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National Toxicology Program

Publications and source records attributed to National Toxicology Program.

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PubMed1990

NTP Toxicology and Carcinogenesis Studies of 3,3'-Dimethoxybenzidine Dihydrochloride (CAS No. 20325-40-0) in F344/N Rats (Drinking Water Studies).

3,3'-Dimethoxybenzidine dihydrochloride is an off-white powder with a melting point of 274 degrees C. 3,3'-Dimethoxybenzidine is used principally as an intermediate in the production of commercial bisazobiphenyl dyes for coloring textiles, paper, plastic, rubber, and leather. In the synthesis of the bisazobiphenyl dyes, the amine groups of 3,3'-dimethoxybenzidine are chemically linked with other aromatic amines. A small quantity of 3,3'-dimethoxybenzidine is also used as an intermediate in the production of o-dianisidine diisocyanate, which is used in isocyanate-based adhesive systems and as a component of polyurethane elastomers. 3,3'-Dimethoxybenzidine dihydrochloride was evaluated in toxicity and carcinogenicity studies as part of the National Toxicology Program's Benzidine Dye Initiative. This Initiative was designed to evaluate the representative benzidine congeners and benzidine congener-derived and benzidine-derived dyes. 3,3'-Dimethoxybenzidine dihydrochloride was nominated for study because of the potential for human exposure during production of bisazobiphenyl dyes and because benzidine, a structurally related chemical, is a known human carcinogen. NTP Toxicology and Carcinogenesis studies were conducted by administering 3,3'-dimethoxybenzidine dihydrochloride (greater than 97.5% pure) in drinking water to groups of F344/N rats of each sex for 14 days, 13 weeks, 9 months, or 21-months. The 21-month studies were intended to last 24 months but were terminated early because of rapidly declining survival due to neoplasia. Studies were performed only in rats because similar studies are being performed in mice at the National Center for Toxicology Research. Genetic toxicology studies were conducted with Salmonella typhimurium, Chinese hamster over (CHO) cells, and Drosophila melanogaster. Fourteen-Day Studies: All rats receiving drinking water concentrations up to 4,500 ppm lived to the end of the studies. Rats that received water containing 4,500 ppm 3,3'-dimethoxybenzidine dihydrochloride lost weight. Water consumption decreased with increasing concentration of chemical and at 4,500 ppm was less than one-fourth that by the controls. Lymphoid depletion of the thymus in males and hypocellularity of the bone marrow in males and females were seen at the 4,500-ppm concentration, but not at the next lower concentration or in controls. Thirteen-Week Studies: All rats receiving concentrations up to 2,500 ppm lived to the end of the studies. Final mean body weights of rats given drinking water containing 1,250 or 2,500 ppm 3,3'-dimethoxybenzidine dihydrochloride were 5%-20% lower than those of controls. Water consumption at these concentrations was 40%-60% that consumed by controls. Compound-related effects in rats given water containing 2,500 ppm 3,3'-dimethoxybenzidine dihydrochloride included a mind exacerbation of naturally occurring nephropathy and the presence of a yellow-brown pigment (lipofuscin) in the cytoplasm of thyroid follicular cells. Serum triiodothyronine (T3) and thyroxin (T4) concentrations in females receiving 330 ppm or more and T4 concentrations in males receiving 170 ppm or more were significantly lower than in controls. Thyrotropin (TSH) concentrations were comparable in controls and exposed rats. Based on the chemical-related nephropathy and reductions in water consumption and body weight gain observed in the 13-week studies, doses for the long-term studies in male and female rats were 0 or 330 ppm 3,3'-dimethoxybenzidine dihydrochloride in drinking water administered for 9 months and 0, 80, 170, or 330 ppm administered for 21 months. Nine-Month Studies: Ten rats of each sex in control and 330-ppm groups were evaluated after 9 months. Significant decreases in T3 and T4 concentrations were seen in exposed male and female rats. Other lesions seen in exposed rats included foci of alteration in the liver, a carcinoma of the preputial gland in one male, a carcinoma of the clitoral gland in one female, and carcinoma of the Zymbal gland in two males. Body Weights and Survival in the Twenty-One-Month Studies: The average amount of 3,3'-dimethoxybenzidine dihydrochloride consumed per day was approximately 6, 12, or 21 mg/kg for low, mid, or high dose male rats and 7, 14, or 23 mg/kg for low, mid, or high dose female rats. Mean body weights of male and female rats began to decrease relative to those of controls after about 1 year of exposure at 170 or 330 ppm and were 6%-22% lower for males and 7%-17% lower for females. Survival of rats exposed to 3,3'-dimethoxybenzidine dihydrochloride was reduced because animals were dying with neoplasms or being killed in a moribund condition (survival at 21 months--male: control, 44/60, 73%; low dose, 8/45, 18%; mid dose, 0/75; high dose, 0/60; female: 45/60, 75%; 15/45, 33%; 6/75, 8%; 0/60). Because of these early compound-related deaths, the studies were terminated at 21 months. Nonneoplastic and Neoplastic Effects in the Twenty-One-Month Studies: Increased incidences of several nonneoplastic lesions were observed in exposed rats, including hematopoietic cell proliferation in the spleen and cystic and centrilobular degeneration and necrosis of the liver. Neoplasms attributed to 3,3'-dimethoxybenzidine dihydrochloride exposure were observed in rats at many tissue sites, including the skin, Zymbal gland, preputial and clitoral glands, oral cavity, small and large intestines, liver, brain, mesothelium, mammary gland, and uterus/cervix. The incidences of these neoplasms in male and female rats are given in the abstract summary table (see page 5 of the Technical Report). Genetic Toxicology: 3,3'-Dimethoxybenzidine was mutagenic in S. typhimurium strain TA100 with exogenous metabolic activation and in strain TA98 without activation; a weakly positive response was observed in strain TA1535 with metabolic activation. 3,3'-Dimethoxybenzidine induced sister chromatid exchanges and chromosomal aberrations in CHO cells with and without exogenous metabolic activation. 3,3'-Dimethoxybenzidine did not induce sex-linked recessive lethal mutations in adult male D. melanogaster exposed via feeding or injection. Conclusions: Under the conditions of these 21-month drinking water studies, there was clear evidence of carcinogenic activity of 3,3'-dimethoxybenzidine dihydrochloride for male F344/N rats, as indicated by benign and malignant neoplasms of the skin, Zymbal gland, preputial gland, oral cavity, intestine, liver, and mesothelium. Increased incidences of astrocytomas of the brain may have been related to chemical administration. There was clear evidence of carcinogenic activity of 3,3'-dimethoxybenzidine dihydrochloride for female F344/N rats, as indicated by benign and malignant neoplasms of the Zymbal gland, clitoral gland, and mammary gland. Increases in neoplasms of the skin, oral cavity, large intestine, liver, and uterus/cervix were also considered to be related to chemical administration of 3,3'-dimethoxybenzidine dihydrochloride. Synonyms: o-dianisidine dihydrochloride; 3,3'-dimethoxy-1,1-biphenyl)-4,4'-diamine dihydrochloride; 3,3'-dimethoxy-4,4'-diaminobiphenyl dihydrochloride

Journal Article↗
PubMed1990

NTP Toxicology and Carcinogenesis Studies of Toluene (CAS No.108-88-3) in F344/N Rats and B6C3F1 Mice (Inhalation Studies).

Toluene is used to back-blend gasoline, as a chemical intermediate, and as a solvent; 920 million gallons were produced in the United States in 1988. Toxicology studies were conducted by administering toluene (greater than 99% pure) in corn oil by gavage to groups of F344/N rats and B6C3F1 mice of each sex for 13 weeks or by whole-body inhalation exposure for 14 or 15 weeks. NTP Toxicology and Carcinogenesis studies were conducted by whole-body inhalation exposure of F344/N rats and B6C3F1 mice of each sex for 15 months or 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium, mouse L5178Y lymphoma cells, and Chinese hamster ovary cells. Thirteen-Week Gavage Studies: All rats that received the top dose of 5,000 mg/kg died during the first week, and 8/10 male rats that received 2,500 mg/kg died early. The final mean body weight of male rats that received 2,500 mg/kg was 19% lower than that of vehicle controls. Relative liver, kidney, and heart (female only) weights for rats that received the higher doses were greater than those for vehicle controls. Necrosis of the brain and hemorrhage of the urinary bladder were seen at increased incidences in dosed rats. All mice that received the top dose of 5,000 mg/kg died during the first week, and 40% of those that received 2,500 mg/kg died before the end of the 13-week gavage studies. The final mean body weight of males at 2,500 mg/kg was 16% lower than that of vehicle controls. At the higher doses, relative liver weights were increased for mice. Fifteen-Week and Fourteen-Week Inhalation Studies: Eight of 10 male rats exposed at the top exposure concentration of 3,000 ppm died during week 2. Final mean body weights of rats exposed at concentrations of 2,500 or 3,000 ppm were 14%-25% lower than that of controls. As in the gavage studies, the relative liver, kidney, and heart weights for rats exposed at the top two concentrations were increased compared with those for controls. No compound-related effects were seen on sperm; no adverse effects on the estrous cycle were observed. Five of 10 male mice and all female mice exposed at 3,000 ppm and 70% of female mice at 2,500 ppm died during the first 2 weeks. Final mean body weights of all exposed groups were 7%-13% lower than those of controls. Relative liver weights for mice exposed at 625 ppm or higher, relative lung weights for mice exposed at 1,250 ppm or higher, and relative kidney weights for female mice exposed at 1,250 ppm or higher were greater than those for controls. Centrilobular hypertrophy of the liver was observed in all male mice exposed at 2,500 ppm and 70% of male mice exposed at 3,000 ppm. No effects on sperm or the estrous cycle were observed. Fifteen-Month and Two-Year Inhalation Studies: Long-term studies were conducted by exposing groups of 60 rats of each sex to 0, 600, or 1,200 ppm toluene by inhalation, 6.5 hours per day, 5 days per week. Groups of 60 mice of each sex were exposed at 0, 120, 600, or 1,200 ppm on the same schedule. Ten animals per group (except male mice) were removed for toxicologic evaluation after being exposed for 15 months. All other animals were exposed to toluene for 103 weeks. In the 15-month inhalation studies, the incidences and severity of nonneoplastic lesions of the nasal cavity (degeneration of olfactory and respiratory epithelium and goblet cell hyperplasia) were increased in exposed rats. Minimal hyperplasia of the bronchial epithelium was seen in 4/10 female mice at 1,200 ppm. The severity of nephropathy was slightly increased in exposed female rats. No chemical-induced neoplasms were observed. Body Weight and Survival in the Two-Year Studies: Mean body weights of rats and mice were generally similar (yearly averages within 5%) among groups throughout the 2-year studies. No significant differences in survival were observed among rats or mice of either sex, although survival in all groups of male mice was lower than usual (male rats: control, 30/50; 600 ppm, 28/50; 1,200 ppm, 22/50; female rats: 33/50; 35/50; 30/50; male mice: control, 17/60; 120 ppm, 22/50; female rats: 33/50; 35/50; 30/50; male mice: control, 17/60; 120 ppm, 22/60; 600 ppm, 16/60; 1,200 ppm, 19/60; female mice: 30/50; 33/50; 24/50; 32/50). Scrotal, preputial, and penile lesions observed in male mice were associated with many of the early deaths and with animals killed in a moribund condition. Nonneoplastic and Neoplastic Effects in the Two-Year Studies: Nephropathy was seen in almost all rats, and the severity was somewhat increased in exposed rats. A rare renal tubular cell carcinoma in a female rat and an equally uncommon sarcoma of the kidney in another female rat were seen in the 1,200-ppm exposure group. Erosion of the olfactory epithelium and degeneration of the respiratory epithelium were increased in exposed rats. Inflammation of the nasal mucosa and metaplasia of the olfactory epithelium were increased in exposed female rats. A rare squamous cell carcinoma of the nasal mucosa was seen in one female rat at 1,200 ppm. A squamous cell papilloma of the forestomach was observed in one female rat at 1,200 ppm, and a squamous cell carcinoma was observed in a second female rat at 1,200 ppm. No chemically related neoplasms were found in male rats, and the one nasal, two kidney, and two forestomach neoplasms observed in female rats were considered not to be associated with inhalation exposed to toluene. For mice, no biologically important increases were observed for any nonneoplastic or neoplastic lesions. Genetic Toxicology: Toluene did not induce gene mutations in S. typhimurium strain TA98, TA100, TA1535, or TA1537 with or without exogenous metabolic activation. In the mouse lymphoma assay, toluene gave an equivocal response with and without exogenous metabolic activation. Toluene did not induce sister chromatid exchanges or chromosomal aberrations in Chinese hamster ovary cells in the presence or absence of exogenous metabolic activation. 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 toluene at concentrations of 600 or 1,200 ppm. There was no evidence of carcinogenic activity for male or female B6C3F1 mice exposed by inhalation to toluene at concentrations of 120, 600, or 1,200 ppm for 2 years. Synonyms: monomethylbenzene; methylbenzene; toluol; phenylmethane; tolueen (Dutch); toluen (Czech), tolueno (Spanish); toluolo (Italian) Trade Name: Methacide

