Carcinogenesis: Long-term studies with triamterene/hydrochlorothiazide combination have not been conducted. 

Triamterene: In studies conducted under the auspices of the National Toxicology Program, groups of rats were fed diets containing 0, 150, 300 or 600 ppm triamterene and groups of mice were fed diets containing 0, 100, 200 or 400 ppm triamterene. Male and female rats exposed to the highest tested concentration received triamterene at about 25 and 30 mg/kg/day, respectively. Male and female mice exposed to the highest tested concentration received triamterene at about 45 and 60 mg/kg/day, respectively. 

There was an increased incidence of hepatocellular neoplasia (primarily adenomas) in male and female mice at the highest dosage level. These doses represent 7.5 times and 10 times the MRHD of 300 mg/kg (or 6 mg/kg/day based on a 50 kg patient) for male and female mice, respectively when based on body-weight and 0.7 times and 0.9 times the MRHD when based on body-surface area. Although hepatocellular neoplasia (exclusively adenomas) in the rat study was limited to triamterene-exposed males, incidence was not dose-dependent and there was no statistically significant difference from control incidence at any dose level.

Hydrochlorothiazide: Two-year feeding studies in mice and rats, conducted under the auspices of the National Toxicology Program (NTP), treated mice and rats with doses of hydrochlorothiazide up to 600 and 100 mg/kg/day, respectively. On a body-weight basis, these doses are 600 times (in mice) and 100 times (in rats) the Maximum Recommended Human Dose (MRHD) for the hydrochlorothiazide component of triamterene and hydrochlorothiazide tablets (50 mg/day or 1 mg/kg/day based on a 50 kg patient). On the basis of body-surface area, these doses are 56 times (in mice) and 21 times (in rats) the MRHD. These studies uncovered no evidence of carcinogenic potential of hydrochlorothiazide in rats or female mice, but there was equivocal evidence of hepatocarcinogenicity in male mice. 

Mutagenesis:   
Studies of the mutagenic potential of the triamterene and hydrochlorothiazide combination have not been performed. 

Triamterene: Triamterene was not mutagenic in bacteria (S. typhimurium strains TA 98, TA 100, TA 1535 or TA 1537) with or without metabolic activation. It did not induce chromosomal aberrations in Chinese hamster ovary (CHO) cells in vitro with or without metabolic activation, but it did induce sister chromatid exchanges in CHO cells in vitro with and without metabolic activation. 

Hydrochlorothiazide: Hydrochlorothiazide was not genotoxic in in vitro assays using strains TA 98, TA 100, TA 1535, TA 1537 and TA 1538 of Salmonella typhimurium (the Ames test), in the Chinese hamster ovary (CHO) test for chromosomal aberrations, or in in vivo assays using mouse germinal cell chromosomes, Chinese hamster bone marrow chromosomes, and the Drosophila sex-linked recessive lethal trait gene. Positive test results were obtained in the in vitro CHO sister chromatid exchange (clastogenicity) test, and in the mouse lymphoma cell (mutagenicity) assays, using concentrations of hydrochlorothiazide of 43 to 1300 mcg/mL. Positive test results were also obtained in the Aspergillus nidulans nondisjunction assay using an unspecified concentration of hydrochlorothiazide. 

Impairment of Fertility: Studies of the effects of the triamterene/ hydrochlorothiazide combination, or of triamterene alone on animal reproductive function have not been conducted. 

Hydrochlorothiazide: Hydrochlorothiazide had no adverse effects on the fertility of mice and rats of either sex in studies wherein these species were exposed, via their diet, to doses of up to 100 and 4 mg/kg/day, respectively, prior to mating and throughout gestation. Corresponding multiples of the MRHD are 100 (mice) and 4 (rats) on the basis of body-weight and 9.4 (mice) and 0.8 (rats) on the basis of body-surface area.