Registration Dossier

Administrative data

Description of key information

Acute Oral Toxicity: 

In Acute oral toxicity ,LD50 value was predicted based on OECD QSAR toolbox for target substance 2-hydroxy-p-toluic acid(50-85-1) was estimated to be 1009 mg/kg bw;1009 mg/kg bw (chemid),540 and 730 mg/kg bw Based on the QSAR prediction done using the Danish (Q)SAR Database, ,and for differentstudies available on the structurally similar read across substanceSodium salicylate (54-21-7) was considered to be 500 mg/kg bw and forSalicylic acid (69-72-7)was considered to be 891 mg/kg bw.All these studies concluded that the LD50 value is between 300-2000 mg/kg bw. Thus, comparing this value with the criteria of CLP regulation, 2-hydroxy-p-toluic acid(50-85-1) can be classified as “Category IV” for acute oral toxicity.

Acute Inhalation Toxicity: 

2-Hydroxy-4-methylbenzoic acid (50 -85 -1) has very low vapor pressure of 8.476E-6 mm Hg, so the potential for the generation of inhalable vapours is very low, also the normal conditions of use of this substance will not result in aerosols, particles or droplets of an inhalable size, so exposure to humans via the inhalatory route will be highly unlikely and therefore is end point was considered for waiver.

Acute Dermal Toxicity:

In Acute dermal toxicity, LD50 value was predicted based on OECD QSAR toolbox for target substance 2-hydroxy-p-toluic acid(50-85-1) was estimated to be 3597.90 mg/kg bw, ,and for differentstudies available on structurally similar read across substanceSodium salicylate (54-21-7) was considered to be >2000 mg/kg bw, forSalicylic acid (69-72-7)was considered to be >10000 mg/kg bw and for functionally similar read across substance Methyl p-Toluate(99-75-2) was considered to be >5000 mg/kg bw.All these studies concluded that the LD50 value is greater than 2000 mg/kg bw. Thus, comparing this value with the criteria of CLP regulation, 2-hydroxy-p-toluic acid(50-85-1) cannot be classified for acute dermal toxicity.

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records
Reference
Endpoint:
acute toxicity: oral
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 predicted using OECD QSAR toolbox version 3.3 and the supporting QMRF report has been attached
Reference:
Composition 0
Qualifier:
according to
Guideline:
other: as mentioned below
Principles of method if other than guideline:
Prediction is done using QSAR Toolbox version 3.3
GLP compliance:
not specified
Test type:
other: not specified
Limit test:
no
Test material information:
Composition 1
Specific details on test material used for the study:
Name of test material : 2-hydroxy-p-toluic acid (m cresotic 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:
rat
Strain:
Wistar
Sex:
male
Details on test animals and environmental conditions:
not specified
Route of administration:
oral: gavage
Vehicle:
not specified
Details on oral exposure:
not specified
Doses:
1009 mg/kg bw
No. of animals per sex per dose:
15 animals
Control animals:
no
Details on study design:
not specified
Statistics:
not specified
Preliminary study:
not specified
Sex:
male
Dose descriptor:
LD50
Effect level:
1 009 mg/kg bw
Based on:
test mat.
Remarks on result:
other: 50 % mortality observed
Mortality:
not specified
Clinical signs:
not specified
Body weight:
not specified
Gross pathology:
not specified
Other findings:
not specified

The prediction was based on dataset comprised from the following descriptors: LD50
Estimation method: Takes average value from the 6 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 ( not "o") )  )  and ("p" and ( not "q") )  )  and ("r" and ( not "s") )  )  and ("t" and ( not "u") )  )  and ("v" and "w" )  )

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 Michael addition >> Polarised Alkenes-Michael addition OR Michael addition >> Polarised Alkenes-Michael addition >> Alpha, beta- unsaturated esters 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 No alert found by Protein binding by OASIS v1.3

Domain logical expression index: "m"

Referential boundary: The target chemical should be classified as Acylation OR Acylation >> Ester aminolysis OR Acylation >> Ester aminolysis >> Amides by Protein binding by OASIS v1.3

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 Non-Metals by Groups of elements

