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National Toxicology Program

Publications and source records attributed to National Toxicology Program.

At least 505 records · Page 28Linked to original sources
PubMed1982

Carcinogenesis Bioassay of Zearalenone (CAS No. 17924-92-4) in F344/N Rats and B6C3F1 Mice (Feed Study).

A carcinogenesis bioassay of zearalenone, an estrogenic mycotoxin, was conducted by feeding diets containing 25 or 50 ppm zearalenone to groups of 50 F344/N rats of each sex and 50 or 100 ppm to groups of 50 B6C3F1 mice of each sex for 103 weeks. Groups of 50 rats and 50 mice of each sex served as controls. Estimates based on food consumption data indicate that the low-and high-dose rats received daily doses of about 1 and 2 mg, respectively, of zearalenone per kg of body weight. Low-dose and high-dose mice received estimated daily doses of about 7-10 and 14-20 mg, respectively, of zearalenone per kg of body weight. Survival of dosed and control rats of each sex was comparable. Mean body weight gains of dosed rats of each sex were lower than those of the corresponding controls; depression in mean body weight gain was dose related. Final body weights of dosed rats were <9% lower than those of control rats. The average daily feed consumption of dosed rats of each sex was 91%-102% that of controls. Inflammation of the prostate, testicular atrophy, and hepatocellular cytoplasmic vacuolization (male rats), and nephrosis (male and female rats) were compound-related. Retinopathy and cataracts occurred in low-and high-dose male rats and in low-dose female rats, and were associated with the closeness to fluorescent light. No compound-related, increased tumor incidences were observed in rats in the chronic study. Survival of dosed and control mice of each sex was comparable. Mean body weight gains of high-dose male and low-dose female mice were lower than those of the controls. Terminal body weights of dosed mice were <8% below those of control mice. The average daily feed consumption by dosed mice of each sex was 97-99% that of the controls. Myelofibrosis in the bone marrow, uterine fibrosis, and cystic ducts in the mammary gland were related to the administration of zearalenone in female mice. The incidence of hepatocellular adenomas in female mice was dose related (P</=0.003), and the incidence of these tumors in high-dose female mice was significantly higher (P</=0.006) than those in the controls (control, 0/50; low-dose, 2/49; high-dose, 7/49). Pituitary adenomas occurred with statistically significant positive trends (P</=0.022 for males and P</=0.001 for females). The incidences of these tumors in high-dose mice were significantly increased relative to controls (P</=0.032 for males: 0/40, 4/45, 6/44; and P</=0.003 for females: 3/46, 2/43, 13/42). Under the conditions of this bioassay, zearalenone was not carcinogenic for F344/N rats of either sex. Zearalenone should be considered carcinogenic in B6C3F1 mice, as evidenced by the increased proportion of male and female mice with pituitary adenomas and by the increased proportion of female mice with hepatocellular adenomas. Levels of Evidence of Carcinogenicity: Male Rats: Negative Female Rats: Negative Male Mice: Positive Female Mice: Positive Synonym: trans-zearalenone

Journal Article↗
PubMed1982

Carcinogenesis Bioassay of Allyl Isothiocyanate (CAS No. 57-06-7) in F344/N Rats and B6C3F1 Mice (Gavage Study).

A 2-year carcinogenesis bioassay of food-grade allyl isothiocyanate (greater than 93% purity), a flavoring agent, was conducted by administering 12 or 25 mg/kg allyl isothiocyanate in corn oil five times per week by gavage 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 received corn oil alone and served as vehicle controls. A single-dose study, a 14-day study, and a 13-week study were performed before the chronic study was conducted. Pathologic findings seen in the 14-day study at 50 mg/kg included a thickened mucosal surface of the stomach in rats and mice and a thickened urinary bladder wall in male mice. No gross or microscopic lesions were seen at the highest dose level (25 mg/kg) in the 13-week study. In the chronic study, survival of the dosed and control rats of each sex was comparable. Throughout the study, the mean body weights of high-dose male rats were lower than those of the controls, while during the last half of the study the mean body weights of the low-dose and high-dose female rats were higher than the mean body weights of the control animals. Final body weights in control and dosed groups were comparable. Transitional-cell papillomas in the urinary bladder occurred in dosed male rats with a statistically significant trend (P<0.05; controls, 0/49, 0%; low-dose, 2/49, 4%; high-dose, 4/49, 8%). This tumor has not been observed among 568 untreated male control F344/N rats at this laboratory. The incidence of transitional papillomas in male vehicle control rats in all laboratories in the NCI/NTP Bioassay Program is 1/994 (0.1%). Epithelial hyperplasia in the urinary bladder was also observed at increased incidences in dosed male rats (0/49, 1/49, 6/49). The hyperplasia did not occur in the same animals that had papillomas. Fibrosarcomas in the subcutaneous tissue occurred in female rats with a statistically significant positive trend (P<0.05; controls, 0/50, 0%; low-dose, 0/50, 0%; high-dose, 3/50, 6%), but the incidence in the high-dose group was not significant when compared with that in the control group. The historical incidence of this lesion is 1/591 (0.2%) in untreated control female F344/N rats at this laboratory and 9/999 (0.9%) in female gavage control rats in all laboratories in the Bioassay Program. Survival of control and dosed female mice, although comparable, was unusually low. Mean body weights of high-dose mice of each sex were higher than those of the controls throughout most of the study. Final body weights in the control and dosed groups were comparable. The mice probably did not receive the maximum tolerated dose of allyl isothiocyanate. The increased incidence of cytoplasmic vacuolization in the liver of dosed male mice was related to administration of allyl isothiocyanate (controls, 2/49, 4%; low-dose, 8/49, 16%; high-dose, 13/50, 26%). Under the conditions of this bioassay, allyl isothiocyanate was carcinogenic for male F344/N rats, causing transitional-cell papillomas in the urinary bladder. Evidence for associating allyl isothiocyanate with subcutaneous fibrosarcomas in female F344/N rats was equivocal. Allyl isothiocyanate was not carcinogenic for B6C3F1 mice of either sex. Levels of Evidence of Carcinogenicity: Male Rats: Positive Female Rats: Equivocal Male Mice: Negative Female Mice: Negative

Journal Article↗
PubMed1982

Carcinogenesis Bioassay of 2-Biphenylamine Hydrochloride (CAS No. 2185-92-4) in F344/N Rats and B6C3F1 Mice (Feed Study).