Journal Article↗
PubMed1990

NTP Toxicology and Carcinogenesis Studies of Furfural (CAS No. 98-01-1) in F344/N Rats and B6C3F1 Mice (Gavage Studies).

Furfural is used as a precursor for the manufacture of furan, furfuryl alcohol, tetrahydrofuran, and their derivatives and as an industrial solvent. Furfural is also present in numerous processed food and beverage products. NTP Toxicology and Carcinogenesis studies were conducted by administering furfural (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, Drosophila melanogaster, and mouse bone marrow cells. Sixteen-Day Studies: Rats received doses ranging from 15 to 240 mg/kg, and mice received doses from 25 to 400 mg/kg. Eight of 10 rats that received 240 mg/kg died within 3 days. Final mean body weights of chemically exposed animals were similar to those of vehicle controls; no compound-related histologic lesions were observed in any dosed groups. Thirteen-Week Studies: Rats received doses ranging from 11 to 180 mg/kg, and mice received doses from 75 to 1,200 mg/kg. Most rats that received 180 mg/kg died; mean body weights of chemically exposed rats were similar to those of vehicle controls. Mean relative and absolute liver and kidney weights were increased in male rats that received 90 mg/kg, and cytoplasmic vacuolization of hepatocytes was increased in chemically exposed male rats. Almost all mice that received doses of 600 or 1,200 mg/kg died within the first 3 weeks. Mean body weights of chemically exposed mice were similar to those of vehicle controls throughout the studies. Mean absolute liver weights and liver weight to body weight ratios were increased in females that received 300 mg/kg. Centrilobular coagulative necrosis and/or multifocal subchronic inflammation of the liver were present in chemically exposed mice but not in vehicle control mice. Based on these results, doses selected for the 2-year studies were 0, 30, and 60 mg/kg for rats and 0, 50, 100, and 175 mg/kg for mice. Body Weight and Survival in the Two-Year Studies: Mean body weights of chemically exposed and vehicle control animals were similar throughout the studies for rats and mice. Two-year survival of male rats; low dose female rats, and mice was unaffected by chemical exposure (male rats: vehicle control, 31/50; low dose, 28/50; high dose, 24/50; female rats: 28/50; 32/50; 18/50; male mice: vehicle control, 35/50; low dose, 28/50; mid dose, 24/50; high dose, 27/50; female mice: 33/50; 28/50; 29/50; 32/50). Survival of high dose female rats was reduced by deaths associated with gavage administration; the administration of furfural was considered to be a contributing factor in these gavage-related deaths. Nonneoplastic and Neoplastic Effects in the Two-Year Studies: Centrilobular necrosis of the liver occurred at increased incidences in chemically exposed male rats (vehicle control, 3/50; low dose, 9/50; high dose, 12/50). Two high dose male rats had bile duct dysplasia with fibrosis, and two had cholangiocarcinomas; neither lesion was seen in the other dose groups. The historical incidence of bile duct neoplasms in corn oil vehicle control male rats is 3/2,145 (0.1%). Multifocal pigmentation and chronic inflammation of the subserosa of the liver occurred in chemically exposed mice (pigmentation--male: 0/50; 0/50; 8/49; 18/50; female: 0/50; 0/50; 0/50; 11/50; chronic inflammation--male: 0/50; 0/50; 8/49; 18/50; female: 0/50; 0/50; 1/50; 8/50). The incidences of hepatocellular adenomas and hepatocellular carcinomas in male mice and hepatocellular adenomas in female mice were significantly increased in the high dose group compared with those in the vehicle controls (male--adenomas: 9/50; 13/50; 11/49; 19/50; carcinomas: 7/50; 12/50; 6/49; 21/50; female--adenomas: 1/50; 3/50; 5/50; 8/50; adenomas or carcinomas, combined: 5/50; 3/50; 7/50; 12/50). Three renal cortical adenomas or carcinomas occurred in chemically exposed male mice (0/50; 1/50; 1/49; 1/50), and a renal cortical adenoma was present in one low dose female mouse; the historical incidence oal incidence of renal cortical neoplasms in National Toxicology Program 2-year corn oil gavage studies in male B6C3F1 mice is 8/2,183. Forestomach hyperplasia occurred in chemically exposed female mice, and squamous cell papillomas were increased in high dose female mice (hyperplasia: 0/50; 5/50; 5/50; 3/50; papillomas: 1/50; 0/50; 1/50; 6/50). Genetic Toxicology: In gene mutation tests with four strains of Salmonella (TA98, TA100, TA1535, and TA1537), no mutagenic activity was observed in the presence or absence of exogenous metabolic activation (S9) in one laboratory and an equivocal response was observed in TA100 in the absence of S9 in a second laboratory. Exposure to furfural induced trifluorothymidine resistance in mouse L5178Y lymphoma cells in the absence of S9 (no evaluation was made in the presence of S9), sister chromatid exchanges (SCEs) and chromosomal aberrations in CHO cells in the presence or absence of S9, and an increase in sex-linked recessive lethal mutations but no reciprocal translocations in germ cells of D. melanogaster; furfural did not induce SCEs or chromosomal aberrations in the bone marrow of B6C3F1 mice. Conclusions: Under the conditions of these 2-year gavage studies, there was some evidence of carcinogenic activity of furfural for male F344/N rats based on the occurrence of uncommon cholangiocarcinomas in two animals and bile duct dysplasia with fibrosis in two other animals. There was no evidence of carcinogenic activity for female F344/N rats that received doses of 0, 30, or 60 mg/kg furfural. There was clear evidence of carcinogenic activity for male B6C3F1 mice, based on increased incidences of hepatocellular adenomas and hepatocellular carcinomas. There was some evidence of carcinogenic activity in female B6C3F1 mice, based on increased incidences of hepatocellular adenomas. Renal cortical adenomas or carcinomas in male mice and squamous cell papillomas of the forestomach in female mice may have been related to exposure to furfural. Synonyms: 2-furancarboxaldehyde; 2-furaldehyde; pyromucic aldehyde Common Name: Artificial oil of ants

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↗
PubMed1990

NTP Toxicology and Carcinogenesis Studies of d-Limonene (CAS No. 5989-27-5) in F344/N Rats and B6C3F1 Mice (Gavage Studies).

