Document LKK7ODG1JMXOmpEGMJVw7QR5w

American Journal of lndustrial Medicine 17:617-635 (1990) Dermal Absorption Potential of Industrial Chemicals: Criteria for Skin Notation V. Fiserova-Bergerova, PhD, J. Thomas Pierce, PhD, and P.O. Droz, PhD A dermal penetration rate ( f l u x ) . predicted from physical properties of I32 chemicals. is suggested as an indeh of the dermal absorption potential of industrial chemicals. The prediction is deGgned for organic nonelectrolytes. Two reference vslues are recommended a b criteria for skin notation: I ) dermal absorption potential. which relates to dermal absorption raiwig the JBW of nonvolatile chemicals or biological levels of volatile chemicals 30ci above those observed during inhalation exposure to TLV-TWA only- dermal absorption of chemicals belonging to this category should be considered when data obtained by biological monitoring are interpreted: and 2 ) dermal toxicity potential. which relates to dermal absorption that triples biological levels as compared with levels obser\eJ during inhalation exposure to TLV-TWA only. Chemical3 belonging in this category should carry a skin notation. The toxicity criteria may not be valid for chemicals whose TLVs are based on preventing irritation and discomfort. Key words: bod) burden (effect of dermal absorption on). flux, inhalation exposure (interaction with dermal exposure), model for dermal penetration, prediction of dermal absorption of industrial chemicals. solubilitv (effect on absorption of industrial chemicals) INTRODUCTION Factors affecting dermal absorption of industrial chemicals were recently reviewed and the inconsistencies in the "skin denotation" by different authorities engaged in setting safety criteria were pointed out [Grandjean et al., 1988; Scansetti et al., 1988; Hansen, 19821. These inconsistencies are attributed to the following factors: 1) the lack of systematic studies of dermal absorption of industrial chemicals; 2) disparate information on the dermal absorption rate obtained by different methods; 3) dependence of dermal absorption rate on exposure and environmental conditions; and 4)a lack of criteria defining the significance of dermal absorption in an industrial setting. The skin notation situation cannot be improved without understanding the mechanism of dermal absorption. without the availability of a simple method for quantitative evaluation of dermal absorption potential, and without the establishment of criteria for biological significance of dermal absorption in an industrial setting. Department of Anesthesiolog!. University of Miami School of Medicine. Miami (V.F.-B.1. Medical College of Virginia. Richmond (J.T.P.). Institute for Occupational Health Sciences. Clniversity of Lausanne. Lausanne. Switzerland (P.O.D.). Address reprint requests to Dr Veri Fiserova-Bergerova (Thomas). Dept. of Anesthesiology. University Miami School of Medicine. P.O. BOY.016370. Miami. FL 33101. Zepted lor publication October 26. 1989. C 1990 Wiley-Liss. Inc. * .4 I .I. F.:. 1 .- .. ..I i5 618 Fiserova-Bergerova et al. Theoretical models developed for the evaluation of dermal absorption of drugs [Albery and Hadgraft, 1979; Berner and Cooper. 1987; Dugard, 1983; Guy et al.. 1985; Hansen. 1982; Kuabota and Ishizaki, 1986; Michaels et al., 19751 can be used to elucidate the mechanism of dermal absorption of industrial chemicals and to predict their penetration rate through the stratum corneum from physicochemical properties of the chemicals. These models describe percutaneous penetration as a diffusion process mediated by two pathways: an intercellular (polar) pathway and a transcellular (lipophilic) pathway. Penetration rates of both pathways are directly related to solubility of the chemical in water and lipids, and indirectly to molecular weight. The penetration rate, referred to as flux, can be considered as an index of dermal absorption potential. Flux can be experimentally determined. but the outcome of the measurements depends on the experimental setting. Flux can be determined either in vitro by measuring the diffusion rate across an excised layer of stratum corneum [Dugard et al., 1984; Tsuruta, 19771, or in vivo, by measuring losses of the chemical that had been hermetically applied on a defined area of skin over a certain period of time [Dutkewicz and Tyras, 19681. The absorption rate in vi1.o can be evaluated by measuring the elimination of the chemical and its metabolite(s) after a defined dermal exposure [Berode et al.. 1985; Flek and Sedivec. 1978: Nakaaki et al.. 1985; Sato and Nakajma. 1978; Stewart and Dodd. 19641. Since the absorption rate depends on the thickness and hydration of the stratum corneum [Scheuplein and Blank. 19711 and on the perfusion rate of the dermis [Fiserova-Berzerova. in preparation]. the outcome of the measurements depends on the source of the tested skin. There are significant differences in measurements among animal species [Wester and Maibach. 19771 and among measurements obtained by exposing skin from different parts of the body [Scheuplein and Blauk, 197I ] . The outcome of the measurements also depends on the form in which the chemical is applied (liquid. vapor. solution. or particulates). on the concentration and solubility of the chemical in the vehicle. and on effects of the vehicle on the physiological status of the skin [Dutkieu icz and Tyras. 1967: FiserovaBergerova. in preparation; Scheuplein and Blank. 197I : Wester and Maibach, 1977). Since dermal absorption is a kinetic procehs. the outcome of the measurements depends on exposure duration dnd sampling time. The cffects of these circumstantial factors account tor the differences of dermal absorption rates reported in the literature. For example. the f o h v i n g dermal abwrption rates are reported for styrene: 0.03 mg:cni"hr (rneabured iu 1.irr.o in riit [Tsuruta. 19821) and 0.06 mpcm'ihr [Berode et al.. 19851 and 17 rnp/cm':hr (range 9-15) [Dutkiewicz and Tyras. 19681, both measured in voiunteera. X similar rings of values \vas reported for xylene: 0.006 mgicm'ihr measured in \vitro in rais [Tsuruta. 19821: 0.13 mg!cm'.hr [Riihimaki, 19791 and 7 mg/cni' hr (range 1.5-9.6) [Dutkiewicz and Tyras. 19681 measured in volunteers. Theoretical niodcls relate flus to diffu5ihiIity of chemicals through a hypothetical retrrence skin. the parameters of which (thichness. diffusion channels. and diffusion constants) are compiled as mean values for human skin [Berner and Cooper. 19871. The evaluation of systemic health effects of dermal absorption can be based either on toxicological studies. or on pharmacokinetic studies by comparing biological levels or internal doses resulting from dermal and inhalation elcposures. There are three similarities in the toxicokinetic pattern of inhalation and dermal exposures: 1) Dermal Absorption 619 the absorption rates are dictated by diffusion of chemicals through the cellular structure of parenchymal tissues and are related to biosolubility: 2 1 the absorbed amount is equally dispersed in the entire cardiac output prior to entering the systemic circulation: and 3 ) in an industrial setting. both exposures are enduring. the body exposure tending to reach a steady state. The purpose of this study is to define the significance of dermal absorption potential of indumial chemicals and suggest guidelines for a skin notation. To meer this objective. dermal absorption potential. defined by flux predicted from physical properties of the chemical. is compared with the threshold value\. referred to as critical flux. Critical flux is defined as a hypothetical penetration rate through the stratum corneum. which causes the biological levels to increase above thobe reached during inhalation exposure to ;ITLV-TWA [Threshold Limit Values and Bloioglcai Exposure Indices. 19881. Critical f l u \ is determined by comparing the dermal uptake rate under specified exposure conditions with the pulmonary uptake rate during esposure to TLV-TWA at steady 5tate. Considerations in the Selection of Criteria for Skin Notation To select a criteria for skin notation. the endpoint (further referred to ab critical effect). the exposure condition. and the method for obtaining the information must be defined. Selection of method. In this study. values of flux obtained by a model are preferred over the measured data for the following reasons: 1 ) measured data exhibit Ir-ue variability. for reasons discussed above: 2 ) fluxes. predicted by the theoretical el. proved to fit in the range of experimental data [Fiserova-Bergerova and Pierce, 19891: 3 ) the calculation of flux by the suggested model is simple and requires only physicochemical constants that are readily available: and 4 ) the theoretical basis of the model provides grounds for understanding the effects of variable exposure factors. Critical effect. A "critical effect" for skin notation can be: 1) the appearance of the chemical in a biological specimen obtained from dermally exposed subjects: 1) the increase of biological level of the chemical above the noneffect level: 3 ) biochemical changes: and 4) acute or chronic systemic toxic effect. In this study. an increase of the biolosical level above the noneffect level is considered to be a critical effect. A dose or arterial blood concentration resulting from occupational inhalation exposure to a TLV-TWA will be considered as the noneffect level. The effect of dermal absorption will be evaluated at two biologically significant levels: 1) the dermal absorption potential will be considered to be significant if the dermal penetration rate of nonvolatile chemicals exceeds 30% of the pulmonary uptake rate during an occupational inhalation exposure to TLV-TWA. or if dermal absorption of volatile chemicals increases the arterial blood concentration 30%above the concentration most likely reached during occupational inhalation exposure to TLV-TWA; and 2) potential for systemic toxicity induced by dermal exposure will be considered significant if the biological levels triple compared with the biological levels resulting from inhalation exposure to a TLV-TWA. The chemical should carry a skin notation if the potential for dermal absorption and toxicity. under the exposure conditions defined below, is significant. Exposure conditions in industrial settings. The extent of dermal absorption is directly related to exposure duration and surface area of the exposed skin. and is affected by the form of the chemical contacting the skin. Since dermal and pulmonary .I ..a : .' 4: 620 Fiserova-Bergerova et al. absorptions are pharmacokinetic processes. the absorption rates are a function of time. Moreover. dermal absorption is affected by the physical activity of the worker and the skin temperature [Burton, 19681, namely by increased perfusion of the dermis in the exposed area of the skin. In this study, the critical flux is calculated for exposures of 2% of the body surface area (equivalent to stretched palms and fingers) to a saturated aqueous solution of the chemical. The calculations are made for the apparent steady state conditions using physiological parameters of a worker performing light physical work [Astrand, 19831. Possible biochemical changes in the skin are not taken into account. MATERIALS AND METHODS One hundred seventy-six chemicals that appear in the TLV booklet were studied [Threshold Limit Values and Biological Exposure Indices, 19881. Sixty-six (38%)of these chemicals carry skin notation. Seventy-two chemicals (419 ) .further referred to as volatile chemicals. had a saturated vapor pressure greater than 5 torrs. For simplicity. chemicals with a saturated vapor pressure below 5 torrs will be called nonvolatile. Calculation of Flux .. A two parallel pathway model. proposed by Berner and Cooper [ 19871 for the evaluation of dermal absoprtion of drugs. is used in this study for the calculation of flux. The model is described by equation I. For details and definitions. see Appendix. Calculation of Critical Flux The critical flux was calculated by comparing either pulmonary and dermal uptake rates of nonvolatile chemicals or concentrations of volatile chemicals in arterial blood resulting from inhalation exposure to TLV. and dermal exposure. Two simplified equations were derived as criteria for skin notation of liquids (see Appendi.K). Critical flux for dermal absorption potential 3 FI* = - TLV 3 Critical flux for dermal toxicity potential F1:g" = j TLV (111) Critical flux for volatile and nonvolatile chemicals is the same (see Appendix). However. dermal absorption causes a significant reduction in pulmonary uptake of volatile chemicals with relatively large pulmonary retention. and supresses pulmonary uptake and induces exhalation of dermally absorbed volatile chemicals with relatively small pulmonary retention. Similar criteria were calculated for vapors Dermal Absorption 621 Calculation of Aqueous Solubility Calculation of aqueous solubility of organic nonelectrolytes using melting point (MP) and hydrophobic constant (P)was suggested by Yalkowsky [ 1981: Yalkowsky a i d i'alvani. 