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2-(Chloromethyl)pyridine hydrochloride, an aromatic heterocycle used in a variety of syntheses, was selected for bioassay by the National Cancer Institute because of the structural similarity of this compound to 2-(a,b-dichloroethyl)-pyridine hydrochloride, a carcinogen in rats, mice, Syrian hamsters, and Mongolian gerbils. A bioassay for the possible carcinogenicity of 2-(chloromethyl)pyridine hydrochloride was conducted using Fischer 344 rats and B6C3F1 mice. 2-(Chloromethyl)pyridine hydrochloride was administered by gavage, at either of two dosages, to groups of 50 male and 50 female animals of each species, with the exception of 49 male rats in the high dose group. Twenty animals of each sex and species were placed on test as vehicle controls. The high and low dosages of 2-(chloromethyl)pyridine hydrochloride administered were, respectively, 150 and 75 mg/kg for rats and 250 and 125 mg/kg for mice. The compound was administered for 99 weeks to rats and mice. The period of compound administration was followed by an observation period of 6 weeks for rats and 5 weeks for mice. There were no significant positive associations between the dosages of 2-(chloromethyl)pyridine hydrochloride administered and mortality in rats or mice of either sex. Adequate numbers of animals in all groups survived sufficiently long to be at risk from late-developing tumors. Slight dose-related mean body weight depression was observed in mice of both sexes, indicating that the dosages of 2-(chloromethyl)pyridine hydrochloride administered tothese animals in this bioassay may have approximated the maximum tolerated concentrations. Since no distinct mean body weight depression relative to vehicle controls, no significant accelerated mortality, and no other signs of toxicity were associated with administration of 2-(chloromethyl)pyridine hydrochloride to rats, it is possible that these animals may have been able to tolerate a higher dosage. None of the statistical tests for any site in female rats or in mice of either sex indicated a significant positive association between compound administration and tumor incidence. There was a significant positive trend between the dosages administered and the incidences of subcutaneous fibromas in male rats. The Fisher exact comparisons, however, were not significant. Under the conditions of this bioassay, administration of 2-(chloromethyl)pyridine hydrochloride was not carcinogenic to Fischer 344 rats or B6C3F1 mice. Levels of Evidence of Carcinogenicity: Male Rats: Negative Female Rats: Negative Male Mice: Negative Female Mice: Negative Synonyms: 2-(Cl-methyl)pyridineHCl; 2-pyridylmethyl chloride hydrochloride; 2-picolylchloride hydrochloride
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PMID:Bioassay of 2-(Chloromethyl)Pyridine Hydrochloride for Possible Carcinogenicity (CAS No. 6959-47-3). 1277 75

Phenol ranked 38th in production among U.S. chemicals in 1978 with annual production of 2.38 billion pounds. Approximately 90% of the phenol produced is used in the manufacture of phenolic (phenol formaldehyde) resins, caprolactam, bisphenol A, alkyl phenol, and adipic acid. The remainder of the phenol is used to produce an assortment of end products, including salicylic acid, phenacetin, dyes, metal cleaners, disinfectants, antiseptics, photographic chemicals, wood preservatives (pentachlorophenol), paints, paint and varnish removers, and agricultural chemicals (2,4-D and parathion). A bioassay of phenol to test for possible carcinogenicity was conducted by providing this substance in drinking water to F344 rats and B6C3F1 mice. Groups of 50 rats and 50 mice of each sex were given drinking water containing 2,500 or 5,000 ppm phenol for 103 weeks. As matched controls, groups of 50 rats and 50 mice of each sex received tap water. A dose-related depression in mean body weight gain occurred in rats and mice of each sex. Rats and mice given water containing phenol drank less than did the corresponding controls. A dose-related decrease in water consumption was observed for mice. An increased incidence of leukemia or lymphomas was detected in male rats and may have been associated with the administration of phenol. Although the incidence of these tumors in the low-dose group was significantly higher than that in controls, the incidence in the high-dose group was not. Thus an association with administration of phenol was not established. Under the conditions of this bioassay, phenol was not carcinogenic for either male or female F344 rats or male and female B6C3F1 mice. Levels of Evidence of Carcinogenicity: Male Rats: Negative Female Rats: Negative Male Mice: Negative Female Mice: Negative
