Dermal Absorption and Toxicity Assessment pot

Dermal Absorption
and Toxicity Assessment
Roberts_978-0849375910_TP.indd 1 11/13/07 11:49:32 AM
DRUGS AND THE PHARMACEUTICALSCIENCES
ASeries of Textbooks and Monographs
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Larry L. Augsburger
University of Maryland
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Yuichi Sugiyama
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1. Pharmacokinetics, Milo Gibaldi and Donald Perrier
2. Good Manufacturing Practices for Pharmaceuticals: APlan for Total Quality Control,
Sidney H. Willig, Murray M. Tuckerman, and William S. Hitchings IV
3. Microencapsulation, edited by J. R. Nixon
4. Drug Metabolism: Chemical and Biochemical Aspects, Bernard Testa and
Peter Jenner
5. New Drugs: Discovery and Development, edited by Alan A. Rubin
6. Sustained and Controlled Release Drug Delivery Systems, edited by
Joseph R. Robinson
7. Modern Pharmaceutics, edited by Gilbert S. Banker and Christopher T. Rhodes
8. Prescription Drugs in Short Supply: Case Histories, Michael A. Schwartz
9. Activated Charcoal: Antidotal and Other Medical Uses, David O. Cooney
10. Concepts in Drug Metabolism (in two parts), edited by Peter Jenner and
Bernard Testa
11. Pharmaceutical Analysis: Modern Methods (in two parts), edited by
James W. Munson
12. Techniques of Solubilization of Drugs, edited by Samuel H. Yalkowsky
13. Orphan Drugs, edited by Fred E. Karch
14. Novel Drug Delivery Systems: Fundamentals, Developmental Concepts,
Biomedical Assessments, Yie W. Chien
15. Pharmacokinetics: Second Edition, Revised and Expanded, Milo Gibaldi and
Donald Perrier
16. Good Manufacturing Practices for Pharmaceuticals: APlan for Total Quality Control,
Second Edition, Revised and Expanded, Sidney H. Willig, Murray M. Tuckerman,
and William S. Hitchings IV
17. Formulation of Veterinary Dosage Forms, edited by Jack Blodinger
18. Dermatological Formulations: Percutaneous Absorption, Brian W. Barry
19. The Clinical Research Process in the Pharmaceutical Industry, edited by

Gary M. Matoren
20. Microencapsulation and Related Drug Processes, Patrick B. Deasy
21. Drugs and Nutrients: The Interactive Effects, edited by Daphne A. Roe and
T. Colin Campbell
22. Biotechnology of Industrial Antibiotics, Erick J. Vandamme
23. Pharmaceutical Process Validation, edited by Bernard T. Loftus and
Robert A. Nash
24. Anticancer and Interferon Agents: Synthesis and Properties, edited by
Raphael M. Ottenbrite and George B. Butler
25. Pharmaceutical Statistics: Practical and Clinical Applications, Sanford Bolton
26. Drug Dynamics for Analytical, Clinical, and Biological Chemists, Benjamin J.
Gudzinowicz, Burrows T. Younkin, Jr., and Michael J. Gudzinowicz
27. Modern Analysis of Antibiotics, edited by Adjoran Aszalos
28. Solubility and Related Properties, Kenneth C. James
29. Controlled Drug Delivery: Fundamentals and Applications, Second Edition, Revised
and Expanded, edited by Joseph R. Robinson and Vincent H. Lee
30. New Drug Approval Process: Clinical and Regulatory Management, edited by
Richard A. Guarino
31. Transdermal Controlled Systemic Medications, edited by Yie W. Chien
32. Drug Delivery Devices: Fundamentals and Applications, edited by Praveen Tyle
33. Pharmacokinetics: Regulatory † Industrial † Academic Perspectives, edited by
Peter G. Welling and Francis L. S. Tse
34. Clinical Drug Trials and Tribulations, edited by Allen E. Cato
35. Transdermal Drug Delivery: Developmental Issues and Research Initiatives,
edited by Jonathan Hadgraft and Richard H. Guy
36. Aqueous Polymeric Coatings for Pharmaceutical Dosage Forms, edited by
James W. McGinity
37. Pharmaceutical Pelletization Technology, edited by Isaac Ghebre-Sellassie
38. Good Laboratory Practice Regulations, edited by Allen F. Hirsch
39. Nasal Systemic Drug Delivery, Yie W. Chien, Kenneth S. E. Su, and Shyi-Feu Chang