Toxicology and carcinogenesis studies of d-limonene, a naturally occurring monoterpene found in many volatile oils, especially in citrus oils, were conducted because of its widespread use as a flavor and fragrance additive for food and household cleaning products and its increasing use as an industrial solvent. The d-limonene used in these studies was more than 99% pure and was administered in corn oil by gavage. Short-term studies were conducted in F344/N rats and B6C3F1 mice to identify toxic effects and affected sites and to help establish doses for the 2-year studies. Genetic toxicology studies were conducted in Salmonella typhimurium, mouse L5178Y cells, and Chinese hamster ovary (CHO) cells. The doses selected for the 16-day studies ranged from 413 to 6,600 mg/kg for both rats and mice; deaths and reduction in body weight gain occurred at the two highest doses. No compound-related clinical signs or histopathologic lesions were observed in any of the surviving dose groups. In the 13-week studies, doses of d-limonene ranged from 150 to 2,400 mg/kg for rats and from 125 to 2,000 mg/kg for mice. Deaths occurred in the high dose group of each species and sex. Greater than 10% reductions in body weight gain were observed in the two highest dose groups of male rats and male mice and the high dose female rats. Rough hair coats and decreased activity were observed at the two highest doses in both rats and mice. There were no chemical-related histopathologic lesions in female rats or in mice of either sex. A compound-related increased severity of nephropathy was observed in the kidney of male rats. This lesion was characterized by degeneration of epithelial cells in the convoluted tubules, granular casts in the outer stripe of the outer medulla, and epithelial regeneration. These lesions have been described as reasonably characteristic of the hyaline droplet nephropathy that is associated with an accumulation of liver-generated a2u-globulin in the cytoplasm of tubular epithelial cells. Two-year studies of d-limonene were conducted by administering 0, 75, or 150 mg/kg d-limonene in corn oil by gavage to groups of 50 F344/N male rats, 5 days per week for 103 weeks; groups of 50 female F344/N rats were administered 0, 300, or 600 mg/kg. These doses were selected based on compound-related, potentially life-threatening kidney lesions observed in males at 300 mg/kg and higher and on the large number of deaths of female rats at 2,400 mg/kg. Groups of 50 male B6C3F1 mice were administered 0, 250, or 500 mg/kg according to the same schedule; groups of 50 female B6C3F1 mice were administered 0, 500, or 1,000 mg/kg. These doses were selected based on the deaths observed for both male and female mice at 2,000 mg/kg during the 13-week studies and the body weight depression in male mice at 1,000 mg/kg and higher. Mean body weights of rats dosed with d-limonene were similar to those of vehicle controls throughout the studies. Survival of the high dose female rats after week 39 and of the vehicle control male rats after week 81 was significantly reduced (survival at week 104-- male: vehicle control, 29/50; low dose, 33/50; high dose, 40/50; female: 42/50; 40/50; 26/50). Mean body weights of dosed and vehicle control male mice were similar throughout the studies. Mean body weights of high dose female mice were notably lower than those of the vehicle controls after week 28. Survival of the low dose group of male mice was significantly lower than that of vehicle controls at the end of the study (33/50; 24/50; 39/50). No difference in survival was observed between vehicle control and dosed female mice (43/50; 44/50; 43/50). In the 2-year studies, the kidney was confirmed as the primary target organ for chemically related lesions. No lesions were observed in female rats. For males, the nonneoplastic lesions included exacerbation of the age-related nephropathy, linear deposits of mineral in the renal medulla and papilla, and focal hyperplasia of the transitional epithelium overlying the renal papilla. Uncommon tubular cell adenomas and adenocarc and adenocarcinomas of the kidney also occurred in dosed male rats, and this effect was supported by a dose-related increased incidence of tubular cell hyperplasia, as shown in the table below. INCIDENCES OF MALE RATS WITH RENAL LESIONS IN THE TWO-YEAR GAVAGE STUDY OF d-LIMONENE Site/Lesion Vehicle Control 75 mg/kg 150 mg/kg Renal papilla Mineralization 7/50 43/50 48/50 Epithelial hyperplasia 0/50 35/50 43/50 Kidney Tubular cell hyperplasia 0/50 4/50 7/50 Tubular cell adenoma 0/50 4/50 8/50 Tubular cell adenocarcinoma 0/50 4/50 3/50 In subsequent 21-day studies, male and female F344/N rats were administered d-limonene at doses ranging from 75 to 1,200 mg/kg. Microscopic examination of the kidney sections from these rats indicated a compound-related increase in intracytoplasmic granules in the proximal convoluted tubules of dosed male rats but not of female rats. The granules were shown to contain a2u-globulin by an immunohistochemical strain. a2u-Globulin was shown to be increased in kidney homogenates from dosed male rats by an ELISA test. In mice, no chemically related increases in neoplasms were observed. The incidence of neoplasms of the anterior pituitary gland in high dose female mice was lower than that in vehicle controls (adenomas or carcinomas, combined:vehicle control, 12/49; high dose, 2/48). Cells with an abnormal number of nuclei (8/49; 32/50) and cytomegaly (23/49; 38/50) were observed in the liver of high dose male mice. Genetic Toxicology: d-Limonene was not mutagenic in four strains of S. typhimurium (TA98, TA100, TA1535, or TA1537), did not significantly increase the number of trifluorothymidine (Tft)-resistant cells in the mouse L5178Y/TK± assay, and did not induce chromosomal aberrations or sister chromatid exchanges (SCEs) in cultured CHO cells. All assays were conducted in the presence and absence of exogenous metabolic activation. Conclusions: Under the conditions of these 2-year gavage studies, there was clear evidence of carcinogenic activity of d-limonene for male F344/N rats, as shown by increased incidences of tubular cell hyperplasia, adenomas, and adenocarcinomas of the kidney. There was no evidence of carcinogenic activity of d-limonene for female F344/N rats that received 300 or 600 mg/kg. There was no evidence of carcinogenic activity of d-limonene for male B6C3F1 mice that received 250 or 500 mg/kg. There was no evidence of carcinogenic activity of d-limonene for female B6C3F1 mice that received 500 or 1,000 mg/kg. An increased severity of spontaneous nephropathy, increased incidences of linear mineralization of the renal medulla and papilla, and hyperplasia of the transitional epithelium of the renal papilla were present in dosed male rats. Synonyms: cyclohexene; 4-isopropenyl-1-methyl; 1-methyl-4-(1-methylethenyl)cyclohexene; p-mentha-1,8-diene; carvene; cinene; cajeputene

Journal Article↗
PubMed1990

NTP Toxicology and Carcinogenesis Studies of Iodinated Glycerol (Organidin(R).) (CAS No. 5634-39-9) in F344/N Rats and B6C3F1 Mice (Gavage Studies).

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%) in water gavage vehicle control female B6C3F1 mice and is 18/1,994 (0.9%) 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

Journal Article↗
PubMed1990

NTP Toxicology and Carcinogenesis Studies of Amosite Asbestos (CAS No. 12172-73-5) in F344/N Rats (Feed Studies).

The term "asbestos" has a commercial/industrial derivation limited to naturally occurring fibrous minerals of the serpentine or amphibole series. Chrysotile is the only type of asbestos in the serpentine series, whereas the amphibole series is represented by actinolite, amosite, anthophyllite, crocidolite, and tremolite. The essential characteristic of asbestos minerals is their fibrous nature. Large portions of the population ingest asbestos through consumption of food and water. Asbestos or asbestos-like fibers may gain access to water supplies as a result of mining (Lake Superior), from the presence of natural serpentine or amphibole deposits in watersheds (Seattle, WA, and San Francisco, CA) or, under certain conditions, through the use of asbestos-cement pipes for municipal water supplies. For the latter, erosion of the pipe with release of fibers is associated with the "aggressiveness" of the water, a term representing a mathematical expression of pH, alkalinity, and calcium content. The EPA estimated that 68.5% of water systems in the United States utilize water that is potentially capable of eroding asbestos-cement pipe. Carcinogenesis studies of amosite asbestos alone or in combination with the intestinal carcinogen 1,2-dimethylhydrazine dihydrochloride (DMH) were conducted in male and female rats. Amosite asbestos was administered at a concentration of 1% in pelleted diet for the entire lifetime of the rats, starting with the dams of the study animals. One group of amosite asbestos-exposed rats (amosite preweaning gavage) also received chrysotile asbestos via gavage during lactation. Group sizes varied from 100 to 250. Litter size was the same, but the offspring from mothers exposed to amosite asbestos were smaller at weaning than those from nonexposed mothers and remained smaller throughout their life. The DMH was administered by gavage at a dose of 7.5 mg/kg for males and 15 mg/kg for females every 14 days, starting at 8 weeks of age, for a total of five doses. The administration of DMH did not affect body weight gain either in amosite-exposed or nonexposed animals. The amosite-exposed rats showed enhanced survival compared with that of the nonexposed rats. DMH exposure reduced survival by approximately 1 year, although the survival of the amosite plus DMH groups was slightly greater than that of the DMH group alone. Significant increases in the incidences of C-cell carcinomas of the thyroid gland (untreated control, 11/117; amosite, 50/246, P<0.05; amosite preweaning gavage, 14/100) and of leukemia (38/117; 106/249, P<0.05; 49/100, P<0.01) in male rats were observed in amosite-exposed groups. However, the biologic significance of the C-cell carcinomas in relation to amosite asbestos exposure is discounted because of a lack of significance when C-cell adenomas and carcinomas were combined and because the positive effect was not observed in the amosite preweaning gavage group. The biologic significance of an increased incidence of leukemia is questionable because of a lack of statistical significance in the amosite group when evaluated by life table analysis and because no toxic lesions were observed in the target organs, i.e., gastrointestinal tract and mesothelium. DMH caused a high incidence (62%-74%) of intestinal neoplasia in amosite-exposed and nonexposed groups. Neither an enhanced carcinogenic nor a protective effect was demonstrated by exposure to amosite asbestos. Conclusions: Under the conditions of these feed studies, amosite asbestos was not overtly toxic, did not affect survival, and was not carcinogenic when ingested at a concentration of 1% in the diet by male or female F344/N rats. The cocarcinogenic studies using DMH were considered inadequate because of the high incidence of DMH-induced intestinal neoplasia in both the amosite asbestos-exposed and nonexposed groups. Levels of Evidence of Carcinogenicity: Amosite Asbestos: Male Rats: Negative. Female Rats: Negative. Amosite Asbestos + DMH: Male Rats: Inadequate. Female Rats: Inadequate. Note: Amosite Asbestos was previously tested in Syrmosite Asbestos was previously tested in Syrian Golden Hamsters administered in feed (See TR-249, reported 1983).

Journal Article↗
PubMed1990

NTP Toxicology and Carcinogenesis Studies of 2,6-Xylidine (2,6-Dimethylaniline) (CAS No. 87-62-7) in Charles River CD Rats (Feed Studies).

2,6-Xylidine is a chemical intermediate used principally in the production of dyes. It is also a component of tobacco smoke, a degradation product of aniline-based pesticides, and a metabolite of certain drugs, particularly the xylide group of local anesthetics. The National Toxicology Program (NTP) sponsored single-administration, 2-week, and 13-week studies of 2,6-xylidine by gavage in F344/N rats. The U.S. Environmental Protection Agency (EPA) sponsored short-term gavage studies and 10-week range-finding studies in Charles River CD rats (a Sprague Dawley-derived strain). A carcinogenesis study of 2,6-xylidine was initiated by the EPA, which designed and monitored the study during the 2-year exposure period. The NTP then assumed responsibility for the study, conducting terminal kill, necropsy, histopathologic evaluation, data analysis, and report preparation. Oral LD50 values of 1.2-1.3 g/kg were calculated for F344/N and Charles River CD rats administered single doses of 2,6-xylidine. Marginally toxic effects occurred in the hepatic, renal, and hematopoietic systems of dosed rats in the single-administration, 2-week, 10-week, and 13-week studies. The 56 male and 56 female Charles River CD rats used in the 104-week carcinogenesis studies were the offspring of animals fed diets containing 0, 300, 1,000, or 3,000 ppm 2,6-xylidine before breeding, during pregnancy, and through the lactation period. The concentrations of 2,6-xylidine offered to animals in the 104-week studies were the same as those given to their parents. During most of the 2-year studies, high dose male and female rats showed a reduction (greater than 10%) in body weight gain. Survival in the high dose male rats was significantly reduced (P<0.001) relative to that in controls. Survival also was reduced in the 1,000-ppm group. There was no significant relationship between concentration and mortality in female rats, but mortality was high for all groups of female rats during the second year of the study. The epithelium of the nasal cavity was the primary site of compound-related neoplastic and nonneoplastic lesions. The incidences of both papillomas and carcinomas of the nasal cavity were significantly increased in high dose male and female rats. Carcinomas or adenocarcinomas (combined) occurred in 28/56 high dose males, 24/56 high dose females, and 1/56 mid dose females. Papillary adenomas occurred in 10/56 high dose males, 2/56 mid dose males, and 6/56 high dose females. None occurred in the other groups. The carcinomas were highly invasive and frequently destroyed the nasal turbinates and nasal septum. Metastasis to the brain was present in 5/56 male and 7/56 females high dose rats. Malignant mesenchymal tumors were observed in the nasal cavity. Rhabdomyosarcomas occurred in two high dose male rats and two high dose female rats. These rare malignant tumors have not been previously reported at this site in Sprague Dawley rats. Malignant mixed tumors having features of adenocarcinomas and rhabdomyosarcomas were reported in one high dose male and one high dose female rat. One undifferentiated sarcoma was seen in a high dose female rat. The nonneoplastic lesions observed in the nasal cavity included acute inflammation, epithelial hyperplasia, and squamous metaplasia. The incidences of subcutaneous tissue fibromas were increased in high dose male and female rats (male: control, 0/56; low dose, 1/56; mid dose, 2/56; high dose, 4/56; female: 0/56; 2/56; 1/56; 4/56) and were dose related. Subcutaneous fibrosarcomas were observed in three high dose females, one high dose male, one mid dose female, one low dose male, and one control female. A significant dose-related increase occurred in the incidence of female rats with neoplastic nodules of the liver (0/56; 1/56; 2/56; 4/55). This increase was significant in the high dose group by the incidental tumor test. Conclusions: Under the conditions of these 2-year feed studies, 2,6-xylidine was clearly carcinogenic for male and female Charles River CD rats, causing significant increases in the incidences of adenomas aadenomas and carcinomas of the nasal cavity. A rhabdomyosarcoma, a rare tumor of the nasal cavity, was observed in dosed rats of each sex. In addition, the increased incidences of subcutaneous fibromas and fibrosarcomas in male and female rats and the increased incidence of neoplastic nodules of the liver in female rats may have been related to the administration of 2,6-xylidine. Levels of Evidence of Carcinogenicity: Male Rats: Positive Female Rats: Positive Synonym: 2,6-Dimethylaniline