2-Biphenylamine (2-aminobiphenyl) is a chemical intermediate used in the manufacture of C.I. Acid Red 15. It is present as a contaminant in 4-biphenylamine (a rubber antioxidant) and in diphenylamine (a dye intermediate, stabilizer for nitrocellulose explosives, and a topical agent for prevention of screwworm infestation in animals). Single-dose, 14-day, and 13-week studies were conducted using technical-grade 2-biphenylamine (2-aminobiphenyl) containing up to 2.5% of the carcinogenic contaminant, 4-biphenylamine. When the contamination was recognized, analytical development was begun to purify the material. The salt, 2-biphenylamine hydrochloride, was prepared to obtain a more pure test product, which contained 0.006%-0.049% 4-biphenylamine. The prechronic tests were completed by the time purification was accomplished, so data from a second 14-day study with 2-biphenylamine hydrochloride were used to help set dose levels for the chronic study. The results of the comparative 14-day studies showed that technical-grade 2-biphenylamine was more toxic to mice than rats than 2-biphenylamine hydrochloride as evidenced by greater incidence of splenomegaly and greater weight gain depression. The technical-grade 2-biphenylamine caused a dose-related decrease in hemoglobin concentration and a dose-related increase in leukocyte count in male and female mice in the 13-week study. Hemosiderosis, congestion, and extramedullary hematopoiesis were present in the spleens of nearly all rats receiving 3,000 ppm or more of the chemical, and in nearly all mice with 1,000 ppm or more 2-biphenylamine in their diets. The chronic study was conducted with the purified 2-biphenylamine hydrochloride by feeding diets containing 1,000 or 3,000 ppm 2-biphenylamine hydrochloride to groups of 49 or 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 of dosed male and female rats and dosed female mice was comparable with that of the corresponding controls. Survival of high-dose male mice was significantly (P<0.010) less than that of low-dose and control male mice. There were little or no differences in body weight changes for rats or mice between dosed and control groups, although there was a slight decrease in body weight gain at the end of the study for high-dose male (-11%) and female (-8%) rats. Inflammatory cells and interstitial fibrosis were found in increased incidence in the kidneys of dosed male rats as compared with controls and were considered to be compound related. In addition to the increase in renal inflammation and fibrosis, dosed male rats had more focal cellular changes of the liver than did the controls. There were no increased or decreased incidences of tumors in rats that could be associated with chemical administration. Myelomonocytic leukemia in male rats (control, 14/50; low-dose, 1/50; high-dose, 4/50) and fibroadenomas of the mammary gland in female rats (22/50, 10/49, 9/50) occurred with significantly (P<0.03) decreasing trends and the incidences in the dosed groups were significantly (P<0.02) lower than that in the controls. There were no increased or decreased incidences of tumors in rats that could be associated with chemical administration. Hemangiosarcomas from all sites occurred in female mice with a statistically significant (P</=0.002) positive trend. The observed incidence of hemangiosarcomas was 0/49, 1/50, and 7/50 in the control, low-dose, and high-dose groups, respectively. The incidence in the high-dose group was significantly (P<0.01) higher than that in controls. The conclusion that this was due to 2-biphenylamine rather than the contaminant, 4-biphenylamine, is supported by the absence of urinary bladder tumors, which are common to 4-biphenylamine. Hemangiosarcomas also occurred in male mice with a statistically significant positive trend (P=0.040 by a life table test), with incidences of 0/50, 2/50, and 3/50. None of the pairwise comparisons were statistically different. The development of hemangiosarcomas may have been curtailedment of hemangiosarcomas may have been curtailed in the high-dose group of male mice, since only 21/50 survived until the termination of the study. The hemangiosarcomas found in female mice are uncommon with only 6/816 (0.7&percnt;) previously seen in controls at the same laboratory. The rate for control male mice is equally low: 7/803 (0.9&percnt;). Alveolar/bronchiolar adenomas of the lung occurred at a significantly (P<0.01) decreased rate in male mice with an incidence in dose groups lower (P<0.05) than that in controls. Under the conditions of the bioassay, 2-biphenylamine hydrochloride was not carcinogenic for F344/N rats of either sex. 2-Biphenylamine hydrochloride was carcinogenic for B6C3F1 female mice, inducing hemangiosarcomas at various sites. The evidence for an association between the administration of 2-biphenylamine hydrochloride and the increased incidence of hemangiosarcomas in male mice was equivocal. Levels of Evidence of Carcinogenicity: Male Rats: Negative Female Rats: Negative Male Mice: Equivocal Female Mice: Positive

Journal Article↗
PubMed1982

Carcinogenesis Bioassay of Stannous Chloride (CAS No. 7772-99-8) in F344/N Rats and B6C3F1/N Mice (Feed Study).