40. Modern Pharmaceutics: Second Edition, Revised and Expanded, edited by
Gilbert S. Banker and Christopher T. Rhodes
41. Specialized Drug Delivery Systems: Manufacturing and Production Technology,
edited by Praveen Tyle
42. Topical Drug Delivery Formulations, edited by David W. Osborne and
Anton H. Amann
43. Drug Stability: Principles and Practices, Jens T. Carstensen
44. Pharmaceutical Statistics: Practical and Clinical Applications, Second Edition,
Revised and Expanded, Sanford Bolton
45. Biodegradable Polymers as Drug Delivery Systems, edited by Mark Chasin and
Robert Langer
46. Preclinical Drug Disposition: ALaboratory Handbook, Francis L. S. Tse and
James J. Jaffe
47. HPLC in the Pharmaceutical Industry, edited by Godwin W. Fong and
Stanley K. Lam
48. Pharmaceutical Bioequivalence, edited by Peter G. Welling, Francis L. S. Tse,
and Shrikant V. Dinghe
49. Pharmaceutical Dissolution Testing, Umesh V. Banakar
50. Novel Drug Delivery Systems: Second Edition, Revised and Expanded, Yie W. Chien
51. Managing the Clinical Drug Development Process, David M. Cocchetto and
Ronald V. Nardi
52. Good Manufacturing Practices for Pharmaceuticals: APlan for Total Quality Control,
Third Edition, edited by Sidney H. Willig and James R. Stoker
53. Prodrugs: Topical and Ocular Drug Delivery, edited by Kenneth B. Sloan
54. Pharmaceutical Inhalation Aerosol Technology, edited by Anthony J. Hickey
55. Radiopharmaceuticals: Chemistry and Pharmacology, edited by Adrian D. Nunn
56. New Drug Approval Process: Second Edition, Revised and Expanded, edited by
Richard A. Guarino
57. Pharmaceutical Process Validation: Second Edition, Revised and Expanded,
edited by Ira R. Berry and Robert A. Nash

58. Ophthalmic Drug Delivery Systems, edited by Ashim K. Mitra
59. Pharmaceutical Skin Penetration Enhancement, edited by Kenneth A. Walters
and Jonathan Hadgraft
60. Colonic Drug Absorption and Metabolism, edited by Peter R. Bieck
61. Pharmaceutical Particulate Carriers: Therapeutic Applications, edited by
Alain Rolland
62. Drug Permeation Enhancement: Theory and Applications, edited by Dean S. Hsieh
63. Glycopeptide Antibiotics, edited by Ramakrishnan Nagarajan
64. Achieving Sterility in Medical and Pharmaceutical Products, Nigel A. Halls
65. Multiparticulate Oral Drug Delivery, edited by Isaac Ghebre-Sellassie
66. Colloidal Drug Delivery Systems, edited by Jo
¨
rg Kreuter
67. Pharmacokinetics: Regulatory † Industrial † Academic Perspectives,
Second Edition, edited by Peter G. Welling and Francis L. S. Tse
68. Drug Stability: Principles and Practices, Second Edition, Revised and Expanded,
Jens T. Carstensen
69. Good Laboratory Practice Regulations: Second Edition, Revised and Expanded,
edited by Sandy Weinberg
70. Physical Characterization of Pharmaceutical Solids, edited by Harry G. Brittain
71. Pharmaceutical Powder Compaction Technology, edited by Go
¨
ran Alderborn and
Christer Nystro
¨
m
72. Modern Pharmaceutics: Third Edition, Revised and Expanded, edited by
Gilbert S. Banker and Christopher T. Rhodes
73. Microencapsulation: Methods and Industrial Applications, edited by Simon Benita
74. Oral Mucosal Drug Delivery, edited by Michael J. Rathbone

75. Clinical Research in Pharmaceutical Development, edited by Barry Bleidt and
Michael Montagne
76. The Drug Development Process: Increasing Efficiency and Cost Effectiveness,
edited by Peter G. Welling, Louis Lasagna, and Umesh V. Banakar
77. Microparticulate Systems for the Delivery of Proteins and Vaccines, edited by
Smadar Cohen and Howard Bernstein
78. Good Manufacturing Practices for Pharmaceuticals: APlan for Total Quality Control,
Fourth Edition, Revised and Expanded, Sidney H. Willig and James R. Stoker
79. Aqueous Polymeric Coatings for Pharmaceutical Dosage Forms: Second Edition,
Revised and Expanded, edited by James W. McGinity
80. Pharmaceutical Statistics: Practical and Clinical Applications, Third Edition,
Sanford Bolton
81. Handbook of Pharmaceutical Granulation Technology, edited by Dilip M. Parikh
82. Biotechnology of Antibiotics: Second Edition, Revised and Expanded, edited by
William R. Strohl
83. Mechanisms of Transdermal Drug Delivery, edited by Russell O. Potts and
Richard H. Guy
84. Pharmaceutical Enzymes, edited by Albert Lauwers and Simon Scharpe
´
85. Development of Biopharmaceutical Parenteral Dosage Forms, edited by
John A. Bontempo
86. Pharmaceutical Project Management, edited by Tony Kennedy
87. Drug Products for Clinical Trials: An International Guide to Formulation † Production
† Quality Control, edited by Donald C. Monkhouse and Christopher T. Rhodes
88. Development and Formulation of Veterinary Dosage Forms: Second Edition,
Revised and Expanded, edited by Gregory E. Hardee and J. Desmond Baggot
89. Receptor-Based Drug Design, edited by Paul Leff
90. Automation and Validation of Information in Pharmaceutical Processing, edited by
Joseph F. deSpautz
91. Dermal Absorption and Toxicity Assessment, edited by Michael S. Roberts and

