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Description of key information

Alkyl 2-cyanoacrylates such as ethyl 2-cyanoacrylate (ECA) are known to polymerize rapidly in the presence of water. According to Annex XI of the REACH Regulation, a test can be waived for technical reasons if the test substance is e.g. highly active. Study data shows that the polymerisation of ECA takes at maximum a few minutes to be completed, depending on the specific conditions of reaction (see 7.1.1. Basic toxikokinetics, study on polymerisation speed). This is supported by the statement by Krall et al. (1983) that alkyl 2-cyanoacrylates "polymerize on and adhere to moist living tissues". This effect is the basis for using this substance class as tissue adhesives in medical applications.

Both, the study by Ousterhout et al. included in IUCLID section 7.1.1. and the acute oral study included in section 7.2.1 show, that oral application of fast reacting cyanoacrylates, including ECA, results in the immediate generation of a polymeric material on the mucosa or in the cavities of the gastro-intestinal tract. Effects exerted by this material and its potential degradation products do not represent the intrinsic properties of the monomeric ethyl 2-cyanoacrylate, for which systemic availability at relevant doses can be excluded.

Similar effects would be expected by exposure via the inhalation route, where ECA quickly polymerizes in the humidity of the respiratory tract. For the same reason, a dermal repeated dose study is technically not feasible. Via all routes, exposure will finally occur to the polymer and not to monomeric ECA. The intrinsic property to polymerize in the presence of water limits the absorption of cyanoacrylates via all three routes (oral, dermal, inhalation).

Since the intrinsic hazard of ECA cannot be evaluated in repeated dose studies, the studies are waived according to REACH Annex XI, section 2. This is in accordance with the ECHA guidance (chapter R.5, version 2.1 of December 2011), in which in chapter R.5.2.2 the example of a substance having a high reactivity with water is explicitly mentioned as a case where testing might not be feasible for technical reasons.

References:

Krall R. E., Neuwirth R. S. and Richart R. M., Pharmacology and Toxicology of Methyl Cyanoacrylate, Fem. Transcervic Steril., Proc. Int. Workshop, 1983, pp175 -185

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records
Reference
Endpoint:
chronic toxicity: oral
Data waiving:
study technically not feasible
Justification for data waiving:
other:
Justification for type of information:
We base our waiver justification on the physicochemical properties of ethyl 2-cyanoacrylate. Tests in aqueous media with ethyl 2-cyanoacrylate with the intent to determine effective concentrations or no effect concentrations cannot be performed due to technical reasons.
Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: inhalation - systemic effects

Link to relevant study records
Reference
Endpoint:
chronic toxicity: inhalation
Data waiving:
study technically not feasible
Justification for data waiving:
other:
Justification for type of information:
When in breathing atmosphere, mixing of ethyl 2-cyanoacrylate vapors with moisture (water vapors) of will therefore cause in the air fast polymerization of the substance required to be applied in the inhalation studies. Therefore, the successful competition of these in vivo studies will not be possible since the outcome will be influenced by the in-air polymerization that will lead to extremely low concentrations of the free monomers. Thus, test chemical cannot be generated as a gas, vapour, or aerosol in sufficient concentration to elicit animal toxicity in the optimal conditions of an inhalation chamber.
Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: inhalation - local effects

Link to relevant study records
Reference
Endpoint:
chronic toxicity: inhalation
Data waiving:
study technically not feasible
Justification for data waiving:
other:
Justification for type of information:
When in breathing atmosphere, mixing of ethyl 2-cyanoacrylate vapors with moisture (water vapors) of will therefore cause in the air fast polymerization of the substance required to be applied in the inhalation studies. Therefore, the successful competition of these in vivo studies will not be possible since the outcome will be influenced by the in-air polymerization that will lead to extremely low concentrations of the free monomers. Thus, test chemical cannot be generated as a gas, vapour, or aerosol in sufficient concentration to elicit animal toxicity in the optimal conditions of an inhalation chamber.
Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - systemic effects

Link to relevant study records
Reference
Endpoint:
chronic toxicity: dermal
Data waiving:
study technically not feasible
Justification for data waiving:
other:
Justification for type of information:
Ethyl 2-cyanoacrylate can be considered as highly active, as it rapidly polymerises in the presence of moisture. Study data demonstrates that this polymerisation takes at maximum a few minutes to be completed, depending on the specific conditions of reaction (see IUCLID 7.1.1. Basic toxikokinetics, study on polymerisation speed). Rapid polymerisation results in different technical issues that make testing of the material in a chronic dermal study not feasible. First of all, polymerisation on the skin and the resulting polymeric mass on the skin is challenging in the view that multiple application are required in a repeated dose study. Furthermore, after polymerisation, the skin is exposed to the polymer or its degradation products but not to ethyl 2-cyanoacrylate anymore. Due to this reactivity of ethyl 2-cyanoacrylate upon contact to moisture on the animal skin, testing of this material in a chronic dermal study is technically not feasible and would not inform about an intrinsic hazard of ethyl 2-cyanoacrylate. Hence, this study is waived according to REACH Annex XI, section 2. This is in accordance with the Guidance on information requirements and chemical safety assessment (chapter R.5, version 2.1 of December 2011), in which in chapter R.5.2.2 the example of a substance having a high reactivity with water is explicitly mentioned as a case where testing might not be feasible for technical reasons.
Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - local effects

Link to relevant study records
Reference
Endpoint:
chronic toxicity: dermal
Data waiving:
study technically not feasible
Justification for data waiving:
other:
Justification for type of information:
Ethyl 2-cyanoacrylate can be considered as highly active, as it rapidly polymerises in the presence of moisture. Study data demonstrates that this polymerisation takes at maximum a few minutes to be completed, depending on the specific conditions of reaction (see IUCLID 7.1.1. Basic toxikokinetics, study on polymerisation speed). Rapid polymerisation results in different technical issues that make testing of the material in a chronic dermal study not feasible. First of all, polymerisation on the skin and the resulting polymeric mass on the skin is challenging in the view that multiple application are required in a repeated dose study. Furthermore, after polymerisation, the skin is exposed to the polymer or its degradation products but not to ethyl 2-cyanoacrylate anymore. Due to this reactivity of ethyl 2-cyanoacrylate upon contact to moisture on the animal skin, testing of this material in a chronic dermal study is technically not feasible and would not inform about an intrinsic hazard of ethyl 2-cyanoacrylate. Hence, this study is waived according to REACH Annex XI, section 2. This is in accordance with the Guidance on information requirements and chemical safety assessment (chapter R.5, version 2.1 of December 2011), in which in chapter R.5.2.2 the example of a substance having a high reactivity with water is explicitly mentioned as a case where testing might not be feasible for technical reasons.
Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Justification for classification or non-classification

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