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H A N D B O O K OF

Third Edition
 H A N D B O O K OF

Third Edition

Michael J. Derelanko, PhD, DABT, FATS

Former Director Nonclinical Drug Safety Assessment
Adolor Corporation, Exton, Pennsylvania and Manager of Toxicology and
Risk Assessment Honeywell International Inc. Morristown, New Jersey
Carol S. Auletta, DABT, RAC, MBA
Di rector, Program Management Huntingdon Life Sciences
East Millstone, New Jersey

Boca Raton London New York

CRC Press is an imprint of the

Taylor & Francis Group, an informa business
CRC Press
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Boca Raton, FL 33487-2742

© 2014 by Taylor & Francis Group, LLC

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No claim to original U.S. Government works

Version Date: 20140127

International Standard Book Number-13: 978-1-4398-9014-1 (eBook - PDF)

This book contains information obtained from authentic and highly regarded sources. While all reasonable efforts have been made to publish reliable data and
information, neither the author[s] nor the publisher can accept any legal responsibility or liability for any errors or omissions that may be made. The publishers
wish to make clear that any views or opinions expressed in this book by individual editors, authors or contributors are personal to them and do not necessarily
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The third edition of the Handbook of Toxicology is dedicated to the memory of
Dr. Mannfred Hollinger
Dr. Paul E. Newton
Dr. John C. Peckham
Dr. Richard M. Hoar
The contributions of these individuals to the first and second editions of the
Handbook of Toxicology appear all or in part in this edition.
Their professionalism, knowledge, and expertise are truly missed.
Contents
Preface to the Third Edition...................................................................................................................................................xxxix
Preface to the Second Edition......................................................................................................................................................xli
Preface to the First Edition....................................................................................................................................................... xliii
Helpful Tips for Using This Handbook...................................................................................................................................... xlv
Acknowledgments.....................................................................................................................................................................xlvii
Editors........................................................................................................................................................................................xlix
Contributors...................................................................................................................................................................................li

Chapter 1 Laboratory Animal Management............................................................................................................................. 1

Introduction.............................................................................................................................................................. 3
Animal Husbandry................................................................................................................................................... 3
Regulations and Guidelines...................................................................................................................................... 4
Animal Welfare Act............................................................................................................................................ 4
Public Health Service Regulations...................................................................................................................... 4
Guide for the Care and Use of Laboratory Animals........................................................................................... 5
Institutional Programs.............................................................................................................................................. 6
AAALAC International....................................................................................................................................... 6
IACUC................................................................................................................................................................. 6
Professional and Governmental Organizations........................................................................................................ 7
AALAS................................................................................................................................................................ 7
ACLAM............................................................................................................................................................... 7
ASLAP................................................................................................................................................................ 8
AVMA................................................................................................................................................................. 8
CCAC.................................................................................................................................................................. 8
ECLAM............................................................................................................................................................... 8
ICLAS.................................................................................................................................................................. 8
ILAR.................................................................................................................................................................... 8
SCAW.................................................................................................................................................................. 9
NIH...................................................................................................................................................................... 9
DEA..................................................................................................................................................................... 9
FDA..................................................................................................................................................................... 9
EPA...................................................................................................................................................................... 9
OLAW.................................................................................................................................................................. 9
APHIS................................................................................................................................................................. 9
AWIC................................................................................................................................................................... 9
CAAT.................................................................................................................................................................. 9
NABR................................................................................................................................................................ 10
OECD................................................................................................................................................................ 10
Organizations That Oppose the Use of Animals in Research............................................................................... 10
Animal Pain, the 3 Rs, and Humane End Points................................................................................................... 10
Animal Pain....................................................................................................................................................... 10
The 3 Rs............................................................................................................................................................. 11
Humane End Points........................................................................................................................................... 11
Table 1.1 End Point Guidance for Rodents................................................................................................... 12
Animal Facility Safety........................................................................................................................................... 12
Zoonotic Diseases.................................................................................................................................................. 12
Hepatitis............................................................................................................................................................. 12
Herpesvirus B.................................................................................................................................................... 12
Rabies................................................................................................................................................................ 13
Lymphocytic Choriomeningitis......................................................................................................................... 13

