple routes of exposure, classification is to be conducted for all appropriate routes of exposure. All available information shall be considered. The pictogram and signal word used shall reflect the most severe hazard category and all relevant hazard statements shall be used.  

▼B ▼B

3.1.3.3. In order to make use of all available data for purposes of classifying the hazards of the mixtures, certain assumptions have been made and are applied where appropriate in the tiered approach:

3.1.3.3. In order to make use of all available data for purposes of classifying the hazards of the mixtures, certain assumptions have been made and are applied where appropriate in the tiered approach:  

(a) 

the ‘relevant ingredients’ of a mixture are those which are present in concentrations of 1 % (w/w for solids, liquids, dusts, mists and vapours and v/v for gases) or greater, unless there is a reason to suspect that an ingredient present at a concentration of less than 1 % is still relevant for classifying the mixture for acute toxicity (see Table 1.1).

(a) 
(a) 

the ‘relevant ingredients’ of a mixture are those which are present in concentrations of 1 % (w/w for solids, liquids, dusts, mists and vapours and v/v for gases) or greater, unless there is a reason to suspect that an ingredient present at a concentration of less than 1 % is still relevant for classifying the mixture for acute toxicity (see Table 1.1).

the ‘relevant ingredients’ of a mixture are those which are present in concentrations of 1 % (w/w for solids, liquids, dusts, mists and vapours and v/v for gases) or greater, unless there is a reason to suspect that an ingredient present at a concentration of less than 1 % is still relevant for classifying the mixture for acute toxicity (see Table 1.1).

(b) 

where a classified mixture is used as an ingredient of another mixture, the actual or derived acute toxicity estimate (ATE) for that mixture may be used, when calculating the classification of the new mixture using the formulas in section 3.1.3.6.1 and paragraph 3.1.3.6.2.3.

(b) 
(b) 

where a classified mixture is used as an ingredient of another mixture, the actual or derived acute toxicity estimate (ATE) for that mixture may be used, when calculating the classification of the new mixture using the formulas in section 3.1.3.6.1 and paragraph 3.1.3.6.2.3.

where a classified mixture is used as an ingredient of another mixture, the actual or derived acute toxicity estimate (ATE) for that mixture may be used, when calculating the classification of the new mixture using the formulas in section 3.1.3.6.1 and paragraph 3.1.3.6.2.3.

▼M2 ▼M2

(c) 

If the converted acute toxicity point estimates for all components of a mixture are within the same category, then the mixture should be classified in that category.

(c) 
(c) 

If the converted acute toxicity point estimates for all components of a mixture are within the same category, then the mixture should be classified in that category.

If the converted acute toxicity point estimates for all components of a mixture are within the same category, then the mixture should be classified in that category.

(d) 

When only range data (or acute toxicity hazard category information) are available for components in a mixture, they may be converted to point estimates in accordance with Table 3.1.2 when calculating the classification of the new mixture using the formulas in sections 3.1.3.6.1 and 3.1.3.6.2.3.

(d) 
(d) 

When only range data (or acute toxicity hazard category information) are available for components in a mixture, they may be converted to point estimates in accordance with Table 3.1.2 when calculating the classification of the new mixture using the formulas in sections 3.1.3.6.1 and 3.1.3.6.2.3.

When only range data (or acute toxicity hazard category information) are available for components in a mixture, they may be converted to point estimates in accordance with Table 3.1.2 when calculating the classification of the new mixture using the formulas in sections 3.1.3.6.1 and 3.1.3.6.2.3.

▼B ▼B

Figure 3.1.1

Tiered approach to classification of mixtures for acute toxicity image

Text of image Text of image

Test data on the mixture as a whole

No

Yes

Sufficient data available on similar mixtures to estimate classification hazards

Yes

Apply bridging principles outlined in section 1.1.3.

CLASSIFY

No

Available data for all ingredients

Yes

Apply formula in section 3.1.3.6.1

CLASSIFY

No

Other data available to estimate conversion values for classification

Yes

Apply formula in section 3.1.3.6.1

CLASSIFY

No

Convey hazards of the known ingredients

• Apply formula in section 3.1.3.6.1. (unknown ingredients equal or below 10 %)

• Apply formula in paragraph 3.1.3.6.2.3. (unknown ingredients > 10 %)

CLASSIFY

3.1.3.4.   Classification of mixtures where acute toxicity data are available for the complete mixture Classification of mixtures where acute toxicity data are available for the complete mixture

3.1.3.4.1. Where the mixture itself has been tested to determine its acute toxicity, it shall be classified according to the same criteria as those used for substances, presented in Table 3.1.1. If test data for the mixture are not available, the procedures presented under sections 3.1.3.5 and 3.1.3.6 shall be followed.

3.1.3.4.1. Where the mixture itself has been tested to determine its acute toxicity, it shall be classified according to the same criteria as those used for substances, presented in Table 3.1.1. If test data for the mixture are not available, the procedures presented under sections 3.1.3.5 and 3.1.3.6 shall be followed.  

3.1.3.5.   Classification of mixtures where acute toxicity data are available for the complete mixture: bridging principles Classification of mixtures where acute toxicity data are available for the complete mixture: bridging principles

3.1.3.5.1. Where the mixture itself has not been tested to determine its acute toxicity, but there are sufficient data on the individual ingredients and similar tested mixtures to adequately characterise the hazards of the mixture, these data shall be used in accordance with the bridging rules set out in section 1.1.3.

3.1.3.5.1. Where the mixture itself has not been tested to determine its acute toxicity, but there are sufficient data on the individual ingredients and similar tested mixtures to adequately characterise the hazards of the mixture, these data shall be used in accordance with the bridging rules set out in section 1.1.3.  

▼M2 ▼M2

3.1.3.5.2. If a tested mixture is diluted with a diluent that has an equivalent or lower toxicity classification than the least toxic original components, and which is not expected to affect the toxicity of other components, then the new diluted mixture may be classified as equivalent to the original tested mixture. Alternatively, the formula explained in section 3.1.3.6.1 can be applied.

3.1.3.5.2. If a tested mixture is diluted with a diluent that has an equivalent or lower toxicity classification than the least toxic original components, and which is not expected to affect the toxicity of other components, then the new diluted mixture may be classified as equivalent to the original tested mixture. Alternatively, the formula explained in section 3.1.3.6.1 can be applied.  

▼B ▼B

3.1.3.6.   Classification of mixtures based on ingredients of the mixture (Additivity formula) Classification of mixtures based on ingredients of the mixture (Additivity formula)

3.1.3.6.1.    Data available for all ingredients Data available for all ingredients Data available for all ingredients

In order to ensure that classification of the mixture is accurate, and that the calculation need only be performed once for all systems, sectors, and categories, the acute toxicity estimate (ATE) of ingredients shall be considered as follows:

(a) 

►M12  include ingredients with a known acute toxicity, which fall into any of the acute hazard categories shown in Table 3.1.1; ◄

(a) 
(a) 

►M12  include ingredients with a known acute toxicity, which fall into any of the acute hazard categories shown in Table 3.1.1; ◄

►M12  include ingredients with a known acute toxicity, which fall into any of the acute hazard categories shown in Table 3.1.1; ◄ ►M12 ►M12 ►M12  ◄

(b) 

ignore ingredients that are presumed not acutely toxic (e.g., water, sugar);

(b) 
(b) 

ignore ingredients that are presumed not acutely toxic (e.g., water, sugar);

ignore ingredients that are presumed not acutely toxic (e.g., water, sugar);

▼M2 ▼M2

(c) 

ignore components if the data available are from a limit dose test (at the upper threshold for Category 4 for the appropriate route of exposure as provided in Table 3.1.1) and do not show acute toxicity.

(c) 
(c) 

ignore components if the data available are from a limit dose test (at the upper threshold for Category 4 for the appropriate route of exposure as provided in Table 3.1.1) and do not show acute toxicity.

ignore components if the data available are from a limit dose test (at the upper threshold for Category 4 for the appropriate route of exposure as provided in Table 3.1.1) and do not show acute toxicity.

Components that fall within the scope of this section are considered to be components with a known acute toxicity estimate (ATE). See note (b) to Table 3.1.1 and section 3.1.3.3 for appropriate application of available data to the equation below, and section 3.1.3.6.2.3.

▼B ▼B

The ATE of the mixture is determined by calculation from the ATE values for all relevant ingredients according to the following formula for Oral, Dermal or Inhalation Toxicity:

image image

where:

Ci

=

concentration of ingredient i ( % w/w or % v/v)

Ci

=

concentration of ingredient i ( % w/w or % v/v)

Ci

=

concentration of ingredient i ( % w/w or % v/v)

Ci

Ci i

=

=

concentration of ingredient i ( % w/w or % v/v)

concentration of ingredient i ( % w/w or % v/v)

i

=

the individual ingredient from 1 to n

i

=

the individual ingredient from 1 to n

i

=

the individual ingredient from 1 to n

i

i

=

=

the individual ingredient from 1 to n

the individual ingredient from 1 to n

n

=

the number of ingredients

n

=

the number of ingredients

n

=

the number of ingredients

n

n

=

=

the number of ingredients

the number of ingredients

ATEi

=

Acute Toxicity Estimate of ingredient i.

ATEi

=

Acute Toxicity Estimate of ingredient i.

ATEi

=

Acute Toxicity Estimate of ingredient i.

ATEi

ATEi i

=

=

Acute Toxicity Estimate of ingredient i.

Acute Toxicity Estimate of ingredient i.

3.1.3.6.2.    Classification of mixtures when data are not available for all components Classification of mixtures when data are not available for all components Classification of mixtures when data are not available for all components

3.1.3.6.2.1. Where an ATE is not available for an individual ingredient of the mixture, but available information, such as that listed below, can provide a derived conversion value such as those laid out in Table 3.1.2, the formula in section 3.1.3.6.1 shall be applied.

3.1.3.6.2.1. Where an ATE is not available for an individual ingredient of the mixture, but available information, such as that listed below, can provide a derived conversion value such as those laid out in Table 3.1.2, the formula in section 3.1.3.6.1 shall be applied.  

This includes evaluation of:

(a) 

extrapolation between oral, dermal and inhalation acute toxicity estimates ( 15 ). Such an evaluation could require appropriate pharmacodynamic and pharmacokinetic data;

(a) 
(a) 

extrapolation between oral, dermal and inhalation acute toxicity estimates ( 15 ). Such an evaluation could require appropriate pharmacodynamic and pharmacokinetic data;

extrapolation between oral, dermal and inhalation acute toxicity estimates ( 15 ). Such an evaluation could require appropriate pharmacodynamic and pharmacokinetic data; 15 15

(b) 

evidence from human exposure that indicates toxic effects but does not provide lethal dose data;

(b) 
(b) 

evidence from human exposure that indicates toxic effects but does not provide lethal dose data;

evidence from human exposure that indicates toxic effects but does not provide lethal dose data;

(c) 

evidence from any other toxicity tests/assays available on the substance that indicates toxic acute effects but does not necessarily provide lethal dose data; or

(c) 
(c) 

evidence from any other toxicity tests/assays available on the substance that indicates toxic acute effects but does not necessarily provide lethal dose data; or

evidence from any other toxicity tests/assays available on the substance that indicates toxic acute effects but does not necessarily provide lethal dose data; or

(d) 

data from closely analogous substances using structure/activity relationships.

(d) 
(d) 

data from closely analogous substances using structure/activity relationships.

data from closely analogous substances using structure/activity relationships.

This approach generally requires substantial supplemental technical information, and a highly trained and experienced expert (expert judgement, see section 1.1.1), to reliably estimate acute toxicity. If such information is not available, proceed to paragraph 3.1.3.6.2.3.

▼M4 ▼M4

3.1.3.6.2.2. In the event that a component without any useable information for classification is used in a mixture at a concentration ≥ 1 %, it is concluded that the mixture cannot be attributed a definitive acute toxicity estimate. In this situation the mixture shall be classified based on the known components only, with the additional statement on the label and in the SDS that ‘x per cent of the mixture consists of component(s) of unknown acute toxicity’, taking into account the provisions set out in section 3.1.4.2.

3.1.3.6.2.2. In the event that a component without any useable information for classification is used in a mixture at a concentration ≥ 1 %, it is concluded that the mixture cannot be attributed a definitive acute toxicity estimate. In this situation the mixture shall be classified based on the known components only, with the additional statement on the label and in the SDS that ‘x per cent of the mixture consists of component(s) of unknown acute toxicity’, taking into account the provisions set out in section 3.1.4.2.  

3.1.3.6.2.3. If the total concentration of the relevant ingredient(s) with unknown acute toxicity is ≤ 10 % then the formula presented in section 3.1.3.6.1 shall be used. If the total concentration of the relevant ingredient(s) with unknown toxicity is > 10 %, the formula presented in section 3.1.3.6.1 shall be corrected to adjust for the percentage of the unknown ingredient(s) as follows:

3.1.3.6.2.3. If the total concentration of the relevant ingredient(s) with unknown acute toxicity is ≤ 10 % then the formula presented in section 3.1.3.6.1 shall be used. If the total concentration of the relevant ingredient(s) with unknown toxicity is > 10 %, the formula presented in section 3.1.3.6.1 shall be corrected to adjust for the percentage of the unknown ingredient(s) as follows:  

image image

▼B ▼B

Table 3.1.2

▼M2

Conversion from experimentally obtained acute toxicity range values (or acute toxicity hazard categories) to acute toxicity point estimates for use in the formulas for the classification of mixtures

▼B

Exposure routes

Classification Category or experimentally obtained acute toxicity range estimate

Converted acute toxicity point estimate

(see Note 1)

Oral

(mg/kg bodyweight)

0 < Category 1 ≤ 5

5 < Category 2 ≤ 50

50 < Category 3 ≤ 300

300 < Category 4 ≤ 2 000

0,5

5

100

500

Dermal

(mg/kg bodyweight)

0 < Category 1 ≤ 50

50 < Category 2 ≤ 200

200 < Category 3 ≤ 1 000

1 000 < Category 4 ≤ 2 000

5

50

300

1 100

Gases

(ppmV)

0 < Category 1 ≤ 100

100 < Category 2 ≤ 500

500 < Category 3 ≤ 2 500

2 500 < Category 4 ≤ 20 000

10

100

700

4 500

Vapours

(mg/l)

0 < Category 1 ≤ 0,5

0,5 < Category 2 ≤ 2,0

2,0 < Category 3 ≤ 10,0

10,0 < Category 4 ≤ 20,0

0,05

0,5

3

11

Dust/mist

(mg/l)

0< Category 1 ≤ 0,05

0,05 < Category 2 ≤ 0,5

0,5 < Category 3 ≤ 1,0

1,0 < Category 4 ≤ 5,0

0,005

0,05

0,5

1,5

Table 3.1.2

▼M2 ▼M2

Conversion from experimentally obtained acute toxicity range values (or acute toxicity hazard categories) to acute toxicity point estimates for use in the formulas for the classification of mixtures

▼B ▼B

Exposure routes

Classification Category or experimentally obtained acute toxicity range estimate

Converted acute toxicity point estimate

(see Note 1)

Oral

(mg/kg bodyweight)

0 < Category 1 ≤ 5

5 < Category 2 ≤ 50

50 < Category 3 ≤ 300

300 < Category 4 ≤ 2 000

0,5

5

100

500

Dermal

(mg/kg bodyweight)

0 < Category 1 ≤ 50

50 < Category 2 ≤ 200

200 < Category 3 ≤ 1 000

1 000 < Category 4 ≤ 2 000

5

50

300

1 100

Gases

(ppmV)

0 < Category 1 ≤ 100

100 < Category 2 ≤ 500

500 < Category 3 ≤ 2 500

2 500 < Category 4 ≤ 20 000

10

100

700

4 500

Vapours

(mg/l)

0 < Category 1 ≤ 0,5

0,5 < Category 2 ≤ 2,0

2,0 < Category 3 ≤ 10,0

10,0 < Category 4 ≤ 20,0

0,05

0,5

3

11

Dust/mist

(mg/l)

0< Category 1 ≤ 0,05

0,05 < Category 2 ≤ 0,5

0,5 < Category 3 ≤ 1,0

1,0 < Category 4 ≤ 5,0

0,005

0,05

0,5

1,5

Exposure routes

Classification Category or experimentally obtained acute toxicity range estimate

Converted acute toxicity point estimate

(see Note 1)

Oral

(mg/kg bodyweight)

0 < Category 1 ≤ 5

5 < Category 2 ≤ 50

50 < Category 3 ≤ 300

300 < Category 4 ≤ 2 000

0,5

5

100

500

Dermal

(mg/kg bodyweight)

0 < Category 1 ≤ 50

50 < Category 2 ≤ 200

200 < Category 3 ≤ 1 000

1 000 < Category 4 ≤ 2 000

5

50

300

1 100

Gases

(ppmV)

0 < Category 1 ≤ 100

100 < Category 2 ≤ 500

500 < Category 3 ≤ 2 500

2 500 < Category 4 ≤ 20 000

10

100

700

4 500

Vapours

(mg/l)

0 < Category 1 ≤ 0,5

0,5 < Category 2 ≤ 2,0

2,0 < Category 3 ≤ 10,0

10,0 < Category 4 ≤ 20,0

0,05

0,5

3

11

Dust/mist

(mg/l)

0< Category 1 ≤ 0,05

0,05 < Category 2 ≤ 0,5

0,5 < Category 3 ≤ 1,0

1,0 < Category 4 ≤ 5,0

0,005

0,05

0,5

1,5

Exposure routes

Classification Category or experimentally obtained acute toxicity range estimate

Converted acute toxicity point estimate

(see Note 1)

Exposure routes

Exposure routes

Classification Category or experimentally obtained acute toxicity range estimate

Classification Category or experimentally obtained acute toxicity range estimate

Converted acute toxicity point estimate

(see Note 1)

Converted acute toxicity point estimate

(see Note 1)

Oral

(mg/kg bodyweight)

0 < Category 1 ≤ 5

5 < Category 2 ≤ 50

50 < Category 3 ≤ 300

300 < Category 4 ≤ 2 000

0,5

5

100

500

Oral

(mg/kg bodyweight)

Oral

(mg/kg bodyweight)

0 < Category 1 ≤ 5

5 < Category 2 ≤ 50

50 < Category 3 ≤ 300

300 < Category 4 ≤ 2 000

0 < Category 1 ≤ 5

5 < Category 2 ≤ 50

50 < Category 3 ≤ 300

300 < Category 4 ≤ 2 000

0,5

5

100

500

0,5

5

100

500

Dermal

(mg/kg bodyweight)

0 < Category 1 ≤ 50

50 < Category 2 ≤ 200

200 < Category 3 ≤ 1 000

1 000 < Category 4 ≤ 2 000

5

50

300

1 100

Dermal

(mg/kg bodyweight)

Dermal

(mg/kg bodyweight)

0 < Category 1 ≤ 50

50 < Category 2 ≤ 200

200 < Category 3 ≤ 1 000

1 000 < Category 4 ≤ 2 000

0 < Category 1 ≤ 50

50 < Category 2 ≤ 200

200 < Category 3 ≤ 1 000

1 000 < Category 4 ≤ 2 000

5

50

300

1 100

5

50

300

1 100

Gases

(ppmV)

0 < Category 1 ≤ 100

100 < Category 2 ≤ 500

500 < Category 3 ≤ 2 500

2 500 < Category 4 ≤ 20 000

10

100

700

4 500

Gases

(ppmV)

Gases

(ppmV)

0 < Category 1 ≤ 100

100 < Category 2 ≤ 500

500 < Category 3 ≤ 2 500

2 500 < Category 4 ≤ 20 000

0 < Category 1 ≤ 100

100 < Category 2 ≤ 500

500 < Category 3 ≤ 2 500

2 500 < Category 4 ≤ 20 000

10

100

700

4 500

10

100

700

4 500

Vapours

(mg/l)

0 < Category 1 ≤ 0,5

0,5 < Category 2 ≤ 2,0

2,0 < Category 3 ≤ 10,0

10,0 < Category 4 ≤ 20,0

0,05

0,5

3

11

Vapours

(mg/l)

Vapours

(mg/l)

0 < Category 1 ≤ 0,5

0,5 < Category 2 ≤ 2,0

2,0 < Category 3 ≤ 10,0

10,0 < Category 4 ≤ 20,0

0 < Category 1 ≤ 0,5

0,5 < Category 2 ≤ 2,0

2,0 < Category 3 ≤ 10,0

10,0 < Category 4 ≤ 20,0

0,05

0,5

3

11

0,05

0,5

3

11

Dust/mist

(mg/l)

0< Category 1 ≤ 0,05

0,05 < Category 2 ≤ 0,5

0,5 < Category 3 ≤ 1,0

1,0 < Category 4 ≤ 5,0

0,005

0,05

0,5

1,5

Dust/mist

(mg/l)

Dust/mist

(mg/l)

0< Category 1 ≤ 0,05

0,05 < Category 2 ≤ 0,5

0,5 < Category 3 ≤ 1,0

1,0 < Category 4 ≤ 5,0

0< Category 1 ≤ 0,05

0,05 < Category 2 ≤ 0,5

0,5 < Category 3 ≤ 1,0

1,0 < Category 4 ≤ 5,0

0,005

0,05

0,5

1,5

0,005

0,05

0,5

1,5

Note 1

These values are designed to be used in the calculation of the ATE for classification of a mixture based on its components and do not represent test results.

3.1.4.   Hazard Communication

Hazard Communication

3.1.4.1. Label elements shall be used for substances or mixtures meeting the criteria for classification in this hazard class in accordance with Table 3.1.3. ►M2  Without prejudice to Article 27, combined hazard statements may be used in accordance with Annex III. ◄

3.1.4.1. Label elements shall be used for substances or mixtures meeting the criteria for classification in this hazard class in accordance with Table 3.1.3. ►M2  Without prejudice to Article 27, combined hazard statements may be used in accordance with Annex III. ◄   ►M2 ►M2 ►M2  ◄

▼M4 ▼M4

Table 3.1.3

Acute toxicity label elements

Classification

Category 1

Category 2

Category 3

Category 4

GHS Pictograms

image

image

image

image

Signal Word

Danger

Danger

Danger

Warning

Hazard Statement:

— Oral

H300: Fatal if swallowed

H300: Fatal if swallowed

H301: Toxic if swallowed

H302: Harmful if swallowed

—  Dermal

H310:Fatal in contact with skin

H310:Fatal in contact with skin

H311: Toxic in contact with skin

H312: Harmful in contact with skin

—  Inhalation

(see Note 1)

H330:Fatal if inhaled

H330: Fatal if inhaled

H331: Toxic if inhaled

H332: Harmful if inhaled

Precautionary Statement Prevention (oral)

P264

P270

P264

P270

P264

P270

P264

P270

Precautionary Statement Response (oral)

P301 + P310

P321

P330

P301 + P310

P321

P330

P301 + P310

P321

P330

P301 + P312

P330

Precautionary Statement Storage (oral)

P405

P405

P405

 

Precautionary Statement Disposal (oral)

P501

P501

P501

P501

Precautionary Statement Prevention (dermal)

P262

P264

P270

P280

P262

P264

P270

P280

P280

P280

Precautionary Statement Response (dermal)

P302 + P352

P310

P321

P361 + P364

P302 + P352

P310

P321

P361 + P364

P302 + P352

P312

P321

P361 + P364

P302 + P352

P312

P321

P362 + P364

Precautionary Statement Storage (dermal)

P405

P405

P405

 

Precautionary Statement Disposal (dermal)

P501

P501

P501

P501

Precautionary Statement Prevention (inhalation)

P260

P271

P284

P260

P271

P284

P261

P271

P261

P271

Precautionary Statement Response (inhalation)

P304 + P340

P310

P320

P304 + P340

P310

P320

P304 + P340

P311

P321

P304 + P340

P312

Precautionary Statement Storage (inhalation)

P403 + P233

P405

P403 + P233

P405

P403 + P233

P405

 

Precautionary Statement Disposal (inhalation)

P501

P501

P501

 

Table 3.1.3 Table 3.1.3

Acute toxicity label elements Acute toxicity label elements

Classification

Category 1

Category 2

Category 3

Category 4

GHS Pictograms

image

image

image

image

Signal Word

Danger

Danger

Danger

Warning

Hazard Statement:

— Oral

H300: Fatal if swallowed

H300: Fatal if swallowed

H301: Toxic if swallowed

H302: Harmful if swallowed

—  Dermal

H310:Fatal in contact with skin

H310:Fatal in contact with skin

H311: Toxic in contact with skin

H312: Harmful in contact with skin

—  Inhalation

(see Note 1)

H330:Fatal if inhaled

H330: Fatal if inhaled

H331: Toxic if inhaled

H332: Harmful if inhaled

Precautionary Statement Prevention (oral)

P264

P270

P264

P270

P264

P270

P264

P270

Precautionary Statement Response (oral)

P301 + P310

P321

P330

P301 + P310

P321

P330

P301 + P310

P321

P330

P301 + P312

P330

Precautionary Statement Storage (oral)

P405

P405

P405

 

Precautionary Statement Disposal (oral)

P501

P501

P501

P501

Precautionary Statement Prevention (dermal)

P262

P264

P270

P280

P262

P264

P270

P280

P280

P280

Precautionary Statement Response (dermal)

P302 + P352

P310

P321

P361 + P364

P302 + P352

P310

P321

P361 + P364

P302 + P352

P312

P321

P361 + P364

P302 + P352

P312

P321

P362 + P364

Precautionary Statement Storage (dermal)

P405

P405

P405

 

Precautionary Statement Disposal (dermal)

P501

P501

P501

P501

Precautionary Statement Prevention (inhalation)

P260

P271

P284

P260

P271

P284

P261

P271

P261

P271

Precautionary Statement Response (inhalation)

P304 + P340

P310

P320

P304 + P340

P310

P320

P304 + P340

P311

P321

P304 + P340

P312

Precautionary Statement Storage (inhalation)

P403 + P233

P405

P403 + P233

P405

P403 + P233

P405

 

Precautionary Statement Disposal (inhalation)

P501

P501

P501

 

Classification

Category 1

Category 2

Category 3

Category 4

GHS Pictograms

image

image

image

image

Signal Word

Danger

Danger

Danger

Warning

Hazard Statement:

— Oral

H300: Fatal if swallowed

H300: Fatal if swallowed

H301: Toxic if swallowed

H302: Harmful if swallowed

—  Dermal

H310:Fatal in contact with skin

H310:Fatal in contact with skin

H311: Toxic in contact with skin

H312: Harmful in contact with skin

—  Inhalation

(see Note 1)

H330:Fatal if inhaled

H330: Fatal if inhaled

H331: Toxic if inhaled

H332: Harmful if inhaled

Precautionary Statement Prevention (oral)

P264

P270

P264

P270

P264

P270

P264

P270

Precautionary Statement Response (oral)

P301 + P310

P321

P330

P301 + P310

P321

P330

P301 + P310

P321

P330

P301 + P312

P330

Precautionary Statement Storage (oral)

P405

P405

P405

 

Precautionary Statement Disposal (oral)

P501

P501

P501

P501

Precautionary Statement Prevention (dermal)

P262

P264

P270

P280

P262

P264

P270

P280

P280

P280

Precautionary Statement Response (dermal)

P302 + P352

P310

P321

P361 + P364

P302 + P352

P310

P321

P361 + P364

P302 + P352

P312

P321

P361 + P364

P302 + P352

P312

P321

P362 + P364

Precautionary Statement Storage (dermal)

P405

P405

P405

 

Precautionary Statement Disposal (dermal)

P501

P501

P501

P501

Precautionary Statement Prevention (inhalation)

P260

P271

P284

P260

P271

P284

P261

P271

P261

P271

Precautionary Statement Response (inhalation)

P304 + P340

P310

P320

P304 + P340

P310

P320

P304 + P340

P311

P321

P304 + P340

P312

Precautionary Statement Storage (inhalation)

P403 + P233

P405

P403 + P233

P405

P403 + P233

P405

 

Precautionary Statement Disposal (inhalation)

P501

P501

P501

 

Classification

Category 1

Category 2

Category 3

Category 4

Classification

Classification

Category 1

Category 1

Category 2

Category 2

Category 3

Category 3

Category 4

Category 4

GHS Pictograms

image

image

image

image

GHS Pictograms

GHS Pictograms

image

image image

image

image image

image

image image

image

image image

Signal Word

Danger

Danger

Danger

Warning

Signal Word

Signal Word

Danger

Danger

Danger

Danger

Danger

Danger

Warning

Warning

Hazard Statement:

— Oral

H300: Fatal if swallowed

H300: Fatal if swallowed

H301: Toxic if swallowed

H302: Harmful if swallowed

Hazard Statement:

— Oral

Hazard Statement:

— Oral

— Oral

H300: Fatal if swallowed

H300: Fatal if swallowed

H300: Fatal if swallowed

H300: Fatal if swallowed

H301: Toxic if swallowed

H301: Toxic if swallowed

H302: Harmful if swallowed

H302: Harmful if swallowed

—  Dermal

H310:Fatal in contact with skin

H310:Fatal in contact with skin

H311: Toxic in contact with skin

H312: Harmful in contact with skin

—  Dermal

—  Dermal

H310:Fatal in contact with skin

H310:Fatal in contact with skin

H310:Fatal in contact with skin

H310:Fatal in contact with skin

H311: Toxic in contact with skin

H311: Toxic in contact with skin

H312: Harmful in contact with skin

H312: Harmful in contact with skin

—  Inhalation

(see Note 1)

H330:Fatal if inhaled

H330: Fatal if inhaled

H331: Toxic if inhaled

H332: Harmful if inhaled

—  Inhalation

(see Note 1)

—  Inhalation

(see Note 1)

H330:Fatal if inhaled

H330:Fatal if inhaled

H330: Fatal if inhaled

H330: Fatal if inhaled

H331: Toxic if inhaled

H331: Toxic if inhaled

H332: Harmful if inhaled

H332: Harmful if inhaled

Precautionary Statement Prevention (oral)

P264

P270

P264

P270

P264

P270

P264

P270

Precautionary Statement Prevention (oral)

Precautionary Statement Prevention (oral)

P264

P270

P264

P270

P264

P270

P264

P270

P264

P270

P264

P270

P264

P270

P264

P270

Precautionary Statement Response (oral)

P301 + P310

P321

P330

P301 + P310

P321

P330

P301 + P310

P321

P330

P301 + P312

P330

Precautionary Statement Response (oral)

Precautionary Statement Response (oral)

P301 + P310

P321

P330

P301 + P310

P321

P330

P301 + P310

P321

P330

P301 + P310

P321

P330

P301 + P310

P321

P330

P301 + P310

P321

P330

P301 + P312

P330

P301 + P312

P330

Precautionary Statement Storage (oral)

P405

P405

P405

 

Precautionary Statement Storage (oral)

Precautionary Statement Storage (oral)

P405

P405

P405

P405

P405

P405

 

 

Precautionary Statement Disposal (oral)

P501

P501

P501

P501

Precautionary Statement Disposal (oral)

Precautionary Statement Disposal (oral)

P501

P501

P501

P501

P501

P501

P501

P501

Precautionary Statement Prevention (dermal)

P262

P264

P270

P280

P262

P264

P270

P280

P280

P280

Precautionary Statement Prevention (dermal)

Precautionary Statement Prevention (dermal)

P262

P264

P270

P280

P262

P264

P270

P280

P262

P264

P270

P280

P262

P264

P270

P280

P280

P280

P280

P280

Precautionary Statement Response (dermal)

P302 + P352

P310

P321

P361 + P364

P302 + P352

P310

P321

P361 + P364

P302 + P352

P312

P321

P361 + P364

P302 + P352

P312

P321

P362 + P364

Precautionary Statement Response (dermal)

Precautionary Statement Response (dermal)

P302 + P352

P310

P321

P361 + P364

P302 + P352

P310

P321

P361 + P364

P302 + P352

P310

P321

P361 + P364

P302 + P352

P310

P321

P361 + P364

P302 + P352

P312

P321

P361 + P364

P302 + P352

P312

P321

P361 + P364

P302 + P352

P312

P321

P362 + P364

P302 + P352

P312

P321

P362 + P364

Precautionary Statement Storage (dermal)

P405

P405

P405

 

Precautionary Statement Storage (dermal)

Precautionary Statement Storage (dermal)

P405

P405

P405

P405

P405

P405

 

 

Precautionary Statement Disposal (dermal)

P501

P501

P501

P501

Precautionary Statement Disposal (dermal)

Precautionary Statement Disposal (dermal)

P501

P501

P501

P501

P501

P501

P501

P501

Precautionary Statement Prevention (inhalation)

P260

P271

P284

P260

P271

P284

P261

P271

P261

P271

Precautionary Statement Prevention (inhalation)

Precautionary Statement Prevention (inhalation)

P260

P271

P284

P260

P271

P284

P260

P271

P284

P260

P271

P284

P261

P271

P261

P271

P261

P271

P261

P271

Precautionary Statement Response (inhalation)

P304 + P340

P310

P320

P304 + P340

P310

P320

P304 + P340

P311

P321

P304 + P340

P312

Precautionary Statement Response (inhalation)

Precautionary Statement Response (inhalation)

P304 + P340

P310

P320

P304 + P340

P310

P320

P304 + P340

P310

P320

P304 + P340

P310

P320

P304 + P340

P311

P321

P304 + P340

P311

P321

P304 + P340

P312

P304 + P340

P312

Precautionary Statement Storage (inhalation)

P403 + P233

P405

P403 + P233

P405

P403 + P233

P405

 

Precautionary Statement Storage (inhalation)

Precautionary Statement Storage (inhalation)

P403 + P233

P405

P403 + P233

P405

P403 + P233

P405

P403 + P233

P405

P403 + P233

P405

P403 + P233

P405

 

 

Precautionary Statement Disposal (inhalation)

P501

P501

P501

 

Precautionary Statement Disposal (inhalation)

Precautionary Statement Disposal (inhalation)

P501

P501

P501

P501

P501

P501

 

 

▼B ▼B

Note 1

In addition to classification for inhalation toxicity, if data are available that indicates that the mechanism of toxicity is corrosivity, the substance or mixture shall also be labelled as EUH071: ‘corrosive to the respiratory tract’ — see advice at 3.1.2.3.3. In addition to an appropriate acute toxicity pictogram, a corrosivity pictogram (used for skin and eye corrosivity) may be added together with the statement ‘corrosive to the respiratory tract’.

Note 2

In the event that an ingredient without any useable information at all is used in a mixture at a concentration of 1 % or greater, the mixture shall be labelled with the additional statement that ‘x percent of the mixture consists of ingredient(s) of unknown toxicity’ — see advice at 3.1.3.6.2.2.

▼M4 ▼M4

3.1.4.2. The acute toxicity hazard statements differentiate the hazard based on the route of exposure. Communication of acute toxicity classification should also reflect this differentiation. If a substance or mixture is classified for more than one route of exposure then all relevant classifications should be communicated on the safety data sheet as specified in Annex II to Regulation (EC) No 1907/2006 and the relevant hazard communication elements included on the label as prescribed in section 3.1.3.2. If the statement ‘x % of the mixture consists of ingredient(s) of unknown acute toxicity’ is communicated, as prescribed in section 3.1.3.6.2.2, then, in the information provided in the safety data sheet, it can also be differentiated based on the route of exposure. For example, ‘x % of the mixture consists of ingredient(s) of unknown acute oral toxicity’ and ‘x % of the mixture consists of ingredient(s) of unknown acute dermal toxicity’.

3.1.4.2. The acute toxicity hazard statements differentiate the hazard based on the route of exposure. Communication of acute toxicity classification should also reflect this differentiation. If a substance or mixture is classified for more than one route of exposure then all relevant classifications should be communicated on the safety data sheet as specified in Annex II to Regulation (EC) No 1907/2006 and the relevant hazard communication elements included on the label as prescribed in section 3.1.3.2. If the statement ‘x % of the mixture consists of ingredient(s) of unknown acute toxicity’ is communicated, as prescribed in section 3.1.3.6.2.2, then, in the information provided in the safety data sheet, it can also be differentiated based on the route of exposure. For example, ‘x % of the mixture consists of ingredient(s) of unknown acute oral toxicity’ and ‘x % of the mixture consists of ingredient(s) of unknown acute dermal toxicity’.  

▼M12 ▼M12

3.2.   Skin corrosion/irritation

Skin corrosion/irritation

3.2.1.    Definitions and general considerations

Definitions and general considerations Definitions and general considerations Definitions and general considerations

▼M19 ▼M19

3.2.1.1.

Skin corrosion means the production of irreversible damage to the skin; namely, visible necrosis through the epidermis and into the dermis occurring after exposure to a substance or mixture.

Skin irritation means the production of reversible damage to the skin occurring after exposure to a substance or mixture.

3.2.1.1.

Skin corrosion means the production of irreversible damage to the skin; namely, visible necrosis through the epidermis and into the dermis occurring after exposure to a substance or mixture.

Skin irritation means the production of reversible damage to the skin occurring after exposure to a substance or mixture.

3.2.1.1.

Skin corrosion means the production of irreversible damage to the skin; namely, visible necrosis through the epidermis and into the dermis occurring after exposure to a substance or mixture.

Skin irritation means the production of reversible damage to the skin occurring after exposure to a substance or mixture.

3.2.1.1.

3.2.1.1.

Skin corrosion means the production of irreversible damage to the skin; namely, visible necrosis through the epidermis and into the dermis occurring after exposure to a substance or mixture.

Skin irritation means the production of reversible damage to the skin occurring after exposure to a substance or mixture.

Skin corrosion means the production of irreversible damage to the skin; namely, visible necrosis through the epidermis and into the dermis occurring after exposure to a substance or mixture.

Skin irritation means the production of reversible damage to the skin occurring after exposure to a substance or mixture.

▼M12 ▼M12

3.2.1.2.

In a tiered approach, emphasis shall be placed upon existing human data, followed by existing animal data, followed by in vitro data and then other sources of information. Classification results directly when the data satisfy the criteria. In some cases, classification of a substance or a mixture is made on the basis of the weight of evidence within a tier. In a total weight of evidence approach all available information bearing on the determination of skin corrosion/irritation is considered together, including the results of appropriate validated in vitro tests, relevant animal data, and human data such as epidemiological and clinical studies and well-documented case reports and observations (see Annex I, Part 1, Sections 1.1.1.3, 1.1.1.4 and 1.1.1.5).

3.2.1.2.

In a tiered approach, emphasis shall be placed upon existing human data, followed by existing animal data, followed by in vitro data and then other sources of information. Classification results directly when the data satisfy the criteria. In some cases, classification of a substance or a mixture is made on the basis of the weight of evidence within a tier. In a total weight of evidence approach all available information bearing on the determination of skin corrosion/irritation is considered together, including the results of appropriate validated in vitro tests, relevant animal data, and human data such as epidemiological and clinical studies and well-documented case reports and observations (see Annex I, Part 1, Sections 1.1.1.3, 1.1.1.4 and 1.1.1.5).

3.2.1.2.

In a tiered approach, emphasis shall be placed upon existing human data, followed by existing animal data, followed by in vitro data and then other sources of information. Classification results directly when the data satisfy the criteria. In some cases, classification of a substance or a mixture is made on the basis of the weight of evidence within a tier. In a total weight of evidence approach all available information bearing on the determination of skin corrosion/irritation is considered together, including the results of appropriate validated in vitro tests, relevant animal data, and human data such as epidemiological and clinical studies and well-documented case reports and observations (see Annex I, Part 1, Sections 1.1.1.3, 1.1.1.4 and 1.1.1.5).

3.2.1.2.

3.2.1.2.

In a tiered approach, emphasis shall be placed upon existing human data, followed by existing animal data, followed by in vitro data and then other sources of information. Classification results directly when the data satisfy the criteria. In some cases, classification of a substance or a mixture is made on the basis of the weight of evidence within a tier. In a total weight of evidence approach all available information bearing on the determination of skin corrosion/irritation is considered together, including the results of appropriate validated in vitro tests, relevant animal data, and human data such as epidemiological and clinical studies and well-documented case reports and observations (see Annex I, Part 1, Sections 1.1.1.3, 1.1.1.4 and 1.1.1.5).

In a tiered approach, emphasis shall be placed upon existing human data, followed by existing animal data, followed by in vitro data and then other sources of information. Classification results directly when the data satisfy the criteria. In some cases, classification of a substance or a mixture is made on the basis of the weight of evidence within a tier. In a total weight of evidence approach all available information bearing on the determination of skin corrosion/irritation is considered together, including the results of appropriate validated in vitro tests, relevant animal data, and human data such as epidemiological and clinical studies and well-documented case reports and observations (see Annex I, Part 1, Sections 1.1.1.3, 1.1.1.4 and 1.1.1.5). in vitro in vitro

3.2.2.    Classification criteria for substances

Classification criteria for substances Classification criteria for substances Classification criteria for substances

Substances shall be allocated to one of the following two categories within this hazard class:

(a) 

Category 1 (skin corrosion)

This category is further subdivided in three sub-categories (1A, 1B, 1C). Corrosive substances shall be classified in Category 1 where data is not sufficient for sub-categorisation. When data are sufficient, substances shall be classified in one of the three sub-categories 1A, 1B, or 1C (see Table 3.2.1.)

(a) 
(a) 

Category 1 (skin corrosion)

This category is further subdivided in three sub-categories (1A, 1B, 1C). Corrosive substances shall be classified in Category 1 where data is not sufficient for sub-categorisation. When data are sufficient, substances shall be classified in one of the three sub-categories 1A, 1B, or 1C (see Table 3.2.1.)

Category 1 (skin corrosion)

This category is further subdivided in three sub-categories (1A, 1B, 1C). Corrosive substances shall be classified in Category 1 where data is not sufficient for sub-categorisation. When data are sufficient, substances shall be classified in one of the three sub-categories 1A, 1B, or 1C (see Table 3.2.1.)

(b) 

Category 2 (skin irritation) (see Table 3.2.2).

(b) 
(b) 

Category 2 (skin irritation) (see Table 3.2.2).

Category 2 (skin irritation) (see Table 3.2.2).

3.2.2.1.    Classification based on standard animal test data Classification based on standard animal test data Classification based on standard animal test data

3.2.2.1.1.    Skin corrosion Skin corrosion Skin corrosion

3.2.2.1.1.1. A substance is corrosive to skin when it produces destruction of skin tissue, namely, visible necrosis through the epidermis and into the dermis in at least one tested animal after exposure for up to 4 hours.

3.2.2.1.1.1. A substance is corrosive to skin when it produces destruction of skin tissue, namely, visible necrosis through the epidermis and into the dermis in at least one tested animal after exposure for up to 4 hours.  

3.2.2.1.1.2. Corrosive substances shall be classified in Category 1 where data is not sufficient for sub-categorisation.

3.2.2.1.1.2. Corrosive substances shall be classified in Category 1 where data is not sufficient for sub-categorisation.  

3.2.2.1.1.3. When data are sufficient substances shall be classified in one of the three sub-categories 1A, 1B, or 1C in accordance with the criteria in Table 3.2.1.

3.2.2.1.1.3. When data are sufficient substances shall be classified in one of the three sub-categories 1A, 1B, or 1C in accordance with the criteria in Table 3.2.1.  

3.2.2.1.1.4. Three sub-categories are provided within the corrosion category: sub-category 1A — where corrosive responses are noted following up to 3 minutes exposure and up to 1 hour observation; sub-category 1B — where corrosive responses are described following exposure greater than 3 minutes and up to 1 hour and observations up to 14 days; and sub-category 1C — where corrosive responses occur after exposures greater than 1 hour and up to 4 hours and observations up to 14 days.

3.2.2.1.1.4. Three sub-categories are provided within the corrosion category: sub-category 1A — where corrosive responses are noted following up to 3 minutes exposure and up to 1 hour observation; sub-category 1B — where corrosive responses are described following exposure greater than 3 minutes and up to 1 hour and observations up to 14 days; and sub-category 1C — where corrosive responses occur after exposures greater than 1 hour and up to 4 hours and observations up to 14 days.  

Table 3.2.1

Skin corrosion category and sub-categories

Category

Criteria

Category 1 (1)

Destruction of skin tissue, namely, visible necrosis through the epidermis and into the dermis, in at least one tested animal after exposure ≤ 4 h

Sub-Category 1A

Corrosive responses in at least one animal following exposure ≤ 3 min during an observation period ≤ 1 h

Sub-Category 1B

Corrosive responses in at least one animal following exposure > 3 min and ≤ 1 h and observations ≤ 14 days

Sub-Category 1C

Corrosive responses in at least one animal after exposures > 1 h and ≤ 4 h and observations ≤ 14 days

(1)   

See the conditions for the use of Category 1 in paragraph (a) of Section 3.2.2.

Table 3.2.1 Table 3.2.1

Skin corrosion category and sub-categories Skin corrosion category and sub-categories

Category

Criteria

Category 1 (1)

Destruction of skin tissue, namely, visible necrosis through the epidermis and into the dermis, in at least one tested animal after exposure ≤ 4 h

Sub-Category 1A

Corrosive responses in at least one animal following exposure ≤ 3 min during an observation period ≤ 1 h

Sub-Category 1B

Corrosive responses in at least one animal following exposure > 3 min and ≤ 1 h and observations ≤ 14 days

Sub-Category 1C

Corrosive responses in at least one animal after exposures > 1 h and ≤ 4 h and observations ≤ 14 days

(1)   

See the conditions for the use of Category 1 in paragraph (a) of Section 3.2.2.

Category

Criteria

Category 1 (1)

Destruction of skin tissue, namely, visible necrosis through the epidermis and into the dermis, in at least one tested animal after exposure ≤ 4 h

Sub-Category 1A

Corrosive responses in at least one animal following exposure ≤ 3 min during an observation period ≤ 1 h

Sub-Category 1B

Corrosive responses in at least one animal following exposure > 3 min and ≤ 1 h and observations ≤ 14 days

Sub-Category 1C

Corrosive responses in at least one animal after exposures > 1 h and ≤ 4 h and observations ≤ 14 days

(1)   

See the conditions for the use of Category 1 in paragraph (a) of Section 3.2.2.

Category

Criteria

Category

Category

Criteria

Criteria

Category 1 (1)

Destruction of skin tissue, namely, visible necrosis through the epidermis and into the dermis, in at least one tested animal after exposure ≤ 4 h

Category 1 (1)

Category 1 (1) (1) 1

Destruction of skin tissue, namely, visible necrosis through the epidermis and into the dermis, in at least one tested animal after exposure ≤ 4 h

Destruction of skin tissue, namely, visible necrosis through the epidermis and into the dermis, in at least one tested animal after exposure ≤ 4 h

Sub-Category 1A

Corrosive responses in at least one animal following exposure ≤ 3 min during an observation period ≤ 1 h

Sub-Category 1A

Sub-Category 1A

Corrosive responses in at least one animal following exposure ≤ 3 min during an observation period ≤ 1 h

Corrosive responses in at least one animal following exposure ≤ 3 min during an observation period ≤ 1 h

Sub-Category 1B

Corrosive responses in at least one animal following exposure > 3 min and ≤ 1 h and observations ≤ 14 days

Sub-Category 1B

Sub-Category 1B

Corrosive responses in at least one animal following exposure > 3 min and ≤ 1 h and observations ≤ 14 days

Corrosive responses in at least one animal following exposure > 3 min and ≤ 1 h and observations ≤ 14 days

Sub-Category 1C

Corrosive responses in at least one animal after exposures > 1 h and ≤ 4 h and observations ≤ 14 days

Sub-Category 1C

Sub-Category 1C

Corrosive responses in at least one animal after exposures > 1 h and ≤ 4 h and observations ≤ 14 days

Corrosive responses in at least one animal after exposures > 1 h and ≤ 4 h and observations ≤ 14 days

(1)   

See the conditions for the use of Category 1 in paragraph (a) of Section 3.2.2.

(1)   

See the conditions for the use of Category 1 in paragraph (a) of Section 3.2.2.

(1)   

See the conditions for the use of Category 1 in paragraph (a) of Section 3.2.2.

(1)    1

See the conditions for the use of Category 1 in paragraph (a) of Section 3.2.2.

3.2.2.1.1.5. The use of human data is discussed in Sections 3.2.1.2 and 3.2.2.2 and also in Sections 1.1.1.3, 1.1.1.4 and 1.1.1.5.

3.2.2.1.1.5. The use of human data is discussed in Sections 3.2.1.2 and 3.2.2.2 and also in Sections 1.1.1.3, 1.1.1.4 and 1.1.1.5.  

3.2.2.1.2.    Skin irritation Skin irritation Skin irritation

3.2.2.1.2.1. A substance is irritant to skin when it produces reversible damage to the skin following its application for up to 4 hours. The major criterion for the irritation category is that at least 2 of 3 tested animals have a mean score of ≥ 2,3 and ≤ 4,0.

3.2.2.1.2.1. A substance is irritant to skin when it produces reversible damage to the skin following its application for up to 4 hours. The major criterion for the irritation category is that at least 2 of 3 tested animals have a mean score of ≥ 2,3 and ≤ 4,0.  

3.2.2.1.2.2. A single irritation category (Category 2) is presented in Table 3.2.2, using the results of animal testing.

3.2.2.1.2.2. A single irritation category (Category 2) is presented in Table 3.2.2, using the results of animal testing.  

3.2.2.1.2.3. Reversibility of skin lesions is also considered in evaluating irritant responses. When inflammation persists to the end of the observation period in 2 or more test animals, taking into consideration alopecia (limited area), hyperkeratosis, hyperplasia and scaling, then a material shall be considered to be an irritant.

3.2.2.1.2.3. Reversibility of skin lesions is also considered in evaluating irritant responses. When inflammation persists to the end of the observation period in 2 or more test animals, taking into consideration alopecia (limited area), hyperkeratosis, hyperplasia and scaling, then a material shall be considered to be an irritant.  

3.2.2.1.2.4. Animal irritant responses within a test can be variable, as they are with corrosion. A separate irritant criterion accommodates cases where there is a significant irritant response but less than the mean score criterion for a positive test. For example, a test material might be designated as an irritant if at least 1 of 3 tested animals shows a very elevated mean score throughout the study, including lesions persisting at the end of an observation period of normally 14 days. Other responses could also fulfil this criterion. However, it should be ascertained that the responses are the result of chemical exposure.

3.2.2.1.2.4. Animal irritant responses within a test can be variable, as they are with corrosion. A separate irritant criterion accommodates cases where there is a significant irritant response but less than the mean score criterion for a positive test. For example, a test material might be designated as an irritant if at least 1 of 3 tested animals shows a very elevated mean score throughout the study, including lesions persisting at the end of an observation period of normally 14 days. Other responses could also fulfil this criterion. However, it should be ascertained that the responses are the result of chemical exposure.  

Table 3.2.2

Skin irritation category ()

Category

Criteria

Irritation (Category 2)

(1)  Mean score of ≥ 2,3 and ≤ 4,0 for erythema/eschar or for oedema in at least 2 of 3 tested animals from gradings at 24, 48 and 72 hours after patch removal or, if reactions are delayed, from grades on 3 consecutive days after the onset of skin reactions; or

(2)  Inflammation that persists to the end of the observation period normally 14 days in at least 2 animals, particularly taking into account alopecia (limited area), hyperkeratosis, hyperplasia, and scaling reactions; or

(3)  In some cases where there is pronounced variability of response among animals, with very definite positive effects related to chemical exposure in a single animal but less than the criteria above .

(1)   

Grading criteria are understood as described in Regulation (EC) No 440/2008.

Table 3.2.2 Table 3.2.2

Skin irritation category () Skin irritation category ()

Category

Criteria

Irritation (Category 2)

(1)  Mean score of ≥ 2,3 and ≤ 4,0 for erythema/eschar or for oedema in at least 2 of 3 tested animals from gradings at 24, 48 and 72 hours after patch removal or, if reactions are delayed, from grades on 3 consecutive days after the onset of skin reactions; or

(2)  Inflammation that persists to the end of the observation period normally 14 days in at least 2 animals, particularly taking into account alopecia (limited area), hyperkeratosis, hyperplasia, and scaling reactions; or

(3)  In some cases where there is pronounced variability of response among animals, with very definite positive effects related to chemical exposure in a single animal but less than the criteria above .

(1)   

Grading criteria are understood as described in Regulation (EC) No 440/2008.

Category

Criteria

Irritation (Category 2)

(1)  Mean score of ≥ 2,3 and ≤ 4,0 for erythema/eschar or for oedema in at least 2 of 3 tested animals from gradings at 24, 48 and 72 hours after patch removal or, if reactions are delayed, from grades on 3 consecutive days after the onset of skin reactions; or

(2)  Inflammation that persists to the end of the observation period normally 14 days in at least 2 animals, particularly taking into account alopecia (limited area), hyperkeratosis, hyperplasia, and scaling reactions; or

(3)  In some cases where there is pronounced variability of response among animals, with very definite positive effects related to chemical exposure in a single animal but less than the criteria above .

(1)   

Grading criteria are understood as described in Regulation (EC) No 440/2008.

Category

Criteria

Category

Category

Criteria

Criteria

Irritation (Category 2)

(1)  Mean score of ≥ 2,3 and ≤ 4,0 for erythema/eschar or for oedema in at least 2 of 3 tested animals from gradings at 24, 48 and 72 hours after patch removal or, if reactions are delayed, from grades on 3 consecutive days after the onset of skin reactions; or

(2)  Inflammation that persists to the end of the observation period normally 14 days in at least 2 animals, particularly taking into account alopecia (limited area), hyperkeratosis, hyperplasia, and scaling reactions; or

(3)  In some cases where there is pronounced variability of response among animals, with very definite positive effects related to chemical exposure in a single animal but less than the criteria above .

Irritation (Category 2)

Irritation (Category 2)

(1)  Mean score of ≥ 2,3 and ≤ 4,0 for erythema/eschar or for oedema in at least 2 of 3 tested animals from gradings at 24, 48 and 72 hours after patch removal or, if reactions are delayed, from grades on 3 consecutive days after the onset of skin reactions; or

(2)  Inflammation that persists to the end of the observation period normally 14 days in at least 2 animals, particularly taking into account alopecia (limited area), hyperkeratosis, hyperplasia, and scaling reactions; or

(3)  In some cases where there is pronounced variability of response among animals, with very definite positive effects related to chemical exposure in a single animal but less than the criteria above .

(1)  Mean score of ≥ 2,3 and ≤ 4,0 for erythema/eschar or for oedema in at least 2 of 3 tested animals from gradings at 24, 48 and 72 hours after patch removal or, if reactions are delayed, from grades on 3 consecutive days after the onset of skin reactions; or

(2)  Inflammation that persists to the end of the observation period normally 14 days in at least 2 animals, particularly taking into account alopecia (limited area), hyperkeratosis, hyperplasia, and scaling reactions; or

(3)  In some cases where there is pronounced variability of response among animals, with very definite positive effects related to chemical exposure in a single animal but less than the criteria above .

(1)   

Grading criteria are understood as described in Regulation (EC) No 440/2008.

(1)   

Grading criteria are understood as described in Regulation (EC) No 440/2008.

(1)   

Grading criteria are understood as described in Regulation (EC) No 440/2008.

(1)    1

Grading criteria are understood as described in Regulation (EC) No 440/2008.

3.2.2.1.2.5. The use of human data is discussed in Sections 3.2.1.2 and 3.2.2.2 and also in Sections 1.1.1.3, 1.1.1.4 and 1.1.1.5.

3.2.2.1.2.5. The use of human data is discussed in Sections 3.2.1.2 and 3.2.2.2 and also in Sections 1.1.1.3, 1.1.1.4 and 1.1.1.5.  

3.2.2.2.    Classification in a tiered approach Classification in a tiered approach Classification in a tiered approach

3.2.2.2.1.

A tiered approach to the evaluation of initial information shall be considered, where applicable, recognising that not all elements may be relevant.

3.2.2.2.1.

A tiered approach to the evaluation of initial information shall be considered, where applicable, recognising that not all elements may be relevant.

3.2.2.2.1.

A tiered approach to the evaluation of initial information shall be considered, where applicable, recognising that not all elements may be relevant.

3.2.2.2.1.

3.2.2.2.1.

A tiered approach to the evaluation of initial information shall be considered, where applicable, recognising that not all elements may be relevant.

A tiered approach to the evaluation of initial information shall be considered, where applicable, recognising that not all elements may be relevant.

3.2.2.2.2.

Existing human and animal data including information from single or repeated exposure shall be the first line of evaluation, as they give information directly relevant to effects on the skin.

3.2.2.2.2.

Existing human and animal data including information from single or repeated exposure shall be the first line of evaluation, as they give information directly relevant to effects on the skin.

3.2.2.2.2.

Existing human and animal data including information from single or repeated exposure shall be the first line of evaluation, as they give information directly relevant to effects on the skin.

3.2.2.2.2.

3.2.2.2.2.

Existing human and animal data including information from single or repeated exposure shall be the first line of evaluation, as they give information directly relevant to effects on the skin.

Existing human and animal data including information from single or repeated exposure shall be the first line of evaluation, as they give information directly relevant to effects on the skin.

3.2.2.2.3.

Acute dermal toxicity data may be used for classification. If a substance is highly toxic by the dermal route, a skin corrosion/irritation study is not practicable since the amount of test substance to be applied considerably exceeds the toxic dose and, consequently, results in the death of the animals. When observations are made of skin corrosion/irritation in acute toxicity studies and are observed up through the limit dose, these data may be used for classification, provided that the dilutions used and species tested are equivalent. Solid substances (powders) may become corrosive or irritant when moistened or in contact with moist skin or mucous membranes.

3.2.2.2.3.

Acute dermal toxicity data may be used for classification. If a substance is highly toxic by the dermal route, a skin corrosion/irritation study is not practicable since the amount of test substance to be applied considerably exceeds the toxic dose and, consequently, results in the death of the animals. When observations are made of skin corrosion/irritation in acute toxicity studies and are observed up through the limit dose, these data may be used for classification, provided that the dilutions used and species tested are equivalent. Solid substances (powders) may become corrosive or irritant when moistened or in contact with moist skin or mucous membranes.

3.2.2.2.3.

Acute dermal toxicity data may be used for classification. If a substance is highly toxic by the dermal route, a skin corrosion/irritation study is not practicable since the amount of test substance to be applied considerably exceeds the toxic dose and, consequently, results in the death of the animals. When observations are made of skin corrosion/irritation in acute toxicity studies and are observed up through the limit dose, these data may be used for classification, provided that the dilutions used and species tested are equivalent. Solid substances (powders) may become corrosive or irritant when moistened or in contact with moist skin or mucous membranes.

3.2.2.2.3.

3.2.2.2.3.

Acute dermal toxicity data may be used for classification. If a substance is highly toxic by the dermal route, a skin corrosion/irritation study is not practicable since the amount of test substance to be applied considerably exceeds the toxic dose and, consequently, results in the death of the animals. When observations are made of skin corrosion/irritation in acute toxicity studies and are observed up through the limit dose, these data may be used for classification, provided that the dilutions used and species tested are equivalent. Solid substances (powders) may become corrosive or irritant when moistened or in contact with moist skin or mucous membranes.

Acute dermal toxicity data may be used for classification. If a substance is highly toxic by the dermal route, a skin corrosion/irritation study is not practicable since the amount of test substance to be applied considerably exceeds the toxic dose and, consequently, results in the death of the animals. When observations are made of skin corrosion/irritation in acute toxicity studies and are observed up through the limit dose, these data may be used for classification, provided that the dilutions used and species tested are equivalent. Solid substances (powders) may become corrosive or irritant when moistened or in contact with moist skin or mucous membranes.

3.2.2.2.4.

In vitro alternatives that have been validated and accepted shall be used to make classification decisions.

3.2.2.2.4.

In vitro alternatives that have been validated and accepted shall be used to make classification decisions.

3.2.2.2.4.

In vitro alternatives that have been validated and accepted shall be used to make classification decisions.

3.2.2.2.4.

3.2.2.2.4.

In vitro alternatives that have been validated and accepted shall be used to make classification decisions.

In vitro alternatives that have been validated and accepted shall be used to make classification decisions.

3.2.2.2.5.

Likewise, pH extremes like ≤ 2 and ≥ 11,5 may indicate the potential to cause skin effects, especially when associated with significant acid/alkaline reserve (buffering capacity). Generally, such substances are expected to produce significant effects on the skin. In the absence of any other information, a substance is considered as corrosive to skin (Skin Corrosion Category 1) if it has a pH ≤ 2 or a pH ≥ 11,5. However, if consideration of acid/alkaline reserve suggests the substance may not be corrosive despite the low or high pH value, this needs to be confirmed by other data, preferably by data from an appropriate validated in vitro test.

3.2.2.2.5.

Likewise, pH extremes like ≤ 2 and ≥ 11,5 may indicate the potential to cause skin effects, especially when associated with significant acid/alkaline reserve (buffering capacity). Generally, such substances are expected to produce significant effects on the skin. In the absence of any other information, a substance is considered as corrosive to skin (Skin Corrosion Category 1) if it has a pH ≤ 2 or a pH ≥ 11,5. However, if consideration of acid/alkaline reserve suggests the substance may not be corrosive despite the low or high pH value, this needs to be confirmed by other data, preferably by data from an appropriate validated in vitro test.

3.2.2.2.5.

Likewise, pH extremes like ≤ 2 and ≥ 11,5 may indicate the potential to cause skin effects, especially when associated with significant acid/alkaline reserve (buffering capacity). Generally, such substances are expected to produce significant effects on the skin. In the absence of any other information, a substance is considered as corrosive to skin (Skin Corrosion Category 1) if it has a pH ≤ 2 or a pH ≥ 11,5. However, if consideration of acid/alkaline reserve suggests the substance may not be corrosive despite the low or high pH value, this needs to be confirmed by other data, preferably by data from an appropriate validated in vitro test.

3.2.2.2.5.

3.2.2.2.5.

Likewise, pH extremes like ≤ 2 and ≥ 11,5 may indicate the potential to cause skin effects, especially when associated with significant acid/alkaline reserve (buffering capacity). Generally, such substances are expected to produce significant effects on the skin. In the absence of any other information, a substance is considered as corrosive to skin (Skin Corrosion Category 1) if it has a pH ≤ 2 or a pH ≥ 11,5. However, if consideration of acid/alkaline reserve suggests the substance may not be corrosive despite the low or high pH value, this needs to be confirmed by other data, preferably by data from an appropriate validated in vitro test.

Likewise, pH extremes like ≤ 2 and ≥ 11,5 may indicate the potential to cause skin effects, especially when associated with significant acid/alkaline reserve (buffering capacity). Generally, such substances are expected to produce significant effects on the skin. In the absence of any other information, a substance is considered as corrosive to skin (Skin Corrosion Category 1) if it has a pH ≤ 2 or a pH ≥ 11,5. However, if consideration of acid/alkaline reserve suggests the substance may not be corrosive despite the low or high pH value, this needs to be confirmed by other data, preferably by data from an appropriate validated in vitro test.

3.2.2.2.6.

In some cases, sufficient information may be available from structurally related substances to make classification decisions.

3.2.2.2.6.

In some cases, sufficient information may be available from structurally related substances to make classification decisions.

3.2.2.2.6.

In some cases, sufficient information may be available from structurally related substances to make classification decisions.

3.2.2.2.6.

3.2.2.2.6.

In some cases, sufficient information may be available from structurally related substances to make classification decisions.

In some cases, sufficient information may be available from structurally related substances to make classification decisions.

3.2.2.2.7.

The tiered approach provides guidance on how to organize existing information on a substance and to make a weight of evidence decision about hazard assessment and hazard classification.

Although information might be gained from the evaluation of single parameters within a tier (see Section 3.2.2.2.1.), consideration shall be given to the totality of existing information and making an overall weight of evidence determination. This is especially true when there is conflict in information available on some parameters.

3.2.2.2.7.

The tiered approach provides guidance on how to organize existing information on a substance and to make a weight of evidence decision about hazard assessment and hazard classification.

Although information might be gained from the evaluation of single parameters within a tier (see Section 3.2.2.2.1.), consideration shall be given to the totality of existing information and making an overall weight of evidence determination. This is especially true when there is conflict in information available on some parameters.

3.2.2.2.7.

The tiered approach provides guidance on how to organize existing information on a substance and to make a weight of evidence decision about hazard assessment and hazard classification.

Although information might be gained from the evaluation of single parameters within a tier (see Section 3.2.2.2.1.), consideration shall be given to the totality of existing information and making an overall weight of evidence determination. This is especially true when there is conflict in information available on some parameters.

3.2.2.2.7.

3.2.2.2.7.

The tiered approach provides guidance on how to organize existing information on a substance and to make a weight of evidence decision about hazard assessment and hazard classification.

Although information might be gained from the evaluation of single parameters within a tier (see Section 3.2.2.2.1.), consideration shall be given to the totality of existing information and making an overall weight of evidence determination. This is especially true when there is conflict in information available on some parameters.

The tiered approach provides guidance on how to organize existing information on a substance and to make a weight of evidence decision about hazard assessment and hazard classification.

Although information might be gained from the evaluation of single parameters within a tier (see Section 3.2.2.2.1.), consideration shall be given to the totality of existing information and making an overall weight of evidence determination. This is especially true when there is conflict in information available on some parameters.

3.2.3.    Classification criteria for mixtures

Classification criteria for mixtures Classification criteria for mixtures Classification criteria for mixtures

3.2.3.1.    Classification of mixtures when data are available for the complete mixture Classification of mixtures when data are available for the complete mixture Classification of mixtures when data are available for the complete mixture

3.2.3.1.1.

The mixture shall be classified using the criteria for substances, taking into account the tiered approach to evaluate data for this hazard class.

3.2.3.1.1.

The mixture shall be classified using the criteria for substances, taking into account the tiered approach to evaluate data for this hazard class.

3.2.3.1.1.

The mixture shall be classified using the criteria for substances, taking into account the tiered approach to evaluate data for this hazard class.

3.2.3.1.1.

3.2.3.1.1.

The mixture shall be classified using the criteria for substances, taking into account the tiered approach to evaluate data for this hazard class.

The mixture shall be classified using the criteria for substances, taking into account the tiered approach to evaluate data for this hazard class.

3.2.3.1.2.

When considering testing of the mixture, classifiers are encouraged to use a tiered weight of evidence approach as included in the criteria for classification of substances for skin corrosion and irritation (Sections 3.2.1.2 and 3.2.2.2), to help ensure an accurate classification as well as to avoid unnecessary animal testing. In the absence of any other information, a mixture is considered corrosive to skin (Skin Corrosion Category 1) if it has a pH ≤ 2 or a pH ≥ 11,5. However, if consideration of acid/alkaline reserve suggests the mixture may not be corrosive despite the low or high pH value, this needs to be confirmed by other data, preferably by data from an appropriate validated in vitro test.

