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National Toxicology Program

Publications and source records attributed to National Toxicology Program.

At least 487 records · Page 27Linked to original sources

PubMed1984

NTP Toxicology and Carcinogenesis Studies of Tris(2-ethylhexyl)phosphate (CAS No. 78-42-2) In F344/N Rats and B6C3F1 Mice (Gavage Studies).

Tris(2-ethylhexyl)phosphate is one of a family of triakyl phosphates that have been widely used as fire retardants and plasticizers. Another triakyl phosphate, tris(2,3-dibromopropyl)phosphate (Tris-BP), once used as a flame retardant in children's sleepwear, has been shown to be carcinogenic, but tris(2-ethylhexyl)phosphate has not been previously studied. Tris(2-ethylhexyl)phosphate, a clear, viscous liquid, is used as a component of vinyl stabilizers, grease additives, and flame-proofing compositions; however, it is used primarily as a plasticizer for vinyl plastic and synthetic rubber compounds. In 1974, approximately 3 million pounds of tris(2-ethylhexyl)phosphate was produced in the United States; imports during that year were negligible. Substantial human exposure probably occurs during production of tris(2-ethylhexyl)phosphate and during the manufacture and use of products containing it, but data on the magnitude of exposure are not available. Two-year toxicology and carcinogenesis studies of tris(2-ethylhexyl)phosphate were conducted by administering the test chemical in corn oil by gavage, 5 days per week for 103 weeks, to groups of 50 male and 50 female F344/N rats and B6C3F1 mice. Male rats received doses of 2,000 or 4,000 mg/kg body weight, female rats received 1,000 or 2,000 mg/kg, and male and female mice received 500 or 1,000 mg/kg. Fifty vehicle control animals of each sex and species received 10 ml/kg body weight (rats) or 3.3 ml/kg (mice) corn oil by gavage on the same schedule. Inflammation of the gastric mucosa in mice and mild weight depression in rats and mice were the only dose-related effects observed in the preliminary studies. In the 2-year studies, survival rates and mean body weight gains of dosed female rats and dosed mice were comparable to those of their perspective controls. Survival rates of dosed male rats were comparable to that of the vehicle controls, but body weight gains were depressed. One nonneoplastic lesion, follicular cell hyperplasia of the thyroid, was observed at increased incidences in dosed male and female mice. Two compound-related increased incidences of neoplasms could not be discounted. In male rats, the incidence of pheochromocytoma of adrenal glands increased with dose (2/50, 4%; 9/50, 18%; 12/50, 24%). There were also two additional malignant pheochromocytomas in the high dose group. However, the incidence of adrenal pheochromocytoma in vehicle controls of this study (2/50, 4%) was low compared with the 25% incidence observed in two previous studies in this laboratory or the overall historical incidence of 18% observed throughout the Program, and thus the evidence of carcinogenicity was considered to be equivocal. In female mice, the incidence of hepatocellular carcinoma (0/48; 4/50; 7/50) in high dose animals (1,000 mg/kg) was significantly increased relative to that of the vehicle controls. Decreased incidences were observed for acinar cell adenomas of the pancreas in dosed male rats (14/50, 28%; 5/48, 10%; 2/49, 4%) and for fibroadenomas of the mammary glands in low dose female rats (11/50, 22%; 2/50, 4%; 7/50, 14%). Hemangiosarcomas of the circulatory system in male mice (7/50, 14%; 0/50; 1/49, 2%) and lymphomas of the hematopoietic system in female mice (14/49, 29%; 10/50, 20%; 6/50, 12%) were decreased compared with vehicle controls. A decrease in the incidence of lymphomas and an increased incidence of carcinomas of the liver in female mice (both seen in this study) were observed in studies of di(2-ethylhexyl)adipate. Increased incidences of liver carcinomas and decreased incidences of mammary fibroadenomas were observed also in female rats in the di(2-ethylhexyl)phthalate studies. A possible link among these three chemicals may be metabolic conversion to 2-ethylhexanol. Tris(2-ethylhexyl)phosphate was not mutagenic in Salmonella typhimurium strains TA98, TA100, TA1535, or TA1537 in the presence or absence of 9000 x g (S9) fractions from Aroclor 1254-induced Sprague-Dawley rat or Syrian hamster liver. An audit of the experimental data from these carcinogeneoclor 1254-induced Sprague-Dawley rat or Syrian hamster liver. An audit of the experimental data from these carcinogenesis studies was conducted by the National Toxicology Program. No data discrepancies were found that significantly influenced the final interpretations of these experiments. Under the conditions of these studies, a comparison of concurrent and historical controls indicated that there was equivocal evidence of carcinogenicity in male F344/N rats receiving 2,000 and 4,000 mg/kg tris(2-ethylhexyl)phosphate, as evidenced by increased incidences of pheochromocytomas of the adrenal glands. There was no evidence of carcinogenicity in female F344/N rats or in male B6C3F1 mice receiving tris(2-ethylhexyl)phosphate. There was some evidence of carcinogenicity in female B6C3F1 mice that received 1,000 mg/kg tris(2-ethylhexyl)phosphate, as shown by an increased incidence of hepatocellular carcinoma. Tris(2-ethylhexyl)phosphate was associated with increased incidences of follicular cell hyperplasia of the thyroid gland in male and female B6C3F1 mice. Synonyms and Trade Names: TOF; trioctyl phosphate; phosphoric acid tri(2-ethylhexyl) ester; Flexolreg. TOF; Kronitexreg.

Journal Article↗

PubMed1984

NTP Toxicology and Carcinogenesis Studies of 1,3-Butadiene (CAS No. 106-99-0) in B6C3F1 Mice (Inhalation Studies).

