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Toxicological Effects of
Veterinary Medicinal Products
Published on 31 December 2012 on http://pubs.rsc.org | doi:10.1039/9781849736862-FP001

in Humans
Volume 2

Kevin N. Woodward
TSGE, Concordia House, St James Business Park, Grimbald Crag Court,
Knaresborough, North Yorkshire, HG5 8QB, UK
Email: [email protected]
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Issues in Toxicology No. 15

ISBN: 978-1-84973-684-8
ISSN: 1757-7179

A catalogue record for this book is available from the British Library

r The Royal Society of Chemistry 2013

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Preface
The term ‘‘veterinary medicinal product’’ describes those medicines devel-
oped specifically for use in animals. The development of these products
involves an enormous amount of intellectual effort and physical labour as
well as a considerable amount of financial investment in order to ensure that
animals have available products that are of the appropriate quality and with
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the correct degree of effectiveness. These products also need to be safe for
the animal patient as well as for the user, for the consumer of edible animal
products and for the environment. On the other hand, the term ‘‘veterinary
drug’’ is misleading, as the majority of drugs used in veterinary medicine,
with very few exceptions, either are used in human medicine or have been
used in the past in human medicine. As a consequence, we tend to know a
considerable amount about the toxicity of veterinary drugs from their use in
human medicine. We only know a little regarding the safety of veterinary
medicinal products in humans from their use in animals.
This books attempts to bring together some of this knowledge and experi-
ence to assess the safety of veterinary medicinal products. As described in the
pages that follow, this involves user safety and safety of those who consume
products derived from animals treated with veterinary medicines, and for the
most part this means examining their toxicological and pharmacological
properties. However, some veterinary drugs are also microbiologically active,
and this presents certain hazards that also need to be taken into account.
Finally, like human drugs, these products also eventually find their way into the
environment. As a result, to examine the potential hazards arising from
veterinary medicine, we need to evaluate their toxicological and pharmacolo-
gical properties, and we need to consider their microbiological properties and
their eventual fate in the natural environment. This latter aspect is of concern
not only because organisms might encounter the remnants of veterinary
medicines as a result of environmental contamination, but also because of the
potential effects for human health from the contamination of land and drinking

Issues in Toxicology No. 15

Toxicological Effects of Veterinary Medicinal Products in Humans: Volume 2
By Kevin N. Woodward
r The Royal Society of Chemistry 2013
Published by the Royal Society of Chemistry, www.rsc.org

v
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vi Preface
water. I have tried to reach a balance, and review the main issues that might
impact on human safety arising from the use of veterinary medicinal products.
It is not possible to cover every product or drug in a work of this nature, and I
have made no attempt to do so. Some products are used infrequently, and some
Published on 31 December 2012 on http://pubs.rsc.org | doi:10.1039/9781849736862-FP005

are only used in certain countries. Many others are human drugs that are used
off-label in animals. I have attempted to cover the major drug classes as well as
some individual drugs of interest. Some of these are now of historical interest as
many have fallen out of use or have been replaced with more effective and safer
alternatives. Nevertheless, it would be remiss to avoid discussion of these where
they may have impacted human safety in the past, so I have included them here.
I would like to thank the authors who have invested significant efforts by
providing chapters for this book – Dr Tim Marrs, Derek Renshaw and Pro-
fessor Peter Silley. I would also like to thank my family – and dogs – for their
forbearance and patience while I have been working on this project.

Kevin Woodward
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Surrey
Published on 31 December 2012 on http://pubs.rsc.org | doi:10.1039/9781849736862-FP007

Contents

Volume 1

Chapter 1 Occupational Health and Safety Among Veterinarians and

Veterinary Workers 1
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1.1 Introduction 1
1.2 Physical Injuries 2
1.2.1 Accidents and Related Incidents 2
1.2.2 Needlestick Injuries 4
1.2.3 Zoonotic Diseases 5
1.2.4 Dermatoses 5
1.2.5 Allergies 6
1.2.6 Neoplastic Diseases 6
1.2.7 Specific Risks for Women 7
1.2.8 Mental Health 7
1.3 Conclusions 8
References 8

Chapter 2 Regulation of Veterinary Medicines 21

2.1 Introduction 21
2.2 Criteria for Evaluation and Authorisation of
Veterinary Medicinal Products 22
2.3 European Union Legislation 24
2.3.1 The National Procedure 25
2.3.2 The Mutual Recognition Procedure 25
2.3.3 The Decentralised Procedure 27
2.3.4 The Centralised Procedure 27

