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National Toxicology Program

Publications and source records attributed to National Toxicology Program.

At least 667 records · Page 37Linked to original sources
PubMed1978

Bioassay of 1-nitronaphthalene for possible carcinogenicity.

A bioassay of technical-grade 1-nitronaphthalene for possible carcinogenicity was conducted using Fischer 344 rats and B6C3F1 mice. 1-Nitronaphthalene 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 time-weighted average concentrations used in the chronic study were, respectively, 0.18 and 0.06 percent for rats and 0.12 and 0.06 percent for mice. After a 78-week period of chemical administration, the rats were observed for an additional period of up to 31 weeks and the mice for an additional period of up to 20 weeks. For rats 50 animals of each sex were placed on test as controls for the low dose groups and 25 of each sex for the high dose groups. For mice 50 animals of each sex were placed on test as controls for each dosed group. In both species adequate numbers of animals in all groups survived sufficiently long for the development of late-appearing tumors; however, no compound-related increase in the incidence of neoplasms, nonneoplastic lesions, or other toxic effects was evident. Under the conditions of this bioassay 1-nitronaphthalene was not demonstrated to be carcinogenic in Fischer 344 rats or B6C3F1 mice.

Journal Article↗
PubMed1978

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

A bioassay for the possible carcinogenicity of technical-grade 4-chloro-o-phenylenediamine was conducted using Fischer 344 rats and B6C3F1 mice. 4-Chloro-o-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. For male and female rats, the high and low time-weighted average dietary concentrations of 4-chloro-o-phenylenediamine were 1.0 and 0.5 percent, respectively. For male and female mice, the high and low time-weighted average dietary concentrations were 1.4 and 0.7 percent, respectively. After a 78-week period of chemical administration, observation of the rats continued for up to an additional 28 weeks and observation of the mice continued for up to an additional 18 weeks. Fifty animals of each species and sex were placed on test as controls for the chronic bioassay. There was a statistically significant positive association between increased dosage and accelerated mortality in female rats and male mice; however, survival among all groups was adequate for meaningful statistical analysis of late-developing tumors. In male and female rats receiving the test chemical, a significantly increased incidence of neoplasms of the urinary bladder occurred. Neoplastic nodules in the liver and tumors of the forestomach may also have been related to administration of the chemical. A significantly increased incidence of hepatocellular carcinomas occurred in chemically treated male and female mice. It is concluded that under the conditions of this bioassay 4-chloro-o-phenylenediamine was carcinogenic in Fischer 344 rats and B6C3F1 mice, inducing tumors of the urinary bladder and forestomach in both sexes of rats and hepatocellular carcinomas in both sexes of mice.

Journal Article↗
PubMed1978

Bioassay of endosulfan for possible carcinogenicity.

A bioassay of technical-grade endosulfan for possible carcinogenicity was conducted using Osborne-Mendel rats and B6C3F1 mice. Endosulfan 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 endosulfan were, respectively, 952 and 408 ppm for the male rats, and 445 and 223 ppm for the female rats. In mice the high and low time-weighted average concentrations were, respectively, 6.9 and 3.5 ppm for the males and 3.9 and 2.0 ppm for the females. Twenty animals of each sex and species were placed on test as controls. The bioassay of high dose male rats was terminated during week 82, and the bioassay of low dose male rats was terminated during week 74. After a 78-week period of chemical administration, observation of female rats continued for 33 additional weeks and observation of mice continued for 14 additional weeks. At the doses administered to rats in this study endosulfan was toxic, inducing a high incidence of toxic nephropathy in both sexes and testicular atrophy in males. In both species high early mortality was observed in the male groups and no conclusions concerning the carcinogenicity of endosulfan can be drawn from this part of the bioassay. However, survival among females of both species was sufficient for meaningful statistical evaluation of the incidence of late-developing tumors. It is concluded that under the conditions of this bioassay, technical-grade endosulfan was not carcinogenic in female Osborne-Mendel rats or in female B6C3F1 mice.

Journal Article↗
PubMed1978

Bioassay of pentachloronitrobenzene for possible carcinogenicity.

A bioassay of technical-grade pentachloronitrobenzene (PCNB) for possible carcinogenicity was conducted using Osborne-Mendel rats and B6C3F1 mice. PCNB 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 dietary concentrations of PCNB were, respectively, 10,064 and 5,417 ppm for male rats, 14,635 and 7,875 ppm for female rats, 5,213 and 2,606 ppm for male mice, and 8,187 and 4,093 ppm for female mice. After a 78-week period of compound administration, observation of the rats continued for an additional 33 to 35 weeks and observation of the mice continued for 14 or 15 additional weeks. For each species, 20 animals of each sex were placed on test as controls and fed only the basal diet. No rare or unusual tumors were observed during the histopathologic examinations and no statistically significant positive associations were demonstrated between chemical administration and the incidence of neoplasms in either sex of either species. It is concluded that under the conditions of this bioassay PCNB was not carcinogenic in either Osborne-Mendel rats or B6C3F1 mice.

Journal Article↗
PubMed1978

Bioassay of phenesterin for possible carcinogenicity.