19801. log c = - 10sP - 0.01 MP - 0.69 (\I) For poorly soluble chemicals (c < 0.01 mM). an adjustment for the molarit! of water is necessary [Yalkowsky and Valvani. 19801. Thus the concentration of saturated aqueous solution. expressed in mgiml. is given by equation VI1 55.5 . MW C,,I = P exp (-0.01 MP - 0.69) For more soluble chemicals. an adjustment for the volume <ifdisplaced water is recdmmended [Yalkowsky and Valvani. 19801. 1.000 . MW exp ( - 0.01 MP - 0.69) Csat = P 18 + (MW - 18) * exp (-log P - 0.01 MP - 0.69) (VIII) If the chemical exists at room temperature as a liquid, 25 was substituted for MP [Yalkowsky and Valvani, 19801. Berner and Cooper [ 19871 proposed a similar equation for nonelectrolytes with log p > l . 'Equations VI1 and VI11 were used to calculate aqueous solubility, and the calculated values were compared with measured values using regression log c,, measured versus log cSatcalculated. RESULTS AND DISCUSSION Calculated and experimental solubilities for 176chemicals were compared (Fig. 11, and 44 chemicals were not included in further study since the calculated and experimentally determined solubilities differed in multiples larger than 5 . Flux. and the ratio of critical flux to flux calculated for aqueous solutions of the remaining 71 nonvolatile chemicals. using equations 1 and 11. are shown in Table I: flux. and the ratio of critical flux to flux calculated for aqueous solutions and vapors of the remaining 61 volatile chemicals, using equations 1. 11, and IV, are shown in Table 11. ...... ., 1 7 Fiserova-Bergerova et ai. VOLATILE =!===== I ..- ! uw) 3 5d NONVOLATILE -6 -4 - 2 0 2 log of MEASURED VALUES 4 Fig. 1 , Correlation betwecii I ~ I C ~ W I C L Im d calculated aqueous solubility cf !75 indfihtrial chcmic?.!s. The solubilities are expre\wd as ;I logarlthrn ot a murated wlution in water (rng,ml): the solid line indicates the ideal 5ituation when measured and calculated value5 would be the same: the broken line indicates the hurdsrlinr between acceptable and unacccptable values. When FI*/FI < I . the dermal absorption potential is considered significant. Under such circumstances. dermal absorption is expected to raise the biological levels 3 0 4 above those occurring during inhalation exposure to TLV. The significant dermal absorption potential is indicated by "0" on the left side of the tables. When biological levels triple compared with levels reached during exposure to TLV only (that is. FI**/FI < I or FI*/FI < 0.15). the chemical is considered to have the potential for Dermal Absorption 623 TABLE 1. Constants Used for the Calculation of Flux and Critical Flux of Nonvolatile Chemicals (SVP < 5 Torrs)* Chemical TL\ bf\i MP WS log p FI FIXFI I e Acetylsalicylic acid e 2-Aniinop>ridinr 0.0050 180.1 I31 1o.OOo I .23 0.0981 0.04 0.00'0 Y 1 . l 58 55.000 0.54 0.4625 0.00 0 n - . h y I acetate 0.5250 130.2 -70 2.000 2.26 0.4629 0.85 e Aniline skin 0.0100 9.3. I -6 31.ooo 0.90 O.61U5 0.01 0 Atrdzine O.(H)50 215.7 I76 0.070 2.63 0 .(1097 0.39 e Biphenyl 0.0015 154.2 71 0.008 4.01 0.0759 0.01 e n-Butanol skin 0.1500 74.1 -90 77.000 0.88 1. X X O I 0.06 0 n-Butyl acetate 0.7100 116.2 -77 14.OOO 1.73 I .'003 0 44 e n-Butyl a c p h t e 0.0550 128.2 -64 I .bo0 2 36 0.48IS 0.04, 0 p-ter-Butyltoluenr 0.0600 148.0 -. _C i 0.007 4.60 0.2663 0.17 e o-Crewl >kin 0.0220 108.I 3 I 25.o(x) 2.00 4.5.338 0.00 e m-Cresol \kin 0.0220 lox. 1 I2 23.500 2 00 4.26lX 0.00 e p-Cresol skin 0.0220 108. I 35 74.ooo I .93 3.7061 0.00 e Cyclohexanol Am 0.2ooo 100.8 24 36.ooO I .23 1.2612 0. I 2 c Cyclohexanone >kin 0.1ooo 98.1 -31 23.00() 0.81 0 . 3 2 7 1 0.23 0 o-Dichlorohen7i.ne 0 . 3 ~ ~ 1)47.0 - I8 0. IN) 3.3X 0 . 23 2u 0 . ~ 7 p-Dichlorohenzcne 0.4?00 14'0 _5 3. 0.07Y j . 38 0 .I840 I .s.q e Dichloroethyl ether skin 0.0300 143.0 -50 10.200 1.2Y 0.2085 0.11 e Dicyclopentadiene 0.0300 172.2 34 0.050 4.10 I ,5448 0.01 e Dieldrin skin 0.0003 380.9 I76 O . O o 0 5 .48 0.0013 0. I4 e Diethanolamine 0.0150 103.1 e 2-Diethylaminoethanol skin 0.0500 117.2 28 954.000 - I .13 0.5 I67 0.02 25 885,000 0.35 3.4428 0.01 Diethylene triamine skin 0.0040 103.2 - 39 959.000 - I .10 0.5410 0.01 Diethyl ketone '1 N.N-dimethyl aniline skin e Dimethyl phthalate e Diphenylamine 0.7050 0.0250 0.0050 0.0100 86.1 121.2 191.2 169.2 -42 -3 0 53 17.000 1.120 5.OOO 0.300 0.79 0.7755 '31 0.3359 2.00 0.2287 3.50 0.6455 0.68 0.06 0.02 0.01 0 Diuron e DMAC skin e DMF skin e Ethanolamine e 2-Ethoxyethanol skin e Ethyl butyl ketone e Ethylene glycol e Formaldehyde e Formarnide skin * Furfural skin e Glycerin 0 Hexachloroethane e Hexylene glycol 0 Isoamyl alcohol e Lindane skin 0 Methoxychlor e 2-Methoxyethanol skin e 4-Methoxyphenol C Methyl n-amyl ketone e n-Methyl aniline skin e Methyl n-butyl ketone C Methyl isoamyl ketone 0 Methyl isobutyl ketone s Metribuzin e Morpholine skin s Naphthalene 0.0100 0.0350 0.0300 0.0080 0.0190 0.2300 0.1250 0.0015 0.0150 0.0080 0.0100 0.0100 0.1250 0.3600 0.0005 0.0100 0.0160 0.0050 0.2350 0.0020 0.0200 0.2400 0.2050 0.0050 0.0700 0.0500 233.1 87.1 73.1 61.1 90.1 114.2 62.1 30.0 45.0 96.1 92.1 236.7 118.2 88.2 290.9 345.7 76.1 124.2 114.2 107.2 I(H).2 114.2 100.2 214.3 87.1 128.2 I58 -20 -61 I0 - 70 -39 -13 -92 3 -37 18 I87 -40 -117 I12 98 25 53 -30 -57 -60 - 74 -74 I25 -5 80 0.042 943.000 944.000 1018.000 93 1.000 14.300 I 1 13.Ooo 300.000 1133.000 83.000 1264.Ooo 0.050 923.000 30.000 0.017 0.040 966.000 16.000 4.300 34.000 26.000 5.400 19.000 I ,200 1007.000 0.030 3.00 -0.77 - 1.01 -1.31 -0.54 1.80 - 1.93 0.00 - I .65 0.99 -2.56 3.30 -0.14 1.28 3.72 4.03 0.00 I .34 2.03 I .74 1.38 1.88 I .38 1.52 - I .08 3.37 0.0103 0.9980 1.0347 1.1619 1.2054 1.4865 1.0938 2.3626 I ,522I I ,823I 0.7419 0.0230 1.3826 1.4415 0.0087 0.0173 3.6402 0.4954 0.7580 3.4473 I ,294 0.6712 0.9459 0.0132 0.8449 0.09'3 0.73 0.03 0.02 0.01 0.01 0.12 0.09 0.00 0.01 0.00 0.01 0.33 0.07 0.19 0.04 0.43 0.00 0.01 0.23 0.00 0.01 0.27 0. I6 0.28 0.06 0.41 i t !' .I 624 Fiserova-Bergerova et al. TABLE I. Constants Used for the Calculation of Flux and Critical Flux of Nonvolatile Chemicals (SVP < 5 Torrs)* (Continued) Chemical TLV MW MP WS log p FI e p-Nitroaniline \kin e p-Nitrotoluene skin 0 PCP skin 0 Pentaerythritol e p-Phenylene diamine skin 0 Phenyl ether 0 Phenyl mercaptan 0 Propoxur 0 Ronnel 0 Strychnine 0 Styrene skin 0 o-Toluidine skin e p-Toluidine skin e Tributyl phosphate e Trichloroacetic acid 3 1.2.4-Trichlorobenzene Trichlorofluoromethant. : Trimethyl benzene 0.0030 0.01 10 0.0005 0.0100 o.Oo0 I 0.0070 0.0020 0.0005 0.0100 O.Oo02 0.2150 0.00YO 0.0090 0.0025 0.0070 0.0400 5.600 0.1250 138.1 137.1 266.1 136.I lox. I 170.2 110.2 209.2 321.6 334.4 IW.0 107.2. 