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

Eye irritation

Administrative data

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.

Data source

Reference

Reference Type:

other: Software

Title:

Unnamed

Year:

2012

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 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'

Test material

Test material information

Constituent 1

Reference substance name:

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

EC Number:

252-907-8

EC Name:

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

Cas Number:

36196-44-8

Molecular formula:

C18H27N3O9S3

IUPAC Name:

2-[2,4,6-trioxo-3,5-bis({2-[(3-sulfanylpropanoyl)oxy]ethyl})-1,3,5-triazinan-1-yl]ethyl 3-sulfanylpropanoate

Test material form:

liquid: viscous

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

Test animals / tissue source

Species:

rabbit

Results and discussion

In vivo

Results

Irritation parameter:

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

Remarks on result:

no 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; 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.

Applicant's summary and conclusion

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.

.