Issues in Toxicology No. 15

Toxicological Effects of Veterinary Medicinal Products in Humans: Volume 2
By Kevin N. Woodward
r The Royal Society of Chemistry 2013
Published by the Royal Society of Chemistry, www.rsc.org

vii
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viii Contents
2.3.5 Maximum Residue Limits 28
2.3.6 Pharmacovigilance 29
2.4 Conclusions 36
References 37
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Chapter 3 Consumer Safety – Maximum Residue Limits 40

3.1 Introduction 40
3.2 Establishment of MRLs in the EU 41
3.3 MRLs – Other Considerations 46
3.4 The Joint FAO/WHO Expert Committee on
Food Additives (JECFA) 50
3.5 Practical Uses of MRLs 51
3.6 Residues Surveillance 53
3.6.1 Residues and Residues Studies 54
3.6.2 Residues Surveillance for Veterinary Drugs in
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the UK 56
3.7 Residues Avoidance 59
3.8 Conclusions 62
References 63

Chapter 4 The Assessment of User Safety 81

4.1 Introduction 81
4.2 The Assessment Process 83
4.2.1 Hazard Identification and Assessment 83
4.2.2 Exposure Assessment 86
4.3 Biological Monitoring 92
4.4 Risk Assessment 93
4.5 Risk Management 95
4.6 Risk Communication 96
4.7 Conclusions 97
References 98

Chapter 5 General Anaesthetics 117

5.1 Introduction 117

5.2 Human Health Concerns 118
5.3 Inhalation Anaesthetics 118
5.3.1 Nitrous Oxide 119
5.3.2 Halothane 119
5.3.3 Isoflurane 121
5.3.4 Sevoflurane 123
5.3.5 Enflurane 124
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Contents ix
5.4 Injectable Anaesthetics 124
5.4.1 Propofol 124
5.4.2 Barbiturates 126
5.4.3 Etomidate 127
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5.4.4 Ketamine 128

5.5 Conclusions 130
References 130

Chapter 6 Veterinary Products Containing Pesticide Active

Ingredients 150

6.1 Introduction 150

6.2 Toxicity of Individual Substances 151
6.2.1 Pyrethroids 151
6.2.2 Overview of the Toxic Effects of the
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Pyrethroids in Animals 164

6.2.3 Toxicity to Humans 165
6.3 Imidacloprid 166
6.3.1 Effects in Humans 167
6.4 Organophosphorus Compounds 167
6.4.1 Diazinon 168
6.4.2 Azamethiphos 170
6.5 Metaflumizone 172
6.6 Indoxacarb 174
6.7 Fipronil 176
6.7.1 Toxicity to Humans 179
6.8 Amitraz 179
6.8.1 Toxicity to Humans 181
6.9 Dicyclanil 182
6.10 Cyromazine 184
6.10.1 Effects in Humans 187
6.11 Benzoylureas – Diflubenzuron/Lufenuron/
Teflubenzuron 187
6.12 Spinosad 190
6.13 Macrocyclic Lactones 192
6.13.1 Metabolism 194
6.13.2 Toxicology 195
6.13.3 Summary of Laboratory Animal Toxicity
Studies 198
6.13.4 Factors Affecting Toxicity 199
6.14 Adverse Effects in Target Species 200
6.15 Human Toxicity 202
6.16 Conclusions 203
References 203
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x Contents
Chapter 7 Antineoplastic Drugs 244

7.1 Introduction 244

7.2 Classification of Antineoplastic Drugs 244
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7.2.1 The Alkylating Agents 245

7.2.2 Inhibitors of Mitosis 245
7.2.3 Antimetabolites 246
7.2.4 Antibiotics 248
7.2.5 Platinum Drugs 251
7.3 Toxicity 251
7.4 Conclusions 256
References 256

Chapter 8 Antimicrobial Drugs 273

8.1 Introduction 273

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8.2 The b-Lactam Drugs 274

8.2.1 The Penicillins 274
8.2.2 The Cephalosporins 276
8.2.3 Aminoglycosides 280
8.2.4 Aminocyclitols 282
8.2.5 The Quinolones 283
8.2.6 Macrolides 285
8.2.7 The Phenicols 289
8.2.8 Tetracyclines 291
8.2.9 Polyether Ionophore Antibiotics 298
8.2.10 Lincosamides 298
8.2.11 Polymixins 300
8.2.12 Pleuromutilins 301
8.2.13 Bacitracin 302
8.2.14 Avilamycin 303
8.2.15 Trimethoprim, Baquiloprim and
Sulfonamides 303
8.2.16 Quinoxaline-N-Oxides 306
8.2.17 Other Antibiotic Growth Promoters 308
8.2.18 Nitrofurans 308
8.2.19 Fusidic Acid 310
8.2.20 Novobiocin 310
8.2.21 Rifaximin 311
8.2.22 Dapsone 312
8.2.23 Chlorhexidine 313
8.3 Conclusions 314
References 315

Subject Index 381

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Contents xi
Volume 2

Chapter 9 Human Safety of Coccidiostats: A European Perspective 1

Derek W. Renshaw
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9.1 Introduction 1
9.1.1 Coccidiosis, Coccidiostats and Anticoccidial
Medicines 1
9.1.2 Human Exposure 2
9.1.3 Committees that Evaluate the Safety of
Coccidiostats 2
9.2 Approaches Taken to Ensure the Human Safety of
Coccidiostats 2
9.2.1 Consumer Safety 2
9.2.2 User Safety 3
9.2.3 Inconsistencies in the Values of ADIs 3
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9.2.4 Inconsistencies in the Approaches Used to

Establish MRLs 4
9.2.5 Cross-contamination of Feed with
Coccidiostats 5
9.3 The Safety of Authorised Coccidiostats 5
9.3.1 Ionophoric Polyether Coccidiostats 5
9.3.2 Non-ionophoric Coccidiostats 15
9.3.3 Other Anticoccidial Substances 25
9.4 Conclusions 25
References 26

Chapter 10 Organophosphorus Veterinary Medicines 33

Timothy C. Marrs

10.1 Introduction 33
10.2 Anticholinesterase Activity 38
10.3 Clinical Effects 39
10.3.1 Syndromes Associated with OP
Exposure 39
10.3.2 Other Effects of OPs 44
10.3.3 Diagnostic Tests and Biomarkers 47
10.3.4 Management of OP Poisoning 49
10.4 Exposure and Regulatory Aspects 50
10.4.1 European Union 50
10.4.2 USA 51
10.4.3 Interpretation of Regulatory Studies 51
10.4.4 Pharmacovigilance 52
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xii Contents
10.5 Sheep Dips in the United Kingdom 52
10.5.1 Introduction 52
10.5.2 Treatments 53
10.5.3 Organophosphate Plunge
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Dips 53
10.6 Conclusion 54
References 54

Chapter 11 Antifungal Drugs 71

11.1 Introduction 71
11.2 Griseofulvin 72
11.3 Amphotericin B and Other Polyenes 74
11.4 The Azoles 76
11.4.1 Steroidogenesis Inhibition 76
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11.4.2 Hepatotoxicity 79
11.4.3 Other Effects 79
11.5 Conclusions 80
References 81

Chapter 12 Antiparasitic Drugs 95

12.1 Introduction 95
12.2 Individual Drugs or Groups of Drugs 95
12.2.1 The Benzimidazoles 95
12.2.2 Levamisole 98
12.2.3 Salicylanilides 99
12.2.4 Clorsulon 101
12.2.5 Tetrahydropyrimidines 102
12.2.6 Pyrazinoisoquinolones 104
12.2.7 Monepantel 107
12.2.8 Piperazine 108
12.2.9 Diethylcarbamazine 110
12.2.10 Nitroxynil 111
12.2.11 Halofuginone 112
12.2.12 Nitroimidazoles 113
12.2.13 Imidocarb 116
12.2.14 The Trypanocidal Drugs – Isometamidium
and Diminazene 118
12.2.15 Emodepside 122
12.3 Conclusions 123
References 126
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Contents xiii
Chapter 13 Some Other Pharmacologically Active Drugs 155

13.1 Introduction 155

13.2 Opiates and Synthetic Opiates 155
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13.2.1 Etorphine 155

13.2.2 Butorphanol 157
13.2.3 Buprenorphine 158
13.2.4 Fentanyl 159
13.3 Euthanasia Agents 161
13.4 Neuroactive Steroids 161
13.5 Sedative Agents 163
13.5.1 a2-Receptor Adrenergic Agonists 163
13.5.2 Phenothiazines 166
13.5.3 Butyrophenone Neuroleptic Agents 167
13.6 Carazolol 169
13.7 Clenbuterol 170
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13.8 Non-steroidal Anti-inflammatory Drugs 175

