4,5-dihydro-5-oxo-4-[[4-[[2-(sulphooxy)ethyl]sulphonyl]phenyl]azo]-1-(4-sulphophenyl)-1H-pyrazole-3-carboxylic acid

Endpoint summary

Description of key information

Acute oral toxicity: 

Acute oral toxicity dose (LD50) of 4,5-dihydro-5-oxo-4-[[4-[[2-(sulphooxy)ethyl]sulphonyl] phenyl]azo]-1-(4-sulphophenyl)-1H-pyrazole-3-carboxylic acid (CAS no: 10149-98-1) was predicted based on OECD QSAR toolbox 8100 mg/kg bw and different studies available on structurally similar read across substances Aluminium, 6-hydroxy-5-[(4-sulfophenyl)azo]- 2-naphthalenesulfonic acid complex (CAS No: 15790-07-5) >2000 mg/kg bw and Tartrazine (CAS No: 1934-21-0) >6250 mg/kg bw. All these studies concluded that the LD50 value is >2000 mg/kg bw. Thus, comparing this value with the criteria of CLP regulation, 4,5-dihydro-5-oxo-4-[[4-[[2-(sulphooxy)ethyl]sulphonyl]phenyl]azo]-1-(4-sulphophenyl)- 1H-pyrazole-3-carboxylic acid cannot be classified for acute oral toxicity.

Acute Inhalation toxicity: 

4,5-dihydro-5-oxo-4-[[4-[[2-(sulphooxy)ethyl]sulphonyl] phenyl]azo]-1-(4-sulphophenyl)-1H-pyrazole-3-carboxylic acid (CAS no: 10149-98-1) has very low vapour pressure (6.62E-26 Pa at 25°C), 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 was considered for waiver.

Acute Dermal toxicity: 

Acute Dermal toxicity dose (LD50) for 4,5-dihydro-5-oxo-4-[[4-[[2-(sulphooxy)ethyl] sulphonyl]phenyl]azo]-1-(4-sulphophenyl)-1H-pyrazole-3-carboxylic acid (CAS no: 10149-98-1) was predicted based on OECD QSAR toolbox 3617 mg/kg bwand differentstudies available for the structurally similar read across substance Aluminium, 6-hydroxy-5-[(4-sulfophenyl) azo]-2-naphthalenesulfonic acid complex (CAS No: 15790-07-5) >2000 mg/kg bw and for the functionally similar read across substance Tetrasodium 1-acetamido-2-hydroxy-3-(4-((4-sulphonatophenylazo)-7-sulphonato-1-naphthylazo))naphthalene-4,6-disulphonate (CAS No. 2519-30-4) >2000 mg/kg bw. All these studies concluded that the LD50 value is >2000 mg/kg bw. Thus, comparing this value with the criteria of CLP regulation, 4,5-dihydro-5-oxo-4-[[4-[[2-(sulphooxy)ethyl]sulphonyl]phenyl]azo]

-1-(4-sulphophenyl)-1H-pyrazole-3-carboxylic acid cannot be classified for acute dermal toxicity.

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 data

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: 4,5-dihydro-5-oxo-4-[[4-[[2-(sulphooxy)ethyl]sulphonyl]phenyl]azo]-1-(4-sulphophenyl)-1H-pyrazole-3-carboxylic acid
SMILES:OC(=O)C1C(N=Nc2ccc(S(=O)(=O)CCOS(O)(=O)=O)cc2)C(=O)N(c2ccc(S(O)(=O)=O)cc2)N=1
InChI:1S/C18H16N4O12S3/c23-17-15(16(18(24)25)21-22(17)12-3-7-14(8-4-12)36(28,29)30)20-19-11-1-5-13(6-2-11)35(26,27)10-9-34-37(31,32)33/h1-8,15H,9-10H2,(H,24,25)(H,28,29,30)(H,31,32,33)/b20-19+
Molecular Formula:C18H16N4O12S3
Molecular Weight:576.538 g/mole

