Turmeric oleoresin is the organic extract of turmeric, a ground powder from the root of the Curcuma plant, and is added to food items as a spice and coloring agent. Turmeric oleoresin, turmeric, and curcumin (the major component found in turmeric) were nominated by the National Cancer Institute and the Food and Drug Administration for study because these chemicals are used in food items and curry powders, and there was little information on their toxic or carcinogenic properties. Pure curcumin was not available in sufficient quantities for study, and a turmeric oleoresin with a high curcumin content (79% to 85%) was selected for evaluation. Toxicity and carcinogenicity studies were conducted by administering turmeric oleoresin in feed to groups of male and female F344/N rats and B6C3F1 mice for 13 weeks and 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium and cultured Chinese hamster ovary cells. 13-WEEK STUDY IN RATS: Groups of 10 male and 10 female F344/N rats were fed diets containing 0, 1,000, 5,000, 10,000, 25,000, or 50,000 ppm turmeric oleoresin. All rats survived until the end of the study. The final mean body weight of males receiving 50,000 ppm was 5% lower than that of the controls. Feed consumption by exposed male and female rats was similar to that by the controls. Dietary levels of 1,000, 5,000,10,000, 25,000, or 50,000 ppm turmeric oleoresin were estimated to deliver average daily doses of 50, 250, 480, 1,300, or 2,600 mg/kg body weight to males and 60, 300, 550, 1,450, or 2,800 mg/kg to females. The absolute and relative liver weights of female rats and the relative liver weights of male rats receiving 5,000, 10,000, 25,000, and 50,000 ppm were significantly greater than those of the controls. There were no biologically significant differences in hematologic, clinical chemistry, or urinalysis parameters. Clinical findings included stained fur, and discolored feces and urine of exposed animals, presumably due to the parent compound or its metabolites. Hyperplasia of the mucosal epithelium was observed in the cecum and colon of male and female rats that received 50,000 ppm. 13-WEEK STUDY IN MICE: Groups of 10 male and 10 female B6C3F1 mice were fed diets containing 0,1,000, 5,000,10,000, 25,000, or 50,000 ppm turmeric oleoresin. There were no deaths attributed to turmeric oleoresin and the final mean body weight gains and final mean body weights of all exposed groups of male and female mice were similar to those of the controls. Feed consumption by exposed male and female mice was similar to that by the controls. Dietary levels of 1,000, 5,000,10,000, 25,000, or 50,000 ppm turmeric oleoresin were estimated to deliver average daily doses of 150, 750, 1,700, 3,850, or 7,700 mg/kg body weight to males and 200, 1,000, 1,800, 4,700 or 9,300 mg/kg to females. Absolute and relative liver weights of male mice that received 5,000 ppm and male and female mice that received 10,000, 25,000 and 50,000 ppm were significantly greater than those of the controls. Clinical findings in mice included stained fur, and discolored feces and urine. There were no biologically significant differences in hematologic, clinical chemistry, or urinalysis parameters, and there were no chemical related histopathologic lesions. 2-YEAR STUDY IN RATS: The exposure level selection for the 2-year study was based on the 13-week study, which showed that rats could tolerate diets containing up to 50,000 ppm. Groups of 60 male and 60 female F344/N rats were fed diets containing 2,000, 10,000, or 50,000 ppm turmeric oleoresin for 104 (males) or 103 (females) weeks, which were estimated to deliver average daily doses of 80, 460, or 2,000 mg/kg to males and 90, 440, or 2,400 mg/kg to females. Nine or 10 rats from each exposure group were evaluated after 15 months. Survival, Mean Body Weights, Feed Consumption, and Clinical Findings: Survival of exposed male and female rats was similar to that of the controls (male: O ppm, 18/50; 2,000 ppm, 17/50; 10,000 ppm, 15/50; 50,000 ppm, 17/50; female: 33/50, 27/50, 28/50, 34/50). Th50, 28/50, 34/50). The final mean body weights of all exposed male rats and female rats receiving 2,000 and 10,000 ppm were similar to those of the controls. The final mean body weights of male and female rats that received 50,000 ppm were slightly lower (up to 10%) than those of the controls throughout much of the study. Feed consumption by exposed male and female rats was similar to that by controls throughout the study. The absolute and relative liver weights of female rats receiving 10,000 or 50,000 ppm were significantly greater than those of controls at the 15-month interim evaluation. There were no clinical findings related to toxicity. Hematology and Clinical Chemistry: In male and female rats receiving 50,000 ppm the hematocrit values, hemoglobin concentrations, and erythrocyte counts at the 15-month interim evaluation were significantly lower than those in the controls. In addition, platelet counts in male and female rats that received 50,000 ppm and reticulocyte counts in male rats that received 50,000 ppm were significantly higher than those in the controls. No biologically significant differences were observed in clinical chemistry parameters. Pathology Findings: Chemical-related nonneoplastic lesions occurred in the gastrointestinal tract of rats that received 50,000 ppm. Males receiving 50,000 ppm had increased incidences of ulcers, hyperplasia, and hyperkeratosis of the forestomach. Male and female rats that received 50,000 ppm had ulcers, chronic active inflammation, and hyperplasia of the cecum. Similar lesions also occurred in the colon of males receiving 50,000 ppm. Male and female rats that received 50,000 ppm and male rats that received 10,000 ppm had significantly increased incidences of sinus ectasia of the mesenteric Iymph node. The incidences of clitoral gland adenoma in all exposed groups of female rats were significantly increased. Clitoral gland carcinomas occurred in one control female and in four 2,000 ppm females, but not in females that received 10,000 or 50,000 ppm. The incidences of clitoral gland adenoma or carcinoma (combined) in all exposed groups of female rats were similar (6/50, 16/48, 15/47, 16/49) and did not increase with exposure level. The incidence of clitoral gland hyperplasia was similar among exposed and control groups of female rats (7/50, 5/48, 4/47, 7149). 