vii
viii Contents

Other Zoonoses................................................................................................................................................. 13
Table 1.2 Other Zoonotic Diseases............................................................................................................... 13
Recognition and Control of Disease...................................................................................................................... 15
Table 1.3 Abnormal Conditions in Laboratory Animals.................................................................................. 15
Animal Nutrition.................................................................................................................................................... 16
Table 1.4 Types and Sources of Commercial Laboratory Diets........................................................................ 16
Table 1.5 Nutritional Deficiencies of Laboratory Animals............................................................................... 17
Food and Water Requirements.......................................................................................................................... 17
Table 1.6 Approximate Daily Food and Water Requirements for Various Species..................................... 18
Fasting............................................................................................................................................................... 18
Anesthesia and Analgesia...................................................................................................................................... 18
General Considerations..................................................................................................................................... 18
Controlled Substances....................................................................................................................................... 18
Relevant Definitions.......................................................................................................................................... 18
General Principles Regarding Anesthesia, Analgesia, and Tranquilization..................................................... 19
Stages of Anesthesia.......................................................................................................................................... 19
Methods of Administration............................................................................................................................... 19
Commonly Used Anesthetic, Analgesic, and Tranquilizing Agents................................................................. 19
Table 1.7 Typical Routes and Dosages of Several Sedative, Analgesic, and Anesthetic Agents................. 20
Species Peculiarities and Contraindications..................................................................................................... 21
Mouse........................................................................................................................................................... 21
Rat................................................................................................................................................................. 21
Guinea Pig.................................................................................................................................................... 21
Rabbit............................................................................................................................................................ 21
Cat................................................................................................................................................................. 21
Primate.......................................................................................................................................................... 21
Euthanasia.............................................................................................................................................................. 21
Modes of Action................................................................................................................................................ 21
Euthanasia Methods and Agents....................................................................................................................... 22
Table 1.8 Acceptable and “Conditionally Acceptable” Methods for Euthanasia of Several Common
Laboratory Species���������������������������������������������������������������������������������������������������������������������� 22
Table 1.9 Summary of the Characteristics of Several Euthanasia Methods................................................. 22
Inhalant Agents............................................................................................................................................. 23
Carbon Dioxide............................................................................................................................................. 23
Carbon Monoxide......................................................................................................................................... 24
Inert Gases.................................................................................................................................................... 24
Chloroform................................................................................................................................................... 24
Barbiturates and Barbiturate Combination Drugs........................................................................................ 24
Chloral Hydrate............................................................................................................................................ 24
T-61 Euthanasia Solution.............................................................................................................................. 24
Unacceptable Injectable Agents.................................................................................................................... 24
Cervical Dislocation and Decapitation......................................................................................................... 24
Verification of Death.................................................................................................................................... 24
Sources of Laboratory Animals............................................................................................................................. 24
Table 1.10 Names, Addresses, and Phone Numbers of Several Animal Suppliers........................................... 25
Species Data........................................................................................................................................................... 27
Mouse (Mus musculus)...................................................................................................................................... 27
Stocks and Strains........................................................................................................................................ 27
Handling and Restraint................................................................................................................................. 27
Housing......................................................................................................................................................... 27
Environmental Conditions............................................................................................................................ 27
Physical and Physiological Parameters......................................................................................................... 27
Identification, Bleeding, Anesthesia, and Euthanasia Methods for Mice..................................................... 27
Diseases........................................................................................................................................................ 27
Table 1.11 Common Stocks and Strains of Laboratory Mice...................................................................... 28
Table 1.12 Minimum Cage Space Requirements for Mice.......................................................................... 28
Table 1.13 Physical and Physiological Parameters of Mice......................................................................... 29
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Contents ix

