Disodium [5-chloro-3-[[4,5-dihydro-3-methyl-5-oxo-1-(3-sulphophenyl)-1H-pyrazol-4-yl]azo]-2-hydroxybenzene-1-sulphonato(4-)]hydroxychromate(2-)

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Description of key information

NOAEL was estimated to be 771 mg/kg bw when rats were orally exposed with Disodium [5-chloro-3-[[4,5-dihydro-3-methyl-5-oxo-1-(3-sulphophenyl)-1H-pyrazol-4-yl]azo]-2-hydroxybenzene-1-sulphonato(4-)]hydroxychromate(2-).  

Thus, as per criteria of CLP regulation, Disodium [5-chloro-3-[[4,5-dihydro-3-methyl-5-oxo-1-(3-sulphophenyl)-1H-pyrazol-4-yl]azo]-2-hydroxybenzene-1-sulphonato(4-)]hydroxychromate(2-) can be not classified for reproductive toxicity.   

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 predicted using OECD QSAR toolbox version 3.4 and the supporting QMRF report has been attached

Qualifier:

according to guideline

Guideline:

other: as below

Principles of method if other than guideline:

Prediction is done using QSAR Toolbox version 3.3

GLP compliance:

not specified

Limit test:

no

Specific details on test material used for the study:

Name: Disodium [5-chloro-3-[[4,5-dihydro-3-methyl-5-oxo-1-(3-sulphophenyl)-1H-pyrazol-4-yl]azo]-2-hydroxybenzene-1-sulphonato(4-)]hydroxychromate(2-)
SMILES:CC1C2C(N(c3cccc(S(O)(=O)=O)c3)N=1)=O[Cr]1(O)N2=Nc2cc(Cl)cc(S(O)(=O)=O)c2O1
InChI:1S/C16H12ClN4O8S2.Cr.2Na.H2O/c1-8-14(19-18-12-5-9(17)6-13(15(12)22)31(27,28)29)16(23)21(20-8)10-3-2-4-11(7-10)30(24,25)26;;;;/h2-7,22H,1H3,(H,24,25,26)(H,27,28,29);;;;1H2/q-1;;2*+1;/p-4/b19-18+;;;;
Molecular Weight: 599.835 g/mole
Mol. formula: C16H13ClCrN4O9S2

Species:

rat

Strain:

other: HsdBrl: wistar Han

Sex:

male/female

Route of administration:

oral: feed

Type of inhalation exposure (if applicable):

not specified

Vehicle:

unchanged (no vehicle)

Details on exposure:

not specified

Details on mating procedure:

not specified

Analytical verification of doses or concentrations:

not specified

Details on analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

Approx 42 days

Frequency of treatment:

Daily

Details on study schedule:

not specified

Dose / conc.:

771 mg/kg bw/day

No. of animals per sex per dose:

10 males and females

Control animals:

yes, plain diet

Details on study design:

not specified

Positive control:

not specified

Parental animals: Observations and examinations:

not specified

Oestrous cyclicity (parental animals):

not specified

Sperm parameters (parental animals):

not specified

Litter observations:

not specified

Postmortem examinations (parental animals):

not specified

Postmortem examinations (offspring):

not specified

Statistics:

not specified

Reproductive indices:

not specified

Offspring viability indices:

not specified

Clinical signs:

not specified

Dermal irritation (if dermal study):

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

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:

not specified

Dose descriptor:

NOAEL

Effect level:

771 mg/kg bw/day

Based on:

test mat.

Sex:

male/female

Basis for effect level:

reproductive performance

Remarks on result:

other: No effect observed

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:

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

Sexual maturation:

not specified

Organ weight findings including organ / body weight ratios:

not specified

Gross pathological findings:

not specified

Histopathological findings:

not specified

Other effects:

not specified

Behaviour (functional findings):

not specified

Developmental immunotoxicity:

not specified

Dose descriptor:

other: not specified

Generation:

other: not specified

Based on:

not specified

Sex:

not specified

Basis for effect level:

other: not specified

Remarks on result:

other: not specified

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" or "d" or "e" or "f" )  and ("g" and ( not "h") )  )  and "i" )  and "j" )  and ("k" and ( not "l") )  )  and ("m" and "n" )  )

Domain logical expression index: "a"

Referential boundary: The target chemical should be classified as Phenols (Acute toxicity) by US-EPA New Chemical Categories

Domain logical expression index: "b"

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

Domain logical expression index: "c"

