Regulatory toxicology in the European Union

636 Pages·2018·6.808 MB·English

by  Marrs, Timothy C., Woodward, Kevin N

Regulatory Toxicology in the European Union
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Issues in Toxicology
Series editors:
Diana Anderson, University of Bradford, UK
01 Michael D. Waters, Michael Waters Consulting, USA
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FP Timothy C. Marrs, Edentox Associates, UK
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2 Editorial advisor:
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8 Alok Dhawan, CSIR-Indian Institute of Toxicology Research, Lucknow, India
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9/ Titles in the Series:
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10 1: Hair in Toxicology: An Important Bio-Monitor
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1 2: Male-mediated Developmental Toxicity
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d 3: Cytochrome P450: Role in the Metabolism and Toxicity of Drugs and
org | other Xenobiotics
sc. 4: Bile Acids: Toxicology and Bioactivity
bs.r 5: The Comet Assay in Toxicology
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p:// 6: Silver in Healthcare
htt 7: In Silico Toxicology: Principles and Applications
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1 9: Biomarkers and Human Biomonitoring, Volume 1: Ongoing Programs
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Fe of Current Interest
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2 11: Hormone-Disruptive Chemical Contaminants in Food
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d o 12: Mammalian Toxicology of Insecticides
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14: Toxicological Effects of Veterinary Medicinal Products in Humans:
Volume 1
15: Toxicological Effects of Veterinary Medicinal Products in Humans:
Volume 2
16: Aging and Vulnerability to Environmental Chemicals: Age-related
Disorders and their Origins in Environmental Exposures
17: Chemical Toxicity Prediction: Category Formation and Read-Across
18: The Carcinogenicity of Metals: Human Risk Through Occupational and
Environmental Exposure
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19: Reducing, Refining and Replacing the Use of Animals in Toxicity Testing
20: Advances in Dermatological Sciences
21: Metabolic Profiling: Disease and Xenobiotics
22: Manganese in Health and Disease
1 23: Toxicology, Survival and Health Hazards of Combustion Products
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22- Relevance
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22 25: Aerobiology: The Toxicology of Airborne Pathogens and Toxins
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82 26: Chemical Warfare Toxicology, Volume 1: Fundamental Aspects
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81 27: Chemical Warfare Toxicology, Volume 2: Management of Poisoning
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9/9 28: Toxicogenomics in Predictive Carcinogenicity
03 29: Human Stem Cell Toxicology
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0. 30: The Comet Assay in Toxicology, 2nd edition
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g | 32: Ecotoxicology and Genotoxicology: Non-traditional Terrestrial Models
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c. 33: Ecotoxicology and Genotoxicology: Non-traditional Aquatic Models
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p:// 36: Regulatory Toxicology in the European Union
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Regulatory Toxicology in the
European Union
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82 Edited by
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39/ Issues in Toxicology No. 36
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1 Print ISBN: 978-1-78262-066-2
doi: PDF ISBN: 978-1-78262-222-2
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c. ISSN: 1757-7179
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ub A catalogue record for this book is available from the British Library
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http:// © The Royal Society of Chemistry 2018
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22 Preface
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1 Toxicology has been described as the science of poisons. While partly true,
doi: it is more than that. It is a scientific discipline with roots in pharmacol-
org | ogy, medicine, pathology and areas of biology that involves the study of the
c. adverse effects (if any) of chemicals on living organisms. One of its roles is to
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bs.r attempt to predict whether toxicity observed in model systems, such as ani-
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p://p mals or in in vitro tests, is likely to be expressed in humans if they are exposed
htt to the chemical in question. Regulatory toxicology is the application of toxi-
n cological knowledge and expertise by governments and their agencies to the
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18 control of chemical substances in order to protect human and animal health,
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y 2 and the well-being of the wider environment. Substances are classified on
uar their main uses, for example into human and veterinary pharmaceuticals,
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21 times a substance may have one or more uses. For example, substances of
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he as pesticides (or plant protection products), but these same substances may
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How chemicals are regulated depends on their uses and, in most areas of
regulation, on their benefits versus any potential risks arising from knowl-
edge of their toxic properties – their hazards. Sometimes these benefits are
relatively easy to identify, although quantifying the benefits may be more
problematic. For example, pharmaceutical products used in the treatment
of human cancer frequently have toxic properties, but the benefits, the treat-
ment and possibly the cure of the disease are self-evident, and if the benefits
are deemed to outweigh the risks, then their clinical use will be permitted.
On the other hand, some substances, for example environmental pollut-
ants, might pose toxicological hazards with associated risks but offer no

