Two-year toxicity and carcinogenicity study of methyleugenol in F344/N rats and B6C3F(1) mice

Methyleugenol (MEG) was tested for toxicity/carcinogenicity in a 2-yr carci nogenesis bioassay because of its widespread use in a variety of foods, bev erages, and cosmetics as well as its structural resemblance to the known ca rcinogen safrole. F344/N rats and B6C3F(1) mice (50 animals/sex/dose group) were given MEG suspended in 0.5% methylcellulose by gavage at doses of 37, 75, or 150 mg/kg/day for 2 yr. Control groups (60 rats/sex and 50 mice/sex ) received only the vehicle. A stop-exposure group of 60 rats/sex received 300 mg/kg/day by gavage for 53 weeks followed by the vehicle only for the r emaining 52 weeks of the study. A special study group (10 animals/sex/speci es/dose group) were used for toxicokinetic studies. All male rats given 150 and 300 mg/kg/day died before the end of the study; survival of female rat s given 150 mg/kg/day and all treated female mice was decreased. Mean body weights of treated male and female rats and mice were decreased when compar ed to control. Area under the curve results indicated that greater than dos e proportional increases in plasma MEG occurred for male 150 and 300 mg/kg/ day group rats (6 and 12 month) and male 150 mg/kg/day mice (12 month). Tar get organs included the liver, glandular stomach, forestomach (female rats) and kidney, mammary gland, and subcutaneous tissue (male rats). Liver neop lasms occurred in all dose groups of rats and mice and included hepatoadeno ma, hepatocarcinoma, hepatocholangioma (rats only), hepatocholangiocarcinom a, and hepatoblastoma (mice only). Nonneoplastic liver lesions included eos inophilic and mixed cell foci (rats only), hypertrophy, oval cell hyperplas ia, cystic degeneration (rats only), and bile duct hyperplasia. Mice also e xhibited necrosis, hematopoietic cell proliferation, and hemosiderin pigmen tation. Glandular stomach lesions in rats and mice included benign and mali gnant neuroendocrine tumors, neuroendocrine cell hyperplasia, and atrophy a nd in mice included glandular ectasia/chronic active inflammation. In femal e rats, the forestomach showed a positive trend in the incidences of squamo us cell papilloma or carcinoma (combined). Male rats also exhibited kidney (renal tubule hyperplasia, nephropathy, and adenomacarcinoma), mammary glan d (fibroadenoma), and subcutaneous tissue (fibroma, fibrosarcoma) lesions. Male rats also exhibited malignant mesotheliomas and splenic fibrosis. Thes e data demonstrate that MEG is a multisite, multispecies carcinogen.