Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0001430 (adenoma)
 21,222 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The prostates of 1775 (614 control and 1161 experimental) 2-year-old F344 rats from 12 different carcinogen bioassays conducted by the Bioassay Program of the NCI and the NTP were evaluated histologically. The incidence of prostatic lesions including (atypical) hyperplastic foci, adenomas, and carcinomas was 6.8%. There was no difference in the type or incidence of the lesions between treated and untreated animals. Adenomas or carcinomas were found in 71 (4.0%) of the rats, primarily as incidental findings. The number of tumors and hyperplastic foci varied from laboratory to laboratory depending on the anatomical localization of the plane of the section. Most of the neoplasms were found in the ventrolateral lobes of the prostate (ventral prostate). When adequate sections were prepared of the ventral lobe, 10-20% of the prostates had these proliferative lesions. The lesions were usually small and originated in the epithelium of the alveoli and small ducts and were usually small and originated in the epithelium of the alveoli and small ducts and were not associated with the common inflammatory lesions of the rat prostate. Thin fibrous capsules were formed in a few of the larger tumors. Metastases were not observed but there was local invasion into alveoli, ducts and interstitial connective tissue. Evidence is presented that the atypical hyperplasias progress to adenoma and carcinoma. The F344 rat offers a potential model for the study of latent prostatic preneoplastic and neoplastic lesions.
 ...
PMID:Prostatic hyperplasia and neoplasia in aging F344 rats. 617 Sep 67

While the rat pancreas is susceptible to experimental cancer induction, the spontaneous incidence of pancreatic cancer in this species is reported to be very low. However, we observed unusually high incidences of focal acinar hyperplasia and acinar adenoma in vehicle control male F344/N rats of some NCI/NTP 2-year toxicological studies. The vehicle in these studies was corn oil given by gavage. Focal acinar hyperplasia, acinar adenoma, and acinar carcinoma (found rarely) represent a continuous spectrum of proliferative lesions of the exocrine pancreas. While the carcinomas have clear morphological indications of malignancy, the biological behavior of focal acinar hyperplasia and acinar adenoma is not known. Although induction of acinar carcinomas is considered clear evidence of carcinogenicity of a test chemical, significantly increased incidences in treated rats of acinar adenomas but not carcinomas provides some evidence of carcinogenicity. The association of acinar hyperplasia and adenoma with vegetable oil gavage complicates the interpretation when marginally elevated incidences of these lesions are observed in rats administered the test chemical in vegetable oil vehicle. Studies of the biological behavior of exocrine pancreatic lesions in male rats would be helpful in assessing the significance of their presence when found after test compound administration.
 ...
PMID:Proliferative lesions of the exocrine pancreas in male F344/N rats. 643

Oxazepam and related benzodiazepines are used in the treatment of anxiety. Carcinogenicity studies of oxazepam were performed with the F344 rat because of marked differences in tumor responses observed in NTP studies with B6C3F1 and Swiss-Webster mice compared to the results of Sprague-Dawley rat studies submitted to the FDA by a manufacturer to support registration of the drug. Groups of 50 male and 50 female F344/N rats were fed diets containing 0, 625, 2500, or 5000 ppm oxazepam for up to 105 weeks. A stop-exposure group of 50 males and 50 females received 10,000 ppm oxazepam in diet for 26 weeks, after which animals received control diet. All 5000- and 10, 000-ppm stop-exposure males died before the end of the study. Survival of 2500-ppm males and females was lower than that of controls. Body weight gains of 2500- and 5000-ppm males and females were less than those of controls. Male rats exposed to 2500 ppm had an increased incidence of renal tubule adenoma and hyperplasia. In addition, the incidences of renal tubule adenoma and hyperplasia were increased in the 10,000-ppm stop-exposure group. The incidences of nephropathy in exposed females were greater than those in controls, and the severity of nephropathy increased in exposed males. Epithelial hyperplasia and chronic inflammation of the nonglandular stomach were increased in males given 2500 and 5000 ppm and the incidence of ulcers of the nonglandular stomach in 2500-ppm males was also greater than that in controls. In males exposed to 5000 ppm, mineralization of the glandular stomach and erosion of the duodenum were observed. In females exposed to 2500 ppm, the incidences of epithelial hyperplasia, chronic inflammation, and ulcers of the nonglandular stomach and the incidence of erosion in the glandular stomach were increased. The incidences of centrilobular hepatocyte hypertrophy in males and females given 2500 and 5000 ppm were greater than those in controls. In summary, there was equivocal evidence of carcinogenicity in males based on increased renal tubule adenomas in groups which also had significantly enhanced nephropathy. There was no evidence of carcinogenicity of oxazepam in females given a diet containing 625, 2500, or 5000 ppm for 2 years or 10,000 ppm for 6 months.
 ...
PMID:Toxicity and carcinogenicity studies of oxazepam in the Fischer 344 rat. 953 42

Oxymetholone is a synthetic anabolic steroid used to treat a variety of conditions, including hypogonadism and delayed puberty. It is also used to correct hereditary angioneurotic edema, manage carcinoma of the breast, promote a positive nitrogen balance following injury or surgery, and stimulate erythropoiesis. Considerable amounts of androgens are consumed by athletes in attempts to improve athletic performance. The National Institute of Environmental Health Sciences and the National Cancer Institute nominated oxymetholone for study based on its extensive illicit pharmaceutical use and the limited evidence that it is a potential human carcinogen. Male and female F344/N rats received oxymetholone (greater than 99% pure) in 0.5% methylcellulose by gavage for 16 days, 14 weeks, or 2 years, and male and female B6C3F1 mice received oxymetholone in 0.5% methylcellulose by gavage for 16 days or 14 weeks. Genetic toxicology studies were conducted in Salmonella typhimurium, cultured Chinese hamster ovary cells, and mouse peripheral blood erythrocytes. 16-DAY STUDY IN RATS: Groups of five male and five female F344/N rats were administered 0, 160, 315, 625, 1,250, or 2,500 mg oxymetholone/kg body weight in 0.5% methylcellulose by gavage for 16 days. All male rats survived to the end of the study; one 2,500 mg/kg female died on day 14. The mean body weights of all dosed groups of males were significantly less than those of the vehicle controls, while those of 160 and 315 mg/kg females were significantly greater. 16-DAY STUDY IN MICE: Groups of five male and five female B6C3F1 mice were administered 0, 320, 630, 1,250, 2,500, or 5,000 mg/kg in 0.5% methylcellulose by gavage for 16 days. All mice survived to the end of the study. The final mean body weights of all dosed groups of females were greater than those of the vehicle controls. 14-WEEK STUDY IN RATS: Groups of 10 male and 10 female F344/N rats were administered 0, 80, 160, 315, 625, or 1,250 mg/kg in 0.5% methylcellulose by gavage for 14 weeks. One male rat each in the 625 and 1,250 mg/kg groups died before the end of the study. The mean body weights of males administered 160 mg/kg or greater were significantly less than those of the vehicle controls; in contrast, the mean body weights of all dosed groups of females were significantly greater. A dose-related erythrocytosis, evidenced by increases in erythrocyte counts, total hemoglobin concentrations, and hematocrit values, occurred in dosed groups of rats at week 14. A dose-related hypocholesterolemia occurred at all time points in all dosed groups of rats. Dose- and time-related decreases in 5 -nucleotidase activity occurred in treated rats. There was a transient, treatment-related increase in the activity of alanine aminotransferase in males and females. For male rats administered oxymetholone, cauda epididymis, epididymis, and testis weights and spermatid counts and total spermatid heads per testis were significantly less than those of the vehicle controls, and total spermatid heads per gram testis were significantly greater. Female rats in the 80 mg/kg group spent more time in diestrus and less time in estrus than did the vehicle controls. Kidney weights of males and females and liver and uterus weights of females were increased compared to vehicle controls in rats that received 315 mg/kg or greater; thymus weights of males and females and sartorius muscle and testis weights of males were less. Compared to the vehicle controls, rats that received 160 mg/kg or greater had increased incidences of nonneoplastic lesions of the kidney and mammary gland, and the incidences of hydrometra of the uterus and dysgenesis of the ovary were increased in dosed groups of females. Female rats administered 315 mg/kg or greater had increased incidences of cytoplasmic vacuolization of the adrenal gland and myocardial degeneration of the heart. The severities of these lesions generally increased with increasing dose. 14-WEEK STUDY IN MICE: Groups of 10 male and 10 female B6C3F1 mice were administered 0, 160, 320, 630, 1,250, or 2,500 mg/kged 0, 160, 320, 630, 1,250, or 2,500 mg/kg in 0.5% methylcellulose by gavage for 14 weeks. All mice administered oxymetholone survived until the end of the study. The mean body weights of all dosed groups were similar to those of the vehicle controls. The percentages of motile sperm in 1,250 and 2,500 mg/kg males were significantly less than those of the vehicle controls. The estrous cycle lengths of 630, 1,250, and 2,500 mg/kg females were significantly longer, and females in the 1,250 and 2,500 mg/kg groups spent more time in diestrus and less time in estrus. Kidney and liver weights of males and females were greater and thymus weights of females were less than those of the vehicle controls. All dosed females had hyperplasia of the clitoral gland, metaplasia of the parietal layer epithelium of the Bowman's capsule in the kidney, and cytoplasmic alteration of the submandibular gland; these lesions were not observed in the vehicle control group. The incidences of hypoplasia of the ovary in 320 mg/kg or greater females and of parotid gland atrophy in 1,250 and 2,500 mg/kg females were increased. The results of the 14-week oral gavage studies were generally similar in rats and mice, but rats were much more sensitive to oxymetholone. Because it was not likely that a long-term mouse study would provide significant additional toxicity information, the NTP decided to conduct a 2-year study in rats only. 2-YEAR STUDY IN RATS: Groups of 90 male F344/N rats were administered 0, 3, 30, or 150 mg/kg in 0.5% methylcellulose by gavage, and 90 female F344/N rats were administered 0, 3, 30, or 100 mg/kg in 0.5% methylcellulose by gavage for up to 104 weeks, with 9 or 10 rats per group evaluated at 3, 6, 12, or 18 months. Survival and Body Weights: Survival of all dosed groups was similar to that of the vehicle controls. The mean body weights of the 30 mg/kg male group were generally within 10% of those of the vehicle controls, but those of the 150 mg/kg group were markedly decreased. Mean body weights of 3 and 30 mg/kg females were generally greater than those of the vehicle controls throughout the study. Determinations of Oxymetholone in Plasma: The concentrations of oxymetholone in plasma of male and female rats receiving 3 mg/kg for 6, 12, or 18 months were generally below the limits of quantification; therefore, all plasma concentrations in the 3 mg/kg group are considered to be estimates (Table 8). The plasma concentrations at 30 mg/kg were approximately one order of magnitude greater than those of the estimates for males and females receiving 3 mg/kg. There were no dose-related differences in plasma concentrations in female rats receiving 30 or 100 mg/kg, but plasma concentrations in males were significantly elevated in the 150 mg/kg group. It was concluded that