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EC number: 875-892-5 | CAS number: 1375799-59-9
- Life Cycle description
- Uses advised against
- Endpoint summary
- Appearance / physical state / colour
- Melting point / freezing point
- Boiling point
- Density
- Particle size distribution (Granulometry)
- Vapour pressure
- Partition coefficient
- Water solubility
- Solubility in organic solvents / fat solubility
- Surface tension
- Flash point
- Auto flammability
- Flammability
- Explosiveness
- Oxidising properties
- Oxidation reduction potential
- Stability in organic solvents and identity of relevant degradation products
- Storage stability and reactivity towards container material
- Stability: thermal, sunlight, metals
- pH
- Dissociation constant
- Viscosity
- Additional physico-chemical information
- Additional physico-chemical properties of nanomaterials
- Nanomaterial agglomeration / aggregation
- Nanomaterial crystalline phase
- Nanomaterial crystallite and grain size
- Nanomaterial aspect ratio / shape
- Nanomaterial specific surface area
- Nanomaterial Zeta potential
- Nanomaterial surface chemistry
- Nanomaterial dustiness
- Nanomaterial porosity
- Nanomaterial pour density
- Nanomaterial photocatalytic activity
- Nanomaterial radical formation potential
- Nanomaterial catalytic activity
- Endpoint summary
- Stability
- Biodegradation
- Bioaccumulation
- Transport and distribution
- Environmental data
- Additional information on environmental fate and behaviour
- Ecotoxicological Summary
- Aquatic toxicity
- Endpoint summary
- Short-term toxicity to fish
- Long-term toxicity to fish
- Short-term toxicity to aquatic invertebrates
- Long-term toxicity to aquatic invertebrates
- Toxicity to aquatic algae and cyanobacteria
- Toxicity to aquatic plants other than algae
- Toxicity to microorganisms
- Endocrine disrupter testing in aquatic vertebrates – in vivo
- Toxicity to other aquatic organisms
- Sediment toxicity
- Terrestrial toxicity
- Biological effects monitoring
- Biotransformation and kinetics
- Additional ecotoxological information
- Toxicological Summary
- Toxicokinetics, metabolism and distribution
- Acute Toxicity
- Irritation / corrosion
- Sensitisation
- Repeated dose toxicity
- Genetic toxicity
- Carcinogenicity
- Toxicity to reproduction
- Specific investigations
- Exposure related observations in humans
- Toxic effects on livestock and pets
- Additional toxicological data
Developmental toxicity / teratogenicity
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:
- 2 015
- 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
- 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
Constituent 1
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
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