(3-aminophenyl)urea

Endpoint summary

Description of key information

Skin Irritation:

The dermal irritation potential of 1-(3-aminophenyl)urea was estimated using OECD QSAR toolbox v3.3 with logPow as the primary descriptor.

1-(3-aminophenyl)urea was estimated to be not irritating to the skin of New Zealand White rabbits.

Based on the estimated results, 1-(3-aminophenyl)urea can be considered not irritating to skin and can be classified under the category “Not Classified” as per CLP regulation.

Eye Irritation:

The ocular irritation potential of 1-(3-aminophenyl)urea was estimated using OECD QSAR toolbox v3.3 with logPow as the primary descriptor.

1-(3-aminophenyl)urea was estimated to be irritating to the eyes of Vienna White rabbits.

Based on the estimated results, 1-(3-aminophenyl)urea can be considered irritating to eyes and can be classified under the category “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 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 (as cited in study report): 1-(3-aminophenyl)urea
- Molecular formula: C7H9N3O
- Molecular weight: 151.168 g/mol
- Substance type: Organic
- Physical state: Solid

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:

unchanged (no vehicle)

Controls:

not specified

Amount / concentration applied:

0.5 ml

Duration of treatment / exposure:

4 hours

Observation period:

72 hours

Number of animals:

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:

72 h

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 8 nearest neighbours
Domain  logical expression:Result: In Domain

(((((("a" or "b" or "c" or "d" )  and "e" )  and ("f" and ( not "g") )  )  and ("h" and ( not "i") )  )  and ("j" and ( not "k") )  )  and ("l" and "m" )  )

Domain logical expression index: "a"

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

Domain logical expression index: "b"

Referential boundary: The target chemical should be classified as Radical AND Radical >> Radical mechanism via ROS formation (indirect) AND Radical >> Radical mechanism via ROS formation (indirect) >> Single-Ring Substituted Primary Aromatic Amines AND SN1 AND SN1 >> Nucleophilic attack after metabolic nitrenium ion formation AND 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: "c"

Referential boundary: The target chemical should be classified as SN1 OR SN1 >> Nitrenium Ion formation OR SN1 >> Nitrenium Ion formation >> Aromatic phenylureas OR SN1 >> Nitrenium Ion formation >> Primary aromatic amine by DNA binding by OECD ONLY

Domain logical expression index: "d"

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

Domain logical expression index: "e"

Referential boundary: The target chemical should be classified as Radical AND Radical >> Radical mechanism via ROS formation (indirect) AND Radical >> Radical mechanism via ROS formation (indirect) >> Single-Ring Substituted Primary Aromatic Amines AND SN1 AND SN1 >> Nucleophilic attack after metabolic nitrenium ion formation AND SN1 >> Nucleophilic attack after metabolic nitrenium ion formation >> Single-Ring Substituted Primary Aromatic Amines by DNA binding by OASIS v.1.3 ONLY

Domain logical expression index: "f"

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

Domain logical expression index: "g"

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

Domain logical expression index: "h"

Referential boundary: The target chemical should be classified as No alert found by rtER Expert System ver.1 - USEPA

Domain logical expression index: "i"

Referential boundary: The target chemical should be classified as 4-Alkylanilines by rtER Expert System ver.1 - USEPA

Domain logical expression index: "j"

Referential boundary: The target chemical should be classified as No alert found by Protein binding alerts for Chromosomal aberration by OASIS v1.1

Domain logical expression index: "k"

Referential boundary: The target chemical should be classified as Ac-SN2 OR Ac-SN2 >> Acylation involving an activated (glucuronidated) carboxamide group OR Ac-SN2 >> Acylation involving an activated (glucuronidated) carboxamide group >> Carboxylic Acid Amines OR Ac-SN2 >> Direct acylation involving a leaving group OR Ac-SN2 >> Direct acylation involving a leaving group >> Carboxylic Acid Amines OR AN2 OR AN2 >> Michael addition to the quinoid type structures OR AN2 >> Michael addition to the quinoid type structures >> Substituted Anilines OR AN2 >> Michael-type addition to quinoid structures OR AN2 >> Michael-type addition to quinoid structures >> Carboxylic Acid Amines by Protein binding alerts for Chromosomal aberration by OASIS v1.1