Kenneth A. Walters
92. Pharmaceutical Experimental Design, Gareth A. Lewis, Didier Mathieu, and
Roger Phan-Tan-Luu
93. Preparing for FDA Pre-Approval Inspections, edited by Martin D. Hynes III
94. Pharmaceutical Excipients: Characterization by IR, Raman, and NMR Spec-
troscopy, David E. Bugay and W. Paul Findlay
95. Polymorphism in Pharmaceutical Solids, edited by Harry G. Brittain
96. Freeze-Drying/Lyophilization of Pharmaceutical and Biological Products, edited by
Louis Rey and Joan C.May
97. Percutaneous Absorption: Drugs–Cosmetics–Mechanisms–Methodology,
Third Edition, Revised and Expanded, edited by Robert L. Bronaugh and
Howard I. Maibach
98. Bioadhesive Drug Delivery Systems: Fundamentals, Novel Approaches, and
Development, edited by Edith Mathiowitz, Donald E. Chickering III, and Claus-
Michael Lehr
99. Protein Formulation and Delivery, edited by Eugene J. McNally
100. New Drug Approval Process: Third Edition, The Global Challenge, edited by
Richard A. Guarino
101. Peptide and Protein Drug Analysis, edited by Ronald E. Reid
102. Transport Processes in Pharmaceutical Systems, edited by Gordon L. Amidon,
Ping I. Lee, and Elizabeth M. Topp
103. Excipient Toxicity and Safety, edited by Myra L. Weiner and Lois A. Kotkoskie
104. The Clinical Audit in Pharmaceutical Development, edited by Michael R. Hamrell
105. Pharmaceutical Emulsions and Suspensions, edited by Francoise Nielloud and
Gilberte Marti-Mestres
106. Oral Drug Absorption: Prediction and Assessment, edited by Jennifer B. Dressman
and Hans Lennerna
¨
s
107. Drug Stability: Principles and Practices, Third Edition, Revised and Expanded,

edited by Jens T. Carstensen and C. T. Rhodes
108. Containment in the Pharmaceutical Industry, edited by James P. Wood
109. Good Manufacturing Practices for Pharmaceuticals: APlan for Total Quality
Control from Manufacturer to Consumer, Fifth Edition, Revised and Expanded,
Sidney H. Willig
110. Advanced Pharmaceutical Solids, Jens T. Carstensen
111. Endotoxins: Pyrogens, LAL Testing, and Depyrogenation, Second Edition,
Revised and Expanded, Kevin L. Williams
112. Pharmaceutical Process Engineering, Anthony J. Hickey and David Ganderton
113. Pharmacogenomics, edited by Werner Kalow, Urs A. Meyer and Rachel F. Tyndale
114. Handbook of Drug Screening, edited by Ramakrishna Seethala and
Prabhavathi B. Fernandes
115. Drug Targeting Technology: Physical † Chemical † Biological Methods, edited by
Hans Schreier
116. Drug–Drug Interactions, edited by A. David Rodrigues
117. Handbook of Pharmaceutical Analysis, edited by Lena Ohannesian and
Anthony J. Streeter
118. Pharmaceutical Process Scale-Up, edited by Michael Levin
119. Dermatological and Transdermal Formulations, edited by Kenneth A. Walters
120. Clinical Drug Trials and Tribulations: Second Edition, Revised and Expanded,
edited by Allen Cato, Lynda Sutton, and Allen Cato III
121. Modern Pharmaceutics: Fourth Edition, Revised and Expanded, edited by
Gilbert S. Banker and Christopher T. Rhodes
122. Surfactants and Polymers in Drug Delivery, Martin Malmsten
123. Transdermal Drug Delivery: Second Edition, Revised and Expanded, edited by
Richard H. Guy and Jonathan Hadgraft
124. Good Laboratory Practice Regulations: Second Edition, Revised and Expanded,
edited by Sandy Weinberg
125. Parenteral Quality Control: Sterility, Pyrogen, Particulate, and Package Integrity
Testing: Third Edition, Revised and Expanded, Michael J. Akers, Daniel S.

Larrimore, and Dana Morton Guazzo
126. Modified-Release Drug Delivery Technology, edited by Michael J. Rathbone,
Jonathan Hadgraft, and Michael S. Roberts
127. Simulation for Designing Clinical Trials: APharmacokinetic-Pharmacodynamic
Modeling Perspective, edited by Hui C. Kimko and Stephen B. Duffull
128. Affinity Capillary Electrophoresis in Pharmaceutics and Biopharmaceutics,
edited by Reinhard H. H. Neubert and Hans-Hermann Ru
¨
ttinger
129. Pharmaceutical Process Validation: An International Third Edition, Revised and
Expanded, edited by Robert A. Nash and Alfred H. Wachter
130. Ophthalmic Drug Delivery Systems: Second Edition, Revised and Expanded,
edited by Ashim K. Mitra
131. Pharmaceutical Gene Delivery Systems, edited by Alain Rolland and
Sean M. Sullivan
132. Biomarkers in Clinical Drug Development, edited by John C. Bloom and
Robert A. Dean
133. Pharmaceutical Extrusion Technology, edited by Isaac Ghebre-Sellassie and
Charles Martin
134. Pharmaceutical Inhalation Aerosol Technology: Second Edition, Revised and
Expanded, edited by Anthony J. Hickey
135. Pharmaceutical Statistics: Practical and Clinical Applications, Fourth Edition,
Sanford Bolton and Charles Bon
136. Compliance Handbook for Pharmaceuticals, Medical Devices, and Biologics,
edited by Carmen Medina
137. Freeze-Drying/Lyophilization of Pharmaceutical and Biological Products:
Second Edition, Revised and Expanded, edited by Louis Rey and Joan C. May
138. Supercritical Fluid Technology for Drug Product Development, edited by Peter York,
Uday B. Kompella, and Boris Y. Shekunov
139. New Drug Approval Process: Fourth Edition, Accelerating Global Registrations,

