Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0019158 (hepatitis)
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Theophylline is an alkaloid found in tea (Thea sinensis) and chocolate and is structurally related to caffeine and theobromine. Theophylline is used as a pharmaceutical agent. It stimulates the heart and central nervous system, relaxes the smooth muscles of the bronchi and blood vessels, and causes diuresis. The drug is used mainly as a bronchodilator in obstructive airway diseases, such as bronchial asthma, and for myocardial stimulation. Theophylline was nominated for toxicologic and carcinogenicity testing as a representative of the purine structural subclass, particularly because of its relationship to purines such as caffeine, 1-methyl-3-hydroxyguanine, and 3-hydroxy-1-methylxanthine, the latter two compounds having been shown to induce sarcomas in rats. Additional reasons for testing theophylline included its widespread use in humans as a pharmaceutical agent, its possible genotoxicity in vitro, and the lack of information on its potential toxicity and/or carcinogenicity under conditions of chronic oral usage. Based on reported teratogenicity and testicular toxicity, it was also recommended that reproductive studies be included in the evaluation of theophylline. The oral route of administration was selected because it is the primary route of human exposure, and the gavage route was selected because it mimics the pharmaceutical use of theophylline in humans. Male and female F344/N rats and B6C3F1 mice were given theophylline (greater than 99% pure) in feed or in corn oil by gavage for 16 days or 14 weeks or in corn oil by gavage for 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium, cultured Chinese hamster ovary cells, mouse bone marrow, and mouse peripheral blood. 16-DAY FEED STUDY IN RATS: Groups of five male and five female F344/N rats were given 0, 500, 1,000, 2,000, 4,000, or 8,000 ppm theophylline in feed for 16 days, which resulted in approximate daily doses of 50, 100, 250, 450, or 1,000 mg theophylline/kg body weight to males and 75, 150, 250, 450, or 1,100 mg/kg to females. All rats survived until the end of the study. The final mean body weights and body weight gains of 8,000 ppm males and females were significantly less than those of the controls. The absolute and relative testis weights of 4,000 ppm males were significantly greater than those of the controls. Increased incidences of uterine hypoplasia were observed microscopically in exposed groups of females. 16-DAY GAVAGE STUDY IN RATS: Groups of five male and five female F344/N rats were given 0, 12.5 (twice daily), 25 (once daily), 50 (once daily), 50 (twice daily), 100 (once daily), 200 (once daily), 200 (twice daily), or 400 (once daily) mg theophylline/kg body weight in corn oil by gavage. All rats receiving 400 mg/kg once daily and all but one female receiving 200 mg/kg twice daily died during the study. In groups dosed once daily, final mean body weights and body weight gains of males receiving 100 or 200 mg/kg and mean body weight gains of females receiving 50, 100, or 200 mg/kg were less than those of controls. The final mean body weights and body weight gains of groups receiving theophylline twice daily were generally similar to those of groups receiving the same daily dosages once daily. Clinical findings included rapid or labored respiration, hunched posture, and squinting. In groups dosed once daily, absolute and relative uterus weights of females receiving 100 or 200 mg/kg once daily were significantly less than those of the controls, and the absolute and relative uterus weights of females receiving 100 mg/kg once daily were significantly less than those of females receiving 50 mg/kg twice daily. Uterine atrophy was observed in three females receiving 200 mg/kg twice daily. Periarteritis of the mesenteric arteries was observed in two males and two females receiving 400 mg/kg once daily. 16-DAY FEED STUDY IN MICE: Groups of five male and five female B6C3F1 mice were given 0, 500, 1,000, 2,000, 4,000, or 8,000 ppm theophylline in feed for 16 days, resulting in approximate daily doses of 250, 475, 950, 1,800, or800, or 2,000 mg theophylline/kg body weight to males and 300, 450, 1,225, 2,000, or 4,375 mg/kg to females. All mice survived until the end of the study. Final mean body weights of 4,000 and 8,000 ppm females and mean body weight gains of 2,000, 4,000, and 8,000 ppm females were significantly greater than those of the controls. Feed consumption by exposed groups was similar to that by the controls, except that by the 8,000 ppm males, which was approximately 40% the amount of feed consumed by the control group. Histopathologic examinations were not performed due to the absence of mortality and significant exposure-related lesions. 