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Description of key information

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 oral toxicity was predicted for the test compound 4-[(E)-2-(5-{[(2Z,4E)-6-chloro-4-[(3-sulfophenyl)imino]-1,2,3,4-tetrahydro-1,3,5-triazin-2-ylidene]amino} -2-sulfophenyl) diazen-1-yl]-5-oxo-1- (4-sulfophenyl)- 4,5-dihydro -1H-pyrazole-3-carboxylic acid (93858-25-4). The study assumed the use of male and female Wistar strain in chronic study of 24 months. No significant alterations were noted at the dose level of 757.0mg/Kg bw/day. The predicted No Observed Adverse Effect Level (NOAEL) for compound 4-[(E)-2-(5-{[(2Z,4E)-6-chloro-4-[(3-sulfophenyl)imino]-1,2,3,4-tetrahydro-1,3,5-triazin-2-ylidene]amino} -2-sulfophenyl) diazen-1-yl]-5-oxo-1- (4-sulfophenyl)- 4,5-dihydro -1H-pyrazole-3-carboxylic acid is considered to be 757.0mg/Kg bw/day. Based on this value it can be concluded that the substance is considered to 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:
Prediction is done using OECD QSAR Toolbox version 3.3 and the supporting QMRF report has been attached.
Qualifier:
according to guideline
Guideline:
other: As mention below
Principles of method if other than guideline:
Prediction is done using OECD QSAR Toolbox version 3.3, 2018.
GLP compliance:
not specified
Limit test:
no
Specific details on test material used for the study:
- Name of test material (IUPAC name):4-[(E)-2-(5-{[(2Z,4E)-6-chloro-4- [(3-sulfophenyl)imino]-1,2,3,4-tetrahydro-1,3,5 -triazin-2-ylidene]amino}-2-sulfophenyl)diazen- 1-yl]-5-oxo-1- (4-sulfophenyl)- 4,5-dihydro -1H-pyrazole-3-carboxylic acid
- Molecular formula: C25H18ClN9O12S3
- Molecular weight: 768.1192 g/mol
- Smiles notation: C1=CC(=CC(=C1)S(=O)(=O)O)NC2=NC(=NC(=N2)NC3=CC(=C(C=C3)S(=O)(=O)O)N=NC4C(=NN(C4=O)C5=CC=C(C=C5)S(=O)(=O)O)C(=O)O)Cl
- InChl: 1S/C25H18ClN9O12S3/c26-23-29-24(27-12-2-1-3-16(10-12)49(42,43)44)31-25(30-23)28-13-4-9-18(50(45,46)47)17(11-13)32-33-19-20(22(37)38)34-35(21(19)36)14-5-7-15(8-6-14)48(39,40)41/h1-11,19H,(H,37,38)(H,39,40,41)(H,42,43,44)(H,45,46,47)(H2,27,28,29,30,31)/b33-32+
- Substance type: Organic
- Physical state: Solid
Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals or test system and environmental conditions:
Not specified.
Route of administration:
oral: gavage
Vehicle:
not specified
Details on oral exposure:
Not specified.
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
24 months
Frequency of treatment:
Not specified.
Remarks:
Not specified.
No. of animals per sex per dose:
Not specified.
Control animals:
not specified
Details on study design:
Not specified.
Positive control:
Not specified.
Observations and examinations performed and frequency:
Not specified.
Sacrifice and pathology:
Not specified.
Other examinations:
Not specified.
Statistics:
Not specified.
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
Dose descriptor:
NOAEL
Effect level:
757 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: No significant effect were observed at this dose
Remarks on result:
other: No toxic effect were observed.
Critical effects observed:
not specified
Treatment related:
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" )  and "f" )  and ("g" and ( not "h") )  )  and "i" )  and ("j" and "k" )  )

Domain logical expression index: "a"

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

Domain logical expression index: "b"

Referential boundary: The target chemical should be classified as Acid moiety OR Amides OR Hydrazines OR Triazines, Aromatic by Aquatic toxicity classification by ECOSAR ONLY

Domain logical expression index: "c"

Referential boundary: The target chemical should be classified as Acylation OR Acylation >> Direct Acylation Involving a Leaving group OR Acylation >> Direct Acylation Involving a Leaving group >> Acetates OR SN2 OR SN2 >> SN2 reaction at sp3 carbon atom OR SN2 >> SN2 reaction at sp3 carbon atom >> Alkyl diazo OR SNAr OR SNAr >> Nucleophilic aromatic substitution OR SNAr >> Nucleophilic aromatic substitution >> Halo-triazines by Protein binding by OECD ONLY

Domain logical expression index: "d"

Referential boundary: The target chemical should be classified as Schiff base formation OR Schiff base formation >> Pyrazolones and Pyrazolidinones derivatives OR Schiff base formation >> Pyrazolones and Pyrazolidinones derivatives >> Pyrazolones and Pyrazolidinones  OR SNAr OR SNAr >> Nucleophilic aromatic substitution on activated aryl and heteroaryl compounds OR SNAr >> Nucleophilic aromatic substitution on activated aryl and heteroaryl compounds >> Activated aryl and heteroaryl compounds by Protein binding by OASIS v1.3 ONLY

