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Abstract for TR-512

Toxicology and Carcinogenesis Studies of Elmiron® in F344/N Rats and B6C3F1 Mice (Gavage Studies)

CASRN: 37319-17-8
Chemical Formula: H-[C10H12O5(OSO3Na)4] -H (where n=2 to 12)
Molecular Weight: 1,500 to 5,000
Synonyms/Common Names: PZ68; pentosan polysulfate sodium; sodium xylan polysulfate; xylan hydrogen sulfate, sodium salt
Report Date: May 2004

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Abstract

Elmiron®, a white powder, is the sodium salt of pentosan polysulfate, a semisynthetic sulfated polyanion composed of b-D-xylopyranose residues with biological properties similar to heparin. Elmiron® is used in the United States for the relief of urinary bladder pain associated with interstitial cystitis. Because of its stimulating effect on fibrinolysis, Elmiron® has been used clinically in the treatment and prevention of thrombotic disorders. The United States Food and Drug Administration nominated Elmiron® for toxicology and carcinogenicity testing by the National Toxicology Program because of its orphan drug status. Male and female F344/N rats and B6C3F1 mice received Elmiron®, which met product specifications provided by the manufacturer, in deionized water by gavage for 2 weeks, 3 months, or 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium, rat and mouse bone marrow cells, and mouse peripheral blood erythrocytes.

2-Week Study in Rats

Groups of five male and five female rats were administered 0, 33, 111, 333, 1,000, or 3,000 mg Elmiron®/kg body weight in deionized water by gavage, 5 days per week, for 16 days. Elmiron® administration had no effect on survival or body weight gain. Activated partial thromboplastin time was significantly increased in 3,000 mg/kg rats. Liver weights of 3,000 mg/kg rats were significantly greater than those of the vehicle controls. Hepatocellular cytoplasmic vacuolization occurred in all 3,000 mg/kg females.

2-Week Study in Mice

Groups of five male and five female mice were administered Elmiron® in deionized water by gavage at doses of 0, 33, 111, 333, 1,000, or 3,000 mg/kg, 5 days per week, for 16 days. All mice survived to the end of the study. Mean body weight gains of male mice administered 333 mg/kg or greater were significantly greater than that of the vehicle control group. Liver weights of 1,000 and 3,000 mg/kg males were significantly increased.

3-Month Study in Rats

Groups of 10 male and 10 female rats were administered Elmiron® in deionized water by gavage at doses of 0, 63, 125, 250, 500, or 1,000 mg/kg, 5 days per week, for 14 weeks. No deaths were attributed to administration of Elmiron®. Mean body weights of 125 mg/kg males were less than those of vehicle controls and the mean body weights of all dosed groups of females were greater. Hematology results indicated that Elmiron®, at the doses selected, induced a minimal erythron decrease and leukocyte and platelet count increases that may have been secondarily related to the inflammatory lesions observed in various tissues of rats. Liver and spleen weights of males administered 250 mg/kg or greater were significantly increased. Liver weights of all dosed groups of females, and kidney, lung, and spleen weights of 1,000 mg/kg females were significantly increased. Histiocytic cellular infiltration, chronic active inflammation, and ulcers of the rectum occurred in most 500 and 1,000 mg/kg rats. Administration of Elmiron® was associated with the presence of vacuolated histiocytes in the mandibular and mesenteric lymph nodes, lung, kidney, and liver of male and female rats. Histochemical investigations of the vacuolated histiocytes indicated the presence of neutral and acidic mucins and lipid material within the vacuoles. Transmission electron microscopy identified these vacuoles as lysosomal structures that exhibited a variety of contents.

3-Month Study of Mice

Groups of 10 male and 10 female mice were administered Elmiron® in deionized water by gavage at doses of 0, 63, 125, 250, 500, or 1,000 mg/kg, 5 days per week, for 14 weeks. One 250 mg/kg female mouse was sacrificed moribund on day 84; all other mice survived to the end of the study. Mean body weights of dosed groups were similar to those of the vehicle control groups. Hematology results indicated that Elmiron®, at the doses selected, induced a minimal erythron decrease and leukocyte and platelet count increases that may have been secondarily related to the inflammatory lesions observed in various tissues of mice. Liver weights of 500 mg/kg males and 1,000 mg/kg males and females, and spleen weights of 1,000 mg/kg males were significantly increased. Histiocytic cellular infiltration and chronic active inflammation of the rectum occurred in most 1,000 mg/kg mice. Administration of Elmiron® was associated with the presence of vacuolated histiocytes in the mandibular and mesenteric lymph nodes, liver, and spleen of males and females. Histochemical investigations of the vacuolated histiocytes indicated the presence of neutral and acidic mucins within the vacuoles. Transmission electron microscopy identified these vacuoles as lysosomal structures that exhibited a variety of contents.

