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Book Details
Abstract
Consumer and environmental protection depend on the careful regulation of all classes of chemicals. Toxicology is the key science used to evaluate safety and so underpins regulatory decisions on chemicals. With the growing body of EU legislation involved in chemical regulation, there is a concomitant need to understand the toxicological principles underlying safety assessments
Regulatory Toxicology in the European Union is the first book to cover regulatory toxicology specifically in Europe. It addresses the need for a wider understanding of the principles of regulatory toxicology and their application and presents the relationship between toxicology and legislative processes in regulating chemical commodities across Europe. This title has a broad scope, covering historical and current chemical regulation in Europe, the role of European agencies and institutions, and also the use of toxicology data for important classes of chemicals, including human and veterinary medicines, animal feed and food additives, biocides, pesticides and nanomaterials. This book is therefore extremely pertinent and timely in the toxicology field at present.
This book is an essential reference for regulatory authorities, industrialists, academics, undergraduates and postgraduates working within safety and hazards, toxicology, the biological sciences, and the medicinal and pharmaceutical sciences across the European Union.
Table of Contents
| Section Title | Page | Action | Price |
|---|---|---|---|
| Cover | Cover | ||
| Regulatory Toxicology in the European Union | i | ||
| Preface | vii | ||
| Contents | ix | ||
| Chapter 1 - Introduction and General Aspects of Risk Assessment | 1 | ||
| 1.1 History of Regulation in the European Union (EU) | 1 | ||
| 1.2 Philosophical Aspects of Risk | 2 | ||
| 1.3 Types of Regulatory Regime | 2 | ||
| 1.4 Quality of Data | 3 | ||
| 1.4.1 Proprietary Data Versus Studies in the Peer-reviewed Literature | 3 | ||
| 1.4.2 Proprietary Data | 4 | ||
| 1.4.2.1 Good Laboratory Practice | 5 | ||
| 1.4.2.2 Guidelines | 5 | ||
| 1.4.3 Data from the Peer-reviewed Literature | 6 | ||
| 1.4.4 Human Data | 8 | ||
| 1.5 Expertise | 9 | ||
| 1.6 General Aspects of Risk Assessment | 10 | ||
| 1.6.1 Derivation of Standards | 11 | ||
| 1.6.1.1 Uncertainty (Safety) Factors (UFs) | 12 | ||
| 1.6.1.2 New Developments in Risk Assessment | 13 | ||
| 1.6.2 Standards | 13 | ||
| 1.6.2.1 Prohibition of Use | 13 | ||
| 1.6.2.2 Maximum Residue Limits or Levels (MRLs) | 14 | ||
| 1.6.2.3 ALARA | 14 | ||
| 1.6.2.4 Limit of Quantification | 14 | ||
| 1.6.2.5 Ranges | 15 | ||
| 1.6.2.6 Standards for Air Pollutants | 15 | ||
| 1.6.3 Risk Management | 16 | ||
| 1.7 Conclusions | 16 | ||
| Acknowledgements | 17 | ||
| References | 17 | ||
| Chapter 2 - Regulation of Medicinal Products for Human Use in the European Union | 22 | ||
| 2.1 Introduction | 22 | ||
| 2.2 What Are Medicinal Products for Human Use? | 23 | ||
| 2.3 Background to the Legislation | 23 | ||
| 2.4 EU Legislation | 24 | ||
| 2.5 Legislation: Differences Between Regulations, Directives and Guidelines | 25 | ||
| 2.6 The EU Regulatory System for Medicinal Products | 26 | ||
| 2.7 European Medicines Agency (EMA): Role, Tasks and Functioning | 27 | ||
| 2.8 EMA: Scientific Committees | 28 | ||
| 2.8.1 Committee for Medicinal Products for Human Use (CHMP) | 28 | ||
| 2.8.2 The Pharmacovigilance Risk Assessment Committee (PRAC) | 30 | ||
| 2.8.3 The Committee for Orphan Medicinal Products (COMP) | 31 | ||
| 2.8.4 The Committee on Herbal Medicinal Products (HMPC) | 31 | ||
| 2.8.5 The Committee for Advanced Therapies (CAT) | 31 | ||
| 2.8.6 The Paediatric Committee (PDCO) | 32 | ||
| 2.9 Composition of Committees | 33 | ||
| 2.10 Scientific Guidelines | 34 | ||
| 2.11 Marketing Authorisation Procedures | 34 | ||
| 2.11.1 Centralised Procedures | 34 | ||
| 2.11.2 Support for Early Access to Medicines | 35 | ||
| 2.11.3 Accelerated Assessment | 36 | ||
| 2.11.4 Conditional Marketing Authorisation | 36 | ||
| 2.11.5 Exceptional Circumstances Authorisation | 37 | ||
| 2.11.6 Compassionate Use | 38 | ||
| 2.11.7 PRIME (PRIority MEdicines) Scheme | 38 | ||
| 2.12 Decentralised Procedure (DCP) | 39 | ||
