Isoeugenol is one of several structurally similar phenylpropenoid compounds produced by plants. It has been extracted from calamus, savory, basil, ylang-ylang, clove, tuberose, jonquil, nutmeg, tobacco, sandalwood, dill seed,
mace, gardenia, petunia, and other flowers.
Isoeugenol can also be produced by isomerization of
eugenol, which occurs naturally in clove, pimento, bay leaf, and cinnamon. As a fragrance with a spicy, carnation-like odor,
isoeugenol is incorporated into numerous household and personal hygiene products, including perfumes, cream lotions,
soaps, and
detergents. As a
flavoring agent,
isoeugenol is added to nonalcoholic drinks, baked foods, and
chewing gums.
Isoeugenol was nominated by the National Cancer Institute and was selected for carcinogenicity testing because of widespread human exposure through its use as a flavoring and fragrance agent and because of its structural similarity to phenylpropenoids such as
safrole,
isosafrole,
eugenol,
methyleugenol,
estragole, and
anethole, most of which are known rodent
carcinogens. Male and female F344/N rats and B6C3F1 mice were administered
isoeugenol (99% or greater pure) in
corn oil by gavage for 3 months or 2 years. Genetic toxicity tests were conducted in Salmonella typhimurium, Escherichia coli, cultured Chinese hamster ovary cells, and mouse peripheral blood erythrocytes. 3-MONTH STUDY IN RATS: Groups of 10 male and 10 female rats were exposed to
isoeugenol in
corn oil by gavage at doses of 0, 37.5, 75, 150, 300, or 600 mg/kg, 5 days per week for 14 weeks. All rats survived to the end of the study except one 600 mg/kg male and one 37.5 mg/kg female that were killed in dosing accidents. Mean
body weights of all exposed groups of males were significantly less than that of the vehicle control group; however, only the decrease for the 600 mg/kg group exceeded 10% and was considered related to
isoeugenol exposure. Liver weights were significantly increased in 300 and 600 mg/kg females. The incidences of minimal
atrophy of the olfactory epithelium of the nose were significantly increased in 150 mg/kg or greater males and in 300 or 600 mg/kg females. The incidence of
atrophy of olfactory nerve bundles was significantly increased in 600 mg/kg females. Minimal to mild periportal hepatocellular cytoplasmic alteration occurred in all 300 or 600 mg/kg females. 3-MONTH STUDY IN MICE: Groups of 10 male and 10 female mice were exposed to
isoeugenol in
corn oil by gavage at doses of 0, 37.5, 75, 150, 300, or 600 mg/kg, 5 days per week for 14 weeks. All mice survived to the end of the study. The mean
body weight of 600 mg/kg males was significantly less (12%) than that of the vehicle controls. Liver weights of 300 and 600 mg/kg males were significantly greater than those of the vehicle controls. Minimal to moderate
atrophy of olfactory epithelial tissue and nerve bundles was observed in 600 mg/kg males and females. 2-YEAR STUDY IN RATS: Groups of 50 male and 50 female rats were exposed to
isoeugenol in
corn oil by gavage at doses of 0, 75, 150, or 300 mg/kg, 5 days per week for 105 weeks. Survival rates of exposed male and female rats were similar to those of vehicle controls. Mean
body weights of 300 mg/kg male rats were 9% greater than the vehicle controls at the end of the study. The general lack of toxicity and nonneoplastic lesions indicates that rats might have been able to tolerate higher doses. Two male rats in the 300 mg/kg group had rare benign or malignant
thymomas, while two other males in this group had rare mammary gland
carcinomas. Low incidences of minimal
atrophy and minimal to mild respiratory
metaplasia of the olfactory epithelium were increased in 150 mg/kg males and 300 mg/kg males and females. Similar incidences of minimal to mild olfactory epithelial degeneration in 300 mg/kg males were also increased. Incidences of
keratoacanthoma of the skin were decreased in 150 and 300 mg/kg males. 2-YEAR STUDY IN MICE: Groups of 50 male and 50 female mice were exposed to
isoeugenol in
corn oil by gavage at doses of 0, 75, 150, or 300 mg/kg, 5 days per week for 104 (females) or 105 (males) weeks. Survival of 300 mg/kg males was significantly decreased compared to the vehicle controls. Mean
body weights of 300 mg/kg male and female groups were less than those of vehicle controls at the end of the study, 10% and 15% less, respectively. In all groups of exposed males, the incidences of
hepatocellular adenoma,
hepatocellular carcinoma, and
hepatocellular adenoma or
carcinoma (combined) were significantly greater than those in the vehicle control group; incidences of multiple
hepatocellular adenoma were also significantly increased. Incidences of clear cell focus were significantly increased in 75 and 150 mg/kg male mice. There was a significant positive trend in the incidences of
histiocytic sarcoma in females, and this
neoplasm occurred in multiple tissues. Incidences of respiratory
metaplasia in olfactory epithelium in all exposed groups and of
atrophy and hyaline droplet accumulation in all exposed groups except 75 mg/kg females were significantly greater than those in corresponding vehicle control groups. Incidences of minimal to marked
hyperplasia of Bowman's gland were increased significantly in all exposed groups. Incidences of minimal to mild
necrosis of renal papilla and mild to moderate
necrosis of renal tubules were increased significantly in 300 mg/kg females. Incidences of forestomach squamous
hyperplasia,
inflammation, and ulceration (males only) increased with exposure and were significant in the 300 mg/kg groups. The incidence of glandular
stomach ulcers was low but significantly increased in the 300 mg/kg groups.
GENETIC TOXICOLOGY: