Safety evaluation of certain food additives - ipcs inchem

62 ETHYL LAUROYL ARGINATE
arginate preparation at 2000 mg/kg bw per day during days 6–12 of gestation.
Animals were then culled on day 13 of gestation. The animals were weighed and
examined daily. At termination, each animal was examined macroscopically and
checked for pregnancy. If lesions were evident, tissue samples were taken for
possible histopathological examination.
The general condition of all females was unaffected by treatment, and no
deaths occurred. Salivation was recorded for all animals for a short period
immediately following dosing. Body weights and body weight gain in non-pregnant
and pregnant animals were unaffected by treatment. All females were pregnant at
termination, and there were no adverse findings at necropsy. The authors concluded
that the highest dose for use in a subsequent preliminary embryo-fetal study in the
rat should be 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, 1998a).
In the subsequent preliminary embryo-fetal toxicity study, ethyl lauroyl
arginate (purity, 69.1% ethyl-N -lauroyl-L-arginate HCl) was administered by
gavage at doses of 0, 200, 600 or 2000 mg/kg bw per day to groups of six pregnant
rats (Crl:CD BR) during days 6–19 of gestation. The study was conducted in
accordance with GLP and OECD guidelines. Allowing for composition of the test
material, the doses were equal to 0, 138, 415 and 1382 mg ethyl-N -lauroyl-Larginate
HCl/kg bw per day. The objective of this preliminary study was to assess
the effects of repeated oral administration of ethyl lauroyl arginate on the progress
and outcome of pregnancy in the rat, in order to establish suitable doses for a main
embryo-fetal toxicity study. All animals were observed at least twice daily for clinical
condition and signs of reaction to treatment. Body weight and food consumption
were recorded at regular intervals throughout the study. On gestation day 20,
females were culled and examined macroscopically. The reproductive tract was
dissected out, and the following were recorded: number of corpora lutea in each
ovary, number of implantation sites, number of resorption sites, and number and
distribution of fetuses in each uterine horn. In addition, fetal examinations were
performed (body weight, sex, external abnormalities and placental weight). Half of
each litter were dissected, and the neck, thoracic and abdominal cavities were
examined.
No treatment-related clinical signs were observed during the study, and 22
animals were pregnant (only 4/6 in the control group). One female in the 200 mg/
kg bw per day dose group was killed in extremis on day 19 of gestation after showing
reduced food intake (2 g/day) on days 18–19 and a body weight loss of 40 g over
the same period. This female showed signs of pallor, piloerection, brown staining
around the left eye, red urine and a perigenital discharge. Necropsy revealed a large
amount of red fluid within the vagina and both uterine horns, and the uterus
contained 15 late resorptions. The authors concluded that, in the absence of similar
findings in animals of the higher dose groups, the findings in this female were
unrelated to treatment with ethyl lauroyl arginate.
Salivation was recorded on a number of occasions for a short period
immediately after dosing at 600 mg/kg bw per day and more frequently at 2000 mg/
kg bw per day. Respiratory noises were noted for one female in each of the