health and the environment from exposure to chemicals, through international peer review processes, as a prerequisite for the promotion of chemical safety,

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This report contains the collective views of an international group of experts and does not necessarily re present the decisions or the stated policy of the United Nations Environment Programme, the International Labour Organization or the World Health Organization. Environmental Health Criteria 235 DERMAL ABSORPTION First draft prepared by Drs Janet Kielhorn, Stephanie Melching- Kollmuß, and Inge Mangelsdorf, Fraunhofer Institute of Toxicology and Experimental Medicine, Hanover, Germany Published under the joint sponsorship of the United Nations Environment Programme, the International Labour Organization and the World Health Organization, and produced within the framework of the Inter-Organization Programme for the Sound Management of Chemicals.

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The International Programme on Chemical Safety (IPCS) , established in 1980, is a joint venture of the United Nations Environment Programme (UNEP), the International Labour Organization (ILO) and the World Health Organization (WHO). The overall objec- tives of the IPCS are to establish the scientific basis for assessment of the risk to human health and the environment from exposure to chemicals, through international peer review processes, as a prerequisite for the promotion of chemical safety, and to provide technical assistance in strengthening national capacities for the sound management of chemicals. The Inter-Organization Programme for the Sound Management of Chemicals (IOMC) was established in 1995 by UNEP, ILO, the Food and Agriculture Organization of the United Nations, WHO, the United Nations Industrial Development Organization, the United Nations Institute for Training and Research and the Organisation for Economic Co-operation and Development (Participating Organizations), following recommendations made by the 1992 UN Conference on Environment and Development to strengthen coop- eration and increase coordination in the field of chemical safety. The purpose of the IOMC is to promote coordination of the policies and activities pursued by the Participating Organizations, jointly or separately, to achieve the sound management of chemicals in relation to human health and the environment. WHO Library Cataloguing-in-Publication Data Dermal absorption. (Environmental health criteria ; 235) 1.Skin absorption. 2.Risk assessment. 3.Environmental exposure. I.World Health Organization. II.International Programme on Chemical Safety. III.Series. ISBN 92 4 157235 3 (NLM classification: WR 102) ISBN 978 92 4 157235 4 ISSN 0250-863X © World Health Organization 2006 All rights reserved. Publications of the World Health Organization can be obtained from WHO Press, World Health Organization, 20 Avenue Appia, 1211 Geneva 27, ). Requests for permission to reproduce or translate WHO publications – whether for sale or for noncommercial distribution – should be addressed to WHO Press, at the above address The designations employed and the presentation of the material in this publication do not imply the expression of any opinion whatsoever on the part of the World Health Organization concerning the legal status of any country, territory, city or area or of its authorities, or concerning the delimitation of its frontiers or boundaries. Dotted lines on maps represent approximate border lines for which there may not yet be full agreement. The mention of specific companies or of certain manufacturers’ products does not imply that they are endorsed or recommended by the World Health Organization in preference to others of a similar nature that are not mentioned. Errors and omissions excepted, the names of proprietary products are distinguished by initial capital letters. All reasonable precautions have been taken by the World Health Organization to verify the information contained in this publication. However, the published material is being distributed without warranty of any kind, either expressed or implied. The responsibility for the interpretation and use of the material lies with the reader. In no event shall the World Health Organization be liable for damages arising from its use. This document was technically and linguistically edited by Marla Sheffer, Ottawa, Canada, and printed by Wissenchaftliche Verlagsgesellschaft mbH, Stuttgart, Germany. Switzerland (tel.: +41 22 791 3264; fax: +41 22 791 4857; e-mail: +41 22 791 4806; e-mail:

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iiiCONTENTS ENVIRONMENTAL HEALTH CRITERIA FOR DERMAL ABSORPTION PREAMBLE x ACRONYMS AND ABBREVIATIONS xvii 1.SUMMARY 1 2.INTRODUCTION AND DEFINITIONS 6 2.1 Scope of the document 6 2.2 Definition of dermal absorption 8 2.3 Factors influencing dermal absorption 8 3.SKIN STRUCTURE AND FUNCTION 10 3.1 Functions of the skin 10 3.1.1 Barrier function 10 3.1.2 Temperature control 11 3.1.3 Defence and repair 11 3.2Skin structure 12 3.2.1 Epidermis 12 3.2.2 Dermis 16 3.2.3 Skin appendages 16 3.3The transport of chemicals through the skin 17 3.4Variability in skin permeability 17 3.4.1 Species 17 3.4.2 Age, sex, and race 18 3.4.3 Anatomical site 19 3.4.4 Skin condition 19 3.4.5 Temperature and blood flow rate 19 3.4.6 Hydration 20 3.5 Reservoir effects 20

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EHC 235: Dermal Absorption iv4.SKIN TRANSPORT MECHANISMS AND THEORETICAL CONCEPTS 23 4.1Transport through the skin 23 4.2Theoretical aspects of diffusion 23 4.3Physicochemical factors affecting skin permeation 26 4.3.1 Physical state 27 4.3.2 Molecular size/molecular weight 27 4.3.3 Maximum flux 28 4.3.4 Ionization 28 4.3.5 Binding properties 29 4.4Concepts of finite and infinite dose 29 5.METABOLISM IN THE SKIN 32 5.1The drug-metabolizing systems of the skin 33 5.2Methodology for evaluating skin metabolism in in vitro systems 35 5.3Effects of skin metabolism 35 5.4Importance of metabolism for percutaneous absorption 36 6.IN VITRO TESTS FOR DERMAL ABSORPTION 38 6.1Test guidelines 38 6.2Principles of the standard in vitro tests using skin samples 39 6.2.1 Test chambers 39 Static diffusion cells 40 Flow-through cells 40 Comparison of different in vitro cell systems 42 6.2.2 Finite/infinite dosing 43 6.2.3 Skin preparations 44 Choice of skin 44 Preparation of tissue samples 45 Checking of barrier integrity 46 6.2.4 Application of test substance 47 Test substance 47 Vehicle 48 Receptor fluid 48 Application dose levels 50

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v 6.2.5 Duration of exposure and sampling time 50 6.2.6 Evaluation of the results 50 Dermal absorption results after finite dosing 51 Dermal absorption results after infinite dosing 52 6.3 Other in vitro methods 52 6.3.1 Artificial skin 52 6.3.2 Tape-stripping technique in vitro 52 6.4 Examination of skin reservoir characteristics 53 6.5 Experimental factors affecting dermal absorption in vitro 54 6.5.1 Species differences 54 6.5.2 Temperature 55 6.5.3 Occlusion 56 6.5.4 Thickness of skin 56 6.5.5 Further observations on application vehicle effects 58 7.IN VIVO TESTS FOR DERMAL ABSORPTION 60 7.1Laboratory animal studies 60 7.1.1 Test guidelines for laboratory animal studies 61 7.1.2 Principles of the standard in vivo tests 61 Preparation of the application site 62 Dose levels 62 Application of the test substance to the skin 62 Duration of exposure 63 Sacrifice and time of termination 63 Evaluation of the results 64 7.2Studies with human volunteers 65 7.2.1 Assessment using plasma, excreta, and breath analysis 66 Methodology 66 Examples of in vivo human volunteer Biomonitoring of occupational exposure 67 7.2.2 Cutaneous microdialysis 68 7.2.3 Tape stripping 70 Contents studies 66

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EHC 235: Dermal Absorption vi 7.3 Other methods 73 7.3.1 Whole-body autoradiography 73 7.3.2 Skin biopsy 73 7.4 Factors affecting dermal absorption in vivo 74 7.4.1 Species, strain, and sex 74 7.4.2 Age 75 7.4.3 Anatomical site 75 7.4.4 Type of application and vehicle 77 7.4.5 Temperature and humidity conditions 78 8.COMPARATIVE STUDIES 79 8.1Comparison between in vitro and in vivo skin absorption results 79 8.2 Inter- and intralaboratory variation in in vitro percutaneous absorption methodology 84 9.DATA COLLECTIONS 86 9.1Data sets from homologous or closely related 9.2 Flynn data set 87 9.3 Expanded permeability coefficient data sets 88 9.4 EDETOX database 88 9.5 Maximum flux databases 89 10.ESTIMATION/PREDICTION OF DERMAL PENETRATION 90 10.1QSAR analysis 91 10.1.1 Prerequisites for QSPeR analysis 91 10.1.2 Historical overview 92 QSPeRs for skin permeability prior to the 1990s 92 The Flynn (1990) data set and subsequent analyses 93 Other data sets 97 10.1.3 Other approaches to QSPeR 97 10.1.4 Variability of data and its relevance for QSPeRs 98 10.1.5 Statistical analysis (linear vs non- linear) methods 98 molecules 86

