UMLS:C0036572 - FACTA Search

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Query: UMLS:C0036572 (seizures)
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Mitochondrial and cytosolic creatine kinase (CK) isozymes are active in cells with high and variable ATP metabolic rates. beta-Guanidinopropionic acid (GPA), a competitive inhibitor of creatine transport, was used to study the hypothesis that the creatine-CK-phosphocreatine (PCr) system is important in regulating brain ATP metabolism. The CK-catalyzed reaction rate and reactant concentrations were measured in vivo with 31P nuclear magnetic resonance spectroscopy during energy deficit (hypoxia) or high-energy turnover (seizures) states in urethane-anesthetized mice fed GPA, creatine, or standard chow (controls). Brain phosphagen (i.e., cellular energy reserves) or PCr plus phosphorylated GPA (GPAP) concentrations were equal. The phosphagen-to-NTP ratio was lower than in controls. In vivo CK reaction rate decreased fourfold, whereas ex vivo CK activity that was biochemically measured was doubled. During seizures, CK-catalyzed fluxes increased only in GPA-fed mice. Phosphagen increased in GPA-fed mice, whereas PCr decreased in controls. Survival was higher and brain phosphagen and ATP losses were less for hypoxic GPA-fed mice than for controls. In contrast to mice fed GPA, hypoxic survival and CK reactant concentrations during hypoxia and seizures were the same in creatine-fed mice and controls. Thus GPA, GPAP, or adaptive changes in ATP metabolism stabilize brain ATP and enhance survival during hypoxia in mice.
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PMID:In vivo brain phosphocreatine and ATP regulation in mice fed a creatine analog. 917 48

Primidone is used alone or with other anticonvulsants in the control of grand mal, psychomotor, and focal epileptic seizures. It may control grand mal seizures refractory to other anticonvulsant therapy. Primidone was nominated by the National Cancer Institute for 2-year toxicology and carcinogenicity studies due to its human use as an anticonvulsant. Male and female F344/N rats and B6C3F1 mice received primidone (greater than 99% pure) in feed for 14 days, 14 weeks, or 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium, cultured Chinese hamster ovary cells, and mouse bone marrow cells. 14-DAY STUDY IN RATS: Five male and five female rats were exposed to 0, 1,250, 2,500, 5,000, 10,000 or 20,000 ppm primidone (equivalent to average daily doses of approximately 120, 240, 500, 970, or 1,100 mg primidone/kg body weight to males and 120, 240, 500, or 900 mg/kg to females) in feed for 14 days. All 20,000 ppm females died before the end of the study as did one 10,000 ppm male and two 20,000 ppm males. The mean body weights of 10,000 ppm males and females and 20,000 ppm males were significantly less than those of the controls. Feed consumption by all exposed rats was generally similar to that by the controls. Males and females in the 10,000 and 20,000 ppm groups were observed to have eye discharge, ataxia, and abnormal posture and were thin and lethargic. 14-DAY STUDY IN MICE: Five male and five female mice were exposed to 0, 625, 1,250, 2,500, 5,000 or 10,000 ppm primidone (equivalent to average daily doses of approximately 100, 200, 400, or 800 mg/kg body weight to males and 100, 250, 500, or 900 mg/kg to females) in feed for 14 days. All mice in the 10,000 ppm groups and one male and one female mouse in the 5,000 ppm groups died on day 3 of the study. The mean body weights of mice in the 625, 1,250, 2,500, and 5,000 ppm groups were similar to those of the controls. Feed consumption by all exposed mice was generally similar to that by the controls. Males and females in the 10,000 ppm groups were observed to have abnormal posture, ataxia, and lethargy. 14-WEEK STUDY IN RATS: Groups of 10 male and 10 female rats were exposed to 0, 300, 600, 1,300, 2,500, or 5,000 ppm primidone (equivalent to average daily doses of approximately 20, 40, 100, 200, or 400 mg/kg) in feed for 14 weeks. All rats survived to the end of the study. The mean body weights of male and female rats in the 2,500 and 5,000 ppm groups were significantly less than those of the controls. Feed consumption by all exposed rats was generally similar to that by the controls. A minimal to mild exposure-related thrombocytosis occurred on day 22 and at week 14 in all exposed groups of male rats and in females in the 1,300 ppm or greater groups. A minimal decrease in hemoglobin concentration occurred in 2,500 and 5,000 ppm male and female rats on day 22 and at week 14. The incidences of centrilobular hepatocyte hypertrophy in male rats exposed to 600 ppm or greater and in female rats exposed to 1,300 ppm or greater were significantly greater than those in the controls. The severity of chronic nephropathy in male rats exposed to 1,300 ppm or greater increased with increasing exposure concentration. 14-WEEK STUDY IN MICE: Groups of 10 male and 10 female mice were exposed to 0, 300, 600, 1,300, 2,500, or 5,000 ppm primidone (equivalent to average daily doses of approximately 50, 100, 200, 400, or 1,000 mg/kg to males and 60, 120, 220, 440, or 1,100 mg/kg to females) in feed for 14 weeks. Three male and two female mice in the 5,000 ppm group died during week 1 of the study. The final mean body weights of all exposed groups were similar to those of the controls. Feed consumption by male mice in the 5,000 ppm group was slightly greater than that by the controls; this may have been due to feed spillage. Male and female mice in the 5,000 ppm groups were ataxic and lethargic. Compared to controls, the estrous cycle lengths of females exposed to 1,300, 2,500, or 5,000 ppm were significantly longer. The liver weights of male and female mice exposed to 600 po 600 ppm or greater were significantly greater than those of the controls. The incidences of centrilobular hepatocyte hypertrophy in all exposed males and in females exposed to 600 ppm or greater and the incidences of cytoplasmic alteration of the adrenal gland and hematopoietic cell proliferation of the spleen in 2,500 and 5,000 ppm males and in 5,000 ppm females were significantly greater than in the controls. 2-YEAR STUDY IN RATS: Groups of 50 male and 50 female F344/N rats were exposed to 0, 600, 1,300, or 2,500 ppm primidone (equivalent to average daily doses of approximately 25, 50, or 100 mg/kg) in feed for 2 years. Survival, Body Weights, and Feed Consumption Survival of the 1,300 and 2,500 ppm males was sig nificantly less than that of the controls. The mean body weights of males and females in the 2,500 ppm groups were less than those of the controls, beginning at week 29 for males and week 17 for females; the mean body weights of 1,300 ppm males and females were less than those of the controls during the second year of the study. Feed consumption by all exposed groups of rats was generally similar to that by the controls. Pathology Findings Male rats exposed to primidone had increased inci dences of thyroid gland follicular cell neoplasms (adenoma and/or carcinoma). All exposed groups of male rats had follicular cell adenomas or carcinomas (combined) at incidences above the historical control range, with the highest incidence in the 1,300 ppm group. Hepatocyte cytoplasmic vacuolation and centrilobular hypertrophy were associated with primidone exposure in male and female rats. These changes were more severe in females than in males and the incidences in all exposed groups of females were significantly greater than those in the controls. Females in the 2,500 ppm group had an increased incidence of hepatocellular eosinophilic foci. In 2,500 ppm males, the incidence of renal tubule hyperplasia was greater than that in the controls in the standard evaluation. Additional hyperplasias were found in the extended evaluation, and the incidences in exposed groups of males were significantly greater than that in the controls. In the extended evaluation, the incidence of renal tubule adenoma in 2,500 ppm males was significantly increased. The incidence of adenoma or carcinoma (combined) in 2,500 ppm males in the combined standard and extended evaluations were marginally increased over those in the controls. Male rats had an exposure-related increase in the severity of chronic nephropathy, which probably accounted for the reduced survival in the 1,300 and 2,500 ppm groups. The incidences of kidney cysts were increased in 1,300 and 2,500 ppm males. Hyperparathyroidism, secondary to the loss of renal function, was present in many exposed male rats. The incidences of parathyroid gland hyperplasia in all groups of exposed males were significantly greater than that in the controls. 2-YEAR STUDY IN MICE: Groups of 50 male and 50 female mice were exposed to dietary levels of 0, 300, 600, or 1,300 ppm primidone (equivalent to average daily doses of approximately 30, 65, or 150 mg/kg to males and 25, 50, or 100 mg/kg to females) in feed for 2 years. Survival, Body Weights, Feed Consumption, and Clinical Findings Survival of the 1,300 ppm males was significantly less than that of the controls. During the second year of the study, the mean body weights of 1,300 ppm male and female mice were less than those of the controls. The final mean body weights of 600 ppm males and females were less than those of the controls. Feed consumption by all exposed groups of mice was similar to that by the controls. During the latter part of the study, a treatment-related increase in the number of animals with swelling of the abdominal area was observed; necropsy revealed that the swelling was due to liver nodules/masses. Pathology Findings The liver was a target organ in both male and female mice. The incidences and multiplicities of hepatocellular neoplasms (hepatocellular adenoma, hepatocellular carcinoma, and hepatoblastoma) in all exposed groups of males and females (except hepatoblastoma in females) were significantly greater than those in the controls. The incidences of hepatocellular adenoma or carcinoma (combined) and hepatocellular adenoma, hepatocellular carcinoma, or hepatoblastoma (combined) in all exposed groups exceeded the historical control ranges in 2-year NTP studies. The incidences of centrilobular hepatocyte hypertrophy were increased in exposed groups of males and females, and the severities increased with increasing exposure concentration. The incidences of cytoplasmic vacuolization were increased in all exposed groups of females and in 300 ppm males. Incidences of eosinophilic focus in all exposed groups of females were significantly greater than those in the controls. Proliferative changes occurred in the thyroid gland in an exposure-related manner in male and female mice. Incidences of follicular cell hyperplasia were increased in all exposed groups of males and in 600 and 1,300 ppm females, but incidences of follicular cell adenomas were increased only in male mice. GENETIC TOXICOLOGY: Primidone was mutagenic in Salmonella typhimurium strain TA1535 in the absence of S9 activation only; no mutagenicity was detected in strain TA98, TA100, or TA1537, with or without S9. Primidone did not induce sister chromatid exchanges or chromosomal aberrations in cultured Chinese hamster ovary cells, with or without S9. The single in vivo study with primidone, a mouse bone marrow micronucleus test, also gave negative results. CONCLUSIONS: Under the conditions of these 2-year feed studies, there was equivocal evidence of carcinogenic activity of primidone in male F344/N rats based on a marginal increase in thyroid gland follicular cell neoplasms, primarily adenomas, and a marginal increase in renal tubule neoplasms. There was no evidence of carcinogenic activity of primidone in female F344/N rats exposed to 600, 1,300, or 2,500 ppm. There was clear evidence of carcinogenic activity of primidone in male B6C3F1 mice based on the increased incidences of hepatocellular neoplasms, and the increased incidence of thyroid gland follicular cell adenomas was also considered to be chemical related. There was clear evidence of carcinogenic activity of primidone in female B6C3F1 mice based on the increased incidences of hepatocellular neoplasms. Exposure of rats to primidone resulted in increased incidences of hepatocyte cytoplasmic vacuolization and centrilobular hypertrophy in males and females and eosinophilic foci in females. The increased severity of nephropathy and increased incidence of renal tubule hyperplasia in male rats were related to primidone exposure. Exposure of male mice to primidone resulted in hepatocyte centrilobular hypertrophy and thyroid gland follicular cell hyperplasia. Exposure of female mice to primidone resulted in hepatocyte centrilobular hypertrophy and cytoplasmic vacuolization, eosinophilic focus, and thyroid gland follicular cell hyperplasia. Synonyms: 5-Aethyl-5-phenyl-hexahydropyrimidin-4,6-dion; 2-deoxyphenobarbital; 2-desoxyphenobarbital; desoxyphenobarbitone; 5-ethyldihydro-5-phenyl-4,6 (1H,5H)-pyrimidinedione; 5-ethylhexahydro-4,6-dioxo-5-phenylphrimidine; 5-ethylhexahydro-5-phenylpyrimidine-4,6-dione; 5-ethyl-5-phenylhexahydropyrimidine-4,6-dione Trade names: Cyral; Hexadiona; Hexamidine; Lepimidin; Lepsiral; Majsolin; Midone; Milepsin; Misodine; Misolyne; Mizodin; Mizolin; Mylepsin; Mylepsinum; Mysedon; Mysoline; Prilepsin; Primacione; Primaclone; Primacone; Primakton; Primadon; Prysoline; Pyrimidone; ROE 101; Sertan
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PMID:NTP Toxicology and Carcinogenesis Studies of Primidone (CAS No. 125-33-7) in F344/N Rats and B6C3F1 Mice (Feed Studies). 1257 87

1-Trans-delta(9)-tetrahydrocannabinol (THC) was nominated by the National Cancer Institute to the NTP for study because it is the major psychoactive component of marijuana and a widely used Schedule I substance. Male and female F344/N rats and B6C3F1 mice received THC (97% pure) in corn oil by gavage for 13 weeks, 13 weeks with a 9-week recovery period, or 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium, cultured Chinese hamster ovary cells, and mouse peripheral blood cells. 13-WEEK STUDY IN RATS: Groups of 10 male and 10 female rats received 0, 5, 15, 50, 150, or 500 mg THC/kg body weight in corn oil by gavage, 5 days per week for 13 weeks. Six male and six female rats receiving 500 mg/kg died before the end of the study. The final mean body weights and weight gains of all dosed groups of males and females, except 5 mg/kg females, were significantly lower than those of the controls. Feed consumption by dosed groups was similar to that by controls. Clinical findings observed during the study included lethargy, sensitivity to touch, convulsions, tremors, and aggressiveness. There were no clinical pathology differences considered to be directly related to the administration of THC. The absolute and relative uterus weights of 50, 150, and 500 mg/kg females were significantly lower than those of the controls. Treatment-related multifocal atrophy was observed in the testes of 150 and 500 mg/kg males; uterine and ovarian hypoplasia observed in 150 and 500 mg/kg females was also considered to be related to THC administration. Based on final mean body weights and mortality observed in the 13-week study, doses selected for the 2-year rat study were 12.5, 25, and 50 mg/kg. 13-WEEK STUDY IN MICE: Groups of 10 male and 10 female mice received 0, 5, 15, 50, 150, or 500 mg THC/kg body weight in corn oil by gavage, 5 days per week for 13 weeks. There were no treatment-related deaths. The final mean body weight and weight gain of 500 mg/kg males were significantly lower than those of the controls. Clinical findings included lethargy and aggressiveness, and both male and female mice in all dosed groups were easily startled. There were no absolute or relative organ weight differences, clinical pathology differences, or microscopic changes observed that were considered to be related to the administration of THC. Due to the minimal THC-related effects observed in the 13-week study, doses selected for the 2-year mouse study were 125, 250, and 500 mg/kg. 13-WEEK WITH 9-WEEK RECOVERY STUDY IN RATS: Groups of 10 male and 10 female rats received 0, 5, 15, 50, 150, or 500 mg THC/kg body weight in corn oil by gavage, 5 days per week for 13 weeks, and then were allowed to recover during a 9-week treatment-free period. Five male and eight female 500 mg/kg rats, five male and two female 150 mg/kg rats, and three male and two female 50 mg/kg rats died before the end of the study. During the 13-week dosing period, mean body weight gains of all dosed groups of rats were lower than those of the controls but returned to normal during the recovery period. Final mean body weights of all dosed groups were similar to those of the controls. Clinical findings observed during the recovery period included sensitivity to touch, convulsions, and aggressiveness. The absolute right testis weight of 500 mg/kg males was significantly lower than that of the controls. Treatment-related multifocal atrophy of the testis was observed in 150 and 500 mg/kg males. There were no treatment-related lesions observed in females administered THC. 13-WEEK WITH 9-WEEK RECOVERY STUDY IN MICE: Groups of 10 male and 10 female mice received 0, 5, 15, 50, 150, or 500 mg THC/kg body weight in corn oil by gavage, 5 days per week for 13 weeks, and then were allowed to recover during a 9-week treatment-free period. The final mean body weights of all dosed groups were similar to those of the controls. Clinical findings observed during the study included lethargy and aggressiveness, and both male and female mice in all dosed groups were easily startled. The absolutebsolute and relative uterus weights of 150 and 500 mg/kg female mice were significantly lower than those of the controls, as was the absolute uterus weight of 50 mg/kg females. 2-YEAR STUDY IN RATS: Groups of 62 vehicle control male rats, 60 low-dose male rats, 70 mid- and high-dose male rats, and 60 female rats were administered 0, 12.5, 25, or 50 mg THC/kg body weight in corn oil by gavage for 104 to 105 weeks. Nine or ten animals from each group were evaluated at 15 months. Survival, Body Weights, and Clinical Findings: Survival of all dosed groups was generally significantly greater than that of the controls. Mean body weights of dosed groups of males and females were lower than those of the controls throughout the study. Convulsions and seizures were observed in all dosed groups of male and female rats, usually following dosing or handling. Hematology and Clinical Chemistry: At the 15-month interim evaluation, total leukocyte and lymphocyte counts in all dosed groups of females were greater than those of the controls, and platelet counts in these groups were lower than that of the controls. Levels of follicle stimulating and luteinizing hormones in all dosed groups of males were significantly greater than those of the controls, as was the serum corticosterone level of 25 mg/kg females. Pathology Findings: No increased incidences of neoplasms were considered related to administration of THC. The incidences of mammary gland fibroadenoma and uterine stromal polyps were decreased in dosed groups of females, as were the incidences of pituitary gland adenomas, interstitial cell adenomas of the testis, and pancreatic adenomas in dosed males. 2-YEAR STUDY IN MICE: Groups of 62 vehicle control male mice, 60 low-dose male mice, 61 mid-dose male mice, and 60 high-dose male mice and 60 female mice were administered 0, 125, 250, or 500 mg THC/kg body weight in corn oil by gavage for 104 to 105 weeks (males) or 105 to 106 weeks (females). Survival, Body Weights, and Clinical Findings: Survival of 500 mg/kg males was significantly less than that of the controls; survival of all other groups of males and of all dosed groups of females was similar to that of the controls. Mean body weights of all dosed groups were markedly lower than those of the controls throughout the study. Clinical findings in dosed groups included hyperactivity, convulsions, and seizures which occurred following dosing or handling. Hematology: At the 15-month interim evaluation, total leukocyte and lymphocyte counts in all dosed groups of males were significantly lower than those of the controls. Pathology Findings: Increased incidences of thyroid gland follicular cell adenoma occurred in 125 mg/kg males and females, but the increase was not dose-related. Increased incidences of thyroid gland follicular cell hyperplasia occurred in all dosed groups of males and females. Increased incidences of forestomach hyperplasia and ulcers occurred in all groups of males administered THC. Incidences of hepatocellular adenoma and of hepatocellular adenoma or carcinoma (combined) occurred with a significant negative trend in male and female mice, as did incidences of eosinophilic foci and fatty change in the liver. GENETIC TOXICOLOGY: THC was not mutagenic in Salmonella typhimurium strains TA97, TA98, TA100, or TA1535 with or without rat and hamster liver S9 fractions. In cultured Chinese hamster ovary cells, THC induced sister chromatid exchanges at the highest dose tested in the presence of S9; at this dose level, cell cycle delay indicative of toxicity was observed. THC did not induce chromosomal aberrations in cultured Chinese hamster ovary cells with or without S9 metabolic activation enzymes. In vivo, no increase in the frequency of micronucleated erythrocytes was observed in the peripheral blood of male or female mice administered THC by gavage for 13 weeks. CONCLUSIONS: Under the conditions of these 2-year gavage studies, there was no evidence of carcinogenic activity of 1-trans-delta(9)-tetrahydrocannabinol in male or female F344/N rats administered 12.5, 25, or 50 mg/kg. There was equivocal evidence of carcinogenic activity of THC in male and female B6C3F1 mice based on the increased incidences of thyroid gland follicular cell adenomas in 125 mg/kg groups. Increased incidences of thyroid gland follicular cell hyperplasia occurred in male and female mice, and increased incidences of hyperplasia and ulcers of the forestomach were observed in male mice. The incidences of mammary gland fibroadenomas and uterine stromal polyps were decreased in dosed groups of female rats, as were the incidences of pancreatic adenomas, pituitary gland adenomas, and interstitial cell adenomas of the testis in dosed male rats and liver neoplasms in dosed mice. These decreases were likely related to lower body weights in dosed animals. Synonyms: 3-Pentyl-6,6,9-trimethyl-6a,7,8,10a-tetrahydro-6h-dibenzo(b,d)pyran-1-ol; delta1-tetrahydrocannabinol; (-)-delta1-3,4-trans- tetrahydrocannabinol; delta(9)-tetrahydrocannabinon; THC; delta1-THC; delta(9)-THC
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PMID:NTP Toxicology and Carcinogenesis Studies of 1-Trans-Delta(9)-Tetrahydrocannabinol (CAS No. 1972-08-3) in F344 Rats and B6C3F1 Mice (Gavage Studies). 1259 29

5,5-Diphenylhydantoin and its sodium salt are primarily used in the treatment of grand mal and psychomotor seizures, often in combination with other anticonvulsants, including phenobarbital. 5,5-Diphenylhydantoin is a suspected human carcinogen and was one of three compounds selected by the NTP to investigate the potential value of perinatal exposures in assessing chemical carcinogenicity. Chronic toxicity and carcinogenicity studies of 5,5-diphenylhydantoin were conducted in male and female F344/N rats and B6C3F1 mice. The studies were designed to determine the following: a) the effects of 5,5-diphenylhydantoin in the diet given to rats and mice during the adult (F1) period only (a typical carcinogenicity study), b) the toxic and carcinogenic effects of 5,5-diphenylhydantoin 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 5,5-diphenylhydantoin. Genetic toxicology studies were conducted in Salmonella typhimurium, mouse Iymphoma cells, cultured Chinese hamster ovary cells, Drosophila melanogaster, and mouse bone marrow cells. STUDIES IN F344/N RATS: A 13-week toxicity study was conducted to select the exposure levels for adults in the 2-year study. The exposure levels for the 13-week study ranged from 300 to 4,800 ppm 5,5-diphenylhydantoin in the diet. The final mean body weights of males and females exposed to 2,400 or 4,800 ppm were significantly decreased. All groups showed a net weight gain over the study period, although the mean body weight gain of females in the 4,800 ppm group was only one-half that of the controls. Feed consumption also decreased with increasing exposure level. No chemical-related gross lesions were present in the tissues of exposed rats. Microscopically, centrilobular hypertrophy of hepatocytes was observed in the liver of rats in the 4,800 ppm groups. Based on these results, 2,400 ppm was selected as the highest exposure for the adult-only portion of the 2-year carcinogenicity study. A gestational study was performed to select the exposure levels for the perinatal portion of the 2-year study. The exposure levels ranged from 80 to 2,400 ppm 5,5-diphenylhydantoin in the diet of the dams. The 2,400 ppm exposure level was found to have reproductive and embryotoxic effects, as none of the sperm-positive females delivered litters. In the 800 ppm group, a greater number of pups died between postnatal day 1 and day 28 than in the control group. No gross external malformations were observed among fetuses or pups surviving to term in any exposure group, and no gross or histopathologic lesions were observed in the animals exposed to 800 ppm for 4 weeks following weaning. Based on these results, 630 ppm was selected as the highest exposure level for the perinatal portion of the 2-year carcinogenicity study. The eight F0:F1 exposure combinations selected for the 2-year study are listed in the table (contained in full report - page 6). In the 2-year study, male and female rats in the 630:2,400 ppm groups evaluated at 9 months had increased relative liver weights. Hematologic evaluations indicated mild but consistent chemical-related increases in erythrocyte and platelet counts in male and female rats. Mild decreases in triglyceride concentrations and alanine aminotransferase enzyme activity were seen generally in the high-exposure groups. In the 2-year study, the survival of exposed rats was similar to that of the controls. However, body weights of exposed rats were lower than those of the controls, and body weights were 11% to 35~ lower in rats receiving adult exposure of 2,400 ppm 5,5-diphenylhydantoin. Feed consumption was similar for exposed and control groups. Hepatocellular neoplasms, primarily adenomas, occurred with a positive trend in male rats fed 5,5-diphenylhydantoin only as adults (0:0 ppm, 0/50; 0:800 ppm, 2/50; 0:2,400 ppm, 4/50). There were no increased neoplasm incidences at other sites in exposed males or at any site in exposed females.emales. Perinatal-only or combined perinatal and adult exposure to 5,5-diphenylhydantoin did not enhance the overall incidences of liver neoplasms in male or female rats. However, the finding of 5/49 hepatocellular adenomas in the 630:2,400 male rat group was consistent with the marginally elevated liver neoplasm rate observed in the 0:2,400 group. Decreased incidences of a number of different neoplasms in exposed groups were most likely related to the lower body weights. STUDIES IN B6C3F1 MICE: A 13-week toxicity study was conducted to select the exposure levels for adults in the 2-year study. The exposure levels for the 13-week study ranged from 75 to 1,200 ppm 5,5-diphenylhydantoin in the diet. With the exception of one male, all mice exposed to 1,200 ppm died before the end of the study. No other chemical-related deaths occurred. All groups of mice except the 1,200 ppm groups gained weight over the 13-week period; however, an exposure related decrease in body weight gain was seen in males and females. Feed consumption by exposed and control groups was generally similar. Chemical related histomorphologic lesions were present in the liver of exposed mice, particularly 600 ppm males, and consisted of centrilobular hypertrophy of hepatocytes. Females appeared to be less sensitive than males to the effects of 5,5-diphenylhydantoin on growth and on histomorphologic liver lesions. Based on these results, 300 ppm (males) and 600 ppm (females) were selected as the highest exposure levels for the adult-only portion of the 2-year carcinogenicity study. A gestational study was performed to select the exposure levels for the perinatal portion of the 2-year study. The exposure levels for males and females ranged from 20 to 600 ppm 5,5-diphenylhydantoin in the diet. In general, reproductive performance and maternal care were poor in all groups, including the controls, thus restricting the sample size and sensitivity of this evaluation. There were no litters in the 600 ppm group, and maternal weight gain was depressed. There were no gross external malformations among pups surviving to term, and no gross or histopathologic lesions were observed in any mice exposed for 4 weeks following weaning. Based on these results, 210 ppm was selected as the highest exposure level for the perinatal portion of the 2-year carcinogenicity study. The F0:F1 exposure combinations selected for the 2-year study are listed in the following table (contained in full report - page 7). For mice evaluated at 9 months, males and females receiving the highest F0:F1 exposure levels had increased relative liver weights. In the 2-year study, the survival of exposed animals was similar to that of the controls; however, body weights were lower for exposed groups, and decreased body weights were most severe in adult females receiving 600 ppm 5,5-diphenylhydantoin. Feed consumption was similar for exposed and control groups. The incidences of hepatocellular neoplasms were increased in female mice receiving adult-only exposure (0:0 ppm, 5/48; 0:200 ppm, 14/49; 0:600 ppm, 30/50) or combined perinatal and adult exposure (210:200 ppm, 16/50; 210:600 ppm, 34/50). A marginally increased incidence of liver neoplasms (12/49) occurred in females in the perinatal-only (210:0) exposure group. There were no chemical-related increased incidences of liver neoplasms in males receiving adult-only or perinatal-only exposure. However, males receiving the high-exposure combined perinatal and adult exposure regimen (210:300 ppm) had an increased incidence of liver neoplasms (41/50) compared to the 0:0 (29/50), 0:300 (26/49), and 210:0 (33/50) groups. As a result, there was a significant enhancement (interaction) associated with combined perinatal and adult exposure. Such enhancement of neoplasia did not occur in female mice. Decreased incidences of malignant neoplasms in exposed groups were most likely related to the lower body weights. GENETIC TOXICOLOGY: In general, tests for genotoxic activity of 5,5-diphenylhydantoin were negative. All in vitro testing was performed in the presence and the absence of exogenous metabolic activation (S9). 5,5-Diphenylhydantoin did not induce mutations in Salmonella typhimurium, in L5178Y mouse Iymphoma cells, or in germ cells of male Drosophila melanogaster, nor did it induce chromosomal aberrations in cultured Chinese hamster ovary cells. A small but statistically significant increase was obtained in the cultured Chinese hamster ovary cell test for induction of sister chromatid exchanges in the presence of S9; without S9, no increase in sister chromatid exchanges was observed. In vivo, 5,5-diphenylhydantoin did not induce micronuclei polychromatic erythrocytes or chromosomal aberrations in bone marrow cells of male mice; equivocal results were obtained in an in vivo test for induction of sister chromatid exchanges in mouse bone marrow cells. CONCLUSIONS: Adult-Only Exposure: Under the conditions of these 2-year, adult-only, dietary exposure studies, there was equivocal evidence of carcinogenic activity of 5,5-diphenylhydantoin in male F344/N rats based on marginally increased incidences of hepatocellular neoplasms. There was no evidence of carcinogenic activity of 5,5-diphenylhydantoin in female F344/N rats given 240, 800, or 2,400 ppm. There was no evidence of carcinogenic activity of 5,5-diphenylhydantoin in male B6C3F1 mice given 30,100, or 300 ppm. There was clear evidence of carcinogenic activity of 5,5-diphenylhydantoin in female B6C3F1 mice based on increased incidences of hepatocellular neoplasms. Perinatal-Only Exposure: Perinatal exposure alone (through dietary administration of 210 ppm 5,5-diphenylhydantoin during the perinatal period) caused a marginal increase in the incidences of hepatocellular neoplasms in female B6C3F1 mice evaluated 2 years after cessation of exposure. In male and female F344/N rats, exposure to 630 ppm during the perinatal period did not influence the incidences of hepatocellular or other neoplasms. Similarly, exposure of male B6C3F1 mice to dietary levels of 210 ppm 5,5-diphenylhydantoin during the perinatal period did not affect neoplasm incidences. No teratologic effects were observed. Combined Perinatal and Adult Exposure: Combined perinatal and adult dietary exposure to 5,5-diphenylhydantoin confirmed the findings of the increased incidences of hepatocellular neoplasms for adult-only exposures in male F344/N rats and female B6C3F1 mice, although combined exposure did not enhance these neoplastic effects. However, in male B6C3F1 mice, combined perinatal and adult exposure resulted in increased incidences of hepatocellular neoplasms (hepatocellular carcinomas and multiple adenomas) that were not seen when dietary exposure was limited to the adult exposure period only. Synonyms: Diphenylhydantoin; 5,5-diphenyl-2,4-imidazolidinedione Trade names: Difhydan; Dihycon; Di-Hydan; Di-Lan; Dilabid; Dilantin; Ekko; Hydantol; Lehydan; Zentropil
