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Diethylphthalate and dimethylphthalate are used as phthalate plasticizers, in an extensive array of products. The chronic dermal toxicity of diethylphthalate was evaluated in male and female F344/N rats and B6C3F1 mice in 2-year studies. In a series of special studies, the tumor initiation or promotion potential of diethylphthalate or dimethylphthalate was evaluated in male Swiss (CD-1(R)) mice by an initiation/promotion model of skin carcinogenesis. The genetic toxicity of diethylphthalate and dimethylphthalate in Salmonella typhimurium and cultured Chinese hamster ovary cells was also evaluated. 4-WEEK STUDY IN F344/N RATS: Groups of 10 male and 10 female rats were dermally administered diethylphthalate at volumes of 0, 37.5, 75, 150, or 300 &mgr;L (0, 46, 92, 184, or 369 &mgr;g) applied neat, 5 days per week for 4 weeks. All male and female rats survived to the end of the study. No evidence of dermatotoxicity was observed, with no adverse clinical signs observed and no effects on weight gain or feed consumption. Relative liver weights of 300 &mgr;L males and females and 150 &mgr;L females were greater than those of controls. Relative kidney weights of 150 and 300 &mgr;L males and 150 &mgr;L females were greater than those of controls. No other adverse effects were observed in this study. 4-WEEK STUDY IN B6C3F1 MICE: Groups of 10 male and 10 female mice were dermally administered diethylphthalate at volumes of 0, 12.5, 25, 50, or 100 &mgr;L (0, 15, 31, 62, or 123 &mgr;) applied neat, five days per week for 4 weeks. One control female died before the end of the study; all other mice survived. No evidence of dermatotoxicity or other adverse clinical signs were observed, and no clear adverse effects on weight gain or feed consumption were seen. Absolute and relative liver weights of 25 and 100 &mgr;L females were greater than those of the controls. Based on these 4-week study results, doses of 0, 35, and 100 &mgr;L diethylphthalate were recommended for the 2-year mouse studies. A chronic study in male and female B6C3F1 mice at 0, 35, and 100 &mgr;L (applied neat, once per day, 5 days per week) was started and subsequently stopped after 32 weeks when significant body weight reductions were noted in treated animals (males and females, 100 &mgr;L groups: 19% lower; males, 35 &mgr;L group: 12% lower; females, 35 &mgr;L group: 10% lower than controls). Based on these body weight reductions, doses of 0, 7.5, 15, and 30 &mgr;L in 100 &mgr;L acetone were recommended for the restart of the 2-year mouse study. 2-YEAR STUDY IN F344/N RATS: Based upon the results of the 4-week study, doses of 0, 100, or 300 &mgr;L diethylphthalate (0, 123, or 369 &mgr;) were chosen for the 2-year rat study. Groups of 60 male and 60 female rats received the doses applied neat 5 days per week for 103 weeks and up to 10 animals per group were evaluated after 15 months. Survival, Body Weights, and Clinical Findings: Survival of dosed rats during the first 15 months was similar to that of controls. However, 2-year survival was significantly reduced in all groups of male rats (survival probabilities, males: 0 &mgr;L, 8%; 100 &mgr;L, 12%; and 300 &mgr;L, 12%). The mean body weights of 300 &mgr;L males were slightly less than those of the controls throughout the study. No adverse clinical signs were observed, including no evidence of dermatotoxicity. Pathology Findings: No morphological evidence of dermal or systemic toxicity was observed in male or female rats. Skin neoplasms were not observed in female rats and were only rarely observed in male rats. A high incidence of anterior pituitary adenoma occurred in all groups of male and female rats. The incidence of anterior pituitary adenomas in the 0, 100, and 300 &mgr;L groups were: males, 39/44, 41/49, 41/49; females, 38/50, 33/49, 33/48. The incidence of this benign tumor in control males (84%) exceeded the historical control mean incidence [feed controls, (28.7%)] and range (12% to 60%). Anterior pituitary adenomas were considered a primary contributing factor in the increased mortality observed in all grtor in the increased mortality observed in all groups, regardless of treatment. A dose-related decreasing trend in the incidence of mammary gland fibroadenomas was observed in female rats (21/50, 12/48, 7/50). The incidence of mononuclear cell leukemia in male rats in this study was lower than the historical incidence and may be attributable to the shortened life span of male rats. Similarly, the incidence of interstitial cell tumors of the testes was markedly decreased in all groups of males (4/50, 3/50, 8/50), relative to historical control rates (90.1%; range 74%-98%). The incidence of fatty liver degeneration was notably lower in dosed rats than in controls (males: 26/50, 8/50, 4/51; females: 23/50, 11/50, 3/50). 2-YEAR STUDY IN B6C3F1 MICE: Groups of 60 male and 60 female mice received doses of 0, 7.5, 15, or 30 μL diethylphthalate (0, 9, 18, or 37 μ) in 100 μL acetone 5 days per week for 103 weeks with a 1 week recovery period, and up to 10 animals per group were evaluated after 15 months. Survival, Body Weights, and Clinical Findings: Two-year survival of dosed mice was similar to that of controls: 43/50, 41/48, 46/50, and 43/50 (males), and 41/50, 38/51, 37/49, and 36/49 (females). Mean body weights of dosed male and female mice were similar to those of the controls throughout the study. No adverse clinical signs were observed in mice, including no gross evidence of dermatotoxicity. Feed consumption by male and female mice was similar to or up to 13% greater than that by controls. Pathology Findings: No morphological evidence of dermal toxicity was observed in male or female mice. No skin neoplasms were observed in dosed male mice. In female mice receiving 30 μL, one squamous cell carcinoma and one basal cell carcinoma were seen at the site of application. An increased incidence of liver neoplasms was observed in dosed male and female mice. The incidence of hepatocellular adenoma or carcinoma (combined) in B6C3F1 mice in the 0, 7.5, 15, and 30 μL groups were: (males) 9/50, 14/50, 14/50, and 18/50; (females) 7/50, 16/51, 19/50, and 12/50. The incidence of adenoma or carcinoma (combined) was increased in 30 μL male mice and the incidences of adenoma and of adenoma or carcinoma (combined) were increased in 7.5 and 15 μL females. A positive dose-related trend in the incidence of adenoma or carcinoma (combined) was also observed in male mice. The incidence of basophilic hepatic foci was increased in 15 μL male mice (0/50, 1/50, 9/50, 3/50). The increased incidence of liver neoplasms in this study was considered equivocal because the incidence of hepatocellular neoplasms in control and dosed males was within the historical range and because there was no clear dose-response relationship in females. No other treatment-related findings were observed in this study. 