Annex VIII

02006R1907-20220501 → 02006R1907-20221014

ANNEX VIII STANDARD INFORMATION REQUIREMENTS FOR SUBSTANCES MANUFACTURED OR IMPORTED IN QUANTITIES OF 10 TONNES OR MORE This Annex shall apply to producers of articles that are required to register in accordance with Article 7 and to other downstream users that are … 729 unchanged words … 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. 8.4. Mutagenicity 8.4. The studies referred to in points 8.4.2 and 8.4.3 do not need to be conducted in any of the following cases: 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. 8.4.2. In vitro cytogenicity mammalian chromosomal aberration study in mammalian cells or in vitro mammalian 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 the substance is known to be carcinogenic category 1A or 1B or germ cell mutagenic category 1A, 1B … 633 unchanged words … 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, 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. 8.7. Reproductive toxicity 8.7.1. Screening for reproductive/developmental toxicity, one species toxicity (OECD TG 421 or 422), TG 422); the preferred species is the rat. The route of administration shall be oral if there is no evidence from available information on structurally related substances, from (Q)SAR estimates or from in vitro methods that the substance is a solid or liquid, and inhalation if the substance is a gas; deviations may be a developmental toxicant made if scientifically justified, for example through evidence of equivalent or higher systemic exposure via another relevant route of human exposure or route-specific toxicity. 8.7.1. This study does not need to be conducted if: in any of the following cases: the substance is known to be a genotoxic carcinogen 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, or the substance is known to be a germ cell mutagen mutagen, meeting the criteria for classification in the hazard class germ cell mutagenicity category 1A or 1B and appropriate risk management measures are implemented, or relevant human exposure can be excluded in accordance with Annex XI section XI, Section 3, or a pre-natal developmental toxicity study (Annex (OECD TG 414) referred to in Annex IX, 8.7.2) or, either point 8.7.2 or an Extended One-Generation Reproductive Toxicity Study (B.56, OECD (OECD TG 443) (Annex referred to in Annex IX, section 8.7.3) point 8.7.3 is available or proposed by the registrant; or a two-generation study (B.35, OECD Two-Generation Reproductive Toxicity Study (OECD TG 416), 416) is available. If available, a substance is known to have an adverse effect on sexual function or fertility, meeting the criteria for classification as toxic for reproduction 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, 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 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, then no further testing for developmental toxicity will be necessary. However, testing for effects on fertility must be considered. assessment. In cases where there are case of serious concerns about the potential for 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 (Annex (OECD TG 443), referred to in Annex IX, section 8.7.3) point 8.7.3, or a pre-natal developmental toxicity study (Annex (OECD TG 414), referred to in Annex IX, section 8.7.2) may, as appropriate, be proposed by the registrant point 8.7.2, instead of the screening study. 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. 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. For nanoforms without high dissolution rate in biological media a toxicokinetics study shall be proposed by the registrant or may be required by the Agency in accordance with Article 40 or 41 in case such an assessment cannot be performed on the basis of relevant available information, including from the study conducted in accordance with 8.6.1. 8.6.1 The choice of the study will depend on the remaining information gaps and the results of the chemical safety assessment. 9. ECOTOXICOLOGICAL INFORMATION COLUMN 1 STANDARD INFORMATION REQUIRED COLUMN 2 SPECIFIC RULES FOR ADAPTATION FROM COLUMN 1 9.1. Aquatic toxicity 9.1. Long-term aquatic toxicity testing referred to in Annex IX, subsection 9.1, in addition to short-term toxicity testing shall be proposed by the registrant or may be required by the Agency if the chemical safety assessment performed in accordance with Annex I indicates that it is needed to further investigate the effects on aquatic organisms, for example when further information is needed for the refinement of the PNEC or if additional toxicity information as set out in Annex XIII, point 3.2.3, would be necessary to assess PBT or vPvB properties of the substance. The choice of the appropriate test(s) shall be made on the basis of the results of the chemical safety assessment. 