Table 1.14 Identification, Bleeding, Anesthesia, and Euthanasia Methods for Laboratory Mice............... 29
Table 1.15 Various Diseases and Adverse Health Conditions of Laboratory Mice..................................... 30
Rat (Rattus norvegicus)..................................................................................................................................... 31
Stocks and Strains........................................................................................................................................ 31
Handling and Restraint................................................................................................................................. 31
Housing......................................................................................................................................................... 31
Environmental Conditions............................................................................................................................ 31
Physical and Physiological Parameters......................................................................................................... 31
Identification, Bleeding, Anesthesia, and Euthanasia Methods for Rats...................................................... 31
Diseases........................................................................................................................................................ 31
Table 1.16 Common Stocks and Strains of Laboratory Rats....................................................................... 32
Table 1.17 Minimum Cage Space Requirements for Rats........................................................................... 32
Table 1.18 Physical and Physiological Parameters of Rats.......................................................................... 33
Table 1.19 Identification, Bleeding, Anesthesia, and Euthanasia Methods for Laboratory Rats................. 33
Table 1.20 Various Diseases and Adverse Health Conditions of Laboratory Rats..................................... 34
Guinea Pig (Cavia porcellus)............................................................................................................................ 34
Breeds and Strains........................................................................................................................................ 34
Handling and Restraint................................................................................................................................. 34
Housing......................................................................................................................................................... 35
Environmental Conditions............................................................................................................................ 35
Physical and Physiological Parameters......................................................................................................... 35
Identification, Bleeding, Anesthesia, and Euthanasia Methods for Guinea Pigs......................................... 35
Diseases........................................................................................................................................................ 35
Table 1.21 Minimum Cage Space Requirements for Guinea Pigs.............................................................. 35
Table 1.22 Physical and Physiological Parameters of Guinea Pigs............................................................. 35
Table 1.23 Identification, Bleeding, Anesthesia, and Euthanasia Methods for Laboratory
Guinea Pigs������������������������������������������������������������������������������������������������������������������������������� 36
Table 1.24 Various Diseases and Adverse Health Conditions of Guinea Pigs............................................ 36
Rabbit (Oryctolagus cuniculus)......................................................................................................................... 37
Breeds and Strains........................................................................................................................................ 37
Handling and Restraint................................................................................................................................. 37
Housing......................................................................................................................................................... 37
Environmental Conditions............................................................................................................................ 37
Physical and Physiological Parameters......................................................................................................... 37
Identification, Bleeding, Anesthesia, and Euthanasia Methods for Rabbits................................................. 37
Diseases........................................................................................................................................................ 37
Table 1.25 Minimum Cage Space Requirements for Rabbits...................................................................... 37
Table 1.26 Physical and Physiological Parameters of Rabbits..................................................................... 38
Table 1.27 Identification, Bleeding, Anesthesia, and Euthanasia Methods for Laboratory Rabbits........... 38
Table 1.28 Various Diseases and Adverse Health Conditions of Rabbits................................................... 39
Dog (Canis familaris)........................................................................................................................................ 40
Breeds and Strains........................................................................................................................................ 40
Receipt.......................................................................................................................................................... 40
Handling and Restraint................................................................................................................................. 41
Housing......................................................................................................................................................... 41
Environmental Conditions............................................................................................................................ 41
Exercise......................................................................................................................................................... 42
Physical and Physiological Parameters......................................................................................................... 42
Identification, Bleeding, Anesthesia, and Euthanasia Methods for Dogs.................................................... 42
Diseases........................................................................................................................................................ 42
Table 1.29 Minimum Cage Space Requirements for Dogs......................................................................... 42
Table 1.30 Physical and Physiological Parameters of Dogs........................................................................ 42
Table 1.31 Identification, Bleeding, Anesthesia, and Euthanasia Methods for Laboratory Dogs............... 42
Table 1.32 Various Diseases and Adverse Health Conditions of Dogs....................................................... 43
Swine (Sus scrofa)............................................................................................................................................. 44
Breeds........................................................................................................................................................... 44
Transportation and Receipt........................................................................................................................... 44
x Contents

