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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:
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 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.