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EC number: 841-499-2 | CAS number: 1340593-59-0
- 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
Repeated dose toxicity: oral
Administrative data
- Endpoint:
- short-term repeated dose toxicity: oral
- 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:
- 2 018
Materials and methods
Test guideline
- Qualifier:
- no guideline followed
- Principles of method if other than guideline:
- - Principle of test:
7-day repeat-dose range-finding study
- GLP compliance:
- no
- Limit test:
- no
Test material
- 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
Constituent 1
Test animals
- Species:
- rat
- Strain:
- Sprague-Dawley
- Details on species / strain selection:
- not specified
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- not specified
Administration / exposure
- Route of administration:
- oral: unspecified
- Vehicle:
- other: 20% Cremophor EL
- Details on oral exposure:
- not specified
- Analytical verification of doses or concentrations:
- not specified
- Details on analytical verification of doses or concentrations:
- not specified
- Duration of treatment / exposure:
- 7 days
- Frequency of treatment:
- once daily
Doses / concentrationsopen allclose all
- Dose / conc.:
- 0 mg/kg bw/day (nominal)
- Remarks:
- Control
- Dose / conc.:
- 30 mg/kg bw/day (nominal)
- Remarks:
- Low dose
- Dose / conc.:
- 100 mg/kg bw/day (nominal)
- Remarks:
- Mid dose
- Dose / conc.:
- 300 mg/kg bw/day (nominal)
- Remarks:
- High dose
- No. of animals per sex per dose:
- 3
- Control animals:
- yes
- Details on study design:
- not specified
- Positive control:
- no
Examinations
- Observations and examinations performed and frequency:
- no specified
- Sacrifice and pathology:
- Rats were sacrificed moribund on Days 6 and 7 in the 100 and 300 mg/kg bw groups.
- Statistics:
- no specified
Results and discussion
Results of examinations
- Clinical signs:
- effects observed, treatment-related
- Description (incidence and severity):
- For futher details see section below "details on results"
- Mortality:
- not specified
- Body weight and weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- For futher details see section below "details on results"
- Food consumption and compound intake (if feeding study):
- effects observed, treatment-related
- Description (incidence and severity):
- For futher details see section below "details on results"
- Food efficiency:
- not specified
- Water consumption and compound intake (if drinking water study):
- not specified
- Ophthalmological findings:
- not specified
- Haematological findings:
- not specified
- Clinical biochemistry findings:
- effects observed, treatment-related
- Description (incidence and severity):
- For futher details see section below "details on results"
- Urinalysis findings:
- not specified
- Behaviour (functional findings):
- not examined
- Immunological findings:
- not examined
- Organ weight findings including organ / body weight ratios:
- effects observed, treatment-related
- Description (incidence and severity):
- For futher details see section below "details on results"
- Gross pathological findings:
- effects observed, treatment-related
- Description (incidence and severity):
- For futher details see section below "details on results"
- Neuropathological findings:
- not examined
- Histopathological findings: non-neoplastic:
- effects observed, treatment-related
- Description (incidence and severity):
- For futher details see section below "details on results"
- Histopathological findings: neoplastic:
- not examined
- Details on results:
- Rats were sacrificed moribund on Days 6 and 7 in the 100 and 300 mg/kg bw groups. Rats dosed at 100 and 300 mg/kg bw/day exhibited decreased feces, salivation, stained/rough haircoat, ataxia, hunched/low posture, labored breathing, anogenital staining, decreased activity, head tilt, temperature that was cold to the touch, scabbed skin, and drooping eyelids. Body weights and food consumption were generally lower for the animals dosed at 100 and 300 mg/kg bw/day when compared to the control group throughout this study.
Increased alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase, lactate dehydrogenase, gamma-glutamyl transferase (GGT) levels, glucose, and cholesterol values were observed.
