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National Toxicology Program

Publications and source records attributed to National Toxicology Program.

At least 631 records · Page 35Linked to original sources
PubMed1978

Bioassay of 2-aminoanthraquinone for possible carcinogenicity.

A bioassay of 2-aminoanthraquinone for possible carcinogenicity was conducted using Fischer 344 rats and B6C3F1 mice. 2-Aminoanthraquinone was administered in the feed, at either of two concentrations (except for female rats), to groups of 50 male and 50 female animals of each species. The time-weighted average dietary concentrations used in the chronic bioassay were 0.69 and 0.35 percent for high and low dose male rats, respectively, 0.2 percent for the treated female rats, and 1.0 and 0.5 percent, respectively, for high and low dose mice of both sexes. After a 78-week period of chemical administration (80 weeks for high dose mice), observation of the rats continued for up to an additional 32, weeks and observation of the mice continued for up to an additional 16 weeks. In both species adequate numbers of animals in all groups, except the treated female rats, survived sufficiently long to be at risk from late-developing tumors. The survival among treated female rats was poor and, as a result, no conclusions could be made regarding the carcinogenicity of the compound in these animals. When male rats having either hepatocellular carcinomas or neoplastic nodules of the liver were combined and the resulting tumor incidences were analyzed statistically, there was a significant positive association between dosage and the incidences of these combined neoplasms. Hepatocellular carcinomas were observed at significantly higher incidences when dosed mice were compared to controls. There was a significantly higher incidence of malignant hematopoietic lymphomas in high dose female mice when compared to controls. Under the conditions of this bioassay, dietary administration of 2-aminoanthraquinone was carcinogenic in male Fischer 344 rats, causing a combination of hepatocellular carcinomas and neoplastic nodules of the liver. The compound was also carcinogenic in B6C3F1 mice, causing hepatocellular carcinomas in both sexes and malignant hematopoietic lymphomas in females.

Journal Article↗
PubMed1978

Bioassay of 1,5-naphthalenediamine for possible carcinogenicity.

A bioassay of 1,5-naphthalenediamine for possible carcinogenicity was conducted using Fischer 344 rats and B6C3F1 mice. 1,5-Naphthalenediamine was administered in the feed, at either of two concentrations, to groups of 50 male and 50 female animals of each species. The high and low dietary concentrations utilized in the chronic bioassay were, respectively, 0.1 and 0.05 percent for rats and 0.2 and 0.1 percent for mice. The compound was administered in the diet for 103 weeks, followed by up to 4 weeks of observation. Fifty mice of each sex and 25 rats of each sex were placed on test as controls. These animals were observed for up to 110 weeks. There were no significant positive associations between the administered concentrations of 1,5-naphthalenediamine and mortality in either sex of rats or mice. In all groups adequate numbers of animals survived sufficiently long to be at risk from late-developing tumors. Among dosed female rats, a statistically significant increase in endometrial stromal polyps was observed. Several of these tumors underwent malignant transformation to endometrial stromal sarcomas. The incidence of female rats having either adenoma or carcinoma of the clitoral gland was statistically significant. No neoplasms were observed at significantly increased incidences in dosed male rats. Based on lack of clinical signs or weight loss, the male rats may have been able to withstand a higher dose. In mice, dose-related increases in thyroid neoplasms were observed in both sexes. The incidence of thyroid C-cell carcinomas was significant for high dose female mice. The combined incidences of papillary adenomas, follicular-cell adenomas and papillary cystadenomas of the thyroid were significant for mice of both sexes. The incidence of hepatocellular carcinomas and the incidence of alveolar/bronchiolar adenomas were each significant for dosed female mice. Under the conditions of this bioassay, 1,5-naphthalenediamine was carcinogenic in female Fischer 344 rats, causing clitoral and uterine neoplasms. 1,5-Naphthalenediamine was also carcinogenic for B6C3F1 mice, producing thyroid neoplasms in males and neoplasms of the thyroid, liver, and lung in females. Insufficient evidence was provided for the carcinogenicity of the compound in male Fischer 344 rats.

Journal Article↗
PubMed1978

Bioassay of 1-phenyl-3-methyl-5-pyrazolone for possible carcinogenicity.

A bioassay of 1-phenyl-3-methyl-5-pyrazolone for possible carcinogenicity was conducted using Fischer 344 rats and B6C3F1 mice. 1-Phenyl-3-methyl-5-pyrazolone was administered in the feed, at either of two concentrations, to groups of 49 or 50 male and 50 female animals of each species. The high and low concentrations of 1-phenyl-3-methyl-5-pyrazolone utilized were, respectively, 5,000 and 2,500 ppm for rats and 15,000 and 7,500 ppm for mice. Twenty animals of each species and sex were placed on test as controls. After a 103-week period of chemical administration, there was an additional observation period of 2 weeks for rats. A 102-week period of chemical administration was followed by an additional 2-week observation period for mice. In both species adequate numbers of animals survived sufficiently long to be at risk from late-developing tumors. Compound-related mean body weight depression was observed in mice, but not in rats. In addition, no significant accelerated mortality or other signs of toxicity were associated with the dietary administration of 1-phenyl-3-methyl-5-pyrazolone to rats; therefore, it is possible that the compound was not administered to rats at the maximum tolerated concentration. There were no tumors in either sex of rats or mice for which a significant positive association could be established between chemical administration and incidence. Under the conditions of this bioassay, there was no evidence for the carcinogenicity of 1-phenyl-3-methyl-5-pyrazolone to Fischer 344 rats or B6C3F1 mice.

Journal Article↗
PubMed1978

Bioassay of pivalolactone for possible carcinogenicity.

The bioassay of pivalolactone for possible carcinogenicity was conducted using Fischer 344 rats and B6C3F1 mice. Pivalolactone in water was administered by gavage, at either of two dosages, to groups of 50 male and 50 female animals of each species. The high and low dosages of pivalolactone utilized were, respectively, 300 and 150 mg/kg/day for rats and 150 and 75 mg/kg/day for mice. After a 103-week period of compound administration for rats and a 102-week period of compound administration for mice, rats were observed for 2 additional weeks and mice for 1 additional week. Twenty animals of each sex and species were placed on test as vehicle controls. There was no significant positive association between dosage and mortality for either rats or mice, and in both species, adequate numbers of animals survived sufficiently long to be at risk from late-developing tumors. Compound-related mean body weight depression was not observed in either sex of either species. In addition, no adverse clinical signs were observed among dosed mice. This evidence, plus the relatively fast decomposition of pivalolactone in water, suggests the possibility that the animals, and in particular the mice, may have been able to tolerate a higher dose. Statistically significant incidences of squamous-cell papillomas and squamous-cell carcinomas of the forestomach were observed in rats but not in mice. No other rare or unusual tumors were observed in either species. Under the conditions of this bioassay, pivalolactone was found to be carcinogenic to both male and female Fischer 344 rats, producing squamous-cell carcinomas and squamous-cell papillomas of the forestomach. This study provided no evidence for the carcinogenicity of pivalolactone in B6C3F1 mice of either sex.

Journal Article↗
PubMed1978

Bioassay of 3-sulfolene for possible carcinogenicity (CAS No. 77-79-2).

A bioassay of 3-sulfolene for possible carcinogenicity was conducted using Osborne-Mendel rats and B6C3F1 mice. 3-Sulfolene in corn oil was administered by gavage, at either of two dosages, to groups of 50 male and 50 female animals of each species. The 78-week period of chemical administration was followed by an observation period of 33 weeks for the high dose female rats and low dose rats of both sexes. The last high dose male rat died in week 60. All treated groups of mice were observed for an additional 13 weeks following chemical administration. Initial dosage levels for the chronic bioassay were selected on the basis of a preliminary subchronic toxicity test. Subsequent dosage adjustments were made during the course of the chronic bioassay. The time-weighted average high and low doses of 3-sulfolene in the chronic study were respectively, 372 and 197 mg/kg/day for male rats, 240 and 120 mg/kg/day for female rats, 622 and 311 mg/kg/day for male mice and 768 and 384 mg/kg/day for the female mice. For each species, 20 animals of each sex were placed on test as vehicle controls. These animals were gavaged with corn oil at the same time that dosed animals were gavaged with the 3-sulfolene mixtures. Twenty animals of each sex were placed on test as untreated controls for each species. These animals were not intubated. There was a significant positive association between the administered dosages of 3-sulfolene and mortality in both sexes of rats and mice. In all groups, except the high dose male rats and the high dose male and female mice, adequate numbers of animals survived sufficiently long to be at risk from late-developing tumors. There were no tumors in either sex of rats or mice for which a significant positive association could be established between chemical administration and incidence. Under the conditions of this bioassay, there was no evidence for the carcinogenicity of 3-sulfolene to Osborne-Mendel rats or B6C3F1 mice.

Journal Article↗
PubMed1978

Bioassay of formulated fenaminosulf for possible carcinogenicity (CAS No. 140-56-7).

A bioassay of formulated fenaminosulf for possible carcinogenicity was conducted using Fischer 344 rats and B6C3F1 mice. Fenaminosulf was administered in the feed, at either of two concentrations, to groups of 50 male and 50 female animals of each species. The time-weighted average high and low dietary concentrations of fenaminosulf were, respectively, 0.10 and 0.05 percent for rats, 0.19 and 0.10 percent for male mice, and 0.10 and 0.05 percent for female mice. After a 78-week period of compound administration, observation of the rats continued for up to an additional 31 weeks and observation of the mice continued for up to an additional 19 weeks. Fifty male mice and 50 rats of each sex were placed on test as controls and fed only the basal diet. For female mice, 50 animals served as controls for the high dose group and 50 as controls for the low dose group. For female rats there was no significant association between fenaminosulf dosage and mortality and, if the 21 male rats that died in the first two weeks of the bioassay were excluded from consideration, the same was true for male rats. For both male and female mice there was a significant positive association between dosage and mortality. In all groups of both species, however, adequate numbers of animals survived sufficiently long to be at risk from late-developing tumors. No convincing, statistically significant positive associations were demonstrated between administration and the incidence of neoplasms in either sex of either species. An increased incidence of necrosis and mineralization of the tubular cells of the renal papilla occurred in treated rats and mice. These nonneoplastic lesions were not present in control animals of either species. Under the conditions of this bioassay, dietary administration of formulated fenaminosulf was not carcinogenic in either Fischer 344 rats or B6C3F1 mice.

