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8.: TOXICOLOGICAL INFORMATION


COLUMN 1

STANDARD INFORMATION REQUIRED

COLUMN 2

SPECIFIC RULES FOR ADAPTATION FROM COLUMN 1

 

8.4.  If there is a positive result in any of the in vitro genotoxicity studies in Annexes VII or VIII, a second in vivo somatic cell test may be necessary, depending on the quality and relevance of all the available data.

If there is a positive result from an in vivo somatic cell study available, the potential for germ cell mutagenicity should be considered on the basis of all available data, including toxicokinetic evidence. If no clear conclusions about germ cell mutagenicity can be made, additional investigations shall be considered.

 

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.

 

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

8.7.  The studies need not be conducted if:

— the substance is known to be a genotoxic carcinogen and appropriate risk management measures are implemented, or

— the substance is known to be a germ cell mutagen and appropriate risk management measures are implemented, or

— the substance is of low toxicological activity (no evidence of 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 fertility, meeting the criteria for classification as toxic for reproduction 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 fertility will be necessary. However, testing for developmental toxicity must be considered.

If a substance is known to cause developmental toxicity, meeting the criteria for classification as toxic for reproduction 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 will be necessary. However, testing for effects on fertility must be considered.

8.7.2.  Developmental toxicity study, one species, most appropriate route of administration, having regard to the likely route of human exposure (OECD 414).

 

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8.7.3.  Extended One-Generation Reproductive Toxicity Study (B.56 of the Commission Regulation on test methods as specified in Article 13(3) or OECD 443), basic test design (cohorts 1A and 1B without extension to include a F2 generation), one species, most appropriate route of administration, having regard to the likely route of human exposure, unless already provided as part of Annex IX requirements.

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 in accordance with Article 40 or 41, 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.

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 accordance with Article 40 or 41, 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.

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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

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— 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.

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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.