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EC number: 928-729-8 | CAS number: 188416-20-8
- 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:
- key study
- Study period:
- From 19 May 1999 to 17 June 1999
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- other: Study run to a method comparable with current guidelines and to GLP.
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 1 999
- Report date:
- 1999
Materials and methods
Test guideline
- Qualifier:
- according to guideline
- Guideline:
- EU Method B.7 (Repeated Dose (28 Days) Toxicity (Oral))
- Deviations:
- no
- GLP compliance:
- yes
- Limit test:
- no
Test material
- Reference substance name:
- 3-(6-chloro-5-fluoropyrimidin-4-yl)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol hydrochloride
- EC Number:
- 928-729-8
- Cas Number:
- 188416-20-8
- Molecular formula:
- C16H13ClF3N5O.HCl
- IUPAC Name:
- 3-(6-chloro-5-fluoropyrimidin-4-yl)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol hydrochloride
- Details on test material:
- Lot/batch No.:109496/F/33
Purity: not specified
Constituent 1
Test animals
- Species:
- rat
- Strain:
- Crj: CD(SD)
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source:Charles River(UK) Limited, Margate, Kent, England
- Age at study initiation:34 to 38 days of age
- Weight at study initiation:The male animals used on the study weighed 136-157 g on the day that treatment commenced; the females were within the bodyweight range 124-139 g at this time.
- Fasting period before study:The animals were allowed free access, except overnight before routine blood sampling, to an expanded rodent diet, Rat and Mouse No.1 Matentiance Diet (Special Diets Services Limited, Witham, Essex, England).
- Housing:yes, a stainless steel body with a stainless steel mesh lid and floor
- Diet (e.g. ad libitum):This diet contained no added antibiotic or chemotherapeutic or prophylactic agent.
- Water (e.g. ad libitum):Water taken from the public supply was freely available, via polycarbonate bottles fitted with sipper tubes.
- Acclimation period:yes, eight days
ENVIRONMENTAL CONDITIONS
- Temperature (°C):21°C for temperature (acceptable range 19-25°C)
- Humidity (%):55% for relative humidity(acceptable range 40-70%)
- Air changes (per hr):
- Photoperiod (hrs dark / hrs light):a 12-hour light: 12-hour dark cycle
IN-LIFE DATES: From:1999-5-19 To:1999-6-17
Administration / exposure
- Route of administration:
- oral: gavage
- Vehicle:
- corn oil
- Details on oral exposure:
- DIET PREPARATION
- Rate of preparation of diet (frequency):Weighed amounts of diet were provided at intervals during each week.
- Mixing appropriate amounts with (Type of food):
- Storage temperature of food:
VEHICLE
- Justification for use and choice of vehicle (if other than water):Uk-103,446-01 was homogenous and stable in corn oil for up to 15 days when stored at 4°C.
- Concentration in vehicle:at 1.0 and 100 mg/mL
- Amount of vehicle (if gavage):at a constant volume-dosage of 5mL/kg bodyweight
- Lot/batch no. (if required):
- Purity: - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- HPLC
- Duration of treatment / exposure:
- 28 days
- Frequency of treatment:
- once each day, seven days per week.
Doses / concentrations
- Remarks:
- Doses / Concentrations:
15,150 and 500 mg/kg/day
Basis:
actual ingested
- No. of animals per sex per dose:
- 5 male and 5 female
- Control animals:
- yes, concurrent vehicle
Examinations
- Observations and examinations performed and frequency:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule:Immediately before dosing. Immediately after dosing on return of the animal to its cage. On completion of dosing of each group. Between one and two hours after completion of dosing of all groups. As late as possible in the working day.
- Cage side observations checked in table [No.?] were included.
BODY WEIGHT: Yes
- Time schedule for examinations:Each animal was weighed during the acclimatisation period, on the day that treatment commenced, twice weekly throughout the treatment period and before necropsy.
FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: No. Weighed amounts of diet were provided at intervals during each week to each cage. At the end of each treatment week the weight of uneaten food was recorded. The uneaten diet may have been included in that returned to the cage, after appropriate measurement.
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: No data
FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: Yes
HAEMATOLOGY: Yes
- Time schedule for collection of blood:On Day 29 of treatment, blood samples were obtained from all animals.
- Anaesthetic used for blood collection: No data
- Animals fasted: Yes
- How many animals:40
- Parameters checked in table [No.?] were examined. - Sacrifice and pathology:
- GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes
Results and discussion
Results of examinations
- Clinical signs:
- effects observed, treatment-related
- Mortality:
- mortality observed, treatment-related
- Body weight and weight changes:
- effects observed, treatment-related
- Food consumption and compound intake (if feeding study):
- effects observed, treatment-related
- Food efficiency:
- no effects observed
- Water consumption and compound intake (if drinking water study):
- no effects observed
- Ophthalmological findings:
- not specified
- Haematological findings:
- no effects observed
- Clinical biochemistry findings:
- effects observed, treatment-related
- Urinalysis findings:
- not specified
- Behaviour (functional findings):
- no effects observed
- Organ weight findings including organ / body weight ratios:
- effects observed, treatment-related
- Gross pathological findings:
- no effects observed
- Histopathological findings: non-neoplastic:
- no effects observed
- Histopathological findings: neoplastic:
- no effects observed
- Details on results:
- No animals died.
Salivation after dose administration was observed from Day2 onwards in males and females receiving 150 or 500 mg/kg/day, with a few animals receiving 15 mg/kg/day also being affected transiently.
Bodyweight gain and food intake was high, compared with the Controls, in females receiving 500 mg/kg/day and bodyweight gain was high in females receiving 150 mg/kg/day. The bodyweight gain and food intake of males was unaffected. Food conversion efficiency in both sexes was unaffected by treatment.
No clear effect of treatment was identified at the functional observation battery investigations.
There were no treatment-related haematological changes after four weeks of treatment.
Biochemical changes in the plasma that were attributed to treatment comprised: high alkaline phosphatase and alanine and aspartate amino-transferase activities and high urea concentrations in males receiving 500mg/kg/day; high creatinine and phosphorus concentrations in males and females receiving 500mg/kg/day; low glucose concentrations in females receiving 500mg/kg/day; slightly high calcium concentrations in females receiving 150 or 500 mg/kg/day.
After four weeks of treatment liver weights were slightly high in females receiving 500mg/kg/day and spleen weights were slightly low in males at this dosage.
There were no treatment-related macroscopic or histopathological changes.
Effect levels
open allclose all
- Dose descriptor:
- NOAEL
- Effect level:
- ca. 500 mg/kg bw/day (actual dose received)
- Based on:
- act. ingr.
- Sex:
- male/female
- Basis for effect level:
- other: no findings at toxicological significance at highest dose level
- Dose descriptor:
- LOEL
- Effect level:
- ca. 15 mg/kg bw/day (actual dose received)
- Based on:
- act. ingr.
- Sex:
- male/female
- Basis for effect level:
- other: overall effects clinical signs; body weight; food consumption; food efficiency; water consumption and compound intake; haematology; gross pathology; organ weights; histopathology
Target system / organ toxicity
- Critical effects observed:
- not specified
Applicant's summary and conclusion
- Conclusions:
- It is concluded that oral administration of this substance to CD rats at dosages up 500mg/kg/day for four weeks was well-tolerated, producing no toxicologically significant finding. This study provided no evidence for any neurotoxic potential. An adaptive response by the liver was indicated at the high dosage. There were no changes at 500mg/kg/day that were considered to be of any toxicological significance and this dosage is, therefore, considered to be the no-observed-adverse-effect(NOAEL) in this study.The lowest observed effect level(LOEL) was considered to be 15 mg/kg/day.
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