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EC number: 406-850-2 | CAS number: 133855-98-8 BAS 480 F
- 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:
- Mar 31, 1989 - April 27, 1989
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 1 990
- Report date:
- 1990
Materials and methods
Test guidelineopen allclose all
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 414 (Prenatal Developmental Toxicity Study)
- Version / remarks:
- 1981
- Deviations:
- no
- Qualifier:
- according to guideline
- Guideline:
- EPA OPP 83-3 (Prenatal Developmental Toxicity Study)
- Version / remarks:
- Nov 1984
- Deviations:
- no
- Qualifier:
- according to guideline
- Guideline:
- other: Testing Guidelines for Toxicology Studies, pp. 48-49 (Japan/MAFF)
- Version / remarks:
- 1985
- Deviations:
- no
- GLP compliance:
- yes (incl. QA statement)
- Limit test:
- no
Test material
- Reference substance name:
- (2RS,3RS)-3-(2-chlorophenyl)-2-(4-fluorophenyl)-[(1H-1,2,4-triazol-1-yl)methyl]oxirane
- EC Number:
- 406-850-2
- EC Name:
- (2RS,3RS)-3-(2-chlorophenyl)-2-(4-fluorophenyl)-[(1H-1,2,4-triazol-1-yl)methyl]oxirane
- Cas Number:
- 133855-98-8
- Molecular formula:
- C17 H13 Cl F N3 O
- IUPAC Name:
- 1-{[(2R,3R)-3-(2-chlorophenyl)-2-(4-fluorophenyl)oxiran-2-yl]methyl}-1H-1,2,4-triazole
Constituent 1
Test animals
- Species:
- rat
- Strain:
- Wistar
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Karl Thomae, Biberach an der Riss, FRG
- Age at study initiation: 11-12 weeks
- Weight at study initiation: ca. 242 g
- Fasting period before study: no
- Housing: single
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: at least 5 days
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20-24
- Humidity (%): 30-70
- Air changes (per hr): not specified
- Photoperiod (hrs dark / hrs light): 12/12 (illumination: 6 am to 6 pm)
IN-LIFE DATES: From: March 30/April 5/April 6, 1989 To: April 20/April 26/April 27, 1989
Administration / exposure
- Route of administration:
- oral: gavage
- Vehicle:
- CMC (carboxymethyl cellulose)
- Remarks:
- doubly distilled water with 0.5% CMC
- Details on exposure:
- PREPARATION OF DOSING SOLUTIONS: Freshly prepared each day before treatment of animals
- Volume of administration: 5 ml/kg
- Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- Analytical verifications of the stability of the test substance in doubly distilled water and its distribution were carried out before the beginning of the study. Furthermore, samples of each preparation of the test substance in . doubly distilled water with 0.5% carboxymethyl were sent to the analytical laboratories twice during the study period for verification of the concentrations.The test substance suspensions were analyzed by HPLC.
- Details on mating procedure:
- - Impregnation procedure: cohoused
- If cohoused:
- M/F ratio per cage: 1:1-4
- Length of cohabitation: From about 16.00 hours to 7.30 hours the following morning
- Further matings after two unsuccessful attempts: no
- Verification of same strain and source of both sexes: yes
- Proof of pregnancy: sperm in vaginal smear referred to as day 0 of pregnancy - Duration of treatment / exposure:
- From Day 6 through Day 15 post coitum
- Frequency of treatment:
- once daily
- Duration of test:
- 15 days (without acclimatization)
Doses / concentrationsopen allclose all
- Dose / conc.:
- 5 mg/kg bw/day (nominal)
- Dose / conc.:
- 15 mg/kg bw/day (nominal)
- Dose / conc.:
- 45 mg/kg bw/day (nominal)
- No. of animals per sex per dose:
- 25
- Control animals:
- yes, concurrent vehicle
- Details on study design:
- - Dose selection rationale: An acute oral toxicity study, single intraperitoneal administration, preceding test study in which pregnant rats were dosed, range-finding study
- Rationale for animal assignment (if not random): random
- Rationale for strain selection: This strain was selected since extensive experience is available on Wistar rats and this strain has been proved to be sensitive to substances with a teratogenic potential.
Examinations
- Maternal examinations:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily for clinical symptoms, twice daily for mortality
DETAILED CLINICAL OBSERVATIONS: Yes / No / No data
- Time schedule:
BODY WEIGHT: Yes
- Time schedule for examinations: All animals were weighed on days 0, 1. 3. 6. 8. 10, 13. 15, 17 and 20 p.c. Furthermore, the corrected body weight gain was calculated after terminal sacrifice
FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): Yes
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes
WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No
POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day 20
- Organs examined: Uterus, ovaries
- 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
- Dead fetuses: Yes - Fetal examinations:
- - External examinations: Yes: all per litter
- Soft tissue examinations: Yes: half per litter
- Skeletal examinations: Yes: half per litter
- Head examinations: No - Statistics:
- Dunnett's Test (1955, 1964) was used for statistical evaluation of food consumption, body weight, body weight change, corrected body weight gain (net maternal body weight change), weight of the uterus before it was opened, weight of fetuses, weight of placentae, corpora lutea, implantations, pre- and postimplantation losses, resorptions and live fetuses.
Fisher's Exact Test (1981) was used for statistical evaluation of conception rate, mortality (of the dams) and all fetal findings.
Significances resulting from these tests have been indicated in the tables (a for p < 0.05; b for p < 0.01). - Indices:
- Conception rate, preimplantation loss, postimplantation loss
- Historical control data:
- available
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, treatment-related
- Description (incidence and severity):
- - 45 mg/kg bw/day: reduced body weight gains during the first days of the treatment period (days 6 - 8 p.c.)
