Registration Dossier

Administrative data

Description of key information

Skin irritation / corrosion: not irritating upon one contact, but a repeat-dose DNEL can be set from the data of the 3-week dermal study in rabbits. For this purpose, a repeat-dose local NOAEC was derived as 0.22 mg/cm2/day.

Eye irritation: not irritating

Key value for chemical safety assessment

Skin irritation / corrosion

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed (not irritating)

Eye irritation

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed (not irritating)

Additional information

SKIN

The following concentration-response data are available for single application in rabbits:

- study N° EB3413: highly irritant at an excessive concentration (vs recommendation) of 0.5 mL over 2.5 cm2 skin (too small surface) over 4h = 192 mg/cm2;

- study N° 3552 TAL: non irritant at the recommended level of 0.5 mL over 6 cm2 skin over 4h = 0.962 * 0.5 / 6 g/cm2 = 80 mg/cm2; a minimal erythema started at 48 or 72h and lasted for <1 week;

- study N° 80-2189A, on day 1: non-irritant (at most: one grade 2 edema out of 3 animals, no other reaction) at 7.7 mg/cm2 (high-dose), applied over 6h to non-abraded animals.

These data show that single application leads to concentration-dependent results. The relevant conclusion is that of the test performed at the recommended concentration. The importance and persistence of reactions in the first (excessive concentration) study may also suggest an impact of impurities.

The substance induced delayed atypical skin reactions (there is no classification for such properties) as suggested by the standard assay above, and largely confirmed by marked irritation and skin cracking after repeated applications to rabbits (the same animals showed no relevant effect within the first three applications). As indicated in the sensitisation section (7.4), this was not attributable to sensitisation in the absence of histological signs of immunological reaction in Magnusson and Kligman assays. It seems possible that this effect partly corresponds to vasodilation (2-ethylhexyl nitrate being an organic nitrate so possibly a nitric oxide donor). However, skin cracking was also observed in the repeated application study in rabbits, and could also suggest interaction with skin lipids due to the very high log Kow value. Last, an impact of impurities could be suspected: 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.

EYES

Minimally irritant (this is the minimal possible conclusion grade) in vitro (BCOP). Non irritant in vivo in rabbits.

It is noteworthy that the IUCLID4 file of the synthesis precursor 2EH (see attached file), which may be present as an impurity in some studies (no data), shows that this substance induces some eye irritation but apparently not of a level requiring classification.

RESPIRATORY TRACT

No data. Based on absence of irritation for skin and eyes, no irritation to respiratory tract is expected.

Effect level: empty Endpoint conclusion: Adverse effect observed

Justification for classification or non-classification

Non irritant to skin and eyes based on standard single-application studies in rabbits.

NB: for the skin, this conclusion is only valid for a sufficiently pure substance due to a possible impact of impurities (e.g. 2EH).

EUH 066 and R66 are applicable due to skin cracking and dryness after repeated dermal exposure.

No conclusion for respiratory tract.