Cinnamyl butyrate

Endpoint summary

Key value for chemical safety assessment

Genetic toxicity in vitro

Description of key information

Based on the prediction done using the OECD QSAR toolbox version 3.3 with log kow as the primary descriptor and considering the five closest read across substances, gene mutation was predicted for (2E)-3-phenylprop-2-en-1-yl butanoate. The study assumed the use of Salmonella typhimurium strains TA 1535, TA 1537, TA 98, TA 100 and TA 102 with S9 metabolic activation system. (2E)-3-phenylprop-2-en-1-yl butanoate was predicted to not induce gene mutation in Salmonella typhimurium strains TA 1535, TA 1537, TA 98, TA 100 and TA 102 in the presence of S9 metabolic activation system and hence, according to the prediction made, it is not likely to classify as a gene mutant in vitro.

Based on the predicted result it can be concluded that the substance is considered to not toxic as per the criteria mentioned in CLP regulation.

Link to relevant study records

Reference

Endpoint:

in vitro gene mutation study in bacteria

Remarks:

Type of genotoxicity: gene mutation

Type of information:

(Q)SAR

Adequacy of study:

weight of evidence

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 limited documentation / justification

Justification for type of information:

Data is from OECD QSAR Toolbox version 3.3 and the supporting QMRF report has been attached

Qualifier:

according to guideline

Guideline:

other: Refer below principle

Principles of method if other than guideline:

Prediction is done using OECD QSAR Toolbox version 3.3, 2017

GLP compliance:

not specified

Type of assay:

bacterial reverse mutation assay

Specific details on test material used for the study:

- Name of the test material: Cinnamyl butyrate
- IUPAC name: (2E)-3-phenylprop-2-en-1-yl butanoate
- Molecular formula: C13H16O2
- Molecular weight: 204.267 g/mol
- Substance type: Organic
- Smiles: c1(\C=C\COC(CCC)=O)ccccc1

Target gene:

Histidine

Species / strain / cell type:

S. typhimurium TA 1535, TA 1537, TA 98, TA 100 and TA 102

Details on mammalian cell type (if applicable):

Not applicable

Additional strain / cell type characteristics:

not specified

Cytokinesis block (if used):

No data

Metabolic activation:

with

Metabolic activation system:

S9 metabolic activation system

Test concentrations with justification for top dose:

No data

Vehicle / solvent:

No data

Untreated negative controls:

not specified

Negative solvent / vehicle controls:

not specified

True negative controls:

not specified

Positive controls:

not specified

Positive control substance:

not specified

Details on test system and experimental conditions:

No data

Rationale for test conditions:

No data

Evaluation criteria:

Prediction is done considering a dose dependent increase in the number of revertants/plate

Statistics:

No data

Species / strain:

S. typhimurium, other: TA 1535, TA 1537, TA 98, TA 100 and TA 102

Metabolic activation:

with

Genotoxicity:

negative

Cytotoxicity / choice of top concentrations:

not specified

Vehicle controls validity:

not specified

Untreated negative controls validity:

not specified

Positive controls validity:

not specified

Additional information on results:

No data

Remarks on result:

no mutagenic potential (based on QSAR/QSPR prediction)

The prediction was based on dataset comprised from the following descriptors: "Gene mutation"
Estimation method: Takes highest mode value from the 5 nearest neighbours
Domain  logical expression:Result: In Domain

(((((("a" or "b" or "c" )  and ("d" and ( not "e") )  )  and ("f" and ( not "g") )  )  and ("h" and ( not "i") )  )  and "j" )  and ("k" and "l" )  )

Domain logical expression index: "a"

Referential boundary: The target chemical should be classified as Esters OR Vinyl/Allyl Esters by Aquatic toxicity classification by ECOSAR ONLY

Domain logical expression index: "b"

Referential boundary: The target chemical should be classified as SN2 OR SN2 >> SN2 reaction at sp3 carbon atom OR SN2 >> SN2 reaction at sp3 carbon atom >> Allyl acetates and related chemicals by Protein binding by OECD ONLY

Domain logical expression index: "c"

Referential boundary: The target chemical should be classified as SN2 OR SN2 >> SN2 Reaction at a sp3 carbon atom OR SN2 >> SN2 Reaction at a sp3 carbon atom >> Activated alkyl esters and thioesters  by Protein binding by OASIS v1.3 ONLY

Domain logical expression index: "d"

Referential boundary: The target chemical should be classified as No alert found by DNA binding by OASIS v.1.3

Domain logical expression index: "e"

