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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
Toxicity to reproduction
Administrative data
- Endpoint:
- fertility, other
- 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: Fertility study in male rats
- GLP compliance:
- yes
- 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
- Specific details on test material used for the study:
- not specified
Test animals
- Species:
- rat
- Strain:
- Sprague-Dawley
- Details on species / strain selection:
- not specified
- Sex:
- male
- 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% - Details on mating procedure:
- not specified
- Analytical verification of doses or concentrations:
- not specified
- Details on analytical verification of doses or concentrations:
- not specified
- Duration of treatment / exposure:
- 75 days
- Frequency of treatment:
- daily
- Details on study schedule:
- Male Sprague-Dawley rats were administered daily oral doses of 0, 0.5, 3, or 10 mg/kg (n, 25/group) in 0.5% CMC beginning 42 days prior to pairing with untreated females, through the mating and post-mating period until euthanasia on Day 76 of treatment.
Doses / concentrationsopen allclose all
- Dose / conc.:
- 0 mg/kg bw/day (nominal)
- Remarks:
- Control
- Dose / conc.:
- 0.5 mg/kg bw/day (nominal)
- Remarks:
- Low dose
- Dose / conc.:
- 3 mg/kg bw/day (nominal)
- Remarks:
- Mid dose
- Dose / conc.:
- 10 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: Approximately 15 males of the 0 and 10 mg/kg bw/day groups were assigned to a 12-week recovery period. Additional animals (n, 6/group) were dosed for TK evaluation and sperm analysis.
- Positive control:
- no
Examinations
- Parental animals: Observations and examinations:
- not specified
- Sperm parameters (parental animals):
- not specified
- Litter observations:
- not specified
- Postmortem examinations (parental animals):
- not specified
- Postmortem examinations (offspring):
- not specified
- Statistics:
- not specified
- Reproductive indices:
- not specified
- Offspring viability indices:
- not specified
Results and discussion
Results: P0 (first parental generation)
General toxicity (P0)
- Clinical signs:
- no effects observed
- Description (incidence and severity):
- The test item did not affect clinical observations.
- Dermal irritation (if dermal study):
- not examined
- Mortality:
- no mortality observed
- Description (incidence):
- The test item did not affect mortality.
- Body weight and weight changes:
- effects observed, non-treatment-related
- Description (incidence and severity):
- For futher details see section "details on results" below.
- Food consumption and compound intake (if feeding study):
- effects observed, non-treatment-related
- Description (incidence and severity):
- For futher 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 examined
- 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
- Histopathological findings: non-neoplastic:
- effects observed, treatment-related
- Description (incidence and severity):
- For futher details see section "details on results" below.
- Histopathological findings: neoplastic:
- not specified
Reproductive function / performance (P0)
- Reproductive function: sperm measures:
- effects observed, treatment-related
- Description (incidence and severity):
- For futher details see section "details on results" below.
- Reproductive performance:
- no effects observed
Details on results (P0)
- Mean sperm motility (78.6%) was considered low after treatment for 75 days at 3 mg/kg bw/day compared with controls (82.3%) and was statistically significantly lower than controls at 10 mg/kg/day (60.7%). In addition, at 10 mg/kg/day, total sperm count per cauda epididymis and sperm concentration per gram cauda epididymis were lower, and while these values were within recent historical control data, the values were 20-25% lower than controls and considered test article-related. At 3 and 10 mg/kg bw/day, percent abnormal sperm was significantly higher (8.08% and 23.55%, respectively, compared with 3.55% abnormal in controls) and considered test article-related.
- Treatment-related microscopic findings in the epididymides (increased cellular debris, residual bodies) at 10 mg/kg bw/day which, ingeneral, correlated with increased percentages of morphologic abnormalities in sperm. Leydig cell hypertrophy/hyperplasia was observed at 10 mg/kg/day. A trend towards complete resolution of sperm parameters and microscopic changes in the epididymides and testes was observed at 10 mg/kg/day following the 12-week recovery period.
Effect levels (P0)
open allclose all
- Dose descriptor:
- NOAEL
- Remarks:
- general toxicity
- Effect level:
- 10 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male
- Basis for effect level:
- other: no adverse effects observed
- Dose descriptor:
- NOAEL
- Remarks:
- fertility
- Effect level:
- 10 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male
- Basis for effect level:
- other: Mating parameters, fertility and fecundity were not affected after 42 days of dosing
- Dose descriptor:
- NOAEL
- Remarks:
- sperm measures
- Effect level:
- 3 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male
- Basis for effect level:
- reproductive function (sperm measures)
Applicant's summary and conclusion
- Conclusions:
- Under the given conditions reported, the NOAEL for general toxicity and for reproductive and fertility parameters in male rats was determined to be 10 mg/kg bw/day. The NOAEL for sperm parameters was 3 mg/kg bw/day, based on statistically significant decreases in sperm motility, an increase in the percent of abnormal sperm, and a decrease in epididymal sperm count observed at 10 mg/kg bw/day.
- Executive summary:
In reproductive toxicity study, the test item in 0.5% CMC was administered to 25 male SD ,rats/dose orally at dose levels of 0, 0.5, 3, or 10mg/kg bw/day for 75 days (treatment started 42 days prior to pairing with untreated females, through the mating and post-mating period until euthanasia on Day 76 of treatment). Approximately 15 males of the 0 and 10 mg/kg bw/day groups were assigned to a 12-week recovery period. Additional animals (n, 6/group) were dosed for TK evaluation and sperm analysis. The treatment did not affect mortality or clinical observations. Mating parameters, fertility, and fecundity were also not affected after 42 days of dosing. However, decreases in mean body weight gain and/or body weight loss was observed at 3 and 10 mg/kg bw/day sporadically throughout the dosing period, correlating with slightly decreased food consumption during weeks 3-5 only at 10 mg/kg bw/day.
The mean sperm motility (78.6%) was considered low after treatment for 75 days at 3 mg/kg bw/day compared with controls (82.3%) and was statistically significantly lower than controls at 10 mg/kg/day (60.7%). In addition, at 10 mg/kg/day, total sperm count per cauda epididymis and sperm concentration per gram cauda epididymis were lower, and while these values were within recent historical control data, the values were 20-25% lower than controls and considered test article related. At 3 and 10 mg/kg bw/day, percent abnormal sperm was significantly higher (8.08% and 23.55%, respectively, compared with 3.55% abnormal in controls) and considered test article related. Furthermore, treatment-related microscopic findings in the epididymides (increased cellular debris, residual bodies) at 10 mg/kg bw/day which, in general, correlated with increased percentages of morphologic abnormalities in sperm. Leydig cell hypertrophy/hyperplasia was observed at 10 mg/kg/day.
Based on these results, a NOAEL for general toxicity and for reproductive and fertility parameters in males was determined to be 10 mg/kg bw/day. The NOAEL for sperm parameters was 3 mg/kg bw/day, based on statistically significant decreases in sperm motility, an increase in the percent of abnormal sperm, and a decrease in epididymal sperm count after treatment at 10 mg/kg bw/day. These effects on sperm motility, count, and morphology as well as the microscopic changes were trending towards complete resolution during the 12-week recovery period.
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