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Description of key information

Key value for chemical safety assessment

Carcinogenicity: via oral route

Endpoint conclusion
Dose descriptor:
10.2 mg/kg bw/day

Justification for classification or non-classification

In a 2 -year study to asses the carcinogenicity of Cure-rite 18, lesions of the kidney, ureter and urinary bladder were considered attributable to Cure-rite 18.

Additional information

This study was designed to assess the toxicity and carcinogenicity of Cure-Rite 18 when administered via dietary admixture 7 days per week for 24 to 30 months at dose levels of: 20, 60, 200, and 600 ppm. A control group was administered untreated feed. A total of 600 animals were randomly divided into five groups of 60 rats/sex/ group. After 12 months, 10 rats/sex/group were selected for an interim sacrifice. All surviving animals were sacrificed after 26 months of treatment. Body weights, food consumption and environmental conditions were monitored periodically. Selected hematology, clinical chemistry and urinalysis parameters were evaluated pretest and after 6, 12, 18 and 24 months. Complete gross necropsy examinations were performed on all animals; organs were weighed and organ/body weight ratios were calcuated at Months 12 and 26. Microscopic examinations were performed on selected tissues. Excluding animals killed accidentally or for reasons unrelated to test material administration, mortality occurred in 36 of 60 males in the 200 ppm group and 34 of 60 males in the 600 ppm group as compared to 27 of 60 males in the control group. Although these differences are not statistically significant,they do suggest a possible slight effect of Cure-Rite 18 on long-termsurvival in males. Mortality in females was comparable among groups. Temperature and humidity in the room housing these animals varied over the course of the study; the majority of values were within ranges specifiedin the protocol. Average monthly values were 68-73°F and 34-63% relative humidity. Room air changes ranged from 10.3 to 12.4 fresh air changes per hour.

A clear treatment-related increase in the presence of rales wasseen in animals receiving the highest dose level (600 ppm) of Cure-Rite 18,with almost 100% of the high-dose animals being affected. This first becameevident after approximately three months of treatment and persisted throughoutthe remainder of the study. The incidence of rales in animals at lower doseswas considered comparable to that seen in control animals. No other physicalabnormalities attributed to test material administration were seen.Body weights of high-dose males and females were statisticallysignificantly lower than weights of control animals throughout the study. Meanweights were within 10% of control values through Month 15 for the males andthrough Month 12 for the females but exceeded 10% thereafter. No consistentdifferences in food consumption values considered to be related to Cure-Rite 18 administration were apparent. Mean hemoglobin, hematocrit and total erythrocyte values for females in the high dose group were slightly lower than concurrent control means at Months 6, 12 and 18 {but not at Month 24}. The consistency of these slight decreases over the first 18 months of the study suggests a possible minimal effect of the test material on these parameters. However, most values for this group were within normal physiologic ranges. Evaluation of platelet counts, prothrombin times and total and differential leukocyte counts revealed no consistent dose-related differences considered attributable to administration of Cure-Rite 18. Except for isolated instances of increased blood urea nitrogen values in individual high-dose animals, clinical chemistry evaluations revealed no differences between control and treated groups considered attributable to Cure-Rite 18 administration. Urinalysis values of control and treated animals were considered to be comparable.Kidney weights and kidney/body weight ratios for high-dose males andfemales were higher than control values at both the 12 month and 26 month{terminal} necropsy intervals. Other organ weight changes occurred sporadically with no apparent relationship to test material administration. Gross and microscopic postmortem examinations revealed lesions in the organs of the urinary system (kidneys, ureters and urinary bladders) of high-dose animals which were attributed to administration of Cure-Rite 18. The

most significant finding was the presence of neoplasms {benign and malignant} of the urothelium of the kidneys, ureters and/or urinary bladders of 16 of the 60 males and 15 of the 60 females in this group. The only other urothelial neoplasm seen in this study was a benign urothelial papilloma of the renal pelvis of one of 60 male rats in the control group. Other microscopically observed abnormalities which occurred at a higher incidence in the high-dosegroup than in other groups included cortical or medullary mineralization, hydronephrosis, papillary necrosis and hemorrhage, blood in the kidneys,urothelial hyperplasia and blood in the urinary bladder. Grossly observed abnormalities of the urinary system seen at a high incidence in this group included enlargements, thickening or distention, surface irregularities, thepresence of blood in the lumen, grossly evident masses or nodules and dilation of the renal pelvis. 

Other neoplastic and non-neoplastic abnormalities occurred with comparable incidences in control and treated groups or were considered to be spontaneous occurrences unrelated to Cure-Rite 18 administration. There were no neoplastic or non-neoplastic changes in lower dose group (20, 60 or 200 ppm) were considered attributable to Cure-Rite 18 administration.

Carcinogenicity: via oral route (target organ): urogenital: kidneys; urogenital: urinary bladder; urogenital: other