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EC number: 609-256-3 | CAS number: 365400-11-9
- 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
Basic toxicokinetics
Administrative data
- Endpoint:
- basic toxicokinetics in vivo
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 21 Apr 2003 - 18 Feb 2005
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 005
- Report date:
- 2005
Materials and methods
- Objective of study:
- absorption
- distribution
- excretion
- metabolism
Test guideline
- Qualifier:
- according to guideline
- Guideline:
- EPA OPPTS 870.7485 (Metabolism and Pharmacokinetics)
- Version / remarks:
- Aug 1995
- Deviations:
- no
- GLP compliance:
- yes
Test material
- Reference substance name:
- 4-[2-methanesulfonyl-4-(trifluoromethyl)benzoyl]-1,3-dimethyl-1H-pyrazol-5-ol
- EC Number:
- 609-256-3
- Cas Number:
- 365400-11-9
- Molecular formula:
- C14H13F3N2O4S
- IUPAC Name:
- 4-[2-methanesulfonyl-4-(trifluoromethyl)benzoyl]-1,3-dimethyl-1H-pyrazol-5-ol
Constituent 1
- Radiolabelling:
- yes
Test animals
- Species:
- rat
- Strain:
- Wistar
- Sex:
- male
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Charles River Laboratories (Raleigh, NC, USA)
- Age at study initiation: approximately 9 weeks
- Weight at study initiation: for oral experiments: 188 - 225 g, for intravenous experiments: 193 - 250 g
- Housing: following dosing, rats were housed individually in Nalgene rodent metabolism cages which allowed collection of urine, faeces, and respired 14CO2 and volatile metabolites
- Diet: Certified Rodent Diet 5002 Meal (PMI Nutrition International, St. Louis, USA), ad libitum
- Water: not further specified, ad libitum
- Acclimation period: 6 - 7 days
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22
- Humidity (%): 50 - 58
- Photoperiod (hrs dark / hrs light):12/12
Administration / exposure
- Route of administration:
- other: oral or intravenous
- Vehicle:
- other: oral formulation: water; intravenous formulation: 0.9% sodium chloride
- Details on exposure:
- PREPARATION OF DOSING SOLUTIONS:
[Phenyl-UL-14C] 5-hydroxy-1,3-dimethylpyrazol-4-yl)(α,α,α-trifluoro-2-mesyl-p-tolyl) methanone Oral Dose Experiment (O-LDE-M)
A 0.2-mL aliquot of the [phenyl-UL-14C] 5-hydroxy-1,3-dimethylpyrazol-4-yl)(α,α,α-trifluoro-2-mesyl-p-tolyl) methanone stock solution was transferred into a 5-mL volumetric flask, and the aliquot was diluted to 5 mL with acetonitrile (ACN). The solution was radioassayed and concentrated slightly using a stream of nitrogen gas. An additional aliquot (0.03 mL) of the [phenyl-UL-14C] AE 0317309 stock solution was transferred into the 5-mL volumetric flask, and the solution was diluted to 5 mL with ACN. The solution was radioassayed and transferred to a 50-mL pear-shaped flask. A nonradioactive test substance stock solution was prepared by transferring 65.5 mg of nonradioactive test substance (K-1196) into a 10-mL volumetric flask and diluting the contents to mark with ACN. A 1.77-mL aliquot of the nonradioactive test substance stock solution was transferred to the 50-mL pear-shaped flask. The sample was concentrated to dryness at 30 to 35°C using a rotary evaporator (Büchi; Westbury, NY). The sample was transferred to a 10-mL, graduated mixing cylinder using multiple 1-mL rinses with H2O, and the sample was diluted to 7.0 mL with H2O. The dose solution was mixed, radioassayed (0.056 mCi/mL; 8.54 mCi/mmol; 2.37 mg/mL), and aliquots were analyzed by HPLC and mass spectrometry.
