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EC number: 810-161-6 | CAS number: 1229654-66-3
- 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:
- key study
- Study period:
- 14 Aug 2013 - 18 Sep 2014
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 014
- Report date:
- 2014
Materials and methods
Test guidelineopen allclose all
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 414 (Prenatal Developmental Toxicity Study)
- Version / remarks:
- adopted in 2001
- Deviations:
- no
- Qualifier:
- according to guideline
- Guideline:
- EU Method B.31 (Prenatal Developmental Toxicity Study)
- Version / remarks:
- adopted in 2004
- Deviations:
- no
- Qualifier:
- according to guideline
- Guideline:
- EPA OPPTS 870.3700 (Prenatal Developmental Toxicity Study)
- Version / remarks:
- adopted in 1998
- Deviations:
- no
- Qualifier:
- according to guideline
- Guideline:
- other: M.A.F.F. in Japan, notification 12 Nousan N°8147 guideline
- Version / remarks:
- adopted in 2000
- Deviations:
- no
- GLP compliance:
- yes
- Limit test:
- no
Test material
- Reference substance name:
- 1-(3-chloropyridin-2-yl)-N-[4-cyano-2-methyl-6-(methylcarbamoyl)phenyl]-3-{[5-(trifluoromethyl)-2H-1,2,3,4-tetrazol-2-yl]methyl}-1H-pyrazole-5-carboxamide
- EC Number:
- 810-161-6
- Cas Number:
- 1229654-66-3
- Molecular formula:
- C22 H16 Cl F3 N10 O2
- IUPAC Name:
- 1-(3-chloropyridin-2-yl)-N-[4-cyano-2-methyl-6-(methylcarbamoyl)phenyl]-3-{[5-(trifluoromethyl)-2H-1,2,3,4-tetrazol-2-yl]methyl}-1H-pyrazole-5-carboxamide
Constituent 1
Test animals
- Species:
- rat
- Strain:
- other: Crl:CD (SD) Sprague-Dawley
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Charles River Laboratories, Sulzfeld, Germany
- Age at study initiation: 11 - 13 weeks
- Weight at study initiation: 239 - 328 g (at mating)
- Housing: individual in suspended polycarbonate wire mesh cages
- Diet: A04C-10 pelleted rodent diet (Scientific Animal Food and Engineering, Augy, France), ad libitum
- Water: filtered and softened tap water from the municipal water supply, ad libitum
- Acclimation period: at least 12 days
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 - 24
- Humidity (%): 40 - 70
- Air changes (per hr): 10 - 15
- Photoperiod (hrs dark / hrs light): 12/12
Administration / exposure
- Route of administration:
- oral: gavage
- Vehicle:
- other: 0.5% aqueous methylcellulose 400
- Details on exposure:
- PREPARATION OF DOSING SOLUTIONS:
Two dosing solutions were prepared during the study by dissolving appropriate amounts of the test material in an aqueous solution of methylcellulose 400 at 0.5% yielding final concentrations of 6.25, 25 and 100 g/L. A complementary formulation at the highest dose level for the last two days of the study was prepared for the treatment of one animal.
VEHICLE
- Concentration in vehicle: 6.25, 25 and 100 g/L
- Amount of vehicle (if gavage): 10 mL/kg bw - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- The first formulation (F1) prepared for the study was evaluated for homogeneity and concentration using HPLC-UV analysis. Triplicate samples were collected of the lowest and the highest dietary concentrations from the top, the middle and the bottom of the formulation. In addition triplicate samples of the intermediate dose level (F1) and all dose levels of the second formulation (F2) were collected from the surface, middle and the bottom of the formulation for concentration analysis. One of the three collected samples was analyzed and the others were stored for possible verification analysis. Data indicate homogenous mixture of the test material in the vehicle. The measured values for the individual homogeneity samples ranged between 97 and 101% of nominal. Additionally, samples were at the targeted concentration (98 – 100% of nominal). The stability of test item in 0.5% aqueous methylcellulose was demonstrated in a previous study at concentrations of 0.3 and 250 g/L for up to 28 days under similar conditions of usage and storage to those of the current study (2012).
