7-[[2-[(aminocarbonyl)amino]-4-[(4-amino-6-chloro-1,3,5-triazin-2-yl)amino]phenyl]azo]naphthalene-1,3,6-trisulphonic acid

Carcinogenicity

Description of key information

The carcinogenic potential of 7-[[2-[(aminocarbonyl)amino]-4-[(4-amino-6-chloro-1,3,5-triazin-2-yl)amino]phenyl]azo]naphthalene-1,3,6-trisulphonic acid (35642-64-9)was estimated by SSS (2017) using OECD QSAR toolbox v 3.4 with log kow as the primary descriptor and considering the six closest read across substances of 7-[[2-[(aminocarbonyl)amino]-4-[(4-amino-6-chloro-1,3,5-triazin-2-yl)amino]phenyl]azo]naphthalene-1,3,6-trisulphonic acid (35642-64-9) was predicted to be non neoplastic in male and female rats. Based on this annotation it can be concluded that the substance is considered to not toxic as per the criteria mentioned in CLP regulation.

Key value for chemical safety assessment

Carcinogenicity: via oral route

Link to relevant study records

Reference

Endpoint:

carcinogenicity

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 Tolbox version 3.4 and the supporting QMRF report has been attached

Qualifier:

according to guideline

Guideline:

other: As mention below

Principles of method if other than guideline:

Prediction is done using OECD QSAR Toolbox version 3.4 with respect to the descriptor log Kow.

GLP compliance:

not specified

Specific details on test material used for the study:

- Name of the test material: 7-[(E)-2-{4-[(4-amino-6-chloro-1,3,5-triazin-2-yl)amino]-2-(carbamoylamino)phenyl}diazen-1-yl]naphthalene-1,3,6-trisulfonic acid
- IUPAC name: 7-[(E)-2-{4-[(4-amino-6-chloro-1,3,5-triazin-2-yl)amino]-2-(carbamoylamino)phenyl}diazen-1-yl]naphthalene-1,3,6-trisulfonic acid
- Molecular formula: C20H16ClN9O10S3
- Molecular weight: 674.0504 g/mol
- Substance type: Organic
- Smiles: S(=O)(=O)(c1c(/N=N/c2c(NC(=O)N)cc(Nc3nc(nc(n3)Cl)N)cc2)cc2c(S(=O)(=O)O)cc(S(=O)(=O)O)cc2c1)O

Species:

rat

Strain:

Osborne-Mendel

Sex:

male/female

Details on test animals or test system and environmental conditions:

Not specified.

Route of administration:

oral: feed

Vehicle:

not specified

Details on exposure:

Not specified.

Analytical verification of doses or concentrations:

not specified

Details on analytical verification of doses or concentrations:

Not specified.

Duration of treatment / exposure:

2 years

Frequency of treatment:

Not specified.

Post exposure period:

Not specified.

Remarks:

Not specified.

No. of animals per sex per dose:

Not specified.

Control animals:

not specified

Details on study design:

Not specified.

Positive control:

Not specified.

Observations and examinations performed and frequency:

Not specified.

Sacrifice and pathology:

Not specified.

Other examinations:

Not specified.

Statistics:

Not specified.

Clinical signs:

not specified

Dermal irritation (if dermal study):

not specified

Mortality:

not specified

Body weight and weight changes:

not specified

Food consumption and compound intake (if feeding study):

not specified

Food efficiency:

not specified

Water consumption and compound intake (if drinking water study):

not specified

Ophthalmological findings:

not specified

Haematological findings:

not specified

Clinical biochemistry findings:

not specified

Urinalysis findings:

not specified

Behaviour (functional findings):

not specified

Immunological findings:

not specified

Organ weight findings including organ / body weight ratios:

not specified

Gross pathological findings:

not specified

Neuropathological findings:

not specified

Histopathological findings: non-neoplastic:

not specified

Histopathological findings: neoplastic:

not specified

Description (incidence and severity):

Negative

Other effects:

not specified

Details on results:

not specified

Dose descriptor:

NOAEL

Effect level:

1 000 mg/kg bw/day

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: No significant effect were observed at this dose.

