Practical guide to chemical safety testing : regulatory consequences : chemicals, food packaging and medical devices

1. Introduction .................................................................................................. 1 1.1 Purpose of the Book ........................................................................ 1 1.2 Purpose of Safety Evaluation .......................................................... 1 1.3 Safety Studies .................................................................................. 2 1.4 Risk Assessment and Safety Data .................................................. 5 1.5 Regulatory Schemes ....................................................................... 6 1.6 Summary ......................................................................................... 8 Part I. Safety Testing and Assessment 2. Mammalian Toxicology ................................................................................ 9 2.1 Introduction ...................................................................................... 9 2.2 Acute Toxicity Studies ..................................................................... 9 2.2.1 Nature and Relevance of Tests ........................................ 9 2.2.2 Methodology ..................................................................... 11 2.2.3 Acute Oral Toxicity Studies ............................................... 12 2.2.4 Dermal Toxicity Studies .................................................... 13 2.2.5 Inhalation Toxicity Studies ................................................ 14 2.2.6 Alternative Acute Oral Toxicity Methods ........................... 15 2.2.7 Local Tolerance Tests ....................................................... 17 2.2.8 Contact Sensitisation ........................................................ 18 2.3 Repeated Dose Toxicity Studies ...................................................... 20 2.3.1 Nature and Relevance of Tests ........................................ 20 2.3.2 Importance of Repeated Dose Toxicity ............................. 22 2.3.3 Methodology ..................................................................... 23 2.4 Reproduction Toxicology ................................................................. 25 2.4.1 Nature and Relevance of Tests ........................................ 25 2.4.2 Methodology ..................................................................... 26 2.4.3 Alternative Approaches ..................................................... 29 viii Contents 2.5 Carcinogenicity ................................................................................ 30 2.5.1 Nature and Relevance of Tests ........................................ 30 2.5.2 Methodology ..................................................................... 31 2.5.3 Dose Levels ...................................................................... 32 2.5.4 Conduct of Study .............................................................. 32 2.5.5 Data Evaluation ................................................................. 33 2.5.6 Risk Assessment .............................................................. 33 2.5.7 Alternative Approaches ..................................................... 34 2.6 Medical Device Testing .................................................................... 34 2.6.1 Exposure Routes .............................................................. 35 2.6.2 Dose Preparation .............................................................. 35 2.6.3 Cytotoxicity Testing of Medical Devices ............................ 35 3. Genetic Toxicology ...................................................................................... 43 3.1 Introduction ...................................................................................... 43 3.2 Mechanisms of Mutation – Genes and Chromosomes .................... 44 3.3 Standard Genetic Toxicology Assays .............................................. 47 3.4 Bacterial Mutagenicity Assays ......................................................... 47 3.5 Chromosome Aberration Tests in Vitro ............................................ 50 3.6 Mammalian Cell Gene Mutation Assays in Vitro .............................. 53 3.7 The in Vivo Micronucleus Test ......................................................... 55 3.8 The Unscheduled DNA Synthesis Assay ......................................... 57 3.9 Conclusions ..................................................................................... 59 4. Ecotoxicology .............................................................................................. 63 4.1 Introduction ...................................................................................... 63 4.2 Bacterial Toxicity Testing ................................................................. 65 4.3 Biodegradation Tests ....................................................................... 65 4.3.1 Ready Biodegradation Tests ............................................. 66 4.3.2 Inherent Biodegradation Tests .......................................... 70 4.3.3 Simulation Tests ............................................................... 71 4.3.4 Anaerobic Biodegradation Tests ....................................... 71 4.4 Aquatic Toxicity Testing ................................................................... 72 4.4.1 Acute Tests ....................................................................... 73 4.4.2 Analytical Measurements .................................................. 77 4.4.3 Difficult Substances .......................................................... 78 4.4.4 Chronic Tests .................................................................... 79 Contents ix 4.5 Fish Bioaccumulation Test ............................................................... 81 4.6 Sediment Toxicity Tests ................................................................... 81 4.7 Terrestrial Toxicity Tests .................................................................. 82 4.7.1 Earthworms ....................................................................... 82 4.7.2 Bees and Beneficials ........................................................ 82 4.7.3 Plant Growth Tests ........................................................... 