Domain logical expression index: "q"

Referential boundary: The target chemical should be classified as Alkali Earth OR Halogens by Groups of elements

Domain logical expression index: "r"

Referential boundary: The target chemical should be classified as Phenols by Skin irritation/corrosion Inclusion rules by BfR

Domain logical expression index: "s"

Referential boundary: The target chemical should be classified as Aldehydes OR Inclusion rules not met OR Ketones by Skin irritation/corrosion Inclusion rules by BfR

Domain logical expression index: "t"

Referential boundary: The target chemical should be classified as No alert found by rtER Expert System ver.1 - USEPA

Domain logical expression index: "u"

Referential boundary: The target chemical should be classified as Alkoxyphenols OR Alkylphenols OR Parabens OR Salicylates by rtER Expert System ver.1 - USEPA

Domain logical expression index: "v"

Parametric boundary:The target chemical should have a value of log Kow which is >= 1.03

Domain logical expression index: "w"

Parametric boundary:The target chemical should have a value of log Kow which is <= 3.21

Interpretation of results:
Category 4 based on GHS criteria
Conclusions:
The LD50 value was estimated to be 1009 mg/kg bw,when Wistar male rats were orally exposed with 2-Hydroxy-4-methylbenzoic acid.
Executive summary:

In a prediction done by SSS (2017) using the OECD QSAR toolbox with log kow as the primary descriptor, the acute oral toxicity was estimated for 2-Hydroxy-4-methylbenzoic acid. The LD50 was estimated to be 1009 mg/kg bw,when Wistar male rats were orally exposed with 2-Hydroxy-4-methylbenzoic acid.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LD50
1 009 mg/kg bw
Quality of whole database:
Data is Klimisch 2 and from OECD QSAR toolbox

Acute toxicity: via inhalation route

Link to relevant study records
Reference
Endpoint:
acute toxicity: inhalation
Data waiving:
other justification
Justification for data waiving:
other:
Endpoint conclusion
Quality of whole database:
Waiver

Acute toxicity: via dermal route

Link to relevant study records
Reference
Endpoint:
acute toxicity: dermal
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 predicted using OECD QSAR toolbox version 3.3 and QMRF report has been attached
Reference:
Composition 0
Qualifier:
according to
Guideline:
other: as mentioned below
Principles of method if other than guideline:
Prediction was done by using OECD QSAR toolbox v3.3,2018
GLP compliance:
not specified
Test type:
other: estimated data
Limit test:
no
Test material information:
Composition 1
Specific details on test material used for the study:
Name of test material : 2-hydroxy-p-toluic acid (m cresotic 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:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals and environmental conditions:
No data available
Type of coverage:
occlusive
Vehicle:
unchanged (no vehicle)
Details on dermal exposure:
No data available
Duration of exposure:
24 hours
Doses:
3597.90 mg/kg bw
No. of animals per sex per dose:
No data available
Control animals:
not specified
Details on study design:
No data available
Statistics:
No data available
Preliminary study:
No data available
Sex:
male/female
Dose descriptor:
LD50
Effect level:
3 597.9 mg/kg bw
Based on:
test mat.
Remarks on result:
other: 50% mortality was observed
Mortality:
No data available
Clinical signs:
No data available
Body weight:
No data available
Gross pathology:
No data available
Other findings:
No data available

The prediction was based on dataset comprised from the following descriptors: LD50
Estimation method: Takes average 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 ( 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 Acid moiety AND Phenols by Aquatic toxicity classification by ECOSAR

Domain logical expression index: "e"

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: "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 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) >> 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 >> 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 >> 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 SN2 OR SN2 >> Alkylation, direct acting epoxides and related OR SN2 >> Alkylation, direct acting epoxides and related >> Epoxides and Aziridines OR SN2 >> Nucleophilic substitution at sp3 Carbon atom OR SN2 >> Nucleophilic substitution at sp3 Carbon atom >> Haloalkanes Containing Heteroatom 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 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 >> 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 by DNA binding by OECD

Domain logical expression index: "j"

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

Domain logical expression index: "k"

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 by Protein binding by OECD

Domain logical expression index: "l"

