5-oxo-1-(4-sulphophenyl)-2-pyrazoline-3-carboxylic acid

Endpoint summary

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records

Reference

Endpoint:

short-term repeated dose toxicity: oral

Type of information:

(Q)SAR

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Justification for type of information:

QSAR prediction: migrated from IUCLID 5.6

Qualifier:

according to guideline

Guideline:

other:

Principles of method if other than guideline:

Prediction is done using QSAR Toolbox version 3.3

GLP compliance:

not specified

Limit test:

no

Species:

rat

Strain:

not specified

Sex:

not specified

Route of administration:

oral: gavage

Vehicle:

not specified

Details on oral exposure:

No data available

Analytical verification of doses or concentrations:

not specified

Details on analytical verification of doses or concentrations:

No data available

Duration of treatment / exposure:

No data available

Frequency of treatment:

No data available

Remarks:

Doses / Concentrations:
No data available
Basis:

No. of animals per sex per dose:

No data available

Details on study design:

No data available

Positive control:

No data available

Observations and examinations performed and frequency:

No data available

Sacrifice and pathology:

No data available

Other examinations:

No data available

Statistics:

No data available

Clinical signs:

no effects observed

Mortality:

no mortality observed

Body weight and weight changes:

no effects observed

Food consumption and compound intake (if feeding study):

no effects observed

Food efficiency:

no effects observed

Water consumption and compound intake (if drinking water study):

no effects observed

Ophthalmological findings:

no effects observed

Haematological findings:

no effects observed

Clinical biochemistry findings:

not specified

Urinalysis findings:

no effects observed

Behaviour (functional findings):

no effects observed

Organ weight findings including organ / body weight ratios:

no effects observed

Gross pathological findings:

no effects observed

Histopathological findings: non-neoplastic:

no effects observed

Histopathological findings: neoplastic:

no effects observed

Details on results:

No data available

Dose descriptor:

NOAEL

Effect level:

267.276 mg/kg bw (total dose)

Based on:

test mat.

Sex:

not specified

Basis for effect level:

other: estimated

Critical effects observed:

not specified

The prediction was based on dataset comprised from the following descriptors: NOEL
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 "g" )  and "h" )  and ("i" and "j" )  )

Domain logical expression index: "a"

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: "b"

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: "c"

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

Domain logical expression index: "d"

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

Domain logical expression index: "e"

Referential boundary: The target chemical should be classified as AN2 OR AN2 >>  Michael-type addition, quinoid structures OR AN2 >>  Michael-type addition, quinoid structures >> Quinoneimines 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 >> Shiff base formation after aldehyde release OR AN2 >> Shiff base formation after aldehyde release >> Specific Acetate Esters 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 and Aminoalkylamine 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) >> Coumarins OR Radical >> Radical mechanism via ROS formation (indirect) >> Specific Imine and Thione Derivatives OR Radical >> ROS formation after GSH depletion (indirect) OR Radical >> ROS formation after GSH depletion (indirect) >> Quinoneimines OR SN1 OR SN1 >> Nucleophilic attack after carbenium ion formation OR SN1 >> Nucleophilic attack after carbenium ion formation >> Pyrrolizidine Derivatives OR SN1 >> Nucleophilic attack after carbenium ion formation >> Specific Acetate Esters OR SN1 >> Nucleophilic substitution on diazonium ion OR SN1 >> Nucleophilic substitution on diazonium ion >> Specific Imine and Thione Derivatives OR SN2 OR SN2 >> Acylation OR SN2 >> Acylation >> Specific Acetate Esters OR SN2 >> Alkylation, direct acting epoxides and related OR SN2 >> Alkylation, direct acting epoxides and related >> Epoxides and Aziridines 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 >> Nucleophilic substitution at sp3 Carbon atom OR SN2 >> Nucleophilic substitution at sp3 Carbon atom >> Specific Acetate Esters OR SN2 >> SN2 at sulfur atom OR SN2 >> SN2 at sulfur atom >> Sulfonyl Halides by DNA binding by OASIS v.1.4

Domain logical expression index: "f"

Referential boundary: The target chemical should be classified as Bioavailable by Lipinski Rule Oasis ONLY

Domain logical expression index: "g"

Similarity boundary:Target: OC(=O)C1CC(=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: "h"

Referential boundary: The target chemical should be classified as No superfragment by Superfragments ONLY

Domain logical expression index: "i"

Parametric boundary:The target chemical should have a value of log Kow which is >= -2.29

Domain logical expression index: "j"

Parametric boundary:The target chemical should have a value of log Kow which is <= 1.8

Conclusions:

The No Observed Adverse Effect Level (NOAEL) for the test compound Pyrazolone T in rats is found to be 267.275543213 mg/Kg bw/day.