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PMID:Bioassay of Phenol for Possible Carcinogenicity (CAS No.108-95-2). 1277 76

2,6-Toluenediamine is used as an intermediate in the production of dyes for furs and textiles, and of flexible polyurethane foams and elastomers. A bioassay of 2,6-toluenediamine dihydrochloride for possible carcinogenicity was conducted by feeding diets containing the test chemical to F344 rats and B6C3F1 mice. Groups of 50 rats of each sex were fed the test chemical at two doses, 250 or 500 ppm, for 103 weeks and observed for 1 additional week. Groups of 50 mice of each sex were fed the test chemical at two doses, 50 or 100 ppm, for 103 weeks and then observed for 1 additional week. Groups of 50 untreated rats and 50 untreated mice of each sex were used as matched controls. All surviving animals were killed and necropsied at 104 weeks. Weight gain depression was less than 10% for dosed groups of male rats and male and female mice, when compared with controls. Mean body weight gain was depressed 17% in low-dose female rats and 27% in high-dose female rats. Mortality was not increased in rats or mice of either sex by the test chemical. No clinical evidence indicated that mice of either sex received a maximum tolerated dose of the compound. In male rats, islet-cell adenomas of the pancreas and neoplastic nodules or carcinomas of the liver occurred in dose-related trends that were significant using the Cochran-Armitage test (P=0.025 and P=0.037, respectively). The results of the Fisher exact test were not significant for either lesion. The occurrences of tumors in dosed female rats were not significantly different from those in control rats. Significant results in the negative direction were observed in the incidences of C-cell tumors of the thyroid in male rats and of fibroadenomas of the mammary gland in female rats. In male mice, in the low-dose group, lymphomas occurred at an incidence significantly higher (P=0.046) than that of the corresponding control group; however, the incidence was not significant when the Bonferroni criterion for multiple comparison was used. The occurrence of hepatocellular carcinomas in female mice was dose related, but the result of the Fisher exact test comparing the incidence in the high-dose group with that in the controls was not significant. It was concluded that, under the conditions of the bioassay, 2,6-toluenediamine dihydrochloride was not carcinogenic for male and female F344 rats or for male and female B6C3F1 mice. Levels of Evidence of Carcinogenicity: Male Rats: Negative Female Rats: Negative Male Mice: Negative Female Mice: Negative
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PMID:Bioassay of 2,6-Toluenediamine Dihydrochloride for Possible Carcinogenicity (CAS No. 15481-70-6). 1277 79

Hexachlorodibenzo-p-dioxins (HCDD) are formed during the manufacture of certain chlorophenols. They have been found in trichlorophenol, tetrachlorophenol, and pentachlorophenol and in the chlorophenol-derived herbicides, 2,4-dichlorophenoxyacetic acid (2,4-D) and 2,4,5-trichlorophenoxyacetic acid (2,4,5-T). From 1967 to 1970, the concentration of HCDD in commercial pentachlorophenol ranged from 0.03 to 38 ppm. Since then, HCDD levels in pentachlorophenol have been less than 1 ppm. A bioassay of a mixture of 1,2,3,6,7,8- and 1,2,3,7,8,9-hexachlorodibenzo-p-dioxin (HCDD) for possible carcinogenicity was conducted by administering the test material by gavage to Osborne-Mendel rats and B6C3F1 mice for 104 weeks. Fifty rats and 50 mice of each sex were administered HCDD suspended in a vehicle of 9:1 corn oil-acetate 2 days per week for 104 weeks at doses of 1.25, 2.5, or 5 &mgr;g/kg/wk for rats and male mice and 2.5, 5, or 10 &mgr;g/kg/wk for female mice. Seventy-five rats and 75 mice of each sex served as vehicle controls. In addition, one untreated control group containing 25 rats and 25 mice of each sex was present in the HCDD treatment room, and one untreated control group containing 25 rats and 25 mice of each sex was present in the vehicle control room. All surviving animals were killed at 105 to 108 weeks. In rats, a dose-related depression in mean body weight gain became evident in the males after week 68 of the bioassay and in the females after week 33. In mice, the mean body weight gain in the dosed groups was comparable with that of the vehicle control groups. No other toxic clinical signs were reported in either the rats or the mice. Administration of HCDD had no adverse effect on the survival of either species. In male rats, hepatocellular carcinomas or neoplastic nodules occurred at low incidences that were dose related (P=0.003). In a direct comparison, the incidence of these tumors in the high-dose