edited by Richard A. Guarino
140. Microbial Contamination Control in Parenteral Manufacturing, edited by
Kevin L. Williams
141. New Drug Development: Regulatory Paradigms for Clinical Pharmacology and
Biopharmaceutics, edited by Chandrahas G. Sahajwalla
142. Microbial Contamination Control in the Pharmaceutical Industry, edited by
Luis Jimenez
143. Generic Drug Product Development: Solid Oral Dosage Forms, edited by
Leon Shargel and Isadore Kanfer
144. Introduction to the Pharmaceutical Regulatory Process, edited by Ira R. Berry
145. Drug Delivery to the Oral Cavity: Molecules to Market, edited by Tapash K. Ghosh
and William R. Pfister
146. Good Design Practices for GMP Pharmaceutical Facilities, edited by
Andrew Signore and Terry Jacobs
147. Drug Products for Clinical Trials, Second Edition, edited by Donald Monkhouse,
Charles Carney, and Jim Clark
148. Polymeric Drug Delivery Systems, edited by Glen S. Kwon
149. Injectable Dispersed Systems: Formulation, Processing, and Performance,
edited by Diane J. Burgess
150. Laboratory Auditing for Quality and Regulatory Compliance, Donald Singer,
Raluca- Ioana Stefan, and Jacobus van Staden
151. Active Pharmaceutical Ingredients: Development, Manufacturing, and Regulation,
edited by Stanley Nusim
152. Preclinical Drug Development, edited by Mark C. Rogge and David R. Taft
153. Pharmaceutical Stress Testing: Predicting Drug Degradation, edited by
Steven W. Baertschi
154. Handbook of Pharmaceutical Granulation Technology: Second Edition,
edited by Dilip M. Parikh
155. Percutaneous Absorption: Drugs–Cosmetics–Mechanisms–Methodology,
Fourth Edition, edited by Robert L. Bronaugh and Howard I. Maibach

156. Pharmacogenomics: Second Edition, edited by Werner Kalow, Urs A. Meyer and
Rachel F. Tyndale
157. Pharmaceutical Process Scale-Up, Second Edition, edited by Michael Levin
158. Microencapsulation: Methods and Industrial Applications, Second Edition,
edited by Simon Benita
159. Nanoparticle Technology for Drug Delivery, edited by Ram B. Gupta and
Uday B. Kompella
160. Spectroscopy of Pharmaceutical Solids, edited by Harry G. Brittain
161. Dose Optimization in Drug Development, edited by Rajesh Krishna
162. Herbal Supplements-Drug Interactions: Scientific and Regulatory Perspectives,
edited by Y. W. Francis Lam, Shiew-Mei Huang, and Stephen D. Hall
163. Pharmaceutical Photostability and Stabilization Technology, edited by
Joseph T.Piechocki and Karl Thoma
164. Environmental Monitoring for Cleanrooms and Controlled Environments,
edited by Anne Marie Dixon
165. Pharmaceutical Product Development: In Vitro-In Vivo Correlation, edited by
Dakshina Murthy Chilukuri, Gangadhar Sunkara, and David Young
166. Nanoparticulate Drug Delivery Systems, edited by Deepak Thassu, Michel Deleers,
and Yashwant Pathak
167. Endotoxins: Pyrogens, LAL Testing and Depyrogenation, Third Edition,
edited by Kevin L. Williams
168. Good Laboratory Practice Regulations, Fourth Edition, edited by
Anne Sandy Weinberg
169. Good Manufacturing Practices for Pharmaceuticals, Sixth Edition, edited by
Joseph D. Nally
170. Oral-Lipid Based Formulations: Enhancing the Bioavailability of Poorly
Water-soluble Drugs, edited by David J. Hauss
171. Handbook of Bioequivalence Testing, edited by Sarfaraz K. Niazi
172. Advanced Drug Formulation Design to Optimize Therapeutic Outcomes,
edited by Robert O. Williams III, David R. Taft, and Jason T. McConville

173. Clean-in-Place for Biopharmaceutical Processes, edited by Dale A. Seiberling
174. Filtration and Purification in the Biopharmaceutical Industry, Second Edition,
edited by Maik W. Jornitz and Theodore H. Meltzer
175. Protein Formulation and Delivery, Second Edition, edited by Eugene J. McNally
and Jayne E. Hastedt
176. Aqueous Polymeric Coatings for Pharmaceutical Dosage Forms, Third Edition,
edited by James McGinity and Linda A. Felton
177. Dermal Absorption and Toxicity Assessment, Second Edition, edited by
Michael S. Roberts and Kenneth A. Walters
178. Preformulation Solid Dosage Form Development, edited by Moji C. Adeyeye and
Harry G. Brittain
179. Drug-Drug Interactions, Second Edition, edited by A. David Rodrigues
180. Generic Drug Product Development: Bioequivalence Issues, edited by
Isadore Kanfer and Leon Shargel

