NTP Toxicology and Carcinogenesis Studies of Methyleugenol (CAS NO. 93-15-2) in F344/N Rats and B6C3F1 Mice (Gavage Studies).
- 1 July 2000
- journal article
- Vol. 491, 1-412
Abstract
Methyleugenol is used as a flavoring agent in jellies, baked goods, nonalcoholic beverages, chewing gum, candy, pudding, relish, and ice cream. It is also used as a fragrance in perfumes, creams, lotions, detergents, and soaps. Methyleugenol has also been used as an insect attractant in eradication programs and as an anesthetic in rodents. Methyleugenol was nominated for testing because of its widespread use and because of its structural resemblance to safrole, a known carcinogen, and isosafrole and estragole. Male and female F344/N rats and B6C3F1 mice received methyleugenol (approximately 99% pure) in 0.5% methylcellulose by gavage for 14 weeks or 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium, cultured Chinese hamster ovary cells, and mouse peripheral blood erythrocytes. 14-WEEK STUDY IN RATS: Groups of 9 or 10 male and 10 female F344/N rats were administered 0, 10, 30, 100, 300, or 1,000 mg methyleugenol/kg body weight in 0.5% methylcellulose by gavage 5 days per week for 14 weeks. A water control group of 10 male and 10 female rats received deionized water by gavage. All rats survived until the end of the study. The final mean body weights of 300 and 1,000 mg/kg males and of all dosed groups of females were significantly less than those of the vehicle controls. Erythrocyte microcytosis was demonstrated by decreased mean cell volumes in 300 mg/kg males and 1,000 mg/kg males and females. There was evidence of a thrombocytosis at all time points, demonstrated by increased platelet counts in the 100 mg/kg or greater groups. The serum activities of alanine aminotransferase and sorbitol dehydrogenase were increased in the 100 mg/kg or greater rats at various time points, suggesting hepatocellular injury. Additionally, bile acid concentrations were generally increased in the 300 and 1,000 mg/kg groups at all time points, consistent with cholestasis or altered hepatic function. A hypoproteinemia and hypoalbuminemia, evidenced by decreased total protein and albumin concentrations, occurred in rats in the 300 and 1,000 mg/kg groups at all time points. Liver weights of 100, 300, and 1,000 mg/kg males and 300 and 1,000 mg/kg females and testis weights of 1,000 mg/kg males were significantly increased. Increased incidences of liver lesions occurred in 300 and 1,000 mg/kg males and females and hepatocellular adenoma occurred in one 1,000 mg/kg male. The incidences of atrophy and chronic inflammation of the mucosa of the glandular stomach were significantly increased in rats administered 300 or 1,000 mg/kg. Increased incidences of adrenal gland cortical hypertrophy and/or cytoplasmic alteration in the submandibular gland occurred in the 100 mg/kg or greater groups. 14-WEEK STUDY IN MICE: Groups of 10 male and 10 female B6C3F1 mice received methyleugenol in 0.5% methylcellulose by gavage at doses of 0, 10, 30, 100, 300, or 1,000 mg/kg, 5 days per week for 14 weeks. A water control group of 10 male and 10 female mice received deionized water by gavage. All but one male and all females receiving 1,000 mg/kg died before the end of the study. The mean body weight gains of mice in the 300 mg/kg groups were significantly less than those of the vehicle controls. The only clinical finding was toxicity manifested as generalized morbidity in mice administered 1,000 mg/kg. Liver weights of 30, 100, and 300 mg/kg males and of 300 mg/kg females were significantly increased. Male mice administered 10 or 30 mg/kg had significantly lower cauda epididymis, epididymis, and testis weights; males receiving 100 mg/kg had significantly lower spermatozoal concentrations. Increased incidences of liver lesions occurred in 1,000 mg/kg males and 300 and 1,000 mg/kg females. The incidences of lesions of the glandular stomach were increased in one or more groups administered 30 mg/kg or greater. 2-YEAR STUDY IN RATS: Groups of 50 male and 50 female rats received methyleugenol in 0.5% methylcellulose by gavage at doses of 37, 75, or 150 mg/kg, 5 days per week for 105 weeks; groups of 60 male and 60 female rats received the 0.5% me60 female rats received the 0.5% methylcellulose vehicle only. Stop-exposure groups of 60 male and 60 female rats received 300 mg/kg in 0.5% methylcellulose by gavage for 52 weeks followed by just the 0.5% methylcellulose vehicle for the remaining 53 weeks of the study. Special study groups of 10 male and 10 female rats administered 36, 75, 150, or 300 mg/kg were designated for toxicokinetic studies. Survival and Body Weights: All 150 and 300 mg/kg males died before the end of the study, and survival of 150 mg/kg females was slightly less than that of the vehicle controls. Mean body weights of all dosed groups of rats were less than those of the vehicle controls throughout most of the 2-year study. Pathology Findings: Chemical-related liver neoplasms occurred in all dosed groups of rats and included hepatocellular adenoma, hepatocellular carcinoma, hepatocholangioma, and hepatocholangiocarcinoma; at 2 years, there were positive trends in the incidences of hepatocellular adenoma, carcinoma, and adenoma or carcinoma (combined) in core study rats and in the numbers of rats with multiple liver neoplasms. Nonneoplastic lesions included eosinophilic and mixed cell foci, hepatocellular hypertrophy, oval cell hyperplasia, cystic degeneration, and bile duct hyperplasia (females); the incidences of these lesions in dosed groups of male and female rats were increased at 6 months, 12 months, and/or 2 years. Chemical-related neoplasms and nonneoplastic lesions of the glandular stomach included benign and malignant neuroendocrine tumors in the 150 and 300 mg/kg groups and females in the 75 mg/kg group. In all dosed groups of rats at all time points, the incidences of mucosal atrophy were significantly greater than in the vehicle controls. Neuroendocrine cell hyperplasia was observed in females at 6 months and males and females at 12 months and at 2 years. In...This publication has 0 references indexed in Scilit: