Tetrahydro-2-methylfuran

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics in vivo

Type of information:

experimental study

Adequacy of study:

supporting study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: The study was well documented and meets generally accepted scientific principles, but was not conducted in compliance with GLP.

Data source

Reference

Reference Type:

publication

Title:

Unnamed

Year:

2007

Materials and methods

Objective of study:

absorption

distribution

excretion

metabolism

Test guideline

Qualifier:

no guideline followed

Principles of method if other than guideline:

ADME study

GLP compliance:

no

Test material

Test material information

Constituent 1

Reference substance name:

Tetrahydro-2-methylfuran

EC Number:

202-507-4

EC Name:

Tetrahydro-2-methylfuran

Cas Number:

96-47-9

Molecular formula:

C5H10O

IUPAC Name:

2-methyltetrahydrofuran

Test material form:

other: solution

Details on test material:

- Name of test material (as cited in study report): Methyltetrahydrofuran
- Analytical purity: 99% (non radio-labelled)
- Lot/batch No.: AA09508AA Sigma Chemical Company (non radio-labelled). 3462-105 Perkin Elmer (radio-labelled)
- Radiochemical purity (if radiolabelling): 93 to 98%
- Specific activity (if radiolabelling): 1.56 mCi/mmol
- Locations of the label (if radiolabelling): 14C in 2-methyl position

Radiolabelling:

yes

Test animals

Species:

other: Rats and Mice

Strain:

other: F344 rats and B6C3F1 mice

Sex:

male

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River, Wilmington, MA
- Age at study initiation: 10-11 weeks
- Weight at study initiation: 208-235g (rats), 25-30g (mice)
- Individual metabolism cages: yes
- Diet: Harlan Teklad, ad libitum
- Water: Municipal supply, ad libitum
- Acclimation period: 2 weeks

Administration / exposure

Route of administration:

other: oral gavage or intravenous

Vehicle:

other: water for oral, 0.9% saline for intravenous

Duration and frequency of treatment / exposure:

Single dose

Doses / concentrations

Remarks:

Doses / Concentrations:
1, 10 or 100 mg/kg orally at 10ml/kg (mice) or 5ml/kg (rats)
1 mg/kg intravenously at 4ml/kg (mice) or 1 ml/kg (rats)

No. of animals per sex per dose / concentration:

4

Control animals:

no

Details on study design:

- Dose selection rationale: The doses chosen were to provide a range ofdoses that might include one high dose above the level that could be completely metabolized by the animals. The high dose was also chosen to be high enough to detect any overt toxicity of the compound.

Details on dosing and sampling:

PHARMACOKINETIC STUDY (Absorption, distribution, excretion)
- Tissues and body fluids sampled: urine, faeces, blood, expired air, adipose (perirenal, reproductive), muscle (hind leg, trapezius), skin (ears), brain, heart, lung, spleen, kidneys, testes, liver, small intestines and contents, large intestine and contents, stomach and contents, urinary bladder and carcass.
- Time and frequency of sampling:
Urine - 3 (iv only) 6, 12, 24, 48 and 72 hours after dosing. Bladder urine also collected.
Faeces - 12, 24, 48 and 72 hours after dosing.
Expired air - traps changed 3 (iv only), 6, 12, 24, 48 or 72 hours after dosing.


METABOLITE CHARACTERISATION STUDIES
- Tissues and body fluids sampled: urine and expired air
- Time and frequency of sampling: as above
- From how many animals: all individually
- Method type(s) for identification: HPLC, HPLC-MS-MS, Liquid scintillation counting

Results and discussion

Main ADME results

Main ADME results 1

Type:

absorption

Results:

93-100%

Main ADME results 2

Type:

distribution

Results:

No accumulation in any tissue

Main ADME results 3

Type:

metabolism

Results:

Rapid in both rats and mice (3 polar peaks in mouse urine, 2 polar peaks in rat urine)

Main ADME results 4

Type:

excretion

Results:

Major route urine (mice) or exhaled CO2 (rats)

Toxicokinetic / pharmacokinetic studies

Details on absorption:

Following oral dosing absorption 93-100%.

Details on distribution in tissues:

No one tissue accumulated the radiolabel in either species. For all oral doses in both species the highest concentration of radiolabel at termination was in the kidney. For intravenous dosing, the highest concentration in tissues was in the liver.