Housing......................................................................................................................................................... 45
Environmental Conditions............................................................................................................................ 45
Physical and Physiological Parameters......................................................................................................... 45
Identification, Bleeding, Anesthesia, and Euthanasia Methods for Pigs...................................................... 45
Diseases........................................................................................................................................................ 45
Table 1.33 Minimum Cage Space Requirements for Pigs........................................................................... 45
Table 1.34 Physical and Physiological Parameters of Miniature Swine . ................................................... 45
Table 1.35 Identification, Bleeding, Anesthesia, and Euthanasia Methods for Laboratory Swine............. 46
Table 1.36 Diseases in Pigs.......................................................................................................................... 46
Nonhuman Primates.......................................................................................................................................... 46
Species.......................................................................................................................................................... 46
Housing......................................................................................................................................................... 47
Table 1.37 Minimum Cage Space Requirements for Monkeys............................................................... 47
Environmental Conditions............................................................................................................................ 47
Physical and Physiological Parameters......................................................................................................... 47
Identification, Bleeding, Anesthesia, and Euthanasia Methods for Monkeys.............................................. 47
Diseases........................................................................................................................................................ 47
Table 1.38 Physical and Physiological Parameters of Old World Monkeys ............................................... 48
Table 1.39 Physical and Physiological Parameters of New World Monkeys . ............................................ 48
Table 1.40 Identification, Bleeding, Anesthesia, and Euthanasia Methods for Laboratory
Monkeys������������������������������������������������������������������������������������������������������������������������������������ 48
Table 1.41 Diseases in Nonhuman Primates (NHPs).................................................................................. 49
References.............................................................................................................................................................. 49
Appendix: Additional Related Information........................................................................................................... 50
Table 1.A.1 Guiding Principles in Use of Animals in Toxicology.................................................................... 50
Table 1.A.2 General Information Sources for Care and Use of Research Animals.......................................... 50
Table 1.A.3 Commonly Used Anesthetics........................................................................................................ 51
Table 1.A.4 Advantages and Disadvantages of Anesthetic Agents and Adjuncts............................................. 54

Chapter 2 General Toxicology................................................................................................................................................ 57

Introduction............................................................................................................................................................ 58
Sample Study Designs............................................................................................................................................ 58
Table 2.1 Standard Toxicity Study Designs....................................................................................................... 59
Table 2.2 MTD/Repeat-Dose Range-Finding Toxicity Study in Rodents (Non-GLP)..................................... 60
Table 2.3 A MTD/Repeat-Dose Range-Finding Toxicity Study in Nonrodents (Non-GLP)............................ 60
Regulatory Guidelines: Study Requirements......................................................................................................... 61
List of Guidelines and Agencies........................................................................................................................ 61
Toxicology Testing........................................................................................................................................ 61
Regulatory Guidelines: Good Laboratory Practices.................................................................................... 62
Summary/Comparison Tables........................................................................................................................... 62
Age of Dogs.................................................................................................................................................. 62
Table 2.4 Animal Requirements—Standard Study Guidelines................................................................... 62
Table 2.5 Body Weight and Food Consumption Intervals—Standard Study Guidelines............................ 63
Table 2.6 Ophthalmology lntervals—Standard Study Guidelines (Subchronic and Chronic Studies)........ 63
Table 2.7 Clinical Pathology Intervals—Standard Study Guidelines (Subchronic and Chronic Studies).......64
Table 2.8 Hematology Parameters of Subchronic and Chronic Studies—Standard Study Guidelines........64
Table 2.9 Clinical Chemistry Parameters of Subchronic and Chronic Studies—Standard Study
Guidelines������������������������������������������������������������������������������������������������������������������������������������ 65
Table 2.10 Urinalysis Parameters of Subchronic and Chronic Studies—Standard Study Guidelines......... 65
Table 2.11 Organ Weight Requirements—Standard Study Guidelines........................................................ 66
Table 2.12 Microscopic Pathology Requirements of Subchronic and Chronic Studies
(Rodents)—General—Standard Study Guidelines�������������������������������������������������������������������� 66
Table 2.13 Microscopic Pathology Requirements—Tissues Most Often Recommended
for Subchronic Studies—Standard Study Guidelines���������������������������������������������������������������� 67
Table 2.14 Microscopic Pathology Requirements—Tissues Occasionally Recommended
for Subchronic Studies—Standard Study Guidelines���������������������������������������������������������������� 67
Contents xi

