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EC number: 258-436-4
CAS number: 53220-22-7
The purpose of this Combined Repeated Dose
Toxicity Study with the Reproduction/Developmental toxicity screening
test was to provide initial information concerning the toxic potential
of ditetradecyl peroxydicarbonate and on its possible effects on male
and female reproductive performance such as gonadal function, mating
behavior, conception, pregnancy, parturition as well as on development
of the F1 offspring from conception to day 4 post-partum associated with
oral administration to rats at repeated doses. Four groups of
Hsd.Brl.Han:Wist rats (n=12/sex/group) were administered orally (by
gavage) once a day at 0 (vehicle only), 1000, 300 and 100 mg/kg bw/day
at concentrations of 200 mg/mL, 60 mg/mL and 20 mg/mL, respectively,
corresponding to 5 mL/kg bw dose volume. The suitability of the chosen
vehicle for the test item at the intended concentrations was
analytically verified up front. Ditetradecyl peroxydicarbonate was
stable at room temperature for one day and in a refrigerator (5 ± 3 °C)
for 3 days. Concentration of the test item in the dosing formulations
varied in the range of 90 % to 110 % in comparison to the nominal
values, thereby confirming proper dosing. All animals of the parent (P)
generation received test item or vehicle prior to mating (14 days) and
throughout mating. Test item or vehicle was administered to male animals
post mating up to the day before the necropsy. For females with living
pups, test item was administered through the gestation period and up to
lactation days 3 – 8, i.e. up to the day before the necropsy.
Observations included mortality, clinical signs, body weight, food
consumption, mating, pregnancy and delivery process, as well as
development of pups. Five dams and males cohabited were selected from
each group for further toxicity examinations such as functional
observations, hematology, clinical chemistry, gross necropsy, organ
weighing and histopathology. The dams were allowed to litter, and rear
their young up to termination on days 4 postpartum and offspring were
euthanized. Pups were weighed and observed for possible abnormalities.
All parental animals were subjected to gross pathology one day after the
last treatment. Selected organs were weighed. Full histopathology was
performed in the selected animals of control and high dose groups.
Histopathology examination was performed on reproductive organs and
pituitary of the remaining animals in the control and high dose groups.
The reproductive organs and pituitary of non-pregnant and not mated
female animals and males cohabited with in the low and mid dose groups
were also processed and evaluated histologically. The results were
interpreted comparing treatment groups with respect to controls, which
were treated concurrently with vehicle (PEG 400) only.
There was no test item related mortality at
any dose level (1000, 300 or 100 mg/kg bw/day).
Test item related salivation was observed in
male animals at 1000, 300 and 100 mg/kg bw/day with variable occurrence
within a group in a dose related onset and frequency after the daily
treatment. Salivation appeared in less incidence in female animals
administered with 1000 mg/kg bw/day. No toxic signs related to the test
item were found at the detailed weekly and terminal functional
observations. The behavior and physical condition of animals were
considered to be normal during the entire observation period
(pre-mating, mating, post-mating, gestation and lactation periods).
Individual dermal changes (alopecia and scars on the skin) were observed
in single animals in control, 1000 and 100 mg/kg bw/day group, which are
common findings in this strain of experimental rats and had no
toxicological meaning. Piloerection and dyspnea was noted for one dam at
100 mg/kg bw/day during and one day after the parturition.
Body weight and body weight gain
The body weight development of parental male
and female animals was undisturbed in the course of the entire study. No
test item-related body weight, or body weight gain changes were observed
with respect to controls at any dose level during the pre-mating,
mating, post-mating, gestation and lactation periods.
The mean daily food consumption was not
influenced by the test item.
No test item-related changes were observed
in investigated hematology parameters.
Clinical chemistry examinations did not
reveal any pathologic changes in the examined parameters.
Specific macroscopic alterations related to
the test item were not found during the necropsy.
There were no test item related changes in
the examined organ weights.
Histological examination did not detect any
toxic or test item related lesions in the genital and other organs of
the experimental animals.
There was no test item effect on the
reproductive performance (gonad function, mating behavior, conception,
Negative effects of the test item on
offspring development (mortality, clinical signs, body weight, and
necropsy findings) were not detected between postnatal days 0 and 4.
Under the conditions of the present study,
ditetradecyl peroxydicarbonate caused salivation (male and female
animals) following an oral administration at 1000 mg/kg bw/day to
Hsd.Brl.Han:Wistar rats during the Combined Repeated Dose Toxicity Study
with the Reproduction/Developmental Toxicity Screening Test. At 300 and
100 mg/kg bw/day, salivation was observed in male animals. Ditetradecyl
peroxydicarbonate did not influence male and female reproductive
performance (gonad function, mating behavior, conception, pregnancy,
parturition) in parental male and female Hsd.Brl.Han: Wistar rats or
development of the F1 offspring from conception to day 4 post-partum
after repeated dose oral administration at 1000, 300 or 100 mg/kg
bw/day. Based on these observations the No Observed (Adverse) Effect
Levels (NO(A)EL) were determined as follows:
NO(A)EL for reproductive performance of the
male and female rats: 1000 mg/kg bw/day
NO(A)EL for F1 Offspring:1000 mg/kg bw/day
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