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Key value for chemical safety assessment

Effects on developmental toxicity

Description of key information

The NOAEL of CJ302 in rat’s maternal toxicity, or teratogenic and embyo-/fetotoxicity performance was 1000 mg/kg/day (OECD TG414).

Link to relevant study records
Reference
Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Study period:
From April 18, 2018 to March 01, 2019
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
GLP compliance:
yes
Species:
rat
Strain:
Sprague-Dawley
Details on test animals and environmental conditions:
- Source: Beijing Vital River Laboratory Animal Technology Co., Ltd.
- Age at study initiation: 84-90 days old
- Weight at study initiation: Males: 402-475 g; Females: 234-309 g
- Housing: There were two rats at most per cage, and mated females were housed individually in cages.
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: 6 days
- Temperature (°C): 21.7-24.0 °C
- Humidity (%): 46-73 %
- Photoperiod: 12-hrs dark / 12-hrs light
Route of administration:
oral: gavage
Vehicle:
water
Analytical verification of doses or concentrations:
yes
Dose / conc.:
0 mg/kg bw/day (nominal)
Remarks:
Solvent control
Dose / conc.:
100 mg/kg bw/day (nominal)
Remarks:
Low-dose level
Dose / conc.:
300 mg/kg bw/day (nominal)
Remarks:
Mid-dose level
Dose / conc.:
1 000 mg/kg bw/day (nominal)
Remarks:
High-dose level
No. of animals per sex per dose:
For Solvent control: 31, females
For Low-dose level: 30, females
For Mid-dose level: 30, females
For High-dose level: 30, females
Control animals:
yes, concurrent vehicle
Clinical signs:
effects observed, non-treatment-related
Description (incidence and severity):
One rat in low-dose group (No. 2107) was dehairing on its right forelimb or/and hindlimb during GD8~20; one rat in the mid-dose group (No. 2223) was dehairing on its right breast during GD18~20; one rat in high-dose group (No. 2312) was dehairing on its right prothorax during GD6~20, and another rat (No. 2327) was dehairing on its breast during GD18~20. As dehairing in the dosed groups was incidental without dose-relationship, it is not considered to be toxicologically insignificant. Most of rats in the mid- and high- dose groups had red faeces after being administrated, but which was considered to be caused with the color of the test item and without adverse effect.
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
Water consumption and compound intake (if drinking water study):
no effects observed
Pre- and post-implantation loss:
effects observed, non-treatment-related
Description (incidence and severity):
In the mid-dose group, the post-implantion loss had a significant decrease with the control group (P≤0.05), but that was considered without toxicological significance.
Early or late resorptions:
effects observed, non-treatment-related
Description (incidence and severity):
In the mid-dose group, the percent of absorbed fetuses had a significant decrease with the control group (P≤0.05), but that was considered without toxicological significance.
Dead fetuses:
no effects observed
Dose descriptor:
NOAEL
Effect level:
1 000 mg/kg bw/day (nominal)
Based on:
test mat.
Basis for effect level:
clinical signs
mortality
body weight and weight gain
food consumption and compound intake
water consumption and compound intake
pre and post implantation loss
early or late resorptions
dead fetuses
Fetal body weight changes:
effects observed, non-treatment-related
Description (incidence and severity):
A statistically significant increase in the body weight of live fetuses was observed in the low- and mid- dose groups compared with the control group (P≤0.05 or P≤0.01), but that was considered without toxicological significance.
Changes in sex ratio:
no effects observed
External malformations:
no effects observed
Skeletal malformations:
effects observed, non-treatment-related
Description (incidence and severity):
One fetus in the low-dose group showed signs of incomplete ossification of skull bone, but the frequency of these abnormalities in the dose groups had no significant difference compared with the control group (P>0.005) and which were considered as incidental findings. Some examined fetuses had less than six sternal ossification points, but there was no difference in the mean number of sternal ossification points in all dose groups (P>0.05).
Visceral malformations:
effects observed, non-treatment-related
Description (incidence and severity):
4, 2 and 2 fetuses in the control group, mid- and high- dose group showed signs of hydronephrosis in one or double kindeys, but the frequency of these abnormalities in the dose groups had no significant difference compared with the control group (P>0.005) and which were considered as incidental findings.
Dose descriptor:
NOAEL
Effect level:
1 000 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
changes in sex ratio
fetal/pup body weight changes
external malformations
skeletal malformations
visceral malformations
Abnormalities:
no effects observed
Developmental effects observed:
no
Lowest effective dose / conc.:
1 000 mg/kg bw/day (nominal)
Treatment related:
no
Conclusions:
According to OECD 414 test method, the no observed adverse effect level of CJ302 in rat’s maternal toxicity, or teratogenic and embyo-/fetotoxicity performance was 1000 mg/kg.d.
Executive summary:

This test using the procedures outlined in the SYRICI Study Plan for G1863B0030 and OECD 414. There were thirty or thirty-one mated female rats in each group, which resulted in 31, 29, 26 and 27 pregnant rats in vehicle control group and the low-, mid- and high-, respectively. CJ302 (100, 300 or 1000 mg/kg.d.) was given orally by gavage daily during the day 5~19 of pregnancy (GD5~19), and were euthanized with CO2 on GD20.

No deaths or treatment-related clinical toxicity were observed in the course of this study. Most of rats in the mid- and high-dose groups had red faeces after being administrated, but which was considered to be caused with the color of CJ302 and without adverse effect. During the administration period, the mean body weights and body weight change of pregnant rats in all dosed groups had no statistically significant difference compared with the control group. At the same time, no significant effect in food aonsumption of the pregnant rat during the treated period was observed in all dose groups. In all dose groups, no adverse effect was observed in all prenatal reproductive parameters.

The fetal examination showed that no adverse effect in body weight and sex distribution of live fetuses was observed in all dosed group. No adverse effect attribution to treatment was observed across all groups with respect to examined, soft-tissue and skeletal malformations or variations except that some examined fetuses had less than six sternal ossification points, but there was no difference in the mean number of sternal ossification points in all dosed groups as compared with the control group.

Therefore, the no observed adverse effect levelof CJ302 in rat’s maternal toxicity, or teratogenic and embyo-/fetotoxicity performance was 1000 mg/kg.d.

Effect on developmental toxicity: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
1 000 mg/kg bw/day
Study duration:
subacute
Species:
rat
Additional information

Effect on developmental toxicity: via oral route

There were thirty or thirty-one mated female rats in each group, which resulted in 31, 29, 26 and 27 pregnant rats in vehicle control group and the low-, mid- and high-, respectively. CJ302 (100, 300 or 1000 mg/kg.d.) was given orally by gavage daily during the day 5~19 of pregnancy (GD5~19), and were euthanized with CO2 on GD20.

No deaths or treatment-related clinical toxicity were observed in the course of this study. Most of rats in the mid- and high-dose groups had red faeces after being administrated, but which was considered to be caused with the color of CJ302 and without adverse effect. During the administration period, the mean body weights and body weight change of pregnant rats in all dosed groups had no statistically significant difference compared with the control group. At the same time, no significant effect in food aonsumption of the pregnant rat during the treated period was observed in all dose groups. In all dose groups, no adverse effect was observed in all prenatal reproductive parameters.

The fetal examination showed that no adverse effect in body weight and sex distribution of live fetuses was observed in all dosed group. No adverse effect attribution to treatment was observed across all groups with respect to examined, soft-tissue and skeletal malformations or variations except that some examined fetuses had less than six sternal ossification points, but there was no difference in the mean number of sternal ossification points in all dosed groups as compared with the control group.

Therefore, the no observed adverse effect level of CJ302 in rat’s maternal toxicity, or teratogenic and embyo-/fetotoxicity performance was 1000 mg/kg.d.

Justification for classification or non-classification