1-YEAR INITIATION/PROMOTION STUDY IN MALE SWISS (CD-1®) MICE: Groups of 50 male mice were dosed dermally with diethylphthalate or dimethylphthalate to study their effect as initiators and promoters. Diethylphthalate and dimethylphthalate were tested as initiators with and without the known skin tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA). Diethyl phthalate and dimethylphthalate were tested as promoters with and without the known skin tumor initiator 7,12-dimethylbenzanthrancene (DMBA). Comparative control groups used during the study of diethylphthalate and dimethylphthalate included: vehicle control (acetone/acetone); initiation/promotion control (DMBA/TPA); initiator control (DMBA/acetone); and promoter control (acetone/TPA). Based on the incidence of skin neoplasms diagnosed histologically and the multiplicity of skin neoplasms, there was no suggestion that either diethylphthalate or dimethylphthalate was able to initiate skin carcinogenesis when chronically promoted by TPA. Further, there was no evidence that either diethylphthalate or dimethylphthalate was able to promote skin carcinogenesis in skin previously initiated with DMBA. High incidences of both squamous cell papillomas and squamous cell carcinomas occurred among the initiation/promotion control animals initiated with DMBA and promoted with TPA. All TPA-dosed groups had significantly greater incidences of dermal acanthosis, ulceration, exudation, and hyperkeratosis than controls. GENETIC TOXICOLOGY: Neither diethylphthalate (10-10,000 μ/plate) nor dimethylphthalate (33-6,666 μ/plate) induced gene mutations in Salmonella typhimurium strains TA98, TA100, TA1535, or TA1537, with or without rat and hamster liver S9. In cultured Chinese hamster ovary cells, both diethylphthalate and dimethylphthalate induced sister chromatid exchanges in the presence of S9. Neither induced sister chromatid exchanges in the absence of S9. Neither chemical induced chromosomal aberrations, with or without S9, in cultured Chinese hamster ovary cells. CONCLUSIONS: Under the conditions of these 2-year dermal studies, there was no evidence of carcinogenic activity of diethylphthalate in male or female F344/N rats receiving 100 or 300 μL. The sensitivity of the male rat study was reduced due to low survival in all groups. There was equivocal evidence of carcinogenic activity of diethylphthalate in male and female B6C3F1 mice based on increased incidences of hepatocellular neoplasms, primarily adenomas. In an initiation/promotion model of skin carcinogenesis, there was no evidence of initiating activity of diethylphthalate or dimethylphthalate in male Swiss (CD-1®) mice. Further, there was no evidence of promotion activity of diethylphthalate or dimethylphthalate in male Swiss (CD-1®) mice. The promoting activity of TPA following DMBA initiation was confirmed in these studies. Minor dermal acanthosis was observed following dermal application of diethylphthalate in male and female F344/N rats dosed for 2 years and in male Swiss (CD-1®) mice dosed for 1 year. Synonyms: Diethylphthalate (CAS No. 84-66-2): 1,2-benzenedicarboxylic acid, diethyl ester; DEP; diethyl 1,2-benzenedicarboxylate; diethyl o-phthalate; diethyl phthalate; ethyl phthalate; o-benzenedicarboxylic acid diethyl ester; phthalic acid, diethyl ester; RCRA U088 Dimethylphthalate (CAS No. 131-11-3): 1,2-benzenedicarboxylic acid, dimethyl ester; dimethyl 1,2-benzenedicarboxylate; dimethyl benzene-o-dicarboxylate; dimethyl benzeneorthodicarboxylate; dimethyl o-phthalate; dimethyl phthalate; DMP; FIFRA 028002; methyl phthalate; go-dimethyl phthalate; phthalic acid, dimethyl ester; phthalic acid methyl ester; RCRA U102
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PMID:NTP Toxicology and Carcinogenesis Studies of Diethylphthalate (CAS No. 84-66-2) in F344/N Rats and B6C3F1 Mice (Dermal Studies) with Dermal Initiation/ Promotion Study of Diethylphthalate and Dimethylphthalate (CAS No. 131-11-3) in Male Swiss (CD-1(R)) Mice. 1261 2

The types and levels of fats in the diet are known to affect the incidence of certain neoplasms in humans and rodents. In long-term toxicity and carcinogenicity studies in rodents, the level of dietary fat is altered by using oil as a vehicle to administer unpalatable or volatile chemicals. Control male rats receiving a corn oil vehicle have a higher incidence of pancreatic proliferative lesions and a lower incidence of mononuclear cell leukemia than untreated control males. Therefore, the National Toxicology Program (NTP) designed studies to evaluate the role of several oils in altering cancer rates in male rats. The NTP study reported here was part of a larger program that included cooperative agreements with Dartmouth Medical School, Northwestern Medical School, and the University of Missouri. The program was designed to study the mechanisms by which corn oil induces pancreatic cancer. To evaluate corn oil as well as two other gavage vehicles for potential toxicity, corn oil, safflower oil, and tricaprylin were administered by gavage to male F344/N rats for 2 years. The rats that received corn oil were also made available to the university investigators for study of the corn oil-induced pancreatic lesions. Each vehicle was administered by gavage at volumes of 2.5, 5, or 10 mL/kg body weight once daily for 5 days per week. In the corn oil study, a control of 10 mL saline/kg was also included. To evaluate the potential role of corn oil in promoting a pancreatic proliferative effect, 500 mg dichloromethane/kg body weight was administered in 2.5, 5, or 10 mL corn oil/kg body weight for 2 years to male F344/N rats. Dichloromethane was chosen because the chemical appeared to cause pancreatic proliferative lesions when administered by gavage in a corn oil vehicle but not when the exposure was by inhalation. In each of these studies, the term "dose" refers to the volume of gavage vehicle administered. 2-YEAR STUDIES OF CORN OIL, SAFFLOWER OIL, AND TRICAPRYLIN: Survival and Body Weights: Two-year survival was increased in male rats receiving corn oil (untreated control, 26/50; saline control, 32/50; 2.5 mL/kg, 33/50; 5 mL/kg, 38/50; 10 mL/kg, 40/50) primarily due to a dose-related decreased incidence of mononuclear cell leukemia. The mean body weights of all dosed groups were at least 5% higher than those of the untreated and saline controls by week 48, but the mean body weights of groups receiving 2.5 or 5 mL corn oil/kg decreased during the final weeks of the study (after week 89) and were similar to those of the controls at the end of the study. Two-year survival was slightly increased in male rats receiving safflower oil relative to that of the controls (untreated control, 30/50; 2.5 mL/kg, 33/50; 5 mL/kg, 40/50; 10 mL/kg, 36/50). The mean body weight of male rats receiving 10 mL safflower oil/kg was at least 5% greater than that of the controls after week 45 and was 16% greater by the end of the study. Two-year survival of high-dose tricaprylin males was lower than that of the controls (untreated control, 31/50; 2.5 mL/kg, 30/50; 5 mL/kg, 31/50; 10 mL/kg, 23/53) due to moribund kills and deaths that appeared to be related to toxicity. The mean body weight of the high-dose group was lower than that of the controls throughout the study, although the difference was less than 5% after week 61. Pathology Findings: In the corn oil study, there were significant dose-related increased incidences of pancreatic exocrine hyperplasia and adenoma (hyperplasia: 8/50, 28/47, 28/50, 35/50; adenoma: 1/50, 8/47, 10/50, 23/50; carcinoma: 0/50, 0/47, 1/50, 0/50 in the untreated control, 2.5, 5, and 10 mL/kg groups, respectively). The incidence and severity of nephropathy decreased with dose (incidence [mean severity grade]: 47/50 [2.1], 43/48 [1.8], 45/50 [1.4], 40/49 [1.2]). The incidences of pheochromocytomas (benign, malignant, or complex) of the adrenal medulla were also decreased in dosed rats (23/49, 21/50, 5/50, 9/50). The incidence of mononuclear cell leukemia was significantly decreased in rats dosed with corn oil (27/50, 16/50, 11h corn oil (27/50, 16/50, 11/50, 7/50). In rats receiving safflower oil, the incidences of pancreatic exocrine hyperplasia and adenoma increased significantly with dose (hyperplasia: 8/50, 14/50, 29/49, 30/50; adenoma: 1/50, 7/50,15/49, 28/50; carcinoma: 0/50, 0/50, 0/49, 1/50 in the untreated control, 2.5, 5, and 10 mL/kg groups, respectively). There was a decrease in the severity, but not in the incidence, of nephropathy, a common lesion in aging F344/N rats (incidence [mean severity grade]: 49/50 [2.0], 50/50 [1.8], 47/50 [1.1], 49/49 [1.1]). There were decreased incidences of mononuclear cell leukemia (33/50, 19/50, 18/50, 7/51). In the tricaprylin study, there were significant dose-related increased incidences of pancreatic exocrine hyperplasia and adenoma (hyperplasia: 8/49, 9/49, 18/49, 28/50; adenoma: 2/49, 6/49,13/49,18/50 in the untreated control, 2.5, 5, and 10 mL/kg groups, respectively). The incidence of proliferative lesions of the forestomach increased significantly with dose (basal cell hyperplasia: 4/50, 7/50, 12/49, 21/52; squamous cell papilloma: 0/50, 0/50, 3/50, 10/53). The incidence of nephropathy was significantly decreased in high-dose rats, and the severity of nephropathy decreased with dose (incidence [mean severity grade]: 46/50 [2.0], 42/50 [1.5], 45/50 [1.7], 27/49 [0.9]). In high-dose rats, the incidence of mononuclear cell leukemia was decreased (23/50, 28/50, 22/50, 9/53). 