2-YEAR STUDY IN MICE: The exposure level selection for the 2-year study was based on the 13-week study, which showed that mice could tolerate diets containing up to 50,000 ppm. Groups of 60 male and 60 female B6C3F1 mice were fed diets containing 2,000, 10,000, or 50,000 ppm turmeric oleoresin for 103 weeks, which were estimated to deliver average daily doses of 220, 520, or 6,000 mg/kg to males and 320,1,620, or 8,400 mg/kg to females. Nine or 10 mice from each exposure group were evaluated after 15 months. Survival, Mean Body Weights, Feed Consumption, and Clinical Findings: Survival of exposed male and female mice was similar to that of the controls (male: O ppm, 43/50; 2,000 ppm, 43/50; 10,000 ppm, 37/50; 50,000 ppm 42/50; female: 39/50, 41/50, 34/50, 42/50). The mean body weight of female mice receiving 50,000 ppm was slightly lower (up to 12%) than that of the controls from about week 25. The final mean body weights of males that received 50,000 ppm and females that received 10,000 and 50,000 ppm were significantly lower than those of controls. The final mean body weights of other exposed groups of male and female mice were similar to those of the controls. Feed consumption by exposed male and female mice was similar to that by the controls throughout the study. The absolute and relative liver weights of male and female mice receiving 10,000 and 50,000 ppm were significantly greater than those of the controls at the l5-month interim evaluation. There were no clinical findings related to toxicity. Hematology and Clinical Chemistry: No biologically significant differences were observed in hematologic parameters. The alkaline phosphatase values of male and female mice that received 10,000 and 50,000 ppm were significantly higher than those of controls at the 15-month interim evaluation. Pathology Findings: The incidences of hepatocellular adenoma in male and female mice receiving 10,000 ppm, but not those in mice receiving 2,000 or 50,000 ppm, were significantly increased (male: 25/50, 28/50, 35/50, 30/50; female: 7/50, 8/50, 19/51, 14/50). The number of male and female mice in the 10,000 and 50,000 ppm groups with multiple hepatocellular neoplasms was significantly greater than that in the controls. The incidences of hepatocellular carcinoma were similar among exposed and control groups. In contrast to rats, there were no chemical-related nonneoplastic lesions of the gastrointestinal tract in mice. Three males that received 2,000 ppm and three males that received 10,000 ppm had carcinomas of the small intestine; neoplasms of the small intestine were not observed in control males or in males that received 50,000 ppm. Female mice receiving 50,000 ppm had a significantly increased incidence of thyroid gland follicular cell hyperplasia. GENETIC TOXICOLOGY: Turmeric oleoresin was not mutagenic in Salmonella typhimurium strains TA100, TA1535, TA1537, or TA98 with or without exogenous metabolic activation (S9). It induced small but significant increases in sister chromatid exchanges and chromosomal aberrations in cultured Chinese hamster ovary cells. The positive response in the sister chromatid exchange test occurred in the presence of S9, whereas the aberrations response occurred without S9. CONCLUSIONS: Under the conditions of these 2-year feed studies, there was no evidence of carcinogenic activity of turmeric oleoresin in male F344/N rats administered 2,000, 10,000, or 50,000 ppm. There was equivocal evidence of carcinogenic activity of turmeric oleoresin in female F344/N rats based on increased incidences of clitoral gland adenomas in the exposed groups. There was equivocal evidence of carcinogenic activity of turmeric oleoresin in male B6C3F1 mice based on a marginally increased incidence of hepatocellular adenoma at the 10,000 ppm level, and the occurrence of carcinomas of the small intestine in the 2,000 and 10,000 ppm groups. There was equivocal evidence of carcinogenic activity of turmeric oleoresin in female B6C3F1 mice based on an increased incidence of hepatocellular adenomas in the 10,000 ppm group. Turmeric oleoresin ingestion was also associated with increased incidences of ulcers, hyperplasia, and inflammation of the forestomach, cecum, and colon in male rats and of the cecum in female rats. In female mice, ingestion of diets containing turmeric oleoresin was also associated with an increased incidence of thyroid gland follicular cell hyperplasia. Synonyms for Turmeric Oleoresin: curcuma oil; oil of turmeric; turmeric oil; curcuma longa oils; curcuma long oil; Curcumin Synonyms for Curcumin: 1,7-Bis(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dione; C.I. Natural Yellow 3; C.I. 75300; Curcuma; diferuloylmethane; E 100; Haidr; Halad; Haldar; Halud; HSDB 4334; Indian Saffron; kacha haldi; Kurkumin; merita earth; Souchet; Turmeric Yellow; yellow ginger; yellow root; Yo-kin; Zlut Prirodni 3; NCI-C613253