Safety evaluation of certain food additives - ipcs inchem

ETHYL LAUROYL ARGINATE 51
weight changes attributable to treatment. The only histopathological findings that
were considered to be related to treatment were in the stomach (in the area adjacent
to the entry of the oesophagus) of animals receiving 15 000 and 50 000 mg/kg diet.
The predominant change was parakeratosis; ulceration, erosions and epithelial
hyperplasia were also seen to a lesser degree. The authors suggested that these
findings indicated an irritant action of ethyl lauroyl arginate on the mucosal tissue
and concluded that the no-observed-adverse-effect level (NOAEL) was 5000 mg
ethyl lauroyl arginate/kg diet (equal to 384 mg ethyl lauroyl arginate/kg bw per day)
(Huntingdon Life Sciences Ltd, 2001c).
The irritation observed in the forestomachs was localized and was
considered not to be indicative of direct systemic toxicity (Laboratorios Miret S.A.,
2008). Furthermore, the irritant action of ethyl lauroyl arginate was considered by a
consultant haematologist (commissioned by Laboratorios Miret S.A. for Huntingdon
Life Sciences Ltd, where the study was performed) to correlate with the reduction
in white cells. The reduction of mature white cells in the peripheral blood was
reported to be the result of a normal response to the changes induced in the stomach
lining, resulting in migration of white blood cells into the tissues (Brown, 2008).
(b) Commercial formulation
Similar studies conducted to GLP and in accordance with OECD guidelines
were performed with a commercial product proposed for use as a preservative in
food, containing 19.5% ethyl-N -lauroyl-L-arginate HCl in a propylene glycol/water
(73%/27%) formulation. Groups of five male and five female Crl:CD BR rats were
given diets containing the commercial material at concentrations of 0, 3200, 12 800
or 50 000 mg/kg (equal to 0, 336, 1393 and 5269 mg/kg bw per day for males; and
0, 352, 1400 and 5846 mg/kg bw per day for females) continuously for 4 weeks.
Correcting for the fact that the test formulation contained only 19.5% of the active
ingredient, these doses were equal to ethyl-N -lauroyl-L-arginate HCl doses of 0,
66, 272 and 1027 mg/kg bw per day for males and 0, 69, 275 and 1140 mg/kg bw
per day for females. This was a preliminary toxicity study to determine acceptable
dosages for a 13-week dietary study. During the treatment period, clinical signs,
body weight, and food and water consumption were recorded. During week 4, blood
samples were taken from the orbital sinus, and an extensive range of
haematological and blood chemistry tests were performed. Animals were subjected
to a detailed necropsy, including postmortem examination, organ weight analysis
and histopathology.
There were no mortalities or treatment-related findings at any dose level.
The no-observed-effect level (NOEL) was therefore reported to be 50 000 mg/kg
diet, and it was concluded that that concentration was acceptable for a subsequent
13-week dietary study of the formulation (Huntingdon Life Sciences Ltd, 1995).
In the 13-week study, groups of 10 male and 10 female Crl:CD(SD) BR rats
were administered the formulation at the same dietary concentrations. Correcting
for the fact that the test formulation contained only 19.5% of the active ingredient,
the doses of ethyl-N -lauroyl-L-arginate HCl were equal to 0, 43, 175 and 645 mg/
kg bw per day for males; and 0, 51, 208 and 766 mg/kg bw per day for females.