Safety evaluation of certain food additives - ipcs inchem

PHYTOSTEROLS, PHYTOSTANOLS AND THEIR ESTERS 137
per sex per dose group were selected at random and fed the same dietary
concentrations as their parents. The same procedure that was followed for the F1
group was followed for raising the F2 generation. Body weights of F0 and F1 animals,
food consumption, reproductive performance parameters (e.g. females pregnant,
fertility indices, implantation losses) and developmental toxicity parameters (e.g.
litter numbers, pup numbers, viability indices, sex ratio) were investigated.
Macroscopic postmortem examinations were performed on all animals of the F0 and
F1 generation, and selected organs of animals from the control and high-dose
groups were examined microscopically.
Food consumption was increased at the middle and high dose levels. Body
weights of female animals were not affected by treatment. No treatment-related
effects on reproductive performance were observed. Reproductive organ weights
were also unaffected. With respect to developmental toxicity parameters, the only
significant treatment-related effects concerned decreased pup body weights of both
the F0 and F1 generations in the high-dose group on PND 14 and PND 21
(Waalkens-Berendsen et al., 1999b) (Table 5). According to the authors of the study,
the reduced pup weight may have been caused by the reduction in the caloric value
of the diet. A NOAEL for reproductive and developmental toxicity of 4.38% VODPSE
(or 2.5% phytostanols) in the diet can be derived from this study. This dietary
concentration equals 1.8–9.8 g VODPSE/kg bw per day, corresponding to an intake
of 1.0–5.6 g phytostanols/kg bw per day. As reduced pup weights were not observed
before PND 14 and exposure levels were higher during lactation (2.5–5.6 g
phytostanols/kg bw per day) than during other exposure periods, the Committee
concluded that the NOAEL of this study can be set based on the exposure level
during lactation, which averaged 4.1 g phytostanols/kg bw per day. The LOAEL in
this study was concluded to be 8.1 g phytostanols/kg bw per day (average exposure
during lactation at the highest concentration tested).
This study contained five satellite groups (10 animals per sex per group),
which received VODPSE in the diet at levels of 0, 2, 2.5, 3 or 4% for 94 days. Plasma
levels of vitamins E and K1 were significantly decreased at all dose levels in both
sexes; those of vitamin A were significantly decreased at all dose levels in males
only. Vitamin D concentrations were decreased in males at 2.5–4% VODPSE.
A prenatal developmental toxicity study conducted according to OECD Test
Guideline 414 was performed with VODPSE. The test material was administered in
the diet to 28 mated female Wistar rats (HsdCpb:WU) per group during gestation
days 0–21 at concentrations of 0, 1.75, 4.38 and 8.76% phytostanol esters, which
correspond to concentrations in the diet of 0, 1, 2.5 and 5% phytostanols. End-points
investigated included, among others, numbers of animals pregnant, corpora lutea,
implantations, live and dead fetuses, early or late resorptions, and pre- or postimplantation
losses, fetal body weight, sex ratio, placental weight, external
appearance, and visceral and skeletal examinations for malformations, anomalies
or variations. In the high-dose group, maternal body weights were significantly
reduced (about 3%) on gestation days 7 and 14, but not on gestation day 21. No
significant observation related to treatment was made with respect to malformations
or for any of the developmental toxicity parameters (Waalkens-Berendsen, 1998).
A NOEL for developmental toxicity of 5% phytostanols in the diet can be derived
from this study, which is equal to 3.2 g phytostanols/kg bw per day, the average of
weekly intakes given by the authors for the exposure period from gestation days
0 to 21.