oxymetholone kinetics was saturated at 30 mg/kg in female but not male rats. Pathology Findings: A wide spectrum of neoplasms and nonneoplastic lesions was seen in rats administered oxymetholone for 2 years. The incidences of hepatocellular adenoma and hepatocellular adenoma or carcinoma (combined) were significantly increased in 100 mg/kg females as were the incidences of basophilic and clear cell foci in 150 mg/kg males and 100 mg/kg females compared to vehicle controls. The incidences of alveolar/bronchiolar adenoma and adenoma or carcinoma (combined) were significantly increased in 30 mg/kg females. The incidences of mineralization in the lung of 150 mg/kg males and 30 and 100 mg/kg females were significantly increased. The incidence of keratoacanthoma was increased in 30 mg/kg females, and the combined incidence of squamous cell papilloma, keratoacanthoma, basal cell adenoma, squamous cell carcinoma, or carcinoma of the sweat gland was significantly increased in 100 mg/kg females. The incidences of subcutaneous tissue fibroma and fibroma or fibrosarcoma (combined) were significantly increased in 3 mg/kg males. At 2 years, the incidences of benign pheochromocytoma and benign or malignant pheochromocytoma (combined) of the adrenal gland in 150 mg/kg males and medullary hyperplasia in 100 mg/kg females were significantly increased. The incidences of cytoplasmic vacuolization of adrenal cortical cells were significantly increased in 30 and 150 mg/kg males at 18 months and 2 years and in 100 mg/kg females beginning at 12 months and in 30 mg/kg females at 2 years. The incidences of renal tubule adenoma in 3 and 150 mg/kg males were slightly increased. An extended evaluation of the kidney was conducted, and additional incidences of renal tubule adenoma were observed in step sections in vehicle control and dosed male rats. The combined single- and step-section incidence of renal tubule adenoma was significantly increased in 3 mg/kg males. The incidences of nephropathy were significantly increased in 30 and 150 mg/kg males at 2 years and in 100 mg/kg females beginning at 3 months. The severities of nephropathy were significantly increased in dosed groups of males at 2 years and in 100 mg/kg females at 18 months and 2 years. The incidences of mineralization of the kidney were significantly increased in 150 mg/kg males at all time points. The incidences of ovarian dysgenesis were significantly increased in 100 mg/kg females beginning at 3 months and in 30 mg/kg females beginning at 6 months, and severities increased with increasing dose. The incidences of chronic myocardial degeneration (cardiomyopathy) were significantly increased in 100 mg/kg females at 6 months and 2 years and the severity was increased at 2 years. The incidences of lobular hyperplasia were increased in 150 mg/kg males at 18 months and 2 years and in 30 and 100 mg/kg females at all time points. The incidences of seminiferous tubule degeneration were significantly increased in 30 and 150 mg/kg males at 2 years, and the incidences of mineralization of the testis were increased in 150 mg/kg males at 12 months and in 30 mg/kg males at 18 months and at 2 years. Decreased incidences of neoplasms occurred in male and female rats. The incidence of uterine stromal polyp or stromal sarcoma (combined) was significantly decreased in 100 mg/kg females at 2 years. The incidences of mammary gland fibroadenoma and fibroadenoma or carcinoma (combined) were significantly decreased in all dosed groups of females. The incidences of pituitary gland pars distalis adenoma were significantly decreased in 30 and 100 mg/kg females at 2 years. The incidences of testicular interstitial cell adenoma were significantly decreased in 30 and 150 mg/kg males at 18 months and in all dosed groups at 12 months and 2 years. The incidences of mononuclear cell leukemia were significantly decreased in 30 and 150 mg/kg males and 100 mg/kg females at 2 years. GENETIC TOXICOLOGY: Oxymetholone was not mutagenic in S. typhimurium strain TA97, TA98, TA100, or TA1535, with or without S9 metabolic activation. It did not induce chromosomal aberrations in cultured Chinese hamster ovary cells, with or without S9, and no increase in the frequency of micronucleated normochromatic erythrocytes was noted in peripheral blood samples from male or female mice treated for 14 weeks with oxymetholone. CONCLUSIONS: Under the conditions of this 2-year gavage study, there was equivocal evidence of carcinogenic activity of oxymetholone in male F344/N rats based on increased incidences of subcutaneous tissue fibromas and fibromas or fibrosarcomas (combined) of the skin, variably increased incidences of benign and benign or malignant pheochromocytomas (combined) of the adrenal gland, and increased incidences of renal tubule adenomas. There was clear evidence of carcinogenic activity of oxymetholone in female F344/N rats based on increased incidences of hepatocellular neoplasms. Increased incidences of alveolar/bronchiolar neoplasms and skin neoplasms in female rats were also related to oxymetholone administration. Decreased incidences of alveolar/bronchiolar neoplasms and testicular interstitial cell adenomas in males; uterine stromal polyps or stromal sarcomas (combined), mammary gland neoplasms, and pituitary gland pars distalis adenomas in females; and mononuclear cell leukemia in males and females were related to oxymetholone administration. In addition, gavage administration of oxymetholone to male and female F344/N rats resulted in a spectrum of nonneoplastic effects frequently reported with administration of synthetic anabolic androgens. Synonyms: Adroidin; anadroyd; anasteron; anasteronal; anasterone; androstan-3-one, androstano[2,3-c]1,2,5-oxadiazol-17-ol, 17-methyl-, (5-a,17-b)-; becorel; 4,5-dihydro-2-hydroxymethylene-17-a-methyltestosterone; dynasten; HMD; 17b-hydroxy-2- (hydroxymethyl)-17-methyl-5-a-androstan-3-one; 17-hydroxy-2-(hydroxymethylene)-17-methyl-(5-a,17-b)-; 17-hydroxy- 2-(hydroxymethylene)-17-methyl-5-a-17-b-androst-3-one; 17b-hydroxy-2-(hydroxymethylene)-17-a-methyl-5-a-androstan-3-one; 17b-hydroxy-2-(hydroxymethylene)-17-methyl-5a-androstan-3-one; 17-hydroxy-2-(hydroxymethylene)-17-methyl-5-a-17- b-androstan-3-one; 17b-hydroxy-2-hydroxymethylene-17a-methyl-3-androstanone; 2-hydroxymethylene-17-a-methyl-5- a-androstan-17-b-ol-3-one; 2-hydroxymethylene-17a-methyl dihydrotestosterone; 2-hydroxymethylene-17-a-methyl-17-b- hydroxy-3-androstanone; methabol; 17a-methyl-2-hydroxymethylene-17-hydroxy-5-a-androstan-3-one; oximetholonum; oximetolona; oxitosona-50; oxymethenolone; roboral; zenalosyn Trade names: Adroyd; Anadrol; Anapolon; Anapolon 50; Nastenon; Pardroyd; Pavisoid; Plenastril; Protanabol; Synasteron
 ...
PMID:NTP Toxicology and Carcinogenesis Studies of Oxymetholone (CAS NO. 434-07-1) in F344/N Rats and Toxicology Studies of Oxymetholone in B6C3F1 Mice (Gavage Studies). 1257 78

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
 ...
