Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: UMLS:C0019204 (hepatocellular carcinoma)
71,386 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Methylphenidate hydrochloride is a drug used in the treatment of narcolepsy and attention deficit hyperactivity disorders. This drug was nominated for study by the Food and Drug Administration and the National Cancer Institute because of its widespread use in human medicine and because of lack of data on its potential carcinogenicity. Oral administration is the most common route of human exposure. Toxicology and carcinogenicity studies were conducted by administering methylphenidate hydrochloride (USP grade) ad libitum in feed to groups of male and female F344/N rats and B6C3F1, mice for 14 days, 13 weeks, or 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium and in cultured Chinese hamster ovary cells. 14-DAY STUDY IN RATS: Groups of five male and five female F344/N rats were fed diets containing 0, 16, 62, 250, 1,000, or 4,000 ppm methylphenidate hydrochloride for 14 days. All rats survived to the end of the study. The final mean body weights of 4,000 ppm male and female rats were 9% lower than those of the controls. Absolute and relative liver weights of 4,000 ppm males and females were significantly greater than those of the controls. Clinical findings during the first week of the study included hyperactivity in 4,000 ppm males and females, but these animals appeared to be normal during the second week of treatment. No treatment-related gross lesions were observed; however, centrilobular hypertrophy was observed in 4,000 ppm males and females. 14-DAY STUDY IN MICE: Groups of five male and five female B6C3F1, mice were fed diets containing 0, 16, 62, 250, 1,000, or 4,000 ppm methylphenidate hydrochloride for 14 days. Three 4,000 ppm males died during the second week of the study; all other mice survived to the end of the study. The final mean body weight of 4,000 ppm females was 11% lower than that of the controls, and the mean body weight gains of 1,000 and 4,000 ppm males and females were also significantly lower than those of the controls. Absolute and relative liver weights of all exposed groups of males and of 4,000 ppm females were significantly greater than those of the controls. Hyperactivity was observed during the second week of the study in some 4,000 ppm males. Degeneration and necrosis of the renal tubule epithelium were observed in two 4,000 ppm males. Hepatocellular hypertrophy was observed in males and females exposed to 1,000 or 4,000 ppm and in males exposed to 250 ppm. 13-WEEK STUDY IN RATS: Groups of 10 male and 10 female F344/N rats were fed diets containing 0, 125, 250, 500, 1,000, or 2,000 ppm methylphenidate hydrochloride for 13 weeks. There were no chemical-related effects on survival. Mean body weight gains of 500, 1,000, and 2,000 ppm males and females and of 250 ppm females were significantly lower than those of the controls. Final mean body weights of exposed males and females were similar to those of the controls. During the first week of the study, feed consumption by 2,000 ppm rats was less than that by controls, but during the remainder of the study feed consumption by exposed and control groups was similar. Rats exposed to 125, 250, 500, 1,000, or 2,000 ppm received approximate doses of 8, 15, 30, 70, or 130 mg methylphenidate hydrochloride per kilogram body weight per day (males) or 9, 18, 30, 70, or 150 mg/kg per day (females). Clinical findings in 1,000 and 2,000 ppm females included slight hypersensitivity to touch, hyperactivity, and increased vocalization during handling periods. Absolute and relative liver weights of 2,000 ppm males and females were significantly greater than those of the controls, as were the relative liver weights of 1,000 ppm males and females. No chemical-related differences in bone length, bone density, or nose-to-rump lengths were noted in males or females, nor were there treatment related histopathologic lesions. 13-WEEK STUDY IN MICE: Groups of 10 male and 10 female B6C3F1, mice were fed diets containing 0, 125, 250, 500, 1,000, or 2,000 ppm methylphenidate hydrochloride for 13 weeks. There were no chemical-related effects on ed effects on survival. Final mean body weights of males exposed to 250, 500, 1,000, or 2,000 ppm and of 2,000 ppm females were significantly lower than those of the controls. The final mean body weights of other exposed male and female groups were similar to those of the controls. During the first week of the study, feed consumption by 2,000 ppm mice was less than that by controls; feed consumption by exposed groups was similar to that by the controls throughout the remainder of the study. Mice exposed to 125, 250, 500, 1,000, or 2,000 ppm received approximate doses of 15, 30, 70, 115, or 230 mg/kg per day (males) or 15, 30, 70, 125, or 260 mg/kg per day (females). No chemical-related clinical findings were observed. Absolute and relative liver weights of 1,000 and 2,000 ppm males and females were significantly greater than those of the controls, as were the relative liver weights of 125, 250, and 500 ppm males. Centrilobular hypertrophy and hepatocellular degeneration or necrosis were observed in males exposed to 500, 1,000, or 2,000 ppm methylphenidate hydrochloride. 2-YEAR STUDY IN RATS: Based on the increased liver weights and lower body weight gains in 2,000 ppm rats in the 13-week study, the high dose selected for the 2-year rat study was 1,000 ppm. Groups of 70 male and 70 female F344/N rats were fed diets containing 0, 100, 500, or 1,000 ppm methylphenidate hydrochloride for up to 2 years. As many as 10 male and 10 female rats per exposure group were evaluated at 9 or 15 months. Survival, Body Weights, Feed and Compound Consumption, and Clinical Findings: Survival of exposed rats was similar to that of the controls at the end of the study. Mean body weights of 500 and 1,000 ppm males were 3% to 10% lower than those of the controls from week 30 to the end of the study; during the same time period, mean body weights of 500 and 1,000 ppm females were 4% to 24% less than those of the controls. Final mean body weights of rats exposed to 100, 500, or 1,000 ppm were 102%, 95%, or 90% (males) and 96%, 89%, or 78% (females) those of the controls. Rats exposed to 100, 500, or 1,000 ppm methylphenidate hydrochloride in feed received approximate doses of 5, 25, or 50 mg/kg per day (males and females). The only chemical-related clinical finding was an increased incidence of fighting among group-housed males exposed to 1,000 ppm. Hematology and Clinical Chemistry: No biologically significant differences in hematology or clinical chemistry parameters occurred at 9 or 15 months. Pathology Findings: In female rats exposed to 500 or 1,000 ppm, the incidence of mammary gland fibroadenomas was decreased (0 ppm, 15/49; 100 ppm, 13/50; 500 ppm, 6/ 48; 1,000 ppm, 5/50), and the decrease was considered to be related to chemical administration. No significant chemical-related increases in neoplasm incidences were observed in male or female rats. 2-YEAR STUDY IN MICE: Based on the liver toxicity and lower body weight gains observed in 1,000 and 2,000 ppm mice in the 13-week study, the high dose selected for the 2-year study was 500 ppm. Groups of 70 male and 70 female B6C3F1 mice were fed diets containing 0, 50, 250, or 500 ppm methylphenidate hydrochloride for 2 years. As many as 10 male and 10 female mice per exposure group were evaluated at 9 or 15 months. Survival, Body Weights, Feed and Compound Consumption, and Clinical Findings: Survival of exposed mice was similar to that of the controls at the end of the study. Mean body weights of mice exposed to 250 or 500 ppm were 3% to 11% lower than those of the controls throughout much of the study; during the same time period, mean body weights of 250 ppm females were 3% to 7% lower than those of the controls. Final mean body weights of mice exposed to 50, 250, or 500 ppm were 97%, 89%, or 93% (males) and 98%, 93%, or 97% (females) that of the controls. Mice exposed to 50, 250, or 500 ppm methylphenidate hydrochloride in feed were estimated to have received 6, 30, or 60 mg/kg body weight per day (males) or 8, 40, or 80 mg/kg per day (females). There were no chemical related clinical findings. Hematology and Clinical Chemistry: No biologically significant differences in hematology or clinical chemistry parameters occurred at 9 or 15 months. Pathology Findings: The principal lesions associated with the administration of methylphenidate hydrochloride occurred in the liver. A few hepatocellular neoplasms were observed in control and exposed male mice at the 9-and 15-month interim evaluations, but the incidences in exposed groups were not significantly increased. At the end of the 2-year study, incidences of eosinophilic foci were increased in 500 ppm males and females. Increased incidences of hepatoblastoma occurred in 500 ppm males (0 ppm, 0/50; 50 ppm, 1/50; 250 ppm, 1/50; 500 ppm, 5/50). Increased incidences of hepatocellular adenoma also occurred in 500 ppm males (18/50, 18/50, 16/50, 29/50) and females (6/49, 10/48, 10/49, 28/50). The incidences of hepatocellular carcinoma were similar among control and exposed mice. GENETIC TOXICOLOGY: Methylphenidate hydrochloride was not mutagenic in Salmonella typhimurium strains TA97, TA98, TA100, TA1535, or TA1537, with or without exogenous metabolic activation (S9). Methylphenidate hydrochloride was also tested for induction of sister chromatid exchanges and chromosomal aberrations in cultured Chinese hamster ovary cells. In the chromosomal aberrations tests, positive results were not consistently dependent upon the presence or absence of S9 activation. Sister chromatid exchanges were not increased in the presence of S9, but one laboratory did obtain a positive response without S9 by testing higher doses than were used in tests With S9. CONCLUSIONS: Under the conditions of these 2-year feed studies, there was no evidence of carcinogenic activity of methylphenidate hydrochloride in male or female F344/ N rats receiving 100, 500, or 1,000 ppm. There was some evidence of carcinogenic activity of methylphenidate hydrochloride in male and female B6C3F1 mice based on the occurrence of hepatocellular neoplasms. Treatment of female rats with methylphenidate hydrochloride was associated with a decrease in the incidence of mammary gland fibroadenomas. Administration of methylphenidate hydrochloride to male and female mice resulted in increased incidences of eosinophilic foci. Synonyms: a-phenyl-2-piperidineacetic acid methyl ester hydrochloride; methylphenidylacetate hydrochloride; a-phenyl-a-(2-piperidyl)acetic acid methyl ester hydrochloride; methyl a-phenyl-a-(2-piperidyl)acetate hydrochloride
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PMID:NTP Toxicology and Carcinogenesis Studies of Methylphenidate Hydrochloride (CAS No. 298-59-9) in F344/N Rats and B6C3F1 Mice (Feed Studies). 1259 24

3,4-Dihydrocoumarin was nominated by the Food and Drug Administration and the National Cancer Institute for study because of its widespread use as a flavoring agent in beverages, gelatins, puddings, candy, and other food items; as a fragrance in perfumes, creams, and cosmetics; and because of interest in the structure-activity relationships of the coumarin derivatives. Toxicity and carcinogenicity studies were conducted by administering 3,4-dihydrocoumarin (99% pure) in corn oil by gavage to groups of male and female F344/N rats and B6C3F1 mice for 16 days, 13 weeks, and 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium, cultured Chinese hamster ovary cells, and peripheral blood cells of mice. 16-DAY STUDY IN RATS: Groups of five male and five female rats received 3,4-dihydrocoumarin in corn oil by gavage at doses of 0, 190, 375, 750, 1,500, or 3,000 mg/kg body weight 5 days per week for a total of 12 doses in a 16-day period. All male and female rats given 3,000 mg/kg, and four male rats and five female rats given 1,500 mg/kg died. Body weight gains and final mean body weights of rats receiving 190, 375, or 750 mg/kg were similar to those of the controls. There were no clinical findings of organ-specific toxicity or evidence of impaired blood coagulation. 16-DAY STUDY IN MICE: Groups of five male and five female mice received 3,4-dihydrocoumarin in corn oil by gavage at doses of 0, 140, 280, 560, 1,125, or 2,250 mg/kg body weight 5 days per week for a total of 12 doses in a 16-day period. All mice given 2,250 mg/kg died. Body weight gains and final mean body weights of mice receiving 140, 280, 560, and 1,125 mg/kg were similar to those of the controls. There were no clinical findings of organ-specific toxicity or evidence of impaired blood coagulation. 13-WEEK STUDY IN RATS: Groups of 10 male and 10 female rats received 3,4-dihydrocoumarin in corn oil by gavage at doses of 0, 75, 150, 300, 600, or 1,200 mg/kg body weight 5 days per week for 13 weeks. Two male rats and five female rats given 1,200 mg/kg died. The body weight gain and final mean body weight of male rats that received 1,200 mg/kg were significantly lower than those of the controls, but the final mean body weights of other dosed groups of male rats and all dosed groups of female rats were similar to or slightly greater than those of the controls. Platelet counts were significantly lower in males and females receiving 600 and 1,200 mg/kg and in females receiving 300 mg/kg. Hemoglobin and hematocrit values and erythrocyte counts were significantly lower in males that received 300 mg/kg or more. The absolute and relative liver and kidney weights of males and females receiving 600 and 1,200 mg/kg were significantly greater than those of the controls. Hepatocellular hypertrophy was observed in rats given 300, 600, and 1,200 mg/kg. The high dose selected for the 2-year study was 600 mg/kg, which was below the level at which mortality, lower final mean body weights, and treatment-related liver lesions were observed. 13-WEEK STUDY IN MICE: Groups of 10 male and 10 female mice received 3,4-dihydrocoumarin in corn oil by gavage at doses of 0, 100, 200, 400, 800, or 1,600 mg/kg body weight 5 days per week for 13 weeks. Eight male and five female mice receiving 1,600 mg/kg died. Deaths in other groups were attributed to dosing accidents. Final mean body weights of dosed male and female mice were similar to those of the controls, and there were no treatment-related changes in any hematologic parameters. The absolute and relative liver weights of males and females that received 1,600 mg/kg and the relative kidney weight of males that received 1,600 mg/kg were significantly greater than those of the controls. No treatment-related lesions were noted. The high dose selected for the 2-year study was 600 mg/kg, which was below the level at which mortality, lower final mean body weights, and treatment-related liver lesions were observed. 2-YEAR STUDY IN RATS: Groups of 60 male and 60 female rats received 3,4-dihydrocoumarin in corn oil by gavage at age at doses of 0, 150, 300, or 600 mg/kg body weight. After 15 months, up to 10 animals from each group were evaluated. Survival, Body Weights, and Clinical Findings: Survival rates of dosed male rats were lower than that of the controls (O mg/kg, 28/51; 150 mg/kg, 12/50; 300 mg/kg, 8/50; 600 mg/kg, 2/50) but survival rates of dosed female rats were similar to that of the controls (31/50, 21/51, 26/50, 23/51). The decreased survival in dosed male rats was attributed to a chemical-related increase in the severity of nephropathy. The final mean body weight of male rats receiving 600 mg/kg was lower than that of the controls, but the final mean body weights of other dosed groups of male rats and all dosed groups of female rats were similar to those of the controls. No clinical findings related to chemical administration were observed. Hematology and Clinical Chemistry: At the 15-month interim evaluation, the hemoglobin concentrations, mean erythrocyte volumes, or mean erythrocyte hemoglobin concentrations in the 300 and 600 mg/kg female rats were slightly, but significantly, lower than those of the controls. In males, only the hemoglobin concentration in the 600 mg/kg group was significantly lower. Serum levels of alkaline phosphatase, alanine aminotransferase, sorbitol dehydrogenase, or g-glutamyltransferase in the 300 and 600 mg/kg male rats were significantly higher than those in the controls. In females, alkaline phosphatase and g-glutamyltransferase levels were significantly higher in the 600 mg/kg group. Pathology Findings: The principal lesions associated with the administration of 3,4-dihydrocoumarin to rats occurred in the kidney and forestomach. There was a chemical related increase in the severity of nephropathy in all dosed male rats and in 300 and 600 mg/kg female rats. There was a corresponding increased incidence of parathyroid gland hyperplasia, probably as a result of compromised renal function. In the standard evaluation of single kidney sections, renal tubule adenomas were observed in one 150 and two 600 mg/kg males and one each in the control, 150, and 300 mg/kg females. Transitional cell carcinomas were also observed in two 600 mg/kg male rats. However, an extended evaluation of step sections identified significantly higher incidences of focal hyperplasia and adenoma in the 600 mg/kg males than in controls (hyperplasia: 0/50, 5/48, 6/47, 8/50; adenoma: 1/50,1/48, 3/47, 6/50). The incidence of forestomach ulcers in all groups of dosed male rats was significantly greater than that of the controls (4/47, 14/48, 20/50, 16/46). STOP-EXPOSURE EVALUATION: A group of 40 male rats received 600 mg/kg 3,4-dihydrocoumarin in corn oil by gavage for 9 months, when 20 of the animals were necropsied and evaluated. The remainder of the male rats received only the corn oil vehicle until they died or until the end of the study. Similarly, a group of 30 male rats received 600 mg/kg 3,4-dihydrocoumarin in corn oil by gavage for 15 months, when 10 of the rats were necropsied and evaluated. The remaining 20 rats received only corn oil until the end of the study. A group of 20 vehicle control male rats was necropsied at 9 months, and another 10 vehicle control male rats were necropsied at 15 months. The severity of nephropathy in male rats of the stop-exposure groups was significantly greater than that of males examined at the 9- and 15-month interim evaluations. This was expected because nephropathy is a progressive degenerative disease that naturally increases in severity with age. 2-YEAR STUDY IN MICE: Groups of 70 male and 70 female mice received 3,4-dihydrocoumarin in corn oil by gavage at doses of 0, 200, 400, or 800 mg/kg body weight. After 15 months, five to 10 animals from each group were evaluated. Additional groups of 8 to 10 animals were evaluated for clinical pathology after 15 months. Survival, Body Weights, and Clinical Findings Survival rates of dosed male and female mice were similar to those of the controls (males: O mg/kg, 42/50; 200 mg/kg, 39/51; 400 mg/kg, 34/51; 800 mg/kg, 38/50; females: 36/51, 39/50, 41/50, 28/52). Final mean body weights of dosed male and female mice were similar to those of the controls. No clinical findings were noted that were related to chemical administration. Hematology and Clinical Chemistry: There were no differences in hematology or clinical chemistry parameters that were considered to be chemical related. Pathology Findings: The principal neoplasms associated with the administration of 3,4-dihydrocoumarin to mice occurred in the liver. There were significantly increased incidences of hepatocellular adenomas in all groups of dosed female mice. Further, the incidences of multiple hepatocellular adenomas in dosed female mice were greater than that of the controls (control, 0/51; 200 mg/kg, 6/50; 400 mg/kg, 9/50; 800 mg/kg, 9/52). However, there was no corresponding increased incidence of hepatocellular carcinoma in dosed female mice (3/51, 2/50, 4/50, 6/52), and the incidences of hepatocellular adenoma or carcinoma were similar between dosed and control male groups (adenoma: 29/50, 23/51, 36/51, 31/50; carcinoma: 11/50, 11/51, 11/51, 6/50). The incidence of alveolar/bronchiolar adenoma in the 200 and 400 mg/kg male mice was marginally greater than that of the controls (8/50,15/50,15/51,10/50). However, these neoplasms were not considered chemical related because the increased incidence was slight and there was no corresponding increased incidence in the 800 mg/kg group. The incidence of alveolar/bronchiolar neoplasms in female mice was similar between the dosed and control groups (adenoma: 2/51, 5/50, 1/48, 3/51; carcinoma: 0/51, 1/50, 0/48, 0/51). In the standard evaluation of single sections of kidney, focal hyperplasia and adenoma or carcinoma of the renal tubule were identified in several dosed male mice, but not in controls [adenoma or carcinoma (combined): 0/50,1/51, 2/51,1/49; hyperplasia: 2/50, 2/51, 5/51, 2/49]. In an extended evaluation of step sections, a few additional males with focal hyperplasia or renal tubule adenomas were identified in the dosed groups. However, the incidences of these lesions in dosed groups of male mice were not significantly greater than those of the controls, and did not increase with dose (hyperplasia: 0/50,1/51, 3/51, 1/49; renal tubule adenoma: 0/50, 0/51, 2/51, 1/49). Therefore, the low number of renal tubule neoplasms in male mice was not considered to be chemical related. GENETIC TOXICOLOGY: 3,4-Dihydrocoumarin did not induce gene mutations in Salmonella typhimurium strains TA98, TA100, TA1535, or TA1537 with or without exogenous metabolic activation (S9). It induced sister chromatid exchanges but not chromosomal aberrations in cultured Chinese hamster ovary cells, with and without S9. No induction of micronuclei was noted in peripheral blood erythrocyte samples obtained from male and female B6C3F1 mice at the end of the 13-week toxicology study. CONCLUSIONS: Under the conditions of these 2-year gavage studies, there was some evidence of carcinogenic activity of 3,4-dihydrocoumarin in male F344/N rats based on increased incidences of renal tubule adenomas and focal hyperplasia. The transitional cell carcinomas in two 600 mg/kg males may also have been chemical related. There was no evidence of carcinogenic activity of 3,4-dihydrocoumarin in female F344/N rats receiving 150, 300, or 600 mg/kg. There was no evidence of carcinogenic activity of 3,4-dihydrocoumarin in male B6C3F1 mice receiving 200, 400, or 800 mg/kg. There was some evidence of carcinogenic activity in female B6C3F1 mice based on increased incidences of hepatocellular adenoma and hepatocellular adenoma or carcinoma (combined). 3,4-Dihydrocoumarin caused ulcers, hyperplasia, and inflammation of the forestomach, parathyroid gland hyperplasia, and increased severity of nephropathy in male rats. Synonyms: 1,2-benzodihydropyrone, 2H-1-benzopyran-2-one, 2-chromanone, 3,4-dihydro-2H-1-benzopyran-2-one, dihydrocoumarin, hydrocoumarin, o-hydroycinnamic acid, delta-lactone-hydrocinnamic acid, melilotin, melilotine, melilotol, 2-oxochroman
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PMID:NTP Toxicology and Carcinogenesis Studies of 3,4-Dihydrocoumarin (CAS No. 119-84-6) in F344/N Rats and B6C3F1 Mice (Gavage Studies). 1261 88

C.I. Direct Blue 218 is a copper chelated dye used for cellulose, acetate, nylon, silk, wool, tissue, papers, and textile goods with a urea-formaldehyde finish. C.I. Direct Blue 218 is one of five chemicals/dyes that are part of the National Toxicology Program's Benzidine Dye Initiative, established to determine the toxicity and carcinogenicity of representative benzidine congeners, congener-derived dyes, and benzidine-derived dyes. Industrial grade C.I. Direct Blue 218 was selected for study because of its widespread use. Because of the high salt content, the dye was desalted prior to use. Toxicology and carcinogenesis studies were conducted by administering C.I. Direct Blue 218 in feed to groups of male and female F344/N rats and B6C3F1 mice for 14 days, 13 weeks, and 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium, cultured Chinese hamster ovary cells, and Drosophila melanogaster. 14-DAY STUDY IN RATS: Groups of five male and five female F344/N rats were fed diets containing 0, 1,000, 3,000, 7,000, 15,000, or 30,000 ppm C.I. Direct Blue 218. All rats survived until the end of the study. Rats receiving 30,000 ppm lost weight, and the mean body weight gain of males receiving 15,000 ppm was significantly lower than that of the controls. Feed consumption by rats receiving 30,000 ppm was lower than that by the controls. Decreased organ weights at the 30,000 ppm level were related to the decreased body weights at this exposure level. 14-DAY STUDY IN MICE: Groups of five male and five female mice were fed diets containing 0, 1,000, 3,000, 7,000, 15,000, or 30,000 ppm C.I. Direct Blue 218. All mice survived until the end of the study. The final mean body weight of males receiving 30,000 ppm was 25% lower than that of controls and that of 30,000 ppm females was 20% lower than that of controls. Feed consumption by exposed and control groups was similar except for the 15,000 and 30,000 ppm groups. Feed spillage, due to reduced palatability, precluded the accurate determination of feed consumption by these two groups. Male and female mice receiving 30,000 ppm appeared hyperactive and emaciated during the last week of the study. Decreased organ weights were noted at 30,000 ppm and were attributed to the decreased mean body weights at this exposure level. 13-WEEK STUDY IN RATS: Groups of 10 male and 10 female rats were fed diets containing 0, 3,000, 10,000, or 20,000 ppm C.I. Direct Blue 218. All male and female rats survived until the end of the study. Rats exposed to 3,000,10,000, or 20,000 ppm C.I. Direct Blue 218 received approximate daily doses of 200, 600 or 1,300 mg dye/kg body weight (males) and 200, 800, or 1,400 mg/kg (females). The final mean body weight of male rats receiving 20,000 ppm was 24% lower than that of the controls and the final mean body weight of female rats receiving 20,000 ppm was 15% lower than that of the controls. Feed consumption by exposed and control groups was similar except in the 20,000 ppm groups where feed spillage was noted. Absolute and relative kidney weights of rats receiving 10,000 or 20,000 ppm were significantly greater than those of controls. Significantly decreased organ weights were noted, particularly in the 20,000 ppm groups, and were attributed to the lower mean body weights at this exposure level. The hematocrit, hemoglobin, mean erythrocyte volume, and mean erythrocyte hemoglobin values in male and female rats receiving 10,000 and 20,000 ppm were significantly lower than those of controls. Serum levels of alanine aminotransferase and sorbitol dehydrogenase in male and female rats receiving 20,000 ppm were significantly higher than those of controls, which is consistent with hepatocellular injury. Male rats receiving 10,000 ppm and male and female rats receiving 20,000 ppm had hepatic lesions consisting of intracytoplasmic pigment in periportal Kupffer cells, minimal to mild individual hepatocyte necrosis, increased numbers of binucleated and multinucleated hepatocytes, and minimal bile duct hyperplasia. Male and female rats receiving 20,000 ppm had ys receiving 20,000 ppm had yellow-green pigment within the cytoplasm of proximal convoluted tubules of the kidney. Microconcretions of mineral were observed along the corticomedullary junction of the kidney in most female rats, but the numbers of microconcretions in kidney sections were increased in females that received 20,000 ppm. 13-WEEK STUDY IN MICE: Groups of 10 male and 10 female B6C3F1 mice were fed diets containing 0, 3,000, 10,000, or 20,000 ppm C.I. Direct Blue 218. There were no deaths attributed to C.I. Direct Blue 218. Mice exposed to 3,000, 10,000, or 20,000 ppm C.I. Direct Blue 218 received approximate daily doses of 400, 1,500, or 3,600 mg dye/kg body weight (males) and 400, 1,800, or 4,000 mg/kg (females). The final mean body weight of males that received 20,000 ppm was 24% lower than that of the controls, and the final mean body weight of females that received 20,000 ppm was 14% lower than that of controls. Feed consumption by exposed mice was similar to that by controls except in the 20,000 ppm groups where feed spillage was noted. Significant differences in organ weights were noted at 20,000 ppm which were attributed primarily to the lower mean body weights in these exposure groups. The hematocrit, hemoglobin, mean erythrocyte volume, and mean erythrocyte volume, and mean erythrocyte hemoglobin values were significantly lower in males and females receiving 10,000 and 20,000 ppm. Serum levels of alanine aminotransferase and sorbitol dehydrogenase in male and female mice receiving 10,000 and 20,000 ppm were significantly higher than those of controls, indicating hepatic injury. Male and female mice receiving 20,000 ppm had hepatic lesions consisting of centrilobular hepatocyte hypertrophy and karyomegaly, multifocal individual hepatocyte necrosis, oval cell proliferation, and periportal Kupffer cells with intracytoplasmic pigment. Males and females receiving 20,000 ppm also had increased numbers of pigmented macrophages within the red pulp of the spleen. 2-YEAR STUDY IN RATS: The doses selected for the 2-year study of C.I. Direct Blue 218 were based on the lower final mean body weights and the occurrence of hepatic lesions in the 20,000 ppm groups in the 13-week study. Groups of 60 male and 60 female rats were fed diets containing 0, 1,000, 3,000, or 10,000 ppm C.I. Direct Blue 218 for 103 weeks. Nine or 10 rats from each group were evaluated after 15 months. Survival, Body Weights, Feed and Compound Consumption, and Clinical Findings: Survival of female rats receiving 10,000 ppm was slightly, but not significantly, lower than that of the controls. Mean body weights of male and female rats in the 10,000 ppm groups were approximately 5% to 14% lower than those of the controls after week 15, and the final mean body weights of male and female rats at this level were 11% and 9% lower than those of the controls, respectively. Feed consumption by exposed male and female rats was similar to that by the controls and was estimated to deliver daily doses of 40, 120, and 440 mg dye/kg body weight to males and 50, 140, and 470 mg/kg to females. No chemical-related clinical signs of toxicity were noted. Hematology and Clinical Chemistry: The hematocrit, hemoglobin, mean erythrocyte volume, and mean erythrocyte hemoglobin values in 10,000 ppm female rats were significantly lower than those of controls, while in males only the mean erythrocyte hemoglobin value was significantly lower. Serum levels of alanine aminotransferase and sorbitol dehydrogenase in male and female rats receiving 10,000 ppm were significantly higher than those of the controls at the 15-month interim evaluation. Pathology Findings: Squamous cell papillomas of the oral mucosa (pharynx) occurred in five males receiving 10,000 ppm but not in the lower exposure groups or in controls. A squamous cell carcinoma occurred in one 10,000 ppm male and a benign basosquamous tumor was observed in another. The incidence of oral mucosal neoplasms in the 10,000 ppm males was significantly greater than that in controls and exceeded the range observed in untreated historical controls (lO/l,253, 0.8%; range 0%-4%). These neoplasms were considered chemical related. Administration of C.I. Direct Blue 218 to rats produced significantly increased incidences of forestomach basal cell hyperplasia in males receiving 3,000 or 10,000 ppm (0 ppm, 0/50; 1,000 ppm, 2/50; 3,000 ppm, 10/50;10,000 ppm, 19/50) and in females receiving 10,000 ppm (1/50, 1/49, 5/50, 11/49). Further, there were marginal increased incidences of focal squamous hyperplasia in the 3,000 and 10,000 ppm males (1/50,1/50, 6/50, 4/50). Squamous cell papillomas of the forestomach were seen in two 3,000 ppm males and in one 10,000 ppm male; no papillomas were observed in the controls. A squamous cell carcinoma was also seen in one 3,000 ppm male. Because of the uncommon occurrence of forestomach neoplasms in untreated control male rats (4/1,253, 0.3%; range 0%-2%) and the slight increase in the incidence of focal hyperplasia, these neoplasms may have been chemical related. The incidence of uterine endometrial stromal polyps in each exposed group of female rats was significantly greater than that of the controls (1/50,12/50,10/50, 10/50). Because the incidences in the exposed groups did not increase in a dose-related manner and the incidence in the controls was unusually low (historical incidence: 205/1,251,16.4%; range 2%-30%), the higher incidence of stromal polyps in the exposed groups was not considered chemical related. 2-YEAR STUDY IN MICE: The dose selection for the 2-year study was based on the lower final mean body weights and the liver lesions observed at the 20,000 ppm level in the 13-week study. Groups of 60 male and 60 female mice were fed diets containing 0, 1,000, 3,000, or 10,000 ppm C.I. Direct Blue 218 for 103 weeks. Nine or 10 mice from each exposure group were evaluated after 15 months. Survival, Body Weights, Feed and Compound Consumption, and Clinical Findings: Survival of exposed male and female mice was similar to that of the controls. Mean body weights of male and female mice receiving 10,000 ppm were 10% to 29% lower than those of the controls during most of the study, and the final mean body weights in these groups were 19% lower than that of the controls for males and 27% lower than that of the controls for females. Feed consumption by exposed mice was similar to that by controls and the diets were estimated to deliver daily doses of approximately 120, 360, and 1,520 mg of dye/kg body weight to males and 140, 470, and 2,050 mg/kg to females. No chemical-related clinical signs of toxicity were noted. Hematology and Clinical Chemistry: Hematocrit, hemoglobin, and mean erythrocyte volume values in males and females receiving 10,000 ppm were significantly lower than those of the controls. Serum levels of alanine aminotransferase and/or sorbitol dehydrogenase values in male and female mice that received 10,000 ppm were significantly higher than those of controls, which is consistent with hepatocellular damage. Pathology Findings: The administration of C.I. Direct Blue 218 to mice produced significantly increased incidences of hepatocellular adenoma (0 ppm, 16/50; 1,000 ppm, 19/50; 3,000 ppm, 17/50; 10,000 ppm, 40/50) and hepatocellular carcinoma (7/50, 3/50, 8/50,17/50) in males receiving 10,000 ppm, and a significantly increased incidence of hepatocellular adenoma in females receiving 3,000 or 10,000 ppm (7/49, 12/50, 17/49, 41/49). In females that received 10,000 ppm, the incidence of hepatocellular carcinoma was marginally increased. Consistent with these findings, the incidence of hepatocellular foci of cytologic alteration, a preneoplastic lesion, was also increased in males and females in the 10,000 ppm groups. The increased incidences of hepatocellular foci, adenomas, and carcinomas were considered chemical related. Uncommon renal tubule neoplasms also occurred at low incidences in male mice receiving C.I. Direct Blue 218, but not in controls. Renal tubule adenomas were seen in two males receiving 1,000 ppm, one male receiving 3,000 ppm, and one male receiving 10,000 ppm. A renal tubule carcinoma was also seen in one male that received 1,000 ppm. Because renal tubule neoplasms are uncommon in male mice (4/1,366, 0.3%; range 0%-2%), these neoplasms may have been chemical related. Carcinomas of the small intestine occurred in four male mice receiving 10,000 ppm. One was observed at the 15-month interim evaluation, while the other three were observed in mice at the end of the study. One control male mouse also had a carcinoma of the small intestine. Because of the uncommon occurrence of small intestine neoplasms in untreated male mice (12/1,374, 0.9%; range 0%-4%), the slightly higher incidence of these neoplasms in males receiving 10,000 ppm may have been chemical related. Carcinomas of the small intestine also occurred in one 3,000 ppm and one 10,000 ppm female, but the low incidences precluded drawing an association with chemical administration. GENETIC TOXICOLOGY: C.I Direct Blue 218 was not mutagenic in Salmonella typhimurium strains TA98, TA100, TA1535, or TA1537 tested with and without exogenous metabolic activation (S9). It was also tested in a modified Salmonella test protocol which employed reductive metabolism supplied by flavin mononucleotide or rat cecal bacteria, followed by oxidative metabolism; results of this test using strain TA1538 were also negative. C.I. Direct Blue 218 induced a small but significant increase in sister chromatid exchanges in Chinese hamster ovary cells at the highest dose tested without S9. No increase in chromosomal aberrations were observed in Chinese hamster ovary cells with or without S9. C.I. Direct Blue 218 did not induce sex-linked recessive lethal mutations in germ cells of male Drosophila melanogaster. CONCLUSIONS: Under the conditions of these 2-year feed studies, there was some evidence of carcinogenic activity of C.I. Direct Blue 218 in male F344/N rats based on the occurrence of pharyngeal neoplasms. Squamous cell neoplasms of the forestomach may have been chemical related. There was no evidence of carcinogenic activity of C.I Direct Blue 218 in female F344/N rats given 1,000, 3,000, or 10,000 ppm. There was clear evidence of carcinogenic activity of C.I. Direct Blue 218 in male and female B6C3F1 mice based on increased incidences of hepatocellular adenomas and carcinomas. The occurrence of a few neoplasms of the kidney and small intestine in male mice may have been related to C.I. Direct Blue 218 treatment. The administration of C.I. Direct Blue 218 produced an increased incidence of forestomach basal cell hyperplasia in rats and hepatocellular foci of cytologic alteration in mice. Synonyms: cuprate(4-), [mu-[(3,3'-dihydroxy[1,1'-biphenyl]-4,4'-diyl)bis[5-amino-4-hydroxy- 2,7-naphthalnedisulfonato]](8-)]]di-, tetrasodium; copper, [tetrahydrogen-3,3'-[(3,3'-dihydroxy-4,4'-biphenylylene)bis(azo)]bis [5-amino-4-hdroxy-2,7-naphthalenedisulfonato](4-)]di-, tetrasodium salt; 1-naphthol-3,6-disulfonic acid, 2,2'-(3,3'-dihydroxy-4,4'-biphenylylenebisazo)bis [8-amino-, dicopper deriv., tetrasodium salt
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PMID:NTP Toxicology and Carcinogenesis Studies of C.I. Direct Blue 218 (CAS No. 28407-37-6) in F344/N Rats and B6C3F1 Mice (Feed Studies). 1261 1

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
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PMID:NTP Toxicology and Carcinogenesis Studies of Turmeric Oleoresin (CAS No. 8024-37-1) (Major Component 79%-85% Curcumin, CAS No. 458-37-7) in F344/N Rats and B6C3F1 Mice (Feed Studies). 1261 4

Ethylene thiourea is a white crystalline solid used extensively in the rubber industry as an accelerator in the vulcanization of elastomers. It is also a trace contaminant and metabolic degradation product of a widely used class of ethylene bisdithiocarbamate fungicides. Ethylene thiourea is known to produce thyroid neoplasms in rats and liver neoplasms in mice following long-term administration; thus, it was chosen by the National Toxicology Program in an investigation of the potential value of perinatal exposures in assessing chemical carcinogenicity. Chronic toxicity and carcinogenicity studies of ethylene thiourea, 99% pure, were conducted in F344/N rats and B6C3F1 mice of each sex. The studies were designed to determine 1) the effects of ethylene thiourea in rats and mice receiving adult exposure only (a typical carcinogenicity study), 2) the toxic and carcinogenic effects of ethylene thiourea on rats and mice receiving perinatal exposure only (dietary exposure of dams prior to breeding and throughout gestation and lactation), and 3) the effects of combined perinatal and adult exposure to ethylene thiourea. STUDIES IN F344/N RATS: In a preliminary study to determine the perinatal dietary concentrations for the 2-year studies, female F344/N rats were fed 0, 8, 25, 83, or 250 ppm ethylene thiourea in the feed beginning 2 weeks prior to breeding and continuing throughout gestation and lactation, and the pups were fed at these same concentrations up to 9 weeks postweaning. Based on decreased survival of rat pups between postnatal days 0 to 4 and reduction in body weight gains in male weanling rats receiving 250 ppm, dietary concentrations of 0, 9, 30, and 90 ppm were selected for the perinatal (F0) exposure levels in the 2-year studies. Groups of 10 male and 10 female rats, 8 to 9 weeks of age, were fed diets containing 0, 60, 125, 250, 500, or 750 ppm ethylene thiourea for 13 weeks to determine the adult dietary concentrations. Because of reduced weight gains and decreased feed consumption in rats receiving 500 or 750 ppm ethylene thiourea, dietary concentrations of 0, 25, 83, and 250 ppm were selected for the adult (F1) exposure during the 2-year studies. In the 2-year studies, perinatal and adult exposures to ethylene thiourea were applied separately and together to groups of male or female rats as shown in the following table. The principal toxic effects of ethylene thiourea involved the thyroid gland. Serum levels of thyroxine (T4) and/or triiodothyronine (T3) were significantly decreased in rats receiving adult concentrations of 83 or 250 ppm, and thyrotropin (thyroid-stimulating hormone, TSH) was significantly increased at these concentrations. In male and female rats receiving adult-only exposure of 83 or 250 ppm, the incidences of follicular cell hyperplasia or follicular cell adenoma of the thyroid gland were significantly increased relative to the controls. The incidences of follicular cell carcinoma were significantly increased in the 250 ppm groups, and carcinomas occurred more frequently in males than in females. Exposure Groups of Rats in the 2-Year Feed Studies of Ethylene Thiourea a F1 Concentration (ppm)b F0(ppm)c 0 25 83 250 0 60 -- 60 60 9 -- 60 -- -- 30 -- -- 60 -- 90 60 -- 60 60 a Ten rats from each group were sacrificed and evaluated at 9 months b Concentration of ethylene thiourea in feed given to rats beginning at 8 weeks of age for 24 months c Concentration of ethylene thiourea in feed through breeding, gestation, and lactation until pups were 8 weeks of age Perinatal-only exposure to 90 ppm had no effect on the incidence of thyroid neoplasms in these studies, although there was a marginal increase in follicular cell hyperplasia relative to the controls. However, for groups of rats receiving combined perinatal and adult exposure (F0:F1), males and females receiving concentrations of 90:250 ppm ethylene thiourea had significantly increased incidences of thyroid follicular cell neoplasms relative to those receiving adult-only exposure to 250 ppm. Further, groups of male rats receiving 90:83 ppm 83 ppm showed a significantly increased incidence of follicular cell hyperplasia. Final mean body weights of males and survival of males and females receiving combined perinatal (90 ppm) and adult (250 ppm) exposure were lower than those receiving adult-only exposure of 250 ppm. Thus, in rats, combined perinatal and adult exposure slightly enhanced the toxicity and proliferative effects on the thyroid gland observed with adult-only exposure to ethylene thiourea. Neoplasms of the Zymbal's gland were marginally increased in rats receiving 90:250 ppm (males - 0:0, 1/50; 90:250, 5/50; females - 0:0, 1/50; 90:250, 4/50). Mononuclear cell leukemia occurred with a significant trend in groups of male and female rats receiving perinatal exposure of 90 ppm and increasing adult concentrations (90:0, 90:83, and 90:250 ppm), and for female rats without perinatal exposure (0:0, 0:83, and 0:250 ppm). The incidences of mononuclear cell leukemia in males receiving 90:83 ppm and males and females receiving 90:250 ppm were statistically significant relative to the respective 0:0 ppm groups. Low incidences of renal tubule cell adenomas occurred in most dose groups of male rats, but not in the highest dose group or the controls. STUDIES IN B6C3F1 MICE: In a preliminary study to determine the perinatal dietary concentrations for the 2-year studies, adult female C57BL/6N mice were fed 0, 33, 100, 330, or 1,000 ppm ethylene thiourea in the feed beginning 2 weeks prior to breeding and continuing throughout gestation and lactation and up to 9 weeks postweaning. Because of reduced survival of mouse pups at postnatal day 28 and lower final mean body weights in weanlings receiving perinatal exposure of 1,000 ppm, dietary concentrations of 0, 33, 110, and 330 ppm were selected for the perinatal exposure levels in the 2-year studies. Groups of 10 male and 10 female mice, 8 to 9 weeks of age, were fed diets containing 0, 125, 250, 500, 1,000, or 2,000 ppm ethylene thiourea for 13 weeks to determine the adult dietary concentrations. Moderately severe diffuse follicular cell hyperplasia in the thyroid gland and centrilobular cytomegaly of the liver occurred in mice receiving 2,000 ppm. Because the severity of the thyroid lesion (and degree of hypothyroidism) at this concentration was considered potentially life threatening in 2-year studies, dietary concentrations of 0, 100, 330, and 1,000 ppm ethylene thiourea were selected for adult exposure during the 2-year studies. In the 2-year studies, perinatal and adult exposures to ethylene thiourea were applied separately and together to groups of male or female mice as shown in the following table. Exposure Groups of Mice in the 2-Year Feed Studies of Ethylene Thiourea a F1 Concentration (ppm)b F0(ppm)c 0 100 330 1,000 0 69 -- 60 60 33 -- 34/29d -- -- 110 -- -- 60 -- 330 60 -- 60 60 a Ten mice from each group except the 33:100 ppm group were sacrificed and evaluated at 9 months b Concentration of ethylene thiourea in feed given to mice beginning at 8 weeks of age for 24 months c Concentration of ethylene thiourea in feed through breeding, gestation, and lactation until pups were 8 weeks of age d 34 males and 29 females assigned to group The principal toxic effects of ethylene thiourea in mice occurred in the thyroid gland, liver, and pituitary gland. Serum levels of T3 were significantly decreased in groups of mice receiving adult concentrations of 1,000 ppm; TSH was significantly increased in mice receiving 330 and 1,000 ppm. The incidences of follicular cell hyperplasia and neoplasia increased principally in males receiving 1,000 ppm and in females receiving 330 or 1,000 ppm. Follicular cell carcinomas were significantly increased in mice receiving 1,000 ppm. Incidences of centrilobular hepatocellular cytomegaly (males and females), hepatocellular adenoma (females), hepatocellular carcinoma (males and females), and adenoma or carcinoma combined (males and females) also were significantly increased in mice receiving F1 concentrations of 330 or 1,000 ppm. In the pituitary gland, incidences of focal hyperplasia (males) or adenoma (males and females) of the pars distalis were significantly increased in groups of mice receiving 1,000 ppm ethylene thiourea. Perinatal exposure to concentrations of 330 ppm had no effect on the incidences of nonneoplastic lesions or neoplasms in mice. For groups of mice receiving combined perinatal and adult exposure, females receiving F0:F1 concentrations of 330:330 ppm had significantly increased incidences of follicular cell adenoma relative to those receiving adult-only exposure to 330 ppm. Similarly, male mice receiving F0:F1 concentrations of 330:330 ppm had significantly increased incidences of follicular cell hyperplasia. Thus, in mice, perinatal exposure slightly enhanced the proliferative effects on the thyroid gland of adult exposure. There were no effects of perinatal exposure in mice at sites other than in the thyroid gland. CONCLUSIONS: 2-Year Adult-Only Exposure:Under the conditions of these 2-year adult-only dietary exposures, there was clear evidence of carcinogenic activity of ethylene thiourea in male and female F344/N rats, as shown by increased incidences of thyroid follicular cell neoplasms. There was clear evidence of carcinogenic activity of ethylene thiourea in male and female B6C3F1 mice as shown by increased incidences of thyroid follicular cell neoplasms, hepatocellular neoplasms, and adenomas of the pars distalis of the pituitary gland. Nonneoplastic lesions associated with the administration of ethylene thiourea included follicular cell hyperplasia in rats and mice and follicular cell cytoplasmic vacuolation, centrilobular hepatocellular cytomegaly, and focal hyperplasia of the pars distalis of the pituitary gland in mice. Other effects associated with the administration of ethylene thiourea included decreased serum levels of T4 and/or T3 in rats and increased serum levels of TSH in rats and mice. Perinatal-Only Exposure:Perinatal exposure alone had no effect on the incidences of neoplasms in rats or mice after 2 years. Animals may have been able to tolerate higher perinatal exposure concentrations. Combined Perinatal and 2-Year Adult Exposures:Combined perinatal and 2-year adult dietary exposure to ethylene thiourea confirmed the findings of the 2-year adult-only exposures for the incidences of neoplasms in the thyroid gland of rats and mice and the liver and pituitary gland of mice. In male and female rats, combined perinatal and adult exposure to 90:250 ppm was associated with marginal increases, relative to the untreated (0:0 ppm) controls, in Zymbal's gland neoplasms and mononuclear cell leukemia, which may have been related to chemical administration. In rats receiving adult exposure to 250 ppm ethylene thiourea, perinatal exposure to 90 ppm was associated with a slightly enhanced incidence of thyroid neoplasms compared to adult-only exposure. However, increasing perinatal exposure from 0 to 90 ppm had no effect on incidences of thyroid neoplasms in rats receiving adult exposure to 83 ppm. Increasing perinatal exposure from 0 to 330 ppm was associated with a marginally increased incidence of thyroid neoplasms in female mice receiving adult exposure to 330 ppm, but there were no enhancing effects of perinatal exposure in mice receiving adult exposure to 1,000 ppm. Synonyms: 2-Imidazolidinethione; Imidazoline-2-thiol; 2-mercaptoimidazoline; N,N'-ethylenethiourea; 1,3-ethylenethiourea; 2-imadazoline-2-thiol
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PMID:NTP Toxicology and Carcinogenesis Studies of Ethylene Thiourea (CAS: 96-45-7) in F344 Rats and B6C3F1 Mice (Feed Studies). 1263 71

Tetralin is used as an industrial solvent primarily for naphthalene, fats, resins, oils, and waxes; as a solvent and stabilizer for shoe polishes and floor waxes; as a solvent for pesticides, rubber, asphalt, and aromatic hydrocarbons (e.g., anthracene); as a dye solvent carrier in the textile industry; as a substitute for turpentine in lacquers, paints, and varnishes; in paint thinners and as a paint remover; in alkali-resistant lacquers for cleaning printing ink from rollers and type; as a constituent of motor fuels and lubricants; for the removal of naphthalene in gas distribution systems; and as an insecticide for clothes moths. Tetralin was nominated by the National Cancer Institute for carcinogenicity and disposition studies because of its structure, high production volume, and high potential for worker and consumer exposure. Male and female F344/N rats and B6C3F1 mice were exposed to tetralin (at least 97% pure) by inhalation for 2 weeks, 3 months, or 2 years; male NCI Black Reiter (NBR) rats were exposed to tetralin by inhalation for 2 weeks. Male NBR rats do not produce 2u-globulin; the NBR rats were included to study the relationship of 2u-globulin and renal lesion induction. Genetic toxicology studies were conducted in Salmonella typhimurium, Escherichia coli, and mouse peripheral blood erythrocytes. 2-WEEK STUDY IN RATS: Groups of five male (F344/N and NBR) and five female (F344/N) rats were exposed to tetralin at air concentrations of 0, 7.5, 15, 30, 60, or 120 ppm, 6 hours plus T90 (12 minutes) per day, 5 days per week for 12 exposures. All rats survived to the end of the studies. The final mean body weight of female rats exposed to 120 ppm and mean body weight gains of female rats exposed to 30 ppm or greater were significantly less than those of the chamber controls. Final mean body weights of exposed groups of male NBR rats and mean body weight gains of all exposed groups of male rats were significantly less than those of the chamber controls. Dark-stained urine was observed in all 120 ppm rats. Squinting, weeping, or matted fur around the eyes were noted in the majority of F344/N rats exposed to 120 ppm. The 2u-globulin concentrations in the kidney of male F344/N rats were significantly greater in all exposed groups than in the chamber control group. The absolute kidney weight of 60 ppm females and the relative kidney weights of male F344/N rats exposed to 30 ppm or greater and female rats exposed to 15 ppm or greater were significantly increased. The absolute liver weight of 120 ppm NBR male rats and the relative liver weights of male and female rats exposed to 60 or 120 ppm were significantly increased. In the nose, the incidences of mononuclear cell cellular infiltration were generally significantly increased in all exposed groups of rats, and incidences of olfactory epithelium degeneration and glandular hypertrophy occurred in all male F344/N rats exposed to 120 ppm. 2-WEEK STUDY IN MICE: Groups of five male and five female mice were exposed to tetralin at air concentrations of 0, 7.5, 15, 30, 60, or 120 ppm, 6 hours plus T90 (12 minutes) per day, 5 days per week for 13 exposures. All mice survived to the end of the study. Mean body weights of male and female mice were similar to those of the chamber controls. Dark-stained urine was observed in most of the exposed mice. The absolute and relative liver weights of 60 and 120 ppm males and 30 and 120 ppm females and the relative liver weights of 60 ppm females were significantly greater than those of the chamber controls. In the nose, the incidences of olfactory epithelium atrophy were significantly increased in 60 and 120 ppm males and females. Glandular dilatation occurred in all 120 ppm females, and glandular hyperplasia occurred in all 120 ppm males and females. 3-MONTH STUDY IN RATS: Groups of 10 male and 10 female rats were exposed to tetralin at air concentrations of 0, 7.5, 15, 30, 60, or 120 ppm, 6 hours plus T90 (12 minutes) per day, 5 days per week for 14 weeks. The same exposure concentrations were given to additional groups of 10 male and 10 female clinical pathology study rats for up to 6 weeks and five male renal toxicity rats for 2 weeks. All rats survived to the end of the study. During the first 4 weeks of exposure, dark-stained urine was observed in the catch pans of rats exposed to 30, 60, or 120 ppm. Tetralin induced a minimal decrease in the erythron in both sexes that resulted in a hematopoietic response. Tetralin increased urine aspartate aminotransferase and urine lactate dehydrogenase activities (males and females) and glucose/creatinine ratio (males), suggestive of renal injury. The absolute kidney weights of 60 and 120 ppm females and the relative kidney weights of males and females exposed to 15 ppm or greater were significantly greater than those of the chamber controls. Concentrations of 2u-globulin in the kidney of exposed male rats were generally greater than those of the chamber controls at all time points and greater at 6 and 14 weeks than at 2 weeks. There were significantly increased incidences of olfactory epithelium necrosis in rats exposed to 30 ppm or greater and of olfactory epithelium regeneration in 60 and 120 ppm rats. 3-MONTH STUDY IN MICE: Groups of 10 male and 10 female mice were exposed to tetralin at air concentrations of 0, 7.5, 15, 30, 60, or 120 ppm, 6 hours plus T90 (12 minutes) per day, 5 days per week for 14 weeks. All mice survived to the end of the study. Mean body weights of 120 ppm males were significantly less than those of the chamber controls. Dark-stained urine was observed in the catch pans of mice exposed to 30, 60, or 120 ppm during the first month of the study. Tetralin induced a minimal decrease in the erythron in both sexes that resulted in a hematopoietic response. The relative liver weights of 120 ppm males and 30 ppm or greater females were significantly greater than those of the chamber controls. Incidences of olfactory epithelium metaplasia in 60 and 120 ppm males and females, respiratory epithelium hyaline droplet accumulation in 120 ppm males and 60 and 120 ppm females, cytoplasmic eosinophilic granules within the transitional epithelium lining the urinary bladder in all exposed groups of males and females, and ovarian atrophy and uterine atrophy in 60 and 120 ppm females were significantly increased. 2-YEAR STUDY IN RATS: Groups of 50 male and 50 female rats were exposed to tetralin at air concentrations of 0, 30, 60, or 120 ppm, 6 hours plus T90 (12 minutes) per day, 5 days per week for 105 weeks. Additional groups of five male and five female rats were exposed to the same concentrations for 12 months. Survival of all exposed groups of rats was similar to that of the chamber controls. Mean body weights of 120 ppm females were 6% less than those of the chamber controls after week 29. Dark-stained urine was observed in all exposed groups of rats. Creatinine-adjusted levels of all urinary metabolites increased with increasing exposure concentration in males and females. In the standard evaluation of the kidney, there were slightly increased incidences of cortical renal tubule adenoma in male rats. In the combined analysis of single and step sections, the incidence of cortical renal tubule adenoma was significantly increased in the 120 ppm group. In the combined analysis, there was also a significantly increased incidence of renal tubule hyperplasia in the 120 ppm group. In 120 ppm males in the standard evaluation, the severity of chronic nephropathy was increased and the incidence of transitional epithelial hyperplasia in the renal pelvis was significantly increased. Three hepatocellular adenomas occurred in 120 ppm females, and one hepatocellular carcinoma each was observed in the 60 and 120 ppm groups. The incidences of uterine stromal polyp and endometrium hyperplasia were significantly increased in 120 ppm females. Incidences of interstitial cell adenoma and germinal epithelium atrophy of the testis in 30 and 120 ppm males were significantly greater than those in the chamber controls. The incidences of olfactory epithelium degeneration, metaplasia, basal cell hyperplasia, suppurative inflammation, and mineralization (except 30 ppm females) in the nose were significantly increased in all exposed groups of rats. The incidences of glandular dilatation were significantly increased in 120 ppm males and all exposed groups of females. The incidences of respiratory epithelium chronic inflammation were significantly increased in males exposed to 60 or 120 ppm and all exposed groups of females. The incidences of lens cataract in 120 ppm females were significantly increased. 2-YEAR STUDY IN MICE: Groups of 50 male and 50 female mice were exposed to tetralin at air concentrations of 0, 30, 60, or 120 ppm, 6 hours plus T90 (12 minutes) per day, 5 days per week for 105 weeks. Additional groups of five male and five female mice were exposed to the same concentrations for 12 months. Survival of 60 and 120 ppm female mice was significantly greater than that of the chamber controls. The mean body weights of all exposed groups of male and female mice were similar to those of the chamber controls by the end of the study. Dark-stained urine was observed in all exposed groups of male mice and in females exposed to 60 or 120 ppm. Creatinine-adjusted levels of all urinary metabolites increased with increasing exposure concentration in males and females. The incidence of hemangiosarcoma of the spleen was increased in 120 ppm females and exceeded the historical control range for inhalation studies. The incidences of olfactory epithelium atrophy, respiratory metaplasia, glandular hyperplasia, and suppurative inflammation in exposed groups of mice were significantly greater than those in the chamber controls. Transitional epithelium cytoplasmic eosinophilic granules were present in the urinary bladder of all exposed mice. (ABSTRACT TRUNCATED)
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PMID:Toxicology and carcinogenesis studies of tetralin (CAS No. 119-64-2) in F344/N rats and B6C3F1 mice (inhalation studies). 2168 56

Several essential oils contain pulegone and are used for flavoring foods, drinks, and dental products, as fragrance agents, and in herbal medicines. Pulegone was nominated for study by the National Institute of Environmental Health Sciences based on the potential for human exposure and the absence of carcinogenicity data. Male and female F344/N rats and B6C3F1 mice received pulegone (approximately 96% pure) by gavage for 2 weeks, 3 months, or 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium, Escherichia coli, and mouse peripheral blood erythrocytes. 2-WEEK STUDY IN RATS: Groups of five male and five female rats were administered 0, 37.5, 75, 150, 300, or 600 mg pulegone/kg body weight in corn oil by gavage, 5 days per week for 16 days. All male rats and nearly all female rats in the 300 and 600 mg/kg groups died prior to the end of the study. All moribund sacrifices and early deaths were attributed to liver toxicity. Mean body weight gains of males administered 37.5 or 150 mg/kg were significantly less than that of the vehicle controls. Clinical findings in 300 and 600 mg/kg rats included nasal/eye discharge, thinness, lethargy, and ruffled fur. Liver and kidney weights of dosed groups of females were generally significantly greater than those of the vehicle control group. The incidences of necrosis and cytoplasmic vacuolization of the liver in 300 and 600 mg/kg males and females were significantly greater than those in the vehicle control groups. 2-WEEK STUDY IN MICE: Groups of five male and five female mice were administered 0, 18.75, 37.5, 75, 150, or 300 mg pulegone/kg body weight in corn oil by gavage, 5 days per week for 16 days. Four females and one male in the 300 mg/kg groups died by study day 5. All early deaths were attributed to liver toxicity. Mean body weights of the dosed groups were similar to those of the vehicle controls. Clinical findings were observed only in 300 mg/kg mice and included thinness, lethargy, and ruffled fur. Liver weights of 300 mg/kg males were significantly greater than those of the vehicle controls. The incidences of cytoplasmic vacuolization and diffuse fatty change in 300 mg/kg females and necrosis in 300 mg/kg males were significantly greater than those in the vehicle controls. 3-MONTH STUDY IN RATS: Groups of 10 male and 10 female rats were administered 0, 9.375, 18.75, 37.5, 75, or 150 mg pulegone/kg body weight in corn oil by gavage, 5 days per week for 14 weeks. All rats survived until the end of the study except for one female in the 150 mg/kg group that died on day 9. Mean body weights of 75 and 150 mg/kg males and 150 mg/kg females were significantly less than those of the vehicle controls. At the end of the study, there was a small dose-related decrease in the erythron, evidenced by decreases in the hematocrit and hemoglobin values and the erythrocyte counts. An apparent erythroid response to the decreased erythron was evidenced by increased reticulocyte counts. Reduced and oxidized glutathione levels were generally increased in 75 and 150 mg/kg males and in 37.5 mg/kg or greater females. Absolute and relative liver weights of 75 and 150 mg/kg females and relative liver weights of males administered 18.75 mg/kg or greater were significantly greater than those of the vehicle controls. The absolute kidney weight of 150 mg/kg females and the relative kidney weights of all dosed groups, except 9.375 mg/kg males, were significantly greater than those of the vehicle controls. Absolute and relative thymus weights of 150 mg/kg males and females and the absolute thymus weight of 75 mg/kg males were significantly less than those of the vehicle controls. In the kidney, there was hyaline glomerulopathy in 75 mg/kg males and 150 mg/kg males and females. The incidence of renal tubule protein casts was significantly increased in the 150 mg/kg females. In the liver, incidences of bile duct hyperplasia and hepatocyte hypertrophy in 75 and 150 mg/kg males and 150 mg/kg females, hepatocyte focal necrosis in 150 mg/kg males, and oval cell hyperplasia and periportal fibrosis in 150 mg/kg males and females were increased. Incidences of bone marrow hyperplasia in 37.5 mg/kg males and 75 and 150 mg/kg males and females, heart mineralization in 150 mg/kg males, glandular stomach mineralization in 75 and 150 mg/kg females, and cellular histiocytic infiltration in the lung and ovarian cyst in 150 mg/kg females were significantly increased. 3-MONTH STUDY IN MICE: Groups of 10 male and 10 female mice were administered 0, 9.375, 18.75, 37.5, 75, or 150 mg pulegone/kg body weight in corn oil by gavage, 5 days per week for 14 weeks. All mice survived to the end of the study. Mean body weights of dosed mice were similar to those of the vehicle controls. Reduced and oxidized glutathione levels were generally greater than vehicle control levels in 150 mg/kg males and in 75 and 150 mg/kg females. Liver weights of 150 mg/kg males and 75 and 150 mg/kg females were significantly greater than those of the vehicle controls. No histopathologic lesions were observed that could be attributed to the administration of pulegone. 2-YEAR STUDY IN RATS: Groups of 50 male and 50 female rats were administered 0, 18.75 (males only), 37.5, 75, or 150 (females only) mg pulegone/kg body weight in corn oil by gavage, 5 days per week for up to 104 weeks. Due to excessive morbidity and mortality, 75 mg/kg males and 150 mg/kg females were not administered pulegone after week 60 (stop-exposure); these groups were administered the corn oil vehicle until the end of the study. Survival of 37.5 mg/kg males was significantly less than that of the vehicle controls; only two 75 mg/kg stop-exposure males survived, and no 150 mg/kg stop-exposure females survived to the end of the study. Compared to those of the vehicle controls, mean body weights were less in 75 mg/kg stop-exposure males after week 13 and in 75 mg/kg and 150 mg/kg stop-exposure females after weeks 21 and 9, respectively. Clinical findings included thinness, lethargy, and ruffled fur in the 75 mg/kg stop-exposure males and 150 mg/kg stop-exposure females. The incidences of urinary bladder papilloma and of papilloma or carcinoma (combined) were significantly increased in 150 mg/kg stop-exposure females. In the kidney, incidences of hyaline glomerulopathy were significantly increased in 37.5 mg/kg and 75 mg/kg stop-exposure males and in all dosed groups of females. The severity of chronic progressive nephropathy was increased in 37.5 mg/kg and 75 mg/kg stop-exposure males and in 75 mg/kg and 150 mg/kg stop-exposure females; the incidences of nephropathy were significantly increased in 75 mg/kg and 150 mg/kg stop-exposure females. The incidence of renal cyst was significantly increased in 75 mg/kg stop-exposure males. In the liver, incidences of diffuse hepatocyte cellular alteration were significantly increased in 37.5 mg/kg and 75 mg/kg stop-exposure males and 75 mg/kg and 150 mg/kg stop-exposure females. There were significant increases in the incidences of other liver lesions including fatty change, bile duct cyst, hepatocyte necrosis, oval cell hyperplasia, bile duct hyperplasia, and portal fibrosis. In the nose, 37.5 mg/kg and 75 mg/kg stop-exposure males and all dosed groups of females had significantly increased incidences of olfactory epithelium degeneration. All dosed groups of females had significantly increased incidences of respiratory metaplasia of the olfactory epithelium and nasal inflammation. In the forestomach, incidences of inflammation and ulcer were significantly increased in 37.5 mg/kg and 75 mg/kg stop-exposure males, and incidences of epithelial hyperplasia and perforation were increased in 75 mg/kg stop-exposure males. In the glandular stomach, the incidence of inflammation was significantly increased in 75 mg/kg stop-exposure males. 2-YEAR STUDY IN MICE: Groups of 50 male and 50 female mice were administered 0, 37.5, 75, or 150 mg pulegone/kg body weight in corn oil by gavage, 5 days per week for 105 weeks. Survival of all dosed groups was similar to that of the vehicle controls. Mean body weights of 150 mg/kg males and females were less than those of the vehicle controls after weeks 25 and 33, respectively. The incidences of multiple hepatocellular adenoma were significantly increased in all dosed groups of males, and the incidences of hepatocellular adenoma (includes multiple) and hepatoblastoma (includes multiple) were significantly increased in the 75 mg/kg males. The combined incidences of hepatocellular adenoma, hepatocellular carcinoma, or hepatoblastoma occurred with positive trends and were significantly increased in 75 mg/kg males and 150 mg/kg females. The incidence of hepatocellular adenoma was significantly increased in 150 mg/kg females. The incidences of several nonneoplastic liver lesions were significantly increased, primarily in the 75 and 150 mg/kg groups. These nonneoplastic lesions included clear cell, eosinophilic, and mixed cell foci; focal fatty change; centrilobular hepatocyte hypertrophy; intravascular hepatocyte; necrosis; pigmentation; bile duct cyst and hyperplasia; and oval cell hyperplasia. In the kidney, incidences of hyaline glomerulopathy were significantly increased in all dosed groups of males and 75 and 150 mg/kg females. The incidence of mineralization was significantly increased in 150 mg/kg females, and the incidence of nephropathy in 150 mg/kg females and severity of nephropathy in 150 mg/kg males were increased. Incidences of congestion of the glomerulus were increased in 150 mg/kg males and females. The incidence of osteoma or osteosarcoma (combined) in all organs of 75 mg/kg females exceeded the historical control ranges. One 150 mg/kg male and one 75 mg/kg female had nasal osteoma; no nasal osteomas have been observed in historical control mice. (ABSTRACT TRUNCATED)
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PMID:Toxicology and carcinogenesis studies of pulegone (CAS No. 89-82-7) in F344/N rats and B6C3F1 mice (gavage studies). 2192 62

N,N-dimethyl-p-toluidine was nominated for toxicology and carcinogenesis studies by the National Cancer Institute based on the potential for human exposure through its use in dental materials and bone cements and the lack of toxicity and carcinogenicity data. Male and female F344/N rats and B6C3F1/N mice were administered N,N-dimethyl-p-toluidine (greater than 99% pure) in corn oil by gavage for 3 months or 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium and Escherichia coli, mouse peripheral blood, and mouse and rat liver. 3-MONTH STUDY IN RATS: Groups of 10 male and 10 female rats were administered 0, 62.5, 125, 250, 500, or 1,000 mg N,N-dimethyl-p-toluidine/kg body weight in corn oil by gavage, 5 days per week for 14 weeks. Additional groups of 10 male and 10 female rats (clinical pathology study) were administered the same doses, 5 days per week for 25 days. On day 88, blood was collected from core study rats for hemoglobin and methemoglobin analyses only. All 1,000 mg/kg male and female rats and one 500 mg/kg male rat died by study day 3. Mean body weights of all surviving dosed groups of males and females were significantly less than those of the vehicle controls. Clinical findings associated with exposure to N,N-dimethyl-p-toluidine included cyanosis, abnormal breathing, and lethargy in groups administered 250 mg/kg or greater. Methemoglobinemia appeared to be the primary hematologic toxic response, and many other lesions could be explained as secondary to methemoglobin formation including Heinz body formation; a macrocytic, hypochromic, responsive anemia; and increased hematopoietic cell proliferation in the spleen and bone marrow. In general, hematologic changes were dose-related and occurred at both evaluated timepoints in all dosed groups. Anemia was evidenced by decreases in hematocrit values, hemoglobin concentrations, and erythrocyte counts; erythrocyte macrocytosis was characterized by increases in mean cell volume and mean cell hemoglobin values; erythrocyte hypochromia was evidenced by decreases in mean cell hemoglobin concentration values; and an erythropoietic response to the anemia was characterized by substantially increased reticulocyte and nucleated erythrocyte counts. Liver weights of all surviving dosed groups of males and females were significantly greater than those of the vehicle controls. Kidney weights of all surviving dosed groups of females were significantly greater than those of the vehicle controls. There were significant decreases in left cauda epididymis and left epididymis weights in 250 mg/kg males. There was a dose-related decrease in the number of cycling females, with only four females in the 250 mg/kg group having regular cycles and females in the 125 and 250 mg/kg groups spending a significantly higher proportion of time in extended diestrus compared to the vehicle control group. In the surviving groups of rats, there were significantly increased incidences of pigmentation in the liver of all dosed groups, hepatocyte hypertrophy in groups administered 125 mg/kg or greater, and hepatocyte necrosis in 62.5, 250, and 500 mg/kg females. In the olfactory epithelium of the nose, there were dose-related increases in the incidences and severities of degeneration in all dosed groups and significantly increased incidences of metaplasia in the 250 and 500 mg/kg groups. In the respiratory epithelium of the nose, there were significantly increased incidences of hyperplasia and squamous metaplasia in all of the groups administered 125 mg/kg or greater. The incidences of glandular hyperplasia of the nose were significantly increased in males and females administered 125, 250, or 500 mg/kg. In the spleen, there were significantly increased incidences of capsule fibrosis, congestion, mesothelial hypertrophy, and lymphoid follicle atrophy primarily in groups administered 125 mg/kg or greater. Hematopoietic cell proliferation and pigmentation were increased in severity in treated groups. In the kidney, there were significantly increased incidences of nephropathy (females), pigmentation (males and females), papillary necrosis (males and females), and mineralization (males). Other treatment-related lesions included inflammation of the forestomach in males, mesenteric lymph node atrophy in females, and bone marrow hyperplasia in males and females. 3-MONTH STUDY IN MICE: Groups of 10 male and 10 female mice were administered 0, 15, 30, 60, 125, or 250 mg N,N-dimethyl-p-toluidine/kg body weight in corn oil by gavage, 5 days per week for 14 weeks. All 250 mg/kg male and female mice (except for one male mouse) died before day 10, and three males and two females administered 125 mg/kg died before the end of the study. The final mean body weight of 125 mg/kg males and the mean body weight gains of 125 mg/kg males and females were significantly less than those of the vehicle controls. Clinical findings associated with administration of N,N-dimethyl-p-toluidine included abnormal breathing, thinness, lethargy, cyanosis, and ruffled fur in 125 and 250 mg/kg males and females. Methemoglobinemia appeared to be the primary hematologic toxic response; however there were less severe erythron changes compared to the 3-month study in rats. In females, no erythron changes were detected up to 125 mg/kg. In males, inconsistent and minor decreases in hematocrit values, hemoglobin concentrations, and erythrocyte counts, and increased reticulocyte counts occurred in groups administered 60 mg/kg or greater. Methemoglobin values were minimally increased in males and females administered 30 mg/kg or greater. Heinz bodies were slightly increased in 60 mg/kg females, 125 mg/kg males and females, and the one surviving 250 mg/kg male; Heinz body formation was considered secondary to methemoglobin formation. Liver weights of all dosed groups of mice were significantly greater than those of the vehicle controls. In the surviving groups of mice, there were significantly increased incidences of bronchiolar epithelium degeneration, bronchiolar epithelium regeneration, and peribronchiolar chronic active inflammation in the lung of 125 mg/kg groups, and histiocytic infiltrates of the alveoli in 125 mg/kg females. In the nose, there were significantly increased incidences of glandular hyperplasia and olfactory epithelium metaplasia in the 125 mg/kg groups and olfactory epithelium degeneration in 60 mg/kg females and 125 mg/kg males and females. In the thymus, the incidences of thymocyte necrosis in the 125 mg/kg groups were significantly increased. In the liver, the severities of cytoplasmic vacuolization of the hepatocytes were increased in dosed groups of males and females. 2-YEAR STUDY IN RATS: Groups of 50 male and 50 female rats were administered 0, 6, 20, or 60 mg N,N-dimethyl-p-toluidine/kg body weight in corn oil by gavage, 5 days per week for 104 or 105 weeks. Additional groups of 10 male and 10 female rats (clinical pathology study) were administered the same doses for 86 days. Survival of 60 mg/kg males was significantly less than that of the vehicle controls. Mean body weights of 60 mg/kg males and females were more than 10% less than those of the vehicle controls after week 61 and week 33, respectively. Clinical findings included signs of pallor in 60 mg/kg females and hyperactivity and boxing behavior in 20 mg/kg females and 60 mg/kg males and females. The hematology findings at the 3-month timepoint were consistent with those in the 3-month study in rats which indicated that methemoglobinemia was the primary hematologic toxic response. In the 20 and 60 mg/kg groups, there were dose-related decreases in hematocrit values, hemoglobin concentrations, and erythrocyte counts. There were similar trends toward erythrocyte macrocytosis and hypochromia and increased erythropoiesis as seen in the 3-month study. While the magnitudes of the erythron decreases were not sufficient to classify the responses as anemias, the patterns of the erythron changes were identical to those in the 3-month study. In the liver of 60 mg/kg males and females, there were significantly increased incidences of hepatocellular carcinoma and hepatocellular adenoma or hepatocellular carcinoma (combined). Numerous nonneoplastic liver lesions occurred in dosed males and females primarily in the 20 and 60 mg/kg groups. In the nose, there were significantly increased incidences of transitional epithelium adenoma and transitional epithelium adenoma or carcinoma (combined) in 60 mg/kg males; transitional epithelium adenoma also occurred in female rats administered 6 or 60 mg/kg. In the nose, there were significantly increased incidences of nonneoplastic lesions in the olfactory, respiratory, and transitional epithelia of dosed rats. These lesions occurred with the greatest incidence and severity in the 60 mg/kg groups. The incidences of inflammation and nerve atrophy were significantly increased in males and females administered 60 mg/kg. There were increased incidences of follicular cell adenoma or carcinoma (combined) of the thyroid gland in all dosed groups of males, and an increased incidence of follicular cell adenoma in 20 mg/kg females. In the spleen, there were significantly increased incidences of hematopoietic cell proliferation in all dosed groups of males and females. The incidences of congestion and mesothelial hypertrophy of the capsule were significantly increased in 60 mg/kg males and all dosed groups of females. There were also significantly increased incidences of capsular fibrosis and atrophy of the lymphoid follicle in the 60 mg/kg groups. The incidences of pigmentation were significantly increased in all dosed groups of males and in 60 mg/kg females. In all dosed groups of female rats, there were significantly increased incidences of nephropathy. (ABSTRACT TRUNCATED)
