Registration Dossier

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Administrative data

Description of key information

Woodard (1971): non-guideline, pre-GLP, Klimisch 4. Guinea pigs were treated with 0.1% (intradermal) and 1% (epicutaneous). No sensitizing effect.

Human data do not lead to the classification as a skin sensitizer.

Key value for chemical safety assessment

Skin sensitisation

Link to relevant study records
Reference
Endpoint:
skin sensitisation: in vivo (non-LLNA)
Type of information:
experimental study
Adequacy of study:
weight of evidence
Reliability:
4 (not assignable)
Rationale for reliability incl. deficiencies:
secondary literature
Principles of method if other than guideline:
no further details given
GLP compliance:
no
Type of study:
not specified
Justification for non-LLNA method:
The study has been conducted prior to the implementation of the LLNA.
Specific details on test material used for the study:
SOURCE OF TEST MATERIAL
- Source: Matheson Company
- Purity: 99.7% by weight minimum
- Physical appearance: liquid

TREATMENT OF TEST MATERIAL PRIOR TO TESTING
- Treatment of test material prior to testing: Solutions were made with distilled water within an hour or two of use.
- Final dilution of a stock liquid: 25 mg/ml
Species:
guinea pig
Strain:
Hartley
Sex:
male
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Flow Laboratories
- Housing: individually
- Diet: ad libitum
- Water: ad libitum

ENVIRONMENTAL CONDITIONS
- Temperature (°C): temperature-controlled environment
Route:
intradermal
Concentration / amount:
0.1% / 0.1 ml
Route:
epicutaneous, occlusive
Concentration / amount:
1% / 0.5 ml
Route:
intradermal
Concentration / amount:
0.1 ml
Route:
epicutaneous, occlusive
Concentration / amount:
0.5 ml
No. of animals per dose:
10
Details on study design:
Three applications per week for three weeks with a challenge two weeks after the last application.
The dermal application wad made using 0.5 ml of the test sustance on a 1 x 1 inch, four layer pad covered by an Elastopatch and further covered by rubber damming. The animals were then placed in a specially designed holder for a 6-hour exposure period. The intracutaneous application was made by injecting 0.1 ml of the test material.
Remarks on result:
no indication of skin sensitisation
Interpretation of results:
study cannot be used for classification
Conclusions:
The results were entirely negative.
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed (not sensitising)
Additional information:

Animal data

Experimentally, there is one negative animal study of insufficient validity available (secondary source; unclear and possibly multicomponental composition of test material). No guideline was specified and the study was conducted pre-GLP. Ten guinea pigs were treated with 0.1% (intradermal) and 1% (epicutaneous) with the test substance. The results indicated no sensitizing effect (Woodard, 1971).

Human data

A 53 -year-old woman showed an acute inflammatory dermatitis on her face with erythema and vesicular lesions where the oxygen mask had been in contact (nose, cheeks, chin) (Alomar, 1981).

Monbaliu et al. (2010) concluded: When ethylene oxide-sensitized patients with chronic kidney disease stage V are considered for transplantation, the surgery represents a substantial risk to induce a severe allergic anaphylactic reaction. At the same time, it may be possible that EO allergy could be regarded as a relative contra-indication for kidney transplantation in some centers.

A single chronic hemodialysis patient, who was experiencing recurrent acute reactions during hemodialysis, was found to have become allergic to ethylene oxide gas.

Serum was obtained from 27 reacting patients and tested in a radioallergosorbent test (RAST) for antibodies to EO. The test was positive for 22 of these sera. Test substance-related specificity of the antibodies was confirmed (Donovich, 1984).

A series of experiments were performed on the skin of human subjects with concentrated ethylene oxide and various aqueous dilutions. Of the eight subjects studied, sensitization developed in three 19 to 20 days after the first experiment and 5 to 9 days after the last experiment. Upon dermal contact with liquid EO material (rapid evaporation and burns from freezing and cytotoxicity) toxic dermatitis has occurred (Sexton, 1950).

One subject, who developed sensitivity to EO, showed a mild delayed reaction to approximately 100 ppm of EO in PVC. The nature of the delayed reaction noted in this single individual does not conform to the typical description of allergic hypersensitivity reactions (Shupack, 1981).

Respiratory sensitisation

Endpoint conclusion
Endpoint conclusion:
no study available

Justification for classification or non-classification

Classification, Labelling, and Packaging Regulation (EC) No 1272/2008

The following is quoted from the RAC opinion proposing a harmonized classification and labelling at the EU level of ethylene oxide ( CLH-O-0000001412-86-164/F, adopted 22nd September 2017):

Skin sensitisation: With regard to human data, the CLP criteria (a) require evidence on sensitisation by skin contact in a substantial number of individuals. The data presented in the dossier contains only a few case reports, each presenting one individual with skin reactions after exposure. Taking into consideration that ethylene oxide has been extensively used for sterilisation purposes for decades, the number of case reports is considered very low. The case reports do not clearly identify the observed reactions as outcomes of ethylene oxide sensitisation. As the substance causes skin irritation/corrosivity, it is possible that the reported eczema may also have occurred due to irritation.

Severe allergic-type reactions and ethylene oxide IgE antibodies among dialysis patients have been reported in several clinical surveillance studies and case reports. All of these reports focused on situations in which individuals were exposed to ethylene oxide parenterally (sterilised medical equipment). As these reports do not include information on sensitisation following skin contact, RAC does not consider them relevant for the evaluation of classification for skin sensitisation. No appropriate animal tests have been performed. Based on the reactions following upon dermal and parenteral exposure, the DS concluded that ethylene oxide should be classified as Skin Sens. 1; H317. RAC considers that there is a lack of evidence for a potential to cause skin sensitisation. RAC therefore concludes that no classification is warranted for ethylene oxide for this hazard class.

Respiratory sensitisation: Substances shall be classified as respiratory sensitisers if there is evidence in humans that they may cause specific respiratory hypersensitivity and/or if there are positive results from animal tests. The available human data presents a few cases of asthmatic symptoms and bronchial hyper reactivity. High exposures to irritant gases/vapours, such as ethylene oxide, may result in irritant induced asthma or RADS. These are not, however, caused by specific sensitisation. The available data on asthmatic symptoms do not present evidence that justifies classification for specific respiratory sensitisation to ethylene oxide. RAC supports the proposal of the DS for no classification for respiratory sensitisation.

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