Edited by
Michael S. Roberts
School of Medicine, University of Queensland
Princess Alexandra Hospital
Buranda, Australia
Kenneth A. Walters
An-eX Analytical Services Ltd.
Cardiff, United Kingdom
Dermal Absorption
and Toxicity Assessment
Second Edition
Roberts_978-0849375910_TP.indd 2 11/13/07 11:49:32 AM
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1. Dermatotoxicology.2.Dermatologicagents–Toxicology.3.Cosmetics–Toxi-
cology.4.Skin absorption. 5. Healthrisk assessment.I.Roberts, Michael S., 1949– II.
Walters, Kenneth A., 1949– III. Series.
[DNLM: 1. Skin Absorption–physiology. 2. Cosmetics–adverse effects.
3. Cosmetics–pharmacokinetics. 4. Environmental Exposure. 5. Pharmaceutical
Preparations–adverse effects. 6. Risk Assessment. W1 DR893B v.1172007/WR 102
D434 2007]
RL803.D44 2007
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Preface to the Second Edition
Since this book was first published in 1998, there have been significant advances in
our understanding of the morphology of the skin and the properties that govern the
transport of molecules into and across the three major strata. The multitude of data
that has been generated has allowed the development of predictive models for both
the rate and extent of dermal absorption and has increased our ability to predictthe
likelihood of local toxic events subsequent to solute penetration and permeation. In
this second edition we have completely revised and updated many of the chapters
that appeared in the earlier version and we have expanded the scope of the volume
to include coverage of the morerecent exciting and innovative areas of research.
Those chapters concerned with dermatological and cosmeceutical therapy have
been moved to acompanion publication, Dermatologic, Cosmeceutic, and Cosmetic
Development: Therapeutic and Novel Approaches.
This second edition has been divided into six parts covering skin structure
and absorption, measurement of absorption, modeling of dermal absorption and

risk assessment, skin toxicity and its prevention, regulatory issues, and specific
examples of the absorption of environmental materials. As in the first edition, this
book provides an overview of the dermal absorption process, with particular
emphasis on thedeterminants fortoxicity arisingfromdermal exposure.
Ageneral introduction, covering the structure of human and animal skin and its
relationship to dermal absorption, is followed by Part I, which expands on the
specific barrier properties of the skin, such as its physical structure, biosensor
properties, cutaneous metabolism, skin lipid morphology,and dermal blood and
lymphatic flow.The range of methods used to assess skin absorption is fully
discussed in Part II. There, the use of standard established laboratory methods,
such as diffusion cell technology,are covered together with some of the newer
techniques, such as the use of cultured skin equivalents. Many of the techniques
used for measurement and modeling of dermal absorption and risk assessment are
discussed in Part III. This section also includes the use of mathematical models,
many of which have been refined to provide more realistic predictions, together
with structure-penetration relationships as principles for estimating dermal risk
assessment. In addition, this part covers the estimation of systemic exposure
subsequent to dermal absorption, pharmacodynamics and the pharmacokinetics of
skin delivery,and the use of various real life exposurescenarios in dermal risk
assessment.
The next two parts of the book focus on local toxicity and its prevention and
regulatory initiatives. Within the local toxicity section, issues such as skin damage,
irritation, sensitisation, phototoxicity,and the prevention of toxicity arecovered.
The regulatory section provides information on the various governmental and
industrial programs concerningthe issues surroundingskinpermeationand
toxicity,including alternative in silico, in vitro, and in vivo strategies to conduct
studies for regulatory approval.
The final section provides some examples of substances absorbed through the
skin, givingparticular emphasis to environmental contaminants andcosmetic
iii

ingredients. This sectionincludesthe U.S. Environmental Protection Agency’s
defined common environmental substances,togetherwithdiscussionsonthe
percutaneous absorptionofcompounds from soil andbathing water,and the
permeation of pesticides, metals, fragrances, and other cosmetic ingredients.
This book is intended for scientists involved in dermal absorption and for
those concerned with the marketing of products that may be absorbed through the
skin intentionally or unintentionally.Tothisend, we have been fortunatein
obtaining the agreement of many internationally recognized experts in the field
of dermal absorption and toxicity assessment to provide coverage of their specific
fields of expertise. To all of our authors we extend our sincere thanks for their
unreserved efforts and time.
Michael S. Roberts
Kenneth A. Walters
Preface to the Second Editioniv
Preface from the First Edition
The development and use of chemicals, especially those in the pharmaceutical,
general chemical, and cosmetic fields, are associated with hazards arising from
human exposure. For these compounds, absorption into the skin may represent a
major route of entry into the body.Inaddition, anumber of such substances are
applied to the skin for therapeutic or cosmetic purposes. The rate and extent of
penetration into and absorption through the skin aredefined by anumber of
variables,including environmentalconditions,skinphysiology, permeant
structure, method of application, and species differences.
This volume provides and overview of the dermal absorption process, with
particular emphasis on the determinants for toxicity arising from dermal exposure.
Part Iisconcerned with the structure of the skin and the underlying principles
defining percutaneous absorption and toxicity.InPart II, the concept of dermal risk
assessment,predictedfromepidemiologicalfactors, physiologicalmodels, in
vitro/in vivo experimentation, and chemical structures, is examined by experts in
these areas. This section also describes the use of mathematical models together

