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8.: TOXICOLOGICAL INFORMATION


COLUMN 1

STANDARD INFORMATION REQUIRED

COLUMN 2

SPECIFIC RULES FOR ADAPTATION FROM COLUMN 1

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8.1.  Skin corrosion/irritation

8.1.  An in vivo study for skin corrosion/irritation shall be considered only if the in vitro studies under points 8.1.1 and 8.1.2 in Annex VII are not applicable, or the results of these studies are not adequate for classification and risk assessment.

The study does not need to be conducted if:

— the substance is a strong acid (pH ≤ 2,0) or base (pH ≥ 11,5), or

— the substance is spontaneously flammable in air or in contact with water or moisture at room temperature, or

— the substance is classified as acute toxicity by the dermal route (Category 1), or

— an acute toxicity study by the dermal route does not indicate skin irritation up to the limit dose level (2 000  mg/kg body weight).

8.2.  Serious eye damage/eye irritation

8.2.  An in vivo study for eye corrosion/irritation shall be considered only if the in vitro study(ies) under point 8.2.1 in Annex VII are not applicable, or the results obtained from these study(ies) are not adequate for classification and risk assessment.

The study does not need to be conducted if:

— the substance is classified as skin corrosion, or

— the substance is a strong acid (pH ≤ 2,0) or base (pH ≥ 11,5), or

— the substance is spontaneously flammable in air or in contact with water or moisture at room temperature.

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8.4.  Mutagenicity

8.4.2.  In vitro cytogenicity study in mammalian cells or in vitro micronucleus study

8.4.2.  The study does not usually need to be conducted

— if adequate data from an in vivo cytogenicity test are available, or

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— the substance is known to be carcinogenic category 1A or 1B or germ cell mutagenic category 1A, 1B or 2.

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8.4.3.  In vitro gene mutation study in mammalian cells, if a negative result in Annex VII, Section 8.4.1. and Annex VIII, Section 8.4.2.

8.4.3.  The study does not usually need to be conducted if adequate data from a reliable in vivo mammalian gene mutation test are available.

 

8.4.  Appropriate in vivo mutagenicity studies shall be considered in case of a positive result in any of the genotoxicity studies in Annex VII or VIII.

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8.5.  Acute toxicity

8.5.  The study/ies do(es) not generally need to be conducted if:

— the substance is classified as skin corrosion.

In addition to the oral route (Annex VII, 8.5.1.), for substances other than gases, the information mentioned under 8.5.2 to 8.5.3 shall be provided for at least one other route. The choice for the second route will depend on the nature of the substance and the likely route of human exposure. If there is only one route of exposure, information for only that route needs to be provided.

8.5.2.  By inhalation

8.5.2.  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.

8.5.3.  By dermal route

8.5.3.  Testing by the dermal route is appropriate if:

(1)  inhalation of the substance is unlikely; and

(2)  skin contact in production and/or use is likely; and

(3)  the physicochemical and toxicological properties suggest potential for a significant rate of absorption through the skin.

Testing by the dermal route does not need to be conducted if:

— the substance does not meet the criteria for classification as acute toxicity or STOT SE by the oral route and

— no systemic effects have been observed in in vivo studies with dermal exposure (e.g. skin irritation, skin sensitisation) or, in the absence of an in vivo study by the oral route, no systemic effects after dermal exposure are predicted on the basis of non-testing approaches (e.g. read across, QSAR studies).

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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.

8.6.1.  The short-term toxicity study (28 days) does not need to be conducted if:

— a reliable sub-chronic (90 days) or chronic toxicity study is available, provided that an appropriate species, dosage, solvent and route of administration were used, or

— where a substance undergoes immediate disintegration and there are sufficient data on the cleavage products, or

— relevant human exposure can be excluded in accordance with Annex XI Section 3.

The appropriate route shall be chosen on the following basis:

Testing by the dermal route is appropriate if:

(1)  inhalation of the substance is unlikely; and

(2)  skin contact in production and/or use is likely; and

(3)  the physicochemical and toxicological properties suggest potential for a significant rate of absorption through the skin.

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.

The sub-chronic toxicity study (90 days) (Annex IX, Section 8.6.2) shall be proposed by the registrant if: the frequency and duration of human exposure indicates that a longer term study is appropriate;

and one of the following conditions is met:

— other available data indicate that the substance may have a dangerous property that cannot be detected in a short-term toxicity study, or

— appropriately designed toxicokinetic studies reveal accumulation of the substance or its metabolites in certain tissues or organs which would possibly remain undetected in a short-term toxicity study but which are liable to result in adverse effects after prolonged exposure.

Further studies shall be proposed by the registrant or may be required by the Agency in accordance with Article 40 or 41 in case of:

— failure to identify a NOAEL in the 28 or 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

— the route of exposure used in the initial repeated dose study was inappropriate in relation to the expected route of human exposure and route-to-route extrapolation cannot be made, 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), or

— effects shown in substances with a clear relationship in molecular structure with the substance being studied, were not detected in the 28 or the 90 days study.

8.7.  Reproductive toxicity

8.7.1.  Screening for reproductive/developmental toxicity, one species (OECD 421 or 422), if there is no evidence from available information on structurally related substances, from (Q)SAR estimates or from in vitro methods that the substance may be a developmental toxicant

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8.7.1.  This study does 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

— relevant human exposure can be excluded in accordance with Annex XI section 3, or

— a pre-natal developmental toxicity study (Annex IX, 8.7.2) or, either an Extended One-Generation Reproductive Toxicity Study (B.56, OECD TG 443) (Annex IX, section 8.7.3) or a two-generation study (B.35, OECD TG 416), is available.


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.
In cases where there are serious concerns about the potential for adverse effects on fertility or development, either an Extended One-Generation Reproductive Toxicity Study (Annex IX, section 8.7.3) or a pre-natal developmental toxicity study (Annex IX, section 8.7.2) may, as appropriate, be proposed by the registrant instead of the screening study.  ◄

8.8.  Toxicokinetics

8.8.1.  Assessment of the toxicokinetic behaviour of the substance to the extent that can be derived from the relevant available information