3-phenylpropionic acid

Endpoint summary

Description of key information

Skin Irritation:

The dermal irritation potential of 3-phenylpropanoic acid was estimated using OECD QSAR toolbox v3.4 with logPow as the primary descriptor.

3-phenylpropanoic acid was estimated to be not irritating to the skin of New Zealand White rabbits.

Based on the estimated results, 3-phenylpropanoic acid can be considered to be not irritating to skin and can be classified under the category “Not Classified” as per CLP regulation.

Eye Irritation:

The ocular irritation potential of 3-phenylpropanoic acid was estimated using OECD QSAR toolbox v3.4 with logPow as the primary descriptor.

3-phenylpropanoic acid was estimated to be not irritating to the eyes of New Zealand White rabbits.

Based on the estimated results, 3-phenylpropanoic acid can be considered to be not irritating to eyes and can be classified under the category “Not Classified” 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:

calculation (if not (Q)SAR)

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

accepted calculation method

Justification for type of information:

data is from modelling database

Qualifier:

according to guideline

Guideline:

other: estimated data

Principles of method if other than guideline:

To estimate the skin irritation potential of 3-phenylpropanoic acid

GLP compliance:

not specified

Specific details on test material used for the study:

Name of the test chemical: 3-phenylpropanoic acid
Molecular weight: 150.176 g/mol
Molecular formula: C9H10O2
SMILES: c1(CCC(O)=O)ccccc1
Substance type: Organic
Physical State: Solid

Species:

rabbit

Strain:

not specified

Details on test animals or test system and environmental conditions:

estimated data

Type of coverage:

not specified

Preparation of test site:

not specified

Vehicle:

unchanged (no vehicle)

Controls:

not specified

Amount / concentration applied:

estimated data

Duration of treatment / exposure:

estimated data

Observation period:

estimated data

Number of animals:

estimated data

Details on study design:

estimated data

Other effects / acceptance of results:

No data available

Irritation parameter:

overall irritation score

Basis:

mean

Time point:

other: estimated data

Score:

0

Reversibility:

not specified

Remarks on result:

no indication of irritation

Irritant / corrosive response data:

No irrritation observed

Table showing skin irritation estimation by three different models i.e, Leadscope, battery and SciQSAR &CASE Ultra,the average skin irritation results was given by the fourth model i.e, Battery model.

DK	Battery	SciQSAR	CASE Ultra	Leadscope
Skin irritation in rabbit	NEG	NEG	NEG	NEG
Domain	IN	IN	IN	OUT

 

Where,

IN = inside applicability domain

Interpretation of results:

other: not irritating

Conclusions:

No Severe skin irritation effects of 3-phenypropanoic acid were estimated in rabbit skin by four different models i.e, Battery, Leadscope, SciQSAR and CASE Ultra used within Danish QSAR database.

Executive summary:

Skin irritation effects were estimated by four different models i.e, Battery, Leadscope, SciQSAR and CASE Ultra used within Danish QSAR database for 3-phenylpropanoic acid. Based on estimation, no severe skin irritation effects were known when 3-phenylpropanoic acid was exposed to rabbit skin.

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 v3.4 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 v3.4

GLP compliance:

not specified

Specific details on test material used for the study:

Name of the test chemical: 3-phenylpropanoic acid
Molecular weight: 150.176 g/mol
Molecular formula: C9H10O2
SMILES: c1(CCC(O)=O)ccccc1
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:

unchanged (no vehicle)

Controls:

not specified

Amount / concentration applied:

0.1g

Duration of treatment / exposure:

single administration

Observation period (in vivo):

14 days

Duration of post- treatment incubation (in vitro):

no data available

Number of animals or in vitro replicates:

6

Details on study design:

no data available

Other effects / acceptance of results:

no data available

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 observed

Estimation method: Takes mode value from the 7 nearest neighbours
Domain  logical expression:Result: In Domain

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

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 (nested)

Domain logical expression index: "c"

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 [-CH2-] AND Aromatic Carbon [C] AND Carbonyl, aliphatic attach [-C(=O)-] AND Miscellaneous sulfide (=S) or oxide (=O) AND Olefinic carbon [=CH- or =C<] by Organic functional groups (US EPA)

