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Toxicology and carcinogenesis studies of chloroethane (99.5% pure), an alkylating agent and chemical intermediate, as well as a topical and inhalation anesthetic, were conducted by exposing groups of F344/N rats and B6C3F1 mice of each sex to chloroethane by whole-body inhalation once for 4 hours or for 6 hours per day, 5 days per week for 14 days, 13 weeks, or 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium. Single-Exposure, Fourteen-Day, and Thirteen-Week Studies: In the single-exposure and 14-day inhalation studies, all rats and mice exposed to 19,000 ppm chloroethane survived. The animals were not exposed at lower concentrations. No clinical signs of toxicity were seen. In the 14-day studies, final mean body weights of exposed male rats and exposed mice were higher than those of controls. Mean body weights of exposed and control female rats were similar. In the 13-week studies, rats and mice were exposed to 0, 2,500, 5,000, 10,000, or 19,000 ppm chloroethane. No compound-related deaths occurred in rats or mice. The final mean body weight of rats exposed to 19,000 ppm was 8% lower than that of controls for males and 4% lower for females. Final mean body weights of exposed mice were generally higher than those of controls. No compound-related clinical signs or gross or microscopic pathologic effects were seen in rats or mice. The liver weight to body weight ratios for male rats and female mice exposed to 19,000 ppm were greater than those for controls. Although no chemically related toxic effects were observed in the short-term studies, concerns about potential flammability and explosion led to the selection of 0 and 15,000 ppm as the exposure concentrations for rats and mice for the 2-year studies. Body Weight and Survival in the Two-Year Studies: Mean body weights of exposed male rats were 4%-8% lower than those of controls after week 33. Mean body weights of exposed female rats were generally 5%-13% lower than those of controls throughout the study. Although survival of male rats and exposed female rats was low at the end of the studies (male: control, 16/50; exposed, 8/50; female: 31/50; 22/50), no statistically significant differences in survival were observed between exposed and control groups of either sex. Survival at week 90 for male rats was 37/50 (control) and 31/50 (exposed) and for females, 43/50 (control) and 33/50 (exposed). The high incidence of mononuclear cell leukemia may have contributed to the high mortality. Mean body weights of exposed male mice were up to 13% higher than those of controls throughout the study. Mean body weights of exposed and control female mice were generally similar throughout the study. The survival of the exposed groups of both male (after day 330) and female (after day 574) mice was significantly lower than that of controls (final survival-- male: 28/50; 11/50; female: 32/50; 2/50). The majority of exposed female mice died as a result of uterine carcinomas. Male mice, and particularly exposed mice, died early as a result of an ascending urinary tract infection. Nonneoplastic and Neoplastic Effects in the Two-Year Studies: Malignant astrocytomas of the brain were seen in three exposed female rats, and gliosis was observed in a fourth. The historical incidence of glial cell neoplasms in untreated control female F344/N rats is 23/1,969. The highest incidence observed in an untreated control group is 3/50. Trichoepitheliomas (1/50), sebaceous gland adenomas (1/50), basal cell carcinomas (3/50), and squamous cell carcinomas (2/50) of the skin were observed only in exposed male rats. Keratoacanthomas occurred in four control and two exposed male rats. Exposure of female mice to chloroethane caused a high incidence of uterine carcinomas of endometrial origin (control, 0/49; exposed, 43/50). One control female did have a uterine carcinoma, although it was not of endometrial origin. The tumors observed in 34 exposed females were highly malignant, invading the uterine myometrium and metastasizing to a wide variety of organs, primarily lung (23), ovary (2 a wide variety of organs, primarily lung (23), ovary (22), lymph nodes (18), kidney (8), adrenal gland (8), pancreas (7), mesentery (7), urinary bladder (7), spleen (5), and heart (4), and to a lesser extent, colon, stomach, gallbladder, small intestine, ureter, and liver. Two marginally increased incidences of other neoplasms were observed in exposed male and female mice. The incidence of hepatocellular carcinomas in exposed female mice was greater than that in controls (3/49; 7/48). One other exposed female had a hepatocellular adenoma. The incidence of alveolar/bronchiolar neoplasms of the lung in exposed male mice was greater than that in controls (adenomas or carcinomas, combined: 5/50; 10/48). Genetic Toxicology: Chloroethane, tested within the closed environment of a desiccator, was mutagenic with and without exogenous metabolic activation in S. typhimuriumstrain TA1535; in strain TA100, a positive response was observed only with activation. No mutagenic activity was observed in S. typhimurium strain TA98 with or without metabolic activation. Conclusions: Under the conditions of these 2--year inhalation studies, there was equivocal evidence of carcinogenic activity of chloroethane for male F344/N rats, as indicated by benign and malignant epithelial neoplasms of the skin. For female F344/N rats, there was equivocal evidence of carcinogenic activity, as indicated by three uncommon malignant astrocytomas of the brain in the exposed group. The study of male B6C3F1 mice was considered to be an inadequate study of carcinogenicity because of reduced survival in the exposed group. However, there was an increased incidence of alveolar/bronchiolar neoplasms of the lung. There was clear evidence of carcinogenic activity for female B6C3F1 mice, as indicated by carcinomas of the uterus. A marginally increased incidence of hepatocellular neoplasms was observed in the exposed group. Synonyms: monochloroethane; chloroethyl; ether hydrochloric; ether muriatic; aethylis; aethylis chloridum; ether chloridum; ether chloratus Trade Names: Kelene; Chelen; Anodynon; Chloryl Anesthetic; Narcotile
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PMID:NTP Toxicology and Carcinogenesis Studies of Chloroethane (Ethyl Chloride) (CAS No. 75-00-3) in F344/N Rats and B6C3F1 Mice (Inhalation Studies). 1270 38

Toxicology and carcinogenesis studies of dichlorvos (99% pure), a contact and stomach poison for control of insects and parasites, were conducted by administering dichlorvos in corn oil by gavage to groups of F344/N rats and B6C3F1 mice of each sex for 13 weeks or 2 years. Previous feed studies were done by the National Cancer Institute using Osborne-Mendel rats and B6C3F1 mice. Thirteen-Week Studies: Thirteen-week studies with groups of 10 rats of each sex were conducted at doses of 0, 2, 4, 8, 16, 32, or 64 mg/kg dichlorvos in corn oil. All rats that received 32 or 64 mg/kg dichlorvos and 4/10 females that received 16 mg/kg died before the end of the studies. Final mean body weights of dosed and vehicle control rats were similar. Thirteen-week studies with groups of 10 mice of each sex were conducted at doses of 0, 5, 10, 20, 40, 80, or 160 mg/kg. All 10 male mice and 9/10 female mice that received 160 mg/kg and 5/10 male mice that received 80 mg/kg dichlorvos died before the end of the studies. Final mean body weights of dosed and vehicle control mice were similar. No compound-related gross or microscopic pathologic effects were observed in rats or mice. Two-year studies of dichlorvos were conducted by administering 0, 4, or 8 mg/kg dichlorvos, 5 days per week for 103 weeks, to groups of 50 F344/N rats of each sex. Groups of 50 male B6C3F1 mice were administered 0, 10, or 20 mg/kg dichlorvos on the same schedule, and groups of 50 B6C3F1 female mice were administered 0, 20, or 40 mg/kg dichlorvos. Body Weight and