with structure-penetration relationships as principles for estimating dermal risk
assessment.
Parts III and IV are concerned with dermal absorption and risk assessment as
applied to specific product types: pharmaceuticals and cosmetics. The individual
chapters discussspecificproduct classessuchasdrugs used forpain and
inflammation, fragrances, sunscreens, and hair dyes. The final section, Part V,
provides information on skin permeation following environmental exposureand
includes discussions on the percutaneous absorption of compounds fromsoil and
bathing water.Throughout this volume, pharmacokinetic data and models often
used in dermal risk assessment are fully described.
The book has been written for scientists interested in dermal absorption and
those concerned with the marketing of products that may be absorbed through the
skin either intentionally or unintentionally.Wehope that this book will prove useful
to those involved in researchand development in the pharmaceutical, cosmetic,
agrochemical, household, and general chemical industries.
Michael S. Roberts
Kenneth A. Walters
v

Contents
Preface to the Second Edition iii
Preface fromthe First Edition v
Contributors xi
INTRODUCTION
1. Human Skin Morphology and Dermal Absorption 1
Michael S. Roberts and Kenneth A. Walters
2. Animal Skin Morphology and Dermal Absorption 17
Nancy A. Monteiro-Riviere, Ronald E. Baynes, and Jim E. Riviere
PART I: SKIN BARRIER PROPERTIES AND ABSORPTION
3. The Physical Structure of the Skin Barrier 37

Lars Norle
´
n
4. Morphology of Epidermal Lipids 69
Jennifer R. Hill and Philip W. Wertz
5. Stratum Corneum as aBiosensor 79
Peter M. Elias, Kenneth R. Feingold, and Mitsuhiro Denda
6. Cutaneous Metabolism 89
Simon C. Wilkinson and Faith M. Williams
7. Formulation Issues 117
U. F. Schaefer,B.C.Lippold, and C. S. Leopold
PART II: MEASUREMENT OF SKIN ABSORPTION
8. Interpretation of In Vitro Skin Absorption Studies
of Lipophilic Chemicals 135
Robert L. Bronaugh
9. Use of Skin Equivalents for Dermal Absorption and Toxicity 141
Monika Scha
¨
fer-Korting and Sylvia Schreiber
vii
10. Skin Absorption as Studied by Spectroscopic Methods 161
Ulrike Gu
¨
nther,Siegfried Wartewig, Hendrik Metz, and
Reinhard H. H. Neubert
PART III: MODELING OF DERMAL ABSORPTION
AND RISK ASSESSMENT
11. Physiologically Based Pharmacokinetics and Pharmacodynamics
of Skin 179
Yuri Dancik, Owen G. Jepps, and Michael S. Roberts

12. Beyond Stratum Corneum 209
Yuri Dancik, Owen G. Jepps, and Michael S. Roberts
13. Biophysical Models for Skin Transport and Absorption 251
Johannes M. Nitsche and Gerald B. Kasting
14. Mathematical Models for Different Exposure Conditions 271
Yuri G. Anissimov
15. Modeling Skin Permeability in Risk Assessment 287
Dara Fitzpatrick, Darach Golden, and John Corish
16. In Vitro–In Vivo Correlations in Transdermal Drug Delivery 299
Jonathan Hadgraft and Majella E. Lane
17. Estimation of Subsequent Systemic Exposure—Physiological Models 309
James N. McDougal
18. RISKOFDERM: Predictions Based on In Vivo Factors 323
WimJ.A.Meuling, Johannes J. M. van de Sandt, and Joop J. van Hemmen
PART IV: SKIN TOXICITY AND PREVENTION
19. Quantitative Structure–Activity Relationships for Skin Corrosivity
and Sensitization 339
Mark T. D. Cronin, Steven J. Enoch, and Judith C. Madden
20. Allergic Contact Dermatitis 359
Haw-Yueh Thong and Howard I. Maibach
21. Irritancy of To pical Chemicals in Transdermal Drug
Delivery Systems 371
Heidi P. Chan, Cheryl Y. Levin, and Howard I. Maibach
22. Photosensitivity Induced by Exogenous Agents:
Phototoxicity and Photoallergy 391
Haw-Yueh Thong and Howard I. Maibach
Contentsviii
23. Systemic Toxicity Caused by Absorption of Drugs and Chemicals
Through Skin 405
Haw-Yueh Thong, Susi Freeman, and Howard I. Maibach

24. Solvent and Vehicle Effects on the Skin 433
Michael S. Roberts, Audrey Gierden, Jim E. Riviere, and Nancy A. Monteiro-Riviere
PART V: REGULATORY ISSUES
25. United States Environmental Protection Agency Perspectives on
Skin Absorption and Exposure 449
Michael Dellarco
26. Dermal Absorption of Chemicals: Some Australian
Regulatory Considerations 459
Utz Mueller,Andrew Bartholomaeus, and Mark Jenner
27. International Perspectives in Dermal Absorption 471
Janet Kielhorn and Stephanie Melching-Kollmuß
28. Structure–Activity Relationships and Prediction of Photoallergic
and Phototoxic Potential 483
Martin D. Barratt
29. Potential Regulatory Use of (Q)SARs to Develop Dermal Irritation
and Corrosion Assessment Strategies 495
Ingrid Gerner,Etje Hulzebos, Emiel Rorije, Betty Hakkert, John D. Walker,
Matthias Herzler,and Horst Spielmann
30. Development of (Q)SARs for Dermal Irritation and Corrosion
Assessment Using European Union New Chemicals Notification Data 507
Ingrid Gerner,Etje Hulzebos, Emiel Rorije, Matthias Herzler,Manfred Liebsch,
John D. Walker,and Horst Spielmann
31. Regulatory Assessment of Skin Sensitization 523
Winfried Steiling and Hans-Werner Vohr
32. Assessment of Topical Bioequivalence Using Microdialysis
and Other Techniques 537
Eva Benfeldt, Edward D. Bashaw,and Vinod P. Shah
33. An Industry Perspective of Topical Dermal Bioequivalence 549
Dawn McCleverty,Richard Lyons, and Brian Henry
PART VI: SPECIFIC EXAMPLES OF ABSORPTION

