Abstract for TR-538

Toxicology and Carcinogenesis Studies of Methyl Isobutyl Ketone in F344/N Rats and B6C3F1 Mice (Inhalation Studies)

CASRN: 108-10-1
Chemical Formula: C6H12O
Molecular Weight: 100.16
Synonyms/Common Names: Hexanone, hexone, isobutylmethyl ketone, isopropyl-acetone, 4-methyl-2-oxopentane, 4-methyl pentan-2-one, 2-methyl-4-pentanone, 4-methyl-2-pentanone, 2-methyl propyl methyl ketone, MIBK, MIK
Report Date: February 2007

Methyl isobutyl ketone is used as a denaturant for rubbing alcohol; as a solvent for paints, varnishes, nitrocellulose, lacquers, and protective coatings; in industrial extraction processes; in dry-cleaning preparations; and in the synthesis of methyl isobutyl carbinol. Methyl isobutyl ketone was nominated for study by the National Cancer Institute and the United States Environmental Protection Agency because of its widespread use, the high potential for worker exposure due to its many industrial applications, and its high production volume. Male and female F344/N rats and B6C3F1 mice were exposed to methyl isobutyl ketone (greater than 99% pure) by inhalation for 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium.

Two-year study in rats

Groups of 50 males and 50 females were exposed to methyl isobutyl ketone at concentrations of 0, 450, 900, or 1,800 ppm by inhalation, 6 hours plus T90 (12 minutes) per day, 5 days per week for 104 weeks. Survival of males exposed to 1,800 ppm was significantly less than that of the chamber controls. The mean body weights of the 900 and 1,800 ppm males were less than those of the chamber controls after weeks 97 and 89, respectively.

In the standard evaluation of the kidney, there were slightly increased incidences of renal tubule adenoma and renal tubule adenoma or carcinoma (combined) in males exposed to 900 or 1,800 ppm, and renal tubule carcinoma in males exposed to 1,800 ppm. The incidences of renal tubule hyperplasia were also significantly increased in the 450 and 1,800 ppm males, and the severities were greater than in the chamber controls. Chronic nephropathy occurred in all males exposed to 1,800 ppm and in 70% to 88% of exposed females, and the severity was increased in 1,800 ppm males. The incidences of transitional epithelial hyperplasia of the renal pelvis in males exposed to 900 or 1,800 ppm and mineralization of the renal papilla in all groups of exposed males were significantly increased. In addition, two female rats exposed to 1,800 ppm had renal mesenchymal tumors. In the extended evaluation of the kidney, renal tubule adenomas and renal tubule hyperplasia occurred in all groups of exposed male rats. In the combined single and step section analysis, the incidences of renal tubule adenoma and renal tubule adenoma or carcinoma (combined) were significantly increased in males exposed to 1,800 ppm. The incidences of renal tubule hyperplasia were also significantly increased in all exposed groups of males.

There was a positive trend in the incidences of mononuclear cell leukemia in males, and the incidence in the 1,800 ppm group was significantly increased. The incidence of adrenal medulla hyperplasia in the 1,800 ppm males was significantly increased.

Two-year study in mice

Groups of 50 males and 50 females were exposed to methyl isobutyl ketone at concentrations of 0, 450, 900, or 1,800 ppm by inhalation, 6 hours plus T90 (12 minutes) per day, 5 days per week for 105 weeks. Survival of males and females was similar to that of the chamber controls. The mean body weights of females exposed to 1,800 ppm were less than those of the chamber controls after week 17.

The incidences of hepatocellular adenoma and hepatocellular adenoma or carcinoma (combined) were significantly increased in males and females exposed to 1,800 ppm. The incidences of eosinophilic foci were significantly increased in 450 and 1,800 ppm females.

Genetic toxicology

Methyl isobutyl ketone was not mutagenic in Salmonella typhimurium strains TA97, TA98, TA100, or TA1535 when tested with and without hamster or rat liver metabolic activation enzymes.

Conclusions

Under the conditions of these 2-year studies, there was some evidence of carcinogenic activity of methyl isobutyl ketone in male F344/N rats based on increased incidences of renal tubule neoplasms. Increased incidences of mononuclear cell leukemia in 1,800 ppm male F344/N rats may have been related to methyl isobutyl ketone exposure. There was equivocal evidence of carcinogenic activity of methyl isobutyl ketone in female F344/N rats based on the occurrence of renal mesenchymal tumors in the 1,800 ppm group. There was some evidence of carcinogenic activity of methyl isobutyl ketone in male and female B6C3F1 mice based on increased incidences of liver neoplasms.

Exposure to methyl isobutyl ketone resulted in nonneoplastic lesions of the kidney characteristic of α2u-globulin accumulation in male rats and nephropathy in female rats.