13.8.1 Gastrointestinal Effects 176
13.8.2 Cardiac Effects 177
13.8.3 Nephrotoxicity 178
13.8.4 Phenylbutazone 180
13.9 Tropane Alkaloids 180
13.10 Local Anaesthetics 182
13.11 Antiepileptic Drugs 184
13.11.1 Potassium Bromide 184
13.12 Substances with Hormonal Activity 185
13.12.1 Insulin 185
13.12.2 Steroid Hormones 187
13.13 Corticosteroids 194
13.14 Prostaglandins 195
13.15 Somatotropins 198
13.16 Conclusions 199
References 202

Chapter 14 Human Safety of Veterinary Vaccines 248

14.1 Introduction 248

14.2 Zoonotic Diseases 252
14.3 Physical Injury – High-pressure Injection
Injuries 253
14.4 Human Consumer Safety of Vaccine
Excipients 255
14.5 Conclusions 257
References 257
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xiv Contents
Chapter 15 Adverse Drug Reactions in Humans – Data from Veterinary
Pharmacovigilance Schemes 273

15.1 Introduction 273

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15.2 The Suspected Adverse Reactions Reporting

Scheme – United Kingdom 273
15.2.1 Dog and Cat Products Containing
Imidacloprid 275
15.2.2 Sprays Containing Dichlorvos 276
15.2.3 Organophosphorus Sheep Dips 276
15.3 Adverse Reaction Reporting in the USA 282
15.4 Conclusions 355
References 355

Chapter 16 Veterinary Medicines and the Environment 365

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16.1 Introduction 365

16.2 Human Pharmaceuticals 366
16.3 Veterinary Pharmaceuticals 366
16.3.1 Regulation of Veterinary Medicinal
Products and Environmental Safety 367
16.3.2 Adverse Environmental Effects of
Veterinary Medicinal Products 372
16.3.3 Reporting of Environmental Adverse
Events and Incidents with Veterinary
Medicines 375
16.4 Conclusions 376
References 378

Chapter 17 Potential Adverse Microbiological Effects of

Antimicrobials 403
P. Silley

17.1 Introduction 403

17.2 Antimicrobial Resistance and Campylobacter
Species 405
17.2.1 Why is Campylobacter Important? 405
17.2.2 What Do We Know About Resistance
Development in Campylobacter? 408
17.3 Acceptable Daily Intake of Antimicrobial Residues 413
17.3.1 Steps in Determining the Need for a
Microbiological ADI 415
17.3.2 How the Data are Handled – Colonization
Barrier 416
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Contents xv
17.3.3 Calculations 417
17.3.4 How the Data are Handled – Resistance
Development 419
17.3.5 Guideline Revision 420
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17.4 Concluding Thoughts 420

References 422

Subject Index 429

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CHAPTER 9

Human Safety of Coccidiostats:

A European Perspective
DEREK W. RENSHAW

Independent toxicologist, London, UK.

E-mail: [email protected]
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9.1 Introduction
In the European Union (EU) substances and preparations used to treat or prevent
diseases in animals are normally regarded as veterinary medicinal products and are
regulated under the veterinary medicines and related legislation (Chapters 2 and 3).
The only exception to this is the coccidiostats group of substances and their related
formulations. These may be regulated as veterinary medicinal products or they may
be controlled under the EU’s feed additives legislation. The main legal instrument
for the regulation of feed additives was Directive 70/524/EEC but this has now been
replaced by Regulation (EC) No 1831/2003 (on additives for use in animal feed)
and its implementing rules under Regulation (EC) No 429/2008. Substances being
evaluated for use in animal feed are assessed in much the same way as veterinary
medicinal products, particularly for safety and efficacy. Once approved, they
are entered into the European Union Register of Feed Additives. The majority
of substances in this Register are micronutrients, flavouring agents, defined
botanicals, digestibility enhances, preservatives, colouring agents, enzymes and
microorganisms. However, the Register contains a small number of coccidiostats.

9.1.1 Coccidiosis, Coccidiostats and Anticoccidial Medicines

Coccidiosis is a disease caused by protozoal intracellular parasites known as
coccidia, which commonly occur in animals, including poultry, cattle, pigs,

Issues in Toxicology No. 15

Toxicological Effects of Veterinary Medicinal Products in Humans: Volume 2
By Kevin N. Woodward
r The Royal Society of Chemistry 2013
Published by the Royal Society of Chemistry, www.rsc.org