Percutaneous uptake rate of 2-butoxyethanol in the guinea pig

The percutaneous absorption rate and elimination kinetics of 2-butoxyethanol (ethylene glycol monobutyl ether) were estimated in the guinea pig. An intravenous bolus dose of 42 or 92 mumol/kg of body weight was administered into the jugular vein of 10 pentobarbital-anesthetized animals. Epicutaneous administration of 2-butoxyethanol followed 2.5 h later in one or two sealed glass rings on the clipped back of the animal. Arterial blood samples were obtained and then analyzed for 2-butoxyethanol by gas chromatography. Following the intravenous dose, the apparent total clearance and mean residence time of 2-butoxyethanol were calculated to be 128 ml X min-1 X kg-1 (SD 30%) and 4.7 min (SD 30%), respectively. During the latter part of the 2-h skin exposure, the concentration of 2-butoxyethanol in the blood appeared to level off at an average concentration of 21 mumol/l (SD 45%). The absorption rate through the skin was estimated to be 0.25 (range 0.05-0.46) mumol X min-1 X cm-2 (SD 49%). The skin uptake rate in the guinea pig was extrapolated to man for a comparison of the percutaneous absorption of liquid solvent with respiratory uptake of solvent vapor. The extrapolation indicated a risk of acute adverse effects when large areas of the skin are exposed to 2-butoxyethanol.     

Percutaneous absorption of 2-butoxyethanol in man

The percutaneous absorption of the commonly used glycol ether 2-butoxyethanol (ethylene glycol monobutyl ether) was investigated in 12 exposure experiments with five men. The subject kept two or four fingers immersed in neat butoxyethanol for 2 h. Arterialized capillary blood samples were collected from the other hand before, during, and up to 4 h after the exposure and analyzed for butoxyethanol by gas chromatography. Urine was collected for 24 h and analyzed for the metabolite butoxyacetic acid, also by gas chromatography. The presence of butoxyethanol in blood and of butoxyacetic acid in urine confirmed that butoxyethanol enters the systemic circulation in man in vivo during dermal exposure. Percutaneous uptake rates were calculated from measured blood levels of butoxyethanol with the use of kinetic parameters (clearance and volume of distribution) obtained in earlier experiments with the same subjects. The uptake rates ranged from 7 to 96 nmol.min-1.cm-2. The results indicate that persons exposing large portions of their skin to butoxyethanol are at risk of absorbing acutely toxic doses.     

Toxicokinetics of toluene and urinary excretion of hippuric acid after human exposure to 2H8-toluene.

Nine male volunteers were exposed to 2H8-toluene (200 mg/m3 for two hours during a workload of 50 W) via inspiratory air with the aid of a breathing valve and mouthpiece. Labelled toluene was used to differentiate between hippuric acid originating from exposure to toluene and hippuric acid normally excreted in urine. The total uptake of toluene was 2.2 (standard deviation (SD) 0.2) mmol, or 50% of the amount inhaled. Four hours after the end of exposure 1.4 (SD 0.3) mmol or 65% of the total uptake had been excreted in urine as 2H-hippuric acid and 20 hours after the end of exposure the cumulative excretion of 2H-hippuric acid was 1.8 (SD 0.3) mmol, or 78% of the total uptake. By contrast the cumulative excretion of labelled plus unlabelled hippuric acid exceeded the total uptake of toluene already after four hours. The excretion rate of 2H-hippuric acid was highest, about 5 mumol/min, during exposure and the SD between the subjects was low. The background concentrations of unlabelled hippuric acid in urine were high, however, and there were large differences between subjects. These findings confirm earlier indications that for low exposure, urinary hippuric acid concentration cannot be used for biological monitoring of exposure to toluene.     

Kinetics of tetrachloroethylene in volunteers; influence of exposure concentration and work load

Summary Six male volunteers were exposed for 4 h to 72 ppm tetrachloroethylene (PERC) at rest, to 144 ppm PERC at rest, and to 142 ppm PERC at rest combined with work load (2 times 30 min, 100 W). Minute volume and concentrations in exhaled air were measured to estimate the uptake. Concentrations of PERC and trichloroacetic acid (TCA) were determined in blood. Exhaled air was analysed for PERC; urine for TCA.The uptake/min decreased in the course of the exposure to 60 % of the initial uptake. The total uptake was influenced more by (lean) body mass than by respiratory minute volume or adipose tissue. During work load the uptake and minute volume increased to 3 fold the value at rest. In the post exposure period the quotient of the bloodconcentrations and exhaled air concentrations of PERC remained nearly constant at 23. Following exposure about 80–100 % of the uptake was excreted unchanged by the lungs, whereas till 70 h after exposure the amount of TCA excreted in urine represented about 1 % of the uptake.     

Gaschromatographic determination of butoxyacetic acid after hydrolysis of conjugated metabolites in urine from workers exposed to 2-butoxyethanol

For the gaschromatographic determination of total butoxyacetic acid (BAA), i.e., free plus conjugated BAA in urine, we studied the acid hydrolysis condition to cleave the conjugate. The optimum condition for hydrolysis was chosen to be 60 min boiling of the mixture of 1 ml twofold diluted urine and 1.2 ml hydrochloric acid. For the biological monitoring of workers exposed to 2-butoxyethanol (BE), we applied our acid hydrolysis method to the urine from 6 workers exposed to the solvent for 7 days and determined total BAA as well as free BAA and conjugated BAA, which was calculated as the difference between the concentrations of free and conjugated BAA. The percentages of conjugated BAA vs. total BAA varied from 44.4% to 92.2% (mean value 71.1 %) among 6 individual workers over 7 days and decreased gradually over the consecutive work days. In the latter half of the work week, free BAA comparatively accounted for the larger portion of urinary BAA. Significant correlations were found between urinary BAA concentrations and BE levels in the breathing-zone air (TWA). The correlation coefficients of urinary concentrations of total or conjugated BAA vs. BE levels was higher than that of free BAA concentrations vs. BE levels. Hence, the determination of total BAA in urine is a suitable test for the biological monitoring of BE exposure, because of the simplicity in procedures and the good agreement with BE exposure levels.     

Propylene glycol monomethyl ether occupational exposure. 3. Exposure of human volunteers

OBJECTIVE: Propylene glycol monomethyl ether (PGME) is a widely used additive in industrial and consumer products (paints, inks, diluents, cleaning products, cosmetics.). The aim of the present study was to determine uptake and disposition of PGME alpha-isomer in humans. METHOD: Six healthy male volunteers were exposed to PGME-alpha vapour (15, 50 and 95 ppm) with and without respiratory protection for 6 h including a 30-min break. Free PGME and total PGME (free and conjugated) were analysed in urine. The analytical method involved hydrolysis with HCl (only for the analysis of total PGME in urine), a solid phase extraction on LC-18 columns and a gas chromatograph-flame ionisation detector (GC/FID) analysis after derivatisation with trimethylsilylimidazole. RESULTS: End-exposure levels of free PGME in urine were found to reach 1.3 (+/-0.3), 4.4 (+/-1.6) and 7.9 (+/-2.5) mg/l for 15, 50 and 95-ppm exposure, respectively, without respiratory protection. End-exposure levels of total PGME in urine were found to reach 2.5 (+/-0.8), 6.2 (+/-1.6) and 10.3 (+/-2.3) mg/l for 15, 50 and 95-ppm exposure respectively. Levels of free PGME were also monitored in exhaled air (0.4 (+/-0.1), 1.4 (+/-0.4) and 2.9 (+/-0.9) ppm at the end of 15, 50 and 95-ppm exposure, respectively) and in blood (2.0 (+/-0.9), 4.9 (+/-2.3) and 11.8 (+/-2.4) mg/l at the end of 15, 50 and 95-ppm exposure, respectively). PGME is rapidly excreted in urine and in exhaled air; the half-lives were calculated to be approximately 3.5 h in urine and 10 min in exhaled air. PGME was below detection limits in breath (<0.1 ppm), in blood (<1 mg/l) and in urine (<1 mg/l) after dermal-only exposure to vapour. CONCLUSIONS: This study has demonstrated the relatively high pulmonary uptake compared with the dermal uptake. It has also shown the rapid excretion in urine (3.5 h) and in expired air (10 min). With regard to metabolism, this study has established the presence of conjugated PGME in urine.     

