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Basic toxicokinetics

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Administrative data

Endpoint:
basic toxicokinetics in vivo
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Non-GLP, near guideline study published in peer reviewed literature, minor restrictions in design and/or reporting but otherwise adequate for assessment
Cross-referenceopen allclose all
Reason / purpose:
reference to same study
Reason / purpose:
reference to other study

Data source

Reference
Reference Type:
publication
Title:
Species differences in butadiene metabolism between mice and rats evaluated by inhalation pharmacokinetics
Author:
Kreiling R, Laib RJ, Filser JG and Bolt HM
Year:
1986
Bibliographic source:
Arch. Toxicol. 58, 235-238

Materials and methods

Objective of study:
toxicokinetics
Principles of method if other than guideline:
The higher susceptibility of mice to 1,3-butadiene (compared to rats) was investigated, to assess whether the difference was due to quantitative differences metabolism between these two species.

GLP compliance:
not specified

Test material

Reference
Name:
Unnamed
Type:
Constituent
Type:
Constituent
Details on test material:
1,3-Butadiene (99.0 %) was obtained from Messer-Griesheim, Dusseldorf, FRG
Radiolabelling:
no

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male
Details on test animals and environmental conditions:
TEST ANIMALS
- Male Sprague-Dawley rats
- Source: Ivanovas, Kissleg, FRG
- Weight: 150-280 g

- Male B6C3FI mice
- Source: Zentralinstitut fur Versuchstierzucht, Hannover, FRG
- Weight: 25-30 g


Administration / exposure

Route of administration:
inhalation
Vehicle:
other: air
Details on exposure:
TYPE OF INHALATION EXPOSURE: whole body

GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: a closed 6.4 L desiccator jar chamber
- Method of conditioning air: equipped with 135 g soda lime for CO2 absorption and an oxygen supply
- Concentration changes in the gas phase of the system were measured by gas chromatography after injection of buta-1,3-diene into the system (animals with and without dithiocarb pretreatment) or after IP administration of butadiene to the animals (IP studies: three mice, 2.8 1itre dessiccator, 63 g soda lime). Concentration changes were recorded for up to 15 hr.
- Buta-1,3-diene concentrations determined by gas chromatography using a 5 mL gas sample loop and flame ionisation detection.
- Butadiene was chromatographically separated on a 1 m stainless steel 1/8 Porapak Q GC column (80-100 mesh) at an oven temperature of 135°C.
- The FID temperature was 200°C.
- Gas flow rates were as follows: carrier gas (N2), 60 mL/min; hydrogen, 25 mL/min; synthetic air, 240 mL/min. Under these conditions the retention time for buta-1,3-diene was 1.3 min.
Duration and frequency of treatment / exposure:
Up to 15 hours in a closed system
Doses / concentrations
Remarks:
Doses / Concentrations:
The animals were exposed to initial concentrations between 10 ppm and 5000 ppm 1,3-butadiene
No. of animals per sex per dose:
2 rats per time point
8 mice per time point
Control animals:
no
Positive control:
none
Details on study design:
Starting from different initial concentrations between 10 ppm and 5000 ppm, the time-dependent decline of 1,3-butadiene in the exposure system was investigated.

To analyze the initial process of equilibration between uptake, exhalation and metabolism of buta-1,3-diene, which is determined by the rate constants of equilibration K12 and K21 and the rate constant for first order metabolic elimination (Kel) (Filser and Bolt 1981,1983), additional experiments were performed:
The equilibration of buta-1,3-diene between gas phase and animal compartment was measured after pretreatment of the animals with dithiocarb as a metabolic inhibitor. From this experiment the coefficient of static distribution, Keq, was calculated according to Filser and Bolt (1979).

Metabolic elimination of buta-1,3-diene in mice under inhalation conditions was practically limited by the uptake rate of the compound from the gas phase into the animal and the rate constant for first-order metabolic elimination of buta-1,3-diene could not be obtained from the inhalation experiments alone. Buta-1,3-diene was therefore administered IP to mice (as above).

