Phenethyl isovalerate

Endpoint summary

Key value for chemical safety assessment

Genetic toxicity in vitro

Description of key information

The test material Phenethyl isovalerate is not mutagenic in vitro in Salmonella typhimurium strain TA 97 and TA 102 with and without S9 metabolic activation system.

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)

Justification for type of information:

QSAR prediction: migrated from IUCLID 5.6

Qualifier:

according to guideline

Guideline:

other: Predicted data

Principles of method if other than guideline:

Prediction is done using QSAR Toolbox version 3.3

GLP compliance:

not specified

Type of assay:

bacterial reverse mutation assay

Target gene:

No data

Species / strain / cell type:

S. typhimurium, other: TA 97 and TA 102

Details on mammalian cell type (if applicable):

Not applicable

Additional strain / cell type characteristics:

not specified

Metabolic activation:

with and without

Metabolic activation system:

S9 mix

Test concentrations with justification for top dose:

No data

Vehicle / solvent:

Yes

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:

METHOD OF APPLICATION:in agar

Evaluation criteria:

No data

Statistics:

No data

Species / strain:

S. typhimurium, other: TA 97 and TA 102

Metabolic activation:

with and without

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

Remarks on result:

other: all strains/cell types tested

Remarks:

Migrated from field 'Test system'.

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" or "d" or "e" )  and ("f" and ( not "g") )  )  and ("h" and ( not "i") )  )  and "j" )  and "k" )  and ("l" and ( not "m") )  )  and "n" )  and ("o" and ( not "p") )  )  and ("q" and ( not "r") )  )  and ("s" and ( not "t") )  )  and ("u" and "v" )  )

Domain logical expression index: "a"

Referential boundary: The target chemical should be classified as Esters (Acute toxicity) by US-EPA New Chemical Categories

Domain logical expression index: "b"

Referential boundary: The target chemical should be classified as Aryl AND Carboxylic acid ester AND Isopropyl by Organic Functional groups

Domain logical expression index: "c"

Referential boundary: The target chemical should be classified as Aryl AND Carboxylic acid ester AND Isopropyl by Organic Functional groups (nested)

Domain logical expression index: "d"

Referential boundary: The target chemical should be classified as Aliphatic Carbon [CH] AND Aliphatic Carbon [-CH2-] AND Aliphatic Carbon [-CH3] AND Aromatic Carbon [C] AND Carbonyl, aliphatic attach [-C(=O)-] AND Ester, aliphatic attach [-C(=O)O] AND Miscellaneous sulfide (=S) or oxide (=O) AND Olefinic carbon [=CH- or =C<] AND Tertiary Carbon by Organic functional groups (US EPA)

Domain logical expression index: "e"

Referential boundary: The target chemical should be classified as Aromatic compound AND Carbonic acid derivative AND Carboxylic acid derivative AND Carboxylic acid ester by Organic functional groups, Norbert Haider (checkmol)

Domain logical expression index: "f"

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

Domain logical expression index: "g"

