Safety evaluation of certain food additives - ipcs inchem

ETHYL LAUROYL ARGINATE 59
first 4 days after birth and were killed on day 4 of age for humane reasons. The
predominant finding at necropsy was the absence of milk in their stomachs; the
authors concluded that this reflected reduced lactation by the two dams in the early
postnatal period. There was also a small reduction in survival of the offspring within
the remaining litters at 15 000 mg/kg diet, although this was not associated with any
effect on growth. The authors concluded that a possible association between
treatment and postnatal offspring death could not be excluded.
Sex ratio and body weight of the offspring at day 1 of age were unaffected
by treatment. F1 body weight gain throughout the pre-weaning period and to
termination was unaffected by treatment (from both indirect exposure via the milk
and direct exposure via independent feeding). Sexual maturation of the F1 males
was unaffected by treatment, but vaginal opening of the F1 females at 15 000 mg/
kg diet was delayed by 4 days. There was no consistent treatment-related
relationship between body weight and time of vaginal opening. The authors
considered that the delay in vaginal opening was treatment related but had no
lasting impact upon the normal sexual development of F1 females, because normal
estrous cycles were established in all treatment groups. There were no findings at
necropsy of either the F0 or F1 animals. Of the two F0 females whose litters were
terminated, the mammary tissue appeared inactive or had only small amounts of
milk present. The authors concluded that a maximum dietary concentration of
15 000 mg ethyl lauroyl arginate/kg diet (equal to 1151 mg ethyl lauroyl arginate/kg
bw per day) could be used in a subsequent two-generation study in the rat
(Huntingdon Life Sciences Ltd, 2003b).
(a) Multigeneration reproductive toxicity
The influence of ethyl lauroyl arginate (purity, 88.2% ethyl-N -lauroyl-Larginate
HCl) on reproductive performance was assessed in compliance with GLP
and OECD guidelines by administration to Crl:CD(SD)IGS BR rats continuously in
the diet through two successive generations. F0 animals (groups of 28 males and
28 females) received diets containing ethyl lauroyl arginate at concentrations of 0,
2500, 6000 or 15 000 mg/kg diet (equal to 0, 181, 434 and 1073 mg/kg bw per day
for males; and 0, 207, 502 and 1226 mg/kg bw per day for females) for 10 weeks
before pairing, throughout pairing, gestation and lactation, and until termination.
F1 animals (groups of 24 males and 24 females) were similarly treated from 4 weeks
of age, with dietary concentrations equal to 0, 224, 537 and 1356 mg/kg bw per day
for males; and 0, 246, 582 and 1489 mg/kg bw per day for females. The F2
generation was raised to weaning, following which the study was terminated.
Throughout the study, data were recorded on clinical condition and general
health, body weight, food consumption, estrous cycles, mating performance and
fertility, gestation length and parturition observations. F0 and F1 animals were culled
when their litters had weaned and subjected to a detailed necropsy, including
macroscopic and microscopic investigations. Organs were weighed and subjected
to histological examination. Seminal analysis was performed on all F0 and F1 males.
All litters were assessed for clinical condition, litter size and survival, sex ratio, body
weight, sexual maturation (F1 generation only) and physical development. F2