Safety evaluation of certain food additives - ipcs inchem

ALKOXY-SUBSTITUTED ALLYLBENZENES 357
2.1.1 Absorption, distribution and elimination
(a) Rodents
Based on data in rodents, the pharmacokinetics of alkoxy-substituted
allylbenzenes are strongly dose dependent.
Male Sprague-Dawley rats were administered oral doses of [1-14C]safrole ranging from 0.63 to 750 mg/kg bw. Groups of three rats were sacrificed at intervals
up to 48 h, and plasma, liver and kidney tissues were collected. Plasma levels in
rats administered [1-14C]safrole at 4.2 mg/kg bw reached a maximum (2–3 μg/ml)
at 1–3 h, followed by a rapid decrease by 8 h. Unchanged [1-14C]safrole, which
accounted for a small fraction of the total radioactivity, reached a maximum at 1 h
and rapidly decreased to less than 2% (0.01 μg/ml) at 8 h. At 750 mg/kg bw, plasma
total radioactivity increased slightly up to 8 h and remained essentially constant up
to 24 h. At this dose level, unchanged safrole accounted for 50% of radioactivity up
to 24 h after dosing. Urinary elimination of total radioactivity was rapid at the lowest
dose of 0.63 mg/kg bw (88% at 24 h) compared with the elimination at 750 mg/kg
bw (25% at 24 h). These data correlated with total tissue radioactivity levels. At the
750 mg/kg bw dose, liver and kidney radioactivity levels remained high up to 48 h,
and the tissue to plasma radioactivity ratio and unchanged safrole levels were much
greater than recorded at the low dose of 4.2 mg/kg bw. Collection of bile from rats
given [1-14C]safrole at either 0.8 or 750 mg/kg bw showed that 20% of total
radioactivity was eliminated in the bile in 24 h at the low dose and only 3% at the
high dose (Benedetti et al., 1977).
Orally administered [ 14 C-methylene]myristicin and [ 14 C-methylene]safrole
have been studied in rats and mice (Casida et al., 1966; Kamienski & Casida, 1970;
Peele, 1976). Male Swiss-Webster mice were given radiolabelled safrole or
myristicin at 5 μmol/kg bw (approximately 0.60 mg/kg bw) by stomach tube, and
urine, faeces and carbon dioxide were collected at regular intervals over 48 h. Liver
and intestines were removed and analysed for radioactivity. After 48 h, 61% and
73% of the radioactivity were recovered from administered safrole and myristicin,
respectively, as expired carbon dioxide, presumably arising from Odemethylenation
metabolism. In addition, 23% and 3% of the radiolabelled safrole
and 15% and 3% of the radiolabelled myristicin were recovered from the urine and
faeces, respectively. Less than 2.5% of the radioactivity was detected in the liver
for either safrole or myristicin (Kamienski & Casida, 1970).
Female rats given a 50 mg/kg bw oral dose of 14 C-methoxy-labelled estragole
eliminated more than 71% in the first 24 h, with an additional 3.5% eliminated in the
following 24 h. Approximately 1% remained in the carcass at 48 h. Approximately
38% was eliminated in the urine, 31% in expired air and 1.3% in the faeces
(Zangouras, 1982). With oral administration to female Wistar rats of [ 14 C]estragole
at doses of 0.05, 5, 50, 500 or 1000 mg/kg bw, the majorities of the low doses (0.05–
50 mg/kg bw) were eliminated as 14 C-labelled carbon dioxide in expired air (average
of 55% on day 1 and 2.7% on day 2). Urinary elimination at these dose levels
accounted for, on average, 32.4% of the total radioactivity after 2 days. At the higher
dose levels (500 and 1000 mg/kg bw), elimination of radioactivity via expired air was