| 2.13 Mutual Recognition Procedure (MRP) | 40 | ||
| 2.14 National Authorisation Procedures | 40 | ||
| 2.15 Special Procedures | 40 | ||
| 2.15.1 Article 58 Applications | 40 | ||
| 2.15.2 Compassionate Use | 41 | ||
| 2.16 Referral Procedures | 41 | ||
| 2.17 Data Submission on Medicines | 41 | ||
| 2.18 Scientific Assessments | 42 | ||
| 2.19 Adopting a Committee Opinion or Recommendation | 43 | ||
| 2.20 Transparency | 43 | ||
| 2.21 European Public Assessment Reports (EPARs) | 43 | ||
| 2.22 Standing and Temporary Working Parties | 44 | ||
| Scientific Advisory Groups | 45 | ||
| Other CHMP-associated Groups | 45 | ||
| 2.22.1 The Safety Working Party (SWP) | 46 | ||
| 2.22.2 The Scientific Advice Working Party (SAWP) | 46 | ||
| 2.22.3 The Biologics Working Party (BWP) | 47 | ||
| 2.22.4 The Joint Committee for Medicinal Products for Human Use/Committee for Medicinal Products for Veterinary Use Quality Worki... | 47 | ||
| 2.22.5 Healthcare Professionals’ Working Party (HCPWP) | 48 | ||
| 2.22.6 Patients’ and Consumers’ Working Party (PCWP) | 48 | ||
| 2.23 Safety Monitoring of Medicines | 48 | ||
| 2.24 Inspections | 49 | ||
| 2.25 The Co-ordination Group for Mutual Recognition and Decentralised Procedures – Human (CMDh) | 49 | ||
| 2.26 Regulatory Rules for Specific Types of Medicinal Products or Investigations | 50 | ||
| 2.26.1 Clinical Trials | 50 | ||
| 2.26.2 Orphan Medicinal Products | 52 | ||
| 2.26.3 Paediatric Medicines | 53 | ||
| 2.26.4 Geriatric Medicines | 56 | ||
| 2.26.5 Advanced Therapy Medicinal Products (ATMPs) | 56 | ||
| 2.26.6 Biological Medicinal Products and Similar Biological Product | 57 | ||
| 2.26.7 Generic Medicines | 58 | ||
| 2.26.8 Hybrid Medicines | 59 | ||
| 2.26.9 Herbal Medicines | 59 | ||
| 2.26.10 Homeopathic Medicines | 60 | ||
| 2.26.11 Non-prescription Medicines | 61 | ||
| 2.27 Innovation in Medicines | 62 | ||
| 2.28 Scientific Advice | 63 | ||
| 2.29 Conclusion | 64 | ||
| References | 64 | ||
| Chapter 3 - Regulatory Toxicology for Human Medicines in the European Union | 72 | ||
| 3.1 Introduction | 72 | ||
| 3.2 Life Cycle of a Typical Human Medicine | 73 | ||
| 3.3 Clinical Trials | 74 | ||
| 3.4 Guidelines | 75 | ||
| 3.5 Scientific Flexibility in Interpretation of Regulatory Guidelines | 76 | ||
| 3.6 ICH Guidelines‡ | 76 | ||
| 3.6.1 Safety Guidelines | 78 | ||
| 3.6.1.1 Carcinogenicity Studies | 78 | ||
| 3.6.1.2 Genotoxicity Studies | 78 | ||
| 3.6.1.3 Toxicokinetics and Pharmacokinetics | 78 | ||
| 3.6.1.4 Repeat-dose Toxicity | 78 | ||
| 3.6.1.5 Reproductive Toxicology | 78 | ||
| 3.6.1.6 Biotechnological Products | 78 | ||
| 3.6.1.7 Safety Pharmacology Studies | 78 | ||
| 3.6.1.8 Immunotoxicology Studies | 79 | ||
| 3.6.1.9 Therapeutic Area-specific | 79 | ||
| 3.6.1.10 Photosafety Evaluation | 79 | ||
| 3.6.2 Multidisciplinary Guidelines | 79 | ||
| 3.7 The Common Technical Document (CTD) | 79 | ||
| 3.8 CHMP (EU) Guidelines | 82 | ||
| 3.9 Purpose of Non-clinical Testing | 83 | ||
| 3.10 Predictive Value of Animal Studies in the Risk Assessment of Human Medicines | 84 | ||
| 3.10.1 Use of Recovery Phase Animals | 85 | ||
| 3.10.2 Statistical Considerations | 85 | ||
| 3.11 3Rs (Replacement, Reduction and Refinement) in the Regulatory Testing of Human Medicinal Products | 86 | ||
| 3.12 Study Design in Regulatory Toxicology Studies | 87 | ||
| 3.13 Dose Selection for Non-clinical Testing | 87 | ||
| 3.14 Biological Medicinal Products | 89 | ||
| 3.15 Interpretation of Data | 91 | ||
| 3.16 Weight of Evidence Approach in the Interpretation of Data | 92 | ||
| 3.17 Types of Non-clinical Studies in Regulatory Toxicology | 93 | ||
| 3.17.1 Pharmacodynamics | 95 | ||
| 3.17.2 Secondary Pharmacodynamics | 95 | ||
| 3.17.3 Safety Pharmacodynamics | 96 | ||
| 3.17.4 Pharmacodynamic Drug Interactions | 96 | ||
| 3.17.5 Pharmacokinetics | 96 | ||
| 3.17.5.1 Methods of Analysis | 96 | ||
| 3.17.5.2 Absorption | 97 | ||
| 3.17.5.3 Distribution | 97 | ||
| 3.17.5.4 Metabolism | 97 | ||
| 3.17.5.5 Excretion | 98 | ||
| 3.17.5.6 Pharmacokinetic Drug Interactions | 98 | ||
| 3.17.6 The Role of Pharmacokinetics in the Drug Development Process | 99 | ||
| 3.17.7 Toxicokinetics | 99 | ||
| 3.17.8 Single Dose/Acute Toxicity Studies | 100 | ||
| 3.17.9 Repeated Dose Toxicity | 100 | ||
