Safety evaluation of certain food additives - ipcs inchem

402 ALKOXY-SUBSTITUTED ALLYLBENZENES
(iii) Dogs
Two male and two female dogs were orally administered safrole at 5 and
20 mg/kg bw per day for 6 years. No tumours were observed at either dose, but liver
changes were reported. At the higher dose, there was liver enlargement with a
nodular surface. At the lower dose, the liver changes were focal necrosis, bile duct
proliferation, fatty metamorphosis, hepatic cell atrophy and leukocytic infiltration
(Hagan et al., 1967).
(d) Elemicin-, myristicin- and apiole-related substances and their
metabolites
(i) Mice
Newborn male B6C3F1 mice (50–60 per group) were given four
intraperitoneal injections of one of the following test compounds: elemicin, myristicin,
apiole, anethole, dill apiole (2,3-dimethoxy-3,4-methylenedioxyallylbenzene), 1hydroxyelemicin
and 3-hydroxyanethole. The doses were administered on days 1,
8, 15 and 22 of life, with fractions of the total dose increasing with the age of the
mice corresponding to the ratio 1:2:4:12 (i.e. 0.25, 0.5, 1.0 and 3.0 mg), respectively.
A vehicle control group (trioctanoin) and an untreated group were also included in
the study. There was no evidence of increased incidence of hepatomas for mice
treated with any of the test compounds (Miller et al., 1983).
2.2.4 Reproductive and developmental toxicity
Studies of reproductive and developmental toxicity are available for a mixture
of alkoxy-substituted allylbenzenes present in nutmeg oil in three different species
at multiple dose levels (Morgareidge, 1972), and effects on reproductive organs
have been reported in 90-day studies on estragole in mice and rats (National
Toxicology Program, 2008).
In a study sponsored by the United States Food and Drug Administration
(FDA) (Morgareidge, 1972) that evaluated both reproductive and developmental
toxicity parameters, nutmeg oil containing a mixture of alkoxy-substituted
allylbenzenes (myristicin, safrole, elemicin and methyl eugenol; 10–20%) and
bicyclic terpene C10H16 hydrocarbons (-pinene, -pinene and sabinene; 80–90%)
was given to pregnant CD-1 mice, Wistar rats or golden hamsters.
In the mouse study, groups (20–21 per group) of pregnant female CD-1
outbred mice were given 0, 6, 26, 120 or 560 mg/kg bw of the test material (FDA
71-28) by gavage in corn oil on days 6 through 15 of gestation. A positive control
group received 150 mg aspirin/kg bw per day. Maternal body weights were recorded
on days 0, 6, 11, 15 and 17 of gestation. Females were observed daily for
appearance and behaviour. Food consumption and body weight were monitored to
eliminate any abnormalities that may be associated with anorexia in pregnant
females. On day 17, all dams were subjected to caesarean sections, and the
numbers of implantation sites, resorption sites, live fetuses and dead fetuses and
body weights of live pups were recorded. Gestation index, mortality, number of
implantation sites, number of corpora lutea, litter size and weights, sex and sex ratio