Safety evaluation of certain food additives - ipcs inchem

378 ALKOXY-SUBSTITUTED ALLYLBENZENES
of the study. The persistence of adducts at 0.001 mg was not assessed. Evidence
of UDS occurred only at 2, 3 and 7 days for the 10 mg dose (Gupta et al., 1993).
In experiments using labelled 1-hydroxyestragole, adult female CD-1 mice
(mean weight 35 g) were given 12 μmol of [2,3- 3 H]1-hydroxyestragole per mouse
(58 mg/kg bw) by intraperitoneal injection in trioctanoin, and DNA adduct formation
was monitored over 20 days post-exposure. Similarly, 9-day-old male or female
B6C3F1 mice (mean weight 6 g) were injected intraperitoneally with a dose of
0.5 μmol (14 mg/kg bw) of labelled estragole and sacrificed after 23 h. Three
adducts were formed by reaction on the exocyclic amino group (N 2 ) of
deoxyguanosine with estragole at either the 1 or 3 position (cis or trans isomers).
An additional adduct was formed by the reaction of the 3 position of estragole and
the N 6 position of deoxyadenosine. Unlike adducts of aromatic amines (e.g. Nacetyl-2-aminofluorene),
which persist at near maximum levels of binding for
several weeks, the three adducts of estragole–deoxyribonucleoside were removed
rapidly from mouse liver DNA. Time course quantification of DNA adducts indicated
a biphasic loss curve, with a sharp decline in one of the two major 1hydroxyestragole
adducts by day 1, followed by relatively constant levels of liver
DNA adducts from day 3 to day 20. This suggests that at least one of the adducts
undergoes excision repair. Dose levels of the 1-hydroxyestragole in the adult
female and pre-weanling male and female mice were approximately 58 mg/kg bw
and 14 mg/kg bw, respectively (Phillips et al., 1981).
Adult female CD-1 mice (mean weight 25 g) received intraperitoneal
injections of 2 or 10 mg estragole, methyl eugenol, safrole, apiole, elemicin,
myristicin, anethole, allylbenzene or isosafrole, and liver DNA samples were
collected 24 h later. The dose levels in this study were equivalent to 100 or 500 mg/
kg bw of each test substance. 32 P-Postlabelling analysis revealed that safrole,
methyl eugenol and estragole showed higher DNA-binding activities relative to the
other alkoxy-substituted allylbenzene substances examined in the study. Similar to
the previous experiment, a rapid drop in total adduct formation occurred within 7
days after dosing and was followed by a relatively constant level over the next 140
days, suggesting that DNA repair processes were operative shortly after dosing
(Randerath et al., 1984).
In a related 32 P-postlabelling experiment (Phillips et al., 1984), newborn male
B6C3F1 mice received intraperitoneal injections of 0.25, 0.5, 1.0 and 3.0 μmol of
the same series of alkoxy-substituted allylbenzenes on days 1, 8, 15 and 22 after
birth, respectively. Dose levels of 1-hydroxyestragole and 1-hydroxysafrole were
estimated to be approximately 27 and 35 mg/kg bw, respectively. Mice were
terminated on days 23, 29 and 43, and their liver DNA was isolated and analysed.
The highest DNA adduct levels were measured for methyl eugenol (72.7 pmol/mg
DNA), estragole (30 pmol/mg DNA) and safrole (17.5 pmol/mg DNA), and a
significant (P < 0.05) amount of adduct was detected at 43 days. Lower levels of
DNA binding by myristicin (7.8 pmol/mg DNA) and elemicin (3.7 pmol/mg DNA) were
also found; in the former case, the adducts were less persistent. Very low levels of
DNA adducts (