Journal Article↗
PubMed1978

Bioassay of cupferron for possible carcinogenicity (CAS No. 135-20-6).

A bioassay of cupferron for possible carcinogenicity was conducted using Fischer 344 rats and B6C3F1 mice. Cupferron was administered in the feed, at either of two concentrations, to groups of 49 or 50 male and 50 female animals of each species. The time-weighted average high and low dietary concentrations of cupferron were, respectively, 0.30 and 0.15 percent for male and female rats, and 0.4 and 0.2 percent for male and female mice. After a 78-week period of compound administration, observation of the rats continued for an additional period of up to 28 weeks and observation of the mice continued for an additional period of up to 18 weeks. For each species, 50 animals of each sex were placed on test as controls and fed only the basal diet. Among both sexes of rats and mice there was a significant positive association between the dose of cupferron administered and mortality; however, in all groups of animals sufficient numbers survived long enough to establish the carcinogenicity of this compound. There were significant positive associations between the concentrations of cupferron administered to male and female rats and the incidences of: squamous-cell carcinomas of the forestomach, hepatocellular carcinomas and neoplastic nodules, and hemangiosarcomas. When a binomial distribution and a spontaneous incidence rate corresponding to the appropriate historical control incidence were assumed, the incidences of auditory sebaceous gland neoplasms in female rats and female mice were significant. There were significant positive associations between the concentrations administered and the incidences of hepatocellular carcinomas in female mice, the incidences of hemangiosarcomas in both sexes of mice, and the incidence of Harderian gland adenomas in both sexes of mice. Under the conditions of this bioassay cupferron was carcinogenic in Fischer 344 rats, causing hemangiosarcomas, hepatocellular carcinomas, and squamous-cell carcinomas of the forestomach in males and females as well as carcinomas of the auditory sebaceous gland in females. The chemical was also carcinogenic in B6C3F1 mice, causing hemangiosarcomas in males and hepatocellular carcinomas, carcinomas of the auditory sebaceous gland, a combination of hemangiosarcomas and hemangiomas, and adenomas of the Harderian gland in females.

Journal Article↗
PubMed1978

Bioassay of phenazopyridine hydrochloride for possible carcinogenicity.

A bioassay of phenazopyridine hydrochloride for possible carcinogenicity was conducted by administering the test chemical in feed to Fischer 344 rats and B6C3F1 mice. Groups of 35 rats and 35 mice of each sex were administered phenazopyridine hydrochloride at one of the following doses, either 3,700 or 7,500 ppm for rats and either 600 or 1,200 ppm for mice. The rats were administered the chemical for 78 weeks, then observed for 26 or 27 additional weeks; the mice were administered the chemical for 80 weeks, then observed for 25-27 additional weeks. Matched controls consisted of 15 untreated rats and 15 untreated mice of each sex. All surviving rats were killed at 104 or 105 weeks, all surviving mice at 105-107 weeks. Mean body weights of the dosed rats and mice of each sex were consistently lower than those of corresponding control animals, and the depressions in mean body weight were dose related. Mortality in the groups of rats and mice did not, however, show dose-related trends, and sufficient numbers of animals of both dosed and control groups were at risk for the development of late-appearing tumors. In male rats, adenomas or adenocarcinomas of the large intestine (colon or rectum) occurred at incidences having a significant dose-related trend (P=0.015). The direct comparison of the incidences in each of the dosed groups with that in the control group was not significant (controls 0/14, low-dose 4/34, high-dose 8/35). In the females, 3/33 low-dose and 5/32 high-dose animals, but no control animals, had this tumor. In addition, sarcomas were observed in the colon of one low-dose male and one high-dose female. The laboratory historical records showed no incidence of adenomas or adenocarcinomas of the large intestine in 260 females and only one adenomatous polyp in 260 males. Assuming a spontaneous incidence of 1/261 (0.038%) and a binomial distribution of such tumors, the occurrence seen in the male and female high-dose groups are both significantly (P<0.001) different from the expected value. Thus, these tumors are considered to be related to administration of the test chemical. In female mice, the combined incidence of hepatocellular adenomas and carcinomas showed a significant dose-related trend (P=0.002), and the incidence in the high-dose group was significant (P=0.003) when compared with that in the control group (controls 2/15, low-dose 11/34, high-dose 19/32). The incidence of hepatocellular carcinomas, considered alone, also was significant in female mice, showing a dose-related trend (P=0.010) and a P value of 0.039 for the comparison of the high-dose group with the control group. In the males, the combined incidence of hepatocellular adenomas and carcinomas was not significant. It is concluded that under the conditions of this bioassay, phenazopyridine hydrochloride was carcinogenic in Fischer 344 rats, inducing adenocarcinomas of the colon in both males and females. Although phenazopyridine hydrochloride was not carcinogenic in male B6C3F1 mice, the chemical was carcinogenic in females, inducing hepatocellular adenomas and carcinomas.

