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Toxicological information

Genetic toxicity: in vivo

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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

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:
- 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 / concentrationsopen allclose all
Dose / conc.:
50 ppm (nominal)
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.