Table 2.15 Microscopic Pathology Requirements—Standard Study Guidelines—Tissues Most Often

Recommended for Chronic Studies������������������������������������������������������������������������������������������� 68
Table 2.16 Microscopic Pathology Requirements—Tissues Occasionally Recommended for Chronic
Studies—Standard Study Guidelines����������������������������������������������������������������������������������������� 68
Table 2.17 Suggested Clinical Pathology, Organ Weights, and Tissues for Histopathology—
Pharmaceutical Studies�������������������������������������������������������������������������������������������������������������� 69
Study Implementation............................................................................................................................................ 71
Protocol Components Checklist........................................................................................................................ 71
Study Initiation Checklist.................................................................................................................................. 73
GLP Protocol Review Checklist........................................................................................................................ 75
Test and/or Control Material Handling Information......................................................................................... 76
Flowchart/Time Lines for Conduct of Study.................................................................................................... 77
Figure 2.1 Flowchart/time line for rodent studies........................................................................................ 77
Figure 2.2 Flowchart/time line for nonrodent studies.................................................................................. 77
Sample Study Schedule..................................................................................................................................... 78
Animal Selection: Randomization Procedures................................................................................................. 79
Dose/Vehicle Selection and Dose Formulation...................................................................................................... 79
Definitions Relative to Doses/Dose Selection................................................................................................... 79
Acute Studies................................................................................................................................................ 79
General Studies............................................................................................................................................. 79
Subchronic and Chronic Studies.................................................................................................................. 79
Chronic Studies............................................................................................................................................ 79
Geometric Progression Tables for Dose Selection............................................................................................ 79
Table 2.18 Geometric Progressions.............................................................................................................. 79
Vehicles: Guidelines for Dosing........................................................................................................................ 80
Dose Volume, Rate, and Needle-Size Guidelines............................................................................................. 80
Table 2.19 Suggested Dose Volumes (mL/kg) for Test Material Administration........................................ 80
Table 2.20 Suggested Dosing Apparatus/Needle Sizes (Gauge) for Test Material Administration............. 80
Table 2.21 Guidelines for Dose Administration for Intravenous Infusion Studies...................................... 81
Body Weight/Surface Area Conversion Tables................................................................................................. 81
Table 2.22 Body Weight: Surface Area Conversion Table........................................................................... 81
Table 2.23 Equivalent Surface Area Dosage Conversion Factors................................................................ 82
Dose Calculations: Oral, Dermal, or Parenteral Administration...................................................................... 82
Dose Volume................................................................................................................................................. 82
Concentration of Dosing Mixture................................................................................................................. 82
Individual Animal Doses.............................................................................................................................. 82
Adjustment for Active Ingredient................................................................................................................. 82
Dose Solution Conversions........................................................................................................................... 82
Calculations for Dietary and Drinking Water Administration......................................................................... 83
Calculation of Concentration: General......................................................................................................... 83
Adjustment of Concentration for Body Weight............................................................................................ 83
Test Material Intake (for Dietary Studies).................................................................................................... 84
Approximate Conversion Factors (ppm to mg/kg/day)................................................................................ 84
Table 2.24 Conversion Factors (ppm to mg/kg).......................................................................................... 84
Calculation of Test Material Requirements....................................................................................................... 84
Amount of Material Needed for Capsule Administration or Dermal Administration of Neat
Material............................................................................................................................................... 84
Amount of Material Needed for Administration in Solution or Suspension................................................ 84
Amount of Material Needed for Dietary Administration............................................................................ 85
Examples of Calculation Sheets Used in Our Laboratory............................................................................ 85
Procedures for Preparation of Dose Solutions/Suspensions and Test Diets...................................................... 88
Preparation of Dose Solutions/Suspensions................................................................................................. 88
Preparation of Test Diets.............................................................................................................................. 88
Analyses of Dosing Solutions/Suspensions and Diets....................................................................................... 89
Method Validation........................................................................................................................................ 89
Homogeneity Analyses................................................................................................................................. 89
Stability Analyses......................................................................................................................................... 89
xii Contents

Confirmation of Concentrations during Study............................................................................................. 89

