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EC number: 228-408-6
CAS number: 6259-76-3
A guideline-compliant study of skin irritation in the rabbit is
available for hexyl salicylate.
A guideline-compliant study of eye irritation in the rabbit is available
for hexyl salicylate.
The irritation potential of hexyl salicylate was tested in a study by
Haynes (1986), after exposure for 4 hours under semi-occlusive
conditions in the rabbit, both as 100% and as 50% in DEP. The mean score
for erythema over the 24-72 hour period was 2.0 for the 100% pure
substance. The mean score for oedema over the 24-72 hour period was 2.16
for the 100% pure substance. Hexyl salicylate was found to be a moderate
skin irritant under the conditions of this study. The mean scores for
skin irritation do not trigger classification as a skin irritant;
however as the reactions were not reversible within the study period,
classification is appropriate.
No additional information
Hexyl salicylate was investigated for its ability to induce eye
irritation. The test substance was applied undiluted to the left eye of
each of 4 female SPF albino rabbits in a volume of 0.1ml. The right eye
of each animal served as the untreated control. The eyes were examined
and the changes graded according to a numerical scale at one, 24, 48 and
72 hours after dosing. The cornea, iris and conjunctivae were examined
and scored based on their reactions to the test material. Slight to
well-defined signs of irritation were observed in the treated eyes at
the 1, 24 and 48 hour examination time-points. However, all effects were
fully reversible and no signs of irritation were observed after 72
hours. Under the conditions of this study hexyl salicylate does not
induce irritation of the eyes following its application. Based on these
results, it does not need to be classified according to Regulation EC
Hexyl salicylate was found to be a moderate skin irritant in a study in
the rabbit. The mean scores for skin irritation do not trigger
classification as a skin irritant; however the reactions were not
reversible within the study period, which would normally result in
Hexyl salicylate is used as one of the non-irritant reference substances
for validation of reconstructed human epidermis (RhE) models under OECD
TG 439 (1) and also specified by ECVAM (2). OECD 439 includes four RhE
models; EpiSkin™ (SM), EpiDerm™ (EPI-200), SkinEthic™ RHE and LabCyte
EPI-MODEL24 SIT. Data from Cyprotex (3) performed
using the EpiDerm™ (MatTek) model reports a mean viability of 106.2
(compared to 100.0 for controls), showing an absence of irritation. Validation
data for LabCyte EPI-MODEL24 (4) (5) report mean viabilities for hexyl
salicylate of 103.1, 110.8 and 101.1 in three independent assessments. These
results are considered by the authors to be ‘false’ predictions (i.e.
false negatives) based on the in vivo data for hexyl salicylate; however
it is also noted that findings are consistent with those with
EpiSkin™(6). A further validation study for the
(not yet adopted) open source reconstructed epidermis model (OS-REp)
reports mean viabilities of 95.6, 98.3 and 105.3 for 3-5 triplicate
assays performed at three different laboratories (7) (8).
The negative responses seen in RhE models contrast with the irritation
reported in rabbit studies in vivo; however it is also noted that the
irritation seen in rabbit studies is not consistent with experience
showing that hexyl salicylate is not an irritant in human skin in vivo
(9). No classification is therefore proposed for hexyl
salicylate, based on the weight of evidence from in vitro studies and
the lack of consistency between the rabbit and human data.
(1) OECD Guidelines for the Testing of Chemicals, Section 4 Health
Effects. Test No. 439: In Vitro Skin Irritation:
Reconstructed Human Epidermis Test Method. OECD,
Paris; 28th July 2015.
(2) EUROPEAN COMMISSION JOINT RESEARCH CENTRE Institute for Health and
Consumer Protection In-Vitro Methods Unit: European Centre for the
Validation of Alternative Methods (ECVAM). Performance
Standards for In-Vitro Skin Irritation Test Methods based on
Reconstructed Human Epidermis (RhE). 24th August 2009.
(3) Cyprotex. Skin and Ocular Testing: Skin
irritation, Background Information.
(4) Katoh M, Hamajima F, Ogasawara T & Hata K (2009). Assessment
of human epidermal model LabCyte EPI-MODEL for in vitro skin irritation
testing according to European Centre for the Validation of Alternative
Methods (ECVAM)-validated protocol. Journal of
Toxicological Sciences 34 (3): 327-334.
(5) JSAAE REPORT: VALIDATION STUDY OF IN VITRO SKIN IRRITATION TEST
USING LABCYTE EPIMODEL 24 (FINAL REPORT). OCTOBER 5,
2009. LABCYTE VALIDATION MANAGEMENT TEAM.
(6) Liebsch M, Gamer, AO, Curren RD, Frank J, Genschow E, Tharmann J,
Remmele M, Bauer B, Raabe H, Barnes N, Hilberer A, Wilt N,
Lornejad-Schäfer MR, Schäfer C, Hayden P & Kandárová H. Follow-up
Validation of the EpiDerm Skin Irritation Test (SIT): Results of a
Multi-centre Study of Twenty Reference Test Substances.
(7) Mewes KR, Fischer A, Zöller NN, Laubach V, Bernd
A, Jacobs A, van Rompay A, Liebsch M, Pirowd R & Petersohn D (2016). Catch-up
validation study of an in vitro skin irritation test method based on an
open source reconstructed epidermis (phase I). Toxicology
in Vitro 36: 238-253.
(8) Groeber F, Schober L, Schmid FF, Traube A, Kolbus-Hernandez S, Daton
K, Hoffmann S, Petersohn D, Schäfer-Korting M, Walles H & Mewes KR
(2016). Catch-up validation study of an in vitro skin
irritation test method based on an open source reconstructed epidermis
(phase II). Toxicology in Vitro 36: 254-261.
(9) ESAC Peer review of submission of the follow-up validation study of
the Modified EpiDermTM Skin Irritation Test (SIT) for hazard
identification and labelling of chemicals according to EU classification
In an eye irritation study, slight to well-defined signs of irritation
were observed in the treated eyes at the 1, 24 and 48 hour examination
time-points. However, all effects were fully reversible and no signs of
irritation were observed after 72 hours.
No evidence of local effects was seen in a 28 -day inhalation toxicity
study with hexyl salicylate
Based a weight of evidence from the in vivo and in vitro data, hexyl
salicylate does not require classification for skin irriation. No
classification is required for eye irritation based on the results of a
rabbit study. No evidence of local effects was seen in a 28 -day
inhalation study; no classification is therefore proposed for
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