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Toxicological information

Genetic toxicity: in vitro

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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 2.1.2.

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

3. SMILES OR OTHER IDENTIFIERS USED AS INPUT FOR THE MODEL:
Structural formula: C7H14O2S
Structural codes:
a. SMILES: CCCCOC(=O)CCS
b. InChI: InChI=1S/C7H14O2S/c1-2-3-5-9-7(8)4-6-10/h10H,2-6H2,1H3
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 BuMP is within the applicability domain, since 10 structural features were found and 65 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: 10 model structural features were identified in the target (majority of negative features, i.e. features mainly represented in negative training set compounds).
- Similarity with analogues in the training set: For the target BuMP, 65 analogues with a similarity >30% were identified in the training set. Among these analogues, 16 compounds exhibit moderate similarity with respect to the target (similarity index ranging from 0.50 to 0.59), almost consistent negative experimental Ames test results (14 negative and two positive analogues), and good prediction accuracy (except for the two positive compounds, which are erroneously predicted as negative).
Please see attached QPRF for structural analogues and further details.

6. ADEQUACY OF THE RESULT
The target BuMP is predicted negative for Salmonella in vitro mutagenicity (Ames test) and the prediction is assessed as moderate reliable. This QSAR prediction indicates that the target BuMP doesn’t 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 mutagenicity).
This negative Salmonella in vitro mutagenicity QSAR prediction is 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 2.1.2
- 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

Constituent 1
Chemical structure
Reference substance name:
Butyl 3-mercaptopropionate
EC Number:
240-343-5
EC Name:
Butyl 3-mercaptopropionate
Cas Number:
16215-21-7
Molecular formula:
C7H14O2S
IUPAC Name:
butyl 3-mercaptopropionate
Specific details on test material used for the study:
SMILES: CCCCOC(=O)CCS
InChI: InChI=1S/C7H14O2S/c1-2-3-5-9-7(8)4-6-10/h10H,2-6H2,1H3

Results and discussion

Test results
Key result
Species / strain:
other: S. typhimurium
Genotoxicity:
negative
Additional information on results:
The uncertainty of the prediction was evaluated with the two parameters which guide the applicability of model domain, i.e., number of model features and number of 30% similarity training neighbors, as well as by assessing the degree of similarity of training neighbors and consistency of their experimental data.

Limited uncertainty was associated to the negative prediction generated for the target BuMP since:
- 10 model fragments were found in BuMP, the majority of them are mainly represented in negative training compounds;
- 65 training compounds structurally similar to the target were identified, meaning that the target is well represented in the model training set.
- 16 training set analogues exhibit moderate similarity, almost consistent negative experimental Ames test results, and good prediction accuracy.
Overall, Salmonella in vitro mutagenicity QSAR prediction was assessed as moderate reliable.
Remarks on result:
no mutagenic potential (based on QSAR/QSPR prediction)

Applicant's summary and conclusion

Conclusions:
The target BuMP is predicted negative for Salmonella in vitro mutagenicity (Ames test). The prediction is assessed as moderate reliable and adequate for regulatory purposes.
Executive summary:

This study was designed to generate in silico (non-testing) genotoxicity data as Salmonella in vitro mutagenicity for Butyl-3-mercaptopropionate (BuMP). 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 2.1.2), 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 0.03. The target compound was included in the applicability domain of the model since 10 model features and 65 analogues with a similarity >30% were identified in the training set. Among these analogues, 16 compounds exhibit moderate similarity with respect to the target (similarity index ranging from 0.50 to 0.59).

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

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