group was higher (P=0.022) than that in the corresponding vehicle-control groups, but the Bonferroni requirement of P=0.017 for the multiple comparison of three dosed groups with a control group was not met. In female rats, hepatocellular carcinomas, adenomas, or neoplastic nodules occurred at incidences that were dose related (P<0.001), and in direct comparisons the incidences of these tumors in the mid-and high-dosed groups were significantly higher (P=0.006 and P<0.001, respectively) than those in the corresponding vehicle-control group. In male mice, hepatocellular carcinomas or adenomas occurred at incidences that were dose related (P=0.001), and in a direct comparison the incidence of these tumors in the high-dose group was significantly higher (P=0.001) than that in the corresponding vehicle-control group. In female mice, hepatocellular carcinomas or adenomas occurred at incidences that were dose-related (P=0.002), and the incidence of these tumors in the high-dose group was significantly higher (P=0.004) than that in the corresponding vehicle-control group. Complex nonneoplastic toxic liver lesions were seen in all dosed groups of rats and mice. Compound-associated hyperplastic lesions of the lung were also found in both male and female rats. Under the conditions of this bioassay, HCDD administered by gavage was carcinogenic, causing increased incidences of hepatocellular carcinomas or neoplastic nodules in female Osborne-Mendel rats and inducing hepatocellular carcinomas and adenomas in male and female B6C3F1 mice. HCDD was not demonstrated to be carcinogenic for male rats. Levels of Evidence of Carcinogenicity: Male Rats: Equivocal Female Rats: Positive Male Mice: Positive Female Mice: Positive Synonym: HCDD
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PMID:Bioassay of a Mixture of 1,2,3,6,7,8-Hexachlorodibenzo-p-dioxin and 1,2,3,7,8,9-Hexachlorodibenzo-p-dioxin (Gavage) for Possible Carcinogenicity (CAS No. 57653-85-7,CAS No. 19408-74-3). 1277 81

p-Nitrosodiphenylamine is used to accelerate the vulcanization of rubber. It is also used as an intermediate in the manufacture of dyes and pharmaceutical compounds and as an inhibitor of polymerization during the production of vinyl monomers such as styrene. A bioassay for the possible carcinogenicity of p-nitrosodiphenylamine was conducted using Fisher 344 rats and B6C3F1 mice. p-Nitrosodiphenylamine was administered in the feed, at either of two concentrations, to groups of 50 male and female animals of each species. Twenty animals of each sex and species were placed on test as controls. The high and low dietary concentrations of p-nitrosodiphenylamine were, respectively, 5000 and 2500 ppm for rats. The high and low time-weighted average concentrations for mice were 9000 and 4254 ppm, respectively. The compound was administered for 78 weeks to rats, for 50 weeks to high dose mice and for 57 weeks to low dose mice. The period of compound administration was followed by an observation period of 27 weeks for rats and 35 weeks for mice. There were significant positive associations between the concentrations of p- nitrosodiphenylamine administered and mortality among male and female mice, but not for rats of either sex. Although 19/50 high dose male mice and 21/50 high dose female mice died before week 52, adequate numbers of mice and rats survived sufficiently long to be at risk from late-developing tumors. The toxicity observed in mice and the dose-related mean body weight depression apparent in male and female rats indicated that the concentrations of p-nitrosodiphenylamine administered to these animals in this bioassay may have approached or exceeded the maximum tolerated concentrations. In male rats, there was a significant positive association between concentration administered and the incidence of a combination of hepatocellular carcinomas and neoplastic nodules. In addition, both the high dose to control and thelow dose to control Fisher exact comparisons were significant. There was also a significant positive association between concentration administered and the incidence of alveolar/bronchiolar adenomas in male rats; however, neither of the Fisher exact comparisons were significant. There were no positive, significant statistical tests for tumor incidence at any site in female rats. Due to the large number of early deaths among high dose mice of both sexes, the statistical conclusion concerning carcinogenicity was based on comparisons between the low dose and control groups. The incidence of hepatocellular carcinomas was significantly higher among the low dose males than among their controls. Although hepatocellular neoplasms were observed in dosed females, there were no tumors occurring with a statistically increased incidence when low dose females were compared to their controls. Under the conditions of this bioassay, p-nitrosodiphenylamine was carcinogenic when administered in the diet to male B6C3F1 mice, causing hepatocellular carcinomas. The chemical was also carcinogenic in male Fisher 344 rats, causing liver neoplasms. No evidence was provided for the carcinogenicity of p-nitrosodiphenylamine in female B6C3F1 mice or in female Fisher 344 rats. Levels of Evidence of Carcinogenicity: Male Rats: Positive Female Rats: Negative Male Mice: Positive Female Mice: Negative Synonyms: 4-nitroso-N-phenylbenzeneamine; 4-nitrosodiphenylamine; p-nitroso-N-phenylaniline; TKB
