3-methylbutanone

Acute Toxicity: inhalation

Administrative data

Endpoint:

acute toxicity: inhalation

Type of information:

experimental study

Adequacy of study:

key study

Study period:

6 hour inhalation exposure followed by a 14-day observation period

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: see 'Remark'

Remarks:

Study was conducted according to GLPs. Study was conducted by procedures comparable to Toxic Substances Control Act Test Guidelines (EPA, September 27, 1985); Guidelines for Testing of Chemicals: TG-403, Acute Inhalation Toxicity (Organization for Economic Cooperation and Development, May 1981); and Annex V.B.2, Acute Inhalation Toxicity (European Economic Community, September, 1984).

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1987

Report date:

1987

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

OECD Guideline 403 (Acute Inhalation Toxicity)

Deviations:

yes

Remarks:

One deviation was noted, but it did not impact the quality or integrity of the study.

GLP compliance:

yes

Test type:

standard acute method

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

3-methyl-2-butanone

IUPAC Name:

3-methyl-2-butanone

Constituent 2

Reference substance name:

3-methylbutanone

EC Number:

209-264-3

EC Name:

3-methylbutanone

Cas Number:

563-80-4

Molecular formula:

C5H10O

IUPAC Name:

3-methylbutan-2-one

Constituent 3

Reference substance name:

methylbutanone; methyl isopropyl ketone; MIPK

IUPAC Name:

methylbutanone; methyl isopropyl ketone; MIPK

Details on test material:

-Test substance (as cited in report): Methyl Isopropyl Ketone
-Source: Tennessee Eastman Company, Kingsport TN
-Molecular formula: C5H10O
-Molecular weight: 86.13
-Appearance: colorless liquid
-Boiling point: 94 °C at 760 mm Hg
-Specific gravity (water = 1): 0.803 at 20 °C
-Vapor pressure: 42 mm Hg at 20 °C
-Vapor density (air = 1): 3.0
-Solubility in water: slight
-Surface tension: predicted to be 21.4 dyne/cm
-Purity analysis: Two samples of MIPK were analyzed by GC-FID at Eastman Kodak Company and were found to be 98.7 and 98.4% pure.
-Structure confirmation: was performed by GC-MS

Test animals

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

Test animals:
-Strain: CRL:CD®(SD)BR rats (Charles River Laboratories, Inc., Wilmington, MA)
-Acclimation: 5 days
-Sex: Male and Female
-Age (at study initiation): 7 (male) and 9 (female) weeks old
-Mean body weight (at study initiation): 252 ± 10 g (male) and 201 ± 8 g (female)
-Identification: unique numbered metal ear tag
-Randomization: Animals were randomized prior to study start using an internal computer program.
-Housing: group housed in stainless steel suspended cages during the acclimation period and then singly housed during the study period. Cages and racks were washed once per week; absorbent paper under the cages was changed three times per week.
-Feed: Agway Prolab Animal Diet (RMH 3000, pellets) ad libitum except during inhalation exposure
-Water: Monroe County Water Authority ad libitum except during inhalation exposure.

Environmental conditions:
-Temperature: 68-74 °F
-Humidity: 45-58%
-Light cycle: 12:12 light:dark


In-Life study Dates:
Study Initiation Date: February 3, 1987
Study Termination Date: February 17, 1987

Administration / exposure

Route of administration:

inhalation: vapour

Type of inhalation exposure:

whole body

Vehicle:

other: Filtered air

Details on inhalation exposure:

Exposures were to target vapor concentrations of 0, 4000, 6000, and 9000 ppm and were conducted in 420 L stainless steel and glass inhalation chambers. Animals were exposed to MIPK vapors for 6 hours and then observed for 14 days. Males and females were exposed in the same chambers; the exposures were run concurrently and each chamber was maintained under negative pressure (0.5 inch of water) with 10-13 air changes per hour. The controls were treated similarly to MIPK animals except controls were exposed to filtered air only.

Vapors were generated by metering the test substance dropwise into a heated glass bead-packed column supplied with metered dried oil-free compressed air. Chamber vapor concentrations were determined nine times throughout the six hour exposure by a MIRAN® IA infrared analyzer equipped for automated sampling and analysis. In addition, temperature and humidity were determined once per hour and nominal vapor concentration for the exposures was calculated. Twice during the exposure, the concentration of background nongaseous material was measured in the 9000 ppm chamber relative to that of the air control chamber in order to insure that exposures were to vapor and not aerosol.

Prior to the study, distribution of the test substance was determined by measurements of the concentration of the test substance from ten positions throughout the chamber. These were compared to the concentration at a fixed reference position. Based on the homogeneity which was observed, determinations of chamber vapor concentration during the study were done remotely from the fixed reference position.

Analytical verification of test atmosphere concentrations:

yes

Remarks on duration:

Duration was 6 hours for all groups

Concentrations:

0, 4000, 6000, 9000 ppm

No. of animals per sex per dose:

5 animals/sex/group

Control animals:

yes

Details on study design:

Rats were exposed to MIPK at target concentrations of 0, 4000, 6000, and 9000 ppm for 6 hours followed by a 14 day observation period. Signs of toxicity, including mortality, were recorded.

