Hydrocarbons, C4, n-butene conc.

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, 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:

Uptake, distribution, and formation of hemoglobin and DNA adducts after inhalation of C2-C8 1-alkenes (olefins) in the rat.

Author:

Eide I, Hagemann R, Zahlsen K, Tareke E, Törnqvist M, Kumar R, Vodicka P and Hemminki K.

Year:

1995

Bibliographic source:

Carcinogenesis 16:1603-1609

Materials and methods

Objective of study:

absorption

distribution

excretion

other: haemoglobin and DNA adduct formation

Principles of method if other than guideline:

A homologous series of C2-C8 1-alkenes (olefins) were investigated in inhalation experiments with rats. The structure activity approach gave information about uptake, distribution and formation of haemoglobin and DNA adducts in relation to the number of carbon atoms in the olefins.

GLP compliance:

not specified

Test material

Test material information

Constituent 1

Reference substance name:

1-butene

IUPAC Name:

1-butene

Details on test material:

1-butene (>99%) was obtained from HydroGas AS, Norway

Radiolabelling:

no

Test animals

Species:

rat

Strain:

Sprague-Dawley

Sex:

male

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Mǿllgaard A/S, Ll. Skensved, Denmark
- Age at study initiation: no data
- Weight at study initiation: 180-225 g.
- Housing: There were eight animals in each cage and a maximum of four cages in each inhalation chamber.
- Diet: ad libitum except during exposure.
- Water: ad libitum except during exposure.
- Acclimation period: At least 5 days

ENVIRONMENTAL CONDITIONS
- Temperature: 21±1°C
- Humidity: 65± 5%
- Air changes (per hr): 10 per hr
- Photoperiod: 10 hrs dark / 14 hrs light

IN-LIFE DATES: no data

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: conically shaped 0.7 m3 steel chambers with glass front doors and walls
- System of generating test atmosphere: The aimed concentrations of C2 to C4 gases in the exposure chambers were generated by introducing a controlled stream of pure gas delivered by a two-stage precision pressure regulator.

TEST ATMOSPHERE
- Monitored hourly by gas chromatography

Duration and frequency of treatment / exposure:

12 h/day for 3 consecutive days

Doses / concentrations

Remarks:

Doses / Concentrations:
300 ppm

No. of animals per sex per dose / concentration:

A minimum of 8 males

Control animals:

yes, concurrent no treatment

Positive control reference chemical:

none

Details on study design:

see below

Details on dosing and sampling:

see below

Statistics:

none

Results and discussion

Preliminary studies:

not applicable

Toxicokinetic / pharmacokinetic studies

Details on absorption:

not determined

Details on distribution in tissues:

see below

Transfer into organs

Transfer type:

other:

Details on excretion:

not determined

Toxicokinetic parameters

Toxicokinetic parameters:

other:

Metabolite characterisation studies

Metabolites identified:

not measured

Details on metabolites:

Concentrations of 1-alkenes in blood and organs reached a steady-state level after the first 12 h exposure, and the concentrations 12 h after the last exposure were generally low, except in fat tissue. Concentrations of 1-alkenes in blood and the different tissues increased with increasing number of carbon atoms. Levels of haemoglobin and DNA adducts decreased with increasing number of carbon atoms with the most pronounced decrease from C2 to C3. The decrease through the whole homologous series from C2 to C8 was most pronounced for haemoglobin adducts followed by the DNA adducts in the lymphocytes. Detectable levels of haemoglobin and DNA adducts were produced by all 1-alkenes, although the levels of haemoglobin adducts after C4-C8 exposure were low.