Stannous chloride is an inorganic tin compound used as a food preservative, a stabilizer for colors, perfumes, and soaps, and as a reducing agent in tin plating. It is also used as a mordant in printing, a silvering agent for glass and plastics, a catalyst for curing phenolic resins, an additive to drilling muds, and an antisludge agent for oils. The chronic phase of a carcinogenesis bioassay for stannous chloride was conducted by feeding diets containing 1,000 or 2,000 ppm stannous chloride to groups of 50 F344/N rats and 50 B6C3F1/N mice of each sex for 105 weeks. Similar groups of untreated rats and mice served as controls. In this study, the concentrations of tin in bone, kidney, and liver were no higher than those attained in other lifetime studies utilizing 1/100 of the dose, suggesting that organ accumulation of tin was not dose dependent, but probably limited by absorption. Mean body weight gain and feed consumption of dosed and control rats and mice were comparable. Survival of high-dose male rats was somewhat lower than that of the control and low-dose groups (37/50, control; 39/50, low-dose; 30/50, high-dose). Survival of control male mice was less (P<0.05) than that of either dosed group (32/50, 42/50, 45/50); survival of the female mice appeared to be dose related (38/50, 33/50, 28/50). C-cell adenomas of the thyroid (2/50, 9/49, 5/50), C-cell adenomas or carcinomas combined (2/50, 13/49, 8/50), and adenomas of the lung (0/50, 0/50, 3/50) in male rats; and hepatocellular carcinomas or adenomas combined (3/49, 4/49, 8/49) and histiocytic malignant lymphomas (0/50, 0/49, 4/49) in female mice occurred with significant (P<0.05) positive trends and/or with significantly (P<0.05) increased incidences in the dosed groups when compared with the paired controls. However, when the lung adenomas in male rats are combined with lung carcinomas and when all lymphomas in female mice are considered, no statistical significance remains. For the thyroid C-cell tumors in male rats and for the liver tumors in female mice, the incidences in the high-dose groups were not significantly different from the historical control rates at that laboratory (C-cell tumors: 32/288, 11.1%; liver tumors: 24/297, 8%). When the historical control rate is used as a basis for comparison, the low-dose incidence of thyroid C-cell tumors remains significant (P<0.01). Under the conditions of this bioassay, stannous chloride was judged not to be carcinogenic for male or female F344/N rats or B6C3F1/N mice, although C-cell tumors of the thyroid gland in male rats may have been associated with the administration of the test chemical. Levels of Evidence of Carcinogenicity: Male Rats: Equivocal Female Rats: Negative Male Mice: Negative Female Mice: Negative

Journal Article↗
PubMed1982

Carcinogenesis Bioassay of Agar (CAS No. 9002-18-0) in F344 Rats and B6C3F1 Mice (Feed Study).

A carcinogenesis bioassay of agar isolated from Pterocladia, a gelling agent used in foods and pharmaceuticals, was conducted on groups of 50 F344 rats and 50 B6C3F1 mice of either sex which were fed diets containing 25,000 or 50,000 ppm of the test substance for 103 weeks. Groups of 50 untreated rats and mice of either sex served as controls. Mean body weights of dosed and control male rats were comparable throughout the study. After week 80, mean body weights of dosed female rats were slightly lower than those of the controls. Mean body weights of dosed and control male mice were comparable throughout the study. The mean body weights of dosed female mice were lower than those of the controls at week 20 and remained lower throughout the study. No compound-related effects on survival, feed consumption, clinical signs of toxicity, or tumor incidence were observed. Although the rats of either sex and male mice might have been able to tolerate higher doses, 50,000 ppm was the administered high-dose level since that is the maximum concentration of a test substance in feed recommended in the guidelines of the BioassayProgram. A statistically significant trend (P=0.015) was observed for the increased incidence of cortical adenomas of the adrenal gland (control, 0/50; low-dose, 0/50; high-dose, 4/50) in female rats; the difference between control and high-dose groups was not significant. In male mice the incidence of hepatocellular adenomas (control, 0/49; low-dose, 3/50; high-dose, 7/50) was significantly (P=0.007) increased in the high-dose group when compared with controls; likewise, the overall trend was significant (P=0.005). The incidence of total liver tumors (control, 9/49; low-dose, 8/50; high-dose, 13/50) did not differ significantly among the groups. Neither of these increases (in cortical adenomas or in liver tumors) was considered to be compound related. Under the conditions of this bioassay, the agar isolated from Pterocladia was not carcinogenic for F344 rats or B6C3F1 mice of either sex. Levels of Evidence of Carcinogenicity: Male Rats: Negative Female Rats: Negative Male Mice: Negative Female Mice: Negative

Journal Article↗
PubMed1982

Carcinogenesis Bioassay of Guar Gum (CAS No. 9000-30-0) in F344 Rats and B6C3F1 Mice (Feed Study).

A carcinogenesis bioassay of guar gum, a widely used food stabilizer, was conducted by feeding diets containing 25,000 or 50,000 ppm of the test substance from two batches having purities of 83.5% and 91.9% to 50 F344 rats and 50 B6C3F1 mice of either sex for 103 weeks. Groups of 50 untreated rats and mice of either sex served as controls. The rodents might have tolerated higher doses but 50,000 ppm (5% of diet) is the upper limit for chronic feeding studies in the Bioassay Program, and this level represented the maximum tolerated dose (MTD) for females of both species in the present study. After week 20 in mice and week 40 in rats, mean body weights of high-dose females were lower than those of the untreated controls. No compound-related clinical signs or adverse effects on survival were observed. Feed consumption by dosed rats and dosed mice of either sex was lower than that of the controls. There were increased incidences of adenomas of the pituitary (8/45, 18% controls; 17/46, 37% low dose; 17/43, 40% high dose) in male rats and pheochromocytomas of the adrenal (0/50, 0%; 5/50, 10%; 6/50, 12%) in female rats, but these differences (P<0.035) were considered to be unrelated to administration of guar gum. When pituitary adenomas or carcinomas and when pheochromocytomas or malignant pheochromocytomas are combined, the statistical differences disappear. Hepatocellular carcinomas (15/44, 34%; 6/50, 12%; 6/49, 12%) occurred in treated male mice at incidences significantly (P</=0.011) lower than that in controls. The combined incidence of male mice with either hepatocellular adenomas or carcinomas (16/44, 36%; 12/50, 24%; 7/49, 14%) was also significantly (P=0.013) lower in the high-dose group. Under the conditions of this bioassay, guar gum was not carcinogenic for F344 rats or B6C3F1 mice of either sex. Levels of Evidence of Carcinogenicity: Male Rats: Negative Female Rats: Negative Male Mice: Negative Female Mice: Negative

Journal Article↗
PubMed1982

Carcinogenesis Bioassay of Vinylidene Chloride (CAS No. 75-35-4) in F344 Rats and B6C3F1 Mice (Gavage Study).

