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ECETOC Guidance on Dose Selection Technical Report No. 138 EUROPEAN CENTRE OFOR EC TOXICOLOGY AND TOXICOLOGY OF CHEMICALS ECETOC Guidance on Dose Selection ECETOC Guidance on Dose Selection Technical Report No. 138 Brussels, March 2021 ISSN-2079-1526-138 (online) ECETOC TR No. 138 1 ECETOC Guidance on Dose Selection 224504 ECETOC Technical Report No. 138 © Copyright – ECETOC AISBL European Centre for Ecotoxicology and Toxicology of Chemicals Rue Belliard 40, B-1040 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. 138 2 ECETOC Guidance on Dose Selection ECETOC Guidance on Dose Selection Table of Contents 1. SUMMARY 6 2. INTRODUCTION, BACKGROUND AND PRINCIPLES 9 2.1. Background and Principles 9 2.2. Current Regulatory Framework and Guidance 10 2.2.1. Historical perspectives and the evolution of test guidelines 10 2.2.2. The evolution of guidance on dose level selection 11 2.2.3. The Maximum Tolerated Dose concept 14 2.2.4. The use of toxicity studies for Classification and labelling 16 2.2.5. Classification outcomes and their relationship to applied dose 17 2.3. Maternal toxicity in developmental toxicity studies 18 2.4. Animal Welfare considerations 20 2.5. Scientific Considerations 22 2.5.1. Relevance of high dose testing to humans 22 2.5.2. Kinetically informed dose level selection 23 2.6. Summary 24 3. USE OF TOXICOKINETICS TO INFORM DOSE SELECTION 26 3.1. TK requirements in each sector 26 3.2. How TK can be used for dose selection? 29 3.3. TK testing strategy 33 3.4. TK studies and TK models 34 3.4.1. Module 1 - Early in vivo studies 34 3.4.2. Module 2 - Integrated toxicokinetics 37 3.4.3. Module 3 - Full ADME 38 3.4.4 Additional considerations for assessment of in vivo data 38 3.4.5. Supporting evidence 42 3.5. Conclusion 45 4. TOXICODYNAMICS AND MODE OF ACTION 46 4.1. Approaches to investigating mode of action and working within defined mode of action groups 46 5. CROSS SECTOR PRE-REQUISITES FOR DOSE SELECTION 47 5.1. Dosing information from previous studies 47 5.2. Hazardous properties (e.g., irritant, corrosive, sensitisation) 47 5.3. Toxicokinetic data and bioavailability 48 5.4. QSARs 48 5.5. Data from structurally similar molecules 51 5.6. Estimate of human/worker exposure 51 5.7. Routes of relevance (oral gavage, dietary, dermal or inhalation) 52 6. SECTOR SPECIFIC REQUIREMENTS AND APPROACHES 65 ECETOC TR No. 138 3 ECETOC Guidance on Dose Selection 6.1. Pharmaceuticals 65 6.1.1. Dose selection for pharmaceuticals 65 6.1.2. General repeat dose toxicity studies 66 6.1.3. Maximum Tolerated Dose (MTD) Studies 67 6.1.4. Body weight as an indicator of toxicity 68 6.1.5. Specific guidance 68 6.1.6. Biotherapeutics, ICH S6 (R1) 68 6.1.7. Conclusion and Approaches 72 6.2. Agrochemicals 72 6.2.1. Relevant Regulations 72 6.2.2. Human Exposure 73 6.2.3. Existing Guidance for dose level selection 73 6.2.4. In vivo genetic toxicity studies 75 6.2.5. ECETOC Recommendations for dose level selection 75 6.3 Industrial Chemicals 78 6.3.1 Relevant regulations (e.g., REACH and CLP) 78 6.3.2 Human exposure 78 6.3.3 Existing recommendations for dose selection 78 6.3.4 ECETOC recommendations for dose selection 80 6.3.5 Specific cases 84 6.4 Food Ingredients 87 6.4.1 Relevant Regulations 87 6.4.2 Human Exposure 88 6.4.3 Existing Guidance on Dose Level Selection 88 6.4.4 ECETOC Recommendations for Dose Level Selection 92 7. CONCLUSIONS AND RECOMMENDATIONS 93 8. REFERENCES 95 APPENDIX A – ACRONYMS, GLOSSARY AND ABBREVIATIONS 106 Acronyms 106 Glossary 111 APPENDIX B – MODE OF ACTION CASE STUDIES 112 Mechanistic factors 112 Issues related to dose selection: 117 Dose Selection for the 90-day toxicity according to OECD TG 408 study and the outcome. 118 Dose Selection for the developmental toxicity study according to OECD TG 414 and the outcome 118 Evaluation of the appropriateness of the selected dose levels 119 Dose level sections approaches when working with known modes of Action 120 Peroxisome Proliferator-Activated Receptor (PPAR) Agonist Therapeutics 120 HPPD Inhibitor Herbicides and Ocular Toxicity 121 Toxicodynamic factors and Dose level selection in carcinogenicity studies 124 Dose level selection in reproductive toxicity studies 126 APPENDIX C – TK CASE STUDIES 127 Saturation of metabolism (Ethylene Glycol) 127 Saturation of Metabolism (Afidopyropen) 130 Saturation of Metabolism (Ethylbenzene) 131 Saturation of Metabolism (Ethyl tertiary-butyl ether, ETBE) 133 Saturation of renal clearance (2,4-D) 134 APPENDIX D - AGROCHEMICALS CASE STUDIES 136 ECETOC TR No. 138 4 ECETOC