Safety evaluation of certain food additives - ipcs inchem

ALIPHATIC BRANCHED-CHAIN SATURATED AND UNSATURATED ALCOHOLS 311
metabolic transformation. It is not exactly clear how these inhibitors act in the
citric acid cycle, but, according to the authors, this indicates that methyl
2-methyl-2-propenoate enters the citric acid cycle as pyruvate (Pantucek, 1969).
In an in vivo metabolism study involving methyl 2-methyl-2-propenoate, the
percentage of 14 CO2 was measured with respect to the amount of administered
radiolabelled methyl [ 14 C]2-methyl-2-propenoate via intragastric and intravenous
routes. Irrespective of the route of administration, the major metabolite detected
was 14 CO2. Other minor metabolites were identified as [ 14 C]methylmalonate,
[ 14 C]succinate and possibly [ 14 C]-hydroxyisobutyrate and [ 14 C]2-formylpropionate.
In addition, formation of 14 C-labelled normal physiological metabolites may be
expected owing to anabolism from 14 CO2 and from [ 14 C]acetate via the citric acid
cycle (see Figure 2) (Bratt & Hathway, 1977). According to Pantucek (1969), methyl
2-methyl-2-propenoate enters the citric acid cycle via the formation of pyruvate
rather than via the formation of succinyl coenzyme A (CoA). However, in both cases,
eventually methyl 2-methyl-2-propenoate will be fully oxidized in the citric acid cycle.
Figure 2. Proposed metabolism of methyl 2-methyl-2-propenoate
C
H 2
C
H 3
HO
O
HO
C
H 3
O
O
O CH 3
O
O CoA
O
O CoA
O
H 2
C
H 2
C
H 3
methyl 2-methyl-2-propenoate methacrylate methacryl-CoA
methyl malonyl
mutase
succinyl CoA
NADH
NAD +
CoA
2.3.2 Toxicological studies
(a) Acute toxicity
H
C
H 3
O
O
OH
methyl malonyl
semialdehyde
O
OH
NADH
C
H 3
CoA
To citric acid cycle
OH
NAD +
β-hydroxy-isobutyric
acid dehydrogenase
C
H 2
C
H 3
H
C
H 3
OH
O
CoA
O
H 2
O
OH
β-hydroxy-isobutyric acid
Oral median lethal dose (LD50) values have been reported for 11 of the
20 substances in this group, 1 of them being tested in mice, rats, guinea-pigs and