Safety evaluation of certain food additives - ipcs inchem

PHYTOSTEROLS, PHYTOSTANOLS AND THEIR ESTERS 127
Table 1 (contd)
End-point Test
system
Unscheduled
DNA synthesis
Micronucleus
induction
2.2.3 Reproductive toxicity
(a) Rats
Male rats,
liver
Male
mice,
blood
Test material Concentration/
dose
Phytosterol
esters c
Triols and
epoxides of a
mixture of sitosterol
and
campesterol
800 or 2000 mg/
kg bw
Epoxides: up to
67 mg/kg bw;
triols: up to 9.4
mg/kg bw
Result Reference
Negative Wolfreys &
Hepburn
(2002)
Negative Abramsson-
Zetterberg
et al. (2007)
a Phytosterol composition: 26.7% campesterol, 17.7% stigmasterol, 51% -sitosterol.
b With and without metabolic activation (S9 mix from Aroclor 1254–induced rat liver).
c Phytosterol composition: 28.1% campesterol, 18.7% stigmasterol, 45.5% -sitosterol.
In a reproductive toxicity study performed according to OECD Test Guideline
416 in accordance with GLP, 28 Wistar outbred (Crl:(WI)WU BR) rats per dose
and sex were fed, over two successive generations, diets containing phytosterol
esters at levels 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 phytosterol esters/kg bw per day, respectively (ranges of weekly
averages), depending on the administration period. Females were treated during a
10-week premating period, the mating period (up to 3 weeks) and gestation until
weaning (postnatal day [PND] 21). Males were treated only during the premating
period. Twenty-eight male and female pups per group were selected randomly from
litters produced to form the F1 generation, which was treated analogously. A
wide range of reproductive and developmental parameters, including sexual
maturation parameters and estrous cycle length, were investigated. Macroscopic
and microscopic examinations included a histological examination of selected
organs from F1 and F2 weanlings and from F0 and F1 parental animals. Reproductive
performance was determined by measuring precoital time, mating index, male and
female fertility index, female fecundity index, gestation index and time, and postimplantation
losses. Developmental toxicity was assessed by measuring number of
pups, the live birth index, pup mortality and viability, and the sex ratio. Clinical
observations did not reveal any unusual findings. Fertility was unaffected. Food
consumption, food efficiency and body weight gain of male and female animals of
the high-dose F0 and F1 groups were slightly, but significantly, decreased. There
were no treatment-related histopathological effects on organs examined. Pup
weights of both generations were unaffected (data shown in the test report only).
The viability index at day 4 for the pups from both the F0 (all dose levels) and the
F1 (two highest doses) generations was slightly, but significantly, decreased.