Registration, Evaluation, Authorisation and Restriction of Chemicals

02006R1907-20211001 → 02006R1907-20220108

ANNEX VII STANDARD INFORMATION REQUIREMENTS FOR SUBSTANCES MANUFACTURED OR IMPORTED IN QUANTITIES OF ONE TONNE OR MOREThis Annex shall apply to producers of articles that are required to register in accordance with Article 7 and to other downstream users that are … 385 unchanged words … from structurally related substances (read-across approach) shall be assessed first. In vivo testing with corrosive substances at concentration/dose levels causing corrosivity shall be avoided. Prior to testing, further guidance on testing strategies should be consulted in addition to this Annex. Where a test method offers flexibility in the study design, for example in relation to the choice of dose levels, the chosen study design shall ensure that the data generated are adequate for hazard identification and risk assessment. To this end, testing shall be performed at appropriately high dose levels. If dose (concentration) selection is limited by the physicochemical properties or biological effects of the test substance, justification shall be provided. When, for certain endpoints, information is not provided for other reasons than those mentioned in column 2 of this Annex or in Annex XI, this fact and the reasons shall also be clearly stated. 7. INFORMATION ON THE PHYSICOCHEMICAL PROPERTIES OF THE SUBSTANCE COLUMN 1 STANDARD INFORMATION REQUIRED COLUMN 2 SPECIFIC RULES FOR ADAPTATION FROM COLUMN 1 7.1. State of the substance at 20 °C and 101,3 kPa 7.2. Melting/freezing point 7.2. The study does not need to be conducted below a lower limit of - 20 °C. 7.3. Boiling point 7.3. The study does not need to be conducted: for gases, or for solids which either melt above 300 °C or decompose before boiling. In such cases the boiling point under reduced pressure may be estimated or measured, or for substances which decompose before boiling (e.g. auto-oxidation, rearrangement, degradation, decomposition, etc.). 7.4. Relative density 7.4. The study does not need to be conducted if: the substance is only stable in solution in a particular solvent and the solution density is similar to that of the solvent. In such cases, an indication of whether the solution density is higher or lower than the solvent density is sufficient, or the substance is a gas. In this case, an estimation based on calculation shall be made from its molecular weight and the Ideal Gas Laws. 7.5. Vapour pressure 7.5. The study does not need to be conducted if the melting point is above 300 °C. If the melting point is between 200 °C and 300 °C, a limit value based on measurement or a recognised calculation method is sufficient. 7.6. Surface tension of an aqueous solution 7.6. The study need only be conducted if: based on structure, surface activity is expected or can be predicted, or surface activity is a desired property of the material. If the water solubility is below 1 mg/l at 20 °C the test does not need to be conducted. 7.7. Water solubility For nanoforms, in addition the testing of dissolution rate in water as well as in relevant biological and environmental media shall be considered. 7.7. The study does not need to be conducted if: the substance is hydrolytically unstable at pH 4, 7 and 9 (half-life less than 12 hours), or the substance is readily oxidisable in water. If the substance appears insoluble in water, a limit test up to the detection limit of the analytical method shall be performed. For nanoforms the potential confounding effect of dispersion shall be assessed when conducting the study. For metals and sparingly soluble metal compounds, information on transformation/dissolution in aqueous media shall be provided. 7.8. Partition coefficient n-octanol/water 7.8. The study does not need to be conducted if the substance is inorganic. If the test cannot be performed (e.g. the substance decomposes, has a high surface activity, reacts violently during the performance of the … 879 unchanged words … room temperature. 8.2.1. Serious eye damage/eye irritation, in vitro 8.2.1. If results from a first in vitro study do not allow a conclusive decision on the classification of a substance or on the absence of eye irritation potential, (an)other in vitro study/ies) study/studies for this endpoint shall be considered. performed by the registrant or may be required by the Agency. 8.3. Skin sensitisation Information allowing: a conclusion whether the substance is a skin sensitiser and whether it can be presumed to have the potential to produce significant sensitisation in humans (Cat. 1A), and risk assessment, where required. The study(ies) under point 8.3.1 and … 634 unchanged words … basis of high insolubility in water alone. 9.2. Degradation 9.2.1. Biotic 9.2.1.1. Ready biodegradability 9.2.1.1. The study does not need to be conducted if the substance is inorganic. Any other relevant physicochemical, toxicological and ecotoxicological information that is available shall be provided.

02006R1907-20211001 → 02006R1907-20220108

ANNEX VIII STANDARD INFORMATION REQUIREMENTS FOR SUBSTANCES MANUFACTURED OR IMPORTED IN QUANTITIES OF 10 TONNES OR MOREThis Annex shall apply to producers of articles that are required to register in accordance with Article 7 and to other downstream users that are … 341 unchanged words … from structurally related substances (read-across approach) shall be assessed first. In vivo testing with corrosive substances at concentration/dose levels causing corrosivity shall be avoided. Prior to testing, further guidance on testing strategies should be consulted in addition to this Annex. Where a test method offers flexibility in the study design, for example in relation to the choice of dose levels, the chosen study design shall ensure that the data generated are adequate for hazard identification and risk assessment. To this end, testing shall be performed at appropriately high dose levels. If dose (concentration) selection is limited by the physicochemical properties or biological effects of the test substance, justification shall be provided. When, for certain endpoints, information is not provided for other reasons than those mentioned in column 2 of this Annex or in Annex XI, this fact and the reasons shall also be clearly stated. 7. INFORMATION ON THE PHYSICOCHEMICAL PROPERTIES OF THE SUBSTANCE 7.14ter. Further information on physicochemical properties Only for nanoforms Further testing for nanoforms covered by the registration shall be considered by the registrant or may be required by the Agency in accordance with Article 41, if there is an indication that specific additional particle properties significantly influence the hazard of or the exposure to those nanoforms. 8. TOXICOLOGICAL INFORMATION COLUMN 1 STANDARD INFORMATION REQUIRED COLUMN 2 SPECIFIC RULES FOR ADAPTATION FROM COLUMN 1 8.1. Skin corrosion/irritation 8.1. An in vivo study for skin corrosion/irritation shall be considered conducted only if the in vitro studies study/studies under points 8.1.1 and and/or 8.1.2 in of Annex VII are is(are) not applicable, or the results of these studies are this/these study/studies is/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 (2000 mg/kg body weight). 8.2. Serious eye damage/eye irritation 8.2. An in vivo study for serious eye corrosion/irritation damage/eye irritation shall be considered conducted only if the in vitro study(ies) study/studies) under point 8.2.1 in of Annex VII are is/are not applicable, or the results obtained from these study(ies) of this/these study/studies) 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 … 398 unchanged words … 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 da reliable sub-chronic (90 days) or chronic toxicity study is available, available or proposed by the registrant, provided that an appropriate species, dosage, solvent and route of administration were 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. The appropriate route shall be chosen on the following basis: Testing by the dermal route is appropriate if: 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. 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. For nanoforms toxicokinetics without high dissolution rate in biological media, the study shall be considered including include toxicokinetic investigations on, among others, the recovery period and, where relevant, lung clearance. Toxicokinetic investigations do not need to be performed if equivalent toxicokinetic information on the nanoform is already available. The sub-chronic toxicity study (90 days) (Annex IX, Section point 8.6.2) shall be proposed by the registrant registrant, or may be required by the Agency 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 … 1,055 unchanged words … 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.

