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PubMed1990

NTP Toxicology and Carcinogenesis Studies of 2-Chloroacetophenone (CAS No. 532-27-4) in F344/N Rats and B6C3F1 Mice (Inhalation Studies).

2-Chloroacetophenone is a potent lacrimator that has been used as a riot control agent and in tear gas formulations for personal protection devices. NTP Toxicology and Carcinogenesis studies were conducted by exposing groups of F344/N rats and B6C3F1 mice of each sex to air containing 2-chloroacetophenone vapor for 14 days, 13 weeks, 15 months, or 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium and Chinese hamster ovary (CHO) cells. Fourteen-Day Studies: In 14-day studies, exposure concentrations of 2-chloroacetophenone ranged from 4.8 to 64 mg/m3. All rats exposed to 19, 43, or 64 mg/m3 died during the first week of the studies and 1/5 male rats exposed to 10 mg/m3 died during the second week of the study. Rats exposed to 10 mg/m3 lost weight; the final mean body weights of male or female rats exposed to 4.8 mg/m3, the lowest concentration used, were 23% or 15% lower than that of controls. During the exposure, rats showed partial closure of the eyelids, excessive lacrimation (dacryorrhea), dyspnea, and erythema. All mice exposed to 10 mg/m3 or higher concentrations of 2-chloroacetophenone died during the first week of the studies. The final mean body weights of mice exposed to 4.8 mg/m3 were similar to those of controls. Dacryorrhea was observed in exposed mice. Thirteen-Week Studies: The exposure concentrations of 2-chloroacetophenone ranged from 0.25 to 4 mg/m3 for rats and mice. All rats lived to the end of the studies. The final mean body weights of rats exposed to 4 mg/m3 were 9% lower than those of controls. Eye irritation during exposure was evident in rats exposed to 0.5 mg/m3 or higher concentrations of 2-chloroacetophenone. One of 10 female mice exposed to 4 mg/m3 and 1/10 female mice exposed to 0.5 mg/m3 died before the end of the study. The final mean body weights of exposed mice were 7%-12% lower than that of controls for males and 12%-15% lower for females. No chemical-related gross or microscopic lesions were observed in rats or mice. In the 2-year studies, groups of 60 rats of each sex were exposed to a vapor of 0 (chamber control), 1, or 2 mg/m3 (0, 0.15, or 0.3 ppm) 2-chloroacetophenone, 6 hours per day, 5 days per week. Groups of 60 mice of each sex were exposed to 0 (chamber control), 2, or 4 mg/m3 (0, 0.3, or 0.6 ppm) on the same schedule. Ten animals from each group were killed and examined at 15 months; the remaining animals continued on study for 2 years. Fifteen-Month Studies: In the 15-month studies, minimal-to-mild focal squamous metaplasia and hyperplasia of the respiratory epithelium were seen at increased incidences in rats exposed to 2 mg/m3. No exposure-related lesions were observed in mice of either sex. Body Weight and Survival in the Two-Year Studies: Mean body weights and survival of exposed and chamber control rats were similar throughout most of the studies (survival-male: control, 14/50; 1 mg/m3, 22/50; 2 mg/m3, 17/50; female: 23/50; 20/50; 24/50). Mean body weights of male mice exposed to 4 mg/m3 were about 5%-12% lower than those of controls after week 30; small differences between mean body weights of exposed and control female mice were not clearly exposure related. The survival of female mice exposed to 2 mg/m3 was significantly lower than that of chamber controls after week 98. No other differences in survival were observed between any groups of mice (male: control, 34/50; 2 mg/m3, 36/50; 4 mg/m3, 33/50; female: 40/50; 28/50; 32/50). Nonneoplastic and Neoplastic Effects in the Two-Year Studies: Fibroadenomas of the mammary gland occurred in female rats with positive trends, and the incidence in the 2 mg/m3 group was greater than that in chamber controls (control, 12/50; 1 mg/m3, 19/50; 2 mg/m3, 23/50). The incidences of adenomas or adenocarcinomas of the mammary gland were not increased in the exposed groups. Minimal-to-mild suppurative inflammation of the nasal mucosa was observed at increased incidences in exposed male rats. Hyperplasia and squamous metaplasia of the nasal respiratory epithelium were observed at increased incidences in exposed ry epithelium were observed at increased incidences in exposed male and female rats. In mice, squamous metaplasia of the respiratory epithelium of the nasal passage was seen in four females and two males exposed to 4 mg/m3 2-chloroacetophenone. Inflammation, ulcers, and squamous hyperplasia of the forestomach were observed at increased incidences in exposed female rats. Genetic Toxicology: 2-Chloroacetophenone was not mutagenic in S. typhimurium strains TA98, TA100, TA1535, or TA1537 with or without exogenous metabolic activation. In cytogenetic tests with CHO cells, 2-chloroacetophenone did not induce sister chromatid exchanges with or without activation, but a weak positive increase in chromosomal aberrations was observed in the absence of metabolic activation. Conclusions: Under the conditions of these 2-year inhalation studies, there was no evidence of carcinogenic activity of 2-chloroacetophenone for male rats exposed to 1 or 2 mg/m3. There was equivocal evidence of carcinogenic activity for female F344/N rats, based on a marginal increase in fibroadenomas of the mammary gland. There was no evidence of carcinogenic activity for male or female B6C3F1 mice exposed to 2 or 4 mg/m3 2-chloroacetophenone. Synonyms: a-chloroacetophenone; 2-chloro-1-phenylethanone; CN; phenacyl chloride; phenylchloromethylketone Trade Names: Mace®.; Chemical Mace®.

Journal Article↗
PubMed1990

NTP Toxicology and Carcinogenesis Studies of Benzaldehyde (CAS No. 100-52-7) in F344/N Rats and B6C3F1 Mice (Gavage Studies).

Benzaldehyde is an aromatic aldehyde used in the food, beverage, pharmaceutical, perfume, soap, and dyestuff industries. NTP Toxicology and Carcinogenesis studies were conducted by administering benzaldehyde (99% pure) in corn oil by gavage to groups of F344/N rats and B6C3F1 mice of each sex for 16 days, 13 weeks, or 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium, mouse lymphoma cells, Chinese hamster ovary (CHO) cells, and Drosophila melanogaster. Sixteen-Day Studies: All rats that received 1,600 mg/kg died by day 2, and 2/5 males and 2/5 females that received 800 mg/kg died before the end of the studies. Final mean body weights of dosed and vehicle control rats were similar, with the exception of the 800 mg/kg groups, in which males were 14% lighter and females were 11% lighter than vehicle controls. All mice that received 1,600 or 3,200 mg/kg died by day 3. Final mean body weights of dosed and vehicle control mice were similar. No gross lesions attributable to benzaldehyde were detected upon necropsy. Thirteen-Week Studies: Six of 10 male rats and 3/10 female rats that received 800 mg/kg and 1/10 female rats that received 400 mg/kg died near the end of the studies. Final mean body weights of dosed and vehicle control rats were similar, with the exception of male rats receiving 800 mg/kg, which were 26% lighter than vehicle controls. Compound-related lesions seen in rats receiving 800 mg/kg, but not in those receiving 400 mg/kg, included degeneration and necrosis in the cerebellum, necrosis in the hippocampus, hyperplasia and/or hyperkeratosis in the forestomach, and degeneration or necrosis of the liver and of the tubular epithelium in the kidney. Nine of 10 male mice and 1/10 female mice that received 1,200 mg/kg benzaldehyde died by the end of the first week. Compound-related renal tubule degeneration and/or necrosis and reduction in final body weight were observed in the 600 mg/kg group of male mice. No reductions in body weight or compound-related lesions were seen in female mice. Based on observations of compound-related lesions involving the brain, forestomach, kidney, and liver of male and female rats and the kidney of male mice in the 13-week studies, 2-year studies were conducted by administering 0, 200, or 400 mg/kg benzaldehyde in corn oil by gavage, 5 days per week for 103 weeks to groups of 50 male and 50 female rats and for 104 weeks to groups of 50 male mice. Based on survival data from the 16-day and 13-week studies, groups of 50 female mice were administered 0, 300, or 600 mg/kg benzaldehyde for 103 weeks. Body Weights and Survival in the Two-Year Studies: Mean body weights of dosed rats and mice were similar to their respective vehicle controls throughout the studies. The survival of the high dose group of male rats was lower than that of the vehicle controls after 1 year; no other significant differences were observed between any groups of rats or mice (survival--male rats; vehicle control, 37/50; low dose, 29/50; high dose, 21/50; female rats: 33/50; 33/50; 29/50; male mice: 32/50; 33/50; 31/50, female mice: 30/50; 27/50; 35/50). Nonneoplastic and Neoplastic Effects in the Two-Year Studies: The only effects of benzaldehyde were those seen in the forestomach of mice. The incidences of uncommonly occurring squamous cell papillomas of the forestomach in both exposure groups were significantly greater than those in vehicle controls (male: vehicle control, 1/50; low dose, 2/50; high dose, 5/50; female: 0/50; 5/50; 6/50). The increased incidences of papillomas were accompanied by dose-related increases in the incidences in forestomach hyperplasia (male: 7/50; 8/50; 16/50; female: 12/50; 23/50; 39/50). Genetic Toxicology: Benzaldehyde was not mutagenic in six strains of S. typhimurium and did not induce chromosomal aberrations in CHO cells, with or without exogenous metabolic activation. Benzaldehyde induced increases in trifluorothymidine-resistant mouse lymphoma cells in the absence exogenous metabolic activation and increased sister chromatid exchanges in CHO cells in boexchanges in CHO cells in both the presence and absence of metabolic activation. Sex-linked recessive lethal mutations were not induced in the germ cells of adult male D. melanogaster administered benzaldehyde by feeding or by injection. Conclusions: Under the conditions of these 2-year gavage studies, there was no evidence of carcinogenic activity of benzaldehyde for male or female F344/N rats receiving 200 or 400 mg/kg per day. There was some evidence of carcinogenic activity of benzaldehyde for male or female B6C3F1 mice, as indicated by increased incidences of squamous cell papillomas and hyperplasia of the forestomach. Female rats and male and female mice might have been able to tolerate higher doses. Synonyms: artificial almond oil; artificial essential oil of almond; benzenecarbonal; benzene carbaldehyde; benzoic aldehyde; phenylmethanal

Journal Article↗
PubMed1990

NTP Toxicology and Carcinogenesis Studies of CS2 (94% o-Chlorobenzalmalononitrile, CAS No. 2698-41-1) in F344/N Rats and B6C3F1 Mice (Inhalation Studies).

CS2 (94% o-chlorobenzalmalononitrile [CS]; 5% Cab-O-Sil(R). colloidal silica; 1% hexamethyldisilizane), an eye and respiratory irritant, is used as an aerosol to control riots. NTP Toxicology and Carcinogenesis studies were conducted by exposing groups of F344/N rats and B6C3F1 mice of each sex for 6 hours per day, 5 days per week for 2 weeks, 13 weeks, or 2 years, to a CS2 aerosol. Genetic toxicology studies with CS2 were conducted in Salmonella typhimurium, mouse lymphoma cells, and Chinese hamster ovary (CHO) cells. Fourteen-Day Studies: At exposure concentrations of 0, 1, 3, 10, 30, or 100 mg/m3 CS2, all rats exposed to 30 or 100 mg/m3 and all mice exposed to 10, 30, or 100 mg/m3 died before the end of the studies. Compound-related clinical signs observed included erythema, blepharospasm, listlessness, nasal discharge, and mouse breathing. Thirteen-Week Studies: At exposure concentrations of 0, 0.4, 0.75, 1.5, 3, or 6 mg/m3, 1/10 male rats exposed to 6 mg/m3 died before the end of the studies. Final mean body weights of rats exposed to 1.5 mg/m3 or more were 17%-44% lower than that of controls for males and 10%-24% lower for females. The absolute and relative thymus weights were reduced for exposed male and female rats, particularly at 6 mg/m3. Compound-related lesions of the nasal passage in rats included focal erosion with regenerative hyperplasia and squamous metaplasia of the respiratory epithelium and suppurative inflammation. Acute inflammation and hyperplasia of the respiratory epithelium were seen in the larynx and trachea of some exposed rats. All mice exposed to 6 mg/m3 and 1/10 males and 1/10 females exposed to 3 mg/m3 died before the end of the studies. Final mean body weights of mice exposed to 3 mg/m3 were 13% lower than that of controls for males and 9% lower for females. Compound-related lesions of the nasal passage in mice included squamous metaplasia of the nasal respiratory epithelium and inflammation. Based on these results, CS2 exposure concentrations for the 2-year studies were 0, 0.075, 0.25, or 0.75 mg/m3 for 6 hours per day, 5 days per week for 105 weeks for groups of 50 rats of each sex. Groups of 50 mice of each sex were exposed to 0, 0.75, or 1.5 mg/m3 on the same schedule. Body Weights and Survival in the Two-Year Studies: Final mean body weights of rats exposed to 0.75 mg/m3 were 7%-11% lower than those of controls. Final mean body weights of mice exposed to CS2 were lower than those of controls (male: 5% and 9%; female: 10% and 17%). No compound-related clinical signs were observed. No significant differences in survival were seen for any group of rats or mice of either sex. Nonneoplastic and Neoplastic Effects in the Two-Year Studies: Compound-related nonneoplastic lesions occurred in the nasal passage of exposed rats and mice. In exposed rats, hyperplasia and squamous metaplasia of the respiratory epithelium and degeneration of the olfactory epithelium with ciliated columnar and/or squamous metaplasia were observed. Focal chronic inflammation and proliferation of the periosteum of the turbinate bones were increased slightly in rats at the top exposure concentration. Suppurative inflammation with hyperplasia and squamous metaplasia of the respiratory epithelium occurred in exposed mice. There were no compound-related increased incidences of neoplasms in rats or mice exposed to CS2. In exposed female mice, there were pronounced decreases in the incidences of adenomas of the pituitary pars distalis (control, 13/47; 0.75 mg/m3, 5/46; 1.5 mg/m3, 1/46) and decreased incidences of malignant lymphomas (21/50; 12/50; 8/50). Genetic Toxicology: The responses in Salmonella gene mutation tests with CS2 were equivocal in one laboratory for strain TA100 in the absence of exogenous metabolic activation (S9) and equivocal in another laboratory for TA97 with S9; in all other strains tested, CS2 was clearly negative with or without S9. CS2 induced trifluorothymidine resistance in mouse L5178Y/TK lymphoma cells in the absence of S9; it was not tested with S9. CS2 induced both sister chromatid exchangeslymphoma cells in the absence of S9; it was not tested with S9. CS2 induced both sister chromatid exchanges and chromosomal aberrations in CHO cells with and without S9. Conclusions: Under the conditions of these inhalation studies, there was no evidence of carcinogenic activity of CS2 for male or female F344/N rats exposed to 0.075, 0.25, or 0.75 mg/m3 in air for up to 2 years. There was no evidence of carcinogenic activity for male or female B6C3F1 mice exposed to 0.75 or 1.5 mg/m3 in air for up to 2 years. Concentration-related decreases in the incidences of pituitary gland adenomas and lymphomas were observed in female mice. Exposure to CS2 caused degeneration and squamous metaplasia of the olfactory epithelium, hyperplasia and metaplasia of the respiratory epithelium, and proliferation of the periosteum of the nasal passage of rats. In mice, exposure to this compound caused suppurative inflammation and hyperplasia and squamous metaplasia of the respiratory epithelium of the nasal passage.

