Registration Dossier

Repeated dose toxicity: Oral

Based on the prediction done using the OECD QSAR toolbox version 3.3 with log kow as the primary descriptor and considering the five closest read across substances, repeated dose toxicity was predicted for 2-hydroxy-p-toluic acid. The study assumed the use of male and female rats in a 28 days toxicity study. Since no significant treatment related effects were observed at the mentioned dose level, hence the No Observed Adverse Effect Level (NOAEL) for 2-hydroxy-p-toluic acid is predicted to be 419.0 mg/Kg bw/day.

Based on this value it can be concluded that the substance is considered to be not toxic as per the criteria mentioned in CLP regulation.

Repeated dose toxicity: Inhalation

2 -hydroxy-p-toluic acid 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

Repeated dose toxicity: Dermal

The acute dermal toxicity value for 2 -hydroxy-p-toluic acid (as provided in section 7.2.3) is >2000 mg/kg body weight. The substance was also found to be not sensitizing to the skin. Based on these considerations, the end point for repeated dermal toxicity is considered as waiver.

Reference

Endpoint:

repeated dose 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 from OECD QSAR Toolbox version 3.3 and the supporting QMRF report has been attached

Qualifier:

according to guideline

Guideline:

other: Refer below principle

Principles of method if other than guideline:

Prediction is done using OECD QSAR Toolbox version 3.3, 2018

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)
- 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

Details on species / strain selection:

No data

Sex:

male/female

Details on test animals or test system and environmental conditions:

No data

Route of administration:

oral: gavage

Details on route of administration:

No data

Vehicle:

not specified

Details on oral exposure:

No data

Analytical verification of doses or concentrations:

not specified

Details on analytical verification of doses or concentrations:

No data

Frequency of treatment:

Daily

Remarks:

No data

No. of animals per sex per dose:

No data

Control animals:

not specified

Details on study design:

No data

Positive control:

No data

Observations and examinations performed and frequency:

No data

Sacrifice and pathology:

No data

Other examinations:

No data

Statistics:

No data

Clinical signs:

not specified

Mortality:

not specified

Body weight and weight changes:

not specified

Food consumption and compound intake (if feeding study):

not specified

Food efficiency:

not specified

Water consumption and compound intake (if drinking water study):

not specified

Ophthalmological findings:

not specified

Haematological findings:

not specified

Clinical biochemistry findings:

not specified

Urinalysis findings:

not specified

Behaviour (functional findings):

not specified

Immunological findings:

not specified

Organ weight findings including organ / body weight ratios:

not specified

Gross pathological findings:

not specified

Neuropathological findings:

not specified

Histopathological findings: non-neoplastic:

not specified

Histopathological findings: neoplastic:

not specified

Other effects:

not specified

Details on results:

No data

Dose descriptor:

NOAEL

Effect level:

419 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: No significant alterations were noted at the mentioned dose level

Critical effects observed:

not specified

The prediction was based on dataset comprised from the following descriptors: NOAEL
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 ( not "r") ) ) and ("s" and ( not "t") ) ) and ("u" and ( not "v") ) ) and ("w" and ( not "x") ) ) and ("y" and ( not "z") ) ) and ("aa" and ( not "ab") ) ) and ("ac" and ( not "ad") ) ) and ("ae" and ( not "af") ) ) and ("ag" and ( not "ah") ) ) and ("ai" and "aj" ) )

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 >> Fused-Ring Primary Aromatic Amines OR Radical 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) >> Single-Ring Substituted Primary Aromatic Amines OR SN1 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 by DNA binding by OASIS v.1.3

Domain logical expression index: "h"

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

Domain logical expression index: "i"

Referential boundary: The target chemical should be classified as Moderate binder, NH2 group OR Moderate binder, OH grooup by Estrogen Receptor Binding

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 Non binder, non cyclic structure OR Non binder, without OH or NH2 group by Estrogen Receptor Binding

Domain logical expression index: "l"

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

Domain logical expression index: "m"

Referential boundary: The target chemical should be classified as Very strong binder, OH group OR Weak binder, NH2 group by Estrogen Receptor Binding

Domain logical expression index: "n"

Referential boundary: The target chemical should be classified as No superfragment by Superfragments ONLY

Domain logical expression index: "o"

