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Administrative data

Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Study period:
From January 14, 2020 to August 25, 2020
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2020
Report date:
2020

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
GLP compliance:
yes

Test material

Constituent 1
Chemical structure
Reference substance name:
5-({4-chloro-6-[ethyl(phenyl)amino]-1,3,5-triazin-2-yl}amino)-4-hydroxy-3-[(1-sulfo-2-naphthyl)diazenyl]naphthalene-2,7-disulfonic acid, lithium sodium salts
EC Number:
942-803-7
Molecular formula:
Not applicable; this UVCB substance contains: C31H21ClN7O10S3.xLi.yNa, (x + y) = 3; 0 < (x,y) < 3 with 804.0 < MW < 852.1 g/mol (UVCB substance), C31H22N7O11S3.xLi.yNa, (x + y) = 3; 0 < (x,y) < 3 with 785.5 < MW < 833.7 g/mol (UVCB substnace), and traces of NaCl and Na2SO4.
IUPAC Name:
5-({4-chloro-6-[ethyl(phenyl)amino]-1,3,5-triazin-2-yl}amino)-4-hydroxy-3-[(1-sulfo-2-naphthyl)diazenyl]naphthalene-2,7-disulfonic acid, lithium sodium salts
Test material form:
solid: particulate/powder
Remarks:
migrated information: powder

Test animals

Species:
rat
Strain:
Sprague-Dawley
Details on test animals or test system and environmental conditions:
- Source: SPF (Beijing) biotechnology Co., Ltd.
- Age at study initiation: 70 days old
- 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: 35 days
- Temperature (°C): 22.9-26.3 °C
- Humidity (%): 41-82 %
- Photoperiod: 12-hrs dark / 12-hrs light

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
water
Doses / concentrations
Dose / conc.:
1 000 mg/kg bw/day (nominal)
Control animals:
yes, concurrent vehicle

Results and discussion

Results: maternal animals

General toxicity (maternal animals)

Clinical signs:
effects observed, non-treatment-related
Description (incidence and severity):
All of rats in the dosed group had red faeces after being administrated but without any other obvious signs, so red faeces were considered to be caused with the color of the test item and without adverse effects.
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
Histopathological findings: non-neoplastic:
effects observed, non-treatment-related
Description (incidence and severity):
In both control group and dosed group, no abnormalities in the macroscopic examiantion were observed. Thyroid gland ectopic thymus and thytoid gland ultimobranchial cyst were observed in some animals in both control group and dosed group, but the histopathological findings were low incidence and the severity was mild, the histopathological finings were considered to be spontaneous lesions in SD rats.
In the dosed group, no statistically significant difference was observed in the mean weights of thyroid glands, and the T3 and T4 level in serum compared with the control group (P>0.005). TSH value of all animals was lower than 0.005μIU/ml that was the lowest detection limit of the lab, so no statistically significant difference can be observed ubder the conditions of this study, but based on the results of T3 and T4 levels in serum, it can be inferred that the thyroid function is not affected.
According to the above results, it is considered that no treatment-related adverse effects on the thyroid function and parenchyma can be produced in the pregnant rats after the prenatal exposure of the test item.

Maternal developmental toxicity

Pre- and post-implantation loss:
no effects observed
Early or late resorptions:
no effects observed
Dead fetuses:
no effects observed
Changes in pregnancy duration:
no effects observed

Effect levels (maternal animals)

Dose descriptor:
NOAEL
Effect level:
1 000 mg/kg bw/day (nominal)
Based on:
test mat.
Basis for effect level:
body weight and weight gain
changes in pregnancy duration
clinical signs
dead fetuses
early or late resorptions
food consumption and compound intake
histopathology: non-neoplastic
mortality
pre and post implantation loss

Results (fetuses)

Fetal body weight changes:
no effects observed
Changes in sex ratio:
no effects observed
External malformations:
no effects observed
Skeletal malformations:
effects observed, non-treatment-related
Description (incidence and severity):
Some examined fetuses had lessthan six sternal ossification points, but the mean number of sternal ossification points in the dosed group had no ststistically difference compared with the control group (P>0.05). Twelve and twenty fetuses in the control group and the dosed group showed signs of parietal imcomplete ossification, respectively. The total incidence of above abnormalities frequency in the dosed group was significantly higher than that of the control group (P≤0.05 or P≤0.01), but most of these abnormalities occurred in an individual litter (Animal No.: 2309), and there was no significant difference in the abnormal frequency of litter level compared with that of the control group (P>0.05), which were considered as incidental findings.
Visceral malformations:
effects observed, non-treatment-related
Description (incidence and severity):
Six fetuses in the dosed group showed signs of small brain, and 3 fetuses showed signs of pyelectasis in unilateral or bilateral kidneys. The total incidence of above abnormalities frequency in the dosed group was significantly higher than that of the control group (P≤0.05 or P≤0.01), but most of these abnormalities occurred in an individual litter (Animal No.: 2309), and there was no significant difference in the abnormal frequency of litter level compared with that of the control group (P>0.05), which were considered as incidental findings.

Effect levels (fetuses)

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

Overall developmental toxicity

Developmental effects observed:
no
Lowest effective dose / conc.:
1 000 mg/kg bw/day (nominal)
Treatment related:
no

Applicant's summary and conclusion

Conclusions:
According to OECD 414 test method, the no observed adverse effect level of CJ306 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 G1963B0040 and OECD 414. There were twenty-eight mated female rats in each group, which resulted in 28 and 21 pregnant rats in solvent control group and dosed group, respectively. CJ306 (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. All of rats in the dosed groups had red faeces after being administrated, but which was considered to be caused with the color of CJ306 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, sex distribution and examined malformations of fetuses was observed in the dosed group. No adverse effect attribution to treatment was observed across the dosed groups with respect to skeletal and visceral 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 the dosed groups as compared with the control group.

Therefore, the no observed adverse effect level of CJ306 in rat’s maternal toxicity, or teratogenic and embyo-/fetotoxicity performance was 1000 mg/kg.d.

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