PMID:NTP Toxicology and Carcinogenesis Studies of Primidone (CAS No. 125-33-7) in F344/N Rats and B6C3F1 Mice (Feed Studies). 1257 87

Tetrahydrofuran is used as a reaction medium for Grignard and metal hydride reactions; in the synthesis of butyrolactone, succinic acid, and 1,4-butanediol diacelate; in the fabrication of articles for packaging, transporting, and storing of foods; as a solvent for dyes and lacquers; and as a chemical intermediate in polymerization solvent for fat oils, unvulcanized rubber, resins, and plastics. Tetrahydrofuran is also an indirect food additive when it is in contact with the surface of articles intended for use in food processing. Tetrahydrofuran was nominated for study because of the potential for occupational exposure in humans. Male and female F344/N rats and B6C3F1 mice were exposed to tetrahydrofuran (approximately 99% pure) by inhalation for 13 weeks or 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium, cultured Chinese hamster ovary cells, Drosophila melanogaster, mouse bone marrow cells, and mouse peripheral blood cells erythrocites. 14-WEEK STUDY IN RATS: Groups of 10 male and 10 female rats were exposed to 0 (chamber control), 66, 200, 600, 1,800, or 5,000 ppm tetrahydrofuran by inhalation, 6 hours per day, 5 days per week, for 14 weeks. All rats survived until the end of the study. Final mean body weights and mean body weight gains of exposed groups of male and female rats were similar to those of the chamber controls. Immediately after exposure, male and female rats in the 5,000 ppm groups exhibited ataxia. Hematologic and serum chemistry changes were minimal, with most values falling within physiologic ranges. Absolute and relative thymus and spleen weights of male and female rats exposed to 5,000 ppm were significantly less than those of the chamber controls. Absolute and relative liver weights of female rats exposed to 5,000 ppm were significantly greater than those of the chamber controls. Increased incidences of minimal to mild hyperplasia of the forestomach were observed in male and female rats exposed to 5,000 ppm. Minimal suppurative inflammation was associated with forestomach hyperplasia in two male rats and four female rats exposed to 5,000 ppm. 14-WEEK STUDY IN MICE: Groups of 10 male and 10 female B6C3F1 mice were exposed to 0, 66, 200, 600, 1,800, or 5,000 ppm tetrahydrofuran by inhalation, 6 hours per day, 5 days per week, for 14 weeks. Two male mice exposed to 5,000 ppm died during weeks 2 and 8 of the study; one male mouse from the 5,000 ppm group was killed in a moribund state during week 4. All female mice survived until the end of the study. The final mean body weights and mean body weight gains of all exposed groups of male mice were similar to those of the chamber controls. The final mean body weight and mean body weight gain of the 5,000 ppm female mice were significantly greater than those of the chamber controls. Male and female mice exposed to 1,800 or 5,000 ppm were observed in a state of narcosis (described by stupor) during exposure periods. Mice exposed to 1,800 ppm were fully awake and alert immediately after exposure; however, mice exposed to 5,000 ppm required up to 2 hours for recovery. Absolute and relative liver weights of male mice exposed to 600 ppm or greater and of female mice exposed to 1800 or 5,000 ppm were significantly greater than those of the chamber controls. Absolute and relative thymus weights of male mice exposed to 600, 1,800, or 5,000 ppm were significantly less than those of the chamber controls. The incidences of minimal to mild centrilobular cytomegaly of the liver in male and female mice exposed to 5,000 ppm were significantly greater than those in the chamber controls. The adrenal glands of all female mice exposed to 5,000 ppm had mild degeneration of the X-zone of the innermost cortex. Uterine atrophy was observed in all female mice exposed to 5,000 ppm. 2-YEAR STUDY IN RATS: Groups of 50 male and 50 female rats were exposed to 0, 200, 600, or 1,800 ppm tetrahydrofuran by inhalation, 6 hours per day, 5 days per week, for 105 weeks. Survival, Body Weights, and Clinical Findings Survival and mean body weights of male and femand female rats exposed to tetrahydrofuran were similar to those of the chamber controls. Pathology Findings: The incidences of renal tubule epithelial adenoma or carcinoma (combined) in exposed males occurred with a positive trend, and the incidences in 600 and 1,800 ppm males exceeded the historical range for chamber controls in 2-year NTP inhalation studies. 2-YEAR STUDY IN MICE: Groups of 50 male and 50 female mice were exposed to 0, 200, 600, or 1,800 ppm tetrahydrofuran by inhalation, 6 hours per day, 5 days per week, for 105 weeks. Survival, Body Weights, and Clinical Findings After week 36, the survival of male mice exposed to 1,800 ppm was significantly less than that of the chamber controls. Mean body weights of male and female mice exposed to tetrahydrofuran were similar to those of the chamber controls throughout the study. Male mice exposed to 1,800 ppm were observed to be in a state of narcosis during and up to 1 hour after the exposure periods. Pathology Findings: The incidences andmultiplicity of hepatocellular neoplasms were significantly greater in female mice exposed to 1,800 ppm than in the chamber controls. The incidence of nephropathy in 200 ppm male mice was significantly greater than that in the chamber control group. Male mice exposed to 1,800 ppm had significantly greater incidences of nonneoplastic lesions of the urogenital tract than did the chamber controls. The incidences of inflammation of the penis and urethra and necrosis of the urethra in 1,800 ppm males were slightly greater than those in the chamber controls; these may have been secondary effects of ascending urinary tract infection. GENETIC TOXICOLOGY: Tetrahydrofuran showed little evidence of mutagenic activity in a variety of in vitro and in vivo assays. It was not mutagenic in Salmonella typhimurium, and it did not induce sister chromatid exchanges or chromosomal aberrations in cultured Chinese hamster ovary cells. These in vitro tests were conducted with and without exogenous metabolic activation from induced liver S9 enzymes. No increase in sex-linked recessive lethal mutations was detected in germ cells of male D. melanogaster exposed to tetrahydrofuran by feeding or injection. Results of in vivo assays for induction of chromosomal aberrations and sister chromatid exchanges in mouse bone marrow cells were negative. A micronucleus test in male and female mice exposed to tetrahydrofuran for 14 weeks showed no significant increases in the frequency of micronucleated erythrocytes in peripheral blood of female mice, but in male mice, analysis of micronucleated normochromatic erythrocyte levels revealed a small increase above baseline that was concluded to be equivocal. CONCLUSIONS: Under the conditions of these 2-year inhalation studies, there was some evidence of carcinogenic activity of tetrahydrofuran in male F344/N rats based on increased incidences of renal tubule adenoma or carcinoma (combined). There was no evidence of carcinogenic activity of tetrahydrofuran in female F344/N rats exposed to 200, 600, or 1,800 ppm or male B6C3F1 mice exposed to 200, 600, or 1,800 ppm. There was clear evidence of carcinogenic activity of tetrahydrofuran in female B6C3F1 mice based on increased incidences of hepatocellular neoplasms. Synonyms: Butylene oxide; cyclotetramethylene oxide; diethylene oxide; 1,4-epoxybutane; furanidine; hydrofuran; oxacyclopentane; oxolane; tetramethylene oxide
 ...