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

not specified

Route of administration:

oral: gavage

Vehicle:

unchanged (no vehicle)

Details on oral exposure:

not specified

Doses:

8100 mg/kg

No. of animals per sex per dose:

10

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:

8 100 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 8 nearest neighbours
Domain  logical expression:Result: In Domain

((((((((("a" or "b" or "c" or "d" or "e" )  and ("f" and ( not "g") )  )  and "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 "s" )  )

Domain logical expression index: "a"

Referential boundary: The target chemical should be classified as Vinyl Sulfones by US-EPA New Chemical Categories

Domain logical expression index: "b"

Referential boundary: The target chemical should be classified as Acid moiety OR Amides OR Hydrazines by Aquatic toxicity classification by ECOSAR ONLY

Domain logical expression index: "c"

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 OR SN2 OR SN2 >> SN2 reaction at sp3 carbon atom OR SN2 >> SN2 reaction at sp3 carbon atom >> Alkyl diazo by Protein binding by OECD ONLY

Domain logical expression index: "d"

Referential boundary: The target chemical should be classified as Schiff base formation OR Schiff base formation >> Pyrazolones and Pyrazolidinones derivatives OR Schiff base formation >> Pyrazolones and Pyrazolidinones derivatives >> Pyrazolones and Pyrazolidinones  by Protein binding by OASIS v1.3 ONLY

Domain logical expression index: "e"

Referential boundary: The target chemical should be classified as SN1 OR SN1 >> Nitrenium Ion formation OR SN1 >> Nitrenium Ion formation >> Aromatic azo OR SN1 >> Nitrenium Ion formation >> Unsaturated heterocyclic azo by DNA binding by OECD ONLY

Domain logical expression index: "f"

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

Domain logical expression index: "g"

Referential boundary: The target chemical should be classified as AN2 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 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 >> 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 >> Radical mechanism via ROS formation (indirect) OR Radical >> Radical mechanism via ROS formation (indirect) >> Geminal Polyhaloalkane Derivatives OR Radical >> Radical mechanism via ROS formation (indirect) >> Specific Imine and Thione Derivatives OR SN1 OR SN1 >> Nucleophilic attack after carbenium ion formation OR SN1 >> Nucleophilic attack after carbenium ion formation >> Specific Acetate Esters 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, ring opening SN2 reaction OR SN2 >> Alkylation, ring opening SN2 reaction >> Four- and Five-Membered Lactones OR SN2 >> DNA alkylation 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 >> 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 by DNA binding by OASIS v.1.3

Domain logical expression index: "h"

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 AND SN2 AND SN2 >> SN2 reaction at sp3 carbon atom AND SN2 >> SN2 reaction at sp3 carbon atom >> Alkyl diazo by Protein binding by OECD ONLY

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 Allantoin and dimethadione-like derivatives (17b) OR Known precedent reproductive and developmental toxic potential OR Miscellaneous cyclic chemicals (18) OR Piperazine-, dioxane-, morpholine-, tetrahydrothiopyran-like derivatives and cyclohexanamine (17c) OR Triarylmethane dyes (12c) by DART scheme v.1.0

Domain logical expression index: "k"

Similarity boundary:Target: OC(=O)C1C(N=Nc2ccc(S(=O)(=O)CCOS(O)(=O)=O)cc2)C(=O)N(c2ccc(S(O)(=O)=O)cc2)N=1
Threshold=20%,
Dice(Atom centered fragments)
Atom type; Count H attached; Hybridization

Domain logical expression index: "l"

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

Domain logical expression index: "m"

Referential boundary: The target chemical should be classified as Allyl esters (Hepatotoxicity) Rank A OR Perhexiline (Hepatotoxicity) Alert OR Tamoxifen (Hepatotoxicity) Alert by Repeated dose (HESS)

Domain logical expression index: "n"

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 log Kow < -3.1 AND Group All Melting Point > 200 C AND Group CNS log Kow < 0.5 AND Group CNS log Kow < -2 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: "o"

