Title: Alternative Sweeteners

140 Stargel et al.
study strains included the Sprague-Dawley–derived CD ® rat, the CD-1 mouse,
the beagle dog, and the New Zealand white rabbit. Microscopic examinations
were done on tissues from all animals at all doses in all key toxicity studies. In
addition, standard and supplemental parameters were evaluated for evidence of
immunotoxicity or neurotoxicity. Findings in these studies are summarized in
the following.
C. General Toxicology and Carcinogenicity
The safety of neotame was established in dietary studies in rats, mice, and dogs.
These studies used a wide range of dose levels for neotame. Test species evaluations
included clinical observations, body weight, body weight gain, food and
water consumption, hematology, clinical chemistry, urinalysis parameters, ophthalmologic
examinations, electrocardiograms (in dogs), and assessments of
gross necropsy findings and microscopic evaluations.
Neotame was well-tolerated in all subchronic studies and was without adverse
effects even at high doses (3000 mg/kg/day in the rat, 8000 mg/kg/day in
the mouse, and 1200 mg/kg/day in the dog). There was no test article-related
mortality, and there were no changes in appearance or behavior at any time during
these subchronic studies at dietary doses 24,000 to 160,000 times the anticipated
90th percentile level of human consumption.
Food refusal or spillage was observed when neotame was present at higher
concentrations in the diet. Diets containing extremely high levels of neotame
(providing 1200 to 8000 mg/kg/day) were immediately disliked and partially
rejected. The immediate decrease in food consumption generally followed by
accommodation to near control values suggests poor palatability of the diet. Furthermore,
the effect of neotame on food consumption was a function of the concentration
of neotame in food and not the dosage of neotame consumed. For
example, dogs consumed a higher dosage of neotame when offered a diet containing
3.5% neotame than when offered a diet containing 5% neotame. Special
dietary preference studies in rats confirmed that sufficiently high concentrations
of neotame reduced palatability of diet. Poor palatability of neotame-containing
diet was observed, particularly in rats and mice, as small but consistent reductions
in food consumption as animals approached the body weight plateau of adulthood.
One-year dietary studies were done in rats and dogs; 2-year carcinogenicity
studies were done in rats and mice. In rats, both the 1-year and carcinogenicity
studies included parental exposure before mating and in utero exposures for offspring;
thus, animals used in safety studies were exposed to neotame from conception,
during prenatal and postnatal development, and throughout the duration
of the studies. The highest maximum tolerated doses (MTD) in the 1-year studies
were 1000 mg/kg/day in rats and 800 mg/kg/day in dogs. There was no target