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in vitro


PREAMBLE: REACH - Registration, Evaluation, Authorisation and Restriction of Chemicals     [go to this PREAMBLE]
... (40) The Commission, Member States, industry and other stakeholders should continue to contribute to the promotion of alternative test methods on an international and national level including computer supported methodologies, in vitro methodologies, as appropriate, those based on toxicogenomics, and other relevant methodologies. The Community's strategy to promote alternative test methods is a priority and the Commission should ensure that within its future Research Framework Programmes and initiatives such as the Community Action Plan on the Protection and Welfare of Animals 2006 to 2010 this remains a priority topic. Participation of stakeholders and initiatives involving all interested parties should be sought. ...


ARTICLE-13: General requirements for generation of information on intrinsic properties of substances     [go to this ARTICLE]
... 1. Information on intrinsic properties of substances may be generated by means other than tests, provided that the conditions set out in Annex XI are met. In particular for human toxicity, information shall be generated whenever possible by means other than vertebrate animal tests, through the use of alternative methods, for example, in vitro methods or qualitative or quantitative structure-activity relationship models or from information from structurally related substances (grouping or read-across). Testing in accordance with Annex VIII, Sections 8.6 and 8.7, Annex IX and Annex X may be omitted where justified by information on exposure and implemented risk management measures as specified in Annex XI, section 3. ...


ARTICLE-60: Granting of authorisations     [go to this ARTICLE]
... The Commission shall not consider the risks to human health arising from the use of a substance in a medical device regulated by Council Directive 90/385/EEC of 20 June 1990 on the approximation of the laws of the Member States relating to active implantable medical devices (48), Council Directive 93/42/EEC of 14 June 1993 concerning medical devices (49) or Directive 98/79/EC of the European Parliament and of the Council of 27 October 1998 on in vitro diagnostic medical devices (50). ...


ARTICLE-I: GENERAL PROVISIONS FOR ASSESSING SUBSTANCES AND PREPARING CHEMICAL SAFETY REPORTS     [go to this ARTICLE]
... 1.1.3. All non-human information used to assess a particular effect on humans and to establish the dose (concentration)-response (effect) relationship, shall be briefly presented, if possible in the form of a table or tables, distinguishing between in vitro, in vivo and other information. The relevant test results (e.g. LD50, NO(A)EL or LO(A)EL) and test conditions (e.g. test duration, route of administration) and other relevant information shall be presented, in internationally recognised units of measurement for that effect. ...


ARTICLE-VI: INFORMATION REQUIREMENTS REFERRED TO IN ARTICLE 10     [go to this ARTICLE]
... The registrant should gather all existing available test data on the substance to be registered, this would include a literature search for relevant information on the substance. Wherever practicable, registrations should be submitted jointly, in accordance with Articles 11 or 19. This will enable test data to be shared, thereby avoiding unnecessary testing and reducing costs. The registrant should also collect all other available and relevant information on the substance regardless whether testing for a given endpoint is required or not at the specific tonnage level. This should include information from alternative sources (e.g. from (Q)SARs, read-across from other substances, in vivo and in vitro testing, epidemiological data) which may assist in identifying the presence or absence of hazardous properties of the substance and which can in certain cases replace the results of animal tests. ...


ARTICLE-VII: STANDARD INFORMATION REQUIREMENTS FOR SUBSTANCES MANUFACTURED OR IMPORTED IN QUANTITIES OF ONE TONNE OR MORE [64]     [go to this ARTICLE]
... Before new tests are carried out to determine the properties listed in this Annex, all available in vitro data, in vivo data, historical human data, data from valid (Q)SARs and data 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. ...
... 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). | ...
... 8.1.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; | ...
... 8.4.1.In vitro gene mutation study in bacteria | | ...


ARTICLE-VIII: STANDARD INFORMATION REQUIREMENTS FOR SUBSTANCES MANUFACTURED OR IMPORTED IN QUANTITIES OF 10 TONNES OR MORE [66]     [go to this ARTICLE]
... Before new tests are carried out to determine the properties listed in this Annex, all available in vitro data, in vivo data, historical human data, data from valid (Q)SARs and data 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. ...
... 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. | ...
... 8.4.2.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. | ...
... 8.7.1.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. | ...


ARTICLE-IX: STANDARD INFORMATION REQUIREMENTS FOR SUBSTANCES MANUFACTURED OR IMPORTED IN QUANTITIES OF 100 TONNES OR MORE [68]     [go to this ARTICLE]
... Before new tests are carried out to determine the properties listed in this Annex, all available in vitro data, in vivo data, historical human data, data from valid (Q)SARs and data 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. ...
... | 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. | ...


ARTICLE-X: STANDARD INFORMATION REQUIREMENTS FOR SUBSTANCES MANUFACTURED OR IMPORTED IN QUANTITIES OF 1000 TONNES OR MORE [70]     [go to this ARTICLE]
... Before new tests are carried out to determine the properties listed in this Annex, all available in vitro data, in vivo data, historical human data, data from valid (Q)SARs and data 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. ...
... | 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. | ...


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