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Description of key information

Skin Irritation:

The dermal irritation potential of 2-Hydroxy-4-methylbenzoic acid (CAS No: 50-85-1) was estimated using OECD QSAR toolbox version 3.3 with logPow as the primary descriptor. The substance 2-Hydroxy-4-methylbenzoic acid (CAS No: 50-85-1) was estimated to be severely irritating to the skin of New Zealand White rabbits. Based on the estimated result 2-Hydroxy-4-methylbenzoic acid (CAS No: 50-85-1) can be considered as irritating to skin and can be classified under the category ˋ Category 2 (irritant)’ as per CLP regulation.

Eye Irritation:

The average Draize scores after 21 days were as follows: CORNEA = 33.9/80, iris = 0.6, conjunctiva = 5.1.

4-methylsalicylic acid caused moderate eye irritation recovering within 21 days of treatment.

Hence, 4-methylsalicylic acid can be considered irritating to eyes.

Key value for chemical safety assessment

Skin irritation / corrosion

Link to relevant study records
Reference
Endpoint:
skin irritation: 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:
other: estimated data
Principles of method if other than guideline:
Prediction is done using QSAR Toolbox version 3.3
GLP compliance:
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:
rabbit
Strain:
New Zealand White
Details on test animals and environmental conditions:
No data available
Type of coverage:
semiocclusive
Preparation of test site:
clipped
Vehicle:
not specified
Controls:
not specified
Amount / concentration applied:
No data available
Duration of treatment / exposure:
4 hours
Observation period:
72 hours
Number of animals:
No data available
Irritation parameter:
overall irritation score
Basis:
mean
Time point:
72 h
Reversibility:
not specified
Remarks on result:
positive indication of irritation
Irritant / corrosive response data:
severe skin irritation was observed.

Estimation method: Takes mode value from the 7 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 ( not "m") )  )  and "n" )  and ("o" and ( not "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) >> p-Aminobiphenyl Analogs OR Radical >> Radical mechanism via ROS formation (indirect) >> p-Substituted Mononitrobenzenes 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 >> p-Aminobiphenyl Analogs 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 >> Nitrobiphenyls and Bridged Nitrobiphenyls 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 SN1 >> Nucleophilic attack after reduction and nitrenium ion formation >> p-Substituted Mononitrobenzenes 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 at sulfur atom OR SN2 >> SN2 at sulfur atom >> Sulfonyl Halides 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, NH2 group OR 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 Group 14 - Carbon C AND Group 16 - Oxygen O by Chemical elements

Domain logical expression index: "m"

Referential boundary: The target chemical should be classified as Group 1 - Alkali Earth Li,Na,K,Rb,Cs,Fr OR Group 15 - Nitrogen N OR Group 17 - Halogens Cl OR Group 17 - Halogens F OR Group 17 - Halogens F,Cl,Br,I,At by Chemical elements

Domain logical expression index: "n"

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: "o"

Referential boundary: The target chemical should be classified as Alkyl arenes AND Carboxylic acid AND Overlapping groups AND Phenol by Organic Functional groups (nested)

Domain logical expression index: "p"

Referential boundary: The target chemical should be classified as Alcohol OR Aldehyde OR Alkane branched with quaternary carbon OR Alkane, branched with tertiary carbon OR Alkene OR Alkoxy OR Carboxylic acid ester OR Cycloalkane OR Ether OR Fused carbocyclic aromatic OR Isopropyl OR Ketone OR Naphtalene OR tert-Butyl by Organic Functional groups (nested)

Domain logical expression index: "q"

Parametric boundary:The target chemical should have a value of log Kow which is >= 1.51

Domain logical expression index: "r"

Parametric boundary:The target chemical should have a value of log Kow which is <= 3.91

Interpretation of results:
Category 2 (irritant) based on GHS criteria
Conclusions:
 The substance 2-Hydroxy-4-methylbenzoic acid (CAS No: 50-85-1) was estimated to be severely irritating to the skin of New Zealand White rabbits. Based on the estimated result 2-Hydroxy-4-methylbenzoic acid (CAS No: 50-85-1) can be considered as irritating to skin.
Executive summary:

The dermal irritation potential of 2-Hydroxy-4-methylbenzoic acid (CAS No: 50-85-1) was estimated using OECD QSAR toolbox version 3.3 with logPow as the primary descriptor. The substance 2-Hydroxy-4-methylbenzoic acid (CAS No: 50-85-1) was estimated to be severely irritating to the skin of New Zealand White rabbits. Based on the estimated result 2-Hydroxy-4-methylbenzoic acid (CAS No: 50-85-1) can be considered as irritating to skin and can be classified under the category ˋ Category 2 (irritant)’ as per CLP regulation.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed (irritating)

Eye irritation

Link to relevant study records
Reference
Endpoint:
eye irritation: in vivo
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
data from handbook or collection of data
Justification for type of information:
data is from peer reviewed journals
Qualifier:
according to
Guideline:
other: Draize test
Principles of method if other than guideline:
The primary eye irritation potential of 4-methylsalicylic acid was evaluated according to Draize method
GLP compliance:
not specified
Specific details on test material used for the study:
Name of test material: 2-hydroxy-p-toluic acid (m cresotic acid)
Common Name: 4-Methylsalicylic 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
Purchased from: Tokyo Kasei Kogyo Co. Ltd, Tokyo, Japan
Species:
rabbit
Strain:
other: Japanese White
Details on test animals or tissues and environmental conditions:
TEST ANIMALS
- Sex: Female
- Source: Takeo Breeder, Shizuoka, Japan
- Age at study initiation: no data available
- Weight at study initiation: 2.0-2.2 kg
- Fasting period before study: no data available
- Housing:metal cages (39*40*44 cm)
- Diet (e.g. ad libitum): RC4 diet (Oriental Yeast Co.Ltd, Tokyo, Japan), ad libitum
- Water (e.g. ad libitum): Water, ad libitum
- Acclimation period: bo data available

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 25±1 deg C
- Humidity (%): 55±5%
- Air changes (per hr): no data available
- Photoperiod (hrs dark hrs light): constant 12 hour light: dark cycle
Vehicle:
unchanged (no vehicle)
Controls:
yes, concurrent no treatment
Amount / concentration applied:
100mg
Duration of treatment / exposure:
single exposure
Observation period (in vivo):
1, 4, 24, 48, 72, 96 hours, 7, 14, 21 days after administration of chemical
Duration of post- treatment incubation (in vitro):
no data available
Number of animals or in vitro replicates:
3
Details on study design:
SCORING SYSTEM: Corneal opacity, erythema, chemosis, secreta and iritis were classified according to the Draize method. The sum of values recorded for cornea, conjunctivae, iris was divided by the number of observations times and the average scores (Draize score) were used as the grade of eye irritation potential of the test chemical. Maximum value of Draize score for cornea, conjunctivae and iris was 80, 20, 5 respectively.
Irritation parameter:
cornea opacity score
Basis:
mean
Time point:
21 d
Score:
33.9
Max. score:
80
Reversibility:
not specified
Remarks on result:
positive indication of irritation
Irritation parameter:
iris score
Basis:
mean
Time point:
7 d
Score:
0.6
Max. score:
5
Reversibility:
not specified
Remarks on result:
positive indication of irritation
Irritation parameter:
conjunctivae score
Basis:
mean
Time point:
21 d
Score:
5.1
Max. score:
8
Reversibility:
not specified
Remarks on result:
positive indication of irritation
Irritant / corrosive response data:
4-methylsalicylic acid caused moderate eye irritation recovering within 21 days of treatment

Table 1: Physchem Parameters and Primary Irritation Scores

Name of the test chemical

Log P*

Draize Scores

Cornea

Iris

Conjunctiva

4-methylsalicylic acid

2.82

33.9 (21)

0.6(7)

5.1 (21)

*= Hansch and Leo, 1979, -=not evaluated due to corneal opacity

Figures in parenthesis indicate the days of recovery.