Journal Article↗
PubMed1978

Bioassay of 3-(chloromethyl) pyridine hydrochloride for possible carcinogenicity.

A bioassay of 3-(chloromethyl)pyridine hydrochloride for possible carcinogenicity was conducted by administering the test chemical by gavage to Fischer 344 rats and B6C3F1 mice. Groups of 50 rats and 50 mice of each sex were administered 3-(chloromethyl)pyridine hydrochloride in a vehicle of distilled water three times per week at one of the following doses, either 75 or 150 mg/kg body weight for the rats and either 100 or 200 mg/kg body weight for the mice. The low-dose rats were dosed for 103 weeks and the low-dose mice for 102 weeks. Because of early deaths in the high-dose animals, the high-dose rats were dosed for only 83 weeks and the high-dose mice for only 81 weeks. Controls consisted of groups of 20 rats and 20 mice of each sex which were administered the vehicle only for 104 weeks. All surviving rats and mice were killed at 104 weeks. Mean body weights of the male and female rats were lower in the dosed groups than in the corresponding control groups, and the depressions in weight were dose related. At the termination of the administration of the test chemical to the high-dose groups of rats, the mean body weights of these groups recovered rapidly. The mean body weights of the male mice were unaffected by the administration of the chemical; those of the females were only slightly affected. Mortality was generally higher in the dosed groups of rats and mice than in the corresponding control groups and was dose related in all tests except those using the female mice; however, sufficient numbers of animals of each species and sex were at risk for the development of late-appearing tumors. In rats, proliferative squamous-cell lesions of the forestomach were observed in the dosed males (carcinomas: high-dose 1/50; papillomas: low-dose 1/47; high-dose 2/50; hyperplasias: low-dose 1/47, high-dose 2/50) and the dosed females (carcinomas: high-dose 1/48), but not in the male or female vehicle controls. The results of the Fischer exact test were not significant for squamous-cell papillomas or carcinomas. However, comparison of the incidence of these tumors in the high-dose males with that in 99 historical vehicle controls shows that the probability that three or more such tumors did not occur by chance, given that none have been observed in the controls in this laboratory, is P=0.014. In mice, squamous-cell papillomas or carcinomas of the forestomach occurred in the low- and high-dose groups of each sex, but not in the corresponding control groups. The incidence in the high-dose males was significantly higher (P=0.025) than that in the control males (males: vehicle controls 0/19; low-dose 2/43; high dose 10/47 [21%]; females: vehicle controls 0/19, low-dose 1/45, high-dose 5/48 [10%]). Comparison of the incidences of these tumors in the high-dose males and females with those observed in the corresponding control groups of 100 historical vehicle controls of each sex shows that the probability that their occurrence was not due to chance is P<0.001. Also, a life-table analysis of the incidence in males indicated a significant (P=0.003) increase in tumors over the period of observation (58 weeks to 104 weeks) in relation to an increase in dose. Although the incidence of squamous-cell papillomas and carcinomas in male and female rats was significant only in males compared with historical vehicle controls, these tumors are of the same type as those appearing at the same site in male and female mice. Because these tumors are rare and not found in controls, and because they were found in dosed animals of both species, they are considered to be related to administration of the test chemical by gavage. It is concluded that under the conditions of this bioassay, 3-(chloromethyl)pyridine hydrochloride was carcinogenic in male Fischer 344 rats and B6C3F1 mice of both sexes, producing papillomas and carcinomas at the site of topical application, the stomach.

Journal Article↗
PubMed1978

Bioassay of 4-amino-2-nitrophenol for possible carcinogenicity.

A bioassay of 4-amino-2-nitrophenol for possible carcinogenicity was conducted by administering the test chemical in feed to Fischer 344 rats and B6C3F1 mice. Groups of 50 rats and 50 mice of each sex were administered 4-amino-2-nitrophenol at one of two doses, either 1,250 or 2,500 ppm, for 103 weeks. Matched controls consisted of groups of 20 untreated rats and 20 untreated mice of each sex. All dosed and matched-control groups of each species and sex were killed at 105 weeks. Mean body weights of dosed rats of each sex were not appreciably affected by administration of the 4-amino-2-nitrophenol, and mean body weights of dosed mice of each sex were only slightly lower than those of corresponding matched controls. Survival of neither rats nor mice was affected by the test chemical, and sufficient numbers of animals in dosed and control groups were at risk for the development of late-appearing tumors. Since both male and female mice receiving 4-amino-2-nitrophenol had little or no depression in mean weights and their survival was comparable to that of controls, they may have been able to tolerate a higher dose. In rats, transitional-cell carcinomas of the urinary bladder showed a dose-related trend in the males (P<0.001) and occurred at a significantly higher incidence (P=0.018) in the high-dose males than in the matched-control males (controls 0/15, low-dose 0/46, high-dose 11/39 [28%]). Carcinomas of the bladder also occurred in one low-dose female and two high-dose females, but in none of the control females. Transitional-cell papillomas of the bladder occurred in two additional high-dose males, and transitional-cell hyperplasia of the bladder occurred in four additional high-dose males, but neither lesion occurred in control males. No tumors of the bladder were found among 220 male and 220 female historical-control rats at this laboratory. In mice, no tumors occurred in dosed groups of males or females at incidences that were significantly higher than those in the corresponding matched-control groups. Deposition of pigment occurred in the lamina propria of the small intestine in at least 91% of the animals in the dosed groups of rats and in at least 89% of the animals in the dosed groups of mice, but in none of the control groups of either species. It is concluded that under the conditions of the bioassay, 4-amino-2-nitrophenol was carcinogenic for male Fischer 344 rats, inducing transitional-cell carcinomas of the urinary bladder; the transitional-cell carcinomas of the urinary bladder observed in three dosed female rats may also have been associated with administration of the 4-amino-2-nitrophenol. The test chemical was not carcinogenic for male or female B6C3F1 mice at the doses tested.

