Registration Dossier

Skin Irritation:

The dermal irritation potential of 4-Hydroxyphenylacetic Acid was estimated using OECD QSAR toolbox version 3.3 with logPow as the primary descriptor.

4-Hydroxyphenylacetic Acid was estimated to be not irritating to the skin of New Zealand White rabbits.

Based on the estimated result; 4-Hydroxyphenylacetic Acid can be considered not irritating to skin and can be classified under the category “Not Classified” as per CLP regulation.

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 v3.3 and the QMRF report has been attached

Qualifier:

according to guideline

Guideline:

other: Estimated data

Principles of method if other than guideline:

Prediction was done using OECD QSAR toolbox v3.3

GLP compliance:

not specified

Specific details on test material used for the study:

- Name of test material: p-hydroxyphenylacetic acid
- IUPAC name: 4-Hydroxyphenylacetic Acid
- Molecular formula: C8H8O3
- Molecular weight: 152.148 g/mole
- Smiles : c1(ccc(O)cc1)CC(O)=O
- Inchl: 1S/C8H8O3/c9-7-3-1-6(2-4-7)5-8(10)11/h1-4,9H,5H2,(H,10,11)
- Substance type: Organic
- Physical state: Solid crystalline powder (off white)

Species:

rabbit

Strain:

New Zealand White

Details on test animals or test system and environmental conditions:

no data available

Type of coverage:

semiocclusive

Preparation of test site:

shaved

Vehicle:

not specified

Controls:

not specified

Amount / concentration applied:

0.5 g

Duration of treatment / exposure:

4 hours

Observation period:

72 hours

Number of animals:

3

Details on study design:

no data available

Irritation parameter:

overall irritation score

Basis:

mean

Time point:

72 h

Reversibility:

not specified

Remarks on result:

no indication of irritation

Irritant / corrosive response data:

no signs of irritation observed

Estimation method: Takes mode value from the 5 nearest neighbours
Domain logical expression:Result: In Domain

(((((((((("a" or "b" or "c" or "d" ) and ("e" and ( not "f") ) ) and "g" ) and ("h" and ( not "i") ) ) and "j" ) and ("k" and ( not "l") ) ) and ("m" and ( not "n") ) ) and ("o" and ( not "p") ) ) and "q" ) and ("r" and "s" ) )

Domain logical expression index: "a"

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

Domain logical expression index: "b"

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

Domain logical expression index: "c"

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: "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 No alert found by DNA binding by OASIS v.1.3

Domain logical expression index: "f"

Referential boundary: The target chemical should be classified as 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: "g"

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

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 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: "j"

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

Domain logical expression index: "k"

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

Domain logical expression index: "l"

Referential boundary: The target chemical should be classified as No alert found by in vivo mutagenicity (Micronucleus) alerts by ISS

Domain logical expression index: "m"

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

Domain logical expression index: "n"

Referential boundary: The target chemical should be classified as Simple aldehyde by in vivo mutagenicity (Micronucleus) alerts by ISS

Domain logical expression index: "o"

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

Domain logical expression index: "p"

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

Domain logical expression index: "q"

Similarity boundary:Target: OC(=O)Cc1ccc(O)cc1
Threshold=10%,
Dice(Atom centered fragments)
Atom type; Count H attached; Hybridization

Domain logical expression index: "r"

Parametric boundary:The target chemical should have a value of log Kow which is >= 0.268

Domain logical expression index: "s"

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

Interpretation of results:

other: not irritating

Conclusions:

4-Hydroxyphenylacetic Acid was estimated to be not irritating to the skin of New Zealand White rabbits.

Executive summary:

The dermal irritation potential of 4-Hydroxyphenylacetic Acid was estimated using OECD QSAR toolbox version 3.3 with logPow as the primary descriptor.

4-Hydroxyphenylacetic Acid was estimated to be not irritating to the skin of New Zealand White rabbits.

Based on the estimated result; 4-Hydroxyphenylacetic Acid can be considered not irritating to skin and can be classified under the category “Not Classified” as per CLP regulation.