02006R1907-20211001 → 02006R1907-20220108

ANNEX IX STANDARD INFORMATION REQUIREMENTS FOR SUBSTANCES MANUFACTURED OR IMPORTED IN QUANTITIES OF 100 TONNES OR MOREThis Annex shall apply to producers of articles that are required to register in accordance with Article 7 and to other downstream users that are … 386 unchanged words … from structurally related substances (read-across approach) shall be assessed first. In vivo testing with corrosive substances at concentration/dose levels causing corrosivity shall be avoided. Prior to testing, further guidance on testing strategies should be consulted in addition to this Annex. Where a test method offers flexibility in the study design, for example in relation to the choice of dose levels, the chosen study design shall ensure that the data generated are adequate for hazard identification and risk assessment. To this end, testing shall be performed at appropriately high dose levels. If dose (concentration) selection is limited by the physicochemical properties or biological effects of the test substance, justification shall be provided. When, for certain endpoints, it is proposed not to provide information for other reasons than those mentioned in column 2 of this Annex or in Annex XI, this fact and the reasons shall also be clearly stated. 7. INFORMATION ON THE PHYSICOCHEMICAL PROPERTIES OF THE SUBSTANCE COLUMN 1 STANDARD INFORMATION REQUIRED COLUMN 2 SPECIFIC RULES FOR ADAPTATION FROM COLUMN 1 7.15. Stability in organic solvents and identity of relevant degradation products Only required if stability of the substance is considered to be critical. 7.15. The study does not need to be conducted if the substance is inorganic. 7.16. Dissociation constant 7.16. The study does not need to be conducted if: the substance is hydrolytically unstable (half-life less than 12 hours) or is readily oxidisable in water, or it is scientifically not possible to perform the test for instance if the analytical method is not sensitive enough. or based on the structure, the substance does not have any chemical group that can dissociate. 7.17. Viscosity For hydrocarbon substances the kinematic viscosity shall be determined at 40 °C. 8. TOXICOLOGICAL INFORMATION 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 meeting the criteria for classifying the substance as R48, STOT RE (category 1 or 2), 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, available or proposed by the registrant, provided that an appropriate species and route of administration were are used, or 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. For nanoforms toxicokinetics without high dissolution rate in biological media, the study shall be considered including include toxicokinetic investigations on, among others, the recovery period and, where relevant, lung clearance. Toxicokinetic investigations do not need to be performed if equivalent toxicokinetic information on the nanoform is already available. 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, and in particular for nanoforms indirect genotoxicity), 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 carcinogen, meeting the criteria for classification both in the hazard class germ cell mutagenicity (category 1A or 1B or 2) and 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 the substance is of low toxicological activity (no evidence of (a comprehensive and informative dataset showing no 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. If a substance is known to have an adverse effect on sexual function and fertility, meeting the criteria for classification as toxic for reproduction category in the hazard class reproductive toxicity (category 1A or 1B: May damage fertility (H360F), (H360F)), and the available data are adequate to support a robust risk assessment, then no further testing for sexual function and fertility will shall 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 in the hazard class reproductive toxicity (category 1A or 1B: May damage the unborn child (H360D), (H360D)), and the available data are adequate to support a robust risk assessment, then no further testing for developmental toxicity will shall 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 … 854 unchanged words … 9.3.2. The study need not be conducted if: the substance has a low potential for bioaccumulation (for instance a log Kow ≤ 3) and/or a low potential to cross biological membranes, or direct and indirect exposure of the aquatic compartment is unlikely. The study may not be waived on the basis of low octanol-water partition coefficient alone, unless the potential for bioaccumulation of the substance is 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, dissolution rate, dispersion stability) as a reason for waiving the study shall include adequate justification of its relevance to low potential for bioaccumulation or unlikely direct and indirect exposure of the aquatic compartment. 9.3.3. Further information on adsorption/desorption depending on the results of the study required in Annex VIII 9.3.3. The study need not 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 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, dissolution rate, dispersion stability) as a reason for waiving the study shall include adequate justification of its relevance to low potential for adsorption. 9.4. Effects on terrestrial organisms 9.4. These studies do not need to be conducted if direct and indirect exposure of the soil compartment is unlikely. In the absence of toxicity data for soil organisms, the equilibrium partitioning method may be applied to assess the hazard to soil organisms. Where the equilibrium partitioning method is applied to nanoforms, this shall be scientifically justified. The choice of the appropriate tests depends on the outcome of the chemical safety assessment. In particular for substances that have a high potential to adsorb to soil or that are very persistent, the registrant shall consider long-term toxicity testing instead of short-term. 9.4.1. Short-term toxicity to invertebrates 9.4.2. Effects on soil micro-organisms 9.4.3. Short-term toxicity to plants 10. METHODS OF DETECTION AND ANALYSIS Description of the analytical methods shall be provided on request, for the relevant compartments for which studies were performed using the analytical method concerned. If the analytical methods are not available this shall be justified.