Referential boundary: The target chemical should be classified as Methyldopa (Hepatotoxicity) Alert by Repeated dose (HESS)

Domain logical expression index: "p"

Referential boundary: The target chemical should be classified as Phenols (Mucous membrane irritation) Rank C by Repeated dose (HESS)

Domain logical expression index: "q"

Referential boundary: The target chemical should be classified as Methyldopa (Hepatotoxicity) Alert by Repeated dose (HESS)

Domain logical expression index: "r"

Referential boundary: The target chemical should be classified as Aliphatic amines (Mucous membrane irritation) Rank C by Repeated dose (HESS)

Domain logical expression index: "s"

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

Domain logical expression index: "t"

Referential boundary: The target chemical should be classified as Alcohol by Organic functional groups, Norbert Haider (checkmol)

Domain logical expression index: "u"

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

Domain logical expression index: "v"

Referential boundary: The target chemical should be classified as Aryl fluoride by Organic functional groups, Norbert Haider (checkmol)

Domain logical expression index: "w"

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

Domain logical expression index: "x"

Referential boundary: The target chemical should be classified as Carbonyl compound by Organic functional groups, Norbert Haider (checkmol)

Domain logical expression index: "y"

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

Domain logical expression index: "z"

Referential boundary: The target chemical should be classified as Suflur {v+4} or {v+6} by Organic functional groups (US EPA)

Domain logical expression index: "aa"

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

Domain logical expression index: "ab"

Referential boundary: The target chemical should be classified as Olefinic carbon [=CH2] by Organic functional groups (US EPA)

Domain logical expression index: "ac"

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

Domain logical expression index: "ad"

Referential boundary: The target chemical should be classified as Ester, aliphatic attach [-C(=O)O] by Organic functional groups (US EPA)

Domain logical expression index: "ae"

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

Domain logical expression index: "af"

Referential boundary: The target chemical should be classified as Hydrazine [>N-N<] by Organic functional groups (US EPA)

Domain logical expression index: "ag"

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: "ah"

Referential boundary: The target chemical should be classified as Aldimine by Organic Functional groups (nested)

Domain logical expression index: "ai"

Parametric boundary:The target chemical should have a value of log Kow which is >= 0.936

Domain logical expression index: "aj"

Parametric boundary:The target chemical should have a value of log Kow which is <= 5.1

Conclusions:

The No Observed Adverse Effect Level (NOAEL) for 2-hydroxy-p-toluic acid is predicted to be 419.0 mg/Kg bw/day.

Executive summary:

Based on the prediction done using the OECD QSAR toolbox version 3.3 with log kow as the primary descriptor and considering the five closest read across substances, repeated dose toxicity was predicted for 2-hydroxy-p-toluic acid. The study assumed the use of male and female rats in a 28 days toxicity study. Since no significant treatment related effects were observed at the mentioned dose level, hence the No Observed Adverse Effect Level (NOAEL) for 2-hydroxy-p-toluic acid is predicted to be 419.0 mg/Kg bw/day.

Based on this value it can be concluded that the substance is considered to be not toxic as per the criteria mentioned in CLP regulation.

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

419 mg/kg bw/day

Species:

rat

Quality of whole database:

Data is from K2 prediction database

Reference

Endpoint:: repeated dose toxicity: inhalation, other
Data waiving:: other justification
Justification for data waiving:: other:

Endpoint conclusion:

no study available

Quality of whole database:

Waiver

Endpoint conclusion:

no study available

Reference

Endpoint:: repeated dose toxicity: dermal, other
Data waiving:: other justification
Justification for data waiving:: other:

Endpoint conclusion:

no study available

Quality of whole database:

Waiver

Endpoint conclusion:

no study available

Repeated dose toxicity: Oral

Prediction model based estimaton for the target chemical and data from read across chemicals has been reviewed to determine the toxic nature of

2-hydroxy-p-toluic acid. The studies are as mentioned below:

Based on the prediction done using the OECD QSAR toolbox version 3.3 with log kow as the primary descriptor and considering the five closest read across substances, repeated dose toxicity was predicted for 2-hydroxy-p-toluic acid. The study assumed the use of male and female rats in a 28 days toxicity study. Since no significant treatment related effects were observed at the mentioned dose level, hence the No Observed Adverse Effect Level (NOAEL) for 2-hydroxy-p-toluic acid is predicted to be 419.0 mg/Kg bw/day.

