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Diss Factsheets

Toxicological information

Developmental toxicity / teratogenicity

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Administrative data

Endpoint:
developmental toxicity
Remarks:
Pilot study
Type of information:
experimental study
Adequacy of study:
supporting study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2015
Report date:
2015

Materials and methods

Test guideline
Qualifier:
no guideline followed
Principles of method if other than guideline:
Evaluation of the maternal and developmental toxicity of the test substance was performed when administered to pregnant rats from around the time of implantation to the end of gestation.
GLP compliance:
no

Test material

1
Chemical structure
Reference substance name:
8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridine-2-carboxylic acid
Cas Number:
353258-35-2
Molecular formula:
C9H4ClF3N2O2
IUPAC Name:
8-chloro-6-(trifluoromethyl)imidazo[1,2-a]pyridine-2-carboxylic acid
Specific details on test material used for the study:
Test substance: IN-QEK31-011
Batch No.: SG0312574
Purity: 98.2%

Test animals

Species:
rat
Strain:
other: Crl:CD(SD)

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
other: 0.5% methylcellulose with 0.1% Tween 80
Analytical verification of doses or concentrations:
no
Duration of treatment / exposure:
GD 6-20
Frequency of treatment:
Once daily
Doses / concentrationsopen allclose all
Dose / conc.:
100 mg/kg bw/day
Dose / conc.:
500 mg/kg bw/day
Dose / conc.:
1 000 mg/kg bw/day
No. of animals per sex per dose:
8 females per group
Control animals:
yes, concurrent vehicle

Results and discussion

Results: maternal animals

General toxicity (maternal animals)

Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
Clinical signs of toxicity were evident at 1000 mg/kg/day and included dehydration (5 animals), hunched over appearance (4 animals), lethargy (3 animals), decreased muscle tone (4 animals), scant feces (2 animals), and prostrate and tremors (1 animal). One animal at 500 mg/kg/day was dehydrated.
Mortality:
mortality observed, treatment-related
Description (incidence):
There were 5 animals found dead from GD 8 to 10 at 1000 mg/kg/day. The remaining 3 animals at this level were subsequently euthanized on GD 10 or 11due to adverse weight gain reductions and/or clinical signs of toxicity.
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
There were treatment-related, statistically significant adverse effects observed on body weight parameters at ≥ 500 mg/kg/day. At 1000 mg/kg/day mean maternal body weights were reduced 11%-23% as compared to control group. During the first few days of dosing (GD 6-8) animals lost an average of 28 grams compared to an average gain of 12 grams for the control group. At 500 mg/kg/day, mean maternal body weights were up to 8% lower than control group throughout the study. These effects were slightly more pronounced towards the end of the study; terminal absolute and adjusted (minus products of conception) were 8% lower than control group. During the first few days of dosing (GD 6-8) animals at this level lost an average of 2 grams compared to an average gain of 12 grams for the control group. Reduced body weight gains persisted at this level resulting in mean overall (GD 6-21) absolute/adjusted body weight gains that were 20%/47% lower than control group, respectively. At 100 mg/kg/day, mean body weights were generally comparable to control group throughout the study; terminal absolute/adjusted body weights were within 3% of control group values. Mean body weight gains were 54% lower than control at this level during the first few days of dosing (GD 6-8). Some recovery was subsequently evident; mean overall absolute/adjusted body weight gains were within 9% of the control group value.
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
There were no treatment-related, statistically significant adverse effects observed on food consumption parameters at ≥ 500 mg/kg/day. At 1000 mg/kg/day, mean food consumption was 71%-75% lower than control from gestation day s 6-10. At 500 mg/kg/day, food consumption was reduced 11-22% as compared to control group throughout the study. Mean overall food consumption was 16% lower than control group at this level. At 100 mg/kg/day mean food consumption was 13% lower than control group during the first few days of dosing (GD 6-8). Thereafter, food consumption was up to 9% lower than control group. Mean overall food consumption was statistically significantly reduced (7% lower than control); however the magnitude was minimal and non-adverse at this level.
Organ weight findings including organ / body weight ratios:
no effects observed
Description (incidence and severity):
There were no treatment-related, statistically significant effects observed on kidney weight parameters at any level tested. Kidney weights were not collected for animals that were euthanized prior to scheduled sacrifice (including all animals at 1000 mg/kg/day).
Gross pathological findings:
effects observed, treatment-related
Description (incidence and severity):
Black discoloration of the glandular portion of the stomach was observed in 5/8 animals at 1000 mg/kg/day. There were no other maternal gross observations on this study.

Maternal developmental toxicity

Total litter losses by resorption:
no effects observed

Effect levels (maternal animals)

Key result
Remarks on result:
other: Under the conditions of this study, there was no adverse maternal toxicity observed at 100 mg/kg/day.

Results (fetuses)

Fetal body weight changes:
no effects observed
Details on embryotoxic / teratogenic effects:
There were no totally resorbed litters observed on this study. There were no treatment-related effects on mean number of resorptions observed at any level tested. Data from animals at 1000 mg/kg/day was not available since these animals were either found dead or euthanized prior to scheduled sacrifice by gestation day 11. There were no statistically significant, treatment-related effects observed on mean fetal weight at any level tested. Data from animals at 1000 mg/kg/day was not available since these animals were either found dead or euthanized prior to scheduled sacrifice by gestation day 11. There were no treatment-related fetal anomalies observed on this study. Data from animals at 1000 mg/kg/day was not available since these animals were either found dead or euthanized prior to scheduled sacrifice by gestation day 11.

Effect levels (fetuses)

Key result
Remarks on result:
other: There was no developmental toxicity observed at 500 mg/kg/day or lower.

Overall developmental toxicity

Key result
Developmental effects observed:
no

Applicant's summary and conclusion

Conclusions:
Under the conditions of this study, there was no adverse maternal toxicity observed at 100 mg/kg/day. There was no developmental toxicity observed at 500 mg/kg/day or lower.
Executive summary:

The objective of this study was to provide a preliminary evaluation of the maternal and developmental toxicity of the test substance when administered to pregnant rats from around the time of implantation to the end of gestation.


There were treatment-related and adverse effects on body weight and food consumption parameters at ≥500 mg/kg/day and maternal gross findings, clinical signs of toxicity and early mortality observed at 1000 mg/kg/day. There was no developmental toxicity observed at 500 mg/kg/day or lower. The mean number of corpora lutea, implantation sites, resorptions, and live fetuses, as well as sex ratio and fetal weight, were comparable across all groups. There were no test substance-related fetal external malformations or variations observed at any treatment level.


There were no surviving animals after gestation day 11 at 1000 mg/kg/day. Therefore, developmental toxicity at this level could not be properly assessed.


Under the conditions of this study, there was no adverse maternal toxicity observed at 100 mg/kg/day. There was no developmental toxicity observed at 500 mg/kg/day or lower.