02006R1907-20211001 → 02006R1907-20220108

ANNEX X STANDARD INFORMATION REQUIREMENTS FOR SUBSTANCES MANUFACTURED OR IMPORTED IN QUANTITIES OF 1000 TONNES OR MOREThis Annex shall apply to producers of articles that are required to register in accordance with Article 7 and to other downstream users that are … 387 unchanged words … from structurally related substances (read-across approach) shall be assessed first. In vivo testing with corrosive substances at concentration/dose levels causing corrosivity shall be avoided. Prior to testing, further guidance on testing strategies should be consulted in addition to this Annex. Where a test method offers flexibility in the study design, for example in relation to the choice of dose levels, the chosen study design shall ensure that the data generated are adequate for hazard identification and risk assessment. To this end, testing shall be performed at appropriately high dose levels. If dose (concentration) selection is limited by the physicochemical properties or biological effects of the test substance, justification shall be provided. When, for certain endpoints, it is proposed not to provide information for other reasons than those mentioned in column 2 of this Annex or in Annex XI, this fact and the reasons shall also be clearly stated. 8. TOXICOLOGICAL INFORMATION 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. If nanoforms are covered by the registration, physicochemical characteristics, in particular particle size, shape and other morphological parameters, surface functionalisation and surface area, as well as molecular structure shall be taken into consideration when determining if one of the conditions above are met. 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 do not need not to be conducted if: 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 or 1B or 2) and 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 the substance is of low toxicological activity (no evidence of (a comprehensive and informative dataset showing no 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. If a substance is known to have an adverse effect on sexual function and fertility, meeting the criteria for classification as toxic for reproduction category in the hazard class reproductive toxicity (category 1A or 1B: May damage fertility (H360F), (H360F)), and the available data are adequate to support a robust risk assessment, then no further testing for sexual function and fertility will shall 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 in the hazard class reproductive toxicity (category 1A or 1B: May damage the unborn child (H360D), (H360D)), and the available data are adequate to support a robust risk assessment, then no further testing for developmental toxicity will shall 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. Extended One-Generation Reproductive Toxicity Study (B.56 of the Commission Regulation on test methods as specified in Article … 845 unchanged words … level. 10. METHODS OF DETECTION AND ANALYSIS Description of the analytical methods shall be provided on request, for the relevant compartments for which studies were performed using the analytical method concerned. If the analytical methods are not available this shall be justified.

