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

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Description of key information

Toxicity to reproduction

The reproductivetoxicity study of lithium bis[2-[(4,5-dihydro-3-methyl-5-oxo-1-phenyl-1H-pyrazol-4-yl)azo]benzoato(2-)]chromate(1-) (83949-60-4) was estimated by SSS (2018) using OECD QSAR toolbox v3.4 with log Kow as the primary descriptor andNOAEL was estimated to be 825.0mg/kg bw. When male and female wistar rats were exposed withlithium bis[2-[(4,5-dihydro-3-methyl-5-oxo-1-phenyl-1H-pyrazol-4-yl)azo]benzoato(2-)]chromate(1-)(83949-60-4)orally. Thus, based on weight of evidence for target lithium bis[2-[(4,5-dihydro-3-methyl-5-oxo-1-phenyl-1H-pyrazol-4-yl)azo]benzoato(2-)]chromate(1-) (83949-60-4) and it’s read across Pigment yellow 13(3520-72-7) and C.I. Pigment Yellow 12 (6358-85-6) cannot be classified as reproductive toxicant as per the CLP criteria of classification.

Link to relevant study records

Reference

Endpoint:

toxicity to reproduction

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 v3.4 and the QMRF report has been attached.

Qualifier:

according to guideline

Guideline:

other: As mentioned below

Principles of method if other than guideline:

Prediction was done using OECD QSAR toolbox v3.4, 2018

GLP compliance:

not specified

Limit test:

no

Justification for study design:

No data available

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 available

Sex:

male/female

Details on test animals or test system and environmental conditions:

No data available

Route of administration:

oral: gavage

Vehicle:

not specified

Details on exposure:

No data available

Details on mating procedure:

No data available

Analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

54 days

Frequency of treatment:

Daily

Details on study schedule:

No data available

Dose / conc.:

825 mg/kg bw/day (nominal)

No. of animals per sex per dose:

No data available

Control animals:

not specified

Details on study design:

No data available

Positive control:

No data available

Parental animals: Observations and examinations:

No data available

Oestrous cyclicity (parental animals):

No data available

Sperm parameters (parental animals):

No data available

Litter observations:

No data available

Postmortem examinations (parental animals):

No data available

Postmortem examinations (offspring):

No data available

Statistics:

No data available

Reproductive indices:

No data available

Offspring viability indices:

No data available

Clinical signs:

no effects observed

Dermal irritation (if dermal study):

not specified

Mortality:

not specified

Body weight and weight changes:

no effects observed

Food consumption and compound intake (if feeding study):

no effects observed

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

Histopathological findings: non-neoplastic:

not specified

Histopathological findings: neoplastic:

not specified

Other effects:

not specified

Reproductive function: oestrous cycle:

not specified

Reproductive function: sperm measures:

not specified

Reproductive performance:

no effects observed

Dose descriptor:

NOAEL

Effect level:

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

Based on:

test mat.

Sex:

male/female

Basis for effect level:

clinical signs

body weight and weight gain

food consumption and compound intake

reproductive performance

Remarks on result:

other: overall no effects on reproductive performance

Critical effects observed:

not specified

System:

other: not specified

Organ:

not specified

Treatment related:

not specified

Dose response relationship:

not specified

Relevant for humans:

not specified

Clinical signs:

not specified

Dermal irritation (if dermal study):

not specified

Mortality / viability:

no mortality observed

Body weight and weight changes:

no effects observed

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

Sexual maturation:

not specified

Organ weight findings including organ / body weight ratios:

not examined

Gross pathological findings:

no effects observed

Histopathological findings:

not examined

Other effects:

not specified

Behaviour (functional findings):

not specified

Developmental immunotoxicity:

not specified

Dose descriptor:

NOAEL

Generation:

F1

Effect level:

825 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

not specified

Basis for effect level:

viability

body weight and weight gain

gross pathology

Remarks on result:

other: overall no effects on developmental parameters

Critical effects observed:

not specified

System:

other: not specified

Organ:

not specified

Treatment related:

not specified

Dose response relationship:

not specified

Relevant for humans:

not specified

Reproductive effects observed:

not specified

Treatment related:

not specified

Relation to other toxic effects:

not specified

Dose response relationship:

not specified

Relevant for humans:

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 ("j" and "k" )  )

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 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 >> 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 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: "g"