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: "p"

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 log Kow < -3.1 AND Group All Melting Point > 200 C AND Group CNS log Kow < 0.5 AND Group CNS log Kow < -2 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: "q"

Referential boundary: The target chemical should be classified as Group CN Aqueous Solubility < 0.1 g/L by Skin irritation/corrosion Exclusion rules by BfR

Domain logical expression index: "r"

Parametric boundary:The target chemical should have a value of log Kow which is >= -7.06

Domain logical expression index: "s"

Parametric boundary:The target chemical should have a value of log Kow which is <= 1.24

Interpretation of results:

other: Not classified

Conclusions:

LD50 was estimated to be 8100 mg/kg bw, when 10 male and female Sprague-Dawley rats were treated with 4,5-dihydro-5-oxo-4-[[4-[[2-(sulphooxy)ethyl]sulphonyl]phenyl]azo]-1-(4-sulphophenyl)-1H-pyrazole-3-carboxylic acid (CAS no: 10149-98-1) via oral 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 4,5-dihydro-5-oxo-4-[[4-[[2-(sulphooxy)ethyl]sulphonyl]phenyl]azo]-1-(4-sulphophenyl)-1H-pyrazole-3-carboxylic acid (CAS no: 10149-98-1). The LD50 was estimated to be 8100 mg/kg bw, when 10 male and female Sprague-Dawley rats were treated with 4,5-dihydro-5-oxo-4-[[4-[[2-(sulphooxy)ethyl]sulphonyl]phenyl]azo]-1-(4-sulphophenyl)-1H-pyrazole-3-carboxylic acid via oral gavage route.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

8 100 mg/kg bw

Quality of whole database:

Data is Klimisch 2 and from QSAR toolbox 3.3.

Acute toxicity: via inhalation route

Link to relevant study records

Reference

Endpoint:

acute toxicity: inhalation

Data waiving:

other justification

Justification for data waiving:

other:

Endpoint conclusion

Quality of whole database:

Waiver

Acute toxicity: via dermal route

Link to relevant study records

Reference

Endpoint:

acute toxicity: dermal

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 data

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: 4,5-dihydro-5-oxo-4-[[4-[[2-(sulphooxy)ethyl]sulphonyl]phenyl]azo]-1-(4-sulphophenyl)-1H-pyrazole-3-carboxylic acid
SMILES:OC(=O)C1C(N=Nc2ccc(S(=O)(=O)CCOS(O)(=O)=O)cc2)C(=O)N(c2ccc(S(O)(=O)=O)cc2)N=1
InChI:1S/C18H16N4O12S3/c23-17-15(16(18(24)25)21-22(17)12-3-7-14(8-4-12)36(28,29)30)20-19-11-1-5-13(6-2-11)35(26,27)10-9-34-37(31,32)33/h1-8,15H,9-10H2,(H,24,25)(H,28,29,30)(H,31,32,33)/b20-19+
Molecular Formula:C18H16N4O12S3
Molecular Weight:576.538 g/mole

Species:

rabbit

Strain:

New Zealand White

Sex:

male/female

Details on test animals or test system and environmental conditions:

not specified

Type of coverage:

occlusive

Vehicle:

unchanged (no vehicle)

Details on dermal exposure:

not specified

Duration of exposure:

24 hours

Doses:

3617 mg/kg

No. of animals per sex per dose:

10

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:

3 617 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" or "e" )  and ("f" and ( not "g") )  )  and "h" )  and ("i" and ( not "j") )  )  and "k" )  and "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" )  )

Domain logical expression index: "a"

Referential boundary: The target chemical should be classified as Vinyl Sulfones by US-EPA New Chemical Categories

Domain logical expression index: "b"

Referential boundary: The target chemical should be classified as Acid moiety OR Amides OR Hydrazines by Aquatic toxicity classification by ECOSAR ONLY

Domain logical expression index: "c"

