7-acetamido-4-hydroxynaphthalene-2-sulphonic acid

Endpoint summary

Description of key information

Acute oral toxicity: 

LD50 was estimated to be 3089 mg/kg bw when Chbb:THOM (SPF) male and female rats were orally exposed with 7-acetamido-4-hydroxynaphthalene-2-sulfonic acid by gavage route.

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records

Reference

Endpoint:

acute 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 predicted using OECD QSAR toolbox version 3.3 and the supporting QMRF report has been attached

Qualifier:

according to guideline

Guideline:

other: estimated

Principles of method if other than guideline:

Prediction is done using QSAR Toolbox version 3.3

GLP compliance:

not specified

Test type:

other: not specified

Limit test:

no

Specific details on test material used for the study:

- Name of test material: 7-acetamido-4-hydroxynaphthalene-2-sulfonic acid
- Molecular formula: C12H11NO5S
- Molecular weight: 281.2869 g/mol
- Smiles notation: CC(=O)Nc1ccc2c(c1)cc(cc2O)S(=O)(=O)O
- InChl: 1S/C12H11NO5S/c1-7(14)13-9-2-3-11-8(4-9)5-10(6-12(11)15)19(16,17)18/h2-6,15H,1H3,(H,13,14)(H,16,17,18)
- Substance type: Organic

Species:

rat

Strain:

other: Chbb:THOM (SPF)

Sex:

male/female

Details on test animals or test system and environmental conditions:

not specified

Route of administration:

oral: gavage

Vehicle:

not specified

Details on oral exposure:

not specified

Doses:

3089 mg/kg bw

No. of animals per sex per dose:

not specified

Control animals:

not specified

Details on study design:

not specified

Statistics:

not specified

Preliminary study:

not specified

Sex:

male/female

Dose descriptor:

LD50

Effect level:

3 089 mg/kg bw

Based on:

test mat.

Remarks on result:

other: 50% mortality was observed

Mortality:

not specified

Clinical signs:

other: not specified

Gross pathology:

not specified

Other findings:

not specified

The prediction was based on dataset comprised from the following descriptors: LD50
Estimation method: Takes average value from the 6 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 ( 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 "w" )  )

Domain logical expression index: "a"

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

Domain logical expression index: "b"

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: "c"

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: "d"

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

Domain logical expression index: "e"

Referential boundary: The target chemical should be classified as No alert found by DNA binding by OASIS v.1.3

Domain logical expression index: "f"

