ANNEX VIII / STANDARD INFORMATION REQUIREMENTS FOR SUBSTANCES MANUFACTURED OR IMPORTED IN QUANTITIES OF 10 TONNES OR MORE ( 61 )
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Column 1 of this Annex establishes the standard information required for all substances manufactured or imported in quantities of 10 tonnes or more in accordance with Article 12(1)(c). Accordingly, the information required in column 1 of this Annex is additional to that required in column 1 of Annex VII. Any other relevant physicochemical, toxicological and ecotoxicological information that is available shall be provided. Column 2 of this Annex lists specific rules according to which the required standard information may be omitted, replaced by other information, provided at a different stage or adapted in another way. If the conditions are met under which column 2 of this Annex allows adaptations, the registrant shall clearly state this fact and the reasons for each adaptation under the appropriate headings in the registration dossier.
Without prejudice to the information submitted for other forms, any relevant physicochemical, toxicological and ecotoxicological information shall include characterisation of the nanoform tested and test conditions. A justification shall be provided where QSARs are used or evidence is obtained by means other than testing, as well as a description of the range of the characteristics/properties of the nanoforms to which the evidence can be applied.
In addition to these specific rules, a registrant may adapt the required standard information set out in column 1 of this Annex according to the general rules contained in Annex XI. In this case as well, he shall clearly state the reasons for any decision to adapt the standard information under the appropriate headings in the registration dossier referring to the appropriate specific rule(s) in column 2 or in Annex XI ( 62 ).
Before new tests are carried out to determine the properties listed in this Annex, all available in vitro data, in vivo data, historical human data, data from valid (Q)SARs and data from structurally related substances (read-across approach) shall be assessed first. In vivo testing with corrosive substances at concentration/dose levels causing corrosivity shall be avoided. Prior to testing, further guidance on testing strategies should be consulted in addition to this Annex.
Where a test method offers flexibility in the study design, for example in relation to the choice of dose levels, the chosen study design shall ensure that the data generated are adequate for hazard identification and risk assessment. To this end, testing shall be performed at appropriately high dose levels. If dose (concentration) selection is limited by the physicochemical properties or biological effects of the test substance, justification shall be provided.
When, for certain endpoints, information is not provided for other reasons than those mentioned in column 2 of this Annex or in Annex XI, this fact and the reasons shall also be clearly stated.
7. INFORMATION ON THE PHYSICOCHEMICAL PROPERTIES OF THE SUBSTANCE
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7.14ter. Further information on physicochemical properties Only for nanoforms |
Further testing for nanoforms covered by the registration shall be considered by the registrant or may be required by the Agency in accordance with Article 41, if there is an indication that specific additional particle properties significantly influence the hazard of or the exposure to those nanoforms. |
8. TOXICOLOGICAL INFORMATION
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COLUMN 1 STANDARD INFORMATION REQUIRED |
COLUMN 2 SPECIFIC RULES FOR ADAPTATION FROM COLUMN 1 |
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8.1. Skin corrosion/irritation |
8.1. An in vivo study for skin corrosion/irritation shall be conducted only if the in vitro study/studies under points 8.1.1 and/or 8.1.2 of Annex VII is(are) not applicable, or the results of this/these study/studies is/are not adequate for classification and risk assessment. The study does not need to be conducted if: — the substance is a strong acid (pH ≤ 2,0) or base (pH ≥ 11,5), or — the substance is spontaneously flammable in air or in contact with water or moisture at room temperature, or — the substance is classified as acute toxicity by the dermal route (Category 1), or — an acute toxicity study by the dermal route does not indicate skin irritation up to the limit dose level (2 000 mg/kg body weight). |
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8.2. Serious eye damage/eye irritation |
8.2. An in vivo study for serious eye damage/eye irritation shall be conducted only if the in vitro study/studies) under point 8.2.1 of Annex VII is/are not applicable, or the results of this/these study/studies) are not adequate for classification and risk assessment. The study does not need to be conducted if: — the substance is classified as skin corrosion, or — the substance is a strong acid (pH ≤ 2,0) or base (pH ≥ 11,5), or — the substance is spontaneously flammable in air or in contact with water or moisture at room temperature. |
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8.4. Mutagenicity |
►M70
— adequate data from the corresponding in vivo study, (namely in vivo chromosomal aberration (or micronucleus) study regarding point 8.4.2 or in vivo mammalian gene mutation study regarding point 8.4.3), are available, — the substance is known to cause germ cell mutagenicity, meeting the criteria for classification as germ cell mutagen category 1A or 1B, and appropriate risk management measures are implemented, — the substance is known to be a genotoxic carcinogen, meeting the criteria for classification both in the hazard class germ cell mutagenicity category 1A, 1B or 2 and in the hazard class carcinogenicity category 1A or 1B, and appropriate risk management measures are implemented. — In case of a positive result in any of the in vitro genotoxicity studies referred to in Annex VII or this Annex, which gives rise to concern, the registrant shall propose, or the Agency may require, an appropriate in vivo study referred to in Annex IX, point 8.4. The in vivo study shall address the chromosomal aberration concern or the gene mutation concern or both as appropriate. — In case an in vitro mutagenicity study referred to in points 8.4.2 or 8.4.3 is not applicable for the substance, the registrant shall provide a justification and shall propose or the Agency may require an appropriate in vivo study referred to in Annex IX, point 8.4.4. The in vivo study shall address the chromosomal aberration concern or the gene mutation concern or both as appropriate. |
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►M70
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►M70 ◄ |
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8.4.3. In vitro gene mutation study in mammalian cells, if a negative result in Annex VII, Section 8.4.1. and Annex VIII, Section 8.4.2. |
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8.4. Appropriate in vivo mutagenicity studies shall be considered in case of a positive result in any of the genotoxicity studies in Annex VII or VIII. |
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8.5. Acute toxicity |
8.5. The study/ies do(es) not generally need to be conducted if: — the substance is classified as corrosive to the skin. In addition to the oral route (8.5.1.) or to the inhalation route (8.5.2) for nanoforms, for substances other than gases, the information mentioned under 8.5.1. to 8.5.3. shall be provided for at least one other route. The choice for the second route will depend on the nature of the substance and the likely route of human exposure. If there is only one route of exposure, information for only that route needs to be provided. |
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8.5.2. By inhalation |
8.5.2. Testing by the inhalation route is appropriate if exposure of humans via inhalation is likely taking into account the vapour pressure of the substance and/or the possibility of exposure to aerosols, particles or droplets of an inhalable size. |
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8.5.3. By dermal route |
8.5.3. Testing by the dermal route is appropriate if: (1) inhalation of the substance is unlikely; and (2) skin contact in production and/or use is likely; and (3) the physicochemical and toxicological properties suggest potential for a significant rate of absorption through the skin. Testing by the dermal route does not need to be conducted if: — the substance does not meet the criteria for classification as acute toxicity or STOT SE by the oral route and — no systemic effects have been observed in in vivo studies with dermal exposure (e.g. skin irritation, skin sensitisation) or, in the absence of an in vivo study by the oral route, no systemic effects after dermal exposure are predicted on the basis of non-testing approaches (e.g. read across, QSAR studies). |
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8.6. Repeated dose toxicity |
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8.6.1. Short-term repeated dose toxicity study (28 days), one species, male and female, most appropriate route of administration, having regard to the likely route of human exposure. |
8.6.1. The short-term toxicity study (28 days) does not need to be conducted if: ►M64
— da reliable sub-chronic (90 days) or chronic toxicity study is available or proposed by the registrant, provided that an appropriate species, dosage, solvent and route of administration are used, or — where a substance undergoes immediate disintegration and there are sufficient data on the cleavage products, or — relevant human exposure can be excluded in accordance with Annex XI Section 3. The appropriate route shall be chosen on the following basis: Testing by the dermal route is appropriate if: — inhalation of the substance is unlikely, and — skin contact in production and/or use is likely, and — the physicochemical and toxicological properties suggest potential for a significant rate of absorption through the skin. Testing by the inhalation route is appropriate if exposure of humans via inhalation is likely taking into account the vapour pressure of the substance and/or the possibility of