Journal Article↗
PubMed1990

NTP Toxicology and Carcinogenesis Studies of Tremolite (CAS No. 14567-73-8) in F344/N Rats (Feed Studies).

A carcinogenesis bioassay of blocky (nonfibrous) tremolite was conducted with male and female F344/N rats. Tremolite was administered at a concentration of 1% in pelleted diet for the entire lifetime of the rats, starting with the dams of the study animals. The studies were started in 1978 and ended in 1981. Group sizes were 118 male and female controls and 250 male and female tremolite-exposed rats. Litter size was not effected by the administration of tremolite to the dams. The offspring from mothers exposed to tremolite were the same size at birth as the controls but were slightly smaller at weaning and remained so throughout their life. Survival was similar in the exposed and control groups. No toxicity or increase in incidence of neoplasia was observed in the tremolite-exposed animals compared with the concurrent controls. Conclusions: Under the conditions of these feed studies, nonfibrous tremolite was not overly toxic or carcinogenic for male or female F344/N rats, following lifetime ingestion of a diet containing 1% tremolite. Target Organs & Incidences from 2-year Studies

Journal Article↗
PubMed1990

NTP Toxicology and Carcinogenesis Studies of Mirex (1,1a,2,2,3,3a,4,5,5,5a,5b,6-Dodecachlorooctahydro-1,3,4- metheno-1H-cyclouta[cd]pentalene) (CAS No. 2385-85-5) in F344/N Rats (Feed Studies).

Mirex (95% pure), formerly used a systemic insecticide and as a fire retardant, was studied for toxicologic and carcinogenic effects by administering diets containing 0, 0.1, 1.0, 10, 25, or 50 ppm mirex to groups of 52 F344/N rats of each sex for 104 weeks. Doses selected for the 2-year studies were based primarily on the effects on body weights and survival of rats in a 26-week study. During the first 6 months of the 2-year study, because of good survival and the absence of observable toxic effects in female rats, additional groups (termed second study) of 52 F344/N female rats were started at higher dietary concentrations of 0, 50, and 100 ppm mirex. Based on feed consumption data, the estimated average intake per day was 0, 0.007, 0.075, 0.75, 1.95, and 3.85 mg mirex/kg body weight for male rats and female rats in the first study, and 0, 3.9, and 7.7 mg/kg for female rats in the additional study. Body Weights, Feed Consumption, and Survival in Two-Year Studies: Mean body weights of male rats that received 25 or 50 ppm mirex were 5%-18% lower than those of the controls throughout most of the study; mean body weights of female rats that received 50 or 100 ppm mirex were 4%-18% lower than those of the controls after week 40; mean body weights of groups receiving 0.1, 1.0, or 10 ppm were similar to those of controls. Feed consumption by dosed male rats was 83%-91% that by controls, and that by dosed female rats was 86%-99% that by controls. The top dietary exposure groups of rats received the equivalent of 3.85 mg mirex/kg body weight, whereas the 100-ppm group of female rats (second study) averaged 7.7 mg/kg. At the end of the study, survival of male rats that received 25 or 50 ppm of mirex was lower than that of controls, whereas survival of all dosed groups of female rats was similar to that of controls (male: control, 44/52; 0.1 ppm, 37/52; 1 ppm, 36/52; 10 ppm, 37/52; 25 ppm, 19/52; 50 ppm, 15/52; female-- first study: 38/52; 38/52; 35/52; 41/52; 35/52; female-- second study: control, 44/52; 50 ppm, 44/52; 100 ppm, 39/52). Nonneoplastic and Neoplastic Effects in the Two-Year Studies: The most notable compound-related effects were observed in the liver of male and female rats. Fatty metamorphosis, cytomegaly, angiectasis (males only), and necrosis of the liver were observed at increased incidences in dosed rats. The incidences of of neoplastic nodules of the liver were dose related, and in the 10-, 25-, and 50-ppm groups of males and the 50- and 100-ppm groups of females (second study), they were markedly greater than those in controls (52/group-- male: control, 3; 0.1 ppm, 5; 1 ppm, 5;10 ppm, 14; 25 ppm, 15; 50 ppm, 26; female (second study): control, 2; 50 ppm, 23; 100 ppm, 30). In the first study in female rats, the incidences of neoplastic nodules were not significantly different between control and dosed groups (10; 5; 4; 5; 9; 7). The 10 neoplastic nodules of the liver seen in the control group (19%) was significantly greater than the mean incidence observed historically (57/2,015; 2.8%). The incidences of hepatocellular carcinomas in control and dosed groups were relatively low and were not significantly different between groups. The incidences of pheochromocytomas of the adrenal gland occurred with a positive trend in male rats (8/51; 7/52; 13/52; 11/52; 18/51, 19/51); the incidences in the 25- and 50-ppm male rats were greater than that in controls; malignant pheochromocytomas were observed in 2 controls and in 2 mirex-exposed male rats. The incidence of pheochromocytomas in 50-ppm female rats in the first study was marginally greater than that in controls (control, 1/51; 50 ppm, 6/52); this borderline increase was not observed in the second female rat study and thus is not considered to be due to the dietary administration of mirex. Nephropathy occurred at similar incidences in control and mirex-exposed groups of male and female rats; however, the severity of this nonneoplastic lesion was judged to be slightly greater in the groups given 25, 50, or 100 ppm mirex (male: severe vs. moderate in controls; femas given 25, 50, or 100 ppm mirex (male: severe vs. moderate in controls; female: moderate to severe vs. moderate). Hyperplasia of the transitional epithelium of the kidney pelvis was observed in dosed male rats (0/51; 2/51; 2/52; 5/52; 14/51; 9/52). Transitional cell papillomas of the renal pelvis in male rats occurred with a positive trend (P<0.02) (0/51; 0/51; 0/52; 1/51; 3/52). The highest incidence previously observed in untreated male F344/N rats in NTP studies is 1/48, and the mean historical incidence is 5/1,968 (0.3&percnt;). In both the first and second studies in female rats, the incidence of mononuclear cell leukemia showed dosed-related increases (first study: 8/52; 8/52; 11/52; 14/52; 18/52; 18/52; second study: 6/52; 9/52; 14/52). When the data from both studies are combined, the incidences are significantly increased in the 10-, 25-, 50-, and 100-ppm groups. The mean historical incidence is 19&percnt; (375/2,021). For the thyroid gland, there was a positive trend for follicular cell neoplasms in male rats (0/51; 1/50; 0/47; 1/47; 0/35; 4/49) and a negative trend for C-cell neoplasms in male rats (8/51; 6/50; 4/47; 7/47; 3/35; 0/49) and infemale rats in the first study (12/50; 13/50; 7/48; 9/47; 6/48; 2/46). Neither observation is considered to be associated with the dietary administration of mirex. Genetic Toxicology: Mirex was not mutagenic in the Salmonella typhimurium-microsome assay when tested in a preincubation protocol in the presence or absence of exogenous metabolic activation in strains TA98, TA100, TA1535, or TA1537. Mirex did not induce either sister chromatid exchanges or chromosomal aberrations in Chinese hamster ovary cells in the presence or absence of S9. Conclusions: Under the conditions of these 2-year feed studies of mirex, there is clear evidence of carcinogenic activity for male and female F344/N rats, as primarily indicated by marked increased incidences of benign neoplastic nodules of the liver, as well as by increased incidences of pheochromocytomas of the adrenal gland and transitional cell papillomas of the kidney in males and by increased incidences of mononuclear cell leukemia in females. Nonneoplastic effects induced by mirex include cytomegaly, fatty metamorphosis, angiectasis (males only), and cellular necrosis in the liver. Synonyms and Trade Names: 1,1a,2,2,3,3a,4,5,5,5a,5b,6-dodecachlorooctahydro-1,3,4-metheno-1H-cyclobta[cd]pentalene; hexachloropentadiene dimer; dodecachloropentacyclodecane; perchloropentacyclodecane; hexachlorocyclopentadiene dimer; Dechloranereg.; Ferriamicidereg.

Journal Article↗
PubMed1990

NTP Lifetime Carcinogenesis Studies of Chrysotile Asbestos (CAS No. 12001-29-5) in Syrian Golden Hamsters (Feed Studies).