Kinetics of 1,1,1-trichloroethane in volunteers; Influence of exposure concentration and work load

Summary Six male volunteers were exposed for 4 h to 70 ppm 1,1,1-trichloroethane (methylchloroform, MC) at rest, to 145 ppm. MC at rest, and to 142 ppm MC at rest combined with work load (2 times 30 min, 100 W). Minute volume and concentration in exhaled air were measured to estimate the uptake. MC and its metabolites trichloroethanol (TCE) and trichloroacetic acid (TCA) were determined as far as present in blood, exhaled air and urine. The uptake/min decreased in the course of exposure to 30 % of the initial uptake. The total uptake was more influenced by minute volume than by body weight or amount of adipose tissue. During work load the uptake increased to 2.3 fold and the minute volume to 3 fold the value at rest. In the post exposure period the quotients of the concentrations in blood and in exhaled air for MC and TCE remained nearly constant at 8.2 and 14,000, respectively. Following exposure about 60–80% of the amount taken up was excreted unchanged by the lungs, while until 70 h after exposure the amount of TCE and TCA excreted in urine represented about 2% and 0.5% of the uptake.     

Uptake, distribution, metabolism, and elimination of styrene in man. A comparison between single exposure and co-exposure with acetone

Six male subjects were exposed for two hours during light physical exercise to 2.81 mmol/m3 (293 mg/m3) of styrene on one occasion and to a mixture of 2.89 mmol/m3 (301 mg/m3) of styrene and 21.3 mmol/m3 (1240 mg/m3) of acetone on another (combination study). About 68% of the dose (somewhat more than 4 mmol) of styrene was taken up. The arterial blood concentration of styrene reached a relatively stable level after about 75 minutes of exposure of about 18 and 20 mumol/l after the single and combined exposure, respectively. Calculated values of mean blood clearance were 1.9 l/min in the styrene study and 1.6 l/min in the combination study; the half life of styrene in blood was about 40 minutes in both studies. The concentration of non-conjugated styrene glycol increased linearly during exposure and reached about 3 mumol/l at the end of exposure and was eliminated with a half life of about 70 minutes. Styrene-7,8-oxide was detected and quantified in the blood in a complementary study. The half lives for the excretion of mandelic and phenylglyoxylic acid in the urine were about four and nine hours, respectively, in both studies.     

Percutaneous absorption of 2-butoxyethanol vapour in human subjects.

Four male volunteers were exposed at rest for two periods of two hours, separated by a one hour exposure free interval, to 50 ppm 2-butoxyethanol (BE) vapour generated in an exposure chamber. During the first two hour period the men were exposed by mouth only via a respiratory valve connected by tubes to the exposure chamber. During the second exposure period the men were exposed by skin only while sitting inside the exposure chamber, naked except for shorts, and wearing a respiratory protection mask supplied with compressed air. Capillary blood samples were collected at regular intervals and analysed for BE by a gas chromatographic method. Two experiments separated by at least two weeks were carried out with each volunteer, one at "normal" (23 degrees C, 29% relative humidity) and one at raised (33 degrees C, 71% relative humidity) air temperature and humidity in the chamber. The average concentration in blood and the calculated rate of uptake of BE were about three to four times higher during dermal exposure than during inhalation exposure. These experiments suggest that dermal uptake of BE accounts for about 75% (45-85% in individual experiments) of the total uptake during whole body exposure to BE vapour. Thus it appears that the use of a respiratory protection mask will not protect efficiently against exposure to BE vapours. A tendency towards increased percutaneous absorption rate was seen in the raised temperature and humidity condition.     

Percutaneous absorption of 2-butoxyethanol vapour in human subjects

Four male volunteers were exposed at rest for two periods of two hours, separated by a one hour exposure free interval, to 50 ppm 2-butoxyethanol (BE) vapour generated in an exposure chamber. During the first two hour period the men were exposed by mouth only via a respiratory valve connected by tubes to the exposure chamber. During the second exposure period the men were exposed by skin only while sitting inside the exposure chamber, naked except for shorts, and wearing a respiratory protection mask supplied with compressed air. Capillary blood samples were collected at regular intervals and analysed for BE by a gas chromatographic method. Two experiments separated by at least two weeks were carried out with each volunteer, one at "normal" (23 degrees C, 29% relative humidity) and one at raised (33 degrees C, 71% relative humidity) air temperature and humidity in the chamber. The average concentration in blood and the calculated rate of uptake of BE were about three to four times higher during dermal exposure than during inhalation exposure. These experiments suggest that dermal uptake of BE accounts for about 75% (45-85% in individual experiments) of the total uptake during whole body exposure to BE vapour. Thus it appears that the use of a respiratory protection mask will not protect efficiently against exposure to BE vapours. A tendency towards increased percutaneous absorption rate was seen in the raised temperature and humidity condition.     