Referential boundary: The target chemical should be classified as AN2 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 >> Schiff base formation by aldehyde formed after metabolic activation OR AN2 >> Schiff base formation by aldehyde formed after metabolic activation >> Geminal Polyhaloalkane Derivatives OR AN2 >> Shiff base formation after aldehyde release OR AN2 >> Shiff base formation after aldehyde release >> Specific Acetate Esters OR AN2 >> Shiff base formation for aldehydes OR AN2 >> Shiff base formation for aldehydes >> Geminal Polyhaloalkane Derivatives OR AN2 >> Shiff base formation for aldehydes >> Haloalkane Derivatives with Labile Halogen OR Michael addition OR Michael addition >> Quinone type compounds OR Michael addition >> Quinone type compounds >> Quinone methides OR Non-covalent interaction OR Non-covalent interaction >> DNA intercalation OR Non-covalent interaction >> DNA intercalation >> DNA Intercalators with Carboxamide Side Chain 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) >> Geminal Polyhaloalkane Derivatives OR Radical >> Radical mechanism via ROS formation (indirect) >> p-Substituted Mononitrobenzenes OR Radical >> ROS formation after GSH depletion OR Radical >> ROS formation after GSH depletion >> Quinone methides OR SN1 OR SN1 >> Nucleophilic attack after carbenium ion formation OR SN1 >> Nucleophilic attack after carbenium ion formation >> Specific Acetate Esters OR SN1 >> Nucleophilic attack after reduction and nitrenium ion formation 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 >> Acylation involving a leaving group  OR SN2 >> Acylation involving a leaving group  >> Geminal Polyhaloalkane Derivatives OR SN2 >> Acylation involving a leaving group  >> Haloalkane Derivatives with Labile Halogen OR SN2 >> Acylation involving a leaving group after metabolic activation OR SN2 >> Acylation involving a leaving group after metabolic activation >> Geminal Polyhaloalkane Derivatives OR SN2 >> Alkylation, direct acting epoxides and related OR SN2 >> Alkylation, direct acting epoxides and related >> Epoxides and Aziridines 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, nucleophilic substitution at sp3-carbon atom OR SN2 >> Alkylation, nucleophilic substitution at sp3-carbon atom >> Haloalkane Derivatives with Labile Halogen OR SN2 >> Alkylation, ring opening SN2 reaction OR SN2 >> Alkylation, ring opening SN2 reaction >> Four- and Five-Membered Lactones OR SN2 >> DNA alkylation OR SN2 >> DNA alkylation >> Alkylphosphates, Alkylthiophosphates and Alkylphosphonates 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 >> Nucleophilic substitution at sp3 carbon atom after thiol (glutathione) conjugation OR SN2 >> Nucleophilic substitution at sp3 carbon atom after thiol (glutathione) conjugation >> Geminal Polyhaloalkane Derivatives by DNA binding by OASIS v.1.3

Domain logical expression index: "h"

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

Domain logical expression index: "i"

Referential boundary: The target chemical should be classified as Acylation OR Acylation >> Direct Acylation Involving a Leaving group OR Acylation >> Direct Acylation Involving a Leaving group >> Acetates OR Michael addition OR Michael addition >> Polarised Alkenes OR Michael addition >> Polarised Alkenes >> Polarised alkene - esters OR 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

Domain logical expression index: "j"

Referential boundary: The target chemical should be classified as No superfragment by Superfragments ONLY

Domain logical expression index: "k"

Referential boundary: The target chemical should be classified as Bioavailable by Lipinski Rule Oasis ONLY

Domain logical expression index: "l"

Referential boundary: The target chemical should be classified as Not categorized by Repeated dose (HESS)

Domain logical expression index: "m"

Referential boundary: The target chemical should be classified as Chlorphentermine (Hepatotoxicity) Alert OR Oxyphenistain (Hepatotoxicity) Alert OR Phthalate esters (Testicular toxicity) Rank C OR Valproic acid (Hepatotoxicity) Alert by Repeated dose (HESS)

Domain logical expression index: "n"

Similarity boundary:Target: CC(C)CC(=O)OCCc1ccccc1
Threshold=10%,
Dice(Atom centered fragments)
Atom type; Count H attached; Hybridization

Domain logical expression index: "o"

Referential boundary: The target chemical should be classified as Non-Metals by Groups of elements

Domain logical expression index: "p"

Referential boundary: The target chemical should be classified as Halogens by Groups of elements

Domain logical expression index: "q"

Referential boundary: The target chemical should be classified as Group 14 - Carbon C AND Group 16 - Oxygen O by Chemical elements

Domain logical expression index: "r"

Referential boundary: The target chemical should be classified as Group 15 - Nitrogen N by Chemical elements

Domain logical expression index: "s"

Referential boundary: The target chemical should be classified as Not classified by Oncologic Primary Classification

Domain logical expression index: "t"

Referential boundary: The target chemical should be classified as Phenol Type Compounds by Oncologic Primary Classification

Domain logical expression index: "u"

Parametric boundary:The target chemical should have a value of log Kow which is >= 3.48

Domain logical expression index: "v"

Parametric boundary:The target chemical should have a value of log Kow which is <= 4.46

Conclusions:

Interpretation of results (migrated information):negative with and withoutThe test material Phenethyl isovalerate is not mutagenic in vitro in Salmonella typhimurium strain TA 97 and TA 102 with and without S9 metabolic activation system.

Executive summary:

Gene mutation was predicted using SSS QSAR prediction model, 2016. The study used Salmonella typhimurium TA97 and TA102 strain and S9 metabolic activation system. The test material Phenethyl isovalerate is not mutagenic in vitro in Salmonella typhimurium strain TA 97 and TA 102 with and without S9 metabolic activation system.

