(3-aminophenyl)urea

Endpoint summary

Key value for chemical safety assessment

Genetic toxicity in vitro

Description of key information

Based on the prediction done using the OECD QSAR toolbox version 3.3 with log kow as the primary descriptor and considering the five closest read across substances, gene mutation was predicted for 1-(3-aminophenyl)urea. The study assumed the use of Salmonella typhimurium strainsTA 1535, TA 1537, TA 98, TA 100 and TA 102 with S9 metabolic activation system. 1-(3-aminophenyl)urea was predicted to not induce gene mutation in Salmonella typhimurium strains TA 1535, TA 1537, TA 98, TA 100 and TA 102 in the presence of S9 metabolic activation system and hence, according to the prediction made, it is not likely to classify as a gene mutant in vitro.

Based on the predicted result it can be concluded that the substance is considered to not toxic as per the criteria mentioned in CLP regulation.

Link to relevant study records

Reference

Endpoint:

in vitro gene mutation study in bacteria

Remarks:

Type of genotoxicity: gene mutation

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 version 3.3 and the supporting QMRF report has been attached

Qualifier:

according to guideline

Guideline:

other: Refer below principle

Principles of method if other than guideline:

Prediction is done using OECD QSAR Toolbox version 3.3, 2017

GLP compliance:

not specified

Type of assay:

bacterial reverse mutation assay

Specific details on test material used for the study:

- Name of the test material: 1-(3-aminophenyl)urea
- IUPAC name:1-(3-aminophenyl)urea
- Molecular formula: C7H9N3O
- Molecular weight: 151.168 g/mol
- Substance type: Organic
- Smiles: O=C(Nc1cccc(N)c1)N

Target gene:

Histidine

Species / strain / cell type:

S. typhimurium TA 1535, TA 1537, TA 98, TA 100 and TA 102

Details on mammalian cell type (if applicable):

Not applicable

Additional strain / cell type characteristics:

not specified

Cytokinesis block (if used):

No data

Metabolic activation:

with

Metabolic activation system:

S9 metabolic activation system

Test concentrations with justification for top dose:

No data

Vehicle / solvent:

No data

Untreated negative controls:

not specified

Negative solvent / vehicle controls:

not specified

True negative controls:

not specified

Positive controls:

not specified

Positive control substance:

not specified

Details on test system and experimental conditions:

No data

Rationale for test conditions:

No data

Evaluation criteria:

Prediction is done considering a dose dependent increase in the number of revertants/plate

Statistics:

No data

Species / strain:

S. typhimurium, other: TA 1535, TA 1537, TA 98, TA 100 and TA 102

Metabolic activation:

with

Genotoxicity:

negative

Cytotoxicity / choice of top concentrations:

not specified

Vehicle controls validity:

not specified

Untreated negative controls validity:

not specified

Positive controls validity:

not specified

Additional information on results:

No data

The prediction was based on dataset comprised from the following descriptors: "Gene mutation"
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 ("f" and ( not "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 ( 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 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 SN1 AND SN1 >> Nitrenium Ion formation AND SN1 >> Nitrenium Ion formation >> Aromatic phenylureas AND SN1 >> Nitrenium Ion formation >> Primary aromatic amine 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 OASIS v1.3

Domain logical expression index: "g"

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 >> N-Acylsulfonamides  OR Acylation >> Ester aminolysis OR Acylation >> Ester aminolysis >> Amides OR Michael Addition OR Michael Addition >> Michael addition on conjugated systems with electron withdrawing group OR Michael Addition >> Michael addition on conjugated systems with electron withdrawing group >> Activated electrophilic ethenylarenes  OR Michael Addition >> Quinoide type compounds OR Michael Addition >> Quinoide type compounds >> Quinone methide(s)/imines; Quinoide oxime structure; Nitroquinones, Naphthoquinone(s)/imines  OR SN2 OR SN2 >> Nucleophilic substitution at sp3 carbon atom OR SN2 >> Nucleophilic substitution at sp3 carbon atom >> (Thio)Phosphates  OR SN2 >> SN2 Reaction at a sp3 carbon atom OR SN2 >> SN2 Reaction at a sp3 carbon atom >> Activated alkyl esters and thioesters  OR SN2 >> SN2 reaction at a sulfur atom OR SN2 >> SN2 reaction at a sulfur atom >> Isothiazolidin-3-ones (sulphur) and Isothiazolone derivatives  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: "h"