3.2.3.1.2.

When considering testing of the mixture, classifiers are encouraged to use a tiered weight of evidence approach as included in the criteria for classification of substances for skin corrosion and irritation (Sections 3.2.1.2 and 3.2.2.2), to help ensure an accurate classification as well as to avoid unnecessary animal testing. In the absence of any other information, a mixture is considered corrosive to skin (Skin Corrosion Category 1) if it has a pH ≤ 2 or a pH ≥ 11,5. However, if consideration of acid/alkaline reserve suggests the mixture may not be corrosive despite the low or high pH value, this needs to be confirmed by other data, preferably by data from an appropriate validated in vitro test.

3.2.3.1.2.

When considering testing of the mixture, classifiers are encouraged to use a tiered weight of evidence approach as included in the criteria for classification of substances for skin corrosion and irritation (Sections 3.2.1.2 and 3.2.2.2), to help ensure an accurate classification as well as to avoid unnecessary animal testing. In the absence of any other information, a mixture is considered corrosive to skin (Skin Corrosion Category 1) if it has a pH ≤ 2 or a pH ≥ 11,5. However, if consideration of acid/alkaline reserve suggests the mixture may not be corrosive despite the low or high pH value, this needs to be confirmed by other data, preferably by data from an appropriate validated in vitro test.

3.2.3.1.2.

3.2.3.1.2.

When considering testing of the mixture, classifiers are encouraged to use a tiered weight of evidence approach as included in the criteria for classification of substances for skin corrosion and irritation (Sections 3.2.1.2 and 3.2.2.2), to help ensure an accurate classification as well as to avoid unnecessary animal testing. In the absence of any other information, a mixture is considered corrosive to skin (Skin Corrosion Category 1) if it has a pH ≤ 2 or a pH ≥ 11,5. However, if consideration of acid/alkaline reserve suggests the mixture may not be corrosive despite the low or high pH value, this needs to be confirmed by other data, preferably by data from an appropriate validated in vitro test.

When considering testing of the mixture, classifiers are encouraged to use a tiered weight of evidence approach as included in the criteria for classification of substances for skin corrosion and irritation (Sections 3.2.1.2 and 3.2.2.2), to help ensure an accurate classification as well as to avoid unnecessary animal testing. In the absence of any other information, a mixture is considered corrosive to skin (Skin Corrosion Category 1) if it has a pH ≤ 2 or a pH ≥ 11,5. However, if consideration of acid/alkaline reserve suggests the mixture may not be corrosive despite the low or high pH value, this needs to be confirmed by other data, preferably by data from an appropriate validated in vitro test.

3.2.3.2.    Classification of mixtures when data are not available for the complete mixture: bridging principles Classification of mixtures when data are not available for the complete mixture: bridging principles Classification of mixtures when data are not available for the complete mixture: bridging principles

3.2.3.2.1.

Where the mixture itself has not been tested to determine its skin corrosion/irritation potential, but there are sufficient data on the individual ingredients and similar tested mixtures to adequately characterise the hazards of the mixture, these data shall be used in accordance with the bridging rules set out in Section 1.1.3.

3.2.3.2.1.

Where the mixture itself has not been tested to determine its skin corrosion/irritation potential, but there are sufficient data on the individual ingredients and similar tested mixtures to adequately characterise the hazards of the mixture, these data shall be used in accordance with the bridging rules set out in Section 1.1.3.

3.2.3.2.1.

Where the mixture itself has not been tested to determine its skin corrosion/irritation potential, but there are sufficient data on the individual ingredients and similar tested mixtures to adequately characterise the hazards of the mixture, these data shall be used in accordance with the bridging rules set out in Section 1.1.3.

3.2.3.2.1.

3.2.3.2.1.

Where the mixture itself has not been tested to determine its skin corrosion/irritation potential, but there are sufficient data on the individual ingredients and similar tested mixtures to adequately characterise the hazards of the mixture, these data shall be used in accordance with the bridging rules set out in Section 1.1.3.

Where the mixture itself has not been tested to determine its skin corrosion/irritation potential, but there are sufficient data on the individual ingredients and similar tested mixtures to adequately characterise the hazards of the mixture, these data shall be used in accordance with the bridging rules set out in Section 1.1.3.

3.2.3.3.    Classification of mixtures when data are available for all ingredients or only for some ingredients of the mixture Classification of mixtures when data are available for all ingredients or only for some ingredients of the mixture Classification of mixtures when data are available for all ingredients or only for some ingredients of the mixture

3.2.3.3.1.

In order to make use of all available data for purposes of classifying the skin corrosion/irritation hazards of mixtures, the following assumption has been made and is applied where appropriate in the tiered approach:

The ‘relevant ingredients’ of a mixture are those which are present in concentrations ≥ 1 % (w/w for solids, liquids, dusts, mists and vapours and v/v for gases), unless there is a presumption (e.g., in the case of skin corrosive ingredients) that an ingredient present at a concentration < 1 % can still be relevant for classifying the mixture for skin corrosion/irritation.

3.2.3.3.1.

In order to make use of all available data for purposes of classifying the skin corrosion/irritation hazards of mixtures, the following assumption has been made and is applied where appropriate in the tiered approach:

The ‘relevant ingredients’ of a mixture are those which are present in concentrations ≥ 1 % (w/w for solids, liquids, dusts, mists and vapours and v/v for gases), unless there is a presumption (e.g., in the case of skin corrosive ingredients) that an ingredient present at a concentration < 1 % can still be relevant for classifying the mixture for skin corrosion/irritation.

3.2.3.3.1.

In order to make use of all available data for purposes of classifying the skin corrosion/irritation hazards of mixtures, the following assumption has been made and is applied where appropriate in the tiered approach:

The ‘relevant ingredients’ of a mixture are those which are present in concentrations ≥ 1 % (w/w for solids, liquids, dusts, mists and vapours and v/v for gases), unless there is a presumption (e.g., in the case of skin corrosive ingredients) that an ingredient present at a concentration < 1 % can still be relevant for classifying the mixture for skin corrosion/irritation.

3.2.3.3.1.

3.2.3.3.1.

In order to make use of all available data for purposes of classifying the skin corrosion/irritation hazards of mixtures, the following assumption has been made and is applied where appropriate in the tiered approach:

The ‘relevant ingredients’ of a mixture are those which are present in concentrations ≥ 1 % (w/w for solids, liquids, dusts, mists and vapours and v/v for gases), unless there is a presumption (e.g., in the case of skin corrosive ingredients) that an ingredient present at a concentration < 1 % can still be relevant for classifying the mixture for skin corrosion/irritation.

In order to make use of all available data for purposes of classifying the skin corrosion/irritation hazards of mixtures, the following assumption has been made and is applied where appropriate in the tiered approach:

The ‘relevant ingredients’ of a mixture are those which are present in concentrations ≥ 1 % (w/w for solids, liquids, dusts, mists and vapours and v/v for gases), unless there is a presumption (e.g., in the case of skin corrosive ingredients) that an ingredient present at a concentration < 1 % can still be relevant for classifying the mixture for skin corrosion/irritation.

3.2.3.3.2.

In general, the approach to classification of mixtures as corrosive or irritant to skin when data are available on the ingredients, but not on the mixture as a whole, is based on the theory of additivity, such that each skin corrosive or skin irritant ingredient contributes to the overall skin corrosive or skin irritant properties of the mixture in proportion to its potency and concentration. A weighting factor of 10 is used for skin corrosive ingredients when they are present at a concentration below the generic concentration limit for classification with Category 1, but are at a concentration that will contribute to the classification of the mixture as skin irritant. The mixture is classified as corrosive or irritant to skin when the sum of the concentrations of such ingredients exceeds a concentration limit.

3.2.3.3.2.

In general, the approach to classification of mixtures as corrosive or irritant to skin when data are available on the ingredients, but not on the mixture as a whole, is based on the theory of additivity, such that each skin corrosive or skin irritant ingredient contributes to the overall skin corrosive or skin irritant properties of the mixture in proportion to its potency and concentration. A weighting factor of 10 is used for skin corrosive ingredients when they are present at a concentration below the generic concentration limit for classification with Category 1, but are at a concentration that will contribute to the classification of the mixture as skin irritant. The mixture is classified as corrosive or irritant to skin when the sum of the concentrations of such ingredients exceeds a concentration limit.

3.2.3.3.2.

In general, the approach to classification of mixtures as corrosive or irritant to skin when data are available on the ingredients, but not on the mixture as a whole, is based on the theory of additivity, such that each skin corrosive or skin irritant ingredient contributes to the overall skin corrosive or skin irritant properties of the mixture in proportion to its potency and concentration. A weighting factor of 10 is used for skin corrosive ingredients when they are present at a concentration below the generic concentration limit for classification with Category 1, but are at a concentration that will contribute to the classification of the mixture as skin irritant. The mixture is classified as corrosive or irritant to skin when the sum of the concentrations of such ingredients exceeds a concentration limit.

3.2.3.3.2.

3.2.3.3.2.

In general, the approach to classification of mixtures as corrosive or irritant to skin when data are available on the ingredients, but not on the mixture as a whole, is based on the theory of additivity, such that each skin corrosive or skin irritant ingredient contributes to the overall skin corrosive or skin irritant properties of the mixture in proportion to its potency and concentration. A weighting factor of 10 is used for skin corrosive ingredients when they are present at a concentration below the generic concentration limit for classification with Category 1, but are at a concentration that will contribute to the classification of the mixture as skin irritant. The mixture is classified as corrosive or irritant to skin when the sum of the concentrations of such ingredients exceeds a concentration limit.

In general, the approach to classification of mixtures as corrosive or irritant to skin when data are available on the ingredients, but not on the mixture as a whole, is based on the theory of additivity, such that each skin corrosive or skin irritant ingredient contributes to the overall skin corrosive or skin irritant properties of the mixture in proportion to its potency and concentration. A weighting factor of 10 is used for skin corrosive ingredients when they are present at a concentration below the generic concentration limit for classification with Category 1, but are at a concentration that will contribute to the classification of the mixture as skin irritant. The mixture is classified as corrosive or irritant to skin when the sum of the concentrations of such ingredients exceeds a concentration limit.

3.2.3.3.3.

Table 3.2.3 provides the generic concentration limits to be used to determine if the mixture is considered to be corrosive or irritant to the skin.

3.2.3.3.3.

Table 3.2.3 provides the generic concentration limits to be used to determine if the mixture is considered to be corrosive or irritant to the skin.

3.2.3.3.3.

Table 3.2.3 provides the generic concentration limits to be used to determine if the mixture is considered to be corrosive or irritant to the skin.

3.2.3.3.3.

3.2.3.3.3.

Table 3.2.3 provides the generic concentration limits to be used to determine if the mixture is considered to be corrosive or irritant to the skin.

Table 3.2.3 provides the generic concentration limits to be used to determine if the mixture is considered to be corrosive or irritant to the skin.

3.2.3.3.4.1.

Particular care must be taken when classifying certain types of mixtures containing substances such as acids and bases, inorganic salts, aldehydes, phenols, and surfactants. The approach explained in Sections 3.2.3.3.1 and 3.2.3.3.2 may not be applicable given that many such substances are corrosive or irritant to the skin at concentrations < 1 %.

3.2.3.3.4.1.

Particular care must be taken when classifying certain types of mixtures containing substances such as acids and bases, inorganic salts, aldehydes, phenols, and surfactants. The approach explained in Sections 3.2.3.3.1 and 3.2.3.3.2 may not be applicable given that many such substances are corrosive or irritant to the skin at concentrations < 1 %.

3.2.3.3.4.1.

Particular care must be taken when classifying certain types of mixtures containing substances such as acids and bases, inorganic salts, aldehydes, phenols, and surfactants. The approach explained in Sections 3.2.3.3.1 and 3.2.3.3.2 may not be applicable given that many such substances are corrosive or irritant to the skin at concentrations < 1 %.

3.2.3.3.4.1.

3.2.3.3.4.1.

Particular care must be taken when classifying certain types of mixtures containing substances such as acids and bases, inorganic salts, aldehydes, phenols, and surfactants. The approach explained in Sections 3.2.3.3.1 and 3.2.3.3.2 may not be applicable given that many such substances are corrosive or irritant to the skin at concentrations < 1 %.

Particular care must be taken when classifying certain types of mixtures containing substances such as acids and bases, inorganic salts, aldehydes, phenols, and surfactants. The approach explained in Sections 3.2.3.3.1 and 3.2.3.3.2 may not be applicable given that many such substances are corrosive or irritant to the skin at concentrations < 1 %.

3.2.3.3.4.2.

For mixtures containing strong acids or bases the pH shall be used as a classification criterion (see Section 3.2.3.1.2) since pH is a better indicator of skin corrosion than the concentration limits in Table 3.2.3.

3.2.3.3.4.2.

For mixtures containing strong acids or bases the pH shall be used as a classification criterion (see Section 3.2.3.1.2) since pH is a better indicator of skin corrosion than the concentration limits in Table 3.2.3.

3.2.3.3.4.2.

For mixtures containing strong acids or bases the pH shall be used as a classification criterion (see Section 3.2.3.1.2) since pH is a better indicator of skin corrosion than the concentration limits in Table 3.2.3.

3.2.3.3.4.2.

3.2.3.3.4.2.

For mixtures containing strong acids or bases the pH shall be used as a classification criterion (see Section 3.2.3.1.2) since pH is a better indicator of skin corrosion than the concentration limits in Table 3.2.3.

For mixtures containing strong acids or bases the pH shall be used as a classification criterion (see Section 3.2.3.1.2) since pH is a better indicator of skin corrosion than the concentration limits in Table 3.2.3.

3.2.3.3.4.3.

A mixture containing ingredients that are corrosive or irritant to the skin and that cannot be classified on the basis of the additivity approach (Table 3.2.3), due to chemical characteristics that make this approach unworkable, shall be classified as Skin Corrosion Category 1 if it contains ≥ 1 % of an ingredient classified as Skin Corrosion or as Skin Irritation (Category 2) when it contains ≥ 3 % of an skin irritant ingredient. Classification of mixtures with ingredients for which the approach in Table 3.2.3 does not apply is summarised in Table 3.2.4.

3.2.3.3.4.3.

A mixture containing ingredients that are corrosive or irritant to the skin and that cannot be classified on the basis of the additivity approach (Table 3.2.3), due to chemical characteristics that make this approach unworkable, shall be classified as Skin Corrosion Category 1 if it contains ≥ 1 % of an ingredient classified as Skin Corrosion or as Skin Irritation (Category 2) when it contains ≥ 3 % of an skin irritant ingredient. Classification of mixtures with ingredients for which the approach in Table 3.2.3 does not apply is summarised in Table 3.2.4.

3.2.3.3.4.3.

A mixture containing ingredients that are corrosive or irritant to the skin and that cannot be classified on the basis of the additivity approach (Table 3.2.3), due to chemical characteristics that make this approach unworkable, shall be classified as Skin Corrosion Category 1 if it contains ≥ 1 % of an ingredient classified as Skin Corrosion or as Skin Irritation (Category 2) when it contains ≥ 3 % of an skin irritant ingredient. Classification of mixtures with ingredients for which the approach in Table 3.2.3 does not apply is summarised in Table 3.2.4.

3.2.3.3.4.3.

3.2.3.3.4.3.

A mixture containing ingredients that are corrosive or irritant to the skin and that cannot be classified on the basis of the additivity approach (Table 3.2.3), due to chemical characteristics that make this approach unworkable, shall be classified as Skin Corrosion Category 1 if it contains ≥ 1 % of an ingredient classified as Skin Corrosion or as Skin Irritation (Category 2) when it contains ≥ 3 % of an skin irritant ingredient. Classification of mixtures with ingredients for which the approach in Table 3.2.3 does not apply is summarised in Table 3.2.4.

A mixture containing ingredients that are corrosive or irritant to the skin and that cannot be classified on the basis of the additivity approach (Table 3.2.3), due to chemical characteristics that make this approach unworkable, shall be classified as Skin Corrosion Category 1 if it contains ≥ 1 % of an ingredient classified as Skin Corrosion or as Skin Irritation (Category 2) when it contains ≥ 3 % of an skin irritant ingredient. Classification of mixtures with ingredients for which the approach in Table 3.2.3 does not apply is summarised in Table 3.2.4.

3.2.3.3.5.

On occasion, reliable data may show that the skin corrosion/irritation hazard of an ingredient will not be evident when present at a level at or above the generic concentration limits mentioned in Tables 3.2.3 and 3.2.4 in Section 3.2.3.3.6. In these cases the mixture shall be classified according to that data (see also Articles 10 and 11). On other occasions, when it is expected that the skin corrosion/irritation hazard of an ingredient is not evident when present at a level at or above the generic concentration limits mentioned in Tables 3.2.3 and 3.2.4, testing of the mixture shall be considered. In those cases the tiered weight of evidence approach shall be applied, as described in Section 3.2.2.2.

3.2.3.3.5.

On occasion, reliable data may show that the skin corrosion/irritation hazard of an ingredient will not be evident when present at a level at or above the generic concentration limits mentioned in Tables 3.2.3 and 3.2.4 in Section 3.2.3.3.6. In these cases the mixture shall be classified according to that data (see also Articles 10 and 11). On other occasions, when it is expected that the skin corrosion/irritation hazard of an ingredient is not evident when present at a level at or above the generic concentration limits mentioned in Tables 3.2.3 and 3.2.4, testing of the mixture shall be considered. In those cases the tiered weight of evidence approach shall be applied, as described in Section 3.2.2.2.

3.2.3.3.5.

On occasion, reliable data may show that the skin corrosion/irritation hazard of an ingredient will not be evident when present at a level at or above the generic concentration limits mentioned in Tables 3.2.3 and 3.2.4 in Section 3.2.3.3.6. In these cases the mixture shall be classified according to that data (see also Articles 10 and 11). On other occasions, when it is expected that the skin corrosion/irritation hazard of an ingredient is not evident when present at a level at or above the generic concentration limits mentioned in Tables 3.2.3 and 3.2.4, testing of the mixture shall be considered. In those cases the tiered weight of evidence approach shall be applied, as described in Section 3.2.2.2.

3.2.3.3.5.

3.2.3.3.5.

On occasion, reliable data may show that the skin corrosion/irritation hazard of an ingredient will not be evident when present at a level at or above the generic concentration limits mentioned in Tables 3.2.3 and 3.2.4 in Section 3.2.3.3.6. In these cases the mixture shall be classified according to that data (see also Articles 10 and 11). On other occasions, when it is expected that the skin corrosion/irritation hazard of an ingredient is not evident when present at a level at or above the generic concentration limits mentioned in Tables 3.2.3 and 3.2.4, testing of the mixture shall be considered. In those cases the tiered weight of evidence approach shall be applied, as described in Section 3.2.2.2.

On occasion, reliable data may show that the skin corrosion/irritation hazard of an ingredient will not be evident when present at a level at or above the generic concentration limits mentioned in Tables 3.2.3 and 3.2.4 in Section 3.2.3.3.6. In these cases the mixture shall be classified according to that data (see also Articles 10 and 11). On other occasions, when it is expected that the skin corrosion/irritation hazard of an ingredient is not evident when present at a level at or above the generic concentration limits mentioned in Tables 3.2.3 and 3.2.4, testing of the mixture shall be considered. In those cases the tiered weight of evidence approach shall be applied, as described in Section 3.2.2.2.

3.2.3.3.6.

If there are data showing that (an) ingredient(s) is/are corrosive or irritant to skin at a concentration of < 1 % (skin corrosive) or < 3 % (skin irritant), the mixture shall be classified accordingly.

Table 3.2.3

Generic concentration limits of ingredients classified as skin corrosion (Category 1, 1A, 1B or 1C)/skin irritation (Category 2) that trigger classification of the mixture as skin corrosion/skin irritation where the additivity approach applies

Sum of ingredients classified as:

Concentration triggering classification of a mixture as:

 

Skin corrosion

Skin irritation

 

Category 1 (see note below)

Category 2

Skin corrosion Sub-Category 1A, 1B, 1C or Category 1

≥ 5 %

≥ 1 % but < 5 %

Skin irritation Category 2

 

≥ 10 %

(10 × Skin corrosion Sub-Category 1A, 1B, 1C or Category 1) + Skin irritation Category 2

 

≥ 10 %

Note:

The sum of all ingredients of a mixture classified as Skin Corrosion Sub-Category 1A, 1B, or 1C respectively, shall each be ≥ 5 % in order to classify the mixture as either Skin Corrosion Sub-Category 1A, 1B or 1C. If the sum of the ingredients classified as Skin Corrosion Sub-Category 1A is < 5 % but the sum of ingredients classified as Skin Corrosion Sub-Category 1A + 1B is ≥ 5 %, the mixture shall be classified as Skin Corrosion Sub-Category 1B. Similarly, if the sum of ingredients classified as Skin Corrosion Sub-Category 1A + 1B ingredients is < 5 % but the sum of ingredients classified as Sub-Category 1A + 1B + 1C is ≥ 5 % the mixture shall be classified as Skin Corrosion Sub-Category 1C. Where at least one relevant ingredient in a mixture is classified as Category 1 without sub-categorisation, the mixture shall be classified as Category 1 without sub-categorisation if the sum of all ingredients corrosive to skin is ≥ 5 %.

Table 3.2.4

Generic concentration limits of ingredients that trigger classification of the mixture as skin corrosion/skin irritation, where the additivity approach does not apply

Ingredient:

Concentration:

Mixture classified as:

Acid with pH ≤ 2

≥ 1 %

Skin corrosion Category 1

Base with pH ≥ 11,5

≥ 1 %

Skin corrosion Category 1

Other skin corrosive (Sub-Categories 1A, 1B, 1C or Category 1) ingredients

≥ 1 %

Skin corrosion Category 1

Other skin irritant (Category 2) ingredients, including acids and bases

≥ 3 %

Skin irritation Category 2

3.2.3.3.6.

If there are data showing that (an) ingredient(s) is/are corrosive or irritant to skin at a concentration of < 1 % (skin corrosive) or < 3 % (skin irritant), the mixture shall be classified accordingly.

Table 3.2.3

Generic concentration limits of ingredients classified as skin corrosion (Category 1, 1A, 1B or 1C)/skin irritation (Category 2) that trigger classification of the mixture as skin corrosion/skin irritation where the additivity approach applies

Sum of ingredients classified as:

Concentration triggering classification of a mixture as:

 

Skin corrosion

Skin irritation

 

Category 1 (see note below)

Category 2

Skin corrosion Sub-Category 1A, 1B, 1C or Category 1

≥ 5 %

≥ 1 % but < 5 %

Skin irritation Category 2

 

≥ 10 %

(10 × Skin corrosion Sub-Category 1A, 1B, 1C or Category 1) + Skin irritation Category 2

 

≥ 10 %

Note:

The sum of all ingredients of a mixture classified as Skin Corrosion Sub-Category 1A, 1B, or 1C respectively, shall each be ≥ 5 % in order to classify the mixture as either Skin Corrosion Sub-Category 1A, 1B or 1C. If the sum of the ingredients classified as Skin Corrosion Sub-Category 1A is < 5 % but the sum of ingredients classified as Skin Corrosion Sub-Category 1A + 1B is ≥ 5 %, the mixture shall be classified as Skin Corrosion Sub-Category 1B. Similarly, if the sum of ingredients classified as Skin Corrosion Sub-Category 1A + 1B ingredients is < 5 % but the sum of ingredients classified as Sub-Category 1A + 1B + 1C is ≥ 5 % the mixture shall be classified as Skin Corrosion Sub-Category 1C. Where at least one relevant ingredient in a mixture is classified as Category 1 without sub-categorisation, the mixture shall be classified as Category 1 without sub-categorisation if the sum of all ingredients corrosive to skin is ≥ 5 %.

Table 3.2.4

Generic concentration limits of ingredients that trigger classification of the mixture as skin corrosion/skin irritation, where the additivity approach does not apply

Ingredient:

Concentration:

Mixture classified as:

Acid with pH ≤ 2

≥ 1 %

Skin corrosion Category 1

Base with pH ≥ 11,5

≥ 1 %

Skin corrosion Category 1

Other skin corrosive (Sub-Categories 1A, 1B, 1C or Category 1) ingredients

≥ 1 %

Skin corrosion Category 1

Other skin irritant (Category 2) ingredients, including acids and bases

≥ 3 %

Skin irritation Category 2

3.2.3.3.6.

If there are data showing that (an) ingredient(s) is/are corrosive or irritant to skin at a concentration of < 1 % (skin corrosive) or < 3 % (skin irritant), the mixture shall be classified accordingly.

Table 3.2.3

Generic concentration limits of ingredients classified as skin corrosion (Category 1, 1A, 1B or 1C)/skin irritation (Category 2) that trigger classification of the mixture as skin corrosion/skin irritation where the additivity approach applies

Sum of ingredients classified as:

Concentration triggering classification of a mixture as:

 

Skin corrosion

Skin irritation

 

Category 1 (see note below)

Category 2

Skin corrosion Sub-Category 1A, 1B, 1C or Category 1

≥ 5 %

≥ 1 % but < 5 %

Skin irritation Category 2

 

≥ 10 %

(10 × Skin corrosion Sub-Category 1A, 1B, 1C or Category 1) + Skin irritation Category 2

 

≥ 10 %

Note:

The sum of all ingredients of a mixture classified as Skin Corrosion Sub-Category 1A, 1B, or 1C respectively, shall each be ≥ 5 % in order to classify the mixture as either Skin Corrosion Sub-Category 1A, 1B or 1C. If the sum of the ingredients classified as Skin Corrosion Sub-Category 1A is < 5 % but the sum of ingredients classified as Skin Corrosion Sub-Category 1A + 1B is ≥ 5 %, the mixture shall be classified as Skin Corrosion Sub-Category 1B. Similarly, if the sum of ingredients classified as Skin Corrosion Sub-Category 1A + 1B ingredients is < 5 % but the sum of ingredients classified as Sub-Category 1A + 1B + 1C is ≥ 5 % the mixture shall be classified as Skin Corrosion Sub-Category 1C. Where at least one relevant ingredient in a mixture is classified as Category 1 without sub-categorisation, the mixture shall be classified as Category 1 without sub-categorisation if the sum of all ingredients corrosive to skin is ≥ 5 %.

Table 3.2.4

Generic concentration limits of ingredients that trigger classification of the mixture as skin corrosion/skin irritation, where the additivity approach does not apply

Ingredient:

Concentration:

Mixture classified as:

Acid with pH ≤ 2

≥ 1 %

Skin corrosion Category 1

Base with pH ≥ 11,5

≥ 1 %

Skin corrosion Category 1

Other skin corrosive (Sub-Categories 1A, 1B, 1C or Category 1) ingredients

≥ 1 %

Skin corrosion Category 1

Other skin irritant (Category 2) ingredients, including acids and bases

≥ 3 %

Skin irritation Category 2

3.2.3.3.6.

3.2.3.3.6.

If there are data showing that (an) ingredient(s) is/are corrosive or irritant to skin at a concentration of < 1 % (skin corrosive) or < 3 % (skin irritant), the mixture shall be classified accordingly.

Table 3.2.3

Generic concentration limits of ingredients classified as skin corrosion (Category 1, 1A, 1B or 1C)/skin irritation (Category 2) that trigger classification of the mixture as skin corrosion/skin irritation where the additivity approach applies

Sum of ingredients classified as:

Concentration triggering classification of a mixture as:

 

Skin corrosion

Skin irritation

 

Category 1 (see note below)

Category 2

Skin corrosion Sub-Category 1A, 1B, 1C or Category 1

≥ 5 %

≥ 1 % but < 5 %

Skin irritation Category 2

 

≥ 10 %

(10 × Skin corrosion Sub-Category 1A, 1B, 1C or Category 1) + Skin irritation Category 2

 

≥ 10 %

Note:

The sum of all ingredients of a mixture classified as Skin Corrosion Sub-Category 1A, 1B, or 1C respectively, shall each be ≥ 5 % in order to classify the mixture as either Skin Corrosion Sub-Category 1A, 1B or 1C. If the sum of the ingredients classified as Skin Corrosion Sub-Category 1A is < 5 % but the sum of ingredients classified as Skin Corrosion Sub-Category 1A + 1B is ≥ 5 %, the mixture shall be classified as Skin Corrosion Sub-Category 1B. Similarly, if the sum of ingredients classified as Skin Corrosion Sub-Category 1A + 1B ingredients is < 5 % but the sum of ingredients classified as Sub-Category 1A + 1B + 1C is ≥ 5 % the mixture shall be classified as Skin Corrosion Sub-Category 1C. Where at least one relevant ingredient in a mixture is classified as Category 1 without sub-categorisation, the mixture shall be classified as Category 1 without sub-categorisation if the sum of all ingredients corrosive to skin is ≥ 5 %.

Table 3.2.4

Generic concentration limits of ingredients that trigger classification of the mixture as skin corrosion/skin irritation, where the additivity approach does not apply

Ingredient:

Concentration:

Mixture classified as:

Acid with pH ≤ 2

≥ 1 %

Skin corrosion Category 1

Base with pH ≥ 11,5

≥ 1 %

Skin corrosion Category 1

Other skin corrosive (Sub-Categories 1A, 1B, 1C or Category 1) ingredients

≥ 1 %

Skin corrosion Category 1

Other skin irritant (Category 2) ingredients, including acids and bases

≥ 3 %

Skin irritation Category 2

If there are data showing that (an) ingredient(s) is/are corrosive or irritant to skin at a concentration of < 1 % (skin corrosive) or < 3 % (skin irritant), the mixture shall be classified accordingly.

Table 3.2.3

Generic concentration limits of ingredients classified as skin corrosion (Category 1, 1A, 1B or 1C)/skin irritation (Category 2) that trigger classification of the mixture as skin corrosion/skin irritation where the additivity approach applies

Sum of ingredients classified as:

Concentration triggering classification of a mixture as:

 

Skin corrosion

Skin irritation

 

Category 1 (see note below)

Category 2

Skin corrosion Sub-Category 1A, 1B, 1C or Category 1

≥ 5 %

≥ 1 % but < 5 %

Skin irritation Category 2

 

≥ 10 %

(10 × Skin corrosion Sub-Category 1A, 1B, 1C or Category 1) + Skin irritation Category 2

 

≥ 10 %

Table 3.2.3 Table 3.2.3

Generic concentration limits of ingredients classified as skin corrosion (Category 1, 1A, 1B or 1C)/skin irritation (Category 2) that trigger classification of the mixture as skin corrosion/skin irritation where the additivity approach applies Generic concentration limits of ingredients classified as skin corrosion (Category 1, 1A, 1B or 1C)/skin irritation (Category 2) that trigger classification of the mixture as skin corrosion/skin irritation where the additivity approach applies

Sum of ingredients classified as:

Concentration triggering classification of a mixture as:

 

Skin corrosion

Skin irritation

 

Category 1 (see note below)

Category 2

Skin corrosion Sub-Category 1A, 1B, 1C or Category 1

≥ 5 %

≥ 1 % but < 5 %

Skin irritation Category 2

 

≥ 10 %

(10 × Skin corrosion Sub-Category 1A, 1B, 1C or Category 1) + Skin irritation Category 2

 

≥ 10 %

Sum of ingredients classified as:

Concentration triggering classification of a mixture as:

 

Skin corrosion

Skin irritation

 

Category 1 (see note below)

Category 2

Skin corrosion Sub-Category 1A, 1B, 1C or Category 1

≥ 5 %

≥ 1 % but < 5 %

Skin irritation Category 2

 

≥ 10 %

(10 × Skin corrosion Sub-Category 1A, 1B, 1C or Category 1) + Skin irritation Category 2

 

≥ 10 %

Sum of ingredients classified as:

Concentration triggering classification of a mixture as:

Sum of ingredients classified as:

Sum of ingredients classified as:

Concentration triggering classification of a mixture as:

Concentration triggering classification of a mixture as:

 

Skin corrosion

Skin irritation

 

 

Skin corrosion

Skin corrosion

Skin irritation

Skin irritation

 

Category 1 (see note below)

Category 2

 

 

Category 1 (see note below)

Category 1 (see note below)

Category 2

Category 2

Skin corrosion Sub-Category 1A, 1B, 1C or Category 1

≥ 5 %

≥ 1 % but < 5 %

Skin corrosion Sub-Category 1A, 1B, 1C or Category 1

Skin corrosion Sub-Category 1A, 1B, 1C or Category 1

≥ 5 %

≥ 5 %

≥ 1 % but < 5 %

≥ 1 % but < 5 %

Skin irritation Category 2

 

≥ 10 %

Skin irritation Category 2

Skin irritation Category 2

 

 

≥ 10 %

≥ 10 %

(10 × Skin corrosion Sub-Category 1A, 1B, 1C or Category 1) + Skin irritation Category 2

 

≥ 10 %

(10 × Skin corrosion Sub-Category 1A, 1B, 1C or Category 1) + Skin irritation Category 2

(10 × Skin corrosion Sub-Category 1A, 1B, 1C or Category 1) + Skin irritation Category 2

 

 

≥ 10 %

≥ 10 %

Note: Note:

The sum of all ingredients of a mixture classified as Skin Corrosion Sub-Category 1A, 1B, or 1C respectively, shall each be ≥ 5 % in order to classify the mixture as either Skin Corrosion Sub-Category 1A, 1B or 1C. If the sum of the ingredients classified as Skin Corrosion Sub-Category 1A is < 5 % but the sum of ingredients classified as Skin Corrosion Sub-Category 1A + 1B is ≥ 5 %, the mixture shall be classified as Skin Corrosion Sub-Category 1B. Similarly, if the sum of ingredients classified as Skin Corrosion Sub-Category 1A + 1B ingredients is < 5 % but the sum of ingredients classified as Sub-Category 1A + 1B + 1C is ≥ 5 % the mixture shall be classified as Skin Corrosion Sub-Category 1C. Where at least one relevant ingredient in a mixture is classified as Category 1 without sub-categorisation, the mixture shall be classified as Category 1 without sub-categorisation if the sum of all ingredients corrosive to skin is ≥ 5 %.

Table 3.2.4

Generic concentration limits of ingredients that trigger classification of the mixture as skin corrosion/skin irritation, where the additivity approach does not apply

Ingredient:

Concentration:

Mixture classified as:

Acid with pH ≤ 2

≥ 1 %

Skin corrosion Category 1

Base with pH ≥ 11,5

≥ 1 %

Skin corrosion Category 1

Other skin corrosive (Sub-Categories 1A, 1B, 1C or Category 1) ingredients

≥ 1 %

Skin corrosion Category 1

Other skin irritant (Category 2) ingredients, including acids and bases

≥ 3 %

Skin irritation Category 2

Table 3.2.4 Table 3.2.4

Generic concentration limits of ingredients that trigger classification of the mixture as skin corrosion/skin irritation, where the additivity approach does not apply Generic concentration limits of ingredients that trigger classification of the mixture as skin corrosion/skin irritation, where the additivity approach does not apply

Ingredient:

Concentration:

Mixture classified as:

Acid with pH ≤ 2

≥ 1 %

Skin corrosion Category 1

Base with pH ≥ 11,5

≥ 1 %

Skin corrosion Category 1

Other skin corrosive (Sub-Categories 1A, 1B, 1C or Category 1) ingredients

≥ 1 %

Skin corrosion Category 1

Other skin irritant (Category 2) ingredients, including acids and bases

≥ 3 %

Skin irritation Category 2

Ingredient:

Concentration:

Mixture classified as:

Acid with pH ≤ 2

≥ 1 %

Skin corrosion Category 1

Base with pH ≥ 11,5

≥ 1 %

Skin corrosion Category 1

Other skin corrosive (Sub-Categories 1A, 1B, 1C or Category 1) ingredients

≥ 1 %

Skin corrosion Category 1

Other skin irritant (Category 2) ingredients, including acids and bases

≥ 3 %

Skin irritation Category 2

Ingredient:

Concentration:

Mixture classified as:

Ingredient:

Ingredient:

Concentration:

Concentration:

Mixture classified as:

Mixture classified as:

Acid with pH ≤ 2

≥ 1 %

Skin corrosion Category 1

Acid with pH ≤ 2

Acid with pH ≤ 2

≥ 1 %

≥ 1 %

Skin corrosion Category 1

Skin corrosion Category 1

Base with pH ≥ 11,5

≥ 1 %

Skin corrosion Category 1

Base with pH ≥ 11,5

Base with pH ≥ 11,5

≥ 1 %

≥ 1 %

Skin corrosion Category 1

Skin corrosion Category 1

Other skin corrosive (Sub-Categories 1A, 1B, 1C or Category 1) ingredients

≥ 1 %

Skin corrosion Category 1

Other skin corrosive (Sub-Categories 1A, 1B, 1C or Category 1) ingredients

Other skin corrosive (Sub-Categories 1A, 1B, 1C or Category 1) ingredients

≥ 1 %

≥ 1 %

Skin corrosion Category 1

Skin corrosion Category 1

Other skin irritant (Category 2) ingredients, including acids and bases

≥ 3 %

Skin irritation Category 2

Other skin irritant (Category 2) ingredients, including acids and bases

Other skin irritant (Category 2) ingredients, including acids and bases

≥ 3 %

≥ 3 %

Skin irritation Category 2

Skin irritation Category 2

3.2.4.    Hazard Communication

Hazard Communication Hazard Communication Hazard Communication

3.2.4.1.

Label elements shall be used for substances or mixtures meeting the criteria for classification in this hazard class in accordance with Table 3.2.5.

Table 3.2.5

Label elements for skin corrosion/irritation

Classification

Sub-Categories 1A/1B/1C and Category 1

Category 2

GHS Pictograms

image

image

Signal Word

Danger

Warning

Hazard Statement

H314: Causes severe skin burns and eye damage

H315: Causes skin irritation

Precautionary Statement Prevention

P260

P264

P280

P264

P280

Precautionary Statement Response

P301 + P330 + P331

P303 + P361 + P353

P363

P304 + P340

P310

P321

P305 + P351 + P338

P302 + P352

P321

P332 + P313

P362 + P364

Precautionary Statement Storage

P405

 

Precautionary Statement Disposal

P501

 

3.2.4.1.

Label elements shall be used for substances or mixtures meeting the criteria for classification in this hazard class in accordance with Table 3.2.5.

Table 3.2.5

Label elements for skin corrosion/irritation

Classification

Sub-Categories 1A/1B/1C and Category 1

Category 2

GHS Pictograms

image

image

Signal Word

Danger

Warning

Hazard Statement

H314: Causes severe skin burns and eye damage

H315: Causes skin irritation

Precautionary Statement Prevention

P260

P264

P280

P264

P280

Precautionary Statement Response

P301 + P330 + P331

P303 + P361 + P353

P363

P304 + P340

P310

P321

P305 + P351 + P338

P302 + P352

P321

P332 + P313

P362 + P364

Precautionary Statement Storage

P405

 

Precautionary Statement Disposal

P501

 

3.2.4.1.

Label elements shall be used for substances or mixtures meeting the criteria for classification in this hazard class in accordance with Table 3.2.5.

Table 3.2.5

Label elements for skin corrosion/irritation

Classification

Sub-Categories 1A/1B/1C and Category 1

Category 2

GHS Pictograms

image

image

Signal Word

Danger

Warning

Hazard Statement

H314: Causes severe skin burns and eye damage

H315: Causes skin irritation

Precautionary Statement Prevention

P260

P264

P280

P264

P280

Precautionary Statement Response

P301 + P330 + P331

P303 + P361 + P353

P363

P304 + P340

P310

P321

P305 + P351 + P338

P302 + P352

P321

P332 + P313

P362 + P364

Precautionary Statement Storage

P405

 

Precautionary Statement Disposal

P501

 

3.2.4.1.

3.2.4.1.

Label elements shall be used for substances or mixtures meeting the criteria for classification in this hazard class in accordance with Table 3.2.5.

Table 3.2.5

Label elements for skin corrosion/irritation

Classification

Sub-Categories 1A/1B/1C and Category 1

Category 2

GHS Pictograms

image

image

Signal Word

Danger

Warning

Hazard Statement

H314: Causes severe skin burns and eye damage

H315: Causes skin irritation

Precautionary Statement Prevention

P260

P264

P280

P264

P280

Precautionary Statement Response

P301 + P330 + P331

P303 + P361 + P353

P363

P304 + P340

P310

P321

P305 + P351 + P338

P302 + P352

P321

P332 + P313

P362 + P364

Precautionary Statement Storage

P405

 

Precautionary Statement Disposal

P501

 

Label elements shall be used for substances or mixtures meeting the criteria for classification in this hazard class in accordance with Table 3.2.5.

Table 3.2.5

Label elements for skin corrosion/irritation

Classification

Sub-Categories 1A/1B/1C and Category 1

Category 2

GHS Pictograms

image

image

Signal Word

Danger

Warning

Hazard Statement

H314: Causes severe skin burns and eye damage

H315: Causes skin irritation

Precautionary Statement Prevention

P260

P264

P280

P264

P280

Precautionary Statement Response

P301 + P330 + P331

P303 + P361 + P353

P363

P304 + P340

P310

P321

P305 + P351 + P338

P302 + P352

P321

P332 + P313

P362 + P364

Precautionary Statement Storage

P405

 

Precautionary Statement Disposal

P501

 

Table 3.2.5 Table 3.2.5

Label elements for skin corrosion/irritation Label elements for skin corrosion/irritation

Classification

Sub-Categories 1A/1B/1C and Category 1

Category 2

GHS Pictograms

image

image

Signal Word

Danger

Warning

Hazard Statement

H314: Causes severe skin burns and eye damage

H315: Causes skin irritation

Precautionary Statement Prevention

P260

P264

P280

P264

P280

Precautionary Statement Response

P301 + P330 + P331

P303 + P361 + P353

P363

P304 + P340

P310

P321

P305 + P351 + P338

P302 + P352

P321

P332 + P313

P362 + P364

Precautionary Statement Storage

P405

 

Precautionary Statement Disposal

P501

 

Classification

Sub-Categories 1A/1B/1C and Category 1

Category 2

GHS Pictograms

image

image

Signal Word

Danger

Warning

Hazard Statement

H314: Causes severe skin burns and eye damage

H315: Causes skin irritation

Precautionary Statement Prevention

P260

P264

P280

P264

P280

Precautionary Statement Response

P301 + P330 + P331

P303 + P361 + P353

P363

P304 + P340

P310

P321

P305 + P351 + P338

P302 + P352

P321

P332 + P313

P362 + P364

Precautionary Statement Storage

P405

 

Precautionary Statement Disposal

P501

 

Classification

Sub-Categories 1A/1B/1C and Category 1

Category 2

Classification

Classification

Sub-Categories 1A/1B/1C and Category 1

Sub-Categories 1A/1B/1C and Category 1

Category 2

Category 2

GHS Pictograms

image

image

GHS Pictograms

GHS Pictograms

image

image image

image

image image

Signal Word

Danger

Warning

Signal Word

Signal Word

Danger

Danger

Warning

Warning

Hazard Statement

H314: Causes severe skin burns and eye damage

H315: Causes skin irritation

Hazard Statement

Hazard Statement

H314: Causes severe skin burns and eye damage

H314: Causes severe skin burns and eye damage

H315: Causes skin irritation

H315: Causes skin irritation

Precautionary Statement Prevention

P260

P264

P280

P264

P280

Precautionary Statement Prevention

Precautionary Statement Prevention

P260

P264

P280

P260

P264

P280

P264

P280

P264

P280

Precautionary Statement Response

P301 + P330 + P331

P303 + P361 + P353

P363

P304 + P340

P310

P321

P305 + P351 + P338

P302 + P352

P321

P332 + P313

P362 + P364

Precautionary Statement Response

Precautionary Statement Response

P301 + P330 + P331

P303 + P361 + P353

P363

P304 + P340

P310

P321

P305 + P351 + P338

P301 + P330 + P331

P303 + P361 + P353

P363

P304 + P340

P310

P321

P305 + P351 + P338

P302 + P352

P321

P332 + P313

P362 + P364

P302 + P352

P321

P332 + P313

P362 + P364

Precautionary Statement Storage

P405

 

Precautionary Statement Storage

Precautionary Statement Storage

P405

P405

 

 

Precautionary Statement Disposal

P501

 

Precautionary Statement Disposal

Precautionary Statement Disposal

P501

P501

 

 

3.3.   Serious eye damage/eye irritation

Serious eye damage/eye irritation

3.3.1.    Definitions and general considerations

Definitions and general considerations Definitions and general considerations Definitions and general considerations

▼M19 ▼M19

3.3.1.1.

Serious eye damage means the production of tissue damage in the eye, or serious physical decay of vision, which is not fully reversible, occurring after exposure of the eye to a substance or mixture.

Eye irritation means the production of changes in the eye, which are fully reversible, occurring after the exposure of the eye to a substance or mixture.

3.3.1.1.

Serious eye damage means the production of tissue damage in the eye, or serious physical decay of vision, which is not fully reversible, occurring after exposure of the eye to a substance or mixture.

Eye irritation means the production of changes in the eye, which are fully reversible, occurring after the exposure of the eye to a substance or mixture.

3.3.1.1.

Serious eye damage means the production of tissue damage in the eye, or serious physical decay of vision, which is not fully reversible, occurring after exposure of the eye to a substance or mixture.

Eye irritation means the production of changes in the eye, which are fully reversible, occurring after the exposure of the eye to a substance or mixture.

3.3.1.1.

3.3.1.1.

Serious eye damage means the production of tissue damage in the eye, or serious physical decay of vision, which is not fully reversible, occurring after exposure of the eye to a substance or mixture.

Eye irritation means the production of changes in the eye, which are fully reversible, occurring after the exposure of the eye to a substance or mixture.

Serious eye damage means the production of tissue damage in the eye, or serious physical decay of vision, which is not fully reversible, occurring after exposure of the eye to a substance or mixture.

Eye irritation means the production of changes in the eye, which are fully reversible, occurring after the exposure of the eye to a substance or mixture.

▼M12 ▼M12

3.3.1.2.

In a tiered approach, emphasis shall be placed upon existing human data, followed by existing animal data, followed by in vitro data, and then other sources of information. Classification results directly when the data satisfy the criteria. In other cases, classification of a substance or a mixture is made on the basis of the weight of evidence within a tier. In a total weight of evidence approach all available information bearing on the determination of serious eye damage/eye irritation is considered together, including the results of appropriate validated in vitro tests, relevant animal data, and human data such as epidemiological and clinical studies and well-documented case reports and observations (see Annex I, Part 1, Section 1.1.1.3).

3.3.1.2.

In a tiered approach, emphasis shall be placed upon existing human data, followed by existing animal data, followed by in vitro data, and then other sources of information. Classification results directly when the data satisfy the criteria. In other cases, classification of a substance or a mixture is made on the basis of the weight of evidence within a tier. In a total weight of evidence approach all available information bearing on the determination of serious eye damage/eye irritation is considered together, including the results of appropriate validated in vitro tests, relevant animal data, and human data such as epidemiological and clinical studies and well-documented case reports and observations (see Annex I, Part 1, Section 1.1.1.3).

3.3.1.2.

In a tiered approach, emphasis shall be placed upon existing human data, followed by existing animal data, followed by in vitro data, and then other sources of information. Classification results directly when the data satisfy the criteria. In other cases, classification of a substance or a mixture is made on the basis of the weight of evidence within a tier. In a total weight of evidence approach all available information bearing on the determination of serious eye damage/eye irritation is considered together, including the results of appropriate validated in vitro tests, relevant animal data, and human data such as epidemiological and clinical studies and well-documented case reports and observations (see Annex I, Part 1, Section 1.1.1.3).

3.3.1.2.

3.3.1.2.

In a tiered approach, emphasis shall be placed upon existing human data, followed by existing animal data, followed by in vitro data, and then other sources of information. Classification results directly when the data satisfy the criteria. In other cases, classification of a substance or a mixture is made on the basis of the weight of evidence within a tier. In a total weight of evidence approach all available information bearing on the determination of serious eye damage/eye irritation is considered together, including the results of appropriate validated in vitro tests, relevant animal data, and human data such as epidemiological and clinical studies and well-documented case reports and observations (see Annex I, Part 1, Section 1.1.1.3).

In a tiered approach, emphasis shall be placed upon existing human data, followed by existing animal data, followed by in vitro data, and then other sources of information. Classification results directly when the data satisfy the criteria. In other cases, classification of a substance or a mixture is made on the basis of the weight of evidence within a tier. In a total weight of evidence approach all available information bearing on the determination of serious eye damage/eye irritation is considered together, including the results of appropriate validated in vitro tests, relevant animal data, and human data such as epidemiological and clinical studies and well-documented case reports and observations (see Annex I, Part 1, Section 1.1.1.3).

3.3.2.    Classification criteria for substances

Classification criteria for substances Classification criteria for substances Classification criteria for substances

Substances are allocated to one of the categories within this hazard class, Category 1 (serious eye damage) or Category 2 (eye irritation), as follows:

(a) 

Category 1 (serious eye damage):

substances that have the potential to seriously damage the eyes (see Table 3.3.1).

(a) 
(a) 

Category 1 (serious eye damage):

substances that have the potential to seriously damage the eyes (see Table 3.3.1).

Category 1 (serious eye damage):

substances that have the potential to seriously damage the eyes (see Table 3.3.1).

(b) 

Category 2 (eye irritation):

substances that have the potential to induce reversible eye irritation (see Table 3.3.2).

(b) 
(b) 

Category 2 (eye irritation):

substances that have the potential to induce reversible eye irritation (see Table 3.3.2).

Category 2 (eye irritation):

substances that have the potential to induce reversible eye irritation (see Table 3.3.2).

3.3.2.1.    Classification based on standard animal test data Classification based on standard animal test data Classification based on standard animal test data

3.3.2.1.1.    Serious eye damage (Category 1) Serious eye damage (Category 1) Serious eye damage (Category 1)

3.3.2.1.1.1. A single hazard category (Category 1) is adopted for substances that have the potential to seriously damage the eyes. This hazard category includes as criteria the observations listed in Table 3.3.1. These observations include animals with grade 4 cornea lesions and other severe reactions (e.g. destruction of cornea) observed at any time during the test, as well as persistent corneal opacity, discoloration of the cornea by a dye substance, adhesion, pannus, and interference with the function of the iris or other effects that impair sight. In this context, persistent lesions are considered those which are not fully reversible within an observation period of normally 21 days. Hazard classification as Category 1 also contains substances fulfilling the criteria of corneal opacity ≥ 3 or iritis > 1,5 observed in at least 2 of 3 tested animals, because severe lesions like these usually do not reverse within a 21-day observation period.

3.3.2.1.1.1. A single hazard category (Category 1) is adopted for substances that have the potential to seriously damage the eyes. This hazard category includes as criteria the observations listed in Table 3.3.1. These observations include animals with grade 4 cornea lesions and other severe reactions (e.g. destruction of cornea) observed at any time during the test, as well as persistent corneal opacity, discoloration of the cornea by a dye substance, adhesion, pannus, and interference with the function of the iris or other effects that impair sight. In this context, persistent lesions are considered those which are not fully reversible within an observation period of normally 21 days. Hazard classification as Category 1 also contains substances fulfilling the criteria of corneal opacity ≥ 3 or iritis > 1,5 observed in at least 2 of 3 tested animals, because severe lesions like these usually do not reverse within a 21-day observation period.  

3.3.2.1.1.2. The use of human data is discussed in Section 3.3.2.2 and also in Sections 1.1.1.3, 1.1.1.4 and 1.1.1.5.

3.3.2.1.1.2. The use of human data is discussed in Section 3.3.2.2 and also in Sections 1.1.1.3, 1.1.1.4 and 1.1.1.5.  

Table 3.3.1

Serious eye damage ()

Category

Criteria

Category 1

A substance that produces:

(a)  in at least one animal effects on the cornea, iris or conjunctiva that are not expected to reverse or have not fully reversed within an observation period of normally 21 days; and/or

(b)  in at least 2 of 3 tested animals, a positive response of:

(i)  corneal opacity ≥ 3; and/or

(ii)  iritis > 1,5;

calculated as the mean scores following grading at 24, 48 and 72 hours after instillation of the test material.

(1)   

Grading criteria are understood as described in Regulation (EC) No 440/2008.

Table 3.3.1 Table 3.3.1

Serious eye damage () Serious eye damage ()

Category

Criteria

Category 1

A substance that produces:

(a)  in at least one animal effects on the cornea, iris or conjunctiva that are not expected to reverse or have not fully reversed within an observation period of normally 21 days; and/or

(b)  in at least 2 of 3 tested animals, a positive response of:

(i)  corneal opacity ≥ 3; and/or

(ii)  iritis > 1,5;

calculated as the mean scores following grading at 24, 48 and 72 hours after instillation of the test material.

(1)   

Grading criteria are understood as described in Regulation (EC) No 440/2008.

Category

Criteria

Category 1

A substance that produces:

(a)  in at least one animal effects on the cornea, iris or conjunctiva that are not expected to reverse or have not fully reversed within an observation period of normally 21 days; and/or

(b)  in at least 2 of 3 tested animals, a positive response of:

(i)  corneal opacity ≥ 3; and/or

(ii)  iritis > 1,5;

calculated as the mean scores following grading at 24, 48 and 72 hours after instillation of the test material.

(1)   

Grading criteria are understood as described in Regulation (EC) No 440/2008.

Category

Criteria

Category

Category

Criteria

Criteria

Category 1

A substance that produces:

(a)  in at least one animal effects on the cornea, iris or conjunctiva that are not expected to reverse or have not fully reversed within an observation period of normally 21 days; and/or

(b)  in at least 2 of 3 tested animals, a positive response of:

(i)  corneal opacity ≥ 3; and/or

(ii)  iritis > 1,5;

calculated as the mean scores following grading at 24, 48 and 72 hours after instillation of the test material.

Category 1

Category 1 Category 1

A substance that produces:

(a)  in at least one animal effects on the cornea, iris or conjunctiva that are not expected to reverse or have not fully reversed within an observation period of normally 21 days; and/or

(b)  in at least 2 of 3 tested animals, a positive response of:

(i)  corneal opacity ≥ 3; and/or

(ii)  iritis > 1,5;

calculated as the mean scores following grading at 24, 48 and 72 hours after instillation of the test material.

A substance that produces:

(a)  in at least one animal effects on the cornea, iris or conjunctiva that are not expected to reverse or have not fully reversed within an observation period of normally 21 days; and/or

(b)  in at least 2 of 3 tested animals, a positive response of:

(i)  corneal opacity ≥ 3; and/or

(ii)  iritis > 1,5;

calculated as the mean scores following grading at 24, 48 and 72 hours after instillation of the test material.

(1)   

Grading criteria are understood as described in Regulation (EC) No 440/2008.

(1)   

Grading criteria are understood as described in Regulation (EC) No 440/2008.

(1)   

Grading criteria are understood as described in Regulation (EC) No 440/2008.

(1)    1

Grading criteria are understood as described in Regulation (EC) No 440/2008.

3.3.2.1.2.    Eye irritation (Category 2) Eye irritation (Category 2) Eye irritation (Category 2)

3.3.2.1.2.1. Substances that have the potential to induce reversible eye irritation shall be classified in Category 2 (eye irritation).

3.3.2.1.2.1. Substances that have the potential to induce reversible eye irritation shall be classified in Category 2 (eye irritation).  

3.3.2.1.2.2. For those substances where there is pronounced variability among animal responses, this information shall be taken into account in determining the classification.

3.3.2.1.2.2. For those substances where there is pronounced variability among animal responses, this information shall be taken into account in determining the classification.  

3.3.2.1.2.3. The use of human data is addressed in Sections 3.3.2.2, and also in Sections 1.1.1.3, 1.1.1.4 and 1.1.1.5.

3.3.2.1.2.3. The use of human data is addressed in Sections 3.3.2.2, and also in Sections 1.1.1.3, 1.1.1.4 and 1.1.1.5.  

Table 3.3.2

Eye irritation ()

Category

Criteria

Category 2

Substances that produce in at least 2 of 3 tested animals a positive response of:

(a)  corneal opacity ≥ 1; and/or

(b)  iritis ≥ 1; and/or

(c)  conjunctival redness ≥ 2; and/or

(d)  conjunctival oedema (chemosis) ≥ 2

calculated as the mean scores following grading at 24, 48 and 72 hours after instillation of the test material, and which fully reverses within an observation period of normally 21 days.

(1)   

Grading criteria are understood as described in Regulation (EC) No 440/2008.

Table 3.3.2 Table 3.3.2

Eye irritation () Eye irritation ()

Category

Criteria

Category 2

Substances that produce in at least 2 of 3 tested animals a positive response of:

(a)  corneal opacity ≥ 1; and/or

(b)  iritis ≥ 1; and/or

(c)  conjunctival redness ≥ 2; and/or

(d)  conjunctival oedema (chemosis) ≥ 2

calculated as the mean scores following grading at 24, 48 and 72 hours after instillation of the test material, and which fully reverses within an observation period of normally 21 days.

(1)   

Grading criteria are understood as described in Regulation (EC) No 440/2008.

Category

Criteria

Category 2

Substances that produce in at least 2 of 3 tested animals a positive response of:

(a)  corneal opacity ≥ 1; and/or

(b)  iritis ≥ 1; and/or

(c)  conjunctival redness ≥ 2; and/or

(d)  conjunctival oedema (chemosis) ≥ 2

calculated as the mean scores following grading at 24, 48 and 72 hours after instillation of the test material, and which fully reverses within an observation period of normally 21 days.

(1)   

Grading criteria are understood as described in Regulation (EC) No 440/2008.

Category

Criteria

Category

Category

Criteria

Criteria

Category 2

Substances that produce in at least 2 of 3 tested animals a positive response of:

(a)  corneal opacity ≥ 1; and/or

(b)  iritis ≥ 1; and/or

(c)  conjunctival redness ≥ 2; and/or

(d)  conjunctival oedema (chemosis) ≥ 2

calculated as the mean scores following grading at 24, 48 and 72 hours after instillation of the test material, and which fully reverses within an observation period of normally 21 days.

Category 2

Category 2 Category 2

Substances that produce in at least 2 of 3 tested animals a positive response of:

(a)  corneal opacity ≥ 1; and/or

(b)  iritis ≥ 1; and/or

(c)  conjunctival redness ≥ 2; and/or

(d)  conjunctival oedema (chemosis) ≥ 2

calculated as the mean scores following grading at 24, 48 and 72 hours after instillation of the test material, and which fully reverses within an observation period of normally 21 days.

Substances that produce in at least 2 of 3 tested animals a positive response of:

(a)  corneal opacity ≥ 1; and/or

(b)  iritis ≥ 1; and/or

(c)  conjunctival redness ≥ 2; and/or

(d)  conjunctival oedema (chemosis) ≥ 2

calculated as the mean scores following grading at 24, 48 and 72 hours after instillation of the test material, and which fully reverses within an observation period of normally 21 days.

(1)   

Grading criteria are understood as described in Regulation (EC) No 440/2008.

(1)   

Grading criteria are understood as described in Regulation (EC) No 440/2008.

(1)   

Grading criteria are understood as described in Regulation (EC) No 440/2008.

(1)    1

Grading criteria are understood as described in Regulation (EC) No 440/2008.

3.3.2.2.    Classification in a tiered approach Classification in a tiered approach Classification in a tiered approach

3.3.2.2.1.

A tiered approach to the evaluation of initial information shall be considered where applicable, recognizing that not all elements may be relevant.

3.3.2.2.1.

A tiered approach to the evaluation of initial information shall be considered where applicable, recognizing that not all elements may be relevant.

3.3.2.2.1.

A tiered approach to the evaluation of initial information shall be considered where applicable, recognizing that not all elements may be relevant.

3.3.2.2.1.

3.3.2.2.1.

A tiered approach to the evaluation of initial information shall be considered where applicable, recognizing that not all elements may be relevant.

A tiered approach to the evaluation of initial information shall be considered where applicable, recognizing that not all elements may be relevant.

3.3.2.2.2.

Existing human and animal data shall be the first line of evaluation as they give information directly relevant to effects on the eye. Possible skin corrosion has to be evaluated prior to consideration of any testing for serious eye damage/eye irritation in order to avoid testing for local effects on eyes with skin corrosive substances. Skin corrosive substances shall be considered as leading to serious eye damage (Category 1) as well, while skin irritant substances may be considered as leading to eye irritation (Category 2).

3.3.2.2.2.

Existing human and animal data shall be the first line of evaluation as they give information directly relevant to effects on the eye. Possible skin corrosion has to be evaluated prior to consideration of any testing for serious eye damage/eye irritation in order to avoid testing for local effects on eyes with skin corrosive substances. Skin corrosive substances shall be considered as leading to serious eye damage (Category 1) as well, while skin irritant substances may be considered as leading to eye irritation (Category 2).

3.3.2.2.2.

Existing human and animal data shall be the first line of evaluation as they give information directly relevant to effects on the eye. Possible skin corrosion has to be evaluated prior to consideration of any testing for serious eye damage/eye irritation in order to avoid testing for local effects on eyes with skin corrosive substances. Skin corrosive substances shall be considered as leading to serious eye damage (Category 1) as well, while skin irritant substances may be considered as leading to eye irritation (Category 2).

3.3.2.2.2.

3.3.2.2.2.

Existing human and animal data shall be the first line of evaluation as they give information directly relevant to effects on the eye. Possible skin corrosion has to be evaluated prior to consideration of any testing for serious eye damage/eye irritation in order to avoid testing for local effects on eyes with skin corrosive substances. Skin corrosive substances shall be considered as leading to serious eye damage (Category 1) as well, while skin irritant substances may be considered as leading to eye irritation (Category 2).

Existing human and animal data shall be the first line of evaluation as they give information directly relevant to effects on the eye. Possible skin corrosion has to be evaluated prior to consideration of any testing for serious eye damage/eye irritation in order to avoid testing for local effects on eyes with skin corrosive substances. Skin corrosive substances shall be considered as leading to serious eye damage (Category 1) as well, while skin irritant substances may be considered as leading to eye irritation (Category 2).

3.3.2.2.3.

In vitro alternatives that have been validated and accepted shall be used to make classification decisions.

3.3.2.2.3.

In vitro alternatives that have been validated and accepted shall be used to make classification decisions.

3.3.2.2.3.

In vitro alternatives that have been validated and accepted shall be used to make classification decisions.

3.3.2.2.3.

3.3.2.2.3.

In vitro alternatives that have been validated and accepted shall be used to make classification decisions.

In vitro alternatives that have been validated and accepted shall be used to make classification decisions.

3.3.2.2.4.

Likewise, pH extremes like ≤ 2 and ≥ 11,5, may indicate serious eye damage, especially when associated with significant acid/alkaline reserve (buffering capacity). Generally such substances are expected to produce significant effects on the eyes. In the absence of any other information, a substance is considered to cause serious eye damage (Category 1) if it has a pH ≤ 2 or ≥ 11,5. However, if consideration of acid/alkaline reserve suggests the substance may not cause serious eye damage despite the low or high pH value, this needs to be confirmed by other data, preferably by data from an appropriate validated in vitro test.

3.3.2.2.4.

Likewise, pH extremes like ≤ 2 and ≥ 11,5, may indicate serious eye damage, especially when associated with significant acid/alkaline reserve (buffering capacity). Generally such substances are expected to produce significant effects on the eyes. In the absence of any other information, a substance is considered to cause serious eye damage (Category 1) if it has a pH ≤ 2 or ≥ 11,5. However, if consideration of acid/alkaline reserve suggests the substance may not cause serious eye damage despite the low or high pH value, this needs to be confirmed by other data, preferably by data from an appropriate validated in vitro test.

3.3.2.2.4.

Likewise, pH extremes like ≤ 2 and ≥ 11,5, may indicate serious eye damage, especially when associated with significant acid/alkaline reserve (buffering capacity). Generally such substances are expected to produce significant effects on the eyes. In the absence of any other information, a substance is considered to cause serious eye damage (Category 1) if it has a pH ≤ 2 or ≥ 11,5. However, if consideration of acid/alkaline reserve suggests the substance may not cause serious eye damage despite the low or high pH value, this needs to be confirmed by other data, preferably by data from an appropriate validated in vitro test.

3.3.2.2.4.

3.3.2.2.4.

Likewise, pH extremes like ≤ 2 and ≥ 11,5, may indicate serious eye damage, especially when associated with significant acid/alkaline reserve (buffering capacity). Generally such substances are expected to produce significant effects on the eyes. In the absence of any other information, a substance is considered to cause serious eye damage (Category 1) if it has a pH ≤ 2 or ≥ 11,5. However, if consideration of acid/alkaline reserve suggests the substance may not cause serious eye damage despite the low or high pH value, this needs to be confirmed by other data, preferably by data from an appropriate validated in vitro test.

Likewise, pH extremes like ≤ 2 and ≥ 11,5, may indicate serious eye damage, especially when associated with significant acid/alkaline reserve (buffering capacity). Generally such substances are expected to produce significant effects on the eyes. In the absence of any other information, a substance is considered to cause serious eye damage (Category 1) if it has a pH ≤ 2 or ≥ 11,5. However, if consideration of acid/alkaline reserve suggests the substance may not cause serious eye damage despite the low or high pH value, this needs to be confirmed by other data, preferably by data from an appropriate validated in vitro test.

3.3.2.2.5.

In some cases sufficient information may be available from structurally related substances to make classification decisions.

3.3.2.2.5.

In some cases sufficient information may be available from structurally related substances to make classification decisions.

3.3.2.2.5.

In some cases sufficient information may be available from structurally related substances to make classification decisions.

3.3.2.2.5.

3.3.2.2.5.

In some cases sufficient information may be available from structurally related substances to make classification decisions.

In some cases sufficient information may be available from structurally related substances to make classification decisions.

3.3.2.2.6.

The tiered approach provides guidance on how to organize existing information and to make a weight-of-evidence decision about hazard assessment and hazard classification. Animal testing with corrosive substances shall be avoided whenever possible. Although information might be gained from the evaluation of single parameters within a tier (see 3.3.2.1.1) consideration shall be given to the totality of existing information and making an overall weight of evidence determination. This is especially true when there is conflict in information available on some parameters.

3.3.2.2.6.