16-DAY GAVAGE STUDY IN MICE: Groups of five male and five female B6C3F1 mice were given 0, 12.5 (twice daily), 25 (once daily), 50 (once daily), 50 (twice daily), 100 (once daily), 200 (once daily), 200 (twice daily), or 400 (once daily) mg theophylline/kg body weight in corn oil by gavage. Three males and all females receiving 400 mg/kg once daily died on day 1. There were no significant differences in final mean body weights or body weight gains. There were no histopathologic findings attributed directly to theophylline. 14-WEEK FEED STUDY IN RATS: Groups of 10 male and 10 female F344/N rats were given 0, 1,000, 2,000, or 4,000 ppm theophylline in feed for 14 weeks, which resulted in approximate daily doses of 75, 125, or 250 mg theophylline/kg body weight to males and 75, 125, or 275 mg/kg to females. The final mean body weight of 1,000 ppm females was significantly greater than that of the control group. Feed consumption by exposed groups was similar to that by the controls. Mean cell volume and mean cell hemoglobin were significantly greater in males exposed to 2,000 or 4,000 ppm than those in the control group. Segmented neutrophil counts of all groups of exposed females were significantly greater than that of the control group. The absolute and relative kidney weights of 4,000 ppm males were significantly greater than those of the controls, and there was an exposure-related increase in the severity of nephropathy in males. Exposure-related increases in the incidences of mesenteric and/or pancreatic periarteritis were observed in males and females. 14-WEEK GAVAGE STUDY IN RATS: Groups of 10 male and 10 female F344/N rats were given 0, 37.5, 75, or 150 mg theophylline/kg body weight in corn oil by gavage for 14 weeks. One male and one female receiving 150 mg/kg died before the end of the study. The mean body weight gain of 150 mg/kg females was significantly greater than that of the controls. Mean cell volume of 150 mg/kg males and mean cell hemoglobin of all groups of dosed males were significantly greater than those of the control group. There were slight dose-dependent increases in the incidences of mesenteric periarteritis in dosed males and females. 14-WEEK FEED STUDY IN MICE: Groups of 10 male and 10 female B6C3F1 mice were given 0, 1,000, 2,000, or 4,000 ppm theophylline in feed for 14 weeks, resulting in approximate daily doses of 175, 400, or 800 mg theophylline/kg body weight to males and 225, 425, or 850 mg/kg to females. All mice survived until the end of the study. The final mean body weights and body weight gains of all exposed groups of males and females were significantly less than those of the controls. Feed consumption by exposed groups was similar to that by the controls. Leukocyte, segmented neutrophil, and lymphocyte counts of 4,000 ppm males were significantly greater than those of the controls. Leukocyte and segmented neutrophil counts of 2,000 or 4,000 ppm females were significantly greater than those of the controls. There were no histopathologic findings attributed directly to theophylline exposure. 14-WEEK GAVAGE STUDY IN MICE: Groups of 10 male and 10 female B6C3F1 mice were given 0, 75, 150, or 300 mg theophylline/kg body weight in corn oil by gavage for 14 weeks. Three males and all females receiving 300 mg/kg, one 75 mg/kg male, and one control female died before the end of the study. Final mean body weights and body weight gains of 150 and 300 mg/kg males were significantly less than those of the controls. Mean cell volume and mean cell hemoglobin of 300 mg/kg males were significantly greater than those of the controls. There were no histopathologic findings attributed directly to theophylline treatment. 2-YEAR GAVAGE STUDY IN RATS: Groups of 50 male and 50 female rats were given 7.5, 25, or 75 mg theophylline/kg body weight in corn oil by gavage for 2 years. Survival and Body Weights: There were no significant differences in survival between dosed and control groups. Final mean body weights of all groups of dosed males and females were significantly less than those of the controls. Pathology Findings: There were no significantly increased incidences of neoplasms in dosed rats. The incidence of chronic inflammation of the mesenteric arteries was significantly increased in males receiving 75 mg/kg compared to the controls. There were doserelated negative trends in the incidences of mammary gland fibroadenoma and fibroadenoma or carcinoma (combined) in females; these differences correlated with decreased body weights. 