| 3.17.10 Genotoxicity | 103 | ||
| 3.17.10.1 Option 1 | 104 | ||
| 3.17.10.2 Option 2 | 104 | ||
| 3.17.11 Carcinogenicity | 106 | ||
| 3.17.11.1 Carcinogenicity Testing and the Use of Transgenic Animals | 108 | ||
| 3.17.11.2 ILSI Programme – Alternative Carcinogenicity Testing (ACT) Models Evaluated | 108 | ||
| 3.17.11.3 Dose Selection | 109 | ||
| 3.17.11.4 Animal Survival | 110 | ||
| 3.17.11.5 Recent Developments | 110 | ||
| 3.17.12 Reproductive Toxicity | 111 | ||
| 3.17.13 Juvenile Animal Toxicity | 112 | ||
| 3.17.14 Local Tolerance | 113 | ||
| 3.17.15 Sensitising Potential | 114 | ||
| 3.17.16 Photosafety Evaluation | 114 | ||
| 3.17.17 Immunotoxicity | 115 | ||
| 3.17.18 Antigenicity | 115 | ||
| 3.17.19 Dependence Potential | 116 | ||
| 3.17.20 Impurities | 116 | ||
| 3.17.21 Environmental Risk Assessment (ERA) | 117 | ||
| 3.18 Risk Assessment: the Integration of Clinical and Non-clinical Data | 119 | ||
| 3.18.1 Conclusion | 120 | ||
| 3.18.2 General Aspects | 121 | ||
| 3.19 Good Laboratory Practice (GLP) | 122 | ||
| 3.20 Conclusion | 122 | ||
| References | 123 | ||
| Chapter 4 - Pharmacovigilance for Authorised Human Medicinal Products in the European Union | 129 | ||
| 4.1 The Global System for Pharmacovigilance | 129 | ||
| 4.2 Development of the Current EU Pharmacovigilance System for Authorised Medicines | 135 | ||
| 4.3 Re-organisation of the EU Regulatory System Concerning Pharmacovigilance | 138 | ||
| 4.4 Quality Management, Compliance and Inspections | 142 | ||
| 4.5 Pharmacovigilance Obligations of Being an EU Marketing Authorisation Holder | 143 | ||
| 4.6 Risk Management | 146 | ||
| 4.7 Reporting Requirements for Individual Cases and Periodic Reports | 149 | ||
| 4.8 Reporting Requirements for Periodic Reports | 153 | ||
| 4.9 Signal Management | 154 | ||
| 4.10 Post-authorisation Safety Studies (PASS) | 155 | ||
| 4.11 What Would an Ideal Global Pharmacovigilance System Look Like for a Company | 157 | ||
| Further Recommended Reading | 158 | ||
| References | 158 | ||
| Chapter 5 - Veterinary Medicinal Products | 163 | ||
| 5.1 Introduction | 163 | ||
| 5.2 Pre-clinical Safety | 166 | ||
| 5.3 Consumer Safety | 166 | ||
| 5.3.1 Establishment of MRLs in the EU | 167 | ||
| 5.3.2 Elaboration of MRLs | 173 | ||
| 5.3.3 The Joint FAO/WHO Expert Committee on Food Additives (JECFA) | 176 | ||
| 5.3.4 Practical Uses of MRLs | 177 | ||
| 5.3.5 Residues Surveillance | 180 | ||
| 5.3.5.1 Residues and Residue Studies | 181 | ||
| 5.3.5.2 Residues Surveillance for Veterinary Drugs in the UK | 183 | ||
| 5.3.6 Residues Avoidance | 186 | ||
| 5.4 User Safety | 188 | ||
| 5.4.1 The Assessment Process | 190 | ||
| 5.4.2 Hazard Identification and Assessment | 190 | ||
| 5.4.3 Exposure Assessment | 192 | ||
| 5.4.3.1 Dermal Exposure | 193 | ||
| 5.4.3.2 Accidental Self-injection | 194 | ||
| 5.4.3.3 Inhalation Exposure | 195 | ||
| 5.4.3.4 Oral Exposure | 197 | ||
| 5.4.3.5 Exposure to Topically Applied Products | 198 | ||
| 5.4.4 Biological Monitoring | 198 | ||
| 5.4.5 Risk Assessment | 199 | ||
| 5.4.6 Risk Management | 201 | ||
| 5.4.7 Risk Communication | 202 | ||
| 5.5 Conclusions | 203 | ||
| Acknowledgements | 205 | ||
| References | 205 | ||
| Chapter 6 - Pharmacovigilance for Veterinary Medicinal Products | 243 | ||
| 6.1 Introduction | 243 | ||
| 6.2 Regulation of Veterinary Medicinal Products in the EU | 245 | ||
| 6.2.1 Historical Context | 245 | ||
| 6.2.2 The Current Situation – up to 2017 | 246 | ||
| 6.3 Pharmacovigilance for VMPs | 247 | ||
| 6.3.1 Requirements of Directive 2001/82/EC | 247 | ||
| 6.3.2 Requirements of Regulation (EC) No 2309/93 | 256 | ||
| 6.3.3 Revision in 2004 and Onwards | 257 | ||
| 6.3.4 Good Pharmacovigilance Practices | 260 | ||
| 6.4 Some Findings from Pharmacovigilance Activities | 261 | ||
| 6.4.1 Pharmacovigilance in the UK | 262 | ||
| 6.4.2 Data Available from the EMA | 264 | ||
| 6.5 Assessment of Adverse Reaction Reports | 269 | ||
| 6.5.1 Temporal Relationships | 269 | ||
| 6.5.2 Dechallenge/Rechallenge | 270 | ||
| 6.5.3 Anatomical Site of the Reaction | 270 | ||
| 6.5.4 Time Course of the Reaction | 270 | ||
| 6.5.5 Previous Adverse Drug Reactions | 270 | ||
| 6.5.6 Type of Adverse Reaction | 271 | ||
| 6.5.7 Drug–Drug Interactions | 271 | ||