107.1 266.3 163.1 181.5 137.4 120.2 i 48 55 I90 26 I 147 28 - I5 92 41 270 -31 -10 U - 80 38 17 - 111 -44 0.800 0.440 0.001 55.600 41.500 0.021 0.170 2.OOo 0.040 0.143 0.300 15.m 7.400 S.900 I?.o(x) 0.019 1.10 0.060 I .39 2.40 5.01 - I .70 -0.26 1.28 2.52 I .58 4.88 I .93 2.95 I .30 I .10 2.36 1.13 4.23 7 i3 3.60 0.0222 0.1258 0.01 18 0.0172 0.0599 0.2680 0.2726 0.0275 O.IX04 0.ooo6 0.5166 0.5366 0.3448 0.1947 0.1334 0.1804 0.422.2 0.3561 FI*,FI 0.IO 0.07 0.03 0.44 0.00 0.02 0.01 0.01 0.04 0. I9 0.3 I 0.01 0.02 0.01 0.04 0.17 9.95 0 26 ;VTLV. TLV-TLV.4 (mgLI: MW.molecular weight: MP. melting point ("C): WS. wlubility in water (mg/ml at room temperature): log p. decadic logarithm of octanol-water partition coefficient: FI. flux. calculated for a saturated aqueou\ w l u t i o n using equation 4 Img/cm' hr,: FI". critical flux calculated for aqueous solution using equation 9 Img,cin"hr): 2 . potential for dermal absorption ( 0 .15 < FI" FI < I ) : 0 . potential tor dermal toxicit! (FI* FI < 0.13). dermal toxicity. Potential for dermal toxicity is indicated by "0" on the left side of the tables. Predicted significant absorption of vapors is indicated by "X" on the left hand side of the table. Tables 111-VI list tho studied chemicals with dermal toxicity potential. with dermal absorption potential only. with no significant dermal absorption. and outsiders. Skin notation as shown in the TLV-BE1 booklet is also indicated [Threshold Limit \'due5 and Biological Expowre Indice\. 988 I. Expediency of Calculated Aqueous Solubility Equation 1 in the Appendix shows that the dermal penetration rate is directly related to aqueouh wlubility of chemicals. Therefore the accuracy of f l u s prediction depends. to a large extent. on the accuracy of c,,, values. The c,,, values of some chemicals var! dependinp on the source of information: for some important chemicals. the values were not found. (This is especially true for chemicals poorly soluble in \vater). A n existing model [Yalliowsky and Valvani. 19801 was employed to predict aqueous solubility of the studied chemicals (equations VI1 and VIII). Large differences between calculated and tabular value5 were Iounci tor 11 chemicals (Fig. I ). These outsiders are mainly poorly soluble chemical3 m hose wlubility is difficult to measure. or acids and bases with solubility dependent on pH. The correlation between calculated and tabular values for the remaining 132 chemicals was in the expected range (for correlation of log-log values. r = 0.886).and the tabular values were used for calculation of flux. A disagreement between calculated and tabular values of solubility can be considered as an indicator that one or both values of log P and c,,~ are incorrect or that additional molecular properties. such as polar- Dermal Absorption 625 TABLE 11. Constants Used for the Calculation of Flux and Critidl Flux of Volatile Chemicals (SVP > 5 Torrs)* Chemical TLV M W MP H'S PC log p FI FI* FI Fl*vap FI .Acetic acid Acetone Acct~iniirile4 i n . A l \ ~ ~ J ~ cA~ n) h t ~ ~ Ben7ens I ..~-BulJdlsne Sec butanol n-Butylamine 4.m Carhon d i ~ l f i d eA i n Carhon tetrachltiridc Ain Chlorohcnirnc Chlorolorm Chloropicrins Cunicnu 4 i n C\ clohcsanc C! ckihc\snc I. 1-Dichlorc~thane I .2-Dichlororth~lene Diiwprop>lamine shin Dioxane shin Enflurane Ethanol I acetate .:. lamine Ethyl hcnzene Ethylchloride Ethyl ether Ethyl formate Ethyl mercaptane Formic acid Halothane n-Heptane n-Hexane ( X I Hydrazine skin Isobutyl alcohol ( X I Isopropyl alcohol sopr ropylamine Mesityl oxide Methanol skin Methyl acetate Methylal Methylamine Methyl chloride Methyl chloroform Methylene chloride Methyl ethyl ketone Methyl iodide skin ( X I Methyl propyl ketone Nitromcthane "-Propyl acetate n-Propyl alcohol skin Propylene dichloride I ' l.2-Tetrachloroethane skin 0.025(l 60.I I- I .7Xo(l 5x I -Y4 O.O7(Kl 41.1 - 43 I).005(I 5h I -124 0 03O(I 7X. I h (I.22(MI 4x.o - IOU 0 305(1 74 I - 100 0.015(1 73. I -511 0.O3Ou 7h. I - 112 O.OZ(U I 153 x - 2 ; 0 35oti I l2.h -45 II.O5(M) I I Y 4 -64 0 (HM); IM 4 -hi (l.245(1 120.2 -Yh I .(15(MI s4 2 1.010(1 S' I - 1 1 1 1 0.x100 YY.O -Y? 0.7900 Yh Y -X(I 0.0200 101.2 - Y h 0.0900 nx. I 10 0.5750 IX1.5 0 1.9000 46. I -114 I .400 xx. I - 83 0 Ol80 45.1 - 81 0.4350 106.2 -95 2.h W 0 b4.5 - I39 1.2000 74.I -Ilh 0.30OO 74. I -xo 0.0010 62.I - 147 0 . 0 0 Y ~ l 46 0 x 0 JO(H1 197.4 0 I ,6000 100.2 -91 0.i n 0 0 86.2 -95 o.Oo01 0.1500 0.9noo 32.0 2 74. I - I08 60.I -89 0.0120 59. I -101 0.0600 9x. I -59 0.2600 32.0 -98 -0.6100 74. I 98 3.1000 76. I -105 0.0120 31.1 -94 0.1050 50.5 -97 I.9OOo 133.4 - 33 0. I750 n4.9 -97 0.5900 72 I -86 0.0100 142.0 -h7 0.7Ow 8h.2 - 78 0.2500 61.(I -29 O.X4(KJ 102. I -93 0.SOKW) w. I - 127 0.3500 113.0 - IOU 0.0070 lh7.Y -44 l O 4 Y (X)O 50i).(x, -0 '4 .?.37 7'8 MKI 395.00 -0.24 1 5 x 7 8 ; (HWI Io(XI (MI -0.i4 2 Y 2 h i 4 t I I N 1 2MMI (IO . 0 . 1 7 CY4 I 7x0 2.X0 2 . 1 3 0.70 (1 735 0.50 I .YY 0 , u I 2 5 O()O 2OO.OU 0 hl I.hX -.7.7 (MK) 50.00 - I.22 0 72 2 940 IO0 'O.XO 2.00 0 89 0.25 s.3 0 5Y 0 500 4. IO 2 4h 0.24 (i.150 4.(MI I 9- I.I5 2 . I H W I I O (MI 2 44 41 t).05(1 I 40 I. bb l).Z4 (I035 II YO 3 14 0 40 (1.21.; 5 IN1 2.Sh 0.42 .T ..i(K) 2.70 1.79 0.71 Y OW 2.50 I .4x 0.59 K.(K)o 10.00 I .66 0.74 I 0.33 ,000 500.00 -0.42 1.62 10.000 0.80 2.10 0.67 789.000 1906.00 -0.31 2.84 x7.000 193.(K) 0.70 1.14 684.000 2o00.00 -0.13 3.36 0 200 I .70 3.15 0.53 I O 1100 1.20 1.43 0.99 69. W M 5.00 0.83 1.51 I 10 OOO IO 000 5.Ou 0.26 0.71 I.oo 1.17 0.57 1 2 2 0 . 0 w Io(Wl.(HI -0.54 3 2 0 4.500 0.70 2.30 0.39 2.400 0.50 2.70 2.47 0.014 1.10 3.94 0.31 100.1.Oo0 500.00 - I .23 1.88 95.000 2o00.00 0.76 1.78 785.000 1000.00 0.05 4.20 694.000 3.00 -0.03 3.15 28.Oo0 10.00 I .24 1.05 791.000 1900.00 -0.77 2.02 319.000 100.00 0.18 1.75 330.000 10.00 0.00 1.24 1213.o00 I .00 -0.57 3.89 88.OOO 0.20 0.91 3.35 4.400 0.93 2.49 1.64 20.000 7.20 1.25 0.95 353.000 254.00 0.28 2.4s IU.