Uptake, distribution, metabolism, and elimination of styrene in man. A comparison between single exposure and co-exposure with acetone.

Six male subjects were exposed for two hours during light physical exercise to 2.81 mmol/m3 (293 mg/m3) of styrene on one occasion and to a mixture of 2.89 mmol/m3 (301 mg/m3) of styrene and 21.3 mmol/m3 (1240 mg/m3) of acetone on another (combination study). About 68% of the dose (somewhat more than 4 mmol) of styrene was taken up. The arterial blood concentration of styrene reached a relatively stable level after about 75 minutes of exposure of about 18 and 20 mumol/l after the single and combined exposure, respectively. Calculated values of mean blood clearance were 1.9 l/min in the styrene study and 1.6 l/min in the combination study; the half life of styrene in blood was about 40 minutes in both studies. The concentration of non-conjugated styrene glycol increased linearly during exposure and reached about 3 mumol/l at the end of exposure and was eliminated with a half life of about 70 minutes. Styrene-7,8-oxide was detected and quantified in the blood in a complementary study. The half lives for the excretion of mandelic and phenylglyoxylic acid in the urine were about four and nine hours, respectively, in both studies.     

Percutaneous absorption of neat and aqueous solutions of 2-butoxyethanol in volunteers

Objectives To study the influence of the presence of water on the dermal absorption of 2-butoxyethanol (BE) in volunteers.Methods Six male volunteers were dermally exposed to 50%, 90% or neat w/w BE for 4 h on the volar forearm over an area of 40 cm². An inhalation exposure with a known input rate and duration served as a reference dosage. The dermal absorption parameters were calculated from 24-h excretion of total (free + conjugated) butoxyacetic acid (BAA) in urine and BE in blood, measured after both inhalation and dermal exposure. Results The dermal absorption of BE from aqueous solutions was markedly higher than that of neat BE. The time-weighted average dermal fluxes were calculated from the urine and blood data and expressed in milligrammes per square centimetre per hour. The dermal fluxes obtained from cumulative 24-h excretion of BAA amounted to 1.34±0.49, 0.92±0.60 and 0.26±0.17 mg cm^–2 h^–1 for 50%, 90% and neat BE, respectively. The dermal fluxes calculated from the BE blood data amounted to 0.92±0.34 and 0.74±0.25 mg cm^–2 h^–1 for 50% and 90% BE, respectively. The permeation rates into the blood reached a plateau between 60 and 120 min after the start of exposure, indicating achievement of steady-state permeation. The apparent permeability coefficient K_p, was 1.75±0.53×10^–3 and 0.88±0.42×10^–3 cm h^–1 for 50% and 90% BE, respectively. Conclusion The percutaneous absorption of BE from aqueous solution increased markedly when compared with neat BE. Even water content as low as 10% led to an approximate fourfold increase in the permeation rates. These findings are important for the health risk assessment of occupational exposure to BE, since BE is commonly used in mixtures that contain water. Exposure to aqueous solutions of 50% and 90% of BE may result in substantial skin absorption: if a 60-min skin contact of 1,000 cm² is assumed, dermal uptake would be four-times higher than the pulmonary uptake of an 8-h occupational exposure at a TLV of 100 mg m^–3. This clearly justifies the skin notation for BE. For the purpose of biological monitoring, both BE in blood and BAA in urine were shown to be reliable indicators of exposure.     

Exposure to acetone. Uptake and elimination in man

Eight male subjects were exposed to acetone vapor on two occasions for 2 h in the laboratory. On the first occasion they were exposed to about 1,300 mg/m3 during rest and on the second occasion to about 700 mg/m3 during rest (30 min) and exercise at different work loads on a bicycle ergometer (90 min). The total uptake of acetone was 0.6--1.2 g, and the relative uptake was about 45%. The concentration of acetone in alveolar air was 30--40% of that in the inspiratory air, and it was not affected by exposure time or work load. The concentration of acetone in blood increased continuously with increased uptake during exposure, and there was no tendency towards equilibrium. The half-time of acetone in alveolar air as about 4 h, and in venous and arterial blood it was about 6 and 4 h, respectively. The highest concentrations of acetone in urine were measured 3--3.5 h after exposure. The elimination of acetone via the lungs corresponded to about 20% of the total uptake. Only about 1% of the uptake was excreted via urine.     

Kinetics of styrene in workers from a plastics industry after controlled exposure: a comparison with subjects not previously exposed.