Summary of the Two-year Carcinogenesis Studies of Methyl Isobutyl Ketone
	Male F344/N Rats	Female F344/N Rats	Male B6C3F1 Mice	Female B6C3F1 Mice
Concentrations in air	Chamber control, 450, 900, or 1,800 ppm	Chamber control, 450, 900, or 1,800 ppm	Chamber control, 450, 900, or 1,800 ppm	Chamber control, 450, 900, or 1,800 ppm
Body weights	900 and 1,800 ppm groups less than the chamber controls	Exposed groups similar to the chamber controls	Exposed groups similar to the chamber controls	1,800 ppm group less than the chamber controls
Survival rates	32/50, 28/50, 25/50, 19/50	35/50, 34/50, 26/50, 32/50	40/50, 42/50, 35/50, 37/50	35/50, 37/50, 39/50, 38/50
Nonneoplastic effects	Kidney: renal tubule hyperplasia (standard evaluation - 1/50, 11/50, 3/50, 18/50; standard and extended evaluation combined - 1/50, 14/50, 7/50, 21/50); nephropathy (42/50, 45/50, 47/50, 50/50); severity (2.0, 2.6, 2.4, 3.1); pelvis transitional epithelium hyperplasia (1/50, 5/50, 6/50, 19/50); papilla mineralization (1/50, 6/50, 22/50, 29/50) Adrenal gland: adrenal medulla hyperplasia (13/50, 18/48, 18/50, 24/50)	Kidney: nephropathy (19/50, 35/50, 38/50, 44/50)	None	None
Neoplastic effects	Kidney: renal tubule adenoma (standard evaluation - 0/50, 0/50, 2/50, 3/50; standard and extended evaluation combined - 2/50, 3/50, 3/50, 10/50); renal tubule carcinoma (standard evaluation - 0/50, 1/50, 0/50, 2/50); renal tubule adenoma or carcinoma (combined) (standard evaluation - 0/50, 1/50, 2/50, 4/50; standard and extended evaluation - 2/50, 4/50, 3/50, 11/50)	None	Liver: hepatocellular adenoma (17/50, 25/50, 23/50, 34/50); hepatocellular adenoma or carcinoma (27/50, 34/50, 28/50, 37/50)	Liver: hepatocellular adenoma (13/50, 15/50, 20/50, 23/50); hepatocellular adenoma or carcinoma (17/50, 17/50, 22/50, 27/50)
Equivocal findings	Mononuclear cell leukemia: (25/50, 26/50, 32/50, 35/50)	Kidney: mesenchymal tumor malignant (0/50, 0/50, 0/50, 2/50)	None	None
Level of evidence of carcinogenic activity	Some evidence	Equivocal evidence	Some evidence	Some evidence

Summary of the Two-year Carcinogenesis Studies of Methyl Isobutyl Ketone

Male
F344/N Rats

Female
F344/N Rats

Male
B6C3F1 Mice

Female
B6C3F1 Mice

Concentrations in
air

Chamber control, 450, 900, or 1,800 ppm

Body weights

900 and 1,800 ppm groups less than the chamber controls

Exposed groups similar to the chamber controls

1,800 ppm group less than the chamber controls

Survival rates

32/50, 28/50, 25/50, 19/50

35/50, 34/50, 26/50, 32/50

40/50, 42/50, 35/50, 37/50

35/50, 37/50, 39/50, 38/50

Nonneoplastic effects

Kidney: renal tubule hyperplasia (standard evaluation - 1/50, 11/50, 3/50, 18/50; standard and extended evaluation combined - 1/50, 14/50, 7/50, 21/50); nephropathy (42/50, 45/50, 47/50, 50/50); severity (2.0, 2.6, 2.4, 3.1); pelvis transitional epithelium hyperplasia (1/50, 5/50, 6/50, 19/50); papilla mineralization (1/50, 6/50, 22/50, 29/50)

Adrenal gland: adrenal medulla hyperplasia (13/50, 18/48, 18/50, 24/50)

Kidney: nephropathy (19/50, 35/50, 38/50, 44/50)

None

Neoplastic effects

Kidney: renal tubule adenoma (standard evaluation - 0/50, 0/50, 2/50, 3/50; standard and extended evaluation combined - 2/50, 3/50, 3/50, 10/50); renal tubule carcinoma (standard evaluation - 0/50, 1/50, 0/50, 2/50); renal tubule adenoma or carcinoma (combined) (standard evaluation - 0/50, 1/50, 2/50, 4/50; standard and extended evaluation - 2/50, 4/50, 3/50, 11/50)

None

Liver: hepatocellular adenoma (17/50, 25/50, 23/50, 34/50); hepatocellular adenoma or carcinoma (27/50, 34/50, 28/50, 37/50)

Liver: hepatocellular adenoma (13/50, 15/50, 20/50, 23/50); hepatocellular adenoma or carcinoma (17/50, 17/50, 22/50, 27/50)

Equivocal findings

Mononuclear cell leukemia: (25/50, 26/50, 32/50, 35/50)

Kidney: mesenchymal tumor malignant (0/50, 0/50, 0/50, 2/50)

None

Level of evidence of carcinogenic activity

Some evidence

Equivocal evidence

Some evidence

Genetic Toxicology
Assay	Test System	Results
Bacterial mutagenicity	Salmonella typhimurium gene mutations:	Negative in strains TA97, TA98, TA100, and TA1535 with and without S9

Genetic Toxicology

Assay

Test System

Results

Bacterial mutagenicity

Salmonella typhimurium gene mutations:

Negative in strains TA97, TA98, TA100, and TA1535 with and without S9