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: "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 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

Domain logical expression index: "e"

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

Domain logical expression index: "f"

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

Domain logical expression index: "g"

Referential boundary: The target chemical should be classified as No alert found by DNA binding by OASIS v.1.4

Domain logical expression index: "h"

Referential boundary: The target chemical should be classified as AN2 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 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) >> Nitroaniline Derivatives OR Radical >> Radical mechanism via ROS formation (indirect) >> Nitrophenols, Nitrophenyl Ethers and Nitrobenzoic Acids OR Radical >> Radical mechanism via ROS formation (indirect) >> Polynitroarenes OR Radical >> Radical mechanism via ROS formation (indirect) >> Single-Ring Substituted Primary Aromatic Amines OR SN1 OR SN1 >> Nucleophilic attack after nitrenium ion formation OR SN1 >> Nucleophilic attack after 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 >> Nitroaniline Derivatives OR SN1 >> Nucleophilic attack after reduction and nitrenium ion formation >> Nitrophenols, Nitrophenyl Ethers and Nitrobenzoic Acids OR SN1 >> Nucleophilic attack after reduction and nitrenium ion formation >> Polynitroarenes OR SN2 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 >> 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.1.4

Domain logical expression index: "i"

Similarity boundary:Target: CC1C2C(N(c3cccc(S(O)(=O)=O)c3)N=1)=O[Cr]1(O)N2=Nc2cc(Cl)cc(S(O)(=O)=O)c2O1
Threshold=10%,
Dice(Atom centered fragments)
Atom type; Count H attached; Hybridization

Domain logical expression index: "j"

Similarity boundary:Target: CC1C2C(N(c3cccc(S(O)(=O)=O)c3)N=1)=O[Cr]1(O)N2=Nc2cc(Cl)cc(S(O)(=O)=O)c2O1
Threshold=30%,
Dice(Atom centered fragments)
Atom type; Count H attached; Hybridization

Domain logical expression index: "k"

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

Domain logical expression index: "l"

Referential boundary: The target chemical should be classified as Phenols (Mucous membrane irritation) Rank C by Repeated dose (HESS)

Domain logical expression index: "m"

Parametric boundary:The target chemical should have a value of Molecular weight which is >= 326 Da

Domain logical expression index: "n"

Parametric boundary:The target chemical should have a value of Molecular weight which is <= 835 Da

Conclusions:

NOAEL was estimated to be 771 mg/kg bw when rats were orally exposed with Disodium [5-chloro-3-[[4,5-dihydro-3-methyl-5-oxo-1-(3-sulphophenyl)-1H-pyrazol-4-yl]azo]-2-hydroxybenzene-1-sulphonato(4-)]hydroxychromate(2-).

Executive summary:

In a prediction done by SSS (2017) using the OECD QSAR toolbox with log kow as the primary descriptor, the reproductive toxicity was estimated for Disodium [5-chloro-3-[[4,5-dihydro-3-methyl-5-oxo-1-(3-sulphophenyl)-1H-pyrazol-4-yl]azo]-2-hydroxybenzene-1-sulphonato(4-)]hydroxychromate(2-). The NOAEL was estimated to be 771 mg/kg bw when rats were orally exposed with Disodium [5-chloro-3-[[4,5-dihydro-3-methyl-5-oxo-1-(3-sulphophenyl)-1H-pyrazol-4-yl]azo]-2-hydroxybenzene-1-sulphonato(4-)]hydroxychromate(2-).  

Effect on fertility: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

771 mg/kg bw/day

Study duration:

subchronic

Species:

rat

Quality of whole database:

Data is Klimisch 2 and from OECD QSAR toolbox

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, Disodium [5-chloro-3-[[4,5-dihydro-3-methyl-5-oxo-1-(3-sulphophenyl)-1H-pyrazol-4-yl]azo]-2-hydroxybenzene-1-sulphonato(4-)]hydroxychromate(2-) has been investigated for reproductive oral 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 Disodium [5-chloro-3-[[4,5-dihydro-3-methyl-5-oxo-1-(3-sulphophenyl)-1H-pyrazol-4-yl]azo]-2-hydroxybenzene-1-sulphonato(4-)]hydroxychromate(2-) along with the study available on structurally similar read across substance 3-carboxy-5-hydroxy-1-(4'- sulphophenyl)-4-(4'-sulphophenylazo) pyrazole trisodium salt (CAS no 1934-21-0). The predicted data using the OECD QSAR toolbox has also been compared with the experimental studies.

