Simulation of repeated dose kinetics of methyl isobutyl ketone in humans from experimental single-dose inhalation exposure.

Methyl isobutyl ketone (MIBK) is a solvent used in numerous products and processes and may be present in the air of the workplace as a vapor. The American Conference of Governmental Industrial Hygienists (ACGIH) threshold limit value-time-weighted average (TLV-TWA) and TLV-short term exposure limit (TLV-STEL) for MIBK are 50 and 75 ppm, respectively. These workplace air concentration limits were set to protect workers from irritation, neurasthenic symptoms and possible adverse effects to their livers and kidneys. A recent revision of the ACGIH limit value has been proposed, to reduce the current TLV-TWA to 30 ppm. This article predicts the kinetics and accumulation of MIBK in humans exposed repeatedly in various exposure scenarios (8, 12, and 24h/day for 7 days) to the current ACGIH TLV-TWA of 50 ppm. The kinetic parameters of the model were derived from published human time-course blood MIBK data from a single 2h inhalation exposure to 48.9 ppm MIBK. The model correctly simulated single exposure experimental data with a rapid rise in blood concentration to 1.06 microg/ml within 1h and approached >or=99% steady-state blood level in 4h of exposure. MIBK was predicted to be rapidly eliminated from blood after terminating the exposure, reaching 0.53 microg/ml and 0.13 microg/ml within 0.5 and 2h post-exposure, respectively. Within 4h after the termination of exposure, blood concentration would be expected to <1% of the steady-state concentration. On the basis of these results, it is concluded that accumulation of MIBK in workers due to repeated inhalation exposure is not likely to occur at the current TLV-TWA concentration of 50 ppm.

Safety assessment of MIBK (methyl isobutyl ketone).

MIBK (Methyl Isobutyl Ketone) is an aliphatic ketone that functions as both a denaturant and solvent in cosmetic products. Current use in cosmetic products is very limited, but MIBK is reported to be used in one nail correction pen (volume = 3 ml) at a concentration of 21%. The maximum percutaneous absorption rate in guinea pigs is 1.1 micromol/min/cm2 at 10 to 45 min. Metabolites include 4-hydroxy-4-methyl-2-pentanone (oxidation product) and 4-methyl-2-pentanol (4-MPOL) (reduction product). Values for the serum half-life and total clearance time of MIBK in animals were 66 min and 6 h, respectively. In clinical tests, most of the absorbed MIBK had been eliminated from the body 90 min post exposure. MIBK was not toxic via the oral or dermal route of exposure in acute, short-term, or subchronic animal studies, except that nephrotoxicity was observed in rats dosed with 1 g/kg in a short-term study. MIBK was an ocular and skin irritant in animal tests. Ocular irritation was noted in 12 volunteers exposed to 200 ppm MIBK for 15 min in a clinical test. A depression of the vestibulo-oculomotor reflex was seen with intravenous infusion of MIBK (in an emulsion) at 30 microM/kg/min in female rats. The no-observed-effect level in rats exposed orally to MIBK was 50 mg/kg. Both gross and microscopic evidence of lung damage were reported in acute inhalation toxicity studies in animals. Short-term and subchronic inhalation exposures (as low as 100 ppm) produced effects in the kidney and liver that were species and sex dependent. Dermal doses of 300 or 600 mg/kg for 4 months in rats produced reduced mitotic activity in hair follicles, increased thickness of horny and granular cell layers of the epidermis, a decrease in the number of reactive centers in follicles (spleen), an increase in the number of iron-containing pigments in the area of the red pulp (spleen), and a reduction in the lipid content of the cortical layer of the adrenal glands. Neuropathological changes in the most distal portions of the tibial and ulnar nerves were observed in young adult rats which inhaled 1500 ppm MIBK for up to 5 months. No adverse effects were seen in any other neurological end point by any route of exposure in other studies using rats or other animal species. Clinical tests demonstrated a threshold for MIBK-induced irritation of the lungs at 0.03 to 0.1 mg/L after 1 min of respiration. MIBK was not mutagenic in the Ames test or in a mitotic gene-conversion assay in bacteria. Mammalian mutagenicity test results were also negative in the following assays: mouse lymphoma, unscheduled DNA synthesis, micronucleus, cell transformation, and chromosome damage. MIBK did not induce any treatment-related increases in embryotoxicity or fetal malformations in pregnant Fischer 344 rats or CD-1 mice that inhaled MIBK at concentrations of 300, 1000, or 3000 ppm. There was evidence of treatment-related maternal toxicity only at the highest concentration tested. MIBK applied to the tail of rats daily at doses of 300 or 600 mg/kg for 4 months produced changes in the testes, including a reduction in the number of spermatocytes, spermatids, and spermatozoa. An ongoing carcinogenicity study of MIBK being conducted by the National Toxicology Program will be considered when the results are available. On the basis of the information that is currently available, MIBK is considered safe as used in nail polish removers and as an alcohol denaturant in cosmetic products.