1,3-Butadiene is used as an intermediate in the production of elastomers, polymers, and other chemicals. Of the 1,3-butadiene used in 1978, 44% was used to manufacture styrene-butadiene rubber (a substitute for natural rubber, produced by copolymerization of 1,3-butadiene with styrene), and 19% was used to produce polybutane elastomer (a substance that increases resistance of tire products to wear, heat degradation, and blowouts). Chloroprene monomer, derived from 1,3-butadiene, is used exclusively to manufacture neoprene elastomers for non-tire and latex applications. Commercial nitrile rubber, used largely in rubber hoses, seals, and gaskets for automobiles, is a copolymer of 1,3-butadiene and acrylonitrile. Acrylonitrile- butadiene- styrene resins, usually containing 20%-30% 1,3-butadiene by weight, are used to make parts for automobiles and appliances. Other polymer uses include specialty polybutadiene polymers, thermoplastic elastomers, nitrile barrier resins, and K resins(R). 1,3-Butadiene is used as an intermediate in the production of a variety of industrial chemicals, including two fungicides, captan and captofol. It is approved by the U.S. Food and Drug Administration for use in the production of adhesives used in articles for packaging, transporting, or holding food; in components of paper and paperboard that are in contact with dry food; and as a modifier in the production of semigrid and rigid vinyl chloride plastic food-contact articles. No information was located on the levels of monomer or on its elution rate from any of the commercially available polymers. It is not known if unreacted 1,3-butadiene migrated from packaging materials. Male and female B6C3F1 mice were exposed to air containing 1,3-butadiene (greater than 99% pure) at concentrations of 0-8,000 ppm in 15-day and 14-week inhalation studies. In the 15-day studies, survival was unaffected by dose, and no pathologic effects were observed; slight decreases in mean body weight occurred at the high concentrations. In the 14-week studies, mean body weight gain decreased with dose, and survival in the 5,000-ppm and 8,000-ppm groups of males was markedly reduced; no other compound-related effects were reported. Inhalation carcinogenesis studies of 1,3-butadiene were conducted by exposing groups of 50 male and female B6C3F1 mice 6 hours per day for 5 days per week to air containing the test chemical at concentrations of 0 (chamber controls), 625, or 1,250 ppm. These studies were planned for 103-week exposures but were terminated at week 60 for male mice and week 61 for female mice because of the rapidly declining survival, primarily due to neoplasia. Body weights were not affected by 1,3-butadiene. Significantly increased incidences of neoplasms at multiple sites were observed in mice exposed to 1,3-butadiene. Hemangiosarcomas of the heart occurred at increased incidences in exposed males and females (male: control, 0/50; low dose, 16/49; high dose, 7/49; female: 0/50; 11/48; 18/49). Hemangiosarcomas were also observed in the peritoneal cavity (one high dose male), subcutaneous tissue (two low dose females), and liver (one high dose female). Malignant lymphomas, diagnosed as early as week 20, were observed at increased incidences in exposed male and female mice (male: 0/50; 23/50; 29/50; female: 1/50; 10/49; 10/49). Alveolar/bronchiolar adenomas and alveolar/bronchiolar (both separately and combined) occurred at increased incidences in exposed male and female mice (combined incidences -- male: 2/50; 14/49; 15/49; female: 3/49; 12/48; 23/49). Epithelial hyperplasia of the forestomach occurred at increased incidences in dosed mice (male: 0/49; 5/40; 7/44; female: 0/49; 5/42; 9/49). Papillomas of the forestomach occurred in low dose male and in low dose and high dose female mice (male: 0/49; 5/40; 0/44; female: 0/49; 4/42; 10/49). Squamous cell carcinomas of the forestomach were observed in dosed mice (male: 0/49, 2/40, 1/44; female: 0/49, 1/42, 1/49). Acinar cell carcinomas of the mammary gland were observed at an increased incidence in high dose female reased incidence in high dose female mice (0/50; 2/49; 6/49); adenosquamous carcinomas were found in four low dose females. The incidences of granulosa cell tumors of the ovary were increased in dosed females (0/49; 6/45; 12/48). A granulosa cell carcinoma was observed in another high dose female. Gliomas were observed in two 68- to 69-week-old low dose and one high dose male mice; brain tumors are uncommon even in 2-year old mice. Liver necrosis occurred at increased incidences in dosed male and low dose female mice (male; 1/50, 8/49, 8/49; female: 6/50, 15/47, 6/49). Hepatocellular adenomas or carcinomas (combined) were observed at an increased incidence in high dose female mice (0/50, 2/47 5/49). No neoplastic lesions of the nasal cavity were observed at any dose level. The following nonneoplastic lesions of the nasal cavity occurred in mice exposed at 1,250 ppm: chronic inflammation (male, 35/50; female, 2/49); fibrosis (male, 33/50; female, 2/49); cartilaginous metaplasia (male, 16/50; female, 1/49); osseous metaplasia (male, 11/50; female, 2/49); and atrophy of the sensory epithelium (male, 32/50). No nonneoplastic lesions of the nasal cavity were found in the controls. The incidence of testicular atrophy (0/50, 19/49, 11/48) or ovarian atrophy (2/49, 40/45, 40/48) was increased in exposed male or female mice. An audit of the experimental data from these studies on 1,3-butadiene was conducted by the National Toxicology Program. No data discrepancies were found that influenced the final interpretation of these experiments. Under the conditions of these studies, there was clear evidence of carcinogenicity for 1,3-butadiene in male and female B6C3F1 mice, as shown by increased incidences and early induction of hemangiosarcomas of the heart, malignant lymphomas, alveolar/bronchiolar adenomas and carcinomas, and papillomas of the stomach in males and females; and of acinar cell carcinomas of the mammary gland, granulosa cell tumors of the ovary, and hepatocellular adenomas and adenomas or carcinomas (combined) in females. 1,3-Butadiene was associated with nonneoplastic lesions in the respiratory epithelium, liver necrosis, and testicular or ovarian atrophy. Synonyms: butadiene; biethylene; bivinyl; divinyl; erythrene; vinylethylene; pyrrolylene

Journal Article↗

PubMed1983

NTP Lifetime Carcinogenesis Studies of Amosite Asbestos (CAS No. 12172-73-5) in Syrian Golden Hamsters (Feed Studies).

Carcinogenesis studies of amosite asbestos were conducted by administering diets containing 1% of the asbestos in pellets from the conception of the mothers through the lifetime of male and female Syrian golden hamsters. Control groups consisted of 127 male and 126 female hamsters and the amosite asbestos groups consisted of 252 male and 254 female hamsters. No adverse effect on body weight gain or survival was observed from treatment with amosite asbestos. Neither of the amosite asbestos groups showed increased neoplasia in any organ or tissue compared to the control groups. Under the conditions of these studies, the ingestion of amosite asbestos at a level of 1% in the diet for their lifetime was not toxic and did not cause a carcinogenic response in male and female Syrian golden hamsters. Levels of Evidence of Carcinogenicity: Male Hamsters: Negative Female Hamsters: Negative

Journal Article↗

PubMed1983

Carcinogenesis Studies of Allyl Isovalerate (CAS No. 2835-39-4) in F344/N Rats and B6C3F1 Mice (Gavage Studies).

Allyl isovalerate, a synthetic fragrance and flavoring ingredient in use since the 1950's, may be found in various products at the following concentrations: soap, 30 ppm; detergent, 3 ppm; creams, 15 ppm; perfume, 50 ppm; nonalcoholic beverages, 9 ppm; ice cream, 18 ppm; candy, 22 ppm; baked goods, 15-48 ppm; and gelatins and puddings, 1 ppm. A colorless liquid with an apple-like odor and taste, allyl isovalerate is approved by the U.S. Food and Drug Administration for use in foods. Specific production figures are not available, but U.S. production in 1980 exceeded 1,000 pounds. Carcinogenesis studies of allyl isovalerate (96% pure) were conducted by administering the test chemical in corn oil gavage to groups of 50 male and 50 female F344/N rats and to groups of 50 male and 50 female B6C3F1 mice at doses of 31 or 62 mg/kg. The doses selected were based on the chemically-induced toxic effects and depressed weight gains obtained from the 13-week studies. Doses were administered five times per week for 103 weeks. Groups of 50 rats and 50 mice of each sex received corn oil by gavage on the same dosing schedule and served as vehicle controls. Survival and mean body weight gain of rats of each sex and male mice were not adversely affected by the administration of allyl isovalerate. The significantly lower survival (P=0.001) and the lower mean body weight of low-dose female as compared with controls are likely consequences of the high incidence of a genital tract infection in the low-dose females. This infection was probably responsible for the deaths of 11/19 control, 22/33 low-dose, and 13/25 high-dose female mice that died before the end of the study. Squamous cell papillomas and epithelial hyperplasia of the nonglandular stomach were observed in dosed male mice in the 2-year studies (squamous cell papillomas: 0/50, 1/50, 2%, 3/48, 6%; epithelial hyperplasia: 1/50, 2%, 1/50, 2%, 7/48, 15%). The papillomas occurred with a significant positive trend (P<0.05). The incidence of high-dose male mice with squamous cell papillomas of the nonglandular stomach was also higher (P<0.01) than the historical rate for vehicle control male B6C3F1 mice in the Bioassay Program (5/881, 0.6%). Forestomach lesions were also observed in female mice: squamous cell papillomas (1/50, 0/50, 2/50) and epithelial hyperplasia of the nonglandular stomach (0/50, 2/50, 3/50). Pancreatic acinar-cell adenomas occurred at higher incidences in the dosed male rats than in the controls (control, 1/50, 2%; low-dose, 4/50, 8%; high-dose, 2/50, 4%). Pancreatic acinar-cell tumors were not observed in female rats. Preputial gland adenomas were observed in increased incidence in low-dose male rats (0/50, 4/50, 8%; P<0.05, 1/50, 2%). Mononuclear-cell leukemias in rats and lymphomas in mice occurred with increased incidences. This consistent dose-response increase among both rats and mice indicates that allyl isovalerate adversely affects the hematopoietic system. Cholangiofibrosis, nodular regeneration, cirrhosis, focal necrosis, fatty metamorphosis, and cytoplasmic vacuolization were observed at increased incidences in the livers of high-dose male and female rats in the 2-year study. No compound-related nonneoplastic lesions were observed in the mice of either sex. Liver neoplasms were not increased in either dosed rats or mice of either sex. Significant (P<0.05) decreases in tumor incidences were observed in male mice for hepatocellular carcinomas (18/50, 6/50, 9/50), for alveolar/bronchiolar adenomas or carcinomas (13/50, 6/50, 5/49), and for follicular-cell adenomas of the thyroid gland (5/47, 0/46, 1/49). Allyl isovalerate was not mutagenic for Salmonella typhimurium (tester strains TA 98, 100, 1535, and 1537) with or without metabolic activation. Under the conditions of these studies, allyl isovalerate was carcinogenic for F344/N rats and B6C3F1 mice, causing increased incidences of hematopoietic system neoplasms (mononuclear-cell leukemia in male rats and lymphoma in female mice). Levels of Evidence of Carcinogenicity: Male Rats: Positive Female Rats: Negativen female mice). Levels of Evidence of Carcinogenicity: Male Rats: Positive Female Rats: Negative Male Mice: Negative Female Mice: Positive

Journal Article↗

PubMed1983

NTP Carcinogenesis Bioassay of Ziram (CAS No. 137-30-4) in F344/N Rats and B6C3F1 Mice (Feed Study).