Journal Article↗
PubMed1990

NTP Toxicology and Carcinogenesis Studies of Allyl Glycidyl Ether (CAS No. 106-92-3) in Osborne-Mendel Rats and B6C3F1 Mice (Inhalation Studies).

Allyl glycidyl ether is used as a resin intermediate and as a stabilizer of chlorinated compounds, vinyl resins, and rubber. NTP Toxicology and Carcinogenesis studies were conducted by exposing groups of Osborne-Mendel rats and B6C3F1 of each sex to allyl gylcidyl ether (greater than 97% pure) by inhalation for 6 hours per day, 5 days per week for 2 weeks, 13 weeks, or 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium, Chinese hamster ovary (CHO) cells, and Drosophila melanogaster. Studies of reproductive effects were conducted in rats and mice exposed to allyl glycidyl ether for 8 weeks. Two-Week Studies: Exposure concentrations ranged up to 500 ppm in rats and 100 ppm in mice. All rats that were exposed to 500 ppm died; no deaths occurred at the next lower (200 ppm) exposure concentration. All male mice and 3/5 female mice exposed to 100 ppm and 2/5 male mice and 1/5 female mice exposed to 50 ppm died. Compound-related lesions in rats and mice included acute inflammation of the nasal passage and major airways. Eight-Week Studies of Reproductive Effects: Rats were exposed to 0-200 ppm allyl glycidyl ether, and mice were exposed to 0-30 ppm, 6 hours per day, 5 days per week for 8 weeks. The mating performance of exposed male rats was markedly reduced; however, sperm motility and number were not affected. No deficiencies were seen in the reproductive performance of exposed female rats or male or female mice. Thirteen-Week Studies: Exposure concentrations ranged up to 200 ppm for rats and 30 ppm for mice. All rats lived to the end of the studies. The final mean body weights of male rats exposed to 10-200 ppm were 7%-24% lower than that of controls. Clinical signs attributable to irritation of the upper respiratory tract and eyes were seen in exposed animals. Histologic lesions included squamous metaplasia of the nasal passage in all exposure groups (4 ppm, lowest concentration) and involved both the respiratory epithelium and the olfactory epithelium. The lesions were more severe anteriorly and dorsally and with increasing concentration. At 30 ppm and higher, erosion was seen in the nasal passage and squamous metaplasia was seen in the upper airways. There were no compound-related deaths in mice. The final mean body weights of mice exposed to 30 ppm were 12% lower than those of controls for both males and females. Mice exposed to 10 or 30 ppm allyl glycidyl ether had squamous metaplasia of the nasal passage, involving both the respiratory epithelium and the olfactory epithelium, which tended to be more severe in the anterior and dorsal portions of the nasal passage. In mice exposed to 30 ppm, epithelial erosions were also found. Body Weights and Survival in the Two-Year Studies: Two-year studies were conducted by exposing groups of 50 Osborne-Mendel rats and B6C3F1 mice of each sex to 0, 5, or 10 ppm allyl glycidyl ether by inhalation for 6 hours per day, 5 days per week for 102 or 103 weeks. Mean body weights of the exposed rats were within 8% of those of controls throughout the studies. Mean body weights of mice exposed to 5 or 10 ppm were 5%-20% lower than those of controls. Deaths were seen in all groups of male rats beginning at 1 year of age (final survival-- control, 12/50; 5 ppm, 11/50; 10 ppm, 8/50). Survival of female rats was not exposure related (24/50; 30/50; 25/50). Exposed mice had slightly increased survival (male mice: 38/50; 39/50; 46/50; female mice: 33/50; 42/50; 41/50). Nonneoplastic and Neoplastic Effects in the Two-Year Studies: In male rats exposed to 10 ppm allyl glycidyl ether, three apparently unrelated neoplasms of the nasal passage were found. Two neoplasms, a papillary adenoma and a squamous cell carcinoma, appeared to arise from different cell types in the respiratory epithelium. One poorly differentiated adenocarcinoma in the olfactory region was also found. One papillary adenoma of respiratory epithelial origin was found in a female rat exposed to 5 ppm. Exposure-related nonneoplastic lesions of the nasal passages in rats included inflammation, squamous metaplasiin rats included inflammation, squamous metaplasia, respiratory metaplasia (replacement of olfactory epithelium by ciliated epithelium), hyperplasia of the respiratory epithelium, and degeneration of the olfactory epithelium. In male mice exposed to 10 ppm allyl glycidyl ether, a hemangioma and three papillary adenomas were present in the nasal passage. In female mice exposed to 10 ppm, a hemangioma and an adenoma were found in the nasal passage. Nonneoplastic lesions of the nasal passages in mice included inflammation, squamous metaplasia, hyperplasia, basal cell hyperplasia, dysplasia of the respiratory epithelium, and metaplasia of the olfactory epithelium. In male mice, there was an exposure-related decrease in the incidences of hepatocellular neoplasms; in female mice, there was a decrease in the incidences of pituitary gland adenomas. Genetic Toxicology: Allyl glycidyl ether was mutagenic in S. typhimurium strains TA100 and TA1535 with and without exogenous metabolic activation; no mutagenic activity was observed in strains TA98 or TA1537. Allyl glycidyl ether induced sister chromatid exchanges and chromosomal aberrations in CHO cells both in the presence and the absence of metabolic activation. A significant increase in sex-linked recessive lethal mutations was recorded in the germ cells of male D. melanogaster fed a sucrose solution containing allyl glycidyl ether, but no increase in reciprocal translocations occurred in these cells. Conclusions: Under the conditions of these 2-year inhalation studies, there was equivocal evidence of carcinogenic activity of allyl glycidyl ether for male Osborne-Mendel rats, based on the presence of one papillary adenoma of respiratory epithelial origin, one squamous cell carcinoma of respiratory epithelial origin, and one poorly differentiated adenocarcinoma of olfactory epithelial origin, all occurring in the nasal passage of males exposed to 10 ppm. There was no evidence of carcinogenic activity of allyl glycidyl ether for female rats. One papillary adenoma of the respiratory epithelium was present in a female rat exposed to 5 ppm. There was some evidence of carcinogenic activity of allyl glycidyl ether for male B6C3F1 mice, based on the presence of three adenomas of the respiratory epithelium, dysplasia in four males, and focal basal cell hyperplasia of the respiratory epithelium in seven males in the nasal passage of mice exposed to 10 ppm. There was equivocal evidence of carcinogenic activity of allyl glycidyl ether for female mice, based on the presence of one adenoma of the respiratory epithelium and focal basal cell hyperplasia of the respiratory epithelium in seven females exposed to 10 ppm. The sensitivity of the assay to detect potential carcinogenicity may have been reduced in male rats because of poor survival in all groups. In exposed mice, body weights were decreased 10% or more, mortality was decreased, and there were lower incidences of liver neoplasms (males) and pituitary gland adenomas (females) compared with controls. Significant exposure-related nonneoplastic lesions were restricted to the nasal passage in both rats and mice and induced inflammation, metaplasia, respiratory epithelial hyperplasia, and olfactory epithelial degeneration. Basal cell hyperplasia and dysplasia of the respiratory epithelium of the nasal passage were found only in the mice. Synonyms: allyl 2,3-epoxypropyl ether; 1-allyloxy-2,3-epoxypropane; 1,2-epoxy-3-allyloxypropane; glycidyl allyl ether; ((2-propenyloxy)methyl)oxirane; 1-(allyloxy)-2,3-epoxypropane

Journal Article↗
PubMed1990

NTP Toxicology and Carcinogenesis Studies of Vinyl Toluene (Mixed Isomers) (65%-71% meta-isomer and 32-35% para-isomer) (CAS No. 25013-15-4) in F344/N Rats and B6C3F1 Mice (Inhalation Studies).

Vinyl Toluene is used as a monomer in the plastics and surface-coating industries. NTP Toxicology and Carcinogenesis studies were conducted by exposing groups of F344/N rats and B6C3F1 mice of each sex to vinyl toluene (mixed isomers: 65%-71% meta and 32%-35% para) by inhalation 6 hours per day, 5 days per week, for 15 days, 13 weeks, or 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium, mouse L5178Y cells, and Chinese hamster ovary (CHO) cells. Fifteen-Day Studies: Rats were exposed to 0, 200, 400, 800, or 1,300 ppm vinyl toluene, and mice were exposed to 0, 10, 25, 50, 100, or 200 ppm. All rats lived to the end of the studies. The mean body weights at necropsy of rats exposed to 400-1,300 ppm were 13%-19% lower than that of controls for males and 9%-13% lower for females. Most male rats exposed to 1,300 ppm had centrilobular necrosis and focal inflammatory cell infiltration of the liver, whereas minimal centrilobular vacuolization of the liver was seen in all female rats exposed to 1,300 ppm. Dysplasia of the bronchial epithelial lining, chronic bronchitis, and lymphoid hyperplasia of the lung were observed in all rats exposed to 1,300 ppm. Three of five male mice exposed to 200 ppm vinyl toluene died before the end of the studies. Four of five male mice exposed to 200 ppm had moderate-to-severe hepatocellular necrosis; all female mice exposed to 200 ppm had hyperplasia of the epithelium of the intrapulmonary bronchi and centrilobular necrosis, vacuolization, and inflammatory cell infiltrates in the liver. Thirteen-Week Studies: Rats were exposed to 0, 25, 60, 160, 400, or 1,000 ppm vinyl toluene. All rats lived to the end of the studies. The final mean body weights of rats exposed to 400-1,000 ppm were 8%-19% lower than that of controls for males and 6%-12% lower for females. Relative liver weights for rats at 1,000 ppm were significantly greater than those for controls. The severity of nephropathy was increased in male rats exposed to 160, 400, or 1,000 ppm. Compound-related lesions were not observed in female rats. Mice were exposed to 0, 10, 25, 60, or 160 ppm vinyl toluene. The final mean body weights of mice exposed to 25-160 ppm were 12%-20% lower than that of controls for males and 13%-16% lower for females. Inflammation of the lung was observed in 5/10 male and 3/9 female mice exposed to 160 ppm. Metaplasia of the nasal turbinates was seen in all exposed groups. Based on these results, 2-year studies were conducted by exposing groups of 49 or 50 rats of each sex to 0, 100, or 300 ppm vinyl toluene by inhalation, 6 hours per day, 5 days per week for 103 weeks. Groups of 50 mice of each sex were exposed to 0, 10, or 25 ppm on the same schedule. Body Weights and Survival in the Two-Year Studies: Mean body weights of male rats exposed to 300 ppm vinyl toluene and those of female rats exposed to 100 and 300 ppm were generally 4%-11% lower than those of controls. No significant differences in survival were seen between any groups of rats of either sex (male: control, 19/49; low dose, 17/50; high dose, 19/50; female: 31/50; 28/50; 26/50). Mean body weights of mice exposed to 25 ppm were 10%-23% lower than those of controls after week 8, whereas mice exposed to 10 ppm showed a weight decrement that was generally less than 10%. The survival of male mice exposed to 25 ppm was significantly greater than that of controls. No other significant differences in survival were seen between any groups of mice of either sex (male: 33/50; 30/50; 41/50; female: 36/50; 37/50; 34/50). Nonneoplastic and Neoplastic Effects in the Two-Year Studies: Degenerative and nonneoplastic proliferative lesions of the nasal mucosa were observed at increased incidences in exposed rats. These lesions included diffuse hyperplasia (goblet cell) of the respiratory epithelium with intraepithelial mucous cysts and focal erosion of the olfactory epithelium with cystic dilation (cysts) of the Bowman's glands. Focal respiratory epithelial metaplasia of the olfactory epithelium was seen in some exposed males, and cells with homoge) of the Bowman's glands. Focal respiratory epithelial metaplasia of the olfactory epithelium was seen in some exposed males, and cells with homogeneous eosinophilic cytoplasm in the olfactory epithelium occurred at increased incidences in exposed female rats. Neoplasms of the nasal mucosa were not seen in male or female rats. There were no chemically related increases in neoplasm incidence in exposed male or female rats. Degenerative and inflammatory lesions of the nasal mucosa were observed at increased incidences in exposed mice. These lesions included focal chronic active inflammation and diffuse hyperplasia of the respiratory epithelium. Chronic active inflammation of the bronchioles occurred in many exposed mice but not in controls. Neoplasms of the nasal passage were not observed in mice. There were no chemically related increases in neoplasm incidence in exposed male or female mice. Exposure-related decreased incidences included alveolar/bronchiolar neoplasms (control, 12/50; 10 ppm, 5/49; 25 ppm, 2/49) and malignant lymphomas (7/50; 3/50; 0/50) in males and hepatocellular neoplasms (9/48; 5/16; 2/49) in females. Genetic Toxicology: Vinyl toluene did not induce gene mutations in S. typhimurium strains TA98, TA100, TA1535, or TA1537 with or without exogenous metabolic activation (S9). Vinyl toluene was positive in the mouse lymphoma assay for induction of trifluorothymidine resistance in L5178Y/TK cells in the absence of S9; it was not tested with S9. Vinyl toluene did not induce sister chromatid exchanges or chromosomal aberrations in CHO cells with or without S9. Conclusions: Under the conditions of these 2-year inhalation studies, there was no evidence of carcinogenic activity for male or female F344/N rats exposed to 100 or 300 ppm vinyl toluene and no evidence of carcinogenic activity for male or female B6C3F1 mice exposed to 10 or 25 ppm. There was evidence of chemical-related toxicity to the nasal passage in both rats and mice. Synonyms: 3-vinyl toluene and 4-vinyl toluene (mixed isomers)

Journal Article↗
PubMed1990

NTP Toxicology and Carcinogenesis Studies of Glycidol (CAS No. 556-52-5) In F344/N Rats and B6C3F1 Mice (Gavage Studies).

Glycidol is a viscous liquid that is used as a stabilizer in the manufacture of vinyl polymers, as an additive for oil and synthetic hydraulic fluids, and as a diluent in some epoxy resins. NTP Toxicology and Carcinogenesis studies were conducted by administering glycidol (94% pure, containing 1.2% 3-methoxy-1,2-propanediol, 0.4% 3-chloro-1,2-propanediol, 2.8% diglycidyl ether, and 1.1% 2,6-dimethanol-1,4-dioxane) in water by gavage to groups of F344/N rats and B6C3F1 mice of each sex for 16 days, 13 weeks, or 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium, Chinese hamster ovary (CHO) cells, Drosophila melanogaster, and the bone marrow of male B6C3F1 mice. Sixteen-Day Studies: Glycidol doses for groups of five rats or five mice of each sex ranged from 37.5 to 600 mg/kg; vehicle controls received distilled water. All rats that received 600 mg/kg died between days 3 and 13. Edema and degeneration of the epididymal stroma, atrophy of the testis, and granulomatous inflammation of the epididymis occurred in males that received 300 mg/kg. All mice that received 600 mg/kg and two males and two females that received 300 mg/kg died by day 4 of the studies. Focal demyelination in the medulla and thalamus of the brain occurred in all female mice that received 300 mg/kg. Thirteen-Week Studies: Doses for groups of 10 rats ranged from 25 to 400 mg/kg, and doses for groups of 10 mice ranged from 19 to 300 mg/kg; vehicle controls received distilled water. All rats that received 400 mg/kg died by week 2; three males and one female that received 200 mg/kg died during weeks 11-12. Final mean body weights of male rats that received 50, 100, or 200 mg/kg were 96%-85% that of vehicle controls; final mean body weights of female rats receiving the same doses were 95%-89% that of vehicle controls. Sperm count and sperm motility were reduced in male rats that received 100 or 200 mg/kg. Necrosis of the cerebellum, demyelineation in the medulla of the brain, tubular degeneration and/or necrosis of the kidney, lymphoid necrosis of the thymus, and testicular atrophy and/or degeneration occurred in rats that received 400 mg/kg. All mice that received 300 mg/kg died by week 2; deaths of mice that received 150 mg/kg occurred during weeks 4-8 for males and weeks 1-5 for females. Mean body weights of chemically exposed mice surviving to the end of the studies were generally 90%-94% those of vehicle controls. Sperm count and sperm motility were reduced in dosed male mice. Compound-related histopathologic lesions included demyelination of the brain in males and females that received 150 or 300 mg/kg, testicular atrophy in males at all doses, and renal tubular cell degeneration in male mice that received 300 mg/kg. Based on reduced survival, reduced weight gain, and histopathologic lesions in the brain and kidney in rats that received 200 or 400 mg/kg and on reduced survival and histopathologic lesions of the brain in mice that received 150 or 300 mg/kg, doses selected for the 2-year studies of glycidol were 37.5 and 75 mg/kg for rats and 25 and 50 mg/kg for mice. Body Weights and Survival in the Two-Year Studies: Mean body weights of chemically exposed male rats generally ranged from 80% to 94% of those of vehicle controls, and mean body weights of chemically exposed female rats were from 90% to 97% those of vehicle controls. Mean body weights of chemically exposed male mice were similar to those of vehicle controls; mean body weights of chemically exposed female mice were 79%-95% of those of vehicle controls. Virtually all male and female rats that received glycidol died or were killed in a moribund condition as a result of the early induction of neoplastic disease (final survival--male: vehicle control, 16/50; low dose, 0/50; high dose, 0/50; female: 28/50; 4/50; 0/50). Survival of vehicle control male rats was lower than that usually observed; however, specific causes of deaths could not be determined. The survival of male mice and low dose female mice was similar to that of vehicle controls; survival of female mice that resurvival of male mice and low dose female mice was similar to that of vehicle controls; survival of female mice that received 50 mg/kg was lower than that of vehicle controls after week 101 (final survival--male: 33/50; 25/50; 27/50; female: 29/50; 27/50; 17/50). Nonneoplastic and Neoplastic Effects in the Two-Year Studies: Chemical-related nonneoplastic lesions in both rats and mice included hyperkeratosis and epithelial dysplasia of the forestomach. Fibrosis of the spleen was also present in rats of each sex, and cysts of the preputial gland and kidney were present in male mice. Exposure to glycidol induced dose-related increases in the incidences of neoplasms in numerous tissues in both rats and mice (see summary table on page 5 of the Technical Report). In male rats, mesotheliomas arising in the tunica vaginalis and frequently metastasizing to the peritoneum were considered the major cause of early death. Early deaths in female rats were associated with the presence of mammary gland neoplasms. Genetic Toxicology: Glycidol was mutagenic in a variety of in vitro and in vivo short-term tests. Mutagenic activity was observed in S. typhimurium strains TA97, TA98, TA100, TA1535, and TA1537 exposed to glycidol with and without exogenous metabolic activation. Glycidol was positive in the absence of exogenous metabolic activation in the mouse lymphoma assay for induction of trifluorothymidine resistance in L5178Y/TK cells; it was not tested with activation. In cytogenetic tests with CHO cells, glycidol induced both sister chromatid exchanges and chromosomal aberrations in the presence and absence of exogenous metabolic activation. Glycidol induced sex-linked recessive lethal mutations and reciprocal translocations in the germ cells of male D. melanogaster exposed by feeding. The incidence of micronucleated polychromatic erythrocytes was increased in the bone marrow of male B6C3F1 mice administered glycidol by intraperitoneal injection. Conclusions: Under the conditions of these 2-year gavage studies, there was clear evidence of carcinogenic activity of glycidol for male F344/N rats, based on increased incidences of mesotheliomas of the tunica vaginalis; fibroadenomas of the mammary gland; gliomas of the brain; and neoplasms of the forestomach, intestine, skin, Zymbal gland, and thyroid gland. There was clear evidence of carcinogenic activity for female F344/N rats, based on increased incidences of fibroadenomas and adenocarcinomas of the mammary gland; gliomas of the brain; neoplasms of the oral mucosa, forestomach, clitoral gland, and thyroid gland; and leukemia. There was clear evidence of carcinogenic activity for male B6C3F1 mice based on increased incidences of neoplasms of the harderian gland, forestomach, skin, liver, and lung. There was clear evidence of carcinogenic activity for female B6C3F1 mice, based on increased incidences of neoplasms of the harderian gland, mammary gland, uterus, subcutaneous tissue, and skin. Other neoplasms that may have been related to the administration of glycidol were fibrosarcomas of the glandular stomach in female rats and carcinomas of the urinary bladder and sarcomas of the epididymis in male mice. Synonym: 2,3-epoxy-1-propanol

Journal Article↗
PubMed1990

NTP Toxicology and Carcinogenesis Studies of Succinic Anhydride (CAS No. 108-30-5) in F344/N Rats and B6C3F1 Mice (Gavage Studies).

Succinic anhydride, a food additive, is also used in the manufacture of polymeric materials, pharmaceuticals, and agricultural and industrial chemicals. NTP Toxicology and Carcinogenesis studies were conducted by administering suspensions of succinic anhydride (97% pure) in corn oil by gavage to groups of F344/N rats and B6C3F1 mice of each sex for 16 or 20 days, 13 weeks, or 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium and Chinese hamster ovary (CHO) cells. Twenty-Day or Sixteen-Day and Thirteen-Week Studies: In the 20-day studies in rats, doses of succinic anhydride given on 14 exposure days ranged from 47 to 750 mg/kg. Compound-related deaths occurred in the groups of males that received 375 mg/kg or higher doses and in females that received 187 mg/kg or higher doses. Necrosis and inflammation of the upper respiratory tract were seen in 3/10 male and 3/10 female rats given 750 mg/kg and 2/10 female rats given 375 mg/kg. In the 16-day studies in mice, doses of succinic anhydride given on 12 exposure days ranged from 219 to 3,500 mg/kg. All animals that received 875 mg/kg or higher doses of succinic anhydride died before the end of the studies. No compound-related lesions were seen in male or female mice examined from the 438 mg/kg dose group. In the 13-week studies in rats, doses of succinic anhydride ranged from 25 to 400 mg/kg for males and from 12.5 to 200 mg/kg for females. Deaths of 8/10 male rats that received 400 mg/kg and 4/10 males and 5/10 females that received 200 mg/kg were compound related. At necropsy, the mean body weights of male rats that received 200 or 400 mg/kg were 9% or 15% lower than that of vehicle controls, whereas the mean body weights of dosed and vehicle control female rats were similar. No compound-related gross or microscopic lesions were observed. In the 13-week studies in mice, doses of succinic anhydride ranged from 37 to 600 mg/kg. All 10 males and 8/10 females that received 600 mg/kg and 2/10 males and 2/10 females that received 300 mg/kg died before the end of the studies. The final mean body weights of mice that received 150 or 300 mg/kg were 13% or 9% lower than that of vehicle controls for males and 8% or 7% lower for females. Mild inflammation of the stomach was observed in 7/10 male mice that received 150 mg/kg and 5/10 males that received 300 mg/kg compared with 2/10 vehicle controls. Based primarily on the effects of administration of succinic anhydride on survival and mean body weights of rats and mice, doses for the 2-year studies were 0, 50, or 100 mg/kgto groups of 60 rats of each sex; 0, 38, or 75 mg/kg to groups of 50 male mice; and 0, 75, or 150 mg/kg to groups of 50 female mice. Succinic anhydride was administered as a suspension in corn oil by gavage, 5 days per week for 103 weeks. Body Weights and Survival in the Two-Year Studies: Mean body weights of high dose rats were 5%-11% lower than those of vehicle controls during the second year of the studies. No significant differences in survival after 2 years were observed between any groups of rats of either sex (male: vehicle control, 36/60; low dose, 33/60; high dose, 32/60; female: 31/60; 27/60; 27/60). For mice, mean body weights of high dose males were generally 5%-12% lower than those of vehicle controls throughout the study. Mean body weights of high dose female mice were 10%-32% lower than those of vehicle controls; mean body weights of low dose female mice were 10%-20% lower than those of vehicle controls. The survival of high dose male mice was significantly greater than that of vehicle controls after week 77 (survival after 2 years--male: 27/50; 30/50; 42/50; female: 37/50; 38/50; 41/50). No other differences in survival were observed between any groups of mice of either sex. Nonneoplastic and Neoplastic Effects in the Two-Year Studies: At no site in rats or mice was there a chemical-related increase in the incidence of nonneoplastic or neoplastic lesions. A sufficient number of animals in each dose group lived long enough to allow evaluation of the potential carcinogenicity ofr of animals in each dose group lived long enough to allow evaluation of the potential carcinogenicity of succinic anhydride. Genetic Toxicology: Succinic anhydride was not mutagenic in S. typhimurium with or without exogenous metabolic activation. The chemical did not induce sister chromatid exchanges or chromosomal aberrations in cultured CHO cells in the presence or absence of exogenous metabolic activation. Conclusions: Under the conditions of these 2-year studies, there was no evidence of carcinogenic activity of succinic anhydride for male or female F344/N rats given 50 or 100 mg/kg succinic anhydride. There was no evidence of carcinogenic activity for male B6C3F1 mice given 38 or 75 mg/kg succinic anhydride or for female B6C3F1 mice given 75 or 150 mg/kg. Synonyms: butanedioic anhydride; dihydro-2,5-furandione; 2,5-diketotetrahydrofuran; succinic acid anhydride; succinyl anhydride; succinyl oxide; tetrahydro-2,5-dioxofuran

Journal Article↗
PubMed1993

NTP Toxicology and Carcinogenesis of 1,2,3-Trichloropropane (CAS No. 96-18-4) in F344/N Rats and B6C3F1 Mice (Gavage Studies).