[Pyrazole-3-14C] 5-hydroxy-1,3-dimethylpyrazol-4-yl)(α,α,α-trifluoro-2-mesyl-p-tolyl) methanone Oral Dose Experiment (O-LDE-M)
A 0.2-mL aliquot of the [pyrazole-3-14C] 5-hydroxy-1,3-dimethylpyrazol-4-yl)(α,α,α-trifluoro-2-mesyl-p-tolyl)methanone stock solution was transferred into a 10-mL volumetric flask, and the aliquot was diluted to 10 mL with ACN. The solution was radioassayed and transferred to a 50-mL pear-shaped flask. A nonradioactive test substance stock solution was prepared by transferring 72.4 mg of nonradioactive test substance (K-1196) into a 10-mL volumetric flask and diluting the contents to mark with ACN. A 1.87-mL aliquot of the nonradioactive test substance stock solution was transferred to the 50-mL pear-shaped flask. The sample was concentrated to dryness at 30 to 35°C using a rotary evaporator. The sample was transferred to a 10-mL, Reacti-Vial reaction vial (Pierce; Rockford, IL) containing a magnetic stir bar, using multiple 1-mL rinses with H2O, and the sample was diluted to 7.0 mL with H2O. The dose solution was stirred, radioassayed (0.054 mCi/mL; 8.72 mCi/mmol; 2.26 mg/mL), and aliquots were analyzed by HPLC and mass spectrometry.
[Phenyl-UL-14C] 5-hydroxy-1,3-dimethylpyrazol-4-yl)(α,α,α-trifluoro-2-mesyl-p-tolyl) methanone Intravenous Experiment (IV-LDE-M)
A 3.6-mL aliquot of the [phenyl-UL-14C] 5-hydroxy-1,3-dimethylpyrazol-4-yl)(α,α,α-trifluoro-2-mesyl-p-tolyl) methanone stock solution (C-938B) was transferred into a 10-mL volumetric flask, and the aliquot was diluted to 10 mL with ACN. The solution was radioassayed and concentrated slightly using a stream of nitrogen gas. An additional aliquot (1.0-mL) of the [phenyl-UL-14C] 5-hydroxy-1,3-dimethylpyrazol-4-yl)(α,α,α-trifluoro-2-mesyl-p-tolyl) methanone stock solution was transferred into the 10-mL volumetric flask, and the solution was diluted to 10 mL with ACN. The solution was radioassayed and transferred to a 50-mL pear-shaped flask. A nonradioactive test substance stock solution was prepared by transferring 65.0 mg of nonradioactive test substance (K-1267) into a 10-mL volumetric flask and diluting the contents to mark with ACN. A 1.90-mL aliquot of the nonradioactive test substance stock solution was transferred to the 50-mL pear-shaped flask. The sample was concentrated to dryness at 30 to 35°C using a rotary evaporator. The sample was transferred to a 10-mL, Reacti-Vial reaction vial containing a magnetic stir bar, using multiple 1-mL rinses with saline solution, and the sample was diluted to 8.3 mL with saline solution. The dose solution was stirred, radioassayed, and filtered using a syringe filter (0.22 μm). The filtered dose solution was mixed and radioassayed (0.063 mCi/mL; 10.0 mCi/mmol; 2.29 mg/mL), and aliquots were analyzed by HPLC and mass spectrometry.
[Pyrazole-3-14C] 5-hydroxy-1,3-dimethylpyrazol-4-yl)(α,α,α-trifluoro-2-mesyl-p-tolyl) methanone Intravenous Experiment (IV-LDE-M)
A 3.0-mL aliquot of the [pyrazole-3-14C] 5-hydroxy-1,3-dimethylpyrazol-4-yl)(α,α,α-trifluoro-2-mesyl-p-tolyl) methanone stock solution (C-1024A) was transferred into a 10-mL volumetric flask, and the aliquot was diluted to 10 mL with ACN. The solution was radioassayed and transferred to a 50-mL pear-shaped flask. A 12.8 mg aliquot of nonradioactive test substance (K-1267) was transferred to the 50-mL pear-shaped flask. The sample was mixed and concentrated to dryness at 30 to 35°C using a rotary evaporator. The sample was transferred to a 10-mL, Reacti-Vial reaction vial containing a magnetic stir bar, using multiple 1-mL rinses with saline solution, and the sample was diluted to 7.1 mL with saline solution. The dose solution was stirred, radioassayed and filtered using a syringe filter. The filtered dose solution was stirred and radioassayed (0.062 mCi/mL; 9.97 mCi/mmol; 2.24 mg/mL), and aliquots were analyzed by HPLC and mass spectrometry. - Duration and frequency of treatment / exposure:
- single administration
Doses / concentrationsopen allclose all
- Dose / conc.:
- 10 mg/kg bw/day
- Remarks:
- oral dose of [phenyl-UL-14C] AE 0317309
- Dose / conc.:
- 9.81 mg/kg bw/day
- Remarks:
- intravenous dose of [phenyl-UL-14C] AE 0317309
- Dose / conc.:
- 9.88 mg/kg bw/day
- Remarks:
- oral dose of [pyrazole-3-14C] AE 0317309
- Dose / conc.:
- 9.6 mg/kg bw/day
- Remarks:
- intravenous dose of [pyrazole-3-14C] AE 0317309
- No. of animals per sex per dose / concentration:
- 5 males per radiolabel (oral administration)
4 - 5 males per radiolabel (intravenous administration) - Control animals:
- no
- Details on study design:
- - Rationale for animal assignment: Each rat was assigned a unique consecutive number at the time of arrival from Charles River Laboratories. The rats were chosen for inclusion in the experimental group based on overall healthy appearance, gradual weight gain over the acclimation period, and similar weights.
