Document YDQJqEb0OaL3zeBQnnVm2GNn8

.. 38 Ocrupational and Environmental Medicine 1997;54:3843 Dermal absorption of vaporous and liquid 2-methoxyethanol and 2&mxyethanol in volunteers Sank Keiik, K a M Mahieu, Aart C Monster, Frederik A de Wolff Coronel Laboratonum, VMep Gezondheidkunde, Academisch Medisch Centrum, Meibergdreef 15,1105 AZ Amsterdam, The Netherlands S KeiiC K Mahieu A C Monster F A de Wolf Correspondence to: Dr S Keiic, Coronel Iaboratorium, Vakgroep Gczondheidkunde, Acadcmisch Medisch Centrum, Meibergdreef 15, 1105 AZ Amsterdam, The Nctberlands. Accepted 12 July 1996 Abstract Objectives--To estimate dermal absorption of vaporous and liquid 2-methoxy- ethanol (ME)and 2-ethoxyethanol (EE) in volunteers. Methods-Five volunteers (two men and three women) were dermally exposed to vaporised and liquid ME and EE. Dermal exposure on an area of about 1000 cm' (forearm and hand) to vapours of ME and EE (4000 mg/m3ME and 3700 mg/m3EE) lasted for 45 minutes. Duration of exposure to liquid ME and EE on an area of 27 Em2 (forearm) was 15 minutes. Dermal uptake was assessed by measurement of the main metabolites in urinary methoxyacetic acid (MAA) and ethoxyacetic acid (EAA). For each volunteer, excretion of metabolites was compared with a reference inhalatory exposure. Results-Mean (SD) absorption rates of ME and EE vapour were 36 (11) and 19 (6) c m h respectively. The mean (SD) absorption rates of the liquid ME and EE amounted to 2-9 (2-0) and 0.7 (0.3) mg/cm2.h. Conclusions-Vaporised and liquid ME and EE are readily absorbed through the skin. In the combined inhalatory and dermal exposure when whole body surface is exposed to vapour, the uptake through the skin is estimated to be 55% of the total uptake of ME and 42B/0 of EE. Dermal uptake resulting fkom skin contact ofboth hands and forearms (about 2000 cm*)with liquid ME and EE for 60 minutes would exceed inhalatory uptake of the eight hour occupational exposure limit by 100 dmes at 16 mg/m3 of ME and 20 times at 19mglm3 of EE. The substantial skin uptake of ME and EE indicates that in assessing the health risks biological monitoring and use of biological exposure indices are preferable to environmental monitoring. (Occup Environ Med 1997;54:3843) Keywords: 2-merhoxyethanol; 2-ethoxyethano1, dermal exposure Although often comprising 10% of the final product, 2-methoxyethanol (ME) and 2-ethoxyethanol (EE) are key ingredients in water or solvent based paints and coatings and industrial and domestic hard surface cleaning products.' The usefulness of glycol ethers can be attributed to their physical properties, particularly their miscibility or high solubility in water and organic solvents, and their low vapour pressure. Studies on rodents indicate that ME and EE are compounds causing ter- atogenic, fetotoxic, haematotoxic, and testicular effects.' The toxic metabolites of ME and EE are the corresponding alkoxyacetic acids, methoxyacetic acid (h4A.4) and ethoxyacetic acid ( E A A ) . Z - + In humans, 8 5 5 % of absorbed ME is excreted as urinary MAA with a half life of 77 hours.' On average, within 42 hours, 22% of absorbed EA was excreted as EAA with a mean (SD) half life of 42 (4.7) hours3 The main concern for human exposure is the occupational environment. The occupational exposure limits (OEL) of ME and EE are set in The Netherlands5 and United States6 at 5 ppm (16 and 19 mg/m3, respectively). A skin notation assigned to ME and EE in these OEL documents implies that skin absorption might be an important route of entry. Despite hard evidence that both glycol ethers as liquids are readily absorbed through human skin in vitro7there are few human data on skin absorption of ME and EE in the liquid as well as in the vapour phase. Human data for skin uptake of another glycol ether 2-butoxyethanol have been published,8 reporting that dermal exposure to 2-butoxyethanol, both liquid and vapour, was even more important than respiratory uptake. The purpose of this study was, therefore, to estimate the percutaneous absorption of ME and