Domain logical expression index: "e"

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

Domain logical expression index: "f"

Referential boundary: The target chemical should be classified as No alert found by DNA binding by OASIS v.1.3 ONLY

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 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 by Estrogen Receptor Binding

Domain logical expression index: "i"

Similarity boundary:Target: OC(=O)C1C(N=Nc2cc(Nc3nc(Nc4cccc(S(O)(=O)=O)c4)nc(Cl)n3)ccc2S(O)(=O)=O)C(=O)N(c2ccc(S(O)(=O)=O)cc2)N=1
Threshold=10%,
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 >= -1.68

Domain logical expression index: "k"

Parametric boundary:The target chemical should have a value of log Kow which is <= 5

Conclusions:
The predicted No Observed Adverse Effect Level (NOAEL) for 4-[(E)-2-(5-{[(2Z,4E)-6-chloro-4-[(3-sulfophenyl)imino]-1,2,3,4-tetrahydro-1,3,5-triazin-2-ylidene]amino} -2-sulfophenyl) diazen-1-yl]-5-oxo-1- (4-sulfophenyl)- 4,5-dihydro -1H-pyrazole-3-carboxylic acid (93858-25-4) is considered to be 757.0mg/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 oral toxicity was predicted for the test compound 4-[(E)-2-(5-{[(2Z,4E)-6-chloro-4-[(3-sulfophenyl)imino]-1,2,3,4-tetrahydro-1,3,5-triazin-2-ylidene]amino} -2-sulfophenyl) diazen-1-yl]-5-oxo-1- (4-sulfophenyl)- 4,5-dihydro -1H-pyrazole-3-carboxylic acid (93858-25-4). The study assumed the use of male and female Wistar strain in chronic study of24 months. No significant alterations were noted at the dose level of 757.0mg/Kg bw/day. The predicted No Observed Adverse Effect Level (NOAEL) for compound 4-[(E)-2-(5-{[(2Z,4E)-6-chloro-4-[(3-sulfophenyl)imino]-1,2,3,4-tetrahydro-1,3,5-triazin-2-ylidene]amino} -2-sulfophenyl) diazen-1-yl]-5-oxo-1- (4-sulfophenyl)- 4,5-dihydro -1H-pyrazole-3-carboxylic acid is considered to be 757.0mg/Kg bw/day. Based on this value it can be concluded that the substance is considered to not toxic as per the criteria mentioned in CLP regulation.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
757 mg/kg bw/day
Study duration:
chronic
Species:
rat
Quality of whole database:
K2 data from OECD QSAR toolbox 3.3 version

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: via oral route;

Various experimental studies were reviewed to determine the toxic nature of target substance 4-[(E)-2-(5-{[(2Z,4E)-6-chloro-4-[(3-sulfophenyl)imino] -1,2,3,4-tetrahydro-1,3,5-triazin-2-ylidene]amino} -2-sulfophenyl) diazen-1-yl]-5-oxo-1- (4-sulfophenyl)- 4,5-dihydro -1H-pyrazole-3-carboxylic acid (93858-25-4) upon repeated exposure by oral route. 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 oral toxicity was predicted for the test compound 4-[(E)-2-(5-{[(2Z,4E)-6-chloro-4-[(3-sulfophenyl)imino]-1,2,3,4-tetrahydro-1,3,5-triazin-2-ylidene]amino} -2-sulfophenyl) diazen-1-yl]-5-oxo-1- (4-sulfophenyl)- 4,5-dihydro -1H-pyrazole-3-carboxylic acid (93858-25-4). The study assumed the use of male and female Wistar strain in chronic study of24 months. No significant alterations were noted at the dose level of 757.0mg/Kg bw/day. The predicted No Observed Adverse Effect Level (NOAEL) for compound 4-[(E)-2-(5-{[(2Z,4E)-6-chloro-4-[(3-sulfophenyl)imino]-1,2,3,4-tetrahydro-1,3,5-triazin-2-ylidene]amino} -2-sulfophenyl) diazen-1-yl]-5-oxo-1- (4-sulfophenyl)- 4,5-dihydro -1H-pyrazole-3-carboxylic acid is considered to be 757.0mg/Kg bw/day. Based on this value it can be concluded that the substance is considered to not toxic as per the criteria mentioned in CLP regulation.