Summary...................................................................................................................................................... 89
Experimental Evaluations...................................................................................................................................... 89
Clinical Signs of Toxicity.................................................................................................................................. 89
Table 2.25 Clinical Signs of Toxicity........................................................................................................... 89
Table 2.26 Autonomic Signs......................................................................................................................... 91
Table 2.27 Toxic Signs of Acetylcholinesterase Inhibition.......................................................................... 91
Historical Control Data—Rodent Body Weights.............................................................................................. 92
Table 2.28 Body Weights (g) of Control CD1 Mice in Chronic Toxicity Studies Conducted between
2006 and 2011���������������������������������������������������������������������������������������������������������������������������� 92
Table 2.29 Body Weights (g) of Control Sprague–Dawley Rats in Chronic Toxicity Studies
Conducted between 2006 and 2011������������������������������������������������������������������������������������������� 92
Effect of Decreased Body Weights on Organ Weights of Rats......................................................................... 93
Table 2.30 Effect of Decreased Body Weights on Relative Organ Weights of Rats.................................... 93
Rodent Survival Rates....................................................................................................................................... 93
Table 2.31 Monthly Survival Rates of Control CD1 Mice in Chronic Toxicity Studies Conducted
between 2006 and 2011�������������������������������������������������������������������������������������������������������������� 93
Table 2.32 Monthly Survival Rates of Control Sprague–Dawley Rats in Chronic Toxicity Studies
Conducted between 2006 and 2011������������������������������������������������������������������������������������������� 94
References.............................................................................................................................................................. 94

Chapter 3 Dermal Toxicology................................................................................................................................................. 95

Introduction............................................................................................................................................................ 95
Comparison of Major Study Designs..................................................................................................................... 96
Table 3.1 Comparison of Dermal Irritation Study Designs............................................................................... 96
Table 3.2 Comparison of Sensitization Study Designs..................................................................................... 97
Comparison of Regulatory Guidelines................................................................................................................... 99
Table 3.3 Quick Reference Chart for Common US Test Guidelines................................................................. 99
Table 3.4 Quick Reference Chart for Common Foreign Test Guidelines.......................................................... 99
Table 3.5 Quick Reference Chart for Miscellaneous Test Guidelines............................................................ 100
Table 3.6 Comparison of Excerpts from Selected Dermal Irritation Test Guidelines.....................................101
Table 3.7 Comparison of Excerpts from Selected Sensitization Test Guidelines........................................... 106
Materials and Procedures for Performing Dermal Irritation Studies...................................................................114
Occluded Dermal Irritation Test in Rabbits.....................................................................................................114
Semioccluded Dermal Irritation Test in Rabbits..............................................................................................114
Nonoccluded Dermal Irritation Test in Rabbits...............................................................................................115
Dermal Irritation/Corrosivity Test in Rabbits..................................................................................................115
Photoirritation Test in Rabbits..........................................................................................................................116
Photoirritation Test in Guinea Pigs..................................................................................................................117
Materials and Procedures for Performing Dermal Sensitization Studies.............................................................118
Modified Buehler Sensitization Test in Guinea Pigs........................................................................................118
Standard Buehler Sensitization Test in Guinea Pigs....................................................................................... 120
Guinea Pig Maximization Test........................................................................................................................ 122
Murine Local Lymph Node Assay (Radiolabeled Design)............................................................................. 124
Murine Local Lymph Node Assay (DA Test Method, a Nonradioactive Assay)............................................ 125
Murine Local Lymph Node Assay (BrdU-ELISA or Enzyme-Linked Immunosorbent Assay,
a Nonradioactive Assay).................................................................................................................................. 126
Photosensitization Test in Mice....................................................................................................................... 127
Photosensitization Test in Guinea Pigs............................................................................................................ 128
Comparison of Scoring Systems.......................................................................................................................... 130
Table 3.8 Draize Dermal Irritation Scoring System....................................................................................... 130
Table 3.9 Human Patch Test Dermal Irritation Scoring System..................................................................... 130
Table 3.10 Chamber Scarification Dermal Irritation Scoring System.............................................................131
Contents xiii

