3-phenylpropionyl chloride

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  3 phenylpropionyl chloride. The study assumed the use of Salmonella typhimurium strainsTA 1535, TA 1537, TA 98, TA 100 and TA 102 with S9 metabolic activation system 3 phenylpropionyl chloride 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:

equivalent or similar to guideline

Guideline:

other: Refer below principle

Principles of method if other than guideline:

Prediction was done using OECD QSAR toolbox v3.3, 2017

GLP compliance:

not specified

Type of assay:

bacterial reverse mutation assay

Specific details on test material used for the study:

- Name of test material (as cited in study report): 3 phenylpropionyl chloride- Molecular formula:C9H9ClO- Molecular weight :168.622- Substance type: organic- Physical state: solid -Purity: No data available - Impurities (identity and concentrations): No data avaliable

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):

No data avaliable

Additional strain / cell type characteristics:

not specified

Cytokinesis block (if used):

No data avaliable

Metabolic activation:

with

Metabolic activation system:

S9 metabolic activation system

Test concentrations with justification for top dose:

No data avaliable

Vehicle / solvent:

No data avaliable

Untreated negative controls:

not specified

Negative solvent / vehicle controls:

not specified

True negative controls:

not specified

Positive controls:

not specified

Details on test system and experimental conditions:

No data avaliable

Rationale for test conditions:

No data avaliable

Evaluation criteria:

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

Statistics:

No data avaliable

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

The prediction was based on dataset comprised from the following descriptors: "Gene mutation"
Estimation method: Takes highest mode value from the 6 nearest neighbours
Domain  logical expression:Result: In Domain

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

Domain logical expression index: "a"

Referential boundary: The target chemical should be classified as Acylation OR Acylation >> Direct Addition of an Acyl Halide OR Acylation >> Direct Addition of an Acyl Halide >> Acyl halide OR Michael addition 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 by DNA binding by OECD ONLY

Domain logical expression index: "b"

Referential boundary: The target chemical should be classified as Acylation AND Acylation >> Direct acylation involving a leaving group AND Acylation >> Direct acylation involving a leaving group >> (Thio)Acyl and (thio)carbamoyl halides and cyanides  by Protein binding by OASIS v1.3

Domain logical expression index: "c"

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 >> (Thio)Acyl and (thio)carbamoyl halides and cyanides  by Protein binding by OASIS v1.3 ONLY

Domain logical expression index: "d"

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 >> Acyl halides (including benzyl and carbamoyl deriv.) by Protein binding by OECD

Domain logical expression index: "e"

Referential boundary: The target chemical should be classified as Acylation AND Acylation >> Direct acylation involving a leaving group AND Acylation >> Direct acylation involving a leaving group >> (Thio)Acyl and (thio)carbamoyl halides and cyanides  by Protein binding alerts for skin sensitization by OASIS v1.3

Domain logical expression index: "f"

