Guidance on information requirements and chemical safety assessment Chapter R.6: QSARs and grouping of chemicals May 2008 Guidance for the implementation of REACH LEGAL NOTICE This document contains guidance on REACH explaining the REACH obligations and how to fulfil them. However, users are reminded that the text of the REACH regulation is the only authentic legal reference and that the information in this document does not constitute legal advice. The European Chemicals Agency does not accept any liability with regard to the contents of this document. © European Chemicals Agency, 2008 Reproduction is authorised provided the source is acknowledged. 2 CHAPTER R.6 – QSARS AND GROUPING OF CHEMICALS PREFACE This document describes the information requirements under REACH with regard to substance properties, exposure, use and risk management measures, and the chemical safety assessment. It is part of a series of guidance documents that are aimed to help all stakeholders with their preparation for fulfilling their obligations under the REACH regulation. These documents cover detailed guidance for a range of essential REACH processes as well as for some specific scientific and/or technical methods that industry or authorities need to make use of under REACH. The guidance documents were drafted and discussed within the REACH Implementation Projects (RIPs) led by the European Commission services, involving stakeholders from Member States, industry and non-governmental organisations. These guidance documents can be obtained via the website of the European Chemicals Agency (http://echa.europa.eu/reach_en.asp). Further guidance documents will be published on this website when they are finalised or updated. This document relates to the REACH Regulation (EC) No 1907/2006 of the European Parliament and of the Council of 18 December 20061 1 Corrigendum to Regulation (EC) No 1907/2006 of the European Parliament and of the Council of 18 December 2006 concerning the Registration, Evaluation, Authorisation and Restriction of Chemicals (REACH), establishing a European Chemicals Agency, amending Directive 1999/45/EC and repealing Council Regulation (EEC) No 793/93 and Commission Regulation (EC) No 1488/94 as well as Council Directive 76/769/EEC and Commission Directives 91/155/EEC, 93/67/EEC, 93/105/EC and 2000/21/EC (OJ L 396, 30.12.2006); amended by Council Regulation (EC) No 1354/2007 of 15 November 2007 adapting Regulation (EC) No 1907/2006 of the European Parliament and of the Council on the Registration, Evaluation, Authorisation and Restriction of Chemicals (REACH) by reason of the accession of Bulgaria and Romania (OJ L 304, 22.11.2007, p. 1). 3 CHAPTER R.6 – QSARS AND GROUPING OF CHEMICALS Convention for citing the REACH regulation Where the REACH regulation is cited literally, this is indicated by text in italics between quotes. Table of Terms and Abbreviations See Chapter R.20 Pathfinder The figure below indicates the location of chapter R.6 within the Guidance Document R6 Information: available – required/needed Hazard Assessment (HA) Exposure Assessment (EA) n Y Dangerous Stop Or PBT? Risk Characterisation (RC) Document in y Risk n Iteration CSR controlled? Communicate ES via eSDS 4 CHAPTER R.6 – QSARS AND GROUPING OF CHEMICALS CONTENTS R.6 OTHER APPROACHES FOR EVALUATING INTRINSIC PROPERTIES OF CHEMICALS ....................................................................................................................... 9 R.6.1 Guidance on QSARs ........................................................................................................................................... 9 R.6.1.1 Explanation of the (Q)SAR concept ........................................................................................................... 9 R.6.1.2 The REACH framework for using (Q)SARs and grouping approaches ................................................... 10 R.6.1.3 The validity, applicability and acceptance of (Q)SARs ............................................................................ 11 R.6.1.3.1 OECD principles for (Q)SAR validation ......................................................................................... 12 R.6.1.3.2 Validity of (Q)SAR model .............................................................................................................. 14 R.6.1.3.3 Reliability of (Q)SAR prediction .................................................................................................... 14 R.6.1.3.4 Adequacy of (Q)SAR prediction ..................................................................................................... 15 R.6.1.4 Regulatory use of QSARs – current experience........................................................................................ 16 R.6.1.4.1 Use of (Q)SARs for risk assessment ............................................................................................... 16 R.6.1.4.2 Use of (Q)SARs for classification and labelling ............................................................................. 18 R.6.1.4.3 Use of (Q)SARs for PBT (vPvB) assessment ................................................................................. 19 R.6.1.5 Regulatory use of QSARs – a framework for REACH ............................................................................. 20 R.6.1.5.1 Steps in assessing adequacy of (Q)SAR results .............................................................................. 20 R.6.1.5.2 Evaluation of the model validity ..................................................................................................... 20 R.6.1.5.3 Assessment of the reliability of the individual model prediction .................................................... 24 R.6.1.5.4 Assessment of adequacy .................................................................................................................. 26 R.6.1.5.5 The acceptance of (Q)SAR data under REACH.............................................................................. 27 R.6.1.6 QSAR Reporting Formats ......................................................................................................................... 28 R.6.1.6.1 The need for appropriate documentation on (Q)SARs .................................................................... 28 R.6.1.6.2 Different types of QSAR Reporting Formats (QRFs) ..................................................................... 28 R.6.1.6.3 The (Q)SAR Model Reporting Format (QMRF) ............................................................................. 29 R.6.1.6.4 The (Q)SAR Prediction Reporting Format (QPRF) ........................................................................ 30 R.6.1.6.5 Conclusions ..................................................................................................................................... 31 R.6.1.7 Stepwise approach for the use of non-testing data .................................................................................... 31 R.6.1.7.1 Meeting regulatory requirements with computational tools ............................................................ 31 R.6.1.7.2 Structured workflow for the generation and use of non-testing data ............................................... 31 R.6.1.7.3 Step 0 - Information collection ........................................................................................................ 33 R.6.1.7.4 Step 1 - Preliminary analysis of reactivity, uptake and fate ............................................................ 35 R.6.1.7.5 Step 2 - Use classification schemes for endpoint of interest ........................................................... 36 R.6.1.7.6 Step 3 - Search for structural alerts for endpoint of interest ............................................................ 36 R.6.1.7.7 Step 4 – Preliminary assessment of expected type of reactivity, uptake, toxicity and fate.............. 37 R.6.1.7.8 Step 5 – Read-across ....................................................................................................................... 37 R.6.1.7.9 Step 6 – (Q)SAR ............................................................................................................................. 39 R.6.1.7.10 Step 7 – Overall assessment ............................................................................................................ 40 R.6.1.8 Computational tools for applying (Q)SARs .............................................................................................. 40 R.6.1.8.1 Molecular descriptors ...................................................................................................................... 41 R.6.1.8.2 Computational tools developed by CEFIC ...................................................................................... 44 R.6.1.8.3 Computational tools developed/implemented by the ECB .............................................................. 44 R.6.1.8.4 Computational tools in development by the OECD ........................................................................ 46 R.6.1.8.5 Computational tools developed by the US-EPA ............................................................................. 46 R.6.1.8.6 Tools and databases to help in the assessment of metabolism ........................................................ 50 R.6.1.9 The QSAR Model Reporting Format (QMRF) ......................................................................................... 52 R.6.1.9.1 QMRF – version 1.2 .......................................................................................................................