Ethylene oxide

Genetic toxicity: in vivo

Administrative data

Endpoint:

in vivo mammalian cell study: DNA damage and/or repair

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:

chronic toxicity: inhalation

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:

The current study was designed to investigate the mutagenic potential of EO and PO in monkeys following 2-year exposures under controlled experimental conditions.

GLP compliance:

not specified

Specific details on test material used for the study:

- Purity: 99.7%
- Physical appearance: gas

Species:

monkey

Strain:

Macaca fascicularis

Sex:

male

Details on test animals or test system and environmental conditions:

60 adult male cynomolgus monkeys were randomly assigned to 5 groups, each consisting of 12 monkeys. A shared common control group was employed. Body weight was 5.31 +/- 0.82 kg at the start of the study. The monkeys were housed in stainless-steel housing cages with automatic watering in animal rooms except during the exposure period. A 12 h on : 12 h off lighting system was maintained. Monkeys were fed a standard pellet diet of Purina, once daily at the end of the exposure day, with fresh fruit provided 2 - 3 times per week. Water was provided ad libitum except during exposures.

Route of administration:

inhalation: vapour

Type of inhalation exposure:

whole body

Details on inhalation exposure:

Control monkeys were exposed in chambers to filtered air. 50 ppm concentrations were selected since they were the current federal workplace standards for EO, at the time the exposures were started. EO 100 ppm concentrations were chosen since they approximate maximum tolerated airborne concentrations for monkeys.
Animal exposures were conducted using 4.5-m3 stainless-steel and glass inhalation chambers. Chambers were operated under dynamic flow conditions with tangential airfeed manifolds maintained at 40 liters/min with a pressure of -0.25 cm water. Chamber airflows provided 12 - 15 air changes/hr. Temperature and humidity were maintained at 24 +/- 3°C and 50 +/- 10%, respectively. EO was vaporized using an Atinco EO vapor generator, and the vapors were metered into the filtered air intake of the chamber. Chamber concentrations were monitored 2 to 4 times per hour in an infrared analyzer. Charcoal tube samples of the test atmospheres analyzed by gas chromatography verified that the chamber concentrations were within 10% of the target values, and that the control chamber atmosphere was free of EO.
Blood collection: About 4 ml blood was collected from the femoral vein of each monkey while the animal was tranquilized following im ketamine hydrochloride. Blood was immediately placed in sterile stoppered tubes, two per animal, containing 0.1 ml sodium heparin, mixed thoroughly for at least 15 min, and stored at room temperature until cultured. Blood collections were initiated during the final month of exposure and were completed prior to the termination of the 2-year exposures.

Duration of treatment / exposure:

2 years

Frequency of treatment:

7 h/d, 5 d/w

Dose / conc.:

50 ppm

Dose / conc.:

100 ppm

No. of animals per sex per dose:

12

Control animals:

yes

Details on results:

Monkeys, with the exception of the EO 100 ppm group, tolerated the exposures well. The EO 100 ppm group had a statistically significant reduced mean body weight compared to the control group beginning at Week 19 and continuing through Week 104. Five monkeys died during the 2-year exposures, one each in the EO 50 and EO 100 ppm groups. These deaths did not appear to be related to oxide exposure. In addition, 10 monkeys, 2 per group, were killed at the termination of exposures. The remaining 44 monkeys are still being maintained and are being examined quarterly for body weight and hematological changes.

Dose descriptor:

NOAEC

Effect level:

< 50 ppm

Based on:

test mat.

Sex:

male/female

Remarks on result:

not determinable

Remarks:

no NOAEC identified

Critical effects observed:

no

Data source

Reference

Reference Type:

publication

Title:

Sister-Chromatid Exchanges and Chromosome Aberrations in Lymphocytes from Monkeys Exposed to Ethylene Oxide and Propylene Oxide by Inhalation.

Author:

Lynch, D.W., Lewis, T.R., Moorman, W.J., Burg, J.R., Gulati, D.K., Kaur, P., Sabharwal, P.S.

Year:

1984

Bibliographic source:

Tox. Appl. Pharmacol. 76, 85 - 95

Materials and methods

Principles of method if other than guideline:

The current study was designed to investigate the mutagenic potential of EO and PO in monkeys following 2-year exposures under controlled experimental conditions.

GLP compliance:

not specified

Type of assay:

sister chromatid exchange assay

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:

- Physical appearance: gas
- Purity: 99.7%

Test animals

Species:

monkey

Strain:

Macaca fascicularis

Sex:

male

Administration / exposure

Route of administration:

inhalation

Duration of treatment / exposure:

2 years

Frequency of treatment:

7 h/d, 5 d/w

Doses / concentrations

Doses / concentrations 1

Dose / conc.:

50 ppm (nominal)

Doses / concentrations 2

Dose / conc.:

100 ppm (nominal)

No. of animals per sex per dose:

12

Control animals:

yes, concurrent no treatment

Results and discussion

Test results

Sex:

male

Genotoxicity:

ambiguous

Toxicity:

not specified

Vehicle controls validity:

not specified

Negative controls validity:

not specified

Positive controls validity:

not specified

Additional information on results:

Toxic effects of the EO exposure were encountered during attempts to culture blood samples from EO-exposed monkeys. In 1 out of 11 animals exposed at 50 ppm EO and 3 out of 12 monkeys exposed at 100 ppm EO, there were minimal (if any) mitosis. In one of these three EO 100 ppm monkeys, where only two metaphases could be evaluated, the SCEs/metaphase were 20 and 42, respectively. Further attempts employing different culture times and varying phytohemagglutinin concentrations and sources were also unsuccessful.

Applicant's summary and conclusion

Conclusions:

In conclusion, the test substance revealed an ambiguous test result under the conditions chosen in the sister chromatid exchange assay and chromosome aberration assay.