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Scopolamine hydrobromide trihydrate is used in ophthalmic preparations and as a preanesthetic sedative. Its major use is in transdermal patches for the treatment of motion sickness. Scopolamine hydrobromide trihydrate was selected for study because of considerable human exposure resulting from its use in prescription and over-the-counter preparations. Scopolamine was a suspect carcinogen because it contains an aliphatic epoxide moiety which may act as a biological alkylating agent. Male and female F344/N rats and B6C3F1 mice received scopolamine hydrobromide trihydrate (89% pure) in distilled water by gavage for 16 days, 14 weeks, or 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium, cultured Chinese hamster ovary cells, and mouse peripheral blood erythrocytes. 16-DAY STUDY IN RATS: Groups of five male and five female rats were administered 0, 75, 150, 300, 600, or 1,200 mg scopolamine hydrobromide trihydrate/kg body weight in distilled water by gavage for 16 days. All rats survived to the end of the study. The final mean body weights and body weight gains of males receiving 600 and 1,200 mg/kg and the mean body weight gain of males receiving 300 mg/kg were significantly lower than those of the control group. Clinical findings included bilateral pupillary dilation in all dosed animals and red eyelids in males and females receiving 1,200 mg/kg. There were no significant treatment-related gross or microscopic lesions. 16-DAY STUDY IN MICE: Groups of five male and five female mice were administered 0, 150, 250, 450, 900, or 1,800 mg scopolamine hydrobromide trihydrate/kg body weight in distilled water by gavage for 16 days. One male and two females receiving 1,800 mg/kg and one female receiving 150 mg/kg died during the study. The final mean body weights and body weight gains of dosed mice were similar to those of the control groups. Clinical findings related to scopolamine hydrobromide trihydrate administration included bilateral pupillary dilation and squinting in all dosed males and females. The relative liver weights of males receiving 1,800 mg/kg and of females in all dosed groups were significantly greater than those of the control groups. There were no significant treatment-related gross or microscopic lesions. 14-WEEK STUDY IN RATS: Groups of 10 male and 10 female rats were administered 0, 15, 45, 135, 400, or 1,200 mg scopolamine hydrobromide trihydrate/kg body weight in distilled water by gavage for 14 weeks. One female receiving 45 mg/kg, one male and one female receiving 135 mg/kg, six males and one female receiving 400 mg/kg, and eight males and seven females receiving 1,200 mg/kg died during the study. The final mean body weights and mean body weight gains of all dosed males and females were significantly lower than those of the control groups. Clinical findings included bilateral pupillary dilation in all dosed males and females and reddening of the eyes in 15 mg/kg males and 135, 400, and 1,200 mg/kg males and females. Hematocrit, hemoglobin concentration, and/or erythrocyte count in male and female rats receiving 45 mg/kg or greater were slightly higher than those of the control groups. In general, these changes were most prominent in rats in the 400 and 1,200 mg/kg groups. Higher hematocrit, hemoglobin concentration, and erythrocyte count were likely due to hemoconcentration from dehydration (relative erythrocytosis). A minimal to mild mature neutrophilia, evidenced by higher segmented neutrophil numbers than in the control group, occurred in all dosed male rats. Sperm morphology and vaginal cytology parameters in dosed rats were similar to those in the control groups. Nine male and five female dosed rats died from esophageal obstructions consisting of feed and bedding material in the posterior pharynx. Tracheal obstruction occurred concurrently with esophageal obstruction as a result of food build-up in the oropharyngeal region. This condition is considered to be secondary to the inhibitory effects of scopolamine hydrobromide trihydrate on salivary gland secretions and on esopon esophageal smooth muscle involved in swallowing. There were no other significant treatment-related gross or microscopic findings. 14-WEEK STUDY IN MICE: Groups of 10 male and 10 female mice were administered 0, 15, 45, 135, 400, or 1,200 mg scopolamine hydrobromide trihydrate/kg body weight in distilled water by gavage for 14 weeks. One male receiving 135 mg/kg and two males and one female receiving 1,200 mg/kg died during the study. The final mean body weights and mean body weight gains of all dosed male groups and females receiving 45 mg/kg and above were significantly lower than those of the control groups. Clinical observations included bilateral pupillary dilation, hyperactivity, and hypoactivity. A minimal to mild mature neutrophilia, similar to that which occurred in the 14-week rat study, occurred in male mice receiving 45 mg/kg or greater. As in the rat study, there was no microscopic evidence of inflammation that could account for the neutrophilia. The estrous cycle length of 1,200 mg/kg females was significantly greater than that in the control group. There were no significant treatment-related gross or microscopic lesions. 2-YEAR STUDY IN RATS: Groups of 60 male and 60 female rats were administered 0, 1, 5, or 25 mg scopolamine hydrobromide trihydrate/kg body weight in distilled water by gavage for 104 weeks. Ten males and ten females from each dose group, excluding the 1 mg/kg female group, were evaluated at 15 months. Survival, Body Weights, Clinical Findings, and Ophthalmic Examination Findings: The survival rates of female rats receiving 1 and 25 mg/kg were significantly lower than that of the control group. Mean body weights of 1 and 5 mg/kg males and females were similar to those of the controls throughout the study. However, mean body weights of 25 mg/kg males and females were generally lower than those of the control groups after about week 25. Clinical findings included bilateral pupillary dilation in all dosed males and females. Ophthalmic examination revealed no significant findings. Hematology: Compared to controls, hematocrit was slightly higher in the 25 mg/kg male rats, similar to the effects observed in the 14-week study; this is consistent with dehydration resulting in hemoconcentration. Reticulocyte numbers in the 25 mg/kg female rats were slightly lower than those in the controls. This result is consistent with the lower body weights, and thus a decreased nutritional status, exhibited by these animals. Plasma Scopolamine Determinations: The serum scopolamine concentrations were 6 ng scopolamine/mL serum for the 5 mg/kg female sample and 12 and 28 ng/mL for the 25 mg/kg male and female samples, respectively. The amounts of scopolamine in the other serum samples were below the minimum detection limit (4 ng/mL) of the analysis method. Neurobehavioral Findings: Horizontal motor activity of 25 mg/kg females was significantly greater than that of the control group on days 90, 180, and 360. Startle response of 5 and 25 mg/kg females was significantly lower than that of the control group on day 90. On day 180, passive avoidance of 25 mg/kg males was significantly lower than that of the control group. Pathology Findings: The incidences of adenoma of the pituitary gland pars distalis decreased with increasing dose in both male and female rats; however, this trend was only significant in males (males: vehicle control, 19/49; 1 mg/kg, 17/49; 5 mg/kg, 13/50; 25 mg/kg, 10/50; females: 20/50, 13/60, 14/50, 10/50). The incidences of adenoma of the pituitary gland pars distalis in 25 mg/kg males and all groups of dosed females were below the NTP historical control range. The incidences of hyperplasia were not significantly different from those in the control groups. The incidences of mononuclear cell leukemia in 25 mg/kg males and females were significantly lower than those of the control groups (males: 33/50, 21/50, 26/50, 24/50; females: 20/50, 6/60, 13/50, 4/50). The incidence of mononuclear cell leukemia in females receiving 25 mg/kg was well below the NTP historical range. 2-YEAR STUDY IN MICE: Groups of 70 male and 70 female mice were administered 0, 1, 5, or 25 mg scopolamine hydrobromide trihydrate/kg body weight in distilled water by gavage for 104 to 105 weeks. Ten control animals and ten animals from each dose level were evaluated at 15 months. Survival, Body Weights, Clinical Findings, and Ophthalmic Examination Findings Survival of dosed males and females was similar to that of the controls. The mean body weights of males and females receiving 1 mg/kg were similar to those of the control groups throughout the majority of the study. The mean body weights of 5 mg/kg males and females were slightly lower than those of the controls. The mean body weights of males and females receiving 25 mg/kg were lower than those of the control groups after week 13. Clinical findings included bilateral pupillary dilation in all dosed male and female groups. Ophthalmic examination revealed no significant findings. Hematology: Hematocrit, hemoglobin concentration, and erythrocyte count in 25 mg/kg female mice were slightly lower than those in the control group. These results are consistent with development of a minimal normocytic, normochromic nonresponsive anemia. The anemia may be related to the lower body weights exhibited by these animals and are presumed to be due to a decreased nutritional status. Pathology Findings: The combined incidences of hepatocellular neoplasms (adenoma or carcinoma) occurred with a significant negative trend in males and females (males: vehicle control, 30/50; 1 mg/kg, 33/50; 5 mg/kg, 14/50; 25 mg/kg, 15/50; females: 22/51, 21/50, 16/50, 9/51). The combined incidences of hepatocellular neoplasms in 5 and 25 mg/kg males were within the NTP historical control range. The incidences of clear cell foci and eosinophilic foci in dosed male groups, and eosinophilic foci in 25 mg/kg females, were significantly lower than those of the control groups. The incidences of many spontaneously occurring nonneoplastic lesions were significantly lower in dosed mice than in the control groups and usually decreased with increasing dose. These included kidney nephropathy, alveolar epithelial hyperplasia, hyperplasia of the pancreatic islets, bone marrow myelofibrosis, hyperplasia of the pituitary gland pars distalis, cystic hyperplasia of the uterus, and hematopoietic cell proliferation of the spleen. The decreased incidences of these spontaneous lesions were most likely a result of lower body weights in dosed animals. GENETIC TOXICOLOGY: Scopolamine hydrobromide trihydrate did not induce mutations in any of five strains of Salmonella typhi murium, with or without S9 metabolic activation enzymes, nor did it induce sister chromatid exchanges in cultured Chinese hamster ovary cells, with or without S9. A weakly positive response was obtained, however, in a chromosomal aberrations test conducted in cultured Chinese hamster ovary cells with very high doses of scopolamine hydrobromide trihydrate in the presence of S9; without S9, no increase in aberrations was noted. Despite the evidence for chromosomal damage observed in vitro, no increase in the frequencies of micronucleated normochromatic erythrocytes was observed in peripheral blood samples of male or female mice exposed to scopolamine hydrobromide trihydrate for 14 weeks by gavage. CONCLUSIONS: Under the conditions of these 2-year gavage studies, there was no evidence of carcinogenic activity of scopolamine hydrobromide trihydrate in male or female F344/N rats or B6C3F1 mice administered 1, 5, or 25 mg/kg. Synonyms: Scopolamine hydrobromide, 6,7-epoxytropan-3-yl, euscopol, hydroscine hydrobromide, hyoscine bromide, (-)-hyoscine hydrobromide, hysco, isoscopil, scopolammonium bromide, (s)-tropate hydrobromide trihydrate, lα-tropyl-a-scopine
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PMID:NTP Toxicology and Carcinogenesis Studies of Scopolamine Hydrobromide Trihydrate (CAS No. 6533-68-2) in F344 Rats and B6C3F1 Mice (Gavage Studies). 1259 30