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 OR SN2 OR SN2 >> SN2 reaction at sp3 carbon atom OR SN2 >> SN2 reaction at sp3 carbon atom >> Alkyl diazo by Protein binding by OECD ONLY

Domain logical expression index: "d"

Referential boundary: The target chemical should be classified as Schiff base formation OR Schiff base formation >> Pyrazolones and Pyrazolidinones derivatives OR Schiff base formation >> Pyrazolones and Pyrazolidinones derivatives >> Pyrazolones and Pyrazolidinones  by Protein binding by OASIS v1.3 ONLY

Domain logical expression index: "e"

Referential boundary: The target chemical should be classified as SN1 OR SN1 >> Nitrenium Ion formation OR SN1 >> Nitrenium Ion formation >> Aromatic azo OR SN1 >> Nitrenium Ion formation >> Unsaturated heterocyclic azo by DNA binding by OECD ONLY

Domain logical expression index: "f"

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

Domain logical expression index: "g"

Referential boundary: The target chemical should be classified as AN2 OR AN2 >>  Michael-type addition, quinoid structures OR AN2 >>  Michael-type addition, quinoid structures >> Quinones 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 >> Amino Anthraquinones OR Non-covalent interaction >> DNA intercalation >> Coumarins OR Non-covalent interaction >> DNA intercalation >> DNA Intercalators with Carboxamide Side Chain OR Non-covalent interaction >> DNA intercalation >> Fused-Ring Primary Aromatic Amines OR Non-covalent interaction >> DNA intercalation >> Quinones 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) >> Amino Anthraquinones OR Radical >> Radical mechanism via ROS formation (indirect) >> Coumarins OR Radical >> Radical mechanism via ROS formation (indirect) >> Fused-Ring Primary Aromatic Amines OR Radical >> Radical mechanism via ROS formation (indirect) >> Geminal Polyhaloalkane Derivatives OR Radical >> Radical mechanism via ROS formation (indirect) >> Hydrazine Derivatives OR Radical >> Radical mechanism via ROS formation (indirect) >> Nitro Azoarenes OR Radical >> Radical mechanism via ROS formation (indirect) >> Nitroarenes with Other Active Groups OR Radical >> Radical mechanism via ROS formation (indirect) >> p-Substituted Mononitrobenzenes OR Radical >> Radical mechanism via ROS formation (indirect) >> Quinones 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 >> Amino Anthraquinones OR SN1 >> Nucleophilic attack after metabolic nitrenium ion formation >> Fused-Ring Primary Aromatic Amines 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 >> Nitroarenes with Other Active Groups 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 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, 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 >> DNA alkylation 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 >> 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 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: "h"

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 AND SN2 AND SN2 >> SN2 reaction at sp3 carbon atom AND SN2 >> SN2 reaction at sp3 carbon atom >> Alkyl diazo by Protein binding by OECD ONLY

Domain logical expression index: "i"

Referential boundary: The target chemical should be classified as Not possible to classify according to these rules (GSH) by Protein binding potency

Domain logical expression index: "j"

Referential boundary: The target chemical should be classified as Moderately reactive (GSH) OR Moderately reactive (GSH) >> 2-Chloroacetamides (SN2) OR Moderately reactive (GSH) >> 2-Vinyl carboxamides (MA) OR Moderately reactive (GSH) >> Substituted 1-Alken-3-ones (MA) by Protein binding potency

Domain logical expression index: "k"

Referential boundary: The target chemical should be classified as Not bioavailable by Lipinski Rule Oasis ONLY

Domain logical expression index: "l"

Similarity boundary:Target: OC(=O)C1C(N=Nc2ccc(S(=O)(=O)CCOS(O)(=O)=O)cc2)C(=O)N(c2ccc(S(O)(=O)=O)cc2)N=1
Threshold=30%,
Dice(Atom centered fragments)
Atom type; Count H attached; Hybridization

Domain logical expression index: "m"

