p-hydroxyphenylacetic acid

Endpoint summary

Description of key information

Skin Sensitization:

The skin sensitization potential of 4-Hydroxyphenylacetic Acid was estimated by SSS (2018) using OECD QSAR toolbox v3.3 with log kow as the primary descriptor. 4-Hydroxyphenylacetic Acid was predicted to be not sensitizing to the skin of Hartley female guinea pigs.

 

Key value for chemical safety assessment

Skin sensitisation

Link to relevant study records

Reference

Endpoint:

skin sensitisation

Remarks:

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

Type of study:

other: Estimated data

Justification for non-LLNA method:

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:

guinea pig

Strain:

Hartley

Sex:

female

Details on test animals and environmental conditions:

no data available

Route:

intradermal and epicutaneous

Vehicle:

not specified

Adequacy of induction:

not specified

No.:

#1

Route:

epicutaneous, occlusive

Vehicle:

not specified

Adequacy of challenge:

not specified

No. of animals per dose:

no data available

Details on study design:

no data available

Challenge controls:

no data available

Positive control substance(s):

not specified

Concentration:

no data available

Reading:

1st reading

Group:

test chemical

Clinical observations:

No reactions observed

Remarks on result:

no indication of skin sensitisation

The prediction was based on dataset comprised from the following descriptors: "Skin Sensitisation"
Estimation method: Takes highest mode value from the 6 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 ("i" and ( not "j") )  )  and ("k" and ( not "l") )  )  and ("m" and ( not "n") )  )  and "o" )  and ("p" and ( not "q") )  )  and ("r" and ( not "s") )  )  and "t" )  and "u" )  and "v" )  and "w" )  and "x" )  and ("y" and ( not "z") )  )  and ("aa" and ( not "ab") )  )  and ("ac" and "ad" )  )

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) >> Single-Ring Substituted Primary Aromatic Amines OR SN1 OR SN1 >> Nucleophilic attack after diazonium or carbenium ion formation OR SN1 >> Nucleophilic attack after diazonium or carbenium ion formation >> Nitroarenes with Other Active Groups OR SN1 >> Nucleophilic attack after metabolic nitrenium ion formation OR SN1 >> Nucleophilic attack after metabolic nitrenium ion formation >> Fused-Ring Primary Aromatic Amines OR SN1 >> Nucleophilic attack after metabolic nitrenium ion formation >> Single-Ring Substituted Primary Aromatic Amines OR SN1 >> Nucleophilic attack after reduction and nitrenium ion formation OR SN1 >> Nucleophilic attack after reduction and nitrenium ion formation >> Nitroaniline Derivatives OR SN1 >> Nucleophilic attack after reduction and nitrenium ion formation >> Nitroarenes with Other Active Groups OR SN1 >> Nucleophilic attack after reduction and nitrenium ion formation >> Nitrophenols, Nitrophenyl Ethers and Nitrobenzoic Acids OR SN1 >> Nucleophilic attack after reduction and nitrenium ion formation >> Polynitroarenes OR SN2 OR SN2 >> Alkylation, direct acting epoxides and related OR SN2 >> Alkylation, direct acting epoxides and related >> Epoxides and Aziridines OR SN2 >> Direct acting epoxides formed after metabolic activation OR SN2 >> Direct acting epoxides formed after metabolic activation >> Quinoline Derivatives OR SN2 >> DNA alkylation OR SN2 >> DNA alkylation >> Alkylphosphates, Alkylthiophosphates and Alkylphosphonates OR SN2 >> Nucleophilic substitution at sp3 Carbon atom OR SN2 >> Nucleophilic substitution at sp3 Carbon atom >> Haloalkanes Containing Heteroatom OR SN2 >> SN2 at an activated carbon atom OR SN2 >> SN2 at an activated carbon atom >> Quinoline Derivatives OR SN2 >> SN2 attack on activated carbon Csp3 or Csp2 OR SN2 >> SN2 attack on activated carbon Csp3 or Csp2 >> Nitroarenes with Other Active Groups by DNA binding by OASIS v.1.3

Domain logical expression index: "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 No alert found by Protein binding by OASIS v1.3 ONLY

Domain logical expression index: "i"

Referential boundary: The target chemical should be classified as Not possible to classify according to these rules (GSH) by Protein binding potency

Domain logical expression index: "j"

Referential boundary: The target chemical should be classified as Moderately reactive (GSH) OR Moderately reactive (GSH) >> Alkyl 2-alkenoates (MA) by Protein binding potency

Domain logical expression index: "k"

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

Domain logical expression index: "l"

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

Domain logical expression index: "m"

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

Domain logical expression index: "n"

Referential boundary: The target chemical should be classified as Sulfonic acids or their salts by Skin irritation/corrosion Inclusion rules by BfR

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 OR Halogens by Groups of elements

Domain logical expression index: "r"

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: "s"

