Safety evaluation of certain food additives - ipcs inchem

ALKOXY-SUBSTITUTED ALLYLBENZENES 377
minor adducts were detected in liver tissue. A clear linear dose–response
relationship existed between total DNA adducts in rats treated with single oral doses
at 10 (3.2 total adducts/10 7 nucleotides), 100 (16.3/10 7 nucleotides), 250
(30.3/10 7 nucleotides) or 500 (72/10 7 nucleotides) mg/kg bw by gavage or in rats
administered five successive daily doses of 62.5 (43/10 7 nucleotides), 125 (67/10 7
nucleotides) or 250 (90/10 7 nucleotides) mg/kg bw by gavage (see Figure 4). There
was no difference between levels of DNA adducts of controls and those at the 1 mg/
kg bw dose level. The lack of DNA adducts at 1 mg/kg bw is consistent with the lack
of any detectable adducts in rats fed 1 mg methyl eugenol/kg bw per day in the diet
for 28 days (Ellis et al., 2006).
Figure 4. Dose–response relationship for safrole–DNA adduct formation in
rats (Daimon et al., 1998)
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DNA adducts/10 7 nucleotides
Female CD-1 mice were administered 0, 0.001, 0.01, 0.10, 1.0 or 10 mg of
safrole (corresponding to roughly 0.040–400 mg/kg bw) by intraperitoneal injection
and then sacrificed at various time intervals (0.5, 1, 2, 3, 7, 18 and 30 days). Groups
of animals (three per group) at the 10 mg dose were also sacrificed at 1, 3 and 6 h.
Determination of peak liver safrole–DNA adducts that occurred at 2 days showed a
linear (slope = 1) relationship between total relative adduct levels and concentration.
Relative adduct levels were in the range from 1000 adducts/10 8 nucleotides at the 10 mg dose (~400 mg/kg bw), with the
mid-dose of 0.10 mg (~4 mg/kg bw) showing 30–40 adducts/10 8 nucleotides at 2
days. Two of the four adducts detected were identified as N 2 -(trans-isosafrole-3yl)-2-deoxyguanosine
and N 2 -(safrole-1-yl)-2-deoxyguanosine. For doses of 0.01–
10 mg, total adduct levels peaked at day 2 and were present for the 30-day duration