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study

PREAMBLE: REACH - Registration, Evaluation, Authorisation and Restriction of Chemicals [go to this PREAMBLE]

... (15) There is a need to ensure effective management of the technical, scientific and administrative aspects of this Regulation at Community level. A central entity should therefore be created to fulfil this role. A feasibility study on the resource requirements for this central entity concluded that an independent central entity offered a number of long-term advantages over other options. A European Chemicals Agency (hereinafter referred to as the Agency) should therefore be established. ...

... (53) In order to allow a potential registrant of a phase-in substance to proceed with his registration, even if he cannot reach agreement with a previous registrant, the Agency, on request, should allow use of any summary or robust study summary of tests already submitted. The registrant who receives these data should be obliged to pay a contribution to the costs to the owner of the data. For non-phase-in substances, the Agency may ask for evidence that a potential registrant has paid the owner of a study before the Agency gives permission for the potential registrant to use that information in his registration. ...

... (54) In order to avoid duplication of work, and in particular to avoid duplication of testing, registrants of phase-in substances should pre-register as early as possible with a database managed by the Agency. A system should be established in order to provide for the establishment of Substance Information Exchange Forums (SIEF) to help exchange of information on the substances that have been registered. SIEF participants should include all relevant actors submitting information to the Agency on the same phase-in substance. They should include both potential registrants, who must provide and be supplied with any information relevant to the registration of their substances, and other participants, who may receive financial compensation for studies they hold but are not entitled to request information. In order to ensure the smooth functioning of that system they should fulfil certain obligations. If a member of a SIEF does not fulfil his obligations, he should be penalised accordingly but other members should be enabled to continue preparing their own registration. In cases where a substance has not been pre-registered, measures should be taken to help downstream users find alternative sources of supply. ...

... (64) In order to prevent unnecessary animal testing, interested parties should have a period of 45 days during which they may provide scientifically valid information and studies that address the relevant substance and hazard end-point, which is addressed by the testing proposal. The scientifically valid information and studies received by the Agency should be taken into account for decisions on testing proposals. ...

ARTICLE-3: Definitions [go to this ARTICLE]

... 27. full study report: means a complete and comprehensive description of the activity performed to generate the information. This covers the complete scientific paper as published in the literature describing the study performed or the full report prepared by the test house describing the study performed; ...

... 28. robust study summary: means a detailed summary of the objectives, methods, results and conclusions of a full study report providing sufficient information to make an independent assessment of the study minimising the need to consult the full study report; ...

... 29. study summary: means a summary of the objectives, methods, results and conclusions of a full study report providing sufficient information to make an assessment of the relevance of the study; ...

ARTICLE-10: Information to be submitted for general registration purposes [go to this ARTICLE]

... (vi) study summaries of the information derived from the application of Annexes VII to XI; ...

... (vii) robust study summaries of the information derived from the application of Annexes VII to XI, if required under Annex I; ...

... Except in cases covered under Article 25(3), Article 27(6) or Article 30(3), the registrant shall be in legitimate possession of or have permission to refer to the full study report summarised under (vi) and (vii) for the purpose of registration; ...

ARTICLE-13: General requirements for generation of information on intrinsic properties of substances [go to this ARTICLE]

... 5. If a substance has already been registered, a new registrant shall be entitled to refer to the study summaries or robust study summaries, for the same substance submitted earlier, provided that he can show that the substance that he is now registering is the same as the one previously registered, including the degree of purity and the nature of impurities, and that the previous registrant(s) have given permission to refer to the full study reports for the purpose of registration. ...

... A new registrant shall not refer to such studies in order to provide the information required in Section 2 of Annex VI. ...

ARTICLE-17: Registration of on-site isolated intermediates [go to this ARTICLE]

... (d) any available existing information on physicochemical, human health or environmental properties of the intermediate. Where a full study report is available, a study summary shall be submitted; ...

ARTICLE-18: Registration of transported isolated intermediates [go to this ARTICLE]

ARTICLE-25: Objectives and general rules [go to this ARTICLE]

... 3. Any study summaries or robust study summaries of studies submitted in the framework of a registration under this Regulation at least 12 years previously can be used for the purposes of registration by another manufacturer or importer. ...

ARTICLE-26: Duty to inquire prior to registration [go to this ARTICLE]

... (c) which information requirements would require new studies involving vertebrate animals to be carried out by him; ...

... (d) which information requirements would require other new studies to be carried out by him. ...

... 3. If the same substance has previously been registered less than 12 years earlier, the Agency shall inform the potential registrant without delay of the names and addresses of the previous registrant(s) and of the relevant summaries or robust study summaries, as the case may be, already submitted by them. ...

... Studies involving vertebrate animals shall not be repeated. ...

... The Agency shall simultaneously inform the previous registrants of the name and address of the potential registrant. The available studies shall be shared with the potential registrant in accordance with Article 27. ...

ARTICLE-27: Sharing of existing data in the case of registered substances [go to this ARTICLE]

... 4. On agreement on the sharing of the information, the previous registrant shall make available to the new registrant the agreed information and shall give the new registrant the permission to refer to the previous registrant's full study report. ...

... 6. Within one month from the receipt of the information referred to in paragraph 5, the Agency shall give the potential registrant permission to refer to the information requested by him in his registration dossier, subject to the potential registrant providing, upon request by the Agency, proof that he has paid the previous registrant(s) for that information a share of cost incurred. The previous registrant(s) shall have a claim on the potential registrant for a proportionate share of the cost incurred by him. Calculation of the proportionate share may be facilitated by the guidance adopted by the Agency in accordance with Article 77(2)(g). Provided he makes the full study report available to the potential registrant, the previous registrant(s) shall have a claim on the potential registrant for an equal share of the cost incurred by him, which shall be enforceable in the national courts. ...

ARTICLE-29: Substance Information Exchange Forums [go to this ARTICLE]

... (a) facilitate, for the purposes of registration, the exchange of the information specified in Article 10(a) (vi) and (vii) between potential registrants, thereby avoiding the duplication of studies; and ...

... 3. SIEF participants shall provide other participants with existing studies, react to requests by other participants for information, collectively identify needs for further studies for the purposes of paragraph 2(a) and arrange for such studies to be carried out. Each SIEF shall be operational until 1 June 2018. ...

ARTICLE-30: Sharing of data involving tests [go to this ARTICLE]

... 1. Before testing is carried out in order to meet the information requirements for the purposes of registration, a SIEF participant shall inquire whether a relevant study is available by communicating within his SIEF. If a relevant study involving tests on vertebrate animals is available within the SIEF, a participant of that SIEF shall request that study. If a relevant study not involving tests on vertebrate animals is available within the SIEF, a SIEF participant may request that study. ...

... Within one month of the request, the owner of the study shall provide proof of its cost to the participant(s) requesting it. The participant(s) and the owner shall make every effort to ensure that the costs of sharing the information are determined in a fair, transparent and non discriminatory way. This may be facilitated by following any cost sharing guidance which is based on those principles and is adopted by the Agency in accordance with Article 77(2)(g). If they cannot reach such an agreement, the cost shall be shared equally. The owner shall give permission to refer to the full study report for the purpose of registration within two weeks of receipt of payment. Registrants are only required to share in the costs of information that they are required to submit to satisfy their registration requirements. ...

... 2. If a relevant study involving tests is not available within the SIEF, only one study shall be conducted per information requirement within each SIEF by one of its participants acting on behalf of the others. They shall take all reasonable steps to reach an agreement within a deadline set by the Agency as to who is to carry out the test on behalf of the other participants and to submit a summary or robust study summary to the Agency. If no agreement is reached, the Agency shall specify which registrant or downstream user shall perform the test. All participants of the SIEF who require a study shall contribute to the costs for the elaboration of the study with a share corresponding to the number of participating potential registrants. Those participants that do not carry out the study themselves shall have the right to receive the full study report within two weeks following payment to the participant that carried out the study. ...

... 3. If the owner of a study as referred to in paragraph 1 which involves testing on vertebrate animals refuses to provide either proof of the cost of that study or the study itself to (an)other participant(s), he shall not be able to proceed with registration until he provides the information to the other participants(s). The other participant(s) shall proceed with registration without fulfilling the relevant information requirement, explaining the reason for this in the registration dossier. The study shall not be repeated unless within 12 months of the date of registration of the other participant(s), the owner of this information has not provided it to them and the Agency decides that the test should be repeated by them. However, if a registration containing this information has already been submitted by another registrant, the Agency shall give the other participant(s) permission to refer to the information in his registration dossier(s). The other registrant shall have a claim on the other participant(s) for an equal share of the cost, provided he makes the full study report available to the other participant(s), which shall be enforceable in the national courts. ...