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PMID:Bioassay of p-Nitrosodiphenylamine for Possible Carcinogenicity (CAS No. 156-10-5). 1277 89

p-Chloroaniline, a dye and chemical intermediate, was selected for bioassay by the National Cancer Institute because of the high incidence of bladder cancer observed among dye manufacturing industry workers. A bioassay for the possible carcinogenicity of p-chloroaniline was conducted using Fisher 344 rats and B6C3F1 mice. p-Chloroaniline was administered in the feed, at either of two concentrations, to groups of 50 male and 50 female animals of each species. Twenty animals of each sex and species were placed on test as controls. The high and low dietary concentrations of p-chloroaniline were, respectively, 500 and 250 ppm for rats and 5000 and 2500 ppm for mice. The compound was administered in the diet for 78 weeks, followed by an observation period of 24 weeks for rats and 13 weeks for mice. There were no significant positive associations between the dietary concentrations of p-chloroaniline administered and mortality in female rats or in mice of either sex; however, there was a significantly positive association between concentration and mortality in male rats. Adequate numbers of animals in all groups survived sufficiently long to be at risk from late-developing tumors. Mean body weight depression, in relation to controls, was observed in high dose female rats and dosed mice of both sexes, indicating that the concentration of p-chloroaniline administered to these animals may have approximated the maximum tolerated concentrations. Although splenic lesions were observed in male rats, no mean body weight depression relative to controls was associated with administration of p-chloroaniline to these animals. Therefore, it is possible that these animals may have been able to tolerate a higher dietary concentration of the compound. The only neoplastic lesions found that might be related to administration of the compound were mesenchymal tumors in the spleens of male rats and hemangiomatous tumors in mice. In male rats, there was a significant positive association between compound administration and the incidences of fibroma or fibrosarcoma of the spleen. Theincidences of these tumors were not significantly elevated when compared to those in control rats, but the rarity of these tumors in male Fisher 344 rats (0/360 in historical male control rats in this laboratory) strongly suggests a chemically related effect. In addition, three sarcomas of other types were found in high dose male rats. In mice of both sexes, hemangiomas and hemangiosarcomas were found at elevated incidences, when compared to control mice, in the spleen, liver, kidney, and multiple body sites. The increased incidences in dosed mice were statistically related to dose but were not statistically significant when compared directly to matched control animals. In comparison to historical control data, the incidences of hemangiomatous tumors in the dosed mice were elevated, but not greatly. The evidence was considered insufficient to conclusively relate the hemangiomatous tumors in mice to compound administration. Nonneoplastic proliferative and chronic inflammatory lesions were also found in the spleens of dosed rats and mice. The findings of small numbers of fibromas and sarcomas in the spleens of male rats was considered strongly suggestive of carcinogenicity because of the rarity of these tumors in the spleens of control rats. Hemangiomatous tumors in dosed mice may also have been associated with administration of p-chloroaniline. However, it is concluded that, under the conditions of this bioassay, sufficient evidence was not found to establish the carcinogenicity of p-chloroaniline for Fisher 344 rats or B6C3F1 mice. Levels of Evidence of Carcinogenicity: Male Rats: Equivocal Female Rats: Negative Male Mice: Equivocal Female Mice: Equivocal Synonyms: 4-chlorobenzeneamine; 4-chlorophenylamine; 4-chloroaniline; 4-CA; 1-amino-4-chlorobenzene
