(2,4,6-trioxo-1,3,5-triazine-1,3,5(2H,4H,6H)-triyl)triethane-2,1-diyl tris(3-mercaptopropionate)

Endpoint summary

Description of key information

No structural alerts for skin irritation were identified in the target by using two different QSAR models (rule based and statistical model based).

Key value for chemical safety assessment

Skin irritation / corrosion

Link to relevant study records

Reference

Endpoint:

skin irritation / corrosion, other

Remarks:

Based on expert system - decision tree

Type of information:

(Q)SAR

Adequacy of study:

key study

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: Skin Irritation/corrosion

3. SMILES OR OTHER IDENTIFIERS USED AS INPUT FOR THE MODEL:
Structural formula: C18H27N3O9S3
Structural codes:
a. SMILES: O=C(OCCn1c(=O)n(c(=O)n(CCOC(=O)CCS)c1=O)CCOC(=O)CCS)CCS
b. InChI: InChI=1S/C18H27N3O9S3/c22-13(1-10-31)28-7-4-19-16(25)20(5-8-29-14(23)2-11-32)18(27)21(17(19)26)6-9-30-15(24)3-12-33/h31-33H,1-12H2
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: Decision tree by physico-chemical property ranges and structural alert rules (Skin Irritation Corrosion Rules Estimation Tool - SICRET). 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: Classification rules based on limit values for physicochemical data: this method doesn't have a clear mechanistic basis but reflects the
chemical reactivity of the chemical substance when in contact with skin. Classification rules based on structural alerts: the alerts were gathered for chemicals with skin irritation or skin corrosion potential. The structural alerts used to identify chemicals with skin irritation or corrosion potential were selected a priori from existing mechanistic
knowledge (based on measured data).


5. APPLICABILITY DOMAIN
Applicability domain of this decision tree is not defined.
- descriptor domain: not applicable.
- structural fragment domain: not applicable.
- mechanism domain: not applicable.

Please see attached QPRF for further details.

6. ADEQUACY OF THE RESULT
TEMPIC was predicted negative for skin irritation/corrosion based on the exceedance of the melting point physico-chemical limit, which corresponds to 200°C, as implemented in the decision tree of Toxtree. The prediction was assessed as moderately reliable. This QSAR prediction indicated a negative skin irritation/corrosion potential of the target TEMPIC and could be used to support the conclusion for no classification.
This skin irritation QSAR prediction was assessed as adequate for regulatory purposes.

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 v. 2.6.13, skin irritation/skin 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'

Specific details on test material used for the study:

SMILES: O=C(OCCn1c(=O)n(c(=O)n(CCOC(=O)CCS)c1=O)CCOC(=O)CCS)CCS
InChI: InChI=1S/C18H27N3O9S3/c22-13(1-10-31)28-7-4-19-16(25)20(5-8-29-14(23)2-11-32)18(27)21(17(19)26)6-9-30-15(24)3-12-33/h31-33H,1-12H2

Species:

rabbit

Irritation parameter:

other: Not irritating or corrosive to the skin (for the target a physico-chemical property exclusion rule was fulfilled, i.e. melting point (MP) greater than 200°C.)

Remarks on result:

no indication of irritation

Remarks:

Based on (Q)SAR prediction

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

An overall limited uncertainty was attributed to the negative skin irritating/corrosive prediction generated for TEMPIC, which was then assessed as moderately reliable.

Interpretation of results:

GHS criteria not met

Remarks:

This QSAR prediction could be used to support the conclusion for no classification.

Conclusions:

TEMPIC was predicted negative for skin irritation/corrosion based on the exceedance of the melting point physico-chemical limit, which corresponds to 200°C, as implemented in the decision tree of Toxtree. The prediction was assessed as moderately reliable. This QSAR prediction indicated a negative skin irritation/corrosion potential of the target TEMPIC and could be used to support the conclusion for no classification.

