4-methoxyphenylacetic acid

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 3.4 with log kow as the primary descriptor and considering the five closest read across substances, gene mutation was predicted for 4-methoxyphenylacetic acid. The study assumed the use of Salmonella typhimurium strain TA100 with S9 metabolic activation system. 4-methoxyphenylacetic acid failed to induce mutation in Salmonella typhimurium strain TA100 with S9 metabolic activation system and hence is predicted to not classify for gene mutation in vitro.

Based on this value 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:

Prediction is done using OECD QSAR toolbox version 3.4 and the supporting QMRF report has been attached.

Qualifier:

no guideline available

Principles of method if other than guideline:

Prediction is done using QSAR Toolbox version 3.4 with respect to the descriptor log Kow

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: 4-methoxyphenylacetic acid
- Molecular formula: C9H10O3
- Molecular weight: 166.175 g/mol
- Substance type: Organic
- Purity: No data

Target gene:

Histidine

Species / strain / cell type:

S. typhimurium TA 100

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 TA 100

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

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" )  )

Domain logical expression index: "a"

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

Domain logical expression index: "b"

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

Domain logical expression index: "c"

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

Domain logical expression index: "d"

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

Domain logical expression index: "e"

Referential boundary: The target chemical should be classified as No alert found by DNA binding by OASIS v.1.4

Domain logical expression index: "f"

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 and Trihydroxybenzenes OR AN2 >> Schiff base formation OR AN2 >> Schiff base formation >> Polarized Haloalkene Derivatives 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 AN2 >> Thioacylation via nucleophilic addition after cysteine-mediated thioketene formation >> Polarized Haloalkene Derivatives OR Non-covalent interaction OR Non-covalent interaction >> DNA intercalation OR Non-covalent interaction >> DNA intercalation >> DNA Intercalators with Carboxamide and Aminoalkylamine Side Chain OR Non-covalent interaction >> DNA intercalation >> Fused-Ring Nitroaromatics OR Non-covalent interaction >> DNA intercalation >> Polycyclic Aromatic Hydrocarbon and Naphthalenediimide Derivatives OR Non-covalent interaction >> DNA intercalation >> Quinones and Trihydroxybenzenes 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) >> Fused-Ring Nitroaromatics OR Radical >> Radical mechanism via ROS formation (indirect) >> Quinones and Trihydroxybenzenes OR SN1 OR SN1 >> Alkylation after metabolically formed carbenium ion species OR SN1 >> Alkylation after metabolically formed carbenium ion species >> Polycyclic Aromatic Hydrocarbon and Naphthalenediimide Derivatives 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 >> Fused-Ring Nitroaromatics 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 and Sulfur 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 >> Polarized Haloalkene Derivatives OR SN2 >> Alkylation, direct acting epoxides and related after P450-mediated metabolic activation >> Polycyclic Aromatic Hydrocarbon and Naphthalenediimide Derivatives OR SN2 >> Alkylation, nucleophilic substitution at sp3-carbon atom OR SN2 >> Alkylation, nucleophilic substitution at sp3-carbon atom >> Haloalkanes Containing Heteroatom 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 >> SN2 at sp3 and activated sp2 carbon atom OR SN2 >> SN2 at sp3 and activated sp2 carbon atom >> Polarized Haloalkene Derivatives by DNA binding by OASIS v.1.4

Domain logical expression index: "g"

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

Domain logical expression index: "h"

Referential boundary: The target chemical should be classified as 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 >> 5-alkoxyindoles OR Michael addition >> P450 Mediated Activation to Quinones and Quinone-type Chemicals >> Alkyl phenols 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 ketones OR Schiff base formers OR Schiff base formers >> Chemicals Activated by P450 to Glyoxal  OR Schiff base formers >> Chemicals Activated by P450 to Glyoxal  >> Ethanolamines (including morpholine) 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 by DNA binding by OECD

Domain logical expression index: "i"

Referential boundary: The target chemical should be classified as No alert found by Protein binding by OASIS v1.4

Domain logical expression index: "j"

Referential boundary: The target chemical should be classified as Acylation OR Acylation >> Ester aminolysis OR Acylation >> Ester aminolysis >> Amides OR Acylation >> Ester aminolysis or thiolysis OR Acylation >> Ester aminolysis or thiolysis >> Activated aryl esters  OR Michael addition OR Michael addition >> Michael addition on conjugated systems with electron withdrawing group OR Michael addition >> Michael addition on conjugated systems with electron withdrawing group >> Cyanoalkenes OR Nucleophilic addition OR Nucleophilic addition >> Addition to carbon-hetero double bonds OR Nucleophilic addition >> Addition to carbon-hetero double bonds >> Ketones by Protein binding by OASIS v1.4

Domain logical expression index: "k"

Referential boundary: The target chemical should be classified as No alert found by Carcinogenicity (genotox and nongenotox) alerts by ISS

Domain logical expression index: "l"

Referential boundary: The target chemical should be classified as Halogenated benzene (Nongenotox) OR Structural alert for nongenotoxic carcinogenicity by Carcinogenicity (genotox and nongenotox) alerts by ISS

Domain logical expression index: "m"

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

Domain logical expression index: "n"

Parametric boundary:The target chemical should have a value of log Kow which is >= 0.493

Domain logical expression index: "o"

Parametric boundary:The target chemical should have a value of log Kow which is <= 2.9

Conclusions:

4-methoxyphenylacetic acid failed to induce mutation in Salmonella typhimurium strain TA100 in the presence of S9 metabolic activation system and hence is predicted to not classify for gene mutation in vitro.