Survival in the Two-Year Studies: Mean body weights of dosed and vehicle control rats and mice were similar. No significant differences in survival were observed between any groups of rats or mice of either sex (rats--male: vehicle control, 31/50; low dose, 25/50; high dose, 24/50; female: 31/50; 26/50; 26/50; mice-- male: 35/50; 27/50; 29/50; female: 26/50; 29/50; 34/50). Neoplastic Effects in the Two-Year Studies: Adenomas of the exocrine pancreas occurred at greater incidences in dosed rats than in vehicle controls (male: vehicle control, 25/50; low dose, 30/49; high dose, 33/50; female: 2/50; 3/47; 6/50). Mononuclear cell leukemia in both dosed groups of male rats occurred more frequently than in vehicle controls (11/50; 20/50; 21/50). Mammary gland fibroadenomas and fibroadenomas or adenomas (combined) in dosed female rats occurred at increased incidences relative to the vehicle controls (9/50; 19/50; 17/50). Multiple fibroadenomas occurred in dosed female rats but not in vehicle controls (0/50; 6/50; 3/50); carcinomas occurred in two vehicle control and two low dose female rats. In mice, incidences of squamous cell papillomas of the forestomach were increased in the high dose groups compared with those in the vehicle controls (male: 1/50; 1/50; 5/50; female: 5/49; 6/49; 18/50). Two high dose female mice developed forestomach squamous cell carcinomas. Genetic Toxicology: Dichlorvos was mutagenic in Salmonella typhimurium strain TA100 with and without metabolic activation but was not mutagenic in strain TA98. Dichlorvos was mutagenic in the mouse lymphoma L5178Y/TK+/- assay without metabolic activation. Dichlorvos induced sister chromatid exchanges and chromosomal aberrations in Chinese hamster ovary cells in the absence and presence of metabolic activation. Conclusions: Under the conditions of these 2-year gavage studies, there was some evidence of carcinogenic activity of dichlorvos for male F344/N rats, as shown by increased incidences of adenomas of the exocrine pancreas and mononuclear cell leukemia. There was equivocal evidence of carcinogenic activity of dichlorvos for female F344/N rats, as shown by increased incidences of adenomas of the exocrine pancreas and mammary gland fibroadenomas. There was some evidence of carcinogenic activity of dichlorvos for male B6C3F1 mice, as shown by increased incidences of forestomach squamous cell papillomas. There was clear evidence of carcinogenic activity of dichlorvos for female B6C3F1 mice, as shown by increased incidences of forestomach squamous cell papils cell papillomas. Synonyms: 2,2-dichloroethenyl dimethyl phosphate; 2,2-dichlorovinyl dimethyl phosphate; O,O-dimethyl-O-(2,2-dichlorovinyl)phosphate; DDVP Trade Names: BAY-19149; DDVF; ENT-20738; OMS-14; SD 1750; Canogard®.; Crossman's Fly-Cake®.; Dedevap®.; De-Pester Insect Strip®.; Estrosol®.; Herkol®.; Kill-fly Resin Strip®.; Lethalaire®.; Mafu®.; Misect®.; Nogos®.; Nuvan®.; No-Pest Strip®.; Oko®.; Phoracide®.; Phosvit®.; Vapona®.; Vaponicide®.; Vaporette Bar®. Anthelmintics: Atgard®.; Dichlorman®.; Equigard®.; Task®.
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PMID:NTP Toxicology and Carcinogenesis Studies of Dichlorvos (CAS No. 62-73-7) in F344/N Rats and B6C3F1 Mice (Gavage Studies). 1272 83

Toxicology and carcinogenesis studies of iodinated glycerol (Organidin(R)., a complex mixture prepared by the reaction of iodine with glycerol and found to contain 33% 3-iodo-1,2-propanediol as the major component) were conducted because of human exposure to iodinated glycerol as an expectorant and its possible relationship to the formation of alkyl iodides, e.g., methyl iodide, a suspected animal carcinogen. These studies were conducted by giving iodinated glycerol in water by gavage (5 days per week) to groups of F344/N rats and B6C3F1 mice for 16 days, 13 weeks, or 2 years. Genetic toxicology studies were conducted with iodinated glycerol in Salmonella typhimurium, mouse L5178Y lymphoma cells, Chinese hamster ovary (CHO) cells, and B6C3F1 mice (in vivo bone marrow micronucleus test). Also, 3-iodo-1,2-propanediol was tested in S. typhimurium and B6C3F1 mice (in vivo micronucleus assay). Sixteen-Day and Thirteen-Week Studies: Sixteen-day studies were conducted by giving iodinated glycerol at doses up to 1,000 mg/kg to rats and up to 500 mg/kg to mice. All female rats and 4/5 male mice in the highest dose group died before the end of the studies; there were no dose-related effects on body weights of male or female rats or male mice at the end of the studies. The forestomach of 2/5 female mice that received 500 mg/kg was thickened and granular. Thirteen-week studies were conducted by administering iodinated glycerol at doses up to 500 mg/kg to rats and mice. During these studies, 3/10 female rats and 1/10 female mice that received 500 mg/kg died. Final mean body weights of rats and mice that received 500 mg/kg were 4% lower than those of vehicle controls for males and 6%-7% lower for females. Kidney tubular cell lesions, including cortical necrosis, regeneration, and calcification, were observed at increased incidences in the highest dose group of female rats. Lymphoid hyperplasia of the stomach was observed in dosed male and female rats. Kidney tubular cell regeneration was also observed in dosed female mice. Inflammation or abscesses of mild-to-moderate severity and hyperplasia, acanthosis, and/or hyperkeratosis of mild-to-moderate severity were observed in the forestomach of the highest dosed group of female mice. Body Weight and Survival in the Two-Year Studies: Two-year studies were conducted by administering 0, 125, or 250 mg/kg iodinated glycerol in deionized water by gavage, 5 days per week for 103 weeks, to groups of 50 male F344/N rats and 50 male B6C3F1 mice. Groups of 50 female F344/N rats and 50 female B6C3F1 mice were administered iodinated glycerol on the same schedule at lower doses of 0, 62, or 125 mg/kg because of the increased severity of kidney and stomach lesions in the 13-week studies. Mean body weights of high dose male rats were 5%-10% lower than those of vehicle controls from week 43 to week 68 and 10%-13% lower from week 72 to the end of the studies. Mean body weights of low dose male rats and high dose female rats were 4%-9% lower than those of vehicle controls from week 88 to the end of the studies. The survival of the high dose group of male rats was considerably lower than that of the vehicle controls after week 86. No other significant differences in survival were observed between any groups of rats of either sex (male: vehicle control, 28/50; low dose, 20/50, high dose, 2/50; female: 31/50; 30/50; 27/50). Mean body weights of dosed and vehicle control male mice were similar. Mean body weights of high dose female mice were 6%-8% lower than those of vehicle controls from week 40 to week 64 and were 9%-13% lower thereafter. No significant differences in survival were observed between any groups of mice of either sex (male: 36/50; 40/50; 32/50; female: 40/50; 33/50; 38/50). Nonneoplastic and Neoplastic Effects in the Two-Year Studies: The incidence of mononuclear cell leukemia were increased in dosed male rats (vehicle control, 14/50; low dose, 29/50; high dose, 24/50). Follicular cell carcinomas of the thyroid gland in male rats occurred at an increased incidence in low dose male rats (0/49; s of the thyroid gland in male rats occurred at an increased incidence in low dose male rats (0/49; 5/49; 1/49). Reduced survival of high dose male rats may have been responsible for the decreased tumor incidence in this group relative to that in the low dose group. Follicular cell carcinomas were observed in one low dose and one high dose female rat. Follicular cell carcinomas of the thyroid gland have been observed in 3/293 water gavage vehicle control male F344/N rats and in 10/1,904 untreated control male F344/N rats. Adenomas of the nasal cavity were observed in two high dose male rats. Adenomas of the nasal cavity have