Referential boundary: The target chemical should be classified as Alcohol, olefinic attach [-OH] AND Aliphatic Carbon [CH] AND Aliphatic Carbon [-CH2-] AND Aliphatic Nitrogen, one aromatic attach [-N] AND Amide, aliphatic attach [-C(=O)N] AND Amino, aliphatic attach [-N<] AND Amino-carbonyl compound [NCC(=O)-C] AND Aromatic Carbon [C] AND Azo [-N=N-] AND Azomethine, aliphatic attach [-N=C] AND Carbonyl, aliphatic attach [-C(=O)-] AND Carbonyl, olefinic attach [-C(=O)-] AND Hydrazine [>N-N<] AND Hydroxy, sulfur attach [-OH] AND Miscellaneous sulfide (=S) or oxide (=O) AND Nitrogen, two or tree olefinic attach [>N-] AND Olefinic carbon [=CH- or =C<] AND Suflur {v+4} or {v+6} AND Sulfate, linear [-O-SO2-O-] AND Sulfinic acid [-S(=O)OH] AND Sulfite, linear [-OS(=O)O-] AND Sulfonate, aromatic attach [-SO2-O] AND Sulfonic [SO2(-OH)-O] by Organic functional groups (US EPA)

Domain logical expression index: "n"

Referential boundary: The target chemical should be classified as Tertiary Carbon by Organic functional groups (US EPA)

Domain logical expression index: "o"

Referential boundary: The target chemical should be classified as Aryl AND Azo AND Carboxylic acid AND Pyrazolone AND Sulfate AND Sulfone AND Sulfonic acid AND Unsaturated heterocyclic amine AND Unsaturated heterocyclic fragment by Organic Functional groups

Domain logical expression index: "p"

Referential boundary: The target chemical should be classified as Alkyl arenes by Organic Functional groups

Domain logical expression index: "q"

Referential boundary: The target chemical should be classified as Aryl AND Azo AND Carboxylic acid AND Overlapping groups AND Pyrazolone AND Sulfate AND Sulfone AND Sulfonic acid by Organic Functional groups (nested)

Domain logical expression index: "r"

Referential boundary: The target chemical should be classified as Diketone by Organic Functional groups (nested)

Domain logical expression index: "s"

Referential boundary: The target chemical should be classified as Aryl AND Azo AND Carboxylic acid AND Overlapping groups AND Pyrazolone AND Sulfate AND Sulfone AND Sulfonic acid by Organic Functional groups (nested)

Domain logical expression index: "t"

Referential boundary: The target chemical should be classified as Carboxylic acid ester by Organic Functional groups (nested)

Domain logical expression index: "u"

Parametric boundary:The target chemical should have a value of log Kow which is >= -8.3

Domain logical expression index: "v"

Parametric boundary:The target chemical should have a value of log Kow which is <= 7.69

Interpretation of results:

other: Not classified

Conclusions:

LD50 was estimated to be 3617 mg/kg bw, when 10 male and female New Zealand White rabbits were treated with 4,5-dihydro-5-oxo-4-[[4-[[2-(sulphooxy)ethyl]sulphonyl]phenyl]azo]-1-(4-sulphophenyl)-1H-pyrazole-3-carboxylic acid (CAS no: 10149-98-1) for 24 hours by dermal application occlusively.

Executive summary:

In a prediction done by SSS (2017) using the OECD QSAR toolbox with log kow as the primary descriptor, the acute dermal toxicity was estimated for 4,5-dihydro-5-oxo-4-[[4-[[2-(sulphooxy)ethyl]sulphonyl]phenyl]azo]-1-(4-sulphophenyl)-1H-pyrazole-3-carboxylic acid (CAS no: 10149-98-1). The LD50 was estimated to be 3617 mg/kg bw, when 10 male and female New Zealand White rabbits were treated with 4,5-dihydro-5-oxo-4-[[4-[[2-(sulphooxy)ethyl]sulphonyl]phenyl]azo]-1-(4-sulphophenyl)-1H-pyrazole-3-carboxylic acid for 24 hours by dermal application occlusively.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

3 617 mg/kg bw

Quality of whole database:

Data is Klimisch 2 and from QSAR toolbox 3.3.

Additional information

Acute oral toxicity:

In different studies, 4,5-dihydro-5-oxo-4-[[4-[[2-(sulphooxy)ethyl]sulphonyl]phenyl]azo]-1-(4-sulphophenyl)-1H-pyrazole-3-carboxylic acid (CAS no: 10149-98-1) 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 4,5-dihydro-5-oxo-4-[[4-[[2-(sulphooxy)ethyl]sulphonyl]phenyl]azo]-1-(4-sulphophenyl)-1H-pyrazole-3-carboxylic acid along with the study available on structurally similar read across substances Aluminium, 6-hydroxy-5-[(4-sulfophenyl)azo]-2-naphthalenesulfonic acid complex (CAS No: 15790-07-5) and Tartrazine (CAS No: 1934-21-0).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 4,5-dihydro-5-oxo-4-[[4-[[2-(sulphooxy)ethyl]sulphonyl]phenyl]azo]-1-(4-sulphophenyl)-1H-pyrazole-3-carboxylic acid (CAS no: 10149-98-1). The LD50 was estimated to be 8100 mg/kg bw, when 10 male and female Sprague-Dawley rats were treated with 4,5-dihydro-5-oxo-4-[[4-[[2-(sulphooxy)ethyl]sulphonyl]phenyl]azo]-1-(4-sulphophenyl)-1H-pyrazole-3-carboxylic acid via oral gavage route.

The above study is supported by Sustainability Support Services (Europe) AB (study no.201303, 2013) was designed and conducted for the structurally similar read across substance Aluminium, 6-hydroxy-5-[(4-sulfophenyl)azo]-2-naphthalenesulfonic acid complex (CAS No: 15790-07-5) in Wistar albino female rats. The study was conducted under the OECD Guideline-423 for testing of chemicals. The healthy Wistar albino rats of body weight 200±20 gm were selected for study after acclimatization to standard laboratory condition and divided into test compound and vehicle control group each having three animals. Initially, the test compound was mixed with distilled water and administered orally at the dose level of 2000 mg/kg body weight (dose volume 10ml/kg) to three female rats. However; vehicle control group treated with distilled water at the dose level of 10 ml/kg bw. The treated animals were closely observed for clinical signs of intoxication during first 4 hours of test compound administration. Thereafter, all the animals were observed periodically at 1 hour interval for 24 hrs and twice daily for a period of 14 days. The necropsy was performed on all animals at the termination of the study. The test compound did not produce any mortality at the dose level of 2000 mg/kg body weight during the entire observation period. Animals did not produce any clinical signs of toxicity during the entire observation period. Animals showed normal gain in body weight on day 7th and 14th as compared to control group. No significant gross pathological changes related to compound toxicity were observed. Skin and hair coat was observed wet. It was concluded that the test compound Aluminium, 6-hydroxy-5-[(4-sulfophenyl)azo]-2-naphthalenesulfonic acid complex (CAS No. 15790-07-5) is non-toxic at the tested dose level 2000 mg/kg body weight. According to criteria of CLP, it comes under the “Category Unclassified".

This study is further supported by Lamia et al. (International Journal of Pharm Tech Research, Vol 9, No.4, pp 364-367, 2016), for the structurally similar read across substance Tartrazine (CAS No: 1934-21-0). Acute oral toxicity test was conducted in male Sprague- Dawly white mice using tartrazine at the dose concentration of 1250 mg/kg, 2500 mg/kg, 3750 mg/kg 5000 mg/kg, 6250 mg/kg to 6 animals per dose by oral route. Control animals received distilled water only. The mice were observed for 3 days for the signs and symptoms of toxicity as well as the death rate of each group were recorded. Tartrazine dye administration at single dose has not been found to be any toxic effects even at higher dose used (6250 mg/Kg BW) at the same time there is no mortality or morbidity was recorded in all grouped animals treated with tartrazine dye. Hence, LD50 was considered to be >6250 mg/kg bw when male Sprague- Dawly white mice was treated with Tartrazine for 3 days via oral route.

