Toxicity and carcinogenicity of Elmiron in F344/N rats and B6C3F1 mice following 2 years of gavage administration

Elmiron (sodium pentosan polysulfate) is used for the relief of urinary bladder pain associated with interstitial cystitis. The National Toxicology Program (NTP) tested this compound because of its orphan drug status and lack of information about its chronic toxicity and carcinogenicity. Groups of 50 male and 50 female F344/N rats were given Elmiron in de-ionized water by gavage at doses of 0, 14, 42, or 126 mg/kg to males and 0, 28, 84, or 252 mg/kg to females once daily, 5 days per week, for up to 2 years. The same numbers of male and female B6C3F1 mice were dosed similarly with 0, 56, 168, or 504 mg/kg. Elmiron administration produced no effect on the body weight of rats, male mice, or low- and mid-dose groups of female mice. The body weights of the high-dose female mice were significantly decreased relative to those of controls. Pairwise comparison showed that survival of all dosed groups of rats and mice was similar to that of the controls. Elmiron was not carcinogenic in F344/N rats. An increased incidence of liver hemangiosarcoma provided evidence of some carcinogenic activity for Elmiron in male B6C3F1 mice. Increased incidences of liver hemangiosarcoma, hepatocellular neoplasms (predominantly adenomas), and malignant lymphomas revealed carcinogenic activity of Elmiron in female B6C3F1 mice. Elmiron administration produced elevated occurrences of nonneoplastic lesions, such as vacuolated histiocytes in the rectum, lung, spleen (males only), and mesenteric lymph node in rats and liver, rectum, mesenteric lymph node, and spleen in mice. Myxomatous change, chronic inflammation, and squamous metaplasia (mice only) were observed in the large intestine, and lymphohistiocytic hyperplasia was found to be increased in the spleen of rats of both sexes treated with the highest dose. In the latter lesion, the histiocytes contained pale, finely granular cytoplasm and were not considered to represent the same change as the vacuolated histiocytes seen in the mesenteric lymph node and rectum. Under the conditions of these 2-year studies, Elmiron was carcinogenic to mice but not rats.