(KKI 300.00 I .hY 0.93 43.000 IXI.00 O.Y I 0.93 107.000 400.00 0.0s 0.60 18.900 50.00 I.so 1.20 505.O00 lOOO.00 0.25 3.99 2 . 7 0 0 600 2. I4 0.h2 2.voO 36.00 2.7U 1.01 0.01 0.52 0 (12 (I.(Hl 0.0.3 0 4x (114 0 02 0.03 0.04 I.ox 0.03 O.O(I 0.54 I.Yh I.7Y 0.85 I.O(I 0.02 0.04 0.64 0.50 0.92 0.00 0.62 LYX 0.m (1 32 0.00 O.(KI 0.77 0.49 0.43 0.00 0.06 0.18 0.00 0.04 0.10 0.26 1.R7 0.00 0.02 0.87 0.14 0.IX 0.01 0.57 0.31 0.53 0.09 0.42 0.01 9.34 I I .43 4 112 I.os 11.5h 64 71 5.57 ZOh .Y 1 h1,Yh 1111 Sh 7 5.; 2h.54 7 411 I57 2 2x 1.31 42 Xh 91.1.: 16.16 19 I h 278.Y9 2.19 5.93 I .53 3.35 126.62 137.37 465.43 264 10 5 ?2 247.47 29. I5 0.61 15.99 0.40 2.81 I067 .97 40.I I 3.09 27.32 398.06 4673.79 1969.24 43.21 '44.06 8.52 0 97 3 x5 6.73 4.73 I .w I0.XI I .20 \- I; !I 1 626 Fiserova-Bergerova et al. TABLE 11. Constants Used for the Calculation of Flux and Critical Flux of Volatile Chemicals (SVP > 5 Torrs)* (Continued) Chemical TLV MW MP ws PC log p FI FI*'FI F1*vap/R 0 Thioslycolic acid skin Toluene 0 1.1.2-Trichloroethane rhin c) Trichloroethylene 0 Tnerhylamine 3 o-Xylene 0.0040 0.3750 0.0450 0.2700 0.0400 0.4350 92.1 91.1 133.1 131.5 101.2 106.2 -17 -Y5 - 37 -87 -115 -25 1325.000 0.600 1.300 1.100 15.000 0.180 2OOO.00 1.10 17 I 0 1.50 5.00 2.60 0.09 2.69 2.12 2.29 1.35 3.14 4.58 0.69 0.72 0.27 0.69 0.46 0.00 0.41 0.05 0.76 0.04 0.70 2.17 5.95 5.50 41.17 65.61 2.24 0 m-Xylene 0 PXvlene 0.4350 106.2 0.1350 106.2 - - 47 13 0.180 0.200 1.70 3.20 0.53 0.61 1.60 3.15 0.53 0.62 2.98 3.56- *PC. water-gas partition coefficient at body temperature: Fl*,,p, critical flux calculated for vapors using equation I4 (mg!cm';hr): ( X ) . significant dermal absorption of vapors (Fl*,,AFI < I ) : other symbols are the same as in Table 1. izability or decomposition affect the solubility and possibly. dermal absorption. Flux for these outsiders is not reported (Table VI). Comparison of Predicted Dermal Absorption With Skin Notation A dermal absorption potential is predicted for 122 chemicals. of which only 43 (35%)can-y a skin notation. A significant dermal toxicity potential is indicated for 77 chemicals. of which 40 ( 5 2 % ) carry skin notations. A dermal absorption potential. but not a toxicity potential. was predicted for three chemicals carrqing the skin notation (cumene. cyclohexanone. and styrene). In most instances. a skin notation is lacking for chemicals with TLVs designed to protect against irritation. Since the threshold for systemic toxicity of irritants is usually larger than the threshold for irritation. the critical flux for irritants is likely underestimated. Examples are acetic and formic acids. acetone. chloropicrin, methyl acetate. and some amines, ketones. and alcohols. It is probably justified that these irritants do not carry a skin notation. although dermal absorption of some of these irritants was predicted and documented [Schaefer et al.. 19821. The absence of a skin notation for nonirritants with predicted significant dermal absorption was further investigated. and the following causes were indicated. The absence of skin notation can be the result of the lack of information. Biological effects of the majority of chemicals included in this c a t e p y were insufficiently studied. and their TLVs are based on a relatively small amount of information [Documentation of the Threshold Limit Values and Biological Exposcre Indices. 19861. Examples are p-ter-butyl toluene. dicyclopentadiene. ethyl butyl ketone. and metribuzin. Lack of cognizance of information can be another reason for absence of skin notation. For ruample. dermal absorption of aspirin [Schaefer et al.. 1981; Wester and Maibach. 19771. benzene [Tsuiuta. 1982). n-butyl acrylate [Carpenter et al., 19741. ethylbenzene [Dutkiewicz and Tyras. 1967: Tsuruta. 19821. methyl chloroform [Fukabori et al.. 1977: Stewart and Dodd. 19641. methylene chloride and perchloroethylene [Stewart and Dodd. 1964). phenylmercaptan (Fairchild and Stokinger, 1958: Schafer, 1972). o-dichlorobenzene [Documentation of the Threshold Limit Values and Biological Exposure indices, 19861. toluene [Sato Dermal Absorption TABLE 111. Chemicals With Dermal Toxicity Potential Acetic acid Acetonitrile" Acetylsalicylic acid Allylalcohol" 2-Aminopyridine Aniline" Benzene Biphen! I n-Butanol" sec-Butanol n-Butyl acrylate n-Butylamine" Carbon disullide" Carbon tetrachloride" Chlorolomi Chloropicrine o-crewl.' m-Cresol p-Cresol" Cyclohe\anol" Dichloroethyl ether" Dicyclopentadiene Dieldrin" Diethanolamine 2-Diethy laminoethanol' Diethylene triamine" Diisopropy lamine" N.N-dimethyl aniline" Dimenthyl phthalate Dioxane" Diphenylamine DMAP DMF" Ethanolamine 2-Ethoxyethanol" Ethylamine Ethyl butyl ketone Ethylene glycol Ethyl mercaptane Formaldehyde Formamide" Formic acid Furfural" GI! cerin Hexylene glycol Hydrazine" Isobutyl alcohol Isoprop!lamine Lindane" Mesit!l o\ide Methanol" 2-Methox!rthanol" I-Metho\! phenol Meth? lamine n-Mrth!l aniline" Meth>I n-hutyl ketone Meth! I chloride Meth! lenc chloride Meth? I iodide* Morpholine" p-Nitroaniline" p-Nitrotoluene" Pcp" p-Phenylene diamine" Phenyl ether Phenyl mercaptan Propoxur n-Propyl alcohol" Ronnel 1. I.2.2-Tetrachloroethanea Thiogl!colic acid" o-Toluidine" p-Toluidine" Tributyl phosphate Trichloroacetic acid 1,1 .2-Trichloroethanea Triethvlamine "Skin notation in 1987-1988 TLV-BE1 booklet. 627 and Nakajma, 1978; Tsuruta, 19821, trichloroethylene [Sato and Nakajima, 1978; Stewart and Dodd, 1964: Tsuruta, 19771, and some alcohols [Schaefer et al.. 19821 was experimentally documented. but the information is not evaluated in the TLV-documentations [Documentation of the Threshold Limit Values and Biological Exposure Indices, 19861. 3. Skin notation can be based on information related to an inappropriate biological effect. For example, tests showed that dermal absorption of aspirin is too small to produce a therapeutic dose. However. the dose produced by inhalation exposure to TLV-TWA is about 100 times smaller than the minimal therapeutic dose. Another example is hexachloroethane, whose TLV was recently reduced from 0.1 to 0.01 mg/l. based on systemic toxicity [Threshold Limit Values and Biological 1! 1: !I 628 Fiserova-Bergerova et al. TABLE 1V. Chemicals With Dermal Absorption Potential Only Acetone n-ArnLI acetate Isopropyl alcohol Methoxychlor Atrazine Methyl acetate 1.3-Butadiene Methyl n-amyl ketone n-But>l acrtiite Methyl chloroform p-ter-Butyltoluenc Methyl ethyl ketone Cumene" Methyl isoamyl ketone Cyclohexanone" Methyl isobutyl ketone o-Dichlorobenzene Methyl propyl ketone I . I -Dichloroethane Metribuzin I .?