2-[methyl[(nonafluorobutyl)sulphonyl]amino]ethyl methacrylate

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics in vivo

Type of information:

experimental study

Adequacy of study:

key study

Study period:

2016

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2018

Report date:

2018

Materials and methods

Objective of study:

absorption

distribution

excretion

metabolism

Test guideline

Qualifier:

no guideline followed

Principles of method if other than guideline:

- Principle of test: The serum uptake, liver distribution, and excretion profile of the test article was examined.
- Short description of test conditions: This study was undertaken to evaluate the serum uptake, liver distribution, and excretion profile of MTDID 19536 (FZ-9262, C4 methacrylate) in male and female SpragueDawley rats after a single oral dose. The test article was prepared in corn oil and administered to non-fasted rats (N = 3/sex/dose group) via oral gavage at 10, 30, 100, or 300 mg/kg/body weight.
- Parameters analysed / observed: Each animal was observed immediately following dosing and throughout the study for mortality and morbidity. Body weights were recorded prior to treatment and daily thereafter. Interim urine and feces were collected daily (~24-hour interval) from all animals for up to 96 hours post-dose. At 96 hours post-dose, all animals were euthanized via CO2 asphyxiation followed by gross necropsies. Blood (processed to serum) and liver were harvested during necropsy. All specimens collected during the study (urine, feces, serum, and liver) were stored at -70 C pending analysis.

GLP compliance:

no

Test material

Test material information

Constituent 1

Reference substance name:

C4 sulfonamido methacrylate

IUPAC Name:

C4 sulfonamido methacrylate

Details on test material:

- Name of test material (as cited in study report): 2-Propenoic acid, 2-Methyl-, 2-[Methyl[(Nonafluorobutyl)Sulfonyl]Amino]Ethyl ester, FZ-9262
- Physical state: white to grey waxy solid
- Analytical purity: 99.5%
- Storage condition of test material: at room temperature in the dark

Specific details on test material used for the study:

SOURCE OF TEST MATERIAL
- Source and lot/batch No.of test material: 3M Company, Lot 040004
- Expiration date of the lot/batch: No data
- Purity test date: 16 October, 2016

STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material: Shelf stable
- Stability under test conditions: No data
- Solubility and stability of the test substance in the solvent/vehicle: Soluble in corn oil up to 60 mg/mL

TREATMENT OF TEST MATERIAL PRIOR TO TESTING
- Treatment of test material prior to testing: The test article was mixed in corn oil.
- Preliminary purification step (if any):
- Final dilution of a dissolved solid, stock liquid or gel:
- Final preparation of a solid: 2, 6, 20, 60 mg/mL

Radiolabelling:

no

Test animals

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Envigo Laboratories
- Age at study initiation: 6-8 weeks
- Weight at study initiation: 129-185 grams
- Housing: All animals were group-housed in solid-bottom cages prior to the study. All animals were single house in wired bottom metabolism cages during the in-life portion of the study until study termination.
- Diet (e.g. ad libitum): Harlan Teklad Rat/Mouse 2018 Diet ad libitum
- Water (e.g. ad libitum): Tap water ad libitum
- Acclimation period: No data

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20.6- 23.9
- Humidity (%): 30-70
- Air changes (per hr): At least 10
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: From: 17 October, 2016 To: 21 October, 2016

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

corn oil

Details on exposure:

PREPARATION OF DOSING SOLUTIONS: The test article was mixed in corn oil.

Duration and frequency of treatment / exposure:

A single dose was administered to each animal via oral gavage.

Doses / concentrations

Doses / concentrations 1

Dose / conc.:

10 mg/kg bw/day (nominal)

Remarks:

3 animals/sex

Doses / concentrations 2

Dose / conc.:

30 mg/kg bw/day (nominal)

Remarks:

3 animals/sex

Doses / concentrations 3

Dose / conc.:

100 mg/kg bw/day (nominal)

Remarks:

3 animals/sex

Doses / concentrations 4

Dose / conc.:

300 mg/kg bw/day (nominal)

Remarks:

3 animals/sex

No. of animals per sex per dose / concentration:

3

Control animals:

no

Positive control reference chemical:

Not applicable

Details on study design:

- Dose selection rationale: No data
- Rationale for animal assignment: No data

Details on dosing and sampling:

TOXICOKINETIC / PHARMACOKINETIC STUDY (Absorption, distribution, excretion)
- Tissues and body fluids sampled: urine, faeces, serum, liver

METABOLITE CHARACTERISATION STUDIES
- Tissues and body fluids sampled: urine, faeces, serum, liver
- Time and frequency of sampling: Serum and liver were collected at necropsy (96 hours). Urine and feces were samples at the following time-points: 0-24 hours, 24-48 hours, 48-72 hours, 72-96 hours.
- From how many animals: All animals, samples not pooled.
- Method type(s) for identification: LC-MS-MS, GC-MS/MS, NMR
- Limits of detection and quantification: 1 ng/mL, 5 ng/g, and 4 ng/g for serum, liver, and feces, respectively

Results and discussion

Main ADME results

Main ADME results 1

Type:

absorption

Results:

The test article appeared to be partially absorbed due to some unaltered parent compound and C4 methyl alcohol metabolite detected in all fecal samples 0-24 hours post-dose. Parent compound and metabolites made up 23% of administered dose in feces.