| 6.5.8 Neonatal and Geriatric Patients | 271 | ||
| 6.5.9 Test Results | 271 | ||
| 6.5.10 Use of Pharmacology and Toxicology Data | 271 | ||
| 6.5.11 Algorithms for Causality in Pharmacovigilance | 272 | ||
| 6.5.12 Consideration of Expectedness | 278 | ||
| 6.6 Some Examples of Adverse Reactions to Veterinary Medicinal Products | 283 | ||
| 6.6.1 Adverse Reactions in Animals | 283 | ||
| 6.6.1.1 Macrocyclic Lactones | 283 | ||
| 6.6.1.2 Permethrin and Synthetic Pyrethroids | 287 | ||
| 6.6.1.3 Alphaxalone and Alphadolone | 287 | ||
| 6.6.1.4 Griseofulvin | 287 | ||
| 6.6.1.5 Enrofloxacin | 288 | ||
| 6.6.1.6 Ionophores | 288 | ||
| 6.6.2 Adverse Reactions in Humans | 288 | ||
| 6.6.2.1 Etorphine | 288 | ||
| 6.6.2.2 Cytotoxic Drugs | 290 | ||
| 6.6.2.3 Tilmicosin | 293 | ||
| 6.6.2.4 Euthanasia Agents | 294 | ||
| 6.6.2.5 Clenbuterol | 295 | ||
| 6.6.2.6 Organophosphorus Sheep Dips | 296 | ||
| 6.7 Conclusions | 302 | ||
| References | 302 | ||
| Chapter 7 - Animal Feed Additives | 355 | ||
| 7.1 Animal Feedstuffs | 355 | ||
| 7.2 Feed Additives | 356 | ||
| 7.2.1 Regulatory Framework | 356 | ||
| 7.2.1.1 Directive 70/524/EEC | 357 | ||
| 7.2.1.2 Regulation (EC) No 1831/2003 | 357 | ||
| 7.3 The European Food Safety Authority | 360 | ||
| 7.4 The Committees | 361 | ||
| 7.4.1 The Scientific Committee on Animal Nutrition (SCAN) | 361 | ||
| 7.4.2 The FEEDAP Panel and Its Working Groups | 361 | ||
| 7.4.2.1 Guidance Documents of the FEEDAP Panel | 363 | ||
| 7.4.3 Other EFSA Panels Working on Animal Feed | 364 | ||
| 7.4.3.1 Mercury Contamination of Animal Feed – CONTAM Panel | 364 | ||
| 7.4.3.2 Gossypol Contamination of Animal Feed – CONTAM Panel | 364 | ||
| 7.4.3.3 Risks of Transmissible Spongiform Encephalopathies (TSEs) from Animal Feeds – BIOHAZ Panel | 365 | ||
| 7.4.3.4 Risk Assessment of Genetically Modified Feed Additives and Feeds – GMO Panel | 365 | ||
| 7.4.4 The Standing Committee on Plants, Animals, Food and Feed (SCoPAFF) | 366 | ||
| 7.4.5 Other Bodies Whose Work May Affect the Use of Feed Additives in the EU | 367 | ||
| 7.5 Evaluation of the Safety of Feed Additives | 367 | ||
| 7.5.1 Mandate from the Commission | 367 | ||
| 7.5.2 Sources of Data | 368 | ||
| 7.5.3 Drafting an Opinion | 368 | ||
| 7.5.4 Quality and Reliability of Data | 369 | ||
| 7.5.5 Target Animal Safety | 370 | ||
| 7.5.6 Consumer Safety | 372 | ||
| 7.5.6.1 The Acceptable Daily Intake (ADI) | 374 | ||
| 7.5.6.2 Maximum Residue Limits (MRLs) | 378 | ||
| 7.5.6.3 Carry-over Residues | 380 | ||
| 7.5.6.4 Special Arrangements for Some Classes of Feed Additives | 380 | ||
| 7.5.6.4.1 Flavouring Agents.The feed additives that are classed as flavouring agents include sweeteners (which are a separate class when u... | 380 | ||
| 7.5.6.4.2 Micro-organisms.The FFEDAP Panel has published guidelines on how to assess microbiological aspects of the safety of micro-organi... | 381 | ||
| 7.5.6.4.3 Enzymes.The FEEDAP Panel considers that pure enzymes fed to animals will not leave toxic residues in foods derived from the anim... | 382 | ||
| 7.5.6.4.4 Colouring Agents.Colouring agents can be used as feed additives to make feed more attractive to animals or to people purchasing ... | 382 | ||
| 7.5.6.4.5 Silage Agents.Advice on testing silage additives is given in the guidance document on assessment of silage agents.52 The FEEDAP ... | 383 | ||
| 7.5.6.5 Examples of Interesting Evaluations | 383 | ||
| 7.5.6.5.1 Allura Red AC and Other Sulfonated Azo Dyes.The FEEDAP Panel published an Opinion57 which stated that it had concerns about the ... | 383 | ||
| 7.5.6.5.2 Formaldehyde.When the FEEDAP Panel evaluated the safety of formaldehyde as part of an assessment of a proposal to use it as a pr... | 384 | ||
| 7.5.7 User Safety | 384 | ||
| 7.5.8 Environmental Safety | 387 | ||
| 7.5.9 Post-market Monitoring | 389 | ||
| 7.6 Risk Communication | 389 | ||
| 7.7 Challenges for the Future | 390 | ||
| 7.7.1 The PROMETHEUS Project | 390 | ||
| 7.7.2 Uncertainty | 390 | ||
| 7.7.3 Weight of Evidence | 391 | ||
| 7.7.4 Mixtures | 391 | ||
| 7.7.5 Ultra-fine Particles | 393 | ||
| 7.8 Future Amendments to Legislation | 393 | ||
| 7.9 Concluding Remarks | 394 | ||
| References | 395 | ||
| Chapter 8 - Regulatory Toxicology of Pesticides: Concepts | 402 | ||