Referential boundary: The target chemical should be classified as (!Undefined)Group All Lipid Solubility < 0.01 g/kg AND Group C Melting Point > 55 C by Eye irritation/corrosion Exclusion rules by BfR

Domain logical expression index: "m"

Referential boundary: The target chemical should be classified as (!Undefined)Group CN Lipid Solubility < 0.4 g/kg OR Group All Aqueous Solubility < 0.000005 g/L OR Group All Aqueous Solubility < 0.00002 g/L OR Group All Melting Point > 200 C OR Group C Aqueous Solubility < 0.0001 g/L OR Group C Aqueous Solubility < 0.0005 g/L OR Group CHal log Kow > 4.5 OR Group CHal Melting Point > 65 C OR Group CHal Molecular Weight > 280 g/mol OR Group CHal Molecular Weight > 370 g/mol OR Group CN Aqueous Solubility < 0.1 g/L OR Group CN log Kow > 4.5 by Eye irritation/corrosion Exclusion rules by BfR

Domain logical expression index: "n"

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

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 Aryl OR Biphenyl OR Ether OR Ketone by Organic Functional groups (nested)

Domain logical expression index: "q"

Parametric boundary:The target chemical should have a value of log Kow which is >= 1.03

Domain logical expression index: "r"

Parametric boundary:The target chemical should have a value of log Kow which is <= 3.64

Interpretation of results:
other: not classified
Conclusions:
The LD50 value was estimated to be 3597.90 mg/kg bw,when male and female wistar rats were occlusively exposed with 2-hydroxy-p-toluic acid (50-85-1) by dermal application for 24 hours.
Executive summary:

In a prediction done by SSS (2018) using the OECD QSAR toolbox with log kow as the primary descriptor, the acute dermal toxicity was estimated for 2-hydroxy-p-toluic acid  (50-85-1).The LD50 was estimated to be 3597.09 mg/kg bw,when male and female wistar rats were occlusively exposed with 2-hydroxy-p-toluic acid  (50-85-1) by dermal application for 24 hours.  

Endpoint conclusion
Endpoint conclusion:
no study available
Dose descriptor:
LD50
3 597.9 mg/kg bw
Quality of whole database:
Data is Klimisch 2 and from OECD QSAR toolbox

Additional information

Acute Oral Toxicity: 

In different studies, 2-hydroxy-p-toluic acid(50-85-1) has been investigated for acute oral toxicity to a greater or lesser extent. Often the studies are based on in vivo experiments and estimated data in rodents, i.e. most commonly in rats for 2-hydroxy-p-toluic acid(50-85-1) along with the study available on the structurally similar read across substance Sodium salicylate (54-21-7) and for Salicylic acid (69-72-7). The predicted data using the OECD QSAR toolbox has also been compared with the experimental studies. The studies are summarized as below –

In a prediction done by SSS (2017) using the OECD QSAR toolbox with log kow as the primary descriptor, the acute oral toxicity was estimated for 2-Hydroxy-4-methylbenzoic acid. The LD50 was estimated to be 1009 mg/kg bw,when Wistar male rats were orally exposed with 2-Hydroxy-4-methylbenzoic acid.

The above study was further supported by U.S. National Library of Medicine (Chemidplus Database,U.S. National Library of Medicine,2017) for target substance 2-hydroxy-p-toluic acid(50-85-1). In a acute oral toxicity study, mice were treated with 2-Hydroxy-4-methylbenzoic acid in the conctration of 1800 mg/kg bw orally. 50 % mortality was observed in treated mice at 1800 mg/kg bw. Therefore, LD50 was considered to be 1800 mg/kg bw when mice were treated with 2-Hydroxy-4-methylbenzoic acid orally.

