8.   TOXICOLOGICAL INFORMATION

— 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).

— 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.

— adequate data from the corresponding in vivo study, (namely in vivo chromosomal aberration (or micronucleus) study regarding point 8.4.2 or in vivo mammalian gene mutation study regarding point 8.4.3), are available,

— the substance is known to cause germ cell mutagenicity, meeting the criteria for classification as germ cell mutagen 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, 1B or 2 and in the hazard class carcinogenicity category 1A or 1B, and appropriate risk management measures are implemented.

— In case of a positive result in any of the in vitro genotoxicity studies referred to in Annex VII or this Annex, which gives rise to concern, the registrant shall propose, or the Agency may require, an appropriate in vivo study referred to in Annex IX, point 8.4. The in vivo study shall address the chromosomal aberration concern or the gene mutation concern or both as appropriate.

— In case an in vitro mutagenicity study referred to in points 8.4.2 or 8.4.3 is not applicable for the substance, the registrant shall provide a justification and shall propose or the Agency may require an appropriate in vivo study referred to in Annex IX, point 8.4.4. The in vivo study shall address the chromosomal aberration concern or the gene mutation concern or both as appropriate.

— the substance is classified as corrosive to the skin.

— 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).

— da reliable sub-chronic (90 days) or chronic toxicity study is available or proposed by the registrant, provided that an appropriate species, dosage, solvent and route of administration are 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.

— inhalation of the substance is unlikely, and

— skin contact in production and/or use is likely, and

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

— 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.

— 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, and in particular for nanoforms indirect genotoxicity), 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.

— the substance is known to be a genotoxic carcinogen, meeting the criteria for classification both in the hazard class germ cell mutagenicity category 1A, 1B or 2 and in the hazard class carcinogenicity category 1A or 1B, and appropriate risk management measures are implemented,

— 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,

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

— a pre-natal developmental toxicity study (OECD TG 414) referred to in Annex IX, point 8.7.2 or an Extended One-Generation Reproductive Toxicity Study (OECD TG 443) referred to in Annex IX, point 8.7.3 is available or proposed by the registrant; or a Two-Generation Reproductive Toxicity Study (OECD TG 416) is available,

— a substance is known to have an adverse effect on sexual function or 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,

— 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.

— In case of serious concerns about potential adverse effects on sexual function, fertility or development, the registrant shall propose, or the Agency may require either an Extended One-Generation Reproductive Toxicity Study (OECD TG 443), referred to in Annex IX, point 8.7.3, or a pre-natal developmental toxicity study (OECD TG 414), referred to in Annex IX, point 8.7.2, instead of the screening study (OECD TG 421 or 422) to address those concerns. Those serious concerns include among others:

— adverse effects related to sexual function, fertility or development based on available information, not meeting the criteria for classification as reproductive toxicity category 1A or 1B,

— possible developmental or reproductive toxicity of the substance predicted from information on structurally related substances, (Q)SAR estimates or in vitro methods.