1,2,3-Trichloropropane is a colorless liquid used as a paint and varnish remover, solvent, and degreasing agent, and as a crosslinking agent in the synthesis of polysulfides and hexafluoropropylene. 1,2,3-Trichloropropane may be found as an impurity in certain nematocides and soil fumigants and as a contaminant of drinking and ground water. Studies on the toxic and carcinogenic effects of 1,2,3-trichloropropane were initiated because of the close structural relationship of this chemical to other short-chain halogenated compounds that were demonstrated to be carcinogenic in experimental animals, and because of the potential for human exposure. Toxicology and carcinogenicity studies were conducted by administering 1,2,3-trichloropropane (greater than 99% pure) in corn oil by gavage to groups of F344/N rats and B6C3FI mice for 17 weeks and 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium strains, mouse lymphoma cells, and Chinese hamster ovary cells. 17-Week Studies: Groups of 20 male and 20 female rats received 1,2,3-trichloropropane in corn oil by gavage at doses of 8, 16, 32, 63, 125, or 250 mg/kg body weight 5 days per week for up to 17 weeks; 30 male and 30 female rats received corn oil alone and served as controls. Animals were evaluated at 8 or 17 weeks. All rats in the 250 mg/kg groups died by week 5. One male and four female rats in the 125 mg/kg groups died during the study. The mean body weight gains and final mean body weights of males receiving 63 mg/kg and of males and females receiving 125 mg/kg were lower than those of the controls. Hematocrit values, hemoglobin concentrations, and erythrocyte counts decreased with dose in males and females. Serum alanine aminotransferase, aspartate aminotransferase, and sorbitol dehydrogenase activities were significantly increased in some female rats receiving 125 mg/kg. Serum pseudocholinesterase activity decreased with dose in females. Increases in kidney and liver weights were related to chemical administration. The principal toxic lesions associated with the administration of 1,2,3-trichloropropane to rats were hepatocellular necrosis, karyomegaly, and biliary hyperplasia of the liver; renal tubule necrosis, regeneration, and karyomegaly of the kidney; and necrosis and inflammation of the nasal olfactory and respiratory epithelium. Groups of 20 male and 20 female mice received 1,2,3-trichloropropane in corn oil by gavage at doses of 8, 16, 32, 63, 125, or 250 mg/kg 5 days per week for up to 17 weeks; 30 male and 30 female mice received corn oil alone and served as controls. Sixteen male and seven female mice in the 250 mg/kg groups died by week 4. The final mean body weights and mean body weight gains of dosed mice were similar to those of the controls, except those of 250 mg/kg males, which were lower than those of controls. The principal toxic lesions associated with the administration of 1,2,3-trichloropropane were hepatocellular necrosis and karyomegaly of the liver; necrosis, regeneration, and hyperplasia of the bronchiolar epithelium in the lung; and acanthosis (hyperplasia) and hyperkeratosis of the forestomach epithelium. 2-Year Studies: Groups of 60 male and 60 female rats received 0, 3, 10, or 30 mg 1,2,3-trichloropropane/kg body weight in corn oil by gavage 5 days per week for up to 104 weeks. Selection of 30 mg/kg as the high dose in these studies was based on the following chemical-related effects in the 17-week studies: deaths and liver and kidney lesions at 125 and 250 mg/kg and reduced final mean body weights and mean body weight gains at 63 mg/kg or greater. Groups of 60 male and 60 female mice received 0, 6, 20, or 60 mg 1,2,3-trichloropropane/kg body weight in corn oil by gavage 5 days per week for up to 104 weeks. Selection of 60 mg/kg as the high dose was based on chemical-related deaths and lesions of the liver, lung, and forestomach at 125 and 250 mg/kg in the 17-week studies. 15-Month Interim Evaluations: Up to 10 rats and 10 mice from each dose group were evaluated at 15 months. Absolute and relative liver and kidned kidney weights of dosed rats were significantly greater than those of the controls. Chemical-related nonneoplastic lesions and neoplasms of the forestomach, oral mucosa, pancreas (males), kidney, mammary gland (females), preputial gland, and clitoral gland were observed in dosed rats. Chemical-related nonneoplastic lesions and neoplasms of the forestomach and liver (females) were observed in dosed mice. Survival and Body Weight in the 2-Year Studies: Survival of male and female rats receiving 10 or 30 mg/kg 1,2,3-trichloropropane was significantly lower than that of controls. Two-year survival rates of male rats were: control, 34/50; 3 mg/kg, 32/50; 10 mg/kg, 14/49; 30 mg/kg, 0/52; and of females were: 31/50, 30/49, 8/52, 0/52. At 30 mg/kg, survival was markedly reduced due to chemical-related neoplasms, and survivors were killed in weeks 67 (females) or 77 (males). Final mean body weights of 30 mg/kg rats were 13% lower for males and 12% lower for females than those of controls; mean body weights of 3 and 10 mg/kg rats were similar to controls. Survival rates of mice receiving 6, 20, or 60 mg/kg 1,2,3-trichloropropane were also significantly lower than those of controls. Two-year survival rates of male mice were: 42/52, 18/51, 0/54, 0/56; and of female mice were: 41/50, 13/50, 0/51, 0/55. Because of reduced survival at 20 and 60 mg/kg due to chemical-related neoplasms, survivors were killed in weeks 73 (60 mg/kg females), 79 (60 mg/kg males), or 89 (20 mg/kg males and females). Final mean body weights were 16% lower for 60 mg/kg males, 18~ lower for 60 mg/kg females, and 13% lower for 20 mg/kg males than those of controls. Final mean body weights of 6 mg/kg males and females and 20 mg/kg females were similar to controls. Neoplasms and Nonneoplastic Lesions in the 2-Year Studies: Administration of 1,2,3-trichloropropane to rats induced benign and malignant neoplasms of the oral mucosa (pharynx and tongue), forestomach, and preputial and clitoral glands in males and females; benign neoplasms of the exocrine pancreas and kidney in males, and malignant neoplasms of the mammary gland in females. The incidences of squamous cell papillomas and carcinomas of the oral mucosa were significantly increased in 10 and 30 mg/kg rats, while the incidences of squamous cell papillomas or carcinomas (combined) of the forestomach were significantly increased in all dosed groups. The incidence of pancreatic acinar adenoma was significantly increased in dosed males, but not in dosed females. Similarly, the incidence of adenoma of the kidney was significantly increased in 10 and 30 mg/kg male rats only. The incidences of adenoma or carcinoma (combined) of the preputial gland in 30 mg/kg males and of the clitoral gland in 10 and 30 mg/kg females (homologous organs) were significantly increased. The incidence of adenocarcinoma of the mammary gland was significantly increased in the 10 and 30 mg/kg females. The incidences of Zymbal's gland carcinomas were increased in 30 mg/kg males and females. Adenocarcinomas of the intestine occurred in small numbers of dosed rats and may have been chemical related. In mice, the incidence of squamous cell carcinoma of the oral mucosa was significantly increased only in 60 mg/kg females. In contrast, the incidences of squamous cell papilloma and carcinoma of the forestomach were significantly increased in all groups of dosed mice. The incidences of hepatocellular adenoma or carcinoma (combined) were significantly increased in all dosed groups of males and 60 mg/kg females. The incidences of harderian gland adenoma were significantly increased in 20 mg/kg males and in 60 mg/kg males and females. The incidences of uterine adenoma, adenocarcinoma, and stromal polyp were significantly increased in 60 mg/kg females. Genetic Toxicology: 1,2,3-Trichloropropane was mutagenic in vitro in the presence of S9 metabolic activation. At two laboratories, positive responses were obtained for mutagenicity in Salmonella typhimurium strains TA97, TA98, TA100, and TA1535 in the presence of S9; no mutagenic activity was observed in TA1537, with or without S9. 1,2,3-Trichloropropane induced trifluorothymidine resistance in L5178Y mouse lymphoma cells with, but not without, S9. In cultured Chinese hamster ovary cells, sister chromatid exchanges and chromosomal aberrations were induced by 1,2,3-trichloropropane; however, significant increases in the endpoints of both cytogenetic effects occurred only in the presence of S9. Conclusions: Under the conditions of these 2-year gavage studies, there was clear evidence of carcinogenic activity of 1,2,3-trichloropropane in male F344/N rats based on increased incidences of squamous cell papillomas and carcinomas of the oral mucosa and forestomach, adenomas of the pancreas and kidney, adenomas or carcinomas of the preputial gland, and carcinomas of the Zymbal's gland. Adenomatous polyps and adenocarcinomas of the intestine may have been related to chemical administration. There was clear evidence of carcinogenic activity of 1,2,3-trichloropropane in female F344/N rats based on increased incidences of squamous cell papillomas and carcinomas of the oral mucosa and forestomach, adenomas or carcinomas of the clitoral gland, adenocarcinomas of the mammary gland, and carcinomas of the Zymbal's gland. Adenocarcinomas of the intestine may have been related to chemical administration. There was clear evidence of carcinogenic activity of 1,2,3-trichloropropane in male B6C3F1 mice based on increased incidences of squamous cell papillomas and carcinomas of the forestomach, hepatocellular adenomas or carcinomas of the liver, and harderian gland adenomas. Squamous cell papillomas of the oral mucosa may have been related to chemical administration. There was clear evidence of carcinogenic activity of 1,2,3-trichloropropane in female B6C3F1, mice based on increased incidences of squamous cell carcinomas of the oral mucosa, squamous cell papillomas and carcinomas of the forestomach, hepatocellular adenomas or carcinomas of the liver, harderian gland adenomas, and uterine adenomas, adenocarcinomas, and stromal polyps. Nonneoplastic lesions associated with exposure to 1,2,3-trichloropropane included increased severity of nephropathy in male rats and increased incidences of basal cell and squamous hyperplasia of the forestomach, acinar hyperplasia of the pancreas, renal tubule hyperplasia, and preputial or clitoral gland hyperplasia in male and female rats. Increased incidences of squamous hyperplasia of the forestomach and eosinophilic foci in the liver in male and female mice were chemical related. Synonyms: Allyl trichloride, glycerol tnchlorohydrin, glyceryl tnchlorohydrin, trichlorohydrin

Journal Article↗
PubMed1996

NTP Toxicology and Carcinogenesis Studies of 1-Amino-2,4-Dibromoanthraquinone (CAS No. 81-49-2) in F344/N Rats and B6C3F1 Mice (Feed Studies).

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

Journal Article↗
PubMed1990

NTP Toxicology and Carcinogenesis Studies of d-Carvone (CAS No. 2244-16-8) in B6C3F1 Mice (Gavage Studies).

d-Carvone occurs naturally in caraway and dill seeds and in many essential oils; it has been used as a carminative and in perfumes and soaps. Toxicity and carcinogenesis studies were conducted by administering d-carvone (approximately 96% pure) in corn oil by gavage to groups of male and female B6C3F1 mice for 16 days, 13 weeks, or 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium and Chinese hamster ovary (CHO) cells. Sixteen-Day Studies: All mice that received 1,600 or 3,500 mg/kg died within 7 days. Relative liver weights were increased for dosed male mice, and relative thymus weights were decreased for dosed female mice. No compound-related lesions were observed. Thirteen-Week Studies: All male mice and 9/10 female mice that received the top dose of 1,500 mg/kg died before the end of the studies. No compound-related histopathologic changes were observed. Based on survival at the high doses in the 13-week studies, 2-year NTP Toxicology and Carcinogenesis studies were conducted by administering d-carvone in corn oil by gavage to groups of 50 male and 50 female mice at doses of 375 or 750 mg/kg, 5 days per week for 103 weeks. Two-Year Studies: Mean body weights of dosed and vehicle control mice were similar throughout the studies. Survival of dosed male mice was similar to that of vehicle controls (vehicle control, 37/50; low dose, 42/50; high dose, 36/50); survival of dosed female mice was greater than that of vehicle control female mice (14/50; 29/50; 38/50). Apparently, abscesses in the urogenital system caused the early deaths of many vehicle control female mice. No neoplastic lesions attributed to d-carvone dosing were observed in mice. Genetic Toxicology: d-Carvone was not mutagenic in S. typhimurium but induced sister chromatid exchanges and chromosomal aberrations in CHO cells. Conclusions: Under the conditions of these 2-year gavage studies, there was no evidence of carcinogenic activity of d-carvone for male or female B6C3F1 mice administered 375 or 750 mg/kg, 5 days per week for 2 years. Synonyms for d-carvone: (+)-carvone; d(+)-carvone; (S)-carvone; (S)-(+)carvone; (S)-2-methyl-5-(1-methylethenyl)-2-cyclohexen-1-one; (S)-d-p-mentha-6-8,(9)-dien-2-one; (S)-(+)-p-mentha-6,8-dien-2-one; d-1-methyl-4-isopropenyl-6-cyclohexen-2-one. Carvol is a synonym for carvone (d, l not specified)

Journal Article↗
PubMed1989

Toxicology and Carcinogenesis Studies of Bromoethane (Ethyl Bromide) (CAS No. 74-96-4) in F344/N Rats and B6C3F1 Mice (Inhalation Studies).