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PMID:Toxicology and Carcinogenesis Studies of 5,5-Diphenylhydantoin (CAS No. 57-41-0) (Phenytoin) in F344/N Rats and B6C3F1 Mice (Feed Studies). 1262 14

Nitrofurazone is a synthetic furan derivative, active against a broad spectrum of bacteria, which has been widely used in veterinary and human medicine. Toxicology and carcinogenesis studies were conducted by feeding diets containing nitrofurazone (99% pure) to groups of F344/N rats and B6C3F1 mice of each sex for 14 days, 13 weeks, or 2 years. Fourteen-Day and Thirteen-Week Studies: Groups of five males and five females of each species were fed diets containing 0, 630, 1,250, 2,500, 5,000, or 10,000 ppm for 14 consecutive days. Early deaths occurred in all groups of rats receiving 5,000 or 10,000 ppm nitrofurazone. The surviving rats in the lower two dose groups gained weight, but weight gain was decreased as the dose of nitrofurazone was increased. Feed consumption by rats of each sex was decreased at all doses above 630 ppm. In all dosed groups, clinical signs of toxicity included rough hair coats and lethargy. At doses of 2,500 ppm and above, rats of each sex exhibited intermittent episodes of seizures and lethargy. All mice that received 2,500, 5,000, or 10,000 ppm nitrofurazone and 3/5 males that received 1,250 ppm died before the end of the 14-day studies; the surviving dosed mice (except females at 630 ppm) lost weight. A dose-related decrease in feed consumption was observed at all doses above 630 ppm. Clinical signs included rough hair coats and convulsive seizures. In the 13-week studies, groups of 10 rats of each sex were given diets containing 0, 150, 310, 620, 1,250, or 2,500 ppm nitrofurazone. No deaths were observed and all animals gained weight, but the magnitude of weight gain was dose dependent with decrements in final mean body weight for the highest dose group reaching 55% in males and 36% in females. Other evidence of chemically related toxicity included convulsive seizures, osteoporosis, degenerative arthropathy, and gonadal hypoplasia in both sexes at the two highest doses. Groups of 10 mice of each sex were given diets containing 0, 70, 150, 310, 620, or 1,250 ppm nitrofurazone for 13 weeks. Early deaths were observed in the two highest dose groups of each sex. The final mean body weights of male and female mice in the 1,250-ppm groups were about 20% lower than those of the controls; weight gains of the other dosed mice were comparable to those of the controls. Stimulus-induced convulsive seizures were observed for all mice in the two highest dose groups. Testicular hypoplasia was observed in the two highest dose groups of male mice. Body Weight and Survival in the Two-Year Studies: Dietary concentrations for the 2-year studies were 0, 310, or 620 ppm for rats and 0, 150, or 310 ppm for mice (50 animals per dose group). Mean body weights of high dose male rats were lower than those of the controls after week 39; mean body weights of low dose male rats and of the controls were comparable throughout the study. Final mean body weights of low and high dose female rats were 9% and 21% lower than those of the controls. Dosed rats consumed less feed than did the controls. The average amount of nitrofurazone consumed per day was approximately 11-12 or 24-26 mg/kg by low or high dose male and female rats. The survival of the high dose group of male rats was lower than that of the controls after week 92 (final survival-- male: control, 33/50; low dose, 30/50; high dose, 20/50; female: 28/50; 37/50; 31/50). Mean body weights of dosed mice were similar to or somewhat greater than those of controls throughout most of the studies. The average daily feed consumption by dosed mice was similar to that of controls. The average amount of nitrofurazone consumed per day was approximately 14-16 or 29-33 mg/kg for low or high dose male and female mice. The survival of the high dose group of male mice was lower than that of the controls after week 88 (final survival-- male: 39/50; 31/50; 27/50; female: 39/50; 40/50; 35/50). In mice of each sex, nitrofurazone administration induced stimulus-sensitive convulsive seizures beginning at week 4 or 5 for high dose mice and week 24 for low dose female mice. These seizures were low dose female mice. These seizures were observed primarily in the first year of the study. Nonneoplastic and Neoplastic Effects in the Two-Year Studies: Degenerative changes involving the vertebral and femoro-tibial (knee) joints were observed at increased incidences in dosed rats. The degenerative changes primarily affected the articular cartilage and were similar to those seen in the 13-week studies. Degeneration of the sternal synchondroses was increased in high dose female rats. The osteoporosis seen in the 13-week studies was not observed in the 2-year studies. Testicular degeneration, characterized by atrophy of the germinal epithelium and aspermatogenesis, was observed at increased incidences in dosed male rats (control, 12/50; low dose, 49/50; high dose, 47/50). Adenomas of the sebaceous glands and trichoepitheliomas or sebaceous adenomas (combined) of the skin were observed in high dose male rats (0/50; 0/50; 5/50). Carcinomas of the preputial gland were increased in dosed male rats (1/50; 8/50; 5/50). The incidences of preputial gland adenomas or carcinomas (combined) in dosed male rats were not statistically greater than that in the controls (9/50; 16/50; 7/50). However, in the low dose group, the incidence is greater than the highest incidence observed in historical untreated control groups (9/50). In addition, hyperplasia of the preputial gland was observed in six low dose male rats in which neither adenomas nor carcinomas occurred. The incidence of mesotheliomas of the tunica vaginalis in low dose male rats was greater than that in the controls (0/50; 7/50; 2/50). Fibroadenomas of the mammary gland occurred at markedly increased incidences in dosed female rats (8/49; 36/50; 36/50). Three adenocarcinomas were also observed (1/49; 0/50; 2/50). Ovarian atrophy (7/47; 44/50; 38/50) and tubular cell hyperplasia of the ovary (1/47; 