 

Interpretation of results:
Category 2 (irritating to eyes) based on GHS criteria
Conclusions:
The average Draize scores after 21 days were as follows: CORNEA = 33.9/80, iris = 0.6, conjunctiva = 5.1.
4-methylsalicylic acid caused moderate eye irritation recovering within 21 days of treatment.
Hence, 4-methylsalicylic acid can be considered irritating to eyes.
Executive summary:

The primary eye irritation potential of 4-methylsalicylic acid was evaluated according to Draize method.

3 female Japanese White rabbits (2.0-2.2 kg) were used for the study. The chemical (if solid= 100 mg, if liquid = 0.1ml) was instilled into the conjunctival sac of the left eye.Right eye (untreated eye) served as blank control.The eyes were examined and the grade of ocular lesions was recorded at 1, 24, 48, 72, 96 hours and 7, 14, 21 days after administration of test chemical.Corneal opacity, erythema, chemosis, secreta and iritis were recorded and classified under Draize method (Draize et.al, 1944)

The sum of values, recorded for cornea, conjunctiva and iris was divided by the number of observation times and the average scores (Draize scores) were used as grades of ocular irritation potential of the chemical

The maximum value of Draize score are as follows: Cornea =80, Conjunctiva = 20 and Iris = 5

The average Draize scores after 21 days were as follows:CORNEA = 33.9/80, iris = 0.6, conjunctiva = 5.1.

4-methylsalicylic acid caused moderate eye irritation recovering within 21 days of treatment.

Hence,4-methylsalicylic acid can be considered irritating to eyes.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed (irritating)

Respiratory irritation

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Skin Irritation:

In different studies,2-hydroxy-p-toluic acid (m cresotic acid)has been investigated for potential for dermal irritation to a greater or lesser extent. The studies are based on in vivo experiments in rabbits along with human data for target chemical and its structurally similar read across substances,Methylbenzoate [CAS: 93-58-3],Methyl salicylate [CAS: 119-36-8], Pentyl Salicylate[CAS: 2050-08-0].The experimental results are also being compared with predicted data obtained from OECD QSAR toolbox.

In a prediction done by SSS (2017) using the OECD QSAR toolbox v3.3 with log kow as the primary descriptor, the dermal irritation potential was estimated for2-hydroxy-p-toluic acid (m cresotic acid). 2-hydroxy-p-toluic acid (m cresotic acid) was estimated to be irritating to the skin of New Zealand White rabbits.

This is supported by the experimental result summarized in International Journal of Toxicology, November/December 2012 vol. 31 no. 6 suppl 342S-372S; for the structurally similar read across substance, Methylbenzoate[CAS: 93-58-3]. Undiluted methyl benzoate was applied to the clipped dorsum (0.5mL) and external surface of the outer ear (0.2mL)of 14 male New Zealand albino rabbits The rabbits were observed for 6 days for signs of irritation. On the dorsum there were marked cellular reactions and dermal edema beginning on day 2 followed by dermal hemorrhage, desquamated crust, and thickening of the malpighian stratum beginning on day 5 were observed and on the inner ear, there was slight hyperkeratosis on day 6.

Since the test chemical was rated as grade 1, Methylbenzoate (CAS No: 93-58-3) was considered to be irritating to the clipped dorsum and external surface of the outer ear of male new Zealand albino rabbits.

These results are supported by the experimental study summarized in International Journal of Toxicology 2003;22 Suppl 3:1-108.; for the structurally similar read across substance, Methyl Salicylate [CAS: 119-36-8].Methyl salicylate was applied on the intact skin of each of three rabbits at concentration of 1% , 3% or 6% in Water suspension, PEG 400, 70% ethanol or 70% ethanol plus emollients. Skin reactions were evaluated at 24 and 72 hours.The irritation was observed greatest with 70% ethanol. Necrosis was seen in all three animals dosed with 3% and 6% methyl salicylate in 70% ethanol. With 70% ethanol plus emollients necrosis and intradermal and SC hemorrhage were seen at all doses.