2-YEAR STUDY OF DICHLOROMETHANE IN CORN OIL: Survival and Body Weights: Two-year survival increased slightly with dose in the three groups receiving 500 mg dichloromethane/kg in 2.5, 5, or 10 mL corn oil/kg (23/50, 28/50, 31/50) due to a dose-related decrease in the incidence of mononuclear cell leukemia. The rats receiving 500 mg dichloromethane/kg without corn oil were sacrificed within the first 3 weeks of the study due to the severe toxicity of dichloromethane. The final mean body weight of the high-dose rats was greater than the final mean body weights of groups receiving dichloromethane in 2.5 or 5 mL corn oil/kg. Pathology Findings: There was a dose-related increase in the incidence of pancreatic proliferative exocrine lesions in rats receiving dichloromethane in 2.5, 5, and 10 mL corn oil/kg (hyperplasia: 28/50, 38/50, 44/50; adenoma: 9/50,19/50, 41/50; carcinoma: 0/50,1/50, 3/50). The incidences of pancreatic exocrine hyperplasia and adenoma in rats receiving dichloromethane in 5 or 10 mL, but not 2.5 mL, corn oil were increased compared to the incidences in rats receiving comparable volumes of corn oil alone (hyperplasia: 2.5 mL, 28/47; 5 mL, 28/50;10 mL, 35/50; adenoma: 8/47,10/50, 23/50; carcinoma: 0/47,1/50, 0/50). There were significantly increased incidences of pituitary gland pars distalis adenoma in rats receiving dichloromethane in corn oil (20/50, 18/49, 16/49) when compared to those in rats receiving comparable volumes of corn oil alone (10/50, 6/49, 7/50). The incidence of mammary gland adenoma and fibroadenoma (combined) was significantly increased in rats receiving dichloromethane in 10 mL corn oil/kg (7/50) when compared to rats receiving dichloromethane in 2.5 mL corn oil/kg (1/50), but was not significantly increased when compared to the group receiving 10 mL of corn oil alone (3/50). The incidences of mammary gland adenoma and fibroadenoma (combined) were 7/50 for the untreated safflower oil controls and 6/50 for the untreated tricaprylin controls. The incidence of mononuclear cell leukemia decreased in the group receiving dichloromethane in 10 mL corn oil/kg (13/50,14/50, 5/50). GENETIC TOXICOLOGY: Neither safflower oil nor corn oil was mutagenic in Salmonella typhimurium strains TA97, TA98, TA100, or TA1535, with or without S9. Tricaprylin, in contrast, was mutagenic in strain TA1535 with, but not without, S9. Tricaprylin did not induce mutations in strains TA97, TA98, or TA100, with or without S9. SUMMARY: These studies were designed to evaluate the effects of various concentrations of an oil very high in polyunsaturated fat (safflower oil), an oil containing high levels of polyunsaturated and monounsaturated fats (corn oil), and an oil containing saturated medium-chain fatty acids (tricaprylin) on the incidence and pattern of neoplasms in the F344/N rat. In addition, safflower oil and tricaprylin were evaluated as replacements for the corn oil vehicle. These studies demonstrate that safflower oil and tricaprylin do not offer significant advantages over corn oil as a gavage vehicle in long-term rodent studies. Corn oil, safflower oil, and tricaprylin each caused hyperplasia and adenoma of the exocrine pancreas, decreased incidences of mononuclear cell leukemia, and reduced incidences or severity of nephropathy in male F344/N rats. There was an increased incidence of squamous cell papillomas of the forestomach in F344/N rats receiving 10 mL tricaprylin/kg. Further, the use of corn oil as a gavage vehicle may have a confounding effect on the interpretation of chemical-induced proliferative lesions of the exocrine pancreas and mononuclear cell leukemia in male F344/N rats. Synonyms: Corn Oil - Maize oil, Maydol Tricaprylin - Trioctanoin; 1,2,3-trioctanoyl glycerol; Glycerol trioctanoate
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PMID:NTP Comparative Toxicology Studies of Corn Oil, Safflower Oil, and Tricaprylin (CAS Nos. 8001-30-7, 8001-23-8, and 538-23-8) in Male F344/N Rats as Vehicles for Gavage. 1261 5

g-Butyrolactone is an intermediate in the synthesis of polymers used as film formers in hair sprays, blood plasma extenders, and clarifying agents in beer and wine. Toxicology and carcinogenesis studies were conducted by administering g-butyrolactone (greater than 97% pure) in corn oil by gavage to groups of F344/N rats and B6C3F1 mice of each sex, 5 days per week for 16 days, 13 weeks, and 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium, Drosophila melanogaster, and Chinese hamster ovary cells. 16-Day Studies: Groups of five rats of each sex received doses of 0, 75, 150, 300, 600, or 1,200 mg of g-butyrolactone per kg of body weight and groups of five mice of each sex received doses of 0, 87, 175, 350, 700, or 1,400 mg/kg. All male and female rats given 1,200 mg/kg and one male rat given 600 mg/kg died within 3 days. The mean body weight gain of female rats given 600 mg/kg was significantly lower than that of the controls. Mean body weight gains of the other female dose groups and all male dose groups were similar to those of the controls. All of the male and four female mice receiving 1,400 mg/kg died during the studies. Mean body weight gains of dosed mice were generally similar to those of the controls. Rats receiving 600 or 1,200 mg/kg and mice receiving 350 mg/kg or more became inactive or recumbent with irregular respiration following dosing. 13-Week Studies: Groups of 10 rats of each sex received doses of 0, 56, 112, 225, 450, or 900 mg of g-butyrolactone per kg of body weight and groups of 10 mice of each sex received doses of 0, 65, 131, 262, 525, or 1,050 mg/kg. One female and all male rats given 900 mg/kg died during the studies. The final mean body weight and mean body weight gain of male rats receiving 450 mg/kg were significantly lower than those of the controls; final mean body weights and body weight gains of all female rat dose groups were similar to those of the controls. There was an increased incidence of focal inflammation of the nasal mucosa in rats administered g-butyrolactone. Three male mice and one female receiving 1,050 mg/kg died from g-butyrolactone toxicity during the studies. The mean body weight gain and final mean body weight of high-dose male mice were lower than those of the controls; the mean body weight gains and final mean body weights of dosed female mice were similar to those of the controls. No lesions related to the administration of g-butyrolactone occurred in mice of either sex. 2-Year Studies: The doses administered to groups of 50 animals per sex were 0, 112, and 225 mg ofg-butyrolactone