A subchronic and a chronic carcinogenesis study of vinylidene chloride (99% pure), a widely used chemical intermediate and monomer, were conducted in F344/N rats and B6C3F1/N mice. In subchronic studies, groups of 10 rats and 10 mice of either sex were administered vinylidene chloride in corn oil by gavage five times per week at 0, 5, 15, 50, 100, or 250 mg/kg body weight for 13 weeks. At the end of this study, representative tissues from these animals were subjected to histopathological examination. The liver was identified as a target organ for vinylidene chloride toxicity. In the 104-week chronic exposure study, conducted primarily to determine possible carcinogenic potential of vinylidene chloride by the oral route, 50 F344/N rats and 50 B6C3F1/N mice of either sex were gavaged with vinylidene chloride suspended in corn oil at dose levels of 1 or 5 mg/kg (rats) and 2 or 10 mg/kg (mice). Groups of 50 rats and 50 mice of either sex received corn oil alone and served as vehicle controls. Throughout most of the study, mean body weights of the dosed rats of either sex and high-dose female mice were slightly lower than those of the controls. The absence of compound-related effects on survival or clinical signs suggests that the rats and mice of either sex could have tolerated higher doses. While no significant differences in survival were observed for any group of rats, 12 control and 10 low-dose males were killed accidentally during week 82; this may have compromised the sensitivity of the male rats study. The results of histopathological examination indicated an increased incidence of necrosis of the liver in high-dose male and low-dose female mice and chronic renal inflammation in high-dose rats of either sex. The only observed significant (P>0.05) increase in tumor incidence occurred in low-dose female mice: lymphoma (2/48, 9/49, 6/50) and lymphoma or leukemia (7/48, 15/49, 7/50). These increases were not considered to be related to vinylidene chloride administration because similar effects were not found in the high-dose female mice or in male mice or rats. Under the conditions of this bioassay, vinylidene chloride administered by gavage was not carcinogenic for F344/N rats or B6C3F1/N mice of either sex. However, since the use of a maximum tolerated dose in this study has not been clearly demonstrated and since previously reported studies have shown that carcinogenicity is associated with inhalation exposure to vinylidene chloride, this study should not be taken as proof that the chemical is not a carcinogen. Levels of Evidence of Carcinogenicity: Male Rats: Negative Female Rats: Negative Male Mice: Negative Female Mice: Negative Synonyms: 1,1-dichloroethylene; VDC; 1,1-DCE

Journal Article↗
PubMed1982

Carcinogenesis Bioassay of Gum Arabic (CAS No. 9000-01-5) in F344 Rats and B6C3F1 Mice (Feed Study).

A carcinogenesis bioassay of gum arabic (81-86% pure), a widely used food stabilizer, was conducted by feeding diets containing 25,000 or 50,000 ppm of the test substance to 50 F344 rats and 50 B6C3F1 mice of each sex for 103 weeks. Groups of untreated rats and mice of each sex served as controls. Throughout most of the study, mean body weights of dosed male and female mice and of dosed male rats were comparable with those of the controls; mean body weights of the dosed female rats were slightly lower than those of the controls. No other compound-related clinical signs or effects on survival were observed. Mean daily feed consumption by high-dose rats and mice of either sex was 85% to 94% that of the controls. The high dose (50,000 ppm) used in this bioassay is the maximum concentration (5%) currently used in feed studies. Statistically significant (P<0.05) increasing trends were observed for the number of female mice with hepatocellular carcinomas (1/49, 2/50, 6/50), and with total liver tumors (4/49, 2/50, 10/50). No statistically significant differences were obtained when comparing the control rates with those observed in the treated groups. These observations were not considered to be clearly associated with the dietary administration of gum arabic. Thus, no compound-related neoplastic or nonneoplastic lesions were found in rats or mice of either sex. Under the conditions of this bioassay, gum arabic was not carcinogenic for F344 rats or B6C3F1 mice of either sex. Levels of Evidence of Carcinogenicity: Male Rats: Negative Female Rats: Negative Male Mice: Negative Female Mice: Negative Synonym: gum acacia

Journal Article↗
PubMed1982

Carcinogenesis Bioassay of C.I. Solvent Yellow 14 (CAS No. 842-07-9) in F344/N Rats and B6C3F1 Mice (Feed Study).

A carcinogenesis bioassay of C.I. Solvent Yellow 14 (94.1% pure), a widely used monoazo dye, was conducted by feeding diets containing 250 or 500 ppm of C.I. Solvent Yellow 14 to groups of 50 F344 rats of either sex for 103 weeks. Similar groups of 50 B6C3F1 mice received diets containing 500 or 1,000 ppm of C.I. Solvent Yellow 14 for 103 weeks. Groups of 50 untreated rats and mice of either sex served as controls. Throughout the bioassay, mean body weights of dosed rats and mice were slightly lower than those of controls. No compound-related clinical signs or effects on survival were observed. Increases in nonneoplastic lesions included cardiac valve fibrosis for male and female rats, lymphoid hyperplasia of the lung for male rats, and for female rats, bile duct hyperplasia, focal atrophy of the pancreatic acinus, and nephropathy. None of these effects were observed in mice. Neoplastic nodules of the liver occurred in rats of either sex with a dose-related trend that was significant (male, P<0.001; female, P=0.005), and the incidences in the high-dose groups were significantly higher than those in the controls (male: control, 5/50; low-dose, 10/50; high-dose, 30/50, P<0.001 and female: control, 2/50; low-dose, 3/49; high-dose, 10/48, P=0.011). Lymphomas or leukemias occurred in low-dose female mice at an incidence significantly (P<0.05) higher than that in the controls (12/50, 23/50, 17/50). Because of the lack of a dose-related trend and because the incidence in the high-dose group was not significant, the association between the increased incidence of hematopoietic tumors in the low-dose group and the administration of C.I. Solvent Yellow 14 is not clearly established. The incidence of lymphomas or leukemias in male mice was higher (not statistically significant) than that in the corresponding controls (5/49, 10/50, 10/50); in both low-and high-dose rats of either sex the incidence was significantly (P<0.001) lower than that in controls. Under the conditions of this bioassay, C.I. Solvent Yellow 14 was carcinogenic in male and female F344/N rats, as evidenced by increased incidences of neoplastic nodules of the liver. C.I. Solvent Yellow 14 was not carcinogenic for B6C3F1 mice of either sex. Levels of Evidence of Carcinogenicity: Male Rats: Positive Female Rats: Positive Male Mice: Negative Female Mice: Negative Synonym: 1-(phenylazo)-2-naphthol

Journal Article↗
PubMed1982

Carcinogenesis Bioassay of D & C Red No. 9 (CAS No. 5160-02-1) in F344 Rats and B6C3F1 Mice (Feed Study).