PMID:NTP Toxicology and Carcinogenesis Studies of Tetrahydrofuran (CAS No. 109-99-9) in F344/N Rats and B6C3F1 Mice (Inhalation Studies). 1257 88

Sodium xylenesulfonate is used as a hydrotrope, an organic compound that increases the ability of water to dissolve other molecules. Sodium xylenesulfonate is a component in a variety of widely used shampoos and liquid household detergents where it can constitute up to 10% of the total solution. Because of its widespread use, the potential for human exposure to sodium xylenesulfonate is great. Male and female F344/N rats and B6C3F1 mice were administered sodium xylenesulfonate in water or 50% ethanol dermally for 17 days, 14 weeks, or 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium, L5178Y mouse lymphoma cells, and cultured Chinese hamster ovary cells. 17-DAY STUDY IN RATS: Groups of five male and five female rats were administered 300 mL of 0, 5, 15, 44, 133, or 400 mg/mL sodium xylenesulfonate in distilled water by dermal application 5 days per week for 17 days. All rats survived to the end of the study. Final mean body weights and body weight gains of dosed rats were similar to those of the control groups. Dermal applications of 300 mL of 5, 15, 44, 133, and 400 mg/mL delivered average daily doses of approximately 10, 30, 90, 260, and 800 mg sodium xylenesulfonate/kg body weight to males and 13, 40, 120, 330, and 1,030 mg/kg to females. Clinical findings generally involved the skin of dosed animals and included tan or brown skin discoloration and crusty white deposits (presumed to be dried chemical) at the site of application. Neither of these observations were considered significant findings. The relative liver weights of 133 and 400 mg/mL male and female rats were significantly greater than those of the control groups, but the absolute liver weights were not increased and the biological significance of the relative differences in liver weight was unclear. In males and females, the few lesions observed grossly and microscopically were generally attributed to repeated clipping and were not considered related to chemical administration. 17-DAY STUDY IN MICE: Groups of five male and five female mice were administered 100 mL of 0, 5, 15, 44, 133, or 400 mg/mL sodium xylenesulfonate in distilled water by dermal application 5 days per week for 17 days. All mice survived to the end of the study. Final mean body weights and body weight gains of dosed mice were similar to those of the controls. Dermal applications of 5, 15, 44, 133, and 400 mg/mL delivered average daily doses of approximately, 20, 60, 190, 540, and 1,600 mg sodium xylenesulfonate/kg body weight to males and 26, 80, 220, 680, and 2,000 mg/kg to females. Clinical findings included crusty white deposits (presumed to be dried chemical) at the site of application in two 133 mg/mL males and in all 400 mg/mL males and females. The absolute and relative liver weights of 15 and 44 mg/mL males and 400 mg/mL males and females were significantly greater than those of the control groups, but the biological significance of these differences was unclear. The few skin lesions observed grossly and microscopically in males and females were generally attributed to repeated clipping and were not considered related to chemical administration. 14-WEEK STUDY IN RATS: Groups of 10 male and 10 female rats were administered 300 mL of 0, 5, 15, 44, 133, or 400 mg/mL sodium xylenesulfonate in 50% ethanol by dermal application for 14 weeks. For special hematology and clinical pathology studies, additional groups of 10 male and 10 female rats were administered 0, 5, 15, 44, 133, or 400 mg/mL sodium xylenesulfonate in 50% ethanol by dermal application for 14 weeks. All rats survived to the end of the study. Final mean body weights and body weight gains of dosed male and female rats were similar to those of the control groups. Dermal applications of 5, 15, 44, 133, and 400 mg/mL delivered average daily doses of approximately 6, 20, 60, 170, and 500 mg sodium xylenesulfonate/kg body weight to males and 10, 30, 90, 260, and 800 mg/kg to females. The only notable clinical finding was brown discoloration of the skin at the site of application in dosed animals. Hemaation in dosed animals. Hematology and clinical chemistry parameters of dosed groups of males and females were significantly different from those of the controls in several instances, but these differences were sporadic and did not demonstrate a treatment relationship. The absolute and relative liver weights of males receiving 44, 133, or 400 mg/mL were significantly less than those of the control group, but the biological significance of these differences was unclear, and there were no treatment-related histopathologic effects in the liver. There were no significant differences in liver weights in female rats. Minimal hyperplasia of the epidermis at the site of application occurred in both male and female rats in the control group as well as most dosed groups. The incidence of epidermal hyperplasia in 400 mg/mL males was possibly chemical related. 14-Week Study in Mice: Groups of 10 male and 10 female mice were administered 100 mL of 0, 5, 15, 44, 133, or 400 mg/mL sodium xylenesulfonate in 50% ethanol by dermal application for 14 weeks. There were no chemical-related deaths. The mean body weight gain of the 400 mg/mL males was significantly greater than that of the control group. Dermal applications of 5, 15, 44, 133, and 400 mg/mL delivered average daily doses of approximately 17, 40, 140, 440, and 1,300 mg sodium xylenesulfonate/kg body weight to males and 20, 60, 170, 530, and 1,630 mg/kg to females. There were no clinical findings related to sodium xylenesulfonate administration. Epidermal hyperplasia occurred in one 44 mg/mL female, two 133 mg/mL males, five 400 mg/mL males, and four 400 mg/kg females. Hyperplasia of the epidermis in 400 mg/mL males and females was probably related to chemical administration. Chronic inflammation of the skin occurred primarily in the control groups of males and females. These lesions consisted of mononuclear inflammatory cells in the dermis. 2-YEAR STUDY IN RATS: Groups of 50 male and 50 female rats were dermally administered 0, 60, 120, or 240 mg sodium xylenesulfonate/kg body weight in 50% ethanol for 104 weeks. Survival, Body Weights, and Clinical Findings: Survival of dosed males and females was similar to that of the control groups. Mean body weights of dosed males and females were similar to those of the controls throughout the study. In male groups, there were no clinical findings considered treatment related. In females, clinical findings were limited to irritation at the site of application in one control female, four 120 mg/kg females, and two 240 mg/kg females. Pathology Findings: There were no neoplasms at any site (including the skin) that were considered treatment related.Low incidences of hyperplasia of the epidermis at the site of application occurred in males in the 60, 120, and 240 mg/kg groups. Low incidences of hyperplasia of the epidermis at the site of application also occurred in females in the 120 and 240 mg/kg groups, and they occurred with a significant positive trend. Low incidences of hyperplasia of the sebaceous gland occurred in control and 60 mg/kg males and in control, 120 mg/kg, and 240 mg/kg females. 2-YEAR STUDY IN MICE: Groups of 50 male and 50 female mice were dermally administered 0, 182, 364, or 727 mg sodium xylenesulfonate/kg body weight in 50% ethanol for 104 to 105 weeks. Survival, Body Weights, and Clinical Findings: Survival of dosed males and females was similar to that of the control groups. Mean body weights of dosed males and females were generally similar to those of the controls throughout the study; however, the mean body weights of 727 mg/kg females were greater than those of the control group from week 85 to week 97. With the exception of irritation at the site of application in one 364 mg/kg female, there were no clinical findings related to sodium xylenesulfonate administration. Pathology Findings: There were no neoplasms at any site (including the skin) that were considered treatment related.Hyperplasia of the epidermis occurred in control,364 mg/kg, and 727 mg/kg males and in control and dosed females. In male mice, the incidences occurred with a significant positive trend. Focal ulceration occurred in one 727 mg/kg male and in one female in each dose group. In males and females from control and dosed groups, the incidences of hepatocellular adenoma, hepatocellular carcinoma, and hepato- cellular adenoma or carcinoma (combined) were generally higher than those expected by spontaneous occurrence. The incidences of hepatocellular neoplasms in some groups of males and females exceeded the NTP historical control range. Male mice had a pattern of nonneoplastic liver lesions along with silver stained positive helical organisms within the liver which suggests an infection with Helicobacter hepaticus. The findings in this study of sodium xylenesulfonate were not considered to have been significantly impacted by the infection with H. hepaticus or its associated hepatitis. GENETIC TOXICOLOGY: Sodium xylenesulfonate was not mutagenic in Salmonella typhimurium strain TA98, TA100, TA1535, or TA1537 with or without induced liver S9. Equivocal results were obtained in a mutation assay with mouse lymphoma cells in the presence of induced S9; no evidence of mutagenicity was noted without S9 in this assay. In cytogenetic tests with sodium xylenesulfonate in cultured Chinese hamster ovary cells, significant increases in sister chromatid exchanges were observed in the absence of S9 only, and no increases in chromosomal aberrations were observed with or without S9. CONCLUSIONS: Under the conditions of these 2-year dermal studies, there was no evidence of carcinogenic activity of sodium xylenesulfonate in male or female F344/N rats administered 60, 120, or 240 mg/kg or in male or female B6C3F1 mice administered 182, 364, or 727 mg/kg. Increased incidences of epidermal hyperplasia in female rats and male mice may have been related to exposure to sodium xylenesulfonate. Synonyms: Benzenesulfonic acid, dimethyl-, sodium salt; xylenesulfonic acid, sodium salt; sodium dimethylbenzenesulfonate; xylenesulfonic acid, sodium salt Trade names: Conco SXS; Cyclophil; SXS 30; Eletesol SX 30; Naxonate; Naxonate G; Richonate SXS; Stepanate SXS; Stepanate X; SXS 40; Ultrawet 40SX
 ...