Journal Article↗
PubMed1978

Bioassay of 3-amino-9-ethylcarbazole hydrochloride for possible carcinogenicity.

A bioassay of 3-amino-9-ethylcarbazole (hydrochloride) for possible carcinogenicity was conducted by administering the test chemical in feed to Fischer 344 rats and B6C3F1 mice. Both the free amine and the hydrochloride salt were used. Groups of 50 rats of each sex and 50 mice of each sex were administered the test chemical at one of two doses, either 800 or 2,000 ppm for rats and either 800 or 1,200 ppm for mice, for 78 weeks. The rats were then observed for an additional 26-29 weeks, and the mice for an additional 16-17 weeks. Controls consisted of groups of 50 untreated rats of each sex and 50 untreated mice of each sex; separate controls were used for the groups of animals administered the different doses. All surviving rats were killed at 104-110 weeks; all surviving mice were killed at 94-97 weeks. Since the suppliers of the low-dose rats and mice differed from those of the corresponding low-dose controls, while the suppliers for the high-dose rats and mice were the same as those of the corresponding high-dose controls, comparisons of the high-dose groups with their corresponding controls were the most appropriate. Furthermore, since the low-dose animals did not receive the same regimen of administration of the test compound as that received by the high-dose animals, and since tests using the low-dose groups were not performed concurrently with those using the high-dose groups, analyses of the dose-related trends were not possible. Although the interpretation of results of the study was based primarily on comparisons of high-dose groups with their respective controls, the results obtained with the low-dose groups, regardless of the indicated complicating factors, supported the interpretation. Neoplasms of the liver were observed in significant incidences in rats and mice of both sexes. In male rats, hepatocellular carcinomas alone were significantly higher (P</=0.020) in both the low- and high-dose groups. When neoplastic nodules of the liver were combined with hepatocellular carcinomas, the combination occurred at significant incidences (P</= 0.012) in the low- and high-dose male rats and in the high-dose female rats (males: low-dose controls 0/36, low-dose 12/42; high-dose controls 1/48, high-dose 22/48; females: high-dose controls 0/50, high-dose 6/48). Hepatocellular carcinomas alone similarly occurred at significant incidences (P<0.001) in the low- and high-dose male and female mice (males: low-dose controls 7/48, low-dose 32/44; high-dose controls 6/44, high-dose 41/49; females: low-dose controls 1/47, low-dose 36/43; high-dose controls 1/45; high-dose 43/49). Papillomas or carcinomas of the integumentary system occurred at significant incidences (P</= 0.013) in both the low- and high-dose male rats (low-dose controls 0/36, low-dose 8/44; high-dose controls 0/48, high-dose 6/48); these tumors also occurred in low- and high-dose female rats, but not at incidences high enough to be statistically significant (low-dose control 0/39, low-dose 4/44; high-dose controls 0/50, high-dose 4/49). Carcinomas of the Zymbal's glands of the ear occurred at significant incidences (P</= 0.045) in the low- and high-dose male and female rats (males: low-dose controls 0/36, low-dose 5/44; high-dose controls 0/48, high-dose 7/48; females: low-dose controls 0/39, low-dose 10/44; high-dose controls 0/50, high-dose 12/49). These tumors were first observed as early as week 47 on study. Adenocarcinomas of the uterus or endometrium occurred at a significant incidence (P=0.002) only in the high-dose female rats (high-dose controls 1/50, high-dose 11/49); these tumors also occurred in the low-dose females, but not at an incidence high enough to be statistically significant (low-dose controls 4/38, low dose 11/43). It is concluded that under the conditions of this bioassay, 3-amino-9-ethylcarbazole (hydrochloride) was carcinogenic for the liver, inducing hepatocellular carcinomas in Fischer 344 rats and B6C3F1 mice of both sexes. Other tumors induced in the rats were carcinomas or papillomas of the integumentary system in males, carcinomas of the Zymbal's gland of the ear in males and females, and adenocarcinomas of the uterus.

Journal Article↗
PubMed1978

Bioassay of hydrazobenzene for possible carcinogenicity.