Executive summary:

This study was designed to generate estimated in silico (non-testing) data of skin irritation/corrosion for Tris[2-(3-mercaptopropionyloxy)-ethyl] isocyanurate (TEMPIC). A reliability score of 2 was assigned to the prediction, since results were derived from a valid (Q)SAR model. The skin irritation model implemented in Toxtree v 2.6.13 was employed, which estimates the potential of a chemical to cause skin irritation based on expert rule-based decission tree. A physico-chemical property exclusion rule, i.e. melting point (MP) greater than 200°C was fullfield for the target i.e. the estimated MP value of the target (313.86°C, EPI Suite) exceeded the property limit of 200°C, thus suggesting a lack of skin irritation or corrosion potential for the target TEMPIC. Uncertainty of the prediction was evaluated considering the following aspects associated with the applicability domain: i) physico-chemical rules; ii) structural rules/alerts. An overall limited uncertainty was attributed to the negative skin irritating/corrosive prediction generated for TEMPIC, which was then assessed as moderately reliable. The skin irritation prediction was thus assessed as adequate for regulatory purposes.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (not irritating)

Eye irritation

Link to relevant study records

Reference

Endpoint:

eye irritation, other

Remarks:

Standard Draize test

Type of information:

(Q)SAR

Adequacy of study:

key 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: Eye Irritation

3. SMILES OR OTHER IDENTIFIERS USED AS INPUT FOR THE MODEL:
Structural formula: C18H27N3O9S3
Structural codes:
a. SMILES: O=C(OCCn1c(=O)n(c(=O)n(CCOC(=O)CCS)c1=O)CCOC(=O)CCS)CCS
b. InChI: InChI=1S/C18H27N3O9S3/c22-13(1-10-31)28-7-4-19-16(25)20(5-8-29-14(23)2-11-32)18(27)21(17(19)26)6-9-30-15(24)3-12-33/h31-33H,1-12H2
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: 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 eye 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 eye irritating properties, e.g. high acidity, basicity, electrophilicity, etc.

5. APPLICABILITY DOMAIN
For the target TEMPIC, one structural analogue was identified in the training set, suggesting that the target is partially included in the applicability domain of the model. No structural alerts for eye 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
TEMPIC was predicted negative for eye irritation/corrosion in standard rabbit Draize test based on a predicted probability to cause severe/moderate eye irritation equal to 0.13. The prediction was assessed as moderately reliable. This QSAR prediction indicated an absence of eye irritation/corrosion potential for the target TEMPIC and could be used in a weight of evidence approach to support the conclusion for no classification.
This negative eye irritation QSAR prediction was assessed as adequate for regulatory purposes.

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 Eye 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'

Specific details on test material used for the study:

SMILES: O=C(OCCn1c(=O)n(c(=O)n(CCOC(=O)CCS)c1=O)CCOC(=O)CCS)CCS
InChI=1S/C18H27N3O9S3/c22-13(1-10-31)28-7-4-19-16(25)20(5-8-29-14(23)2-11-32)18(27)21(17(19)26)6-9-30-15(24)3-12-33/h31-33H,1-12H2

Species:

rabbit

Irritation parameter:

other: Probability to cause severe/moderate eye irritation = 0.13

Remarks on result:

no indication of irritation

Remarks:

Based on QSAR prediction

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

Limited uncertainty was associated with the negative eye irritation prediction generated for the target TEMPIC based on the following consideration: one structural analogue with a negative experimental value (i.e. not irritating) was identified in the training set.

Overall, the eye irritation prediction was assessed as moderately reliable.

Interpretation of results:

GHS criteria not met

Remarks:

This QSAR prediction could be used in a weight of evidence approach to support the conclusion for no classification.

Conclusions:

TEMPIC was predicted negative for eye irritation/corrosion in standard rabbit Draize test based on a predicted probability to cause severe/moderate eye irritation equal to 0.13. The prediction was assessed as moderately reliable. This QSAR prediction indicated absence of eye irritation/corrosion potential for the target TEMPIC and could be used in a weight of evidence approach to support the conclusion for no classification.

Executive summary:

This study was designed to generate estimated in silico (non-testing) data of eye irritation for TEMPIC. A reliability score of 2 was assigned, since results derived from a valid (Q)SAR model and falling into its applicability domain, with adequate and reliable documentation/justification.

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

ACD/Percepta eye irritation model predicted the target as an eye irritant, based on a probability to cause severe/moderate eye irritation equal to 0.13. The uncertainty of the prediction was evaluated considering the following aspects: i) positive predicted probability; ii) identified structural alerts; ii) similarity of the target compound to the training set and consistency of experimental values for similar compounds. A limited uncertainty was associated with the negative eye irritation prediction generated for the target TEMPIC, since one structural analogue with a negative experimental value (i.e. not irritating) was identified in the training set.

Overall, the negative eye irritation prediction was assessed as moderately reliable and adequate for regulatory purposes.

.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (not irritating)

Respiratory irritation

Endpoint conclusion

Endpoint conclusion:

no study available

Justification for classification or non-classification

The criteria for classification as corrosive or irritating to the eye or the skin are not fulfilled by assessing these endpoint using adequate QSAR tools.