02006R1907-20211001 → 02006R1907-20220108

ANNEX XI GENERAL RULES FOR ADAPTATION OF THE STANDARD TESTING REGIME SET OUT IN ANNEXES VII TO X Annexes VII to X set out the information requirements for all substances manufactured or imported in quantities of: one tonne or more in accordance with Article 12(1)(a), 10 tonnes or more in accordance with Article 12(1)(c), 100 tonnes or more in accordance with Article 12(1)(d), and 1000 tonnes or more in accordance with Article 12(1)(e). In addition to the specific rules set out in column 2 of Annexes VII to X, a registrant may adapt the standard testing regime in accordance with the general rules set out in Section 1 of this Annex. Under dossier evaluation the Agency may assess these adaptations to the standard testing regime. The requirements specific to nanoforms in this Annex are without prejudice to requirements applicable to other forms of a substance. 1. TESTING DOES NOT APPEAR SCIENTIFICALLY NECESSARY 1.1. Use of existing data Any data generated as from 1 June 2008 shall not be considered as existing data and shall not be subject to the general rules for adaptation laid down in this point (1.1). 1.1.1. Data on physical-chemical properties from experiments not carried out according to GLP or the test methods referred to in Article 13(3) Data shall be considered to be equivalent to data generated by the corresponding test methods referred to in Article 13(3) if the following conditions are met: (1) adequacy for the purpose of classification and labelling and/or risk assessment; (2) sufficient documentation is provided to assess the adequacy of the study; and (3) the data are valid for the endpoint being investigated and the study is performed using an acceptable level of quality assurance. 1.1.2. Data on human health and environmental properties from experiments not carried out according to GLP or the test methods referred to in Article 13(3) Data shall be considered to be equivalent to data generated by the corresponding test methods referred to in Article 13(3) if the following conditions are met: (1) adequacy for the purpose of classification and labelling and/or risk assessment; (2) adequate and reliable coverage of the key parameters foreseen to be investigated in the corresponding test methods referred to in Article 13(3); (3) exposure duration comparable to or longer than the corresponding test methods referred to in Article 13(3) if exposure duration is a relevant parameter; and (4) adequate and reliable documentation of the study is provided. 1.1.3. Historical human data Historical human data, such as epidemiological studies on exposed populations, accidental or occupational exposure data and clinical studies, shall be considered. The strength of the data for a specific human health effect depends, among other things, on the type of analysis and on the parameters covered and on the magnitude and specificity of the response and consequently the predictability of the effect. Criteria for assessing the adequacy of the data include: (1) the proper selection and characterisation of the exposed and control groups; (2) adequate characterisation of exposure; (3) sufficient length of follow-up for disease occurrence; (4) valid method for observing an effect; (5) proper consideration of bias and confounding factors; and (6) a reasonable statistical reliability to justify the conclusion. In all cases adequate and reliable documentation shall be provided. When nanoforms are covered by the registration the above approach shall address the nanoforms separately. 1.2. Weight of evidence There may be is sufficient weight of evidence when information from several independent sources of together enable, through a reasoned justification, a conclusion on the information leading to the assumption/conclusion that a substance has or has not a particular dangerous property, requirement, while the information from each single source alone is regarded insufficient to support fulfil the information requirement. The justification must have regard to the information that would otherwise be obtained from the study that shall normally be performed for this notion. information requirement. There may also be sufficient weight of evidence from the use of newly developed test methods, not yet included in the test methods referred to in Article 13(3) or from an international test method recognised by 13(3), leading to a reasoned justification that they provide the Commission or information that would enable a conclusion on the Agency as being equivalent, leading information requirement. Weight of evidence may lead to the conclusion that a substance has or has not a particular dangerous property. Where If there is sufficient weight of evidence for evidence, the presence or absence of a particular dangerous property information requirement is available: fulfilled. Consequently, further testing on vertebrate animals for that property shall be omitted, omitted and further testing not involving vertebrate animals may be omitted. In all cases cases, the information provided shall be adequate for the purpose of classification, labelling and/or risk assessment, and adequate and reliable documentation shall be provided. provided, including: robust study summaries of the studies used as sources of information; a justification explaining why the sources of information together provide a conclusion on the information requirement. When nanoforms are covered by the registration registration, the above approach shall address the nanoforms separately. 1.3. Qualitative or Quantitative structure-activity relationship ((Q)SAR) Results obtained from valid qualitative or quantitative structure-activity relationship models ((Q)SARs) may indicate the presence or absence of a certain dangerous property. Results of (Q)SARs may be used instead of testing when the following conditions are met: results are derived from a (Q)SAR model whose scientific validity has been established, the substance falls within the applicability domain of the (Q)SAR model, results are adequate for the purpose of classification and labelling and/or risk assessment, and adequate and reliable documentation of the applied method is provided. The Agency in collaboration with the Commission, Member States and interested parties shall develop and provide guidance in assessing which (Q)SARs will meet these conditions and provide examples. When nanoforms are covered by the registration the above approach shall address the nanoforms separately. 1.4. In vitro methods Results obtained from suitable in vitro methods may indicate the presence of a certain dangerous property or may be important in relation to a mechanistic understanding, which may be important for the assessment. In this context, suitable means sufficiently well developed according to internationally agreed test development criteria (e.g. the European Centre for the Validation of Alternative Methods (ECVAM)) criteria for the entry of a test into the prevalidation process). Depending on the potential risk, immediate confirmation requiring testing beyond the information foreseen in Annexes VII or VIII or proposed confirmation requiring testing beyond the information foreseen in Annexes IX or X for the respective tonnage level may be necessary. If the results obtained from the use of such in vitro methods do not indicate a certain dangerous property, the relevant test shall nevertheless be carried out at the appropriate tonnage level to confirm the negative result, unless testing is not required in accordance with Annexes VII to X or the other rules in this Annex. Such confirmation may be waived if the following conditions are met: (1) results are derived from an in vitro method whose scientific validity has been established by a validation study, according to internationally agreed validation principles; (2) results are adequate for the purpose of classification and labelling and/or risk assessment; and (3) adequate and reliable documentation of the applied method is provided. When nanoforms are covered by the registration the above approach in points (1) to (3) shall address the nanoforms separately. 