Domain logical expression index: "l"

Parametric boundary:The target chemical should have a value of log Kow which is >= -1.54

Domain logical expression index: "m"

Parametric boundary:The target chemical should have a value of log Kow which is <= 3.99

Interpretation of results:

other: not irritating

Conclusions:

1-(3-aminophenyl)urea was estimated to be not irritating to the skin of New Zealand White rabbits.

Executive summary:

The dermal irritation potential of 1-(3-aminophenyl)urea was estimated using OECD QSAR toolbox v3.3 with logPow as the primary descriptor.

1-(3-aminophenyl)urea was estimated to be not irritating to the skin of New Zealand White rabbits.

Based on the estimated results, 1-(3-aminophenyl)urea can be considered not irritating to skin and can be classified under the category “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 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 v 3.3

GLP compliance:

not specified

Specific details on test material used for the study:

- Name of test material (as cited in study report): 1-(3-aminophenyl)urea
- Molecular formula: C7H9N3O
- Molecular weight: 151.168 g/mol
- Substance type: Organic
- Physical state: Solid

Species:

rabbit

Strain:

Vienna White

Details on test animals or tissues and environmental conditions:

no data available

Vehicle:

unchanged (no vehicle)

Controls:

not specified

Amount / concentration applied:

50 microliters

Duration of treatment / exposure:

1 hour

Observation period (in vivo):

8 days

Duration of post- treatment incubation (in vitro):

no data available

Number of animals or in vitro replicates:

2

Details on study design:

no data available

Other effects / acceptance of results:

no data available

Irritation parameter:

overall irritation score

Basis:

mean

Time point:

other: 8 days

Reversibility:

not specified

Remarks on result:

positive indication of irritation

Irritant / corrosive response data:

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" )  and ("e" and ( not "f") )  )  and ("g" and ( not "h") )  )  and "i" )  and ("j" and ( not "k") )  )  and "l" )  and "m" )  and ("n" and ( not "o") )  )  and ("p" and ( not "q") )  )  and "r" )  and "s" )  and ("t" and "u" )  )

Domain logical expression index: "a"

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

Domain logical expression index: "b"

Referential boundary: The target chemical should be classified as Radical AND Radical >> Radical mechanism via ROS formation (indirect) AND Radical >> Radical mechanism via ROS formation (indirect) >> Single-Ring Substituted Primary Aromatic Amines AND SN1 AND SN1 >> Nucleophilic attack after metabolic nitrenium ion formation AND 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: "c"

Referential boundary: The target chemical should be classified as SN1 OR SN1 >> Nitrenium Ion formation OR SN1 >> Nitrenium Ion formation >> Aromatic phenylureas OR SN1 >> Nitrenium Ion formation >> Primary aromatic amine by DNA binding by OECD ONLY

Domain logical expression index: "d"

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

Domain logical expression index: "e"

Referential boundary: The target chemical should be classified as No alert found by Protein binding by OASIS v1.3

Domain logical expression index: "f"

Referential boundary: The target chemical should be classified as Acylation OR Acylation >> Ester aminolysis OR Acylation >> Ester aminolysis >> Amides OR SN1 OR SN1 >> Carbenium ion formation (enzymatic) OR SN1 >> Carbenium ion formation (enzymatic) >> Carbenium ion OR SN2 OR SN2 >> SN2 Reaction at a sp3 carbon atom OR SN2 >> SN2 Reaction at a sp3 carbon atom >> Activated alkyl esters and thioesters  OR SNAr OR SNAr >> Nucleophilic aromatic substitution on activated aryl and heteroaryl compounds OR SNAr >> Nucleophilic aromatic substitution on activated aryl and heteroaryl compounds >> Activated aryl and heteroaryl compounds by Protein binding by OASIS v1.3