Remarks on result:

other: No carcinogenic effect were observed

Critical effects observed:

not specified

Treatment related:

not specified

Dose response relationship:

not specified

Relevant for humans:

not specified

The prediction was based on dataset comprised from the following descriptors: "Summary carcinogenicity"
Estimation method: Takes highest mode value from the 7 nearest neighbours
Domain  logical expression:Result: In Domain

((((((((((("a" or "b" or "c" or "d" or "e" or "f" )  and ("g" and ( not "h") )  )  and ("i" and ( not "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 "v" )  and ("w" and "x" )  )

Domain logical expression index: "a"

Referential boundary: The target chemical should be classified as Naphthalene sulfonic acids, condensates by OECD HPV Chemical Categories

Domain logical expression index: "b"

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

Domain logical expression index: "c"

Referential boundary: The target chemical should be classified as SN1 AND SN1 >> Nitrenium Ion formation AND SN1 >> Nitrenium Ion formation >> Aromatic phenylureas by DNA binding by OECD

Domain logical expression index: "d"

Referential boundary: The target chemical should be classified as SNAr AND SNAr >> Nucleophilic aromatic substitution on activated aryl and heteroaryl compounds AND SNAr >> Nucleophilic aromatic substitution on activated aryl and heteroaryl compounds >> Activated aryl and heteroaryl compounds by Protein binding by OASIS v1.4

Domain logical expression index: "e"

Referential boundary: The target chemical should be classified as SNAr AND SNAr >> Nucleophilic aromatic substitution AND SNAr >> Nucleophilic aromatic substitution >> Halo-triazines by Protein binding by OECD

Domain logical expression index: "f"

Referential boundary: The target chemical should be classified as Acid moiety AND Anilines (Unhindered) AND Substituted Ureas AND Triazines, Aromatic by Aquatic toxicity classification by ECOSAR

Domain logical expression index: "g"

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

Domain logical expression index: "h"

Referential boundary: The target chemical should be classified as AN2 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 >> Schiff base formation by aldehyde formed after metabolic activation >> N-methylol derivatives OR Radical OR Radical >> Radical mechanism by ROS formation OR Radical >> Radical mechanism by ROS formation >> Five-Membered Aromatic Nitroheterocycles OR Radical >> Radical mechanism via ROS formation (indirect) OR Radical >> Radical mechanism via ROS formation (indirect) >> Conjugated Nitro Compounds OR Radical >> Radical mechanism via ROS formation (indirect) >> Geminal Polyhaloalkane Derivatives OR Radical >> Radical mechanism via ROS formation (indirect) >> Polynitroarenes OR Radical >> Radical mechanism via ROS formation (indirect) >> Single-Ring Substituted Primary Aromatic Amines OR SN1 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 >> Conjugated Nitro Compounds OR SN1 >> Nucleophilic attack after reduction and nitrenium ion formation >> Polynitroarenes OR SN2 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 >> Alkylation OR SN2 >> Alkylation >> Alkylphosphates, Alkylthiophosphates and Alkylphosphonates 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: "i"

Referential boundary: The target chemical should be classified as Aromatic diazo (Genotox) AND Structural alert for genotoxic carcinogenicity by Carcinogenicity (genotox and nongenotox) alerts by ISS

Domain logical expression index: "j"

Referential boundary: The target chemical should be classified as Aromatic mono-and dialkylamine (Genotox) by Carcinogenicity (genotox and nongenotox) alerts by ISS

Domain logical expression index: "k"

Referential boundary: The target chemical should be classified as Aromatic diazo (Genotox) AND Structural alert for genotoxic carcinogenicity by Carcinogenicity (genotox and nongenotox) alerts by ISS

Domain logical expression index: "l"

Referential boundary: The target chemical should be classified as Benzenesulfonic ethers, methylation (Nongenotox) by Carcinogenicity (genotox and nongenotox) alerts by ISS

