National Toxicology Program

National Toxicology Program
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Abstract for TR-497 - Methacrylonitrile (CASRN 126-98-7)

Toxicology and Carcinogenesis Studies of Methacrylonitrile (CAS No. 126-98-7) in F344/N Rats and B6C3F1 Mice (Gavage Studies)

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Chemical Formula: C4 H5 N

Methacrylonitrile is an unsaturated aliphatic nitrile. It is widely used in the preparation of homopolymers and copolymers, elastomers, and plastics and as a chemical intermediate in the preparation of acids, amides, amines, esters, and other nitriles. Methacrylonitrile is also used as a replacement for acrylonitrile in the manufacture of an acrylonitrile/butadiene/styrene-like polymer that provides improved barrier properties to gases such as carbon dioxide in carbonated beverage containers. Methacrylonitrile was nominated for study by the National Cancer Institute because of the potential for human exposure, structural similarity to the known carcinogen acrylonitrile, demonstrated toxic effects in several animal species, and a lack of toxicity and carcinogenicity data. Male and female F344/N rats and B6C3F1 mice received methacrylonitrile (greater than 99% pure) in deionized water by gavage for 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium, Drosophila melanogaster, rat and mouse bone marrow cells, and mouse peripheral blood erythrocytes.

2-YEAR STUDY IN RATS

Groups of 50 male and 50 female rats were administered 0, 3, 10, or 30 mg methacrylonitrile/kg body weight in deionized water by gavage, 5 days per week for 104 to 105 weeks. This dose selection was based on the results of an NTP 13-week gavage study where rats were administered 0, 7.5, 15, 30, 60, or 120 mg methacrylonitrile/kg body weight. In the 13-week study, clinical signs of toxicity were observed early in the study. In addition, lower mean body weights and survival were observed in male and female rats administered 60 or 120 mg/kg.

In the 2-year study, survival of all dosed groups of rats was similar to that of the vehicle control groups. Mean body weights of the 30 mg/kg groups were less than those of the vehicle controls after weeks 21 and 37 for males and females, respectively. No changes in the incidences of neoplasms were attributed to exposure to methacrylonitrile. The incidences of olfactory epithelial atrophy and metaplasia of the nose were significantly greater for 30 mg/kg males and females than for the vehicle controls. Increased incidences of cytoplasmic vacuolization occurred in the liver of males and females.

2-YEAR STUDY IN MICE

Groups of 50 male and 50 female mice were administered methacrylonitrile in deionized water by gavage at doses of 0, 1.5, 3, or 6 mg/kg, 5 days per week for 104 to 105 weeks. This dose selection was based on the results of an NTP 13-week gavage study; where methacrylonitrile was administered at doses of 0, 0.75, 1.5, 3, 6, or 12 mg/kg for 32 days or 13 weeks. Mice administered 6 or 12 mg/kg exhibited clinical signs of toxicity. In addition, slight decreases in the mean body weight gains of 12 mg/kg male and female mice were observed at 13 weeks. Additionally, one 12 mg/kg male from the 32-day interim evaluation and one 12 mg/kg female from the 13-week study died during the first week of treatment; other deaths were accidental.

In the 2-year study, methacrylonitrile had no effect on survival. The mean body weights of all dosed groups were generally similar to those of the vehicle controls throughout the study. No neoplasms or nonneoplastic lesions were attributed to the methacrylonitrile -administration.

GENETIC TOXICOLOGY

Methacrylonitrile did not induce mutations in any of five strains of Salmonella typhimurium, with or without S9 activation, and did not induce sex-linked recessive lethal mutations in germ cells of male Drosophila melanogaster fed methacrylonitrile during the larval stage. Results of in vivo bone marrow micronucleus tests with methacrylonitrile in male rats and mice were also negative. Finally, no increase in the frequency of micronucleated erythrocytes was seen in peripheral blood of male or female mice treated with methacrylonitrile for 13 weeks by gavage.

CONCLUSIONS

Under the conditions of these 2-year gavage studies,there was no evidence of carcinogenic activity of methacrylonitrile in male or female F344/N rats administered 3,10,or 30 mg/kg. There was no evidence of carcinogenic activity of methacrylonitrile in male or female B6C3F1 mice administered 1.5,3,or 6 mg/kg.

In male and female rats, methacrylonitrile administration caused significant increases in the incidences of nonneoplastic lesions of the nose and liver.

Synonyms: 2-Cyanopropene; 2-cyano-1-propene; isobutenenitrile; isopropene cyanide; isopropenylnitrile; methylacrylonitrile; a-methylacrylonitrile; 2-methyl-2-propenenitrile

Summary of the 2-Year Carcinogenesis and Genetic Toxicology Studies of Methacrylonitrile
 

Male
F344/N Rats

Female
F344/N Rats

Male
B6C3F1 Mice

Female
B6C3F1 Mice

Doses in water by gavage

0, 3, 10, or 30 mg/kg

0, 3, 10, or 30 mg/kg

0, 1.5, 3, or 6 mg/kg

0, 1.5, 3, or 6 mg/kg

Body weights

30 mg/kg group less than the vehicle control group

30 mg/kg group less than the vehicle control group

Dosed groups similar to control group

Dosed groups similar to control group

Survival rates

25/50, 34/50, 35/50, 31/50

38/50, 33/50, 34/50, 36/50

35/49, 43/50, 43/50, 22/50a

35/50, 35/50, 43/50, 25/50a

Nonneoplastic effects

Nose: olfactory epithelial atrophy (0/50, 0/50, 0/49, 48/50); olfactory epithelial metaplasia (0/50, 0/50, 0/49, 47/50)

Liver: cytoplasmic vacuolization (14/50, 18/50, 23/50, 28/49)

Nose: olfactory epithelial atrophy (0/50, 0/50, 1/50, 19/50); olfactory epithelial metaplasia (0/50, 0/50, 0/50, 47/50)

Liver: cytoplasmic vacuolization (7/50, 14/49, 17/48, 30/50)

None

None

Neoplastic effects

None

None

None

None

Level of evidence of carcinogenic activity

No evidence

No evidence

No evidence

No evidence

aTwenty-four males and 15 females in the 6 mg/kg groups died due to dosing accidents during week 69.

Genetic Toxicology
Assay Results
Salmonella typhimurium gene mutations:

Negative in strains TA97, TA98, TA100, TA1535, and TA1537, with and without S9

Sex-linked recessive lethal mutations
Drosophila melanogaster:
Negative when administered in feed
Micronucleated erythrocytes
Rat bone marrow in vivo :
Negative
Mouse bone marrow in vivo :

Negative

Mouse peripheral blood in vivo :

Negative

Report Date: November 2001

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

Target Organs & Incidences from 2-year Studies Return to Long Term Abstracts

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