Practical Guide to Chemical Safety Testing

Practical Guide to Chemical Safety Testing

Author: D.J. Knight and M.B. Thomas
ISBN 978-1-85957-372-3 

Published: 2003
pages 474
There are many different chemicals and materials in use today. These are subject to stringent regulations, which include a requirement for physicochemical and toxicity testing. In some countries, existing chemicals are also undergoing safety checks. The aim is to determine their hazardous properties and the risks involved in using substances.

Health and safety of the environment and the individual are becoming of prime importance to society and extensive legislation has been developed. To the R&D chemist, this is a maze to negotiate when trying to introduce a new material or chemical into a different marketplace. What tests are required and for which markets? What do the test results mean? Who are the key organisations in each global region? Legislation varies between applications and often the quantity of chemical in use is critical to determining the level of testing required.

A Practical Guide to Chemical Safety Testing describes the different tests that must be performed on new chemicals and other materials to demonstrate to the regulatory authorities that they are safe for use. Tests vary from physico-chemical, measuring properties such as melting point and density, through genetic toxicity studies, to mammalian toxicology and studies to investigate effects on the environment. Animal testing is carried out to look for potential irritants, harmful substances, corrosive agents, allergens, cancer causing potential, etc. Each test type is described here and the validity of the test methods is debated. For example, there are sometimes major differences between simple model systems using cell lines or bacteria, effects in laboratory animals and, most importantly, with effects on humans. This can give rise to a misleading interpretation of results.

There is a chapter devoted to alternatives to animal testing for safety evaluation. Many non-animal screening tests are available. It is also becoming increasingly possible to cross-match many new chemicals with existing toxicity data to predict potential carcinogenicity, allergenicity, etc. These approaches can reduce the test requirements for the chemical, although a structural alert showing the presence of a suspect chemical moiety can trigger definitive toxicological assessment.

Ecotoxicological testing is carried out to determine the level of hazard to organisms in the environment. Important properties used to estimate environmental fate include the solubility of the test material in water, its ability to adsorb to soil and its potential for accumulation in animals.

Regulations vary depending on the intended purpose of a material, and this book describes the requirements for general chemicals, polymers, food contact materials, medical devices, and biocides. Often the quantity imported into a region determines the stringency of the testing required. The EU, the USA, Japan and other geographical regions each have its own set of regulations. These are outlined here. In some instances, approval of a chemical in one country will lead to automatic approval in a second country. In other cases, new testing is required. This is a very complex situation. The second half of this book sets out to untangle the web of legal issues facing manufacturers and suppliers.

This book is essential reading for chemical and material manufacturers and suppliers. It describes clearly the process of obtaining approval for use in a variety of global regions and across different applications. It also explains why different tests are performed and the implications of the results.

