Chronic oral toxicity of N-[N-[3-(3-hydroxy-4-methoxyphenyl) propyl]-α-aspartyl]-l-phenylalanine 1-methyl ester, monohydrate (advantame) in the dog

Advantame (N-[N-[3-(3-hydroxy-4-methoxyphenyl) propyl]-α-aspartyl]-l-phenylalanine 1-methyl ester, monohydrate), an N-substituted analog of aspartame, has been developed as a high-intensity sweetener. Groups of 4 dogs of each sex were treated at 0, 2000, 10,000, or 50,000 ppm of advantame in the diet for 52 weeks. Additional groups of 2 dogs/sex at the control, and mid- and high-dose groups were treated for 52 weeks followed by a 6-week recovery period. There was no effect of treatment on mortality, body weight, organ weights, food consumption, or the results of ophthalmological, electrocardiographic, haematological, clinical chemistry or urinalysis examinations. No histopathological changes were associated with advantame treatment. The NOAEL was considered to be 50,000 ppm, the highest concentration tested, which was equivalent to 2057 and 2139 mg/kg body weight/day in males, and females, respectively. The results of the study support the safety of advantame for use as a high-intensity sweetener.

► Advantame has been developed as a high intensity sweetener. ► Advantame was tested in a 1-year study oral toxicity study in beagle dogs. ► Advantame was administered in the diet at 0, 2000, 10,000, or 50,000 ppm. ► There were no toxicological significant effects noted at any dose level. ► The NOAEL was considered to be 50,000 ppm in the diet (∼2100 mg/kg bw/day).