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Description of key information

Skin Sensitization:

The skin sensitization potential of 2-Hydroxy-4-methylbenzoic acid (CAS No: 50-85-1) was estimated using OECD QSAR toolbox version 3.3 with log Pow as the primary descriptor. 2-Hydroxy-4-methylbenzoic acid (CAS No: 50-85-1) was estimated to be not sensitising to the skin of Pirbright-Hartley guinea pigs.

Key value for chemical safety assessment

Skin sensitisation

Link to relevant study records
Reference
Endpoint:
skin sensitisation: in vivo (non-LLNA)
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:
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:
Freund's complete adjuvant test
Justification for non-LLNA method:
not specified
Specific details on test material used for the study:
- Name of test material : 2-Hydroxy-4-methylbenzoic acid
- Molecular formula :C8H8O3
- Molecular weight :152.148 g/mol
- Smiles notation : Cc1ccc(c(c1)O)C(=O)O
- InChl :1S/C8H8O3/c1-5-2-3-6(8(10)11)7(9)4-5/h2-4,9H,1H3,(H,10,11)
- Substance Type: Organic
- Physical State: Solid
Species:
guinea pig
Strain:
Pirbright-Hartley
Sex:
not specified
Details on test animals and environmental conditions:
No data available
Route:
intradermal
Vehicle:
not specified
Concentration / amount:
No data available
Adequacy of induction:
not specified
No.:
#1
Route:
intradermal and epicutaneous
Vehicle:
not specified
Adequacy of challenge:
not specified
No. of animals per dose:
No data available
Details on study design:
No data available
Challenge controls:
No data available
Reading:
1st reading
Group:
test group
Dose level:
No data available
No. with + reactions:
0
Clinical observations:
no skin sensitization was observed.
Remarks on result:
no indication of skin sensitisation
Cellular proliferation data / Observations:
no skin sensitization was observed.

The prediction was based on dataset comprised from the following descriptors: "Skin Sensitisation"
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 ( not "k") )  )  and "l" )  and "m" )  and ("n" and ( not "o") )  )  and "p" )  and ("q" and "r" )  )

Domain logical expression index: "a"

Referential boundary: The target chemical should be classified as m,p - Cresols by OECD HPV Chemical Categories

Domain logical expression index: "b"

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

Domain logical expression index: "c"

Referential boundary: The target chemical should be classified as Weak binder, OH group by Estrogen Receptor Binding

Domain logical expression index: "d"

Referential boundary: The target chemical should be classified as Class 2 (less inert compounds) by Acute aquatic toxicity classification by Verhaar (Modified)

Domain logical expression index: "e"

Referential boundary: The target chemical should be classified as Acid moiety AND Phenols by Aquatic toxicity classification by ECOSAR