p-Nitrobenzoic acid is produced in large volumes for organic synthesis and as an intermediate in the manufacture of pesticides, dyes, and industrial solvents. Groups of male and female F344/N rats and B6C3F1 mice were exposed to p-nitrobenzoic acid (>99% pure) in feed for 14 days, 13 weeks, or 2 years for toxicity and carcinogenicity studies. Genetic toxicology studies were conducted in in vitro assays with Salmonella typhimurium and cultured Chinese hamster ovary cells, and in studies of erythrocyte micronucleus formation in mice in the 13-week study. 14-DAY STUDY IN RATS: Groups of five male and five female rats were given 0, 2,500, 5,000, 10,000, 20,000, or 40,000 ppm p-nitrobenzoic acid in feed for 14 days. All rats survived until the end of the study. Male and female rats given 20,000 and 40,000 ppm lost weight. The final mean body weights of 10,000, 20,000, and 40,000 ppm males were 82%, 60%, or 52% that of the controls, and the final mean body weights of 10,000, 20,000, and 40,000 ppm females were 87%, 68%, and 65% that of the controls. There were no clinical findings that were characteristic of organ-specific toxicity. Absolute and relative spleen weights were significantly increased in rats exposed to 10,000, 20,000, and 40,000 ppm. There were decreases in erythrocyte count and hemoglobin and hematocrit values and increases in reticulocyte count, nucleated erythrocytes, and methemoglobin concentration that were most pronounced in the 20,000 and 40,000 ppm groups. Congestion of the spleen occurred in 10,000 ppm males and in 20,000 and 40,000 ppm females. Hypertrophy of the follicular epithelium of the thyroid gland was present in male and female rats exposed to 10,000, 20,000, or 40,000 ppm p-nitrobenzoic acid, while follicular hyperplasia was observed in the 40,000 ppm males and females. Atrophy of the testis was observed in 20,000 and 40,000 ppm males. Other lesions observed in 20,000 and 40,000 ppm rats included atrophy of the thymus in males and atrophy of the ovary, bone marrow, and thymus in females. 14-DAY STUDY IN MICE: Groups of five male and five female mice were given 0, 2,500, 5,000, 10,000, 20,000, or 40,000 ppm p-nitrobenzoic acid in feed for 14 days. Three males and two females given 40,000 ppm died during the study. All other animals survived until the end of the study. Male mice given 20,000 and 40,000 ppm and females given 20,000 ppm lost weight. Mean body weight gains of 20,000 and 40,000 ppm males and 10,000, 20,000, and 40,000 ppm females were significantly lower than those of the controls. There were no clinical findings related to organ-specific toxicity although lethargy and ataxia were observed in 40,000 ppm mice. Relative liver weights were significantly increased in 20,000 and 40,000 ppm males and females and in 10,000 ppm females. Absolute and relative thymus weights of 20,000 and 40,000 ppm males and of 10,000, 20,000, and 40,000 ppm females were reduced. No significant differences in hematology parameters occurred in exposed mice. Testicular degeneration was observed in three 20,000 ppm and two 40,000 ppm males. Bone marrow hemorrhage and atrophy occurred in 40,000 ppm females. 13-WEEK STUDY IN RATS: Groups of 10 male and 10 female rats were given 0, 630, 1,250, 2,500, 5,000, or 10,000 ppm pnitrobenzoic acid in feed for 13 weeks resulting in approximate daily doses of 40, 70, 160, 310, or 660 mg/kg to males and 40, 80, 170, 340, or 680 mg/kg to females. All rats survived until the end of the study. Mean body weight gains and final mean body weights were significantly less than those of the controls in 2,500, 5,000, and 10,000 ppm males and in 5,000 and 10,000 ppm females. There were no clinical findings related to organ-specific toxicity. Differences in spleen weights and hematology parameters characteristic of regenerative anemia were observed in males and females, primarily in groups given 10,000 ppm. The absolute and relative spleen weights were significantly increased in 10,000 ppm males and females and the relative spleen weights were significantly increased in 5,000 ppm males hts were significantly increased in 5,000 ppm males and females. Methemoglobin, Heinz bodies, and reticulocyte counts were increased and erythrocyte counts, hemoglobin, and hematocrit values were decreased in 10,000 ppm males and females. Congestion, pigmentation, and accumulation of macrophages in the spleen and pigmentation in the kidney occurred in 2,500, 5,000, and 10,000 ppm males. Congestion and pigmentation of the spleen occurred in 10,000 ppm females. A yellowish brown pigment (hemosiderin) in the spleen and kidney was associated with hemolytic anemia. Mild cytoplasmic hyaline droplet accumulation was present in renal tubule epithelial cells in 10,000 ppm males while karyomegaly was present in male and female rats exposed to 2,500, 5,000, and 10,000 ppm p-nitrobenzoic acid. A chemical-related testicular lesion, consisting of atrophy of the seminiferous tubules, occurred in 10,000 ppm males. 13-WEEK STUDY IN MICE: Groups of 10 male and 10 female mice were given 0, 1,250, 5,000, 10,000, or 20,000 ppm pnitrobenzoic acid in feed for 13 weeks resulting in approximate daily doses of 170, 330, 670, 1,900, or 4,000 mg/kg body weight to males and 240, 460, 970, 2,500, or 4,900 mg/kg to females. All mice survived until the end of the study, except one 1,250 ppm female that was killed accidentally. Final mean body weights and mean body weight gains of all exposed males and of 5,000, 10,000, and 20,000 ppm females were significantly lower than those of the controls. No clinical findings or differences in organ weights or histopathology related to organ-specific toxicity were observed in exposed mice. 2-YEAR STUDY IN RATS: Groups of 60 male and 60 female rats were given 0, 1,250, 2,500, or 5,000 ppm p-nitrobenzoic acid in feed for 2 years. Ten males and 10 females from each exposure group were evaluated at 15 months. Survival, Body Weights, Feed Consumption, and Clinical Findings: Two-year survival rates of 1,250 and 2,500 ppm males were similar to that of the controls. Two-year survival of 5,000 ppm males was marginally greater than that of the controls and was attributed in part to a decrease in the severity of nephropathy and a decrease in the incidence of mononuclear cell leukemia. Survival of exposed females was similar to that of the controls. Mean body weights of 5,000 ppm males were 2&percnt; to 8&percnt; lower than those of the controls through week 80. Final mean body weights of exposed males were similar to that of the controls. Mean body weights of 5,000 ppm females were 2&percnt; to 9&percnt; lower than those of the controls during the first year of the study and were 10&percnt; to 16&percnt; lower during the second year of the study. Final mean body weights of exposed females were 97&percnt; (1,250 ppm), 92&percnt; (2;500 ppm), and 84&percnt; (5,000 ppm) that of the controls. Feed consumption by exposed males and females was similar to that by the controls. Dietary levels of 1,250, 2,500, or 5,000 ppm p-nitrobenzoic acid delivered approximately 50, 100, or 210 mg/kg body weight per day to males and 60, 125, or 250 mg/kg per day to females. There were no clinical findings attributable to organ-specific toxicity. Pathology Findings: There were increases in the incidences of clitoral gland adenoma and of clitoral gland adenoma or carcinoma (combined) (4/50, 14/49, 15/49, 15/50) in exposed females. The incidences of clitoral gland adenoma or carcinoma (combined) in the exposed groups (29&percnt; to 31&percnt;) exceeded the historical control mean incidence (11&percnt;) and range (2&percnt; to 21&percnt;) in female F344/N rats in recent 2-year NTP feed studies. The increased incidences of clitoral gland neoplasms were considered to be some evidence of carcinogenic activity in female rats exposed to p-nitrobenzoic acid. The incidences of hyperplasia of the clitoral gland in exposed females were marginally lower than that of the controls (10/50, 6/49, 6/ 49, 7/50). There was a chemical-related decrease in the severity of nephropathy in male rats. Male rat kidneys were examined using both single and step-section analyses, and the incidences of renal tubule neoplasms were not statistically greater than those of the controls. Mild hyaline droplet accumulation was observed in renal tubule epithelial cells in 10,000 ppm males in the 13-week study, but this effect was not severe enough to lead to a chemical-related neoplastic response in the 2-year study as has been observed with other chemicals. At the 15-month interim evaluation, hematologic parameters characteristic of a mild regenerative anemia and significant differences in spleen weights were noted in 5,000 ppm females. These differences included decreases in erythrocyte count, hemoglobin, and hematocrit, increases in spleen weights, and hemosiderin accumulation in splenic macrophages. At 2 years, significant decreases in the incidences of mononuclear cell leukemia were observed in 5,000 ppm males and 2,500 and 5,000 ppm females (males: 29/50, 35/50, 26/50, 2/50; females: 17/50, 11/50, 3/50, 0/50). While the mechanism for this decrease is unknown, decreases in the incidence of mononuclear cell leukemia have also been observed in 2year studies with other amine/nitro compounds. 2-YEAR STUDY IN MICE: Groups of 60 male and 60 female mice were given 0, 1,250, 2,500, or 5,000 ppm p-nitrobenzoic acid in feed for 2 years. Ten males and 10 females from each exposure group were evaluated at 15 months. Survival, Body Weights, Feed Consumption, and Clinical Findings: Two-year survival rates of exposed mice were similar to those of the controls. Mean body weights of 5,000 ppm males were 6&percnt; to 12&percnt; lower than those of the controls after week 17, and mean body weights of 5,000 ppm females were 12&percnt; to 24&percnt; lower than those of the controls after week 16. The final mean body weight of 5,000 ppm females was 19&percnt; less than that of the controls; final mean body weights of males were similar to that of the controls. Feed consumption by exposed mice was similar to that by the controls. Dietary levels of 1,250, 2,500, or 5,000 ppm p-nitrobenzoic acid delivered approximately 150, 300, or 675 mg/kg per day to males and 170, 365, or 905 mg/kg per day to females. There were no clinical findings of organ-specific toxicity. No chemical-related effects on hematology parameters were noted at the 15-month interim evaluation. Pathology Findings: There were no increases or decreases in neoplasms in male or female mice that were considered to be related to chemical administration. GENETIC TOXICOLOGY: p-Nitrobenzoic acid was mutagenic in Salmonella typhimurium strain TA100 with and without S9. No mutagenic activity was noted in strains TA98, TA1535, or TA1537, with or without S9. p-Nitrobenzoic acid induced sister chromatid exchanges and chromosomal aberrations in cultured Chinese hamster ovary cells in the absence of S9; with S9, results of both tests were negative. In vivo, no increase in micronuclei was observed in peripheral blood erythrocytes of male or female mice administered p-nitrobenzoic acid in dosed feed for 13 weeks. CONCLUSIONS: Under the conditions of these 2-year feed studies, there was no evidence of carcinogenic activity of p-nitrobenzoic acid in male F344/N rats exposed to 1,250, 2,500, or 5,000 ppm. There was some evidence of carcinogenic activity of p-nitrobenzoic acid in female F344/N rats based on increases in the incidences of clitoral gland adenoma and of clitoral gland adenoma or carcinoma (combined). There was no evidence of carcinogenic activity of p-nitrobenzoic acid in male or female B6C3F1 mice exposed to 1,250, 2,500, or 5,000 ppm. There were chemical-related decreases in the incidences of mononuclear cell leukemia in exposed male and female rats. p-Nitrobenzoic acid caused mild hematologic toxicity in female rats. Synonyms: 4-Nitrobenzoic acid; nitrodracylic acid; p-nitrobenzenecarboxylic acid; p-carboxynitrobenzene
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PMID:NTP Toxicology and Carcinogenesis Studies of p-Nitrobenzoic Acid (CAS No. 62-23-7) in F344/N Rats and B6C3F1 Mice (Feed Studies). 1259 21

C.I. Acid Red 114 is one of five chemicals being evaluated in 2-year carcinogenicity and toxicity studies as part of the NTP's Benzidine Dye Initiative. This Initiative was designed to evaluate representative benzidine congeners, benzidine congener-derived dyes, and benzidine-derived dyes. C.I. Acid Red 114 was nominated for study because of the potential for human exposure during production of bisazobiphenyl dyes and because benzidine, a structurally related chemical, is a known human carcinogen. Toxicology and carcinogenesis studies were conducted by administering desalted, industrial grade C.I. Acid Red 114 in drinking water to groups of F344/N rats of each sex for 13 days, 13 weeks, 9 or 15 months, or 2 years. These studies were performed only in rats because studies of benzidine congeners were being performed in mice at the National Center for Toxicological Research (NCTR). Genetic toxicology studies were conducted in Salmonella typhimurium, Chinese hamster ovary cells, and Drosophila melanogaster. 13-Day Studies: Rats were exposed to C.I. Acid Red 114 in drinking water at doses of 0, 10,000, 20,000, or 30,000 ppm. All control and dosed rats survived except one male rat in the 20,000 ppm dose group. Final mean body weights in the three dosed groups were 94%, 83%, or 77% of controls for males and 92%, 88%, or 80% of controls for females. Water consumption declined with increased dose. Clinical findings included red stained fur, ears, and tail in all test animals. On gross necropsy, organs and tissues were also stained red. 13-Week Studies: C.I. Acid Red 114 was administered in drinking water at doses of 0, 600, 1,200, 2,500, 5,000, or 10,000 ppm. All control and dosed animals survived until the end of the study. Final mean body weights in the five dosed groups were 97%, 89%, 87%, 87%, or 85% of controls for males and 97%, 94%, 94%, 92%, or 89% of controls for females. Water consumption was decreased in dosed animals. As was seen in the 13-day studies, major organs and tissues from treated animals were stained red. Kidney toxicity characterized by regeneration and karyomegaly of tubule epithelial cells with chronic inflammation was observed in female rats at doses of 1,200 ppm or above. Treatment-related increases in relative liver weights and elevated liver enzyme levels were seen in males and females, centrilobular pallor in the liver was seen in all male dose groups. Because of these body weight differences, decreases in water consumption, and organ toxicity, the doses chosen for the 2-year studies were 70,150, and 300 ppm for males and 150, 300, and 600 for females. 