Safety evaluation of certain food additives - ipcs inchem

STEVIOL GLYCOSIDES (addendum) 197
animals were selected from each group. In the F1 and F2 generations, pre-weaning
righting, auditory and visual reflexes were measured. After termination of the
animals, all F0 and F1 adult animals were subject to a detailed examination of the
tissues. Any abnormal organs were recorded and tissues preserved for histological
examination, and many organs were weighed. Abnormal offspring were thoroughly
examined in a similar way to the adults. Food conversion efficiency, estrous cycle,
mating performance, fertility, gestation length, gestation index, pregnancy outcome,
general condition of offspring, litter size, survival, sex ratio, surface- and air-righting
reflexes, auditory startle responses, pupil reflex and reproductive capability were all
considered to be unaffected by treatment in the F0 and F1 generations. No treatmentrelated
deaths occurred, and macropathology and histopathology showed no
treatment-related effects in the F0, F1 or F2 generation. Slight differences in food
consumption and body weight gain were noted in the F0 and F1 generations, but
these were not consistent and therefore not considered to be treatment dependent.
The authors concluded that none of the effects observed were treatment related,
as they did not show a dose–response relationship. The authors identified a NOAEL
for reproductive performance and survival, growth and general condition of the
offspring of 25 000 mg/kg in the diet (Stamp, 2007b; Curry et al., 2008). Expressed
as steviol, this was equal to 674 mg/kg bw per day in males and 748 mg/kg bw per
day in females.
(b) Developmental toxicity
A number of studies were available on steviol-related material of unspecified
composition, for which the administered dose of steviol could not be identified
(Nunes & Pereira, 1988; Sincholle & Marcorelles, 1989; Aritajat et al., 2000;
Saenphet et al., 2006).
2.2.6 Special studies on glucose metabolism and insulin sensitivity
Groups of male Wistar rats (numbers not specified) received treatment to
simulate diabetes. One group received an intravenous injection of streptozotocin,
and one group received fructose-rich chow containing 60% fructose for 4 weeks. A
further control group received standard laboratory chow. Measurements of plasma
glucose and insulin were carried out in fructose-induced diabetic animals, with one
group receiving stevioside (purity 98.6%) in three daily doses of 0.5, 1 or 5 mg/kg
bw each by gavage and one group receiving just the vehicle with no stevioside
added. The doses expressed as steviol were 0.59, 1.17 and 5.85 mg/kg bw per day.
A non-diabetic group also received the vehicle with no stevioside. It is not clear
whether a non-diabetic group received stevioside. Plasma glucose levels were
measured at regular intervals following dosing and were found to be significantly
reduced by stevioside dosing, whether glucose was absorbed from the diet or
injected intraperitoneally. This occurred in a dose-dependent manner. Animals fed
60% fructose concomitantly with 0.5, 1 or 5 mg stevioside/kg bw per day were
studied for effects on insulin resistance. Body weights, plasma glucose and plasma
insulin levels of animals fed high-fructose chow were significantly higher than those
of animals consuming standard chow, but those of animals consuming high-fructose
chow and 5 mg stevioside/kg bw were significantly reduced compared with those