A NTP Carcinogenesis bioassay of ziram (89% pure, with 6.5% thiram), a fungicide and a rubber vulcanization accelerator, was conducted in F344/N rats and in B6C3F1 mice. Groups of 50 rats of each sex received diets containing 300 or 600 ppm of commercial grade ziram for 103 weeks; groups of 49 or 50 mice of each sex received diets containing 600 or 1,200 ppm ziram; and groups of 50 rats and 50 mice of each sex served as untreated controls. The average daily consumption of ziram by low-and high-dose rats, through the majority of the study, was about 11 and 22 mg/kg for males and 13 and 26 for females. The average daily consumption of ziram by low-and high-dose mice, through the majority of the study, was 122 and 196 mg/kg for males and about 131 and 248 mg/kg for females. Survival and feed consumption and mean body weights of rats of each sex were not adversely affected by ziram; rats of each sex could have tolerated higher doses. C-Cell carcinomas of the thyroid in male rats occurred with a statistically significant positive trend (P<0.01) and the incidence in the high-dose group was significantly higher (P<0.05) than that in the controls (control, 0/50, 0%; low-dose, 2/49, 4%; high-dose, 7/49, 14%) and higher than that previously observed in control male rats at the same laboratory (18/584, 3%; range 0% to 8%). The combined incidence of males with either C-cell adenoma or carcinoma also showed a statistically significant (P<0.05) positive trend (control, 4/50, 8%; low-dose, 9/49, 18%; high-dose, 12/49, 24%). There were no significant histopathologic changes noted in the follicular cells. Survival of male and female mice was not adversely affected by ziram in feed; mean body weight gain by dosed male mice throughout the study and by high-dose female mice after week 80 was depressed by 15% to 20% relative to the controls. Average daily feed consumption by high-dose males and high-dose females was, respectively, 78% and 85% that of the controls. Mice probably could not have tolerated higher doses. The incidence of alveolar/bronchiolar adenomas was significantly (P<0.05) increased in female mice (control, 2/50, 4%; low-dose, 5/49, 10%; high-dose, 10/50, 20%). The combined incidence of alveolar/bronchiolar adenomas or carcinomas in female mice showed a statistically significant (P<0.05) positive trend. The incidence in the high-dose group was significantly (P<0.05) higher than that in the controls (control, 4/50, 8%; low-dose, 6/49, 12%; high-dose, 11/50, 22%). Pulmonary adenomatous hyperplasia consistent with chronic Sendai virus infection (confirmed by serologic analysis performed on untreated animals from the same animal shipment and present in the same room) was observed in control and dosed male mice (control, 15/49, 31%; low-dose, 19/50, 38%; high-dose, 16/49, 33%) as well as in control and dosed female mice (control, 18/50, 36%; low-dose, 27/49, 55%; high-dose, 26/50, 52%). Six of the 26 high-dose females without pulmonary adenomatous hyperplasia had pulmonary tumors, whereas 4 of the 24 high-dose females without pulmonary adenomatous hyperplasia also had pulmonary tumors. Only 1 of 27 low-dose females with adenomatous hyperplasia had a pulmonary tumor. There was a significant decrease in the incidence of mammary fibroadenomas in high-dose female rats (control, 16/50, 32%; low-dose, 17/50, 34%; high-dose, 8/50, 16%). Significant dose-related decreased incidences of liver carcinomas in male mice (control, 13/49, 27%; low-dose, 8/50, 16%; high-dose, 1/49, 2%) and of liver adenomas in female mice (control, 7/50, 14%; low-dose, 2/50, 4%; high-dose, 0/50, 0%) were observed. Under the conditions of these studies, ziram was carcinogenic for male F344/N rats, causing increased incidences of C-cell carcinomas of the thyroid gland. Ziram was not carcinogenic for either female F344/N rats or for male B6C3F1 mice. Increased incidences of alveolar/bronchiolar adenomas and of combined alveolar/bronchiolar adenomas or carcinomas occurred in female B6C3F1 mice. However, the interpretation of this increase in lung tumors is complicat either female F344/N rats or for male B6C3F1 mice. Increased incidences of alveolar/bronchiolar adenomas and of combined alveolar/bronchiolar adenomas or carcinomas occurred in female B6C3F1 mice. However, the interpretation of this increase in lung tumors is complicated by an intercurrent Sendai virus infection. Levels of Evidence of Carcinogenicity: Male Rats: Positive Female Rats: Negative Male Mice: Negative Female Mice: Equivocal Synonym: zinc dimethyldithiocarbamate

Journal Article↗

PubMed1983

NTP Carcinogenesis Studies of 4,4'-Methylenedianiline Dihydrochloride (CAS No. 13552-44-8) in F344/N Rats and B6C3F1 Mice (Drinking Water Studies).

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

Journal Article↗

PubMed1983

NTP Carcinogenesis Bioassay of L-Ascorbic Acid (Vitamin C) (CAS No. 50-81-7) in F344/N Rats and B6C3F1 Mice (Feed Study).

L-Ascorbic acid is essential for many physiologic functions in animals and humans, mostly biochemical reactions involving oxidation. L-Ascorbic acid is approved for use as a dietary supplement and chemical preservative by the U.S. Food and Drug Administration and is on the FDA's list of substances generally recognized as safe. L-Ascorbic acid may be used in soft drinks as an antioxidant for flavor ingredients, in meat and meat-containing products, for curing and pickling, in flour to improve baking quality, in beer as a stabilizer, in fats and oils as an antioxidant, and in a wide variety of foods for vitamin C enrichment. L-Ascorbic acid may also find use in stain removers, hair waving preparations; plastics manufacture, photography, and water treatment. A NTP Carcinogenesis bioassay of L-ascorbic acid (>97% pure) was conducted by administering diets containing 25,000 or 50,000 ppm L-ascorbic acid to groups of 50 F344/N rats and 50 B6C3F1 mice of each sex for 103 weeks. Controls consisted of 50 untreated rats and untreated mice of each sex. Fifty-thousand ppm is the highest dose recommended for chronic studies. Survival of dosed and control female rats and of dosed and control female mice were comparable. Survival of high-dose male rats was slightly greater than that of the controls (P=0.087). Survival of high-dose male mice was significantly greater (P=0.009) than that of the controls. Throughout most of the study, mean body weights of dosed female rats and dosed female mice were lower than those of the controls. Final body weights were comparable among groups, except for the high-dose female rats (<13%); marginal differences (<8%) were observed for low-dose female rats and for dosed female mice (8%-11%). Food consumption was equivalent among groups. Most observational differences were confined to the female rat. The incidence of low-dose female rats with undifferentiated (mononuclear-cell) leukemias (control, 6/50, 12%; low-dose, 17/50, 34%; high-dose, 12/50, 24%) was significantly higher (P<0.02) than that in controls. These tumors were not considered to be related to administration of L-ascorbic acid because they did not occur in the female high-dose group at incidences significantly greater (P>0.07) than those in the controls, the trend test was not significant (P>/=0.07), and no increases were observed for male rats. Under the conditions of this bioassay, L-ascorbic acid was not carcinogenic for male and female F344/N rats or male and female B6C3F1 mice. Levels of Evidence of Carcinogenicity: Male Rats: Negative Female Rats: Negative Male Mice: Negative Female Mice: Negative Synonym: vitamin C

Journal Article↗

PubMed1983

NTP Carcinogenesis Bioassay of Melamine (CAS No. 108-78-1) in F344/N Rats and B6C3F1 Mice (Feed Study).