not been observed in 300 water gavage vehicle control male F344/N rats or in 1,936 untreated control male F344/N rats. Squamous metaplasia and focal atrophy of the salivary glands were observed at increased incidences in dosed rats (squamous metaplasia--male: 0/48; 47/50; 48/49; female:1/49; 48/50; 49/50; focal atrophy--male: 1/48; 10/50; 30/49; female: 0/49; 4/50; 11/50). In dosed female mice, adenomas of the anterior pituitary gland were increased (10/47; 15/45; 24/46). The incidences of adenomas of the harderian gland in dosed female mice were increased (6/50; 8/40; 13/50). A carcinoma of the harderian gland was observed in another high dose female mouse. Dilatation of the thyroid gland follicle and follicular cell hyperplasia were observed at increased incidences in dosed mice (dilatation--male: 0/48; 28/50; 32/50; female: 4/48; 11/48; 10/48; hyperplasia--male: 3/48; 46/50; 34/50; female: 2/48; 25/48; 35/48). The incidences of follicular cell adenomas were 3/48, 6/50, and 0/50 for males and 2/48, 3/48, and 4/48 for females. Hyperkeratosis and acanthosis of the forestomach were observed at increased incidences in high dose male mice (hyperkeratosis: 0/49; 0/49; 5/50; acanthosis: 0/49; 1/49; 5/50). Squamous cell papillomas were observed in female mice (1/49; 2/50; 5/49). The historical incidence of forestomach squamous cell neoplasms is 4/339 (1.2&percnt;) in water gavage vehicle control female B6C3F1 mice and is 18/1,994 (0.9&percnt;) in untreated control female B6C3F1 mice. Squamous cell neoplasms were not observed in male mice. Genetic Toxicology: Treatment of the base-substitution mutant S. typhimurium strains TA100 and TA1535 with iodinated glycerol in a preincubational protocol with and without S9 resulted in a dose-related increase in the number of revertant colonies; no increase in revertants was observed with the frame-shift mutant strains TA98 or TA1537. 3-Iodo-1,2-propanediol was also mutagenic in TA100 with or without S9; it was not mutagenic in TA98. Iodinated glycerol increased the number of trifluorothymidine-resistant cells in mouse lymphoma L5178Y/TK± assay in the absence of exogenous metabolic activation; it was not tested with activation. Iodinated glycerol induced sister chromatid exchanges (SCEs) and chromosomal aberrations in CHO cells without S9; with S9, the frequency of SCEs was increased more than without S9 but no chromosomal aberrations were induced. No increase in micronucleated polychromatic erythrocytes was observed in the bone marrow of B6C3F1 mice after injection with either iodinated glycerol or 3-iodo-1,2-propanediol. Conclusions: Under the conditions of these 2-year gavage studies, there was some evidence of carcinogenic activity for male F344/N rats administered iodinated glycerol, as indicated by increased incidences of mononuclear cell leukemia and follicular cell carcinomas of the thyroid gland. Adenomas of the nasal cavity in two high dose male rats may have been related to the administration of iodinated glycerol. There was no evidence of carcinogenic activity for female F344/N rats administered 62 or 125 mg/kg iodinated glycerol by gavage for 103 weeks. There was no evidence of carcinogenic activity for male B6C3F1 mice administered 125 or 250 mg/kg iodinated glycerol by gavage for 103 weeks. There was some evidence of carcinogenic activity for female B6C3F1 mice administered iodinated glycerol, as indicated by increased incidences of adenomas of the anterior pituitary gland and neoplasms of the harderian gland. Squamous cell papillomas of the forestomach may have been related to the administration of iodinated glycerol. Significant nonneoplastic lesions considered related to exposure of iodinated glycerol were squamous metaplasia and focal atrophy of the salivary gland in male and female rats. Dilatation of the thyroid gland follicle and follicular cell hyperplasia were observed in male and female mice. Synonyms or Trade Names: Organidin®.; iodopropylidene glycerol
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PMID:NTP Toxicology and Carcinogenesis Studies of Iodinated Glycerol (Organidin(R).) (CAS No. 5634-39-9) in F344/N Rats and B6C3F1 Mice (Gavage Studies). 1272 85

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

N-Phenyl- 2- naphthylamine, formerly used as a antioxidant in the rubber industry, was selected for toxicology and carcinogenesis studies because at the time of nomination (1976) it had a large annual production and widespread human exposure. Additional reasons for selection included it structural similarity and possible metabolism to the known human urinary bladder carcinogen, 2-naphthylamine. Toxicology and carcinogenesis studies were conducted by feeding diets containing N-phenyl-2-naphthylamine (approximately 98% pure and containing less than 1 ppm 2-naphthylamine) at various concentrations to groups of F344/N rats and B6C3F1 mice of each sex for 14 days, 13 weeks, or 2 years. Fourteen-Day and Thirteen-Week Studies: In 14-day studies, 3/5 male and 4/5 female rats that received 50,000 ppm N-phenyl-2-naphthylamine died before the end of the studies. Final mean body weights of rats that received 12,500 ppm or more were considerably lower (18%-57%) than those of the controls. Arched backs, rough coats, and diarrhea were observed for males that received 12,500 ppm or more and for females that received 25,000 or 50,000 ppm. All mice were alive at the end of the studies, and no compound-related clinical signs of toxicity were observed in mice given feed containing up to 20,000 ppm. In 13-week studies, deaths occurred in 4/10 male and 9/10 female rats that received the highest dose (40,000 ppm) of N-phenyl-2-naphthylamine. Final mean body weights of rats that received 5,000-40,000 ppm were 9%-60% lower than those of the controls. The liver weight to body weight ratios increased with increasing dose, with the ratios for male rats at 10,000 ppm or more and for female rats at 5,000 ppm being greater (P<0.05) than those of controls. A compound-related nephropathy occurred in rats and was characterized by renal tubular epithelial degeneration and hyperplasia. Other effects in rats included hematopoietic hypoplasia or atrophy of the femoral bone marrow, testicular hypospermatogenesis, lymphoid degeneration of the thymus, and lymphoid depletion of the spleen. In mice, 2/10 males and 7/10 females that received 40,000 ppm died before the end of the 13-week studies. The final mean body weights of mice that received 10,000, 20,000, or 40,000 ppm were 9%-32% lower than those of the controls. The liver weight to body weight ratios for mice increased with increasing dose. Those for male mice at 10,000 ppm or more and for female mice at 20,000 ppm or more were greater (P<0.05) than those for the controls. Nephropathywas observed at increased incidences and severity in dosed mice. Because of kidney lesions, liver enlargement, lower weight gain, and increased mortality in the shorter term studies, dietary concentrations of N-phenyl-2-naphthylamine selected for the 2-year studies in rats and mice were 0, 2,5000, and 5,000 ppm. Body Weight and Survival in the Two-Year Studies: The mean body weights of dosed rats were lower than those of the controls throughout the studies (12% and 16% lower for dosed males and 15% and 31% lower for dosed females at the end of the studies). The average daily feed consumption for rats was 94%-87% that of the controls for dosed males and 88% that of the controls for dosed females. The estimated average amount of N-phenyl-2-naphthylamine consumed per day was 100 mg/kg and 225 mg/kg for male rats and 120 mg/kg and 260 mg/kg for female rats. The survival of the high dose group of male rats was greater (P<0.05) than that of the controls after week 101 (male: control, 24/50; low dose, 28/50; high dose, 34/50; female: 26/50; 44/50; 38/50). Final mean body weights of high dose male and female mice were lower (male, 9%; female, 23%) than those of the controls. The estimated