Safety evaluation of certain food additives - ipcs inchem

ALKOXY-SUBSTITUTED ALLYLBENZENES 367
At higher dose levels, the proportion of excreted 1-hydroxysafrole increases
(Borchert et al., 1973; Stillwell et al., 1974). Groups of rats received a single dose
of safrole at 300 mg/kg bw by intraperitoneal injection with and without bile duct
ligation or pretreatment with CYP inducers 3-methylcholanthrene or phenobarbital.
Without pretreatment, 1.6% and 1.1–1.3% of the dose were excreted in the urine
as either 1-hydroxysafrole or its conjugated metabolite by adult male and female
rats, respectively. A small amount of 3-hydroxyisosafrole was also detected in the
urine. Rats with bile duct ligation excreted 2.8% of 1-hydroxysafrole in the urine.
Adult and 4-week-old male rats showed significant increases (15–29%) in urinary
1-hydroxysafrole when pretreated with either 3-methylcholanthrene or
phenobarbital. When safrole as added to the diet of male rats at levels calculated
to provide an intake similar to that used in the intraperitoneal experiment, 5–10%
was excreted as 1-hydroxysafrole for the first 18 days, and an average of 3–4%
was excreted thereafter. With continuous administration of phenobarbital, the
urinary excretion of 1-hydroxysafrole averaged 7% of the safrole dietary level over
an 11-week period (Borchert et al., 1973). After administration of a single
intraperitoneal dose of safrole at 300 mg/kg bw to male guinea-pigs or hamsters,
the percentage of the dose excreted in the urine as 1-hyroxysafrole was 2.1–2.5%
and 3.5% without pretreatment, 2.7% and 0.9–1.0% after bile duct ligation, and
2.3–4.2% and 1.1% after phenobarbital treatment, respectively. In male and female
mice, 33% and 13–22%, respectively, of the administered dose were excreted in
the urine as 1-hydroxysafrole.
Urinary metabolites that were identified by GC/MS after a single dose of
safrole was administered by intraperitoneal injection to rats (50 mg/kg bw) or guineapigs
(125 mg/kg bw) included the O-demethylenation metabolite (1,2-dihydroxy-4allylbenzene),
1-hydroxysafrole, the hydrolysis metabolite of the epoxide (3,4methylenedioxy-1-(2,3-dihydroxypropyl)benzene),
the oxidized metabolite of the
epoxidized/hydrolysed product (2-hydroxy-3-(3,4-methylenedioxyphenyl)propanoic
acid and 3,4-methylenedioxybenzoylglycine) and the metabolite formed from
O-demethylenation and epoxidation/hydrolysis (1,2-dihydroxy-4-(2,3-dihydroxypropyl)benzene).
When safrole-2,3-epoxide was administered to rats and guineapigs,
the same epoxide-derived metabolites were observed in the urine of both
species. A small amount of unchanged safrole-2,3-epoxide was also found in the
urine of both species, indicating that the epoxide was sufficiently stable in vivo to
circulate in the blood and to be excreted in urine (Stillwell et al., 1974).
Specific pathogen-free male Sprague-Dawley rats were orally administered
myristicin dissolved in propylene glycol at 100 mg/kg bw. The urine was collected
for 24 h and treated with -glucuronidase, and the metabolites were analysed.
The O-demethylenation metabolite (5-methoxy-3,4-dihydroxyallylbenzene) and
1-hydroxymyristicin were found as the two primary metabolites present in the urine,
predominantly as glucuronic acid conjugates (Lee et al., 1998).
A dose of either estragole or safrole at 1.85 mmol/kg bw was administered
by intraperitoneal injection to 21-day-old mice, and the urine was analysed for
1-hydroxy metabolites 24 h later. The doses correspond to 274 mg estragole/kg bw
and 300 mg safrole/kg bw. Approximately 23% of the estragole and 12% of the
safrole were recovered as the corresponding 1-hydroxy metabolites from the urine