83 4.8 Microcosm and Mesocosm Studies ................................................. 83 4.9 Conclusion ....................................................................................... 83 5. Physico-Chemical Properties ...................................................................... 87 5.1 Introduction ...................................................................................... 87 5.2 Performance of the General Physico-Chemical Tests ..................... 89 5.2.1 Melting Temperature/Melting Range (OECD Test Guideline 102) ................................................................... 89 5.2.2 Boiling Point (OECD Test Guideline 103) ......................... 90 5.2.3 Vapour Pressure (OECD Test Guideline 104) .................. 91 5.2.4 Water Solubility (OECD Test Guideline 105) .................... 93 5.2.5 Partition Coefficient (OECD Test Guidelines 107 and 117) ................................................................................... 95 5.2.6 Adsorption Coefficient (OECD Test Guidelines 106 and 121) ............................................................................ 97 5.2.7 Density/Relative Density (OECD Test Guideline 109) ...... 99 5.2.8 Particle Size Distribution (OECD Test Guideline 110) ...... 100 5.2.9 Hydrolysis as a Function of pH (OECD Test Guideline 111) ................................................................................... 101 5.2.10 Dissociation Constant (OECD Test Guideline 112) .......... 103 5.2.11 Surface Tension (OECD Test Guideline 115) ................... 104 5.2.12 Fat Solubility (OECD Test Guideline 116) ........................ 106 5.3 Performance of the Polymer Specific Physico-Chemical Tests ....... 106 5.3.1 Number-Average Molecular Weight and Molecular Weight Distribution of Polymers (OECD Test Guideline 118) ................................................................... 107 5.3.2 Solution/Extraction Behaviour of Polymers in Water (OECD Test Guideline 120) .............................................. 108 5.4 Performance of the Hazardous Physico-Chemical Tests ................ 108 5.4.1 Flash Point (EC Method A9) ............................................. 109 5.4.2 Flammable Solids (EC Method A10) ................................. 109 x Contents 5.4.3 Flammable Gases (EC Method A11), Flammable Substances on Contact with Water (EC Method A12) and Substances Liable to Spontaneous Combustion (EC Method A13) .............................................................. 110 5.4.4 Explosive Properties (EC Method A14) ............................ 111 5.4.5 Auto-Ignition Temperature, Liquids and Gases (EC Method A15) and Relative Self–Ignition Temperature, Solids (EC Method A16) ................................................... 112 5.4.6 Oxidizing Properties (EC Method A17) ............................. 113 5.5 Order in Which Physico-Chemical Tests are Performed ................. 114 5.6 Conclusion ....................................................................................... 115 6. Alternatives to Animal Testing for Safety Evaluation ................................... 119 6.1 Introduction ...................................................................................... 119 6.2 Validation of Alternative Methods .................................................... 120 6.3 Aspects of Human Toxicity Targeted by in Vitro Assays ................. 122 6.3.1 Systemic Toxicological Properties .................................... 122 6.3.2 Validated Tests Currently in Use in the EU ....................... 125 6.4 Structure-Activity Relationships and Prediction of Properties .......... 129 6.5 Strategies to Minimise Use of Animals ............................................ 131 6.6 Future Developments and Conclusions ........................................... 132 7. Toxicological Assessment within a Risk Assessment Framework .............. 137 7.1 Introduction ...................................................................................... 137 7.2 Definitions and Concepts ................................................................. 137 7.2.1 Risk ................................................................................... 138 7.2.2 Toxicology ......................................................................... 144 7.3 Exposure Scenarios ......................................................................... 148 7.3.1 Routes of Administration ................................................... 148 7.3.2 Exposure Prediction .......................................................... 151 7.4 Judgements ..................................................................................... 152 7.4.1 The ‘Precautionary Principle’ ............................................ 153 7.4.2 What Test and When? ...................................................... 154 7.4.3 The Interpretation of Toxicity Test Results for Classification and Labeling Purposes ............................... 154 7.4.4 Risk Assessment and Risk Evaluation – Interpretation of General Toxicity ............................................................ 155 Contents xi 7.4.5 Mutagenicity, Carcinogenicity and Reproductive Toxicity .............................................................................. 157 7.5 Risk Management ............................................................................ 159 7.6 Final Word ....................................................................................... 160 8. Environmental Risk Assessment ................................................................. 163 8.1 Introduction ...................................................................................... 163 8.2 Exposure Assessment ..................................................................... 164 8.2.1 Identification of the Target Compartments ........................ 165 8.2.2 Estimation of Emissions or Releases ................................ 167 8.2.3 Distribution and Degradation in the Environment (Environmental Fate) ........................................................ 168 8.2.4 Predicted Environmental Concentrations .......................... 175 8.3 Effects Assessment ......................................................................... 