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ixNOTE TO READERS OF THE CRITERIA MONOGRAPHS Every effort has been made to present information in the criteria monographs as accurately as possible without unduly delaying their publication. In the interest of all users of the Environmental Health Criteria monographs, readers are requested to communicate any errors that may have occurred to the Director of the International Programme on Chemical Safety, World Health Organization, Geneva, Switzerland, in order that they may be included in corri- genda.

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xEnvironmental Health Criteria PREAMBLE Objectives In 1973, the WHO Environmental Health Criteria Programme was initiated with the following objectives: (i) to assess information on the relationship between exposure to environmental pollutants and human health, and to provide guidelines for setting exposure limits; (ii) to identify new or potential pollutants; (iii) to identify gaps in knowledge concerning the health effects of pollutants; (iv) to promote the harmonization of toxicological and epidemio- logical methods in order to have internationally comparable results. The first Environmental Health Criteria (EHC) monograph, on mercury, was published in 1976, and since that time an ever- increasing number of assessments of chemicals and of physical effects have been produced. In addition, many EHC monographs have been devoted to evaluating to xicological methodology, e.g. for genetic, neurotoxic, teratogenic, and nephrotoxic effects. Other publications have been concerned w ith epidemiological guidelines, evaluation of short-term tests for carcinogens, biomarkers, effects on the elderly, and so forth. Since its inauguration, the EHC Programme has widened its scope, and the importance of environmental effects, in addition to health effects, has been increasingly emphasized in the total evaluation of chemicals. The original impetus for the Programme came from World Health Assembly resolutions and the recommendations of the 1972 UN Conference on the Human Environment. Subsequently, the work became an integral part of the International Programme on Chemical Safety (IPCS), a cooperative programme of WHO, ILO, and UNEP. In this manner, with the strong support of the new partners, the

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xiimportance of occupational health and environmental effects was fully recognized. The EHC monographs have become widely estab- lished, used, and recognized throughout the world. The recommendations of the 1992 UN Conference on Environ- ment and Development and the subsequent establishment of the Intergovernmental Forum on Chemical Safety with the priorities for action in the six programme areas of Chapter 19, Agenda 21, all lend further weight to the need for EHC assessments of the risks of chemicals. Scope Two different types of EHC documents are available: 1) on specific chemicals or groups of related chemicals; and 2) on risk assessment methodologies. The criteria monographs are intended to provide critical reviews on the effect on human health and the environment of chemicals and of combinations of chemicals and physical and biological agents and risk assessment methodologies. As such, they include and review studies that are of direct relevance for evaluations. However, they do not describe every study carried out. Worldwide data are used and are quoted from original studies, not from abstracts or reviews. Both published and unpublished reports are considered, and it is incumbent on the authors to assess all the articles cited in the references. Preference is always given to published data. Unpublished data are used only when relevant pub- lished data are absent or when they are pivotal to the risk assess- ment. A detailed policy statement is available that describes the procedures used for unpublished proprietary data so that this infor- mation can be used in the evaluation without compromising its confidential nature (WHO (1990) Revised Guidelines for the Prep- aration of Environmental Health Criteria Monographs. PCS/90.69, Geneva, World Health Organization). In the evaluation of human health risks, sound human data, whenever available, are preferred to animal data. Animal and in vitro studies provide support and are used mainly to supply evidence missing from human studies. It is mandatory that research on human subjects is conducted in full accord with ethical principles, including the provisions of the Helsinki Declaration. Preamble

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