Referential boundary: The target chemical should be classified as Group 16 - Sulfur S by Chemical elements

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"

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: "w"

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: "x"

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: "y"

Referential boundary: The target chemical should be classified as Not categorized by Repeated dose (HESS)

Domain logical expression index: "z"

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

Domain logical expression index: "aa"

Referential boundary: The target chemical should be classified as Not categorized by Repeated dose (HESS)

Domain logical expression index: "ab"

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

Domain logical expression index: "ac"

Parametric boundary:The target chemical should have a value of log Kow which is >= 0.269

Domain logical expression index: "ad"

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

Interpretation of results:

other: Negative

Conclusions:

4-Hydroxyphenylacetic Acid was predicted to be not sensitizing to the skin of Hartley female guinea pigs.
 

Executive summary:

The skin sensitization potential of 4-Hydroxyphenylacetic Acid was estimated by SSS (2018) using OECD QSAR toolbox v3.3 with log kow as the primary descriptor. 4-Hydroxyphenylacetic Acid was predicted to be not sensitizing to the skin of Hartley female guinea pigs.

 

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (not sensitising)

Additional information:

Skin Sensitization:

Various studies were summarized to ascertain the degree of dermal sensitization caused by 4-Hydroxyphenylacetic Acid in living organisms.The studies are based on in vivo experiments in humans, guinea pigs, mice along with predicted data for target chemical and its structurally similar read across substances,4 methoxy phenylacetic acid (MPAA) [CAS: 104-01-8], 4-Hydroxybenzoic acid[CAS: 99-96-7] and Phenylacetic acid[CAS: 103-82-2].The predicted data using the OECD QSAR toolbox v3.3 has also been compared with the experimental data.

The skin sensitization potential of 4-Hydroxyphenylacetic Acid was estimated by SSS (2018) using OECD QSAR toolbox v3.3 with log kow as the primary descriptor. 4 -Hydroxyphenylacetic Acid was predicted to be not sensitizing to the skin of Hartley female guinea pigs.

This is 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 shaved skin of twenty Hartley male guinea pigs was treated with the test material (a solid) by intrademal injection (as a 5% solution in propylene glycol as vehicle with and without Freund's adjuvant) and then by topical application (5% in propylene glycol) eight days later. Two weeks after the final induction administration, animals were challenged with the test material as a 75% preparation in petrolatum using a 24-hour dermal exposure. Ten non-induced animals were also challenged and Served as control. The site of exposure was examined for erythema and edema 24 and 48 hours following removal of the test material. 'The dose levels for challenge (75% in petrolatum) was based on a topical range-finding study to select the highest non-irritating dose which was also the highest practical dose for this material. At the 24hour examination, 1/20 animals demonstrated a slight response to the challenge dose no animal demonstrated a response at the 48 hour examination. Negative controls showed minimal response with 1/10 animals showing minimal irritation at 24 hours only. Positive control (DNCB) demonstrated a 100% response. 4-Methoxyphenylacetic Acid (MPAA) was found to be a non sensitizing to guinea pig under test condition. Therefore 4-Methoxyphenylacetic Acid (MPAA, CAS no-104 -1 -8) was considered to be a non sensitizing .

These results are further supported by the experimental study summarized in SIDS Initial Assessment Report For 4-HYDROXYBENZOIC ACID CAS N°: 99-96-7- OECD SIDS- June 29-July 1, 1999; for the structurally similar read across chemical, 4-Hydroxybenzoic acid[CAS: 99-96-7]. In this assay, 4 animals were inducted by daily topical application of 2.5 – 15.0 % for three consecutive days. Five days after the initiation of exposure, [3H] methyl thymidine was injected and the labeling in lymph node cells was measured. The ratio of labeling incorporation by tested lymph node cells to that recorded for control lymph node cells, (T/C) ratio was 0.6 – 1.5 (more than 3.0 is positive).

 Since the (T/C) ratio was less than 3, the test chemical 4-Hydroxybenzoic acid (CAS No: 99-96-7) was considered to be non-sensitizing in Mouse local lymph node assay (LLNA).

The above results were supported by the experimental study summarized in Food and Cosmetics Toxicology Volume(issue)/page/year: 13,901,1975; for the structurally similar read across substance, Phenylacetic acid[CAS: 103-82-2]. Phenylacetic acid 2% in petrolatum was applied to skin of 25 human volunteers and observed for dermal reactions (duration of exposure and observation period not mentioned). No skin reactions were observed. Hence, Phenylacetic acid can be considered as not skin sensitizer for human skin.

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

Respiratory sensitisation

Endpoint conclusion

Endpoint conclusion:

no study available

Justification for classification or non-classification

Available data for 4-Hydroxyphenylacetic Acid indicates that it is not likely to cause any dermal sensitization to skin.

4-Hydroxyphenylacetic Acid can be considered to be not sensitizer to skin and can be classified under the category “Not Classified” as per CLP regulation.