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 [-CH2-] AND Aromatic Carbon [C] AND Carbonyl, aliphatic attach [-C(=O)-] AND Miscellaneous sulfide (=S) or oxide (=O) AND Olefinic carbon [=CH- or =C<] by Organic functional groups (US EPA)

Domain logical expression index: "e"

Referential boundary:The target chemical should be classified as No alert found by DNA binding by OASIS v.1.4

Domain logical expression index: "f"

Referential boundary:The target chemical should be classified as AN2 OR AN2 >> Nucleophilic addition reaction with cycloisomerization OR AN2 >> Nucleophilic addition reaction with cycloisomerization >> Hydrazine Derivatives OR AN2 >> Schiff base formation by aldehyde formed after metabolic activation OR AN2 >> Schiff base formation by aldehyde formed after metabolic activation >> Geminal Polyhaloalkane Derivatives 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 and Aminoalkylamine Side Chain OR Radical OR Radical >> Radical mechanism via ROS formation (indirect) OR Radical >> Radical mechanism via ROS formation (indirect) >> Geminal Polyhaloalkane Derivatives OR Radical >> Radical mechanism via ROS formation (indirect) >> Hydrazine 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 Radical >> Radical mechanism via ROS formation (indirect) >> Single-Ring Substituted Primary Aromatic Amines 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 nitrenium ion formation OR SN1 >> Nucleophilic attack after 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 >> 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 >> Acylation involving a leaving group after metabolic activation OR SN2 >> Acylation involving a leaving group after metabolic activation >> Geminal Polyhaloalkane Derivatives OR SN2 >> Direct nucleophilic attack on diazonium cation OR SN2 >> Direct nucleophilic attack on diazonium cation >> Hydrazine Derivatives OR SN2 >> Nucleophilic substitution at sp3 Carbon atom OR SN2 >> Nucleophilic substitution at sp3 Carbon atom >> Specific Acetate Esters OR SN2 >> Nucleophilic substitution at sp3 carbon atom after thiol (glutathione) conjugation OR SN2 >> Nucleophilic substitution at sp3 carbon atom after thiol (glutathione) conjugation >> Geminal Polyhaloalkane Derivatives by DNA binding by OASIS v.1.4

Domain logical expression index: "g"

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

Domain logical expression index: "h"

Referential boundary:The target chemical should be classified as High reactive OR High reactive >> alpha,beta-carbonyl compounds with polarized multiple bonds OR High reactive >> Organic disulfides by DPRA Cysteine peptide depletion

Domain logical expression index: "i"

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

Domain logical expression index: "j"

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

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

Domain logical expression index: "l"

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

Domain logical expression index: "m"

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: "n"

Similarity boundary:Target: OC(=O)CCc1ccccc1
Threshold=80%,
Dice(Atom centered fragments)
Atom type; Count H attached; Hybridization

Domain logical expression index: "o"

Similarity boundary:Target: OC(=O)CCc1ccccc1
Threshold=20%,
Dice(Atom centered fragments)
Atom type; Count H attached; Hybridization

Domain logical expression index: "p"

Similarity boundary:Target: OC(=O)CCc1ccccc1
Threshold=30%,
Dice(Atom centered fragments)
Atom type; Count H attached; Hybridization

Domain logical expression index: "q"

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

Domain logical expression index: "r"

Referential boundary:The target chemical should be classified as Substituted indoles by Eye irritation/corrosion Inclusion rules by BfR

Domain logical expression index: "s"

Referential boundary:The target chemical should be classified as No alert found by Protein binding alerts for skin sensitization by OASIS v1.4

Domain logical expression index: "t"

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 >> Anhydrides (sulphur analogues of anhydrides)  OR Acylation >> Direct acylation involving a leaving group >> Carbamates  by Protein binding alerts for skin sensitization by OASIS v1.4

Domain logical expression index: "u"

Referential boundary:The target chemical should be classified as No alert found by Respiratory sensitisation

Domain logical expression index: "v"

Referential boundary:The target chemical should be classified as Pro-Michael Addition OR Pro-Michael Addition >> Pro-quinone and related OR Pro-Michael Addition >> Pro-quinone and related >> Phenylenediamines by Respiratory sensitisation

Domain logical expression index: "w"

Parametric boundary:The target chemical should have a value of log Kow which is >= 1.3

Domain logical expression index: "x"

Parametric boundary:The target chemical should have a value of log Kow which is <= 3.05

Interpretation of results:

other: not irritating

Conclusions:

3-phenylpropanoic acid was estimated to be not irritating to the eyes of New Zealand White rabbits.