Thus, based on the above studies on 4,5-dihydro-5-oxo-4-[[4-[[2-(sulphooxy)ethyl] sulphonyl] phenyl]azo]-1-(4-sulphophenyl)-1H-pyrazole-3-carboxylic acid (CAS no: 10149-98-1) and it’s read across substances, it can be concluded that LD50 value is >2000 mg/kg bw. Thus, comparing this value with the criteria of CLP regulation, 4,5-dihydro-5-oxo-4-[[4-[[2-(sulphooxy)ethyl]sulphonyl] phenyl]azo]-1-(4-sulphophenyl)-1H-pyrazole-3-carboxylic acid cannot be classified for acute oral toxicity.

Acute Inhalation toxicity: 

4,5-dihydro-5-oxo-4-[[4-[[2-(sulphooxy)ethyl]sulphonyl] phenyl]azo]-1-(4-sulphophenyl)-1H-pyrazole-3-carboxylic acid (CAS no: 10149-98-1) has very low vapour pressure (6.62E-26 Pa at 25°C), 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 was considered for waiver.

Acute Dermal toxicity:

In different studies, 4,5-dihydro-5-oxo-4-[[4-[[2-(sulphooxy)ethyl]sulphonyl]phenyl]azo]-1-(4-sulphophenyl)-1H-pyrazole-3-carboxylic acid (CAS no: 10149-98-1) has been investigated for acute dermal toxicity to a greater or lesser extent. Often are the studies based on in vivo experiments in rodents, i.e. most commonly in rabbits and rats for 4,5-dihydro-5-oxo-4-[[4-[[2-(sulphooxy)ethyl]sulphonyl]phenyl]azo]-1-(4-sulphophenyl)-1H-pyrazole-3-carboxylic acid along with the study available on the structurally similar read across substance Aluminium, 6-hydroxy-5-[(4-sulfophenyl)azo]-2-naphthalenesulfonic acid complex (CAS No: 15790-07-5) and on the functionally similar read across substance Tetrasodium 1-acetamido-2-hydroxy-3-(4-((4-sulphonatophenylazo)-7-sulphonato-1-naphthylazo)) naphthalene-4,6-disulphonate (CAS No. 2519-30-4). 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 dermal toxicity was estimated for 4,5-dihydro-5-oxo-4-[[4-[[2-(sulphooxy)ethyl]sulphonyl]phenyl]azo]-1-(4-sulphophenyl)-1H-pyrazole-3-carboxylic acid (CAS no: 10149-98-1). The LD50 was estimated to be 3617 mg/kg bw, when 10 male and female New Zealand White rabbits were treated with 4,5-dihydro-5-oxo-4-[[4-[[2-(sulphooxy)ethyl]sulphonyl]phenyl]azo]-1-(4-sulphophenyl)-1H-pyrazole-3-carboxylic acid for 24 hours by dermal application occlusively.

This study is supported by Sustainability Support Services (Europe) AB (study no.201303, 2013) was designed and conducted for the structurally similar read across substance Aluminium, 6-hydroxy-5-[(4-sulfophenyl)azo]-2-naphthalenesulfonic acid complex (CAS No: 15790-07-5)in wistar albino rats. The study was conducted under the OECD Guideline-402 for testing of chemicals. In limit test, healthy wistar albino rats of body weight 200±20 gm were selected for study after acclimatization. Approximate 10% back skin of total body surface area was prepared 24 hrs prior to application of test compound. Test drug was applied dermally at the dose of 2000 mg/kg bw for each animal. The treated animals were observed for clinical signs of intoxication. The body weight of all the animals was observed weekly on day 0 (pre treatment), 7th and 14th (post treatment). The Necropsy was performed on all at the termination of the study. After 72 hrs, a confirmatory test was conducted in same species of animals to confirm the limit test of the test compound. Rats were observed for mortality at 30 minutes time interval for first 6 hous on the day of test compund and therafter twice a day for 14 days. All the rats were observed at least twice daily with the purpose of recording any symptoms of ill-health or behavioral changes. The organ which showed gross pathological change during necropsy subjected for histopathological study. No mortality was observed at 2000 mg/kg bw. Animals did not produce any clinical signs of intoxication throughout the period of observation. Animals showed normal gain in body weight on day 7th and 14th as compared to control group. No significant gross pathological changes related to compound toxicity were observed. Skin and hair coat was observed wet. Therefore, it was concluded that the test compound Aluminium, 6-hydroxy-5-[(4-sulfophenyl)azo]-2-naphthalenesulfonic acid complex (CAS No. 15790-07-5)is non-toxic at the tested dose level 2000 mg/kg body weight. According to criteria of CLP, it comes under the “Category Unclassified".