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PMID:Bioassay of p-Chloroaniline for Possible Carcinogenicity (CAS No. 106-47-8). 1277 90

5-Chloro-o-toluidine, an aromatic amine and dye intermediate, was selected for bioassay by the National Cancer Institute because of the high incidence of bladder cancer observed among dye manufacturing industry workers. A bioassay for the possible carcinogenicity of 5-chloro-o-toluidine was conducted using Fisher 344 rats and B6C3F1 mice. 5-Chloro-o-toluidine was administered in the feed, at either of two concentrations, to groups of 50 male and 50 female animals of each species. Twenty animals of each sex and species were placed on test as controls. The high and low dietary concentrations of 5-chloro-o-toluidine were 5,000 and 2,500 ppm for rats and 4,000 and 2,000 ppm for mice. The compound was administered in the diet for 78 weeks, followed by an observation period of 26 weeks for rats and 13 weeks for mice. There were significant positive associations between the concentrations of 5-chloro-o-toluidine administered and mortality among male and female mice, but not among rats of either sex. Adequate numbers of animals in all groups survived sufficiently long to be at risk from late-developing tumors. Distinct mean body weight depression was apparent when dosed female rats and dosed mice of both sexes were compared to their controls, indicating that the concentrations administered to these animals in this bioassay may have approximated the maximum tolerated concentrations. Since no mean body weight depression, relative to controls, no significantly accelerated mortality, and no signs of toxicity other than fatty metamorphosis of the liver were associated with administration of 5-chloro-o-toluidine to male rats, it is possible that these animals may have been able to tolerate a higher dietary concentration of the compound. There was a significant positive association between the concentration of 5-chloro-o-toluidine administered to male rats and the incidence of adrenal pheochromocytomas in these animals; however, neither of the Fisher comparisons was significant. None of the other statistical tests fortumors at any site in male and female rats indicated a significant positive association between dosage and incidence. In mice of both sexes there were significant positive associations between concentration administered and the incidence of hemangiosarcomas. In addition, the high dose to control Fisher exact comparisons for both sexes were significant. The Cochran-Armitage tests were also significant and positive for the incidences of hepatocellular carcinomas in both sexes of mice. For males and females the high dose to control Fisher exact comparisons were significant, and for females the low dose to control comparison was also significant. Under the conditions of this bioassay, 5-chloro-o-toluidine was carcinogenic to B6C3F1 mice, inducing hemangiosarcomas and hepatocellular carcinomas in both males and females. There was no conclusive evidence of the carcinogenicity of the compound in Fisher 344 rats. Levels of Evidence of Carcinogenicity: Male Rats: Negative Female Rats: Negative Male Mice: Positive Female Mice: Positive Synonyms: 5-chloro-2-methylbenzeneamine; p-chloro-o-aminotoluene; 4-chloro-2-aminotoluene; 2-amino-4-chlorotoluene; o-amino-p-chlorotoluene; 5-chloro-2-methylaniline; 2-methyl-5-chloroaniline; 1-amino-2-methyl-5-chlorobenzene; 1-amino-3-chloro-6-methylbenzene; Fast Red KB Base; Azogene Fast Red KB; Brentamine Fast Red KB Base; Naphthosol Fast Red Base; Naphthanil Red KB Base
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PMID:Bioassay of 5-Chloro-o-toluidine for Possible Carcinogenicity (CAS No. 95-79-4). 1277 91

4,4'-Methylenebis(N,N-dimethyl)benzeneamine, a bicyclic aromatic amine and an intermediate in dye manufacture, was selected for bioassay by the National Cancer Institute because of a high incidence of bladder cancer observed among dye manufacturing industry workers. A bioassay for the possible carcinogenicity of 4,4'-methylenebis-(N,N-dimethyl)benzeneamine was conducted using Fisher 344 rats and B6C3F1 mice. 4,4'-Methylenebis-(N,N-dimethyl)benzeneamine was administered in the feed, at either of two concentrations, to groups of 50 male and 50 female animals of each species. Twenty animals of each sex and species were placed on test as controls. The high and low dietary concentrations of 4,4'-methylenebis-(N,N-dimethyl)benzeneamine were, respectively, 750 and 375 ppm for rats and 2500 and 1250 ppm for mice. The compound was administered for 59 weeks to rats and for 78 weeks to mice. The period of compound administration was followed by an observation period of 45 weeks for rats and 13 weeks for mice. There were no