The tiered approach provides guidance on how to organize existing information and to make a weight-of-evidence decision about hazard assessment and hazard classification. Animal testing with corrosive substances shall be avoided whenever possible. Although information might be gained from the evaluation of single parameters within a tier (see 3.3.2.1.1) consideration shall be given to the totality of existing information and making an overall weight of evidence determination. This is especially true when there is conflict in information available on some parameters.

3.3.2.2.6.

The tiered approach provides guidance on how to organize existing information and to make a weight-of-evidence decision about hazard assessment and hazard classification. Animal testing with corrosive substances shall be avoided whenever possible. Although information might be gained from the evaluation of single parameters within a tier (see 3.3.2.1.1) consideration shall be given to the totality of existing information and making an overall weight of evidence determination. This is especially true when there is conflict in information available on some parameters.

3.3.2.2.6.

3.3.2.2.6.

The tiered approach provides guidance on how to organize existing information and to make a weight-of-evidence decision about hazard assessment and hazard classification. Animal testing with corrosive substances shall be avoided whenever possible. Although information might be gained from the evaluation of single parameters within a tier (see 3.3.2.1.1) consideration shall be given to the totality of existing information and making an overall weight of evidence determination. This is especially true when there is conflict in information available on some parameters.

The tiered approach provides guidance on how to organize existing information and to make a weight-of-evidence decision about hazard assessment and hazard classification. Animal testing with corrosive substances shall be avoided whenever possible. Although information might be gained from the evaluation of single parameters within a tier (see 3.3.2.1.1) consideration shall be given to the totality of existing information and making an overall weight of evidence determination. This is especially true when there is conflict in information available on some parameters.

3.3.3.    Classification criteria for mixtures

Classification criteria for mixtures Classification criteria for mixtures Classification criteria for mixtures

3.3.3.1.    Classification of mixtures when data are available for the complete mixture Classification of mixtures when data are available for the complete mixture Classification of mixtures when data are available for the complete mixture

3.3.3.1.1.

The mixture shall be classified using the criteria for substances, and taking into account the tiered approach to evaluate data for this hazard class.

3.3.3.1.1.

The mixture shall be classified using the criteria for substances, and taking into account the tiered approach to evaluate data for this hazard class.

3.3.3.1.1.

The mixture shall be classified using the criteria for substances, and taking into account the tiered approach to evaluate data for this hazard class.

3.3.3.1.1.

3.3.3.1.1.

The mixture shall be classified using the criteria for substances, and taking into account the tiered approach to evaluate data for this hazard class.

The mixture shall be classified using the criteria for substances, and taking into account the tiered approach to evaluate data for this hazard class.

3.3.3.1.2.

When considering testing of the mixture classifiers are encouraged to use a tiered weight of evidence approach as included in the criteria for classification of substances for skin corrosion and serious eye damage/eye irritation to help ensure an accurate classification, as well as to avoid unnecessary animal testing. In the absence of any other information, a mixture is considered to cause serious eye damage (Category 1) if it has a pH ≤ 2 or ≥ 11,5. However, if consideration of acid/alkali reserve suggests the mixture may not cause serious eye damage despite the low or high pH value, this needs to be confirmed by other data, preferably data from an appropriate validated in vitro test.

3.3.3.1.2.

When considering testing of the mixture classifiers are encouraged to use a tiered weight of evidence approach as included in the criteria for classification of substances for skin corrosion and serious eye damage/eye irritation to help ensure an accurate classification, as well as to avoid unnecessary animal testing. In the absence of any other information, a mixture is considered to cause serious eye damage (Category 1) if it has a pH ≤ 2 or ≥ 11,5. However, if consideration of acid/alkali reserve suggests the mixture may not cause serious eye damage despite the low or high pH value, this needs to be confirmed by other data, preferably data from an appropriate validated in vitro test.

3.3.3.1.2.

When considering testing of the mixture classifiers are encouraged to use a tiered weight of evidence approach as included in the criteria for classification of substances for skin corrosion and serious eye damage/eye irritation to help ensure an accurate classification, as well as to avoid unnecessary animal testing. In the absence of any other information, a mixture is considered to cause serious eye damage (Category 1) if it has a pH ≤ 2 or ≥ 11,5. However, if consideration of acid/alkali reserve suggests the mixture may not cause serious eye damage despite the low or high pH value, this needs to be confirmed by other data, preferably data from an appropriate validated in vitro test.

3.3.3.1.2.

3.3.3.1.2.

When considering testing of the mixture classifiers are encouraged to use a tiered weight of evidence approach as included in the criteria for classification of substances for skin corrosion and serious eye damage/eye irritation to help ensure an accurate classification, as well as to avoid unnecessary animal testing. In the absence of any other information, a mixture is considered to cause serious eye damage (Category 1) if it has a pH ≤ 2 or ≥ 11,5. However, if consideration of acid/alkali reserve suggests the mixture may not cause serious eye damage despite the low or high pH value, this needs to be confirmed by other data, preferably data from an appropriate validated in vitro test.

When considering testing of the mixture classifiers are encouraged to use a tiered weight of evidence approach as included in the criteria for classification of substances for skin corrosion and serious eye damage/eye irritation to help ensure an accurate classification, as well as to avoid unnecessary animal testing. In the absence of any other information, a mixture is considered to cause serious eye damage (Category 1) if it has a pH ≤ 2 or ≥ 11,5. However, if consideration of acid/alkali reserve suggests the mixture may not cause serious eye damage despite the low or high pH value, this needs to be confirmed by other data, preferably data from an appropriate validated in vitro test.

3.3.3.2.    Classification of mixtures when data are not available for the complete mixture: bridging principles Classification of mixtures when data are not available for the complete mixture: bridging principles Classification of mixtures when data are not available for the complete mixture: bridging principles

3.3.3.2.1.

Where the mixture itself has not been tested to determine its skin corrosivity or potential to cause serious eye damage/eye irritation, but there are sufficient data on the individual ingredients and similar tested mixtures to adequately characterise the hazards of the mixture, these data shall be used in accordance with the bridging rules set out in Section 1.1.3.

3.3.3.2.1.

Where the mixture itself has not been tested to determine its skin corrosivity or potential to cause serious eye damage/eye irritation, but there are sufficient data on the individual ingredients and similar tested mixtures to adequately characterise the hazards of the mixture, these data shall be used in accordance with the bridging rules set out in Section 1.1.3.

3.3.3.2.1.

Where the mixture itself has not been tested to determine its skin corrosivity or potential to cause serious eye damage/eye irritation, but there are sufficient data on the individual ingredients and similar tested mixtures to adequately characterise the hazards of the mixture, these data shall be used in accordance with the bridging rules set out in Section 1.1.3.

3.3.3.2.1.

3.3.3.2.1.

Where the mixture itself has not been tested to determine its skin corrosivity or potential to cause serious eye damage/eye irritation, but there are sufficient data on the individual ingredients and similar tested mixtures to adequately characterise the hazards of the mixture, these data shall be used in accordance with the bridging rules set out in Section 1.1.3.

Where the mixture itself has not been tested to determine its skin corrosivity or potential to cause serious eye damage/eye irritation, but there are sufficient data on the individual ingredients and similar tested mixtures to adequately characterise the hazards of the mixture, these data shall be used in accordance with the bridging rules set out in Section 1.1.3.

3.3.3.3.    Classification of mixtures when data are available for all ingredients or only for some ingredients of the mixture Classification of mixtures when data are available for all ingredients or only for some ingredients of the mixture Classification of mixtures when data are available for all ingredients or only for some ingredients of the mixture

3.3.3.3.1.

In order to make use of all available data for purposes of classifying the serious eye damage/eye irritation properties of the mixtures, the following assumption has been made and is applied where appropriate in the tiered approach:

The ‘relevant ingredients’ of a mixture are those which are present in concentrations ≥ 1 % (w/w for solids, liquids, dusts, mists and vapours and v/v for gases), unless there is a presumption (e.g. in the case of skin corrosive ingredients) that an ingredient present at a concentration < 1 % can still be relevant for classifying the mixture for serious eye damage/eye irritation.

3.3.3.3.1.

In order to make use of all available data for purposes of classifying the serious eye damage/eye irritation properties of the mixtures, the following assumption has been made and is applied where appropriate in the tiered approach:

The ‘relevant ingredients’ of a mixture are those which are present in concentrations ≥ 1 % (w/w for solids, liquids, dusts, mists and vapours and v/v for gases), unless there is a presumption (e.g. in the case of skin corrosive ingredients) that an ingredient present at a concentration < 1 % can still be relevant for classifying the mixture for serious eye damage/eye irritation.

3.3.3.3.1.

In order to make use of all available data for purposes of classifying the serious eye damage/eye irritation properties of the mixtures, the following assumption has been made and is applied where appropriate in the tiered approach:

The ‘relevant ingredients’ of a mixture are those which are present in concentrations ≥ 1 % (w/w for solids, liquids, dusts, mists and vapours and v/v for gases), unless there is a presumption (e.g. in the case of skin corrosive ingredients) that an ingredient present at a concentration < 1 % can still be relevant for classifying the mixture for serious eye damage/eye irritation.

3.3.3.3.1.

3.3.3.3.1.

In order to make use of all available data for purposes of classifying the serious eye damage/eye irritation properties of the mixtures, the following assumption has been made and is applied where appropriate in the tiered approach:

The ‘relevant ingredients’ of a mixture are those which are present in concentrations ≥ 1 % (w/w for solids, liquids, dusts, mists and vapours and v/v for gases), unless there is a presumption (e.g. in the case of skin corrosive ingredients) that an ingredient present at a concentration < 1 % can still be relevant for classifying the mixture for serious eye damage/eye irritation.

In order to make use of all available data for purposes of classifying the serious eye damage/eye irritation properties of the mixtures, the following assumption has been made and is applied where appropriate in the tiered approach:

The ‘relevant ingredients’ of a mixture are those which are present in concentrations ≥ 1 % (w/w for solids, liquids, dusts, mists and vapours and v/v for gases), unless there is a presumption (e.g. in the case of skin corrosive ingredients) that an ingredient present at a concentration < 1 % can still be relevant for classifying the mixture for serious eye damage/eye irritation.

3.3.3.3.2.

In general, the approach to classification of mixtures as seriously damaging to the eye/eye irritant when data are available on the ingredients, but not on the mixture as a whole, is based on the theory of additivity, such that each skin corrosive or serious eye damaging/eye irritant ingredient contributes to the overall serious eye damage/eye irritation properties of the mixture in proportion to its potency and concentration. A weighting factor of 10 is used for skin corrosive and serious eye damaging ingredients when they are present at a concentration below the generic concentration limit for classification with Category 1, but are at a concentration that will contribute to the classification of the mixture as eye irritant. The mixture is classified as seriously damaging to the eye or eye irritant when the sum of the concentrations of such ingredients exceeds a concentration limit.

3.3.3.3.2.

In general, the approach to classification of mixtures as seriously damaging to the eye/eye irritant when data are available on the ingredients, but not on the mixture as a whole, is based on the theory of additivity, such that each skin corrosive or serious eye damaging/eye irritant ingredient contributes to the overall serious eye damage/eye irritation properties of the mixture in proportion to its potency and concentration. A weighting factor of 10 is used for skin corrosive and serious eye damaging ingredients when they are present at a concentration below the generic concentration limit for classification with Category 1, but are at a concentration that will contribute to the classification of the mixture as eye irritant. The mixture is classified as seriously damaging to the eye or eye irritant when the sum of the concentrations of such ingredients exceeds a concentration limit.

3.3.3.3.2.

In general, the approach to classification of mixtures as seriously damaging to the eye/eye irritant when data are available on the ingredients, but not on the mixture as a whole, is based on the theory of additivity, such that each skin corrosive or serious eye damaging/eye irritant ingredient contributes to the overall serious eye damage/eye irritation properties of the mixture in proportion to its potency and concentration. A weighting factor of 10 is used for skin corrosive and serious eye damaging ingredients when they are present at a concentration below the generic concentration limit for classification with Category 1, but are at a concentration that will contribute to the classification of the mixture as eye irritant. The mixture is classified as seriously damaging to the eye or eye irritant when the sum of the concentrations of such ingredients exceeds a concentration limit.

3.3.3.3.2.

3.3.3.3.2.

In general, the approach to classification of mixtures as seriously damaging to the eye/eye irritant when data are available on the ingredients, but not on the mixture as a whole, is based on the theory of additivity, such that each skin corrosive or serious eye damaging/eye irritant ingredient contributes to the overall serious eye damage/eye irritation properties of the mixture in proportion to its potency and concentration. A weighting factor of 10 is used for skin corrosive and serious eye damaging ingredients when they are present at a concentration below the generic concentration limit for classification with Category 1, but are at a concentration that will contribute to the classification of the mixture as eye irritant. The mixture is classified as seriously damaging to the eye or eye irritant when the sum of the concentrations of such ingredients exceeds a concentration limit.

In general, the approach to classification of mixtures as seriously damaging to the eye/eye irritant when data are available on the ingredients, but not on the mixture as a whole, is based on the theory of additivity, such that each skin corrosive or serious eye damaging/eye irritant ingredient contributes to the overall serious eye damage/eye irritation properties of the mixture in proportion to its potency and concentration. A weighting factor of 10 is used for skin corrosive and serious eye damaging ingredients when they are present at a concentration below the generic concentration limit for classification with Category 1, but are at a concentration that will contribute to the classification of the mixture as eye irritant. The mixture is classified as seriously damaging to the eye or eye irritant when the sum of the concentrations of such ingredients exceeds a concentration limit.

3.3.3.3.3.

Table 3.3.3 provides the generic concentration limits to be used to determine if the mixture shall be classified as seriously damaging to the eye or as eye irritant.

3.3.3.3.3.

Table 3.3.3 provides the generic concentration limits to be used to determine if the mixture shall be classified as seriously damaging to the eye or as eye irritant.

3.3.3.3.3.

Table 3.3.3 provides the generic concentration limits to be used to determine if the mixture shall be classified as seriously damaging to the eye or as eye irritant.

3.3.3.3.3.

3.3.3.3.3.

Table 3.3.3 provides the generic concentration limits to be used to determine if the mixture shall be classified as seriously damaging to the eye or as eye irritant.

Table 3.3.3 provides the generic concentration limits to be used to determine if the mixture shall be classified as seriously damaging to the eye or as eye irritant.

3.3.3.3.4.1.

Particular care must be taken when classifying certain types of mixtures containing substances such as acids and bases, inorganic salts, aldehydes, phenols, and surfactants. The approach explained in Sections 3.3.3.3.1 and 3.3.3.3.2 might not work given that many such substances are seriously damaging to the eye/eye irritant at concentrations < 1 %.

3.3.3.3.4.1.

Particular care must be taken when classifying certain types of mixtures containing substances such as acids and bases, inorganic salts, aldehydes, phenols, and surfactants. The approach explained in Sections 3.3.3.3.1 and 3.3.3.3.2 might not work given that many such substances are seriously damaging to the eye/eye irritant at concentrations < 1 %.

3.3.3.3.4.1.

Particular care must be taken when classifying certain types of mixtures containing substances such as acids and bases, inorganic salts, aldehydes, phenols, and surfactants. The approach explained in Sections 3.3.3.3.1 and 3.3.3.3.2 might not work given that many such substances are seriously damaging to the eye/eye irritant at concentrations < 1 %.

3.3.3.3.4.1.

3.3.3.3.4.1.

Particular care must be taken when classifying certain types of mixtures containing substances such as acids and bases, inorganic salts, aldehydes, phenols, and surfactants. The approach explained in Sections 3.3.3.3.1 and 3.3.3.3.2 might not work given that many such substances are seriously damaging to the eye/eye irritant at concentrations < 1 %.

Particular care must be taken when classifying certain types of mixtures containing substances such as acids and bases, inorganic salts, aldehydes, phenols, and surfactants. The approach explained in Sections 3.3.3.3.1 and 3.3.3.3.2 might not work given that many such substances are seriously damaging to the eye/eye irritant at concentrations < 1 %.

3.3.3.3.4.2.

For mixtures containing strong acids or bases the pH shall be used as classification criterion (see Section 3.3.3.1.2) since pH will be a better indicator of serious eye damage (subject to consideration of acid/alkali reserve) than the generic concentration limits in Table 3.3.3.

3.3.3.3.4.2.

For mixtures containing strong acids or bases the pH shall be used as classification criterion (see Section 3.3.3.1.2) since pH will be a better indicator of serious eye damage (subject to consideration of acid/alkali reserve) than the generic concentration limits in Table 3.3.3.

3.3.3.3.4.2.

For mixtures containing strong acids or bases the pH shall be used as classification criterion (see Section 3.3.3.1.2) since pH will be a better indicator of serious eye damage (subject to consideration of acid/alkali reserve) than the generic concentration limits in Table 3.3.3.

3.3.3.3.4.2.

3.3.3.3.4.2.

For mixtures containing strong acids or bases the pH shall be used as classification criterion (see Section 3.3.3.1.2) since pH will be a better indicator of serious eye damage (subject to consideration of acid/alkali reserve) than the generic concentration limits in Table 3.3.3.

For mixtures containing strong acids or bases the pH shall be used as classification criterion (see Section 3.3.3.1.2) since pH will be a better indicator of serious eye damage (subject to consideration of acid/alkali reserve) than the generic concentration limits in Table 3.3.3.

3.3.3.3.4.3.

A mixture containing skin corrosive or serious eye damaging/eye irritating ingredients that cannot be classified based on the additivity approach (Table 3.3.3) due to chemical characteristics that make this approach unworkable, shall be classified as Serious Eye Damage (Category 1) if it contains ≥ 1 % of a skin corrosive or serious eye damaging ingredient and as Eye Irritation (Category 2) when it contains ≥ 3 % of an eye irritant ingredient. Classification of mixtures with ingredients for which the approach in Table 3.3.3 does not apply is summarised in Table 3.3.4.

3.3.3.3.4.3.

A mixture containing skin corrosive or serious eye damaging/eye irritating ingredients that cannot be classified based on the additivity approach (Table 3.3.3) due to chemical characteristics that make this approach unworkable, shall be classified as Serious Eye Damage (Category 1) if it contains ≥ 1 % of a skin corrosive or serious eye damaging ingredient and as Eye Irritation (Category 2) when it contains ≥ 3 % of an eye irritant ingredient. Classification of mixtures with ingredients for which the approach in Table 3.3.3 does not apply is summarised in Table 3.3.4.

3.3.3.3.4.3.

A mixture containing skin corrosive or serious eye damaging/eye irritating ingredients that cannot be classified based on the additivity approach (Table 3.3.3) due to chemical characteristics that make this approach unworkable, shall be classified as Serious Eye Damage (Category 1) if it contains ≥ 1 % of a skin corrosive or serious eye damaging ingredient and as Eye Irritation (Category 2) when it contains ≥ 3 % of an eye irritant ingredient. Classification of mixtures with ingredients for which the approach in Table 3.3.3 does not apply is summarised in Table 3.3.4.

3.3.3.3.4.3.

3.3.3.3.4.3.

A mixture containing skin corrosive or serious eye damaging/eye irritating ingredients that cannot be classified based on the additivity approach (Table 3.3.3) due to chemical characteristics that make this approach unworkable, shall be classified as Serious Eye Damage (Category 1) if it contains ≥ 1 % of a skin corrosive or serious eye damaging ingredient and as Eye Irritation (Category 2) when it contains ≥ 3 % of an eye irritant ingredient. Classification of mixtures with ingredients for which the approach in Table 3.3.3 does not apply is summarised in Table 3.3.4.

A mixture containing skin corrosive or serious eye damaging/eye irritating ingredients that cannot be classified based on the additivity approach (Table 3.3.3) due to chemical characteristics that make this approach unworkable, shall be classified as Serious Eye Damage (Category 1) if it contains ≥ 1 % of a skin corrosive or serious eye damaging ingredient and as Eye Irritation (Category 2) when it contains ≥ 3 % of an eye irritant ingredient. Classification of mixtures with ingredients for which the approach in Table 3.3.3 does not apply is summarised in Table 3.3.4.

3.3.3.3.5.

On occasion, reliable data may show that the effects of serious eye damage/eye irritation of an ingredient will not be evident when present at a level at or above the generic concentration limits mentioned in Tables 3.3.3 and 3.3.4 in Section 3.3.3.3.6. In these cases the mixture shall be classified according to those data (see also Articles 10 and 11). On other occasions, when it is expected that the skin corrosion/irritation hazards or the effects of serious eye damage/eye irritation of an ingredient will not be evident when present at a level at or above the generic concentration limits mentioned in Tables 3.3.3 and 3.3.4, testing of the mixture shall be considered. In those cases, the tiered weight of evidence approach shall be applied.

3.3.3.3.5.

On occasion, reliable data may show that the effects of serious eye damage/eye irritation of an ingredient will not be evident when present at a level at or above the generic concentration limits mentioned in Tables 3.3.3 and 3.3.4 in Section 3.3.3.3.6. In these cases the mixture shall be classified according to those data (see also Articles 10 and 11). On other occasions, when it is expected that the skin corrosion/irritation hazards or the effects of serious eye damage/eye irritation of an ingredient will not be evident when present at a level at or above the generic concentration limits mentioned in Tables 3.3.3 and 3.3.4, testing of the mixture shall be considered. In those cases, the tiered weight of evidence approach shall be applied.

3.3.3.3.5.

On occasion, reliable data may show that the effects of serious eye damage/eye irritation of an ingredient will not be evident when present at a level at or above the generic concentration limits mentioned in Tables 3.3.3 and 3.3.4 in Section 3.3.3.3.6. In these cases the mixture shall be classified according to those data (see also Articles 10 and 11). On other occasions, when it is expected that the skin corrosion/irritation hazards or the effects of serious eye damage/eye irritation of an ingredient will not be evident when present at a level at or above the generic concentration limits mentioned in Tables 3.3.3 and 3.3.4, testing of the mixture shall be considered. In those cases, the tiered weight of evidence approach shall be applied.

3.3.3.3.5.

3.3.3.3.5.

On occasion, reliable data may show that the effects of serious eye damage/eye irritation of an ingredient will not be evident when present at a level at or above the generic concentration limits mentioned in Tables 3.3.3 and 3.3.4 in Section 3.3.3.3.6. In these cases the mixture shall be classified according to those data (see also Articles 10 and 11). On other occasions, when it is expected that the skin corrosion/irritation hazards or the effects of serious eye damage/eye irritation of an ingredient will not be evident when present at a level at or above the generic concentration limits mentioned in Tables 3.3.3 and 3.3.4, testing of the mixture shall be considered. In those cases, the tiered weight of evidence approach shall be applied.

On occasion, reliable data may show that the effects of serious eye damage/eye irritation of an ingredient will not be evident when present at a level at or above the generic concentration limits mentioned in Tables 3.3.3 and 3.3.4 in Section 3.3.3.3.6. In these cases the mixture shall be classified according to those data (see also Articles 10 and 11). On other occasions, when it is expected that the skin corrosion/irritation hazards or the effects of serious eye damage/eye irritation of an ingredient will not be evident when present at a level at or above the generic concentration limits mentioned in Tables 3.3.3 and 3.3.4, testing of the mixture shall be considered. In those cases, the tiered weight of evidence approach shall be applied.

3.3.3.3.6.

If there are data showing that (an) ingredient(s) may be corrosive to the skin or seriously damaging to the eye/eye irritating at a concentration of < 1 % (corrosive to the skin or seriously damaging to the eye) or < 3 % (eye irritant), the mixture shall be classified accordingly.

3.3.3.3.6.

If there are data showing that (an) ingredient(s) may be corrosive to the skin or seriously damaging to the eye/eye irritating at a concentration of < 1 % (corrosive to the skin or seriously damaging to the eye) or < 3 % (eye irritant), the mixture shall be classified accordingly.

3.3.3.3.6.

If there are data showing that (an) ingredient(s) may be corrosive to the skin or seriously damaging to the eye/eye irritating at a concentration of < 1 % (corrosive to the skin or seriously damaging to the eye) or < 3 % (eye irritant), the mixture shall be classified accordingly.

3.3.3.3.6.

3.3.3.3.6.

If there are data showing that (an) ingredient(s) may be corrosive to the skin or seriously damaging to the eye/eye irritating at a concentration of < 1 % (corrosive to the skin or seriously damaging to the eye) or < 3 % (eye irritant), the mixture shall be classified accordingly.

If there are data showing that (an) ingredient(s) may be corrosive to the skin or seriously damaging to the eye/eye irritating at a concentration of < 1 % (corrosive to the skin or seriously damaging to the eye) or < 3 % (eye irritant), the mixture shall be classified accordingly.

Table 3.3.3

Generic concentration limits of ingredients classified as skin corrosion (Category 1, 1A, 1B or 1C) and/or serious eye damage (Category 1) or eye irritation (Category 2) that trigger classification of the mixture as serious eye damage/eye irritation where the additivity approach applies

Sum of ingredients classified as:

Concentration triggering classification of a mixture as:

Serious eye damage

Eye irritation

Category 1

Category 2

Skin corrosion Sub-Category 1A, 1B, 1C or Category 1 + Serious eye damage (Category 1) ()

≥ 3 %

≥ 1 % but < 3 %

Eye irritation (Category 2)

 

≥ 10 %

10 × (Skin corrosion Sub-Category 1A, 1B, 1C or Skin corrosion Category 1 + Serious eye damage (Category 1)) + Eye irritation (Category 2)

 

≥ 10 %

(1)   

If an ingredient is classified as both Skin Corrosion Sub-Category 1A, 1B, 1C or Category 1 and Serious Eye Damage (Category 1), its concentration is considered only once in the calculation.

Table 3.3.3 Table 3.3.3

Generic concentration limits of ingredients classified as skin corrosion (Category 1, 1A, 1B or 1C) and/or serious eye damage (Category 1) or eye irritation (Category 2) that trigger classification of the mixture as serious eye damage/eye irritation where the additivity approach applies Generic concentration limits of ingredients classified as skin corrosion (Category 1, 1A, 1B or 1C) and/or serious eye damage (Category 1) or eye irritation (Category 2) that trigger classification of the mixture as serious eye damage/eye irritation where the additivity approach applies

Sum of ingredients classified as:

Concentration triggering classification of a mixture as:

Serious eye damage

Eye irritation

Category 1

Category 2

Skin corrosion Sub-Category 1A, 1B, 1C or Category 1 + Serious eye damage (Category 1) ()

≥ 3 %

≥ 1 % but < 3 %

Eye irritation (Category 2)

 

≥ 10 %

10 × (Skin corrosion Sub-Category 1A, 1B, 1C or Skin corrosion Category 1 + Serious eye damage (Category 1)) + Eye irritation (Category 2)

 

≥ 10 %

(1)   

If an ingredient is classified as both Skin Corrosion Sub-Category 1A, 1B, 1C or Category 1 and Serious Eye Damage (Category 1), its concentration is considered only once in the calculation.

Sum of ingredients classified as:

Concentration triggering classification of a mixture as:

Serious eye damage

Eye irritation

Category 1

Category 2

Skin corrosion Sub-Category 1A, 1B, 1C or Category 1 + Serious eye damage (Category 1) ()

≥ 3 %

≥ 1 % but < 3 %

Eye irritation (Category 2)

 

≥ 10 %

10 × (Skin corrosion Sub-Category 1A, 1B, 1C or Skin corrosion Category 1 + Serious eye damage (Category 1)) + Eye irritation (Category 2)

 

≥ 10 %

(1)   

If an ingredient is classified as both Skin Corrosion Sub-Category 1A, 1B, 1C or Category 1 and Serious Eye Damage (Category 1), its concentration is considered only once in the calculation.

Sum of ingredients classified as:

Concentration triggering classification of a mixture as:

Sum of ingredients classified as:

Sum of ingredients classified as:

Concentration triggering classification of a mixture as:

Concentration triggering classification of a mixture as:

Serious eye damage

Eye irritation

Serious eye damage

Serious eye damage

Eye irritation

Eye irritation

Category 1

Category 2

Category 1

Category 1

Category 2

Category 2

Skin corrosion Sub-Category 1A, 1B, 1C or Category 1 + Serious eye damage (Category 1) ()

≥ 3 %

≥ 1 % but < 3 %

Skin corrosion Sub-Category 1A, 1B, 1C or Category 1 + Serious eye damage (Category 1) ()

Skin corrosion Sub-Category 1A, 1B, 1C or Category 1 + Serious eye damage (Category 1) () ()

≥ 3 %

≥ 3 %

≥ 1 % but < 3 %

≥ 1 % but < 3 %

Eye irritation (Category 2)

 

≥ 10 %

Eye irritation (Category 2)

Eye irritation (Category 2)

 

 

≥ 10 %

≥ 10 %

10 × (Skin corrosion Sub-Category 1A, 1B, 1C or Skin corrosion Category 1 + Serious eye damage (Category 1)) + Eye irritation (Category 2)

 

≥ 10 %

10 × (Skin corrosion Sub-Category 1A, 1B, 1C or Skin corrosion Category 1 + Serious eye damage (Category 1)) + Eye irritation (Category 2)

10 × (Skin corrosion Sub-Category 1A, 1B, 1C or Skin corrosion Category 1 + Serious eye damage (Category 1)) + Eye irritation (Category 2)

 

 

≥ 10 %

≥ 10 %

(1)   

If an ingredient is classified as both Skin Corrosion Sub-Category 1A, 1B, 1C or Category 1 and Serious Eye Damage (Category 1), its concentration is considered only once in the calculation.

(1)   

If an ingredient is classified as both Skin Corrosion Sub-Category 1A, 1B, 1C or Category 1 and Serious Eye Damage (Category 1), its concentration is considered only once in the calculation.

(1)   

If an ingredient is classified as both Skin Corrosion Sub-Category 1A, 1B, 1C or Category 1 and Serious Eye Damage (Category 1), its concentration is considered only once in the calculation.

(1)    1

If an ingredient is classified as both Skin Corrosion Sub-Category 1A, 1B, 1C or Category 1 and Serious Eye Damage (Category 1), its concentration is considered only once in the calculation.

Table 3.3.4

Generic concentration limits of ingredients that trigger classification of the mixture as serious eye damage (Category 1) or eye irritation (Category 2), where the additivity approach does not apply

Ingredient

Concentration

Mixture classified as:

Acid with pH ≤ 2

≥ 1 %

Serious eye damage (Category 1)

Base with pH ≥ 11,5

≥ 1 %

Serious eye damage (Category 1)

Other ingredient classified as skin corrosion (Sub-Category 1A, 1B, 1C or Category 1) or serious eye damage (Category 1)

≥ 1 %

Serious eye damage (Category 1)

Other ingredient classified as eye irritation (Category 2)

≥ 3 %

Eye irritation (Category 2)

Table 3.3.4 Table 3.3.4

Generic concentration limits of ingredients that trigger classification of the mixture as serious eye damage (Category 1) or eye irritation (Category 2), where the additivity approach does not apply Generic concentration limits of ingredients that trigger classification of the mixture as serious eye damage (Category 1) or eye irritation (Category 2), where the additivity approach does not apply

Ingredient

Concentration

Mixture classified as:

Acid with pH ≤ 2

≥ 1 %

Serious eye damage (Category 1)

Base with pH ≥ 11,5

≥ 1 %

Serious eye damage (Category 1)

Other ingredient classified as skin corrosion (Sub-Category 1A, 1B, 1C or Category 1) or serious eye damage (Category 1)

≥ 1 %

Serious eye damage (Category 1)

Other ingredient classified as eye irritation (Category 2)

≥ 3 %

Eye irritation (Category 2)

Ingredient

Concentration

Mixture classified as:

Acid with pH ≤ 2

≥ 1 %

Serious eye damage (Category 1)

Base with pH ≥ 11,5

≥ 1 %

Serious eye damage (Category 1)

Other ingredient classified as skin corrosion (Sub-Category 1A, 1B, 1C or Category 1) or serious eye damage (Category 1)

≥ 1 %

Serious eye damage (Category 1)

Other ingredient classified as eye irritation (Category 2)

≥ 3 %

Eye irritation (Category 2)

Ingredient

Concentration

Mixture classified as:

Ingredient

Ingredient

Concentration

Concentration

Mixture classified as:

Mixture classified as:

Acid with pH ≤ 2

≥ 1 %

Serious eye damage (Category 1)

Acid with pH ≤ 2

Acid with pH ≤ 2

≥ 1 %

≥ 1 %

Serious eye damage (Category 1)

Serious eye damage (Category 1)

Base with pH ≥ 11,5

≥ 1 %

Serious eye damage (Category 1)

Base with pH ≥ 11,5

Base with pH ≥ 11,5

≥ 1 %

≥ 1 %

Serious eye damage (Category 1)

Serious eye damage (Category 1)

Other ingredient classified as skin corrosion (Sub-Category 1A, 1B, 1C or Category 1) or serious eye damage (Category 1)

≥ 1 %

Serious eye damage (Category 1)

Other ingredient classified as skin corrosion (Sub-Category 1A, 1B, 1C or Category 1) or serious eye damage (Category 1)

Other ingredient classified as skin corrosion (Sub-Category 1A, 1B, 1C or Category 1) or serious eye damage (Category 1)

≥ 1 %

≥ 1 %

Serious eye damage (Category 1)

Serious eye damage (Category 1)

Other ingredient classified as eye irritation (Category 2)

≥ 3 %

Eye irritation (Category 2)

Other ingredient classified as eye irritation (Category 2)

Other ingredient classified as eye irritation (Category 2)

≥ 3 %

≥ 3 %

Eye irritation (Category 2)

Eye irritation (Category 2)

3.3.4.    Hazard Communication

Hazard Communication Hazard Communication Hazard Communication

3.3.4.1.

Label elements shall be used for substances or mixtures meeting the criteria for classification in this hazard class in accordance with Table 3.3.5.

Table 3.3.5

Label elements for serious eye damage/eye irritation ()

Classification

Category 1

Category 2

GHS Pictograms

image

image

Signal Word

Danger

Warning

Hazard Statement

H318: Causes serious eye damage

H319: Causes serious eye irritation

Precautionary Statement Prevention

P280

P264

P280

Precautionary Statement Response

P305 + P351 + P338

P310

P305 + P351 + P338

P337 + P313

Precautionary Statement Storage

 

 

Precautionary Statement Disposal

 

 

(1)   

Where a chemical is classified as skin corrosion Sub-Category 1A, 1B, 1C or Category 1, labelling for serious eye damage/eye irritation can be omitted as this information is already included in the hazard statement for skin corrosion Category 1 (H314).

3.3.4.1.

Label elements shall be used for substances or mixtures meeting the criteria for classification in this hazard class in accordance with Table 3.3.5.

Table 3.3.5

Label elements for serious eye damage/eye irritation ()

Classification

Category 1

Category 2

GHS Pictograms

image

image

Signal Word

Danger

Warning

Hazard Statement

H318: Causes serious eye damage

H319: Causes serious eye irritation

Precautionary Statement Prevention

P280

P264

P280

Precautionary Statement Response

P305 + P351 + P338

P310

P305 + P351 + P338

P337 + P313

Precautionary Statement Storage

 

 

Precautionary Statement Disposal

 

 

(1)   

Where a chemical is classified as skin corrosion Sub-Category 1A, 1B, 1C or Category 1, labelling for serious eye damage/eye irritation can be omitted as this information is already included in the hazard statement for skin corrosion Category 1 (H314).

3.3.4.1.

Label elements shall be used for substances or mixtures meeting the criteria for classification in this hazard class in accordance with Table 3.3.5.

Table 3.3.5

Label elements for serious eye damage/eye irritation ()

Classification

Category 1

Category 2

GHS Pictograms

image

image

Signal Word

Danger

Warning

Hazard Statement

H318: Causes serious eye damage

H319: Causes serious eye irritation

Precautionary Statement Prevention

P280

P264

P280

Precautionary Statement Response

P305 + P351 + P338

P310

P305 + P351 + P338

P337 + P313

Precautionary Statement Storage

 

 

Precautionary Statement Disposal

 

 

(1)   

Where a chemical is classified as skin corrosion Sub-Category 1A, 1B, 1C or Category 1, labelling for serious eye damage/eye irritation can be omitted as this information is already included in the hazard statement for skin corrosion Category 1 (H314).

3.3.4.1.

3.3.4.1.

Label elements shall be used for substances or mixtures meeting the criteria for classification in this hazard class in accordance with Table 3.3.5.

Table 3.3.5

Label elements for serious eye damage/eye irritation ()

Classification

Category 1

Category 2

GHS Pictograms

image

image

Signal Word

Danger

Warning

Hazard Statement

H318: Causes serious eye damage

H319: Causes serious eye irritation

Precautionary Statement Prevention

P280

P264

P280

Precautionary Statement Response

P305 + P351 + P338

P310

P305 + P351 + P338

P337 + P313

Precautionary Statement Storage

 

 

Precautionary Statement Disposal

 

 

(1)   

Where a chemical is classified as skin corrosion Sub-Category 1A, 1B, 1C or Category 1, labelling for serious eye damage/eye irritation can be omitted as this information is already included in the hazard statement for skin corrosion Category 1 (H314).

Label elements shall be used for substances or mixtures meeting the criteria for classification in this hazard class in accordance with Table 3.3.5.

Table 3.3.5

Label elements for serious eye damage/eye irritation ()

Classification

Category 1

Category 2

GHS Pictograms

image

image

Signal Word

Danger

Warning

Hazard Statement

H318: Causes serious eye damage

H319: Causes serious eye irritation

Precautionary Statement Prevention

P280

P264

P280

Precautionary Statement Response

P305 + P351 + P338

P310

P305 + P351 + P338

P337 + P313

Precautionary Statement Storage

 

 

Precautionary Statement Disposal

 

 

(1)   

Where a chemical is classified as skin corrosion Sub-Category 1A, 1B, 1C or Category 1, labelling for serious eye damage/eye irritation can be omitted as this information is already included in the hazard statement for skin corrosion Category 1 (H314).

Table 3.3.5 Table 3.3.5

Label elements for serious eye damage/eye irritation () Label elements for serious eye damage/eye irritation ()

Classification

Category 1

Category 2

GHS Pictograms

image

image

Signal Word

Danger

Warning

Hazard Statement

H318: Causes serious eye damage

H319: Causes serious eye irritation

Precautionary Statement Prevention

P280

P264

P280

Precautionary Statement Response

P305 + P351 + P338

P310

P305 + P351 + P338

P337 + P313

Precautionary Statement Storage

 

 

Precautionary Statement Disposal

 

 

(1)   

Where a chemical is classified as skin corrosion Sub-Category 1A, 1B, 1C or Category 1, labelling for serious eye damage/eye irritation can be omitted as this information is already included in the hazard statement for skin corrosion Category 1 (H314).

Classification

Category 1

Category 2

GHS Pictograms

image

image

Signal Word

Danger

Warning

Hazard Statement

H318: Causes serious eye damage

H319: Causes serious eye irritation

Precautionary Statement Prevention

P280

P264

P280

Precautionary Statement Response

P305 + P351 + P338

P310

P305 + P351 + P338

P337 + P313

Precautionary Statement Storage

 

 

Precautionary Statement Disposal

 

 

(1)   

Where a chemical is classified as skin corrosion Sub-Category 1A, 1B, 1C or Category 1, labelling for serious eye damage/eye irritation can be omitted as this information is already included in the hazard statement for skin corrosion Category 1 (H314).

Classification

Category 1

Category 2

Classification

Classification

Category 1

Category 1

Category 2

Category 2

GHS Pictograms

image

image

GHS Pictograms

GHS Pictograms

image

image image

image

image image

Signal Word

Danger

Warning

Signal Word

Signal Word

Danger

Danger

Warning

Warning

Hazard Statement

H318: Causes serious eye damage

H319: Causes serious eye irritation

Hazard Statement

Hazard Statement

H318: Causes serious eye damage

H318: Causes serious eye damage

H319: Causes serious eye irritation

H319: Causes serious eye irritation

Precautionary Statement Prevention

P280

P264

P280

Precautionary Statement Prevention

Precautionary Statement Prevention

P280

P280

P264

P280

P264

P280

Precautionary Statement Response

P305 + P351 + P338

P310

P305 + P351 + P338

P337 + P313

Precautionary Statement Response

Precautionary Statement Response

P305 + P351 + P338

P310

P305 + P351 + P338

P310

P305 + P351 + P338

P337 + P313

P305 + P351 + P338

P337 + P313

Precautionary Statement Storage

 

 

Precautionary Statement Storage

Precautionary Statement Storage

 

 

 

 

Precautionary Statement Disposal

 

 

Precautionary Statement Disposal

Precautionary Statement Disposal

 

 

 

 

(1)   

Where a chemical is classified as skin corrosion Sub-Category 1A, 1B, 1C or Category 1, labelling for serious eye damage/eye irritation can be omitted as this information is already included in the hazard statement for skin corrosion Category 1 (H314).

(1)   

Where a chemical is classified as skin corrosion Sub-Category 1A, 1B, 1C or Category 1, labelling for serious eye damage/eye irritation can be omitted as this information is already included in the hazard statement for skin corrosion Category 1 (H314).

(1)   

Where a chemical is classified as skin corrosion Sub-Category 1A, 1B, 1C or Category 1, labelling for serious eye damage/eye irritation can be omitted as this information is already included in the hazard statement for skin corrosion Category 1 (H314).

(1)    1

Where a chemical is classified as skin corrosion Sub-Category 1A, 1B, 1C or Category 1, labelling for serious eye damage/eye irritation can be omitted as this information is already included in the hazard statement for skin corrosion Category 1 (H314).

▼B ▼B

3.4.   Respiratory or skin sensitisation

Respiratory or skin sensitisation

3.4.1.   Definitions and general considerations

Definitions and general considerations

▼M19 ▼M19

3.4.1.1. Respiratory sensitisation means hypersensitivity of the airways occurring after inhalation of a substance or a mixture.

3.4.1.1. Respiratory sensitisation means hypersensitivity of the airways occurring after inhalation of a substance or a mixture.  

3.4.1.2. Skin sensitisation means an allergic response occurring after skin contact with a substance or a mixture.

3.4.1.2. Skin sensitisation means an allergic response occurring after skin contact with a substance or a mixture.  

▼B ▼B

3.4.1.3. For the purpose of section 3.4, sensitisation includes two phases: the first phase is induction of specialised immunological memory in an individual by exposure to an allergen. The second phase is elicitation, i.e. production of a cell-mediated or antibody-mediated allergic response by exposure of a sensitised individual to an allergen.

3.4.1.3. For the purpose of section 3.4, sensitisation includes two phases: the first phase is induction of specialised immunological memory in an individual by exposure to an allergen. The second phase is elicitation, i.e. production of a cell-mediated or antibody-mediated allergic response by exposure of a sensitised individual to an allergen.  

3.4.1.4. For respiratory sensitisation, the pattern of induction followed by elicitation phases is shared in common with skin sensitisation. For skin sensitisation, an induction phase is required in which the immune system learns to react; clinical symptoms can then arise when subsequent exposure is sufficient to elicit a visible skin reaction (elicitation phase). As a consequence, predictive tests usually follow this pattern in which there is an induction phase, the response to which is measured by a standardised elicitation phase, typically involving a patch test. The local lymph node assay is the exception, directly measuring the induction response. Evidence of skin sensitisation in humans normally is assessed by a diagnostic patch test.

3.4.1.4. For respiratory sensitisation, the pattern of induction followed by elicitation phases is shared in common with skin sensitisation. For skin sensitisation, an induction phase is required in which the immune system learns to react; clinical symptoms can then arise when subsequent exposure is sufficient to elicit a visible skin reaction (elicitation phase). As a consequence, predictive tests usually follow this pattern in which there is an induction phase, the response to which is measured by a standardised elicitation phase, typically involving a patch test. The local lymph node assay is the exception, directly measuring the induction response. Evidence of skin sensitisation in humans normally is assessed by a diagnostic patch test.  

3.4.1.5. Usually, for both skin and respiratory sensitisation, lower levels are necessary for elicitation than are required for induction. Provisions for alerting sensitised individuals to the presence of a particular sensitiser in a mixture can be found ►M2  in Annex II, section 2.8. ◄ .

3.4.1.5. Usually, for both skin and respiratory sensitisation, lower levels are necessary for elicitation than are required for induction. Provisions for alerting sensitised individuals to the presence of a particular sensitiser in a mixture can be found ►M2  in Annex II, section 2.8. ◄ .   ►M2 ►M2 ►M2  ◄

3.4.1.6. The hazard class Respiratory or Skin Sensitisation is differentiated into:

3.4.1.6. The hazard class Respiratory or Skin Sensitisation is differentiated into:  

— 
Respiratory Sensitisation ►M2  and ◄ ;
— 
— 
Respiratory Sensitisation ►M2  and ◄ ;
Respiratory Sensitisation ►M2  and ◄ ;
►M2 ►M2 ►M2  ◄
— 
Skin Sensitisation.
— 
— 
Skin Sensitisation.
Skin Sensitisation.

▼M2 ▼M2

3.4.2.   Classification criteria for substances

Classification criteria for substances

3.4.2.1.   Respiratory sensitisers Respiratory sensitisers

3.4.2.1.1.   Hazard categories Hazard categories

3.4.2.1.1.1.

Respiratory sensitisers shall be classified in Category 1 where data are not sufficient for sub-categorisation.

3.4.2.1.1.1.

Respiratory sensitisers shall be classified in Category 1 where data are not sufficient for sub-categorisation.

3.4.2.1.1.1.

Respiratory sensitisers shall be classified in Category 1 where data are not sufficient for sub-categorisation.

3.4.2.1.1.1.

3.4.2.1.1.1.

Respiratory sensitisers shall be classified in Category 1 where data are not sufficient for sub-categorisation.

Respiratory sensitisers shall be classified in Category 1 where data are not sufficient for sub-categorisation.

3.4.2.1.1.2.

Where data are sufficient a refined evaluation according to 3.4.2.1.1.3 shall allow the allocation of respiratory sensitisers into sub-category 1A, strong sensitisers, or sub-category 1B for other respiratory sensitisers.

3.4.2.1.1.2.

Where data are sufficient a refined evaluation according to 3.4.2.1.1.3 shall allow the allocation of respiratory sensitisers into sub-category 1A, strong sensitisers, or sub-category 1B for other respiratory sensitisers.

3.4.2.1.1.2.

Where data are sufficient a refined evaluation according to 3.4.2.1.1.3 shall allow the allocation of respiratory sensitisers into sub-category 1A, strong sensitisers, or sub-category 1B for other respiratory sensitisers.

3.4.2.1.1.2.

3.4.2.1.1.2.

Where data are sufficient a refined evaluation according to 3.4.2.1.1.3 shall allow the allocation of respiratory sensitisers into sub-category 1A, strong sensitisers, or sub-category 1B for other respiratory sensitisers.

Where data are sufficient a refined evaluation according to 3.4.2.1.1.3 shall allow the allocation of respiratory sensitisers into sub-category 1A, strong sensitisers, or sub-category 1B for other respiratory sensitisers.

3.4.2.1.1.3.

Effects seen in either humans or animals will normally justify classification in a weight of evidence approach for respiratory sensitisers. Substances may be allocated to one of the two sub-categories 1A or 1B using a weight of evidence approach in accordance with the criteria given in Table 3.4.1 and on the basis of reliable and good quality evidence from human cases or epidemiological studies and/or observations from appropriate studies in experimental animals.

3.4.2.1.1.3.

Effects seen in either humans or animals will normally justify classification in a weight of evidence approach for respiratory sensitisers. Substances may be allocated to one of the two sub-categories 1A or 1B using a weight of evidence approach in accordance with the criteria given in Table 3.4.1 and on the basis of reliable and good quality evidence from human cases or epidemiological studies and/or observations from appropriate studies in experimental animals.

3.4.2.1.1.3.

Effects seen in either humans or animals will normally justify classification in a weight of evidence approach for respiratory sensitisers. Substances may be allocated to one of the two sub-categories 1A or 1B using a weight of evidence approach in accordance with the criteria given in Table 3.4.1 and on the basis of reliable and good quality evidence from human cases or epidemiological studies and/or observations from appropriate studies in experimental animals.

3.4.2.1.1.3.

3.4.2.1.1.3.

Effects seen in either humans or animals will normally justify classification in a weight of evidence approach for respiratory sensitisers. Substances may be allocated to one of the two sub-categories 1A or 1B using a weight of evidence approach in accordance with the criteria given in Table 3.4.1 and on the basis of reliable and good quality evidence from human cases or epidemiological studies and/or observations from appropriate studies in experimental animals.

Effects seen in either humans or animals will normally justify classification in a weight of evidence approach for respiratory sensitisers. Substances may be allocated to one of the two sub-categories 1A or 1B using a weight of evidence approach in accordance with the criteria given in Table 3.4.1 and on the basis of reliable and good quality evidence from human cases or epidemiological studies and/or observations from appropriate studies in experimental animals.

3.4.2.1.1.4.

Substances shall be classified as respiratory sensitisers in accordance with the criteria in Table 3.4.1:

Table 3.4.1

Hazard category and sub-categories for respiratory sensitisers

Category

Criteria

Category 1

Substances shall be classified as respiratory sensitisers (Category 1) where data are not sufficient for sub-categorisation in accordance with the following criteria:

(a)  if there is evidence in humans that the substance can lead to specific respiratory hypersensitivity; and/or

(b)  if there are positive results from an appropriate animal test.

Sub-category 1A:

Substances showing a high frequency of occurrence in humans; or a probability of occurrence of a high sensitisation rate in humans based on animal or other tests (1). Severity of reaction may also be considered.

Sub-category 1B:

Substances showing a low to moderate frequency of occurrence in humans; or a probability of occurrence of a low to moderate sensitisation rate in humans based on animal or other tests (1). Severity of reaction may also be considered.

(1)   

At present, recognised and validated animal models for the testing of respiratory hypersensitivity are not available. Under certain circumstances, data from animal studies may provide valuable information in a weight of evidence assessment.

3.4.2.1.1.4.

Substances shall be classified as respiratory sensitisers in accordance with the criteria in Table 3.4.1:

Table 3.4.1

Hazard category and sub-categories for respiratory sensitisers

Category

Criteria

Category 1

Substances shall be classified as respiratory sensitisers (Category 1) where data are not sufficient for sub-categorisation in accordance with the following criteria:

(a)  if there is evidence in humans that the substance can lead to specific respiratory hypersensitivity; and/or

(b)  if there are positive results from an appropriate animal test.

Sub-category 1A:

Substances showing a high frequency of occurrence in humans; or a probability of occurrence of a high sensitisation rate in humans based on animal or other tests (1). Severity of reaction may also be considered.

Sub-category 1B:

Substances showing a low to moderate frequency of occurrence in humans; or a probability of occurrence of a low to moderate sensitisation rate in humans based on animal or other tests (1). Severity of reaction may also be considered.

(1)   

At present, recognised and validated animal models for the testing of respiratory hypersensitivity are not available. Under certain circumstances, data from animal studies may provide valuable information in a weight of evidence assessment.

3.4.2.1.1.4.

Substances shall be classified as respiratory sensitisers in accordance with the criteria in Table 3.4.1:

Table 3.4.1

Hazard category and sub-categories for respiratory sensitisers

Category

Criteria

Category 1

Substances shall be classified as respiratory sensitisers (Category 1) where data are not sufficient for sub-categorisation in accordance with the following criteria:

(a)  if there is evidence in humans that the substance can lead to specific respiratory hypersensitivity; and/or

(b)  if there are positive results from an appropriate animal test.

Sub-category 1A:

Substances showing a high frequency of occurrence in humans; or a probability of occurrence of a high sensitisation rate in humans based on animal or other tests (1). Severity of reaction may also be considered.

Sub-category 1B:

Substances showing a low to moderate frequency of occurrence in humans; or a probability of occurrence of a low to moderate sensitisation rate in humans based on animal or other tests (1). Severity of reaction may also be considered.

(1)   

At present, recognised and validated animal models for the testing of respiratory hypersensitivity are not available. Under certain circumstances, data from animal studies may provide valuable information in a weight of evidence assessment.

3.4.2.1.1.4.

3.4.2.1.1.4.

Substances shall be classified as respiratory sensitisers in accordance with the criteria in Table 3.4.1:

Table 3.4.1

Hazard category and sub-categories for respiratory sensitisers

Category

Criteria

Category 1

Substances shall be classified as respiratory sensitisers (Category 1) where data are not sufficient for sub-categorisation in accordance with the following criteria:

(a)  if there is evidence in humans that the substance can lead to specific respiratory hypersensitivity; and/or

(b)  if there are positive results from an appropriate animal test.

Sub-category 1A:

Substances showing a high frequency of occurrence in humans; or a probability of occurrence of a high sensitisation rate in humans based on animal or other tests (1). Severity of reaction may also be considered.

Sub-category 1B:

Substances showing a low to moderate frequency of occurrence in humans; or a probability of occurrence of a low to moderate sensitisation rate in humans based on animal or other tests (1). Severity of reaction may also be considered.

(1)   

At present, recognised and validated animal models for the testing of respiratory hypersensitivity are not available. Under certain circumstances, data from animal studies may provide valuable information in a weight of evidence assessment.

Substances shall be classified as respiratory sensitisers in accordance with the criteria in Table 3.4.1:

Table 3.4.1

Hazard category and sub-categories for respiratory sensitisers

Category

Criteria

Category 1

Substances shall be classified as respiratory sensitisers (Category 1) where data are not sufficient for sub-categorisation in accordance with the following criteria:

(a)  if there is evidence in humans that the substance can lead to specific respiratory hypersensitivity; and/or

(b)  if there are positive results from an appropriate animal test.

Sub-category 1A:

Substances showing a high frequency of occurrence in humans; or a probability of occurrence of a high sensitisation rate in humans based on animal or other tests (1). Severity of reaction may also be considered.

Sub-category 1B:

Substances showing a low to moderate frequency of occurrence in humans; or a probability of occurrence of a low to moderate sensitisation rate in humans based on animal or other tests (1). Severity of reaction may also be considered.

(1)   

At present, recognised and validated animal models for the testing of respiratory hypersensitivity are not available. Under certain circumstances, data from animal studies may provide valuable information in a weight of evidence assessment.

Table 3.4.1

Hazard category and sub-categories for respiratory sensitisers

Category

Criteria

Category 1

Substances shall be classified as respiratory sensitisers (Category 1) where data are not sufficient for sub-categorisation in accordance with the following criteria:

(a)  if there is evidence in humans that the substance can lead to specific respiratory hypersensitivity; and/or

(b)  if there are positive results from an appropriate animal test.

Sub-category 1A:

Substances showing a high frequency of occurrence in humans; or a probability of occurrence of a high sensitisation rate in humans based on animal or other tests (1). Severity of reaction may also be considered.

Sub-category 1B:

Substances showing a low to moderate frequency of occurrence in humans; or a probability of occurrence of a low to moderate sensitisation rate in humans based on animal or other tests (1). Severity of reaction may also be considered.

(1)   

At present, recognised and validated animal models for the testing of respiratory hypersensitivity are not available. Under certain circumstances, data from animal studies may provide valuable information in a weight of evidence assessment.

Category

Criteria

Category 1

Substances shall be classified as respiratory sensitisers (Category 1) where data are not sufficient for sub-categorisation in accordance with the following criteria:

(a)  if there is evidence in humans that the substance can lead to specific respiratory hypersensitivity; and/or

(b)  if there are positive results from an appropriate animal test.

Sub-category 1A:

Substances showing a high frequency of occurrence in humans; or a probability of occurrence of a high sensitisation rate in humans based on animal or other tests (1). Severity of reaction may also be considered.

Sub-category 1B:

Substances showing a low to moderate frequency of occurrence in humans; or a probability of occurrence of a low to moderate sensitisation rate in humans based on animal or other tests (1). Severity of reaction may also be considered.

(1)   

At present, recognised and validated animal models for the testing of respiratory hypersensitivity are not available. Under certain circumstances, data from animal studies may provide valuable information in a weight of evidence assessment.

Category

Criteria

Category

Category

Criteria

Criteria

Category 1

Substances shall be classified as respiratory sensitisers (Category 1) where data are not sufficient for sub-categorisation in accordance with the following criteria:

(a)  if there is evidence in humans that the substance can lead to specific respiratory hypersensitivity; and/or

(b)  if there are positive results from an appropriate animal test.

Category 1

Category 1

Substances shall be classified as respiratory sensitisers (Category 1) where data are not sufficient for sub-categorisation in accordance with the following criteria:

(a)  if there is evidence in humans that the substance can lead to specific respiratory hypersensitivity; and/or

(b)  if there are positive results from an appropriate animal test.

Substances shall be classified as respiratory sensitisers (Category 1) where data are not sufficient for sub-categorisation in accordance with the following criteria:

(a)  if there is evidence in humans that the substance can lead to specific respiratory hypersensitivity; and/or

(b)  if there are positive results from an appropriate animal test.

Sub-category 1A:

Substances showing a high frequency of occurrence in humans; or a probability of occurrence of a high sensitisation rate in humans based on animal or other tests (1). Severity of reaction may also be considered.

Sub-category 1A:

Sub-category 1A:

Substances showing a high frequency of occurrence in humans; or a probability of occurrence of a high sensitisation rate in humans based on animal or other tests (1). Severity of reaction may also be considered.

Substances showing a high frequency of occurrence in humans; or a probability of occurrence of a high sensitisation rate in humans based on animal or other tests (1). Severity of reaction may also be considered. (1) 1

Sub-category 1B:

Substances showing a low to moderate frequency of occurrence in humans; or a probability of occurrence of a low to moderate sensitisation rate in humans based on animal or other tests (1). Severity of reaction may also be considered.

Sub-category 1B:

Sub-category 1B:

Substances showing a low to moderate frequency of occurrence in humans; or a probability of occurrence of a low to moderate sensitisation rate in humans based on animal or other tests (1). Severity of reaction may also be considered.

Substances showing a low to moderate frequency of occurrence in humans; or a probability of occurrence of a low to moderate sensitisation rate in humans based on animal or other tests (1). Severity of reaction may also be considered. (1) 1

(1)   

At present, recognised and validated animal models for the testing of respiratory hypersensitivity are not available. Under certain circumstances, data from animal studies may provide valuable information in a weight of evidence assessment.

(1)   

At present, recognised and validated animal models for the testing of respiratory hypersensitivity are not available. Under certain circumstances, data from animal studies may provide valuable information in a weight of evidence assessment.

(1)   

At present, recognised and validated animal models for the testing of respiratory hypersensitivity are not available. Under certain circumstances, data from animal studies may provide valuable information in a weight of evidence assessment.

(1)    1

At present, recognised and validated animal models for the testing of respiratory hypersensitivity are not available. Under certain circumstances, data from animal studies may provide valuable information in a weight of evidence assessment.

3.4.2.1.2.   Human evidence Human evidence

3.4.2.1.2.1.

Evidence that a substance can lead to specific respiratory hypersensitivity will normally be based on human experience. In this context, hypersensitivity is normally seen as asthma, but other hypersensitivity reactions such as rhinitis/conjunctivitis and alveolitis are also considered. The condition will have the clinical character of an allergic reaction. However, immunological mechanisms do not have to be demonstrated.

3.4.2.1.2.1.

Evidence that a substance can lead to specific respiratory hypersensitivity will normally be based on human experience. In this context, hypersensitivity is normally seen as asthma, but other hypersensitivity reactions such as rhinitis/conjunctivitis and alveolitis are also considered. The condition will have the clinical character of an allergic reaction. However, immunological mechanisms do not have to be demonstrated.

3.4.2.1.2.1.

Evidence that a substance can lead to specific respiratory hypersensitivity will normally be based on human experience. In this context, hypersensitivity is normally seen as asthma, but other hypersensitivity reactions such as rhinitis/conjunctivitis and alveolitis are also considered. The condition will have the clinical character of an allergic reaction. However, immunological mechanisms do not have to be demonstrated.

3.4.2.1.2.1.

3.4.2.1.2.1.

Evidence that a substance can lead to specific respiratory hypersensitivity will normally be based on human experience. In this context, hypersensitivity is normally seen as asthma, but other hypersensitivity reactions such as rhinitis/conjunctivitis and alveolitis are also considered. The condition will have the clinical character of an allergic reaction. However, immunological mechanisms do not have to be demonstrated.

Evidence that a substance can lead to specific respiratory hypersensitivity will normally be based on human experience. In this context, hypersensitivity is normally seen as asthma, but other hypersensitivity reactions such as rhinitis/conjunctivitis and alveolitis are also considered. The condition will have the clinical character of an allergic reaction. However, immunological mechanisms do not have to be demonstrated.

3.4.2.1.2.2.

When considering the human evidence, it is necessary for a decision on classification to take into account, in addition to the evidence from the cases:

(a) 

the size of the population exposed;

(b) 

the extent of exposure.

The use of human data is discussed in sections 1.1.1.3, 1.1.1.4 and 1.1.1.5.

3.4.2.1.2.2.

When considering the human evidence, it is necessary for a decision on classification to take into account, in addition to the evidence from the cases:

(a) 

the size of the population exposed;

(b) 

the extent of exposure.

The use of human data is discussed in sections 1.1.1.3, 1.1.1.4 and 1.1.1.5.

3.4.2.1.2.2.

When considering the human evidence, it is necessary for a decision on classification to take into account, in addition to the evidence from the cases:

(a) 

the size of the population exposed;

(b) 

the extent of exposure.

The use of human data is discussed in sections 1.1.1.3, 1.1.1.4 and 1.1.1.5.

3.4.2.1.2.2.

3.4.2.1.2.2.

When considering the human evidence, it is necessary for a decision on classification to take into account, in addition to the evidence from the cases:

(a) 

the size of the population exposed;

(b) 

the extent of exposure.

The use of human data is discussed in sections 1.1.1.3, 1.1.1.4 and 1.1.1.5.

When considering the human evidence, it is necessary for a decision on classification to take into account, in addition to the evidence from the cases:

(a) 

the size of the population exposed;

(a) 
(a) 

the size of the population exposed;

the size of the population exposed;

(b) 

the extent of exposure.

(b) 
(b) 

the extent of exposure.

the extent of exposure.

The use of human data is discussed in sections 1.1.1.3, 1.1.1.4 and 1.1.1.5.

3.4.2.1.2.3.

The evidence referred to above could be:

(a) 

clinical history and data from appropriate lung function tests related to exposure to the substance, confirmed by other supportive evidence which may include:

(i) 

in vivo immunological test (e.g. skin prick test);

(ii) 

in vitro immunological test (e.g. serological analysis);

(iii) 

studies that indicate other specific hypersensitivity reactions where immunological mechanisms of action have not been proven, e.g. repeated low-level irritation, pharmacologically mediated effects;

(iv) 

a chemical structure related to substances known to cause respiratory hypersensitivity;

(b) 

data from one or more positive bronchial challenge tests with the substance conducted according to accepted guidelines for the determination of a specific hypersensitivity reaction.

3.4.2.1.2.3.

The evidence referred to above could be:

(a) 

clinical history and data from appropriate lung function tests related to exposure to the substance, confirmed by other supportive evidence which may include:

(i) 

in vivo immunological test (e.g. skin prick test);

(ii) 

in vitro immunological test (e.g. serological analysis);

(iii) 

studies that indicate other specific hypersensitivity reactions where immunological mechanisms of action have not been proven, e.g. repeated low-level irritation, pharmacologically mediated effects;

(iv) 

a chemical structure related to substances known to cause respiratory hypersensitivity;

(b) 

data from one or more positive bronchial challenge tests with the substance conducted according to accepted guidelines for the determination of a specific hypersensitivity reaction.

3.4.2.1.2.3.

The evidence referred to above could be:

(a) 

clinical history and data from appropriate lung function tests related to exposure to the substance, confirmed by other supportive evidence which may include:

(i) 

in vivo immunological test (e.g. skin prick test);

(ii) 

in vitro immunological test (e.g. serological analysis);

(iii) 

studies that indicate other specific hypersensitivity reactions where immunological mechanisms of action have not been proven, e.g. repeated low-level irritation, pharmacologically mediated effects;

(iv) 

a chemical structure related to substances known to cause respiratory hypersensitivity;

(b) 

data from one or more positive bronchial challenge tests with the substance conducted according to accepted guidelines for the determination of a specific hypersensitivity reaction.

3.4.2.1.2.3.

3.4.2.1.2.3.

The evidence referred to above could be:

(a) 

clinical history and data from appropriate lung function tests related to exposure to the substance, confirmed by other supportive evidence which may include:

(i) 

in vivo immunological test (e.g. skin prick test);

(ii) 

in vitro immunological test (e.g. serological analysis);

(iii) 

studies that indicate other specific hypersensitivity reactions where immunological mechanisms of action have not been proven, e.g. repeated low-level irritation, pharmacologically mediated effects;

(iv) 

a chemical structure related to substances known to cause respiratory hypersensitivity;

(b) 

data from one or more positive bronchial challenge tests with the substance conducted according to accepted guidelines for the determination of a specific hypersensitivity reaction.

The evidence referred to above could be:

(a) 

clinical history and data from appropriate lung function tests related to exposure to the substance, confirmed by other supportive evidence which may include:

(i) 

in vivo immunological test (e.g. skin prick test);

(ii) 

in vitro immunological test (e.g. serological analysis);

(iii) 

studies that indicate other specific hypersensitivity reactions where immunological mechanisms of action have not been proven, e.g. repeated low-level irritation, pharmacologically mediated effects;

(iv) 

a chemical structure related to substances known to cause respiratory hypersensitivity;

(a) 
(a) 

clinical history and data from appropriate lung function tests related to exposure to the substance, confirmed by other supportive evidence which may include:

(i) 

in vivo immunological test (e.g. skin prick test);

(ii) 

in vitro immunological test (e.g. serological analysis);

(iii) 

studies that indicate other specific hypersensitivity reactions where immunological mechanisms of action have not been proven, e.g. repeated low-level irritation, pharmacologically mediated effects;

(iv) 

a chemical structure related to substances known to cause respiratory hypersensitivity;

clinical history and data from appropriate lung function tests related to exposure to the substance, confirmed by other supportive evidence which may include:

(i) 

in vivo immunological test (e.g. skin prick test);

(i) 
(i) 

in vivo immunological test (e.g. skin prick test);

in vivo immunological test (e.g. skin prick test);

(ii) 

in vitro immunological test (e.g. serological analysis);

(ii) 
(ii) 

in vitro immunological test (e.g. serological analysis);

in vitro immunological test (e.g. serological analysis);

(iii) 

studies that indicate other specific hypersensitivity reactions where immunological mechanisms of action have not been proven, e.g. repeated low-level irritation, pharmacologically mediated effects;

(iii) 
(iii) 

studies that indicate other specific hypersensitivity reactions where immunological mechanisms of action have not been proven, e.g. repeated low-level irritation, pharmacologically mediated effects;

studies that indicate other specific hypersensitivity reactions where immunological mechanisms of action have not been proven, e.g. repeated low-level irritation, pharmacologically mediated effects;

(iv) 

a chemical structure related to substances known to cause respiratory hypersensitivity;

(iv) 
(iv) 

a chemical structure related to substances known to cause respiratory hypersensitivity;

a chemical structure related to substances known to cause respiratory hypersensitivity;

(b) 

data from one or more positive bronchial challenge tests with the substance conducted according to accepted guidelines for the determination of a specific hypersensitivity reaction.

