arbete och hälsa | vetenskaplig skriftserie

isbn 978-91-85971-02-2 issn 0346-7821

nr 2008;42:2

Basis for skin notation. Part 1.Dermal penetration data for substances

on the Swedish OEL listGunnar Johanson, Matias Rauma

Arbete och Hälsa

Arbete och Hälsa (Work and Health) is a scien-tific report series published by Occupational and Environmental Medicine, Sahlgrenska Academy, Göteborg University. The series publishes scientific original work, review articles, criteria documents and dissertations. All articles are peer-reviewed.Arbete och Hälsa has a broad target group and welcomes articles in different areas. Instructions and templates for manuscript editing are available at http://www.amm/se/aohSummaries in Swedish and English as well as the complete originial text as from 1997 are also available online.

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© Göteborg University & authors 2008

Arbete och Hälsa, Göteborg University, S-405 30 Göteborg, Sweden

ISBN 978-91-85971-02-2ISSN 0346–7821 http://www.amm.se/aohPrinted at Elanders Gotab, Stockholm

Editorial Board: Tor Aasen, BergenBerit Bakke, OsloLars Barregård, GöteborgJens Peter Bonde, ÅrhusJörgen Eklund, LinköpingMats Eklöf, GöteborgMats Hagberg, GöteborgKari Heldal, OsloKristina Jakobsson, LundMalin Josephson, UppsalaBengt Järvholm, UmeåAnette Kærgaard, HerningAnn Kryger, KöpenhamnSvend Erik Mathiassen, GävleSigurd Mikkelsen, GlostrupGunnar D. Nielsen, KöpenhamnCatarina Nordander, LundKarin Ringsberg, GöteborgTorben Sigsgaard, ÅrhusStaffan Skerfving, LundKristin Svendsen, TrondheimGerd Sällsten, GöteborgAllan Toomingas, StockholmEwa Wikström, GöteborgEva Vingård, Uppsala

Preface

Skin notations are used by many organizations and in many countries including Sweden. Thus, substances that may easily be absorbed percutaneously are marked with an “H” in the Swedish provisions on occupational exposure limits (OELs) (AFS 2005). This procedure started already with the first list of OELs introduced in 1974. OELs are given for 368 substances or substance groups in the present provisions (AFS 2005). Out of these, 101 substances/groups (27%) have a skin notation.

No formal or quantitative criteria have been developed in Sweden. The intent was originally that the skin notation would give a qualitative indication of possible dermal absorption of the chemical at work. In other words, the attempt was mainly to evaluate the ability of penetration through intact “healthy” skin, i.e. the intrinsic properties of the chemical relative to skin.

In an international perspective the criteria for assigning a skin notation vary widely but are generally qualitative rather than quantitative in nature. During the last few years, however, focus has shifted towards more quantitative assessments, either by expressing the intrinsic properties of the chemical in numerical terms, such as dermal absorption rate (flux) at defined conditions or by expressing the systemic exposure (absorbed dose), i.e. a combination of the intrinsic properties and the exposure conditions (exposed skin area, exposure duration etc).

In view of the large and increasing numbers of H-labeled substances, there is a need for more formal criteria. There is also a risk that the warning effect of the label is diminished if too many substances are labeled.

In view of these concerns, the Swedish Work Environment Authority (SWEA) has initiated a project with the aim to develop new criteria and procedures for skin notation. As input for the project, SWEA requested the Division of Work Environment Toxicology at the Institute for Environmental Medicine, Karolinska Institutet to produce two reports on dermal absorption in relation to skin notations and OELs.

The aim of the first report, presented herein, is to describe methods used to measure dermal absorption and to compile and evaluate published quantitative data on dermal absorption focusing on substances listed in the ordinance on Swedish OELs (AFS 2005). The second report will address different approaches to skin notation.

Literature searches, compilations and writing of the report were carried out by MSc Matias Rauma and professor Gunnar Johanson at the Division of Work Environment Toxicology. The final literature search was performed in January 2007. The cited papers were to a large extent supplied by the library at the Swedish National Institute for Working Life.

The major sources used were:

- Medline,

- the EDETOX database on the web (www.ncl.ac.uk/edetox/),

- consensus reports and criteria documents (and publications cited therein) published by the Swedish Criteria Group for Occupational Standards at the National Institute for Working Life,

- criteria documents (and publications cited therein) published by the Nordic Expert Group for Criteria Documentation of Health Risks from Chemicals (NEG),

- the documentation (and publications cited therein) published by the Chemical Substance - Threshold Limit Values (CS-TLV) Committee of the American Conference of Industrial Governmental Hygienists (ACGIH), and

- secondary sources, i.e. references given in the above sources. We wish to express our gratitude to associate professor Anders Boman (Occupational and Environmental Dermatology, Karolinska Institutet, Stockholm), professor Magnus Lindberg (Dermatology Unit, Örebro University Hospital), associate professor Pierre-Olivier Droz (Institute of Occupational Health, Lausanne), Dr. Karin Sørig Hougaard (National Research Centre for the Working Environment, Copenhagen) and associate professor Margareta Warholm (SWEA, Solna) for valuable comments on the manuscript. We are also grateful to MSc Tina Isaksson for compilation of some of the data. The investigation was financially supported by the Swedish Work Environment Authority.

Stockholm July 2007

Gunnar Johanson Matias Rauma

Contents

1. Introduction 1 2. Anatomy of the skin 2 3. Skin as a diffusion barrier 4 4. Fick’s law of diffusion 6 5. Factors affecting dermal penetration 7 Concentration 7 Properties of the chemical 8 Properties of the skin 8 Summary 11 6. Assessment of dermal penetration 12 In vivo tests 12 In vitro tests 13 Structure-activity based methods 15 7. Dermal penetration data for substances on the Swedish OEL list 17 Approach 17 Conclusions 19 8. Summary 31 9. References 32 Appendices A. Tabular data for individual substances A1-A181 B. References to individual substances Octanol:water partition coefficients B1 Other physical properties B1-B2 Scientific bases B2 Other physical properties B3 - B16

1

1. Introduction

The aim of this report is to review the published data on dermal penetration of workplace chemicals, as a basis for assignment of skin notations.

Dermal exposure is a major route of systemic exposure at work. Along with reductions in OELs and occupational exposure via air, the dermal route has become even more important.

Data on dermal absorption are input for so called skin notations. Skin notations are used as warning signals for chemicals that may easily be taken up via the skin, thereby causing - or increasing the risk of - systemic toxicity (see e.g. AFS 2005, SCOEL 1999). The decision to assign a skin notation is largely based on the ability of the chemical to penetrate skin. Sometimes experience from work practice is also considered, so that chemicals for which health effects have been seen at work after (presumed) dermal exposure are also assigned with a skin notation. Direct effects on the skin, such as irritation, corrosion and sensitization, are usually not considered.

The criteria for skin notations and their practical application are beyond the scope of the present report but will be described and discussed in a second report. Nevertheless, it should be mentioned that the relations between the presence of a chemical in the work environment and dermal dose, as well as that between dermal dose and systemic dose is very complex and highly variable. Thus, the first relationship is affected by a number of factors, such as the volatility and other properties of the chemical, how the chemical is used, the work process, the individual’s behavior and work practices, type of clothing and protective equipment, and so on. The influence of some of these factors may be highly variable and is often difficult to predict. The second relationship (and the focus of this report) depends on the properties of the chemical and the skin and is, at least in principle, more easily described and measured.

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2. Anatomy of the skin

The skin provides a barrier between the human body and its environment. The major function is to prevent loss of water and heat to the environment. It also protects the body from mechanical, biological and chemical hazards.

The skin is the largest organ of the human body (15% of total adult body weight). The skin consists of three layers (from inside to outside): hypodermis, dermis, epidermis (figure 1). The hypodermis (subcutis) is the deepest part of the skin and contains mainly adipose tissue. The subcutaneous layer is important for protection from mechanical injuries, energy provision, thermoregulation and insulation.

Hair

Nerve

Capillaries

Epidermis

Dermis

Hypodermis

Sebaceousgland

Muscle

Sweatgland

VenuleArteriole

Hair

Nerve

Capillaries

Epidermis

Dermis

Hypodermis

Sebaceousgland

Muscle

Sweatgland

VenuleArteriole

Figure 1. Drawing of the skin (adapted from http://www.nku.edu/~dempseyd/SKIN.htm). The dermis contains connective tissue and provides elasticity, flexibility, strength and stability to the skin. The main cells are fibroblasts (synthesizing the collagen fibres), dermal dendrocytes and mast cells (belonging to the immune system). The dermis is in close contact with the abundant ridges and grooves of the epidermis. The ridges are enlarging the surface area between dermis and epidermis, allowing for a better adhesion and a more efficient exchange of nutrients and waste.

Both the dermis and hypodermis are richly innervated and vascularized. The skin appendages (hair, nails, sweat glands, sebaceous glands) originate in these parts of the skin, mostly in the dermis.

The epidermal layer consists mainly of keratinocytes (90-95%), Langerhan’s cells (skin immune response), melanocytes (skin color and UV protection) and Merkel cells (slow-adapting mechanoreceptors for touch). The keratinocytes are constantly being replaced. The shape of the cells changes during their migration from the innermost part of the epidermis towards the surface of the skin (figure 2).

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Based on the appearance in the microscope, the epidermis is subdivided in five different layers (from inside to outside): stratum basale, stratum spinosum, stratum granulosum, stratum lucidum and stratum corneum (figure 3).

Cells flatten as they migrate toward the surface

Stratum basale with dividing stem cells

Stratum corneum, with dead keratinized cells at surface

Cells flatten as they migrate toward the surface

Stratum basale with dividing stem cells

Stratum corneum, with dead keratinized cells at surface

Figure 2. The maintenance of the epidermis (adapted from http://www.mhhe.com/biosci/ap /histology_mh/stratepi.html).

The stratum corneum consists of several layers of completely keratinized dead cells without a nucleus (corneocytes). The cells are stacked, leaving little space between them. Keratin is a tough, insoluble protein that is also the chief structural constituent of hair, nails, and hooves. Thus, the stratum corneum mainly consists of keratin and highly resistant to diffusion of water and other molecules (figure 3).

Thick skin has many layers of corneocytes cemented together. Thin skin has fewer layers of living and dead cells but the same overall structure.

Stratum corneum, 10-30 cell layers

Stratum lucidum, 1 cell layerStratum granulosum, 2-3 cell layers

Stratum spinosum, 2-7 cell layers

Basal membrane

Stratum basale, 1-2 cell layers

Dermis

Stratum corneum, 10-30 cell layers

Stratum lucidum, 1 cell layerStratum granulosum, 2-3 cell layers

Stratum spinosum, 2-7 cell layers

Basal membrane

Stratum basale, 1-2 cell layers

Dermis

Figure 3. The five layers of the epidermis (adapted from Forslind & Lindberg 2004).

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3. Skin as a diffusion barrier

A major function of the skin is to prevent loss of water to the environment. The humidity in the ambient air is often low and without an effective barrier the organism would rapidly loose large amounts of water. This would preclude life on land.

The major diffusion barrier is the stratum corneum. However, this skin layer is not entirely impermeable. Water as well as other small molecules diffuse more or less slowly through the skin. Water is very important to maintain the flexibility of the skin. Dry skin becomes rough and flaky and completely dried stratum corneum is reduced to a very brittle, thin sheet. Water is also important for thermoregulation, as the heat used to evaporate the water excreted via sweat glands lowers the temperature of the skin.

In principle, there are three possible diffusion pathways through the skin. The major route, especially for fat soluble, nonpolar molecules, is likely to be the intercellular lipid pathway. Due to the brick and mortar structure (figure 4), the “true” diffusion path is very much longer than the thickness of the stratum corneum. The diffusional pathlength has been estimated to be as long as 500 µm for stratum corneum of 20 µm thickness (Hadgraft 2004). Further, since impermeable corneocytes make up most of the skin and intercellular lipids constitute only a small part, the area accessible for diffusion is very small compared to the total skin area. Another factor that complicates diffusion is that the intercellular spaces contain structured lipids and a diffusing molecule has to cross a variety of lipophilic and hydrophilic domains.

Corneocytes

Intercellular lipids

Diffusion pathway

Corneocytes

Intercellular lipids

Diffusion pathway

Figure 4. Brick and mortar structure of the stratum corneum showing dense, keratinized corneocytes, intercellular lipid layers and one of the diffusion pathways.

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The second possibility is that of transcellular permeation, i.e. that the molecules diffuse through the corneocytes.

A third route of absorption is through the appendages (hair follicles). In most cases, this route is insignificant as the area of appendages is very small compared to the total skin area. However, in the initial phase of the absorption and for very slowly permeating chemicals, this route may be of importance.

The structure of the skin and the stratum corneum contrasts that of the lungs and the respiratory airways. Thus, whereas the skin is designed to resist diffusion (and loss of water) the lungs are built to facilitate diffusion (uptake of oxygen and release of carbon dioxide). In the skin, this is manifested by:

- a relatively small surface area (approximately 2 m2 in a human adult), and

- a stratum corneum consisting of several densely packed layers of cells filled with highly resistant protein (keratin), resulting in high resistance long diffusion pathways (figures 2-4).

In contrast, the alveolae in the lungs have:

- a relatively large surface area (approximately 80 m2 in a human adult), and

- only two thin cell layers (alveolar epithelium and capillary endothelium), resulting in a low resistance, short diffusion distance from ambient air to blood (figure 5).

Figure 5. Transmission electron micrograph of the lung showing as: the alveolar airspace and c: the capillary lumen, separated by two thin cell layers with a total thickness of about 1 µm (taken from http://www.cf.ac.uk/phrmy/PCB/PageLungAlveolarepithelium.htm).

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4. Fick’s law of diffusion

The driving force for dermal absorption of practically all chemicals is diffusion, i.e. the spontaneous movement of molecules. The flux of molecules from the outer side to the inner side of a barrier (for example the skin) is proportional to the number of molecules at the outer side and the resistance of the barrier. Likewise, the flux from the inner to the outer side is proportional to the number of molecules at the inner side and the resistance of the barrier. The net flux is the difference between the two fluxes and can be described mathematically as: P = Kp x ( A1 – A2 ) (1)

Equation 1 is known as Fick’s first law of diffusion. The parameter P is the net flux (number of molecules per time unit) and Kp is the permeability coefficient (resistance to diffusion). A1 and A2 the number of freely moving molecules outside and inside the barrier, respectively. Chemical activity is a measure of how different molecules in a non-ideal gas or solution interact with each other. For very dilute gases and solutions, molecular interactions are negligible and activity is also proportional to concentration. For gases, activity is proportional to partial pressure. A can thus be substituted by thermodynamic activity, partial pressure or, for dilute solutions, concentration. Such substitution will only alter the value of Kp, as these parameters are directly proportional to the number of molecules.

In most cases with dermal exposure to chemicals, the concentration at the inner side (in the body) is negligible compared to the outer side (skin surface) and may be approximated to zero. In this case, the flux depends only on the Kp and the concentration at the outer skin surface.

Obviously, the value of, Kp depends on the properties of both the skin and the chemical. Further, the numerical value and units of Kp depend on the units chosen for P and A. It is common to express Kp in cm/h, from which follows that suitable units for P are µmol/h/cm2 or mg/h/cm2. A is then expressed as µmol/cm3 (mM) or mg/cm3.

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5. Factors affecting dermal penetration

In this report the term dermal penetration is used for the amount of chemical that passes through the skin and reaches the systemic circulation. A synonymous term is percutaneous absorption. These two terms are different from dermal absorption which denotes the amount of chemical that has entered the skin from the outer environment. The dermally absorbed chemical may stay in the skin, diffuse back to the outer environment, be metabolized or pass on to the inner environment (penetration). If excess chemical is applied on the skin for a sufficiently long time (so that a steady-state is reached) and if metabolism in the skin is negligible, penetration equals absorption.

From equation 1 in Chapter 4 follows that the unit penetration rate (flux) across the skin is directly proportional to:

- the concentration (activity, partial pressure) of the chemical at the skin surface (provided that the inner concentration is negligible) of the chemical, and

- the permeability of the skin (expressed by Kp).

The permeability depends on the properties of the chemical as well as the properties of the skin. The total penetration is proportional to (in addition to concentration and permeability):

- the exposed area (since Kp is expressed per area unit), and

- the duration of exposure.

5.1 Concentration

Other factors held constant, the flux is always proportional to chemical activity (figure 6, left), the slope is determined by the permeability coefficient (Kp). At high concentrations, e.g. when the skin is exposed to neat chemical, the molecules begin to interact so that the concentration is no longer proportional to the number of freely moving “particles”. Hence, the relation between flux and concentration becomes sublinear at high concentrations (figure 6, right). In conclusion, dermal absorption rates cannot easily be translated from one concentration to the other and experimentally determined values for Kp are concentration-dependent.

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Conc. gradient

Der

mal

abs

. rat

e

Activity gradient (A1-A2)

Der

mal

abs

. rat

e

Figure 6. According to Fick’s first law of diffusion (see also Chapter 4), the dermal absorption rate is proportional to the activity gradient (A1-A2) over the skin. The rate is further proportional to the concentration gradient for diluted, but not concentrated, chemicals.

5.2 Properties of the chemical

Molecular size and solubility are the major physical properties that determine the diffusion coefficient. Small molecules diffuse more easily through the skin than big molecules. Further, substances such as many organic solvents that easily dissolve in nonpolar (lipids) as well as polar (water) media, diffuse more easily through the skin. Conversely, substances that are either ionized, highly lipophobic or highly hydrophobic exhibit low skin permeability.

5.3 Properties of the skin

A thicker keratin layer of the stratum corneum will make the diffusion path length longer and, hence, the permeability lower (=higher resistance). Roughly, the Kp is inversely proportional to the thickness of the stratum corneum. The number of cell layers as well as the thickness varies widely between different parts of the body. At the extreme ends are the genitals with as little as 6 and the heels with as much as 86 cell layers (table 1).

9

Table 1. Number of stratum corneum cell layers at different locations (from Ya-Xian, Suetake et al. 1999).

Location Number of cell layers (mean±sd)

Genital 6±2 Ear 7±2 Eyelid 8±2 Face 9±2 Lip 10 Scalp 12±2 Trunk 13±4 Extremities 15±4 Dorsum of hand 25±11 Dorsum of foot 30±6 Palm 50±10 Sole 55±14 Heel 86±36

The palms and soles, and especially the heels, have the thickest stratum corneum of as much as 1.5 mm, whereas that of the eyelids is as little as 0.05 mm. Densely furred species such as rats and mice have a much thinner skin than hairless species, such as humans and pigs. This difference includes the stratum corneum, as well as the epidermis (figure 7).

0

10

20

30

40

50

60

Cat

Cow Dog

Hor

se

Hum

an

Mon

key

Mou

se Pig

Rab

bit

Rat

Thic

knes

s (µ

m)

0

1

2

3

4

5

No.

of e

pide

rmal

cel

l laye

rs

Stratum corneum thicknessEpidermal thicknessEpidermal cell layers

Figure 7. Thickness of stratum corneum and epidermis. The figure is based on measurements of the skin over the shoulder (animal data from Monteiro-Riviere, Bristol et al. 1990, human data from Sandby-Möller, Poulsen et al. 2003).

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The stratum corneum is optimized to provide minimum permeability (maximum resistance) at “normal” conditions. Various conditions and factors may affect the structure of the stratum corneum, thereby increasing permeability. These conditions include skin damage caused, e.g. by disease, detergents or ultraviolet radiation, as well as temperature and humidity.

There is little data on the influence of skin lesions on dermal penetration in exposed human populations. A recent case report on four workers with different skin status (healthy, erythematous and burned skin and dishydrotic eczema) envolved in exposed to ortho-toluidine during rubber vulcanisation suggests that the absorption of o-toluidine is 1.5- to 2-fold higher through damaged than through healthy skin (Korinth, Weiss et al. 2006). In a follow-up study with 51 workers occupationally exposed to aniline and o-toluidine, the hemoglobin-aromatic amine-adduct levels in workers with erythema were on average 73% higher than in workers with healthy skin (Korinth, Weiss et al. 2007).

Similar results have been obtained in animal experiments. The permeation of hydrocortisone was studied in vitro using skin from a monkey diagnosed as having eczematous dermatitis. The permeation was approximately twice as high in eczematous skin, as compared to unaffected skin from the same individual. The absorption of another anti-inflammatory steroid, triamcinolone acetonide, was also enhanced through the eczematous skin (Bronaugh, Weingarten et al. 1986).

Soap washing and dermal exposure to solvents causes extraction of stratum corneum lipids, and increased permeability. Thus, for example, experimental 3-h treatment of human skin in vitro with 0.1% or 0.3% sodium lauryl sulphate caused an impaired barrier function as indicated by up to three-fold increases in the penetration of tritiated water and various pesticides (Nielsen 2005). In hairless mice topically treated with acetone, the permeation of hydrophilic substances (sucrose, caffeine, hydrocortisone) increased through stratum corneum as well as whole skin in vitro. In contrast, the permeation of lipophilic substances (propegesterone, estradiol) increased through stratum corneum but not whole skin (Tsai, Sheu et al. 2001).

Considering ultraviolet radiation, the permeation methanol and ethanol nearly tripled through UVA-treated as compared to untreated human human epidermis. In contrast, the permeation of higher, more lipophilic primary alcohols (propanol, butanol, hexanol, and heptanol) was not significantly altered (McAuliffe & Blank 1991).

Increased skin temperature increases the kinetic energy, .i.e. the movements, of the molecules, thereby affecting the lipid structure in the stratum corneum. Also, skin humidity increases as a result of sweating. All these factors may increase the dermal penetration. Johanson and Boman (1991) demonstrated that the percutaneous absorption of 2-butoxyethanol vapour was slightly increased at 33ºC ambient air temperature and 71% relative humidity, as compared to 23ºC and 29% relative humidity. In vitro experiments with freshly prepared human skin showed that the permeability coefficient of benzene in water nearly doubled at 50ºC and decreased slightly at 15ºC, as compared to 26ºC (Nakai, Chu et al. 1997).

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5.4 Summary

The permeability of a given piece of skin for a specific substance is reflected by the permeability coefficient. The permeability coefficient is mainly determined by the:

- properties of the chemical,

- properties of the vehicles (if present),

- thickness of the keratin layer in stratum corneum,

- condition of the skin, e.g. skin damage.

The thickness of stratum corneum varies widely between species and between different parts of the body. The condition of the skin varies with, e.g. the temperature and the degree of hydration of the skin.

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6. Assessment of dermal penetration

In principle, studies of dermal absorption measures the diffusion of the test substance from a test preparation placed on the skin through the stratum corneum and into the skin. The methods can be divided into two categories: in vivo and in vitro.

6.1 In vivo tests

The rat is the most commonly used species for in vivo testing. However, a wide variety of other species and strains are being used, including (hairless) rats, humans, monkeys, dogs, pigs, mini pigs, (hairless) guinea pigs, and (hairless) mice.

In vivo studies in laboratory animals are preferably conducted as described by OECD (2004). In brief, the exposed area, ideally about 10 cm2 in rats, should be defined by a device that is attached to the skin surface. The test sample is applied to the surface of skin and allowed to remain for a specified period of time, relevant to human exposure. At the end of the exposure period excess sample is removed. During the study, animals are housed individually in metabolism cages from which excreta are collected. If measurable volatile metabolites (such as radiolabelled carbon dioxide) are expected, exhaled breath is also collected. At the end of the study, the removable remains of the dose are washed from the skin surface. The animals are then killed and the amount of parent chemical and metabolites in skin, carcass and excreta is determined. These data allow for an estimate of the total recovery of the test substance.

Test chemical remaining in the skin after wash-off will disappear over time by four pathways, by diffusion into the environment, by desquamation (shedding of the outer layers of the skin), by ingestion when the animal grooms itself, and by diffusion into the systemic circulation. To avoid overestimation of the systemically absorbed dose, measures have to be taken to prevent grooming of the site of application, and to prevent desquamated skin from falling into the urine and fecal collection systems.

The skin absorption of the test substance can be expressed as the percentage of dose absorbed per unit time or, preferably, as an average absorption rate per unit area of skin, e.g. μg/cm2/h.

By necessity, in vivo studies in humans must use a different experimental protocol, as the total recovery cannot be directly determined. The dermal dose is thus determined indirectly, by comparison to a known dose, for instance the net uptake by inhalation exposure (Dinhaled), where the bioavailability is known to be 100%. The dermal uptake, or rather, the systemic dose via the dermal route (Ddermal), may then be calculated for example by comparing the urinary recoveries of the chemical or its metabolite(s) (R). Alternatively, since the area under of the

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concentration-time curve (AUC) in e.g. plasma or blood is proportional to dose, dermal uptake may be obtained by comparing the two AUCs. Thus:

inhaled

dermalinhaleddermal

inhaled

inhaled

dermal

dermal

RRD

DRD

RD ⋅

=⇒= (2)

or

inhaled

dermalinhaleddermal

inhaled

inhaled

dermal

dermal

AUCAUCD

DAUC

DAUC

D ⋅=⇒= (3)

For examples of this approach, see e.g. studies by Johanson and colleagues (Johanson & Boman 1991, Johanson, Boman et al. 1988, Johanson & Fernström 1986, 1988). A different approach to measure dermal absorption is that of microdialysis. A small probe equipped with a semi permeable hollow fiber is inserted superficially into the dermis, parallel to the skin surface. A physiological solution is slowly pumped through the fiber, allowing the solutes of interest to equilibrate with the surrounding extracellular space. For overviews, see e.g. Anderson (2006), Schnetz & Fartasch (2001) or Stahl, Bouwet et al. (2002).

Human pharmacokinetic microdialysis has only been carried out for two decades and there is limited data, mainly on pharmaceutical drugs, on dermal absorption using this technique. There are several difficulties in obtaining quantitative measures, maybe the major one being that concentration and not flux is measured. The concentration will depend not only on influx via stratum corneum but also on outflux via the blood stream. Other related difficulties reside in determining the position of the probe (since the concentration decreases with distance from the skin surface) and in defining the exposed skin area.

6.2 In vitro tests

Skin from many mammalian species, including humans, as well as non-mammalian species, e.g. snakes, can be used. The receptor compartment of a so-called static diffusion cell or Franz cell (figure 8) is filled with a suitable fluid. An excised skin sample is mounted on top of the cell so that the inner side is in close contact with the receptor medium. The test sample is applied in the donor compartment so that it covers the skin surface. For more detailed descriptions, see e.g. the OECD guideline (2004).

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Donor compartment containing chemical or preparation to be studied

Skin piece is mounted here

Sampling site

Magnetic stirrer.

Heated water compartment, connected to a thermostatted water bath

Receptor compartment containing buffered saline or other suitable medium

Donor compartment containing chemical or preparation to be studied

Skin piece is mounted here

Sampling site

Magnetic stirrer.

Heated water compartment, connected to a thermostatted water bath

Receptor compartment containing buffered saline or other suitable medium

Figure 8. Static diffusion cell for dermal absorption studies in vitro.

As in the in vivo studies, the exposure duration should be relevant for human situations. At the end of exposure, excess sample is removed from the skin by appropriate cleansing.

The receptor fluid is sampled at defined time points throughout the experiment and the concentration of the parent chemical as well as any significant metabolite(s) is determined by a suitable method, e.g. gas chromatography, to ascertain the mass of the test substance (including any significant metabolite) that has passed through the skin. At the end of the study, the dislodgeable dose, the amount contained in the skin and the amount in the receptor fluid are determined. These data are necessary to calculate the total skin absorption, and allow for an estimate of the total recovery of the test substance.

When calculating the dermal penetration rate, the concentration in the receptor fluid translated to absolute mass by multiplying with the volume. The absolute mass rate, i.e. the increase in mass with time during steady-state condition, is obtained as the slope of the linear part of the mass versus time curve (figure 9). Finally, the unit penetration rate or flux is obtained by dividing the mass rate by the exposed skin area.

15

0

5

10

15

20

25

0 10 20 30

Time

Mas

s

C

B

A

Figure 9. Mass of chemical versus time in the receptor medium static diffusion cell. A: Lag time of skin penetration, B: Steady-state, slope of increase equals penetration rate, C: Penetration rate decreases (curve levels off), either due to back diffusion (limited solubility in receptor medium) or depletion at donor site.

It has to be assured that the test chemical is sufficiently soluble in the receptor medium. For highly water soluble chemicals this is no problem and physiological saline or isotonic buffer are sufficient as solvents. However, if this kind of receptor medium is used with non-polar, poorly soluble chemicals such as hexane, an equilibrium will soon be established between the donor and the receptor compartment (phase C in figure 9). Thus, the net movement of chemical approaches zero and the flux and permeability coefficient may be seriously underestimated.

The static diffusion cells may be replaced by a flow-through, so-called Bronaugh cell. Advantages of the latter type of cell are that saturation of the receptor medium can be avoided and that the system can easily be automated by connecting to an autosampler.

6.3 Structure-activity based methods

Several regression equations have been developed that relates permeability coefficients to easily obtained chemical properties, such as the octanol:water partition coefficient (Kow) and molecular weight (MW). The Kow is thought to represent the solubility and MW the size and hence diffusivity of the molecule in the skin. The equations are often of the form (McCarley & Bunge 2001): MWcKbaK owp ⋅+⋅+= loglog (4)

16

The constants a, b, and c are determined by fitting the equation to specific experimental data sets. One of the most commonly referred equations was developed by Potts and Guy (1992): MWKK owp ⋅−⋅+−= 0061.0log71.072.2log (5) where Kp is expressed in cm/h. More complicated models have also been developed, e.g. the modified Guy (Wilschut, ten Berge et al. 1995), the Cleek and Bunge (1993), the McKone and Howd (1992), the modified Robinson (Wilschut, ten Berge, Robinson & McKone 1995) and the Frasch model (2002). The US National Institute of Occupational Safety and Health (NIOSH) has developed an on-line skin permeation calculator that makes use of the Potts and Guy, the modified Robinson and the Frasch models (figure 10).

These equations generally work well within homologous series and structurally related chemicals, but are often unreliable outside that range. The error may be up to one or two orders of magnitude, compared to experimental data.

Figure 10. Screen dump of the US NIOSH skin permeation calculator available at http://www.cdc.gov/niosh/topics/skin/skinPermCalc.html.

17

7. Dermal penetration data for substances on the Swedish OEL list

7.1 Approach

Published percutaneous absorption data were searched for 165 substances. The compilation includes all 117 substances denoted with “H”, i.e. a skin notation in the ordinance on Swedish OELs (AFS 2005). In addition, 50 listed substances without skin notation but with published quantitative data on dermal absorption were included. Detailed information on each substance is given in the Appendix.

All substances in the Appendix except nicotine correspond to a defined entry with its own value in the Swedish ordinance. For nicotine the indicative OEL value of the European Commission should be used as a recommendation pending the introduction of a Swedish OEL. A few closely related substances, e.g. the PCB congeners, the mercury salts and the dinitrotoluene, butyl amine and cresol isomers, are given a single OEL in the Swedish list. Thus, the 165 substances correspond to 150 OEL entries.

All published dermal uptake data were listed for each substance. The compilations include information on species, type of experiment (in vitro/in vivo), type of diffusion cell, skin location, thickness and area, vehicle, concentration, number of experiments, exposure duration, observation time, lag time of penetration and percent absorbed chemical. Abbreviations and terms are given in table 2. Flux and permeability (Kp) are either listed as stated by the authors or calculated by us (numbers in italic).

In addition, physico-chemical properties are provided for each substance. This includes molecular weight, density at 25ºC, melting and boiling points, vapor pressure at 25ºC and evaporation rate relative to n-butyl acetate. These properties were obtained from Chemfinder (http://chemfinder.cambridgesoft.com), Swedish consensus reports published in Arbete och Hälsa, the NIOSH Pocket Guide to Chemical Hazards, and data on the internet supplied by various companies and organizations (see Appendix for references). Octanol:water partition coefficients were obtained using the KowWin software from Syracuse Research Corporation (http://www.syrres.com/esc/kowwin.htm).

In cases with multiple data, a preferred data set (marked by dots in figure 12) was selected according to the following criteria:

1. Human skin preferred over animal skin

2. In vivo studies preferred over in vitro studies

3. Neat liquid preferred over vapor or diluted liquid

4. Water preferred over other vehicles

5. Infinite or large dose preferred over low dose

18

Infinite or large doses, although perhaps unrealistic considering workplace conditions, were preferred over low doses as they allow for assessment of steady-state fluxes.

Although experimental exposure to neat (pure) chemical may affect the skin barrier and may reflect reality less well than exposures to vapors and dilutions, the former type of studies was preferred for two reasons; (a) they are more common facilitating comparisons between and ranking of chemicals and (b) they are less dependent on exposure conditions and thus more closely reflect the intrinsic properties of the chemical. The motives for selecting the preferred study for each individual chemical are given in the Assessment section of each substance in Appendix A.

Based on the preferred Kp value, substances were grouped in seven categories, from “Extremely low” to “Extremely high” permeability, according to a logarithmic scheme (figure 11) slightly modified from Marzulli et al. (1965) and Barber et al. (1995).

Extremely high

10-2

100

10-3

10-4

10-5

10-7

10-1

10-6

Very high

High

Moderate

Low

Very low

Extremely low

Kp ,

cm/h

Figure 11. Grouping scheme according to skin permeability (Kp). The grouping does not take toxic potency into account.

For chemicals lacking quantitative data, indirect data such as comparisons between oral and dermal LD50 values and other statements on dermal penetration ability were identified in the documentation published by the Swedish Criteria Group and by the Threshold Limit Value Committee of the American Conference for Governmental Industrial Hygienists. These statements, if any, are also provided in the Assessment section.

19

7.2 Conclusions

Quantitative dermal penetration data were missing for 53 of the 165 substances, i.e. about one third of the substances. Figure 12 summarizes the permeability coefficients for the 108 substances where a permeability coefficient could be obtained (see appendix for details). As can be seen in the figure, there is a trillionfold (1012) range in permeability. Moreover, multiple Kp values are reported for many substances (represented by vertical lines in figure 12) and these within-substance deviations are sometimes several orders of magnitude.

The wide within-substance range of permeability indicates that experimental design is critical. Thus, the Kp depends on the type of skin (species, location etc.) as well as the exposure conditions (solid, liquid or vapor, neat or diluted, vehicle, exposure duration etc.).

One major issue is that of using concentrated versus diluted chemicals. Two concerns already mentioned above is that exposure to neat chemical may affect the skin barrier and may also be unrealistic from the occupational viewpoint. An additional concern is that, at least for some chemicals, the permeability is heavily influenced by dilution with water. Thus, the flux of 2-butoxyethanol reaches its maximum at about 50% dilution and the permeability coefficient increases approximately 100-fold moving from neat to very dilute aqueous solutions (Johanson & Fernström 1988, Korinth, Schaller et al. 2005).

Another aspect not covered by our preferred studies approach is that of evaporation. Thus, following exposures of short duration, such as when spills occur at a workplace, some chemical will evaporate back to the atmosphere. This reduces the amount available for dermal penetration. The extent of evaporation depends on the volatility and skin permeability of the chemical, the exposure duration, and the lag time of penetration (Kasting & Miller 2006, N’Dri-Stempfer & Bunge 2005). Theoretical calculations suggest that the fraction lost by evaporation may be significant for volatile chemicals. For example, it has been estimated that following a 1-h exposure to chloroform, 73% of the chemical in the skin evaporates (N’Dri-Stempfer & Bunge 2005). To date, no systematic evaluation of the impact of evaporation has been performed for industrial chemicals.

About two thirds of the chemicals with dermal permeability data have a skin notation (table 3 and figure 13). One might expect that skin notations would occur more frequently among chemicals with higher permeability. However, no clear relation between permeability and frequency of skin notation was seen (figure 13).

20

1E-1

1

1E-1

0

1E-0

9

1E-0

8

1E-0

7

1E-0

6

1E-0

5

1E-0

4

1E-0

3

1E-0

2

1E-0

1

1E+0

0

1E+0

1

1E+0

27439-97-6

75-21-888-06-275-15-079-11-8

151-67-780-62-6

1634-04-426675-46-7

106-44-595-48-767-68-579-09-4

108-39-410112-91-1

67-56-167-66-3

127-19-568-12-274-90-8

872-50-4108-10-1

64-17-575-01-454-11-5

6423-43-4598-56-1100-41-4

62-53-32807-30-9

420-04-2107-06-2108-95-2

75-09-271-23-8

102-71-6111-15-9124-17-4

10025-73-7628-96-6

7775-11-3107-13-1110-80-5

71-36-37487-94-7

50-00-059-50-7

107-98-2120-80-9

7646-79-9591-78-6

71-43-287-86-579-01-656-23-5

112-34-5111-76-2143-33-9108-38-3

71-55-6108-46-3

25013-15-4123-86-4

91-20-3121-14-2

67-63-0108-88-3

1303-96-41330-20-7

98-01-1606-20-2127-18-4111-90-0107-15-3118-96-7107-21-1

1327-53-3100-42-5

79-06-1108-94-1109-99-9141-43-5

78-93-3131-11-3111-42-2

95-47-67778-39-4

55-63-067-64-1

25167-83-384-66-2

123-31-97778-50-9

111-46-627323-18-825512-42-9

84-74-2110-54-3

26914-33-050-32-8

26601-64-9142-82-5107-83-5117-81-7

13463-67-77440-48-4

109-66-01327-41-9

111-65-9

CA

S n

umbe

r

Permeability coefficient (cm/h)

Fi

gure

12.

Sum

mar

y of

exp

erim

enta

lly d

eter

min

ed p

erm

eabi

lity

coef

ficie

nts (

Kp,

cm/h

) for

the

inve

stig

ated

che

mic

al. T

he c

hem

ical

s are

sorte

d in

dec

reas

ing

orde

r with

resp

ect t

o th

e pr

efer

red

valu

e (d

ots)

. Ran

ges o

f val

ues a

re g

iven

as v

ertic

al li

nes.

Not

e th

e lo

garit

hmic

scal

e of

the

y ax

is.

21

It should be pointed out that this grouping solely according to permeability (such as in figure 13) does not take toxic potency into account. The European Centre for Ecotoxicology & Toxicology of Chemicals has suggested a skin notation should be assigned when the amount of chemical absorbed upon exposure of both hands and lower arms (2000 cm2) for one hour is expected to contribute more than 10% to the systemic dose, compared to the amount absorbed via inhalation exposure at the OEL during a full work day (assuming that 10 m3 air is inhaled during an 8-h workday and that 50% is absorbed). This applies only for chemicals for which the OEL is based on systemic toxicity (ECETOC 1993).

0

10

20

30

40

50

60

No

conc

lusi

on

No

data

Ext

rem

ely

low

Very

low

Low

Mod

erat

e

Hig

h

Ver

y hi

gh

Ext

rem

ely

high

Skin permeability

Num

ber o

f sub

stan

ces

No skin notationSkin notation

Figure 13. Number of substances with and without a skin notation in the Swedish OEL list, grouped by experimentally determined skin permeability. This grouping does not take the toxic potency into account.

A comparison between the ECETOC criteria and the Swedish skin notations produces some interesting results (table 3 and figure 14). Thus, two (o-xylene and diethylene glycol) of 12 substances with a dermal/inhalation ratio of less than 0.1 (i.e. should not have a notation according to ECETOC) do have a skin notation in the Swedish list. For o-xylene this is maybe not so controversial, as another study with mixed xylenes in solution yields a ratio above 0.1. On the other hand, 6 out of 14 substances with a ratio between 0.1 and 1 lack a skin notation. Even more remarkable is that 30 out of 82 with a ratio above 1 lack the notation. For the latter chemicals the dermal route contributes to more than 90% of the total dose, according to the ECETOC calculation. For some substances (such as formaldehyde) it may be argued that the systemic dose, and hence the dermal/inhalation ratio, is irrelevant since the OEL is based on a non-systemic effect (such as irritation). Nevertheless these comparisons suggest that a revision of the Swedish skin notations would be appropriate.

22

0

20

40

60

80

100

<0.1 0.1-1.0 >1.0 No dataDermal/inhalation ratio

Num

ber o

f sub

stan

ces

No skin notationSkin notation

Figure 14. Number of substances with and without a skin notation in the Swedish OEL list, categorized by the ratio between dermal and inhalation uptake rate. As inhalation is calculated at the OEL, this ratio does take toxic potency into account. The ECETOC criterion for skin notation (>0.1) is marked by a dotted line.

23

Table 2. Abbreviations and terms as used in tables and appendix.

A Area of exposed skin Me Methanol Ab Abdomen Mon Monkey Abs Per cent absorbed chemical Mou Mouse Ac Acetone MP Minipig AoH Arbete och Hälsa n Number of experiments Ax Axilla NaCl Physiological saline (0.9% NaCl) Ba Back n-Bu n-Butanol Br Breast NC Nitrocellulose Bw Body weight Ne Neck C Concentration of chemical in vehicle Neat Undiluted chemical CAS Chemical Abstracts Service Registry No. DMF Dimethylformamide Chf Chloroform Oct Octane Der Dermis OiW Oil in water emulsion EB Elbow PB Phosfate buffer Epi Epidermis PCP Pentachlorophenol Et Ethanol PG Propyleneglycol FH Forehead Ph Phenol Fi Finger Ph/NaCl Phenol and saline Fk Flank PHD Permanent Hair Dye Fl Flow-through diffusion cell Pit Armpit FS Fore skin Pol fab Polyester fabric FS/TM Fore skin, cultured Rab Rabbit Full Full thickness skin Sat Vap Saturated vapour Gas Gasoline Sc Scalp GP Guinea pig SC Stratum corneum H:M Hexane:Methylene chloride Sn Snake Ha Hand Solv Solvent Ham Hamster Sp Examined species Has Hands SpSt Explosive (Sprengstoff in German) HD Hexadecane St Static diffusion cell HDP Hair Dye Precursors TCP Tetrachlorophenol Hep n-Heptane Texp Duration of exposure Hex n-Hexane Th Thigh HGP Hairless guinea pig Ti Tinker soil HM Hairless mouse Tlag Time lag for penetration HR Hairless rat Tobs Duration of observation Hum Human Tol Toluene JP-8 Jet fuel, type JP-8 V Applied volume Kp Permeability coefficient Vap Vapor L Thickness of exposed skin VIC Vaseline Intensive Care Loc Body location of the skin WB Whole body Log Kow Log octanol:water partition coefficient Yo Yolo soil Ma Marmoset

24

Tab

le 3

. Sum

mar

y de

scrip

tors

on

derm

al a

bsor

ptio

n fo

r the

inve

stig

ated

che

mic

als.

Q

uant

itativ

e da

ta

avai

labl

e on

ECET

OC

der

mal

/in

hala

tion

ratio

Skin

not

atio

na Su

bsta

nce

Y

ear o

f lis

ting

CA

S nu

mbe

r V

apor

pr

essu

re

Der

mal

ab

sorp

tion

Phys

ical

stat

e

<0.1

0.1-

1 >1

by

EC

ETO

C

in

Swed

en

A

ceto

ne

1993

67

-64-

1 Y

es

Yes

N

eat l

iqui

d X

N

o N

o A

ceto

nitri

le; m

ethy

l cya

nide

19

93

75-0

5-8

Yes

N

o

No

Acr

ylam

ide

1993

79

-06-

1 Y

es

Yes

A

q. so

l.

X

Y

es

Yes

A

cryl

onitr

ile

1993

10

7-13

-1

Yes

Y

es

Nea

t liq

uid

X

Yes

Y

es

Ally

l alc

ohol

; 2-p

rope

n-1-

ol

1993

10

7-18

-6

Yes

N

o

Yes

A

llyla

min

e; 3

-am

inop

rope

ne

1984

10

7-11

-9

Yes

N

o

Yes

A

llylc

hlor

ide;

3-c

hlor

opre

ne

1993

10

7-05

-1

Yes

N

o

Yes

A

lum

iniu

m c

hlor

ohyd

rate

19

96

1327

-41-

9 N

o Y

es

Aq.

sol.

X

No

No

Ani

line

1993

62

-53-

3 Y

es

Yes

A

q. so

l.

X

Y

es

Yes

A

rsen

ic a

cid

2004

77

78-3

9-4

No

Yes

A

q. so

l.

X

Y

es

No

Ars

enic

trio

xide

20

04

1327

-53-

3 N

o Y

es

Aq.

sol.

X

Yes

N

o B

enze

ne

1990

71

-43-

2 Y

es

Yes

N

eat l

iqui

d

X

Y

es

Yes

B

enzo

apyr

ene

1993

50

-32-

8 N

o Y

es

Nea

t sol

id

X

Yes

Y

es

Bor

ax

1978

13

03-9

6-4

No

Yes

A

q. so

l.

X

Y

es

Yes

B

utan

ol, i

so-

1987

78

-83-

1 Y

es

No

Y

es

But

anol

, n-

1989

71

-36-

3 Y

es

Yes

N

eat l

iqui

d

X

Y

es

Yes

B

utan

ol, s

ek-

1987

78

-92-

2 Y

es

No

Y

es

But

anol

, ter

t- 19

87

75-6

5-0

Yes

N

o

Yes

B

utyl

ace

tate

, n-

2000

12

3-86

-4

Yes

Y

es

Nea

t liq

uid

X

Yes

N

o B

utyl

amin

e, is

o-

1984

78

-81-

9 Y

es

No

Y

es

But

ylam

ine,

n-

1984

10

9-73

-9

Yes

N

o

Yes

B

utyl

amin

e, se

c-

1984

13

952-

84-6

Y

es

No

Y

es

But

ylam

ine,

tert-

19

84

75-6

4-9

Yes

N

o

Yes

C

arbo

n di

sulfi

de

1978

75

-15-

0 Y

es

Yes

A

q. so

l.

X

Y

es

Yes

a B

old

text

is u

sed

to h

ighl

ight

dis

cord

anci

es b

etw

een

the

Swed

ish

ordi

nanc

e an

d th

e EC

ETO

C p

ropo

sal

25

Q

uant

itativ

e da

ta

avai

labl

e on

ECET

OC

der

mal

/in

hala

tion

ratio

Skin

not

atio

n Su

bsta

nce

Y

ear o

f lis

ting

CA

S nu

mbe

r V

apor

pr

essu

re

Der

mal

ab

sorp

tion

Phys

ical

stat

e

<0.1

0.1-

1 >1

by

EC

ETO

C

in

Swed

en

Car

bon

tetra

chlo

ride

1978

56

-23-

5 Y

es

Yes

N

eat l

iqui

d

X

Y

es

Yes

C

atec

hol

1993

12

0-80

-9

Yes

Y

es

Solu

tion

X

Yes

Y

es

Chl

orin

ated

bip

heny

ls, p

oly-

(PC

B)

1978

13

36-3

6-3

No

No

Y

es

Chl

oro-

1,3-

buta

dien

e, 2

-; ch

loro

pren

e 19

90

126-

99-8

Y

es

No

Y

es

Chl

orob

iphe

nyl,

di- (

DC

B)

1978

b 25

512-

42-9

N

o Y

es

Nea

t sol

id

X

Yes

Y

esb

Chl

orob

iphe

nyl,

hexa

- (H

CB

) 19

78b

2660

1-64

-9

No

Yes

N

eat s

olid

X

Y

es

Yes

b C

hlor

obip

heny

l, m

ono-

(MC

B)

1978

b 27

323-

18-8

N

o Y

es

Nea

t liq

uid

X

Yes

Y

esb

Chl

orob

iphe

nyl,

tetra

- (TC

B)

1978

b 26

914-

33-0

N

o Y

es

Nea

t sol

id

X

Yes

Y

esb

Chl

oroc

reso

l; 4-

chlo

ro-3

-met

hylp

heno

l 19

93

59-5

0-7

Yes

Y

es

Aq.

sol.

X

Yes

N

o C

hlor

oeth

anol

, 2-

1981

10

7-07

-3

Yes

N

o

Yes

C

hlor

ofor

m; t

richl

orom

etha

ne

1978

67

-66-

3 Y

es

Yes

N

eat l

iqui

d

X

Y

es

No

Chr

omat

e, p

otas

sium

di-

2004

77

78-5

0-9

Yes

Y

es

Aq.

sol.

X

Yes

N

o C

hrom

ate,

sodi

um d

i- 20

04

7775

-11-

3 N

o Y

es

Aq.

sol.

X

Yes

N

o C

hrom

ic c

hlor

ide

2004

10

025-

73-7

N

o Y

es

Aq.

sol.

X

Yes

N

o C

obal

t 19

78

7440

-48-

4 N

o Y

es

Solu

tion

X

Yes

N

o C

obal

t dic

hlor

ide

1978

76

46-7

9-9

Yes

Y

es

Aq.

sol.

X

Yes

N

o C

reso

l, m

- 20

00

108-

39-4

Y

es

Yes

A

q. so

l.

X

Y

es

No

Cre

sol,

o-

2000

95

-48-

7 Y

es

Yes

A

q. so

l.

X

Y

es

No

Cre

sol,

p-

2000

10

6-44

-5

Yes

Y

es

Aq.

sol.

X

Yes

N

o C

yana

mid

e, h

ydro

gen

2000

42

0-04

-2

No

Yes

A

q. so

l.

X

Y

es

No

Cyc

lohe

xano

ne

2004

10

8-94

-1

Yes

Y

es

Nea

t liq

uid

X

Yes

Y

es

Di-(

2-et

hylh

exyl

)pht

hala

te (D

EHP)

19

87

117-

81-7

Y

es

Yes

N

eat l

iqui

d X

N

o N

o D

ibut

yl p

htha

late

(DB

P)

1987

84

-74-

2 Y

es

Yes

N

eat l

iqui

d

X

Y

es

No

Dic

hlor

oeth

ane,

1,2

- 19

81

107-

06-2

Y

es

Yes

N

eat l

iqui

d

X

Y

es

Yes

D

ieth

anol

amin

e 19

93

111-

42-2

Y

es

Yes

A

q. so

l.

X

Y

es

Yes

D

ieth

yl p

htha

late

(DEP

) 19

87

84-6

6-2

Yes

Y

es

Nea

t liq

uid

X

Yes

N

o

b R

efer

s to

PCB

, CA

S no

. 133

6-36

-3

26

Qua

ntita

tive

data

av

aila

ble

on

EC

ETO

C d

erm

al

/inha

latio

n ra

tio

Sk

in n

otat

ion

Subs

tanc

e

Yea

r of

listin

g C

AS

num

ber

Vap

or

pres

sure

D

erm

al

abso

rptio

n Ph

ysic

al st

ate

<0

.1

0.

1-1

>1

by

ECET

OC

in

Sw

eden

Die

thyl

amin

e 19

84

109-

89-7

Y

es

No

Y

es

Die

thyl

amin

oeth

anol

, 2-

1996

10

0-37

-8

Yes

N

o

Yes

D

ieth

ylen

e gl

ycol

19

93

111-

46-6

Y

es

Yes

N

eat l

iqui

d X

N

o Y

es

Die

thyl

ene

glyc

ol m

onob

utyl

eth

er (D

EGB

E)

1996

11

2-34

-5

Yes

Y

es

Nea

t liq

uid

X

Yes

N

o D

ieth

ylen

e gl

ycol

mon

obut

yl e

ther

ace

tate

(D

EGB

EA)

1996

12

4-17

-4

Yes

Y

es

Nea

t liq

uid

X

Yes

N

o D

ieth

ylen

e gl

ycol

mon

oeth

yl e

ther

(DEG

EE)

2000

11

1-90

-0

Yes

Y

es

Nea

t liq

uid

X

Yes

Y

es

Die

thyl

ene

glyc

ol m

onoe

thyl

eth

er a

ceta

te

(DEG

EEA

) 20

00

112-

15-2

Y

es

No

Y

es

Die

thyl

entri

amin

e 19

96

111-

40-0

Y

es

No

Y

es

Diis

opro

pyla

min

e 19

93

108-

18-9

Y

es

No

Y

es

Dim

ethy

l pht

hala

te

1987

13

1-11

-3

Yes

Y

es

Nea

t liq

uid

X

Yes

N

o D

imet

hyla

ceta

mid

e, N

- 19

96

127-

19-5

Y

es

Yes

N

eat l

iqui

d

X

Y

es

Yes

D

imet

hyla

nilli

ne, N

,N-

1993

12

1-69

-7

Yes

N

o

Yes

D

imet

hyle

thyl

amin

e 19

93

598-

56-1

Y

es

Yes

So

lutio

n

X

Y

es

No

Dim

ethy

lform

amid

e 19

87

68-1

2-2

Yes

Y

es

Nea

t liq

uid

X

Yes

Y

es

Dim

ethy

lsul

foxi

de

1993

67

-68-

5 Y

es

Yes

N

eat l

iqui

d

X

Y

es

Yes

D

initr

oben

zene

19

78

2515

4-54

-5

Yes

N

o

Yes

D

initr

otol

uene

19

93

2532

1-14

-6

Yes

N

o

Yes

D

initr

otol

uene

, 2,4

- 19

93

121-

14-2

Y

es

Yes

So

lutio

n

X

Y

es

Yes

D

initr

otol

uene

, 2,6

- 19

93

606-

20-2

Y

es

Yes

So

lutio

n

X

Y

es

Yes

D

ioxa

ne

1996

12

3-91

-1

Yes

N

o

Yes

D

ipro

pyle

ne g

lyco

l mon

omet

hyl e

ther

(D

PGM

E)

1993

34

590-

94-8

Y

es

No

Y

es

Epic

hlor

ohyd

rin

1978

10

6-89

-8

Yes

N

o

Yes

Et

hano

l 19

93

64-1

7-5

Yes

Y

es

Nea

t liq

uid

X

Yes

N

o Et

hano

lam

ine

1993

14

1-43

-5

Yes

Y

es

Aq.

sol.

X

Yes

Y

es

27

Q

uant

itativ

e da

ta

avai

labl

e on

ECET

OC

der

mal

/in

hala

tion

ratio

Skin

not

atio

n Su

bsta

nce

Y

ear o

f lis

ting

CA

S nu

mbe

r V

apor

pr

essu

re

Der

mal

ab

sorp

tion

Phys

ical

stat

e

<0.1

0.1-

1 >1

by

EC

ETO

C

in

Swed

en

Ethy

l 2-c

yano

acry

late

20

00

7085

-85-

0 Y

es

No

Y

es

Ethy

l acr

ylat

e 19

87

140-

88-5

Y

es

No

Y

es

Ethy

l ben

zene

19

87

100-

41-4

Y

es

Yes

N

eat l

iqui

d

X

Y

es

No

Ethy

l eth

er

1996

60

-29-

7 Y

es

No

N

o Et

hyla

min

e 19

84

75-0

4-7

Yes

N

o

Yes

Et

hyle

ne g

lyco

l 19

93

107-

21-1

Y

es

Yes

N

eat l

iqui

d

X

Y

es

Yes

Et

hyle

ne g

lyco

l din

itrat

e 19

90

628-

96-6

Y

es

Yes

So

lutio

n

X

Y

es

Yes

Et

hyle

ne o

xide

19

89

75-2

1-8

Yes

Y

es

Solu

tion

X

Yes

Y

es

Ethy

lene

diam

ine

1978

10

7-15

-3

Yes

Y

es

Aq.

sol.

X

Yes

Y

es

Ethy

lene

gly

col m

onob

utyl

eth

er (E

GB

E)

1993

11

1-76

-2

Yes

Y

es

Nea

t liq

uid

X

Yes

Y

es

Ethy

lene

gly

col m

onob

utyl

eth

er a

ceta

te

(EG

BEA

) 19

93

112-

07-2

Y

es

No

Y

es

Ethy

lene

gly

col m

onoe

thyl

eth

er (E

GEE

) 20

00

110-

80-5

Y

es

Yes

N

eat l

iqui

d

X

Y

es

Yes

Et

hyle

ne g

lyco

l mon

oeth

yl e

ther

ace

tate

(E

GEE

A)

2000

11

1-15

-9

Yes

Y

es

Nea

t liq

uid

X

Yes

Y

es

Ethy

lene

gly

col m

onoi

sopr

opyl

eth

er ( E

GiP

E)

1996

10

9-59

-1

Yes

N

o

Yes

Et

hyle

ne g

lyco

l mon

oiso

prop

yl e

ther

ace

tate

(E

GiP

EA)

1996

19

234-

20-9

N

o N

o

Yes

Et

hyle

ne g

lyco

l mon

opro

pyl e

ther

(EG

PE)

1996

28

07-3

0-9

Yes

Y

es

Nea

t liq

uid

X

Yes

Y

es

Ethy

l mor

phol

ine,

N-

1984

10

0-74

-3

Yes

N

o

Yes

Fo

rmal

dehy

de

1987

50

-00-

0 N

o Y

es

Aq.

sol.

X

Yes

N

o Fo

rmam

ide

1993

75

-12-

7 Y

es

No

Y

es

Furf

ural

19

90

98-0

1-1

Yes

Y

es

Nea

t liq

uid

X

Yes

Y

es

Furf

uryl

alc

ohol

19

90

98-0

0-0

Yes

N

o

Yes

H

alot

hane

19

90

151-

67-7

Y

es

Yes

V

apou

r

X

Y

es

No

Hep

tane

, n-

1989

14

2-82

-5

Yes

Y

es

Nea

t liq

uid

X

No

No

Hex

ane,

n-

1989

11

0-54

-3

Yes

Y

es

Nea

t liq

uid

X

No

No

Hex

anon

e, 2

-; m

ethy

l n-b

utyl

ket

one

1993

59

1-78

-6

Yes

Y

es

Nea

t liq

uid

X

Yes

Y

es

28

Q

uant

itativ

e da

ta

avai

labl

e on

ECET

OC

der

mal

/in

hala

tion

ratio

Skin

not

atio

n Su

bsta

nce

Y

ear o

f lis

ting

CA

S nu

mbe

r V

apor

pr

essu

re

Der

mal

ab

sorp

tion

Phys

ical

stat

e

<0.1

0.1-

1 >1

by

EC

ETO

C

in

Swed

en

Hyd

roge

n cy

anid

e 19

74

74-9

0-8

Yes

Y

es

Vap

our

X

Yes

Y

es

Hyd

roqu

inon

e 19

93

123-

31-9

Y

es

Yes

A

q. so

l.

X

Y

es

No

Hyd

roxy

ethy

lacr

ylat

e, 2

-; pr

open

oic

acid

, 2-

1981

81

8-61

-1

Yes

N

o

Yes

Is

oflu

rane

19

90

2667

5-46

-7

Yes

Y

es

Vap

our

X

Yes

N

o Is

opro

pano

l 19

89

67-6

3-0

Yes

Y

es

Aq.

sol.

X

Yes

N

o Is

opro

pylb

enze

ne; c

umen

e 19

84

98-8

2-8

Yes

N

o

Yes

M

ercu

ry b

ichl

orid

e; d

ichl

orom

ercu

ry

1993

74

87-9

4-7

No

Yes

A

q. so

l.

X

Y

es

Yes

M

ercu

ry c

hlor

ide;

dim

ercu

ry d

ichl

orid

e

1993

10

112-

91-1

N

o Y

es

Aq.

sol.

X

Yes

Y

es

Mer

cury

, dim

ethy

l 19

93

593-

74-8

Y

es

No

Y

es

Mer

cury

, met

al

1993

74

39-9

7-6

Yes

Y

es

Vap

our

X

Yes

Y

es

Met

hano

l 19

90

67-5

6-1

Yes

Y

es

Nea

t liq

uid

X

Yes

Y

es

Met

hyl e

thyl

ket

one

(MEK

); 2-

buta

none

19

87

78-9

3-3

Yes

Y

es

Nea

t liq

uid

X

No

No

Met

hyl i

odid

e 19

81

74-8

8-4

Yes

N

o

Yes

M

ethy

l iso

buty

l ket

one

(MiB

K)

1989

10

8-10

-1

Yes

Y

es

Nea

t liq

uid

X

Yes

N

o M

ethy

l ter

t-but

yl e

ther

(MTB

E)

2000

16

34-0

4-4

Yes

Y

es

Aq.

sol.

X

Yes

N

o M

ethy

l-2-p

enta

nol,

4-

1996

10

8-11

-2

Yes

N

o

Yes

M

ethy

l-2-p

yrro

lidon

e, n

- (N

MP)

19

90

872-

50-4

Y

es

Yes

N

eat l

iqui

d

X

Y

es

No

Met

hyl a

cryl

ate

1987

96

-33-

3 Y

es

No

Y

es

Met

hyla

min

e 19

84

74-8

9-5

Yes

N

o

Yes

M

ethy

l bro

mid

e 19

90

74-8

3-9

Yes

N

o

Yes

M

ethy

lene

chl

orid

e; d

ichl

orom

etha

ne

1989

75

-09-

2 Y

es

Yes

N

eat l

iqui

d

X

Y

es

Yes

M

ethy

l met

acry

late

19

87

80-6

2-6

Yes

Y

es

Nea

t liq

uid

X

Yes

Y

es

Met

hyl m

orph

olin

e, N

- 19

84

109-

02-4

Y

es

No

Y

es

Met

hylp

enta

ne, 2

- 19

89

107-

83-5

Y

es

Yes

N

eat l

iqui

d X

N

o N

o M

onoc

hlor

oace

tic a

cid

1993

79

-11-

8 Y

es

Yes

So

lutio

n

X

Y

es

Yes

M

orph

olin

e 20

00

110-

91-8

Y

es

No

Y

es

Nap

htal

enes

, chl

orin

ated

19

78

1321

-65-

9 Y

es

No

Y

es

Nap

htha

lene

20

00

91-2

0-3

Yes

Y

es

Solu

tion

X

Yes

N

o

29

Q

uant

itativ

e da

ta

avai

labl

e on

ECET

OC

der

mal

/in

hala

tion

ratio

Skin

not

atio

n Su

bsta

nce

Y

ear o

f lis

ting

CA

S nu

mbe

r V

apor

pr

essu

re

Der

mal

ab

sorp

tion

Phys

ical

stat

e

<0.1

0.1-

1 >1

by

EC

ETO

C

in

Swed

en

N

icot

ine

54

-11-

5 Y

es

Yes

A

q. so

l.

X

Y

es

Yes

N

itrob

enze

ne

1974

98

-95-

3 Y

es

No

Y

es

Nitr

ogly

cerin

19

90

55-6

3-0

Yes

Y

es

Nea

t liq

uid

X

Yes

Y

es

Nitr

otol

uene

19

93

1321

-12-

6 Y

es

No

Y

es

Oct

anes

19

89

111-

65-9

Y

es

Yes

N

eat l

iqui

d X

N

o N

o Pe

ntac

hlor

ophe

nol

1974

87

-86-

5 Y

es

Yes

A

q. so

l.

X

Y

es

Yes

Pe

ntan

e 19

78

109-

66-0

Y

es

Yes

N

eat l

iqui

d X

N

o N

o Ph

enol

19

87

108-

95-2

Y

es

Yes

A

q. so

l.

X

Y

es

Yes

Pr

opan

ol, n

- 19

89

71-2

3-8

Yes

Y

es

Nea

t liq

uid

X

Yes

N

o Pr

opio

nic

acid

19

90

79-0

9-4

Yes

Y

es

Nea

t liq

uid

X

Yes

N

o Pr

opyl

ene

glyc

ol d

initr

ate

1987

64

23-4

3-4

Yes

Y

es

Solu

tion

X

Yes

Y

es

Prop

ylen

e gl

ycol

mon

omet

hyl e

ther

(P

GM

E); 1

-met

hoxy

-2-p

ropa

nol

1990

10

7-98

-2

Yes

Y

es

Nea

t liq

uid

X

Yes

Y

es

-“- a

ceta

te (P

GM

EA)

1990

10

8-65

-6

Yes

N

o

Yes

R

esor

cino

l 19

93

108-

46-3

Y

es

Yes

A

q. so

l.

X

Y

es

Yes

So

dium

cya

nide

19

74

143-

33-9

N

o Y

es

Aq.

sol.

X

Yes

Y

es

Styr

ene

1990

10

0-42

-5

Yes

Y

es

Nea

t liq

uid

X

Yes

Y

es

Tetra

chlo

roet

hyle

ne

1989

12

7-18

-4

Yes

Y

es

Nea

t liq

uid

X

Yes

N

o Te

trach

loro

phen

ol

1990

25

167-

83-3

N

o Y

es

Aq.

sol.

X

Yes

Y

es

Tetra

ethy

l lea

d 19

81

78-0

0-2

Yes

N

o

Yes

Te

trahy

drof

uran

19

93

109-

99-9

Y

es

Yes

N

eat l

iqui

d

X

Y

es

No

Tetra

met

hyl l

ead

1981

75

-74-

1 Y

es

No

Y

es

Thio

glyc

olic

aci

d 19

96

68-1

1-1

Yes

N

o

Yes

Ti

tani

um d

ioxi

de

1990

13

463-

67-7

N

o Y

es

Aq.

sol.

