4-methylpentan-2-one

Endpoint summary

Description of key information

Experimental studies of acute inhalation exposures to MIBK in human volunteers indicated transient sensory irritation, neurological effects, and/or strong odor sensation during exposure. No decrements in task performance were observed in three studies.

Additional information

Occupational exposure

Workers near a centrifuge were exposed up to 500 ppm of MIBK for 20-30 min/d (Linari et al., 1964; Armeli et al., 1968). Elsewhere in the room the level was 80 ppm. Over half of the 19 workers complained of weakness, loss of appetite, headache, burning in the eyes, stomach ache, nausea, vomiting and sore throat. Insomnia, somnolence, heartburn, intestinal pain and some unsteadiness were experienced by a few of the workers. Four had slightly enlarged livers and six had complaints indicative of a nonspecific form of colitis. Clinical chemistry tests on all the workers were normal. The wearing of respiratory for the centrifuging process reduced MIBK exposure considerably. Five years later it was found that work practices had greatly improved and that the MIBK concentration near the centrifuge was 100-105 ppm and elsewhere in the room was 50 ppm. Workers were required to wear respiratory protection but a few still complained of gastrointestinal and central nervous system effects. Slight liver enlargement had persisted in two workers, but earlier symptoms had disappeared.

Studies with human volunteers

Basic toxicokinetics

Eight adult male volunteers were exposed in an exposure chamber on three separate occasions for 2 hours under conditions of light exercise to atmospheres of 10, 100, or 200 mg/m3 MIBK (2.4, 24, or 49 ppm), followed by 2-hour observation periods.No sham exposures were used as negative controls (Hjelm et al., 1990). The duration of the rest period between exposure occasions was not reported. MIBK vapor is absorbed relatively well. Regardless of the exposure concentration, about 60% of the inhaled MIBK was retained by the body. The respiratory retention rate was fairly constant during the 2-h exposure.The blood concentration of MIBK rose quite rapidly, and no plateau was reached during the 2-h exposure. About 0.04% of the MIBK dose was excreted in the urine as MIBK within 3 h after a 2-h inhalation. The urinary concentrations of MIBK's metabolites, 4-methyl-2-pentanol and 4-hydroxy-4-methyl-2-pentanone, were below the detection limit of 5 nmol/L at 0.5 or 3 h post-exposure. The total body clearance of MIBK was 1.6 L of blood per hour per kilogram of body weight in these men.

Respiratory tract irritation

There were five studies of MIBK's irritation properties in human volunteers, but none of them were conducted without sham-exposed controls.

Alarie and Polise (1965) exposed, groups of six adult volunteers via full face mask to 0.402, 0.915, 1.393, 1.68, 2.301, or 2.827 mg/L (402, 915, 1393, 1680, 2301, or 2827 mg/m3) of MIBK during a 7-minute exposure period, followed 2 weeks later by a second 7-minute exposure to 0.845, 1.493, or 2.066 mg/L (845, 1493, or 2066 mg/m3). Volunteers indicated the presence and disappearance of eye, nose, and throat irritation throughout the exposures, which provided a continuous subjective assessment of irritation relative to known exposure levels. The incidence of volunteers reporting nose, eye, and throat irritation generally increased with exposure level; the thresholds for odor and irritation were reported to be 402 and 1393 mg/m3, respectively, estimated from graphs of the number of individual reports of irritation at various exposure

Dick et al. (1992) reported a properly controlled human study in which 17 volunteers exposed to MIBK at 88 ppm for 4 h did not find the exposure objectionable. There were no significant differences in the incidence of throat irritation, lacrimation, nausea, or headache between the two groups. Dick et al. (1992) concluded that their data support the contention that the short-term exposure limit of 75 ppm proposed by the Occupational Safety and Health Administration would prevent irritation.

Silverman et al. (1946) exposed 12 human subjects to various concentrations of MIBK for 15 min while diverting their thoughts from the exposure by showing them a movie; however, no sham exposure was done. MIBK exposures at concentrations higher than 200 ppm produced nose or throat irritation in the majority of the subjects. An exposure at 200 ppm resulted in eye irritation and an objectionable odor in the majority of the subjects. Most of the subjects estimated that an exposure at 100 ppm would be tolerable for 8 h.

