Safety evaluation of certain food additives - ipcs inchem

STEVIOL GLYCOSIDES (addendum) 211
to steviol is greater after administration of stevioside than after administration of
rebaudioside A in rats, whereas systemic exposure in humans is primarily to steviol
glucuronide and is similar for stevioside and rebaudioside A.
The older studies identified in the submission mainly involved material of
unknown composition or not meeting the present specification and were not
informative for the evaluation. The results of the new studies in animals were
consistent with the results of previous studies. In two new 13-week studies in rats
fed diets containing rebaudioside A, no adverse effects were observed at dietary
concentrations of up to 36 000 mg/kg and up to 50 000 mg/kg, respectively. The
latter concentration is considered to be a NOEL, equal to doses of 4161 mg/kg bw
per day in males and 4645 mg/kg bw per day in females, expressed as rebaudioside
A (1370 mg/kg bw per day in males and 1530 mg/kg bw per day in females,
expressed as steviol).
At its fifty-first meeting, the Committee reviewed a number of studies of reproductive
and developmental toxicity with stevioside and Stevia extracts and noted
that administration of stevioside (purity 90–96%) at doses of up to 2500 mg/kg bw
per day in hamsters and 3000 mg/kg bw per day in rats had no effect. The Committee
also noted that, although an aqueous infusion of S. rebaudiana administered
orally to female rats was reported to cause a severe, long-lasting reduction in
fertility, the contraceptive effect of Stevia was probably not due to stevioside.
Stevioside (purity 95.6%) had neither teratogenic nor embryotoxic effects at doses
of up to 1000 mg/kg bw per day in rats treated by gavage. The multigeneration study
of reproductive toxicity reviewed at the present meeting did not reveal adverse
effects with rebaudioside A at the highest dose tested, 2048–4066 mg/kg bw per
day (674–1339 mg/kg bw per day expressed as steviol). This supports the previous
conclusion of the Committee that administration of steviol glycosides was unlikely
to be associated with adverse reproductive effects.
The new studies in humans were designed to address the issues that the
Committee raised at its sixty-third meeting concerning evidence to demonstrate that
the putative pharmacological effects of steviol glycosides would not be found at the
exposure levels resulting from the proposed use as a food additive.
Steviol glycosides did not have adverse effects on diabetic control or on
blood pressure in patients with type 2 diabetes given 1000 mg of rebaudioside A
per day (mean dose of rebaudioside A, 10.2 mg/kg bw per day, equivalent to
3.4 mg/kg bw per day expressed as steviol) for 16 weeks. No studies were
conducted in patients with type 1 diabetes. However, the Committee at its present
meeting noted that the purported mechanism of action of steviol glycosides on
glucose homeostasis involves enhanced secretion of insulin from the pancreas
when there is impaired response to glucose stimulation. In contrast, type 1 diabetes
is characterized by a permanent inability of the pancreatic -cell to produce insulin,
and therefore effects of steviol glycosides were considered unlikely in this subgroup.
No clinically significant changes in blood pressure parameters were seen in
normotensive individuals or in a subset of these individuals with blood pressure
below the median who took rebaudioside A at a dose of 1000 mg/day (mean dose
of rebaudioside A, 14 mg/kg bw per day, or 4.6 mg/kg bw per day expressed as
steviol) for 4 weeks.