2-Year Studies: Male rats received doses of 0, 70, 150, or 300 ppm of C.I. Acid Red 114, and female rats received 0, 150, 300, or 600 ppm. Seventy animals were in the control and high-dose groups, 45 in the low-dose groups, and 75 in the mid-dose groups. Ten animals were evaluated from the control and high-dose groups at 9 months, and ten animals from all dose groups were evaluated at 15 months. The average amount of compound consumed per day was 4, 8, or 20 mg/kg for males and 9, 20, or 70 mg/kg for females. Survival and Body Weights: Survival at 105 weeks for male rats receiving 0, 70, 150, or 300 ppm was 24/50, 15/35, 26/65, and 1/50; for females receiving 0, 150, or 300 ppm, survival was 36/50, 13/35, and 6/64. All female rats receiving 600 ppm died by week 89. The decreased survival in treated groups was due primarily to the development of chemical-related neoplasms. Of the surviving animals, the final mean body weights for males receiving 70 or 150 ppm were 94% and 90% of control and for females receiving 150 or 300 ppm, 99% and 84% of control. These weight differences began in the second year of the studies and were attributed in part to the development of neoplasms in the dosed groups. Histopathologic Effects in the 2-Year Studies: At 9 and 15 months, a few neoplasms were seen in the liver, lung, clitoral gland, skin, Zymbal's gland, oral cavity epithelium, and small and large intestine, and the number of neoplasms at these sites increased as gland, skin, Zymbal's gland, oral cavity epithelium, and small and large intestine, and the number of neoplasms at these sites increased as the studies progressed. At 2 years, there was a clear carcinogenic response in the skin, Zymbal's gland, and liver of male and female rats, and in the clitoral gland, oral cavity epithelium, small and large intestine, and lung in female rats. Treatment-related increases were also seen in the incidence in neoplasms of the oral cavity epithelium, adrenal gland, and lung of male rats, and in mononuclear cell leukemia and in neoplasms of the mammary gland and adrenal gland in female rats. The incidence of these neoplasms was generally lower, but was significant and considered to be marginally related to chemical treatment. The same neoplastic effects have been previously observed in some or all of the NTP studies with dimethoxybenzidine, dimethylbenzidine, or C.I. Direct Blue 15. Genetic Toxicology: In a standard preincubation protocol, C.I. Acid Red 114 was mutagenic in Salmonella typhimurium strain TA98 in the presence of induced hamster liver S9, and an equivocal response was noted in strain TA100 with hamster liver S9. However, no significant mutagenic activity was noted in strains TA1535 or TA1537 with or without S9 activation. In a modified S. typhimurium gene mutation test which employed reductive metabolism followed by oxidative metabolism with S9 liver enzymes, C.I. Acid Red 114 was strongly mutagenic in strain TA1538. C.I. Acid Red 114 did not induce sister chromatid exchanges or chromosomal aberrations in Chinese hamster ovary cells with or without S9 activation; reductive metabolism was not used in these cytogenetic tests. No increase in sex-linked recessive lethal mutations was observed in germ cells of male Drosophila melanogaster administered C.I. Acid Red 114 by feeding or injection. Conclusions: Under the conditions of these 2-year drinking water studies, there was clear evidence of carcinogenic activity of C.I. Acid Red 114 for male F344/N rats, as indicated by benign and malignant neoplasms of the skin, Zymbal's gland, and liver. Increased incidences of neoplasms of the oral cavity epithelium, adrenal gland, and lung may have been related to chemical administration. There was clear evidence of carcinogenic activity for female F344/N rats, as indicated by benign and malignant neoplasms of the skin, Zymbal's gland, clitoral gland, liver, oral cavity epithelium, small and large intestines, and lung. Increased incidences of mononuclear cell leukemia, mammary gland adenocarcinoma, and adrenal gland pheochromocytomas may have been related to chemical administration. Synonyms: 1,3-Naphthalenedisulfonic acid, 8-((3,3'-dimethyl-4'-((4-(((4-methylphenyl)sulfonyl)oxy)phenyl)azo)(1,1'-bipheny)-4-yl)azo)-7-hydroxy, disodium salt, Acid Leather Red BG, Acid Red 114, Amacid Milling Red PRS, Benzyl Fast Red BG, Benzyl Red BR, Cerven Kysela, C.I. 23635, Erionyl Red RS, Folan Red B, Kayanol Milling Red RS, Leather Fast Red B, Levanol Red GG, Midlon Red PRS, Milling Red B, Milling Red BB, Milling Red SWB, NCI C61096, Polar Red RS, Sandolan Red N-RS, Sella Fast Red RS, Sulphonol Fast Red R, Supranol Fast Red GG, Supranol Red PBX-CF, Supranol Red R, Telon Fast Red GG, Tertracid Milling Red B, Vondamol Fast Red RS
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PMID:Toxicology and Carcinogenesis Studies of C.I. Acid Red 114 (CAS No. 6459-94-5) in F344/N Rats (Drinking Water Studies). 1262 13

C.I. Pigment Red 3, a yellowish red solid, is widely used for coloring paints, inks, plastics, and rubber, and in textile printing. It is used in a wide range of consumer items such as wallpaper, typewriter ribbons, carbon paper, and art materials. Toxicology and carcinogenicity studies were conducted by feeding groups of F344/N rats and B6C3F1 mice of each sex diets containing C.I. Pigment Red 3 (97% pure) for 2 weeks, 13 weeks, and 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium and cultured Chinese hamster ovary cells. 2-Week Studies: Groups of five rats and five mice of each sex were given feed containing 0, 6,000, 12,500, 25,000, 50,000, or 100,000 ppm C.I. Pigment Red 3 for 2 weeks. No chemical-related deaths occurred in rats or mice. Final mean body weights of exposed rats and male mice were lower than controls; female mice that received 6,000 and 50,000 ppm had significantly increased final mean body weights compared to that of the controls. The feed consumption of treated rats and mice was slightly greater than that of the controls, suggesting that C.I. Pigment Red 3 had no adverse effects on the feed palatability. Dose-related decreases in erythrocyte counts and hematocrit values and an increase in reticulocyte counts were observed in rats. Changes in these parameters were observed in mice, but there were no clear, dose-related trends. 13-Week Studies: Groups of ten rats and ten mice of each sex were given feed containing 0, 3,000, 6,000, 12,500, 25,000, or 50,000 ppm C.I. Pigment Red 3 for 13 weeks. No chemical-related deaths were observed in rats or mice. The final mean body weights of exposed female rats were significantly lower than that of the controls; the final mean body weights of exposed male rats and exposed mice were similar to controls. There were significant increases in relative liver and kidney weights of exposed male rats. Increases in the relative liver weights in mice did not occur with a dose-related trend and thus they were not considered related to chemical administration. Sites for the toxicity of C.I. Pigment Red 3 were the bone marrow, kidney, liver, and spleen in rats. Lesions observed in rats included bone marrow hyperplasia, congestion and hematopoietic cell proliferation of the spleen, and iron-positive pigmentation of the spleen, kidney, and liver. Sites for the toxicity of C.I. Pigment Red 3 in mice were the liver, kidney, and spleen in males and the liver and spleen in females. Lesions noted among mice in the spleen were hematopoietic cell proliferation and iron-positive pigmentation. In the liver, there was hematopoietic cell proliferation in male and female mice. Cytomegaly occurred in the renal tubule epithelium of the male mouse kidney. 2-Year Studies: Doses selected for the 2-year feed studies were 0, 6,000, 12,500, and 25,000 ppm for rats and 0, 12,500, 25,000, and 50,000 ppm for mice. The dose selection for rats was based on body weight changes observed for females that received 50,000 ppm; the dose selection for mice was based on the lack of body weight depression or death at the doses tested during the 13-week studies. Concentrations higher than 50,000 ppm in the feed were not used because higher levels might have adversely affected the nutritional value of the diet during the 2-year studies. Body Weight, Feed Consumption, Clinical Findings, and Survival in the 2-Year Studies: Final mean body weights for male rats that received 25,000 ppm, female rats that received 12,500 and 25,000 ppm, and male and female mice that received 50,000 ppm were more than 10% lower than those of the controls. Feed consumption of exposed rats and mice was similar to that of the controls. No clinical findings indicative of toxicity were observed in rats or mice. The survival of low-dose male rats was greater than that of the controls (0 ppm, 28/50; 6,000 ppm, 40/50; 12,500 ppm, 28/50; 25,000 ppm, 20/50). Survival of exposed female rats and exposed male mice was similar to the controls; the survival of high-dose female mice was significantly decreased compared to thcompared to that of the controls (39/50, 37/50, 31/50, 25/50). The reduced survival in this dose group may have been due to the increased incidence of ovarian abscesses. Neoplasms and Nonneoplastic Lesions in the 2-Year Studies: Benign adrenal pheochromocytomas were significantly increased in the 12,500 and 25,000 ppm groups of male rats compared to the controls (22/50, 29/50, 35/50, 34/50). However, malignant neoplasms were not increased in incidence (6/50, 7/50, 10/50, 4/50). The incidence of adrenal pheochromocytomas in dosed groups exceeded the range for NTP historical controls for feed studies (22&percnt;-48&percnt;), and the increased incidence of this neoplasm was attributed to C.I. Pigment Red 3 administration. Squamous cell papillomas of the skin occurred with a positive trend in male rats (0/50, 4/50, 2/50, 6/50), and the incidence in the high-dose group was significantly greater than that of the controls. A poorly differentiated squamous cell carcinoma (diagnosed as carcinoma) was observed in a control male. The historical control rate for squamous cell papillomas in NTP feed studies is low (16/800 or 2&percnt;, range 0&percnt;-4&percnt;), and the higher incidence of this tumor in male rats may have been caused by the administration of C.I. Pigment Red 3. Hepatocellular adenomas occurred with a positive trend in female rats, with a significantly greater incidence in the high-dose group than in the control group (0/50, 0/50, 1/50, 10/50). This neoplasm has occurred in only one historical control group in NTP feed studies (3/800, range 0&percnt;-6&percnt;), and the increase in hepatocellular adenomas in female rats was attributed to chemical administration. Chemical-related nonneoplastic lesions observed in the livers of male and female rats included eosinophilic or mixed type foci of cellular alteration. Foci were often accompanied by angiectasis and cystic degeneration in males and by granulomas and cholesterol pigmentation in females. Chronic nephropathy occurred with increased severity in exposed male and female rats. The lesions were more severe in males than in females. Other lesions considered secondary to renal disease included parathyroid gland hyperplasia, fibrous osteodystrophy of the bone, and mineralization of various organs (stomach, intestine, heart, and blood vessels). The increased incidence of hyperplasia of the transitional epithelium of the renal papilla observed in treated rats was considered to be part of the chronic nephropathy. Zymbal's gland carcinoma incidences were marginally increased in the mid- and high-dose male rats (0/50, 0/50, 2/50, 3/50). The incidence in the high-dose group was outside the NTP historical control range (0&percnt;-4&percnt;), and the Zymbal's gland carcinomas may have been related to C.I. Pigment Red 3 administration. Mononuclear cell leukemias, mammary gland fibroadenomas, and preputial gland/clitoral gland adenomas occurred at lower incidences in exposed male and female rats. The decrease in mononuclear cell leukemia was attributed to the direct effect of C.I. Pigment Red 3 or its metabolites on the mechanism responsible for inducing leukemias in aging rats, while the decreased incidence of mammary gland fibroadenomas might be attributed to decreased body weights in female rats. The cause of the decreased incidences of preputial and clitoral gland tumors is unknown. Tubule adenomas of the renal cortex occurred at a significantly higher incidence in high-dose male mice than in controls (0 ppm, 0/50; 12,500 ppm, 0/50; 25,000 ppm, 0/50; 50,000 ppm, 6/50). Because this tumor occurred only in exposed males and was outside the