Referential boundary: The target chemical should be classified as AN2 OR AN2 >>  Michael-type addition, quinoid structures OR AN2 >>  Michael-type addition, quinoid structures >> Quinones OR AN2 >> Carbamoylation after isocyanate formation OR AN2 >> Carbamoylation after isocyanate formation >> N-Hydroxylamines OR AN2 >> Michael-type addition on alpha, beta-unsaturated carbonyl compounds OR AN2 >> Michael-type addition on alpha, beta-unsaturated carbonyl compounds >> Four- and Five-Membered Lactones OR AN2 >> Shiff base formation after aldehyde release OR AN2 >> Shiff base formation after aldehyde release >> Specific Acetate Esters OR AN2 >> Thioacylation via nucleophilic addition after cysteine-mediated thioketene formation OR AN2 >> Thioacylation via nucleophilic addition after cysteine-mediated thioketene formation >> Haloalkenes with Electron-Withdrawing Groups OR Non-covalent interaction OR Non-covalent interaction >> DNA intercalation OR Non-covalent interaction >> DNA intercalation >> Coumarins OR Non-covalent interaction >> DNA intercalation >> Fused-Ring Nitroaromatics OR Non-covalent interaction >> DNA intercalation >> Quinones OR Radical OR Radical >> Generation of ROS by glutathione depletion (indirect) OR Radical >> Generation of ROS by glutathione depletion (indirect) >> Haloalkanes Containing Heteroatom OR Radical >> Radical mechanism via ROS formation (indirect) OR Radical >> Radical mechanism via ROS formation (indirect) >> Conjugated Nitro Compounds OR Radical >> Radical mechanism via ROS formation (indirect) >> Coumarins OR Radical >> Radical mechanism via ROS formation (indirect) >> Fused-Ring Nitroaromatics OR Radical >> Radical mechanism via ROS formation (indirect) >> N-Hydroxylamines OR Radical >> Radical mechanism via ROS formation (indirect) >> Nitroaniline Derivatives OR Radical >> Radical mechanism via ROS formation (indirect) >> p-Substituted Mononitrobenzenes OR Radical >> Radical mechanism via ROS formation (indirect) >> Quinones OR SN1 OR SN1 >> Alkylation after metabolically formed carbenium ion species OR SN1 >> Alkylation after metabolically formed carbenium ion species >> Polycyclic Aromatic Hydrocarbon Derivatives OR SN1 >> Nucleophilic attack after carbenium ion formation OR SN1 >> Nucleophilic attack after carbenium ion formation >> Pyrrolizidine Derivatives OR SN1 >> Nucleophilic attack after carbenium ion formation >> Specific Acetate Esters OR SN1 >> Nucleophilic attack after metabolic nitrenium ion formation OR SN1 >> Nucleophilic attack after metabolic nitrenium ion formation >> N-Hydroxylamines OR SN1 >> Nucleophilic attack after reduction and nitrenium ion formation OR SN1 >> Nucleophilic attack after reduction and nitrenium ion formation >> Conjugated Nitro Compounds OR SN1 >> Nucleophilic attack after reduction and nitrenium ion formation >> Fused-Ring Nitroaromatics OR SN1 >> Nucleophilic attack after reduction and nitrenium ion formation >> Nitroaniline Derivatives OR SN1 >> Nucleophilic attack after reduction and nitrenium ion formation >> Nitrobiphenyls and Bridged Nitrobiphenyls OR SN1 >> Nucleophilic attack after reduction and nitrenium ion formation >> p-Substituted Mononitrobenzenes OR SN2 OR SN2 >> Acylation OR SN2 >> Acylation >> Specific Acetate Esters OR SN2 >> Alkylation, direct acting epoxides and related after cyclization OR SN2 >> Alkylation, direct acting epoxides and related after cyclization >> Nitrogen Mustards OR SN2 >> Alkylation, direct acting epoxides and related after P450-mediated metabolic activation OR SN2 >> Alkylation, direct acting epoxides and related after P450-mediated metabolic activation >> Haloalkenes with Electron-Withdrawing Groups OR SN2 >> Alkylation, direct acting epoxides and related after P450-mediated metabolic activation >> Polycyclic Aromatic Hydrocarbon Derivatives OR SN2 >> Alkylation, nucleophilic substitution at sp3-carbon atom OR SN2 >> Alkylation, nucleophilic substitution at sp3-carbon atom >> Sulfonates and Sulfates OR SN2 >> Alkylation, ring opening SN2 reaction OR SN2 >> Alkylation, ring opening SN2 reaction >> Four- and Five-Membered Lactones OR SN2 >> Direct acting epoxides formed after metabolic activation OR SN2 >> Direct acting epoxides formed after metabolic activation >> Coumarins OR SN2 >> Direct acting epoxides formed after metabolic activation >> Quinoline Derivatives OR SN2 >> Nucleophilic substitution at sp3 Carbon atom OR SN2 >> Nucleophilic substitution at sp3 Carbon atom >> Haloalkanes Containing Heteroatom OR SN2 >> Nucleophilic substitution at sp3 Carbon atom >> Specific Acetate Esters OR SN2 >> Ring opening SN2 reaction OR SN2 >> Ring opening SN2 reaction >> Sultones OR SN2 >> SN2 at an activated carbon atom OR SN2 >> SN2 at an activated carbon atom >> Quinoline Derivatives by DNA binding by OASIS v.1.3