Main ADME results 2

Type:

distribution

Results:

The parent test article was not detected in serum or liver upon necropsy nor in urine at 48-hours. Parent compound was found in urine and feces.

Main ADME results 3

Type:

excretion

Results:

Parent test article was not detected in the serum or liver at 96 hours nor was it detected in urine 48 hours post-dose.

Main ADME results 4

Type:

metabolism

Results:

NMR urine analysis revealed 7 potential metabolites that can be generated in both male and female rats. Urinary metabolites constituted 21% recovered of the administered dose.

Toxicokinetic / pharmacokinetic studies

Details on absorption:

Several metabolites were identified in the serum, liver, urine and feces, which suggested that the test article can be systemically absorbed.

Details on distribution in tissues:

The parent test article was not deteced in serum or liver upon necropsy nor in urine at 48-hours. Parent compound was found in urine and feces.

Details on excretion:

Parent test article was not detected in the serum or liver at 96 hours nor was it detected in urine 48 hours post-dose.

Metabolite characterisation studies

Metabolites identified:

yes

Details on metabolites:

The parent compound appeared to undergo rapid metabolism as it was not detected in serum or liver upon necropsy (at 96 hours post-dose) nor was it being detected in urine 48 hours post-dose. It is worth noting that, in all serum samples, there appeared to be a dose-dependent increase in a metabolite identified as C4 methyl glycine acid (C4F9SO2N(CH3)CH2CO2H) at 96 hours post-dose, with higher concentrations reported for males than females. While liver and fecal samples were not analyzed for this metabolite, the significance of this observation may require further investigation.
Urine NMR analysis revealed 7 potential metabolites that can be generated in both male and female rats when administered with the test article. On the basis of molar equivalency to the test article, the urinary metabolites constituted an overall mean of 21% of the administered dose.

Applicant's summary and conclusion

Conclusions:

Although not comprehensive, several metabolites were identified in the serum, liver, urine, and feces, which suggested that the test article can be systemically absorbed, metabolized, and excreted via both urinary and fecal routes. Within the limits of the study design, these data suggest that the test article underwent rapid metabolism upon oral administration in rats and up to 50% of the administered test material can be recovered in rats under the study conditions.

Executive summary:

This study was undertaken to evaluate the serum uptake, liver distribution, and excretion profile of the test article in male and female Sprague Dawley rats after a single oral dose. The test article was prepared in corn oil and administered to non-fasted rats (N = 3/sex/dose group) via oral gavage at 10, 30, 100, or 300 mg/kg/body weight. Each animal was observed immediately following dosing and throughout the study for mortality and morbidity.

Body weights were recorded prior to treatment and daily thereafter. Interim urine and feces were collected daily (~24-hour interval) from all animals for up to 96 hours post-dose. At 96 hours post-dose, all animals were euthanized via CO2 asphyxiation followed by gross necropsies. Blood (processed to serum) and liver were harvested during necropsy. All specimens collected during the study (urine, feces, serum, and liver) were stored at -70 C pending analysis.

All animals appeared normal during the study and they all survived until the scheduled necropsy. Due to project prioritization, a limited number of 300 mg/kg dose group urine samples were subjected to NMR analysis from time points 0 - 24 and 24 - 48 hours post-dose only. Given that the concentrations of urinary metabolites from 24 – 48 hours post-dose were much lower than that from 0 – 24 hours post-dose, no further NMR was performed on the remaining urine samples collected from 48 – 72 and 72 – 96 hours post-dose. Serum, liver, and feces were analyzed for parent compound as well as selected metabolites (as identified by NMR) with LC-MS/MS and/or GC-MS/MS.

Although not comprehensive, several metabolites were identified in the serum, liver, urine, and feces, which suggested that the test article can be systemically absorbed, metabolized, and excreted via both urinary and fecal routes.

The parent compound appeared to undergo rapid metabolism as it was not detected in serum or liver upon necropsy (at 96 hours post-dose) nor was it detected in urine after 48 hours post-dose. It is worth noting that, in all serum samples, there appeared to be a dose-dependent increase in a metabolite identified as C4 methyl glycine acid (C4F9SO2N(CH3)CH2CO2H) at 96 hours post-dose, with higher concentrations reported for males than females. While liver and fecal samples were not analyzed for this metabolite, the significance of this observation may require further investigation.

Urine NMR analysis revealed 7 potential metabolites that can be generated in both male and female rats when administered with MTDID 19536. On the basis of molar equivalency to the test article the urinary metabolites constituted an overall mean of 21% recovered of the administered dose. 

The test article appeared to be partially absorbed as there was some unaltered parent compound (MTDID 19536) as well as C4 methyl alcohol metabolite (C4F9SO2N(CH3)CH2CH2OH, presumably hydrolyzed product of the test article) detected in all fecal samples within the first 24 hours post-dose. While there might be other potential metabolite(s) present in feces, on the basis of molar equivalency to the test article, they constituted an overall mean of 23% recovered of the administered dose. Within the limits of the study design, these data suggest that the test article underwent rapid metabolism upon oral administration in rats and up to 50% of the administered test material can be recovered in rats under the study conditions.