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

Domain logical expression index: "i"

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 by Protein binding by OECD

Domain logical expression index: "j"

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

Domain logical expression index: "k"

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

Domain logical expression index: "l"

Referential boundary: The target chemical should be classified as Alkali Earth OR Halogens OR Metalloids by Groups of 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 4,4'-Methylenedianilines/benzidines (Hepatobiliary toxicity) Rank B  OR Anilines (Hemolytic anemia with methemoglobinemia) Rank A OR Anilines (Hepatotoxicity) Rank C OR Benzene/ Naphthalene sulfonic acids (Less susceptible) Rank C OR Methyldopa (Hepatotoxicity) Alert OR Nitrophenols/ Halophenols (Energy metabolism dysfuntion) Rank B OR o-/ p-Aminophenols (Hemolytic anemia with methemoglobinemia) Rank B OR p-Aminophenols (Renal toxicity) Rank B OR Thiocarbamates/Sulfides (Hepatotoxicity) No rank by Repeated dose (HESS)

Domain logical expression index: "o"

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

Domain logical expression index: "p"

Referential boundary: The target chemical should be classified as Aldehyde Type Compounds OR Not classified OR Phenol Type Compounds OR Urea Type Compounds by Oncologic Primary Classification

Domain logical expression index: "q"

Referential boundary: The target chemical should be classified as H-acceptor-path3-H-acceptor AND Primary aromatic amine, hydroxyl amine and its derived esters by in vivo mutagenicity (Micronucleus) alerts by ISS

Domain logical expression index: "r"

Referential boundary: The target chemical should be classified as 1-phenoxy-benzene OR Heterocyclic Polycyclic Aromatic Hydrocarbons OR Polycyclic Aromatic Hydrocarbons OR Quinones by in vivo mutagenicity (Micronucleus) alerts by ISS

Domain logical expression index: "s"

Referential boundary: The target chemical should be classified as No alert found by DNA alerts for AMES, MN and CA by OASIS v.1.3

Domain logical expression index: "t"

Referential boundary: The target chemical should be classified as Non-covalent interaction OR Non-covalent interaction >> DNA intercalation OR Non-covalent interaction >> DNA intercalation >> Fused-Ring Primary Aromatic Amines OR Non-specific OR Non-specific >> Incorporation into DNA/RNA, due to structural analogy with  nucleoside bases    OR Non-specific >> Incorporation into DNA/RNA, due to structural analogy with  nucleoside bases    >> Specific Imine and Thione Derivatives OR Radical 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) >> p-Aminobiphenyl Analogs OR Radical >> Radical mechanism via ROS formation (indirect) >> Single-Ring Substituted Primary Aromatic Amines OR Radical >> Radical mechanism via ROS formation (indirect) >> Specific Imine and Thione Derivatives OR SN1 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 substitution on diazonium ion OR SN1 >> Nucleophilic substitution on diazonium ion >> Specific Imine and Thione Derivatives by DNA alerts for AMES, MN and CA by OASIS v.1.3

Domain logical expression index: "u"

Referential boundary: The target chemical should be classified as Aromatic amine   [-NH2  or  -NH-] AND Aromatic-H by Biodegradation fragments (BioWIN MITI)

Domain logical expression index: "v"

Referential boundary: The target chemical should be classified as Aliphatic acid   [-C(=O)-OH] OR Aliphatic alcohol  [-OH] OR Aliphatic amine   [-NH2  or  -NH-] OR Aliphatic ether  [C-O-C] OR Amide   [-C(=O)-N  or -C(=S)-N] OR Aromatic acid   [-C(=O)-OH] OR Aromatic ether  [-O-aromatic carbon] OR Aromatic-CH OR Aromatic-CH2 OR Aromatic-CH3 OR -C=CH  [alkenyl hydrogen] OR Carbon with 4 single bonds & no hydrogens OR -CH-   [linear] OR -CH2-  [linear] OR Cyanide / Nitriles   [-C#N] OR Ester   [-C(=O)-O-C] OR Ketone   [-C-C(=O)-C-] OR Methyl  [-CH3] OR Pyridine ring by Biodegradation fragments (BioWIN MITI)

