Diphenylacetic acid

Endpoint summary

Description of key information

Skin Irritation:

The dermal irritation potential of diphenylacetic acid (CAS No: 117-34-0) was estimated using OECD QSAR toolbox version 3.3 with logPow as the primary descriptor.

Diphenylacetic acid (CAS No: 117-34-0) was estimated to be not irritating to the skin of New Zealand White rabbits.

Based on the estimated result diphenylacetic acid (CAS No: 117-34-0) can be considered to be not irritating to skin and can be classified under the category ˋNot Clssified’ as per CLP regulation.

Eye Irritation:

The ocular irritation potential of diphenylacetic acid (CAS No: 117-34-0) was estimated using OECD QSAR toolbox version 3.3 with logPow as the primary descriptor.

Diphenylacetic acid (CAS No: 117-34-0) was estimated to be highly irritating to the eyes of New Zealand White rabbits.

Based on the estimated result diphenylacetic acid (CAS No: 117-34-0) can be considered to be irritating to eye and can be classified under the category ˋ Category 2’ as per CLP regulation

Key value for chemical safety assessment

Skin irritation / corrosion

Link to relevant study records

Reference

Endpoint:

skin irritation: in vivo

Type of information:

(Q)SAR

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

results derived from a valid (Q)SAR model and falling into its applicability domain, with limited documentation / justification

Justification for type of information:

Data is from OECD QSAR Toolbox 3.3 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 version 3.3

GLP compliance:

not specified

Specific details on test material used for the study:

- Name of test material (as cited in study report): diphenyl acetic acid
- Molecular formula: C14H12O2
- Molecular weight: 212.247 g/mol
- SMILES: C(c1ccccc1)(c1ccccc1)C(O)=O
- Substance type: Organic
- Physical state: Solid

Species:

rabbit

Strain:

New Zealand White

Type of coverage:

occlusive

Preparation of test site:

not specified

Vehicle:

physiological saline

Controls:

not specified

Amount / concentration applied:

0.5 ml

Duration of treatment / exposure:

4 hours

Observation period:

14 days

Number of animals:

3

Details on study design:

The test substance was applied once to skin with a patch

Irritation parameter:

overall irritation score

Basis:

mean

Time point:

14 d

Score:

0

Reversibility:

not specified

Remarks on result:

no indication of irritation

Irritant / corrosive response data:

No irritation was observed.

Estimation method: Takes mode 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 ("m" and ( not "n") )  )  and ("o" and ( not "p") )  )  and ("q" and "r" )  )

Domain logical expression index: "a"

Referential boundary: The target chemical should be classified as Aryl AND Carboxylic acid by Organic Functional groups

Domain logical expression index: "b"

Referential boundary: The target chemical should be classified as Aryl AND Carboxylic acid by Organic Functional groups

Domain logical expression index: "c"

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

Domain logical expression index: "d"

Referential boundary: The target chemical should be classified as Acid, aliphatic attach [-COOH] AND Alcohol, olefinic attach [-OH] AND Aliphatic Carbon [CH] AND Aliphatic Carbon, two phenyl attach [-C-]  AND Aromatic Carbon [C] AND Carbonyl, aliphatic attach [-C(=O)-] AND Miscellaneous sulfide (=S) or oxide (=O) AND Olefinic carbon [=CH- or =C<] AND Tertiary Carbon by Organic functional groups (US EPA)

Domain logical expression index: "e"