Domain logical expression index: "m"

Referential boundary: The target chemical should be classified as Aromatic diazo (Genotox) AND Structural alert for genotoxic carcinogenicity by Carcinogenicity (genotox and nongenotox) alerts by ISS

Domain logical expression index: "n"

Referential boundary: The target chemical should be classified as Halogenated benzene (Nongenotox) by Carcinogenicity (genotox and nongenotox) alerts by ISS

Domain logical expression index: "o"

Referential boundary: The target chemical should be classified as Aromatic diazo (Genotox) AND Structural alert for genotoxic carcinogenicity by Carcinogenicity (genotox and nongenotox) alerts by ISS

Domain logical expression index: "p"

Referential boundary: The target chemical should be classified as Hydrazine (Genotox) by Carcinogenicity (genotox and nongenotox) alerts by ISS

Domain logical expression index: "q"

Referential boundary: The target chemical should be classified as Aromatic diazo (Genotox) AND Structural alert for genotoxic carcinogenicity by Carcinogenicity (genotox and nongenotox) alerts by ISS

Domain logical expression index: "r"

Referential boundary: The target chemical should be classified as Primary aromatic amine,hydroxyl amine and its derived esters (Genotox) by Carcinogenicity (genotox and nongenotox) alerts by ISS

Domain logical expression index: "s"

Referential boundary: The target chemical should be classified as Aromatic diazo (Genotox) AND Structural alert for genotoxic carcinogenicity by Carcinogenicity (genotox and nongenotox) alerts by ISS

Domain logical expression index: "t"

Referential boundary: The target chemical should be classified as Thiocarbonyl (Nongenotox) by Carcinogenicity (genotox and nongenotox) alerts by ISS

Domain logical expression index: "u"

Similarity boundary:Target: NC(=O)Nc1cc(Nc2nc(N)nc(Cl)n2)ccc1N=Nc1cc2c(cc1S(O)(=O)=O)cc(S(O)(=O)=O)cc2S(O)(=O)=O
Threshold=20%,
Dice(Atom centered fragments)
Atom type; Count H attached; Hybridization

Domain logical expression index: "v"

Similarity boundary:Target: NC(=O)Nc1cc(Nc2nc(N)nc(Cl)n2)ccc1N=Nc1cc2c(cc1S(O)(=O)=O)cc(S(O)(=O)=O)cc2S(O)(=O)=O
Threshold=10%,
Dice(Atom centered fragments)
Atom type; Count H attached; Hybridization

Domain logical expression index: "w"

Parametric boundary:The target chemical should have a value of log Kow which is >= -2.25

Domain logical expression index: "x"

Parametric boundary:The target chemical should have a value of log Kow which is <= 0.00225

Conclusions:

The carcinogenic potential of 7-[[2-[(aminocarbonyl)amino]-4-[(4-amino-6-chloro-1,3,5-triazin-2-yl)amino]phenyl]azo]naphthalene-1,3,6-trisulphonic acid (35642-64-9) was estimated by SSS (2017) using OECD QSAR toolbox v3.4 with log kow as the primary descriptor and considering the six closest read across substances was predicted to be non neoplastic in rats .

Executive summary:

The carcinogenic potential of 7-[[2-[(aminocarbonyl)amino]-4-[(4-amino-6-chloro-1,3,5-triazin-2-yl)amino]phenyl]azo]naphthalene-1,3,6-trisulphonic acid (35642-64-9)was estimated by SSS (2017) using OECD QSAR toolbox v 3.4 with log kow as the primary descriptor and considering the six closest read across substances of 7-[[2-[(aminocarbonyl)amino]-4-[(4-amino-6-chloro-1,3,5-triazin-2-yl)amino]phenyl]azo]naphthalene-1,3,6-trisulphonic acid (35642-64-9) was predicted to be non neoplastic in male and female rats. Based on this annotation 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

Dose descriptor:

NOAEL

1 000 mg/kg bw/day

Study duration:

chronic

Species:

rat

Quality of whole database:

K2 data from OECD QSAR prediction 3.4 version

Carcinogenicity: via inhalation route

Endpoint conclusion

Endpoint conclusion:

no study available

Carcinogenicity: via dermal route

Endpoint conclusion

Endpoint conclusion:

no study available

Justification for classification or non-classification

Thus based on the above annotation and CLP criteria the target chemical 7-[[2-[(aminocarbonyl)amino] -4-[(4-amino-6-chloro-1,3,5-triazin-2-yl) amino]phenyl]azo]naphthalene- 1,3,6-trisulphonic acid (35642-64-9) can be classified as non-neoplastic .