significantly positive associations between the concentrations of 4,4'-methylenebis-(N,N-dimethyl)benzeneamine administered and mortality among rats or mice of either sex. Adequate numbers of animals survived sufficiently long to be at risk from late-developing tumors. There was slight dose-related mean body weight depression among female rats, the mean body weight of high dose male rats was slightly less than that for controls, and the mean body weights of dosed mice were significantly lower than their controls, indicating that the concentrations of 4,4'-methylenebis-(N,N-dimethyl)benzeneamine administered to these animals in this bioassay may have approximated the maximum tolerated concentrations. For both male and female rats, there was a significant positive association between the concentrations of 4,4'-methylenebis-(N,N-dimethyl)benzeneamine administered and the incidences of follicular-cell carcinomas of the thyroid (i.e., 1/18, 4/50, and 21/46 in the control, low dose, and high dose males, respectively; and 0/20, 3/46, and 23/45 in the control, low dose, and high dose females, respectively). The high dose to control Fisher exact comparisons were also significant for each sex. Liver neoplasms were observed among male and female mice. There were elevated incidences of hepatocellular adenomas in dosed mice when compared to controls (i.e., 2/20, 3/50, and 16/48 in control, low dose, and high dose males, respectively; and 1/19, 18/49, and 22/48 in control, low dose, and high dose females). The incidences of hepatocellular carcinomas in dosed mice did not differ greatly from those in controls (i.e., 3/20, 9/50, and 6/48 in control, low dose, and high dose males, respectively; and 0/19, 1/49, and 1/48 in control, low dose, and high dose females). Among both sexes of mice, there was a significant positive association between the concentrations of the chemical administered and the incidences of a combination of hepatocellular adenomas and hepatocellular carcinomas. For male mice, the Fisher exact comparisons were not significant; however, for females, both the high dose to control and the low dose to control comparisons were significant. In both sexes of both species nonneoplastic proliferative lesions of the thyroid occurred in dosed animals but not in any of the controls. Under the conditions of this bioassay, 4,4'-methylenebis-(N,N-dimethyl)benzeneamine was carcinogenic in Fisher 344 rats, inducing thyroid follicular-cell carcinomas in both males and females. Administration of the compound was carcinogenic in female B6C3F1 mice, inducing liver neoplasms. There was no conclusive evidence that 4,4'-methylenebis-(N,N-dimethyl)benzeneamine was carcinogenic in male B6C3F1 mice. Levels of Evidence of Carcinogenicity: Male Rats: Positive Female Rats: Positive Male Mice: Equivocal Female Mice: Positive Synonyms: 4,4'-methylenebis(N,N-dimethyl)aniline; tetramethyldiaminodiphenylmethane; 4,4'-bis(dimethylamino) diphenylmethane; Tetra base; Methane base; Michler's base; Michler's hydride; Michler's methane
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PMID:Bioassay of 4,4'-Methylenebis-(N,N-dimethyl)benzeneamine for Possible Carcinogenicity (CAS No. 101-61-1). 1277 92

Styrene, a widely used intermediate in the manufacture of plastics, elastomers, and resins, was selected for bioassay by the National Cancer Institute because of the widespread use of this compound and a lack of adequate carcinogenicity data. A bioassay for the possible carcinogenicity of styrene was conducted using Fischer 344 rats and B6C3F1 mice. Styrene was administered by gavage to groups of 50 male and 50 female animals of each species. Forty rats of each sex and twenty mice of each sex were placed on test as vehicle controls. The high, medium, and low dosages of styrene administered to rats were, respectively, 2,000, 1,000, and 500 mg/kg. The high and low dosages administered to mice were 300 and 150 mg/kg, respectively. The compound was administered for 78 weeks to high and medium dose rats, for 103 weeks to low dose rats, and for 78 weeks to mice. The period of compound administration was followed by an observation period of 27 weeks for high and medium dose rats, 1 week for low dose rats, and 13 weeks for mice. Mortality among male and female high dose rats was significantly higher than that among their respective vehicle controls. In response to this elevated and early mortality, an additional dosed group of each sex was included in the chronic bioassay. No significant positive association was apparent between dosage and mortality among any other dosed rat groups. For mice, there was a significant positive association between mortality and the dosages of styrene administered to males, but not