Safety evaluation of certain food additives - ipcs inchem

134 PHYTOSTEROLS, PHYTOSTANOLS AND THEIR ESTERS
groups (20 animals per group and sex) received 0, 0.36, 1.8 and 8.9% (w/w) of
VODPSE, which correspond to the same levels of phytostanols in the feed as with
WDPSE: 0, 0.2, 1 and 5%. Intake of WDPSE was 0, 0.17, 0.87 and 4.6 g/kg bw per
day for males and 0, 0.19, 0.98 and 5.1 g/kg bw per day for females (mean intakes
over the study period). Intake of VODPSE was 0, 0.19, 0.94 and 4.9 g/kg bw per
day for males and 0, 0.21, 1.1 and 5.5 g/kg bw per day for females (mean intakes
over the study period). This corresponds to intake levels of phytostanols for both
test materials of 0, 0.1, 0.5 and 2.7 g/kg bw per day for males and 0, 0.1, 0.6 and
3.0 g/kg bw per day for females. Parameters examined in this study included growth,
food and water consumption, food conversion efficiency, haematology, clinical
chemistry, urinalysis, plasma levels of fat-soluble vitamins, estrous cycle length,
faecal neutral steroid and bile acid levels, serum sterol and stanol levels, organ
weights, and gross and microscopic pathology. Daily clinical observations were
made, ophthalmoscopic examinations were performed in the last week of the study,
and gross and microscopic organ and tissue examinations were performed at
autopsy.
Absolute kidney weights in male, but not female, rats at the highest dose
for both WDPSE and VODPSE were slightly (8–9%), but significantly, reduced.
Absolute and relative liver weights were reduced in all treated males (change in
absolute liver weights 5–13%, statistically significant with the exception of the
VODPSE low-dose group). The only treatment-related finding upon histopathological
examination was a slightly more pronounced depletion of glycogen in all
treated male rats. In haematological examinations, female rats of the highest
VODPSE dose group showed significant shifts in the percentage of neutrophils
(increase) and lymphocytes (decrease). Thrombocyte count was significantly
increased in female rats of the high-dose WDPSE group. Plasma concentrations of
vitamins E (-tocopherol), D (25-hydroxy-cholecalciferol) and K1 (phylloquinone)
were decreased in both sexes at the highest dose of both test materials. Plasma
concentrations of vitamin A and -carotene were unaffected at all dietary
concentrations (Table 3). Clinical chemistry analysis showed the following
treatment-related changes: alkaline phosphatase plasma activity was elevated in
VODPSE high-dose females, albumin concentration was decreased in VODPSE
(low- and middle-dose) and WDPSE (high-dose) females, and total protein was
decreased in WDPSE males (middle- and high-dose) and females (high-dose)
(Jonker, 1998).
Based on the low degree of the changes in haematological and clinical
chemistry parameters and the absence of significant histopathological changes, the
Committee concluded that these findings were not of toxicological significance. The
most prominent effects observed in this study were changes of vitamin plasma
levels at dietary concentrations of 1.7% WDPSE and 1.8% VODPSE, which both
correspond to 1% phytostanols in food, equal to 0.5 g phytostanols/kg bw per day.
As discussed below, corresponding effects on concentrations of vitamin A, D or K
were not observed in human studies with up to 1 year of exposure. Therefore, the
Committee concluded that these effects were of unclear human relevance and are
not to be considered further in this evaluation.