Table 3.11 Magnusson Sensitization Scoring System.......................................................................................131

Table 3.12 Split Adjuvant Sensitization Scoring System..................................................................................131
Table 3.13 Buehler Sensitization Scoring System............................................................................................131
Table 3.14 Contact Photosensitization Scoring System....................................................................................131
Table 3.15 Human Patch Test Sensitization Scoring System...........................................................................131
Table 3.16 Local Lymph Node Ear Scoring System........................................................................................131
Comparison of Classification Systems................................................................................................................. 132
Table 3.17 Environmental Protection Agency (EPA) Method of Calculating the Primary Irritation
Index (PII) for Dermal Irritation Studies�������������������������������������������������������������������������������������� 132
Table 3.18 Federal Hazardous Substances Act (CPSC/FHSA) Method of Calculating the Primary
Irritation Index (PII) for Dermal Irritation Studies���������������������������������������������������������������������� 132
Table 3.19 European Economic Community’s (EEC) Method of Calculating the Primary Irritation
Index (PII) for Dermal Irritation Studies�������������������������������������������������������������������������������������� 132
Table 3.20 Environmental Protection Agency (EPA) Dermal Classification System..................................... 132
Table 3.21 Environmental Protection Agency (EPA) Standard Evaluation Procedure Dermal
Classification System�������������������������������������������������������������������������������������������������������������������� 133
Table 3.22 Federal Fungicide, Insecticide, and Rodenticide Act (EPAFIFRA) Dermal Classification
System������������������������������������������������������������������������������������������������������������������������������������������� 133
Table 3.23 European Economic Community (EEC) Dermal Classification System...................................... 133
Table 3.24 Federal Hazardous Substances Act (CPSC/FHSA) Dermal Classification System...................... 133
Table 3.25 Draize Dermal Classification System............................................................................................ 133
Table 3.26 Department of Transportation (DOT), Occupational Safety and Health Administration
(OSHA), and International Maritime Organization (IMO) Packing Group Classification
System������������������������������������������������������������������������������������������������������������������������������������������� 134
Table 3.27 Maximization Sensitization Classification System........................................................................ 134
Table 3.28 Optimization Sensitization Classification System......................................................................... 134
Table 3.29 OECD AND EPA Sensitization Classification Systems................................................................ 134
Table 3.30 Local Lymph Node Classification Systems................................................................................... 134
Materials That Produce Dermal Irritation and/or Sensitization.......................................................................... 135
Table 3.31 Common Materials Used as Positive Controls.............................................................................. 135
Table 3.32 Materials Categorized by Their Ability to Produce Dermal Irritation or Sensitization............... 136
Table 3.33 Dermal Irritants and Sensitizers Listed by Occupation.................................................................147
References............................................................................................................................................................ 151
Appendix: Additional Related Information......................................................................................................... 153
Table 3.A.1 Relative Ranking of the Skin Permeability in Different Animal Species................................... 153
Table 3.A.2 In Vivo Human Percutaneous Absorption Rates of Some Neat Chemical Liquids..................... 154
Table 3.A.3 In Vitro Human Percutaneous Permeability Coefficients of Aqueous Solutions of Some
Industrial Chemicals������������������������������������������������������������������������������������������������������������������� 154

Chapter 4 Ocular Toxicology................................................................................................................................................ 155

Anatomy of the Eye.............................................................................................................................................. 156
Figure 4.1 Sagittal section of the anterior chamber angle of the human eye showing the structure
associated with the ciliary body, iris, cornea, and lens.��������������������������������������������������������������� 157
Ocular Mucosa................................................................................................................................................ 157
Ocular Globe................................................................................................................................................... 157
Fibrous Tunic.............................................................................................................................................. 157
Figure 4.2 Sagittal section of the human eye showing internal structures............................................ 158
Uveal Tract.................................................................................................................................................. 159
Figure 4.3 Saggital section of the human eye showing the vascular supply.......................................... 159
Lens............................................................................................................................................................ 159
Aqueous Humor.......................................................................................................................................... 159
Vitreous Humor.......................................................................................................................................... 159
Retina.......................................................................................................................................................... 159
Figure 4.4 Sagittal section of the rabbit eye showing the basic structures............................................ 160
xiv Contents