A NTP Carcinogenesis bioassay of melamine (>95% pure), a chemical intermediate in the manufacture of amino resins and plastics, was conducted by feeding diets containing 2,250 or 4,500 ppm melamine to groups of 50 male F344/N rats and 50 B6C3F1 mice of each sex for 103 weeks. Groups of 49 male rats, 50 female rats, 49 male mice, and 50 female mice served as controls. Mean body weights of dosed rats of each sex were lower than those of the controls after week 20. Survival of high-dose male rats was significantly lower (P</=0.05) than that of the controls. Survival of all other dosed rat groups was comparable with that of the respective controls. Transitional-cell carcinomas in the urinary bladder of male rats occurred with a statistically significant positive trend (P</=0.002; controls, 0/45; low-dose, 0/50; high-dose, 8/49, 16%) and the incidence in the high-dose group was significantly higher (P</=0.016) than that in the controls. A transitional-cell papilloma was observed in the urinary bladder of an additional high-dose male rat. These tumors were not observed in statistically significant proportions in female rats. Seven of the eight high-dose male rats with the transitional-cell carcinomas also had bladder stones. An association (P</=0.001) was found between bladder stones and bladder tumors in male rats. Chronic inflammation, distinguishable from the nephropathy observed in aging F344/N rats, was significantly increased (P</=0.01) in the kidney of dosed female rats (controls, 4/50,8%; low-dose, 17/50, 34%; high-dose, 41/50, 82%) and is attributed to the administration of melamine. The mean body weight of high-dose male mice was lower than that of controls after week 50 of the study. The mean body weights of dosed and control female mice were comparable throughout the study. Survival of high-dose male mice was significantly less (P<0.02) than that of the controls. Survival of all other dosed groups was similar to that of the respective controls. Acute and chronic inflammation and epithelial hyperplasia of the urinary bladder were found in increased incidence in dosed male mice. The incidence of bladder stones in dosed male mice was increased relative to controls (control, 2/45, 4%; low dose, 40/47, 85%; high-dose, 41/45, 93%); however, there was no evidence of bladder tumor development in this species. Also, four high-dose female mice had bladder stones without any tumors. Under the conditions of this bioassay, melamine was carcinogenic for male F344/N rats, causing transitional-cell carcinomas in the urinary bladder. With one exception, urinary bladder stones were observed in male rats that had transitional-cell carcinomas. Melamine was not carcinogenic for female F344/N rats or for B6C3F1 mice of either sex. Levels of Evidence of Carcinogenicity: Male Rats: Positive Female Rats: Negative Male Mice: Negative Female Mice: Negative Synonyms: 2,4,6-triamino-s-triazine; cyanurotriamide

Journal Article↗

PubMed1983

Toxicology and NTP Carcinogenesis Studies of a Polybrominated Biphenyl Mixture (Firemaster FF-1) in F344/N Rats and B6C3F1 Mice (Gavage Studies).

Firemaster FF-1, a flame retardant composed of polybrominated biphenyls (PBB), was responsible for widespread environmental contamination and animal losses in Michigan starting in 1973. This study was undertaken to characterize the long-term toxic and carcinogenic potential of this PBB mixture in rats and mice of each sex. Fisher 344/N rats and B6C3F1 mice were given 125 oral doses of PBB over a 6-month period--0, 0.1, 0.3, 1.0, 3.0, or 10.0 mg/kg body weight/day (5 days/week). A dose-related decrease in body weight gain was observed in both male and female rats and male mice, although there was no significant difference in food consumption. At the end of the 6-month exposure, there was a dose-dependent decrease in thymus weights in rats. The liver appeared to be the primary target organ. Dose-related hepatotoxic effects were characterized by a marked increase in liver weight, with accentuation of hepatic lobular markings. Microscopically, there was moderate to marked hepatocellular swelling, disorganization and single cell necrosis of hepatocytes, fatty infiltration, and bile duct proliferation. At the 6-month observation, atypical hepatocellular foci were observed at a low incidence in dosed rats and mice. Hepatic porphyrin levels were markedly increased in both rats and mice, excessively in females. Levels of porphyrin tended to decrease gradually, primarily in mice, following cessation of exposure. The significant decreases in serum thyroxine (T4) and triiodothyronine (T3) in rats suggest that PBB may interfere with thyroid hormone secretion. Total serum protein was decreased in dose-related fashion in female rats primarily due to dose-related decreases in albumin. There was a significant increase in the serum levels of gamma glutamyl transpeptidase (GGTP) in female rats given 10.0 mg/kg of PBB. There was a dose-related decrease in serum glucose in female rats, a dose-related decrease in the serum triglyceride level in dosed male rats, except at the lowest dose (0.1 mg/kg), and a dose-related increase in the serum levels of cholesterol in both male and female rats. Serum levels of GGTP were increased only in female mice given 10.0 mg/kg of PBB. There was a 5- to 6-fold increase in the activity of serum glutamic pyruvic transaminase (SGPT) in male and female mice in the 10.0 mg/kg groups. Serum enzyme activity of alkaline phosphate (AP) was also increased in mice given the highest dose of PBB. There was a significant dose-related increase in the serum levels of cholesterol in female mice, and the highest dose group was significantly greater than the control female mice. Serum glucose was significantly decreased in female mice administered 10.0 mg/kg of PBB. To determine the carcinogenic potential of PBB, rats and mice dosed for 6 months were observed without exposure to PBB for an additional 23 or 24 months, respectively (lifetime observation). The dosing (0.3 mg/kg or higher dose levels) shortened the survival time in male rats, whereas no such effect was observed in dosed females. There was also evidence of shortened survival time in the 10.0 mg/kg PBB-dosed mice. A significantly higher incidence of atypical hepatocellular foci, neoplastic nodules, hepatocellular carcinomas, and cholangiocarcinomas was observed in dosed rats. The incidence of hepatocellular carcinoma was increased in both male and female mice (highest dose level) compared with control male and female mice. The incidence of hepatic neoplasms appeared to be dose dependent in rats and mice. Liver tumors were observed primarily in those groups of animals to which PBB was given in doses sufficient to induce readily observable hepatic toxicity. Under the conditions of these studies, polybrominated biphenyl mixture (Firemaster FF-1) was carcinogenic for Fisher 344/N rats and B6C3F1 mice of each sex, inducing neoplastic nodules, hepatocellular carcinomas, and cholangiocarcinomas in rats and hepatocellular carcinomas in mice. Other toxicities included porphyrogenic effects and hepatotoxicity. Levels of Evidence of Carcinogenicity: Male Rats: Positive Female Rats: Positive Male Mice: Positive Female Mice: Positive Synonym: Firemaster FF-1

Journal Article↗

PubMed1983

NTP Carcinogenesis Bioassay of Diallyl Phthalate (CAS No. 131-17-9) in B6C3F1 Mice (Gavage Study).

