Safety evaluation of certain food additives - ipcs inchem

316 ALIPHATIC BRANCHED-CHAIN SATURATED AND UNSATURATED ALCOHOLS
months (equivalent to 0, 400, 800, 1600 and 3200 mg/kg bw per day, assuming a
water consumption of 10% of the body weight). No effects were seen on survival
rate, food and water consumption or body weight. Seven rats in the 3.2% exposure
group and one rat in the 0.8% group showed partial atrophy of the lining epithelium
of the seminal vesicles. The seminal vesicles of the remaining rats showed normal
histology, as did the testes, epididymis and vas deferens of all rats. Testosterone
levels varied considerably between groups, both before and after treatment, and
observed changes were not consistent (Fakhouri et al., 2008a, 2008b).
(i) Neurotoxicity
Methyl 2-methyl-2-propenoate (No. 1834) has also been evaluated by the
European Chemicals Bureau within the framework of Council Regulation (EEC)
793/93 on the evaluation and control of the risks of “existing” substances (Hansen
et al., 2002) and by the European Food Safety Authority within the framework of
Commission Regulation (EC) No. 1565/2000 relating to the implications for human
health of flavouring substances used in or on foodstuffs (European Food Safety
Authority, 2008). Both evaluations mention an effect of methyl 2-methyl-
2-propenoate on the nervous system in humans exposed occupationally (via
inhalation and dermal routes) and in some short-term, but not in long-term,
inhalation studies with rats. There are only two studies available for evaluation
investigating the neurotoxic potential of methyl 2-methyl-2-propenoate after oral
administration. Both studies are summarized below.
In a 21-day oral study, two groups of 30 male Wistar rats were administered
either methyl 2-methyl-2-propenoate at 500 mg/kg bw per day or the vehicle (olive
oil) alone, presumably via gavage. Behavioural tests (spontaneous locomotor
activity, conditional avoidance response and aggressive behaviour) were carried
out on the 1st and 2nd days after treatment on batches of six rats from both groups.
From a separate batch of six rats from each group, brains were removed after
sacrifice and dissected into seven regions, followed by analysis of biogenic amines
(noradrenaline, dopamine and 5-hydroxytryptamine) in these regions. Three rats
treated with methyl 2-methyl-2-propenoate died (cause of death not reported). Body
weight and brain weight did not differ between treated rats and controls. Treated
rats had a shaggy appearance, were sluggish and showed changes in gait and rear
leg function for a brief period of 10 min after each treatment. Locomotor activity and
learning ability were also impaired, whereas aggressive behaviour was increased.
These changes were accompanied by changes in regional brain biogenic amine
levels. The authors remarked in this study that “no effect on behaviour was noted
at 100 and 200 mg/kg doses (unpublished data)” (Husain et al., 1985).
In a follow-up study, two groups of 20 male Wistar rats were administered
by gavage either methyl 2-methyl-2-propenoate at 500 mg/kg bw per day or the
vehicle (olive oil) alone for 21 consecutive days. Rats were monitored for body
weight gain (weekly), gross appearance and righting reflexes (daily) during the
course of the treatment. Twenty-four hours after the last treatment, animals were
sacrificed and brains and segments of sciatic nerves were removed, followed by
determination of lipid content (total lipids, triglycerides, phospholipids and
cholesterol) in brain, brain myelin, sciatic nerve and sciatic nerve myelin. No deaths