Reaction mass of 2,2'-thiodiethanethiol and 1095071-01-4 and α-sulfanyl-ω-{2-[(2-sulfanylethyl)sulfanyl]ethyl}bis[ethane- 1,2-diylsulfanediylethane- 1,2-diylsulfanediyl(3-hydroxypropane-1,1-diyl) sulfanediyl]

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: Leadscope Model Applier, version 2.2.

2. MODEL: Leadscope QSAR Genetic Toxicity - Salmonella, v3

3. SMILES OR OTHER IDENTIFIERS USED AS INPUT FOR THE MODEL:
Structural formula: C4H10S3
Structural codes:
a. SMILES:SCCSCCS
b. InChI: InChI=1S/C4H10S3/c5-1-3-7-4-2-6/h5-6H,1-4H2
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: The predictive algorithm is based on a Partial Logistic Regression (PLS), which uses structural features and eight calculated properties (i.e., MW, LogP, polar surface area, H bond acceptors, H bond donors, no. rotational bonds and Lipinski score (rule violation)) as molecular descriptors.
- Defined domain of applicability: Leadscope uses two parameters to guide the applicability of model domain: 1) having at least one structural feature defined in the model in addition to all the property descriptors; 2) having at least one chemical in a training neighbourhood with at least 30% global similarity to the test structure.
- Appropriate measures of goodness-of-fit and robustness and predictivity: Please see attached QMRF.
- Mechanistic interpretation: not applicable.

5. APPLICABILITY DOMAIN
The target DMDS is included in the applicability domain, since 1 structural feature was found and 9 training compounds were identified in the model training set being structurally similar to the test compound
- Descriptor domain: property descriptors for the target compound have values inside the descriptor range of the compounds of the training set.
- Structural fragment domain: 1 model structural features were identified in the target (majority of negative features, i.e. features mainly represented in negative training compounds).
- Similarity with analogues in the training set: For the target DMDS, 9 analogues with a similarity >30% were identified in the training set. Despite the limited similarity (<50%), it is worth noting that both of the two most similar analogues hold the –SH group as in the target DMDS, along with negative experimental results..
Please see attached QPRF for structural analogues and further details.

6. ADEQUACY OF THE RESULT
The target DMDS was predicted negative for Salmonella in vitro mutagenicity (Ames test) and the prediction was assessed as moderately reliable. This QSAR prediction indicates that the target DMDS 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).
The Salmonella in vitro mutagenicity QSAR prediction was assessed as adequate for regulatory purposes

Data source

Reference

Reference Type:

other: Software

Title:

Unnamed

Year:

2013

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: Leadscope Model Applier, version 2.2
- Model used:Leadscope QSAR Genetic Toxicity - Salmonella v3
- Model description: see fields 'Justification for type of information' and 'Attached justification'
- Justification of QSAR prediction: see fields '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:

2,2'-thiodiethanethiol

EC Number:

222-671-0

EC Name:

2,2'-thiodiethanethiol

Cas Number:

3570-55-6

Molecular formula:

C4H10S3

IUPAC Name:

2,2'-sulfanediyldiethanethiol

Test material form:

liquid

Specific details on test material used for the study:

SMILES: SCCSCCS
InChI: InChI=1S/C4H10S3/c5-1-3-7-4-2-6/h5-6H,1-4H2

Results and discussion

Test results

Key result

Species / strain:

other: S. typhimurium

Genotoxicity:

negative

Additional information on results:

Limited uncertainty was associated with the negative prediction generated for the target DMDS due to the following considerations:
- low predicted probability (positive prediction probability equal to 0.20);
- 1 negative model feature was found in DMDS;
- the most similar training set analogues (despite the limited similarity index) contained the –SH group of the target DMDS and were experimentally negative.
Overall, the negative Salmonella in vitro mutagenicity QSAR prediction was assessed as moderately reliable.

Remarks on result:

no mutagenic potential (based on QSAR/QSPR prediction)

Applicant's summary and conclusion

Conclusions:

The target DMDS was predicted negative for Salmonella in vitro mutagenicity (Ames test) and the prediction was assessed as moderately reliable.

Executive summary:

This study was designed to generate in silico (non-testing) genotoxicity data as Salmonella in vitro mutagenicity for 2,2′-Thiodiethanethiol (DMDS). A reliability score of 2 was assigned, since results were derived from a valid QSAR model with adequate and reliable documentation/justification.

The Leadscope QSAR Genetic Toxicity - Salmonella v3 model, implemented in Leadscope Model Applier (version 2.2), was employed. This QSAR model estimates the probability that a compound will result positive in the Ames test. Leadscope results include a mutagenicity prediction (positive, negative or not in domain), a positive prediction probability and two parameters which assess model applicability domain, i.e. Model Features Count and 30% Similarity Training Neighbours Count.

Leadscope predicted the target as negative for Salmonella in vitro mutagenicity, based on a positive prediction probability of 0.20. The target compound was included in the applicability domain of the model since 1 model features and 9 analogues with a similarity >30% were identified in the training set. Despite the limited similarity (<50%), it is worth noting that both of the two most similar analogues hold the –SH group as in the target DMDS, along with negative experimental results.

The prediction was assessed as moderately reliable, and adequate for regulatory purposes.