Comparative metabolism of methyl isobutyl carbinol and methyl isobutyl ketone in male rats.

Methyl isobutyl carbinol (MIBC) is an oxygenated solvent that is metabolized to methylisobutyl ketone (MIBK) and then to 4-hydroxymethyl-4-methyl-2-pentanone (HMP). Plasma levels of MIBC, MIBK and HMP were determined up to 12 h after a single oral 5 mmol/kg dose of MIBC or MIBK to male rats. The major material in the plasma in both cases was HMP, with similar areas-under-the-curve (AUC) and C(max) at 9 h after dosing. MIBK plasma levels and AUC were also comparable after MIBK or MIBC administration. MIBC AUC was only about 6% of the total material in the blood after MIBC, and insignificant after MIBK administration. No other metabolites were detected in the plasma under the analytical conditions used. The extent of metabolism of MIBC to MIBK, by comparing combined AUCs for MIBK and HMP, was at least 73%. The limited systemic toxicity data for MIBC are consistent with those for MIBK, which has been well studied. The metabolic equivalency of MIBC with MIBK indicates that MIBC will have a low potential for toxicity similar to that of MIBK, and reduces the need for additional animal studies.

Metabolic fate of methyl n-butyl ketone, methyl isobutyl ketone and their metabolites in mice.

The metabolic fate of methyl n-butyl ketone (MnBK) and its isomer methyl isobutyl ketone (MiBK) was studied in mice. The concentrations of both ketones and their metabolites in blood and brain were measured at different time intervals after their administration. The principal metabolites of MnBK were 2-hexanol (2-HOL) and 2,5-hexanedione (2,5-HD), while those of MiBK were 4-methyl-2-pentanol (4-MPOL) and 4-hydroxy-4 methyl-2-pentanone (HMP). The administration of 2-hexanol by itself led to the appearance of both MnBK and 2,5-hexanedione which, when administered by itself, did not lead to the appearance of either MnBK or 2-hexanol. The administration of 4-methyl-2-pentanol resulted in the appearance of MiBK and HMP. The administration of HMP did not result in the appearance of MiBK or 4-MPOL. These results indicate that the metabolic fate of MnBK and MiBK is similar to that reported in other species.

Human experimental MIBK exposure: effects on heart rate, performance, and symptoms.

Heart rate, performance, and symptoms were studied in six female and six male volunteers, aged 19 to 47 years, during experimental 2-hr exposures to 10 and to 200 mg/m3 of methyl isobutyl ketone (MIBK). No effects from exposure on performance of a reaction time task or an arithmetic test could be demonstrated, and no consistent effects on heart rate were found. Subjects reported significantly more symptoms from the central nervous system, e.g., fatigue, due to the exposure. There was also an indication of an increase in ratings of irritation to the airways. A reduction of the threshold limit value (TLV) of 205 mg/m3 for MIBK exposure presently indicated by the American Conference of Governmental Industrial Hygienists, is therefore recommended.

Neurobehavioral effects from acute exposures to methyl isobutyl ketone and methyl ethyl ketone.

