Urolithiasis and bladder carcinogenicity of melamine in rodents.
Melamine (2,4,6-triamino-s-triazine) was administered in the diet to F344 rats or B6C3F1 mice for 13 weeks (subchronic) or for 103 weeks (chronic) to determine its toxicologic profile, including carcinogenic potential in the chronic study. The dose levels of melamine in the subchronic studies ranged from 750 to 18,000 ppm for rats, and 6000 to 18,000 ppm for mice. In the chronic studies the dose levels of melamine were 2250 or 4500 ppm for male rats and mice of each sex, and 4500 or 9000 ppm for female rats. In these studies, compound-related lesions were observed in the urinary tract. Most noticeable was the development of uroliths (urinary bladder stones), which occurred at a greater frequency in males than females of either species. Increased incidences of urinary bladder stones and hyperplasia of the bladder epithelium were observed at 13 weeks in male rats fed diets containing melamine. In the chronic study, transitional-cell carcinomas in the urinary bladder of male rats occurred at a significantly (p less than or equal to 0.016) higher incidence in the 4500 ppm (high dose) group (8/49) than in the controls (0/45). Seven of the eight male rats with transitional-cell carcinomas of the urinary bladder also had bladder stones. There was a statistically significant association (p less than or equal to 0.001) between bladder stones and bladder tumors in male rats fed melamine (4500 ppm). Urinary bladder tumors were not observed in the low-dose (2250 ppm) male rat group, while bladder stones were observed in one rat in this group. In the female rat chronic study, chronic inflammation of the kidney was observed at an increased incidence (relative to controls) in both the low (4500 ppm) and high (9000 ppm) dose groups. Ulceration of the bladder epithelium was observed in male and female mice in the 13-week study. The distribution of these toxic lesions was not correlated statistically with the distribution of urinary bladder stones. Acute and chronic inflammation and epithelial hyperplasia of the urinary bladder were found in increased incidence in dosed male mice (2250 and 4500 ppm) in the chronic study. In addition, a high incidence of urinary bladder stones was observed in dosed male mice relative to controls. However, there was no evidence of bladder tumor development in this species.
D000284:Administration, Oral; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D002273:Carcinogens / Q000633:toxicity*; D002295:Carcinoma, Transitional Cell / Q000139:chemically induced* / Q000473:pathology; D005260:Female; D007928:Lethal Dose 50; D008297:Male; D051379:Mice; D051381:Rats; D011916:Rats, Inbred F344; D014227:Triazines / Q000633:toxicity*; D001749:Urinary Bladder Neoplasms / Q000139:chemically induced* / Q000473:pathology; D014545:Urinary Calculi / Q000139:chemically induced*
D002273:Carcinogens; D014227:Triazines; C011907:melamine