Any other information on results incl. tables

Concentrations of individual 1-alkenes after the third 12 h exposure to 300 ppm and concentrations in fat 12 h after the final exposure

	blood	liver	lung	brain	kidneys	fat	Fat 12 h elim
Ethane	0.3±0.1	0.4±0.1	2.3±0.5	0.7±0.1	0.7±0.1	7±1	nd
Propene	1.1 ±0.2	0.3±0.2	2.9± 1.3	1.7±0.3	1.8±0.2	36±4	nd
1-butene	1.9±0.1	0.8±0.3	4.9± 1.1	3.0±0.3	5.7±1.4	70±8	0.3±0.1
1-pentene	8.6±1.4	51.6±12.9	31.4±10.6	41.0±4.9	105.7±13.7	368±79	19±9
1-hexene	18.2±1.1	66.8±1.2	59.7± 17.7	59.7±4.6	188.0±21.7	1031±54	77±49
1-heptene	37.0±1.8	138.3±9.7	85.6±8.2	109.3±5.5	269.3±21.8	2598±253	293±167
1-octene	60.1±2.2	443.7±26.9	202.4±29.5	270.0±9.5	385.1±32.6	4621±468	943±480

N=4, mean +/- SD

All concentrations are in µmol/kg; nd = not detectable

Adjustment factors for exhalatory loss of C2 -C4 1 -alkenes ranged from 1.00 to 1.10.

 

Mean levels of N-(2-hydroxyalkyl)valine in haemoglobin (pmol/g) and 7-alkylguanine adducts in lymphocytes and liver (adducts/10⁷normal nucleotides) formed after exposing rats to the 1-alkenes.

	haemoglobin	lymphocytes	liver
Ethane	2730±100	5.8±2.2	7.4±1.0
Propene	740 ±50	1.8 ±0.9	2.8 ±0.9
1-butene	20±1	0.8±0.4	2.1±0.5
1-pentene	51±3	0.5±0.2	1.8±0.6
1-hexene	39±1	0.3±0.3	1.4±0.2
1-heptene	11±1	0.4±0.1	1.3±0.4
1-octene	1.7±0.5	0.2±0.2	1.3±0.6
C2 background	25±3	1.6±0.2	3.0±0.7
C3 background	1.3±0.3	nd	nd

Background values have been subtracted

N = 3-8 for haemoglobin and 4 for DNA adduct analysis

ND = not detectable

Applicant's summary and conclusion

Conclusions:

Interpretation of results (migrated information): low bioaccumulation potential based on study results
Rats exposed to 300ppm of 1-alkenes of from C2-C8 (including 1-butene) for 12h for 3 days had increased concentrations of the alkenes in blood and tissues proportional to increasing numbers of carbon atoms. In contrast, levels of haemoglobin and DNA adducts decreased with increasing numbers of carbon atoms. The 1-alkenes were widely distributed within the body with the lowest concentrations in blood and the highest in fat. Concentrations of 1-butene (micromol/kg tissue) were: blood 1.9, liver 0.8, lung 4.9, brain 3.0, kidneys 5.7, fat 70. DNA adducts (N-7 alkyl guanine) (adducts/107 nucleotides) were: lymphocytes 0.8, liver 2.1 after exposure to 1-butene.

Executive summary:

The absorption, distribution, elimination, haemoglobin adduct formation and DNA adduct formation of individual C2-C8 1-alkenes was studied in the rat after exposure to 300 ppm (688mg/m3), 12 h a day for 3 consecutive days. The concentrations of the alkenes were measured in blood, lung, brain, liver, kidney and peri-renal fat immediately after each exposure and 12 h after the third exposure. DNA adducts were determined by 32P-postlabeling in liver. Haemoglobin adducts were determined in erythrocytes by GC/MS and GC/MS/MS. Concentrations of 1-alkenes in blood and organs reached a steady-state level after the first 12 h exposure, and the concentrations 12 h after the last exposure were generally low, except in fat. Concentrations of 1-alkenes in blood and the different tissues increased with increasing number of carbon atoms. However, DNA adducts and haemoglobin adducts decreased with increasing number of carbon atoms with the most pronounced decrease being from C2 to C3. The decrease in haemoglobin adducts was more pronounced than DNA adducts. All 1-alkenes caused formation of detectable levels of haemoglobin and DNA adducts, although the levels of haemoglobin adducts after C4-C8 exposure were low. These results also indicate that extrapolation within the homologous series is possible.