per kg of body weight for male rats; 0, 225, and 450 mg/kg for female rats; and 0, 262, and 525 mg/kg for male and female mice. Body Weight and Survival in the 2-Year Studies: The mean body weights of male rats administered g-butyrolactone were similar to those of the controls throughout the study. The mean body weight of high-dose females was lower than that of the controls after week 5 and was 10% to 20% lower than that of the controls throughout the second year. The survival of high-dose male rats was slightly higher than that of the controls (control, 24/50; low-dose, 27/50, high-dose, 32/50) due primarily to a lower incidence of mononuclear cell leukemia in the high-dose group (16/50, 15/50, 9/50). The survival of dosed females was similar to that of the controls (28/50, 27/50, 28/50). The mean body weights of dosed male mice were lower than those of the controls throughout the study, but the differences in mean body weights decreased when male mice were housed individually at week 67. The final mean body weights of dosed male mice were 6% lower than that of the controls. Mean body weights of dosed female mice were also lower than those of the controls throughout the study, and the final mean body weights were from 14% to 17% lower than that of the controls. The survival in high-dose male mice was significantly lower than that of the controls (35/50, 30/50, 12/50) due to bite wounds and fighting in high-dose males recovering from the sedative effects of g-becovering from the sedative effects of g-butyrolactone. The survival of female dosed mice was similar to that of the controls (38/50, 34/50, 38/50). Neoplasms and Nonneoplastic Lesions in the 2-Year Studies: No increased incidences of neoplasms or nonneoplastic lesions in male rats were related to the administration of g-butyrolactone for 2 years. In female rats, negative trends were observed in the incidences of cysts (42/50, 35/50, 23/50) and fibroadenomas of the mammary gland (22/50, 14/50, 6/50) and in cysts of the pituitary pars distalis (25/49, 13/37, 11/48). These decreases were considered to be related to g-butyrolactone administration. Increased incidences of proliferative lesions, primarily hyperplasia, of the adrenal medulla in low-dose male mice were associated with g-butyrolactone administration (pheochromocytoma, benign or malignant: 2/48, 6/50, 1/50; hyperplasia: 2/48, 9/50, 4/50). The incidence of hepatocellular neoplasms in both dose groups of male mice was lower than the incidence in the controls (hepatocellular adenoma or carcinoma: 24/50, 8/50, 9/50). Genetic Toxicology: g-Butyrolactone was not mutagenic, with or without exogenous metabolic activation (S9), in Salmonella typhimurium strains TA98, TA100, TA1535, and TA1537, nor did it induce sex-linked recessive lethal mutations in germ cells of male Drosophila melanogaster when administered in feed or by injection. Positive results were obtained, however, in cytogenetic tests with Chinese hamster ovary cells; g-butyrolactone induced sister chromatid exchanges and chromosomal aberrations in trials conducted in the presence of S9 activation. Conclusions: Under the conditions of these 2-year gavage studies, there was no evidence of carcinogenic activity of g-butyrolactone in male F344/N rats given 112 or 225 mg/kg or in female F344/N rats given 225 or 450 mg/kg in corn oil. There was equivocal evidence of carcinogenic activity of g-butyrolactone in male B6C3F1 mice based on marginally increased incidences of adrenal medulla pheochromocytomas and hyperplasia in the low-dose group. The sensitivity of the study in male mice to detect a carcinogenic effect was reduced by the low survival of the high-dose group associated with fighting. There was no evidence of carcinogenic activity of g-butyrolactone in female B6C3F1 mice given 262 or 525 mg/kg in corn oil. A decreased incidence of hepatocellular neoplasms in dosed male mice and decreased incidences of mammary gland fibroadenomas and cysts and pituitary cysts in female rats were associated with the administration of g-butyrolactone. Synonyms: Dihydro-2(3H)-furanone (8CI) (9CI), 1,2-butanolide, butyrolactone, 1,4-butanolide, 4-butyrolactone, 4-hydroxybutanoic acid lactone, g-hydroxybutyric acid cyclic ester, g-hydroxybutyric acid lactone, g-lactone 4-hydroxy-butanoic acid, butyric acid lactone, butyryl lactone, 4-hydroxybutyric acid lactone, tetrahydro-2-furanone, 4-butanolide, 4-deoxytetronic acid, g-hydroxybutyrolactone
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PMID:Toxicology and Carcinogenesis Studies of g-Butyrolactone (CAS No. 96-48-0) in F344/N Rats and B6C3F1 Mice (Gavage Studies). 1262 12

Furan serves as an intermediate in the synthesis and preparation of numerous linear polymers used to prepare temperature-resistant structural laminates and to prepare copolymers used in machine dishwashing products as alternatives to phosphorus- and nitrogen-containing detergents. Toxicology and carcinogenesis studies were conducted by administering furan (purity > 99%) in corn oil by gavage to groups of F344/N rats and B6C3F1 mice of each sex for 16 days, 13 weeks, and 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium, Drosophila melanogaster, mouse bone marrow cells, mouse L5178Y lymphoma cells, and Chinese hamster ovary cells. 16-Day Studies: Groups of five male rats received doses of 0, 5, 10, 20, 40, or 80 mg of furan per kg of body weight and groups of five female rats and five mice of each sex received doses of 0, 10, 20, 40, 80, and 160 mg/kg in corn oil by gavage. All male and female mice and female rats that received 160 mg/kg, all male and female rats and all male and four female mice that received 80 mg/kg, and three male mice that received 40 mg/kg died by day 8. Final mean body weights of male rats that received 20 mg/kg and of male and female rats that received 40 mg/kg were significantly lower than controls. Final mean body weights of male mice that received 10 or 20 mg/kg were significantly greater than controls. Mottled and enlarged livers were observed at necropsy in male rats that received 20, 40, or 80 mg/kg and in females that received 40, 80, or 160 mg/kg. No lesions were observed at necropsy that were considered related to furan administration in mice. 13-Week Studies: Groups of 10 rats of each sex and groups of 10 female mice received doses of 0, 4, 8, 15, 30, or 60 mg of furan per kg of body weight, and groups of 10 male mice received doses of 0, 2, 4, 8, 15, or 30 mg/kg in corn oil by gavage. Nine male and four female rats that received 60 mg/kg died before the end of the studies. There were no chemical-related deaths in mice. Final mean body weights of male rats that received 15 or 30 mg/kg and female rats that received 60 mg/kg were significantly lower than controls. Final mean body weights of male mice that received 60 mg/kg were significantly lower than controls. Relative and absolute liver weights in both sexes of rats and mice were increased in groups that received furan, as were relative and absolute kidney weights in female rats that received furan. Thymus weights were decreased in all groups of rats that received furan. Toxic lesions of the liver (bile duct hyperplasia, cholangiofibrosis, cytomegaly and degeneration of hepatocytes, and nodular hyperplasia of hepatocytes) were associated with furan administration in all dose groups of rats; the severity of the lesions increased with dose. Kidney lesions (tubule dilatation and necrosis of tubule epithelium) were present in rats that received 30 or 60 mg/kg. Thymic atrophy and testicular or ovarian atrophy were also observed in rats exposed to 60 mg/kg furan. Toxic liver lesions (cytomegaly, degeneration, and necrosis of hepatocytes) were also present in all groups of furan-exposed mice. Bile duct hyperplasia and cholangiofibrosis were observed in groups of mice receiving 30 or 60 mg/kg. Doses selected for the 2-year studies of rats and mice were based on the hepatotoxicity associated with exposure to furan. 