[X1ANNEX IX U.K. STANDARD INFORMATION REQUIREMENTS FOR SUBSTANCES MANUFACTURED OR IMPORTED IN QUANTITIES OF 100 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 Annex VII or VIII and there are no results available from an in vivo study already, an appropriate in vivo somatic cell genotoxicity study shall be proposed by the registrant.

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. Repeated dose toxicity
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, unless already provided as part of Annex VIII requirements or if tests according to Section 8.6.2 of this Annex is proposed. In this case, Section 3 of Annex XI shall not apply.
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 according to the criteria for classifying the substance as R48, 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, provided that an appropriate species and route of administration were 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.

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), 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).

8.7. Reproductive toxicity
8.7. The studies do not need to 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. Pre-natal developmental toxicity study, one species, most appropriate route of administration, having regard to the likely route of human exposure (B.31 of the Commission Regulation on test methods as specified in Article 13(3) or OECD 414).
8.7.2. The study shall be initially performed on one species. A decision on the need to perform a study at this tonnage level or the next on a second species should be based on the outcome of the first test and all other relevant available data.
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, if the 28-day or 90-day study indicates adverse effects on reproductive organs or tissues.
8.7.3. The study shall be initially performed on one species. A decision on the need to perform a study at this tonnage level or the next on a second species should be based on the outcome of the first test and all other relevant available date.]

Textual Amendments

(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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