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Diss Factsheets

Toxicological information

Developmental toxicity / teratogenicity

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Administrative data

Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
supporting study
Reliability:
4 (not assignable)
Rationale for reliability incl. deficiencies:
secondary literature

Data source

Reference
Reference Type:
other company data
Title:
Unnamed
Year:
2018

Materials and methods

Test guideline
Qualifier:
no guideline followed
Principles of method if other than guideline:
- Principle of test: Embryo-Fetal Developmental Toxicity in Rats
GLP compliance:
yes
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-1,2,3,4-tetrazol-1-yl)-1-{5-[4-(2,2,2-trifluoroethoxy)phenyl]pyridin-2-yl}propan-2-ol
EC Number:
841-499-2
Cas Number:
1340593-59-0
Molecular formula:
C23H16F7N5O2
IUPAC Name:
2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-1,2,3,4-tetrazol-1-yl)-1-{5-[4-(2,2,2-trifluoroethoxy)phenyl]pyridin-2-yl}propan-2-ol
Specific details on test material used for the study:
not specified

Test animals

Species:
rat
Strain:
Sprague-Dawley
Details on test animals or test system and environmental conditions:
not specified

Administration / exposure

Route of administration:
oral: unspecified
Vehicle:
CMC (carboxymethyl cellulose)
Details on exposure:
VEHICLE
- Concentration of vehicle : 0.5%
Analytical verification of doses or concentrations:
not specified
Details on analytical verification of doses or concentrations:
not specified
Details on mating procedure:
not specified
Duration of treatment / exposure:
Gestation Day (GD) 6 through 17
Frequency of treatment:
daily
Doses / concentrationsopen allclose all
Dose / conc.:
0 mg/kg bw/day (nominal)
Remarks:
Control
Dose / conc.:
3 mg/kg bw/day (nominal)
Remarks:
Low dose
Dose / conc.:
10 mg/kg bw/day (nominal)
Remarks:
Mid dose
Dose / conc.:
40 mg/kg bw/day (nominal)
Remarks:
High dose
No. of animals per sex per dose:
25
Control animals:
yes, concurrent vehicle
Details on study design:
- Other: Blood for TK assessments was collected from satellite groups of 3-5 animals on GD 6 and 17

Examinations

Maternal examinations:
Not specified
Ovaries and uterine content:
Not specified
Fetal examinations:
Not specified
Statistics:
Not specified
Indices:
Not specified
Historical control data:
Not specified

Results and discussion

Results: maternal animals

General toxicity (maternal animals)

Clinical signs:
no effects observed
Dermal irritation (if dermal study):
not examined
Mortality:
no mortality observed
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
For further details see section "details on results" below.
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
For further details see section "details on results" below.
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
not examined
Haematological findings:
not specified
Clinical biochemistry findings:
not examined
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
not specified
Gross pathological findings:
not specified
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
not specified
Histopathological findings: neoplastic:
not specified
Other effects:
not specified
Details on results:
Maternal toxicity was evident at 40 mg/kg bw/day and consisted of significantly lower gestation body weights, lower body weight gain, and reduced food consumption.

Maternal developmental toxicity

Number of abortions:
not specified
Pre- and post-implantation loss:
not specified
Total litter losses by resorption:
not specified
Early or late resorptions:
not specified
Dead fetuses:
not specified
Changes in pregnancy duration:
not specified
Changes in number of pregnant:
not specified
Other effects:
effects observed, treatment-related
Description (incidence and severity):
For further details see section "details on maternal toxicity effects" below.
Details on maternal toxic effects:
Maternal toxicity was evident at 40 mg/kg bw/day and consisted of significantly lower gestation body weights.

Effect levels (maternal animals)

open allclose all
Dose descriptor:
LOAEL
Remarks:
maternal toxicity
Effect level:
40 mg/kg bw/day (nominal)
Based on:
test mat.
Basis for effect level:
body weight and weight gain
food consumption and compound intake
Dose descriptor:
NOAEL
Effect level:
10 mg/kg bw/day (nominal)
Based on:
test mat.
Basis for effect level:
other: no adverse signs of toxicity observed

Maternal abnormalities

Abnormalities:
no effects observed

Results (fetuses)

Fetal body weight changes:
no effects observed
Reduction in number of live offspring:
not specified
Changes in sex ratio:
not specified
Changes in litter size and weights:
not specified
Changes in postnatal survival:
not specified
External malformations:
no effects observed
Skeletal malformations:
no effects observed
Visceral malformations:
no effects observed
Other effects:
no effects observed
Details on embryotoxic / teratogenic effects:
Mean fetal body weights (males, females, and combined) and fetal external, visceral, and skeletal malformations or variations were unaffected at any of the dose levels evaluated.

Effect levels (fetuses)

Dose descriptor:
NOAEL
Effect level:
40 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: No developmental toxicity observed at the highest dose evaluated

Fetal abnormalities

Abnormalities:
no effects observed

Overall developmental toxicity

Developmental effects observed:
no

Applicant's summary and conclusion

Conclusions:
In an embryo-fetal developmental toxicity study, the test item in 0.5% CMC was administered to 25 time-mated female SD rats per dose orally at dose levels of 0,3, 10 and 40 mg/kg bw/day from day 6 through 17 of gestation. Maternal toxicity was evident at 40 mg/kg bw/day and consisted of significantly lower gestation body weights, lower body weight gain, and reduced food consumption. Thus, NOAEL for maternal toxicity is 10 mg/kg bw/day. There were no treatment-related effects in developmental parameters. Thus, the NOAEL for developmental toxicity is 40 mg/kg bw/day.
Executive summary:

In an embryo-fetal developmental toxicity study, the test item in 0.5% CMC was administered to 25 time-mated female SD rats per dose orally at dose levels of 0,3, 10 and 40 mg/kg bw/day from day 6 through 17 of gestation. Maternal toxicity was evident at 40 mg/kg bw/day and consisted of significantly lower gestation body weights, lower body weight gain, and reduced food consumption. Thus, NOAEL for maternal toxicity is 10 mg/kg bw/day. There were no treatment-related effects in developmental parameters. Thus, the NOAEL for developmental toxicity is 40 mg/kg bw/day.