Endpoint conclusion:

no adverse effect observed (not irritating)

Reference

Endpoint:

eye 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 v3.3 and the QMRF report has been attached

Qualifier:

according to guideline

Guideline:

other: Estimated data

Principles of method if other than guideline:

Prediction was done using OECD QSAR toolbox v3.3

GLP compliance:

not specified

Specific details on test material used for the study:

- Name of test material: p-hydroxyphenylacetic acid
- IUPAC name: 4-Hydroxyphenylacetic Acid
- Molecular formula: C8H8O3
- Molecular weight: 152.148 g/mole
- Smiles : c1(ccc(O)cc1)CC(O)=O
- Inchl: 1S/C8H8O3/c9-7-3-1-6(2-4-7)5-8(10)11/h1-4,9H,5H2,(H,10,11)
- Substance type: Organic
- Physical state: Solid crystalline powder (off white)

Species:

rabbit

Strain:

New Zealand White

Details on test animals or tissues and environmental conditions:

no data available

Vehicle:

not specified

Controls:

not specified

Amount / concentration applied:

0.1g

Duration of treatment / exposure:

1 hour

Observation period (in vivo):

21 days

Duration of post- treatment incubation (in vitro):

no data available

Number of animals or in vitro replicates:

3

Details on study design:

no data available

Other effects / acceptance of results:

no data available

Irritation parameter:

overall irritation score

Basis:

mean

Time point:

21 d

Reversibility:

not specified

Remarks on result:

positive indication of irritation

Irritant / corrosive response data:

Signs of irritation observed

Estimation method: Takes mode value from the 6 nearest neighbours
Domain logical expression:Result: In Domain

(((((((((((((("a" or "b" or "c" or "d" ) and "e" ) and "f" ) and ("g" and ( not "h") ) ) and ("i" and ( not "j") ) ) and ("k" and ( not "l") ) ) and ("m" and ( not "n") ) ) and "o" ) and ("p" and ( not "q") ) ) and "r" ) and "s" ) and "t" ) and "u" ) and ("v" and "w" ) )

Domain logical expression index: "a"

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

Domain logical expression index: "b"

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

Domain logical expression index: "c"

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: "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 No alert found by DNA binding by OECD ONLY

Domain logical expression index: "f"

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

Domain logical expression index: "g"

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

Domain logical expression index: "h"

Referential boundary: The target chemical should be classified as 1-phenoxy-benzene OR Aromatic diazo OR Hydrazine OR No alert found OR Primary aromatic amine, hydroxyl amine and its derived esters OR Simple aldehyde by in vivo mutagenicity (Micronucleus) alerts by ISS

Domain logical expression index: "i"

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: "j"

Referential boundary: The target chemical should be classified as (!Undefined)Group CN Lipid Solubility < 0.4 g/kg by Eye irritation/corrosion Exclusion rules by BfR

Domain logical expression index: "k"

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: "l"

Referential boundary: The target chemical should be classified as (!Undefined)Group CNHal Lipid Solubility < 400 g/kg by Eye irritation/corrosion Exclusion rules by BfR

Domain logical expression index: "m"

Referential boundary: The target chemical should be classified as Phenol Type Compounds by Oncologic Primary Classification

Domain logical expression index: "n"

Referential boundary: The target chemical should be classified as Acrylate Reactive Functional Groups by Oncologic Primary Classification

Domain logical expression index: "o"

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

Domain logical expression index: "p"

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

Domain logical expression index: "q"

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

Domain logical expression index: "r"

Referential boundary: The target chemical should be classified as Aryl AND Carboxylic acid AND Phenol AND Precursors quinoid compounds by Organic Functional groups ONLY

Domain logical expression index: "s"

Referential boundary: The target chemical should be classified as Aryl AND Carboxylic acid AND Phenol AND Precursors quinoid compounds by Organic Functional groups ONLY

Domain logical expression index: "t"

Referential boundary: The target chemical should be classified as Aryl AND Carboxylic acid AND Phenol AND Precursors quinoid compounds by Organic Functional groups ONLY

Domain logical expression index: "u"

Referential boundary: The target chemical should be classified as Aryl AND Carboxylic acid AND Phenol AND Precursors quinoid compounds by Organic Functional groups ONLY

Domain logical expression index: "v"

Parametric boundary:The target chemical should have a value of log Kow which is >= 0.0466

Domain logical expression index: "w"

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

Interpretation of results:

Category 2 (irritating to eyes) based on GHS criteria

Conclusions:

4-Hydroxyphenylacetic Acid was estimated to be irritating to the eyes of New Zealand White rabbits.

Executive summary:

The ocular irritation potential of 4-Hydroxyphenylacetic Acid was estimated using OECD QSAR toolbox version 3.3 with logPow as the primary descriptor.

4-Hydroxyphenylacetic Acid was estimated to be irritating to the eyes of New Zealand White rabbits.

Based on the estimated result; 4-Hydroxyphenylacetic Acid can be considered irritating to the eyes and can be classified under the category “Category 2” as per CLP regulation.

Endpoint conclusion:

adverse effect observed (irritating)

Endpoint conclusion:

no study available

Skin Irritation:

In different studies,4-Hydroxyphenylacetic Acidhas 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 predicted data for target chemicaland its structurally similar read across chemicals,Terephthalic acid [CAS: 100-21-0] and 4 methoxy phenylacetic acid (MPAA) [CAS: 104-01-8].The predicted data using the OECD QSAR toolbox has also been compared with the experimental data.