range for NTP historical controls in feed studies (0&percnt;-2&percnt;), renal cortical tubule adenomas in male mice were considered to be related to the administration of C.I. Pigment Red 3. Follicular cell adenoma of the thyroid gland occurred with a positive trend in male mice (0/50, 0/49, 1/50, 5/50). Theincidence in the high-dose group was significantly greater than that in the controls. This chemical-related effect is supported by the increased incidence of follicular cell hyperplasia. Because the incidence of this tumor exceeded the range of the historical controls from NTP feed studies (0&percnt;-4&percnt;), the increase of follicular cell adenoma was attributed to chemical administration. Female mice receiving C.I. Pigment Red 3 had a significant increase in follicular cell hyperplasia but showed no increase in tumor incidence at this site. Focal renal tubule hyperplasia and cystic hyperplasia occurred in exposed male mice but not in the controls. Cytomegaly (karyomegaly) of the renal tubule epithelium was seen in all treated male mice. The severity of the accompanying chronic nephropathy was increased in both male and female mice. Genetic Toxicology: C.I. Pigment Red 3 was mutagenic in Salmonella typhimurium strains TA100 and TA98 in the presence of exogenous metabolic activation (S9); no increases in gene mutation were observed in strains TA1535 and TA1537, with or without S9. C.I. Pigment Red 3 did not induce sister chromatid exchanges or chromosomal aberrations in Chinese hamster ovary cells in either the presence or the absence of S9. Conclusions: Under the conditions of these 2-year feed studies, there was some evidence of carcinogenic activity of C.I. Pigment Red 3 in male F344/N rats as exhibited by increased incidences of benign pheochromocytomas of the adrenal gland. The marginal increase in the incidences of squamous cell papillomas of the skin and Zymbal's gland carcinomas may have been related to C.I. Pigment Red 3 administration. There was some evidence of carcinogenic activity of C.I. Pigment Red 3 in female F344/N rats as indicated by the increased incidence of hepatocellular adenomas. There was some evidence of carcinogenic activity of C.I. Pigment Red 3 in male B6C3F1 mice as exhibited by the increased incidences of tubule adenomas of the renal cortex and follicular cell adenomas of the thyroid gland. There was no evidence of carcinogenic activity of C.I. Pigment Red 3 in female B6C3F1 mice that received 12,500, 25,000, or 50,000 ppm. The incidences of mononuclear cell leukemia and preputial gland tumors in male rats and mononuclear cell leukemia, mammary gland fibroadenoma, and clitoral gland tumors in female rats were lower in the exposed groups. The incidences of liver foci were markedly increased in exposed male and female rats. The severity of chronic nephropathy was increased in male rats and to a lesser extent in female rats given C.I. Pigment Red 3. An increase in the severity of nephropathy was observed in male and female mice; cytomegaly (karyomegaly) of renal tubule epithelium was observed in male mice. Thyroid follicular cell hyperplasia occurred with an increased incidence in male and female mice receiving C.I. Pigment Red 3. Synonyms: 2-Naphthalenol, 1-((4-methyl-2-nitrophenyl)azo)-; Calcotone Toluidine Red YP; Fast Red A; Pigment Scarlet R; Recolite Fast Red RBL; Sengale Light Red B
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PMID:Toxicology and Carcinogenesis Studies of C.I. Pigment Red 3 (CAS No. 2425-85-6) in F344/N Rats and B6C3F1 Mice (Feed Studies). 1262 23

C.I. Direct Blue 15 is one of five chemicals being evaluated in 2-year carcinogenicity and toxicity studies as part of the NTP's Benzidine Dye Initiative. This Initiative was designed to evaluate representative benzidine congeners, benzidine congener-derived dyes, and benzidine-derived dyes. The dye, industrial grade C.I. Direct Blue 15, was chosen for study as a product to which workers are potentially exposed. Because of the high salt content, the dye was desalted prior to use. The purity was determined to be approximately 50%, with high-performance liquid chromatography indicating one major peak and approximately 35 impurities. Toxicology and carcinogenesis studies were conducted by administering the dye, C.I. Direct Blue 15, in drinking water to groups of F344/N rats of each sex for 14 days, 13 weeks, or 22 months. Planned as 24-month studies, the 22-month studies were terminated early because of rapidly declining animal survival, which was due primarily to neoplasia. These studies were performed only in rats because studies of benzidine congeners were being performed in mice at the National Center for Toxicological Research (NCTR). Genetic toxicology studies were conducted in Salmonella typhimurium and Chinese hamster ovary cells. 14-Day Studies: Rats were given C.I. Direct Blue 15 in drinking water at doses of 1,250, 2,500, 5,000, 10,000, or 30,000 ppm. All control and treated rats survived. Body weight gain in high-dose females was less than that in controls. Water consumption declined as the dose increased. Male and female rats receiving 30,000 ppm had slight degeneration and necrosis of individual hepatocytes in the liver, and females also had mild to moderate renal tubule degeneration and thymic lymphoid depletion. 13-Week Studies: C.I. Direct Blue 15 was administered in drinking water at doses of 0, 1,250, 2,500, 5,000, 10,000, or 30,000 ppm to male rats, and at doses of 0, 630, 1,250, 2,500, 5,000, or 10,000 ppm to female rats. Seven of 10 male rats receiving 30,000 ppm died; all rats in the other groups survived until the end of the studies. Mean final body weights of males receiving 10,000 or 30,000 ppm were 92% and 69% of those of controls, and mean final body weights of females receiving 5,000 or 10,000 ppm were 97% and 94% of those of controls. Tissues from treated animals were stained blue. Compound-related lesions were seen in the kidney and liver of male rats given 30,000 ppm and in the kidney of males and females given 10,000 ppm. The renal lesions included necrosis, degeneration, pigmentation and regeneration of the tubule epithelium, and tubule mineralization. Liver lesions included centrilobular hepatocellular degeneration, fatty metamorphosis, and individual cell necrosis with slight periportal hepatocellular hypertrophy. Lymphoid depletion in the thymus was also seen in the high-dose males. Based on the results of the 14-day and 13-week studies, the high dose chosen for the 22-month studies was 2,500 ppm. 22-Month Studies: At study initiation, 70 rats of each sex were given 0 or 2,500 ppm C.I. Direct Blue 15, 45 rats of each sex were given 630 ppm, and 75 rats of each sex were given 1,250 ppm. Interim evaluations were made at 9 and 15 months. The average amounts of compound consumed per day by the six dose groups after week 52 of the studies were estimated to be 45, 90, and 215 mg/kg for male rats and 50, 100, and 200 mg/kg for female rats. Survival and Body Weights: The studies were terminated at 22 months due to extensive mortality associated with chemical-related neoplasia. Survival of control, 630, 1,250, and 2,500 ppm males at 22 months was 37/50, 8/35, 11/65, and 2/50; survival of females was 40/50, 13/35, 22/65, and 4/50. At 22 months, the mean final body weights of the 630, 1,250, and 2,500 ppm groups were 95%, 91%, and 81% of those of the control for male rats and 91% of those of the control for all female dose groups. Histopathologic Effects in the 22-Month Studies: At the 9-month interim evaluations, one adenoma of the Zymbal's gland was seen in a high-dose male rat, and three carcinmbal's gland was seen in a high-dose male rat, and three carcinomas of the clitoral gland were seen in the high-dose females. At the 15-month interim evaluations, Zymbal's gland neoplasms were seen in low- and high-dose males and all treated female dose groups. Mid- and high-dose males and females also had preputial or clitoral gland neoplasms, and a few neoplasms were present in the skin, small and large intestine, liver, and oral cavity of treated animals at 15 months. At the end of the study, neoplasms related to chemical administration were found in the Zymbal's gland, skin, oral cavity, and the preputial or clitoral gland in both male and female rats. Neoplasms related to chemical administration were also seen at other sites including the small and large intestine, liver, uterus, and brain. The incidence of mononuclear cell leukemia was also increased in treated rats. Genetic Toxicology: C.I. Direct Blue 15 was not mutagenic in Salmonella typhimurium strains TA100, TA1535, TA1537, and TA98 when tested in a standard preincubation protocol with or without exogenous metabolic activation; however, when a specialized reductive metabolism protocol was used, C.I. Direct Blue demonstrated mutagenic activity in Salmonella strain TA1538. C.I. Direct Blue 15 did not induce sister chromatid exchanges or chromosomal aberrations in Chinese hamster ovary cells with or without S9 activation; reductive metabolism was not used in these cytogenetic tests. Conclusions: Under the conditions of these 22-month drinking water studies, there was clear evidence of carcinogenic activity of C.I. Direct Blue 15 (desalted industrial grade) in male F344/N rats, as indicated by benign and malignant neoplasms of the skin, Zymbal's gland, preputial gland, liver, oral cavity, and small and large intestine. Increased incidences of mononuclear cell leukemia and neoplasms of the brain may have been related to chemical administration. There was clear evidence of carcinogenic activity of C.I. Direct Blue 15 in female F344/N rats, as indicated by benign and malignant neoplasms of the skin, Zymbal's gland, clitoral gland, liver, oral cavity, small and large intestine, and uterus, and by mononuclear cell leukemia. Synonyms: Airedale Blue D, Aizen Direct Sky Blue 5BH, Amanil Sky Blue, Atlantic Sky Blue A, Atul Direct Sky Blue, Azine Sky Blue 5B, Belamine Sky Blue A, Benzanil Sky Blue, Benzo Sky Blue S, Benzo Sky Blue A-CF, Cartasol Blue 2GF, Chloramine Sky Blue A, Chloramine Sky Blue 4B, Chrome Leather Pure Blue, C.I. 24400, Cresotine Pure Blue, Diacotton Sky Blue 5B, Diamine Blue 6B, Diamine Sky Blue, Diaphtamine Pure Blue, Diazol Pure Blue 4B, 3,3'-[(3,3'-dimethoxy[1,1'-biphenyl]-4,4'-diyl)bis(azo)]bis[5-amino-4-hydroxy-2,-naphthalenedisulfonic acid] tetrasodium salt, Diphenyl Brilliant Blue, Diphenyl Sky Blue 6B, Direct Blue 10G, Direct Blue HH, Direct Pure Blue, Direct Pure Blue M, Direct Sky Blue (6CI), Direct Sky Blue A, Direct Sky Blue 5B, Enianil Pure Blue AN, Fenamin Sky Blue, Hispamin Sky Blue 3B, Kayafect Blue Y, Kayaku Direct Sky Blue 5B, Mitsui Direct Sky Blue 5B, Naphtamine Blue 10G, Niagara Blue 4B, Niagara Sky Blue, Nippon Direct Sky Blue, Nitto Direct Sky Blue 5B, Paper Blue S, Phenamine Sky Blue A, Pontamine Sky Blue 5BX, Shikiso Direct Sky Blue 5B, Sky Blue 4B, Sky Blue 5B, Tertrodirect Blue F, Vondacel Blue HH
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PMID:NTP Toxicology and Carcinogenesis Studies of C.I. Direct Blue 15 (CAS No. 2429-74-5) in F344 Rats (Drinking Water Studies). 1263 62

3,3'-Dimethylbenzidine dihydrochloride is one of five chemicals being evaluated in 2-year carcinogenicity and toxicity studies as part of the NTP's Benzidine Dye Initiative. This Initiative was designed to evaluate representative benzidine congeners, benzidine congener-derived dyes, and benzidine-derived dyes. 3,3'-Dimethylbenzidine dihydrochloride was nominated for study because of the potential for human exposure during production of bisazobiphenyl dyes and because benzidine, a structurally related chemical, is a known human carcinogen. Toxicology and carcinogenesis studies were conducted by administering 3,3'-dimethylbenzidine dihydrochloride (approximately 99% pure) in drinking water to groups of F344/N rats of each sex for 14 days, 13 weeks, or 9 or 14 months. The 14-month exposures were planned as 24-month exposures but were terminated early because of rapidly declining animal survival, due primarily to neoplasia. These studies were performed only in rats because similar studies were being performed in mice at the National Center for Toxicological Research (NCTR). Hematologic and serum chemical analyses and thyroid hormone determinations were conducted in conjunction with the 13-week and 9-month studies. Genetic toxicology studies were conducted in Salmonella typhimurium, Chinese hamster ovary (CHO) cells, and Drosophila melanogaster. 14-Day Studies: Rats were exposed to 3,3'-dimethylbenzidine dihydrochloride in drinking water at doses ranging from 600 to 7,500 ppm. All five males and one female in the 7,500 ppm group and 1/5 males in the 5,000 ppm group died. Final mean body weights were decreased in males receiving 1,250 ppm or more and in all exposed females, and final mean body weights of animals receiving 2,500 ppm or more were lower than initial weights. Water consumption decreased with increasing chemical concentration. Compound-related effects observed in rats receiving 5,000 ppm or more included minimal to slight hepatocellular necrosis, accumulation of brown pigment (presumably bile) in individual hepatocytes, increased severity of nephropathy relative to controls, and severe lymphocytic atrophy of the thymus. Treated animals also showed an increased severity of atrophy of the bone marrow relative to controls, varying degrees of lymphocytic atrophy of the mandibular and mesenteric lymph nodes and spleen, increased vacuolization and necrosis of cells of the adrenal cortex, focal acinar cell degeneration in the pancreas, and, in males, increased immature sperm forms in the testis and epididymis. 