Domain logical expression index: "g"

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

Domain logical expression index: "h"

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 >> Acetates OR SNAr OR SNAr >> Nucleophilic aromatic substitution OR SNAr >> Nucleophilic aromatic substitution >> Activated halo-benzenes by Protein binding by OECD

Domain logical expression index: "i"

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

Domain logical expression index: "j"

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

Domain logical expression index: "k"

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

Domain logical expression index: "l"

Similarity boundary:Target: Nc1cccc(NC(N)=O)c1
Threshold=20%,
Dice(Atom centered fragments)
Atom type; Count H attached; Hybridization

Domain logical expression index: "m"

Referential boundary: The target chemical should be classified as Intermediate (Class II) by Toxic hazard classification by Cramer (original) ONLY

Domain logical expression index: "n"

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: "o"

Referential boundary: The target chemical should be classified as Low reactive OR Low reactive >> Sulfanilic acid derivatives by DPRA Cysteine peptide depletion

Domain logical expression index: "p"

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

Domain logical expression index: "q"

Referential boundary: The target chemical should be classified as Esters (Acute toxicity) OR Not categorized OR Phenols (Acute toxicity) by US-EPA New Chemical Categories

Domain logical expression index: "r"

Referential boundary: The target chemical should be classified as Discrete chemical by Substance Type ONLY

Domain logical expression index: "s"

Referential boundary: The target chemical should be classified as Does NOT Biodegrade Fast by Biodeg probability (Biowin 5) ONLY

Domain logical expression index: "t"

Parametric boundary:The target chemical should have a value of log Kow which is >= -2.08

Domain logical expression index: "u"

Parametric boundary:The target chemical should have a value of log Kow which is <= 1.08

Interpretation of results:

Category 2 (irritating to eyes) based on GHS criteria

Conclusions:

1-(3-aminophenyl)urea was estimated to be irritating to the eyes of Vienna White rabbits.

Executive summary:

The ocular irritation potential of 1-(3-aminophenyl)urea was estimated using OECD QSAR toolbox v3.3 with logPow as the primary descriptor.

1-(3-aminophenyl)urea was estimated to be irritating to the eyes of Vienna White rabbits.

Based on the estimated results, 1-(3-aminophenyl)urea can be considered irritating to eyes and can be classified under the category “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, 1-(3-aminophenyl)urea 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 closely related read across substances, Urea [CAS: 57-13-6], 3,5 Dimethylaniline [CAS: 108-69-0] and 6-Ethyl-o-toluidine [CAS: 24549-06-2].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 dermal irritation potential was estimated for 1-(3-aminophenyl)urea . 1-(3 -aminophenyl)urea was estimated to be not irritating to the skin of New Zealand White rabbits.

This result is supported by the experimental study summarized in International Journal of Toxicology;24 Suppl 3:1-56,2005; for the closely related read across substance, Urea [CAS: 57-13 -6]. 1, 10, 25, 50, 75 or 100% urea was exposed to the skin of 3 male nude mice for 24 hours.3 animals were exposed to each formulation and maintained 3/cage. Urea was placed in a PVC (Polyvinyl chloride) cup with a surface area of 0.8 sq cm and surface volume of 0.3 cubic cm. The cup was fastened to the dorsal side of the animal using surgical tape and secured with Superglue. The mice were killed immediately after the 24 hours exposure period. Specimens of the exposed areas and of the adjacent untreated skin were taken for histological evaluation. Histological assessment included examination for epidermal changes, hyperkeratosis, spongiosis, destruction of the epidermis hyperemia, and increase in the cell layer of the stratum granulosum, increase in the density and thickness of the collagen bundles, fractured collagen, infiltration of the dermis and intracellular edema. Urea did not cause any microscopic changes over the 24 hour period at the concentrations tested.

Hence, urea can be considered to be not irritating to the skin of male nude mice.

