2-Amino-5-nitrothiazole is an antiprotozoal drug for animals which is now used in the form of the acetyl derivative to control histomoniasis (blackhead) in turkeys. The use of acetyl-2-amino-5-nitrothiazole in animal feed and the allowable residues in food products from treated animals (0.1 ppm) are regulated by the Food and Drug Administration.
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.