Executive summary:

Repeated dose oral toxicity was predicted for the test compound Pyrazolone T by SSS QSAR prediction database, 2016. The study was assumed to be performed using rats by the oral (gavage) route. The No Observed Adverse Effect Level (NOAEL) for the test compound Pyrazolone T in rats is found to be 267.275543213 mg/Kg bw/day.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

267.276 mg/kg bw/day

Study duration:

subacute

Species:

rat

Quality of whole database:

K2 predicted data

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 oral toxicity:

Prediction model based estimation of the repeated dose toxicity for the target test chemical and data from read across have been summarized to determine the toxic nature of Pyrazole T upon repeated exposure by the oral route.

Repeated dose oral toxicity was predicted for the test compound Pyrazolone T by SSS QSAR prediction database, 2016. The study was assumed to be performed using rats by the oral (gavage) route. The No Observed Adverse Effect Level (NOAEL) for the test compound Pyrazolone T in rats is found to be 267.275543213 mg/Kg bw/day.

13 week subchronic toxicity study was conducted by Himri et al (2011) to evaluate the repeated dose toxic nature of the test compound tartrazine (RA CAS no 1934 -21 -0) on Wistar rats of both sexes. The animals were divided into 5 groups of 6 animals each, 3 of each sex, and fed a diet containing 5, 7.5, or 10 mg/kg b.w of Tartrazine.There were no treatment‐related adverse effects with regard to body weight, food and water consumption. Their blood samples were analyzed for hematological measurements, Glucose, Creatinine, Blood urea nitrogen, Cholesterol total, Triglecerid, alanine amino-transferase, aspartate amino-transferase.Tartrazine induced a morphological change from the discoid shape to an echinocytic form in rat RBCs. Relative weights of the liver were significantly increased in group treated with 10 mg/kg b.w, of Tartrazine. An increase in GLU, CREA, CHOL, TG, AST, and total Protein in serum of rats treated with Tartrazine and Sulfanilic acid compared to control rats was observed and these significant changes were more apparent in high doses than low ones. The histopathological changes of Liver and Kidney were in accordance with the biochemical findings. The Low Observed adverse effect level (LOAEL) for the test compound tartrazine is found to 7.5 mg/Kg bw.

Amother study was conducted by Shinnawy et al (2013) to evaluate the possible influence of an azo dye (tartrazine RA CAS no 1934 -21 -0) on some hematological and biochemical parameters of male albino rat Rattus norvegicus. Sixty adult male rats weighing 100-110g were divided into 3 groups; the first one served as a control, the second received 10mg/kg b.w. of tartrazine and the third group was treated with 25mg/kg b.w. of tartrazine. Rats were treated orally for 30 days followed a recovery for another 30 days.The data obtained reveal a marked decrease in the percentage of body weight gain, red blood cells (R.B.Cs) counts, hemoglobin (Hb) content, mean corpuscular hemoglobin concentration (MCHC), serum total lipids and serum total cholesterol of rats treated with the high dose of tartrazine. On the other hand, a noticeable increase in hematocrit (Hct) value, mean corpuscular volume (MCV), activities of serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), glucose level, serum total protein and globulin were found in rats treated with the high dose of tartrazine. In general, there was appreciable improvement after the recovery period. The Low observed adverse effect level (LOAEL) for the test compound tartrazine is found to be 10 mg/Kg bw.

13 week subchronic toxicity study was conducted by Maekawa et al (1987) to evaluate the toxic nature of the test compound tartrazine (RA CAS no 1934 -21 -0). The test compound was administered in drinking water at a dose level of 0(control), 0.3, 0.6, 1.25, 2.5 or 5.0% (w/v) (0, 150, 300, 625, 1250 or 2500 mg/Kg bw). All rats were observed daily and clinical signs and deaths were recorded. Body weights were measured once a week. At the end of the study, all survivors were killed and organs and tissues were taken for gross and microscopical examination. The probable maximum tolerable dose of tartrazine in the drinking-water was found to be between 1.25 and 2.5%. Based on the results observed, the low observed adverse effect level (LOAEL) for the test compound tartrazine is found to be 2.5 % (1250 mg/Kg bw).

90 days repeated dose oral toxicity study was performed (Scientific Committee on Consumer Products, 2006) to evaluate the toxic nature of the test compound 1-Phenyl-3-methyl-5-pyrazolone (PMP; RA CAS no 89 -25-8) in Sprague Dawley rats. The test compound was tested at dose levels of 20, 100 or 500 mg/Kg bw. 10 animals of each sex were used at each dose level. The animals were observed for mortlaity, clinical signs, changes in body weight, hemoatological parameters, clinical chemistry signs and urinary analysis was also performed. No effecrs were noted at the 20 mg/Kg bw dose level. The No observed Adverse Effect level (NOAEL) for the test compound 1-Phenyl-3-methyl-5-pyrazolone (PMP) is found to be 20 mg/Kg bw, a dose level associated in week 13 with systemic exposure (AUC 0-24) values of 4.3 μg.h/ml in males and 15.1 μg.h/ml in females.

Based on the data presented, the test chemical Pyrazolone T in not toxic upon repeated exposure by the oral route.

Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:
The study is taken using SSS QSAR predicted database

Justification for classification or non-classification

Based on the data presented, the test chemical Pyrazolone T in not toxic upon repeated exposure by the oral route.

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