Lithium bis[2-[(4,5-dihydro-3-methyl-5-oxo-1-phenyl-1H-pyrazol-4-yl)azo]benzoato(2-)]chromate(1-)

Endpoint summary

Description of key information

Repeated dose toxicity: Oral

Based on the prediction done using the OECD QSAR toolbox version 3.3 with log kow as the primary descriptor and considering the five closest read across substances, repeated dose toxicity was predicted for Lithium bis[2-[(4,5-dihydro-3-methyl-5-oxo- 1-phenyl-1H-pyrazol -4-yl) azo]benzoato(2-)]chromate(1-). The study assumed the use of male and female Wistar rats in a 28- 49 days toxicity study. Since no significant treatment related effects were observed at the mentioned dose level, hence the No Observed Adverse Effect Level (NOAEL) for Lithium bis[2-[(4,5-dihydro-3-methyl-5-oxo-1-phenyl-1H-pyrazol-4-yl) azo] benzoato(2-)]chromate(1-) is predicted to be 820.0 mg/Kg bw/day.  

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

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 3.4 and the supporting QMRF report has been attached

Qualifier:

according to guideline

Guideline:

other: Refer below principle

Principles of method if other than guideline:

Prediction is done using OECD QSAR Toolbox version 3.3, 2018

GLP compliance:

not specified

Specific details on test material used for the study:

- Name of test material: Lithium bis[2-[(4,5-dihydro-3-methyl-5-oxo-1-phenyl-1H-pyrazol-4-yl)azo]benzoato(2-)]chromate(1-)
- IUPAC name: lithium bis[2-[(4,5-dihydro-3-methyl-5-oxo-1-phenyl-1H-pyrazol-4-yl)azo]benzoato(2-)]chromate(1-)
- Molecular formula: C34H24CrN8O6.Li
- Molecular weight: 699.5506 g/mole
- Smiles :[Li+].CC1=NN(C(=O)C1\2[Cr-]3(OC(=O)c4c(cccc4)/N=N/C35C(=O)N(N=C5C)c6ccccc6)OC(=O)c7c(cccc7)/N=N2)c8ccccc8
- Inchl: 1S/2C17H13N4O3.Cr.Li/c2*1-11-15(16(22)21(20-11)12-7-3-2-4-8-12)19-18-14-10-6-5-9-13(14)17(23)24;;/h2*2-10H,1H3,(H,23,24);;/q;;2*+1/ p-2/b2*19-18+;;
- Substance type: Organic
- Physical state: Solid

Species:

rat

Strain:

Wistar

Details on species / strain selection:

No data

Sex:

male/female

Details on test animals or test system and environmental conditions:

No data

Route of administration:

oral: gavage

Details on route of administration:

No data

Vehicle:

not specified

Details on oral exposure:

No data

Analytical verification of doses or concentrations:

not specified

Details on analytical verification of doses or concentrations:

No data

Duration of treatment / exposure:

Males: Minimum 4 weeks
Females: Approximately 7 weeks

Frequency of treatment:

Daily

Remarks:

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:

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

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: No significant adverse effects 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" )  and ("d" and ( not "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 "r" )  )

Domain logical expression index: "a"

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: "b"

Referential boundary: The target chemical should be classified as AN2 AND AN2 >> Michael addition to activated double bonds in heterocyclic ring systems AND AN2 >> Michael addition to activated double bonds in heterocyclic ring systems >> Pyrazolone and Pyrazolidine Derivatives AND AN2 >> Schiff base formation with carbonyl compounds (AN2) AND AN2 >> Schiff base formation with carbonyl compounds (AN2) >> Pyrazolone and Pyrazolidine Derivatives AND Schiff base formation AND Schiff base formation >> Schiff base on pyrazolones and pyrazolidinones AND Schiff base formation >> Schiff base on pyrazolones and pyrazolidinones >> Pyrazolones and Pyrazolidinones by Protein binding by OASIS v1.4

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 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: "e"