| 8.1 Introduction | 402 | ||
| 8.2 Risk Assessment of Pesticides | 403 | ||
| 8.2.1 Pesticidal Active Substances | 404 | ||
| 8.2.2 Plant Protection Products | 410 | ||
| 8.2.3 Biocidal Products | 414 | ||
| 8.2.4 Risk Assessment | 418 | ||
| 8.3 Future Trends in Regulatory Toxicology | 418 | ||
| 8.3.1 New Methodologies | 418 | ||
| 8.3.2 Development of Test Guidelines | 419 | ||
| 8.3.3 Cumulative Risk Assessment | 422 | ||
| 8.3.4 Metabolites | 426 | ||
| 8.3.5 Micro-organisms | 427 | ||
| List of Abbreviations | 428 | ||
| Acknowledgements | 429 | ||
| References | 430 | ||
| Chapter 9 - Legal Background and Procedures on Pesticides | 439 | ||
| 9.1 Introduction | 439 | ||
| 9.2 Plant Protection Products | 440 | ||
| 9.2.1 Approval of Active Substances | 441 | ||
| 9.2.1.1 Data Requirements | 443 | ||
| 9.2.1.2 Exclusion Criteria | 444 | ||
| 9.2.2 Authorisation of Plant Protection Products | 445 | ||
| 9.2.2.1 Data Requirements | 445 | ||
| 9.2.2.2 Zonal/National Authorisation | 446 | ||
| 9.2.2.3 Mutual Recognition | 447 | ||
| 9.2.2.4 Simplified Procedures | 448 | ||
| 9.2.2.4.1 Simplified Authorisation Procedure for Minor Uses.Where a plant protection product is already authorised but additional applicat... | 448 | ||
| 9.2.2.4.2 Approval/Authorisation of Basic Substances.According to Article 23 of Regulation (EC) No. 1107/2009,1 a basic substance is defin... | 448 | ||
| 9.2.3 Setting of Maximum Residue Levels | 449 | ||
| 9.2.3.1 Procedure for Setting of Maximum Residue Levels | 450 | ||
| 9.2.3.2 Data Requirements | 451 | ||
| 9.2.3.3 Residues in Food | 452 | ||
| 9.2.3.4 Residues in Drinking Water | 453 | ||
| 9.2.3.5 Multiple Residues | 453 | ||
| 9.2.3.6 Import Tolerances | 454 | ||
| 9.3 Biocidal Products | 454 | ||
| 9.3.1 Approval of Active Substances | 456 | ||
| 9.3.1.1 Data Requirements | 458 | ||
| 9.3.1.2 Exclusion Criteria | 458 | ||
| 9.3.2 Authorisation of Biocidal Products | 459 | ||
| 9.3.2.1 Data Requirements | 459 | ||
| 9.3.2.2 National Authorisation | 460 | ||
| 9.3.2.3 Mutual Recognition | 461 | ||
| 9.3.2.4 Union Authorisation | 462 | ||
| 9.3.2.5 Simplified Authorisation Procedure | 462 | ||
| 9.4 Regulation on Classification, Labelling and Packaging | 463 | ||
| List of Abbreviations | 464 | ||
| Acknowledgements | 465 | ||
| References | 465 | ||
| Chapter 10 - REACH | 468 | ||
| 10.1 Introduction | 468 | ||
| 10.2 The Aims of REACH | 469 | ||
| 10.2.1 Substance Identification | 469 | ||
| 10.2.2 Substance Registration | 469 | ||
| 10.2.3 Substance Evaluation | 470 | ||
| 10.2.4 Substance Authorisation | 470 | ||
| 10.2.5 Substance Restriction | 471 | ||
| 10.3 REACH Data Requirements | 471 | ||
| 10.3.1 Substance Data Requirements | 471 | ||
| 10.3.2 Intermediate Data Requirements | 471 | ||
| 10.3.3 General Principles | 471 | ||
| 10.3.4 Data Requirement Waiving | 472 | ||
| 10.3.5 Annex XI Waivers | 472 | ||
| 10.3.5.1 Testing is Not Scientifically Necessary | 472 | ||
| 10.3.5.1.1 Using Existing Data.REACH data requirements specify that toxicological studies should be performed to Good Laboratory Practice (... | 472 | ||
| 10.3.5.1.2 Using a Weight of Evidence Approach.It may be possible to use a number of separate studies or other sources of information to de... | 472 | ||
| 10.3.5.1.3 Using (Q)SAR.The results of (Quantitative) Structure-Activity Relationship ((Q)SAR) analyses may be sufficient to indicate the a... | 473 | ||
| 10.3.5.1.4 Using in vitro Methods.The REACH Regulation states that results obtained from suitable in vitro methods may be used to indicate ... | 473 | ||
| 10.3.5.1.5 Read-across.Read-across is an important concept and has the potential to reduce the extent of toxicological testing by relying i... | 473 | ||
| 10.3.5.2 Where Testing is Not Possible for Technical Reasons | 473 | ||
| 10.3.5.3 Substance-tailored Exposure-driven Testing | 473 | ||
| 10.3.6 Annex III Criteria | 474 | ||
| 10.3.7 Vertebrate Animal Testing and Alternative Methods Under REACH | 474 | ||
| 10.3.8 The ‘Testing Proposal’ Concept | 474 | ||
| 10.3.9 Read-across | 475 | ||
| 10.3.9.1 Analogue Approaches to Read-across | 476 | ||
| 10.3.9.2 Category Approaches to Read-across | 477 | ||
| 10.4 REACH Toxicological Data Requirements | 478 | ||
| 10.4.1 Skin Irritation/Corrosion and Eye Irritation | 479 | ||