Bromoethane is an alkylating agent used primarily as a chemical intermediate in various organic syntheses. In toxicology and carcinogenesis studies, groups of F344/N rats and B6C3F1 mice of each sex received whole-body exposure to bromoethane (greater than 98% pure) once for 4 hours or for 6 hours per day, 5 days per week, for 14 days, 14 weeks, or 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium and Chinese hamster ovary (CHO) cells. Single-Exposure, Fourteen-Day, and Fourteen-Week Studies: Single-exposure inhalation studies were conducted in rats and mice at target concentrations of 625, 1,250, 2,500, 5,000, or 10,000 ppm bromoethane. All rats exposed to 10,000 ppm bromoethane and 3/5 female rats exposed to 5,000 ppm died before the end of the single-exposure studies. All mice exposed to 5,000 or 10,000 ppm bromoethane and 2/5 female mice exposed to 1,250 ppm died before the end of the studies. Fourteen-day inhalation studies were conducted in rats and mice at target concentrations of 0, 250, 500, 1,000, 2,000, or 4,000 ppm bromoethane. All rats and mice exposed to 2,000 or 4,000 ppm died before the end of the 14-day studies. Final mean body weights of exposed and control rats were similar. Fourteen-week inhalation studies were conducted in rats and mice at target concentrations of 0, 100, 200, 400, 800, or 1,600 ppm bromoethane. Four of 10 male and 2/10 female rats exposed to 1,600 ppm died before the end of the 14-week studies. The final mean body weights of rats exposed to 1,600 ppm were lower than the initial mean body weights. Compound-related lesions observed in rats at 1,600 ppm, but not at lower concentrations, included minimal atrophy of the thigh muscle, minimal-to-moderate multifocal mineralization in the cerebellum of the brain, minimal-to-severe hemosiderosis of the spleen, marked atrophy of the testis, and minimal-to- mild atrophy of the uterus. The effects in the testis and uterus are probably due to chemical-related loss in body weight during the studies. In mice, compound-related deaths included 3/10 male and 1/10 female mice exposed to 1,600 ppm, 1/9 males exposed to 800 ppm, and 1/10 males exposed to 400 ppm. The final mean body weights of male and female mice exposed to 1,600 ppm were about 15% lower than those of controls. Compound-related effects included atrophy of the uterus and involution of the ovary in females exposed to 1,600 ppm bromoethane. Based on these results, 2-year studies were conducted by exposing groups of 49 or 50 rats or mice of each sex to bromoethane at 0, 100, 200, or 400 ppm, 6 hours per day, 5 days per week. Body Weight and Survival in the Two-Year Studies: Mean body weights of exposed and control rats were generally similar throughout the studies. No significant differences in survival were observed between any groups of male rats (control, 17/49; 100 ppm, 26/50; 200 ppm, 27/50; 400 ppm, 21/50); survival of the 100-ppm group of female rats was greater than that of controls (19/50; 29/50; 24/49; 23/50), and the number of control and 400-ppm male rats and control female rats surviving to the end of the studies was low. Mean body weights of the 400-ppm group of male mice were up to 9% lower than those of controls throughout the study. Mean body weights of the 400-ppm group of female mice were generally 6%-16% lower than those of controls after week 29. No differences in survival were observed between any group of male mice (35/50; 37/50; 30/50; 34/50). The survival of the 400-ppm group of female mice was lower than that of controls at the end of the study (36/50; 37/50; 37/49; 23/49). Nonneoplastic and Neoplastic Effects in the Two-Year Studies: The incidences of pheochromocytomas or malignant pheochromocytomas (combined) of the adrenal medulla were increased in exposed male rats (control, 8/40; 100 ppm, 23/45; 200 ppm, 18/46; 400 ppm, 21/46). Granular cell neoplasms of the brain were seen in exposed male rats but not in controls (0/49; 3/50; 1/50; 1/50). A glioma, an astrocytoma, or an oligodendroglioma was seen in 3/50 male rats exposed to 100 p in 3/50 male rats exposed to 100 ppm. Gliomas were not observed in control female rats, but they occurred in exposed female rats with a significant positive trend (0/50; 1/50; 1/48; 3/50). The historical incidence of granular cell tumors in male F344/N rat chamber controls at the study laboratory is 0/297. The incidences of gliomas in the exposed female groups were not significantly greater than that in the controls and were within the historical incidence range for glial cell neoplasms for untreated controls in NTP studies (mean: 23/1,969, 1%; range: 0/50-3/50), but they exceeded the historical incidence range for chamber controls at the study laboratory (mean: 1/297, 0.3%; range: 0/50-1/50). Alveolar epithelial hyperplasia was increased in rats exposed to 400 ppm bromoethane (male: 3/48; 7/49; 7/48; 18/48; female: 5/50; 4/48; 5/47; 10/49). Alveolar/bronchiolar adenomas or carcinomas (combined) were seen in four male rats exposed to 200 ppm and in one exposed to 400 ppm. Alveolar/bronchiolar adenomas were observed in 3/49 female rats at 400 ppm but not at lower concentrations or in controls. The incidences in exposed male and female rats were not significantly greater than those in controls; however, the historical incidence in rat chamber controls for alveolar/bronchiolar adenomas or carcinomas (combined) at the study laboratory is 6/299 (2%) for males and 4/297 (1.3%) for females. The incidences of epithelial hyperplasia and squamous metaplasia of the nasal cavity were increased in rats exposed to 400 ppm. The incidence of suppurative inflammation of the nasal cavity was increased in exposed male rats, and the incidences of suppurative inflammation of the larynx and metaplasia of the olfactory sensory epithelium were increased in exposed male and female rats. An adenoma of the nose was seen in one 400-ppm male rat and in one 400-ppm female mouse. Suppurative inflammation and dilatation of the salivary gland ducts were observed at increased incidences in the 200- and 400-ppm groups of female rats. Animals were found to be positive for rat coronavirus/sialodacryoadenitis virus antibodies. The incidence of mammary gland neoplasms was significantly lower in female rats at 400 ppm than in controls (18/50; 15/50; 10/48; 7/50). Adenomas (0/50; 1/50; 1/47; 6/48), adenocarcinomas (0/50; 2/50; 3/47; 19/48), and squamous cell carcinomas (0/50; 1/50; 1/47; 3/48) of the uterus occurred in exposed female mice and not in control mice. The incidence of alveolar/bronchiolar neoplasms was greater in male mice at 400 ppm than in controls (adenomas or carcinomas, combined: 7/50; 6/50; 12/50; 15/50). Acute/chronic inflammation of the lung was observed at increased incidences in female mice at 200 and 400 ppm. Genetic Toxicology: Bromoethane, tested in a closed environment of a desiccator, was mutagenic in S. typhimurium strain TA100 with and without exogenous metabolic activation; it was not mutagenic in strain TA98. In cultured CHO cells, bromoethane induced sister chromatid exchanges (SCEs) but not chromosomal aberrations in both the presence and absence of exogenous metabolic activation. Conclusions: Under the conditions of these 2-year inhalation studies, there was some evidence of carcinogenic activity of bromoethane for male F344/N rats, as indicated by increased incidences of pheochromocytomas of the adrenal gland; neoplasms of the brain and lung may also have been related to exposure to bromoethane. For female F344/N rats, there was equivocal evidence of carcinogenic activity, as indicated by marginally increased incidences of neoplasms of the brain and lung. For male B6C3F1 mice, there was equivocal evidence of carcinogenic activity, based on marginally increased incidences of neoplasms of the lung. There was clear evidence of carcinogenic activity for female B6C3F1 mice, as indicated by neoplasms of the uterus. Synonyms: monobromoethane; bromic ether; hydrobromic ether

Journal Article↗
PubMed1989

Toxicology and Carcinogenesis Studies of Hexachloroethane (CAS No. 67-72-1) in F344/N Rats (Gavage Studies).

Hexachloroethane is used in organic synthesis as a retarding agent in fermentation, as a camphor substitute in nitrocellulose, in pyrotechnics and smoke devices, in explosives, and as a solvent. In previous long-term gavage studies with B6C3F1 mice and Osbourne-Mendel rats (78 weeks of exposure followed by 12-34 weeks of observation), hexachloroethane caused increased incidences of hepatocellular carcinomas in mice. However, survival of low and high dose rats was reduced compared with that of vehicle controls, and the effects on rats were inconclusive. Therefore, additional toxicology and carcinogenesis studies were conducted in F344/N rats by administering hexachloroethane (approximately 99% pure) in corn oil by gavage to groups of males and females for 16 days, 13 weeks, or 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium and in Chinese hamster ovary (CHO) cells. Urinalysis was performed in conjunction with the 13-week studies. Sixteen-Day Studies: In the 16-day studies (dose range, 187-3,000 mg/kg), all rats that received 1,500 or 3,000 mg/kg and 1/5 males and 2/5 females that received 750 mg/kg died before the end of the studies. Final mean body weights of rats that received 750 mg/kg were 25% lower than that of vehicle controls for males and 37% lower for females. Compound-related clinical signs seen at 750 mg/kg or more included dyspnea, ataxia, prostration, and excessive lacrimation. Other compound-related effects included hyaline droplet formation in the tubular epithelial cells in all dosed males and tubular cell regeneration and granular casts in the tubules at the corticomedullary junction in the kidney in males receiving 187 and 375 mg/kg. Thirteen-Week Studies: In the 13-week studies (dose range, 47-750 mg/kg), 5/10 male rats and 2/10 female rats that received 750 mg/kg died before the end of the studies. The final mean body weight of male rats that received 750 mg/kg was 19% lower than that of vehicle controls. Compound-related clinical signs for both sexes included hyperactivity at doses of 94 mg/kg or higher and convulsions at doses of 375 or 750 mg/kg. The relative weights of liver, heart, and kidney were increased for exposed males and females. Kidney lesions were seen in all dosed male groups, and the severity increased with dose. Papillary necrosis and tubular cell necrosis and degeneration in the kidney and hemorrhagic necrosis in the urinary bladder were observed in the five male rats that received 750 mg/kg and died before the end of the studies; at all lower doses, hyaline droplets, tubular regeneration, and granular casts were present in the kidney. No chemical-related kidney lesions were observed in females. Foci of hepatocellular necrosis were observed in several male and female rats at doses of 188 mg/kg or higher. Dose selection for the 2-year studies was based primarily on the lesions of the kidney in males and of the liver in females. Studies were conducted by administering hexachloroethane in corn oil by gavage at 0, 10, or 20 mg/kg body weight, 5 days per week, to groups of 50 male rats. Groups of 50 female rats were administered 0, 80, or 160 mg/kg on the same schedule. Body Weight and Survival in the Two-Year Studies: Mean body weights of high dose rats were slightly (5%-9%) lower than those of vehicle controls toward the end of the studies. No significant differences in survival were observed between any groups of rats (male: vehicle control, 31/50; 10 mg/kg, 29/50; 20 mg/kg, 26/50; female: vehicle control, 32/50; 80 mg/kg, 27/50; 160 mg/kg, 32/50). Nonneoplastic and Neoplastic Effects in the Two-Year Studies: Incidences of kidney mineralization (vehicle control, 2/50; low dose, 15/50; high dose, 32/50) and hyperplasia of the pelvic transitional epithelium (0/50; 7/50; 7/50) were increased in dosed male rats. Renal tubule hyperplasia was observed at an increased incidence in high dose male rats (2/50; 4/50; 11/50). These lesions have been described as characteristic of the hyaline droplet nephropathy that is associated with an accumulation of liver-generateted with an accumulation of liver-generated a2μ-globulin in the cytoplasm of tubular epithelial cells. The severity of nephropathy was increased in high dose male rats (moderate vs. mild), and the incidences and severity of nephropathy were increased in dosed females (22/50; 42/50; 45/50). The incidences of adenomas (1/50; 2/50; 4/50), carcinomas (0/50; 0/50; 3/50), and adenomas or carcinomas (combined) (1/50; 2/50; 7/50) of the renal tubule were also increased in the high dose male group. One of the carcinomas in the high dose group metastasized to the lung. No compound-related neoplasms were observed in females. The incidence of pheochromocytomas of the adrenal gland in low dose male rats was significantly greater than that in vehicle controls (15/50; 28/50; 21/49), and the incidences for both dosed groups were greater than the mean historical control incidence (28% ± 11%). Genetic Toxicology: Hexachloroethane was not mutagenic in S. typhimurium strains TA98, TA100, TA1535, or TA1537 when tested with and without exogenous metabolic activation. In CHO cells, hexachloroethane did not induce chromosomal aberrations with or with out metabolic activation but did produce sister chromatid exchanges in the presence of exogenous metabolic activation. Audit: The data, documents, and pathology materials from the 2-year studies of hexachloroethane have been audited. The audit findings show that the conduct of the studies is documented adequately and support the data and results given in this Technical Report. Conclusions: Under the conditions of these 2-year gavage studies, there was clear evidence of carcinogenic activity of hexachloroethane for male F344/N rats, based on the increased incidences of renal neoplasms. The marginally increased incidences of pheochromocytomas of the adrenal gland may have been related to hexachloroethane administration to male rats. There was no evidence of carcinogenic activity of hexachloroethane for female F344/N rats administered 80 or 160 mg/kg by gavage for 103 weeks. The severity of nephropathy and incidences of linear mineralization of the renal papillae and hyperplasia of the transitional epithelium of the renal pelvis were increased in dosed male rats. The incidences and severity of nephropathy were increased in dosed female rats. Synonyms: carbon hexachloride; ethane hexachloride; hexachlorethane; hexachloroethylene; 1,1,1,2,2,2-hexachloroethane; perchloroethane Trade Names: Avlothane; Distokal; Distopan; Distopin; Egitol; Falkitol; Fasciolin; Mottenhexe; Phenohep

Journal Article↗
PubMed1989

Toxicology and Carcinogenesis Studies of N,N-Dimethylaniline (CAS No. 121-69-7) in F344/N Rats and B6C3F1 Mice (Gavage Studies).