1 Introduction
1.1 Purpose of the Book
1.2 Purpose of Safety Evaluation
1.3 Safety Studies
1.4 Risk Assessment and Safety Data
1.5 Regulatory Schemes
1.6 Summary
2 Mammalian Toxicology
2.1 Introduction
2.2 Acute Toxicity Studies
2.2.1 Nature and Relevance of Tests
2.2.2 Methodology
2.2.3 Acute Oral Toxicity Studies
2.2.4 Dermal Toxicity Studies
2.2.5 Inhalation Toxicity Studies
2.2.6 Alternative Acute Oral Toxicity Methods
2.2.7 Local Tolerance Tests
2.2.8 Contact Sensitisation
2.3 Repeated Dose Toxicity Studies
2.3.1 Nature and Relevance of Tests
2.3.2 Importance of Repeated Dose Toxicity
2.3.3 Methodology
2.4 Reproduction Toxicology
2.4.1 Nature and Relevance of Tests
2.4.2 Methodology
2.4.3 Alternative Approaches
2.5 Carcinogenicity
2.5.1 Nature and Relevance of Tests
2.5.2 Methodology
2.5.3 Dose Levels
2.5.4 Conduct of Study
2.5.5 Data Evaluation
2.5.6 Risk Assessment
2.5.7 Alternative Approaches
2.6 Medical Device Testing
2.6.1 Exposure Routes
2.6.2 Dose Preparation
2.6.3 Cytotoxicity Testing of Medical Devices
3 Genetic Toxicology
3.1 Introduction
3.2 Mechanisms of Mutation – Genes and Chromosomes
3.3 Standard Genetic Toxicology Assays
3.4 Bacterial Mutagenicity Assays
3.5 Chromosome Aberration Tests In Vitro
3.6 Mammalian Cell Gene Mutation Assays In Vitro
3.7 The In Vivo Micronucleus Test
3.8 The Unscheduled DNA Synthesis Assay
3.9 Conclusions
4 Ecotoxicology
4.1 Introduction
4.2 Bacterial Toxicity Testing
4.3 Biodegradation Tests
4.3.1 Ready Biodegradation Tests
4.3.2 Inherent Biodegradation Tests
4.3.3 Simulation Tests
4.3.4 Anaerobic Biodegradation Tests
4.4 Aquatic Toxicity Testing
4.4.1 Acute Tests
4.4.2 Analytical Measurements
4.4.3 Difficult Substances
4.4.4 Chronic Tests
4.5 Fish Bioaccumulation Test
4.6 Sediment Toxicity Tests
4.7 Terrestrial Toxicity Tests
4.7.1 Earthworms
4.7.2 Bees and Beneficial
4.7.3 Plant Growth Tests
4.8 Microcosm and Mesocosm Studies
4.9 Conclusion
5 Physico-Chemical Properties
5.1 Introduction
5.2 Performance of the General Physico-Chemical Tests
5.2.1 Melting Temperature/Melting Range (OECD Test Guideline 102)
5.2.2 Boiling Point (OECD Test Guideline 103)
5.2.3 Vapour Pressure (OECD Test Guideline 104)
5.2.4 Water Solubility (OECD Test Guideline 105)
5.2.5 Partition Coefficient (OECD Test Guidelines and 117)
5.2.6 Adsorption Coefficient (OECD Test Guidelines 106 and 121)
5.2.7 Density/Relative Density (OECD Test Guideline 109)
5.2.8 Particle Size Distribution (OECD Test Guideline 110)
5.2.9 Hydrolysis as a Function of pH (OECD Test Guideline 111)
5.2.10 Dissociation Constant (OECD Test Guideline 112)
5.2.11 Surface Tension (OECD Test Guideline 115)
5.2.12 Fat Solubility (OECD Test Guideline 116)
5.3 Performance of the Polymer Specific Physico-Chemical Tests
5.3.1 Number-Average Molecular Weight and Molecular Weight Distribution of Polymers (OECD Test Guideline 118)
5.3.2 Solution/Extraction Behaviour of Polymers in Water (OECD Test Guideline 120)
5.4 Performance of the Hazardous Physico-Chemical Tests
5.4.1 Flash Point (EC Method A9)
5.4.2 Flammable Solids (EC Method A10)
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)
5.4.4 Explosive Properties (EC Method A14)
5.4.5 Auto-ignition Temperature, Liquids and Gases (EC Method A15) and Relative Self–ignition Temperature, Solids (EC Method A16)
5.4.6 Oxidising Properties (EC Method A17)
5.5 Order in which Physico-Chemical Tests are Performed
5.6 Conclusion
6 Alternatives to Animal Testing for Safety Evaluation
6.1 Introduction
6.2 Validation of Alternative Methods
6.3 Aspects of Human Toxicity Targeted By In Vitro Assays
6.3.1 Systemic Toxicological Properties
6.3.2 Validated Tests Currently in Use in the EU
6.4 Structure-Activity Relationships and Prediction of Properties
6.5 Strategies to Minimise Use of Animals
6.6 Future Developments and Conclusions
7 Toxicological Assessment within a Risk Assessment Framework
7.1 Introduction
7.2 Definitions and Concepts
7.2.1 Risk
7.2.2 Toxicology
7.3 Exposure Scenarios
7.3.1 Routes of Administration
7.3.2 Exposure Prediction
7.4 Judgements
7.4.1 The ‘Precautionary Principle’
7.4.2 What Test and When?
7.4.3 The Interpretation of Toxicity Test Results for Classification and Labelling Purposes
7.4.4 Risk Assessment and Risk Evaluation – Interpretation of General Toxicity
7.4.5 Mutagenicity, Carcinogenicity and Reproductive Toxicity
7.5 Risk Management
7.6 Final Word
8 Environmental Risk Assessment
8.1 Introduction
8.2 Exposure Assessment
8.2.1 Identification of the Target Compartments
8.2.2 Estimation of Emissions or Releases
8.2.3 Distribution and Degradation in the Environment (Environmental Fate)
8.2.4 Predicted Environmental Concentrations
8.3 Effects Assessment
8.3.1 Estimating PNECs by Applying Uncertainty Factors
8.3.2 The Statistical Extrapolation Method
8.4 Risk Characterisation
8.5 Conclusion
9 EU Chemical Legislation
9.1 EU Legislation within the European Economic Area and Europe
9.2 Notification of New Substances
9.2.1 History of the Notification Process
9.2.2 Data Sharing
9.2.3 Base Set Studies for Full Notification
9.2.4 Reduced Notification Studies
9.2.5 Level 1 and Level 2 Notification Studies
9.2.6 The Notification Summary Form
9.2.7 The Sole-Representative Facility
9.2.8 Polymers
9.2.9 Derogations/Exemptions from Notification
9.2.10 Confidentiality
9.3 Risk Assessment
9.3.1 Human Health Risk Assessment
9.3.2 Environment Risk Assessment
9.4 Existing Chemicals Regulation
9.4.1 Data Collection
9.4.2 Priority Setting
9.4.3 Risk Assessment
9.5 Chemical Hazard Communication
9.5.1 Classification and Labelling of Dangerous Substances
9.5.2 Classification and Labelling of Dangerous Preparations
9.5.3 Safety Data Sheets
9.6 Transport Regulations
9.6.1 Introduction
9.6.2 The United Nations Transportation Classification Scheme
9.6.3 Transport of Marine Pollutants
9.7 National Chemical Control Measures
9.7.1 National Product Registers
9.7.2 German Water Hazard Classification Scheme
9.8 Other EU Legislation for Specific Product Types
9.8.1 Control of Cosmetics in the EU
9.8.2 Detergents
9.8.3Offshore Chemical Notification Scheme: Oslo and Paris Convention for the Protection of the North East Atlantic
9.9 Summary and Future Developments
10 Chemical Control in Japan
10.1 Introduction to the Japanese Regulatory Culture
10.2 The Ministry of Economy, Trade and Industry and Ministry of Health, Labour and Welfare Chemical Substances Control Law
10.2.1 Introduction
10.2.2 The Inventory of Existing Substances
10.2.3 Exemptions from Notification
10.2.4 Standard Notification
10.2.5 Polymer Notification
10.2.6 Class I and II Specified and Designated Substances
10.3 The Ministry of Health, Labour and Welfare Industrial Safety and Health Law
10.4 Hazard Communication and Product Liability
10.5 Other Chemical Legislation
10.6 Summary
11 Chemical Control in the US and the Rest of the World
11.1 Introduction
11.2 US Chemical Legislation: The Toxic Substances Control Act (TSCA)
11.2.1 Key Objectives of TSCA
11.2.2 The TSCA Inventory
11.2.3 Testing of Existing Substances
11.2.4 Manufacturing and Processing Notices
11.2.5 PMN Requirements
11.2.6 Significant New Use Rules (SNURs)
11.2.7 Exemptions from PMN
11.3 US Occupational Safety and Health Act (OSHA)
11.4 The US Chemical Right-to-Know Initiative for High Production Volume Chemicals
11.4.1 Voluntary Challenge Programme
11.4.2 Persistent Bioaccumulative Toxic (PBT) Chemicals
11.4.3 US Voluntary Children’s Chemical Evaluation Program
11.5 Chemical Control Legislation in Canada
11.5.1 The Canadian Environmental Protection Act
11.5.2 Inventories
11.5.3 Environmental Assessment Regulations
11.5.4 Data Requirements for Notification
11.5.5 Significant New Activity Notice
11.5.6 Administration
11.5.7 Inspection, Enforcement and Penalties
11.5.8 Future Changes
11.5.9 The Workplace Hazardous Materials Information System
11.6 Chemical Control Legislation in Switzerland
11.6.1 The Federal Law on Trade in Toxic Substances
11.6.2 The Federal Law on Environmental Protection
11.7 Notification of New Chemical Substances in Australia
11.7.1 National Industrial Chemicals (Notification and Assessment) Scheme
11.7.2 Inventory
11.7.3 Data Requirements for Notification
11.7.4 Existing Substances
11.7.5 Hazard Communication
11.8 Chemical Control in Korea
11.8.1 The Toxic Chemicals Control Law and Ministry of Environment Notification