1.5. Grouping of substances and read-across approach Substances whose physicochemical, toxicological and eco-toxicological ecotoxicological properties are likely to be similar or follow a regular pattern as a result of structural similarity similarity, may be considered as a group, or category category, of substances. Application of the group concept requires that physicochemical properties, human health effects and environmental effects or environmental fate may be predicted from data for reference substance(s) within the group by interpolation to other substances in the group (read-across approach). This avoids the need to test every substance for every endpoint. The Agency, after consulting with relevant stakeholders and other interested parties, shall issue guidance on technically and scientifically justified methodology for the grouping of substances sufficiently in advance of the first registration deadline for phase-in substances. When nanoforms are covered by the registration registration, the above approach shall address the nanoforms separately. For grouping different nanoforms of the same substance substance, the molecular structural similarities alone cannot may not serve as a justification. If nanoforms covered by a registration are grouped or placed in a category with other forms, including other nanoforms, of the substance in the same registration the obligations above shall apply in the same manner. The similarities may be based on: on any of the following: (1) a common functional group; (2) the common precursors and/or the likelihood of common breakdown products via physical and biological processes, which result in structurally similar chemicals; or (3) a constant pattern in the changing of the potency of the properties across the category. Structural similarity for UVCB substances shall be established on the basis of similarities in the structures of the constituents, together with the concentration of these constituents and variability in the concentration of these constituents. If it can be demonstrated that the identification of all individual constituents is not technically possible or impractical, the structural similarity may be demonstrated by other means, to enable a quantitative and qualitative comparison of the actual composition between substances. If the group concept is applied, substances shall be classified and labelled on this basis. In all cases cases, results should: shall fulfil all of the following conditions: be adequate for the purpose of classification and labelling and/or risk assessment, have adequate and reliable coverage of the key parameters addressed in the corresponding test method referred to in Article 13(3), study that shall normally be performed for a particular information requirement, cover an exposure duration comparable to or longer than the corresponding test method referred to in Article 13(3) study that shall normally be performed for a particular information requirement if exposure duration is a relevant parameter, and parameter. In all cases, adequate and reliable documentation of the applied method shall be provided. Such documentation shall include: a robust study summary for each source study used in the adaptation; an explanation why the properties of the registered substance may be predicted from other substances in the group; supporting information to scientifically justify such explanation for prediction of properties. 2. TESTING IS TECHNICALLY NOT POSSIBLE Testing for a specific endpoint may be omitted, if it is technically not possible to conduct the study as a consequence of the properties of the substance: e.g. very volatile, highly reactive or unstable substances cannot be used, mixing of the substance with water may cause danger of fire or explosion or the radio-labelling of the substance required in certain studies may not be possible. The guidance given in the test methods referred to in Article 13(3), more specifically on the technical limitations of a specific method, shall always be respected. 3. SUBSTANCE-TAILORED EXPOSURE-DRIVEN TESTING 3.1. Testing in accordance with Sections 8.6 and Section 8.7 of Annex VIII and in accordance with Annex IX and Annex X may be omitted, based on the exposure scenario(s) developed in the Chemical Safety Report. Testing in accordance with Section 8.6.1 of Annex VIII may be omitted only for registrants producing less than 100 tonnes per year per manufacturer or importer, based on the exposure scenario(s) developed in the Chemical Safety Report. 3.2. In all cases, adequate justification and documentation shall be provided. The justification shall be based on a thorough and rigorous exposure assessment in accordance with section 5 of Annex I and shall meet any one of the following criteria: (a) the manufacturer or importer demonstrates and documents that all of the following conditions are fulfilled: (i) the results of the exposure assessment covering all relevant exposures throughout the life cycle of the substance demonstrate the absence of or no significant exposure in all scenarios of the manufacture and all identified uses as referred to in Annex VI section 3.5; (ii) a DNEL or a PNEC can be derived from results of available test data for the substance concerned taking full account of the increased uncertainty resulting from the omission of the information requirement, and that DNEL or PNEC is relevant and appropriate both to the information requirement to be omitted and for risk assessment purposesFor the purposes. For this purpose of subparagraph 3.2(a)(ii), and without prejudice to column 2 of Section Sections 8.6 and 8.7 of Annexes IX and X, a DNEL derived from a screening test for reproductive/developmental toxicity shall not be considered appropriate to omit a prenatal developmental toxicity study or a two-generation reproductive toxicity study. For the purpose of subparagraph 3.2(a)(ii), without prejudice to column 2 of section 8.6 of Annexes IX and X, a DNEL derived from a 28-day repeated dose toxicity study shall not be considered appropriate to omit a 90-day repeated dose toxicity study.; study, and a DNEL derived from a screening test for reproductive/developmental toxicity shall not be considered appropriate to omit a prenatal developmental toxicity study or an extended one-generation reproductive toxicity study. (iii) the comparison of the derived DNEL or PNEC with the results of the exposure assessment shows that exposures are always well below the derived DNEL or PNEC; (b) where the substance is not incorporated in an article the manufacturer or importer demonstrates and documents for all relevant scenarios that throughout the life cycle strictly controlled conditions as set out in Article 18(4)(a) to (f) apply; (c) where the substance is incorporated in an article in which it is permanently embedded in a matrix or otherwise rigorously contained by technical means, it is demonstrated and documented that all of the following conditions are fulfilled: (i) the substance is not released during its life cycle; (ii) the likelihood that workers or the general public or the environment are exposed to the substance under normal or reasonably foreseeable conditions of use is negligible; and (iii) the substance is handled according to the conditions set out in Article 18(4)(a) to (f) during all manufacturing and production stages including the waste management of the substance during these stages. 3.3. The specific conditions of use must be communicated through the supply chain in accordance with Article 31 or 32, as the case may be.