Additional information

Various experimental studies were reviewed to determine the carcinogenic nature of target substance 7-[[2-[(aminocarbonyl)amino]-4-[(4-amino-6-chloro-1,3,5-triazin-2-yl) amino]phenyl]azo]naphthalene-1,3,6-trisulphonic acid (35642-64-9) upon repeated exposure by different route. The studies are as mentioned below:

The carcinogenic potential of 7-[[2-[(aminocarbonyl)amino]-4-[(4-amino-6-chloro-1,3,5-triazin-2-yl)amino]phenyl]azo]naphthalene-1,3,6-trisulphonic acid (35642-64-9)was estimated by SSS (2017) using OECD QSAR toolbox v 3.4 with log kow as the primary descriptor and considering the six closest read across substances of 7-[[2-[(aminocarbonyl)amino]-4-[(4-amino-6-chloro-1,3,5-triazin-2-yl)amino]phenyl]azo]naphthalene-1,3,6-trisulphonic acid (35642-64-9) was predicted to be non neoplastic in male and female rats. Based on this annotation it can be concluded that the substance is considered to not toxic as per the criteria mentioned in CLP regulation.

Another  Sub-chronic carcinogenic study for Read across was performed by K. J. DAVIS et al.( TOXICOLOGY AND APPLIED PHARAMACOLOGY,1966) to determine the carcinogenic nature of Ponceau SX;IUPAC ; disodium 3-[(2,4-dimethyl-5-sulfonatophenyl)diazenyl]-4-hydroxynaphthalene-1-sulfonate (4548-53-2). The read across substances share high similarity in structure and log kow .Therefore, it is acceptable to derive information on toxicity from the analogue substance. The carcinogenicity test was performed on Osborne-Mendel rats. Different concentrations of Ponceau SX (4548-53-2)0, 1% and 2%were used. For treated group 50 animals per sex per dose and control group 100 animals per sex per dose were used. Various parameters were tested are, number of survivors at 80 weeks,number received by Pathology,number of males and female with tumors,Tumor type,Other pathology were studied. From various other findings, such as liver enlargement, abscesses, distendedurinary bladders, ovarian cysts, distended uteri, enlarged parathyroids, enlarged seminal vesicles and other miscellaneous changes, and were present in approximately equal incidence and degree in test and control rats. Thus NOAEL for this study considered to be 1000 mg/kg .Therefore, after 2 yrs study Ponceau SX (4548-53-2) was considered to be non-carcinogen to Osborne-Mendel rats at dose concentration 1000 mg/kg. 

Thus based on the above predictions on7-[[2-[(aminocarbonyl)amino]-4-[(4-amino-6-chloro-1,3,5-triazin-2-yl)amino]phenyl]azo]naphthalene-1,3,6-trisulphonic acid (35642-64-9) as well as its read across substances and applying weight of evidence, it can be concluded that27-[[2-[(aminocarbonyl)amino] -4-[(4-amino-6-chloro-1,3,5-triazin-2-yl) amino]phenyl]azo]naphthalene-1,3,6-trisulphonic acid isnot a carcinogen . Thus comparing the above annotations with the criteria of CLP regulation, 7-[[2-[(aminocarbonyl)amino ]-4-[(4-amino-6-chloro-1,3,5-triazin-2-yl)amino]phenyl]azo]naphthalene-1,3,6-trisulphonic acid (35642-64-9)can be considered as non-neoplastic .