Another  Sub-chronic toxicity study for Read across was performed by A. Maekawa et al.( Food and cosmetics toxicology,1987) to determine the oral toxic nature of Tartrazine IUPAC ; trisodium 5-hydroxy-1-(4-sulphophenyl)-4-(4-sulphophenylazo) pyrazole-3-carboxylate ( 1934-21-0). The read across isfunctionally similar to target substanceTherefore, it is acceptable to derive information on toxicity from the analogue substance. 13 week subchronic toxicity study was conducted to evaluate the toxic nature of the test compound tartrazine. 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. Six of the male rats and all of the female rats given tartrazine at 5% in drinking-water died during the study. None of the rats in any of the other groups died. In all but the highest (5%) dose group, there was < 10% depression of body-weight gain compared with the control group. The absolute organ weights of the thymus, lungs, heart, liver, spleen, kidneys and testes of the males given 5% tartrazine and of the liver in the males and females given 2.5% tartrazine were significantly lower than those of the corresponding control groups. However, the relative organ weights (g/100 g body weight) of the brain, lungs, adrenals, kidneys and testes of males in the 5% dose group were increased, and those of the thymus in the males in the highest dose group and of the liver in the females given 2.5% tartrazine were significantly decreased. Histological examination revealed toxic changes only in rats of both sexes in the highest (5%) dose group. In rats that died during the experimental period, severe atrophy and/or degeneration of the haematopoietic organs such as the thymus, bone marrow, lymph nodes or spleen was observed, although no marked changes were detected in other organs. Based on the results observed, the no observed adverse effect level (NOAEL) for the test compound tartrazine is considered to be 2.5 % (1250 mg/Kg bw) when male and female F344 rats were exposed to the test chemical for 13 weeks.

Repeated inhalation study:

According to Annex IX of the REACH regulation, testing by the inhalation route is appropriate only if exposure of humans via inhalation is likely. Taking into account the low vapour pressure of the substance4-[(E)-2-(5-{[(2Z,4E)-6-chloro-4-[(3-sulfophenyl)imino]-1,2,3,4-tetrahydro-1,3,5-triazin-2-ylidene]amino} -2-sulfophenyl) diazen-1-yl]-5-oxo-1- (4-sulfophenyl)- 4,5-dihydro -1H-pyrazole-3-carboxylic acid (93858-25-4) ,which is reported as 1.177E-36 Pa at 25 C. Also considering the particle size distribution of the substance the majority of the particles was found to be in the size of 150 micron to 53 micron which is much larger size range compared to the inhalable particulate matter. Thus, exposure to inhalable dust, mist and vapour of the chemical4-[(E)-2-(5-{[(2Z,4E)-6-chloro-4-[(3-sulfophenyl)imino]-1,2,3,4-tetrahydro-1,3,5-triazin-2-ylidene]amino} -2-sulfophenyl) diazen-1-yl]-5-oxo-1- (4-sulfophenyl)- 4,5-dihydro -1H-pyrazole-3-carboxylic acid is highly unlikely. Therefore this study is considered for waiver.

 

Repeated dermal study;

The acute toxicity value for 4-[(E)-2-(5-{[(2Z,4E)-6-chloro-4-[(3-sulfophenyl)imino]-1,2,3,4-tetrahydro-1,3,5-triazin-2-ylidene]amino} -2-sulfophenyl) diazen-1-yl]-5-oxo-1- (4-sulfophenyl)- 4,5-dihydro -1H-pyrazole-3-carboxylic acid (93858-25-4)(as provided in section 7.2.3) is 9466mg/kg body weight. Also, given the use of the chemical; repeated exposure by the dermal route is unlikely since the use of gloves is common practice in industries. Thus, it is expected that 4-[(E)-2-(5-{[(2Z,4E)-6-chloro-4-[(3-sulfophenyl)imino]-1,2,3,4-tetrahydro-1,3,5-triazin-2-ylidene]amino} -2-sulfophenyl) diazen-1-yl]-5-oxo-1- (4-sulfophenyl)- 4,5-dihydro -1H-pyrazole-3-carboxylic acid shall not exhibit 28 day repeated dose toxicity by the dermal route. In addition, there is no data available that suggests that 4-[(E)-2-(5-{[(2Z,4E)-6-chloro-4-[(3-sulfophenyl)imino]-1,2,3,4-tetrahydro-1,3,5-triazin-2-ylidene]amino} -2-sulfophenyl) diazen-1-yl]-5-oxo-1- (4-sulfophenyl)- 4,5-dihydro -1H-pyrazole-3-carboxylic acid shall exhibit repeated dose toxicity by the dermal route. Hence this end point was considered for waiver.

 

Based on the data available for the target chemical and its prediction, 24-[(E)-2-(5-{[(2Z,4E)-6-chloro-4-[(3-sulfophenyl)imino]-1,2,3,4-tetrahydro-1,3,5-triazin-2-ylidene]amino} -2-sulfophenyl) diazen-1-yl]-5-oxo-1- (4-sulfophenyl)- 4,5-dihydro -1H-pyrazole-3-carboxylic acid (93858-25-4)does not exhibit toxic nature upon repeated exposure by oral, inhalation and dermal route of exposure and hence is not likely to classify 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 prediction, 24-[(E)-2-(5-{[(2Z,4E)-6-chloro-4-[(3-sulfophenyl)imino]-1,2,3,4-tetrahydro-1,3,5-triazin-2-ylidene]amino} -2-sulfophenyl) diazen-1-yl]-5-oxo-1- (4-sulfophenyl)- 4,5-dihydro -1H-pyrazole-3-carboxylic acid (93858-25-4)does not exhibit toxic nature upon repeated exposure by oral, inhalation and dermal route of exposure and hence is not likely to classify as per the criteria mentioned in CLP regulation.