Kinetic parameters were determined based on a two-compartment, open pharmacokinetic model developed by Filser and Bolt (1983). This model implies a one-compartment description of the experimental animal. The gas phase in the desiccator with volume Vi represented compartment l (Cp 1) the animals with volume V2 compartment 2 (Cp 2).

Details on dosing and sampling:
Some mice were also given 1,3-butadiene by ip injection (see above).
In some tests, animals were pretreated with a single dose of diethyldithiocarbamate as a metabolic inhibitor, 45 min before the experiment, at 300 mg/kg weight (mice) or 200 mg/kg weight (rats), IP, in saline (solution of 50 mg dithiocarb/mL saline).
Statistics:
none

Results and discussion

Preliminary studies:
none

Toxicokinetic / pharmacokinetic studies

Details on absorption:
Below approximately 1000 ppm elimination was first order but at the higher concentrations saturation kinetics became apparent. Maximal metabolic elimination rate (Vmax) in mouse was 400 pmol/h/kg and 220 pmol/h/kg in rats.
Details on distribution in tissues:
not determined
Details on excretion:
Metabolic elimination in mice was about twice that of rats under conditions of low and high exposure concentrations (mice: 7300 mL/h; rat: 4500 mL/h).

Metabolite characterisation studies

Metabolites identified:
not measured

Any other information on results incl. tables

The time-dependent decline of 1,3-butadiene in the closed system starting at initial concentrations of 10 to 5000 ppm showed that the curves for became flatter at higher concentrations indicating saturable elimination. Below about 1000ppm elimination was first order but at the higher concentrations saturation kinetics became apparent. Km and Vmax are shown below.

 

 A constant equilibrium was achieved in both mice and rats after a distribution-dependent decline in the gas phase. The metabolism of 1,3-butadiene was inhibited by dithiocarb in both species.

 

1,3-Butadiene is exhaled after IP administration to mice. Kinetic parameters were then computed and calculated from the inhalation exposures and IP experiments. The pharmacokinetic model of Filser and Bolt fitted the kinetic behaviour of 1,3-butadiene. Metabolic elimination rates were then calculated. A comparison of the two species showed that metabolic elimination in mice is about twice that of rats under conditions of low and high exposure concentrations (mice: 7300 mL/h; rat: 4500 mL/h).

The table shows the pharmacokinetic parameters for 1,3-butadiene in rats and mice. The first order rate constants K21and Kel and co-efficient of static distribution (Keq) are similar in rats and mice. However, the maximum metabolic rate Vmax is higher and clearance (K12xV1) is 2-fold higher in mice than in rats. Therefore, under conditions of first order elimination, the steady-state concentration of 1,3-butadiene in mice is 2-fold higher than in rats.

 

 

Pharmacokinetc parameters for distribution and metabolism of 1,3-butadiene in rats and mice

 

 

Mouse

Rat

Dimension

K12.V1

10280

5750

ml/h

K21

3.2

2.5

/h

Keq

2.7

2.3

-

Kel

7.6

8.8

/h

Vmax

400

220

µmol/h/kg

 

                                 

Applicant's summary and conclusion

Conclusions:
Interpretation of results (migrated information): bioaccumulation potential cannot be judged based on study results
1,3-Butadiene is metabolized in mice at higher rates than in rats.
Executive summary:

The pharmacokinetics of 1,3-butadiene in mice after inhalation exposure of 10 to 5000 ppm (22-11063 mg/m3) in a closed system were investigated and compared with that of rats. Linear pharmacokinetics applied in both species at exposure concentrations below 1000 ppm, saturation of metabolism was observed at concentrations of about 2000 ppm. Metabolic clearance in the lower concentration range where first order metabolism applies was 7300 mL/h (rat) and 4500 mL/h (mice). Maximal metabolic elimination rate (Vmax) in mouse was 400 pmol/h/kg compared with 220 pmol/h/kg in rats. The results show that the higher rate of 1,3-butadiene metabolism in mice when compared to rats may only in part be responsible for the considerable difference in the susceptibility of both species to 1,3-butadiene -induced carcinogenesis.