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 Non-covalent interaction OR Non-covalent interaction >> DNA intercalation OR Non-covalent interaction >> DNA intercalation >> DNA Intercalators with Carboxamide Side Chain OR Non-covalent interaction >> DNA intercalation >> Fused-Ring Primary Aromatic Amines 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 by ROS formation OR Radical >> Radical mechanism by ROS formation >> Polynitroarenes OR Radical >> Radical mechanism via ROS formation (indirect) OR Radical >> Radical mechanism via ROS formation (indirect) >> Fused-Ring Primary Aromatic Amines OR Radical >> Radical mechanism via ROS formation (indirect) >> Nitroaniline Derivatives OR Radical >> Radical mechanism via ROS formation (indirect) >> Nitroarenes with Other Active Groups OR Radical >> Radical mechanism via ROS formation (indirect) >> Nitrophenols, Nitrophenyl Ethers and Nitrobenzoic Acids OR Radical >> Radical mechanism via ROS formation (indirect) >> Single-Ring Substituted Primary Aromatic Amines OR SN1 OR SN1 >> Nucleophilic attack after diazonium or carbenium ion formation OR SN1 >> Nucleophilic attack after diazonium or carbenium ion formation >> Nitroarenes with Other Active Groups OR SN1 >> Nucleophilic attack after metabolic nitrenium ion formation OR SN1 >> Nucleophilic attack after metabolic nitrenium ion formation >> Fused-Ring Primary Aromatic Amines OR SN1 >> Nucleophilic attack after metabolic nitrenium ion formation >> Single-Ring Substituted Primary Aromatic Amines OR SN1 >> Nucleophilic attack after reduction and nitrenium ion formation OR SN1 >> Nucleophilic attack after reduction and nitrenium ion formation >> Nitroaniline Derivatives OR SN1 >> Nucleophilic attack after reduction and nitrenium ion formation >> Nitroarenes with Other Active Groups OR SN1 >> Nucleophilic attack after reduction and nitrenium ion formation >> Nitrophenols, Nitrophenyl Ethers and Nitrobenzoic Acids OR SN1 >> Nucleophilic attack after reduction and nitrenium ion formation >> Polynitroarenes OR SN2 OR SN2 >> Alkylation, direct acting epoxides and related OR SN2 >> Alkylation, direct acting epoxides and related >> Epoxides and Aziridines OR SN2 >> Direct acting epoxides formed after metabolic activation OR SN2 >> Direct acting epoxides formed after metabolic activation >> Quinoline Derivatives 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 >> SN2 at an activated carbon atom OR SN2 >> SN2 at an activated carbon atom >> Quinoline Derivatives OR SN2 >> SN2 attack on activated carbon Csp3 or Csp2 OR SN2 >> SN2 attack on activated carbon Csp3 or Csp2 >> Nitroarenes with Other Active Groups 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 DNA binding by OECD

Domain logical expression index: "i"

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 >> Benzylamines-Acylation 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 >> Alkyl phenols 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 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 azo OR SN1 >> Nitrenium Ion formation >> Aromatic nitro OR SN1 >> Nitrenium Ion formation >> Primary 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 >> Aliphatic halides by DNA binding by OECD

Domain logical expression index: "j"

Referential boundary: The target chemical should be classified as Weak binder, OH group by Estrogen Receptor Binding

Domain logical expression index: "k"

Referential boundary: The target chemical should be classified as Moderate binder, OH grooup OR Non binder, impaired OH or NH2 group OR Non binder, MW>500 OR Non binder, non cyclic structure OR Non binder, without OH or NH2 group OR Strong binder, NH2 group OR Strong binder, OH group OR Very strong binder, OH group OR Weak binder, NH2 group by Estrogen Receptor Binding

Domain logical expression index: "l"

Referential boundary: The target chemical should be classified as Low (Class I) by Toxic hazard classification by Cramer (original) ONLY

Domain logical expression index: "m"

Similarity boundary:Target: Cc1ccc(C(O)=O)c(O)c1
Threshold=20%,
Dice(Atom centered fragments)
Atom type; Count H attached; Hybridization

Domain logical expression index: "n"

Referential boundary: The target chemical should be classified as No alert found by Respiratory sensitisation

Domain logical expression index: "o"

Referential boundary: The target chemical should be classified as Pro-SN2 OR Pro-SN2 >> Pro-ring opening SN2 OR Pro-SN2 >> Pro-ring opening SN2 >> Vinyl benzenes by Respiratory sensitisation

Domain logical expression index: "p"

Referential boundary: The target chemical should be classified as Low (Class I) by Toxic hazard classification by Cramer (with extensions) ONLY

Domain logical expression index: "q"

Parametric boundary:The target chemical should have a value of log Kow which is >= 2.49

Domain logical expression index: "r"

Parametric boundary:The target chemical should have a value of log Kow which is <= 3.42

Interpretation of results:
other: not sensitising
Conclusions:
The substance 2-Hydroxy-4-methylbenzoic acid (CAS No: 50-85-1) was estimated to be not sensitising to the skin of Pirbright-Hartley guinea pigs.
Executive summary:

The skin sensitization potential of 2-Hydroxy-4-methylbenzoic acid (CAS No: 50-85-1) was estimated using OECD QSAR toolbox version 3.3 with log Pow as the primary descriptor. 2-Hydroxy-4-methylbenzoic acid (CAS No: 50-85-1) was estimated to be not sensitising to the skin of Pirbright-Hartley guinea pigs.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed (not sensitising)
Additional information:

Skin Sensitization:

Various studies were summarized to ascertain the degree of dermal sensitization caused by 2-hydroxy-p-toluic acid (m cresotic acid) in living organisms.The studies are based on in vivo experiments in humans, guinea pigs, mice along with predicted data for target chemical and its structurally similar read across substances,Sodium Salicylate [CAS: 54-21-7]; Methyl salicylate [CAS: 119-36-8]; Salicylic Acid[ CAS: 69-72-7].The predicted data using the OECD QSAR toolbox v3.3 has also been compared with the experimental data.

