Hydrocarbons, C4, 1,3-butadiene-free

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics in vivo

Type of information:

migrated information: read-across based on grouping of substances (category approach)

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Non-GLP, non guideline study, published in peer reviewed literature, no restrictions, fully adequate for assessment

Justification for type of information:

Justification for Category/Read-across approach:
See justification document for category approach and read-across to individual UVCB constituents in section 13.2.

Cross-reference

Cross-reference 1

Reason / purpose for cross-reference:

reference to same study

Cross-reference 2

Reason / purpose for cross-reference:

reference to other study

Data source

Reference

Reference Type:

publication

Title:

Investigation of species differences in isobutene (2-methylpropene) metabolism between mice and rats.

Author:

Csanady GA, Freise G, Denk B, Filser JG, Cornet M, Rogers V and Laib RJ.

Year:

1991

Bibliographic source:

Arch. Toxicol. 65:100-105

Materials and methods

Objective of study:

metabolism

toxicokinetics

Principles of method if other than guideline:

The metabolism of isobutene, and the formation of its primary reactive intermediate 1,1-dimethyloxirane, in rats following inhalation of isobutene was investigated. Comparative investigations of the pharmacokinetics of isobutene were carried out in rats and mice.

GLP compliance:

not specified

Test material

Test material information

Constituent 1

Reference substance name:

isobutene

IUPAC Name:

isobutene

Constituent 2

Reference substance name:

2-methylpropene

EC Number:

204-066-3

EC Name:

2-methylpropene

Cas Number:

115-11-7

Molecular formula:

C4H8

IUPAC Name:

2-methylprop-1-ene

Details on test material:

- Source: Messer Griesheim
- purity >99%

Radiolabelling:

no

Test animals

Species:

other: Rat and mouse

Strain:

other: Sprague-Dawley rat; B6C3F1 mice

Sex:

male

Details on test animals or test system and environmental conditions:

TEST ANIMALS -
- RATS
- Source: Zentralinstitut fur Versuchstierzucht, Hannover, Germany
- Weight at study initiation: 200-300 g
- Diet: Standard diet ad libitum
- Water: ad libitum

- MICE
- Source: Zentralinstitut fur Versuchstierzucht, Hannover, Germany
- Weight at study initiation: 200-300 g
- Diet: Standard diet ad libitum
- Water: ad libitum

Administration / exposure

Route of administration:

inhalation

Vehicle:

other: air

Details on exposure:

TYPE OF INHALATION EXPOSURE: Exposure was carried out as described in Filser and Bolt (1983) Mut Res 120, 57-60

GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: closed exposure system (6.4 dm3)

TEST ATMOSPHERE
- The atmosphere was sampled at appropriate time intervals and analyzed with a gas chromatograph equipped with a flame ionization detector

Duration and frequency of treatment / exposure:

Kinetic studies: Exposure was in a closed system, the duration of exposure was not given.
Identification of 1,1-dimethyloxirane: Exposure for 4 hours.

Doses / concentrations

Remarks:

Doses / Concentrations:
Kinetic studies: Varying starting concentrations (between 100 and 12,000 ppm ) were used in a closed system.
Identification of 1,1-dimethyloxirane: A constant concentration of 10,000 ppm isobutene was used .

No. of animals per sex per dose / concentration:

Kinetic studies: Either two rats or eight mice (in each experiment).
Identification of 1,1-dimethyloxirane: Two rats.

Control animals:

no

Positive control reference chemical:

none

Details on study design:

In kinetic studies on isobutene in rats and mice were exposed in closed systems. Pharmacokinetic parameters were calculated using a two-compartment model. In some studies animals were pre-treated with diethyldithiocarbamate or pyrazole to inhibit cytochrome P450.

In studies to identify production of the epoxide metabolite, rats were exposed to a constant concentration of isobutene.

Details on dosing and sampling:

The cytochrome P450 inhibitors diethyldithiocarbamate (300 mg/kg) or pyrazole (320 mg/kg) were administered i.p.(in saline) as a single dose prior to the start of the experiment.

Statistics:

none

Results and discussion

Preliminary studies:

not applicable

Toxicokinetic / pharmacokinetic studies

Details on absorption:

Not determined

Details on distribution in tissues:

Not determined

Details on excretion:

The metabolic elimination of isobutene followed Michaelis-Menten kinetics and showed a classical saturation pattern in both species. Vmax is the maximum metabolic rate and Km(app) is the hypothetical average concentration when metabolic rate is half Vmax. At concentrations up to 500ppm (1140mg/m3) metabolic elimination was first order. In rats Vmax was 340 ± 40 µmol/kg/h and Km (app) was 8,100 ± 2,700 ppm. In mice Vmax was 560 ± 50 µmol/kg/h and Km (app) was 11,000 ± 3,800 ppm. The atmospheric concentration at which Vmax/2 was reached was 1200 ppm for rats and 1800 ppm for mice. Metabolism was saturable in both species and was blocked by diethyldithiocarbamate and pyrazole.

Metabolite characterisation studies

Metabolites identified:

yes

Details on metabolites:

1,1 -Dimethyloxirane was formed as a primary reactive metabolite of isobutene in rats and was detected in exhaled air. Under conditions of metabolic saturation (10,000 ppm) the epoxide concentration increased to a maximum of about 0.05 ppm within 104 min.

Applicant's summary and conclusion

Conclusions:

Interpretation of results (migrated information): bioaccumulation potential cannot be judged based on study results
The metabolism of isobutene (2-methylpropene) in Sprague Dawley rats and B6C3F1 mice follows Michaelis-Menten kinetics. The maximal metabolic elimination rates in rats is half that in mice. The epoxide is a primary reactive metabolite of isobutene in both species.

Executive summary:

Sprague Dawley rats and B6C3F1 mice were exposed to isobutene (2-methylpropene). At concentrations up to 500ppm (1147mg/m³) metabolic elimination was first order. The maximal metabolic elimination rates were 340 µmol/kg/h for rats and 560 µmol/kg/h for mice. The atmospheric concentration at which Vmax/2 was reached was 1200 ppm (2754 mg/m3) for rats and 1800 ppm (4131 mg/m3) for mice. Below atmospheric concentrations of about 500 ppm (1147mg/m³), at steady state, the rate of metabolism of isobutene is directly proportional to its concentration. The epoxide 1,1-dimethyloxirane is formed as a primary reactive metabolite of isobutene in both species and can be detected in exhaled air. Metabolism is saturable in both species and can be blocked by inhibitors of P450 enzymes. When isobutene metabolism is saturated, the concentration of the epoxide in the atmosphere of a closed exposure system is only about 1/15 of that observed for ethene oxide and about 1/100 of that observed for 1,2-epoxy-3-butene as intermediates in the metabolism of ethene or 1,3-butadiene.