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Rebaudioside A is one of several glycosides found in the leaves of Stevia rebaudiana (Bertoni) Bertoni (Compositae) stevia that has been identified as a potential sweetener. The present study (initiated in April 2006 and completed in October 2006) evaluated the safety of this sweetener when administered as a dietary admix at target exposure levels of 500, 1000, and 2000 mg/kg/day to Sprague-Dawley rats for 90 days. There were no treatment-related effects on the general condition and behavior of the animals as determined by clinical observations, functional observational battery, and locomotor activity assessments. Evaluation of clinical pathology parameters revealed no toxicologically relevant, treatment-related effects on hematology, serum chemistry, or urinalysis. Macroscopic and microscopic findings revealed no treatment-related effects on any organ evaluated. Lower mean body weight gains were noted in males in the 2000 mg/kg/day group throughout the study, which was considered to be test article related; however, given the small magnitude of the difference as compared to controls, this effect was not considered to be adverse. Results of this study clearly demonstrate that dietary administration of high concentrations of rebaudioside A for 90 consecutive days to Sprague-Dawley rats was not associated with any signs of toxicity.

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Rebaudioside D (Reb D) is one of the several glycosides found in the leaves of Stevia rebaudiana (Bertoni) Bertoni (Compositae) which has been identified as a potential sweetener. The metabolism of Reb A and Reb D was evaluated in various in vitro matrices (simulated gastrointestinal fluids, rat liver microsomes, and rat cecal contents) and through analysis of plasma collected from rats in a dietary toxicity study. Reb A and Reb D showed similar stability when exposed to simulated stomach and small intestine fluids, with susceptibility to hydrolytic degradation by enteric bacteria collected from the cecum. Incubations with rat liver microsomes indicated that neither compound is expected to be metabolized by the liver enzymes. Plasma concentrations of Reb D, Reb A, and/or the final hydrolysis product of each compound, free/conjugated steviol, were consistent between animals administered either Reb D or Reb A in the diet. A repeated exposure dietary toxicity study was conducted to compare the safety of Reb D, when administered at target exposure levels of 500, 1000, and 2000 mg/kg body weight (bw)/d to Sprague-Dawley rats for 28 days, to that of Reb A administered at a target exposure level of 2000 mg/kg bw/d. There were no treatment-related effects on the general condition and behavior of the animals and no toxicologically relevant, treatment-related effects on hematology, serum chemistry, or urinalysis. Macroscopic and microscopic findings revealed no treatment-related effects on any organ evaluated. Results were comparable between the group administered 2000 mg/kg/d Reb D and the group administered 2000 mg/kg/d Reb A.