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EC number: 260-906-9
CAS number: 57693-14-8
Aim of the study was to assess the
possible effects of test substance after repeated dose administration in
The test item was administered daily in
graduated doses to 3 groups of test animals, one dose level per group
for a treatment period of maximally 54 days for females and minimum of
28 days for males.
The following doses were evaluated:
Control: 0 mg/kg bw/day
Low Dose: 100 mg/kg bw/day
Medium Dose: 300 mg/kg bw/day
High Dose: 1000 mg/kg bw/day
The test item formulation was prepared
freshly on each day of administration. The test item was suspended in
sterile water and administered daily during 14 days of pre-mating and
during mating period in both male and female animals, during the
gestation period and up to post-natal day 3 in females. Males were dosed
for 28 days. Non pregnant females and females with no evidence of mating
were treated until day 25 after confirmed mating or from the end of
mating period. Dose volumes were adjusted individually based on weekly
body weight measurements. The administration volume was 5 ml/kg body
Animals of control group were handled
identically as the dose groups but received same dose volume of the
vehicle used in this study. Each of the 4 groups comprised 10 male and
10 female Wistar rats.
Concentration analysis of formulation
samples was determined in study week 1, 3, 5, and 7 for all dose groups.
The mean recoveries observed in LD, MD and HD groups were 86.3 %, 91.7 %
and 82.5 % of the nominal concentration, respectively.
Homogeneity of formulation samples was
determined in study week 1 and 5 for LD, MD and HD dose groups. The mean
recovery observed for LD dose group was between 98.6 and 99.6 % of the
nominal value, for MD dose group between 93.7 and 99.5 % and for HD dose
group between 80.5 and 94.1 %. The coefficients of variation of the
different sampling locations (top, middle, bottom) were between 0.9 and
3.3 % in LD dose group, between 1.8 and 2.1 % in MD dose group and
between 0.7 and 1.4 % in HD dose group.
During the period of administration, the
animals were observed each day for signs of toxicity. At the conclusion
of the test, surviving animals were sacrificed and observed
Body weight and food consumption were
measured weekly, except for food consumption measurements which were not
taken during the mating period in female animals and the mating and
post-mating period in male animals.
Haematological and clinical biochemistry
evaluations were performed on blood samples collected at terminal
sacrifice from 5 males and 5 randomly selected females from each group.
Urinalysis was performed on samples collected at terminal sacrifice from
5 randomly selected males from each group.
Functional observations including sensory
reactivity to different stimuli, grip strength, motor activity
assessments and other behaviour observations were performed in the week
before the treatment and at the end of the study on 5 randomly selected
males and females.
After 14 days of treatment to both male
and female animals were mated (1:1) for a maximum of 14 days. From
subsequent morning onwards the vaginal smears of females were checked to
confirm the evidence of mating. After the confirmation of the mating,
females were separated and housed individually. Each litter was examined
as soon as possible after delivery of the dam to establish the number
and sex of pups, stillbirths, live births, runts and the presence of
gross abnormalities. Live pups were counted, sexed and litters weighed
within 24 hours off parturition and on day 4 post-partum.
The males were sacrificed after completion
of the mating period on days 29/30 and the females along with their pups
were sacrificed on post natal day 4. Non-pregnant females were
sacrificed on day 26 from the day of confirmed mating.
Pups sacrificed on postnatal day 4 and
those found dead (1 pup from animal 48), were carefully examined for
gross external abnormalities.
A full histopathological evaluation of the
tissues was performed on high dose and control animals. Organs showing
gross alterations were also examined histopathologically. The
examinations of kidney, lung, thymus and mesenteric lymph node were also
evaluated from five randomly selected males and females of the low and
medium dose due to changes in high dose group.
In the kidney, minimal amounts of brown
pigment in tubuloepithelial cells of the cortex were observed in the
majority of animals of HD group and in one single male of MD group.
In the mesenteric lymph node, minimal
numbers of foamy/brown pigmented macrophages were seen in a dose-related
manner in MD and HD groups. In addition, the incidence of sinus
histiocytosis was higher in HD group than controls. Altogether, these
changes were considered to be due to test item deposition.
