Hydrogen bis[2-(3-chlorophenyl)-2,4-dihydro-4-[[2-hydroxy-5-mesylphenyl]azo]-5-methyl-3H-pyrazol-3-onato(2-)]chromate(1-)

Endpoint summary

Description of key information

Acute oral toxicity: 

Acute oral toxicity dose (LD50) for target chemical chromium(3+) ion hydrogen bis(1-(3-chlorophenyl)-4-[(E)-2-(5-methanesulfonyl-2-oxidophenyl)diazen-1-yl]-3-methyl-1H-pyrazol-5-olate)(CAS no: 71598-35-1) was predicted based on OECD QSAR toolbox, the value estimated to be 4200 mg/kg bw and different studies available on structurally similar read across substances 4,4'-(1E,1'E)-(3,3'-dichlorobiphenyl-4,4'-diyl)bis(diazene-2,1-diyl)bis(3-methyl-1-phenyl-1H-pyrazol-5(4H)-one) (CAS no: 3520-72-7), the LD50 was considered to be >5000 mg/kg bw and 4,4'-[(3,3'-dichlorobiphenyl-4,4'-diyl) didiazene-2,1-diyl]bis[5-methyl-2-(4-methylphenyl) -2,4-dihydro-3H-pyrazol-3-one] (CAS no: 15793-73-4), the LD50 was considered to be >16000 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, chromium (3+) ion hydrogen bis(1-(3-chlorophenyl)-4-[(E)-2-(5-methanesulfonyl-2-oxidophenyl)diazen-1-yl]-3-methyl-1H-pyrazol-5-olate) cannot be classified for acute oral 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: chromium(3+) ion hydrogen bis(1-(3-chlorophenyl)-4-[(E)-2-(5-methanesulfonyl-2-oxidophenyl)diazen-1-yl]-3-methyl-1H-pyrazol-5-olate)
SMILES:CC1C{-}(N=Nc2cc(S(C)(=O)=O)ccc2O{-}.[Cr]{3+}2.C{-}3(C(C)=NN(c4cccc(Cl)c4)C3=O)N=Nc3cc(S(C)(=O)=O)ccc3O{-}.2)C(=O)N(c2cccc(Cl)c2)N=1
InChI:1S/2C17H14ClN4O4S.Cr/c2*1-10-16(17(24)22(21-10)12-5-3-4-11(18)8-12)20-19-14-9-13(27(2,25)26)6-7-15(14)23;/h2*3-9,23H,1-2H3;/q2*-1;+3/p-1/b2*20-19+;
Molecular Formula: C34H26Cl2CrN8O8S2.H
Molecular Weight: 862.669 g/mole

Species:

rat

Strain:

other: CFE (RAC, SPF) strain

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:

4200 mg/kg bw

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

Dose descriptor:

LD50

Effect level:

4 200 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 5 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 ("j" and ( not "k") )  )  and ("l" and ( not "m") )  )  and ("n" and ( not "o") )  )  and ("p" and ( not "q") )  )  and "r" )  and ("s" and ( not "t") )  )  and ("u" and ( not "v") )  )  and ("w" and "x" )  )

Domain logical expression index: "a"

Referential boundary: The target chemical should be classified as Anion by Substance Type

Domain logical expression index: "b"

Referential boundary: The target chemical should be classified as Schiff base formation AND Schiff base formation >> Pyrazolones and Pyrazolidinones derivatives AND Schiff base formation >> Pyrazolones and Pyrazolidinones derivatives >> Pyrazolones and Pyrazolidinones  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 SN1 AND SN1 >> Nitrenium Ion formation AND SN1 >> Nitrenium Ion formation >> Aromatic azo AND SN1 >> Nitrenium Ion formation >> Unsaturated heterocyclic azo by DNA binding by OECD

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) >> Nitroarenes with Other Active Groups 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 >> 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 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 >> 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 Non binder, MW>500 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, non cyclic structure OR Non binder, without OH or NH2 group OR Strong binder, OH 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 High (Class III) by Toxic hazard classification by Cramer (original) ONLY

Domain logical expression index: "j"

Referential boundary: The target chemical should be classified as No Data by Ultimate biodeg

Domain logical expression index: "k"

Referential boundary: The target chemical should be classified as > 100 days by Ultimate biodeg

Domain logical expression index: "l"

Referential boundary: The target chemical should be classified as Group 14 - Carbon C AND Group 15 - Nitrogen N AND Group 16 - Oxygen O AND Group 16 - Sulfur S AND Group 17 - Halogens Cl AND Group 17 - Halogens F,Cl,Br,I,At AND Group 6 - Trans.Metals Cr,Mo,W by Chemical elements

Domain logical expression index: "m"

Referential boundary: The target chemical should be classified as Group 1 - Alkali Earth Li,Na,K,Rb,Cs,Fr OR Group 12 - Trans.Metals Zn,Cd,Hg by Chemical elements

Domain logical expression index: "n"

Referential boundary: The target chemical should be classified as Group 14 - Carbon C AND Group 15 - Nitrogen N AND Group 16 - Oxygen O AND Group 16 - Sulfur S AND Group 17 - Halogens Cl AND Group 17 - Halogens F,Cl,Br,I,At AND Group 6 - Trans.Metals Cr,Mo,W by Chemical elements

Domain logical expression index: "o"

Referential boundary: The target chemical should be classified as Group 17 - Halogens F by Chemical elements

Domain logical expression index: "p"

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

Domain logical expression index: "q"

Referential boundary: The target chemical should be classified as Thiocarbamates/Sulfides (Hepatotoxicity) No rank by Repeated dose (HESS)

Domain logical expression index: "r"

Similarity boundary:Target: CC1C{-}(N=Nc2cc(S(C)(=O)=O)ccc2O{-}.[Cr]{3+}2.C{-}3(C(C)=NN(c4cccc(Cl)c4)C3=O)N=Nc3cc(S(C)(=O)=O)ccc3O{-}.2)C(=O)N(c2cccc(Cl)c2)N=1
Threshold=10%,
Dice(Atom centered fragments)
Atom type; Count H attached; Hybridization

Domain logical expression index: "s"

Referential boundary: The target chemical should be classified as Aryl AND Aryl halide AND Azo AND Fused carbocyclic aromatic AND Phenol AND Pyrazolone AND Sulfone AND Unsaturated heterocyclic amine AND Unsaturated heterocyclic fragment by Organic Functional groups

Domain logical expression index: "t"

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

Domain logical expression index: "u"

Referential boundary: The target chemical should be classified as Aryl AND Aryl halide AND Azo AND Fused carbocyclic aromatic AND Phenol AND Pyrazolone AND Sulfone AND Unsaturated heterocyclic amine AND Unsaturated heterocyclic fragment by Organic Functional groups

Domain logical expression index: "v"

Referential boundary: The target chemical should be classified as Carbohydrate/ Monosaccharide by Organic Functional groups

Domain logical expression index: "w"

Parametric boundary:The target chemical should have a value of Molecular weight which is >= 520 Da

Domain logical expression index: "x"

Parametric boundary:The target chemical should have a value of Molecular weight which is <= 920 Da

Interpretation of results:

other: Not classified

Conclusions:

LD50 was estimated to be 4200 mg/kg bw, when 10 male and female CFE (RAC, SPF) rats were treated with chromium(3+) ion hydrogen bis(1-(3-chlorophenyl)-4-[(E)-2-(5-methanesulfonyl-2-oxidophenyl)diazen-1-yl]-3-methyl-1H-pyrazol-5-olate)(CAS no: 71598-35-1) via oral gavage route.

Executive summary:

In a prediction done by SSS (2018) using the OECD QSAR toolbox with log kow as the primary descriptor, the acute oral toxicity was estimated for chromium (3+) ion hydrogen bis(1-(3-chlorophenyl)-4-[(E)-2-(5-methanesulfonyl-2-oxidophenyl)diazen-1-yl]-3-methyl-1H-pyrazol-5-olate)(CAS no: 71598-35-1). The LD50 was estimated to be 4200 mg/kg bw, when 10 male and female CFE (RAC, SPF) rats were treated with chromium (3+) ion hydrogen bis(1-(3-chlorophenyl)-4-[(E)-2-(5-methanesulfonyl-2-oxidophenyl)diazen-1-yl]-3-methyl-1H-pyrazol-5-olate) via oral gavage route.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

4 200 mg/kg bw

Quality of whole database:

Data is Klimisch 2 and from QSAR toolbox 3.3.