Executive summary:

The ocular irritation potential of 3-phenylpropanoic acid was estimated using OECD QSAR toolbox v3.4 with logPow as the primary descriptor.

3-phenylpropanoic acid was estimated to be not irritating to the eyes of New Zealand White rabbits.

Based on the estimated results, 3-phenylpropanoic acid can be considered to be not irritating to eyes and can be classified under the category “Not Classified” as per CLP regulation.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (not irritating)

Respiratory irritation

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

Skin irritation:

In different studies, 3-phenylpropanoic 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 structurally similar read across substancesBenzoic acid(CAS:65-85-0)and Sodium Benzoate(CAS:532-32-1). 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 for3-phenylacetic acid. 3 -phenylacetic 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 3 -phenylpropanoic acid. Based on estimation, no severe skin irritation effects were known when 3-phenylpropanoic acid was exposed to rabbit skin.

 

Both estimated results indicate the possibility of 3-phenylpropanoic acid being not irritating to skin.

Also these results are further supported by the experimental study summarized in SCCP OPINION ON Benzoic Acid and Sodium Benzoate, Adopted by the SCCP during the 4th plenary of 21 June 2005, for thestructurally similar read across substanceBenzoic acid(CAS:65-85-0).The study was performed according to OECD 404 (1981), EEC test method B.4, Annex V of EEC Directive 84/449/EEC (September 1984). A paste, (0.5 g benzoic acid and 0.25 ml water), was applied evenly to 6 cm2 Metalline on a permeable tape (Micropore). This was applied to the right flank of 3 females New Zealand albino rabbits. A control patch without the test substance was applied to the left flank. These were left in place for 4 hours. The test site was cleaned first with a dry tissue and then by swabbed with a dampened tissue. The skin was examined for erythema, eschar formation and oedema at 1, 24, 48 and 72 hours after removal of the patches. Two animals showed slight erythema initially. 1 of these also showed slight edema up to 24 h. These effects were resolved by 48 h. There was no indication of a systemic effect. The modified primary irritation index (PII) of 0.5 was recorded when benzoic acid was applied to the intact rabbit skin under semi-occlusive patch conditions.

Based on the scores, Benzoic acid can be considered to be not irritating to New Zealand albino rabbit skin.

The above results are further supported by the experimental study summarized in SCCP OPINION ON Benzoic Acid and Sodium Benzoate, Adopted by the SCCP during the 4th plenary of 21 June 2005, for thestructurally similar read across substance Sodium benzoate (CAS: 532-32-1).The study was performed according to OECD 404 (1981), EEC test method B.4, Annex V of EEC Directive 84/449/EEC (September 1984).Approximately 24 hours prior to the treatment, the dorsal fur was shaved. A paste, (0.5 g sodium benzoate and 0.25 ml water), was applied evenly to 6 cm² Metalline on a permeable tape (Micropore). The 6 cm² patch was removed four hours after semi-occlusive contact. The skin reactions were assessed approx. 1 hour, 24, 48 and 72 hours after termination of the exposure. The animals did not show any symptoms of systemic intoxication.

Under the conditions of the study, sodium benzoate was neither corrosive nor irritating (PII 0) when applied to the intact rabbit skin under semi-occlusive patch conditions for four hours. Sodium benzoate can be considered as not irritating to New Zealand albino rabbit skin.

Based on the available data for the target and read across substances and applying the weight of evidence approach, 3-phenylpropanoic 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, 3-phenylpropanoic 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 structurally similar read across substancesBenzyl propionate (CAS: 122-63-4) andSodium Benzoate(CAS:532-32 -1). 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 for3-phenylacetic acid. 3-phenylacetic acidwas not irritating to New Zealand White rabbit eyes.