The above results are further supported by the experimental study summarized in GESTIS for CAS: 108-69-0; Institut für Arbeitsschutz der Deutschen Gesetzlichen Unfallversicherung (IFA) GESTIS-database on hazardous substance, 2016; for the closely related read across substance, 3,5 Dimethylaniline [CAS: 108-69-0]. The study was performed according to a standardized rabbit skin test (OECD 404). 3,5-xylidine was applied into rabbit skin and effects were observed (dose, duration not mentioned).

3,5-xylidine did not cause any irritation to rabbit skin. Hence, 3,5-xylidine can be considered not irritating to rabbit skin.

These results are also supported by the experimental study summarized in GESTIS for CAS: 24549-06-2; Institut für Arbeitsschutz der Deutschen Gesetzlichen Unfallversicherung (IFA) GESTIS-database on hazardous substance, 2017; for the closely related read across substance, 6-Ethyl-o-toluidine [CAS: 24549-06-2]. The study was performed according to a standardized rabbit skin test (OECD 404).6-Ethyl-o-toluidine was applied into rabbit skin and effects were observed (dose, duration not mentioned).

6-Ethyl-o-toluidinedid not cause any irritation to rabbit skin. Hence,6-Ethyl-o-toluidine can be considered not irritating to rabbit skin.

Based on the available data for the target as well as read across chemicals and applying the weight of evidence approach, 1-(3-aminophenyl)urea can be 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, 1-(3-aminophenyl)urea 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 closely related read across substances, p-phenylenediamine [CAS: 106-50-3] and o-phenylenediamine [CAS: 95-54-5]. 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 for 1-(3-aminophenyl)urea . 1-(3 -aminophenyl)urea was estimated to be not irritating to the eyes of Vienna White rabbits.

This result is supported by the experimental study summarized in Cosmetic Ingredient Review, 2007; for the closely related read across substance, p-phenylenediamine [CAS: 106-50-3]. The study was performed according to Draize method. 100% p-phenylenediamine was instilled into rabbit eyes and observed for signs of irritation (duration not mentioned).The ocular reactions were scored according to Draize method. The maximum irritation score reported for p-phenylenediamine was 17.0 of a possible 110. Based on the scores, p-phenylenediamine can be considered mildly irritating to rabbit eyes.

The above results are also supported by the experimental study summarized in Hazardous Substances Databank (HSDB),U.S National Library of Medicine, last updated 2013; for the closely

related read across substance, o-phenylenediamine [CAS: 95-54-5]. 100mg of undiluted o-phenylene diamine was instilled into the eyes of 3 albino rabbits. The treated eyes remained unwashed throughout the exposure and observation period. The rabbits were observed for signs of irritation at 1 hour, 72 hours, day 7 and day 14 post-instillation and the reactions were scored.Ocular irritation was maximal in all 3 rabbits 1 hour after treatment. A mean irritation score was 31.7/110. One rabbit remained unimproved at 72nd hour observation, developing corneal ulceration and vascularization by the 7thday, while Day 7 found complete resolution of all irritative signs in the other 2 treated rabbits. By 14th day observation period, one rabbit continued to show corneal vascularization and ulceration with slight conjunctival redness comprising an individual irritation score of 12/110 and a mean score (3 rabbits) of 4.0/110

Based on the scores and observations, o-phenylene diamine was considered to be moderately irritating to rabbit eyes.

Based on the available data for the target as well as read across chemicals and applying the weight of evidence approach, 1-(3-aminophenyl)urea can be considered irritating to eyes.Comparing the above annotations with the criteria of CLP regulation, test chemical can be classified under the category “Category 2”.

Justification for classification or non-classification

Available data for1-(3-aminophenyl)urea suggest that it is not likely to cause any irritation to skin but it is irritating to eyes.

Hence, 1-(3-aminophenyl)urea can be classified under the category “Not Classified” for Skin Irritation and “Category 2” for Eye Irritation as per CLP regulation.