A bioassay of phenesterin for possible carcinogenicity was conducted by administering the chemical by gavage to Sprague-Dawley rats and B6C3F1 mice. Groups of 35 rats of each sex were administered phenesterin at one of two doses, either 5 or 10 mg/kg body weight, three times per week for 52 weeks, then observed for an additional 32 or 33 weeks. The vehicle used was 0.05% polysorbate 80 in buffered saline. Controls consisted of groups of 10 rats of each sex which received the vehicle (vehicle control) and 10 rats of each sex which were untreated (untreated control). All surviving rats were killed at 84 or 85 weeks. Groups of 35 mice of each sex were administered the chemical at one of two doses, either 15 or 30 mg/kg body weight, three times per week for 52 weeks. The males receiving 15 mg/kg were observed for an additional period of 29 weeks, and those surviving to this time were then killed; the animals of the remaining groups were observed for additional periods of only 10-22 weeks, due to early deaths. Seventy-seven weeks after the foregoing groups were started, additional groups of 40 mice of each sex were started and were administered the chemical at 7 mg/kg body weight three times per week; administration of the chemical terminated at week 102 for the males and at week 88 for the females, due to deaths of all females at this time. Controls for the low-dose (7 mg/kg) groups of mice consisted of groups of 20 mice of each sex which received the vehicle (vehicle control) and 20 mice of each sex which were untreated (untreated control); controls for the mid-dose (15 mg/kg) and the high-dose (30 mg/kg) controls consisted of groups of 15 mice of each sex similarly receiving the vehicle or untreated. All surviving low-dose controls were killed at 104 weeks, and all surviving mid- and high-dose controls were killed at 81-84 weeks. Phenesterin was toxic to rats and mice at the doses used, as shown by reduced mean body weights and survival. Time-adjusted analyses were used for evaluation of incidences of tumors in the female mice. In female rats, a dose-related trend (P=0.019) was present in adenocarcinoma of the mammary gland, using the pooled controls, and the incidences of the tumor in the individual dosed groups were significant (P<0.009) when compared with those in the pooled controls (controls 1/18, low-dose 12/29, high-dose 12/30). In male mice, the incidence of alveolar/bronchiolar carcinomas or combined alveolar/bronchiolar adenomas and carcinomas in the low-dose group (18/40) was significantly higher (P<0.020) than that in the low-dose vehicle-control group (0/16). In female mice, seven low-dose animals had alveolar/bronchiolar adenomas and eight other low-dose animals had alveolar/bronchiolar carcinomas. When these tumors were combined, their time-adjusted incidence was significant (P=0.004) when compared with that in the low-dose vehicle controls (controls 1/18, low-dose 15/35). The lower and nonsignificant incidences of these tumors observed in the mid- and high-dose groups may be due to the earlier mortality in these groups compared with the low-dose groups. In each sex of mid- and high-dose mice, incidences of lymphoma and leukemia were dose related (P<0.005), using vehicle controls; they were also significant (P<0.018) in direct comparisons of mid- and high-dose groups of both sexes with respective vehicle controls (males: controls 0/14, mid-dose 9/29, high-dose 11/25; females, time-adjusted: controls 0/15, mid-dose 14/18, high-dose 17/19). The significance of the incidence of lymphoma and leukemia in the mid- and high-dose groups of males was increased (P<0.001) when the pooled-control group was used, both in the test for dose-related trend and in tests for direct comparisons of dosed groups with the controls. In each sex of mice, sarcomas of the myocardium were found in all groups of dosed animals, but in no control animals (males: low-dose 5/40, mid-dose 7/29, high-dose 2/25; females: low-dose 8/34, mid-dose 2/7, high-dose 3/7). In males, the incidence in the mid-dose group was significant when compared with that in the pooled controls (P=0.006); in females, the incidences in the low- and high-dose groups were significant (P<0.023). It is concluded that under the conditions of this bioassay, phenesterin was carcinogenic in female Sprague-Dawley rats, producing adenocarcinomas of the mammary gland, and in both sexes of B6C3F1 mice, producing alveolar/bronchiolar carcinomas, hematopoietic tumors, and myocardial sarcomas.

Journal Article↗
PubMed1978

Bioassay of Estradiol Mustard for Possible Carcinogenicity (CAS No. 22966-79-6).

A bioassay of the experimental anticancer drug estradiol mustard for possible carcinogenicity was conducted by administering the chemical by gavage to Sprague-Dawley rats and B6C3F1 mice. Groups of 35 rats and 34-36 mice of each sex were administered estradiol mustard at one of the following doses, either 0.62 or 1.25 mg/kg body weight for rats and either 15 or 30 mg/kg body weight for mice. The vehicle used for the test chemical consisted of 0.05% polysorbate 80 in phosphate-buffered saline. The rats and mice were dosed three times per week for 52 weeks, then observed for an additional 30-34 weeks. Controls consisted of groups of 10 rats and 15 mice of each sex that were not administered the chemical (untreated controls) and also of groups of 10 rats of each sex, 14 male mice, and 16 female mice administered the vehicle alone (vehicle controls). Pooled controls were also used. All surviving rats were killed at 84-86 weeks and all surviving mice at 82-86 weeks. Mean body weights of male rats and male and female mice administered estradiol mustard were lower throughout the greater part of the study than those of corresponding vehicle or untreated controls; mean body weights of dosed female rats were unaffected. Administration of the test chemical had no significant effect on the survival of either male or female rats. A large number of dosed mice died prior to the end of the study. The numbers of dosed male mice which were at risk as long as 52 weeks were sufficient, however, for development of tumors appearing up to that time. Time-adjusted analysis and life-table analyses were applied to data obtained with the mice. In rats, no tumors were observed in a statistically significant incidence in the animals administered estradiol mustard. In mice, lymphoma or lymphocytic leukemia occurred at significant incidences in low-dose (P=0.018) and high-dose (P<0.001) groups of males compared with those in the pooled vehicle controls (controls 0/28, low-dose 6/32, high-dose 17/29) and at significant incidences in low-dose (P=0.020) and high-dose (P=0.002) groups of females compared with those in the corresponding vehicle controls (controls 0/14, low-dose 9/30, high-dose 11/23). In addition, the incidences of lymphoma were statistically significant for dose-related trend for both the males (P<0.001) and the females (P=0.003). Since lymphoma was observed in male mice as early as 25 weeks, life-table analyses of the incidence in each sex were performed. The results indicated a dose association (P=0.001) between the administration of estradiol mustard and the time of observation of lymphoma in either sex of mice. In mice, alveolar/bronchiolar adenoma or carcinoma occurred at a significant incidence (P=0.004) in the low-dose group of males compared with the pooled vehicle controls (controls 2/28, low-dose 12/30, high-dose 5/24) and at a significant incidence (P=0.022) in the low-dose group of females compared with the pooled vehicle controls (controls 1/28, low-dose 7/27, high-dose 1/18). Sarcoma of the myocardium similarly occurred at a significant incidence (P=0.015) in the low-dose group of males compared with the pooled vehicle controls (controls 0/28, low-dose 6/30, high-dose 2/24) and at a significant incidence (P=0.002) in the low-dose group of females compared with the pooled vehicle controls (controls 0/28, low-dose 8/27, high-dose 1/12). The survival of both high-dose males and high-dose females was slightly lower than that of the respective low-dose groups and may account for the higher numbers of pulmonary tumors and myocardial sarcomas among low-dose mice of both sexes. The association of myocardial sarcoma with administration of the chemical in both dosed groups of each sex is strengthened by the fact that these tumors of the myocardium have not occurred in the more than 500 male and 500 female historical-control mice of this strain at the laboratory. Squamous cell carcinoma of the stomach occurred in the dosed male mice (high-dose 2/29) and in the dosed female mice (low-dose 2/26, high-dose 2/14) but was absent in all controls. Although the incidences in this bioassay were too low to be statistically significant, the fact that no squamous-cell carcinomas of the stomach have occurred in the more than 500 male and 500 female historical-control mice of this strain at this laboratory indicates that these gastric tumors were related to the administration of the estradiol mustard. It is concluded that under the conditions of this bioassay, estradiol mustard administered in a buffered saline vehicle was not carcinogenic in Sprague-Dawley rats. Estradiol mustard was carcinogenic in both male and female B6C3F1 mice, inducing lymphoma, sarcoma of the myocardium, alveolar adenoma or carcinoma, and squamous-cell carcinoma of the stomach. Levels of Evidence of Carcinogenicity: Male Rats: Negative Female Rats: Negative Male Mice: Positive Female Mice: Positive Synonym: estradiol, bis((p-bis(2-chloroethyl)-amino)phenyl)acetate