Iregren et al.(1993) exposed six men and six women to MIBK at 10 or 200 mg/m3 (2.4 or 49 ppm) for 2 h (with light exercise at 50 W in the first 1.5 h and resting in bed in the remaining 0.5 h). Unfortunately, no air-exposed controls were used. Irritation was determined by asking the subjects to give a rating in a questionnaire one time before exposure and six times during the exposure. The irritation ratings during the 49-ppm exposure were consistently higher than those in the 2.4-ppm exposure (higher by at least one arbitrary unit). However, the irritation ratings at 49 ppm were not statistically different from those at 2.4 ppm. That is because "the irritation level is fairly high already at exposure to 10 mg/m3 of MIBK" (in the first four questionnaires administered during the exposure at 10 mg/m3 (2.4 ppm), the irritation ratings were higher than the pre-exposure ratings by 1.5 to 2.5 arbitrary units). The authors stated that that "finding may be interpreted as an indication of a high potential for MIBK to induce irritation already at low concentrations. " However, they did not reveal the severity of the irritation represented by one arbitrary unit. In addition, the absence of a sham-exposed control group makes the interpretation of the data difficult.

Another human study with no control exposure was conducted by Hjelm et al. (1990), who reported that nose and throat irritation were the most common symptoms. Three of eight men exposed to MIBK at 100 or 200 mg/m3 (24 or 49 ppm) for 2 h during light exercise experienced nose and throat irritation, and one of eight experienced the irritation at 10 mg/m3 (2.4 ppm). Based on the ordinal data, no clear concentration-response relationship was seen. The subjects rated the irritation from 0 to 5 and gave an average rating of about 0.2, 0.4, or 0.3 at 20-50 min into the 2-h exposure to MIBK at 2.4, 24, or 49 ppm, respectively.Hjelm et al.(1990) did not reveal the qualitative equivalents of the numerical scores (e. g., whether a score of 1 represented mild irritation), so the severity of the irritation reported during MIBK exposure in the responsive men is unknown. More important, no sham-exposed control group was used. The same test subjects were exposed to MIBK at three concentrations on different days after having been informed of the maximum exposure concentration. Even though they did not know of the sequence of the exposure, the fact that they were aware that each 2-h exposure involved MIBK could create a bias in their reporting symptoms.

Neurobehavioral effects

Three studies of the effects of MIBK on the CNS in humans were found (Hjelm et al 1990; Dick et al. 1992; Iregren et al. 1993). The overall conclusion from these three studies is that MIBK has no detrimental CNS effects for acute exposures at concentrations up to 88 ppm.

A properly controlled study was conducted by Dick et al. (1992), who reported that during a 4-h exposure of 10 men and 7 women to MIBK at 88 ppm, there were no significant changes in the choice reaction time, simple reaction time, ability to simultaneously perform an auditory tone discrimination task together with a compensatory visual tracking task, memory scanning, postural steadiness, and mood states after 45 min or 2.75 h of exposure. The exposure also did not change the average score in visual vigilance. However, the performance of female volunteers in the visual vigilance test was positively correlated with the MIBK concentrations in blood (Dick et al. 1992). That means women with higher MIBK concentrations in blood performed better than women with lower MIBK concentrations, so it was not an adverse effect.

Iregren et al. (1993) exposed six men and six women to MIBK at 10 or 200 mg/m3 (2.4 or 49 ppm) for 2 h (with light exercise at 50 W in the first 1.5 h and resting in bed in the remaining 0.5 h), but no air-exposed controls were used. During the exposure at 49 ppm, significantly more complaints of fatigue and other unnamed CNS symptoms were recorded than during the exposure at 2.4 ppm. However, there were no differences in simple reaction time and the ability to add between the 49- and the 2.4-ppm groups.

In a study without a sham-exposed control group, Hjelm et al. (1990) reported that a 2-h exposure at 10, 100, or 200 mg/m3 (2.4, 24, or 49 ppm) had no effects on mood, reaction time, and ability to do addition in eight men. However, an exposure at 24 or 49 ppm resulted in headache and vertigo in two of the eight subjects, and 2.4 ppm caused vertigo but no headache in one subject. Because the test subjects knew that they would be exposed to MIBK, these isolated cases of headache and vertigo could be a result of their subjective bias toward chemical exposures.