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, chromium (3+) ion hydrogen bis(1-(3-chlorophenyl)-4-[(E)-2-(5-methanesulfonyl-2-oxidophenyl)diazen-1-yl]-3-methyl-1H-pyrazol-5-olate)(CAS no: 71598-35-1) 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 for chromium (3+) ion hydrogen bis(1-(3-chlorophenyl)-4-[(E)-2-(5-methanesulfonyl-2-oxidophenyl)diazen-1-yl]-3-methyl-1H-pyrazol-5-olate) along with the study available on structurally similar read across substances 4,4'-(1E,1'E)-(3,3'-dichlorobiphenyl-4,4'-diyl)bis(diazene-2,1-diyl)bis(3-methyl-1-phenyl-1H-pyrazol-5(4H)-one) (CAS no: 3520-72-7) and 4,4'-[(3,3'-dichlorobiphenyl-4,4'-diyl) didiazene-2,1-diyl]bis[5-methyl-2-(4-methylphenyl) -2,4-dihydro-3H-pyrazol-3-one] (CAS no: 15793-73-4). 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 (2018) using the OECD QSAR toolbox with log kow as the primary descriptor, the acute oral toxicity was estimated for chromium (3+) ion hydrogen bis(1-(3-chlorophenyl)-4-[(E)-2-(5-methanesulfonyl-2-oxidophenyl)diazen-1-yl]-3-methyl-1H-pyrazol-5-olate)(CAS no: 71598-35-1). The LD50 was estimated to be 4200 mg/kg bw, when 10 male and female CFE (RAC, SPF) rats were treated with chromium (3+) ion hydrogen bis(1-(3-chlorophenyl)-4-[(E)-2-(5-methanesulfonyl-2-oxidophenyl)diazen-1-yl]-3-methyl-1H-pyrazol-5-olate) via oral gavage route.

The above study is supported by U.S. National Library of Medicine (ChemIDplus, 2017), for the structurally similar read across substance 4,4'-(1E,1'E)-(3,3'-dichlorobiphenyl-4,4'-diyl)bis(diazene-2,1-diyl)bis(3-methyl-1-phenyl-1H-pyrazol-5(4H)-one) (3520-72-7).Acute oral toxicity study was conducted in rats at the concentration of 5000 mg/kg bw. No Mortality was observed at dose 5000 mg/kg bw. Hence, LD50 value was considered to be >5000 mg/kg bw, when rats were treated with4,4'-(1E,1'E)-(3,3'-dichlorobiphenyl-4,4'-diyl)bis(diazene-2,1-diyl)bis(3-methyl-1-phenyl-1H-pyrazol-5(4H)-one) via oral route.

This study is also supported by European Commission (EC) - Scientific Committee on Cosmetology (SCC, 1988), for the structurally similar read across substance 4,4'-[(3,3'-dichlorobiphenyl-4,4'-diyl) didiazene-2,1-diyl]bis[5-methyl-2-(4-methylphenyl) -2,4-dihydro-3H-pyrazol-3-one] (CAS no: 15793-73-4).The acute oral toxicity study was conducted in rats at the concentration of 16000 mg/kg bw. No Mortality was observed at dose 16000 mg/kg bw. Hence,LD50 value was considered to be >16000 mg/kg bw, when rats were treated with 4,4'-[(3,3'-dichlorobiphenyl-4,4'-diyl) didiazene-2,1-diyl]bis[5-methyl-2-(4-methylphenyl) -2,4-dihydro-3H-pyrazol-3-one] (CAS no: 15793-73-4) via oral route.

Thus, based on the above studies on chromium (3+) ion hydrogen bis(1-(3-chlorophenyl)-4-[(E)-2-(5-methanesulfonyl-2-oxidophenyl)diazen-1-yl]-3-methyl-1H-pyrazol-5-olate)(CAS no: 71598-35-1) 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, chromium (3+) ion hydrogen bis(1-(3-chlorophenyl)-4-[(E)-2-(5-methanesulfonyl-2-oxidophenyl)diazen-1-yl]-3-methyl-1H-pyrazol-5-olate) cannot be classified for acute oral toxicity.

Justification for classification or non-classification

Based on the above studies and prediction on chromium (3+) ion hydrogen bis(1-(3-chlorophenyl)-4-[(E)-2-(5-methanesulfonyl-2-oxidophenyl)diazen-1-yl]-3-methyl-1H-pyrazol-5-olate)(CAS no: 71598-35-1) and it’s read across substances, it can be concluded that LD50 value is >2000 mg/kg bw for acute oral toxicity. Thus, comparing this value with the criteria of CLP regulation, chromium (3+) ion hydrogen bis(1-(3-chlorophenyl)-4-[(E)-2-(5-methanesulfonyl-2-oxidophenyl)diazen-1-yl]-3-methyl-1H-pyrazol-5-olate) cannot be classified for acute oral toxicity.