13-Week Studies: 3,3'-Dimethylbenzidine dihydrochloride was administered in drinking water at doses of 300, 500, 1,000, 2,000, and 4,000 ppm. All rats receiving 4,000 ppm and 4/10 males and 1/10 females receiving 2,000 ppm died before the end of the studies. Depressions in final mean body weight relative to controls ranged from 12% to 48% for males and from 9% to 42% for females. Water consumption decreased with increasing dose. At compound concentrations of 300 to 2,000 ppm, mean water consumption was 29% to 83% of control values. Compound-related effects included an increase in the severity of nephropathy relative to controls; hepatocellular necrosis and accumulation of brown pigment (presumably bile) in sinusoidal lining cells; lymphocytic atrophy of the thymus, spleen, and mandibular and mesenteric lymph nodes; atrophy of the bone marrow in the higher-dose groups; degeneration of pancreatic acinar cells; and, in males, immature sperm forms in the testis and epididymis. Decreases in serum triiodothyronine (T3) values were observed in exposed females, and decreases in mean thyroxin (T4) concentrations in exposed males and females; no significant changes were observed in thyroid stimulating hormone (TSH) levels in exposed rats. Based on the decreased survival, reductions in water consumption and body weight gain, and chemical-induced hepatocellular and renal lesions observed in the 13-week studies, the doses selected for the 9- and 14-month drinking water studies of 3,3'-dimethylbenzidine dihydrochloride were 0, 3 3,3'-dimethylbenzidine dihydrochloride were 0, 30, 70, and 150 ppm. Seventy rats of each sex were used in the control group, 45 in the low-dose group, 75 in the mid-dose group, and 70 in the high-dose group. 9-Month Studies: Ten rats of each sex in the control and 150 ppm dose groups were evaluated after 9 months. Chemical-related effects observed in exposed animals included alveolar/bronchiolar carcinoma in one male, basal cell carcinoma of the skin in one male, a squamous cell carcinoma of the oral cavity in one female, preputial gland carcinoma in two males, clitoral gland carcinoma in three females, adenocarcinoma of the small intestine in two males, Zymbal's gland carcinoma in two males and three females, hepatocellular carcinoma in two males, and adenomatous polyps of the large intestine in three males. Other effects seen in dosed rats included focal cellular alteration in the liver, lymphoid atrophy in the spleen, and increased severity of nephropathy relative to controls. An increase in serum T3 values was observed in exposed males, and a decrease in mean T4 concentrations in exposed males and females. TSH concentrations were increased in exposed male and female rats. Body Weights and Survival in the 14-Month Studies: The average amount of 3,3'-dimethylbenzidine dihydrochloride consumed per day was approximately 1.8, 4.0, or 11.2, mg/kg for low-, mid-, or high-dose male rats and 3.0, 6.9, or 12.9 mg/kg for low-, mid-, or high-dose female rats. The mean body weight of high-dose males was about 85&percnt; of the control value by week 28. By the end of the study, mean body weights of low-, mid-, and high-dose males were 97&percnt;, 92&percnt;, and 70&percnt; of the control values, respectively. Mean body weights of high- and mid-dose females were about 85&percnt; of the control values at week 32 and week 44, respectively. At the end of the study, mean body weights of exposed females were about 94&percnt;, 81&percnt;, and 74&percnt; of the control values for low-, mid-, and high-dose groups, respectively. Because of extensive neoplasia, many exposed males and females were dying or were sacrificed moribund in the first year, and all high-dose males died by week 55. The studies were terminated at weeks 60 to 61, at which time the group survivals were male: control, 60/60, low dose, 41/45; mid dose, 50/75; high dose, 0/60; female: 59/60; 39/45; 32/75; 10/60. Nonneoplastic Effects in the 14-Month Studies: Increases in nonneoplastic lesions in dosed rats included cystic degeneration and foci of cellular alteration in the liver; exacerbation of nephropathy; and focal or multifocal hyperplasia of the Zymbal's gland, preputial and clitoral glands, and alveolar epithelium. Neoplastic Effects in the 14-Month Studies: Neoplasms were observed in exposed rats at many sites: skin, Zymbal's gland, preputial and clitoral glands, liver, oral cavity, small and large intestine, mammary gland, lung, brain, and mesothelium. The incidence of these neoplastic effects in male and female rats is summarized in the table at the end of this section (see page 8 of the Technical Report). Genetic Toxicology: 3,3'-Dimethylbenzidine dihydrochloride was mutagenic in Salmonella typhimurium strain TA98 with exogenous metabolic activation; it was not mutagenic in strains TA100, TA1535, or TA97 with or without activation. 3,3'-Dimethylbenzidine dihydrochloride induced sister-chromatid exchanges (CHO) and chromosomal aberrations in CHO cells in the absence of exogenous metabolic activation; these effects were not evident in test with S9 activation. Sex-linked recessive lethal mutations were induced in germ cells of adult male Drosophila melanogaster administered 3,3'-dimethylbenzidine dihydrochloride in feed or by injection. No reciprocal translocations occurred in D. melanogaster germ cells following exposure to 3,3'-dimethylbenzidine dihydrochloride. Conclusions: Under the conditions of these 14-month drinking water studies, there was clear evidence of carcinogenic activity of 3,3'-dimethylbenzidine dihydrochloride for male F344/N rats, as indicated by benign and malignant neoplasms of the skin, Zymbal's gland, preputial gland, liver, oral cavity, small and large intestine, lung, and mesothelium. Increased incidences of neoplasms of the brain may have been related to chemical administration. There was clear evidence of carcinogenic activity for female F344/N rats, as indicated by benign and malignant neoplasms of the skin, Zymbal's gland, clitoral gland, liver, oral cavity, small and large intestine, mammary gland, and lung. Increased incidences of neoplasms of the brain and mononuclear cell leukemia may have been related to chemical administration. Synonyms: o-tolidine dihydrochloride; 3,3'-dimethylbiphenyl-4,4'-diamine dihydrochloride; 3,3'-dimethylbiphenyl-4,4'-biphenyldiamine dihydrochloride; 4,4'-diamino-3,3'-dimethylbiphenyl dihydrochloride
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PMID:NTP Toxicology and Carcinogenesis Studies of 3,3'-Dimethylbenzidine Dihydrochloride (CAS No. 612-82-8) in F344/N Rats (Drinking Water Studies). 1263 69

Nalidixic acid is an antimicrobial agent to treat bacterial infections of the urinary tract. NTP Toxicology and Carcinogenesis studies were conducted by feeding diets containing nalidixic acid (approximately 99% pure) to groups of F344/N rats and B6C3F1 mice of each sex for 13 weeks or 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium, mouse lymphoma cells, and Chinese hamster ovary (CHO) cells. Thirteen-Week Studies: Nalidixic acid was administered at dietary concentrations ranging from 1,000 to 16,000 ppm. One female rat that received 16,000 ppm nalidixic acid died before the end of the studies; no other compound-related deaths occurred in rats and mice. The final mean body weights of rats that received 8,000 or 16,000 ppm were 23% or 49% lower than those of controls for males and 11% or 31% lower for females. Feed consumption by rats receiving 16,000 ppm was approximately two-thirds that by controls. Liver weight to body weight ratios for male rats that received 2,000 ppm or more and female rats that received 8,000 ppm or more were significantly greater than those for controls. Degeneration of the germinal epithelium in the seminiferous tubules of the testis was observed in 10/10 male rats that received 16,000 ppm; no other compound-related histopathologic effects were observed in rats. The final mean body weights of mice that received 8,000 or 16,000 ppm were 10%-20% lower than those of controls. Feed consumption by dosed mice was similar to that by controls. Liver weight to body weight ratios were significantly greater for male mice receiving 2,000, 8,000, or 16,000 ppm and for female mice receiving 4,000, 8,000, or 16,000 ppm than for the controls. No compound-related histopathologic effects were observed in mice. Based on these results, 2-year studies of nalidixic acid were conducted by feeding diets containing 0, 2,000, or 4,000 ppm nalidixic acid to groups of 50 male and 50 female F344/N rats and 50 male and 50 female B6C3F1 mice. Body Weight and Survival in the Two-Year Studies: Mean body weights of high dose rats were 7%-23% lower than those of controls, and those of low dose male rats were 6%-11% lower than those of controls. The average daily feed consumption by dosed rats ranged from 89% to 96% that by controls. The average amount of nalidixic acid consumed per day was approximately 80 or 175 mg/kg for low dose or high dose rats. Mean body weights of high dose male mice were 1%-8% lower than those of controls throughout the study. Mean body weights of dosed female mice were 5%-17% lower than those of controls. Average daily feed consumption by dosed mice was within 3% of that by controls. The estimated average amount of nalidixic acid consumed per day was approximately 220 or 475 mg/kg for low dose or high dose mice. No significant differences in survival were seen between any groups of rats or mice of either sex after 2 years (male rats: control, 27/50; low dose, 28/50; high dose, 27/50; female rats: 22/50; 31/50; 29/50; male mice: 33/50; 34/50; 31/50; female mice: 40/50; 43/50; 32/50). Nonneoplastic and Neoplastic Effects in the Two-Year Studies: The incidences of preputial gland neoplasms in dosed male rats and of clitoral gland neoplasms in dosed female rats were significantly greater than those in controls (male--preputial gland adenomas, papillomas, or carcinomas, combined: control, 3/49; low dose, 19/49; high dose, 20/47; female--clitoral gland adenomas, papillomas, or carcinomas, combined: 5/46; 15/46; 16/47). A squamous cell carcinoma of the tongue was seen in two high dose male rats. The historical incidence of oral cavity neoplasms in untreated control male F344/N rats is 7/1,596 (0.4%). There were decreased incidences of leukemia (20/50; 9/50; 7/50) and mammary gland neoplasms (10/50; 7/50; 2/50) in dosed female rats and of pituitary gland neoplasms (11/49; 2/50; 2/50) in dosed male rats. Retinal degeneration and cataracts of the eye were observed at increased incidences in dosed rats (degeneration--male: 4/48; 41/48; 47/49; female: 2/47; 40/48; 46/50; cataracts--malee observed at increased incidences in dosed rats (degeneration--male: 4/48; 41/48; 47/49; female: 2/47; 40/48; 46/50; cataracts--male: 11/48; 23/48; 38/49; female: 0/47; 18/48; 14/50). The cause of these cataracts and retinal degeneration is uncertain because cages were not rotated and low and high dose groups of rats may have been exposed to greater light intensity than were the controls. Subcutanous tissue fibrosarcomas and fibromas or fibrosarcomas (combined) were increased in dosed male mice (fibromas or fibrosarcomas, combined: 5/50; 9/50; 14/50). There were no increased incidences of neoplasms in dosed female mice. Genetic Toxicology: Nalidixic acid was not mutagenic in any of several in vitro short-term tests. No gene reversion was observed in S. typhimurium strains TA97, TA98, TA100, or TA1535 after exposure to nalidixic acid in either the presence or absence of exogenous metabolic activation. Results of tests for induction of trifluorothymidine resistance in mouse L5178Y/TK lymphoma cells were negative with or without metabolic activation. In CHO cells, nalidixic acid did not induce sister chromatid exchanges or chromosomal aberrations in either the presence or absence of activation. Conclusions: Under the conditions of these 2-year feed studies, there was clear evidence of carcinogenic activity of nalidixic acid for F344/N rats, as indicated by increased incidences of preputial gland neoplasms in males and clitoral gland neoplasms in females. There was equivocal evidence of carcinogenic activity for male B6C3F1 mice fed diets containing nalidixic acid, as indicated by marginally increased incidences of subcutaneous tissue neoplasms. There was no evidence of carcinogenic activity for female B6C3F1 mice fed diets containing 2,000 or 4,000 ppm nalidixic acid for 2 years. Synonym: 1-ethyl-1,4-dihydro-7-methyl-4-oxo-1,8-naphthyridine-3-carboxylic acid Trade Names: NegGram®.; Dixiben®.; Nalidixan®.; Nalurin®.; Nogram®.; UroNeg®.; Uralgin®.; Urisal®.