Issues in Toxicology No. 36
Regulatory Toxicology in the European Union
Edited by Timothy C. Marrs and Kevin N. Woodward
© The Royal Society of Chemistry 2018
Published by the Royal Society of Chemistry, www.rsc.org
vii
View Online
viii Preface
significant benefits to those potentially exposed. Do we then consider the
benefits of the objects that create the pollutants, such as motor vehicles and
power stations? Workers in chemical industries may be exposed to poten-
tially toxic chemicals, and it is easy to conclude that such substances should
7 be prohibited. However, what if the substance is a precursor for some other
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22- regulate this type of chemical and its exposure?
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22 Regulation of chemicals is not new. At the time of Henry VIII of England,
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82 physicians were concerned over what they regarded as ‘adulterated drugs’
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81 being supplied and used by apothecaries. Henry enacted the first English
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9/9 law (1540) to control medicines and authorised physicians to inspect the
03 premises of apothecaries to examine their products. Prior to the establish-
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0. ment of the European Union (EU) and its predecessor organisations, and in
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oi: many cases for some time after, countries that are now members of the EU
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g | regulated chemicals on the basis of their own laws. This frequently meant
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c. that the level of regulation differed widely from country to country. In some
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p:// have gradually been brought under the umbrella of regulation at the EU level,
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n either directly by the intervention of EU agencies or indirectly by the appli-
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8 cation of harmonised regulatory requirements for enactment by EU member
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2 states. This has resulted in a comprehensive web of legislation and regula-
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ar tory requirements covering most classes of chemical, including human and
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1 well as various types of pollutant.
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on In this book, we have attempted to describe the regulation of chemicals
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looked, this is a book about regulatory toxicology, so we have not focussed
on these other areas. We have, though, invited authors regarded as experts in
their own speciality areas to contribute chapters to this book. Without such
experts, there would be no book!
As editors, we would like to thank all of our contributors for their time and
expertise, and to apologise for the myriad editorial requests and changes that
we have inflicted on them. We are very grateful indeed for their efforts and
understanding. We would also like to thank our colleagues at the Royal Society
of Chemistry for their magnificent efforts in putting all of this together. They
have been patient and understanding, and we are most grateful to them too.
Timothy C. Marrs
Kevin N. Woodward
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22 Contents
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1 Chapter 1 Introduction and General Aspects of Risk Assessment 1
doi: Timothy C. Marrs and Robert L. Maynard
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c. 1.1 History of Regulation in the European Union (EU) 1
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n 1.4.1 Proprietary Data Versus Studies in the Peer-
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1.7 Conclusions 16
Acknowledgements 17
References 17
Chapter 2 Regulation of Medicinal Products for Human Use in the
European Union 22
Henry E. Stemplewski
2.1 Introduction 22
2.2 What Are Medicinal Products for Human Use? 23

Issues in Toxicology No. 36
Regulatory Toxicology in the European Union
Edited by Timothy C. Marrs and Kevin N. Woodward
© The Royal Society of Chemistry 2018
Published by the Royal Society of Chemistry, www.rsc.org
ix
View Online
x Contents
2.3 Background to the Legislation 23
2.4 EU Legislation 24
2.5 Legislation: Differences Between Regulations,
Directives and Guidelines 25
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03 2.8.2 The Pharmacovigilance Risk Assessment
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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
2.22.1 The Safety Working Party (SWP) 46