Styrax benzoin, ext.

Endpoint summary

Key value for chemical safety assessment

Genetic toxicity in vitro

Link to relevant study records

Reference

Reference 1

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

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 three major constituents (cinnamic acid, p-coumaryl cinnamate and coniferyl cinnamate), which correspond to more than 90% of the composition.

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 three major constituents

Remarks on result:

no mutagenic potential (based on QSAR/QSPR prediction)

Results

TEST - Ames Mutagenicity Test
Name	SMILES	Mutagenicity value	Mutagenicity result	Prediction statistics for similar chemicals - External and Training Dataset
				Concordance	Sensitivity	Specificity
p-Coumaryl cinnamate	Oc1ccc(C=CCOC(=O)C=Cc2ccccc2)cc1	0.11	Negative	0.90 and 0.80	0.80 and 0.50	1 and 0.88
Cinnamic acid	C1=CC=C(C=C1)C=CC(=O)O	0.00*	Negative	-	-	-
Coniferyl cinnamate	COc1cc(C=CCOC(=O)C=Cc2ccccc2)ccc1O	0.16	Negative	0.80 and 0.80	0.67 and 0.50	1 and 0.88

*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.

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

Conclusions:

Based on the negative mutagenicity predictions for the major 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 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 predictions were performed for the three major constituents (cinnamic acid, p-coumaryl cinnamate and coniferyl cinnamate), which correspond to more than 90% of the composition. SMILES codes were used as the input parameters. All three 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 cinnamic acid, the domain evaluation of the remaining two 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 statistical 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. Based on respective scores for the three statistical parameters, which were above the required cut-offs the mutagenicity predictions for the 2 constituents can be considered to be accurate. Therefore, considering the applicability domain and prediction accuracy evaluations, the mutagenicity predictions for the two constituents based on Consensus method are overall considered to be reliable.

Reference 2

Endpoint:

in vitro gene mutation study in bacteria

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

4 (not assignable)

Rationale for reliability incl. deficiencies:

secondary literature

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 471 (Bacterial Reverse Mutation Assay)

GLP compliance:

not specified

Type of assay:

bacterial reverse mutation assay

Species / strain / cell type:

S. typhimurium TA 1535, TA 1537, TA 98 and TA 100

Species / strain / cell type:

S. typhimurium TA 1538

Metabolic activation:

with and without

Test concentrations with justification for top dose:

No details on concentrations; max non-toxic dose - 1000 mcg/plate

Key result

Species / strain:

S. typhimurium TA 1535

Metabolic activation:

with and without

Genotoxicity:

negative

Cytotoxicity / choice of top concentrations:

not specified

Vehicle controls validity:

valid

True negative controls validity:

valid

Positive controls validity:

valid

Key result

Species / strain:

S. typhimurium TA 1537

Metabolic activation:

with and without

Genotoxicity:

negative

Cytotoxicity / choice of top concentrations:

not specified

Vehicle controls validity:

valid

True negative controls validity:

valid

Positive controls validity:

valid

Key result

Species / strain:

S. typhimurium TA 98

Metabolic activation:

with and without

Genotoxicity:

negative

Cytotoxicity / choice of top concentrations:

not specified

Vehicle controls validity:

valid

True negative controls validity:

valid

Positive controls validity:

valid

Key result

Species / strain:

S. typhimurium TA 100

Metabolic activation:

with and without

Genotoxicity:

negative

Cytotoxicity / choice of top concentrations:

not specified

Vehicle controls validity:

valid

True negative controls validity:

valid

Positive controls validity:

valid

Key result

Species / strain:

S. typhimurium TA 1538

Metabolic activation:

with and without

Genotoxicity:

negative

Cytotoxicity / choice of top concentrations:

not specified

Vehicle controls validity:

valid

True negative controls validity:

valid

Positive controls validity:

valid

Executive summary:

A study was conducted to determine the mutagenic potential of the constituent in an Ames assay. S. typhimurium strains TA 98, TA 100, TA 1535, TA 1537 and TA 1538 were exposed to the constituent up to a maximum non-toxic dose of 1000 mcg/plate in a liquid pre-incubation method. Under the study conditions, the constituent was found to be non-mutagenic (Bickers, 2005).

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (negative)

Genetic toxicity in vivo

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

Genetic toxicity in vitro

QSAR for three major constituents:

The mutagenicity potential of the test substance 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 predictions were performed for the three major constituents (cinnamic acid, p-coumaryl cinnamate and coniferyl cinnamate), which correspond to more than 90% of the composition. SMILES codes were used as the input parameters. All three 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 cinnamic acid, the domain evaluation of the remaining two 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 statistical 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. Based on respective scores for the three statistical parameters, which were above the required cut-offs the mutagenicity predictions for the 2 constituents can be considered to be accurate. Therefore, considering the applicability domain and prediction accuracy evaluations, the mutagenicity predictions for the two constituents based on Consensus method are overall considered to be reliable.

Experimental data:

A study was conducted to determine the mutagenic potential of the constituent in an Ames assay. S. typhimurium strains TA 98, TA 100, TA 1535, TA 1537 and TA 1538 were exposed to the constituent up to a maximum non-toxic dose of 1000 mcg/plate in a liquid pre-incubation method. Under the study conditions, the constituent was found to be non-mutagenic (Bickers, 2005).

Based on experimental data on one of the major constituents and QSAR predictions for the three major constituents (which constitute more than 90% of the composition), the substance is overall considered to be non-mutagenic.

Justification for classification or non-classification

Based on experimental data on one of the major constituents and QSAR predictions for the three major constituents (which constitute more than 90% of the composition), the substance is overall considered to be non-mutagenic and therefore, does not warrant classification according to EU CLP (1272/2008/EC) criteria.