Executive summary:

Based on the prediction done using the OECD QSAR toolbox version 3.4 with log kow as the primary descriptor and considering the six closest read across substances, gene mutation was predicted for 4-methoxyphenylacetic acid. The study assumed the use of Salmonella typhimurium strain TA100 with S9 metabolic activation system. 4-methoxyphenylacetic acid failed to induce mutation in Salmonella typhimurium strain TA100 with S9 metabolic activation system and hence is predicted to not classify for gene mutation in vitro.

Based on this value 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 toxicity in vitro:

Prediction model based estimation and data from target and read across chemical have been reviewed to determine the mutagenic nature of 4 -methoxy phenylacetic acid. 5 studies are summarized as below.

Study 1 and Study 2- Predicted data:

Based on the prediction done using the OECD QSAR toolbox version 3.4 with log kow as the primary descriptor and considering the five closest read across substances, gene mutation was predicted for 4-methoxyphenylacetic acid. The study assumed the use of Salmonella typhimurium strain TA100 with S9 metabolic activation system and strain TA1535 without S9 metabolic activation system. 4-methoxyphenyl)acetic acid failed to induce mutation in Salmonella typhimurium strain TA100 in the presence of S9 metabolic activation system and in strain TA1535 in the absence of S9 metabolic activation system and hence is predicted to not classify for gene mutation in vitro.

Study 3:

Ames Salmonella/ Microsome Reverse Mutation test was performed (NTRL Report, 1991) to test the mutagenic activity of 4 -methoxyphenylacetic acid (CAS no 104 -01 -8) in five Salmonella typhimurium tester strains with five concentrations ranging between 100-10000 µg/plate both in the presence and absence of S9 metabolic activation system. The doses were selected on the basis of dose range finding study to determine toxicity. The preliminary study was performed using Salmonella typhimurium strain TA100 in the presence and absence of S9 metabolic activation system. No toxicity was noted at the mentioned dose level. The main study was performed in triplicate with concurrent negative and positive controls by the plate incorporation protocol. No positive responses were noted in the preliminary and confirmatory mutagenicity studies. 4-methoxyphenylacetic acid (MPAA) did not exhibit mutagenicity in salmonella typhimurium strains under the test conditions with and without metabolic activation system.

Study 4:

Gene mutation toxicity study was performed by kadotani et al (1984) to determine the mutagenic nature of 60 -70 % structurally similar Naproxen (RA CAS no 22204 -53 -1). The study was performed using Salmonella typhimurium strain TA100, TA1537, TA1538 and TA98 and E. coli B/r WP2 uvr-with S9 metabolic activation system. Naproxen was studied at dose level of 5.7-5714µg/plate and the plates were incubated for 44 hrs at 37°C. The plates were observed for a dose dependent increase in the number of revertants/plate and the colonies were counted by a TOYO Colony Analyzer CA-7. Naproxen failed to induce mutation in Salmonella typhimurium strain TA100, TA1537, TA1538 and TA98 and E. coli B/r WP2 uvr-in the presence of S9 metabolic activation system and hence does classify as a gene mutation in vitro.

Study 5:

Ames Salmonella plate-incorporation assay was also performed for structurally and funtionally similar read across chemical by Ball et al (1984) to determine the mutagenic nature of p-methylbenzyl alcohol (RA CAS no 105 -13 -5). The study was performed on Salmonella typhimurium strain TA100 and TA98 as per the plate incorporation assay. A compound was considered to be mutagenic if the number of revertants/plate exceeded the 99.9% confidence limit and a concentration-dependent increase in the mutagenicity was observed. The 99.9% confidence limit was 99 revertants above spontaneous revertant levels for TA100 (spontaneous revertants = 196±29 revertants/plate) and 40 revertants above spontaneous revertants for TA98 (spontaneous revertants = 40±12 revertants/plate). p-methylbenzyl alcohol failed to induce mutation in Salmonella typhimurium strain TA100 and TA98 and hence does not classify as a gene mutant in vitro.

Based on the information observed for the test chemical and its various read across, it is summarized that 4-methoxyphenylacetic acid (MPAA) is not likely to exhibit genetic toxicity. Thus, the chemical is not classified as a genetic toxicant.

Justification for classification or non-classification

Based on the weight of evidence data summarized, 4-methoxyphenylacetic acid (MPAA; CAS no 104-01-8) is not likely to exhibit genetic toxicity. Thus, the chemical is not classified as a genetic toxicant.