The predicted data is further supported by the data from read across chemicals as mentioned below:

Shirota et al (The Journal of Toxicological Sciences, 2008), performed 28 days repeated dose oral toxicity study to determine the toxic nature of 60 -70% structurally similar read across chemical 4-methoxybenzoic acid (RA CAS no 99 -94 -5). The study was performed using male and female Sprague Dawley rats for 28 days. The test chemical wassuspended in 0.5% sodium carboxumethylcellulose solution to give dose levels of 0, 100, 300 or 1000 mg/kg bw/day. During the study period, the animals were observed for clinical signs, mortality, changes in body weight and food consumption, hematology, clinical chemistry, urinalaysis, neurobehavioral changes and were subjected to gross and histopathology.No mortality and murbidity was noted. Some animals of the 1000 mg/kg bw/day group showed temporary salivation after dosing. No other clinical signs were observed. Body weight of males and females in the compound treated groups changes similarly to those of the control group at any period. Food consumption in females of 1000 mg/Kg bw/day was slightly higher than in the controls from day 7-8 of treatment. No difference in food intake was observed for male rats of any group. Increase in water changes was observed, which was confined by an observation of water feeding bottles in the metabolic cages. At the end of treatment period, an increase in AST activity and a slight decrease in the protein concentration were noted in the 1000 mg/kg bw treated females compared to the controls. No significant differences were observed between the compound related and control groups for males and those at the end of the recovery period from animals of both sexes. Urine volume measured on day 23 of treatment was larger in the males given 300 mg/Kg nw/day or more of the compound and in females given 1000 mg/Kg bw/day when compared to the control animals. Also, usine specific gravities were decreased in the males of these groups. Urinanalysis showed some minor changes and control groups and were suggestive of any toxic effects. No abnormalities were noted in the neurobehavioral test at the last week of treatment. No significant differences from the control were observed in absolute organ weights or in organ weights relative to body weight in any of the compound treated group of males or females. No abnormality suggestive of any toxic effects were observed in any organs or tissues on gross and histopathological examination at necropsy. Based on the observations made, the No observed adverse effects level (NOAEL) for 4-methoxybenzoic acid is considered to be 300 mg/Kg bw/day when male and female Sprague Dawley rats were treated with the test chemical for 28 days.

Repeated dose oral toxicity study (HPVIS, 2018) was also performed to determine the toxic nature of another read across chemical Methyl 2-hydroxybenzoate (RA CAS no 119 -36 -8). The test chemical was mixed with feed and used at dose level of0, 0.6, 0.9, 1.2, or 2.0% (0, 300, 450, 600, or 1,000 mg/kg bw/d)in order to determine the progression of the bone lesions. The study was performed using male and female Sprague Dawley rats (10/sex). Each week, 2 rats from each group were X-rayed and one week following the X-rays, the same rats were killed and the femurs of some of the rats were histopathologically examined following sectioning and decalcification. No bone lesions were observed in rats fed 0.9% methyl salicylate or less. In addition, there was a good correlation in the evaluation of bone lesions using whole body X-rays and histopathological examinations. Based on these considerations, No observed adverse effect level for methyl salicylate is considered to be 450 mg/Kg bw/day when male and female Sprague Dawley rats were treated with the test chemical for 11 weeks.

Repeated dose toxicity: Inhalation

2 -hydroxy-p-toluic acid 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

Repeated dose toxicity: Dermal

The acute dermal toxicity value for 2 -hydroxy-p-toluic acid (as provided in section 7.2.3) is >2000 mg/kg body weight. The substance was also found to be not sensitizing to the skin. Based on these considerations, the end point for repeated dermal toxicity is considered as waiver.

Based on the data available for the target chemical and its read across, 2-hydroxy-p-toluic acid is not likely to be toxic upon repeated exposure by oral route as per the criteria mentioned in CLP regulation.

Based on the data available for the target chemical and its read across, 2-hydroxy-p-toluic acid (CAS no 50 -85 -1) is not likely to be toxic upon repeated exposure by oral route as per the criteria mentioned in CLP regulation.