Referential boundary: The target chemical should be classified as Acylation >> Acyl transfer via nucleophilic addition reaction OR Acylation >> Acyl transfer via nucleophilic addition reaction >> Carbodiimides OR Acylation >> Acyl transfer via nucleophilic addition reaction >> Isocyanates, Isothiocyanates  OR Acylation >> Direct acylation involving a leaving group >> (Thio)Acetates  OR Acylation >> Direct acylation involving a leaving group >> Anhydrides (sulphur analogues of anhydrides)  OR Acylation >> Direct acylation involving a leaving group >> Azlactones and unsaturated lactone derivatives  OR Acylation >> Direct acylation involving a leaving group >> Carbamates  OR Acylation >> Direct acylation involving a leaving group >> Diacyl peroxides, anhydrides (sulphur analogues of diacyl peroxides)   OR Acylation >> Direct acylation involving a leaving group >> N-Acylated heteroaromatic amines  OR Acylation >> Direct acylation involving a leaving group >> N-Acylsulfonamides  OR Acylation >> Direct acylation involving a leaving group >> N-Haloacylamides  OR Acylation >> Direct acylation involving a leaving group >> Sulphonyl halides or cyanides  OR Acylation >> Ester aminolysis OR Acylation >> Ester aminolysis >> Amides OR Acylation >> Ester aminolysis >> Dithiocarbamates OR Acylation >> Ester aminolysis or thiolysis OR Acylation >> Ester aminolysis or thiolysis >> Activated aryl esters  OR Acylation >> Ring opening acylation OR Acylation >> Ring opening acylation >> Active cyclic agents  OR Acylation >> Ring opening acylation >> beta-Lactams  OR Michael Addition OR Michael Addition >> alpha,beta-Unsaturated carbonyl compounds OR Michael Addition >> alpha,beta-Unsaturated carbonyl compounds >> Lactones OR Michael Addition >> Michael addition on conjugated systems with electron withdrawing group OR Michael Addition >> Michael addition on conjugated systems with electron withdrawing group >> Activated electrophilic ethenylarenes  OR Michael Addition >> Michael addition on conjugated systems with electron withdrawing group >> alpha,beta-Carbonyl compounds with polarized double bonds  OR Michael Addition >> Michael addition on conjugated systems with electron withdrawing group >> Conjugated systems with electron withdrawing groups  OR Michael Addition >> Michael type addition on azoxy compounds OR Michael Addition >> Michael type addition on azoxy compounds >> Azoxy compounds  OR Michael Addition >> Polarised Alkenes OR Michael Addition >> Polarised Alkenes >> Polarised Alkene - alkenyl pyridines, pyrazines, pyrimidines or triazines  OR Michael Addition >> Quinoide type compounds OR Michael Addition >> Quinoide type compounds >> Quinone methide(s)/imines; Quinoide oxime structure; Nitroquinones, Naphthoquinone(s)/imines  OR Michael Addition >> Quinone type chemicals OR Michael Addition >> Quinone type chemicals >> Pyranones, Pyridones (and related nitrogen chemicals)  OR No alert found OR Nucleophilic addition OR Nucleophilic addition >> Addition to carbon-hetero double bonds OR Nucleophilic addition >> Addition to carbon-hetero double bonds >> Ketones OR Nucleophilic addition >> Nucleophilic addition reaction at polarized N-functional double bond OR Nucleophilic addition >> Nucleophilic addition reaction at polarized N-functional double bond >> C-Nitroso compounds  OR Radical reactions OR Radical reactions >> Free radical formation OR Radical reactions >> Free radical formation >> Hydroperoxides OR Schiff base formation OR Schiff base formation >> Direct acting Schiff base formers OR Schiff base formation >> Direct acting Schiff base formers >> 1,2-Dicarbonyls and 1,3-Dicarbonyls  OR Schiff base formation >> Pyrazolones and Pyrazolidinones derivatives OR Schiff base formation >> Pyrazolones and Pyrazolidinones derivatives >> Pyrazolones and Pyrazolidinones  OR Schiff base formation >> Schiff base formation with carbonyl compounds OR Schiff base formation >> Schiff base formation with carbonyl compounds >> Aldehydes OR SN2 OR SN2 >> Interchange reaction with sulphur containing compounds OR SN2 >> Interchange reaction with sulphur containing compounds >> Thiols and disulfide compounds  OR SN2 >> Nucleophilic substitution at a Nitrogen atom OR SN2 >> Nucleophilic substitution at a Nitrogen atom >> N-Nitroso compounds  OR SN2 >> Nucleophilic substitution at a Nitrogen atom >> N-Oxicarbonyl amides, N-Acyloxy-N-alkoxyamides  OR SN2 >> Nucleophilic substitution at sp3 carbon atom OR SN2 >> Nucleophilic substitution at sp3 carbon atom >> (Thio)Phosphates  OR SN2 >> Nucleophilic substitution at sp3 carbon atom >> Alkyl halides  OR SN2 >> Nucleophilic substitution at sp3 carbon atom >> alpha-Activated haloalkanes  OR SN2 >> Nucleophilic substitution at sp3 carbon atom >> N-Nitroso compounds  OR SN2 >> Nucleophilic substitution at the central carbon atom of N-nitroso compounds OR SN2 >> Nucleophilic substitution at the central carbon atom of N-nitroso compounds >> N-Nitroso_compounds  OR SN2 >> Nucleophilic substitution on benzilyc carbon atom OR SN2 >> Nucleophilic substitution on benzilyc carbon atom >> alpha-Activated benzyls  OR SN2 >> Ring opening SN2 reaction OR SN2 >> Ring opening SN2 reaction >> Epoxides, Aziridines and Sulfuranes  OR SN2 >> SN2 Reaction at a sp3 carbon atom OR SN2 >> SN2 Reaction at a sp3 carbon atom >> Activated alkyl esters and thioesters  OR SN2 >> SN2 reaction at a sulfur atom OR SN2 >> SN2 reaction at a sulfur atom >> Thiocyanates OR SNAr OR SNAr >> Nucleophilic aromatic substitution on activated aryl and heteroaryl compounds OR SNAr >> Nucleophilic aromatic substitution on activated aryl and heteroaryl compounds >> Activated aryl and heteroaryl compounds OR SNVinyl OR SNVinyl >> SNVinyl at a vinylic (sp2) carbon atom OR SNVinyl >> SNVinyl at a vinylic (sp2) carbon atom >> Vinyl type compounds with electron withdrawing groups  by Protein binding alerts for skin sensitization by OASIS v1.3