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PMID:NTP Toxicology and Carcinogenesis Studies of Nalidixic Acid (CAS No. 389-08-2) in F344/N Rats and B6C3F1 Mice (Feed Studies). 1269 36

Hydroquinone is used an antioxidant in the rubber industry and as a developing agent in photography. It is also an intermediate in the manufacture of rubber and food antioxidants and monomer inhibitors. Hydroquinone and products containing hydroquinone are used as depigmenting agents to lighten skin. NTP Toxicology and Carcinogenesis studies were conducted by administering hydroquinone (greater than 99% pure) in corn oil or water by gavage to groups of F344/N rats and B6C3F1 mice of each sex for 14 days, 13 weeks, or 2 years. Additionally, genetic toxicology studies were conducted in Salmonella typhimurium, mouse lymphoma cells, Chinese hamster ovary (CHO) cells, and Drosophila melanogaster. Preliminary 3-day dermal studies were conducted with rats and mice using sufficient hydroquinone in 95% ethanol to crystallize on the skin (4 or 40 mg per animal); conjugated metabolites of hydroquinone were detected in the urine. Fourteen-day dermal studies were conducted at doses up to 3,840 mg/kg for rats and 4,800 mg/kg for mice. No toxic effects were seen in the 3- or 14-day dermal studies. Therefore, in further evaluations of hydroquinone, the gavage route of administration was used. Results of Fourteen-Day and Thirteen-Week Studies: Fourteen-day gavage studies were conducted by administering hydroquinone in corn oil to rats at doses ranging from 63 to 1,000 mg/kg body weight and to mice at doses ranging from 31 to 500 mg/kg. All rats receiving 1,000 mg/kg and 1/5 male and 4/5 female rats receiving 500 mg/kg died before the end of the 14 days. Compound-related clinical signs in rats included tremors lasting up to 30 minutes after each dosing at 500 and 1,000 mg/kg. In the 14-day gavage studies with mice, 4/5 male mice and 5/5 female mice receiving 500 mg/kg and 3/5 males receiving 250 mg/kg died before the end of the studies. Tremors followed by convulsions were seen at 250 and 500 mg/kg. In the 13-week studies, doses for rats and mice ranged from 25 to 400 mg/kg. All rats receiving 400 mg/kg and 3/10 female rats receiving 200 mg/kg died before the end of the studies. The mean body weight at necropsy of male rats administered 100 or 200 mg/kg was about 8%-9% lower than that of vehicle controls. Mean body weights of vehicle control and dosed female rats at necropsy were similar. Tremors and convulsions were observed after dosing in most rats receiving 400 mg/kg and in several female rats receiving 200 mg/kg. Inflammation and/or epithelial hyperplasia (acanthosis) of the forestomach were seen in 4/10 male rats and 1/10 female rats receiving 200 mg/kg. Toxic nephropathy, characterized by tubular cell degeneration in the renal cortex, was seen in 7/10 male and 6/10 female rats receiving 200 mg/kg and in 1/10 females receiving 100 mg/kg. In the 13-week studies in mice, 8/10 males and 8/10 females receiving 400 mg/kg and 2/10 male mice receiving 200 mg/kg died early. Mean body weights of dosed and vehicle control mice at necropsy were similar. Liver weight to body weight ratios for dosed male mice were significantly greater than for vehicle controls. Ulceration, inflammation, or epithelial hyperplasia of the forestomach was found in 3/10 male and 2/10 female mice receiving 400 mg/kg and 1/10 females receiving 200 mg/kg. Based on these collective results, 2-year studies were conducted by administering 0, 25, or 50 mg/kg hydroquinone in deionized water by gavage to groups of 65 rats of each sex, 5 days per week. Groups of 65 mice of each sex were administered 0, 50, or 100 mg/kg on the same schedule. Ten rats and 10 mice from each group were killed after 15 months for an interim evaluation. Observations at Fifteen Months: In the rats killed at 15 months, the relative kidney weight for high dose male rats was greater than that for vehicle controls. The hematocrit value, hemoglobin concentration, and erythrocyte count for high dose female rats were decreased. Compound-related increased severity of nephropathy was observed in male rats. In mice killed at 15 months, the relative liver weights for high dose male and female mice were signif and female mice were significantly greater than those for vehicle controls. Lesions seen in the liver of male mice included increased syncytial cells and diffuse cytomegaly. Body Weights, Organ Weights, and Survival in the Two-Year Studies: Mean body weights of high dose male rats were 5&percnt;-13&percnt; lower than those of vehicle controls after week 73, and those of low dose male rats were 5&percnt;-9&percnt; lower than those of vehicle controls after week 89. Mean body weights of dosed female rats were similar to those of vehicle controls throughout the study. The relative kidney and liver weights for high dose male rats were higher than those for vehicle controls. Mean body weights of high dose male mice were 5&percnt;-8&percnt; lower than those of vehicle controls after week 93, and those of high dose female mice were 5&percnt;-14&percnt; lower after week 20. Relative liver weights were increased for dosed male and high dose female mice. No significant differences in survival were observed between any groups of rats or mice of either sex after 2 years (male rats: vehicle control, 27/55; low dose, 18/55; high dose, 18/55; female rats: 40/55; 27/55; 32/55; male mice: 33/55; 37/54; 36/55; female mice: 37/55; 39/55; 36/55). Nonneoplastic and Neoplastic Effects in the Two-Year Studies: Nearly all male rats and most female rats in all vehicle control and dosed groups had nephropathy. The severity of this disease was judged to be greater in high dose male rats. Hyperplasia of the renal pelvic transitional epithelium and renal cortical cysts, changes observed with advanced renal disease, were increased in male rats. Renal tubular hyperplasia was seen in 2 high dose male rats, and renal tubular adenomas were seen in 4/55 low dose and 8/55 high dose male rats; none was seen in vehicle controls. Mononuclear cell leukemia in female rats occurred with a positive trend, and the incidences in the dosed groups were greater than that in the vehicle controls (vehicle control, 9/55; low dose, 15/55; high dose, 22/55). The historical incidence of leukemia in water gavage vehicle control female F344/N rats is 25&percnt; ± 15&percnt; and in untreated controls is 19&percnt; ± 7&percnt;. Compound-related lesions observed in the liver of high dose male mice included anisokaryosis (0/55; 2/54; 12/55), syncytial alteration (5/55; 3/54; 25/55), and basophilic foci (2/55; 5/54; 11/55). The incidences of hepatocellular adenomas were increased in dosed male mice (9/55; 21/54; 20/55), but these increases were offset by decreases in the incidences of hepatocellular carcinomas (13/55; 11/54; 7/55). The incidences of hepatocellular neoplasms, primarily adenomas, were increased in dosed female mice (3/55; 16/55; 13/55). Follicular cell hyperplasia of the thyroid gland was increased in dosed mice (male: 5/55; 15/53; 19/54; female: 13/55; 47/55; 45/55). Follicular cell adenomas were seen in 2/55 vehicle control, 1/53 low dose, and 2/54 high dose male mice and in 3/55 vehicle control, 5/55 low dose, and 6/55 high dose female mice, a follicular cell carcinoma was seen in a seventh high dose female mouse. The highest observed incidence of follicular cell adenomas or carcinomas(combined) in historical water gavage vehicle control female B6C3F1 mice is 3/48 (6&percnt;). Genetic Toxicology: Hydroquinone was not mutagenic in S. typhimurium strains TA98, TA100, TA1535, or TA1537 with or without exogenous metabolic activation. It induced trifluorothymidine (Tft) resistance in mouse L5178Y/TK lymphoma cells in the presence or absence of metabolic activation. An equivocal response was obtained in tests for induction of sex-linked recessive lethal mutations in Drosophila administered hydroquinone by feeding. Hydroquinone induced sister chromatid exchanges (SCEs) in CHO cells both with or without exogenous metabolic activation and caused chromosomal aberrations in the presence of activation. Conclusions: Under the conditions of these 2-year gavage studies, there was some evidence of carcinogenic activity of hydroquinone for male F344/N rats, as shown by marked increases in tubular cell adenomas of the kidney. There was some evidence of carcinogenic activity of hydroquinone for female F344/N rats, as shown by increases in mononuclear cell leukemia. There was no evidence of carcinogenic activity of hydroquinone for male B6C3F1 mice administered 50 or 100 mg/kg in water by gavage. There was some evidence of carcinogenic activity of hydroquinone for female B6C3F1 mice, as shown by increases in hepatocellular neoplasms, mainly adenomas. Administration of hydroquinone was associated with thyroid follicular cell hyperplasia in both male and female mice and anisokaryosis, multinucleated hepatocytes, and basophilic foci of the liver in male mice. Synonyms: 1,4-benzenediol; p-benzenediol; benzohydroquinone; benzoquinol; 1,4-dihydroxybenzene; p-dihydroxybenzene; p-dioxobenzene; p-dioxybenzene; hydroquinol; hydroquinole; a-hydroquinone; p-hydroquinone; p-hydroxyphenol; quinol; b-quinol
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PMID:NTP Toxicology and Carcinogenesis Studies of Hydroquinone (CAS No. 123-31-9) in F344/N Rats and B6C3F1 Mice (Gavage Studies). 1269 38

Glycidol is a viscous liquid that is used as a stabilizer in the manufacture of vinyl polymers, as an additive for oil and synthetic hydraulic fluids, and as a diluent in some epoxy resins. NTP Toxicology and Carcinogenesis studies were conducted by administering glycidol (94% pure, containing 1.2% 3-methoxy-1,2-propanediol, 0.4% 3-chloro-1,2-propanediol, 2.8% diglycidyl ether, and 1.1% 2,6-dimethanol-1,4-dioxane) in water by gavage to groups of F344/N rats and B6C3F1 mice of each sex for 16 days, 13 weeks, or 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium, Chinese hamster ovary (CHO) cells, Drosophila melanogaster, and the bone marrow of male B6C3F1 mice. Sixteen-Day Studies: Glycidol doses for groups of five rats or five mice of each sex ranged from 37.5 to 600 mg/kg; vehicle controls received distilled water. All rats that received 600 mg/kg died between days 3 and 13. Edema and degeneration of the epididymal stroma, atrophy of the testis, and granulomatous inflammation of the epididymis occurred in males that received 300 mg/kg. All mice that received 600 mg/kg and two males and two females that received 300 mg/kg died by day 4 of the studies. Focal demyelination in the medulla and thalamus of the brain occurred in all female mice that received 300 mg/kg. Thirteen-Week Studies: Doses for groups of 10 rats ranged from 25 to 400 mg/kg, and doses for groups of 10 mice ranged from 19 to 300 mg/kg; vehicle controls received distilled water. All rats that received 400 mg/kg died by week 2; three males and one female that received 200 mg/kg died during weeks 11-12. Final mean body weights of male rats that received 50, 100, or 200 mg/kg were 96%-85% that of vehicle controls; final mean body weights of female rats receiving the same doses were 95%-89% that of vehicle controls. Sperm count and sperm motility were reduced in male rats that received 100 or 200 mg/kg. Necrosis of the cerebellum, demyelineation in the medulla of the brain, tubular degeneration and/or necrosis