Ethylene oxide

Epidemiological data

Administrative data

Endpoint:

epidemiological data

Type of information:

experimental study

Adequacy of study:

supporting study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Cross-reference

Reason / purpose for cross-reference:

reference to same study

Reference

Endpoint:

specific investigations: other studies

Remarks:

Concentration of the test substance in blood

Type of information:

experimental study

Adequacy of study:

supporting study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Reason / purpose for cross-reference:

reference to same study

Qualifier:

no guideline followed

Principles of method if other than guideline:

It was the goal to determine the EO concentrations in blood of mice, rats, and volunteers exposed to various constant ethylene concentrations ranging from 1 up to 10,000 ppm in male B6C3F1 mice and male Fischer 344/N rats and from 5 up to 50 ppm in humans.

GLP compliance:

not specified

Type of method:

in vivo

Endpoint addressed:

basic toxicokinetics

Specific details on test material used for the study:

SOURCE OF TEST MATERIAL
- Source: Linde, Unterschleißheim, Germany
- Purity: > 99.9% (ethylene oxide 3.0)

Species:

other: mice and rat

Strain:

other: B6C3F1 and Fischer 344

Sex:

male

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Wiga Deutschland, Sulzfeld, Germany
- Weight at study initiation: 230-290 g (rats), 23-30 g (mice)
- Housing: Group housing of 2 (rats) or 5 (mice)
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: At least 5 days

ENVIRONMENTAL CONDITIONS
- Photoperiod (hrs dark / hrs light): 12 h

Route of administration:

inhalation: vapour

Vehicle:

unchanged (no vehicle)

Details on exposure:

Animals were exposed to ethylene concentrations and ethylene oxide was measured in exhaled air and blood.

Duration of treatment / exposure:

6 h

Details on results:

Half-lives of EO, estimated from the concentration-time courses of EO in blood at 30 ppm ET, were 8.9 min in mice and 15 min in rats. From the half-lives, elimination rate constants of 4.7 and 2.8/h were calculated for mice and rats, respectively. At identical ET exposure concentrations, EO concentrations are higher in rats than that in mice.

Data source

Reference

Reference Type:

publication

Title:

Ethylene Oxide in Blood of Ethylene-Exposed B6C3F1 Mice, Fischer 344 Rats, and Humans

Author:

Johannes Georg Filser, Winfried Kessler, Anna Artati, Eva Erbach, Thomas Faller, Paul Erich Kreuzer,
Qiang Li, Josef Lichtmannegger, Wanwiwa Numtip, Dominik Klein, Christian Pütz, Brigitte Semder, and
György Andras Csanady

Year:

2013

Bibliographic source:

Toxicological Sciences 136 (2), 344-358 2013

Report date:

2013

Materials and methods

Study type:

cohort study (prospective)

Endpoint addressed:

basic toxicokinetics

Test guideline

Qualifier:

no guideline followed

Principles of method if other than guideline:

It was the goal to determine the EO concentrations in blood of mice, rats, and volunteers exposed to various constant ethylene concentrations ranging from 1 up to 10,000 ppm in male B6C3F1 mice and male Fischer 344/N rats and from 5 up to 50 ppm in humans.

GLP compliance:

not specified

Test material

Test material information

Constituent 1

Reference substance name:

Ethylene oxide

EC Number:

200-849-9

EC Name:

Ethylene oxide

Cas Number:

75-21-8

Molecular formula:

C2H4O

IUPAC Name:

oxirane

Specific details on test material used for the study:

SOURCE OF TEST MATERIAL
- Source: Linde, Unterschleißheim, Germany
- Purity: > 99.9% (ethylene oxide 3.0)

Method

Type of population:

general

Ethical approval:

confirmed, but no further information available

Details on study design:

HYPOTHESIS TESTED (if cohort or case control study): In order to provide a reliable basis for cancer risk assessment of ethylene, it was the goal to determine the ethylene oxide concentrations in blood

METHOD OF DATA COLLECTION
- Type: Clinical tests
- Details: Respiratory parameters were established by determining breathing frequencies and tidal volumes using a spirometer

STUDY PERIOD:

STUDY POPULATION
- Total number of subjects participating in study: 4
- Sex/age/race: Male/62, 49, 61, 42 years old
- Smoker/nonsmoker: Nonsmoker
- Total number of subjects at end of study: 4

HEALTH EFFECTS STUDIED
- Other health effects: Respiratory parameters

OTHER DESCRIPTIVE INFORMATION ABOUT STUDY: The shortest time interval between exposures was 2 days

Exposure assessment:

measured

Details on exposure:

TYPE OF EXPOSURE: inhalation

TYPE OF EXPOSURE MEASUREMENT: Area air sampling, venous blood sampling. EO concentrations in exhaled air were measured once an hour. Blood samples were taken at the start of the exposure and hourly thereafter

EXPOSURE LEVELS: 5, 20, and 50 ppm (3 males); 5 and 20 ppm (1 male)

EXPOSURE PERIOD: 4 h

Results and discussion

Results:

EXPOSURE
- Number of measurements: 3 measurements per participant for exhaled air and measured concentration in blood
- Average concentrations: 2.76, 6.76, 16.1, 2.32, 7.7, 26.6, 1.37, 7.42, 16.0, 1.71, 9.00 (exhaled air); 6.82, 23.6, 57.9, 6.87, 35.9, 81.8, 6.53, 32.7, 70.9, 6.90, 42.0 (blood)
- Standard deviation: 0.404, 1.58, 2.75, 0.316, 1.11, 2.24, 0.176, 0.471, 2.59, 0.020, 1.18 (exahled air); 0.818, 0.288, 3.44, 0.536, 7.29, 2.86, 0.599, 0.919, 12.2, 0.743, 9.60 (blood)

FINDINGS

OTHER OBSERVATIONS: The linear relationship between the EO concentration in blood and the ET concentration in air agrees with ealier findings showing that the rate of ET metabolism follows first-order kinetics up to an ET exposure concnetration of at least 50 ppm.

Strengths and weaknesses:

Weakness: No negative control has been used

Applicant's summary and conclusion

Executive summary:

The gaseous olefin ethylene (ET) is metabolized in mammals to the carcinogenic epoxide ethylene oxide (EO). Although ET is the largesl volume organic chemical worldwide, the EO burden in ET-exposed humans is still uncertain, and only limited data are availablc on thc EO burdcn in ET-exposcd rodents. Therefore, EO was quantified in blood of mice, rats, or 4 volunteers that were exposed once to constant atmospheric ET concentrations of

between 1 and 10000 ppm (rodents) or 5 and 50 ppm (humans).

Both the compounds were determined by gas chromatography.

At ET concentrations of between 1 and 10 000 ppm, areas under the concentration-time curves of EO in blood (μmol x h/l) ranged from 0.039 to 3.62 in mice and from 0.086 to 11.6 in rats. At ET

concentrations lower or equal to 30 ppm, EO concentrations in blood were 8.7-fold higher in rats and 3.9-fold higher in mice than that in the volunteer with the highest EO burdens. Based on measured EO concentrations,

levels of EO adducts to hemoglobin and lymphocyte DNA were calculated for diverse ET concentrations and compared with published adduct levels. For given ET exposure concentrations, there were good agreements between calculated and measured levels of adducts to hemoglobin in rats and humans and to DNA in rats and mice. Reported hemoglobin adduct levels in mice were higher than calculated ones. Furthermore, information is given on

species-specific background adduct levels. In summary, the study provides most relevant data for an improved assessment of the human health risk from exposure to ET.