 

Since the skin lesions were observed in all treated animal at all doses, the chemical Methyl salicylate (CAS no: 119-36-8) was considered to be irritating to therabbit’s skin.

The above results are further supported by the experimental study summarized in Food and Chemical Toxicology, 45, (2007), S460–S466; for the structurally similar read across substance, Pentyl Salicylate[CAS: 2050-08-0].Irritation was evaluated as part of acute dermal LD50 study. Neat 5.0 g/kg of pentyl salicylate was applied to the clipped abdomen skin of 10 healthy albino rabbits for 24 hours under occlusive patches. Reactions were read at patch removal, 7 days later, and 14 days later.

Well-defined to moderate erythema and very slight to moderate edema were observed on day 1; very slight to severe erythema and very slight to moderate edema were observed on days 7 and 14.

Since the effects were not reversible even after 14 days of observations, pentyl salicylate can be considered to be irritating to skin.

Based on the available data for the target as well as its structurally similar read across substances, and applying the weight of evidence approach, 2-hydroxy-p-toluic acid (m cresotic acid) can be considered to be irritating to skin. Comparing the above annotations with the criteria of CLP regulation, it can be classified under the category “Category 2”.

Eye Irritation:

In different studies,2-hydroxy-p-toluic acid (m cresotic acid)has been investigated for potential for ocular irritation to a greater or lesser extent. The studies are based on in vivo experiments in rabbits for target chemical and its structurally similar read across substances,Methylbenzoate [CAS: 93-58-3],Methyl salicylate [CAS: 119-36-8], Salicylic Acid[CAS: 69-72-7] and Sodium Salicylate[CAS: 54-21-7].

A study was performed by Syoichoiroh Sugai et.al to evaluate the primary eye irritation potential of 4-methylsalicylic acid[CAS: 50-85-1] and the structurally similar read across chemical, Salicylic acid [69-72-7]. The study was conducted according to Draize method.

3 female Japanese White rabbits (2.0-2.2 kg) were used for the study. The chemical (if solid= 100 mg, if liquid = 0.1ml) was instilled into the conjunctival sac of the left eye. Right eye (untreated eye) served as blank control. The eyes were examined and the grade of ocular lesions was recorded at 1, 24, 48, 72, 96 hours and 7, 14, 21 days after administration of test chemical. Corneal opacity, erythema, chemosis, secreta and iritis were recorded and classified under Draize method (Draize et.al, 1944)

The sum of values, recorded for cornea, conjunctiva and iris was divided by the number of observation times and the average scores (Draize scores) were used as grades of ocular irritation potential of the chemical. The maximum value of Draize score are as follows: Cornea =80, Conjunctiva = 20 and Iris = 5

The average Draize scores for 4-methylsalicylic acid after 21 days were as follows: CORNEA = 33.9/80, iris = 0.6, conjunctiva = 5.1. 4-methylsalicylic acid caused moderate eye irritation recovering within 21 days of treatment.

The average Draize scores after 21 days for Salicylic acid were as follows: CORNEA = 54.1/80, iris = could not be determined, conjunctiva = 10.3/20. Salicylic acid induced severe eye irritation not recovering within 21 days of treatment.

Salicylic acid[CAS:69-72-7] and 4-methylsalicylic acid[CAS: 50-85-1] can be assessed as irritating to rabbit eyes.

The above results are supported by the experimental study summarized in International Journal of Toxicology, November/December 2012 vol. 31 no. 6 suppl 342S-372S; for the structurally similar read across substance, Methylbenzoate[CAS: 93-58-3]. Neat (100%) methyl benzoate was applied to the center of the cornea of 5 rabbits. One minute later the lids were released. The eyes were examined 18–24 h later in strong diffuse daylight and then stained with fluorescein. Methyl benzoate was given a grade 1 (iritis and slight internal congestion) after 24 hours of observation.

Based on this rating, methyl benzoate can be considered as an eye irritant.