Referential boundary: The target chemical should be classified as Group 16 - Sulfur S OR Group 17 - Halogens Cl OR Group 17 - Halogens F,Cl,Br,I,At by Chemical elements

Domain logical expression index: "h"

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=10%,
Dice(Atom centered fragments)
Atom type; Count H attached; Hybridization

Domain logical expression index: "i"

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: "j"

Parametric boundary:The target chemical should have a value of log Kow which is >= 1.81

Domain logical expression index: "k"

Parametric boundary:The target chemical should have a value of log Kow which is <= 8.24

Conclusions:

In reproductive toxicity study, NOAEL was estimated to be 825.0mg/kg bw. When male and female wistar rats were exposed with lithium bis[2-[(4,5-dihydro-3-methyl-5-oxo-1-phenyl-1H-pyrazol-4-yl)azo]benzoato(2-)]chromate(1-)(83949-60-4)orally.

Executive summary:

The reproductive toxicity study of lithium bis[2-[(4,5-dihydro-3-methyl-5-oxo-1-phenyl-1H-pyrazol-4-yl)azo]benzoato(2-)]chromate(1-) (83949-60-4) was estimated by SSS (2018) using OECD QSAR toolbox v3.4 with log Kow as the primary descriptor andNOAEL was estimated to be 825.0mg/kg bw. When male and female wistar rats were exposed with lithium bis[2-[(4,5-dihydro-3-methyl-5-oxo-1-phenyl-1H-pyrazol-4-yl)azo]benzoato(2-)]chromate(1-)(83949-60-4)orally.

Effect on fertility: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

825 mg/kg bw/day

Study duration:

subchronic

Species:

rat

Quality of whole database:

Data is Klimicsh 2 and from QSAR Toolbox 3.4. (2018)

Effect on fertility: via inhalation route

Endpoint conclusion:

no study available

Effect on fertility: via dermal route

Endpoint conclusion:

no study available

Additional information

Reproductive toxicity

In different studies on lithium bis[2-[(4,5-dihydro-3-methyl-5-oxo-1-phenyl-1H-pyrazol-4-yl)azo]benzoato(2-)]chromate(1-) (83949-60-4) has been investigated for reproductive toxicity to a greater or lesser extent. Often are the studies based on in vivo experiments and estimated data in rodents, i.e. most commonly in rats for lithium bis[2-[(4,5-dihydro-3-methyl-5-oxo-1-phenyl-1H-pyrazol-4-yl)azo]benzoato(2-)]chromate(1-) (83949-60-4).The predicted data using the OECD QSAR toolbox has also been compared with the experimental studies performed on structurally similar read across substance.

The reproductive toxicity study of lithium bis[2-[(4,5-dihydro-3-methyl-5-oxo-1-phenyl-1H-pyrazol-4-yl)azo]benzoato(2-)]chromate(1-) (83949-60-4) was estimated by SSS (2018) using OECD QSAR toolbox v3.4 with log Kow as the primary descriptor and NOAEL was estimated to be 825.0mg/kg bw. When male and female wistar rats were exposed with lithium bis[2-[(4,5-dihydro-3-methyl-5-oxo-1-phenyl-1H-pyrazol-4-yl)azo]benzoato(2-)]chromate(1-)(83949-60-4)orally.

 It is supported by experimental study conducted by National Institute of Health Sciences (Japan Chemicals Collaborative Knowledge Database, 2017) on structurally similar read across substance treated with Pigment yellow 13(3520-72-7).Combined repeated dose and reproduction / developmental screening was performed to evaluate the toxic nature of Pigment Orange 13. 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, urinalysis, haematology, blood chemistry, organ weight changes and histopathology reproductive and developmental parameters. No adverse effects were noted in the various parameters studied. Based on the observations made, The No Observed Adverse Effect Level (NOAEL) for reproductive and developmental toxicity is considered to be 1000 mg/Kg/day. When male and female Crl:CD (SD)were treated with Pigment yellow 13(3520-72-7)orally.