Domain logical expression index: "w"

Parametric boundary:The target chemical should have a value of log Kow which is >= -1.07

Domain logical expression index: "x"

Parametric boundary:The target chemical should have a value of log Kow which is <= 2.84

Conclusions:

1-(3-aminophenyl)urea was predicted to not induce gene mutation in Salmonella typhimurium strains TA 1535, TA 1537, TA 98, TA 100 and TA 102 in the presence of S9 metabolic activation system and hence, according to the prediction made, it is not likely to classify as a gene mutant in vitro. 118

Executive summary:

Based on the prediction done using the OECD QSAR toolbox version 3.3 with log kow as the primary descriptor and considering the five closest read across substances, gene mutation was predicted for 1-(3-aminophenyl)urea. The study assumed the use of Salmonella typhimurium strainsTA 1535, TA 1537, TA 98, TA 100 and TA 102 with S9 metabolic activation system. 1-(3-aminophenyl)urea was predicted to not induce gene mutation in Salmonella typhimurium strains TA 1535, TA 1537, TA 98, TA 100 and TA 102 in the presence of S9 metabolic activation system and hence, according to the prediction made, it is not likely to classify as a gene mutant in vitro.

Based on the predicted result it can be concluded that the substance is considered to not toxic as per the criteria mentioned in CLP regulation.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (negative)

Genetic toxicity in vivo

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

Gene mutation in vitro:

Prediction model based estimation and data from read across chemicals were reviewed to determine the muatgenic nature of 1-(3-aminophenyl)urea. The studies are as mentioned below

Based on the prediction done using the OECD QSAR toolbox version 3.3 with log kow as the primary descriptor and considering the five closest read across substances, gene mutation was predicted for 1-(3-aminophenyl)urea. The study assumed the use of Salmonella typhimurium strains TA 1535, TA 1537, TA 98, TA 100 and TA 102 with S9 metabolic activation system. 1-(3-aminophenyl)urea was predicted to not induce gene mutation in Salmonella typhimurium strains TA 1535, TA 1537, TA 98, TA 100 and TA 102 in the presence of S9 metabolic activation system and hence, according to the prediction made, it is not likely to classify as a gene mutant in vitro.

Lavoie et al (Mutation Research, 1979) performed gene mutation toxicity study on structurally and functionally similar read across chemical.

4-Aminophenyl sulfone (RA CAS no 80 -08 -0; IUPAC name: 4,4'-Diaminodiphenyl Sulphone) was studied for its ability to induce mutations in strains of Salmonella typhimurium. The test compound was dissolved in DMSO and was tested at concentration of 0, 25, 50, 100, 250 or 500 µg/plate using Salmonella typhimurium TA100 and TA98 in the presence and absence of S9 metabolic activation system. 4-Aminophenyl sulfoneis not mutagenic to theSalmonella typhimurium TA100 and TA98 in the presence and absence of S9 metabolic activation system.

In another study for structurally and functionally similar read across chemical by Ioannides et al (Carcinogenesis, 1989), 3-Aminobiphenyl (RA CAS no 2243 -47 -2) was studied for its ability to induce mutations in strains of Salmonella typhimurium. The test compound was dissolved in DMSO and was tested at concentration of 0, 10, 20, 30 or 40 µg/plate using Salmonella typhimurium TA100 and TA98 in the presence and absence of S9 metabolic activation system. 3-Aminobiphenyl is not mutagenic to the Salmonella typhimurium TA100 and TA98 in the presence and absence of S9 metabolic activation system.

Based on the data available for the target chemical and its read across, 1-(3-aminophenyl)urea does not exhibit gene mutation in vitro. Hence the test chemical is not likely to classify as a gene mutant in vitro.

Justification for classification or non-classification

Based on the data available for the target chemical and its read across, 1-(3-aminophenyl)urea (CAS no 25711 -72 -2) does not exhibit gene mutation in vitro. Hence the test chemical is not likely to classify as a gene mutant in vitro.