Absolute and relative liver weights of the rats dosed orally at 30 and 100 mg/kg bw/day were increased compared to the controls. For animals dosed at 100 mg/kg bw/day, absolute and relative prostate weight in males, absolute thymus weight, and absolute and relative spleen weight were lower when compared to the controls. Test-item related microscopic findings were present in the liver of the males and females dosed orally at 30, 100, and 300 mg/kg bw/day and in the epididymides and testes of males dosed orally at 100 and 300 mg/kg bw/day. Microscopic findings in the liver were dose-dependent and consisted of mild to moderate, diffuse hepatocellular hypertrophy in males and females (30, 100, and 300 mg/kg bw/day) and minimal to moderate multifocal vacuolation of midzonal and centrilobular hepatocytes in rats dosed at 100 and 300 mg/kg bw/day. At 100 mg/kg bw/day and 300 mg/kg bw/day, microscopic findings in the epididymides consisted of minimal, multifocal, bilateral, multinucleate spermatids (symplasts) in the epididymidal tubules. At 100 mg/kg bw/day and 300 mg/kg bw/day, findings in the testes consisted of mild, multifocal, bilateral, multinucleate spermatids (symplasts) in the seminiferous tubules with mild, multifocal, bilateral degeneration of the seminiferous tubules.
Effect levels
open allclose all
- Dose descriptor:
- LOAEL
- Effect level:
- 30 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- histopathology: non-neoplastic
- organ weights and organ / body weight ratios
- Dose descriptor:
- NOEL
- Effect level:
- < 30 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: at 30 mg/kg bw/day effects on the organ weight and in the histopathology were observed
Target system / organ toxicity
- Critical effects observed:
- no
Any other information on results incl. tables
Blood analysis:
On Day 7, the 30 mg/kg bw/day Cmax was 80,100 ng/mL for males and 77,200 ng/mL for females. Corresponding AUC^2-24 values were 1,530,000 h x ng/mL for males and 1,520,000 h x ng/mL for females.
Applicant's summary and conclusion
- Conclusions:
- In a 7-day repeated dose range finding study, rats were orally exposed to the test item at doses of 0, 30, 100 and 300 mg/kg bw/day. Based on the organ weight and histopathology data, the no-observed-effect-level (NOEL) was considered to be less than 30 mg/kg bw/day.
- Executive summary:
In a 7-day repeated dose range finding study, the test item in 20% Cremophor EL was administered to three Sprague Dawley rats/sex/dose via the oral route with dose levels of 0, 30, 100, or 300 mg/kg bw/day. Rats dosed at 100 and 300 mg/kg bw/day exhibited clinical signs. Body weights and food consumption were generally lower for the animals dosed at 100 and 300 mg/kg bw/day, when compared to the control group throughout this study. The clinical chemistry parameter values were increased. Absolute and relative liver weights of the rats dosed orally at 30 and 100 mg/kg bw/day were increased compared to the controls. For animals dosed at 100 mg/kg bw/day, absolute and relative prostate weight in males, absolute thymus weight, and absolute and relative spleen weight were lower when compared to the controls. Test item-related microscopic findings were present in the liver of the males and females dosed orally at 30, 100, and 300 mg/kg bw/day and in the epididymides and testes of males dosed orally at 100 and 300 mg/kg/day.
Microscopic findings in the liver were dose-dependent and consisted of mild to moderate, diffuse hepatocellular hypertrophy in males and females (30, 100, and 300 mg/kg bw/day) and minimal to moderate multifocal vacuolation of midzonal and centrilobular hepatocytes in rats dosed at 100 and 300 mg/kg bw/day. At 100 mg/kg bw/day and 300 mg/kg bw/day, microscopic findings in the epididymides consisted of minimal, multifocal, bilateral, multinucleate spermatids (symplasts) in the epididymidal tubules. At 100 mg/kg bw/day and 300 mg/kg bw/day, findings in the testes consisted of mild, multifocal, bilateral, multinucleate spermatids (symplasts) in the seminiferous tubules with mild, multifocal, bilateral degeneration of the seminiferous tubule. Based on the organ weight and histopathology data in the limited number of animals, the NOEL was considered to be less than 30 mg/kg bw/day, the lowest dose tested.
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