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Toxicological information

Direct observations: clinical cases, poisoning incidents and other

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Administrative data

direct observations: clinical cases, poisoning incidents and other
Type of information:
experimental study
Adequacy of study:
supporting study
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Study well documented, meets generally accepted scientific principles, acceptable for assessment

Data source

Reference Type:
Neurobehavioral effects from acute exposures to methyl isobutyl ketone and methyl ethyl ketone
Dick RB, Krieg EF, Setzer J and Taylor B
Bibliographic source:
Fund Appl Toxicol, 19, 453–473.

Materials and methods

Study type:
study with volunteers
Endpoint addressed:
Principles of method if other than guideline:
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)
GLP compliance:

Test material

Constituent 1
Chemical structure
Reference substance name:
EC Number:
EC Name:
Cas Number:
Molecular formula:
Details on test material:
- Purity: 99.5%


Type of population:
other: volunteers
- Number of subjects exposed: 68 males and 75 females
- Age: from 18 to 32 years
- Race: no data
- Demographic information: recruited from local universities
- Known diseases: Prior to testing, subjects were required to pass a medical examination. Medical disqualification criteria included obesity, pregnancy, hypertension, elevated values on liver function tests, diabetes, abnormal EKG, and substance abuse. Subjects were required to be drug free (i.e., tested for 10 drugs of abuse at the medical exam, and repeated on exposure day if results from the medical exam were positive), to abstain from alcohol for at least 12 hr (i.e., tested on the day of exposure), and to be free of medication (unless approved by the examining physician) for 24 hr prior to the experiment
- Other: Subjects were required to eat a breakfast before the exposure test session and to eat two lunches (i.e., sandwich and noncaffeinated pop or juice) during the test session (onehalf hour before the exposure/alcohol ingestion, and at the end of the 4-hr exposure period)
Ethical approval:
confirmed and informed consent free of coercion received
Route of exposure:
Exposure assessment:
Details on exposure:
Experimental Design:
Subjects were randomly assigned to the treatment groups: control placebo; MIBK-100 ppm, 95% ethanol-0.84 ml/kg; and alcohol-placebo. Random assignment was compromised only as necessary to maintain equal numbers of subjects for each treatment condition by gender or to avoid violating the State of Ohio drinking age regulations (i.e., subjects had to be over 21 years old to consume alcohol). (A one-way ANOVA showed no significant age differences between the six treatment groups; F[5,137] = 0.27, p = 0.93.) The alcohol group was used as a positive control for determining the sensitivity of the neurobehavioral tests. Two additional control groups were used: One (the chemical-control group) served as a control for the chemical exposure groups, and the other (alcohol-control group) served as a control for the alcohol ingestion group. The chemical-control exposure consisted of a 5-min, 25 ppm MEK-MIBK mixture presented at the beginning of each 2-hr exposure period. The alcohol-control group consumed the alcohol drink mixture without ethanol.
The experimental test sessions took place on 3 consecutive days and consisted of a 2-hr practice session the day before the exposure session (Day 1), an 8-hr exposure session on Day 2, and a 2-hr postexposure session on Day 3. On the exposure day (i.e., Day 2), subjects reported to the laboratory at 7:45 AM for preexposure breath testing. The test session commenced with a 2-hr preexposure period (Pre), followed by a 4-hr exposure period (divided into two, 2-hr periods, Exp-l and Exp-2), and a 2-hr postexposure period (Post-1). Subjects returned the next day at 7:45 AM for the last 2-hr test period (Post-2). Neurobehavioral tests, which were sedentary in nature (i.e., required no physical exertion) were administered during each of the 2-hr test periods. The number of subjects run per test session varied between 2 and 4.
Five expired breath samples and five venous blood samples were collected from the subjects in accordance with the following schedule: (1) Preexposure (collected the aflernoon prior to the exposure session for blood, and immediately prior to the exposure session for breath); (2) after 2 hr of exposure (Exp-I); (3) after 4 hr of exposure (Exp-2); (4) 90 min after the exposure ended (Post-1); and, (5) prior to the Post-2 test session. The 4-hr exposure (Exp-1 and Exp-2) was continuous except for a brief period when subjects exited the chamber to provide blood samples.
Experimental sessions were conducted double blind (i.e., only the chamber operator had knowledge of the exposure condition). In accordance with the guidelines of the National Institute for Occupational Safety and Health (NIOSH) Human Subjects Review Board and the ethical principles of the American Psychological Association (American Psychologist, 1990), subjects were duly informed about the nature of the exposure and test conditions and were required to sign a consent form to that effect. Testing was administered inside an environmental chamber (Forma-Scientific) that measured 2.5-m wide x 5.3-m long x 2.2-m high and was configured with four test stations. Each test station was equipped with one monopanel keyboard, one video display terminal (VDT), one custom-made reaction time panel, one cylindrical microswitch, one pressure-type joystick, two box-mounted toggle
switches, one custom-made electrode box, and one set of earphones.
Five psychomotor tests (choice reaction lime [CRT], simple reaction time [SRT], visuel 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.

Results and discussion

Clinical signs:
The principal effects resulting from exposures to MIBK at the durations and concentrations used in the study are limited to sensory and irritant effects.
Results of examinations:
During the 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.

Any other information on results incl. tables

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 thon for males. Significant odor sensations and irritant effects were reported by the subjects during the chemical exposures.

Applicant's summary and conclusion

Executive summary:

In a study conducted by the National Institute for Occupational Safety and Health of the U.S. Department of Health and Human Services, a group of 13 adult male and 12 adult female volunteers was exposed in an environmental chamber to 100 ppm (410 mg/m3) MIBK for two consecutive 2-hour exposure periods. Another group received placebo treatment during the exposure periods. Subjects underwent double-blind evaluations of performance on five psychomotor tests, one sensorimotor test, and a test of mood on the day before exposure, immediately prior to exposure, during each of the two consecutive 2-hour exposure sessions, immediately after exposure, and on the day following exposure. Subjective assessments of irritation and other symptoms were also solicited. No changes attributable to MIBK exposure were detected with respect to any of the performance tests or to the percentage of subjects experiencing various neurological or irritation symptoms, but a significant increase in percentage of subjects detecting a strong odor sensation was reported in the MIBK-treated group. Simple reaction time performance, simple arithmetic test performance, mood rating, and heart rate were not related to exposure level in groups of six male and six female volunteers exposed to MIBK vapors in an exposure chamber at either 10 mg/m3 (considered to be the control exposure level by the authors) or 200 mg/m3 for 2-hour exposure periods at 1-week intervals for an unspecified total number of exposures (Iregren et al., 1993). Volunteers performed light exercise during the first 90 minutes and rested during the final 30 minutes of each exposure. Performance tests were conducted immediately prior to and following exposure, heart rate was monitored throughout exposure, and central nervous system (CNS) and irritation symptoms were assessed using a 17-point questionnaire. Sensory irritation ratings were not significantly different between the two exposure levels. Neurological symptoms were evaluated by questionnaire prior to, during, and following each exposure. An index of the prevalence and intensity of neurological symptoms was significantly increased in the group exposed to 200 mg/m3 as compared to the 10 mg/m3 group.