Buta-1,3-diene

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: Non-GLP, near guideline study published in peer reviewed literature, minor restrictions in design and/or reporting but otherwise adequate for assessment

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:

Comparison of blood concentrations of 1,3-butadiene and butadiene epoxides in mice and rats exposed to 1,3-butadiene by inhalation

Author:

Himmelstein MW, Turner MJ, Asgharian B and Bond JA

Year:

1994

Bibliographic source:

Carcinogenesis. 15; 1479-1486

Materials and methods

Objective of study:

absorption

metabolism

Principles of method if other than guideline:

To investigate species differences in 1,3-butadiene metabolism, the in vivo blood concentrations of 1,3-butadiene, butadiene monoxide and butadiene diepoxide in rats and mice were measured during and following 6 hr exposures to inhaled 1,3-butadiene.

GLP compliance:

not specified

Test material

Test material information

Constituent 1

Reference substance name:

Reference substance 001

Cas Number:

106-99-0

Molecular formula:

C4 H6

Constituent 2

Reference substance name:

1,3-Butadiene

Cas Number:

106-99-0

Molecular formula:

C4H6

IUPAC Name:

1,3-Butadiene

Details on test material:

- Name of test material (as cited in study report): 1,3-Butadiene
- Source: obtained from two sources:
- BD 15,000 ppm (certified concentration) in nitrogen from Scott Specialty Gases (Plumsteadville, PA).
- Pure buta-1,3-diene (>99%): Aldrich Chemical Company (Milwaukee, WI, USA).

Radiolabelling:

no

Test animals

Species:

other: rat and mouse

Strain:

other: Sprague-Dawley CD and B6C3F1

Sex:

male

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Male Sprague-Dawley CD rats (Crl:CDIBR) and male B6C3F1 mice (B6C3FI/Cr1BR)
- Source: Charles River
- Age: 8-11 weeks
- Weight: 25-33 g for mice and 321-403 g for rats
- Housing: No data
- Diet: A standard rodent diet (NIH-07; Zeigler Brothers) ad libitum, except during exposure
- Water: Ad libitum, except during exposure
- Acclimation period: At least 10 days
- Determined to be free of viral antibodies

ENVIRONMENTAL CONDITIONS
- Temperature: 22±2°C
- Humidity: 55%
- Photoperiod: 12 hrs dark / 12 hrs light

IN-LIFE DATES: No data

Administration / exposure

Route of administration:

inhalation

Vehicle:

other: air

Details on exposure:

TYPE OF INHALATION EXPOSURE: nose only

GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Concentrated 1,3-butadiene (15,000 ppm) from a cylinder was mixed with clean dry air to achieve target concentrations in the nose-only exposure unit.
- The resulting mixture was conducted through an infrared gas analyzer to continuously monitor the concentration of 1,3-butadiene at the inlet to the unit. A second gas analyzer was used to measure the concentration of buta-1,3-diene at the inlet, exposure port and chamber exhaust. The latter gas analyzer automatically rotated through the three sampling locations at 10 min intervals.

Duration and frequency of treatment / exposure:

Up to 6 hours in a continuous exposure system

Doses / concentrations

Remarks:

Doses / Concentrations:
Target concentrations of 62.5, 625 and 1250 ppm buta-1,3-diene. Actual concentrations were very similar to the targets.

No. of animals per sex per dose / concentration:

5-12 rats per exposure
13-19 mice per exposure.

Control animals:

no

Positive control reference chemical:

none

Details on study design:

1,3-Butadiene, butadiene monoxide and butadiene diepoxide were quantified in the blood of rats and mice during and following inhalation of 1,3-butadiene at the three exposure concentrations. Respiratory measurements were also made on the rats and mice.

Buta-1,3-diene was determined using a head-space equilibration technique followed by gas chromatography. The epoxides were quantified by electron-impact ionization gas chromatography-mass spectrometry

Details on dosing and sampling:

Measurement of breathing frequency and tidal volume: Rats or mice (one animal per exposure) were placed in body plethysmograph tubes. Minute volume was calculated as the product of breathing frequency and tidal volume.