2-YEAR GAVAGE STUDY IN MICE: Groups of 50 male B6C3F1 mice were given 0, 15, 50, or 150 mg theophylline/kg body weight and groups of 50 female B6C3F1 mice were given 0, 7.5, 25, or 75 mg/kg in corn oil by gavage for 2 years. Survival and Body Weights: Survival of 150 mg/kg males was significantly less than that of the controls. The final mean body weights of 150 mg/kg males, 25 mg/kg females, and 75 mg/kg females were significantly less than those of the control groups. Pathology Findings: There were no treatment-related increases in incidences of nonneoplastic lesions or neoplasms. In males and females, there were decreased incidences of hepatocellular adenoma and of the combined incidences of hepatocellular adenoma or carcinoma compared to the controls. Male mice had a pattern of nonneoplastic liver lesions along with silver-staining helical organisms in the liver consistent with Helicobacter hepaticus infection. The incidences of these liver lesions in 150 mg/kg males were significantly lower than those in control males. Increases in the incidences of hepatocellular neoplasms in male mice have been shown to be associated with H. hepaticus infection when hepatitis is also present. Because of this association, interpretation of the decreased incidence of liver neoplasms in male mice was more difficult. Incidences of lesions at other sites in this study were not considered to have been significantly impacted by H. hepaticus infection or its associated hepatitis. GENETIC TOXICOLOGY: Theophylline was not mutagenic in Salmonella typhimurium, with or without metabolic activation (S9). It induced sister chromatid exchanges but not chromosomal aberrations in cultured Chinese hamster ovary cells. The positive sister chromatid exchange response was noted only in the absence of S9. In vivo, a mouse bone marrow sister chromatid exchange test showed positive results at a standard 23-hour harvest time; however, this test was not repeated and the response is unconfirmed. An in vivo mouse bone marrow chromosomal aberrations test, that employed both standard and extended exposure protocols, gave negative results. The frequency of micronucleated erythrocytes was determined in peripheral blood of male and female mice exposed to theophylline in dosed feed or in corn oil by gavage for 14 weeks. No significant increases in the frequencies of micronucleated cells were seen in male or female mice in either of the studies. CONCLUSIONS: Under the conditions of these 2-year gavage studies, there was no evidence of carcinogenic activity of theophylline in male or female F344/N rats administered 7.5, 25, or 75 mg/kg. There was no evidence of carcinogenic activity of theophylline in male B6C3F1 mice administered 15, 50, or 150 mg/kg or female B6C3F1 mice administered 7.5, 25, or 75 mg/kg. Gavage administration of theophylline caused chronic inflammation of the mesenteric arteries in dosed male rats. Decreased incidences of mammary neoplasms in female rats were likely associated with lower body weights. There were dose-related decreases in the incidences of hepatocellular adenoma and hepatocellular carcinoma in male and female mice. Synonyms: 3,7-dihydro-1,3-dimethyl-1H-purine-2,6-dione; 1,3-dimethylxanthine; 1H-purine-2,6-dione; NSC 2066; pseusdotheophylline; theocin; theophyllin; theophylline, anhydrous Trade names: Accurbron; Aerobin; Aerolate III; Afonilum; Aminophylline; Aquaphyllin; Armophylline; Asmalix; Bilordyl; Bronchoretard; Bronkodyl; Cetraphylline; Constant-T; Diffumal; Duraphyl; Duraphyllin; Elixicon; Elixophyllin; Euphylline L.A.; Euphylong; LaBID; Labophylline; Lanophyllin; Lasma; Liquophylline; Optiphyllin; Parkophyllin; Phylocontin; Physpan; Pro-Vent; PulmiDur; Pulmo-Timelets; Quibron; Respbid; Rona-Phyllin; Sabidal; Slo-bid; Slo-Phyllin; Solosin; Sustaire; Tefamin; Teobid; Teofyllamin; Tesona; Theal tablets; Theo-24; Theobid; Theocap; Theochron; Theoclear; Theocontin; Theo-Dur; Theofol; Theograd; Theolair; Theolan; Theolix; Theophyl; Theoplus; Theo-Sav; Theosol; Theospan; Theostat; Theovent; TheoX; T-Phyl; Truphylline; Uni-Dur; Unifyl; Uniphyl; Uniphyllin; Xanthium
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PMID:NTP Toxicology and Carcinogenesis Studies of Theophylline (CAS No. 58-55-9) in F344/N Rats and B6C3F1 Mice (Feed and Gavage Studies). 1257 77