PMID:NTP Toxicology and Carcinogenesis Studies of Technical Grade Sodium Xylenesulfonate (CAS No. 1300-72-7) in F344/N Rats and B6C3F1 Mice (Dermal Studies). 1257

Cobalt sulfate is used in the electroplating and electro chemical industries. It is also used as a coloring agent for ceramics and as a drying agent in inks, paints, varnishes, and linoleum. Cobalt sulfate may be added to animal feed as a mineral supplement and has been used as a top dressing on pasture lands. Cobalt sulfate was nominated by the National Cancer Institute for study based on a lack of information on the toxicity of soluble salts. Male and female F344/N rats and B6C3F1 mice were exposed to cobalt sulfate heptahydrate (approximately 99% pure) by inhalation for 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium. The results of prechronic inhalation toxicity studies were reported previously (Bucher et al., 1990; NTP, 1991). 2-YEAR STUDY IN RATS: Groups of 50 male and 50 female rats were exposed to aerosols containing 0, 0.3, 1.0, or 3.0 mg/m3 cobalt sulfate heptahydrate 6 hours per day, 5 days per week, for 105 weeks. Survival and Body Weights Survival of exposed males and females was similar to that of the chamber controls. Mean body weights of exposed male and female rats were similar to those of the chamber controls throughout the study. Pathology Findings The incidences and severities of proteinosis, alveolar epithelial metaplasia, granulomatous alveolar inflammation, and interstitial fibrosis were markedly greater in all exposed groups of male and female rats than in the chamber controls. The incidences of alveolar epithelial hyperplasia in all groups of exposed males and in females exposed to 3.0 mg/m3 were significantly greater than those in the chamber control groups, as were the incidences of squamous metaplasia in 1.0 mg/m3 females and atypical alveolar epithelial hyperplasia in 3.0 mg/m3 females. In 3.0 mg/m3 males, the combined incidence of alveolar/ bronchiolar neoplasms (adenoma and/or carcinoma) was significantly greater than in the chamber controls. In female rats exposed to 1.0 or 3.0 mg/m3, the incidences of alveolar/bronchiolar neoplasms were significantly greater than those in the chamber control group and exceeded the NTP historical control ranges. A squamous cell carcinoma was observed in one 1.0 mg/m3 and one 3.0 mg/m3 female. The incidences of benign, complex, or malignant pheochromocytoma (combined) in 1.0 mg/m3 males and in 3.0 mg/m3 females were significantly greater than those in the chamber controls and exceeded the historical control ranges. Hyperplasia of the lateral wall of the nose, atrophy of the olfactory epithelium, and squamous metaplasia of the epiglottis were observed in all exposed groups of males and females, and the severities of these lesions increased with increasing exposure concentration. The incidences of squamous metaplasia of the lateral wall of the nose and metaplasia of the olfactory epithelium were increased in 3.0 mg/m3 males and females. 2-YEAR STUDY IN MICE: Groups of 50 male and 50 female mice were exposed to aerosols containing 0, 0.3, 1.0, or 3.0 mg/m3 cobalt sulfate heptahydrate 6 hours per day, 5 days per week, for 105 weeks. Survival and Body Weights Survival of exposed males and females was similar to that of the chamber controls. Mean body weights of 3.0 mg/m3 male mice were less than those of the chamber controls from week 96 until the end of the study. The mean body weights of all exposed groups of female mice were generally greater than those of the chamber controls from week 20 until the end of the study. Pathology Findings The incidences of diffuse histiocytic cell infiltration in 3.0 mg/m3 males and of focal histiocytic cell infil tration in 3.0 mg/m3 females were significantly greater than those in the chamber controls. The incidences of alveolar/bronchiolar neoplasms in 3.0 mg/m3 males and females were significantly greater than those in the chamber control groups. The combined incidences of alveolar/bronchiolar adenoma or carcinoma and the incidences of alveolar/bronchiolar carcinoma in 3.0 mg/m3 males and females and the incidence of alveolar/bronchiolar adenoma in 3.0 mg/m3 females exceeded the NTP historical crical control ranges for inhalation studies. The incidences of atrophy of the olfactory epithelium in 1.0 and 3.0 mg/m3 males and females and hyper plasia of the olfactory epithelium in 3.0 mg/m3 males and females were significantly greater than in the chamber controls. Squamous metaplasia of the larynx was observed in all exposed groups of males and females. Male mice had a pattern of nonneoplastic liver lesions along with silver-staining helical organisms within the liver, characteristic of an infection with Helico bacter hepaticus. In NTP studies with H. hepaticus- associated hepatitis, increased incidences of hemangiosarcoma were seen in the liver of male mice. In this study of cobalt sulfate heptahydrate, incidences of hemangiosarcoma were increased in exposed groups of male mice. Because of the above association, interpretation of the increased incidences of hemangiosarcoma in the livers of male mice was confounded. Incidences of lesions at other sites in this study of cobalt sulfate heptahydrate were not considered to have been significantly impacted by the infection with H. hepaticus or its associated hepatitis. GENETIC TOXICOLOGY: Cobalt sulfate heptahydrate was mutagenic in S. typhimurium strain TA100 with and without liver S9 metabolic activation enzymes; no mutagenic activity was detected in strain TA98 or TA1535, with or without S9. CONCLUSIONS: Under the conditions of these 2-year inhalation studies, there was some evidence of carcinogenic activity of cobalt sulfate heptahydrate in male F344/N rats based on increased incidences of alveolar/bronchiolar neoplasms. Marginal increases in incidences of pheochromocytomas of the adrenal medulla may have been related to exposure to cobalt sulfate heptahydrate. There was clear evidence of carcinogenic activity in female F344/N rats based on increased incidences of alveolar/bronchiolar neo-plasms and pheochromocytomas of the adrenal medulla in groups exposed to cobalt sulfate heptahydrate. There was clear evidence of carcinogenic activity of cobalt sulfate heptahydrate in male and female B6C3F1 mice based on increased incidences of alveolar/bronchiolar neoplasms. Exposure to cobalt sulfate heptahydrate caused a spectrum of inflammatory, fibrotic, and proliferative lesions in the respiratory tract of male and female rats and mice. Synonyms: Bieberite; cobalt(II) sulfate (1:1) heptahydrate; cobalt monosulfate heptahydrate; cobalt(II) sulphate heptahydrate; sulfuric acid, cobalt(2+) salt (1:1) heptahydrate
 ...
