3 REACH Context1….. This Regulation should ensure a high level of protection of Human Health (HH) and Environment (ENV) as well as….. …… This regulation should also promote the development of alternative methods for the assessment of hazards of substances16 …..The Regulation is based on the principle that industry should manufacture, import or use substances or place them on the market with such responsibility and care as may be required to ensure that….HH and ENV are not adversely affected.
4 REACH Context: Information Requirements Annex VI Guidance on fulfilling requirements of Annexes VII-XIGather and assessment informationAnnex VII to X:Information Requirements is tonnage dependent (number substances):≥ 1 tonne/y: Annex VII in vitro (20,000)≥ 10 tonnes/y: Annex VIII base set (5,000)≥ 100 tonnes/y: Annex IX additional testing (2500)≥ 1000 tonnes/y: Annex X additional testing (2700)Annex XIGeneral rules for adaptation of the standard testingAnnex XI(1): Testing does not appear scientifically necessaryAnnex XI(2): Testing is technically not possibleAnnex XI(3): Exposure-driven waiving/testing
5 REACH Context Can be used if: Annex XI (1) testing does not appear scientifically necessaryUse of existing information, weight of evidence, (Q)SARs, in vitro methods, grouping/read acrossCan be used if:Suitable methods are usedResults are adequate for the purpose of Classification and Labelling and/or Risk AssessmentAdequate and reliable documentation is given
6 REACH Context: Information Requirements Adequate for Classification and LabellingImportant driver under REACH and several otherlegislations (e.g. consumer products, transport)Adequate for Risk AssessmentInformation suited to derive a (semi)quantitative dose descriptorAdequate for PBT, vPvB assessment
7 REACH Implementation Projects (RIPs) RIP 3.3 on information requirements provides guidance for industries how to comply with Annexes VI-XI of the RegulationThis guidance was prepared by experts from Industries, Member States and Commission. Joined action!
8 Lessons from RIPs 3.3 (not exhaustive) Importance of close collaboration between Industries and Member States/RegulatorsRealisation there are few, if any, alternative methods that could be used as stand alone replacement for C&L, RA and/or PBT assessmentFurther development should focus on regulatory needs and usesA method stated to be scientifically validated is not necessarily applicable for a given regulatory purposeThere is a need for further development and evaluation of integrated testing strategies and refinement of methods (e.g. EU-project OSIRIS)
9 Lessons RIPs 3.3: example Three in vitro methods for embryotoxicity that have been considered scientifically valid(ated)*However, these methods are no replacement of OECD 414 and are (as yet) not suited for (certain) regulatory purposes because:They do (as yet) not provide a dose descriptor suited for RAThey do not include a metabolic systemThe evaluations is based on a limited chemical domainThere is a need for further refinement for discrimination between non, weak and strong embryotoxicantsEtcFor use in testing strategies more experience/guidance is neededBy ECVAM advisory committee ESAC
10 Challenges Regulators and Industries Regulators should be involved throughout the process of method/testing strategy development in order to assure the methods comply with the regulatory needs
12 OECD416OECD414OECD42170% of experimental animals is required for reproductive toxicity testing in REACHVan der Jagt et al., ECB 2004
13 Retrospective analyses of existing data Can hazard assessment be simplified by changing the testing strategy?Impact of the second generation in the 2-generation study(Janer, Hakkert, Slob, Vermiere, Piersma Reprod. Toxicol. 24: (2007))Comparison of NOELs and critical end points in subchronic versus 2-generation study in the rat(Janer Hakkert, Piersma, Vermiere, Slob, Reprod. Toxicol. 24: (2007))
14 Toxicological tests and reproductive toxicity Subacute toxicity testSubchronic toxicity testChronic toxicity testReproductive/Developmental toxicity screening testsRat two-generation reproductive toxicity testRat developmental toxicity testRabbit developmental toxicity testWhat is the impact on C&L and on NOAEL of the rat two-generation study when a subchronic study is available ?What is the added value of the 2nd generation
15 Subchronic study: C<he subchronic study did not always detect toxicity to fertility the two-generation studies had an impact on C&L
16 Two-generation vs. Subchronic study: NOAEL Classified for reproductive toxicity (n = 47)Not classified for reproductive toxicity (n = 75)The two generation and the subchronic toxicity tests led to similar overall NOAELs
17 P0 (parental animals) F1 (first generation) F2 (second generation) What is the impact on C&L and on NOAEL of omitting the second generation in a two-generation reproductive toxicity study ?Rat two-generation reproductive toxicity testP0 (parental animals) F1 (first generation) F2 (second generation)
18 Main findings added value 2nd generation Impact on Classification and Labelling (n=176)In general no impact on C&L was observed for the second generationImpact on NOAELs (n=176)In general no impact on overall NOAELImpact leaving out F1 adults (n=176)Not maintaining F1 until adulthood could lead to “missing” of effects relevant for C&L and for NOAELNote: leaving out 2nd generation saves 1200 animals/study
19 CONCLUSIONS present repro-analyses not exhaustive Data base analysis provides important input in refinement/revision of test guidelines/strategiesSubchronic study is (as yet) insufficient for C&L2-gen reproduction study may not be needed to define an overall NOAELOmitting the second generation in a 2-gen-reproduction study may go without consequences for C&L and NOAELNot maintaining F1 until adulthood may miss effects relevant for C&L and NOAELThe findings support the proposal of an extended 1-generation study (Cooper et al., 2006; Critical Reviews in Toxicology, pg 69-98)It is important that additional (confidential) data of industry are made available to further substantiate these conclusions and increase the chemical domain
20 Further work repro-analyses These analyses have been brought into the OECD Test Guideline Programme in the project on the extended F1-generation reproduction study (MS, IND, other stakeholders). Importance of mutual acceptance of the revised method because of the high number of animals involvedNeed for more information to increase data base a.o. to obtain clear alerts when to conduct 2nd generationWork in progress by industries/regulatory bodies on conduct of extended F1-generation study
21 Challenges Regulators and Industries 1 Methods should be developed in order to fulfil the regulatory requirementsRegulators/industries should be involved/consulted in all stages of the development of alternative methods/testing strategies (regulatory needs/capacity building)Development of high quality data basses is essential forRefinement in vivo methods (e.g. example repro)Validation/evaluation alternative methods (e.g. in vitro, “omics”, integrated methods)Development of modelsApplication of category approaches/reading across
22 Challenges Regulators and Industries (2) Challenge to find (acceptable) ways to get/use confidential information from industries to develop/refine methods/testing strategiesIn view of the reduction of animals use it is important that methods are widely accepted (e.g mutual acceptance of data of OECD TGs)Validation/evaluation process should be Transparent and Review Groups should include experts from various field (incl. regulatory knowledge).