N,N-Dimethylaniline is used as a chemical intermediate in the synthesis of dyestuffs. Toxicology and carcinogenesis studies were conducted by administering N,N-dimethylaniline (greater than 98% pure) in corn oil by gavage to groups of F344/N rats and B6C3F1 mice of each sex for 2 weeks, 13 weeks, or 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium, mouse lymphoma cells, and Chinese hamster ovary (CHO) cells. Two-Week and Thirteen-Week Studies: In the 2-week studies, doses were 94-1,500 mg/kg; deaths of rats and mice were observed in groups given doses of 750 or 1,500 mg/kg. The final mean body weights of male rats that received 375 or 750 mg/kg were 15% or 47% lower than that of vehicle controls; final mean body weights of other groups of rats and mice were similar to those of vehicle controls. Compound-related clinical signs observed included cyanosis in rats and lethargy and tremors in rats and mice. Splenomegaly occurred in nearly all dosed groups of rats and mice, and the incidences were dose related. In the 13-week studies, doses were 32-500 mg/kg; no compound-related deaths occurred. The final mean body weights of male rats that received 250 or 500 mg/kg were 15% or 27% lower than that of vehicle controls. The final mean body weights of all groups of dosed female rats and male and female mice were within 12% of those of vehicle controls. Compound-related clinical signs included lethargy in rats and mice and cyanosis in rats. Splenomegaly was observed in all dosed groups of rats and mice; the severity was dose related. Compound-related extramedullary hematopoiesis and hemosiderosis occurred in the kidney or testis of dosed rats and liver and spleen of dosed rats and mice. Two-year studies were conducted by administering 0, 3, or 30 mg/kg N,N-dimethylaniline in corn oil by gavage, 5 days per week for 103 weeks, to groups of 50 rats of each sex. The lower dose was selected to be one-tenth the higher dose to increase the likelihood that one dose would cause only a minimal nonneoplastic response. Groups of 50 mice of each sex were administered 0, 15, or 30 mg/kg on the same schedule. Body Weight and Survival in the Two-Year Studies: Mean body weights of vehicle control and dosed rats and mice were similar throughout the studies. Survival rates of all respective groups were similar after 2 years, except for the lowered survival of vehicle control female rats (vehicle control, 21/50; low dose 32/50; high dose, 36/50). This may reflect the large number (24/50) of vehicle control female rats killed when observed to be in a moribund state. Final survival for other groups was as follows: male rats--29/50; 32/50; 28/50; male mice-- 34/50; 30/50; 34/50; female mice--35/50; 39/50; 33/50. Nonneoplastic and Neoplastic Effects in the Two-Year Studies: In these 2-year studies, the spleen was the expected site of chemical-related effects. Fatty metamorphosis and fibrosis in the spleen of high dose male rats were increased (fatty metamorphosis: vehicle control, 0/49; low dose, 1/49; high dose, 10/50; fibrosis: 5/49; 2/49; 22/50). Splenic hemosiderosis and hematopoiesis were present at an incidence greater than 85% in all groups of rats; however, the severity of the lesions was greater in dosed groups than in vehicle controls. Sarcomas of the spleen were seen in 3/50 high dose male rats, and an osteosarcoma was seen in another high dose male rat. One additional high dose male rat had a sarcoma of the thymus. Splenic sarcomas are uncommon in corn oil vehicle control male F344/N rats (NTP historical incidence 3/2,081, 0.1%), and thus, these neoplasms in high dose male rats (4/50, 8%) were considered to be chemically related. Lower incidences of mononuclear cell leukemia (which apparently originates in the spleen) were seen in dosed male and female rats than in vehicle controls (male: 13/50; 4/50; 3/50; female: 11/50; 7/50; 0/50). The incidence of squamous cell papillomas of the forestomach in high dose female mice was marginally greater than that in vehicle controls (2/50; 2/50; 8/50). No malignant forestomacin vehicle controls (2/50; 2/50; 8/50). No malignant forestomach neoplasms were observed. Genetic Toxicology: N,N-Dimethylaniline was not mutagenic in S. typhimurium strains TA98, TA100, TA1535, or TA1537 in the presence or absence of exogenous metabolic activation. In the mouse lymphoma assay, N,N-dimethylaniline produced a positive response with and without metabolic activation. In CHO cells, N,N-dimethylaniline induced both sister chromatid exchanges (SCEs) and chromosomal aberrations in the presence of exogenous metabolic activation. Without activation, an increase in chromosomal aberrations was observed, but no increase in SCEs occurred. Conclusions: Under the conditions of these 2-year gavage studies, there was some evidence of carcinogenic activity of N,N-dimethylaniline for male F344/N rats, as indicated by the increased incidences of sarcomas or osteosarcomas(combined) of the spleen. There was no evidence of carcinogenic activity of N,N-dimethylaniline for female F344/N rats given 3 or 30 mg/kg body weight by gavage for 2 years. There was no evidence of carcinogenic activity of N,N-dimethylaniline for male B6C3F1 mice given 15 or 30 mg/kg body weight by gavage for 2 years. There was equivocal evidence of carcinogenic activity of N,N-dimethylaniline for female B6C3F1 mice, as indicated by an increased incidence of squamous cell papillomas of the forestomach. Both rats and mice could have tolerated doses higher than those used in these studies. There were decreased incidences of mononuclear cell leukemia in dosed male and high dose female rats. Compound-related splenic fibrosis, hemosiderosis, and fatty metamorphosis were increased in male rats. Synonyms: dimethylaminobenzene; N,N-dimethylbenzeneamine; dimethylaniline; dimethylphenylamine; N,N-dimethylphenylamine

Journal Article↗
PubMed1989

Toxicology and Carcinogenesis Studies of 8-Methoxypsoralen (CAS No. 298-81-7) in F344/N Rats (Gavage Studies).

Oral administration of 8-methoxypsoralen followed by exposure to longwave ultraviolet light (primarily ultraviolet A, 320-400 nm) is used in the treatment of vitiligo and psoriasis. 8-Methoxypsoralen also occurs naturally in a variety of vegetables. Toxicology and carcinogenesis studies of 8-methoxypsoralen without ultraviolet A were conducted by administering USP-grade 8-methoxypsoralen (99% pure) in corn oil by gavage to groups of F344/N rats once or for 16 days, 13 weeks, or 2 years. In vitro genetic toxicology tests were performed with bacteria and mammalian cells. Single-Administration, Sixteen-Day, and Thirteen-Week Studies: In the single-administration studies, the chemical was administered at doses of 0 and 63-1,000 mg/kg. Four of five male rats and 5/5 female rats that received 1,000 mg/kg 8-methoxypsoralen died within 2 days. In the 16-day studies, the chemical was administered at doses of 0 and 50-800 mg/kg. All rats receiving 800 mg/kg died within 5 days, and one male and one female at 400 mg/kg and one female at 200 mg/kg also died before the end of the studies. The final mean body weights of animals at 200 or 400 mg/kg were 14% or 30% lower than those of vehicle controls. No compound-related effects were observed at necropsy. In the 13-week studies, the chemical was administered at doses of 0 and 25-400 mg/kg. Six of 10 male rats and 8/10 female rats that received 400 mg/kg died before the end of the studies. The final mean body weight of male rats that received 100, 200, or 400 mg/kg was 12%, 22%, or 45% lower than that of vehicle controls. The final mean body weight of female rats that received 200 or 400 mg/kg was 15% or 35% lower than that of vehicle controls. The liver weight to body weight ratios for all dosed groups of rats except the lowest (25 mg/kg) were greater than those for vehicle controls. Compound-related effects included fatty change in the liver in males and females and atrophy of the testis, seminal vesicles, and prostate. Based on these results, 2-year studies were conducted by administering 0, 37.5 or 75 mg/kg 8-methoxypsoralen in corn oil by gavage, 5 days per week for 103 weeks, to groups of 50 F344/N rats of each sex. Body Weight and Survival in the Two-Year Studies: The mean body weights of dosed male rats were generally 3%-14% lower than those of vehicle controls, and the mean body weights of high dose female rats were 5%-17% lower. The survival of both the low and the high dose groups of male rats was lower than that of the vehicle controls (male: vehicle control, 30/50; low dose, 16/50; high dose, 16/50; female: 39/50; 33/50; 36/50), likely because of kidney toxicity and neoplasia. Nonneoplastic and Neoplastic Effects in the Two-Year Studies: Mineralization of the renal papilla was observed in high dose male rats (vehicle control, 0/50; low dose, 0/50; high dose, 31/49). The severity of nephropathy was increased in dosed male rats. Focal hyperplasia of renal tubular cells was observed in dosed male rats (0/50; 8/50; 8/49). The incidences of tubular cell adenomas (1/50; 11/50; 8/49), adenocarcinomas (0/50; 1/50; 3/49), and adenomas or adenocarcinomas (combined) (1/50; 12/50; 11/49) were increased in dosed male rats. Hyperplasia of the parathyroid glands (2/49; 22/47; 18/48) and fibrous osteodystrophy (2/50; 10/50; 12/49) in male rats were secondary to chronic nephropathy. The incidences of carcinomas or squamous cell carcinomas (combined) of the Zymbal gland were increased in dosed male rats (1/50; 7/50; 4/49). The mean historical incidence for carcinomas or squamous cell carcinomas (combined) in corn oil vehicle control male F344/N rats is 0.8% (16/1,949); the highest incidence in any one group is 4% (2/49). Fibromas of the subcutaneous tissue in male rats occurred with a positive trend (1/50; 5/50; 7/49). An additional high dose male had a sarcoma. The mean historical incidence of fibromas or fibrosarcomas (combined) of subcutaneous tissue in corn oil vehicle control male F344/N rats is 9% (171/1,949). Alveolar/bronchiolar adenomas occurred with a positive trend in male rats (4ts is 9% (171/1,949). Alveolar/bronchiolar adenomas occurred with a positive trend in male rats (4/50; 9/50; 9/49). The mean historical incidence of alveolar/bronchiolar neoplasms in corn oil vehicle control male F344/N rats is 3% (68/1,944); the highest incidence is 10% (5/50). Chronic inflammation, ulcers, and epithelial hyperplasia of the forestomach were observed at increased incidences in dosed male rats (chronic inflammation: 1/50; 6/50; 5/49; ulcers: 5/50; 13/50; 11/49; epithelial hyperplasia: 4/50; 19/50; 20/49). Squamous cell papillomas were observed in two low dose male rats. Squamous cell papillomas were observed in the palate or tongue of one low dose and three high dose female rats; none were observed in vehicle controls. These papillomas were not considered to be related to chemical administration. Diffuse hypertrophy of the thyroid gland was observed at increased incidences in dosed male rats (2/50; 31/50; 39/49). Genetic Toxicology: 8-Methoxypsoralen was mutagenic in Salmonella typhimurium strain TA104 in the presence and absence of activation and in strains TA98, TA100, and TA102 when tests were conducted with exogenous metabolic activation; 8-methoxypsoralen was not mutagenic with or without activation in strain TA1535. Treatment with 8-methoxypsoralen induced both sister chromatid exchanges (SCEs) and chromosomal aberrations in Chinese hamster ovary (CHO) cells in the absence of exogenous metabolic activation; in the presence of activation, in the presence of activation, induction of SCEs occurred, but no significant increases in chromosomal aberrations was observed. Audit: The data, documents, and pathology materials from the 2-year studies of 8-methoxypsoralen have been audited at the NTP Archives. The audit findings show that the conduct of the studies is documented adequately and support the data and results given in this Technical Report. Conclusions: Under the conditions of these 2-year gavage studies, there was clear evidence of carcinogenic activity of 8-methoxypsoralen (without ultraviolet radiation) for male F344/N rats, as shown by increased incidences of tubular cell hyperplasia, adenomas, and adenocarcinomas of the kidney and carcinomas of the Zymbal gland. Subcutaneous tissue fibromas and alveolar/bronchiolar adenomas of the lung in male F344/N rats may have been related to chemical administration. Dose-related nonneoplastic lesions in male F344/N rats included increased severity of nephropathy and mineralization of the kidney and forestomach lesions. There was no evidence of carcinogenic activity of 8-methoxypsoralen for female F344/N rats given the chemical at 37.5 or 75 mg/kg per day for 2 years. Synonyms: 9-methoxy-7H-furo[3,2-g]benzopyran-7-one; 6-hydroxy-7-methoxy-5-benzofuranacrylic acid d-lactone; 8-MP; 8-MOP; 8-methoxy-(furano-3',2':6,7-coumarin); 8-methoxy-4',5':6,7-furocoumarin; 9-methoxypsoralen; 8-methoxypsoralene; methoxsalen; oxypsoralen Trade Names: Ammoidin; Meladinin (VAN); Meladinine; Meladoxen; Meloxine; Methoxa-Dome; Mopsoralen; Oxsoralen; Soloxsalen; Trioxun; Xanthotoxin; Xanthotoxine

Journal Article↗
PubMed1989

Toxicology and Carcinogenesis Studies of Ochratoxin A (CAS No. 303-47-9) in F344/N Rats (Gavage Studies).