NTP Carcinogenesis studies of short range (SR), intermediate range (IR), or intermediate range chrysotile asbestos in combination with the intestinal carcinogen 1,2-dimethylhydrazine dihydrochloride (DMH) were conducted with male and female Syrian golden hamsters. Both forms of chrysotile asbestos were administered at the concentration of 1% in pelleted diet for the entire lifetime of the hamsters starting with mothers of the test animals. Group sizes varied from 125 to 253. Starting at 6 weeks of age, male and female hamsters in the intermediate range chrysotile/DMH study were given oral doses of DMH (4 mg/kg) every other week for a total of 5 doses. There was no adverse effect on body weight gain or survival by either form of asbestos or by asbestos in combination with DMH. A significant increase (P< 0.05) in adrenal cortical adenomas was observed in male hamsters exposed to SR and IR chrysotile asbestos and in females treated with IR chrysotile asbestos when compared to the pooled control groups (males: pooled controls, 25/466, 5%; SR chrysotile, 26/299, 11%; IR chrysotile, 24/244, 10%; females: pooled controls, 15/468, 3%; IR chrysotile, 18/234, 8%). However, statistical significance was lost when these dosed groups were compared with concurrent control groups (males: SR control, 7/115, 6%; IR control, 7/115, 6%; females: SR control, 4/112, 4%; IR control, 6/118, 5%). The results of the combination study (IR chrysotile plus DMH) did not yield a significant increase in tumors above the background level observed in the DMH group alone or in the untreated control group. The DMH failed to yield a background level of intestinal tumors high enough to provide a valid test of the cocarcinogenic potential of chrysotile asbestos. For this reason, the cocarcinogenic potential of orally administered asbestos should be considered untested. Under the conditions of these studies, neither short range chrysotile nor intermediate range chrysotile asbestos was carcinogenic when ingested at 1% levels in the diet by male and female Syrian golden hamsters. While there were increases in the rates of adrenal cortical adenomas in male and female hamsters exposed to intermediate range chrysotile asbestos compared to the pooled groups, these incidence rates were not different when compared with the concurrent control groups. Additionally, the biologic importance of adrenal tumors in the absence of target organ (gastrointestinal tract) neoplasia is questionable. The coNTP Carcinogenesis studies using IR chrysotile asbestos and 1,2-dimethylhydrazine dihydrochloride were considered inadequate because there was no increase in intestinal neoplasia in the DMH group. Levels of Evidence of Carcinogenicity: Intermediate Range: Male Hamsters: Negative Female Hamsters: Negative Intermediate Range + dimethyl hydrazine: Male Hamsters: Inadequate Female Hamsters: Inadequate Short Range: Male Hamsters: Negative Female Hamsters: Negative.

Journal Article↗
PubMed1990

NTP Carcinogenesis Studies of Trichloroethylene (Without Epichlorohydrin) (CAS No. 79-01-6) in F344/N Rats and B6C3F1 Mice (Gavage Studies).

Trichloroethylene (TCE) is an industrial solvent used for vapor degreasing and cold cleaning of fabricated metal parts. TCE has also been used as a carrier solvent for the active ingredients of insecticides and fungicides, as a solvent for waxes, fats, resins, and oils, as an anesthetic for medical and dental use, and as an extractant for spice oleoresins and for caffeine from coffee. Trichloroethylene may be found in printing inks, varnishes, adhesives, paints, lacquers, spot removers, rug cleaners, disinfectants, and cosmetic cleansing fluids. TCE may also be used as a chain terminator in polyvinyl chloride production and as an intermediate in the production of pentachloroethane. Trichloroethylene is no longer used with food, drugs, or cosmetics. NTP Carcinogenesis studies of epichlorohydrin-free trichloroethylene were conducted by administering the test chemical in corn oil by gavage to groups of 50 male and 50 female F344/N rats and B6C3F1 mice. Dosage levels were 500 and 1,000 mg/kg for rats and 1,000 mg/kg for mice. Trichloroethylene was administered five times per week for 103 weeks, and surviving animals were killed between weeks 103 and 107. Groups of 50 rats and 50 mice of each sex received corn oil by gavage on the same schedule and served as vehicle controls. Groups of 50 male and 50 female rats were used as untreated controls. The dosage levels selected for the 2-year study were based on the results of the 13-week studies. Groups of 10 male and 10 female rats received TCE by gavage at doses of 125 to 2,000 mg/kg (males) and 62.5 to 1,000 mg/kg (females) for 13 weeks. Groups of 10 male and 10 female mice received gavage doses of 375 to 6,000 mg/kg of TCE for 13 weeks. Survival, body weight gains, and previous experience with TCE were used to select doses for the 2-year study. All rats survived the 13-week study, but males receiving 2,000 mg/kg exhibited a 24% difference in final body weight. At the 1,000 mg/kg dose, final body weights for males (-3%) and for females (-2%) were similar to those of controls. The doses selected for the 2-year study in rats were 500 and 1,000 mg/kg for both sexes. The initial doses used in the earlier bioassay in Osborne-Mendel rats were 549 and 1,097 mg/kg for both sexes. A total of 8/10 male mice and 10/10 female mice receiving doses of TCE as high as 1,500 mg/kg survived the 13-week experimental period. The single dosage level selected for the 2-year study in mice was 1,000 mg/kg for both sexes. This dose was less than the high dose used in the earlier bioassay in B6C3F1 mice (2,339 mg/kg for males and 1,739 for females) and was similar to the previous low doses (1,169 mg/kg for males and 869 for females). In the 2-year study, the survival of both low and high dose male rats and dosed male mice was less (P</=0.005) than that of the vehicle controls. Mean body weights of dosed rats of each sex were lower than those of the vehicle controls, and after week 65, the decrements in body weight gains were dose related. The mean body weight of dosed male mice was lower than that of the vehicle controls throughout the study, while those of the dosed and vehicle control female mice were comparable. Cytomegaly (toxic nephrosis) of the kidney was observed in 96/98 male and in 97/97 female rats given TCE, with none being found in male or female vehicle control rats. This lesion was more severe in males, particularly in the high dose group. Cytomegaly was observed in 45/50 male mice and in 48/49 female mice administered TCE, and in none of the vehicle controls. Renal tubular cell adenocarcinomas were found in the three high dose male rats; these neoplasms were observed in those male rats killed at the end of the study (0/33, 0/20, and 3/16, 19%). The incidence in the high dose male rats at the end of the study was greater (P<0.05) than that in the controls. Renal tubular cell adenocarcinomas are considered uncommon occurrences in F344/N rats, with 3/748 (0.4%) being observed in historical vehicle gavage controls. Additional renal tumors in dosed male rats included one transitional cell carcats included one transitional cell carcinoma of the renal pelvis and two tubular cell adenomas in low dose animals and one carcinoma of the renal pelvis in a high dose animal. No renal neoplasms were found in vehicle control rats; one untreated control male rat had a transitional cell papilloma of the renal pelvis. In female rats, one tubular cell adenocarcinoma was found in the high dose group. An increased incidence (P<0.05, life table) of peritoneal mesotheliomas was detected in low dose male rats (control, 1/50; low dose, 5/50; high dose, 1/49). Mesotheliomas have been diagnosed in 16/752 (2.1&percnt;) historical vehicle control male F344/N rats, and the increased incidence in the present study may have been related to the administration of TCE. The results in male F344/N rats were considered equivocal for detecting a carcinogenic response because both groups receiving TCE showed significantly reduced survival compared to vehicle controls (35/50, 70&percnt;, 20/50, 40&percnt;; 16/50, 32&percnt;) and because 20&percnt; of the animals in the high dose group were killed accidently by gavage error. Negative trends were observed for chromophobe adenomas of the pituitary gland and for endometrial stomal polyps in female rats. These decreases were not considered to be related to the administration of TCE. The administration of TCE to mice caused increased incidences of hepatocellular carcinoma in males (control, 8/48; dosed, 31/50; P<0.001) and in females (control, 2/48; dosed, 13/49; P<0.005). Hepatocellular carcinomas metastasized to the lungs in five dosed male mice and one control male mouse, and none were observed in females. The incidence of hepatocellular adenomas was increased in male mice (control, 7/48; dosed 14/50) and in female mice (control, 4/48; dosed, 16/49; P<0.05). Under the conditions of these studies, epichlorohydrin-free trichloroethylene caused renal tubular-cell neoplasms in male F344/N rats, produced toxic nephrosis in both sexes, and shortened the survival time of males. This experiment in male F344/N rats was considered to be inadequate to evaluate the presence or absence of a carcinogenic response to trichloroethylene. For female F344/N rats receiving trichloroethylene, containing no epichlorohydrin, there was no evidence of carcinogenicity. Trichloroethylene (without epichlorohydrin) was carcinogenic for B6C3F1 mice, causing increased incidences of hepatocellular carcinomas in males and females and of hepatocellular adenomas in females. Levels of Evidence of Carcinogenicity: Male Rats: Inadequate Study Female Rats: Negative Male Mice: Positive Female Mice: Positive Synonym: TCE

Journal Article↗
PubMed1989

NTP Toxicology and Carcinogenesis Studies of Nalidixic Acid (CAS No. 389-08-2) in F344/N Rats and B6C3F1 Mice (Feed Studies).