2-Year Study in Rats

Groups of 50 males and 50 females were administered Elmiron® in deionized 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, 5 days per week, for 104 or 105 weeks. Survival of all dosed groups of rats was similar to that of the vehicle control groups. Mean body weights of all dosed groups were similar to those of the vehicle controls throughout the 2-year study.

Microscopically, myxomatous changes were present in the rectum of 56% of 126 mg/kg males and 83% of 252 mg/kg females. The incidences of chronic active focal alveolar inflammation of the lung were increased in all dosed groups. The incidences of histiocytic cellular infiltration of the mesenteric lymph nodes were increased in 42 and 126 mg/kg males and in 84 and 252 mg/kg females, and lymphohistiocytic hyperplasia was present in the spleen of 126 mg/kg males and 252 mg/kg females.

2-Year Study in Mice

Groups of 50 males and 50 females were administered Elmiron® in deionized water by gavage at doses of 0, 56, 168, or 504 mg/kg, 5 days per week, for 104 or 105 weeks. Survival of all dosed groups of mice was similar to that of the vehicle control groups. Mean body weights of males were similar to those of vehicle controls. Mean body weights of 504 mg/kg females were progressively less than those of the vehicle controls during the second year of the study.

Increased incidences of hemangiosarcomas of the liver and hepatocellular neoplasms were observed in male and female mice. The incidences of hemangiosarcomas in the 504 mg/kg groups exceeded the historical control ranges for males and females; both the trend and the incidence in the 504 mg/kg groups were significant for males. Hemangiosarcomas in males and females were attributed to Elmiron® administration. The incidence of hepatocellular adenoma in 504 mg/kg females was significantly increased and exceeded the historical control range; the trends for hepatocellular adenoma and for hepatocellular adenoma or carcinoma (combined) were also significant in females and were attributed to Elmiron® administration. There was also a marginal increase in the incidences of hepatocellular neoplasms in male mice, which may have been associated with Elmiron® administration.

Malignant lymphomas occurred with a positive trend in female mice; the incidence in the 504 mg/kg group was also significantly increased and matched the upper limit of the historical control range. These malignant lymphomas may have been associated with Elmiron® administration.

Nonneoplastic lesions related to the administration of Elmiron® occurred in the liver, rectum, mesenteric lymph node, and spleen of 504 mg/kg mice and to a lesser extent in 168 mg/kg mice. These lesions were similar to those observed in the 3-month study.

Genetic Toxicology

Elmiron® was not mutagenic in S. typhimurium strains TA97, TA98, TA100, or TA1535 with or without induced hamster or rat liver S9 enzymes. No increases in the frequency of micronucleated polychromatic erythrocytes were seen in bone marrow cells of rats or mice administered Elmiron® by gavage three times at 24-hour intervals. No significant alterations in the frequency of micronucleated normochromatic erythrocytes were seen in peripheral blood samples from male or female mice administered Elmiron® for 3 months by gavage.

Conclusions

Under the conditions of these 2-year gavage studies, there was no evidence of carcinogenic activity of Elmiron® in male F344/N rats administered 14, 42, or 126 mg/kg or in female F344/N rats administered 28, 84, or 252 mg/kg. There was some evidence of carcinogenic activity of Elmiron® in male B6C3F1 mice based on increased incidences of liver hemangiosarcoma. The increased incidences of hepatocellular neoplasms in male mice may have been related to Elmiron® administration. There was some evidence of carcinogenic activity of Elmiron® in female B6C3F1 mice based on the increased incidences of liver hemangiosarcoma and hepatocellular neoplasms. The increased incidences of malignant lymphomas in female mice may have been related to Elmiron® administration.

Elmiron® administration caused increased incidences of nonneoplastic lesions (presence of vacuolated histiocytes) of the rectum, lung, mesenteric lymph node, and spleen (males) in rats and of the liver, rectum, mesenteric lymph node, and spleen in mice.