of the kidney, lymphoid necrosis of the thymus, and testicular atrophy and/or degeneration occurred in rats that received 400 mg/kg. All mice that received 300 mg/kg died by week 2; deaths of mice that received 150 mg/kg occurred during weeks 4-8 for males and weeks 1-5 for females. Mean body weights of chemically exposed mice surviving to the end of the studies were generally 90%-94% those of vehicle controls. Sperm count and sperm motility were reduced in dosed male mice. Compound-related histopathologic lesions included demyelination of the brain in males and females that received 150 or 300 mg/kg, testicular atrophy in males at all doses, and renal tubular cell degeneration in male mice that received 300 mg/kg. Based on reduced survival, reduced weight gain, and histopathologic lesions in the brain and kidney in rats that received 200 or 400 mg/kg and on reduced survival and histopathologic lesions of the brain in mice that received 150 or 300 mg/kg, doses selected for the 2-year studies of glycidol were 37.5 and 75 mg/kg for rats and 25 and 50 mg/kg for mice. Body Weights and Survival in the Two-Year Studies: Mean body weights of chemically exposed male rats generally ranged from 80% to 94% of those of vehicle controls, and mean body weights of chemically exposed female rats were from 90% to 97% those of vehicle controls. Mean body weights of chemically exposed male mice were similar to those of vehicle controls; mean body weights of chemically exposed female mice were 79%-95% of those of vehicle controls. Virtually all male and female rats that received glycidol died or were killed in a moribund condition as a result of the early induction of neoplastic disease (final survival--male: vehicle control, 16/50; low dose, 0/50; high dose, 0/50; female: 28/50; 4/50; 0/50). Survival of vehicle control male rats was lower than that usually observed; however, specific causes of deaths could not be determined. The survival of male mice and low dose female mice was similar to that of vehicle controls; survival of female mice that resurvival of male mice and low dose female mice was similar to that of vehicle controls; survival of female mice that received 50 mg/kg was lower than that of vehicle controls after week 101 (final survival--male: 33/50; 25/50; 27/50; female: 29/50; 27/50; 17/50). Nonneoplastic and Neoplastic Effects in the Two-Year Studies: Chemical-related nonneoplastic lesions in both rats and mice included hyperkeratosis and epithelial dysplasia of the forestomach. Fibrosis of the spleen was also present in rats of each sex, and cysts of the preputial gland and kidney were present in male mice. Exposure to glycidol induced dose-related increases in the incidences of neoplasms in numerous tissues in both rats and mice (see summary table on page 5 of the Technical Report). In male rats, mesotheliomas arising in the tunica vaginalis and frequently metastasizing to the peritoneum were considered the major cause of early death. Early deaths in female rats were associated with the presence of mammary gland neoplasms. Genetic Toxicology: Glycidol was mutagenic in a variety of in vitro and in vivo short-term tests. Mutagenic activity was observed in S. typhimurium strains TA97, TA98, TA100, TA1535, and TA1537 exposed to glycidol with and without exogenous metabolic activation. Glycidol was positive in the absence of exogenous metabolic activation in the mouse lymphoma assay for induction of trifluorothymidine resistance in L5178Y/TK cells; it was not tested with activation. In cytogenetic tests with CHO cells, glycidol induced both sister chromatid exchanges and chromosomal aberrations in the presence and absence of exogenous metabolic activation. Glycidol induced sex-linked recessive lethal mutations and reciprocal translocations in the germ cells of male D. melanogaster exposed by feeding. The incidence of micronucleated polychromatic erythrocytes was increased in the bone marrow of male B6C3F1 mice administered glycidol by intraperitoneal injection. Conclusions: Under the conditions of these 2-year gavage studies, there was clear evidence of carcinogenic activity of glycidol for male F344/N rats, based on increased incidences of mesotheliomas of the tunica vaginalis; fibroadenomas of the mammary gland; gliomas of the brain; and neoplasms of the forestomach, intestine, skin, Zymbal gland, and thyroid gland. There was clear evidence of carcinogenic activity for female F344/N rats, based on increased incidences of fibroadenomas and adenocarcinomas of the mammary gland; gliomas of the brain; neoplasms of the oral mucosa, forestomach, clitoral gland, and thyroid gland; and leukemia. There was clear evidence of carcinogenic activity for male B6C3F1 mice based on increased incidences of neoplasms of the harderian gland, forestomach, skin, liver, and lung. There was clear evidence of carcinogenic activity for female B6C3F1 mice, based on increased incidences of neoplasms of the harderian gland, mammary gland, uterus, subcutaneous tissue, and skin. Other neoplasms that may have been related to the administration of glycidol were fibrosarcomas of the glandular stomach in female rats and carcinomas of the urinary bladder and sarcomas of the epididymis in male mice. Synonym: 2,3-epoxy-1-propanol
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PMID:NTP Toxicology and Carcinogenesis Studies of Glycidol (CAS No. 556-52-5) In F344/N Rats and B6C3F1 Mice (Gavage Studies). 1269 47

1-Amino-2,4-dibromoanthraquinone is an anthraquinone-derived vat dye, a member of a class of insoluble dyes that are impregnated into textile fibers. Five anthraquinone-derived dyes with representative and diverse structures, as well as the parent chemical, anthraquinone, were selected for NTP Toxicology and Carcinogenesis evaluation. Similar to the benzidine dye initiative, the rationale for selecting these vat dyes was to generate sufficient toxicologic data to permit more reliable predictions of carcinogenicity to be made on other chemicals in this class, thereby eliminating or reducing the need to study every anthraquinone dye. 1-Amino-2,4-dibromoanthraquinone is the last anthraquinone-derived dye in this group to be studied. Groups of male and female F344/N rats and B6C3F1 mice were exposed to 1-amino-2,4-dibromoanthraquinone (87% to 97% pure) for 13 weeks or for 9, 15, or 24 months. Because 1-amino-2,4-dibromoanthraquinone was predicted to be carcinogenic, these studies were designed to evaluate the potential for tumor progression and regression. Absorption and excretion studies were carried out in male F344/N rats. Genetic toxicity was determined in vitro using Salmonella typhimurium and cultured Chinese hamster ovary cells. Extensive chemical analyses were performed to identify and characterize impurities of the 1-amino-2,4-dibromoanthraquinone used in these studies. 13-WEEK STUDY IN RATS: Groups of 10 male and 10 female rats were given 0, 2,500, 5,000, 10,000, 25,000, or 50,000 ppm 1-amino-2,4-dibromoanthraquinone in feed for 13 weeks. These levels correspond to approximately 150 to 3,200 mg 1-amino-2,4-dibromoanthraquinone/kg body weight per day for males and to approximately 170 to 3,200 mg/kg for females. Chemical-related mortality was limited to one male and one female in the 50,000 ppm groups. Final mean body weights and body weight gains of all exposed groups of rats were significantly lower than those of the controls. Feed consumption by all exposed groups was less than that by the controls throughout the study and generally decreased with increasing exposure concentration. Pink-red staining of the fur and tail was observed in all exposed groups. Absolute and relative liver weights of all exposed groups were generally significantly greater than those of the controls. Chemical-related lesions were present in the liver, kidney, and spleen of male and female rats. Nonneoplastic lesions in the liver included foci of hepatocellular alteration, diffuse hepatocellular hypertrophy (cytomegaly), hepatocellular cytoplasmic vacuolation, bile duct hyperplasia, inflammation, and pigmentation. These differences were observed primarily in the 25,000 and 50,000 ppm groups of males and females; the spectrum of proliferative lesions of the bile ducts (hyperplasia, fibrosis, and necrotizing cholangitis) in the 25,000 and 50,000 ppm groups was morphologically consistent with the lesion described as cholangiofibrosis. Pigmentation was present in the renal tubule epithelium of all groups of exposed rats; nuclear enlargement (karyomegaly) was also present in the renal tubule epithelium in some of the exposed rats. Accumulation of hyaline droplets in the cytoplasm of the renal tubule epithelium and tubule lumina was present in 2,500, 5,000, 10,000, and 25,000 ppm males. Incidences of hematopoiesis of the spleen in exposed groups of males and females were increased compared to those in the controls. 13-WEEK STUDY IN MICE: Groups of 10 male and 10 female mice were given 0, 2,500, 5,000, 10,000, 25,000, or 50,000 ppm 1-amino-2,4-dibromoanthraquinone in feed for 13 weeks. These levels correspond to approximately 500 to 10,600 mg 1-amino-2,4-dibromoanthraquinone/kg body weight per day for males and approximately 660 to 11,700 mg/kg per day for females. There was no chemical-related mortality. Feed consumption and final mean body weights of exposed groups were similar to those of the controls. Red staining of the fur was observed in all exposed groups. Absolute and relative liver weights of the exposed groups were greater than those er than those of the controls except for the absolute liver weight of 2,500 ppm males. Absolute and relative kidney weights of 25,000 and 50,000 ppm males were lower than those of the controls. Chemical-related lesions were limited to the livers of males and consisted of pigmentation of hepatocytes at all exposure concentrations and centrilobular hepatocellular hypertrophy at 10,000, 25,000, and 50,000 ppm. Minimal pigment was present in the liver of one female in the 25,000 ppm group and in one female in the 50,000 ppm group. 