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

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 AN2 OR AN2 >> Shiff base formation after aldehyde release OR AN2 >> Shiff base formation after aldehyde release >> Specific Acetate Esters OR 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 >> Radical mechanism via ROS formation (indirect) OR Radical >> Radical mechanism via ROS formation (indirect) >> Nitroaniline Derivatives OR Radical >> Radical mechanism via ROS formation (indirect) >> Nitrophenols, Nitrophenyl Ethers and Nitrobenzoic Acids OR Radical >> Radical mechanism via ROS formation (indirect) >> p-Substituted Mononitrobenzenes OR SN1 OR SN1 >> Nucleophilic attack after carbenium ion formation OR SN1 >> Nucleophilic attack after carbenium ion formation >> Specific Acetate Esters 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 >> Nitrophenols, Nitrophenyl Ethers and Nitrobenzoic Acids OR SN1 >> Nucleophilic attack after reduction and nitrenium ion formation >> p-Substituted Mononitrobenzenes OR SN2 OR SN2 >> Acylation OR SN2 >> Acylation >> Specific Acetate Esters OR SN2 >> Nucleophilic substitution at sp3 Carbon atom OR SN2 >> Nucleophilic substitution at sp3 Carbon atom >> Specific Acetate Esters by DNA binding by OASIS v.1.3

Domain logical expression index: "h"

Referential boundary: The target chemical should be classified as Not possible to classify according to these rules by DPRA Lysine peptide depletion

Domain logical expression index: "i"

Referential boundary: The target chemical should be classified as Low reactive OR Low reactive >> Organic disulfides OR Moderate reactive OR Moderate reactive >> Unsaturated carboxylic acid anhydrides by DPRA Lysine peptide depletion

Domain logical expression index: "j"

Referential boundary: The target chemical should be classified as Non binder, without OH or NH2 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 Strong binder, OH group OR Weak binder, OH group by Estrogen Receptor Binding

Domain logical expression index: "l"

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

Domain logical expression index: "m"

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: "n"

Referential boundary: The target chemical should be classified as Group 1 - Alkali Earth Li,Na,K,Rb,Cs,Fr OR Group 15 - Nitrogen N OR Group 15 - Phosphorus P OR Group 16 - Sulfur S OR Group 17 - Halogens Br OR Group 17 - Halogens Cl OR Group 17 - Halogens F OR Group 17 - Halogens F,Cl,Br,I,At by Chemical elements

Domain logical expression index: "o"

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

Domain logical expression index: "p"

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

Domain logical expression index: "q"

Parametric boundary:The target chemical should have a value of log Kow which is >= 1.76

Domain logical expression index: "r"

Parametric boundary:The target chemical should have a value of log Kow which is <= 3.78

Interpretation of results:

other: not irritating

Conclusions:

Diphenylacetic acid (CAS No: 117-34-0) was estimated to be not irritating to the skin of New Zealand White rabbits.

Executive summary:

The skin irritation potential of diphenylacetic acid (CAS No: 117-34-0) was estimated using OECD QSAR toolbox version 3.3 with logPow as the primary descriptor.

Diphenylacetic acid (CAS No: 117-34-0) was estimated to be not irritating to the skin of New Zealand White rabbits.

Based on the estimated result diphenylacetic acid (CAS No: 117-34-0) can be considered to be not irritating to eye and can be classified under the category ˋ Not Classified’ as per CLP regulation.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (not irritating)

Eye irritation

Link to relevant study records

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 3.3 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 version 3.3

GLP compliance:

not specified

Specific details on test material used for the study:

- Name of test material (as cited in study report): diphenyl acetic acid
- Molecular formula: C14H12O2
- Molecular weight: 212.247 g/mol
- SMILES: C(c1ccccc1)(c1ccccc1)C(O)=O
- Substance type: Organic
- Physical state: Solid

Species:

rabbit

Strain:

New Zealand White

Details on test animals or tissues and environmental conditions:

No data available

Vehicle:

other: polyethylene glycol 400

Controls:

other: untreated eye served as control

Amount / concentration applied:

100 mg test substance mixed with 0.1 ml polyethylene glycol 400

Duration of treatment / exposure:

24 hours

Observation period (in vivo):

14 days

Number of animals or in vitro replicates:

3

Details on study design:

No data available

Irritation parameter:

overall irritation score

Basis:

mean

Time point:

14 d

Reversibility:

not specified

Remarks on result:

probability of severe irritation

Irritant / corrosive response data:

Severe irritation was obseved.

