Registration Dossier

Diss Factsheets

Toxicological information

Genetic toxicity: in vitro

Currently viewing:

Administrative data

Endpoint:
in vitro gene mutation study in bacteria
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: Vega Application (version 1.1.4)

2. MODEL (incl. version number): CAESAR Mutagenicity model (version 2.1.13)

3. SMILES OR OTHER IDENTIFIERS USED AS INPUT FOR THE MODEL:
Structural formula: C25H42O12S5
a. SMILES: SCCC(=O)OCC(CO)(COC(=O)CCS)COCC(COC(=O)CCS)(COC(=O)CCS)COC(=O)CCS
b. InChI=1S/C25H42O12S5/c26-11-24(14-33-19(27)1-6-38,15-34-20(28)2-7-39)12-32-13-25(16-35-21(29)3-8-40,17-36-22(30)4-9-41)18-37-23(31)5-10-42/h26,38-42H,1-18H2
c. Other structural representation: mol file used and included in the test material information.

4. SCIENTIFIC VALIDITY OF THE (Q)SAR MODEL
- Defined endpoint: Mutagenicity - microbial in vitro Salmonella
- Unambiguous algorithm: Integrated model arranged cascading two models, a trained Support Vector Machine (SVM) classifier, and an additional model for false negatives (FNs) removal based on Structural Alerts (SAs) matching (please see attached QMRF for further details)
- Defined domain of applicability: The applicability domain of predictions was assessed using an Applicability Domain Index (ADI) that has values from 0 (not reliable) to 1 (fully reliable). The ADI is calculated by grouping several other indices, each one taking into account a particular issue of the applicability domain, i.e. similar molecules with known experimental value, accuracy of prediction for similar molecules, concordance for similar molecules, model descriptors range check and Atom Centered Fragments (ACF) similarity check. In more details: ADI>0.9 (target compound is into model AD), ADI<0.7 (target compound is out model AD), 0.7- Appropriate measures of goodness-of-fit and robustness and predictivity: please see attached QMRF.
- Mechanistic interpretation: The model includes SAs to identify toxic compounds, according to the mechanistic basis described by the Benigni-Bossa rules. In addition a stochastic model is included, to provide basis also for negative results.

5. APPLICABILITY DOMAIN
The ADI value calculated for di-PETMP constituent-2 was equal to 0.774, meaning that the target compound could be outside the applicability domain of the model. The global ADI was based on: Similarity index = 0.732 (not optimal), Accuracy index = 0.67 (not optimal), Concordance index = 1 (good), Descriptors range check = True (good), ACF index = 1 (good).
-descriptor domain: descriptors for the target compound have values inside the descriptor range of the compounds of the training set.
- structural fragment domain: all atom centered fragments of the target compound have been found in the compounds of the training set.
- mechanism domain: no structural alerts related to mutagenicity or suspect mutagenicity (Benigni/Bossa structural alerts) have been found in the target compound.
Overall, it was concluded that the target di-PETMP constituent-2 is included in the applicability domain of the model.
For di-PETMP constituent-2 a similarity index of 0.732 was derived, meaning that moderately similar compounds are included in the training set.
The three mostly similar compounds from the training set exhibited moderate similarity with respect to the target di-PETMP (similarity indices in the range 0.72-0.75), along with consistent negative experimental Ames test results, while prediction accuracy is not optimal.

6. ADEQUACY OF THE RESULT
di-PETMP constituent-2 was predicted negative for bacterial in vitro mutagenicity (Ames test) and the prediction was assessed as borderline reliable. This QSAR prediction indicates that the target di-PETMP constituent-2 does not have the potential to induce gene mutation and could be used to assess the mutagenic potential of the substance (e.g., to support the conclusion for no classification for germ cell mutagenicity).
This negative bacterial in vitro mutagenicity QSAR prediction was assessed as adequate for regulatory purposes.

