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EC number: 701-162-1
CAS number: -
REPRODUCTION, BREEDING AND PUP DATA
Breeding for F1 Litters
Number of females paired
Number of females mated
Number of females not pregnant (A)
Numbers of females, which lost their litters before first litter check (B)
Number of females, which lost their litters during lactation (C)
Number of females which reared their pups until day 4 post partum
Nos. 59, 70, 81, 82 and 88.
Nos. 68, 78, 79, 80, 83, 84, 85, 86 and 87 had no living pups at first
PERFORMANCE AND FERTILITY
performance and fertility were considered not to be affected by the
treatment at any dose level.
of mating was 100% in all groups. With the exception of one female at
the high dose level (no. 79) mating of all females was recorded during
the first pairing period. After 14 days of unsuccessful pairing of
female no. 79 with male no. 35, a second pairing of this female with
male no. 39 was commenced. Mating of this female was confirmed on day
two of the pairing with male no. 39.
(median) precoital times calculated for the first pairing period were
2.4 (3), 2.3 (3), 2.8 (3) and 3.8 (4) days in order of ascending dose
at the dose level of 40 mg/kg bw/day (no. 59), one female at the dose
level of 200 mg/kg bw/day (no.
70) and three females at the dose level of 1000 mg/kg bw/day (nos. 81,
82 and 88) were not pregnant. Consequently, fertility indexes (numbers
of females pregnant as percentages of females paired) and conception
rates (numbers of females pregnant as percentages of females mated) were
100%, 90.9%, 90.9% and 72.7% at the dose levels of 0, 40, 200 and 1000
mg/kg bw/day, respectively.
fertility at the high dose level was considered to be possibly related
to the treatment with the test item.
on corpora lutea count were observed at any dose level. Mean number of
corpora lutea per dam was 11.3, 11.1, 9.8 and 12.1 in order of ascending
on duration of gestation were observed at any dose level. Mean duration
of gestation was 21.6, 21.9, 22.1 and 22.4 days, in order of ascending
RATE AND POST-IMPLANTATION LOSS
At the dose
level of 1000 mg/kg bw/day, a lower number of implantations was noted.
Mean number of implantations per dam was 8.5 at this dose level,
compared to 12.2 in the control group. This difference was not
statistically significant but below the historical control range
(containing values from 11.4 to 13.7). For this reason reduction in mean
number of implantation sites was considered to be related to the
treatment with the test item.
with the test item caused an increase in post-implantation loss at all
dose levels with a total post implantation loss in six litters at the
high dose level. Mean incidence of post implantation loss per dam was
0.4, 2.0, 3.8 and 8.5 at the dose levels of 0, 40, 200 and 1000 mg/kg
bw/day, respectively. The differences to the control value were
statistically significant in all dose groups.
AT FIRST LITTER CHECK
with the test item caused reduction of litter size at first litter check
in all dose groups.
At the dose
level of 1000 mg/kg bw/day, no living pups were found at first litter
litters (nos. 83 and 87) dead pups were found at first litter check. In
remaining litters, beginning of delivery was noticed; first delivered
pups were noted or supposed in the cage, but no living pups were found
in the cages during the first litter check. It should be considered that
at least some of the females at the high dose level delivered their pups
but cannibalized them shortly thereafter.
At the dose
level of 200 mg/kg bw/day, 24 pups (from 4 litters) were found dead at
first litter check whereas mean number of living pups per dam was 8.8.
At the dose level of 40 mg/kg bw/day 5 pups (from 4 litters) were found
dead at first litter check whereas mean number of living pups per dam
was 10.7. In the control group, no dead pups at first litter check were
noted; mean number of living pups per dam was 11.9.
at the mid- and low-dose levels were not statistically significant.
However, lower litter size resulted from test item-related increase of
post-implantation loss and values at these dose levels were beyond the
historical control background (containing values of mean number of
living pups per dam from 10.3 to 13.2). For these reasons, reduction of
litter size at the mid-, and low-dose levels were considered to be test
In all dose
groups, statistically significant reduction in birth index (number of
pups born alive as a percentage of implantation sites) was noted. Mean
birth index was 96.7%, 84.3%, 68.8% and 0.0% at the dose levels of 0,
40, 200 and 1000 mg/kg bw/day, respectively. This effect was considered
to be test item-related.