PMID:NTP Toxicology and Carcinogenesis Studies of Cobalt Sulfate Heptahydrate (CAS No. 10026-24-1) in F344/N Rats and B6C3F1 Mice (Inhalation Studies). 1257 2

Oxazepam and related benzodiazepine drugs are used in the treatment of anxiety. All benzodiazepines currently in use share a number of effects, including sedation, hypnosis, decreased anxiety, muscle relaxation, amnesia, and anticonvulsant activity. Oxazepam and four other benzodiazepines (chlordiazepoxide, chlorazepate, diazepam, and flurazepam) were nominated for study by the Food and Drug Administration (FDA) and by the NIEHS based on their widespread use, use by pregnant women, and the lack of adequate rodent carcinogenicity studies. Oxazepam was evaluated in 14-week and 2-year studies by the NTP, and Technical Report No. 443 contains the results of the studies performed with the Swiss-Webster and B6C3F1 strains of mice. Studies with rats were not initiated at the same time as the mouse studies because adequate carcinogenicity studies of oxazepam with the Sprague-Dawley rat strain had been submitted to the FDA. Subsequently, because of the marked neoplastic responses found in the two mouse strains, the NTP initiated 2-year studies of oxazepam with the F344/N rat. Groups of male and female F344/N rats were exposed to oxazepam (greater than 99% pure) in feed for 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium and cultured Chinese hamster ovary cells, and mouse peripheral blood samples were analyzed for the frequency of micronucleated normochromatic erythrocytes. 2-YEAR STUDY: Groups of 50 male and 50 female F344/N rats were fed diets containing 0, 625, 2,500, or 5,000 ppm oxazepam for up to 105 weeks. A stop-exposure group of 50 males and 50 females received 10,000 ppm oxazepam in feed for 26 weeks, after which animals received undosed feed for the remainder of the 2-year study. The continuous-exposure concentrations resulted in average daily doses of 25, 100, or 250 mg oxazepam/kg body weight to males and 25, 110, or 220 mg/kg to females. Stop- exposure males and females received an average daily dose of 630 mg/kg during the exposure period. Survival, Body Weights, and Clinical Findings: All 5,000 ppm continuous-exposure and 10,000 ppm stop-exposure males died before the end of the study. Survival of 2,500 ppm continuous-exposure males and females was significantly less than that of the controls. The mean body weight gains of 2,500 and 5,000 ppm males and females were less than those of the controls throughout the study. The mean body weights of 10,000 ppm stop-exposure males were generally less than those of the controls throughout the study; those of 10,000 ppm stop-exposure females were less than those of the controls during the exposure portion of the study but increased steadily after the cessation of dosing at week 27. Feed consumption by exposed groups was similar to that by the controls after week 1 of the study. Treatment-related eye/nasal discharge, hyperactivity when handled, and/or ataxia were observed in exposed male and female rats on or about day 2 of exposure but were no longer apparent after day 7. Plasma Oxazepam Determinations: Plasma oxazepam concentrations were measured at the end of the study. The concentrations ranged from approximately 0.5 (625 ppm males) to 2.8 &mgr;g/mL (5,000 ppm females). Pathology Findings: In the standard histopathologic evaluation, the incidence of renal tubule adenoma was slightly increased in male rats exposed to 2,500 ppm and was at the upper limit of the historical control range for this neoplasm in 2-year NTP feed studies. In an extended evaluation (step section) of the kidneys of male rats, the incidences of renal tubule adenoma occurred with a positive trend in exposed groups. In standard and step sections (combined), male rats exposed to 2,500 or 5,000 ppm showed a significant increase in the incidences of renal tubule adenoma and hyperplasia. In addition, the incidences of renal tubule adenoma and hyperplasia were significantly increased in the 10,000 ppm stop-exposure group. The incidences of nephropathy in continuously exposed female rats were significantly greater than in the controls, and the severity of nephropathy increased wised with increasing exposure concentration in males. The incidences of epithelial hyperplasia and chronic inflammation of the forestomach in males exposed to 2,500 and 5,000 ppm and of ulcers in 2,500 ppm males were significantly greater than in the controls. Incidences of mineralization of the glandular stomach in 5,000 ppm and 10,000 ppm (stop-exposure) males and of erosion of the duodenum in 5,000 ppm males were significantly greater than in the controls. Female rats exposed to 2,500 ppm had greater incidences of epithelial hyperplasia, chronic inflammation, and ulcers of the forestomach and of erosion in the glandular stomach. Centrilobular hepatocyte hypertrophy occurred more frequently in 2,500 and 5,000 ppm males and females than in the controls. GENETIC TOXICOLOGY: Oxazepam was not mutagenic in any of several strains of S. typhimurium, nor did it induce sister chromatid exchanges or chromosomal aberrations in cultured Chinese hamster ovary cells. These in vitro tests were performed with and without S9 metabolic activation. Results from an in vivo mouse peripheral blood micronucleus test performed on B6C3F1 mice used in a 14-week study were also negative. CONCLUSIONS: In summary, under the conditions of these 2-year dosed-feed studies, there was equivocal evidence of carcinogenic activity in male F344/N rats, based on small increases in the incidences of renal tubule adenomas in exposed groups also exhibiting significantly enhanced nephropathy. There was no evidence of carcinogenic activity of oxazepam in female F344/N rats exposed to feed containing 625, 2,500, or 5,000 ppm for 2 years or 10,000 ppm for 6 months. Administration of oxazepam to rats resulted in nonneoplastic lesions in the forestomach, glandular stomach, and small intestine as well as centrilobular hypertrophy of hepatocytes in the liver. In addition, nephropathy was increased in incidence in female rats and was markedly increased in severity in male rats, resulting in early mortality at the higher exposure concentrations. Synonym: 7-Chloro-1,3-dihydro-3-hydroxy-5-phenyl-2H-1,4-benzodiazepin-2-one Trade Names: Tazepam, Wy-3498, Serax
 ...
