Safety evaluation of certain food additives - ipcs inchem

STEVIOL GLYCOSIDES (addendum) 203
glucose tolerance and 96.1 ± 2.2 kg for subjects with diabetes. The study was compliant
with ICH ethics guidelines and Good Clinical Practice guidelines. Participants
received either rebaudioside A (97.4% rebaudioside A, remaining content other
steviol glycosides) or placebo on two separate occasions, 1 week apart. Doses
were randomly assigned, with individuals receiving 500 mg, 750 mg or 1000 mg
rebaudioside A or placebo; all individuals received one dose of rebaudioside A
and one placebo dose. Based on the mean body weight of the test subjects at
the beginning of the study, the mean doses of rebaudioside A were 6.4, 9.5 and
12.7 mg/kg bw (2.1, 3.1 and 4.2 mg/kg bw expressed as steviol) for subjects with
normal glucose tolerance and 5.2, 7.8 and 10.4 mg/kg bw (1.7, 2.6 and 3.4 mg/kg
bw expressed as steviol) for those with type 2 diabetes mellitus. Blood pressure,
diet, physical activity, vital signs and adverse events were recorded at each clinic
visit. Blood samples were taken 30, 60, 90, 120, 150, 180, 210 and 240 min after
the start of each dose period in all subjects and 270, 300, 330 and 360 min after the
start of each dose period in those with normal glucose tolerance. Blood samples
were analysed for glucose, insulin, C-peptide and glucagon. No statistically
significant differences were found with any parameter at any dose in the test and
control groups in either of the subgroups. The authors concluded that 1000 mg of
rebaudioside A (equivalent to 329 mg steviol) did not have adverse effects on blood
pressure or glucose homeostasis in healthy individuals or individuals with type
2 diabetes mellitus (Maki et al., 2007).
A randomized double-blind placebo-controlled parallel group trial was
carried out in 100 healthy subjects with normal blood pressure (21 males and
79 females aged 18–73 years). The study was compliant with ICH ethics guidelines.
One group received 1000 mg rebaudioside A/day (97.4% purity, equivalent to
4.6 mg/kg bw per day expressed as steviol, based on the mean body weight of the
test subjects), and the other group received a placebo. All subjects consumed four
capsules daily, two with breakfast and two with the evening meal, for 4 weeks. Vital
signs and adverse events were recorded at each clinic visit, along with changes in
the laboratory assessments. Blood pressure was recorded at screening and weekly
during dosing, and assessments were taken when seated, supine and standing.
Twenty-four-hour ambulatory measurements were also taken in weeks 0 and 4. Two
individuals in the placebo group withdrew from the study during dosing, but their
reasons were unrelated to the treatment. Sixteen subjects receiving the test
compound experienced one or more adverse events, compared with 18 in the
placebo group. Only one event in the placebo group was classified as a serious
adverse event, and one event in each group was considered to be severe in
intensity. These events included back pain, headache, rhinitis and upper respiratory
tract infection. All events in the test compound group were considered to be
unrelated or unlikely to be related to the treatment, and one event in the placebo
group (pruritis) was considered to be possibly related to the placebo used. There
was no evidence of any adverse effects of treatment from the haematology,
biochemistry or urinalysis. At week 0, there were no significant differences between
groups in the changes from pre-meal to post-meal values in seated, supine or
standing blood pressures (systolic, diastolic or mean arterial pressure) or heart rate.
At week 4, there were small post-meal increases in some of the blood pressure
parameters in the rebaudioside A group, compared with small decreases in the