4-ethoxybenzoic acid

Endpoint summary

Description of key information

The skin sensitization potential of 4-Ethoxybenzoic acid (CAS No: 619-86-3) was estimated using OECD QSAR toolbox version 3.3 with log Pow as the primary descriptor. The substance 4-Ethoxybenzoic acid (CAS No: 619-86-3) was estimated to be not sensitizing to the skin of guinea pigs. Based on the estimated result 4-Ethoxybenzoic acid (CAS No: 619-86-3) failed to induce skin sanitization effects and hence is considered to be not sensitizing to guinea pigs and can be classified under the category“Not Classified”as per CLP regulation.

Key value for chemical safety assessment

Skin sensitisation

Link to relevant study records

Reference

Endpoint:

skin sensitisation

Remarks:

in vivo

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 QMRF report has been attached.

Qualifier:

according to guideline

Guideline:

other: estimated data

Principles of method if other than guideline:

Prediction is done using QSAR Toolbox version 3.3

GLP compliance:

not specified

Type of study:

guinea pig maximisation test

Justification for non-LLNA method:

not specified

Specific details on test material used for the study:

- Name of test material: 4-Ethoxybenzoic acid
- Molecular formula: C9H10O3
- Molecular weight: 166.175 g/mol
- Smiles notation: c1(ccc(OCC)cc1)C(O)=O
- InChl: 1S/C9H10O3/c1-2-12-8-5-3-7(4-6-8)9(10)11/h3-6H,2H2,1H3,(H,10,11)
- Substance type: Organic
- Physical state: Solid

Species:

guinea pig

Strain:

not specified

Sex:

male

Details on test animals and environmental conditions:

not specified

Route:

intradermal and epicutaneous

Vehicle:

not specified

Concentration / amount:

not specified

Day(s)/duration:

not specified

Adequacy of induction:

not specified

No.:

#1

Route:

epicutaneous, occlusive

Vehicle:

not specified

Concentration / amount:

not specified

Adequacy of challenge:

not specified

No. of animals per dose:

not specified

Details on study design:

not specified

Reading:

1st reading

Group:

test chemical

No. with + reactions:

0

Clinical observations:

no skin sensitization reactions were observed.

Remarks on result:

no indication of skin sensitisation

Cellular proliferation data / Observations:

no skin sensitization reactions were observed.

The prediction was based on dataset comprised from the following descriptors: "Skin Sensitisation"
Estimation method: Takes highest mode value from the 7 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 ( not "n") )  )  and "o" )  and ("p" and ( not "q") )  )  and ("r" and ( not "s") )  )  and "t" )  and "u" )  and ("v" and ( not "w") )  )  and ("x" and "y" )  )

Domain logical expression index: "a"

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

Domain logical expression index: "b"

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

Domain logical expression index: "c"

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

Domain logical expression index: "d"

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

Domain logical expression index: "e"

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

Domain logical expression index: "f"

Referential boundary: The target chemical should be classified as AN2 OR AN2 >> Nucleophilic addition to alpha, beta-unsaturated carbonyl compounds OR AN2 >> Nucleophilic addition to alpha, beta-unsaturated carbonyl compounds >> alpha, beta-Unsaturated Aldehydes OR AN2 >> Schiff base formation OR AN2 >> Schiff base formation >> alpha, beta-Unsaturated Aldehydes OR AN2 >> Shiff base formation after aldehyde release OR AN2 >> Shiff base formation after aldehyde release >> Specific Acetate Esters OR Michael addition OR Michael addition >> Quinone type compounds OR Michael addition >> Quinone type compounds >> Quinone methides OR Radical OR Radical >> Generation of reactive oxygen species OR Radical >> Generation of reactive oxygen species >> Thiols OR Radical >> Radical mechanism by ROS formation (indirect) or direct radical attack on DNA OR Radical >> Radical mechanism by ROS formation (indirect) or direct radical attack on DNA >> Organic Peroxy Compounds OR Radical >> ROS formation after GSH depletion OR Radical >> ROS formation after GSH depletion >> Quinone methides 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 >> Specific Acetate Esters OR SN2 OR SN2 >> Acylation OR SN2 >> Acylation >> Specific Acetate Esters 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 P450-mediated metabolic activation OR SN2 >> Alkylation, direct acting epoxides and related after P450-mediated metabolic activation >> Polycyclic Aromatic Hydrocarbon Derivatives OR SN2 >> Direct acting epoxides formed after metabolic activation 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 >> Specific Acetate Esters 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: "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 Acylation OR Acylation >> P450 Mediated Activation to Isocyanates or Isothiocyanates OR Acylation >> P450 Mediated Activation to Isocyanates or Isothiocyanates >> Formamides 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 OR Michael addition >> P450 Mediated Activation to Quinones and Quinone-type Chemicals >> Hydroquinones OR Michael addition >> P450 Mediated Activation to Quinones and Quinone-type Chemicals >> Polycyclic (PAHs) and heterocyclic (HACs) aromatic hydrocarbons-Michael addition OR Michael addition >> Polarised Alkenes-Michael addition OR Michael addition >> Polarised Alkenes-Michael addition >> Alpha, beta- unsaturated amides OR Michael addition >> Polarised Alkenes-Michael addition >> Alpha, beta- unsaturated esters OR SN1 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 OECD

