4-[(3-aminobenzoyl)amino]-5-hydroxynaphthalene-1,7-disulphonic acid

Endpoint summary

Description of key information

Repeated dose toxicity: Oral

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, repeated dose toxicity was predicted for 4-[(3-aminobenzoyl)amino]-5-hydroxynaphthalene-1,7-disulphonic acid. The study assumed the use of male and female Crj: CD (SD) rats in a study for 28 days. Since no significant treatment related effects were observed at the mentioned dose level, hence the No Observed Adverse Effect Level (NOAEL) for 4-[(3-aminobenzoyl)amino]-5-hydroxynaphthalene-1,7-disulphonic acid is predicted to be 435.833343506 mg/Kg bw/day.

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

Repeated dose toxicity: Inhalation

4-[(3-aminobenzoyl)amino]-5-hydroxynaphthalene-1,7-disulphonic acid has very low vapor pressure (2.61E-022 Pa), so the potential for the generation of inhalable vapours is very low. Also the normal conditions of use of this substance will not result in aerosols, particles or droplets of an inhalable size, so exposure to humans via the inhalatory route will be highly unlikely and therefore this end point for repeated inhalation toxicity was considered for waiver

Repeated dose toxicity: Dermal

The acute dermal toxicity value for4-[(3-aminobenzoyl)amino]-5-hydroxynaphthalene-1,7-disulphonic acid(as provided in section 7.2.3) is >2000 mg/kg body weight. The substance was also found to be not irritating and not sensitizing to the skin. Based on these considerations, the end point for repeated dermal toxicity is considered as waiver.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records

Reference

Endpoint:

repeated dose toxicity: oral

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

Specific details on test material used for the study:

- Name of test material: 4-[(3-aminobenzoyl)amino]-5-hydroxynaphthalene-1,7-disulphonic acid
- IUPAc name: 4-[(3-aminobenzoyl)amino]-5-hydroxynaphthalene-1,7-disulphonic acid
- Molecular formula: C17H14N2O8S2
- Molecular weight: 438.4356 g/mol
- Smiles notation: c1cc(cc(c1)N)C(=O)Nc2ccc(c3c2c(cc(c3)S(=O)(=O)O)O)S(=O)(=O)O
-InChl:1S/C17H14N2O8S2/c18-10-3-1-2-9(6-10)17(21)19-13-4-5-15(29(25,26)27)12-7-11(28(22,23)24)8-14(20)16(12)13/h1-8,20H,18H2,(H,19,21)(H,22,23,24)(H,25,26,27)
- Substance type: Organic

Species:

rat

Strain:

Crj: CD(SD)

Details on species / strain selection:

No data

Sex:

male/female

Details on test animals or test system and environmental conditions:

No data

Route of administration:

oral: gavage

Details on route of administration:

No data

Vehicle:

not specified

Details on oral exposure:

No data

Analytical verification of doses or concentrations:

not specified

Details on analytical verification of doses or concentrations:

No data

Duration of treatment / exposure:

28 days

Frequency of treatment:

No data

No. of animals per sex per dose:

No data

Control animals:

not specified

Details on study design:

No data

Positive control:

No data

Observations and examinations performed and frequency:

No data

Sacrifice and pathology:

No data

Other examinations:

No data

Statistics:

No data

Clinical signs:

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

Other effects:

not specified

Details on results:

No data

Dose descriptor:

NOAEL

Effect level:

435.833 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: No significant alterations were noted at the mentioned dose level

Critical effects observed:

not specified

The prediction was based on dataset comprised from the following descriptors: NOAEL
Estimation method: Takes average value from the 5 nearest neighbours
Domain  logical expression:Result: In Domain

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

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 Anilines (Acute toxicity) by US-EPA New Chemical Categories

Domain logical expression index: "c"

Referential boundary: The target chemical should be classified as Non-covalent interaction AND Non-covalent interaction >> DNA intercalation AND Non-covalent interaction >> DNA intercalation >> DNA Intercalators with Carboxamide Side Chain by DNA binding by OASIS v.1.3

Domain logical expression index: "d"

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

Domain logical expression index: "e"

Referential boundary: The target chemical should be classified as Strong binder, NH2 group AND Strong binder, OH group by Estrogen Receptor Binding

Domain logical expression index: "f"