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
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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
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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

Triethanolamine is widely used as an ingredient in emulsifiers, thickeners, wetting agents, detergents, and alkalinizing agents in cosmetic products; as a chemical intermediate for anionic and nonionic surfactants and surface active agents in household cleaning agents, textiles, herbicides, pharmaceutical ointments, and other products; as a vulcanization accelerator in the manufacture of rubber; and in many other industrial applications. The National Cancer Institute nominated triethanolamine for study because of its widespread use in cosmetics and other consumer products, its high potential for worker exposure due to its many industrial uses, and its potential for conversion to the carcinogen N -nitrosodiethanolamine. Dermal application was chosen as the route of exposure to mimic the principal means of human exposure to triethanolamine and because considerable systemic exposure is achieved with this route. Male and female F344/N rats and B6C3F1 mice received triethanol amine (purity 98% or greater) by dermal application for 13 weeks or 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium, cultured Chinese hamster ovary cells, Drosophila melano gaster, and mouse peripheral blood erythrocytes. 13-WEEK STUDY IN RATS: Groups of 10 male and 10 female rats were topically administered 0, 125, 250, 500, or 1,000 mg triethanolamine per kilogram body weight in acetone or 2,000 mg/kg neat triethanolamine, 5 days per week, for 13 weeks. All rats survived to the end of the study. Final mean body weights and weight gains of males and females administered 2,000 mg/kg and the mean body weight gain of females administered 1,000 mg/kg were significantly less than those of the vehicle controls. Clinical observations included irritation, scaliness, and crustiness of the skin at the site of application for males and females. Males also had discoloration, and two males administered 2,000 mg/kg had ulceration at the site of application. Changes in clinical pathology parameters were minor and consistent with inflammation at the site of application. Kidney weights were generally greater in males and females administered 500, 1,000, or 2,000 mg/kg than in the vehicle controls. Microscopic lesions attributed to triethanolamine administration included acanthosis and inflammation at the site of application, nephropathy in females, and hypertrophy of the pituitary gland pars intermedia in males and females. These lesions generally occurred with dose-related increases in incidence and severity in males and females. 13-WEEK STUDY IN MICE: Groups of 10 male and 10 female mice were topically administered 0, 250, 500, 1,000, or 2,000 mg triethanolamine per kilogram body weight in acetone or 4,000 mg/kg neat triethanolamine, 5 days per week, for 13 weeks. All mice survived to the end of the study. The final mean body weight and weight gain of males in the 250 mg/kg group were less than those of the vehicle controls. Clinical findings were observed only in mice in the 4,000 mg/kg groups and included scaliness, irritation, and discoloration at the site of triethanolamine application for males and females and skin erosion at this site in one male. The absolute kidney and liver weights of males and females administered 4,000 mg/kg were greater than those of the vehicle controls; relative kidney weights of males administered 1,000 mg/kg or greater and females in all dosed groups were also greater than those of the vehicle controls. Microscopic examination of the skin of dosed mice indicated acanthosis and inflammation at the site of application. Acanthosis occurred in all dosed groups and in one vehicle control female; the severity increased with increasing dose in males and females. Inflammation was observed in males and females in the 4,000 mg/kg groups and in one female in the 2,000 mg/kg group. 