Subjects were tested for neurobehavioral performance in an environmental chamber to detect the presence of subclinical central nervous system effects from 4-hr exposures to methyl isobutyl ketone (MIBK) at 100 ppm, methyl ethyl ketone (MEK) at 200 ppm, MIBK at 50 ppm with MEK at 100 ppm, or a placebo (i.e., a 5-min presentation of 25 ppm MEK-MIBK at each exposure period outset). Subjects were 68 males and 75 females recruited from local universities; ages ranged from 18 to 32 years. Ethanol by ingestion (95%-0.84 ml/kg) was used as a positive control. Five psychomotor tests (choice reaction time [CRT], simple reaction time [SRT], visual vigilance, dual task [auditory tone discrimination and tracking], memory scanning), one sensorimotor test (postural sway), and a test of mood (profile of mood states) were used to measure neurobehavioral effects. Additionally, chemical measurements (blood and breath) and reports of sensory and irritant effects were measured. The chemical exposures produced statistically significant performance effects on only 4 of 32 measures (% correct responses-visual vigilance, movement time-CRT, SRT, % incorrect responses-dual task). These effects, however, were not substantial and could not be attributed directly to the chemical exposures. Alcohol ingestion, however, produced significant decrements on every performance test except memory scanning and mood. An interaction occurred between gender and alcohol ingestion, such that more statistically significant performance decrements were found for females than for males. Significant odor sensations and irritant effects were reported by the subjects during the chemical exposures. The MEK results agree with earlier MEK experiments at comparable exposure conditions, and the MIBK results are consistent with a recent Swedish study that used MIBK exposures and showed no significant behavioral performance decrements from single MIBK exposures at 50 ppm with 50 W exercise. Additionally, the MIBK-MEK combination exposure showed no evidence of any interaction effects on either the behavioral or chemical measurements. The principal effects resulting from exposures to MEK and MIBK at the durations and concentrations used in the study are limited to sensory and irritant effects.

Percutaneous uptake and kinetics of methyl isobutyl ketone (MIBK) in the guinea-pig.

Continuous intravenous infusion of 0.478 mumol/min methyl isobutyl ketone (MIBK) was performed for 30 min in pentobarbital-anesthetized guinea-pigs. Epicutaneous exposure for 150 min was carried out 2.5 h later after administration of MIBK to a sealed glass ring on the clipped back of the animals. Arterial blood was analyzed for MIBK by gas chromatography. Blood clearance averaged 201 ml.min-1.kg-1 body wt. A maximum percutaneous uptake of 1.1 mumol.min-1.cm-2 was reached 10-45 min after the onset of exposure and decreased to 0.56 mumol.min-1.cm-2 during the latter part of exposure.

Mechanism of transport and distribution of organic solvents in blood.

Little is known about the mechanism of transport and distribution of volatile organic compounds in blood. Studies were conducted on five typical organic solvents to investigate how these compounds are transported and distributed in blood. Groups of four to five rats were exposed for 2 hr to 500 ppm of n-hexane, toluene, chloroform, methyl isobutyl ketone (MIBK), or diethyl ether vapor; 94, 66, 90, 51, or 49%, respectively, of these solvents in the blood were found in the red blood cells (RBCs). Very similar results were obtained in vitro when aqueous solutions of these solvents were added to rat blood. In vitro studies were also conducted on human blood with these solvents; 66, 43, 65, 49, or 46%, respectively, of the added solvent was taken up by the RBCs. These results indicate that RBCs from humans and rats exhibited substantial differences in affinity for the three more hydrophobic solvents studied. When solutions of these solvents were added to human plasma and RBC samples, large fractions (51-96%) of the solvents were recovered from ammonium sulfate-precipitated plasma proteins and hemoglobin. Smaller fractions were recovered from plasma water and red cell water. Less than 10% of each of the added solvents in RBC samples was found in the red cell membrane ghosts. These results indicate that RBCs play an important role in the uptake and transport of these solvents. Proteins, chiefly hemoglobin, are the major carriers of these compounds in blood. It can be inferred from the results of the present study that volatile lipophilic organic solvents are probably taken up by the hydrophobic sites of blood proteins.

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.