Domain logical expression index: "j"

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 Acylation >> Direct Acylation Involving a Leaving group >> Anhydrides OR Michael addition OR Michael addition >> Polarised Alkenes OR Michael addition >> Polarised Alkenes >> Polarised alkene - esters OR Michael addition >> Polarised Alkenes >> Polarised alkene - ketones OR Michael addition >> Polarised Alkenes >> Polarised alkene - pyridines by Protein binding by OECD

Domain logical expression index: "k"

Referential boundary: The target chemical should be classified as Not possible to classify according to these rules (GSH) by Protein binding potency

Domain logical expression index: "l"

Referential boundary: The target chemical should be classified as Highly reactive (GSH) OR Highly reactive (GSH) >> Furamates (MA) OR Moderately reactive (GSH) OR Moderately reactive (GSH) >> Alkyl 2-alkenoates (MA) OR Slightly reactive (GSH) OR Slightly reactive (GSH) >> 2-Alkenyl carbonitriles (MA) by Protein binding potency

Domain logical expression index: "m"

Referential boundary: The target chemical should be classified as H-acceptor-path3-H-acceptor by in vivo mutagenicity (Micronucleus) alerts by ISS

Domain logical expression index: "n"

Referential boundary: The target chemical should be classified as 1-phenoxy-benzene OR alpha,beta-unsaturated aliphatic alkoxy group OR alpha,beta-unsaturated carbonyls OR Aromatic mono- and dialkylamine OR Hydrazine OR No alert found OR Primary aromatic amine, hydroxyl amine and its derived esters by in vivo mutagenicity (Micronucleus) alerts by ISS

Domain logical expression index: "o"

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

Domain logical expression index: "p"

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

Domain logical expression index: "q"

Referential boundary: The target chemical should be classified as Alkali Earth OR Alkaline Earth OR Metalloids OR Metals OR Rare Earth OR Transition Metals by Groups of elements

Domain logical expression index: "r"

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: "s"

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

Domain logical expression index: "t"

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

Domain logical expression index: "u"

Similarity boundary:Target: CCOc1ccc(C(O)=O)cc1
Threshold=30%,
Dice(Atom centered fragments)
Atom type; Count H attached; Hybridization

Domain logical expression index: "v"

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

Domain logical expression index: "w"

Referential boundary: The target chemical should be classified as Carboxylic acids (Hepatotoxicity) No rank OR Tamoxifen (Hepatotoxicity) Alert by Repeated dose (HESS)

Domain logical expression index: "x"

Parametric boundary:The target chemical should have a value of log Kow which is >= 1.7

Domain logical expression index: "y"

Parametric boundary:The target chemical should have a value of log Kow which is <= 3.67

Interpretation of results:

other: not sensitizing

Conclusions:

The substance 4-Ethoxybenzoic acid (CAS No: 619-86-3) was estimated to be not sensitizing to the skin of guinea pigs. Based on the estimated result 4-Ethoxybenzoic acid (CAS No: 619-86-3) failed to induce skin sanitization effects and hence is considered to be not sensitizing to guinea pigs.