These results are further supported by the experimental study performed Y. Ohno et.al(Toxicology in Vitro 13 (1999) 73 – 98) to determine the ocular irritation potential of the structurally similar read across substance, Sodium Salicylate[CAS: 54-21-7]. Draize tests were conducted according to the OECD guidelines for Sodium salicylate.

In the first validation, 100 ml aqueous solution or a suspension of Sodium salicylate(10%) was applied to the right eyes of male New Zealand white rabbits (2.30±2.98 kg, 13 wk of age). Left eyes remained untreated as a control. Eyes were observed at 1 hr, 4 hr, and every 24 hr thereafter for 7 days. Three rabbits were used for test. MAS [Maximum average scores] and scores at 24 hr after application calculated for cornea, iris, conjunctivae and the sum of these scores (total average score) were used for comparison with in vitro data. Isotonic sodium chloride solution was also used as a negative control

According to the classification by Kay and Calandra (1962), chemicals can be classified as follows based on their MAS scores: non-irritants = (0≤MAS <0.5), slight irritants = (0.5≤MAS< 15), mild irritants = (15≤MAS< 25), moderate irritants = (25≤MAS <50), severe irritants  = (50≤MAS)

The Maximum Average Score[MAS] obtained for 100% Sodium salicylate instilled in rabbits eyes was 83.7; whereas for 10% solution the MAS score was 0.0 According to the classification based on the MAS scores Sodium Salicylate can be considered to be an eye irritant at higher concentrations.

It falls under the category - Eye Irritation 2 [GHS classification (United Nations, 2009)].

These results are also supported by the experimental studies summarized in Food and Chemical Toxicology 45 (2007) S428–S452; for the structurally similar read across substance, Methyl Salicylate [CAS: 119-36-8]. A 0.005 ml aliquot of neat methyl salicylate was applied to the center of the cornea of 5 healthy albino rabbits while the lids were retracted. One minute later the lids were released. The eyes were examined 18–24 h later in strong diffuse daylight and then stained with fluorescein. Methyl salicylate was assigned grade 3 – necrosis since 13–37% of the cornea was visible after fluorescein staining.

Therefore, methyl salicylate can be considered to be irritating to rabbit eyes.

In another study summarized in American Journal of Ophthalmology, 29, 1363–1372, 1946; for the structurally similar read across substance, Methyl Salicylate [CAS: 119-36-8].

Normal albino rabbit eyes were selected on the basis of absence of grossly visible staining by a 5-percent aqueous solution of fluorescein sodium, flushed with distilled water 20 seconds after application. A 2 hour interval was given so that the eye could return back to normal condition. Then, 0.005 ml of the undiluted test material was applied to the center of the cornea while the lids were retracted. About one minute later, the lids were released. This procedure is necessary to prevent the removal of a portion of the dose by the very efficient wiping system of the lids before intimate contact has been made with the eye. 18 to 24 hours later, the eyes were examined in strong diffuse daylight, then stained with fluorescein, and the injury was scored.

Methyl salicylate was grouped under Grade 3 injury (0.1 ml undiluted gives injury of up to 5 points (0.5 ml gives over 5)) and Grade 9 injury (Excess of 1% solution gives injury up to 5 points (5% gives over 5)) when rabbit eyes were observed for injuries. Methyl salicylate was known to have caused loss of vision or very slowly healing corneal burns. Based on these grades, it can be inferred that methyl salicylate was irritating to rabbit eyes.

The available data for the target chemical as well as its structurally similar read across substances, indicate a very strong possibility of 2-hydroxy-p-toluic acid (m cresotic acid) being irritating to eyes. Hence, 2-hydroxy-p-toluic acid (m cresotic acid) can be considered to be an eye irritant. . Comparing the above annotations with the criteria of CLP regulation, it can be classified under the category “Category 2”.

Justification for classification or non-classification

Available data for indicates 2-hydroxy-p-toluic acid (m cresotic acid) that it is likely to cause irritation to eyes and skin.

2-hydroxy-p-toluic acid (m cresotic acid) can be considered to be irritating to skin and eyes. It can be classified under the category “Category 2” as per CLP regulation.