-Dithloroethylene Naphthalene Diethyl ketone Nitromethane Diuron Pentaerythritol Enflurane n-Propyl acetate Ethanol Propylene dichloride .,,-, Ethyl acetate .t-4 .. -I ..I Ethy I benzene Ethyl ether ..,. . Ethyl formate Strychnine Styrene" Toluene 1.2 .J-Trichlorobenzene Halothane n-Heptane Trichloroethylene Trimethyl benzene Hexachloroethane o-X ylene n-Hexane rn-Xylene Isoamyl alcohol p-Xylene .. ... . "Skin notation in 1987-1988 TLV-BEL booklet. .. . -.!. TABLE V. Chemicals Without Significant Dermal Absorption Chlorobenrene Cyclohexane p-Dichlorobenzene Eth) Ichloride Cyclohcxene \Ic.rh! 1.11 Trichlorut luoroniethane Exposure Indices. 19SSl. Dermal absorption potential related to the old TLV (based on protection against irritation) wa.s insignificant. but it is significant with respect to the proposed TLV. Another example is benzene. whose TLV was reduced tenfold. and therefore a skin notation became appropriate. Hansen [ 19821 was the first to use a theoretical model to predict skin notation. His moaei calls ful a skin notation for an additional 44 chemicals in the T1.V table. Our study also calls for additional skin notations. There is a difference in his and our approach in identifying the significance of dermal absorption. Hansen's criteria are based on the swelling of psoriasis scales. while our criteria are toxicolosically based. Despite this difference. both studies conclude thdt the list of chemicals with skin notation is incumplete. A Reference Value for Flux in an Industrial Setting In the workplace. the threshold for flux can vary depending on the exposed areas. dermal exposure duration. and selected threshold for the biological level. To Dermal Absorption TABLE V1. Chemicals Excluded From the Study (Outsiders) Acrylarnidea Acrylic acid Acrylonitrile" Aldrin" Benzidine" n-Butane ?-Butox\ ethanol* n-But! I mercaptan Captan Carbanl Catechol Chlordane" Cilorpyiios" Cyclohexylamine 2.1-D DDT Diazinon" 3.3'-Dichlorobenzidine" Dichlorodifluoromethans Dieth! lamins rn-Dinitrobenzene" o-Dinitrobenzene" p-Dinitrobenzene" Dinitrotoluene" Fenthion" Hydroquinone Malathion" Methyl acetylene Methyl bromide" Methyl parathion" Nitrobenzene" Nitroglycerin" I -Nitropropane o-Nitrotoluene" m-hitrotoluene' Nitroub oxids Parathion ' Perchloroeth? lene Phenol" Picric acid" Propionic acid Pyridine Resorcinol Tetrahydrofuran "Skin notation in 1987-1988 TLV-BE1 booklet 629 estimate a reference value (RV) for a dermal exposure existing in the workplace mditions, the following formula can be derived from equation 5 in the Appendix. ABL% . RV=-. Val, . TLV . 100 . _8 100 EA% . SA hrs and after substitution ABL%. TLV RV = 0.4 EA% hrs where ABL% denotes the chosen increase of biological levels expressed in percentage of levels reached during exposure to TLV-TWA only, EA% denotes percentage of body surface dermally exposed. hrs denotes duration of dermal exposure in hours, and TLV is TLV-TWA in mg/l. If predicted flux, calculated by equation I, exceeds the reference value (F1 > RV), then a dermal overexposure at the selected BL-level is predicted. For practical purposes, two ABL% are of main interest: 1 ) levels at which dermal exposure affects the relationship between air monitoring and biological monitoring (usually related to A B L 8 = 30%); and 2) levels at which dermal exposure contributes to systemic toxicity (usually related to ABL% = 300%). Dermal Absorption of Vapors and Gases Dermal absorption of vapors and gases is usually considered negligible compared with pulmonary uptake [Riihimaki and Pfaffli. 19781. Critical flux for whole 630 Fiserova-Bergerova et al. body exposure to gases and vapors is not affected by exposure concentration (equation 14 in the Appendix). However, its application is restricted to concentration\ considerably smaller than the concentrations corresponding to saturated vapor pres. sure; otherwise. the condensation distorts the prediction of dermal penetration of the vapor. Furfural is an example of how condensation significantly increases **absorption of vapors" [Flek and Sedivec. 19781. Signiticant dermal absorption potential for vapors and gases can be predicted by comparing FL*,,p with FI (Table 11). Of 61 volatile chemicals, only 3 show a dermal absorption potential for vapors: n-hexane, isobutyl alcohol. and methyl iodide. CONCLUSIONS A dermal penetration rate [flux (FI)], predicted from physical properties of the chemicals, is suggested as an index of the dermal absorption potential of industrial -..cIe-, chemicals. The prediction is designed for organic nonelectrolytes. Since published 1 .4 . .. data on log P and aqueous solubility are sometimes inconsistent. it is advisable to test the information on the octanol-water partition coefficient and on aqueous solubilitv (equations VI1 and VIII) before using it for the prediction of flux. Two reference values are recommended as criteria for skin notation. 1 Critical flux (F1") for dermal absorption potential relates to dermal absorption raising the dose of nonvolatile chemicals or biological levels of volatile chemicals 30% above those observed during inhalation exposure to TLV-TW.4 only. If dermal exposure of 1 9 of body surface to saturated aqueous solution raises the levels by 30% (FI > FI*). the chemical should be classified as a chemical with dermal absorption potential and identified as such in the TLV booklet. Biological monitoring of these chemicals is advisable. especiallq. if dermal exposure to a significant fraction of body surface is prolonged. Biological levels of indicators of exposure to these chemicals are not necessarily quantitative indicators of inhalation exposure. Critical flux ( FL:3'i') for dermal toxicity potential relates tu dermal absorption. which triples biological levels as compared with levels observed during inhalation exposure to TLV-TWA only. If dermal exposure of 2ri of body surface to saturated aqueous solution triples biological levels. the chemical should be classified as a chemical with dermal toxicity potential and should carry a skin notation; biological monitoring. if a method is available. should be instituted. If biological levels persistently exceed BEIs. steps should be tahen to reduce dermal exposure. unless other origins