Safety evaluation of certain food additives - ipcs inchem

52 ETHYL LAUROYL ARGINATE
During the treatment period, clinical signs, body weight, and food and water
consumption were recorded, and food conversion ratios were calculated. During
week 13, blood samples were taken from the orbital sinus, and an extensive range
of haematological and blood chemistry tests were performed. Also during week 13,
the eyes of all the animals in the control and high-dose groups were examined, and
urine was also collected for urinalysis and microscopy. Animals were subjected to
a detailed necropsy, including organ weight analysis and histopathology.
There were no treatment-related clinical signs observed during the study.
There was one unscheduled death in a control male during week 1. No clinical signs
had been noted for this animal, and the cause of death was determined to be a
ruptured liver. The mean body weight gains for the female rats were significantly
reduced (88%, 79% and 86% of control values for the three doses, respectively).
There was no effect on male body weight, and so the effect on females was
considered by the authors to be of uncertain relationship to treatment. Mean
cumulative food consumption was unaffected by treatment in any of the treatment
groups. Females had slightly lower food utilization efficiencies, with no dose–
response relationship. Group mean water intakes were generally comparable with
those of controls, apart from males receiving 50 000 mg/kg diet, which had a slightly
higher water consumption (117% of that of the controls). There were no ocular
lesions considered to be attributable to treatment. There was a slightly lower total
white blood cell count among males and females receiving 12 800 and 50 000 mg/
kg diet compared with controls, although there was no consistency in the type of
white blood cell affected, and significance was attained only for females (76% and
72% of that of the controls for the 12 800 and 50 000 mg/kg diet groups,
respectively). There were no treatment-related biochemical changes. Males
receiving 50 000 mg/kg diet had a slightly higher urine volume compared with
controls, consistent with the increase in water intake. Females receiving 50 000 mg/
kg diet had a slightly higher group mean relative liver weight compared with controls,
although no microscopic changes were observed. At necropsy, an increased
incidence of alopecia was noted among females receiving 12 800 and 50 000 mg/
kg diet, although this was considered of uncertain biological significance. Minor nonsignificant
changes (dilation, local inflammation, nodules) were observed
macroscopically in the forestomach lining of animals receiving 12 800 and 50 000
mg/kg diet. No other treatment-related changes were observed macroscopically or
microscopically. The authors concluded that the no-effect level for the formulation
was likely to be 12 800 mg/kg diet (equal to 175 mg ethyl-N -lauroyl-L-arginate HCl/
kg bw per day) (Huntingdon Life Sciences Ltd, 1996).
A review of this study by a consultant haematologist (commissioned by
Laboratorios Miret S.A. for Huntingdon Life Sciences Ltd, where the study was
performed) suggested that although a slight reduction in white blood cell count
occurred with only minor visible damage to the stomach lining, such an effect is not
uncommon in toxicological studies. The results suggested pre-ulcerative or preirritation
changes that, owing to the nature of the formulation, had not progressed
to positive damage, although they had been detected by the white blood cells owing
to their sensitivity. The reduction of mature white blood cells in the peripheral blood
was reported to be the result of a normal response to the changes induced in the