Domain logical expression index: "f"

Referential boundary: The target chemical should be classified as No alert found by DNA binding by OECD

Domain logical expression index: "g"

Referential boundary: The target chemical should be classified as Michael addition OR Michael addition >> P450 Mediated Activation of Heterocyclic Ring Systems OR Michael addition >> P450 Mediated Activation of Heterocyclic Ring Systems >> Furans OR Michael addition >> P450 Mediated Activation to Quinones and Quinone-type Chemicals OR Michael addition >> P450 Mediated Activation to Quinones and Quinone-type Chemicals >> Arenes OR Michael addition >> P450 Mediated Activation to Quinones and Quinone-type Chemicals >> Hydroquinones OR Michael addition >> Polarised Alkenes-Michael addition OR Michael addition >> Polarised Alkenes-Michael addition >> Alpha, beta- unsaturated esters OR SN1 OR SN1 >> Carbenium Ion Formation OR SN1 >> Carbenium Ion Formation >> Allyl benzenes OR SN1 >> Iminium Ion Formation OR SN1 >> Iminium Ion Formation >> Aliphatic tertiary amines OR SN1 >> Nitrenium Ion formation OR SN1 >> Nitrenium Ion formation >> Aromatic nitro OR SN1 >> Nitrenium Ion formation >> Primary aromatic amine OR SN1 >> Nitrenium Ion formation >> Secondary aromatic amine OR SN1 >> Nitrenium Ion formation >> Tertiary aromatic amine OR SN2 OR SN2 >> SN2 at an sp3 Carbon atom OR SN2 >> SN2 at an sp3 Carbon atom >> Sulfonates by DNA binding by OECD

Domain logical expression index: "h"

Referential boundary: The target chemical should be classified as Non binder, without OH or NH2 group by Estrogen Receptor Binding

Domain logical expression index: "i"

Referential boundary: The target chemical should be classified as Non binder, impaired OH or NH2 group OR Non binder, MW>500 OR Non binder, non cyclic structure by Estrogen Receptor Binding

Domain logical expression index: "j"

Referential boundary: The target chemical should be classified as SN2 AND SN2 >> SN2 Reaction at a sp3 carbon atom AND SN2 >> SN2 Reaction at a sp3 carbon atom >> Activated alkyl esters and thioesters  by Protein binding by OASIS v1.3 ONLY

Domain logical expression index: "k"

Parametric boundary:The target chemical should have a value of log Kow which is >= 3.35

Domain logical expression index: "l"

Parametric boundary:The target chemical should have a value of log Kow which is <= 13.4

Conclusions:

(2E)-3-phenylprop-2-en-1-yl butanoate was predicted to not induce gene mutation in Salmonella typhimurium strains TA 1535, TA 1537, TA 98, TA 100 and TA 102 in the presence of S9 metabolic activation system and hence, according to the prediction made, it is not likely to classify as a gene mutant in vitro.

Executive summary:

Based on the prediction done using the OECD QSAR toolbox version 3.3 with log kow as the primary descriptor and considering the five closest read across substances, gene mutation was predicted for (2E)-3-phenylprop-2-en-1-yl butanoate. The study assumed the use of Salmonella typhimurium strains TA 1535, TA 1537, TA 98, TA 100 and TA 102 with S9 metabolic activation system. (2E)-3-phenylprop-2-en-1-yl butanoate was predicted to not induce gene mutation in Salmonella typhimurium strains TA 1535, TA 1537, TA 98, TA 100 and TA 102 in the presence of S9 metabolic activation system and hence, according to the prediction made, it is not likely to classify as a gene mutant in vitro.

Based on the predicted result it can be concluded that the substance is considered to not toxic as per the criteria mentioned in CLP regulation.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (negative)

Genetic toxicity in vivo

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

Gene mutation in vitro:

Prediction model based estimation and data from read across chemicals have been reviewed to determine the mutagenic nature of Cinnamyl butyrate. The studies are as mentioned below:

Based on the prediction done using the OECD QSAR toolbox version 3.3 with log kow as the primary descriptor and considering the five closest read across substances, gene mutation was predicted for (2E)-3-phenylprop-2-en-1-yl butanoate. The study assumed the use of Salmonella typhimurium strains TA 1535, TA 1537, TA 98, TA 100 and TA 102 with and without S9 metabolic activation system. (2E)-3-phenylprop-2-en-1-yl butanoate was predicted to not induce gene mutation in Salmonella typhimurium strains TA 1535, TA 1537, TA 98, TA 100 and TA 102 in the presence and absence of S9 metabolic activation system and hence, according to the prediction made, it is not likely to classify as a gene mutant in vitro.