of the increased biological levels are indicated (nonoccupational exposure. interference by medication. enzyme induction. c'tc.) . Absence of a skin notation for chemicals with predicted dcrnial to\icity potential should be investigated and experimental testing encouraged. Critical flux relates to systemic effect and can be overestimated for chemicals whose TLVs are based on preventing irritation and discomfort. Critical flux should be lowered if a large area of body surface is exposed to aerosol. particles. liquids. or solutions. Equation X is suggested for the calculation of a reference value for dermal exposure in an industrial setting. Potential for significant dermal absorption or toxicity of gases or vapors of Dermal Absorption 631 volatile chemicals is rare. However. condensation of vapors on the body surface can raise the penetration rate above the predicted flux. Vapors of chemicals with low saturated vapor pressure are more likely to condense .on the body surface than are gases or vapors of highly volatile chemicals. The proposed formulas are meant for practical use: therefore certain simplifications are made. For example. the calculation of critical flux is based on steady state conditions. not takins into account the raising of biological levels in time or deposition in subcutaneous fat. The biochemical changes in skin induced by the cheniical or by the vehicle are not included in the calculation of flux. nor is the regional variation in skin composition taken into account. REFERENCES Alber). N'J. Hltdprait J ( IY791. Percutaneous absorption: Theoretical description. J Pharm Pharmacol 3 I :12Y-I 39. Astrand I ( 198.;1: Effect o t ph!\ical e\ercise on uptake. distribution. and elimination of \ q x ) r > in man In Fiwx<>va-Brrgsroa\ \' led): "Modeling of Inhalation E x p o w e IOVapors: Uptake. Digributlon. and Eliminaticin." \'t)l. 11. Boca Raron. FL: CRC Press. pp 107-130. Berner B. Cooper ER I % - ) : Modelr ol d i n permeahilit!. In Kydonieu AF. Berner B (edsi: "Transdermal Deliver) ot Drugs." c'ol. 11. Boca Raton. FL: CRC Press. pp 4l-S5. Berode M . Droz PO. Guillrmin M ( 19851: Human exposure to styrene. VI. Percutaneous absorption in human \olunteers. Int Arch Occup Environ Health 55:33 1-336. Burton AC ( 19681: "Physiology and Biophysics of the Circulation." Chicago: Year Book Medical Publishers. Inc.. pp 13-22. Carpenter CP. Weil CS. Smyth HF J r (1974): Range-finding toxicity data: List VIII. Toxicol Appl Pharmacol 28:313-719. .I JA (edl 1979): "Lanpe'\ Handbook of Chemist? .'. ed 12. New York: McGraw-Hill Book Co. &mxnenration of the Threshold Liniit Values and Biological Exposure Indices ( 1986): 5th ed and Suppls. 1987 and 1988. Cincinnati. OH: American Conference of Governmental Industrial Hygienists. h g a r d PH I 1983):Skin permeabilit! theorj in relation to measurements of percutaneous absorption in toxicolog!. In Marzulli FN. Maihach HI (eds) "Dermatotoxicology." ed 2. Washington. DC: Hemi5phere Pub. Corp.. pp 05-1 16. Dugard PH. \Valker M. Mawdsle) SJ. Scott RC ( 1984): Absorption of some glycol ethers through human skin in vitro. Environ Health Perspect 57:193-197. btkiewicz T. Tyras H (1967): A study of the skin absorption of ethylbenzene in man. Br J Ind Med 24:330-332. htkiewicz T. Tyras H ( 1968): Skin absorption of toluene. styrene. and xylene by man. Br J Ind Med 25243. Fairchild U.Stokinger HE ( 1958):Toxicologic studies on organic sulfur compounds. Am Ind Hyg Assoc J 19:171-189. krova-Bergerova V ( 1983): Gases and their solubility: A revieu of fundamentals. In Fiserova-Berg- erova V (ed): "Modeling of Inhalation Exposure to Vapors: Uptake. Distribution, and Elimination." Vol. I . Boca Raton. FL: CRC Press. pp 3-28. Fiserova-Bergerova c': Interaction between inhalation and dermal exposure: Simulation model. (in preparation ) Fkrova-Bergerova (Thomas)V. Pierce JT ( 1989):Biological monitoring V. Dermal absorption. Appl Ind Hyg 4:FI4-F2I. Flek J. Sedivec V (19781:The abwrption. metabolism and excretion of furfural in man. Int Arch Occup Environ Health 31:159-168. Fukabori S. h'akaaki K. Yonemoto J. Tada 0 ( 1977):On the cutaneous absorption of I . I . I-trichloroethane f 2 i . J Sci Labour 53:89-Y5. Grandjean P. Berlin A. Gilbert M, Penning W ( 1988): Preventing percutaneous absorption of industrial chemicals: The "skin" denotation. Am J Ind Med 1497-107. '! i: I 632 Fiserova-Bergerova et al. Guy RH. Hadgraft J. Maibach HI (IY85): Percutaneous absorption in man: A kinetic approach. Toxicol Appl Philmacol 78:123-129. Hansch C. Leo A ( 1979): "Substituent Conhtants for Correlation Xnalysis in Chemistry and Biology." New York: Wiley-Interscience Pub. Hansen CM ( 1982): "The Absorption of Liquids Into the Skin." Report T3-82. Horsholm. Denmark: Scand Paint Printing Ink Res. Imt. Kuabota K, lshizaki T f 1986):A calculation of percutaneous drug absorption-[. Theoretical. Comput Bioi Med 16:7-19. Michaels AS. Chandraskaran SK, Shaw JE ( 1975): Drug permeation through human skin: Theory ana in vitro experimental measurement. AlCHE J 2 I :985-996. Nakaaki K. Fukabori S. Tada 0 ( 1985): An experimental study on percutaneous absorption of mixed organic solvents. J Sci Labour 61:l-IO. Riihimaki V (1979): Percutaneous absorption of m-xylene from a mixture of m-xylene and isobutyl alcohol in man. Scand J Work Environ Health 5:143-I50. Riihimaki V. Pfaffli. P ( 1978): Percutaneous absorption of solvent vapors in man. Scand J Work Environ Health 473-85. Sato A. Nakajima T ( 1978): Differences following skin or inhalation exposure in the absorption and excretion kinetics of trichloroethylene and toluene. Br J Ind Med 35:43-49. Scansetti G, Pilatto G, Rubino GF ( 1988):Skin notation in the context of workplace exposure standards. Am J Ind Med 14:775-732. Schaefer H. Zesch A. Stuttgen G (1982);Flux. In: "Skin Permeability." New York: Springer-Verlag. pp 829-83I. . . Schafer EW ( 1972):The acute ord toxicity of 369 pesticidal. pharmaceutical and other chemicals to wild I - birds. Toxic01 .\PPI Pharmacol ?1.?15-3?0. Scheuplein RJ. Blank IH (1971): Permcabilit> of the skin. Physiol Rev jI:702-747. ..... .I Stewart RD. Dodd HC I196-1);Absorption of carbon tetrachloride. trichloroethylene. tetrachloroethylene. methylene chloride and I . 1 . 1 4chloroethane through the human skin. Ind Hyg J 25:439-446. 