- Details on dosing and sampling:
- PHARMACOKINETIC STUDY (Absorption, distribution, excretion)
- Tissues and body fluids sampled: urine, faeces, blood, tissues (bone, brain, fat, heart, kidney, liver, lung, muscle, skin, spleen, testes, and thyroid), cage washes
- Time and frequency of sampling:
urine: 6, 12, 24 and 48 hours post-treatment (in the [phenyl-UL-14C] AE 0317309 oral experiment also after 52 hours)
faeces: at 24-hour intervals until sacrifice (in the [phenyl-UL-14C] AE 0317309 oral experiment also after 52 hours)
blood and tissues: at sacrifice (in general 48 hours post-treatment; 52 hours in the [phenyl-UL-14C] AE 0317309 oral experiment)
METABOLITE CHARACTERISATION STUDIES
- Tissues and body fluids sampled: urine, faeces
- Time and frequency of sampling:
urine: 6, 12, 24 and 48 hours post-treatment (in the [phenyl-UL-14C] AE 0317309 oral experiment also after 52 hours)
faeces: at 24-hour intervals until sacrifice (in the [phenyl-UL-14C] AE 0317309 oral experiment also after 52 hours)
- From how many animals: 4-5 (pooled samples)
- Method type(s) for identification: radioassay and HPLC-MS-MS - Statistics:
- All calculations were performed using Microsoft Excel 2002 (10.5815.4219; SP-2).
Results and discussion
- Preliminary studies:
- A preliminary experiment was conducted in which male and female rats were administered a single oral dose of [phenyl-UL-14C] 5-hydroxy-1,3-dimethylpyrazol-4-yl)(α,α,α-trifluoro-2-mesyl-p-tolyl) methanone at a rate of 100 mg/kg bw. In this preliminary experiment, the [phenyl-UL-14C] 5-hydroxy-1,3-dimethylpyrazol-4-yl)(α,α,α-trifluoro-2-mesyl-p-tolyl)methanone was well absorbed, with absorption of approximately 91% of the administered dose for the females and 88% for the males. The elimination of the [phenyl-UL-14C] 5-hydroxy-1,3-dimethylpyrazol-4-yl)(α,α,α-trifluoro-2-mesyl-p-tolyl) methanone was very rapid, with the majority of the administered dose being excreted via urine during the first 24 hours following dosing for both male and female rats.
Radioactivity in the tissues was below 0.5% of the administered dose for both sexes at 72 hours after the administration. 5-hydroxy-1,3-dimethylpyrazol-4-yl)(α,α,α-trifluoro-2-mesyl-p-tolyl) methanone was observed as the major radioactive component in the urine and faeces, representing approximately 82% and 89% of the total excreted radioactivity in males and females, respectively.
Main ADME resultsopen allclose all
- Type:
- absorption
- Results:
- The test substance was readily absorbed with 57 - 62% of the dose recovered in urine within 6 hours and 73 and 75% within 52 and 48 hours, respectively.
- Type:
- distribution
- Results:
- ≤ 2% of the administered dose remained in the carcass and tissues at sacrifice. Residue levels were highest in liver and kidney.
- Type:
- metabolism
- Results:
- 87 - 95% was excreted unchanged; three minor metabolites were identified in urine and faeces. The major metabolic pathway occurred via N-demethylation of the test substance.