PMID:NTP Toxicology and Carcinogenesis Studies of Oxazepam (CAS No. 604-75-1) in F344/N Rats (Feed Studies). 1257 5

Ethylbenzene is mainly used in the manufacture of styrene. Ethylbenzene is also a major component of mixed xylenes used as solvents in agricultural and home insecticide sprays, rubber and chemical manufacturing, and household degreasers, paints, adhesives, and rust preventives. Ethylbenzene is also used as an antiknock agent in aviation and motor fuels. Ethylbenzene was nominated for study by the National Institute for Occupational Safety and Health (NIOSH) and the Occupational Safety and Health Administration (OSHA) because of its potential for widespread human exposure and because of its structural similarity to benzene and toluene. Male and female F344/N rats and B6C3F1 mice were exposed to ethylbenzene (greater than 99% pure) by inhalation for 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium, mouse lymphoma cells, cultured Chinese hamster ovary cells, and mouse peripheral blood erythrocytes. In previously reported 13-week toxicity studies in which F344/N rats and B6C3F1 mice were exposed to ethylbenzene by whole body inhalation exposure, no histopathologic changes were observed (NTP, 1992). 2-YEAR STUDY IN RATS: Groups of 50 male and 50 female F344/N rats were exposed to 0, 75, 250, or 750 ppm ethylbenzene by inhalation, 6 hours per day, 5 days per week, for 104 weeks. Survival, Body Weights, and Clinical Findings Survival of male rats in the 750 ppm group was significantly less than that of the chamber controls. Mean body weights of 250 and 750 ppm males were generally less than those of the chamber controls beginning at week 20. Mean body weights of exposed groups of females were generally less than those of chamber controls during the second year of the study. Pathology Findings In male rats exposed to 750 ppm, the incidences of renal tubule adenoma and adenoma or carcinoma (combined) were significantly greater than the chamber control incidences. In addition, the incidence of renal tubule hyperplasia in 750 ppm males was significantly greater than that in the chamber controls. The findings from an extended evaluation (step section) of the kidneys showed a significant increase in the incidences of renal tubule adenoma and hyperplasia in 750 ppm males and females; the incidence of renal tubule adenoma or carcinoma (combined) was significantly increased in 750 ppm males. The severities of nephropathy in 750 ppm male and all exposed female rats were significantly increased relative to the chamber controls. The incidence of interstitial cell adenoma in the testis of 750 ppm males was significantly greater than that in the chamber control group and slightly exceeded the historical control range for inhalation studies. 2-YEAR STUDY IN MICE: Groups of 50 male and 50 female B6C3F1 mice were exposed to 0, 75, 250, or 750 ppm ethylbenzene by inhalation, 6 hours per day, 5 days per week, for 103 weeks. Survival, Body Weights, and Clinical Findings Survival of exposed groups of male and female mice was similar to that of the chamber controls. Mean body weights of female mice exposed to 75 ppm were greater than those of the chamber controls from week 72 until the end of the study. Pathology Findings In 750 ppm males, the incidences of alveolar/ bronchiolar adenoma and alveolar/bronchiolar adenoma or carcinoma (combined) were significantly greater than those in the chamber control group but were within the NTP historical control ranges. The incidence of alveolar epithelial metaplasia in 750 ppm males was significantly greater than that in the chamber controls. In 750 ppm females, the incidences of hepatocellular adenoma and hepatocellular adenoma or carcinoma (combined) were significantly greater than those in the chamber control group but were within the historical control ranges. The incidence of eosinophilic foci in 750 ppm females was significantly increased compared to that in the chamber controls. There was a spectrum of nonneoplastic liver changes related to ethylbenzene exposure in male mice, including syncytial alteration of hepatocytes, hepatocellular hypertrophy, and hepatocyte necrosis. rosis. The incidences of hyperplasia of the pituitary gland pars distalis in 250 and 750 ppm females and the incidences of thyroid gland follicular cell hyperplasia in 750 ppm males and females were significantly increased compared to those in the chamber control groups. GENETIC TOXICOLOGY: Ethylbenzene gave little indication of mutagenicity, in vitro or in vivo. No induction of mutations was noted in Salmonella typhimurium strain TA97, TA98, TA100, or TA1535 with or without S9 metabolic activation, and no increases in sister chromatid exchanges or chromosomal aberrations were observed in cultured Chinese hamster ovary cells treated with ethylbenzene, with or without S9. In the mouse lymphoma assay, a significant mutagenic response was noted in the absence of S9, but only at the highest nonlethal dose tested and with accompanying cytotoxicity; the test was not performed with S9. No increases in the frequency of micronucleated erythrocytes were observed in vivo in peripheral blood samples from male and female mice exposed to ethylbenzene for 13 weeks. CONCLUSIONS: Under the conditions of these 2-year inhalation studies, there was clear evidence of carcinogenic activity of ethylbenzene in male F344/N rats based on increased incidences of renal tubule neoplasms. The incidences of testicular adenoma were also increased. There was some evidence of carcinogenic activity of ethylbenzene in female F344/N rats based on increased incidences of renal tubule adenomas. There was some evidence of carcinogenic activity of ethylbenzene in male B6C3F1 mice based on increased incidences of alveolar/bronchiolar neoplasms. There was some evidence of carcinogenic activity of ethylbenzene in female B6C3F1 mice based on increased incidences of hepatocellular neoplasms. Exposure of male and female rats to ethylbenzene resulted in increased incidences of renal tubule hyperplasia and increased severities of nephropathy. Exposure of male mice to ethylbenzene resulted in increased incidences of alveolar epithelial metaplasia, syncytial alteration of hepatocytes, hepatocellular hypertrophy, hepatocyte necrosis, and thyroid gland follicular cell hyperplasia. In female mice, ethylbenzene exposure resulted in increased incidences of eosinophilic foci of the liver, pituitary gland pars distalis hyperplasia, and thyroid gland follicular cell hyperplasia. Synonyms: EB; ethylbenzol; phenylethane
 ...
PMID:NTP Toxicology and Carcinogenesis Studies of Ethylbenzene (CAS No. 100-41-4) in F344/N Rats and B6C3F1 Mice (Inhalation Studies). 1257 7


1 2 3 4 5 Next >>