9.1.3. Short-term toxicity testing on fish: the registrant may consider long-term toxicity testing instead of short-term. fish 9.1.3. The study does not need to be conducted if: in any of the following cases: there are mitigating factors indicating that short-term aquatic toxicity is unlikely to occur, for instance if the substance is highly insoluble in water or the substance is unlikely to cross biological membranes, or a long-term aquatic toxicity study on fish is available. For nanoforms, the study may not be waived on the basis of high insolubility in water alone. The registrant may propose long-term toxicity testing instead of short-term toxicity testing. Long-term toxicity testing on fish referred to in Annex IX, point 9.1.6, shall be proposed by the registrant or may be required by the Agency when it is unlikely that short-term toxicity testing can provide a true measure of the intrinsic aquatic toxicity testing as described in Annex IX shall be considered if the chemical safety assessment according to Annex I indicates the need to investigate further effects on aquatic organisms. The choice of the appropriate test(s) will depend on the results of the chemical safety assessment. The long-term aquatic toxicity study on fish (Annex IX, Section 9.1.6) shall be considered substance, for instance: if the substance is poorly water soluble, soluble (below 1 mg/L), or for nanoforms if they have with low dissolution rate in the relevant test media. 9.1.4. Activated sludge respiration inhibition testing 9.1.4. The study does not need to be conducted if: there is no emission to a sewage treatment plant, or there are mitigating factors indicating that microbial toxicity is unlikely to occur, for instance the substance is highly insoluble in water, or the substance is found to be readily biodegradable and the applied test concentrations are in the range of concentrations that can be expected in the influent of a sewage treatment plant. For nanoforms, the study may not be waived on the basis of high insolubility in water alone. The study may be replaced by a nitrification inhibition test if available data show that the substance is likely to be an inhibitor of microbial growth or function, in particular nitrifying bacteria. 9.2. Degradation 9.2. Further information on degradation shall be generated or further degradation testing as described in Annex IX shall be considered proposed if the chemical safety assessment according to performed in accordance with Annex I indicates the need that it is needed to further investigate further the degradation of the substance. That could for example be the case if additional information on degradation as set out in Annex XIII, point 3.2.1, is required to assess PBT or vPvB properties of the substance in accordance with subsection 2.1 of that Annex. For nanoforms that are not soluble, nor have high dissolution rate, such test(s) shall consider morphological transformation (e.g. irreversible changes in particle size, shape and surface properties, loss of coating), chemical transformation (e.g. oxidation, reduction) and other abiotic degradation (e.g. photolysis). The choice of the appropriate test(s) will depend shall be made on the basis of the results of the chemical safety assessment. In case the generation of additional information requires further testing in accordance with Annex IX, the registrant shall propose or the Agency may require such testing. 9.2.2. Abiotic 9.2.2.1. Hydrolysis as a function of pH. 9.2.2.1. The study does not need to be conducted if: in any of the following cases: the substance is readily biodegradable, or the substance is highly insoluble in water. water, based on the structure, the substance does not have chemical groups that can hydrolyse. For nanoforms, the study may not be waived on the basis of high insolubility in water alone. 9.3. Fate and behaviour in the environment 9.3. Further information on bioaccumulation shall be generated if additional information on bioaccumulation as set out in Annex XIII, point 3.2.2, is required to assess PBT or vPvB properties of the substance in accordance with subsection 2.1 of that Annex. In case the generation of additional information requires further testing in accordance with Annex IX or Annex X, the registrant shall propose or the Agency may require such testing. 9.3.1. Adsorption/desorption screening 9.3.1. The study does not need to be conducted if: based on the physicochemical properties the substance can be expected to have a low potential for adsorption (e.g. the substance has a low octanol-water partition coefficient), or the substance and its relevant degradation products decompose rapidly. The study may not be waived on the basis of low octanol-water partition coefficient alone, unless the adsorptive properties of the substance are solely driven by lipophilicity. For instance, the study may not be waived on the basis of low octanol-water partition coefficient alone if the substance is surface active or ionisable at environmental pH (pH 4 – 9). For nanoforms, use of any physicochemical property (e.g. octanol-water partition coefficient) as a reason for waiving the study shall include adequate justification of its relevance to low potential for adsorption.