Fatty acids, C16 and C18-20 (even numbered, unsaturated), 2-ethylhexyl esters

Skin sensitisation

Administrative data

Endpoint:

skin sensitisation, other

Remarks:

QSAR

Type of information:

(Q)SAR

Adequacy of study:

supporting study

Study period:

Not stated

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

results derived from a valid (Q)SAR model and falling into its applicability domain, with limited documentation / justification

Data source

Reference

Reference Type:

publication

Title:

A quantitative structure-toxicity relationships model for the dermal sensitization guinea pig maximisation assay

Author:

Enslien, K., Gombar,V.K., Blake, B.W., Maibach, H.I., Hostynek,J.J., Sigman, C.G. and Bagheri, D.

Year:

1997

Bibliographic source:

Food and Chemcal Toxicology 35 (1997) 1091-1098

Materials and methods

Test guideline

Qualifier:

no guideline followed

Principles of method if other than guideline:

The authors developed quantitative structure-toxicity relationship (QSTR) models for assessing dermal sensitization using guinea pig maximization test (GPMT) results. The models are derived from 315 carefully evaluated chemicals. There are two models, one for aromatics (excluding one-benzene-ring compounds), and the other for aliphatics and one-benzene-ring compounds. For sensitizers, the models can resolve whether they are weak/moderate or severe sensitizers. The statistical methodology, based on linear discriminant analysis, incorporates an optimum prediction space (OPS) algorithm. This algorithm ensures that the QSTR model will be used only to make predictions on query structures which fall within its domain. Calculation of the similarities between a query structure and the database compounds from which the applicable model was developed are used to validate each skin sensitization assessment, the cross-validated specificity of the equations ranges between 81 and 91%, and the sensitivity between 85 and 95%. For an independent test set, specificity is 79%, and sensitivity 82%.

GLP compliance:

not specified

Test material

Test material information

Constituent 1

Reference substance name:

2-ethylhexyl palmitate

EC Number:

249-862-1

EC Name:

2-ethylhexyl palmitate

Cas Number:

29806-73-3

Molecular formula:

C24H48O2

IUPAC Name:

2-ethylhexyl palmitate

Details on test material:

315 chemicals were assessed for sensitising potential - divided into two groups - aliphatics and single benzene ring compounds and aromatics excluding single benzene ring structures. One of te test materials used to assess the predictivity ofthe QSAR model compared with maximisation results from a guinea pig Magnuson & Kligman design study was, 2-ethylhexyl palmitate. No further test material details are available

In vivo test system

Test animals

Species:

other: QSAR modelling

Strain:

not specified

Sex:

not specified

Details on test animals and environmental conditions:

The QSAR results are compared with data from guinea pig studies entered into TOPKAT - no further details available

Results and discussion

Positive control results:

Not applicable

In vivo (non-LLNA)

Results

Reading:

other: QSAR evaluation

Group:

other: QSAR

Remarks on result:

other: Reading: other: QSAR evaluation. Group: other: QSAR.

Any other information on results incl. tables

Ethylhexyl palmitate was identified as a non-sensitiser.

Applicant's summary and conclusion

Interpretation of results:

not sensitising

Remarks:

Migrated information

Conclusions:

Ethylhexyl palmitate was identified as a non-sensitiser in literature and this evaluation was confirmed by the QSAR model described in this paper

Executive summary:

The salient differences of this QSTR model for skin sensitization based on the GPMT assay compared with prior publications include: (1) a considerably larger training set, and thus broader application domain encompassing wider chemical diversity.

(2) that the model resolves the strength of sensitization into weak/moderate and strong categories

(3) that the use of OPS ensures that only query compounds that fit within the model's domain will be assessed, thus avoiding the production and distribution of invalid results--this capability does not, and cannot, exist in expert systems such as DEREK.

The limitations of this QSTR model are basically:

(I) that the GPMT, due to its very nature, tends to overpredict sensitization compared with assays in humans,

(2) that the training set, extensive though it may be, does not encompass as many compounds and as much chemical diversity as one might wish --the release of proprietary data by manufacturers would greatly remediate this problem; and

(3) no account has been taken of previously identified modes of a c t i o n - - b e t t e r models would probably result if submodels were limited to compounds with a single mode of action

Despite these relative pros and cons, the QSAR model did predict the nonsensitising nature of Ethylhexyl palmitate, as indicated in prior literature.