Safety evaluation of certain food additives - ipcs inchem

PHYTOSTEROLS, PHYTOSTANOLS AND THEIR ESTERS 153
carotenoid and vitamin concentrations was also investigated in numerous studies
in humans (see below). In several of these studies (with doses of up to 3 g/person
per day), decreases in plasma concentrations of carotenoids (-carotene,
-carotene, lycopene) and of -tocopherol could be observed, but concentrations
of vitamins A, D and K were unaffected. This is in contrast to the effects on vitamin
concentrations observed in the study in rats mentioned above, which renders the
significance of these findings for humans unclear. The effects on plasma
concentrations of vitamins were not investigated in the 90-day study of toxicity with
phytosterol esters; thus, it remained unclear whether the effects observed with
phytostanol esters are unique to this mixture. Taking into consideration the fact that
the respective effects on vitamin concentrations were not observed in studies in
humans, the Committee concluded that these effects were not to be considered in
this evaluation.
4.1.4 Studies of reproductive toxicity with phytosterol ester mixtures
In a two-generation study of reproductive toxicity, rats were fed diets
containing phytosterol esters at concentrations of 0, 1.6, 3.2 and 8.1% (w/w), equal
to 0, 0.5–2.3, 0.9–4.5 and 2.3–12.6 g/kg bw per day, respectively (ranges of weekly
averages). The only treatment-related observations were slight, but significant,
decreases in food consumption, food efficiency and body weight gain of F0 and F1
males and females at the highest dose. The viability index of pups at PND 4 for F0
and F1 pups was slightly decreased, but no differences in pup mortality were
observed when analysed on a litter basis, and pup weights of both generations were
unaffected. The NOEL was 8.1% phytosterol esters in the diet, equal to 2.7 g/kg bw
per day expressed as phytosterols (average exposure during premating and
gestation for F0 and F1 females).
4.1.5 Studies of reproductive toxicity with phytostanol ester mixtures
In a two-generation study of reproductive toxicity, rats were given feed
containing a mixture of phytostanol esters at a concentration of 0, 1, 2.5 or 5%
phytostanols. Intakes of phytostanols in F0 and F1 were 0.6–1.3, 0.4–0.7 and
1.0–2.1 g/kg bw per day for the low dose group females during premating, gestation
and lactation, respectively (ranges of weekly averages). For the middle-dose
females, intake levels were 1.5–3.4, 1.0–1.7 and 2.5–5.6 g/kg bw per day during
premating, gestation and lactation, respectively. For high-dose females, intake
levels were 3.2–7.3, 2.1–3.6 and 5.2–11.1 g/kg bw per day during premating,
gestation and lactation, respectively. Intakes by F0 and F1 males during premating
were 0.5–1.4, 1.3–3.5 and 2.8–7.7 g/kg bw per day for low-, middle- and high-dose
animals, respectively. The only treatment-related effect observed was decreased
pup body weights in both generations at the highest dose at PND 14 and PND 21.
Based on these effects observed in the highest dose group (dietary concentration
5%, equal to a LOAEL of 8.1 g phytostanols/kg bw per day, calculated as the
average dose during lactation), the dietary concentration of 2.5% phytostanols was
considered the NOAEL for reproductive and developmental toxicity in this study,
which equals 4.1 g phytostanols/kg bw per day (average dose during lactation).