178 8.3.1 Estimating PNECs by Applying Uncertainty Factors ......... 179 8.3.2 The Statistical Extrapolation Method ................................ 182 8.4 Risk Characterisation ....................................................................... 184 8.5 Conclusion ....................................................................................... 184 Part II. Regulatory Framework 9. EU Chemical Legislation ............................................................................. 191 9.1 EU Legislation within the European Economic Area and Europe ............................................................................................. 191 9.2 Notification of New Substances ....................................................... 192 9.2.1 History of the Notification Process .................................... 193 9.2.2 Data Sharing ..................................................................... 193 9.2.3 Base Set Studies for Full Notification ................................ 193 9.2.4 Reduced Notification Studies ............................................ 194 9.2.5 Level 1 and Level 2 Notification Studies ........................... 194 9.2.6 The Notification Summary Form ....................................... 199 9.2.7 The Sole-Representative Facility ...................................... 200 9.2.8 Polymers ........................................................................... 200 9.2.9 Derogations/Exemptions from Notification ........................ 200 9.2.10 Confidentiality ................................................................... 201 9.3 Risk Assessment ............................................................................. 202 9.3.1 Human Health Risk Assessment ...................................... 203 9.3.2 Environment Risk Assessment ......................................... 204 xii Contents 9.4 Existing Chemicals Regulation ........................................................ 207 9.4.1 Data Collection .................................................................. 208 9.4.2 Priority Setting ................................................................... 211 9.4.3 Risk Assessment .............................................................. 211 9.5 Chemical Hazard Communication ................................................... 212 9.5.1 Classification and Labeling of Dangerous Substances ....................................................................... 212 9.5.2 Classification and Labeling of Dangerous Preparations ...................................................................... 214 9.5.3 Safety Data Sheets ........................................................... 215 9.6 Transport Regulations ..................................................................... 215 9.6.1 Introduction ....................................................................... 215 9.6.2 The United Nations Transportation Classification Scheme ............................................................................. 217 9.6.3 Transport of Marine Pollutants .......................................... 218 9.7 National Chemical Control Measures .............................................. 219 9.7.1 National Product Registers ............................................... 220 9.7.2 German Water Hazard Classification Scheme ................. 220 9.8 Other EU Legislation for Specific Product Types ............................. 222 9.8.1 Control of Cosmetics in the EU ......................................... 223 9.8.2 Detergents ........................................................................ 224 9.8.3 Offshore Chemical Notification Scheme: Oslo and Paris Convention for the Protection of the North East Atlantic .............................................................................. 225 9.9 Summary and Future Developments ............................................... 226 10. Chemical Control in Japan .......................................................................... 235 10.1 Introduction to the Japanese Regulatory Culture ............................ 235 10.2 The Ministry of Economy, Trade and Industry and Ministry of Health, Labour and Welfare Chemical Substances Control Law 236 10.2.1 Introduction ....................................................................... 236 10.2.2 The Inventory of Existing Substances ............................... 238 10.2.3 Exemptions from Notification ............................................ 239 10.2.4 Standard Notification ......................................................... 241 10.2.5 Polymer Notification .......................................................... 244 10.2.6 Class I and II Specified and Designated Substances ....... 245 Contents xiii 10.3 The Ministry of Health, Labour and Welfare Industrial Safety and Health Law ....................................................................................... 246 10.4 Hazard Communication and Product Liability .................................. 247 10.5 Other Chemical Legislation .............................................................. 249 10.6 Summary ......................................................................................... 252 11. Chemical Control in the US and the Rest of the World ............................... 255 11.1 Introduction ...................................................................................... 255 11.2 US Chemical Legislation: the Toxic Substances Control Act (TSCA) ............................................................................................. 256 11.2.1 Key Objectives of TSCA ................................................... 256 11.2.2 The TSCA Inventory ......................................................... 256 11.2.3 Testing of Existing Substances ......................................... 261 11.2.4 Manufacturing and Processing Notices ............................ 261 11.2.5 PMN Requirements ........................................................... 261 11.2.6 Significant New Use Rules (SNURs) ................................ 262 11.2.7 Exemptions from PMN ...................................................... 262 11.3 US Occupational Safety and Health Act (OSHA) ............................ 