Journal Article↗
PubMed1978

Bioassay of thio-TEPA for possible carcinogenicity.

A bioassay of thio-TEPA for possible carcinogenicity was conducted by administering the test chemical by intraperitoneal injection to Sprague-Dawley rats and B6C3F1 mice. Groups of 31-39 rats of each sex were administered thio-TEPA in phosphate-buffered saline at one of three doses, either 0.7, 1.4, or 2.8 mg/kg body weight, three times per week for a maximum of 52 weeks, then observed for additional periods of time. The maximum time on study (administration of chemical and observation) was 86 weeks. The groups at the low dose were started 69 weeks after those at the mid and high doses, because of high mortalities observed in the groups at the higher doses. Matched controls consisted of groups of 10 untreated rats and 10 vehicle-control rats of each sex. Pooled-control groups also were used. Surviving control rats were killed at 82-87 weeks; surviving dosed rats were killed at 81 or 82 weeks. Groups of 35 mice of each sex were administered thio-TEPA at one of two doses, either 1.15 or 2.3 mg/kg body weight, three times per week for a maximum of 52 weeks, then observed for a maximum additional period of 34 weeks. Matched controls consisted of groups of 15 untreated mice and 15 vehicle-control mice of each sex. Pooled controls also were used. Surviving control and dosed mice were killed at 86 or 87 weeks. Thio-TEPA was toxic to both rats and mice, causing decreased mean body weight gains and early deaths in the mid- and high-dose rats and in the high-dose mice. Because of the early deaths, statistical analyses were based only on time-adjusted incidences of tumors. Since all high-dose male and female rats had died by 21 weeks, microscopic evaluation of tissues was performed only on the low- and mid-dose animals. In rats, the incidence of combined neoplasms of the hematopoietic system (lymphoma, lymphocytic leukemia, or granulocytic leukemia) was significant in the males in both the low-dose (P=0.020) and mid-dose (P=0.001) groups, using pooled controls (pooled controls 0/29, low-dose 6/34; pooled controls 0/30, mid-dose 6/16). Squamous-cell carcinoma of the skin or ear canal occurred at a significant incidence in the male rats in both the low-dose (P=0.009) and mid-dose (P=0.023) groups, using pooled controls (pooled controls 0/29, low-dose 7/33; pooled controls 0/30, mid-dose 3/13) and in the mid-dose females (P<0.001), using pooled controls (pooled controls 0/28, mid-dose 8/21); in addition, two low-dose females had such tumors, with none occurring in the corresponding low-dose controls. The incidence of adenocarcinoma of the uterus was significant in the mid-dose female rats (P=0.001), using pooled controls (pooled controls 0/28, mid-dose 7/21); in addition, two low-dose females had adenocarcinoma of the uterus, with no such tumor occurring in the corresponding low-dose controls. In rats, neuroepitheliomas (neuroblastomas) or nasal carcinomas occurred in three low-dose males, two low-dose females, and two mid-dose females. Although these are not statistically significant incidences, these tumors did not occur among control animals and no such tumors have occurred in 380 Sprague-Dawley control rats of each sex in other bioassays at the same laboratory. Thus, they may be associated with administration of the chemical. In the high-dose groups of both male and female mice, but not in the low-dose groups, the incidences of lymphoma or lymphocytic leukemia were significantly higher (P<0.001) for each sex than those of either the vehicle or pooled controls (males: vehicle controls 1/8, pooled controls 1/18, low-dose 2/24, high-dose 26/28; females: vehicle controls 0/14, pooled controls 0/29, low-dose 5/26, high-dose 32/32). In the low-dose male mice squamous-cell carcinoma was found in the skin of seven animals, in the preputial glands of six animals, and in the ear canal of two animals. A carcinoma of the preputial gland was also found in a high-dose male. When the incidences of the tumors at the different sites were combined, the incidence in the low-dose group was statistically significant using either the vehicle (P=0.004) or the pooled (P<0.001) controls (vehicle controls 0/8, pooled controls 0/18, low-dose 14/24, high-dose 1/2). It is concluded that under the conditions of this bioassay, thio-TEPA was carcinogenic in both Sprague-Dawley rats and B6C3F1 mice. In the rats, the chemical induced squamous-cell carcinoma of the skin or ear canal in both males and females, and hematopoietic neoplasms in the males; in the mice, it induced lymphoma or lymphocytic leukemia in both sexes and squamous-cell carcinoma in the skin and associated glands of males.

