Reaction mass of didodecyl 3,3'-thiodipropionate and dioctadecyl 3,3'-thiodipropionate and octadecyl 3-[[3-(dodecyloxy)-3-oxopropyl]thio]propionate

Genetic toxicity: in vitro

Administrative data

Endpoint:

in vitro gene mutation study in bacteria

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 (incl. version number): ACD/Percepta (Impurity Profiling) QSAR model for bacterial in vitro mutagenicity (composite)

3. SMILES OR OTHER IDENTIFIERS USED AS INPUT FOR THE MODEL:
Structural formula: C36H70O4S
a. SMILES: O=C(OCCCCCCCCCCCC)CCSCCC(=O)OCCCCCCCCCCCCCCCCCC
b. InChI: InChI=1S/C36H70O4S/c1-3-5-7-9-11-13-15-16-17-18-19-20-22-24-26-28-32-40-36(38)30-34-41-33-29-35(37)39-31-27-25-23-21-14-12-10-8-6-4-2/h3-34H2,1-2H3
c. Other structural representation: mol file used and included in the test material information.

4. SCIENTIFIC VALIDITY OF THE (Q)SAR MODEL
- Defined endpoint: Bacterial in vitro mutagenicity
- Unambiguous algorithm: Probabilistic Model based on GALAS (Global, Adjusted Locally According to Similarity) modeling methodology. The GALAS model consists of two parts: 1) Global (baseline) model, built using binomial PLS method based on fragmental descriptors, that reflects a “cumulative” mutagenicity potential; 2) Local corrections applied to baseline predictions using a special similarity-based routine, after performing an analysis for the most similar compounds used in the training set. Experimental values for microbial in vitro mutagenicity are used during the local part of the modeling to yield final GALAS model (please see attached QMRF for further details).
- Defined domain of applicability: The confidence of predictions is evaluated via a Reliability Index (RI) calculated for each prediction. The RI is a value ranging from 0 and 1 (0 – unreliable prediction, 1 – idealistic, fully reliable prediction) and is an indicator of how well a particular compound is represented within the training set of the model. Two criteria are applied for reliability estimation: 1) Similarity of the analyzed molecular structure to compounds in the Self-training Library (prediction is considered unreliable if no similar compounds have been found in the training set). 2) Consistency of experimental data for similar compounds (inconsistent data for similar molecules lead to lower RI values). RI can serve as a valuable tool for interpreting prediction results. If a compound obtains RI lower than a certain cut-off value (here set at 0.3), it means that this compound falls outside the applicability domain of the model and the respective prediction may be less accurate (please see attached QMRF for further details).
- Appropriate measures of goodness-of-fit and robustness and predictivity: please see attached QMRF.
- Mechanistic interpretation: Predictions obtained by the probabilistic model are combined with and supported by the Genotoxicity Hazard System, which is a knowledge-based expert system that identifies structural fragments that may be responsible for the mutagenic activity of the analyzed molecules. The Genotoxicity Hazard system searches through a list of 70 structural alerts, of which 33 represent mutagens, 24–clastogens, and 13–epigenetic carcinogens (fragments collected from toxicological literature). Each identified hazard is accompanied by information describing its mechanism of action, literature references and z-scores. Z-scores show whether the presence of the fragment leads to a statistically significant increase in the proportion of compounds with a positive test result for the specific assay. This information provides further evidence regarding the possible mechanisms of action.

5. APPLICABILITY DOMAIN
The target compound E1218 is included in the model applicability domain since the RI is greater than 0.3.
- descriptor domain: not applicable.
- structural fragment domain: not applicable.
- mechanism domain: no structural alerts for mutagenicity
Five compounds were identified as analogues of E1218. These training compounds exhibited high similarity with respect to E1218 (similarity index ranging from 0.88 to 1.00), and all were characterised by negative results.

6. ADEQUACY OF THE RESULT
The target E1218 was predicted negative for bacterial in vitro mutagenicity based on a positive predicted probability equal to 0.006. The prediction was assessed as highly reliable. This QSAR prediction indicates that the target E1218 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 of mutagenicity).
This negative bacterial in vitro mutagenicity QSAR prediction was assessed as adequate for regulatory purposes.

Data source

Reference

Reference Type:

other: software

Title:

Unnamed

Year:

2011

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 (Impurity Profiling) QSAR model for bacterial in vitro mutagenicity (composite)
- 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

Test material information

Constituent 1

Reference substance name:

Octadecyl 3-[[3-(dodecyloxy)-3-oxopropyl]thio]propionate

EC Number:

236-025-0

EC Name:

Octadecyl 3-[[3-(dodecyloxy)-3-oxopropyl]thio]propionate

Cas Number:

13103-52-1

Molecular formula:

C36H70O4S

IUPAC Name:

Dodecyl octadecyl 3,3'-sulfanediyldipropanoate

Test material form:

solid: pellets

Specific details on test material used for the study:

SMILES: O=C(OCCCCCCCCCCCCCCCCCC)CCS
InChI=1S/C21H42O2S/c1-2-3-4-5-6-7-8-9-10-11-12-13-14-15-16-17-19-23-21(22)18-20-24/h24H,2-20H2,1H3

Results and discussion

Test results

Key result

Species / strain:

other: S. typhimurium, E. coli

Genotoxicity:

negative

Additional information on results:

For the target E1218, the prediction was assessed as highly reliable, based on a reliability index equal to 0.85 and the following considerations:
- Training set analogues similarity: high.
- Experimental data of structural analogues: negative experimental results in agreement with target’s prediction.

Remarks on result:

no mutagenic potential (based on QSAR/QSPR prediction)

Applicant's summary and conclusion

Conclusions:

The target E1218 was predicted negative for bacterial in vitro mutagenicity based on a positive predicted probability equal to 0.006. The prediction was assessed as highly reliable. This QSAR prediction indicates that the target E1218 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 of no classification for mutagenicity).

Executive summary:

This study was designed to generate in silico (non-testing) genotoxicity data as bacterial in vitro mutagenicity for  Lauryl stearyl thiodipropionate (E1218). A reliability score of 2 was assigned, since results were derived from a valid (Q)SAR model, falling into its applicability domain, with adequate and reliable documentation/justification.

The ACD/Percepta (Impurity Profiling) QSAR model for bacterial in vitro mutagenicity (composite), implemented in ACD/Labs Percepta (2016 Release) was used, and it estimates the probability that a compound will result positive in the Ames test.

The ACD/Percepta model predicted the target E1218 as negative for bacterial in vitro mutagenicity, based on the positive prediction probability of 0.006. The prediction was assessed to be highly reliable, based on the reliability index of 0.85, and to the fact that the five identified structural analogues exhibited high similarity towards the target E1218, and were all characterised by negative experimental results, which were in agreement with the target’s negative prediction.

Based on these considerations, the negative prediction was assessed as highly reliable, and adequate for regulatory purposes.