average daily feed consumption by dosed mice was within 10% that of the controls. The average amount of N-phenyl-2-naphthylamine consumed per day was approximately 500 or 1,000 mg/kg for male mice and 450 or 900 mg/kg for female mice. No significant differences in survival were observed between any groups of mice of either sex (male: control, 33/50; male mice. No significant differences in survival were observed between any groups of mice of either sex (male: control, 33/50; low dose, 36/50; high dose, 28/50; female: 36/50; 30/50; 35/50). Nonneoplastic and Neoplastic Effects in the Two-Year Studies: As in the 13-week studies, the kidney was the principal target for toxic effects of N-phenyl-2-naphthylamine. Mineralization of the kidney, necrosis of the renal papilla, and epithelial hyperplasia and calculi of the kidney pelvis were observed at increased incidences in high dose female rats. Hydronephrosis, atrophy, fibrosis, and chronic focal inflammation of the kidney were observed at increased incidences in high dose female rats. Cysts and acute suppurative inflammation of the kidney were observed at increased incidences in dosed male and high dose female rats. No compound-related renal neoplasms were observed in rats. Nuclear enlargement of renal tubular epithelial cells and nephropathy were observed at increased incidences in high dose female mice. Atypical tubular cell hyperplasia occurred in two high dose female mice. A tubular cell adenoma was found in one high dose female mouse, and a tubular cell adenocarcinoma was found in another high dose female mouse. No renal neoplasms were observed in dosed male mice. Neoplasms of several organs occurred in rats with negative trends and/or at significantly lower incidences in high dose groups. These included thyroid gland C-cell neoplasms in males and females and mammary gland fibroadenomas, pituitary gland adenomas, and mononuclear cell leukemia in females. The lack of carcinogenicity in rats may be related to an inability to metabolize this compound to the known animal and human carcinogen 2-napththylamine. Genetic Toxicity: N-Phenyl-2-naphthylamine was not mutagenic in the Salmonella typhimurium/microsome assay with strains TA97, TA98, TA100, or TA1535 with or without induced hamster or rat liver S9. The chemical did not induce chromosomal aberrations in cultured Chinese hamster ovary (CHO) cells with or without metabolic activation. No increase in sister chromatid exchanges (SCEs) was observed in the absence of metabolic activation; in the presence of rat liver S9, the SCE results were judged to be equivocal. Data Audit: The data, documents, and pathology materials from the 2-year studies of N-phenyl-2-naphthylamine were audited at the NTP Archives. The audit findings show thatthe 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 or female F344/N rats fed diets containing 2,500 or 5,000 ppm N-phenyl-2-naphthylamine. Decreased incidences of several neoplasms were observed in dosed rats: thyroid gland C-cell neoplasms in males and females and mononuclear cell leukemia, pituitary gland adenomas, and mammary gland fibroadenomas in females. There was no evidence of carcinogenic activity for male B6C3F1 mice fed diets containing 2,500 or 5,000 ppm N-phenyl-2-naphthylamine. There was equivocal evidence of carcinogenic activity of N-phenyl-2-naphthylamine for female B6C3F1 mice as indicated by the occurrence of two rare kidney neoplasms. Chemical-related nonneoplastic lesions (nephropathy, karyomegaly, and hyperplasia) occurred in the kidney of rats and mice. Synonyms: N-(2-naphthyl)aniline; 2-naphthylphenylamine; b-naphthylphenylamine; 2-phenylaminonaphthalene; phenyl-b-naphthylamine; N-phenyl-b-naphthylamine Trade Names: Aceto PBN; Agerite Powder: Antioxidant 116; Neosone D; Neozon D; Nilox PBNA; Nonox D; PBNA; Stabilizator AR
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PMID:NTP Toxicology and Carcinogenesis Studies of N-Phenyl-2-naphthylamine (CAS No. 135-88-6) in F344/N Rats and B6C3F1 Mice (Feed Studies). 1273 3

Benzene ranks 16th in production volume for chemicals produced in the United States, with approximately 9.9 billion pounds being produced in 1984, 9.1 billion pounds in 1983, and 7.8 billion pounds in 1982. This simplest aromatic chemical in used in the synthesis of styrene (polystyrene plastics and synthetic rubber), phenol (phenolic resins), cyclohexane (nylon), aniline, maleic anhydride (polyester resins), alkylbenzenes (detergents), chlorobenzenes, and other products used in the production of drugs, dyes, insecticides, and plastics. Benzene, along with other light, high-octane aromatic hydrocarbons, such as toluene and xylenes, is a component of motor gasoline. Benzene is also used as a solvent, but for most applications, it has been replaced by less hazardous solvents. During the 17-week studies, groups of 10 or 15 male and female F344/N rats and B6C3F1 mice were gavaged 5 days per week with benzene in corn oil (5 ml/kg) at doses of 0 to 600 mg/kg. No benzene-related deaths occurred; in rats that received benzene, final mean body weights were 14%-22% lower compared with vehicle controls and in mice, slight dose-related reductions were observed (less than 10% differences). Doses for the 2-year studies were selected based on clinical observations (tremors in higher dosed mice), on clinical pathologic findings (lymphoid depletion in rats and leukopenia in mice), and on body weight effects. Two-year toxicology and carcinogenesis studies of benzene (greater than 99.7% pure) were conducted in groups of 50 F344/N rats and 50 B6C3F1 mice of each sex and for each dose. Doses of 0, 50, 100, or 200 mg/kg body weight benzene in corn oil (5 ml/kg) were administered by gavage to male rats, 5 days per week, for 103 weeks. Doses of 0, 25, 50, or 100 mg/kg benzene in corn oil were administered by gavage to female rats and to male and female mice for 103 weeks. Ten additional animals in each of the 16 groups were killed at 12 months and necropsies were performed. Hematologic profiles were performed at 3-month intervals. These studies were designed and conducted because of large production volume and potential human exposure, because of the epidemiologic association with leukemia, and because previous experiments were considered inadequate or inconclusive for determining potential carcinogenicity in laboratory animals. In the 2-year studies, mean body weights of the 200 mg/kg male rats (-23%) and the 100 mg/kg mice (-14% to -19%) were lower than those of the vehicle controls, and survival of dosed groups decreased with increasing dose (rats--male: vehicle control, 32/50; low dose, 29/50; mid dose, 25/50; high dose, 16/50; female: 46/50; 38/50; 34/50; 25/50; mice--male: 28/50; 23/50; 18/50; 7/50; female: 30/50; 26/50; 24/50; 18/50). At week 92 for rats and week 91 for mice, survival was greater than 60% in all groups; most of the dosed animals that died before week 103 had neoplasia. Compound-related nonneoplastic or neoplastic effects on the hematopoietic system, Zymbal gland, forestomach, and adrenal gland were found both for rats and mice. Further, the oral cavity was affected in rats, and the lung, liver, harderian gland, preputial gland, ovary, and mammary gland were affected in mice. Significantly increased (P<0.05) incidences of neoplasms were observed at multiple sites for male and female rats and for male and female mice. Primary neoplasms observed in rats and mice are summarized in Table 1 (see page 12 of the Technical Report). Hematologic data from vehicle control and dosed rats and mice were obtained at 3-month intervals from 0 to 24 months. Reliably identifiable hematologic effects were limited to lymphocytopenia and associated leukocytopenia in benzene-dosed rats and mice. These effects were seen from 3 to 18 months in dosed male rats and in dosed male mice; a similar but less pronounced response was observed in dosed female rats during this same time period. The effect in female