Safety evaluation of certain food additives - ipcs inchem

186 STEVIOL GLYCOSIDES (addendum)
when converted to steviol. In order to determine the plasma profile, three rats per
sex per substance were dosed and blood samples taken 0.5, 1, 4, 8, 12 and 24 h
after dosing. Peak plasma concentrations (Cmax) of the three test compounds were
recorded at 8, 4 and 0.5 h following dosing with [ 14 C]rebaudioside A, [ 14 C]stevioside
and [ 14 C]steviol, respectively. In the main study, 27 animals per sex per compound
were used, and blood samples were taken 0.25, 0.5, 1, 2, 4, 8, 24, 28 and 72 h after
dosing. Concentrations of radioactivity were found to decline between 15 min and
1 h following dosing with [ 14 C]rebaudioside A and [ 14 C]stevioside and then increased
from 1 to 2–8 h before declining again. The Cmax and the area under the plasma
concentration–time curve (AUC) of steviol were lower for rebaudioside A than for
stevioside, indicating slightly greater formation of steviol from stevioside than from
rebaudioside A. Following an oral dose of [ 14 C]steviol, the Cmax occurred in the first
15 min after administration and declined rapidly between 15 min and 1 h. A small
increase was observed at 2 h, followed by a further decline.
A single dose of test compound was administered to five intact rats per sex
and five bile duct–cannulated rats per sex. For intact rats, urine and faeces were
collected regularly up to 96 h after dosing. For each cannulated rat, bile, urine and
faeces were collected regularly up to 48 h after dosing. Of the total dose in intact
rats, 97–98% of [ 14 C]rebaudioside A and [ 14 C]stevioside and 90% of [ 14 C]steviol
were recovered in the faeces. For all compounds, the majority of the faecal
radioactivity was excreted in the first 24 h after dosing (64–89%), with a further
10–22% excreted in the faeces between 24 and 48 h. No radioactivity was detected
in the carcasses of the animals given any of the test compounds at 96 h after dosing.
In cannulated rats, 70–80% of the [ 14 C]rebaudioside A and [ 14 C]stevioside dosage
was excreted in the bile within 24 h. The remaining dose was excreted in the faeces
(21–30%) and in the urine and cage washings (1–2%). The biliary excretion of
steviol was more rapid, with 50–70% of the dose eliminated in the first 3 h after
dosing. Only 1–2% of the dose was excreted in the faeces, with urine and cage
washings accounting for another 1% (Roberts & Renwick, 2008).
A randomized double-blind cross-over study was carried out to assess
the comparative pharmacokinetics of steviol and steviol glucuronide following
single oral doses of rebaudioside A (purity 98.7%) and stevioside (purity 96.6%) in
eight healthy adult male volunteers (aged 18–45 years, mean age 28 years; mean
body mass index [BMI] 23.8 kg/m 2 ). Doses were equivalent to a steviol dose of
1.65 mg/kg bw, with the doses of rebaudioside A and stevioside being 5 mg/kg bw
and 4.2 mg/kg bw, respectively. Physical examinations were carried out before
and after dosing, and blood, urine and faeces samples were collected daily for 72 h
after dosing. Steviol glucuronide appeared in the plasma of all subjects after administration
of rebaudioside A or stevioside, with median times taken to reach the
maximum concentration (Tmax) of 12 and 8 h, respectively, and was eliminated from
the plasma with a half-life of 14 h for both compounds. The AUC for steviol
glucuronide was similar following administration of rebaudioside A and stevioside.
Steviol glucuronide was excreted primarily in the urine during the 72-h collection
period, accounting for 59% and 62% of the rebaudioside A and stevioside doses,
respectively. No steviol glucuronide was detected in the faeces. Steviol was
detected in the plasma of only one subject following administration of both