8. TOXICOLOGICAL INFORMATION
|
COLUMN 1 STANDARD INFORMATION REQUIRED |
COLUMN 2 SPECIFIC RULES FOR ADAPTATION FROM COLUMN 1 |
|
8.4. Mutagenicity |
8.4. The studies referred to in points 8.4.6 and 8.4.7 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 or 1B or 2 and in the hazard class carcinogenicity category 1A or 1B, and appropriate risk management measures are implemented. |
|
8.4.6. A second 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 both chromosomal aberration concern and gene mutation concern. The second study shall address chromosomal aberration or gene mutation, as appropriate, which has not been addressed by the first in vivo mammalian somatic cell genotoxicity study. |
|
|
8.4.7. A second in vivo mammalian germ cell genotoxicity study, if there is a positive result in in vivo mammalian somatic cell genotoxicity studies, which gives rise to both chromosomal aberration concern and gene mutation concern. The second study shall address the chromosomal aberration or gene mutation, as appropriate, which has not been addressed by the first in vivo mammalian germ cell genotoxicity study. |
8.4.7. The study does not need to be conducted if there is clear evidence that neither the substance nor its metabolites reach the germ cells. |
|
|
8.6.3. A long-term repeated toxicity study (≥ 12 months) may be proposed by the registrant or required by the Agency in accordance with Articles 40 or 41 if the frequency and duration of human exposure indicates that a longer term study is appropriate and one of the following conditions is met: — serious or severe toxicity effects of particular concern were observed in the 28-day or 90-day study for which the available evidence is inadequate for toxicological evaluation or risk characterisation, or — effects shown in substances with a clear relationship in molecular structure with the substance being studied were not detected in the 28-day or 90-day study, or — the substance may have a dangerous property that cannot be detected in a 90-day study. If nanoforms are covered by the registration, physicochemical characteristics, in particular particle size, shape and other morphological parameters, surface functionalisation and surface area, as well as molecular structure shall be taken into consideration when determining if one of the conditions above are met. |
|
|
8.6.4. 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: — toxicity of particular concern (e.g. serious/severe effects), or — indications of an effect for which the available evidence is inadequate for toxicological evaluation 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), 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 is observed). |
|
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 seen 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. ◄ |
|
8.7.2. Pre-natal developmental toxicity study (OECD TG 414) in a second species, the preferred species is the rat or the rabbit, whichever was not used in the first study under Annex IX. 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. |
Deviations from the default route of administration and deviations in the choice of species shall be scientifically justified. |
|
►M70
|
8.7.3. ►M70 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. |
|
8.9.1. Carcinogenicity study |
8.9.1. A carcinogenicity study may be proposed by the registrant or may be required by the Agency in accordance with Articles 40 or 41 if: — the substance has a widespread dispersive use or there is evidence of frequent or long-term human exposure, and
— the substance is classified as germ cell mutagen category 2 or there is evidence from the repeated dose study(ies) that the substance is able to induce hyperplasia and/or pre-neoplastic lesions. If the substance is classified as germ cell mutagen category 1A or 1B, the default presumption would be that a genotoxic mechanism for carcinogenicity is likely. In these cases, a carcinogenicity test will normally not be required. |