to females. Adequate numbers of animals in all groups, except for the high dose male and female rats, survived sufficiently long to be at risk from late-developing tumors. Slight dose-related mean body weight depression was apparent when male rats and female mice were compared to their respective vehicle controls, indicating that the dosages administered to these animals during the chronic bioassay may have approximated the maximum tolerated dosages. There was no distinct depression in mean body weight when dosed female rats anddosed male mice were compared to their respective vehicle controls. However, since there was significant accelerated mortality among high dose female rats, it is possible that the dosage administered to the medium dose female rats may have exceeded the maximum tolerated dosage. In male mice, there was a significant positive association between styrene dosage and the incidences of a combination of adenomas and carcinomas of the lung. This finding was supported by the high dose to control Fisher exact comparison. However, the variation of the incidence of these neoplasms in historical control male mice at this laboratory does not permit a firm conclusion of carcinogenicity. There was no significant difference between tumor incidence at any other site in male mice, or at any site in rats or female mice, when dosed groups were compared to vehicle controls. The findings of an increased incidence of a combination of adenomas and carcinomas of the lung provided suggestive evidence for the carcinogenicity of styrene in male B6C3F1 mice. However, it is concluded that, under the conditions of this bioassay, no convincing evidence for the carcinogenicity of the compound was obtained in Fischer 344 rats or B6C3F1 mice of either sex. Levels of Evidence of Carcinogenicity: Male Rats: Negative Female Rats: Negative Male Mice: Equivocal Female Mice: Negative Synonyms: ethenylbenzene; vinylbenzene; vinylbenzol; styrolene; styrol; styrole; styropol; styropor; styron; cinnamene; cinnamol; phenethylene; phenylethylene; phenylethene
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PMID:Bioassay of Styrene for Possible Carcinogenicity (CAS No.100-42-5). 1277 93

Nitrofen, a substituted diphenyl ether, is one of several agricultural pesticides selected for bioassay by the National Cancer Institute because of a lack of carcinogenicity data. A bioassay for the possible carcinogenicity of nitrofen was conducted using Fischer 344 rats and B6C3F1 mice. Nitrofen was administered in the feed, at either of two concentrations, to groups of 50 male and 50 female animals of each species. Twenty animals of each sex and species were placed on test as controls. The high and low dietary concentrations of nitrofen were 6000 and 3000 ppm for both species. The compound was administered to rats and mice for 78 weeks, followed by a period of no compound administration of 26 weeks for rats and 13 weeks for mice. There were no significant positive associations between the concentrations of nitrofen administered and mortality in rats or mice of either sex. Adequate numbers of animals in all groups survived sufficiently long to be at risk from late-developing tumors. Dose-related mean body weight depression, relative to controls, was observed for males and females of both species, indicating that the concentrations of nitrofen administered to the animals in this bioassay may have approximated the maximum tolerated concentrations. None of the statistical tests for any site in rats of either sex indicated a significant positive association between compound administration and tumor incidence. There was a significant positive association between the concentrationof nitrofen administered and the incidences of hepatocellular carcinomas in mice of both sexes. In another bioassay of nitrofen for possible carcinogenicity, the compound was found to induce hepatocellular carcinomas in B6C3F1 mice of both sexes and hemangiosarcomas of the liver in male B6C3F1 mice. In addition, adenocarcinomas of the pancreas were induced in female Osbourne-Mendel rats. Under the conditions of this bioassay, dietary administration of nitrofen was carcinogenic to B6C3F1 mice, causing hepatocellular carcinomas in both sexes. There was no evidence for carcinogenicity in Fischer 344 rats. Levels of Evidence of Carcinogenicity: Male Rats: Negative Female Rats: Negative Male Mice: Positive Female Mice: Positive Synonyms: 2,4-dichloro-1-(4-nitrophenoxy)-benzene, 2,4-dichlorophenyl-p-nitrophenyl ether, nitrophene, Tok E-25, Nip
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PMID:Bioassay of Nitrofen for Possible Carcinogenicity (CAS No. 1836-75-5). 1277 94


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