Nalidixic acid is an antimicrobial agent to treat bacterial infections of the urinary tract. NTP Toxicology and Carcinogenesis studies were conducted by feeding diets containing nalidixic acid (approximately 99% pure) to groups of F344/N rats and B6C3F1 mice of each sex for 13 weeks or 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium, mouse lymphoma cells, and Chinese hamster ovary (CHO) cells. Thirteen-Week Studies: Nalidixic acid was administered at dietary concentrations ranging from 1,000 to 16,000 ppm. One female rat that received 16,000 ppm nalidixic acid died before the end of the studies; no other compound-related deaths occurred in rats and mice. The final mean body weights of rats that received 8,000 or 16,000 ppm were 23% or 49% lower than those of controls for males and 11% or 31% lower for females. Feed consumption by rats receiving 16,000 ppm was approximately two-thirds that by controls. Liver weight to body weight ratios for male rats that received 2,000 ppm or more and female rats that received 8,000 ppm or more were significantly greater than those for controls. Degeneration of the germinal epithelium in the seminiferous tubules of the testis was observed in 10/10 male rats that received 16,000 ppm; no other compound-related histopathologic effects were observed in rats. The final mean body weights of mice that received 8,000 or 16,000 ppm were 10%-20% lower than those of controls. Feed consumption by dosed mice was similar to that by controls. Liver weight to body weight ratios were significantly greater for male mice receiving 2,000, 8,000, or 16,000 ppm and for female mice receiving 4,000, 8,000, or 16,000 ppm than for the controls. No compound-related histopathologic effects were observed in mice. Based on these results, 2-year studies of nalidixic acid were conducted by feeding diets containing 0, 2,000, or 4,000 ppm nalidixic acid to groups of 50 male and 50 female F344/N rats and 50 male and 50 female B6C3F1 mice. Body Weight and Survival in the Two-Year Studies: Mean body weights of high dose rats were 7%-23% lower than those of controls, and those of low dose male rats were 6%-11% lower than those of controls. The average daily feed consumption by dosed rats ranged from 89% to 96% that by controls. The average amount of nalidixic acid consumed per day was approximately 80 or 175 mg/kg for low dose or high dose rats. Mean body weights of high dose male mice were 1%-8% lower than those of controls throughout the study. Mean body weights of dosed female mice were 5%-17% lower than those of controls. Average daily feed consumption by dosed mice was within 3% of that by controls. The estimated average amount of nalidixic acid consumed per day was approximately 220 or 475 mg/kg for low dose or high dose mice. No significant differences in survival were seen between any groups of rats or mice of either sex after 2 years (male rats: control, 27/50; low dose, 28/50; high dose, 27/50; female rats: 22/50; 31/50; 29/50; male mice: 33/50; 34/50; 31/50; female mice: 40/50; 43/50; 32/50). Nonneoplastic and Neoplastic Effects in the Two-Year Studies: The incidences of preputial gland neoplasms in dosed male rats and of clitoral gland neoplasms in dosed female rats were significantly greater than those in controls (male--preputial gland adenomas, papillomas, or carcinomas, combined: control, 3/49; low dose, 19/49; high dose, 20/47; female--clitoral gland adenomas, papillomas, or carcinomas, combined: 5/46; 15/46; 16/47). A squamous cell carcinoma of the tongue was seen in two high dose male rats. The historical incidence of oral cavity neoplasms in untreated control male F344/N rats is 7/1,596 (0.4%). There were decreased incidences of leukemia (20/50; 9/50; 7/50) and mammary gland neoplasms (10/50; 7/50; 2/50) in dosed female rats and of pituitary gland neoplasms (11/49; 2/50; 2/50) in dosed male rats. Retinal degeneration and cataracts of the eye were observed at increased incidences in dosed rats (degeneration--male: 4/48; 41/48; 47/49; female: 2/47; 40/48; 46/50; cataracts--malee observed at increased incidences in dosed rats (degeneration--male: 4/48; 41/48; 47/49; female: 2/47; 40/48; 46/50; cataracts--male: 11/48; 23/48; 38/49; female: 0/47; 18/48; 14/50). The cause of these cataracts and retinal degeneration is uncertain because cages were not rotated and low and high dose groups of rats may have been exposed to greater light intensity than were the controls. Subcutanous tissue fibrosarcomas and fibromas or fibrosarcomas (combined) were increased in dosed male mice (fibromas or fibrosarcomas, combined: 5/50; 9/50; 14/50). There were no increased incidences of neoplasms in dosed female mice. Genetic Toxicology: Nalidixic acid was not mutagenic in any of several in vitro short-term tests. No gene reversion was observed in S. typhimurium strains TA97, TA98, TA100, or TA1535 after exposure to nalidixic acid in either the presence or absence of exogenous metabolic activation. Results of tests for induction of trifluorothymidine resistance in mouse L5178Y/TK lymphoma cells were negative with or without metabolic activation. In CHO cells, nalidixic acid did not induce sister chromatid exchanges or chromosomal aberrations in either the presence or absence of activation. Conclusions: Under the conditions of these 2-year feed studies, there was clear evidence of carcinogenic activity of nalidixic acid for F344/N rats, as indicated by increased incidences of preputial gland neoplasms in males and clitoral gland neoplasms in females. There was equivocal evidence of carcinogenic activity for male B6C3F1 mice fed diets containing nalidixic acid, as indicated by marginally increased incidences of subcutaneous tissue neoplasms. There was no evidence of carcinogenic activity for female B6C3F1 mice fed diets containing 2,000 or 4,000 ppm nalidixic acid for 2 years. Synonym: 1-ethyl-1,4-dihydro-7-methyl-4-oxo-1,8-naphthyridine-3-carboxylic acid Trade Names: NegGram&reg;.; Dixiben&reg;.; Nalidixan&reg;.; Nalurin&reg;.; Nogram&reg;.; UroNeg&reg;.; Uralgin&reg;.; Urisal&reg;.

Journal Article↗
PubMed1989

NTP Toxicology and Carcinogenesis Studies of Hydroquinone (CAS No. 123-31-9) in F344/N Rats and B6C3F1 Mice (Gavage Studies).

Hydroquinone is used an antioxidant in the rubber industry and as a developing agent in photography. It is also an intermediate in the manufacture of rubber and food antioxidants and monomer inhibitors. Hydroquinone and products containing hydroquinone are used as depigmenting agents to lighten skin. NTP Toxicology and Carcinogenesis studies were conducted by administering hydroquinone (greater than 99% pure) in corn oil or water by gavage to groups of F344/N rats and B6C3F1 mice of each sex for 14 days, 13 weeks, or 2 years. Additionally, genetic toxicology studies were conducted in Salmonella typhimurium, mouse lymphoma cells, Chinese hamster ovary (CHO) cells, and Drosophila melanogaster. Preliminary 3-day dermal studies were conducted with rats and mice using sufficient hydroquinone in 95% ethanol to crystallize on the skin (4 or 40 mg per animal); conjugated metabolites of hydroquinone were detected in the urine. Fourteen-day dermal studies were conducted at doses up to 3,840 mg/kg for rats and 4,800 mg/kg for mice. No toxic effects were seen in the 3- or 14-day dermal studies. Therefore, in further evaluations of hydroquinone, the gavage route of administration was used. Results of Fourteen-Day and Thirteen-Week Studies: Fourteen-day gavage studies were conducted by administering hydroquinone in corn oil to rats at doses ranging from 63 to 1,000 mg/kg body weight and to mice at doses ranging from 31 to 500 mg/kg. All rats receiving 1,000 mg/kg and 1/5 male and 4/5 female rats receiving 500 mg/kg died before the end of the 14 days. Compound-related clinical signs in rats included tremors lasting up to 30 minutes after each dosing at 500 and 1,000 mg/kg. In the 14-day gavage studies with mice, 4/5 male mice and 5/5 female mice receiving 500 mg/kg and 3/5 males receiving 250 mg/kg died before the end of the studies. Tremors followed by convulsions were seen at 250 and 500 mg/kg. In the 13-week studies, doses for rats and mice ranged from 25 to 400 mg/kg. All rats receiving 400 mg/kg and 3/10 female rats receiving 200 mg/kg died before the end of the studies. The mean body weight at necropsy of male rats administered 100 or 200 mg/kg was about 8%-9% lower than that of vehicle controls. Mean body weights of vehicle control and dosed female rats at necropsy were similar. Tremors and convulsions were observed after dosing in most rats receiving 400 mg/kg and in several female rats receiving 200 mg/kg. Inflammation and/or epithelial hyperplasia (acanthosis) of the forestomach were seen in 4/10 male rats and 1/10 female rats receiving 200 mg/kg. Toxic nephropathy, characterized by tubular cell degeneration in the renal cortex, was seen in 7/10 male and 6/10 female rats receiving 200 mg/kg and in 1/10 females receiving 100 mg/kg. In the 13-week studies in mice, 8/10 males and 8/10 females receiving 400 mg/kg and 2/10 male mice receiving 200 mg/kg died early. Mean body weights of dosed and vehicle control mice at necropsy were similar. Liver weight to body weight ratios for dosed male mice were significantly greater than for vehicle controls. Ulceration, inflammation, or epithelial hyperplasia of the forestomach was found in 3/10 male and 2/10 female mice receiving 400 mg/kg and 1/10 females receiving 200 mg/kg. Based on these collective results, 2-year studies were conducted by administering 0, 25, or 50 mg/kg hydroquinone in deionized water by gavage to groups of 65 rats of each sex, 5 days per week. Groups of 65 mice of each sex were administered 0, 50, or 100 mg/kg on the same schedule. Ten rats and 10 mice from each group were killed after 15 months for an interim evaluation. Observations at Fifteen Months: In the rats killed at 15 months, the relative kidney weight for high dose male rats was greater than that for vehicle controls. The hematocrit value, hemoglobin concentration, and erythrocyte count for high dose female rats were decreased. Compound-related increased severity of nephropathy was observed in male rats. In mice killed at 15 months, the relative liver weights for high dose male and female mice were signif and female mice were significantly greater than those for vehicle controls. Lesions seen in the liver of male mice included increased syncytial cells and diffuse cytomegaly. Body Weights, Organ Weights, and Survival in the Two-Year Studies: Mean body weights of high dose male rats were 5&percnt;-13&percnt; lower than those of vehicle controls after week 73, and those of low dose male rats were 5&percnt;-9&percnt; lower than those of vehicle controls after week 89. Mean body weights of dosed female rats were similar to those of vehicle controls throughout the study. The relative kidney and liver weights for high dose male rats were higher than those for vehicle controls. Mean body weights of high dose male mice were 5&percnt;-8&percnt; lower than those of vehicle controls after week 93, and those of high dose female mice were 5&percnt;-14&percnt; lower after week 20. Relative liver weights were increased for dosed male and high dose female mice. No significant differences in survival were observed between any groups of rats or mice of either sex after 2 years (male rats: vehicle control, 27/55; low dose, 18/55; high dose, 18/55; female rats: 40/55; 27/55; 32/55; male mice: 33/55; 37/54; 36/55; female mice: 37/55; 39/55; 36/55). Nonneoplastic and Neoplastic Effects in the Two-Year Studies: Nearly all male rats and most female rats in all vehicle control and dosed groups had nephropathy. The severity of this disease was judged to be greater in high dose male rats. Hyperplasia of the renal pelvic transitional epithelium and renal cortical cysts, changes observed with advanced renal disease, were increased in male rats. Renal tubular hyperplasia was seen in 2 high dose male rats, and renal tubular adenomas were seen in 4/55 low dose and 8/55 high dose male rats; none was seen in vehicle controls. Mononuclear cell leukemia in female rats occurred with a positive trend, and the incidences in the dosed groups were greater than that in the vehicle controls (vehicle control, 9/55; low dose, 15/55; high dose, 22/55). The historical incidence of leukemia in water gavage vehicle control female F344/N rats is 25&percnt; &plusmn; 15&percnt; and in untreated controls is 19&percnt; &plusmn; 7&percnt;. Compound-related lesions observed in the liver of high dose male mice included anisokaryosis (0/55; 2/54; 12/55), syncytial alteration (5/55; 3/54; 25/55), and basophilic foci (2/55; 5/54; 11/55). The incidences of hepatocellular adenomas were increased in dosed male mice (9/55; 21/54; 20/55), but these increases were offset by decreases in the incidences of hepatocellular carcinomas (13/55; 11/54; 7/55). The incidences of hepatocellular neoplasms, primarily adenomas, were increased in dosed female mice (3/55; 16/55; 13/55). Follicular cell hyperplasia of the thyroid gland was increased in dosed mice (male: 5/55; 15/53; 19/54; female: 13/55; 47/55; 45/55). Follicular cell adenomas were seen in 2/55 vehicle control, 1/53 low dose, and 2/54 high dose male mice and in 3/55 vehicle control, 5/55 low dose, and 6/55 high dose female mice, a follicular cell carcinoma was seen in a seventh high dose female mouse. The highest observed incidence of follicular cell adenomas or carcinomas(combined) in historical water gavage vehicle control female B6C3F1 mice is 3/48 (6&percnt;). Genetic Toxicology: Hydroquinone was not mutagenic in S. typhimurium strains TA98, TA100, TA1535, or TA1537 with or without exogenous metabolic activation. It induced trifluorothymidine (Tft) resistance in mouse L5178Y/TK lymphoma cells in the presence or absence of metabolic activation. An equivocal response was obtained in tests for induction of sex-linked recessive lethal mutations in Drosophila administered hydroquinone by feeding. Hydroquinone induced sister chromatid exchanges (SCEs) in CHO cells both with or without exogenous metabolic activation and caused chromosomal aberrations in the presence of activation. Conclusions: Under the conditions of these 2-year gavage studies, there was some evidence of carcinogenic activity of hydroquinone for male F344/N rats, as shown by marked increases in tubular cell adenomas of the kidney. There was some evidence of carcinogenic activity of hydroquinone for female F344/N rats, as shown by increases in mononuclear cell leukemia. There was no evidence of carcinogenic activity of hydroquinone for male B6C3F1 mice administered 50 or 100 mg/kg in water by gavage. There was some evidence of carcinogenic activity of hydroquinone for female B6C3F1 mice, as shown by increases in hepatocellular neoplasms, mainly adenomas. Administration of hydroquinone was associated with thyroid follicular cell hyperplasia in both male and female mice and anisokaryosis, multinucleated hepatocytes, and basophilic foci of the liver in male mice. Synonyms: 1,4-benzenediol; p-benzenediol; benzohydroquinone; benzoquinol; 1,4-dihydroxybenzene; p-dihydroxybenzene; p-dioxobenzene; p-dioxybenzene; hydroquinol; hydroquinole; a-hydroquinone; p-hydroquinone; p-hydroxyphenol; quinol; b-quinol

