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EC number: 931-295-2
CAS number: -
In a prenatal developmental toxicity study
rats were exposed to 0, 3, 7 or 15 mg/kg bw/d of the test substance once
daily by oral gavage from days 6 to 20 post-coitum inclusive. The
control group received the vehicle propylene glycol. Examinations were
according to OECD 414 (2001) with additional histopathology of the
stomach, small intestine and mesenteric lymph nodes.
Two high dose
females at 15 mg/kg were euthanized moribund on Days 15 and 17
post-coitum, respectively. Toxicologically
relevant clinical signs (lethargy, hunched posture, piloerection, and
lean appearance) were noted at 15 mg/kg only. Treatment at 7 and
15 mg/kg resulted in reduced body weights, body weight
gains, body weight corrected for uterine weight, and food consumption.
Treatment related adverse
morphological alterations were present in the small intestine and the
draining mesenteric lymph node of animals in all treated groups. At
necropsy, a thickened wall of the duodenum, ileum and/or jejunum was
noted which at the microscopic level correlated with (foamy) macrophages
in the lamina propria and/or granulocytic (necrotizing) inflammation of
the duodenum, jejunum and ileum. In general, these changes were dose
related with the highest incidence and severity seen in the ileum.
Enlarged mesenteric lymph nodes recorded at necropsy correlated with
granulomas with or without necrosis (up to marked), extranodal
inflammation with or without peritonitis, increased incidence, severity
of increased macrophage foci, increased cellularity of cortex and/or
medullary cords. Some of these findings were also noted in the 2 high
dose females sacrificed moribund after 9 or 12 treatment days.
on the morphological data it is most likely that the (necrotizing)
inflammation in the intestine caused by exposure to the test substance
spreads to the draining mesenteric lymph nodes with possible
breakthrough of granulomas into the abdominal cavity.
at 15 mg/kg resulted in significantly lower fetal body weights (both
sexes).This is most likely related to the reduced food
consumption and body weight loss seen in the mothers.
A higher incidence of unossified
metatarsal #1 was noted for all treated groups. The mean litter
proportion was 8.6%, 10.2% and 18.9% in the 3, 7 and 15 mg/kg groups,
respectively, as compared to 2.9% in the control group. None of these
changes was statistically significant. It should, however, be noted that
the litter proportion for the high dose group was in actuality even
higher, since the 7 dead fetuses from litter 77 were not included in the
group mean count.
There was also a trend towards a
higher incidence of unossified sternebae in the 7 and 15 mg/kg groups.
The mean litter proportion of unossified sternebra #5 was 1.6%, 4.5% and
4.6% in the 3, 7 and 15 mg/kg groups, respectively, as compared to 2.4%
in the control group. In addition, unossified sternebra #2 with or
without unossified vertebral centra and reduced ossification of the
pubis was noted for 3 fetuses from the same litter.
It should be noted that necropsy was
performed on Day 21 post-coitum. At this time point, ossification of the
skeleton should be almost complete. As such the higher incidence of
unossified metatarsals and/or unossified sternebrae noted in all treated
groups was regarded as treatment related. The exact cause of the delayed
ossification is unknown. The (necrotizing) inflammation of the small
intestine seen in the mothers may have resulted in impaired absorption
of nutrition factors necessary for bone calcification. However, there
were no data (like blood parameters) available from this study to
substantiate this hypothesis.
toxicologically significant changes were noted in any of the remaining
developmental parameters investigated in this study (i.e. litter size,
visceral and skeletal developmental malformations, external and visceral
NOAEL maternal toxicity:
Based on the Granulocytic (necrotizing)
inflammation in the ileum and granulomas with or without necrosis in the
mesenteric lymph nodes in females starting at 3 mg/kg, no NOAEL for
maternal toxicity could be derived. These findings are in agreement with
the results obtained in other repeated dose studies for this substance.
NOAEL developmental toxicity:
The study report concluded that on the basis
of the observed incidence of unossified metatarsal #1 also at the lowest
dose of 3 mg/kg, no developmental NOAEL for Etherdiamine C13i/acetate
could be derived. However, there are some additional comments that can
be made to this:
- None of these increased incidences of
delayed ossifications was statistically significant.
- The effects as such is not severe
(classified as variation) and are also commonly seen in control groups.
Higer incidences of such delayed ossifications are often seen at levels
that result to maternal toxicity, and these delays are considered to be
rapidly catching up after birth under normal feeding conditions.
- When a delayed development is noted
(secondary to maternal toxicity), which is plausible considering the
lower fetal body weights observed in the high dose fetuses, the
evaluation for skeletal variation in principal shows a pattern of
delayed ossifications. It seems that the data in this study point a
narrow impact on the ossification of metatarsal #1 alone which is also
visible at lower dose levels, but do not indicate a delayed ossification
of other structures that would also be expected. For
example, the reported proportion of unossified sternebrae was even lower
in the 3 mg/kg group than in the control.
Looking at the total picture, there is
a clear dose related effects on maternal health and nutritional status,
already visible from the lowest dose, that clearly has a dose related
effect on fetal development as shown by decreased fetal BW and delayed
fetal growth. For both a dose effect relation is visible, and effects
are certainly clear at the highest dose level.
However, for the low and mid-dose
levels the effects seem to show increased incidence of delayed
ossification as observed compared to control specifically of the
metatarsalis, however not so clear as for the high dose, and adversity
Based on the arguments above, we
consider the reported small, statistically non-significant, increased
incidence of unossified metatarsal #1 as observed at 3 and 7 mg/kg bw,
as not adverse.
The NOAEL for developmental toxicity
therefore is set at 7 mg/kg bw., based on adecreased fetal BW at 15
mg/kg bw correlated with a trend towards a higher incidence of
unossified metatarsal #1. Metatarsals of digit #1 is the last one that
will ossify (starts on gestation Day 21).No teratogenic effects were
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