Executive summary:

The skin sensitization potential of 4-Ethoxybenzoic acid (CAS No: 619-86-3) was estimated using OECD QSAR toolbox version 3.3 with log Pow as the primary descriptor. The substance 4-Ethoxybenzoic acid (CAS No: 619-86-3) was estimated to be not sensitizing to the skin of guinea pigs. Based on the estimated result 4-Ethoxybenzoic acid (CAS No: 619-86-3) failed to induce skin sanitization effects and hence is considered to be not sensitizing to guinea pigs and can be classified under the category“Not Classified”as per CLP regulation.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (not sensitising)

Additional information:

Various studies has been investigated for the test chemical Pyrazine-2-carboxylic acid (CAS No: 98 -97 -5) to observe the potential for skin sensitization to a greater or lesser extent. The studies are based on in vivo experiments in guinea pigs and humans for target chemicalPyrazine-2-carboxylic acid (CAS No: 98 -97 -5) and its structurally similar read across substancesNiacinamide (CAS No: -98-92-0) and Nicotinic acid (CAS no: 59-67-6).The predicted data using the OECD QSAR toolbox has also been compared with the experimental data and summarized as below;

 

 

The skin sensitization potential of 4-Ethoxybenzoic acid (CAS No: 619-86-3) was estimated using OECD QSAR toolbox version 3.3 with log Pow as the primary descriptor. The substance 4-Ethoxybenzoic acid (CAS No: 619-86-3) was estimated to be not sensitizing to the skin of guinea pigs. Based on the estimated result 4-Ethoxybenzoic acid (CAS No: 619-86-3) failed to induce skin sanitization effects and hence is considered to be not sensitizing to guinea pigs.

 

 

The Cosmetic Ingredients Review Expert Panel (CIR, 1984) conducted A repeated insult patch test (RIPT)for structurally similar read across substanceMethylparaben (CAS No: 99-76-3) on skin of 50 subjects (25M/25F) which supports the above mentioned result.During the induction exposure, 5% ofMethylparaben wasapplied to the skin of 50 subjects (25M/25F) for 4 to 8 hr every other day for 3 weeks (10 applications). Following a 3-week rest, the animals were challenged at same concentration used in induction for 24 to 48 hours.None of the subject showed any signs of contact allergy. HenceMethylparaben (CAS No: 99-76-3)was considered to be not sensitizing to the human’ skin.

 

 

The above results were further supported by the Guinea pig maximisation test reported by NTRL (1991) forstructurally similar read across substance4-MethoxyphenyIacetic Acid (MPAA)(CAS No: 104-01-8) in Hartley male guinea pigs. In induction, the shaved skin of twenty Hartley male guinea pigs was treated with the chemical (a solid) by intradermal injection (as a 5% solution in propylene glycol as vehicle with and without Freund's adjuvant) and then by topical application (5% in propylene glycol) eight days later. Two weeks after the final induction administration, animals were challenged with 75% preparation in petrolatum using a 24-hour dermal exposure. Ten non-induced animal were also challenged and served as control. The site of exposure was examined for erythema and edema 24 and 48 hours following removal of the test material. The dose level for challenge (75% in petrolatum) was based on a topical range-finding study to select the highest non-irritating dose which was also the highest practical dose for this material.At the 24hour examination, 1/20 animals demonstrated a slight response to the challenge dose no animal demonstrated a response at the 48 hour examination. Negative controls showed minimal response with 1/10 animals showing minimal irritation at 24 hours only. Positive control (DNCB) demonstrated a 100% response.

 

 

Thus on the basis of available data for thetarget chemical4-Ethoxybenzoic acid (CAS No: 619-86-3) and its structurally similar read across substances4-MethoxyphenyIacetic Acid (MPAA)(CAS No: 104-01-8)andMethylparaben (CAS No: 99-76-3),it can be concluded thatchemical 4-Ethoxybenzoic acid (CAS No: 619-86-3) is unable to cause skin sensitization and considered as non skin sensitizer.Comparing the above annotations with the criteria of CLP regulation, it can be classified under the category “Not Classified”.

Respiratory sensitisation

Endpoint conclusion

Endpoint conclusion:

no study available

Justification for classification or non-classification

The skin sensitization potential of test substance 4-Ethoxybenzoic acid (CAS No: 619-86-3) and its structurally similar read across substances 4-MethoxyphenyIacetic Acid (MPAA)(CAS No: 104-01-8)andMethylparaben (CAS No: 99-76-3) were observed in various studies. From the results obtained from these studies it is concluded that the chemical 4-Ethoxybenzoic acid (CAS No: 619-86-3) is not likely to cause skin sensitization and hence can be classified as non skin sensitizer.