Diallyl phthalate is a widely used crosslinking agent for unsaturated polyesters. Diallyl phthalate or diallyl phthalate polyester blends are used primarily as plasticizers and carriers for adding catalysts and pigments to polyesters and in molding, electrical parts, laminating compounds, and impregnation of metal castings. Rubber compounds, epoxy formulations, and polyurethane foams may also contain diallyl phthalate. Annual production of diallyl phthalate in the United States exceeds 5,000 pounds; precise figures are not available. A NTP Carcinogenesis bioassay of diallyl phthalate (99% pure) was conducted by administering 0 (vehicle control), 150, or 300 mg/kg diallyl phthalate in corn oil by gavage, 5 days per week for 103 weeks, to groups of 50 male and 50 female B6C3F1 mice. Survival rates and mean body weights of dosed mice were not different from those of the controls, and pathological lesions unrelated to proliferative changes were not observed. Therefore, a maximally tolerated dose for the purposes of carcinogenicity testing may not have been achieved. The incidences of lymphoma and either lymphoma or leukemia in dosed male mice were no significantly greater than those in the controls according to pairwise comparisons (P=0.051 to P=0.096), but the trend tests were statistically significant by either life table or incidental tumor analysis (P=0.031 to P=0.045). The incidence of lymphomas in the high-dose male mice was 12/50 (24%) in comparison with 6/50 (12%) in the controls. Recent historical incidences at the performing laboratory and in the NTP Bioassay Program were 18/120 (15%) and 71/661 (11%), respectively. Since the incidence of high-dose male mice with leukemia was not significantly greater than that of concurrent or historical controls at the performing laboratory by pairwise comparisons, this marginal increase was considered only to be equivocally related to diallyl phthalate administration. Increased incidences of squamous cell papillomas, hyperplasia, and inflammatory lesions of the forestomach were observed in diallyl phthalate-dosed mice of both sexes in a dose-related manner. Papillomas of the forestomach were observed in 0%, 2%, and 4% of the control, low-dose, and high-dose mice of both sexes. The recent historical incidence of this tumor in gavage control mice from both the performing laboratory and other laboratories within the Bioassay Program was less than 1%. Forestomach hyperplasia was diagnosed in 0%, 15%, and 18%, and in 8%, 2%, and 29% of the control, low-dose, and high-dose male and female mice, respectively; chronic inflammation of the forestomach was diagnosed in 0%, 9%, and 16% and in 4%, 2%, and 18% of the control, low-dose, and high-dose male and female mice, respectively. Because of the numerical elevation of the forestomach papillomas in the high-dose mice of both sexes, the concomitant observation of dose related forestomach hyperplasia, and the rarity of this tumor in corn oil (gavage) control B6C3F1 mice, the development of squamous cell papillomas of the forestomach may have been related to diallyl phthalate administration. Under the conditions of this bioassay, the development of chronic inflammation and hyperplasia of the forestomach in both male and female B6C3F1 mice was considered to be related to the administration of diallyl phthalate. The development of squamous cell papillomas of the forestomach may also have been related to chemical administration, but the available data are insufficient to indicate a clear cause and effect relationship. An increase in the incidence of male mice with lymphomas was observed, but this increase was considered only to be equivocally related to diallyl phthalate administration. The results of this bioassay, therefore, do not indicate that diallyl phthalate is carcinogenic in B6C3F1 mice, although a maximum tolerated dose may not have been achieved. A carcinogenicity study by the National Toxicology Program of diallyl phthalate in male and female Fisher 344/N rats, employing daily gavage doses of 0 (vehicle control), 50, or 100 mg/kg boicology Program of diallyl phthalate in male and female Fisher 344/N rats, employing daily gavage doses of 0 (vehicle control), 50, or 100 mg/kg body weight is currently being evaluated. Levels of Evidence of Carcinogenicity: Male Mice: Equivocal Female Mice: Equivocal

Journal Article↗

PubMed1983

Carcinogenesis Studies of 1,1,1,2-Tetrachloroethane (CAS: 630-20-6) in F344/N Rats and B6C3F1 Mice (Gavage Studies).

Carcinogenesis studies of technical grade 1,1,1,2-tetrachloroethane (>99% pure) were conducted by administering the test chemical in corn oil by gavage to groups of 50 male and 50 female F344/N rats at doses of 125 or 250 mg/kg body weight and to groups of 50 male and 50 female B6C3F1 mice at doses of 250 or 500 mg/kg. (1,1,1,2-tetrachloroethane is used as a chemical intermediate in the production of trichloroethylene and tetrachloroethylene). Doses were administered five times per week for 103 weeks. Due to chemically induced toxicity, high-dose mice received the chemical for only 65 weeks. Groups of 50 rats and 50 mice of each sex received corn oil by gavage on the same dosing schedule and served as vehicle controls. The chemical produced cumulative toxic effects with signs of central nervous system involvement from week 44 forward in the chronic study, resulting in significantly lower survival of high-dose male rats (P=0.001), and possibly decreasing the incidence of late-developing tumors in this group. Mean body weights of dosed and control rats of each sex were similar. Fourteen control, 10 low-dose, and 3 high-dose male rats and 2 control, 5 low-dose, and 8 high-dose female rats were killed accidentally during the study; of these, 11 control and 7 low-dose males died apparently from heat stress during week 62 as a result of a 6-hour elevated temperature (>34 degrees C) in the animal room. Neither hepatocellular neoplastic nodules alone nor hepatocellular carcinomas alone occurred in statistically significant incidences in male rats, but the combined incidence of male rats with either hepatocellular neoplastic nodules or carcinomas occurred with a statistically significant positive trend (P<0.05) in the life table test (controls, 0/49, 0%; low-dose, 1/49, 2%; high-dose, 3/48, 6%). A single hepatocellular carcinoma occurred in the high-dose group. The combined incidence of liver tumors in the high-dose males (3/48, 6%) did not greatly exceed the historical incidences of liver tumors in groups of vehicle controls in other studies at this laboratory (5/243, 2.1%; range 0%-4%). However, reduced survival of the high-dose group in the present study may have reduced the sensitivity of this bioassay for detecting liver tumors. Mineralization of the kidney increased in a dose-related fashion in the male rats (12/48, 19/50, 26/48). Fibroadenomas in the mammary gland of female rats occurred with a statistically significant (P<0.05) increased incidence in the low-dose group as compared with the controls (6/49, 15/49, 7/46). The incidence in the high-dose group was not different than that in the controls. The combined incidence of adenomas, adenocarcinomas, and carcinomas in the pituitary gland of female rats showed a statistically significant (P<0.05) negative trend and the incidence in the high dose group was significantly (P<0.05) less than that in the controls (18/39, 16/45, 7/42). Mean body weight of high-dose mice was less than that of controls after week 20 in males and after week 40 in females. Clinical signs of central nervous system toxicity occurred at week 51 in both sexes of high-dose mice and by week 66 they were dead or moribund and were killed. Survival of low-dose females was also significantly (P<0.05) less than that of controls. The maximum tolerated dose was exceeded in high-dose mice. Inflammation, necrosis, fatty metamorphosis, and hepatocytomegaly were observed in increased incidences in the livers of high-dose male and female mice. The major neoplastic histopathological effects occurred in the liver, where dose-related statistically significant (P<0.05) increases in the incidence of hepatocellular adenomas occurred in both male and female mice: vehicle controls, low-, and high-dose male mice had rates of 13% (6/48), 30% (14/46), and 42%, (21/50); corresponding percentages in female mice were 8% (4/49), 17% (8/46), and 50% (24/48). Evidence for the association between 1,1,1,2-tetrachloroethane and development of hepatocellular carcinomas in mice was limited because of poor survival in the high-dose grouporoethane and development of hepatocellular carcinomas in mice was limited because of poor survival in the high-dose groups. Nevertheless, there was an increased incidence of hepatocellular carcinomas in female mice despite the reduced survival in the dosed groups (controls, 1/49, 2&percnt;; low-dose, 5/46, 11&percnt;; high-dose, 6/48, 13&percnt;). There was no clear effect in male mice. Under the conditions of these studies, 1,1,1,2-tetrachloroethane was not demonstrated to be carcinogenic in F344/N rats, although the observed increase in the proportion of male rats with liver tumors may have been associated with the administration of 1,1,1,2-tetrachloroethane; accidental killing of 27 male and 15 female rats reduced the sensitivity of this bioassay for detecting a carcinogenic response. 1,1,1,2-Tetrachloroethane was carcinogenic for B6C3F1 mice, causing an increased proportion of female mice with hepatocellular carcinomas and an increased proportion of male and female mice with hepatocellular adenomas; the decreased survival in high-dose male and female mice compromised the ability of this bioassay to further determine the presence or absence of a carcinogenic effect and gave clear evidence that these doses were toxic. Levels of Evidence of Carcinogenicity: Male Rats: Equivocal Female Rats: Negative Male Mice: Positive Female Mice: Positive

Journal Article↗

PubMed1983

Carcinogenesis Studies of Pentachloroethane (CAS No. 76-01-7) in F344/N Rats and B6C3F1 Mice (Gavage Study).