23/50; 21/50) were observed at markedly increased incidences in dosed female mice. The incidences of benign mixed tumors (0/47; 17/50; 20/50), granulosa cell tumors (1/47; 4/50; 9/50), and granulosa cell tumors or luteomas (combined) (3/47; 6/50; 9/50) of the ovary were increased in exposed female mice. Mononuclear cell leukemia in rats occurred with negative trends (male: 21/50; 23/50; 6/50; female: 15/49; 2/50; 2/50). In female mice, the incidences of adenomas or carcinomas (combined) of the anterior pituitary gland occurred with a negative trend (10/50; 7/50; 2/49). The incidences of testicular interstitial cell tumors were decreased in dosed male rats (45/50; 30/50; 28/50). Genetic Toxicity: Nitrofurazone was mutagenic in Salmonella typhimurium strains TA98 and TA100 both with and without exogenous metabolic activation. The responses in strains TA1535 and TA1537 were more varied: nitrofurazone was mutagenic in strain TA1535 only in the presence of S9 and produced no consistent increase in gene reversions in strain TA1537 with or without S9. In the absence of metabolic activation, nitrofurazone induced forward mutations at the TK+/- locus of mouse L5178Y lymphoma cells; the chemical was not tested with S9. Treatment of cultured Chinese hamster ovary cells with nitrofurazone in the absence of S9 produced a dose-related increase in sister chromatid exchanges and chromosomal aberrations; with S9, sister chromatid exchanges were increased, but no induction of chromosomal aberrations was observed. Audit: The data, documents, and pathology materials from the 2-year studies of nitrofurazone were audited at the NTP Archives. The audit findings show that the conduct of the studies is documented adequately and support the data and results given in this Technical Report. Conclusions: Under the conditions of these 2-year feed studies, there was equivocal evidence of carcinogenic activity of nitrofurazone for male F344/N rats as shown by the occurrence of sebaceous gland adenomas and trichoepitheliomas of the skin, mesotheliomas of the tunica vaginalis, and preputial gland tumors. There was clear evidence of carcinogenic activity of nitrofurazone for female F344/N rats as shown by a markedly increased incidence of fibroadenomas of the mammary gland. There was no evidence of carcinogenic activity for male B6C3F1 mice fed diets containing nitrofurazone at concentrations of 150 or 310 ppm. There was clear evidence of carcinogenic activity of nitrofurazone for female B6C3F1 mice as shown by increased incidences of benign mixed tumors and granulosa cell tumors of the ovary. Administration of nitrofurazone was associated with decreased incidences of mononuclear cell leukemia in male and female rats, testicular interstitial cell tumors in male rats, and pituitary gland neoplasms in female mice. Convulsive seizures in mice of each sex, ovarian atrophy in female mice, testicular degeneration in rats, and degeneration of articular cartilage in rats were all associated with the administration of nitrofurazone. Synonyms: 5-nitro-2-furaldehyde semicarbazone; 2-[(5-nitro-2-furanyl)methylene]hydrazine carboximide Trade Names: Aldomycin; Amifur; Chemfuran; Coxistat; Furacin; Furacinetten; Furaplast; Furazol W; Furesol; Furracoccid; Mammex; Nefco; Nifuzon; Nitrofural; Vabrocid
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PMID:NTP Toxicology and Carcinogenesis Studies of Nitrofurazone (CAS No. 59-87-0) in F344/N Rats and B6C3F1 Mice (Feed Studies). 1273 99

Toxicology and carcinogenesis studies of technical-grade 2-mercaptobenzothiazole (96%-97% pure), a rubber accelerant and preservative, were conducted by administering the chemical by gavage in a corn oil vehicle to groups of F344/N rats and B6C3F1 mice of each sex for 16 days, 13 weeks, or 2 years. 2-Mercaptobenzothiazole was nominated for study by the National Institute of Environmental Health Sciences and the National Institute for Occupational Safety and Health. Sixteen-Day and Thirteen-Week Studies: In 16-day studies, mean body weight gains of rats receiving 2,500 mg/kg were 6-7 g lower than those of vehicle controls; 4/5 male and 5/5 female mice dosed with 3,000 mg/kg and 4/5 female mice dosed with 1,500 mg/kg died; lethargy and prostration occurred in most of these animals after gavage. Based on these results, doses were selected for both species in the 13-week studies were 0, 94 (mice only), 188, 375, 750, and 1,500 mg/kg. In the 13-week studies, no chemical-related deaths occurred in rats, but body weight gains in males dosed with 1,500 mg/kg and in females dosed with 750 or 1,500 mg/kg were lower than those in the vehicle control groups. Hepatomegaly occurred at the two highest doses in males and at all doses in females; however, no microscopic pathologic changes were noted in any tissue. More than half the mice dosed with 1,500 mg/kg died, but no compound-related body weight changes occurred. Clinical signs in mice were dose related and included lethargy in animals dosed with 375 mg/kg and lacrimation, salivation, and clonic seizure in some dosed with 750 or 1,500 mg/kg. No association between these clinical signs of toxicity and gross or microscopic pathologic effects were observed. Doses selected for the 2-year studies were 0, 375, and 750 mg/kg for male rats and for mice of each sex and 0, 188, or 375 mg/kg for female rats. Body weight and Survival in the Two-Year Studies: Fifty animals of each species and sex were administered 2-mercaptobenzothiazole in corn oil by gavage 5 days per week for 103 weeks. Administration of 2-mercaptobenzothiazole resulted in decreased survival in dosed male rats (vehicle control, 42/50; low dose, 22/50; high dose, 20/50) and in the high dose group of female mice (37/50; 39/50; 22/50) but not in female rats (28/50; 31/50; 25/50) or in male mice (38/50; 33/50; 30/50). No effect on body weight gain in dosed rats was observed; in dosed mice, minor reductions occurred between weeks 3 and 64, withrecovery thereafter. Postgavage lethargy and prostration occurred frequently in dosed rats and mice. Nonneoplastic and Neoplastic Effects in the Two-Year Studies: The severity of nephropathy was increased in dosed male rats. Ulcers and inflammation of the forestomach were prevalent in dosed rats, as were increased incidences of epithelial hyperplasia and hyperkeratosis in male rats, but no neoplasms of the forestomach were observed. There were no increases of nonneoplastic lesions in mice which were considered to be compound related. The incidences of a variety of tumors were increased in rats dosed with 2-mercaptobenzothiazole; some of the increased incidences were not dose related. In low dose male