Referential boundary: The target chemical should be classified as Acylation AND Acylation >> Ester aminolysis AND Acylation >> Ester aminolysis >> Amides by Protein binding by OASIS v1.3

Domain logical expression index: "g"

Referential boundary: The target chemical should be classified as Acylation AND Acylation >> Direct Acylation Involving a Leaving group AND Acylation >> Direct Acylation Involving a Leaving group >> Acetates by Protein binding by OECD

Domain logical expression index: "h"

Referential boundary: The target chemical should be classified as Acid moiety AND Amides AND Anilines (Unhindered) AND Phenol Amines AND Phenols by Aquatic toxicity classification by ECOSAR

Domain logical expression index: "i"

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

Domain logical expression index: "j"

Referential boundary: The target chemical should be classified as Acrylamides (Neurotoxicity) Rank C OR Allyl esters (Hepatotoxicity) Rank A OR Anilines (Hemolytic anemia with methemoglobinemia) Rank A OR Anilines (Hepatotoxicity) Rank C OR Benzene/ Naphthalene sulfonic acids (Less susceptible) Rank C OR Nitrobenzenes (Hemolytic anemia with methemoglobinemia) Rank A OR Nitrobenzenes (Hepatotoxicity) Rank C OR o-/ p-Aminophenols (Hemolytic anemia with methemoglobinemia) Rank B OR p-Aminophenols (Renal toxicity) Rank B OR Thiocarbamates/Sulfides (Hepatotoxicity) No rank OR Valproic acid (Hepatotoxicity) Alert by Repeated dose (HESS)

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 No alert found by Protein binding alerts for Chromosomal aberration by OASIS v1.1

Domain logical expression index: "m"

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 Ac-SN2 >> Ring opening acylation reaction OR Ac-SN2 >> Ring opening acylation reaction >> Carboxylic acid Anhydrides 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 activated double bond of pyrimidine bases OR AN2 >> Michael type addition to activated double bond of pyrimidine bases >> Pyrimidines and Purines OR AN2 >> Michael-type addition to quinoid structures OR AN2 >> Michael-type addition to quinoid structures >> Carboxylic Acid Amines OR AN2 >> Shiff base formation with carbonyl group of pyrimidine or purine bases OR AN2 >> Shiff base formation with carbonyl group of pyrimidine or purine bases >> Pyrimidines and Purines by Protein binding alerts for Chromosomal aberration by OASIS v1.1

Domain logical expression index: "n"

Referential boundary: The target chemical should be classified as No alert found by in vitro mutagenicity (Ames test) alerts by ISS

Domain logical expression index: "o"

Referential boundary: The target chemical should be classified as Aliphatic halogens OR alpha,beta-unsaturated aliphatic alkoxy group OR alpha,beta-unsaturated carbonyls OR Hydrazine OR Nitro-aromatic OR N-methylol derivatives OR Primary aromatic amine,hydroxyl amine and its derived esters by in vitro mutagenicity (Ames test) alerts by ISS

Domain logical expression index: "p"

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: "q"

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

Domain logical expression index: "r"

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

Domain logical expression index: "s"

Referential boundary: The target chemical should be classified as Acylation OR Acylation >> Ring opening acylation at a carbonyl OR Acylation >> Ring opening acylation at a carbonyl >> Anhydrides OR 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: "t"

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

Domain logical expression index: "u"

Referential boundary: The target chemical should be classified as Esters including acrylic and methacrylic esters by Skin irritation/corrosion Inclusion rules by BfR

Domain logical expression index: "v"

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

Domain logical expression index: "w"

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

Domain logical expression index: "x"

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

Domain logical expression index: "y"

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

Domain logical expression index: "z"

Parametric boundary:The target chemical should have a value of log Kow which is >= -2.36

Domain logical expression index: "aa"

Parametric boundary:The target chemical should have a value of log Kow which is <= 0.0224

Conclusions:

The No Observed Adverse Effect Level (NOAEL) for 4-[(3-aminobenzoyl)amino]-5-hydroxynaphthalene-1,7-disulphonic acid is predicted to be 435.833343506 mg/Kg bw/day.