A carcinogenesis bioassay of technical grade pentachloroethane (95.5% pure, with 4.2% hexachloroethane) was conducted by administering the test chemical in corn oil by gavage to groups of 50 male and 50 female F344/ N rats at doses of 75 or 150 mg/ kg body weight and to groups of 50 male and 50 female B6C3F1 mice at doses of 250 or 500 mg/ kg. (Pentachloroethane is a solvent that was used primarily as an intermediate in the manufacture of tetrachloroethylene.) Doses were administered for 103 weeks for rats and 41-103 weeks for mice. Groups of 50 rats and 50 mice of each sex received corn oil by gavage on the same dosing schedule and served as vehicle controls. Prechronic testing (single-dose and 14-day and 13-week repeated-dose studies) did not indicate target organ toxicity for pentachloroethane. The dosage levels for the 2-year study were selected on the basis of survival and body weight gains during the prechronic test phase. Survival of high-dose rats of each sex was significantly (P<0.05) less than that of the controls. Mean body weights of dosed male and female rats were lower than those of the corresponding controls during the second year of the study. Final mean body weights for rats were 4%-5% lower for male rats and 8%-12% lower for female rats when compared to controls. Chronic, diffuse inflammation of the kidney, distinguishable from nephropathy seen in aging F344/ N rats, was found in male rats in a significant (P<0.001) and dose-related incidence (control, 4/50, 8%; low-dose, 14/49, 29%; high-dose, 33/50, 66%). Mineralization of the renal papilla, considered to be secondary to chronic inflammation, was also observed at increased incidences in dosed male rats. Pentachloroethane administration did not cause any increased incidences of tumors in either male or female rats. [See Note Added Subsequent to Peer Review.] Statistically significant negative trends were detected for subcutaneous tissue fibromas among males and for pituitary adenomas in both sexes. Forty-two high-dose male mice died by week 41, and the 8 remaining animals in the group were killed at that time. Twenty-five male control mice were killed at week 44 to serve as controls for the high-dose males. Only 22/50 (44%) of the low-dose male mice survived to the end of the study. All high-dose female mice were dead by week 74, and only 9/50 (18%) low-dose females survived to the end of the study. Mean body weights of mice were lower than those of controls. The incidence of hepatocellular carcinoma was significantly elevated in all groups of dosed mice (male: 4/48, 8%; 26/44, 59%, P<0.001; 7/45,16%; female: 1/46, 2%; 28/42, 67%, P<0.001; 13/45, 29% P<0.001). Early mortalities in the high-dose male mice precluded an evaluation of their lifetime incidence of hepatocellular carcinoma. There was a significant increase in incidence over that observed among 25 controls killed at week 44 (0/25 versus 7/45, P<0.05). There was also a significant (P<0.001) dose-related increase in hepatocellular adenoma in female mice (2/46, 4%; 8/42, 19%; 19/45, 42%). Under the conditions of this bioassay, technical grade pentachloroethane containing 4.2% hexachloroethane (a known carcinogen in mice) was not carcinogenic in F344/N rats. The decreased survival of dosed rats might have reduced the sensitivity for a carcinogenic response in this species. Pentachloroethane was nephrotoxic to male rats. Technical grade pentachloroethane was carcinogenic for B6C3F1 mice, causing hepatocellular carcinomas in males and females, and adenomas in females. NOTE ADDED SUBSEQUENT TO PEER REVIEW: After the Peer Review Panel meeting in June 1981, the National Toxicology Program determined that the kidney (especially in male F344/N rats) was a target organ for the short-chain chlorinated aliphatic hydrocarbons. This awareness came from the nonneoplastic and neoplastic diagnoses made on related chemicals in this class. Alerted to this lead, the NTP re-examined the originally-prepared histology slides on the rat kidney from the pentachloroethane bioassay. During the re-reading, additional renato this lead, the NTP re-examined the originally-prepared histology slides on the rat kidney from the pentachloroethane bioassay. During the re-reading, additional renal tubular adenomas were discovered. Unfortunately, these slides were lost after they arrived at the Gulf South Research Institute laboratory; by necessity, a new set of slides was prepared. In the second set of slides, three additional renal tubular-cell adenomas were discovered: one in a low-dose male and two in high-dose males; none were found in treated females or in male and female vehicle controls. Thus, rare tubular-cell adenomas of the kidney occurred in male rats with a dose-related trend (P<0.05), and the incidence in the high-dose group was suggestive (P<0.06; 0/50, 1/49, 4/50). Additionally, one control and one low-dose male each had an adenocarcinoma and another low-dose male had a carcinoma of the kidney (not otherwise specified); combining tubular-cell tumors reduced the statistical differences (1/50, 2/49, 4/50). These tumors are uncommon in male vehicle controls in the bioassay program, occurring in 1/293 (0.3&percnt;) at this bioassay testing laboratory and in 4/998 (0.4&percnt;) in all NCI/ NTP bioassay testing laboratories. All tumors in these gavage controls were adenocarcinomas. The National Toxicology Program considers that these rare tubular-cell tumors of the kidney in male rats indicate a target organ and may have been associated with the administration of pentachloroethane. These additional tumor diagnoses were not presented to the Peer Review Panel. These are, however, the incidence rates recorded and analyzed statistically in this technical report (See Table 5, Table Al, and Table A3 in the full document). Levels of Evidence of Carcinogenicity: Male Rats: Equivocal Female Rats: Negative Male Mice: Positive Female Mice: Positive Synonyms: pentalin

Journal Article↗

PubMed1983

Carcinogenesis Studies of Eugenol (CAS No. 97-53-0) in F344/N Rats and B6C3F1 Mice (Feed Studies).

Carcinogenesis studies of eugenol (>99% pure), a widely used flavor additive and chemical intermediate, were conducted by feeding diets containing 6,000 or 12,500 ppm of eugenol to groups of 50 female F344/N rats and by feeding diets containing 3,000 or 6,000 ppm to groups of 50 male F344/N rats and B6C3F1 mice of each sex for 103 weeks. Groups of 40 rats and 50 mice of each sex served as controls. Dose levels selected for the two year studies were based on thirteen-week (91-day) studies in which dietary concentrations for the six groups ranged from 0 to 12,500 ppm. Other than a -10% difference from controls in body weights in the 12,500 ppm male rats, no chemically related gross or histopathologic effects were observed. In the two-year studies, with the exception of the high dose female rats and female mice, final body weights of the treated groups were comparable to their respective controls. No significant differences in survival were apparent for any of the eight groups receiving eugenol and for the appropriate controls. Food consumption among groups was not different in comparison with controls-- rats: males equal to or greater than 97%, females equal to or greater than 91%; mice: males equal to or greater than 94%, females equal to or greater than 90%. There were no significant observable differences between treated and control groups of rats for either nonneoplastic (toxic) lesions or neoplasms that could be attributed to eugenol. Increases in tumor incidences were diagnosed for low dose male rats with alveolar, bronchiolar adenomas or carcinomas (combined), for C-cell adenomas of the thyroid gland in low dose female rats, and for endometrial stromal polyps of the uterus in high dose female rats. Fibroadenomas of the mammary gland were decreased in dosed groups of female rats compared with controls. None of these differences were considered to be associated with the dietary administration of eugenol. In male mice, the low dose animals had an increased incidence (P<0.05) of both hepatocellular adenomas (control, 4/50; low dose, 13/50; high dose, 10/49) and hepatocellular carcinomas (10/50, 20/50, 9/49) when compared with control animals. A significant increase in hepatic neoplasms was not observed in high dose animals. No single liver tumor type was observed in female mice with a statistically significant increased incidence. When the incidences of female mice with hepatocellular adenoma or carcinoma were combined (2/50, 7/49, 9/49), there was a dose-related positive trend and the incidence of liver neoplasms in high dose animals was higher than in controls (P<0.05). Eugenol was given in the diets of female F344/N rats (0, 0.6, or 1.25%) and of male F344/N rats and male and female B6C3F1 mice (0, 0.3, or 0.6%) for 103 weeks. Under these experimental conditions, there was no evidence of carcinogenicity observed for male or female rats. For mice there was equivocal evidence of carcinogenicity since eugenol caused increased incidences of both carcinomas and adenomas of the liver in male mice at the 3,000 ppm dietary level and because eugenol was associated with an increase in the combined incidences of hepatocellular carcinomas or adenomas in female mice. Levels of Evidence of Carcinogenicity: Male Rats: Negative Female Rats: Negative Male Mice: Equivocal Female Mice: Equivocal Synonym: 1-allyl-3-methoxy-4-hydroxybenzene