2-Year Studies: Groups of 70 rats of each sex were administered 2, 4, or 8 mg furan per kg body weight in corn oil by gavage 5 days per week for 2 years. After 9 and 15 months of chemical exposure, 10 rats per group were evaluated for the presence of treatment-associated lesions. Groups of 50 mice of each sex received doses of 8 or 15 mg/kg furan 5 days per week for 2 years. Body Weight and Survival: Mean body weights of male rats that received 8 mg/kg furan were lower than controls from approximately week 73 to the end of the study. Survival of male and female rats that received 8 mg/kg was lower than controls from approximately week 85 to the end of the studies as a result of moribund condition associatedassociated with liver and biliary tract neoplasms and mononuclear cell leukemia. Mean body weights of male and female mice that received 15 mg/kg furan were lower than controls during the studies. Survival of low- and high-dose male and high-dose female mice was lower than controls from approximately week 80 to the end of the studies as a result of moribund condition associated with liver neoplasms. Neoplastic and Nonneoplastic Lesions: Cholangiocarcinoma of the liver occurred in all groups of dosed rats (males: control, 0/50; low dose, 43/50; mid dose, 48/50; high dose, 49/50; females: 0/50; 49/50; 50/50; 48/50) and was present in many rats of each sex at the 9- and 15-month interim evaluations (9-month: males - 0/10, 5/10, 7/10, 10/10; females - 0/10, 4/10, 9/10, 10/10; 15-month: males - 0/10, 7/10, 9/10, 6/10; females - 0/10, 9/10, 9/10, 7/10). Hepatocellular adenomas or carcinomas (combined) were significantly increased in male rats after 2 years of chemical administration (1/50, 5/50, 22/50, 35/50) and hepatocellular adenomas were significantly increased in female rats (0/50, 2/50, 4/50, 7/50); hepatocellular neoplasms were not observed at the 9- or 15-month interim evaluations. Increased incidences of numerous nonneoplastic liver lesions were present in rats administered furan. These lesions included biliary tract fibrosis, hyperplasia, chronic inflammation, and proliferation and hepatocyte cytomegaly, cytoplasmic vacuolization, degeneration, nodular hyperplasia, and necrosis. The incidence of mononuclear cell leukemia was increased in male and female rats that received 4 or 8 mg/kg furan (males: 8/50, 11/50, 17/50, 25/50; females: 8/50, 9/50, 17/50, 21/50); the incidence in the 8 mg/kg groups of each sex exceeded the historical control ranges for corn oil gavage studies. The severity of nephropathy increased with dose and the incidence was significantly increased in all groups of dosed rats; this increased severity was accompanied by an associated increased incidence of parathyroid hyperplasia (renal secondary hyperparathyroidism). The incidence of forestomach hyperplasia was increased in male and female rats (males: 1/50, 4/49, 7/50, 6/50; females: 0/50, 2/50, 5/50, 5/50) and the incidence of subacute inflammation of the forestomach was increased in female rats (0/50, 1/50, 5/50, 6/50). No forestomach neoplasms were observed in males; a squamous papilloma was present in one low-dose female. The incidences of hepatocellular adenomas and carcinomas were significantly increased in mice receiving furan (males: adenoma - 20/50, 33/50, 42/50; carcinoma - 7/50, 32/50, 34/50; females: adenoma - 5/50, 31/50, 48/50; carcinoma - 2/50, 7/50, 27/50). The incidences of numerous nonneoplastic hepatocellular lesions were increased in dosed mice. These lesions included hepatocyte cytomegaly, degeneration, necrosis, multifocal hyperplasia, and cytoplasmic vacuolization and biliary tract dilatation, fibrosis, hyperplasia, and inflammation. The incidences of benign pheochromocytoma and focal hyperplasia of the adrenal medulla were increased in low- and high-dose male and in high-dose female mice (benign pheochromocytoma: males - 1/49, 6/50, 10/50; females - 2/50, 1/50, 6/50). The incidences of squamous papilloma, focal inflammation, and papillary hyperplasia of the forestomach were increased in male mice (squamous papilloma: 0/49, 1/50, 3/50; focal inflammation: 9/49, 13/50, 21/50; papillary hyperplasia: 7/49, 14/50, 22/50). Stop-Exposure Study: A separate 2-year study was conducted in which 50 male rats were administered 30 mg/kg furan in corn oil by gavage 5 days per week for 13 weeks and then maintained for the remainder of the 2 years without additional furan administration. Groups of 10 animals were evaluated for the presence of treatment-related lesions at the end of the 13-week period of furan administration and at 9 and 15 months. Neoplastic and Nonneoplastic Lesions: Cholangiocarcinoma of the liver occurred with an overall incidence of 100% (40/40) and hepatocellular carcinoma occurred with an overall incidence of 15% (6/40) in stop-exposure male rats that survived at least 9 months. Cholangiocarcinoma was observed in all 10 males at both the 9-month and 15-month interim evaluations. Hepatocellular carcinoma was first observed in 2 males at the 15-month interim evaluation. Genetic Toxicology: Furan was negative for induction of gene mutations in Salmonella typhimurium strains TA100, TA1535, TA1537, and TA98 in the presence and the absence of exogenous metabolic activation (S9). Furan was negative for the induction of sex-linked recessive lethal mutations in germ cells of male Drosophila melanogaster when administered either by feeding or by injection. In vitro tests for genotoxicity in mammalian cells, however, were positive. Furan induced trifluorothymidine resistance in mouse L5178Y lymphoma cells in the absence of S9, and sister chromatid exchanges and chromosomal aberrations in Chinese hamster ovary cells, with and without S9. Furan administered to male B6C3F1 mice by intraperitoneal injection induced chromosomal aberrations but not sister chromatid exchanges in bone marrow cells. Conclusions: Under the conditions of these 2-year gavage studies there was clear evidence of carcinogenic activity of furan in male and female F344/N rats based on increased incidences of cholangiocarcinoma and hepatocellular neoplasms of the liver and on increased incidences of mononuclear cell leukemia. There was clear evidence of carcinogenic activity of furan in male and female B6C3F1 mice based on increased incidences of hepatocellular neoplasms of the liver and benign pheochromocytomas of the adrenal gland. Nonneoplastic liver lesions associated with furan administration in rats and mice included biliary tract fibrosis, hyperplasia, inflammation, and proliferation, as well as hepatocellular cytomegaly, degeneration, hyperplasia, necrosis, and vacuolization. In rats, increased severity of nephropathy with an associated increased incidence of parathyroid hyperplasia was associated with exposure to furan. Synonyms: Divinylene oxide, tetrole, furfuran, oxole, 1,4-epoxy-1,3-butadiene, axole, oxacyclopentadiene
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PMID:Toxicology and Carcinogenesis Studies of Furan (CAS No. 110-00-9) in F344 Rats and B6C3F1 Mice(Gavage Studies). 1262 16

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%-48%), 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%, range 0%-4%), 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%-6%), 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%-4%), 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%-2%), 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%-4%), 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