2-YEAR STUDY IN RATS: Based on the presence of acanthosis and inflammation at the site of application at the higher doses in the 13-week study, triethanolamine doses selected for the 2-year study in rats were 32, 63, and 125 mg/kg for malesr males and 63, 125, and 250 mg/kg for females. Groups of 60 male and 60 female rats were topically administered triethanolamine in acetone 5 days per week for 103 weeks. Ten male and ten female rats from each group were evaluated at 15 months for organ weights and histopathology. Survival, Body Weights, Clinical Findings, and Organ Weights: The survival rate of females in the 250 mg/kg group was slightly less than that of the vehicle controls. The mean body weight of females administered 250 mg/kg ranged from 9% to 12% less than that of the vehicle controls between weeks 73 and 93. Male and female rats receiving triethanolamine had irritated skin at the site of application; in dosed females, the site of application also had a crusty appearance. The number of animals in which these findings were observed increased with increasing dose. At the 15-month interim evaluation, the absolute left and right kidney weights and relative right kidney weight of females administered 250 mg/kg were significantly greater than those of the vehicle controls. Pathology Findings: The incidence of acanthosis at the site of application in males administered 125 mg/kg and the incidences of acanthosis, inflammation, and ulceration in dosed females were greater than in the vehicle controls at the 15-month interim evaluation and at the end of the 2-year study. Males in the 125 mg/kg group also had greater incidences of inflammation and ulceration than the vehicle controls, and females receiving 125 or 250 mg/kg had greater incidences of epidermal erosion than the vehicle controls at 2 years. There were no skin neoplasms at or away from the site of application that were considered related to treatment with triethanolamine. At the end of the study, renal tubule adenomas were observed in seven dosed males and in one vehicle control female and one female in the 63 mg/kg group. One male in the 125 mg/kg group and one female in the 250 mg/kg group had renal tubule hyperplasia. Extended (step-section) evaluation of the kidneys of all male rats revealed additional renal tubule adenomas in one vehicle control male, one male in the 32 mg/kg group, two males in the 63 mg/kg group, and three males in the 125 mg/kg group (including one male from the 15-month interim evaluation). An oncocytoma was also identified in one male in the 32 mg/kg group. Hyperplasia was identified in eight additional vehicle control males and in 19 additional dosed males. The total incidences (combined standard and extended evaluations) of renal tubule adenoma in dosed male rats were slightly greater than the vehicle control incidence (vehicle control, 1/50; 32 mg/kg, 2/50; 63 mg/kg, 6/49; 125 mg/kg, 4/50). The total incidence of hyperplasia in dosed and vehicle control males was similar (9/50, 8/50, 7/49, 6/50). The severity of hyperplasia in males in the 32 and 125 mg/kg groups was greater than that in the vehicle controls. 2-YEAR STUDY IN MICE: Based on dose-related inflammation at the site of application in the 13-week study, triethanolamine doses selected for the 2-year study in mice were 200, 630, and 2,000 mg/kg for males and 100, 300, and 1,000 mg/kg for females. Groups of 60 male and 60 female mice were topically administered triethanolamine in acetone 5 days per week for 103 weeks. Ten male and ten female mice from each group were evaluated at 15 months for organ weights and histopathology. Survival, Body Weights, Clinical Findings, and Organ Weights: Survival rates of all dosed groups of males and females were similar to those of the vehicle controls. The mean body weight of males administered 2,000 mg/kg ranged from 8% to 10% less than that of the vehicle controls from week 69 through the end of the study. Clinical findings included irritation and discoloration of the skin at the site of application for most males in the 2,000 mg/kg group and a few females in the 1,000 mg/kg group; males administered 200 or 630 mg/kg also had skin irritation. At the 15-month interim evaluation, the right kidney weights of male mice that received 630 or 2,000 mg/kg and the left kidney weights of males that received 2,000 mg/kg were significantly greater than those of the vehicle controls. Pathology Findings: Acanthosis and inflammation of the skin were observed at the site of application in male and female mice at the 15-month interim evaluation and at the end of the 2-year study. In males in the 2,000 mg/kg group, the incidences of both lesions were significantly greater than those in the vehicle controls at both time points; however, the severities of acanthosis and inflammation did not increase with dose. At the end of the study, the incidence of inflammation in