Safety evaluation of certain food additives - ipcs inchem

ALKOXY-SUBSTITUTED ALLYLBENZENES 387
chemistry changes were reported in females. Measurement of organ weights on
day 29 revealed statistically significant increases in absolute and relative liver
weights and decreased thymus weights in the 500 mg/kg bw per day groups of both
sexes. Male rats showed statistically significant increases in absolute and relative
kidney weights at the 100 and 500 mg/kg bw per day dose levels and decreased
testis weights at the 500 mg/kg bw per day dose level. The histopathological
evaluation was consistent with organ weight data, in that degenerative and
regenerative changes were present in the kidneys at all dose levels and
degenerative changes were present in the testes at the highest dose level. The
authors noted that the renal effects were consistent with male rat nephropathy, a
condition specific to male rats. Therefore, the renal effects in the male rat were not
considered to be a toxicity of the test material that was relevant to humans. There
was no evidence of lesions related to the administration of the test material in female
rats. Other studies using myristicin or safrole have shown that the liver is the primary
target organ. Based on the alkoxy-substituted allylbenzene composition of nutmeg
oil, the alkoxy-substituted allylbenzene lowest-observed-adverse-effect level
(LOAEL) for liver effects in both sexes is approximately 41.5 mg/kg bw per day
(8.3% alkoxy-substituted allylbenzenes × 500 mg/kg bw per day), and the noobserved-adverse-effect
level (NOAEL) is 8.3 mg/kg bw per day. The LOAEL for
renal effects in males, in all probability due to the presence of the significant amount
of terpene hydrocarbons (80%) in nutmeg oil, is 16 mg/kg bw per day (80% of
20 mg/kg bw per day) (Wenk, 1992).
(b) Estragole (No. 1789)
(i) Mice
In a 93-day study with estragole, groups of 10 male and 10 female mice were
administered estragole (99% pure) at 0 (control), 37.5, 75, 150, 300 or 600 mg/kg
bw by gavage once per day, 5 days a week. Animals were housed five per cage
and fed ad libitum. Body weights and clinical observations were made on day 1,
weekly and at study termination (day 93). At termination, blood was taken for clinical
chemistry determinations and haematological evaluation, and body and organ
weights (heart, brain, liver, right kidney, right testes, lungs and thymus) were
recorded. Histopathological examination was performed on a wide variety of
tissues.
In male mice, survival was 100% in all dosed groups except at the 600 mg/
kg bw per day dose level. Statistically significant decreases in body weights were
recorded for the 300 and 600 mg/kg bw per day dosed groups compared with the
controls. Haematological examinations revealed decreases in erythrocytes and
increases in the number of leukocytes, lymphocytes, reticulocytes and platelets in
the 300 and 600 mg/kg bw per day dose groups. Organ weight changes included
increased relative (to body weight) liver weights and decreased body weights at 300
and 600 mg/kg bw per day. Histopathological examination revealed liver alterations
at 300 and 600 mg/kg bw per day, including oval cell hyperplasia, hepatocyte
hypertrophy and hepatocyte degeneration, all of which were described as being
minimal or mild in severity.