LOSS DAYS 0 - 4 POST PARTUM
postnatal loss was noted in all dose groups.
At the dose
level of 200 mg/kg bw/day, 27 pups (from 5 litters) were lost during
At the dose
level of 40 mg/kg bw/day, 9 pups (from 1 litter) were lost during
control group, one pup was lost during lactation.
statistically significant reduction in viability index (number of pups
on day 4 post partum as a percentage of pups born alive) was noted in
mid- and low-dose groups. Mean viability index was 99.2%, 91.6% and
69.3% at the dose levels of 0, 40 and 200 mg/kg bw/day, respectively.
This effect was considered to be test item-related.
EXAMINATION AT FIRST LITTER CHECK AND DURING LACTATION
findings were considered to be related to the treatment with the test
item: no milk in the stomach and pups cold to touch.
first litter check, no milk in the stomach was noted in one pup at the
dose level of 1000 mg/kg bw/day, 15 pups (dead) (from 2 litters) at the
dose level of 200 mg/kg bw/day and 3 pups (from 2 litters) at the dose
level of 40 mg/kg bw/day; all these pups were dead at first litter
check. At the low-dose level 2 further pups (from 1 litter) had no milk
in the stomach on day 2 post partum.
pups dead at first litter check: 6 (from 2 litters) at the dose level of
1000 mg/kg bw/day and 4 (from 2 litters) at the dose level of 200 mg/kg
bw/day were found partially cannibalized.
control group, one fetus was found with malpositioned left hind leg and
malpositioned base of tail.
findings were noted at first litter check or during the first 4 days
post partum in pups at any dose level.
ratio was not affected by exposure to the test item at any dose level.
litter check, percentages of male pups were 53%, 44% and 51% at the dose
levels of 0, 40 and 200 mg/kg bw/day.
WEIGHTS TO DAY 4 POST PARTUM
only dead pups were found at the dose level of 1000 mg/kg bw/day, no
data on body weights of pups at the high-dose level were obtained.
At the dose
level of 200 mg/kg bw/day, lower body weight and lower body weight gain
of pups during lactation were noted. The differences to the control
value were not statistically significant but reduction in body weights
and body weight gain occurred in litters with increased mortality.
Because of this correlation effects on body weights and body weight gain
in mid-dose group were considered to be test item-related.
weights of pups on day 1 post partum were: 6.4 g, 6.6 g and 5.9 g and
mean body weight gains during lactation were +47.5%, +48.5%, and
+40.2%, at the dose levels of 0, 40, and 200 mg/kg/day, respectively.
were found during necropsy of pups at any dose level.
The repeated dose toxicity of the registration substance was
assessed based on data on the read-across substances,
(Pentapropylensuccinimido)-hexanoic acid, sodium and triethanolamine
(Pentapropylensuccinimido)-hexanoic acid, sodium and
triethanolamine salts was investigated for its repeated dose toxicity
according to the OECD Guideline 422. The applies doses were 0, 40, 200
and 1000 mg/kg bw, using water as vehicle.
No mortality and no apparent signs for the clinical observation
was found as well as no effect in the functional observational battery.
Effects on food consumption and body weight development were observed
At dose of 1000 mg/kg bw, changes in clinical chemistry and
hematology parameters comprised increased prothormbin time, increased
potassium level and increased total protein. No comparable effects were
found for 200 or 40 mg/kg bw.
At dose of 1000 mg/kg bw, increased liver and spleen weights were
found. No comparable effects were found for 200 or 40 mg/kg bw.
There was no macroscopic finding for all treated animals.
The histopathological alteration comprised central to diffuse
hepatocellular hypertrophy in males and females of 1000 mg/kg bw,
hyaline droplets in the kidney epithelium in males of 1000 mg/kg bw, follicular
cell hypertrophy in thyroid at 1000 mg/kg bw and squamous hyperplasia of
the forestomach that occurred down to the 40 mg/kg bw group.
The NOALE of 40 mg/kg bw was obtained.
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