The above study is further supported by Sustainability Support Services (Europe) AB (study no.18818, 2016) was designed and conducted for the functionally similar read across substance Tetrasodium 1-acetamido-2-hydroxy-3-(4-((4-sulphonatophenylazo)-7-sulphonato-1-naphthylazo))naphthalene-4,6-disulphonate (CAS No. 2519-30-4) in Sprague Dawley rats. The test item was applied to shorn skin of 5 male and 5 female animals at 2000 mg/kg body weight. Administration of the test item at 2000 mg/kg did not result in any skin reaction at the site of application during the study period of 14 days. Administration of the test item did not result in any signs of toxicity and mortality during the study period of 14 days. Animals exhibited normal body weight gain through the study period of 14 days. Gross pathological examination did not reveal any abnormalities attributable to the treatment. It was concluded that the acute dermal median lethal dose (LD50) of Tetra sodium 1-acetamido-2-hydroxy-3-(4-((4-sulphonatophenylazo)-7-sulphonato-1-naphthylazo)) naphthalene-4,6-disulphonate, when administered to male and female Sprague Dawley rats was found to be >2000 mg/kg body weight. Thus, according to CLP criteria for acute toxicity rating for the chemicals, it infers that Tetra sodium 1-acetamido-2-hydroxy-3-(4-((4-sulphonatophenylazo)-7-sulphonato-1-naphthylazo)) naphthalene-4,6-disulphonate (CAS No. 2519-30-4) does not classify as an acute dermal toxicant. CLP Classification: “Unclassified”.

Thus, based on the above studies on 4,5-dihydro-5-oxo-4-[[4-[[2-(sulphooxy)ethyl] sulphonyl]phenyl]azo]-1-(4-sulphophenyl)-1H-pyrazole-3-carboxylic acid (CAS no: 10149-98-1) and it’s read across substances, it can be concluded that LD50 value is >2000 mg/kg bw. Thus, comparing this value with the criteria of CLP regulation, 4,5-dihydro-5-oxo-4-[[4-[[2-(sulphooxy)ethyl]sulphonyl]phenyl]azo]-1-(4-sulphophenyl)-1H-pyrazole-3-carboxylic acid cannot be classified for acute dermal toxicity.

Justification for classification or non-classification

Based on the above studies and prediction on 4,5-dihydro-5-oxo-4-[[4-[[2-(sulphooxy)ethyl] sulphonyl]phenyl]azo]-1-(4-sulphophenyl)-1H-pyrazole-3-carboxylic acid (CAS no: 10149-98-1) and it’s read across substances, it can be concluded that LD50 value is >2000 mg/kg bw for acute oral and dermal toxicity. Thus, comparing this value with the criteria of CLP regulation, 4,5-dihydro-5-oxo-4-[[4-[[2-(sulphooxy)ethyl]sulphonyl]phenyl]azo]-1-(4-sulphophenyl)-1H-pyrazole-3-carboxylic acid cannot be classified for acute oral and dermal toxicity.For Acute Inhalation toxicity wavier was added so, not possible to classify.