Eight male workers from a glass reinforced plastics industry were experimentally exposed for 2 hours to 2.84 mmol/m3 (296 mg/m3) styrene during light physical exercise (50 W). About 63% of the amount supplied (4.6 mmol styrene) was taken up in the body. The arterial blood concentration of styrene reached a relatively stable level of 15 mumol/l at the end of exposure which was about 70% of the blood concentration in a group of volunteers with no previous exposure to solvents. The apparent blood clearance was significantly higher in the occupationally exposed subjects 2.01/h X kg compared with 1.51/h X kg. Contrary to the relatively stable level of styrene at the end of exposure the concentration of non-conjugated styrene glycol increased throughout the exposure and reached about 3 mumol/l in both groups. Like styrene, the non-conjugated styrene glycol seemed to be eliminated faster from the occupationally exposed workers. The blood concentration of styrene-7,8-oxide was low and seldom exceeded the detection limit of 0.02 mumol/l. The results show that long term exposure in a glass reinforced plastics industry may facilitate the metabolism of styrene.     

Biological monitoring of occupational exposure to tetrahydrofuran

Occupational exposure to tetrahydrofuran (THF) was studied by analysis of environmental air, blood, alveolar air, and urine from 58 workers in a video tape manufacturing plant. Head space gas chromatography (GC) with an FID detector was used for determination of THF concentration in alveolar air, urine, and blood. Environmental exposure to THF was measured by personal sampling with a carbon felt passive dosimeter. When the end of shift urinary THF concentrations were compared with environmental time weighted average (TWA) values, urinary THF concentration corrected for specific gravity correlated well with THF concentration in air (r = 0.88), and uncorrected urinary THF concentration gave a similar result (r = 0.86). Correction for creatinine in urine weakened the correlation (r = 0.56). For exposure at the TWA concentration of 200 ppm the extrapolated concentration of THF was 33 mumol/l in blood and 111.9 mumol/l (61 mumol/g creatinine) or 109 mumol/l at a specific gravity of 1.018 in urine. The correlation between exposure to THF and its concentration in exhaled breath and blood was low (r = 0.61 and 0.68 respectively). Laboratory methodological considerations together with the good correlation between urinary THF concentration and the environmental concentration suggest that THF concentration in urine is a useful biological indicator of occupational exposure to THF.     

Biological monitoring of occupational exposure to tetrahydrofuran.

Occupational exposure to tetrahydrofuran (THF) was studied by analysis of environmental air, blood, alveolar air, and urine from 58 workers in a video tape manufacturing plant. Head space gas chromatography (GC) with an FID detector was used for determination of THF concentration in alveolar air, urine, and blood. Environmental exposure to THF was measured by personal sampling with a carbon felt passive dosimeter. When the end of shift urinary THF concentrations were compared with environmental time weighted average (TWA) values, urinary THF concentration corrected for specific gravity correlated well with THF concentration in air (r = 0.88), and uncorrected urinary THF concentration gave a similar result (r = 0.86). Correction for creatinine in urine weakened the correlation (r = 0.56). For exposure at the TWA concentration of 200 ppm the extrapolated concentration of THF was 33 mumol/l in blood and 111.9 mumol/l (61 mumol/g creatinine) or 109 mumol/l at a specific gravity of 1.018 in urine. The correlation between exposure to THF and its concentration in exhaled breath and blood was low (r = 0.61 and 0.68 respectively). Laboratory methodological considerations together with the good correlation between urinary THF concentration and the environmental concentration suggest that THF concentration in urine is a useful biological indicator of occupational exposure to THF.     

Jejunal uptake of thiamin hydrochloride in man: influence of alcoholism and alcohol

The jejunal uptake of 35S-thiamin hydrochloride was examined using an intestinal perfusion technique in six young students (group 1), 12 recently drinking alcoholic men (group 3) and in 6 non-drinking men age-matched with the alcoholic men (group 2). The acute effect of alcohol on thiamin uptake was also examined in the alcoholic subjects. At a perfusate thiamin concentration of 0.5 mumol/l, median thiamin uptake was 34.4, 10.4, and 6.8 ng/cm/min in groups 1, 2, and 3 respectively, while for 8.0 mumol thiamin/l, median uptake was 277.2, 102.3, and 98.0 ng/cm/min for these groups respectively. Alcohol, 50 g/l, added to the perfusate gave a 28.9% decrease in uptake of 0.5 microM thiamin, which was not statistically significant. These findings suggest that neither alcoholism nor acute exposure to alcohol limits jejunal uptake of thiamin hydrochloride. Differences noted between young and old controls need further study.     