Ochratoxin A is a naturally occurring fungal toxin that is a contaminant in corn, peanuts, storage grains, cottonseed, meats, dried fish, and nuts. Toxicology and carcinogenesis studies were conducted by administering ochratoxin A (98% pure) in corn oil by gavage to groups of F344/N rats of each sex for 16 days, 13 weeks, 9 months, 15 months, or 2 years. Only rats were studied because ochratoxin A has been shown to be carcinogenic in mice. Genetic toxicology tests were performed with bacterial and mammalian cells. Urinalysis, hematologic and serum chemical analyses, and bone marrow cellularity determinations were conducted at 9, 15, and 24 months in the 2-year studies. Sixteen-Day and Thirteen-Week Studies: Rats were administered 0, 1, 4, or 16 mg/kg ochratoxin A in corn oil by gavage 5 days per week for a total of 12 doses over 16 days. All rats that received 16 mg/kg ochratoxin A died within 6 days. Rats that received 4 mg/kg lost weight. Compound-related lesions in rats included bone marrow hyperplasia, thymic atrophy, necrosis and hyperplasia of the forestomach epithelium, renal tubular cell degenerative and regenerative changes (nephropathy), and adrenal gland hemorrhage. Renal tubular changes were most severe in animals that received 4 mg/kg. Rats that received 16 mg/kg had less severe renal lesions than those at 4 mg/kg, perhaps because the acute toxicity and early death did not allow sufficient time for full development of lesions. No compound-related deaths occurred in the 13-week studies (doses were 0 and 0.0625 to 1 mg/kg). The final mean body weight of rats that received 0.25, 0.5, or 1 mg/kg was 7%, 11%, or 19% lower than that of vehicle controls for males and 3%, 4%, or 9% lower for females. Compound-related lesions in the kidney were characterized as degeneration and regeneration of the epithelium of the proximal convoluted tubules with individual cell necrosis of moderate severity (see page 3 of the Technical Report). Karyomegaly of tubular epithelial cells was widespread but most pronounced in the straight portion of the tubules just above the corticomedullary junction. Karyomegaly was present in all dosed groups, and the severity increased as the dose increased. At lower doses, atrophy of the straight portions of the tubules at the corticomedullary junction and in the medulla was observed. Based on mortality and on the presence and severity of renal lesions, groups of 80 rats per sex and dose group were administered 0, 21, 70, or 210 ug/kg ochratoxin A in corn oil by gavage 5 days per week for up to 2 years. Groups of 15 rats per sex and dose were killed at 9 or at 15 months and the remaining animals at 2 years. Nine-Month and Fifteen-Month Studies: Administration of ochratoxin A by gavage for 9 months or 15 months to F344/N rats was associated with increased incidences of renal tubular cell neoplasms in males and hyperplasia, degeneration, and karyomegaly of renal tubular epithelial cells in both males and females (see page 4 of the Technical Report). Body Weight and Survival in the Two-Year Studies: Mean body weights of high dose rats were generally 4%-7% lower than those of vehicle controls. No significant differences in survival were observed between any groups of female rats (vehicle control, 32/50; low dose, 23/51; mid dose, 35/50; high dose, 34/50). Survival was decreased after 77 weeks in high dose male rats and after 96 weeks in low and mid dose male rats (39/50; 26/51; 26/51; 23/50). Clinical Pathology: Minor differences were observed for hematologic values between dosed and vehicle control animals, but these were not considered to be of biologic significance. Results of serum chemistry analysis were not clearly compound related. Ochratoxin A-dosed animals had slight increases compared with vehicle controls in urine volume and decreases in urine specific gravity in concentration tests, suggesting that exposure resulted in mild to moderate decreases in the ability to concentrate urine. Nonneoplastic and Neoplastic Effects in the Two-Year Studies: A spectrum of degenerative and proliferative cho-Year Studies: A spectrum of degenerative and proliferative changes occurred in the kidney of male and female rats given ochratoxin A for 2 years. Degeneration of the renal tubular epithelium with formation of tubular cysts, proliferation of the tubular epithelium, and karyomegaly of the nuclei of tubular epithelial cells occurred at increased incidences in dosed rats (see page 5 of the Technical Report). Hyperplasia of the renal tubular epithelium and renal tubular adenomas and carcinomas also occurred at increased incidences in the dosed rats; the tumors were frequently multiple within a single kidney or were bilateral, and many metastasized to other organs. The incidence of fibroadenomas of the mammary gland in high dose female rats was significantly greater than that in vehicle controls (vehicle control, 17/50; low dose, 23/51; mid dose, 22/50; high dose, 28/50). Multiple fibroadenomas of the mammary gland were observed at an increased incidence in high dose female rats (4/50; 4/51; 5/50; 14/50). One mammary gland adenoma was seen in a mid dose female, and two mammary gland adenocarcinomas were seen in each dosed group; one adenocarcinoma was seen in the vehicle control group. An adenoma of the pars intermedia of the pituitary gland was observed in one mid dose female rat, and a carcinoma was observed in a second mid dose female rat. Squamous cell papillomas of the tongue were seen in two low dose and two mid dose male rats. Neither the pituitary neoplasms nor the papillomas of the tongue were considered related to ochratoxin A exposure. Genetic Toxicology: Ochratoxin A was not mutagenic in four strains of Salmonella typhimurium (TA97, TA98, TA100, or TA1535) when tested both with and without exogenous metabolic activation. In cultured Chinese hamster ovary (CHO) cells, ochratoxin A induced sister chromatid exchanges (SCEs) in the presence, but not the absence, of metabolic activation; it did not significantly increase the number of chromosomal aberrations in these cells. Audit: The data, documents, and pathology materials from the 2-year studies of ochratoxin A have been audited. The audit findings show that the conduct of the studies is documented adequately and support the data and results given in this Technical Report. Conclusions: Under the conditions of these 2-year gavage studies, there was clear evidence of carcinogenic activity of ochratoxin A for male F344/N rats as shown by substantially increased incidences of uncommon tubular cell adenomas and of tubular cell carcinomas of the kidney. There was clear evidence of carcinogenic activity for female F344/N rats shown by increased incidences of uncommon tubular cell adenomas and of tubular cell carcinomas of the kidney and by increased incidences and multiplicity of fibroadenomas of the mammary gland. Ochratoxin A administration also caused nonneoplastic renal changes including tubular cell hyperplasia, tubular cell proliferation, cytoplasmic alteration, karyomegaly, and degeneration of the renal tubular epithelium. Synonym: (R)-N-[(5-chloro-3,4-dihydro-8-hydroxy-3-methyl-1-oxo-1H-2-enzopyran-7-yl)-carbonyl](-L-)phenylalanine

Journal Article↗
PubMed1989

Toxicology and Carcinogenesis Studies of Hydrochlorothiazide (CAS No. 58-93-5) in F344/N Rats and B6C3F1 Mice (Feed Studies).

Hydrochlorothiazide is a diuretic active at the distal convoluted tubule and collecting duct. Toxicology and carcinogenesis studies were conducted by feeding diets containing hydrochlorothiazide (USP grade, greater than 98% pure) to groups of F344/N rats and B6C3F1 mice of each sex for 15 days, 13 weeks, 1 year, or 2 years. Additional studies were performed to evaluate teratologic effects in CD(R). rats and CD(R).-1 mice. Genetic toxicology studies were performed with Salmonella, Chinese hamster ovary (CHO) cells, mouse lymphoma cells, and Drosophila. Fifteen-Day and Thirteen-Week Studies: All rats and mice lived to the end of the 15-day studies (dietary concentrations of 0 and 3,125-50,000 ppm). The final mean body weights of all dosed rat groups were 5%-11% lower than those of controls. The final mean body weights of the groups of male mice that received 6,250-50,000 ppm were 10%-14% lower than that of controls. The final mean body weights of dosed and control female mice were similar. Calculi were seen in the urinary bladder of 2/5 male and 2/5 female mice at 50,000 ppm and in 1/5 male and 1/5 female mice at 25,000 ppm. All rats lived to the end of the first 13-week studies (dietary concentrations of 0 and 3,125-50,000 ppm). Final body weights of dosed rats were 7%-16% lower than those of controls. Mineralization in the kidney was observed in all dosed rats and because of this, additional 13-week studies in rats were conducted at lower dietary concentrations. All rats lived to the end of the second 13-week studies (dietary concentrations of 0 and 250-4,000 ppm). The final mean body weights of all dosed rat groups were 5%-10% lower than those of controls. Renal mineralization was dose related and judged to be minimal to mild at the lowest dose. In the 13-week studies in mice, 7/10 males and 1/10 females that received 50,000 ppm hydrochlorothiazide died. The final mean body weights of mice that received 50,000 ppm were 11% lower than those of controls for males and females. Calculi were seen in the urinary bladder of mice that received hydrochlorothiazide at 12,500 ppm and above. Nephrosis occurred with dose-related incidences in mice receiving 12,500 ppm and above. Based on these results, 2-year studies were conducted by feeding diets containing 0, 250, 500, or 2,000 ppm hydrochlorothiazide to groups of 50 male and 50 female rats for 105-106 weeks. Diets containing 0, 2,500, or 5,000 ppm hydrochlorothiazide were fed to groups of 50 male and 50 female mice for 103-104 weeks. Ten additional rats per sex and dose group were placed on study and killed at 1 year for blood-clotting studies and histopathologic examination. Effects in the One-Year Studies: One of 10 female rats in the 1-year study group that received 2,000 ppm died with internal hemorrhage. In addition, evidence of hemorrhage was found in 11 of the 16 dosed female rats that died during the first year of the 2-year study. Hematologic analyses revealed no compound-related effects; however, activated partial thromboplastin times (APTTs) were highly variable and were lengthened in some dosed male rats. No effects on APTTs were seen for females, and no effects on prothrombin times or on the fibrinogen content of plasma were observed for dosed male or female rats. Nephropathy occurred in dosed and control rats, and the severity was judged to be greater in dosed male and high dose female rats. Increased incidences of mild focal renal mineralization were also seen in mid and high dose male rats and dosed female rats. Body Weight and Survival in the Two-Year Studies: Mean body weights of dosed rats were 8%-25% lower than those of controls. Mean body weights of dosed and control mice were similar throughout the studies. No significant differences in survival were observed between rats or mice of either sex (rats-- male: control, 18/50; low dose, 16/50; mid dose, 9/50; high dose, 11/50; female: 31/50; 26/50; 30/50; 27/50; mice--male: control, 43/50; low dose, 42/50; high dose, 43/50; female: 38/50; 40/50; 35/50). Survival of all groups of male rats was low because a lar female: 38/50; 40/50; 35/50). Survival of all groups of male rats was low because a large number of animals were killed in a moribund condition late in the study. The average daily feed consumption by dosed rats was 89%-94% that by controls. The average amount of hydrochlorothiazide consumed per day was approximately 11, 23, or 89 mg/kg for low, mid, or high dose rats. The average daily feed consumption by dosed mice was 100%-105% that by controls. The average amount of hydrochlorothiazide consumed per day was approximately 280 or 575 mg/kg for low dose or high dose mice. Nonneoplastic and Neoplastic Effects in the Two-Year Studies: Nephropathy occurred in nearly all male and female rats, but the severity of this disease was greater in dosed rats, as evidenced by increases in renal cysts and epithelial hyperplasia of the renal pelvis in dosed rats shown in the following table (see page 4 of the Technical Report). Mineralization was observed at increased incidences in dosed male and dosed female rats. Changes associated with or secondary to renal injury were increased in dosed rats. These lesions included parathyroid hyperplasia, fibrous osteodystrophy of bone, and mineralization of multiple organs. Adenomas or carcinomas (combined) of the Zymbal gland in male rats occurred in 1/50 control, 1/49 low dose, 2/50 mid dose, and 4/50 high dose animals. The historical incidence of Zymbal gland neoplasms in untreated F344/N rats is 19/1,936 (1.0%), and the highest observed control group incidence is 4/50. This marginal increase was not considered to be chemically related. The incidences of fibroadenomas of the mammary gland were decreased in dosed female rats (30/50; 12/50; 11/49; 5/50). The incidence of hepatocellular neoplasms was increased in high dose male mice (adenomas or carcinomas, combined: control, 7/48; low dose, 10/49; high dose, 21/50). The historical incidence of hepatocellular adenomas or carcinomas (combined) is 609/2,032 (30%) in untreated controls. Teratology: Hydrochlorothiazide produced no teratologic effects in the offspring of CD®. rats or CD®.-1 mice after gavage administration to pregnant females on day 6 through day 15 of gestation. Genetic Toxicology: In the absence of exogenous metabolic activation, hydrochlorothiazide produced an equivocal increase in revertant colonies in Salmonella typhimurium strain TA98; no increase was observed in strains TA100, TA1535, or TA1537 with or without activation. Hydrochlorothiazide induced an increase in trifluorothymidine (Tft)-resistant cells in a mouse lymphoma L5178Y/TK+/- assay without exogenous metabolic activation; this assay was not performed with activation. In cultured CHO cells, hydrochlorothiazide induced sister chromatid exchanges (SCEs) in the presence and absence of exogenous metabolic activation but did not induce chromosomal aberrations. Hydrochlorothiazide did not increase the frequency of sex-linked recessive lethal mutations when administered by feeding or injection to adult male Drosophila melanogaster. Audit: The data, documents, and pathology materials from the 2-year studies of hydrochlorothiazide have been audited. The audit findings show that the conduct of the studies is documented adequately and support the data and results given in this Technical Report. Conclusions: Under the conditions of these 2-year feed studies, there was no evidence of carcinogenic activity of hydrochlorothiazide for male or female F344/N rats given feed containing 250, 500, or 2,000 ppm hydrochlorothiazide. There was equivocal evidence of carcinogenic activity of hydrochlorothiazide for male B6C3F1 mice, based on increased incidences of hepatocellular neoplasms. There was no evidence of carcinogenic activity for female B6C3F1 mice given diets containing 2,500 or 5,000 ppm hydrochlorothiazide. Chronic renal disease was more severe in rats administered hydrochlorothiazide, and increased incidences of secondary lesions (parathyroid hyperplasia, fibrous osteodystrophy, and mineralization in multiple organs) occurred in dosed rats. Synonym: 6-chloro-3,4-dihydro-2H-1,2,4-benzothia-diazine-7-sulfonamide 1,1-dioxide Trade Names: Aquarius; Bremil; Chlorzide; Cidrex; Dichlorosal; Dichlotride; Diclotride; Direma; Disalunil; Esidrix; Fluvin; Hidroronol; Hydril; Hydro-Aquil; Hydro-Diuril; Hydrosaluric; Hydrothide; Hypothiazide; Ivaugan; Jen-Diril; Maschitt; Nefrix; Neo-Codema; Neoflumen; Oretic; Panurin; Ro-Hydrazide; Thiaretic; Thiuretic; Urodiazin; Vetidrex

Journal Article↗
PubMed1989

Toxicology and Carcinogenesis Studies of Furosemide (CAS No. 54-31-9) in F344/N Rats and B6C3F1 Mice (Feed Studies).