 

This result was supported by the study conductedin an OECD GLP laboratory (Sustainability Support Services (Europe) AB has the letter of access) for thestructurally similar read across substanceBenzyl propionate (CAS: 122-63-4). This study was performed as per OECD guideline No. 405.Rabbits free from injury of eye were selected for the study. The eyes of all the rabbits were examined 24 hours prior to treatment. One eye of each rabbit served as control and other as treated. Control eye was left untreated whereas; 0.1 ml of test item (as such) was instilled in the other (treated) eye of rabbits. The eye was observed at 1, 24, 48, 72 hours after test item instillation. Ophthalmoscope was used for scoring of eye lesions. In the initial test, 0.1 ml of test item was applied into the conjunctival sac of the right eye of Animal No.1. The left eye of the rabbit served as the control. Animal No. 1 presented ocular lesions at 1 hour observation period. Hence the confirmatory test was conducted on additional two rabbits (Animal No. 2 and 3); 0.1 ml of test item was instilled into the conjunctival sac of right eye and left eye served as the control. Ocular lesions were observed at 1, 24 and 48 hour in Animal Number 2 whereas in Animal Number 3 ocular lesions presented only at 1 hour observation period. Untreated eye of the treated rabbits was normal throughout the experimental period of 72 hours. The following grading scores were observed in treated eye of tested rabbits.

Observation at 1 hour after instillation of test item revealed: Cornea-No ulceration or opacity in all 3 animals; Area of Opacity-Zero in all the animals; Iris: Normal in all the animals. Conjunctivae -Some blood vessels definitely hyperaemic (injected) in all the animals; Chemosis: Some swelling above normal (includes nictating membranes) were observed in animal number 1 and 3 whereas animal number 2 was normal. Observation at 24 hours after instillation of test item revealed: Cornea-No ulceration or opacity in all the animals; Area of Opacity-Zero in all the animals; Iris: Normal in all the animals. Conjunctivae -Some blood vessels definitely hyperaemic (injected) was observed in animal no. 2. Animal no. 1 and 3 recovered to normal; Chemosis: No swelling was observed in all the Animals. At 24 hours observation the rabbits were examined for corneal epithelium cell damage using sodium fluorescein strips and noticed 0 % damage in Animal Nos 1, 2 and 3, respectively. Observation at 48 and 72 hours after instillation of test item revealed: Cornea-No ulceration or opacity in all the animals; Area of Opacity-Zero in all the animals; Iris: Normal in all the animals. Conjunctivae -Some blood vessels definitely hyperaemic (injected) was observed in animal no. 3 at 48 hours which was recovered to normal at 72 hours observation whereas blood vessels were normal in Animal Numbers 1 and 3 at 48 and 72 hours observation; Chemosis: No swelling was observed in all the animals.

The individual mean score for Animal Nos. 1, 2 and 3at 24, 48, 72 hours for Corneal opacity, iris, conjunctiva, chemosis were found 0.00, 0.00, 0.00, 0.00; 0.00, 0.00, 0.67, 0.00 and 0.00, 0.00, 0.00, 0.00, respectively. Under the experimental conditions tested, eye irritation and reversibility of effects on eyes of rabbits was observed at 72 hours. 

Hence under the experimental test conditions, Benzyl propionate (CAS No: 122-63-4) is “Non Irritant” to New Zealand White Male rabbit eyes and is being classified as “Not Classified” as per the CLP regulation.

The above results are further supported by the experimental study summarized inSIDS Initial Assessment Report for 13th SIAM - Benzoates, 2001, for thestructurally similar read across substance Sodium benzoate (CAS: 532-32-1). The study was performed according to Directive 84/449/EEC in rabbits. Sodium benzoate was instilled into rabbit eyes and effects were observed (duration and dose not specified). Under the conditions of the study, sodium benzoate was not irritating to rabbit eyes.

These results are also supported by the experimental study summarized in GESTIS - Substance Database (Information system on hazardous substances of the Berufsgenossenschaften), 2017,for thestructurally similar read across substance Sodium benzoate (CAS: 532-32-1). Sodium benzoate was instilled into human eyes and effects were observed (dose and duration not specified).

Under the conditions of the study, sodium benzoate was not irritating to human eyes.

Based on the available data for the target and read across substances and applying the weight of evidence approach, 3-phenylpropanoic acid can be considered to be not irritating to eyes.Comparing the above annotations with the criteria of CLP regulation, it can be classified under the category “Not Classified”.

Justification for classification or non-classification

Available studies for 3-phenylpropanoic acid suggest that it is not irritating to eyes and skin. Hence, 3-phenylpropanoic acid can be classified under the category “Not Classified” as per CLP regulation.