Category Approaches, Read-Across, (Q)SAR Technical Report No

Category approaches, Read-across, (Q)SAR Technical Report No. 116 EUROPEAN CENTRE FOR ECOTOXICOLOGY AND TOXICOLOGY OF CHEMICALS Category approaches, Read-across, (Q)SAR Technical Report No. 116 Brussels, November 2012 ISSN-0773-8072-116 (print) ISSN-2079-1526-116 (online) Category approaches, Read-across, (Q)SAR ECETOC Technical Report No. 116 © Copyright – ECETOC AISBL European Centre for Ecotoxicology and Toxicology of Chemicals 2 Avenue E. Van Nieuwenhuyse (Bte 8), B-1160 Brussels, Belgium. All rights reserved. No part of this publication may be reproduced, copied, stored in a retrieval system or transmitted in any form or by any means, electronic, mechanical, photocopying, recording or otherwise without the prior written permission of the copyright holder. Applications to reproduce, store, copy or translate should be made to the Secretary General. ECETOC welcomes such applications. Reference to the document, its title and summary may be copied or abstracted in data retrieval systems without subsequent reference. The content of this document has been prepared and reviewed by experts on behalf of ECETOC with all possible care and from the available scientific information. It is provided for information only. ECETOC cannot accept any responsibility or liability and does not provide a warranty for any use or interpretation of the material contained in the publication. ECETOC TR No. 116 Category approaches, Read-across, (Q)SAR Category approaches, Read-across, (Q)SAR TABLE OF CONTENTS SUMMARY 1 1. INTRODUCTION 3 1.1 Terms of reference 4 1.2 Scope 5 1.3 Roadmap of the report 6 2. DEFINITIONS FOR NON-TESTING APPROACHES 8 2.1 Data gap filling 9 2.1.1 Read-across 9 2.1.2 Trend analysis and computational methods based on internal models 13 2.1.3 External (Q)SAR models and expert systems 14 3. RESOURCES FOR NON-TESTING APPROACHES 15 3.1 Regulatory guidance 15 3.1.1 ECHA guidance 15 3.1.2 OECD guidance 17 3.1.3 USA EPA High Production Volume (HPV) Challenge Program 20 3.1.4 Canada Substance Groupings Initiative 21 3.1.5 Japan HPV Challenge Program 21 3.1.6 China New Chemical Substance Notification 22 3.1.7 TSCA New Chemicals Program (NCP) Chemical Categories 22 3.2 Scientific literature 22 3.3 Software resources 24 3.3.1 (Q)SAR/Expert systems 25 3.3.2 Prediction of metabolism 32 3.3.3 Grouping tools 34 4. END APPLICATIONS – FITNESS FOR PURPOSE 38 4.1 Top-down: screening/prioritisation 38 4.2 Bottom-up: regulatory purposes 40 4.3 Top-down/Bottom-up: special class considerations 41 5. CONSIDERATIONS FOR THE USE OF NON-TESTING APPROACHES 44 6. SYSTEMATIC WORKFLOW 47 6.1 Analogue identification 47 ECETOC TR No. 116 Category approaches, Read-across, (Q)SAR 6.2 Rationale for grouping: analogue evaluation 52 6.2.1 Common functional group(s) 53 6.2.2 Incremental and constant change across the category 54 6.2.3 Common constituents or chemical classes 55 6.2.4 Other considerations for analogue evaluation 55 6.2.5 The metabolic pathway justification 56 6.2.6 Read-across considerations for metal compounds 59 6.3 Considerations of impurities/purities 59 6.4 List of endpoints covered 60 6.5 Endpoint by endpoint justification 64 6.5.1 Physicochemical parameters 64 6.5.2 Aquatic toxicity 65 6.5.3 Biodegradation 66 6.5.4 Bioaccumulation 68 6.5.5 Acute mammalian toxicity 71 6.5.6 Irritation 73 6.5.7 Skin sensitisation 74 6.5.8 Respiratory sensitisation 78 6.5.9 Mutagenicity 78 6.5.10 Repeated-dose toxicity 80 6.5.11 Reproductive and developmental toxicity 83 6.6 Classification and labelling comparison 87 7. RECOMMENDATIONS 88 8. RESEARCH NEEDS/ACTIVITIES 90 ABBREVIATIONS 93 BIBLIOGRAPHY 97 APPENDIX A: WORKFLOWS 112 APPENDIX B: Case Studies 115 B.1. Cycla-esters 115 B.2. Alkyldimethylamines (ADA) 129 B.3. Montan wax derived chemicals 132 B.4. Glycol ethers E series category 135 B.5. Lower alkyl methacrylate esters 160 B.6. Molybdenum compounds 174 MEMBERS OF THE TASK FORCE 181 MEMBERS OF THE SCIENTIFIC COMMITTEE 182 ECETOC TR No. 116 Category approaches, Read-across, (Q)SAR SUMMARY Considerable practical experience has been gained in applying non-testing approaches for regulatory purposes, most recently driven by the demands of the REACH legislation (EC, 2006). This ECETOC Task Force was convened to summarise guidance and tools available, to review their practical utility and to consider what technical recommendations and learnings could be shared more widely to refine and inform on the current use of read-across. A number of case studies were formulated and the generic insights of developing, evaluating, justifying and documenting read-across approaches were extracted as far as possible. Sharing this experience aims to inform users about the pitfalls and challenges associated with read-across approaches as well as about feasible practical strategies available to develop appropriate scientific justifications. The report is intended to lay down the foundations of robust yet practical read-across approaches whilst encouraging consistent application across industry. Currently read-across strategies