Polybrominated biphenyls are synthetic chemicals used as flame retardants. The technical product used in these studies, Firemaster FF-1(R)), is a mixture of brominated biphenyls. Firemaster FF-1(R)) is a known liver carcinogen in rats and mice and is one of three compounds chosen by the National Toxicology Program to investigate the potential value of perinatal exposures in assessing chemical carcinogenicity. Chronic toxicity and carcinogenicity studies of polybrominated biphenyls (Firemaster FF-1(R)) were conducted in F344/N rats and B6C3F1 mice of each sex. The studies were designed to determine: a) the effects of polybrominated biphenyls in rats and mice receiving adult ( F1) exposure only (a typical carcinogenicity study), b) the toxic and carcinogenic effects of polybrominated biphenyls in rats and mice receiving perinatal (F0) exposure only (dietary exposure of dams prior to breeding and throughout gestation and lactation), and c) the effects of combined perinatal and adult exposure to polybrominated biphenyls. STUDIES IN F344/N RATS: The exposure levels selected for F1 exposure, based on studies of polybrominated biphenyls in the literature, were 3, 10, and 30 ppm. In a preliminary study to determine the perinatal dietary concentrations for the 2-year study, female rats were administered 1 to 30 ppm polybrominated biphenyls in the feed beginning 60 days prior to breeding and continuing throughout gestation, lactation, and up to 4 weeks postweaning. The mean preweaning litter weight of the 30 ppm group was less than 80% of the mean litter weight of the control group at days 0, 4, and 12. At weaning, the mean weight of litters in this group was 80% of the control group mean. The final mean body weights (28 days after weaning) of males and females receiving 30 ppm were 13% to 19% lower than the final mean body weights of the controls. Therefore, dietary concentrations of 0, 1, 3, and 10 ppm were selected for the F0 exposure levels in the 2-year study. The eight F0 F1 exposure combinations selected for the 2-year study are shown in the following table (see page 6 of full technical report). Adult-Only Exposure The major organ affected by toxicity of polybrominated biphenyls was the liver. Rats evaluated at 9 months had decreased body weights, hepatomegaly, nonneoplastic histopathologic changes in the liver, mild anemia, increases in serum cholesterol concentrations, and decreases in serum triglyceride concentrations (males only). In rats receiving adult only exposure (F0 F1 concentrations of 0:10 or 0:30 ppm), there were no significant effects on survival. Mean body weights were significantly reduced in 0:10 and 0:30 ppm male rats and in 0:30 ppm female rats. Males and females exposed to 0:10 or 0:30 ppm had increased incidences of hepatocellular neoplasms (males: 0:0 ppm, 1/50; 0:10 ppm, 12/49; 0:30 ppm, 41/50; females: 0/50,12/50, 39/50). Increased incidences of the following nonneoplastic lesions were associated with the administration of polybrominated biphenyls: eosinophilic foci, cytoplasmic vacuolization, oval cell hyperplasia, and hypertrophy in the liver of males and females; acanthosis, inflammation, and ulceration of the forestomach in exposed males; and cystic endometrial hyperplasia of the uterus in 0:30 ppm females. Perinatal-Only Exposure For rats receiving only perinatal exposure (10:0 ppm), there were no changes in survival or body weights compared to the 0:0 ppm control groups. In female rats, there were no effects on neoplasm incidences, but perinatal exposure was associated with a marginally increased incidence of hepatocellular adenoma in male rats (0:0 ppm, 1/50; 10:0 ppm, 5/50). The incidences of nonneoplastic lesions in the liver were increased in exposed males (eosinophilic foci and cytoplasmic vacuolization) and females (eosinophilic foci). Combined Perinatal and Adult Exposure Combined perinatal and adult exposure resulted in marginally reduced survival compared to the 0:0 ppm control group for male rats in the 3:10, 10:10, and 10:30 ppm groups. No significant survival differences were obseant survival differences were observed in female rats. The final mean body weights of male and female rats receiving 3:10,10:10, or 10:30 ppm were lower than those of the 0:0 ppm controls. In male rats, there were no enhancing effects of combined perinatal and adult exposure on the incidence of hepatocellular neoplasms. However, perinatal exposure enhanced the development of liver neoplasms in female rats receiving 10 or 30 ppm adult exposure. A combined analysis of all male and female exposure groups also revealed increased incidences of mononuclear cell leukemia that were considered related to polybrominated biphenyls exposure. STUDIES IN B6C3F1 MICE: The exposure levels selected for the F1 exposure, based on studies of polybrominated biphenyls in the literature, were 3,10, and 30 ppm. In a preliminary study to determine the perinatal dietary concentrations for the 2-year study, female C57BL/6N mice were exposed to 1 to 30 ppm polybrominated biphenyls in the feed beginning 60 days before breeding to C3H/HeN males, continuing throughout gestation and lactation and up to 4 weeks postweaning. There were no clear chemical-related effects on survival or growth at any phase of the study; therefore, 0, 3,10, and 30 ppm dietary concentrations were selected for the F0 exposure levels in the 2-year study. The eight F0 F1 exposure combinations selected for the 2-year study are shown in the table below (see page 7 of full technical report). Adult-Only Exposure The major organ affected by toxicity of polybrominated biphenyls was the liver. Animals evaluated at 9 months had lower body weights than the controls, hepatomegaly, and histopathologic changes in the liver. In mice receiving adult-only exposure, no males or females in the 0:30 ppm group survived to the end of the study. Neither survival nor body weights were affected in the 0:10 ppm groups. Males and females receiving 0:10 or 0:30 ppm had markedly increased incidences of hepatocellular neoplasms (males: 0:0 ppm, 16/50; 0:10 ppm, 48/49; 0:30 ppm, 48/50; females: 5/50, 42/50, 47/48). Increased incidences of nonneoplastic liver lesions including cytomegaly (hypertrophy), fatty change (cytoplasmic vacuolization), bile duct hyperplasia, eosinophilic and clear cell foci, and necrosis of individual hepatocytes were related to treatment with polybrominated biphenyls. Increased incidences and severity of chronic nephropathy in the kidney and excessive hematopoiesis in the spleen of 0:30 ppm males and females were also considered to be related to exposure to polybrominated biphenyls. Perinatal-Only Exposure There were no survival or body weight differences in mice receiving only perinatal exposure (30:0 ppm). Perinatal exposure resulted in significantly increased incidences of hepatocellular neoplasms in males and females. The incidences of nonneoplastic lesions (cytomegaly, eosinophilic foci, clear cell foci) were increased in males and females. Combined Perinatal and Adult Exposure Combined perinatal and adult exposure resulted in markedly reduced survival for females in the 30:10 ppm group; no mice receiving 30:30 ppm survived to the end of the study. In those groups receiving adult exposure of 30 ppm, mean body weights were not affected. The incidence of hepatocellular neoplasms in male and female mice was significantly increased. At the 9-month interim evaluation the incidence of hepatocellular adenomas was significantly increased in males (0:30 