Collection of blood: During exposure, blood samples for the measurement of buta-1,3-diene and butadiene monoxide were collected at 2, 3, 4 and 6 h of exposure. Blood samples for the measurement of butadiene diepoxide were collected at 3 and 6 h of exposure. After exposure, blood samples for all of these were collected at 2-10 min intervals up to 30 min post-exposure. A minimum of three blood samples per time point were collected.

Statistics:

none

Results and discussion

Preliminary studies:

none

Toxicokinetic / pharmacokinetic studies

Details on absorption:

1,3-Butadiene concentrations in blood were at steady state levels 2 hr after the start of exposure and remained constant during exposure to 62.5, 625 and 1250 ppm. The concentration in mice blood was 2-fold that of rats. 1,3-Butadiene levels in blood were not proportional to the inhaled concentrations suggesting saturable uptake in both species. Levels declined rapidly after exposure, such that by 30 min they were 1-12% of the steady state concentration.

Details on distribution in tissues:

not determined

Details on excretion:

not determined

Metabolite characterisation studies

Metabolites identified:

yes

Details on metabolites:

Butadiene monoxide was detected in blood of rats and mice but levels in mice were 4-8 times higher than in rats. Levels declined rapidly after exposure, such that by 20 min they were 10-40% of the steady state concentration. Butadiene diepoxide was only detected in the blood of mice.

Any other information on results incl. tables

1,3-Butadiene, and butadiene mono and diepoxide were quantified in the blood of rats and mice during and following inhalation of 1,3-butadiene at the three exposure concentrations.

The respiratory measurements in rats and mice were unaffected by 1,3-butadiene.

Blood concentrations of buta-1,3-diene and its mono and diepoxide are shown in the table.

1,3-Butadiene exposure concentration (ppm)	Mouse	Rat
1,3-Butadiene concentration in blood (µM)
62.5	2.4± 0.2	1.3± 0.04
625	37± 3	18± 0.7
1250	58± 3	37± 1.4
1,3-Butadiene monoxide concentration in blood (µM)
62.5	0.56± 0.04	0.07± 0.01
625	3.7± 0.4	0.94± 0.04
1250	8.6± 0.6	1.3± 0.09
1,3-Butadiene diepoxide concentration in blood (µM)
62.5	0.65± 0.1	ND
625	1.9± 0.2	ND
1250	2.5± 0.4	ND

ND= not detected

 

These data suggest that the greater sensitivity of mice to 1,3-butadiene-induced toxicity and carcinogenicity compared to rats, may be partially explained by the increased metabolism resulting in higher concentrations of the mono and diepoxides.

Applicant's summary and conclusion

Conclusions:

Interpretation of results: bioaccumulation potential cannot be judged based on study results
The greater sensitivity of mice to 1,3-butadiene-induced toxicity and carcinogenicity compared to rats, may be partially explained by increased metabolism resulting in higher concentrations of the mono and diepoxides.

Executive summary:

The concentrations of 1,3-butadiene and its mono and diepoxides were determined in the blood of rats and mice during and after exposure to inhaled buta-1,3-diene at 62.5, 625 or 1250 ppm (138, 1383 or 2766 mg/m³) for 6 hr. Steady-state blood concentrations of 1,3-butadiene were higher in mice than in rats. The concentration of 1,3-butadiene in blood was not directly proportional to the inhaled concentration of 1,3-butadiene, suggesting that the uptake of 1,3-butadiene was saturable at the highest inhaled concentration. In mice the respective 1,3-butadiene steady-state monoxide concentrations in blood were 0.6, 3.7 and 8.6 µM, compared to concentrations of 0.07, 0.94 and 1.3 µM in rats. Mice, but not rats, had quantifiable levels of the diepoxide in the blood. These data suggest that the greater sensitivity of mice to 1,3-butadiene-induced toxicity and carcinogenicity compared to rats, may be partially explained by the increased metabolism resulting in higher concentrations of the mono and diepoxides.