Title: Alternative Sweeteners

Neotame 141
organ toxicity in chronic studies in either the rat or dog. In addition, there was
no evidence of target organ toxicity or carcinogenicity when neotame was administered
for 2 years to rats with in utero exposure at dosages up to 1000 mg/kg/
day, or to mice at dosages up to 4000 mg/kg/day. All nonneoplastic findings
were consistent with those expected of aging rodents.
The no-observed adverse effect levels (NOAELs) were the highest doses
tested in definitive toxicology studies in rats, mice, and dogs. On the basis of the
results of the chronic toxicity and carcinogenicity studies, the NOAEL is at least
1000 mg/kg body weight/day in rats, 4000 mg/kg body weight/day in mice, and
800 mg/kg body weight/day in dogs. Given that consumer exposure to neotame
even at the 90th percentile is so small, margins of safety based on each of these
species are tens of thousands times greater than projected human exposure.
D. Reproduction and Teratology
Sprague-Dawley rats were fed doses of neotame up to 1000 mg/kg for 10 weeks
in males and 4 weeks in females before pairing. Dosing continued throughout
pairing, gestation, and lactation to weaning of the F1 offspring at day 21 of age.
At approximately 4 weeks of age, animals were selected for the F1 generation
and were exposed for 10 more weeks before being bred to produce the F2 generation.
The F2 generation was raised to day 21. Consumption of high doses of
dietary neotame by animals through two successive generations did not result in
any effects on reproductive performance, postnatal development, or development
of the embryo or fetus.
In a teratology study, female Sprague-Dawley rats were fed a neotamecontaining
diet to provide doses up to 1000 mg/kg/day for 4 weeks before pairing
and throughout gestation until day 20 after mating. There were no effects on
clinical signs, food consumption, body weights, or weight gains or any evidence
of treatment-related effects on the dams or on their litters. Examination of the
fetuses for external, visceral, and skeletal abnormalities revealed no fetotoxic or
teratogenic effects.
No teratogenicity occurred in rabbits dosed with neotame up to 500 mg/
kg/day by oral gavage between days 6 and 19 after mating. There were no test
article–related clinical observations or postmortem effects in dams or in litters.
There were no teratogenic effects of neotame on fetal examination. The rat and
rabbit reproductive and teratology studies demonstrated that neotame even at high
doses had no effect on reproduction or development of the embryo or fetus.
E. Genetic Toxicology
Neotame was not mutagenic in the Ames assay in five strains of Salmonella
typhimurium and a strain of Escherichia coli when tested at concentrations of up