Safety evaluation of certain food additives - ipcs inchem

ALIPHATIC BRANCHED-CHAIN SATURATED AND UNSATURATED ALCOHOLS 317
were reported, but the majority of the methyl 2-methyl-2-propenoate–treated rats
were lethargic. Gait defects and hindlimb weakness were seen for about 10 min
following treatment, after which the rats recovered their normal gait completely.
Total lipids, phospholipids, cholesterol and triglycerides remained unchanged in
whole brain of methyl 2-methyl-2-propenoate–treated rats. Although total lipids
remained unchanged in sciatic nerve, the constituents were all affected in treated
rats: concentrations of cholesterol and triglycerides were statistically significantly
increased (by 26% and 65%, respectively), whereas the concentration of
phospholipids was statistically significantly decreased (by 17%). Some alterations
were observed in brain myelin lipids (decreases in triglycerides and cholesterol
content, increase in phospholipids content), but these changes were not statistically
significant when compared with control values. In sciatic nerve myelin, cholesterol
content was statistically significantly increased (42%), whereas triglycerides content
was (not statistically significantly) decreased (17%) in treated rats. Myelin protein
was stated to remain unaltered upon treatment (data not shown). The authors
suggested that the alterations in lipid composition, particularly in the cholesterol and
phospholipids in sciatic nerve, may be related to the peripheral neurotoxicity of
methyl 2-methyl-2-propenoate (Husain et al., 1989).
The Committee noted that there is a structural similarity between methyl
2-methyl-2-propenoate and ethyl methacrylate, a substance reported by the
European Food Safety Authority (2008) to be neurotoxic, based on morphological
alterations in sections of brain, spinal cord and sciatic nerve of rats treated with 0,
0.1, 0.2 and 0.5% ethyl methacrylate in their drinking-water for 60 days (equivalent
to 0, 50, 100 and 250 mg/kg bw per day, assuming a daily water consumption of
5% of the body weight) (Abou-Donia et al., 2000). Methyl 2-methyl-2-propenoate
and ethyl methacrylate share a common metabolite, methacrylic acid. Methacrylic
acid, however, is unlikely to be a neurotoxicant because it is more polar and
therefore considered less likely to cross the blood–brain barrier.
(c) Genotoxicity
Only for 2 of the 20 substances in this group have studies of genotoxicity in
vitro (Nos 1830 and 1834) and in vivo (No. 1834) been reported. The results of these
studies are summarized in Table 5 and described below. The Committee noted that
for methyl 2-methyl-2-propenoate, a number of studies not available for review were
evaluated earlier by the International Agency for Research on Cancer (1994) and
by the European Food Safety Authority (2008). These studies have been included
in Table 5 as well.
(i) In vitro
Hardly any evidence of mutagenicity was observed in standard or modified
(preincubation method) Ames assays when methyl 2-methyl-2-propenoate (No.
1834, up to 25 mg/plate) and (±)-dihydrofarnesol (No. 1830, up to 5000 μg/plate)
were incubated with Salmonella typhimurium strains TA97, TA97a, TA98, TA100,
TA102, TA104, TA1535, TA1537 and TA1538 and/or Escherichia coli strain
WP2uvrA with and without metabolic activation (Dupont, 1975, 1979a, 1979b; ICI,
1976a; Lijinsky & Andrews, 1980; Hatchitani et al., 1981, 1982; Waegemaekers &