2-YEAR STUDY IN RATS: Groups of 70 male and 70 female rats were given 0, 5,000, or 10,000 ppm 1-amino-2,4-dibromoanthraquinone in feed for 103 weeks. In addition, groups of 50 male and 50 female rats were given 2,000 ppm 1-amino-2,4-dibromoanthraquinone in feed for 104 weeks. These exposure concentrations were approximately equal to 90, 240, or 490 mg 1-amino-2,4-dibromoanthraquinone/kg body weight for males and 110, 285, or 600 mg/kg for females. Ten animals from each group were evaluated for histopathology at 9 months. Additional groups of 10 animals from the 0 and 10,000 ppm groups were evaluated for histopathology at 15 months. Survival, Body Weights, Feed Consumption, and Clinical Findings In the 2-year study, survival of the 10,000 ppm males and females was significantly lower than that of the controls. Survival of the 2,000 and 5,000 ppm groups was similar to that of the controls. During the last year of the study, the mean body weights of exposed males were 80&percnt; to 91&percnt; those of controls, and the mean body weights of exposed females were 67&percnt; to 84&percnt; those of controls. Feed consumption among exposed groups was generally similar, but was less than that by controls. The fur and urine of all exposed male and female groups were discolored. Pathology Findings In the 2-year study, 1-amino-2,4-dibromoanthraquinone was associated with significant chemical-related increases in the incidences of benign and malignant neoplasms in the liver, large intestine, kidney, and urinary bladder of males and females. Chemical-related nonneoplastic proliferative and degenerative lesions occurred in the liver, kidney, urinary bladder, and forestomach of males and females. The incidences of foci of hepatocellular alteration and pigmentation in the liver of males and females were increased at the 9-month interim evaluation, and a hepatocellular adenoma was present in one 5,000 ppm male. At the 15-month interim evaluation, hepatocellular adenoma or carcinoma (combined) occurred in all males and nine females in the 10,000 ppm groups. By the end of the 2-year study, hepatocellular adenoma, carcinoma, cholangioma, or cholangiocarcinoma were observed in males and females in the 5,000 and 10,000 ppm groups. In the 2,000 ppm groups, similar liver neoplasms were present in 63&percnt; of the males and in 83&percnt; of the females. Of the hepatocellular carcinomas in the 5,000 and 10,000 ppm groups of males and females, 31&percnt; to 49&percnt; were metastatic to the lungs or other sites. Increases in the incidences of foci of hepatocellular alteration (basophilic, eosinophilic, and clear cell) and pigmentation of the liver were also observed in exposed groups of males and females. Adenomatous polyps (adenoma) of the large intestine were present in six 10,000 ppm males at the 15-month interim evaluation. Incidences of adenomatous polyp (adenoma) and carcinoma of the large intestine were significantly increased in exposed groups of males and females after 2 years; multiple benign and malignant intestinal neoplasms were observed in many of these rats. In the kidney, incidences of renal tubule adenoma and carcinoma were significantly increased in exposed groups of males and females after 2 years. Renal tubule adenomas were present in two 10,000 ppm males at 15 months. There were also chemical-related increases in the incidences and severities of renal tubule epithelial hyperplasia, pigmentation, and transitional cell hyperplasia in the kidney of males and females. Hyaline droplet accumulation was present in all exposed male rats at 9 months. Incidences of transitional cell papilloma and carcinoma of the urinary bladder were increased at 2 years in males and females in the 10,000 ppm groups. Transitional cell hyperplasia was observed in exposed males and females at the 15-month interim evaluation. Other nonneoplastic lesions observed in the urinary bladder at 2 years included metaplasia of the transitional epithelium and submucosal stromal tissue. In the forestomach, the incidences and severities of inflammation, ulceration, hyperkeratosis, and hyperplasia of the squamous mucosa were increased in all exposed groups of males and females at 2 years, but not at the 9- or 15-month interim evaluations. In exposed males and females, the incidences of mononuclear cell leukemia were significantly decreased. The incidences of atrophy of the seminal vesicle were increased in exposed male rats in the 2-year study. Stop-Exposure Evaluation in Rats Groups of 40 male and 40 female rats were given 20,000 ppm 1-amino-2,4-dibromoanthraquinone in feed for 9 or 15 months. At 9 months, 10 males and 10 females were evaluated for histopathology (9-month interim evaluation groups). After 9 months of exposure, an additional 10 males and 10 females were fed control diet until the end of the 15-month evaluation (9-month stop-exposure groups), and 20 males and 20 females continued to receive 20,000 ppm 1-amino-2,4-dibromoanthraquinone until the end of the evaluation (15-month exposure groups). The approximate daily consumption of 1-amino-2,4-dibromoanthraquinone was 1,335 mg/kg for males and 1,790 mg/kg for females in the 9-month stop-exposure groups and 1,115 mg/kg for males and 1,435 mg/kg for females in the 15-month exposure groups. Survival was similar among groups except for the females in the 15-month exposure group; the survival of this group was lower than that of the controls. Lower mean body weights were related to increased exposure duration. The mean body weights of exposed males were 76&percnt; to 82&percnt; that of controls, and the mean body weights of exposed females were 73&percnt; to 84&percnt; that of controls. For the stop-exposure evaluation, similar chemical-related neoplasms and nonneoplastic lesions were observed in the same sites as in the 2-year study: liver, large intestine, kidney, urinary bladder, and forestomach. After 9 months of dietary exposure to a concentration of 20,000 ppm 1-amino-2,4-dibromoanthraquinone, hepatocellular adenoma and carcinoma occurred in males and females. Nonneoplastic chemical-related lesions in the liver of exposed rats included pigmentation, focal hepatocellular alteration, and bile duct hyperplasia. Neoplasms at other sites in males included one adenomatous polyp (adenoma) in the large intestine and one transitional cell papilloma in the urinary bladder. Hyaline droplet accumulation was present in the kidney of exposed males at 9 months. In the stop-exposure groups examined at 15 months, hepatocellular adenoma and carcinoma were present in most males and females. Adenomatous polyp (adenoma) of the colon, renal tubule cell adenoma, and urinary bladder transitional cell papilloma and carcinoma also occurred in males and females. Nonneoplastic chemical-related lesions included foci of hepatocellular alteration in the liver and hyperplasia of the renal tubule epithelium and urinary bladder transitional epithelium. Hyperplasia, hyperkeratosis, inflammation, and ulceration were observed in the forestomach of some male and female rats continuously exposed for 15 months. 2-YEAR STUDY IN MICE: Groups of 60 male and 60 female mice were given 0, 10,000, or 20,000 ppm 1-amino-2,4-dibromoanthraquinone in feed for 104 weeks. The daily compound consumption was approximately 1,690 or 3,470 mg 1-amino-2,4-dibromoanthraquinone/kg body weight for males and 1,950 or 4,350 mg/kg for females. Ten animals from each group were evaluated for histopathology at 15 months. Survival, Body Weights, Feed Consumption, and Clinical Findings In the 2-year study, survival of exposed males was significantly lower than that of the controls. Survival of exposed females was similar to that of the controls. The final mean body weights of exposed males were 83&percnt; to 85&percnt; that of controls, and the final mean body weights of exposed females were 81&percnt; to 86&percnt; that of controls. Feed consumption by exposed groups was generally similar to that by controls. Discoloration of the fur, urine, and feces was observed in all exposed groups. Pathology Findings In the 2-year study, 1-amino-2,4-dibromoanthraquinone was associated with significant chemical-related increases in the incidences of benign and malignant neoplasms in the liver, forestomach, and lung of males and females. Incidences of hepatocellular adenoma and carcinoma were increased in exposed groups at the 15-month interim evaluation and at 2 years. At 2 years, there were significant increases in the incidences of multiple hepatocellular adenoma and carcinoma in males and females and in the incidences of hepatoblastoma in males. Centrilobular hypertrophy of hepatocytes in males and foci of hepatocellular alteration and pigmentation in the liver of males and females were also chemical-related changes. Sqamous cell papilloma of the forestomach mucosa occurred in 10,000 ppm females and 20,000 ppm males and females at the 15-month interim evaluation, and the incidences of squamous cell papilloma and carcinoma were significantly increased in exposed groups of males and females at 2 years. Chemical-related hyperplasia of forestomach epithelium was also present at 15 months and at 2 years. Alveolar/bronchiolar adenomas were present only in the exposed groups of males and females at 15 months, and the incidences of alveolar/bronchiolar adenoma were significantly increased in exposed males and females at 2 years. The incidences of multiple alveolar/bronchiolar adenomas were also increased in exposed males. In the kidney, pigmentation was present in the renal tubules of most mice after 2 years of exposure. DISPOSITION AND METABOLISM STUDIES: Adult male F344/N rats were given [14C]-labeled 1-amino-2,4-dibromoanthraquinone as a single intravenous dose of 0.4 mg/kg body weight or as a single oral dose of 2, 23, 118, 814, or 1,473 mg/kg. A 6-hour bile cannulation study was also performed. From day 0 through day 3 after intravenous administration, about 50&percnt; of the 14C was excreted in the feces, 15&percnt; in the urine, and 6&percnt; in expired air. Unmetabolized 1-amino-2,4-dibromoanthraquinone accounted for less than 3&percnt; of the excreted 14C after intravenous administration. For oral doses administered, the amount of the dose that was absorbed fit the equation: absorbed dose = 6.6 x log(dose). After intravenous administration, the metabolites of 1-amino-2,4-dibromoanthraquinone in blood were primarily in the plasma fraction (blood:plasma ratio of approximately 0.5:1). The highest concentrations of 14C in tissues 15 minutes after intravenous dosing were in excretory organs, lung, kidney, small intestine, liver, adipose tissue, and adrenal gland. GENETIC TOXICOLOGY: 1-Amino-2,4-dibromoanthraquinone was mutagenic in Salmonella typhimurium strains TA98 and TA1537 in the absence of S9; with S9, an equivocal response was observed in TA1537. 1-Amino-2,4-dibromoanthraquinone resulted in an equivocal response in TA100 with and without S9, and no mutagenic activity was detected with strain TA1535. In cultured Chinese hamster ovary cells, 1-amino-2,4-dibromoanthraquinone induced sister chromatid exchanges with and without S9; chromosomal aberrations were induced in the absence of S9. CONCLUSIONS: Under the conditions of these 2-year feed studies, there was clear evidence of carcinogenic activity of 1-amino-2,4-dibromoanthraquinone in male and female F344/N rats based on increased incidences of neoplasms in the liver, large intestine, kidney, and urinary bladder. There was clear evidence of carcinogenic activity of 1-amino-2,4-dibromoanthraquinone in male and female B6C3F1 mice based on increased incidences of neoplasms in the liver, forestomach, and lung. Exposure of male and female rats to 1-amino-2,4-dibromoanthraquinone for 2 years was associated with basophilic focus (males only), clear cell focus, eosinophilic focus, and pigmentation in the liver; renal tubule hyperplasia, renal tubule pigmentation, and transitional cell hyperplasia in the kidney; transitional cell hyperplasia, squamous metaplasia, and stromal metaplasia (females only) in the urinary bladder; squamous hyperplasia, hyperkeratosis, ulceration, and inflammation of the forestomach mucosa; and seminal vesicle atrophy. Exposure of male and female mice to 1-amino-2,4-dibromoanthraquinone for 2 years was associated with centrilobular hepatocellular hypertrophy (males only), basophilic focus, clear cell focus (females only), eosinophilic focus, and pigmentation in the liver; pigmentation in the kidney; and hyperplasia, basal cell hyperplasia, hyperkeratosis, and inflammation of the forestomach mucosa. Synonym: ADBAQ
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PMID:NTP Toxicology and Carcinogenesis Studies of 1-Amino-2,4-Dibromoanthraquinone (CAS No. 81-49-2) in F344/N Rats and B6C3F1 Mice (Feed Studies). 1269 53

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