exposure to aerosols, particles or droplets of an inhalable size. For nanoforms without high dissolution rate in biological media, the study shall include toxicokinetic investigations on, among others, the recovery period and, where relevant, lung clearance. Toxicokinetic investigations do not need to be performed if equivalent toxicokinetic information on the nanoform is already available. The sub-chronic toxicity study (90 days) (Annex IX, point 8.6.2) shall be proposed by the registrant, or may be required by the Agency if: the frequency and duration of human exposure indicates that a longer term study is appropriate; and one of the following conditions is met: — other available data indicate that the substance may have a dangerous property that cannot be detected in a short-term toxicity study, or — appropriately designed toxicokinetic studies reveal accumulation of the substance or its metabolites in certain tissues or organs which would possibly remain undetected in a short-term toxicity study but which are liable to result in adverse effects after prolonged exposure. ►M70 Further studies shall be proposed by the registrant or may be required by the Agency in case of: ◄ — failure to identify a NOAEL in the 28 or the 90 days study, unless the reason for the failure to identify a NOAEL is absence of adverse toxic effects, or — toxicity of particular concern (e.g. serious/severe effects), or — indications of an effect for which the available evidence is inadequate for toxicological and/or risk characterisation. In such cases it may also be more appropriate to perform specific toxicological studies that are designed to investigate these effects (e.g. immunotoxicity, neurotoxicity, and in particular for nanoforms indirect genotoxicity), or — the route of exposure used in the initial repeated dose study was inappropriate in relation to the expected route of human exposure and route-to-route extrapolation cannot be made, or — particular concern regarding exposure (e.g. use in consumer products leading to exposure levels which are close to the dose levels at which toxicity to humans may be expected), or — effects shown in substances with a clear relationship in molecular structure with the substance being studied, were not detected in the 28 or the 90 days study. |
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8.7. Reproductive toxicity |
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8.7.1. Screening for reproductive/developmental toxicity (OECD TG 421 or TG 422); the preferred species is the rat. The route of administration shall be oral if the substance is a solid or liquid, and inhalation if the substance is a gas; deviations may be made if scientifically justified, for example through evidence of equivalent or higher systemic exposure via another relevant route of human exposure or route-specific toxicity. |
8.7.1. This study does not need to be conducted in any of the following cases: — the substance is known to be a genotoxic carcinogen, meeting the criteria for classification both in the hazard class germ cell mutagenicity category 1A, 1B or 2 and in the hazard class carcinogenicity category 1A or 1B, and appropriate risk management measures are implemented, — the substance is known to be a germ cell mutagen, meeting the criteria for classification in the hazard class germ cell mutagenicity category 1A or 1B and appropriate risk management measures are implemented, — relevant human exposure can be excluded in accordance with Annex XI, Section 3, — a pre-natal developmental toxicity study (OECD TG 414) referred to in Annex IX, point 8.7.2 or an Extended One-Generation Reproductive Toxicity Study (OECD TG 443) referred to in Annex IX, point 8.7.3 is available or proposed by the registrant; or a Two-Generation Reproductive Toxicity Study (OECD TG 416) is available, — a substance is known to have an adverse effect on sexual function or fertility, meeting the criteria for classification in the hazard class reproductive toxicity category 1A or 1B: May damage fertility (H360F), and the available data are adequate to support a robust risk assessment, — a substance is known to cause developmental toxicity, meeting the criteria for classification in the hazard class reproductive toxicity category 1A or 1B: May damage the unborn child (H360D), and the available data are adequate to support a robust risk assessment. — In case of serious concerns about potential adverse effects on sexual function, fertility or development, the registrant shall propose, or the Agency may require either an Extended One-Generation Reproductive Toxicity Study (OECD TG 443), referred to in Annex IX, point 8.7.3, or a pre-natal developmental toxicity study (OECD TG 414), referred to in Annex IX, point 8.7.2, instead of the screening study (OECD TG 421 or 422) to address those concerns. Those serious concerns include among others: — adverse effects related to sexual function, fertility or development based on available information, not meeting the criteria for classification as reproductive toxicity category 1A or 1B, — possible developmental or reproductive toxicity of the substance predicted from information on structurally related substances, (Q)SAR estimates or in vitro methods. |