Referential boundary: The target chemical should be classified as AN2 OR AN2 >> Carbamoylation after isocyanate formation OR AN2 >> Carbamoylation after isocyanate formation >> N-Hydroxylamines OR AN2 >> Michael-type addition on alpha, beta-unsaturated carbonyl compounds OR AN2 >> Michael-type addition on alpha, beta-unsaturated carbonyl compounds >> Four- and Five-Membered Lactones OR AN2 >> Schiff base formation OR AN2 >> Schiff base formation >> Dicarbonyl compounds 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 >> Shiff base formation after aldehyde release OR AN2 >> Shiff base formation after aldehyde release >> Specific Acetate Esters OR AN2 >> Shiff base formation for aldehydes OR AN2 >> Shiff base formation for aldehydes >> Geminal Polyhaloalkane Derivatives OR Non-covalent interaction OR Non-covalent interaction >> DNA intercalation OR Non-covalent interaction >> DNA intercalation >> Coumarins OR Non-covalent interaction >> DNA intercalation >> DNA Intercalators with Carboxamide Side Chain 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 >> Generation of ROS by glutathione depletion (indirect) OR Radical >> Generation of ROS by glutathione depletion (indirect) >> Haloalkanes Containing Heteroatom OR Radical >> Radical mechanism via ROS formation (indirect) OR Radical >> Radical mechanism via ROS formation (indirect) >> Coumarins OR Radical >> Radical mechanism via ROS formation (indirect) >> Geminal Polyhaloalkane Derivatives OR Radical >> Radical mechanism via ROS formation (indirect) >> N-Hydroxylamines OR Radical >> Radical mechanism via ROS formation (indirect) >> Nitro Azoarenes OR Radical >> Radical mechanism via ROS formation (indirect) >> Nitroaniline Derivatives OR Radical >> Radical mechanism via ROS formation (indirect) >> Nitroarenes with Other Active Groups OR Radical >> Radical mechanism via ROS formation (indirect) >> Nitrophenols, Nitrophenyl Ethers and Nitrobenzoic Acids OR Radical >> Radical mechanism via ROS formation (indirect) >> p-Substituted Mononitrobenzenes 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 >> Alkylation after metabolically formed carbenium ion species OR SN1 >> Alkylation after metabolically formed carbenium ion species >> Polycyclic Aromatic Hydrocarbon Derivatives OR SN1 >> Nucleophilic attack after carbenium ion formation OR SN1 >> Nucleophilic attack after carbenium ion formation >> Specific Acetate Esters OR SN1 >> Nucleophilic attack after diazonium or carbenium ion formation OR SN1 >> Nucleophilic attack after diazonium or carbenium ion formation >> Nitroarenes with Other Active Groups OR SN1 >> Nucleophilic attack after metabolic nitrenium ion formation OR SN1 >> Nucleophilic attack after metabolic nitrenium ion formation >> N-Hydroxylamines OR SN1 >> Nucleophilic attack after metabolic 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 >> Nitro Azoarenes OR SN1 >> Nucleophilic attack after reduction and nitrenium ion formation >> Nitroaniline Derivatives OR SN1 >> Nucleophilic attack after reduction and nitrenium ion formation >> Nitroarenes with Other Active Groups OR SN1 >> Nucleophilic attack after reduction and nitrenium ion formation >> Nitrophenols, Nitrophenyl Ethers and Nitrobenzoic Acids OR SN1 >> Nucleophilic attack after reduction and nitrenium ion formation >> p-Substituted Mononitrobenzenes OR SN1 >> Nucleophilic substitution on diazonium ions OR SN1 >> Nucleophilic substitution on diazonium ions >> Specific Imine and Thione Derivatives OR SN2 OR SN2 >> Acylation OR SN2 >> Acylation >> Specific Acetate Esters OR SN2 >> Acylation involving a leaving group  OR SN2 >> Acylation involving a leaving group  >> Geminal Polyhaloalkane Derivatives 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, direct acting epoxides and related OR SN2 >> Alkylation, direct acting epoxides and related >> Epoxides and Aziridines OR SN2 >> Alkylation, direct acting epoxides and related after P450-mediated metabolic activation OR SN2 >> Alkylation, direct acting epoxides and related after P450-mediated metabolic activation >> Polycyclic Aromatic Hydrocarbon Derivatives OR SN2 >> Alkylation, nucleophilic substitution at sp3-carbon atom OR SN2 >> Alkylation, nucleophilic substitution at sp3-carbon atom >> Sulfonates and Sulfates OR SN2 >> Alkylation, ring opening SN2 reaction OR SN2 >> Alkylation, ring opening SN2 reaction >> Four- and Five-Membered Lactones OR SN2 >> Direct acting epoxides formed after metabolic activation OR SN2 >> Direct acting epoxides formed after metabolic activation >> Coumarins OR SN2 >> Direct acting epoxides formed after metabolic activation >> Quinoline Derivatives OR SN2 >> Direct acylation involving a leaving group OR SN2 >> Direct acylation involving a leaving group >> Acyl Halides OR SN2 >> DNA alkylation OR SN2 >> DNA alkylation >> Alkylphosphates, Alkylthiophosphates and Alkylphosphonates OR SN2 >> DNA alkylation >> Vicinal Dihaloalkanes OR SN2 >> Internal SN2 reaction with aziridinium and/or cyclic sulfonium ion formation (enzymatic) OR SN2 >> Internal SN2 reaction with aziridinium and/or cyclic sulfonium ion formation (enzymatic) >> Vicinal Dihaloalkanes OR SN2 >> Nucleophilic substitution at sp3 Carbon atom OR SN2 >> Nucleophilic substitution at sp3 Carbon atom >> Haloalkanes Containing Heteroatom OR SN2 >> Nucleophilic substitution at sp3 Carbon atom >> Specific Acetate Esters 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 OR SN2 >> SN2 at an activated carbon atom OR SN2 >> SN2 at an activated carbon atom >> Quinoline Derivatives OR SN2 >> SN2 at sulfur atom OR SN2 >> SN2 at sulfur atom >> Sulfonyl Halides OR SN2 >> SN2 attack on activated carbon Csp3 or Csp2 OR SN2 >> SN2 attack on activated carbon Csp3 or Csp2 >> Nitroarenes with Other Active Groups by DNA binding by OASIS v.1.3

Domain logical expression index: "g"

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

Domain logical expression index: "h"

Referential boundary: The target chemical should be classified as Moderate binder, OH grooup OR Non binder, impaired OH or NH2 group OR Non binder, MW>500 OR Non binder, non cyclic structure OR Non binder, without OH or NH2 group OR Very strong binder, OH group OR Weak binder, OH group by Estrogen Receptor Binding

Domain logical expression index: "i"

Referential boundary: The target chemical should be classified as Not known precedent reproductive and developmental toxic potential by DART scheme v.1.0

Domain logical expression index: "j"