Based on the QSAR prediction done using the Danish (Q)SAR Database, the LD50 was estimated to be 540 mg/kg bw on rat for 2-Hydroxy-4-methylbenzoic acid (50 -85 -1) having Reliability Index: 0.59 (moderate prediction quality)

Based on the QSAR prediction done using the Danish (Q)SAR Database, the LD50 was estimated to be 730 mg/kg bw on mouse for 2-Hydroxy-4-methylbenzoic acid (50 -85 -1) having Reliability Index: 0.62 (moderate prediction quality)

In another experimental study conducted by Sustainability Support Service (Europe) AB (study number: IIRT-350, 2012-11-23) for the target substanceSodium salicylate (54-21-7).The acute oral toxicity profile of sodium salicylate (CAS No. 54-21-7) in female wistar albino rats according to OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method).The test substance was dissolved in Distilled water to obtain final concentration of 30 and 200 mg/ml which was administered by oral route by using oral cannula.Body weight,mortality and clinical signs were observed in treated animals.at dose level 300 mg/kg bw,Test compound did not produce any clinical signs of intoxication throughout the observation period of 14 days.atdose level 2000 mg/kg bw,Test compound produced high to sever signs of intoxication viz; abdominal respiration, convulsion, tremor and hind leg paralysis and finally death after 4 hrs.All the animals treated with CAS No. 54-21-7 at the dose level of 300 mg/kg bw showed decrease in normal gain in body weight on day 7th as compared to control group. Whereas, on day 14th all the rats showed normal gain weight as compared to control group.Hence,The lethal concentration (LD50) cut-off value for acute oral toxicity test was considered to be 500 mg/kg bw,when female wistar albino rats were treated with sodium salicylate (CAS No. 54-21-7) orally via gavage according to OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method).

The above study is further supported byCosmetics Ingredient Review Expert Panel(International Journal of Toxicology, 22(Suppl. 3):1–108, 2003); U.S. National Library of Medicine (Chemidplus Database,U.S. National Library of Medicine,2017) and U.S. National Library of Medicine (HSDB (Hazardous Substances Data Bank); US national Library of Medicine,2017) for structurally similar read across substance Salicylic acid (69-72-7). Acute oral toxicity study was performed in rats using test material Salicylic acid (69-72-7).50% mortality was observed at dose 891 mg/kg bw.Clinical signs like behavioral muscle weakness and behavioral somnolence (general depressed activity) were observed.Hence,LD50 value was considered to be891 mg/kg bw,when rats were treated with Salicylic acid (69-72-7)orally.

Thus, based on the above studies on 2-Hydroxy-4-methylbenzoic acid (50 -85 -1) and it’s structurally similar read across substances, it can be concluded that LD50 value is between 300-2000 mg/kg bw. Thus, comparing this value with the criteria of CLP regulation, 2-Hydroxy-4-methylbenzoic acid (50 -85 -1) can be classified as “Category IV” for acute oral toxicity.

Acute Inhalation Toxicity: 

2-Hydroxy-4-methylbenzoic acid (50 -85 -1) has very low vapor pressure of 8.476E-6 mm Hg, so the potential for the generation of inhalable vapours is very low, also the normal conditions of use of this substance will not result in aerosols, particles or droplets of an inhalable size, so exposure to humans via the inhalatory route will be highly unlikely and therefore is end point was considered for waiver.

Acute Dermal Toxicity:

In different studies,2-Hydroxy-4-methylbenzoic acid (50 -85 -1) has been investigated for acute dermal toxicity to a greater or lesser extent. Often the studies are based on in vivo experiments and estimated data in rodents, i.e. most commonly in rabbits for 2-Hydroxy-4-methylbenzoic acid (50 -85 -1) along with the study available on structurally similar read across substance Sodium salicylate (54-21-7), for Salicylic acid (69-72-7)and on functionally similar read across substance Methyl p-Toluate(99-75-2). The predicted data using the OECD QSAR toolbox has also been compared with the experimental studies. The studies are summarized as below –

In a prediction done by SSS (2018) using the OECD QSAR toolbox with log kow as the primary descriptor, the acute dermal toxicity was estimated for 2-hydroxy-p-toluic acid  (50-85-1).The LD50 was estimated to be 3597.09 mg/kg bw,when male and female wistar rats were occlusively exposed with 2-hydroxy-p-toluic acid  (50-85-1) by dermal application for 24 hours.  