... 4. If the owner of a study as referred to in paragraph 1 which does not involve testing on vertebrate animals refuses to provide either proof of the cost of that study or the study itself to (an)other participant(s), the other SIEF participants shall proceed with registration as if no relevant study was available in the SIEF. ...

... 6. The owner of the study who has refused to provide either proof of the cost or the study itself, as referred to in paragraph 3 or 4 of this Article, shall be penalised in accordance with Article 126. ...

ARTICLE-40: Examination of testing proposals [go to this ARTICLE]

... 2. Information relating to testing proposals involving tests on vertebrate animals shall be published on the Agency website. The Agency shall publish on its website the name of the substance, the hazard end-point for which vertebrate testing is proposed, and the date by which any third party information is required. It shall invite third parties to submit, using the format provided by the Agency, scientifically valid information and studies that address the relevant substance and hazard end-point, addressed by the testing proposal, within 45 days of the date of publication. All such scientifically valid information and studies received shall be taken into account by the Agency in preparing its decision in accordance with paragraph 3. ...

... (a) a decision requiring the registrant(s) or downstream user(s) concerned to carry out the proposed test and setting a deadline for submission of the study summary, or the robust study summary if required by Annex I; ...

ARTICLE-53: Cost sharing for tests without an agreement between registrants and/or downstream users [go to this ARTICLE]

... 2. If a registrant or downstream user performs a test on behalf of others, they shall all share the cost of that study equally. ...

... 3. In the case referred to in paragraph 1, the registrant or downstream user who performs the test shall provide each of the others concerned with a copy of the full study report. ...

... 4. The person performing and submitting the study shall have a claim against the others accordingly. Any person concerned shall be able to make a claim in order to prohibit another person from manufacturing, importing or placing the substance on the market if that other person either fails to pay his share of the cost or to provide security for that amount or fails to hand over a copy of the full study report of the study performed. All claims shall be enforceable in the national courts. Any person may choose to submit their claims for remuneration to an arbitration board and accept the arbitration order. ...

ARTICLE-119: Electronic public access [go to this ARTICLE]

... (e) the result of each toxicological and ecotoxicological study; ...

... (c) the study summaries or robust study summaries of the information referred to in paragraph 1(d) and (e); ...

ARTICLE-I: GENERAL PROVISIONS FOR ASSESSING SUBSTANCES AND PREPARING CHEMICAL SAFETY REPORTS [go to this ARTICLE]

... 1.1.4. If one study is available then a robust study summary should be prepared for that study. If there are several studies addressing the same effect, then, having taken into account possible variables (e.g. conduct, adequacy, relevance of test species, quality of results, etc.), normally the study or studies giving rise to the highest concern shall be used to establish the DNELs and a robust study summary shall be prepared for that study or studies and included as part of the technical dossier. Robust summaries will be required of all key data used in the hazard assessment. If the study or studies giving rise to the highest concern are not used, then this shall be fully justified and included as part of the technical dossier, not only for the study being used but also for all studies demonstrating a higher concern than the study being used. It is important irrespective of whether hazards have been identified or not that the validity of the study be considered. ...

... 3.1.5. If one study is available then a robust study summary should be prepared for that study. Where there is more than one study addressing the same effect, then the study or studies giving rise to the highest concern shall be used to draw a conclusion and a robust study summary shall be prepared for that study or studies and included as part of the technical dossier. Robust summaries will be required of all key data used in the hazard assessment. If the study or studies giving rise to the highest concern are not used, then this shall be fully justified and included as part of the technical dossier, not only for the study being used but also for all studies reaching a higher concern than the study being used. For substances where all available studies indicate no hazards an overall assessment of the validity of all studies should be performed. ...

ARTICLE-VII: STANDARD INFORMATION REQUIREMENTS FOR SUBSTANCES MANUFACTURED OR IMPORTED IN QUANTITIES OF ONE TONNE OR MORE [64] [go to this ARTICLE]

... 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, orfor 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, orfor 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, orthe 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 | 7.6.The study need only be conducted if:based on structure, surface activity is expected or can be predicted, orsurface 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 | 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), orthe 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. | ...

... 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 test or does not dissolve in water or in octanol, or it is not possible to obtain a sufficiently pure substance), a calculated value for log P as well as details of the calculation method shall be provided. | ...

... 7.9.Flash-point | 7.9.The study does not need to be conducted if:the substance is inorganic, orthe substance only contains volatile organic components with flash-points above 100 °C for aqueous solutions, orthe estimated flash-point is above 200 °C, orthe flash-point can be accurately predicted by interpolation from existing characterised materials. | ...