Referential boundary: The target chemical should be classified as Known precedent reproductive and developmental toxic potential OR NO2-alkyl/NO2-benzene derivatives (8b) OR Non-steroid nucleus derived estrogen receptor (ER) and androgen receptor (AR) OR Non-steroid nucleus derived estrogen receptor (ER) and androgen receptor (AR) >> 4-alkylphenol-like derivatives (2b-3) OR Piperazine-, dioxane-, morpholine-, tetrahydrothiopyran-like derivatives and cyclohexanamine (17c) OR Steroid derivatives OR Steroid nucleus derived ER and AR binders OR Steroid nucleus derived ER and AR binders >> Androgens, anti-androgens (2a-4) OR Steroid nucleus derived ER and AR binders >> Glucocorticoid and mineralcorticoid receptor binders (2a-2) OR Steroid nucleus derived ER and AR binders >> Progesterones, anti-androgens (2a-3) OR Toluene and small alkyl toluene derivatives (8a) by DART scheme v.1.0

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 Benzene/ Naphthalene sulfonic acids (Less susceptible) Rank C by Repeated dose (HESS)

Domain logical expression index: "m"

Referential boundary: The target chemical should be classified as 3-Methylcholantrene (Hepatotoxicity) Alert by Repeated dose (HESS)

Domain logical expression index: "n"

Referential boundary: The target chemical should be classified as Benzene/ Naphthalene sulfonic acids (Less susceptible) Rank C by Repeated dose (HESS)

Domain logical expression index: "o"

Referential boundary: The target chemical should be classified as Methyldopa (Hepatotoxicity) Alert OR Nitrophenols/ Halophenols (Energy metabolism dysfuntion) Rank B by Repeated dose (HESS)

Domain logical expression index: "p"

Referential boundary: The target chemical should be classified as Benzene/ Naphthalene sulfonic acids (Less susceptible) Rank C by Repeated dose (HESS)

Domain logical expression index: "q"

Referential boundary: The target chemical should be classified as Oxyphenistain (Hepatotoxicity) Alert by Repeated dose (HESS)

Domain logical expression index: "r"

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

Domain logical expression index: "s"

Referential boundary: The target chemical should be classified as Inclusion rules not met by Skin irritation/corrosion Inclusion rules by BfR

Domain logical expression index: "t"

Referential boundary: The target chemical should be classified as (!Undefined)Group All Lipid Solubility < 0.01 g/kg AND (!Undefined)Group CNS Surface Tension > 62 mN/m AND Group All Melting Point > 200 C AND Group CNS log Kow < 0.5 AND Group CNS Melting Point > 120 C AND Group CNS Melting Point > 50 C by Skin irritation/corrosion Exclusion rules by BfR

Domain logical expression index: "u"

Referential boundary: The target chemical should be classified as (!Undefined)Group C Surface Tension > 62 mN/m by Skin irritation/corrosion Exclusion rules by BfR

Domain logical expression index: "v"

Parametric boundary:The target chemical should have a value of log Kow which is >= -3.22

Domain logical expression index: "w"

Parametric boundary:The target chemical should have a value of log Kow which is <= 4.67

Interpretation of results:

Category 5 based on GHS criteria

Conclusions:

LD50 was estimated to be 3089 mg/kg bw when Chbb:THOM (SPF) male and female rats were orally exposed with 7-acetamido-4-hydroxynaphthalene-2-sulfonic acid by gavage route.

Executive summary:

In a prediction done by SSS (2017) using the OECD QSAR toolbox with log kow as the primary descriptor, the acute oral toxicity was estimated for  7-acetamido-4-hydroxynaphthalene-2-sulfonic acid (6334 -97 -0). The LD50 was estimated to be 3089 mg/kg bw when Chbb:THOM (SPF) male and female rats were orally exposed with 7-acetamido-4-hydroxynaphthalene-2-sulfonic acid by gavage route.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

3 089 mg/kg bw

Quality of whole database:

Data is Klimicsh 2 and from QSAR Toolbox 3.3 (2017)

Acute toxicity: via inhalation route

Endpoint conclusion

Endpoint conclusion:

no study available

Acute toxicity: via dermal route

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

Acute oral toxicity:

In different studies, 7-acetamido-4-hydroxynaphthalene-2-sulfonic acid (CAS no: 6334-97-0) has been investigated for acute oral toxicity to a greater or lesser extent. Often are the studies based on in vivo experiments in rodents, i.e. most commonly in rats and mice for 7-acetamido-4-hydroxynaphthalene-2-sulfonic acid along with the study available on structurally similar read across substance 3-acetamido-5-amino-4-hydroxybenzenesulphonic acid (CAS no 40306-75-0) and Disodium 6-hydroxy-5-[(4-sulphonatophenyl)azo] naphthalene-2-sulphonate(2783-94-0). The predicted data using the OECD QSAR toolbox has also been compared with the experimental studies. The studies are summarized as below –

In a prediction done by SSS (2017) using the OECD QSAR toolbox with log kow as the primary descriptor, the acute oral toxicity was estimated for 7-acetamido-4-hydroxynaphthalene-2-sulfonic acid (6334 -97 -0). The LD50 was estimated to be 3089 mg/kg bw when Chbb:THOM (SPF) male and female rats were orally exposed with 7-acetamido-4-hydroxynaphthalene-2-sulfonic acid by gavage route.