Estimation method: Takes mode 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 ("i" and ( not "j") )  )  and ("k" and ( not "l") )  )  and ("m" and ( not "n") )  )  and ("o" and "p" )  )

Domain logical expression index: "a"

Referential boundary: The target chemical should be classified as Aryl AND Carboxylic acid by Organic Functional groups

Domain logical expression index: "b"

Referential boundary: The target chemical should be classified as Aryl AND Carboxylic acid by Organic Functional groups

Domain logical expression index: "c"

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

Domain logical expression index: "d"

Referential boundary: The target chemical should be classified as Acid, aliphatic attach [-COOH] AND Alcohol, olefinic attach [-OH] AND Aliphatic Carbon [CH] AND Aliphatic Carbon, two phenyl attach [-C-]  AND Aromatic Carbon [C] AND Carbonyl, aliphatic attach [-C(=O)-] AND Miscellaneous sulfide (=S) or oxide (=O) AND Olefinic carbon [=CH- or =C<] AND Tertiary Carbon by Organic functional groups (US EPA)

Domain logical expression index: "e"

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

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 AN2 OR AN2 >> Shiff base formation after aldehyde release OR AN2 >> Shiff base formation after aldehyde release >> Specific Acetate Esters OR 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 >> Radical mechanism via ROS formation (indirect) OR Radical >> Radical mechanism via ROS formation (indirect) >> Nitrophenols, Nitrophenyl Ethers and Nitrobenzoic Acids OR Radical >> Radical mechanism via ROS formation (indirect) >> p-Substituted Mononitrobenzenes OR SN1 OR SN1 >> Nucleophilic attack after carbenium ion formation OR SN1 >> Nucleophilic attack after carbenium ion formation >> Specific Acetate Esters OR SN1 >> Nucleophilic attack after reduction and nitrenium ion formation 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 >> p-Substituted Mononitrobenzenes OR SN2 OR SN2 >> Acylation OR SN2 >> Acylation >> Specific Acetate Esters OR SN2 >> Nucleophilic substitution at sp3 Carbon atom OR SN2 >> Nucleophilic substitution at sp3 Carbon atom >> Specific Acetate Esters by DNA binding by OASIS v.1.3

Domain logical expression index: "h"

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

Domain logical expression index: "i"

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

Domain logical expression index: "j"

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

Domain logical expression index: "k"

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: "l"

Referential boundary: The target chemical should be classified as Group 15 - Nitrogen N OR Group 15 - Phosphorus P OR Group 16 - Sulfur S by Chemical elements

Domain logical expression index: "m"

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

Domain logical expression index: "n"

Referential boundary: The target chemical should be classified as 3-Methylcholantrene (Hepatotoxicity) Alert OR Methyldopa (Hepatotoxicity) Alert by Repeated dose (HESS)

Domain logical expression index: "o"

Parametric boundary:The target chemical should have a value of log Kow which is >= 1.87

Domain logical expression index: "p"

Parametric boundary:The target chemical should have a value of log Kow which is <= 3.78

Interpretation of results:

Category 2 (irritating to eyes) based on GHS criteria

Conclusions:

Diphenylacetic acid (CAS No: 117-34-0) was estimated to be highly irritating to the eyes of New Zealand White rabbits.

Executive summary:

The ocular irritation potential of diphenylacetic acid (CAS No: 117-34-0) was estimated using OECD QSAR toolbox version 3.3 with logPow as the primary descriptor.

Diphenylacetic acid (CAS No: 117-34-0) was estimated to be highly irritating to the eyes of New Zealand White rabbits.

