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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8.4. Mutagenicity |
8.4. The studies referred to in points 8.4.4 and 8.4.5 do not need to be conducted in any of the following cases: — the substance is known to cause germ cell mutagenicity, meeting the criteria for classification in the hazard class germ cell mutagenicity 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. |
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8.4.4. An appropriate in vivo mammalian somatic cell genotoxicity study, if there is a positive result in any of the in vitro genotoxicity studies referred to in Annex VII or Annex VIII, which gives rise to concern. The in vivo mammalian somatic cell genotoxicity study shall address the chromosomal aberration concern or the gene mutation concern or both, as appropriate. |
8.4.4. The in vivo mammalian somatic cell genotoxicity study does not need to be conducted if there are adequate results available from an appropriate in vivo mammalian somatic cell genotoxicity study. |
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8.4.5. An appropriate in vivo mammalian germ cell genotoxicity study, if there is a positive result in an available in vivo mammalian somatic cell genotoxicity study, which gives rise to concern. The in vivo mammalian germ cell genotoxicity study shall address the chromosomal aberration concern or the gene mutation concern or both, as appropriate. |
8.4.5. The study does not need to be conducted if there is clear evidence that neither the substance nor its metabolites reach the germ cells. |
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8.6. Repeated dose toxicity |
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▼M64 ————— |
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8.6.2. Sub-chronic toxicity study (90-day), one species, rodent, male and female, most appropriate route of administration, having regard to the likely route of human exposure. |
8.6.2. The sub-chronic toxicity study (90 days) does not need to be conducted if: — a reliable short-term toxicity study (28 days) is available showing severe toxicity effects meeting the criteria for classifying the substance as STOT RE (category 1 or 2), for which the observed NOAEL-28 days, with the application of an appropriate uncertainty factor, allows the extrapolation towards the NOAEL-90 days for the same route of exposure, or — a reliable chronic toxicity study is available or proposed by the registrant, provided that an appropriate species and route of administration are used, or; — a substance undergoes immediate disintegration and there are sufficient data on the cleavage products (both for systemic effects and effects at the site of uptake), or — the substance is unreactive, insoluble and not inhalable and there is no evidence of absorption and no evidence of toxicity in a 28-day ‘limit test’, particularly if such a pattern is coupled with limited human exposure. The appropriate route shall be chosen on the following basis: Testing by the dermal route is appropriate if: (1) skin contact in production and/or use is likely; and (2) the physicochemical properties suggest a significant rate of absorption through the skin; and (3) one of the following conditions is met: — toxicity is observed in the acute dermal toxicity test at lower doses than in the oral toxicity test, or — systemic effects or other evidence of absorption is observed in skin and/or eye irritation studies, or — in vitro tests indicate significant dermal absorption, or — significant dermal toxicity or dermal penetration is recognised for structurally-related substances. 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. Further studies shall be proposed by the registrant or may be required by the Agency in accordance with Articles 40 or 41 in case of: — failure to identify a NOAEL in 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 — 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). |
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8.7. Reproductive toxicity |
►M64
— the substance is known to be a genotoxic carcinogen, meeting the criteria for classification both in the hazard class germ cell mutagenicity (category 1A or 1B or 2) and carcinogenicity (category 1A or 1B), and appropriate risk management measures are implemented, or — 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, or — the substance is of low toxicological activity (a comprehensive and informative dataset showing no toxicity in any of the tests available), it can be proven from toxicokinetic data that no systemic absorption occurs via relevant routes of exposure (e.g. plasma/blood concentrations below detection limit using a sensitive method and absence of the substance and of metabolites of the substance in urine, bile or exhaled air) and there is no or no significant human exposure. If a substance is known to have an adverse effect on sexual function and 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, then no further testing for sexual function and fertility shall be necessary. If 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, then no further testing for developmental toxicity shall be necessary. ◄ |
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8.7.2. Pre-natal developmental toxicity study (OECD TG 414) on one species; the preferred species is the rat or the rabbit. 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. |
8.7.2. An additional pre-natal developmental toxicity study in a second species, that is the other preferred species to the one used in the first study, shall be proposed by the registrant or may be required by the Agency if there is a concern for developmental toxicity based on the outcome of the first study and all other relevant data. That could be the case for example if the study on the first species shows developmental toxicity not meeting the criteria for classification in the hazard class reproductive toxicity category 1A or 1B; May damage the unborn child (H360D). Deviations from the default route of administration and deviations in the choice of species shall be scientifically justified. |
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►M70
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8.7.3. An Extended One-Generation Reproductive Toxicity Study with the extension of cohort 1B to include the F2 generation shall be proposed by the registrant or may be required by the Agency if: (a) the substance has uses leading to significant exposure of consumers or professionals, taking into account, inter alia, consumer exposure from articles, and (b) any of the following conditions are met: — the substance displays genotoxic effects in somatic cell mutagenicity tests in vivo which could lead to classifying it as Mutagen Category 2, or — there are indications that the internal dose for the substance and/or any of its metabolites will reach a steady state in the test animals only after an extended exposure, or — there are indications of one or more relevant modes of action related to endocrine disruption from available in vivo studies or non-animal approaches. ►M70 An Extended One-Generation Reproductive Toxicity Study including cohorts 2A/2B (developmental neurotoxicity) and/or cohort 3 (developmental immunotoxicity) shall be proposed by the registrant or may be required by the Agency in case of particular concerns on (developmental) neurotoxicity or (developmental) immunotoxicity justified by any of the following: ◄ — existing information on the substance itself derived from relevant available in vivo or non-animal approaches (e.g. abnormalities of the CNS, evidence of adverse effects on the nervous or immune system in studies on adult animals or animals exposed prenatally), or — specific mechanisms/modes of action of the substance with an association to (developmental) neurotoxicity and/or (developmental) immunotoxicity (e.g. cholinesterase inhibition or relevant changes in thyroidal hormone levels associated to adverse effects), or — existing information on effects caused by substances structurally analogous to the substance being studied, suggesting such effects or mechanisms/modes of action. Other studies on developmental neurotoxicity and/or developmental immunotoxicity instead of cohorts 2A/2B (developmental neurotoxicity) and/or cohort 3 (developmental immunotoxicity) of the Extended One-Generation Reproductive Toxicity Study may be proposed by the registrant in order to clarify the concern on developmental toxicity. Two-generation reproductive toxicity studies (B.35, OECD TG 416) that were initiated before 13 March 2015 shall be considered appropriate to address this standard information requirement. The study shall be performed on one species. The need to perform a study at this tonnage level or the next on a second strain or a second species may be considered and a decision should be based on the outcome of the first test and all other relevant available data. |