X

No

No

Tolu

ene

1987

10

8-88

-3

Yes

Y

es

Nea

t liq

uid

X

Yes

Y

es

Trib

utyl

tin

1978

56

573-

85-4

Y

es

No

Y

es

Tric

hlor

etha

ne, 1

,1,1

- 19

89

71-5

5-6

Yes

Y

es

Nea

t liq

uid

X

Yes

N

o Tr

ichl

oroe

thyl

ene,

1,1

,2-

1989

79

-01-

6 Y

es

Yes

N

eat l

iqui

d

X

Y

es

No

30

Q

uant

itativ

e da

ta

avai

labl

e on

ECET

OC

der

mal

/in

hala

tion

ratio

Skin

not

atio

n Su

bsta

nce

Y

ear o

f lis

ting

CA

S nu

mbe

r V

apor

pr

essu

re

Der

mal

ab

sorp

tion

Phys

ical

stat

e

<0.1

0.1-

1 >1

by

EC

ETO

C

in

Swed

en

Tric

hlor

ophe

nol

1990

25

167-

82-2

N

o N

o

Yes

Tr

ichl

orop

heno

l, 2,

4,6-

19

90

88-0

6-2

Yes

Y

es

Solu

tion

X

Yes

Y

es

Trie

than

olam

ine

1984

10

2-71

-6

Yes

Y

es

Nea

t sol

id

X

Yes

N

o Tr

initr

otol

uene

, 2,4

,6-

1993

11

8-96

-7

Yes

Y

es

Solu

tion

X

Yes

Y

es

Turp

entin

e 19

90

8006

-64-

2 Y

es

No

Y

es

Vin

yl c

hlor

ide

1974

75

-01-

4 Y

es

Yes

G

as

X

Yes

Y

es

Vin

yl to

luen

e; m

ethy

l sty

rene

19

93

2501

3-15

-4

Yes

Y

es

Nea

t liq

uid

X

Yes

Y

es

Xyl

ene,

m-

1987

10

8-38

-3

Yes

Y

es

Nea

t liq

uid

X

Yes

Y

es

Xyl

ene,

o-

1987

95

-47-

6 Y

es

Yes

N

eat l

iqui

d X

N

o Y

es

Xyl

ene,

p-

1987

10

6-42

-3

Yes

N

o

Yes

X

ylen

es

1987

13

30-2

0-7

Yes

Y

es

Sol

utio

n

X

Y

es

Yes

31

8. Summary

Johanson G & Rauma M. Basis for skin notation. Part 1. Dermal penetration data for substances on the Swedish OEL list. Arbete och Hälsa 2008;42:2. The aim of this report is to review the published data on dermal penetration of workplace chemicals, as a basis for assignment of skin notations. Short chapters describe the anatomy of the skin, the skin as a diffusion barrier, Fick’s law of diffusion, factors affecting dermal penetration and methods to assess dermal penetration.

The major part of the report is devoted to compilation of data assessment of dermal penetration (fluxes and permeability coefficients) for 165 substances corresponding to 150 entries listed in the Swedish ordinance (AFS 2005) on Occupational Expsoure Limits (OELs). The compilation covers all 117 substances marked with an “H” in the ordinance and, in addition, 50 substances that have not been given a skin notation. The compiled data can be used in future revision of skin notations.

An analysis of the data shows that quantitative information on dermal penetration is lacking for 53 or about one third of the 165 substances. For those who have quantitative data, a variety of species and experimental techniques have been used. There is a trillion-fold (1012) span in permeability coefficients between the substances. Moreover, for many chemicals with several experimental data sets on permeability, there is a huge intra-chemical span, sometimes several orders of magnitude. In these cases, a preferred study was selected, mainly based on the following criteria: human skin, in vivo studies, neat liquid, water as vehicle and infinite or large dose were preferred over animal skin, in vitro studies, vapor or diluted liquid, other vehicles and low dose, respectively.

Notably, more than one third of the chemicals with high skin permeability and with a dermal/inhalation ratio higher than 0.1 according to the ECETOC criteria (1993) lacks a skin notation. This suggests a need for revision of all substances, including those without a skin notation, in the Swedish list.

32

9. References

AFS (2005) Hygieniska gränsvärden och åtgärder mot luftföroreningar, AFS 2005:17, Solna, Sweden, Arbetsmiljöverket.

Anderson CD (2006) Cutaneous microdialysis: Is it worth the sweat? Journal of Investigative Dermatology, 126, 1207-1209.

Barber ED, Hill T, Schum DB (1995) The percutaneous absorption of hydroquinone (hq) through rat and human skin in vitro. Toxicology Letters, 80, 167-172.

Bronaugh RL, Weingarten DP, Lowe NJ (1986) Differential rates of percutaneous absorption through the eczematous and normal skin of a monkey. Journal of Investigative Dermatology, 87, 451-453.

Cleek RL, Bunge AL (1993) A new method for estimating dermal absorption from chemical exposure. 1. General approach. Pharmaceutical Research, 10, 497-506.

ECETOC (1993) Strategy for assigning a "Skin notation", Report no. 31, Bruxelles, Belgium, European Centre for Ecotoxicology & Toxicology of Chemicals.

Forslind B, Lindberg M, eds. (2004) Skin, hair, and nails. New York: Marcel Dekker. Frasch HF (2002) A random walk model of skin permeation. Risk Analysis, 22, 265-276. Hadgraft J (2004) Skin deep. European Journal of Pharmaceutics & Biopharmaceutics, 58,

291-299. Johanson G, Boman A (1991) Percutaneous absorption of 2-butoxyethanol vapour in

human subjects. British Journal of Industrial Medicine, 48, 788-792. Johanson G, Boman A, Dynesius B (1988) Percutaneous absorption of 2-butoxyethanol in

man. Scandinavian Journal of Work, Environment & Health, 14, 101-109. Johanson G, Fernström P (1986) Percutaneous uptake rate of 2-butoxyethanol in the guinea

pig. Scandinavian Journal of Work, Environment & Health, 12, 499-503. Johanson G, Fernström P (1988) Influence of water on the percutaneous absorption of 2-

butoxyethanol in guinea pigs. Scandinavian Journal of Work, Environment & Health, 14, 95-100.

Kasting GB, Miller MA (2006) Kinetics of finite dose absorption through skin 2: Volatile compounds. Journal of Pharmaceutical Sciences, 95, 268-280.

Korinth G, Schaller KH, Drexler H (2005) Is the permeability coefficient kp a reliable tool in percutaneous absorption studies? Archives of Toxicology, 79, 155-159.

Korinth G, Weiss T, Angerer J, Drexler H (2006) Dermal absorption of aromatic amines in workers with different skin lesions: A report on 4 cases. Journal of Occupational Medicine and Toxicology, 1, 17.

Korinth G, Weiss T, Penkert S, Schaller KH, Angerer J, Drexler H (2007) Percutaneous absorption of aromatic amines in rubber industry workers: Impact of impaired skin and skin barrier creams. Occupational and Environmental Medicine, 64, 366-372.

Marzulli FN, Callahan JF, Brown DW (1965) Chemical structure and skin penetrating capacity of a short series of organic phosphates and phosphoric acid. Journal of Investigative Dermatology, 44, 339-344.

McAuliffe DJ, Blank IH (1991) Effects of uva (320-400 nm) on the barrier characteristics of the skin. Journal of Investigative Dermatology, 96, 758-762.

McCarley KD, Bunge AL (2001) Pharmacokinetic models of dermal absorption. Journal of Pharmaceutical Sciences, 90, 1699-1719.

McKone TE, Howd RA (1992) Estimating dermal uptake of nonionic organic chemicals from water and soil: I. Unified fugacity-based models for risk assessments. Risk Analysis, 12, 543-557.

Monteiro-Riviere NA, Bristol DG, Manning TO, Rogers RA, Riviere JE (1990) Interspecies and interregional analysis of the comparative histologic thickness and

33

laser doppler blood flow measurements at five cutaneous sites in nine species. Journal of Investigative Dermatology, 95, 582-586.

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App

endi

x A

Subs

tanc

e: A

ceto

neM

olec

ular

wei

ght:

58.1

CA

S: 6

7-64

-1D

ensi

ty:0

.786

g/c

m³

Scie

ntifi

c ba

sis:

AoH

198

8:32

Mel

ting

poin

t:-9

4.3°

CB

oilin

g po

int:

56.2

°CSk

in n

otat

ion:

No

Vap

our

pres

sure

:24

kPa

(at 2

5°C

)Sk

in p

erm

eabi

lity:

Low

Eva

pora

tion

rate

:10

Log

Kow

:-0.

24

Sp

Loc

C

ell

L

(µm

) A

(c

m²)

V

(ml)

Veh

icle

C

(m

g/m

l) n

TE

xp

(h)

TO

bs

(h)

TL

ag

(h)

Abs

(%

) K

P

(10-4

cm

/h)

Flux

(µ

g/cm

²/h) R

efer

ence

Hum

Br

Fl28

00.

640.

2N

eat

524

240.

310.

050.

1310

Wilk

inso

n et

al.

(200

1)H

umB

rFl

280

0.64

0.2

H2O

3

524

240.

380.

4114

4.2

Wilk

inso

n et

al.

(200

1)

Hum

FiIn

fH

2O1%

1215

s0.

30.

280.

22N

aito

h et

al.

(200

2)H

umFi

Inf

H2O

1%12

15s

0.3

129.

5N

aito

h et

al.

(200

2)

The

only

ava

ilabl

e in

viv

o st

udy

is th

at o

f Nai

toh

et a

l. (2

002)

. An

unco

nven

tiona

l tec

hniq

ue w

as u

sed

in th

at o

ne th

umb

was

dipp

ed o

nce

or se

vera

l tim

es (1

5 se

c/oc

casi

on) i

n an

aqu

eous

solu

tion.

The

flux

was

cal

cula

ted

from

the

evap

orat

ion

from

the

thum

b.Th

e ev

apor

atio

n pr

ofile

was

bip

hasi

c, th

us tw

o di

ffer

ent f

luxe

s wer

e re

porte

d. T

he re

porte

d flu

xes r

efle

cts a

bsor

ptio

n in

to

(and

out

of)

rath

er th

an th

roug

h sk

in. T

hus t

he c

alcu

late

d K

p m

ay re

pres

ent a

n se

rious

ove

rest

imat

e of

the

"tru

e" v

alue

.

The

perm

eabi

lity

for n

eat a

ceto

ne (1

·10-5

) may

be

cons

ider

ed a

s "lo

w",

whe

reas

the

perm

eabi

lity

in w

ater

(1·1

0-3) i

s abo

ut

100-

fold

hig

her a

nd m

ay b

e co

nsid

ered

as "

high

". T

hus,

ther

e is

a st

rong

veh

icle

eff

ect o

f wat

er.

Bas

ed o

n ne

at so

lven

t, th

e pe

rmea

bilit

y is

con

side

red

"low

".

Rep

orte

d da

ta

In v

itro

In v

ivo

Ase

ssm

ent

A1

App

endi

x A

Subs

tanc

e: A

ceto

nitri

le; m

ethy

l cya

nide

Mol

ecul

ar w

eigh

t:41

.1C

AS:

75-

05-8

Den

sity

:0.7

857

g/cm

³Sc

ient

ific

basi

s: A

oH 1

991:

8M

eltin

g po

int:

-45°

CB

oilin

g po

int:

81.6

°CSk

in n

otat

ion:

No

Vap

our

pres

sure

:9.7

kPa

(at 2

0°C

)Sk

in p

erm

eabi

lity:

No

data

Eva

pora

tion

rate

:5.7

9L

og K

ow:-

0.34

Sp

Loc

C

ell

L

(µm

) A

(c

m²)

V

(ml)

Veh

icle

C

(m

g/m

l) n

TE

xp

(h)

TO

bs

(h)

TL

ag

(h)

Abs

(%

) K

P

(10-4

cm

/h)

Flux

(µ

g/cm

²/h) R

efer

ence

N

o da

ta a

vaila

ble

N

o da

ta a

vaila

ble

No

quan

titat

ive

expe

rimen

tal d

ata

on d

erm

al u

ptak

e w

ere

foun

d in

the

liter

atur

e.

The

Swed

ish

cons

ensu

s rep

ort (

AoH

199

1:8)

doe

s not

men

tion

derm

al u

ptak

e of

ace

toni

trile

.

Acc

ordi

ng to

AC

GIH

(200

1), t

he o

ral L

D50

val

ue v

arie

s muc

h be

twee

n sp

ecie

s, i.

e. ra

t 650

0-24

000

mg/

kg b

w

and

mou

se 1

80 m

g/kg

bw

. The

bas

is fo

r ski

n no

tatio

n is

a c

ase

repo

rt w

here

a tw

o-ye

ar-o

ld c

hild

was

der

mal

ly e

xpos

ed

to 3

0 m

l of a

ceto

nitri

le n

ail p

olis

h re

mov

er (c

onc.

98-

100%

). Ei

ght h

ours

late

r, vo

miti

ng a

nd p

ain

appe

ared

.Th

e in

toxi

catio

n w

as re

solv

ed w

ith o

xyge

n an

d de

xtro

se su

ppor

t the

rapy

.

Rep

orte

d da

ta

In v

itro

In v

ivo

Ase

ssm

ent

A2

App

endi

x A

Subs

tanc

e: A

cryl

amid

eM

olec

ular

wei

ght:

71.1

CA

S: 7

9-06

-1D

ensi

ty:1

.13

g/cm

³Sc

ient

ific

basi

s: A

oH 1

992:

6M

eltin

g po

int:

84.5

°CB

oilin

g po

int:

192.

6°C

Skin

not

atio

n: Y

esV

apou

r pr

essu

re:0

.9 P

a (a

t 25°

C)

Skin

per

mea

bilit

y: L

owE

vapo

ratio

n ra

te:N

ot a

vaila

ble

Log

Kow

:-0.

67

Sp

Loc

C

ell

L

(µm

) A

(c

m²)

V

(ml)

Veh

icle

C

(m

g/m

l) n

TE

xp

(h)

TO

bs

(h)

TL

ag

(h)

Abs

(%

) K

P

(10-4

cm

/h)

Flux

(µ

g/cm

²/h) R

efer

ence

N

o da

ta a

vaila

ble

Hum

Arm

24H

2O50

% (2

.5 m

g/kg

bw

)5

7272

320.

6432

Fenn

ell e

t al.

(200

5)R

atB

a2.

5N

eat (

160

mg/

kg b

w)

424

2414

-30

0.85

-1.8

95-2

00Su

mne

r et a

l. (2

003)

Onl

y %

abso

rbed

dos

e ha

s bee

n re

porte

d.

The

rat a

nd h

uman

stud

ies a

re in

agr

eem

ent.

The

perm

eabi

lity

of a

cryl

amid

e m

ay b

e co

nsid

ered

as "

low

".

Rep

orte

d da

ta

In v

itro

In v

ivo

Ase

ssm

ent

A3

App

endi

x A

Subs

tanc

e: A

cryl

onitr

ileM

olec

ular

wei

ght:

53.1

CA

S: 1

07-1

3-1

Den

sity

:0.8

08 g

/cm

³Sc

ient

ific

basi

s: A

oH 1

987:

39M

eltin

g po

int:

-83.

6°C

Boi

ling

poin

t:77

.3°C

Skin

not

atio

n: Y

esV

apou

r pr

essu

re:1

3 kP

a (a

t 22.

8°C

)Sk

in p

erm

eabi

lity:

Mod

erat

eE

vapo

ratio

n ra

te:5

.8L

og K

ow:0

.25

Sp

Loc

C

ell

L

(µm

) A

(c

m²)

V

(ml)

Veh

icle

C

(m

g/m

l) n

TE

xp

(h)

TO

bs

(h)

TL

ag

(h)

Abs

(%

) K

P

(10-4

cm

/h)

Flux

(µ

g/cm

²/h) R

efer

ence

N

o da

ta a

vaila

ble

Hum

Arm

Nea

t4

7.5

600

Rog

acze

wsk

a et

al.

(196

8)

No

quan

titat

ive

expe

rimen

tal d

ata

on d

erm

al u

ptak

e w

as fo

und

in th

e lit

erat

ure,

exc

ept f

or R

ogac

zew

ska

et a

l. (1

968)

ci

ted

in W

HO

(198

3).

The

perm

eabi

lity

of a

cryl

onitr

ile m

ay b

e co

nsid

ered

as "

mod

erat

e".

Rep

orte

d da

ta

In v

itro

In v

ivo

Ase

ssm

ent

A4

App

endi

x A

Subs

tanc

e: A

llyl a

lcoh

ol; 2

-pro

pen-

1-ol

M

olec

ular

wei

ght:

58.1

CA

S: 1

07-1

8-6

Den

sity

:0.8

54 g

/cm

³Sc

ient

ific

basi

s: A

oH 1

987:

39M

eltin

g po

int:

-129

°CB

oilin

g po

int:

97°C

Skin

not

atio

n: Y

esV

apou

r pr

essu

re:3

.2 k

Pa (a

t 25°

C)

Skin

per

mea

bilit

y: N

o da

taE

vapo

ratio

n ra

te:1

Log

Kow

:0.7

Sp

Loc

C

ell

L

(µm

) A

(c

m²)

V

(ml)

Veh

icle

C

(m

g/m

l) n

TE

xp

(h)

TO

bs

(h)

TL

ag

(h)

Abs

(%

) K

P

(10-4

cm

/h)

Flux

(µ

g/cm

²/h) R

efer

ence

N

o da

ta a

vaila

ble

N

o da

ta a

vaila

ble

No

quan

titat

ive

expe

rimen

tal d

ata

on d

erm

al u

ptak

e w

ere

foun

d in

the

liter

atur

e.

Acc

ordi

ng to

the

Swed

ish

cons

ensu

s rep

ort (

AoH

198

7:39

) the

LD

50 v

alue

in a

nim

al st

udie

s sho

w th

at

ally

l alc

ohol

is a

bsor

bed

via

the

skin

. No

furth

er d

etai

ls a

re g

iven

.

Smyt

h et

al.

(194

8) re

port

sim

ilar o

ral a

nd d

erm

al L

D50

val

ues (

oral

LD

50 in

rat 6

4 m

g/kg

bw

, de

rmal

LD

50 in

rabb

its 4

5 m

g/kg

bw

), su

gges

ting

effic

ient

der

mal

pen

etra

tion.

Theo

retic

al c

alcu

latio

ns b

y Fi

sero

va-B

erge

rova

et a

l. (1

990)

sugg

est t

hat t

he p

oten

tial f

or d

erm

alab

sorp

tion

and

resu

lting

toxi

city

is si

gnifi

cant

.

Rep

orte

d da

ta

In v

itro

In v

ivo

Ase

ssm

ent

A5

App

endi

x A

Subs

tanc

e: A

llyla

min

e; 3

-am

inop

rope

neM

olec

ular

wei

ght:

57.1

CA

S: 1

07-1

1-9

Den

sity

:0.7

61 g

/cm

³Sc

ient

ific

basi

s: A

oH 1

983:

36M

eltin

g po

int:

-88°

CB

oilin

g po

int:

53°C

Skin

not

atio

n: Y

esV

apou

r pr

essu

re:2

6 kP

a (a

t 20°

C)

Skin

per

mea

bilit

y: N

o da

taE

vapo

ratio

n ra

te:N

ot a

vaila

ble

Log

Kow

:0.0

3

Sp

Loc

C

ell

L

(µm

) A

(c

m²)

V

(ml)

Veh

icle

C

(m

g/m

l) n

TE

xp

(h)

TO

bs

(h)

TL

ag

(h)

Abs

(%

) K

P

(10-4

cm

/h)

Flux

(µ

g/cm

²/h) R

efer

ence

N

o da

ta a

vaila

ble

N

o da

ta a

vaila

ble

No

quan

titat

ive

expe

rimen

tal d

ata

on d

erm

al u

ptak

e w

ere

foun

d in

the

liter

atur

e.

Acc

ordi

ng to

the

Swed

ish

cons

ensu

s doc

umen

t (A

oH 1

983:

36) s

kin

upta

ke m

ay o

ccur

with

mas

sive

exp

osur

e.N

o fu

rther

det

ails

are

giv

en.

Cla

yton

et a

l. (1

981)

(pag

e 31

46) r

efer

s to

a de

rmal

LD

50 o

f 27

mg/

kg b

w in

rabb

its. T

his v

ery

low

LD

50

is e

ven

low

er th

an th

e or

al L

D50

in ra

ts o

f 81

mg/

kg b

w.

Rep

orte

d da

ta

In v

itro

In v

ivo

Ase

ssm

ent

A6

App

endi

x A

Subs

tanc

e: A

llylc

hlor

ide;

3-c

hlor

opre

neM

olec

ular

wei

ght:

76.5

CA

S: 1

07-0

5-1

Den

sity

:0.9

38 g

/cm

³Sc

ient

ific

basi

s: A

oH 1

989:

32M

eltin

g po

int:

-134

.5°C

Boi

ling

poin

t:44

to 4

6°C

Skin

not

atio

n: Y

esV

apou

r pr

essu

re:3

9 kP

a (a

t 20°

C)

Skin

per

mea

bilit

y: N

o da

taE

vapo

ratio

n ra

te:7

Log

Kow

:1.9

3 (e

stim

ated

)

Sp

Loc

C

ell

L

(µm

) A

(c

m²)

V

(ml)

Veh

icle

C

(m

g/m

l) n

TE

xp

(h)

TO

bs

(h)

TL

ag

(h)

Abs

(%

) K

P

(10-4

cm

/h)

Flux

(µ

g/cm

²/h) R

efer

ence

N

o da

ta a

vaila

ble

N

o da

ta a

vaila

ble

No

quan

titat

ive

expe

rimen

tal d

ata

on d

erm

al u

ptak

e w

ere

foun

d in

the

liter

atur

e.

No

info

rmat

ion

rega

rdin

g de

rmal

toxi

city

is g

iven

in th

e sc

ient

ific

basi

s (A

oH 1

989)

.

The

prop

osal

of a

skin

not

atio

n by

AC

GIH

(200

1) is

bas

ed u

pon

an u

npub

lishe

d in

dust

rial r

epor

t.

Rep

orte

d da

ta

In v

itro

In v

ivo

Ase

ssm

ent

A7

App

endi

x A

Subs

tanc

e: A

lum

iniu

m c

hlor

ohyd

rate

Mol

ecul

ar w

eigh

t:N

ot a

vaila

ble

CA

S: 1

327-

41-9

Den

sity

:1.1

5 g/

cm³

Scie

ntifi

c ba

sis:

Not

ava

ilabl

e M

eltin

g po

int:

Not

ava

ilabl

eB

oilin

g po

int:

Not

ava

ilabl

eSk

in n

otat

ion:

No

Vap

our

pres

sure

:Not

ava

ilabl

eSk

in p

erm

eabi

lity:

Ext

rem

ely

low

Eva

pora

tion

rate

:Not

ava

ilabl

eL

og K

ow:N

ot a

vaila

ble

Sp

Loc

C

ell

L

(µm

) A

(c

m²)

V

(ml)

Veh

icle

C

(m

g/m

l) n

TE

xp

(h)

TO

bs

(h)

TL

ag

(h)

Abs

(%

) K

P

(10-4

cm

/h)

Flux

(µ

g/cm

²/h) R

efer

ence

N

o da

ta a

vaila

ble

Hum

Pit

770.

4H

2O

21%

(13m

g A

l)2

144

1272

~63.

6 µg

0.00

0015

0.00

032

Flar

end

et a

l. (2

001)

The

stud

y of

Fla

rend

et a

l. (2

001)

is p

erfo

rmed

on

hum

ans s

ubje

cts b

y ex

posi

ng th

em to

deo

dora

nts c

onta

inin

g al

umin

ium

.

The

perm

eabi

lity

corr

espo

nds t

o "e

xtre

mel

y lo

w".

Rep

orte

d da

ta

In v

itro

In v

ivo

Ase

ssm

ent

A8

App

endi

x A

Subs

tanc

e: A

nilin

eM

olec

ular

wei

ght:

93.1

CA

S: 6

2-53

-3D

ensi

ty:1

.022

g/c

m³

Scie

ntifi

c ba

sis:

AoH

198

9:32

Mel

ting

poin

t:-6

.2°C

Boi

ling

poin

t:18

4°C

Skin

not

atio

n: Y

esV

apou

r pr

essu

re:4

0 Pa

(at 2

0°C

)Sk

in p

erm

eabi

lity:

Hig

hE

vapo

ratio

n ra

te:0

.048

Log

Kow

:0.9

0

Sp

Loc

C

ell

L

(µm

) A

(c

m²)

V

(ml)

Veh

icle

C

(m

g/m

l) n

TE

xp

(h)

TO

bs

(h)

TL

ag

(h)

Abs

(%

) K

P

(10-4

cm

/h)

Flux

(µ

g/cm

²/h) R

efer

ence

Hum

Ab

320

Nea

t4-

69

927

1900

Bar

ry e

t al.

(198

5)H

umA

b32

0V

apSa

tura

ted

4-6

99

2426

0B

arry

et a

l. (1

985)

HM

Ba

0.8

0.01

Nea

t10

24

220

µg1.

314

0Su

sten

et a

l. (1

990)

Hum

Arm

260.

25N

eat

50.

524

39 m

g27

3000

Bar

anow

ska-

Dut

kiew

icz

(198

2b)

Hum

Arm

260.

25H

2O

97%

60.

524

33 m

g24

2500

Bar

anow

ska-

Dut

kiew

icz

(198

2b)

Hum

Ha

350-

460

Inf

H2O

2%

40.

524

230

mg

600

1220

Bar

anow

ska-

Dut

kiew

icz

(198

2b)

Hum

Ha

350-

370

Inf

H2O

2%

21

2430

0 m

g39

082

0B

aran

owsk

a-D

utki

ewic

z (1

982b

)H

umH

a35

0-42

0In

fH

2O

1%4

0.5

2458

mg

3232

0B

aran

owsk

a-D

utki

ewic

z (1

982b

)H

umH

a35

0-44

0In

fH

2O

1%4

124

80 m

g20

020

0B

aran

owsk

a-D

utki

ewic

z (1

982b

)

The

stud

ies w

ith m

inut

e vo

lum

es a

pplie

d (≤

0.2

5 m

l) ar

e ex

clud

ed si

nce

depl

etio

n m

ay h

ave

occu

rred

,re

sulti

ng in

und

eres

timat

es o

f flu

x an

d K

p.A

num

ber o

f qua

ntita

tive

stud

ies a

re a

vaila

ble,

ther

efor

e th

e hu

man

in v

ivo

stud

ies a

re p

refe

rred

.

The

Kp

valu

es o

f nea

t ani

line

rang

e fr

om 2

·10-3

to 3

·10-3

cm

/h, c

orre

spon

ding

to "

high

" pe

rmea

bilit

y.

Rep

orte

d da

ta

In v

itro

In v

ivo

Ase

ssm

ent

A9

App

endi

x A

Subs

tanc

e: A

rsen

ic a

cid

Mol

ecul

ar w

eigh

t:14

1.9

CA

S: 7

778-

39-4

Den

sity

:2 g

/cm

³Sc

ient

ific

basi

s: A

oH 1

984:

44M

eltin

g po

int:

35°C

Boi

ling

poin

t:16

0°C

Skin

not

atio

n: N

oV

apou

r pr

essu

re:N

ot a

vaila

ble

Skin

per

mea

bilit

y: L

owE

vapo

ratio

n ra

te:N

ot a

vaila

ble

Log

Kow

:-3.

14 (e

stim

ated

)

Sp

Loc

C

ell

L

(µm

) A

(c

m²)

V

(ml)

Veh

icle

C

(m

g/m

l) n

TE

xp

(h)

TO

bs

(h)

TL

ag

(h)

Abs

(%

) K

P

(10-4

cm

/h)

Flux

(µ

g/cm

²/h) R

efer

ence

Hum

Fl50

01

Soil

0.6

µg/c

m²

924

240.

40.

0001

1W

este

r et a

l. (1

993a

)H

umFl

500

10.

01H

2O0.

429

2424

0.9

0.03

80.

0016

Wes

ter e

t al.

(199

3a)

Hum

Br

Fl0.

3240

0H

2O0.

011

>65-

62.

50.

310.

0003

1B

erns

tam

et a

l. (2

002)

Hum

Br

Fl0.

3240

0H

2O0.

11

>65-

61.

30.

160.

0016

Ber

nsta

m e

t al.

(200

2)H

umB

rFl

0.32

400

H2O

0.25

1>6

5-6

4.7

0.59

0.01

5B

erns

tam

et a

l. (2

002)

Hum

Br

Fl0.

3240

0H

2O0.

51

>65-

65.

40.

680.

034

Ber

nsta

m e

t al.

(200

2)H

umB

rFl

0.32

400

H2O

11

>65-

67.

53.

90.

39B

erns

tam

et a

l. (2

002)

Pig

Ab

Fl20

00.

640.

01Et

2.5

µg14

1616

0.4

0.03

90.

0009

8Tu

rkal

l et a

l. (2

003)

Mon

Ab

12So

il

424

168

3.2

Wes

ter e

t al.

(199

3a)

Mon

Ab

120.

06H

2O

0.42

324

168

20.

042

0.00

18W

este

r et a

l. (1

993a

)M

on10

00.

5H

2O2.

7 (1

430

µg)

38

962.

80.

180.

05Lo

wne

y et

al.

(200

5)M

on10

0So

il1.

4 m

g/g

(560

µg)

38

960.

10.

60.

0008

4Lo

wne

y et

al.

(200

5)R

atTa

ilH

2O0.

01-0

.2M

11

0.02

71.

1-33

Dut

kiew

icz

(197

7)

The

Kp

of D

utki

ewic

z (1

977)

was

cal

cula

ted

by B

erns

tam

et a

l. (2

002)

.B

erns

tam

et a

l. (2

002)

use

d ar

tific

ial h

uman

skin

(cul

ture

d ke

ratin

ocyt

es),

ther

efor

e th

e va

lidity

of t

he re

sults

is q

uest

iona

ble.

The

sam

e pr

oble

m a

pplie

s to

the

stud

ies b

y W

este

r et a

l. (1

993a

) tha

t use

d so

il as

"ve

hicl

e" o

r use

d a

very

smal

l ap

plie

d vo

lum

e of

0.0

1 m

l.Th

e pr

efer

red

stud

y is

that

of L

owne

y et

al.

(200

5) w

ho a

pplie

d an

aqu

eous

solu

tion

of a

rsen

ic a

cid

on th

e sk

in o

f R

hesu

s mon

keys

for 8

h. T

he 9

6-h

excr

etio

n in

urin

e an

d fa

eces

was

com

pare

d to

that

of a

kno

wn

i.v. d

ose

of a

rsen

ic.

The

perm

eabi

lity

of a

rsen

ic in

mon

keys

cor

resp

onds

to "

low

".

Rep

orte

d da

ta

In v

itro

In v

ivo

Ase

ssm

ent

A10

App

endi

x A

Subs

tanc

e: A

rsen

ic tr

ioxi

deM

olec

ular

wei

ght:

395.

7C

AS:

132

7-53

-3D

ensi

ty:3

.74

g/cm

³Sc

ient

ific

basi

s: A

oH 1

984:

44M

eltin

g po

int:

193°

CB

oilin

g po

int:

465°

CSk

in n

otat

ion:

No

Vap

our

pres

sure

:Not

ava

ilabl

eSk

in p

erm

eabi

lity:

Mod

erat

eE

vapo

ratio

n ra

te:N

ot a

vaila

ble

Log

Kow

:-0.

13 (e

stim

ated

)

Sp

Loc

C

ell

L

(µm

) A

(c

m²)

V

(ml)

Veh

icle

C

(m

g/m

l) n

TE

xp

(h)

TO

bs

(h)

TL

ag

(h)

Abs

(%

) K

P

(10-4

cm

/h)

Flux

(µ

g/cm

²/h) R

efer

ence

Hum

Br

Fl0.

3240

0H

2O0.

11

>65-

60.

940.

0094

Ber

nsta

m e

t al.

(200

2)H

umB

rFl

0.32

400

H2O

0.25

1>6

5-6

0.96

0.02

4B

erns

tam

et a

l. (2

002)

Hum

Br

Fl0.

3240

0H

2O0.

51

>65-

60.

790.

04B

erns

tam

et a

l. (2

002)

Hum

Br

Fl0.

3240

0H

2O1

1>6

5-6

1.3

0.13

Ber

nsta

m e

t al.

(200

2)

N

o da

ta a

vaila

ble

The

only

foun

d st

udy

on a

rsen

ic tr

ioxi

de w

as th

e on

e by

Ber

nsta

m e

t al.

(200

2).

In th

e st

udy,

arti

ficia

l hum

an sk

in (c

ultu

red

kera

tinoc

ytes

) was

use

d, th

eref

ore

the

valid

ity o

f the

resu

lts a

re q

uest

iona

ble.

The

repo

rted

Kp

valu

es c

orre

spon

d to

"m

oder

ate"

per

mea

bilit

y.

Rep

orte

d da

ta

In v

itro

In v

ivo

Ase

ssm

ent

A11

App

endi

x A

Subs

tanc

e: B

enze

neM

olec

ular

wei

ght:

78.1

CA

S: 7

1-43

-2D

ensi

ty:0

.879

g/c

m³

Scie

ntifi

c ba

sis:

AoH

198

8:32

Mel

ting

poin

t:5.

5°C

Boi

ling

poin

t:80

.1°C

Skin

not

atio

n: Y

esV

apou

r pr

essu

re:7

.3 k

Pa (a

t 20°

C)

Skin

per

mea

bilit

y: M

oder

ate

Eva

pora

tion

rate

:Not

ava

ilabl

eL

og K

ow:2

.13

Sp

Loc

C

ell

L

(µm

) A

(c

m²)

V

(ml)

Veh

icle

C

(m

g/m

l) n

TE

xp

(h)

TO

bs

(h)

TL

ag

(h)

Abs

(%

) K

P

(10-4

cm

/h)

Flux

(µ

g/cm

²/h) R

efer

ence

Hum

Ab

StEp

iIn

fH

2O1.

813

44

1100

0.19

Bla

nk e

t al.

(198

5)H

umA

bSt

Epi

Inf

HD

4414

09.

40.

044

Bla

nk e

t al.

(198

5)H

umA

bSt

Epi

Inf

Oct

4411

037

0.17

Bla

nk e

t al.

(198

5)H

umA

bSt

Epi

Inf

Hex

440

240.

11B

lank

et a

l. (1

985)

Hum

Ab

StEp

iIn

fG

as44

90

140.

061

Bla

nk e

t al.

(198

5)H

umA

bSt

40N

eat

44

2118

00B

lank

et a

l. (1

985)

Hum

Ab

St40

Vap

0.36

(Sa

tura

ted)

44

2500

091

0B

lank

et a

l. (1

985)

Hum

Ab

St40

H2O

1.

8 (2

µl/m

l)13

44

1100

190

Bla

nk e

t al.

(198

5)H

umB

rFu

ll0.

350.

035

Nea

t10

0.5

0.5

0.25

mg/

cm²

5.7

500

Lode

n (1

986a

)H

umB

rFl

Full

Nea

t7

13.5

13.5

~3.7

1.1

99Lo

den

(198

6b)

Hum

Ab/

Br

Fl20

0-40

00.

240

0H

2O15

-50

µg/l

210

88

0.8

600-

3300

Nak

ai e

t al.

(199

7)H

um5

µl/c

m²T

ol0.

44 µ

g/cm

² (0

.01%

)4

1-12

0.12

0.00

5-0.

060.

0000

44-0

.000

53W

este

r et a

l. (2

000)

Hum

5 µl

/cm

²Tol

4.4

µg/c

m²

(0.1

%)

41-

120.

110.

0004

6-0.

055

0.00

04-0

.004

8W

este

r et a

l. (2

000)

Hum

5 µl

/cm

²Tol

6.6

µg/c

m²

(0.1

5%)

41-

120.

10.

0042

-0.0

50.

0005

5-0.

0066

Wes

ter e

t al.

(200

0)H

um5

µl/c

m²T

ol22

µg/

cm²

(0.5

%)

41-

120.

080.

0034

-0.0

40.

0015

-0.0

176

Wes

ter e

t al.

(200

0)H

um5

µl/c

m²H

2O4.

4 µg

/cm

² (0

.1%

)4

1-12

50.

2-2.

50.

018-

0.22

Wes

ter e

t al.

(200

0)H

um5

µl/c

m²H

2O22

µg/

cm²

(0.5

%)

41-

123.

90.

16-2

0.07

2-0.

86W

este

r et a

l. (2

000)

Mon

Nea

t2.

52.

51.

816

0Fr

anz

(198

4)M

PFl

900

3.1

Nea

t6

1818

2.4

210

Jaco

bs e

t al.

(199

3)M

PFl

900

3.1

Vap

0.36

(Sat

urat

ed)

618

1838

0014

0Ja

cobs

et a

l. (1

993)

Rat

Ab

StFu

ll2.

61

Nea

t46

0.5-

2.5

0.5-

2.5

0.67

41-9

20 µ

g2.

219

0Ts

urut

a (1

982)

Rep

orte

d da

ta

In v

itro

A12

App

endi

x A

Sp

Loc

C

ell

L

(µm

) A

(c

m²)

V

(ml)

Veh

icle

C

(m

g/m

l) n

TE

xp

(h)

TO

bs

(h)

TL

ag

(h)

Abs

(%

) K

P

(10-4

cm

/h)

Flux

(µ

g/cm

²/h) R

efer

ence

HM

Ba

0.8

0.00

45N

eat

752

s4

39 µ

g38

3400

Sust

en e

t al.

(198

5)H

MW

BV

ap0.

0097

(30

00pp

m)

62-

62-

662

005.

9Ts

urut

a (1

989)

HM

WB

Vap

0.00

32 (

1000

ppm

)6

2-6

2-6

6200

1.9

Tsur

uta

(198

9)H

MW

BV

ap0.

0006

4 (2

00pp

m)

62-

62-

662

000.

32Ts

urut

a (1

989)

Hum

Arm

35-4

5N

eat

52

2410

mg

2.8-

4.7

240-

400

Han

ke e

t al.

(200

0)M

onA

rm13

0.05

Nea

t (3.

4 m

g/cm

²)3

412

00.

170.

016

1.4

Mai

bach

et a

l. (1

981)

Mon

Arm

13N

eat (

68 m

g/cm

²)3

2.5

168

0.85

2.6

230

Mai

bach

et a

l. (1

981)

Rat

WB

Vap

0.13

(40

000

ppm

)5

44

0.8

1500

19M

cDou

gal e

t al.

(199

0)

Due

to la

ck o

f inf

orm

atio

n (n

o e.

g. a

rea,

vol

ume,

dur

atio

n) in

Wes

ter e

t al.

(200

0) th

e du

ratio

n of

the

expo

sure

was

ass

umed

to b

e be

twee

n 1

and

12h

due

to th

e sm

all a

mou

nt (5

µl/c

m²)

appl

ied,

resu

lting

in w

ide

span

s for

the

fluxe

s and

per

mea

bilit

ies.

The

perm

eabi

lity

thro

ugh

hum

an sk

in in

vitr

o va

ries t

rem

endo

usly

bet

wee

n st

udie

s, w

ith K

p va

lues

bet

wee

n 1·

10-4 c

m/h

for n

eat b

enze

ne a

nd 3

cm

/h fo

r sat

urat

ed v

apou

r. Th

e on

ly h

uman

in v

ivo

stud

y is

that

of H

anke

et a

l. (2

000)

(196

1, tr

ansl

ated

in 2

000)

, with

a K

p of

3·1

0-4 to

5·1

0-4 c

m/h

. Th

is is

in a

gree

men

t with

the

in v

itro

stud

ies u

sing

hum

an sk

in a

nd n

eat b

enze

ne (1

, 6 a

nd 2

1·10

-4 c

m/h

).

The

perm

eabi

lity

corr

espo

nds t

o "m

oder

ate"

.

In v

ivo

Ase

ssm

ent

A13

App

endi

x A

Subs

tanc

e: B

enzo

apyr

ene

Mol

ecul

ar w

eigh

t:25

2.3

CA

S: 5

0-32

-8D

ensi

ty:1

.351

g/c

m³

Scie

ntifi

c ba

sis:

Not

ava

ilabl

e M

eltin

g po

int:

176.

5°C

Boi

ling

poin

t:49

5°C

Skin

not

atio

n: Y

esV

apou

r pr

essu

re:N

ot a

vaila

ble

Skin

per

mea

bilit

y: E

xtre

mel

y lo

wE

vapo

ratio

n ra

te:N

ot a

vaila

ble

Log

Kow

:6.1

3

Sp

Loc

C

ell

L

(µm

) A

(c

m²)

V

(ml)

Veh

icle

C

(m

g/m

l) n

TE

xp

(h)

TO

bs

(h)

TL

ag

(h)

Abs

(%

) K

P

(10-4

cm

/h)

Flux

(µ

g/cm

²/h) R

efer

ence

GP

Ba

Fl50

00.

640.

01A

cN

eat (

13 µ

g/cm

²)4

2448

280.

0011

0.15

Moo

dy e

t al.

(199

5)G

PB

aFl

200

0.64

0.01

Ac

Nea

t (8

µg/c

m²)

524

2437

0.00

090.

12N

g et

al.

(199

2)G

PB

aFl

200

0.64

0.01

Ac

Nea

t (8

µg/c

m²)

524

2410

0.00

025

0.03

4N

g et

al.

(199

2)G

PB

aFl

200

0.64

0.01

Ac

Nea

t (74

µg/

cm²)

524

247.

20.

0016

0.22

Ng

et a

l. (1

992)

GP

Full

5N

eat (

10 µ

g)4

2424

0.33

0.00

0001

90.

0002

5K

ao e

t al.

(198

5)H

GP

Fl20

00.

640.

01A

c 0.

19 (

3µg/

cm²)

2-5

2424

4.6

0.31

0.00

58St

orm

et a

l. (1

990)

HM

Ba

FlFu

ll2

0.01

-0.0

2A

cN

eat (

2.5

µg/c

m²)

1016

162.

90.

0000

330.

0045

Kao

et a

l. (1

988)

HM

Ba

FlFu

ll2

0.01

-0.0

2A

cN

eat (

2.5

µg/c

m²)

916

162

0.00

0023

0.00

31K

ao e

t al.

(198

8)H

umA

bFl

500

0.64

0.01

Ac

Nea

t (9.

8 µg

/cm

²)4

2448

3.3

0.00

0096

0.01

3M

oody

et a

l. (1

995)

Hum

Ab

Fl50

00.

640.

01A

cN

eat (

8.4

µg/c

m²)

424

481.

50.

0000

390.

0053

Moo

dy e

t al.

(199

5)H

umFS

/TM

Fl30

00.

640.

01A

cN

eat (

9.1

µg/c

m²)

424

480.

20.

0000

056

0.00

076

Moo

dy e

t al.

(199

5)H

umSt

350

1.8

18 m

gSo

il92

0 m

g so

il/kg

4-5

9696

110

13St

roo

et a

l. (2

005)

Hum

St35

01.

818

mg

Soil

140

mg

soil/

kg4-

596

9654

6.7

Stro

o et

al.

(200

5)H

umSt

350

1.8

18 m

gSo

il17

00 m

g so

il/kg

4-5

9696

160

20St

roo

et a

l. (2

005)

Hum

St35

01.

818

mg

Soil

110

mg

soil/

kg4-

596

9627

3.3

Stro

o et

al.

(200

5)H

umSt

350

1.8

18 m

gSo

il38

mg

soil/

kg4-

596

9627

3.3

Stro

o et

al.

(200

5)H

umSt

350

1.8

18 m

gSo

il82

0 m

g so

il/kg

4-5

9696

160

20St

roo

et a

l. (2

005)

Hum

St35

01.

818

mg

Soil

630

mg

soil/

kg4-

596

9611

013

Stro

o et

al.

(200

5)H

umFl

500

140

mg

Soil

0.01

4 (1

0 pp

m)

624

240.

0112

0.01

7W

este

r et a

l. (1

990)

Hum

Fl50

01

0.6

Ac

Nea

t (5

8 µg

)6

2424

0.09

0.00

0016

0.00

22W

este

r et a

l. (1

990)

Hum

Fl20

00.

640.

01A

c 0.

19 (

3 µg

/cm

²)2-

524

240.

80.

053

0.00

1St

orm

et a

l. (1

990)

Hum

Ab

Fl10

000.

84

µg/c

m²

1H

awki

ns e

t al.

(198

6)H

umFu

ll5

Nea

t (10

µg)

424

242.

70.

0000

170.

0023

Kao

et a

l. (1

985)

Rep

orte

d da

ta

In v

itro

A14

App

endi

x A

Sp

Loc

C

ell

L

(µm

) A

(c

m²)

V

(ml)

Veh

icle

C

(m

g/m

l) n

TE

xp

(h)

TO

bs

(h)

TL

ag

(h)

Abs

(%

) K

P

(10-4

cm

/h)

Flux

(µ

g/cm

²/h) R

efer

ence

Mon

Full

5N

eat (

10 µ

g)4

2424

3.3

0.00

0021

0.00

28K

ao e

t al.

(198

5)M

ouB

aFl

Full

20.

01-0

.02

Ac

Nea

t (2.

5 µg

/cm

²)5

1616

6.8

0.00

0081

0.01

1K

ao e

t al.

(198

8)M

ouB

aFl

Full

20.

01-0

.02

Ac

Nea

t (2.

5 µg

/cm

²)10

1616

6.8

0.00

0081

0.01

1K

ao e

t al.

(198

8)M

ouB

aFl

Full

20.

01-0

.02

Ac

Nea

t (2.

5 µg

/cm

²)10

1616

9.4

0.00

011

0.01

5K

ao e

t al.

(198

8)M

ouB

aFl

Full

20.

01-0

.02

Ac

Nea

t (2.

5 µg

/cm

²)10

1616

9.2

0.00

010.

014

Kao

et a

l. (1

988)

Mou

Ba

FlFu

ll2

0.01

-0.0

2A

cN

eat (

2.5

µg/c

m²)

1016

164.

40.

0000

50.

0068

Kao

et a

l. (1

988)

Mou

Ba

FlFu

ll2

0.01

Ac

Nea

t (10

ng)

1717

150.

0000

0033

0.00

0044

Hol

land

et a

l. (1

984)

Mou

Ba

FlFu

ll2

0.01

Ac

Nea

t (10

0 ng

)17

1730

0.00

0006

0.00

088

Hol

land

et a

l. (1

984)

Mou

Ba

FlFu

ll2

0.01

Ac

Nea

t (10

00 n

g)17

1725

0.00

0054

0.00

73H

olla

nd e

t al.

(198

4)M

ouB

aFl

Full

20.

01A

cN

eat (

2500

ng)

1717

160.

0000

90.

012

Hol

land

et a

l. (1

984)

Mou

Ba

FlFu

ll2

0.01

Ac

Nea

t (50

00 n

g)17

1714

0.00

016

0.02

1H

olla

nd e

t al.

(198

4)M

ouB

aFl

Full

20.

01A

cN

eat (

5000

ng)

2016

1611

0.00

013

0.01

7H

olla

nd e

t al.

(198

4)M

ouB

aFl

Full

20.

01A

cN

eat (

1000

0 ng

)17

178

0.00

018

0.02

4H

olla

nd e

t al.

(198

4)M

ouFl

Full

0.64

0.01

Ac

0.19

(3µ

g/cm

²)2-

524

243.

10.

210.

0039

Stor

m e

t al.

(199

0)M

ouB

aFl

Full

0.8

4 µg

/cm

²6

Haw

kins

et a

l. (1

986)

Mou

Ba

Full

50.

02A

cN

eat (

5 µg

)4

2424

240.

0000

740.

01K

ao e

t al.

(198

4)M

ouB

aFu

ll5

0.02

Ac

Nea

t (10

µg)

424

2417

0.00

010.

014

Kao

et a

l. (1

984)

Mou

Ba

Full

50.

02A

cN

eat (

20 µ

g)4

2424

120.

0001

50.

02K

ao e

t al.

(198

4)M

ouB

aFu

ll5

0.02

Ac

Nea

t (30

µg)

424

247.

20.

0001

30.

018

Kao

et a

l. (1

984)

Mou

Full

5N

eat (

10 µ

g)4

2424

100.

0000

610.

0083

Kao

et a

l. (1

985)

Pig

Ba

Fl10

000.

84

µg/c

m²

0.6

Haw

kins

et a

l. (1

986)

Rab

Full

5N

eat (

10 µ

g)4

2424

1.7

0.00

001

0.00

14K

ao e

t al.

(198

5)R

atB

aFl

500

0.64

0.01

Ac

Nea

t (11

µg/

cm²)

424

4851

0.00

170.

23M

oody

et a

l. (1

995)

Rat

Fl20

00.

640.

01A

c 0.

19 (

3µg/

cm²)

2-5

2424

3.8

0.25

0.00

48St

orm

et a

l. (1

990)

Rat

Ba

St35

01.

8O

il10

0ppm

(90

µg/c

m²)

596

9638

0.27

0.36

Yan

g et

al.

(198

9)R

atB

aSt

350

1.8

Soil

1% (9

mg

soil/

cm²)

596

968.

40.

058

0.07

9Y

ang

et a

l. (1

989)

Rat

Ba

St32

01.

8So

lvN

eat (

9.3

- 9.9

µg/

cm²)

412

012

02.

10.

0000

130.

0017

Yan

g et

al.

(198

6)R

atB

aSt

Full

1.8

Solv

Nea

t (9.

3 - 9

.9 µ

g/cm

²)4

120

120

280.

0001

70.

023

Yan

g et

al.

(198

6)R

atB

aSt

350

1.8

Solv

Nea

t (9.

3 - 9

.9 µ

g/cm

²)4

120

120

500.

0003

0.04

Yan

g et

al.

(198

6)R

atFl

300

0.64

0.00

96A

cN

eat?

(2-

5 µg

/cm

²)3

168

168

3.7

0.00

0003

-0.0

0000

810.

0004

4-0.

0011

Bro

naug

h et

al.

(198

6)R

atFl

300

0.64

0.00

96A

cN

eat?

(2-

5 µg

/cm

²)3

168

168

560.

0000

5-0.

0001

30.

0067

-0.0

17B

rona

ugh

et a

l. (1

986)

Rat

Full

5N

eat (

10 µ

g)4

2424

20.

0000

130.

0017

Kao

et a

l. (1

985)

A15

App

endi

x A

Sp

Loc

C

ell

L

(µm

) A

(c

m²)

V

(ml)

Veh

icle

C

(m

g/m

l) n

TE

xp

(h)

TO

bs

(h)

TL

ag

(h)

Abs

(%

) K

P

(10-4

cm

/h)

Flux

(µ

g/cm

²/h) R

efer

ence

GP

Ba

80.

1A

c N

eat (

17 µ

g/cm

²)4

66

4.1

0.00

090.

12C

hu e

t al.

(199

6)G

PB

a8

0.1

Ac

Nea

t (22

µg/

cm²)

424

2417

0.00

110.

15C

hu e

t al.

(199

6)G

PB

a8

0.1

Ac

Nea

t (32

µg/

cm²)

424

4823

0.00

220.

3C

hu e

t al.

(199

6)G

PB

a8

0.1

Ac

Nea

t (87

µg/

cm²)

424

168

240.

0065

0.87

Chu

et a

l. (1

996)

GP

Ba

4.2

0.05

Ac

Nea

t (9.

1 µg

/cm

²)4

2433

668

0.00

190.

26M

oody

et a

l. (1

995)

GP

Ba

40.

05A

c N

eat (

28 µ

g)5

2416

873

0.00

160.

22N

g et

al.

(199

2)M

onA

b12

480

mg

Soil

0.01

4 (1

0 pp

m)

424

144

131.

60.

0022

Wes

ter e

t al.

(199

0)M

onA

b12

Ac

Nea

t (5

8 µg

)4

2414

451

0.00

074

0.1

Wes

ter e

t al.

(199

0)M

ouB

a1.

8≤0

.015

Ac

15 (1

30 µ

g/cm

²)5-

624

2441

1.4

2.1

Sand

ers e

t al.

(198

4)M

ouB

a1.

8≤0

.015

Ac

15 (1

30 µ

g/cm

²)5-

624

2484

0.29

0.43

Sand

ers e

t al.

(198

4)M

ouB

a1.

8≤0

.015

Ac

15 (1

30 µ

g/cm

²)5-

624

2482

0.02

90.

043

Sand

ers e

t al.

(198

4)R

atB

a4.

20.

05A

c N

eat (

6.1

µg/c

m²)

424

336

690.

0013

0.17

Moo

dy e

t al.

(199

5)R

atB

a7

Oil

100p

pm (9

0 µg

/cm

²)5

9696

350.

240.

33Y

ang

et a

l. (1

989)

Rat

Ba

7So

il1%

(9 m

g so

il/cm

²)5

9696

9.2

0.06

40.

086

Yan

g et

al.

(198

9)R

atB

a1.

2N

eat (

9.2

µg/c

m²)

412

012

046

0.00

026

0.03

5Y

ang

et a

l. (1

986)

Rat

Ba

1.25

0.01

9A

cN

eat?

(2-

5 µg

/cm

²)5

2419

248

0.00

03-0

.000

740.

04-0

.1B

rona

ugh

et a

l. (1

986)

Nea

rly a

ll st

udie

s onl

y re

port

perc

ent a

bsor

bed

dose

. Flu

xes a

nd K

p va

lues

wer

e ca

lcul

ated

ass

umin

g co

nsta

nt

flux

durin

g th

e ex

posu

re.

The

in v

ivo

stud

y by

Chu

et a

l. (1

996)

is p

refe

rred

sinc

e a

rela

tivel

y la

rge

amou

nt o

f ben

zo[a

]pyr

ene

was

app

lied.

Furth

er it

repr

esen

ts th

e m

id-r

ange

of c

alcu

late

d K

p va

lues

.

The

Kp

of 1

·10-7

to 7

·10-7

cm

/h su

gges

ts "

extre

mel

y lo

w"

perm

eabi

lity

In v

ivo

Ase

ssm

ent

A16

App

endi

x A

Subs

tanc

e: B

orax

Mol

ecul

ar w

eigh

t:38

1.4

CA

S: 1

303-

96-4

Den

sity

:1.7

3 g/

cm³

Scie

ntifi

c ba

sis:

AoH

198

3:36

Mel

ting

poin

t:75

°CB

oilin

g po

int:

320°

CSk

in n

otat

ion:

Yes

Vap

our

pres

sure

:Not

ava

ilabl

eSk

in p

erm

eabi

lity:

Mod

erat

eE

vapo

ratio

n ra

te:N

ot a

vaila

ble

Log

Kow

:Not

ava

ilabl

e

Sp

Loc

C

ell

L

(µm

) A

(c

m²)

V

(ml)

Veh

icle

C

(m

g/m

l) n

TE

xp

(h)

TO

bs

(h)

TL

ag

(h)

Abs

(%

) K

P

(10-4

cm

/h)

Flux

(µ

g/cm

²/h) R

efer

ence

Hum

Leg

Fl50

01

1H

2O50

624

240.

411.

78.

5W

este

r et a

l. (1

998a

)

Hum

Ba

900

1.8

H2O

50

(2 µ

l/cm

²)8

2416

80.

210.

0018

0.00

9W

este

r et a

l. (1

998b

)

The

very

low

flux

and

Kp

in th

e in

viv

o st

udy

(Wes

ter e

t al.

(199

8b))

is li

kely

due

to th

e sm

all a

mou

nt a

pplie

d (2

µl/c

m² o

r 6 µ

g/cm

²).

The

perm

eabi

lity,

of t

he in

vitr

o st

udy

(Wes

ter e

t al.

(199

8a))

, cor

resp

onds

to "

mod

erat

e".

Rep

orte

d da

ta

In v

itro

In v

ivo

Ase

ssm

ent

A17

App

endi

x A

Subs

tanc

e: B

utan

ol, i

so-

Mol

ecul

ar w

eigh

t:74

.1C

AS:

78-

83-1

Den

sity

:0.8

02 g

/cm

³Sc

ient

ific

basi

s: A

oH 1

984:

44M

eltin

g po

int:

-108

°CB

oilin

g po

int:

107.

9°C

Skin

not

atio

n: Y

esV

apou

r pr

essu

re:1

.2 k

Pa (a

t 20°

C)

Skin

per

mea

bilit

y: N

o da

taE

vapo

ratio

n ra

te:2

Log

Kow

:0.7

6

Sp

Loc

C

ell

L

(µm

) A

(c

m²)

V

(ml)

Veh

icle

C

(m

g/m

l) n

TE

xp

(h)

TO

bs

(h)

TL

ag

(h)

Abs

(%

) K

P

(10-4

cm

/h)

Flux

(µ

g/cm

²/h) R

efer

ence

N

o da

ta a

vaila

ble

N

o da

ta a

vaila

ble

The

perm

eabi

lity

prop

ertie

s can

be

assu

med

to b

e si

mila

r to

that

of n

-but

anol

.

Rep

orte

d da

ta

In v

itro

In v

ivo

Ase

ssm

ent

A18

App

endi

x A

Subs

tanc

e: B

utan

ol, n

-M

olec

ular

wei

ght:

74.1

CA

S: 7

1-36

-3D

ensi

ty:0

.81

g/cm

³Sc

ient

ific

basi

s: A

oH 1

984:

44M

eltin

g po

int:

-89.

5°C

Boi

ling

poin

t:11

7.6°

CSk

in n

otat

ion:

Yes

Vap

our

pres

sure

:0.7

kPa

(at 2

0°C

)Sk

in p

erm

eabi

lity:

Mod

erat

eE

vapo

ratio

n ra

te:0

.46

Log

Kow

:0.8

8

Sp

Loc

C

ell

L

(µm

) A

(c

m²)

V

(ml)

Veh

icle

C

(m

g/m

l) n

TE

xp

(h)

TO

bs

(h)

TL

ag

(h)

Abs

(%

) K

P

(10-4

cm

/h)

Flux

(µ

g/cm

²/h) R

efer

ence

Dog

Br

StFu

ll1

5%5

55

2811

1M

ills e

t al.

(200

3)H

umA

bSt

26.6

2.5

H2O

7.

48

2519

Sche

uple

in e

t al.

(197

3)H

umA

bSt

2500

2.5

H2O

7.

43

300

220

Sche

uple

in e

t al.

(197

3)H

umA

bSt

26.6

2.5

Nea

t7

0.6

48Sc

heup

lein

et a

l. (1

973)

Hum

Ab

St25

002.

5N

eat

810

820

Sche

uple

in e

t al.

(197

3)H

umFl

250

10.

2-0.

3N

eat

324

241.

8 (9

h)4.

1-6.

233

0-50

0B

oman

et a

l. (2

000)

Hum

Fl25

01

0.2-

0.3

Tol

50%

521

2170

(10h

)14

0-20

056

00-8

400

Bom

an e

t al.

(200

0)H

umFl

250

10.

2-0.

3C

hf +

Me

50%

621

2122

21-3

284

0-13

00B

oman

et a

l. (2

000)

Mou

Ab/

Ba

StFu

ll0.

61.

4N

aCl

0.00

01M

40.

30.

365

Beh

l et a

l. (1

980)

Mou

Ab/

Ba

StFu

ll0.

61.

4N

aCl

0.00

01M

44.

34.

382

Beh

l et a

l. (1

980)

Mou

Ab/

Ba

StFu

ll0.

61.

4N

aCl

0.00

01M

47.

87.

812

0B

ehl e

t al.

(198

0)M

ouA

b/B

aSt

Full

0.6

1.4

NaC

l0.

0001

M4

11.3

11.3

120

Beh

l et a

l. (1

980)

Mou

Ab/

Ba

StFu

ll0.

61.

4N

aCl

0.00

01M

414

.314

.312

0B

ehl e

t al.

(198

0)M

ouA

b/B

aSt

Full

0.6

1.4

NaC

l0.

0001

M1

26.3

26.3

120

Beh

l et a

l. (1

980)

Mou

Ab/

Ba

StFu

ll0.

61.

4N

aCl

0.00

01M

40.

30.

342

Beh

l et a

l. (1

980)

Mou

Ab/

Ba

StFu

ll0.

61.

4N

aCl

0.00

01M

45.

85.

868

Beh

l et a

l. (1

980)

Mou

Ab/

Ba

StFu

ll0.

61.

4N

aCl

0.00

01M

49.

89.

873

Beh

l et a

l. (1

980)

Mou

Ab/

Ba

StFu

ll0.

61.

4N

aCl

0.00

01M

413

.811

.375

Beh

l et a

l. (1

980)

Mou

Ab/

Ba

StFu

ll0.

61.

4N

aCl

0.00

01M

417

.814

.373

Beh

l et a

l. (1

980)

Mou

Ab/

Ba

StFu

ll0.

61.

4N

aCl

0.00

01M

426

.326

.379

Beh

l et a

l. (1

980)

Mou

Ab

StFu

ll0.

60.

2N

aCl

32

237

Beh

l et a

l. (1

984)

Mou

Ab

StFu

ll0.

60.

2N

aCl

22

242

Beh

l et a

l. (1

984)

Mou

Ab

StFu

ll0.

60.

2N

aCl

42

287

Beh

l et a

l. (1

984)

Mou

Ab

StFu

ll0.

60.

2N

aCl

52

213

0B

ehl e

t al.

(198

4)

Rep

orte

d da

ta

In v

itro

A19

App

endi

x A

Sp

Loc

C

ell

L

(µm

) A

(c

m²)

V

(ml)

Veh

icle

C

(m

g/m

l) n

TE

xp

(h)

TO

bs

(h)

TL

ag

(h)

Abs

(%

) K

P

(10-4

cm

/h)

Flux

(µ

g/cm

²/h) R

efer

ence

Mou

Ab

StFu

ll0.

60.

2N

aCl

42

241

Beh

l et a

l. (1

984)

Mou

Ab

StFu

ll0.

60.

2N

aCl

52

265

Beh

l et a

l. (1

984)

Mou

Ab

StFu

ll0.

60.

2N

aCl

42

240

Beh

l et a

l. (1

984)

Mou

Ba

StFu

ll0.

60.

2N

aCl

32

287

Beh

l et a

l. (1

984)

Mou

Ba

StFu

ll0.

60.

2N

aCl

22

210

0B

ehl e

t al.

(198

4)M

ouB

aSt

Full

0.6

0.2

NaC

l2

22

170

Beh

l et a

l. (1

984)

Mou

Ba

StFu

ll0.

60.

2N

aCl

52

224

0B

ehl e

t al.

(198

4)M

ouB

aSt

Full

0.6

0.2

NaC

l4

22

62B

ehl e

t al.

(198

4)M

ouB

aSt

Full

0.6

0.2

NaC

l5

22

65B

ehl e

t al.

(198

4)M

ouB

aSt

Full

0.6

0.2

NaC

l5

22

51B

ehl e

t al.

(198

4)M

ouA

bSt

Full

0.6

NaC

l0.

0001

M5

22

76B

ehl e

t al.

(198

1)M

ouA

bSt

Full

0.79

NaC

l≤1

0-4M

22

29D

urrh

eim

et a

l. (1

980)

Mou

Ab

StFu

ll0.

79N

aCl

≤10-

4M2

244

Dur

rhei

m e

t al.

(198

0)M

ouA

bSt

Full

0.79

NaC

l≤1

0-4M

22

150

Dur

rhei

m e

t al.

(198

0)M

PFl

900

3.1

Nea

t6

17.5

17.5

3.7

300

Jaco

bs &

Pha

npra

sit (

1993

)M

PFl

900

3.1

Vap

0.02

6 (S

at.)

617

.517

.533

000

86Ja

cobs

& P

hanp

rasi

t (19

93)

Dog

Br

56N

eat

21

829

mg

6.5

530

DiV

ince

nzo

et a

l. (1

979)

Bas

ed o

n ne

at so

lven

t, th

e pe

rmea

bilit

y is

con

side

red

"mod

erat

e" w

ith K

p va

lues

of 4

·10-4

to 1

·10-3

cm/h

(h

uman

full

thic

knes

s ski

n in

vitr

o) a

nd 7

·10-4

cm

/h (d

og in

viv

o).

It sh

ould

be

note

d th

at th

ere

seem

s to

be a

stro

ng v

ehic

le e

ffec

t of w

ater

. Thu

s, th

e pe

rmea

bilit

yin

mou

se sk

in o

f n-b

utan

ol in

phy

siol

ogic

al sa

line

rang

es fr

om 4

·10-3

to 2

·10-2

cm

/h.

Sim

ilar v

alue

s (3·

10-3

for s

tratu

m c

orne

um a

nd 3

·10-2

cm

/h fo

r ful

l thi

ckne

ss sk

in) a

re re

porte

d fo

r hum

an sk

in.

In v

ivo

Ase

ssm

ent

A20

App

endi

x A

Subs

tanc

e: B

utan

ol, s

ek-

Mol

ecul

ar w

eigh

t:74

.1C

AS:

78-

92-2

Den

sity

:0.8

06 g

/cm

³Sc

ient

ific

basi

s: A

oH 1

984:

44M

eltin

g po

int:

-115

°CB

oilin

g po

int:

99.5

°CSk

in n

otat

ion:

Yes

Vap

our

pres

sure

:1.6

kPa

(at 2

0°C

)Sk

in p

erm

eabi

lity:

No

data

Eva

pora

tion

rate

:1.3

Log

Kow

:0.6

1

Sp

Loc

C

ell

L

(µm

) A

(c

m²)

V

(ml)

Veh

icle

C

(m

g/m

l) n

TE

xp

(h)

TO

bs

(h)

TL

ag

(h)

Abs

(%

) K

P

(10-4

cm

/h)

Flux

(µ

g/cm

²/h) R

efer

ence

N

o da

ta a

vaila

ble

N

o da

ta a

vaila

ble

The

perm

eabi

lity

prop

ertie

s can

be

assu

med

to b

e si

mila

r to

that

of n

-but

anol

.