mice was limited to 12-18 months. The technical quality of certain of these data was questionable; thus, more detailed analyses (e.g., investig questionable; thus, more detailed analyses (e.g., investigation of the association between hematologic and pathologic changes) are deemed inappropriate for these data. Benzene increased the frequency of micronucleated normchromatic peripheral erythrocytes in male and female mice (rats were not examined); males were more sensitive than females. The hematopoietic system of rats and mice of each sex was affected by benzene in the 2-year studies. The incidences of malignant lymphomas in all dosed groups of mice were greater than those in the vehicle controls (male: 4/49; 9/48; 9/50; 15/49; female: 15/49; 24/45; 24/50; 20/49). Lymphoid depletion of the splenic follicles (rats) and thymus (male rats) was observed at increased incidences. Bone marrow hematopoietic hyperplasia was observed at increased incidences in dosed mice of each sex (male: 0/49; 11/48; 10/50; 25/49; female: 3/49; 14/45; 8/50; 13/49). The incidences of Zymbal gland carcinomas in mid and high dose male rats and in dosed female rats were greater than those in the vehicle controls (male: 2/32; 6/46; 10/42; 17/42; female: 0/45; 5/40; 5/44; 14/46). The incidences of Zymbal gland carcinomas in mid and high dose male mice and in high dose female mice were greater than those in the vehicle controls (male: 0/43; 1/34; 4/40; 21/39; female: 0/43; 0/32; 1/37; 3/31). In mid and high dose male mice and in high dose female mice, the incidences of epithelial hyperplasia of the Zymbal gland were also increased (male: 0/43; 3/34; 12/40; 10/39; female: 1/43; 1/32; 2/37; 6/31). Hyperplasia of the adrenal capsule was observed at increased incidences in dosed mice of each sex (male: 2/47; 32/48; 14/49; 4/46; female: 5/49; 19/44; 34/50; 30/48). The incidence of pheochromocytomas in mid dose male mice was greater than that in the vehicle controls (male: 1/47; 1/48; 7/49; 1/46), whereas the incidences in dosed female mice were lower than that in the vehicle controls (female: 6/49; 1/44; 1/50; 1/48). Hyperplasia of the zona fasciculata of the adrenal cortex was observed at increased incidences in low dose rats of each sex (male: 0/50; 13/49; 0/48; 2/49; female: 0/50; 17/50; 0/47; 0/49). Benzene was associated with increased incidences of neoplasms of the skin and oral cavity of rats. The incidences of squamous cell papillomas and squamous cell carcinomas of the skin in high dose male rats were greater than those in the vehicle controls (squamous cell papilloma: 0/50; 2/50; 1/50; 5/50; squamous cell carcinoma: 0/50; 5/50; 3/50; 8/50). Increased incidences of uncommon squamous cell papillomas or squamous cell carcinomas (combined) of the oral cavity were observed in dosed male and female rats (male: 1/50; 9/50; 16/50; 19/50; female: 1/50; 5/50; 12/50; 9/50). Incidences of squamous cell papillomas or carcinomas (combined) (male: 2/45; 2/42; 3/44; 5/38; female: 1/42; 3/40; 6/45; 5/42), hyperkeratosis, and epithelial hyperplasia of the forestomach were increased in some dosed groups of male and female mice; incidences of hyperkeratosis and acanthosis were increased in high dose male rats. Compound-related effects in the lung, harderian gland, preputial gland, ovary, mammary gland, and liver were seen in mice but not in rats. Administration of benzene was associated with increased incidences of alveolar epithelial hyperplasia in mid and high dose mice (male: 2/49; 3/48; 7/50; 10/49; female: 1/49; 1/42; 9/50; 6/49). Increased incidences of alveolar/bronchiolar carcinomas and alveolar/bronchiolar adenomas or carcinomas (combined) were observed in high dose male mice (carcinomas: 5/49; 11/48; 12/50; 14/49; adenomas or carcinomas: 10/49; 16/48; 19/50; 21/49). Alveolar/bronchiolar adenomas were seen at increased incidences in high dose female mice (4/49; 2/42; 5/50; 9/49), as were alveolar/bronchiolar carcinomas (0/49; 3/42; 6/50; 6/49) and alveolar/bronchiolar adenomas or carcinomas combined (4/49; 5/42; 10/50; 13/49) in mid and high dose female mice. The incidences of focal or diffuse hyperplasia of the harderian gland were increased in dosed mice of each sex (male: 0/49; 5/46; 11/49; 7/48; female: 6/48; 10/44; 11/50; 10/47). The incidences of harderian gland adenomas (0/49; 9/46; 13/49; 11/48) in dosed male mice were greater than that in the vehicle controls. A marginal increase in the incidence of adenomas or carcinomas (combined) of the harderian gland was seen in high dose female mice (5/48; 6/44; 10/50; 10/47). The administration of benzene to male mice was associated with increased incidences of hyperplasia (1/21; 18/28; 9/29; 1/35) and squamous cell carcinomas (0/21; 3/28; 18/29; 28/35) of the preputial gland. Increased incidences of mammary gland carcinomas were found in mid dose and high dose female mice (0/49; 2/45; 5/50; 10/49) and carcinosarcomas in high dose female mice (0/49; 0/45; 1/50; 4/49). Increased incidences of various uncommon neoplastic and nonneoplastic lesions of the ovary (papillary cystadenoma, luteoma, granulosa cell tumor, tubular adenoma, benign mixed tumor, epithelial hyperplasia, and senile atrophy) were associated with the administration of benzene to female mice. In mid and high dose female mice, the incidences of granulosa cell tumors (1/47; 1/44; 6/49; 7/48) and benign mixed tumors (0/47; 1/44; 12/49; 7/48) were greater than those in the vehicle controls. Increased incidences of hepatocellular adenomas were observed in low dose female mice (1/49; 8/44; 5/50; 4/49) and hepatocellular adenomas or carcinomas (combined) in low dose and mid dose female mice (4/49; 12/44; 13/50; 7/49). An audit of the experimental data was conducted for these 2-year carcinogenesis studies on benzene. No data discrepancies were found that influenced the final interpretations. Under the conditions of these 2-year gavage studies, there was clear evidence of carcinogenicity of benzene for male F344/N rats, for female F344/N rats, for male B6C3F1 mice, and for female B6C3F1 mice. For male rats, benzene caused increased incidences of Zymbal gland carcinomas, squamous cell papillomas and squamous cell carcinomas of the oral cavity, and squamous cell papillomas and squamous cell carcinomas of the skin. For female rats, benzene caused increased incidences of Zymbal gland carcinomas and squamous cell papillomas and squamous cell carcinomas of the oral cavity. For male mice, benzene caused increased incidences of Zymbal gland squamous cell carcinomas, malignant lymphomas, alveolar/bronchiolar carcinomas and alveolar/bronchiolar adenomas or carcinomas (combined), harderian gland adenomas, and squamous cell carcinomas of the preputial gland. For female mice, benzene caused increased incidences of malignant lymphomas, ovarian granulosa cell tumors, ovarian benign mixed tumors, carcinomas and carcinosarcomas of the mammary gland, alveolar/bronchiolar adenomas, alveolar/bronchiolar carcinomas, and Zymbal gland squamous cell carcinomas. Dose-related lymphocytopenia was observed for male and female F344/N rats and male and female B6C3F1 mice. Synonyms: benzol, cyclohexatriene, pyrobenzol
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PMID:NTP Toxicology and Carcinogenesis Studies of Benzene (CAS No. 71-43-2) in F344/N Rats and B6C3F1 Mice (Gavage Studies). 1274 14