A bioassay of technical-grade hydrazobenzene for possible carcinogenicity was conducted using Fischer 344 rats and B6C3F1 mice. Hydrazobenzene was administered in the feed, at either of two concentrations, to groups of 50 male and 47 to 50 females animals of each species. The time-weighted average dietary concentrations used in the rat bioassay were 0.008, 0.03, 0.004, and 0.01 percent for low dose males, high dose males, low dose females, and high dose females, respectively. The time-weighted average dietary concentrations used in the mouse bioassay were 0.008, 0.04, 0.004, and 0.04 percent for low dose males, high dose males, low dose females, and high dose females, respectively. After a 78-week period of compound administration, observation of the rats continued for an additional 28 to 30 weeks and observation of the mice continued for an additional 17 or 18 weeks. For each species, 47 to 50 animals of each sex were placed on test as controls. In both, species, adequate numbers of animals in all groups survived sufficiently long to be at risk from late-appearing tumors. The incidence of hepatocellular carcinomas was significantly increased in dosed male rats and the incidence of neoplastic nodules of the liver was significantly increased in dosed female rats. A significant increase in the combined incidence of squamous-cell carcinomas or squamous-cell papillomas of the Zymbal's gland, the ear canal, or the skin of the ear was observed among high dose male rats. A significant increase in mammary adenocarcinomas was observed among dosed female rats. The incidence of hepatocellular carcinomas was significantly increased among female mice, but no significant increase in liver tumors was observed among male mice. Under the conditions of this bioassay, hydrazobenzene was carcinogenic to Fischer 344 rats of both sexes, causing increased incidences of hepatocellular carcinoma and Zymbal's gland squamous-cell neoplasms in male rats, neoplastic nodules of the liver in female rats, and mammary adenocarcinomas in female rats. Hydrazobenzene was also carcinogenic to female B6C3F1 mice, causing an increased incidence of hepatocellular carcinomas. The compound was not carcinogenic to male B6C3F1 mice.

Journal Article↗
PubMed1978

Bioassay of clonitralid for possible carcinogenicity.

A bioassay for possible carcinogenicity of clonitralid was conducted using Osborne-Mendel rats and B6C3F1 mice. Clonitralid 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 time-weighted average high and low dietary concentrations of clonitralid were, respectively, 28,433 and 14,216 ppm for rats and 549 and 274 ppm for mice. After a 78-week period of compound administration, there was an additional observation period of 32 to 33 weeks for rats and 13 to 14 weeks for mice. Adequate numbers of male rats, female rats, and female mice survived long enough to be at risk from late-developing tumors. Because of inadequate survival among male mice, however, results obtained from observation of the male mouse groups cannot be considered conclusive. The incidences of mammary adenocarcinomas in treated female rats were not significantly higher than the incidences observed in control female rats. However, the incidences of this lesion in dosed female rats were greater than or equal to 22 percent, while the highest incidence observed in 15 control groups at this laboratory was only 10 percent with a mean incidence of 2.6 percent. The occurrence in high dose female rats (2/45) of carcinomas in the glandular portion of the stomach with metastases to other sites was not statistically significant. This incidence, however, is much greater than the historical control incidence and suggests an association between administration of clonitralid and the development of these tumors. No statistically significant increased tumor incidences were observed among male rats or mice of either sex dosed with clonitralid. Under the conditions of this bioassay, there was no convincing evidence that clonitralid was carcinogenic to Osborne-Mendel rats or to female B6C3F1 mice. Poor survival of male mice did not permit an evaluation of carcinogenicity in these animals.

Journal Article↗
PubMed1978

Bioassay of dicofol for possible carcinogenicity.

A bioassay of technical-grade dicofol for possible carcinogenicity was conducted using Osborne-Mendel rats and B6C3F1 mice. Dicofol was administered in the feed, at either of two concentrations, to groups of 50 males and 50 females of each species. The high and low time-weighted average concentrations of dicofol were, respectively, 942 and 471 ppm for male rats, 760 and 380 ppm for female rats, 528 and 264 ppm for male mice, and 243 and 122 ppm for female mice. For each species, 20 animals of each sex were placed on test as controls. The period of compound administration was 78 weeks, followed by 34 weeks of observation in rats and 14 or 15 weeks in mice. There was no statistically significant positive association between dietary concentration and mortality in either sex or species. Hepatocellular carcinomas in dosed male mice were the only neoplasms that occurred in any dosed group of either species in statistically significant increased incidences when compared to controls. The Cochran-Armitage test as well as the Fischer exact test for both the high and low dose groups supported the association between compound administration and increased incidences of this tumor in the male mice. No increase in hepatocellular carcinomas was observed in dosed female mice. Under the conditions of this bioassay, technical-grade dicofol was carcinogenic in male B6C3F1 mice, causing hepatocellular carcinomas. No evidence for carcinogenicity was obtained for this compound in Osborne-Mendel rats of either sex or in female B6C3F1 mice.

Journal Article↗
PubMed1978

Bioassay of o-anisidine hydrochloride for possible carcinogenicity.