(b) 
(b) 

data from one or more positive bronchial challenge tests with the substance conducted according to accepted guidelines for the determination of a specific hypersensitivity reaction.

data from one or more positive bronchial challenge tests with the substance conducted according to accepted guidelines for the determination of a specific hypersensitivity reaction.

3.4.2.1.2.4.

Clinical history shall include both medical and occupational history to determine a relationship between exposure to a specific substance and development of respiratory hypersensitivity. Relevant information includes aggravating factors both in the home and workplace, the onset and progress of the disease, family history and medical history of the patient in question. The medical history shall also include a note of other allergic or airway disorders from childhood, and smoking history.

3.4.2.1.2.4.

Clinical history shall include both medical and occupational history to determine a relationship between exposure to a specific substance and development of respiratory hypersensitivity. Relevant information includes aggravating factors both in the home and workplace, the onset and progress of the disease, family history and medical history of the patient in question. The medical history shall also include a note of other allergic or airway disorders from childhood, and smoking history.

3.4.2.1.2.4.

Clinical history shall include both medical and occupational history to determine a relationship between exposure to a specific substance and development of respiratory hypersensitivity. Relevant information includes aggravating factors both in the home and workplace, the onset and progress of the disease, family history and medical history of the patient in question. The medical history shall also include a note of other allergic or airway disorders from childhood, and smoking history.

3.4.2.1.2.4.

3.4.2.1.2.4.

Clinical history shall include both medical and occupational history to determine a relationship between exposure to a specific substance and development of respiratory hypersensitivity. Relevant information includes aggravating factors both in the home and workplace, the onset and progress of the disease, family history and medical history of the patient in question. The medical history shall also include a note of other allergic or airway disorders from childhood, and smoking history.

Clinical history shall include both medical and occupational history to determine a relationship between exposure to a specific substance and development of respiratory hypersensitivity. Relevant information includes aggravating factors both in the home and workplace, the onset and progress of the disease, family history and medical history of the patient in question. The medical history shall also include a note of other allergic or airway disorders from childhood, and smoking history.

3.4.2.1.2.5.

The results of positive bronchial challenge tests are considered to provide sufficient evidence for classification on their own. It is however recognised that in practice many of the examinations listed above will already have been carried out.

3.4.2.1.2.5.

The results of positive bronchial challenge tests are considered to provide sufficient evidence for classification on their own. It is however recognised that in practice many of the examinations listed above will already have been carried out.

3.4.2.1.2.5.

The results of positive bronchial challenge tests are considered to provide sufficient evidence for classification on their own. It is however recognised that in practice many of the examinations listed above will already have been carried out.

3.4.2.1.2.5.

3.4.2.1.2.5.

The results of positive bronchial challenge tests are considered to provide sufficient evidence for classification on their own. It is however recognised that in practice many of the examinations listed above will already have been carried out.

The results of positive bronchial challenge tests are considered to provide sufficient evidence for classification on their own. It is however recognised that in practice many of the examinations listed above will already have been carried out.

3.4.2.1.3.   Animal studies Animal studies

▼M19 ▼M19

3.4.2.1.3.1.

Data from appropriate animal studies ( 16 ) which may be indicative of the potential of a substance to cause sensitisation by inhalation in humans ( 17 ) may include:

(a) 

measurements of Immunoglobulin E (IgE) and other specific immunological parameters, for example in mice;

(b) 

specific pulmonary responses in guinea pigs.

3.4.2.1.3.1.

Data from appropriate animal studies ( 16 ) which may be indicative of the potential of a substance to cause sensitisation by inhalation in humans ( 17 ) may include:

(a) 

measurements of Immunoglobulin E (IgE) and other specific immunological parameters, for example in mice;

(b) 

specific pulmonary responses in guinea pigs.

3.4.2.1.3.1.

Data from appropriate animal studies ( 16 ) which may be indicative of the potential of a substance to cause sensitisation by inhalation in humans ( 17 ) may include:

(a) 

measurements of Immunoglobulin E (IgE) and other specific immunological parameters, for example in mice;

(b) 

specific pulmonary responses in guinea pigs.

3.4.2.1.3.1.

3.4.2.1.3.1.

Data from appropriate animal studies ( 16 ) which may be indicative of the potential of a substance to cause sensitisation by inhalation in humans ( 17 ) may include:

(a) 

measurements of Immunoglobulin E (IgE) and other specific immunological parameters, for example in mice;

(b) 

specific pulmonary responses in guinea pigs.

Data from appropriate animal studies ( 16 ) which may be indicative of the potential of a substance to cause sensitisation by inhalation in humans ( 17 ) may include: 16 16 17 17

(a) 

measurements of Immunoglobulin E (IgE) and other specific immunological parameters, for example in mice;

(a) 
(a) 

measurements of Immunoglobulin E (IgE) and other specific immunological parameters, for example in mice;

measurements of Immunoglobulin E (IgE) and other specific immunological parameters, for example in mice;

(b) 

specific pulmonary responses in guinea pigs.

(b) 
(b) 

specific pulmonary responses in guinea pigs.

specific pulmonary responses in guinea pigs.

▼M2 ▼M2

3.4.2.2.   Skin sensitisers Skin sensitisers

3.4.2.2.1.   Hazard categories Hazard categories

3.4.2.2.1.1.

Skin sensitisers shall be classified in Category 1 where data are not sufficient for sub-categorisation.

3.4.2.2.1.1.

Skin sensitisers shall be classified in Category 1 where data are not sufficient for sub-categorisation.

3.4.2.2.1.1.

Skin sensitisers shall be classified in Category 1 where data are not sufficient for sub-categorisation.

3.4.2.2.1.1.

3.4.2.2.1.1.

Skin sensitisers shall be classified in Category 1 where data are not sufficient for sub-categorisation.

Skin sensitisers shall be classified in Category 1 where data are not sufficient for sub-categorisation.

3.4.2.2.1.2.

Where data are sufficient a refined evaluation according to section 3.4.2.2.1.3 allows the allocation of skin sensitisers into sub-category 1A, strong sensitisers, or sub-category 1B for other skin sensitisers.

3.4.2.2.1.2.

Where data are sufficient a refined evaluation according to section 3.4.2.2.1.3 allows the allocation of skin sensitisers into sub-category 1A, strong sensitisers, or sub-category 1B for other skin sensitisers.

3.4.2.2.1.2.

Where data are sufficient a refined evaluation according to section 3.4.2.2.1.3 allows the allocation of skin sensitisers into sub-category 1A, strong sensitisers, or sub-category 1B for other skin sensitisers.

3.4.2.2.1.2.

3.4.2.2.1.2.

Where data are sufficient a refined evaluation according to section 3.4.2.2.1.3 allows the allocation of skin sensitisers into sub-category 1A, strong sensitisers, or sub-category 1B for other skin sensitisers.

Where data are sufficient a refined evaluation according to section 3.4.2.2.1.3 allows the allocation of skin sensitisers into sub-category 1A, strong sensitisers, or sub-category 1B for other skin sensitisers.

3.4.2.2.1.3.

Effects seen in either humans or animals will normally justify classification in a weight of evidence approach for skin sensitisers as described in section 3.4.2.2.2. Substances may be allocated to one of the two sub-categories 1A or 1B using a weight of evidence approach in accordance with the criteria given in Table 3.4.2 and on the basis of reliable and good quality evidence from human cases or epidemiological studies and/or observations from appropriate studies in experimental animals according to the guidance values provided in sections 3.4.2.2.2.1 and 3.4.2.2.3.2 for sub-category 1A and in sections 3.4.2.2.2.2 and 3.4.2.2.3.3 for sub-category 1B.

3.4.2.2.1.3.

Effects seen in either humans or animals will normally justify classification in a weight of evidence approach for skin sensitisers as described in section 3.4.2.2.2. Substances may be allocated to one of the two sub-categories 1A or 1B using a weight of evidence approach in accordance with the criteria given in Table 3.4.2 and on the basis of reliable and good quality evidence from human cases or epidemiological studies and/or observations from appropriate studies in experimental animals according to the guidance values provided in sections 3.4.2.2.2.1 and 3.4.2.2.3.2 for sub-category 1A and in sections 3.4.2.2.2.2 and 3.4.2.2.3.3 for sub-category 1B.

3.4.2.2.1.3.

Effects seen in either humans or animals will normally justify classification in a weight of evidence approach for skin sensitisers as described in section 3.4.2.2.2. Substances may be allocated to one of the two sub-categories 1A or 1B using a weight of evidence approach in accordance with the criteria given in Table 3.4.2 and on the basis of reliable and good quality evidence from human cases or epidemiological studies and/or observations from appropriate studies in experimental animals according to the guidance values provided in sections 3.4.2.2.2.1 and 3.4.2.2.3.2 for sub-category 1A and in sections 3.4.2.2.2.2 and 3.4.2.2.3.3 for sub-category 1B.

3.4.2.2.1.3.

3.4.2.2.1.3.

Effects seen in either humans or animals will normally justify classification in a weight of evidence approach for skin sensitisers as described in section 3.4.2.2.2. Substances may be allocated to one of the two sub-categories 1A or 1B using a weight of evidence approach in accordance with the criteria given in Table 3.4.2 and on the basis of reliable and good quality evidence from human cases or epidemiological studies and/or observations from appropriate studies in experimental animals according to the guidance values provided in sections 3.4.2.2.2.1 and 3.4.2.2.3.2 for sub-category 1A and in sections 3.4.2.2.2.2 and 3.4.2.2.3.3 for sub-category 1B.

Effects seen in either humans or animals will normally justify classification in a weight of evidence approach for skin sensitisers as described in section 3.4.2.2.2. Substances may be allocated to one of the two sub-categories 1A or 1B using a weight of evidence approach in accordance with the criteria given in Table 3.4.2 and on the basis of reliable and good quality evidence from human cases or epidemiological studies and/or observations from appropriate studies in experimental animals according to the guidance values provided in sections 3.4.2.2.2.1 and 3.4.2.2.3.2 for sub-category 1A and in sections 3.4.2.2.2.2 and 3.4.2.2.3.3 for sub-category 1B.

3.4.2.2.1.4.

Substances shall be classified as skin sensitisers in accordance with the criteria in Table 3.4.2:

Table 3.4.2

Hazard category and sub-categories for skin sensitisers

Category

Criteria

Category 1

Substances shall be classified as skin sensitisers (Category 1) where data are not sufficient for sub-categorisation in accordance with the following criteria:

(a)  if there is evidence in humans that the substance can lead to sensitisation by skin contact in a substantial number of persons; or

(b)  if there are positive results from an appropriate animal test (see specific criteria in section 3.4.2.2.4.1).

Sub-category 1A:

Substances showing a high frequency of occurrence in humans and/or a high potency in animals can be presumed to have the potential to produce significant sensitisation in humans. Severity of reaction may also be considered.

Sub-category 1B:

Substances showing a low to moderate frequency of occurrence in humans and/or a low to moderate potency in animals can be presumed to have the potential to produce sensitisation in humans. Severity of reaction may also be considered.

3.4.2.2.1.4.

Substances shall be classified as skin sensitisers in accordance with the criteria in Table 3.4.2:

Table 3.4.2

Hazard category and sub-categories for skin sensitisers

Category

Criteria

Category 1

Substances shall be classified as skin sensitisers (Category 1) where data are not sufficient for sub-categorisation in accordance with the following criteria:

(a)  if there is evidence in humans that the substance can lead to sensitisation by skin contact in a substantial number of persons; or

(b)  if there are positive results from an appropriate animal test (see specific criteria in section 3.4.2.2.4.1).

Sub-category 1A:

Substances showing a high frequency of occurrence in humans and/or a high potency in animals can be presumed to have the potential to produce significant sensitisation in humans. Severity of reaction may also be considered.

Sub-category 1B:

Substances showing a low to moderate frequency of occurrence in humans and/or a low to moderate potency in animals can be presumed to have the potential to produce sensitisation in humans. Severity of reaction may also be considered.

3.4.2.2.1.4.

Substances shall be classified as skin sensitisers in accordance with the criteria in Table 3.4.2:

Table 3.4.2

Hazard category and sub-categories for skin sensitisers

Category

Criteria

Category 1

Substances shall be classified as skin sensitisers (Category 1) where data are not sufficient for sub-categorisation in accordance with the following criteria:

(a)  if there is evidence in humans that the substance can lead to sensitisation by skin contact in a substantial number of persons; or

(b)  if there are positive results from an appropriate animal test (see specific criteria in section 3.4.2.2.4.1).

Sub-category 1A:

Substances showing a high frequency of occurrence in humans and/or a high potency in animals can be presumed to have the potential to produce significant sensitisation in humans. Severity of reaction may also be considered.

Sub-category 1B:

Substances showing a low to moderate frequency of occurrence in humans and/or a low to moderate potency in animals can be presumed to have the potential to produce sensitisation in humans. Severity of reaction may also be considered.

3.4.2.2.1.4.

3.4.2.2.1.4.

Substances shall be classified as skin sensitisers in accordance with the criteria in Table 3.4.2:

Table 3.4.2

Hazard category and sub-categories for skin sensitisers

Category

Criteria

Category 1

Substances shall be classified as skin sensitisers (Category 1) where data are not sufficient for sub-categorisation in accordance with the following criteria:

(a)  if there is evidence in humans that the substance can lead to sensitisation by skin contact in a substantial number of persons; or

(b)  if there are positive results from an appropriate animal test (see specific criteria in section 3.4.2.2.4.1).

Sub-category 1A:

Substances showing a high frequency of occurrence in humans and/or a high potency in animals can be presumed to have the potential to produce significant sensitisation in humans. Severity of reaction may also be considered.

Sub-category 1B:

Substances showing a low to moderate frequency of occurrence in humans and/or a low to moderate potency in animals can be presumed to have the potential to produce sensitisation in humans. Severity of reaction may also be considered.

Substances shall be classified as skin sensitisers in accordance with the criteria in Table 3.4.2:

Table 3.4.2

Hazard category and sub-categories for skin sensitisers

Category

Criteria

Category 1

Substances shall be classified as skin sensitisers (Category 1) where data are not sufficient for sub-categorisation in accordance with the following criteria:

(a)  if there is evidence in humans that the substance can lead to sensitisation by skin contact in a substantial number of persons; or

(b)  if there are positive results from an appropriate animal test (see specific criteria in section 3.4.2.2.4.1).

Sub-category 1A:

Substances showing a high frequency of occurrence in humans and/or a high potency in animals can be presumed to have the potential to produce significant sensitisation in humans. Severity of reaction may also be considered.

Sub-category 1B:

Substances showing a low to moderate frequency of occurrence in humans and/or a low to moderate potency in animals can be presumed to have the potential to produce sensitisation in humans. Severity of reaction may also be considered.

Table 3.4.2

Hazard category and sub-categories for skin sensitisers

Category

Criteria

Category 1

Substances shall be classified as skin sensitisers (Category 1) where data are not sufficient for sub-categorisation in accordance with the following criteria:

(a)  if there is evidence in humans that the substance can lead to sensitisation by skin contact in a substantial number of persons; or

(b)  if there are positive results from an appropriate animal test (see specific criteria in section 3.4.2.2.4.1).

Sub-category 1A:

Substances showing a high frequency of occurrence in humans and/or a high potency in animals can be presumed to have the potential to produce significant sensitisation in humans. Severity of reaction may also be considered.

Sub-category 1B:

Substances showing a low to moderate frequency of occurrence in humans and/or a low to moderate potency in animals can be presumed to have the potential to produce sensitisation in humans. Severity of reaction may also be considered.

Category

Criteria

Category 1

Substances shall be classified as skin sensitisers (Category 1) where data are not sufficient for sub-categorisation in accordance with the following criteria:

(a)  if there is evidence in humans that the substance can lead to sensitisation by skin contact in a substantial number of persons; or

(b)  if there are positive results from an appropriate animal test (see specific criteria in section 3.4.2.2.4.1).

Sub-category 1A:

Substances showing a high frequency of occurrence in humans and/or a high potency in animals can be presumed to have the potential to produce significant sensitisation in humans. Severity of reaction may also be considered.

Sub-category 1B:

Substances showing a low to moderate frequency of occurrence in humans and/or a low to moderate potency in animals can be presumed to have the potential to produce sensitisation in humans. Severity of reaction may also be considered.

Category

Criteria

Category

Category

Criteria

Criteria

Category 1

Substances shall be classified as skin sensitisers (Category 1) where data are not sufficient for sub-categorisation in accordance with the following criteria:

(a)  if there is evidence in humans that the substance can lead to sensitisation by skin contact in a substantial number of persons; or

(b)  if there are positive results from an appropriate animal test (see specific criteria in section 3.4.2.2.4.1).

Category 1

Category 1

Substances shall be classified as skin sensitisers (Category 1) where data are not sufficient for sub-categorisation in accordance with the following criteria:

(a)  if there is evidence in humans that the substance can lead to sensitisation by skin contact in a substantial number of persons; or

(b)  if there are positive results from an appropriate animal test (see specific criteria in section 3.4.2.2.4.1).

Substances shall be classified as skin sensitisers (Category 1) where data are not sufficient for sub-categorisation in accordance with the following criteria:

(a)  if there is evidence in humans that the substance can lead to sensitisation by skin contact in a substantial number of persons; or

(b)  if there are positive results from an appropriate animal test (see specific criteria in section 3.4.2.2.4.1).

Sub-category 1A:

Substances showing a high frequency of occurrence in humans and/or a high potency in animals can be presumed to have the potential to produce significant sensitisation in humans. Severity of reaction may also be considered.

Sub-category 1A:

Sub-category 1A:

Substances showing a high frequency of occurrence in humans and/or a high potency in animals can be presumed to have the potential to produce significant sensitisation in humans. Severity of reaction may also be considered.

Substances showing a high frequency of occurrence in humans and/or a high potency in animals can be presumed to have the potential to produce significant sensitisation in humans. Severity of reaction may also be considered.

Sub-category 1B:

Substances showing a low to moderate frequency of occurrence in humans and/or a low to moderate potency in animals can be presumed to have the potential to produce sensitisation in humans. Severity of reaction may also be considered.

Sub-category 1B:

Sub-category 1B:

Substances showing a low to moderate frequency of occurrence in humans and/or a low to moderate potency in animals can be presumed to have the potential to produce sensitisation in humans. Severity of reaction may also be considered.

Substances showing a low to moderate frequency of occurrence in humans and/or a low to moderate potency in animals can be presumed to have the potential to produce sensitisation in humans. Severity of reaction may also be considered.

3.4.2.2.2.   Human evidence Human evidence

3.4.2.2.2.1.

Human evidence for sub-category 1A can include:

(a) 

positive responses at ≤ 500 μg/cm2 (HRIPT, HMT — induction threshold);

(b) 

diagnostic patch test data where there is a relatively high and substantial incidence of reactions in a defined population in relation to relatively low exposure;

(c) 

other epidemiological evidence where there is a relatively high and substantial incidence of allergic contact dermatitis in relation to relatively low exposure.

3.4.2.2.2.1.

Human evidence for sub-category 1A can include:

(a) 

positive responses at ≤ 500 μg/cm2 (HRIPT, HMT — induction threshold);

(b) 

diagnostic patch test data where there is a relatively high and substantial incidence of reactions in a defined population in relation to relatively low exposure;

(c) 

other epidemiological evidence where there is a relatively high and substantial incidence of allergic contact dermatitis in relation to relatively low exposure.

3.4.2.2.2.1.

Human evidence for sub-category 1A can include:

(a) 

positive responses at ≤ 500 μg/cm2 (HRIPT, HMT — induction threshold);

(b) 

diagnostic patch test data where there is a relatively high and substantial incidence of reactions in a defined population in relation to relatively low exposure;

(c) 

other epidemiological evidence where there is a relatively high and substantial incidence of allergic contact dermatitis in relation to relatively low exposure.

3.4.2.2.2.1.

3.4.2.2.2.1.

Human evidence for sub-category 1A can include:

(a) 

positive responses at ≤ 500 μg/cm2 (HRIPT, HMT — induction threshold);

(b) 

diagnostic patch test data where there is a relatively high and substantial incidence of reactions in a defined population in relation to relatively low exposure;

(c) 

other epidemiological evidence where there is a relatively high and substantial incidence of allergic contact dermatitis in relation to relatively low exposure.

Human evidence for sub-category 1A can include:

(a) 

positive responses at ≤ 500 μg/cm2 (HRIPT, HMT — induction threshold);

(a) 
(a) 

positive responses at ≤ 500 μg/cm2 (HRIPT, HMT — induction threshold);

positive responses at ≤ 500 μg/cm2 (HRIPT, HMT — induction threshold); 2

(b) 

diagnostic patch test data where there is a relatively high and substantial incidence of reactions in a defined population in relation to relatively low exposure;

(b) 
(b) 

diagnostic patch test data where there is a relatively high and substantial incidence of reactions in a defined population in relation to relatively low exposure;

diagnostic patch test data where there is a relatively high and substantial incidence of reactions in a defined population in relation to relatively low exposure;

(c) 

other epidemiological evidence where there is a relatively high and substantial incidence of allergic contact dermatitis in relation to relatively low exposure.

(c) 
(c) 

other epidemiological evidence where there is a relatively high and substantial incidence of allergic contact dermatitis in relation to relatively low exposure.

other epidemiological evidence where there is a relatively high and substantial incidence of allergic contact dermatitis in relation to relatively low exposure.

3.4.2.2.2.2.

Human evidence for sub-category 1B can include:

(a) 

positive responses at > 500 μg/cm2 (HRIPT, HMT — induction threshold);

(b) 

diagnostic patch test data where there is a relatively low but substantial incidence of reactions in a defined population in relation to relatively high exposure;

(c) 

other epidemiological evidence where there is a relatively low but substantial incidence of allergic contact dermatitis in relation to relatively high exposure.

The use of human data is discussed in sections 1.1.1.3, 1.1.1.4 and 1.1.1.5.

3.4.2.2.2.2.

Human evidence for sub-category 1B can include:

(a) 

positive responses at > 500 μg/cm2 (HRIPT, HMT — induction threshold);

(b) 

diagnostic patch test data where there is a relatively low but substantial incidence of reactions in a defined population in relation to relatively high exposure;

(c) 

other epidemiological evidence where there is a relatively low but substantial incidence of allergic contact dermatitis in relation to relatively high exposure.

The use of human data is discussed in sections 1.1.1.3, 1.1.1.4 and 1.1.1.5.

3.4.2.2.2.2.

Human evidence for sub-category 1B can include:

(a) 

positive responses at > 500 μg/cm2 (HRIPT, HMT — induction threshold);

(b) 

diagnostic patch test data where there is a relatively low but substantial incidence of reactions in a defined population in relation to relatively high exposure;

(c) 

other epidemiological evidence where there is a relatively low but substantial incidence of allergic contact dermatitis in relation to relatively high exposure.

The use of human data is discussed in sections 1.1.1.3, 1.1.1.4 and 1.1.1.5.

3.4.2.2.2.2.

3.4.2.2.2.2.

Human evidence for sub-category 1B can include:

(a) 

positive responses at > 500 μg/cm2 (HRIPT, HMT — induction threshold);

(b) 

diagnostic patch test data where there is a relatively low but substantial incidence of reactions in a defined population in relation to relatively high exposure;

(c) 

other epidemiological evidence where there is a relatively low but substantial incidence of allergic contact dermatitis in relation to relatively high exposure.

The use of human data is discussed in sections 1.1.1.3, 1.1.1.4 and 1.1.1.5.

Human evidence for sub-category 1B can include:

(a) 

positive responses at > 500 μg/cm2 (HRIPT, HMT — induction threshold);

(a) 
(a) 

positive responses at > 500 μg/cm2 (HRIPT, HMT — induction threshold);

positive responses at > 500 μg/cm2 (HRIPT, HMT — induction threshold);

(b) 

diagnostic patch test data where there is a relatively low but substantial incidence of reactions in a defined population in relation to relatively high exposure;

(b) 
(b) 

diagnostic patch test data where there is a relatively low but substantial incidence of reactions in a defined population in relation to relatively high exposure;

diagnostic patch test data where there is a relatively low but substantial incidence of reactions in a defined population in relation to relatively high exposure;

(c) 

other epidemiological evidence where there is a relatively low but substantial incidence of allergic contact dermatitis in relation to relatively high exposure.

(c) 
(c) 

other epidemiological evidence where there is a relatively low but substantial incidence of allergic contact dermatitis in relation to relatively high exposure.

other epidemiological evidence where there is a relatively low but substantial incidence of allergic contact dermatitis in relation to relatively high exposure.

The use of human data is discussed in sections 1.1.1.3, 1.1.1.4 and 1.1.1.5.

3.4.2.2.3.   Animal studies Animal studies

3.4.2.2.3.1.

For Category 1, when an adjuvant type test method for skin sensitisation is used, a response of at least 30 % of the animals is considered as positive. For a non-adjuvant Guinea pig test method a response of at least 15 % of the animals is considered positive. For Category 1, a stimulation index of three or more is considered a positive response in the local lymph node assay. Test methods for skin sensitisation are described in the OECD Guideline 406 (the Guinea Pig Maximisation test and the Buehler guinea pig test) and Guideline 429 (Local Lymph Node Assay). Other methods may be used provided that they are well-validated and scientific justification is given. For example, the mouse ear swelling test (MEST) could be a reliable screening test to detect moderate to strong sensitisers, and could be used as a first stage in the assessment of skin sensitisation potential.

3.4.2.2.3.1.

For Category 1, when an adjuvant type test method for skin sensitisation is used, a response of at least 30 % of the animals is considered as positive. For a non-adjuvant Guinea pig test method a response of at least 15 % of the animals is considered positive. For Category 1, a stimulation index of three or more is considered a positive response in the local lymph node assay. Test methods for skin sensitisation are described in the OECD Guideline 406 (the Guinea Pig Maximisation test and the Buehler guinea pig test) and Guideline 429 (Local Lymph Node Assay). Other methods may be used provided that they are well-validated and scientific justification is given. For example, the mouse ear swelling test (MEST) could be a reliable screening test to detect moderate to strong sensitisers, and could be used as a first stage in the assessment of skin sensitisation potential.

3.4.2.2.3.1.

For Category 1, when an adjuvant type test method for skin sensitisation is used, a response of at least 30 % of the animals is considered as positive. For a non-adjuvant Guinea pig test method a response of at least 15 % of the animals is considered positive. For Category 1, a stimulation index of three or more is considered a positive response in the local lymph node assay. Test methods for skin sensitisation are described in the OECD Guideline 406 (the Guinea Pig Maximisation test and the Buehler guinea pig test) and Guideline 429 (Local Lymph Node Assay). Other methods may be used provided that they are well-validated and scientific justification is given. For example, the mouse ear swelling test (MEST) could be a reliable screening test to detect moderate to strong sensitisers, and could be used as a first stage in the assessment of skin sensitisation potential.

3.4.2.2.3.1.

3.4.2.2.3.1.

For Category 1, when an adjuvant type test method for skin sensitisation is used, a response of at least 30 % of the animals is considered as positive. For a non-adjuvant Guinea pig test method a response of at least 15 % of the animals is considered positive. For Category 1, a stimulation index of three or more is considered a positive response in the local lymph node assay. Test methods for skin sensitisation are described in the OECD Guideline 406 (the Guinea Pig Maximisation test and the Buehler guinea pig test) and Guideline 429 (Local Lymph Node Assay). Other methods may be used provided that they are well-validated and scientific justification is given. For example, the mouse ear swelling test (MEST) could be a reliable screening test to detect moderate to strong sensitisers, and could be used as a first stage in the assessment of skin sensitisation potential.

For Category 1, when an adjuvant type test method for skin sensitisation is used, a response of at least 30 % of the animals is considered as positive. For a non-adjuvant Guinea pig test method a response of at least 15 % of the animals is considered positive. For Category 1, a stimulation index of three or more is considered a positive response in the local lymph node assay. Test methods for skin sensitisation are described in the OECD Guideline 406 (the Guinea Pig Maximisation test and the Buehler guinea pig test) and Guideline 429 (Local Lymph Node Assay). Other methods may be used provided that they are well-validated and scientific justification is given. For example, the mouse ear swelling test (MEST) could be a reliable screening test to detect moderate to strong sensitisers, and could be used as a first stage in the assessment of skin sensitisation potential.

3.4.2.2.3.2.

Animal test results for sub-category 1A can include data with values indicated in Table 3.4.3

Table 3.4.3

Animal test results for sub-category 1A

Assay

Criteria

Local lymph node assay

EC3 value ≤ 2 %

Guinea pig maximisation test

≥ 30 % responding at ≤ 0,1 % intradermal induction dose or

≥ 60 % responding at > 0,1 % to ≤ 1 % intradermal induction dose

Buehler assay

≥ 15 % responding at ≤ 0,2 % topical induction dose or

≥ 60 % responding at > 0,2 % to ≤ 20 % topical induction dose

3.4.2.2.3.2.

Animal test results for sub-category 1A can include data with values indicated in Table 3.4.3

Table 3.4.3

Animal test results for sub-category 1A

Assay

Criteria

Local lymph node assay

EC3 value ≤ 2 %

Guinea pig maximisation test

≥ 30 % responding at ≤ 0,1 % intradermal induction dose or

≥ 60 % responding at > 0,1 % to ≤ 1 % intradermal induction dose

Buehler assay

≥ 15 % responding at ≤ 0,2 % topical induction dose or

≥ 60 % responding at > 0,2 % to ≤ 20 % topical induction dose

3.4.2.2.3.2.

Animal test results for sub-category 1A can include data with values indicated in Table 3.4.3

Table 3.4.3

Animal test results for sub-category 1A

Assay

Criteria

Local lymph node assay

EC3 value ≤ 2 %

Guinea pig maximisation test

≥ 30 % responding at ≤ 0,1 % intradermal induction dose or

≥ 60 % responding at > 0,1 % to ≤ 1 % intradermal induction dose

Buehler assay

≥ 15 % responding at ≤ 0,2 % topical induction dose or

≥ 60 % responding at > 0,2 % to ≤ 20 % topical induction dose

3.4.2.2.3.2.

3.4.2.2.3.2.

Animal test results for sub-category 1A can include data with values indicated in Table 3.4.3

Table 3.4.3

Animal test results for sub-category 1A

Assay

Criteria

Local lymph node assay

EC3 value ≤ 2 %

Guinea pig maximisation test

≥ 30 % responding at ≤ 0,1 % intradermal induction dose or

≥ 60 % responding at > 0,1 % to ≤ 1 % intradermal induction dose

Buehler assay

≥ 15 % responding at ≤ 0,2 % topical induction dose or

≥ 60 % responding at > 0,2 % to ≤ 20 % topical induction dose

Animal test results for sub-category 1A can include data with values indicated in Table 3.4.3

Table 3.4.3

Animal test results for sub-category 1A

Assay

Criteria

Local lymph node assay

EC3 value ≤ 2 %

Guinea pig maximisation test

≥ 30 % responding at ≤ 0,1 % intradermal induction dose or

≥ 60 % responding at > 0,1 % to ≤ 1 % intradermal induction dose

Buehler assay

≥ 15 % responding at ≤ 0,2 % topical induction dose or

≥ 60 % responding at > 0,2 % to ≤ 20 % topical induction dose

Table 3.4.3

Animal test results for sub-category 1A

Assay

Criteria

Local lymph node assay

EC3 value ≤ 2 %

Guinea pig maximisation test

≥ 30 % responding at ≤ 0,1 % intradermal induction dose or

≥ 60 % responding at > 0,1 % to ≤ 1 % intradermal induction dose

Buehler assay

≥ 15 % responding at ≤ 0,2 % topical induction dose or

≥ 60 % responding at > 0,2 % to ≤ 20 % topical induction dose

Assay

Criteria

Local lymph node assay

EC3 value ≤ 2 %

Guinea pig maximisation test

≥ 30 % responding at ≤ 0,1 % intradermal induction dose or

≥ 60 % responding at > 0,1 % to ≤ 1 % intradermal induction dose

Buehler assay

≥ 15 % responding at ≤ 0,2 % topical induction dose or

≥ 60 % responding at > 0,2 % to ≤ 20 % topical induction dose

Assay

Criteria

Assay

Assay

Criteria

Criteria

Local lymph node assay

EC3 value ≤ 2 %

Local lymph node assay

Local lymph node assay

EC3 value ≤ 2 %

EC3 value ≤ 2 %

Guinea pig maximisation test

≥ 30 % responding at ≤ 0,1 % intradermal induction dose or

≥ 60 % responding at > 0,1 % to ≤ 1 % intradermal induction dose

Guinea pig maximisation test

Guinea pig maximisation test

≥ 30 % responding at ≤ 0,1 % intradermal induction dose or

≥ 60 % responding at > 0,1 % to ≤ 1 % intradermal induction dose

≥ 30 % responding at ≤ 0,1 % intradermal induction dose or

≥ 60 % responding at > 0,1 % to ≤ 1 % intradermal induction dose

Buehler assay

≥ 15 % responding at ≤ 0,2 % topical induction dose or

≥ 60 % responding at > 0,2 % to ≤ 20 % topical induction dose

Buehler assay

Buehler assay

≥ 15 % responding at ≤ 0,2 % topical induction dose or

≥ 60 % responding at > 0,2 % to ≤ 20 % topical induction dose

≥ 15 % responding at ≤ 0,2 % topical induction dose or

≥ 60 % responding at > 0,2 % to ≤ 20 % topical induction dose

3.4.2.2.3.3.

Animal test results for sub-category 1B can include data with values indicated in Table 3.4.4 below:

Table 3.4.4

Animal test results for sub-category 1B

Assay

Criteria

Local lymph node assay

EC3 value > 2 %

Guinea pig maximisation test

≥ 30 % to < 60 % responding at > 0,1 % to ≤ 1 % intradermal induction dose or

≥ 30 % responding at > 1 % intradermal induction dose

Buehler assay

≥ 15 % to < 60 % responding at > 0,2 % to ≤ 20 % topical induction dose or

≥ 15 % responding at > 20 % topical induction dose

3.4.2.2.3.3.

Animal test results for sub-category 1B can include data with values indicated in Table 3.4.4 below:

Table 3.4.4

Animal test results for sub-category 1B

Assay

Criteria

Local lymph node assay

EC3 value > 2 %

Guinea pig maximisation test

≥ 30 % to < 60 % responding at > 0,1 % to ≤ 1 % intradermal induction dose or

≥ 30 % responding at > 1 % intradermal induction dose

Buehler assay

≥ 15 % to < 60 % responding at > 0,2 % to ≤ 20 % topical induction dose or

≥ 15 % responding at > 20 % topical induction dose

3.4.2.2.3.3.

Animal test results for sub-category 1B can include data with values indicated in Table 3.4.4 below:

Table 3.4.4

Animal test results for sub-category 1B

Assay

Criteria

Local lymph node assay

EC3 value > 2 %

Guinea pig maximisation test

≥ 30 % to < 60 % responding at > 0,1 % to ≤ 1 % intradermal induction dose or

≥ 30 % responding at > 1 % intradermal induction dose

Buehler assay

≥ 15 % to < 60 % responding at > 0,2 % to ≤ 20 % topical induction dose or

≥ 15 % responding at > 20 % topical induction dose

3.4.2.2.3.3.

3.4.2.2.3.3.

Animal test results for sub-category 1B can include data with values indicated in Table 3.4.4 below:

Table 3.4.4

Animal test results for sub-category 1B

Assay

Criteria

Local lymph node assay

EC3 value > 2 %

Guinea pig maximisation test

≥ 30 % to < 60 % responding at > 0,1 % to ≤ 1 % intradermal induction dose or

≥ 30 % responding at > 1 % intradermal induction dose

Buehler assay

≥ 15 % to < 60 % responding at > 0,2 % to ≤ 20 % topical induction dose or

≥ 15 % responding at > 20 % topical induction dose

Animal test results for sub-category 1B can include data with values indicated in Table 3.4.4 below:

Table 3.4.4

Animal test results for sub-category 1B

Assay

Criteria

Local lymph node assay

EC3 value > 2 %

Guinea pig maximisation test

≥ 30 % to < 60 % responding at > 0,1 % to ≤ 1 % intradermal induction dose or

≥ 30 % responding at > 1 % intradermal induction dose

Buehler assay

≥ 15 % to < 60 % responding at > 0,2 % to ≤ 20 % topical induction dose or

≥ 15 % responding at > 20 % topical induction dose

Table 3.4.4

Animal test results for sub-category 1B

Assay

Criteria

Local lymph node assay

EC3 value > 2 %

Guinea pig maximisation test

≥ 30 % to < 60 % responding at > 0,1 % to ≤ 1 % intradermal induction dose or

≥ 30 % responding at > 1 % intradermal induction dose

Buehler assay

≥ 15 % to < 60 % responding at > 0,2 % to ≤ 20 % topical induction dose or

≥ 15 % responding at > 20 % topical induction dose

Assay

Criteria

Local lymph node assay

EC3 value > 2 %

Guinea pig maximisation test

≥ 30 % to < 60 % responding at > 0,1 % to ≤ 1 % intradermal induction dose or

≥ 30 % responding at > 1 % intradermal induction dose

Buehler assay

≥ 15 % to < 60 % responding at > 0,2 % to ≤ 20 % topical induction dose or

≥ 15 % responding at > 20 % topical induction dose

Assay

Criteria

Assay

Assay

Criteria

Criteria

Local lymph node assay

EC3 value > 2 %

Local lymph node assay

Local lymph node assay

EC3 value > 2 %

EC3 value > 2 %

Guinea pig maximisation test

≥ 30 % to < 60 % responding at > 0,1 % to ≤ 1 % intradermal induction dose or

≥ 30 % responding at > 1 % intradermal induction dose

Guinea pig maximisation test

Guinea pig maximisation test

≥ 30 % to < 60 % responding at > 0,1 % to ≤ 1 % intradermal induction dose or

≥ 30 % responding at > 1 % intradermal induction dose

≥ 30 % to < 60 % responding at > 0,1 % to ≤ 1 % intradermal induction dose or

≥ 30 % responding at > 1 % intradermal induction dose

Buehler assay

≥ 15 % to < 60 % responding at > 0,2 % to ≤ 20 % topical induction dose or

≥ 15 % responding at > 20 % topical induction dose

Buehler assay

Buehler assay

≥ 15 % to < 60 % responding at > 0,2 % to ≤ 20 % topical induction dose or

≥ 15 % responding at > 20 % topical induction dose

≥ 15 % to < 60 % responding at > 0,2 % to ≤ 20 % topical induction dose or

≥ 15 % responding at > 20 % topical induction dose

3.4.2.2.4.   Specific considerations Specific considerations

3.4.2.2.4.1.

For classification of a substance, evidence should include any or all of the following using a weight of evidence approach:

(a) 

positive data from patch testing, normally obtained in more than one dermatology clinic;

(b) 

epidemiological studies showing allergic contact dermatitis caused by the substance. Situations in which a high proportion of those exposed exhibit characteristic symptoms are to be looked at with special concern, even if the number of cases is small;

(c) 

positive data from appropriate animal studies;

(d) 

positive data from experimental studies in man (see section 1.3.2.4.7);

(e) 

well documented episodes of allergic contact dermatitis, normally obtained in more than one dermatology clinic;

(f) 

severity of reaction may also be considered.

3.4.2.2.4.1.

For classification of a substance, evidence should include any or all of the following using a weight of evidence approach:

(a) 

positive data from patch testing, normally obtained in more than one dermatology clinic;

(b) 

epidemiological studies showing allergic contact dermatitis caused by the substance. Situations in which a high proportion of those exposed exhibit characteristic symptoms are to be looked at with special concern, even if the number of cases is small;

(c) 

positive data from appropriate animal studies;

(d) 

positive data from experimental studies in man (see section 1.3.2.4.7);

(e) 

well documented episodes of allergic contact dermatitis, normally obtained in more than one dermatology clinic;

(f) 

severity of reaction may also be considered.

3.4.2.2.4.1.

For classification of a substance, evidence should include any or all of the following using a weight of evidence approach:

(a) 

positive data from patch testing, normally obtained in more than one dermatology clinic;

(b) 

epidemiological studies showing allergic contact dermatitis caused by the substance. Situations in which a high proportion of those exposed exhibit characteristic symptoms are to be looked at with special concern, even if the number of cases is small;

(c) 

positive data from appropriate animal studies;

(d) 

positive data from experimental studies in man (see section 1.3.2.4.7);

(e) 

well documented episodes of allergic contact dermatitis, normally obtained in more than one dermatology clinic;

(f) 

severity of reaction may also be considered.

3.4.2.2.4.1.

3.4.2.2.4.1.

For classification of a substance, evidence should include any or all of the following using a weight of evidence approach:

(a) 

positive data from patch testing, normally obtained in more than one dermatology clinic;

(b) 

epidemiological studies showing allergic contact dermatitis caused by the substance. Situations in which a high proportion of those exposed exhibit characteristic symptoms are to be looked at with special concern, even if the number of cases is small;

(c) 

positive data from appropriate animal studies;

(d) 

positive data from experimental studies in man (see section 1.3.2.4.7);

(e) 

well documented episodes of allergic contact dermatitis, normally obtained in more than one dermatology clinic;

(f) 

severity of reaction may also be considered.

For classification of a substance, evidence should include any or all of the following using a weight of evidence approach:

(a) 

positive data from patch testing, normally obtained in more than one dermatology clinic;

(a) 
(a) 

positive data from patch testing, normally obtained in more than one dermatology clinic;

positive data from patch testing, normally obtained in more than one dermatology clinic;

(b) 

epidemiological studies showing allergic contact dermatitis caused by the substance. Situations in which a high proportion of those exposed exhibit characteristic symptoms are to be looked at with special concern, even if the number of cases is small;

(b) 
(b) 

epidemiological studies showing allergic contact dermatitis caused by the substance. Situations in which a high proportion of those exposed exhibit characteristic symptoms are to be looked at with special concern, even if the number of cases is small;

epidemiological studies showing allergic contact dermatitis caused by the substance. Situations in which a high proportion of those exposed exhibit characteristic symptoms are to be looked at with special concern, even if the number of cases is small;

(c) 

positive data from appropriate animal studies;

(c) 
(c) 

positive data from appropriate animal studies;

positive data from appropriate animal studies;

(d) 

positive data from experimental studies in man (see section 1.3.2.4.7);

(d) 
(d) 

positive data from experimental studies in man (see section 1.3.2.4.7);

positive data from experimental studies in man (see section 1.3.2.4.7);

(e) 

well documented episodes of allergic contact dermatitis, normally obtained in more than one dermatology clinic;

(e) 
(e) 

well documented episodes of allergic contact dermatitis, normally obtained in more than one dermatology clinic;

well documented episodes of allergic contact dermatitis, normally obtained in more than one dermatology clinic;

(f) 

severity of reaction may also be considered.

(f) 
(f) 

severity of reaction may also be considered.

severity of reaction may also be considered.

3.4.2.2.4.2.

Evidence from animal studies is usually much more reliable than evidence from human exposure. However, in cases where evidence is available from both sources, and there is conflict between the results, the quality and reliability of the evidence from both sources must be assessed in order to resolve the question of classification on a case-by-case basis. Normally, human data are not generated in controlled experiments with volunteers for the purpose of hazard classification but rather as part of risk assessment to confirm lack of effects seen in animal tests. Consequently, positive human data on skin sensitisation are usually derived from case-control or other, less defined studies. Evaluation of human data must therefore be carried out with caution as the frequency of cases reflect, in addition to the inherent properties of the substances, factors such as the exposure situation, bioavailability, individual predisposition and preventive measures taken. Negative human data should not normally be used to negate positive results from animal studies. For both animal and human data, consideration should be given to the impact of vehicle.

3.4.2.2.4.2.

Evidence from animal studies is usually much more reliable than evidence from human exposure. However, in cases where evidence is available from both sources, and there is conflict between the results, the quality and reliability of the evidence from both sources must be assessed in order to resolve the question of classification on a case-by-case basis. Normally, human data are not generated in controlled experiments with volunteers for the purpose of hazard classification but rather as part of risk assessment to confirm lack of effects seen in animal tests. Consequently, positive human data on skin sensitisation are usually derived from case-control or other, less defined studies. Evaluation of human data must therefore be carried out with caution as the frequency of cases reflect, in addition to the inherent properties of the substances, factors such as the exposure situation, bioavailability, individual predisposition and preventive measures taken. Negative human data should not normally be used to negate positive results from animal studies. For both animal and human data, consideration should be given to the impact of vehicle.

3.4.2.2.4.2.

Evidence from animal studies is usually much more reliable than evidence from human exposure. However, in cases where evidence is available from both sources, and there is conflict between the results, the quality and reliability of the evidence from both sources must be assessed in order to resolve the question of classification on a case-by-case basis. Normally, human data are not generated in controlled experiments with volunteers for the purpose of hazard classification but rather as part of risk assessment to confirm lack of effects seen in animal tests. Consequently, positive human data on skin sensitisation are usually derived from case-control or other, less defined studies. Evaluation of human data must therefore be carried out with caution as the frequency of cases reflect, in addition to the inherent properties of the substances, factors such as the exposure situation, bioavailability, individual predisposition and preventive measures taken. Negative human data should not normally be used to negate positive results from animal studies. For both animal and human data, consideration should be given to the impact of vehicle.

3.4.2.2.4.2.

3.4.2.2.4.2.

Evidence from animal studies is usually much more reliable than evidence from human exposure. However, in cases where evidence is available from both sources, and there is conflict between the results, the quality and reliability of the evidence from both sources must be assessed in order to resolve the question of classification on a case-by-case basis. Normally, human data are not generated in controlled experiments with volunteers for the purpose of hazard classification but rather as part of risk assessment to confirm lack of effects seen in animal tests. Consequently, positive human data on skin sensitisation are usually derived from case-control or other, less defined studies. Evaluation of human data must therefore be carried out with caution as the frequency of cases reflect, in addition to the inherent properties of the substances, factors such as the exposure situation, bioavailability, individual predisposition and preventive measures taken. Negative human data should not normally be used to negate positive results from animal studies. For both animal and human data, consideration should be given to the impact of vehicle.

Evidence from animal studies is usually much more reliable than evidence from human exposure. However, in cases where evidence is available from both sources, and there is conflict between the results, the quality and reliability of the evidence from both sources must be assessed in order to resolve the question of classification on a case-by-case basis. Normally, human data are not generated in controlled experiments with volunteers for the purpose of hazard classification but rather as part of risk assessment to confirm lack of effects seen in animal tests. Consequently, positive human data on skin sensitisation are usually derived from case-control or other, less defined studies. Evaluation of human data must therefore be carried out with caution as the frequency of cases reflect, in addition to the inherent properties of the substances, factors such as the exposure situation, bioavailability, individual predisposition and preventive measures taken. Negative human data should not normally be used to negate positive results from animal studies. For both animal and human data, consideration should be given to the impact of vehicle.

3.4.2.2.4.3.

If none of the abovementioned conditions are met, the substance need not be classified as a skin sensitiser. However, a combination of two or more indicators of skin sensitisation as listed below may alter the decision. This shall be considered on a case-by-case basis.

(a) 

Isolated episodes of allergic contact dermatitis;

(b) 

epidemiological studies of limited power, e.g. where chance, bias or confounders have not been ruled out fully with reasonable confidence;

(c) 

data from animal tests, performed according to existing guidelines, which do not meet the criteria for a positive result described in section 3.4.2.2.3, but which are sufficiently close to the limit to be considered significant;

(d) 

positive data from non-standard methods;

(e) 

positive results from close structural analogues.

3.4.2.2.4.3.

If none of the abovementioned conditions are met, the substance need not be classified as a skin sensitiser. However, a combination of two or more indicators of skin sensitisation as listed below may alter the decision. This shall be considered on a case-by-case basis.

(a) 

Isolated episodes of allergic contact dermatitis;

(b) 

epidemiological studies of limited power, e.g. where chance, bias or confounders have not been ruled out fully with reasonable confidence;

(c) 

data from animal tests, performed according to existing guidelines, which do not meet the criteria for a positive result described in section 3.4.2.2.3, but which are sufficiently close to the limit to be considered significant;

(d) 

positive data from non-standard methods;

(e) 

positive results from close structural analogues.

3.4.2.2.4.3.

If none of the abovementioned conditions are met, the substance need not be classified as a skin sensitiser. However, a combination of two or more indicators of skin sensitisation as listed below may alter the decision. This shall be considered on a case-by-case basis.

(a) 

Isolated episodes of allergic contact dermatitis;

(b) 

epidemiological studies of limited power, e.g. where chance, bias or confounders have not been ruled out fully with reasonable confidence;

(c) 

data from animal tests, performed according to existing guidelines, which do not meet the criteria for a positive result described in section 3.4.2.2.3, but which are sufficiently close to the limit to be considered significant;

(d) 

positive data from non-standard methods;

(e) 

positive results from close structural analogues.

3.4.2.2.4.3.

3.4.2.2.4.3.

If none of the abovementioned conditions are met, the substance need not be classified as a skin sensitiser. However, a combination of two or more indicators of skin sensitisation as listed below may alter the decision. This shall be considered on a case-by-case basis.

(a) 

Isolated episodes of allergic contact dermatitis;

(b) 

epidemiological studies of limited power, e.g. where chance, bias or confounders have not been ruled out fully with reasonable confidence;

(c) 

data from animal tests, performed according to existing guidelines, which do not meet the criteria for a positive result described in section 3.4.2.2.3, but which are sufficiently close to the limit to be considered significant;

(d) 

positive data from non-standard methods;

(e) 

positive results from close structural analogues.

If none of the abovementioned conditions are met, the substance need not be classified as a skin sensitiser. However, a combination of two or more indicators of skin sensitisation as listed below may alter the decision. This shall be considered on a case-by-case basis.

(a) 

Isolated episodes of allergic contact dermatitis;

(a) 
(a) 

Isolated episodes of allergic contact dermatitis;

Isolated episodes of allergic contact dermatitis;

(b) 

epidemiological studies of limited power, e.g. where chance, bias or confounders have not been ruled out fully with reasonable confidence;

(b) 
(b) 

epidemiological studies of limited power, e.g. where chance, bias or confounders have not been ruled out fully with reasonable confidence;

epidemiological studies of limited power, e.g. where chance, bias or confounders have not been ruled out fully with reasonable confidence;

(c) 

data from animal tests, performed according to existing guidelines, which do not meet the criteria for a positive result described in section 3.4.2.2.3, but which are sufficiently close to the limit to be considered significant;

(c) 
(c) 

data from animal tests, performed according to existing guidelines, which do not meet the criteria for a positive result described in section 3.4.2.2.3, but which are sufficiently close to the limit to be considered significant;

data from animal tests, performed according to existing guidelines, which do not meet the criteria for a positive result described in section 3.4.2.2.3, but which are sufficiently close to the limit to be considered significant;

(d) 

positive data from non-standard methods;

(d) 
(d) 

positive data from non-standard methods;

positive data from non-standard methods;

(e) 

positive results from close structural analogues.

(e) 
(e) 

positive results from close structural analogues.

positive results from close structural analogues.

3.4.2.2.4.4.

Immunological contact urticaria

Substances meeting the criteria for classification as respiratory sensitisers may in addition cause immunological contact urticaria. Consideration should be given to classifying these substances also as skin sensitisers. Substances which cause immunological contact urticaria without meeting the criteria for respiratory sensitisers should also be considered for classification as skin sensitisers.

There is no recognised animal model available to identify substances which cause immunological contact urticaria. Therefore, classification will normally be based on human evidence which will be similar to that for skin sensitisation.

3.4.2.2.4.4. Immunological contact urticaria

Substances meeting the criteria for classification as respiratory sensitisers may in addition cause immunological contact urticaria. Consideration should be given to classifying these substances also as skin sensitisers. Substances which cause immunological contact urticaria without meeting the criteria for respiratory sensitisers should also be considered for classification as skin sensitisers.

There is no recognised animal model available to identify substances which cause immunological contact urticaria. Therefore, classification will normally be based on human evidence which will be similar to that for skin sensitisation.

3.4.2.2.4.4. Immunological contact urticaria

Substances meeting the criteria for classification as respiratory sensitisers may in addition cause immunological contact urticaria. Consideration should be given to classifying these substances also as skin sensitisers. Substances which cause immunological contact urticaria without meeting the criteria for respiratory sensitisers should also be considered for classification as skin sensitisers.

There is no recognised animal model available to identify substances which cause immunological contact urticaria. Therefore, classification will normally be based on human evidence which will be similar to that for skin sensitisation.

3.4.2.2.4.4.

3.4.2.2.4.4. Immunological contact urticaria

Substances meeting the criteria for classification as respiratory sensitisers may in addition cause immunological contact urticaria. Consideration should be given to classifying these substances also as skin sensitisers. Substances which cause immunological contact urticaria without meeting the criteria for respiratory sensitisers should also be considered for classification as skin sensitisers.

There is no recognised animal model available to identify substances which cause immunological contact urticaria. Therefore, classification will normally be based on human evidence which will be similar to that for skin sensitisation.

Substances meeting the criteria for classification as respiratory sensitisers may in addition cause immunological contact urticaria. Consideration should be given to classifying these substances also as skin sensitisers. Substances which cause immunological contact urticaria without meeting the criteria for respiratory sensitisers should also be considered for classification as skin sensitisers.

There is no recognised animal model available to identify substances which cause immunological contact urticaria. Therefore, classification will normally be based on human evidence which will be similar to that for skin sensitisation.

▼B ▼B

3.4.3.   Classification criteria for mixtures

Classification criteria for mixtures

3.4.3.1.   Classification of mixtures when data are available for the complete mixture Classification of mixtures when data are available for the complete mixture

3.4.3.1.1. When reliable and good quality evidence from human experience or appropriate studies in experimental animals, as described in the criteria for substances, is available for the mixture, then the mixture can be classified by weight of evidence evaluation of these data. Care shall be exercised in evaluating data on mixtures, that the dose used does not render the results inconclusive.

3.4.3.1.1. When reliable and good quality evidence from human experience or appropriate studies in experimental animals, as described in the criteria for substances, is available for the mixture, then the mixture can be classified by weight of evidence evaluation of these data. Care shall be exercised in evaluating data on mixtures, that the dose used does not render the results inconclusive.  

3.4.3.2.   Classification of mixtures when data are not available for the complete mixture: bridging principles Classification of mixtures when data are not available for the complete mixture: bridging principles

3.4.3.2.1. Where the mixture itself has not been tested to determine its sensitising properties, but there are sufficient data on the individual ingredients and similar tested mixtures to adequately characterise the hazards of the mixture, these data shall be used in accordance with the bridging rules set out in section 1.1.3.

3.4.3.2.1. Where the mixture itself has not been tested to determine its sensitising properties, but there are sufficient data on the individual ingredients and similar tested mixtures to adequately characterise the hazards of the mixture, these data shall be used in accordance with the bridging rules set out in section 1.1.3.  

3.4.3.3.   Classification of mixtures when data are available for all ingredients or only for some ingredients of the mixture Classification of mixtures when data are available for all ingredients or only for some ingredients of the mixture

3.4.3.3.1. The mixture shall be classified as a respiratory or skin sensitiser when at least one ingredient has been classified as a respiratory or skin sensitiser and is present at or above the appropriate generic concentration limit as shown in ►M2  Table 3.4.5  ◄ for solid/liquid and gas respectively.

3.4.3.3.1. The mixture shall be classified as a respiratory or skin sensitiser when at least one ingredient has been classified as a respiratory or skin sensitiser and is present at or above the appropriate generic concentration limit as shown in ►M2  Table 3.4.5  ◄ for solid/liquid and gas respectively.   ►M2 ►M2 ►M2  ◄

3.4.3.3.2. Some substances that are classified as sensitisers may elicit a response, when present in a mixture in quantities below the concentrations established in ►M2  Table 3.4.5 ◄ , in individuals who are already sensitised to the substance or mixture (see Note 1 to ►M2  Table 3.4.6 ◄ ).

3.4.3.3.2. Some substances that are classified as sensitisers may elicit a response, when present in a mixture in quantities below the concentrations established in ►M2  Table 3.4.5 ◄ , in individuals who are already sensitised to the substance or mixture (see Note 1 to ►M2  Table 3.4.6 ◄ ).   ►M2 ►M2 ►M2  ◄ ►M2 ►M2 ►M2  ◄

▼M2 ▼M2

Table 3.4.5

Generic concentration limits of components of a mixture classified as either respiratory sensitisers or skin sensitisers that trigger classification of the mixture

Component classified as:

Generic concentration limits triggering classification of a mixture as:

Respiratory sensitiser

Category 1

Skin sensitiser

Category 1

Solid/liquid

Gas

All physical states

Respiratory sensitiser

Category 1

≥ 1,0 %

≥ 0,2 %

 

Respiratory sensitiser

Sub-category 1A

≥ 0,1 %

≥ 0,1 %

 

Respiratory sensitiser

Sub-category 1B

≥ 1,0 %

≥ 0,2 %

 

Skin sensitiser

Category 1

 

 

≥ 1,0 %

Skin sensitiser

Sub-category 1A

 

 

≥ 0,1 %

Skin sensitiser

Sub-category 1B

 

 

≥ 1,0 %

Table 3.4.5

Generic concentration limits of components of a mixture classified as either respiratory sensitisers or skin sensitisers that trigger classification of the mixture

Component classified as:

Generic concentration limits triggering classification of a mixture as:

Respiratory sensitiser

Category 1

Skin sensitiser

Category 1

Solid/liquid

Gas

All physical states

Respiratory sensitiser

Category 1

≥ 1,0 %

≥ 0,2 %

 

Respiratory sensitiser

Sub-category 1A

≥ 0,1 %

≥ 0,1 %

 

Respiratory sensitiser

Sub-category 1B

≥ 1,0 %

≥ 0,2 %

 

Skin sensitiser

Category 1

 

 

≥ 1,0 %

Skin sensitiser

Sub-category 1A

 

 

≥ 0,1 %

Skin sensitiser

Sub-category 1B

 

 

≥ 1,0 %

Component classified as:

Generic concentration limits triggering classification of a mixture as:

Respiratory sensitiser

Category 1

Skin sensitiser

Category 1

Solid/liquid

Gas

All physical states

Respiratory sensitiser

Category 1

≥ 1,0 %

≥ 0,2 %

 

Respiratory sensitiser

Sub-category 1A

≥ 0,1 %

≥ 0,1 %

 

Respiratory sensitiser

Sub-category 1B

≥ 1,0 %

≥ 0,2 %

 

Skin sensitiser

Category 1

 

 

≥ 1,0 %

Skin sensitiser

Sub-category 1A

 

 

≥ 0,1 %

Skin sensitiser

Sub-category 1B

 

 

≥ 1,0 %

Component classified as:

Generic concentration limits triggering classification of a mixture as:

Component classified as:

Component classified as:

Generic concentration limits triggering classification of a mixture as:

Generic concentration limits triggering classification of a mixture as:

Respiratory sensitiser

Category 1

Skin sensitiser

Category 1

Respiratory sensitiser

Category 1

Respiratory sensitiser

Category 1

Skin sensitiser

Category 1

Skin sensitiser

Category 1

Solid/liquid

Gas

All physical states

Solid/liquid

Solid/liquid

Gas

Gas

All physical states

All physical states

Respiratory sensitiser

Category 1

≥ 1,0 %

≥ 0,2 %

 

Respiratory sensitiser

Category 1

Respiratory sensitiser

Category 1

≥ 1,0 %

≥ 1,0 %

≥ 0,2 %

≥ 0,2 %

 

 

Respiratory sensitiser

Sub-category 1A

≥ 0,1 %

≥ 0,1 %

 

Respiratory sensitiser

Sub-category 1A

Respiratory sensitiser

Sub-category 1A

≥ 0,1 %

≥ 0,1 %

≥ 0,1 %

≥ 0,1 %

 

 

Respiratory sensitiser

Sub-category 1B

≥ 1,0 %

≥ 0,2 %

 

Respiratory sensitiser

Sub-category 1B

Respiratory sensitiser

Sub-category 1B

≥ 1,0 %

≥ 1,0 %

≥ 0,2 %

≥ 0,2 %

 

 

Skin sensitiser

Category 1

 

 

≥ 1,0 %

Skin sensitiser

Category 1

Skin sensitiser

Category 1

 

 

 

 

≥ 1,0 %

≥ 1,0 %

Skin sensitiser

Sub-category 1A

 

 

≥ 0,1 %

Skin sensitiser

Sub-category 1A

Skin sensitiser

Sub-category 1A

 

 

 

 

≥ 0,1 %

≥ 0,1 %

Skin sensitiser

Sub-category 1B

 

 

≥ 1,0 %

Skin sensitiser

Sub-category 1B

Skin sensitiser

Sub-category 1B

 

 

 

 

≥ 1,0 %

≥ 1,0 %

▼M2 ▼M2

Table 3.4.6

Concentration limits for elicitation of components of a mixture

Component classified as:

Concentration limits for elicitation

Respiratory sensitiser

Category 1

Skin sensitiser

Category 1

Solid/liquid

Gas

All physical states

Respiratory sensitiser

Category 1

≥ 0,1 % (Note 1)

≥ 0,1 % (Note 1)

 

Respiratory sensitiser

Sub-category 1A

≥ 0,01 % (Note 1)

≥ 0,01 % (Note 1)

 

Respiratory sensitiser

Sub-category 1B

≥ 0,1 % (Note 1)

≥ 0,1 % (Note 1)

 

Skin sensitiser

Category 1

 

 

≥ 0,1 % (Note 1)

Skin sensitiser

Sub-category 1A

 

 

≥ 0,01 % (Note 1)

Skin sensitiser

Sub-category 1B

 

 

≥ 0,1 % (Note 1)

Table 3.4.6

Concentration limits for elicitation of components of a mixture

Component classified as:

Concentration limits for elicitation

Respiratory sensitiser

Category 1

Skin sensitiser

Category 1

Solid/liquid

Gas

All physical states

Respiratory sensitiser

Category 1

≥ 0,1 % (Note 1)

≥ 0,1 % (Note 1)

 

Respiratory sensitiser

Sub-category 1A

≥ 0,01 % (Note 1)

≥ 0,01 % (Note 1)

 

Respiratory sensitiser

Sub-category 1B

≥ 0,1 % (Note 1)

≥ 0,1 % (Note 1)

 

Skin sensitiser

Category 1

 

 

≥ 0,1 % (Note 1)

Skin sensitiser

Sub-category 1A

 

 

≥ 0,01 % (Note 1)

Skin sensitiser

Sub-category 1B

 

 

≥ 0,1 % (Note 1)

Component classified as:

Concentration limits for elicitation

Respiratory sensitiser

Category 1

Skin sensitiser

Category 1

Solid/liquid

Gas

All physical states

Respiratory sensitiser

Category 1

≥ 0,1 % (Note 1)

≥ 0,1 % (Note 1)

 

Respiratory sensitiser

Sub-category 1A

≥ 0,01 % (Note 1)

≥ 0,01 % (Note 1)

 

Respiratory sensitiser

Sub-category 1B

≥ 0,1 % (Note 1)

≥ 0,1 % (Note 1)

 

Skin sensitiser

Category 1

 

 

≥ 0,1 % (Note 1)

Skin sensitiser

Sub-category 1A

 

 

≥ 0,01 % (Note 1)

Skin sensitiser

Sub-category 1B

 

 

≥ 0,1 % (Note 1)

Component classified as:

Concentration limits for elicitation

Component classified as:

Component classified as:

Concentration limits for elicitation

Concentration limits for elicitation

Respiratory sensitiser

Category 1

Skin sensitiser

Category 1

Respiratory sensitiser

Category 1

Respiratory sensitiser

Category 1

Skin sensitiser

Category 1

Skin sensitiser

Category 1

Solid/liquid

Gas

All physical states

Solid/liquid

Solid/liquid

Gas

Gas

All physical states

All physical states

Respiratory sensitiser

Category 1

≥ 0,1 % (Note 1)

≥ 0,1 % (Note 1)

 

Respiratory sensitiser

Category 1

Respiratory sensitiser

Category 1

≥ 0,1 % (Note 1)

≥ 0,1 % (Note 1)

≥ 0,1 % (Note 1)

≥ 0,1 % (Note 1)

 

 

Respiratory sensitiser

Sub-category 1A

≥ 0,01 % (Note 1)

≥ 0,01 % (Note 1)

 

Respiratory sensitiser

Sub-category 1A

Respiratory sensitiser

Sub-category 1A

≥ 0,01 % (Note 1)

≥ 0,01 % (Note 1)

≥ 0,01 % (Note 1)

≥ 0,01 % (Note 1)

 

 

Respiratory sensitiser

Sub-category 1B

≥ 0,1 % (Note 1)

≥ 0,1 % (Note 1)

 

Respiratory sensitiser

Sub-category 1B

Respiratory sensitiser

Sub-category 1B

≥ 0,1 % (Note 1)

≥ 0,1 % (Note 1)

≥ 0,1 % (Note 1)

≥ 0,1 % (Note 1)

 

 

Skin sensitiser

Category 1

 

 

≥ 0,1 % (Note 1)

Skin sensitiser

Category 1

Skin sensitiser

Category 1

 

 

 

 

≥ 0,1 % (Note 1)

≥ 0,1 % (Note 1)

Skin sensitiser

Sub-category 1A

 

 

≥ 0,01 % (Note 1)

Skin sensitiser

Sub-category 1A

Skin sensitiser

Sub-category 1A

 

 

 

 

≥ 0,01 % (Note 1)

≥ 0,01 % (Note 1)

Skin sensitiser

Sub-category 1B

 

 

≥ 0,1 % (Note 1)

Skin sensitiser

Sub-category 1B

Skin sensitiser

Sub-category 1B

 

 

 

 

≥ 0,1 % (Note 1)

≥ 0,1 % (Note 1)

▼M19 ▼M19

Note 1: Note 1:

This concentration limit for elicitation is used for the application of the special labelling requirements of section 2.8 of Annex II to protect already sensitised individuals. A SDS is required for the mixture containing a component at or above this concentration. For sensitising substances with a specific concentration limit, the concentration limit for elicitation shall be set at a tenth of the specific concentration limit.