In another study based on the QSAR prediction done using the Danish (Q)SAR Database, the acute oral toxicity was estimated for the 7-acetamido-4-hydroxynaphthalene-2-sulfonic acid (6334-97-0). The LD50 was estimated to be 6600 mg/kg bw with Reliability Index 0.56 (0.5-0.75 = moderate prediction quality), when rats were treated with 7-acetamido-4-hydroxynaphthalene-2-sulfonic acid (6334-97-0) orally.

The above study supported by Sustainability Support Services (Europe) AB (2017), for the structurally similar read across substance 3-acetamido-5-amino-4-hydroxybenzenesulphonic acid (CAS no 40306-75-0). In acute oral toxicity study, Wistar female rat were treated with 3-acetamido-5-amino-4-hydroxybenzenesulphonic acid in the concentration of 0 (Group I) and 2000 mg/kg bw (Group II and III) in distilled water orally by gavage. No mortality and any clinical signs of toxicity were observed in treated rat at 2000 mg/kg bw. Normal gain in body weight and Skin and hair coat was observed wet, all external orifices were normal and no gross pathological changes were observed in treated rat. Therefore, LD50 cutoff was considered to be 5000 mg/kg bw when Wistar female rat were treated with 3-acetamido-5-amino-4-hydroxybenzenesulphonic acid orally.

This is further supported by Gaunt et al. (Fd Cosmet. ToxicoL Vol. 5, pp. 747-754, 1967) and U.S. National Library of Medicine (ChemIDplus, 2017), for the structurally similar read across substance Disodium 6-hydroxy-5-[(4-sulphonatophenyl)azo]naphthalene-2-sulphonate (2783-94-0). The Acute oral toxicity study was conducted in 10 Carworth Farm E strain male and female rats at the concentration of 10000 mg/kg bw. Test material which was 85% pure and supplied through the Food Colours Committee of the Association of British Chemical Manufacturers was dissolved in water (Vehicle) and given via gavage route.The animals were fasted for 18 hr before treatment and observed for 7 days after treatment.No Mortality was observed at dose10000 mg/kg bw. Slight diarrhoea lasted for 24 hr after dosing. The faeces and urine were coloured orange. Autopsies were carried out on those animals which died and on selected survivors. There were no macroscopic changes were seen after treatment. Therefore, LD50 was considered to be >10000 mg/kg bw, when Carworth Farm E strain male and female rats were treated with Disodium 6-hydroxy-5-[(4 sulphonatophenyl)azo]naphthalene-2-sulphonate (2783-94-0) orally.

Also these results are further supported by Gaunt et al. (Fd Cosmet. ToxicoL Vol. 5, pp. 747-754, 1967) and U.S. National Library of Medicine (ChemIDplus, 2017), for the structurally similar read across substance Disodium 6-hydroxy-5-[(4-sulphonatophenyl)azo] naphthalene -2-sulphonate (2783-94-0). The Acute oral toxicity study was conducted in 10 male and female ICI Alderley Park strain mice. Test material which was 85% pure and supplied through the Food Colours Committee of the Association of British Chemical Manufacturers was dissolved in water (Vehicle) and given via gavage route. The animals were fasted for 18 hr before treatment and observed for 7 days after treatment. No Mortality was observed at dose 6000 mg/kg bw. Slight diarrhoea lasted for 24 hr after dosing. The faeces and urine were coloured orange. Autopsies were carried out on those animals which died and on selected survivors. There were no macroscopic changes were seen after treatment. Therefore, LD50 was considered to be >6000 mg/kg bw, when ICI Alderley Park strain mice were treated with Disodium 6-hydroxy-5-[(4 sulphonatophenyl)azo]naphthalene-2-sulphonate (2783-94-0)orally.

Thus, based on the above studies on 7-acetamido-4-hydroxynaphthalene-2-sulfonic acid (CAS no: 6334-97-0) and it’s read across substances, it can be concluded that LD50 value is greater than 2000 mg/kg bw. Thus, comparing this value with the criteria of CLP regulation, 7-acetamido-4-hydroxynaphthalene-2-sulfonic acid can be classified as category V of acute oral toxicity.

Justification for classification or non-classification

Based on the above studies and prediction on 7-acetamido-4-hydroxynaphthalene-2-sulfonic acid (CAS no: 6334-97-0) and its read across substances, it can be concluded that LD50 value is greater than 2000 mg/kg bw. Thus, comparing this value with the criteria of CLP regulation, 7-acetamido-4-hydroxynaphthalene-2-sulfonic acid can be classified as category V for acute oral toxicity.