ppm, 1/10; 30:30 ppm, 7/10). The incidence of hepatocellular adenomas in 30:30 ppm females was similar to that of 0:30 ppm females (0:30 ppm, 0/10; 30:30 ppm, 3/10). At the end of the study the incidence of hepatocellular adenomas in males was statistically increased (0:30 ppm, 42/50; 30:30 ppm, 48/50). The incidence of hepatocellular adenomas in 30:30 ppm females was statistically decreased compared to that of 0:30 ppm females (0:30 ppm, 46/48; 30:30 ppm, 41/47). It was not possible to assess the potential enhancing effect of combined perinatal and adult exposure on hepatocellular neoplasms because adult-only exposure resulted in such high (84% to 98%) liver neoplasm incidences. CONCLUSIONS: Adult-Only Exposure Under the conditions of these 2-year, adult-only, dietary exposure studies, there was clear evidence of carcinogenic activity for polybrominated biphenyls in male and female F344/N rats and male and female B6C3F1 mice based on increased incidences of hepatocellular neoplasms. Perinatal-Only Exposure Perinatal exposure alone (through dietary administration of 10:0 ppm polybrominated biphenyls to the dams) had no effect on the incidences of neoplasms in female F344/N rats, but in male F344/N rats, perinatal exposure was associated with a marginally increased incidence of hepatocellular adenomas that may have been related to chemical administration. In male and female B6C3F1 mice, perinatal exposure to 30:0 ppm polybrominated biphenyls resulted in significantly increased incidences of hepatocellular neoplasms. The incidences of a number of nonneoplastic lesions in the liver (cytomegaly, eosinophilic focus, and clear cell focus) were increased in male and female B6C3F1 mice. Combined Perinatal and Adult Exposure Combined perinatal and adult dietary exposure to polybrominated biphenyls confirmed findings of the adult-only exposures for the increased incidences of hepatocellular neoplasms in F344/N rats and B6C3F1 mice. In male F344/N rats, there were no enhancing effects of combined perinatal and adult exposure. However, perinatal exposure enhanced the susceptibility of female F344/N rats receiving adult exposure of 10 or 30 ppm to the induction of liver neoplasms. For male and female F344/N rats, a combined analysis of the incidences of leukemia in the adult-only, perinatal-only, and combined perinatal and adult exposure groups revealed an apparent association between increasing incidences of mononuclear cell leukemia and exposure to polybrominated biphenyls. In male and female B6C3F1 mice, it was not possible to adequately assess the enhancing effects of combined perinatal and adult exposure on hepatocellular neoplasms, because adult-only exposure to 10 or 30 ppm polybrominated biphenyls resulted in high incidences (84% to 98%) of liver neoplasms. However, with increased perinatal exposure, there were increases in the numbers of B6C3F1 mice with hepatocellular carcinomas and in the numbers of B6C3F1 mice with multiple hepatocellular adenomas, which suggests an enhancement of polybrominated biphenyls-related hepatocellular carcinogenicity associated with perinatal exposure. Synonyms: PBBs; polybrominated biphenyl mixture; hexabromobiphenyl (technical grade); brominated biphenyls; polybromobiphenyls
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PMID:NTP Toxicology and Carcinogenesis Studies of Polybrominated Biphenyls (CAS No. 67774-32-7)(Firemaster FF-1(R)) in F344/N Rats and B6C3F1 Mice (Feed Studies). 1263 61

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

Acetaminophen is a widely consumed analgesic found in several nonprescription pharmaceuticals. Toxicology and carcinogenesis studies were conducted by administering acetaminophen (purity >99%) in feed to groups of F344/N rats and B6C3F1 mice of each sex for 14 days, 13 weeks, and 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium and Chinese hamster ovary cells. 14-DAY STUDIES: Rats were fed diets containing 0, 800, 1,600, 3,100, 6,200, or 12,500 ppm acetaminophen, and mice were fed diets containing 0, 250, 500, 1,000, 2,000, or 4,000 ppm acetaminophen. There were no deaths among any groups during the study; the final mean body weight of male rats that received 12,500 ppm was significantly lower than that of the controls. Final mean body weights of male and female mice and female rats that received acetaminophen were similar to those of the controls. Feed consumption by male and female rats that received 12,500 ppm acetaminophen was lower than that of the controls; feed consumption by all other exposed groups was higher than that of the controls. 13-WEEK STUDIES: Rats and mice were fed diets containing 0, 800, 1,600, 3,200, 6,200, 12,500, or 25,000 ppm acetaminophen. Two male and two female rats, and one male and one female mouse that received 25,000 ppm, and two male mice that received 12,500 ppm died from acetaminophen-related toxicity before the end of the studies. Final mean body weights of male and female rats and mice that received 12,500 or 25,000 ppm were lower than those of the controls. The patterns of feed consumption and reduced body weights that occurred among rats and mice that received diets containing 12,500 or 25,000 ppm were indicative of poor feed palatability. Acetaminophen-related lesions were observed in the liver (necrosis, chronic active inflammation, hepatocytomegaly), kidney (tubule cast, tubule necrosis, tubule regeneration), reproductive organs (atrophy of testis, ovary, and uterus), thymus and lymph nodes (lymphoid depletion) of rats that received 25,000 ppm, and of the live (chronic active inflammation, hepatocytomegaly) and testis (atrophy) of male rats receiving 12,500 ppm. Compound-related lesions in mice were found in the liver (hepatocytomegaly, focal calcification, pigmentation, necrosis) of males that received 6,200, 12,500, or 25,000 ppm and females that received 12,000 or 25,000 ppm. Dose selection for the 2-year studies was based on reduced body weights and the liver lesions observed in rats and mice at 12,500 and 25,000 ppm. 2-YEAR STUDIES: Diets containing 0, 600, 3,000, or 6,000 ppm acetaminophen were given continuously to groups of 60 rats and mice of each sex for up to 104 weeks. After 65 weeks of exposure, 10 animals from each group were evaluated for histopathology and for hematology, urinalysis, and clinical chemistry parameters. Survival and mean body weights of rats that received acetaminophen were similar to those of the controls throughout the study. The average severity of nephropathy was increased in exposed male and female rats. In males this was associated with an increased incidence of parathyroid hyperplasia (renal hyperparathyroidism). The incidence of focal renal tubule hyperplasia was also increased in exposed male rats. The incidence of mononuclear cell leukemia was increased in exposed female rats and was significantly increased in the 6,000 ppm group (9/50; 17/50; 15/50; 24/50). Survival of exposed and control mice was similar throughout the study. Mean body weights of mice that received acetaminophen were generally lower than those of the controls throughout the study. Although the incidence of thyroid follicular cell hyperplasia increased with dose among groups of exposed male and female mice, there was no increase in the incidence of follicular cell neoplasms. Renal tubule hyperplasia occurred in one low-dose and two high-dose males and a renal tubule adenoma was present in one low-dose and one high-dose male. GENETIC TOXICOLOGY: Acetaminophen was not mutagenic in Salmonella typhimurium strains TA100, TA1535, TA1537, or TA98 witr TA98 with or without S9. In cytogenetic tests with Chinese hamster ovary cells, acetaminophen induced sister chromatid exchanges and chromosomal aberrations in both the presence and absence of S9. CONCLUSIONS: Under the conditions of these 2-year feed studies, there was no evidence of carcinogenic activity of acetaminophen in male F344/N rats that received 600, 3,000, or 6,000 ppm. There was equivocal evidence of carcinogenic activity of acetaminophen in female F344/N rats based on increased incidences of mononuclear cell leukemia. There was no evidence of carcinogenic activity of acetaminophen in male and female B6C3F1 mice that received 600, 3,000, or 6,000 ppm. Nonneoplastic lesions associated with exposure to acetaminophen included increased severity of nephropathy and increased incidences of renal tubule hyperplasia and parathyroid hyperplasia in male rats, increased severity of nephropathy in female rats, and increased incidences of thyroid follicular cell hyperplasia in male and female mice. Synonyms: 4-Hydroxyacetanilide, N-Acetyl-p-aminophenol, Paracetamol