A carcinogenesis bioassay of D & C Red No. 9, a pigment used in topical drugs and cosmetics, was conducted by feeding diets containing 1,000 or 3,000 ppm of the test substance (89.8% pure) to groups of 50 F344 rats of either sex for 103 weeks. Similar groups of 50 B6C3F1 mice received diets containing 1,000 or 2,000 ppm of the test substance for 103 weeks. Groups of 50 untreated rats and mice of either sex served as controls. In a 13-week subchronic study, the spleens of most dosed rats were enlarged and pigment (unidentified) was present in the renal tubular epithelium. Lymphoreticular hyperplasia of thymic lymph nodes was found in 75-100% of females receiving 6,000-50,000 ppm D & C Red No. 9 and in 70-100% of male rats receiving 3,000-25,000 ppm. Hemosiderosis of the liver was observed at the high-dose levels in male and female rats. Mice receiving 1,250 ppm or more D & C Red No. 9 had congestion of the spleen and hemosiderin deposits. Thus, the selection of doses for the chronic study was based on the appearance of hemosiderosis and the incidences and severity of splenic lesions observed in the 91-day subchronic study. In the chronic study, mean body weights of dosed rats of either sex and of male mice were comparable with those of controls. After week 50, the mean body weight of high-dose female mice was lower than that of the controls. No compound-related effects on survival or clinical signs were observed for rats or mice of either sex. With the possible exception of female mice, all other dosed groups of rats or mice might have tolerated higher doses, thus a clear maximum tolerated dose may not have been utilized in this study. Splenic sarcomas (0/50, 0/50, 26/48; P<0.001) and neoplastic nodules of the liver (0/50, 6/50, 7/49; P<0.01) were observed in high-dose male rats at incidences significantly higher than those in the controls. Incidences of neoplastic nodules in the livers (1/50, 1/50, 5/50) of female rats showed a statistically significant (P<0.05) trend. Nonneoplastic splenic lesions were also observed in dosed male and female rats. Lymphocytic leukemia was observed in dosed male (10/50, 2/50, 2/50) and female (10/50, 2/50, 1/50) rats at statistically significant (P<0.05) decreased incidences, compared with controls. Adenomas or carcinomas of the preputial gland in male rats (7/50, 2/50, 0/50) occurred with a statistically significant (P<0.01) negative relationship to dose of D & C Red No. 9 (P=0.007). Under the conditions of this bioassay, D & C Red No. 9 was carcinogenic for male F344 rats causing an increased incidence of sarcomas of the spleen and a dose-related increase in neoplastic nodules of the liver. D & C Red No. 9 was not considered to be carcinogenic to female F344 rats, although the increased incidence of neoplastic nodules of the liver may have been associated with administration of the test chemical. D & C Red No. 9 was not carcinogenic for B6C3F1 mice of either sex. Levels of Evidence of Carcinogenicity: Male Rats: Positive Female Rats: Equivocal Male Mice: Negative Female Mice: Negative Synonyms: 5-chloro-2-[(2-hydroxy-1-naphthalenyl)azo]-4-methylbenzene sulfonic acid, barium salt; C.I. Pigment Red; C.I. Pigment Red 53:1; C.I. Pigment Red, barium salt

Journal Article↗
PubMed1982

Carcinogenesis Bioassay of Tara Gum (CAS No. 39300-88-4) in F344 Rats and B6C3F1 Mice (Feed Study).

A carcinogenesis bioassay of tara gum, a potential stabilizer for cosmetics and foods, was conducted by feeding diets containing 25,000 or 50,000 ppm of the test substance to 50 F344 rats and 50 B6C3F1 mice of either sex for 103 weeks. Groups of 50 untreated rats and mice of either sex served as controls. In the chronic bioassay, mean body weights of dosed and control rats of either sex were comparable over the course of the study. Feed consumption by low-and high-dose male rats was 92% and 95% that of the controls, and feed consumption by low-and high-dose female rats was 87% and 79% that of the controls. Mean body weights of high-dose mice of either sex were lower than those of controls; feed consumption by dosed mice was comparable with that of controls. Although the rats and mice might have been able to tolerate higher doses, 50,000 ppm (5%) is the recommended maximum concentration of a test substance mixed in feed, according to the guidelines of the Bioassay Program. No tumors were observed in increased incidences that were considered to be related to administration of tara gum to either species. Interstitial cell tumors of the testis in male rats were observed in a statistically significant (P </= 0.003 for trend and group comparisons) positive relationship (40/48 controls; 46/46 low dose; 48/48 high dose); because these tumors are present in almost all aged F344 male rats and because of the marginal statistical significance when time-adjusted analyses are applied, these increases are not regarded as being related to tara gum administration. A significant (P<0.05) negative trend was observed in the proportion of male rats with pancreatic islet cell adenoma (5/45 controls, 1/44 low dose, 0/45 high dose), of female mice with alveolar/bronchiolar adenomas (7/50, 2/49, 2/50), and of female mice with hepatocellular adenomas (9/49, 4/49, 1/50). Under the conditions of this bioassay, tara gum was not carcinogenic for F344 rats or B6C3F1 mice of either sex. Levels of Evidence of Carcinogenicity: Male Rats: Negative Female Rats: Negative Male Mice: Negative Female Mice: Negative

Journal Article↗
PubMed1982

Carcinogenesis Bioassay of Disperse Yellow 3 (CAS No. 2832-40-8) in F344 Rats and B6C3F1 Mice (Feed Study).