Journal Article↗
PubMed1989

NTP Toxicology and Carcinogenesis Studies of Pentaerythritol Tetranitrate (CAS No. 78-11-5) with 80% D-Lactose Monohydrate (PETN, NF) in F344/N Rats and B6C3F1 Mice (Feed Studies).

Pentaerythritol tetranitrate (PETN, NF) is a drug used to prevent angina pectoris. PETN without a lactose stabilizer is used as an explosive. NTP Toxicology and Carcinogenesis studies were conducted by administering PETN, NF, to groups of F344/N rats and B6C3F1 mice of each sex once by gavage or in feed for 14 days, 13 or 14 weeks, or 2 years. The PETN component was greater than 99% pure. Genetic toxicology studies were conducted with Salmonella typhimurium and Chinese hamster ovary (CHO) cells. Fourteen-Day and Thirteen-Week Studies: All rats and mice lived to the end of the 14-day studies (dietary concentrations up to 50,000 ppm). Final mean body weights of dosed and control rats were comparable. The final mean body weight of female mice that received 50,000 ppm was 13% lower than that of controls. No clinical signs or toxic lesions were attributed to PETN, NF, administration. All rats and mice lived to the end of the 13-week (mice) and 14-week (rats) studies (dietary concentrations up to 50,000 ppm). Final mean body weights of dosed and control rats and mice were similar, although weight gains of female rats at 25,000 and 50,000 ppm were less than that of controls. The nitrite level in urine of rats and methemoglobin levels in whole blood of rats and mice were not affected by administration of PETN, NF. An adenoma of the Zymbal gland was seen in a female rat that received 50,000 ppm. A hepatocellular adenoma was seen in a female mouse that received 50,000 ppm. Based on these results and the NTP convention of limiting concentrations in 2-year feed studies to 5% of the diet, the 2-year studies were conducted by administering 0, 25,000 or 50,000 ppm PETN, NF, in feed for 104 weeks to groups of 50 male rats and for 103 weeks to groups of 49 or 50 mice of each sex. Groups of 50 female rats were given feed containing 0, 6,200, or 12,500 ppm PETN, NF, for 104 weeks. Body Weight and Survival in the Two-Year Studies: Mean body weights of high dose male rats were 2%-9% lower than those of controls throughout the study; body weights of all groups of female rats were similar. No significant differences in survival were observed between any groups of rats of either sex (male: control, 23/50; low dose, 29/50; high dose, 29/50; female: 33/50; 33/50; 31/50). Mean body weights of dosed and control mice were similar. The survival of both groups of dosed male mice was significantly greater than that of the controls (26/49; 38/50; 38/50). No significant differences in survival were observed between any groups of female mice (38/50; 30/50; 38/50). Nonneoplastic and Neoplastic Effects in the Two-Year Studies: No nonneoplastic lesions were attributed to PETN, NF, administration in rats or mice. Neoplasms of the Zymbal gland occurred in dosed male (control, 0/49; low dose, 3/45; high dose, 2/41) and dosed female (0/36; 1/37; 3/35) rats. The historical incidence of these neoplasms is 1% +/- 2% in untreated males and 0.6% +/- 1% in females. At no site was a significantly increased incidence of neoplasms observed in dosed male or female mice. Genetic Toxicology: PETN, NF, was not mutagenic in S. typhimurium strains TA98, TA100, TA1535, or TA1537 when tested with or without exogenous metabolic activation (S9). When tested for cytogenetic effects in cultured CHO cells, PETN, NF, induced sister chromatid exchanges (SCEs) in the presence and absence of metabolic activation; no induction of chromosomal aberrations was observed in CHO cells with or without activation. Audit: The data, documents, and pathology materials from the 2-year studies of PETN, NF, 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 equivocal evidence of carcinogenic activity of PETN, NF, for male and female F344/N rats, based on a marginal increase in neoplasms of the Zymbal gland. Female rats might have tolerated a higher dose. There was no evidence of carcinogenic activity of PETN, NF, forher dose. There was no evidence of carcinogenic activity of PETN, NF, for male or female B6C3F1 mice fed diets containing 25,000, or 50,000 ppm for 2 years. No nonneoplastic lesions were attributed to PETN, NF, administration. Synonyms for PETN: 2,2-bis((nitrooxy)methyl)-1,3-propanediol dinitrate (ester); 2,2-bisdihydroxy-methyl-1,3-propanediol tetranitrate; niperyt; nitropentaerythritol; pentaerythrityl tetranitrate; penthrit Trade Names for PETN, NF: Angitet; Cardiacap; Dilcoran-80; Dipentrate; Hasethrol; Lentrat; Metranil; Mycardol; Neo-Corovas; Nitropenta; Nitropenton; Pentafin; Pentanitrine; Pentitrate; Pentral 80; Pentrite; Pentritol; Pentryate; Peridex; Pergitral; Peritrate; Perityl; Prevangor; Quintrate; Subicard; Terpate; Vasodiatol

Journal Article↗
PubMed1989

NTP Toxicology and Carcinogenesis Studies of Rhodamine 6G (C.I. Basic Red 1) (CAS No. 989-38-8) in F344/N Rats and B6C3F1 Mice (Feed Studies).

NTP Toxicology and Carcinogenesis studies of rhodamine 6G were conducted because of potential human exposure related to its use as a dye for natural and synthetic fibers and as a research chemical. These studies were conducted by administering rhodamine 6G (greater than 95% pure) in feed 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: In the 14-day studies (0, 310, 620, 1,250, 2,500, or 5,000 ppm), all five male and five female rats that received 5,000 ppm and 1/5 male rats that received 2,500 ppm died before the end of the studies; all mice lived to the end of the study. The final mean body weights of rats that received 2,500 ppm were lower than the initial weights. The final mean body weights of mice that received 2,500 or 5,000 ppm were 8% or 18% lower than that of controls for males and 2% or 8% lower for females. In the 13-week studies, all rats lived to the end of the studies (dietary concentrations of 0 or 120-2,000 ppm). The final mean body weights of rats that received 500, 1,000 or 2,000 ppm were 12%, 13%, or 32% lower than that of controls for males and 4%, 8%, or 20% lower for females. Feed consumption by rats that received 2,000 ppm was somewhat lower than that by controls. Bone marrow atrophy was observed at increased incidences and severity in dosed rats. In the 13-week study (0 or 500-8,000 ppm), 1/10 male mice that received the highest concentration died before the end of the studies. The final mean body weights of mice that received 8,000 ppm were lower than the initial mean body weights. The final mean body weights of male mice that received 4,000 ppm and of female mice that received 2,000 or 4,000 ppm were 13%-19% lower than those of controls. Feed consumption was not related to dose. Minimal-to-moderate cytoplasmic vacuolization of hepatocytes was seen in 8/10 male mice that received 8,000 ppm. Based on these results, dietary concentrations selected for the 2-year studies were 0, 120, or 250 ppm rhodamine 6G for rats, 0, 1,000, or 2,000 ppm for male mice, and 0, 500, 1,000 ppm for female mice. Body Weight and Survival in the Two-Year Studies: Mean body weights of dosed rats were similar to those of controls throughout the studies. The average daily feed consumption by dosed rats was within 5% that by controls for all dosed groups. The average amount of rhodamine 6G consumed per day was approximately 5 mg/kg for low dose rats and 10 or 12 mg/kg for high dose male or female rats. Mean body weights of high dose male and dosed female mice were generally 5%-14% lower than those of controls. The average daily feed consumption by dosed mice was within 5% that by controls for all dosed groups. The average amount of rhodamine 6G consumed per day was approximately 210 or 440 mg/kg for low dose or high dose male mice and 125 or 250 mg/kg for low dose or high dose female mice. No significant differences in survival were observed between any groups of rats or mice (male rats: control, 22/50; low dose, 21/50; high dose, 27/50; female rats: 29/50; 30/50; 30/50; male mice: 36/50; 32/50; 38/50; female mice: 39/50; 35/50; 36/50). Nonneoplastic and Neoplastic Effects in the Two-Year Studies: No chemically related nonneoplastic lesions in male or female rats and no chemically related neoplastic or nonneoplastic lesions in male or female mice were observed in these studies. The incidences of keratoacanthomas of the skin was increased in high dose male rats (control, 1/50; low dose, 2/50; high dose, 8/50). The historical incidence of keratoacanthomas in untreated control male F344/N rats is 31/1,936 (1.6%; range, 0/50-7/49). Both fur and skin of rats in the dosed groups apparently were exposed to feed dust containing rhodamine 6G; the intensity of staining was proportional to the concentration of rhodamine 6G in feed. Because of the variable background incidence of keratoacanthomas in F344/N rats, the incideentration of rhodamine 6G in feed. Because of the variable background incidence of keratoacanthomas in F344/N rats, the incidence of keratoacanthomas cannot be conclusively related to exposure to rhodamine 6G. The incidences of pheochromocytomas (3/50; 3/50; 8/50) or malignant pheochromocytomas (combined: 3/50; 3/50; 10/50) of the adrenal gland were increased in high dose female rats. The historical incidence of adrenal medullary neoplasms in untreated control F344/N female rats is 99/1,968 (5&percnt;; range, 0/50-8/50). This marginal increase may be related to the administration of rhodamine 6G. Genetic Toxicology: Rhodamine 6G was not mutagenic in S. typhimurium strains TA98, TA100, TA1535, or TA1537 when tested with and without exogenous metabolic activation (S9). Rhodamine 6G gave a positive response in the absence of S9 in the mouse lymphoma assay for induction of trifluorothymidine (Tft) resistance in L5178Y cells; in the presence of S9, rhodamine 6G was negative. Rhodamine 6G induced sister chromatid exchanges (SCEs) and chromosomal aberrations in cultured CHO cells in the presence, but not the absence, of S9. Conclusions: Under the conditions of these 2-year feed studies, there was equivocal evidence of carcinogenic activity for male F344/N rats administered rhodamine 6G, as indicated by a marginally increased incidence of integumentary keratoacanthomas. There was equivocal evidence of carcinogenic activity for female F344/N rats administered rhodamine 6G, as indicated by a marginal increase in pheochromocytomas or malignant pheochromocytomas (combined) of the adrenal gland. There was no evidence of carcinogenic activity for male B6C3F1 mice administered 1,000 or 2,000 ppm rhodamine 6G in the diet. There was no evidence of carcinogenic activity for female B6C3F1 mice administered 500 or 1,000 ppm rhodamine 6G in the diet. There were no significant nonneoplastic lesions attributed to rhodamine 6G administration to male or female rats or male or female mice. Male and female rats might have been able to tolerate a higher concentration of rhodamine 6G in the feed. Synonym: 2-[6-(ethylamino)-3-(ethylimino)2,7-dimethyl-3H-xanthen-9-yl] benzoic acid ethyl ester, monohydrochloride Common Names: Basic Red 1; Basic Rhodamine Yellow; Basic Rhodaminic Yellow; Calcozine Red 6G; Calcozine Rhodamine 6GX; C.I. Basic Red 1, Monohydrochloride; Elcozine Rhodamine 6GDN; Eljon Pink Toner; Fanal Pink GFK; Fanal Red 25532; Flexo Red 482; Heliostable Brilliant Pink B extra; Mitsui Rhodamine 6GCP; Nyco Liquid Red GF; Rhodamine 69DN Extra; Rhodamine F4G; Rhodamine F5G; Rhodamine F5G chloride; Rhodamine 6GB; Rhodamine 6GBN; Rhodamine 6GCP; Rhodamine 6GD; Rhodamine 4GD; Rhodamine GDN; Rhodamine 5GDN; Rhodamine 6 GDN; Rhodamine GDN Extra; Rhodamine 6GEx ethyl ester; Rhodamine 6G Extra; Rhodamine 6G Extra Base; Rhodamine 4GH; Rhodamine 6GH; Rhodamine 5GL; Rhodamine 6G lake; Rhodamine 6GX; Rhodamine J; Rhodamine 6JH; Rhodamine 7JH; Rhodamine Lake Red 6G; Rhodamine Y 20-7425; Rhodamine Zh; Rhodamine 6ZH-DN; Silosuper Pink B; Valley Fast Red 1308