for REACH have tended to rely on the so-called ‘analogue approach’ as opposed to a ‘category approach’, in addition to (quantitative) structure activity relationship [(Q)SAR] approaches. (Q)SAR approaches have been extensively relied upon to address data gaps for physicochemical properties such as log Kow, environmental fate parameters such as biodegradation, hydrolysis, bioaccumulation potential and ecotoxicity endpoints such as acute aquatic toxicity in the standard species (fish, daphnia and algae). For the aforementioned properties, such (Q)SAR approaches have been used as direct replacements to experimental testing. There are many expert systems available to facilitate these assessments including the Organisation for Economic Cooperation and Development (OECD) (Q)SAR Toolbox or the United States Environmental Protection Agency (US EPA) EPISUITE programme. For mammalian endpoints, (Q)SAR have been applied less frequently with the exception of endpoints such as Ames mutagenicity and, to a lesser extent, skin sensitisation where the mechanisms of action are relatively well understood and where the underlying data are more readily available. Read-across approaches have been attempted as a means to address data gaps for longer-term effects such as 90-day repeated-dose toxicity studies or reproductive/developmental effects. For such complex endpoints, (Q)SAR have been applied, but their role has been as supporting information as a means to highlight potential chemical modes of action or to offer indications for similarity in effect. For such endpoints in particular, information on likely transformation products and the rate of formation of these products as derived from experimental studies are strongly recommended to substantiate the overall read-across justification. Whilst toxicokinetic information is not a requirement under REACH per se, such information is viewed as key to help rationalise certain read-across approaches, particularly for endpoints like reproductive/developmental effects where current (Q)SAR approaches are still in early development. Absence of toxicity is a particular challenge to justify. Despite provisions in REACH calling for the use of read- across and (Q)SAR for both the absence and presence of toxicity (see Annex XI in EC, 2006), the justification of ‘absence’ is not to be underestimated. In many cases, toxicokinetic information or physiologically-based pharmacokinetic (PBPK) modelling is considered desirable to provide valuable supporting evidence. Read-across approaches for longer-term effects should ideally be structured to present an overall ‘weight of evidence’ (WoE) argument (SCENIHR, 2012). A justification needs to rely on several lines of corroborating evidence whether it be consistent metabolic profiles, similarity in effects at shorter exposures, (Q)SAR estimates or other supporting analogues with experimental data that are not necessarily part of the main ECETOC TR No. 116 1 Category approaches, Read-across, (Q)SAR category/analogue approach. In the latter case, tools such as Toxmatch, Leadscope or the OECD (Q)SAR Toolbox may prove helpful to identify related analogues (Patlewicz et al, 2011). It is recommended that justifications are structured using a template such as the category/analogue reporting format (CRF/ARF) as outlined in OECD (OECD, 2007a) and REACH guidance documents (ECHA REACH TGD). These templates are an effective means of structuring the arguments on an endpoint per endpoint basis as well as presenting an overall data matrix for the analogue or category member under evaluation. A justification is strengthened by the presentation of an explicit data matrix which demonstrates a consistent profile for the members of the category or analogues under consideration. Presenting data for the source analogues for the endpoint that is proposed to be read across alone may not be sufficient. By default, read-across is considered to be associated with additional uncertainty due to the fact that information on a target substance is being inferred from that available on a source substance(s). Whilst assessment factors can be a route by which uncertainty is addressed, these should be used on a case by case basis and driven by the confidence associated with the underlying similarity hypothesis as well as the quality of the study data forming part of the supporting WoE information. In the future, less ‘classical’ toxicity data will be anticipated for each individual analogue member, and rather more ‘omics data (van Ravenzwaay et al, 2012). Thus, there will likely be a commensurate shift towards deriving larger categories as contrasted with analogue approaches. This should facilitate analysis of trends, although the data gap-filling approaches will likely be contingent on the application of non-standard, alternative toxicity testing data including that from high throughput/high content technologies. Whilst this will be a challenge in interpretation, it does present a cost-efficient means of generating data in a relatively short time frame.

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