A carcinogenesis bioassay of C.I. Disperse Yellow 3 (87.6% dye), a textile dye, was conducted by feeding diets containing 5,000 or 10,000 ppm of the test substance to groups of 50 F344 rats of either sex for 103 weeks. Similar groups of 50 B6C3F1 mice received diets containing 2,500 or 5,000 ppm of the test substance for 103 weeks. Groups of 50 untreated rats and mice of each sex served as controls. Throughout the bioassay, mean body weights of dosed rats and mice of either sex were lower than those of the controls. Survival of dosed rats of either sex was significantly greater than that of the corresponding controls. No other compound-related clinical signs or effects on survival were observed. A significant increase in neoplastic nodules of the liver occurred in dosed male rats as compared to controls (controls 1/49, 2%; low-dose 15/50, 30%; P<0.001; high-dose, 10/50, 20%; P<0.01). No increase was observed for female rats. Stomach tumors, rare in F344 rats (10/2960, 0.3%), were found in the dosed male rats: one adenocarcinoma and a sarcoma in a high-dose male and in the low-dose group a squamous cell papilloma, fibrosarcoma, adenoma, and mucinous adenocarcinoma. The incidence of these tumors was not significantly greater than that in controls; thus, the association between the administration of C.I. Disperse Yellow 3 and the stomach tumors in male rats is not clearly established. Negative trends in the incidences of certain primary tumors in dosed rats included: decreased lymphocytic leukemia in both sexes; decreased malignant mesothelioma and C-cell carcinoma of the thyroid in males; and decreased pituitary chromophobe adenoma and endometrial stromal polyps in females. Hepatocellular adenomas occurred in dosed female mice at incidences significantly higher than that in the controls (control 0/50, 0%; low-dose 6/50, 12%, P<0.05; high-dose 12/50, 24%, P<0.001). The incidences of hepatocellular carcinomas were also higher in the dosed female mice than in the controls, but the increased incidences were not statistically significant (2/50, 4/50, 5/50). A significantly (P<0.05) lower incidence of hepatocellular adenomas was detected among low-dose (7/50, 1/49, 7/49) male mice. Alveolar/bronchiolar adenomas occurred in high-dose male mice at an incidence significantly (P%lt;0.05) higher than that in the controls (control 2/50, 4%; low-dose 6/49, 12%; high-dose 9/49, 18%). However, the high-dose effect was not significant when adenomas and carcinomas were combined; the incidence among low-dose female mice was significantly reduced as compared with controls. Thus, the incidence of alveolar/bronchiolar adenomas among males is not considered to be related to treatment with C.I. Disperse Yellow 3. Malignant lymphomas occurred in a dose-related (P<0.05) trend in female mice and at incidences greater (P<0.05) in the high-dose group than that in the controls (10/50; 16/50; 19/50). However, because of the range of variability in the historical incidence of this tumor and because of the lack of a similar effect in male mice or in male and female rats, this increase was not regarded as being unequivocally related to the administration of C.I. Disperse Yellow 3. Under the conditions of this bioassay, C.I. Disperse Yellow 3 was considered to be carcinogenic for male F344 rats, causing an increased incidence of neoplastic nodules of the liver; this dye was not carcinogenic for female F344 rats. In addition, the stomach tumors found in the male rats may have been induced by the administration of the test chemical. C.I. Disperse Yellow 3 was carcinogenic for female B6C3F1 mice, as evidenced by the increased incidence of hepatocellular adenomas; C.I. Disperse Yellow 3 was not carcinogenic for male B6C3F1 mice. Also, the increased incidence of malignant lymphoma in female mice may have been associated with the administration of C.I. Disperse Yellow 3. Levels of Evidence of Carcinogenicity: Male Rats: Positive Female Rats: Negative Male Mice: Negative Female Mice: Positive Synonyms: Disperse Fast Yellow 6; Acetamine Yellow CG

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PubMed1982

Carcinogenesis Bioassay of Locust Bean Gum (CAS No. 9000-40-2) in F344 Rats and B6C3F1 Mice (Feed Study).

A carcinogenesis bioassay of locust bean gum, a widely used food stabilizer, was conducted by feeding diets containing 25,000 or 50,000 ppm of the test substance to 50 F344 rats and 50 B6C3F1 mice of either sex for 103 weeks. Groups of 50 untreated rats and mice of either sex served as controls. Mean body weights of high-and low-dose rats of either sex, of low-dose male mice, and of high-and low-dose female mice were comparable with those of the controls; mean body weights of high-dose male mice were slightly lower than those of controls. No other compound-related clinical signs or effects on survival were observed. Although the rats and mice might have been able to tolerate higher doses, 50,000 ppm (5%) is the recommended maximum concentration of a test chemical mixed in feed according to the guidelines of the Bioassay Program. Although alveolar/bronchiolar adenomas occurred in low-dose male mice at a significantly (P=0.017) higher incidence than that in the controls (7/50, 17/50, 11/50), no significant statistical results were obtained when the combined incidence of animals with either alveolar/bronchiolar adenomas or carcinomas was analyzed (14/50, 21/50, 14/50). Cortical adenomas in the adrenal gland of female rats occurred with a statistically significant (P=0.042) positive trend (1/50, 4/50, 6/50), but comparisons between test groups and the control group were not statistically different. Under the conditions of this bioassay, locust bean gum was not carcinogenic for male or female F344 rats or B6C3F1 mice. Levels of Evidence of Carcinogenicity: Male Rats: Negative Female Rats: Negative Male Mice: Negative Female Mice: Negative

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PubMed1982

Carcinogenesis Bioassay of C.I. Acid Red 14 (CAS No. 3567-69-9) in F344/N Rats and B6C3F1 Mice (Feed Study).