34. Dermal Absorption of Chemical Contaminants from Soil 563
John C. Kissel, Elizabeth W. Spalt, Jeffry H. Shirai, and Annette L. Bunge
Contents ix
35. Percutaneous Absorption of Pesticides 575
Jon R. Heylings and David J. Esdaile
36. Bathing Water: Percutaneous Absorption of Water Contaminants 593
Richard P. Moody
37. Percutaneous Absorption of Prodrugs and Soft Drugs 605
Kenneth B. Sloan and Scott C. Wasdo
38. Skin Penetration of Cosmetic Ingredients and Contaminants 623
Keith R. Brain and Kenneth A. Walters
39. Percutaneous Absorption of Hair Dyes 635
William E. Dressler
40. Dermal Absorption of Fragrance Materials 651
Keith R. Brain and Jon Lalko
Index 665
Contentsx
Contributors
Yuri G. Anissimov School of Biomolecular and Physical Sciences, Griffith
University,Nathan, Queensland, Australia
Martin D. Barratt Marlin Consultancy,Carlton, Bedford, U.K.
Andrew Bartholomaeus Drug Safety and Evaluation Branch, Therapeutic
Goods Administration, Woden, Australia
Edward D. Bashaw Division III, Office of Clinical Pharmacology,U.S. Food and
Drug Administration, Rockville, Maryland, U.S.A.
Ronald E. Baynes Center for Chemical Toxicology Research and
Pharmacokinetics, College of Veterinary Medicine, North Carolina State
University,Raleigh, North Carolina, U.S.A.
Eva Benfeldt Department of Dermatology,Gentofte Hospital, University
of Copenhagen, Hellerup, Denmark

Keith R. Brain An-eX Analytical Services, Ltd., and CardiffUniversity,
Cardiff,U.K.
Robert L. Bronaugh Office of Cosmetics and Colors, Food and Drug
Administration, College Park, Maryland, U.S.A.
Annette L. Bunge Department of Chemical Engineering, Colorado School
of Mines, Golden, Colorado, U.S.A.
Heidi P. Chan Department of Dermatology,School of Medicine,
University of California San Francisco, San Francisco, California, U.S.A.
John Corish School of Chemistry,Trinity College, University of Dublin,
Dublin, Ireland
Mark T. D. Cronin School of Pharmacy and Chemistry,Liverpool John
Moores University,Liverpool, U.K.
Yuri Dancik Department of Medicine, Princess Alexandra Hospital,
University of Queensland, Woolloongabba, Queensland, Australia
Michael Dellarco U.S. Environmental Protection Agency,National Center for
Environmental Assessment, Washington, D.C., U.S.A.
Mitsuhiro Denda Shiseido Research Center,Yokohama, Japan
William E. Dressler Independent Consultant, Huntington, Connecticut, U.S.A.
xi
Peter M. Elias Dermatology and Medical (Metabolism) Services,
Veterans Affairs Medical Center,and Departments of Dermatology and Medicine,
University of California, San Francisco, California, U.S.A.
Steven J. Enoch School of Pharmacy and Chemistry,Liverpool John Moores
University,Liverpool, U.K.
David J. Esdaile LAB International Research Centre, Szabadsa
´
gpuszta,
Veszpre
´
m, Hungary

Kenneth R. Feingold Dermatology and Medical (Metabolism) Services,
Veterans Affairs Medical Center,and Departments of Dermatology and Medicine,
University of California, San Francisco, California, U.S.A.
Dara Fitzpatrick Department of Chemistry,University College Cork,
Cork, Ireland
Susi Freeman Department of Dermatology,School of Medicine,
University of California San Francisco, San Francisco, California, U.S.A.
Ulrike Gu
¨
nther Institute of Pharmaceutics and Biopharmaceutics,
Martin Luther University of Halle-Wittenberg, Halle, Germany
Ingrid Gerner Weidenauer Weg, Berlin, Germany
Audrey Gierden Department of Medicine, Princess Alexandra Hospital,
University of Queensland, Woolloongabba, Queensland, Australia
Darach Golden Centre for High Performance Computing, Trinity College,
University of Dublin, Dublin, Ireland
Jonathan Hadgraft The School of Pharmacy,University of London,
London, U.K.
Betty Hakkert National Institute for Public Health and the Environment,
Expertise Centrefor Substances, Bilthoven, The Netherlands
Brian Henry Pfizer Global Research and Development, Sandwich, Kent, U.K.
Matthias Herzler Federal Institute for Risk Assessment,
Safety of Substances and Preparations, Thielallee, Berlin, Germany
Jon R. Heylings Research and Investigative Toxicology,Syngenta Central
Toxicology Laboratory,Macclesfield, Cheshire, U.K.
Jennifer R. Hill Dows Institute, University of Iowa, Iowa City,Iowa, U.S.A.
Etje Hulzebos National Institute for Public Health and the Environment,
Expertise Centrefor Substances, Bilthoven, The Netherlands
Mark Jenner Scitox Assessment Services, Kambah, Australia
Contributorsxii