Acc

ordi

ng to

theo

retic

al c

alcu

latio

ns b

y Fi

sero

va-B

erge

rova

et a

l. (1

990)

the

pote

ntia

l for

der

mal

abso

rptio

n an

d re

sulti

ng to

xici

ty is

sign

ifica

nt.

Rep

orte

d da

ta

In v

itro

In v

ivo

Ase

ssm

ent

A21

App

endi

x A

Subs

tanc

e: B

utan

ol, t

ert-

Mol

ecul

ar w

eigh

t:74

.1C

AS:

75-

65-0

Den

sity

:0.7

86 g

/cm

³Sc

ient

ific

basi

s: A

oH 1

984:

44M

eltin

g po

int:

25.5

°CB

oilin

g po

int:

82.2

°CSk

in n

otat

ion:

Yes

Vap

our

pres

sure

:3.4

kPa

(at 2

0°C

)Sk

in p

erm

eabi

lity:

No

data

Eva

pora

tion

rate

:1.1

Log

Kow

:0.3

5

Sp

Loc

C

ell

L

(µm

) A

(c

m²)

V

(ml)

Veh

icle

C

(m

g/m

l) n

TE

xp

(h)

TO

bs

(h)

TL

ag

(h)

Abs

(%

) K

P

(10-4

cm

/h)

Flux

(µ

g/cm

²/h) R

efer

ence

N

o da

ta a

vaila

ble

N

o da

ta a

vaila

ble

The

perm

eabi

lity

prop

ertie

s can

be

assu

med

to b

e si

mila

r to

that

of n

-but

anol

.

Rep

orte

d da

ta

In v

itro

In v

ivo

Ase

ssm

ent

A22

App

endi

x A

Subs

tanc

e: B

utyl

ace

tate

, n-

Mol

ecul

ar w

eigh

t:11

6.2

CA

S: 1

23-8

6-4

Den

sity

:0.8

82 g

/cm

³Sc

ient

ific

basi

s: A

oH 1

984:

44M

eltin

g po

int:

-106

.2°C

Boi

ling

poin

t:12

6.1°

CSk

in n

otat

ion:

No

Vap

our

pres

sure

:1.2

kPa

(at 2

0°C

)Sk

in p

erm

eabi

lity:

Mod

erat

eE

vapo

ratio

n ra

te:1

Log

Kow

:1.7

8

Sp

Loc

C

ell

L

(µm

) A

(c

m²)

V

(ml)

Veh

icle

C

(m

g/m

l) n

TE

xp

(h)

TO

bs

(h)

TL

ag

(h)

Abs

(%

) K

P

(10-4

cm

/h)

Flux

(µ

g/cm

²/h) R

efer

ence

Hum

Br

St30

0-60

00.

64N

eat

36

62.

220

0U

rsin

et a

l. (1

995)

N

o da

ta a

vaila

ble

Urs

in e

t al.

(199

5) st

retc

hed

the

skin

whe

n m

ount

ing

it in

the

diff

usio

n ce

ll, re

achi

ng a

fina

l thi

ckne

ss o

f abo

ut

one-

third

of t

he o

rigin

al th

ickn

ess.

This

pro

cedu

re m

ay g

ive

over

estim

ates

of t

he fl

ux a

nd K

p va

lues

.

The

perm

eabi

lity

corr

espo

nds t

o "m

oder

ate"

.

Rep

orte

d da

ta

In v

itro

In v

ivo

Ase

ssm

ent

A23

App

endi

x A

Subs

tanc

e: B

utyl

amin

e, is

o-M

olec

ular

wei

ght:

73.1

CA

S: 7

8-81

-9D

ensi

ty:0

.724

g/c

m³

Scie

ntifi

c ba

sis:

AoH

198

3:36

Mel

ting

poin

t:-8

5°C

Boi

ling

poin

t:66

°CSk

in n

otat

ion:

Yes

Vap

our

pres

sure

:13

kPa

(at 1

8.8°

C)

Skin

per

mea

bilit

y: N

o da

taE

vapo

ratio

n ra

te:N

ot a

vaila

ble

Log

Kow

:0.7

3

Sp

Loc

C

ell

L

(µm

) A

(c

m²)

V

(ml)

Veh

icle

C

(m

g/m

l) n

TE

xp

(h)

TO

bs

(h)

TL

ag

(h)

Abs

(%

) K

P

(10-4

cm

/h)

Flux

(µ

g/cm

²/h) R

efer

ence

N

o da

ta a

vaila

ble

N

o da

ta a

vaila

ble

No

quan

titat

ive

expe

rimen

tal d

ata

on d

erm

al u

ptak

e w

ere

foun

d in

the

liter

atur

e.

Acc

ordi

ng to

the

Swed

ish

cons

ensu

s doc

umen

t (A

oH 1

983:

36) s

kin

upta

ke m

ay o

ccur

with

mas

sive

exp

osur

e.N

o fu

rther

det

ails

are

giv

en.

See

also

info

rmat

ion

on n

-but

ylam

ine.

Rep

orte

d da

ta

In v

itro

In v

ivo

Ase

ssm

ent

A24

App

endi

x A

Subs

tanc

e: B

utyl

amin

e, n

-M

olec

ular

wei

ght:

73.1

CA

S: 1

09-7

3-9

Den

sity

:0.7

41 g

/cm

³Sc

ient

ific

basi

s: A

oH 1

983:

36M

eltin

g po

int:

-50°

CB

oilin

g po

int:

77°C

Skin

not

atio

n: Y

esV

apou

r pr

essu

re:1

1 kP

a (a

t 20°

C)

Skin

per

mea

bilit

y: N

o da

taE

vapo

ratio

n ra

te:7

.3L

og K

ow:0

.97

Sp

Loc

C

ell

L

(µm

) A

(c

m²)

V

(ml)

Veh

icle

C

(m

g/m

l) n

TE

xp

(h)

TO

bs

(h)

TL

ag

(h)

Abs

(%

) K

P

(10-4

cm

/h)

Flux

(µ

g/cm

²/h) R

efer

ence

N

o da

ta a

vaila

ble

N

o da

ta a

vaila

ble

No

quan

titat

ive

expe

rimen

tal d

ata

on d

erm

al u

ptak

e w

ere

foun

d in

the

liter

atur

e.

Acc

ordi

ng to

the

Swed

ish

cons

ensu

s doc

umen

t (A

oH 1

983:

36) s

kin

upta

ke m

ay o

ccur

with

mas

sive

exp

osur

e.N

o fu

rther

det

ails

are

giv

en.

Cla

yton

et a

l. (1

981)

(pag

e 31

46) r

efer

s to

a th

e de

rmal

LD

50 o

f 370

mg/

kg b

w in

gui

nea

pig.

This

is lo

wer

than

the

oral

LD

50 in

rat (

500

mg/

kg b

w).

Theo

retic

al c

alcu

latio

ns b

y Fi

sero

va-B

erge

rova

et a

l. (1

990)

sugg

est t

hat t

he p

oten

tial f

or d

erm

alab

sorp

tion

and

resu

lting

toxi

city

is si

gnifi

cant

.

Rep

orte

d da

ta

In v

itro

In v

ivo

Ase

ssm

ent

A25

App

endi

x A

Subs

tanc

e: B

utyl

amin

e, se

c-M

olec

ular

wei

ght:

73.1

CA

S: 1

3952

-84-

6D

ensi

ty:0

.724

g/c

m³

Scie

ntifi

c ba

sis:

AoH

198

3:36

Mel

ting

poin

t:-8

5°C

Boi

ling

poin

t:66

°CSk

in n

otat

ion:

Yes

Vap

our

pres

sure

:18

kPa

(at 2

0°C

)Sk

in p

erm

eabi

lity:

No

data

Eva

pora

tion

rate

:Not

ava

ilabl

eL

og K

ow:0

.74

Sp

Loc

C

ell

L

(µm

) A

(c

m²)

V

(ml)

Veh

icle

C

(m

g/m

l) n

TE

xp

(h)

TO

bs

(h)

TL

ag

(h)

Abs

(%

) K

P

(10-4

cm

/h)

Flux

(µ

g/cm

²/h) R

efer

ence

N

o da

ta a

vaila

ble

N

o da

ta a

vaila

ble

No

quan

titat

ive

expe

rimen

tal d

ata

on d

erm

al u

ptak

e w

ere

foun

d in

the

liter

atur

e.

Acc

ordi

ng to

the

Swed

ish

cons

ensu

s doc

umen

t (A

oH 1

983:

36) s

kin

upta

ke m

ay o

ccur

with

mas

sive

exp

osur

e.N

o fu

rther

det

ails

are

giv

en.

See

also

info

rmat

ion

on n

-but

ylam

ine.

Rep

orte

d da

ta

In v

itro

In v

ivo

Ase

ssm

ent

A26

App

endi

x A

Subs

tanc

e: B

utyl

amin

e, te

rt-M

olec

ular

wei

ght:

73.1

CA

S: 7

5-64

-9D

ensi

ty:0

.696

g/c

m³

Scie

ntifi

c ba

sis:

AoH

198

3:36

Mel

ting

poin

t:-6

7.5°

CB

oilin

g po

int:

44.4

°CSk

in n

otat

ion:

Yes

Vap

our

pres

sure

:48

kPa

(at 2

5°C

)Sk

in p

erm

eabi

lity:

No

data

Eva

pora

tion

rate

:1L

og K

ow:0

.40

Sp

Loc

C

ell

L

(µm

) A

(c

m²)

V

(ml)

Veh

icle

C

(m

g/m

l) n

TE

xp

(h)

TO

bs

(h)

TL

ag

(h)

Abs

(%

) K

P

(10-4

cm

/h)

Flux

(µ

g/cm

²/h) R

efer

ence

N

o da

ta a

vaila

ble

N

o da

ta a

vaila

ble

No

quan

titat

ive

expe

rimen

tal d

ata

on d

erm

al u

ptak

e w

ere

foun

d in

the

liter

atur

e.

Acc

ordi

ng to

the

Swed

ish

cons

ensu

s doc

umen

t (A

oH 1

983:

36) s

kin

upta

ke m

ay o

ccur

with

mas

sive

exp

osur

e.N

o fu

rther

det

ails

are

giv

en.

See

also

info

rmat

ion

on n

-but

ylam

ine.

Rep

orte

d da

ta

In v

itro

In v

ivo

Ase

ssm

ent

A27

App

endi

x A

Subs

tanc

e: C

arbo

n di

sulfi

deM

olec

ular

wei

ght:

76.1

CA

S: 7

5-15

-0D

ensi

ty:1

.263

g/c

m³

Scie

ntifi

c ba

sis:

Not

ava

ilabl

e M

eltin

g po

int:

-110

°CB

oilin

g po

int:

46.2

°CSk

in n

otat

ion:

Yes

Vap

our

pres

sure

:35

kPa

(at 2

0°C

)Sk

in p

erm

eabi

lity:

Ver

y hi

ghE

vapo

ratio

n ra

te:2

3L

og K

ow:1

.94

Sp

Loc

C

ell

L

(µm

) A

(c

m²)

V

(ml)

Veh

icle

C

(m

g/m

l) n

TE

xp

(h)

TO

bs

(h)

TL

ag

(h)

Abs

(%

) K

P

(10-4

cm

/h)

Flux

(µ

g/cm

²/h) R

efer

ence

N

o da

ta a

vaila

ble

Hum

Ha

Inf

H2O

0.

3-1.

721

18

7-37

mg

250-

830

20-9

6B

aran

owsk

a (1

965)

The

only

ava

ilabl

e st

udy

is th

at o

f Bar

anow

ska

(196

5) (i

n G

erm

an) w

ere

the

subj

ect p

lace

d on

e ha

nd in

an

aque

ous

carb

on d

isul

fide

solu

tion

for 1

hou

r. Th

e up

take

of t

he su

bsta

nce

was

mea

sure

d vi

a br

eath

mon

itorin

g.

The

repo

rted

Kp

valu

es ra

nge

betw

een

3·10

-2 a

nd 9

·10-2

cm

/h, s

ugge

stin

g "v

ery

high

" pe

rmea

bilit

y.

Rep

orte

d da

ta

In v

itro

In v

ivo

Ase

ssm

ent

A28

App

endi

x A

Subs

tanc

e: C

arbo

n te

trach

lorid

eM

olec

ular

wei

ght:

153.

8C

AS:

56-

23-5

Den

sity

:1.5

94 g

/cm

³Sc

ient

ific

basi

s: N

ot a

vaila

ble

Mel

ting

poin

t:-2

2.9°

CB

oilin

g po

int:

76.7

°CSk

in n

otat

ion:

Yes

Vap

our

pres

sure

:10

kPa

(at 2

0°C

)Sk

in p

erm

eabi

lity:

Mod

erat

eE

vapo

ratio

n ra

te:1

3L

og K

ow:2

.83

Sp

Loc

C

ell

L

(µm

) A

(c

m²)

V

(ml)

Veh

icle

C

(m

g/m

l) n

TE

xp

(h)

TO

bs

(h)

TL

ag

(h)

Abs

(%

) K

P

(10-4

cm

/h)

Flux

(µ

g/cm

²/h) R

efer

ence

Rat

Ab

StFu

ll3.

71

Nea

t24

2-4

2-4

1.4

52-2

10 µ

g0.

1321

Tsur

uta

(197

7)

Mou

Ab

0.5

Nea

t6

0.25

360

µg3.

149

0Ts

urut

a (1

975)

The

in v

itro

stud

y of

Tsu

ruta

(197

7) u

sed

phys

iolo

gica

l sal

ine

as th

e re

cept

or m

ediu

m, t

his i

s uns

uita

ble

for h

ighl

y lip

ophi

lic su

bsta

nces

.Ts

urut

a (1

975)

mea

sure

d ab

sorp

tion

by h

omog

eniz

ing

the

who

le a

nim

al.

Der

mal

upt

ake

of c

arbo

n te

trach

lorid

e ha

s als

o be

en sh

own

in h

uman

s (St

ewar

t et a

l. (1

964)

), ho

wev

er, t

hat s

tudy

do

es n

ot c

onta

in su

ffic

ient

dat

a to

cal

cula

te fl

ux o

f Kp.

The

pref

erre

d st

udy

is T

suru

ta (1

975)

, wer

e th

e ca

lcul

ated

Kp

valu

e su

gges

ts "

mod

erat

e" p

erm

eabi

lity.

Rep

orte

d da

ta

In v

itro

In v

ivo

Ase

ssm

ent

A29

App

endi

x A

Subs

tanc

e: C

atec

hol

Mol

ecul

ar w

eigh

t:11

0.1

CA

S: 1

20-8

0-9

Den

sity

:1.3

g/c

m³

Scie

ntifi

c ba

sis:

AoH

199

2:47

Mel

ting

poin

t:10

4°C

Boi

ling

poin

t:24

5°C

Skin

not

atio

n: Y

esV

apou

r pr

essu

re:6

60 P

a (a

t 104

°C)

Skin

per

mea

bilit

y: M

oder

ate

Eva

pora

tion

rate

:Not

ava

ilabl

eL

og K

ow:0

.88

Sp

Loc

C

ell

L

(µm

) A

(c

m²)

V

(ml)

Veh

icle

C

(m

g/m

l) n

TE

xp

(h)

TO

bs

(h)

TL

ag

(h)

Abs

(%

) K

P

(10-4

cm

/h)

Flux

(µ

g/cm

²/h) R

efer

ence

Hum

Ab

Fl20

0-32

00.

640.

01PH

D6

30.

524

0.4

1.6

0.98

Jung

et a

l. (2

003)

Hum

Ab

Fl20

0-32

00.

640.

01H

DP

60.

524

1.8

7.3

4.4

Jung

et a

l. (2

003)

Rat

Ba

Fl20

0-32

00.

640.

01PH

D6

0.5

240.

20.

810.

49Ju

ng e

t al.

(200

3)R

atB

aFl

200-

320

0.64

0.01

HD

P6

0.5

242

8.1

4.9

Jung

et a

l. (2

003)

Rat

Ba

Fl20

0-32

00.

640.

01Et

68

0.5

246.

928

17Ju

ng e

t al.

(200

3)R

atB

aFl

200-

320

0.64

0.01

Et6

2424

423.

52.

1Ju

ng e

t al.

(200

3)R

atB

aFl

200-

320

0.64

0.01

Et6

2472

494.

12.

5Ju

ng e

t al.

(200

3)R

atB

aFl

200-

320

0.64

0.01

Et6

424

2478

6.6

3.9

Jung

et a

l. (2

003)

Rat

Ba

Fl20

0-32

00.

640.

01Et

64

2424

554.

72.

8Ju

ng e

t al.

(200

3)R

atB

aFl

200-

320

0.64

0.01

Et40

924

2481

6.8

27Ju

ng e

t al.

(200

3)R

atB

aFl

200-

320

0.64

0.01

Et40

924

7281

6.9

27Ju

ng e

t al.

(200

3)

Rat

Ba

90.

18Et

40

324

2445

3.7

15Ju

ng e

t al.

(200

3)R

atB

a9

0.18

Et

403

2472

534.

418

Jung

et a

l. (2

003)

A n

umbe

r of d

iffer

ent e

xper

imen

ts y

ield

sim

ilar r

esul

ts.

The

hum

an in

vitr

o an

d ra

t in

vivo

exp

erim

ents

giv

e K

p va

lues

bet

wee

n 2·1

0-4an

d 7·

10-4

cm/h

, co

rres

pond

ing

to "

mod

erat

e" p

erm

eabi

lity.

It sh

ould

be

note

d th

at e

ither

eth

anol

or h

air d

ye c

hem

ical

s wer

e us

ed a

s veh

icle

s, th

is m

ay h

ave

alte

red

the

perm

eabi

lity.

Rep

orte

d da

ta

In v

itro

In v

ivo

Ase

ssm

ent

A30

App

endi

x A

Subs

tanc

e: C

hlor

inat

ed b

iphe

nyls

, pol

y- (P

CB

)M

olec

ular

wei

ght:

291.

98 to

360

.86

CA

S: 1

336-

36-3

Den

sity

:1.4

to 1

.5 g

/cm

³Sc

ient

ific

basi

s: N

ot a

vaila

ble

Mel

ting

poin

t:N

ot a

vaila

ble

Boi

ling

poin

t:34

0 to

375

°CSk

in n

otat

ion:

Yes

Vap

our

pres

sure

:Not

ava

ilabl

eSk

in p

erm

eabi

lity:

No

data

Eva

pora

tion

rate

:Not

ava

ilabl

eL

og K

ow:6

.34

(est

imat

ed)

Sp

Loc

C

ell

L

(µm

) A

(c

m²)

V

(ml)

Veh

icle

C

(m

g/m

l) n

TE

xp

(h)

TO

bs

(h)

TL

ag

(h)

Abs

(%

) K

P

(10-4

cm

/h)

Flux

(µ

g/cm

²/h) R

efer

ence

N

o da

ta a

vaila

ble

N

o da

ta a

vaila

ble

No

Swed

ish

cons

ensu

s doc

umen

t or T

LV d

ocum

enta

tion

is p

rese

nt.

Gar

ner e

t al.

(199

8) sh

owed

that

the

less

chl

orin

ated

PC

Bs p

enet

rate

the

skin

mor

e ra

pidl

y. H

owev

er th

e m

etab

olis

mis

mor

e ra

pid

for t

hese

smal

ler m

olec

ules

, res

ultin

g in

a h

ighe

r bod

y bu

rden

for t

he h

ighe

r chl

orin

ated

PC

Bs.

Dat

a on

four

con

gene

rs (s

ee m

ono-

, di-,

tetra

- and

hex

achl

orob

iphe

nyl)

sugg

ests

that

the

perm

eabi

lity

of P

CB

is "

extre

mel

y lo

w"

to "

very

low

".

Rep

orte

d da

ta

In v

itro

In v

ivo

Ase

ssm

ent

A31

App

endi

x A

Subs

tanc

e: C

hlor

o-1,

3-bu

tadi

ene,

2-;

chlo

ropr

ene

Mol

ecul

ar w

eigh

t:88

.5C

AS:

126

-99-

8D

ensi

ty:N

ot a

vaila

ble

Scie

ntifi

c ba

sis:

AoH

198

6:35

Mel

ting

poin

t:-1

30°C

Boi

ling

poin

t:59

.4°C

Skin

not

atio

n: Y

esV

apou

r pr

essu

re:2

3 kP

a (a

t 20°

C)

Skin

per

mea

bilit

y: N

o da

taE

vapo

ratio

n ra

te:N

ot a

vaila

ble

Log

Kow

:2.5

3 (e

stim

ated

)

Sp

Loc

C

ell

L

(µm

) A

(c

m²)

V

(ml)

Veh

icle

C

(m

g/m

l) n

TE

xp

(h)

TO

bs

(h)

TL

ag

(h)

Abs

(%

) K

P

(10-4

cm

/h)

Flux

(µ

g/cm

²/h) R

efer

ence

N

o da

ta a

vaila

ble

N

o da

ta a

vaila

ble

No

quan

titat

ive

expe

rimen

tal d

ata

on d

erm

al u

ptak

e w

ere

foun

d in

the

liter

atur

e.

Acc

ordi

ng to

the

Swed

ish

crite

ria g

roup

(AoH

198

6) a

nd A

CG

IH (2

001)

an

old

stud

y (v

on O

ettin

gen

et a

l. (1

936)

)m

entio

ns th

at th

e su

bsta

nce

prob

ably

can

be

abso

rbed

thro

ugh

the

skin

in a

mou

nts l

arge

eno

ugh

to c

ause

acu

te e

ffec

ts.

Rep

orte

d da

ta

In v

itro

In v

ivo

Ase

ssm

ent

A32

App

endi

x A

Subs

tanc

e: C

hlor

obip

heny

l, di

- (D

CB

)M

olec

ular

wei

ght:

Not

ava

ilabl

eC

AS:

255

12-4

2-9

Den

sity

:1.4

g/c

m³

Scie

ntifi

c ba

sis:

Not

ava

ilabl

e M

eltin

g po

int:

149°

CB

oilin

g po

int:

Not

ava

ilabl

eSk

in n

otat

ion:

Yes

Vap

our

pres

sure

:Not

ava

ilabl

eSk

in p

erm

eabi

lity:

Ver

y lo

wE

vapo

ratio

n ra

te:N

ot a

vaila

ble

Log

Kow

:5.5

9 (e

stim

ated

)

Sp

Loc

C

ell

L

(µm

) A

(c

m²)

V

(ml)

Veh

icle

C

(m

g/m

l) n

TE

xp

(h)

TO

bs

(h)

TL

ag

(h)

Abs

(%

) K

P

(10-4

cm

/h)

Flux

(µ

g/cm

²/h) R

efer

ence

N

o da

ta a

vaila

ble

Rat

Ba

1(0

.15

ml/k

g bw

)A

cN

eat (

0.4

mg/

kg b

w)

1848

336

85 (2

4h)

0.02

63.

5G

arne

r & M

atth

ews (

1998

)R

atB

a1

(0.1

5 m

l/kg

bw)

Ac

Nea

t (0.

4 m

g/kg

bw

)18

4833

666

(24h

)0.

022.

8G

arne

r et a

l. (2

006)

The

two

stud

ies b

y G

arne

r wer

e co

nduc

ted

in si

mila

r fas

hion

exc

ept f

or m

etho

d of

mea

surin

g ab

sorb

ed a

mou

nt.

This

was

don

e in

car

cass

(Gar

ner &

Mat

thew

s (19

98))

and

in u

rine

and

faec

es (G

arne

r et a

l. (2

006)

), re

spec

tivel

y.

The

two

stud

ies s

how

con

sist

ent r

esul

ts, w

ith th

e ca

lcul

ated

Kp

valu

es ra

ngin

g be

twee

n 2·

10-6

and

3·1

0-6 c

m/h

, sug

gest

ing

"ver

y lo

w"

perm

eabi

lity.

Rep

orte

d da

ta

In v

itro

In v

ivo

Ase

ssm

ent

A33

App

endi

x A

Subs

tanc

e: C

hlor

obip

heny

l, he

xa- (

HC

B)

Mol

ecul

ar w

eigh

t:36

0.9

CA

S: 2

6601

-64-

9D

ensi

ty:1

.8 g

/cm

³Sc

ient

ific

basi

s: N

ot a

vaila

ble

Mel

ting

poin

t:20

1 to

202

°CB

oilin

g po

int:

Not

ava

ilabl

eSk

in n

otat

ion:

Yes

Vap

our

pres

sure

:Not

ava

ilabl

eSk

in p

erm

eabi

lity:

Ext

rem

ely

low

Eva

pora

tion

rate

:Not

ava

ilabl

eL

og K

ow:7

.75

Sp

Loc

C

ell

L

(µm

) A

(c

m²)

V

(ml)

Veh

icle

C

(m

g/m

l) n

TE

xp

(h)

TO

bs

(h)

TL

ag

(h)

Abs

(%

) K

P

(10-4

cm

/h)

Flux

(µ

g/cm

²/h) R

efer

ence

N

o da

ta a

vaila

ble

Rat

Ba

1(0

.15

ml/k

g bw

)A

cN

eat (

0.4

mg/

kg b

w)

1848

336

9 (2

4h)

0.00

20.

38G

arne

r & M

atth

ews (

1998

)R

atB

a1

(0.1

5 m

l/kg

bw)

Ac

Nea

t (0.

4 m

g/kg

bw

)18

4833

619

(24h

)0.

0044

0.8

Gar

ner e

t al.

(200

6)

The

two

stud

ies b

y G

arne

r wer

e co

nduc

ted

in si

mila

r fas

hion

exc

ept f

or m

etho

d of

mea

surin

g ab

sorb

ed a

mou

nt.

This

was

don

e in

car

cass

(Gar

ner &

Mat

thew

s (19

98))

and

in u

rine

and

faec

es (G

arne

r et a

l. (2

006)

), re

spec

tivel

y.

The

two

stud

ies s

how

con

sist

ent r

esul

ts, w

ith th

e ca

lcul

ated

Kp

valu

es ra

ngin

g be

twee

n 2·

10-7

and

4·1

0-7 c

m/h

, sug

gest

ing

"ext

rem

ely

low

" pe

rmea

bilit

y.

Rep

orte

d da

ta

In v

itro

In v

ivo

Ase

ssm

ent

A34

App

endi

x A

Subs

tanc

e: C

hlor

obip

heny

l, m

ono-

(MC

B)

Mol

ecul

ar w

eigh

t:N

ot a

vaila

ble

CA

S: 2

7323

-18-

8D

ensi

ty:1

.1 g

/cm

³Sc

ient

ific

basi

s: N

ot a

vaila

ble

Mel

ting

poin

t:10

°CB

oilin

g po

int:

365°

CSk

in n

otat

ion:

Yes

Vap

our

pres

sure

:Not

ava

ilabl

eSk

in p

erm

eabi

lity:

Ver

y lo

wE

vapo

ratio

n ra

te:N

ot a

vaila

ble

Log

Kow

:4.5

8

Sp

Loc

C

ell

L

(µm

) A

(c

m²)

V

(ml)

Veh

icle

C

(m

g/m

l) n

TE

xp

(h)

TO

bs

(h)

TL

ag

(h)

Abs

(%

) K

P

(10-4

cm

/h)

Flux

(µ

g/cm

²/h) R

efer

ence

N

o da

ta a

vaila

ble

Rat

Ba

1(0

.15

ml/k

g bw

)Ac

Nea

t (0.

4 m

g/kg

bw

)18

4833

698

(24h

)0.

037

4.1

Gar

ner &

Mat

thew

s (19

98)

Rat

Ba

1(0

.15

ml/k

g bw

)Ac

Nea

t (0.

4 m

g/kg

bw

)18

4833

669

(24h

)0.

026

2.9

Gar

ner e

t al.

(200

6)

The

two

stud

ies b

y G

arne

r wer

e co

nduc

ted

in si

mila

r fas

hion

exc

ept f

or m

etho

d of

mea

surin

g ab

sorb

ed a

mou

nt.

This

was

don

e in

car

cass

(Gar

ner &

Mat

thew

s (19

98))

and

in u

rine

and

faec

es (G

arne

r et a

l. (2

006)

), re

spec

tivel

y.

The

two

stud

ies s

how

con

sist

ent r

esul

ts, w

ith th

e ca

lcul

ated

Kp

valu

es ra

ngin

g be

twee

n 3·

10-6

and

4·1

0-6 c

m/h

, sug

gest

ing

"ver

y lo

w"

perm

eabi

lity.

Rep

orte

d da

ta

In v

itro

In v

ivo

Ase

ssm

ent

A35

App

endi

x A

Subs

tanc

e: C

hlor

obip

heny

l, te

tra- (

TCB

)M

olec

ular

wei

ght:

292.

0C

AS:

269

14-3

3-0

Den

sity

:1.6

g/c

m³

Scie

ntifi

c ba

sis:

Not

ava

ilabl

e M

eltin

g po

int:

~170

°CB

oilin

g po

int:

~360

°CSk

in n

otat

ion:

Yes

Vap

our

pres

sure

:Not

ava

ilabl

eSk

in p

erm

eabi

lity:

Ext

rem

ely

low

Eva

pora

tion

rate

:Not

ava

ilabl

eL

og K

ow:6

.09

Sp

Loc

C

ell

L

(µm

) A

(c

m²)

V

(ml)

Veh

icle

C

(m

g/m

l) n

TE

xp

(h)

TO

bs

(h)

TL

ag

(h)

Abs

(%

) K

P

(10-4

cm

/h)

Flux

(µ

g/cm

²/h) R

efer

ence

N

o da

ta a

vaila

ble

Rat

Ba

1(0

.15

ml/k

g bw

)Ac

Nea

t (0.

4 m

g/kg

bw

)18

4833

637

(24h

)0.

0096

1.5

Gar

ner &

Mat

thew

s (19

98)

Rat

Ba

1(0

.15

ml/k

g bw

)Ac

Nea

t (0.

4 m

g/kg

bw

)18

4833

68

(24h

)0.

0019

0.3

Gar

ner e

t al.

(200

6)

The

two

stud

ies b

y G

arne

r wer

e co

nduc

ted

in si

mila

r fas

hion

exc

ept f

or m

etho

d of

mea

surin

g ab

sorb

ed a

mou

nt.

This

was

don

e in

car

cass

(Gar

ner &

Mat

thew

s (19

98))

and

in u

rine

and

faec

es (G

arne

r et a

l. (2

006)

), re

spec

tivel

y.

The

two

stud

ies s

how

rath

er c

onsi

sten

t res

ults

, with

the

calc

ulat

ed K

p va

lues

rang

ing

betw

een

2·10

-7 a

nd 1

·10-6

cm

/h, s

ugge

stin

g "e

xtre

mel

y lo

w"

perm

eabi

lity.

Rep

orte

d da

ta

In v

itro

In v

ivo

Ase

ssm

ent

A36

App

endi

x A

Subs

tanc

e: C

hlor

ocre

sol;

4-ch

loro

-3-m

ethy

lphe

nol

Mol

ecul

ar w

eigh

t:14

2.6

CA

S: 5

9-50

-7D

ensi

ty:0

.9 g

/cm

³Sc

ient

ific

basi

s: N

ot a

vaila

ble

Mel

ting

poin

t:67

°CB

oilin

g po

int:

235°

CSk

in n

otat

ion:

No

Vap

our

pres

sure

:13

Pa (a

t 20°

C)

Skin

per

mea

bilit

y: M

oder

ate

Eva

pora

tion

rate

:Not

ava

ilabl

eL

og K

ow:3

.10

Sp

Loc

C

ell

L

(µm

) A

(c

m²)

V

(ml)

Veh

icle

C

(m

g/m

l) n

TE

xp

(h)

TO

bs

(h)

TL

ag

(h)

Abs

(%

) K

P

(10-4

cm

/h)

Flux

(µ

g/cm

²/h) R

efer

ence

Hum

Ab

StEp

i2.

5In

fH

2O4

28

80.

355

022

0R

ober

ts e

t al.

(197

7)

GP

80.

2H

2O +

Gel

5% (1

0 m

g)19

2496

758.

739

And

erse

n et

al.

(198

5)G

P8

0.2

H2O

0.4%

(Sat

urat

ed. 0

.8 m

g)20

2496

545.

82.

3A

nder

sen

et a

l. (1

985)

GP

80.

2oi

l/ac

5% (1

0 m

g)20

2496

344

18A

nder

sen

et a

l. (1

985)

GP

80.

2PG

5% (1

0 m

g)20

2496

354

18A

nder

sen

et a

l. (1

985)

In th

e ex

perim

ents

by

Rob

erts

et a

l. (1

977)

, epi

derm

al sh

eets

wer

e se

para

ted

by e

xpos

ing

skin

to a

mm

onia

vap

our

for 3

0 m

in. A

mm

onia

is w

ell k

now

n to

cau

se se

vere

skin

dam

age

Am

shel

et a

l. (2

000)

. The

alk

alin

e na

ture

of

am

mon

ia q

uick

ly sa

poni

fies t

he e

pide

rmal

fats

, thu

s des

troyi

ng th

e pr

otec

tive

stru

ctur

e of

the

epid

erm

is.

Ther

efor

e, th

e m

etho

d us

ed b

y R

ober

ts e

t al.

(197

7) is

like

ly to

resu

lt in

seve

re o

vere

stim

ates

of t

he fl

ux a

nd K

pva

lue

of u

ndam

aged

skin

.

The

pref

erre

d in

viv

o ex

perim

ent i

s by

And

erse

n et

al.

(198

5) u

sing

wat

er a

s veh

icle

.

The

repo

rted

Kp

valu

e fo

r sat

urat

ed c

hlor

ophe

nol i

n w

ater

of 6

·10-4

cm

/h, s

ugge

sts "

mod

erat

e" p

erm

eabi

lity.

Rep

orte

d da

ta

In v

itro

In v

ivo

Ase

ssm

ent

A37

App

endi

x A

Subs

tanc

e: C

hlor

oeth

anol

, 2-

Mol

ecul

ar w

eigh

t:80

.5C

AS:

107

-07-

3D

ensi

ty:1

.201

g/c

m³

Scie

ntifi

c ba

sis:

Not

ava

ilabl

e M

eltin

g po

int:

-89°

CB

oilin

g po

int:

130°

CSk

in n

otat

ion:

Yes

Vap

our

pres

sure

:0.6

6 kP

a (a

t 20°

C)

Skin

per

mea

bilit

y: N

o da

taE

vapo

ratio

n ra

te:N

ot a

vaila

ble

Log

Kow

:0.0

3

Sp

Loc

C

ell

L

(µm

) A

(c

m²)

V

(ml)

Veh

icle

C

(m

g/m

l) n

TE

xp

(h)

TO

bs

(h)

TL

ag

(h)

Abs

(%

) K

P

(10-4

cm

/h)

Flux

(µ

g/cm

²/h) R

efer

ence

N

o da

ta a

vaila

ble

N

o da

ta a

vaila

ble

No

quan

titat

ive

expe

rimen

tal d

ata

on d

erm

al u

ptak

e w

ere

foun

d in

the

liter

atur

e.

No

docu

men

tatio

n by

the

Swed

ish

cons

ensu

s gro

up o

r AC

GIH

was

foun

d fo

r thi

s sub

stan

ce.

The

acut

e de

rmal

toxi

city

is e

xtre

mel

y hi

gh. T

hus,

appl

icat

ion

of 2

ml o

n th

e sk

in c

ause

d 80

% m

orta

lity

in 1

hou

r and

a d

ose

of 1

ml c

ause

d 80

-100

% m

orta

lity

with

in 1

wee

k in

gui

nea

pigs

(Wah

lber

g et

al.

(197

9)).

Rep

orte

d da

ta

In v

itro

In v

ivo

Ase

ssm

ent

A38

App

endi

x A

Subs

tanc

e: C

hlor

ofor

m; t

richl

orom

etha

neM

olec

ular

wei

ght:

119.

4C

AS:

67-

66-3

Den

sity

:1.4

98 g

/cm

³Sc

ient

ific

basi

s: N

ot a

vaila

ble

Mel

ting

poin

t:-6

3.7°

CB

oilin

g po

int:

61.7

°CSk

in n

otat

ion:

No

Vap

our

pres

sure

:18

kPa

(at 2

0°C

)Sk

in p

erm

eabi

lity:

Ver

y hi

ghE

vapo

ratio

n ra

te:0

.09

Log

Kow

:1.9

7

Sp

Loc

C

ell

L

( µm

) A

(c

m²)

V

(ml)

Veh

icle

C

(m

g/m

l) n

TE

xp

(h)

TO

bs

(h)

TL

ag

(h)

Abs

(%

) K

P

(10-4

cm

/h)

Flux

(µ

g/cm

²/h) R

efer

ence

Hum

Ab

Fl30

00.

641

H2O

400

µg/l

(0.6

2 µg

/cm

²)4

44.

1 (2

h)32

00.

013

Dic

k et

al.

(199

5)H

umA

bFl

300

0.64

0.05

H2O

0.9

(70

µg/c

m²)

44

6.5

(2h)

262.

3D

ick

et a

l. (1

995)

Hum

Ab

Fl20

0-40

00.

2In

fH

2O14

0-29

0 µg

/l19

66

1400

Nak

ai e

t al.

(199

9)H

umA

bFl

200-

400

0.2

Inf

H2O

140-

290

µg/l

196

617

00N

akai

et a

l. (1

999)

HG

PW

B~3

00In

fH

2O19

-52

ppb

61.

22-

4w13

00B

ogen

et a

l. (1

992)

HR

WB

460

Inf

H2O

0.

443

0.5

0.5

20 m

g29

0013

0Is

lam

et a

l. (1

995)

HR

WB

510

Inf

H2O

0.

444

0.5

610

mg

900

40Is

lam

et a

l. (1

996)

HR

Ba

5.46

0.35

Nea

t3

1 m

in6

2.8

mg

210

3100

0Is

lam

et a

l. (1

999)

HR

Ba

5.46

0.35

Nea

t3

3 m

in6

3.5

mg

8513

000

Isla

m e

t al.

(199

9)H

RB

a5.

460.

35N

eat

38

min

613

mg

120

1800

0Is

lam

et a

l. (1

999)

Hum

Arm

3.1

0.05

H2O

1

(50

µg)

38

728.

21.

70.

17D

ick

et a

l. (1

995)

Hum

Arm

3.1

0.05

Et

5 (2

50 µ

g)4

872

1.7

0.34

0.17

Dic

k et

al.

(199

5)H

umW

BIn

fH

2O40

µg/

l6

0.5

2.5

150

0.00

06X

u et

al.

(200

5)H

umW

BIn

fH

2O60

-150

µg/

l(4

0-97

ppb

)9

0.5

~112

-44

µg60

00.

0036

-0.0

09C

orle

y et

al.

(200

0)M

ouA

b2.

90.

5N

eat

100.

2517

00 µ

g16

2400

Tsur

uta

(197

5)

The

expe

rimen

t usi

ng e

than

ol a

s veh

icle

is d

isre

gard

ed a

s ski

n pe

rmea

bilit

y m

ay b

e af

fect

ed.

The

in v

itro

Kp

valu

e of

Dic

k et

al.

(199

5) is

cal

cula

ted

durin

g th

e fir

st 2

h of

exp

osur

e, d

ue to

pos

sibl

e de

plet

ion.

The

in v

ivo

stud

y of

Dic

k et

al.

(199

5) w

as p

erfo

rmed

uno

cclu

ded,

hen

ce th

e lo

w a

bsor

ptio

n/K

p va

lues

.Ts

urut

a (1

975)

mea

sure

d ab

sorp

tion

by h

omog

eniz

ing

the

who

le a

nim

al. T

his m

etho

d m

ay se

vere

ly u

nder

estim

ate

skin

per

mea

bilit

y.Th

e pr

efer

red

expe

rimen

t is t

hat o

f Isl

am e

t al.

(199

9), u

sing

nea

t chl

orof

orm

and

hai

rless

rat i

n vi

vo a

nd th

e lo

nges

tex

posu

re d

urat

ion

(8 m

in).

The

Kp

valu

e of

1·10

-2 su

gges

t "ve

ry h

igh"

per

mea

bilit

y.

Rep

orte

d da

ta

In v

itro

In v

ivo

Ase

ssm

ent

A39

App

endi

x A

Subs

tanc

e: C

hrom

ate,

pot

assi

um d

i-M

olec

ular

wei

ght:

294.

2C

AS:

777

8-50

-9D

ensi

ty:2

.676

g/c

m³

Scie

ntifi

c ba

sis:

AoH

200

0:22

Mel

ting

poin

t:39

8°C

Boi

ling

poin

t:50

0°C

Skin

not

atio

n: N

oV

apou

r pr

essu

re:N

ot a

vaila

ble

Skin

per

mea

bilit

y: V

ery

low

Eva

pora

tion

rate

:Not

ava

ilabl

eL

og K

ow:-

3.59

(est

imat

ed)

Sp

Loc

C

ell

L

(µm

) A

(c

m²)

V

(ml)

Veh

icle

C

(m

g/m

l) n

TE

xp

(h)

TO

bs

(h)

TL

ag

(h)

Abs

(%

) K

P

(10-4

cm

/h)

Flux

(µ

g/cm

²/h) R

efer

ence

Hum

Ab

StFu

ll0.

7/1.

855

6 µl

/cm

²H2O

0.5%

(0.0

34 M

)3

190

190

0.00

014

0.00

019

Gam

mel

gaar

d et

al.

(199

2)

Hum

WB

~130

00In

fH

2O0.

022

43

960.

068

0.00

015

Cor

bett

et a

l. (1

997)

Onl

y on

e st

udy

was

foun

d on

pot

assi

um d

ichr

omat

e. In

Gam

mel

gaar

d et

al.

(199

2), h

uman

abd

omin

alsk

in w

as e

xpos

ed to

aqu

eous

solu

tion.

The

repo

rted

Kp

valu

e su

gges

ts "

extre

mel

y lo

w"

perm

eabi

lity.

It sh

ould

be

note

d th

at th

e re

porte

d K

p va

lue

of so

dium

chr

omat

e is

two

orde

rs o

f mag

nitu

de h

ighe

r.

Rep

orte

d da

ta

In v

itro

In v

ivo

Ase

ssm

ent

A40

App

endi

x A

Subs

tanc

e: C

hrom

ate,

sodi

um d

i-M

olec

ular

wei

ght:

162.

0C

AS:

777

5-11

-3D

ensi

ty:2

.7 g

/cm

³Sc

ient

ific

basi

s: A

oH 2

000:

22M

eltin

g po

int:

792°

CB

oilin

g po

int:

Not

ava

ilabl

eSk

in n

otat

ion:

No

Vap

our

pres

sure

:Not

ava

ilabl

eSk

in p

erm

eabi

lity:

Hig

hE

vapo

ratio

n ra

te:N

ot a

vaila

ble

Log

Kow

:Not

ava

ilabl

e

Sp

Loc

C

ell

L

( µm

) A

(c

m²)

V

(ml)

Veh

icle

C

(m

g/m

l) n

TE

xp

(h)

TO

bs

(h)

TL

ag

(h)

Abs

(%

) K

P

(10-4

cm

/h)

Flux

(µ

g/cm

²/h) R

efer

ence

GP

Ba

FlFu

ll3.

1H

2O5.

5 (0

.034

M)

1048

4811

6.2

Wah

lber

g (1

965)

GP

Ba

Full

3.1

1H

2O2.

8 (0

.017

M)

524

2419

5.2

Wah

lber

g (1

970)

GP

Ba

Full

3.1

1H

2O13

(0.

080

M)

524

2415

20W

ahlb

erg

(197

0)G

PB

aFu

ll3.

11

H2O

39 (0

.239

M)

524

2414

54W

ahlb

erg

(197

0)G

PB

aFu

ll3.

11

H2O

65 (0

.398

M)

524

2412

75W

ahlb

erg

(197

0)H

umA

bFl

Full

3.1

H2O

5.5

(0.0

34 M

)10

4848

3.3

1.8

Wah

lber

g (1

965)

Hum

Ab

Full

3.1

1H

2O2.

8 (0

.017

M)

524

248.

72.

4W

ahlb

erg

(197

0)H

umA

bFu

ll3.

11

H2O

13 (

0.08

0 M

)5

2424

1317

Wah

lber

g (1

970)

Hum

Ab

Full

3.1

1H

2O39

(0.2

39 M

)5

2424

1454

Wah

lber

g (1

970)

Hum

Ab

Full

3.1

1H

2O65

(0.3

98 M

)5

2424

1597

Wah

lber

g (1

970)

GP

H2O

2.8-

65 (0

.017

-0.3

98 M

)20

55

17-1

84.

9-12

0W

ahlb

erg

et a

l. (1

965)

GP

Ba

3.1

H2O

5.5

(0.0

34 M

)10

4848

126.

8W

ahlb

erg

(196

5)G

PB

a1

H2O

2.8

(0.0

17 M

)5

2424

184.

9W

ahlb

erg

et a

l. (1

963)

GP

Ba

1H

2O13

(0.

080

M)

524

2413

17W

ahlb

erg

et a

l. (1

963)

GP

Ba

1H

2O42

(0.2

61 M

)5

2424

2611

0W

ahlb

erg

et a

l. (1

963)

GP

Ba

1H

2O65

(0.3

98 M

)5

2424

1812

0W

ahlb

erg

et a

l. (1

963)

Hum

Arm

H2O

1.

6 (0

.01M

)9

11

6.9

1.1

Bar

anow

ska-

Dut

kiew

icz

(198

1)H

umA

rmH

2O

16 (0

.1M

)9

11

4.1

6.5

Bar

anow

ska-

Dut

kiew

icz

(198

1)H

umA

rmH

2O

32 (0

.2M

)9

11

3.1

10B

aran

owsk

a-D

utki

ewic

z (1

981)

Hum

an a

nd g

uine

a pi

g da

ta su

gges

t "hi

gh"

perm

eabi

lity

of so

dium

dic

hrom

ate,

with

Kp

valu

es b

etw

een

3·10

-4 a

nd 3

·10-3

cm

/h.

It sh

ould

be

note

d th

at th

e re

porte

d K

p va

lue

for p

otas

sium

dic

hrom

ate

is tw

o or

ders

of m

agni

tude

low

er.

Rep

orte

d da

ta

In v

itro

In v

ivo

Ase

ssm

ent

A41

App

endi

x A

Subs

tanc

e: C

hrom

ic c

hlor

ide

Mol

ecul

ar w

eigh

t:15

8.4

CA

S: 1

0025

-73-

7D

ensi

ty:2

.76

g/cm

³Sc

ient

ific

basi

s: A

oH 2

000:

22M

eltin

g po

int:

1152

°CB

oilin

g po

int:

Not

ava

ilabl

eSk

in n

otat

ion:

No

Vap

our

pres

sure

:Not

ava

ilabl

eSk

in p

erm

eabi

lity:

Hig

hE

vapo

ratio

n ra

te:N

ot a

vaila

ble

Log

Kow

:1.1

6 (e

stim

ated

)

Sp

Loc

C

ell

L

(µm

) A

(c

m²)

V

(ml)

Veh

icle

C

(m

g/m

l) n

TE

xp

(h)

TO

bs

(h)

TL

ag

(h)

Abs

(%

) K

P

(10-4

cm

/h)

Flux

(µ

g/cm

²/h) R

efer

ence

GP

Ba

Full

3.1

1H

2O2.

7 (0

.017

M)

524

2420

5.5

Wah

lber

g (1

970)

GP

Ba

Full

3.1

1H

2O13

(0.

080

M)

524

2420

26W

ahlb

erg

(197

0)G

PB

aFu

ll3.

11

H2O

38(0

.239

M)

524

2421

81W

ahlb

erg

(197

0)G

PB

aFu

ll3.

11

H2O

63(0

.398

M)

524

2415

91W

ahlb

erg

(197

0)G

PB

aFl

Full

3.1

H2O

2.7

(0.0

17 M

)10

4848

154

Wah

lber

g (1

965)

GP

Ba

FlFu

ll3.

1H

2O13

(0.0

80 M

)10

4848

1013

Wah

lber

g (1

965)

GP

Ba

FlFu

ll3.

1H

2O20

(0.1

26 M

)10

4848

1224

Wah

lber

g (1

965)

GP

Ba

FlFu

ll3.

1H

2O38

(0.2

39 M

)10

4848

1350

Wah

lber

g (1

965)

GP

Ba

FlFu

ll3.

1H

2O41

(0.2

61 M

)10

4848

1352

Wah

lber

g (1

965)

Hum

Ab

Full

3.1

1H

2O2.

7 (0

.017

M)

524

2415

4W

ahlb

erg

(197

0)H

umA

bFu

ll3.

11

H2O

13 (

0.08

0 M

)5

2424

1316

Wah

lber

g (1

970)

Hum

Ab

Full

3.1

1H

2O38

(0.2

39 M

)5

2424

1140

Wah

lber

g (1

970)

Hum

Ab

Full

3.1

1H

2O63

(0.3

98 M

)5

2424

1275

Wah

lber

g (1

970)

N

o da

ta a

vaila

ble

The

calc

ulat

ed K

p va

lues

(tw

o st

udie

s onl

y) o

n ch

rom

ate

chlo

ride

are

cons

iste

nt.

The

pref

erre

d ex

perim

ents

are

thos

e on

hum

an sk

in, w

ith c

alcu

late

d K

p va

lues

cor

resp

ondi

ng to

"hi

gh"

perm

eabi

lity.

Rep

orte

d da

ta

In v

itro

In v

ivo

Ase

ssm

ent

A42

App

endi

x A

Subs

tanc

e: C

obal

tM

olec

ular

wei

ght:

58.9

CA

S: 7

440-

48-4

Den

sity

:8.9

2 g/

cm³

Scie

ntifi

c ba

sis:

AoH

200

4:16

Mel

ting

poin

t:14

95°C

Boi

ling

poin

t:28

70°C

Skin

not

atio

n: N

oV

apou

r pr

essu

re:N

ot a

vaila

ble

Skin

per

mea

bilit

y: E

xtre

mel

y lo

wE

vapo

ratio

n ra

te:N

ot a

vaila

ble

Log

Kow

:0.2

3 (e

stim

ated

)

Sp

Loc

C

ell

L

(µm

) A

(c

m²)

V

(ml)

Veh

icle

C

(m

g/m

l) n

TE

xp

(h)

TO

bs

(h)

TL

ag

(h)

Abs

(%

) K

P

(10-4

cm

/h)

Flux

(µ

g/cm

²/h) R

efer

ence

Hum

Ab

StFu

ll1

NaC

l50

724

241.

550.

0025

0.01

2La

rese

Filo

n et

al.

(200

4)

Hum

Ha

390

Inf

Pow

der

5-15

% (0

.05-

0.25

mg/

m³)

41.

572

0.00

03-0

.000

90.

04Sc

anse

tti e

t al.

(199

4)

The

two

foun

d st

udie

s rep

ort f

airly

con

sist

ent K

p va

lues

, ran

ging

bet

wee

n 3·

10-7

and

3·1

0-8 c

m/h

.

The

pref

erre

d st

udy

is th

at o

f Sca

nset

ti et

al.

(199

4). T

he K

p va

lue

corr

espo

nds t

o "e

xtre

mel

y lo

w"

perm

eabi

lity.

Rep

orte

d da

ta

In v

itro

In v

ivo

Ase

ssm

ent

A43

App

endi

x A

Subs

tanc

e: C

obal

t dic

hlor

ide

Mol

ecul

ar w

eigh

t:12

9.8

CA

S: 7

646-

79-9

Den

sity

:3.3

56 g

/cm

³Sc

ient

ific

basi

s: A

oH 2

004:

16M

eltin

g po

int:

735°

CB

oilin

g po

int:

1049

°CSk

in n

otat

ion:

No

Vap

our

pres

sure

:5.3

kPa

(at 7

70°C

)Sk

in p

erm

eabi

lity:

Mod

erat

eE

vapo

ratio

n ra

te:N

ot a

vaila

ble

Log

Kow

:0.8

5 (e

stim

ated

)

Sp

Loc

C

ell

L

(µm

) A

(c

m²)

V

(ml)

Veh

icle

C

(m

g/m

l) n

TE

xp

(h)

TO

bs

(h)

TL

ag

(h)

Abs

(%

) K

P

(10-4

cm

/h)

Flux

(µ

g/cm

²/h) R

efer

ence

GP

Ba

FlFu

ll3.

1H

2O

5.0

(0.0

85M

)10

4848

126.

2W

ahlb

erg

(196

5)H

umA

b/B

rFl

Full

3.1

H2O

5.

0 (0

.085

M)

1048

484.

42.

2W

ahlb

erg

(196

5)

GP

Ba

3.1

H2O

5.

0 (0

.085

M)

1048

4813

-22

6.6-

11W

ahlb

erg

(196

5)H

amB

a0.

1N

aCl/E

t20

448

4860

Lacy

et a

l. (1

996)

The

stud

y by

Lac

y et

al.

(199

6) g

ives

no

area

of e

xpos

ure,

ther

efor

e no

Kp

or fl

ux v

alue

can

be

calc

ulat

ed.

The

high

abs

orpt

ion

show

s tha

t cob

alt d

ichl

orid

e re

adily

pen

etra

tes t

he sk

in.

The

thre

e st

udie

s of W

ahlb

erg

(196

5) sh

ow c

onsi

sten

t res

ults

. Th

e pr

efer

red

expe

rimen

t is t

hat w

ith h

uman

skin

. The

Kp

valu

e co

rres

pond

s to

"mod

erat

e" p

erm

eabi

lity.

Rep

orte

d da

ta

In v

itro

In v

ivo

Ase

ssm

ent

A44

App

endi

x A

Subs

tanc

e: C

reso

l, m

-M

olec

ular

wei

ght:

108.

1C

AS:

108

-39-

4D

ensi

ty:1

.034

g/c

m³

Scie

ntifi

c ba

sis:

AoH

199

8:25

Mel

ting

poin

t:11

.5°C

Boi

ling

poin

t:20

2.2°

CSk

in n

otat

ion:

No

Vap

our

pres

sure

:13

Pa (a

t 20°

C)

Skin

per

mea

bilit

y: V

ery

high

Eva

pora

tion

rate

:Not

ava

ilabl

eL

og K

ow:1

.96

Sp

Loc

C

ell

L

(µm

) A

(c

m²)

V

(ml)

Veh

icle

C

(m

g/m

l) n

TE

xp

(h)

TO

bs

(h)

TL

ag

(h)

Abs

(%

) K

P

(10-4

cm

/h)

Flux

(µ

g/cm

²/h) R

efer

ence

Hum

Ab

StEp

i2.

5In

fH

2O4

28

80.

2515

060

Rob

erts

et a

l. (1

977)

SnB

aSt

Full

1.8

PBS

1-3

46

699

9.9-

30Ito

h et

al.

(199

0)

N

o da

ta a

vaila

ble

In th

e st

udy

by It

oh e

t al.

(199

0), s

nake

skin

was

use

d. A

s thi

s is v

ery

diff

eren

t fro

m h

uman

skin

, thi

s dat

a is

dis

rega

rded

.

The

pref

erre

d st

udy

is th

at o

f Rob

erts

et a

l. (1

977)

, whe

re th

e re

porte

d K

p va

lue

of 2

·10-2

cm

/h su

gges

t "hi

gh"

perm

eabi

lity.

It sh

ould

be

note

d th

at in

the

expe

rimen

ts b

y R

ober

ts e

t al.

(197

7), e

pide

rmal

shee

ts w

ere

sepa

rate

d by

exp

osin

g sk

in to

am

mon

ia v

apou

r fo

r 30

min

. Am

mon

ia is

wel

l kno

wn

to c

ause

seve

re sk

in d

amag

e A

msh

el e

t al.

(200

0). T

he a

lkal

ine

natu

re

of a

mm

onia

qui

ckly

sapo

nifie

s the

epi

derm

al fa

ts, t

hus d

estro

ying

the

prot

ectiv

e st

ruct

ure

of th

e ep

ider

mis

. Th

eref

ore,

the

met

hod

used

by

Rob

erts

et a

l. (1

977)

is li

kely

to re

sult

in se

vere

ove

rest

imat

es o

f the

flux

and

Kp

valu

e of

und

amag

ed sk

in.

Rep

orte

d da

ta

In v

itro

In v

ivo

Ase

ssm

ent

A45

App

endi

x A

Subs

tanc

e: C

reso

l, o-

Mol

ecul

ar w

eigh

t:10

8.1

CA

S: 9

5-48

-7D

ensi

ty:1

.048

g/c

m³

Scie

ntifi

c ba

sis:

AoH

199

8:25

Mel

ting

poin

t:30

.9°C

Boi

ling

poin

t:19

1°C

Skin

not

atio

n: N

oV

apou

r pr

essu

re:3

3 Pa

(at 2

5°C

)Sk

in p

erm

eabi

lity:

Ver

y hi

ghE

vapo

ratio

n ra

te:N

ot a

vaila

ble

Log

Kow

:1.9

5

Sp

Loc

C

ell

L

(µm

) A

(c

m²)

V

(ml)

Veh

icle

C

(m

g/m

l) n

TE

xp

(h)

TO

bs

(h)

TL

ag

(h)

Abs

(%

) K

P

(10-4

cm

/h)

Flux

(µ

g/cm

²/h) R

efer

ence

Hum

Ab

StEp

i2.

5In

fH

2O4

28

80.

2516

064

Rob

erts

et a

l. (1

977)

N

o da

ta a

vaila

ble

Onl

y on

e st

udy

was

foun

d on

o-c

reso

l. Th

e st

udy

by R

ober

ts e

t al.

(197

7) re

porte

da

Kp

valu

e of

2·1

0-2 c

m/h

, sug

gest

ing

"hig

h" p

erm

eabi

lity.

It sh

ould

be

note

d th

at in

the

expe

rimen

ts b

y R

ober

ts e

t al.

(197

7), e

pide

rmal

shee

ts w

ere

sepa

rate

d by

exp

osin

g sk

in to

am

mon

ia v

apou

r fo

r 30

min

. Am

mon

ia is

wel

l kno

wn

to c

ause

seve

re sk

in d

amag

e A

msh

el e

t al.

(200

0). T

he a

lkal

ine

natu

re

of a

mm

onia

qui

ckly

sapo

nifie

s the

epi

derm

al fa

ts, t

hus d

estro

ying

the

prot

ectiv

e st

ruct

ure

of th

e ep

ider

mis

. Th

eref

ore,

the

met

hod

used

by

Rob

erts

et a

l. (1

977)

is li

kely

to re

sult

in se

vere

ove

rest

imat

es o

f the

flux

and

Kp

valu

e of

und

amag

ed sk

in.

Rep

orte

d da

ta

In v

itro

In v

ivo

Ase

ssm

ent

A46

App

endi

x A

Subs

tanc

e: C

reso

l, p-

Mol

ecul

ar w

eigh

t:10

8.1

CA

S: 1

06-4

4-5

Den

sity

:1.0

34 g

/cm

³Sc

ient

ific

basi

s: A

oH 1

998:

25M

eltin

g po

int:

32 to

34°

CB

oilin

g po

int:

201.

8°C

Skin

not

atio

n: N

oV

apou

r pr

essu

re:1

5 Pa

(at 2

5°C

)Sk

in p

erm

eabi

lity:

Ver

y hi

ghE

vapo

ratio

n ra

te:N

ot a

vaila

ble

Log

Kow

:1.9

4

Sp

Loc

C

ell

L

(µm

) A

(c

m²)

V

(ml)

Veh

icle

C

(m

g/m

l) n

TE

xp

(h)

TO

bs

(h)

TL

ag

(h)

Abs

(%

) K

P

(10-4

cm

/h)

Flux

(µ

g/cm

²/h) R

efer

ence

Hum

Ab

StEp

i2.

5In

fH

2O4

28

80.

2718

072

Rob

erts

et a

l. (1

977)

N

o da

ta a

vaila

ble

Onl

y on

e st

udy

was

foun

d on

o-c

reso

l. Th

e st

udy

by R

ober

ts e

t al.

(197

7) re

porte

da

Kp

valu

e of

2·1

0-2 c

m/h

, sug

gest

ing

"hig

h" p

erm

eabi

lity.

It sh

ould

be

note

d th

at in

the

expe

rimen

ts b

y R

ober

ts e

t al.

(197

7), e

pide

rmal

shee

ts w

ere

sepa

rate

d by

exp

osin

g sk

in to

am

mon

ia v

apou

r fo

r 30

min

. Am

mon

ia is

wel

l kno

wn

to c

ause

seve

re sk

in d

amag

e A

msh

el e

t al.

(200

0). T

he a

lkal

ine

natu

re

of a

mm

onia

qui

ckly

sapo

nifie

s the

epi

derm

al fa

ts, t

hus d

estro

ying

the

prot

ectiv

e st

ruct

ure

of th

e ep

ider

mis

. Th

eref

ore,

the

met

hod

used

by

Rob

erts

et a

l. (1

977)

is li

kely

to re

sult

in se

vere

ove

rest

imat

es o

f the

flux

and

Kp

valu

e of

und

amag

ed sk

in.

Rep

orte

d da

ta

In v

itro

In v

ivo

Ase

ssm

ent

A47

App

endi

x A

Subs

tanc

e: C

yana

mid

e, h

ydro

gen

Mol

ecul

ar w

eigh

t:42

.0C

AS:

420

-04-

2D

ensi

ty:1

.06

g/cm

³Sc

ient

ific

basi

s: A

oH 1

999:

25M

eltin

g po

int:

42°C

Boi

ling

poin

t:26

0°C

Skin

not

atio

n: N

oV

apou

r pr

essu

re:N

ot a

vaila

ble

Skin

per

mea

bilit

y: H

igh

Eva

pora

tion

rate

:Not

ava

ilabl

eL

og K

ow:-

0.82

Sp

Loc

C

ell

L

(µm

) A

(c

m²)

V

(ml)

Veh

icle

C

(m

g/m

l) n

TE

xp

(h)

TO

bs

(h)

TL

ag

(h)

Abs

(%

) K

P

(10-4

cm

/h)

Flux

(µ

g/cm

²/h) R

efer

ence

N

o da

ta a

vaila

ble

Hum

Arm

161

H2O

1% (1

0mg)

66

487.

7 (2

.3 m

g)24

24M

erts

chen

k et

al.

(199

1)

The

only

stud

y fo

und

on c

yana

mid

e w

as th

at b

y M

erts

chen

k et

al.

(199

1)w

here

the

calc

ulat

ed K

p va

lue

corr

espo

nds t

o "h

igh"

per

mea

bilit

y.

Rep

orte

d da

ta

In v

itro

In v

ivo

Ase

ssm

ent

A48

App

endi

x A

Subs

tanc

e: C

yclo

hexa

none

Mol

ecul

ar w

eigh

t:98

.1C

AS:

108

-94-

1D

ensi

ty:0

.947

g/c

m³

Scie

ntifi

c ba

sis:

AoH

199

9:25

Mel

ting

poin

t:-4

7°C

Boi

ling

poin

t:15

5.6°

CSk

in n

otat

ion:

Yes

Vap

our

pres

sure

:0.6

9 kP

a (a

t 25°

C)

Skin

per

mea

bilit

y: L

owE

vapo

ratio

n ra

te:0

.23

Log

Kow

:0.8

1

Sp

Loc

C

ell

L

(µm

) A

(c

m²)

V

(ml)

Veh

icle

C

(m

g/m

l) n

TE

xp

(h)

TO

bs

(h)

TL

ag

(h)

Abs

(%

) K

P

(10-4

cm

/h)

Flux

(µ

g/cm

²/h) R

efer

ence

N

o da

ta a

vaila

ble

Hum

Ha

Inf

Nea

t3

0.5

720.

5956

Mra

z et

al.

(199

4)

A si

ngle

hum

an in

viv

o st

udy

was

foun

d (M

raz

et a

l. (1

994)

).Th

e flu

x w

as o

btai

ned

by a

naly

zing

the

urin

ary

excr

etio

n of

1,4

-cyc

lohe

xane

diol

afte

r bot

h de

rmal

and

inha

latio

nal e

xpos

ure.

The

calc

ulat

ed K

p va

lue

of 6

·10-5

cm

/h, s

ugge

sts "

low

" pe

rmea

bilit

y.

Rep

orte

d da

ta

In v

itro

In v

ivo

Ase

ssm

ent

A49

App

endi

x A

Subs

tanc

e: D

i-(2-

ethy

lhex

yl)p

htha

late

(DEH

P)M

olec

ular

wei

ght:

390.

6C

AS:

117

-81-

7D

ensi

ty:0

.973

g/c

m³

Scie

ntifi

c ba

sis:

AoH

198

3:36

Mel

ting

poin

t:-5

0°C

Boi

ling

poin

t:28

6.9°

CSk

in n

otat

ion:

No

Vap

our

pres

sure

:1 P

a (a

t 20°

C)

Skin

per

mea

bilit

y: E

xtre

mel

y lo

wE

vapo

ratio

n ra

te:<

0.00

5L

og K

ow:7

.60

Sp

Loc

C

ell

L

(µm

) A

(c

m²)

V

(ml)

Veh

icle

C

(m

g/m

l) n

TE

xp

(h)

TO

bs

(h)

TL

ag

(h)

Abs

(%

) K

P

(10-4

cm

/h)

Flux

(µ

g/cm

²/h) R

efer

ence

GP

Ba

Fl20

00.