- Food consumption and compound intake (if feeding study):
- effects observed, treatment-related
- Description (incidence and severity):
- - 45 mg/kg bw/day: reduced food consumption during the treatment period, especially on days 6 — 8 and 13 - 15 p.c.
- 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:
- effects observed, treatment-related
- Description (incidence and severity):
- 15 mg/kg bw and above: slight increase in placental weights; within historical controls; considered non-adverse
- Gross pathological findings:
- effects observed, non-treatment-related
- Description (incidence and severity):
- - 5 mg/kg bw/day: one animal, which did not become pregnant, showed hydrometra
Lung edema and/or marginal emphysema (findings. which have to be related to the sacrifice of the animals) were noted for several dams of test groups 0, 5 and 15 mg/kg body weight/day without any dose-response relationship. - Neuropathological findings:
- not examined
- Histopathological findings: non-neoplastic:
- not examined
- Other effects:
- no effects observed
- Description (incidence and severity):
- - The conception rate varied between 84% (control) and 96% (test group 5 mg/kg body weight)
Maternal developmental toxicity
- Number of abortions:
- no effects observed
- Pre- and post-implantation loss:
- effects observed, treatment-related
- Description (incidence and severity):
- - 45 mg/kg bw/day: marginally increased postimplantation loss (as a consequence of increased resorptions)
- no adverse effects on pre-implantation loss - Total litter losses by resorption:
- no effects observed
- Early or late resorptions:
- effects observed, treatment-related
- Description (incidence and severity):
- - 45 mg/kg bw/day: slightly increased number of resorptions (especially late ones)
- Dead fetuses:
- no effects observed
- Changes in pregnancy duration:
- not examined
- Changes in number of pregnant:
- no effects observed
- Other effects:
- no effects observed
- Description (incidence and severity):
- - number of corpora lutea
- conception rate
- implantation sites
Effect levels (maternal animals)
- Dose descriptor:
- NOAEL
- Effect level:
- 15 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Basis for effect level:
- body weight and weight gain
- early or late resorptions
- food consumption and compound intake
- pre and post implantation loss
Maternal abnormalities
- Abnormalities:
- no effects observed
Results (fetuses)
- Fetal body weight changes:
- 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
- Description (incidence and severity):
- - mg/kg bw/day: malformations (micrognathis, cleft palate, microtia) observed in just one fetus are assessed as being of spontaneous nature due to a missing dose-response relationship
- Skeletal malformations:
- effects observed, treatment-related
- Description (incidence and severity):
- - 45 mg/kg bw/day: Variations: markedly increased number of fetuses with skeletal variations (especially rudimentary cervical and/or accessory 14th rib(s))
- Visceral malformations:
- effects observed, non-treatment-related
- Description (incidence and severity):
- - mg/kg bw/day: Two malformations (dilation of one or both heart ventricles) in two fetuses
- Other effects:
- effects observed, treatment-related
- Description (incidence and severity):
- - 45 mg/kg bw/day: statistically significantly increased placental weights
- 15 mg/kg bw/day: statistically significantly increased placental weights (within historical controls; considered non-adverse) - Details on embryotoxic / teratogenic effects:
- Taking into account the summarized results of the external, soft tissue and skeletal examinations of the fetuses, the only findings, which are assessed as substance-induced ones, are the increased occurrence of high dose fetuses with rudimentary cervical and/or accessory 14th rib(s).
Due to the high frequency of both findings in the 45 mg/ kg fetuses, the incidence of skeletal and overall variations is statistically significantly increased in comparison to the control group.
A number of publications deals with the finding of supernumerary ribs in fetuses.
Various interpretations and assessments are given in these papers about the significance of increased occurrence of supernumerary ribs in rat fetuses for prenatal toxicity studies.
According to WICKRAMARATNE (1988) an increase in supernumerary ribs "should be considered not as indicative of fetal dysmorphogenesis but as a manifestation of a non—specific stress the dam is placed under in such (i.e. prenatal toxicity) studies.... An increase in frequency of supernumerary ribs could therefore be evidence that a minimal toxic dose had been achieved...."
KIMMEL and WILSON (1973) state that "when an increase in either rudimentary or extra ribs occurs during teratogenicity testing. it may be assumed that the maternal animal is being stressed sufficiently to express the developmental instability inherent in the species. The expectation would be if other teratogenic effects did not occur at that dose level. that at a higher dose, frank embryotoxicity would become evident“.
The latter statement is exactly in—line with the results of the preceding range-finding study in which at the highest dose level (180 mglkg body weight/day) and in the presence of overt maternal toxicity clear signs of embryotoxicity (including teratogenicity) were obvious.
Therefore, the increased number of 45 mglkg fetuses with rudimentary cervical and/or accessory 14th rib(s) in the present study is finally assessed as an embryotoxic effect representing a manifestation of a non-specific stress on the dams: it is, however. not interpreted as being a teratogenic effect of the test substance at this dose level.
All other differences between the actual control group and the substance-treated groups concerning fetal external. soft tissue and/or skeletal observations are without biological relevance and/or appear to about the same extent in the historical control data.
Effect levels (fetuses)
- Dose descriptor:
- NOAEL
- Effect level:
- 15 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: increase in number of resorptions, postimplantation losses, skeletal variations
Fetal abnormalities
- Abnormalities:
- effects observed, treatment-related
- Localisation:
- skeletal: rib
Overall developmental toxicity
- Developmental effects observed:
- yes
- Lowest effective dose / conc.:
- 45 mg/kg bw/day (nominal)
- Treatment related:
- yes
- Relation to maternal toxicity:
- developmental effects occurring together with maternal toxicity effects, but not as a secondary non-specific consequence of maternal toxicity effects
- Dose response relationship:
- yes
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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