Journal Article↗

PubMed1982

NTP Carcinogenesis Bioassay of Propyl Gallate (CAS No. 121-79-9) in F344/N Rats and B6C3F1 Mice (Feed Study).

Propyl gallate is a white to nearly white odorless powder having a slightly bitter taste. Solutions of propyl gallate turn dark in the presence of iron or iron salts. Propyl gallate has been used since 1948 as an antioxidant to stabilize cosmetics, food packaging materials, and foods containing fats. As an additive, it may be found in edible fats, oils, mayonnaise, shortening, baked goods, candy, dried meat, fresh pork sausage, and dried milk, and it is used in hair grooming products, pressure-sensitive adhesives, lubricating oil additives, and transforming oils. A NTP Carcinogenesis bioassay of propyl gallate was conducted by feeding diets containing 6,000 or 12,000 ppm propyl gallate to groups of 50 F344/N rats and 50 B6C3F1 mice of each sex for 103 weeks. Groups of 50 untreated rats and 50 untreated mice of each sex served as controls. Survival of rats and mice was not adversely affected by propyl gallate, but mean body weights of dosed rats and mice of each sex were lower than those of the controls. At 104 weeks, mean body weights of low-and high-dose rats were 4% and 8% lower than those of the controls for males and 11% and 19% lower than those of the controls for females. Similarly, mean body weights of low-and high-dose mice were 5% and 8% lower than those of the controls for males and 11% (both dose groups) lower than those of the controls for females. Thyroid follicular-cell adenomas or carcinomas (combined) occurred in male rats with a statistically significant (P<0.05) positive trend, but the incidences in the dosed groups were not statistically significant in direct comparisons with the control groups. Moreover, the incidence of high-dose male rats with follicular-cell tumors (3/50, 6%) was not statistically different from the historical control rate (14/584, 2.4%) for the laboratory that conducted this bioassay. Rare tumors (an astrocytoma or a glioma) were found in the brains of two low-dose female rats. The incidence of all brain tumors in the Bioassay Program is only 0.86%. The absence of this tumor in the high-dose female rat group reduces the likelihood that this tumor is related to propyl gallate administration. Increased incidences of hepatic cytoplasmic vacuolization and suppurative inflammation of the prostate were observed in dosed male rats. These findings were considered to be related to administration of propyl gallate. Tumors (mostly benign) of the preputial gland, islet-cell tumors of the pancreas, and pheochromocytomas of the adrenal gland were observed with significantly (P<0.05) higher incidences in the low- dose male rats, but there was little evidence of an effect in the high-dose group. The incidences of male rats with tumors of the preputial gland were 1/50 (2%) for controls, 8/50 (16%) for the low-dose, and 0/50 (0%) for the high-dose group. Islet-cell tumors of the pancreas occurred in 2/50 (4%) control males, 9/50 (18%) low-dose males, and 4/50 (8%) for high-dose males. Pheochromocytomas of the adrenal gland were observed in 4/50 (8%) control males, 13/48 (25%) low-dose males, and 8/50 (16%) high-dose males. Negative trends (P<0.05) were observed for leukemia in male rats (16/50, 7/50, 6/50) and for fibroadenomas of the mammary gland in female rats (11/50, 2/50, 5/50). In male mice, malignant lymphoma was observed with a significantly (P</=0.014) positive trend (control, 1/50, 2%; low-dose, 3/49, 6%; high-dose, 8/50, 16%), and the incidence in the high-dose group was significantly (P</=0.028) higher than that observed in the concurrent controls. However, the high-dose incidence was not statistically different from the historical rate (60/640, 9.4%) for the laboratory that conducted this bioassay. Adenomas of the liver in female mice occurred with a statistically significant (P</=0.022) positive trend, and the incidence in the high-dose group was significantly (P</=0.039) higher than that of the controls (0/50, 0%; 2/50, 4%; 5/49, 10%). The incidences of hepatocellular adenomas or carcinomas (combined) were similar in control and dosed groups (3/50, 6%; 3/50, 6%; 5/49, 10%). Negative&percnt;; 2/50, 4&percnt;; 5/49, 10&percnt;). The incidences of hepatocellular adenomas or carcinomas (combined) were similar in control and dosed groups (3/50, 6&percnt;; 3/50, 6&percnt;; 5/49, 10&percnt;). Negative trends (P<0.05) were obtained for fibromas of the skin or subcutaneous tissue in male mice (5/50, 1/49, 0/50). Under the conditions of this bioassay, propyl gallate was not considered carcinogenic for F344/N rats, although there was evidence of an increased proportion of low-dose male rats with preputial gland tumors, islet-cell tumors of the pancreas, and pheochromocytomas of the adrenal glands; rare tumors of the brain occurred in two low-dose females. Propyl gallate was not considered to be carcinogenic for B6C3F1 mice of either sex, although the increased incidence of malignant lymphoma in male mice may have been related to the dietary administration of propyl gallate. Levels of Evidence of Carcinogenicity: Male Rats: Equivocal Female Rats: Negative Male Mice: Equivocal Female Mice: Negative Synonyms: 2,4,5 trihydroxybenzoic acid propyl ester; gallic acid propyl ester; Progallin P; Tennox PG

Journal Article↗

PubMed1982

NTP Carcinogenesis Bioassay of Bis(2-chloro-1-methylethyl)ether (~70%) (CAS No. 108-60-1) Containing 2-Chloro-1-methylethyl(2-chloropropyl)ether (~30%) (CAS No. 83270-31-9) in B6C3F1 Mice (Gavage Study).