640.

01A

c0.

895

2424

6.1

0.4

0.03

5N

g et

al.

(199

2)G

PB

aFl

200

0.64

0.01

Ac

0.89

524

245

0.33

0.02

9N

g et

al.

(199

2)G

PB

aFl

200

0.64

0.01

Ac

3.8

524

242.

40.

160.

06N

g et

al.

(199

2)G

PB

aFl

200

0.64

0.01

Ac

7.8

524

242.

50.

160.

12N

g et

al.

(199

2)H

umSt

Epi

0.64

/1.0

Nea

t4

3232

1-2

0.00

1110

0B

arbe

r et a

l. (1

992)

Hum

Ab

StEp

i1.

80.

5N

eat

972

723.

10.

057

5.6

Scot

t et a

l. (1

987)

Pig

Full

100.

05Et

3.7

58

80.

10.

0088

0.00

32W

este

r et a

l. (1

998d

)R

atSt

Full

0.64

/1.0

Nea

t11

3232

1-2

0.00

4342

0B

arbe

r et a

l. (1

992)

Rat

Ba

FlEp

i0.

640.

05A

c1.

68

7272

2.58

519.

51.

5Pe

lling

et a

l. (1

998)

Rat

Ba

FlD

erm

0.64

0.05

Ac

1.6

1172

721.

175.

60.

980.

15Pe

lling

et a

l. (1

998)

Rat

Ba

FlEp

i0.

640.

05A

c1.

69

7272

2.47

1.2

0.13

0.02

1Pe

lling

et a

l. (1

998)

Rat

Ba

FlD

erm

0.64

0.05

Ac

1.6

972

720.

911.

70.

480.

076

Pelli

ng e

t al.

(199

8)R

atB

aSt

Epi

1.8

0.5

Nea

t9

5353

3.9

0.23

22Sc

ott e

t al.

(198

7)

GP

Ba

80.

1A

c 9.

54

2424

130.

670.

63C

hu e

t al.

(199

6)G

PB

a8

0.1

Ac

8.6

424

4819

0.97

0.83

Chu

et a

l. (1

996)

GP

Ba

80.

1A

c 35

424

168

190.

983.

5C

hu e

t al.

(199

6)G

PB

a8

0.1

Ac

424

2433

69.

70.

512.

1C

hu e

t al.

(199

6)G

PB

a4

0.05

Ac

4.2

524

168

532.

81.

2N

g et

al.

(199

2)H

umA

rm10

0.05

Et

3.7

624

168

1.8

0.03

80.

014

Wes

ter e

t al.

(199

8d)

Rat

Ba

15Fi

lm40

0mg

424

240.

10.

0025

0.24

Dei

sing

er e

t al.

(199

8)R

atB

a1.

35-

8 m

g/cm

²3

168

168

70.

034

3.3

Elsi

si e

t al.

(198

9)

Rep

orte

d da

ta

In v

itro

In v

ivo

A50

App

endi

x A

The

derm

al a

bsor

ptio

n of

DEH

P sh

ows h

uge

varia

bilit

y be

twee

n st

udie

s with

Kp

valu

es ra

ngin

g fr

om 1·

10-7

to 2

·10-5

cm

/h

(dat

a w

ith n

eat D

EHP

only

).Sc

ott e

t al.

(198

7) u

sed

phys

iolo

gica

l sal

ine/

etha

nol (

50/5

0) a

s rec

epto

r med

ium

. The

eth

anol

may

seve

rely

aff

ect s

kin

perm

eabi

lity.

The

pref

erre

d st

udy

is th

at o

f Bar

ber e

t al.

(199

2) w

ho u

sed

buff

ered

isot

onic

wat

er w

ith a

n ad

ditio

n of

po

lyet

hyle

ne g

lyco

l 20

oley

l eth

er to

ach

ieve

suff

icie

nt so

lubi

lity

of D

EHP

in th

e re

cept

or m

ediu

m.

The

Kp

valu

e of

1·1

0-7 c

m/h

for h

uman

skin

cor

resp

onds

to "

extre

mel

y lo

w"

perm

eabi

lity.

Ase

ssm

ent

A51

App

endi

x A

Subs

tanc

e: D

ibut

yl p

htha

late

(DB

P)M

olec

ular

wei

ght:

278.

3C

AS:

84-

74-2

Den

sity

:1.0

43 g

/cm

³Sc

ient

ific

basi

s: A

oH 1

983:

36M

eltin

g po

int:

-35°

CB

oilin

g po

int:

340°

CSk

in n

otat

ion:

No

Vap

our

pres

sure

:<10

Pa

(at 2

0°C

)Sk

in p

erm

eabi

lity:

Ver

y lo

wE

vapo

ratio

n ra

te:<

0.00

5L

og K

ow:4

.50

Sp

Loc

C

ell

L

(µm

) A

(c

m²)

V

(ml)

Veh

icle

C

(m

g/m

l) n

TE

xp

(h)

TO

bs

(h)

TL

ag

(h)

Abs

(%

) K

P

(10-4

cm

/h)

Flux

(µ

g/cm

²/h) R

efer

ence

HR

Ba

StFu

ll1.

8In

fN

eat

924

240.

3739

Paya

n et

al.

(200

1)H

umA

bSt

Epi

1.8

0.5

Nea

t15

3030

2.9

0.02

30.

07Sc

ott e

t al.

(198

7)H

umLe

gSt

7.1

0.5

Ac

202

4848

3.1

0.2

0.4

Sher

ertz

et a

l. (1

988)

Mou

StFu

ll7.

10.

5A

c20

348

482.

333

8.5

17Sh

erer

tz e

t al.

(198

8)R

atB

aSt

Full

1.8

Inf

Nea

t9

2424

0.25

26Pa

yan

et a

l. (2

001)

Rat

Ba

StEp

i1.

80.

5N

eat

98

80.

40.

99.

3Sc

ott e

t al.

(198

7)

Hum

Arm

14-1

62-

6PG

+ H

2OSa

tura

ted

126

652

03.

8H

aged

orn-

Lew

eke

et a

l. (1

995)

Rat

Ba

100.

1N

eat

872

7274

1.1

110

Paya

n et

al.

(200

1)R

atB

a10

0.1

Nea

t8

4848

631.

314

0Pa

yan

et a

l. (2

001)

Rat

Ba

100.

1N

eat

824

2431

1.2

130

Paya

n et

al.

(200

1)R

atB

a10

0.1

Nea

t8

88

3.3

0.38

40Pa

yan

et a

l. (2

001)

Rat

Ba

100.

1N

eat

84

41.

90.

3840

Paya

n et

al.

(200

1)R

atB

a10

0.1

Nea

t3

22

1.1

0.57

60Pa

yan

et a

l. (2

001)

Rat

Ba

100.

1N

eat

31

10.

50.

5760

Paya

n et

al.

(200

1)R

atB

a10

0.1

Nea

t3

0.5

0.5

0.3

0.57

60Pa

yan

et a

l. (2

001)

The

mos

t rel

evan

t stu

dy is

that

of S

cott

et a

l. (1

987)

, usi

ng h

uman

skin

in v

itro.

The

othe

r stu

dies

use

d ro

dent

skin

and

/or v

ehic

les (

acet

one,

pro

pyle

ne g

lyco

l) th

at m

ay a

ffec

t ski

n pe

rmea

bilit

y.

The

Kp

valu

e of

2·1

0-6 c

m/h

for h

uman

skin

cor

resp

onds

to "

very

low

" pe

rmea

bilit

y.

Rep

orte

d da

ta

In v

itro

In v

ivo

Ase

ssm

ent

A52

App

endi

x A

Subs

tanc

e: D

ichl

oroe

than

e, 1

,2-

Mol

ecul

ar w

eigh

t:99

.0C

AS:

107

-06-

2D

ensi

ty:1

.253

g/c

m³

Scie

ntifi

c ba

sis:

AoH

198

1:21

Mel

ting

poin

t:-3

5.3°

CB

oilin

g po

int:

83.5

°CSk

in n

otat

ion:

Yes

Vap

our

pres

sure

:8.7

kPa

(at 2

0°C

)Sk

in p

erm

eabi

lity:

Hig

hE

vapo

ratio

n ra

te:6

.5L

og K

ow:1

.48

Sp

Loc

C

ell

L

(µm

) A

(c

m²)

V

(ml)

Veh

icle

C

(m

g/m

l) n

TE

xp

(h)

TO

bs

(h)

TL

ag

(h)

Abs

(%

) K

P

(10-4

cm

/h)

Flux

(µ

g/cm

²/h) R

efer

ence

Rat

Ab

StFu

ll3.

71

Nea

t27

1-3

1-3

0.6

1-9

mg

810

00Ts

urut

a (1

977)

Mou

Ab

2.9

0.5

Nea

t3

0.3

2100

µg

2328

00Ts

urut

a (1

975)

Phys

iolo

gica

l sal

ine

was

use

d as

rece

ptor

med

ium

in th

e in

vitr

o st

udy,

this

may

resu

lt in

und

eres

timat

es o

f flu

x an

d K

p.Th

e in

viv

o st

udy

with

mic

e is

pre

ferr

ed.

The

Kp

valu

e of

2·1

0-3 c

orre

spon

ds to

"hi

gh"

perm

eabi

lity.

Rep

orte

d da

ta

In v

itro

In v

ivo

Ase

ssm

ent

A53

App

endi

x A

Subs

tanc

e: D

ieth

anol

amin

eM

olec

ular

wei

ght:

105.

1C

AS:

111

-42-

2D

ensi

ty:1

.09

g/cm

³Sc

ient

ific

basi

s: A

oH 1

992:

47M

eltin

g po

int:

28°C

Boi

ling

poin

t:26

8.8°

CSk

in n

otat

ion:

Yes

Vap

our

pres

sure

:<2

Pa (a

t 20°

C)

Skin

per

mea

bilit

y: L

owE

vapo

ratio

n ra

te:<

0.00

1L

og K

ow:-

1.43

Sp

Loc

C

ell

L

(µm

) A

(c

m²)

V

(ml)

Veh

icle

C

(m

g/m

l) n

TE

xp

(h)

TO

bs

(h)

TL

ag

(h)

Abs

(%

) K

P

(10-4

cm

/h)

Flux

(µ

g/cm

²/h) R

efer

ence

Hum

Br

FlFu

ll1.

80.

04N

eat

66

63.

20.

10.

055.

7Su

n et

al.

(199

6)H

umB

rFl

Full

1.8

0.1

H2O

20

mg/

cm²

66

62.

40.

20.

3413

Sun

et a

l. (1

996)

Hum

Br

St~1

000

10.

2H

2O1%

2224

24~6

0.4

0.5

0.55

Bra

in e

t al.

(200

5)H

umB

rSt

~100

01

0.2

H2O

1%20

2424

~80.

10.

088

0.09

6B

rain

et a

l. (2

005)

Mou

FlFu

ll1.

80.

04N

eat

36

60.

91.

30.

4246

Sun

et a

l. (1

996)

Mou

FlFu

ll1.

80.

1H

2O

20 m

g/cm

²3

66

0.8

6.7

7.6

290

Sun

et a

l. (1

996)

Rab

FlFu

ll1.

80.

04N

eat

36

61.

30

0.01

0.9

Sun

et a

l. (1

996)

Rab

FlFu

ll1.

80.

1H

2O

20 m

g/cm

²3

66

1.5

2.8

3.4

130

Sun

et a

l. (1

996)

Rat

FlFu

ll1.

80.

04N

eat

36

60.

60

0.02

1.8

Sun

et a

l. (1

996)

Rat

FlFu

ll1.

80.

1H

2O

20 m

g/cm

²3

66

0.8

0.6

0.6

23Su

n et

al.

(199

6)

Mou

10.

0295

% E

t 13

448

4858

2.4

3.2

Mat

hew

s et a

l. (1

997)

Mou

10.

0295

% E

t 38

548

4834

1.4

5.4

Mat

hew

s et a

l. (1

997)

Mou

10.

0295

% E

t 14

05

4848

2.9

0.12

1.6

Mat

hew

s et a

l. (1

997)

Rat

20.

0395

% E

t 14

548

482.

90.

091

0.13

Mat

hew

s et a

l. (1

997)

Rat

20.

0395

% E

t 50

548

4811

0.33

1.6

Mat

hew

s et a

l. (1

997)

Rat

20.

0395

% E

t 18

04

4848

160.

519.

2M

athe

ws e

t al.

(199

7)

The

in v

ivo

stud

ies (

Mat

hew

s et a

l. (1

997)

) use

d 95

% e

than

ol a

s veh

icle

and

can

not b

e us

ed.

The

repo

rted

perm

eabi

litie

s usi

ng n

eat d

ieth

anol

amin

e ar

e co

ntra

dict

ive

with

Kp

valu

es ra

ngin

g fr

om 1

·10-6

to 4

·10-5

cm

/h.

The

perm

eabi

lity

of d

ieth

anol

amin

e in

wat

er so

lutio

n is

hig

her w

ith K

p va

lues

bet

wee

n 1·

10-5

and

8·1

0-4 c

m/h

. Th

e pr

efer

red

stud

y is

that

of B

rain

et a

l. (2

005)

who

app

lied

exce

ss v

olum

e of

1%

die

than

olam

ine

in w

ater

usi

ng a

stat

ic

diff

usio

n ce

ll an

d fr

esh

or fr

ozen

hum

an b

reas

t.Th

e K

p va

lues

of 9

·10-6

(fre

sh sk

in) a

nd 5

·10-5

(fro

zen

skin

) cm

/h c

orre

spon

d to

"lo

w"

perm

eabi

lity.

Rep

orte

d da

ta

In v

itro

In v

ivo

Ase

ssm

ent

A54

App

endi

x A

Subs

tanc

e: D

ieth

yl p

htha

late

(DEP

)M

olec

ular

wei

ght:

222.

2C

AS:

84-

66-2

Den

sity

:1.1

18 g

/cm

³Sc

ient

ific

basi

s: N

ot a

vaila

ble

Mel

ting

poin

t:-3

°CB

oilin

g po

int:

298°

CSk

in n

otat

ion:

No

Vap

our

pres

sure

:0.3

Pa

(at 2

0°C

)Sk

in p

erm

eabi

lity:

Low

Eva

pora

tion

rate

:<0.

005

Log

Kow

:2.4

2

Sp

Loc

C

ell

L

(µm

) A

(c

m²)

V

(ml)

Veh

icle

C

(m

g/m

l) n

TE

xp

(h)

TO

bs

(h)

TL

ag

(h)

Abs

(%

) K

P

(10-4

cm

/h)

Flux

(µ

g/cm

²/h) R

efer

ence

GP

Ab

St35

00.

64In

fPB

0.44

65

50.

6721

09.

2Fr

asch

et a

l. (2

005)

Hum

Br

FlFu

ll0.

320.

01N

eat (

17m

g/cm

²)4

7272

0.09

811

Min

t et a

l. (1

994)

Hum

Ab

StEp

i1.

80.

5N

eat

1130

306

0.11

1.3

Scot

t et a

l. (1

987)

Hum

*B

rFl

Full

0.32

0.01

Nea

t (17

mg/

cm²)

372

720.

1314

Min

t et a

l. (1

994)

Rat

Ba

FlFu

ll0.

320.

01N

eat (

17m

g/cm

²)4

7272

0.84

94M

int e

t al.

(199

4)R

atB

aSt

Epi

1.8

0.5

Nea

t11

88

1.1

3.7

41Sc

ott e

t al.

(198

7)R

at*

Ba

FlFu

ll0.

320.

01N

eat (

17m

g/cm

²)3

7272

0.92

103

Min

t et a

l. (1

994)

N

o da

ta a

vaila

ble

Two

diff

eren

t stu

dies

(Min

t et a

l. (1

994)

, Sco

tt et

al.

(198

7)) u

sing

hum

an sk

in in

vitr

o, re

port

cons

iste

nt re

sults

.Th

e tw

o da

ta se

ts fr

om M

int e

t al.

(199

4) fo

r rat

and

hum

an sk

in re

pres

ent n

on-o

cclu

ded

(*) a

nd o

cclu

ded

appl

icat

ion

of

diet

hyl p

htha

late

.

The

Kp

valu

e of

1·1

0-5 c

orre

spon

ds to

"lo

w"

perm

eabi

lity.

Rep

orte

d da

ta

In v

itro

In v

ivo

Ase

ssm

ent

A55

App

endi

x A

Subs

tanc

e: D

ieth

ylam

ine

Mol

ecul

ar w

eigh

t:73

.1C

AS:

109

-89-

7D

ensi

ty:0

.707

g/c

m³

Scie

ntifi

c ba

sis:

AoH

198

3:36

Mel

ting

poin

t:-5

0°C

Boi

ling

poin

t:55

.5°C

Skin

not

atio

n: Y

esV

apou

r pr

essu

re:2

6 kP

a (a

t 20°

C)

Skin

per

mea

bilit

y: N

o da

taE

vapo

ratio

n ra

te:1

7L

og K

ow:0

.58

Sp

Loc

C

ell

L

(µm

) A

(c

m²)

V

(ml)

Veh

icle

C

(m

g/m

l) n

TE

xp

(h)

TO

bs

(h)

TL

ag

(h)

Abs

(%

) K

P

(10-4

cm

/h)

Flux

(µ

g/cm

²/h) R

efer

ence

N

o da

ta a

vaila

ble

N

o da

ta a

vaila

ble

No

quan

titat

ive

expe

rimen

tal d

ata

on d

erm

al u

ptak

e w

ere

foun

d in

the

liter

atur

e.

The

derm

al L

D50

in ra

bbits

is 8

20 m

g/kg

bw

, as c

ompa

red

to a

n or

al L

D50

of 1

30 m

g/kg

bw

in m

ice

(AC

GIH

(200

1)).

Rep

orte

d da

ta

In v

itro

In v

ivo

Ase

ssm

ent

A56

App

endi

x A

Subs

tanc

e: D

ieth

ylam

inoe

than

ol, 2

-M

olec

ular

wei

ght:

117.

2C

AS:

100

-37-

8D

ensi

ty:0

.884

g/c

m³

Scie

ntifi

c ba

sis:

AoH

199

5:19

Mel

ting

poin

t:-7

0°C

Boi

ling

poin

t:16

2°C

Skin

not

atio

n: Y

esV

apou

r pr

essu

re:0

.19

kPa

(at 2

0°C

)Sk

in p

erm

eabi

lity:

No

data

Eva

pora

tion

rate

:Not

ava

ilabl

eL

og K

ow:0

.05

(est

imat

ed)

Sp

Loc

C

ell

L

(µm

) A

(c

m²)

V

(ml)

Veh

icle

C

(m

g/m

l) n

TE

xp

(h)

TO

bs

(h)

TL

ag

(h)

Abs

(%

) K

P

(10-4

cm

/h)

Flux

(µ

g/cm

²/h) R

efer

ence

N

o da

ta a

vaila

ble

N

o da

ta a

vaila

ble

No

quan

titat

ive

expe

rimen

tal d

ata

on d

erm

al u

ptak

e w

ere

foun

d in

the

liter

atur

e.

The

skin

not

atio

n by

AC

GIH

(200

1) is

bas

ed o

n th

e re

porte

d de

rmal

LD

50 o

f 0.9

g/k

g bw

in ra

bbits

.Fo

r com

paris

on, t

he o

ral L

D50

in ra

ts is

in th

e ra

nge

of 1

.3 to

5.7

g/k

g bw

.

Acc

ordi

ng to

theo

retic

al c

alcu

latio

ns (b

ased

on

the

phys

ical

pro

perti

es o

f the

subs

tanc

e)

by F

iser

ova-

Ber

gero

va e

t al.

(199

0), t

he p

oten

tial f

or d

erm

al a

bsor

ptio

n an

d re

sulti

ng to

xici

ty is

sign

ifica

nt.

Rep

orte

d da

ta

In v

itro

In v

ivo

Ase

ssm

ent

A57

App

endi

x A

Subs

tanc

e: D

ieth

ylen

e gl

ycol

Mol

ecul

ar w

eigh

t:10

6.1

CA

S: 1

11-4

6-6

Den

sity

:1.1

18 g

/cm

³Sc

ient

ific

basi

s: N

ot a

vaila

ble

Mel

ting

poin

t:-1

0°C

Boi

ling

poin

t:24

5°C

Skin

not

atio

n: Y

esV

apou

r pr

essu

re:0

.5 P

a (a

t 20°

C)

Skin

per

mea

bilit

y: V

ery

low

Eva

pora

tion

rate

:Not

ava

ilabl

eL

og K

ow:-

1.47

(est

imat

ed)

Sp

Loc

C

ell

L

(µm

) A

(c

m²)

V

(ml)

Veh

icle

C

(m

g/m

l) n

TE

xp

(h)

TO

bs

(h)

TL

ag

(h)

Abs

(%

) K

P

(10-4

cm

/h)

Flux

(µ

g/cm

²/h) R

efer

ence

N

o da

ta a

vaila

ble

Rat

Ba

120.

045

Nea

t (50

mg)

572

729.

10.

047

5.3

Mat

hew

s et a

l. (1

991)

Nea

t lab

elle

d di

ethy

lene

gly

col w

as a

pplie

d to

the

clip

ped

back

of r

ats a

nd to

tal r

adio

activ

ity w

as m

easu

red

in b

reat

h an

d ur

ine

up to

72h

.

The

calc

ulat

ed p

erm

eabi

lity

is c

onsi

dere

d as

"ve

ry lo

w".

Rep

orte

d da

ta

In v

itro

In v

ivo

Ase

ssm

ent

A58

App

endi

x A

Subs

tanc

e: D

ieth

ylen

e gl

ycol

mon

obut

yl e

ther

(DEG

BE)

Mol

ecul

ar w

eigh

t:16

2.2

CA

S: 1

12-3

4-5

Den

sity

:0.9

67 g

/cm

³Sc

ient

ific

basi

s: A

oH 1

995:

19M

eltin

g po

int:

-68.

1°C

Boi

ling

poin

t:23

0.4°

CSk

in n

otat

ion:

No

Vap

our

pres

sure

:4.4

Pa

(at 2

0°C

)Sk

in p

erm

eabi

lity:

Mod

erat

eE

vapo

ratio

n ra

te:0

.003

Log

Kow

:0.5

6

Sp

Loc

C

ell

L

(µm

) A

(c

m²)

V

(ml)

Veh

icle

C

(m

g/m

l) n

TE

xp

(h)

TO

bs

(h)

TL

ag

(h)

Abs

(%

) K

P

(10-4

cm

/h)

Flux

(µ

g/cm

²/h) R

efer

ence

Hum

StEp

i0.

64/1

.0N

eat

108

81-

23.

129

0B

arbe

r et a

l. (1

992)

Hum

Ab

StEp

i1.

81-

5N

eat

98

82

0.36

35D

ugar

d et

al.

(198

4)R

atSt

Full

0.64

/1.0

Nea

t12

88

1-2

5.3

510

Bar

ber e

t al.

(199

2)

Rat

Ba

4.3

Nea

t4

2416

87.

7-16

730-

1500

Boa

tman

et a

l. (1

993)

All

thre

e st

udie

s use

d si

mila

r tec

hniq

ues;

stat

ic F

ranz

cel

ls, h

eat-s

epar

ated

epi

derm

is (6

0°C

in w

ater

), fr

ozen

and

thaw

ed h

uman

or

rat s

kin.

The

resu

lts o

f Bar

ber e

t al.

(199

2) a

nd B

oatm

an e

t al.

(199

3) a

re c

onsi

sten

t, w

here

as D

ugar

d et

al.

(198

4) re

ports

10

-fol

d lo

wer

flux

and

Kp.

The

pref

erre

d st

udy

is th

at o

f Bar

ber e

t al.

(199

2) u

sing

hum

an sk

in.

The

Kp

valu

e of

3·1

0-4 c

m/h

cor

resp

onds

to "

mod

erat

e" p

erm

eabi

lity.

Rep

orte

d da

ta

In v

itro

In v

ivo

Ase

ssm

ent

A59

App

endi

x A

Subs

tanc

e: D

ieth

ylen

e gl

ycol

mon

obut

yl e

ther

ace

tate

(DEG

BEA

)M

olec

ular

wei

ght:

204.

3C

AS:

124

-17-

4D

ensi

ty:0

.98

g/cm

³Sc

ient

ific

basi

s: A

oH 1

995:

19M

eltin

g po

int:

-32°

CB

oilin

g po

int:

246°

CSk

in n

otat

ion:

No

Vap

our

pres

sure

:5.3

Pa

(at 2

0°C

)Sk

in p

erm

eabi

lity:

Hig

hE

vapo

ratio

n ra

te:0

.001

Log

Kow

:1.3

0 (e

stim

ated

)

Sp

Loc

C

ell

L

(µm

) A

(c

m²)

V

(ml)

Veh

icle

C

(m

g/m

l) n

TE

xp

(h)

TO

bs

(h)

TL

ag

(h)

Abs

(%

) K

P

(10-4

cm

/h)

Flux

(µ

g/cm

²/h) R

efer

ence

N

o da

ta a

vaila

ble

Rat

Ba

4.3

Nea

t4

2416

813

-16

1300

-160

0B

oatm

an e

t al.

(199

3)

Onl

y ra

t in

vivo

dat

a ar

e av

aila

ble.

Not

ably

, the

flux

and

Kp

of D

EGB

EA is

sim

ilar t

o th

at o

f DEG

BE.

The

Kp

valu

e fo

r rat

skin

cor

resp

onds

to "

high

" pe

rmea

bilit

y.

Rep

orte

d da

ta

In v

itro

In v

ivo

Ase

ssm

ent

A60

App

endi

x A

Subs

tanc

e: D

ieth

ylen

e gl

ycol

mon

oeth

yl e

ther

(DEG

EE)

Mol

ecul

ar w

eigh

t:13

4.2

CA

S: 1

11-9

0-0

Den

sity

:0.9

99 g

/cm

³Sc

ient

ific

basi

s: A

oH 1

997:

24M

eltin

g po

int:

-76°

CB

oilin

g po

int:

197°

CSk

in n

otat

ion:

Yes

Vap

our

pres

sure

:19

Pa (a

t 25°

C)

Skin

per

mea

bilit

y: M

oder

ate

Eva

pora

tion

rate

:0.0

2L

og K

ow:-

0.54

Sp

Loc

C

ell

L

(µm

) A

(c

m²)

V

(ml)

Veh

icle

C

(m

g/m

l) n

TE

xp

(h)

TO

bs

(h)

TL

ag

(h)

Abs

(%

) K

P

(10-4

cm

/h)

Flux

(µ

g/cm

²/h) R

efer

ence

Hum

Ab

StEp

i1.

81-

5N

eat

108

8<1

1.3

130

Dug

ard

et a

l. (1

984)

N

o da

ta a

vaila

ble

The

only

stud

y fo

und

is th

at o

f Dug

ard

et a

l. (1

984)

wer

e hu

man

skin

was

exp

osed

to n

eat D

EGEE

in v

itro.

The

repo

rted

Kp

valu

e of

1·1

0-4 c

m/h

, cor

resp

onds

to "

mod

erat

e" p

erm

eabi

lity.

It sh

ould

be

note

d th

at D

ugar

d et

al.

(198

4) h

as a

lso

pres

ente

d K

p da

ta o

n so

me

rela

ted

glyc

ol e

ther

s, e.

g. D

EGB

E, th

at w

ere

appr

oxim

atel

y te

n tim

es lo

wer

that

that

of o

ther

inve

stig

ator

s.

Rep

orte

d da

ta

In v

itro

In v

ivo

Ase

ssm

ent

A61

App

endi

x A

Subs

tanc

e: D

ieth

ylen

e gl

ycol

mon

oeth

yl e

ther

ace

tate

(DEG

EEA

)M

olec

ular

wei

ght:

176.

2C

AS:

112

-15-

2D

ensi

ty:1

.01

g/cm

³Sc

ient

ific

basi

s: A

oH 1

997:

24M

eltin

g po

int:

-25°

CB

oilin

g po

int:

210

to 2

20°C

Skin

not

atio

n: Y

esV

apou

r pr

essu

re:7

Pa

(at 2

0°C

)Sk

in p

erm

eabi

lity:

No

data

Eva

pora

tion

rate

:0.0

08L

og K

ow:0

.32

(est

imat

ed)

Sp

Loc

C

ell

L

(µm

) A

(c

m²)

V

(ml)

Veh

icle

C

(m

g/m

l) n

TE

xp

(h)

TO

bs

(h)

TL

ag

(h)

Abs

(%

) K

P

(10-4

cm

/h)

Flux

(µ

g/cm

²/h) R

efer

ence

N

o da

ta a

vaila

ble

N

o da

ta a

vaila

ble

No

quan

titat

ive

expe

rimen

tal d

ata

on d

erm

al u

ptak

e w

ere

foun

d in

the

liter

atur

e.

The

Swed

ish

cons

ensu

s rep

ort (

AoH

199

7:25

) sta

tes t

hat "

… it

is re

ason

able

to a

ssum

e th

at (D

EGEE

A),

like

othe

r gly

col e

ther

s, ar

e ef

ficie

ntly

abs

orbe

d vi

a bo

th sk

in a

nd in

hala

tion"

.

Rep

orte

d da

ta

In v

itro

In v

ivo

Ase

ssm

ent

A62

App

endi

x A

Subs

tanc

e: D

ieth

ylen

triam

ine

Mol

ecul

ar w

eigh

t:10

3.2

CA

S: 1

11-4

0-0

Den

sity

:0.9

51 g

/cm

³Sc

ient

ific

basi

s: A

oH 1

995:

19M

eltin

g po

int:

-33°

CB

oilin

g po

int:

207°

CSk

in n

otat

ion:

Yes

Vap

our

pres

sure

:0.0

5 kP

a (a

t 20°

C)

Skin

per

mea

bilit

y: N

o da

taE

vapo

ratio

n ra

te:0

.01

Log

Kow

:-2.

13 (e

stim

ated

)

Sp

Loc

C

ell

L

(µm

) A

(c

m²)

V

(ml)

Veh

icle

C

(m

g/m

l) n

TE

xp

(h)

TO

bs

(h)

TL

ag

(h)

Abs

(%

) K

P

(10-4

cm

/h)

Flux

(µ

g/cm

²/h) R

efer

ence

N

o da

ta a

vaila

ble

N

o da

ta a

vaila

ble

No

quan

titat

ive

expe

rimen

tal d

ata

on d

erm

al u

ptak

e w

ere

foun

d in

the

liter

atur

e.

The

Swed

ish

cons

ensu

s rep

ort (

AoH

199

5:19

) sta

tes t

hat t

he su

bsta

nce

can

be ta

ken

up b

y sk

in, w

ithou

t fur

ther

det

ails

.

The

oral

(2.3

3 an

d 1.

08 g

/kg

bw in

rats

, Sm

yth

et a

l. (1

949)

and

Hin

e et

al.

(195

8)) a

nd d

erm

al (1

.09

g/kg

bw

in ra

bbit,

Sm

yth

et a

l. (1

949)

) LD

50 a

re n

ot v

ery

diff

eren

t fro

m o

ne a

noth

er, s

ugge

stin

g ex

tens

ive

derm

al u

ptak

e.

Acc

ordi

ng to

theo

retic

al c

alcu

latio

ns b

y Fi

sero

va-B

erge

rova

et a

l. (1

990)

the

pote

ntia

l for

der

mal

abso

rptio

n an

d re

sulti

ng to

xici

ty is

sign

ifica

nt.

Rep

orte

d da

ta

In v

itro

In v

ivo

Ase

ssm

ent

A63

App

endi

x A

Subs

tanc

e: D

iisop

ropy

lam

ine

Mol

ecul

ar w

eigh

t:10

1.2

CA

S: 1

08-1

8-9

Den

sity

:0.7

22 g

/cm

³Sc

ient

ific

basi

s: A

oH 1

991:

8M

eltin

g po

int:

-61°

CB

oilin

g po

int:

84°C

Skin

not

atio

n: Y

esV

apou

r pr

essu

re:8

kPa

(at 2

0°C

)Sk

in p

erm

eabi

lity:

No

data

Eva

pora

tion

rate

:Not

ava

ilabl

eL

og K

ow:1

.40

Sp

Loc

C

ell

L

(µm

) A

(c

m²)

V

(ml)

Veh

icle

C

(m

g/m

l) n

TE

xp

(h)

TO

bs

(h)

TL

ag

(h)

Abs

(%

) K

P

(10-4

cm

/h)

Flux

(µ

g/cm

²/h) R

efer

ence

N

o da

ta a

vaila

ble

N

o da

ta a

vaila

ble

No

quan

titat

ive

expe

rimen

tal d

ata

on d

erm

al u

ptak

e w

ere

foun

d in

the

liter

atur

e.

The

Swed

ish

cons

ensu

s rep

ort (

AoH

199

1:8)

stat

es th

at d

iisop

ropy

lam

ine

can

be ta

ken

up b

y th

e sk

in. N

o fu

rther

det

ails

are

giv

en.

The

sour

ce (A

nder

sson

et a

l. (1

985)

) con

tain

s no

info

rmat

ion

on d

erm

al a

bsor

ptio

n.

Acc

ordi

ng to

theo

retic

al c

alcu

latio

ns b

y Fi

sero

va-B

erge

rova

et a

l. (1

990)

the

pote

ntia

l for

der

mal

abso

rptio

n an

d re

sulti

ng to

xici

ty is

sign

ifica

nt.

Rep

orte

d da

ta

In v

itro

In v

ivo

Ase

ssm

ent

A64

App

endi

x A

Subs

tanc

e: D

imet

hyl p

htha

late

Mol

ecul

ar w

eigh

t:19

4.2

CA

S: 1

31-1

1-3

Den

sity

:1.1

9 g/

cm³

Scie

ntifi

c ba

sis:

AoH

198

3:36

Mel

ting

poin

t:2°

CB

oilin

g po

int:

283.

7°C

Skin

not

atio

n: N

oV

apou

r pr

essu

re:0

.8 P

a (a

t 20°

C)

Skin

per

mea

bilit

y: L

owE

vapo

ratio

n ra

te:<

0.00

5L

og K

ow:1

.60

Sp

Loc

C

ell

L

(µm

) A

(c

m²)

V

(ml)

Veh

icle

C

(m

g/m

l) n

TE

xp

(h)

TO

bs

(h)

TL

ag

(h)

Abs

(%

) K

P

(10-4

cm

/h)

Flux

(µ

g/cm

²/h) R

efer

ence

Hum

Ab

StEp

i1.

80.

5N

eat

1430

300.

10.

334

Scot

t et a

l. (1

987)

Rat

Ab

StEp

i1.

80.

5N

eat

88

0.5

3.5

42Sc

ott e

t al.

(198

7)

N

o da

ta a

vaila

ble

The

only

ava

ilabl

e st

udy

(Sco

tt et

al.

(198

7)) r

epor

ts 1

0-fo

ld d

iffer

ent p

erm

eabi

litie

s for

hum

an a

nd ra

t ski

n.H

uman

epi

derm

al m

embr

anes

wer

e pr

epar

ed b

y he

atin

g in

wat

er (6

0°C

), w

here

as ra

t mem

bran

es w

ere

prep

ared

usi

ng 2

M N

aBr.

How

ever

, the

aut

hors

cla

im th

at th

e tw

o pr

epar

atio

n te

chni

ques

giv

e th

e sa

me

perm

eabi

lity

prop

ertie

s.

The

hum

an in

vitr

o da

ta su

gges

ts "

low

" pe

rmea

bilit

y.

Rep

orte

d da

ta

In v

itro

In v

ivo

Ase

ssm

ent

A65

App

endi

x A

Subs

tanc

e: D

imet

hyla

ceta

mid

e, N

-M

olec

ular

wei

ght:

87.1

CA

S: 1

27-1

9-5

Den

sity

:0.9

37 g

/cm

³Sc

ient

ific

basi

s: A

oH 1

994:

30M

eltin

g po

int:

-20°

CB

oilin

g po

int:

166.

1°C

Skin

not

atio

n: Y

esV

apou

r pr

essu

re:0

.2 k

Pa (a

t 20°

C)

Skin

per

mea

bilit

y: V

ery

high

Eva

pora

tion

rate

:0.1

4L

og K

ow:-

0.77

Sp

Loc

C

ell

L

(µm

) A

(c

m²)

V

(ml)

Veh

icle

C

(m

g/m

l) n

TE

xp

(h)

TO

bs

(h)

TL

ag

(h)

Abs

(%

) K

P

(10-4

cm

/h)

Flux

(µ

g/cm

²/h) R

efer

ence

Hum

Br

St30

0-60

00.

64N

eat

36

612

011

000

Urs

in e

t al.

(199

5)

N

o da

ta a

vaila

ble

The

only

stud

y fo

und

was

that

of U

rsin

et a

l. (1

995)

whe

re h

uman

skin

was

exp

osed

to n

eat n

-dim

ethy

lace

tam

ide

in v

itro.

The

repo

rted

Kp

valu

e of

1·1

0-2 c

m/h

, sug

gest

s "ve

ry h

igh"

per

mea

bilit

y

Rep

orte

d da

ta

In v

itro

In v

ivo

Ase

ssm

ent

A66

App

endi

x A

Subs

tanc

e: D

imet

hyla

nilli

ne, N

,N-

Mol

ecul

ar w

eigh

t:12

1.2

CA

S: 1

21-6

9-7

Den

sity

:0.9

56 g

/cm

³Sc

ient

ific

basi

s: A

oH 1

991:

8M

eltin

g po

int:

2.5°

CB

oilin

g po

int:

194°

CSk

in n

otat

ion:

Yes

Vap

our

pres

sure

:0.0

67 k

Pa (a

t 20°

C)

Skin

per

mea

bilit

y: N

o da

taE

vapo

ratio

n ra

te:<

1L

og K

ow:2

.31

Sp

Loc

C

ell

L

(µm

) A

(c

m²)

V

(ml)

Veh

icle

C

(m

g/m

l) n

TE

xp

(h)

TO

bs

(h)

TL

ag

(h)

Abs

(%

) K

P

(10-4

cm

/h)

Flux

(µ

g/cm

²/h) R

efer

ence

N

o da

ta a

vaila

ble

N

o da

ta a

vaila

ble

No

quan

titat

ive

expe

rimen

tal d

ata

on d

erm

al u

ptak

e w

ere

foun

d in

the

liter

atur

e.

The

Swed

ish

cons

ensu

s rep

ort (

AoH

199

1:8)

stat

es th

at d

imet

hyla

nilin

e ca

n be

abs

orbe

d vi

a th

e sk

in.

No

addi

tiona

l dat

a ar

e gi

ven.

Acc

ordi

ng to

theo

retic

al c

alcu

latio

ns b

y Fi

sero

va-B

erge

rova

et a

l. (1

990)

the

pote

ntia

l for

der

mal

abso

rptio

n an

d re

sulti

ng to

xici

ty is

sign

ifica

nt.

Rep

orte

d da

ta

In v

itro

In v

ivo

Ase

ssm

ent

A67

App

endi

x A

Subs

tanc

e: D

imet

hyle

thyl

amin

eM

olec

ular

wei

ght:

73.1

CA

S: 5

98-5

6-1

Den

sity

:0.6

75 g

/cm

³Sc

ient

ific

basi

s: A

oH 1

992:

6M

eltin

g po

int:

-140

°CB

oilin

g po

int:

36°C

Skin

not

atio

n: N

oV

apou

r pr

essu

re:5

5 kP

a (a

t 20°

C)

Skin

per

mea

bilit

y: H

igh

Eva

pora

tion

rate

:Not

ava

ilabl

eL

og K

ow:0

.70

Sp

Loc

C

ell

L

(µm

) A

(c

m²)

V

(ml)

Veh

icle

C

(m

g/m

l) n

TE

xp

(h)

TO

bs

(h)

TL

ag

(h)

Abs

(%

) K

P

(10-4

cm

/h)

Flux

(µ

g/cm

²/h) R

efer

ence

GP

FlFu

ll0.

1H

2O0.

676

4848

710

8Lu

ndh

et a

l. (1

997)

GP

FlFu

ll0.

1H

2O0.

676

4848

105

Lund

h et

al.

(199

7)G

PFl

Full

0.1

NaC

l0.

676

4848

340

25Lu

ndh

et a

l. (1

997)

GP

FlFu

ll0.

1N

aCl

0.67

648

488

209

Lund

h et

al.

(199

7)H

umFl

250

0.1

H2O

0.67

640

26Lu

ndh

et a

l. (1

997)

Hum

Fl25

00.

1H

2O0.

676

2011

Lund

h et

al.

(199

7)H

umFl

250

0.1

NaC

l0.

676

120

16Lu

ndh

et a

l. (1

997)

Hum

Arm

870

Inf

Vap

0.00

027

34

844

µg

500

0.01

3Lu

ndh

et a

l. (1

997)

Hum

Arm

870

Inf

Vap

0.00

053

34

864

µg

320

0.02

Lund

h et

al.

(199

7)H

umA

rm87

0In

fV

ap0.

001

34

888

µg

250

0.02

6Lu

ndh

et a

l. (1

997)

The

one

foun

d st

udy

by L

undh

et a

l. (1

997)

show

s con

sist

ent r

esul

ts b

etw

een

vapo

ur a

nd a

queo

us so

lutio

ns.

The

pref

erre

d ex

perim

ents

are

thos

e on

hum

an sk

in in

vitr

o w

ith re

porte

d K

p va

lues

bet

wee

n 2·

10-3

to 4

·10-3

cm

/h,

whi

ch c

orre

spon

ds to

"hi

gh"

perm

eabi

lity.

Rep

orte

d da

ta

In v

itro

In v

ivo

Ase

ssm

ent

A68

App

endi

x A

Subs

tanc

e: D

imet

hylfo

rmam

ide

Mol

ecul

ar w

eigh

t:73

.1C

AS:

68-

12-2

Den

sity

:0.9

44 g

/cm

³Sc

ient

ific

basi

s: A

oH 1

983:

36M

eltin

g po

int:

-61°

CB

oilin

g po

int:

153°

CSk

in n

otat

ion:

Yes

Vap

our

pres

sure

:0.4

9 kP

a (a

t 25°

C)

Skin

per

mea

bilit

y: V

ery

high

Eva

pora

tion

rate

:0.1

7L

og K

ow:-

1.01

Sp

Loc

C

ell

L

(µm

) A

(c

m²)

V

(ml)

Veh

icle

C

(m

g/m

l) n

TE

xp

(h)

TO

bs

(h)

TL

ag

(h)

Abs

(%

) K

P

(10-4

cm

/h)

Flux

(µ

g/cm

²/h) R

efer

ence

Hum

Ab

StFu

ll3.

10.

2N

eat

6?4

41

9684

00La

rese

et a

l. (1

994)

Hum

Br

St30

0-60

00.

64N

eat

36

614

013

000

Urs

in e

t al.

(199

5)

Hum

Ha

Inf

Nea

t18

0.03

3-0.

3324

100

9400

Mra

z et

al.

(199

2)

The

thre

e di

ffer

ent s

tudi

es sh

ow c

onsi

sten

t res

ults

. The

pre

ferr

ed st

udy

is th

e hu

man

in v

ivo

stud

y by

Mra

z et

al.

(199

2).

The

Kp

valu

e of

1·1

0-2 c

m/h

cor

resp

onds

to "

very

hig

h" p

erm

eabi

lity.

Rep

orte

d da

ta

In v

itro

In v

ivo

Ase

ssm

ent

A69

App

endi

x A

Subs

tanc

e: D

imet

hyls

ulfo

xide

Mol

ecul

ar w

eigh

t:78

.1C

AS:

67-

68-5

Den

sity

:1.0

96 g

/cm

³Sc

ient

ific

basi

s: A

oH 1

992:

47M

eltin

g po

int:

18.5

°CB

oilin

g po

int:

189°

CSk

in n

otat

ion:

Yes

Vap

our

pres

sure

:0.0

49 k

Pa (a

t 20°

C)

Skin

per

mea

bilit

y: V

ery

high

Eva

pora

tion

rate

:4.3

Log

Kow

:-1.

35

Sp

Loc

C

ell

L

(µm

) A

(c

m²)

V

(ml)

Veh

icle

C

(m

g/m

l) n

TE

xp

(h)

TO

bs

(h)

TL

ag

(h)

Abs

(%

) K

P

(10-4

cm

/h)

Flux

(µ

g/cm

²/h) R

efer

ence

Hum

Br

St30

0-60

00.

64N

eat

36

616

018

000

Urs

in e

t al.

(199

5)

Hum

EB25

088

0 (8

0%. 1

7 g)

0.5

504

25-4

038

0-61

033

000-

5300

0W

ong

et a

l. (1

971)

Hum

WB

2000

0H

2O77

0 (7

0%. 1

g/k

g B

W)

28

2013

0.74

57H

ucke

r et a

l. (1

967)

MP

Ba

250

880

(80%

. 17

g)4

144

100

190

1700

0W

ong

et a

l. (1

971)

Rat

Ab

25N

eat (

260

mg)

0.25

4837

140

1600

0M

cDer

mot

et a

l. (1

967)

Rat

Ab

25N

eat (

240

mg)

0.5

4867

120

1300

0M

cDer

mot

et a

l. (1

967)

Rat

Ab

25N

eat (

350

mg)

0.75

4890

160

1700

0M

cDer

mot

et a

l. (1

967)

Rat

Ab

25N

eat (

270

mg)

148

9492

1000

0M

cDer

mot

et a

l. (1

967)

The

diff

eren

t stu

dies

show

con

sist

ent r

esul

ts w

ith K

p va

lues

rang

ing

from

1·1

0-3 to

6·1

0-2 c

m/h

,w

ith a

pre

ferr

ed st

udy

of U

rsin

et a

l. (1

995)

wer

e hu

man

skin

was

exp

osed

to n

eat c

hem

ical

.

Thes

e K

p va

lues

cor

resp

ond

to "

high

" pe

rmea

bilit

y.

Rep

orte

d da

ta

In v

itro

In v

ivo

Ase

ssm

ent

A70

App

endi

x A

Subs

tanc

e: D

initr

oben

zene

Mol

ecul

ar w

eigh

t:16

8.1

CA

S: 2

5154

-54-

5D

ensi

ty:1

.368

g/c

m³

Scie

ntifi

c ba

sis:

Not

ava

ilabl

e M

eltin

g po

int:

88 to

90°

CB

oilin

g po

int:

~300

°CSk

in n

otat

ion:

Yes

Vap

our

pres

sure

:<10

0 Pa

(at 2

0°C

)Sk

in p

erm

eabi

lity:

No

data

Eva

pora

tion

rate

:Not

ava

ilabl

eL

og K

ow:N

ot a

vaila

ble

Sp

Loc

C

ell

L

(µm

) A

(c

m²)

V

(ml)

Veh

icle

C

(m

g/m

l) n

TE

xp

(h)

TO

bs

(h)

TL

ag

(h)

Abs

(%

) K

P

(10-4

cm

/h)

Flux

(µ

g/cm

²/h) R

efer

ence

N

o da

ta a

vaila

ble

N

o da

ta a

vaila

ble

No

quan

titat

ive

expe

rimen

tal d

ata

on d

erm

al u

ptak

e w

ere

foun

d in

the

liter

atur

e.

The

cont

ribut

ion

of d

erm

al e

xpos

ure

to th

e sy

stem

ic to

xici

ty o

f din

itrob

enze

ne is

wel

l est

ablis

hed

(AC

GIH

(200

1)).

Rep

orte

d da

ta

In v

itro

In v

ivo

Ase

ssm

ent

A71

App

endi

x A

Subs

tanc

e: D

initr

otol

uene

Mol

ecul

ar w

eigh

t:18

2.1

CA

S: 2

5321

-14-

6D

ensi

ty:1

.321

g/c

m³

Scie

ntifi

c ba

sis:

AoH

199

2:6

Mel

ting

poin

t:70

°CB

oilin

g po

int:

250°

CSk

in n

otat

ion:

Yes

Vap

our

pres

sure

:2.4

Pa

(at 2

0°C

)Sk

in p

erm

eabi

lity:

No

data

Eva

pora

tion

rate

:Not

ava

ilabl

eL

og K

ow:2

.18

(est

imat

ed)

Sp

Loc

C

ell

L

(µm

) A

(c

m²)

V

(ml)

Veh

icle

C

(m

g/m

l) n

TE

xp

(h)

TO

bs

(h)

TL

ag

(h)

Abs

(%

) K

P

(10-4

cm

/h)

Flux

(µ

g/cm

²/h) R

efer

ence

N

o da

ta a

vaila

ble

N

o da

ta a

vaila

ble

No

quan

titat

ive

expe

rimen

tal d

ata

on d

erm

al u

ptak

e w

ere

foun

d in

the

liter

atur

e.

Bio

mon

itorin

g st

udie

s in

wor

kers

show

hig

her u

rine

leve

ls o

f met

abol

ites t

han

wou

ld b

e ex

pect

ed fr

om in

hala

tion

expo

sure

only

(AoH

199

2:6,

AC

GIH

(200

1), T

chou

nwou

et a

l. (2

003)

).

Rep

orte

d da

ta

In v

itro

In v

ivo

Ase

ssm

ent

A72

App

endi

x A

Subs

tanc

e: D

initr

otol

uene

, 2,4

-M

olec

ular

wei

ght:

182.

1C

AS:

121

-14-

2D

ensi

ty:1

.521

g/c

m³

Scie

ntifi

c ba

sis:

AoH

199

2:6

Mel

ting

poin

t:69

°CB

oilin

g po

int:

300°

CSk

in n

otat

ion:

Yes

Vap

our

pres

sure

:130

Pa

(at 1

03°C

)Sk

in p

erm

eabi

lity:

Mod

erat

eE

vapo

ratio

n ra

te:N

ot a

vaila

ble

Log

Kow

:1.9

8

Sp

Loc

C

ell

L

(µm

) A

(c

m²)

V

(ml)

Veh

icle

C

(m

g/m

l) n

TE

xp

(h)

TO

bs

(h)

TL

ag

(h)

Abs

(%

) K

P

(10-4

cm

/h)

Flux

(µ

g/cm

²/h) R

efer

ence

Pig

Ba

St50

0-90

00.

811

mg/

cm²S

oil (

Ti)

0.93

(6.

8 µg

/cm

²)6

88

5.3

0.49

0.04

5R

eife

nrat

h et

al.

(200

2)Pi

gB

aSt

500-

900

0.8

12 m

g/cm

²Soi

l (Y

o)1.

5 (1

2 µg

/cm

²)6

88

141.

40.

21R

eife

nrat

h et

al.

(200

2)Pi

gB

aSt

500-

900

0.8

0.00

5A

c2.

4 (1

2 µg

/cm

²)6

88

342.

10.

49R

eife

nrat

h et

al.

(200

2)

N

o da

ta a

vaila

ble

The

only

foun

d st

udy

was

that

of R

eife

nrat

h et

al.

(200

2), w

here

pig

skin

was

exp

osed

to 2

,4-d

initr

otol

uene

and

2,

6-di

nitro

tolu

ene

with

soil

or a

ceto

ne a

s veh

icle

. It s

houl

d be

not

ed th

at th

e us

e of

ace

tone

as v

ehic

le

may

hav

e se

vere

ly a

ffec

ted

the

skin

pro

perti

es.

The

repo

rted

Kp

valu

es a

re c

onsi

sten

t bet

wee

n ex

perim

ents

and

isom

ers,

and

rang

e be

twee

n 1·

10-4

and

2·1

0-4 c

m/h

,su

gges

ting

a "m

oder

ate"

per

mea

bilit

y.

Rep

orte

d da

ta

In v

itro

In v

ivo

Ase

ssm

ent

A73

App

endi

x A

Subs

tanc

e: D

initr

otol

uene

, 2,6

-M

olec

ular

wei

ght:

182.

1C

AS:

606

-20-

2D

ensi

ty:1

.283

g/c

m³

Scie

ntifi

c ba

sis:

AoH

199

2:6

Mel

ting

poin

t:65

°CB

oilin

g po

int:

300°

CSk

in n

otat

ion:

Yes

Vap

our

pres

sure

:130

Pa

(at 2

0°C

)Sk

in p

erm

eabi

lity:

Mod

erat

eE

vapo

ratio

n ra

te:N

ot a

vaila

ble

Log

Kow

:2.1

0

Sp

Loc

C

ell

L

(µm

) A

(c

m²)

V

(ml)

Veh

icle

C

(m

g/m

l) n

TE

xp

(h)

TO

bs

(h)

TL

ag

(h)

Abs

(%

) K

P

(10-4

cm

/h)

Flux

(µ

g/cm

²/h) R

efer

ence

Pig

Ba

St50

0-90

00.

817

mg/

cm²S

oil (

Ti)

0.47

(6.

1 µg

/cm

²)6

88

3.7

0.94

0.04

4R

eife

nrat

h et

al.

(200

2)Pi

gB

aSt

500-

900

0.8

11 m

g/cm

²Soi

l (Y

o)1.

1 (9

.7 µ

g/cm

²)6

88

151.

70.

2R

eife

nrat

h et

al.

(200

2)Pi

gB

aSt

500-

900

0.8

0.00

5A

c1.

9 (9

.6 µ

g/cm

²)6

88

221.

50.

29R

eife

nrat

h et

al.

(200

2)

N

o da

ta a

vaila

ble

The

only

foun

d st

udy

was

that

of R

eife

nrat

h et

al.

(200

2), w

here

pig

skin

was

exp

osed

to 2

,4-d

initr

otol

uene

and

2,

6-di

nitro

tolu

ene

with

soil

or a

ceto

ne a

s veh

icle

. It s

houl

d be

not

ed th

at th

e us

e of

ace

tone

as v

ehic

le

may

hav

e se

vere

ly a

ffec

ted

the

skin

pro

perti

es.

The

repo

rted

Kp

valu

es a

re c

onsi

sten

t bet

wee

n ex

perim

ents

and

isom

ers,

and

rang

e be

twee

n 1·

10-4

and

2·1

0-4 c

m/h

,su

gges

ting

a "m

oder

ate"

per

mea

bilit

y.

Rep

orte

d da

ta

In v

itro

In v

ivo

Ase

ssm

ent

A74

App

endi

x A

Subs

tanc

e: D

ioxa

neM

olec

ular

wei

ght:

88.1

CA

S: 1

23-9

1-1

Den

sity

:1.0

33 g

/cm

³Sc

ient

ific

basi

s: A

oH 1

992:

47M

eltin

g po

int:

11.8

°CB

oilin

g po

int:

101.

1°C

Skin

not

atio

n: Y

esV

apou

r pr

essu

re:4

.9 k

Pa (a

t 25°

C)

Skin

per

mea

bilit

y: N

o co

nclu

sion

Eva

pora

tion

rate

:2.7

Log

Kow

:-0.

27

Sp

Loc

C

ell

L

(µm

) A

(c

m²)

V

(ml)

Veh

icle

C

(m

g/m

l) n

TE

xp

(h)

TO

bs

(h)

TL

ag

(h)

Abs

(%

) K

P

(10-4

cm

/h)

Flux

(µ

g/cm

²/h) R

efer

ence

N

o da

ta a

vaila

ble

Mon

Arm

3-15

Me

4 µg

/cm

²3-

624

120

2.3

0.00

0037

0.00

38M

arzu

lli e

t al.

(198

1)M

onA

rm3-

15C

ream

4 µg

/cm

²3-

624

120

3.4

0.00

57M

arzu

lli e

t al.

(198

1)

Mar

zulli

et a

l. (1

981)

stud

ied

derm

al u

ptak

e in

viv

o in

Rhe

sus m

onke

ys. T

he sm

all a

mou

nt a

pplie

d an

d th

e no

n-oc

clud

ed

cond

ition

mos

t pos

sibl

y le

d to

mas

sive

loss

es o

f dio

xane

via

eva

pora

tion.

Thu

s the

cal

cula

ted

fluxe

s and

Kp

valu

es a

re n

ot re

liabl

e.

Rep

orte

d da

ta

In v

itro

In v

ivo

Ase

ssm

ent

A75

App

endi

x A

Subs

tanc

e: D

ipro

pyle

ne g

lyco

l mon

omet

hyl e

ther

(DPG

ME)

Mol

ecul

ar w

eigh

t:14

8.2

CA

S: 3

4590

-94-

8D

ensi

ty:0

.95

g/cm

³Sc

ient

ific

basi

s: A

oH 1

992:

6M

eltin

g po

int:

-83°

CB

oilin

g po

int:

190°

CSk

in n

otat

ion:

Yes

Vap

our

pres

sure

:0.0

5 kP

a (a

t °C

)Sk

in p

erm

eabi

lity:

No

data

Eva

pora

tion

rate

:0.0

2L

og K

ow:-

0.35

(est

imat

ed)

Sp

Loc

C

ell

L

(µm

) A

(c

m²)

V

(ml)

Veh

icle

C

(m

g/m

l) n

TE

xp

(h)

TO

bs

(h)

TL

ag

(h)

Abs

(%

) K

P

(10-4

cm

/h)

Flux

(µ

g/cm

²/h) R

efer

ence

N

o da

ta a

vaila

ble

N

o da

ta a

vaila

ble

No

quan

titat

ive

expe

rimen

tal d

ata

on d

erm

al u

ptak

e w

ere

foun

d in

the

liter

atur

e.

Acc

ordi

ng to

Sm

yth

et a

l. (1

962)

the

rat o

ral L

D50

is 5

.7 g

/kg

bw. F

or c

ompa

rison

, the

rabb

it de

rmal

LD

50 is

10

g/kg

bw

.

Rep

orte

d da

ta

In v

itro

In v

ivo

Ase

ssm

ent

A76

App

endi

x A

Subs

tanc

e: E

pich

loro

hydr

inM

olec

ular

wei

ght:

92.5

CA

S: 1

06-8

9-8

Den

sity

:1.1

83 g

/cm

³Sc

ient

ific

basi

s: A

oH 1

981:

10M

eltin

g po

int:

-57°

CB

oilin

g po

int:

117.

9°C

Skin

not

atio

n: Y

esV

apou

r pr

essu

re:1

.5 k

Pa (a

t 20°

C)

Skin

per

mea

bilit

y: N

o da

taE

vapo

ratio

n ra

te:N

ot a

vaila

ble

Log

Kow

:0.4

5

Sp

Loc

C

ell

L

(µm

) A

(c

m²)

V

(ml)

Veh

icle

C

(m

g/m

l) n

TE

xp

(h)

TO

bs

(h)

TL

ag

(h)

Abs

(%

) K

P

(10-4

cm

/h)

Flux

(µ

g/cm

²/h) R

efer

ence

N

o da

ta a

vaila

ble

N

o da

ta a

vaila

ble

No

quan

titat

ive

expe

rimen

tal d

ata

on d

erm

al u

ptak

e w

ere

foun

d in

the

liter

atur

e.

Acc

ordi

ng to

NEG

(198

1) e

pich

loro

hydr

in p

enet

rate

s the

skin

and

muc

ous m

embr

anes

. No

furth

er d

etai

ls a

re g

iven

.A

ccor

ding

to A

CG

IH (2

001)

the

rabb

it de

rmal

LD

50 is

755

mg/

kg b

w. F

or c

ompa

rison

, the

rat a

nd m

ouse

ora

l LD

50 v

alue

s ar

e 26

0 an

d 23

7 m

g/kg

bw

, res

pect

ivel

y.

Rep

orte

d da

ta

In v

itro

In v

ivo

Ase

ssm

ent

A77

App

endi

x A

Subs

tanc

e: E

than

olM

olec

ular

wei

ght:

46.1

CA

S: 6

4-17

-5D

ensi

ty:0

.789

g/c

m³

Scie

ntifi

c ba

sis:

AoH

199

1:8

Mel

ting

poin

t:-1

14.1

°CB

oilin

g po

int:

78.3

°CSk

in n

otat

ion:

No

Vap

our

pres

sure

:6.7

kPa

(at 2

5°C

)Sk

in p

erm

eabi

lity:

Hig

hE

vapo

ratio

n ra

te:N

ot a

vaila

ble

Log

Kow

:-0.

31

Sp

Loc

C

ell

L

(µm

) A

(c

m²)

V

(ml)

Veh

icle

C

(m

g/m

l) n

TE

xp

(h)

TO

bs

(h)

TL

ag

(h)

Abs

(%

) K

P

(10-4

cm

/h)

Flux

(µ

g/cm

²/h) R

efer

ence

Dog

Br

StFu

ll3.

11

PBS

55

56.

2M

ills e

t al.

(200

4)D

ogN

eSt

Full

3.1

1PB

S5

55

7.9

Mill

s et a

l. (2

004)

Dog

Ba

StFu

ll3.

11

PBS

55

59.

1M

ills e

t al.

(200

4)D

ogTh

StFu

ll3.

11

PBS

55

54.

8M

ills e

t al.

(200

4)D

ogA

xSt

Full

3.1

1PB

S5

55

8.4

Mill

s et a

l. (2

004)

GP

Ba

FlFu

ll5

0.1

Nea

t9

1919

272.

922

5G

umm

er e

t al.

(198

6)H

umA

bSt

272.

5H

2O

7.4

358

3.7

Sche

uple

in &

Bla

nk (1

973)

Hum

Ab

St25

002.

5H

2O

7.4

835

016

0Sc

heup

lein

& B

lank

(197

3)H

umA

bSt

272.

5N

eat

197.

257

0Sc

heup

lein

& B

lank

(197

3)H

umA

bSt

2500

2.5

Nea

t4

7055

00Sc

heup

lein

& B

lank

(197

3)H

umA

bSt

Full

2.5

0.1

H2O

56

63.

2Sc

ott e

t al.

(199

1)H

umB

rSt

300-

600

0.64

Nea

t3

66

1515

00U

rsin

et a

l. (1

995)

Hum

Ba

StSC

0.5

H2O

45-7

5%9

23-6

180

0-36

00B

erne

r et a

l. (1

989)

Hum

Ba

StSC

0.5

H2O

20%

925

400

Ber

ner e

t al.

(198

9)M

aA

bSt

Full

2.5

0.1

H2O

36

63.

8Sc

ott e

t al.

(199

1)M

aB

aSt

Full

2.5

0.1

H2O

36

63.

2Sc

ott e

t al.

(199

1)M

aA

rmSt

Full

2.5

0.1

H2O

66

68

Scot

t et a

l. (1

991)

Ma

Leg

StFu

ll2.

50.

1H

2O6

66

5.6

Scot

t et a

l. (1

991)

Ma

ScSt

Full

2.5

0.1

H2O

46

63.

9Sc

ott e

t al.

(199

1)M

aLe

gSt

Full

2.5

0.1

H2O

36

64.

1Sc

ott e

t al.

(199

1)M

aB

rSt

Full

2.5

0.1

H2O

36

65.

8Sc

ott e

t al.

(199

1)M

aA

rmSt

Full

2.5

0.1

H2O

56

66.

5Sc

ott e

t al.

(199

1)

Rep

orte

d da

ta

In v

itro

A78

App

endi

x A

Sp

Loc

C

ell

L

(µm

) A

(c

m²)

V

(ml)

Veh

icle

C

(m

g/m

l) n

TE

xp

(h)

TO

bs

(h)

TL

ag

(h)

Abs

(%

) K

P

(10-4

cm

/h)

Flux

(µ

g/cm

²/h) R

efer

ence

Mou

Ab/

Ba

StFu

ll0.

61.

4N

aCl

0.00

01M

80.

50.

521

Beh

l et a

l. (1

980)

Mou

Ab/

Ba

StFu

ll0.

61.

4N

aCl

0.00

01M

85.

55.

522

Beh

l et a

l. (1

980)

Mou

Ab/

Ba

StFu

ll0.

61.

4N

aCl

0.00

01M

810

.510

.523

Beh

l et a

l. (1

980)

Mou

Ab/

Ba

StFu

ll0.

61.

4N

aCl

0.00

01M

815

.515

.522

Beh

l et a

l. (1

980)

Mou

Ab/

Ba

StFu

ll0.

61.

4N

aCl

0.00

01M

820

.520

.521

Beh

l et a

l. (1

980)

Mou

Ab/

Ba

StFu

ll0.

61.

4N

aCl

0.00

01M

825

.525

.520

Beh

l et a

l. (1

980)

Mou

Ab/

Ba

StFu

ll0.

61.

4N

aCl

0.00

01M

829

.529

.519

Beh

l et a

l. (1

980)

Mou

Ab/

Ba

StFu

ll0.

61.

4N

aCl

0.00

01M

40.

30.

320

Beh

l et a

l. (1

980)

Mou

Ab/

Ba

StFu

ll0.

61.

4N

aCl

0.00

01M

45.

85.

820

Beh

l et a

l. (1

980)

Mou

Ab/

Ba

StFu

ll0.

61.

4N

aCl

0.00

01M

49.

89.

821

Beh

l et a

l. (1

980)

Mou

Ab/

Ba

StFu

ll0.

61.

4N

aCl

0.00

01M

413

.813

.823

Beh

l et a

l. (1

980)

Mou

Ab/

Ba

StFu

ll0.

61.

4N

aCl

0.00

01M

417

.817

.821

Beh

l et a

l. (1

980)

Mou

Ab/

Ba

StFu

ll0.

61.

4N

aCl

0.00

01M

426

.326

.322

Beh

l et a

l. (1

980)

Mou

Ab

StFu

ll0.