rats, increased incidences (P<0.01) were observed for mononuclear cell leukemia (7/50; 16/50; 3/50) and pancreatic acinar cell adenomas (2/50; 13/50; 6/49). Increased tumor incidences with dose-related trends (P<0.05) included pituitary gland adenomas in females (15/49; 24/50; 25/50), preputial gland adenomas or carcinomas (combined) in males (1/50; 6/50; 5/50), adrenal gland pheochromocytomas or malignant pheochromocytomas (combined) in males (18/50; 27/50; 24/49), and pheochromocytomas in females (1/50; 5/50; 6/50). These tumors were observed at significantly greater incidences (P</=0.05) in the high dose groups than in the vehicle controls. An increased incidence (P=0.028) of hepatocellular adenomas or carcinomas (combined) was observed only in low dose female mice (4/50; 12/49; 4/50). No significant increases in tumor incidences were seen in male mice. Genetic Toxicology: 2-Mercaptobenzothgy: 2-Mercaptobenzothiazole was not mutagenic in Salmonella typhimurium strains TA98, TA100, TA1535, or TA1537 with or without metabolic activation. In the presence of rat liver S9, 2-mercaptobenzothiazole increased the frequency of chromosomal aberrations and sister chromatid exchanges (SCEs) in Chinese hamster ovary (CHO) cells, as well as mutations at the TK locus of mouse L5178Y lymphoma cells. Audit: The data, documents, and pathology materials from the 2-year studies of 2-mercaptobenzothiazole were audited at the NTP Archives. The audit findings show that the conduct of the studies is documented adequately and support the data and results given in this Technical Report. Conclusions: Under the conditions of these 2-year gavage studies, there was some evidence of carcinogenic activity of 2-mercaptobenzothiazole for male F344/N rats, indicated by increased incidences of mononuclear cell leukemia, pancreatic acinar cell adenomas, adrenal gland pheochromocytomas, and preputial gland adenomas or carcinomas (combined). There was some evidence of carcinogenic activity for female F344/N rats, indicated by increased incidences of adrenal gland pheochromocytomas and pituitary gland adenomas. There was no evidence of carcinogenic activity of 2-mercaptobenzothiazole for maleB6C3F1 mice dosed with 375 or 750 mg/kg. There was equivocal evidence of carcinogenic activity for female B6C3F1 mice, indicated by increased incidences of hepatocellular adenomas or carcinomas (combined). Synonyms and Trade Names: Captax; Dermacid; Mertax; Thiotax; 2(3H)-benzothiazolethione; 2-benzothiazolyl mercaptan
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PMID:NTP Toxicology and Carcinogenesis Studies of 2-Mercaptobenzothiazole (CAS No. 149-30-4) in F344/N Rats and B6C3F1 Mice (Gavage Studies). 1273 4

Dicyclohexylcarbodiimide (DCC) and Diisopropylcarbodiimide (DIC) are two representative chemicals in the carbodiimide class of chemicals used in industry as stabilizing agents. There is a potential of dermal exposure to these agents in chemical, pharmaceutical and recombinant DNA industries. The National Toxicology Program conducted a number of animal studies to characterize toxicity and carcinogenicity of DIC and DCC. Dermal administration of DCC and DIC in F344/N rats and B6C3F1 mice for 90-days induced skin irritation at the site of application in a dose-dependent manner. Microscopically, dose-dependent increases in epidermal hyperplasia and chronic inflammation were observed. We further evaluated the effects of dermal exposure of DCC and DIC in p53 haploinsufficient and Tg.AC mouse models. Results revealed the skin as the primary target of DCC and DIC exposure as indicated by dose - dependent skin lesions (hyperplasia, inflammation and necrosis). DCC induced squamous cell papillomas in Tg.AC mice but did not induce any neoplastic lesions in p53 haploinsufficient mice. Dermal application of DIC did not induce any neoplastic lesions in Tg.AC mice and p53 haploinsufficient mice. Based on these studies, it was predicted that DIC would be negative and DCC positive for carcinogenic activity in the traditional two-year bioassay. In the subsequent studies, the carcinogenic potential of DIC only in F344 rats and B6C3F1 mice in a traditional 2-year chronic carcinogenicity bioassay was evaluated by the dermal route. Findings revealed the skin as the major target organ of toxicity in both sexes in rats and in male mice. There were no neoplastic lesions observed in rats or mice with the administration of DIC. In rats, there were clinical signs of toxicity in the highest dose-group which included ataxia, excitability, impaired gait, low muscle tone, abnormal breathing, lethargy, and seizures. This was accompanied by non-neoplastic lesions in the brain and lung only at the highest dose level. In conclusion, both DIC and DCC are dermal toxicants. DIC did not have any carcinogenic activity in transgenic mouse models or in the traditional NTP two-year carcinogenicity studies in F344 rats and B6C3F1 mice. DCC was positive in the Tg.AC mouse model and likely to be carcinogenic in the 2-year bioassay as well.
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PMID:Comparative dermal toxicity of dicyclohexylcarbodiimide and diisopropylcarbodiimide in rodents. 2206 Aug 20

Inosine triphosphate pyrophosphatase (ITPA) hydrolyzes inosine triphosphate (ITP) and other deaminated purine nucleotides to the corresponding nucleoside monophosphates. In humans, ITPA deficiency causes severe encephalopathy with epileptic seizure, microcephaly, and developmental retardation. In this study, we established neural stem cell-specific Itpa-conditional KO mice (Itpa-cKO mice) to clarify the effects of ITPA deficiency on the neural system. The Itpa-cKO mice showed growth retardation and died within 3 weeks of birth. We did not observe any microcephaly in the Itpa-cKO mice, although the female Itpa-cKO mice did show adrenal hypoplasia. The Itpa-cKO mice showed limb-clasping upon tail suspension and spontaneous and/or audiogenic seizure. Whole-cell patch-clamp recordings from entorhinal cortex neurons in brain slices revealed a depolarized resting membrane potential, increased firing, and frequent spontaneous miniature excitatory postsynaptic current and miniature inhibitory postsynaptic current in the Itpa-cKO mice compared with ITPA-proficient controls. Accumulated ITP or its metabolites, such as cyclic inosine monophosphates, or RNA containing inosines may cause membrane depolarization and hyperexcitability in neurons and induce the phenotype of ITPA-deficient mice, including seizure.
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PMID:Neural stem cell-specific ITPA deficiency causes neural depolarization and epilepsy. 3320 50