Abstract for TR-99

Bioassay of Phenazopyridine Hydrochloride for Possible Carcinogenicity 

CASRN: 136-40-3
Chemical Formula: C11H11N5.ClH
Molecular Weight: 249.7038
Synonyms/Common Names: 2,6-diamino-3-(phenylazo)-pyridine monohydrochloride
Report Date: 1978

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Phenazopyridine hydrochloride is the generic name for an azo dye which has been used for 40 years as an analgesic drug to reduce pain associated with urinary tract infections. It is marketed both alone and in combination with the sulfonamide urinary tract antiseptics.

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 adenomas and carcinomas.