EE in volunteers under controlled experimental conditions. Subjectsand methods SUBJECTS The volunteers (two men and three women) ranged in age from 22 to 25. All were without a history of serious diseases and their skins appeared normal. None of them took medicines or alcohol fkom at least 12 hours before exposure until the end of collection of urine. The experimental protocol was submitted to and approved by the medical ethics committee of the Academic Medical Center, University of Amsterdam. An informed consent form was signed by each subject. Given the very long half life of MAA (74 and of EAA (44 hours),' the period between the two exposures in each volunteer was at least three weeks. GENERATION OF GLYCOL ETHER VAPOUR Medical air at a flow rate of about 3l/min from a compressed air cylinder was led through a bottle filled with neat ME or EE. The vapour stream was led through teflon tubes into and out of the exposure cylinder. EXPEZUMFNTAL SETTING Dermal exposure to vapour and liquid The volunteer was situated in a clean air cabin with a slightly increased pressure to avoid additional inhalatory exposure. The exposure lasted for 45 minutes. The arm of the subject was the only part of the body outside the cabin. During the vapour exposure experiments, the subject placed the lower arm into the exposure cylinder into which the glycol ether vapour was led. The exposure cylinder (volume 6.5 1) was provided with one large opening for the forearm and five small openings of about 3 mm internal diameter: two inlets, two outlets, and an opening for the vapour sampling. The vapour concentrations of ME and EE were about 10 times below the saturation concentration. To minimise the intluence of temperature and humidity in the cylinder on the skin absorption and to prevent condensation on the skin, the flow of ME and EE of about 3l/min was used. The temperature varied from 22C to 25C and the relative humidity from 60% to 65%. T o avoid contamination of inhaled air through leakage, the opening in the cylinder and on the cabin were provided with cuffs.The concentrations of ME and EE in the cylinder were measured every five minutes throughout exposure. During exposure to liquid ME and EE, a glass chamber with an area of 2 7 m 2 was placed on the volar forearm and filled with ME or EE. After 15 minutes the exposure vessel was removed and the remaining solvent gently wiped off with a tissue. At the end of exposure the subject stayed for another 15 minutes in the cabin to allow the glycol ether to evaporate from the skin surface and to prevent possible inhalatory uptake. Inhalatoly exposure Each volunteer was exposed during four periods of 15 minutes to a concentration of about three times the current OEL value in The Netherlands (16 and 19 mg/m3 for ME and EE respectively). The time between the exposures was 10 minutes. Volunteers were in a sitting position and inhaled through a mouthpiece with a one way valve connected to a Tedlar (DuPont, Delaware, USA) bag containing ME and EE. During exposure the total amount of exhaled air was collected in another Tedlar bag. To prevent condensation of water in the exhaled air bag, a cold water trap (held at 0C) was placed between the mouthpiece and exhaled air bag. To correct for the amount of ME and EE possibly absorbed in the water trap, we measured the amount of ME and EE absorbed in the condensate in the cold trap after consecutive 15 minute exposures of four subjects; this amount was taken into account when calculating the respiratory uptake. To determine the actual exposure concentration, air samples were taken from the inhalation bag before and during exposure from a point situated in the system before the mouthpiece. Urine collection All urine was collected for the first two days; for practical reasons, on days three to five only a morning and last evening sample were taken. One person collected all urine for seven days. For each sample, volume, creatinine, and specific gravity were measured and the samples were stored at - 20C until analysis. Analysis