60.

2N

aCl

32

29

Beh

l et a

l. (1

984)

Mou

Ab

StFu

ll0.

60.

2N

aCl

22

29

Beh

l et a

l. (1

984)

Mou

Ab

StFu

ll0.

60.

2N

aCl

42

225

Beh

l et a

l. (1

984)

Mou

Ab

StFu

ll0.

60.

2N

aCl

52

235

Beh

l et a

l. (1

984)

Mou

Ab

StFu

ll0.

60.

2N

aCl

62

213

Beh

l et a

l. (1

984)

Mou

Ab

StFu

ll0.

60.

2N

aCl

42

29

Beh

l et a

l. (1

984)

Mou

Ab

StFu

ll0.

60.

2N

aCl

52

212

Beh

l et a

l. (1

984)

Mou

Ab

StFu

ll0.

60.

2N

aCl

52

29

Beh

l et a

l. (1

984)

Mou

Ba

StFu

ll0.

60.

2N

aCl

42

224

Beh

l et a

l. (1

984)

Mou

Ba

StFu

ll0.

60.

2N

aCl

22

229

Beh

l et a

l. (1

984)

Mou

Ba

StFu

ll0.

60.

2N

aCl

42

244

Beh

l et a

l. (1

984)

Mou

Ba

StFu

ll0.

60.

2N

aCl

52

275

Beh

l et a

l. (1

984)

Mou

Ba

StFu

ll0.

60.

2N

aCl

42

214

Beh

l et a

l. (1

984)

Mou

Ba

StFu

ll0.

60.

2N

aCl

52

212

Beh

l et a

l. (1

984)

Mou

Ba

StFu

ll0.

60.

2N

aCl

52

210

Beh

l et a

l. (1

984)

Mou

Ab

StFu

ll0.

6N

aCl

0.00

01M

52

232

Beh

l & B

arre

tt (1

981)

Mou

Ab

StFu

ll0.

79N

aCl

≤10-

4M2

27.

2D

urrh

eim

et a

l. (1

980)

Mou

Ab

StFu

ll0.

79N

aCl

≤10-

4M2

212

Dur

rhei

m e

t al.

(198

0)M

ouA

bSt

Full

0.79

NaC

l≤1

0-4M

22

48D

urrh

eim

et a

l. (1

980)

A79

App

endi

x A

Sp

Loc

C

ell

L

(µm

) A

(c

m²)

V

(ml)

Veh

icle

C

(m

g/m

l) n

TE

xp

(h)

TO

bs

(h)

TL

ag

(h)

Abs

(%

) K

P

(10-4

cm

/h)

Flux

(µ

g/cm

²/h) R

efer

ence

Pig1

Ba

FlFu

ll0.

390.

01N

eat

324

241

0.05

24.

1Pe

ndlin

gton

et a

l. (2

001)

Pig2

Ba

FlFu

ll0.

390.

01N

eat

324

2421

1.1

89Pe

ndlin

gton

et a

l. (2

001)

Rat

Ba

StFu

ll2.

50.

1H

2O8

66

4.2

Scot

t et a

l. (1

991)

Hum

FiIn

fH

2O1%

1215

s0.

30.

230.

18N

aito

h et

al.

(200

2)H

umFi

Inf

H2O

1%12

15s

0.3

3024

Nai

toh

et a

l. (2

002)

1 Non

occ

lude

d 2 O

cclu

ded

The

only

ava

ilabl

e in

viv

o st

udy

is th

at o

f Nai

toh

et a

l. (2

002)

. An

unco

nven

tiona

l tec

hniq

ue w

as u

sed

in th

at o

ne th

umb

was

di

pped

onc

e or

seve

ral t

imes

(15

sec/

occa

sion

) in

an a

queo

us so

lutio

n. T

he fl

ux w

as c

alcu

late

d fr

om th

e ev

apor

atio

n fr

om th

e th

umb.

The

evap

orat

ion

prof

ile w

as b

ipha

sic,

thus

two

diff

eren

t flu

xes w

ere

repo

rted.

The

repo

rted

fluxe

s ref

lect

s abs

orpt

ion

into

(a

nd o

ut o

f) ra

ther

than

thro

ugh

skin

. Thu

s the

cal

cula

ted

Kp

may

repr

esen

t an

serio

us o

vere

stim

ate

of th

e "t

rue"

val

ue.

Mos

t in

vitro

stud

ies r

epor

t Kp

valu

es in

the

rang

e 3·

10-4

to 8

·10-3

cm

/h, a

lthou

gh lo

wer

and

hig

her v

alue

s hav

e oc

casi

onal

ly

been

giv

en.

The

high

er e

nd, 7

·10-3

cm

/h, c

orre

spon

ds to

"hi

gh"

perm

eabi

lity.

In v

ivo

Ase

ssm

ent

A80

App

endi

x A

Subs

tanc

e: E

than

olam

ine

Mol

ecul

ar w

eigh

t:61

.1C

AS:

141

-43-

5D

ensi

ty:1

.012

g/c

m³

Scie

ntifi

c ba

sis:

AoH

199

2:47

Mel

ting

poin

t:10

.3°C

Boi

ling

poin

t:17

1°C

Skin

not

atio

n: Y

esV

apou

r pr

essu

re:0

.05

kPa

(at 2

0°C

)Sk

in p

erm

eabi

lity:

Low

Eva

pora

tion

rate

:0.0

15L

og K

ow:-

1.31

Sp

Loc

C

ell

L

(µm

) A

(c

m²)

V

(ml)

Veh

icle

C

(m

g/m

l) n

TE

xp

(h)

TO

bs

(h)

TL

ag

(h)

Abs

(%

) K

P

(10-4

cm

/h)

Flux

(µ

g/cm

²/h) R

efer

ence

Hum

Br

FlFu

ll1.

80.

03H

2O

4 m

g/cm

²6

66

2.4

1.1

0.43

9.7

Sun

et a

l. (1

996)

Hum

Br

FlFu

ll1.

80.

01N

eat

66

63.

80.

60.

087.

9Su

n et

al.

(199

6)M

ouFl

Full

1.8

0.03

H2O

4

mg/

cm²

36

60.

125

4.6

170

Sun

et a

l. (1

996)

Mou

FlFu

ll1.

80.

01N

eat

36

60.

417

1.2

120

Sun

et a

l. (1

996)

Pig

Ba

Fl10

000.

80.

01Et

0.8

(4 µ

g/cm

²)50

505

0.06

30.

005

Kla

in e

t al.

(198

5)R

abFl

Full

1.8

0.01

Nea

t3

66

1.3

8.7

0.72

74Su

n et

al.

(199

6)R

abFl

Full

1.8

0.03

H2O

4

mg/

cm²

36

63.

11.

91.

125

Sun

et a

l. (1

996)

Rat

FlFu

ll1.

80.

01N

eat

36

61.

56

0.42

43Su

n et

al.

(199

6)R

atFl

Full

1.8

0.03

H2O

4

mg/

cm²

36

61.

71.

30.

5312

Sun

et a

l. (1

996)

N

o da

ta a

vaila

ble

The

stud

y by

Kla

in e

t al.

(198

5) u

sed

etha

nol a

s veh

icle

and

is th

eref

ore

disr

egar

ded

as it

may

aff

ect s

kin

perm

eatio

n.

The

stud

y by

Sun

et a

l. (1

996)

show

s con

sist

ent r

esul

ts c

onsi

derin

g kn

own

spec

ies d

iffer

ence

s and

eff

ect o

f dilu

tion.

The

expe

rimen

t usi

ng h

uman

skin

and

aqu

eous

dilu

tion

repo

rted

a K

p of

4·1

0-5 c

m/h

sugg

estin

g "l

ow"

perm

eabi

lity.

Rep

orte

d da

ta

In v

itro

In v

ivo

Ase

ssm

ent

A81

App

endi

x A

Subs

tanc

e: E

thyl

2-c

yano

acry

late

Mol

ecul

ar w

eigh

t:12

5.1

CA

S: 7

085-

85-0

Den

sity

:1.0

6 g/

cm³

Scie

ntifi

c ba

sis:

Not

ava

ilabl

e M

eltin

g po

int:

-22.

5°C

Boi

ling

poin

t:N

ot a

vaila

ble

Skin

not

atio

n: Y

esV

apou

r pr

essu

re:1

7 Pa

(at 2

0°C

)Sk

in p

erm

eabi

lity:

No

data

Eva

pora

tion

rate

:Not

ava

ilabl

eL

og K

ow:1

.42

(est

imat

ed)

Sp

Loc

C

ell

L

(µm

) A

(c

m²)

V

(ml)

Veh

icle

C

(m

g/m

l) n

TE

xp

(h)

TO

bs

(h)

TL

ag

(h)

Abs

(%

) K

P

(10-4

cm

/h)

Flux

(µ

g/cm

²/h) R

efer

ence

N

o da

ta a

vaila

ble

N

o da

ta a

vaila

ble

No

quan

titat

ive

expe

rimen

tal d

ata

on d

erm

al u

ptak

e w

ere

foun

d in

the

liter

atur

e.

In O

uste

rhou

t et a

l. (1

968)

, the

radi

olab

elle

d ho

mol

ogou

s sub

stan

ces m

ethy

l α-c

yano

acry

late

and

n-b

utyl

α-c

yano

acry

late

wer

e st

udie

d. T

he n

eat s

ubst

ance

s (50

ml/5

00 0

00 µ

g) w

ere

plac

ed o

n th

e ba

ck o

f rat

s (29

cm

²) an

d th

e ur

ine

was

ana

lyze

d fo

r rad

ioac

tivity

.Th

e ex

posu

re a

nd o

bser

vatio

n tim

e w

as 6

day

s (14

4 h)

. Fro

m fi

gure

1, t

he %

radi

oact

ivity

in u

rine

was

~4

and

0.25

%, r

espe

ctiv

ely.

From

thes

e fig

ures

the

stea

dy-s

tate

flux

and

per

mea

bilit

y ca

n be

cal

cula

ted

(e.g

. for

met

hyl α

-cya

noac

ryla

te):

Flux

Con

c.

The

corr

espo

ndin

g va

lues

for n

-but

yl α

-cya

noac

ryla

te a

re 0

.3 µ

g/cm

²/h a

nd 3·

10-7

cm/h

.

Thes

e pe

rmea

bilit

ies c

orre

spon

d to

"ve

ry lo

w"

and

"ext

rem

ely

low

", re

spec

tivel

y.

=

5 µ

g/cm

²/hA

rea·

Dur

atio

n·10

029

·144

Kp

= =

4.8

=

5·10

-6 c

m/h

1000

000

Flux

=

%A

bsor

bed·

App

lied

amou

nt=

0.04

·500

000

Rep

orte

d da

ta

In v

itro

In v

ivo

Ase

ssm

ent

A82

App

endi

x A

Subs

tanc

e: E

thyl

acr

ylat

eM

olec

ular

wei

ght:

100.

1C

AS:

140

-88-

5D

ensi

ty:0

.924

g/c

m³

Scie

ntifi

c ba

sis:

AoH

198

5:32

Mel

ting

poin

t:-7

1.2°

CB

oilin

g po

int:

99.8

°CSk

in n

otat

ion:

Yes

Vap

our

pres

sure

:3.5

kPa

(at 2

0°C

)Sk

in p

erm

eabi

lity:

No

data

Eva

pora

tion

rate

:3.3

Log

Kow

:1.3

2

Sp

Loc

C

ell

L

(µm

) A

(c

m²)

V

(ml)

Veh

icle

C

(m

g/m

l) n

TE

xp

(h)

TO

bs

(h)

TL

ag

(h)

Abs

(%

) K

P

(10-4

cm

/h)

Flux

(µ

g/cm

²/h) R

efer

ence

N

o da

ta a

vaila

ble

N

o da

ta a

vaila

ble

No

quan

titat

ive

expe

rimen

tal d

ata

on d

erm

al u

ptak

e w

ere

foun

d in

the

liter

atur

e.

Acc

ordi

ng to

the

Swed

ish

cons

ensu

s rep

ort (

AoH

198

5:32

) acr

ylat

es a

re ta

ken

up fa

irly

slow

ly v

ia th

e sk

in.

No

furth

er d

etai

ls a

re g

iven

on

ethy

l acr

ylat

e.

The

rat o

ral L

D50

is re

porte

d to

be

appr

oxim

atel

y 10

20 m

g/kg

bw

. The

der

mal

LD

50 fo

r rab

bits

is in

the

sam

e ra

nge

(179

0 m

g/kg

bw

) sug

gest

ing

that

skin

abs

orpt

ion

may

be

exte

nsiv

e (A

CG

IH (2

001)

).

Rep

orte

d da

ta

In v

itro

In v

ivo

Ase

ssm

ent

A83

App

endi

x A

Subs

tanc

e: E

thyl

ben

zene

Mol

ecul

ar w

eigh

t:10

6.2

CA

S: 1

00-4

1-4

Den

sity

:0.8

67 g

/cm

³Sc

ient

ific

basi

s: A

oH 1

987:

39M

eltin

g po

int:

-94.

9°C

Boi

ling

poin

t:13

6.2°

CSk

in n

otat

ion:

No

Vap

our

pres

sure

:2 k

Pa (a

t 20°

C)

Skin

per

mea

bilit

y: H

igh

Eva

pora

tion

rate

:Not

ava

ilabl

eL

og K

ow:3

.15

Sp

Loc

C

ell

L

(µm

) A

(c

m²)

V

(ml)

Veh

icle

C

(m

g/m

l) n

TE

xp

(h)

TO

bs

(h)

TL

ag

(h)

Abs

(%

) K

P

(10-4

cm

/h)

Flux

(µ

g/cm

²/h) R

efer

ence

Rat

Ba

St56

04.

92

JP-8

0.15

%8

44

0.5

3.1

0.38

McD

ouga

l et a

l. (2

000)

Rat

Ab

StFu

ll2.

61

Nea

t31

3-6

3-6

218

-68

µg0.

076.

3Ts

urut

a (1

982)

HM

Ba

0.8

0.01

Nea

t11

0.08

34

3.4

(150

µg)

2622

00Su

sten

et a

l. (1

990)

Hum

Arm

170.

2N

eat

70.

17-0

.25

199

mg

320

2800

0D

utki

ewic

z et

al.

(196

7)H

umH

a40

0In

fH

2O

0.11

71

1439

mg

1100

012

0D

utki

ewic

z et

al.

(196

7)H

umH

a40

0In

fH

2O

0.16

71

1471

mg

1400

022

0D

utki

ewic

z et

al.

(196

7)H

umH

as80

0H

2O

0.14

52

2411

mg

500

7D

utki

ewic

z et

al.

(196

7)

Tsur

uta

(198

2) u

sed

phys

iolo

gica

l sal

ine

as th

e re

cept

or m

ediu

m, t

his i

s uns

uita

ble

for h

ighl

y lip

ophi

lic su

bsta

nces

like

et

hyl b

enze

ne. M

cDou

gal e

t al.

(200

0) u

sed

jet f

uel a

s veh

icle

, thi

s may

hav

e af

fect

ed th

e pe

rmea

tion

of e

thyl

ben

zene

.In

the

first

thre

e ex

perim

ents

by

Dut

kiew

icz

et a

l. (1

967)

, abs

orbe

d am

ount

was

obt

aine

d as

the

diff

eren

ce b

etw

een

appl

ied

and

rem

aini

ng a

mou

nt a

fter d

ippi

ng o

ne h

and

in a

bea

ker f

or 1

h. T

hese

mea

sure

s inc

lude

s abs

orpt

ion

into

the

skin

as w

ell a

s ev

apor

atio

n an

d m

ay h

eavi

ly o

vere

stim

ate

the

syst

emic

abs

orpt

ion.

In th

e 4t

h, a

bsor

ptio

n ra

te w

as o

btai

ned

from

mea

surin

gth

e m

etab

olite

man

delic

aci

d, in

urin

e. T

he e

xtre

mel

y hi

gh K

p va

lue

is u

nrea

listic

.

The

Sust

en e

t al.

(199

0) st

udy,

alth

ough

usi

ng h

airle

ss m

ice

in v

ivo,

is c

hose

n as

the

pref

erre

d st

udy.

The

Kp

valu

e of

3·1

0-3 c

m/h

cor

resp

onds

to "

high

" pe

rmea

tion.

Rep

orte

d da

ta

In v

itro

In v

ivo

Ase

ssm

ent

A84

App

endi

x A

Subs

tanc

e: E

thyl

eth

erM

olec

ular

wei

ght:

74.1

CA

S: 6

0-29

-7D

ensi

ty:0

.713

g/c

m³

Scie

ntifi

c ba

sis:

Not

ava

ilabl

e M

eltin

g po

int:

-116

.3°C

Boi

ling

poin

t:34

.6°C

Skin

not

atio

n: N

oV

apou

r pr

essu

re:4

8 kP

a (a

t 20°

C)

Skin

per

mea

bilit

y: N

o co

nclu

sion

Eva

pora

tion

rate

:38

Log

Kow

:0.8

9

Sp

Loc

C

ell

L

(µm

) A

(c

m²)

V

(ml)

Veh

icle

C

(m

g/m

l) n

TE

xp

(h)

TO

bs

(h)

TL

ag

(h)

Abs

(%

) K

P

(10-4

cm

/h)

Flux

(µ

g/cm

²/h) R

efer

ence

N

o da

ta a

vaila

ble

Hum

FiIn

fH

2O0.

05%

1215

s0.

39.

80.

35N

aito

h et

al.

(200

2)H

umFi

Inf

H2O

0.05

%12

15s

0.3

210

7.6

Nai

toh

et a

l. (2

002)

The

only

ava

ilabl

e st

udy

is th

at o

f Nai

toh

et a

l. (2

002)

. An

unco

nven

tiona

l tec

hniq

ue w

as u

sed

in th

at o

ne th

umb

was

dip

ped

once

or s

ever

al ti

mes

(15

sec/

occa

sion

) in

an a

queo

us so

lutio

n. T

he fl

ux w

as c

alcu

late

d fr

om th

e ev

apor

atio

n fr

om th

e th

umb.

The

evap

orat

ion

prof

ile w

as b

ipha

sic,

thus

two

diff

eren

t flu

xes w

ere

repo

rted.

The

repo

rted

fluxe

s ref

lect

s abs

orpt

ion

into

(and

out

of)

rath

er th

an th

roug

h sk

in.

Thus

the

calc

ulat

ed K

p m

ay re

pres

ent a

n se

rious

ove

rest

imat

e of

the

"tru

e" v

alue

.

Rep

orte

d da

ta

In v

itro

In v

ivo

Ase

ssm

ent

A85

App

endi

x A

Subs

tanc

e: E

thyl

mor

phol

ine,

N-

Mol

ecul

ar w

eigh

t:11

5.2

CA

S: 1

00-7

4-3

Den

sity

:0.9

05 g

/cm

³Sc

ient

ific

basi

s: N

ot a

vaila

ble

Mel

ting

poin

t:-6

3°C

Boi

ling

poin

t:13

8°C

Skin

not

atio

n: Y

esV

apou

r pr

essu

re:0

.8 k

Pa (a

t 20°

C)

Skin

per

mea

bilit

y: N

o da

taE

vapo

ratio

n ra

te:0

.74

Log

Kow

:0.1

4 (e

stim

ated

)

Sp

Loc

C

ell

L

(µm

) A

(c

m²)

V

(ml)

Veh

icle

C

(m

g/m

l) n

TE

xp

(h)

TO

bs

(h)

TL

ag

(h)

Abs

(%

) K

P

(10-4

cm

/h)

Flux

(µ

g/cm

²/h) R

efer

ence

N

o da

ta a

vaila

ble

N

o da

ta a

vaila

ble

No

quan

titat

ive

expe

rimen

tal d

ata

on d

erm

al u

ptak

e w

ere

foun

d in

the

liter

atur

e.

AC

GIH

has

ass

igne

d a

skin

not

atio

n by

ana

logy

with

mor

phol

ine

(AC

GIH

(200

1)).

Rep

orte

d da

ta

In v

itro

In v

ivo

Ase

ssm

ent

A86

App

endi

x A

Subs

tanc

e: E

thyl

amin

eM

olec

ular

wei

ght:

45.1

CA

S: 7

5-04

-7D

ensi

ty:0

.8 g

/cm

³Sc

ient

ific

basi

s: A

oH 1

983:

36M

eltin

g po

int:

-81°

CB

oilin

g po

int:

16.6

°CSk

in n

otat

ion:

Yes

Vap

our

pres

sure

:120

kPa

(at 2

0°C

)Sk

in p

erm

eabi

lity:

No

data

Eva

pora

tion

rate

:Not

ava

ilabl

eL

og K

ow:-

0.13

Sp

Loc

C

ell

L

(µm

) A

(c

m²)

V

(ml)

Veh

icle

C

(m

g/m

l) n

TE

xp

(h)

TO

bs

(h)

TL

ag

(h)

Abs

(%

) K

P

(10-4

cm

/h)

Flux

(µ

g/cm

²/h) R

efer

ence

N

o da

ta a

vaila

ble

N

o da

ta a

vaila

ble

No

quan

titat

ive

expe

rimen

tal d

ata

on d

erm

al u

ptak

e w

ere

foun

d in

the

liter

atur

e.

The

Swed

ish

cons

ensu

s doc

umen

t (A

oH 1

983:

36) s

tate

s tha

t der

mal

upt

ake

of a

min

es m

ay o

ccur

follo

win

g ve

ry h

igh

expo

sure

s, w

ithou

t fur

ther

spec

ifica

tion.

The

skin

not

atio

n by

AC

GIH

(200

1) is

bas

ed o

n th

e lo

w d

erm

al L

D50

in ra

bbits

of 3

90 m

g/kg

bw

, whi

ch is

sim

ilar t

o th

e or

al L

D50

(400

mg/

kg b

w in

rats

).

Acc

ordi

ng to

theo

retic

al c

alcu

latio

ns b

y Fi

sero

va-B

erge

rova

et a

l. (1

990)

the

pote

ntia

l for

der

mal

abs

orpt

ion

and

resu

lting

toxi

city

is si

gnifi

cant

.

Rep

orte

d da

ta

In v

itro

In v

ivo

Ase

ssm

ent

A87

App

endi

x A

Subs

tanc

e: E

thyl

ene

glyc

olM

olec

ular

wei

ght:

62.1

CA

S: 1

07-2

1-1

Den

sity

:1.1

16 g

/cm

³Sc

ient

ific

basi

s: A

oH 1

982:

24M

eltin

g po

int:

-13°

CB

oilin

g po

int:

195°

CSk

in n

otat

ion:

Yes

Vap

our

pres

sure

:13

Pa (a

t 25°

C)

Skin

per

mea

bilit

y: M

oder

ate

Eva

pora

tion

rate

:0.0

1L

og K

ow:-

1.36

Sp

Loc

C

ell

L

(µm

) A

(c

m²)

V

(ml)

Veh

icle

C

(m

g/m

l) n

TE

xp

(h)

TO

bs

(h)

TL

ag

(h)

Abs

(%

) K

P

(10-4

cm

/h)

Flux

(µ

g/cm

²/h) R

efer

ence

Hum

Br

FlFu

llN

eat

816

.516

.5~0

.51.

112

0Lo

den

(198

6b)

Hum

Leg

Fl50

01

Ac

1.6

324

2418

0.56

0.09

Driv

er e

t al.

(199

3)H

umSt

900

0.64

0.13

H2O

10%

88

29

µg0.

212.

3K

orin

th e

t al.

(200

3)H

umSt

900

0.64

0.13

H2O

50%

88

230

µg

0.14

7.8

Kor

inth

et a

l. (2

003)

Mou

Ba

1N

eat (

10 m

g/kg

bw

)4

9696

770.

014

1.6

Fran

tz e

t al.

(199

6a)

Mou

Ba

1N

eat (

1000

mg/

kg b

w)

496

9684

1.6

180

Fran

tz e

t al.

(199

6a)

Mou

Ba

1H

2O50

% (1

000

mg/

kg b

w)

496

9660

2.2

130

Fran

tz e

t al.

(199

6a)

Rat

Ba

1N

eat (

10 m

g/kg

bw

)4

9696

320.

059

6.6

Fran

tz e

t al.

(199

6a)

Rat

Ba

1N

eat (

1000

mg/

kg b

w)

496

9629

5.5

610

Fran

tz e

t al.

(199

6a)

Rat

Ba

1H

2O50

% (1

000

mg/

kg b

w)

496

9626

9.7

540

Fran

tz e

t al.

(199

6a)

Rat

Ba

1N

eat (

10 m

g/kg

bw

)4

9696

320.

059

6.6

Fran

tz e

t al.

(199

6b)

Rat

Ba

1N

eat (

1000

mg/

kg b

w)

496

9636

6.6

740

Fran

tz e

t al.

(199

6b)

Rat

Ba

1H

2O50

% (1

000

mg/

kg b

w)

496

9622

8.3

460

Fran

tz e

t al.

(199

6b)

The

expe

rimen

t usi

ng a

ceto

ne a

s veh

icle

is d

isre

gard

ed, a

s ski

n pe

rmea

bilit

y m

ay b

e af

fect

ed.

The

pref

erre

d st

udy

is th

at o

f Lod

en (1

986b

) usi

ng n

eat e

thyl

ene

glyc

ol a

nd h

uman

skin

.Th

e K

p va

lue

of 1

·10-4

cm

/h, c

orre

spon

ds to

"m

oder

ate"

per

mea

bilit

y.

Rep

orte

d da

ta

In v

itro

In v

ivo

Ase

ssm

ent

A88

App

endi

x A

Subs

tanc

e: E

thyl

ene

glyc

ol d

initr

ate

Mol

ecul

ar w

eigh

t:15

2.1

CA

S: 6

28-9

6-6

Den

sity

:1.4

9 g/

cm³

Scie

ntifi

c ba

sis:

AoH

198

5:32

Mel

ting

poin

t:-2

3°C

Boi

ling

poin

t:11

4°C

Skin

not

atio

n: Y

esV

apou

r pr

essu

re:5

-6.6

Pa

(at 2

0°C

)Sk

in p

erm

eabi

lity:

Hig

hE

vapo

ratio

n ra

te:N

ot a

vaila

ble

Log

Kow

:1.1

6

Sp

Loc

C

ell

L

(µm

) A

(c

m²)

V

(ml)

Veh

icle

C

(m

g/m

l) n

TE

xp

(h)

TO

bs

(h)

TL

ag

(h)

Abs

(%

) K

P

(10-4

cm

/h)

Flux

(µ

g/cm

²/h) R

efer

ence

N

o da

ta a

vaila

ble

Hum

Arm

122

mg

SpSt

22%

67

72.

3-2.

8 m

g10

-12

330-

400

Gro

ss e

t al.

(196

0)R

atB

r/Ab

110

0 m

gN

C93

%36

192

192

35 m

g (1

2h)

2129

00G

ross

et a

l. (1

960)

Rat

Br/A

b1

200

mg

NC

93%

3619

219

243

mg

(12h

)26

3600

Gro

ss e

t al.

(196

0)R

atB

r/Ab

130

0 m

gN

C93

%36

192

192

59 m

g (1

2h)

3649

00G

ross

et a

l. (1

960)

Rat

Br/A

b1

400

mg

NC

93%

3619

219

260

mg

(12h

)36

5000

Gro

ss e

t al.

(196

0)R

atB

r/Ab

150

0 m

gN

C93

%36

192

192

80 m

g (1

2h)

4867

00G

ross

et a

l. (1

960)

Rat

Br/A

b1

600

mg

NC

93%

3619

219

285

mg

(12h

)51

7100

Gro

ss e

t al.

(196

0)

The

only

ava

ilabl

e st

udy

is a

Ger

man

pub

licat

ion

by G

ross

et a

l. (1

960)

wer

e th

e sk

in a

bsor

ptio

n in

viv

o in

rats

and

hum

ans

was

mea

sure

d af

ter a

pplic

atio

n of

eth

ylen

e gl

ycol

din

itrat

e in

"ge

latin

" (n

itroc

ellu

lose

, NC

) and

"sp

reng

stof

f" (S

pSt).

The

abso

rptio

n w

as o

btai

ned

as th

e di

ffer

ence

bet

wee

n ap

plie

d an

d re

cove

red

amou

nt. T

he c

alcu

late

d flu

xes (

and

Kp

valu

es)

incr

ease

d w

ith a

pplie

d do

se, i

n sp

ite o

f usi

ng th

e sa

me

conc

entra

tion

with

in th

e ex

perim

ent.

This

sugg

est t

hat

depl

etio

n of

eth

ylen

e gl

ycol

din

itrat

e oc

curs

in th

e la

yers

clo

sest

to th

e sk

in.

The

pref

erre

d ex

perim

ent i

s tha

t of h

uman

s in

vivo

, wer

e a

calc

ulat

ed K

p va

lue

of 1

·10-3

cm

/h c

orre

spon

ds to

"hi

gh"

perm

eabi

lity.

Rep

orte

d da

ta

In v

itro

In v

ivo

Ase

ssm

ent

A89

App

endi

x A

Subs

tanc

e: E

thyl

ene

glyc

ol m

onob

utyl

eth

er (E

GB

E)M

olec

ular

wei

ght:

118.

2C

AS:

111

-76-

2D

ensi

t y:0

.903

g/c

m³

Scie

ntifi

c ba

sis:

AoH

198

3:3 6

Mel

ting

poin

t:-7

0°C

Boi

ling

poin

t:17

1°C

Skin

not

atio

n: Y

esV

a pou

r pr

essu

re:0

.12

kPa

(at 2

5°C

)Sk

in p

erm

eabi

lity:

Mod

erat

eE

vapo

ratio

n ra

te:0

.07

Lo g

Kow

:0.8

3

Sp

Loc

C

ell

L

(µm

) A

(c

m²)

V

(ml)

Veh

icle

C

(m

g/m

l) n

TE

xp

(h)

TO

bs

(h)

TL

ag

(h)

Abs

(%

) K

P

(10-4

cm

/h)

Flux

(µ

g/cm

²/h) R

efer

ence

HR

Ba

StFu

ll5

0.03

Nea

t3

11

1912

1100

Bar

tnik

et a

l. (1

987)

HR

Ba

StFu

ll5

0.03

Nea

t3

11

5.6

3.4

303

Bar

tnik

et a

l. (1

987)

HR

Ba

StFu

ll5

0.03

H2O

10%

31

163

3834

0B

artn

ik e

t al.

(198

7)H

RB

aSt

Full

50.

03H

2O10

%3

11

106.

256

Bar

tnik

et a

l. (1

987)

HR

Ba

StFu

ll5

0.03

H2O

3.50

%3

11

4626

82B

artn

ik e

t al.

(198

7)H

RB

aSt

Full

50.

03H

2O3.

50%

31

111

6.3

20B

artn

ik e

t al.

(198

7)H

RB

aSt

Full

50.

05H

2O10

% (1

000

µg/c

m²)

31

111

2.4

22B

artn

ik e

t al.

(198

7)H

RB

aSt

Full

50.

05H

2O10

% (1

000

µg/c

m²)

31

143

9.6

87B

artn

ik e

t al.

(198

7)H

RB

aSt

Full

50.

03H

2O10

% (6

00 µ

g/cm

²)3

11

152

18B

artn

ik e

t al.

(198

7)H

RB

aSt

Full

50.

03H

2O10

% (6

00 µ

g/cm

²)3

11

638.

375

Bar

tnik

et a

l. (1

987)

Hum

Ab

StEp

i1.

81-

5N

eat

88

8<1

2.1

200

Dug

ard

et a

l. (1

984)

Hum

Br

Fl30

00.

640.

2H

2O

65

247

2318

011

0W

ilkin

son

et a

l. (2

002)

Hum

Br

Fl30

00.

640.

1H

2O

35

247

0.36

1610

031

Wilk

inso

n et

al.

(200

2)H

umB

rFl

300

0.64

0.2

H2O

3

524

240.

327

210

64W

ilkin

son

et a

l. (2

002)

Hum

Br

Fl30

00.

640.

011

Nea

t5

2424

9.5

851

Wilk

inso

n et

al.

(200

2)H

umA

rmSt

Full

30.

03H

2O10

% (1

000

µg/c

m²)

31

16.

92.

523

Bar

tnik

et a

l. (1

987)

Hum

Arm

StFu

ll3

0.03

H2O

10%

(100

0 µg

/cm

²)3

11

176.

458

Bar

tnik

et a

l. (1

987)

Hum

Br

Fl33

00.

640.

01M

e50

%5

2424

110.

4822

Lock

ley

et a

l. (2

004)

Hum

Br

Fl28

00.

640.

01N

eat

524

243.

90.

1918

Lock

ley

et a

l. (2

004)

Pig

Ba

StFu

ll5

0.03

Nea

t3

66

111.

110

1B

artn

ik e

t al.

(198

7)Pi

gB

aSt

Full

50.

03H

2O10

%3

66

373.

733

Bar

tnik

et a

l. (1

987)

Pig

Ba

StFu

ll5

0.03

H2O

3.50

%3

66

484.

414

Bar

tnik

et a

l. (1

987)

Pig

Ba

StFu

ll5

0.05

H2O

10%

(100

0 µg

/cm

²)3

11

8.6

1.9

17B

artn

ik e

t al.

(198

7)Pi

gB

aSt

Full

50.

05H

2O10

% (1

000

µg/c

m²)

31

118

3.9

35B

artn

ik e

t al.

(198

7)Pi

gB

aSt

Full

50.

03H

2O10

% (6

00 µ

g/cm

²)3

11

137.

816

Bar

tnik

et a

l. (1

987)

Pig

Ba

StFu

ll5

0.03

H2O

10%

(600

µg/

cm²)

31

121

2.8

25B

artn

ik e

t al.

(198

7)

Rep

orte

d da

ta

In v

itro

A90

App

endi

x A

Sp

Loc

C

ell

L

(µm

) A

(c

m²)

V

(ml)

Veh

icle

C

(m

g/m

l) n

TE

xp

(h)

TO

bs

(h)

TL

ag

(h)

Abs

(%

) K

P

(10-4

cm

/h)

Flux

(µ

g/cm

²/h) R

efer

ence

Rat

Ba

FlFu

ll0.

640.

01M

e50

%5

2424

150.

8137

Lock

ley

et a

l. (2

004)

Rat

Ba

Fl28

00.

640.

01M

e50

%5

2424

231.

464

Lock

ley

et a

l. (2

004)

Rat

Ba

FlFu

ll0.

640.

01N

eat

524

247.

90.

3229

Lock

ley

et a

l. (2

004)

Rat

Ba

Fl28

00.

640.

01N

eat

524

2416

0.92

83Lo

ckle

y et

al.

(200

4)R

atB

aFl

280

0.64

0.01

Nea

t5

2424

181.

199

Lock

ley

et a

l. (2

004)

GP

Ba

6.3

Nea

t10

24.

50.

35-1

2018

00Jo

hans

on e

t al.

(198

6)G

PB

a3.

11

H2O

5%

22

410

052

5Jo

hans

on e

t al.

(198

8c)

GP

Ba

3.1

1H

2O

10%

22

460

525

Joha

nson

et a

l. (1

988c

)G

PB

a3.

11

H2O

20

%2

24

4070

0Jo

hans

on e

t al.

(198

8c)

GP

Ba

3.1

1H

2O

40%

22

420

700

Joha

nson

et a

l. (1

988c

)G

PB

a3.

11

H2O

80

%2

24

860

0Jo

hans

on e

t al.

(198

8c)

GP

Ba

3.1

1N

eat

142

23

350

Joha

nson

et a

l. (1

988c

)H

umFi

79-1

90In

fN

eat

122

2415

-220

mg

1.5

50-6

80Jo

hans

on e

t al.

(198

8a)

Hum

WB

Vap

0.00

024

42

459

0000

14Jo

hans

on e

t al.

(199

1)H

umW

B20

000

49pp

m18

234

11Jo

nes e

t al.

(200

3)H

umA

rm40

H2O

50%

64

818

-30

920-

1340

Jaka

sa e

t al.

(200

4)H

umA

rm40

H2O

90%

34

88.

8-11

740-

920

Jaka

sa e

t al.

(200

4)H

umA

rm40

Nea

t6

48

2.9

260

Jaka

sa e

t al.

(200

4)H

umA

rm40

8H

2O50

%6

448

5324

00K

ezic

et a

l. (2

004b

)R

atB

a12

0.07

2N

eat

(200

mg/

kg B

W)

1248

4827

0.26

23B

artn

ik e

t al.

(198

7)R

atB

a9.

40.

09A

c0.

0001

6 (1

20 µ

mol

/rat)

472

7225

0.34

0.00

0005

4Sa

bour

in e

t al.

(199

2)R

atB

a9.

40.

09A

c0.

0004

8 (3

70 µ

mol

/rat)

472

7226

0.35

0.00

0017

Sabo

urin

et a

l. (1

992)

Rat

Ba

9.4

0.09

Ac

0.00

085

(650

µm

ol/ra

t)4

7272

210.

270.

0000

23Sa

bour

in e

t al.

(199

2)R

atB

a9.

60.

1N

eat

524

2428

1.2

111

Lock

ley

et a

l. (2

004)

The

stud

ies u

sing

ace

tone

or m

etha

nol a

s veh

icle

are

exc

lude

d as

they

may

aff

ect s

kin

perm

eatio

n.

The

Kp

for v

apou

r is a

n ov

eres

timat

e of

the

"tru

e" K

p, si

nce

EGB

E ha

s an

extre

mel

y hi

gh w

ater

:air

parti

tion

coef

ficie

nt

of 7

000

(Joh

anso

n et

al.

(198

8b))

and

is th

eref

ore

conc

entra

ted

on th

e sk

in.

The

pref

erre

d st

udy

is th

at o

f Jak

asa

et a

l. (2

004)

wer

e hu

man

skin

in v

ivo

is u

sed,

with

a re

porte

d K

p va

lue

of n

eat E

GB

E is

3·1

0-4 c

m/h

, whi

ch c

orre

spon

ds to

"m

oder

ate"

per

mea

bilit

y.It

shou

ld b

e no

ted

that

the

perm

eabi

lity

of E

GB

E in

aqu

eous

solu

tions

is a

ppro

xim

atel

y on

e or

der o

f mag

nitu

de h

ighe

r.

10-5

1

0-4

10-3

1

0-2

10-1

1

00

1

01

1

02

N

eat

Aq.

dilu

tion

V

apou

r

In v

ivo

Ase

ssm

ent

A91

App

endi

x A

Subs

tanc

e: E

thyl

ene

glyc

ol m

onob

utyl

eth

er a

ceta

te (E

GB

EA)

Mol

ecul

ar w

eigh

t:16

0.2

CA

S: 1

12-0

7-2

Den

sity

:0.9

4 g/

cm³

Scie

ntifi

c ba

sis:

Not

ava

ilabl

e M

eltin

g po

int:

5.5°

CB

oilin

g po

int:

192°

CSk

in n

otat

ion:

Yes

Vap

our

pres

sure

:31

Pa (a

t 20°

C)

Skin

per

mea

bilit

y: N

o da

taE

vapo

ratio

n ra

te:0

.03

Log

Kow

:1.5

7 (e

stim

ated

)

Sp

Loc

C

ell

L

(µm

) A

(c

m²)

V

(ml)

Veh

icle

C

(m

g/m

l) n

TE

xp

(h)

TO

bs

(h)

TL

ag

(h)

Abs

(%

) K

P

(10-4

cm

/h)

Flux

(µ

g/cm

²/h) R

efer

ence

N

o da

ta a

vaila

ble

N

o da

ta a

vaila

ble

No

quan

titat

ive

expe

rimen

tal d

ata

on d

erm

al u

ptak

e w

ere

foun

d in

the

liter

atur

e.

The

subs

tanc

e ha

s not

bee

n as

sess

ed b

y th

e Sw

edis

h C

riter

ia G

roup

, nor

the

AC

GIH

-TLV

com

mitt

ee.

Bas

ed o

n co

mpa

rison

bet

wee

n et

hyle

ne g

lyco

l mon

oeth

yl e

ther

(EG

EE) a

nd e

thyl

ene

glyc

ol m

onoe

thyl

eth

er a

ceta

te (E

GEE

A)

Joha

nson

(199

6), i

t may

be

assu

med

that

the

skin

per

mea

bilit

y of

eth

ylen

e gl

ycol

mon

obut

yl e

ther

ace

tate

(EG

BEA

)is

sim

ilar t

o th

at o

f eth

ylen

e gl

ycol

mon

obut

yl e

ther

(EG

BE)

.

Rep

orte

d da

ta

In v

itro

In v

ivo

Ase

ssm

ent

A92

App

endi

x A

Subs

tanc

e: E

thyl

ene

glyc

ol m

onoe

thyl

eth

er (E

GEE

)M

olec

ular

wei

ght:

90.1

CA

S: 1

10-8

0-5

Den

sity

:0.9

31 g

/cm

³Sc

ient

ific

basi

s: A

oH 1

983:

36M

eltin

g po

int:

-90°

CB

oilin

g po

int:

135.

6°C

Skin

not

atio

n: Y

esV

apou

r pr

essu

re:0

.71

kPa

(at 2

5°C

)Sk

in p

erm

eabi

lity:

Mod

erat

eE

vapo

ratio

n ra

te:0

.3L

og K

ow:-

0.32

Sp

Loc

C

ell

L

(µm

) A

(c

m²)

V

(ml)

Veh

icle

C

(m

g/m

l) n

TE

xp

(h)

TO

bs

(h)

TL

ag

(h)

Abs

(%

) K

P

(10-4

cm

/h)

Flux

(µ

g/cm

²/h) R

efer

ence

Hum

Ab

StEp

i1.

81-

5N

eat

118

8<1

8.4

800

Dug

ard

et a

l. (1

984)

Hum

Ab

FlFu

ll3.

10.

02N

eat

44

18.

882

0La

rese

et a

l. (1

994)

Hum

Ab

FlFu

ll3.

10.

02A

c27

9.3

44

0.72

7.4

3083

0La

rese

et a

l. (1

994)

Hum

Br

Fl28

00.

640.

01M

e93

524

247.

50.

595.

5Lo

ckle

y et

al.

(200

2)H

umB

rFl

280

0.64

0.01

Nea

t5

2424

8.3

0.74

69Lo

ckle

y et

al.

(200

2)H

umB

rFl

500

0.64

0.2

H2O

34

2424

5.1

4313

Wilk

inso

n &

Will

iam

s (20

02)

Hum

Br

Fl50

00.

640.

1H

2O3

524

2414

200

59W

ilkin

son

& W

illia

ms (

2002

)H

umB

rFl

500

0.64

0.2

H2O

66

2424

1816

098

Wilk

inso

n &

Will

iam

s (20

02)

Hum

Br

Fl50

00.

640.

2H

2O3

424

2411

8325

Wilk

inso

n &

Will

iam

s (20

02)

Hum

Br

Fl50

00.

640.

2H

2O3

524

2413

100

31W

ilkin

son

& W

illia

ms (

2002

)H

umB

rFl

500

0.64

0.2

H2O

35

2424

1280

24W

ilkin

son

& W

illia

ms (

2002

)H

umB

rFl

500

0.64

0.01

Nea

t5

2424

6.2

580

Wilk

inso

n &

Will

iam

s (20

02)

Hum

Br

Fl50

00.

640.

2N

eat

424

2412

1100

Wilk

inso

n &

Will

iam

s (20

02)

Rat

Ba

Fl33

00.

640.

01M

e93

524

2430

0.78

7.3

Lock

ley

et a

l. (2

002)

Rat

Ba

FlFu

ll0.

640.

01M

e93

524

2411

2.3

21Lo

ckle

y et

al.

(200

2)R

atB

aFl

330

0.64

0.01

Nea

t5

2424

201.

514

0Lo

ckle

y et

al.

(200

2)R

atB

aFl

Full

0.64

0.01

Nea

t5

2424

110.

7570

Lock

ley

et a

l. (2

002)

Rat

Ba

Fl33

00.

640.

01N

eat

524

2422

4.7

440

Lock

ley

et a

l. (2

002)

Hum

Arm

1000

Vap

0.00

375

0.75

100

58 m

g19

0000

Kez

ic e

t al.

(199

7)H

umA

rm27

Nea

t5

0.25

100

5.2

mg

7.5

700

Kez

ic e

t al.

(199

7)R

atB

a9.

60.

1N

eat

324

2425

1.1

100

Lock

ley

et a

l. (2

002)

Rat

Ba

9.4

0.09

Ac

0.00

012

(120

µm

ol/ra

t)4

7272

270.

360.

0000

044

Sabo

urin

et a

l. (1

992)

Rat

Ba

9.4

0.09

Ac

0.00

039

(390

µm

ol/ra

t)4

7272

170.

230.

0000

089

Sabo

urin

et a

l. (1

992)

Rat

Ba

9.4

0.09

Ac

0.00

088

(880

µm

ol/ra

t)4

7272

200.

260.

0000

23Sa

bour

in e

t al.

(199

2)

Rep

orte

d da

ta

In v

itro

In v

ivo

A93

App

endi

x A

The

stud

ies u

sing

ace

tone

or m

etha

nol a

s veh

icle

are

exc

lude

d as

they

may

aff

ect s

kin

perm

eatio

n.

How

ever

, the

Kp

for v

apou

r is a

n ov

eres

timat

e of

the

"tru

e" K

p, si

nce

EGEE

has

an

extre

mel

y hi

gh w

ater

:air

parti

tion

coef

ficie

nt o

f 230

00 (J

ohan

son

et a

l. (1

988b

)) a

nd is

ther

efor

e co

ncen

trate

d on

the

ski n

The

pref

erre

d st

udy

is th

at o

f Kez

ic e

t al.

(199

7) w

ere

hum

an sk

in in

viv

o is

use

d, w

ith a

repo

rted

Kp

valu

eof

nea

t EG

EE is

8·1

0-4 c

m/h

, whi

ch c

orre

spon

ds to

"m

oder

ate"

per

mea

bilit

y.

It sh

ould

be

note

d th

at th

e pe

rmea

bilit

y of

EG

EE in

aqu

eous

solu

tions

is o

ne o

r tw

o or

ders

of m

agni

tude

hig

her.

10-5

1

0-4

10-3

1

0-2

10-1

1

00

1

01

1

02

N

eat

Aq.

dilu

tion

Vap

our

Ase

ssm

ent

A94

App

endi

x A

Subs

tanc

e: E

thyl

ene

glyc

ol m

onoe

thyl

eth

er a

ceta

te (E

GEE

A)

Mol

ecul

ar w

eigh

t:13

2.2

CA

S: 1

11-1

5-9

Den

sity

:0.9

75 g

/cm

³Sc

ient

ific

basi

s: N

ot a

vaila

ble

Mel

ting

poin

t:-6

1.7°

CB

oilin

g po

int:

156°

CSk

in n

otat

ion:

Yes

Vap

our

pres

sure

:0.2

7 kP

a (a

t 20°

C)

Skin

per

mea

bilit

y: H

igh

Eva

pora

tion

rate

:0.2

1L

og K

ow:0

.59

(est

imat

ed)

Sp

Loc

C

ell

L

(µm

) A

(c

m²)

V

(ml)

Veh

icle

C

(m

g/m

l) n

TE

xp

(h)

TO

bs

(h)

TL

ag

(h)

Abs

(%

) K

P

(10-4

cm

/h)

Flux

(µ

g/cm

²/h) R

efer

ence

Dog

Br

StFu

ll0.

9N

eat

97

71.

623

2200

Gue

st e

t al.

(198

4)H

umSt

Epi

0.64

/1.0

Nea

t12

88

1-2

1514

00B

arbe

r et a

l. (1

992)

Hum

Ab

StEp

i1.

81-

5N

eat

108

8<1

8.1

800

Dug

ard

et a

l. (1

984)

Rat

StFu

ll0.

64/1

.0N

eat

128

81-

225

2400

Bar

ber e

t al.

(199

2)

Dog

Br

56N

eat

50.

5-1

248.

886

0G

uest

et a

l. (1

984)

Hum

an, a

nim

al, i

n vi

tro a

nd in

viv

o da

ta sh

ow fa

irly

cons

iste

nt re

sults

in th

ree

diff

eren

t stu

dies

with

Kp

valu

es

betw

een

8·10

-4 a

nd 2

·10-3

cm

/h.

Thes

e va

lues

sugg

est "

high

" pe

rmea

bilit

y.

Rep

orte

d da

ta

In v

itro

In v

ivo

Ase

ssm

ent

A95

App

endi

x A

Subs

tanc

e: E

thyl

ene

glyc

ol m

onoi

sopr

opyl

eth

er (E

GiP

E)M

olec

ular

wei

ght:

104.

1C

AS:

109

-59-

1D

ensi

ty:0

.903

g/c

m³

Scie

ntifi

c ba

sis:

AoH

199

5:19

Mel

ting

poin

t:-6

0°C

Boi

ling

poin

t:~1

40°C

Skin

not

atio

n: Y

esV

apou

r pr

essu

re:0

.69

kPa

(at 2

5°C

)Sk

in p

erm

eabi

lity:

No

data

Eva

pora

tion

rate

:Not

ava

ilabl

eL

og K

ow:0

.05

Sp

Loc

C

ell

L

(µm

) A

(c

m²)

V

(ml)

Veh

icle

C

(m

g/m

l) n

TE

xp

(h)

TO

bs

(h)

TL

ag

(h)

Abs

(%

) K

P

(10-4

cm

/h)

Flux

(µ

g/cm

²/h) R

efer

ence

N

o da

ta a

vaila

ble

N

o da

ta a

vaila

ble

No

quan

titat

ive

expe

rimen

tal d

ata

on d

erm

al u

ptak

e w

ere

foun

d in

the

liter

atur

e.

The

Swed

ish

cons

ensu

s rep

ort (

AoH

199

5:19

) sta

tes t

hat b

ased

on

anal

ogy

with

oth

er e

.g. e

ther

s, sk

in a

bsor

ptio

n m

ay b

e hi

gh.

Rep

orte

d da

ta

In v

itro

In v

ivo

Ase

ssm

ent

A96

App

endi

x A

Subs

tanc

e: E

thyl

ene

glyc

ol m

onoi

sopr

opyl

eth

er a

ceta

te (E

GiP

EA)

Mol

ecul

ar w

eigh

t:14

6.2

CA

S: 1

9234

-20-

9D

ensi

ty:0

.95

g/cm

³Sc

ient

ific

basi

s: A

oH 1

995:

19M

eltin

g po

int:

Not

ava

ilabl

eB

oilin

g po

int:

164°

CSk

in n

otat

ion:

Yes

Vap

our

pres

sure

:Not

ava

ilabl

eSk

in p

erm

eabi

lity:

No

data

Eva

pora

tion

rate

:Not

ava

ilabl

eL

og K

ow:1

.01

(est

imat

ed)

Sp

Loc

C

ell

L

(µm

) A

(c

m²)

V

(ml)

Veh

icle

C

(m

g/m

l) n

TE

xp

(h)

TO

bs

(h)

TL

ag

(h)

Abs

(%

) K

P

(10-4

cm

/h)

Flux

(µ

g/cm

²/h) R

efer

ence

N

o da

ta a

vaila

ble

N

o da

ta a

vaila

ble

No

quan

titat

ive

expe

rimen

tal d

ata

on d

erm

al u

ptak

e w

ere

foun

d in

the

liter

atur

e.

The

Swed

ish

cons

ensu

s rep

ort (

AoH

199

5:19

) sta

tes t

hat b

ased

on

anal

ogy

with

oth

er e

.g. e

ther

s, sk

in a

bsor

ptio

n m

ay b

e hi

gh.

Rep

orte

d da

ta

In v

itro

In v

ivo

Ase

ssm

ent

A97

App

endi

x A

Subs

tanc

e: E

thyl

ene

glyc

ol m

onop

ropy

l eth

er (E

GPE

)M

olec

ular

wei

ght:

104.

1C

AS:

280

7-30

-9D

ensi

ty:0

.931

g/c

m³

Scie

ntifi

c ba

sis:

AoH

199

4:30

Mel

ting

poin

t:-1

90°C

Boi

ling

poin

t:14

9°C

Skin

not

atio

n: Y

esV

apou

r pr

essu

re:1

70-3

90 P

a (a

t 25°

C)

Skin

per

mea

bilit

y: H

igh

Eva

pora

tion

rate

:0.2

Log

Kow

:0.0

8

Sp

Loc

C

ell

L

(µm

) A

(c

m²)

V

(ml)

Veh

icle

C

(m

g/m

l) n

TE

xp

(h)

TO

bs

(h)

TL

ag

(h)

Abs

(%

) K

P

(10-4

cm

/h)

Flux

(µ

g/cm

²/h) R

efer

ence

Hum

StEp

i0.

64/1

.0N

eat

58

81-

26.

458

0B

arbe

r et a

l. (1

992)

Rat

StFu

ll0.

64/1

.0N

eat

58

81-

225

2300

Bar

ber e

t al.

(199

2)

N

o da

ta a

vaila

ble

Qua

ntita

tive

upta

ke d

ata

on ra

t and

hum

an sk

in in

vitr

o ar

e av

aila

ble

(Bar

ber e

t al.

(199

2)).

Hum

an e

pide

rmis

was

pre

pare

d us

ing

hot (

60°C

) wat

er, w

hich

may

hav

e af

fect

ed th

e pe

rmea

tion

prop

ertie

s. Th

e pr

efer

red

stud

y is

the

one

usin

g in

tact

rat s

kin.

The

Kp

valu

e of

3·1

0-3 c

m/h

cor

resp

onds

to "

high

" pe

rmea

bilit

y.

Rep

orte

d da

ta

In v

itro

In v

ivo

Ase

ssm

ent

A98

App

endi

x A

Subs

tanc

e: E

thyl

ene

oxid

eM

olec

ular

wei

ght:

44.1

CA

S: 7

5-21

-8D

ensi

ty:0

.882

g/c

m³

Scie

ntifi

c ba

sis:

AoH

198

2:24

Mel

ting

poin

t:-1

11.3

°CB

oilin

g po

int:

10.7

°CSk

in n

otat

ion:

Yes

Vap

our

pres

sure

:150

kPa

(at 2

0°C

)Sk

in p

erm

eabi

lity:

Ext

rem

ely

high

Eva

pora

tion

rate

:Not

ava

ilabl

eL

og K

ow:-

0.30

Sp

Loc

C

ell

L

(µm

) A

(c

m²)

V

(ml)

Veh

icle

C

(m

g/m

l) n

TE

xp

(h)

TO

bs

(h)

TL

ag

(h)

Abs

(%

) K

P

(10-4

cm

/h)

Flux

(µ

g/cm

²/h) R

efer

ence

Hum

St50

01

Pol f

ab0.

0033

(18

00pp

m)

224

241.

328

00.

0000

92W

este

r et a

l. (1

997)

Hum

St50

01

Pol f

ab0.

0033

(18

00pp

m)

224

2446

1000

00.

0033

Wes

ter e

t al.

(199

7)

N

o da

ta a

vaila

ble

The

skin

not

atio

n by

AC

GIH

(200

1) is

bas

ed o

n a

case

repo

rt (S

exto

n et

al.

(194

9)) w

here

thre

e w

orke

rs th

at

wer

e ac

cide

ntal

ly e

xpos

ed to

a 1

% E

O so

lutio

n de

velo

ped

naus

ea a

nd v

omiti

ng. I

t is h

owev

er u

ncle

ar to

wha

t ext

ent

inha

latio

n ex

posu

re c

ontri

bute

d.

In th

e fir

st e

xper

imen

t of W

este

r et a

l. (1

997)

, pol

yest

er fa

bric

(Pol

fab)

was

satu

rate

d w

ith e

thyl

ene

oxid

e. T

he sk

in p

iece

was

then

exp

osed

to th

e sa

tura

ted

fabr

ic in

an

non-

occl

uded

fash

ion.

Thu

s, m

ost o

f the

eth

ylen

e ox

ide

evap

orat

ed in

toth

e ai

r as s

een

in th

e lo

w a

bsor

ptio

n pe

rcen

tage

.

The

seco

nd e

xper

imen

t was

sim

ilar e

xcep

t tha

t the

pol

yest

er fa

bric

was

cov

ered

by

a do

uble

-laye

r lat

ex g

love

.Th

e 46

% a

bsor

ptio

n oc

curr

ed w

ithin

the

first

4h

sugg

estin

g hi

gh p

erm

eabi

lity

of e

thyl

ene

oxid

e.

The

fluxe

s and

Kp

valu

es in

the

tabl

e w

ere

calc

ulat

ed a

ssum

ing

a th

ickn

ess o

f the

fabr

ic o

f 0.5

mm

and

, hen

ce,

an a

pplie

d am

ount

of 1

7 ng

.

This

hig

hly

unce

rtain

exe

rcis

e su

gges

ts a

"ve

ry h

igh"

or e

ven

"ext

rem

ely

high

" pe

rmea

bilit

y of

eth

ylen

e ox

ide.

Rep

orte

d da

ta

In v

itro

In v

ivo

Ase

ssm

ent

A99

App

endi

x A

Subs

tanc

e: E

thyl

ened

iam

ine

Mol

ecul

ar w

eigh

t:60

.1C

AS:

107

-15-

3D

ensi

ty:0

.899

g/c

m³

Scie

ntifi

c ba

sis:

AoH

198

3:36

Mel

ting

poin

t:8.

5°C

Boi

ling

poin

t:11

6.5°

CSk

in n

otat

ion:

Yes

Vap

our

pres

sure

:1.4

kPa

(at 2

0°C

)Sk

in p

erm

eabi

lity:

Mod

erat

eE

vapo

ratio

n ra

te:0

.91

Log

Kow

:-2.

04

Sp

Loc

C

ell

L

(µm

) A

(c

m²)

V

(ml)

Veh

icle

C

(m

g/m

l) n

TE

xp

(h)

TO

bs

(h)

TL

ag

(h)

Abs

(%

) K

P

(10-4

cm

/h)

Flux

(µ

g/cm

²/h) R

efer

ence

N

o da

ta a

vaila

ble

Rat

Ba

490.

2H

2O25

% (1

000

µg/c

m²)

4-6

2424

551

23Y

ang

et a

l. (1

987)

Rat

Ba

490.

2H

2O50

% (2

000

µg/c

m²)

4-6

2424

611.

252

Yan

g et

al.

(198

7)

Onl

y ra

t in

vivo

dat

a w

ere

foun

d. T

he K

p va

lue

of 1

·10-4

cm

/h su

gges

ts "

mod

erat

e" p

erm

eabi

lity.

Rep

orte

d da

ta

In v

itro

In v

ivo

Ase

ssm

ent

A10

0

App

endi

x A

Subs

tanc

e: F

orm

alde

hyde

Mol

ecul

ar w

eigh

t:30

.0C

AS:

50-

00-0

Den

sity

:1.0

9 g/

cm³

Scie

ntifi

c ba

sis:

AoH

198

3:36

Mel

ting

poin

t:-1

18°C

Boi

ling

poin

t:-1

9.5°

CSk

in n

otat

ion:

No

Vap

our

pres

sure

:Not

ava

ilabl

eSk

in p

erm

eabi

lity:

Mod

erat

eE

vapo

ratio

n ra

te:N

ot a

vaila

ble

Log

Kow

:0.3

5

Sp

Loc

C

ell

L

(µm

) A

(c

m²)

V

(ml)

Veh

icle

C

(m

g/m

l) n

TE

xp

(h)

TO

bs

(h)

TL

ag

(h)

Abs

(%

) K

P

(10-4

cm

/h)

Flux

(µ

g/cm

²/h) R

efer

ence

Hum

Br

Full

0.35

0.03

5H

2O +

MeO

H (1

0-15

%)

370

110.

50.

50.

10 m

g/cm

²5.

721

0Lo

den

(198

6a)

Hum

Br

FlFu

ll0.

35H

2O +

MeO

H (1

-1.5

%)

375

2121

~1.4

4.6

17Lo

den

(198

6b)

Hum

Br

FlFu

ll0.

35H

2O +

MeO

H (1

0-15

%)

370

515

15~1

.48.

632

0Lo

den

(198

6b)

Rat

Ba

820

0 m

gC

ream

0.10

%8

4848

6.1

0.32

0.03

2B

artn

ik e

t al.

(198

5)R

atB

a8

200

mg

Cre

am0.

10%

448

489.

20.

480.

048

Bar

tnik

et a

l. (1

985)

Rat

Ba

820

0 m

gC

ream

0.10

%2

4848

3.4

0.18

0.01

8B

artn

ik e

t al.

(198

5)

The

in v

ivo

stud

y w

ith ra

t ski

n B

artn

ik e

t al.

(198

5) u

sed

skin

cre

am a

s veh

icle

, thi

s may

cha

nge

the

perm

eabi

lity

prop

ertie

s sig

nific

antly

. Th

e pr

efer

red

stud

y is

that

of L

oden

(198

6b),

usin

g hu

man

full

thic

knes

s ski

n in

vitr

o.

The

Kp

valu

es ra

nge

betw

een

5·10

-4 a

nd 9

·10-4

cm

/h, c

orre

spon

ds to

"m

oder

ate"

per

mea

bilit

y.

Rep

orte

d da

ta

In v

itro

In v

ivo

Ase

ssm

ent

A10

1

App

endi

x A

Subs

tanc

e: F

orm

amid

eM

olec

ular

wei

ght:

45.0

CA

S: 7

5-12

-7D

ensi

ty:1

.134

g/c

m³

Scie

ntifi

c ba

sis:

AoH

199

1:8

Mel

ting

poin

t:2.

5°C

Boi

ling

poin

t:21

0°C

Skin

not

atio

n: Y

esV

apou

r pr

essu

re:0

.013

kPa

(at 3

0°C

)Sk

in p

erm

eabi

lity:

No

data

Eva

pora

tion

rate

:0.0

04L

og K

ow:-

1.51

Sp

Loc

C

ell

L

(µm

) A

(c

m²)

V

(ml)

Veh

icle

C

(m

g/m

l) n

TE

xp

(h)

TO

bs

(h)

TL

ag

(h)

Abs

(%

) K

P

(10-4

cm

/h)

Flux

(µ

g/cm

²/h) R

efer

ence

N

o da

ta a

vaila

ble

N

o da

ta a

vaila

ble

No

quan

titat

ive

expe

rimen

tal d

ata

on d

erm

al u

ptak

e w

ere

foun

d in

the

liter

atur

e.

No

info

rmat

ion

rega

rdin

g sk

in u

ptak

e is

giv

en in

the

Swed

ish

cons

ensu

s rep

ort (

AoH

199

1:8)

.A

ccor

ding

to th

e A

CG

IH (2

001)

doc

umen

tatio

n, fo

rmam

ide

is re

lativ

ely

non-

toxi

c by

skin

app

licat

ion,

with

a d

erm

al L

D50

of 6

g/k

g in

rabb

its. H

owev

er, 3

mon

ths d

aily

der

mal

trea

tmen

t (5

d/w

k) w

ith 3

g/k

g pr

oduc

ed

gene

ral s

yste

mic

toxi

city

in ra

ts.

Acc

ordi

ng to

theo

retic

al c

alcu

latio

ns b

y Fi

sero

va-B

erge

rova

et a

l. (1

990)

the

pote

ntia

l for

der

mal

abso

rptio

n an

d re

sulti

ng to

xici

ty is

sign

ifica

nt.

Rep

orte

d da

ta

In v

itro

In v

ivo

Ase

ssm

ent

A10

2

App

endi

x A

Subs

tanc

e: F

urfu

ral

Mol

ecul

ar w

eigh

t:96

.1C

AS:

98-

01-1

Den

sity

:1.1

59 g

/cm

³Sc

ient

ific

basi

s: A

oH 1

984:

44M

eltin

g po

int:

-36.

5°C

Boi

ling

poin

t:16

7°C

Skin

not

atio

n: Y

esV

apou

r pr

essu

re:0

.14

kPa

(at 2

0°C

)Sk

in p

erm

eabi

lity:

Mod

erat

eE

vapo

ratio

n ra

te:N

ot a

vaila

ble

Log

Kow

:0.4

1

Sp

Loc

C

ell

L

(µm

) A

(c

m²)

V

(ml)

Veh

icle

C

(m

g/m

l) n

TE

xp

(h)

TO

bs

(h)

TL

ag

(h)

Abs

(%

) K

P

(10-4

cm

/h)

Flux

(µ

g/cm

²/h) R

efer

ence

N

o da

ta a

vaila

ble

Hum

Ha

Nea

t6

0.25

2027

mg

1.6

180

Flek

et a

l. (1

978)

Hum

WB

Vap

30 m

g/m

³6

820

1800

000.

53Fl

ek e

t al.

(197

8)

The

flux

mea

sure

men

t is b

ased

on

reco

very

of f

urfu

ral m

etab

olite

in u

rine

afte

r dip

ping

one

han

d in

nea

t fur

fura

l. Th

is m

etho

d m

easu

res t

he ra

te o

f pen

etra

tion

into

skin

, rat

her t

han

the

stea

dy-s

tate

flux

, and

may

thus

be

an o

vere

stim

atio

n.

This

stud

y gi

ves a

Kp

valu

e of

2·1

0-4 c

m/h

, cor

resp

ondi

ng to

"m

oder

ate"

per

mea

bilit

y.

