Safety evaluation of certain food additives - ipcs inchem

ETHYL LAUROYL ARGINATE 45
arginine. Plasma concentrations of [ 13 C]N -lauroyl-L-arginine were quantifiable up
to 12 h post-dosing, and those of [ 13 C]arginine were quantifiable up to 4 or 8 h postdosing.
Concentrations of [ 13 C]arginine were generally higher than those of [ 13 C]-
N -lauroyl-L-arginine, indicating extensive breakdown of ethyl lauroyl arginate and
N -lauroyl-L-arginine to arginine. The rate and extent of systemic exposure to both
[ 13 C]N -lauroyl-L-arginine and [ 13 C]arginine increased over the dose range, although
the Cmax and AUCt values at the highest dose level were approximately 20% lower
for [ 13 C]N -lauroyl-L-arginine and about 1.2-fold higher for [ 13 C]arginine compared
with those values predicted from a linear relationship. The t½ of [ 13 C]N -lauroyl-Larginine
appeared to be independent of dose, and the t½ of [ 13 C]arginine was similar
to that of [ 13 C]N -lauroyl-L-arginine. The authors concluded that there were
insufficient data to allow a meaningful assessment of the pharmacokinetics of [ 13 C]ethyl
lauroyl arginate; however, pharmacokinetic parameters were determined for
[ 13 C]N -lauroyl-L-arginine and [ 13 C]arginine (CentraLabS Clinical Research Ltd,
2005b).
2.1.2 Biotransformation
The biotransformation pathways of ethyl lauroyl arginate (Figure 1) have
been established from in vitro and in vivo metabolism studies (Huntingdon Life
Sciences Ltd, 2001d; Ruckman et al., 2004; European Food Safety Authority, 2007;
Laboratorios Miret S.A., 2008). Ethyl lauroyl arginate is rapidly hydrolysed by loss
of the lauroyl side-chain to form L-arginine ethyl ester and/or by cleavage of the
ethyl ester to form N -lauroyl-L-arginine. Further hydrolysis of either intermediate
results in the amino acid L-arginine. L-Arginine is further metabolized to ornithine
and urea. Ornithine can then be incorporated into endogenous compounds via the
urea and citric acid cycles and finally degraded to carbon dioxide. Both ethyl lauroyl
arginate and N -lauroyl-L-arginine have been shown to be rapidly metabolized to
arginine in rats and humans. EFSA concluded that, on ingestion by humans, ethyl
lauroyl arginate will be broken down to products of normal metabolism (European
Food Safety Authority, 2007). Based on the human data, which show higher plasma
concentrations of arginine than of N -lauroyl-L-arginine, it was suggested that the
majority of ethyl lauroyl arginate is metabolized prior to absorption (Hawkins, 2005).
(a) In vivo
[ 14 C]Ethyl lauroyl arginate (purity, >97% ethyl-N -lauroyl-L-arginate HCl) was
administered orally via gavage at a dose of 180 mg/kg bw to four male Sprague-
Dawley rats in compliance with GLP and OECD guidelines. Urine and expired air
were collected at 0–8 h, at 8–24 h and at 24-h intervals, up to 5 days after dosing.
Faeces were collected at 24-h intervals up to 5 days after dosing. At 5 days postdosing,
animals were sacrificed, and the gastrointestinal tract, including contents,
liver and carcass were removed for analysis. Radioactivity was measured by liquid
scintillation counting.
During the 5 days following dosing, 36.6 ± 5.4% (mean ± standard deviation)
of the dose was excreted as carbon dioxide in the expired air, 11.8 ± 0.9%
was excreted in the urine, 4.3 ± 1.2% was excreted in the faeces, 0.5 ± 0.3%
was recovered from the cage washout and 46.4 ± 6.7% was retained in the