1,4-Dichlorobenzene is commonly used as a space deodorant in toilets and for moth control. Because of its extensive production and use and the absence of carcinogenicity data, carcinogenesis studies were conducted by administering 1,4-dichlorobenzene (greater than 99% pure) in corn oil by gavage (5 days per week) to male F344/N rats at doses of 0, 150, or 300 mg/kg and to female F344/N rats and male and female B6C3F1 mice at doses of 0, 300, or 600 mg/kg per day for 2 years (50 animals per group). Fourteen-day and 13-week studies were performed to characterize the toxicity, identify affected sites, and set doses for the 2-year studies. Clinical chemistry and hematologic studies were performed during the 13-week studies to assess the effects of 1,4-dichlorobenzene on the liver, kidney, and hematopoietic system and to assess whether the compound produced hepatic porphyria. Two 13-week studies were performed in rats. In the first study, rats were dosed with 300-1,500 mg/kg 1,4-dichlorobenzene. Because histologic changes were observed in the kidney of male rats at all doses, a second 13-week study was performed at doses of 38-600 mg/kg. In the 13-week studies, survival was decreased in groups of male rats given 1,200 or 1,500 mg/kg and in female rats given 1,500 mg/kg. Weight gain was decreased in male rats receiving doses of 300 mg/kg or more and in female rats given doses of 1,200 or 1,500 mg/kg. Doses of 1,200 or 1,500 mg/kg produced degeneration and necrosis of hepatocytes, hypoplasia of the bone marrow, lymphoid depletion of the spleen and thymus, and epithelial necrosis of the nasal turbinates in male and female rats. Renal tubular cell degeneration was observed in male rats receiving 300 mg/kg or more in the first study, but only slight changes were seen at 300 mg/kg in the second study. Liver weight to brain weight ratios were increased at 900 mg/kg or more for both male and female rats. The kidney weight to brain weight ratio was increased in male rats receiving doses of 600 mg/kg or more. Administration of 1,4-dichlorobenzene to rats for 13 weeks produced slight but statistically significant decreases in the hematocrit, red blood cell count, and hemoglobin level in all males receiving doses of 300-1,200 mg/kg. No clear hematologic changes were observed in female rats. 1,4-Dichlorobenzene produced minimal changes in clinical chemistry parameters in the 13-week studies. Serum cholesterol levels were increased by doses of 600 mg/kg or more in male rats and 900 mg/kg or more in female rats. Serum triglycerides were reduced by doses of 300 mg/kg or more in male rats. The blood urea nitrogen level was increased slightly in male rats dosed with 900 mg/kg or more. Urinary porphyrins were increased slightly in male rats administered 1,200 or 1,500 mg/kg and female rats receiving 1,200 mg/kg. However, these increases were modest and indicative of a mild porphyrinuria rather than hepatic porphyria. Liver porphyrins were not increased at any dose. Two 13-week studies were performed in mice. The doses selected for the first study were 600-1,800 mg/kg. Survival was decreased in male and female mice receiving doses of 1,500 mg/kg or more, and body weight gain was decreased at all doses. Hepatocellular degeneration was observed in both sexes at all doses, and the liver weight to brain weight ratio was increased at doses of 900 mg/kg or more. Serum cholesterol levels were increased in male mice at doses of 900 mg/kg or more, whereas serum protein and triglycerides were increased at doses of 1,500 mg/kg or more. These relatively modest clinical chemistry changes probably reflect the hepatic effects of this compound. The white blood cell count was reduced significantly in male mice receiving doses of 600 mg/kg or more and female mice receiving 1,000 mg/kg or more, but this effect was not dramatic. Hepatic porphyria was not found in mice at any dose in the 13-week study. Because hepatic effects were seen in all dose groups in the first study, a second 13-week study was performed at doses of 85-900 mg/kg. In this study, hepatocellularellular cytomegaly was observed im male and female mice at doses of 675 mg/kg or more but not at 338 mg/kg. Renal damage was not observed in mice in either 13-week study. Based on the histopathologic findings in the kidney of male rats and in the liver of both sexes of rats and mice in the 13-week studies, the doses selected for the 2-year studies were 150 and 300 mg/kg for male rats and 300 and 600 mg/kg for female rats and male and female mice. In the 2-year studies, survival of female rats and of both sexes of mice was comparable to that of the vehicle controls; survival of high dose male rats was significantly lower than that of the vehicle controls (vehicle control, 32/50; low dose, 31/50; high dose, 20/50). Mean body weights of high dose male rats were 5&percnt;-8&percnt; lower than those of vehicle controls after week 38, and those of high dose female rats were 5&percnt;-7&percnt; lower than those of vehicle controls after week 55. Mean body weights of mice dosed with 1,4-dichlorobenzene were comparable to those of vehicle controls throughout the studies. Administration of 1,4-dichlorobenzene to male rats increased the average seveity of nephropathy and caused epithelial hyperplasia of the renal pelvis (1/50; 30/50; 31/50), mineralization of the collecting tubules in the renal medulla (4/50; 46/50; 47/50), and focal hyperplasia of renal tubular epithelium (0/50; 1/50; 9/50). There were increased incidences of nephropathy in both low and high dose female rats compared with vehicle controls (21/49; 32/50; 41/49). 1,4-Dichlorobenzene produced a dose-related increase in the incidence of tubular cell adenocarcinomas of the kidney in male rats (1/50; 3/50; 7/50); one tubular cell adenoma was observed in a high dose male rat. These malignant tumors are uncommon in male F344/N rats. They have been diagnosed in only 4/1,098 (0.4&percnt;) corn oil gavage controls in previous NTP studies. There were no tubular cell tumors in dosed or vehicle control female rats. There was a marginal increase in the incidence of mononuclear cell leukemia in dosed male rats compared with that in vehicle controls (5/50; 7/50; 11/50). 1,4-Dichlorobenzene increased the incidences of nonneoplastic liver lesions in male and female mice, including alteration in cell size (cytomegaly and karyomegaly), hepatocellular degeneration, and individual cell necrosis. 1,4-Dichlorobenzene also increased the incidences of nephropathy in male mice and renal tubular regeneration in female mice. 1,4-Dichlorobenzene increased the incidences of hepatocellular carcinomas in high dose male (14/50; 11/49; 32/50) and female (5/50; 5/48; 19/50) mice and hepatocellular adenomas in dosed male (5/50; 13/49; 16/50) and high dose female (10/50; 6/48; 21/50) mice. Hepatoblastomas were observed in four high dose male mice but not in vehicle controls. This rare tumor has not occurred in 1,091 male vehicle control mice in NTP studies. An increase in thyroid gland follicular cell hyperplasia was observed in dosed male mice (1/47; 4/48; 10/47), and there was a marginal positive trend in the incidence of follicular cell adenomas of the thyroid gland in female mice (0/48; 0/45; 3/46). Pheochromocytomas (benign or malignant, combined) of the adrenal gland occurred with a positive trend in dosed male mice, and the incidence in the high dose group was significantly greater than in vehicle controls (0/47; 2/48; 4/49). The incidence of adrenal gland medullary hyperplasia in male mice was 2/47; 4/48; and 4/49. Focal hyperplasia of the adrenal gland capsule was also observed in dosed male mice (11/47;21/48; 28/49). 1,4-Dichlorobenzene was not mutagenic in Salmonella typhimurium strains TA98, TA100, TA1535, or TA1537 with or without activation by Aroclor 1254-induced male Sprague-Dawley rat or male Syrian hamster liver S9 when tested according to a preincubational protocol at concentrations up to 100 ug/plate. 1,4-Dichlorobenzene did not induce forward mutations in the mouse lymphoma L5178Y/TK± assay in the absence of exogenous metabolic activation; however, the results were equivocal in this system in the presence of metabolic activation. 1,4-Dichlorobenzene did not produce an increase in sister-chromatid exchanges or chromosomal aberrations in Chinese hamster ovary cells in culture with or without exogenous metabolic activation. No increase in micronucleated cells was seen in erythrocytes of mice from the first 13-week studies. An audit of the experimental data was conducted for the 2-year studies of 1,4-dichlorobenzene. No data discrepancies were found that influenced the final interpretations. Under the conditions of these 2-year gavage studies, 1,4-dichlorobenzene produced clear evidence of carcinogenicity for male F344/N rats, as shown by an increased incidence of renal tubular cell adenocarcinomas. There was no evidence of carcinogenicity for female F344/N rats receiving doses of 300 or 600 mg/kg. There was clear evidence of carcinogenicity for both male and female B6C3F1 mice, as shown by increased incidences of hepatocellular carcinomas and hepatocellular adenomas. Marginal increases were observed in the incidences of pheochromocytomas of the adrenal gland in male mice. Nonneoplastic effects in the kidney of male and female rats, in the liver of male and female mice, and in the thyroid gland and adrenal gland of male mice were also associated with the administration of 1,4-dichlorobenzene. Synonyms: p-dichlorobenzene; para-dichlorobenzene; para-chlorophenyl chloride