Studies

Summary of the 2-Year Carcinogenesis Studies of Elmiron®
 

Male
F344/N Rats

Female
F344/N Rats

Male
B6C3F1 Mice

Female
B6C3F1 Mice

Doses in deionized water by gavage

0, 14, 42, or 126 mg/kg

0, 28, 84, or 252 mg/kg

0, 56, 168, or 504 mg/kg

0, 56, 168, or 504 mg/kg

Body weights

Dosed groups similar to the vehicle control group

Dosed groups similar to the vehicle control group

Dosed groups similar to the vehicle control group

504 mg/kg group less than the vehicle control group

Survival rates

26/50, 29/50, 25/50, 28/50

30/50, 31/50, 28/50, 27/50

39/50, 40/50, 38/50, 30/50

37/50, 38/50, 37/50, 34/50

Nonneoplastic effects

Large intestine, rectum: myxomatous change (0/48, 1/48, 3/49, 25/45) infiltration cellular, histiocyte (0/48, 0/48, 0/49, 4/45)
Lung: alveolus, inflammation, chronic active, focal (0/50, 6/50, 11/50, 14/50)
Lymph node, mesenteric: infiltration cellular, histiocyte (1/50, 1/50, 18/50, 39/49)
Spleen: lymphohistiocytic hyperplasia (2/50, 2/50, 2/50, 8/50)

Large intestine, rectum: myxomatous change (0/46, 1/43, 12/44, 35/42) infiltration cellular, histiocyte (0/46, 0/43, 0/44, 18/42)
Lung: alveolus, inflammation, chronic active, focal (2/50, 25/50, 27/50, 34/50)
Lymph node, mesenteric: infiltration cellular, histiocyte (0/50, 3/50, 27/50, 42/49)

Liver: inflammation, chronic (11/50, 15/50, 23/50, 33/50)
Large intestine, rectum: inflammation, chronic active (0/49, 0/47, 1/46, 8/44); necrosis (0/49, 0/47, 0/46, 5/44); metaplasia, squamous (0/49, 0/47, 0/46, 5/44); infiltration cellular, histiocyte (0/49, 0/47, 0/46, 6/44); myxomatous change (0/49, 0/47, 0/46, 13/44)
Lymph node, mesenteric: infiltration cellular, histiocyte (0/48, 15/46, 34/45, 37/41)
Spleen: infiltration cellular, histiocyte (0/49, 1/50, 1/49, 23/49)

Liver: clear cell focus (0/50, 4/49, 1/50, 21/49)
Large intestine, rectum: inflammation, chronic active (0/45, 0/45, 2/44, 32/46); necrosis (0/45, 0/45, 1/44, 24/46); metaplasia, squamous (0/45, 0/45, 1/44, 26/46); infiltration cellular, histiocyte (0/45, 0/45, 2/44, 10/46); myxomatous change (0/45, 3/45, 21/44, 31/46)
Lymph node, mesenteric: infiltration cellular, histiocyte (0/47, 23/44, 35/42, 25/45)
Spleen: infiltration cellular, histiocyte (0/47, 3/48, 12/47, 28/46)

Neoplastic effects

None

None

Liver: hemangiosarcoma (2/50, 0/50, 4/50, 9/50)

Liver: hemangiosarcoma (1/50, 1/49, 1/50, 4/49); hepatocellular adenoma (7/50, 5/49, 4/50, 15/49); hepatocellular adenoma or carcinoma (10/50, 8/49, 9/50, 18/49)

Equivocal Findings

None

None

Liver: hepatocellular adenoma or carcinoma (23/50, 23/50, 26/50, 31/50)

All Organs: malignant lymphoma (7/50, 8/50, 6/50, 16/50)

Level of evidence of carcinogenic activity

No evidence

No evidence

Some evidence

Some evidence

Genetic Toxicology of Elmiron®
Assay Test System Results
Bacterial Mutagenicity Salmonella typhimurium gene mutations: Negative in strains TA97, TA98, TA100, and TA1535 with and without S9
Micronucleated erythrocytes Rat bone marrow in vivo: Negative
Micronucleated erythrocytes Mouse bone marrow in vivo: Negative
Micronucleated erythrocytes Mouse peripheral blood in vivo: Negative