Reaction mass of 2,2'-thiodiethanethiol and 1095071-01-4 and α-sulfanyl-ω-{2-[(2-sulfanylethyl)sulfanyl]ethyl}bis[ethane- 1,2-diylsulfanediylethane- 1,2-diylsulfanediyl(3-hydroxypropane-1,1-diyl) sulfanediyl]

Skin irritation / corrosion

Administrative data

Endpoint:

skin irritation / corrosion, other

Remarks:

Standard Draize test

Type of information:

(Q)SAR

Adequacy of study:

supporting study

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 adequate and reliable documentation / justification

Justification for type of information:

1. SOFTWARE: ACD Labs/Percepta (2016 Release).

2. MODEL: ACD/Percepta: Skin Irritation

3. SMILES OR OTHER IDENTIFIERS USED AS INPUT FOR THE MODEL:
Structural formula: C11H24OS6
Structural codes:
a. SMILES: SCCSCCSC(CCO)SCCSCCS
b. InChI: InChI=1S/C11H24OS6/c12-2-1-11(17-9-7-15-5-3-13)18-10-8-16-6-4-4/h11-14H,1-10H2
c. Other structural representation: mol file used and included in the test material information.

4. SCIENTIFIC VALIDITY OF THE (Q)SAR MODEL
- Defined endpoint: Skin irritation/corrosion
- Unambiguous algorithm: Binomial PLS probabilistic model supplemented by an expert system that identifies structural alerts relevant to irritating properties of compounds (see attached QMRF for further details).
- Defined domain of applicability: Detailed structural and/or response limits of the applicability domain are not defined. However, for each prediction, a list of all the rules (alerts) applicable to the calculation of irritation potential of the target molecule is provided, as well as the percentage of training set chemicals containing these alerts and exhibiting moderate or stronger skin irritation. In addition, the software displays up to five most similar structures from the training set along with experimental results.
- Appropriate measures of goodness-of-fit and robustness and predictivity: Please see attached QMRF.
- Mechanistic interpretation: The structural alerts used for classifying chemicals were derived from existing mechanistic knowledge. Fragmental descriptors used in the analysis have been predefined to represent certain features of the compounds known to be related to their skin irritating properties, e.g. high acidity, basicity, electrophilicity, etc.

5. APPLICABILITY DOMAIN
For the target HIDT, two structural analogues were identified in the training set, suggesting that the target compound should be included in the applicability domain of the model. No structural alerts for skin irritation were identified.
- descriptor domain: not applicable.
- structural fragment domain: not applicable.
- mechanism domain: not applicable.
Please see attached QPRF for structural analogues and further details.

6. ADEQUACY OF THE RESULT
The target HIDT was predicted as positive for skin irritation/corrosion in standard rabbit Draize test based on a predicted probability to cause severe/moderate skin irritation equal to 0.89. The prediction was assessed as borderline reliable. This QSAR prediction indicated a positive skin irritation/corrosion potential of the target HIDT and could be used to support the conclusion for classification.
This skin irritation QSAR prediction was assessed as adequate for regulatory purposes.

Data source

Reference

Reference Type:

other: Software

Title:

Toxtree v. 2.6.13, skin irritation/skin corrosion.

Author:

Ideaconsult Ltd

Year:

2005

Bibliographic source:

[1] Gerner et al. (2004) QSAR Comb. Sci.,23:726-733 [2] Hulzebos et al. (2005) QSAR Comb. Sci.,24:332-342. [3] Walker et al. (2005) QSAR Comb. Sci., 24:378-384.

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

other: REACH Guidance on QSARs R.6 (2008)

Principles of method if other than guideline:

- Software tool(s) used including version: ACD/Labs (2016 release)
- Model(s) used: ACD/Percepta Skin Irritation
- Model description: see field 'Justification for type of information' and 'Attached justification'
- Justification of QSAR prediction: see field 'Justification for type of information' and 'Attached justification'

Test material

Test material information

Constituent 1

Reference substance name:

3,3-bis({2-[(2-sulfanylethyl)sulfanyl]ethyl}sulfanyl)propan-1-ol

Cas Number:

1095071-01-4

Molecular formula:

C11H24OS6

IUPAC Name:

3,3-bis({2-[(2-sulfanylethyl)sulfanyl]ethyl}sulfanyl)propan-1-ol

Test material form:

liquid

Specific details on test material used for the study:

SMILES: SCCSCCSC(CCO)SCCSCCS
InChI=1S/C11H24OS6/c12-2-1-11(17-9-7-15-5-3-13)18-10-8-16-6-4-4/h11-14H,1-10H2

Test animals

Species:

rabbit

Results and discussion

In vivo

Results

Irritation parameter:

other: Probability to cause severe/moderate skin irritation = 0.89

Remarks on result:

positive indication of irritation

Remarks:

Based on QSAR prediction

Any other information on results incl. tables

The uncertainty of the prediction was evaluated considering the following aspects: i) positive predicted probability; ii) identified structural alerts; iii) similarity of the target compound to the training set and consistency of experimental values for similar compounds.

Moderate uncertainty was associated with the skin irritation prediction generated for the target HIDT since:

- the identified analogues exhibit limited similarity

-  the experimental data of the identified training set analogues were not consistent with the target prediction

Overall, the positive skin irritation prediction was assessed as borderline reliable.

Applicant's summary and conclusion

Interpretation of results:

other: This QSAR prediction could be used to support the conclusion of classification as skin corrosive or irritant.

Conclusions:

The target HIDT was predicted as positive for skin irritation/corrosion in standard rabbit Draize test based on a predicted probability to cause severe/moderate skin irritation equal to 0.89. The prediction was assessed as borderline reliable. This QSAR prediction indicated a positive skin irritation/corrosion potential of the target HIDT and could be used to support the conclusion for classification.

Executive summary:

This study was designed to generate in silico (non-testing) data of skin irritation/corrosion for 1-propanol, 2,3-bis[[2-[(2-mercaptoethyl)thio]ethyl]thio] (HIDT). A reliability score of 2 was assigned, since results derived from a valid (Q)SAR model, falling into its applicability domain, with adequate and reliable documentation/justification.

The skin irritation model implemented in ACD/Percepta (2016 Release) was employed, which estimates the potential of a chemical to cause skin irritation in a standard rabbit Draize test. The cut-off value for positive/negative skin irritation predictions is 0.5.

ACD/Percepta skin irritation model predicted the target as skin irritant, based on a probability of severe/moderate irritation equal 0.89. The uncertainty of the prediction was evaluated considering the following aspects: i) positive predicted probability; ii) identified structural alerts; iii) similarity of the target compound to the training set and consistency of experimental values for similar compounds.

Moderate uncertainty was associated with the prediction generated for the target HIDT since: i) the identified analogues exhibit limited similarity, ii) the experimental data of the identified training set analogues were not consistent with the target prediction.

Overall, the positive skin irritation prediction was assessed as borderline reliable, and adequate for regulatory purposes.