... 7.10.Flammability | 7.10.The study does not need to be conducted:if the substance is a solid which possesses explosive or pyrophoric properties. These properties should always be considered before considering flammability, orfor gases, if the concentration of the flammable gas in a mixture with inert gases is so low that, when mixed with air, the concentration is all time below the lower limit, orfor substances which spontaneously ignite when in contact with air. | ...

... 7.11.Explosive properties | 7.11.The study does not need to be conducted if:there are no chemical groups associated with explosive properties present in the molecule, orthe substance contains chemical groups associated with explosive properties which include oxygen and the calculated oxygen balance is less than -200, orthe organic substance or a homogenous mixture of organic substances contains chemical groups associated with explosive properties, but the exothermic decomposition energy is less than 500 J/g and the onset of exothermic decomposition is below 500 °C, orfor mixtures of inorganic oxidising substances (UN Division 5.1) with organic materials, the concentration of the inorganic oxidising substance is:less than 15 %, by mass, if assigned to UN Packaging Group I (high hazard) or II (medium hazard),less than 30 %, by mass, if assigned to UN Packaging Group III (low hazard).Note: Neither a test for propagation of detonation nor a test for sensitivity to detonative shock is required if the exothermic decomposition energy of organic materials is less than 800 J/g. | ...

... 7.12.Self-ignition temperature | 7.12.The study does not need to be conducted:if the substance is explosive or ignites spontaneously with air at room temperature, orfor liquids non flammable in air, e.g. no flash point up to 200 °C, orfor gases having no flammable range, orfor solids, if the substance has a melting point ≤ 160 °C, or if preliminary results exclude self-heating of the substance up to 400 °C. | ...

... 7.13.Oxidising properties | 7.13.The study does not need to be conducted if:the substance is explosive, orthe substance is highly flammable, orthe substance is an organic peroxide, orthe substance is incapable of reacting exothermically with combustible materials, for example on the basis of the chemical structure (e.g. organic substances not containing oxygen or halogen atoms and these elements are not chemically bonded to nitrogen or oxygen, or inorganic substances not containing oxygen or halogen atoms).The full test does not need to be conducted for solids if the preliminary test clearly indicates that the test substance has oxidising properties.Note that as there is no test method to determine the oxidising properties of gaseous mixtures, the evaluation of these properties must be realised by an estimation method based on the comparison of the oxidising potential of gases in a mixture with that of the oxidising potential of oxygen in air. | ...

... 7.14.Granulometry | 7.14.The study does not need to be conducted if the substance is marketed or used in a non solid or granular form. | ...

... 8.1.Skin irritation or skin corrosionThe assessment of this endpoint shall comprise the following consecutive steps:(1)an assessment of the available human and animal data,(2)an assessment of the acid or alkaline reserve,(3)in vitro study for skin corrosion,(4)in vitro study for skin irritation. | 8.1.Steps 3 and 4 do not need to be conducted if:the available information indicates that the criteria are met for classification as corrosive to the skin or irritating to eyes, orthe substance is flammable in air at room temperature, orthe substance is classified as very toxic in contact with skin, oran 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.Eye irritationThe assessment of this endpoint shall comprise the following consecutive steps:(1)an assessment of the available human and animal data,(2)an assessment of the acid or alkaline reserve,(3)in vitro study for eye irritation. | 8.2.Step 3 does not need to be conducted if:the available information indicates that the criteria are met for classification as corrosive to the skin or irritating to eyes, orthe substance is flammable in air at room temperature; | ...

... 8.4.Mutagenicity | 8.4.Further mutagenicity studies shall be considered in case of a positive result. | ...

... 8.4.1.In vitro gene mutation study in bacteria | | ...

... 8.5.Acute toxicity | 8.5.The study/ies do(es) not generally need to be conducted if:the substance is classified as corrosive to the skin. | ...

... 8.5.1.By oral route | The study need not be conducted if a study on acute toxicity by the inhalation route (8.5.2) is available. | ...

... 9.1.1.Short-term toxicity testing on invertebrates (preferred species Daphnia)The registrant may consider long-term toxicity testing instead of short-term. | 9.1.1.The study does not need to be conducted if:there are mitigating factors indicating that 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, ora long-term aquatic toxicity study on invertebrates is available, oradequate information for environmental classification and labelling is available.The long-term aquatic toxicity study on Daphnia (Annex IX, section 9.1.5) shall be considered if the substance is poorly water soluble. | ...