▼B ▼B

3.4.4.   Hazard communication

Hazard communication

▼M2 ▼M2

3.4.4.1. Label elements shall be used for substances or mixtures meeting the criteria for classification in this hazard class in accordance with Table 3.4.7.

3.4.4.1. Label elements shall be used for substances or mixtures meeting the criteria for classification in this hazard class in accordance with Table 3.4.7.  

▼M4 ▼M4

Table 3.4.7

Respiratory or skin sensitisation label elements

Classification

Respiratory sensitisation

Skin sensitisation

Category 1 and subcategories 1A and 1B

Category 1 and subcategories 1A and 1B

GHS Pictograms

image

image

Signal Word

Danger

Warning

Hazard Statement

H334: May cause allergy or asthma symptoms or breathing difficulties if inhaled

H317: May cause an allergic skin reaction

Precautionary Statement Prevention

P261

P284

P261

P272

P280

Precautionary Statement Response

P304 + P340

P342 + P311

P302 + P352

P333 + P313

P321

P362 + P364

Precautionary Statement Storage

 

 

Precautionary Statement Disposal

P501

P501

Table 3.4.7 Table 3.4.7

Respiratory or skin sensitisation label elements Respiratory or skin sensitisation label elements

Classification

Respiratory sensitisation

Skin sensitisation

Category 1 and subcategories 1A and 1B

Category 1 and subcategories 1A and 1B

GHS Pictograms

image

image

Signal Word

Danger

Warning

Hazard Statement

H334: May cause allergy or asthma symptoms or breathing difficulties if inhaled

H317: May cause an allergic skin reaction

Precautionary Statement Prevention

P261

P284

P261

P272

P280

Precautionary Statement Response

P304 + P340

P342 + P311

P302 + P352

P333 + P313

P321

P362 + P364

Precautionary Statement Storage

 

 

Precautionary Statement Disposal

P501

P501

Classification

Respiratory sensitisation

Skin sensitisation

Category 1 and subcategories 1A and 1B

Category 1 and subcategories 1A and 1B

GHS Pictograms

image

image

Signal Word

Danger

Warning

Hazard Statement

H334: May cause allergy or asthma symptoms or breathing difficulties if inhaled

H317: May cause an allergic skin reaction

Precautionary Statement Prevention

P261

P284

P261

P272

P280

Precautionary Statement Response

P304 + P340

P342 + P311

P302 + P352

P333 + P313

P321

P362 + P364

Precautionary Statement Storage

 

 

Precautionary Statement Disposal

P501

P501

Classification

Respiratory sensitisation

Skin sensitisation

Classification

Classification

Respiratory sensitisation

Respiratory sensitisation

Skin sensitisation

Skin sensitisation

Category 1 and subcategories 1A and 1B

Category 1 and subcategories 1A and 1B

Category 1 and subcategories 1A and 1B

Category 1 and subcategories 1A and 1B

Category 1 and subcategories 1A and 1B

Category 1 and subcategories 1A and 1B

GHS Pictograms

image

image

GHS Pictograms

GHS Pictograms

image

image image

image

image image

Signal Word

Danger

Warning

Signal Word

Signal Word

Danger

Danger

Warning

Warning

Hazard Statement

H334: May cause allergy or asthma symptoms or breathing difficulties if inhaled

H317: May cause an allergic skin reaction

Hazard Statement

Hazard Statement

H334: May cause allergy or asthma symptoms or breathing difficulties if inhaled

H334: May cause allergy or asthma symptoms or breathing difficulties if inhaled

H317: May cause an allergic skin reaction

H317: May cause an allergic skin reaction

Precautionary Statement Prevention

P261

P284

P261

P272

P280

Precautionary Statement Prevention

Precautionary Statement Prevention

P261

P284

P261

P284

P261

P272

P280

P261

P272

P280

Precautionary Statement Response

P304 + P340

P342 + P311

P302 + P352

P333 + P313

P321

P362 + P364

Precautionary Statement Response

Precautionary Statement Response

P304 + P340

P342 + P311

P304 + P340

P342 + P311

P302 + P352

P333 + P313

P321

P362 + P364

P302 + P352

P333 + P313

P321

P362 + P364

Precautionary Statement Storage

 

 

Precautionary Statement Storage

Precautionary Statement Storage

 

 

 

 

Precautionary Statement Disposal

P501

P501

Precautionary Statement Disposal

Precautionary Statement Disposal

P501

P501

P501

P501

▼B ▼B

3.5.   Germ cell mutagenicity

Germ cell mutagenicity

3.5.1.   Definitions and general considerations

Definitions and general considerations

▼M19 ▼M19

3.5.1.1. Germ cell mutagenicity means heritable gene mutations, including heritable structural and numerical chromosome aberrations in germ cells occurring after exposure to a substance or mixture.

3.5.1.1. Germ cell mutagenicity means heritable gene mutations, including heritable structural and numerical chromosome aberrations in germ cells occurring after exposure to a substance or mixture.  

▼M19 ▼M19

3.5.1.2. A mutation means a permanent change in the amount or structure of the genetic material in a cell. The term ‘mutation’ applies both to heritable genetic changes that may be manifested at the phenotypic level and to the underlying DNA modifications when known (including specific base pair changes and chromosomal translocations). The term ‘mutagenic’ and ‘mutagen’ will be used for agents giving rise to an increased occurrence of mutations in populations of cells and/or organisms.

3.5.1.2. A mutation means a permanent change in the amount or structure of the genetic material in a cell. The term ‘mutation’ applies both to heritable genetic changes that may be manifested at the phenotypic level and to the underlying DNA modifications when known (including specific base pair changes and chromosomal translocations). The term ‘mutagenic’ and ‘mutagen’ will be used for agents giving rise to an increased occurrence of mutations in populations of cells and/or organisms.  

3.5.1.3. The more general terms ‘genotoxic’ and ‘genotoxicity’ apply to agents or processes which alter the structure, information content, or segregation of DNA, including those which cause DNA damage by interfering with normal replication processes, or which in a non- physiological manner (temporarily) alter its replication. Genotoxicity test results are usually taken as indicators for mutagenic effects.

3.5.1.3. The more general terms ‘genotoxic’ and ‘genotoxicity’ apply to agents or processes which alter the structure, information content, or segregation of DNA, including those which cause DNA damage by interfering with normal replication processes, or which in a non- physiological manner (temporarily) alter its replication. Genotoxicity test results are usually taken as indicators for mutagenic effects.  

▼B ▼B

3.5.2.   Classification criteria for substances

Classification criteria for substances

3.5.2.1. This hazard class is primarily concerned with substances that may cause mutations in the germ cells of humans that can be transmitted to the progeny. However, the results from mutagenicity or genotoxicity tests in vitro and in mammalian somatic and germ cells in vivo are also considered in classifying substances and mixtures within this hazard class.

3.5.2.1. This hazard class is primarily concerned with substances that may cause mutations in the germ cells of humans that can be transmitted to the progeny. However, the results from mutagenicity or genotoxicity tests in vitro and in mammalian somatic and germ cells in vivo are also considered in classifying substances and mixtures within this hazard class.  

3.5.2.2. For the purpose of classification for germ cell mutagenicity, substances are allocated to one of two categories as shown in Table 3.5.1.

3.5.2.2. For the purpose of classification for germ cell mutagenicity, substances are allocated to one of two categories as shown in Table 3.5.1.  

Table 3.5.1

Hazard categories for germ cell mutagens

Categories

Criteria

CATEGORY 1:

Substances known to induce heritable mutations or to be regarded as if they induce heritable mutations in the germ cells of humans.

Substances known to induce heritable mutations in the germ cells of humans.

Category 1A:

The classification in Category 1A is based on positive evidence from human epidemiological studies.

Substances to be regarded as if they induce heritable mutations in the germ cells of humans.

Category 1B:

The classification in Category 1B is based on:

— positive result(s) from in vivo heritable germ cell mutagenicity tests in mammals; or

— positive result(s) from in vivo somatic cell mutagenicity tests in mammals, in combination with some evidence that the substance has potential to cause mutations to germ cells. It is possible to derive this supporting evidence from mutagenicity/genotoxicity tests in germ cells in vivo, or by demonstrating the ability of the substance or its metabolite(s) to interact with the genetic material of germ cells; or

— positive results from tests showing mutagenic effects in the germ cells of humans, without demonstration of transmission to progeny; for example, an increase in the frequency of aneuploidy in sperm cells of exposed people.

CATEGORY 2:

Substances which cause concern for humans owing to the possibility that they may induce heritable mutations in the germ cells of humans

The classification in Category 2 is based on:

— positive evidence obtained from experiments in mammals and/or in some cases from in vitro experiments, obtained from:

— 

— somatic cell mutagenicity tests in vivo, in mammals; or

— other in vivo somatic cell genotoxicity tests which are supported by positive results from in vitro mutagenicity assays.

Note: Substances which are positive in in vitro mammalian mutagenicity assays, and which also show chemical structure activity relationship to known germ cell mutagens, shall be considered for classification as Category 2 mutagens.

Table 3.5.1

Hazard categories for germ cell mutagens

Categories

Criteria

CATEGORY 1:

Substances known to induce heritable mutations or to be regarded as if they induce heritable mutations in the germ cells of humans.

Substances known to induce heritable mutations in the germ cells of humans.

Category 1A:

The classification in Category 1A is based on positive evidence from human epidemiological studies.

Substances to be regarded as if they induce heritable mutations in the germ cells of humans.

Category 1B:

The classification in Category 1B is based on:

— positive result(s) from in vivo heritable germ cell mutagenicity tests in mammals; or

— positive result(s) from in vivo somatic cell mutagenicity tests in mammals, in combination with some evidence that the substance has potential to cause mutations to germ cells. It is possible to derive this supporting evidence from mutagenicity/genotoxicity tests in germ cells in vivo, or by demonstrating the ability of the substance or its metabolite(s) to interact with the genetic material of germ cells; or

— positive results from tests showing mutagenic effects in the germ cells of humans, without demonstration of transmission to progeny; for example, an increase in the frequency of aneuploidy in sperm cells of exposed people.

CATEGORY 2:

Substances which cause concern for humans owing to the possibility that they may induce heritable mutations in the germ cells of humans

The classification in Category 2 is based on:

— positive evidence obtained from experiments in mammals and/or in some cases from in vitro experiments, obtained from:

— 

— somatic cell mutagenicity tests in vivo, in mammals; or

— other in vivo somatic cell genotoxicity tests which are supported by positive results from in vitro mutagenicity assays.

Note: Substances which are positive in in vitro mammalian mutagenicity assays, and which also show chemical structure activity relationship to known germ cell mutagens, shall be considered for classification as Category 2 mutagens.

Categories

Criteria

CATEGORY 1:

Substances known to induce heritable mutations or to be regarded as if they induce heritable mutations in the germ cells of humans.

Substances known to induce heritable mutations in the germ cells of humans.

Category 1A:

The classification in Category 1A is based on positive evidence from human epidemiological studies.

Substances to be regarded as if they induce heritable mutations in the germ cells of humans.

Category 1B:

The classification in Category 1B is based on:

— positive result(s) from in vivo heritable germ cell mutagenicity tests in mammals; or

— positive result(s) from in vivo somatic cell mutagenicity tests in mammals, in combination with some evidence that the substance has potential to cause mutations to germ cells. It is possible to derive this supporting evidence from mutagenicity/genotoxicity tests in germ cells in vivo, or by demonstrating the ability of the substance or its metabolite(s) to interact with the genetic material of germ cells; or

— positive results from tests showing mutagenic effects in the germ cells of humans, without demonstration of transmission to progeny; for example, an increase in the frequency of aneuploidy in sperm cells of exposed people.

CATEGORY 2:

Substances which cause concern for humans owing to the possibility that they may induce heritable mutations in the germ cells of humans

The classification in Category 2 is based on:

— positive evidence obtained from experiments in mammals and/or in some cases from in vitro experiments, obtained from:

— 

— somatic cell mutagenicity tests in vivo, in mammals; or

— other in vivo somatic cell genotoxicity tests which are supported by positive results from in vitro mutagenicity assays.

Note: Substances which are positive in in vitro mammalian mutagenicity assays, and which also show chemical structure activity relationship to known germ cell mutagens, shall be considered for classification as Category 2 mutagens.

Categories

Criteria

Categories

Categories

Criteria

Criteria

CATEGORY 1:

Substances known to induce heritable mutations or to be regarded as if they induce heritable mutations in the germ cells of humans.

Substances known to induce heritable mutations in the germ cells of humans.

CATEGORY 1:

CATEGORY 1:

Substances known to induce heritable mutations or to be regarded as if they induce heritable mutations in the germ cells of humans.

Substances known to induce heritable mutations in the germ cells of humans.

Substances known to induce heritable mutations or to be regarded as if they induce heritable mutations in the germ cells of humans.

Substances known to induce heritable mutations in the germ cells of humans.

Category 1A:

The classification in Category 1A is based on positive evidence from human epidemiological studies.

Substances to be regarded as if they induce heritable mutations in the germ cells of humans.

Category 1A:

Category 1A:

The classification in Category 1A is based on positive evidence from human epidemiological studies.

Substances to be regarded as if they induce heritable mutations in the germ cells of humans.

The classification in Category 1A is based on positive evidence from human epidemiological studies.

Substances to be regarded as if they induce heritable mutations in the germ cells of humans.

Category 1B:

The classification in Category 1B is based on:

— positive result(s) from in vivo heritable germ cell mutagenicity tests in mammals; or

— positive result(s) from in vivo somatic cell mutagenicity tests in mammals, in combination with some evidence that the substance has potential to cause mutations to germ cells. It is possible to derive this supporting evidence from mutagenicity/genotoxicity tests in germ cells in vivo, or by demonstrating the ability of the substance or its metabolite(s) to interact with the genetic material of germ cells; or

— positive results from tests showing mutagenic effects in the germ cells of humans, without demonstration of transmission to progeny; for example, an increase in the frequency of aneuploidy in sperm cells of exposed people.

Category 1B:

Category 1B:

The classification in Category 1B is based on:

— positive result(s) from in vivo heritable germ cell mutagenicity tests in mammals; or

— positive result(s) from in vivo somatic cell mutagenicity tests in mammals, in combination with some evidence that the substance has potential to cause mutations to germ cells. It is possible to derive this supporting evidence from mutagenicity/genotoxicity tests in germ cells in vivo, or by demonstrating the ability of the substance or its metabolite(s) to interact with the genetic material of germ cells; or

— positive results from tests showing mutagenic effects in the germ cells of humans, without demonstration of transmission to progeny; for example, an increase in the frequency of aneuploidy in sperm cells of exposed people.

The classification in Category 1B is based on:

— positive result(s) from in vivo heritable germ cell mutagenicity tests in mammals; or

— positive result(s) from in vivo heritable germ cell mutagenicity tests in mammals; or

— positive result(s) from in vivo somatic cell mutagenicity tests in mammals, in combination with some evidence that the substance has potential to cause mutations to germ cells. It is possible to derive this supporting evidence from mutagenicity/genotoxicity tests in germ cells in vivo, or by demonstrating the ability of the substance or its metabolite(s) to interact with the genetic material of germ cells; or

— positive result(s) from in vivo somatic cell mutagenicity tests in mammals, in combination with some evidence that the substance has potential to cause mutations to germ cells. It is possible to derive this supporting evidence from mutagenicity/genotoxicity tests in germ cells in vivo, or by demonstrating the ability of the substance or its metabolite(s) to interact with the genetic material of germ cells; or

— positive results from tests showing mutagenic effects in the germ cells of humans, without demonstration of transmission to progeny; for example, an increase in the frequency of aneuploidy in sperm cells of exposed people.

— positive results from tests showing mutagenic effects in the germ cells of humans, without demonstration of transmission to progeny; for example, an increase in the frequency of aneuploidy in sperm cells of exposed people.

CATEGORY 2:

Substances which cause concern for humans owing to the possibility that they may induce heritable mutations in the germ cells of humans

The classification in Category 2 is based on:

— positive evidence obtained from experiments in mammals and/or in some cases from in vitro experiments, obtained from:

— 

— somatic cell mutagenicity tests in vivo, in mammals; or

— other in vivo somatic cell genotoxicity tests which are supported by positive results from in vitro mutagenicity assays.

Note: Substances which are positive in in vitro mammalian mutagenicity assays, and which also show chemical structure activity relationship to known germ cell mutagens, shall be considered for classification as Category 2 mutagens.

CATEGORY 2:

CATEGORY 2:

Substances which cause concern for humans owing to the possibility that they may induce heritable mutations in the germ cells of humans

The classification in Category 2 is based on:

— positive evidence obtained from experiments in mammals and/or in some cases from in vitro experiments, obtained from:

— 

— somatic cell mutagenicity tests in vivo, in mammals; or

— other in vivo somatic cell genotoxicity tests which are supported by positive results from in vitro mutagenicity assays.

Note: Substances which are positive in in vitro mammalian mutagenicity assays, and which also show chemical structure activity relationship to known germ cell mutagens, shall be considered for classification as Category 2 mutagens.

Substances which cause concern for humans owing to the possibility that they may induce heritable mutations in the germ cells of humans

The classification in Category 2 is based on:

— positive evidence obtained from experiments in mammals and/or in some cases from in vitro experiments, obtained from:

— 

— somatic cell mutagenicity tests in vivo, in mammals; or

— other in vivo somatic cell genotoxicity tests which are supported by positive results from in vitro mutagenicity assays.

— positive evidence obtained from experiments in mammals and/or in some cases from in vitro experiments, obtained from:

— 

— somatic cell mutagenicity tests in vivo, in mammals; or

— somatic cell mutagenicity tests in vivo, in mammals; or

— other in vivo somatic cell genotoxicity tests which are supported by positive results from in vitro mutagenicity assays.

— other in vivo somatic cell genotoxicity tests which are supported by positive results from in vitro mutagenicity assays.

Note: Substances which are positive in in vitro mammalian mutagenicity assays, and which also show chemical structure activity relationship to known germ cell mutagens, shall be considered for classification as Category 2 mutagens.

3.5.2.3.   Specific considerations for classification of substances as germ cell mutagens Specific considerations for classification of substances as germ cell mutagens

3.5.2.3.1. To arrive at a classification, test results are considered from experiments determining mutagenic and/or genotoxic effects in germ and/or somatic cells of exposed animals. Mutagenic and/or genotoxic effects determined in in vitro tests shall also be considered.

3.5.2.3.1. To arrive at a classification, test results are considered from experiments determining mutagenic and/or genotoxic effects in germ and/or somatic cells of exposed animals. Mutagenic and/or genotoxic effects determined in in vitro tests shall also be considered.  

3.5.2.3.2. The system is hazard based, classifying substances on the basis of their intrinsic ability to induce mutations in germ cells. The scheme is, therefore, not meant for the (quantitative) risk assessment of substances.

3.5.2.3.2. The system is hazard based, classifying substances on the basis of their intrinsic ability to induce mutations in germ cells. The scheme is, therefore, not meant for the (quantitative) risk assessment of substances.  

3.5.2.3.3. Classification for heritable effects in human germ cells is made on the basis of well conducted, sufficiently validated tests, preferably as described in Regulation (EC) No 440/2008 adopted in accordance with Article 13(3) of Regulation (EC) No 1907/2006 (‘Test Method Regulation’) such as those listed in the following paragraphs. Evaluation of the test results shall be done using expert judgement and all the available evidence shall be weighed in arriving at a classification.

3.5.2.3.3. Classification for heritable effects in human germ cells is made on the basis of well conducted, sufficiently validated tests, preferably as described in Regulation (EC) No 440/2008 adopted in accordance with Article 13(3) of Regulation (EC) No 1907/2006 (‘Test Method Regulation’) such as those listed in the following paragraphs. Evaluation of the test results shall be done using expert judgement and all the available evidence shall be weighed in arriving at a classification.  

3.5.2.3.4. In vivo heritable germ cell mutagenicity tests, such as:

3.5.2.3.4. In vivo heritable germ cell mutagenicity tests, such as:  

— 
rodent dominant lethal mutation test;
— 
— 
rodent dominant lethal mutation test;
rodent dominant lethal mutation test;
— 
mouse heritable translocation assay.
— 
— 
mouse heritable translocation assay.
mouse heritable translocation assay.

▼M19 ▼M19

3.5.2.3.5. In vivo somatic cell mutagenicity tests, such as:

3.5.2.3.5. In vivo somatic cell mutagenicity tests, such as:  

— 
mammalian bone marrow chromosome aberration test;
— 
— 
mammalian bone marrow chromosome aberration test;
mammalian bone marrow chromosome aberration test;
— 
mammalian erythrocyte micronucleus test
— 
— 
mammalian erythrocyte micronucleus test
mammalian erythrocyte micronucleus test

▼B ▼B

3.5.2.3.6. Mutagenicity/genotoxicity tests in germ cells, such as:

3.5.2.3.6. Mutagenicity/genotoxicity tests in germ cells, such as:  

(a) 

mutagenicity tests:

— 
mammalian spermatogonial chromosome aberration test;
— 
spermatid micronucleus assay;
(a) 
(a) 

mutagenicity tests:

— 
mammalian spermatogonial chromosome aberration test;
— 
spermatid micronucleus assay;

mutagenicity tests:

— 
mammalian spermatogonial chromosome aberration test;
— 
— 
mammalian spermatogonial chromosome aberration test;
mammalian spermatogonial chromosome aberration test;
— 
spermatid micronucleus assay;
— 
— 
spermatid micronucleus assay;
spermatid micronucleus assay;
(b) 

Genotoxicity tests:

— 
sister chromatid exchange analysis in spermatogonia;
— 
unscheduled DNA synthesis test (UDS) in testicular cells.
(b) 
(b) 

Genotoxicity tests:

— 
sister chromatid exchange analysis in spermatogonia;
— 
unscheduled DNA synthesis test (UDS) in testicular cells.

Genotoxicity tests:

— 
sister chromatid exchange analysis in spermatogonia;
— 
— 
sister chromatid exchange analysis in spermatogonia;
sister chromatid exchange analysis in spermatogonia;
— 
unscheduled DNA synthesis test (UDS) in testicular cells.
— 
— 
unscheduled DNA synthesis test (UDS) in testicular cells.
unscheduled DNA synthesis test (UDS) in testicular cells.

3.5.2.3.7. Genotoxicity tests in somatic cells such as:

3.5.2.3.7. Genotoxicity tests in somatic cells such as:  

— 
liver Unscheduled synthesis test (UDS) in vivo;
— 
— 
liver Unscheduled synthesis test (UDS) in vivo;
liver Unscheduled synthesis test (UDS) in vivo;
— 
mammalian bone marrow Sister Chromatid Exchanges (SCE);
— 
— 
mammalian bone marrow Sister Chromatid Exchanges (SCE);
mammalian bone marrow Sister Chromatid Exchanges (SCE);

3.5.2.3.8. In vitro mutagenicity tests such as:

3.5.2.3.8. In vitro mutagenicity tests such as:  

— 
in vitro mammalian chromosome aberration test;
— 
— 
in vitro mammalian chromosome aberration test;
in vitro mammalian chromosome aberration test;
— 
in vitro mammalian cell gene mutation test;
— 
— 
in vitro mammalian cell gene mutation test;
in vitro mammalian cell gene mutation test;
— 
bacterial reverse mutation tests.
— 
— 
bacterial reverse mutation tests.
bacterial reverse mutation tests.

3.5.2.3.9. The classification of individual substances shall be based on the total weight of evidence available, using expert judgement (See 1.1.1). In those instances where a single well-conducted test is used for classification, it shall provide clear and unambiguously positive results. If new, well validated, tests arise these may also be used in the total weight of evidence to be considered. The relevance of the route of exposure used in the study of the substance compared to the route of human exposure shall also be taken into account.

3.5.2.3.9. The classification of individual substances shall be based on the total weight of evidence available, using expert judgement (See 1.1.1). In those instances where a single well-conducted test is used for classification, it shall provide clear and unambiguously positive results. If new, well validated, tests arise these may also be used in the total weight of evidence to be considered. The relevance of the route of exposure used in the study of the substance compared to the route of human exposure shall also be taken into account.  

3.5.3.   Classification criteria for mixtures

Classification criteria for mixtures

3.5.3.1.   Classification of mixtures when data are available for all ingredients or only for some ingredients of the mixture Classification of mixtures when data are available for all ingredients or only for some ingredients of the mixture

3.5.3.1.1. The mixture shall be classified as a mutagen when at least one ingredient has been classified as a Category 1A, Category 1B or Category 2 mutagen and is present at or above the appropriate generic concentration limit as shown in Table 3.5.2 for Category 1A, Category 1B and Category 2 respectively.

3.5.3.1.1. The mixture shall be classified as a mutagen when at least one ingredient has been classified as a Category 1A, Category 1B or Category 2 mutagen and is present at or above the appropriate generic concentration limit as shown in Table 3.5.2 for Category 1A, Category 1B and Category 2 respectively.  

▼M4 ▼M4

Table 3.5.2

Generic concentration limits of ingredients of a mixture classified as germ cell mutagens that trigger classification of the mixture

Ingredient classified as:

Concentration limits triggering classification of a mixture as:

Category 1 mutagen

Category 2 mutagen

Category 1A

Category 1B

Category 1A mutagen

≥ 0,1 %

—

—

Category 1B mutagen

—

≥ 0,1 %

—

Category 2 mutagen

—

—

≥ 1,0 %

Table 3.5.2 Table 3.5.2

Generic concentration limits of ingredients of a mixture classified as germ cell mutagens that trigger classification of the mixture Generic concentration limits of ingredients of a mixture classified as germ cell mutagens that trigger classification of the mixture

Ingredient classified as:

Concentration limits triggering classification of a mixture as:

Category 1 mutagen

Category 2 mutagen

Category 1A

Category 1B

Category 1A mutagen

≥ 0,1 %

—

—

Category 1B mutagen

—

≥ 0,1 %

—

Category 2 mutagen

—

—

≥ 1,0 %

Ingredient classified as:

Concentration limits triggering classification of a mixture as:

Category 1 mutagen

Category 2 mutagen

Category 1A

Category 1B

Category 1A mutagen

≥ 0,1 %

—

—

Category 1B mutagen

—

≥ 0,1 %

—

Category 2 mutagen

—

—

≥ 1,0 %

Ingredient classified as:

Concentration limits triggering classification of a mixture as:

Ingredient classified as:

Ingredient classified as:

Concentration limits triggering classification of a mixture as:

Concentration limits triggering classification of a mixture as:

Category 1 mutagen

Category 2 mutagen

Category 1 mutagen

Category 1 mutagen

Category 2 mutagen

Category 2 mutagen

Category 1A

Category 1B

Category 1A

Category 1A

Category 1B

Category 1B

Category 1A mutagen

≥ 0,1 %

—

—

Category 1A mutagen

Category 1A mutagen

≥ 0,1 %

≥ 0,1 %

—

—

—

—

Category 1B mutagen

—

≥ 0,1 %

—

Category 1B mutagen

Category 1B mutagen

—

—

≥ 0,1 %

≥ 0,1 %

—

—

Category 2 mutagen

—

—

≥ 1,0 %

Category 2 mutagen

Category 2 mutagen

—

—

—

—

≥ 1,0 %

≥ 1,0 %

▼B ▼B

Note

The concentration limits in the table above apply to solids and liquids (w/w units) as well as gases (v/v units).

3.5.3.2.   Classification of mixtures when data are available for the complete mixture Classification of mixtures when data are available for the complete mixture

3.5.3.2.1. Classification of mixtures will be based on the available test data for the individual ingredients of the mixture using concentration limits for the ingredients classified as germ cell mutagens. On a case-by-case basis, test data on mixtures may be used for classification when demonstrating effects that have not been established from the evaluation based on the individual ingredients. In such cases, the test results for the mixture as a whole must be shown to be conclusive taking into account dose and other factors such as duration, observations, sensitivity and statistical analysis of germ cell mutagenicity test systems. Adequate documentation supporting the classification shall be retained and made available for review upon request.

3.5.3.2.1. Classification of mixtures will be based on the available test data for the individual ingredients of the mixture using concentration limits for the ingredients classified as germ cell mutagens. On a case-by-case basis, test data on mixtures may be used for classification when demonstrating effects that have not been established from the evaluation based on the individual ingredients. In such cases, the test results for the mixture as a whole must be shown to be conclusive taking into account dose and other factors such as duration, observations, sensitivity and statistical analysis of germ cell mutagenicity test systems. Adequate documentation supporting the classification shall be retained and made available for review upon request.  

3.5.3.3.   Classification of mixtures when data are not available for the complete mixture: bridging principles Classification of mixtures when data are not available for the complete mixture: bridging principles

3.5.3.3.1. Where the mixture itself has not been tested to determine its germ cell mutagenicity hazard, but there are sufficient data on the individual ingredients and similar tested mixtures (subject to paragraph 3.5.3.2.1), to adequately characterise the hazards of the mixture, these data shall be used in accordance with the applicable bridging rules set out in section 1.1.3.

3.5.3.3.1. Where the mixture itself has not been tested to determine its germ cell mutagenicity hazard, but there are sufficient data on the individual ingredients and similar tested mixtures (subject to paragraph 3.5.3.2.1), to adequately characterise the hazards of the mixture, these data shall be used in accordance with the applicable bridging rules set out in section 1.1.3.  

3.5.4.   Hazard communication

Hazard communication

3.5.4.1. Label elements shall be used in accordance with Table 3.5.3, for substances or mixtures meeting the criteria for classification in this hazard class.

3.5.4.1. Label elements shall be used in accordance with Table 3.5.3, for substances or mixtures meeting the criteria for classification in this hazard class.  

▼M4 ▼M4

Table 3.5.3

Label elements of germ cell mutagenicity

Classification

Category 1

(Category 1A, 1B)

Category 2

GHS Pictograms

image

image

Signal Word

Danger

Warning

Hazard Statement

H340: May cause genetic defects (state route of exposure if it is conclusively proven that no other routes of exposure cause the hazard)

H341: Suspected of causing genetic defects (state route of exposure if it is conclusively proven that no other routes of exposure cause the hazard)

Precautionary Statement Prevention

P201

P202

P280

P201

P202

P280

Precautionary Statement Response

P308 + P313

P308 + P313

Precautionary Statement Storage

P405

P405

Precautionary Statement Disposal

P501

P501

Table 3.5.3 Table 3.5.3

Label elements of germ cell mutagenicity Label elements of germ cell mutagenicity

Classification

Category 1

(Category 1A, 1B)

Category 2

GHS Pictograms

image

image

Signal Word

Danger

Warning

Hazard Statement

H340: May cause genetic defects (state route of exposure if it is conclusively proven that no other routes of exposure cause the hazard)

H341: Suspected of causing genetic defects (state route of exposure if it is conclusively proven that no other routes of exposure cause the hazard)

Precautionary Statement Prevention

P201

P202

P280

P201

P202

P280

Precautionary Statement Response

P308 + P313

P308 + P313

Precautionary Statement Storage

P405

P405

Precautionary Statement Disposal

P501

P501

Classification

Category 1

(Category 1A, 1B)

Category 2

GHS Pictograms

image

image

Signal Word

Danger

Warning

Hazard Statement

H340: May cause genetic defects (state route of exposure if it is conclusively proven that no other routes of exposure cause the hazard)

H341: Suspected of causing genetic defects (state route of exposure if it is conclusively proven that no other routes of exposure cause the hazard)

Precautionary Statement Prevention

P201

P202

P280

P201

P202

P280

Precautionary Statement Response

P308 + P313

P308 + P313

Precautionary Statement Storage

P405

P405

Precautionary Statement Disposal

P501

P501

Classification

Category 1

(Category 1A, 1B)

Category 2

Classification

Classification

Category 1

(Category 1A, 1B)

Category 1

(Category 1A, 1B)

Category 2

Category 2

GHS Pictograms

image

image

GHS Pictograms

GHS Pictograms

image

image image

image

image image

Signal Word

Danger

Warning

Signal Word

Signal Word

Danger

Danger

Warning

Warning

Hazard Statement

H340: May cause genetic defects (state route of exposure if it is conclusively proven that no other routes of exposure cause the hazard)

H341: Suspected of causing genetic defects (state route of exposure if it is conclusively proven that no other routes of exposure cause the hazard)

Hazard Statement

Hazard Statement

H340: May cause genetic defects (state route of exposure if it is conclusively proven that no other routes of exposure cause the hazard)

H340: May cause genetic defects (state route of exposure if it is conclusively proven that no other routes of exposure cause the hazard)

H341: Suspected of causing genetic defects (state route of exposure if it is conclusively proven that no other routes of exposure cause the hazard)

H341: Suspected of causing genetic defects (state route of exposure if it is conclusively proven that no other routes of exposure cause the hazard)

Precautionary Statement Prevention

P201

P202

P280

P201

P202

P280

Precautionary Statement Prevention

Precautionary Statement Prevention

P201

P202

P280

P201

P202

P280

P201

P202

P280

P201

P202

P280

Precautionary Statement Response

P308 + P313

P308 + P313

Precautionary Statement Response

Precautionary Statement Response

P308 + P313

P308 + P313

P308 + P313

P308 + P313

Precautionary Statement Storage

P405

P405

Precautionary Statement Storage

Precautionary Statement Storage

P405

P405

P405

P405

Precautionary Statement Disposal

P501

P501

Precautionary Statement Disposal

Precautionary Statement Disposal

P501

P501

P501

P501

▼B ▼B

3.5.5.   Additional classification considerations

Additional classification considerations

It is increasingly accepted that the process of chemical-induced tumorigenesis in humans and animals involves genetic changes for example in proto-oncogenes and/or tumour suppresser genes of somatic cells. Therefore, the demonstration of mutagenic properties of substances in somatic and/or germ cells of mammals in vivo may have implications for the potential classification of these substances as carcinogens (see also Carcinogenicity, section 3.6, paragraph 3.6.2.2.6).

3.6.   Carcinogenicity

Carcinogenicity

3.6.1.   Definition

Definition

▼M19 ▼M19

3.6.1.1. Carcinogenicity means the induction of cancer or an increase in the incidence of cancer occurring after exposure to a substance or mixture. Substances and mixtures which have induced benign and malignant tumours in well performed experimental studies on animals are considered also to be presumed or suspected human carcinogens unless there is strong evidence that the mechanism of tumour formation is not relevant for humans.

3.6.1.1. Carcinogenicity means the induction of cancer or an increase in the incidence of cancer occurring after exposure to a substance or mixture. Substances and mixtures which have induced benign and malignant tumours in well performed experimental studies on animals are considered also to be presumed or suspected human carcinogens unless there is strong evidence that the mechanism of tumour formation is not relevant for humans.  

Classification of a substance or mixture as posing a carcinogenic hazard is based on its intrinsic properties and does not provide information on the level of the human cancer risk which the use of the substance or mixture may represent. Classification of a substance or mixture as posing a carcinogenic hazard is based on its intrinsic properties and does not provide information on the level of the human cancer risk which the use of the substance or mixture may represent.

▼B ▼B

3.6.2.   Classification criteria for substances

Classification criteria for substances

3.6.2.1. For the purpose of classification for carcinogenicity, substances are allocated to one of two categories based on strength of evidence and additional considerations (weight of evidence). In certain instances, route-specific classification may be warranted, if it can be conclusively proved that no other route of exposure exhibits the hazard.

3.6.2.1. For the purpose of classification for carcinogenicity, substances are allocated to one of two categories based on strength of evidence and additional considerations (weight of evidence). In certain instances, route-specific classification may be warranted, if it can be conclusively proved that no other route of exposure exhibits the hazard.  

Table 3.6.1

Hazard categories for carcinogens

Categories

Criteria

CATEGORY 1:

Known or presumed human carcinogens

A substance is classified in Category 1 for carcinogenicity on the basis of epidemiological and/or animal data. A substance may be further distinguished as:

Category 1A:

Category 1A, known to have carcinogenic potential for humans, classification is largely based on human evidence, or

Category 1B:

Category 1B, presumed to have carcinogenic potential for humans, classification is largely based on animal evidence.

 

The classification in Category 1A and 1B is based on strength of evidence together with additional considerations (see section 3.6.2.2). Such evidence may be derived from:

— human studies that establish a causal relationship between human exposure to a substance and the development of cancer (known human carcinogen); or

— animal experiments for which there is sufficient () evidence to demonstrate animal carcinogenicity (presumed human carcinogen).

 

In addition, on a case-by-case basis, scientific judgement may warrant a decision of presumed human carcinogenicity derived from studies showing limited evidence of carcinogenicity in humans together with limited evidence of carcinogenicity in experimental animals.

CATEGORY 2:

Suspected human carcinogens

The placing of a substance in Category 2 is done on the basis of evidence obtained from human and/or animal studies, but which is not sufficiently convincing to place the substance in Category 1A or 1B, based on strength of evidence together with additional considerations (see section 3.6.2.2). Such evidence may be derived either from limited () evidence of carcinogenicity in human studies or from limited evidence of carcinogenicity in animal studies.

(1)   

Note: See 3.6.2.2.4.

Table 3.6.1

Hazard categories for carcinogens

Categories

Criteria

CATEGORY 1:

Known or presumed human carcinogens

A substance is classified in Category 1 for carcinogenicity on the basis of epidemiological and/or animal data. A substance may be further distinguished as:

Category 1A:

Category 1A, known to have carcinogenic potential for humans, classification is largely based on human evidence, or

Category 1B:

Category 1B, presumed to have carcinogenic potential for humans, classification is largely based on animal evidence.

 

The classification in Category 1A and 1B is based on strength of evidence together with additional considerations (see section 3.6.2.2). Such evidence may be derived from:

— human studies that establish a causal relationship between human exposure to a substance and the development of cancer (known human carcinogen); or

— animal experiments for which there is sufficient () evidence to demonstrate animal carcinogenicity (presumed human carcinogen).

 

In addition, on a case-by-case basis, scientific judgement may warrant a decision of presumed human carcinogenicity derived from studies showing limited evidence of carcinogenicity in humans together with limited evidence of carcinogenicity in experimental animals.

CATEGORY 2:

Suspected human carcinogens

The placing of a substance in Category 2 is done on the basis of evidence obtained from human and/or animal studies, but which is not sufficiently convincing to place the substance in Category 1A or 1B, based on strength of evidence together with additional considerations (see section 3.6.2.2). Such evidence may be derived either from limited () evidence of carcinogenicity in human studies or from limited evidence of carcinogenicity in animal studies.

(1)   

Note: See 3.6.2.2.4.

Categories

Criteria

CATEGORY 1:

Known or presumed human carcinogens

A substance is classified in Category 1 for carcinogenicity on the basis of epidemiological and/or animal data. A substance may be further distinguished as:

Category 1A:

Category 1A, known to have carcinogenic potential for humans, classification is largely based on human evidence, or

Category 1B:

Category 1B, presumed to have carcinogenic potential for humans, classification is largely based on animal evidence.

 

The classification in Category 1A and 1B is based on strength of evidence together with additional considerations (see section 3.6.2.2). Such evidence may be derived from:

— human studies that establish a causal relationship between human exposure to a substance and the development of cancer (known human carcinogen); or

— animal experiments for which there is sufficient () evidence to demonstrate animal carcinogenicity (presumed human carcinogen).

 

In addition, on a case-by-case basis, scientific judgement may warrant a decision of presumed human carcinogenicity derived from studies showing limited evidence of carcinogenicity in humans together with limited evidence of carcinogenicity in experimental animals.

CATEGORY 2:

Suspected human carcinogens

The placing of a substance in Category 2 is done on the basis of evidence obtained from human and/or animal studies, but which is not sufficiently convincing to place the substance in Category 1A or 1B, based on strength of evidence together with additional considerations (see section 3.6.2.2). Such evidence may be derived either from limited () evidence of carcinogenicity in human studies or from limited evidence of carcinogenicity in animal studies.

(1)   

Note: See 3.6.2.2.4.

Categories

Criteria

Categories

Categories

Criteria

Criteria

CATEGORY 1:

Known or presumed human carcinogens

A substance is classified in Category 1 for carcinogenicity on the basis of epidemiological and/or animal data. A substance may be further distinguished as:

CATEGORY 1:

CATEGORY 1:

Known or presumed human carcinogens

A substance is classified in Category 1 for carcinogenicity on the basis of epidemiological and/or animal data. A substance may be further distinguished as:

Known or presumed human carcinogens

A substance is classified in Category 1 for carcinogenicity on the basis of epidemiological and/or animal data. A substance may be further distinguished as:

Category 1A:

Category 1A, known to have carcinogenic potential for humans, classification is largely based on human evidence, or

Category 1A:

Category 1A:

Category 1A, known to have carcinogenic potential for humans, classification is largely based on human evidence, or

Category 1A, known to have carcinogenic potential for humans, classification is largely based on human evidence, or

Category 1B:

Category 1B, presumed to have carcinogenic potential for humans, classification is largely based on animal evidence.

Category 1B:

Category 1B:

Category 1B, presumed to have carcinogenic potential for humans, classification is largely based on animal evidence.

Category 1B, presumed to have carcinogenic potential for humans, classification is largely based on animal evidence.

 

The classification in Category 1A and 1B is based on strength of evidence together with additional considerations (see section 3.6.2.2). Such evidence may be derived from:

— human studies that establish a causal relationship between human exposure to a substance and the development of cancer (known human carcinogen); or

— animal experiments for which there is sufficient () evidence to demonstrate animal carcinogenicity (presumed human carcinogen).

 

 

The classification in Category 1A and 1B is based on strength of evidence together with additional considerations (see section 3.6.2.2). Such evidence may be derived from:

— human studies that establish a causal relationship between human exposure to a substance and the development of cancer (known human carcinogen); or

— animal experiments for which there is sufficient () evidence to demonstrate animal carcinogenicity (presumed human carcinogen).

The classification in Category 1A and 1B is based on strength of evidence together with additional considerations (see section 3.6.2.2). Such evidence may be derived from:

— human studies that establish a causal relationship between human exposure to a substance and the development of cancer (known human carcinogen); or

— human studies that establish a causal relationship between human exposure to a substance and the development of cancer (known human carcinogen); or

— animal experiments for which there is sufficient () evidence to demonstrate animal carcinogenicity (presumed human carcinogen).

— animal experiments for which there is sufficient () evidence to demonstrate animal carcinogenicity (presumed human carcinogen). ()

 

In addition, on a case-by-case basis, scientific judgement may warrant a decision of presumed human carcinogenicity derived from studies showing limited evidence of carcinogenicity in humans together with limited evidence of carcinogenicity in experimental animals.

 

 

In addition, on a case-by-case basis, scientific judgement may warrant a decision of presumed human carcinogenicity derived from studies showing limited evidence of carcinogenicity in humans together with limited evidence of carcinogenicity in experimental animals.

In addition, on a case-by-case basis, scientific judgement may warrant a decision of presumed human carcinogenicity derived from studies showing limited evidence of carcinogenicity in humans together with limited evidence of carcinogenicity in experimental animals.

CATEGORY 2:

Suspected human carcinogens

The placing of a substance in Category 2 is done on the basis of evidence obtained from human and/or animal studies, but which is not sufficiently convincing to place the substance in Category 1A or 1B, based on strength of evidence together with additional considerations (see section 3.6.2.2). Such evidence may be derived either from limited () evidence of carcinogenicity in human studies or from limited evidence of carcinogenicity in animal studies.

CATEGORY 2:

CATEGORY 2:

Suspected human carcinogens

The placing of a substance in Category 2 is done on the basis of evidence obtained from human and/or animal studies, but which is not sufficiently convincing to place the substance in Category 1A or 1B, based on strength of evidence together with additional considerations (see section 3.6.2.2). Such evidence may be derived either from limited () evidence of carcinogenicity in human studies or from limited evidence of carcinogenicity in animal studies.

Suspected human carcinogens

The placing of a substance in Category 2 is done on the basis of evidence obtained from human and/or animal studies, but which is not sufficiently convincing to place the substance in Category 1A or 1B, based on strength of evidence together with additional considerations (see section 3.6.2.2). Such evidence may be derived either from limited () evidence of carcinogenicity in human studies or from limited evidence of carcinogenicity in animal studies. ()

(1)   

Note: See 3.6.2.2.4.

(1)   

Note: See 3.6.2.2.4.

(1)   

Note: See 3.6.2.2.4.

(1)    1

Note: See 3.6.2.2.4.

3.6.2.2.   Specific considerations for classification of substances as carcinogens Specific considerations for classification of substances as carcinogens

3.6.2.2.1. Classification as a carcinogen is made on the basis of evidence from reliable and acceptable studies and is intended to be used for substances which have an intrinsic property to cause cancer. The evaluations shall be based on all existing data, peer-reviewed published studies and additional acceptable data.

3.6.2.2.1. Classification as a carcinogen is made on the basis of evidence from reliable and acceptable studies and is intended to be used for substances which have an intrinsic property to cause cancer. The evaluations shall be based on all existing data, peer-reviewed published studies and additional acceptable data.  

3.6.2.2.2. Classification of a substance as a carcinogen is a process that involves two interrelated determinations: evaluations of strength of evidence and consideration of all other relevant information to place substances with human cancer potential into hazard categories.

3.6.2.2.2. Classification of a substance as a carcinogen is a process that involves two interrelated determinations: evaluations of strength of evidence and consideration of all other relevant information to place substances with human cancer potential into hazard categories.  

3.6.2.2.3. Strength of evidence involves the enumeration of tumours in human and animal studies and determination of their level of statistical significance. Sufficient human evidence demonstrates causality between human exposure and the development of cancer, whereas sufficient evidence in animals shows a causal relationship between the substance and an increased incidence of tumours. Limited evidence in humans is demonstrated by a positive association between exposure and cancer, but a causal relationship cannot be stated. Limited evidence in animals is provided when data suggest a carcinogenic effect, but are less than sufficient. The terms ‘sufficient’ and ‘limited’ have been used here as they have been defined by the International Agency for Research on Cancer (IARC) and read as follows:

3.6.2.2.3. Strength of evidence involves the enumeration of tumours in human and animal studies and determination of their level of statistical significance. Sufficient human evidence demonstrates causality between human exposure and the development of cancer, whereas sufficient evidence in animals shows a causal relationship between the substance and an increased incidence of tumours. Limited evidence in humans is demonstrated by a positive association between exposure and cancer, but a causal relationship cannot be stated. Limited evidence in animals is provided when data suggest a carcinogenic effect, but are less than sufficient. The terms ‘sufficient’ and ‘limited’ have been used here as they have been defined by the International Agency for Research on Cancer (IARC) and read as follows:  

(a) 

Carcinogenicity in humans

The evidence relevant to carcinogenicity from studies in humans is classified into one of the following categories:

— 
sufficient evidence of carcinogenicity: a causal relationship has been established between exposure to the agent and human cancer. That is, a positive relationship has been observed between the exposure and cancer in studies in which chance, bias and confounding could be ruled out with reasonable confidence;
— 
limited evidence of carcinogenicity: a positive association has been observed between exposure to the agent and cancer for which a causal interpretation is considered to be credible, but chance, bias or confounding could not be ruled out with reasonable confidence.
(a) 
(a) 

Carcinogenicity in humans

The evidence relevant to carcinogenicity from studies in humans is classified into one of the following categories:

— 
sufficient evidence of carcinogenicity: a causal relationship has been established between exposure to the agent and human cancer. That is, a positive relationship has been observed between the exposure and cancer in studies in which chance, bias and confounding could be ruled out with reasonable confidence;
— 
limited evidence of carcinogenicity: a positive association has been observed between exposure to the agent and cancer for which a causal interpretation is considered to be credible, but chance, bias or confounding could not be ruled out with reasonable confidence.

Carcinogenicity in humans

The evidence relevant to carcinogenicity from studies in humans is classified into one of the following categories:

— 
sufficient evidence of carcinogenicity: a causal relationship has been established between exposure to the agent and human cancer. That is, a positive relationship has been observed between the exposure and cancer in studies in which chance, bias and confounding could be ruled out with reasonable confidence;
— 
— 
sufficient evidence of carcinogenicity: a causal relationship has been established between exposure to the agent and human cancer. That is, a positive relationship has been observed between the exposure and cancer in studies in which chance, bias and confounding could be ruled out with reasonable confidence;
sufficient evidence of carcinogenicity: a causal relationship has been established between exposure to the agent and human cancer. That is, a positive relationship has been observed between the exposure and cancer in studies in which chance, bias and confounding could be ruled out with reasonable confidence;
— 
limited evidence of carcinogenicity: a positive association has been observed between exposure to the agent and cancer for which a causal interpretation is considered to be credible, but chance, bias or confounding could not be ruled out with reasonable confidence.
— 
— 
limited evidence of carcinogenicity: a positive association has been observed between exposure to the agent and cancer for which a causal interpretation is considered to be credible, but chance, bias or confounding could not be ruled out with reasonable confidence.
limited evidence of carcinogenicity: a positive association has been observed between exposure to the agent and cancer for which a causal interpretation is considered to be credible, but chance, bias or confounding could not be ruled out with reasonable confidence.
(b) 

Carcinogenicity in experimental animals

Carcinogenicity in experimental animals can be evaluated using conventional bioassays, bioassays that employ genetically modified animals, and other in-vivo bioassays that focus on one or more of the critical stages of carcinogenesis. In the absence of data from conventional long-term bioassays or from assays with neoplasia as the end-point, consistently positive results in several models that address several stages in the multistage process of carcinogenesis should be considered in evaluating the degree of evidence of carcinogenicity in experimental animals. The evidence relevant to carcinogenicity in experimental animals is classified into one of the following categories:

— 
sufficient evidence of carcinogenicity: a causal relationship has been established between the agent and an increased incidence of malignant neoplasms or of an appropriate combination of benign and malignant neoplasms in (a) two or more species of animals or (b) two or more independent studies in one species carried out at different times or in different laboratories or under different protocols. An increased incidence of tumours in both sexes of a single species in a well-conducted study, ideally conducted under Good Laboratory Practices, can also provide sufficient evidence. A single study in one species and sex might be considered to provide sufficient evidence of carcinogenicity when malignant neoplasms occur to an unusual degree with regard to incidence, site, type of tumour or age at onset, or when there are strong findings of tumours at multiple sites;
— 
limited evidence of carcinogenicity: the data suggest a carcinogenic effect but are limited for making a definitive evaluation because, e.g. (a) the evidence of carcinogenicity is restricted to a single experiment; (b) there are unresolved questions regarding the adequacy of the design, conduct or interpretation of the studies; (c) the agent increases the incidence only of benign neoplasms or lesions of uncertain neoplastic potential; or (d) the evidence of carcinogenicity is restricted to studies that demonstrate only promoting activity in a narrow range of tissues or organs.
(b) 
(b) 

Carcinogenicity in experimental animals

Carcinogenicity in experimental animals can be evaluated using conventional bioassays, bioassays that employ genetically modified animals, and other in-vivo bioassays that focus on one or more of the critical stages of carcinogenesis. In the absence of data from conventional long-term bioassays or from assays with neoplasia as the end-point, consistently positive results in several models that address several stages in the multistage process of carcinogenesis should be considered in evaluating the degree of evidence of carcinogenicity in experimental animals. The evidence relevant to carcinogenicity in experimental animals is classified into one of the following categories:

— 
sufficient evidence of carcinogenicity: a causal relationship has been established between the agent and an increased incidence of malignant neoplasms or of an appropriate combination of benign and malignant neoplasms in (a) two or more species of animals or (b) two or more independent studies in one species carried out at different times or in different laboratories or under different protocols. An increased incidence of tumours in both sexes of a single species in a well-conducted study, ideally conducted under Good Laboratory Practices, can also provide sufficient evidence. A single study in one species and sex might be considered to provide sufficient evidence of carcinogenicity when malignant neoplasms occur to an unusual degree with regard to incidence, site, type of tumour or age at onset, or when there are strong findings of tumours at multiple sites;
— 
limited evidence of carcinogenicity: the data suggest a carcinogenic effect but are limited for making a definitive evaluation because, e.g. (a) the evidence of carcinogenicity is restricted to a single experiment; (b) there are unresolved questions regarding the adequacy of the design, conduct or interpretation of the studies; (c) the agent increases the incidence only of benign neoplasms or lesions of uncertain neoplastic potential; or (d) the evidence of carcinogenicity is restricted to studies that demonstrate only promoting activity in a narrow range of tissues or organs.

Carcinogenicity in experimental animals

Carcinogenicity in experimental animals can be evaluated using conventional bioassays, bioassays that employ genetically modified animals, and other in-vivo bioassays that focus on one or more of the critical stages of carcinogenesis. In the absence of data from conventional long-term bioassays or from assays with neoplasia as the end-point, consistently positive results in several models that address several stages in the multistage process of carcinogenesis should be considered in evaluating the degree of evidence of carcinogenicity in experimental animals. The evidence relevant to carcinogenicity in experimental animals is classified into one of the following categories:

— 
sufficient evidence of carcinogenicity: a causal relationship has been established between the agent and an increased incidence of malignant neoplasms or of an appropriate combination of benign and malignant neoplasms in (a) two or more species of animals or (b) two or more independent studies in one species carried out at different times or in different laboratories or under different protocols. An increased incidence of tumours in both sexes of a single species in a well-conducted study, ideally conducted under Good Laboratory Practices, can also provide sufficient evidence. A single study in one species and sex might be considered to provide sufficient evidence of carcinogenicity when malignant neoplasms occur to an unusual degree with regard to incidence, site, type of tumour or age at onset, or when there are strong findings of tumours at multiple sites;
— 
— 
sufficient evidence of carcinogenicity: a causal relationship has been established between the agent and an increased incidence of malignant neoplasms or of an appropriate combination of benign and malignant neoplasms in (a) two or more species of animals or (b) two or more independent studies in one species carried out at different times or in different laboratories or under different protocols. An increased incidence of tumours in both sexes of a single species in a well-conducted study, ideally conducted under Good Laboratory Practices, can also provide sufficient evidence. A single study in one species and sex might be considered to provide sufficient evidence of carcinogenicity when malignant neoplasms occur to an unusual degree with regard to incidence, site, type of tumour or age at onset, or when there are strong findings of tumours at multiple sites;
sufficient evidence of carcinogenicity: a causal relationship has been established between the agent and an increased incidence of malignant neoplasms or of an appropriate combination of benign and malignant neoplasms in (a) two or more species of animals or (b) two or more independent studies in one species carried out at different times or in different laboratories or under different protocols. An increased incidence of tumours in both sexes of a single species in a well-conducted study, ideally conducted under Good Laboratory Practices, can also provide sufficient evidence. A single study in one species and sex might be considered to provide sufficient evidence of carcinogenicity when malignant neoplasms occur to an unusual degree with regard to incidence, site, type of tumour or age at onset, or when there are strong findings of tumours at multiple sites;
— 
limited evidence of carcinogenicity: the data suggest a carcinogenic effect but are limited for making a definitive evaluation because, e.g. (a) the evidence of carcinogenicity is restricted to a single experiment; (b) there are unresolved questions regarding the adequacy of the design, conduct or interpretation of the studies; (c) the agent increases the incidence only of benign neoplasms or lesions of uncertain neoplastic potential; or (d) the evidence of carcinogenicity is restricted to studies that demonstrate only promoting activity in a narrow range of tissues or organs.
— 
— 
limited evidence of carcinogenicity: the data suggest a carcinogenic effect but are limited for making a definitive evaluation because, e.g. (a) the evidence of carcinogenicity is restricted to a single experiment; (b) there are unresolved questions regarding the adequacy of the design, conduct or interpretation of the studies; (c) the agent increases the incidence only of benign neoplasms or lesions of uncertain neoplastic potential; or (d) the evidence of carcinogenicity is restricted to studies that demonstrate only promoting activity in a narrow range of tissues or organs.
limited evidence of carcinogenicity: the data suggest a carcinogenic effect but are limited for making a definitive evaluation because, e.g. (a) the evidence of carcinogenicity is restricted to a single experiment; (b) there are unresolved questions regarding the adequacy of the design, conduct or interpretation of the studies; (c) the agent increases the incidence only of benign neoplasms or lesions of uncertain neoplastic potential; or (d) the evidence of carcinogenicity is restricted to studies that demonstrate only promoting activity in a narrow range of tissues or organs.

3.6.2.2.4. Additional considerations (as part of the weight of evidence approach (see 1.1.1)). Beyond the determination of the strength of evidence for carcinogenicity, a number of other factors need to be considered that influence the overall likelihood that a substance poses a carcinogenic hazard in humans. The full list of factors that influence this determination would be very lengthy, but some of the more important ones are considered here.

3.6.2.2.4. Additional considerations (as part of the weight of evidence approach (see 1.1.1)). Beyond the determination of the strength of evidence for carcinogenicity, a number of other factors need to be considered that influence the overall likelihood that a substance poses a carcinogenic hazard in humans. The full list of factors that influence this determination would be very lengthy, but some of the more important ones are considered here.  

3.6.2.2.5. The factors can be viewed as either increasing or decreasing the level of concern for human carcinogenicity. The relative emphasis accorded to each factor depends upon the amount and coherence of evidence bearing on each. Generally there is a requirement for more complete information to decrease than to increase the level of concern. Additional considerations should be used in evaluating the tumour findings and the other factors in a case-by-case manner.

3.6.2.2.5. The factors can be viewed as either increasing or decreasing the level of concern for human carcinogenicity. The relative emphasis accorded to each factor depends upon the amount and coherence of evidence bearing on each. Generally there is a requirement for more complete information to decrease than to increase the level of concern. Additional considerations should be used in evaluating the tumour findings and the other factors in a case-by-case manner.  

3.6.2.2.6. Some important factors which may be taken into consideration, when assessing the overall level of concern are:

3.6.2.2.6. Some important factors which may be taken into consideration, when assessing the overall level of concern are:  

(a) 

tumour type and background incidence;

(a) 
(a) 

tumour type and background incidence;

tumour type and background incidence;

(b) 

multi-site responses;

(b) 
(b) 

multi-site responses;

multi-site responses;

(c) 

progression of lesions to malignancy;

(c) 
(c) 

progression of lesions to malignancy;

progression of lesions to malignancy;

(d) 

reduced tumour latency;

(d) 
(d) 

reduced tumour latency;

reduced tumour latency;

(e) 

whether responses are in single or both sexes;

(e) 
(e) 

whether responses are in single or both sexes;

whether responses are in single or both sexes;

(f) 

whether responses are in a single species or several species;

(f) 
(f) 

whether responses are in a single species or several species;

whether responses are in a single species or several species;

(g) 

structural similarity to a substance(s) for which there is good evidence of carcinogenicity;

(g) 
(g) 

structural similarity to a substance(s) for which there is good evidence of carcinogenicity;

structural similarity to a substance(s) for which there is good evidence of carcinogenicity;

(h) 

routes of exposure;

(h) 
(h) 

routes of exposure;

routes of exposure;

(i) 

comparison of absorption, distribution, metabolism and excretion between test animals and humans;

(i) 
(i) 

comparison of absorption, distribution, metabolism and excretion between test animals and humans;

comparison of absorption, distribution, metabolism and excretion between test animals and humans;

(j) 

the possibility of a confounding effect of excessive toxicity at test doses;

(j) 
(j) 

the possibility of a confounding effect of excessive toxicity at test doses;

the possibility of a confounding effect of excessive toxicity at test doses;

(k) 

mode of action and its relevance for humans, such as cytotoxicity with growth stimulation, mitogenesis, immunosuppression, mutagenicity.

Mutagenicity: it is recognised that genetic events are central in the overall process of cancer development. Therefore evidence of mutagenic activity in vivo may indicate that a substance has a potential for carcinogenic effects.

(k) 
(k) 

mode of action and its relevance for humans, such as cytotoxicity with growth stimulation, mitogenesis, immunosuppression, mutagenicity.

Mutagenicity: it is recognised that genetic events are central in the overall process of cancer development. Therefore evidence of mutagenic activity in vivo may indicate that a substance has a potential for carcinogenic effects.

mode of action and its relevance for humans, such as cytotoxicity with growth stimulation, mitogenesis, immunosuppression, mutagenicity.

Mutagenicity: it is recognised that genetic events are central in the overall process of cancer development. Therefore evidence of mutagenic activity in vivo may indicate that a substance has a potential for carcinogenic effects.

3.6.2.2.7. A substance that has not been tested for carcinogenicity may in certain instances be classified in Category 1A, Category 1B or Category 2 based on tumour data from a structural analogue together with substantial support from consideration of other important factors such as formation of common significant metabolites, e.g. for benzidine congener dyes.

3.6.2.2.7. A substance that has not been tested for carcinogenicity may in certain instances be classified in Category 1A, Category 1B or Category 2 based on tumour data from a structural analogue together with substantial support from consideration of other important factors such as formation of common significant metabolites, e.g. for benzidine congener dyes.  

3.6.2.2.8. The classification shall take into consideration whether or not the substance is absorbed by a given route(s); or whether there are only local tumours at the site of administration for the tested route(s), and adequate testing by other major route(s) show lack of carcinogenicity.

3.6.2.2.8. The classification shall take into consideration whether or not the substance is absorbed by a given route(s); or whether there are only local tumours at the site of administration for the tested route(s), and adequate testing by other major route(s) show lack of carcinogenicity.  

3.6.2.2.9. It is important that whatever is known of the physico-chemical, toxicokinetic and toxicodynamic properties of the substances, as well as any available relevant information on chemical analogues, i.e. structure activity relationship, is taken into consideration when undertaking classification.

3.6.2.2.9. It is important that whatever is known of the physico-chemical, toxicokinetic and toxicodynamic properties of the substances, as well as any available relevant information on chemical analogues, i.e. structure activity relationship, is taken into consideration when undertaking classification.  

3.6.3.   Classification criteria for mixtures

Classification criteria for mixtures

3.6.3.1.   Classification of mixtures when data are available for all ingredients or only for some ingredients of the mixture Classification of mixtures when data are available for all ingredients or only for some ingredients of the mixture

3.6.3.1.1. The mixture will be classified as a carcinogen when at least one ingredient has been classified as a Category 1A, Category 1B or Category 2 carcinogen and is present at or above the appropriate generic concentration limit as shown in Table 3.6.2 for Category 1A, Category 1B and Category 2 respectively.

3.6.3.1.1. The mixture will be classified as a carcinogen when at least one ingredient has been classified as a Category 1A, Category 1B or Category 2 carcinogen and is present at or above the appropriate generic concentration limit as shown in Table 3.6.2 for Category 1A, Category 1B and Category 2 respectively.  

▼M4 ▼M4

Table 3.6.2

Generic concentration limits of ingredients of a mixture classified as carcinogen that trigger classification of the mixture

Ingredient classified as:

Generic concentration limits triggering classification of a mixture as:

Category 1 carcinogen

Category 2 carcinogen

Category 1A

Category 1B

Category 1A carcinogen

≥ 0,1 %

—

—

Category 1B carcinogen

—

≥ 0,1 %

—

Category 2 carcinogen

—

—

≥ 1,0 % [Note 1]

Table 3.6.2 Table 3.6.2

Generic concentration limits of ingredients of a mixture classified as carcinogen that trigger classification of the mixture Generic concentration limits of ingredients of a mixture classified as carcinogen that trigger classification of the mixture

Ingredient classified as:

Generic concentration limits triggering classification of a mixture as:

Category 1 carcinogen

Category 2 carcinogen

Category 1A

Category 1B

Category 1A carcinogen

≥ 0,1 %

—

—

Category 1B carcinogen

—

≥ 0,1 %

—

Category 2 carcinogen

—

—

≥ 1,0 % [Note 1]

Ingredient classified as:

Generic concentration limits triggering classification of a mixture as:

Category 1 carcinogen

Category 2 carcinogen

Category 1A

Category 1B

Category 1A carcinogen

≥ 0,1 %

—

—

Category 1B carcinogen

—

≥ 0,1 %

—

Category 2 carcinogen

—

—

≥ 1,0 % [Note 1]

Ingredient classified as:

Generic concentration limits triggering classification of a mixture as:

Ingredient classified as:

Ingredient classified as:

Generic concentration limits triggering classification of a mixture as:

Generic concentration limits triggering classification of a mixture as:

Category 1 carcinogen

Category 2 carcinogen

Category 1 carcinogen

Category 1 carcinogen

Category 2 carcinogen

Category 2 carcinogen

Category 1A

Category 1B

Category 1A

Category 1A

Category 1B

Category 1B

Category 1A carcinogen

≥ 0,1 %

—

—

Category 1A carcinogen

Category 1A carcinogen

≥ 0,1 %

≥ 0,1 %

—

—

—

—

Category 1B carcinogen

—

≥ 0,1 %

—

Category 1B carcinogen

Category 1B carcinogen

—

—

≥ 0,1 %

≥ 0,1 %

—

—

Category 2 carcinogen

—

—

≥ 1,0 % [Note 1]

Category 2 carcinogen

Category 2 carcinogen

—

—

—

—

≥ 1,0 % [Note 1]

≥ 1,0 % [Note 1]

▼B ▼B

Note

The concentration limits in the table above apply to solids and liquids (w/w units) as well as gases (v/v units).

Note 1

If a Category 2 carcinogen is present in the mixture as an ingredient at a concentration ≥ 0,1  % a SDS shall be available for the mixture upon request.

3.6.3.2.   Classification of mixtures when data are available for the complete mixture Classification of mixtures when data are available for the complete mixture

3.6.3.2.1. Classification of mixtures will be based on the available test data for the individual ingredients of the mixture using concentration limits for the ingredients classified as carcinogens. On a case-by-case basis, test data on mixtures may be used for classification when demonstrating effects that have not been established from the evaluation based on the individual ingredients. In such cases, the test results for the mixture as a whole must be shown to be conclusive taking into account dose and other factors such as duration, observations, sensitivity and statistical analysis of carcinogenicity test systems. Adequate documentation supporting the classification shall be retained and made available for review upon request.

3.6.3.2.1. Classification of mixtures will be based on the available test data for the individual ingredients of the mixture using concentration limits for the ingredients classified as carcinogens. On a case-by-case basis, test data on mixtures may be used for classification when demonstrating effects that have not been established from the evaluation based on the individual ingredients. In such cases, the test results for the mixture as a whole must be shown to be conclusive taking into account dose and other factors such as duration, observations, sensitivity and statistical analysis of carcinogenicity test systems. Adequate documentation supporting the classification shall be retained and made available for review upon request.  