Journal Article↗
PubMed1978

Bioassay of b-TGdR for possible carcinogenicity.

A bioassay of beta-2'-deoxy-6-thioguanosine monohydrate (b-TGdR) for possible carcinogenicity was conducted by administering the test chemical by intraperitoneal injection to Sprague-Dawley rats and B6C3F1 mice. Groups of 35 rats of each sex were administered b-TGdR in a buffered saline and polysorbate 80 vehicle at one of two doses, either 3.5 or 7 mg/kg body weight, three times per week for 52 weeks, then observed for an additional 26 weeks. Controls consisted of groups of 10 rats of each sex, which were either administered the vehicle alone (matched vehicle controls) or were untreated (matched untreated controls). Pooled controls consisted of the matched vehicle controls of each sex from the current bioassay, combined with 20 corresponding vehicle controls of each sex from similar bioassays of two other test chemicals. All surviving rats were killed at 78 or 79 weeks. Groups of 35 mice of each sex were administered the chemical in a buffered saline and polysorbate 80 vehicle at one of two doses, either 2 or 4 mg/kg, three times per week for 52 weeks, then observed for periods of up to 27 weeks, depending on length of survival. Because of severe toxicity at the high dose, resulting in loss of all mice by week 12 (males) or week 25 (females), additional groups of 35 mice of each sex were administered 1 mg/kg on the same schedule. Controls consisted of groups of 15 mice of each sex, which were either administered the vehicle or were untreated. Pooled controls consisted of groups of 15 vehicle-control animals of each sex from studies using the doses of 2 or 4 mg/kg, combined with corresponding groups of 15 vehicle-control animals of each sex from the study using the dose of 1 mg/kg. b-TGdR was toxic to rats at the doses used in this study. Mean body weights of the high- and low-dose rats of both sexes were lower than those of the corresponding vehicle controls throughout the study. There was also severe early mortality in the high-dose groups of both sexes and positive dose-related trends in mortality over the period of the bioassay. However, 66% of the low-dose males and 77% of the low-dose females survived until termination of the study. In mice, b-TGdR was toxic at the doses originally selected. Mean body weights were not consistently affected; however, at the high dose only three males and seven females lived past week 7, and all were dead by week 25. In the mid-dose group, only 14% of the males and 6% of the females survived until termination of the study at week 79; in the low-dose group, the survival rate was 31% for the males and 29% for the females. Because of the high mortality, time-adjusted statistical analyses were performed for both rats and mice. In rats, the incidence of carcinomas of the ear canal (combined carcinomas and squamous-cell carcinomas) was statistically significant in both sexes. In males, the results of the test for dose-related trend were significant using either matched vehicle (P=0.046) or pooled vehicle (P=0.014) controls, but direct comparisons of dosed male rats with matched vehicle or pooled vehicle controls did not show significant differences (matched vehicle controls 0/10, pooled vehicle controls 0/28, low-dose 1/31, high-dose 2/7). In females, the results of the test for dose-related trend were significant using either matched vehicle (P=0.002) or pooled vehicle (P<0.001) controls, and the incidence in the high-dose group was significantly higher than that in either the matched vehicle (P=0.023) or pooled vehicle (P<0.001) controls (matched vehicle controls 0/9, pooled vehicle controls 0/28, low-dose 2/32, high-dose 6/13). There were no such ear canal tumors among 165 historical vehicle controls of either sex or among 220 female untreated controls at the laboratory, and only two such tumors occurred among 215 male untreated controls. In mice, no tumors appeared in statistically significant incidences in the dosed groups compared with the matched vehicle controls, and there was no significant evidence of dose-related trend for any tumors. The incidences of the combination of lymphoma and leukemia were significantly higher in the matched vehicle controls of each sex than in the corresponding matched untreated controls (males: matched untreated controls 1/30, matched vehicle controls 19/29; females: matched untreated controls 2/30, matched vehicle controls 21/29). This high incidence in the matched vehicle controls may have been due to a systematic procedural problem associated with injection of the drug. It is concluded that under the conditions of this bioassay, the low survival of the dosed and vehicle-control groups of mice, as well as the possible procedural problem that may have affected the incidences of tumors in these groups, does not allow a determination to be made of the carcinogenic potential of b-TGdR in this species. b-TGdR in the vehicle of 0.05% polysorbate 80 was, however, carcinogenic in rats, producing carcinomas of the ear canal in the females and possibly also in the males.

Journal Article↗
PubMed1978

Bioassay of N,N'-dicyclohexylthiourea for possible carcinogenicity.

A bioassay of N,N'-dicyclohexylthiourea 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 N,N'-dicyclohexylthiourea at one of two doses, either 25,000 or 50,000 ppm, for 109 weeks for rats or 104 weeks for mice. Matched controls consisted of 50 untreated rats or 50 untreated mice of each sex. Mean body weights of male rats and male mice were unaffected by the compound, whereas mean body weights of the females of each species showed mild dose-related retardation over the bioassay period, when compared with the matched controls. Survival was sufficient to termination of the study in all groups of both rats and mice for the development of late-appearing tumors. In male rats there was an increased incidence of hyperplasia of the follicular cells of the thyroid (males: controls 3/43, low-dose 16/49, high-dose 15/49; females: controls 1/48, low-dose 7/48, high-dose 5/49). The incidences of tumors of the follicular cells of the thyroid, although increased among the dosed male rats, were not statistically significant in either sex. In mice, a variety of neoplasms of the type usually encountered in the B6C3F1 strain were observed in both dosed and control animals. None of the tumors occurred at statistically significant incidences. Follicular-cell hyperplasia of the thyroid was observed at an increased incidence in both the dosed males and females (males: controls 3/39, low-dose 12/46, high-dose 9/45; females: controls 8/38, low-dose 22/46, high-dose 21/46). An increase in proliferative lesions of the follicular cells of the thyroid was associated with the administration of N,N'-dicyclohexylthiourea in both Fischer 344 rats and B6C3F1 mice. However, because statistical significance was not achieved and because thyroid tumors are not rare, spontaneous lesions in these strains of animals and occur with a variable incidence, it is concluded that under the conditions of this bioassay, N,N'-dicyclohexylthiourea was not demonstrated to be carcinogenic in either species.