Data source

Reference
Reference Type:
other: Software
Title:
CAESAR Mutagenicity model (version 2.1.13) implemented in Vega Application (version 1.1.4)
Author:
[1] Thomas Ferrari Department of Electronics and Information (DEI), Politecnico di Milano
[2] Alberto Manganaro Istituto di Ricerche Farmacologiche "Mario Negri"
Year:
2010
Bibliographic source:
Ferrari T, Gini G (2010) An open source multistep model to predict mutagenicity from statistical analysis and relevant structural alerts. Chemistry Central Journal , 4(Suppl 1):S2.

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 used including version: Vega Application (version 1.1.4)
- Model(s) used: CAESAR Mutagenicity model (version 2.1.13)
- 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'
Type of assay:
bacterial reverse mutation assay

Test material

Constituent 1
Reference substance name:
3-(3-hydroxy-2,2-bis{[(3-sulfanylpropanoyl)oxy]methyl}propoxy)-2,2-bis{[(3-sulfanylpropanoyl)oxy]methyl}propyl 3-sulfanylpropanoate
Cas Number:
n/a
Molecular formula:
C25H42O12S5
IUPAC Name:
3-(3-hydroxy-2,2-bis{[(3-sulfanylpropanoyl)oxy]methyl}propoxy)-2,2-bis{[(3-sulfanylpropanoyl)oxy]methyl}propyl 3-sulfanylpropanoate
Specific details on test material used for the study:
SMILES: SCCC(=O)OCC(CO)(COC(=O)CCS)COCC(COC(=O)CCS)(COC(=O)CCS)COC(=O)CCS
InChI: InChI=1S/C25H42O12S5/c26-11-24(14-33-19(27)1-6-38,15-34-20(28)2-7-39)12-32-13-25(16-35-21(29)3-8-40,17-36-22(30)4-9-41)18-37-23(31)5-10-42/h26,38-42H,1-18H2


Results and discussion

Test results
Species / strain:
other: S. typhimurium
Genotoxicity:
negative
Additional information on results:
Moderate uncertainty was associated with the negative prediction generated for the target di-PETMP constituent-2 due to the following considerations:
- the target compound is moderately represented in the training set (i.e., moderately similar compounds found in the training set, target descriptors inside the descriptor range of the training set, all structural fragments of the target found in the training set);
- prediction accuracy for training set analogues was not optimal.
Overall, the negative bacterial in vitro mutagenicity QSAR prediction was assessed as reliable with a borderline level of confidence.
Remarks on result:
no mutagenic potential (based on QSAR/QSPR prediction)

Applicant's summary and conclusion

Conclusions:
di-PETMP constituent-2 was predicted negative for bacterial in vitro mutagenicity (Ames test). The prediction was assessed as borderline reliable and adequate for regulatory purposes.
Executive summary:

This study was designed to generate in silico (non-testing) genotoxicity data as bacterial in vitro mutagenicity for di-PETMP constituent-2. A reliability score of 2 was assigned, since results were derived from a valid (Q)SAR model, and falling into its applicability domain, with adequate and reliable documentation/justification.

The CAESAR Mutagenicity model (version 2.1.13) implemented in Vega Application (version 1.1.4) was employed. Vega/CAESAR model provides a qualitative prediction of mutagenicity on Salmonella typhimurium (Ames test).

Vega/Caesar mutagenicity model predicted the target di.PETMP

constituent-2

as negative for Salmonella in vitro mutagenicity. The target compound was moderately represented in the training set (i.e., moderately similar compounds found in the training set, target descriptors inside the descriptor range of the training set, all structural fragments of the target found in the training set). The three mostly similar compounds from the training set exhibited moderate similarity with respect to the targetdi-PETMP (similarity indices in the range 0.72-0.75), along with consistent negative experimental Ames test results, while prediction accuracy is not optimal. Based on these considerations, the negative prediction was assessed as borderline reliable, and adequate for regulatory purposes.

Categories Display