Based on the estimated result diphenylacetic acid (CAS No: 117-34-0) can be considered to be irritating to eye and can be classified under the category ˋ Category 2’ as per CLP regulation

Endpoint conclusion

Endpoint conclusion:

adverse effect observed (irritating)

Respiratory irritation

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

Skin irritation:

In different studies, diphenyl acetic acid has been investigated for potential for dermal irritation to a greater or lesser extent. The studies are based on in vivo experiments in rabbits along with predicted data for target chemical and its functionally similar read across substances, 4-Tert-Butylbenzoicacid [CAS: 98-73-7] and Benzoic acid [CAS: 65-85-0]. The predicted data using the OECD QSAR toolbox has also been compared with the experimental data.

In a prediction done by SSS (2017) using the OECD QSAR toolbox with log kow as the primary descriptor, the skin irritation potential was estimated fordiphenyl acetic acid. Diphenyl acetic acidwas not irritating to New Zealand White rabbit skin.

Skin irritation effects were also estimated by four different models i.e, Battery, Leadscope, SciQSAR and CASE Ultra used within Danish QSAR database for diphenyl acetic acid. Based on estimation, no severe skin irritation effects were known when diphenyl acetic acid was exposed to rabbit skin.

Results from both estimations indicate the possibility of diphenyl acetic acid being not irritating to skin.

The above results are further supported by the experimental study summarized in GESTIS SUBSTANCE Database (information system in hazardous substance of the Berufsgenossenscheftn), 2017; for thefunctionally similar read across substance, 4-Tert-Butylbenzoicacid [CAS: 98-73-7]. The study was performed on 6 New Zealand albino rabbits in accordance with EU test guideline B4.

Single application of 500 mg of 4-tert-butylbenzoic acid moistened with water was applied to a clipped area of 6 New Zealand albino rabbits and was held in contact with the skin for 4 hours by a semi occlusive dressing. The skin reactions were read at1, 24, 48, and 72 hours after the removal of the dressing. No cutaneous reaction was detected. Hence, 4-Tert-butylbenzoic acid was considered to be not irritating to the rabbit’s skin.

These results are further supported by the experimental study summarized in BENZOATES-SIDS Initial Assessment Report for 13th SIAM- OECD SIDS- (Bern, 7th - 9th November 2001);thefunctionally similar read across substance, Benzoic Acid [CAS: 65-85-0]. Undiluted 500mg of benzoic acid was applied to inner side of the ear of 2 rabbits under semi occlusion conditions for 24 hours. Since the chemical failed to induce any skin reaction, Benzoic acid(CAS No: -65-85-0) was considered to be not irritating to the rabbit’s skin.

Another study was performed (SCIENTIFIC COMMITTEE ON CONSUMER PRODUCTS (SCCP) -21 June 2005- SCCP/0891/05) on humans to assess the dermal irritation potential ofthe functionally similar substance, Benzoic Acid [CAS: 65-85-0].2% benzoic acid in petrolatum was applied to the intact skin of healthy volunteers and exposed for 46 hours. None of the volunteers exhibited any signs of irritation after 46 hours. Hence, Benzoic acid(CAS No: -65-85-0) was considered to be not irritating to the human skin.

Based on the available data for the target and read across substances and applying the weight of evidence approach, diphenyl acetic acid can be considered to be not irritating to skin.Comparing the above annotations with the criteria of CLP regulation, it can be classified under the category “Not Classified”.

Eye Irritation:

In different studies, diphenyl acetic acid has been investigated for potential for ocular irritation to a greater or lesser extent. The studies are based on in vivo experiments in rabbits along with predicted data for target chemical and its functionally similar read across substances, Benzoic acid [CAS: 65-85-0] and 3-Hydroxy-2 -naphthalenecarboxylic acid [CAS: 92-70-6]. The predicted data using the OECD QSAR toolbox has also been compared with the experimental data.

In a prediction done by SSS (2017) using the OECD QSAR toolbox with log kow as the primary descriptor, the ocular irritation potential was estimated fordiphenyl

acetic acid. Diphenyl acetic acidwas highly irritating to New Zealand White rabbit eyes.

