National Toxicology Program

National Toxicology Program
http://ntp.niehs.nih.gov/go/13651

Abstract for TR-535 - 4-Methylimidazole (CASRN 822-36-6)

Toxicology and Carcinogenesis Studies of 4-Methylimidazole (CAS No. 822-36-6) in F344/N Rats and B6C3F1 Mice (Feed Studies)

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Chemical Formula: C4H6N2 - Molecular Weight: 82.11

 

4-Methylimidazole is used in the manufacture of pharmaceuticals, photographic chemicals, dyes and pigments, cleaning and agricultural chemicals, and rubber. It has been identified as a by-product of fermentation in foods and has been detected in mainstream and sidestream tobacco smoke. 4-Methylimidazole was nominated by the National Cancer Institute for a long-term study because of the high potential for human exposure. Male and female F344/N rats and B6C3F1 mice were exposed to 4-methylimidazole (99.5% pure) in feed for 2 years. Fifteen-day and 14-week toxicity studies of 4-methylimidazole in F344/N rats and B6C3F1 mice are reported in NTP Toxicity Report No. 67. Genetic toxicology studies were conducted in Salmonella typhimurium, rat and mouse bone marrow cells, and mouse peripheral blood.

2-YEAR STUDY IN RATS

Groups of 50 male and 50 female rats were fed diets containing 0, 625, 1,250, or 2,500 ppm 4-methylimidazole (males) or 0, 1,250, 2,500, or 5,000 ppm 4-methylimidazole (females) (equivalent to average daily doses of approximately 30, 55, or 115 mg 4-methylimidazole/kg body weight to males and 60, 120, or 260 mg/kg to females) for 106 weeks. Survival of all exposed groups of male and female rats was similar to that of the control groups. Mean body weights of males in the 1,250 and 2,500 ppm groups and females in the 2,500 and 5,000 ppm groups were less than those of the control groups throughout the study; mean body weights of 1,250 ppm females were less after week 41. Feed consumption by 5,000 ppm females was less than that by the controls. Clonic seizures, excitability, hyperactivity, and impaired gait were observed primarily in 2,500 and 5,000 ppm females.

The incidence of mononuclear cell leukemia in 5,000 ppm females was significantly greater than that in the controls, and the incidence exceeded the historical range in feed study controls. The incidences of hepatic histiocytosis, chronic inflammation, and focal fatty change were generally significantly increased in all exposed groups of male and female rats. The incidences of hepatocellular eosinophilic and mixed cell focus were significantly increased in 2,500 ppm males and 5,000 ppm females.

2-YEAR STUDY IN MICE

Groups of 50 male and 50 female mice were fed diets containing 0, 312, 625, or 1,250 ppm 4-methylimidazole (equivalent to average daily doses of approximately 40, 80, and 170 mg 4-methylimidazole/kg body weight to males and females) for 106 weeks. Survival of all exposed groups of male and female mice was similar to that of the control groups. Mean body weights of males and females in the 1,250 ppm groups were less than those of the control groups after weeks 17 and 12, respectively. Mean body weights of 312 and 625 ppm females were less after weeks 85 and 65, respectively. Feed consumption by exposed groups of male and female mice was generally similar to that by the controls.

The incidences of alveolar/bronchiolar adenoma in all exposed groups of females, alveolar/bronchiolar carcinoma in 1,250 ppm males, and alveolar/bronchiolar adenoma or carcinoma (combined) in 1,250 ppm males and 625 and 1,250 ppm females were significantly greater than those in the control groups. The incidence of alveolar epithelium hyperplasia was significantly increased in 1,250 ppm females.

GENETIC TOXICOLOGY

4-Methylimidazole was not mutagenic in the S. typhimurium mutation assay when tested in strains TA97, TA98, TA100, and TA1535, with and without hamster or rat liver metabolic activation enzymes. No consistent or significant increases in the frequencies of micronucleated erythrocytes were seen in the bone marrow of male rats or mice treated with 4-methylimidazole by intraperitoneal injection, or in peripheral blood samples from male and female mice administered the compound in dosed feed for 14 weeks.