02006R1907-20211001 → 02006R1907-20220108

ANNEX XIV LIST OF SUBSTANCES SUBJECT TO AUTHORISATION Date referred to in Article 58(1)(c)(ii) of Regulation (EC) No 1907/2006.Date referred to in Article 58(1)(c)(i) of Regulation (EC) No 1907/2006.1 September 2021 for the use of the substance in the production of spare … 345 unchanged words … August 2014 — — 2. 4,4’-Diaminodiphenylmethane (MDA) EC No 202-974-4 CAS No 101-77-9 Carcinogenic (category 1B) 21 February 2013 21 August 2014 — — 3. Hexabromocyclododecane (HBCDD) EC No 221-695-9, 247-148-4, CAS No 3194-55-6 25637-99-4 alpha-hexabromocyclododecane CAS No 134237-50-6, beta-hexabromocyclododecane CAS No 134237-51-7 gamma-hexabromocyclododecane CAS No 134237-52-8 PBT 21 February 2014 21 August 2015 — — 4. Bis(2-ethylhexyl) phthalate (DEHP) EC No 204-211-0 CAS No 117-81-7 Toxic for reproduction (category 1B) Endocrine disrupting properties (Article 57(f) – human health) Endocrine disrupting properties (Article 57(f) – environment) (a) 21 August 2013 21 February 2015 Uses in (*) (b) By way of derogation from point (a): 14 June 2023 for uses in: food contact materials within the scope of Regulation (EC) No 1935/2004; immediate packaging of medicinal products covered under Regulation (EC) No 726/2004, Directive 2001/82/EC, and/or Directive 2001/83/EC. 2001/83/EC; mixtures containing DEHP at or above 0,1 % and below 0,3 % weight by weight; (c) By derogation of point (a): 27 November 2023 for uses in medical devices within the scope of Directives 90/385/EEC, 93/42/EEC and 98/79/EC. (a) 21 February 2015 (**) (b) By way of derogation from point (a): 14 December 2024 for uses in: food contact materials within the scope of Regulation (EC) No 1935/2004; immediate packaging of medicinal products covered under Regulation (EC) No 726/2004, Directive 2001/82/EC, and/or Directive 2001/83/EC; mixtures containing DEHP at or above 0,1 % and below 0,3 % weight by weight; (c) By derogation of point (a): 27 May 2025 for uses in medical devices within the scope of Directives 90/385/EEC, 93/42/EEC and 98/79/EC. - - 5. Benzyl butyl phthalate (BBP) EC No 201-622-7 CAS No 85-68-7 Toxic for reproduction (category 1B) Endocrine disrupting properties (Article 57(f) – human health) (a) 21 August 2013 21 February 2015 Uses in the (*) (b) By way of derogation from point (a): 14 June 2023 for uses in: immediate packaging of medicinal products covered under Regulation (EC) No 726/2004, Directive 2001/82/EC, and/or Directive 2001/83/EC. 2001/83/EC; mixtures containing BBP at or above 0,1 % and below 0,3 % weight by weight. (a) 21 February 2015 (**) (b) By way of derogation from point (a): 14 December 2024 for uses in: immediate packaging of medicinal products covered under Regulation (EC) No 726/2004, Directive 2001/82/EC, and/or Directive 2001/83/EC; mixtures containing BBP at or above 0,1 % and below 0,3 % weight by weight. - - 6. Dibutyl phthalate (DBP) EC No 201-557-4 CAS No 84-74-2 Toxic for reproduction (category 1B) Endocrine disrupting properties (Article 57(f) – human health) (a) 21 August 2013 21 February 2015 Uses in the (*) (b) By way of derogation from point (a): 14 June 2023 for uses in: immediate packaging of medicinal products covered under Regulation (EC) No 726/2004, Directive 2001/82/EC, and/or Directive 2001/83/EC. 2001/83/EC; mixtures containing DBP at or above 0,1 % and below 0,3 % weight by weight. (a) 21 February 2015 (**) (b) By way of derogation from point (a): 14 December 2024 for uses in: immediate packaging of medicinal products covered under Regulation (EC) No 726/2004, Directive 2001/82/EC, and/or Directive 2001/83/EC; mixtures containing DBP at or above 0,1 % and below 0,3 % weight by weight. - - 7. Diisobutyl phthalate (DIBP) EC No: No 201-553-2 CAS No: No 84-69-5 Toxic for reproduction (category 1B) Endocrine disrupting properties (Article 57(f) – human health) (a) 21 August 2013 (*) (b) By way of derogation from point (a): 14 June 2023 for uses in mixtures containing DIBP at or above 0,1 % and below 0,3 % weight by weight. (a) 21 February 2015 — — (**) (b) By way of derogation from point (a): 14 December 2024 for uses in mixtures containing DIBP at or above 0,1 % and below 0,3 % weight by weight. - - 8. Diarsenic trioxide EC No: 215-481-4 CAS No: 1327-53-3 Carcinogenic (category 1A) 21 November 2013 21 May 2015 — — 9. Diarsenic pentaoxide EC No: 215-116-9 CAS No: 1303-28-2 Carcinogenic (category 1A) 21 November 2013 21 May 2015 — — 10. Lead chromate EC No: 231-846-0 CAS No: 7758-97-6 Carcinogenic (category … 1,085 unchanged words … vPvB 27 May 2022 27 November 2023 — — 53. 2-(2H-benzotriazol-2-yl)-4-(tert-butyl)-6-(sec-butyl)phenol (UV-350) EC No: 253-037-1 CAS No: 36437-37-3 vPvB 27 May 2022 27 November 2023 — — 54. 2-benzotriazol-2-yl-4,6-di-tert-butylphenol (UV-320) EC No: 223-346-6 CAS No: 3846-71-7 PBT, vPvB 27 May 2022 27 November 2023 — —

