Safety evaluation of certain food additives - ipcs inchem

ALKOXY-SUBSTITUTED ALLYLBENZENES 435
these studies, concentrations at which UDS occurs coincide with hepatocellular
cytotoxicity.
In the sex-linked recessive lethal mutation assay in Drosophila
melanogaster, 0.5–5.0 mmol safrole/l administered in the food showed no indication
of genotoxicity (Gocke et al., 1981; Valencia & Houtchens, 1981; Fujikawa et al.,
1985; Zimmering et al., 1989; Batiste-Alentorn et al., 1995; Consuegra et al., 1996).
Sex-linked lethal mutation was observed when 0.34–6.75 mmol safrole/l was
administered to D. melanogaster in the feed (Vogel, 1985; Würgler et al., 1985;
Batiste-Alentorn et al., 1994).
The majority of in vivo micronucleus induction studies produced negative
results, with one equivocal result.
Groups of Swiss mice (two per sex per dose) were administered 0, 55, 110
or 220 mg safrole/kg bw at 0 and 24 h via intraperitoneal injection. At 30 h, the
animals were killed and femoral smears prepared. No increase in micronucleated
polychromatic erythrocytes (MPEs) was reported (Gocke et al., 1981). In another
study, female C57B1/B6 hybrid mice were administered 0.36 mg safrole/kg bw (80%
of LD50) at 0 and 24 h via intraperitoneal injection, and bone marrow was harvested
at 48, 72 and 96 h. Again, there was no increase in the level of MPEs when
compared with controls (Katz et al., 1981). Groups of male ICR mice (four per dose
per sacrifice time) were administered 0, 4.11, 8.23 or 16.5 mg safrole/kg bw at 0
and 24 h via intraperitoneal injection, and femoral bone marrow was harvested at
30 and 48 h. There was no increase in the incidence of MPEs (Kirkhart, 1981).
Groups of CD-1 mice (two per sex per dose) were administered 6.5, 13 or 26 mg
safrole/kg bw via intraperitoneal injection at 0 and 24 h, and femoral bone marrow
was harvested at 30 h. The number of MPEs was comparable with control values
(Tsuchimoto & Matter, 1981). Groups of B6C3F1 mice were administered safrole
at 80% of an LD50 value (not provided) via intraperitoneal injection at 0 and 24 h,
followed by harvesting of femoral bone marrow at 48, 72 and 96 h. One very weak
positive increase in the occurrence of MPEs was reported, but this could not be
confirmed in subsequent tests in the same laboratory using the same protocol. The
authors described safrole as non-clastogenic (Salamone et al., 1981).
There was no increase in the occurrence of micronucleated normochromatic
erythrocytes in peripheral blood samples of B6C3F1 mice (10 per sex per dose)
administered 37.5, 75, 150, 300 or 600 mg estragole/kg bw per day for 90 days via
corn oil gavage (National Toxicology Program, 2008).
No induction of SCEs was observed in the bone marrow of mice when
0.1–20 mg safrole/kg bw was administered via intraperitoneal injection (Paika et al.,
1981). At concentrations of 658, 888 and 1097 mg safrole/kg bw, an increase in the
occurrence of chromosomal aberrations in bone marrow was observed in rats
(Sharma et al., 1982).
2.3.3 Genotoxicity conclusions
The vast majority of the assays reported for this group of agents were
conducted in the early to mid-1980s. Beginning in the late 1980s, researchers began
studying test conditions (osmolality, ionic strength, low pH) that could cause an