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EC number: 209-674-2 | CAS number: 590-19-2
- Life Cycle description
- Uses advised against
- Endpoint summary
- Appearance / physical state / colour
- Melting point / freezing point
- Boiling point
- Density
- Particle size distribution (Granulometry)
- Vapour pressure
- Partition coefficient
- Water solubility
- Solubility in organic solvents / fat solubility
- Surface tension
- Flash point
- Auto flammability
- Flammability
- Explosiveness
- Oxidising properties
- Oxidation reduction potential
- Stability in organic solvents and identity of relevant degradation products
- Storage stability and reactivity towards container material
- Stability: thermal, sunlight, metals
- pH
- Dissociation constant
- Viscosity
- Additional physico-chemical information
- Additional physico-chemical properties of nanomaterials
- Nanomaterial agglomeration / aggregation
- Nanomaterial crystalline phase
- Nanomaterial crystallite and grain size
- Nanomaterial aspect ratio / shape
- Nanomaterial specific surface area
- Nanomaterial Zeta potential
- Nanomaterial surface chemistry
- Nanomaterial dustiness
- Nanomaterial porosity
- Nanomaterial pour density
- Nanomaterial photocatalytic activity
- Nanomaterial radical formation potential
- Nanomaterial catalytic activity
- Endpoint summary
- Stability
- Biodegradation
- Bioaccumulation
- Transport and distribution
- Environmental data
- Additional information on environmental fate and behaviour
- Ecotoxicological Summary
- Aquatic toxicity
- Endpoint summary
- Short-term toxicity to fish
- Long-term toxicity to fish
- Short-term toxicity to aquatic invertebrates
- Long-term toxicity to aquatic invertebrates
- Toxicity to aquatic algae and cyanobacteria
- Toxicity to aquatic plants other than algae
- Toxicity to microorganisms
- Endocrine disrupter testing in aquatic vertebrates – in vivo
- Toxicity to other aquatic organisms
- Sediment toxicity
- Terrestrial toxicity
- Biological effects monitoring
- Biotransformation and kinetics
- Additional ecotoxological information
- Toxicological Summary
- Toxicokinetics, metabolism and distribution
- Acute Toxicity
- Irritation / corrosion
- Sensitisation
- Repeated dose toxicity
- Genetic toxicity
- Carcinogenicity
- Toxicity to reproduction
- Specific investigations
- Exposure related observations in humans
- Toxic effects on livestock and pets
- Additional toxicological data
Basic toxicokinetics
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 for cross-reference:
- reference to same study
- Reason / purpose for cross-reference:
- 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:
- 1 986
- 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 substance name:
- Buta-1,3-diene
- EC Number:
- 203-450-8
- EC Name:
- Buta-1,3-diene
- Cas Number:
- 106-99-0
- Molecular formula:
- C4H6
- IUPAC Name:
- buta-1,3-diene
- Reference substance name:
- 1,3-butadiene
- IUPAC Name:
- 1,3-butadiene
- Details on test material:
- 1,3-Butadiene (99.0 %) was obtained from Messer-Griesheim, Dusseldorf, FRG
Constituent 1
Constituent 2
- Radiolabelling:
- no
Test animals
- Species:
- rat
- Strain:
- Sprague-Dawley
- Sex:
- male
- Details on test animals or test system 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 / concentration:
- 2 rats per time point
8 mice per time point - Control animals:
- no
- Positive control reference chemical:
- 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.
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