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EC number: 226-394-6
CAS number: 5392-40-5
test substance was administered to pregnant New Zealand White rabbits
daily by stomach tube from implantation to one day prior to the expected
day of parturition (GD 6-28) at dose levels of 20, 60 and 200 mg/kg
no toxicologically relevant signs of maternal toxicity were observed in
the control and test groups receiving 20 or 60 mg/kg bw/d. Neither
clinical examinations nor determination of food consumption and body
weights/body weight gain and necropsy revealed any relevant effect on
the animals at these dose levels. However, signs of distinct maternal
toxicity were noted in the high-dose group (200 mg/kg bw/d).
high-dose females were found dead during the last third of the
administration period (on GD 23 and GD 28). Gross pathological
examination revealed a severe confluent reddening of the stomach mucosa
in one of these animals.
· One high-dose
female was sacrificed after abortion ahead of schedule (GD 26). As
multiple ulcerations were found in the stomach of this doe at necropsy,
a relationship of this abortion to the treatment is assumed.
high-dose doe had 4 dead fetuses at term. Alike abortions, this is
considered an expression of maternal toxicity in rabbits, in particular
as this animal also suffered from markedly reduced food consumption (5.5
g/animal /d vs. 101.8 g/animal /d mean of the respective dose group at
GD 28-29) and body weight loss (-150g at GD 28-29) near term.
high dose doe with a litter including 5 cases of malrotated limbs was
particularly affected by maternal toxicity in terms of constantly and
markedly reduced food consumption until it almost stopped eating.
Accordingly, this doe lost more (net)
body weight during the treatment period than the average (net) weight
loss in the high-dose group.
food consumption of the high-dose group (200 mg/kg bw/d) was constantly
below control during the treatment period, but the difference gained
statistical significance only on GD 7-8. However, throughout treatment
period (GD 6-28), the average food consumption of the high-dose does was
almost 10% below the control group. Average carcass weights as well as
gross and corrected (net) body weight change were also not significantly
different from control in all treatment groups, although some high-dose
individuals suffered from more pronounced reductions of food consumption
and (net) body weight losses than the majority of animals.
these findings are indicative of a local irritating potential of the
test item in the gastrointestinal tract which because of the peculiarity
of rabbit digestive system subsequently led to reduced food consumption,
distinct body weight loss, doe mortality, abortion and fetal mortality
in the most sensitive individuals exposed to the top dose of 200 mg/kg
bw/d. It is notable that all casualties occurred towards the end of
pregnancy, when the rapid growth of the offspring makes it a
particularly demanding pregnancy phase to the mothers.
were no differences of biological relevance between the control and the
substance-treated groups (20, 60 and 200 mg/kg body weight/day) in
conception rate, mean number of corpora lutea, total implantations,
resorptions and live fetuses, fetal sex ratio or in the values
calculated for the pre- and the postimplantation losses.
test substance-related differences were recorded for placental and fetal
body weights, or for fetal sex ratio.
one exception the external, soft tissue and skeletal examinations of the
fetuses revealed no differences between the controls and the test
substance-treated groups, which might be related to the test substance.
Number and type of fetal external, soft tissue and skeletal findings,
which were classified as malformations and/or variations, did not show
any differences of toxicological relevance between the groups.
exception are five cases of malrotated limbs which were clustered in one
litter of the high-dose group. These findings were accompanied by pale
discolored placentae in some offspring of this litter. Malrotation of
the limbs is occasionally also observed in untreated control fetuses.
Generally it is seen as a subtle inward rotation of the limb and in many
cases is a result of reduced amnion levels and/or compression of the
uterus caused by maternal toxicity, combined with some influence of
positioning of the foetus in the uterus. This doe was particularly
affected by maternal toxicity. It constantly and markedly reduced its
food consumption from GD 18 (61% of the average in the high-dose group)
onwards until it almost stopped eating from GD 27 onwards. Accordingly,
this doe lost 766.5 g (net) body weight during the treatment period
while the average (net) weight loss in the high-dose group was 192.9 g.
As proven by skeletal examination the limb malrotations were not caused
by any abnormalities of the underlying skeleton. Considering all this,
there is sufficient evidence that these fetal findings are a direct
consequence of the severe maternal toxicity. No similar or less severe
findings of related nature were noted in any doe of the high-dose group
less affected by maternal toxicity.
there is no evidence for selective developmental toxicity of the test
substance. The test substance is not teratogenic in rabbits at the
tested dose levels.
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