Journal Article↗
PubMed1989

NTP Toxicology and Carcinogenesis Studies of Benzofuran (CAS No. 271-89-6) in F344/N Rats and B6C3F1 Mice (Gavage Studies).

Benzofuran is used as an intermediate in the polymerization of coumarone-indene resins found in various corrosion-resistant coatings such as paints and varnishes, in water-resistant coatings for paper products and fabrics, and in adhesives approved for use in food containers. NTP Toxicology and Carcinogenesis studies were conducted by administering benzofuran (approximately 99% pure) in corn oil by gavage to groups of F344/N rats and B6C3F1 mice of each sex for 14 days, 13 weeks, or 2 years. Genetic toxicology tests were conducted in Salmonella typhimurium, mouse lymphoma cells, and Chinese hamster ovary (CHO) cells. Fourteen-Day Studies: Benzofuran doses for groups of five rats ranged from 63 to 1,000 mg/kg and from 16 to 250 mg/kg for mice. All male and female rats that received 1,000 mg/kg and one female rat that received 500 mg/kg died before the end of the studies. The final mean body weights of male rats that received 250 or 500 mg/kg were 13% or 21% lower than that of controls; the final mean body weight of female rats that received 500 mg/kg was 10% lower than that of controls. Final mean body weights of chemically exposed and control mice were similar. No compound-related histologic lesions were found in rats or mice. Thirteen-Week Studies: Doses for groups of 10 rats and 10 mice ranged from 31 to 500 mg/kg. One female rat that received 500 mg/kg and one that received 250 mg/kg died before the end of the study. Final mean body weights of male rats that received 125, 250, or 500 mg/kg were 11%, 17%, or 27% lower than that of vehicle controls; the final mean body weight of female rats that received 500 mg/kg was 11% lower than that of vehicle controls. Histologic lesions observed in chemically exposed rats included minimal hepatocellular necrosis, increased severity of nephropathy, and cytoplasmic vacuolization of the adrenal cortex. Seven male and three female mice that received 500 mg/kg and one male mouse that received 250 mg/kg died before the end of the 13-week studies. The final mean body weight of mice that received 500 mg/kg was 13% lower than that of vehicle controls. Nephrosis was observed in male mice that received 250 mg/kg. Based on reduced mean body weights, increased severity of nephropathy, and hepatocellular necrosis, benzofuran doses selected for the 2-year studies in rats were 30 or 60 mg/kg for males and 60 or 120 mg/kg for female. Based on increased mortality and nephrosis in male mice, doses selected for the 2-year studies in mice were 60 or 120 mg/kg for males and 120 or 240 mg/kg for females. Body Weights and Survival in the Two-Year Studies: Mean body weights of high dose rats and dosed male mice were 4%-11% lower than those of vehicle controls. Mean body weights of chemically exposed female mice were 8%-35% lower than those of vehicle controls. The survival of chemically exposed male rats was reduced after week 92 (survival at week 89: vehicle control, 47/50; low dose, 39/50; high dose, 38/50; final survival: vehicle control, 33/50; low dose, 12/50; high dose, 18/50). Survival of chemically exposed female rats and male mice was similar to that of vehicle controls after 2 years (female rats: 27/50; 23/50; 25/50; male mice: 33/50; 20/50; 28/50). Deaths of 10 low dose male mice at weeks 20-21 were caused by a dosing error; these animals were not included in survival and tumor analyses. Survival of chemically exposed female mice was reduced after week 89 (final survival: 37/50; 19/50; 21/50). Nonneoplastic and Neoplastic Effects in the Two-Year Studies: Nephropathy occurred with increased severity in chemically exposed male rats. The incidences of parathyroid hyperplasia, fibrous osteodystrophy, mineralization of the pulmonary artery, renal cortical cysts, and hyperplasia of the pelvic epithelium were increased in chemically exposed male rats. The incidence of nephropathy was increased in chemically exposed female rats (vehicle control, 29/50; low dose, 48/50; high dose, 39/50). Renal atypical tubular cell hyperplasia and renal tubular cell adenocarcinomas occurred in chemically exposed femacell hyperplasia and renal tubular cell adenocarcinomas occurred in chemically exposed female rats (atypical tubular cell hyperplasia: 0/50; 1/50; 3/50; tubular cell adenocarcinomas: 0/50; 1/50; 4/50). No renal tubular cell adenocarcinomas have been observed in 2,094 female corn oil vehicle control F344/N rats in National Toxicology Program studies. Chronic inflammation, ulcers, and epithelial hyperplasia of the forestomach were observed at increased incidences in chemically exposed male rats (chronic inflammation: 1/50; 11/50; 6/49; ulcers: 1/50; 5/50; 8/49; epithelial hyperplasia: 9/50; 15/50; 18/49). Metaplastic hepatocytes arising within pancreatic islets occurred at an increased incidence in high dose female rats (0/50; 1/50; 11/49). The incidences of neurilemomas were markedly increased above the historical control incidences (0.1&percnt;-0.4&percnt;) in all groups of rats (male: 18/50; 13/50; 14/50; female: 7/50; 9/50; 3/50). Syncytial alteration of the liver occurred at increased incidences in male mice exposed to benzofuran. The incidences of hepatocellular adenomas, hepatoblastomas (high dose male mice) and hepatocellular adenomas, hepatocellular carcinomas, or hepatoblastomas (combined) were increased in chemically exposed mice (male--adenomas: 4/49; 24/39; 34/48; hepatoblastomas: 0/49; 3/39; 18/48; carcinomas, adenomas, or hepatoblastomas, combined: 12/49; 31/39; 40/48; female--adenomas: 1/50; 22/48; 21/47; hepatoblastomas: 0/50; 1/48; 2/47; carcinomas, adenomas, or hepatoblastomas, combined: 4/50; 25/48; 22/47). Squamous cell papillomas or carcinomas (combined) of the forestomach were increased in chemically exposed mice (male: 2/49; 11/39; 13/48; female: 2/50; 9/50; 5/50). The incidences of epithelial hyperplasia of the bronchioles were increased in chemically exposed mice. The incidences of alveolar/bronchiolar adenomas or carcinomas (combined) in high dose males and chemically exposed females were increased (adenomas or carcinomas, combined--male: 10/49; 9/39; 19/48; female: 2/50; 9/48; 14/47). Genetic Toxicology: Benzofuran was not mutagenic in S. typhimurium strains TA98, TA100, TA1535, or TA1537 in the presence or absence of exogenous metabolic activation. Benzofuran induced trifluorothymidine resistance in mouse L5178Y lymphoma cells treated in the absence of metabolic activation; this assay was not conducted with activation. Benzofuran induced sister chromatid exchanges but not chromosomal aberrations in CHO cells in the presence and absence of activation. Conclusions: Under the conditions of these 2-year gavage studies, there was no evidence of carcinogenic activity of benzofuran for male F344/N rats receiving doses of 30 or 60 mg/kg per day. There was some evidence of carcinogenic activity of benzofuran for female F344/N rats, based on increased incidences of tubular cell adenocarcinomas of the kidney. There was clear evidence of carcinogenic activity for male and female B6C3F1 mice, based on increased incidences of neoplasms of the liver, lung, and forestomach. Exposure to benzofuran increased the severity of nephropathy in male rats, increased the incidences of nephropathy in female rats, and induced hepatocellular metaplasia in the pancreas in female rats. Nonneoplastic lesions observed in mice exposed to benzofuran included syncytial alteration of the liver, bronchiolar epithelial hyperplasia, and epithelial hyperplasia of the forestomach. Synonyms: coumarone; cumarone

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&percnt;; range: 0/50-3/50), but they exceeded the historical incidence range for chamber controls at the study laboratory (mean: 1/297, 0.3&percnt;; 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&percnt;) for males and 4/297 (1.3&percnt;) 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

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