Domain logical expression index: "g"

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

Domain logical expression index: "h"

Referential boundary: The target chemical should be classified as Alpha, beta-Haloether Reactive Functional Groups OR Alpha-Haloalkylamine Reactive Functional Groups OR Aromatic Amine Type Compounds OR Carbamyl Halide Type Compounds OR Halogenated Aromatic Hydrocarbon Type Compounds by Oncologic Primary Classification

Domain logical expression index: "i"

Referential boundary: The target chemical should be classified as (!Undefined)Group All Lipid Solubility < 0.01 g/kg by Eye irritation/corrosion Exclusion rules by BfR

Domain logical expression index: "j"

Referential boundary: The target chemical should be classified as Group CHal Melting Point > 65 C by Eye irritation/corrosion Exclusion rules by BfR

Domain logical expression index: "k"

Referential boundary: The target chemical should be classified as Not known precedent reproductive and developmental toxic potential by DART scheme v.1.0

Domain logical expression index: "l"

Referential boundary: The target chemical should be classified as Known precedent reproductive and developmental toxic potential OR Toluene and small alkyl toluene derivatives (8a) by DART scheme v.1.0

Domain logical expression index: "m"

Similarity boundary:Target: O=C(Cl)CCc1ccccc1
Threshold=20%,
Dice(Atom centered fragments)
Atom type; Count H attached; Hybridization

Domain logical expression index: "n"

Similarity boundary:Target: O=C(Cl)CCc1ccccc1
Threshold=100%,
Dice(Atom centered fragments)
Atom type; Count H attached; Hybridization

Domain logical expression index: "o"

Parametric boundary:The target chemical should have a value of log Kow which is >= -0.473

Domain logical expression index: "p"

Parametric boundary:The target chemical should have a value of log Kow which is <= 2.47

Conclusions:

3 phenylpropionyl chloride 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  3 phenylpropionyl chloride. The study assumed the use of Salmonella typhimurium strainsTA 1535, TA 1537, TA 98, TA 100 and TA 102 with S9 metabolic activation system 3 phenylpropionyl chloride 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)

Additional information

Genetic toxicity in vitro

Prediction model based estimation and data from read across chemicals have been reviewed to determine the mutagenic nature of 3 phenylpropionyl chloride. The summary is 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  3 phenylpropionyl chloride. 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 3 phenylpropionyl chloride 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. 

The experimental study given by Tadamichi Ohkubo, Sumio Gotoz, Osamu Endoz, Tetsuhito Hayashi, Etsuo Watanabe and Hideaki Endo (JEC 6 (4), 533-540, 1996) Mutagenicity test of 3-phenylpropionyl chloride was done using pre-incubation method employing Salmonella typhimuriumTA100,TA 98,TA104 and Escherichia Coli WP2 UVRA/pKM101 with and without metabolic activation (S9mix). Enzyme with polychlorinated biphenyl (PCB, kanechlor-500) (p-450) induced Sprague-Dawley male rats (5 weeks old) of the S9 fraction cryopreservation product were prepared from the liver , test sample were diluted in dimethylsulfoxide(DMSO).Culture medium in large incubator (370C ,48-60 hr ), and then the revertant colonies were counted in automatic colony counter. If the response had more than twice the control (natural variation number of colonies) the mutation is positive ; dose –response relationship if accepted , but false positive if the response is two times less than 1.5 times greater than the control (pseudopositive ). Further, if or when the response dose –response relationship was observed is less than 1.5 times the control were negative. 3- phenylpropionyl chloride was mutagenic in Salmonella typhimurium TA100,TA98,TA104 with and without metabolic activation and mutagenic with and non -mutagenic without metabolic activation in Escherichia Coli WP2UVRA/ pKM101 .Therefore it is considered to be positive with metabolic activation ,negative without metabolic activation for gene mutation in vitro.

