CELEX 02008R1272 · v20250901

3.1. Acute toxicity

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.

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3.1.1.2. The hazard class Acute Toxicity is differentiated into:

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Acute oral toxicity;

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Acute dermal toxicity;

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Acute inhalation toxicity.

3.1.2. Criteria for classification of substances as acutely toxic

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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.

Table 3.1.1

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

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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).

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.

(b)

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

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the LD50/LC50 where available,

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the appropriate conversion value from Table 3.1.2 that relates to the results of a range test, or

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the appropriate conversion value from Table 3.1.2 that relates to a classification category.

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(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.

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(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:

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dust: solid particles of a substance or mixture suspended in a gas (usually air),

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mist: liquid droplets of a substance or mixture suspended in a gas (usually air),

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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.

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3.1.2.2. 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.

3.1.2.3. 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.

3.1.2.3.2. ►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.

3.1.2.3.3. 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

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.

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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.

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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).

(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.

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(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.

(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.

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Figure 3.1.1

Tiered approach to classification of mixtures for acute toxicity

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3.1.3.4. 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.

3.1.3.5. 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.

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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.

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

3.1.3.6.1. 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:

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

(b)

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

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(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.

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.

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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:

where:

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

the individual ingredient from 1 to n

the number of ingredients

ATEi

Acute Toxicity Estimate of ingredient i.

3.1.3.6.2. 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.

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;

(b)

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

(d)

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.

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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:

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Table 3.1.2

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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

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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

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

300

1 100

Gases

(ppmV)

0 < Category 1 ≤ 100

100 < Category 2 ≤ 500

500 < Category 3 ≤ 2 500

2 500 < Category 4 ≤ 20 000

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

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

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

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. ◄

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Table 3.1.3

Acute toxicity label elements

Classification	Category 1	Category 2	Category 3	Category 4
GHS Pictograms
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

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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.

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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’.

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3.1. Acute toxicity