- Details on mating procedure:
- - Impregnation procedure: cohoused
- If cohoused:
- M/F ratio per cage: 1/1
- Length of cohabitation: overnight
- Verification of same strain and source of both sexes: yes
- Proof of pregnancy: sperm in vaginal smear or sperm plug in situ referred to as day 0 of pregnancy - Duration of treatment / exposure:
- day 6 - 20 of gestation
- Frequency of treatment:
- daily, 7 days/week
- Duration of test:
- day 21 of gestation
Doses / concentrationsopen allclose all
- Dose / conc.:
- 62.5 mg/kg bw/day
- Dose / conc.:
- 250 mg/kg bw/day
- Dose / conc.:
- 1 000 mg/kg bw/day
- No. of animals per sex per dose:
- 23 females
- Control animals:
- yes, concurrent vehicle
- Details on study design:
- - Dose selection rationale: The range of doses has been selected in agreement with the Sponsor Representative and based on results obtained in a range-finding study where pregnant rats received the test substance at 0, 100, 400 or 800 mg/kg/day from GD 6 through 20 (2010). In this study, reduced mean maternal body weight gain between GD 6 and 8 when compared to controls was observed at 800 mg/kg bw/day. Mean maternal corrected body weight change (body weight gain between GD 6 and 21 independent of the gravid uterus weight recorded at cesarean section) was decreased by 60% in comparison to controls (not statistically significant). Decreased mean maternal corrected body weight change was observed at the mid and low dose (not statistically significant). Therefore, 0, 62.5, 250 and 1000 mg/kg/day were selected as the dose levels for this study. A high dose of 1000 mg/kg/day is a limit dose, which based on the range-finding study was not expected to exceed a maximal tolerated dose (MTD) in the dams. A mid dose of 250 mg/kg/day provided a 4 fold factor between the dose levels. A low dose of 62.5 mg/kg/day was expected to be a No Observed (Adverse) Effect Level for both maternal and fetal toxicity, based on the range-finding data.
- Other: If possible, those females having been paired with the same male were not allocated to the same group. Body weight means were checked after the mating period to ensure similar means among all groups.
Examinations
- Maternal examinations:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice daily (once daily at weekends and public holiday)
- Cage side observations included: mortality, moribundity
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: daily, day 0 - 21 of gestation
BODY WEIGHT: Yes
- Time schedule for examinations: day 0, 6, 8, 10, 12, 14, 16, 18 and 21 of gestation
FOOD CONSUMPTION: Yes
Full feeder weights were measured on GD: 1, 6, 8, 10, 12, 14, 16 and 18. Empty feeder weights were measured on GD: 6, 8, 10, 12, 14, 16, 18 and 21. From these records the mean daily consumption was calculated.
WATER CONSUMPTION: No
POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day 21
- Organs examined: visceral organs (macroscopic examination), liver (weighed), reproductive tract (weighed and dissected; gravid uterine weight), uterine horn(s) without visible implantations (immersed in a 10% solution of ammonium sulfide to visualize any sites which were not apparent) - Ovaries and uterine content:
- The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: Yes
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of early resorptions: Yes
- Number of late resorptions: Yes
- Other: number of live and dead fetuses, sex of live fetuses, individual weights of live fetuses - Fetal examinations:
- - External examinations: Yes: all per litter
- Soft tissue examinations: Yes: half per litter
- Skeletal examinations: Yes: half per litter
- Head examinations: No data - Statistics:
- For most maternal and litter based endpoints Bartlett test was performed to compare the homogeneity of group variances. If the Bartlett test was not significant (p>0.05), means were compared using the analysis of variance (ANOVA). If the ANOVA was not significant (p>0.05), the group means were considered to be homogeneous and no further analysis was performed. If the ANOVA was significant (p≤0.05), means of the exposed groups were compared to the mean of the control group using the Dunnett test (2-sided). If the Bartlett test was significant (p≤0.05), group means were compared using the non- parametric Kruskal-Wallis test. If the Kruskal-Wallis test was not significant (p>0.05), the group means were considered to be homogeneous and no further analysis was performed. If the Kruskal-Wallis test was significant (p≤0.05), means of the exposed groups were compared to the mean of the control group using the Dunn test (2-sided). If the Bartlett test was significant for average food consumption data were transformed using the log transformation the Bartlett test was applied to the transformed data. If the Bartlett test was significant (p≤0.05) even after log transformation, statistical analysis was proceeded as mentioned above (the ANOVA test was also performed with transformed data). For fetal body weight the Levene test was used followed by the ANOVA test in case of non-significance. In case of significance (p≤0.05) data were transformed using the log transformation before the Levene test was applied to the transformed data. If the Levene test was significant (p≤0.05) even after log transformation, statistical analysis was proceeded wth the ANOVA test or the Kruskal-Wallis test as mentioned above (the ANOVA test was also performed with transformed data). If one or more group variance(s) equaled 0, means were compared using non-parametric procedures.