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PMID:NTP Toxicology and Carcinogenesis Studies of 1,4-Dichlorobenzene (CAS No. 106-46-7) in F344/N Rats and B6C3F1 Mice (Gavage Studies). 1274 34

4,4'-Methylenedianiline is used primarily as a chemical intermediate in the closed system production of isocyanates and polyisocyanates. These chemicals are used extensively in the manufacture of rigid polyurethane foams for thermal insulation and in the production of semiflexible polyurethane foams for automobile safety cushioning. The saturated isocyante of 4,4'-methylenedianiline [4,4'-methylene-bis(cyclohexylisocyanate)] is an intermediate in the production of light-stable, high-performance polyurethane coatings. 4,4'-Methylenedianiline is also a curing agent for epoxy resins and urethane elastomers, a dye intermediate, and a corrosion inhibitor. NTP Carcinogenesis studies of 4,4'-methylenedianiline dihydrochloride (98.6% pure) were conducted by administering this chemical in the drinking water of F344/N rats and B6C3F1 mice. Groups of 50 rats and 50 mice of each sex received drinking water containing 150 or 300 ppm 4,4'-methylenedianiline dihydrochloride (dosage expressed as the free base) for 103 weeks. Groups of 50 rats and 50 mice of each sex, given drinking water adjusted with 0.1N HCl to the pH (3.7) of the 300-ppm formulation, served as controls. Survival was comparable among groups except for male mice receiving the high dose of 4,4'-methylenedianiline dihydrochloride; survival in that group was lower (P=0.006) than that in controls. Mean body weight was reduced in high dose female rats and in high dose male and female mice. Water consumption was reduced in a dose-related manner in both sexes of rats. No compound-related clinical effects were observed. Compound-related nonneoplastic lesions of the thyroid in female rats included follicular cysts and hyperplasia. The incidence of thyroid follicular cell hyperplasia was elevated in high dose male and female mice. The incidences of thyroid neoplasms in the high dose groups were elevated compared with those of the control groups for both sexes of both species. Thyroid follicular cell carcinoma was increased in male rats (controls, 0/49; low dose, 0/47; high dose, 7/48, 15%: P</=0.012). Follicular cell adenoma was increased in high dose female rats (0/47; 2/47, 4%; 17/48, 35%: P<0.001), in high dose male mice (0/47; 3/49, 6%; 16/49, 33%: P<0.001), and in high dose female mice (0/50; 1/47, 2%; 13/50, 26%: P<0.001) as compared with controls. In female rats, thyroid C-cell adenoma was also elevated in a dose-related manner (0/47; 3/47, 6%; 6/48, 13%, P</=0.029). Dose-related increases in nonneoplastic lesions were observed for male rats (nonspecific liver dilatation) and for male and female rats (fatty metamorphosis and focal cellular change). Liver degeneration was present in 80% of the low dose and 60% of the high dose male mice but was not found in the controls. Neoplastic nodules of the liver were observed at greater incidences (P</=0.002) for low and high dose male rats as compared with controls (control, 1/50, 2%; low dose, 12/50, 24%, P</=0.002; high dose 25/50, 50%, P<0.001). Hepatocellular adenoma was increased in a dose-related manner in dosed female mice (3/50, 6%; 9/50, 18%; 12/50, 24%, P<0.011). Hepatocellular carcinoma was observed in greater incidence in dosed male mice (10/49, 20%; 33/50, 66%, P<0.001; 29/50, 58%, P<0.001) and in high dose female mice (1/50, 2%; 6/50, 12%; 11/50, 22%, P=0.002). Male rats had a dose related increase in kidney mineralization. Nephropathy was increased in dosed mice of both sexes; renal papillary mineralization was greater in high dose male mice and female mice than in the controls. Other tumors that were elevated in dosed animals included adrenal pheochromocytomas in male mice (control, 2/48, 4%; low dose, 12/49, 24%, P</=0.006; high dose, 14/49, 29%; P</=0.001), alveolar/bronchiolar adenoma in female mice (1/50, 2%; 2/50, 4%; 6/49, 12%, P</=0.05) and malignant lymphomas in female mice (13/50,26%; 28/50, 56%, P=0.002; 29/50, 58%; P=0.001). Uncommon tumors were observed in dosed animals at low incidences but may be important because the historical control incidences are very low; bile duct adenoma in 1/50 high dose male (13/50,26&percnt;; 28/50, 56&percnt;, P=0.002; 29/50, 58&percnt;; P=0.001). Uncommon tumors were observed in dosed animals at low incidences but may be important because the historical control incidences are very low; bile duct adenoma in 1/50 high dose male rats (historical control 3/3,663), transitional-cell papillomas of the urinary bladder in female rats (historical control, 3/3,664, 0.08&percnt;; low dose, 2/50, 4&percnt;; high dose, 1/50, 2&percnt;) and granulosa cell tumors of the ovary in female rats (historical control, 11/3,642, 0.3&percnt;; low dose, 3/50, 6&percnt;; high dose, 2/50, 4&percnt;). Decreases in tumor incidences were observed for leukemia in male rats (control, 12/50, 24&percnt;; low dose, 6/50, 12&percnt;; high dose, 5/50, 10&percnt;, P=0.048) and alveolar or bronchiolar adenomas (combined) in male mice (12/49, 24&percnt;; 9/49, 18&percnt;; 3/49, 6&percnt;, P≤0.011). Under the conditions of these studies, 4,4'-methylenedianiline dihydrochloride was carcinogenic for F344/N rats and B6C3F1 mice of each sex, causing significantly increased incidences of thyroid follicular cell carcinomas in male rats, thyroid follicular cell adenomas in female rats and in mice of each sex, C-cell adenomas of the thyroid gland in female rats, neoplastic nodules in the liver of male rats, hepatocellular carcinomas in mice of each sex, adenomas of the liver and malignant lymphomas in female mice, and adrenal pheochromocytomas in male mice. Levels of Evidence of Carcinogenicity: Male Rats: Positive Female Rats: Positive Male Mice: Positive Female Mice: Positive
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PMID:NTP Carcinogenesis Studies of 4,4'-Methylenedianiline Dihydrochloride (CAS No. 13552-44-8) in F344/N Rats and B6C3F1 Mice (Drinking Water Studies). 1275 Jul 45