A carcinogenesis bioassay of textile grade C.I. Acid Red 14 (67%-71% purity) was conducted by feeding diets containing 6,000 or 12,500 ppm of this dye for 103-104 weeks to groups of 50 male F344 rats, 12,500 or 25,000 ppm to groups of 50 female F344 rats, and 3,000 or 6,000 ppm to groups of 50 B6C3F1 mice of either sex. Groups of 90 untreated rats of either sex and 50 untreated mice of either sex served as controls. Throughout the study, mean body weights of dosed rats of either sex and dosed female mice were comparable with those of the controls, while the mean body weight of high-dose male mice was slightly lower than that of the controls. Fourteen male rats in the low-dose group and 2 in the high-dose group accidentally drowned between weeks 84 and 103; 56% and 60% of these groups survived to terminal kill compared with 78% of the controls. These losses may have reduced the sensitivity of the assay in male rats. Rats and mice may have tolerated higher doses, but the slight depression of mean body weight in high-dose male mice and the non-neoplastic lesions observed in dosed female mice and in rats of both sexes suggest that doses administered in this study could be considered maximum tolerated doses. Endometrial stromal polyps of the uterus were observed in high-dose female rats at an incidence significantly higher (P=0.008) than that seen in the controls (controls: 9/87, 10%; low-dose: 11/50, 22%; high-dose: 14/50, 28%). However, the observed incidence of this tumor in the dosed groups was similar to the historical rate in untreated female F344 rats at this laboratory (65/286, 23%; range 10%-37%). Hence, the increased incidence of this lesion is not regarded as being associated with the administration of C.I. Acid Red 14. Administration of C.I. Acid Red 14 to mice was not associated with an increased incidence of any tumor type. Under the conditions of this bioassay, C.I. Acid Red 14 was not carcinogenic for F344 rats or B6C3F1 mice of either sex. Levels of Evidence of Carcinogenicity: Male Rats: Negative Female Rats: Negative Male Mice: Negative Female Mice: Negative Synonym: 4-hydroxy-3-(4-Sulfo-1-naphthalenyl)azo-1-naphthalenesulfonic acid, disodium

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PubMed1982

Carcinogenesis Bioassay of 2,6-Dichloro-p-Phenylenediamine (CAS No. 609-20-1) in F344 Rats and B6C3F1 Mice (Feed Study).

A carcinogenesis bioassay of 2,6-dichloro-p-phenylenediamine, a chemical intermediate, was conducted in groups of 50 F344 rats and B6C3F1 mice of either sex. Male rats were fed diets containing 1,000 or 2,000 ppm 2,6-dichloro-p-phenylenediamine and female rats were fed 2,000 or 6,000 ppm for 103 weeks. Mice were fed 1,000 or 3,000 ppm of the test chemical for 103 weeks and observed for an additional 8 weeks. Controls consisted of 50 untreated rats and 50 untreated mice of each sex. Throughout the study, mean body weights of dosed rats and mice of either sex were lower than those of the corresponding controls. A dose-related weight gain depression was particularly pronounced for rats. Ectopic hepatocytes were observed at an increased incidence in the pancreas and nephrosis was observed in increased severity in dosed rats of either sex when compared with the corresponding controls. No increase in any tumor type was observed in treated male or female rats when compared to controls. Increased incidences of liver tumors were observed in mice of both sexes. In male mice, the incidence of hepatocellular adenomas exhibited a significant positive dose-related trend (P=0.002), and the increased incidence of hepatocellular adenomas was statistically significant in the high-dose group(4/50, 7/50, 15/50: P=0.005). The combined incidence of hepatocellular adenomas and carcinomas showed a significant positive dose-related trend (P=0.004) and was statistically significant in the high-dose group (16/50, 19/50, 29/50: P=0.008). In female mice, hepatocellular carcinomas exhibited a significant positive dose-related trend (P=0.025), but no single dose group had a statistically significant increased incidence of either adenomas (4/50, 4/50, 9/50; high-dose effect: P=0.12) or carcinomas (2/50, 2/50, 7/50; high-dose effect: P=0.08) alone. When the incidences of hepatocellular adenomas and carcinomas were combined (6/50, 6/50, 16/50), these data gave a positive dose-related trend (P=0.004) and were statistically significant in the high-dose group (P=0.014). Under the conditions of this bioassay, 2,6-dichloro-p-phenylenediamine was carcinogenic for male and female B6C3F1 mice, causing increased incidences of combined hepatocellular adenomas and carcinomas, and for male B6C3F1 mice, causing an increased incidence of hepatocellular adenomas alone. 2,6-Dichloro-p-phenylenediamine was not carcinogenic for male or female F344 rats. Levels of Evidence of Carcinogenicity: Male Rats: Negative Female Rats: Negative Male Mice: Positive Female Mice: Positive

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PubMed1982

Carcinogenesis Bioassay of Di(2-ethylhexyl)phthalate (CAS No. 117-81-7) in F344 Rats and B6C3F1 Mice (Feed Studies).

A bioassay of di(2-ethylhexyl)phthalate, the most commonly used plasticizer for polyvinylchloride polymers, for possible carcinogenicity was conducted by feeding diets containing 6,000 or 12,000 ppm of the test chemical to groups of 50 male and 50 female F344 rats and 3,000 or 6,000 ppm to groups of 50 male and 50 female B6C3F1 mice for 103 weeks. Controls consisted of 50 untreated rats and 50 untreated mice of either sex. Mean body weights of dosed male rats (high- and low-dose), high-dose female rats, and dosed female mice (high- and low-dose) were marginally-to-moderately lower than those of the corresponding controls at the end of the chronic study, reflecting a decrease in body weight gain. Food consumption was reduced slightly in rats of either sex, whereas there was no apparent difference among the mouse groups. Female rats and male and female mice administered di(2-ethylhexyl)phthalate had significantly higher incidences of hepatocellular carcinomas than those observed in the controls (rats -- males: 1/50, 2%; 1/49, 2%; 5/49, 10%; females -- 0/50, 0%; 2/49, 4%; 8/50, 16%, P=0.003; mice -- males: 9/50, 18%; 14/48, 29%; 19/50, 38%, P=0.022; females: 0/50, 0%; 7/50, 14%; P=0.006, 17/50, 34%, P<0.001). Further, a statistically significant positive trend for hepatocellular carcinomas occurred in female rats (P=0.002) and in male (P=0.018) and female (P<0.001) mice. In addition, di(2-ethylhexyl)phthalate caused a statistically significant increased incidence of male rats with either hepatocellular carcinomas or neoplastic nodules (3/50, 6%; 6/49, 12%; 12/49, 24%; P=0.010). Degeneration of the seminiferous tubules was observed in the high-dose male rats (1/49, 2%; 2/44, 5%; 43/48, 90%) and in the high-dose male mice (1/49, 2%; 2/48 4%; 7/49, 14%). Hypertrophy of cells in the anterior pituitary was also found at increased incidences in the high-dose male rats (1/46, 2%; 0/43, 0%; 22/49, 45%). Under the conditions of this bioassay, di(2-ethylhexyl)phthalate was carcinogenic for F344 rats and B6C3F1 mice, causing increased incidences of female rats and male and female mice with hepatocellular carcinomas, and inducing an increased incidence of male rats with either hepatocellular carcinomas or neoplastic nodules. Levels of Evidence of Carcinogenicity: Male Rats: Positive Female Rats: Positive Male Mice: Positive Female Mice: Positive Synonym: DEHP