Rep

orte

d da

ta

In v

itro

In v

ivo

Ase

ssm

ent

A10

3

App

endi

x A

Subs

tanc

e: F

urfu

ryl a

lcoh

olM

olec

ular

wei

ght:

98.1

CA

S: 9

8-00

-0D

ensi

ty:1

.128

g/c

m³

Scie

ntifi

c ba

sis:

AoH

198

5:32

Mel

ting

poin

t:-2

0.2°

CB

oilin

g po

int:

170°

CSk

in n

otat

ion:

Yes

Vap

our

pres

sure

:0.6

9 kP

a (a

t 25°

C)

Skin

per

mea

bilit

y: N

o da

taE

vapo

ratio

n ra

te:N

ot a

vaila

ble

Log

Kow

:0.2

8

Sp

Loc

C

ell

L

(µm

) A

(c

m²)

V

(ml)

Veh

icle

C

(m

g/m

l) n

TE

xp

(h)

TO

bs

(h)

TL

ag

(h)

Abs

(%

) K

P

(10-4

cm

/h)

Flux

(µ

g/cm

²/h) R

efer

ence

N

o da

ta a

vaila

ble

N

o da

ta a

vaila

ble

No

quan

titat

ive

expe

rimen

tal d

ata

on d

erm

al u

ptak

e w

ere

foun

d in

the

liter

atur

e.

Ref

errin

g to

an

indu

stry

repo

rt, th

e Sw

edis

h co

nsen

sus d

ocum

ent (

AoH

198

5) st

ates

that

the

perc

utan

eous

upt

ake

has b

een

dem

onst

rate

d in

ani

mal

s. A

CG

IH (2

001)

giv

es a

sim

ilar s

tate

men

t with

the

addi

tiona

l inf

orm

atio

n of

dos

e-re

late

d m

orta

lity

in a

nim

als.

Rep

orte

d da

ta

In v

itro

In v

ivo

Ase

ssm

ent

A10

4

App

endi

x A

Subs

tanc

e: H

alot

hane

Mol

ecul

ar w

eigh

t:19

7.4

CA

S: 1

51-6

7-7

Den

sity

:1.8

64 g

/cm

³Sc

ient

ific

basi

s: A

oH 1

985:

32M

eltin

g po

int:

-118

°CB

oilin

g po

int:

50.2

°CSk

in n

otat

ion:

No

Vap

our

pres

sure

:32

kPa

(at 2

0°C

)Sk

in p

erm

eabi

lity:

Ver

y hi

ghE

vapo

ratio

n ra

te:N

ot a

vaila

ble

Log

Kow

:2.3

0

Sp

Loc

C

ell

L

(µm

) A

(c

m²)

V

(ml)

Veh

icle

C

(m

g/m

l) n

TE

xp

(h)

TO

bs

(h)

TL

ag

(h)

Abs

(%

) K

P

(10-4

cm

/h)

Flux

(µ

g/cm

²/h) R

efer

ence

N

o da

ta a

vaila

ble

Rat

WB

Vap

5000

0ppm

44

40.

245

018

McD

ouga

l et a

l. (1

990)

The

only

stud

y fo

und

on h

alot

hane

is th

at o

f McD

ouga

l et a

l. (1

990)

wer

e ra

ts w

ere

expo

sed

to h

alot

hane

vap

our.

The

repo

rted

Kp

valu

e of

5·1

0-2 c

m/h

sugg

ests

a "

very

hig

h" p

erm

eabi

lity

It sh

ould

be

note

d th

at h

alot

hane

is v

ery

vola

tile.

Rep

orte

d da

ta

In v

itro

In v

ivo

Ase

ssm

ent

A10

5

App

endi

x A

Subs

tanc

e: H

epta

ne, n

-M

olec

ular

wei

ght:

100.

2C

AS:

142

-82-

5D

ensi

ty:0

.684

g/c

m³

Scie

ntifi

c ba

sis:

Not

ava

ilabl

e M

eltin

g po

int:

-90.

6°C

Boi

ling

poin

t:98

.4°C

Skin

not

atio

n: N

oV

apou

r pr

essu

re:4

.2 k

Pa (a

t 20°

C)

Skin

per

mea

bilit

y: E

xtre

mel

y lo

wE

vapo

ratio

n ra

te:4

.3L

og K

ow:4

.66

Sp

Loc

C

ell

L

(µm

) A

(c

m²)

V

(ml)

Veh

icle

C

(m

g/m

l) n

TE

xp

(h)

TO

bs

(h)

TL

ag

(h)

Abs

(%

) K

P

(10-4

cm

/h)

Flux

(µ

g/cm

²/h) R

efer

ence

Rat

Ab

StFu

ll2.

61

Nea

t30

4-20

4-20

1-7

µg0.

0021

0.14

Tsur

uta

(198

2)

N

o da

ta a

vaila

ble

The

only

foun

d st

udy

on n

-hep

tane

is th

at o

f Tsu

ruta

(198

2) w

ere

rat s

kin

was

exp

osed

to n

eat n

-hep

tane

in v

itro.

The

calc

ulat

ed K

p va

lue

of 2

·10-7

cm

/h su

gges

ts a

n "e

xtre

mel

y lo

w"

perm

eabi

lity.

It sh

ould

be

note

d th

at h

epta

ne h

as v

ery

low

solu

bilit

y in

wat

er a

nd T

suru

ta (1

982)

use

d sa

line

as re

cept

or m

ediu

m.

Hen

ce, t

he K

p m

ay b

e an

und

eres

timat

e.

Rep

orte

d da

ta

In v

itro

In v

ivo

Ase

ssm

ent

A10

6

App

endi

x A

Subs

tanc

e: H

exan

e, n

-M

olec

ular

wei

ght:

86.2

CA

S: 1

10-5

4-3

Den

sity

:0.6

55 g

/cm

³Sc

ient

ific

basi

s: A

oH 1

986:

20M

eltin

g po

int:

-95°

CB

oilin

g po

int:

69°C

Skin

not

atio

n: N

oV

apou

r pr

essu

re:1

4 kP

a (a

t 20°

C)

Skin

per

mea

bilit

y: V

ery

low

Eva

pora

tion

rate

:9L

og K

ow:3

.90

Sp

Loc

C

ell

L

(µm

) A

(c

m²)

V

(ml)

Veh

icle

C

(m

g/m

l) n

TE

xp

(h)

TO

bs

(h)

TL

ag

(h)

Abs

(%

) K

P

(10-4

cm

/h)

Flux

(µ

g/cm

²/h) R

efer

ence

Hum

Br

FlFu

llN

eat

512

12~5

.20.

010.

83Lo

den

(198

6b)

Rat

Ab

StFu

ll2.

61

Nea

t51

2-22

2-22

0.4-

3 µg

0.00

092

0.06

1Ts

urut

a (1

982)

Hum

Arm

/Ha

1000

Vap

1.3

mm

ol/l

50.

56

130

1.5

Kez

ic e

t al.

(200

0)R

atW

BV

ap60

000p

pm5

44

0.1

310

6.5

McD

ouga

l et a

l. (1

990)

Ther

e is

a h

uge

diff

eren

ce in

Kp

valu

es b

etw

een

expe

rimen

ts in

viv

o an

d in

vitr

o.

Tsur

uta

(198

2) u

sed

salin

e as

rece

ptor

med

ium

, thi

s is l

ikel

y to

giv

e a

seve

re u

nder

est

imat

e of

the

flux

and

Kp

due

to th

e lo

w so

lubi

lity

of n

-hex

ane.

The

pref

erre

d st

udy

is th

at b

y Lo

den

(198

6b) w

ere

hum

an sk

in w

as e

xpos

ed to

nea

t n-h

exan

e.

The

calc

ulat

ed K

p va

lue

of 1

·10-6

cm

/h su

gges

ting

a "v

ery

low

" pe

rmea

bilit

y.

Rep

orte

d da

ta

In v

itro

In v

ivo

Ase

ssm

ent

A10

7

App

endi

x A

Subs

tanc

e: H

exan

one,

2-;

met

hyl n

-but

yl k

eton

eM

olec

ular

wei

ght:

100.

2C

AS:

591

-78-

6D

ensi

ty:0

.811

g/c

m³

Scie

ntifi

c ba

sis:

Not

ava

ilabl

e M

eltin

g po

int:

-57°

CB

oilin

g po

int:

127°

CSk

in n

otat

ion:

Yes

Vap

our

pres

sure

:0.3

3 kP

a (a

t 20°

C)

Skin

per

mea

bilit

y: M

oder

ate

Eva

pora

tion

rate

:1.2

Log

Kow

:1.3

8

Sp

Loc

C

ell

L

(µm

) A

(c

m²)

V

(ml)

Veh

icle

C

(m

g/m

l) n

TE

xp

(h)

TO

bs

(h)

TL

ag

(h)

Abs

(%

) K

P

(10-4

cm

/h)

Flux

(µ

g/cm

²/h) R

efer

ence

N

o da

ta a

vaila

ble

Hum

Arm

5615

Nea

t4

112

19 m

g4.

234

0D

iVin

cenz

o et

al.

(197

8)

The

only

foun

d st

udy

is th

at o

f DiV

ince

nzo

et a

l. (1

978)

whi

ch w

as a

n in

viv

o st

udy

wer

e hu

man

skin

was

ex

pose

d to

nea

t 2-h

exan

one.

The

calc

ulat

ed K

p va

lue

corr

espo

nds t

o "m

oder

ate"

per

mea

bilit

y.

Rep

orte

d da

ta

In v

itro

In v

ivo

Ase

ssm

ent

A10

8

App

endi

x A

Subs

tanc

e: H

ydro

gen

cyan

ide

Mol

ecul

ar w

eigh

t:27

.1C

AS:

74-

90-8

Den

sity

:0.6

9 g/

cm³

Scie

ntifi

c ba

sis:

AoH

200

1:19

Mel

ting

poin

t:-1

3.4°

CB

oilin

g po

int:

25.6

°CSk

in n

otat

ion:

Yes

Vap

our

pres

sure

:84

kPa

(at 2

0°C

)Sk

in p

erm

eabi

lity:

Ver

y hi

ghE

vapo

ratio

n ra

te:N

ot a

vaila

ble

Log

Kow

:-0.

25

Sp

Loc

C

ell

L

(µm

) A

(c

m²)

V

(ml)

Veh

icle

C

(m

g/m

l) n

TE

xp

(h)

TO

bs

(h)

TL

ag

(h)

Abs

(%

) K

P

(10-4

cm

/h)

Flux

(µ

g/cm

²/h) R

efer

ence

Hum

Ab

St40

1.8

Vap

1.3

(Sat

urat

ed)

0.1

100

13D

ugar

d (1

987)

N

o da

ta a

vaila

ble

The

sing

le st

udy

foun

d on

hyd

roge

n cy

anid

e w

as th

at o

f Dug

ard

(198

7) w

ere

hum

an sk

in w

as e

xpos

ed to

satu

rate

d cy

anid

e va

pour

(con

cent

ratio

n no

t giv

en, b

ut c

ould

be

calc

ulat

ed fr

om fl

ux a

nd K

p).

The

repo

rted

Kp

valu

e of

1·1

0-2 c

orre

spon

ds to

"ve

ry h

igh"

per

mea

bilit

y.

It sh

ould

be

note

d th

at th

e pe

rmea

bilit

y of

sodi

um c

yani

de is

two

orde

rs o

f mag

nitu

de lo

wer

.

Rep

orte

d da

ta

In v

itro

In v

ivo

Ase

ssm

ent

A10

9

App

endi

x A

Subs

tanc

e: H

ydro

quin

one

Mol

ecul

ar w

eigh

t:11

0.1

CA

S: 1

23-3

1-9

Den

sity

:1.3

32 g

/cm

³Sc

ient

ific

basi

s: A

oH 1

991:

8M

eltin

g po

int:

170°

CB

oilin

g po

int:

285°

CSk

in n

otat

ion:

No

Vap

our

pres

sure

:0.0

024

Pa (a

t 20°

C)

Skin

per

mea

bilit

y: V

ery

low

Eva

pora

tion

rate

:Neg

ligib

leL

og K

ow:0

.59

Sp

Loc

C

ell

L

(µm

) A

(c

m²)

V

(ml)

Veh

icle

C

(m

g/m

l) n

TE

xp

(h)

TO

bs

(h)

TL

ag

(h)

Abs

(%

) K

P

(10-4

cm

/h)

Flux

(µ

g/cm

²/h) R

efer

ence

HG

PFl

250-

300

1.1

OiW

0.08

% (

2.5

µg/c

m²)

924

244.

30.

036

0.00

4H

ood

et a

l. (1

999)

Hum

Ab

StEp

iIn

fH

2O

569

88

0.09

30.

52B

arbe

r et a

l. (1

995)

Hum

Ab

Fl50

01

0.01

Cre

am2%

624

2434

1.1

2.9

Wes

ter e

t al.

(199

8c)

Rat

Ab

StFu

llIn

fH

2O

499

88

0.23

1.1

Bar

ber e

t al.

(199

5)R

atA

bSt

320

0.95

Cre

am50

(5%

)5

77

014

mg

3820

0M

atsu

baya

shi e

t al.

(200

3)

Hum

FH25

Cre

am2%

(2.5

mg)

624

9637

0.71

1.9

Wes

ter e

t al.

(199

8c)

Hum

Arm

25C

ream

2% (2

.5 m

g)6

88

450.

381

Wes

ter e

t al.

(199

8c)

The

stud

y by

Mat

suba

yash

i et a

l. (2

003)

seem

s unr

ealis

tic in

that

no

lag

time

was

obs

erve

d.Th

e ot

her i

n vi

tro st

udie

s are

in a

ccor

danc

e w

ith th

e in

viv

o st

udie

s.

The

in v

itro

stud

y us

ing

hum

an sk

in a

nd w

ater

as v

ehic

le (B

arbe

r et a

l. (1

995)

) is p

refe

rred

. Th

e K

p va

lue

of 9

·10-6

cm

/h c

orre

spon

ds to

"ve

ry lo

w"

perm

eabi

lity.

It sh

ould

be

note

d th

at K

p va

lues

cal

cula

ted

for a

queo

us so

lutio

ns a

re g

ener

ally

muc

h hi

gher

than

thos

e ob

tain

ed

for n

eat s

ubst

ance

s.

Rep

orte

d da

ta

In v

itro

In v

ivo

Ase

ssm

ent

A11

0

App

endi

x A

Subs

tanc

e: H

ydro

xyet

hyla

cryl

ate,

2-;

prop

enoi

c ac

id, 2

-M

olec

ular

wei

ght:

116.

1C

AS:

818

-61-

1D

ensi

ty:1

.101

g/c

m³

Scie

ntifi

c ba

sis:

Not

ava

ilabl

e M

eltin

g po

int:

-60.

2°C

Boi

ling

poin

t:21

0°C

Skin

not

atio

n: Y

esV

apou

r pr

essu

re:7

Pa

(at 2

5°C

)Sk

in p

erm

eabi

lity:

No

data

Eva

pora

tion

rate

:Not

ava

ilabl

eL

og K

ow:-

0.21

Sp

Loc

C

ell

L

(µm

) A

(c

m²)

V

(ml)

Veh

icle

C

(m

g/m

l) n

TE

xp

(h)

TO

bs

(h)

TL

ag

(h)

Abs

(%

) K

P

(10-4

cm

/h)

Flux

(µ

g/cm

²/h) R

efer

ence

N

o da

ta a

vaila

ble

N

o da

ta a

vaila

ble

No

quan

titat

ive

expe

rimen

tal d

ata

on d

erm

al u

ptak

e w

ere

foun

d in

the

liter

atur

e.

No

docu

men

tatio

n w

as fo

und

from

the

Swed

ish

crite

ria g

roup

or t

he A

CG

IH-T

LV c

omm

ittee

.

OEC

D (2

005)

repo

rts th

e fo

llow

ing

LD50

val

ues (

mg/

kg b

w):

oral

rat/m

ouse

601,

107

0, 1

040,

810

, 540

, 650

, 548

derm

al ra

bbit

250,

298

, 154

, >63

, 110

0, 3

000

derm

al ra

t>1

000

The

derm

al a

nd o

ral L

D50

val

ues a

re in

the

sam

e ra

nge,

sugg

estin

g th

at sk

in a

bsor

ptio

n m

ay b

e si

gnifi

cant

.

Als

o a

stud

y ci

ted

in O

ECD

(200

5) sh

owed

that

two

third

s (66

%) o

f der

mal

ly a

pplie

d ra

diol

abel

led

2-hy

drox

yeth

ylac

ryla

te (4

mal

e ra

ts, c

lippe

d fu

r, 12

.5 m

g/kg

bw

, exp

osed

are

a no

t giv

en) w

as re

cove

red

with

in 4

8h.

This

sugg

ests

ext

ensi

ve sk

in p

enet

ratio

n.

Rep

orte

d da

ta

In v

itro

In v

ivo

Ase

ssm

ent

A11

1

App

endi

x A

Subs

tanc

e: Is

oflu

rane

Mol

ecul

ar w

eigh

t:18

4.5

CA

S: 2

6675

-46-

7D

ensi

ty:1

.45

g/cm

³Sc

ient

ific

basi

s: N

ot a

vaila

ble

Mel

ting

poin

t:~-

103°

CB

oilin

g po

int:

48.5

°CSk

in n

otat

ion:

No

Vap

our

pres

sure

:32

kPa

(at 2

0°C

)Sk

in p

erm

eabi

lity:

Ver

y hi

ghE

vapo

ratio

n ra

te:N

ot a

vaila

ble

Log

Kow

:2.0

6

Sp

Loc

C

ell

L

(µm

) A

(c

m²)

V

(ml)

Veh

icle

C

(m

g/m

l) n

TE

xp

(h)

TO

bs

(h)

TL

ag

(h)

Abs

(%

) K

P

(10-4

cm

/h)

Flux

(µ

g/cm

²/h) R

efer

ence

N

o da

ta a

vaila

ble

Rat

WB

Vap

5000

0ppm

64

40.

125

09.

6M

cDou

gal e

t al.

(199

0)

The

only

foun

d st

udy

on is

oflu

rane

is th

at o

f McD

ouga

l et a

l. (1

990)

. Th

e re

porte

d K

p va

lue

of 3

·10-2

cm

/h su

gges

ts a

"ve

ry h

igh"

per

mea

bilit

y.

It sh

ould

be

note

d th

at v

apou

r exp

osur

e us

ually

yie

ld fo

r hig

her K

p va

lues

than

doe

s liq

uid

expo

sure

.

Rep

orte

d da

ta

In v

itro

In v

ivo

Ase

ssm

ent

A11

2

App

endi

x A

Subs

tanc

e: Is

opro

pano

lM

olec

ular

wei

ght:

60.1

CA

S: 6

7-63

-0D

ensi

ty:0

.785

g/c

m³

Scie

ntifi

c ba

sis:

AoH

198

2:24

Mel

ting

poin

t:-8

8.5°

CB

oilin

g po

int:

82.4

°CSk

in n

otat

ion:

No

Vap

our

pres

sure

:3.9

kPa

(at 2

0°C

)Sk

in p

erm

eabi

lity:

Mod

erat

eE

vapo

ratio

n ra

te:2

.9L

og K

ow:0

.05

Sp

Loc

C

ell

L

(µm

) A

(c

m²)

V

(ml)

Veh

icle

C

(m

g/m

l) n

TE

xp

(h)

TO

bs

(h)

TL

ag

(h)

Abs

(%

) K

P

(10-4

cm

/h)

Flux

(µ

g/cm

²/h) R

efer

ence

Hum

St90

00.

640.

13H

2O10

%8

81

26 µ

g (4

h)1.

713

Kor

inth

et a

l. (2

003)

Hum

St90

00.

640.

13H

2O50

%8

81

430

µg2.

496

Kor

inth

et a

l. (2

003)

Rat

Ba

4.3

H2O

70

%4

4814

-15

780-

850

Boa

tman

et a

l. (1

998)

The

hum

an in

vitr

o an

d ra

t in

vivo

giv

e co

ncor

dant

resu

lts.

The

hum

an d

ata

yiel

d a

Kp

valu

e of

2·1

0-4 c

m/h

sugg

estin

g "m

oder

ate"

per

mea

bilit

y.

Rep

orte

d da

ta

In v

itro

In v

ivo

Ase

ssm

ent

A11

3

App

endi

x A

Subs

tanc

e: Is

opro

pylb

enze

ne; c

umen

eM

olec

ular

wei

ght:

120.

2C

AS:

98-

82-8

Den

sity

:0.8

62 g

/cm

³Sc

ient

ific

basi

s: A

oH 1

982:

24M

eltin

g po

int:

-96°

CB

oilin

g po

int:

151°

CSk

in n

otat

ion:

Yes

Vap

our

pres

sure

:610

Pa

(at 2

5°C

)Sk

in p

erm

eabi

lity:

No

data

Eva

pora

tion

rate

:0.4

3L

og K

ow:3

.66

Sp

Loc

C

ell

L

(µm

) A

(c

m²)

V

(ml)

Veh

icle

C

(m

g/m

l) n

TE

xp

(h)

TO

bs

(h)

TL

ag

(h)

Abs

(%

) K

P

(10-4

cm

/h)

Flux

(µ

g/cm

²/h) R

efer

ence

N

o da

ta a

vaila

ble

N

o da

ta a

vaila

ble

No

quan

titat

ive

expe

rimen

tal d

ata

on d

erm

al u

ptak

e w

ere

foun

d in

the

liter

atur

e.

Acc

ordi

ng to

the

Swed

ish

cons

ensu

s rep

ort (

AoH

198

2), t

here

are

indi

catio

ns th

at it

is a

bsor

bed

by th

e sk

in.

Acc

ordi

ng to

AC

GIH

(200

1) th

e ci

ted

stud

y (V

alet

te e

t al.

(195

4)) d

id n

ot d

irect

ly d

emon

stra

te sk

in

abso

rptio

n of

isop

ropy

lben

zene

.

Rep

orte

d da

ta

In v

itro

In v

ivo

Ase

ssm

ent

A11

4

App

endi

x A

Subs

tanc

e: M

ercu

ry b

ichl

orid

e; d

ichl

orom

ercu

ryM

olec

ular

wei

ght:

271.

5C

AS:

748

7-94

-7D

ensi

ty:5

.44

g/cm

³Sc

ient

ific

basi

s: A

oH 1

984:

44M

eltin

g po

int:

277°

CB

oilin

g po

int:

302°

CSk

in n

otat

ion:

Yes

Vap

our

pres

sure

:Not

ava

ilabl

eSk

in p

erm

eabi

lity:

Mod

erat

eE

vapo

ratio

n ra

te:N

ot a

vaila

ble

Log

Kow

:-0.

22

Sp

Loc

C

ell

L

(µm

) A

(c

m²)

V

(ml)

Veh

icle

C

(m

g/m

l) n

TE

xp

(h)

TO

bs

(h)

TL

ag

(h)

Abs

(%

) K

P

(10-4

cm

/h)

Flux

(µ

g/cm

²/h) R

efer

ence

GP

Ba

FlFu

ll3.

1H

2O

1-48

(0.

005-

0.24

M)

3048

4817

-20

2-81

Wah

lber

g (1

965)

Hum

Ab

FlFu

ll3.

1H

2O

1 (0

.005

M)

1048

488

0.8

Wah

lber

g (1

965)

Hum

Ab

FlFu

ll3.

1H

2O

16 (

0.08

0M)

1048

484.

57.

2W

ahlb

erg

(196

5)H

umB

rFl

Full

3.1

H2O

16

(0.

080M

)10

4848

9.4

15W

ahlb

erg

(196

5)H

umA

bFl

Full

3.1

H2O

48

(0.

24M

)10

4848

6.3

30W

ahlb

erg

(196

5)H

umSt

250

11.

5H

2O50

(5%

)10

17.5

17.5

92 µ

g1.

15.

3Pi

lgra

m e

t al.

(200

0)H

umA

bFl

300-

600

0.95

40 m

gSo

il0.

0088

nm

ol/c

m³

572

7214

00.

0000

32Sa

rtore

lli e

t al.

(200

3)H

umA

bFl

300-

600

0.95

40 m

gSo

il0.

061

nmol

/cm

³4

7272

300.

0000

49Sa

rtore

lli e

t al.

(200

3)Pi

gA

bFl

200

0.64

0.00

5Et

0.03

2 (1

60 n

g)16

160.

13 (1

h)0.

140.

0004

6Sk

owro

nski

et a

l. (2

000)

Hum

Arm

220.

3H

2O

27 (

0.1M

)3

0.08

11.

0 m

g21

056

0B

aran

owsk

a-D

utki

ewic

z (1

982a

)H

umA

rm22

0.3

H2O

27

(0.

1M)

30.

171

1.5

mg

150

400

Bar

anow

ska-

Dut

kiew

icz

(198

2a)

Hum

Arm

220.

3H

2O

27 (

0.1M

)3

0.25

11.

9 m

g13

034

0B

aran

owsk

a-D

utki

ewic

z (1

982a

)H

umA

rm22

0.3

H2O

27

(0.

1M)

40.

51

3.0

mg

100

280

Bar

anow

ska-

Dut

kiew

icz

(198

2a)

Hum

Arm

220.

3H

2O

27 (

0.1M

)3

11

3.2

mg

5615

0B

aran

owsk

a-D

utki

ewic

z (1

982a

)

The

stud

ies f

ound

on

mer

cury

bic

hlor

ide

expo

sing

hum

an sk

in to

aqu

eous

solu

tions

are

not

con

sist

ent.

The

rang

e fo

r the

cal

cula

ted

Kp

valu

es is

1·1

0-4 to

1·1

0-2 c

m/h

, i.e

. tw

o or

ders

of m

agni

tude

.Th

e pr

efer

red

stud

y is

that

of W

ahlb

erg

(196

5) w

ith c

alcu

late

d K

p va

lues

rang

ing

betw

een

5·10

-4 a

nd 9

·10-4

cm

/h, s

ugge

stin

g "m

oder

ate"

per

mea

bilit

y.Th

e in

viv

o st

udy

by B

aran

owsk

a-D

utki

ewic

z (1

982a

) sho

w th

at th

e pe

netra

tion

into

skin

is

appr

oxim

atel

y 20

tim

es h

ighe

r. Th

is su

gges

ts th

at a

dep

ot o

f dic

hlor

omer

cury

is c

reat

ed in

the

skin

that

m

ay la

ter b

ecom

e sy

stem

ical

ly a

vaila

ble.

Rep

orte

d da

ta

In v

itro

In v

ivo

Ase

ssm

ent

A11

5

App

endi

x A

Subs

tanc

e: M

ercu

ry c

hlor

ide;

dim

ercu

ry d

ichl

orid

eM

olec

ular

wei

ght:

472.

1C

AS:

101

12-9

1-1

Den

sity

:7.1

5 g/

cm³

Scie

ntifi

c ba

sis:

AoH

198

4:44

Mel

ting

poin

t:40

0 to

500

°CB

oilin

g po

int:

Not

ava

ilabl

eSk

in n

otat

ion:

Yes

Vap

our

pres

sure

:Not

ava

ilabl

eSk

in p

erm

eabi

lity:

Ver

y hi

ghE

vapo

ratio

n ra

te:N

ot a

vaila

ble

Log

Kow

:-0.

55 (e

stim

ated

)

Sp

Loc

C

ell

L

(µm

) A

(c

m²)

V

(ml)

Veh

icle

C

(m

g/m

l) n

TE

xp

(h)

TO

bs

(h)

TL

ag

(h)

Abs

(%

) K

P

(10-4

cm

/h)

Flux

(µ

g/cm

²/h) R

efer

ence

Hum

Ab

StFu

ll0.

64C

ream

290

µg/l

1024

2427

00.

0078

Palm

er e

t al.

(200

0)H

umA

bSt

Full

0.64

H2O

290

µg/l

1024

2415

00.

0044

Palm

er e

t al.

(200

0)

N

o da

ta a

vaila

ble

The

only

stud

y fo

und

on m

ercu

ry c

hlor

ide

was

that

of P

alm

er e

t al.

(200

0).

The

pref

erre

d ex

perim

ent i

s the

one

usi

ng w

ater

as v

ehic

le. T

he re

porte

d K

p va

lue

of 2

·10-2

cm

/hsu

gges

ts a

"ve

ry h

igh"

per

mea

bilit

y.

Rep

orte

d da

ta

In v

itro

In v

ivo

Ase

ssm

ent

A11

6

App

endi

x A

Subs

tanc

e: M

ercu

ry, d

imet

hyl

Mol

ecul

ar w

eigh

t:23

0.7

CA

S: 5

93-7

4-8

Den

sity

:2.9

6 g/

cm³

Scie

ntifi

c ba

sis:

AoH

198

4:44

Mel

ting

poin

t:-4

3°C

Boi

ling

poin

t:93

to 9

4°C

Skin

not

atio

n: Y

esV

apou

r pr

essu

re:6

.7-1

0.9

kPa

(at 2

0°C

)Sk

in p

erm

eabi

lity:

No

data

Eva

pora

tion

rate

:Not

ava

ilabl

eL

og K

ow:2

.59

Sp

Loc

C

ell

L

(µm

) A

(c

m²)

V

(ml)

Veh

icle

C

(m

g/m

l) n

TE

xp

(h)

TO

bs

(h)

TL

ag

(h)

Abs

(%

) K

P

(10-4

cm

/h)

Flux

(µ

g/cm

²/h) R

efer

ence

N

o da

ta a

vaila

ble

N

o da

ta a

vaila

ble

The

Swed

ish

skin

not

atio

n ap

plie

s to

orga

nic

mer

cury

com

poun

ds in

gen

eral

(inc

ludi

ng d

imet

hyl m

ercu

ry).

No

quan

titat

ive

expe

rimen

tal d

ata

on d

erm

al u

ptak

e w

ere

foun

d in

the

liter

atur

e.

A c

ase

repo

rt (N

iere

nber

g et

al.

(199

8)) d

escr

ibes

the

deat

h of

a c

hem

ist 1

0 m

onth

s afte

r spi

lling

dim

ethy

l mer

cury

on th

e do

rsum

of h

er g

love

d ha

nd. T

he e

stim

ated

dos

e w

as 1

344

mg

corr

espo

ndin

g to

0.4

4 m

l nea

t dim

ethy

l mer

cury

.A

lthou

gh a

dditi

onal

exp

osur

e(s)

can

not b

e ex

clud

ed, t

his c

ase

stro

ngly

supp

orts

hig

h po

tent

ial f

or d

erm

al to

xici

ty.

Rep

orte

d da

ta

In v

itro

In v

ivo

Ase

ssm

ent

A11

7

App

endi

x A

Subs

tanc

e: M

ercu

ry, m

etal

Mol

ecul

ar w

eigh

t:20

0.6

CA

S: 7

439-

97-6

Den

sity

:13.

53 g

/cm

³Sc

ient

ific

basi

s: A

oH 1

984:

44M

eltin

g po

int:

-38.

9°C

Boi

ling

poin

t:35

6.5°

CSk

in n

otat

ion:

Yes

Vap

our

pres

sure

:0.1

6 Pa

(at 2

0°C

)Sk

in p

erm

eabi

lity:

Ext

rem

ely

high

Eva

pora

tion

rate

:4L

og K

ow:0

.62

Sp

Loc

C

ell

L

(µm

) A

(c

m²)

V

(ml)

Veh

icle

C

(m

g/m

l) n

TE

xp

(h)

TO

bs

(h)

TL

ag

(h)

Abs

(%

) K

P

(10-4

cm

/h)

Flux

(µ

g/cm

²/h) R

efer

ence

N

o da

ta a

vaila

ble

Hum

Arm

360-

430

Inf

Vap

0.88

-2.1

ng/

ml

50.

45-0

.72

60 d

220-

850

ng61

00-2

4000

0.00

1-0.

005

Hur

sh e

t al.

(198

9)

The

only

foun

d st

udy

on m

etal

mer

cury

was

that

of H

ursh

et a

l. (1

989)

wer

e a

hum

an a

rm w

as e

xpos

edto

mer

cury

vap

our.

The

repo

rted

rang

e of

Kp

valu

es su

gges

ts a

n "e

xtre

mel

y hi

gh"

perm

eabi

lity.

It sh

ould

be

note

d th

at st

udie

s on

vapo

ur e

xpos

ure

tend

to o

vere

stim

ate

the

Kp

valu

e.

Rep

orte

d da

ta

In v

itro

In v

ivo

Ase

ssm

ent

A11

8

App

endi

x A

Subs

tanc

e: M

etha

nol

Mol

ecul

ar w

eigh

t:32

.0C

AS:

67-

56-1

Den

sity

:0.7

91 g

/cm

³Sc

ient

ific

basi

s: A

oH 1

985:

32M

eltin

g po

int:

-98°

CB

oilin

g po

int:

64.6

°CSk

in n

otat

ion:

Yes

Vap

our

pres

sure

:13

kPa

(at 2

0°C

)Sk

in p

erm

eabi

lity:

Ver

y hi

ghE

vapo

ratio

n ra

te:4

.6L

og K

ow:-

0.77

Sp

Loc

C

ell

L

(µm

) A

(c

m²)

V

(ml)

Veh

icle

C

(m

g/m

l) n

TE

xp

(h)

TO

bs

(h)

TL

ag

(h)

Abs

(%

) K

P

(10-4

cm

/h)

Flux

(µ

g/cm

²/h) R

efer

ence

GP

Ba

FlFu

ll5

0.1

Nea

t9

1919

444.

736

8G

umm

er &

Mai

bach

(198

6)H

umA

bSt

272.

5H

2O

7.4

105

1.6

Sche

uple

in &

Bla

nk (1

973)

Hum

Ab

St25

002.

5H

2O

7.4

353

017

0Sc

heup

lein

& B

lank

(197

3)H

umA

bSt

272.

5N

eat

710

083

00Sc

heup

lein

& B

lank

(197

3)H

umA

bSt

2500

2.5

Nea

t2

230

1800

0Sc

heup

lein

& B

lank

(197

3)H

umA

bSt

Epi

10H

2O10

86

60.

3716

1300

Sout

hwel

l et a

l. (1

984)

Hum

Ab

St40

10H

2O3.

2 (0

.1M

)2

5-7

5-7

12-2

13.

8-6.

3So

uthw

ell e

t al.

(198

3)M

ouA

b/B

aSt

Full

0.6

1.4

NaC

l0.

0032

(0.

0001

M)

40.

30.

318

0.00

59B

ehl e

t al.

(198

0)M

ouA

b/B

aSt

Full

0.6

1.4

NaC

l0.

0032

(0.

0001

M)

45.

85.

816

0.00

51B

ehl e

t al.

(198

0)M

ouA

b/B

aSt

Full

0.6

1.4

NaC

l0.

0032

(0.

0001

M)

49.

89.

817

0.00

54B

ehl e

t al.

(198

0)M

ouA

b/B

aSt

Full

0.6

1.4

NaC

l0.

0032

(0.

0001

M)

413

.813

.819

0.00

61B

ehl e

t al.

(198

0)M

ouA

b/B

aSt

Full

0.6

1.4

NaC

l0.

0032

(0.

0001

M)

417

.817

.818

0.00

59B

ehl e

t al.

(198

0)M

ouA

b/B

aSt

Full

0.6

1.4

NaC

l0.

0032

(0.

0001

M)

426

.326

.318

0.00

59B

ehl e

t al.

(198

0)M

ouA

b/B

aSt

Full

0.6

1.4

NaC

l0.

0032

(0.

0001

M)

40.

30.

329

0.00

93B

ehl e

t al.

(198

0)M

ouA

b/B

aSt

Full

0.6

1.4

NaC

l0.

0032

(0.

0001

M)

44.

34.

326

0.00

83B

ehl e

t al.

(198

0)M

ouA

b/B

aSt

Full

0.6

1.4

NaC

l0.

0032

(0.

0001

M)

47.

87.

823

0.00

74B

ehl e

t al.

(198

0)M

ouA

b/B

aSt

Full

0.6

1.4

NaC

l0.

0032

(0.

0001

M)

411

.311

.328

0.00

9B

ehl e

t al.

(198

0)M

ouA

b/B

aSt

Full

0.6

1.4

NaC

l0.

0032

(0.

0001

M)

414

.314

.325

0.00

8B

ehl e

t al.

(198

0)M

ouA

b/B

aSt

Full

0.6

1.4

NaC

l0.

0032

(0.

0001

M)

126

.326

.324

0.00

77B

ehl e

t al.

(198

0)M

ouA

b/B

aSt

Full

0.6

1.4

NaC

l0.

0032

(0.

0001

M)

40.

30.

317

0.00

54B

ehl e

t al.

(198

0)M

ouA

b/B

aSt

Full

0.6

1.4

NaC

l0.

0032

(0.

0001

M)

45.

85.

816

0.00

51B

ehl e

t al.

(198

0)M

ouA

b/B

aSt

Full

0.6

1.4

NaC

l0.

0032

(0.

0001

M)

49.

89.

815

0.00

48B

ehl e

t al.

(198

0)M

ouA

b/B

aSt

Full

0.6

1.4

NaC

l0.

0032

(0.

0001

M)

413

.813

.815

0.00

48B

ehl e

t al.

(198

0)M

ouA

b/B

aSt

Full

0.6

1.4

NaC

l0.

0032

(0.

0001

M)

417

.817

.814

0.00

45B

ehl e

t al.

(198

0)

Rep

orte

d da

ta

In v

itro

A11

9

App

endi

x A

Sp

Loc

C

ell

L

(µm

) A

(c

m²)

V

(ml)

Veh

icle

C

(m

g/m

l) n

TE

xp

(h)

TO

bs

(h)

TL

ag

(h)

Abs

(%

) K

P

(10-4

cm

/h)

Flux

(µ

g/cm

²/h) R

efer

ence

Mou

Ab/

Ba

StFu

ll0.

61.

4N

aCl

0.00

32 (

0.00

01M

)4

26.3

26.3

150.

0048

Beh

l et a

l. (1

980)

Mou

Ab/

Ba

StFu

ll0.

61.

4N

aCl

0.00

32 (

0.00

01M

)8

0.5

0.5

210.

0067

Beh

l et a

l. (1

980)

Mou

Ab/

Ba

StFu

ll0.

61.

4N

aCl

0.00

32 (

0.00

01M

)8

55

180.

0059

Beh

l et a

l. (1

980)

Mou

Ab/

Ba

StFu

ll0.

61.

4N

aCl

0.00

32 (

0.00

01M

)8

1010

190.

0061

Beh

l et a

l. (1

980)

Mou

Ab/

Ba

StFu

ll0.

61.

4N

aCl

0.00

32 (

0.00

01M

)8

1515

190.

0061

Beh

l et a

l. (1

980)

Mou

Ab/

Ba

StFu

ll0.

61.

4N

aCl

0.00

32 (

0.00

01M

)8

2020

190.

0061

Beh

l et a

l. (1

980)

Mou

Ab/

Ba

StFu

ll0.

61.

4N

aCl

0.00

32 (

0.00

01M

)8

2828

200.

0064

Beh

l et a

l. (1

980)

Mou

Ab/

Ba

StFu

ll0.

61.

4N

aCl

0.00

32 (

0.00

01M

)4

0.5

0.5

610.

02B

ehl e

t al.

(198

0)M

ouA

b/B

aSt

Full

0.6

1.4

NaC

l0.

0032

(0.

0001

M)

45

557

0.01

8B

ehl e

t al.

(198

0)M

ouA

b/B

aSt

Full

0.6

1.4

NaC

l0.

0032

(0.

0001

M)

410

1052

0.01

7B

ehl e

t al.

(198

0)M

ouA

b/B

aSt

Full

0.6

1.4

NaC

l0.

0032

(0.

0001

M)

415

1560

0.01

9B

ehl e

t al.

(198

0)M

ouA

b/B

aSt

Full

0.6

1.4

NaC

l0.

0032

(0.

0001

M)

420

2063

0.02

Beh

l et a

l. (1

980)

Mou

Ab/

Ba

StFu

ll0.

61.

4N

aCl

0.00

32 (

0.00

01M

)4

2525

620.

02B

ehl e

t al.

(198

0)M

ouA

b/B

aSt

Full

0.6

1.4

NaC

l0.

0032

(0.

0001

M)

430

3058

0.01

9B

ehl e

t al.

(198

0)M

ouA

b/B

aSt

Full

0.6

1.4

NaC

l0.

0032

(0.

0001

M)

80.

80.

823

0.00

74B

ehl e

t al.

(198

0)M

ouA

b/B

aSt

Full

0.6

1.4

NaC

l0.

0032

(0.

0001

M)

86.

26.

222

0.00

7B

ehl e

t al.

(198

0)M

ouA

b/B

aSt

Full

0.6

1.4

NaC

l0.

0032

(0.

0001

M)

810

1022

0.00

7B

ehl e

t al.

(198

0)M

ouA

b/B

aSt

Full

0.6

1.4

NaC

l0.

0032

(0.

0001

M)

815

1523

0.00

74B

ehl e

t al.

(198

0)M

ouA

b/B

aSt

Full

0.6

1.4

NaC

l0.

0032

(0.

0001

M)

822

2225

0.00

8B

ehl e

t al.

(198

0)M

ouA

b/B

aSt

Full

0.6

1.4

NaC

l0.

0032

(0.

0001

M)

827

2726

0.00

83B

ehl e

t al.

(198

0)M

ouA

bSt

Full

0.6

0.2

NaC

l3

22

10B

ehl e

t al.

(198

4)M

ouA

bSt

Full

0.6

0.2

NaC

l2

22

12B

ehl e

t al.

(198

4)M

ouA

bSt

Full

0.6

0.2

NaC

l4

22

26B

ehl e

t al.

(198

4)M

ouA

bSt

Full

0.6

0.2

NaC

l5

22

34B

ehl e

t al.

(198

4)M

ouA

bSt

Full

0.6

0.2

NaC

l5

22

13B

ehl e

t al.

(198

4)M

ouA

bSt

Full

0.6

0.2

NaC

l5

22

8B

ehl e

t al.

(198

4)M

ouB

aSt

Full

0.6

0.2

NaC

l4

22

27B

ehl e

t al.

(198

4)M

ouB

aSt

Full

0.6

0.2

NaC

l2

22

35B

ehl e

t al.

(198

4)M

ouB

aSt

Full

0.6

0.2

NaC

l4

22

43B

ehl e

t al.

(198

4)M

ouB

aSt

Full

0.6

0.2

NaC

l5

22

68B

ehl e

t al.

(198

4)M

ouB

aSt

Full

0.6

0.2

NaC

l5

22

11B

ehl e

t al.

(198

4)M

ouB

aSt

Full

0.6

0.2

NaC

l5

22

10B

ehl e

t al.

(198

4)M

ouA

bSt

Full

0.6

NaC

l0.

0032

(0.

0001

M)

52

254

Beh

l & B

arre

tt (1

981)

A12

0

App

endi

x A

Sp

Loc

C

ell

L

(µm

) A

(c

m²)

V

(ml)

Veh

icle

C

(m

g/m

l) n

TE

xp

(h)

TO

bs

(h)

TL

ag

(h)

Abs

(%

) K

P

(10-4

cm

/h)

Flux

(µ

g/cm

²/h) R

efer

ence

Mou

Ba

StFu

ll0.

6Ph

/NaC

l4.

0 (0

.5%

)6

2.5

2.5

2610

Beh

l et a

l. (1

983)

Mou

Ba

StFu

ll0.

6Ph

/NaC

l7.

9 (1

.0%

)6

2.5

2.5

3931

Beh

l et a

l. (1

983)

Mou

Ba

StFu

ll0.

6Ph

/NaC

l16

(2.

0%)

62.

52.

569

110

Beh

l et a

l. (1

983)

Mou

Ba

StFu

ll0.

6Ph

/NaC

l32

(4.

0%)

62.

52.

585

027

00B

ehl e

t al.

(198

3)M

ouB

aSt

Full

0.6

Ph/N

aCl

47 (

6.0%

)6

2.5

2.5

1700

8000

Beh

l et a

l. (1

983)

Mou

Ab

StFu

ll0.

79N

aCl

≤10-

4M2

24.

1D

urrh

eim

et a

l. (1

980)

Mou

Ab

StFu

ll0.

79N

aCl

≤10-

4M2

29.

3D

urrh

eim

et a

l. (1

980)

Mou

Ab

StFu

ll0.

79N

aCl

≤10-

4M2

226

Dur

rhei

m e

t al.

(198

0)

Hum

Ha

480

Inf

Nea

t65

0.03

-0.2

77

0.5

1200

mg

100

8100

Bat

term

an e

t al.

(199

7)H

umA

rm11

0.2

Nea

t3

0.25

822

-27

mg

110

8800

Dut

kiew

icz

et a

l. (1

980)

Hum

Arm

110.

2N

eat

30.

338

38-4

1 m

g14

011

000

Dut

kiew

icz

et a

l. (1

980)

Hum

Arm

110.

2N

eat

60.

58

65-8

1 m

g18

014

000

Dut

kiew

icz

et a

l. (1

980)

Hum

Arm

110.

2N

eat

30.

588

81-9

2 m

g16

013

000

Dut

kiew

icz

et a

l. (1

980)

Hum

Arm

110.

2N

eat

30.

758

92-1

10 m

g15

012

000

Dut

kiew

icz

et a

l. (1

980)

Hum

Arm

110.

2N

eat

41

812

0-13

0 m

g14

011

000

Dut

kiew

icz

et a

l. (1

980)

The

data

on

met

hano

l are

abu

ndan

t.

The

stud

y by

Sch

eupl

ein

& B

lank

(197

3) is

dis

rega

rded

sinc

e he

at-s

epar

ated

(60°

C) e

pide

rmis

was

use

d.

The

stud

y by

Beh

l et a

l. (1

983)

is a

lso

disr

egar

ded

as p

heno

l was

use

d as

a v

ehic

le.

The

rem

aini

ng st

udie

s sho

w a

con

sist

ent p

atte

rn w

ith K

p va

lues

rang

ing

betw

een

1·10

-3 a

nd 7

·10-3

cm

/h fo

r mou

se a

nd

hum

an sk

in a

nd a

queo

us so

lutio

ns o

f met

hano

l.

The

pref

erre

d st

udie

s are

thos

e of

Bat

term

an e

t al.

(199

7) a

nd D

utki

ewic

z et

al.

(198

0), s

ince

they

use

d hu

man

skin

in v

ivo

expo

sed

to n

eat m

etha

nol r

epor

ting

high

er K

p va

lues

of 1

·10-2

to 2

·10-2

cm

/h, s

ugge

stin

g "v

ery

high

" pe

rmea

bilit

y.

In v

ivo

Ase

ssm

ent

A12

1

App

endi

x A

Subs

tanc

e: M

ethy

l acr

ylat

eM

olec

ular

wei

ght:

86.1

CA

S: 9

6-33

-3D

ensi

ty:0

.956

g/c

m³

Scie

ntifi

c ba

sis:

Not

ava

ilabl

e M

eltin

g po

int:

-76.

5°C

Boi

ling

poin

t:80

.5°C

Skin

not

atio

n: Y

esV

apou

r pr

essu

re:9

.1 k

Pa (a

t 20°

C)

Skin

per

mea

bilit

y: N

o da

taE

vapo

ratio

n ra

te:N

ot a

vaila

ble

Log

Kow

:0.8

0

Sp

Loc

C

ell

L

(µm

) A

(c

m²)

V

(ml)

Veh

icle

C

(m

g/m

l) n

TE

xp

(h)

TO

bs

(h)

TL

ag

(h)

Abs

(%

) K

P

(10-4

cm

/h)

Flux

(µ

g/cm

²/h) R

efer

ence

N

o da

ta a

vaila

ble

N

o da

ta a

vaila

ble

No

quan

titat

ive

expe

rimen

tal d

ata

on d

erm

al u

ptak

e w

ere

foun

d in

the

liter

atur

e.

No

docu

men

t fro

m th

e Sw

edis

h C

riter

ia G

roup

was

foun

d on

met

hyl a

cryl

ate.

The

derm

al L

D50

val

ues f

or ra

ts a

nd ra

bbits

are

4-6

tim

es h

ighe

r tha

n th

e co

rres

pond

ing

oral

LD

50 v

alue

s, th

is fo

rms t

he b

asis

for a

skin

not

atio

n by

AC

GIH

(200

1).

Rep

orte

d da

ta

In v

itro

In v

ivo

Ase

ssm

ent

A12

2

App

endi

x A

Subs

tanc

e: M

ethy

l bro

mid

eM

olec

ular

wei

ght:

94.9

CA

S: 7

4-83

-9D

ensi

ty:1

.732

g/c

m³

Scie

ntifi

c ba

sis:

AoH

198

8:32

Mel

ting

poin

t:-9

3.7°

CB

oilin

g po

int:

3.6°

CSk

in n

otat

ion:

Yes

Vap

our

pres

sure

:200

kPa

(at 2

3.3°

C)

Skin

per

mea

bilit

y: N

o da

taE

vapo

ratio

n ra

te:N

ot a

vaila

ble

Log

Kow

:1.1

9

Sp

Loc

C

ell

L

(µm

) A

(c

m²)

V

(ml)

Veh

icle

C

(m

g/m

l) n

TE

xp

(h)

TO

bs

(h)

TL

ag

(h)

Abs

(%

) K

P

(10-4

cm

/h)

Flux

(µ

g/cm

²/h) R

efer

ence

N

o da

ta a

vaila

ble

N

o da

ta a

vaila

ble

No

quan

titat

ive

expe

rimen

tal d

ata

on d

erm

al u

ptak

e w

ere

foun

d in

the

liter

atur

e.

Toxi

c am

ount

s can

be

abso

rbed

by

the

skin

, bot

h w

ith d

irect

con

tact

and

with

exp

osur

e to

hig

h ai

r con

cent

ratio

ns (J

ordi

(195

3)).

A c

ase

repo

rt (L

ongl

ey e

t al.

(196

5)) i

s als

o si

ted

in A

CG

IH (2

001)

.

Rep

orte

d da

ta

In v

itro

In v

ivo

Ase

ssm

ent

A12

3

App

endi

x A

Subs

tanc

e: M

ethy

l eth

yl k

eton

e (M

EK);

2-bu

tano

neM

olec

ular

wei

ght:

72.1

CA

S: 7

8-93

-3D

ensi

ty:0

.805

g/c

m³

Scie

ntifi

c ba

sis:

AoH

198

5:32

Mel

ting

poin

t:-8

6.3°

CB

oilin

g po

int:

79.6

°CSk

in n

otat

ion:

No

Vap

our

pres

sure

:11

kPa

(at 2

0°C

)Sk

in p

erm

eabi

lity:

Low

Eva

pora

tion

rate

:5.7

Log

Kow

:0.2

9

Sp

Loc

C

ell

L

(µm

) A

(c

m²)

V

(ml)

Veh

icle

C

(m

g/m

l) n

TE

xp

(h)

TO

bs

(h)

TL

ag

(h)

Abs

(%

) K

P

(10-4

cm

/h)

Flux

(µ

g/cm

²/h) R

efer

ence

Hum

Br

St30

0-60

00.

64N

eat

36

666

5800

Urs

in e

t al.

(199

5)H

umB

rFl

280

0.64

0.2

Nea

t5

2424

0.33

0.13

0.41

33W

ilkin

son

& W

illia

ms (

2001

)H

umB

rFl

280

0.64

0.2

H2O

3

524

240.

350.

7728

8.4

Wilk

inso

n &

Will

iam

s (20

01)

N

o da

ta a

vaila

ble

Urs

in e

t al.

(199

5) st

retc

hed

the

skin

whe

n m

ount

ing

it in

the

diff

usio

n ce

ll, re

achi

ng a

fina

l thi

ckne

ss o

f abo

ut o

ne-th

ird o

f the

orig

inal

thic

knes

s. Th

is p

roce

dure

may

giv

e ov

eres

timat

es o

f the

flux

and

Kp

valu

es.

The

pref

erre

d ex

perim

ent i

s the

one

usi

ng n

eat M

EK (W

ilkin

son

& W

illia

ms (

2001

), da

ta o

nly

pres

ente

d at

a c

onfe

renc

e), w

ith a

repo

rted

Kp

valu

e 4·

10-5

cm

/h, s

ugge

stin

g "l

ow"

perm

eabi

lity.

Rep

orte

d da

ta

In v

itro

In v

ivo

Ase

ssm

ent

A12

4

App

endi

x A

Subs

tanc

e: M

ethy

l iod

ide

Mol

ecul

ar w

eigh

t:14

1.9

CA

S: 7

4-88

-4D

ensi

ty:2

.279

g/c

m³

Scie

ntifi

c ba

sis:

AoH

198

1:21

Mel

ting

poin

t:-6

6.5°

CB

oilin

g po

int:

42.4

°CSk

in n

otat

ion:

Yes

Vap

our

pres

sure

:50

kPa

(at 2

0°C

)Sk

in p

erm

eabi

lity:

No

data

Eva

pora

tion

rate

:Not

ava

ilabl

eL

og K

ow:1

.51

Sp

Loc

C

ell

L

(µm

) A

(c

m²)

V

(ml)

Veh

icle

C

(m

g/m

l) n

TE

xp

(h)

TO

bs

(h)

TL

ag

(h)

Abs

(%

) K

P

(10-4

cm

/h)

Flux

(µ

g/cm

²/h) R

efer

ence

N

o da

ta a

vaila

ble

N

o da

ta a

vaila

ble

No

quan

titat

ive

expe

rimen

tal d

ata

on d

erm

al u

ptak

e w

ere

foun

d in

the

liter

atur

e.

The

Swed

ish

cons

ensu

s rep

ort (

AoH

198

1:21

) sta

tes t

hat m

ethy

l iod

ine

can

be a

bsor

bed

via

skin

, with

no

addi

tiona

l dat

a.

In A

CG

IH (2

001)

, no

dire

ct st

udie

s or c

ase

repo

rts o

n de

rmal

abs

orpt

ion

and

resu

ltant

syst

emic

toxi

city

are

giv

en.

The

skin

not

atio

n is

bas

ed o

n tw

o ca

se re

ports

of f

atal

and

acu

te, p

erm

anen

t CN

S da

mag

e fo

llow

ing

acci

dent

alex

posu

re to

met

hyl i

odin

e w

ith u

nkno

wn

air c

once

ntra

tions

(Gar

land

et a

l. (1

945)

, App

el e

t al.

(197

5)).

Acc

ordi

ng to

theo

retic

al c

alcu

latio

ns b

y Fi

sero

va-B

erge

rova

et a

l. (1

990)

the

pote

ntia

l for

der

mal

abso

rptio

n an

d re

sulti

ng to

xici

ty is

sign

ifica

nt.

Rep

orte

d da

ta

In v

itro

In v

ivo

Ase

ssm

ent

A12

5

App

endi

x A

Subs

tanc

e: M

ethy

l iso

buty

l ket

one

(MiB

K)

Mol

ecul

ar w

eigh

t:10

0.2

CA

S: 1

08-1

0-1

Den

sity

:0.7

98 g

/cm

³Sc

ient

ific

basi

s: N

ot a

vaila

ble

Mel

ting

poin

t:-8

0°C

Boi

ling

poin

t:11

7.4°

CSk

in n

otat

ion:

No

Vap

our

pres

sure

:0.6

3 kP

a (a

t 20°

C)

Skin

per

mea

bilit

y: H

igh

Eva

pora

tion

rate

:1.6

Log

Kow

:1.3

1

Sp

Loc

C

ell

L

(µm

) A

(c

m²)

V

(ml)

Veh

icle

C

(m

g/m

l) n

TE

xp

(h)

TO

bs

(h)

TL

ag

(h)

Abs

(%

) K

P

(10-4

cm

/h)

Flux

(µ

g/cm

²/h) R

efer

ence

N

o da

ta a

vaila

ble

GP

Ba

3.1

Nea

t8

2.5

2.5

8366

00H

jelm

et a

l. (1

991)

The

only

ava

ilabl

e st

udy

is th

at o

f Hje

lm e

t al.

(199

1) w

ere

guin

ea p

ig w

as e

xpos

ed in

viv

o to

nea

t MiB

K.

The

repo

rted

Kp

valu

e of

8·1

0-3 c

m/h

, cor

resp

onds

to "

high

" pe

rmea

bilit

y.

Rep

orte

d da

ta

In v

itro

In v

ivo

Ase

ssm

ent

A12

6

App

endi

x A

Subs

tanc

e: M

ethy

l met

acry

late

Mol

ecul

ar w

eigh

t:10

0.1

CA

S: 8

0-62

-6D

ensi

ty:0

.943

g/c

m³

Scie

ntifi

c ba

sis:

AoH

199

3:37

Mel

ting

poin

t:-4

8°C

Boi

ling

poin

t:10

0°C

Skin

not

atio

n: Y

esV

apou

r pr

essu

re:3

.6 k

Pa (a

t 20°

C)

Skin

per

mea

bilit

y: V

ery

high

Eva

pora

tion

rate

:3.1

Log

Kow

:1.3

8

Sp

Loc

C

ell

L

(µm

) A

(c

m²)

V

(ml)

Veh

icle

C

(m

g/m

l) n

TE

xp

(h)

TO

bs

(h)

TL

ag

(h)

Abs

(%

) K

P

(10-4

cm

/h)

Flux

(µ

g/cm

²/h) R

efer

ence

Hum

1A

bSt

Epi

2.54

2.5

Nea

t6

11

0.17

0.48

110

110

Bet

ts e

t al.

(200

6)

Hum

1A

bSt

Epi

2.54

2.5

Nea

t6

1010

0.17

0.56

3.7

3.5

Bet

ts e

t al.

(200

6)

Hum

2A

bSt

Epi

2.54

2.5

Nea

t6

11

0.17

2.4

290

270

Bet

ts e

t al.

(200

6)

Hum

2A

bSt

Epi

2.54

2.5

Nea

t6

1010

0.17

1516

015

0B

etts

et a

l. (2

006)

N

o da

ta a

vaila

ble

1 Non

occ

lude

d 2 O

cclu

ded

The

only

stud

y fo

und

on m

ethy

l met

acry

late

was

that

by

Bet

ts e

t al.

(200

6) w

here

hum

an sk

in w

as e

xpos

ed to

nea

t MM

A.

The

1h o

cclu

ded

expo

sure

is p

refe

rred

and

the

calc

ulat

ed K

p va

lue

of 3

·10-2

cm

/h c

orre

spon

ds to

"ve

ry h

igh"

per

mea

bilit

y.

Rep

orte

d da

ta

In v

itro

In v

ivo

Ase

ssm

ent

A12

7

App

endi

x A

Subs

tanc

e: M

ethy

l mor

phol

ine,

N-

Mol

ecul

ar w

eigh

t:10

1.1

CA

S: 1

09-0

2-4

Den

sity

:0.9

2 g/

cm³

Scie

ntifi

c ba

sis:

Not

ava

ilabl

e M

eltin

g po

int:

-66°

CB

oilin

g po

int:

115°

CSk

in n

otat

ion:

Yes

Vap

our

pres

sure

:2.3

kPa

(at 2

0°C

)Sk

in p

erm

eabi

lity:

No

data

Eva

pora

tion

rate

:1.8

Log

Kow

:-0.

33

Sp

Loc

C

ell

L

(µm

) A

(c

m²)

V

(ml)

Veh

icle

C

(m

g/m

l) n

TE

xp

(h)

TO

bs

(h)

TL

ag

(h)

Abs

(%

) K

P

(10-4

cm

/h)

Flux

(µ

g/cm

²/h) R

efer

ence

N

o da

ta a

vaila

ble

N

o da

ta a

vaila

ble

No

quan

titat

ive

expe

rimen

tal d

ata

on d

erm

al u

ptak

e w

ere

foun

d in

the

liter

atur

e.

No

Swed

ish

cons

ensu

s or A

CG

IH re

port

was

foun

d on

n-m

ethy

l mor

phol

in.

The

Swed

ish

skin

not

atio

n is

like

ly b

ased

on

anal

ogy

with

the

clos

ely

rela

ted

subs

tanc

e m

orph

olin

e.

Rep

orte

d da

ta

In v

itro

In v

ivo

Ase

ssm

ent

A12

8

App

endi

x A

Subs

tanc

e: M

ethy

l ter

t-but

yl e

ther

(MTB

E)M

olec

ular

wei

ght:

88.1

CA

S: 1

634-

04-4

Den

sity

:0.7

41 g

/cm

³Sc

ient

ific

basi

s: A

oH 1

999:

25M

eltin

g po

int:

-109

°CB

oilin

g po

int:

55.2

°CSk

in n

otat

ion:

No

Vap

our

pres

sure

:33

kPa

(at 2

5°C

)Sk

in p

erm

eabi

lity:

Ver

y hi

ghE

vapo

ratio

n ra

te:8

.1L

og K

ow:0

.94

Sp

Loc

C

ell

L

(µm

) A

(c

m²)

V

(ml)

Veh

icle

C

(m

g/m

l) n

TE

xp

(h)

TO

bs

(h)

TL

ag

(h)

Abs

(%

) K

P

(10-4

cm

/h)

Flux

(µ

g/cm

²/h) R

efer

ence

N

o da

ta a

vaila

ble

Hum

Ha

Inf

H2O

0.05

114

124

280

1400

Prah

et a

l. (2

004)

Rat

Ba

2-5

10 m

l/kgB

WN

aCl

4(4

0 m

g/kb

BW

)12

06

4516

110-

280

43-1

10M

iller

et a

l. (1

997)

Rat

Ba

2-5

10 m

l/kgB

WN

aCl

40(4

00 m

g/kb

BW

)12

06

4534

230-

580

910-

2300

Mill

er e

t al.

(199

7)

The

expo

sed

skin

are

a w

as n

ot g

iven

by

Mill

er e

t al.

(199

7). T

he v

alue

s in

the

tabl

e w

ere

ther

efor

e ca

lcul

ated

usi

ng a

n ar

ea

of 2

-5 c

m² a

nd a

ssum

ing

a bo

dyw

eigh

t of 2

00 g

. The

Kp

valu

es th

us o

btai

ned

agre

e w

ell w

ith th

at re

porte

d fo

r hum

an sk

in.

The

pref

erre

d st

udy

is th

at o

f Pra

h et

al.

(200

4) w

ere

hum

an sk

in in

viv

o w

as u

sed,

and

the

repo

rted

Kp

valu

e of

3·1

0-2 c

m/h

cor

resp

onds

to "

very

hig

h" p

erm

eabi

lity.

It sh

ould

be

note

d th

at th

e ex

perim

ent u

sed

MTB

E di

lute

d in

wat

er. T

his p

roce

dure

tend

s to

give

muc

h hi

gher

Kp

valu

e sth

an th

at o

btai

ned

usin

g ne

at su

bsta

nce.

Rep

orte

d da

ta

In v

itro

In v

ivo

Ase

ssm

ent

A12

9

App

endi

x A

Subs

tanc

e: M

ethy

l-2-p

enta

nol,

4-M

olec

ular

wei

ght:

102.

2C

AS:

108

-11-

2D

ensi

ty:0

.807

g/c

m³

Scie

ntifi

c ba

sis:

AoH

199

3:37

Mel

ting

poin

t:-9

0°C

Boi

ling

poin

t:13

2°C

Skin

not

atio

n: Y

esV

apou

r pr

essu

re:0

.54

kPa

(at 2

0°C

)Sk

in p

erm

eabi

lity:

No

data

Eva

pora

tion

rate

:0.3

Log

Kow

:1.6

8 (e

stim

ated

)

Sp

Loc

C

ell

L

(µm

) A

(c

m²)

V

(ml)

Veh

icle

C

(m

g/m

l) n

TE

xp

(h)

TO

bs

(h)

TL

ag

(h)

Abs

(%

) K

P

(10-4

cm

/h)

Flux

(µ

g/cm

²/h) R

efer

ence

N

o da

ta a

vaila

ble

N

o da

ta a

vaila

ble

No

quan

titat

ive

expe

rimen

tal d

ata

on d

erm

al u

ptak

e w

ere

foun

d in

the

liter

atur

e.

No

data

was

foun

d in

the

Swed

ish

cons

ensu

s rep

ort (

AoH

199

3:37

).

The

AC

GIH

(200

1) re

port

stat

es th

at th

e sk

in n

otat

ion

is b

ased

on

data

from

Sm

yth

et a

l. (1

951)

,su

gges

ting

sim

ilar d

erm

al (3

.6 g

/kg

bw in

rabb

its) a

nd o

ral (

2.6

g/kg

bw

in ra

ts) L

D50

val

ues.

Rep

orte

d da

ta

In v

itro

In v

ivo

Ase

ssm

ent

A13

0

App

endi

x A

Subs

tanc

e: M

ethy

l-2-p

yrro

lidon

e, n

- (N

MP)

Mol

ecul

ar w

eigh

t:99

.1C

AS:

872

-50-

4D

ensi

ty:1

.033

g/c

m³

Scie

ntifi

c ba

sis:

AoH

198

7:39

Mel

ting

poin

t:-2

4°C

Boi

ling

poin

t:20

2°C

Skin

not

atio

n: N

oV

apou

r pr

essu

re:6

6 Pa

(at 2

5°C

)Sk

in p

erm

eabi

lity:

Ver

y hi

ghE

vapo

ratio

n ra

te:0

.06

Log

Kow

:-0.

38

Sp

Loc

C

ell

L

(µm

) A

(c

m²)

V

(ml)

Veh

icle

C

(m

g/m

l) n

TE

xp

(h)

TO

bs

(h)

TL

ag

(h)

Abs

(%

) K

P

(10-4

cm

/h)

Flux

(µ

g/cm

²/h) R

efer

ence

Hum

200-

400

0.64

Inf

Nea

t4-

6.5

4-6.