Analysis of inhaled and exhaled air was performed by gas chromatography. Air samples were injected with gas tight syringes into a gas chromatograph. The MAA and EAA in urine were measured by a slightly modified version of the method of Groesenken er a1.lo To 100 pl urine 25 pl butoxyacetic acid (20 mg/l)(internal standard) and 100 pl phosphate buffer (PH = 7) were added. Thereafter, samples were left at 60C under slightly reduced pressure (20 mm Hg) to evaporate to dryness (about 20 minutes). After cooling down to room temperature 500 p l 5 % derivatisation reagent (2,3,4,5,6-pentafluorobenzyl bromide) (Aldrich Chemie, Germany) in methanol was added. Derivatisation was allowed to proceed for three hours at 70OC; after cooling down to room temperature, 500 pl water was added then 500 pl n-hexane. Samples were vortexed for one minute and then centrifuged for two minutes at 3000g. One pl hexane extract was injected into the gas chromatograph. Under these conditions, the detection limit of the method was 1Opg4 for both MAA and EAA. Gas chromatographic conditionsfor the analysis of metabolites in urine The gas chromatograph used was a Hewlett Packard Model 5890 A, equipped with an electron capture detector and a CP-SIL-13CB column (25 m; 0-25mm internal diameter; film thickness 0.2 p) (Chrompack, Middelburg, The Netherlands). Nitrogen was used as the carrier gas at a flow rate of 1 ml/min. The oven temperature was initially set at 60"C, increased to 166C at a rate of lS"C/min, and subsequently to 200C at a rate of 7O0C/minand the column temperature was then kept at 200C for 10 minutes. Gas chromatographic conditionsfor the analysis of inhaled and exhaled air The gas chromatograph used was a Carlo Erba Mega 5000 (Interscience, The Netherlands) equipped with a flame ionisation detector and a DB-WAX column (30 m; 0.53 mm internal diameter; 1 pm film thickness)a and W Scientific). The analysis was performed isothermally at 80C. Measurement of skin area The skin area of the forearm exposed to vapour was measured with the formula for calculation of the curved area of the frustum of a right cone." The area of the hand was measured as 40 Keiic, Mahieu, Monster, de Wolff Table 1 Inholatoy exposure to M E and EE (4 timesfor 15 minutes): exposure condihm, rupiratoy retention, and uptake of M E and EE and 48 h cumulative urinary excretion of MAA and EAA Exposure (mgtrn Y Subject M E _____- 1 2 3 4 5 Mean SD 41 39 44 44 42 42 2.2 EE 52 46 60 49 59 53 5.9 Resptratorj. retention (%) M E EE 85 85 80 75 77 75 92 86 67 86 80 81 96 Inhalatoy uptake, U,eb(rng, M E EE 18 23 18 20 18 24 23 24 16 29 19 24 2.6 3.2 ,zIAA (EAA), U h (mk) MR4 EAA Inhalawry uptake extrapolated io 8 h exposure at OEL (rng, .ME EE 3.3 5.9 54 67 1.2 1.8 54 58 2.4 5.2 54 70 3.1 5.3 69 70 3.7 6 48 2.7 4.8 57 84 70 0.98 1.8 7.8 9.3 Permeability parameters Exposure w vapour-ne absorbtion rate ( c d ) was calculated by dividing the absorbed amount of ME and EE (Udcr,vap) (mg) by the exposed area (cm'), the duration of exposure @), and the exposure concentration (mgkm'). Exposure to liquid-The dermal penetration rate (dermal flux) (mgicm2.h) was calculated by dividing the total absorbed amount (Ud,,,,,q>(mgb),y the skin exposure area (cm3 and the exposure duration @I). follows: the subject put on a rubber glove which fitted as well as possible without stretching on the hand. The area was then assessed by comparing the weights of the glove and of a piece of glove of a known area. Calculation of uptake The respiratory uptake (Ud and dermal uptake (Uder,vsp and ofud,,,q> ME and EE was calculated from the equatlons (1) and (2): U, (mg) = (e, - c.3 x V (1) where c,,,,,= concentration ME or EE in inhaled air bag; cerh= concentration in exhaled air bag (corrected for the amount absorbed in the water trap); V = volume inhaled ( = exhaled) air, and udcr(mg) = ( m ( E U ) d e r A B - d MAA(EAA),,,IJ u, (2) where h&%4(EAA)de,,,, = amount of excreted MAA(EAA) in urine during the 48 hours after dermal exposure; MAA(EAA),,,, = amount of excreted