As per the CLP classification, the test material is not mutagenic in vitro.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (negative)

Additional information

Additional information from genetic toxicity in vitro:

Prediction model based estimation and data from the read across chemicals have been used to determine the mutagenic nature of the test compound Phenethyl isovalerate (CAS no 140 -26 -1). The summary is as below:

Gene mutation in vitro:

Gene mutation was predicted using SSS QSAR prediction model, 2016. The study used Salmonella typhimurium TA97 and TA102 strain and S9 metabolic activation system. The test material Phenethyl isovalerate is not mutagenic in vitro in Salmonella typhimurium strain TA 97 and TA 102 with and without S9 metabolic activation system.

 

Gene mutation was predicted using SSS QSAR prediction model, 2016. The study used Salmonella typhimuriumTA1535, TA1537, TA98 and TA100 strain and S9 metabolic activation system. The test material Phenethyl isovalerate is not mutagenic in vitro in Salmonella typhimurium strain TA 97 and TA 102 with and without S9 metabolic activation system.

 

Based on the QSAR prediction done using the Danish (Q)SAR Database (2016), the genetic toxicity was estimated to be negative during Ames test in S. typhimurium TA 1535, TA 1537, TA 98 and TA 100. Thus it can be concluded that the substance Phenethyl isovalerate is non mutagenic and based on the CLP criteria for classification it can be not classified for genetic toxicity.

Genetox study for Isoamyl phenylacetate (RA CAS no 102 -19 -2) in Bacillus subtilis strain H17(rec+) and M45 (rec-) by Rec assay was conducted at the concentration of 20 μg/disk. At this concentration the result of Rec assay in Bacillus. Subtilis strainH17(rec+) and M45 (rec-) was found to be negative (Adams et al, 2005).

The mutagenicity of total particulate matter (TPM) in study 1 cigarettes was investigated (Renne et al, 2006) using an Ames assay protocol that conformed to OECD Guideline 471. For this purpose, prototype cigarettes containing a mixture of ingredients, reference cigarettes without these ingredients, and 2R4F cigarettes (a standard reference cigarette). The concentration of benzyl phenylacetate (RA CAS no 102 -16 -2) in the study 1 is 0.0026mg/lt. Each sample was tested with and without S9 metabolic activation in five strains of Salmonella typhimurium: TA98, TA100, TA102, TA1535, and TA1537.Evaluation of the Ames assay data was carried out in terms of the mutagenic response, taking into consideration the reproducibly dose-related increase in number of revertants, even if the increase was less than twofold. The results of Ames assays on test cigarettes from study 1 with and without metabolic activation. TA100, TA98, and TA1537 strains spohowed a positive response only with metabolic activation. No response was observed in TA 102 or TA1535. No sporadic responses in revertants were recorded. The highest sensitivity and specificity of the mutagenic response were observed using TA98 with metabolic activation. From the comparison of the data obtained for the test and reference cigarettes, it was concluded that the addition of ingredients did not result in a positive mutagenic response in any of the strains under the conditions already described. Isoamyl phenylacetate can be considered to be non mutagenic at a test concentration of 0.0065mg/l under the test conditions.

The test substance, benzyl propionate did not induce mutagenicity in an Ames assay conducted on S. typhimurium TA 1535, TA 1537, TA 98, TA 100 and TA 102 strains with and without S9 activation (Renne et al, 2006).

The test substance, benzyl propionate (RA CAS no 122 -63 -4) did not induce mutagenicity in an Ames assay conducted on S. typhimurium TA 1535, TA 1537, TA 98, TA 100 and TA 102 strains with and without rat liver S9 activation. Although positive response is observed in some strains, there were also no apparent trends discernible that would suggest a change in mutagenic activity caused by the addition of the ingredients (Roomer et al, 2002).

As per the CLP classification and the weight of evidence used, the test material Phenethyl isovalerate (CAS no 140 -26 -1) is not likely to be a gene mutagen in vitro.

Justification for selection of genetic toxicity endpoint
Gene mutation was predicted using SSS QSAR prediction model, 2016. The study used Salmonella typhimurium TA97 and TA102 strain and S9 metabolic activation system. The test material Phenethyl isovalerate is not mutagenic in vitro in Salmonella typhimurium strain TA 97 and TA 102 with and without S9 metabolic activation system.

Justification for classification or non-classification

As per the CLP classification and the weight of evidence used, the test material Phenethyl isovalerate (CAS no 140 -26 -1) is not likely to be mutagenic in vitro.