265 11.4 The US Chemical Right-to-Know Initiative for High Production Volume Chemicals ........................................................................... 266 11.4.1 Voluntary Challenge Programme ...................................... 266 11.4.2 Persistent Bioaccumulative Toxic (PBT) Chemicals ......... 268 11.4.3 US Voluntary Children’s Chemical Evaluation Program ............................................................................ 269 11.5 Chemical Control Legislation in Canada .......................................... 270 11.5.1 The Canadian Environmental Protection Act .................... 270 11.5.2 Inventories ........................................................................ 271 11.5.3 Environmental Assessment Regulations .......................... 272 11.5.4 Data Requirements for Notification ................................... 273 11.5.5 Significant New Activity Notice .......................................... 273 11.5.6 Administration ................................................................... 273 11.5.7 Inspection, Enforcement and Penalties ............................ 275 11.5.8 Future Changes ................................................................ 275 11.5.9 The Workplace Hazardous Materials Information System .............................................................................. 276 11.6 Chemical Control Legislation in Switzerland .................................... 276 11.6.1 The Federal Law on Trade in Toxic Substances .............. 276 xiv Contents 11.6.2 The Federal Law on Environmental Protection ................. 277 11.7 Notification of New Chemical Substances in Australia .................... 280 11.7.1 National Industrial Chemicals (Notification and Assessment) Scheme ....................................................... 280 11.7.2 Inventory ........................................................................... 281 11.7.3 Data Requirements for Notification ................................... 281 11.7.4 Existing Substances .......................................................... 282 11.7.5 Hazard Communication .................................................... 282 11.8 Chemical Control in Korea ............................................................... 283 11.8.1 The Toxic Chemicals Control Law and Ministry of Environment Notification ................................................... 283 11.8.2 The Industrial Safety and Health Law and Ministry of Labour Toxicity Examination ............................................. 285 11.8.3 Hazard Communication .................................................... 286 11.9 Chemical Control in the Philippines ................................................. 286 11.9.1 The Toxic Substances and Hazardous and Nuclear Wastes Control Act ........................................................... 286 11.9.2 Inventory ........................................................................... 287 11.9.3 Data Requirements for Notification ................................... 287 11.9.4 Administration ................................................................... 288 11.9.5 Priority Chemicals List (PCL) ............................................ 290 11.10 Chemical Control in the People’s Republic of China ....................... 290 11.10.1 Latest Developments ........................................................ 290 11.10.2 First Import and Toxic Chemicals Regulations ................. 291 11.10.3 Inventory ........................................................................... 291 11.10.4 Hazard Communication .................................................... 292 11.11 Chemical Control in New Zealand ................................................... 292 11.11.1 Toxic Substances Act ....................................................... 292 11.11.2 Resource Management Act .............................................. 292 11.11.3 Hazardous Substances and New Organisms Act ............. 293 11.11.4 Data Requirements for Notification ................................... 294 11.11.5 Hazard Communication .................................................... 295 11.12 Mexico ............................................................................................. 295 11.12.1 Legislation ......................................................................... 295 11.12.2 Safety Data Sheets ........................................................... 296 Contents xv 11.13 Singapore ........................................................................................ 296 11.14 Malaysia ........................................................................................... 297 11.15 Thailand ........................................................................................... 297 11.16 Indonesia ......................................................................................... 297 11.17 Taiwan ............................................................................................. 297 11.18 HPV Programmes ............................................................................ 298 11.18.1 OECD ................................................................................ 298 11.18.2 International Council of Chemical Associations Global Initiative ............................................................................. 299 11.19 Useful Web Sites ............................................................................. 300 12. Notification of Polymers Worldwide ............................................................. 307 12.1 Introduction ...................................................................................... 307 12.2 North America .................................................................................. 308 12.2.1 USA ................................................................................... 308 12.2.2 Canada ............................................................................. 311 12.3 Asia Pacific ...................................................................................... 312 12.3.1 Japan ................................................................................ 312 12.3.2 Australia ............................................................................ 