Referential boundary: The target chemical should be classified as Acylation >> Direct Acylation Involving a Leaving group >> Anhydrides OR Acylation >> Direct Acylation Involving a Leaving group >> Azlactone OR Michael addition OR Michael addition >> Acid imides OR Michael addition >> Acid imides >> Acid imides-MA OR Michael addition >> Polarised Alkenes OR Michael addition >> Polarised Alkenes >> Polarised alkene - amides OR Michael addition >> Polarised Alkenes >> Polarised alkene - ketones OR Michael addition >> Quinones and Quinone-type Chemicals OR Michael addition >> Quinones and Quinone-type Chemicals >> Quinone-imine OR No alert found OR SN2 OR SN2 >> SN2 reaction at sp3 carbon atom OR SN2 >> SN2 reaction at sp3 carbon atom >> Alkyl diazo OR SN2 >> SN2 reaction at sp3 carbon atom >> Alkyl halides OR SN2 >> SN2 reaction at sp3 carbon atom >> Allyl acetates and related chemicals OR SN2 >> SN2 reaction at sp3 carbon atom >> beta-Halo ethers OR SNAr OR SNAr >> Nucleophilic aromatic substitution OR SNAr >> Nucleophilic aromatic substitution >> Activated halo-benzenes by Protein binding by OECD

Domain logical expression index: "f"

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

Domain logical expression index: "g"

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

Domain logical expression index: "h"

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

Domain logical expression index: "i"

Referential boundary: The target chemical should be classified as Group 1 - Alkali Earth Li,Na,K,Rb,Cs,Fr AND Group 14 - Carbon C AND Group 15 - Nitrogen N AND Group 16 - Oxygen O AND Group 6 - Trans.Metals Cr,Mo,W by Chemical elements

Domain logical expression index: "j"

Referential boundary: The target chemical should be classified as Group 17 - Halogens Cl OR Group 17 - Halogens F,Cl,Br,I,At by Chemical elements

Domain logical expression index: "k"

Similarity boundary:Target: [Li]{+}.[Cr]{-}12(C3(C(C)=NN(c4ccccc4)C3=O)N=Nc3ccccc3C(=O)O1)C1(C(C)=NN(c3ccccc3)C1=O)N=Nc1ccccc1C(=O)O2
Threshold=30%,
Dice(Atom centered fragments)
Atom type; Count H attached; Hybridization

Domain logical expression index: "l"

Similarity boundary:Target: [Li]{+}.[Cr]{-}12(C3(C(C)=NN(c4ccccc4)C3=O)N=Nc3ccccc3C(=O)O1)C1(C(C)=NN(c3ccccc3)C1=O)N=Nc1ccccc1C(=O)O2
Threshold=40%,
Dice(Atom centered fragments)
Atom type; Count H attached; Hybridization

Domain logical expression index: "m"

Referential boundary: The target chemical should be classified as Aryl AND Fused carbocyclic aromatic AND Heterocyclic spiro rings AND Pyrazolone AND Unsaturated heterocyclic amine AND Unsaturated heterocyclic fragment by Organic Functional groups

Domain logical expression index: "n"

Referential boundary: The target chemical should be classified as Saturated heterocyclic amine by Organic Functional groups

Domain logical expression index: "o"

Referential boundary: The target chemical should be classified as Aryl AND Fused carbocyclic aromatic AND Heterocyclic spiro rings AND Pyrazolone 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 Quinolone/ Quinolinedione/ Isoquinolinedione by Organic Functional groups

Domain logical expression index: "q"

Parametric boundary:The target chemical should have a value of log Kow which is >= 5.1

Domain logical expression index: "r"

Parametric boundary:The target chemical should have a value of log Kow which is <= 7.81

Conclusions:

The No Observed Adverse Effect Level (NOAEL) for Lithium bis[2-[(4,5-dihydro-3-methyl-5-oxo-1-phenyl-1H-pyrazol-4-yl) azo] benzoato(2-)]chromate(1-) is predicted to be 820.0 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 Lithium bis[2-[(4,5-dihydro-3-methyl-5-oxo- 1-phenyl-1H-pyrazol -4-yl) azo]benzoato(2-)]chromate(1-). The study assumed the use of male and female Wistar rats in a 28- 49 days toxicity study. Since no significant treatment related effects were observed at the mentioned dose level, hence the No Observed Adverse Effect Level (NOAEL) for Lithium bis[2-[(4,5-dihydro-3-methyl-5-oxo-1-phenyl-1H-pyrazol-4-yl) azo] benzoato(2-)]chromate(1-) is predicted to be 820.0 mg/Kg bw/day.