MAA(EA4) in urine during the 48 hours after inhalatory exposure. Results Table 1 shows the experimental conditions of inhalatory exposure to ME and EE. For each volunteer, the calculated respiratory uptake ( U 3 of ME and EE and the 48 hour cumulative excretion of the corresponding acid metabolite are presented along with the respiratory uptake and retention defined as ( C , - C*]CdJ x 100%. Estimation of dermal uptake of vaporised and liquid ME and EE was based on the 48 hour MAA and EAA Urinary excretion, MAA(EAA),,,, ,,. Tables 2 and 3 show the amounts absorbed dennaliy and calculated on an individual basis by comparison with a reference inhalatory exposure and exposure conditions. Tables 2 and 3 also show the permeability parameters for MA and EA vapour (absorbdon rate, d)and for liquid (absorption rate, mg/cm2.h). The results indicate that ME vapour penetrated the skin faster then EE; the absorbtion rate for ME amounted to 36 cm/h and to 19 cm/h for EE (table 2). The difference in penetration between ME and EE is even more pronounced after exposure to liquid; the absorption rate amounted to 2.9 for ME and 0.7mg/cm2.hfor EE (table 3). Table 2 Dermal exposure w vaporised M E and EEjm 45 min: exposure con&, 48 h cumulative unn0y excretion o j MAA and EAA and calculated dennd uptake and absmbtia rates of M E and EE Exposure (mg/rn 9 M E EE Exposed area (C?d? ME EE MAA Dd @&I),u,p ~ r k eLrb (ntk) (mk) MAA EAA M E EE Absorbria rates (cmlh) ME EE Domal uptnkr exuapolated w 8 h whole body exposure at OEL ( m d M E EE Dmallwtal uptake (%) M E EE 1 3835 2959 954 868 12 11 67 42 27 22 40 40 42 37 2 5782 4458 905 883 10 4 153 39 40 13 92 37 63 39 3 3082 2520 1210 1134 18 14 137 67 49 31 82 64 60 48 4 6190 4600 1032 1228 30 24 219 109 46 19 131 104 66 60 5 5032 3705 1086 1086 15 7 66 35 16 12 40 33 45 28 Mean 4854 3648 1037 1040 17 12 128 58 36 19 77 55 55 42 SD 1307 910 119 159 8 8 64 31 14 8 38 29 11 12 Table 3 Exposure to liquid M E and EE for 15 minutes: exposure conditions, cumulative urinaty excrenbn of MAA and EAA, and calculated dermal uptake and absoTption rate of and EE Dermal uptake, z m (m)u,h (4 U, MAA EAA ME EE Absorption rate [rngiim:. h) M E EE Dermal uptake extrapolated w 1 h exposure and w exposed area of 2000 cm2(rnk) _____ M E EE Dermallinhdawy uprnke (8 h, OEL) M E EE 1 2 3 4 5 .Mean SD 3.9 2.2 -2.8 2.4 2.8 0.8 0.8 14 3 2.1 0.4 4144 888 76 13 0.6 35 7 5.2 1.o 10360 2072 192 36 0.9 0.8 21 4 -4 -3.1 0.6 0.5 -6216 1184 1184 115 - 17 17 1.7 10 8 1.6 1.1 0 96 20 5.2 2.9 0.7 0.43 11 2.2 2.0 0.3 2960 5920 3256 2368 1539 651 62 111 58 28 22 10 L E Figure 1 Cumulative urinay excretion of MAA after dermal and inhalatoy exposure M vapoked ME. 40r I 30 r 47.5 GI `. Frequent urine samples I Evening urine samples Figure 2 Cumulative u n n a y excretion o f E A A after dermal and inhalawry exposure w vaporired EE. ` ~ 0 Dermal exposure ~ ~ o Inhalatory exposure '0 I I 10.0 0 25 50 75 Time (h) "\ b 0.0 I I I 0 25 50 75 lime (h) Figure 3 Urinary excretion of MAA a+ dermal exposure to vaponjed ME. I 100 sure route: an initially fast increase in the con- centration then slow and highly irregular excretion (figs 1-3). Before exposure neither MAA nor EAA was present in the urine in concentrations exceeding the detection limit of the analytical method (0.01 mgA). The mean (SD) elimination half life calculated &om the slope of the log linear excretion time curve 72 (24) hours for MAA and 44 (8) hours for FAA. Consequently, in morning urine samples lower concentrations were found; a day and Time (h) night rhythm was illustrated for MAA after dermal exposure to ME vapour (fig 3). Correction for creatinine or specific density To compare dermal uptake and uptake by did not affect this excretion pattern. Slow uri- inhalation &om the same atmosphere we nary excretion ofMAA and EAA is reflected in extrapolated the amount of MAA(EAA)k,48h the shape of the cumulative excretion curves: in both experiments to the identical exposure even after seven days there was hardly any lev- conditions assuming constant absorbtion elling off (measured in a person who collected rates: eight hours of exposure at OEL all urine for seven days). (16 mg/m3ME and 19 mg/m3EE). Assuming that the entire skin area of the body is exposed, the forearm surface area is linearly extrapo- Discussion lated to the whole body surface area of 1e8 m2 Estimation of dermal uptake by comparison of (tables 1 and 2). urinary excretion of MAA and EAA after der- TO compare dermal uptake of liquid ME mal and respiratory exposure is based on the and EE with inhalatory uptake, we exuapo- assumption that their biokinetics is not affected lated the uptake determined in our study by different routes of entry. The elimination (exposed area of 27 cm2 and exposure dura- pattern of MAA and EAA seemed to be similar tion of 15 minutes) to a skin area of 2000 cm2 for both exposure routes (figs 1 and 2) and it (both forearms and hands) and exposure dura- gave us the opportunity to measure dermal tion of 60 minutes. Table 3 shows this extrap- absorption by comparing it with a reference olated uptake compared with the inhalatory inhalatory exposure on an individual basis. uptake after exposure for eight hours at the Excretion of MAA and EAA was highly vari- OEL (table 1). These exposure conditions are able within individual people and there was a proposed by the European Centre for day and night rhythm; morning concentrations Ecotoxicology and Toxicology of Chemicals were always lower than those in the evenings (ECETOC) as a criterion for assigning a "skin (fig 3). The half lives were 72 hours for MAA notation" in the OEL documents. According and 42 hours for EAA and agreed closely with to that criterion a skin notation should be previously reported values of 77 and 42 hours applied if dermal uptake is > 10% of the eight for ME and EE.34As a consequence of such hour inhalatory uptake at the OEL. long half lives, the excretion of MAA and EAA The use of inhalatory exposure as reference was far from complete 48 hours after the start is based on the assumption that the toxicoki- of exposure; on a molar equivalent basis only netics of ME and EE once absorbed in the sys- 12% and 14% of the dose was recovered within temic circulation is identical for both exposure this period as h4AA and E M , respectively. routes. The excretion of both metabolites This was lower than the reported values of showed a similar pattern independent of expo- 28%for ME` and 23% for EE.' 42 f i . f i c , Mahieu, Monster, de Wdff The long half life of MAA and EAA and a circadian excretion pattern could probably be explained by protein binding of MAA and E M in blood or their reabsorption in the kidneys. Binding to proteins and elimination by saturable kinetics in the kidneys were reported by Corely and BormettlZfor butoxyacetic acid (BAA), a compound with a comparable chemical structure to MAA and EAA. A similar urinary excretion pattern, with a circadian variation and a long half life, was also reported by Monster et all' for trichloroacetic acid, a metabolite of trichloroethylene. Circadian excretion rhythm is important if MAA and EA4 are used as generally accepted biological exposure indices. A consistent sampling time has, therefore, to be applied. Respiratory retention of both ME and EE was high, about 80%, as could be expected from the very high blood!air partition coefficients of 32 836 and 22 093 for ME and EE, respectively.14Respiratory retentions estimated in our study were somewhat higher than the values of 76% and 64% for ME and EE reported by Groesenken et ul.34These differ- ences could be explained by Werent exposure conditions (mouth only in our study versus nose and mouth exposure in the studies of Groesenken et al.' This study showed that vaporised and liquid ME and EE are readily absorbed through the skin. The absorbtion rates into the skin normalised by cocentration of ME vapour is 36 cmih and 19 cm/h for EE. Higher absorption of ME was more pronounced in exposure to liquid where an absorption rate of 2.9 for M E and 0.7 mg/cmz.h for EE was estimated. Theoretically, the same ratio in permeability of ME and EE could be expected in exposure both to liquid and vapour. However, a high variation between people in both permeability parameters precludes speculation about the source of this discrepancy. Dugard and Walker' reported that liquid ME has a higher skin damage ratio than EE. This could possibly affect the skin integrity, and consequently increase the absorption of ME, in relation to EE. The absorption rate of liquid M E and EE estimated in our study is in close agreement with findings reported from the in vitro studies of Dugard and Walker' who reported mean (SD) values of 2.82 (2.63) for ME and 0.796 (0.46) mg/cmz.hfor EE. In risk assessment it is important to estimate the relevance of skin uptake in relation to the other exposure routes. Inhalation exposure is assumed to be the most important uptake route for most organic solvents. However, ME and EE penetrate the skin so easily that skin contact of both hands and forearms (about 2000 cm`) with liquid for one hour, greatly exceeds the respiratory uptake at OEL for eight hours (ME 100-fold and EE 20-fold). The question arises as to how realistic is such extensive skin contact with liquid ME and EE in occupational settings. It has to be stressed, however, that if spilling of ME and EE on clothing occurs, an even higher exposed area and exposure time can be expected. This exposure scenario (2000 cm2exposure area for one hour) was proposed by the ECETOCi5as a criterion for assigning a skin notation. According to that criterion, a skin notation should be given if the dermal uptake under these conditions amounted to > 10% of the inhalatory uptake. Dermal absorption of vapours is generally considered to be of minor importance compared with pulmonary uptake. However, it should be realised that a whole body skin area of 1.8 m2 confronted with a mean air velocity of 2 kmlh was swept by a volume of 28 800 m3 in eight hour^,'^ considerably more than the corresponding inhaled volume of 10 m3. On the other hand, difference in the relative sur- face areas (1.8 mzfor the skin v 30-100 mzfor the 1ungs),16 percentages of the cardiac output (100% for the lungs v 3% for the skin), and the distance that the compound must penetrate to reach the blood favour the lungs, generally speaking, as the primary site of absorption in a whole body exposure. However, our study shows that the skin is a significant uptake route for ME and EE vapour. If we assume whole body dermal and inhalatory exposure to vapour, the contibution of the skin to the total uptake would amount to 55% for ME and 42% for EE. Of course, this approach is simplified and some assumptions have been used in making these calculations. Firstly, that skin penetration characteristics of the forearms and hands (about 10 % of the total body area) are representative for the whole body, and secondly that clothing and possibly higher temperature and humidity under the clothing does not notably affect skin penetration. It is well known, however, from several experimental studies, that these factors could have an impact on the skin permeability.l' Previously, Johanson and Bornan* reported that dermal uptake of butoxyethanol accounts for about 75% of the total uptake during whole body exposure to butoxyethanol vapour with a tendency towards increased percutaneous absorption rate under conditions of increased temperature and humidity (33"C, 71% relative humidity in comparison with 23OC and 29% relative humidity) although the differences were not significant. However, with physiologically based pharmacokinetics models, Corely and BormettlZestimated the contribution of dermal uptake to be 21% of the total uptake, pointing out that the dermal uptake of butoxyethanol in the study of Johanson and Boman8was overestimated due to the method of calculating uptake. The contribution of 21% would be more consistent with the assumption that permeability. of homologous glycol ethers decreases with the number of C atoms in the chain, as found in the present