United States Office of Health and EPA/600/8-91/011B Environmental Protection Environmental Assessment January 1992 Agency Washington, DC 20460 Interim Report Research and Development Dermal Exposure Assessment: Principles and Applications EPA/600/8 -91/OllB January 1992 Interim Report DERMAL EXPOSURE ASSESSMENT: PRINCIPLES AND APPLICATIONS Exposure Assessment Group Office of Health and Environmental Assessment U.S. Environmental Protection Agency Washington, D.C. 20460 DISCLAIMER This document is an interim report subject to review by the Science Advisory Board. Mention of trade names or commercial products does not constitute endorsement or recommendation for use. Tables . viii Figures . xii Foreword . xiii Preface, . ..xiv Authors and Reviewers . xv Acknowledgements . xviii Symbols . xvix 1. INTRODUCTION . 1-1 PART 1. PRINCIPLES OF DERMAL EXPOSURE ASSESSMENT . 2-1 2. MECHANISMS OF DERMAL ABSORPTION . ...2-1 2.1. STRUCTURE AND FUNCTION OF THE SKIN . 2-1 2.2. FATE OF COMPOUNDS APPLIED TO THE SKIN . 2-5 2.2.1. Transport Processes Occurring in the Skin . 2-5 2.2.2. Loss Processes Occurring in the Skin . .2-8 2.2.2.1. Evaporation from the surface of the Skin . 2-8 2.2.2.2. Binding of compounds in the Skin . 2-9 2.2.2.3. Metabolism . 2-10 2.3. FACTORS THAT INFLUENCE PERCUTANEOUS ABSORPTION . 2-13 2.3.1. Skin-Specific Factors . 2-13 2.3.1.1. Site of Application or Exposure . 2-13 2.3.1.2. Age of the Skin . 2-19 2.3.1.3. Skin Condition . 2-21 2.3.1.4. Hydration . 2-23 2.3.1.5. Circulation to the Skin . 2-23 2.3.1.6. Skin Temperature . 2-24 2.3.1.7. Miscellaneous Factors. 2-26 2.3.2. Compound-Specific Factors . 2-26 2.3.2.1. Partition Coefficients. 2-26 2.3.2.2. Polarity . 2-28 2.3.2.3. Chemical Structure . 2-30 2.3.2.4. Volatility . 2-31 2.3.2.5. Compound Concentration . 2-32 2.4. SUMMARY AND CONCLUSIONS. 2-33 2.4.1. Structure . 2-34 . 111 CONTENTS (continued) Page 2.4.2. Fate . 2-34 2.4.3. Factors . 2-35 3. TECHNIQUES FOR MEASURING DERMAL ABSORPTION . 3-1 3.1. IN VIVO STUDIES . 3-3 3.1.1. Quantification of Radioactivity, Parent Compound, or Metabolize Levels in Excreta (Indirect Method) . 3-4 3.1.2. Quantitation of Radioactivity, Parent Compound, or Metabolize Levels in Excreta, Air, and Tissues (Direct Method) . 3-5 3.1.3. Quantification of Parent Compound or Metabolize in Blood, Plasma, or Tissues . 3-5 3.1.4. Quantification of the Disappearance of the Compound from the Surface of the Skin or from the Donor Solution . 3-6 3.1.5. Measurement of a Biological Response . 3-7 3.1.6. Stripping Method . 3-8 3.2. IN VITRO TECHNIQUES . 3-9 3.2.1. Diffusion Cells . 3-10 3.2.2. Isolated Perfused Tubed-Skin Preparation . 3-17 3.2.3. Stratum Corneum Binding Technique . 3-18 3.3. COMPARISON OF IN VITRO AND IN VIVO PERCUTANEOUS ABSORPTION VALUES . 3-19 3.4. INTERSPECIES COMPARISON OF PERCUTANEOUS ABSORPTION VALUES 3-21 3.5. SUMMARY, CONCLUSIONS, AND RESEARCH RECOMMENDATIONS . 3-26 4. MATHEMATICAL DESCRIPTION OF DEMAL ABSORPTION . 4-1 4.1. THEORETICAL BASIS OF KP AND Jss VALUES . 4-3 4.2. DERMAL (PERCUTANEOUS) ABSORPTION RATE EQUATION PARAMETERS . ...4-5 4.2.1. Partition Coefficient . ...4-5 4.2.2. Pathlength of Chemical Diffusion. ..4-9 4.2.3. Diffusion Coefficient . 4-10 4.2.4. Concentration Gradient . 4-11 4.3. EVALUATION OF PERMEABILITY COEFFICIENTS KP,S FROM EXPERIMENTAL STUDIES . 4-12 4.3.1. In Vitro Approaches . 4-12 4.3.2. In Vivo Approaches . 4-15 4.4. DEFINITIONS OF PERMEABILITY COEFFICIENTS WHEN THE MEDIUM IS NOT WATER . 4-17 4.4.1. Nonaqueous Solvent . 4-18 4.4.2. Pure Liquid . 4-19 4.4.3. Vapor Phase . 4-19 4.4.4. Soil . 4-20 iv CONTENTS (continued) 4.5. THE VALUE OF THE LIMITING KP,S FOR CHEMICALS OF HIGH LIPOPHILICITY . 4-20 4.6. ESTIMATION OF ABSORBED DOSE.. 4-22 5. DERMAL ABSORPTION OF COMPOUNDS FROM WATER . 5-1 5.1. EXPERIMENTALLY DERIVED KP VALUES. ...5-1 5.1.1. Strategy for Reviewing Experimental Data . 5-1 5.1.2. Recommended KP Values . ...5-8 5.2. METHODS FOR PREDICTING PERMEABILITY COEFFICIENT OF AQUEOUS CONTAMINANTS . 5-11 5.2.1. Empirical Correlations . 5-11 5.2.2. Theoretical Skin Permeation Models.. 5-21 5.2.2.1. Scheuplein Laminate Model with Parallel Follicular Pathway . 5-33 5.2.2.2. Michaels’ Two-Phase Model for Stratum Corneum . 5-33 5.2.2 .3. Two Parallel Pathway Model . 5-34 5.2.2 .4. Albery and Hadgraft Model. 5-34 5.2.2.5. Kasting, Smith, and Cooper Model . 5-35 5.2.3. Statistical Algorithms for K P Based on Literature Data . ...5-38 5.2.4. Conclusions for How to Predict KP values . .5-37 5.3. ESTIMATING THE DERMALLY ABSORBED DOSE PER EVENT . 5-47 5.3.1. Estimating DAevent for Inorganics . 5-48 5.3.2 Estimating DAevent for Organics . 5-49 APPENDIX: SUMMARY OF COMPOUND-SPECIFIC KP DATA . 5-65 6. DERMAL ABSORPTION OF COMPOUNDS FROM SOIL . 6-1 6.1. FACTORS AFFECTING THE DERMAL (PERCUTANEOUS) ABSORPTION OF COMPOUNDS FROM SOIL . ...6-2 6.2. USING EXPERIMENTALLY DERIVED VALUES . .6-9. 6.2.1. 2,3,7,8-Tetrachlorodibenzo- p -dioxin (TCDD) . 6-11 6.2.1.1. Experimental Results . 6-11 6.2.1.2. Analysis of Data . 6-18 6.2.2. 3,3',4,4’-Tetrachlorobiphenyl (TCB) . 6-19 6.2.2.1. Experimental Results . 6-20 6.2.2.2. Analysis of Data . 6-21 6.2.3. 6.2.3. Benzo[a]Pyrene (BaP) . 6-22 6.2.3.1. Experimental Results . 6-23 6.2.3 .2. Analysis of Data . ..