 

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

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

820 mg/kg bw/day

Study duration:

subchronic

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 for the target chemical and data from read across chemicals have been reviewed to determine the toxic nature of Lithium bis[2-[(4,5-dihydro-3-methyl-5-oxo- 1-phenyl-1H-pyrazol -4-yl) azo]benzoato(2-)]chromate(1-). 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 Lithium bis[2-[(4,5-dihydro-3-methyl-5-oxo- 1-phenyl-1H-pyrazol -4-yl) azo]benzoato(2-)]chromate(1-). The study assumed the use of male and female Wistar rats in a 28- 49 days toxicity study. Since no significant treatment related effects were observed at the mentioned dose level, hence the No Observed Adverse Effect Level (NOAEL) for Lithium bis[2-[(4,5-dihydro-3-methyl-5-oxo-1-phenyl-1H-pyrazol-4-yl) azo] benzoato(2-)]chromate(1-) is predicted to be 820.0 mg/Kg bw/day.  

Combined repeated dose and reproduction / developmental screening (J-check, 2018) was performed to evaluate the toxic nature of 60 -70% struturally and functionally similar read across chemical Pigment Orange 13 (RA CAS no 3520 -72 -7). Male and female Crl:CD (SD) were used in the study. The test compound was dissolved in water and used at dose levels of 0, 40, 200 or 1000 mg/Kg/day. The male rats were treated for 42 days and female rats were treated for 41-47 days. Recovery group of 0 and 1000 mg/Kg/day was also included in the study. The treated animals were noted for clinical signs, functional battery observations, body weight, food consumption, urinanalysis, hematology, blood chemistry, organ weight changes and histopathology. No adverse effcets were noted in the various parameters studied. Based on the observations made, the No Observed Adverse Effect Level (NOAEL) for Pigment yellow 13 is considered to be 1000 mg/Kg/day.

Combined repeated dose – carcinogenicity assay was performed to determine the toxic nature of 50 -60% structurally and functionally similar read across chemical Diarylanilide Yellow (RA CAS no 6358 -85 -6) upon repeated exposure by oral route. The study was performed using male and female F344 rats. The test chemical was mixed with feed and used at dose level of 0, 1250 or 2500 mg/Kg/day (0, 2.5 or 5.0%) for 109 weeks including 28 weeks of observation period. The animals were observed for clinical signs, mortality, changes in body weight and food consumption, opthalmology. The animals were subjected to gross pathology and histopathology. All the treated rats, both male and female, appeared bright yellow in color. The only other clinical sign recorded for male or female rats was a hard crusted lesion on the back of one male control animal. No statistically significant positive association was noted in the dosage and mortality. The body weight patterns for control and treated rat groups of both sexes were generally equivalent throughout the treatment period. In addition, the conjunctivas were faintly yellow as were most organs and internal mucosal surfaces. With a few exceptions, the same variety of neoplasms occurred sporadically and randomly in the chemically treated and control groups. No particular organ or system seemed to be the target of this chemical. Sporadic and unusual neoplasms that occurred in the treated but rot in control animals were as follows: a metastatic chordoma of unknown origin occurred in the lung of 1/49 of the low dose males and 1/49 of the low dose females had an osteogenic sarcoma. The incidence-and variety of nonneoplastic degenerative, proliferative, and inflammatory lesions were similar in the control and the chemically treated rats, except for treatment-related basophilic/cytoplasm changes in hepatocytes of treated males and females. Based on the observations made, the No Observed Adverse Effect level (NOAEL) for Diarylanilide Yellow is considered to be 2500 mg/Kg/day.

Based on the data available for the target chemical and its read across, Lithium bis[2-[(4,5-dihydro-3-methyl-5-oxo- 1-phenyl-1H-pyrazol -4-yl) azo]benzoato(2-)]chromate(1-) (CAS no 83949 -60 -4) is not likely to be 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, Lithium bis[2-[(4,5-dihydro-3-methyl-5-oxo- 1-phenyl-1H-pyrazol -4-yl) azo]benzoato(2-)]chromate(1-) (CAS no 83949 -60 -4) is not likely to be toxic as per the criteria mentioned in CLP regulation.