Safety evaluation of certain food additives - ipcs inchem

132 PHYTOSTEROLS, PHYTOSTANOLS AND THEIR ESTERS
premating exposure period. Reproductive parameters (e.g. number of pregnant
females, number of pups) and postnatal development (e.g. pup mortality, pup body
weights) as well as sex organ weights and sex hormone levels were monitored in
the F1 to F4 generations. The authors reported changes in testosterone plasma and
testicular levels and relative uterine weights in some generations. However,
changes were not consistent over generations, and, because of the single dose
design, no dose–response effect could be detected. No effects on number or
viability of pups or other overt signs of developmental toxicity were observed
(Ryökkynen et al., 2005).
2.3.4 Special studies on estrogenic activity
The estrogenic activity of MPSS-SE was assessed in the immature rat
uterotrophic assay. Doses of 0, 500, 1000 or 2500 mg MPSS-SE/kg bw were
administered via gavage twice daily to 10 immature (19 days old) female rats
(Crl:CD (SD)IGS BR VAF/Plus) for 4 consecutive days, yielding daily doses of 0,
1000, 2000 and 5000 mg/kg bw. Ethinyl estradiol was used as a positive control.
Body weight gains of animals in the 2000 and 5000 mg/kg bw per day groups were
significantly reduced. Absolute and relative uterine weights were unaffected in
treated animals compared with the negative control (Dearlove, 2000).
2.4 Toxicological studies: Phytostanol esters
A set of toxicity studies with phytostanol esters, conducted according to
recent guidelines and under GLP conditions, was submitted to the Committee. The
same data set was previously submitted to the USFDA together with human
intervention studies. Based on these data, phytostanol esters in the USA gained the
status of GRAS substances in 1999 (Food Master File 000626). 1 Results from these
toxicological studies were also published in peer-reviewed journals (Slesinski et al.,
1999; Turnbull et al., 1999a, 1999b, 1999c; Whittaker et al., 1999).
Two types of test samples were investigated in the toxicological studies
submitted: 1) wood-derived mixtures of phytostanol esters (WDPSE) (with a stanol
composition of about 94% -sitostanol and about 6% campestanol) and 2)
vegetable oil–derived mixtures of phytostanol esters (VODPSE) (with a stanol
composition of about 68% -sitostanol and about 32% campestanol). If not indicated
otherwise, studies discussed in this section were done with these two test materials.
According to the sponsor, this range of phytostanol ester compositions represents
the mixtures used commercially.
2.4.1 Acute toxicity
(a) Acute oral and dermal toxicity
Both WDPSE and VODPSE were investigated for acute oral and dermal
toxicity. Oral toxicity testing was carried out in compliance with OECD Test
1 Information on GRAS for phytostanol esters is available online at http://www.fda.gov/ohrms/
dockets/dockets/95s0316/rpt0054_01.pdf.