| 10.4.1.1 Skin Irritation/Corrosion | 479 | ||
| 10.4.1.2 Eye Irritation | 479 | ||
| 10.4.1.3 Skin Sensitisation | 481 | ||
| 10.4.1.4 Mutagenicity | 482 | ||
| 10.4.1.4.1 Annex VII Requirements.An in vitro gene mutation study (Ames test) in bacteria (OECD 471)34 is required by Annex VII (8.4.1); th... | 482 | ||
| 10.4.1.4.2 Annex VIII Requirements.ECHA guidance states that, for comprehensive coverage of the potential mutagenicity of a substance, info... | 482 | ||
| In vitro Cytogenicity or Micronucleus Study in Mammalian Cells.A chromosomal aberration study in mammalian cells (OECD 473)35 or... | 482 | ||
| 10.4.1.4.3 Mammalian Cell Mutation Assay.A gene mutation study in mammalian cells (OECD 476 or OECD 490)37,38 is also required at Annex VII... | 483 | ||
| 10.4.1.4.4 Annex IX and X Requirements.In vivo mutagenicity studies are considered at Annex IX and X, but are not standard information requ... | 483 | ||
| 10.4.1.5 Acute Toxicity | 484 | ||
| 10.4.1.5.1 Acute Oral Toxicity.At Annex VII, an acute oral toxicity study, using the fixed dose procedure, the acute toxic class method or ... | 485 | ||
| 10.4.1.5.2 Acute Inhalation Toxicity.For the second acute toxicity study required at Annex VIII, a study of acute inhalation toxicity will ... | 485 | ||
| 10.4.1.5.3 Acute Dermal Toxicity.A study of acute dermal toxicity according to the standard guideline (OECD 402) or Fixed Dose Procedure (O... | 486 | ||
| 10.4.1.6 Repeated Dose Toxicity | 486 | ||
| 10.4.1.6.1 Annex VII.There is no requirement for a study of repeated dose toxicity at this tonnage band (Table 10.8) | 486 | ||
| 10.4.1.6.2 Annex VIII.Requirements for investigating the repeated dose toxicity of a substance are specified from Annex VIII onwards. At An... | 486 | ||
| 10.4.1.6.3 Annex IX.A study of sub-chronic (90 day) toxicity performed to OECD 40859 is required by Annex IX. The Regulation requires that ... | 487 | ||
| 10.4.1.6.4 Annex X.There is no standard data requirement for repeated dose toxicity at this tonnage band. For substances registered in quan... | 488 | ||
| 10.4.1.7 Reproductive Toxicity | 489 | ||
| 10.4.1.7.1 Annex VII.There is no requirement for a study of reproductive toxicity at this tonnage band | 489 | ||
| 10.4.1.7.2 Annex VIII.Investigations of reproductive and developmental toxicity are required from Annex VIII onwards. At this tonnage band,... | 489 | ||
| 10.4.1.7.3 Annex IX.A study to investigate prenatal developmental toxicity in one species (the rat or rabbit) is a standard requirement at ... | 490 | ||
| 10.4.1.7.4 Annex X.A study of pre-natal developmental toxicity (OECD 414) in a second species (the rabbit, if the rat is used as the first ... | 490 | ||
| 10.4.1.8 Toxicokinetics | 491 | ||
| 10.4.1.8.1 Absorption.The likelihood of oral absorption can be predicted for a substance based on aspects of its structure and ph... | 491 | ||
| 10.4.1.8.2 Distribution.In the absence of specific toxicokinetic studies, information on systemic tissue distribution is likely to be limit... | 492 | ||
| 10.4.1.8.3 Metabolism.Useful information on likely metabolic routes may be provided by (Q)SAR predictions, metabolism simulators or read-ac... | 492 | ||
| 10.4.1.8.4 Excretion.Water-soluble substances (or metabolites) of relatively low molecular weight (<300) are likely to be excreted in the u... | 492 | ||
| 10.4.1.8.5 Bioaccumulation.An important part of the theoretical toxi | 492 | ||
| 10.4.1.9 Carcinogenicity | 492 | ||
| 10.5 Data Compilation and Assessment | 493 | ||
| 10.5.1 IUCLID | 493 | ||
| 10.5.2 Key, Supporting and Weight of Evidence Studies | 493 | ||
| 10.5.2.1 Key Studies | 494 | ||
| 10.5.2.2 Supporting Studies | 494 | ||
| 10.5.2.3 Weight of Evidence Studies | 494 | ||
| 10.5.3 Assessment of Data Reliability | 494 | ||
| 10.6 Toxicological Data and Risk Assessment | 495 | ||
| 10.6.1 DNEL Derivation | 495 | ||
| 10.6.1.1 Inhalation DNEL Values | 496 | ||
| 10.6.1.2 Dermal DNEL Values | 496 | ||
| 10.6.1.3 Oral DNEL Values | 497 | ||
| 10.6.1.4 Short-term DNELs | 497 | ||
| 10.6.2 The Chemical Safety Report | 497 | ||
| 10.6.3 Safety Data Sheet | 498 | ||
| 10.7 Conclusion | 499 | ||
| References | 499 | ||
| Chapter 11 - Cosmetic Products | 505 | ||
| 11.1 Introduction | 505 | ||