3.6.3.3.   Classification of mixtures when data are not available for the complete mixture: bridging principles Classification of mixtures when data are not available for the complete mixture: bridging principles

3.6.3.3.1. Where the mixture itself has not been tested to determine its carcinogenic hazard, but there are sufficient data on the individual ingredients and similar tested mixtures (subject to paragraph 3.6.3.2.1) to adequately characterise the hazards of the mixture, these data shall be used in accordance with the applicable bridging rules set out in section 1.1.3.

3.6.3.3.1. Where the mixture itself has not been tested to determine its carcinogenic hazard, but there are sufficient data on the individual ingredients and similar tested mixtures (subject to paragraph 3.6.3.2.1) to adequately characterise the hazards of the mixture, these data shall be used in accordance with the applicable bridging rules set out in section 1.1.3.  

3.6.4.   Hazard Communication

Hazard Communication

3.6.4.1. Label elements shall be used in accordance with Table 3.6.3, for substances or mixtures meeting the criteria for classification in this hazard class.

3.6.4.1. Label elements shall be used in accordance with Table 3.6.3, for substances or mixtures meeting the criteria for classification in this hazard class.  

▼M4 ▼M4

Table 3.6.3

Label elements for carcinogenicity

Classification

Category 1

(Category 1A, 1B)

Category 2

GHS Pictograms

image

image

Signal Word

Danger

Warning

Hazard Statement

H350: May cause cancer (state route of exposure if it is conclusively proven that no other routes of exposure cause the hazard)

H351: Suspected of causing cancer (state route of exposure if it is conclusively proven that no other routes of exposure cause the hazard)

Precautionary Statement Prevention

P201

P202

P280

P201

P202

P280

Precautionary Statement Response

P308 + P313

P308 + P313

Precautionary Statement Storage

P405

P405

Precautionary Statement Disposal

P501

P501

Table 3.6.3 Table 3.6.3

Label elements for carcinogenicity Label elements for carcinogenicity

Classification

Category 1

(Category 1A, 1B)

Category 2

GHS Pictograms

image

image

Signal Word

Danger

Warning

Hazard Statement

H350: May cause cancer (state route of exposure if it is conclusively proven that no other routes of exposure cause the hazard)

H351: Suspected of causing cancer (state route of exposure if it is conclusively proven that no other routes of exposure cause the hazard)

Precautionary Statement Prevention

P201

P202

P280

P201

P202

P280

Precautionary Statement Response

P308 + P313

P308 + P313

Precautionary Statement Storage

P405

P405

Precautionary Statement Disposal

P501

P501

Classification

Category 1

(Category 1A, 1B)

Category 2

GHS Pictograms

image

image

Signal Word

Danger

Warning

Hazard Statement

H350: May cause cancer (state route of exposure if it is conclusively proven that no other routes of exposure cause the hazard)

H351: Suspected of causing cancer (state route of exposure if it is conclusively proven that no other routes of exposure cause the hazard)

Precautionary Statement Prevention

P201

P202

P280

P201

P202

P280

Precautionary Statement Response

P308 + P313

P308 + P313

Precautionary Statement Storage

P405

P405

Precautionary Statement Disposal

P501

P501

Classification

Category 1

(Category 1A, 1B)

Category 2

Classification

Classification

Category 1

(Category 1A, 1B)

Category 1

(Category 1A, 1B)

Category 2

Category 2

GHS Pictograms

image

image

GHS Pictograms

GHS Pictograms

image

image image

image

image image

Signal Word

Danger

Warning

Signal Word

Signal Word

Danger

Danger

Warning

Warning

Hazard Statement

H350: May cause cancer (state route of exposure if it is conclusively proven that no other routes of exposure cause the hazard)

H351: Suspected of causing cancer (state route of exposure if it is conclusively proven that no other routes of exposure cause the hazard)

Hazard Statement

Hazard Statement

H350: May cause cancer (state route of exposure if it is conclusively proven that no other routes of exposure cause the hazard)

H350: May cause cancer (state route of exposure if it is conclusively proven that no other routes of exposure cause the hazard)

H351: Suspected of causing cancer (state route of exposure if it is conclusively proven that no other routes of exposure cause the hazard)

H351: Suspected of causing cancer (state route of exposure if it is conclusively proven that no other routes of exposure cause the hazard)

Precautionary Statement Prevention

P201

P202

P280

P201

P202

P280

Precautionary Statement Prevention

Precautionary Statement Prevention

P201

P202

P280

P201

P202

P280

P201

P202

P280

P201

P202

P280

Precautionary Statement Response

P308 + P313

P308 + P313

Precautionary Statement Response

Precautionary Statement Response

P308 + P313

P308 + P313

P308 + P313

P308 + P313

Precautionary Statement Storage

P405

P405

Precautionary Statement Storage

Precautionary Statement Storage

P405

P405

P405

P405

Precautionary Statement Disposal

P501

P501

Precautionary Statement Disposal

Precautionary Statement Disposal

P501

P501

P501

P501

▼B ▼B

3.7.   Reproductive toxicity

Reproductive toxicity

3.7.1.   Definitions and general considerations

Definitions and general considerations

▼M19 ▼M19

3.7.1.1. Reproductive toxicity means adverse effects on sexual function and fertility in adult males and females, as well as developmental toxicity in the offspring, occurring after exposure to a substance or mixture. The definitions presented below are adapted from those agreed as working definitions in IPCS/EHC Document No 225, Principles for Evaluating Health Risks to Reproduction Associated with Exposure to Chemicals. For classification purposes, the known induction of genetically based inheritable effects in the offspring is addressed in Germ Cell Mutagenicity (Section 3.5), since in the present classification system it is considered more appropriate to address such effects under the separate hazard class of germ cell mutagenicity.

3.7.1.1. Reproductive toxicity means adverse effects on sexual function and fertility in adult males and females, as well as developmental toxicity in the offspring, occurring after exposure to a substance or mixture. The definitions presented below are adapted from those agreed as working definitions in IPCS/EHC Document No 225, Principles for Evaluating Health Risks to Reproduction Associated with Exposure to Chemicals. For classification purposes, the known induction of genetically based inheritable effects in the offspring is addressed in Germ Cell Mutagenicity (Section 3.5), since in the present classification system it is considered more appropriate to address such effects under the separate hazard class of germ cell mutagenicity.  

In this classification system, reproductive toxicity is subdivided into two main headings:

(a) 

adverse effects on sexual function and fertility;

(a) 
(a) 

adverse effects on sexual function and fertility;

adverse effects on sexual function and fertility;

(b) 

adverse effects on development of the offspring.

(b) 
(b) 

adverse effects on development of the offspring.

adverse effects on development of the offspring.

Some reproductive toxic effects cannot be clearly assigned to either impairment of sexual function and fertility or to developmental toxicity. Nonetheless, substances and mixtures with these effects shall be classified as reproductive toxicants with a general hazard statement.

▼B ▼B

3.7.1.2. For the purpose of classification the hazard class Reproductive Toxicity is differentiated into:

3.7.1.2. For the purpose of classification the hazard class Reproductive Toxicity is differentiated into:  

— 
adverse effects
— 
on sexual function and fertility, or
— 
on development;
— 
— 
adverse effects
— 
on sexual function and fertility, or
— 
on development;
adverse effects
— 
on sexual function and fertility, or
— 
on development;
— 
on sexual function and fertility, or
— 
— 
on sexual function and fertility, or
on sexual function and fertility, or
— 
on development;
— 
— 
on development;
on development;
— 
effects on or via lactation.
— 
— 
effects on or via lactation.
effects on or via lactation.

3.7.1.3.   Adverse effects on sexual function and fertility Adverse effects on sexual function and fertility

Any effect of substances that has the potential to interfere with sexual function and fertility. This includes, but is not limited to, alterations to the female and male reproductive system, adverse effects on onset of puberty, gamete production and transport, reproductive cycle normality, sexual behaviour, fertility, parturition, pregnancy outcomes, premature reproductive senescence, or modifications in other functions that are dependent on the integrity of the reproductive systems.

3.7.1.4.   Adverse effects on development of the offspring Adverse effects on development of the offspring

Developmental toxicity includes, in its widest sense, any effect which interferes with normal development of the conceptus, either before or after birth, and resulting from exposure of either parent prior to conception, or exposure of the developing offspring during prenatal development, or postnatally, to the time of sexual maturation. However, it is considered that classification under the heading of developmental toxicity is primarily intended to provide a hazard warning for pregnant women, and for men and women of reproductive capacity. Therefore, for pragmatic purposes of classification, developmental toxicity essentially means adverse effects induced during pregnancy, or as a result of parental exposure. These effects can be manifested at any point in the life span of the organism. The major manifestations of developmental toxicity include (1) death of the developing organism, (2) structural abnormality, (3) altered growth, and (4) functional deficiency.

3.7.1.5. Adverse effects on or via lactation are also included in reproductive toxicity, but for classification purposes, such effects are treated separately (see Table 3.7.1 (b)). This is because it is desirable to be able to classify substances specifically for an adverse effect on lactation so that a specific hazard warning about this effect can be provided for lactating mothers.

3.7.1.5. Adverse effects on or via lactation are also included in reproductive toxicity, but for classification purposes, such effects are treated separately (see Table 3.7.1 (b)). This is because it is desirable to be able to classify substances specifically for an adverse effect on lactation so that a specific hazard warning about this effect can be provided for lactating mothers.  

3.7.2.   Classification criteria for substances

Classification criteria for substances

3.7.2.1.   Hazard categories Hazard categories

3.7.2.1.1. For the purpose of classification for reproductive toxicity, substances are allocated to one of two categories. Within each category, effects on sexual function and fertility, and on development, are considered separately. In addition, effects on lactation are allocated to a separate hazard category.

3.7.2.1.1. For the purpose of classification for reproductive toxicity, substances are allocated to one of two categories. Within each category, effects on sexual function and fertility, and on development, are considered separately. In addition, effects on lactation are allocated to a separate hazard category.  

Table 3.7.1(a)

Hazard categories for reproductive toxicants

Categories

Criteria

CATEGORY 1

Known or presumed human reproductive toxicant

Substances are classified in Category 1 for reproductive toxicity when they are known to have produced an adverse effect on sexual function and fertility, or on development in humans or when there is evidence from animal studies, possibly supplemented with other information, to provide a strong presumption that the substance has the capacity to interfere with reproduction in humans. The classification of a substance is further distinguished on the basis of whether the evidence for classification is primarily from human data (Category 1A) or from animal data (Category 1B).

Category 1A

Known human reproductive toxicant

The classification of a substance in Category 1A is largely based on evidence from humans.

Category 1B

Presumed human reproductive toxicant

The classification of a substance in Category 1B is largely based on data from animal studies. Such data shall provide clear evidence of an adverse effect on sexual function and fertility or on development in the absence of other toxic effects, or if occurring together with other toxic effects the adverse effect on reproduction is considered not to be a secondary non-specific consequence of other toxic effects. However, when there is mechanistic information that raises doubt about the relevance of the effect for humans, classification in Category 2 may be more appropriate.

CATEGORY 2

Suspected human reproductive toxicant

Substances are classified in Category 2 for reproductive toxicity when there is some evidence from humans or experimental animals, possibly supplemented with other information, of an adverse effect on sexual function and fertility, or on development, and where the evidence is not sufficiently convincing to place the substance in Category 1. If deficiencies in the study make the quality of evidence less convincing, Category 2 could be the more appropriate classification.

Such effects shall have been observed in the absence of other toxic effects, or if occurring together with other toxic effects the adverse effect on reproduction is considered not to be a secondary non-specific consequence of the other toxic effects.

Table 3.7.1(a)

Hazard categories for reproductive toxicants

Categories

Criteria

CATEGORY 1

Known or presumed human reproductive toxicant

Substances are classified in Category 1 for reproductive toxicity when they are known to have produced an adverse effect on sexual function and fertility, or on development in humans or when there is evidence from animal studies, possibly supplemented with other information, to provide a strong presumption that the substance has the capacity to interfere with reproduction in humans. The classification of a substance is further distinguished on the basis of whether the evidence for classification is primarily from human data (Category 1A) or from animal data (Category 1B).

Category 1A

Known human reproductive toxicant

The classification of a substance in Category 1A is largely based on evidence from humans.

Category 1B

Presumed human reproductive toxicant

The classification of a substance in Category 1B is largely based on data from animal studies. Such data shall provide clear evidence of an adverse effect on sexual function and fertility or on development in the absence of other toxic effects, or if occurring together with other toxic effects the adverse effect on reproduction is considered not to be a secondary non-specific consequence of other toxic effects. However, when there is mechanistic information that raises doubt about the relevance of the effect for humans, classification in Category 2 may be more appropriate.

CATEGORY 2

Suspected human reproductive toxicant

Substances are classified in Category 2 for reproductive toxicity when there is some evidence from humans or experimental animals, possibly supplemented with other information, of an adverse effect on sexual function and fertility, or on development, and where the evidence is not sufficiently convincing to place the substance in Category 1. If deficiencies in the study make the quality of evidence less convincing, Category 2 could be the more appropriate classification.

Such effects shall have been observed in the absence of other toxic effects, or if occurring together with other toxic effects the adverse effect on reproduction is considered not to be a secondary non-specific consequence of the other toxic effects.

Categories

Criteria

CATEGORY 1

Known or presumed human reproductive toxicant

Substances are classified in Category 1 for reproductive toxicity when they are known to have produced an adverse effect on sexual function and fertility, or on development in humans or when there is evidence from animal studies, possibly supplemented with other information, to provide a strong presumption that the substance has the capacity to interfere with reproduction in humans. The classification of a substance is further distinguished on the basis of whether the evidence for classification is primarily from human data (Category 1A) or from animal data (Category 1B).

Category 1A

Known human reproductive toxicant

The classification of a substance in Category 1A is largely based on evidence from humans.

Category 1B

Presumed human reproductive toxicant

The classification of a substance in Category 1B is largely based on data from animal studies. Such data shall provide clear evidence of an adverse effect on sexual function and fertility or on development in the absence of other toxic effects, or if occurring together with other toxic effects the adverse effect on reproduction is considered not to be a secondary non-specific consequence of other toxic effects. However, when there is mechanistic information that raises doubt about the relevance of the effect for humans, classification in Category 2 may be more appropriate.

CATEGORY 2

Suspected human reproductive toxicant

Substances are classified in Category 2 for reproductive toxicity when there is some evidence from humans or experimental animals, possibly supplemented with other information, of an adverse effect on sexual function and fertility, or on development, and where the evidence is not sufficiently convincing to place the substance in Category 1. If deficiencies in the study make the quality of evidence less convincing, Category 2 could be the more appropriate classification.

Such effects shall have been observed in the absence of other toxic effects, or if occurring together with other toxic effects the adverse effect on reproduction is considered not to be a secondary non-specific consequence of the other toxic effects.

Categories

Criteria

Categories

Categories

Criteria

Criteria

CATEGORY 1

Known or presumed human reproductive toxicant

Substances are classified in Category 1 for reproductive toxicity when they are known to have produced an adverse effect on sexual function and fertility, or on development in humans or when there is evidence from animal studies, possibly supplemented with other information, to provide a strong presumption that the substance has the capacity to interfere with reproduction in humans. The classification of a substance is further distinguished on the basis of whether the evidence for classification is primarily from human data (Category 1A) or from animal data (Category 1B).

CATEGORY 1

CATEGORY 1

Known or presumed human reproductive toxicant

Substances are classified in Category 1 for reproductive toxicity when they are known to have produced an adverse effect on sexual function and fertility, or on development in humans or when there is evidence from animal studies, possibly supplemented with other information, to provide a strong presumption that the substance has the capacity to interfere with reproduction in humans. The classification of a substance is further distinguished on the basis of whether the evidence for classification is primarily from human data (Category 1A) or from animal data (Category 1B).

Known or presumed human reproductive toxicant

Substances are classified in Category 1 for reproductive toxicity when they are known to have produced an adverse effect on sexual function and fertility, or on development in humans or when there is evidence from animal studies, possibly supplemented with other information, to provide a strong presumption that the substance has the capacity to interfere with reproduction in humans. The classification of a substance is further distinguished on the basis of whether the evidence for classification is primarily from human data (Category 1A) or from animal data (Category 1B).

Category 1A

Known human reproductive toxicant

The classification of a substance in Category 1A is largely based on evidence from humans.

Category 1A

Category 1A

Known human reproductive toxicant

The classification of a substance in Category 1A is largely based on evidence from humans.

Known human reproductive toxicant

The classification of a substance in Category 1A is largely based on evidence from humans.

Category 1B

Presumed human reproductive toxicant

The classification of a substance in Category 1B is largely based on data from animal studies. Such data shall provide clear evidence of an adverse effect on sexual function and fertility or on development in the absence of other toxic effects, or if occurring together with other toxic effects the adverse effect on reproduction is considered not to be a secondary non-specific consequence of other toxic effects. However, when there is mechanistic information that raises doubt about the relevance of the effect for humans, classification in Category 2 may be more appropriate.

Category 1B

Category 1B

Presumed human reproductive toxicant

The classification of a substance in Category 1B is largely based on data from animal studies. Such data shall provide clear evidence of an adverse effect on sexual function and fertility or on development in the absence of other toxic effects, or if occurring together with other toxic effects the adverse effect on reproduction is considered not to be a secondary non-specific consequence of other toxic effects. However, when there is mechanistic information that raises doubt about the relevance of the effect for humans, classification in Category 2 may be more appropriate.

Presumed human reproductive toxicant

The classification of a substance in Category 1B is largely based on data from animal studies. Such data shall provide clear evidence of an adverse effect on sexual function and fertility or on development in the absence of other toxic effects, or if occurring together with other toxic effects the adverse effect on reproduction is considered not to be a secondary non-specific consequence of other toxic effects. However, when there is mechanistic information that raises doubt about the relevance of the effect for humans, classification in Category 2 may be more appropriate.

CATEGORY 2

Suspected human reproductive toxicant

Substances are classified in Category 2 for reproductive toxicity when there is some evidence from humans or experimental animals, possibly supplemented with other information, of an adverse effect on sexual function and fertility, or on development, and where the evidence is not sufficiently convincing to place the substance in Category 1. If deficiencies in the study make the quality of evidence less convincing, Category 2 could be the more appropriate classification.

Such effects shall have been observed in the absence of other toxic effects, or if occurring together with other toxic effects the adverse effect on reproduction is considered not to be a secondary non-specific consequence of the other toxic effects.

CATEGORY 2

CATEGORY 2

Suspected human reproductive toxicant

Substances are classified in Category 2 for reproductive toxicity when there is some evidence from humans or experimental animals, possibly supplemented with other information, of an adverse effect on sexual function and fertility, or on development, and where the evidence is not sufficiently convincing to place the substance in Category 1. If deficiencies in the study make the quality of evidence less convincing, Category 2 could be the more appropriate classification.

Such effects shall have been observed in the absence of other toxic effects, or if occurring together with other toxic effects the adverse effect on reproduction is considered not to be a secondary non-specific consequence of the other toxic effects.

Suspected human reproductive toxicant

Substances are classified in Category 2 for reproductive toxicity when there is some evidence from humans or experimental animals, possibly supplemented with other information, of an adverse effect on sexual function and fertility, or on development, and where the evidence is not sufficiently convincing to place the substance in Category 1. If deficiencies in the study make the quality of evidence less convincing, Category 2 could be the more appropriate classification.

Such effects shall have been observed in the absence of other toxic effects, or if occurring together with other toxic effects the adverse effect on reproduction is considered not to be a secondary non-specific consequence of the other toxic effects.

Table 3.7.1(b)

Hazard category for lactation effects

EFFECTS ON OR VIA LACTATION

Effects on or via lactation are allocated to a separate single category. It is recognised that for many substances there is no information on the potential to cause adverse effects on the offspring via lactation. However, substances which are absorbed by women and have been shown to interfere with lactation, or which may be present (including metabolites) in breast milk in amounts sufficient to cause concern for the health of a breastfed child, shall be classified and labelled to indicate this property hazardous to breastfed babies. This classification can be assigned on the:

(a)  human evidence indicating a hazard to babies during the lactation period; and/or

(b)  results of one or two generation studies in animals which provide clear evidence of adverse effect in the offspring due to transfer in the milk or adverse effect on the quality of the milk; and/or

(c)  absorption, metabolism, distribution and excretion studies that indicate the likelihood that the substance is present in potentially toxic levels in breast milk.

Table 3.7.1(b)

Hazard category for lactation effects

EFFECTS ON OR VIA LACTATION

Effects on or via lactation are allocated to a separate single category. It is recognised that for many substances there is no information on the potential to cause adverse effects on the offspring via lactation. However, substances which are absorbed by women and have been shown to interfere with lactation, or which may be present (including metabolites) in breast milk in amounts sufficient to cause concern for the health of a breastfed child, shall be classified and labelled to indicate this property hazardous to breastfed babies. This classification can be assigned on the:

(a)  human evidence indicating a hazard to babies during the lactation period; and/or

(b)  results of one or two generation studies in animals which provide clear evidence of adverse effect in the offspring due to transfer in the milk or adverse effect on the quality of the milk; and/or

(c)  absorption, metabolism, distribution and excretion studies that indicate the likelihood that the substance is present in potentially toxic levels in breast milk.

EFFECTS ON OR VIA LACTATION

Effects on or via lactation are allocated to a separate single category. It is recognised that for many substances there is no information on the potential to cause adverse effects on the offspring via lactation. However, substances which are absorbed by women and have been shown to interfere with lactation, or which may be present (including metabolites) in breast milk in amounts sufficient to cause concern for the health of a breastfed child, shall be classified and labelled to indicate this property hazardous to breastfed babies. This classification can be assigned on the:

(a)  human evidence indicating a hazard to babies during the lactation period; and/or

(b)  results of one or two generation studies in animals which provide clear evidence of adverse effect in the offspring due to transfer in the milk or adverse effect on the quality of the milk; and/or

(c)  absorption, metabolism, distribution and excretion studies that indicate the likelihood that the substance is present in potentially toxic levels in breast milk.

EFFECTS ON OR VIA LACTATION

EFFECTS ON OR VIA LACTATION

EFFECTS ON OR VIA LACTATION

Effects on or via lactation are allocated to a separate single category. It is recognised that for many substances there is no information on the potential to cause adverse effects on the offspring via lactation. However, substances which are absorbed by women and have been shown to interfere with lactation, or which may be present (including metabolites) in breast milk in amounts sufficient to cause concern for the health of a breastfed child, shall be classified and labelled to indicate this property hazardous to breastfed babies. This classification can be assigned on the:

(a)  human evidence indicating a hazard to babies during the lactation period; and/or

(b)  results of one or two generation studies in animals which provide clear evidence of adverse effect in the offspring due to transfer in the milk or adverse effect on the quality of the milk; and/or

(c)  absorption, metabolism, distribution and excretion studies that indicate the likelihood that the substance is present in potentially toxic levels in breast milk.

Effects on or via lactation are allocated to a separate single category. It is recognised that for many substances there is no information on the potential to cause adverse effects on the offspring via lactation. However, substances which are absorbed by women and have been shown to interfere with lactation, or which may be present (including metabolites) in breast milk in amounts sufficient to cause concern for the health of a breastfed child, shall be classified and labelled to indicate this property hazardous to breastfed babies. This classification can be assigned on the:

(a)  human evidence indicating a hazard to babies during the lactation period; and/or

(b)  results of one or two generation studies in animals which provide clear evidence of adverse effect in the offspring due to transfer in the milk or adverse effect on the quality of the milk; and/or

(c)  absorption, metabolism, distribution and excretion studies that indicate the likelihood that the substance is present in potentially toxic levels in breast milk.

Effects on or via lactation are allocated to a separate single category. It is recognised that for many substances there is no information on the potential to cause adverse effects on the offspring via lactation. However, substances which are absorbed by women and have been shown to interfere with lactation, or which may be present (including metabolites) in breast milk in amounts sufficient to cause concern for the health of a breastfed child, shall be classified and labelled to indicate this property hazardous to breastfed babies. This classification can be assigned on the:

(a)  human evidence indicating a hazard to babies during the lactation period; and/or

(b)  results of one or two generation studies in animals which provide clear evidence of adverse effect in the offspring due to transfer in the milk or adverse effect on the quality of the milk; and/or

(c)  absorption, metabolism, distribution and excretion studies that indicate the likelihood that the substance is present in potentially toxic levels in breast milk.

3.7.2.2.   Basis of classification Basis of classification

3.7.2.2.1. Classification is made on the basis of the appropriate criteria, outlined above, and an assessment of the total weight of evidence (see 1.1.1). Classification as a reproductive toxicant is intended to be used for substances which have an intrinsic, specific property to produce an adverse effect on reproduction and substances shall not be so classified if such an effect is produced solely as a non-specific secondary consequence of other toxic effects.

3.7.2.2.1. Classification is made on the basis of the appropriate criteria, outlined above, and an assessment of the total weight of evidence (see 1.1.1). Classification as a reproductive toxicant is intended to be used for substances which have an intrinsic, specific property to produce an adverse effect on reproduction and substances shall not be so classified if such an effect is produced solely as a non-specific secondary consequence of other toxic effects.  

The classification of a substance is derived from the hazard categories in the following order of precedence: Category 1A, Category 1B, Category 2 and the additional Category for effects on or via lactation. If a substance meets the criteria for classification into both of the main categories (for example Category 1B for effects on sexual function and fertility and also Category 2 for development) then both hazard differentiations shall be communicated by the respective hazard statements. Classification in the additional category for effects on or via lactation will be considered irrespective of a classification into Category 1A, Category 1B or Category 2.

3.7.2.2.2. In the evaluation of toxic effects on the developing offspring, it is important to consider the possible influence of maternal toxicity (see section 3.7.2.4).

3.7.2.2.2. In the evaluation of toxic effects on the developing offspring, it is important to consider the possible influence of maternal toxicity (see section 3.7.2.4).  

3.7.2.2.3. For human evidence to provide the primary basis for a Category 1A classification there must be reliable evidence of an adverse effect on reproduction in humans. Evidence used for classification shall ideally be from well conducted epidemiological studies which include the use of appropriate controls, balanced assessment, and due consideration of bias or confounding factors. Less rigorous data from studies in humans shall be supplemented with adequate data from studies in experimental animals and classification in Category 1B shall be considered.

3.7.2.2.3. For human evidence to provide the primary basis for a Category 1A classification there must be reliable evidence of an adverse effect on reproduction in humans. Evidence used for classification shall ideally be from well conducted epidemiological studies which include the use of appropriate controls, balanced assessment, and due consideration of bias or confounding factors. Less rigorous data from studies in humans shall be supplemented with adequate data from studies in experimental animals and classification in Category 1B shall be considered.  

3.7.2.3.   Weight of evidence Weight of evidence

3.7.2.3.1. Classification as a reproductive toxicant is made on the basis of an assessment of the total weight of evidence, see section 1.1.1. This means that all available information that bears on the determination of reproductive toxicity is considered together, such as epidemiological studies and case reports in humans and specific reproduction studies along with sub-chronic, chronic and special study results in animals that provide relevant information regarding toxicity to reproductive and related endocrine organs. Evaluation of substances chemically related to the substance under study may also be included, particularly when information on the substance is scarce. The weight given to the available evidence will be influenced by factors such as the quality of the studies, consistency of results, nature and severity of effects, the presence of maternal toxicity in experimental animal studies, level of statistical significance for inter-group differences, number of endpoints affected, relevance of route of administration to humans and freedom from bias. Both positive and negative results are assembled together into a weight of evidence determination. A single, positive study performed according to good scientific principles and with statistically or biologically significant positive results may justify classification (see also 3.7.2.2.3).

3.7.2.3.1. Classification as a reproductive toxicant is made on the basis of an assessment of the total weight of evidence, see section 1.1.1. This means that all available information that bears on the determination of reproductive toxicity is considered together, such as epidemiological studies and case reports in humans and specific reproduction studies along with sub-chronic, chronic and special study results in animals that provide relevant information regarding toxicity to reproductive and related endocrine organs. Evaluation of substances chemically related to the substance under study may also be included, particularly when information on the substance is scarce. The weight given to the available evidence will be influenced by factors such as the quality of the studies, consistency of results, nature and severity of effects, the presence of maternal toxicity in experimental animal studies, level of statistical significance for inter-group differences, number of endpoints affected, relevance of route of administration to humans and freedom from bias. Both positive and negative results are assembled together into a weight of evidence determination. A single, positive study performed according to good scientific principles and with statistically or biologically significant positive results may justify classification (see also 3.7.2.2.3).  

3.7.2.3.2. Toxicokinetic studies in animals and humans, site of action and mechanism or mode of action study results may provide relevant information which reduces or increases concerns about the hazard to human health. If it is conclusively demonstrated that the clearly identified mechanism or mode of action has no relevance for humans or when the toxicokinetic differences are so marked that it is certain that the hazardous property will not be expressed in humans then a substance which produces an adverse effect on reproduction in experimental animals should not be classified.

3.7.2.3.2. Toxicokinetic studies in animals and humans, site of action and mechanism or mode of action study results may provide relevant information which reduces or increases concerns about the hazard to human health. If it is conclusively demonstrated that the clearly identified mechanism or mode of action has no relevance for humans or when the toxicokinetic differences are so marked that it is certain that the hazardous property will not be expressed in humans then a substance which produces an adverse effect on reproduction in experimental animals should not be classified.  

3.7.2.3.3. If, in some reproductive toxicity studies in experimental animals the only effects recorded are considered to be of low or minimal toxicological significance, classification may not necessarily be the outcome. These effects include small changes in semen parameters or in the incidence of spontaneous defects in the foetus, small changes in the proportions of common foetal variants such as are observed in skeletal examinations, or in foetal weights, or small differences in postnatal developmental assessments.

3.7.2.3.3. If, in some reproductive toxicity studies in experimental animals the only effects recorded are considered to be of low or minimal toxicological significance, classification may not necessarily be the outcome. These effects include small changes in semen parameters or in the incidence of spontaneous defects in the foetus, small changes in the proportions of common foetal variants such as are observed in skeletal examinations, or in foetal weights, or small differences in postnatal developmental assessments.  

3.7.2.3.4. Data from animal studies ideally shall provide clear evidence of specific reproductive toxicity in the absence of other systemic toxic effects. However, if developmental toxicity occurs together with other toxic effects in the dam, the potential influence of the generalised adverse effects shall be assessed to the extent possible. The preferred approach is to consider adverse effects in the embryo/foetus first, and then evaluate maternal toxicity, along with any other factors which are likely to have influenced these effects, as part of the weight of evidence. In general, developmental effects that are observed at maternally toxic doses shall not be automatically discounted. Discounting developmental effects that are observed at maternally toxic doses can only be done on a case-by-case basis when a causal relationship is established or refuted.

3.7.2.3.4. Data from animal studies ideally shall provide clear evidence of specific reproductive toxicity in the absence of other systemic toxic effects. However, if developmental toxicity occurs together with other toxic effects in the dam, the potential influence of the generalised adverse effects shall be assessed to the extent possible. The preferred approach is to consider adverse effects in the embryo/foetus first, and then evaluate maternal toxicity, along with any other factors which are likely to have influenced these effects, as part of the weight of evidence. In general, developmental effects that are observed at maternally toxic doses shall not be automatically discounted. Discounting developmental effects that are observed at maternally toxic doses can only be done on a case-by-case basis when a causal relationship is established or refuted.  

3.7.2.3.5. If appropriate information is available it is important to try to determine whether developmental toxicity is due to a specific maternally mediated mechanism or to a non-specific secondary mechanism, like maternal stress and the disruption of homeostasis. Generally, the presence of maternal toxicity shall not be used to negate findings of embryo/foetal effects, unless it can be clearly demonstrated that the effects are secondary non-specific effects. This is especially the case when the effects in the offspring are significant, e.g. irreversible effects such as structural malformations. In some situations it can be assumed that reproductive toxicity is due to a secondary consequence of maternal toxicity and discount the effects, if the substance is so toxic that dams fail to thrive and there is severe inanition, they are incapable of nursing pups; or they are prostrate or dying.

3.7.2.3.5. If appropriate information is available it is important to try to determine whether developmental toxicity is due to a specific maternally mediated mechanism or to a non-specific secondary mechanism, like maternal stress and the disruption of homeostasis. Generally, the presence of maternal toxicity shall not be used to negate findings of embryo/foetal effects, unless it can be clearly demonstrated that the effects are secondary non-specific effects. This is especially the case when the effects in the offspring are significant, e.g. irreversible effects such as structural malformations. In some situations it can be assumed that reproductive toxicity is due to a secondary consequence of maternal toxicity and discount the effects, if the substance is so toxic that dams fail to thrive and there is severe inanition, they are incapable of nursing pups; or they are prostrate or dying.  

3.7.2.4.   Maternal toxicity Maternal toxicity

3.7.2.4.1. Development of the offspring throughout gestation and during the early postnatal stages can be influenced by toxic effects in the mother either through non-specific mechanisms related to stress and the disruption of maternal homeostasis, or by specific maternally-mediated mechanisms. In the interpretation of the developmental outcome to decide classification for developmental effects it is important to consider the possible influence of maternal toxicity. This is a complex issue because of uncertainties surrounding the relationship between maternal toxicity and developmental outcome. Expert judgement and a weight of evidence approach, using all available studies, shall be used to determine the degree of influence that shall be attributed to maternal toxicity when interpreting the criteria for classification for developmental effects. The adverse effects in the embryo/foetus shall be first considered, and then maternal toxicity, along with any other factors which are likely to have influenced these effects, as weight of evidence, to help reach a conclusion about classification.

3.7.2.4.1. Development of the offspring throughout gestation and during the early postnatal stages can be influenced by toxic effects in the mother either through non-specific mechanisms related to stress and the disruption of maternal homeostasis, or by specific maternally-mediated mechanisms. In the interpretation of the developmental outcome to decide classification for developmental effects it is important to consider the possible influence of maternal toxicity. This is a complex issue because of uncertainties surrounding the relationship between maternal toxicity and developmental outcome. Expert judgement and a weight of evidence approach, using all available studies, shall be used to determine the degree of influence that shall be attributed to maternal toxicity when interpreting the criteria for classification for developmental effects. The adverse effects in the embryo/foetus shall be first considered, and then maternal toxicity, along with any other factors which are likely to have influenced these effects, as weight of evidence, to help reach a conclusion about classification.  

3.7.2.4.2. Based on pragmatic observation, maternal toxicity may, depending on severity, influence development via non-specific secondary mechanisms, producing effects such as depressed foetal weight, retarded ossification, and possibly resorptions and certain malformations in some strains of certain species. However, the limited number of studies which have investigated the relationship between developmental effects and general maternal toxicity have failed to demonstrate a consistent, reproducible relationship across species. Developmental effects which occur even in the presence of maternal toxicity are considered to be evidence of developmental toxicity, unless it can be unequivocally demonstrated on a case-by-case basis that the developmental effects are secondary to maternal toxicity. Moreover, classification shall be considered where there is a significant toxic effect in the offspring, e.g. irreversible effects such as structural malformations, embryo/foetal lethality, significant post-natal functional deficiencies.

3.7.2.4.2. Based on pragmatic observation, maternal toxicity may, depending on severity, influence development via non-specific secondary mechanisms, producing effects such as depressed foetal weight, retarded ossification, and possibly resorptions and certain malformations in some strains of certain species. However, the limited number of studies which have investigated the relationship between developmental effects and general maternal toxicity have failed to demonstrate a consistent, reproducible relationship across species. Developmental effects which occur even in the presence of maternal toxicity are considered to be evidence of developmental toxicity, unless it can be unequivocally demonstrated on a case-by-case basis that the developmental effects are secondary to maternal toxicity. Moreover, classification shall be considered where there is a significant toxic effect in the offspring, e.g. irreversible effects such as structural malformations, embryo/foetal lethality, significant post-natal functional deficiencies.  

3.7.2.4.3. Classification shall not automatically be discounted for substances that produce developmental toxicity only in association with maternal toxicity, even if a specific maternally-mediated mechanism has been demonstrated. In such a case, classification in Category 2 may be considered more appropriate than Category 1. However, when a substance is so toxic that maternal death or severe inanition results, or the dams are prostrate and incapable of nursing the pups, it is reasonable to assume that developmental toxicity is produced solely as a secondary consequence of maternal toxicity and discount the developmental effects. Classification is not necessarily the outcome in the case of minor developmental changes, when there is only a small reduction in foetal/pup body weight or retardation of ossification when seen in association with maternal toxicity.

3.7.2.4.3. Classification shall not automatically be discounted for substances that produce developmental toxicity only in association with maternal toxicity, even if a specific maternally-mediated mechanism has been demonstrated. In such a case, classification in Category 2 may be considered more appropriate than Category 1. However, when a substance is so toxic that maternal death or severe inanition results, or the dams are prostrate and incapable of nursing the pups, it is reasonable to assume that developmental toxicity is produced solely as a secondary consequence of maternal toxicity and discount the developmental effects. Classification is not necessarily the outcome in the case of minor developmental changes, when there is only a small reduction in foetal/pup body weight or retardation of ossification when seen in association with maternal toxicity.  

3.7.2.4.4. Some of the end points used to assess maternal effects are provided below. Data on these end points, if available, need to be evaluated in light of their statistical or biological significance and dose response relationship.

3.7.2.4.4. Some of the end points used to assess maternal effects are provided below. Data on these end points, if available, need to be evaluated in light of their statistical or biological significance and dose response relationship.  

Maternal mortality:

an increased incidence of mortality among the treated dams over the controls shall be considered evidence of maternal toxicity if the increase occurs in a dose-related manner and can be attributed to the systemic toxicity of the test material. Maternal mortality greater than 10 % is considered excessive and the data for that dose level shall not normally be considered for further evaluation.

Mating index

(no. animals with seminal plugs or sperm/no. mated × 100) ( 18 ) 18 18

Fertility index

(no. animals with implants/no. of matings × 100)

Gestation length

(if allowed to deliver)

Body weight and body weight change:

Consideration of the maternal body weight change and/or adjusted (corrected) maternal body weight shall be included in the evaluation of maternal toxicity whenever such data are available. The calculation of an adjusted (corrected) mean maternal body weight change, which is the difference between the initial and terminal body weight minus the gravid uterine weight (or alternatively, the sum of the weights of the foetuses), may indicate whether the effect is maternal or intrauterine. In rabbits, the body weight gain may not be useful indicators of maternal toxicity because of normal fluctuations in body weight during pregnancy.

Food and water consumption (if relevant):

The observation of a significant decrease in the average food or water consumption in treated dams compared to the control group is useful in evaluating maternal toxicity, particularly when the test material is administered in the diet or drinking water. Changes in food or water consumption need to be evaluated in conjunction with maternal body weights when determining if the effects noted are reflective of maternal toxicity or more simply, unpalatability of the test material in feed or water.

Clinical evaluations (including clinical signs, markers, haematology and clinical chemistry studies):

The observation of increased incidence of significant clinical signs of toxicity in treated dams relative to the control group is useful in evaluating maternal toxicity. If this is to be used as the basis for the assessment of maternal toxicity, the types, incidence, degree and duration of clinical signs shall be reported in the study. Clinical signs of maternal intoxication include: coma, prostration, hyperactivity, loss of righting reflex, ataxia, or laboured breathing.

Post-mortem data:

Increased incidence and/or severity of post-mortem findings may be indicative of maternal toxicity. This can include gross or microscopic pathological findings or organ weight data, including absolute organ weight, organ-to-body weight ratio, or organ-to-brain weight ratio. When supported by findings of adverse histopathological effects in the affected organ(s), the observation of a significant change in the average weight of suspected target organ(s) of treated dams, compared to those in the control group, may be considered evidence of maternal toxicity.

3.7.2.5.   Animal and experimental data Animal and experimental data

▼M19 ▼M19

3.7.2.5.1. A number of internationally accepted test methods are available; these include methods for developmental toxicity testing (e.g. OECD Test Guideline 414) and methods for one or two-generation toxicity testing (e.g. OECD Test Guidelines 415, 416, 443).

3.7.2.5.1. A number of internationally accepted test methods are available; these include methods for developmental toxicity testing (e.g. OECD Test Guideline 414) and methods for one or two-generation toxicity testing (e.g. OECD Test Guidelines 415, 416, 443).  

▼B ▼B

3.7.2.5.2. Results obtained from Screening Tests (e.g. OECD Guidelines 421 — Reproduction/Developmental Toxicity Screening Test, and 422 — Combined Repeated Dose Toxicity Study with Reproduction/Development Toxicity Screening Test) can also be used to justify classification, although it is recognised that the quality of this evidence is less reliable than that obtained through full studies.

3.7.2.5.2. Results obtained from Screening Tests (e.g. OECD Guidelines 421 — Reproduction/Developmental Toxicity Screening Test, and 422 — Combined Repeated Dose Toxicity Study with Reproduction/Development Toxicity Screening Test) can also be used to justify classification, although it is recognised that the quality of this evidence is less reliable than that obtained through full studies.  

3.7.2.5.3. Adverse effects or changes, seen in short- or long-term repeated dose toxicity studies, which are judged likely to impair reproductive function and which occur in the absence of significant generalised toxicity, may be used as a basis for classification, e.g. histopathological changes in the gonads.

3.7.2.5.3. Adverse effects or changes, seen in short- or long-term repeated dose toxicity studies, which are judged likely to impair reproductive function and which occur in the absence of significant generalised toxicity, may be used as a basis for classification, e.g. histopathological changes in the gonads.  

3.7.2.5.4. Evidence from in vitro assays, or non-mammalian tests, and from analogous substances using structure-activity relationship (SAR), can contribute to the procedure for classification. In all cases of this nature, expert judgement must be used to assess the adequacy of the data. Inadequate data shall not be used as a primary support for classification.

3.7.2.5.4. Evidence from in vitro assays, or non-mammalian tests, and from analogous substances using structure-activity relationship (SAR), can contribute to the procedure for classification. In all cases of this nature, expert judgement must be used to assess the adequacy of the data. Inadequate data shall not be used as a primary support for classification.  

3.7.2.5.5. It is preferable that animal studies are conducted using appropriate routes of administration which relate to the potential route of human exposure. However, in practice, reproductive toxicity studies are commonly conducted using the oral route, and such studies will normally be suitable for evaluating the hazardous properties of the substance with respect to reproductive toxicity. However, if it can be conclusively demonstrated that the clearly identified mechanism or mode of action has no relevance for humans or when the toxicokinetic differences are so marked that it is certain that the hazardous property will not be expressed in humans then a substance which produces an adverse effect on reproduction in experimental animals shall not be classified.

3.7.2.5.5. It is preferable that animal studies are conducted using appropriate routes of administration which relate to the potential route of human exposure. However, in practice, reproductive toxicity studies are commonly conducted using the oral route, and such studies will normally be suitable for evaluating the hazardous properties of the substance with respect to reproductive toxicity. However, if it can be conclusively demonstrated that the clearly identified mechanism or mode of action has no relevance for humans or when the toxicokinetic differences are so marked that it is certain that the hazardous property will not be expressed in humans then a substance which produces an adverse effect on reproduction in experimental animals shall not be classified.  

3.7.2.5.6. Studies involving routes of administration such as intravenous or intraperitoneal injection, which result in exposure of the reproductive organs to unrealistically high levels of the test substance, or elicit local damage to the reproductive organs, including irritation, must be interpreted with extreme caution and on their own are not normally the basis for classification.

3.7.2.5.6. Studies involving routes of administration such as intravenous or intraperitoneal injection, which result in exposure of the reproductive organs to unrealistically high levels of the test substance, or elicit local damage to the reproductive organs, including irritation, must be interpreted with extreme caution and on their own are not normally the basis for classification.  

3.7.2.5.7. There is general agreement about the concept of a limit dose, above which the production of an adverse effect is considered to be outside the criteria which lead to classification, but not regarding the inclusion within the criteria of a specific dose as a limit dose. However, some guidelines for test methods, specify a limit dose, others qualify the limit dose with a statement that higher doses may be necessary if anticipated human exposure is sufficiently high that an adequate margin of exposure is not achieved. Also, due to species differences in toxicokinetics, establishing a specific limit dose may not be adequate for situations where humans are more sensitive than the animal model.

3.7.2.5.7. There is general agreement about the concept of a limit dose, above which the production of an adverse effect is considered to be outside the criteria which lead to classification, but not regarding the inclusion within the criteria of a specific dose as a limit dose. However, some guidelines for test methods, specify a limit dose, others qualify the limit dose with a statement that higher doses may be necessary if anticipated human exposure is sufficiently high that an adequate margin of exposure is not achieved. Also, due to species differences in toxicokinetics, establishing a specific limit dose may not be adequate for situations where humans are more sensitive than the animal model.  

3.7.2.5.8. In principle, adverse effects on reproduction seen only at very high dose levels in animal studies (for example doses that induce prostration, severe inappetence, excessive mortality) would not normally lead to classification, unless other information is available, e.g. toxicokinetics information indicating that humans may be more susceptible than animals, to suggest that classification is appropriate. Please also refer to the section on maternal toxicity (3.7.2.4) for further guidance in this area.

3.7.2.5.8. In principle, adverse effects on reproduction seen only at very high dose levels in animal studies (for example doses that induce prostration, severe inappetence, excessive mortality) would not normally lead to classification, unless other information is available, e.g. toxicokinetics information indicating that humans may be more susceptible than animals, to suggest that classification is appropriate. Please also refer to the section on maternal toxicity (3.7.2.4) for further guidance in this area.  

3.7.2.5.9. However, specification of the actual ‘limit dose’ will depend upon the test method that has been employed to provide the test results, e.g. in the OECD Test Guideline for repeated dose toxicity studies by the oral route, an upper dose of 1 000  mg/kg has been recommended as a limit dose, unless expected human response indicates the need for a higher dose level.

3.7.2.5.9. However, specification of the actual ‘limit dose’ will depend upon the test method that has been employed to provide the test results, e.g. in the OECD Test Guideline for repeated dose toxicity studies by the oral route, an upper dose of 1 000  mg/kg has been recommended as a limit dose, unless expected human response indicates the need for a higher dose level.  

3.7.3.   Classification criteria for mixtures

Classification criteria for mixtures

3.7.3.1.   Classification of mixtures when data are available for all ingredients or only for some ingredients of the mixture Classification of mixtures when data are available for all ingredients or only for some ingredients of the mixture

3.7.3.1.1. The mixture shall be classified as a reproductive toxicant when at least one ingredient has been classified as a Category 1A, Category 1B or Category 2 reproductive toxicant and is present at or above the appropriate generic concentration limit as shown in Table 3.7.2 for Category 1A, Category 1B and Category 2 respectively.

3.7.3.1.1. The mixture shall be classified as a reproductive toxicant when at least one ingredient has been classified as a Category 1A, Category 1B or Category 2 reproductive toxicant and is present at or above the appropriate generic concentration limit as shown in Table 3.7.2 for Category 1A, Category 1B and Category 2 respectively.  

3.7.3.1.2. The mixture shall be classified for effects on or via lactation when at least one ingredient has been classified for effects on or via lactation and is present at or above the appropriate generic concentration limit as shown in Table 3.7.2 for the additional category for effects on or via lactation.

3.7.3.1.2. The mixture shall be classified for effects on or via lactation when at least one ingredient has been classified for effects on or via lactation and is present at or above the appropriate generic concentration limit as shown in Table 3.7.2 for the additional category for effects on or via lactation.  

▼M4 ▼M4

Table 3.7.2

Generic concentration limits of ingredients of a mixture classified as reproduction toxicants or for effects on or via lactation that trigger classification of the mixture

Ingredient classified as:

Generic concentration limits triggering classification of a mixture as:

Category 1 reproductive toxicant

Category 2 reproductive toxicant

Additional category for effects on or via lactation

Category 1A

Category 1B

Category 1A reproductive toxicant

≥ 0,3 %

[Note 1]

 

 

 

Category 1B reproductive toxicant

 

≥ 0,3 %

[Note 1]

 

 

Category 2 reproductive toxicant

 

 

≥ 3,0 %

[Note 1]

 

Additional category for effects on or via lactation

 

 

 

≥ 0,3 %

[Note 1]

Note:

The concentration limits in Table 3.7.2 apply to solids and liquids (w/w units) as well as gases (v/v units).

Note 1:

If a Category 1 or Category 2 reproductive toxicant or a substance classified for effects on or via lactation is present in the mixture as an ingredient at a concentration at or above 0,1 %, a SDS shall be available for the mixture upon request.

Table 3.7.2 Table 3.7.2

Generic concentration limits of ingredients of a mixture classified as reproduction toxicants or for effects on or via lactation that trigger classification of the mixture Generic concentration limits of ingredients of a mixture classified as reproduction toxicants or for effects on or via lactation that trigger classification of the mixture

Ingredient classified as:

Generic concentration limits triggering classification of a mixture as:

Category 1 reproductive toxicant

Category 2 reproductive toxicant

Additional category for effects on or via lactation

Category 1A

Category 1B

Category 1A reproductive toxicant

≥ 0,3 %

[Note 1]

 

 

 

Category 1B reproductive toxicant

 

≥ 0,3 %

[Note 1]

 

 

Category 2 reproductive toxicant

 

 

≥ 3,0 %

[Note 1]

 

Additional category for effects on or via lactation

 

 

 

≥ 0,3 %

[Note 1]

Note:

The concentration limits in Table 3.7.2 apply to solids and liquids (w/w units) as well as gases (v/v units).

Note 1:

If a Category 1 or Category 2 reproductive toxicant or a substance classified for effects on or via lactation is present in the mixture as an ingredient at a concentration at or above 0,1 %, a SDS shall be available for the mixture upon request.

Ingredient classified as:

Generic concentration limits triggering classification of a mixture as:

Category 1 reproductive toxicant

Category 2 reproductive toxicant

Additional category for effects on or via lactation

Category 1A

Category 1B

Category 1A reproductive toxicant

≥ 0,3 %

[Note 1]

 

 

 

Category 1B reproductive toxicant

 

≥ 0,3 %

[Note 1]

 

 

Category 2 reproductive toxicant

 

 

≥ 3,0 %

[Note 1]

 

Additional category for effects on or via lactation

 

 

 

≥ 0,3 %

[Note 1]

Note:

The concentration limits in Table 3.7.2 apply to solids and liquids (w/w units) as well as gases (v/v units).

Note 1:

If a Category 1 or Category 2 reproductive toxicant or a substance classified for effects on or via lactation is present in the mixture as an ingredient at a concentration at or above 0,1 %, a SDS shall be available for the mixture upon request.

Ingredient classified as:

Generic concentration limits triggering classification of a mixture as:

Ingredient classified as:

Ingredient classified as:

Generic concentration limits triggering classification of a mixture as:

Generic concentration limits triggering classification of a mixture as:

Category 1 reproductive toxicant

Category 2 reproductive toxicant

Additional category for effects on or via lactation

Category 1 reproductive toxicant

Category 1 reproductive toxicant

Category 2 reproductive toxicant

Category 2 reproductive toxicant

Additional category for effects on or via lactation

Additional category for effects on or via lactation

Category 1A

Category 1B

Category 1A

Category 1A

Category 1B

Category 1B

Category 1A reproductive toxicant

≥ 0,3 %

[Note 1]

 

 

 

Category 1A reproductive toxicant

Category 1A reproductive toxicant

≥ 0,3 %

[Note 1]

≥ 0,3 %

[Note 1]

 

 

 

 

 

 

Category 1B reproductive toxicant

 

≥ 0,3 %

[Note 1]

 

 

Category 1B reproductive toxicant

Category 1B reproductive toxicant

 

 

≥ 0,3 %

[Note 1]

≥ 0,3 %

[Note 1]

 

 

 

 

Category 2 reproductive toxicant

 

 

≥ 3,0 %

[Note 1]

 

Category 2 reproductive toxicant

Category 2 reproductive toxicant

 

 

 

 

≥ 3,0 %

[Note 1]

≥ 3,0 %

[Note 1]

 

 

Additional category for effects on or via lactation

 

 

 

≥ 0,3 %

[Note 1]

Additional category for effects on or via lactation

Additional category for effects on or via lactation

 

 

 

 

 

 

≥ 0,3 %

[Note 1]

≥ 0,3 %

[Note 1]

Note:

The concentration limits in Table 3.7.2 apply to solids and liquids (w/w units) as well as gases (v/v units).

Note 1:

If a Category 1 or Category 2 reproductive toxicant or a substance classified for effects on or via lactation is present in the mixture as an ingredient at a concentration at or above 0,1 %, a SDS shall be available for the mixture upon request.

Note:

The concentration limits in Table 3.7.2 apply to solids and liquids (w/w units) as well as gases (v/v units).

Note 1:

If a Category 1 or Category 2 reproductive toxicant or a substance classified for effects on or via lactation is present in the mixture as an ingredient at a concentration at or above 0,1 %, a SDS shall be available for the mixture upon request.

Note: Note:

The concentration limits in Table 3.7.2 apply to solids and liquids (w/w units) as well as gases (v/v units).

Note 1: Note 1:

If a Category 1 or Category 2 reproductive toxicant or a substance classified for effects on or via lactation is present in the mixture as an ingredient at a concentration at or above 0,1 %, a SDS shall be available for the mixture upon request.

▼B ▼B

3.7.3.2.   Classification of mixtures when data are available for the complete mixture Classification of mixtures when data are available for the complete mixture

3.7.3.2.1. Classification of mixtures will be based on the available test data for the individual ingredients of the mixture using concentration limits for the ingredients of the mixture. On a case-by-case basis, test data on mixtures may be used for classification when demonstrating effects that have not been established from the evaluation based on the individual components. In such cases, the test results for the mixture as a whole must be shown to be conclusive taking into account dose and other factors such as duration, observations, sensitivity and statistical analysis of reproduction test systems. Adequate documentation supporting the classification shall be retained and made available for review upon request.

3.7.3.2.1. Classification of mixtures will be based on the available test data for the individual ingredients of the mixture using concentration limits for the ingredients of the mixture. On a case-by-case basis, test data on mixtures may be used for classification when demonstrating effects that have not been established from the evaluation based on the individual components. In such cases, the test results for the mixture as a whole must be shown to be conclusive taking into account dose and other factors such as duration, observations, sensitivity and statistical analysis of reproduction test systems. Adequate documentation supporting the classification shall be retained and made available for review upon request.  

3.7.3.3.   Classification of mixtures when data are not available for the complete mixture: bridging principles Classification of mixtures when data are not available for the complete mixture: bridging principles

3.7.3.3.1. Subject to paragraph 3.7.3.2.1, where the mixture itself has not been tested to determine its reproductive toxicity, but there are sufficient data on the individual ingredients and similar tested mixtures to adequately characterise the hazards of the mixture, these data shall be used in accordance with the applicable bridging rules set out in section 1.1.3.

3.7.3.3.1. Subject to paragraph 3.7.3.2.1, where the mixture itself has not been tested to determine its reproductive toxicity, but there are sufficient data on the individual ingredients and similar tested mixtures to adequately characterise the hazards of the mixture, these data shall be used in accordance with the applicable bridging rules set out in section 1.1.3.  

3.7.4.   Hazard Communication

Hazard Communication

3.7.4.1. Label elements shall be used for substances or mixtures meeting the criteria for classification in this hazard class in accordance with Table 3.7.3

3.7.4.1. Label elements shall be used for substances or mixtures meeting the criteria for classification in this hazard class in accordance with Table 3.7.3  

▼M4 ▼M4

Table 3.7.3

Label elements for reproductive toxicity

Classification

Category 1

(Category 1A, 1B)

Category 2

Additional category for effects on or via lactation

GHS Pictograms

image

image

No pictogram

Signal Word

Danger

Warning

No signal word

Hazard Statement

H360: May damage fertility or the unborn child (state specific effect if known)(state route of exposure if it is conclusively proven that no other routes of exposure cause the hazard)

H361: Suspected of damaging fertility or the unborn child (state specific effect if known) (state route of exposure if it is conclusively proven that no other routes of exposure cause the hazard)

H362: May cause harm to breast-fed children.

Precautionary Statement Prevention

P201

P202

P280

P201

P202

P280

P201

P260

P263

P264

P270

Precautionary Statement Response

P308 + P313

P308 + P313

P308 + P313

Precautionary Statement Storage

P405

P405

 

Precautionary Statement Disposal

P501

P501

 

Table 3.7.3 Table 3.7.3

Label elements for reproductive toxicity Label elements for reproductive toxicity

Classification

Category 1

(Category 1A, 1B)

Category 2

Additional category for effects on or via lactation

GHS Pictograms

image

image

No pictogram

Signal Word

Danger

Warning

No signal word

Hazard Statement

H360: May damage fertility or the unborn child (state specific effect if known)(state route of exposure if it is conclusively proven that no other routes of exposure cause the hazard)

H361: Suspected of damaging fertility or the unborn child (state specific effect if known) (state route of exposure if it is conclusively proven that no other routes of exposure cause the hazard)

H362: May cause harm to breast-fed children.

Precautionary Statement Prevention

P201

P202

P280

P201

P202

P280

P201

P260

P263

P264

P270

Precautionary Statement Response

P308 + P313

P308 + P313

P308 + P313

Precautionary Statement Storage

P405

P405

 

Precautionary Statement Disposal

P501

P501

 

Classification

Category 1

(Category 1A, 1B)

Category 2

Additional category for effects on or via lactation

GHS Pictograms

image

image

No pictogram

Signal Word

Danger

Warning

No signal word

Hazard Statement

H360: May damage fertility or the unborn child (state specific effect if known)(state route of exposure if it is conclusively proven that no other routes of exposure cause the hazard)

H361: Suspected of damaging fertility or the unborn child (state specific effect if known) (state route of exposure if it is conclusively proven that no other routes of exposure cause the hazard)

H362: May cause harm to breast-fed children.

Precautionary Statement Prevention

P201

P202

P280

P201

P202

P280

P201

P260

P263

P264

P270

Precautionary Statement Response

P308 + P313

P308 + P313

P308 + P313

Precautionary Statement Storage

P405

P405

 

Precautionary Statement Disposal

P501

P501

 

Classification

Category 1

(Category 1A, 1B)

Category 2

Additional category for effects on or via lactation

Classification

Classification

Category 1

(Category 1A, 1B)

Category 1

(Category 1A, 1B)

Category 2

Category 2

Additional category for effects on or via lactation

Additional category for effects on or via lactation

GHS Pictograms

image

image

No pictogram

GHS Pictograms

GHS Pictograms

image

image image

image

image image

No pictogram

No pictogram

Signal Word

Danger

Warning

No signal word

Signal Word

Signal Word

Danger

Danger

Warning

Warning

No signal word

No signal word

Hazard Statement

H360: May damage fertility or the unborn child (state specific effect if known)(state route of exposure if it is conclusively proven that no other routes of exposure cause the hazard)

H361: Suspected of damaging fertility or the unborn child (state specific effect if known) (state route of exposure if it is conclusively proven that no other routes of exposure cause the hazard)

H362: May cause harm to breast-fed children.

Hazard Statement

Hazard Statement

H360: May damage fertility or the unborn child (state specific effect if known)(state route of exposure if it is conclusively proven that no other routes of exposure cause the hazard)

H360: May damage fertility or the unborn child (state specific effect if known)(state route of exposure if it is conclusively proven that no other routes of exposure cause the hazard)

H361: Suspected of damaging fertility or the unborn child (state specific effect if known) (state route of exposure if it is conclusively proven that no other routes of exposure cause the hazard)

H361: Suspected of damaging fertility or the unborn child (state specific effect if known) (state route of exposure if it is conclusively proven that no other routes of exposure cause the hazard)

H362: May cause harm to breast-fed children.

H362: May cause harm to breast-fed children.

Precautionary Statement Prevention

P201

P202

P280

P201

P202

P280

P201

P260

P263

P264

P270

Precautionary Statement Prevention

Precautionary Statement Prevention

P201

P202

P280

P201

P202

P280

P201

P202

P280

P201

P202

P280

P201

P260

P263

P264

P270

P201

P260

P263

P264

P270

Precautionary Statement Response

P308 + P313

P308 + P313

P308 + P313

Precautionary Statement Response

Precautionary Statement Response

P308 + P313

P308 + P313

P308 + P313

P308 + P313

P308 + P313

P308 + P313

Precautionary Statement Storage

P405

P405

 

Precautionary Statement Storage

Precautionary Statement Storage

P405

P405

P405

P405

 

 

Precautionary Statement Disposal

P501

P501

 

Precautionary Statement Disposal

Precautionary Statement Disposal

P501

P501

P501

P501

 

 

▼B ▼B

3.8.   Specific target organ toxicity — single exposure

Specific target organ toxicity — single exposure

3.8.1.   Definitions and general considerations

Definitions and general considerations

▼M19 ▼M19

3.8.1.1. Specific target organ toxicity – single exposure means specific, non-lethal toxic effects on target organs occurring after a single exposure to a substance or mixture. All significant health effects that can impair function, both reversible and irreversible, immediate and/or delayed and not specifically addressed in sections 3.1 to 3.7 and 3.10 are included (see also section 3.8.1.6).

3.8.1.1. Specific target organ toxicity – single exposure means specific, non-lethal toxic effects on target organs occurring after a single exposure to a substance or mixture. All significant health effects that can impair function, both reversible and irreversible, immediate and/or delayed and not specifically addressed in sections 3.1 to 3.7 and 3.10 are included (see also section 3.8.1.6).  

▼B ▼B

3.8.1.2. Classification identifies the substance or mixture as being a specific target organ toxicant and, as such, it may present a potential for adverse health effects in people who are exposed to it.

3.8.1.2. Classification identifies the substance or mixture as being a specific target organ toxicant and, as such, it may present a potential for adverse health effects in people who are exposed to it.  

3.8.1.3. These adverse health effects produced by a single exposure include consistent and identifiable toxic effects in humans, or, in experimental animals, toxicologically significant changes which have affected the function or morphology of a tissue/organ, or have produced serious changes to the biochemistry or haematology of the organism, and these changes are relevant for human health.

3.8.1.3. These adverse health effects produced by a single exposure include consistent and identifiable toxic effects in humans, or, in experimental animals, toxicologically significant changes which have affected the function or morphology of a tissue/organ, or have produced serious changes to the biochemistry or haematology of the organism, and these changes are relevant for human health.  

3.8.1.4. Assessment shall take into consideration not only significant changes in a single organ or biological system but also generalised changes of a less severe nature involving several organs.

3.8.1.4. Assessment shall take into consideration not only significant changes in a single organ or biological system but also generalised changes of a less severe nature involving several organs.  

3.8.1.5. Specific target organ toxicity can occur by any route that is relevant for humans, i.e. principally oral, dermal or inhalation.

3.8.1.5. Specific target organ toxicity can occur by any route that is relevant for humans, i.e. principally oral, dermal or inhalation.  

3.8.1.6. Specific target organ toxicity following a repeated exposure is classified as described in Specific target organ toxicity — Repeated exposure (section 3.9) and is therefore excluded from section 3.8. Other specific toxic effects, listed below, are assessed separately and consequently are not included here:

3.8.1.6. Specific target organ toxicity following a repeated exposure is classified as described in Specific target organ toxicity — Repeated exposure (section 3.9) and is therefore excluded from section 3.8. Other specific toxic effects, listed below, are assessed separately and consequently are not included here:  

(a) 

Acute toxicity (section 3.1);

(a) 
(a) 

Acute toxicity (section 3.1);

Acute toxicity (section 3.1);

(b) 

Skin corrosion/irritation (section 3.2);

(b) 
(b) 

Skin corrosion/irritation (section 3.2);

Skin corrosion/irritation (section 3.2);

(c) 

Serious eye damage/eye irritation (section 3.3);

(c) 
(c) 

Serious eye damage/eye irritation (section 3.3);

Serious eye damage/eye irritation (section 3.3);

(d) 

Respiratory or skin sensitisation (section 3.4);

(d) 
(d) 

Respiratory or skin sensitisation (section 3.4);

Respiratory or skin sensitisation (section 3.4);

(e) 

Germ cell mutagenicity (section 3.5);

(e) 
(e) 

Germ cell mutagenicity (section 3.5);

Germ cell mutagenicity (section 3.5);

(f) 

Carcinogenicity (section 3.6);

(f) 
(f) 

Carcinogenicity (section 3.6);

Carcinogenicity (section 3.6);

(g) 

Reproductive toxicity (section 3.7); and

(g) 
(g) 

Reproductive toxicity (section 3.7); and

Reproductive toxicity (section 3.7); and

(h) 

Aspiration toxicity (section 3.10).

(h) 
(h) 

Aspiration toxicity (section 3.10).

Aspiration toxicity (section 3.10).

3.8.1.7. The hazard class Specific Target Organ Toxicity — Single Exposure is differentiated into:

3.8.1.7. The hazard class Specific Target Organ Toxicity — Single Exposure is differentiated into:  

— 
Specific target organ toxicity — single exposure, Category 1 and 2;
— 
— 
Specific target organ toxicity — single exposure, Category 1 and 2;
Specific target organ toxicity — single exposure, Category 1 and 2;
— 
Specific target organ toxicity — single exposure, Category 3.
— 
— 
Specific target organ toxicity — single exposure, Category 3.
Specific target organ toxicity — single exposure, Category 3.

See Table 3.8.1.

Table 3.8.1

Categories for specific target organ toxicity-single exposure

Categories

Criteria

Category 1

Substances that have produced significant toxicity in humans or that, on the basis of evidence from studies in experimental animals, can be presumed to have the potential to produce significant toxicity in humans following single exposure

Substances are classified in Category 1 for specific target organ toxicity (single exposure) on the basis of:

(a)  reliable and good quality evidence from human cases or epidemiological studies; or

(b)  observations from appropriate studies in experimental animals in which significant and/or severe toxic effects of relevance to human health were produced at generally low exposure concentrations. Guidance dose/concentration values are provided below (see 3.8.2.1.9) to be used as part of weight-of-evidence evaluation.

Category 2

Substances that, on the basis of evidence from studies in experimental animals can be presumed to have the potential to be harmful to human health following single exposure

Substances are classified in Category 2 for specific target organ toxicity (single exposure) on the basis of observations from appropriate studies in experimental animals in which significant toxic effects, of relevance to human health, were produced at generally moderate exposure concentrations. Guidance dose/concentration values are provided below (see 3.8.2.1.9) in order to help in classification.

