ENVIRONMENTAL HEALTH CRITERIA FOR DERMAL ABSORPTION

1,64

MB

217

stron

3668

ID

World Health Organization

2006

rok

CONTENTS

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

3.2 Skin structure 12

3.2.1 Epidermis 12

3.2.2 Dermis 16

3.2.3 Skin appendages 16

3.3 The transport of chemicals through the skin 17

3.4 Variability 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

4. SKIN TRANSPORT MECHANISMS AND THEORETICAL CONCEPTS 23

4.1 Transport through the skin 23

4.2 Theoretical aspects of diffusion 23

4.3 Physicochemical 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

4.4 Concepts of finite and infinite dose 29

5. METABOLISM IN THE SKIN 32

5.1 The drug-metabolizing systems of the skin 33

5.2 Methodology for evaluating skin metabolism in in vitro systems 35

5.3 Effects of skin metabolism 35

5.4 Importance of metabolism for percutaneous absorption 36

6. IN VITRO TESTS FOR DERMAL ABSORPTION 38

6.1 Test guidelines 38

6.2 Principles of the standard in vitro tests using skin samples 39

6.2.1 Test chambers 39

6.2.1.1 Static diffusion cells 40

6.2.1.2 Flow-through cells 40

6.2.1.3 Comparison of different in vitro cell systems 42

6.2.2 Finite/infinite dosing 43

6.2.3 Skin preparations 44

6.2.3.1 Choice of skin 44

6.2.3.2 Preparation of tissue samples 45

6.2.3.3 Checking of barrier integrity 46

6.2.4 Application of test substance 47

6.2.4.1 Test substance 47

6.2.4.2 Vehicle 48

6.2.4.3 Receptor fluid 48

6.2.4.4 Application dose levels 50

6.2.5 Duration of exposure and sampling time 50

6.2.6 Evaluation of the results 50

6.2.6.1 Dermal absorption results after finite dosing 51

6.2.6.2 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

7.1 Laboratory animal studies 60

7.1.1 Test guidelines for laboratory animal studies 61

7.1.2 Principles of the standard in vivo tests 61

7.1.2.1 Preparation of the application site 62

7.1.2.2 Dose levels 62

7.1.2.3 Application of the test substance to the skin 62

7.1.2.4 Duration of exposure 63

7.1.2.5 Sacrifice and time of termination 63

7.1.2.6 Evaluation of the results 64

7.2 Studies with human volunteers 65

7.2.1 Assessment using plasma, excreta, and breath analysis 66

7.2.1.1 Methodology 66

7.2.1.2 Examples of in vivo human volunteer

7.2.1.3 Biomonitoring of occupational exposure 67

7.2.2 Cutaneous microdialysis 68

7.2.3 Tape stripping 70

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

8.1 Comparison 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

9.1 Data 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

10.1 QSAR analysis 91

10.1.1 Prerequisites for QSPeR analysis 91

10.1.2 Historical overview 92

10.1.2.1 QSPeRs for skin permeability prior to the 1990s 92

10.1.2.2 The Flynn (1990) data set and subsequent analyses 93

10.1.2.3 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 nonlinear) methods 98

10.1.6 Selection of chemicals for further tests on dermal penetration 98

10.1.7 Applicability domain for QSPeR 99

10.1.8 Maximum fluxes 99

10.1.9 Rules as an alternative to QSPeRs 100

10.2 Mathematical modelling 100

10.3 Mathematical pharmacokinetic models of percutaneous penetration 103

11. USE OF DERMAL PENETRATION STUDIES IN RISK ASSESSMENT 105

11.1 Decision-making process for setting dermal absorption values 106

11.1.1 Default values 107

11.1.2 Measured values 108

11.1.3 Values from mathematical skin permeation models (e.g. QSARs/QSPeRs) 110

11.2 Use of relative absorption values versus flux (and their derived permeability coefficients) 110

11.3 Other topics related to risk assessment 111

12. CONTROVERSIAL TOPICS IN THE ASSESSMENT OF DERMAL ABSORPTION 112

12.1

12.2 Reduction of intralaboratory/interlaboratory variation 112

12.3 Consequences of reservoir effect for risk assessment 113

12.4 Relevance of percutaneous measurements to data required by risk assessors: finite and

infinite exposures 114

12.5 Single- versus multiple-exposure regimes 114

12.6 Barrier integrity test for skin barrier function of human skin in skin penetration tests 115

12.7 Dermal absorption in susceptible populations 115

12.8 Skin notation 117

12.8.1 Skin notation criteria in different countries 118

12.8.2 Quantitative approaches 119

12.8.3 New approaches 120

12.9 Dermal absorption of nanoparticles 121

13. CONCLUSIONS AND RECOMMENDATIONS 124