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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.
Based 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.
Treatment 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.
No toxicologically significant changes were noted in any of the remaining developmental parameters investigated in this study (i.e. litter size, sex ratio,external, visceral and skeletal developmental malformations, external and visceral developmental variations).
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 is debatable.
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 observed.
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