In exceptional cases, human evidence can also be used to place a substance in Category 2 (see 3.8.2.1.6).

Category 3

Transient target organ effects

This category only includes narcotic effects and respiratory tract irritation. These are target organ effects for which a substance does not meet the criteria to be classified in Categories 1 or 2 indicated above. These are effects which adversely alter human function for a short duration after exposure and from which humans may recover in a reasonable period without leaving significant alteration of structure or function. Substances are classified specifically for these effects as laid down in 3.8.2.2.

Note: Attempts shall be made to determine the primary target organ of toxicity and to classify for that purpose, such as hepatotoxicants, neurotoxicants. The data shall be carefully evaluated and, where possible, secondary effects should not be included (e.g. a hepatotoxicant can produce secondary effects in the nervous or gastro-intestinal systems).

Table 3.8.1

Categories for specific target organ toxicity-single exposure

Categories

Criteria

Category 1

Substances that have produced significant toxicity in humans or that, on the basis of evidence from studies in experimental animals, can be presumed to have the potential to produce significant toxicity in humans following single exposure

Substances are classified in Category 1 for specific target organ toxicity (single exposure) on the basis of:

(a)  reliable and good quality evidence from human cases or epidemiological studies; or

(b)  observations from appropriate studies in experimental animals in which significant and/or severe toxic effects of relevance to human health were produced at generally low exposure concentrations. Guidance dose/concentration values are provided below (see 3.8.2.1.9) to be used as part of weight-of-evidence evaluation.

Category 2

Substances that, on the basis of evidence from studies in experimental animals can be presumed to have the potential to be harmful to human health following single exposure

Substances are classified in Category 2 for specific target organ toxicity (single exposure) on the basis of observations from appropriate studies in experimental animals in which significant toxic effects, of relevance to human health, were produced at generally moderate exposure concentrations. Guidance dose/concentration values are provided below (see 3.8.2.1.9) in order to help in classification.

In exceptional cases, human evidence can also be used to place a substance in Category 2 (see 3.8.2.1.6).

Category 3

Transient target organ effects

This category only includes narcotic effects and respiratory tract irritation. These are target organ effects for which a substance does not meet the criteria to be classified in Categories 1 or 2 indicated above. These are effects which adversely alter human function for a short duration after exposure and from which humans may recover in a reasonable period without leaving significant alteration of structure or function. Substances are classified specifically for these effects as laid down in 3.8.2.2.

Note: Attempts shall be made to determine the primary target organ of toxicity and to classify for that purpose, such as hepatotoxicants, neurotoxicants. The data shall be carefully evaluated and, where possible, secondary effects should not be included (e.g. a hepatotoxicant can produce secondary effects in the nervous or gastro-intestinal systems).

Categories

Criteria

Category 1

Substances that have produced significant toxicity in humans or that, on the basis of evidence from studies in experimental animals, can be presumed to have the potential to produce significant toxicity in humans following single exposure

Substances are classified in Category 1 for specific target organ toxicity (single exposure) on the basis of:

(a)  reliable and good quality evidence from human cases or epidemiological studies; or

(b)  observations from appropriate studies in experimental animals in which significant and/or severe toxic effects of relevance to human health were produced at generally low exposure concentrations. Guidance dose/concentration values are provided below (see 3.8.2.1.9) to be used as part of weight-of-evidence evaluation.

Category 2

Substances that, on the basis of evidence from studies in experimental animals can be presumed to have the potential to be harmful to human health following single exposure

Substances are classified in Category 2 for specific target organ toxicity (single exposure) on the basis of observations from appropriate studies in experimental animals in which significant toxic effects, of relevance to human health, were produced at generally moderate exposure concentrations. Guidance dose/concentration values are provided below (see 3.8.2.1.9) in order to help in classification.

In exceptional cases, human evidence can also be used to place a substance in Category 2 (see 3.8.2.1.6).

Category 3

Transient target organ effects

This category only includes narcotic effects and respiratory tract irritation. These are target organ effects for which a substance does not meet the criteria to be classified in Categories 1 or 2 indicated above. These are effects which adversely alter human function for a short duration after exposure and from which humans may recover in a reasonable period without leaving significant alteration of structure or function. Substances are classified specifically for these effects as laid down in 3.8.2.2.

Note: Attempts shall be made to determine the primary target organ of toxicity and to classify for that purpose, such as hepatotoxicants, neurotoxicants. The data shall be carefully evaluated and, where possible, secondary effects should not be included (e.g. a hepatotoxicant can produce secondary effects in the nervous or gastro-intestinal systems).

Categories

Criteria

Categories

Categories

Criteria

Criteria

Category 1

Substances that have produced significant toxicity in humans or that, on the basis of evidence from studies in experimental animals, can be presumed to have the potential to produce significant toxicity in humans following single exposure

Substances are classified in Category 1 for specific target organ toxicity (single exposure) on the basis of:

(a)  reliable and good quality evidence from human cases or epidemiological studies; or

(b)  observations from appropriate studies in experimental animals in which significant and/or severe toxic effects of relevance to human health were produced at generally low exposure concentrations. Guidance dose/concentration values are provided below (see 3.8.2.1.9) to be used as part of weight-of-evidence evaluation.

Category 1

Category 1

Substances that have produced significant toxicity in humans or that, on the basis of evidence from studies in experimental animals, can be presumed to have the potential to produce significant toxicity in humans following single exposure

Substances are classified in Category 1 for specific target organ toxicity (single exposure) on the basis of:

(a)  reliable and good quality evidence from human cases or epidemiological studies; or

(b)  observations from appropriate studies in experimental animals in which significant and/or severe toxic effects of relevance to human health were produced at generally low exposure concentrations. Guidance dose/concentration values are provided below (see 3.8.2.1.9) to be used as part of weight-of-evidence evaluation.

Substances that have produced significant toxicity in humans or that, on the basis of evidence from studies in experimental animals, can be presumed to have the potential to produce significant toxicity in humans following single exposure

Substances are classified in Category 1 for specific target organ toxicity (single exposure) on the basis of:

(a)  reliable and good quality evidence from human cases or epidemiological studies; or

(b)  observations from appropriate studies in experimental animals in which significant and/or severe toxic effects of relevance to human health were produced at generally low exposure concentrations. Guidance dose/concentration values are provided below (see 3.8.2.1.9) to be used as part of weight-of-evidence evaluation.

Category 2

Substances that, on the basis of evidence from studies in experimental animals can be presumed to have the potential to be harmful to human health following single exposure

Substances are classified in Category 2 for specific target organ toxicity (single exposure) on the basis of observations from appropriate studies in experimental animals in which significant toxic effects, of relevance to human health, were produced at generally moderate exposure concentrations. Guidance dose/concentration values are provided below (see 3.8.2.1.9) in order to help in classification.

In exceptional cases, human evidence can also be used to place a substance in Category 2 (see 3.8.2.1.6).

Category 2

Category 2

Substances that, on the basis of evidence from studies in experimental animals can be presumed to have the potential to be harmful to human health following single exposure

Substances are classified in Category 2 for specific target organ toxicity (single exposure) on the basis of observations from appropriate studies in experimental animals in which significant toxic effects, of relevance to human health, were produced at generally moderate exposure concentrations. Guidance dose/concentration values are provided below (see 3.8.2.1.9) in order to help in classification.

In exceptional cases, human evidence can also be used to place a substance in Category 2 (see 3.8.2.1.6).

Substances that, on the basis of evidence from studies in experimental animals can be presumed to have the potential to be harmful to human health following single exposure

Substances are classified in Category 2 for specific target organ toxicity (single exposure) on the basis of observations from appropriate studies in experimental animals in which significant toxic effects, of relevance to human health, were produced at generally moderate exposure concentrations. Guidance dose/concentration values are provided below (see 3.8.2.1.9) in order to help in classification.

In exceptional cases, human evidence can also be used to place a substance in Category 2 (see 3.8.2.1.6).

Category 3

Transient target organ effects

This category only includes narcotic effects and respiratory tract irritation. These are target organ effects for which a substance does not meet the criteria to be classified in Categories 1 or 2 indicated above. These are effects which adversely alter human function for a short duration after exposure and from which humans may recover in a reasonable period without leaving significant alteration of structure or function. Substances are classified specifically for these effects as laid down in 3.8.2.2.

Category 3

Category 3

Transient target organ effects

This category only includes narcotic effects and respiratory tract irritation. These are target organ effects for which a substance does not meet the criteria to be classified in Categories 1 or 2 indicated above. These are effects which adversely alter human function for a short duration after exposure and from which humans may recover in a reasonable period without leaving significant alteration of structure or function. Substances are classified specifically for these effects as laid down in 3.8.2.2.

Transient target organ effects

This category only includes narcotic effects and respiratory tract irritation. These are target organ effects for which a substance does not meet the criteria to be classified in Categories 1 or 2 indicated above. These are effects which adversely alter human function for a short duration after exposure and from which humans may recover in a reasonable period without leaving significant alteration of structure or function. Substances are classified specifically for these effects as laid down in 3.8.2.2.

Note: Attempts shall be made to determine the primary target organ of toxicity and to classify for that purpose, such as hepatotoxicants, neurotoxicants. The data shall be carefully evaluated and, where possible, secondary effects should not be included (e.g. a hepatotoxicant can produce secondary effects in the nervous or gastro-intestinal systems).

Note: Attempts shall be made to determine the primary target organ of toxicity and to classify for that purpose, such as hepatotoxicants, neurotoxicants. The data shall be carefully evaluated and, where possible, secondary effects should not be included (e.g. a hepatotoxicant can produce secondary effects in the nervous or gastro-intestinal systems).

Note: Attempts shall be made to determine the primary target organ of toxicity and to classify for that purpose, such as hepatotoxicants, neurotoxicants. The data shall be carefully evaluated and, where possible, secondary effects should not be included (e.g. a hepatotoxicant can produce secondary effects in the nervous or gastro-intestinal systems). Note:

3.8.2.   Classification criteria for substances

Classification criteria for substances

3.8.2.1.   Substances of Category 1 and Category 2 Substances of Category 1 and Category 2

3.8.2.1.1. Substances are classified for immediate or delayed effects separately, by the use of expert judgement (see 1.1.1) on the basis of the weight of all evidence available, including the use of recommended guidance values (see 3.8.2.1.9). Substances are then placed in Category 1 or 2, depending upon the nature and severity of the effect(s) observed (Table 3.8.1).

3.8.2.1.1. Substances are classified for immediate or delayed effects separately, by the use of expert judgement (see 1.1.1) on the basis of the weight of all evidence available, including the use of recommended guidance values (see 3.8.2.1.9). Substances are then placed in Category 1 or 2, depending upon the nature and severity of the effect(s) observed (Table 3.8.1).  

3.8.2.1.2. The relevant route or routes of exposure by which the classified substance produces damage shall be identified (see 3.8.1.5).

3.8.2.1.2. The relevant route or routes of exposure by which the classified substance produces damage shall be identified (see 3.8.1.5).  

3.8.2.1.3. Classification is determined by expert judgement (see section 1.1.1), on the basis of the weight of all evidence available including the guidance presented below.

3.8.2.1.3. Classification is determined by expert judgement (see section 1.1.1), on the basis of the weight of all evidence available including the guidance presented below.  

3.8.2.1.4. Weight of evidence of all data (see section 1.1.1), including human incidents, epidemiology, and studies conducted in experimental animals, is used to substantiate specific target organ toxic effects that merit classification.

3.8.2.1.4. Weight of evidence of all data (see section 1.1.1), including human incidents, epidemiology, and studies conducted in experimental animals, is used to substantiate specific target organ toxic effects that merit classification.  

3.8.2.1.5. The information required to evaluate specific target organ toxicity comes either from single exposure in humans, such as: exposure at home, in the workplace or environmentally, or from studies conducted in experimental animals. The standard animal studies in rats or mice that provide this information are acute toxicity studies which can include clinical observations and detailed macroscopic and microscopic examination to enable the toxic effects on target tissues/organs to be identified. Results of acute toxicity studies conducted in other species may also provide relevant information.

3.8.2.1.5. The information required to evaluate specific target organ toxicity comes either from single exposure in humans, such as: exposure at home, in the workplace or environmentally, or from studies conducted in experimental animals. The standard animal studies in rats or mice that provide this information are acute toxicity studies which can include clinical observations and detailed macroscopic and microscopic examination to enable the toxic effects on target tissues/organs to be identified. Results of acute toxicity studies conducted in other species may also provide relevant information.  

3.8.2.1.6. In exceptional cases, based on expert judgement, it is appropriate to place certain substances with human evidence of target organ toxicity in Category 2:

3.8.2.1.6. In exceptional cases, based on expert judgement, it is appropriate to place certain substances with human evidence of target organ toxicity in Category 2:  

(a) 

when the weight of human evidence is not sufficiently convincing to warrant Category 1 classification, and/or

(a) 
(a) 

when the weight of human evidence is not sufficiently convincing to warrant Category 1 classification, and/or

when the weight of human evidence is not sufficiently convincing to warrant Category 1 classification, and/or

(b) 

based on the nature and severity of effects.

(b) 
(b) 

based on the nature and severity of effects.

based on the nature and severity of effects.

Dose/concentration levels in humans shall not be considered in the classification and any available evidence from animal studies shall be consistent with the Category 2 classification. In other words, if there are also animal data available on the substance that warrant Category 1 classification, the substance shall be classified as Category 1.

3.8.2.1.7.    Effects considered to support classification for Category 1 and 2 Effects considered to support classification for Category 1 and 2 Effects considered to support classification for Category 1 and 2

3.8.2.1.7.1. Classification is supported by evidence associating single exposure to the substance with a consistent and identifiable toxic effect.

3.8.2.1.7.1. Classification is supported by evidence associating single exposure to the substance with a consistent and identifiable toxic effect.  

3.8.2.1.7.2. Evidence from human experience/incidents is usually restricted to reports of adverse health consequence, often with uncertainty about exposure conditions, and may not provide the scientific detail that can be obtained from well-conducted studies in experimental animals.

3.8.2.1.7.2. Evidence from human experience/incidents is usually restricted to reports of adverse health consequence, often with uncertainty about exposure conditions, and may not provide the scientific detail that can be obtained from well-conducted studies in experimental animals.  

3.8.2.1.7.3. Evidence from appropriate studies in experimental animals can furnish much more detail, in the form of clinical observations, and macroscopic and microscopic pathological examination, and this can often reveal hazards that may not be life-threatening but could indicate functional impairment. Consequently all available evidence, and relevance to human health, must be taken into consideration in the classification process, including but not limited to the following effects in humans and/or animals:

3.8.2.1.7.3. Evidence from appropriate studies in experimental animals can furnish much more detail, in the form of clinical observations, and macroscopic and microscopic pathological examination, and this can often reveal hazards that may not be life-threatening but could indicate functional impairment. Consequently all available evidence, and relevance to human health, must be taken into consideration in the classification process, including but not limited to the following effects in humans and/or animals:  

(a) 

morbidity resulting from single exposure;

(a) 
(a) 

morbidity resulting from single exposure;

morbidity resulting from single exposure;

(b) 

significant functional changes, more than transient in nature, in the respiratory system, central or peripheral nervous systems, other organs or other organ systems, including signs of central nervous system depression and effects on special senses (such as sight, hearing and sense of smell);

(b) 
(b) 

significant functional changes, more than transient in nature, in the respiratory system, central or peripheral nervous systems, other organs or other organ systems, including signs of central nervous system depression and effects on special senses (such as sight, hearing and sense of smell);

significant functional changes, more than transient in nature, in the respiratory system, central or peripheral nervous systems, other organs or other organ systems, including signs of central nervous system depression and effects on special senses (such as sight, hearing and sense of smell);

(c) 

any consistent and significant adverse change in clinical biochemistry, haematology, or urinalysis parameters;

(c) 
(c) 

any consistent and significant adverse change in clinical biochemistry, haematology, or urinalysis parameters;

any consistent and significant adverse change in clinical biochemistry, haematology, or urinalysis parameters;

(d) 

significant organ damage noted at necropsy and/or subsequently seen or confirmed at microscopic examination;

(d) 
(d) 

significant organ damage noted at necropsy and/or subsequently seen or confirmed at microscopic examination;

significant organ damage noted at necropsy and/or subsequently seen or confirmed at microscopic examination;

(e) 

multi-focal or diffuse necrosis, fibrosis or granuloma formation in vital organs with regenerative capacity;

(e) 
(e) 

multi-focal or diffuse necrosis, fibrosis or granuloma formation in vital organs with regenerative capacity;

multi-focal or diffuse necrosis, fibrosis or granuloma formation in vital organs with regenerative capacity;

(f) 

morphological changes that are potentially reversible but provide clear evidence of marked organ dysfunction;

(f) 
(f) 

morphological changes that are potentially reversible but provide clear evidence of marked organ dysfunction;

morphological changes that are potentially reversible but provide clear evidence of marked organ dysfunction;

(g) 

evidence of appreciable cell death (including cell degeneration and reduced cell number) in vital organs incapable of regeneration.

(g) 
(g) 

evidence of appreciable cell death (including cell degeneration and reduced cell number) in vital organs incapable of regeneration.

evidence of appreciable cell death (including cell degeneration and reduced cell number) in vital organs incapable of regeneration.

3.8.2.1.8.    Effects considered not to support classification for Category 1 and 2 Effects considered not to support classification for Category 1 and 2 Effects considered not to support classification for Category 1 and 2

It is recognised that effects may be seen that does not justify classification. Such effects in humans and/or animals include, but are not limited to:

(a) 

clinical observations or small changes in bodyweight gain, food consumption or water intake that may have some toxicological importance but that do not, by themselves, indicate ‘significant’ toxicity;

(a) 
(a) 

clinical observations or small changes in bodyweight gain, food consumption or water intake that may have some toxicological importance but that do not, by themselves, indicate ‘significant’ toxicity;

clinical observations or small changes in bodyweight gain, food consumption or water intake that may have some toxicological importance but that do not, by themselves, indicate ‘significant’ toxicity;

(b) 

small changes in clinical biochemistry, haematology or urinalysis parameters and/or transient effects, when such changes or effects are of doubtful or minimal toxicological importance;

(b) 
(b) 

small changes in clinical biochemistry, haematology or urinalysis parameters and/or transient effects, when such changes or effects are of doubtful or minimal toxicological importance;

small changes in clinical biochemistry, haematology or urinalysis parameters and/or transient effects, when such changes or effects are of doubtful or minimal toxicological importance;

(c) 

changes in organ weights with no evidence of organ dysfunction;

(c) 
(c) 

changes in organ weights with no evidence of organ dysfunction;

changes in organ weights with no evidence of organ dysfunction;

(d) 

adaptive responses that are not considered toxicologically relevant;

(d) 
(d) 

adaptive responses that are not considered toxicologically relevant;

adaptive responses that are not considered toxicologically relevant;

(e) 

substance-induced species-specific mechanisms of toxicity, i.e. demonstrated with reasonable certainty to be not relevant for human health, shall not justify classification.

(e) 
(e) 

substance-induced species-specific mechanisms of toxicity, i.e. demonstrated with reasonable certainty to be not relevant for human health, shall not justify classification.

substance-induced species-specific mechanisms of toxicity, i.e. demonstrated with reasonable certainty to be not relevant for human health, shall not justify classification.

3.8.2.1.9.    Guidance values to assist with classification based on the results obtained from studies conducted in experimental animals for Category 1 and 2 Guidance values to assist with classification based on the results obtained from studies conducted in experimental animals for Category 1 and 2 Guidance values to assist with classification based on the results obtained from studies conducted in experimental animals for Category 1 and 2

3.8.2.1.9.1. In order to help reach a decision about whether a substance shall be classified or not, and to what degree it shall be classified (Category 1 or Category 2), dose/concentration ‘guidance values’ are provided for consideration of the dose/concentration which has been shown to produce significant health effects. The principal argument for proposing such guidance values is that all substances are potentially toxic and there has to be a reasonable dose/concentration above which a degree of toxic effect is acknowledged.

3.8.2.1.9.1. In order to help reach a decision about whether a substance shall be classified or not, and to what degree it shall be classified (Category 1 or Category 2), dose/concentration ‘guidance values’ are provided for consideration of the dose/concentration which has been shown to produce significant health effects. The principal argument for proposing such guidance values is that all substances are potentially toxic and there has to be a reasonable dose/concentration above which a degree of toxic effect is acknowledged.  

3.8.2.1.9.2. Thus, in animal studies, when significant toxic effects are observed that indicate classification, consideration of the dose/concentration at which these effects were seen, in relation to the suggested guidance values, provides useful information to help assess the need to classify (since the toxic effects are a consequence of the hazardous property(ies) and also the dose/concentration).

3.8.2.1.9.2. Thus, in animal studies, when significant toxic effects are observed that indicate classification, consideration of the dose/concentration at which these effects were seen, in relation to the suggested guidance values, provides useful information to help assess the need to classify (since the toxic effects are a consequence of the hazardous property(ies) and also the dose/concentration).  

3.8.2.1.9.3. The guidance value (C) ranges for single-dose exposure which has produced a significant non-lethal toxic effect are those applicable to acute toxicity testing, as indicated in Table 3.8.2.

3.8.2.1.9.3. The guidance value (C) ranges for single-dose exposure which has produced a significant non-lethal toxic effect are those applicable to acute toxicity testing, as indicated in Table 3.8.2.  

Table 3.8.2

Guidance value ranges for single-dose exposures a

 

Guidance value ranges for:

Route of exposure

Units

Category 1

Category 2

Category 3

Oral (rat)

mg/kg body weight

C ≤ 300

2 000 ≥ C > 300

Guidance values do not apply b

Dermal (rat or rabbit)

mg/kg body weight

C ≤ 1 000

2 000 ≥ C > 1 000

Inhalation (rat) gas

ppmV/4h

C ≤ 2 500

20 000 ≥ C > 2 500

Inhalation (rat) vapour

mg/l/4h

C ≤ 10

20 ≥ C > 10

Inhalation (rat) dust/mist/fume

mg/l/4h

C ≤ 1,0

5,0 ≥ C > 1,0

Table 3.8.2

Guidance value ranges for single-dose exposures a a a

 

Guidance value ranges for:

Route of exposure

Units

Category 1

Category 2

Category 3

Oral (rat)

mg/kg body weight

C ≤ 300

2 000 ≥ C > 300

Guidance values do not apply b

Dermal (rat or rabbit)

mg/kg body weight

C ≤ 1 000

2 000 ≥ C > 1 000

Inhalation (rat) gas

ppmV/4h

C ≤ 2 500

20 000 ≥ C > 2 500

Inhalation (rat) vapour

mg/l/4h

C ≤ 10

20 ≥ C > 10

Inhalation (rat) dust/mist/fume

mg/l/4h

C ≤ 1,0

5,0 ≥ C > 1,0

 

Guidance value ranges for:

Route of exposure

Units

Category 1

Category 2

Category 3

Oral (rat)

mg/kg body weight

C ≤ 300

2 000 ≥ C > 300

Guidance values do not apply b

Dermal (rat or rabbit)

mg/kg body weight

C ≤ 1 000

2 000 ≥ C > 1 000

Inhalation (rat) gas

ppmV/4h

C ≤ 2 500

20 000 ≥ C > 2 500

Inhalation (rat) vapour

mg/l/4h

C ≤ 10

20 ≥ C > 10

Inhalation (rat) dust/mist/fume

mg/l/4h

C ≤ 1,0

5,0 ≥ C > 1,0

 

Guidance value ranges for:

 

 

Guidance value ranges for:

Guidance value ranges for:

Route of exposure

Units

Category 1

Category 2

Category 3

Route of exposure

Route of exposure

Units

Units

Category 1

Category 1

Category 2

Category 2

Category 3

Category 3

Oral (rat)

mg/kg body weight

C ≤ 300

2 000 ≥ C > 300

Guidance values do not apply b

Oral (rat)

Oral (rat)

mg/kg body weight

mg/kg body weight

C ≤ 300

C ≤ 300

2 000 ≥ C > 300

2 000 ≥ C > 300

Guidance values do not apply b

Guidance values do not apply b b b

Dermal (rat or rabbit)

mg/kg body weight

C ≤ 1 000

2 000 ≥ C > 1 000

Dermal (rat or rabbit)

Dermal (rat or rabbit)

mg/kg body weight

mg/kg body weight

C ≤ 1 000

C ≤ 1 000

2 000 ≥ C > 1 000

2 000 ≥ C > 1 000

Inhalation (rat) gas

ppmV/4h

C ≤ 2 500

20 000 ≥ C > 2 500

Inhalation (rat) gas

Inhalation (rat) gas

ppmV/4h

ppmV/4h

C ≤ 2 500

C ≤ 2 500

20 000 ≥ C > 2 500

20 000 ≥ C > 2 500

Inhalation (rat) vapour

mg/l/4h

C ≤ 10

20 ≥ C > 10

Inhalation (rat) vapour

Inhalation (rat) vapour

mg/l/4h

mg/l/4h

C ≤ 10

C ≤ 10

20 ≥ C > 10

20 ≥ C > 10

Inhalation (rat) dust/mist/fume

mg/l/4h

C ≤ 1,0

5,0 ≥ C > 1,0

Inhalation (rat) dust/mist/fume

Inhalation (rat) dust/mist/fume

mg/l/4h

mg/l/4h

C ≤ 1,0

C ≤ 1,0

5,0 ≥ C > 1,0

5,0 ≥ C > 1,0

Note

(a) 

The guidance values and ranges mentioned in Table 3.8.2 are intended only for guidance purposes, i.e. to be used as part of the weight of evidence approach, and to assist with decision about classification. They are not intended as strict demarcation values.

(a) 
(a) 

The guidance values and ranges mentioned in Table 3.8.2 are intended only for guidance purposes, i.e. to be used as part of the weight of evidence approach, and to assist with decision about classification. They are not intended as strict demarcation values.

The guidance values and ranges mentioned in Table 3.8.2 are intended only for guidance purposes, i.e. to be used as part of the weight of evidence approach, and to assist with decision about classification. They are not intended as strict demarcation values.

(b) 

Guidance values are not provided for Category 3 substances since this classification is primarily based on human data. Animal data, if available, shall be included in the weight of evidence evaluation.

(b) 
(b) 

Guidance values are not provided for Category 3 substances since this classification is primarily based on human data. Animal data, if available, shall be included in the weight of evidence evaluation.

Guidance values are not provided for Category 3 substances since this classification is primarily based on human data. Animal data, if available, shall be included in the weight of evidence evaluation.

3.8.2.1.10.    Other considerations Other considerations Other considerations

3.8.2.1.10.1. When a substance is characterised only by use of animal data (typical of new substances, but also true for many existing substances), the classification process includes reference to dose/concentration guidance values as one of the elements that contribute to the weight of evidence approach.

3.8.2.1.10.1. When a substance is characterised only by use of animal data (typical of new substances, but also true for many existing substances), the classification process includes reference to dose/concentration guidance values as one of the elements that contribute to the weight of evidence approach.  

3.8.2.1.10.2. When well-substantiated human data are available showing a specific target organ toxic effect that can be reliably attributed to single exposure to a substance, the substance shall normally be classified. Positive human data, regardless of probable dose, predominates over animal data. Thus, if a substance is unclassified because specific target organ toxicity observed was considered not relevant or significant to humans, if subsequent human incident data become available showing a specific target organ toxic effect, the substance shall be classified.

3.8.2.1.10.2. When well-substantiated human data are available showing a specific target organ toxic effect that can be reliably attributed to single exposure to a substance, the substance shall normally be classified. Positive human data, regardless of probable dose, predominates over animal data. Thus, if a substance is unclassified because specific target organ toxicity observed was considered not relevant or significant to humans, if subsequent human incident data become available showing a specific target organ toxic effect, the substance shall be classified.  

3.8.2.1.10.3. A substance that has not been tested for specific target organ toxicity may, where appropriate, be classified on the basis of data from a validated structure activity relationship and expert judgement-based extrapolation from a structural analogue that has previously been classified together with substantial support from consideration of other important factors such as formation of common significant metabolites.

3.8.2.1.10.3. A substance that has not been tested for specific target organ toxicity may, where appropriate, be classified on the basis of data from a validated structure activity relationship and expert judgement-based extrapolation from a structural analogue that has previously been classified together with substantial support from consideration of other important factors such as formation of common significant metabolites.  

3.8.2.1.10.4. Saturated vapour concentration shall be considered, where appropriate, as an additional element to provide for specific health and safety protection

3.8.2.1.10.4. Saturated vapour concentration shall be considered, where appropriate, as an additional element to provide for specific health and safety protection  

3.8.2.2.   Substances of Category 3: Transient target organ effects Substances of Category 3: Transient target organ effects

3.8.2.2.1.    Criteria for respiratory tract irritation Criteria for respiratory tract irritation Criteria for respiratory tract irritation

The criteria for classifying substances as Category 3 for respiratory tract irritation are:

(a) 

respiratory irritant effects (characterised by localised redness, oedema, pruritis and/or pain) that impair function with symptoms such as cough, pain, choking, and breathing difficulties are included. This evaluation will be based primarily on human data;

(a) 
(a) 

respiratory irritant effects (characterised by localised redness, oedema, pruritis and/or pain) that impair function with symptoms such as cough, pain, choking, and breathing difficulties are included. This evaluation will be based primarily on human data;

respiratory irritant effects (characterised by localised redness, oedema, pruritis and/or pain) that impair function with symptoms such as cough, pain, choking, and breathing difficulties are included. This evaluation will be based primarily on human data;

(b) 

subjective human observations could be supported by objective measurements of clear respiratory tract irritation (RTI) (such as electrophysiological responses, biomarkers of inflammation in nasal or bronchoalveolar lavage fluids);

(b) 
(b) 

subjective human observations could be supported by objective measurements of clear respiratory tract irritation (RTI) (such as electrophysiological responses, biomarkers of inflammation in nasal or bronchoalveolar lavage fluids);

subjective human observations could be supported by objective measurements of clear respiratory tract irritation (RTI) (such as electrophysiological responses, biomarkers of inflammation in nasal or bronchoalveolar lavage fluids);

(c) 

the symptoms observed in humans shall also be typical of those that would be produced in the exposed population rather than being an isolated idiosyncratic reaction or response triggered only in individuals with hypersensitive airways. Ambiguous reports simply of ‘irritation’ shall be excluded as this term is commonly used to describe a wide range of sensations including those such as smell, unpleasant taste, a tickling sensation, and dryness, which are outside the scope of classification for respiratory irritation;

(c) 
(c) 

the symptoms observed in humans shall also be typical of those that would be produced in the exposed population rather than being an isolated idiosyncratic reaction or response triggered only in individuals with hypersensitive airways. Ambiguous reports simply of ‘irritation’ shall be excluded as this term is commonly used to describe a wide range of sensations including those such as smell, unpleasant taste, a tickling sensation, and dryness, which are outside the scope of classification for respiratory irritation;

the symptoms observed in humans shall also be typical of those that would be produced in the exposed population rather than being an isolated idiosyncratic reaction or response triggered only in individuals with hypersensitive airways. Ambiguous reports simply of ‘irritation’ shall be excluded as this term is commonly used to describe a wide range of sensations including those such as smell, unpleasant taste, a tickling sensation, and dryness, which are outside the scope of classification for respiratory irritation;

(d) 

there are currently no validated animal tests that deal specifically with RTI, however, useful information may be obtained from the single and repeated inhalation toxicity tests. For example, animal studies may provide useful information in terms of clinical signs of toxicity (dyspnoea, rhinitis etc) and histopathology (e.g. hyperemia, edema, minimal inflammation, thickened mucous layer) which are reversible and may be reflective of the characteristic clinical symptoms described above. Such animal studies can be used as part of weight of evidence evaluation;

(d) 
(d) 

there are currently no validated animal tests that deal specifically with RTI, however, useful information may be obtained from the single and repeated inhalation toxicity tests. For example, animal studies may provide useful information in terms of clinical signs of toxicity (dyspnoea, rhinitis etc) and histopathology (e.g. hyperemia, edema, minimal inflammation, thickened mucous layer) which are reversible and may be reflective of the characteristic clinical symptoms described above. Such animal studies can be used as part of weight of evidence evaluation;

there are currently no validated animal tests that deal specifically with RTI, however, useful information may be obtained from the single and repeated inhalation toxicity tests. For example, animal studies may provide useful information in terms of clinical signs of toxicity (dyspnoea, rhinitis etc) and histopathology (e.g. hyperemia, edema, minimal inflammation, thickened mucous layer) which are reversible and may be reflective of the characteristic clinical symptoms described above. Such animal studies can be used as part of weight of evidence evaluation;

(e) 

this special classification would occur only when more severe organ effects including in the respiratory system are not observed.

(e) 
(e) 

this special classification would occur only when more severe organ effects including in the respiratory system are not observed.

this special classification would occur only when more severe organ effects including in the respiratory system are not observed.

3.8.2.2.2    Criteria for narcotic effects Criteria for narcotic effects Criteria for narcotic effects

The criteria for classifying substances as Category 3 for narcotic effects are:

(a) 

central nervous system depression including narcotic effects in humans such as drowsiness, narcosis, reduced alertness, loss of reflexes, lack of coordination, and vertigo are included. These effects can also be manifested as severe headache or nausea, and can lead to reduced judgment, dizziness, irritability, fatigue, impaired memory function, deficits in perception and coordination, reaction time, or sleepiness;

(a) 
(a) 

central nervous system depression including narcotic effects in humans such as drowsiness, narcosis, reduced alertness, loss of reflexes, lack of coordination, and vertigo are included. These effects can also be manifested as severe headache or nausea, and can lead to reduced judgment, dizziness, irritability, fatigue, impaired memory function, deficits in perception and coordination, reaction time, or sleepiness;

central nervous system depression including narcotic effects in humans such as drowsiness, narcosis, reduced alertness, loss of reflexes, lack of coordination, and vertigo are included. These effects can also be manifested as severe headache or nausea, and can lead to reduced judgment, dizziness, irritability, fatigue, impaired memory function, deficits in perception and coordination, reaction time, or sleepiness;

(b) 

narcotic effects observed in animal studies may include lethargy, lack of coordination, loss of righting reflex, and ataxia. If these effects are not transient in nature, then they shall be considered to support classification for Category 1 or 2 specific target organ toxicity single exposure.

(b) 
(b) 

narcotic effects observed in animal studies may include lethargy, lack of coordination, loss of righting reflex, and ataxia. If these effects are not transient in nature, then they shall be considered to support classification for Category 1 or 2 specific target organ toxicity single exposure.

narcotic effects observed in animal studies may include lethargy, lack of coordination, loss of righting reflex, and ataxia. If these effects are not transient in nature, then they shall be considered to support classification for Category 1 or 2 specific target organ toxicity single exposure.

3.8.3.   Classification criteria for mixtures

Classification criteria for mixtures

3.8.3.1. Mixtures are classified using the same criteria as for substances, or alternatively as described below. As with substances, mixtures shall be classified for specific target organ toxicity following single exposure.

3.8.3.1. Mixtures are classified using the same criteria as for substances, or alternatively as described below. As with substances, mixtures shall be classified for specific target organ toxicity following single exposure.  

3.8.3.2.   Classification of mixtures when data are available for the complete mixture Classification of mixtures when data are available for the complete mixture

3.8.3.2.1. When reliable and good quality evidence from human experience or appropriate studies in experimental animals, as described in the criteria for substances, is available for the mixture, then the mixture shall be classified by weight of evidence evaluation of these data (see 1.1.1.4). Care shall be exercised in evaluating data on mixtures, that the dose, duration, observation or analysis, do not render the results inconclusive.

3.8.3.2.1. When reliable and good quality evidence from human experience or appropriate studies in experimental animals, as described in the criteria for substances, is available for the mixture, then the mixture shall be classified by weight of evidence evaluation of these data (see 1.1.1.4). Care shall be exercised in evaluating data on mixtures, that the dose, duration, observation or analysis, do not render the results inconclusive.  

3.8.3.3.   Classification of mixtures when data are not available for the complete mixture: bridging principles Classification of mixtures when data are not available for the complete mixture: bridging principles

3.8.3.3.1. Where the mixture itself has not been tested to determine its specific target organ toxicity, but there are sufficient data on the individual ingredients and similar tested mixtures to adequately characterise the hazards of the mixture, these data shall be used in accordance with the bridging principles set out in section 1.1.3.

3.8.3.3.1. Where the mixture itself has not been tested to determine its specific target organ toxicity, but there are sufficient data on the individual ingredients and similar tested mixtures to adequately characterise the hazards of the mixture, these data shall be used in accordance with the bridging principles set out in section 1.1.3.  

3.8.3.4.   Classification of mixtures when data are available for all components or only for some components of the mixture Classification of mixtures when data are available for all components or only for some components of the mixture

▼M19 ▼M19

3.8.3.4.1. Where there is no reliable evidence or test data for the specific mixture itself, and the bridging principles cannot be used to enable classification, then classification of the mixture is based on the classification of the ingredient substances. In this case, the mixture shall be classified as a specific target organ toxicant (specific organ specified), following single exposure, when at least one ingredient has been classified as a Category 1 or Category 2 specific target organ toxicant (single exposure) and is present at or above the appropriate generic concentration limit as mentioned in Table 3.8.3 for Category 1 and 2 respectively.

3.8.3.4.1. Where there is no reliable evidence or test data for the specific mixture itself, and the bridging principles cannot be used to enable classification, then classification of the mixture is based on the classification of the ingredient substances. In this case, the mixture shall be classified as a specific target organ toxicant (specific organ specified), following single exposure, when at least one ingredient has been classified as a Category 1 or Category 2 specific target organ toxicant (single exposure) and is present at or above the appropriate generic concentration limit as mentioned in Table 3.8.3 for Category 1 and 2 respectively.  

▼B ▼B

3.8.3.4.2. These generic concentration limits and consequent classifications shall be applied appropriately to single-dose specific target organ toxicants.

3.8.3.4.2. These generic concentration limits and consequent classifications shall be applied appropriately to single-dose specific target organ toxicants.  

3.8.3.4.3. Mixtures shall be classified for either or both single- and repeated-dose toxicity independently.

3.8.3.4.3. Mixtures shall be classified for either or both single- and repeated-dose toxicity independently.  

Table 3.8.3

Generic concentration limits of ingredients of a mixture classified as a specific target organ toxicant that trigger classification of the mixture as Category 1 or 2

Ingredient classified as:

Generic concentration limits triggering classification of the mixture as:

Category 1

Category 2

Category 1

Specific Target Organ Toxicant

Concentration ≥ 10 %

1,0  % ≤ concentration < 10 %

Category 2

Specific Target Organ Toxicant

 

Concentration ≥ 10 % [(Note 1)]

Table 3.8.3

Generic concentration limits of ingredients of a mixture classified as a specific target organ toxicant that trigger classification of the mixture as Category 1 or 2

Ingredient classified as:

Generic concentration limits triggering classification of the mixture as:

Category 1

Category 2

Category 1

Specific Target Organ Toxicant

Concentration ≥ 10 %

1,0  % ≤ concentration < 10 %

Category 2

Specific Target Organ Toxicant

 

Concentration ≥ 10 % [(Note 1)]

Ingredient classified as:

Generic concentration limits triggering classification of the mixture as:

Category 1

Category 2

Category 1

Specific Target Organ Toxicant

Concentration ≥ 10 %

1,0  % ≤ concentration < 10 %

Category 2

Specific Target Organ Toxicant

 

Concentration ≥ 10 % [(Note 1)]

Ingredient classified as:

Generic concentration limits triggering classification of the mixture as:

Ingredient classified as:

Ingredient classified as:

Generic concentration limits triggering classification of the mixture as:

Generic concentration limits triggering classification of the mixture as:

Category 1

Category 2

Category 1

Category 1

Category 2

Category 2

Category 1

Specific Target Organ Toxicant

Concentration ≥ 10 %

1,0  % ≤ concentration < 10 %

Category 1

Specific Target Organ Toxicant

Category 1

Specific Target Organ Toxicant

Concentration ≥ 10 %

Concentration ≥ 10 %

1,0  % ≤ concentration < 10 %

1,0  % ≤ concentration < 10 %

Category 2

Specific Target Organ Toxicant

 

Concentration ≥ 10 % [(Note 1)]

Category 2

Specific Target Organ Toxicant

Category 2

Specific Target Organ Toxicant

 

 

Concentration ≥ 10 % [(Note 1)]

Concentration ≥ 10 % [(Note 1)]

Note 1

If a Category 2 specific target organ toxicant is present in the mixture as an ingredient at a concentration ≥ 1,0  % a SDS shall be available for the mixture upon request.

3.8.3.4.4. Care shall be exercised when toxicants affecting more than one organ system are combined that the potentiation or synergistic interactions are considered, because certain substances can cause target organ toxicity at < 1 % concentration when other ingredients in the mixture are known to potentiate its toxic effect.

3.8.3.4.4. Care shall be exercised when toxicants affecting more than one organ system are combined that the potentiation or synergistic interactions are considered, because certain substances can cause target organ toxicity at < 1 % concentration when other ingredients in the mixture are known to potentiate its toxic effect.  

3.8.3.4.5. Care shall be exercised when extrapolating toxicity of a mixture that contains Category 3 ingredient(s). A generic concentration limit of 20 % is appropriate; however, it shall be recognised that this concentration limit may be higher or lower depending on the Category 3 ingredient(s) and that some effects such as respiratory tract irritation may not occur below a certain concentration while other effects such as narcotic effects may occur below this 20 % value. Expert judgement shall be exercised. ►M2  Respiratory tract irritation and narcotic effects are to be evaluated separately in accordance with the criteria given in section 3.8.2.2. When conducting classifications for these hazards, the contribution of each component should be considered additive, unless there is evidence that the effects are not additive. ◄

3.8.3.4.5. Care shall be exercised when extrapolating toxicity of a mixture that contains Category 3 ingredient(s). A generic concentration limit of 20 % is appropriate; however, it shall be recognised that this concentration limit may be higher or lower depending on the Category 3 ingredient(s) and that some effects such as respiratory tract irritation may not occur below a certain concentration while other effects such as narcotic effects may occur below this 20 % value. Expert judgement shall be exercised. ►M2  Respiratory tract irritation and narcotic effects are to be evaluated separately in accordance with the criteria given in section 3.8.2.2. When conducting classifications for these hazards, the contribution of each component should be considered additive, unless there is evidence that the effects are not additive. ◄   ►M2 ►M2 ►M2  ◄

▼M19 ▼M19

3.8.3.4.6. In cases where the additivity approach is used for Category 3 ingredients, the ‘relevant ingredients’ of a mixture are those which are present in concentrations ≥ 1 % (w/w for solids, liquids, dusts, mists, and vapours and v/v for gases), unless there is a reason to suspect that an ingredient present at a concentration < 1 % is still relevant when classifying the mixture for respiratory tract irritation or narcotic effects.

3.8.3.4.6. In cases where the additivity approach is used for Category 3 ingredients, the ‘relevant ingredients’ of a mixture are those which are present in concentrations ≥ 1 % (w/w for solids, liquids, dusts, mists, and vapours and v/v for gases), unless there is a reason to suspect that an ingredient present at a concentration < 1 % is still relevant when classifying the mixture for respiratory tract irritation or narcotic effects.  

▼B ▼B

3.8.4.   Hazard Communication

Hazard Communication

3.8.4.1 Label elements shall be used in accordance with Table 3.8.4., for substances or mixtures meeting the criteria for classification in this hazard class.

3.8.4.1 Label elements shall be used in accordance with Table 3.8.4., for substances or mixtures meeting the criteria for classification in this hazard class.  

▼M4 ▼M4

Table 3.8.4

Label elements for specific target organ toxicity after single exposure

Classification

Category 1

Category 2

Category 3

GHS Pictograms

image

image

image

Signal Word

Danger

Warning

Warning

Hazard Statement

H370: Causes damage to organs (or state all organs affected, if known) (state route of exposure if it is conclusively proven that no other routes of exposure cause the hazard)

H371: May cause damage to organs (or state all organs affected, if known) (state route of exposure if it is conclusively proven that no other routes of exposure cause the hazard)

H335: May cause respiratory irritation; or

H336: May cause drowsiness or dizziness

Precautionary Statement Prevention

P260

P264

P270

P260

P264

P270

P261

P271

Precautionary Statement Response

P308 + P311

P321

P308 + P311

P304 + P340

P312

Precautionary Statement Storage

P405

P405

P403 + P233

P405

Precautionary Statement Disposal

P501

P501

P501

Table 3.8.4 Table 3.8.4

Label elements for specific target organ toxicity after single exposure Label elements for specific target organ toxicity after single exposure

Classification

Category 1

Category 2

Category 3

GHS Pictograms

image

image

image

Signal Word

Danger

Warning

Warning

Hazard Statement

H370: Causes damage to organs (or state all organs affected, if known) (state route of exposure if it is conclusively proven that no other routes of exposure cause the hazard)

H371: May cause damage to organs (or state all organs affected, if known) (state route of exposure if it is conclusively proven that no other routes of exposure cause the hazard)

H335: May cause respiratory irritation; or

H336: May cause drowsiness or dizziness

Precautionary Statement Prevention

P260

P264

P270

P260

P264

P270

P261

P271

Precautionary Statement Response

P308 + P311

P321

P308 + P311

P304 + P340

P312

Precautionary Statement Storage

P405

P405

P403 + P233

P405

Precautionary Statement Disposal

P501

P501

P501

Classification

Category 1

Category 2

Category 3

GHS Pictograms

image

image

image

Signal Word

Danger

Warning

Warning

Hazard Statement

H370: Causes damage to organs (or state all organs affected, if known) (state route of exposure if it is conclusively proven that no other routes of exposure cause the hazard)

H371: May cause damage to organs (or state all organs affected, if known) (state route of exposure if it is conclusively proven that no other routes of exposure cause the hazard)

H335: May cause respiratory irritation; or

H336: May cause drowsiness or dizziness

Precautionary Statement Prevention

P260

P264

P270

P260

P264

P270

P261

P271

Precautionary Statement Response

P308 + P311

P321

P308 + P311

P304 + P340

P312

Precautionary Statement Storage

P405

P405

P403 + P233

P405

Precautionary Statement Disposal

P501

P501

P501

Classification

Category 1

Category 2

Category 3

Classification

Classification

Category 1

Category 1

Category 2

Category 2

Category 3

Category 3

GHS Pictograms

image

image

image

GHS Pictograms

GHS Pictograms

image

image image

image

image image

image

image image

Signal Word

Danger

Warning

Warning

Signal Word

Signal Word

Danger

Danger

Warning

Warning

Warning

Warning

Hazard Statement

H370: Causes damage to organs (or state all organs affected, if known) (state route of exposure if it is conclusively proven that no other routes of exposure cause the hazard)

H371: May cause damage to organs (or state all organs affected, if known) (state route of exposure if it is conclusively proven that no other routes of exposure cause the hazard)

H335: May cause respiratory irritation; or

H336: May cause drowsiness or dizziness

Hazard Statement

Hazard Statement

H370: Causes damage to organs (or state all organs affected, if known) (state route of exposure if it is conclusively proven that no other routes of exposure cause the hazard)

H370: Causes damage to organs (or state all organs affected, if known) (state route of exposure if it is conclusively proven that no other routes of exposure cause the hazard)

H371: May cause damage to organs (or state all organs affected, if known) (state route of exposure if it is conclusively proven that no other routes of exposure cause the hazard)

H371: May cause damage to organs (or state all organs affected, if known) (state route of exposure if it is conclusively proven that no other routes of exposure cause the hazard)

H335: May cause respiratory irritation; or

H336: May cause drowsiness or dizziness

H335: May cause respiratory irritation; or

H336: May cause drowsiness or dizziness

Precautionary Statement Prevention

P260

P264

P270

P260

P264

P270

P261

P271

Precautionary Statement Prevention

Precautionary Statement Prevention

P260

P264

P270

P260

P264

P270

P260

P264

P270

P260

P264

P270

P261

P271

P261

P271

Precautionary Statement Response

P308 + P311

P321

P308 + P311

P304 + P340

P312

Precautionary Statement Response

Precautionary Statement Response

P308 + P311

P321

P308 + P311

P321

P308 + P311

P308 + P311

P304 + P340

P312

P304 + P340

P312

Precautionary Statement Storage

P405

P405

P403 + P233

P405

Precautionary Statement Storage

Precautionary Statement Storage

P405

P405

P405

P405

P403 + P233

P405

P403 + P233

P405

Precautionary Statement Disposal

P501

P501

P501

Precautionary Statement Disposal

Precautionary Statement Disposal

P501

P501

P501

P501

P501

P501

▼B ▼B

3.9.   Specific target organ toxicity — repeated exposure

Specific target organ toxicity — repeated exposure

3.9.1.   Definitions and general considerations

Definitions and general considerations

▼M19 ▼M19

3.9.1.1. Specific target organ toxicity-repeated exposure means specific toxic effects on target organs occurring after repeated exposure to a substances or mixture. All significant health effects that can impair function, reversible and irreversible, immediate and/or delayed are included. However, other specific toxic effects that are specifically addressed in sections 3.1 to 3.8 and 3.10 are not included here.

3.9.1.1. Specific target organ toxicity-repeated exposure means specific toxic effects on target organs occurring after repeated exposure to a substances or mixture. All significant health effects that can impair function, reversible and irreversible, immediate and/or delayed are included. However, other specific toxic effects that are specifically addressed in sections 3.1 to 3.8 and 3.10 are not included here.  

▼B ▼B

3.9.1.2. Classification for target organ toxicity (repeated exposure) identifies the substance ►M2  or mixture ◄ as being a specific target organ toxicant and, as such, it may present a potential for adverse health effects in people who are exposed to it.

3.9.1.2. Classification for target organ toxicity (repeated exposure) identifies the substance ►M2  or mixture ◄ as being a specific target organ toxicant and, as such, it may present a potential for adverse health effects in people who are exposed to it.   ►M2 ►M2 ►M2  ◄

3.9.1.3. These adverse health effects include consistent and identifiable toxic effects in humans, or, in experimental animals, toxicologically significant changes which have affected the function or morphology of a tissue/organ, or have produced serious changes to the biochemistry or haematology of the organism and these changes are relevant for human health.

3.9.1.3. These adverse health effects include consistent and identifiable toxic effects in humans, or, in experimental animals, toxicologically significant changes which have affected the function or morphology of a tissue/organ, or have produced serious changes to the biochemistry or haematology of the organism and these changes are relevant for human health.  

3.9.1.4. Assessment shall take into consideration not only significant changes in a single organ or biological system but also generalised changes of a less severe nature involving several organs.

3.9.1.4. Assessment shall take into consideration not only significant changes in a single organ or biological system but also generalised changes of a less severe nature involving several organs.  

3.9.1.5. Specific target organ toxicity can occur by any route that is relevant for humans, i.e. principally oral, dermal or inhalation.

3.9.1.5. Specific target organ toxicity can occur by any route that is relevant for humans, i.e. principally oral, dermal or inhalation.  

3.9.1.6. Non-lethal toxic effects observed after a single-event exposure are classified as described in Specific target organ toxicity — Single exposure (section 3.8) and are therefore excluded from section 3.9.

3.9.1.6. Non-lethal toxic effects observed after a single-event exposure are classified as described in Specific target organ toxicity — Single exposure (section 3.8) and are therefore excluded from section 3.9.  

3.9.2.   Classification criteria for substances

Classification criteria for substances

3.9.2.1. Substances are classified as specific target organ toxicants following repeated exposure by the use of expert judgement (see 1.1.1), on the basis of the weight of all evidence available, including the use of recommended guidance values which take into account the duration of exposure and the dose/concentration which produced the effect(s), (see 3.9.2.9), and are placed in one of two categories, depending upon the nature and severity of the effect(s) observed (Table 3.9.1).

3.9.2.1. Substances are classified as specific target organ toxicants following repeated exposure by the use of expert judgement (see 1.1.1), on the basis of the weight of all evidence available, including the use of recommended guidance values which take into account the duration of exposure and the dose/concentration which produced the effect(s), (see 3.9.2.9), and are placed in one of two categories, depending upon the nature and severity of the effect(s) observed (Table 3.9.1).  

Table 3.9.1

Categories for specific target organ toxicity-repeated exposure

Categories

Criteria

Category 1

Substances that have produced significant toxicity in humans or that, on the basis of evidence from studies in experimental animals, can be presumed to have the potential to produce significant toxicity in humans following repeated exposure.

Substances are classified in Category 1 for target organ toxicity (repeat exposure) on the basis of:

— reliable and good quality evidence from human cases or epidemiological studies; or

— observations from appropriate studies in experimental animals in which significant and/or severe toxic effects, of relevance to human health, were produced at generally low exposure concentrations. Guidance dose/concentration values are provided below (see 3.9.2.9), to be used as part of a weight-of- evidence evaluation.

Category 2

Substances that, on the basis of evidence from studies in experimental animals can be presumed to have the potential to be harmful to human health following repeated exposure.

Substances are classified in category 2 for target organ toxicity (repeat exposure) on the basis of observations from appropriate studies in experimental animals in which significant toxic effects, of relevance to human health, were produced at generally moderate exposure concentrations. Guidance dose/concentration values are provided below (see 3.9.2.9) in order to help in classification.

In exceptional cases human evidence can also be used to place a substance in Category 2 (see 3.9.2.6).

Table 3.9.1

Categories for specific target organ toxicity-repeated exposure

Categories

Criteria

Category 1

Substances that have produced significant toxicity in humans or that, on the basis of evidence from studies in experimental animals, can be presumed to have the potential to produce significant toxicity in humans following repeated exposure.

Substances are classified in Category 1 for target organ toxicity (repeat exposure) on the basis of:

— reliable and good quality evidence from human cases or epidemiological studies; or

— observations from appropriate studies in experimental animals in which significant and/or severe toxic effects, of relevance to human health, were produced at generally low exposure concentrations. Guidance dose/concentration values are provided below (see 3.9.2.9), to be used as part of a weight-of- evidence evaluation.

Category 2

Substances that, on the basis of evidence from studies in experimental animals can be presumed to have the potential to be harmful to human health following repeated exposure.

Substances are classified in category 2 for target organ toxicity (repeat exposure) on the basis of observations from appropriate studies in experimental animals in which significant toxic effects, of relevance to human health, were produced at generally moderate exposure concentrations. Guidance dose/concentration values are provided below (see 3.9.2.9) in order to help in classification.

In exceptional cases human evidence can also be used to place a substance in Category 2 (see 3.9.2.6).

Categories

Criteria

Category 1

Substances that have produced significant toxicity in humans or that, on the basis of evidence from studies in experimental animals, can be presumed to have the potential to produce significant toxicity in humans following repeated exposure.

Substances are classified in Category 1 for target organ toxicity (repeat exposure) on the basis of:

— reliable and good quality evidence from human cases or epidemiological studies; or

— observations from appropriate studies in experimental animals in which significant and/or severe toxic effects, of relevance to human health, were produced at generally low exposure concentrations. Guidance dose/concentration values are provided below (see 3.9.2.9), to be used as part of a weight-of- evidence evaluation.

Category 2

Substances that, on the basis of evidence from studies in experimental animals can be presumed to have the potential to be harmful to human health following repeated exposure.

Substances are classified in category 2 for target organ toxicity (repeat exposure) on the basis of observations from appropriate studies in experimental animals in which significant toxic effects, of relevance to human health, were produced at generally moderate exposure concentrations. Guidance dose/concentration values are provided below (see 3.9.2.9) in order to help in classification.

In exceptional cases human evidence can also be used to place a substance in Category 2 (see 3.9.2.6).

Categories

Criteria

Categories

Categories

Criteria

Criteria

Category 1

Substances that have produced significant toxicity in humans or that, on the basis of evidence from studies in experimental animals, can be presumed to have the potential to produce significant toxicity in humans following repeated exposure.

Substances are classified in Category 1 for target organ toxicity (repeat exposure) on the basis of:

— reliable and good quality evidence from human cases or epidemiological studies; or

— observations from appropriate studies in experimental animals in which significant and/or severe toxic effects, of relevance to human health, were produced at generally low exposure concentrations. Guidance dose/concentration values are provided below (see 3.9.2.9), to be used as part of a weight-of- evidence evaluation.

Category 1

Category 1

Substances that have produced significant toxicity in humans or that, on the basis of evidence from studies in experimental animals, can be presumed to have the potential to produce significant toxicity in humans following repeated exposure.

Substances are classified in Category 1 for target organ toxicity (repeat exposure) on the basis of:

— reliable and good quality evidence from human cases or epidemiological studies; or

— observations from appropriate studies in experimental animals in which significant and/or severe toxic effects, of relevance to human health, were produced at generally low exposure concentrations. Guidance dose/concentration values are provided below (see 3.9.2.9), to be used as part of a weight-of- evidence evaluation.

Substances that have produced significant toxicity in humans or that, on the basis of evidence from studies in experimental animals, can be presumed to have the potential to produce significant toxicity in humans following repeated exposure.

Substances are classified in Category 1 for target organ toxicity (repeat exposure) on the basis of:

— reliable and good quality evidence from human cases or epidemiological studies; or

— reliable and good quality evidence from human cases or epidemiological studies; or

— observations from appropriate studies in experimental animals in which significant and/or severe toxic effects, of relevance to human health, were produced at generally low exposure concentrations. Guidance dose/concentration values are provided below (see 3.9.2.9), to be used as part of a weight-of- evidence evaluation.

— observations from appropriate studies in experimental animals in which significant and/or severe toxic effects, of relevance to human health, were produced at generally low exposure concentrations. Guidance dose/concentration values are provided below (see 3.9.2.9), to be used as part of a weight-of- evidence evaluation.

Category 2

Substances that, on the basis of evidence from studies in experimental animals can be presumed to have the potential to be harmful to human health following repeated exposure.

Substances are classified in category 2 for target organ toxicity (repeat exposure) on the basis of observations from appropriate studies in experimental animals in which significant toxic effects, of relevance to human health, were produced at generally moderate exposure concentrations. Guidance dose/concentration values are provided below (see 3.9.2.9) in order to help in classification.

In exceptional cases human evidence can also be used to place a substance in Category 2 (see 3.9.2.6).

Category 2

Category 2

Substances that, on the basis of evidence from studies in experimental animals can be presumed to have the potential to be harmful to human health following repeated exposure.

Substances are classified in category 2 for target organ toxicity (repeat exposure) on the basis of observations from appropriate studies in experimental animals in which significant toxic effects, of relevance to human health, were produced at generally moderate exposure concentrations. Guidance dose/concentration values are provided below (see 3.9.2.9) in order to help in classification.

In exceptional cases human evidence can also be used to place a substance in Category 2 (see 3.9.2.6).

Substances that, on the basis of evidence from studies in experimental animals can be presumed to have the potential to be harmful to human health following repeated exposure.

Substances are classified in category 2 for target organ toxicity (repeat exposure) on the basis of observations from appropriate studies in experimental animals in which significant toxic effects, of relevance to human health, were produced at generally moderate exposure concentrations. Guidance dose/concentration values are provided below (see 3.9.2.9) in order to help in classification.

In exceptional cases human evidence can also be used to place a substance in Category 2 (see 3.9.2.6).

Note

Attempts shall be made to determine the primary target organ of toxicity and classify for that purpose, such as hepatotoxicants, neurotoxicants. One shall carefully evaluate the data and, where possible, not include secondary effects (a hepatotoxicant can produce secondary effects in the nervous or gastro-intestinal systems).

3.9.2.2. The relevant route or routes of exposure by which the classified substance produces damage shall be identified.

3.9.2.2. The relevant route or routes of exposure by which the classified substance produces damage shall be identified.  

3.9.2.3. Classification is determined by expert judgement (see section 1.1.1), on the basis of the weight of all evidence available including the guidance presented below.

3.9.2.3. Classification is determined by expert judgement (see section 1.1.1), on the basis of the weight of all evidence available including the guidance presented below.  

3.9.2.4. Weight of evidence of all data (see section 1.1.1), including human incidents, epidemiology, and studies conducted in experimental animals, is used to substantiate specific target organ toxic effects that merit classification. This taps the considerable body of industrial toxicology data collected over the years. Evaluation shall be based on all existing data, including peer-reviewed published studies and additional acceptable data.

3.9.2.4. Weight of evidence of all data (see section 1.1.1), including human incidents, epidemiology, and studies conducted in experimental animals, is used to substantiate specific target organ toxic effects that merit classification. This taps the considerable body of industrial toxicology data collected over the years. Evaluation shall be based on all existing data, including peer-reviewed published studies and additional acceptable data.  

3.9.2.5. The information required to evaluate specific target organ toxicity comes either from repeated exposure in humans, such as exposure at home, in the workplace or environmentally, or from studies conducted in experimental animals. The standard animal studies in rats or mice that provide this information are 28 day, 90 day or lifetime studies (up to 2 years) that include haematological, clinicochemical and detailed macroscopic and microscopic examination to enable the toxic effects on target tissues/organs to be identified. Data from repeat dose studies performed in other species shall also be used, if available. Other long-term exposure studies, such as on carcinogenicity, neurotoxicity or reproductive toxicity, may also provide evidence of specific target organ toxicity that could be used in the assessment of classification.

3.9.2.5. The information required to evaluate specific target organ toxicity comes either from repeated exposure in humans, such as exposure at home, in the workplace or environmentally, or from studies conducted in experimental animals. The standard animal studies in rats or mice that provide this information are 28 day, 90 day or lifetime studies (up to 2 years) that include haematological, clinicochemical and detailed macroscopic and microscopic examination to enable the toxic effects on target tissues/organs to be identified. Data from repeat dose studies performed in other species shall also be used, if available. Other long-term exposure studies, such as on carcinogenicity, neurotoxicity or reproductive toxicity, may also provide evidence of specific target organ toxicity that could be used in the assessment of classification.  

3.9.2.6. In exceptional cases, based on expert judgement, it is appropriate to place certain substances with human evidence of specific target organ toxicity in Category 2:

3.9.2.6. In exceptional cases, based on expert judgement, it is appropriate to place certain substances with human evidence of specific target organ toxicity in Category 2:  

(a) 

when the weight of human evidence is not sufficiently convincing to warrant Category 1 classification; and/or

(a) 
(a) 

when the weight of human evidence is not sufficiently convincing to warrant Category 1 classification; and/or

when the weight of human evidence is not sufficiently convincing to warrant Category 1 classification; and/or

(b) 

based on the nature and severity of effects.

(b) 
(b) 

based on the nature and severity of effects.

based on the nature and severity of effects.

Dose/concentration levels in humans shall not be considered in the classification and any available evidence from animal studies shall be consistent with the Category 2 classification. In other words, if there are also animal data available on the substance that warrant Category 1 classification, the substance shall be classified as Category 1.

3.9.2.7.   Effects considered to support classification for specific target organ toxicity following repeated exposure Effects considered to support classification for specific target organ toxicity following repeated exposure

3.9.2.7.1. Reliable evidence associating repeated exposure to the substance with a consistent and identifiable toxic effect demonstrates support for the classification.

3.9.2.7.1. Reliable evidence associating repeated exposure to the substance with a consistent and identifiable toxic effect demonstrates support for the classification.  

3.9.2.7.2. Evidence from human experience/incidents is usually restricted to reports of adverse health consequence, often with uncertainty about exposure conditions, and may not provide the scientific detail that can be obtained from well-conducted studies in experimental animals.

3.9.2.7.2. Evidence from human experience/incidents is usually restricted to reports of adverse health consequence, often with uncertainty about exposure conditions, and may not provide the scientific detail that can be obtained from well-conducted studies in experimental animals.  

3.9.2.7.3. Evidence from appropriate studies in experimental animals can furnish much more detail, in the form of clinical observations, haematology, clinical chemistry, and macroscopic and microscopic pathological examination, and this can often reveal hazards that may not be life-threatening but could indicate functional impairment. Consequently all available evidence, and relevance to human health, shall be taken into consideration in the classification process, including but not limited to the following toxic effects in humans and/or animals:

3.9.2.7.3. Evidence from appropriate studies in experimental animals can furnish much more detail, in the form of clinical observations, haematology, clinical chemistry, and macroscopic and microscopic pathological examination, and this can often reveal hazards that may not be life-threatening but could indicate functional impairment. Consequently all available evidence, and relevance to human health, shall be taken into consideration in the classification process, including but not limited to the following toxic effects in humans and/or animals:  

(a) 

morbidity or death resulting from repeated or long-term exposure. Morbidity or death may result from repeated exposure, even to relatively low doses/concentrations, due to bioaccumulation of the substance or its metabolites, and/or due to the overwhelming of the de-toxification process by repeated exposure to the substance or its metabolites;

(a) 
(a) 

morbidity or death resulting from repeated or long-term exposure. Morbidity or death may result from repeated exposure, even to relatively low doses/concentrations, due to bioaccumulation of the substance or its metabolites, and/or due to the overwhelming of the de-toxification process by repeated exposure to the substance or its metabolites;

morbidity or death resulting from repeated or long-term exposure. Morbidity or death may result from repeated exposure, even to relatively low doses/concentrations, due to bioaccumulation of the substance or its metabolites, and/or due to the overwhelming of the de-toxification process by repeated exposure to the substance or its metabolites;

(b) 

significant functional changes in the central or peripheral nervous systems or other organ systems, including signs of central nervous system depression and effects on special senses (e.g. sight, hearing and sense of smell);

(b) 
(b) 

significant functional changes in the central or peripheral nervous systems or other organ systems, including signs of central nervous system depression and effects on special senses (e.g. sight, hearing and sense of smell);

significant functional changes in the central or peripheral nervous systems or other organ systems, including signs of central nervous system depression and effects on special senses (e.g. sight, hearing and sense of smell);

(c) 

any consistent and significant adverse change in clinical biochemistry, haematology, or urinalysis parameters;

(c) 
(c) 

any consistent and significant adverse change in clinical biochemistry, haematology, or urinalysis parameters;

any consistent and significant adverse change in clinical biochemistry, haematology, or urinalysis parameters;

(d) 

significant organ damage noted at necropsy and/or subsequently seen or confirmed at microscopic examination;

(d) 
(d) 

significant organ damage noted at necropsy and/or subsequently seen or confirmed at microscopic examination;

significant organ damage noted at necropsy and/or subsequently seen or confirmed at microscopic examination;

(e) 

multi-focal or diffuse necrosis, fibrosis or granuloma formation in vital organs with regenerative capacity;

(e) 
(e) 

multi-focal or diffuse necrosis, fibrosis or granuloma formation in vital organs with regenerative capacity;

multi-focal or diffuse necrosis, fibrosis or granuloma formation in vital organs with regenerative capacity;

(f) 

morphological changes that are potentially reversible but provide clear evidence of marked organ dysfunction (e.g., severe fatty change in the liver);

(f) 
(f) 

morphological changes that are potentially reversible but provide clear evidence of marked organ dysfunction (e.g., severe fatty change in the liver);

morphological changes that are potentially reversible but provide clear evidence of marked organ dysfunction (e.g., severe fatty change in the liver);

(g) 

evidence of appreciable cell death (including cell degeneration and reduced cell number) in vital organs incapable of regeneration.