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PMID:Toxicology and carcinogenesis studies of N,N-dimethyl-p-toluidine (CAS No. 99-97-8) in F344/N rats and B6C3F1/N mice (gavage studies). 2302 99

Ginkgo biloba extract has been used primarily as a medicinal agent in the treatment or prevention of cardiovascular and cerebrovascular dysfunction. Ginkgo biloba extract was nominated for study by the National Cancer Institute because of its widespread use as an herbal supplement to promote mental function and the limited availability of toxicity and carcinogenicity data. Furthermore, one of the major ingredients in Ginkgo biloba extract, quercetin, is a known mutagen. The Ginkgo biloba extract used in the current studies was procured from a supplier known to provide material to United States companies and contained 31.2% flavonol glycosides, 15.4% terpene lactones (6.94% bilo-balide, 3.74% ginkgolide A, 1.62% ginkgolide B, 3.06% ginkgolide C), and 10.45 ppm ginkgolic acid. Male and female F344/N rats and B6C3F1/N mice were administered Ginkgo biloba extract in corn oil by gavage for 3 months or 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium, Escherichia coli, and mouse peripheral blood erythrocytes. 3-MONTH STUDY IN RATS: Groups of 10 male and 10 female rats were administered 0, 62.5, 125, 250, 500, or 1,000 mg Ginkgo biloba extract/kg body weight in corn oil by gavage, 5 days per week for 14 weeks. Additional groups of 10 male and 10 female rats (clinical pathology study) were administered the same doses, 5 days per week for 23 days. All rats survived to the end of the study. Mean body weights of all dosed groups were similar to those of the vehicle control groups. Liver weights of all dosed groups of males and females were significantly greater than those of the vehicle control groups. The incidences of hepatocyte hypertrophy in all dosed groups of males and in 500 and 1,000 mg/kg females were significantly greater than those in the vehicle control groups; there was a dose-related increase in severity of this lesion in males. Hepatocyte fatty change occurred in all dosed males. The incidences of thyroid gland follicular cell hypertrophy were significantly increased in 500 and 1,000 mg/kg males and in 1,000 mg/kg females. The incidences of pigmentation in the olfactory epithelium of the nose were significantly increased in 500 and 1,000 mg/kg males and in females administered 125 mg/kg or greater. 3-MONTH STUDY IN MICE: Groups of 10 male and 10 female mice were administered 0, 125, 250, 500, 1,000, or 2,000 mg Ginkgo biloba extract/kg body weight in corn oil by gavage, 5 days per week for 14 weeks. One female mouse in the 1,000 mg/kg group died of a dosing accident during week 11. Mean body weights of 2,000 mg/kg females were significantly less than those of the vehicle control group. Ruffled fur was observed in two 1,000 mg/kg males between weeks 7 and 8 and all 2,000 mg/kg males between weeks 5 and 9. Liver weights of 250 mg/kg or greater males and all dosed groups of females were significantly greater than those of the vehicle control groups. Kidney weights of 2,000 mg/kg males were significantly less than those of the vehicle control group. The Markov transition matrix analyses indicate female mice in the 2,000 mg/kg group had a significantly higher probability of extended estrus than did the vehicle control females. The incidences of hepatocytic hypertrophy were significantly increased in males and females in the 250 mg/kg or greater groups. Significantly increased incidences of focal hepatocytic necrosis occurred in 1,000 and 2,000 mg/kg males. The incidences of hyaline droplet accumulation in the respiratory epithelium of the nose were significantly increased in 500 mg/kg males and 1,000 and 2,000 mg/kg females. In the olfactory epithelium of the nose, the incidences of hyaline droplet accumulation were significantly increased in the 125 (female only), 500, and 1,000 mg/kg groups. Incidences of atrophy of the olfactory epithelium were significantly increased in the 1,000 mg/kg groups. The incidences of pigment accumulation in macrophages in the olfactory epithelium were significantly increased in males in the 500 mg/kg or greater groups and in 1,000 and 2,000 mg/kg females. 2-YEAR STUDY IN RATS: Groups of 50 male and 50 female rats were administered 0, 100, 300, or 1,000 mg Ginkgo biloba extract/kg body weight in corn oil by gavage, 5 days per week for 104 or 105 (females) weeks. Additional groups of 10 male and 10 female rats (special study) were administered the same doses, 5 days per week for 14 weeks. Survival of 1,000 mg/kg males was significantly less than that of the vehicle controls. At week 14, all dosed groups of males and 1,000 mg/kg females had increased levels of thyroid stimulating hormone compared to those of the vehicle control groups. There were no significant decreases in the levels of triiodothyronine or total thyroxine. Mean body weights of 300 mg/kg males and females were less (10% or more) than those of the vehicle controls after week 93, and those of 1,000 mg/kg males and females were less after week 89. Clinical findings included ruffled fur in seven, eight, and 10 males in the 100, 300, and 1,000 mg/kg groups, respectively, beginning at week 89; four vehicle control males also had ruffled fur. Liver weights were significantly increased in all dosed groups of special study rats at 14 weeks. In the liver at 2 years, incidences of hepatocellular adenoma were slightly increased in 100 and 300 mg/kg males. Significantly increased incidences of nonneoplastic lesions at 2 years included hepatocyte hypertrophy and bile duct hyperplasia in all dosed groups of males and females, focal fatty change in all dosed groups of females, cystic degeneration in 100 and 1,000 mg/kg males, and oval cell hyperplasia and necrosis in 1,000 mg/kg males. In the thyroid gland, incidences of follicular cell adenoma were slightly increased in 300 and 1,000 mg/kg males and 300 mg/kg females. Single incidences of follicular cell carcinoma occurred in the 300 and 1,000 mg/kg female groups. There were significantly increased incidences of follicular cell hypertrophy in all dosed groups of males and females and follicle hyperplasia in all dosed groups of males. In the nose, adenoma of the respiratory epithelium occurred in two females receiving 300 mg/kg. Except for respiratory epithelium hyperplasia in 100 mg/kg females, the incidences of transitional epithelium and respiratory epithelium hyperplasia were significantly increased in all dosed groups of males and females. Except for olfactory epithelium respiratory metaplasia in 100 mg/kg females, the incidences of atrophy, respiratory metaplasia, nerve atrophy, and pigmentation were significantly increased in the olfactory epithelium of all dosed groups of males and females. Incidences of goblet cell hyperplasia in the respiratory epithelium were significantly increased in 300 and 1,000 mg/kg males and females, and incidences of chronic active inflammation were significantly increased in 1,000 mg/kg males and females. The incidence of submucosa fibrosis was significantly increased in 1,000 mg/kg males. The incidences of mononuclear cell leukemia in 300 and 1,000 mg/kg males were significantly greater than that in the vehicle controls. Dose-related increased severity of kidney nephropathy was noted in all dosed groups of males. 2-YEAR STUDY IN MICE: Groups of 50 male and 50 female mice were administered 0, 200, 600, or 2,000 mg Ginkgo biloba extract/kg body weight in corn oil by gavage, 5 days per week for 104 weeks. Survival of 600 and 2,000 mg/kg males was significantly less than that of the vehicle controls; survival of 600 mg/kg females was significantly greater than that of the vehicle controls. Mean body weights of 600 and 2,000 mg/kg males were less (10% or more) than those of the vehicle controls after weeks 85 and 77, respectively; mean body weights of 2,000 mg/kg females were generally less than those of the vehicle controls between weeks 17 and 69 and after week 93. In the liver, there were significantly increased incidences of hepatocellular adenoma in all dosed groups of females, hepatocellular carcinoma in all dosed groups of males and 2,000 mg/kg females, and hepatoblastoma in all dosed groups of males and 600 and 2,000 mg/kg females. The increased incidences of these neoplasms were primarily due to increased incidences of multiple adenoma, carcinoma, and hepatoblastoma. Except for the incidences of hepatocellular carcinoma or hepatoblastoma (combined) in 200 and 600 mg/kg females, the incidences of hepatocellular adenoma or carcinoma (combined), hepatocellular carcinoma or hepatoblastoma (combined), and hepatocellular adenoma, hepatocellular carcinoma, or hepatoblastoma (combined) were significantly increased in all dosed groups of males and females. Significantly increased incidences of nonneoplastic liver lesions included hypertrophy in all dosed groups of males and females, erythrophagocytosis in all dosed groups of males and in 600 and 2,000 mg/kg females, hematopoietic cell proliferation, inflammation, and necrosis in 600 and 2,000 mg/kg males, and cytoplasmic vacuolization, eosinophilic focus, and mixed cell focus in all dosed groups of females. In the thyroid gland, two incidences each of follicular cell adenoma occurred in the 600 and 2,000 mg/kg male groups. The incidence of follicle hyperplasia was significantly increased in 2,000 mg/kg males, and the incidences of follicular cell hypertrophy were significantly increased in 2,000 mg/kg males and 600 and 2,000 mg/kg females. In the forestomach, the incidences of inflammation, epithelium hyperplasia, and epithelium hyperkeratosis were significantly increased in all dosed groups of males and in 2,000 mg/kg females; the incidences of epithelium ulcer were significantly increased in 2,000 mg/kg males and females. GENETIC TOXICOLOGY Ginkgo biloba extract was mutagenic in S. typhimurium strains TA98 and TA100, and in E. coli strain WP2 uvrA/pKM101, with and without exogenous metabolic activation. (ABSTRACT TRUNCATED)
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PMID:Toxicology and carcinogenesis studies of Ginkgo biloba extract (CAS No. 90045-36-6) in F344/N rats and B6C3F1/N mice (Gavage studies). 2365 21


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