Effect of carnitine supplemented TPN on turnover and muscle utilisation of free fatty acids in patients with persistent post-operative infection

The effect of L-carnitine on FFA turnover and regional utilisation over the leg was investigated using infusion of (14)C-oleic acid and measurement of the respiratory quotient (RQ) in eight artificially ventilated patients with severe post-operative infection and at least 2 weeks of carnitine free TPN. Carnitine or placebo was added to the daily infusion of lipid during two consecutive 4-day periods in a randomised cross-over fashion. The total dose of carnitine was 110 mg/kg over 4 days. Before carnitine supplementation, total plasma carnitine levels ranged between 39 and 152 mumol/l. The RQ was 0.87 +/- 0.02 (SEM). The turnover (185 +/- 64 mumol/min) and fractional turnover (0.39 +/- 0.04/min) of oleic acid as well as the uptake (31 +/- 10 mumol/min) and fractional uptake (0.46 +/- 0.05) over the leg were similar to previously reported values in healthy subjects. Carnitine supplementation, despite a doubling of the average plasma carnitine level, did not influence the RQ or the whole body turnover and regional exchange of oleic acid. The present results suggest that four days of carnitine supplementation in patients with persistent post-operative infection has no measurable effect on FFA utilisation, indicating that the patients' carnitine reserves were sufficient to maintain normal FFA utilisation.     

Exposure to methyl isobutyl ketone: toxicokinetics and occurrence of irritative and CNS symptoms in man

Summary The toxicokinetics as well as irritative effects and CNS symptoms of methyl isobutyl ketone (MIBK) were studied in human volunteers during inhalation exposure. The volunteers were exposed (2 h, 50 W) in an exposure chamber on four different occasions to about 10,100 and 200 mg/m³ MIBK and to a combination of about 100 mg/m³ MIBK and 150 mg/m³ toluene. The relative pulmonary uptake of MIBK was about 60% and the total uptake increased linearly with increasing exposure concentration. The concentration of MIBK in blood rose rapidly after the onset of exposure and no plateau level was reached during exposure. No tendency for saturation kinetics could be observed within the dose interval and the apparent blood clearance was 1.6 l/h/kg at all exposure levels. The concentration of unchanged MIBK in the urine after exposure was proportional with the total uptake. Only 0.04% of the total MIBK dose was eliminated unchanged via the kidneys within 3 h post exposure. The concentrations of the metabolites 4-hydroxy-4-methyl-2-pentanone and 4-methyl-2-pentanol were below the detection limit (5 nmol/l). Irritative and CNS symptoms occurred during exposure. The degree of both irritative and CNS symptoms increased during exposure to 100 and 200 mg/m³ compared with 10 mg/m³, but combination exposure with toluene exhibited the most pronounced effect. There were no significant effects from exposure on the performance of a simple reaction time task or a test of mental arithmetic.     

Exposure to methyl isobutyl ketone: toxicokinetics and occurrence of irritative and CNS symptoms in man

The toxicokinetics as well as irritative effects and CNS symptoms of methyl isobutyl ketone (MIBK) were studied in human volunteers during inhalation exposure. The volunteers were exposed (2h, 50 W) in an exposure chamber on four different occasions to about 10, 100 and 200 mg/m3 MIBK and to a combination of about 100 mg/m3 MIBK and 150 mg/m3 toluene. The relative pulmonary uptake of MIBK was about 60% and the total uptake increased linearly with increasing exposure concentration. The concentration of MIBK in blood rose rapidly after the onset of exposure and no plateau level was reached during exposure. No tendency for saturation kinetics could be observed within the dose interval and the apparent blood clearance was 1.61/h/kg at all exposure levels. The concentration of unchanged MIBK in the urine after exposure was proportional with the total uptake. Only 0.04% of the total MIBK dose was eliminated unchanged via the kidneys within 3 h post exposure. The concentrations of the metabolites 4-hydroxy-4-methyl-2-pentanone and 4-methyl-2-pentanol were below the detection limit (5 nmol/l). Irritative and CNS symptoms occurred during exposure. The degree of both irritative and CNS symptoms increased during exposure to 100 and 200 mg/m3 compared with 10 mg/m3, but combination exposure with toluene exhibited the most pronounced effect. There were no significant effects from exposure on the performance of a simple reaction time task or a test of mental arithmetic.