study and in the study of Dugard and Walker.' Applying another mathematical model from the literature,'8 based on the octanollwater partition coefficient, molecular weight and vapour pressures, we estimated contribution of whole body dermal uptake to be 32%, 40%, and 61% of the total uptake for ME, EE, and BE, respectively. Although these values are of the same order of magnitude as our results, i the permeability coefficient calculated with this model seems to increase with the number excretion of ethoxyacetic acid after experimental human exposure to ethylene glycol monoethyl ether. Br 3 Ind Med 1986;43:615-9. of C atoms and thus contrasts with our results and the in vitro study reported by Dugard and 4 Groesenken D,Veulemans H, Masschelein R, Van Vlem E. Experimental human exposure to ethylene glycol monomerhyl ether. Int Arch Occup Em'ron Health 1989; Walker. h summary, results of the present study 613243-7. 5 De Nanimale MAC-itjst.Den Haag: Arbeidsiipectie, 1994. 6 American Conference of Governmental Industrial show that dermal absorption associated with Hygienists. Threshold iimir values for chemical substnncpr exposure to ME and EE vapour and liquid is of major importance. In the mixed inhalatory and physical agents and biological exposure indues. Cincinnati,OH: ACGIH, 1992. 7 Dugard PH, Walker M. Absorption of some glycol ethers and dermal exposure when the whole body surface is exposed to vapour, dermal uptake would contribute 55% of the total uptake for ME and 42% for EE. Skin contact of both through human skin in vitro. Enwiron Health Perspect 1984;57:193-7. 8 Johanson G, Boman A. Percutaneous absorption of 2- butoxyethanol vapour in human subjects. Br 3 I d Med 1991;48:788-92. 9 Johanson G, Boman A, Dynesius B. Percutaneous absorp- hands and forearms for 15 minutes with liquid tion of 2-buthoxvethanol in man. S a n d 7 Work E n v i m Health 1988,14 1'01-9 ME and EE wodd considerably exceed the 10 Groesenken D, Veulemans H, Masschelem R, Van Vlem E eight hour inhalatory uptake at the OEL. In monitoring exposure at the workplace, sub- An muroved method for the deterrmnaaon m m e of alkoxyketic acids. Inr Arch Ocnrp Envim Health 1989; 61:249-54. stantial skin uptake of ME and EE indicates 1 1 Hursh JB, Clarkson TW, Miles EF, Goldsmith LA. Percutaneous absorption of mercury vapour by men. that biological monitoring is to be preferred Arch Environ Healzh 1989;44:122-7. over environmental monitoring. 12 Corely R4,Bormen GA. Physiological based pharmacokinetics of 2-butoxyethanol and irs major metabolite, 2- Also, the experimental set up used in the butoxyacetic acid, in rats and humans. T o d Appl present study proved to be suitable for mea- Phannacol1994;129:61-79. 13 Monster AC, Boersma G, Duba WC. Kinetics of tri- surement of dermal absorption of chemical chloroethylene in repeated exposure of volunteers. Im vapours and liquids in humans, providing the Arch Oecup Environ Health 1979;42:28392. 14 Johanson G. Dynesius B. Liquid/air partition coefficients of necessary data for the assessment of the health six commonly used glycol ethers. Br f I d Med 1988;45: risks of exposure to these solvents. 5614. 15 European Centre for Ecotoxicology and Toxicology of Chemicals. Pnrutaneour absotptia. Brussels: ECETOC, 1993. 1 National Institute for Occupational Safety and Health. 16 International Commission on Radiological Protection. ompatiaal exponrn w e f h y h &cd wtmwmdyi ether, gcycd monoethyl ether, and their acefofer. Repa of he ratk gmup a referme man.Ncw York ICRP, 1975. i Cincmnan, OH: NIOSH, 1991. 17 Scheuplein RJ, Blank I. Permeability of the skin. 2 Groesenken D, Veulemans H, Masschelein R Respiratory Physiologi2al RNiwr 1971;51:702-47. uptak and elimination of ethylene glycol monoethyl 18 Wilschut A, ten Berge WF, Robinson PJ, McKone TE. ether after experimental human exposure. Br 3I d Med Estimating skin permeation. The validation of fivc mathe- 1986;43:544-9. matical skin permeation models. Chemosphere 1995;30: 3 Groesenken D, Veulemans H, Masschelein R Urinary 1275-96.