Gene mutation toxicity was predicted for cinnamyl butyrate using the battery approach from Danish QSAR database (2017). The study assumed the use of Salmonella typhimurium bacteria in the Ames test. The end point for gene mutation has been modeled in the Danish QSAR using the three software systems Leadscope, CASE Ultra and SciQSAR. Based on predictions from these three systems, a fourth and overall battery prediction is made. The battery prediction is made using the so called Battery algorithm. With the battery approach it is in many cases possible to reduce “noise” from the individual model estimates and thereby improve accuracy and/or broaden the applicability domain. Gene mutation toxicity study as predicted by Danish QSAR forCinnamyl butyrate is negative and hence the chemical is predicted to not classify as a gene mutant in vitro.

The ability of cinnamyl butyrate to induce chromosomal aberration was predicted using Chinese hamster lung (CHL) cells using Danish QSAR database (2017). The end point for chromosome aberrations has been modeled in the Danish QSAR using the three software systems Leadscope, CASE Ultra and SciQSAR. Based on predictions from these three systems, a fourth and overall battery prediction is made. The battery prediction is made using the so called Battery algorithm. With the battery approach it is in many cases possible to reduce “noise” from the individual model estimates and thereby improve accuracy and/or broaden the applicability domain. Cinnamyl butyrate does notinduce chromosome aberrations in Chinese hamster lung (CHL) cells and hence is predicted to not classify as a gene mutant in vitro.

The predicted data for the target chemical is further supported by the data from read across chemicals.

In a study for 91% structurally similar read across chemical by Ishidate et al (Food and Chemical toxiciology, 1984), Gene mutation toxicity study was performed to determine the mutagenic nature of ethyl cinnamate (RA CAS no 103 -36 -6; IUPAC name: ethyl (2E)-3-phenylprop-2-enoate). The study was performed using S. typhimurium strains TA92, TA1535, TA100, TA1537, TA94 and TA98 with and without S9 metabolic activation system. The test was performed as per the preincubation assay at six different concentrations with 5.0 mg/plate being the maximum concentration. The chemical was dissolved in DMSO. Preincubation was performed for 20 mins and the exposure duration was for 48 hrs. The result was considered positive if the number of colonies found was twice the number in the control (exposed to the appropriate solvent or untreated). Ethyl cinnamate did not induce a doubling of revertant colonies over the control using S. typhimurium strains TA92, TA1535, TA100, TA1537, TA94 and TA98 in the presence and absence of S9 metabolic activation system and hence the chemical is not likely to classify as a gene mutant in vitro.

In a study for another 91% structurally similar read across chemical by Wild et al (Food and Chemical Toxicology, 1983), Allyl cinnamate (RA CAS no 1866 -31 -5; IUPAC name: prop-2-en-1-yl (2E)-3-phenylprop-2-enoate) artificial flavouring substance in food products was studied for mutagenic properties by the use of the Salmonella/mammalian microsome test (Ames test). The test was performed by plate incorporation method at 5 different dosesupto 3600 µg/plate using Salmonella typhimurium TA98, TA100, TA1535, TA1537, TA1538 with and without S9 metabolic activation system and the plates were incubated for 48 hrs. Concurrent positive control chemicals were incorporated in the study. A reproducible, dose-related and at least two-fold elevation of the spontaneous revertant frequency. Agents producing reproducible, dose-related and significant (P≤0.01) but less than two-fold elevations were classified as marginally mutagenic under the experimental conditions. Allyl cinnamate did not cause a reproducible, dose-related and at least two-fold elevation of the spontaneous revertant frequency and hence the chemical is not mutagenic in the Salmonella/microsome AMES test performed using Salmonella typhimurium TA98, TA100, TA1535, TA1537, TA1538 in the presence and absence of S9 metabolic activation system.

Based on the data available for the target chemical and it read across, Cinnamyl butyrate does not exhibit gene mutation in vitro. Hence the test chemical is not likely to classify as a gene mutant as per the criteria mentioned in CLP regulation.

Justification for classification or non-classification

Based on the data available for the target chemical and it read across, Cinnamyl butyrate (CAS no 103 -61 -7) does not exhibit gene mutation in vitro. Hence the test chemical is not likely to classify as a gene mutant as per the criteria mentioned in CLP regulation.