This result is supported by the experimental study summarized in SCIENTIFIC COMMITTEE ON CONSUMER PRODUCTS (SCCP) -21 June 2005- SCCP/0891/05; for the functionally similar substance, Benzoic Acid [CAS: 65-85-0].The study was performed in accordance with EEC test method B.5, Annex V of EEC Directive 84/449/EEC. 77 mg of Benzoic acid (as a fine powder) was instilled into the right conjunctival sac of 3 female New Zealand albino rabbits (single application). After application, the lids of the treated eye were held closed for approximately two seconds. The untreated left eye served as a control. The degree of eye irritation was evaluated at immediately after dosing, 1, 24, 48 and 72 hours and 7, 14 and 21 days after treatment. The mean Draize scores were classified according to Kay and Calandra rating for eye irritation.After 60 min, Animal 1 showed no reaction to light, with translucent corneal opacity and iridial injection. The other 2 also had slight corneal opacity. All 3 had moderate chemosis and slight conjunctival redness. The corneal opacity noted in the first animal increased to nacreous areas. This persisted for 72 h. The translucent areas of opacity persisted up to Day 21. In Animal 2, the slight corneal opacity also persisted up to Day 21, but was resolved in Animal 3 by Day 7. By Day 14, in Animal 1, the iridial injection was resolved but no reaction to light. Animal 2 showed iridial injection on Day 2. The slight conjunctival redness in all animals increased to severe with a white/grey discolouration. It persisted in Animals 1 and 2 up to Day 21 and in Animal 3 to Day 7. The chemosis decreased slowly. In Animals 1 and 2, it was not completely resolved by Day 21 but it was resolved in Animal 3 by Day 14. The animals did not show any symptoms of systemic intoxication.

The estimated Draize score of 35 (60 min) is classed as severely irritating according to Kay and Calandra.

Based on these observations and score, Benzoic acid (CAS No: -65-85-0) was considered to be an eye irritant to the female New Zealand albino rabbit.

The above results are also supported by the experimental study summarized in OECD SIDS- SIDS Initial Assessment Report For SIAM 19- Berlin, Germany; 19-22 October 2004; for the functionally similar read across substance, 3-Hydroxy-2-naphthalenecarboxylic acid [CAS: 92-70-6]. The study was performed in accordance with OECD 405 guidelines. 3 -hydroxy-2 -napthalenecarboxylic acid was instilled into the each animal’s eye for 1 hour. The treated eyes were observed for signs of irritation at 24,48, 72 hours and 7,14 days.The moistened test substance caused serious damage to the eyes of rabbits. 1 hour after application, swelling and conjunctival injections as well as secretion (clear, tinted by the test substance) were observed in all three animals. At 24, 48 and 72 hours, conjunctivitis and diffuse corneal opacities were found. One animal showed iritis at 24 and 48 hours. At 7 days after the application, corneal erosion and vascularization were observed in all animals. The effects were not reversible until study end (14 days after treatment). One animal showed iritis at 24 and 48 hours. The Mean Draize scores (24-72 h): corneal opacity: 1.1, iris: 0.2, conjunctivitis: 1.9, conjunctival swelling: 1.3. At 7 days after the application, corneal erosion and vascularization were observed in all animals. The effects were not reversible until study end (14 days after treatment).

Based on the irreversible eye damage caused by 3-Hydroxy-2 naphthalenecarboxylic acid(CAS No: -92-70-6), it can be considered as severe eye irritant.

Based on the available data for the target and read across substances and applying the weight of evidence approach, diphenyl acetic acid can be considered to be severly irritating to eyes.Comparing the above annotations with the criteria of CLP regulation, it can be classified under the category “Category 2”.

Justification for classification or non-classification

Available data for diphenyl acetic acid suggests that it is not likely to cause any irritation to skin and but it causes eye irritation.

Hence, diphenyl acetic acid can be classified under the category “Not Classified” for Skin and “Category 2” for eyes as per CLP regulation.