Details on excretion:

In mice, urine was the primary route of elimination followed by exhalation of 14C02 and volatile organic compounds at all doses and by both routes of administration. In rats the
major route of excretion was exhaled CO2 followed by urinary excretion. The excretion of exhaled volatile organic compounds (VOC) was dose dependent in both species; at lower
doses the exhalation of VOC represented 1- 5% of dose, but at the highest dose (100 mg/kg) this proportion rose to 14% (mice) and 27% (rats). Analysis of the VOC, exhaled at the high dose showed that the increase was due to exhalation of the parent compound. Fecal excretion did not contribute significantly to the removal of MTHF and/or its metabolites from the body.

Metabolite characterisation studies

Details on metabolites:

In mouse urine, three major peaks were observed at retention times of 3.01, 4.02, and 5.15 min. The percent injected radioactivity in the 3.01-min peak was 6%, 29% for the 4.02-min peak and 59% for the 5.15-min peak. In all studies, the amount of measurable radioactivity in the three peaks declined to near baseline by 24 h.

In contrast to the profile observed in mice, one prominent peak was observed at a retention time of approximately 5 min in the 6h urine samples from rats following a single oral dose of 100 mg/kg. One additional peak was seen at 3 min. No clearly defined radioactive chromatographic peaks were observed in urine taken at later time points.

In addition, urine samples collected from a mouse and a rat after the 100 mg/kg oral dose were incubated with B-glucuronidase. which showed no effect on the retention time or abundance of any of these radiolabeled components found in urine.

HPLC radiochromatograms of urine samples collected over timed intervals following a single intravenous dose of 1 mg/kg 14C-MeTHF to rats and mice were similar to that seen following oral dosing. In mouse urine from a 6-h time point, three major peaks were observed at retention times of 2.73 min. 3.70 min. and 4.59 min. The proportion of radioactivity was 14.7%, 46.4% and 34.3% in the first, second and third peak, respectively.

Two peaks were observed at retention times of 2.77 and 4.51 min in the 6-h time point urine samples from rats following a single intravenous dose of 1 mg/kg. The proportion of injected radioactivity in the 2.77-min peak was 35.1% while the 4.51-min peak contained 60.2%.

As was seen following oral dosing, the major urinary metabolites in mice eluted at approximately 3, 4 and 5 min; only 2 major metabolites were seen in rats, eluting at approximately 3 and 5 min. All peaks in both species eluted much earlier than MeTHF, suggesting that they are more polar than the parent compound.

HPLC analysis of derivatized urine samples from both species showed no evidence of levulinic acid as a metabolite of MTHF in the urine.

The nature of the 14C-MeTHF-derived material captured in the VOC traps was investigated by HPLC. One major peak was seen at 13.42 min, which was consistent with the retention time of 14C-MeTHF analyzed under identical conditions.

Additional information on the identity of the radiolabeled material in the VOC traps was obtained by LC/MS/MS analysis. One major peak was seen at a mass-to-charge ratio of 87.1 (m/z amu), consistent with MTHF (FW + l), with an intensity of approximately l.7E+06, which is well above background. In the multiple response monitoring mode, a parent-daughter ratio of 87.0/69.21 (Ql/Q3 masses, amu) was observed and was consistent with the ratio obtained with the MeTHF standard. This confirmed the suspected presence of 14C-MeTHF in exhaled breath.

There are two indications that mice have a higher capacity to metaholize MeTHF than rats. At all doses. by 24 h mice had cleared a slightly higher percentage of the dose than rats. At the high dose rats cleared a higher percentage of the dose as exhaled parent compound than did mice.

Applicant's summary and conclusion

Conclusions:

The dispostion of 14C-MTHF in rats and mice was determined by following chganges in the radioactivity in tissues and excreta with time after dosing. MTHF administered orally at 1, 10 or 100 mg/kg or intravenously at 1 mg/kg to either rats or mice was rapidly metabolised and excreted with <8% (mice) or 8-22% (rats) of the dose remaining in the body after 24 hours (1 and 10 mg/kg doses) or 72 hours (100 mg/kg dose). Based on recovery of radioactivity in excreta (other than feces) and tissues (other than gastrointestinal tract), absorption or orally administered MTHF was esentially complete (93-100%). There were no overt signs of toxicity observed at any dose. The major route of excretion in mice was in urine followed bu exhaled CO2. In rats, the major route of excretion was exhaled CO2 followed by urinary excretion. The excretion of exhaled volatile organic compounds (VOC) was dose-dependent in both species; at lower doses exhaled VOC represented 1-5% of dose, but at the highest dose (100 mg/kg) this proportion rose to 14% (mice) and 27% (rats). Analysis of the VOCs exhaled at the high dose indicated that the increase was due to exhalation of the parent compund. Analysis of urine showed three highly polar peaks in the mouse urine and two polar peaks in the rat urine.