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Endpoint:
additional toxicological information
Type of information:
experimental study
Adequacy of study:
other information
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
test procedure in accordance with generally accepted scientific standards and described in sufficient detail

Data source

Reference
Reference Type:
publication
Title:
Kinetics of Ethylene and Ethylene Oxide in Subcellular Fractions of Lungs and Livers of Male 86C3F1 Mice and Male Fischer 344 Rats and of Human Livers
Author:
Li Q, Csanady G. A., Kessler W, Klein D, Pankratz H, Pütz C, Richter N, Filser J. G.
Year:
2011
Bibliographic source:
Toxicological Sciences 123(2), 384-398 (2011)
Report date:
2011

Materials and methods

Test guideline
Qualifier:
no guideline followed
Principles of method if other than guideline:
The EO formation was measured using pooled liver microsomes of mice, rats, or humans and liver microsomes of individual human subjects as well as pooled lung microsomes of mice or rats.

Test material

Constituent 1
Chemical structure
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%

Results and discussion

Any other information on results incl. tables

The EO formation (k3) was 5.9 min -1 in the mouse, 11.2 min -1 in the rat and 3.2 min -1 in human. The apparent suicide inactivarion rate constant k4 (predominantly of CYP2E1) was 0.06 and 0.306 min -1 in mouse liver and lung, respectively, 0.07 and 0.573 min -1 in rat liver and lung, respectively, and 0.098 min -1 in human liver. The Vmax (EO) values in mice and rats are about double as high as in humans. The KM value in humans is lower than that in rats and higher than that in mice. The mean half-life of EO was 12.4 h. A Vmax of 14.35 nmol/min/mg/protein was derived. The KM in the microsomal environment was 12.74 mmol/l, and the reatio of Vmax to KM was 1.13 µl/min/mg protein.

Applicant's summary and conclusion

Conclusions:
The rate constant of the nonenzymatic elimination could well be determined in this work. EO elimination takes place predominantly in the cytosol and is catalyzed by GST. Neglecting extrahepatic metabolism, one can expect for EO-exposed humans of the GSTT1*0/0 genotype the EO tissue burden to be at most four times higher than in equally exposed humans carrying the active GSTT1 form.
Executive summary:

Ethylene (ET) is metabolized In mammals to the carclnogenic ethylene oxide (EO). Although both gases are of high industrial relevance, only limited data exist on the toxicokinetics of ET in mice and of EO in humans. Metabolism of ET is related to cytochrome P450-dependent mono-oxygenase (CYP) and of EO to epoxide hydrolase (EH) and glutathione S-transferase (GST).

Kinetics of ET metabolism to EO and of elimination of EO were investigated in headspace vessels containing incubations of subcellular fractions of mouse, rat, or human liver or of mouse or rat lung. CYP-associated metabolism of ET and GST-related metabolism of EO were found in microsomes and cytosol, respectively, of each species. EH-related metabolism of EO was not detectable in hepatic microsomes of rats and mice but obeyed saturation kinetics in hepatic microsomes of humans. In ETexposed liver microsomes, metabolism of ET to EO followed Michaelis-Menten-like kinetics. Mean values of Vmax [nmol/(min-mg protein)] and of the apparent Michaelis constant (Km [mmol/1 ET in microsomal suspension]) were 0.567 and 0.0093 (mouse), 0.401 and 0.031 (rat), and 0.219 and 0.013 (human). In lung microsomes, Vmax values were 0.073 (mouse) and 0.055 (rat). During ET exposure, the rate of EO production decreased rapidly.

By modeling a suicide inhibition mechanism, rate constants for CYP-mediated catalysis and CYP inactivation were estimated. In liver cytosol, mean GST activities to EO expressed as Vmax/Km [μl(min mg protein)] were 27.90 (mouse), 5.30 (rat), and 1.14 (human). The parameters are most relevant for reducing uncertainties in the risk assessment of ET and EO.

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