Journal Article↗
PubMed1978

Bioassay of 1,2-dichloroethane for possible carcinogenicity.

A bioassay of technical-grade 1,2-dichloroethane for possible carcinogenicity was conducted using Osborne-Mendel rats and B6C3F1 mice. 1,2-Dichloroethane 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 32 weeks for the low dose rats of both sexes. The last high dose male rat died after 23 weeks of observation and the last high dose female rat died after 15 weeks of observation. All treated groups of mice were observed for an additional 12 or 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 1,2-dichloroethane in the chronic study were 95 and 47 mg/kg/day, respectively, for rats of both sexes. The high and low time-weighted average doses for the male mice were 195 and 97 mg/kg/day, respectively, and 299 and 149 mg/kg/day, respectively, 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 times that dosed animals were gavaged with the 1,2-dichloroethane mixtures. Twenty animals of each sex were placed on test as untreated controls for each species. These animals were not intubated. A statistically significant positive association between dosage and the incidence of squamous-cell carcinomas of the forestomach and hemangiosarcomas of the circulatory system occurred in the male rats, but not in the females. There was also a significantly increased incidence of adenocarcinomas of the mammary gland in female rats. The incidences of mammary adenocarcinomas in female mice were statistically significant. There was a statistically significant positive association between chemical administration and the combined incidences of endometrial stromal polyps and endometrial stromal sarcomas in female mice. The incidence of alveolar/bronchiolar adenomas in both male and female mice was also statistically significant. Under the conditions of this study, 1,2-dichloroethane was carcinogenic to Osborne-Mendel rats, causing squamous-cell carcinomas of the forestomach, hemangiosarcomas, and subcutaneous fibromas in male rats and causing mammary adenocarcinomas in female rats. This compound was also found to be carcinogenic to B6C3F1 mice, causing mammary adenocarcinomas and endometrial tumors in female mice, and causing alveolar/bronchiolar adenomas in mice of both sexes.

Journal Article↗
PubMed1978

Bioassay of 2,4-dinitrotoluene for possible carcinogenicity.

A bioassay of practical-grade 2,4-dinitrotoluene for possible carcinogenicity was conducted using Fischer 344 rats and B6C3F1 mice. 2,4-Dinitrotoluene was administered in the feed, at either of two concentrations, to groups of 50 male and 50 female animals of each species. For male and female rats, the high and low time-weighted average dietary concentrations of 2,4-dinitrotoluene were 0.02 and 0.008 percent, respectively. For male and female mice, the high and low time-weighted average concentrations were 0.04 and 0.008 percent, respectively. After a 78-week period of compound administration, observation of the rats continued for an additional 26 weeks and observation of the mice continued for 13 additional weeks. For the chronic rat bioassay, 25 rats of each sex were placed on test as high dose controls, and 50 rats of each sex served as the low dose controls. For the mice, 50 males and 50 females were placed on test as controls for each of the high dose and low dose groups. In both species the survival in all groups was adequate for statistical analysis of late-appearing tumors. In the male rats, a significantly increased incidence of fibroma of the skin and subcutaneous tissue occurred in both the high and the low dose groups when compared to their respective controls. A statistically significant incidence of fibroadenoma of the mammary gland occurred in the high dose female rats. Among the mice a variety of tumors was observed but none were considered to be associated with the dietary administration of 2,4-dinitrotoluene. Under the conditions of this bioassay dietary administration of 2,4-dinitrotoluene to Fischer 344 rats induced benign tumors (i.e., fibroma of the skin and subcutaneous tissue in males and fibroadenoma of the mammary gland in females). No evidence was provided for the carcinogenicity of the compound in B6C3F1 mice of either sex.

Journal Article↗
PubMed1978

Bioassay of 2-amino-5-nitrothiazole for possible carcinogenicity.

A bioassay of 2-amino-5-nitrothiazole 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 fed 2-amino-5-nitrothiazole at one of the following doses, either 300 or 600 ppm for rats, and either 50 or 100 ppm for mice. The rats were dosed for 110 weeks, followed by 1 week of observation; the mice were dosed for 104 weeks. Matched controls consisted of 50 untreated rats and 50 untreated mice of each sex. All surviving rats were killed at week 111, all surviving mice at week 104. The mean body weights of the groups of rats and mice fed 2-amino-5-nitrothiazole in the diet were slightly lower than those of the controls throughout most of the period of administration. No other clinical signs related to administration of the chemical were noted. There was a dose-related trend in mortality only in the male rats; however, sufficient numbers of rats were at risk in all groups for development of late-appearing tumors. In male rats, there was a significant dose-related trend (P=0.044) in the incidences of malignant lymphomas, lymphocytic leukemias, or undifferentiated leukemias, although the results of direct comparisons of incidences in each of the dosed groups with those in the controls were not significant. There was also a significant dose-related trend in the incidence of granulocytic leukemia in the male rats (P=0.014) and a significantly increased incidence of this tumor (P=0.023) in the high-dose group (matched controls 2/50, low-dose 4/50, high-dose 9/49). When the incidences of all neoplasms of the hematopoietic system lymphomas and all leukemias) were combined, greater significance was attained for both the dose-related trend (P=0.001) and the direct comparison (P=0.002) of the incidence of the high-dose group with that in the matched controls (controls 13/50, low-dose 9/50, high-dose 28/49). The reliability of the incidence of hematopoietic tumors in the male controls was supported by that for male controls observed in a similar bioassay of another test chemical at the same laboratory (13/50). The incidences of the combined hematopoietic tumors in the dosed female rats were not significant when compared with the incidence in the matched controls. In female rats, there was a significant dose-related trend in the incidence of chromophobe adenomas of the pituitary (P=0.016) and a higher incidence (P=0.021) in the high-dose group than in the matched controls (controls 19/45, low-dose 29/47, high-dose 29/44). The incidence of this lesion in dosed male rats was much lower than that in dosed females, and the dose-related trend (P=0.048) was only marginally significant (controls 3/46, low-dose 3/45, high-dose 8/43). The incidences of chromophobe adenomas of the pituitary which were observed in control groups of rats used in a similar bioassay of another test chemical at the same laboratory were 13/49 (27%) for the males and 26/50 (52%) for the females. Because of the variability in incidences of the tumor among different control groups, the occurrence of chromophobe adenomas of the pituitary in the dosed female rats cannot be clearly associated with the administration of 2-amino-5-nitrothiazole. Also in female rats, there was a higher incidence of endometrial stromal polyps of the uterus in the low-dose group (P=0.023) than in the matched controls (controls 2/50, low-dose 9/49, high-dose 3/50). Since, however, only three high-dose animals had this tumor, the occurrence of uterine tumors in the low-dose group cannot be clearly associated with administration of the test chemical. In the mice, no neoplasms were observed at a statistically significant incidence in the dosed groups when compared with the controls. It is concluded that under the conditions of this bioassay, the occurrence of tumors of the hematopoietic system, i.e., lymphoma and granulocytic leukemia, in dosed male Fischer 344 rats was associated with administration of 2-amino-5-nitrothiazole. 2-Amino-5-nitrothiazole was not carcinogenic in female Fischer 344 rats or in male or female B6C3F1 mice.