02006R1907-20211001 → 02006R1907-20220108

compared line by line: this provision is too large to compare word by word, so a marked line is a line that changed somewhere

ANNEX XVII RESTRICTIONS ON THE MANUFACTURE, PLACING ON THE MARKET AND USE OF CERTAIN DANGEROUS SUBSTANCES, MIXTURES AND ARTICLES For substances which have been incorporated in this Annex as a consequence of restrictions adopted in the framework of Directive 76/769/EEC (Entries 1 to 58), the restrictions shall not apply to storage, keeping, treatment, filling into containers, or transfer from one container to another of these substances for export, unless the manufacture of the substances is prohibited. … 1,042 unchanged lines … 8. Mixtures that do not contain the statement Mixture for use in tattoos or permanent make-up shall not be used for tattooing purposes. 9. This entry does not apply to substances that are gases at temperature of 20 °C and pressure of 101,3 kPa, or generate a vapour pressure of more than 300 kPa at temperature of 50 °C, with the exception of formaldehyde (CAS No 50-00-0, EC No 200-001-8). 10. This entry does not apply to the placing on the market of a mixture for use for tattooing purposes, or to the use of a mixture for tattooing purposes, when placed on the market exclusively as a medical device or an accessory to a medical device, within the meaning of Regulation (EU) 2017/745, or when used exclusively as a medical device or an accessory to a medical device, within the same meaning. Where the placing on the market or use may not be exclusively as a medical device or an accessory to a medical device, the requirements of Regulation (EU) 2017/745 and of this Regulation shall apply cumulatively. 76. N,N-dimethylformamide CAS No 68-12-2 EC. No 200-679-5 1. Shall not be placed on the market as a substance on its own, as a constituent of other substances, or in mixtures in a concentration equal to or greater than 0,3 % after 12 December 2023 unless manufacturers, importers and downstream users have included in the relevant chemical safety reports and safety data sheets, Derived No-Effect Levels (DNELs) relating to exposure of workers of 6 mg/m3 for exposure by inhalation and 1,1 mg/kg/day for dermal exposure. 2. Shall not be manufactured, or used, as a substance on its own, as a constituent of other substances, or in mixtures in a concentration equal to or greater than 0,3 % after 12 December 2023 unless manufacturers and downstream users take the appropriate risk management measures and provide the appropriate operational conditions to ensure that exposure of workers is below the DNELs specified in paragraph 1. 3. By way of derogation from paragraphs 1 and 2, the obligations laid down therein shall apply from 12 December 2024 in relation to placing on the market for use, or use, as a solvent in direct or transfer polyurethane coating processes of textiles and paper material or the production of polyurethane membranes, and from 12 December 2025 in relation to placing on the market for use, or use, as a solvent in the dry and wet spinning processes of synthetic fibres. Appendices 1 to 6 FOREWORD Explanations of column headings … 3,126 unchanged lines … Pigment Violet 3 603-635-7 1325-82-2 0,1 % Pigment Violet 39 264-654-0 64070-98-0 0,1 % Solvent Yellow 2 200-455-7 60-11-7 0,1 %