Current challenges from Evaluation point of view - Introduction case studies Expert Workshop Dealing with Uncertainty of Non-Test Methods under REACH 23-24 September 2010 Wim De Coen ECHA Evaluation I Unit
Overview Evaluation processes under REACH Legal framework & process Draft decision rationale Basis for evaluation assessments Evaluation challenges in assessing non-testing methods General & specific challenges Read across, categories & QSAR Evaluation needs Introduction to break out group discussions http://echa.europa.eu
Evaluation processes - 1 MSCAs Dossier evaluation Substance evaluation Evaluation of Testing Proposals Compliance Check Examine any information on a substance OUTCOME: Decisions on further information Follow up via other REACH Processes or other legislation 3
Evaluation processes - 2 Compliance Check (CCH) Aim Verify compliance with information requirements Check adequate justifications for adaptations Which dossiers? Only selected dossiers (Article 41) At least 5% of dossiers from each tonnage band Outcome Formal Decision, Article 41(3): request for further information
Evaluation processes - 3 Testing proposal evaluation (TPE) Aim Examine proposals for tests specified in Annexes IX and X Decide whether a proposed test is justified or adequate Avoid unnecessary (animal) testing public consultation Which dossiers? All dossiers containing a testing proposal Outcome Formal Decision, Article 40(3): Request or reject performance of test Change conditions Request additional testing
Decision making process If proposals for amendment ECHA S DRAFT DECISION REGISTRANT S COMMENTS 30 DAYS MSCA CONSULTING 30 DAYS REGISTRANT S COMMENTS 30 DAYS CCH REGISTRANT S DOSSIER If no proposals for amendment Member State Committee UNANIMOUS AGREEMENT 60 DAYS TPE 3 rd party information Yes No Public consultation ECHA DECISION COMMISSION DECISION MSCA = Member State Competent Authorities 6
The content of the draft decision Draft decision (DD) needs to contain a specific request for information: e.g. referring to specific test guidelines DD does not contain: Recommendations, suggestions etc. Choices for registrants to consider (e.g. end point X or Y) Why? Legal certainty Registrant needs to know what needs to be provided Newly provided info should generate a REACH compliant dossier Decision needs to be enforceable 7
Basis for Evaluation assessments Legal text of REACH is the starting point for evaluation Information requirements Annex VII-X Chemical safety assessment and report Information generated according to Annex VI Important: Step 4: Generate new information or propose a testing strategy New data can be generated by alternative methodologies Animal tests should be done as a last resort If alternative methodologies do not generate adequate information, then the test must be performed: Generate new information (Annexes VII and VIII), or Submit a testing proposal (Annexes IX and X)
Adaptation options of the information requirements (waiving) Specific criteria in column 2 of Annexes VII-X General criteria for adaptation in Annex XI: 1. Testing not scientifically necessary 1. Existing data 2. Weight of evidence 3. QSAR 4. In vitro methods 5. Grouping and read-across approach
Regulatory use of QSARs REACH Annex XI provisions for use of (Q)SARs Results obtained from valid (Q)SAR models may indicate the presence or absence of a certain dangerous property. Results of (Q)SARs may be used instead of testing when following conditions are met: 1. results are derived from (Q)SAR model whose scientific validity has been established, 2. substance falls within applicability domain of (Q)SAR model, 3. results are adequate for purpose of classification and labelling and/or risk assessment, and 4. adequate and reliable documentation of applied method provided
Grouping of substances Annex XI: Substances whose physicochemical, toxicological and ecotoxicological properties are likely to be similar or follow a regular pattern as a result of structural similarity may be considered as a group, or category of substances. Similarities may be based on: common functional group common precursor or break-down products a constant pattern in changing of potency
Read-across approach Annex XI : 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. Similarity criteria same as for grouping
Conditions set in Annex XI Results are adequate for the purpose of classification and labelling and/or risk assessment Adequate and reliable coverage of the key parameters are addressed in the corresponding test methods An exposure duration comparable to or longer than the corresponding test method is covered, if the exposure duration is relevant parameter Adequate and reliable documentation of the applied method is provided
General evaluation challenges - 1 REACH reversed the burden of proof Registrants need to demonstrate safe use of substances Decision making requires scientifically and legally valid argumentation and documentation Transparent and independent assessment of waiving statements So far: varying quality and robustness of justification provided by registrants High output is expected Different scenarios: 400-800 TPEs (Dec 2012) 800-1100 CCH (Dec 2014)
General evaluation challenges - 2 ECHA and MS need to consider: Scientific and legal validity of alternative and non-testing methods How to balance the remaining uncertainty in a wider context of dossier vs need for animal testing? How to communicate to all stakeholders (IND, MS) proactively within confines of REACH in order to ensure availability of high quality information avoid unnecessary animal testing but by avoiding pitfalls of previous regulation
Specific evaluation challenges - 1 Starting point = legal text (Criteria of Annex XI should be met) Experience with CCH and TPE: Missing or inadequate justifications not in line with legal requirements Poor quality of argumentation lack of a solid scientific case In these cases: draft decision used to request specific test information Reminder to registrant to consider Annex XI approaches During decision making process registrant can provide better justification (within relatively short time window) 30 days for comments ECHA s DD 30 days for comments MSCA proposal for amendments In case of clear data gap which cannot be filled with non-test method decision requesting test to be performed
Specific evaluation challenges - 2 Specific bottlenecks for QSAR Well standardized and accepted OECD principles Issues mainly at level of documentation Level of documentation insufficient QMRF, QPRF missing Applicability domain unclear Unclear training datasets & algorithm General issue of well established/commercial QSAR packages
Specific evaluation challenges - 3 Specific bottlenecks for Read-across/Categories No harmonised approaches Documentation provided insufficient Scientific rationale unclear, incorrect or insufficient Selection of reference substance (RS) unclear RS not similar (enough) to read-across substance Intrinsic properties of RS poorly defined Missing bridging studies Wishful thinking rather than scientific argumentation: E.g. no info on kinetics, metabolism, MoA
Specific evaluation needs - 1 Need for scientific harmonised approaches for assessment of non-testing method results Multidisciplinary assessments: (eco)toxicologists, modelers, chemists, risk assessors each with their own perspective Different backgrounds different weighing of scientific elements Different perspectives: hypothesis based vs experimental based approaches Modeling vs experimental approaches
Specific evaluation needs - 2 Policy criteria needed to assess remaining uncertainty on intrinsic properties based on non-testing approaches. Can we accept uncertainty related to non-testing approach in a registration dossier based on level of concern related to safe use of substance? Can we develop criteria (e.g. for each of endpoints based on animal tests from Annex IX and X) that allow the Agency and MS to accept this uncertainty with a commonly agreed perspective? Need for an agreed assessment framework for non-test method: especially for read-across http://echa.europa.eu
Specific evaluation needs - 3 Need for Read across assessment framework Case-by-case generalised approach For example: a targeted questionnaire Addressing and characterising main themes of uncertainty: E.g. Experimental vs hypothesis based Determine level of documentation preferably needed Differentiate between qualitative and quantitative read-across? Allowing standardized and transparent assessments to be made Ensure consistency Important for evaluators (ECHA, MS), dossier creators (IND), 3 rd parties generating information