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PMID:NTP Toxicology and Carcinogenesis Studies of Acetaminophen (CAS No. 103-90-2) in F344 Rats and B6C3F1 Mice (Feed Studies). 1263 65

Tris(2-chloroethyl) phosphate (TRCP), a flame-retardant plasticizer used in plastics, polymeric foams, and synthetic fibers, was studied as part of the National Toxicology Program's class study of trisalkyl phosphate flame retardants. Toxicology and carcinogenesis studies were conducted by administering TRCP (approximately 98% pure) in corn oil by gavage to groups of F344/N rats and B6C3F1 mice of each sex for 16 days, 16 weeks, or 2 years. Genetic toxicology studies were performed in Salmonella typhimurium and Chinese hamster ovary (CHO) cells. 16-Day Studies: There were no chemical-related deaths, differences in final mean body weight, or histopathological lesions in rats receiving 22 to 350 mg/kg TRCP or in mice receiving 44 to 700 mg/kg TRCP for 12 doses over 16 days. Serum cholinesterase activity in female rats receiving 175 or 350 mg/kg TRCP was reduced slightly (80% of control levels), but enzyme activity in dosed male rats and in mice was similar to that in controls. 16-Week Studies: Rats received 22 to 350 mg/kg TRCP for 16 weeks (female) or 18 weeks (male). Several male and female rats in the 175 or 350 mg/kg dose groups died from chemical toxicity. Final mean body weights of female rats receiving 350 mg/kg were 20% greater than those of controls; final mean body weights of the remaining groups of dosed female rats and dosed male rats were similar. Chemical-related neuronal necrosis occurred in the hippocampus and thalamus of female rats and, to a lesser extent, of male rats. Serum cholinesterase activity was reduced in females receiving 175 or 350 mg/kg TRCP. There were no chemical-related deaths, differences in final mean body weight, or differences in cholinesterase activity in mice receiving 44 to 700 mg/kg TRCP for 16 weeks. Tubule epithelial cells with enlarged nuclei (cytomegaly and karyomegaly) were observed in the kidneys of high-dose (700 mg/kg) male and female mice. 2-Year Studies: The 2-year studies in rats were conducted by administering 0, 44, or 88 mg/kg TRCP to groups of 60 males and females, 5 days per week for up to 104 weeks; 9 or 10 rats of each dose group were evaluated at 66 weeks. The survival of high-dose male and female rats was reduced relative to that of controls. Final mean body weights of surviving rats were similar to those of controls. The principal chemical-related effects occurred in the kidney and brain of dosed rats. Focal hyperplasia of the renal tubule epithelium and renal tubule adenomas were markedly increased in male rats receiving 88 mg/kg TRCP and, to a lesser extent, in female rats (renal tubule hyperplasia, male rats: 0/50; 2/50; 24/50; female rats: 0/50; 3/50; 16/50; renal tubule adenoma, male rats: 1/50; 5/50; 24/50; female rats: 0/50; 2/50; 5/50). Renal tubule carcinomas occurred in one control and one high-dose male rat. Degenerative lesions consisting of gliosis, mineralization, hemorrhage, and/or hemosiderin accumulation occurred in the cerebrum and brain stem of more than 50% of female rats receiving 44 or 88 mg/kg TRCP; similar lesions were seen in only a few dosed males. Slightly increased incidences of thyroid gland follicular cell neoplasms (male rats: 5/50; 14/50; 13/50; female rats: 14/50; 16/50; 20/50) occurred in dosed males and females, but it is uncertain whether these were related to chemical administration. The 2-year studies in mice were conducted by administering 0, 175, or 350 mg/kg TRCP to groups of 60 males and females, 5 days per week for up to 104 weeks; 8 to 10 mice of each sex per dose group were evaluated at 66 weeks. There were no significant differences in survival between dosed and control groups of either sex, and final mean body weights of mice were similar among all groups. The principal chemical-related effects occurred in the kidney, in which nuclear enlargement (karyomegaly) of tubule epithelial cells was present in approximately 80% of high-dose mice. In the original diagnosis, renal tubule adenomas were seen in one control male, one high-dose male, and one low-dose female. A carcinoma was also seen in one high-dose male. In a s seen in one high-dose male. In a subsequent examination of step sections of all the mouse kidneys, adenomas were found in one low-dose male and two high-dose males. The incidences of renal tubule neoplasms in the original and step sections combined were 1/50, 1/50, and 4/50 for males. Female mice receiving TRCP demonstrated a marginally increased incidence of neoplasms (primarily adenomas) of the harderian gland (3/50; 8/50; 7/50); in addition, three harderian gland neoplasms occurred in high-dose female mice evaluated after 66 weeks. Genetic Toxicology: TRCP was not mutagenic in Salmonella typhimurium strains TA100, TA1535, TA1537, or TA98 with or without exogenous metabolic activation (S9), and it tested negative for the induction of chromosomal aberrations in Chinese hamster ovary (CHO) cells. TRCP produced an equivocal response in the presence of S9 for the induction of sister chromatid exchanges (SCE) in CHO cells. Conclusions: Under the conditions of these 2-year gavage studies, there was clear evidence of carcinogenic activity for male and female F344/N rats receiving tris(2-chloroethyl)phosphate as shown by increased incidences of renal tubule adenomas. Thyroid follicular cell neoplasms and mononuclear cell leukemia in male and female rats may have been related to chemical administration. There was equivocal evidence of carcinogenic activity for male B6C3F1 mice as shown by a marginally increased incidence of renal tubule cell neoplasms. There was equivocal evidence of carcinogenic activity for female B6C3F1 mice as shown by a marginally increased incidence of harderian gland adenomas. Renal tubule cell hyperplasia in male and female rats and gliosis, hemorrhage, pigmentation (hemosiderin accumulation), and mineralization in the brains of female rats were associated with the administration of tris(2-chloroethyl) phosphate. Karyomegaly of renal tubule epithelial cells in male and female mice was also chemical related. Synonyms: 2-chloroethanol phosphate (3:1); tris(b-chloroethyl) phosphate Trade Names: Fyrol CEF; Disflamoll TCA; NIAX flame retardant
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PMID:NTP Toxicology and Carcinogenesis Studies of Tris(2-chloroethyl) Phosphate (CAS No. 115-96-8) in F344/N Rats and B6C3F1 Mice (Gavage Studies). 1263 68

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


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