Allyl isovalerate, a synthetic fragrance and flavoring ingredient in use since the 1950's, may be found in various products at the following concentrations:
soap, 30 ppm;
detergent, 3 ppm; creams, 15 ppm;
perfume, 50 ppm; nonalcoholic beverages, 9 ppm; ice cream, 18 ppm; candy, 22 ppm; baked goods, 15-48 ppm; and
gelatins and puddings, 1 ppm. A colorless liquid with an apple-like odor and taste,
allyl isovalerate is approved by the U.S. Food and Drug Administration for use in foods. Specific production figures are not available, but U.S. production in 1980 exceeded 1,000 pounds.
Carcinogenesis studies of
allyl isovalerate (96% pure) were conducted by administering the test chemical in
corn oil gavage to groups of 50 male and 50 female F344/N rats and to groups of 50 male and 50 female B6C3F1 mice at doses of 31 or 62 mg/kg. The doses selected were based on the chemically-induced toxic effects and depressed
weight gains obtained from the 13-week studies. Doses were administered five times per week for 103 weeks. Groups of 50 rats and 50 mice of each sex received
corn oil by gavage on the same dosing schedule and served as vehicle controls. Survival and mean
body weight gain of rats of each sex and male mice were not adversely affected by the administration of
allyl isovalerate. The significantly lower survival (P=0.001) and the lower mean
body weight of low-dose female as compared with controls are likely consequences of the high incidence of a
genital tract infection in the low-dose females. This
infection was probably responsible for the deaths of 11/19 control, 22/33 low-dose, and 13/25 high-dose female mice that died before the end of the study.
Squamous cell papillomas and epithelial
hyperplasia of the nonglandular stomach were observed in dosed male mice in the 2-year studies (
squamous cell papillomas: 0/50, 1/50, 2%, 3/48, 6%; epithelial
hyperplasia: 1/50, 2%, 1/50, 2%, 7/48, 15%). The
papillomas occurred with a significant positive trend (P<0.05). The incidence of high-dose male mice with
squamous cell papillomas of the nonglandular stomach was also higher (P<0.01) than the historical rate for vehicle control male B6C3F1 mice in the Bioassay Program (5/881, 0.6%). Forestomach lesions were also observed in female mice:
squamous cell papillomas (1/50, 0/50, 2/50) and epithelial
hyperplasia of the nonglandular stomach (0/50, 2/50, 3/50). Pancreatic acinar-cell
adenomas occurred at higher incidences in the dosed male rats than in the controls (control, 1/50, 2%; low-dose, 4/50, 8%; high-dose, 2/50, 4%). Pancreatic acinar-cell
tumors were not observed in female rats. Preputial gland
adenomas were observed in increased incidence in low-dose male rats (0/50, 4/50, 8%; P<0.05, 1/50, 2%). Mononuclear-cell
leukemias in rats and
lymphomas in mice occurred with increased incidences. This consistent dose-response increase among both rats and mice indicates that
allyl isovalerate adversely affects the hematopoietic system. Cholangiofibrosis, nodular regeneration,
cirrhosis, focal
necrosis, fatty metamorphosis, and cytoplasmic vacuolization were observed at increased incidences in the livers of high-dose male and female rats in the 2-year study. No compound-related nonneoplastic lesions were observed in the mice of either sex.
Liver neoplasms were not increased in either dosed rats or mice of either sex. Significant (P<0.05) decreases in
tumor incidences were observed in male mice for
hepatocellular carcinomas (18/50, 6/50, 9/50), for alveolar/bronchiolar
adenomas or
carcinomas (13/50, 6/50, 5/49), and for follicular-cell
adenomas of the thyroid gland (5/47, 0/46, 1/49).
Allyl isovalerate was not mutagenic for Salmonella typhimurium (tester strains TA 98, 100, 1535, and 1537) with or without metabolic activation. Under the conditions of these studies,
allyl isovalerate was carcinogenic for F344/N rats and B6C3F1 mice, causing increased incidences of hematopoietic system
neoplasms (mononuclear-cell
leukemia in male rats and
lymphoma in female mice). Levels of Evidence of Carcinogenicity: Male Rats: Positive Female Rats: Negativen female mice). Levels of Evidence of Carcinogenicity: Male Rats: Positive Female Rats: Negative Male Mice: Negative Female Mice: Positive