11.8.2 The Industrial Safety and Health Law and Ministry of Labour Toxicity Examination
11.8.3 Hazard Communication
11.9 Chemical Control in the Philippines
11.9.1 The Toxic Substances and Hazardous and Nuclear Wastes Control Act
11.9.2 Inventory
11.9.3 Data Requirements for Notification
11.9.4 Administration
11.9.5 Priority Chemicals List (PCL)
11.10 Chemical Control in The People’s Republic of China
11.10.1 Latest Developments
11.10.2 First Import and Toxic Chemicals Regulations
11.10.3 Inventory
11.10.4 Hazard Communication
11.11 Chemical Control in New Zealand
11.11.1 Toxic Substances Act
11.11.2 Resource Management Act
11.11.3 Hazardous Substances and New Organisms Act
11.11.4 Data Requirements for Notification
11.11.5 Hazard Communication
11.12 Mexico
11.12.1 Legislation
11.12.2 Safety Data Sheets
11.13 Singapore
11.14 Malaysia
11.15 Thailand
11.16 Indonesia
11.17 Taiwan
11.18 HPV Programmes
11.18.1 OECD
11.18.2 International Council of Chemical Associations Global Initiative
11.19 Useful Web Sites
12 Notification of Polymers Worldwide
12.1 Introduction
12.2 North America
12.2.1 USA
12.2.2 Canada
12.3 Asia Pacific
12.3.1 Japan
12.3.2 Australia
12.3.3 New Zealand
12.3.4 Korea
12.3.5 Philippines
12.3.6 China
12.4 Europe
12.4.1 EU
12.4.2 Switzerland
12.5 Overall Comparison of the Nine Polymer Notification Schemes
13 Medical Device Regulation
13.1 Introduction
13.2 European Economic Area
13.2.1 Background
13.2.2 Before Marketing
13.2.3 After Marketing
13.3 United States of America
13.3.1 Background
13.3.2 Before Marketing
13.3.3 After Marketing
13.4 Japan
13.4.1 Background
13.4.2 Before Marketing
13.4.3 After Marketing
13.5 Conclusion
14 Regulation of Food Packaging in the EU and US
14.1 Introduction
14.2 Control of Food Packaging in the EU
14.2.1 EU Framework Directive
14.2.2 Food Contact Plastics in the EU
14.2.3 Future Developments for Food Plastics in the EU
14.2.4 Other EU Food Packaging Measures
14.2.5 Strategy for Food Contact Plastic Approval in the EU
14.3 National Controls on Food Packaging in EU Countries
14.3.1 Germany
14.3.2 France
14.3.3 The Netherlands
14.3.4 Belgium
14.3.5 Italy
14.4 Council of Europe Work on Food Packaging
14.4.1 Introduction
14.4.2 Completed Council of Europe Resolutions
14.4.3 Council of Europe Ongoing Work
14.5 Food Packaging in the USA
14.5.1 Introduction
14.5.2 History and Development of US Food Packaging Legislation
14.5.3 The FDA Petition
14.5.4 Threshold of Regulation Process
14.5.5 The Pre-Marketing Notification Scheme
15 Regulation of Biocides
15.1 Introduction
15.2 Control of Biocides in the EU
15.2.1 Introduction
15.2.2 Main Features of the Directive
15.2.3 System of Approval
15.2.4 Assessment for the Inclusion of Active Substances in Annex I of the Biocidal Products Directive
15.2.5 Authorisation of Biocidal Products
15.2.6 Hazard Communication
15.2.7 The Review Programme for Existing Active Substances
15.2.8 Technical Guidance
15.3 Control of Biocides in the USA
15.3.1 Introduction
15.3.2 Data Requirements for Registration
15.3.3 Registration Applications
15.3.4 Data Compensation
15.3.5 Re-Registration of Existing Pesticides
15.3.6 Petition for a Pesticide Tolerance
15.3.7 Regulation of Food Contact Biocides
15.4 Regulation of Biocides in Other Countries
Abbreviations and Acronyms

Dr. Derek Knight is the Director of Regulatory Affairs at Safepharm Laboratories Ltd. He is an expert in regulatory requirements, providing advice on testing and document submission to regulatory authorities. He has a doctorate in chemistry from Oxford University and is a Fellow of the Royal Society of Chemistry and the British Institute of Regulatory Affairs. He has published extensively on regulatory issues, alternatives to animal testing, food contact materials, and biocides.

Mike Thomas is the Marketing Director for Safepharm Laboratories. He graduated in zoology and chemistry from London University and went on to a career in toxicity testing, including working on a wide range of toxicity studies. Prior to joining Safepharm, he was Director of Biological Services at International Consulting and Laboratory Services Ltd., of London.