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PubMed1978

Bioassay of tolazamide for possible carcinogenicity.

A bioassay of the hypoglycemic drug tolazamide 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 tolazamide at one of two doses, either 5,000 or 10,000 ppm, for 103 weeks. Matched controls consisted of 15 rats and 15 mice of each sex. All surviving rats and mice were killed at 104 or 105 weeks. Survival rates for the dosed rats of each sex were higher than those for the matched controls, and were adequate for the development of late-appearing tumors. Survival rates for the mice were lower than those for the rats, particularly for the dosed females (matched controls 67%, low-dose 34%, high-dose 32%). However, a large number of these deaths in the dosed females occurred after 90 weeks on study, and survival of both males and females was adequate for the development of late-appearing tumors. All observed tumors were of types commonly found in the strains of animals used, and there were no statistically significant increases in the incidence of tumors in the dosed animals as compared with controls. It is concluded that under the conditions of this bioassay, tolazamide was not carcinogenic for Fischer 344 rats or B6C3F1 mice.

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PubMed1978

Bioassay of acetohexamide for possible carcinogenicity.

A bioassay of acetohexamide for possible carcinogenicity was conducted by administering the test chemical in feed to Fischer 344 rats and B6C3F1 mice. Groups of 35 rats of each sex were administered acetohexamide in the diet at one of two doses, either 10,000 or 20,000 ppm, for 103 weeks and then observed for 2 to 4 additional weeks. Matched controls consisted of 15 untreated rats of each sex. All surviving rats were killed at 105 to 107 weeks. Groups of 35 mice of each sex were administered acetohexamide at one of two doses for 103 weeks and then observed for 4 or 5 additional weeks. Time-weighted average doses were 6,359 or 12,718 ppm. Matched controls consisted of 15 untreated mice of each sex. All surviving mice were killed at 107 or 108 weeks. Mean body weights of the dosed rats and mice of both sexes were lower than those of the corresponding matched controls throughout the study, and the depressions in weight were dose related. Except for the female mice, sufficient numbers of animals survived long enough to be at risk for development of late-appearing tumors. In the rats, the only tumor occurring with greater incidence in dosed than in matched-control animals was leukemia (males: matched controls 0/15, low-dose 10/35, high-dose 4/35; females: matched controls 0/14, low-dose 7/35, high-dose 4/34). Only the incidence in the low-dose males was statistically significant (P=0.018). All of these animals had undifferentiated (mononuclear cell) leukemia, which commonly occurs spontaneously in Fischer 344 rats, except for two with lymphocytic leukemia. The incidence of combined leukemia and lymphoma in historical-control male rats at this laboratory in the bioassay program to date is 24/235 (10.2%), which is higher than that in the matched controls. Thus, the incidence in the low-dose males cannot be clearly associated with administration of the test chemical. In the mice, the only neoplasms that occurred at a higher incidence in dosed groups than in matched controls were lymphomas in the males, but the incidences were not statistically significant (matched controls 1/15, low-dose 9/35, high-dose 3/34). These types of lesions are found commonly in untreated B6C3F1 mice. The incidence of lymphomas in the historical-control male mice is 28/536 (5.2%). It is concluded that under the conditions of this bioassay, acetohexamide was not carcinogenic for either Fischer 344 rats or B6C3F1 mice.

Journal Article↗
PubMed1978

Bioassay of 3,3'-iminobis-1-propanol dimethanesulfonate (ester) hydrochloride (IPD) for possible carcinogenicity.

