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Description of key information

The test substance was readily absorbed after oral administration and excretion of the test substance was rapid.

Following oral administration, greater than 96% of the administered dose was excreted within 24 hours. In all experiments, the majority of the radioactivity was excreted in the urine. Fecal 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 metaolites were identified in urine and feces. 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.

Key value for chemical safety assessment

Bioaccumulation potential:
no bioaccumulation potential

Additional information

A reliable study on the absorption, distribution, metabolism and excretion of 5-hydroxy-1,3-dimethylpyrazol-4-yl)(α,α,α-trifluoro-2-mesyl-p-tolyl)methanone after single oral and intravenous doses in rats is available.

 

In the available ADME study (M-258714-01-1) that was conducted according to OPPTS 870.7485 and GLP, radio-labeled test substance was administered to male Wistar rats. Two different radiolabels were used: [phenyl-UL-14C] 5-hydroxy-1,3-dimethylpyrazol-4-yl)(α,α,α-trifluoro-2-mesyl-p-tolyl)methanone and [pyrazole-3-14C] of 5-hydroxy-1,3-dimethylpyrazol-4-yl)(α,α,α-trifluoro-2-mesyl-p-tolyl)methanone, with the radiolabel located in the phenyl ring and at position 3 of the pyrazol ring, respectively. Single oral doses of each radiolabel of the test substance were administered to five rats at dose rates of 10.0 and 9.88 mg/kg body weight, respectively. In two separate experiments, male Wistar rats with surgically implanted jugular cannulae were dosed intravenously with [phenyl-UL-14C] 5-hydroxy-1,3-dimethylpyrazol-4-yl)(α,α,α-trifluoro-2-mesyl-p-tolyl)methanone (four rats) or [pyrazole-3-14C] 5-hydroxy-1,3-dimethylpyrazol-4-yl)(α,α,α-trifluoro-2-mesyl-p-tolyl)methanone (five rats) at dose rates of 9.81 and 9.60 mg/kg body weight to investigate the absorption of the test substance.

In all experiments, urine and feces were collected in separate containers cooled with dry ice. The weight of urine at each interval was determined, and aliquots were radioassayed. Each feces sample was weighed, homogenized and aliquots of the fecal homogenates were oxidized and radioassayed. All urine and feces samples were stored frozen in a freezer (<-18°C) when not in use. Following completion of each experiment, each metabolism cage was washed with methanol/water (Me0H/H2O; 1:1), and the washes from each cage were separately radioassayed. The urine and feces collection containers were also washed with Me0H/H2O (1:1), and the combined washes from the urine and feces containers for each rat were radioassayed.

At the conclusion of each experiment individual rats were anesthetized with halothane and each rat was exsanguinated through cardiac puncture using a 10-mL disposable syringe pretreated with heparin. Triplicate blood samples were pipetted into combustion pads for oxidation and radioassay. In all of the experiments, bone, brain, fat, heart, kidney, liver, lung, muscle, skin, spleen, testes, and thyroid were collected and weighed; aliquots of each tissue were oxidized and radioassayed. The gastrointestinal tract (GIT) of each rat was collected and weighed, and the entire sample was homogenized, oxidized and radioassayed. The remaining carcass was dissolved in 3 N ethanolic potassium hydroxide (KOH) solution and aliquots of the KOH solution were radioassayed. In an attempt to detect and collect respired 14C02 and all other volatile compounds in the [phenyl-UL-

14C] and [pyrazole-3-14C] 5-hydroxy-1,3-dimethylpyrazol-4-yl)(α,α,α-trifluoro-2-mesyl-p-tolyl)methanone oral dose experiments, the rats were housed in metabolism cages equipped with a flow-through system which allowed for the separation and collection of respired gases. Respired gas collection was discontinued 24 hours post-treatment. Respired gases were not collected during the [phenyl-UL-14C] and [pyrazole-3-14C] 5-hydroxy-1,3-dimethylpyrazol-4-yl)(α,α,α-trifluoro-2-mesyl-p-tolyl)methanone intravenous (i.v.) experiments. Identification and quantitation of the metabolites in the urine samples and feces extracts were accomplished by using reverse phase HPLC and C/MS/MS.

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 during the oral experiment, 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 [phenyl-UL-14C] 5-hydroxy-1,3-dimethylpyrazol-4-yl)(α,α,α-trifluoro-2-mesyl-p-tolyl)methanone i.v. experiment showed that 10% of the dose was found in the feces 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 during the oral experiment, 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 [pyrazole-3-14C] 5-hydroxy-1,3-dimethylpyrazol-4-yl)(α,α,α-trifluoro-2-mesyl-p-tolyl)methanone i.v. experiment showed that 8% of the dose was found in the feces at the time of sacrifice (48 hours).

Distribution

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.

 

Excretion

Following dosing, test substance residues were rapidly excreted (96 - 106% of the administered dose was excreted within 24 hours). The total radioactive recoveries ranged from 100 - 111% of the administered dose. The majority of the radioactivity was excreted in the urine (73.1 - 90.7%), with less being excreted in the feces (8.0 - 32.0%). Much of the administered dose was rapidly excreted in the urine within 6 hours of dosing (56.8 - 84.1%).

 

Metabolite Identification and Characterization

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.

 

Proposed Metabolic Pathway

From all experiments, 87% to 95% of the administered dose was excreted as unchanged test substance.

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 feces. Greater than 96% of the administered dose in each experiment was identified. The major metabolic pathway occurred via N-demethylation of the test substance.

 

Conclusions

The excretion of the test substance was rapid. Following oral administration, greater than 96% of the administered dose was excreted within 24 hours. In all experiments, the majority of the radioactivity was excreted in the urine. Fecal 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.

Once absorbed, the test substance was not greatly metabolised, as 87 to 95% of the administered dose was excreted unchanged. 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 feces. Greater than 96% of the administered dose in each experiment was identified. 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.