Guidance on Dose Selection Dose level selection based on predicted human exposure 136 Case study A 140 Case study B 143 APPENDIX E - INDUSTRIAL CHEMICALS CASE STUDIES 146 Case study 1: OECD 422 – N-Nitrosodiphenylamine, CAS # 80-30-6 146 Case study 2: High dose setting with an irritant in oral gavage rat studies 1,3- and 1,4- cyclohexandicarboxyaldehyde, EC # 482-020-3 148 Case study 3: Developmental toxicity study in rabbits – 1,3(4)-bis(tert-butylperoxyisopropyl) benzene, CAS # 25155-25-3 156 Case Study 4: EOGRTs (OECD 443) - Reaction mass of bis(2,3-epoxypropyl) terephthalate and tris(oxiranylmethyl) benzene-1,2,4-tricarboxylate, EC # 940-592-6 157 Case study 5: Mutagenicity - 4,4'-methylenebis [N, N-bis(2,3-epoxypropyl) aniline], CAS # 28768-32-3 160 Case study 6: Mutagenicity – Theobromine, CAS # 83-67-0 166 APPENDIX F - FOOD INGREDIENTS CASE STUDY 170 MEMBERS OF THE TASK FORCE 171 MEMBERS OF THE SCIENTIFIC COMMITTEE 172 ECETOC TR No. 138 5 ECETOC Guidance on Dose Selection 1. SUMMARY Prior to registering and marketing any new pharmaceutical, chemical, agricultural chemical or food ingredient products manufacturers must, by law, generate data to ensure human (and environmental) safety. The safety testing requirements to ensure human safety vary depending on sector, product type and geographical region/country and for many will require repeat-dose testing in animals. Dose level selection is the most important aspect of the specification of repeat dose toxicity studies. It is the means by which we identify if a dose response is present, those exposures leading to relevant hazard and those exposure levels that should be used as the basis for human health risk assessment, normally based on the absence of adverse effects. Repeat dose studies span a wide range of toxicology study types with duration from 28 day systemic toxicity to 2-year carcinogenicity studies in a number of species. Assessment of systemic toxicity is done in the rat and mouse and for some sectors in dogs, while the assessments of reproductive and developmental toxicity is done in rats and rabbits. The advice on dose level selection provided in test guidelines, allied guidance documents and by individual regulatory authorities globally for most sectors is illustrated in this report but is not well harmonised; the pharmaceutical sector being the closest to having a globally aligned approach through the International Council for Harmonisation (ICH). The various criteria used to set the highest dose level are even less well harmonised across the range of studies and geographies. These range from approaches that can be interpreted to allow a proportion of deaths at the highest dose tested to those that encourage high dose level selection based on signs of evident toxicity. The data provided by toxicity studies are used in all sectors to provide a point of departure from normality which can be used as the endpoint underling a human health risk assessment, and to provide information leading to hazard based classification (although the consequence of classification will vary across sectors, from very little practical impact to a denial of a registration). The recommendations of this report represent pragmatic approaches to selecting dose levels that allow accurate risk assessment and also enable hazard-based classification based on identification of relevant hazards. Analysis of classification outcomes supports the conclusion that there is no automatic relationship between positive classification outcomes and increasing dose, especially approaching the limit dose (currently 1000 mg/kg/d) for repeat dose toxicity studies across all major endpoints measured. This ECETOC TR No. 138 6 ECETOC Guidance on Dose Selection provides a reassurance that a workable and acceptable approach can be found that provides accurate information for risk assessment and assigning a hazard-based classification, and that these needs can co-exist and be served by the same study. It is recognised that different sectors have differing degrees of freedom to operate in dose level selection and this is reflected in the overall recommended approaches. These can be applied within the current regulatory frameworks, and also provide future options and approaches to science-based dose level selection. As recommended in test guidelines and guidance documents, wherever practically possible an understanding of internal exposure should be developed, through the deployment of toxicokinetic (TK) approaches, and used to guide dose level selection.
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