A bioassay of 3,3'-iminobis-1-propanol dimethanesulfonate (ester) hydrochloride [IPD] for possible carcinogenicity was conducted by administering the test chemical intraperitoneally to Sprague-Dawley rats and B6C3F1 mice. The IPD was injected three times per week to groups of 35 animals, using doses of 12, 24, or 48 mg/kg for the rats, and 20 or 40 mg/kg for the mice. Rats at 12 mg/kg were treated for 52 weeks. Because of the toxicity of the chemical, administration of IPD for the group receiving 24 mg/kg was discontinued at week 34. Rats receiving 48 mg/kg were treated until all had died at week 23 (males) and week 27 (females). Both groups of mice were treated for 52 weeks. All survivors were killed after post-administration periods that varied among groups. With rats, untreated and vehicle-control groups, each consisting of 10 males and 10 females, were started with the high- and mid-dose groups and additional untreated and vehicle-control groups of the same size were started with the low-dose groups. With mice, untreated and vehicle-control groups each consisted of 15 males and 15 females. The toxicity of IPD was associated with lower mean body weights and lower rates of survival of both the rats and mice. The shortened life spans, particularly in the rats, reduced the likelihood of the development of tumors. In rats, peritonitis and fibrous adhesions, possibly, from direct irritation by the test chemical were observed in most treated rats at necropsy. Sarcoma, fibroma, or fibrosarcoma of the peritoneum occurred in two low-dose male, one mid-dose male, and one mid-dose female rats, but not in any control animals. Because of this low incidence, and because irritation by the test chemical have been involved in the pathogenesis, these tumors may have been due to local effects of the chemical. In mice, lymphomas were observed at the following incidences (males: controls 0/14, low-dose 0/26, high-dose 3/21; females: controls 1/15, low-dose 2/29, high-dose, 6/27). The Tarone test for life-table analysis of the probability of survival without lymphoma indicated a significant positive dose-related increase of lymphomas with a probability level of 0.011 for male mice and 0.003 for female mice. Squamous-cell carcinoma was noted in the mice (low-dose males 6/26, high-dose females 2/27). Seven of these tumors were observed in subcutaneous tissue in the inguinal region near the sites of injection. Although not statistically significant, this tumor may be associated with administration of IPD. Tumors of the peritoneum in rats and tumors in the subcutaneous tissue in mice may have been due to local effects related to administration of the test chemical. The lymphomas in mice, although marginally significant, were too few in number to clearly be related to dosing. Conclusions from this study are limited by early deaths and toxicity, but the appearance of tumors in the peritoneum near the injection sites in both rats and mice indicate the carcinogenic potential of IPD.

Journal Article↗
PubMed1978

Bioassay of acronycine for possible carcinogenicity.

A bioassay of acronycine for possible carcinogenicity was conducted by administering the test chemical by intraperitoneal injection to Sprague-Dawley rats and B6C3F1 mice. Initially, groups of 35 rats of each sex were administered acronycine at one of two doses, either 7.5 or 15 mg/kg body weight, in a vehicle composed of 0.05% polysorbate 80 in phosphate-buffered saline. Control groups of each sex consisted of 10 untreated rats (untreated controls) and 10 rats injected with the vehicle (vehicle controls). Because of high mortality rates in the dosed animals, new dosed groups of 35 rats of each sex were started later at a dose of 3.75 mg/kg. Additional groups of 10 untreated and 10 vehicle controls of each sex were also started. The rats were administered the acronycine or the vehicle for 51 or 52 weeks, then observed for an additional 28-30 weeks. All surviving rats were killed at 80-82 weeks. Initially, groups of 35 mice of each sex were administered acronycine at one of two doses, either 12.5 or 25 mg/kg body weight, in a vehicle composed of 0.05% polysorbate 80 in phosphate-buffered saline. Control groups of each sex consisted of 10 untreated mice (untreated controls) and 10 mice injected with the vehicle (vehicle controls). Because of high mortality rates in the dosed animals, two additional dosed groups were started later: 35 mice of each sex at 6 mg/kg and 40 mice of each sex at 2 mg/kg, together with 10 untreated controls and 10 vehicle controls of each sex for the groups dosed at 6 mg/kg, and 20 untreated controls and 20 vehicle controls for the groups dosed at 2 mg/kg. Periods of administration of the chemical to the mice varied from 25 weeks to 92 weeks, depending on toxicity or length of time of survival. Surviving control animals were killed at 78-105 weeks. Acronycine was toxic to rats and mice of each sex at the doses used in this bioassay, as shown by the high mortality rates in all but the low-dose groups and by the lower mean body weights in dosed rats and mice at all doses throughout most of the bioassay. Because of this high number of deaths, time-adjusted statistics are used for the analyses of all incidences of tumors. In male rats, the dose-related trend in the mid-and high-dose groups for the incidence of osteosarcoma at all sites was significant (P=0.002) using the respective vehicle-control group (vehicle controls 0/8, mid-dose 13/30, high-dose 12/18). Comparisons of the individual groups with respective control groups were also significant for the mid-dose (P=0.022) and high-dose (P=0.002) groups, but not for the low-dose group. In female rats, osteosarcoma was observed only in 1/8 high-dose animals. Sarcomas and other related tumors of the peritoneum were observed in all three dosed groups of both male and female rats, but in none of the control groups (males: low-dose 5/30, mid-dose 3/26, high-dose 7/16; females: low-dose 1/35, mid-dose 5/30, high-dose 13/28). In both sexes, the dose-related trends were significant (males, P=0.006; females, P=0.002), and the comparison of the incidences in the high-dose females with the vehicle-control group was significant (P=0.016). None of the incidences in the individual dosed groups of males were significant when compared with vehicle controls. However, since the tumors were observed in all dosed groups but did not occur in historical-control animals at this laboratory, they are considered to be related to the administration of the chemical. In female rats, the incidence of all tumors of epithelial origin of the mammary gland was significant only at the low dose (low-dose vehicle controls 1/10, low-dose 22/35, P=0.004). Adenocarcinomas of the mammary gland were observed in seven low-dose, five mid-dose, and two high-dose female rats, but in no cs, but in no control females. The reverse dose relationship of both benign and malignant tumors was probably due to the higher number of early deaths which occurred in the high-dose group. In mice, the low survival in all dosed groups except the low-dose animals precluded an evaluation of the significance of the incidences of tumors. Lymphomas occurred in low-dose groups of both males and females; however, the incidence of lymphoma in different control groups was highly variable. The high incidence in the low-dose vehicle controls may have been due to a procedural problem associated with the possibility of transfer of tumor cells or oncogenic viruses during the intraperitoneal injection of the test chemical. It is concluded that under the conditions of this bioassay, the low survival of the dosed and control mice and the possible procedural problems associated with the intraperitoneal injection of the chemical did not allow a determination to be made of the carcinogenicity of acronycine in this species. In Sprague-Dawley rats, acronycine in the vehicle of 0.05% polysorbate 80 in phosphate-buffered saline was carcinogenic, producing tumors of the mammary gland in females, osteosarcomas in males, and sarcomas and other related tumors of the peritoneum in both males and females.

Journal Article↗
PubMed1978

Bioassay of pyrazinamide for possible carcinogenicity.