In experimental study conducted by Sustainability Support Services (Europe) AB (study number:14_49_066) for the target substance Sodium salicylate (54-21-7).Acute dermal Toxicity Study of Sodium salicylate in Rats was performed as per OECD No. 402 (Acute Dermal Toxicity) . Five male and five female healthy young adult rats were randomly selected and used for conducting acute dermal toxicity study. Ratsfree from injury and irritation of skin were selected for the study. Twenty four hours prior to dermal application of test item, approximately 10% of body surface area of each rat was clipped. A limit dose of 2000 mg/ kg body weight of test item moistened with 0.2 ml distilled water was applied directly on the intact skin of clipped area of rats; the porous gauze dressing was put on to the intact skin of clipped area.This porous gauze dressing was covered with a non-irritating tape.After the 24-hour application period, the dressings were removed and theskin was gently wiped with distilled water.The skin reactions were assessed. All animals were observed for clinical signs at approximately 1, 2, 3 and 4 hours after treatment on day 0 and once daily during test days 1‑14. Mortality was recorded after application on test day 0 and twice daily during days 1-14 (at least once on the day of sacrifice). Local signs / Skin reactions were observed daily from test days 1-14 (in common with clinical signs). Body weights were re­corded on day 0 (prior to application) and on day 7 and 14. All animals were necropsied and examined macroscopically. No mortality was observed in any animal till the end of the experimental period. All the animals shows normal clinical signs, mean body weight was observed with gain on day 7 and 14. Gross pathological observation of all terminally sacrificed animals did not show any pathological abnormality.Thus, The LD50 value was considered to be >2000 mg/kg bw,when male and female  wistar rats were occlusively treated with Sodium salicylate (54-21-7)  by dermal application following 14 days of observation period according to OECD Guideline 402 (Acute Dermal Toxicity).

Also these results are further supported by U.S. National Library of Medicine (Chemidplus Database,U.S. National Library of Medicine,2017) and IFA GESTIS (Gestis Substance Database ,2018) for thestructurally similar read across substance Salicylic acid (69-72-7). In acute dermal toxicity study, rabbits were treated with 2-hydroxy benzoic acid (69-72-7)in the concentration of 10000 mg/kg bw by dermal application.No mortality was observed in treated rabbits at dose 10000 mg/kg bw.Therefore, LD50 value was considered to be >10000 mg/kg bw,when rats were treated with 2-hydroxy benzoic acid (69-72-7)by dermal application.  

The above study was further supported by D. L. J. Opdyke (Food and Cosmetics Toxicology,Volume 17, Supplement, December 1979, Pages 873-874); HPVIS (HPVIS,2018); IFA GESTIS (Gestis Substance Database ,2018) andU.S. National Library of Medicine(Chemidplus Database,U.S. National Library of Medicine,2017) for the functionally similar read across substanceMethyl p-Toluate(99-75-2).In acute dermal toxicity study, rabbits were topically treated with Methyl p-methylbenzoate(99-75-2) in the concentration of 5000 mg/kg bw.No mortality was observed in treated rabbits at dose 5000 mg/kg bw.Therefore, LD50 value was considered to be >5000 mg/kg bw,when rabbits were topically treated with Methyl p-methylbenzoate(99-75-2).

Thus, based on the above studies on 2-hydroxy-p-toluic acid  (50-85-1) and it’s structurally and functionally similar read across substances, it can be concluded that LD50 value is greater than 2000 mg/kg bw. Thus, comparing this value with the criteria of CLP regulation, 2-hydroxy-p-toluicacid (50-85-1) cannot be classified for acute dermal toxicity.

Justification for classification or non-classification

Based on the above experimental studies and prediction on 2-hydroxy-p-toluicacid (50-85-1) and it’s structurally and functionally similar read across substances, it can be concluded that LD50 value is between 300-2000 mg/kg bw for acute oral toxicity and greater than 2000 mg/kg bw for acute dermal toxicity. Thus, comparing this value with the criteria of CLP regulation, 2-hydroxy-p-toluicacid (50-85-1) can be classified as “Category IV” for acute oral toxicity and cannot be classified for acute dermal toxicity.For Acute inhalation toxicity wavier was added so, not possible to classify.