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PubMed1982

Carcinogenesis Bioassay of 11-Aminoundecanoic Acid (CAS No. 2432-99-7) in F344 Rats and B6C3F1 Mice.

11-Aminoundecanoic acid is the monomer used in the manufacture of the polyamide, nylon-11. Aminoundecanoic acid is synthesized through a series of reactions from ricinoleic acid isolated from castor bean oil. Nylon-11 is used in automobile parts, industrial fabrics (e.g. filter bags, work clothes, and netting), and brushes because of its resistance to vibration and shock and its stability when in contact with fuels. Nylon-11 resins are approved by the U.S. Food and Drug Administration for use on food contact films. A carcinogenesis bioassay of 11-aminoundecanoic acid was carried out by administering diets containing 7,500 or 15,000 ppm of 11-aminoundecanoic acid to F344 rats and B6C3F1 mice. Groups of 50 rats and 50 mice of either sex were administered the test chemical for 104 weeks (rats) or 103 weeks (mice). Controls consisted of 50 untreated rats and 50 untreated mice of each sex. Nonneoplastic effects included dose-related decreases in mean body weight gain and survival for male rats and for mice of each sex; a dose-related increased incidence of hyperplasia of the transitional epithelium of the kidney and urinary bladder in rats of each sex; and mineralization of the kidney in dosed mice of each sex. Neoplastic nodules of the liver in dosed male rats (control 1/50, 2%; low dose 9/50, 18%; high dose 8/50, 16%; P<0.01) and transitional-cell carcinomas of the urinary bladder in high-dose male rats (control 0/48, 0%; low dose 0/48, 0%; high dose 7/49, 14%: P<0.01) were observed at significantly increased incidences compared with controls. Malignant lymphomas occurred at a significantly (P<0.05) increased rate in low-dose male mice (control 2/50, 4%; low dose 9/50, 18%; high dose 4/50, 8%). Under the conditions of this bioassay, 11-aminoundecanoic acid was carcinogenic for male F344 rats, inducing neoplastic nodules in the liver and transitional-cell carcinomas in the urinary bladder. The test chemical was not carcinogenic for female F344 rats. No clear evidence was found for the carcinogenicity of 11-aminoundecanoic acid in B6C3F1 mice of either sex, although the increase in malignant lymphoma in male mice may have been associated with administration of 11-aminoundecanoic acid. Levels of Evidence of Carcinogenicity: Male Rats: Positive Female Rats: Negative Male Mice: Equivocal Female Mice: Negative

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PubMed1982

Carcinogenesis Bioassay of Bisphenol A (CAS No. 80-05-7) in F344 Rats and B6C3F1 Mice (Feed Study).

A carcinogenesis bioassay of bisphenol A, an intermediate used in the manufacture of epoxy, polycarbonate, and polyester-styrene resins, was conducted by feeding diets containing 1,000 or 2,000 ppm of the test chemical to groups of 50 F344 rats of either sex, 1,000 or 5,000 ppm to groups of 50 male B6C3F1 mice, and 5,000 or 10,000 ppm to groups of 50 female B6C3F1 mice for 103 weeks. Groups of 50 rats and 50 mice of either sex served as controls. Mean body weights of rats of either sex and of high-and low-dose female mice and high-dose male mice were lower than those of the controls throughout the study. Since food consumption of dosed female rats was only 70% to 80% that of the controls throughout most of this study, reduced body weight gain was probably due to reduced food consumption. Food consumption by dosed male rats was 90% that of controls. Food consumption among all groups of mice appear to be similar. Leukemias occurred at increased incidences in dosed rats of both sexes. In male rats, the dose-related (13/50, 12/50, 23/50) trend was statistically significant (P=0.021) by a Cochran-Armitage test, but neither the trend nor the increase in the high-dose group was significant by life table analyses, which adjust for survival differences among groups. The increased incidences in dosed female rats were also not statistically significant (7/50, 13/50, 12/50). Interstitial-cell tumors of the testes occurred at statistically significant incidences in low- and high-dose male rats; however, since this lesion normally occurs at a high incidence in aging F344 male rats, the increased incidence observed in this study was not considered compound related (35/49, 48/50, 46/49). In male mice, there was an increased incidence of leukemias or lymphomas (2/49, 9/50, 5/50), but this increase was not statistically significant. A compound-related increased incidence of multinucleated giant hepatocytes was observed in male mice (1/49, 41/49, 41/50), but there was no increase of liver tumors in male mice. The marginally significant increase in leukemias in male rats, along with an increase (not statistically significant) in leukemias in female rats and a marginally significant increase in the combined incidence of lymphomas and leukemias in male mice, suggests that exposure to bisphenol A may be associated with increased cancers of the hematopoietic system. A statistically significant increase in interstitial-cell tumors of the testes in male rats was also suggestive of carcinogenesis, but was not considered to be convincing evidence of a compound-related effect because this lesion normally occurs at a high incidence in aging F344 rats. Under the conditions of this bioassay, there was no convincing evidence that bisphenol A was carcinogenic for F344 rats or B6C3F1 mice of either sex. Levels of Evidence of Carcinogenicity: Male Rats: Equivocal Female Rats: Equivocal Male Mice: Equivocal Female Mice: Negative Synonym: 4,4'-isopropylidenediphenol

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