Furosemide is a diuretic used in human and veterinary medicine. Toxicology and carcinogenesis studies were conducted by feeding diets containing furosemide (99% pure, USP grade) to groups of F344/N rats and B6C3F1 mice of each sex for 14 days, 13 weeks, or 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium, mouse L5178Y lymphoma cells, and Chinese hamster ovary (CHO) cells. Fourteen-Day and Thirteen-Week Studies: Dietary concentrations of furosemide used in the 14-day studies for rats and mice ranged up to 46,000 ppm. Two of five male and 3/5 female rats that received 46,000 ppm furosemide died before the end of the studies. Rats that received 15,300 or 46,000 ppm lost weight over the course of the studies. The final mean body weights of rats that received 1,700 or 5,100 ppm were 12% or 23% lower than that of controls for males and 8% or 16% lower for females. Nephrosis was dose related in rats. All five male and 1/5 female mice that received 46,000 ppm furosemide died before the end of the 14-day studies. Male mice that received 15,300 ppm and female mice that received 46,000 ppm lost weight. The final mean body weights of male mice that received 1,700 or 5,100 ppm were 16% or 14% lower than that of controls. The final mean body weight of females that received 15,300 ppm was 13% lower than that of controls. Slight dilatation of the renal cortical tubules and/or nephrosis were dose related in mice. Dietary concentrations of furosemide used in the 13-week studies were 0 and 625-10,000 ppm for male rats and 0 and 938-15,000 ppm for female rats and male mice. Concentrations for female mice were 0 and 1,250-20,000 ppm. None of the rats died before the end of the studies. The final mean body weights of male rats that received 2,500, 5,000, or 10,000 ppm furosemide were 11%, 22%, or 44% lower than that of controls. The final mean body weights of female rats that received 3,750, 7,500, or 15,000 ppm were 18%, 26%, or 35% lower than that of controls. Minimal-to-mild nephrosis occurred in the two highest dose groups of male and female rats. Mineralization of minimal to mild severity was observed at the renal corticomedullary junction in dosed male rats receiving 625 ppm or more; the severity and incidence of the mineralization increased with increased dose. No compound-related deaths occurred in mice. The final mean body weights of male mice that received 3,750, 7,500, or 15,000 were 12%, 22%, or 17% lower than that of controls. Final mean body weights of dosed and control female mice were comparable. Compound-related lesions in mice induced minimal-to-mild nephrosis. Because of the lower body weights and the kidney lesions in the 13-week studies, doses selected for the 2-year studies were 0, 350, or 700 ppm furosemide in the diet for groups of 50 F344/N rats of each sex. Groups of 50 B6C3F1 mice of each sex were fed diets containing 0, 700, or 1,400 ppm furosemide for 104 weeks. Body Weight and Survival in the Two-Year Studies: Mean body weights of dosed and control rats were comparable throughout the studies. No significant differences in survival were observed between any groups of rats of either sex (final survival--male: control, 17/50; low dose, 17/50; high dose, 20/50; female: 35/50; 31/50; 34/50). The final survival of all groups of male rats was low, reflecting the large number of moribund animals killed after week 91. Survival at week 90 was 35/50, 28/50, and 34/50. Mean body weights of high dose male mice were up to 17% lower than those of controls, and mean body weights of low dose male mice were about 5%-10% lower than those of controls after week 31. Mean body weights of high dose female mice were up to 22% lower than those of controls. Mean body weights of low dose female mice were 5%-13% lower than those of controls after week 82. The survival of the high dose group of female mice was significantly lower than that of controls after week 99 (final survival--male: 31/50; 24/50; 26/50; female: 36/50; 29/50; 18/50). Feed consumption by dosed rats was similar to that by controls. The estimateer week 99 (final survival--male: 31/50; 24/50; 26/50; female: 36/50; 29/50; 18/50). Feed consumption by dosed rats was similar to that by controls. The estimated average amount of furosemide consumed per day was approximately 14-16 or 29-31 mg/kg for low dose or high dose rats. Feed consumption by dosed mice was approximately 5%-7% greater than that by controls. The average amount of furosemide consumed per day was approximately 91-99 or 191-214 mg/kg for low dose or high dose mice. Nonneoplastic and Neoplastic Effects in the Two-Year Studies: Nephropathy occurred at similar incidences in all groups of rats, but the severity was greater in dosed male rats. Tubular cell hyperplasia was observed in 4/50 control, 2/50 low dose, and 4/50 high dose male rats. Tubular cell adenomas of the kidney occurred in 1/50 control, 3/50 low dose, and 1/50 high dose male rats. Tubular cell adenocarcinomas were seen in a fourth low dose male rat and in a second high dose male rat (adenomas or adenocarcinomas, combined: control, 1/50; low dose, 4/50; high dose, 2/50). The historical incidence of renal tubular cell adenomas or adenocarcinomas (combined) in untreated male F344/N rats is 9/1,928 (0.5%), and the highest incidence observed in controls is 3/50. Malignant meningiomas of the brain occurred in 3/50 low dose male rats; none was observed in other groups. The historical incidence of meningiomas in untreated male F344/N rats is 2/1,928 (0.1%). C-Cell adenomas of the thyroid gland in female rats occurred with a positive trend; the incidence in the high dose group was not statistically greater than that in the controls (4/50; 6/50; 11/50). A C-cell carcinoma occurred in another low dose female rat. The incidence of adenomas of the anterior pituitary gland in low dose male rats was marginally greater than that in controls (4/50; 11/50; 8/50). Neither of these marginal increases was considered to be chemically related. Malignant mixed tumors (adenocarcinoma, type C) of the mammary gland occurred in dosed female mice (0/50; 1/50; 5/48). One mammary gland acinar cell carcinoma occurred in a second low dose female mouse. The historical incidence of all malignant mammary gland neoplasms in untreated female B6C3F1 mice is 40/2,040 (2%). Compound-related nonneoplastic lesions of the kidney in mice included nephropathy and dilatation of the renal pelvis for males and females and tubular cysts, suppurative inflammation, and epithelial hyperplasia of the renal pelvis for males. Kidney lesions may have contributed to the low survival of high dose female mice. Mucosal epithelial hyperplasia and submucosal chronic focal inflammation of the urinary bladder were observed at increased incidences in dosed male mice. Suppurative inflammation of the prostate was observed at an increased incidence in high dose male mice. Fighting may have contributed to urogenital lesions in male mice. Suppurative inflammation of the ovary or uterus was observed at an increased incidence in high dose female mice. Hematopoiesis was observed at increased incidences in the spleen and liver of dosed male and high dose female mice and in the adrenal cortex of high dose female mice. Genetic Toxicology: Furosemide was not mutagenic in S. typhimurium strains TA98, TA100, TA1535, or TA1537 when tested with or without exogenous metabolic activation. In the mouse lymphoma assay for trifluorothymidine (Tft) resistance, furosemide produced an equivocal response in the absence of metabolic activation and a positive response in the presence of activation. Furosemide induced sister chromatid exchanges and chromosomal aberrations in CHO cells in both the presence and absence of exogenous metabolic activation. Audit: The data, documents, and pathology materials from the 2-year studies of furosemide have been audited. The audit findings show that the conduct of the studies is documented adequately and support the data and results given in this Technical Report. Conclusion: Under the conditions of these 2-year feed studies, there was equivocal evidence of carcinogenic activity of furosemide for male F344/N rats, as shown by marginal increases in uncommon tubular cell neoplasms of the kidney and meningiomas of the brain. There was no evidence of carcinogenic activity of furosemide for female F344/N rats fed diets containing 350 or 700 ppm furosemide for 2 years. There was no evidence of carcinogenic activity for male B6C3F1 mice fed diets containing 700 or 1,400 ppm furosemide for 2 years. There was some evidence of carcinogenic activity of furosemide for female mice, as shown by an increase in malignant tumors of the mammary gland. Nephropathy was more severe in the kidney of male rats and of male and female mice fed diets containing furosemide than in controls. Synonyms: 5-(aminosulfonyl)-4-chloro-2-[(2-furanylmethyl)amino]benzoic acid; frusemide; fursemide Trade Names: Aisemide; Aluzine; Beronald; Desdemin; Diural; Dryptal; Errolon; Frusemin; Fulsix; Fuluvamide; Furosemide "Mita"; Katlex; Lasilix; Lasix; Lowpstron; Rosemide; Transit; Urosemide

Journal Article↗
PubMed1989

NTP Toxicology and Carcinogenesis Studies of 2,4-Dichlorophenol (CAS No. 120-83-2) in F344/N Rats and B6C3F1 Mice (Feed Studies).

2,4-Dichlorophenol is a chemical intermediate used principally in the manufacture of the herbicide 2,4-dichlorophenoxyacetic acid. Toxicology and carcinogenesis studies were conducted by feeding diets containing 2,4-dichlorophenol (greater than 99% pure) for 14 days, 13 weeks, or 2 years to groups of F344/N rats and B6C3F1 mice of each sex. Genetic toxicology tests were conducted in Salmonella typhimurium, mouse L5178Y lymphoma cells, and Chinese hamster ovary (CHO) cells. Fourteen-Day and Thirteen-Week Studies: In the 14-day studies, male and female rats and mice were given diets containing 2,4-dichlorophenol at concentrations up to 40,000 ppm. One high dose male mouse died before the end of the studies; no deaths occurred in any other group, and no compound-related lesions were seen at necropsy in rats or mice. In the 13-week studies, groups of 10 rats and 10 mice of each sex were fed diets containing 0, 2,500, 5,000, 10,000, 20,000, or 40,000 ppm 2,4-dichlorophenol. All rats lived to the end of the studies, whereas all mice that received 40,000 ppm died during the first 3 weeks of the studies. Final mean body weights of rats that received 20,000 or 40,000 ppm and of male mice that received 20,000 ppm were at least 10% lower than those of controls. Bone marrow atrophy in rats and necrosis and syncytial alteration (multinucleated hepatocytes) in the liver of male mice were compound-related effects. Two-year studies were conducted by feeding diets containing 0, 5,000, or 10,000 ppm 2,4-dichlorophenol to groups of 50 male rats and 50 male and 50 female mice for 103 weeks. Groups of 50 female rats received diets containing 0, 2,500, or 5,000 ppm. Body Weight and Survival in the Two-Year Studies: Mean body weights of high dose male and female rats, high dose male mice, and both dosed groups of female mice were generally lower than those of controls. No significant differences in survival were observed between any groups of rats or mice of either sex (male rats: control, 33/50; low dose, 25/50; high dose, 32/50; female rats: 34/50; 43/50; 40/50; male mice: 33/50; 32/50; 31/50; female mice: 45/50; 40/50; 43/50). The average daily feed consumption by rats in the low dose and high dose groups was 94%-97% that by the controls. The estimated daily mean consumption of 2,4-dichlorophenol was 210 or 440 mg/kg for low dose or high dose male rats and 120 or 250 mg/kg for low dose or high dose female rats. The average daily feed consumption by mice in the low dose and high dose groups was 97% and 78% of that by the controls for males and 94% and 85% for females. The estimated daily mean consumption of 2,4-dichlorophenol was 800 or 1,300 mg/kg for low dose or high dose male mice and 430 or 820 mg/kg for low dose or high dose female mice. Nonneoplastic and Neoplastic Effects in the Two-Year Studies: There were no compound-related increased incidences of neoplastic lesions in rats or mice. The incidence of mononuclear cell leukemia was decreased in dosed male rats relative to that in controls (control, 31/50; low dose, 17/50; high dose, 17/50); the incidence of malignant lymphomas was decreased in high dose female mice (4/50) relative to that in controls (12/50). Syncytial alteration of hepatocytes was observed at increased incidences in dosed male mice (11/50; 33/49; 42/48). Genetic Toxicology: The mutagenic effect of 2,4-dichlorophenol in S. typhimurium strain TA1535 was considered to be equivocal only in the presence of hamster S9; 2,4-dichlorophenol produced no increases in revertant colonies in strains TA98, TA100, or TA1537 with or without exogenous metabolic activation. 2,4-Dichlorophenol increased trifluorothymidine (Tft) resistance in the mouse L5178Y assay without metabolic activation; it was not tested with activation. In cultured CHO cells, 2,4-dichlorophenol did not induce chromosomal aberrations but did significantly increase the frequency of sister chromatid exchanges (SCEs) both in the presence and absence of S9. Audit: The data, documents, and pathology materials from the 2-year studies of 2,4-dichlorophenol have been auom the 2-year studies of 2,4-dichlorophenol have been audited. The audit findings show that the conduct of the studies is documented adequately and support the data and results given in this Technical Report. Conclusions: Under the conditions of these 2-year feed studies, there was no evidence of carcinogenic activity for male F344/N rats fed diets containing 5,000 or 10,000 ppm 2,4-dichlorophenol or for female F344/N rats fed diets containing 2,500 or 5,000 ppm 2,4-dichlorophenol. There was no evidence of carcinogenic activity for male or female B6C3F1 mice fed diets containing 5,000 or 10,000 ppm 2,4-dichlorophenol. Synonyms: 2,4-DCP; 2,4-dichlorohydroxybenzene

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