CONCLUSIONS

Under the conditions of these 2-year studies, there was no evidence of carcinogenic activity of 4-methylimidazole in male F344/N rats exposed to 625, 1,250, or 2,500 ppm. There was equivocal evidence of carcinogenic activity of 4-methylimidazole in female F344/N rats based on increased incidences of mononuclear cell leukemia. There was clear evidence of carcinogenic activity of 4-methylimidazole in male and female B6C3F1 mice based on increased incidences of alveolar/bronchiolar neoplasms.

Exposure to 4-methylimidazole resulted in nonneoplastic lesions in the liver of male and female rats and the lung of female mice and in clinical findings of neurotoxicity in female rats.

Synonyms: 1H-Imidazole, 4-methyl (9Cl); imidazole, 4-methyl; 4(5)-methylglyoxaline; 4(5),4(5)-methylimidazole; 5-methylimidazole
Trade name: 4-MeI


Summary of the 2-Year Carcinogenesis Studies of 4-Methylimidazole

 


 
Male
F344/N Rats
Female
F344/N Rats
Male
B6C3F1 Mice
Female
B6C3F1 Mice
Concentrations in
feed
0, 625, 1,250, or 2,500 ppm 0, 1,250, 2,500, or 5,000 ppm 0, 312, 625, or 1,250 ppm 0, 312, 625, or 1,250 ppm
Body weights 1,250 and 2,500 ppm groups less than the control group 1,250, 2,500, and 5,000 ppm groups less than the control group 1,250 ppm group less than the control group 625 and 1,250 ppm groups less than the control group
Survival rates 31/50, 34/50, 33/50, 32/50 43/50, 39/50, 34/50, 35/50 45/50, 44/50, 42/50, 46/50 43/50, 40/50, 43/50, 40/50
Nonneoplastic effects

Liver: histiocytosis (38/50, 45/50, 50/50, 50/50); chronic inflammation (18/50, 32/50, 31/50, 36/50); hepatocyte, focal fatty change (21/50, 24/50, 37/50, 33/50); eosinophilic focus (4/50, 3/50, 7/50, 12/50); mixed cell focus (5/50, 7/50, 11/50, 27/50)

Liver: histiocytosis (40/50, 50/50, 48/48, 50/50); chronic inflammation (17/50, 28/50, 34/48, 35/50); hepatocyte, focal fatty change (16/50, 29/50, 29/48, 32/50); eosinophilic focus (1/50, 2/50, 5/48, 11/50); mixed cell focus (10/50, 7/50, 6/48, 18/50)

None

Lung: alveolar epithelium hyperplasia (3/50, 2/50, 3/50, 11/50)

Neoplastic effects None None

Lung: alveolar/bronchiolar carcinoma (2/50, 4/50, 4/50, 8/50); alveolar/bronchiolar adenoma or carcinoma (combined) (9/50, 13/50, 16/50, 22/50)

Lung: alveolar/bronchiolar adenoma (0/50, 8/50, 16/50, 8/50); alveolar/bronchiolar carcinoma (3/50, 0/50, 2/50, 7/50); alveolar/bronchiolar adenoma or carcinoma (combined) (3/50, 8/50, 17/50, 14/50)

Equivocal findings None

Monoluclear cell leukemia: (9/50, 7/50, 16/50, 20/50)

None None
Level of evidence of carcinogenic activity No evidence Equivocal evidence Clear evidence Clear evidence
Genetic Toxicology of 4-Methylimidazole
Assay Test System Results
Bacterial Mutagenicity Salmonella typhimurium gene mutations: Negative in strains TA97, TA98, TA100, and TA1535 with and without S9
Micronucleated erythrocytes Rat bone marrow in vivo Negative when administered by intraperitoneal injection
Micronucleated erythrocytes Mouse marrow in vivo: Negative when administered by intraperitoneal injection
Micronucleated erythrocytes Mouse peripheral blood in vivo: Negative in males and females

Report Date: January 2007

Pathology Tables, Survival and Growth Curves from NTP 2-year Studies

Target Organs & Incidences from 2-year Studies

NTP is located at the National Institute of Environmental Health Sciences, part of the National Institutes of Health.