In the lung, multifocal minor numbers of
brown pigmented macrophages were observed in single animals of the MD
and HD groups. Under the conditions of this study, it could not be
elucidated further whether this change was due to local presence of test
item formulation in the lung (via partial gavaging error or
regurgitation) or due to systemic circulation of test item-laden
Corroborating lower thymus weights
recorded, an increased incidence and severity of atrophy/ regression of
the thymus was noted in females of HD group, but the difference to
controls being small the changes were considered not to be adverse.
No mortality occurred in the control or
any of the dose groups during the treatment period of this study.
The clinical signs reddish nasal
discharge, abnormal breathing, slightly reduced spontaneous activity and
diarrhea were observed transiently in few animals of HD group, which
were considered not likely to be adverse. During the weekly detailed
clinical observation, no significant changes or differences between the
groups were found. There were no ophthalmoscopic findings in any of the
animals of this study.
No relevant effects were observed in any
of the parameters of the functional observation battery before and at
the end of the treatment period. There were no biologically relevant
differences in body temperature between the groups.
In both males and females, no treatment
related changes were considered for body weight, body weight change and
food consumption in treated groups when compared to control.
No treatment-related changes were noted
for number of still births, number of runts, total number of pups born
on PND 0 and number of male and female pups, sex ratio, live pups on PND
0 and PND 4.
There was statistically significant
difference noted for group mean litter weight in HD group. As there was
no marked difference noted biologically, this change was considered not
likely to be adverse.
No treatment related changes were noted
for precoital interval and duration of gestation in treated groups when
compared to control. All pregnancies resulted in normal births.
No treatment related changes were noted
for number of corpora lutea, number of implantation sites, number of
live pups born on PND 0 and percentage of pre- and post implantation
There were no treatment related changes
noted for copulation index (%), fertility index (%) and delivery index
(%) in treated groups when compared to the corresponding control group.
No treatment related changes were noted on
survival of the pups from PND 0 to PND 4 in any treated group when
compared with controls.
No treatment-related gross external
findings were observed in any of the treated groups.
There were no treatment related changes
noted for haematological parameters. However, there was increase noted
for mean Neutrophil values of female treated groups. But the values
being within the historical control range, the changes were considered
not likely to be adverse.
There were no changes noted for
coagulation parameters (prothrombin timeand activated partial
thromboplastin time) in treated groups when compared to control.
There were changes noted in cholesterol
value of male HD group andcreatinineandalkaline phosphatasevalue in
female HD group which was attributed to histological changes noted in
kidney and the histological changes in kidney were due to test item
deposition. The changes in cholesterol,creatinineandalkaline
phosphatasein male or female animals were considered not likely to be
The urinalysis performed in male animals
revealed no test- item related effect in any of the treatment groups
compared to the control group.
At terminal sacrifice, two females of MD
group (Nos. 62 and 65) and one female of HD group (No. 73) were found to
be non-gravid after successful copulation.
Two males of MD group showed yellow(ish)
spot(s) on the epididymis, corresponding histologically to spermatic
granuloma. As this finding was not dose-related and may be seen
spontaneously in male rats of this strain and age, it was not considered
to be test item-related.
Dark or black discoloration of one or
several organs was noted in a dose-related manner in 7/10 females of MD
group and in 10/10 males and 9/10 females of HD group. Whereas in MD
group organs concerned were most often kidney or lymph node (mesenteric
or mandibular), in HD group these were some or all of the following:
kidney, testis, lymph nodes, female reproductive organs, liver, thymus,
adrenal gland, salivary glands. In addition, in HD group, blackish
content was noted in the gastrointestinal tract in one single male rat.
In one female animal of MD group (No. 68), lung was not collapsed and
had black spots. These color changes were considered to be due to the
test item. Other macroscopic organ findings noted were few and not
dose-related and therefore considered incidental.
Lower thymus weights recorded in females
were related to an increased incidence and severity of
atrophy/regression of the thymus was noted in females of HD group, but
the difference to controls was small. Hence, the changes were considered
not to be adverse.
Histopathologically, a minimal amount of
brown pigment in interstitial macrophages of the testis was seen in a
dose-related manner in MD and HD groups and was considered to represent
test item deposition in macrophages. No test item-related changes were
noted in the other male or in the female reproductive organs.
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