Safety evaluation of certain food additives - ipcs inchem

ALIPHATIC BRANCHED-CHAIN SATURATED AND UNSATURATED ALCOHOLS 315
significantly reduced throughout the study in the high-dose animals. Haematological
evaluations and urinalysis showed no treatment-related differences, and the only
statistically significant finding in organ weights was an increase in relative kidney
weight in females from the high-dose group. Histopathological examination showed
no treatment-related abnormalities or lesions (Borzelleca et al., 1964). The NOEL
was 160 mg/kg bw per day for male rats and 200 mg/kg bw per day for female rats,
the highest doses tested. The Committee noted, however, that the reporting was
limited and that the examinations performed were limited compared with current test
guidelines for long-term studies of toxicity.
The same authors conducted a 2-year study of long-term toxicity in dogs
(Borzelleca et al., 1964). Groups of two male and two female beagle dogs were
administered gelatin capsules with methyl 2-methyl-2-propenoate dissolved in corn
oil via their diet, at a dietary equivalent of 0, 10, 100 or 1000 mg/kg (equivalent to
0, 0.25, 2.5 and 25 mg/kg bw per day). The highest concentration was increased
to 1200 mg/kg at 5 weeks, to 1400 mg/kg at 7 weeks and to 1500 mg/kg at 9 weeks
(equivalent to 30, 35 and 37.5 mg/kg bw per day, respectively). The same
examinations as in the 2-year rat study were performed, except that the histopathological
examinations were performed on all groups of dogs.
No significant differences between treated and control animals were noted
in any of the parameters examined, with the exception of a statistically significantly
increased relative spleen weight in dogs (sex not specified) of the mid-dose group
(Borzelleca et al., 1964). The NOEL is 37.5 mg/kg bw per day, the highest dose
tested. The Committee noted, however, that compared with current test guidelines
for long-term studies of toxicity, the number of animals per group was low and the
reporting and examinations performed were limited.
In addition to the studies summarized in Table 4 and described above, some
special investigations with methyl 2-methyl-2-propenoate have been reported.
In a study investigating the relationship between chemically induced
forestomach cell proliferation and carcinogenesis, male F344/N rats were given
methyl 2-methyl-2-propenoate and the structurally related ethyl acrylate (No. 1351;
evaluated by the Committee at its sixty-third meeting; Annex 1, reference 173) by
gavage at a dose of 100 or 200 mg/kg bw per day, 5 days per week, for 2 weeks.
Histopathological examination of the forestomachs of these rats (8 per group for
methyl 2-methyl-2-propenoate and 12 per group for ethyl acrylate) revealed an
increase in the incidence of forestomach mucosal cell proliferation and
hyperkeratosis for ethyl acrylate, a known forestomach carcinogen following chronic
gavage administration. In contrast, for methyl 2-methyl-2-propenoate, which is not
a forestomach carcinogen following chronic inhalation administration, no such
findings were observed, suggesting that methyl 2-methyl-2-propenoate would
also not be a forestomach carcinogen following chronic gavage administration
(Ghanayem et al., 1986).
In a study investigating the effects of methyl 2-methyl-2-propenoate on
testosterone level and male genital tissues, Sprague-Dawley rats were administered
methyl 2-methyl-2-propenoate in their drinking-water at concentrations of 0%
(15 rats), 0.4% (15 rats), 0.8% (10 rats), 1.6% (10 rats) and 3.2% (10 rats) for 8