Propyl gallate is a white to nearly white odorless powder having a slightly bitter taste. Solutions of propyl gallate turn dark in the presence of iron or iron salts. Propyl gallate has been used since 1948 as an antioxidant to stabilize cosmetics, food packaging materials, and foods containing fats. As an additive, it may be found in edible fats, oils, mayonnaise, shortening, baked goods, candy, dried meat, fresh pork sausage, and dried milk, and it is used in hair grooming products, pressure-sensitive adhesives, lubricating oil additives, and transforming oils. A NTP Carcinogenesis bioassay of propyl gallate was conducted by feeding diets containing 6,000 or 12,000 ppm propyl gallate to groups of 50 F344/N rats and 50 B6C3F1 mice of each sex for 103 weeks. Groups of 50 untreated rats and 50 untreated mice of each sex served as controls. Survival of rats and mice was not adversely affected by propyl gallate, but mean body weights of dosed rats and mice of each sex were lower than those of the controls. At 104 weeks, mean body weights of low-and high-dose rats were 4% and 8% lower than those of the controls for males and 11% and 19% lower than those of the controls for females. Similarly, mean body weights of low-and high-dose mice were 5% and 8% lower than those of the controls for males and 11% (both dose groups) lower than those of the controls for females. Thyroid follicular-cell adenomas or carcinomas (combined) occurred in male rats with a statistically significant (P<0.05) positive trend, but the incidences in the dosed groups were not statistically significant in direct comparisons with the control groups. Moreover, the incidence of high-dose male rats with follicular-cell tumors (3/50, 6%) was not statistically different from the historical control rate (14/584, 2.4%) for the laboratory that conducted this bioassay. Rare tumors (an astrocytoma or a glioma) were found in the brains of two low-dose female rats. The incidence of all brain tumors in the Bioassay Program is only 0.86%. The absence of this tumor in the high-dose female rat group reduces the likelihood that this tumor is related to propyl gallate administration. Increased incidences of hepatic cytoplasmic vacuolization and suppurative inflammation of the prostate were observed in dosed male rats. These findings were considered to be related to administration of propyl gallate. Tumors (mostly benign) of the preputial gland, islet-cell tumors of the pancreas, and pheochromocytomas of the adrenal gland were observed with significantly (P<0.05) higher incidences in the low- dose male rats, but there was little evidence of an effect in the high-dose group. The incidences of male rats with tumors of the preputial gland were 1/50 (2%) for controls, 8/50 (16%) for the low-dose, and 0/50 (0%) for the high-dose group. Islet-cell tumors of the pancreas occurred in 2/50 (4%) control males, 9/50 (18%) low-dose males, and 4/50 (8%) for high-dose males. Pheochromocytomas of the adrenal gland were observed in 4/50 (8%) control males, 13/48 (25%) low-dose males, and 8/50 (16%) high-dose males. Negative trends (P<0.05) were observed for leukemia in male rats (16/50, 7/50, 6/50) and for fibroadenomas of the mammary gland in female rats (11/50, 2/50, 5/50). In male mice, malignant lymphoma was observed with a significantly (P</=0.014) positive trend (control, 1/50, 2%; low-dose, 3/49, 6%; high-dose, 8/50, 16%), and the incidence in the high-dose group was significantly (P</=0.028) higher than that observed in the concurrent controls. However, the high-dose incidence was not statistically different from the historical rate (60/640, 9.4%) for the laboratory that conducted this bioassay. Adenomas of the liver in female mice occurred with a statistically significant (P</=0.022) positive trend, and the incidence in the high-dose group was significantly (P</=0.039) higher than that of the controls (0/50, 0%; 2/50, 4%; 5/49, 10%). The incidences of hepatocellular adenomas or carcinomas (combined) were similar in control and dosed groups (3/50, 6%; 3/50, 6%; 5/49, 10%). Negative&percnt;; 2/50, 4&percnt;; 5/49, 10&percnt;). The incidences of hepatocellular adenomas or carcinomas (combined) were similar in control and dosed groups (3/50, 6&percnt;; 3/50, 6&percnt;; 5/49, 10&percnt;). Negative trends (P<0.05) were obtained for fibromas of the skin or subcutaneous tissue in male mice (5/50, 1/49, 0/50). Under the conditions of this bioassay, propyl gallate was not considered carcinogenic for F344/N rats, although there was evidence of an increased proportion of low-dose male rats with preputial gland tumors, islet-cell tumors of the pancreas, and pheochromocytomas of the adrenal glands; rare tumors of the brain occurred in two low-dose females. Propyl gallate was not considered to be carcinogenic for B6C3F1 mice of either sex, although the increased incidence of malignant lymphoma in male mice may have been related to the dietary administration of propyl gallate. Levels of Evidence of Carcinogenicity: Male Rats: Equivocal Female Rats: Negative Male Mice: Equivocal Female Mice: Negative Synonyms: 2,4,5 trihydroxybenzoic acid propyl ester; gallic acid propyl ester; Progallin P; Tennox PG
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PMID:NTP Carcinogenesis Bioassay of Propyl Gallate (CAS No. 121-79-9) in F344/N Rats and B6C3F1 Mice (Feed Study). 1275 Jul 52

A bioassay of lasiocarpine for possible carcinogenicity was conducted by administering the test chemical in the diet to Fischer 344 rats. Groups of 24 rats of each sex were administered lasiocarpine at one of three doses, either 7, 15, or 30 ppm, for 104 weeks. Matched controls consisted of groups of 24 untreated rats of each sex. All surviving rats were killed at 104 weeks. Mean body weights of the high-dose male and female rats were lower than those of the matched-control groups throughout most of the study, while weights of the mid-dose rats were lower only during the second year, and weights of the low-dose groups were unaffected. There was a positive dose-related trend in mortality for both sexes, with none of the high-dose animals, only five of the mid-dose animals, 23 of the low-dose animals, and 43 of the matched controls surviving to termination of the study. In spite of these early deaths, all male rats except one low-dose animal and one high-dose animal developed tumors, and among the females, 23 low-dose and 22 mid-dose animals developed tumors. Time-adjusted analysis of the incidence of tumors was performed in the female rats. In male rats, there was a positive dose-related trend (P<0.001) in the incidence of angiosarcoma of the liver; furthermore, the incidences in the mid- and high-dose groups, but not that in the low-dose, were significantly higher (P<0.001, both groups) than that in the controls (controls 0/24, low-dose 5/24, mid-dose 11/24, high-dose 13/24). In females, the incidences in both the low- and mid-dose groups, but not that in the high-dose, were significantly higher (P=0.002 and P=0.005, respectively) than that in the controls (controls 0/24, low-dose 8/24, mid-dose 7/24, high-dose 2/9). Metastatic angiosarcomas were present in the lungs from a few of the rats in all three treated groups of both sexes. In both male and female rats, there was a positive dose-related trend in the combined incidence of hepatocellular carcinoma and adenoma of the liver (males, P=0.003; females, P<0.001); furthermore, the combined incidence of these tumors in the high-dose females, but not those in the low- and mid-dose, was significantly higher (P<0.001) than that in the controls (controls 0/24, low-dose 5/24, mid-dose 1/24, high-dose 7/9). The P-value of the combined incidence in the high-dose males (P=0.025) is above the 0.016 level required by the Bonferroni inequality criterion, when multiple comparison is considered (controls 0/24, low-dose 0/24, mid-dose 3/24, high-dose 5/24). Nodular hyperplasia was observed in additional animals of each treated group of each sex. Thus, lasiocarpine was associated with proliferative lesions of hepatocytes as well as with angiosarcomas arising from endothelial cells of the liver. The combined incidence of lymphoma or leukemia was significant in both the low- and mid-dose female groups (P</= 0.018), but not in the high-dose group, perhaps because of the early deaths in this group (controls 2/24, low-dose 9/24, mid-dose 11/24, high-dose 1/23). The incidences of these tumors in the males were not significant. It is concluded that under the conditions of this bioassay, lasiocarpine was carcinogenic in Fischer 344 rats producing hepatocellular tumors and angiosarcomas of the liver in both sexes and hematopoietic tumors in female animals.
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PMID:Bioassay of lasiocarpine for possible carcinogenicity. 1284 68

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