The skin sensitization potential of 2-hydroxy-p-toluic acid (m cresotic acid) was estimated by SSS (2017) using OECD QSAR toolbox v3.3 with log kow as the primary descriptor and

considering the six closest read across substances. 2-hydroxy-p-toluic acid (m cresotic acid) was predicted to be non sensitizing to the skin of guinea pig.

This is supported by the experimental study performed by Patriarca, G et.al (Z. Immun.-Forsch. vol. 151, pp. 295-304 (1976)) to determine the allergenic potential ofstructurally similar read across substance,Sodium Salicylate[CAS: 54-21-7]. 19 males and 12 females, with a history of aspirin intolerance were used for the assay. 31 patients were given an intradermal in injection of 0.02 ml of 0.1% Sodium Salicylate; the results were scored 20 min after dosing. There was one positive reaction to Sodium Salicylate in the skin test was observed out of 31 patients. Hence, Sodium Salicylate can be considered to be not sensitizing to skin.

These results are also supported by the Mouse Local Lymphnode Assay performed by Gerberick GF et.al (Dermatitis, 2005 Dec; 16(4):157-202) to assess the dermal sensitization potential ofstructurally similar read across substance,Methyl salicylate [CAS: 119-36-8]. The LLNA was conducted on groups of five female CBA mice (7-12 weeks of age) by mean of topical application of chemical on the dorsum of both ears at a dose of 25µl of 1%, 2.5%, 5%, 10% or 20% in acetone/olive oil (4:1). Treatment was performed daily for 3 consecutive days. Five days after initiation of exposure all mice were injected via the tail vein with 250µl of PBS containing 20µCi of tritiatied thymidine. The mice were sacrificed 5 hours later, and draining the auricular lymph nodes were excised and pooled for each experimental group or each individual animal. The incorporation of tritiated thymidine measured by β-scintillation counting and was reported in disintegrations /minute.

An SI was calculated for each chemical group as the ratio of disintegrations/minute of the treated group to the disintegrations/minute of the concurrent vehicle control group. A substance was classified skin sensitizer, if at one or more than one concentrations, it induced a three-fold or greater increase in local lymph node proliferative activity when treated with the concurrent vehicle treated controls (SI ≥3). The approach to estimation of the relative skin sensitization potential is based on the mathematical estimation of the concentration of chemical necessary to obtain a threshold positive response (SI = 3); this is termed as the EC3 value.

For each concentration of methyl salicylate, a stimulation index (SI) relative to the concurrent vehicle-treated control was calculated. The calculated EC3 value for methyl salicylate was >20.0%. Thus based on the relative potency index Methyl salicylate (CAS no: 119-36-8) was considered to be not sensitizing in the Mouse Local Lymphnode Assay.

The same study was performed by Gerberick GF et.al (Dermatitis, 2005 Dec; 16(4):157-202) for another structurally similar read across substance, Salicylic Acid[CAS: 69-72-7]. The relative potency index of salicylic acid was not calculated since the SI were less than 3. Based on the relative potency, salicylic acid was considered to be not sensitizing to mice skin.

Based on the available data for the target substance as well as read across substances and applying the weight of evidence approach, 2-hydroxy-p-toluic acid (m cresotic acid) can be considered to be not sensitizing to skin.

Respiratory sensitisation

Endpoint conclusion
Endpoint conclusion:
no study available

Justification for classification or non-classification

Available data for indicates 2-hydroxy-p-toluic acid (m cresotic acid) that it is not likely to cause any dermal sensitization to skin.

2-methoxybenzoic acid can be considered to be not sensitizer to skin and can be classified under the category “Not Classified” as per CLP regulation.