Evaluation of the teratogenic potential of N-[N-[3-(3-hydroxy-4-methoxyphenyl) propyl]-r-aspartyl]-Lphenylalanine 1-methyl ester, monohydrate (advantame) in the rat and rabbit

To assess its teratogenic potential, advantame (N-[fusion_builder_container hundred_percent=”yes” overflow=”visible”][fusion_builder_row][fusion_builder_column type=”1_1″ background_position=”left top” background_color=”” border_size=”” border_color=”” border_style=”solid” spacing=”yes” background_image=”” background_repeat=”no-repeat” padding=”” margin_top=”0px” margin_bottom=”0px” class=”” id=”” animation_type=”” animation_speed=”0.3″ animation_direction=”left” hide_on_mobile=”no” center_content=”no” min_height=”none”][N-[3-(3-hydroxy-4-methoxyphenyl)propyl]-R-aspartyl]-L-phenylalanine 1-Me ester, monohydrate) was administered to mated rats (22/group) in the diet at 0, 5000, 15,000, and 50,000 ppm (providing approximately 465, 1418, and 4828 mg/kg body weight/day), and to mated rabbits (24/group) via oral gavage at 0, 500, 1000, and 2000 mg/kg body wt./day throughout gestation. Shortly before delivery (rats: day 20; rabbits: day 29), animals were killed and subjected to a detailed necropsy. Foetuses were examined for external, visceral, and skeletal alterations. Atypical coloration of the faeces and cage liners seen with test diets in both rats and rabbits was attributed to excretion of test material/metabolites in the faeces and urine. Advantame had no adverse effect on rat offspring survival or development. The no-observed-adverse-effect level (NOAEL) for both maternal and developmental toxicity in rats was 50,000 ppm, the highest dietary concentration tested. Due to adverse effects associated with reduced food intake and faecal output, approximately 20% of mated rabbits receiving 2000 mg/kg body weight/day and 1 animal at 1000 mg/kg body weight/day had to be terminated before scheduled necropsy. A NOAEL of 500 mg/kg body weight/day was established for maternal toxicity in rabbits. No teratogenic effects were observed in any animals, and based on a slightly increased incidence of foetal deaths at 2000 mg/kg body weight/day, a finding that was considered to be indirectly related to advantame treatment, 1000 mg/kg body weight/day was considered the NOAEL for developmental toxicity.

Authors: Otabe, A.; Fujieda, T.; Masuyama, T. ;Full Source: Food and Chemical Toxicology 2011, 49(Suppl. 1), S60-S69 (Eng) ;