A two-generation reproductive toxicity study of the high-intensity sweetener advantame in CD rats.

Rats received diets containing 0, 2000, 10,000, or 50,000 ppm advantame (N-[N-[3-(3-hydroxy-4-methoxyphenyl) propyl]-α-aspartyl]-L-phenylalanine 1-methyl ester, monohydrate) for 2 generations. F(0) animals (30/sex/group) were treated from 10 weeks before pairing. Males continued until week 16; females through gestation and lactation. Once weaned, F(1) animals (25/sex/group) continued receiving the same diet until F(2) pups were weaned. Mean advantame intakes from each of the diets were 164, 833, and 4410 mg/kg bw/day among F(0) males, and 204, 1036, and 5431 mg/kg bw/day among F(1) males. F(0) and F(1) females had comparable intakes up to lactation, when intakes increased (up to 8447 mg/kg bw/day from 50,000 ppm diet). No treatment-related effects on mortality, body weights, reproduction, litter observations, or postnatal offspring development were noted. Atypical coloration of the feces and cage liners seen with test diets was attributed to excretion of test material/metabolites in the feces and urine. Slightly higher food consumption was seen in F(0) and F(1) animals, especially males, receiving 50,000 ppm. However, these differences were considered to be a secondary response to the high levels of non-nutritive material in the diet. The no-observed-adverse-effect level for reproductive and developmental toxicity was considered to be 50,000 ppm, the highest dietary concentration tested.