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EC number: 248-363-6
CAS number: 27247-96-7
A total of
6 skin sensitization assays were available within the SIEF. After
thorough review by RSS/CSR author, incl. if necessary change of the
original conclusions, four tests were of appropriate reliability, two
otherswere K3, one of which was not included in IUCLID because it was
not owned by a SIEF member ; all 6 tests are presented below.
Summary of key reliability and sensitivity features of the 6 skin
sensitisation assays available to the 2-ethylhexylnitrate SIEF:
NR: not reported; NA: not assessable or applicable
underlined: limited exposure inappropriately justified
and/or deviating from the guideline
*: indicated in parentheses: method (MK or Buehler 3),
volume for intradermal injection, concentrations for intradermal
injection, topical induction and challenge
**: local or extensive reaction, at least until 48h after
end of challenge, was re-counted as positive by RSS/CSR author
***: study not present in IUCLID dossier
****: animals with bandage slipped were excluded
Out of the four Klimisch 1-2 tests, three MK assays clearly involved
macroscopic persistent reactions in >30% of challenged animals and a
fourth test, a Buehler test, showed no reaction in any animal. Three
main hypotheses could explain this apparent inconsistency:
- Inconsistencies could be related to an impact of
sensitizing impurities and/or inter-lab variability: it was impossible
to localize, decades afterwards, data on impurities in the tested
batches; however, it is notable that studies by
Clouzeau and Manciaux were done in the same lab
for the same Sponsor, limiting this source of variability; furthermore,
the synthesis process is mostly similar for all producers and unlikely
to introduce a sensitizing impurity.
- Reactions could be irritation due to a bad protocol
(too high concentrations): this is not likely if the test is correctly
carried out (choice of a non-irritant challenge dose-level), and has
been taken into account in Klimisch rating and review of conclusions.
- Reactions could be non-related to sensitization: this
hypothesis is supported by four different points:
1) Study by Clouzeau showed macroscopic skin reactions
sufficient for classification as sensitizer, but as opposed to all 5
other tests, this one included an histopathology confirmation that
evidenced lesions evocating irritation (acanthosis and hyperkeratosis)
and an absence of inflammatory cells, so it was concluded to be
2) The substance, being an organic nitrate, has vasodilation
properties (as confirmed by observation of headaches and dizziness
in some workers) which could account for reddening of the skin that does
not reflect the mechanism of standard irritation or sensitisation, but
can be mistaken for it by macroscopic examination.
3) Skin cracking has been noted in rabbits after repeated
dermal exposure (see 7.3) and may be related to interaction with skin
4) The IUCLID4 file (see attached file) of the synthesis
precursor 2EH, which may be present as an impurity in some studies (no
data), is attached and shows that this substance is clearly a skin
irritant, so a possible hypothesis could be delayed formation of a
skin irritant compound (in the tested batch or during the
application time) leading to delayed skin irritation, misinterpreted as
A LLNA assay was not carried out to clarify the issue because it was
considered unethical in the existence of 6 sensitisation assays (incl. 4
reliable ones), and
one test would be unable to answer on the possible impact of impurities.
It may also be noted that the OECD QSAR Toolbox predicts an absence of
protein binding, also in favour of an absence of sensitizing properties.
See the attached document.
Migrated from Short description of key information:
A total of 6 skin sensitization assays were available within the SIEF. After thorough review by RSS/CSR author, four tests were of appropriate reliability, out of which 2 were concluded to be negative and 2 to be positive. One of the negative tests would have been considered positive due to macroscopic skin reactions, but was considered not to represent sensitisation but irritation (possibly delayed) due to an absence of typical inflammatory response at histopathology. This could also account for the other "positive" results in tests not including histopathological confirmation.
No data. The substance is not a skin sensitiser and does not include structural alerts for respiratory sensitisation. It is therefore unlikely to be a respiratory sensitizer.
As the test item induced delayed skin reactions which:
- are not representative of sensitisation (inflammatory cell
infiltration) after histopathological examination,
- may be related to vasodilation (the substance being an organic
nitrate), interaction with skin lipids, or delayed formation of a skin
irritant impurity/degradation product,
And in the absence of predicted protein binding according to OECD QSAR
the substance is considered as non-sensitizing as a
Information on Registered Substances comes from registration dossiers which have been assigned a registration number. The assignment of a registration number does however not guarantee that the information in the dossier is correct or that the dossier is compliant with Regulation (EC) No 1907/2006 (the REACH Regulation). This information has not been reviewed or verified by the Agency or any other authority. The content is subject to change without prior notice.Reproduction or further distribution of this information may be subject to copyright protection. Use of the information without obtaining the permission from the owner(s) of the respective information might violate the rights of the owner.
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