- Indices:
- - Corrected body weight change (CBWC): CBWC = (BW on day 21 of gestation – BW on day 0 of gestation) – (gravid uterine weight)
- Carcass weight: BW on day 21 of gestation – uterus weight
- Total resorptions = early + late resorptions
- Pre-implantation loss %: (number of corpora lutea – number of implantations / number of corpora lutea) x 100
- Post-implantation loss %: (number of implantations – number of live fetuses / number of implantations) x 100
- Percentage of dead fetuse/ fetal death: number of dead fetuses / total number of fetuses x 100
- Percentage of male fetuses: number of live male fetuses / total number of live male and female fetuses x 100
- Mean fetal body weight: sum of individual weights of live fetuses / number of weighed live fetuses
- Mean fetal body weight per sex (example male fetuses): sum of individual weights of live male fetuses / number of weighed live male fetuses
- Fetal death per litter (%): number of litters with dead fetuses / total number of litters x 100
- For external, visceral and skeletal fetal findings, the percentage of fetuses affected per group for a given parameter: sum of live fetuses affected / number of live fetuses examined x 100
- For external, visceral and skeletal fetal findings, the percentage of litters affected per group for a given parameter: sum of litters with live fetuses affected / number of litter with live fetuses examined x 100 - Historical control data:
- Historical control data from studies conducted in-house were referred to in order to allow comparison with concurrent controls. The data were generated from sixteen rat studies between 2003 and 2012 and are presented in the report.
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, non-treatment-related
- Food consumption and compound intake (if feeding study):
- no effects observed
- Food efficiency:
- not examined
- Water consumption and compound intake (if drinking water study):
- not examined
- 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:
- no effects observed
- Gross pathological findings:
- no effects observed
- Neuropathological findings:
- not examined
- Histopathological findings: non-neoplastic:
- not examined
- Histopathological findings: neoplastic:
- not examined
- Details on results:
- For details on results including tables see the attached document.
Maternal developmental toxicity
- Number of abortions:
- no effects observed
- Pre- and post-implantation loss:
- no effects observed
- Total litter losses by resorption:
- no effects observed
- Early or late resorptions:
- effects observed, non-treatment-related
- Dead fetuses:
- no effects observed
- Changes in pregnancy duration:
- not examined
- Description (incidence and severity):
- Migrated Data from removed field(s)
Field "Effects on pregnancy duration" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsMaternalAnimals.MaternalDevelopmentalToxicity.EffectsOnPregnancyDuration): no effects observed - Changes in number of pregnant:
- no effects observed
- Details on maternal toxic effects:
- For details on results including tables see the attached document.
Effect levels (maternal animals)
- Key result
- Dose descriptor:
- NOEL
- Effect level:
- >= 1 000 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Basis for effect level:
- other: highest dose tested
Maternal abnormalities
- Key result
- Abnormalities:
- no effects observed
Results (fetuses)
- Fetal body weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- 1000 mg/kg bw/day: decreased mean fetal body weight (combined and per sex) compared to control (4%, non-adverse)
(see table 3)
Migrated Data from removed field(s)
Field "Fetal/pup body weight changes" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsFetuses.FetalPupBodyWeightChanges): not examined - Reduction in number of live offspring:
- no effects observed
- Changes in sex ratio:
- no effects observed
- Changes in litter size and weights:
- no effects observed
- Changes in postnatal survival:
- not examined
- External malformations:
- effects observed, non-treatment-related
- Skeletal malformations:
- effects observed, non-treatment-related
- Visceral malformations:
- no effects observed
- Other effects:
- effects observed, treatment-related
- Description (incidence and severity):
- SKELETAL FETAL VARIATIONS
1000 mg/kg bw/day: increased incidence of of 2 spontaneous variations; “5th and 6th sternebrae: incomplete ossification” at the fetal level and “5th and/or 6th sternebrae: unossified” at the fetal and litter levels (non-adverse) - Details on embryotoxic / teratogenic effects:
- For details on results including tables see the attached document.
Effect levels (fetuses)
open allclose all
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- >= 1 000 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: highest dose tested
- Key result
- Dose descriptor:
- NOEL
- Effect level:
- 250 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: skeletal fetal variations
Fetal abnormalities
- Key result
- Abnormalities:
- no effects observed
Overall developmental toxicity
- Key result
- Developmental effects observed:
- no
Any other information on results incl. tables
For details on results including tables see the attached document.
Applicant's summary and conclusion
Information on Registered Substances comes from registration dossiers which have been assigned a registration number. The assignment of a registration number does however not guarantee that the information in the dossier is correct or that the dossier is compliant with Regulation (EC) No 1907/2006 (the REACH Regulation). This information has not been reviewed or verified by the Agency or any other authority. The content is subject to change without prior notice.
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