Safety evaluation of certain food additives - ipcs inchem

STEVIOL GLYCOSIDES (addendum) 185
relevant to the specifications. The Committee was also informed that results of an
ongoing toxicity testing programme, including clinical studies, would be available by
August 2007. The Committee considered that the newly available data did not raise
additional concerns regarding the safety of steviol glycosides, but that the ongoing
clinical studies, which more closely addressed the requirements specified at the
sixty-third meeting, would be essential for the evaluation. The Committee therefore
extended the temporary ADI of 0–2 mg/kg bw for steviol glycosides, expressed as
steviol, pending submission of the results of the ongoing studies by the end of 2008.
Also at the sixty-eighth meeting, the existing tentative specifications were
revised by requiring an assay of not less than 95% of the total of seven named
steviol glycosides, by deleting the assay requirement for the sum of stevioside and
rebaudioside A content to be not less than 70%, by adding pH as an identification
test, by increasing the limit for loss on drying and by establishing a limit for residual
solvent. The tentative designation was removed.
At its present meeting, the Committee considered a submission that comprised
a review of all the available information, including studies completed after
the sixty-eighth meeting and some older studies not highlighted in the previous
reviews by the Committee. The new studies included four toxicological studies with
rebaudioside A in experimental animals and clinical trials on the effects of steviol
glycosides on blood pressure in healthy volunteers with normal or low-normal blood
pressure and on glucose homeostasis in men and women with type 2 diabetes
mellitus. Additionally, a literature search was carried out to identify studies published
since the sixty-eighth meeting.
2. BIOLOGICAL DATA
2.1 Biochemical aspects
2.1.1 Absorption, distribution and excretion
Five male Sprague-Dawley rats were administered an intravenous injection
of 8 mg isosteviol/kg bw. Blood samples were taken immediately prior to
dosing and for up to 48 h after dosing. Urine samples were collected up to 24 h
following dosing. Plasma and urine samples were analysed for isosteviol using
liquid chromatography/tandem mass spectrometry (LC-MS/MS). Plasma levels
declined relatively quickly for 150 min, and then a much slower rate of clearance
was observed. Low renal excretion was observed, and a terminal half-life of
406 ± 31.7 min was calculated. This high terminal half-life was due to a large volume
of distribution (suggesting extensive distribution outside of the plasma) and a
relatively low rate of clearance (Bazargan et al., 2007).
In a study designed to compare the absorption, plasma profiles, metabolism
and excretion of [ 14 C]rebaudioside A, [ 14 C]stevioside and [ 14 C]steviol, single oral
gavage doses were administered to intact and bile duct–cannulated male and
female Sprague-Dawley rats. Doses of 5 mg [ 14 C]rebaudioside A/kg bw, 4.2 mg
[ 14 C]stevioside/kg bw and 1.6 mg [ 14 C]steviol/kg bw were administered for the
absorption, metabolism and excretion parts of the study; these doses were equal