In a prediction done by SSS (2017) using the OECD QSAR toolbox with log kow as the primary descriptor, the reproductive toxicity was estimated for Disodium [5-chloro-3-[[4,5-dihydro-3-methyl-5-oxo-1-(3-sulphophenyl)-1H-pyrazol-4-yl]azo]-2-hydroxybenzene-1-sulphonato(4-)]hydroxychromate(2-). The NOAEL was estimated to be 771 mg/kg bw when rats were orally exposed with Disodium [5-chloro-3-[[4,5-dihydro-3-methyl-5-oxo-1-(3-sulphophenyl)-1H-pyrazol-4-yl]azo]-2-hydroxybenzene-1-sulphonato(4-)]hydroxychromate(2-).  

In another experimental study given by European Food Safety Authority (EFSA) (EFSA Journal 2009; 7(11):1331) on structurally similar read across substance 3-carboxy-5-hydroxy-1-(4'- sulphophenyl)-4-(4'-sulphophenylazo) pyrazole trisodium salt (CAS no 1934-21-0), Osborne-Mendel female rat were treated with 3-carboxy-5-hydroxy-1-(4'- sulphophenyl)-4-(4'-sulphophenylazo) pyrazole trisodium salt in the concentration of 0, 60, 100, 200, 400, 600, or 1000 mg/kg bw/day orally by gavage for 19 days. Number and type of implantations were observed in treated rats. Similarly, No effects on fetal viability, gross pathology, fetal skeletal and visceral development were observed as compared to control. Therefore, NOAEL was considered to be 1000 mg/kg/day for P and F1 generation when Osborne-Mendel female rats treated with 3-carboxy-5-hydroxy-1-(4'- sulphophenyl)-4-(4'-sulphophenylazo) pyrazole trisodium salt orally by gavage for 19 days.

Further supported by experimental study given by European Food Safety Authority (EFSA) (EFSA Journal 2009; 7(11):1331) on structurally similar read across substance 3-carboxy-5-hydroxy-1-(4'- sulphophenyl)-4-(4'-sulphophenylazo) pyrazole trisodium salt (CAS no 1934-21-0), Osborne-Mendel female rat were treated with 3-carboxy-5-hydroxy-1-(4'- sulphophenyl)-4-(4'-sulphophenylazo) pyrazole trisodium salt in the concentration of 0, 67, 132, 292, 568, and 1064 mg/kg bw/day orally in drinking water throughout gestation. No effect on clinical sign, Number and type of implantations and fetal size (weight and length) were observed in treated rats. Similarly, No effects on fetal viability, gross pathology, fetal skeletal and visceral development were observed as compared to control. Therefore, NOAEL was considered to be 1000 mg/kg/day for P and F1 generation when Osborne-Mendel female rats treated with 3-carboxy-5-hydroxy-1-(4'- sulphophenyl)-4-(4'-sulphophenylazo) pyrazole trisodium salt orally by gavage for 19 days.

Thus, based on the above study and predictions on Disodium [5-chloro-3-[[4,5-dihydro-3-methyl-5-oxo-1-(3-sulphophenyl)-1H-pyrazol-4-yl]azo]-2-hydroxybenzene-1-sulphonato(4-)]hydroxychromate(2-) and its read across substances, it can be concluded that NOAEL value is 771 mg/kg bw with no effect on reproduction. Thus, as per criteria of CLP regulation, Disodium [5-chloro-3-[[4,5-dihydro-3-methyl-5-oxo-1-(3-sulphophenyl)-1H-pyrazol-4-yl]azo]-2-hydroxybenzene-1-sulphonato(4-)]hydroxychromate(2-) can be not classified for reproductive toxicity.   

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

Based on the above study and predictions on Disodium [5-chloro-3-[[4,5-dihydro-3-methyl-5-oxo-1-(3-sulphophenyl)-1H-pyrazol-4-yl]azo]-2-hydroxybenzene-1-sulphonato(4-)]hydroxychromate(2-) and its read across substances, it can be concluded that NOAEL value is 771 mg/kg bw with no effect on reproduction. Thus, as per criteria of CLP regulation, Disodium [5-chloro-3-[[4,5-dihydro-3-methyl-5-oxo-1-(3-sulphophenyl)-1H-pyrazol-4-yl]azo]-2-hydroxybenzene-1-sulphonato(4-)]hydroxychromate(2-) can be not classified for reproductive toxicity.