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, repeated dose toxicity was predicted for 4-[(3-aminobenzoyl)amino]-5-hydroxynaphthalene-1,7-disulphonic acid. The study assumed the use of male and female Crj: CD (SD) rats in a study for 28 days. Since no significant treatment related effects were observed at the mentioned dose level, hence the No Observed Adverse Effect Level (NOAEL) for 4-[(3-aminobenzoyl)amino]-5-hydroxynaphthalene-1,7-disulphonic acid is predicted to be 435.833343506 mg/Kg bw/day.

Based on this value 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

435.833 mg/kg bw/day

Study duration:

subacute

Species:

rat

Quality of whole database:

Data is from K2 prediction database

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

Repeated dose toxicity: Oral

Prediction model based estimation and data from read across chemicals have been reviewed to determine the toxic nature of

4-[(3-aminobenzoyl)amino]-5-hydroxynaphthalene-1,7-disulphonic acid. 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, repeated dose toxicity was predicted for 4-[(3-aminobenzoyl)amino]-5-hydroxynaphthalene-1,7-disulphonic acid. The study assumed the use of male and female Crj: CD (SD) rats in a study for 28 days. Since no significant treatment related effects were observed at the mentioned dose level, hence the No Observed Adverse Effect Level (NOAEL) for 4-[(3-aminobenzoyl)amino]-5-hydroxynaphthalene-1,7-disulphonic acid is predicted to be 435.833343506 mg/Kg bw/day.

The predicted data for the target chemical is further supported by the data from read across chemical as mentioned below:

In a Chronic repeated dose oral toxicity study mentioned in SCCP (2007), CD1 male and female mice were treated with 50 -60% structurally and functionally similar read across chemical D&C Red 33 (RA CAS no 3567 -66 -6; IUPAC name: disodium 5-amino-4-hydroxy-3-(phenyldiazenyl)naphthalene-2,7-disulfonate) in the concentration of 0, 150, 1500 and 7500 mg/kg bw/day orally in diet. Decrease in survival of male mice at week 57 and female mice at week 74 were observed as compared to control. Changes in colour of hair, skin and faeces were observed in treated mice as compared to control. Changes were considered to be not toxicologically significant because they are directly linked to the colour of the dye.Change in body weight and food consumption were observed in treated mice as compared to control. Anemia and elevated reticulocytes in week 74 were observed at 7500 mg/kg bw/day, anemia and a significant increase in reticulocytes at 18 and 24 month and increased leucocytes at 1500 mg/kg bw/day and increased leucocytes were observed at 150 mg/kg bw/day in treated female mice as compared to control. In addition, increased splenic weights and abnormal changes in kidneys and Pigments in the liver and spleen were observed at 7500 mg/kg bw/day treated mice as compared to control. Therefore, the No Observed Adverse Effect Level (NOAEL) was considered to be 150 mg/kg bw/day when male and female mice were treated with D&C Red 33 orally for 24 months.

Repeated dose toxicity: Inhalation

4-[(3-aminobenzoyl)amino]-5-hydroxynaphthalene-1,7-disulphonic acid has very low vapor pressure (2.61E-022 Pa), so the potential for the generation of inhalable vapours is very low. Also the normal conditions of use of this substance will not result in aerosols, particles or droplets of an inhalable size, so exposure to humans via the inhalatory route will be highly unlikely and therefore this end point for repeated inhalation toxicity was considered for waiver

Repeated dose toxicity: Dermal

The acute dermal toxicity value for4-[(3-aminobenzoyl)amino]-5-hydroxynaphthalene-1,7-disulphonic acid(as provided in section 7.2.3) is >2000 mg/kg body weight. The substance was also found to be not irritating and not sensitizing to the skin. Based on these considerations, the end point for repeated dermal toxicity is considered as waiver.

Based on the data available for the target chemical and its read across data, 4-[(3-aminobenzoyl)amino]-5-hydroxynaphthalene-1,7-disulphonic acid does not exhibit toxic nature upon repeated exposure by oral route. Hence it can be concluded that the substance is considered to be not toxic as per the criteria mentioned in CLP regulation.

Justification for classification or non-classification

Based on the data available for the target chemical and its read across data, 4-[(3-aminobenzoyl)amino]-5-hydroxynaphthalene-1,7-disulphonic acid (CAS no 70239 -77 -9) does not exhibit toxic nature upon repeated exposure by oral route. Hence it can be concluded that the substance is considered to be not toxic as per the criteria mentioned in CLP regulation.