Safety evaluation of certain food additives - ipcs inchem

398 ALKOXY-SUBSTITUTED ALLYLBENZENES
It has been reported for several chemicals (Poynter & Selway, 1991; Thake
et al., 1995) that chronic gastrin stimulation of the enterochromaffin-like
(neuroendocrine) cells results in the formation of neuroendocrine tumours of the
glandular stomach. Parietal cell cytotoxicity and atrophy of the fundic mucosa,
hypochlorhydria and hypergastrinaemia typically accompany the tumorigenic
response. In the case of methyl eugenol, it is likely that severe damage to the
glandular stomach resulted in achlorhydria, leading to chronic gastrinaemia, a
proliferative and ultimately carcinogenic stimulus to the gastric neuroendocrine cells
in the NTP bioassay. In a special study of rats dosed with 600 mg estragole/kg bw
per day for 30 days, serum gastrin concentration and stomach pH were increased
(National Toxicology Program, 2008). Chronic toxicity, probably related to the
toxicity of methyl eugenol, to the glandular stomach was very likely related to
anorexia and abnormal digestion and absorption, leading to malnutrition and further
organ damage and dysfunction. Gastric damage almost certainly significantly
affected the absorption, metabolism and excretion of methyl eugenol, leading to
hepatic, renal and possibly other organ damage. It is recommended that any reevaluation
of the toxicity to the glandular stomach consider administration of the test
substance microencapsulated in the feed.
The increase in kidney neoplasms only in male rats may be related to the
high incidence of nephropathy and increasing severity with dose in this sex.
(c) Safrole (No. 1792)
(i) Mice
In early studies with safrole, very high dose levels were used to induce
tumours. Hybrid 7-day-old (C57BL/6 × C3Hanf)F1 or (C57BL/6 × AKR)F1 mice
(18 males and 18 females per group) were administered safrole by stomach tube
for 21 days (total dose: 464 mg/kg bw per day), followed by dietary administration
(1112 mg/kg bw per day) for 82 weeks (total dose: 1265 mg/kg bw per day). Liver
cell tumours were found in 11/17 (65%) males and 16/16 (100%) females and in
3/17 (18%) males and 16/17 (94%) females of the two strains, respectively, versus
8/79 (11%) male and 0/87 (0%) female controls and 7/90 (8%) male and 1/82 (1%)
female controls, respectively (Borchert et al., 1973). In a 16-month study, groups of
35–40 male CD-1 mice were fed for 13 months with a diet containing 4000 or 5000
mg safrole/kg bw per day. Hepatocellular carcinomas were found in 23/87 (26%)
surviving animals compared with 7/70 (10%) in the controls (Borchert et al., 1973).
In a multipart study of the biological and enzyme histochemical changes in
the livers of safrole-dosed BALB/c mice, groups of 10 male mice maintained on diets
containing 0 or 4000 mg safrole/kg (calculated to provide an average daily intake
of 400 mg/kg bw) dissolved in corn oil were sacrificed at weeks 8, 16, 24, 36, 52
and 75. Histopathological liver alterations at 2–16 weeks included hypertrophy of
centrilobular hepatocytes, oval cell proliferation, fatty change in periportal
hepatocytes and atypical nuclei. At 24–75 weeks, foci of cellular alteration were
noted. At 36 and 52 weeks, hepatocellular adenomas occurred in 4/10 and 7/10
mice, respectively. At 75 weeks, adenomas were reported in 5/5 mice. Of the
adenomas, 0/10 tested grew upon subcutaneous transplantation into syngeneic
hosts. Hepatocellular carcinomas developed in 2/10 mice at 52 weeks and in