598

1000

0D

ick

et a

l. (2

001)

Hum

200-

400

0.64

Inf

H2O

30

%2-

82-

84.

111

0D

ick

et a

l. (2

001)

Hum

200-

400

0.64

0.00

6N

eat

33

1617

00D

ick

et a

l. (2

001)

Hum

200-

400

0.64

0.00

6H

2O

30%

33

1958

0D

ick

et a

l. (2

001)

Hum

Br

St30

0-60

00.

64N

eat

66

616

019

200

Urs

in e

t al.

(199

5)R

at20

0-40

00.

640.

006

Nea

t3

330

3100

Dic

k et

al.

(200

1)R

at20

0-40

00.

640.

006

H2O

30

%3

330

910

Dic

k et

al.

(200

1)R

atB

aSt

Full

1.8

0.04

5/0.

72N

eat

2624

2451

-54

5300

-560

0Pa

yan

et a

l. (2

003)

Rat

FkSt

Full

1.8

0.04

5/0.

72N

eat

2624

2458

-65

6000

-670

0Pa

yan

et a

l. (2

003)

Rat

Ba/

FkSt

Full

1.8

0.04

5N

eat

624

2491

2021

00Pa

yan

et a

l. (2

003)

Rat

Ba/

FkSt

Full

1.8

0.09

Nea

t6

2424

8933

3400

Paya

n et

al.

(200

3)R

atB

a/Fk

StFu

ll1.

80.

18N

eat

424

2451

5300

Paya

n et

al.

(200

3)R

atB

a/Fk

StFu

ll1.

80.

36N

eat

724

2468

6264

00Pa

yan

et a

l. (2

003)

Rat

Ba/

FkSt

Full

1.8

0.72

Nea

t16

2424

5373

7500

Paya

n et

al.

(200

3)R

atB

a/Fk

StFu

ll1.

80.

045

H2O

50%

624

2423

Paya

n et

al.

(200

3)R

atB

a/Fk

StFu

ll1.

80.

18H

2O50

%4

2424

50Pa

yan

et a

l. (2

003)

Rat

Ba/

FkSt

Full

1.8

0.36

H2O

50%

724

2443

-53

Paya

n et

al.

(200

3)R

atB

a/Fk

StFu

ll1.

80.

72H

2O50

%7

2424

51-5

3Pa

yan

et a

l. (2

003)

Rat

Ba/

FkSt

Full

1.8

1.4

H2O

50%

424

2447

Paya

n et

al.

(200

3)R

atB

a/Fk

StFu

ll1.

80.

18H

2O13

%3

2424

51Pa

yan

et a

l. (2

003)

Rat

Ba/

FkSt

Full

1.8

0.72

H2O

13%

324

2476

Paya

n et

al.

(200

3)R

atB

a/Fk

StFu

ll1.

80.

72H

2O6.

30%

324

2457

Paya

n et

al.

(200

3)R

atB

a/Fk

StFu

ll1.

80.

72H

2O3.

20%

324

2447

Paya

n et

al.

(200

3)

Rep

orte

d da

ta

In v

itro

A13

1

App

endi

x A

Sp

Loc

C

ell

L

(µm

) A

(c

m²)

V

(ml)

Veh

icle

C

(m

g/m

l) n

TE

xp

(h)

TO

bs

(h)

TL

ag

(h)

Abs

(%

) K

P

(10-4

cm

/h)

Flux

(µ

g/cm

²/h) R

efer

ence

Hum

Ha

~500

Inf

H2O

5%1

0.17

485.

0 m

g12

60A

krill

et a

l. (2

002)

Hum

Ha

~500

Inf

H2O

5%2

0.25

486.

4 m

g10

52A

krill

et a

l. (2

002)

Hum

Ha

~500

Inf

H2O

10%

20.

2548

14 m

g11

110

Akr

ill e

t al.

(200

2)H

umH

a~5

00In

fH

2O15

%2

0.25

4832

mg

1726

0A

krill

et a

l. (2

002)

Hum

Ha

~500

Inf

H2O

20%

20.

2548

32 m

g13

260

Akr

ill e

t al.

(200

2)H

umH

a~5

00In

fH

2O25

%2

0.25

4852

mg

1742

0A

krill

et a

l. (2

002)

Rat

Ba

100.

2N

eat (

20 µ

l/cm

²)4

0.25

0.25

648

5000

Paya

n et

al.

(200

3)R

atB

a10

0.2

Nea

t (20

µl/c

m²)

40.

50.

518

7274

00Pa

yan

et a

l. (2

003)

Rat

Ba

100.

2N

eat (

20 µ

l/cm

²)4

0.75

0.75

2976

7900

Paya

n et

al.

(200

3)R

atB

a10

0.2

Nea

t (20

µl/c

m²)

41

136

7375

00Pa

yan

et a

l. (2

003)

Rat

Ba

100.

2N

eat (

20 µ

l/cm

²)4

22

6060

6200

Paya

n et

al.

(200

3)

The

in v

ivo

and

in v

itro

data

show

a c

onsi

sten

t pat

tern

for b

oth

neat

and

wat

er-d

ilute

d N

MP,

with

nea

rly a

ll K

p va

lues

bet

wee

n 2·

10-3

and

1·1

0-2 c

m/h

.

Mos

t exp

erim

ents

by

Dic

k et

al.

(200

1) a

nd A

krill

et a

l. (2

002)

with

hum

an sk

in a

lso

show

a c

onsi

sten

t pat

tern

with

Kp

valu

es b

etw

een

1·10

-3 a

nd 3

·10-3

cm

/h.

The

pref

erre

d ex

perim

ent i

s tha

t of D

ick

et a

l. (2

001)

usi

ng h

uman

skin

in v

itro.

The

Kp

valu

e of

1·1

0-2 c

m/h

cor

resp

onds

to "

very

hig

h" p

erm

eabi

lity.

In v

ivo

Ase

ssm

ent

A13

2

App

endi

x A

Subs

tanc

e: M

ethy

lam

ine

Mol

ecul

ar w

eigh

t:31

.1C

AS:

74-

89-5

Den

sity

:0.9

02 g

/cm

³Sc

ient

ific

basi

s: A

oH 1

983:

36M

eltin

g po

int:

-38°

CB

oilin

g po

int:

48°C

Skin

not

atio

n: Y

esV

apou

r pr

essu

re:3

1 kP

a (a

t 20°

C)

Skin

per

mea

bilit

y: N

o da

taE

vapo

ratio

n ra

te:N

ot a

vaila

ble

Log

Kow

:-0.

57

Sp

Loc

C

ell

L

(µm

) A

(c

m²)

V

(ml)

Veh

icle

C

(m

g/m

l) n

TE

xp

(h)

TO

bs

(h)

TL

ag

(h)

Abs

(%

) K

P

(10-4

cm

/h)

Flux

(µ

g/cm

²/h) R

efer

ence

N

o da

ta a

vaila

ble

N

o da

ta a

vaila

ble

No

quan

titat

ive

expe

rimen

tal d

ata

on d

erm

al u

ptak

e w

ere

foun

d in

the

liter

atur

e.

The

Swed

ish

cons

ensu

s rep

ort (

AoH

198

3:36

) sta

tes t

hat;

"With

mas

sive

exp

osur

e, a

min

es c

an b

e ab

sorb

ed v

ia th

e sk

in.

How

ever

we

foun

d no

upt

ake

via

inta

ct sk

in."

Acc

ordi

ng to

AC

GIH

(200

1), t

here

is in

suff

icie

nt d

ata

to a

ssig

n a

skin

not

atio

n, a

nd n

o ac

coun

ts o

f sys

tem

ic re

actio

nsha

ve b

een

repo

rted

in th

e lit

erat

ure.

Theo

retic

al c

alcu

latio

ns b

y Fi

sero

va-B

erge

rova

et a

l. (1

990)

show

ed th

at th

e po

tent

ial f

or d

erm

alab

sorp

tion

and

resu

lting

toxi

city

is si

gnifi

cant

.

Rep

orte

d da

ta

In v

itro

In v

ivo

Ase

ssm

ent

A13

3

App

endi

x A

Subs

tanc

e: M

ethy

lene

chl

orid

e; d

ichl

orom

etha

neM

olec

ular

wei

ght:

84.9

CA

S: 7

5-09

-2D

ensi

ty:1

.326

g/c

m³

Scie

ntifi

c ba

sis:

AoH

198

1:21

Mel

ting

poin

t:-9

6.7°

CB

oilin

g po

int:

39.8

°CSk

in n

otat

ion:

Yes

Vap

our

pres

sure

:47

kPa

(at 2

0°C

)Sk

in p

erm

eabi

lity:

Hig

hE

vapo

ratio

n ra

te:2

8L

og K

ow:1

.25

Sp

Loc

C

ell

L

(µm

) A

(c

m²)

V

(ml)

Veh

icle

C

(m

g/m

l) n

TE

xp

(h)

TO

bs

(h)

TL

ag

(h)

Abs

(%

) K

P

(10-4

cm

/h)

Flux

(µ

g/cm

²/h) R

efer

ence

Hum

Br

St30

0-60

00.

64N

eat

36

618

2700

Urs

in e

t al.

(199

5)R

atA

bSt

Full

3.7

1N

eat

250.

5-3

0.5-

30.

55-

55 m

g44

5800

Tsur

uta

(197

7)

Mou

Ab

2.9

0.5

Nea

t0.

2550

6600

Tsur

uta

(197

5)

Urs

in e

t al.

(199

5) st

retc

hed

the

skin

whe

n m

ount

ing

it in

the

diff

usio

n ce

ll, re

achi

ng a

fina

l thi

ckne

ss o

f abo

ut

one-

third

of t

he o

rigin

al th

ickn

ess.

This

pro

cedu

re m

ay g

ive

over

estim

ates

of t

he fl

ux a

nd K

p va

lues

.

The

thre

e st

udie

s rep

ort f

airly

sim

ilar K

p va

lues

, ran

ging

bet

wee

n 2·

10-3

to 5

·10-3

cm

/h.

The

pref

erre

d st

udy

is th

at o

f Urs

in e

t al.

(199

5), w

ere

hum

an sk

in w

as u

sed

in v

itro.

The

repo

rted

Kp

valu

e of

2·1

0-3 c

m/h

cor

resp

onds

to "

high

" pe

rmea

bilit

y.

Rep

orte

d da

ta

In v

itro

In v

ivo

Ase

ssm

ent

A13

4

App

endi

x A

Subs

tanc

e: M

ethy

lpen

tane

, 2-

Mol

ecul

ar w

eigh

t:86

.2C

AS:

107

-83-

5D

ensi

ty:0

.653

g/c

m³

Scie

ntifi

c ba

sis:

Not

ava

ilabl

e M

eltin

g po

int:

-154

°CB

oilin

g po

int:

62°C

Skin

not

atio

n: N

oV

apou

r pr

essu

re:2

1 kP

a (a

t 20°

C)

Skin

per

mea

bilit

y: E

xtre

mel

y lo

wE

vapo

ratio

n ra

te:8

.3L

og K

ow:3

.21

(est

imat

ed)

Sp

Loc

C

ell

L

(µm

) A

(c

m²)

V

(ml)

Veh

icle

C

(m

g/m

l) n

TE

xp

(h)

TO

bs

(h)

TL

ag

(h)

Abs

(%

) K

P

(10-4

cm

/h)

Flux

(µ

g/cm

²/h) R

efer

ence

Rat

Ab

StFu

ll2.

61

Nea

t15

4-22

4-22

1-6

µg0.

0017

0.11

Tsur

uta

(198

2)

N

o da

ta a

vaila

ble

The

only

stud

y fo

und

sugg

est a

Kp

valu

e of

2·1

0-7 c

m/h

in ra

t ski

n, c

orre

spon

ding

to "

extre

mel

y lo

w"

perm

eabi

lity.

It sh

ould

be

note

d th

at T

suru

ta (1

982)

use

d ph

ysio

logi

cal s

alin

e as

rece

ptor

med

ium

, res

ultin

g in

low

solu

bilit

yfo

r lip

ophi

lic su

bsta

nces

. Thi

s may

lead

to u

nder

estim

ated

per

mea

bilit

y.

Rep

orte

d da

ta

In v

itro

In v

ivo

Ase

ssm

ent

A13

5

App

endi

x A

Subs

tanc

e: M

onoc

hlor

oace

tic a

cid

Mol

ecul

ar w

eigh

t:94

.5C

AS:

79-

11-8

Den

sity

:1.5

8 g/

cm³

Scie

ntifi

c ba

sis:

AoH

199

2:6

Mel

ting

poin

t:61

to 6

2°C

Boi

ling

poin

t:18

8°C

Skin

not

atio

n: Y

esV

apou

r pr

essu

re:0

.1 k

Pa (a

t 23°

C)

Skin

per

mea

bilit

y: V

ery

high

Eva

pora

tion

rate

:1L

og K

ow:0

.22

Sp

Loc

C

ell

L

(µm

) A

(c

m²)

V

(ml)

Veh

icle

C

(m

g/m

l) n

TE

xp

(h)

TO

bs

(h)

TL

ag

(h)

Abs

(%

) K

P

(10-4

cm

/h)

Flux

(µ

g/cm

²/h) R

efer

ence

N

o da

ta a

vaila

ble

Rat

Ba

0.79

0.5

ml/k

gBW

Ac

250

(130

mg/

kg B

W)

432

7648

012

000

Sagh

ir et

al.

(200

3)

The

only

ava

ilabl

e st

udy

is o

n m

onoc

hlor

oace

tic a

cid

is o

n ra

t ski

n in

viv

o w

ith a

ceto

ne a

s veh

icle

.

The

calc

ulat

ed K

p va

lue

sugg

ests

"ve

ry h

igh"

per

mea

bilit

y.

It sh

ould

be

note

d th

at a

ceto

ne m

ay d

amag

e th

e sk

in c

ausi

ng in

crea

sed

pene

tratio

n.

Rep

orte

d da

ta

In v

itro

In v

ivo

Ase

ssm

ent

A13

6

App

endi

x A

Subs

tanc

e: M

orph

olin

eM

olec

ular

wei

ght:

87.1

CA

S: 1

10-9

1-8

Den

sity

:0.9

94 g

/cm

³Sc

ient

ific

basi

s: A

oH 1

996:

25M

eltin

g po

int:

-4.9

°CB

oilin

g po

int:

128.

9°C

Skin

not

atio

n: Y

esV

apou

r pr

essu

re:1

.1 k

Pa (a

t 20°

C)

Skin

per

mea

bilit

y: N

o da

taE

vapo

ratio

n ra

te:0

.66

Log

Kow

:-0.

86

Sp

Loc

C

ell

L

(µm

) A

(c

m²)

V

(ml)

Veh

icle

C

(m

g/m

l) n

TE

xp

(h)

TO

bs

(h)

TL

ag

(h)

Abs

(%

) K

P

(10-4

cm

/h)

Flux

(µ

g/cm

²/h) R

efer

ence

N

o da

ta a

vaila

ble

N

o da

ta a

vaila

ble

No

quan

titat

ive

expe

rimen

tal d

ata

on d

erm

al u

ptak

e w

ere

foun

d in

the

liter

atur

e.

Mor

phol

ine

is w

ell a

bsor

bed

via

inta

ct sk

in, w

here

as n

eutra

lized

mor

phol

ine

is n

ot (A

oH 1

996:

25, 1

982:

32).

The

skin

not

atio

n by

AC

GIH

(200

1) is

bas

ed o

n th

e lo

wer

der

mal

(0.5

g/k

g bw

) com

pare

d to

ora

l (1.

05 g

/kg

bw)

LD50

val

ue in

rats

.Th

ere

is a

lso

a re

port

of h

uman

der

mal

pen

etra

tion

(AC

GIH

(200

1)).

Acc

ordi

ng to

theo

retic

al c

alcu

latio

ns b

y Fi

sero

va-B

erge

rova

et a

l. (1

990)

the

pote

ntia

l for

der

mal

abso

rptio

n an

d re

sulti

ng to

xici

ty is

sign

ifica

nt.

Rep

orte

d da

ta

In v

itro

In v

ivo

Ase

ssm

ent

A13

7

App

endi

x A

Subs

tanc

e: N

apht

alen

es, c

hlor

inat

edM

olec

ular

wei

ght:

231.

5C

AS:

132

1-65

-9D

ensi

ty:1

.58

g/cm

³Sc

ient

ific

basi

s: N

ot a

vaila

ble

Mel

ting

poin

t:93

°CB

oilin

g po

int:

304

to 3

54°C

Skin

not

atio

n: Y

esV

apou

r pr

essu

re:<

0.1

Pa (a

t 20°

C)

Skin

per

mea

bilit

y: N

o da

taE

vapo

ratio

n ra

te:N

ot a

vaila

ble

Log

Kow

:5.1

0 (e

stim

ated

)

Sp

Loc

C

ell

L

(µm

) A

(c

m²)

V

(ml)

Veh

icle

C

(m

g/m

l) n

TE

xp

(h)

TO

bs

(h)

TL

ag

(h)

Abs

(%

) K

P

(10-4

cm

/h)

Flux

(µ

g/cm

²/h) R

efer

ence

N

o da

ta a

vaila

ble

N

o da

ta a

vaila

ble

No

quan

titat

ive

expe

rimen

tal d

ata

on d

erm

al u

ptak

e w

ere

foun

d in

the

liter

atur

e.

The

WH

O d

ocum

ent o

n ch

loro

-nap

htal

enes

(WH

O (2

001)

) sta

tes t

hat:

"Der

mal

and

inha

latio

n ab

sorp

tion

of P

CN

s can

be

conc

lude

d fr

om sy

stem

ic e

ffec

ts in

ani

mal

s and

hum

ans.

A q

uant

ifica

tion

is n

ot p

ossi

ble.

"

The

Dut

ch c

omm

ittee

on

upda

ting

of O

ELs f

ound

no

data

rega

rdin

g de

rmal

upt

ake

of tr

ichl

oron

apht

alen

e.

Rep

orte

d da

ta

In v

itro

In v

ivo

Ase

ssm

ent

A13

8

App

endi

x A

Subs

tanc

e: N

apht

hale

neM

olec

ular

wei

ght:

128.

2C

AS:

91-

20-3

Den

sity

:0.9

97 g

/cm

³Sc

ient

ific

basi

s: A

oH 1

998:

25M

eltin

g po

int:

80.6

°CB

oilin

g po

int:

218°

CSk

in n

otat

ion:

No

Vap

our

pres

sure

:11

Pa (a

t 25°

C)

Skin

per

mea

bilit

y: M

oder

ate

Eva

pora

tion

rate

:<<1

Log

Kow

:3.3

0

Sp

Loc

C

ell

L

(µm

) A

(c

m²)

V

(ml)

Veh

icle

C

(m

g/m

l) n

TE

xp

(h)

TO

bs

(h)

TL

ag

(h)

Abs

(%

) K

P

(10-4

cm

/h)

Flux

(µ

g/cm

²/h) R

efer

ence

Hum

St50

01.

1JP

-824

242.

20.

45K

anik

kann

an e

t al.

(200

1)M

onA

bSt

Full

1.8

0.03

Ac

150

nmol

/cm

²9?

7272

2.17

515.

7Sa

rtore

lli e

t al.

(199

8)M

PEa

rSt

500

1.1

JP-8

2424

1.8

0.38

Kan

ikka

nnan

et a

l. (2

001)

Pig

Ba

Fl20

0-30

00.

32JP

-81.

20%

45

52.

5-3

1.4

0.19

Bay

nes e

t al.

(200

0)Pi

gB

aFl

200-

300

0.32

JP-8

1.20

%4

55

2.5-

31.

40.

19B

ayne

s et a

l. (2

001)

Pig

Fl45

0-55

00.

640.

02JP

-811

(34

0 µg

/cm

²)5

55

2.1

2.2

Muh

amm

ad e

t al.

(200

4)R

atB

aSt

560

4.9

2JP

-80.

26%

84

40.

55.

11

McD

ouga

l et a

l. (2

000)

N

o da

ta a

vaila

ble

The

repo

rted

Kp

valu

es a

re fa

irly

cons

iste

nt, e

ven

betw

een

diff

eren

t spe

cies

.

The

pref

erre

d st

udie

s are

thos

e us

ing

jet f

uel,

rath

er th

at a

ceto

ne, a

s veh

icle

. Jet

fuel

may

als

o af

fect

skin

per

mea

tion,

alth

ough

pro

babl

y to

a le

sser

ext

ent t

han

acet

one.

Hum

an sk

in w

as u

sed

in o

ne e

xper

imen

t by

Kan

ikka

nnan

et a

l. (2

001)

.

The

repo

rted

Kp

valu

e of

2·1

0-4 c

m/h

sugg

ests

a "

mod

erat

e" p

erm

eabi

lity.

Rep

orte

d da

ta

In v

itro

In v

ivo

Ase

ssm

ent

A13

9

App

endi

x A

Subs

tanc

e: N

icot

ine

Mol

ecul

ar w

eigh

t:16

2.2

CA

S: 5

4-11

-5D

ensi

ty:1

.01

g/cm

³Sc

ient

ific

basi

s: A

oH 2

004:

16M

eltin

g po

int:

-7.9

°CB

oilin

g po

int:

247°

CSk

in n

otat

ion:

Yes

Vap

our

pres

sure

:5.7

Pa

(at 2

0°C

)Sk

in p

erm

eabi

lity:

Hig

hE

vapo

ratio

n ra

te:N

ot a

vaila

ble

Log

Kow

:1.1

7

Sp

Loc

C

ell

L

(µm

) A

(c

m²)

V

(ml)

Veh

icle

C

(m

g/m

l) n

TE

xp

(h)

TO

bs

(h)

TL

ag

(h)

Abs

(%

) K

P

(10-4

cm

/h)

Flux

(µ

g/cm

²/h) R

efer

ence

Hum

Ab

StFu

ll1

1.5

H2O

372

7233

Deg

im e

t al.

(199

8)H

umA

b/B

rSt

410

1.8

PB20

(0.0

5 M

)9

2828

100

210

Qvi

st e

t al.

(200

0)H

umA

b/B

rSt

410

1.8

0.36

H2O

10

%6

1.5

1.5

0.13

8488

0Zo

rin e

t al.

(199

9)H

umA

b/B

rSt

410

1.8

0.36

H2O

20

%6

1.5

1.5

0.15

4388

0Zo

rin e

t al.

(199

9)H

umA

b/B

rSt

410

1.8

0.36

H2O

50

%6

1.5

1.5

0.16

2713

00Zo

rin e

t al.

(199

9)H

umA

b/B

rSt

410

1.8

0.1

Nea

t6

1.5

1.5

0.22

0.8

82Zo

rin e

t al.

(199

9)H

umA

bEp

i0.

791

PB1%

612

122.

15.

95.

9Po

ngja

nyak

ul e

t al.

(200

2)M

PB

aSt

770

1.8

PB20

(0.0

5 M

)9

2828

8717

0Q

vist

et a

l. (2

000)

MP

Ba

St77

01.

8PB

20 (0

.05

M)

928

2810

021

0Q

vist

et a

l. (2

000)

MP

Ba

St77

01.

8PB

20 (0

.05

M)

928

2810

020

0Q

vist

et a

l. (2

000)

Pig

Ba

St77

01.

8PB

20 (0

.05

M)

928

2811

022

0Q

vist

et a

l. (2

000)

Pig

Th1.

10.

643.

3PB

5030

3011

056

0N

air e

t al.

(199

7)Pi

gTh

1.1

0.64

3.3

PB50

3030

3618

0N

air e

t al.

(199

7)Pi

gEa

r0.

90.

643.

3PB

5030

3012

061

0N

air e

t al.

(199

7)Pi

gB

a1.

80.

643.

3PB

5030

3034

150

Nai

r et a

l. (1

997)

Pig

Ab

1.2

0.64

3.3

PB50

3030

170

850

Nai

r et a

l. (1

997)

SnSC

0.79

1PB

1%15

1212

0.55

3.5

3.5

Pong

jany

akul

et a

l. (2

002)

SnSC

0.79

1PB

1%15

1212

0.74

4.2

4.2

Pong

jany

akul

et a

l. (2

002)

Rep

orte

d da

ta

In v

itro

A14

0

App

endi

x A

Sp

Loc

C

ell

L

(µm

) A

(c

m²)

V

(ml)

Veh

icle

C

(m

g/m

l) n

TE

xp

(h)

TO

bs

(h)

TL

ag

(h)

Abs

(%

) K

P

(10-4

cm

/h)

Flux

(µ

g/cm

²/h) R

efer

ence

Rat

Ba

2.8

0.1

Ac

0.08

43

7272

442.

20.

018

Shah

et a

l. (1

987)

Rat

Ba

5.6

0.2

Ac

0.06

53

7272

673.

30.

022

Shah

et a

l. (1

987)

Rat

Ba

2.8

0.1

Ac

33

7272

120.

60.

18Sh

ah e

t al.

(198

7)R

atB

a5.

60.

2A

c 2.

43

7272

743.

70.

88Sh

ah e

t al.

(198

7)R

atB

a2.

80.

1A

c 12

372

7276

3.8

4.5

Shah

et a

l. (1

987)

Rat

Ba

5.6

0.2

Ac

123

7272

552.

73.

3Sh

ah e

t al.

(198

7)

The

only

exp

erim

ent f

ound

on

neat

nic

otin

e w

as th

at o

f Zor

in e

t al.

(199

9),

whi

ch re

porte

d a

Kp

valu

e of

8·1

0-5 c

m/h

, cor

resp

ondi

ng to

"lo

w"

perm

eabi

lity.

The

othe

r in

vitro

exp

erim

ents

usi

ng h

uman

skin

hav

e di

lute

d so

lutio

ns. T

he re

porte

d K

p va

lues

rang

ebe

twee

n 6·

10-4

and

1·1

0-2 c

m/h

, sug

gest

ing

"mod

erat

e-ve

ry h

igh"

per

mea

bilit

y.

The

pref

erre

d ex

perim

ents

are

thos

e by

Zor

in e

t al.

(199

9) w

hen

hum

an sk

in is

exp

osed

to d

ilute

d ni

cotin

e (1

0-50

%),

repo

rting

Kp

valu

es b

etw

een

3·10-3

and

8·1

0-3 c

m/h

, whi

ch c

orre

spon

ds to

"hi

gh"

perm

eabi

lity.

In v

ivo

Ase

ssm

ent

A14

1

App

endi

x A

Subs

tanc

e: N

itrob

enze

neM

olec

ular

wei

ght:

123.

1C

AS:

98-

95-3

Den

sity

:1.1

96 g

/cm

³Sc

ient

ific

basi

s: N

ot a

vaila

ble

Mel

ting

poin

t:5.

7°C

Boi

ling

poin

t:21

0.8°

CSk

in n

otat

ion:

Yes

Vap

our

pres

sure

:20

Pa (a

t 20°

C)

Skin

per

mea

bilit

y: N

o co

nclu

sion

Eva

pora

tion

rate

:0.0

29L

og K

ow:1

.85

Sp

Loc

C

ell

L

(µm

) A

(c

m²)

V

(ml)

Veh

icle

C

(m

g/m

l) n

TE

xp

(h)

TO

bs

(h)

TL

ag

(h)

Abs

(%

) K

P

(10-4

cm

/h)

Flux

(µ

g/cm

²/h) R

efer

ence

Hum

Ab

St35

01.

1A

cN

eat

(4 µ

g/cm

²)6

2424

7.8

0.00

011

0.01

3B

rona

ugh

et a

l. (1

985a

)H

umA

bSt

350

1.1

Ac

Nea

t (4

µg/

cm²)

324

2441

0.00

056

0.06

7B

rona

ugh

et a

l. (1

985a

)H

umFl

350

0.64

Ac

Nea

t (4

µg/

cm²)

612

1210

0 ng

(2h)

0.00

067

0.08

Bro

naug

h et

al.

(198

5a)

Mon

Ab

St35

01.

1A

cN

eat

(4 µ

g/cm

²)6

2424

6.2

0.00

0083

0.01

Bro

naug

h et

al.

(198

5a)

Hum

Arm

13A

cN

eat

(4 µ

g/cm

²)6

2412

01.

50.

0000

210.

0025

Feld

man

n et

al.

(197

0)H

umW

B20

000

Vap

5-30

ng/

ml

126

244-

80 m

g17

000-

2000

00.

1-0.

5Pi

otro

wsk

i (19

67)

Mon

Ab

13A

cN

eat

(4 µ

g/cm

²)4

2412

04.

20.

0000

580.

007

Bro

naug

h et

al.

(198

5a)

The

Kp

valu

e ob

tain

ed u

sing

nitr

oben

zene

vap

our d

iffer

by

8-9

orde

rs o

f mag

nitu

de fr

om th

ose

obta

ined

usi

ng

nitro

benz

ene

diss

olve

d in

ace

tone

.Fu

rther

, the

Kp

valu

es in

ace

tone

are

abo

ut 4

ord

ers o

f mag

nitu

de lo

wer

than

for d

i- an

d tri

nitro

tolu

ene.

Thus

, the

Kp

valu

es fo

r nitr

oben

zene

seem

s unr

ealis

tic.

Rep

orte

d da

ta

In v

itro

In v

ivo

Ase

ssm

ent

A14

2

App

endi

x A

Subs

tanc

e: N

itrog

lyce

rinM

olec

ular

wei

ght:

227.

1C

AS:

55-

63-0

Den

sity

:1.6

g/c

m³

Scie

ntifi

c ba

sis:

AoH

198

5:32

Mel

ting

poin

t:13

°CB

oilin

g po

int:

218°

CSk

in n

otat

ion:

Yes

Vap

our

pres

sure

:0.0

35 P

a (a

t 20°

C)

Skin

per

mea

bilit

y: L

owE

vapo

ratio

n ra

te:N

ot a

vaila

ble

Log

Kow

:1.6

2

Sp

Loc

C

ell

L

(µm

) A

(c

m²)

V

(ml)

Veh

icle

C

(m

g/m

l) n

TE

xp

(h)

TO

bs

(h)

TL

ag

(h)

Abs

(%

) K

P

(10-4

cm

/h)

Flux

(µ

g/cm

²/h) R

efer

ence

HM

Ba

FlFu

ll0.

95H

2O

0.1

510

10~1

200

2K

ikko

ji et

al.

(199

1)H

MSt

Full

0.64

Nea

t?5

2424

0.19

31M

ingh

etti

et a

l. (1

999)

HM

Ba

FlFu

ll0.

951

H2O

0.1

66

645

-160

0.45

-1.6

Hig

o et

al.

(199

2a)

HM

Ba

FlFu

ll0.

951

H2O

0.1

810

1045

-190

0.45

-1.9

Hig

o et

al.

(199

2b)

Hum

Ab

StEp

i3.

1H

2O

231

4848

8517

Lang

guth

et a

l. (1

986a

)H

umTh

St20

00.

64N

eat?

524

240.

1422

Min

ghet

ti et

al.

(199

9)H

umTh

St20

00.

64N

eat?

524

240.

2133

Min

ghet

ti et

al.

(199

9)H

umTh

StEp

i0.

64N

eat?

524

240.

1423

Min

ghet

ti et

al.

(199

9)H

umA

bFl

Full

0.34

Patc

h6

2424

15R

ober

ts e

t al.

(199

0)H

umB

rSt

300

0.79

1Et

(5%

) + H

2O0.

05%

310

1047

3.5

Pone

c et

al.

(199

0)H

umB

rSt

SC0.

791

Et (5

%) +

H2O

0.05

%6

1010

413.

1Po

nec

et a

l. (1

990)

Hum

Ba

StSC

0.5

Et (4

0-80

%) +

H2O

10%

62-

1030

-150

Ber

ner e

t al.

(198

9)H

umA

bSt

Epi

3.1

11H

2O2

2548

4885

17La

nggu

th e

t al.

(198

6b)

Hum

824

246-

20N

oona

n et

al.

(198

9-19

90)

Mou

StFu

llN

eat

2424

<10.

2741

Chi

en e

t al.

(198

4)

N

o da

ta a

vaila

ble

The

expe

rimen

ts u

sing

eth

anol

as v

ehic

le a

re d

isre

gard

ed a

s it m

ay a

ffec

t ski

n pe

rmea

bilit

y.Th

ere

seem

s to

be a

veh

icle

eff

ect f

or n

itrog

lyce

rin. T

he re

porte

d K

p va

lues

for n

eat n

itrog

lyce

rin ra

nge

betw

een

1·10

-5 a

nd 3

·10-5

cm

/h, c

orre

spon

ding

to "

low

" pe

rmea

bilit

y.

It sh

ould

be

note

d th

at fo

r dilu

ted

nitro

glyc

erin

the

repo

rted

Kp

valu

es ra

nge

betw

een

5·10

-3 a

nd 2

·10-2

cm

/h,

corr

espo

ndin

g to

"hi

gh/v

ery

high

" pe

rmea

bilit

y.

Rep

orte

d da

ta

In v

itro

In v

ivo

Ase

ssm

ent

A14

3

App

endi

x A

Subs

tanc

e: N

itrot

olue

neM

olec

ular

wei

ght:

137.

1C

AS:

132

1-12

-6D

ensi

ty:1

.16

to 1

.25

g/cm

³Sc

ient

ific

basi

s: A

oH 1

992:

6M

eltin

g po

int:

-10

to 5

4°C

Boi

ling

poin

t:22

2 to

238

°CSk

in n

otat

ion:

Yes

Vap

our

pres

sure

:16-

20 P

a (a

t 20°

C)

Skin

per

mea

bilit

y: N

o da

taE

vapo

ratio

n ra

te:N

ot a

vaila

ble

Log

Kow

:2.3

0

Sp

Loc

C

ell

L

(µm

) A

(c

m²)

V

(ml)

Veh

icle

C

(m

g/m

l) n

TE

xp

(h)

TO

bs

(h)

TL

ag

(h)

Abs

(%

) K

P

(10-4

cm

/h)

Flux

(µ

g/cm

²/h) R

efer

ence

N

o da

ta a

vaila

ble

N

o da

ta a

vaila

ble

No

quan

titat

ive

expe

rimen

tal d

ata

on d

erm

al u

ptak

e w

ere

foun

d in

the

liter

atur

e.

The

Swed

ish

cons

ensu

s rep

ort (

AoH

199

2:6)

refe

rs to

Sax

(198

4), s

tatin

g th

at n

itrot

olue

ne c

an

be ta

ken

up b

y sk

in in

toxi

c am

ount

s.

Acc

ordi

ng to

AC

GIH

(200

1) n

o qu

antit

ativ

e da

ta o

n ni

troto

luen

e w

ere

foun

d. T

he sk

in n

otat

ion

is b

ased

on

anal

ogy

with

ani

line

and

nitro

benz

ene.

OEC

D S

IDS,

judg

e ni

troto

luen

e to

be

rapi

dly

abso

rbed

via

all

rout

es.

Theo

retic

al c

alcu

latio

ns b

y Fi

sero

va-B

erge

rova

et a

l. (1

990)

show

that

the

pote

ntia

l for

der

mal

abso

rptio

n an

d re

sulti

ng to

xici

ty is

sign

ifica

nt.

Rep

orte

d da

ta

In v

itro

In v

ivo

Ase

ssm

ent

A14

4

App

endi

x A

Subs

tanc

e: O

ctan

esM

olec

ular

wei

ght:

114.

2C

AS:

111

-65-

9D

ensi

ty:0

.703

g/c

m³

Scie

ntifi

c ba

sis:

Not

ava

ilabl

e M

eltin

g po

int:

-56.

8°C

Boi

ling

poin

t:12

6°C

Skin

not

atio

n: N

oV

apou

r pr

essu

re:1

.9 k

Pa (a

t 25°

C)

Skin

per

mea

bilit

y: E

xtre

mel

y lo

wE

vapo

ratio

n ra

te:1

.4L

og K

ow:5

.18

Sp

Loc

C

ell

L

(µm

) A

(c

m²)

V

(ml)

Veh

icle

C

(m

g/m

l) n

TE

xp

(h)

TO

bs

(h)

TL

ag

(h)

Abs

(%

) K

P

(10-4

cm

/h)

Flux

(µ

g/cm

²/h) R

efer

ence

Rat

Ab

StFu

ll2.

61

Nea

t14

23-5

123

-51

0.00

0008

0.00

06Ts

urut

a (1

982)

N

o da

ta a

vaila

ble

The

only

ava

ilabl

e st

udy

sugg

ests

a K

p va

lue

of 1

0-9 c

m/h

, cor

resp

ondi

ng to

"ex

trem

ely

low

" pe

rmea

bilit

y.

It sh

ould

be

note

d th

at T

suru

ta (1

982)

use

d ph

ysio

logi

cal s

alin

e as

rece

ptor

med

ium

, re

sulti

ng in

low

er so

lubi

lity

for l

ipop

hilic

subs

tanc

es. T

his m

ay h

ave

led

to a

und

eres

timat

ed K

p va

lue.

Rep

orte

d da

ta

In v

itro

In v

ivo

Ase

ssm

ent

A14

5

App

endi

x A

Subs

tanc

e: P

enta

chlo

roph

enol

Mol

ecul

ar w

eigh

t:26

6.3

CA

S: 8

7-86

-5D

ensi

ty:1

.979

g/c

m³

Scie

ntifi

c ba

sis:

Not

ava

ilabl

e M

eltin

g po

int:

174°

CB

oilin

g po

int:

310°

CSk

in n

otat

ion:

Yes

Vap

our

pres

sure

:0.0

1 Pa

(at 2

5°C

)Sk

in p

erm

eabi

lity:

Mod

erat

eE

vapo

ratio

n ra

te:N

ot a

vaila

ble

Log

Kow

:5.1

2

Sp

Loc

C

ell

L

(µm

) A

(c

m²)

V

(ml)

Veh

icle

C

(m

g/m

l) n

TE

xp

(h)

TO

bs

(h)

TL

ag

(h)

Abs

(%

) K

P

(10-4

cm

/h)

Flux

(µ

g/cm

²/h) R

efer

ence

Pig

Fl5

0.1

Et0.

4 (4

0 µg

/cm

²)4

88

1.1

70.

28R

ivie

re e

t al.

(200

1)Pi

gFl

50.

1Et

(40%

) + H

2O (6

0%)

0.4

(40

µg/c

m²)

48

86.

943

1.7

Riv

iere

et a

l. (2

001)

Pig

Ab

50.

07Et

33

88

1.1

0.4

0.12

Qia

o et

al.

(200

2)H

umFl

500

1So

il17

ppm

(0.7

µg/

cm²)

615

150.

01-0

.07

0.00

28-0

.019

0.00

0004

7-0.

0000

33W

este

r et a

l. (1

993b

)H

umFl

500

1A

c17

ppm

(0.8

µg/

cm²)

615

150.

6-1.

50.

19-0

.47

0.00

032-

0.00

08W

este

r et a

l. (1

993b

)H

umA

bSt

Full?

10.

01H

2O +

TC

P4.

49

2424

0.8

0.03

30.

015

Hor

stm

an e

t al.

(198

9)H

umA

bSt

Full?

10.

01D

iese

l + T

CP

150

924

240.

140.

0058

0.08

8H

orst

man

et a

l. (1

989)

Pig

Ba

Fl20

0-30

00.

64H

2O

4 µg

/cm

²4

88

0.13

µg

1.7

0.03

1B

ayne

s et a

l. (2

002)

Pig

Ba

Fl20

0-30

00.

64H

2O

40 µ

g/cm

²4

88

2.2

2.2

µg3.

70.

92B

ayne

s et a

l. (2

002)

Pig

Ba

Fl20

0-30

00.

64Et

4 µg

/cm

²4

88

0.05

µg

0.5

0.01

4B

ayne

s et a

l. (2

002)

Pig

Ba

Fl20

0-30

00.

64Et

40 µ

g/cm

²4

88

1.8

0.39

µg

0.6

0.14

Bay

nes e

t al.

(200

2)Pi

gA

b50

00.

33Et

3 (4

0 µg

/cm

²)3

88

0.2

0.04

0.01

2Q

iao

et a

l. (2

002)

Mon

Ab

12So

il17

ppm

(0.

7 µg

/cm

²)4

2433

624

4.2

0.00

71W

este

r et a

l. (1

993b

)M

onA

b12

Ac

17pp

m (

0.8

µg/c

m²)

424

336

295.

70.

0097

Wes

ter e

t al.

(199

3b)

Pig

Ab

7.5

100

mg

Soil

40 µ

g/cm

² (30

0µg)

340

840

829

700.

21Q

iao

et a

l. (1

997)

Pig

Ab

7.5

0.1

Et3

326

426

450

0.25

0.07

6Q

iao

et a

l. (2

002)

The

expe

rimen

ts w

ith a

ceto

ne, e

than

ol, d

iese

l or t

etra

chlo

roph

enol

as v

ehic

les a

re d

isre

gard

ed a

s the

sk

in p

erm

eatio

n co

uld

be a

ffec

ted.

The

pref

erre

d st

udy

is th

at o

n pi

g sk

in in

vitr

o w

ith w

ater

as v

ehic

le (B

ayne

s et a

l. (2

002)

).

The

repo

rted

Kp

valu

e of

4·1

0-4 c

m/h

sugg

ests

a "

mod

erat

e" p

erm

eabi

lity.

Rep

orte

d da

ta

In v

itro

In v

ivo

Ase

ssm

ent

A14

6

App

endi

x A

Subs

tanc

e: P

enta

neM

olec

ular

wei

ght:

72.1

CA

S: 1

09-6

6-0

Den

sity

:0.6

26 g

/cm

³Sc

ient

ific

basi

s: N

ot a

vaila

ble

Mel

ting

poin

t:-1

29.7

°CB

oilin

g po

int:

36.1

°CSk

in n

otat

ion:

No

Vap

our

pres

sure

:48

kPa

(at 2

0°C

)Sk

in p

erm

eabi

lity:

Ext

rem

ely

low

Eva

pora

tion

rate

:29

Log

Kow

:3.3

9

Sp

Loc

C

ell

L

(µm

) A

(c

m²)

V

(ml)

Veh

icle

C

(m

g/m

l) n

TE

xp

(h)

TO

bs

(h)

TL

ag

(h)

Abs

(%

) K

P

(10-4

cm

/h)

Flux

(µ

g/cm

²/h) R

efer

ence

Rat

Ab

StFu

ll2.

61

Nea

t39

2.5-

18.5

2.5-

18.5

3.11

5-89

µg

0.00

060.

04Ts

urut

a (1

982)

N

o da

ta a

vaila

ble

The

only

ava

ilabl

e st

udy

sugg

ests

a K

p va

lue

of 1

0-8 c

m/h

, cor

resp

ondi

ng to

"ex

trem

ely

low

" pe

rmea

bilit

y.

It sh

ould

be

note

d th

at T

suru

ta (1

982)

use

d ph

ysio

logi

cal s

alin

e as

rece

ptor

med

ium

, res

ultin

g in

lo

wer

solu

bilit

y fo

r lip

ophi

lic su

bsta

nces

. Thi

s may

hav

e le

d to

a u

nder

estim

ated

Kp

valu

e.

Rep

orte

d da

ta

In v

itro

In v

ivo

Ase

ssm

ent

A14

7

App

endi

x A

Subs

tanc

e: P

heno

lM

olec

ular

wei

ght:

94.1

CA

S: 1

08-9

5-2

Den

sity

:1.0

7 g/

cm³

Scie

ntifi

c ba

sis:

AoH

198

5:32

Mel

ting

poin

t:40

.5°C

Boi

ling

poin

t:18

1.7°

CSk

in n

otat

ion:

Yes

Vap

our

pres

sure

:47

Pa (a

t 29°

C)

Skin

per

mea

bilit

y: H

igh

Eva

pora

tion

rate

:<0.

01L

og K

ow:1

.46

Sp

Loc

C

ell

L

(µm

) A

(c

m²)

V

(ml)

Veh

icle

C

(m

g/m

l) n

TE

xp

(h)

TO

bs

(h)

TL

ag

(h)

Abs

(%

) K

P

(10-4

cm

/h)

Flux

(µ

g/cm

²/h) R

efer

ence

Pig

Full

7.5

0.08

-0.1

Et0.

3 (4

µg/

cm²)

28

85.

52.

40.

072

Bro

oks e

t al.

(199

6)Pi

gFu

ll7.

50.

08-0

.1Et

0.3

(4 µ

g/cm

²)2

88

7.3

3.3

1B

rook

s et a

l. (1

996)

Pig

Full

7.5

0.08

-0.1

Et0.

3 (4

µg/

cm²)

48

89.

26

0.18

Bro

oks e

t al.

(199

6)Pi

gFu

ll7.

50.

08-0

.1Et

3 (4

0 µg

/cm

²)4

88

7.4

3.7

1.1

Bro

oks e

t al.

(199

6)Pi

gFu

ll7.

50.

08-0

.1A

c0.

3 (4

µg/

cm²)

28

82.

91.

30.

038

Bro

oks e

t al.

(199

6)Pi

gFu

ll7.

50.

08-0

.1A

c3

(40

µg/c

m²)

28

82

0.47

0.14

Bro

oks e

t al.

(199

6)Pi

gFu

ll7.

50.

08-0

.1A

c0.

3 (4

µg/

cm²)

48

815

50.

15B

rook

s et a

l. (1

996)

Pig

Full

7.5

0.08

-0.1

Ac

3 (4

0 µg

/cm

²)4

88

115

1.5

Bro

oks e

t al.

(199

6)H

umA

bFl

350

0.32

VIC

4 µg

/cm

²7

2472

260.

13B

rona

ugh

et a

l. (1

985b

)H

umA

bSt

Full

10.

01A

cN

eat

(4 µ

g/cm

²)7

4848

110.

0000

850.

0091

Fran

z (1

975)

Hum

Br

FlFu

ll0.

320.

005-

0.01

Et0.

27 (

2.7

µg/c

m²)

672

7219

-20

0.81

-0.8

90.

022-

0.02

4H

otch

kiss

et a

l. (1

992)

Hum

Br

FlFu

ll0.

320.

005-

0.01

Et0.

27 (

2.7

µg/c

m²)

372

7247

20.

055

Hot

chki

ss e

t al.

(199

2)H

umA

bSt

Epi

2.5

Inf

H2O

42

88

0.25

8233

Rob

erts

et a

l. (1

977)

Hum

Ab

StSC

1H

2O10

3310

100.

551.

51.

5So

uthw

ell e

t al.

(198

4)H

umA

bSt

SC1

H2O

101

1010

0.35

2.6

2.6

Sout

hwel

l et a

l. (1

984)

Hum

Ab

StSC

1H

2O10

210

100.

721.

71.

7So

uthw

ell e

t al.

(198

4)H

umA

bSt

SC1

H2O

101

1010

0.25

1.6

1.6

Sout

hwel

l et a

l. (1

984)

Hum

Ab

StSC

1H

2O10

210

100.

41.

41.

4So

uthw

ell e

t al.

(198

4)H

umA

bSt

SC1

H2O

102

1010

0.43

0.98

0.98

Sout

hwel

l et a

l. (1

984)

Hum

Ab

StSC

1H

2O10

910

100.

932.

22.

2So

uthw

ell e

t al.

(198

4)H

umA

bSt

SC1

H2O

103

1010

0.57

1.1

1.1

Sout

hwel

l et a

l. (1

984)

Hum

Ab

StSC

1H

2O10

410

100.

850.

890.

89So

uthw

ell e

t al.

(198

4)H

umA

bSt

SC1

H2O

104

1010

0.6

1.8

1.8

Sout

hwel

l et a

l. (1

984)

Hum

Ab

StSC

1H

2O10

310

100.

370.

590.

59So

uthw

ell e

t al.

(198

4)H

umA

bSt

Epi

Inf

H2O

1%

337-

107-

100.

551.

51.

5So

uthw

ell e

t al.

(198

4)

Rep

orte

d da

ta

In v

itro

A14

8

App

endi

x A

Sp

Loc

C

ell

L

(µm

) A

(c

m²)

V

(ml)

Veh

icle

C

(m

g/m

l) n

TE

xp

(h)

TO

bs

(h)

TL

ag

(h)

Abs

(%

) K

P

(10-4

cm

/h)

Flux

(µ

g/cm

²/h) R

efer

ence

Mou

Ba

StFu

ll0.

6N

aCl

0.50

%6

2.5

2.5

230

120

Beh

l et a

l. (1

983)

Mou

Ba

StFu

ll0.

6N

aCl

1.00

%6

2.5

2.5

310

330

Beh

l et a

l. (1

983)

Mou

Ba

StFu

ll0.

6N

aCl

2.00

%6

2.5

2.5

470

1000

Beh

l et a

l. (1

983)

Mou

Ba

StFu

ll0.

6N

aCl

4.00

%6

2.5

2.5

170

710

Beh

l et a

l. (1

983)

Mou

Ba

StFu

ll0.

6N

aCl

6.00

%6

2.5

2.5

2000

1300

0B

ehl e

t al.

(198

3)M

ouSt

Full

0.79

330.

1717

0056

00H

uq e

t al.

(198

6)M

ouSt

Full

0.79

Trac

e0.

1719

0H

uq e

t al.

(198

6)Pi

gA

bFl

200

0.64

0.01

EtN

eat

(5.5

µg/

cm²)

616

16~0

.556

0.00

180.

19Sk

owro

nski

et a

l. (1

994)

Rat

Ba

Fl35

00.

32V

IC4

µg/c

m²

624

7216

Bro

naug

h et

al.

(198

5b)

Rat

Ba

FlFu

ll0.

320.

005-

0.01

Et0.

13 (

1.3

µg/c

m²)

672

7236

0.5-

0.51

0.00

65-0

.006

6H

otch

kiss

et a

l. (1

992)

Rat

Ba

FlFu

ll0.

320.

005-

0.01

Et0.

14 (

1.4

µg/c

m²)

672

7225

-27

0.34

-0.3

70.

0048

-0.0

052

Hot

chki

ss e

t al.

(199

2)R

atB

aSt

350

0.64

0.00

5-0.

01Et

0.4

(4 µ

g/cm

²)7

7272

981.

40.

054

Hug

hes e

t al.

(199

3)R

atB

aFl

350

0.32

0.00

5-0.

01Et

0.4

(4 µ

g/cm

²)10

7272

951.

30.

053

Hug

hes e

t al.

(199

3)Sn

Ba

StFu

ll1.

8PB

S1-

34

66

525.

2-16

Itoh

et a

l. (1

990)

Hum

Arm

2.5

0.02

H2O

+Et

5%5

2416

834

2312

0B

ucks

et a

l. (1

989-

1990

)H

umA

rm2.

50.

02H

2O+E

t5%

524

168

2416

86B

ucks

et a

l. (1

989-

1990

)H

umA

rm13

Ac

Nea

t (4

µg/

cm²)

324

120

4.4

0.00

009

0.01

Feld

man

n &

Mai

bach

(197

0)H

umW

BV

ap5-

25 m

g/m

³12

624

5-65

mg

200.

1-0.

5Pi

otro

wsk

i (19

71)

Rat

Ba

2.54

0.02

EtN

eat

(2.4

µg/

cm²)

472

7267

0.00

150.

16H

ughe

s et a

l. (1

995)

The

expe

rimen

ts u

sing

eth

anol

, ace

tone

and

Vas

elin

e ar

e di

sreg

arde

d as

thes

e su

bsta

nces

may

aff

ect s

kin

perm

eabi

lity.

The

expe

rimen

ts u

sing

nea

t phe

nol c

anno

t be

used

, sin

ce th

e su

bsta

nce

appe

ars a

s sol

id c

ryst

als a

t ski

n te

mpe

ratu

re (m

.p. ~

40°C

).

The

pref

erre

d st

udy

is th

at o

f Buc

ks e

t al.

(198

9-19

90) u

sing

5%

phe

nol i

n w

ater

.

The

Kp

valu

e of

2·1

0-3 c

m/h

is c

onsi

sten

t with

the

full

thic

knes

s ski

n in

vitr

o m

ouse

stud

y by

(Beh

l et a

l. (1

983)

) and

sugg

est "

high

" pe

rmea

bilit

y.

In v

ivo

Ase

ssm

ent

A14

9

App

endi

x A

Subs

tanc

e: P

ropa

nol,

n-M

olec

ular

wei

ght:

60.1

CA

S: 7

1-23

-8D

ensi

ty:0

.803

g/c

m³

Scie

ntifi

c ba

sis:

Not

ava

ilabl

e M

eltin

g po

int:

-126

°CB

oilin

g po

int:

97.2

°CSk

in n

otat

ion:

No

Vap

our

pres

sure

:0.5

3 kP

a (a

t 20°

C)

Skin

per

mea

bilit

y: H

igh

Eva

pora

tion

rate

:1.3

Log

Kow

:0.2

5

Sp

Loc

C

ell

L

(µm

) A

(c

m²)

V

(ml)

Veh

icle

C

(m

g/m

l) n

TE

xp

(h)

TO

bs

(h)

TL

ag

(h)

Abs

(%

) K

P

(10-4

cm

/h)

Flux

(µ

g/cm

²/h) R

efer

ence

Hum

Ab

St27

2.5

H2O

7.

421

127.

2Sc

heup

lein

& B

lank

(197

3)H

umA

bSt

2500

2.5

H2O

7.

49

310

190

Sche

uple

in &

Bla

nk (1

973)

Hum

Ab

St27

2.5

Nea

t20

1.6

130

Sche

uple

in &

Bla

nk (1

973)

Hum

Ab

St25

002.

5N

eat

718

1400

Sche

uple

in &

Bla

nk (1

973)

Mou

Ab

StFu

ll0.

79N

aCl

≤10-

4M2

254

Dur

rhei

m e

t al.

(198

0)

N

o da

ta a

vaila

ble

The

only

foun

d st

udy

is th

at o

f Sch

eupl

ein

& B

lank

(197

3), w

ere

hum

an sk

in w

as e

xpos

ed to

nea

t and

dilu

ted

n-pr

opan

ol. T

he p

refe

rred

exp

erim

ent i

s the

one

usi

ng fu

ll th

ickn

ess s

kin.

The

Kp

valu

e of

2·1

0-3 cm

/h, s

ugge

sts "

high

" pe

rmea

bilit

y.

Rep

orte

d da

ta

In v

itro

In v

ivo

Ase

ssm

ent

A15

0

App

endi

x A

Subs

tanc

e: P

ropi

onic

aci

dM

olec

ular

wei

ght:

74.1

CA

S: 7

9-09

-4D

ensi

ty:0

.993

g/c

m³

Scie

ntifi

c ba

sis:

AoH

198

8:32

Mel

ting

poin

t:-2

1.5°

CB

oilin

g po

int:

140.

7°C

Skin

not

atio

n: N

oV

apou

r pr

essu

re:3

90 P

a (a

t 20°

C)

Skin

per

mea

bilit

y: V

ery

high

Eva

pora

tion

rate

:0.2

4L

og K

ow:0

.33

Sp

Loc

C

ell

L

(µm

) A

(c

m²)

V

(ml)

Veh

icle

C

(m

g/m

l) n

TE

xp

(h)

TO

bs

(h)

TL

ag

(h)

Abs

(%

) K

P

(10-4

cm

/h)

Flux

(µ

g/cm

²/h) R

efer

ence

MP

Ba

FlFu

ll1

Hep

744

22

0.07

4000

3000

0Li

ron

et a

l. (1

984a

)M

PB

aFl

Full

1H

ep74

44

40.

1318

0080

00Li

ron

et a

l. (1

984a

)M

PB

aFl

Full

1H

ep74

48

80.

1798

073

00Li

ron

et a

l. (1

984a

)M

PB

aFl

Full

1H

ep74

37

70.

3375

056

00Li

ron

et a

l. (1

984a

)M

PB

aFl

Full

1H

ep74

37

70.

6749

036

00Li

ron

et a

l. (1

984a

)M

PB

aFl

Full

1N

eat

55

~0.5

160

3.3

Liro

n et

al.

(198

4b)

N

o da

ta a

vaila

ble

The

expe

rimen

ts u

sing

n-h

epta

ne a

s veh

icle

are

dis

rega

rded

, as t

he sk

in p

erm

eatio

n co

uld

be a

ffec

ted.

The

only

rem

aini

ng st

udy

is th

at o

f Liro

n et

al.

(198

4b).

The

repo

rted

Kp

valu

e of

2·1

0-2 c

m/h

sugg

ests

a "

very

hig

h" p

erm

eabi

lity.

Rep

orte

d da

ta

In v

itro

In v

ivo

Ase

ssm

ent

A15

1

App

endi

x A

Subs

tanc

e: P

ropy

lene

gly

col d

initr

ate

Mol

ecul

ar w

eigh

t:16

6.1

CA

S: 6

423-

43-4

Den

sity

:1.2

g/c

m³

Scie

ntifi

c ba

sis:

AoH

198

3:36

Mel

ting

poin

t:-8

°CB

oilin

g po

int:

121°

CSk

in n

otat

ion:

Yes

Vap

our

pres

sure

:9 P

a (a

t 20°

C)

Skin

per

mea

bilit

y: H

igh

Eva

pora

tion

rate

:Not

ava

ilabl

eL

og K

ow:1

.59

(est

imat

ed)

Sp

Loc

C

ell

L

(µm

) A

(c

m²)

V

(ml)

Veh

icle

C

(m

g/m

l) n

TE

xp

(h)

TO

bs

(h)

TL

ag

(h)

Abs

(%

) K

P

(10-4

cm

/h)

Flux

(µ

g/cm

²/h) R

efer

ence

N

o da

ta a

vaila

ble

Rat

Ba

4C

orn

oil

10%

(50

mg/

kg b

w)

0.5

0.5

1053

630

Cla

rk &

Litc

hfie

ld (1

969)

Onl

y on

e st

udy

was

foun

d on

pro

pyle

ne g

lyco

l din

itrat

e. In

Cla

rk &

Litc

hfie

ld (1

969)

, rat

s wer

e ex

pose

d to

a

10%

solu

tion

of p

ropy

lene

gly

col d

initr

ate

in c

orn

oil.

The

calc

ulat

ed K

p va

lue

of 5

·10-3

cm

/h su

gges

ts a

"hi

gh"

perm

eabi

lity.

Rep

orte

d da

ta

In v

itro

In v

ivo

Ase

ssm

ent

A15

2

App

endi

x A

Subs

tanc

e: P

ropy

lene

gly

col m

onom

ethy

l eth

er (P

GM

E); 1

-met

hoxy

-2-p

ropa

nol

Mol

ecul

ar w

eigh

t: 9

0.1

CA

S: 1

07-9

8-2

Den

sity

:0.9

24 g

/cm

³Sc

ient

ific

basi

s: A

oH 1

987:

39M

eltin

g po

int:

-97°

CB

oilin

g po

int:

119.

6°C

Skin

not

atio

n: Y

esV

apou

r pr

essu

re: 1

.2 k

Pa (a

t 20°

C)

Skin

per

mea

bilit

y: M

oder

ate

Eva

pora

tion

rate

: 0.7

1L

og K

ow:-

0.49

(est

imat

ed)

Sp

Loc

C

ell

L

(µm

) A

(c

m²)

V

(ml)

Veh

icle

C

(m

g/m

l) n

TE

xp

(h)

TO

bs

(h)

TL

ag

(h)

Abs

(%

) K

P

(10-4

cm

/h)

Flux

(µ

g/cm

²/h) R

efer

ence

Hum

Ab

StEp

i1.

85

Nea

t8

813

1200

Dug

ard

et a

l. (1

984)

Hum

Ab

StEp

i1.

81-

5N

eat

118

8<1

1312

00D

ugar

d et

al.

(198

4)H

umA

bSt

Full

3.1

Nea

t8

44

0.5

5.1

470

Lare

se F

ilon

et a

l. (1

999)

Hum

Br

Fl50

00.

640.

2H

2O3

524

242.

314

4.3

Wilk

inso

n &

Will

iam

s (20

02)

Hum

Br

Fl50

00.

640.

01N

eat

424

240.

6560

Wilk

inso

n &

Will

iam

s (20

02)

Hum

Br

Fl50

00.

640.

2N

eat

524

246.

560

0W

ilkin

son

& W

illia

ms (

2002

)

N

o da

ta a

vaila

ble

The

expe

rimen

t with

a a

pplie

d am

ount

of 0

.011

ml (

Wilk

inso

n &

Will

iam

s (20

02))

is d

isre

gard

ed si

nce

depl

etio

n of

PG

ME

occu

rred

.

The

rem

aini

ng st

udie

s sho

w c

onsi

sten

t res

ults

with

Kp

valu

es ra

ngin

g be

twee

n 5·

10-4

to 1

·10-3

cm

/h.

The

pref

erre

d st

udie

s of W

ilkin

son

& W

illia

ms (

2002

) and

Lar

ese

Filo

n et

al.

(199

9) w

ith h

uman

skin

exp

osed

to

neat

PG

ME

in v

itro,

repo

rts K

p va

lues

cor

resp

ondi

ng to

"m

oder

ate"

per

mea

bilit

y.

Rep

orte

d da

ta

In v

itro

In v

ivo

Ase

ssm

ent

A15

3

App

endi

x A

Subs

tanc

e: P

ropy

lene

gly

col m

onom

ethy

l eth

er a

ceta

te (P

GM

EA)

Mol

ecul

ar w

eigh

t:13

2.2

CA

S: 1

08-6

5-6

Den

sity

:0.9

69 g

/cm

³Sc

ient

ific

basi

s: A

oH 1

987:

39M

eltin

g po

int:

-10°

CB

oilin

g po

int:

145.

8°C

Skin

not

atio

n: Y

esV

apou

r pr

essu

re:0

.5 k

Pa (a

t 20°

C)

Skin

per

mea

bilit

y: N

o da

taE

vapo

ratio

n ra

te:0

.3L

og K

ow:0

.56

Sp

Loc

C

ell

L

(µm

) A

(c

m²)

V

(ml)

Veh

icle

C

(m

g/m

l) n

TE

xp

(h)

TO

bs

(h)

TL

ag

(h)

Abs

(%

) K

P

(10-4

cm

/h)

Flux

(µ

g/cm

²/h) R

efer

ence

N

o da

ta a

vaila

ble

N

o da

ta a

vaila

ble

No

quan

titat

ive

expe

rimen

tal d

ata

on d

erm

al u

ptak

e w

ere

foun

d in

the

liter

atur

e.

Ther

e is

no

men

tion

rega

rdin

g sk

in u

ptak

e of

PG

MEA

in th

e Sw

edis

h co

nsen

sus d

ocum

ent (

AoH

198

7:39

).

No

docu

men

tatio

n ha

s bee

n pr

oduc

ed b

y A

CG

IH.

Rep

orte

d da

ta

In v

itro

In v

ivo

Ase

ssm

ent

A15

4

App

endi

x A

Subs

tanc

e: R

esor

cino

lM

olec

ular

wei

ght:

110.

1C

AS:

108

-46-

3D

ensi

ty:1

.27

g/cm

³Sc

ient

ific

basi

s: A

oH 1

992:

47M

eltin

g po

int:

110°

CB

oilin

g po

int:

281°

CSk

in n

otat

ion:

Yes

Vap

our

pres

sure

:7.1

kPa

(at 1

90°C

)Sk

in p

erm

eabi

lity:

Mod

erat

eE

vapo

ratio

n ra

te:N

ot a

vaila

ble

Log

Kow

:0.8

0

Sp

Loc

C

ell

L

(µm

) A

(c

m²)

V

(ml)

Veh

icle

C

(m

g/m

l) n

TE

xp

(h)

TO

bs

(h)

TL

ag

(h)

Abs

(%

) K

P

(10-4

cm

/h)

Flux

(µ

g/cm

²/h) R

efer

ence

Hum

Ab

StEp

i2.

5In

fH

2O10

02

88

1.33

2.4

24R

ober

ts e

t al.

(197

7)

N

o da

ta a

vaila

ble

Onl

y on

e st

udy

was

foun

d on

reso

rcin

ol. R

ober

ts e

t al.

(197

7) e

xpos

ed h

uman

abd

omin

al sk

in to

an

aque

ous

solu

tion

of re

sorc

inol

.

The

repo

rted

Kp

valu

e of

2·1

0-4 c

m/h

, sug

gest

s a "

mod

erat

e" p

erm

eabi

lity.

It sh

ould

be

note

d th

at in

the

expe

rimen

ts b

y R

ober

ts e

t al.

(197

7), e

pide

rmal

shee

ts w

ere

sepa

rate

d by

exp

osin

g sk

in to

am

mon

ia v

apou

r fo

r 30

min

. Am

mon

ia is

wel

l kno

wn

to c

ause

seve

re sk

in d

amag

e A

msh

el e

t al.

(200

0). T

he a

lkal

ine

natu

re

of a

mm

onia

qui

ckly

sapo

nifie

s the

epi

derm

al fa

ts, t

hus d

estro

ying

the

prot

ectiv

e st

ruct

ure

of th

e ep

ider

mis

. Th

eref

ore,

the

met

hod

used

by

Rob

erts

et a

l. (1

977)

is li

kely

to re

sult

in se

vere

ove

rest

imat

es o

f the

flux

and

Kp

valu

e of

und

amag

ed sk

in.

