Safety evaluation of certain food additives - ipcs inchem

64 ETHYL LAUROYL ARGINATE
dosing and body weight losses. Both were killed on day 17 of gestation for humane
reasons, and necropsy revealed that the gastrointestinal tract was distended with
gaseous material. Both animals were pregnant, and implantation sites were normal.
The general condition of the surviving animals was good, and all were
pregnant. Noisy respiration was observed in all treatment groups, in a dose-related
manner. The authors noted that this may have resulted from aspiration of increased
secretions and/or traces of the dosing material following treatment with the more
concentrated/viscous suspensions at the higher doses. The respiratory distress was
considered by the authors not to be a systemic response. Salivation at the time of
dosing was seen in all animals receiving 2000 mg/kg bw per day on approximately
50% of occasions. Fourteen animals receiving 600 mg/kg bw per day showed
occasional incidences of salivation during the dosing period; at 200 mg/kg bw per
day, only one animal showed salivation on one dosing occasion. Neither noisy
respiration nor salivation was seen in the control group.
There were no overall treatment-related effects on body weight or food
consumption, although occasional animals in all treatment groups showed periods
of body weight loss and reduced food intake that were related to episodes of
respiratory distress. Of the surviving animals, there were no treatment-related
findings upon necropsy. Nor were there any treatment-related effects on fetal
survival, growth or development. The authors concluded that, because of the
maternal deaths at 600 and 2000 mg/kg bw per day, the NOAEL for the dams was
200 mg ethyl lauroyl arginate/kg bw per day (equal to 138 mg ethyl-N -lauroyl-Larginate
HCl/kg bw per day), but the NOAEL for the fetuses of dams that survived
to the end of pregnancy was 2000 mg ethyl lauroyl arginate/kg bw per day (equal
to 1382 mg ethyl-N -lauroyl-L-arginate HCl/kg bw per day; Huntingdon Life
Sciences Ltd, 1998c).
(ii) Rabbits
A similar set of studies was conducted, in accordance with GLP and OECD
guidelines, with the same ethyl lauroyl arginate preparation administered to New
Zealand White rabbits. Ethyl lauroyl arginate was administered by gavage to two
non-pregnant female rabbits at an initial dose of 60 mg/kg bw per day, to determine
tolerance. Every 2 days, the dose was approximately doubled until a maximum
practical dose of 1000 mg/kg bw per day was reached. Allowing for the composition
of the test material, the maximum dose was equal to 691 mg ethyl-N -lauroyl-Larginate
HCl/kg bw per day. The two females were then mated and dosed by gavage
with ethyl lauroyl arginate at 1000 mg/kg bw per day during days 6–12 of gestation.
The females were weighed and examined daily for signs of reaction to treatment.
At termination, each animal was examined macroscopically and checked for
pregnancy. If disease was evident, tissue samples were taken for histopathology.
The general condition of all females was unaffected by treatment, and no
deaths occurred. During the escalating-dose phase, marginal losses (50 g) in body
weight were recorded for one of the females at 500 mg/kg bw per day on 1 day and
for both females (50–120 g) at 1000 mg/kg bw per day on 1 day. During the constantdose
phase, both females showed reduced food and water intake from day 8 of