| 11.2 General Regulatory Aspects | 506 | ||
| 11.2.1 Definition of a Cosmetic Product | 506 | ||
| 11.2.1.1 Borderline Cases | 506 | ||
| 11.2.2 The Cosmetic Product Safety Report | 507 | ||
| 11.2.3 The Safety Assessor | 507 | ||
| 11.2.4 The Scientific Committee on Consumer Safety | 507 | ||
| 11.2.5 Restrictions on Ingredients Used in Cosmetic Products | 509 | ||
| 11.2.5.1 Prohibited Ingredients | 509 | ||
| 11.2.5.2 Restricted Ingredients | 510 | ||
| 11.2.5.3 Colorants, Preservatives and UV Filters | 510 | ||
| 11.2.5.4 Nanomaterials | 510 | ||
| 11.2.5.5 CosIng | 511 | ||
| 11.2.5.6 Cosmetic Product Notification Portal | 511 | ||
| 11.3 Safety Assessment of Cosmetic Products | 512 | ||
| 11.3.1 Microbiological and Stability Testing | 512 | ||
| 11.3.2 Ingredient Toxicological Profiles | 512 | ||
| 11.3.3 Cosmetic Products and Animal Testing | 513 | ||
| 11.3.3.1 REACH and the Cosmetic Products Regulation | 513 | ||
| 11.3.4 Toxicological Data Requirements | 514 | ||
| 11.3.4.1 Toxicokinetics | 514 | ||
| 11.3.4.2 Dermal Absorption | 515 | ||
| 11.3.4.2.1 Design of the Diffusion Cell.Flow-through cells are generally preferred as this enables continuous sampling of the receptor flui... | 515 | ||
| 11.3.4.2.2 Choice of Receptor Fluid.The receptor fluid should generally reflect physiological pH; adequate solubility and stability of the ... | 515 | ||
| 11.3.4.2.3 Skin Membranes.SCCS specify a clear preference for the use of human skin membranes, but also recognise that porcine skin may pro... | 515 | ||
| 11.3.4.2.4 Membrane Integrity.Prior to measuring dermal absorption, the integrity of the skin membranes must be verified experimentally usi... | 515 | ||
| 11.3.4.2.5 Skin Temperature.Dermal absorption is temperature-dependent. The temperature of the skin membrane should be kept at 32 ± 1 °C, t... | 515 | ||
| 11.3.4.2.6 Characterisation of the Test Substance.In addition to the basic physicochemical properties of the substance, its purity (and the... | 516 | ||
| 11.3.4.2.7 Concentration and Vehicle.Dermal absorption is strongly influenced by concentration and formulation type, and it is also recogni... | 516 | ||
| 11.3.4.2.8 Application Volume.The amount applied to the skin membrane should closely resemble the intended use of the product. The SCCS Not... | 516 | ||
| 11.3.4.2.9 Exposure Period and Sampling times.The period of exposure in a dermal absorption study should be representative of the way a pro... | 516 | ||
| 11.3.4.2.10 Methods of Analysis.The validity, sensitivity and detection limits of the analytical method should be documented. The use of a r... | 516 | ||
| 11.3.4.2.11 Data Reporting.The amounts of material remaining on the skin at the end of the exposure period – in the stratum corneum (assesse... | 516 | ||
| 11.3.4.2.12 Reliability and Technical Proficiency.The proficiency of the laboratory performing the dermal absorption study should be assesse... | 517 | ||
| 11.3.4.3 Acute Toxicity | 517 | ||
| 11.3.4.4 Skin Irritation | 517 | ||
| 11.3.4.5 Eye Irritation | 518 | ||
| 11.3.4.6 Skin Sensitisation | 519 | ||
| 11.3.4.7 Repeated Dose Toxicity | 521 | ||
| 11.3.4.8 Reproductive Toxicity | 522 | ||
| 11.3.4.9 Mutagenicity | 523 | ||
| 11.3.4.10 Carcinogenicity | 524 | ||
| 11.3.4.11 Phototoxicity | 524 | ||
| 11.3.4.12 Testing in Humans | 525 | ||
| 11.3.5 Final Conclusion on Product Safety | 525 | ||
| 11.3.6 Use of the Product | 526 | ||
| 11.3.6.1 Intended Use | 526 | ||
| 11.3.6.2 Reasonably Foreseeable Use | 526 | ||
| 11.3.7 Cosmetic Ingredients and Product Exposure | 526 | ||
| 11.3.7.1 Risk Assessment for Individual Ingredients | 527 | ||
| 11.3.7.1.1 Product Usage.Daily amounts for product usage (expressed in terms of g day−1) guidance for commonly encountered product types ar... | 527 | ||
| 11.3.7.1.2 Estimation of Systemic Exposure and Calculation of the SED.The risk assessment of cosmetic product ingredients is based on calcu... | 527 | ||
| 11.3.7.1.3 Calculation of the Margin of Safety.The Margin of Safety (MoS) for a cosmetic ingredient is calculated by dividing the ingredien... | 528 | ||
| 11.3.8 Impact of Impurities and Traces | 529 | ||
| 11.3.8.1 Threshold of Toxicological Concern | 530 | ||
| 11.3.9 Assessment of Product Packaging | 531 | ||
| 11.3.10 Post-marketing Surveillance | 531 | ||