Figure 4.5 Sagittal section of a healthy rabbit cornea with all five histologic layers
clearly visible���������������������������������������������������������������������������������������������������������������160
Optic Nerve................................................................................................................................................. 160
Comparative Anatomy and Physiology of the Eye............................................................................................... 160
Anatomical Comparisons................................................................................................................................ 160
Table 4.1 Corneal Thickness and Area....................................................................................................... 160
Table 4.2 Comparison of the Type of Retinal Vasculature of Various Species...........................................161
Table 4.3 Percentage of Optic Nerve Fibers Decussating at the Optic Chiasm..........................................161
Table 4.4 Comparison of the Tapetum in the Cat, Dog, and Ferret............................................................161
Physiological Comparisons..............................................................................................................................161
Table 4.5 Concentrations of the Principal Components of the Aqueous Humor as Compared
with Plasma of Various Species��������������������������������������������������������������������������������������������������161
Table 4.6 Concentration of the Various Components of the Vitreous........................................................ 163
Table 4.7 Concentration of Mucopolysaccharide and Collagen of the Vitreous in Various Species......... 163
Table 4.8 Distribution of the Anterior Uveal Adrenergic Receptors in Various Species........................... 163
Regulatory Guidelines.......................................................................................................................................... 163
Contact Lens Materials................................................................................................................................... 163
Systemic Injection Test (USP/NF).............................................................................................................. 163
Eye Irritation Test (USP/NF)...................................................................................................................... 163
In Vitro Cytotoxicity Test (USP/NF).......................................................................................................... 163
Contact Lens Care Products (i.e., Solutions, Tablets)...................................................................................... 164
In Vitro Cytotoxicity Test (USP/NF).......................................................................................................... 164
Acute Ocular Irritation Test........................................................................................................................ 164
Acute Oral Toxicity Study.......................................................................................................................... 164
Plastic Ophthalmic Containers........................................................................................................................ 165
Ophthalmic Therapeutic Formulations........................................................................................................... 165
One Day Acute Topical Ocular Irritation Test............................................................................................ 165
Subchronic (1–3 Months) and Chronic (≥1 Year) Topical Ocular Irritation with Systemic
Toxicological Evaluations........................................................................................................................... 165
Chemical Substances (Liquids, Solids, Aerosols, and Liquids under Pressure)............................................. 165
IRLG Guidelines........................................................................................................................................ 165
OECD Guidelines....................................................................................................................................... 167
OCSPP 870.2400 Acute Eye Irritation....................................................................................................... 169
Ocular Scoring Criteria.........................................................................................................................................171
Scale of Weighted Scores for Grading the Severity of Ocular Lesions Developed by Draize et al.................171
Grades for Ocular Lesions............................................................................................................................... 172
Cornea......................................................................................................................................................... 172
Iris............................................................................................................................................................... 172
Conjunctivae............................................................................................................................................... 172
Representative Illustrations of Draize Eye Irritation Scores........................................................................... 172
Figure 4.6 Photographs demonstrating the four grades for conjunctival redness...................................... 172
Figure 4.7 Photographs demonstrating the four grades for corneal opacity................................................173
Figure 4.8 Eyes stained with fluorescein and photographed under UV light..............................................173
Figure 4.9 Two grades for iritis demonstrated.............................................................................................174
Figure 4.10 Photographs intended to indicate the degree of difference between each
conjunctival grade.������������������������������������������������������������������������������������������������������������������174
Figure 4.11 A time sequence of the same eye shown from before administration of an irritant
to 7 days after exposure.����������������������������������������������������������������������������������������������������������175
Scoring Criteria for Ocular Effects Observed in Slit Lamp Microscopy.........................................................176
Ocular Scoring System for Rabbits Based on Slit Lamp Examination............................................................176
Conjunctiva..................................................................................................................................................176
Light Reflex................................................................................................................................................ 177
Iris Involvement.......................................................................................................................................... 177
Cornea......................................................................................................................................................... 177
Lens.............................................................................................................................................................178
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