- Type:
- excretion
- Results:
- Total excretion was rapid, > 96% was excreted within 24 hours (approx. 90% in the urine, 10% in the faeces)
Toxicokinetic / pharmacokinetic studies
- Details on absorption:
- [Phenyl-UL-14C] 5-hydroxy-1,3-dimethylpyrazol-4-yl)(α,α,α-trifluoro-2-mesyl-p-tolyl) methanone:
The [phenyl-UL-14C] 5-hydroxy-1,3-dimethylpyrazol-4-yl)(α,α,α-trifluoro-2-mesyl-p-tolyl) methanone was readily absorbed following oral administration, with 62% of the dose recovered in the urine within 6 hours and a total of 73% of the dose recovered in the urine at the time of sacrifice (52 hours). The intravenous experiment showed that 10% of the dose was found in the faeces at the time of sacrifice (48 hours).
[Pyrazole-3-14C] 5-hydroxy-1,3-dimethylpyrazol-4-yl)(α,α,α-trifluoro-2-mesyl-p-tolyl) methanone:
The [pyrazole-3-14C] 5-hydroxy-1,3-dimethylpyrazol-4-yl)(α,α,α-trifluoro-2-mesyl-p-tolyl) methanone was readily absorbed following oral administration with 57% of the dose recovered in the urine within 6 hours and a total of 75% of the dose recovered in the urine at the time of sacrifice (48 hours). The intravenous experiment showed that 8% of the dose was found in the faeces at the time of sacrifice (48 hours). - Details on distribution in tissues:
- In all experiments, ≤ 2% of the administered dose remained in the carcass and tissues at sacrifice. In all experiments, the highest residues were found in the liver and kidney (see Table 1, attached background material).
- Details on excretion:
- [Phenyl-UL-14C] 5-hydroxy-1,3-dimethylpyrazol-4-yl)(α,α,α-trifluoro-2-mesyl-p-tolyl) methanone - oral experiment
The distribution of [phenyl-UL-14C] 5-hydroxy-1,3-dimethylpyrazol-4-yl)(α,α,α-trifluoro-2-mesyl-p-tolyl) methanone residues among urine, faeces, cage wash, and tissues for each rat in the [phenyl-UL-14C] AE 0317309 O-LDE-M experiment is shown in Table 2 (attached background material). Following oral dosing, [phenyl-UL-14C] AE 0317309 residues were rapidly excreted (102% of the administered dose was excreted within 24 hours). The total radioactive recovery was 108% of the administered dose. The majority of the radioactivity was excreted in the urine (73%), with less being excreted in the faeces (31%). Much of the administered dose was rapidly excreted in the urine within 6 hours of dosing (62%).
[Pyrazole-3-14C] AE 0317309 - oral experiment
The distribution of [pyrazole-3-14C] AE 0317309 residues among urine, faeces, cage wash, and tissues for each rat in the [pyrazole-3-14C] AE 0317309 O-LDE-M experiment is shown in Table 2 (attached background material). Following oral dosing, [pyrazole-3-14C] AE 0317309 residues were rapidly excreted (106% of the administered dose was excreted within 24 hours). The total radioactive recovery was 111% of the administered dose. The majority of the radioactivity was excreted in the urine (75%), with less being excreted in the faeces (32%). Much of the administered dose was rapidly excreted in the urine within 6 hours of dosing (57%).
[Phenyl-UL-14C] AE 0317309 - intravenous experiment
The distribution of [phenyl-UL-14C] AE 0317309 residues among urine, faeces, cage wash, and tissues for each rat in the [phenyl-UL-14C] 5-hydroxy-1,3-dimethylpyrazol-4-yl)(α,α,α-trifluoro-2-mesyl-p-tolyl) methanone IV-LDE-M experiment is shown in Table 2 (attached background material). Following intravenous dosing, [phenyl-UL-14C]5-hydroxy-1,3-dimethylpyrazol-4-yl)(α,α,α-trifluoro-2-mesyl-p-tolyl) methanone residues were rapidly excreted (96% of the administered dose was excreted within 24 hours). The total radioactive recovery was 100% of the administered dose. The majority of the radioactivity was excreted in the urine (87%), with less being excreted in the faeces (10%). Much of the administered dose was rapidly excreted in the urine within 6 hours of dosing (83%).