females in the 1,000 mg/kg group was significantly greater than that in the vehicle controls. One vehicle control male and two males in each of the 630 and 2,000 mg/kg groups had ulcers at the site of application. At the 15-month interim evaluation, hepatocellular carcinomas were observed in dosed and vehicle control males and hepatocellular adenomas in dosed and vehicle control males and females; however, the incidences were not dose related. Nonneoplastic lesions observed at 15 months included foci of cellular alteration in a few dosed males and females; eosinophilic foci were also observed in two vehicle control females. At the end of the 2-year study, females in the 1,000 mg/kg group had significantly greater incidences of hepatocellular adenoma and multiple adenomas and a greater combined incidence of hepatocellular adenoma and carcinoma than the vehicle controls (adenoma: vehicle control, 22/50; 100 mg/kg, 22/50; 300 mg/kg, 24/50; 1,000 mg/kg, 40/50; multiple adenomas: 11/50, 9/50, 13/50, 29/50; combined adenoma and carcinoma: 23/50, 26/50, 28/50, 41/50). Females in the 300 mg/kg group had significantly greater incidences of hepatocellular carcinoma (1/50, 4/50, 7/50, 5/50) and eosinophilic foci (9/50, 10/50, 18/50, 16/50) than the vehicle controls. Incidences of hepatocellular adenoma and multiple adenomas in males in the 2,000 mg/kg group were significantly greater than those in the vehicle controls (adenoma: vehicle control, 27/50; 200 mg/kg, 27/50; 630 mg/kg, 29/50; 2,000 mg/kg, 37/50; multiple adenomas: 17/50, 18/50, 17/50, 29/50). Three males in the 2,000 mg/kg group had hepatoblastomas, and males in this group also had significantly greater incidences of hepatocellular neoplasms (combined) (adenoma, carcinoma, and hepatoblastoma: 31/50, 34/50, 33/50, 42/50) and eosinophilic foci (10/50, 17/50, 11/50, 23/50) than the vehicle controls. Male mice had a pattern of nonneoplastic liver lesions along with silver-staining helical organisms within the liver which suggested an infection with Helicobacter hepaticus. With polymerase chain reaction-based assays and culture, the presence of an organism compatible with H. hepaticus was confirmed. An increased incidence of hepatocellular neoplasms in male mice has been shown to be associated with H. hepaticus infection when hepatitis is also present. Therefore, interpretation of the increased incidence of hepatocellular neoplasms in mice was confounded. GENETIC TOXICOLOGY: Triethanolamine was not mutagenic in any of the in vitro or in vivo short-term tests performed by the NTP. It did not induce mutations in Salmonella typhimurium, and no induction of sister chromatid exchanges or chromosomal aberrations in cultured Chinese hamster ovary cells exposed to triethanolamine was noted. These in vitro tests were conducted with and without S9 metabolic activation. Triethanolamine did not induce sex-linked recessive lethal mutations in germ cells of adult male Drosophila melanogaster exposed by feeding or injection. No increase in the frequency of micronucleated erythrocytes was observed in peripheral blood samples of male and female mice that received dermal applications of triethanolamine for 13 weeks. CONCLUSIONS: Under the conditions of these dermal studies, there was equivocal evidence of carcinogenic activity of triethanolamine in male F344/N rats based on a marginal increase in the incidence of renal tubule cell adenoma. There was no evidence of carcinogenic activity in female F344/N rats receiving 63, 125, or 250 mg triethanolamine per kilogram body weight. The study in male and female B6C3F1 mice was considered inadequate, because the presence of a Helicobacter hepaticus infection complicated inter pretation of the relationship between triethanolamine administration and liver neoplasms in these animals. Dosed rats and mice had varying degrees of acanthosis and inflammation, dosed rats had ulceration, and dosed female rats had epidermal erosion at the site of skin application. Synonyms: Nitrilo-2,2',2"-triethanol; 2,2',2"-nitrilotriethanol; 2,2',2"-nitrilotrisethanol; TEA; triaethanolamin-NG; triethanolamin; triethylolamine; tri(hydroxyethyl)amine; 2,2',2"-trihydroxytriethylamine; trihydroxytriethylamine; tris(hydroxyethyl)amine; tris(2-hydroxyethyl)amine; triethylolamine; trolamine Trade Names: Daltogen; Sterolamide; Thiofaco T-35
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PMID:NTP Toxicology and Carcinogenesis Studies of Triethanolamine (CAS No. 102-71-6) in F344 Rats and B6C3F1 Mice (Dermal Studies). 1259 26