A bioassay of o-anisidine hydrochloride for possible carcinogenicity was conducted by administering the test chemical in feed to Fischer 344 rats and B6C3F1 mice. Groups of 55 rats of each sex and 55 mice of each sex were administered o-anisidine hydrochloride at one of the following doses, either 5,000 or 10,000 ppm for rats and either 2,500 or 5,000 ppm for mice, for 103 weeks, then observed for 1 or 2 additional weeks. Controls consisted of groups of 55 untreated rats of each sex and 55 untreated mice of each sex. All surviving rats were killed at 103-107 weeks, and all surviving mice at 104 or 105 weeks. Mean body weights of the dosed male and female rats and mice were lower than those of the corresponding controls throughout the bioassay. Bloody exudates and stained fur in the urogenital area were noted in many dosed animals. Sufficient numbers of animals were at risk in the mice, but not in the rats, for development of late-appearing tumors; however, survival in the rats was 80% or more at week 52. Transitional-cell carcinomas or papillomas of the urinary bladder occurred at statistically significant incidences (P<0.001) in the low- and high-dose groups of rats (males: controls 0/51, low-dose 52/54, high-dose 52/52; females: controls 0/49, low-dose 1/51, high-dose 22/50); the incidences also had significant dose-related trends (P<0.001) in both species. These lesions were observed as early as week 36 in female rats, week 40 in male rats, and week 45 in male mice. Transitional-cell carcinomas of the pelvis of the kidney occurred with a significant dose-related trend (P=0.005) in the male rats, and the incidence in the high-dose group was significantly higher (P=0.006) than that in the control group (controls 0/53, low-dose 3/55, high-dose 7/53); all rats having this tumor also has a transitional-cell carcinoma of the urinary bladder. Only one animal in the control groups of rats or mice had any tumor of the urinary system (a transitional-cell papilloma of the pelvis of the kidney in a male mouse). Follicular-cell tumors of the thyroid (carcinomas, cystadenocarcinomas, adenomas, cystadenomas, and papillary cystadenomas) occurred at statistically significant incidences (P</= 0.005) in low- and high-dose groups of male rats (controls 0/53, low-dose 7/40, high-dose 6/40); the incidences also had a dose-related trend (P=0.009). These tumors did not occur at significant incidences in dosed groups of female rats. It is concluded that under the conditions of this bioassay, o-anisidine hydrochloride was carcinogenic for Fischer 344 rats and B6C3F1 mice, inducing transitional-cell carcinomas or papillomas of the bladder in both rats and mice and in both sexes of each species, transitional-cell carcinomas of the pelvis of the kidney in male rats, and follicular-cell tumors of the thyroid in male rats.

Journal Article↗
PubMed1978

Bioassay of 1H-benzotriazole for possible carcinogenicity.

A bioassay of 1H-benzotriazole for possible carcinogenicity was conducted by administering the test chemical in feed to Fischer 344 rats and B6C3F1 mice. Groups of 50 rats of each sex were administered 1H-benzotriazole at one of two time-weighted average doses, either 6,700 or 12,100 ppm, for 78 weeks. Except for five control and five high-dose rats of each sex, which were killed at week 78, all animals surviving at that time were observed for 26-27 additional weeks. Controls consisted of groups of 50 untreated rats of each sex and were observed for 105-106 weeks. All rats surviving to weeks 104-106 were then killed. Groups of 50 mice of each sex were administered 1H-benzotriazole at one of two time-weighted average doses, either 11,700 or 23,500 ppm, for 104 weeks, then observed for 2 additional weeks. Controls consisted of groups of 50 untreated mice of each sex and were observed for 109 weeks. All mice surviving to weeks 106-109 were then killed. Mean body weights of the dosed male and female rats and mice were lower than those of the corresponding controls throughout most of the bioassay. Survival of animals in dosed and control groups of both rats and mice was at least 60%, and sufficient numbers of animals were at risk for development of late-appearing tumors. In male rats, neoplastic nodules of the liver occurred at a statistically significant incidence (P=0.024) in the high-dose group when compared with the control group (controls 0/48, low-dose 0/46, high-dose 5/45 [11%]). The incidence of this tumor in control Fischer 344 rats used in similar bioassays of other test chemicals at the same laboratory has varied from 0 to 11%, with 2/13 historical-control groups having incidences of 10-11%. Since the incidence in the high-dose groups is no higher than has been observed in some control groups, these tumors cannot be clearly associated with administration of the test chemical. Brain tumors occurred in three dosed male rats, in one dosed female rat, and in none of the controls. The occurrence of this rare tumor in dosed animals of each sex is suggestive of, but not considered as sufficient evidence of, carcinogenicity. In female rats, the incidence of endometrial stromal polyps in the low-dose group was significantly higher (P=0.010) than that in the corresponding controls (controls 2/48, low-dose 10/45, high-dose 8/50). However, the incidence in the high-dose group was not significant, and when the incidences of endometrial stomal polyps and endometrial stromal sarcomas were combined, they were not significant in either the low- or high-dose groups. Thus, these tumors cannot be associated with administration of the chemical. In male mice, no tumors occurred in dosed groups at incidences that were significantly higher than those in controls. In female mice, alveolar/bronchiolar carcinomas occurred at a statistically significant incidence (P=0.001) only in the low-dose groups when compared with the control group (controls 0/49, low-dose 9/49 [18%], high-dose 3/59 [6%]). The incidence in the high-dose group was not significant, and the data did not show a dose-related trend. It should be noted that the incidence of these tumors in control B6C3F1 female mice from other bioassays at this laboratory has varied from 0 to 7%, with a mean of 4%. Therefore, the occurrence of this tumor in female mice cannot be clearly related to the administration of the test chemical. In female B6C3F1 mice there was an increased incidence of alveolar/bronchiolar carcinomas, suggesting a possible carcinogenic effect of 1H-benzotriazole. In Fischer 344 rats there was an increased incidence of brain tumors, suggesting a possible carcinogenic effect. However, there was no convincing evidence that under the conditions of this bioassay 1H-benzotriazole was carcinogenic in B6C3F1 mice or Fischer 344 rats of either sex.