... 9.1.2.Growth inhibition study aquatic plants (algae preferred) | 9.1.2.The study does not need to be conducted if there are mitigating factors indicating that 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. | ...

... 9.2.1.1.Ready biodegradability | 9.2.1.1.The study does not need to be conducted if the substance is inorganic. | ...

ARTICLE-VIII: STANDARD INFORMATION REQUIREMENTS FOR SUBSTANCES MANUFACTURED OR IMPORTED IN QUANTITIES OF 10 TONNES OR MORE [66] [go to this ARTICLE]

... 8.1.1.In vivo skin irritation | 8.1.1.The study does not need to be conducted if:the substance is classified as corrosive to the skin or as a skin irritant, orthe substance is a strong acid (pH ≤ 2,0) or base (pH ≥ 11,5), orthe substance is flammable in air at room temperature, orthe substance is classified as very toxic in contact with skin, oran acute toxicity study by the dermal route does not indicate skin irritation up to the limit dose level (2000 mg/kg body weight). | ...

... 8.2.1.In vivo eye irritation | 8.2.1.The study does not need to be conducted if:the substance is classified as irritating to eyes with risk of serious damage to eyes, orthe substance is classified as corrosive to the skin and provided that the registrant classified the substance as eye irritant, orthe substance is a strong acid (pH ≤ 2,0) or base (pH ≥ 11,5), orthe substance is flammable in air at room temperature. | ...

... 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 conductedif adequate data from an in vivo cytogenicity test are available, orthe substance is known to be carcinogenic category 1 or 2 or mutagenic category 1, 2 or 3. | ...

... 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. | ...

... 8.5.Acute toxicity | 8.5.The study/ies do(es) not generally need to be conducted if:the substance is classified as corrosive to the skin.In addition to the oral route (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 need be provided. | ...

... 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, orwhere a substance undergoes immediate disintegration and there are sufficient data on the cleavage products, orrelevant 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, orappropriately 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, ortoxicity of particular concern (e.g. serious/severe effects), orindications 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), orthe 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, orparticular 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), oreffects 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. | ...

... 8.7.1.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 | 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, orthe substance is known to be a germ cell mutagen and appropriate risk management measures are implemented, orrelevant human exposure can be excluded in accordance with Annex XI section 3, ora pre-natal developmental toxicity study (Annex IX, 8.7.2) or a two-generation reproductive toxicity study (Annex IX, Section 8.7.3) is available.If a substance is known to have an adverse effect on fertility, meeting the criteria for classification as Repr Cat 1 or 2: R60, and the available data are adequate to support a robust risk assessment, then no further testing for fertility will be necessary. However, testing for development toxicity must be considered.If a substance is known to cause developmental toxicity, meeting the criteria for classification as Repr Cat 1 or 2: R61, 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 a pre-natal developmental toxicity study (Annex IX, Section 8.7.2) or a two-generation reproductive toxicity study (Annex IX, Section 8.7.3) may be proposed by the registrant instead of the screening study. | ...

... 9.1.3.Short-term toxicity testing on fish: the registrant may consider long-term toxicity testing instead of short-term. | 9.1.3.The study does not need to be conducted if:there are mitigating factors indicating that 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, ora long-term aquatic toxicity study on fish is available.Long-term 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 if the substance is poorly water soluble. | ...

... 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, orthere are mitigating factors indicating that microbial toxicity is unlikely to occur, for instance the substance is highly insoluble in water, orthe 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.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. | ...

... 9.2.2.1.Hydrolysis as a function of pH. | 9.2.2.1.The study does not need to be conducted if:the substance is readily biodegradable, orthe substance is highly insoluble in water. | ...

... 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), orthe substance and its relevant degradation products decompose rapidly. | ...

ARTICLE-IX: STANDARD INFORMATION REQUIREMENTS FOR SUBSTANCES MANUFACTURED OR IMPORTED IN QUANTITIES OF 100 TONNES OR MORE [68] [go to this ARTICLE]

... 7.15.Stability in organic solvents and identity of relevant degradation productsOnly 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, orit is scientifically not possible to perform the test for instance if the analytical method is not sensitive enough. | ...

... | 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. | ...