320 12.3.3 New Zealand ..................................................................... 324 12.3.4 Korea ................................................................................ 325 12.3.5 Philippines ......................................................................... 328 12.3.6 China ................................................................................. 331 12.4 Europe ............................................................................................. 331 12.4.1 EU ..................................................................................... 331 12.4.2 Switzerland ....................................................................... 340 12.5 Overall Comparison of the Nine Polymer Notification Schemes ...... 341 13. Medical Device Regulation .......................................................................... 345 13.1 Introduction ...................................................................................... 345 13.2 European Economic Area ................................................................ 345 13.2.1 Background ....................................................................... 345 13.2.2 Before Marketing ............................................................... 351 13.2.3 After Marketing .................................................................. 357 13.3 United States of America ................................................................. 359 13.3.1 Background ....................................................................... 359 13.3.2 Before Marketing ............................................................... 359 xvi Contents 13.3.3 After Marketing .................................................................. 362 13.4 Japan ............................................................................................... 363 13.4.1 Background ....................................................................... 363 13.4.2 Before Marketing ............................................................... 364 13.4.3 After Marketing .................................................................. 365 13.5 Conclusion ....................................................................................... 366 14. Regulation of Food Packaging in the EU and US ........................................ 367 14.1 Introduction ...................................................................................... 367 14.2 Control of Food Packaging in the EU .............................................. 368 14.2.1 EU Framework Directive ................................................... 368 14.2.2 Food Contact Plastics in the EU ....................................... 369 14.2.3 Future Developments for Food Plastics in the EU ............ 376 14.2.4 Other EU Food Packaging Measures ............................... 377 14.2.5 Strategy for Food Contact Plastic Approval in the EU ...... 378 14.3 National Controls on Food Packaging in EU Countries ................... 379 14.3.1 Germany ........................................................................... 379 14.3.2 France ............................................................................... 381 14.3.3 The Netherlands ............................................................... 381 14.3.4 Belgium ............................................................................. 381 14.3.5 Italy ................................................................................... 382 14.4 Council of Europe Work on Food Packaging ................................... 382 14.4.1 Introduction ....................................................................... 382 14.4.2 Completed Council of Europe Resolutions ....................... 383 14.4.3 Council of Europe Ongoing Work ..................................... 385 14.5 Food Packaging in the USA ............................................................. 388 14.5.1 Introduction ....................................................................... 388 14.5.2 History and Development of US Food Packaging Legislation ......................................................................... 389 14.5.3 The FDA Petition ............................................................... 391 14.5.4 Threshold of Regulation Process ...................................... 394 14.5.5 The Pre-Marketing Notification Scheme ........................... 395 15. Regulation of Biocides ................................................................................. 401 15.1 Introduction ...................................................................................... 401 15.2 Control of Biocides in the EU ........................................................... 402 15.2.1 Introduction ....................................................................... 402 Contents xvii 15.2.2 Main Features of the Directive .......................................... 403 15.2.3 System of Approval ........................................................... 403 15.2.4 Assessment for the Inclusion of Active Substances in Annex I of the Biocidal Products Directive ........................ 404 15.2.5 Authorisation of Biocidal Products .................................... 405 15.2.6 Hazard Communication .................................................... 406 15.2.7 The Review Programme for Existing Active Substances ....................................................................... 406 15.2.8 Technical Guidance .......................................................... 407 15.3 Control of Biocides in the USA ........................................................ 409 15.3.1 Introduction ....................................................................... 409 15.3.2 Data Requirements for Registration .................................. 410 15.3.3 Registration Applications .................................................. 411 15.3.4 Data Compensation .......................................................... 413 15.3.5 Re-Registration of Existing Pesticides .............................. 413 15.3.6 Petition for a Pesticide Tolerance ..................................... 415 15.3.7 Regulation of Food Contact Biocides ................................ 415 15.4 Regulation of Biocides in Other Countries ....................................... 417