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EC number: 252-156-6 | CAS number: 34690-00-1
MATERNAL TOXIC EFFECTS BY DOSE LEVEL AND BY SEX Effects with dose level: 0/100/500/1000 mg/kg bw/d Mortality - one female from 100 mg/kg bw/d group moribund and sacrificed on GD6 (first day of treatment) Body weight - no significant differences in maternal bwt gain between groups - body weight gain GD6-15: 50/49/50/44 - 12% (non-significant) reduction in body weight gain at 1000 mg/kg bw/d on GD6-15 Comment: individual body weight gain for dam 822 (high dose) on GD6-15 = 22 g; mean gain for controls = 50 g; mean gain for high dose group = 44 g. Bwt gain for this dam on GD 0-6 (preceding treatment) and on GD 15-21 (post-treatment) was similar or greater than mean bwt gain for control and high dose group. Clinical observations, physical signs - none present Necropsy findings - few adverse changes present, no treatment related effects Reproductive parameters - pregnancy rate comparable between groups (100% in control, mid and high dose groups, 95.6% at 100 mg/kg bw/d), no treatment-related changes. - mean number of corpora lutea (17.2/16.0/16.7/16.8), implantations (14.5/14.7/14.0/13.7) and implantation efficiency (84.3%/91.8%/84.0%/81.2%) comparable; significant 7% decrease in corpora lutea and significant 7.5% increase in implantation efficiency at 100 mg/kg bwt/d (P<0.05 in both instances) considered unrelated to treatment by authors - mean number live fetuses comparable: 14.3/13.9/13.5/12.9 (no dead fetuses in any group) - mean number resorptions: 0.2/0.8(P<0.05)/0.5/0.8(P<0.05); all values within historical control range - non-dose related, non-significant increase in dams with 2 or more resorptions in treated groups (0%/22.7%/8.3%/20.8%); within historical control range FETAL DATA Effects with dose level: 0/100/500/1000 mg/kg bw/d - body weight by sex: males 5.54/5.43/5.71/5.49; females 5.25/5.17/5.34/5.16 (no significant effect) Crown-rump length: males 4.2/4.2/4.3 (P<0.01)/4.2; females 4.1/4.1/4.2 (P<0.01)/4.1 (increase at 500 mg/kg bw/d considered biologically insignificant by authors) Sex: males/litter 6.9/7.0/6.6/6.0; females 7.4/6.9/7.0/6.9 (no significant effect) Sex ratio (m:f): 92.4%/102.0%/94.6%/87.3% (no significant effect) Variation in ossification: fetuses 80.2%/83.5%/79.3%/84.3%; litters 95.8%/100.0%/100.0%/100.0% (no significant effect) External malformations: - incidence: 0 fetuses from 339 examined/0 from 305 examined/0 from 325 examined/6 from 315 examined - in the high dose group, one female (no. 822) had 6 fetuses (from a total litter of 16) with a syndrome of defects that included: flexed forepaws, shortened and thickened torso, abdominal distension and exaggerated forward flexure of the head (see maternal body weight, above). Remaining high dose fetuses (n = 309) unremarkable. Total skeletal malformations - total fetuses examined: 177/158/169/159 - per fetus: 4.0%/1.9%/3.0%/1.3% (no significant effect) - per litter: 20.8%/13.6%/20.8%/8.7% (no significant effect) - type of skeletal malformations control: angulated ribs, cervical rib, wavy rib 100 mg/kg: angulated rib, cervical rib, angulated and wavy rib 500 mg/kg: cervical rib, angulated and wavy rib, 7 lumbar vertebra 1000 mg/kg: 5 lumbar vertebra, fused sternebrae Total soft tissue malformations - total fetuses examined: 162/147/156/150 - per fetus: 4.3%/8.2%/4.5%/4.0% (no significant effect) - per litter: 16.7%/40.9%/29.2%/20.8% (no significant effect) - type of soft tissue malformation control: distended renal pelvis, renal pelvis, ureter, baldder 100 mg/kg: as control + fold in retina 500 mg/kg: as control + ectopic kidney 1000 mg/kg: as control + fold in retina, anophthalmia, malrotation of heart - malrotation of the heart occurred in high dose 2 fetuses, both from litter No. 822 (see "maternal body weight" and "external malformations", above) Visceral malformations - per fetus: 0.6%/1.3%/0.6%/1.9% (no significant effect) - per litter: 4.2%/9.1%/4.2%/12.% (no significant effect) - type of visceral malformation control: distended ureter 100 mg/kg: distended ureter +/- renal pelvis 500 mg/kg: as control 1000 mg/kg: as control + malpositioned testis
In a well documented pre-GLP teratology study (FDA segment II teratological study; reliability score 2) Dequest 2000 was administered by oral gavage to pregnant Charles River CD rats (24/dose), at dose levels of 100, 500 and 1000 mg/kg bw/day, on gestation days 6 to15. Control animals received the vehicle (water) only. Dams were sacrificed on gestation day 21 and recovered fetuses evaluated for external, soft-tissue and skeletal malformations. Maternal mortality, pregnancy rate, body weight gain, uterine implantation data, fetal size, sex data, ossification variation data and teratological evaluations were evaluated. High dose females gained less weight than the controls during the dosing period. A statistically significant increase in the number of resorptions was observed in the low and high dose animals (not the mid-dose). There was also an increase in the number of dams with two or more resorptions. However, the resorption data were within the range of historical values for the laboratory, so it was concluded that there was not a treatment-related effect. There were no teratogenic effects in the low and mid dose group. In the high dose group six fetuses from a single litter had common multiple malformations that included flexed forepaws, shortened and thickened torso, abdominal distention and exaggerated flexure of the head. Soft tissue examination revealed two of these fetuses had a malformation defect of the heart. The remaining high dose fetuses were generally unremarkable. Soft tissue and skeletal malformation data from the high dose group were similar to the control group. Although a possible teratogenic effect could not be excluded, it was most likely that the effects were secondary to maternal toxicity. Therefore the maternal NOAEL was 500 mg/kg bw/day, and the NOAEL for fetotoxicity and teratogenicity was >1000 mg/kg bw/day.
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