9 Threshold Limit Values and Biological Exposure Indices for 1988-1989 ( 1988): Cincinnati. OH: . h e r - ican Conference of Governmental Industrial Hyzienish. Inc. Tsuruta H ( 19771,Percutaneous absorption of organic wlvents. 11. A method for measuring the pene- tration rate of chlorinated wlvents throu_ghexcised rat skin. Ind Health 15:131-13Y. Tsuruta H ( 1982): Percutaneous absorption of organic bolvents. 111. On the pnetration rates of hydro- phobic solvents through the excised rat skin. Ind Health. 20:335-345. Verschueren K ( 1983):"Handbook ofEnvironmental Data on Organic Chemicals." ed 2. New York: Van f'3 Nostrand Reinhold Co. Wester RC. Maibach HI ( 19771: Percutaneous absorption in man and animal: A perspective. In Drill VA. Luznr P ( 4 s ) : "Cutanew5 Toxicity." New York: Academic Press. Inc.. pp I 11-126. Windholz b1 I ~ I 1YI 761: "The S.lcrck Index. d n Encyclopedia otChemical>and Drugs." cd 9. Rahway. NJ: 'Merck & Co.. Inc. Yalkou->kySH ( 198 I I: Soluhilit) and wlubiliration of nonelectrolytes. In Yalkow ksy SH fed): "Tech- niques ut' Solubiliration 01 Drugs." New York: Marcel Dekker. pp 1-14. Yalkou.\ky SH. ValLani SC ( 1980): Solubilit! and panitioning. I:Solubility of nonelectrolytes in water. J Pharmaceut Sci 69:912-932. APPENDIX In the model by Berner and Cooper [ 19871 the two diffusion pathways. polar and lipophilic. are considered to be independent of each other. The diffusion conhtant for both polar and lipophilic pathways (Dp 2nd 0,)have been estimated based on Bueche's t'ree-vo!ume theory for rigid molecules Dermal Absorption 633 where MW is the molecular weight of the studied chemical. The equation describing flux (F1)is a sum of penetration rates mediated by polar and lipophilic pathways. The difference in availability for diffusion either by polar or lipophilic pathways is defined by the hydrophobic constant. P. which denotes the octanol-water partition coefficient where cSaIdenotes the concentration of saturated aqueous solution of the chemical in mg/ml, and I is the thickness of the stratum corneum. which varies from 10 to 40 pm. In this study. it is assumed that I = 15 pm [Berner and Cooper. 19871. A, and A, in equation 3 denote area fractions of the polar and lipophilic pathways. respectively. From fitting water penetration data, Berner and Cooper [ 19871 proposed that the area for the polar pathw,ay accounts for 10% of the total skin area. which means that .4, = 0.1 and A, = 0.9. .4frer substituting in equation 3. a simple equation for the calculation of flux is obtained. The values for qaI.P. and MW were obtained from Dean [1979]. Hansch and Leo [1979], Verschueren [ 19831. and Windholz [ 19761. When more than one value was lorted in the reference sources, the compiled value shown in Tables I and I1 was d e d . For chemicals miscible with water, the density of the liquid multiplied by 1 .OOO was substituted for Calculation of Critical Flux Critical flux (F1*) can be calculated by comparing inflow and outflow, of the chemical across the l u n g At stead) state inflow -- outflow Val,, . TLV + 0 c,, + F1 . EA = Q . c,, + Vatv * Calv (5) where Valvis alveolar ventilation ( = 900 L/hr). Q is cardiac output. calVand can are concentrations (mg/L) in alveolar air and arterial blood. respectively. TLV is TLVW A expressed in mg/L. A concentration of the chemical in mixed venous blood (c,,) reflects the average concentration in venous blood from all tissues but does not include the amount of chemical absorbed by the dermis under the exposed area. EA is area of body surface (in cm') exposed to saturated aqueous solution of the studied chemical, and F1 is predicted flux in mg/cm'/hr. Critical Flux for Dermal Absorption Potential (FI') Fl* for nonvolatile chemicals. Since nonvolatile chemicals are not exhaled, Valv.CaI, = 0. In the absence of dermal exposure EA = 0.and equation 5 is written Valv* TLV = Q . (c,, - cVI) (6) 634 Fiserova-Bergerovaet al. In the presence of dermal exposure, which raises can and c,, by 30%. equation 5 is modified: +Val, * TLV F1 . EA = 1.3 - Q . (can - cVt) (7) After substitution from equation 6. equation 7 can be rearranged to calculate critical flux for any exposed area: 0.3 Val., TLV F1* = EA Critical flux calling for dermal absorption potential notation is obtained after substiting the following values: Val, = 900 L/hr, EA = 360 cm2 F1* = TLV ' (9) .._. 1. ,- .. F1* for volatile chemicals. In the absence of dermal exposure (EA = 0). equation 5 can be written: . .. I. -.1 At steady state, all concentrations in venous blood are equilibrated with tissue con- rl centrations. In the presence of dermal exposure. which raises calv,can, and cVtby 30%. equation 5 is modified. Val" * (TLV - 1.3 c,~,) + F1 . EA = 1.3 * Q * (can - cVt) (1 1) After substitution from equation 10, equation 11 can be rearranged to calculate the dermal absorption rate. F1 * EA = 0.3 . Val, TLV (I?) Critical flux calling for dermal absorption potential is obtained after substituting in equation 12 -4 F1* = TLV 1 (13) FI*,,, for gases-and vapors. Critical flux for dermal absorption potential of vapors and-gases is calculated on the assumptions that the whole body is exposed to a gas or vapor and that the concentration of the chemical in water of the outside layers of stratum corneum (c,) is readily equilibrated with the exposure concentration. Under these assumptions. EA = SA = 18000 cm' and c, = TLV.X, where A is water-gas partition coefficient. Thus, FIsEA in equation 12 is replaced by the ex- pression F~*(c,/c,,,)-SA, where c,,~ denotes an aqueous saturated solution. Critical Dermal Absorption 635 flux for dermal exposure to vapors and gases is obtained after substituting for SA and Valv: Fit,, = 0.3 . Val\ .-.CS,f TLV = 15 -Csat SA TLVA A Values of partition coefficients are taken from Fiserova-Bergerova [ I9831 or estimated by the author,. Critical Flux for Dermal Toxicity Potential (FI") TLV-TWA have incorporated ?. safety facta; :ha; provides for an excursion factor of 3 for concentrations of chemicals in the workplace [Threshold Limit Values and Biological Exposure Indices. 19881. It can therefore be assumed that it provides a safety factor for tripling biological levels. Therefore the proposed threshold for systemic toxicity potential is associated with flux related to. the increase of biological levels by 200%. Such flux for dermal toxicity potential can be calculated using the following equations and for vapors and gases 200 Csai FL:;, = -Fl,,, = 100 30 A (16) i 'I