A bioassay of the tuberculostatic drug pyrazinamide 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 pyrazinamide at one of two doses, either 5,000 or 10,000 ppm, for 78 weeks, and then observed for an additional 26 or 27 weeks. Matched controls consisted of groups of 15 untreated rats and 15 untreated mice of each sex. High-dose male mice died or were killed by week 92; all other surviving animals were killed at weeks 104 or 105. Mean body weights of the dosed male rats were slightly lower than those of the matched controls, while mean body weights of the dosed females were more nearly comparable to those of the controls. A sufficient number of rats in each group was at risk to termination of the study at weeks 104-105 for the development of late-appearing tumors. In mice, administration of pyrazinamide had no consistent effect on mean body weights. Survival to termination of the study was low, particularly among the control groups. In rats, no lesions could clearly be related to administration of the chemical. In mice, interstitial and suppurative myocarditis in the dosed animals and suppurative bronchopneumonias in both dosed and matched control mice of each sex were associated with increased deaths. In the females, there was a significant positive dose-related trend (P=0.037) in the incidence of lymphoma (matched controls 0/13, low-dose 2/25, high-dose 6/29); however, the incidences in each of the dosed groups were not significant when compared with that in the matched controls. In addition, the poor survival and the small size of the control group precluded making a clear association of the incidence of these tumors with administration of the chemical. It is concluded that under the conditions of this bioassay, the early deaths and small size of the control group precluded a conclusion regarding the carcinogenicity of pyrazinamide in female B6C3F1 mice. Pyrazinamide was not carcinogenic for Fischer 344 rats or for male mice.

Journal Article↗
PubMed1978

Bioassay of 4,4'-thiodianiline for possible carcinogenicity.

A bioassay of 4,4'-thiodianiline 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 4,4'-thiodianiline 5 days per week at one of the following doses, either 1,500 or 3,000 ppm for the rats and either 2,500 or 5,000 ppm for the mice. The period of administration of the chemical was 68-72 weeks for the rats and 77 or 79 weeks for the mice, depending on the length of survival time of the animals. Matched controls consisted of groups of 15 untreated rats and 14 untreated mice of each sex. All surviving matched-control rats were killed at 104 weeks; all surviving matched-control mice were killed at 91 weeks. The administration of 4,4'-thiodianiline resulted in marked reduction in mean body weights of the rats and mice of each sex, and all dosed animals died prior to the scheduled end of the study. Tumors of epithelial origin were found in many organs, and all dosed rats except one were affected at one or more sites (males: skin, ear canal, lungs, liver, colon, and thyroid; females: ear canal, lung, liver, thyroid, and uterus). These tumors were not found among any of the matched-control animals. In male rats, several of these neoplastic lesions occurred with statistically significant incidences in one or both of the dosed groups. The incidences of hepatocellular carcinoma (controls 0/15, low-dose 21/33, high-dose 10/33) and of follicular-cell carcinoma of the thyroid (controls 0/15, low-dose 28/33, high-dose 32/33) were significant in each of the groups at P</= 0.014. The combined incidences of squamous-cell carcinoma and squamous-cell papilloma of the ear canal in the low- and high-dose groups of males were both significantly higher (low-dose P=0.001, high-dose P=0.037) than that in the control group (controls 0/15, low-dose 15/33, high dose 8/33). The first such tumor in the high-dose group was observed at 25 weeks. Also in low-dose male rats, squamous-cell papilloma of the skin occurred in 4/33 animals, and squamous-cell carcinoma of the skin in 1/33, but no tumors of either type occurred in the controls. The incidences of these lesions were too low to have statistical significance. The majority of the squamous-cell tumors of the skin were located in one area near the commissure of the mouth. Only one such tumor occurred among the 235 historical-control male rats at this laboratory; thus, the tumors of the skin may be associated with administration of the chemical. Adenocarcinoma of the colon occurred in six low-dose male rats and in one high-dose male rat, but not in any of the controls. This incidence is not statistically significant; however, no such tumors occurred among the 235 historical-control male rats at this laboratory; thus, the tumors of the colon are considered to be related to administration of 4,4'-thiodianiline. In female rats, the incidences of hepatocellular adenoma or carcinoma in the dosed groups were greater than those in the controls, but not statistically significant (controls 0/15, low-dose 6/32, high-dose 3/33). Follicular-cell carcinoma of the thyroid and adenocarcinoma of the uterus occurred in the females administered the test chemical at statistically significant incidences (P<0.001) in both dosed groups (follicular-cell carcinoma: controls 0/14, low-dose 24/33, high-dose 32/32; adenocarcinoma: controls 0/15, low-dose 31/33, high-dose 23/32). Squamous-cell papilloma or carcinoma of the ear canal occurred at increased, but not statistically significant, incidences in female rats (controls 0/15, low-dose 6/33, high-dose 3/33). However, no such tumors occurred among the 235 historical-control female rats at this laboratory; thus, the tumors of the ear canal are considered to be related to administration of the chemical. In mice of each sex, the incidence of hepatocellular carcinoma was statistically significant (P<0.001) in each of the dosed groups (males: controls 1/13, low-dose 32/34, 32/34, high-dose 22/24, females: controls 0/12, low-dose 32/34, high-dose 30/31). In the males, follicular-cell carcinoma of the thyroid occurred at statistically significant incidences (P </= 0.001) in both the low- and high-dose groups (controls 0/14, low-dose 15/33, high-dose 20/23). In the females, the incidence was significant (P=0.002) only at the high dose (controls 0/11, high-dose 15/30); however, when follicular-cell adenoma and carcinoma were combined, the incidences in both the low- and high-dose groups of females were significantly higher (low-dose P=0.025, high-dose P<0.001) than that in the control group (controls 0/11, low-dose 11/33, high-dose 18/30). It is concluded that under the conditions of this bioassay, 4,4'-thiodianiline was carcinogenic for Fischer 344 rats, inducing tumors in the liver, thyroid, colon, and ear canal of male rats, and the thyroid, uterus, and ear canal of female rats. 4,4'-Thiodianiline was carcinogenic for B6C3F1 mice, inducing tumors in the liver and thyroid of both males and females.

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