... 8.6.1.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, ora reliable chronic toxicity study is available, provided that an appropriate species and route of administration were used, ora substance undergoes immediate disintegration and there are sufficient data on the cleavage products (both for systemic effects and effects at the site of uptake), orthe 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, orsystemic effects or other evidence of absorption is observed in skin and/or eye irritation studies, orin vitro tests indicate significant dermal absorption, orsignificant 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, ortoxicity of particular concern (e.g. serious/severe effects), orindications 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), orparticular 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, orthe substance is known to be a germ cell mutagen and appropriate risk management measures are implemented, orthe 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.If a substance is known to have an adverse effect on fertility, meeting the criteria for classification as Repr Cat 1 or 2: R60, and the available data are adequate to support a robust risk assessment, then no further testing for fertility will be necessary. However, testing for development toxicity must be considered.If a substance is known to cause developmental toxicity, meeting the criteria for classification as Repr Cat 1 or 2: R61, 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. | ...

... 9.2.1.2.Simulation testing on ultimate degradation in surface water | 9.2.1.2.The study need not be conducted if:the substances is highly insoluble in water, orthe substance is readily biodegradable. | ...

... 9.2.1.3.Soil simulation testing (for substances with a high potential for adsorption to soil) | 9.2.1.3.The study need not be conducted:if the substance is readily biodegradable, orif direct and indirect exposure of soil is unlikely. | ...

... 9.2.1.4.Sediment simulation testing (for substances with a high potential for adsorption to sediment) | 9.2.1.4.The study need not be conducted:if the substance is readily biodegradable, orif direct and indirect exposure of sediment is unlikely. | ...

... 9.3.2.Bioaccumulation in aquatic species, preferably fish | 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, ordirect and indirect exposure of the aquatic compartment is unlikely. | ...

... 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), orthe substance and its degradation products decompose rapidly. | ...

... 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. 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. | ...

... 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. ...

ARTICLE-X: STANDARD INFORMATION REQUIREMENTS FOR SUBSTANCES MANUFACTURED OR IMPORTED IN QUANTITIES OF 1000 TONNES OR MORE [70] [go to this ARTICLE]

... | 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, oreffects 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, orthe substance may have a dangerous property that cannot be detected in a 90-day study. | ...

... | 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), orindications 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), orparticular 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 need not be conducted if:the substance is known to be a genotoxic carcinogen and appropriate risk management measures are implemented, orthe substance is known to be a germ cell mutagen and appropriate risk management measures are implemented, orthe 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.If a substance is known to have an adverse effect on fertility, meeting the criteria for classification as Repr Cat 1 or 2: R60, and the available data are adequate to support a robust risk assessment, then no further testing for fertility will be necessary. However, testing for development toxicity must be considered.If a substance is known to cause developmental toxicity, meeting the criteria for classification as Repr Cat 1 or 2: R61, 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.Developmental toxicity study, one species, most appropriate route of administration, having regard to the likely route of human exposure (OECD 414). | | ...

... 8.9.1.Carcinogenicity study | 8.9.1.A carcinogenicity study may be proposed by the registrant or may be required by the Agency in accordance with Articles 40 or 41 if:the substance has a widespread dispersive use or there is evidence of frequent or long-term human exposure, andthe substance is classified as mutagen category 3 or there is evidence from the repeated dose study(ies) that the substance is able to induce hyperplasia and/or pre-neoplastic lesions.If the substances is classified as mutagen category 1 or 2, the default presumption would be that a genotoxic mechanism for carcinogenicity is likely. In these cases, a carcinogenicity test will normally not be required. | ...

... 9.4.Effects on terrestrial organisms | 9.4.Long-term toxicity testing shall be proposed by the registrant if the results of the chemical safety assessment according to Annex I indicates the need to investigate further the effects of the substance and/or degradation products on terrestrial organisms. The choice of the appropriate test(s) depends on the outcome of the chemical safety assessment.These studies do not need to be conducted if direct and indirect exposure of the soil compartment is unlikely. | ...

ARTICLE-XI: GENERAL RULES FOR ADAPTATION OF THE STANDARD TESTING REGIME SET OUT IN ANNEXES VII TO X [go to this ARTICLE]

... (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. ...

... (4) adequate and reliable documentation of the study is provided. ...

... Historical human data, such as epidemiological studies on exposed populations, accidental or occupational exposure data and clinical studies, shall be considered. ...

... (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; ...

... 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. ...

ARTICLE-XV: DOSSIERS [go to this ARTICLE]

... For all dossiers any relevant information from registration dossiers shall be considered and other available information may be used. For hazard information which has not been previously submitted to the Agency, a robust study summary shall be included in the dossier. ...

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