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[X1ANNEX X U.K. STANDARD INFORMATION REQUIREMENTS FOR SUBSTANCES MANUFACTURED OR IMPORTED IN QUANTITIES OF 1 000 TONNES OR MORE (1)

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8. TOXICOLOGICAL INFORMATION U.K.

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.

[F1If 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).
8.7.3. Two-generation reproductive toxicity study, one species, male and female, most appropriate route of administration, having regard to the likely route of human exposure, unless already provided as part of Annex IX requirements
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

  • [F1the 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.]

[F1If 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.] ]

(1)

[X1This Annex shall apply to producers of articles that are required to register in accordance with Article 7 and to other downstream users that are required to carry out tests under this Regulation adapted as necessary.]

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