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Key value for chemical safety assessment

Genetic toxicity in vitro

Description of key information

Based on the negative mutagenicity predictions for the constituents using the QSAR models, the test substance is overall considered to be non-mutagenic.

Link to relevant study records

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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, but not (completely) falling into its applicability domain, with adequate and reliable documentation / justification
Justification for type of information:
QSAR prediction from an well known and acknowledged tool. See below under 'Overall remarks, attachments' for applicability domain and 'attached background material section' for methodology.
Qualifier:
according to
Guideline:
other: REACH guidance on QSARs: Chapter R.6. QSARs and grouping of chemicals
Principles of method if other than guideline:
Since the test substance is a UVCB, the mutagenicity potential was predicted for the all the constituents.
GLP compliance:
no
Type of assay:
other: QSAR prediction
Key result
Species / strain:
other: QSAR prediction from TEST v4.2.1
Remarks:
Ames Mutagenicity Test
Metabolic activation:
not specified
Genotoxicity:
negative
Remarks:
predicted for all the constituents
Remarks on result:
no mutagenic potential (based on QSAR/QSPR prediction)

Results

Constituents

Name

SMILES

TEST - Predicted Ames Mutagenicity value from Consensus method

TEST - Predicted Ames Mutagenicity result from Consensus method

Prediction statistics for similar chemicals - External and Training Dataset

Concordance

Sensitivity

Specificity

1

mono- C16 PSE, K+ and mono-C16 PSE

CCCCCCCCCCCCCCCCOP(O)(O)=O

0.14

Negative

0.89 and 0.90

0 and 0

1 and 1

2

di- C16 PSE, K+ and di- C16 PSE

CCCCCCCCCCCCCCCCOP(O)(=O)OCCCCCCCCCCCCCCCC

0.07

Negative

1 and 0.90

1 and 0

1 and 1

3

Cetyl alcohol

CCCCCCCCCCCCCCCCO

-0.06

Negative

1 and 1

N/A and NA

1 and 1

4

Isostearyl alcohol

CC(C)CCCCCCCCCCCCCCCO

-0.09

Negative

1 and 1

N/A and NA

1 and 1

5

Stearic acid/potassium stearate

CCCCCCCCCCCCCCCCCC(=O)O

-0.06

Negative

1 and 1

N/A and NA

1 and 1

6

Cetyl stearate

CCCCCCCCCCCCCCCCCC(=O)O(CCCCCCCCCCCCCCCC)

0

Negative*

-

-

-

7

Cetyl Isostearate

CC(C)CCCCCCCCCCCCCCC(=O)O(CCCCCCCCCCCCCCCC)

0.03

Negative

1 and 0.90

1 and 0

1 and 1

8

Isostearyl Isostearate**

CC(C)CCCCCCCCCCCCCCC(=O)O(CCCCCCCCCCCCCCCC(C)C)

0.06

Negative

1 and 0.90

1 and 0

1 and 1

9

Isostearyl stearate

CC(C)CCCCCCCCCCCCCCCOC(=O)CCCCCCCCCCCCCCCCC

0.06

Negative

1 and 0.90

1 and 0

1 and 1

N/A: Not available

*Experimental result available. So no need to perfprm domain evaluation.

In general, if the concordance is greater than or equal to 0.8, the model is considered to be valid. In addition both the leave-one-out sensitivity and specificity must be at least 0.5 to avoid using models which are heavily biased to predict either active or inactive scores.

**representative component of the 'esters of C18 (branched and linear) fatty acids with C18 (branched and linear alcohols)'

For more details on results, kindly refer the attached background material section of the IUCLID.

Conclusions:
Based on the negative mutagenicity predictions for all the constituents using the Consensus method of the T.E.S.T. v4.2.1 program, the test substance is overall considered to be non-mutagenic
Executive summary:

The mutagenicity potential of the test substance 'Reaction products of hexadecyl dihydrogen phosphate, dihexadecyl hydrogen phosphate, hexadecan-1-ol, stearic acid, esters of C18 (branched and linear) fatty acids with C18 (branched and linear) alcohols, and potassium hydroxide' (UVCB) was predicted using the Consensus method of the T.E.S.T. v4.2.1 program. Since the test substance is a UVCB, the mutagenicity potential was predicted for all the individual constituents, using SMILES as the input parameter. All the constituents were predicted to be negative for mutagenicity (US EPA, 2019), indicating that the test substance can be overall considered to be non-mutagenic. Applicability domain evaluation was performed by checking the descriptor and structural fragment domains of the individual QSAR methods (i.e., FDA, hierarchical clustering and nearest neighbour methods) underlying Consensus model predictions. Since an experimental value could be identified for cetyl stearate, no domain evaluation was necessary for it. The domain evaluation of the remaining all constituents indicated that they were within both descriptor and structural fragment domains of the FDA and hierarchical clustering methods, but not completely within domain for the structural fragments identified for the three nearest neighbours. Further, the prediction accuracy of the binary toxicity endpoints, can be evaluated in terms of the fraction of compounds that are predicted accurately and are described based on three statistics parameters: concordance, sensitivity, and specificity. In general, if the concordance is greater than or equal to 0.8, the model is considered to be valid. And both the leave-one-out sensitivity and specificity must be at least 0.5 to avoid using models which are heavily biased to predict either active or inactive scores. Out of three statistical parameters, the concordance and specificity fractions of all the constituents are above the required cut-offs. For sensitivity, effectively only one chemical was identified to be experimentally active but not predicted correctly for constituent 1. Given the structural differences of this chemical compared to the target, the overall accuracy of the model and its prediction is not expected to be compromised. Therefore, the predictions can be overall considered to be accurate with medium to high confidence.

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, but not (completely) falling into its applicability domain, with adequate and reliable documentation / justification
Justification for type of information:
QSAR prediction from a well-known and acknowledged tool. See below 'attached background material section' for detailed prediction results and applicability domain evaluation.
Qualifier:
according to
Guideline:
other: REACH guidance on QSARs: Chapter R.6. QSARs and grouping of chemicals
Principles of method if other than guideline:
Since the test substance is a UVCB, the mutagenicity potential was predicted for all the individual constituents, using SMILES as the input parameter.
GLP compliance:
no
Type of assay:
other: QSAR prediction
Key result
Species / strain:
other: QSAR prediction from Mutagenicity (Ames test) model (CAESAR) 2.1.13 of the VEGA v1.2.4 program
Remarks:
Ames Mutagenicity Test
Metabolic activation:
not specified
Genotoxicity:
negative
Remarks:
predicted for all the constituents
Remarks on result:
no mutagenic potential (based on QSAR/QSPR prediction)

Results

Constituents Name SMILES VEGA - Mutagenicity (Ames test) model (CAESAR) 2.1.13 Global Applicability domain Index ID/OD
1 mono- C16 PSE, K+ and mono-C16 PSE CCCCCCCCCCCCCCCCOP(O)(O)=O Non-mutagenic 0.93 ID
2 di- C16 PSE, K+ and di- C16 PSE CCCCCCCCCCCCCCCCOP(O)(=O)OCCCCCCCCCCCCCCCC Non-mutagenic 0.935 ID
3 Cetyl alcohol CCCCCCCCCCCCCCCCO Non-mutagenic 0.882 Could be OD
4 Isostearyl alcohol CC(C)CCCCCCCCCCCCCCCO Non-mutagenic 0.877 Could be OD
5 Stearic acid/potassium stearate CCCCCCCCCCCCCCCCCC(=O)O Non-mutagenic* 1 ID
6 Cetyl stearate CCCCCCCCCCCCCCCCCC(=O)O(CCCCCCCCCCCCCCCC) Non-mutagenic 0 OD
7 Cetyl Isostearate CC(C)CCCCCCCCCCCCCCC(=O)O(CCCCCCCCCCCCCCCC) Non-mutagenic 0 OD
8 Isostearyl Isostearate* CC(C)CCCCCCCCCCCCCCC(=O)O(CCCCCCCCCCCCCCCC(C)C) Non-mutagenic 0 OD
9 Isostearyl stearate CC(C)CCCCCCCCCCCCCCCOC(=O)CCCCCCCCCCCCCCCCC Non-mutagenic 0 OD
ID = In domain OD = Out of domain *Experimental result      

*representative component of the 'esters of C18 (branched and linear) fatty acids with C18 (branched and linear alcohols)'

For more detailed prediction results and applicability domain analysis of models, kindly refer the attached background material section of the IUCLID.

Conclusions:
Based on the negative mutagenicity predictions for all the constituents using the Mutagenicity (Ames test) model (CAESAR) 2.1.13 of the VEGA v1.2.4 program, the test substance is overall considered to be non-mutagenic.

Executive summary:

The mutagenicity potential of the test substance 'Reaction products of hexadecyl dihydrogen phosphate, dihexadecyl hydrogen phosphate, hexadecan-1-ol, stearic acid, esters of C18 (branched and linear) fatty acids with C18 (branched and linear) alcohols, and potassium hydroxide' (UVCB) was predicted using the Mutagenicity (Ames test) model (CAESAR) 2.1.13 of the VEGA v1.2.4 program. Since the test substance is a UVCB, the mutagenicity potential was predicted for all the individual constituents, using SMILES as the input parameter. All the constituents were predicted to be negative for mutagenicity (VEGA, 2019), indicating that the test substance can be overall considered to be non-mutagenic.The applicability domain of predictions is assessed using an Applicability Domain Index (ADI) that has values from 0 (worst case) to 1 (best case). A global ADI is calculated by grouping several other indices such as similar molecules with known experimental value, accuracy of prediction for similar molecules, concordance for similar molecules, model's descriptors range check and atom centered fragments similarity checks. Usually values lower than 0.75 indicate that the similar compound has important differences compared to the target. Considering that not all constituents were in domain, the overall predictions can be considered to be reliable with restrictions.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed (negative)

Genetic toxicity in vivo

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Study 1: The mutagenicity potential of the test substance 'Reaction products of hexadecyl dihydrogen phosphate, dihexadecyl hydrogen phosphate, hexadecan-1-ol, stearic acid, esters of C18 (branched and linear) fatty acids with C18 (branched and linear) alcohols, and potassium hydroxide' (UVCB) was predicted using the Mutagenicity (Ames test) model (CAESAR) 2.1.13 of the VEGA v1.2.4 program. Since the test substance is a UVCB, the mutagenicity potential was predicted for all the individual constituents, using SMILES as the input parameter. All the constituents were predicted to be negative for mutagenicity (VEGA, 2019), indicating that the test substance can be overall considered to be non-mutagenic.The applicability domain of predictions is assessed using an Applicability Domain Index (ADI) that has values from 0 (worst case) to 1 (best case). A global ADI is calculated by grouping several other indices such as similar molecules with known experimental value, accuracy of prediction for similar molecules, concordance for similar molecules, model's descriptors range check and atom centered fragments similarity checks. Usually values lower than 0.75 indicate that the similar compound has important differences compared to the target. Considering that not all constituents were in domain, the overall predictions can be considered to be reliable with restrictions.

Study 2: The mutagenicity potential of the test substance 'Reaction products of hexadecyl dihydrogen phosphate, dihexadecyl hydrogen phosphate, hexadecan-1-ol, stearic acid, esters of C18 (branched and linear) fatty acids with C18 (branched and linear) alcohols, and potassium hydroxide' (UVCB) was predicted using the Consensus method of the T.E.S.T. v4.2.1 program. Since the test substance is a UVCB, the mutagenicity potential was predicted for all the individual constituents, using SMILES as the input parameter. All the constituents were predicted to be negative for mutagenicity (US EPA, 2019), indicating that the test substance can be overall considered to be non-mutagenic. Applicability domain evaluation was performed by checking the descriptor and structural fragment domains of the individual QSAR methods (i.e., FDA, hierarchical clustering and nearest neighbour methods) underlying Consensus model predictions. Since an experimental value could be identified for cetyl stearate, no domain evaluation was necessary for it. The domain evaluation of the remaining all constituents indicated that they were within both descriptor and structural fragment domains of the FDA and hierarchical clustering methods, but not completely within domain for the structural fragments identified for the three nearest neighbours. Further, the prediction accuracy of the binary toxicity endpoints, can be evaluated in terms of the fraction of compounds that are predicted accurately and are described based on three statistics parameters: concordance, sensitivity, and specificity. In general, if the concordance is greater than or equal to 0.8, the model is considered to be valid. And both the leave-one-out sensitivity and specificity must be at least 0.5 to avoid using models which are heavily biased to predict either active or inactive scores. Out of three statistical parameters, the concordance and specificity fractions of all the constituents are above the required cut-offs. For sensitivity, effectively only one chemical was identified to be experimentally active but not predicted correctly for constituent 1. Given the structural differences of this chemical compared to the target, the overall accuracy of the model and its prediction is not expected to be compromised. Therefore, the predictions can be overall considered to be accurate with medium to high confidence.

Based on the negative mutagenicity predictions for the constituents using the QSAR models, the test substance is overall considered to be non-mutagenic.

Justification for classification or non-classification

Based on the negative mutagenicity predictions for the constituents using the QSAR models, the test substance is overall not considered to warrant a classification for mutagenicity according to the EU CLP criteria (1272/2008/EC).