Owen G. Jepps Department of Medicine, Princess Alexandra Hospital,
University of Queensland, Woolloongabba, Queensland, Australia
Gerald B. Kasting, James L. Winkle College of Pharmacy,University of
Cincinnati Academic Health Center,Cincinnati, Ohio, U.S.A.
Janet Kielhorn Fraunhofer Institute of Toxicology and Experimental Medicine,
Hannover,Germany
John C. Kissel Department of Environmental and Occupational Health Sciences,
University of Washington, Seattle, Washington, U.S.A.
Jon Lalko Research Institute for Fragrance Materials, WoodcliffLake,
New Jersey,U.S.A.
Majella E. Lane The School of Pharmacy,University of London, London, U.K.
C. S. Leopold Department of Pharmaceutical Technology,Institute of Pharmacy,
University of Hamburg, Hamburg, Germany
Cheryl Y. Levin Department of Dermatology,School of Medicine,
University of California San Francisco, San Francisco, California, U.S.A.
Manfred Liebsch Federal Institute for Risk Assessment, Centre for
Alternative Methods to Animal Experiments—ZEBET,Diedersdorfer Weg,
Berlin, Germany
B. C. Lippold Institute of Pharmaceutics and Biopharmaceutics, Heinrich
Heine University,Duesseldorf, Germany
Richard Lyons Pfizer Global Research and Development, Sandwich, Kent, U.K.
Judith C. Madden School of Pharmacy and Chemistry,Liverpool John
Moores University,Liverpool, U.K.
Howard I. Maibach Department of Dermatology,School of Medicine,
University of California San Francisco, San Francisco, California, U.S.A.
Dawn McCleverty Pfizer Global Research and Development, Sandwich,
Kent, U.K.
James N. McDougal Department of Pharmacology and Toxicology,
Boonschoft School of Medicine, Wright State University,Dayton, Ohio, U.S.A.
Stephanie Melching-Kollmuß Fraunhofer Institute of Toxicology and

Experimental Medicine, Hannover,Germany
Hendrik Metz Institute of Pharmaceutics and Biopharmaceutics, Martin Luther
University of Halle-Wittenberg, Halle, Germany
WimJ.A.Meuling Business Unit Biosciences, TNO Quality of Life, Zeist,
The Netherlands
Contributors xiii
Nancy A. Monteiro-Riviere Center for Chemical Toxicology Research and
Pharmacokinetics, College of Veterinary Medicine, North Carolina State University,
Raleigh, North Carolina, U.S.A.
Richard P. Moody Healthy Environments and Consumer Safety Branch,
Environmental Health Centre, Ottawa, Canada
Utz Mueller Food Standards Australia New Zealand, Canberra BC, Australia
Reinhard H. H. Neubert Institute of Pharmaceutics and Biopharmaceutics,
Martin Luther University of Halle-Wittenberg, Halle, Germany
Johannes M. Nitsche Department of Chemical and Biological Engineering,
University at Buffalo, State University of New York, Buffalo, New York, U.S.A.
Lars Norle
´
n Medical Nobel Institute, Department of Cellular and Molecular
Biology,Karolinska Institute, Stockholm, Sweden
Jim E. Riviere Center for Chemical Toxicology Research and Pharmacokinetics,
College of Veterinary Medicine, North CarolinaState University,Raleigh,
North Carolina, U.S.A.
Michael S. Roberts Department of Medicine, Princess Alexandra Hospital,
University of Queensland, Woolloongabba, Queensland, Australia
Emiel Rorije National Institute for Public Health and the Environment,
Expertise Centrefor Substances, Bilthoven, The Netherlands
Monika Scha
¨
fer-Korting Institut fu

¨
rPharmazie (Pharmakologie und
Toxikologie) der Freien Universita
¨
tBerlin, Berlin, Germany
U. F. Schaefer Biopharmaceutics and Pharmaceutical Technology,
Saarland University,Saarbruecken, Germany
Sylvia Schreiber Institut fu
¨
rPharmazie (Pharmakologie und Toxikologie)
der Freien Universita
¨
tBerlin, Berlin, Germany
Vinod P. Shah Pharmaceutical Consultant, North Potomac, Maryland, U.S.A.
Jeffry H. Shirai Department of Environmental and Occupational Health Sciences,
University of Washington, Seattle, Washington, U.S.A.
Kenneth B. Sloan Department of Medicinal Chemistry,University of Florida,
Gainesville, Florida, U.S.A.
Elizabeth W. Spalt Integral Consulting, Inc., Mercer Island, Washington, U.S.A.
Horst Spielmann Federal Institute for Risk Assessment, Centre for
Alternative Methods to Animal Experiments—ZEBET,Diedersdorfer Weg,
Berlin, Germany
Contributorsxiv