Registration Dossier

Diss Factsheets

Toxicological information

Eye irritation

Currently viewing:

Administrative data

Endpoint:
eye irritation, other
Remarks:
Based on expert system - decision tree
Type of information:
(Q)SAR
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
results derived from a (Q)SAR model, with limited documentation / justification, but validity of model and reliability of prediction considered adequate based on a generally acknowledged source
Justification for type of information:
1. SOFTWARE: Toxtree v. 2.6.13

2. MODEL: Toxtree eye irritation/corrosion

3. SMILES OR OTHER IDENTIFIERS USED AS INPUT FOR THE MODEL:
Structural formula: C28H46O13S6
Structural codes:
a. SMILES: OSCCC(=O)OCC(COC(=O)CCS)(COC(=O)CCS)COCC(COC(=O)CCS)(COC(=O)CCS)COC(=O)CCS
b. InChI=1S/C28H46O13S6/c29-21(1-7-42)36-15-27(16-37-22(30)2-8-43,17-38-23(31)3-9-44)13-35-14-28(18-39-24(32)4-10-45,19-40-25(33)5-11-46)20-41-26(34)6-12-47/h42-47H,1-20H2
c. Other structural representation: mol file used and included in the test material information.

4. SCIENTIFIC VALIDITY OF THE (Q)SAR MODEL
- Defined endpoint: Eye irritation/corrosion
- Unambiguous algorithm: Expert system based on a decision tree built on physico-chemical property ranges and structural alert rules. No mathematical algorithms have been established since the (Q)SAR rules are not calculated, but based on measured data (see attached QMRF for further details).
- Defined domain of applicability: Not applicable.
- Appropriate measures of goodness-of-fit and robustness and predictivity: Not applicable.
- Mechanistic interpretation: The structural alerts used for the prediction of local damage to eyes are derived from the existing knowledge of well-defined substructures within a chemical molecule, which are considered to induce chemical reactivity leading to eye irritation (i.e. resulting in labelling as R36 or R41) or to skin corrosion (i.e. resulting in labelling as R34 or R35). These structural alerts were selected a priori from existing mechanistic knowledge (based on the evaluation of experimental data for 1627 chemicals).

5. APPLICABILITY DOMAIN
The applicability domain of this decision tree is not defined. No structural analogues are provided by the model, since the data set is reported to be confidential.
Please see attached QPRF for further details.

6. ADEQUACY OF THE RESULT
di-PETMP was predicted negative for skin corrosion based on the exceedance of the melting point physico-chemical limit of 200°C, which suggests an unlikely hazardous potential for corrosivity to eyes as well. The prediction was assessed as moderately reliable. This QSAR prediction indicated a negative eye corrosion potential of the target di-PETMP and could be used to support the conclusion for no classification of the substance for irreversible eye effects (Category 1).

Data source

Reference
Reference Type:
other: Software
Title:
Toxtree v. 2.6.13, eye irritation/corrosion.
Author:
Ideaconsult Ltd
Year:
2005
Bibliographic source:
Gerner et al. (2005) Alternatives to Laboratory Animals 33, 215-237.

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: Toxtree v. 2.6.13
- Model(s) used: Toxtree eye irritation/corrosion
- 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

Constituent 1
Chemical structure
Reference substance name:
2-[[3-(3-mercapto-1-oxopropoxy)-2,2-bis[(3-mercapto-1-oxopropoxy)methyl]propoxy]methyl]-2-[(3-mercapto-1-oxopropoxy)methyl]propane-1,3-diyl bis[3-mercaptopropionate]
EC Number:
246-893-2
EC Name:
2-[[3-(3-mercapto-1-oxopropoxy)-2,2-bis[(3-mercapto-1-oxopropoxy)methyl]propoxy]methyl]-2-[(3-mercapto-1-oxopropoxy)methyl]propane-1,3-diyl bis[3-mercaptopropionate]
Cas Number:
25359-71-1
Molecular formula:
C28H46O13S6
IUPAC Name:
3-[(3-sulfanylpropanoyl)oxy]-2-[(3-[(3-sulfanylpropanoyl)oxy]-2,2-bis{[(3-sulfanylpropanoyl)oxy]methyl}propoxy)methyl]-2-{[(3-sulfanylpropanoyl)oxy]methyl}propyl 3-sulfanylpropanoate (non-preferred name)
Specific details on test material used for the study:
SMILES: SCCC(=O)OCC(COC(=O)CCS)(COC(=O)CCS)COCC(COC(=O)CCS)(COC(=O)CCS)COC(=O)CCS
InChI=1S/C28H46O13S6/c29-21(1-7-42)36-15-27(16-37-22(30)2-8-43,17-38-23(31)3-9-44)13-35-14-28(18-39-24(32)4-10-45,19-40-25(33)5-11-46)20-41-26(34)6-12-47/h42-47H,1-20H2

Results and discussion

In vivo

Results
Irritation parameter:
other: An exclusion rule was fulfilled
Remarks on result:
other: No indication of corrosion
Remarks:
Based on QSAR prediction

Any other information on results incl. tables

The uncertainty of the prediction was evaluated considering the following aspects associated with the applicability domain: i) physico-chemical rules; ii) structural rules/alerts.

-A physicochemical property exclusion rules was found to have been satisfied by the target compound, i.e. MP>200°C.

-No structural inclusion/exclusion rules or alerts had been identified by the model, since the first exclusion rule implemented in the decision tree of the model, based on the MP’s limit, was fulfilled by the target compound.

Based on these considerations, an overall limited uncertainty was attributed to the negative eye corrosive prediction generated for di-PETMP.

Applicant's summary and conclusion

Interpretation of results:
other: This QSAR prediction could be used to support the conclusion in a WoE for no classification of the substance for irreversible eye effects (Category 1).
Conclusions:
di-PETMP was predicted negative for skin corrosion based on the exceedance of the melting point physico-chemical limit of 200°C, which suggests an unlikely hazardous potential for corrosivity to eyes as well. The prediction was assessed as moderately reliable. This QSAR prediction indicated a negative eye corrosion potential of the target di-PETMP and could be used to support the conclusion for no classification for irreversible eye effects (Category 1).
Executive summary:

This study was designed to generate in silico (non-testing) data of eye irritation for di-PETMP. A reliability score of 2 was assigned, since results derived from a valid QSAR model, with limited documentation/justification, but validity of model and reliability of prediction were considered adequate based on a generally acknowledged source.

The eye irritation expert system model implemented in Toxtree v. 2.6.13 was employed, where physico-chemical limits and structural alerts are used to identify chemicals with eye irritation/corrosion potential.

The Toxtree model gave a negative prediction for skin corrosion potentailsince the first physico-chemical property exclusion rule implemented in the decision tree of the model, based on the MP’s limit, was fulfilled for the target compound.Based on these considerations, an overall limited uncertainty was attributed to the prediction generated for di-PETMP. Hence, the prediction was assessed asmoderatelyreliable.