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8.8. Toxicokinetics |
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8.8.1. Assessment of the toxicokinetic behaviour of the substance to the extent that can be derived from the relevant available information. |
►M70 For nanoforms without high dissolution rate in biological media a toxicokinetics study shall be proposed by the registrant or may be required by the Agency in case such an assessment cannot be performed on the basis of relevant available information, including from the study conducted in accordance with 8.6.1 ◄ The choice of the study will depend on the remaining information gaps and the results of the chemical safety assessment. |
9. ECOTOXICOLOGICAL INFORMATION
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COLUMN 1 STANDARD INFORMATION REQUIRED |
COLUMN 2 SPECIFIC RULES FOR ADAPTATION FROM COLUMN 1 |
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9.1. Aquatic toxicity |
9.1. Long-term aquatic toxicity testing referred to in Annex IX, subsection 9.1, in addition to short-term toxicity testing shall be proposed by the registrant or may be required by the Agency if the chemical safety assessment performed in accordance with Annex I indicates that it is needed to further investigate the effects on aquatic organisms, for example when further information is needed for the refinement of the PNEC or if additional toxicity information as set out in Annex XIII, point 3.2.3, would be necessary to assess PBT or vPvB properties of the substance. The choice of the appropriate test(s) shall be made on the basis of the results of the chemical safety assessment. |
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9.1.3. Short-term toxicity testing on fish |
9.1.3. The study does not need to be conducted in any of the following cases: — there are factors indicating that short-term aquatic toxicity is unlikely to occur, for instance if the substance is highly insoluble in water or the substance is unlikely to cross biological membranes, — a long-term aquatic toxicity study on fish is available. — For nanoforms, the study may not be waived on the basis of high insolubility in water alone. — The registrant may propose long-term toxicity testing instead of short-term toxicity testing. — Long-term toxicity testing on fish referred to in Annex IX, point 9.1.6, shall be proposed by the registrant or may be required by the Agency when it is unlikely that short-term toxicity testing can provide a true measure of the intrinsic aquatic toxicity of the substance, for instance: — if the substance is poorly water soluble (below 1 mg/L), or — for nanoforms with low dissolution rate in the relevant test media. |
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9.1.4. Activated sludge respiration inhibition testing |
9.1.4. The study does not need to be conducted if: — there is no emission to a sewage treatment plant, or — there are mitigating factors indicating that microbial toxicity is unlikely to occur, for instance the substance is highly insoluble in water, or — the substance is found to be readily biodegradable and the applied test concentrations are in the range of concentrations that can be expected in the influent of a sewage treatment plant. For nanoforms, the study may not be waived on the basis of high insolubility in water alone. The study may be replaced by a nitrification inhibition test if available data show that the substance is likely to be an inhibitor of microbial growth or function, in particular nitrifying bacteria. |
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9.2. Degradation |
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9.2.2. Abiotic 9.2.2.1. Hydrolysis as a function of pH. |
►M70
— the substance is readily biodegradable, — the substance is highly insoluble in water, — based on the structure, the substance does not have chemical groups that can hydrolyse. For nanoforms, the study may not be waived on the basis of high insolubility in water alone. ◄ |
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9.3. Fate and behaviour in the environment |
►M70
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9.3.1. Adsorption/desorption screening |
9.3.1. The study does not need to be conducted if: — based on the physicochemical properties the substance can be expected to have a low potential for adsorption (e.g. the substance has a low octanol-water partition coefficient), or — the substance and its relevant degradation products decompose rapidly. The study may not be waived on the basis of low octanol-water partition coefficient alone, unless the adsorptive properties of the substance are solely driven by lipophilicity. For instance, the study may not be waived on the basis of low octanol-water partition coefficient alone if the substance is surface active or ionisable at environmental pH (pH 4 – 9). For nanoforms, use of any physicochemical property (e.g. octanol-water partition coefficient) as a reason for waiving the study shall include adequate justification of its relevance to low potential for adsorption. |