Rep

orte

d da

ta

In v

itro

In v

ivo

Ase

ssm

ent

A15

5

App

endi

x A

Subs

tanc

e: S

odiu

m c

yani

deM

olec

ular

wei

ght:

49.0

CA

S: 1

43-3

3-9

Den

sity

:1.6

g/c

m³

Scie

ntifi

c ba

sis:

AoH

200

1:19

Mel

ting

poin

t:56

3.7°

CB

oilin

g po

int:

1496

°CSk

in n

otat

ion:

Yes

Vap

our

pres

sure

:Not

ava

ilabl

eSk

in p

erm

eabi

lity:

Mod

erat

eE

vapo

ratio

n ra

te:N

ot a

vaila

ble

Log

Kow

:-1.

69 (e

stim

ated

)

Sp

Loc

C

ell

L

(µm

) A

(c

m²)

V

(ml)

Veh

icle

C

(m

g/m

l) n

TE

xp

(h)

TO

bs

(h)

TL

ag

(h)

Abs

(%

) K

P

(10-4

cm

/h)

Flux

(µ

g/cm

²/h) R

efer

ence

Hum

Ab

St40

1.8

H2O

0.

0012

(0.0

0025

%)

61.

53.

70.

0004

5D

ugar

d (1

987)

Hum

Ab

St40

1.8

H2O

5.

3 (1

%)

51.

54.

32.

3D

ugar

d (1

987)

Hum

Ab

St40

1.8

H2O

53

(10%

)11

1.5

1158

Dug

ard

(198

7)H

umA

bSt

401.

8H

2O

210

(40%

)9

1.5

2.9

62D

ugar

d (1

987)

N

o da

ta a

vaila

ble

Seve

ral i

n vi

tro e

xper

imen

ts w

ith h

uman

skin

exp

osed

to a

queo

us so

lutio

ns o

f sod

ium

cya

nide

are

repo

rted

(Dug

ard

(198

7)).

The

Kp

valu

e of

3·1

0-4 c

m/h

, cor

resp

onds

to "

mod

erat

e" p

erm

eabi

lity.

It sh

ould

be

note

d th

at th

e pe

rmea

bilit

y of

hyd

roge

n cy

anid

e is

two

orde

rs o

f mag

nitu

de h

ighe

r.

Rep

orte

d da

ta

In v

itro

In v

ivo

Ase

ssm

ent

A15

6

App

endi

x A

Subs

tanc

e: S

tyre

neM

olec

ular

wei

ght:

104.

2C

AS:

100

-42-

5D

ensi

ty:0

.905

g/c

m³

Scie

ntifi

c ba

sis:

AoH

199

1:8

Mel

ting

poin

t:-3

0.6°

CB

oilin

g po

int:

145.

2°C

Skin

not

atio

n: Y

esV

apou

r pr

essu

re:0

.86

kPa

(at 2

0°C

)Sk

in p

erm

eabi

lity:

Low

Eva

pora

tion

rate

:0.5

4L

og K

ow:2

.95

Sp

Loc

C

ell

L

(µm

) A

(c

m²)

V

(ml)

Veh

icle

C

(m

g/m

l) n

TE

xp

(h)

TO

bs

(h)

TL

ag

(h)

Abs

(%

) K

P

(10-4

cm

/h)

Flux

(µ

g/cm

²/h) R

efer

ence

Rat

Ab

StFu

ll2.

51

Nea

t28

2.5-

62.

5-6

1.67

43-3

30 µ

g0.

3330

Tsur

uta

(198

2)

Hum

Ha

500

Inf

Nea

t9

0.17

-0.5

215

mg

0.67

60B

erod

e et

al.

(198

5)H

umA

rm/H

aN

eat

10<0

.199

-170

9000

-150

00D

utki

ewic

z et

al.

(196

8b)

Hum

Arm

/Ha

H2O

0.

067-

0.27

101

6000

-670

040

-180

Dut

kiew

icz

et a

l. (1

968b

)H

umW

B19

000

Vap

0.00

26 (

600p

pm)

23.

524

60 m

g35

000.

9R

iihim

aki e

t al.

(197

8)R

atW

BV

ap0.

013

(300

0ppm

)5

44

1800

021

McD

ouga

l et a

l. (1

990)

Tsur

uta

(198

2) u

sed

phys

iolo

gica

l sal

ine

as re

cept

or m

ediu

m, r

esul

ting

in lo

wer

solu

bilit

y fo

r lip

ophi

lic su

bsta

nces

,th

us p

roba

bly

unde

rest

imat

ing

the

perm

eabi

lity.

The

vapo

ur st

udie

s are

als

o di

sreg

arde

d.Th

e st

udie

s by

Dut

kiew

icz

et a

l. (1

968b

) are

onl

y de

scrib

ed v

ery

brie

fly a

nd a

ppea

r to

give

unr

ealis

tic K

p va

lues

.

The

pref

erre

d st

udy

is th

e hu

man

skin

in v

ivo

stud

y w

ith n

eat s

tyre

ne o

f (B

erod

e et

al.

(198

5)).

The

Kp

valu

e of

7·1

0-5 c

m/h

sugg

ests

"lo

w"

perm

eabi

lity.

Rep

orte

d da

ta

In v

itro

In v

ivo

Ase

ssm

ent

A15

7

App

endi

x A

Subs

tanc

e: T

etra

chlo

roet

hyle

neM

olec

ular

wei

ght:

165

.8C

AS:

127

-18-

4D

ensi

ty:1

.623

g/c

m³

Scie

ntifi

c ba

sis:

AoH

198

1:21

Mel

ting

poin

t:-2

2.3°

CB

oilin

g po

int:

121.

1°C

Skin

not

atio

n: N

oV

apou

r pr

essu

re: 1

.9 k

Pa (a

t 20°

C)

Skin

per

mea

bilit

y: M

oder

ate

Eva

pora

tion

rate

: 2.8

Log

Kow

:3.4

0

Sp

Loc

C

ell

L

(µm

) A

(c

m²)

V

(ml)

Veh

icle

C

(m

g/m

l) n

TE

xp

(h)

TO

bs

(h)

TL

ag

(h)

Abs

(%

) K

P

(10-4

cm

/h)

Flux

(µ

g/cm

²/h) R

efer

ence

Hum

Ab

Fl20

0-40

00.

2In

fH

2O0.

13-0

.31

µg/m

l35

66

160-

580

0.00

21-0

.018

Nak

ai e

t al.

(199

9)H

umA

bFl

200-

400

0.2

Inf

H2O

0.12

-0.2

9 µg

/ml

296

611

0-61

00.

0013

-0.0

18N

akai

et a

l. (1

999)

Rat

Ab

StFu

ll3.

71

Nea

t49

2-6

2-6

2.46

5-74

µg

0.03

5Ts

urut

a (1

977)

HG

PW

B~3

00In

fH

2O0.

044-

0.10

µg/

ml

(27-

64 p

pb)

51.

22-

4w37

000.

016-

0.03

7B

ogen

et a

l. (1

992)

HM

WB

Vap

0.00

69 (

1000

ppm

)6

2-6

2-6

1000

06.

9Ts

urut

a (1

989)

HM

WB

Vap

0.02

1 (3

000p

pm)

62-

62-

695

0020

Tsur

uta

(198

9)H

MW

BV

ap0.

0014

(20

0ppm

)6

2-6

2-6

7900

1.1

Tsur

uta

(198

9)H

umA

rm/H

a10

00V

ap1.

1 (6

.7 m

mol

/l)5

0.33

654

060

Kez

ic e

t al.

(200

0)H

umW

B19

000

Vap

0.00

42(6

00pp

m)

33.

524

48 m

g17

000.

72R

iihim

aki &

Pfa

ffli

(197

8)H

umH

a4

kgSo

il30

g/k

g so

il3

22

0.38

20 m

g9

Poet

et a

l. (2

002)

Mou

Ab

2.9

0.5

Nea

t3

0.25

180

µg1.

524

0Ts

urut

a (1

975)

Rat

WB

Vap

0.08

6 (1

2500

ppm

)4

44

6700

54M

cDou

gal e

t al.

(199

0)R

atB

a8

0.5

gSo

il4.

6 g/

kg so

il3

55

5790

0Po

et e

t al.

(200

2)R

atB

a8

0.5

gSo

il15

g/k

g so

il3

55

5588

0Po

et e

t al.

(200

2)R

atB

a8

0.5

gSo

il51

g/k

g so

il3

55

5186

0Po

et e

t al.

(200

2)R

atB

a5

5 g

Soil

16 g

/kg

soil

35

511

1100

Poet

et a

l. (2

002)

Rat

Ba

55

gSo

il53

g/k

g so

il3

55

8.7

1100

Poet

et a

l. (2

002)

Rat

Ba

55

gSo

il16

g/k

g so

il5

55

4911

00Po

et e

t al.

(200

2)R

atB

a5

5 g

Soil

50 g

/kg

soil

55

553

1100

Poet

et a

l. (2

002)

Rep

orte

d da

ta

In v

itro

In v

ivo

A15

8

App

endi

x A

The

in v

itro

stud

y of

Tsu

ruta

(197

7) u

sed

phys

iolo

gica

l sal

ine

as th

e re

cept

or m

ediu

m, t

his m

ay le

ad to

a se

vere

un

dere

stim

ate

of fl

ux a

nd K

p fo

r hig

hly

lipop

hilic

subs

tanc

es.

Bog

en e

t al.

(199

2) a

nd N

akai

et a

l. (1

999)

use

d di

lute

aqu

eous

solu

tion

of te

trach

loro

ethy

lene

.Th

e st

udie

s with

hum

an sk

in u

sed

aque

ous s

olut

ions

, vap

our o

r soi

l, le

adin

g to

ver

y hi

gh K

p va

lues

.

The

pref

erre

d st

udy

is th

at o

f Tsu

ruta

(197

5) u

sing

nea

t tet

rach

loro

ethy

lene

and

mou

se sk

in.

The

Kp

valu

e of

2·1

0-4 c

m/h

sugg

ests

"m

oder

ate"

per

mea

bilit

y.

Ase

ssm

ent

A15

9

App

endi

x A

Subs

tanc

e: T

etra

chlo

roph

enol

Mol

ecul

ar w

eigh

t:23

1.9

CA

S: 2

5167

-83-

3D

ensi

ty:1

.8 g

/cm

³Sc

ient

ific

basi

s: A

oH 1

986:

35M

eltin

g po

int:

~70°

CB

oilin

g po

int:

150

to 2

00°C

Skin

not

atio

n: Y

esV

apou

r pr

essu

re:N

ot a

vaila

ble

Skin

per

mea

bilit

y: L

owE

vapo

ratio

n ra

te:N

ot a

vaila

ble

Log

Kow

:4.4

5

Sp

Loc

C

ell

L

(µm

) A

(c

m²)

V

(ml)

Veh

icle

C

(m

g/m

l) n

TE

xp

(h)

TO

bs

(h)

TL

ag

(h)

Abs

(%

) K

P

(10-4

cm

/h)

Flux

(µ

g/cm

²/h) R

efer

ence

Hum

Ab

StFu

ll?1

0.01

H2O

+ P

CP

169

2424

30.

130.

2H

orst

man

et a

l. (1

989)

Hum

Ab

StFu

ll?1

0.01

Die

sel +

PC

P9.

49

2424

0.5

0.02

10.

02H

orst

man

et a

l. (1

989)

N

o da

ta a

vaila

ble

The

only

stud

y th

at w

as fo

und

on te

trach

loro

phen

ol w

as H

orst

man

et a

l. (1

989)

,w

ere

dies

el a

nd/o

r pen

tach

loro

phen

ol a

s use

d as

veh

icle

.

The

pref

erre

d ex

perim

ent g

ives

a K

p va

lue

of 1

0-5 c

m/h

, sug

gest

ing

"low

" pe

rmea

bilit

y.

Rep

orte

d da

ta

In v

itro

In v

ivo

Ase

ssm

ent

A16

0

App

endi

x A

Subs

tanc

e: T

etra

ethy

l lea

dM

olec

ular

wei

ght:

323.

4C

AS:

78-

00-2

Den

sity

:1.6

59 g

/cm

³Sc

ient

ific

basi

s: N

ot a

vaila

ble

Mel

ting

poin

t:-1

36.8

°CB

oilin

g po

int:

~200

°CSk

in n

otat

ion:

Yes

Vap

our

pres

sure

:27

Pa (a

t 20°

C)

Skin

per

mea

bilit

y: N

o da

taE

vapo

ratio

n ra

te:N

ot a

vaila

ble

Log

Kow

:4.1

5

Sp

Loc

C

ell

L

(µm

) A

(c

m²)

V

(ml)

Veh

icle

C

(m

g/m

l) n

TE

xp

(h)

TO

bs

(h)

TL

ag

(h)

Abs

(%

) K

P

(10-4

cm

/h)

Flux

(µ

g/cm

²/h) R

efer

ence

N

o da

ta a

vaila

ble

N

o da

ta a

vaila

ble

No

quan

titat

ive

expe

rimen

tal d

ata

on d

erm

al u

ptak

e w

ere

foun

d in

the

liter

atur

e.

No

cons

ensu

s doc

umen

t by

the

Swed

ish

Crit

eria

Gro

up.

Acc

ordi

ng to

AC

GIH

(200

1), t

etra

ethy

l lea

d ca

n be

abs

orbe

d pe

rcut

aneo

usly

in

amou

nts t

hat c

ause

syst

emic

poi

soni

ng.

Rep

orte

d da

ta

In v

itro

In v

ivo

Ase

ssm

ent

A16

1

App

endi

x A

Subs

tanc

e: T

etra

hydr

ofur

anM

olec

ular

wei

ght:

72.1

CA

S: 1

09-9

9-9

Den

sity

:0.8

86 g

/cm

³Sc

ient

ific

basi

s: A

oH 1

991:

8M

eltin

g po

int:

-108

.4°C

Boi

ling

poin

t:66

°CSk

in n

otat

ion:

No

Vap

our

pres

sure

:18

kPa

(at 2

0°C

)Sk

in p

erm

eabi

lity:

Low

Eva

pora

tion

rate

:8L

og K

ow:0

.46

Sp

Loc

C

ell

L

(µm

) A

(c

m²)

V

(ml)

Veh

icle

C

(m

g/m

l) n

TE

xp

(h)

TO

bs

(h)

TL

ag

(h)

Abs

(%

) K

P

(10-4

cm

/h)

Flux

(µ

g/cm

²/h) R

efer

ence

Hum

Br

Fl28

00.

640.

2N

eat

524

240.

330.

20.

4641

Wilk

inso

n &

Will

iam

s (20

01)

Hum

Br

Fl28

00.

640.

2H

2O

35

2424

0.35

1.7

6118

Wilk

inso

n &

Will

iam

s (20

01)

N

o da

ta a

vaila

ble

The

only

ava

ilabl

e da

ta a

re th

ose

of W

ilkin

son

& W

illia

ms (

2001

), gi

ven

as a

con

fere

nce

pres

enta

tion.

Hum

an b

reas

t ski

n w

as e

xpos

ed in

vitr

o to

nea

t and

aqu

eous

solu

tions

of t

etra

hydr

ofur

an.

The

Kp

valu

e of

nea

t tet

rahy

drof

uran

cor

resp

onds

to "

low

" pe

rmea

bilit

y.

It sh

ould

be

note

d th

at th

e K

p m

easu

red

from

aqu

eous

solu

tions

is o

ver t

wo

orde

rs o

f mag

nitu

de h

ighe

r,su

gges

ting

a st

rong

veh

icle

eff

ect.

Rep

orte

d da

ta

In v

itro

In v

ivo

Ase

ssm

ent

A16

2

App

endi

x A

Subs

tanc

e: T

etra

met

hyl l

ead

Mol

ecul

ar w

eigh

t:26

7.3

CA

S: 7

5-74

-1D

ensi

ty:2

.0 g

/cm

³Sc

ient

ific

basi

s: N

ot a

vaila

ble

Mel

ting

poin

t:-2

7.5°

CB

oilin

g po

int:

110°

CSk

in n

otat

ion:

Yes

Vap

our

pres

sure

:2.9

kPa

(at 2

0°C

)Sk

in p

erm

eabi

lity:

No

data

Eva

pora

tion

rate

:Not

ava

ilabl

eL

og K

ow:2

.97

Sp

Loc

C

ell

L

(µm

) A

(c

m²)

V

(ml)

Veh

icle

C

(m

g/m

l) n

TE

xp

(h)

TO

bs

(h)

TL

ag

(h)

Abs

(%

) K

P

(10-4

cm

/h)

Flux

(µ

g/cm

²/h) R

efer

ence

N

o da

ta a

vaila

ble

N

o da

ta a

vaila

ble

No

quan

titat

ive

expe

rimen

tal d

ata

on d

erm

al u

ptak

e w

ere

foun

d in

the

liter

atur

e.

The

AC

GIH

-TLV

com

mitt

ee (A

CG

IH (2

001)

) bas

e th

eir s

kin

nota

tion

on a

stud

y w

ith d

ogs

dem

onst

ratin

g to

xici

ty a

fter d

erm

al e

xpos

ure.

Rep

orte

d da

ta

In v

itro

In v

ivo

Ase

ssm

ent

A16

3

App

endi

x A

Subs

tanc

e: T

hiog

lyco

lic a

cid

Mol

ecul

ar w

eigh

t:92

.1C

AS:

68-

11-1

Den

sity

:1.3

25 g

/cm

³Sc

ient

ific

basi

s: A

oH 1

994:

30M

eltin

g po

int:

-16.

5°C

Boi

ling

poin

t:12

0°C

Skin

not

atio

n: Y

esV

apou

r pr

essu

re:1

.3 k

Pa (a

t 18°

C)

Skin

per

mea

bilit

y: N

o da

taE

vapo

ratio

n ra

te:N

ot a

vaila

ble

Log

Kow

:0.0

9

Sp

Loc

C

ell

L

(µm

) A

(c

m²)

V

(ml)

Veh

icle

C

(m

g/m

l) n

TE

xp

(h)

TO

bs

(h)

TL

ag

(h)

Abs

(%

) K

P

(10-4

cm

/h)

Flux

(µ

g/cm

²/h) R

efer

ence

N

o da

ta a

vaila

ble

N

o da

ta a

vaila

ble

No

quan

titat

ive

expe

rimen

tal d

ata

on d

erm

al u

ptak

e w

ere

foun

d in

the

liter

atur

e.

The

skin

not

atio

n as

sign

ed b

y A

CG

IH-T

LV is

bas

ed o

n sy

stem

ic to

xici

ty in

ani

mal

s fol

low

ing

derm

al a

pplic

atio

n.

Acc

ordi

ng to

theo

retic

al c

alcu

latio

ns b

y Fi

sero

va-B

erge

rova

et a

l. (1

990)

the

pote

ntia

l for

der

mal

abso

rptio

n an

d re

sulti

ng to

xici

ty is

sign

ifica

nt.

Rep

orte

d da

ta

In v

itro

In v

ivo

Ase

ssm

ent

A16

4

App

endi

x A

Subs

tanc

e: T

itani

um d

ioxi

deM

olec

ular

wei

ght:

79.9

CA

S: 1

3463

-67-

7D

ensi

ty:4

.26

g/cm

³Sc

ient

ific

basi

s: N

ot a

vaila

ble

Mel

ting

poin

t:18

55°C

Boi

ling

poin

t:29

00°C

Skin

not

atio

n: N

oV

apou

r pr

essu

re:N

ot a

vaila

ble

Skin

per

mea

bilit

y: E

xtre

mel

y lo

wE

vapo

ratio

n ra

te:N

ot a

vaila

ble

Log

Kow

:2.2

3 (e

stim

ated

)

Sp

Loc

C

ell

L

(µm

) A

(c

m²)

V

(ml)

Veh

icle

C

(m

g/m

l) n

TE

xp

(h)

TO

bs

(h)

TL

ag

(h)

Abs

(%

) K

P

(10-4

cm

/h)

Flux

(µ

g/cm

²/h) R

efer

ence

Pig

Ab

St50

01

H2O

+ o

il10

% (2

40 µ

g/cm

²)3

2424

< 0.

10.

001

0.01

Gam

er e

t al.

(200

6)

N

o da

ta a

vaila

ble

Mic

ro fi

ne T

iO2 (

10 w

t%) i

n oi

l/wat

er e

mul

sion

was

app

lied

to th

e sk

in. M

ean

parti

cle

size

was

80

nm w

ith 9

0%

of th

e pa

rticl

es <

160

nm

. Der

mat

omed

pig

skin

was

use

d in

the

stat

ic c

ells

, and

bov

ine

seru

m a

lbum

in (5

%)

was

add

ed to

the

salin

e as

rece

ptor

med

ium

. Hig

h re

cove

ry ra

tes (

98-1

00%

) wer

e ac

hiev

ed,

still

no

TiO

2 was

det

ecte

d in

the

rece

ptor

med

ium

.Th

e re

porte

d de

tect

ion

limit

was

0.3

µg

Ti, c

orre

spon

ding

to 0

.1%

abs

orbe

d do

se.

Thus

, the

cal

cula

ted

Kp

valu

e is

low

er th

an 1

·10-7

cm

/h, s

ugge

stin

g "e

xtre

mel

y lo

w"

perm

eabi

lity

(or l

ower

).

Rep

orte

d da

ta

In v

itro

In v

ivo

Ase

ssm

ent

A16

5

App

endi

x A

Subs

tanc

e: T

olue

neM

olec

ular

wei

ght:

92.1

CA

S: 1

08-8

8-3

Den

sity

:0.8

67 g

/cm

³Sc

ient

ific

basi

s: A

oH 2

002:

18M

eltin

g po

int:

-93°

CB

oilin

g po

int:

110.

6°C

Skin

not

atio

n: Y

esV

apou

r pr

essu

re:3

.7 k

Pa (a

t 20°

C)

Skin

per

mea

bilit

y: M

oder

ate

Eva

pora

tion

rate

:2.2

Log

Kow

:2.7

3

Sp

Loc

C

ell

L

( µm

) A

(c

m²)

V

(ml)

Veh

icle

C

(m

g/m

l) n

TE

xp

(h)

TO

bs

(h)

TL

ag

(h)

Abs

(%

) K

P

(10-4

cm

/h)

Flux

(µ

g/cm

²/h) R

efer

ence

Hum

St50

01.

1JP

-824

242

0.09

5K

anik

kann

an e

t al.

(200

1)H

umB

rSt

300-

600

0.64

Nea

t6

66

113

0U

rsin

et a

l. (1

995)

Hum

Br

Fl28

00.

640.

2N

eat

524

240.

010.

220.

1412

Wilk

inso

n &

Will

iam

s (20

01)

Hum

Br

Fl28

00.

640.

2H

2O

205

2424

079

830

1.7

Wilk

inso

n &

Will

iam

s (20

01)

Hum

Fl25

01

0.2-

0.3

Nea

t3

2424

1.9

1.6-

2.4

140-

210

Bom

an &

Mai

bach

(200

0)H

umFl

250

10.

2-0.

3n-

Bu

430

(50%

)4

2020

9.5

9.2-

1440

0-62

0B

oman

& M

aiba

ch (2

000)

Hum

Fl25

01

0.2-

0.3

Chf

+ M

e43

0(5

0%)

520

202

2-3

85-1

30B

oman

& M

aiba

ch (2

000)

MP

Fl90

03.

1N

eat

614

.514

.53.

732

0Ja

cobs

& P

hanp

rasi

t (19

93)

MP

Fl90

03.

1V

ap0.

12 (S

atur

ated

)6

14.5

14.5

1400

016

0Ja

cobs

& P

hanp

rasi

t (19

93)

MP

Ear

St50

01.

1JP

-824

242.

50.

12K

anik

kann

an e

t al.

(200

1)R

atB

aSt

560

4.9

2JP

-80.

06%

84

40.

511

0.54

McD

ouga

l et a

l. (2

000)

Rat

Ab

StFu

ll2.

61

Nea

t34

1-5

1-5

1.55

10-4

30 µ

g0.

5447

Tsur

uta

(198

2)

HM

Ba

0.8

0.00

45N

eat

120.

033

490

µg

3429

00Su

sten

et a

l. (1

990)

HM

WB

Vap

3000

ppm

62-

62-

612

000

14Ts

urut

a (1

989)

HM

WB

Vap

1000

ppm

62-

62-

612

000

4.6

Tsur

uta

(198

9)H

MW

BV

ap20

0ppm

62-

62-

612

000

0.9

Tsur

uta

(198

9)H

umA

rm17

0.2

Nea

t10

11

71 m

g21

018

000

Dut

kiew

icz

et a

l. (1

968a

)H

umH

aH

2O

0.19

-0.6

116

11

130

mg

6200

-200

0038

0D

utki

ewic

z et

al.

(196

8a)

Hum

Ha

Nea

t10

122

019

000

Dut

kiew

icz

& T

yras

(196

8b)

Hum

Arm

/Ha

1000

Vap

0.06

5 (0

.7 m

mol

/L)

50.

336

1400

9K

ezic

et a

l. (2

000)

Hum

WB

1900

0V

ap0.

0023

(60

0ppm

)2

3.5

2426

mg

1700

0.4

Riih

imak

i & P

faff

li (1

978)

Hum

FiIn

fH

2O1%

1215

s0.

30.

890.

77N

aito

h et

al.

(200

2)H

umFi

Inf

H2O

1%12

15s

0.3

2320

Nai

toh

et a

l. (2

002)

Hum

WB

Inf

H2O

0.00

056

0.3-

0.5

0.75

-130

-200

0.00

15-0

.01

Thra

ll et

al.

(200

2a)

Rep

orte

d da

ta

In v

itro

In v

ivo

A16

6

App

endi

x A

Sp

Loc

C

ell

L

( µm

) A

(c

m²)

V

(ml)

Veh

icle

C

(m

g/m

l) n

TE

xp

(h)

TO

bs

(h)

TL

ag

(h)

Abs

(%

) K

P

(10-4

cm

/h)

Flux

(µ

g/cm

²/h) R

efer

ence

Mou

Ba

0.8

0.00

4N

eat

124

42.

10.

2723

Sust

en e

t al.

(199

0)M

ouA

b3.

10.

5N

eat

150.

25-1

0.01

69Ts

urut

a (1

996)

Mou

Ab

3.1

0.5

Me

50%

150.

25-1

0.1

260

Tsur

uta

(199

6)M

ouA

b3.

10.

5D

MSO

50

%15

0.25

-10.

1231

0Ts

urut

a (1

996)

Mou

Ab

3.1

0.5

DM

F15

0.25

-10.

0822

0Ts

urut

a (1

996)

Rat

WB

64

472

0021

McD

ouga

l et a

l. (1

990)

Rat

Ba

4.9

2H

2O0.

23

55

4576

015

Thra

ll et

al.

(200

2b)

Rat

Ba

4.9

2H

2O0.

53

55

4270

035

Thra

ll et

al.

(200

2b)

The

hum

an sk

in in

vitr

o st

udie

s with

nea

t tol

uene

show

rela

tivel

y co

nsis

tent

resu

lts w

ith K

p va

lues

rang

ing

from

1·1

0-5 to

2·1

0-4 c

m/h

. Th

e in

viv

o st

udie

s by

Dut

kiew

icz

et a

l. (1

968a

) and

Dut

kiew

icz

& T

yras

(196

8b) s

how

two

orde

rs o

f m

agni

tude

hig

her K

p va

lues

.

The

pref

erre

d ex

perim

ent i

s the

one

by

Bom

an &

Mai

bach

(200

0) w

here

hum

an sk

in w

as e

xpos

ed to

nea

t tol

uene

.

The

Kp

valu

e of

2·1

0-4 c

m/h

cor

resp

onds

to "

mod

erat

e" p

erm

eabi

lity.

It sh

ould

be

note

d th

at th

e K

p va

lue

of to

luen

e va

pour

and

in a

queo

us so

lutio

n is

aro

und

4 or

ders

of m

agni

tude

hi

gher

than

in th

e pr

efer

red

stud

y.

Ase

ssm

ent

A16

7

App

endi

x A

Subs

tanc

e: T

ribut

yltin

Mol

ecul

ar w

eigh

t:29

0.0

CA

S: 5

6573

-85-

4D

ensi

ty:N

ot a

vaila

ble

Scie

ntifi

c ba

sis:

Not

ava

ilabl

e M

eltin

g po

int:

53°C

Boi

ling

poin

t:19

3°C

Skin

not

atio

n: Y

esV

apou

r pr

essu

re:N

ot a

vaila

ble

Skin

per

mea

bilit

y: N

o da

taE

vapo

ratio

n ra

te:N

ot a

vaila

ble

Log

Kow

:4.7

6

Sp

Loc

C

ell

L

(µm

) A

(c

m²)

V

(ml)

Veh

icle

C

(m

g/m

l) n

TE

xp

(h)

TO

bs

(h)

TL

ag

(h)

Abs

(%

) K

P

(10-4

cm

/h)

Flux

(µ

g/cm

²/h) R

efer

ence

N

o da

ta a

vaila

ble

N

o da

ta a

vaila

ble

The

Swed

ish

skin

not

atio

n ap

plie

s to

orga

notin

com

poun

ds in

gen

eral

(inc

ludi

ng tr

ibut

yltin

).

Der

mal

app

licat

ion

of v

ario

us o

rgan

otin

com

poun

ds c

ause

s sys

tem

ic to

xici

ty in

labo

rato

ry a

nim

als.

For e

xam

ple,

dai

ly a

pplic

atio

n of

10

mg/

kg tr

ibut

yltin

oxi

de to

the

shav

ed sk

in o

f mal

e gu

inea

pig

s cau

sed

redu

ced

body

wei

ght a

nd re

nal t

ubul

ar d

egen

erat

ion

(AC

GIH

(200

1)).

The

derm

al L

D50

val

ue in

rats

was

repo

rted

to 6

05 m

g/kg

(AC

GIH

(200

1)).

Rep

orte

d da

ta

In v

itro

In v

ivo

Ase

ssm

ent

A16

8

App

endi

x A

Subs

tanc

e: T

richl

oret

hane

, 1,1

,1-

Mol

ecul

ar w

eigh

t:13

3.4

CA

S: 7

1-55

-6D

ensi

ty:1

.338

g/c

m³

Scie

ntifi

c ba

sis:

AoH

198

2:9

Mel

ting

poin

t:-3

2.6°

CB

oilin

g po

int:

74.1

°CSk

in n

otat

ion:

No

Vap

our

pres

sure

:13

kPa

(at 2

0°C

)Sk

in p

erm

eabi

lity:

Mod

erat

eE

vapo

ratio

n ra

te:1

3L

og K

ow:2

.49

Sp

Loc

C

ell

L

(µm

) A

(c

m²)

V

(ml)

Veh

icle

C

(m

g/m

l) n

TE

xp

(h)

TO

bs

(h)

TL

ag

(h)

Abs

(%

) K

P

(10-4

cm

/h)

Flux

(µ

g/cm

²/h) R

efer

ence

N

o da

ta a

vaila

ble

Hum

Arm

/Ha

1000

Vap

1.6

mm

ol/L

50.

336

210

4.4

Kez

ic e

t al.

(200

0)H

umW

B19

000

Vap

600p

pm2

3.5

242

mg

900.

03R

iihim

aki &

Pfa

ffli

(197

8)M

ouA

b2.

90.

5N

eat

60.

2527

0 µg

2.7

370

Tsur

uta

(197

5)

The

stud

y by

Tsu

ruta

(197

5) su

gges

t "m

oder

ate"

per

mea

bilit

y of

nea

t 1,1

,1-tr

ichl

oroe

than

e.H

owev

er, a

bsor

ptio

n w

as m

easu

red

by h

omog

eniz

ing

the

who

le a

nim

al. T

his m

etho

d m

ay se

vere

ly

unde

rest

imat

e sk

in p

erm

eabi

lity.

The

rem

aini

ng e

xper

imen

ts e

xpos

ed th

e sk

in to

1,1

,1-tr

ichl

oroe

than

e va

pour

, whi

ch p

roba

bly

give

s ov

eres

timat

ed K

p va

lues

.

Rep

orte

d da

ta

In v

itro

In v

ivo

Ase

ssm

ent

A16

9

App

endi

x A

Subs

tanc

e: T

richl

oroe

thyl

ene,

1,1

,2-

Mol

ecul

ar w

eigh

t:13

1.3

CA

S: 7

9-01

-6D

ensi

ty:1

.462

g/c

m³

Scie

ntifi

c ba

sis:

AoH

198

1:21

Mel

ting

poin

t:-8

6°C

Boi

ling

poin

t:86

.7°C

Skin

not

atio

n: N

oV

apou

r pr

essu

re:7

.2 k

Pa (a

t 20°

C)

Skin

per

mea

bilit

y: M

oder

ate

Eva

pora

tion

rate

:6.4

Log

Kow

:2.4

2

Sp

Loc

C

ell

L

(µm

) A

(c

m²)

V

(ml)

Veh

icle

C

(m

g/m

l) n

TE

xp

(h)

TO

bs

(h)

TL

ag

(h)

Abs

(%

) K

P

(10-4

cm

/h)

Flux

(µ

g/cm

²/h) R

efer

ence

Hum

Ab

Fl20

0-40

00.

2In

fH

2O32

-82

µg/l

236

612

000.

0038

-0.0

098

Nak

ai e

t al.

(199

9)H

umA

bFl

200-

400

0.2

Inf

H2O

34-7

9 µg

/l17

66

1100

0.00

37-0

.008

7N

akai

et a

l. (1

999)

Hum

Br

FlFu

ll0.

79H

2O7.

3 ng

/ml

(5pp

b)10

50-

10-

128

000.

002

Bog

en e

t al.

(199

8)R

atFk

StFu

ll0.

790.

005

Nea

t5

1010

1.3

0.08

212

McC

orm

ick

et a

l. (1

991)

Rat

FkSt

Full

0.79

0.00

5N

eat

56

101.

10.

1217

McC

orm

ick

et a

l. (1

991)

Rat

FkSt

Full

0.79

0.00

5N

eat

54

101

0.16

23M

cCor

mic

k et

al.

(199

1)R

atFk

StFu

ll0.

790.

005

Nea

t5

310

0.9

0.19

28M

cCor

mic

k et

al.

(199

1)R

atFk

StFu

ll0.

790.

005

Nea

t5

210

0.7

0.22

32M

cCor

mic

k et

al.

(199

1)R

atFk

StFu

ll0.

790.

005

Nea

t5

110

0.5

0.32

46M

cCor

mic

k et

al.

(199

1)R

atFk

StFu

ll0.

790.

005

Nea

t5

0.5

100.

30.

3855

McC

orm

ick

et a

l. (1

991)

Rat

FkSt

Full

0.79

0.00

5N

eat

510

102.

50.

1623

McC

orm

ick

et a

l. (1

991)

Rat

FkSt

Full

0.79

0.00

5N

eat

56

102.

20.

2334

McC

orm

ick

et a

l. (1

991)

Rat

FkSt

Full

0.79

0.00

5N

eat

54

101.

90.

344

McC

orm

ick

et a

l. (1

991)

Rat

FkSt

Full

0.79

0.00

5N

eat

53

101.

70.

3652

McC

orm

ick

et a

l. (1

991)

Rat

FkSt

Full

0.79

0.00

5N

eat

52

101.

40.

4565

McC

orm

ick

et a

l. (1

991)

Rat

FkSt

Full

0.79

0.00

5N

eat

51

101

0.63

92M

cCor

mic

k et

al.

(199

1)R

atFk

StFu

ll0.

790.

005

Nea

t5

0.5

100.

50.

6392

McC

orm

ick

et a

l. (1

991)

Rat

Ab

StFu

ll2.

60.

5N

eat

271-

51-

51.

10.

4668

Tsur

uta

(197

8)

HG

PW

B~3

00In

fH

2O28

-160

ng/

ml

(19-

110

ppb)

51.

22-

4w23

000.

0064

-0.0

37B

ogen

et a

l. (1

992)

HG

PW

B~3

00In

fH

2O0.

15 (

1000

00 p

pb)

51.

22-

4w21

0032

Bog

en e

t al.

(199

2)H

umA

rm/H

a10

00V

ap1.

3 m

mol

/L5

0.33

649

08.

4K

ezic

et a

l. (2

000)

Hum

Arm

5080

H2O

1

32

20.

33

mg

190

19Po

et e

t al.

(200

0)H

umH

a51

040

00H

2O

13

22

0.3

40 m

g15

015

Poet

et a

l. (2

000)

Mou

Ab

2.9

0.5

Nea

t21

0.08

3-0.

2591

-340

µg

3.2

470

Tsur

uta

(197

8)

A w

ide

rang

e of

Kp

valu

es a

re re

porte

d, d

epen

ding

on

vehi

cle

and

spec

ies.

The

pref

erre

d st

udy

is th

at o

f Tsu

ruta

(197

8), u

sing

mou

se sk

in in

viv

o w

ith n

eat t

richl

oroe

thyl

ene.

The

calc

ulat

ed K

p va

lue

of 3

·10-4

cm

/h, s

ugge

sts "

mod

erat

e" p

erm

eabi

lity.

Rep

orte

d da

ta

In v

itro

In v

ivo

Ase

ssm

ent

A17

0

App

endi

x A

Subs

tanc

e: T

richl

orop

heno

lM

olec

ular

wei

ght:

197.

4C

AS:

251

67-8

2-2

Den

sity

:~1.

5 g/

cm³

Scie

ntifi

c ba

sis:

Not

ava

ilabl

e M

eltin

g po

int:

~70°

CB

oilin

g po

int:

150

to 2

00°C

Skin

not

atio

n: Y

esV

apou

r pr

essu

re:N

ot a

vaila

ble

Skin

per

mea

bilit

y: N

o da

taE

vapo

ratio

n ra

te:N

ot a

vaila

ble

Log

Kow

:3.6

9

Sp

Loc

C

ell

L

(µm

) A

(c

m²)

V

(ml)

Veh

icle

C

(m

g/m

l) n

TE

xp

(h)

TO

bs

(h)

TL

ag

(h)

Abs

(%

) K

P

(10-4

cm

/h)

Flux

(µ

g/cm

²/h) R

efer

ence

N

o da

ta a

vaila

ble

N

o da

ta a

vaila

ble

No

quan

titat

ive

expe

rimen

tal d

ata

on d

erm

al u

ptak

e w

ere

foun

d in

the

liter

atur

e.

The

Swed

ish

cons

ensu

s rep

ort (

AoH

198

9:35

) sta

tes t

hat r

epor

ted

case

s of p

oiso

ning

indi

cate

that

the

chlo

roph

enol

s (tri

-, te

tra-,

pent

a-) c

an b

e ab

sorb

ed e

ffec

tivel

y th

roug

h th

e sk

in, a

nd th

at th

is is

pro

babl

y th

e m

ajor

exp

osur

e ro

ute

at sa

wm

ills.

Rep

orte

d da

ta

In v

itro

In v

ivo

Ase

ssm

ent

A17

1

App

endi

x A

Subs

tanc

e: T

richl

orop

heno

l, 2,

4,6-

Mol

ecul

ar w

eigh

t:19

7.4

CA

S: 8

8-06

-2D

ensi

ty:1

.49

g/cm

³Sc

ient

ific

basi

s: N

ot a

vaila

ble

Mel

ting

poin

t:69

.5°C

Boi

ling

poin

t:24

4.5°

CSk

in n

otat

ion:

Yes

Vap

our

pres

sure

:133

Pa

(at 7

6.5°

C)

Skin

per

mea

bilit

y: E

xtre

mel

y hi

ghE

vapo

ratio

n ra

te:N

ot a

vaila

ble

Log

Kow

:3.6

9

Sp

Loc

C

ell

L

(µm

) A

(c

m²)

V

(ml)

Veh

icle

C

(m

g/m

l) n

TE

xp

(h)

TO

bs

(h)

TL

ag

(h)

Abs

(%

) K

P

(10-4

cm

/h)

Flux

(µ

g/cm

²/h) R

efer

ence

Mou

Full

0.79

0.5

0.5

1700

85H

uq e

t al.

(198

6)

N

o da

ta a

vaila

ble

Onl

y on

e st

udy

on 2

,4,6

-tric

hlor

ophe

nol w

as fo

und.

In H

uq e

t al.

(198

6) th

e re

porte

d K

p va

lue

sugg

ests

"ex

trem

ely

high

" pe

rmea

tion.

It sh

ould

be

note

d th

at fo

r phe

nol,

Huq

et a

l. (1

986)

repo

rted

a K

p va

lue

whi

ch w

as tw

o or

ders

of m

agni

tude

high

er th

an th

e pr

efer

red

valu

e.

Rep

orte

d da

ta

In v

itro

In v

ivo

Ase

ssm

ent

A17

2

App

endi

x A

Subs

tanc

e: T

rieth

anol

amin

eM

olec

ular

wei

ght:

149.

2C

AS:

102

-71-

6D

ensi

ty:1

.126

g/c

m³

Scie

ntifi

c ba

sis:

AoH

198

3:36

Mel

ting

poin

t:21

.6°C

Boi

ling

poin

t:33

5.4°

CSk

in n

otat

ion:

No

Vap

our

pres

sure

:<1

Pa (a

t 20°

C)

Skin

per

mea

bilit

y: H

igh

Eva

pora

tion

rate

:<0.

005

Log

Kow

:-1.

00

Sp

Loc

C

ell

L

(µm

) A

(c

m²)

V

(ml)

Veh

icle

C

(m

g/m

l) n

TE

xp

(h)

TO

bs

(h)

TL

ag

(h)

Abs

(%

) K

P

(10-4

cm

/h)

Flux

(µ

g/cm

²/h) R

efer

ence

N

o da

ta a

vaila

ble

Mou

Ba

20.

04-0

.06

Nea

t (20

00 m

g/kg

bw

)24

4848

783.

741

0St

ott e

t al.

(200

0)M

ouB

a2

0.2

Ac

Nea

t (1

000

mg/

kg b

w)

324

2492

4.2

480

Stot

t et a

l. (2

000)

Mou

Ba

20.

2H

2O25

0(2

000

mg/

kg b

w)

324

2479

3382

0St

ott e

t al.

(200

0)M

ou1

Ac

209

2424

380

780

Kna

ak e

t al.

(199

7)M

ou1.

8H

2O23

2148

4817

041

0K

naak

et a

l. (1

997)

Mou

1.8

Nea

t3

2424

360

840

Kna

ak e

t al.

(199

7)M

ou2

Nea

t24

4848

200

410

Kna

ak e

t al.

(199

7)M

ou1.

8N

eat

2448

4818

042

0K

naak

et a

l. (1

997)

Rat

Ba

20.

4N

eat (

1000

mg/

kg b

w)

348

4876

1820

00St

ott e

t al.

(200

0)R

at1.

8N

eat

348

4819

025

00K

naak

et a

l. (1

997)

The

data

pre

sent

ed b

y K

naak

et a

l. (1

997)

are

bas

ed o

n an

indu

stry

repo

rt by

Wae

chte

r 198

8 (u

nava

ilabl

e).

The

orig

inal

dat

a ap

pear

to b

e th

e sa

me

as th

ose

pres

ente

d in

Sto

tt et

al.

(200

0), h

owev

er, t

he c

alcu

latio

nof

con

cent

ratio

n an

d, h

ence

, Kp

valu

es o

f Kna

ak e

t al.

(199

7) a

re se

emin

gly

erro

neou

s.

The

first

two

expe

rimen

ts b

y St

ott e

t al.

(200

0) a

re d

isre

gard

ed d

ue to

smal

l vol

ume

and

acet

one

as v

ehic

le, r

espe

ctiv

ely.

The

next

two

expe

rimen

ts a

re in

goo

d ag

reem

ent c

onsi

derin

g kn

own

spec

ies d

iffer

ence

s bet

wee

n m

ouse

and

rat s

kin.

The

rat s

kin

data

is p

refe

rred

as b

eing

clo

ser t

o hu

man

skin

. The

Kp

valu

e of

2·1

0-3 c

m/h

cor

resp

onds

to "

high

" pe

rmea

bilit

y.

How

ever

, the

exp

erim

ents

of S

tott

et a

l. (2

000)

hav

e hi

gh %

abso

rptio

n, w

hich

sugg

est t

hat t

he fl

uxes

and

Kp

valu

es

may

hav

e be

en u

nder

estim

ated

.

Rep

orte

d da

ta

In v

itro

In v

ivo

Ase

ssm

ent

A17

3

App

endi

x A

Subs

tanc

e: T

rinitr

otol

uene

, 2,4

,6-

Mol

ecul

ar w

eigh

t:22

7.1

CA

S: 1

18-9

6-7

Den

sity

:1.6

54 g

/cm

³Sc

ient

ific

basi

s: A

oH 1

992:

6M

eltin

g po

int:

80.9

°CB

oilin

g po

int:

240°

CSk

in n

otat

ion:

Yes

Vap

our

pres

sure

:0.0

04 k

Pa (a

t 80°

C)

Skin

per

mea

bilit

y: M

oder

ate

Eva

pora

tion

rate

:Not

ava

ilabl

eL

og K

ow:1

.60

Sp

Loc

C

ell

L

(µm

) A

(c

m²)

V

(ml)

Veh

icle

C

(m

g/m

l) n

TE

xp

(h)

TO

bs

(h)

TL

ag

(h)

Abs

(%

) K

P

(10-4

cm

/h)

Flux

(µ

g/cm

²/h) R

efer

ence

Pig

Ba

St50

0-90

00.

89.

9 m

g/cm

²Soi

l (Ti

)1.

5 (9

.5 µ

g/cm

²)6

88

1.3

0.09

50.

015

Rei

fenr

ath

et a

l. (2

002)

Pig

Ba

St50

0-90

00.

810

mg/

cm²S

oil (

Yo)

1.8

(11

µg/c

m²)

68

85

0.39

0.06

8R

eife

nrat

h et

al.

(200

2)Pi

gB

aSt

500-

900

0.8

0.00

5A

c2.

2 (1

1 µg

/cm

²)6

88

191.

20.

25R

eife

nrat

h et

al.

(200

2)

N

o da

ta a

vaila

ble

The

only

foun

d st

udy

was

that

of R

eife

nrat

h et

al.

(200

2), w

here

pig

skin

was

exp

osed

to 2

,4,6

-trin

itrot

olue

new

ith so

il or

ace

tone

as v

ehic

les.

It sh

ould

be

note

d th

at th

e us

e of

ace

tone

as v

ehic

le m

ay h

ave

seve

rely

affe

cted

the

skin

pro

perti

es.

The

pref

erre

d ex

perim

ent i

s tha

t with

ace

tone

, sug

gest

ing

a "m

oder

ate"

per

mea

bilit

y.

Rep

orte

d da

ta

In v

itro

In v

ivo

Ase

ssm

ent

A17

4

App

endi

x A

Subs

tanc

e: T

urpe

ntin

eM

olec

ular

wei

ght:

Not

ava

ilabl

eC

AS:

800

6-64

-2D

ensi

ty:0

.9 g

/cm

³Sc

ient

ific

basi

s: A

oH 1

987:

39M

eltin

g po

int:

-50

to -6

0°C

Boi

ling

poin

t:15

0 to

180

°CSk

in n

otat

ion:

Yes

Vap

our

pres

sure

:0.6

6 kP

a (a

t 25°

C)

Skin

per

mea

bilit

y: N

o da

taE

vapo

ratio

n ra

te:N

ot a

vaila

ble

Log

Kow

:Not

ava

ilabl

e

Sp

Loc

C

ell

L

(µm

) A

(c

m²)

V

(ml)

Veh

icle

C

(m

g/m

l) n

TE

xp

(h)

TO

bs

(h)

TL

ag

(h)

Abs

(%

) K

P

(10-4

cm

/h)

Flux

(µ

g/cm

²/h) R

efer

ence

N

o da

ta a

vaila

ble

N

o da

ta a

vaila

ble

No

quan

titat

ive

expe

rimen

tal d

ata

on d

erm

al u

ptak

e w

ere

foun

d in

the

liter

atur

e.

Acc

ordi

ng to

the

Swed

ish

Crit

eria

Gro

up, α

-pin

ene

(a m

ajor

com

pone

nt o

f tur

pent

ine)

is re

adily

ab

sorb

ed v

ia th

e sk

in (A

oH 1

987:

39).

AC

GIH

(200

1), m

entio

n th

at sk

in m

ay b

e a

sign

ifica

nt ro

ute

of e

xpos

ure

to tu

rpen

tine

but t

hat t

here

is n

o ev

iden

ce o

f org

an d

amag

e as

a re

sult

of th

is a

bsor

ptio

n.

Rep

orte

d da

ta

In v

itro

In v

ivo

Ase

ssm

ent

A17

5

App

endi

x A

Subs

tanc

e: V

inyl

chl

orid

eM

olec

ular

wei

ght:

62.5

CA

S: 7

5-01

-4D

ensi

ty:0

.911

g/c

m³

Scie

ntifi

c ba

sis:

AoH

198

6:17

Mel

ting

poin

t:-1

53.7

°CB

oilin

g po

int:

-13°

CSk

in n

otat

ion:

Yes

Vap

our

pres

sure

:340

kPa

(at 2

0°C

)Sk

in p

erm

eabi

lity:

Hig

hE

vapo

ratio

n ra

te:N

ot a

vaila

ble

Log

Kow

:1.6

2 (e

stim

ated

)

Sp

Loc

C

ell

L

(µm

) A

(c

m²)

V

(ml)

Veh

icle

C

(m

g/m

l) n

TE

xp

(h)

TO

bs

(h)

TL

ag

(h)

Abs

(%

) K

P

(10-4

cm

/h)

Flux

(µ

g/cm

²/h) R

efer

ence

N

o da

ta a

vaila

ble

Mon

WB

Inf

Vap

0.01

8 (7

000

ppm

. 340

0 m

g)1

22

0.02

620.

11H

efne

r et a

l. (1

975)

Mon

WB

3500

Inf

Vap

0.00

21 (

800

ppm

. 390

mg)

12.

52.

50.

0366

0.01

4H

efne

r et a

l. (1

975)

The

only

foun

d st

udy

was

that

of H

efne

r et a

l. (1

975)

, wer

e a

mon

key

was

exp

osed

to

viny

l chl

orid

e va

pour

.

The

repo

rted

Kp

valu

es su

gges

t a "

high

" pe

rmea

bilit

y.

It sh

ould

be

note

d th

at v

inyl

chl

orid

e is

a g

as a

t ski

n te

mpe

ratu

re (b

.p. -

14°C

).

Rep

orte

d da

ta

In v

itro

In v

ivo

Ase

ssm

ent

A17

6

App

endi

x A

Subs

tanc

e: V

inyl

tolu

ene;

met

hyl s

tyre

neM

olec

ular

wei

ght:

118.

2C

AS:

250

13-1

5-4

Den

sity

:0.8

9 g/

cm³

Scie

ntifi

c ba

sis:

AoH

199

2:6

Mel

ting

poin

t:-7

7°C

Boi

ling

poin

t:17

0°C

Skin

not

atio

n: Y

esV

apou

r pr

essu

re:0

.15

kPa

(at 2

0°C

)Sk

in p

erm

eabi

lity:

Mod

erat

eE

vapo

ratio

n ra

te:N

ot a

vaila

ble

Log

Kow

:3.4

8

Sp

Loc

C

ell

L

(µm

) A

(c

m²)

V

(ml)

Veh

icle

C

(m

g/m

l) n

TE

xp

(h)

TO

bs

(h)

TL

ag

(h)

Abs

(%

) K

P

(10-4

cm

/h)

Flux

(µ

g/cm

²/h) R

efer

ence

Hum

Ab

St46

-63

0.64

0.06

4N

eat

648

4825

2.3

200

Fasa

no e

t al.

(200

6)H

umA

bSt

46-6

30.

640.

006

Nea

t6

0.2

0.2

0.74

66Fa

sano

et a

l. (2

006)

Hum

Ab

St46

-63

0.64

0.00

6N

eat

61

11.

110

0Fa

sano

et a

l. (2

006)

N

o da

ta a

vaila

ble

The

only

foun

d st

udy

was

that

of F

asan

o et

al.

(200

6), w

ere

hum

an sk

in w

as e

xpos

ed to

ne

at v

iny

ltolu

ene.

The

repo

rted

Kp

valu

es su

gges

t a "

mod

erat

e" p

erm

eabi

lity.

Rep

orte

d da

ta

In v

itro

In v

ivo

Ase

ssm

ent

A17

7

App

endi

x A

Subs

tanc

e: X

ylen

e, m

-M

olec

ular

wei

ght:

106.

2C

AS:

108

-38-

3D

ensi

ty:0

.868

g/c

m³

Scie

ntifi

c ba

sis:

AoH

200

5:16

Mel

ting

poin

t:-4

7.9°

CB

oilin

g po

int:

139.

1°C

Skin

not

atio

n: Y

esV

apou

r pr

essu

re:0

.86

kPa

(at 2

0°C

)Sk

in p

erm

eabi

lity:

Mod

erat

eE

vapo

ratio

n ra

te:0

.51

Log

Kow

:3.2

0

Sp

Loc

C

ell

L

(µm

) A

(c

m²)

V

(ml)

Veh

icle

C

(m

g/m

l) n

TE

xp

(h)

TO

bs

(h)

TL

ag

(h)

Abs

(%

) K

P

(10-4

cm

/h)

Flux

(µ

g/cm

²/h) R

efer

ence

Hum

Br

Fl28

00.

640.

2N

eat

524

240.

220.

590.

326

Wilk

inso

n &

Will

iam

s (20

01)

Hum

Br

Fl28

00.

640.

2H

2O

205

2424

0.18

5859

00.

15W

ilkin

son

& W

illia

ms (

2001

)

Hum

WB

1900

0In

fV

ap0.

0080

(60

0ppm

)3

3.5

2444

mg

2400

1.9

Riih

imak

i & P

faff

li (1

978)

Hum

WB

1900

0In

fV

ap0.

0040

(30

0ppm

)2

3.5

2421

mg

2400

0.94

Riih

imak

i & P

faff

li (1

978)

Hum

Arm

/Ha

1000

Inf

Vap

0.07

3 (5

500p

pm)

50.

336

1200

8.8

Kez

ic e

t al.

(200

0)H

umH

as81

0-10

00In

fN

eat

90.

256

35 m

g1.

412

0En

gstro

m e

t al.

(197

7)H

umH

as81

0-10

00N

eat

100.

2522

4.4

380

Riih

imak

i (19

79)

Hum

Arm

1178

Inf

Vap

0.00

16

0.33

691

00.

091

Kez

ic e

t al.

(200

4a)

Hum

Arm

1178

Inf

Vap

0.00

16

0.75

672

00.

072

Kez

ic e

t al.

(200

4a)

Hum

Arm

1178

Inf

Vap

0.00

16

26

660

0.06

6K

ezic

et a

l. (2

004a

)H

umA

rm11

78In

fV

ap0.

001

63

661

00.

061

Kez

ic e

t al.

(200

4a)

Rat

WB

Vap

64

472

0015

McD

ouga

l et a

l. (1

990)

Ther

e is

a w

ide

rang

e of

Kp

valu

es (o

-, m

-, p-

xyle

ne a

nd x

ylen

e m

ixtu

re),

depe

ndin

g on

veh

icle

and

spec

ies.

The

pref

erre

d ex

perim

ents

are

thos

e w

ith n

eat x

ylen

e by

Riih

imak

i (19

79) a

nd E

ngst

rom

et a

l. (1

977)

.

The

Kp

valu

e of

4·1

0-4 c

m/h

sugg

ests

"m

oder

ate"

per

mea

bilit

y.

It sh

ould

be

note

d th

at th

e pe

rmea

bilit

ies o

f aqu

eous

and

vap

orou

s xyl

ene

are

seve

ral o

rder

s of m

agni

tude

hig

her.

Rep

orte

d da

ta

In v

itro

In v

ivo

Ase

ssm

ent

A17

8

App

endi

x A

Subs

tanc

e: X

ylen

e, o

-M

olec

ular

wei

ght:

106.

2C

AS:

95-

47-6

Den

sity

:0.8

97 g

/cm

³Sc

ient

ific

basi

s: A

oH 2

005:

16M

eltin

g po

int:

-25.

2°C

Boi

ling

poin

t:14

4°C

Skin

not

atio

n: Y

esV

apou

r pr

essu

re:0

.66

kPa

(at 2

0°C

)Sk

in p

erm

eabi

lity:

Low

Eva

pora

tion

rate

:0.5

1L

og K

ow:3

.12

Sp

Loc

C

ell

L

(µm

) A

(c

m²)

V

(ml)

Veh

icle

C

(m

g/m

l) n

TE

xp

(h)

TO

bs

(h)

TL

ag

(h)

Abs

(%

) K

P

(10-4

cm

/h)

Flux

(µ

g/cm

²/h) R

efer

ence

Hum

Br

Fl28

00.

640.

2N

eat

524

240.

30.

350.

2220

Wilk

inso

n &

Will

iam

s (20

01)

Hum

Br

Fl28

00.

640.

2H

2O

315

2424

0.3

2535

01.

1W

ilkin

son

& W

illia

ms (

2001

)R

atA

bSt

Full

2.6

1N

eat

373-

63-

62.

210

-59

µg0.

076.

2Ts

urut

a (1

982)

N

o da

ta a

vaila

ble

The

pref

erre

d st

udy

is th

e on

e us

ing

neat

o-x

ylen

e an

d hu

man

skin

.

The

Kp

valu

e of

2·1

0-5 c

m/h

, sug

gest

s "lo

w"

perm

eabi

lity.

It sh

ould

be

note

d th

at th

e pr

efer

red

stud

y of

m-x

ylen

e su

gges

t a K

p va

lue

that

is o

ne o

rder

of m

agni

tude

hig

her.

Rep

orte

d da

ta

In v

itro

In v

ivo

Ase

ssm

ent

A17

9

App

endi

x A

Subs

tanc

e: X

ylen

e, p

-M

olec

ular

wei

ght:

106.

2C

AS:

106

-42-

3D

ensi

ty:0

.861

g/c

m³

Scie

ntifi

c ba

sis:

AoH

200

5:16

Mel

ting

poin

t:13

.3°C

Boi

ling

poin

t:13

8.3°

CSk

in n

otat

ion:

Yes

Vap

our

pres

sure

:0.7

9 kP

a (a

t 20°

C)

Skin

per

mea

bilit

y: N

o da

taE

vapo

ratio

n ra

te:0

.51

Log

Kow

:3.1

5

Sp

Loc

C

ell

L

(µm

) A

(c

m²)

V

(ml)

Veh

icle

C

(m

g/m

l) n

TE

xp

(h)

TO

bs

(h)

TL

ag

(h)

Abs

(%

) K

P

(10-4

cm

/h)

Flux

(µ

g/cm

²/h) R

efer

ence

N

o da

ta a

vaila

ble

N

o da

ta a

vaila

ble

Bas

ed o

n si

mila

ritie

s in

chem

ical

stru

ctur

e an

d ph

ysic

al p

rope

rties

, p-x

ylen

e m

ay b

e as

sum

ed to

hav

e si

mila

r pe

rmea

bilit

y to

that

of o

- and

m-x

ylen

e.

Rep

orte

d da

ta

In v

itro

In v

ivo

Ase

ssm

ent

A18

0

App

endi

x A

Subs

tanc

e: X

ylen

esM

olec

ular

wei

ght:

106.

2C

AS:

133

0-20

-7D

ensi

ty:0

.862

g/c

m³

Scie

ntifi

c ba

sis:

AoH

200

5:16

Mel

ting

poin

t:-5

0°C

Boi

ling

poin

t:14

0°C

Skin

not

atio

n: Y

esV

apou

r pr

essu

re:0

.66

kPa

(at 2

0°C

)Sk

in p

erm

eabi

lity:

Mod

erat

eE

vapo

ratio

n ra

te:0

.7L

og K

ow:3

.12

Sp

Loc

C

ell

L

(µm

) A

(c

m²)

V

(ml)

Veh

icle

C

(m

g/m

l) n

TE

xp

(h)

TO

bs

(h)

TL

ag

(h)

Abs

(%

) K

P

(10-4

cm

/h)

Flux

(µ

g/cm

²/h) R

efer

ence

Rat

Ba

St56

04.

92

JP-8

5.1

(0.5

9%)

84

40.

51.

70.

8M

cDou

gal e

t al.

(200

0)

Hum

Arm

Nea

t10

152

-110

4500

-960

0D

utki

ewic

z &

Tyr

as (1

968b

)

No

info

rmat

ion

on th

e co

nten

t of t

he x

ylen

e m

ixtu

re w

as a

vaila

ble

in th

e tw

o st

udie

s.

The

resu

lts o

f the

stud

y by

Dut

kiew

icz

& T

yras

(196

8b) s

eem

s ver

y un

real

istic

. Xyl

ene

abso

rptio

n w

asca

lcul

ated

as d

iffer

ence

bet

wee

n ap

plie

d an

d re

cove

red

amou

nt. A

s xyl

ene

is n

onpo

lar a

nd v

olat

ile

this

met

hod

may

resu

lt in

sign

ifica

nt lo

sses

and

, hen

ce, o

vere

stim

ates

of f

lux

and

Kp.

The

pref

erre

d st

udy

is th

at o

f McD

ouga

l et a

l. (2

000)

, wer

e th

e re

porte

d K

p va

lue

of 2

·10-4

cm

/h su

gges

ts "

mod

erat

e" p

erm

eabi

lity.

It sh

ould

be

note

d th

at th

e pe

rmea

bilit

ies f

or n

eat o

- and

m-x

ylen

e w

ere

dete

rmin

ed a

s"l

ow"

and

"mod

erat

e", r

espe

ctiv

ely.

See

als

o da

ta o

n ea

ch x

ylen

e is

omer

(o-,

m-,

p-)

Rep

orte

d da

ta

In v

itro

In v

ivo

Ase

ssm

ent

A18

1

Appendix B

B1

References

Octanol:water partition coefficients

Syracuse Research Corporation, http://www.syrres.com/esc/kowwin.htm

Other physical properties

Acros Organics (1999) Material safety data sheet. Phenol. http://avogadro.chem.iastate.edu/MSDS/phenol.htm.

Chemfinder (2007) http://www.chemfinder.com/. Elmer's Products (2005) Material safety data sheet. Ethyl 2-cyanoacrylate.

http://krazyglue.com/products/msds/mkg0583_a.htm. Fisher Scientific (2004a) Material safety data sheet. Catechol.

http://www.catalogue.fisher.co.uk/scripts/search.dll?ViewMSDS&SheetNumber=04360. Fisher Scientific (2004b) Material safety data sheet. Hydroquinone.

https://fscimage.fishersci.com/msds/11230.htm. Fisher Scientific (2005) Material safety data sheet. 4-Chloro-m-cresol.

https://fscimage.fishersci.com/msds/90138.htm. Fisher Scientific (2006) Material safety data sheet. Carbon tetrachloride.

https://fscimage.fishersci.com/msds/90116.htm. Fisher Scientific (2007) Material safety data sheet. 2,6-Dinitrotoluene.

https://fscimage.fishersci.com/msds/71341.htm. Huntsman (1999) Comparative solvents data.

http://www.huntsman.com/performance_products/Media/JEFFSOL_Alkylene_Carbonates_Comparative_Solvents_Data.pdf.

Information CaOS (2005) Safety data for 2,4-dinitrotoluene. The Physical and Theoretical Chemistry Laboratory, Oxford University. http://www.physchem.ox.ac.uk/MSDS/DI/2,4-dinitrotoluene.html.

Intergas (2001) Material safety data sheet. Vinyl chloride. http://www.intergas.co.uk/pdf/VINYLCHLORIDE.PDF.

International Furan Chemicals (2003) Safety data sheet. Furfural. http://www.furan.com/_resources/downloads/10195en_rev6.pdf.

J.T. Baker (2004a) Material safety data sheet. 2-Butoxyethanol. http://www.jtbaker.com/msds/englishhtml/b6100.htm.

J.T. Baker (2004b) Material safety data sheet. 4-Methylmorpholine. http://www.jtbaker.com/msds/englishhtml/m5700.htm.

J.T. Baker (2004c) Material safety data sheet. Acetonitrile. http://www.jtbaker.com/msds/englishhtml/a0518.htm.

J.T. Baker (2004d) Material safety data sheet. N,N-Dimethylaniline. http://www.jtbaker.com/msds/englishhtml/d6040.htm.

J.T. Baker (2004e) Material safety data sheet. N,N-Dimethylformamide. http://www.jtbaker.com/msds/englishhtml/d6408.htm.

J.T. Baker (2004f) Material safety data sheet. n-Butylamine. http://www.jtbaker.com/msds/englishhtml/b6340.htm.

J.T. Baker (2004g) Material safety data sheet. tert-Butyl alcohol. http://www.jtbaker.com/msds/englishhtml/b6304.htm.

J.T. Baker (2005a) Material safety data sheet. Cobalt chloride. http://www.jtbaker.com/msds/englishhtml/C4928.htm.

Appendix B

B2

J.T. Baker (2005b) Material safety data sheet. Dimethyl sulfoxide. http://www.jtbaker.com/msds/englishhtml/d7120.htm.

J.T. Baker (2005c) Material safety data sheet. sec-Butyl alcohol. http://www.jtbaker.com/msds/englishhtml/b6302.htm.

J.T. Baker (2006a) Material safety data sheet. 1-Methoxy-2-propanol. http://www.jtbaker.com/msds/englishhtml/m2600.htm.

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