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Toxicological information

Developmental toxicity / teratogenicity

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Administrative data

Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
other information
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study

Data source

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

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
other: ICH guideline S5A: Detection of Toxicity to Reproduction for Medicinal Products; EU: CPMP/ICH/386/95, adopted September 1993
Version / remarks:
1993
GLP compliance:
yes
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
Sodium 1-[6-(morpholin-4-yl)pyrimidin-4-yl]-4-(1H-1,2,3-triazol-1-yl)-1H-pyrazol-5-olate
EC Number:
875-892-5
Cas Number:
1375799-59-9
Molecular formula:
C13 H14 N8 O2 . Na
IUPAC Name:
Sodium 1-[6-(morpholin-4-yl)pyrimidin-4-yl]-4-(1H-1,2,3-triazol-1-yl)-1H-pyrazol-5-olate

Test animals

Species:
rat
Strain:
Wistar
Remarks:
(Hsd Cpb:WU)

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
other: ethanol/Solutol ® HS 15/demineralized water (1:4:5 v/v/v)
Details on exposure:
PREPARATION OF DOSING SOLUTIONS:

The test item was administered by gavage in ethanol/Solutol® HS 15/demineralized water (1:4:5 v/v/v). The purity was taken into account. The administration volume was 10 mL/kg body weight. The formulations were prepared as needed taking into account the analytically determined stability. The test substance was administered as a suspension in the vehicle. The formulation was stored at room temperature. It was stirred with a magnetic stirrer for several minutes (until an obviously homogenous distribution occurred) before administration. It was also stirred during administration.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Before start of treatment, the suitability of the formulation was confirmed by the analysis of concentration, homogeneity, and stability of dosage forms prepared in the same way as it was done in the study (0.5 and 5 mg/mL, covering the concentration range used). Analyses were carried out before the start of the study. Homogeneity tests and content checks of the active ingredient in samples with concentrations of 0.3, 1 (content checks, only), and 3 mg/mL were carried out twice during the study.
Details on mating procedure:
The animals were mated by placing one or two females overnight into a Type IIIh cage together with one male rat. If sperm was detected in the vaginal smear taken on the morning following mating, this day was regarded as day 0 of gestation.
Duration of treatment / exposure:
The females were treated daily from days 6 to 17 of gestation.
Frequency of treatment:
daily
Doses / concentrationsopen allclose all
Dose / conc.:
30 mg/kg bw/day (actual dose received)
Dose / conc.:
10 mg/kg bw/day (actual dose received)
Dose / conc.:
3 mg/kg bw/day (actual dose received)
Dose / conc.:
0 mg/kg bw/day (actual dose received)
No. of animals per sex per dose:
22 females in the main groups and 4 females in the satellite groups
Control animals:
yes, concurrent vehicle

Results and discussion

Results: maternal animals

Effect levels (maternal animals)

Key result
Dose descriptor:
NOAEL
Effect level:
10 mg/kg bw/day (actual dose received)
Based on:
test mat.
Basis for effect level:
body weight and weight gain
pre and post implantation loss

Maternal abnormalities

Abnormalities:
effects observed, treatment-related
Localisation:
placenta

Results (fetuses)

Effect levels (fetuses)

Key result
Dose descriptor:
NOAEL
Effect level:
10 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
reduction in number of live offspring
fetal/pup body weight changes
external malformations

Fetal abnormalities

Abnormalities:
effects observed, treatment-related
Localisation:
external: eye

Overall developmental toxicity

Developmental effects observed:
not specified

Applicant's summary and conclusion

Executive summary:

In the present study 22 inseminated female Wistar rats were exposed to 0, 3, 10, and 30 mg/kg bw of the test item in ethanol/Solutol ® HS 15/demineralized water (1:4:5 v/v/v) as vehicle daily from day 6 to day 17 p.c. The fetuses were delivered by cesarean section on day 21 of gestation. Investigation was performed on general tolerance of the test substance by the females as well as on its effect on intrauterine development. Four additional females per group were treated with the doses of 0, 3, 10, and 30 mg/kg from days 6 to 17 p.c. for determination of test substance in the plasma of the females. Appearance, behavior, and mortality were unaffected at dose levels up to 30 mg/kg bw/day. Mean body weight development was decreased at dose level of 30 mg/kg bw/day. Food intake was transiently decreased at the dose levels of 30 mg/kg bw/day. No treatment related gross pathological findings occurred at dose levels up to 30 mg/kg bw/day.


The gestation rate was unaffected by treatment at dose levels up to 30 mg/kg bw/day. Morphological appearance and weight of placentas were only affected by treatment at dose level 30 mg/kg bw/day. Postimplantation loss was increased in dose level 30 mg/kg. Fetal sex distribution was unaffected by treatment at dose levels up to 30 mg/kg bw/day. Weights of fetuses were statistically significantly decreased at dose levels of 30 mg/kg bw/day. Dosing with Molidustat at 30 mg/kg revealed an increased incidence of ocular malformations. A treatment related effect on skeletal deviations was not seen up to a dose level of 30 mg/kg bw/day.


In summary, treatment-related maternal toxicity and developmental toxicity characterized mainly by ocular malformations, reduced fetal weight and increased postimplantation loss were seen at a daily dose of 30 mg/kg of the test item. Consequently, the following no-observed-adverse-effect levels (NOAELs) were determined:


Maternal toxicity: 10 mg/kg bw/day


Developmental toxicity: 10 mg/kg bw/day