 It is further supported by experimental study given by Errol Zeiger, Beth Anderson, Steve Haworth, Timothy Lawlor, Kristien Mortelmans, and William Speck (Environmental Mutagenesis Volume 9, Supplement 9:1-110,1987) on structurally and functionally similar read across substance,Benzyl 2-hydroxybenzoate(118-58-1).Salmonella Mutagenicity Tests of Benzyl 2-hydroxybenzoate was performed in Salmonella strainTA98, TA100, TA1535, and TA 1537.Both in the presence and absence of S9 metabolic activation system. Preincubation protocol was followed. The test compound Benzyl 2-hydroxybenzoate was dissolved in DMSO to made dose concentration 0.000 , 0.3000 ,1.000 , 3.300 , 10.000 , 20.000 ,33.000 ,100.000 ,330.000 ,666.000µg/plate in triplicate for 48 hr.The S-9 fractions of Aroclor 1254-induced, male Sprague-Dawley rat and male Syrian hamster livers were prepared were as 2-aminoanthracene served positive control with S9 fraction for all strain Salmonella typhimurium and sodium azide (TA1535 and TA 100), 9-aminoacridine (TA97 and TA1S37),and4-nitro-o-phenylenediamine(TA98) served as positive control without S9 fraction . Mutagenicity evaluated by counting histidine revertant (his') colonies arising on these plates. As Benzyl 2-hydroxybenzoate did not produce mutation in Salmonella strain TA98, TA100, TA1535, and TA 1537, Therefore it is considered to be negative for gene mutation in vitro.

It also supported by experiment given by Errol Zeiger, Beth Anderson, Steve Haworth, Timothy Lawlor, and Kristien Mortelmans (Environmental and Molecular Mutagenesis Volume 19, Supplement 21 :2-141 (1992)) SalmonellaMutagenicity Tests of Ethyl benzene was performed in Salmonella strain TA98, TA 100, TA100 and TA1535.Both in the presence and absence of S9 metabolic activation system. Preincubation protocol was followed. The test compound Ethyl benzene was dissolved in DMSO to made dose concentration0.000, 10.000, 33.000, 100.000, 333.000, 666.000, 1000.000µg/plate in duplicate for 48 hr. The S-9 fractions of Aroclor 1254-induced, male Sprague-Dawley rat and male Syrian hamster livers were prepared were as2-aminoanthracene served positive control with S9 fraction for all strain of Salmonella typhimurium and sodium azide (TA1535 and TA 100), 9-aminoacridine (TA97 and TA1S37),and 4-nitro-o-phenylenediamine(TA98) served as positive control without S9 fraction. Mutagenicity evaluated by counting histidine-revertant (his') colonies arising on these plates. As Ethyl benzene did not produce mutation in Salmonella strainTA98, TA 100, TA100 and TA1535, Therefore it is considered to be negative for gene mutation in vitro.

Based on the data available for the target chemical and its read across 3 phenyl propionyl chloride (645-45-4 ) does not exhibit gene mutation in vitro. Expect data form the experimental study given by Tadamichi Ohkuboet.al (JEC 6 (4), 533-540, 1996)3-phenylpropionyl chloride was mutagenic in Salmonella typhimurium TA100, TA98, TA104with and without metabolic activation and mutagenic with metabolic activation and non-mutagenic without metabolic activation in Escherichia Coli WP2 UVRA/pKM101 therefore it is considered to be Positive with metabolic activation, negative without metabolic activation for gene mutation in vitro. But this data has low reliability and in Japanese language not much data has been extracted Since estimated data from using the OECD QSAR toolbox version 3.3 for the target chemical and its read across 3 phenyl propionyl chloride (645-45-4) it is considered to be non-mutagenic in vitro. Hence the test chemical is not likely to classify as a gene mutant in vitro.

Justification for classification or non-classification

Based on the data available for the target chemical and its read across 3 phenyl propionyl chloride (645-45-4 ) does not exhibit gene mutation in vitro. Expect data form the experimental study given by Tadamichi Ohkuboet.al (JEC 6 (4), 533-540, 1996)3-phenylpropionyl chloride was mutagenic in Salmonella typhimurium TA100, TA98, TA104with and without metabolic activation and mutagenic with metabolic activation and non-mutagenic without metabolic activation in Escherichia Coli WP2 UVRA/pKM101 therefore it is considered to be Positive with metabolic activation, negative without metabolic activation for gene mutation in vitro. But this data has low reliability and in Japanese language not much data has been extracted Since estimated data from using the OECD QSAR toolbox version 3.3 for the target chemical and its read across 3 phenyl propionyl chloride (645-45-4) it is considered to be non-mutagenic in vitro. Hence the test chemical is not likely to classify as a gene mutant in vitro.