Safety evaluation of certain food additives - ipcs inchem

154 PHYTOSTEROLS, PHYTOSTANOLS AND THEIR ESTERS
In a prenatal developmental toxicity study, a mixture of phytostanol esters
was fed to female rats during gestation days 0–21 at concentrations of 0, 1.8, 4.4
and 8.8% phytostanol esters, which correspond to concentrations in the diet of 0,
1, 2.5 and 5% phytostanols. In the high-dose group, maternal body weights were
transiently reduced. No treatment-related effects with respect to malformations or
developmental toxicity were observed. The NOEL for developmental toxicity in this
study was 3.2 g phytostanols/kg bw per day.
4.1.6 Genotoxicity
All mixtures were inactive in assays for gene mutations in vitro in bacteria
and in mouse lymphoma cells and did not induce chromosomal aberrations in vitro
in mammalian cells. Phytosterol esters and a mixture of phytosterol esters and
phytostanol esters were inactive in assays for micronuclei induction in the bone
marrow of rodents in vivo. Phytosterol esters did not induce unscheduled DNA
synthesis in rat liver.
4.1.7 Estrogenicity
Phytosterols, a mixture of phytosterols and phytostanols, and phytostanols
were investigated for possible estrogenic activity. They did not reveal uterotrophic
activity in vivo in immature female rats. Phytosterols failed to show estrogenic
activity in vitro in the competitive estrogen receptor binding assay and the
recombinant yeast assay. Also, phytostanols did not induce proliferation of human
mammary adenocarcinoma cells.
4.2 Human studies
In several double-blinded, placebo-controlled human studies, where subjects
received diets containing added phytosterol esters or phytostanol esters,
reduced plasma concentrations of carotenoids and -tocopherol were noted. In
these studies, phytosterol and phytostanol esters were administered over periods
of 3–8 weeks. In most of these studies, no effects on (pro)vitamins were observable
when concentrations were lipid adjusted. In a study of 1-year duration, serum
concentrations of -carotene, -carotene, -tocopherol and lycopene were lower
after phytosterol ester consumption (1.7 g phytosterols/day as esters in fat spread)
in 185 healthy subjects, compared with controls. Decreases of lipid-adjusted carotene
and -carotene levels were statistically significantly higher in the exposed
group. Another 1-year study investigated the effects on carotenoid levels after
administration of sitostanol esters in fat spread (3.0 g -sitostanol/day). Absolute
plasma levels of -carotene, -carotene and -tocopherol were significantly
reduced. If normalized to cholesterol concentration, only reduction of the -carotene
plasma concentration was statistically significant. In some of the human studies, a
possible influence on vitamins A, D and K was also investigated. Plasma
concentrations of these vitamins were generally not affected by consumption of food
enriched with phytosterols, phytostanols or their esters. This indicates that the
marked effects on these vitamins observed in a 90-day study, where rats were fed