Journal Article↗
PubMed1978

Bioassay of 1,2-dibromoethane for possible carcinogenicity.

A bioassay for possible carcinogenicity of technical-grade 1,2-dibromoethane was conducted using Osborne-Mendel rats and B6C3F1 mice. 1,2-Dibromoethane in corn oil was administered by gavage, at either of two dosages, to groups of 50 male and 50 female animals of each species. The time-weighted average high and low doses of 1,2-dibromoethane used in the chronic bioassay were, respectively, 41 and 38 mg/kg/day for male rats, 39 and 37 mg/kg/day for female rats and 107 and 62 mg/kg/day for mice of both sexes. For each species 20 animals of each sex were placed on test as vehicle controls. These animals were gavaged with corn oil with the same frequency that dosed animals were gavaged with 1,2-dibromoethane mixtures. Twenty animals of each sex were placed on test as untreated controls for each species. These animals were not intubated. There was a positive association between increased dosage and accelerated mortality in rats and mice of both sexes. All surviving dosed male rats were sacrificed in week 49 and all surviving dosed female rats were sacrificed after 61 weeks of compound administration. All male mice and high dose female mice died or were sacrificed by week 78, while the low dose mice were observed for an additional 37 weeks after a 53-week period of chemical administration. In rats squamous-cell carcinomas of the forestomach were observed in 45/50, 33/50, 40/50 and 29/50 of the low dose males, high dose males, low dose females and high dose females, respectively, while none were observed in controls. Each of these incidences was statistically significant. These lesions were seen as early as week 12 in rats and week 24 in mice; they invaded locally and eventually metastasized. Increased incidences of hepatocellular carcinomas were observed in dosed rats, but the incidence of this neoplasm was significant only in females. Increased incidences of hemangiosarcomas were observed in each dosed rat group, but was statistically significant only in males, where they appeared as early as week 26. Early development of squamous-cell carcinomas which invaded and metastasized was also observed among mice. Squamous-cell carcinomas were found in 45/50, 29/49, 46/49 and 28/50 of the low dose males, high dose males, low dose females, and high dose females, respectively, but none were found in controls. Each of these incidences was statistically significant. Incidences of alveolar/bronchiolar adenomas were significant for male and female dosed mice. Under the conditions of this bioassay, 1,2-dibromoethane was carcinogenic to Osborne-Mendel rats and B6C3F1 mice. The compound induced squamous-cell carcinomas of the forestomach in rats of both sexes, hepatocellular carcinomas in female rats, and hemangiosarcomas in male rats. In mice of both sexes the compound induced squamous-cell carcinomas of the forestomach and alveolar/bronchiolar adenomas.

Journal Article↗
PubMed1978

Bioassay of 4-chloro-m-phenylenediamine for possible carcinogenicity.

A bioassay of 4-chloro-m-phenylenediamine for possible carcinogenicity was conducted using Fischer 344 rats and B6C3F1 mice. 4-Chloro-m-phenylenediamine was administered in the feed, at either of two concentrations, to groups of 49 or 50 male and 50 female animals of each species. The dietary concentrations of 4-chloro-m-phenylediamine used in the chronic bioassay for low and high dose rats were 0.2 and 0.4 percent, respectively. The time-weighted average dietary concentrations used for low and high dose mice were 0.7 and 1.4 percent, respectively. After a 78-week period of compound administration, observation of the rats continued for an additional 17 weeks. For each species, 50 animals of each sex were placed on test as untreated controls. In both species, adequate numbers of animals in all groups survived long enough to be at risk from late-developing tumors. Among male rats, an increased incidence of adrenal pheochromocytomas was statistically associated with dosage of 4-chloro-m-phenylenediamine. The incidence of these tumors was significantly higher in the high dose group than in the control group. Among female mice, there was a significant increased incidence of hepatocellular carcinomas in the low dose group and a significantly combined incidence of hepatocellular carcinomas and hepatocellular adenomas in both low and high dose groups as compared to controls. No other neoplasms in either species were considered to be related to compound administration. Under the conditions of this bioassay, dietary administration of 4-chloro-m-phenylenediamine was carcinogenic to the experimental animals, causing an increased incidence of hepatocellular tumors in female B6C3F1 mice and an increased incidence of adrenal pheochromocytomas in male Fischer 344 rats.

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