Statistics:

All numerical data were evaluated using the following computer generated statistical tests: one-way analysis of variance (ANOVA), Bartlett’s test, and Duncan’s multiple range test using a p value of ≤ 0.05 to indicate statistical significance. The LC50 value and its 95% confidence limits (Thompson and Weil Method) were estimated using the AATS computer program.

Results and discussion

Effect levels

Effect levels 1

Sex:

female

Dose descriptor:

LC50

Effect level:

6 313 ppm

95% CL:

4 876 - 8 176

Exp. duration:

6 h

Effect levels 2

Sex:

male

Dose descriptor:

LC50

Effect level:

6 428 ppm

95% CL:

5 566 - 7 423

Exp. duration:

6 h

Effect levels 3

Sex:

male/female

Dose descriptor:

LC50

Effect level:

6 377 ppm

95% CL:

5 560 - 7 314

Exp. duration:

6 h

Mortality:

No animals died during inhalation exposure and no animals died in the control or 4000 ppm exposure groups. In the 6000 ppm group, one male and one female died on Day 0 after inhalation exposure, and an additional female died on Day 2 post-dose. Nine animals (5/5 males and 4/5 females) died during the course of the study in the 9000 ppm group; at that concentration, all 5 males and 2 females died on Day 0 after inhalation exposure, and 2 additional females died on Day 1 post-exposure.

Clinical signs:

other: During exposure, all males and females exposed to MIPK exhibited severe central nervous system (CNS) depression and excessive lacrimation. Minor hypoventilation during exposure was also seen in the 4000 and 6000 ppm groups, but was more severe in the 900

Body weight:

Most animals surviving exposure exhibited a weight loss during the three days following exposure. Weight gain was extremely small in those few animals showing an increase. No clear concentration-related change was apparent. After three days, all animals showed a sustained weight gain similar to controls. Terminal body weights in all groups were comparable to the controls.

Gross pathology:

No organ damage sufficient to cause death was seen in rats dying as a result of exposure to the test substance. No test substance-related changes were observed upon gross or histologic examination in animals found dead or in those examined at the termination of the study.

Other findings:

Exposure conditions:
-Mean measured exposure concentrations and standard deviations were 4026 ± 100 ppm, 5708 ± 67 ppm, 8270 ± 240 ppm compared to target concentrations of 4000, 6000, and 9000 ppm, respectively.
-The analytical concentrations were within 22% of calculated nominal concentrations.
-Mean temperature and relative humidity varied from 21-22°C and 50-59% between chambers.
-Particle count data indicated that an aerosol of the test material was not present.
-Distribution of the vapor was uniform throughout the ten cage positions in the cage sample measurements.

Applicant's summary and conclusion

Interpretation of results:

Category 4 based on GHS criteria

Remarks:

Migrated information

Conclusions:

Under conditions used in this study, methyl isopropyl ketone was harmful by the inhalation route in rats. No mortality was observed in either sex exposed to a concentration of 4000 ppm for 6 hours. At the 4000 ppm exposure concentration, treatment-related clinical signs indicating reversible effects on the central nervous system (CNS) included lethargy, narcosis, hypoventilation, excessive lacrimation, and excessive sialorrhea (seen in a single female). Most clinical signs in animals that survived were seen either during or just after exposure but resolved within 48-72 hours. Mortality and severity of clinical signs occurred in a concentration-dependent manner. At 9000 ppm, all males and four of five females died on the day of exposure or on Day 1 post-exposure while at 6000 ppm, 1 male and 1 female died on the day of exposure with an additional female dying on Day 2. More severe central nervous system effects were seen in the higher exposure group animals. The combined calculated (male and female) LC50 for inhalation exposure to methyl isopropyl ketone was determined to be 6377 ppm. The probable cause of death was not determined but was most likely due to severe CNS depression. Applying Haber’s Law to express the 6-hr LC50 value of 6377 ppm in terms of a 4 hour exposure, methyl isopropyl ketone is classifiable as Category IV for classification and labeling for “Acute Toxicity” by the inhalation route under the UN GHS regulations and CLP Regulation (EC) No. 1272/2008.

Executive summary:

In an acute inhalation toxicity study, 5 rats/sex/group were exposed to methyl isopropyl ketone at concentrations of 0, 4000, 6000, and 9000 ppm for a period of 6 hours followed by a fourteen-day observation period. No animals died during exposure and there were no deaths in the 4000 ppm exposure group.  In the 6000 ppm group, one male and one female died shortly after exposure and an additional female died on Day 2 post-exposure. In the 9000 ppm group, nine animals (5/5 males and 4/5 females) died during the course of the study; all 5 males and 2 females died shortly after exposure and 2 females died on Day 1 post-exposure. During and following exposure, there was a concentration-dependent increase in severity of central nervous system effects that included lacrimation, minor hypoventilation, lethargy, sialorrhea, piloerection, and poor body condition. The adverse clinical signs resolved in all surviving animals within 72 hours following the end of the exposure. Based on the results of this study, the calculated combined LC50 for methyl isopropyl ketone in male and female rats was 6377 ppm for a 6-hour inhalation exposure.