In a prediction done by SSS (2018) using the OECD QSAR toolbox v3.3 with log kow as the primary descriptor, the skin irritation potential was estimated for4-Hydroxyphenylacetic Acid. 4-Hydroxyphenylacetic Acidwas estimated to be not irritating to New Zealand White rabbit skin.

This is supported by the experimental study summarized in Hazardous Substance Databank (HSDB), U S National Library of Medicine, last updated 2012; for the structurally similar read across chemical,Terephthalic acid [CAS: 100-21-0]. 10 ml oily paste containing 80% terephthalic acid was applied to the equal sites on the hands of human volunteers (number not specified).The volunteers were observed for signs of irritation (duration not specified).

Terephthalic acid when applied as an oily paste was not irritating to human skin.

The above results are supported by the experimental study summarized in National Technical Information Service, OTS0530656-1 (1991); forthe structurally similar read across chemical,4 methoxy phenylacetic acid (MPAA) [CAS: 104-01-8]. Six New Zealand White rabbits were treated with 0.5 gm of test substance moistened with water. The Area of exposure was 6 square cm of clipped skin and the wrap used was Gauze patch. The cover was removed after 4 hours of exposure and the skin was wiped free of excess test material with absorbant pad. The skin reactions in the rabbits were observed and evaluated according to Draize method after 1 hr of removal of cover and 1, 2,3 days after removal .The minimum mean dermal irritation score at any observation was 0.0 (Maximum possible score is 8.0). No animal showed any indication of dermal irritation.

Thus, it was considered that 4 methoxy phenylacetic acid (MPAA) was not irritating to skin.

Based on the available data for the target and applying the weight of evidence approach, 4-Hydroxyphenylacetic Acid was considered not irritating to skin.Comparing the above annotations with the criteria of CLP regulation, test chemical can be classified under the category “Not Classified”.

Eye Irritation:

In different studies,4-Hydroxyphenylacetic Acidhas 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 predicted data for target chemicaland its structurally similar read across chemicals, Salicylic acid[CAS: 69-72-7] and4 methoxy phenylacetic acid (MPAA) [CAS: 104-01-8].The predicted data using the OECD QSAR toolbox has also been compared with the experimental data.

In a prediction done by SSS (2018) using the OECD QSAR toolbox v3.3 with log kow as the primary descriptor, the eye irritation potential was estimated for4-Hydroxyphenylacetic Acid. 4-Hydroxyphenylacetic Acidwas estimated to be irritating to New Zealand White rabbit eyes.

This is supported by the experimental study performed by Syoichoiroh Sugai et.al (Journal of Toxicological Sciences, 16, 111-130, 1991)to evaluate the primary eye irritation potential of 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 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 = 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.

Hence Salicylic acid can be assessed as irritating to rabbit eyes.

The above results are supported by the experimental study summarized in National Technical Information Service, OTS0530656-1 (1991); forthe structurally similar read across chemical,4 methoxy phenylacetic acid (MPAA) [CAS: 104-01-8]. The study was performed according to the Draize method.

Test is first performed on one New Zealand White rabbit with 0.1gm of test substance, the treated eye showed moderate irritation, Thereafter 8 additional animals were tested and subjected to rinsing with normal saline after 30 seconds of administration .Ocular lesions were scored approx 1 hr, 1 day upto 21 days. Even 21 days after treatment, un-rinsed eyes in 5/6 treated animals displayed corneaI opacity, iritis and conjunctival irritation. The maximum mean irritation score was 71.2 (of 110 possible maximum) which occurred on day 3, the rinsed eyes showed milder effects; however, serious adverse effects persisted to day 21. 4-MethoxyphenyIacetic Acid (MPAA) was considered to be a very severe irritant to the eye of albino New Zealand White rabbits under the conditions of these studies causing effects which were not reversed within 21 days of treatment. Immediate washing of the eyes resulted in reduced irritation and more rapid recovery.

Based on the available data for the target and applying the weight of evidence approach, 4-Hydroxyphenylacetic Acid was considered irritating to eyes.Comparing the above annotations with the criteria of CLP regulation, test chemical can be classified under the category “Category 2”.

Available data for 4-Hydroxyphenylacetic Acid indicates that it is not likely to cause severe irritation or corrosion to skin, but it causes irritation to eyes.

Hence, 4-Hydroxyphenylacetic Acid can be classified under the category “Not Classified” for skin and “Category 2” for eye irritation as per CLP regulation.