| 11.4 Conclusion | 532 | ||
| References | 532 | ||
| Chapter 12 - Regulation of Air Quality in the European Union | 539 | ||
| 12.1 Introduction | 539 | ||
| 12.2 European Legislation | 541 | ||
| 12.2.1 The Need for Standards for Ambient Concentrations of Air Pollutants | 541 | ||
| 12.2.2 Setting Standards for Air Pollutants | 544 | ||
| 12.2.3 Conclusions from Studies of the Effects of Ambient Particles | 545 | ||
| 12.2.4 Setting EU Limit Values | 547 | ||
| 12.2.4.1 From Guidelines to Limit Values | 549 | ||
| 12.2.4.2 Location of Monitors to Assess Compliance with LV | 550 | ||
| 12.2.5 Is There a Better Way of Regulating Ambient Air Pollutants: Is There a Better Sort of “Standard” | 552 | ||
| 12.2.6 Regulating Air Pollutants Within a Multi-national Confederation | 553 | ||
| 12.3 Conclusions | 554 | ||
| References | 555 | ||
| Chapter 13 - Occupational Toxicology in the European Union | 557 | ||
| 13.1 Introduction | 557 | ||
| 13.2 Exposures | 558 | ||
| 13.3 History | 559 | ||
| 13.4 Occupational Exposure Limits (OELs) | 559 | ||
| 13.4.1 Setting of Occupational Exposure Limits at EU Level | 561 | ||
| 13.4.1.1 History | 561 | ||
| 13.4.2 SCOEL Working Practices | 562 | ||
| 13.4.2.1 OELs for Different Durations of Exposure | 563 | ||
| 13.4.2.2 Data Sources | 564 | ||
| 13.4.2.3 Uncertainty/Safety Factors | 564 | ||
| 13.4.2.4 Special Consideration of Chemical Carcinogens and Mutagens | 565 | ||
| 13.4.2.5 Special Consideration of Respiratory Sensitisers | 566 | ||
| 13.4.2.6 Significant Dermal Exposures (Assigning a ‘Skin’ Notation) | 566 | ||
| 13.4.2.7 Noise Notation | 568 | ||
| 13.4.2.8 Health-based Biological Limit Values (BLVs) | 568 | ||
| 13.5 DNELs | 569 | ||
| 13.6 Classification and Labelling | 570 | ||
| 13.7 Protective Equipment | 572 | ||
| 13.8 Conclusion | 573 | ||
| Further Reading | 573 | ||
| References | 574 | ||
| Chapter 14 - Food Additives | 577 | ||
| 14.1 Introduction | 577 | ||
| 14.2 Development of Current Regulation | 578 | ||
| 14.2.1 Harmonisation | 578 | ||
| 14.2.2 Creation of the Internal Market | 578 | ||
| 14.2.3 The European Food Safety Authority and Public Health Protection | 579 | ||
| 14.2.4 Food Improvement Agents Regulations | 579 | ||
| 14.3 Current Regulations and Legislative Procedure Within the European Union | 580 | ||
| 14.3.1 Definition of a Food Additive | 581 | ||
| 14.4 Function of Food Additives | 582 | ||
| 14.4.1 Functional Classes of Food Additives | 582 | ||
| 14.4.2 The Union List of Additives and Their Conditions of Use | 585 | ||
| 14.4.3 E Number Classification | 586 | ||
| 14.5 The Use of Food Additives | 586 | ||
| 14.5.1 Foodstuffs in Which Food Additives May Not be Used | 587 | ||
| 14.5.2 Traditional Foods | 589 | ||
| 14.5.3 Food Categories in Which Food Additives May be Used | 589 | ||
| 14.5.4 Levels of Use of Food Additives (Regulation (EC) No 1333/2008, Article 11)4,16 | 590 | ||
| 14.5.5 Purity and Specifications of Food Additives | 590 | ||
| 14.5.6 Carry-over Principle | 591 | ||
| 14.6 Labelling | 592 | ||
| 14.7 Surveillance and Monitoring of Use of Food Additives | 593 | ||
| 14.8 Reauthorisation of Additives | 593 | ||
| 14.9 Risk Assessment of Food Additives | 593 | ||
| 14.9.1 General Points | 593 | ||
| 14.9.2 Procedure for Risk Assessment of Food Additives10 | 594 | ||
| 14.9.2.1 Information Needed for a Submission for Authorisation | 594 | ||
| 14.9.3 Toxicology Studies | 595 | ||
| 14.9.3.1 Toxicokinetics | 595 | ||
| 14.9.3.2 Genotoxicity | 596 | ||
| 14.9.3.3 Toxicity Testing (Sub Chronic, Chronic and Carcinogenicity) | 596 | ||
| 14.9.3.4 Reproductive and Developmental Toxicity | 596 | ||
| 14.9.4 Exposure Assessment | 597 | ||
| 14.10 Application Procedure | 598 | ||
| 14.11 Risk Management Information for the Evaluation of Food Additives | 598 | ||
| 14.12 Future Developments | 599 | ||
| Further Reading | 599 | ||
| References | 600 | ||
| Appendix I - Agencies of the European UnionConcerned with ChemicalSafety | 604 | ||
| Air Quality | 604 | ||
| Food Additives and Animal Feed Additives | 604 | ||
| Human and Veterinary Medicines | 605 | ||
| REACH and Occupational Safety | 605 | ||
| Pesticides/Crop Protection | 605 | ||
| Biocides | 605 | ||
| Cosmetics | 605 | ||
| Subject Index | 606 |