 It is supported by experimental study conducted by OECD SIDS (SIAM 16, 27-30 May 2003) on structurally similar read across substance treated with Pigment yellow 12(6358-85-6)In a reproductive toxicity study, male and female wistar rats were treated with C.I. Pigment Yellow 12 (6358-85-6)in the concentration of 0, 50, 200 and 1000 mg/kg bw orally by gavage for males 4 weeks; females 6-7 weeks; animals were treated 2 weeks before mating and during mating (1:1) treatment was continued; after successful mating (presence of spermatozoa in a vaginal smear) males were treated until a total treatment time of 28 days; females were dosed during pregnancy, were allowed to litter and dosed during the lactation period until they were scheduled for necropsy (4-6 days of lactation). The test material dissolved in PEG and analysed by spectrophotometrically (accuracy, homogeneity and stability).10 animals/sex /dose group were used. All the animals were observed for Clinical signs, Body weight gain, Food consumption and Examination of uterine content and fetuses were carried out. Macroscopic examination of accessory sex organs, epididymides, ovaries, testes and all macroscopic lesions for all animals; according to OECD 422 for 5 animals/sex/group were done were as Microscopy not performed. No mortality in females was observed while in male 1/10 at untreated, 50 and 200 mg/kg bw .Were observed. Clinical signs like faeces discolouration was observed in all treated females and male ; incidental animals of all dose groups showed lethargy, hunched posture, laboured respiration, salivation, chromodacryorrhoea, alopecia, scabs and piloerection. Diarrhoea and erythema of the anus are attributed to the use of PEG as vehicle. No treatment related effects on Body weight, food consumption, organ weights and histopathology. Gross pathology in female showed 1/10 greenish contents of the caecum at 1000 mg/kg . In male haematological examination showed RBC increased at 50 mg/kg while decreased ALAT/ASAT and increased at 200 mg/kg. In female haematological examination showed RBC, Hb/haematocrit increased at 50 mg/kg while ALAT/ASAT increase at 1000 mg/kg; phosphate decreased and glucose increased at 200 mg/kg; creatinine decreased at 50 mg/kg. Effects on blood parameters showed no relationship with the dose and were observed in one of the sexes only. Therefore they were considered to be not toxicological relevant, The increased liver enzymes in high dosed females can be attributed to a single female. Excluding this female leads to mean group values for ASAT and ALAT that are comparable with control values. The inflammation of the preputial glands seen in 4 of 5 high dosed males was minimal (grade 1-2). No additional findings on the testes were present in any of these animals. The effect on the preputial gland is a common finding in young male rats. No relationship to treatment is suspected No effects on weight and no gross findings in the reproductive organs. Successful mating as no treatment related effects was observed. Number pregnant per dose level: 9/10 for all dose levels. No abortion was observed. No treatment related effects on Number of implantations and duration of gestation. No effects on Viability, Number of dead pups/no litters and Mean live pups/litter was observed. Body weight/sex pups were unchanged. In macroscopic examination of pups at 200 mg/kg one pup with malformations was found (a.o. open back/skull); yellow skin in 2 of 10 litters at 1000 mg/kg was observed. The discolourations observed in parents and pups are considered to be related to the staining effect of test substance. From their location it can be concluded that the test substance did not become available systemically, which is in line with other publications on Diarylide Yellow Pigments. Hence NOAEL was considered to be 1000 mg/kg bw for P and F1 generation when wistar rats were treated with C.I. Pigment Yellow 12 (6358-85-6) orally by gavage according to OECD guideline 422.

 

     Thus, based on weight of evidence for target lithium bis[2-[(4,5-dihydro-3-methyl-5-oxo-1-phenyl-1H-pyrazol-4-yl)azo]benzoato(2-)]chromate(1-) (83949-60-4) and it’s read across Pigment yellow 13(3520-72-7) and C.I. Pigment Yellow 12 (6358-85-6) cannot be classified as reproductive toxicant as per the CLP criteria of classification

Effects on developmental toxicity

Effect on developmental toxicity: via oral route

Endpoint conclusion:

no study available

Effect on developmental toxicity: via inhalation route

Endpoint conclusion:

no study available

Effect on developmental toxicity: via dermal route

Endpoint conclusion:

no study available

Justification for classification or non-classification

Thus, based on weight of evidence for target lithium bis[2-[(4,5-dihydro-3-methyl-5-oxo-1-phenyl-1H-pyrazol-4-yl)azo]benzoato(2-)]chromate(1-) (83949-60-4) and it’s read across Pigment yellow 13(3520-72-7) and C.I. Pigment Yellow 12 (6358-85-6) cannot be classified as reproductive toxicant as per the CLP criteria of classification