Dose–response assessment of nephrotoxicity from a twenty-eight-day combined-exposure to melamine and cyanuric acid in F344 rats

The adulteration of pet food with melamine and derivatives, including cyanuric acid, has been implicated in the kidney failure and death of cats and dogs in the USA and other countries. In a previous 7-day dietary study in F344 rats, we established a no-observed-adverse-effect level (NOAEL) for a co-exposure to melamine and cyanuric acid of 8.6mg/kg bw/day of each compound, and a benchmark dose lower confidence limit (BMDL) of 8.4–10.9mg/kg bw/day of each compound. To ascertain the role played by the duration of exposure, we treated F344 rats for 28days. Groups of male and female rats were fed diet containing 0 (control), 30, 60, 120, 180, 240, or 360ppm of both melamine and cyanuric acid. The lowest dose that produced histopathological alterations in the kidney was 120ppm, versus 229ppm in the 7-day study. Wet-mount analysis of kidney sections demonstrated the formation of melamine cyanurate spherulites in one male and two female rats at the 60ppm dose and in one female rat at the 30ppm dose, establishing a NOAEL of 2.1mg/kg bw/day for males and