Safety evaluation of certain food additives - ipcs inchem

542 HYDROXY- AND ALKOXY-SUBSTITUTED BENZYL DERIVATIVES (addendum)
2.2 Additional considerations on intake
There is no additional information on intake.
2.3 Biological data
2.3.1 Biochemical data: hydrolysis, absorption, distribution, metabolism and
excretion
At low pH similar to that found in the stomach, vanillin 3-(l-menthoxy)propane-1,2-diol
acetal (No. 1879) readily hydrolyses. In a hydrolysis study,
12–39 mmol vanillin 3-(l-menthoxy)propane-1,2-diol acetal/l underwent 91%
hydrolysis at pH 2 within 45 min. At pH 3, approximately 86% of vanillin 3-(lmenthoxy)propane-1,2-diol
acetal hydrolysed within 90 min. At pH 4, approximately
92% of the acetal hydrolysed within 8 h. At pH 5, approximately 12% of the flavouring
agent hydrolysed within 8 h (Reitz, 1995).
Under acidic conditions (pH 2.6), vanillin propylene glycol acetal (No. 1882)
began to hydrolyse immediately, with 92% hydrolysed within 2 h. At pH 1.8,
approximately 90% of vanillin propylene glycol acetal hydrolysed immediately, and
93% hydrolysed within 5 min (Bennett, 1997).
In a disposition study, Wistar rats (three per sex per group) were
administered single doses of sodium [ 14C]4-methoxybenzoyloxyacetate (No. 1880)
either intravenously (50 mg/kg bw) or orally via gavage (500 mg/kg bw). There was
a second group of rats receiving the test material via the oral route that were
pretreated with 1% sodium 4-methoxybenzoyloxyacetate in the diet for 2 weeks
prior to receiving the sodium [ 14C]4-methoxybenzoyloxyacetate. This dietary level
corresponded to measured intakes of 821 and 953 mg/kg bw per day for males and
females, respectively (de Bie, 1999). The plasma radioactivity level reached its peak
for the 500 mg/kg bw groups by 30 min post-administration for both conventional
and pretreated groups. The plasma kinetics of elimination for all three groups are
summarized in Table 3. Independent of route of administration and sex, the plasma
kinetics of elimination follow a biphasic curve. More than 99% of 14C-labelled sodium
4-methoxybenzoyloxyacetate was excreted in the 24-h urine (>95%) and faeces
when administered both intravenously and orally, independent of pretreatment or
sex. Approximately 85% of this was excreted unchanged, and two major
metabolites, 4-methoxybenzoylglycine and 4-hydroxybenzoyloxyacetic acid, were
detected in the urine at 4–7%, depending on the route of administration. Low residue
levels were found in tissues and organs (de Bie, 1999).
Six male human volunteers were orally administered 1 mg sodium
4-methoxybenzoyloxyacetate (No. 1880)/kg bw. On average, 85.9% of this dose
was excreted within 24 h as sodium 4-methoxybenzoyloxyacetate, with 57% of that
excreted within the first 2 h after dosing. There were no detectable amounts of
4-hydroxybenzoyloxyacetic acid or 4-methoxybenzoylglycine found in any urine
samples, although the authors indicated that detecting less than 1–2% would have
been difficult as a result of interfering peaks on the chromatogram (Meuling &
de Bie, 1999).