Bis(2-chloro-1-methylethyl) ether is a beta-haloether that has been used extensively in paint and varnish removers, spotting agents, and cleaning solutions. BCMEE has also been used as an intermediate in the manufacture of dyes, resins, and pharmaceuticals and has been added to soap solutions to aid in textile cleaning. Bis (2-chloro-1- methylethyl) ether has been a by-product in the manufacture of propylene oxide and propylene glycol. It is the active ingredient of a nematocide developed and used on field crops in Japan. A NTP Carcinogenesis bioassay of bis (2-chloro- 1-methylethyl) ether (~70%), containing ~30% 2-chloro-1- methylethyl (2-chloropropyl) ether, was conducted by administering 100 or 200 mg/kg bis (2-chloro- 1-methylethyl) ether in corn oil by gavage 5 times per week for 103 weeks to groups of 50 B6C3F1 mice of each sex. Fifty mice of each sex received corn oil alone and served as vehicle controls. Survival and mean body weights of dosed and control mice of each sex were comparable. The incidence of alveolar/bronchiolar adenomas occurred in a positive dose-related trend for male mice (P<0.05: control 5/50, 10%; low-dose 13/50, 26%; high-dose 11/50, 22%) and for female mice (P<0.02: 1/50, 2%; 4/50, 8%; 8/50, 16%). The number of female mice in the high-dose group with adenomas was significantly (P<0.03) greater than that in controls. The combined incidences in dosed males and in high-dose females were significantly higher (P</=0.04 for males and P</=0.01 for females) than those in the controls (males: 6/50, 12%; 15/50, 30%; 13/50, 26%; females: 1/50, 2%; 4/50, 8%; 10/50, 20%). The incidence of hepatocellular carcinomas (5/50, 10%; 13/50, 26%; 17/50, 34%) and the combined incidence of hepatocellular adenomas and carcinomas (13/50, 26%, 23/50, 46%, 27/50, 54%) in male mice were statistically significant by the trend tests (P<0.01) and the incidences in the high-dose group were significantly higher than those in the controls (P<0.01). Metastases to the lung occurred in 1/50 control, 4/50 low-dose, 3/50 high-dose male mice. Fatty metamorphosis was found in increased incidence in the livers of dosed male mice (control 2/50; 16/50 low-dose; 15/50 high-dose). Squamous cell papillomas were found in the stomach or forestomach in two high-dose females, one low-dose male, and one high-dose male. A squamous cell carcinoma was found in the forestomach of a third high-dose female. These tumors were probably related to administration of the test compound, since they are rarely observed in vehicle control and untreated control B6C3F1 mice. Under the conditions of this bioassay, bis (2-chloro-1-methylethyl) ether, containing 2-chloro-1-methylethyl (2-chloropropyl) ether, was carcinogenic for B6C3F1 mice, causing increased incidences of alveolar/bronchiolar adenomas in male and females and hepatocellular carcinomas in males. In addition, the occurrence of a low incidence of squamous cell papillomas or carcinomas in the stomach or forestomach of females (a rare tumor in B6C3F1 mice) was probably associated with the administration of bis(2-chloro-1-methylethyl)ether. Levels of Evidence of Carcinogenicity: Male Mice: Positive Female Mice: Positive Synonyms for bis(2-chloro-1-methylethyl) ether: BCMEE; bis(2-chloroisopropyl) ether; BCPE

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PubMed1982

Carcinogenesis Bioassay of 2,3,7,8-Tetrachlorodibenzo-p-dioxin (CAS No. 1746-01-6) in Swiss-Webster Mice (Dermal Study).

2,3,7,8-Tetrachlorodibenzo-p-dioxin occurs as a highly toxic impurity found in herbicides containing 2,4,5-trichlorophenoxyacetic acid (2,4,5-T) and 2,4,5-T- derivatives, as well as in other chemicals synthesized using 2,4,5-trichlorophenol. The herbicide 2,4,5-T has been marketed in the United States since 1948. Production increased sharply between 1960 and 1970 when a 1:1 mixture of 2,4,5-T and 2,4-dichlorophenoxyacetic acid (2,4-D) was used as a defoliant in Vietnam under the names of "herbicide agent orange, herbicide orange, agent orange, and orange". During this 10-year period, about 106 million pounds of 2,4,5-T were sprayed. A carcinogenesis bioassay was conducted by applying an acetone suspension of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) to the clipped backs of 30 male and female Swiss-Webster mice 3 days per week for 99 or 104 weeks. Similar groups were pretreated with 1 application of 50 &mgr;g dimethylbenzanthracene (DMBA) in 0.1 ml acetone 1 week before TCDD administration began. Female mice received 0.005 &mgr;g TCDD per application, and the male mice received 0.001 &mgr;g TCDD. As vehicle controls, 45 mice of each sex received 0.1 ml acetone three times per week. Thirty animals of each sex were used as untreated controls. Throughout the bioassay, mean body weights of the male and female mice administered TCDD, or TCDD following DMBA, were essentially the same as those of the corresponding vehicle control group. Mean body weights of dosed and vehicle control groups of males were less thanthose of the untreated control group throughout the study; for the females, mean body weights were less than the untreated controls during the first 80 weeks. In female mice, the incidences of fibrosarcoma in the integumentary system in dosed groups with TCDD were significantly (P=0.007) higher than that in the corresponding controls (2/41, 5%; 8/27, 30%). An increase in the same tumor type, although not statistically significant (P=0.084), was also observed in the male mice (3/42, 7%; 6/28, 21%). In the DMBA-TCDD experiment, failure to have included groups skin painted with only DMBA precluded interpretation of these results. Under the conditions of this bioassay, 2,3,7,8-tetrachlorodibenzo-p-dioxin applied to the skin was not carcinogenic for male Swiss-Webster mice (the increase of fibrosarcomas in the integumentary system may have been associated with the skin application of TCDD). TCDD was carcinogenic for female Swiss-Webster mice causing fibrosarcomas in the integumentary system. Levels of Evidence of Carcinogenicity: Male Mice: Equivocal Female Mice: Positive Synonyms: 2,3,7,8-TCDD; TCDD

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PubMed1982

Bioassay of Reserpine for Possible Carcinogenicity (CAS No. 50-55-5).

A bioassay for possible carcinogenicity of reserpine, an antihypertensive drug for human use, was conducted by administering the test chemical in feed to F344 rats and B6C3F1 mice. Groups of 50 rats and 50 mice of each sex were administered reserpine at two doses, 5 ppm and 10 ppm, for 103 weeks and then observed for an additional 2 weeks. Matched controls consisted of groups of 50 untreated rats and 50 untreated mice of each sex. All surviving animals were killed and necropsied at the end of 104 or 105 weeks. The significant effects that could be related to administration of reserpine at the doses used were decreased body weight and increased tumor formation in dosed male rats and in mice of both sexes. Dosed male rats had an increased incidence of adrenal medullary pheochromocytomas. Among dosed mice, some males developed undifferentiatedcarcinomas of the seminal vesicles, which rarely occur in control mice, and females had an increased incidence of mammary cancer. It was concluded that, under the conditions of the bioassay, reserpine was carcinogenic in male rats and in mice of both sexes, producing three different kinds of cancers. reserpine was not carcinogenic for female rats, but they may not have received a high enough dose for maximum test sensitivity. Levels of Evidence of Carcinogenicity: Male Rats: Positive Female Rats: Negative Male Mice: Positive Female Mice: Positive

Journal Article↗

PubMed1982

Carcinogenesis Bioassay of D-Mannitol (CAS No. 69-65-8) in F344/N Rats and B6C3F1 Mice (Feed Study).

A carcinogenesis bioassay of D-mannitol (98%-100% pure), a food and drug additive, was conducted by feeding diets containing 25,000 or 50,000 ppm D-mannitol to groups of 50 F344/N rats and 50 B6C3F1 mice of each sex for 103 weeks. Groups of 50 rats and 50 mice of each sex served as controls. Survival and mean body weights of dosed and control male rats and of dosed and control mice of each sex were comparable. Survival of high-dose female rats was significantly higher (P<0.05) than that of the low-dose female rats. However, neither the survival of the low-dose group nor that of the high-dose group was significantly different from that of the controls. Throughout the study, mean body weight gain of dosed female rats was depressed (</=10%) relative to that of controls. Feed consumption by dosed and control rats and mice of each sex was similar. Although the rats and mice of each sex might have been able to tolerate higher doses, a dietary level of 50,000 ppm (5%) is the maximum concentration of a test substance infeed recommended in the guidelines of the Bioassay Program. Dilatation of the gastric fundal gland was observed in the increased incidence in dosed female rats when compared with that of controls (control, 6/50, 12%; low dose, 23/50, 46%; high dose, 23/50, 46%). Retinopathy and cataracts occurred at increased incidences in high-dose male and low- and high-dose female rats. A mild nephrosis, characterized by focal vacuolization of the renal tubular epithelium, was observed in increased incidence in dosed mice of each sex and was considered to be related to administration of D-mannitol (males: control, 15/50, 30%; low dose, 29/50, 58%; high dose, 30/47, 64%; females: control, 1/48, 2%; low dose, 3/48, 6%; high dose, 14/49, 29%). Under the conditions of this bioassay, D-mannitol was not carcinogenic for F344/N rats or B6C3F1 mice of either sex. Levels of Evidence of Carcinogenicity: Male Rats: Negative Female Rats: Negative Male Mice: Negative Female Mice: Negative

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