[Pyrazole-3-14C] 5-hydroxy-1,3-dimethylpyrazol-4-yl)(α,α,α-trifluoro-2-mesyl-p-tolyl) methanone - intravenous experiment
The distribution of [pyrazole-3-14C] 5-hydroxy-1,3-dimethylpyrazol-4-yl)(α,α,α-trifluoro-2-mesyl-p-tolyl) methanone residues among urine, faeces, cage wash, and tissues for each rat in the [pyrazole-3-14C] 5-hydroxy-1,3-dimethylpyrazol-4-yl)(α,α,α-trifluoro-2-mesyl-p-tolyl) methanone IV-LDE-M experiment is shown in Table 2 (attached background material). Following intravenous dosing, [pyrazole-3-14C] 5-hydroxy-1,3-dimethylpyrazol-4-yl)(α,α,α-trifluoro-2-mesyl-p-tolyl) methanone residues were rapidly excreted (97% of the administered dose was excreted within 24 hours). The total radioactive recovery was 106% of the administered dose. The majority of the radioactivity was excreted in the urine (91%), with less being excreted in the faeces (8%). Much of the administered dose was rapidly excreted in the urine within 6 hours of dosing (84%).
Metabolite characterisation studies
- Metabolites identified:
- yes
- Remarks:
- , 3 minor metabolites were identified
- Details on metabolites:
- All individual residues which accounted for ≥ 5% of the administered dose were identified; additionally, some components that were present in smaller quantities were also identified. Identification of the residues was accomplished by comparison of the mass spectral data to that of authentic reference standards when available. Some residues were tentatively identified by comparison of their HPLC retention times with those of authentic reference standards or components which had been identified in other matrices.
The total amount of hydroxymethyl (5-hydroxy-1,3-dimethylpyrazol-4-yl)(α,α,α-trifluoro-2-mesyl-p-tolyl) methanone identified in the urine and faeces from both oral experiments was 2% of the administered dose. The total amount of hydroxymethyl (5-hydroxy-1,3-dimethylpyrazol-4-yl)(α,α,α-trifluoro-2-mesyl-p-tolyl) methanone identified in the urine and faeces from both intravenous experiments was 1 - 2% of the administered dose.
The total amount of desmethyl (5-hydroxy-1,3-dimethylpyrazol-4-yl)(α,α,α-trifluoro-2-mesyl-p-tolyl) methanone identified in the urine and faeces from both oral experiments was 8% of the administered dose. The total amount of desmethyl (5-hydroxy-1,3-dimethylpyrazol-4-yl)(α,α,α-trifluoro-2-mesyl-p-tolyl) methanone identified in the urine and faeces from both intravenous experiments was 6% of the administered dose.
The total amount of AE B197555 identified in the urine and faeces from the [phenyl-UL-14C] oral and intravenous experiment was 1% of the administered dose.
From all experiments, 87 to 95% of the administered dose was excreted unchanged as (5-hydroxy-1,3-dimethylpyrazol-4-yl)(α,α,α-trifluoro-2-mesyl-p-tolyl) methanone. Hydroxymethyl (5-hydroxy-1,3-dimethylpyrazol-4-yl)(α,α,α-trifluoro-2-mesyl-p-tolyl) methanone, desmethyl 5-hydroxy-1,3-dimethylpyrazol-4-yl)(α,α,α-trifluoro-2-mesyl-p-tolyl) methanone, and AE B197555 were observed as minor metabolites in the urine and faeces. Greater than 96% of the administered dose in each experiment was identified. The major metabolic pathway occurred via N-demethylation of the test substance.
See Table 3 for the metabolite profile in excreta and Figure 1 for structure, chemical name and common name of standards and metabolites (attached background material).
Applicant's summary and conclusion
- Conclusions:
- The toxicokinetic behaviour of the test compound was investigated in a GLP-compliant study on rats according to EPA OPPTS 870.7485 (Metabolism and Pharmacokinetics). The study is therefore considered valid, scientifically acceptable and appropriate for the assessment of ADME in the rat. With the use of radioactive-labelled test material, the present study demonstrated that (5-hydroxy-1,3-dimethylpyrazol-4-yl)(2-mesyl-4-trifluoromethylphenyl) methanone was readily absorbed after oral administration and excretion was rapid. Greater than 96% of the administered dose was excreted within 24 hours following oral administration. In all experiments, the majority of the radioactivity was excreted in the urine. Faecal excretion represented 8 to 10% of the administered dose during the intravenous experiments.
No volatile residues were detected, and no mineralization was observed. Residue levels in all tissues were highest in liver and kidney.
The test substance was not greatly metabolised, as 87 to 95% of the administered dose was excreted unchanged. Three metabolites were identified in urine and faeces. The major metabolic pathway occurred via N-demethylation of the test substance to yield desmethyl (5-hydroxy-1,3-dimethylpyrazol-4-yl)(α,α,α-trifluoro-2-mesyl-p-tolyl) methanone.
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