(g) 
(g) 

evidence of appreciable cell death (including cell degeneration and reduced cell number) in vital organs incapable of regeneration.

evidence of appreciable cell death (including cell degeneration and reduced cell number) in vital organs incapable of regeneration.

3.9.2.8.   Effects considered not to support classification for specific target organ toxicity following repeated exposure Effects considered not to support classification for specific target organ toxicity following repeated exposure

3.9.2.8.1. It is recognised that effects may be seen in humans and/or animals that do not justify classification. Such effects include, but are not limited to:

3.9.2.8.1. It is recognised that effects may be seen in humans and/or animals that do not justify classification. Such effects include, but are not limited to:  

(a) 

clinical observations or small changes in bodyweight gain, food consumption or water intake that have toxicological importance but that do not, by themselves, indicate ‘significant’ toxicity;

(a) 
(a) 

clinical observations or small changes in bodyweight gain, food consumption or water intake that have toxicological importance but that do not, by themselves, indicate ‘significant’ toxicity;

clinical observations or small changes in bodyweight gain, food consumption or water intake that have toxicological importance but that do not, by themselves, indicate ‘significant’ toxicity;

(b) 

small changes in clinical biochemistry, haematology or urinalysis parameters and/or transient effects, when such changes or effects are of doubtful or minimal toxicological importance;

(b) 
(b) 

small changes in clinical biochemistry, haematology or urinalysis parameters and/or transient effects, when such changes or effects are of doubtful or minimal toxicological importance;

small changes in clinical biochemistry, haematology or urinalysis parameters and/or transient effects, when such changes or effects are of doubtful or minimal toxicological importance;

(c) 

changes in organ weights with no evidence of organ dysfunction;

(c) 
(c) 

changes in organ weights with no evidence of organ dysfunction;

changes in organ weights with no evidence of organ dysfunction;

(d) 

adaptive responses that are not considered toxicologically relevant;

(d) 
(d) 

adaptive responses that are not considered toxicologically relevant;

adaptive responses that are not considered toxicologically relevant;

(e) 

substance-induced species-specific mechanisms of toxicity, i.e. demonstrated with reasonable certainty to be not relevant for human health, shall not justify classification.

(e) 
(e) 

substance-induced species-specific mechanisms of toxicity, i.e. demonstrated with reasonable certainty to be not relevant for human health, shall not justify classification.

substance-induced species-specific mechanisms of toxicity, i.e. demonstrated with reasonable certainty to be not relevant for human health, shall not justify classification.

3.9.2.9.   Guidance values to assist with classification based on the results obtained from studies conducted in experimental animals Guidance values to assist with classification based on the results obtained from studies conducted in experimental animals

3.9.2.9.1. In studies conducted in experimental animals, reliance on observation of effects alone, without reference to the duration of experimental exposure and dose/concentration, omits a fundamental concept of toxicology, i.e. all substances are potentially toxic, and what determines the toxicity is a function of the dose/concentration and the duration of exposure. In most studies conducted in experimental animals the test guidelines use an upper limit dose value.

3.9.2.9.1. In studies conducted in experimental animals, reliance on observation of effects alone, without reference to the duration of experimental exposure and dose/concentration, omits a fundamental concept of toxicology, i.e. all substances are potentially toxic, and what determines the toxicity is a function of the dose/concentration and the duration of exposure. In most studies conducted in experimental animals the test guidelines use an upper limit dose value.  

3.9.2.9.2. In order to help reach a decision about whether a substance shall be classified or not, and to what degree it shall be classified (Category 1 or Category 2), dose/concentration ‘guidance values’ are provided for consideration of the dose/concentration which has been shown to produce significant health effects. The principal argument for proposing such guidance values is that all substances are potentially toxic and there has to be a reasonable dose/concentration above which a degree of toxic effect is acknowledged. Also, repeated-dose studies conducted in experimental animals are designed to produce toxicity at the highest dose used in order to optimise the test objective and so most studies will reveal some toxic effect at least at this highest dose. What is therefore to be decided is not only what effects have been produced, but also at what dose/concentration they were produced and how relevant is that for humans.

3.9.2.9.2. In order to help reach a decision about whether a substance shall be classified or not, and to what degree it shall be classified (Category 1 or Category 2), dose/concentration ‘guidance values’ are provided for consideration of the dose/concentration which has been shown to produce significant health effects. The principal argument for proposing such guidance values is that all substances are potentially toxic and there has to be a reasonable dose/concentration above which a degree of toxic effect is acknowledged. Also, repeated-dose studies conducted in experimental animals are designed to produce toxicity at the highest dose used in order to optimise the test objective and so most studies will reveal some toxic effect at least at this highest dose. What is therefore to be decided is not only what effects have been produced, but also at what dose/concentration they were produced and how relevant is that for humans.  

3.9.2.9.3. Thus, in animal studies, when significant toxic effects are observed that indicate classification, consideration of the duration of experimental exposure and the dose/concentration at which these effects were seen, in relation to the suggested guidance values, can provide useful information to help assess the need to classify (since the toxic effects are a consequence of the hazardous property(ies) and also the duration of exposure and the dose/concentration).

3.9.2.9.3. Thus, in animal studies, when significant toxic effects are observed that indicate classification, consideration of the duration of experimental exposure and the dose/concentration at which these effects were seen, in relation to the suggested guidance values, can provide useful information to help assess the need to classify (since the toxic effects are a consequence of the hazardous property(ies) and also the duration of exposure and the dose/concentration).  

3.9.2.9.4. The decision to classify at all can be influenced by reference to the dose/concentration guidance values at or below which a significant toxic effect has been observed.

3.9.2.9.4. The decision to classify at all can be influenced by reference to the dose/concentration guidance values at or below which a significant toxic effect has been observed.  

3.9.2.9.5. The guidance values refer to effects seen in a standard 90-day toxicity study conducted in rats. They can be used as a basis to extrapolate equivalent guidance values for toxicity studies of greater or lesser duration, using dose/exposure time extrapolation similar to Haber's rule for inhalation, which states essentially that the effective dose is directly proportional to the exposure concentration and the duration of exposure. The assessment shall be done on a case-by-case basis; for a 28-day study the guidance values below is increased by a factor of three.

3.9.2.9.5. The guidance values refer to effects seen in a standard 90-day toxicity study conducted in rats. They can be used as a basis to extrapolate equivalent guidance values for toxicity studies of greater or lesser duration, using dose/exposure time extrapolation similar to Haber's rule for inhalation, which states essentially that the effective dose is directly proportional to the exposure concentration and the duration of exposure. The assessment shall be done on a case-by-case basis; for a 28-day study the guidance values below is increased by a factor of three.  

3.9.2.9.6. Thus classification in Category 1 is applicable, when significant toxic effects observed in a 90-day repeated-dose study conducted in experimental animals are seen to occur at or below the guidance values (C) as indicated in Table 3.9.2:

3.9.2.9.6. Thus classification in Category 1 is applicable, when significant toxic effects observed in a 90-day repeated-dose study conducted in experimental animals are seen to occur at or below the guidance values (C) as indicated in Table 3.9.2:  

Table 3.9.2

Guidance values to assist in Category 1 classification

Route of exposure

Units

Guidance values (dose/concentration)

Oral (rat)

mg/kg body weight/day

C ≤ 10

Dermal (rat or rabbit)

mg/kg body weight/day

C ≤ 20

Inhalation (rat)gas

ppmV/6h/day

C ≤ 50

Inhalation (rat)vapour

mg/litre/6h/day

C ≤ 0,2

Inhalation (rat) dust/mist/fume

mg/litre/6h/day

C ≤ 0,02

Table 3.9.2

Guidance values to assist in Category 1 classification

Route of exposure

Units

Guidance values (dose/concentration)

Oral (rat)

mg/kg body weight/day

C ≤ 10

Dermal (rat or rabbit)

mg/kg body weight/day

C ≤ 20

Inhalation (rat)gas

ppmV/6h/day

C ≤ 50

Inhalation (rat)vapour

mg/litre/6h/day

C ≤ 0,2

Inhalation (rat) dust/mist/fume

mg/litre/6h/day

C ≤ 0,02

Route of exposure

Units

Guidance values (dose/concentration)

Oral (rat)

mg/kg body weight/day

C ≤ 10

Dermal (rat or rabbit)

mg/kg body weight/day

C ≤ 20

Inhalation (rat)gas

ppmV/6h/day

C ≤ 50

Inhalation (rat)vapour

mg/litre/6h/day

C ≤ 0,2

Inhalation (rat) dust/mist/fume

mg/litre/6h/day

C ≤ 0,02

Route of exposure

Units

Guidance values (dose/concentration)

Route of exposure

Route of exposure

Units

Units

Guidance values (dose/concentration)

Guidance values (dose/concentration)

Oral (rat)

mg/kg body weight/day

C ≤ 10

Oral (rat)

Oral (rat)

mg/kg body weight/day

mg/kg body weight/day

C ≤ 10

C ≤ 10

Dermal (rat or rabbit)

mg/kg body weight/day

C ≤ 20

Dermal (rat or rabbit)

Dermal (rat or rabbit)

mg/kg body weight/day

mg/kg body weight/day

C ≤ 20

C ≤ 20

Inhalation (rat)gas

ppmV/6h/day

C ≤ 50

Inhalation (rat)gas

Inhalation (rat)gas

ppmV/6h/day

ppmV/6h/day

C ≤ 50

C ≤ 50

Inhalation (rat)vapour

mg/litre/6h/day

C ≤ 0,2

Inhalation (rat)vapour

Inhalation (rat)vapour

mg/litre/6h/day

mg/litre/6h/day

C ≤ 0,2

C ≤ 0,2

Inhalation (rat) dust/mist/fume

mg/litre/6h/day

C ≤ 0,02

Inhalation (rat) dust/mist/fume

Inhalation (rat) dust/mist/fume

mg/litre/6h/day

mg/litre/6h/day

C ≤ 0,02

C ≤ 0,02

3.9.2.9.7. Classification in Category 2 is applicable, when significant toxic effects observed in a 90-day repeated-dose study conducted in experimental animals are seen to occur within the guidance value ranges as indicated in Table 3.9.3:

3.9.2.9.7. Classification in Category 2 is applicable, when significant toxic effects observed in a 90-day repeated-dose study conducted in experimental animals are seen to occur within the guidance value ranges as indicated in Table 3.9.3:  

Table 3.9.3

Guidance values to assist in Category 2 classification

Route of Exposure

Units

Guidance Value Ranges:

(dose/concentration)

Oral (rat)

mg/kg body weight/day

10 < C ≤ 100

Dermal (rat or rabbit)

mg/kg body weight/day

20 < C ≤ 200

Inhalation (rat) gas

ppmV/6h/day

50 < C ≤ 250

Inhalation (rat)vapour

mg/litre/6h/day

0,2 < C ≤ 1,0

Inhalation (rat) dust/mist/fume

mg/litre/6h/day

0,02 < C ≤ 0,2

Table 3.9.3

Guidance values to assist in Category 2 classification

Route of Exposure

Units

Guidance Value Ranges:

(dose/concentration)

Oral (rat)

mg/kg body weight/day

10 < C ≤ 100

Dermal (rat or rabbit)

mg/kg body weight/day

20 < C ≤ 200

Inhalation (rat) gas

ppmV/6h/day

50 < C ≤ 250

Inhalation (rat)vapour

mg/litre/6h/day

0,2 < C ≤ 1,0

Inhalation (rat) dust/mist/fume

mg/litre/6h/day

0,02 < C ≤ 0,2

Route of Exposure

Units

Guidance Value Ranges:

(dose/concentration)

Oral (rat)

mg/kg body weight/day

10 < C ≤ 100

Dermal (rat or rabbit)

mg/kg body weight/day

20 < C ≤ 200

Inhalation (rat) gas

ppmV/6h/day

50 < C ≤ 250

Inhalation (rat)vapour

mg/litre/6h/day

0,2 < C ≤ 1,0

Inhalation (rat) dust/mist/fume

mg/litre/6h/day

0,02 < C ≤ 0,2

Route of Exposure

Units

Guidance Value Ranges:

(dose/concentration)

Route of Exposure

Route of Exposure

Units

Units

Guidance Value Ranges:

(dose/concentration)

Guidance Value Ranges:

(dose/concentration)

Oral (rat)

mg/kg body weight/day

10 < C ≤ 100

Oral (rat)

Oral (rat)

mg/kg body weight/day

mg/kg body weight/day

10 < C ≤ 100

10 < C ≤ 100

Dermal (rat or rabbit)

mg/kg body weight/day

20 < C ≤ 200

Dermal (rat or rabbit)

Dermal (rat or rabbit)

mg/kg body weight/day

mg/kg body weight/day

20 < C ≤ 200

20 < C ≤ 200

Inhalation (rat) gas

ppmV/6h/day

50 < C ≤ 250

Inhalation (rat) gas

Inhalation (rat) gas

ppmV/6h/day

ppmV/6h/day

50 < C ≤ 250

50 < C ≤ 250

Inhalation (rat)vapour

mg/litre/6h/day

0,2 < C ≤ 1,0

Inhalation (rat)vapour

Inhalation (rat)vapour

mg/litre/6h/day

mg/litre/6h/day

0,2 < C ≤ 1,0

0,2 < C ≤ 1,0

Inhalation (rat) dust/mist/fume

mg/litre/6h/day

0,02 < C ≤ 0,2

Inhalation (rat) dust/mist/fume

Inhalation (rat) dust/mist/fume

mg/litre/6h/day

mg/litre/6h/day

0,02 < C ≤ 0,2

0,02 < C ≤ 0,2

3.9.2.9.8. The guidance values and ranges mentioned in paragraphs 3.9.2.9.6 and 3.9.2.9.7 are intended only for guidance purposes, i.e. to be used as part of the weight of evidence approach, and to assist with decisions about classification. They are not intended as strict demarcation values.

3.9.2.9.8. The guidance values and ranges mentioned in paragraphs 3.9.2.9.6 and 3.9.2.9.7 are intended only for guidance purposes, i.e. to be used as part of the weight of evidence approach, and to assist with decisions about classification. They are not intended as strict demarcation values.  

▼M4 ▼M4

3.9.2.9.9. Thus it is feasible that a specific profile of toxicity occurs in repeat-dose animal studies at a dose/concentration below the guidance value, such as < 100 mg/kg bw/day by the oral route, however the nature of the effect, such as nephrotoxicity seen only in male rats of a particular strain known to be susceptible to this effect may result in the decision not to classify. Conversely, a specific profile of toxicity may be seen in animal studies occurring at or above a guidance value, such as ≥ 100 mg/kg bw/day by the oral route, and in addition there is supplementary information from other sources, such as other long-term administration studies, or human case experience, which supports a conclusion that, in view of the weight of evidence, classification is the prudent action to take.

3.9.2.9.9. Thus it is feasible that a specific profile of toxicity occurs in repeat-dose animal studies at a dose/concentration below the guidance value, such as < 100 mg/kg bw/day by the oral route, however the nature of the effect, such as nephrotoxicity seen only in male rats of a particular strain known to be susceptible to this effect may result in the decision not to classify. Conversely, a specific profile of toxicity may be seen in animal studies occurring at or above a guidance value, such as ≥ 100 mg/kg bw/day by the oral route, and in addition there is supplementary information from other sources, such as other long-term administration studies, or human case experience, which supports a conclusion that, in view of the weight of evidence, classification is the prudent action to take.  

▼B ▼B

3.9.2.10.   Other considerations Other considerations

3.9.2.10.1. When a substance is characterised only by use of animal data (typical of new substances, but also true for many existing substances), the classification process includes reference to dose/concentration guidance values as one of the elements that contribute to the weight of evidence approach.

3.9.2.10.1. When a substance is characterised only by use of animal data (typical of new substances, but also true for many existing substances), the classification process includes reference to dose/concentration guidance values as one of the elements that contribute to the weight of evidence approach.  

3.9.2.10.2. When well-substantiated human data are available showing a specific target organ toxic effect that can be reliably attributed to repeated or prolonged exposure to a substance, the substance shall normally be classified. Positive human data, regardless of probable dose, predominates over animal data. Thus, if a substance is unclassified because no specific target organ toxicity was seen at or below the dose/concentration guidance value for animal testing, if subsequent human incident data become available showing a specific target organ toxic effect, the substance shall be classified.

3.9.2.10.2. When well-substantiated human data are available showing a specific target organ toxic effect that can be reliably attributed to repeated or prolonged exposure to a substance, the substance shall normally be classified. Positive human data, regardless of probable dose, predominates over animal data. Thus, if a substance is unclassified because no specific target organ toxicity was seen at or below the dose/concentration guidance value for animal testing, if subsequent human incident data become available showing a specific target organ toxic effect, the substance shall be classified.  

3.9.2.10.3. A substance that has not been tested for specific target organ toxicity may, where appropriate, be classified on the basis of data from a validated structure activity relationship and expert judgement-based extrapolation from a structural analogue that has previously been classified together with substantial support from consideration of other important factors such as formation of common significant metabolites.

3.9.2.10.3. A substance that has not been tested for specific target organ toxicity may, where appropriate, be classified on the basis of data from a validated structure activity relationship and expert judgement-based extrapolation from a structural analogue that has previously been classified together with substantial support from consideration of other important factors such as formation of common significant metabolites.  

3.9.2.10.4. Saturated vapour concentration shall be considered, where appropriate, as an additional element to provide for specific health and safety protection

3.9.2.10.4. Saturated vapour concentration shall be considered, where appropriate, as an additional element to provide for specific health and safety protection  

3.9.3.   Classification criteria for mixtures

Classification criteria for mixtures

3.9.3.1. Mixtures are classified using the same criteria as for substances, or alternatively as described below. As with substances, mixtures shall be classified for specific target organ toxicity following repeated exposure.

3.9.3.1. Mixtures are classified using the same criteria as for substances, or alternatively as described below. As with substances, mixtures shall be classified for specific target organ toxicity following repeated exposure.  

3.9.3.2.   Classification of mixtures when data are available for the complete mixture Classification of mixtures when data are available for the complete mixture

3.9.3.2.1. When reliable and good quality evidence from human experience or appropriate studies in experimental animals, as described in the criteria for substances, is available for the mixture (see 1.1.1.4), then the mixture shall be classified by weight of evidence evaluation of these data. Care shall be exercised in evaluating data on mixtures, that the dose, duration, observation or analysis, do not render the results inconclusive.

3.9.3.2.1. When reliable and good quality evidence from human experience or appropriate studies in experimental animals, as described in the criteria for substances, is available for the mixture (see 1.1.1.4), then the mixture shall be classified by weight of evidence evaluation of these data. Care shall be exercised in evaluating data on mixtures, that the dose, duration, observation or analysis, do not render the results inconclusive.  

3.9.3.3.   Classification of mixtures when data are not available for the complete mixture: bridging principles Classification of mixtures when data are not available for the complete mixture: bridging principles

3.9.3.3.1. Where the mixture itself has not been tested to determine its specific target organ toxicity, but there are sufficient data on the individual ingredients and similar tested mixtures to adequately characterise the hazards of the mixture, these data shall be used in accordance with the bridging principles set out in section 1.1.3.

3.9.3.3.1. Where the mixture itself has not been tested to determine its specific target organ toxicity, but there are sufficient data on the individual ingredients and similar tested mixtures to adequately characterise the hazards of the mixture, these data shall be used in accordance with the bridging principles set out in section 1.1.3.  

3.9.3.4.   Classification of mixtures when data are available for all components or only for some components of the mixture Classification of mixtures when data are available for all components or only for some components of the mixture

▼M19 ▼M19

3.9.3.4.1. Where there is no reliable evidence or test data for the specific mixture itself, and the bridging principles cannot be used to enable classification, then classification of the mixture is based on the classification of the ingredient substances. In this case, the mixture shall be classified as a specific target organ toxicant (specific organ specified), following repeated exposure when at least one ingredient has been classified as a Category 1 or Category 2 specific target organ toxicant (repeated exposure) and is present at or above the appropriate generic concentration limit as laid out in Table 3.9.4 for Category 1 and 2 respectively.

3.9.3.4.1. Where there is no reliable evidence or test data for the specific mixture itself, and the bridging principles cannot be used to enable classification, then classification of the mixture is based on the classification of the ingredient substances. In this case, the mixture shall be classified as a specific target organ toxicant (specific organ specified), following repeated exposure when at least one ingredient has been classified as a Category 1 or Category 2 specific target organ toxicant (repeated exposure) and is present at or above the appropriate generic concentration limit as laid out in Table 3.9.4 for Category 1 and 2 respectively.  

▼B ▼B

Table 3.9.4

Generic concentration limits of ingredients of a mixture classified as a specific target organ toxicant that trigger classification of the mixture

Ingredient classified as:

Generic concentration limits triggering classification of the mixture as:

Category 1

Category 2

Category 1

Specific Target Organ Toxicant

Concentration ≥ 10 %

1,0  % ≤ concentration < 10 %

Category 2

Specific Target Organ Toxicant

 

Concentration ≥ 10 % [(Note 1)]

Table 3.9.4

Generic concentration limits of ingredients of a mixture classified as a specific target organ toxicant that trigger classification of the mixture

Ingredient classified as:

Generic concentration limits triggering classification of the mixture as:

Category 1

Category 2

Category 1

Specific Target Organ Toxicant

Concentration ≥ 10 %

1,0  % ≤ concentration < 10 %

Category 2

Specific Target Organ Toxicant

 

Concentration ≥ 10 % [(Note 1)]

Ingredient classified as:

Generic concentration limits triggering classification of the mixture as:

Category 1

Category 2

Category 1

Specific Target Organ Toxicant

Concentration ≥ 10 %

1,0  % ≤ concentration < 10 %

Category 2

Specific Target Organ Toxicant

 

Concentration ≥ 10 % [(Note 1)]

Ingredient classified as:

Generic concentration limits triggering classification of the mixture as:

Ingredient classified as:

Ingredient classified as:

Generic concentration limits triggering classification of the mixture as:

Generic concentration limits triggering classification of the mixture as:

Category 1

Category 2

Category 1

Category 1

Category 2

Category 2

Category 1

Specific Target Organ Toxicant

Concentration ≥ 10 %

1,0  % ≤ concentration < 10 %

Category 1

Specific Target Organ Toxicant

Category 1

Specific Target Organ Toxicant

Concentration ≥ 10 %

Concentration ≥ 10 %

1,0  % ≤ concentration < 10 %

1,0  % ≤ concentration < 10 %

Category 2

Specific Target Organ Toxicant

 

Concentration ≥ 10 % [(Note 1)]

Category 2

Specific Target Organ Toxicant

Category 2

Specific Target Organ Toxicant

 

 

Concentration ≥ 10 % [(Note 1)]

Concentration ≥ 10 % [(Note 1)]

Note 1

If a Category 2 specific target organ toxicant is present in the mixture as an ingredient at a concentration ≥ 1,0  % a SDS shall be available for the mixture upon request.

3.9.3.4.2. These generic concentration limits and consequent classifications apply to repeated-dose target organ toxicants.

3.9.3.4.2. These generic concentration limits and consequent classifications apply to repeated-dose target organ toxicants.  

3.9.3.4.3. Mixtures shall be classified for either or both single- and repeated-dose toxicity independently.

3.9.3.4.3. Mixtures shall be classified for either or both single- and repeated-dose toxicity independently.  

3.9.3.4.4. Care shall be exercised when toxicants affecting more than one organ system are combined that the potentiation or synergistic interactions are considered, because certain substances can cause target organ toxicity at < 1 % concentration when other ingredients in the mixture are known to potentiate its toxic effect.

3.9.3.4.4. Care shall be exercised when toxicants affecting more than one organ system are combined that the potentiation or synergistic interactions are considered, because certain substances can cause target organ toxicity at < 1 % concentration when other ingredients in the mixture are known to potentiate its toxic effect.  

3.9.4.   Hazard Communication

Hazard Communication

3.9.4.1. Label elements shall be used in accordance with Table 3.9.5 for substances or mixtures meeting the criteria for classification in this hazard class.

3.9.4.1. Label elements shall be used in accordance with Table 3.9.5 for substances or mixtures meeting the criteria for classification in this hazard class.  

Table 3.9.5

Label elements for specific target organ toxicity after repeated exposure

Classification

Category 1

Category 2

GHS Pictograms

image

image

Signal word

Danger

Warning

Hazard Statement

H372: Causes damage to organs (state all organs affected, if known) through prolonged or repeated exposure (state route of exposure if it is conclusively proven that no other routes of exposure cause the hazard)

H373: May cause damage to organs (state all organs affected, if known) through prolonged or repeated exposure (state route of exposure if it is conclusively proven that no other routes of exposure cause the hazard)

Precautionary Statement Prevention

P260

P264

P270

P260

Precautionary Statement Response

P314

P314

Precautionary Statement Storage

 

 

Precautionary Statement Disposal

P501

P501

Table 3.9.5

Label elements for specific target organ toxicity after repeated exposure

Classification

Category 1

Category 2

GHS Pictograms

image

image

Signal word

Danger

Warning

Hazard Statement

H372: Causes damage to organs (state all organs affected, if known) through prolonged or repeated exposure (state route of exposure if it is conclusively proven that no other routes of exposure cause the hazard)

H373: May cause damage to organs (state all organs affected, if known) through prolonged or repeated exposure (state route of exposure if it is conclusively proven that no other routes of exposure cause the hazard)

Precautionary Statement Prevention

P260

P264

P270

P260

Precautionary Statement Response

P314

P314

Precautionary Statement Storage

 

 

Precautionary Statement Disposal

P501

P501

Classification

Category 1

Category 2

GHS Pictograms

image

image

Signal word

Danger

Warning

Hazard Statement

H372: Causes damage to organs (state all organs affected, if known) through prolonged or repeated exposure (state route of exposure if it is conclusively proven that no other routes of exposure cause the hazard)

H373: May cause damage to organs (state all organs affected, if known) through prolonged or repeated exposure (state route of exposure if it is conclusively proven that no other routes of exposure cause the hazard)

Precautionary Statement Prevention

P260

P264

P270

P260

Precautionary Statement Response

P314

P314

Precautionary Statement Storage

 

 

Precautionary Statement Disposal

P501

P501

Classification

Category 1

Category 2

Classification

Classification

Category 1

Category 1

Category 2

Category 2

GHS Pictograms

image

image

GHS Pictograms

GHS Pictograms

image

image image

image

image image

Signal word

Danger

Warning

Signal word

Signal word

Danger

Danger

Warning

Warning

Hazard Statement

H372: Causes damage to organs (state all organs affected, if known) through prolonged or repeated exposure (state route of exposure if it is conclusively proven that no other routes of exposure cause the hazard)

H373: May cause damage to organs (state all organs affected, if known) through prolonged or repeated exposure (state route of exposure if it is conclusively proven that no other routes of exposure cause the hazard)

Hazard Statement

Hazard Statement

H372: Causes damage to organs (state all organs affected, if known) through prolonged or repeated exposure (state route of exposure if it is conclusively proven that no other routes of exposure cause the hazard)

H372: Causes damage to organs (state all organs affected, if known) through prolonged or repeated exposure (state route of exposure if it is conclusively proven that no other routes of exposure cause the hazard)

H373: May cause damage to organs (state all organs affected, if known) through prolonged or repeated exposure (state route of exposure if it is conclusively proven that no other routes of exposure cause the hazard)

H373: May cause damage to organs (state all organs affected, if known) through prolonged or repeated exposure (state route of exposure if it is conclusively proven that no other routes of exposure cause the hazard)

Precautionary Statement Prevention

P260

P264

P270

P260

Precautionary Statement Prevention

Precautionary Statement Prevention

P260

P264

P270

P260

P264

P270

P260

P260

Precautionary Statement Response

P314

P314

Precautionary Statement Response

Precautionary Statement Response

P314

P314

P314

P314

Precautionary Statement Storage

 

 

Precautionary Statement Storage

Precautionary Statement Storage

 

 

 

 

Precautionary Statement Disposal

P501

P501

Precautionary Statement Disposal

Precautionary Statement Disposal

P501

P501

P501

P501

3.10.   Aspiration hazard

Aspiration hazard

3.10.1.   Definitions and general considerations

Definitions and general considerations

3.10.1.1. These criteria provide a means of classifying substances or mixtures that may pose an aspiration toxicity hazard to humans.

3.10.1.1. These criteria provide a means of classifying substances or mixtures that may pose an aspiration toxicity hazard to humans.  

3.10.1.2. ‘Aspiration’ means the entry of a liquid or solid substance or mixture directly through the oral or nasal cavity, or indirectly from vomiting, into the trachea and lower respiratory system.

3.10.1.2. ‘Aspiration’ means the entry of a liquid or solid substance or mixture directly through the oral or nasal cavity, or indirectly from vomiting, into the trachea and lower respiratory system.  

▼M19 ▼M19

3.10.1.3. Aspiration hazard means severe acute effects such as chemical pneumonia, pulmonary injury or death occurring after aspiration of a substance or mixture.

3.10.1.3. Aspiration hazard means severe acute effects such as chemical pneumonia, pulmonary injury or death occurring after aspiration of a substance or mixture.  

▼B ▼B

3.10.1.4. Aspiration is initiated at the moment of inspiration, in the time required to take one breath, as the causative material lodges at the crossroad of the upper respiratory and digestive tracts in the laryngopharyngeal region.

3.10.1.4. Aspiration is initiated at the moment of inspiration, in the time required to take one breath, as the causative material lodges at the crossroad of the upper respiratory and digestive tracts in the laryngopharyngeal region.  

3.10.1.5. Aspiration of a substance or mixture can occur as it is vomited following ingestion. This has consequences for labelling, particularly where, due to acute toxicity, a recommendation may be considered to induce vomiting after ingestion. However, if the substance/mixture also presents an aspiration toxicity hazard, the recommendation to induce vomiting shall be modified.

3.10.1.5. Aspiration of a substance or mixture can occur as it is vomited following ingestion. This has consequences for labelling, particularly where, due to acute toxicity, a recommendation may be considered to induce vomiting after ingestion. However, if the substance/mixture also presents an aspiration toxicity hazard, the recommendation to induce vomiting shall be modified.  

3.10.1.6.   Specific considerations Specific considerations

3.10.1.6.1. A review of the medical literature on chemical aspiration revealed that some hydrocarbons (petroleum distillates) and certain chlorinated hydrocarbons have been shown to pose an aspiration hazard in humans.

3.10.1.6.1. A review of the medical literature on chemical aspiration revealed that some hydrocarbons (petroleum distillates) and certain chlorinated hydrocarbons have been shown to pose an aspiration hazard in humans.  

3.10.1.6.2. The classification criteria refer to kinematic viscosity. The following provides the conversion between dynamic and kinematic viscosity:

3.10.1.6.2. The classification criteria refer to kinematic viscosity. The following provides the conversion between dynamic and kinematic viscosity:  

image image

▼M2 ▼M2

3.10.1.6.2a Although the definition of aspiration in section 3.10.1.2 includes the entry of solids into the respiratory system, classification according to point (b) in Table 3.10.1 for Category 1 is intended to apply to liquid substances and mixtures only.

3.10.1.6.2a Although the definition of aspiration in section 3.10.1.2 includes the entry of solids into the respiratory system, classification according to point (b) in Table 3.10.1 for Category 1 is intended to apply to liquid substances and mixtures only.  

▼B ▼B

3.10.1.6.3.    Classification of aerosol/mist products Classification of aerosol/mist products Classification of aerosol/mist products

Aerosol and mist forms of a substance or a mixture (product) are usually dispensed in containers such as self-pressurised containers, trigger and pump sprayers. The key to classifying these products is whether a pool of product is formed in the mouth, which then may be aspirated. If the mist or aerosol from a pressurised container is fine, a pool may not be formed. On the other hand, if a pressurised container dispenses product in a stream, a pool may be formed that may then be aspirated. Usually, the mist produced by trigger and pump sprayers is coarse and therefore, a pool may be formed that then may be aspirated. When the pump mechanism may be removed, and the contents are available to be swallowed then the classification of the substance or mixture shall be considered.

3.10.2.   Classification criteria for substances

Classification criteria for substances

Table 3.10.1

Hazard category for aspiration toxicity

Category

Criteria

Category 1

Substances known to cause human aspiration toxicity hazards or to be regarded as if they cause human aspiration toxicity hazard

A substance is classified in Category 1:

(a)  based on reliable and good quality human evidence

or

(b)  if it is a hydrocarbon and has a kinematic viscosity of 20,5  mm2/s or less, measured at 40 oC.

Table 3.10.1

Hazard category for aspiration toxicity

Category

Criteria

Category 1

Substances known to cause human aspiration toxicity hazards or to be regarded as if they cause human aspiration toxicity hazard

A substance is classified in Category 1:

(a)  based on reliable and good quality human evidence

or

(b)  if it is a hydrocarbon and has a kinematic viscosity of 20,5  mm2/s or less, measured at 40 oC.

Category

Criteria

Category 1

Substances known to cause human aspiration toxicity hazards or to be regarded as if they cause human aspiration toxicity hazard

A substance is classified in Category 1:

(a)  based on reliable and good quality human evidence

or

(b)  if it is a hydrocarbon and has a kinematic viscosity of 20,5  mm2/s or less, measured at 40 oC.

Category

Criteria

Category

Category

Criteria

Criteria

Category 1

Substances known to cause human aspiration toxicity hazards or to be regarded as if they cause human aspiration toxicity hazard

A substance is classified in Category 1:

(a)  based on reliable and good quality human evidence

or

(b)  if it is a hydrocarbon and has a kinematic viscosity of 20,5  mm2/s or less, measured at 40 oC.

Category 1

Category 1

Substances known to cause human aspiration toxicity hazards or to be regarded as if they cause human aspiration toxicity hazard

A substance is classified in Category 1:

(a)  based on reliable and good quality human evidence

or

(b)  if it is a hydrocarbon and has a kinematic viscosity of 20,5  mm2/s or less, measured at 40 oC.

Substances known to cause human aspiration toxicity hazards or to be regarded as if they cause human aspiration toxicity hazard

A substance is classified in Category 1:

(a)  based on reliable and good quality human evidence

or

(b)  if it is a hydrocarbon and has a kinematic viscosity of 20,5  mm2/s or less, measured at 40 oC. 2 o

Note:

Substances in Category 1 include but are not limited to certain hydrocarbons, turpentine and pine oil.

3.10.3.   Classification criteria for mixtures

Classification criteria for mixtures

3.10.3.1.   Classification when data are available for the complete mixture Classification when data are available for the complete mixture

A mixture is classified in Category 1 based on reliable and good quality human evidence.

3.10.3.2.   Classification when data are not available for the complete mixture: bridging principles Classification when data are not available for the complete mixture: bridging principles

3.10.3.2.1. Where the mixture itself has not been tested to determine its aspiration toxicity, but there are sufficient data on the individual ingredients and similar tested mixtures to adequately characterise the hazard of the mixture, these data shall be used in accordance with the bridging principles set out in section 1.1.3. However, in the case of application of the dilution bridging principle, the concentration of aspiration toxicant(s) shall be 10 % or more.

3.10.3.2.1. Where the mixture itself has not been tested to determine its aspiration toxicity, but there are sufficient data on the individual ingredients and similar tested mixtures to adequately characterise the hazard of the mixture, these data shall be used in accordance with the bridging principles set out in section 1.1.3. However, in the case of application of the dilution bridging principle, the concentration of aspiration toxicant(s) shall be 10 % or more.  

3.10.3.3.   Classification when data are available for all components or only some components of the mixture Classification when data are available for all components or only some components of the mixture

3.10.3.3.1.    Category 1 Category 1 Category 1

▼M19 ▼M19

3.10.3.3.1.1. The ‘relevant ingredients’ of a mixture are those which are present in concentrations ≥ 1 %.

3.10.3.3.1.1. The ‘relevant ingredients’ of a mixture are those which are present in concentrations ≥ 1 %.  

▼M19 ▼M19

3.10.3.3.1.2. A mixture is classified as Category 1 when the sum of the concentrations of Category 1 ingredients is ≥ 10 % and the mixture has a kinematic viscosity ≤ 20,5 mm2/s, measured at 40 °C.

3.10.3.3.1.2. A mixture is classified as Category 1 when the sum of the concentrations of Category 1 ingredients is ≥ 10 % and the mixture has a kinematic viscosity ≤ 20,5 mm2/s, measured at 40 °C.   2

3.10.3.3.1.3. In the case of a mixture which separates into two or more distinct layers, the entire mixture is classified as Category 1 if in any distinct layer the sum of the concentrations of Category 1 ingredients is ≥ 10 %, and it has a kinematic viscosity ≤ 20,5 mm2/s, measured at 40 °C.

3.10.3.3.1.3. In the case of a mixture which separates into two or more distinct layers, the entire mixture is classified as Category 1 if in any distinct layer the sum of the concentrations of Category 1 ingredients is ≥ 10 %, and it has a kinematic viscosity ≤ 20,5 mm2/s, measured at 40 °C.   2

▼B ▼B

3.10.4.   Hazard Communication

Hazard Communication

3.10.4.1. Label elements shall be used for substances or mixtures meeting the criteria for classification in this hazard class in accordance with Table 3.10.2.

3.10.4.1. Label elements shall be used for substances or mixtures meeting the criteria for classification in this hazard class in accordance with Table 3.10.2.  

Table 3.10.2

Aspiration toxicity label elements

Classification

Category 1

GHS Pictogram

image

Signal Word

Danger

Hazard Statement

H304: May be fatal if swallowed and enters airways

Precautionary Statement

Prevention

 

Precautionary Statement

Response

P301 + P310

P331

Precautionary Statement

Storage

P405

Precautionary Statement

Disposal

P501

Table 3.10.2

Aspiration toxicity label elements

Classification

Category 1

GHS Pictogram

image

Signal Word

Danger

Hazard Statement

H304: May be fatal if swallowed and enters airways

Precautionary Statement

Prevention

 

Precautionary Statement

Response

P301 + P310

P331

Precautionary Statement

Storage

P405

Precautionary Statement

Disposal

P501

Classification

Category 1

GHS Pictogram

image

Signal Word

Danger

Hazard Statement

H304: May be fatal if swallowed and enters airways

Precautionary Statement

Prevention

 

Precautionary Statement

Response

P301 + P310

P331

Precautionary Statement

Storage

P405

Precautionary Statement

Disposal

P501

Classification

Category 1

Classification

Classification

Category 1

Category 1

GHS Pictogram

image

GHS Pictogram

GHS Pictogram

image

image image

Signal Word

Danger

Signal Word

Signal Word

Danger

Danger

Hazard Statement

H304: May be fatal if swallowed and enters airways

Hazard Statement

Hazard Statement

H304: May be fatal if swallowed and enters airways

H304: May be fatal if swallowed and enters airways

Precautionary Statement

Prevention

 

Precautionary Statement

Prevention

Precautionary Statement

Prevention

 

 

Precautionary Statement

Response

P301 + P310

P331

Precautionary Statement

Response

Precautionary Statement

Response

P301 + P310

P331

P301 + P310

P331

Precautionary Statement

Storage

P405

Precautionary Statement

Storage

Precautionary Statement

Storage

P405

P405

Precautionary Statement

Disposal

P501

Precautionary Statement

Disposal

Precautionary Statement

Disposal

P501

P501

▼M32 ▼M32

3.11.    Endocrine disruption for human health

Endocrine disruption for human health Endocrine disruption for human health

3.11.1.    Definitions and general considerations

Definitions and general considerations Definitions and general considerations Definitions and general considerations

3.11.1.1.    Definitions Definitions Definitions

For the purposes of Section 3.11, the following definitions shall apply:

(a) 

‘endocrine disruptor’ means a substance or a mixture that alters one or more functions of the endocrine system and consequently causes adverse effects in an intact organism, its progeny, populations or subpopulations;

(a) 
(a) 

‘endocrine disruptor’ means a substance or a mixture that alters one or more functions of the endocrine system and consequently causes adverse effects in an intact organism, its progeny, populations or subpopulations;

‘endocrine disruptor’ means a substance or a mixture that alters one or more functions of the endocrine system and consequently causes adverse effects in an intact organism, its progeny, populations or subpopulations;

(b) 

‘endocrine disruption’ means the alteration of one or more functions of the endocrine system caused by an endocrine disruptor;

(b) 
(b) 

‘endocrine disruption’ means the alteration of one or more functions of the endocrine system caused by an endocrine disruptor;

‘endocrine disruption’ means the alteration of one or more functions of the endocrine system caused by an endocrine disruptor;

(c) 

‘endocrine activity’ means an interaction with the endocrine system that may result in a response of that system, of target organs or target tissues, and that confers on a substance or the mixture the potential to alter one or more functions of the endocrine system;

(c) 
(c) 

‘endocrine activity’ means an interaction with the endocrine system that may result in a response of that system, of target organs or target tissues, and that confers on a substance or the mixture the potential to alter one or more functions of the endocrine system;

‘endocrine activity’ means an interaction with the endocrine system that may result in a response of that system, of target organs or target tissues, and that confers on a substance or the mixture the potential to alter one or more functions of the endocrine system;

(d) 

‘adverse effect’ means a change in morphology, physiology, growth, development, reproduction or lifespan of an organism, system, population or subpopulation that results in an impairment of functional capacity, an impairment of the capacity to compensate for additional stress or an increase in susceptibility to other influences;

(d) 
(d) 

‘adverse effect’ means a change in morphology, physiology, growth, development, reproduction or lifespan of an organism, system, population or subpopulation that results in an impairment of functional capacity, an impairment of the capacity to compensate for additional stress or an increase in susceptibility to other influences;

‘adverse effect’ means a change in morphology, physiology, growth, development, reproduction or lifespan of an organism, system, population or subpopulation that results in an impairment of functional capacity, an impairment of the capacity to compensate for additional stress or an increase in susceptibility to other influences;

(e) 

‘biologically plausible link’ means the correlation between an endocrine activity and an adverse effect, based on biological processes, where the correlation is consistent with existing scientific knowledge.

(e) 
(e) 

‘biologically plausible link’ means the correlation between an endocrine activity and an adverse effect, based on biological processes, where the correlation is consistent with existing scientific knowledge.

‘biologically plausible link’ means the correlation between an endocrine activity and an adverse effect, based on biological processes, where the correlation is consistent with existing scientific knowledge.

3.11.1.2.    General considerations General considerations General considerations

3.11.1.2.1. Substances and mixtures fulfilling the criteria of endocrine disruptors for human health based on evidence referred to in Table 3.11.1 shall be considered to be known, presumed or suspected endocrine disruptors for human health unless there is evidence conclusively demonstrating that the adverse effects are not relevant to humans.

3.11.1.2.1. Substances and mixtures fulfilling the criteria of endocrine disruptors for human health based on evidence referred to in Table 3.11.1 shall be considered to be known, presumed or suspected endocrine disruptors for human health unless there is evidence conclusively demonstrating that the adverse effects are not relevant to humans.  

3.11.1.2.2. Evidence that is to be considered for classification of substances in accordance with other Sections of this Annex may also be used for classification of substances as an endocrine disruptor for human health where the criteria provided in this Section are met.

3.11.1.2.2. Evidence that is to be considered for classification of substances in accordance with other Sections of this Annex may also be used for classification of substances as an endocrine disruptor for human health where the criteria provided in this Section are met.  

3.11.2.    Classification criteria for substances

Classification criteria for substances Classification criteria for substances Classification criteria for substances

3.11.2.1.    Hazard categories Hazard categories Hazard categories

For the purpose of classification for endocrine disruption for human health, substances shall be allocated to one of two categories.

Table 3.11.1.

Hazard categories for endocrine disruptors for human health

Categories

Criteria

CATEGORY 1

Known or presumed endocrine disruptors for human health

The classification in Category 1 shall be largely based on evidence from at least one of the following:

a)  human data;

b)  animal data;

c)  non-animal data providing an equivalent predictive capacity as data in points a or b.

Such data shall provide evidence that the substance meets all the following criteria:

(a)  endocrine activity;

(b)  an adverse effect in an intact organism or its offspring or future generations;

(c)  a biologically plausible link between the endocrine activity and the adverse effect.

However, where there is information that raises serious doubt about the relevance of the adverse effects to humans, classification in Category 2 may be more appropriate.

CATEGORY 2

Suspected endocrine disruptors for human health

A substance shall be classified in Category 2 where all the following criteria are fulfilled:

(a)  there is evidence of:

i.  an endocrine activity; and

ii.  an adverse effect in an intact organism or its offspring or future generations;

(b)  the evidence referred to in point (a) is not sufficiently convincing to classify the substance in Category 1;

(c)  there is evidence of a biologically plausible link between the endocrine activity and the adverse effect.

Table 3.11.1. Table 3.11.1.

Hazard categories for endocrine disruptors for human health Hazard categories for endocrine disruptors for human health

Categories

Criteria

CATEGORY 1

Known or presumed endocrine disruptors for human health

The classification in Category 1 shall be largely based on evidence from at least one of the following:

a)  human data;

b)  animal data;

c)  non-animal data providing an equivalent predictive capacity as data in points a or b.

Such data shall provide evidence that the substance meets all the following criteria:

(a)  endocrine activity;

(b)  an adverse effect in an intact organism or its offspring or future generations;

(c)  a biologically plausible link between the endocrine activity and the adverse effect.

However, where there is information that raises serious doubt about the relevance of the adverse effects to humans, classification in Category 2 may be more appropriate.

CATEGORY 2

Suspected endocrine disruptors for human health

A substance shall be classified in Category 2 where all the following criteria are fulfilled:

(a)  there is evidence of:

i.  an endocrine activity; and

ii.  an adverse effect in an intact organism or its offspring or future generations;

(b)  the evidence referred to in point (a) is not sufficiently convincing to classify the substance in Category 1;

(c)  there is evidence of a biologically plausible link between the endocrine activity and the adverse effect.

Categories

Criteria

CATEGORY 1

Known or presumed endocrine disruptors for human health

The classification in Category 1 shall be largely based on evidence from at least one of the following:

a)  human data;

b)  animal data;

c)  non-animal data providing an equivalent predictive capacity as data in points a or b.

Such data shall provide evidence that the substance meets all the following criteria:

(a)  endocrine activity;

(b)  an adverse effect in an intact organism or its offspring or future generations;

(c)  a biologically plausible link between the endocrine activity and the adverse effect.

However, where there is information that raises serious doubt about the relevance of the adverse effects to humans, classification in Category 2 may be more appropriate.

CATEGORY 2

Suspected endocrine disruptors for human health

A substance shall be classified in Category 2 where all the following criteria are fulfilled:

(a)  there is evidence of:

i.  an endocrine activity; and

ii.  an adverse effect in an intact organism or its offspring or future generations;

(b)  the evidence referred to in point (a) is not sufficiently convincing to classify the substance in Category 1;

(c)  there is evidence of a biologically plausible link between the endocrine activity and the adverse effect.

Categories

Criteria

Categories

Categories

Criteria

Criteria

CATEGORY 1

Known or presumed endocrine disruptors for human health

The classification in Category 1 shall be largely based on evidence from at least one of the following:

a)  human data;

b)  animal data;

c)  non-animal data providing an equivalent predictive capacity as data in points a or b.

Such data shall provide evidence that the substance meets all the following criteria:

(a)  endocrine activity;

(b)  an adverse effect in an intact organism or its offspring or future generations;

(c)  a biologically plausible link between the endocrine activity and the adverse effect.

However, where there is information that raises serious doubt about the relevance of the adverse effects to humans, classification in Category 2 may be more appropriate.

CATEGORY 1

CATEGORY 1

Known or presumed endocrine disruptors for human health

The classification in Category 1 shall be largely based on evidence from at least one of the following:

a)  human data;

b)  animal data;

c)  non-animal data providing an equivalent predictive capacity as data in points a or b.

Such data shall provide evidence that the substance meets all the following criteria:

(a)  endocrine activity;

(b)  an adverse effect in an intact organism or its offspring or future generations;

(c)  a biologically plausible link between the endocrine activity and the adverse effect.

However, where there is information that raises serious doubt about the relevance of the adverse effects to humans, classification in Category 2 may be more appropriate.

Known or presumed endocrine disruptors for human health

The classification in Category 1 shall be largely based on evidence from at least one of the following:

a)  human data;

b)  animal data;

c)  non-animal data providing an equivalent predictive capacity as data in points a or b.

Such data shall provide evidence that the substance meets all the following criteria:

(a)  endocrine activity;

(b)  an adverse effect in an intact organism or its offspring or future generations;

(c)  a biologically plausible link between the endocrine activity and the adverse effect.

However, where there is information that raises serious doubt about the relevance of the adverse effects to humans, classification in Category 2 may be more appropriate.

CATEGORY 2

Suspected endocrine disruptors for human health

A substance shall be classified in Category 2 where all the following criteria are fulfilled:

(a)  there is evidence of:

i.  an endocrine activity; and

ii.  an adverse effect in an intact organism or its offspring or future generations;

(b)  the evidence referred to in point (a) is not sufficiently convincing to classify the substance in Category 1;

(c)  there is evidence of a biologically plausible link between the endocrine activity and the adverse effect.

CATEGORY 2

CATEGORY 2

Suspected endocrine disruptors for human health

A substance shall be classified in Category 2 where all the following criteria are fulfilled:

(a)  there is evidence of:

i.  an endocrine activity; and

ii.  an adverse effect in an intact organism or its offspring or future generations;

(b)  the evidence referred to in point (a) is not sufficiently convincing to classify the substance in Category 1;

(c)  there is evidence of a biologically plausible link between the endocrine activity and the adverse effect.

Suspected endocrine disruptors for human health

A substance shall be classified in Category 2 where all the following criteria are fulfilled:

(a)  there is evidence of:

i.  an endocrine activity; and

ii.  an adverse effect in an intact organism or its offspring or future generations;

(b)  the evidence referred to in point (a) is not sufficiently convincing to classify the substance in Category 1;

(c)  there is evidence of a biologically plausible link between the endocrine activity and the adverse effect.

Where there is evidence conclusively demonstrating that the adverse effects are not relevant to humans, the substance shall not be considered an endocrine disruptor for human health.

3.11.2.2.    Basis of classification Basis of classification Basis of classification

3.11.2.2.1. Classification shall be made on the basis of the criteria outlined above, and a weight of evidence determination of each of the criteria (see Section 3.11.2.3) and an overall weight of evidence determination (see Section 1.1.1). Classification as an endocrine disruptor for human health is intended to be used for substances which cause or may cause an endocrine-related adverse effect in humans.

3.11.2.2.1. Classification shall be made on the basis of the criteria outlined above, and a weight of evidence determination of each of the criteria (see Section 3.11.2.3) and an overall weight of evidence determination (see Section 1.1.1). Classification as an endocrine disruptor for human health is intended to be used for substances which cause or may cause an endocrine-related adverse effect in humans.  

3.11.2.2.2. Adverse effects that are solely non-specific consequences of other toxic effects shall not be considered for the identification of a substance as endocrine disruptor for human health.

3.11.2.2.2. Adverse effects that are solely non-specific consequences of other toxic effects shall not be considered for the identification of a substance as endocrine disruptor for human health.  

3.11.2.3.    Weight of evidence and expert judgment Weight of evidence and expert judgment Weight of evidence and expert judgment

3.11.2.3.1. Classification as an endocrine disruptor for human health is made on the basis of an assessment of the total weight of evidence using expert judgment (see Section 1.1.1). This means that all available information that bears on the determination of endocrine disruption for human health is considered together, such as:

3.11.2.3.1. Classification as an endocrine disruptor for human health is made on the basis of an assessment of the total weight of evidence using expert judgment (see Section 1.1.1). This means that all available information that bears on the determination of endocrine disruption for human health is considered together, such as:  

(a) 

in vivo studies or other studies (e.g. in vitro, in silico studies) predictive of adverse effects, endocrine activity or biologically plausible link in humans or animals;

(a) 
(a) 

in vivo studies or other studies (e.g. in vitro, in silico studies) predictive of adverse effects, endocrine activity or biologically plausible link in humans or animals;

in vivo studies or other studies (e.g. in vitro, in silico studies) predictive of adverse effects, endocrine activity or biologically plausible link in humans or animals;

(b) 

data from analogue substances using structure-activity relationships (SAR);

(b) 
(b) 

data from analogue substances using structure-activity relationships (SAR);

data from analogue substances using structure-activity relationships (SAR);

(c) 

evaluation of substances chemically related to the substance under study may also be included (grouping, read-across), particularly when information on the substance is scarce;

(c) 
(c) 

evaluation of substances chemically related to the substance under study may also be included (grouping, read-across), particularly when information on the substance is scarce;

evaluation of substances chemically related to the substance under study may also be included (grouping, read-across), particularly when information on the substance is scarce;

(d) 

any additional relevant and acceptable scientific data.

(d) 
(d) 

any additional relevant and acceptable scientific data.

any additional relevant and acceptable scientific data.

3.11.2.3.2. In applying the weight of evidence determination and expert judgment, the assessment of the scientific evidence referred to in Section 3.11.2.3.1 shall, in particular, consider all of the following factors:

3.11.2.3.2. In applying the weight of evidence determination and expert judgment, the assessment of the scientific evidence referred to in Section 3.11.2.3.1 shall, in particular, consider all of the following factors:  

(a) 

both positive and negative results;

(a) 
(a) 

both positive and negative results;

both positive and negative results;

(b) 

the relevance of the study designs for the assessment of adverse effects and of the endocrine activity;

(b) 
(b) 

the relevance of the study designs for the assessment of adverse effects and of the endocrine activity;

the relevance of the study designs for the assessment of adverse effects and of the endocrine activity;

(c) 

the quality and consistency of the data, considering the pattern and coherence of the results within and between studies of a similar design and across different species;

(c) 
(c) 

the quality and consistency of the data, considering the pattern and coherence of the results within and between studies of a similar design and across different species;

the quality and consistency of the data, considering the pattern and coherence of the results within and between studies of a similar design and across different species;

(d) 

the route of exposure, toxicokinetic and metabolism studies;

(d) 
(d) 

the route of exposure, toxicokinetic and metabolism studies;

the route of exposure, toxicokinetic and metabolism studies;

(e) 

the concept of the limit dose (concentration), and international guidelines on maximum recommended doses (concentrations) and for assessing confounding effects of excessive toxicity.

(e) 
(e) 

the concept of the limit dose (concentration), and international guidelines on maximum recommended doses (concentrations) and for assessing confounding effects of excessive toxicity.

the concept of the limit dose (concentration), and international guidelines on maximum recommended doses (concentrations) and for assessing confounding effects of excessive toxicity.

3.11.2.3.3. Using a weight of evidence determination, the link between the endocrine activity and the adverse effects shall be established based on biological plausibility, which shall be determined in light of available scientific knowledge. The biologically plausible link does not need to be demonstrated with substance specific data.

3.11.2.3.3. Using a weight of evidence determination, the link between the endocrine activity and the adverse effects shall be established based on biological plausibility, which shall be determined in light of available scientific knowledge. The biologically plausible link does not need to be demonstrated with substance specific data.  

3.11.2.3.4. Using a weight of evidence determination, evidence considered for the classification of a substance as an endocrine disruptor for the environment referred to in Section 4.2 shall be considered when assessing the classification of the substance as an endocrine disruptor for human health under Section 3.11.

3.11.2.3.4. Using a weight of evidence determination, evidence considered for the classification of a substance as an endocrine disruptor for the environment referred to in Section 4.2 shall be considered when assessing the classification of the substance as an endocrine disruptor for human health under Section 3.11.  

3.11.2.4.    Application in time Application in time Application in time

From 1 May 2025 at the latest, substances shall be classified in accordance with the criteria laid down in Sections 3.11.2.1 to 3.11.2.3.

However, substances which were placed on the market before 1 May 2025 are not required to be classified in accordance with the criteria laid down in Sections 3.11.2.1 to 3.11.2.3 until 1 November 2026.

3.11.3.    Classification criteria for mixtures

Classification criteria for mixtures Classification criteria for mixtures Classification criteria for mixtures

3.11.3.1.    Classification of mixtures where data are available for all components or only for some components of the mixture Classification of mixtures where data are available for all components or only for some components of the mixture Classification of mixtures where data are available for all components or only for some components of the mixture

3.11.3.1.1. A mixture shall be classified as an endocrine disruptor for human health where at least one component has been classified as a Category 1 or Category 2 endocrine disruptor for human health and is present at or above the appropriate generic concentration limit as shown in Table 3.11.2 for Category 1 and Category 2, respectively.

3.11.3.1.1. A mixture shall be classified as an endocrine disruptor for human health where at least one component has been classified as a Category 1 or Category 2 endocrine disruptor for human health and is present at or above the appropriate generic concentration limit as shown in Table 3.11.2 for Category 1 and Category 2, respectively.  

Table 3.11.2.

Generic concentration limits of components of a mixture classified as endocrine disruptor for human health that trigger classification of the mixture

Component classified as:

Generic concentration limits triggering classification of a mixture as:

Category 1 endocrine disruptor for human health

Category 2 endocrine disruptor for human health

Category 1 endocrine disruptor for human health

≥ 0,1 %

 

Category 2 endocrine disruptor for human health

 

≥ 1 %

[Note 1]

Table 3.11.2. Table 3.11.2.

Generic concentration limits of components of a mixture classified as endocrine disruptor for human health that trigger classification of the mixture Generic concentration limits of components of a mixture classified as endocrine disruptor for human health that trigger classification of the mixture

Component classified as:

Generic concentration limits triggering classification of a mixture as:

Category 1 endocrine disruptor for human health

Category 2 endocrine disruptor for human health

Category 1 endocrine disruptor for human health

≥ 0,1 %

 

Category 2 endocrine disruptor for human health

 

≥ 1 %

[Note 1]

Component classified as:

Generic concentration limits triggering classification of a mixture as:

Category 1 endocrine disruptor for human health

Category 2 endocrine disruptor for human health

Category 1 endocrine disruptor for human health

≥ 0,1 %

 

Category 2 endocrine disruptor for human health

 

≥ 1 %

[Note 1]

Component classified as:

Generic concentration limits triggering classification of a mixture as:

Component classified as:

Component classified as:

Generic concentration limits triggering classification of a mixture as:

Generic concentration limits triggering classification of a mixture as:

Category 1 endocrine disruptor for human health

Category 2 endocrine disruptor for human health

Category 1 endocrine disruptor for human health

Category 1 endocrine disruptor for human health

Category 2 endocrine disruptor for human health

Category 2 endocrine disruptor for human health

Category 1 endocrine disruptor for human health

≥ 0,1 %

 

Category 1 endocrine disruptor for human health

Category 1 endocrine disruptor for human health

≥ 0,1 %

≥ 0,1 %

 

 

Category 2 endocrine disruptor for human health

 

≥ 1 %

[Note 1]

Category 2 endocrine disruptor for human health

Category 2 endocrine disruptor for human health

 

 

≥ 1 %

[Note 1]

≥ 1 %

[Note 1]

Note: The concentration limits in this Table shall apply to solids and liquids (w/w units) as well as gases (v/v units).

Note: The concentration limits in this Table shall apply to solids and liquids (w/w units) as well as gases (v/v units).  

Note 1: If a Category 2 endocrine disruptor for human health is present in the mixture as an ingredient at a concentration ≥ 0,1 % a SDS shall be available for the mixture upon request.

Note 1: If a Category 2 endocrine disruptor for human health is present in the mixture as an ingredient at a concentration ≥ 0,1 % a SDS shall be available for the mixture upon request.  

3.11.3.2.    Classification of mixtures when data are available for the complete mixture Classification of mixtures when data are available for the complete mixture Classification of mixtures when data are available for the complete mixture

3.11.3.2.1. Classification of mixtures shall be based on the available test data for the individual components of the mixture using concentration limits for the components classified as endocrine disruptor for human health. On a case-by-case basis, test data on the mixture as a whole may be used for classification when demonstrating endocrine disruption for human health that has not been established from the evaluation based on the individual components. In such cases, the test results for the mixture as a whole must be shown to be conclusive taking into account dose (concentration) and other factors such as duration, observations, sensitivity and statistical analysis of the test systems. Adequate documentation supporting the classification shall be retained and made available for review upon request.

3.11.3.2.1. Classification of mixtures shall be based on the available test data for the individual components of the mixture using concentration limits for the components classified as endocrine disruptor for human health. On a case-by-case basis, test data on the mixture as a whole may be used for classification when demonstrating endocrine disruption for human health that has not been established from the evaluation based on the individual components. In such cases, the test results for the mixture as a whole must be shown to be conclusive taking into account dose (concentration) and other factors such as duration, observations, sensitivity and statistical analysis of the test systems. Adequate documentation supporting the classification shall be retained and made available for review upon request.  

3.11.3.3.    Classification of mixtures where data are not available for the complete mixture: bridging principles Classification of mixtures where data are not available for the complete mixture: bridging principles Classification of mixtures where data are not available for the complete mixture: bridging principles

3.11.3.3.1. Where the mixture itself has not been tested to determine its endocrine disruption for human health, but there are sufficient data on the individual components and similar tested mixtures (subject to paragraph 3.11.3.2.1) to adequately characterise the hazards of the mixture, those data shall be used in accordance with the applicable bridging principles set out in Section 1.1.3.

3.11.3.3.1. Where the mixture itself has not been tested to determine its endocrine disruption for human health, but there are sufficient data on the individual components and similar tested mixtures (subject to paragraph 3.11.3.2.1) to adequately characterise the hazards of the mixture, those data shall be used in accordance with the applicable bridging principles set out in Section 1.1.3.  

3.11.3.4.    Application in time Application in time Application in time

From 1 May 2026 at the latest, mixtures shall be classified in accordance with the criteria laid down in Sections 3.11.3.1, 3.11.3.2 and 3.11.3.3.

However, mixtures which were placed on the market before 1 May 2026 are not required to be classified in accordance with the criteria laid down in Sections 3.11.3.1, 3.11.3.2 and 3.11.3.3 until 1 May 2028.

3.11.4.    Hazard Communication

Hazard Communication Hazard Communication Hazard Communication

3.11.4.1. Label elements shall be used in accordance with Table 3.11.3 for substances and mixtures meeting the criteria for classification in this hazard class (Endocrine disruption for human health).

3.11.4.1. Label elements shall be used in accordance with Table 3.11.3 for substances and mixtures meeting the criteria for classification in this hazard class (Endocrine disruption for human health).  

Table 3.11.3.

Label elements of endocrine disruption for human health

Classification

Category 1

Category 2

Symbol/pictogram

 

 

Signal Word

Danger

Warning

Hazard Statement

EUH380: May cause endocrine disruption in humans

EUH381: Suspected of causing endocrine disruption in humans

Precautionary Statement Prevention

P201

P202

P263

P280

P201

P202

P263

P280

Precautionary Statement Response

P308 + P313

P308 + P313

Precautionary Statement Storage

P405

P405

Precautionary Statement Disposal

P501

P501

Table 3.11.3. Table 3.11.3.

Label elements of endocrine disruption for human health Label elements of endocrine disruption for human health

Classification

Category 1

Category 2

Symbol/pictogram

 

 

Signal Word

Danger

Warning

Hazard Statement

EUH380: May cause endocrine disruption in humans

EUH381: Suspected of causing endocrine disruption in humans

Precautionary Statement Prevention

P201

P202

P263

P280

P201

P202

P263

P280

Precautionary Statement Response

P308 + P313

P308 + P313

Precautionary Statement Storage

P405

P405

Precautionary Statement Disposal

P501

P501

Classification

Category 1

Category 2

Symbol/pictogram

 

 

Signal Word

Danger

Warning

Hazard Statement

EUH380: May cause endocrine disruption in humans

EUH381: Suspected of causing endocrine disruption in humans

Precautionary Statement Prevention

P201

P202

P263

P280

P201

P202

P263

P280

Precautionary Statement Response

P308 + P313

P308 + P313

Precautionary Statement Storage

P405

P405

Precautionary Statement Disposal

P501

P501

Classification

Category 1

Category 2

Classification

Classification

Category 1

Category 1

Category 2

Category 2

Symbol/pictogram

 

 

Symbol/pictogram

Symbol/pictogram

 

 

 

 

Signal Word

Danger

Warning

Signal Word

Signal Word

Danger

Danger

Warning

Warning

Hazard Statement

EUH380: May cause endocrine disruption in humans

EUH381: Suspected of causing endocrine disruption in humans

Hazard Statement

Hazard Statement

EUH380: May cause endocrine disruption in humans

EUH380: May cause endocrine disruption in humans

EUH381: Suspected of causing endocrine disruption in humans

EUH381: Suspected of causing endocrine disruption in humans

Precautionary Statement Prevention

P201

P202

P263

P280

P201

P202

P263

P280

Precautionary Statement Prevention

Precautionary Statement Prevention

P201

P202

P263

P280

P201

P202

P263

P280

P201

P202

P263

P280

P201

P202

P263

P280

Precautionary Statement Response

P308 + P313

P308 + P313

Precautionary Statement Response

Precautionary Statement Response

P308 + P313

P308 + P313

P308 + P313

P308 + P313

Precautionary Statement Storage

P405

P405

Precautionary Statement Storage

Precautionary Statement Storage

P405

P405

P405

P405

Precautionary Statement Disposal

P501

P501

Precautionary Statement Disposal

Precautionary Statement Disposal

P501

P501

P501

P501

3.11.4.2.    Application in time for substances Application in time for substances Application in time for substances

From 1 May 2025 at the latest, substances shall be labelled in accordance with Section 3.11.4.1.

However, substances which were placed on the market before 1 May 2025 are not required to be labelled in accordance with Section 3.11.4.1 until 1 November 2026.

3.11.4.3.    Application in time for mixtures Application in time for mixtures Application in time for mixtures

From 1 May 2026 at the latest, mixtures shall be labelled in accordance with Section 3.11.4.1.

However, mixtures which were placed on the market before 1 May 2026 are not required to be labelled in accordance with Section 3.11.4.1 until 1 May 2028.

▼M2 ▼M2

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