Pentane-2,4-dione

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics in vivo

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Meets generally accepted scientific standards, well documented and acceptable for assessment.

Data source

Reference

Reference 1

Reference Type:

publication

Title:

Unnamed

Year:

1998

Reference 2

Reference Type:

study report

Title:

Unnamed

Year:

1995

Report date:

1995

Reference 3

Reference Type:

secondary source

Title:

Unnamed

Year:

2001

Materials and methods

Objective of study:

toxicokinetics

Principles of method if other than guideline:

Intravenous study: 2,4-pentanedione was given to four adult male Fischer 344 rats per dose by single intravenous injection of 4.3, 43, 148.5, and 430 mg/kg bw. Blood was collected at appropriate intervals from a lateral tail vein until 30 or 36 hr post dosing. At 48 hr a cardiac puncture was performed for a final blood sample with all groups. Urine and feces were collected. For airborne collections, room air was drawn through the metabolism cages at approximately 500 mL/min, expired 14CO2 was trapped. After sacrifice the carcass and the following tissues were used for radioactivity measurements: brain, heart, lungs, kidneys, perirenal fat, muscle, spleen, testes, and bone marrow.

GLP compliance:

not specified

Test material

Test material information

Constituent 1

Details on test material:

Purity: 98%

Radiolabelling:

yes

Remarks:

14C-labelled

Test animals

Species:

rat

Strain:

Fischer 344

Sex:

male

Details on test animals or test system and environmental conditions:

Age: adult

Administration / exposure

Route of administration:

intravenous

Vehicle:

physiological saline

Details on exposure:

PREPARATION OF DOSING SOLUTIONS:
Dosing solutions were prepared by diluting a appropriate amount of unlabeled 2,4-pentanedione with the 14C-labeled test substance in physiological saline (0.9 %). Target radioactivity was 2-5 mCi.

Duration and frequency of treatment / exposure:

single intravenous injection

Doses / concentrations

Remarks:

Doses / Concentrations:
4.3, 43, 148.5, and 430 mg/kg bw

No. of animals per sex per dose / concentration:

4 males

Details on dosing and sampling:

Blood was collected at appropriate intervals from a lateral tail vein until 30 hr (4.3, 43 and 148 .5 mg/kg doses) or 36 hr (430 mg/kg dose group) post dosing. At 48 hr a cardiac puncture was performed for a final blood sample with all groups.
Urine was collected under dry ice freezing conditions at 6, 12, 24, 36 and 48 hr and feces were collected for two 24 hr intervals post dosing.
For airborne collections, room air was drawn through the metabolism cages at approximately 500 mL/min. Expired 14CO2 was trapped at 12, 24 and 48 hr post dosing.
After sacrifice the carcass and the following tissues were used for radioactivity measurements: brain, heart, lungs, kidneys, perirenal fat, muscle, spleen, testes, and bone marrow. Cages were washed with deionized water and methanol (1:1).

Statistics:

Pharmacokinetic description of plasma 14C disposition following intravenous application was derived using RSTRIP, a pharmacokinetic curve-stripping and fitting program.

Results and discussion

Toxicokinetic / pharmacokinetic studies

Details on absorption:

After a single intravenous injection the plasma concentration of 14C-labeled-test substance derived radioactivity declined in a biexponential fashion, with a rapid initial phase followed by a slower terminal phase.
The pharmacokinetic parameters derived were: initial elimination rate constants (k alpha ( hr-1)) of 2.30, 0.97, 1 .32 and 26.02; initial half-life (alpha t1/2 (hr)) of 0.30, 0.71, 0.53 and 0.03; terminal elimination constants (k beta (hr-1)) of 0.045, 0.037, 0.053 and 0.065; terminal half-life (beta t1/2 (hr)) of 15.40, 18.73, 13.08 and 10.66; maximum plasma concentrations (Cmax (µg/g)) of 16.13, 110.8, 499.40 and 4369.46; apparent volumes of distribution (Vd (L/kg)) of 1.79, 2.49, 1.28 and 0.78, mean residence time (MRT (hr)) of 12.8, 12.1, 10.3 and 10.5; and areas under the curve to infinity (AUC (µg hr/g)) of 53.28, 467.09, 2196.61 and 8505.12 for the 4.3, 43, 148.5 and 430 mg/kg bw doses, respectively.
The overall form of the 14C plasma concentration-time curves and derived pharmacokinetic parameters indicated that dose-linear kinetics occurred in the dose range of 4.3-148.5 mg/kg, but not with 433 mg/kg.

Details on excretion:

Metabolism of 2,4-pentanedione was quite rapid as the concentration of unmetabolized test substance declined steadily to undetectable after 8 hr in the 430 mg/kg dose group. 14C test substance derived radioactivity was eliminated mainly as 14CO2 and in urine . For the 4.3, 43 and 148.5 mg/kg doses 14CO2 elimination was relatively constant (36.8, 38.8 and 42.3 % in 48 hr samples, respectively) and greater than urinary excretion ( 17.9, 14.3 and 29 .6% in 48 hr samples, respectively). At 430 mg/kg there was a reversal of the excretion pattern, with urine 14C excretion (54.7 %) becoming greater than that for 14CO2 (27.3 %). Excretion in expired volatiles and faeces was small. Radiochromatograms of urine showed free 2,4-pentanedione in the 12 hr sample, together with 7 other metabolites. Most of the urinary radiolable was excreted within the first 24 hr post dosing. Unmetabolized 2,4-pentanedione and 6 of the metabolites decreased or were not detectable in the 24 or 48 hr urine samples, but one peak was still detectable in these. Carcass radioactivity ranged from 5.32 to 9.07%. Total recovery of radioactivity ranged from 69.0 % at the 4.3 mg/kg dose to 95.18% at the 430 mg/kg dose.

Toxicokinetic parameters

Toxicokinetic parameters 1

Toxicokinetic parameters:

half-life 1st: initial half-life (alpha t1/2 (hr)) of 0.30, 0.71, 0.53 and 0.03

Toxicokinetic parameters 2

Toxicokinetic parameters:

half-life 2nd: terminal half-life ( beta t1/2 (hr)) of 15.40, 18.73, 13.08 and 10.66

Toxicokinetic parameters 3

Toxicokinetic parameters:

Cmax: maximum plasma concentrations (Cmax (µg/g)) of 16.13, 110.8, 499.40 and 4369.46

Toxicokinetic parameters 4

Toxicokinetic parameters:

AUC: areas under the curve to infinity (AUC (µg hr/g)) of 53.28, 467.09, 2196.61 and 8505.12

Metabolite characterisation studies

Metabolites identified:

yes

Details on metabolites:

Radiochromatograms of urine showed free 2,4-pentanedione in the 12 hr sample, together with 7 other metabolites. Most of the urinary radiolabel was excreted within the first 24 hr post dosing. Unmetabolized 2,4-pentanedione and 6 of the metabolites decreased or were not detectable in the 24 or 48 hr urine samples, but one peak was still detectable in these.