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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 toxicity was predicted for trisodium 2-[(E)-2-(3-methyl-5-oxo-1-{4-[2-(sulfonatooxy)ethanesulfonyl]phenyl} -4,5-dihydro-1H- pyrazol-4-yl) diazen-1-yl] naphthalene-1,5-disulfonate. The study assumed the use of male and female Wistar rats in a sub-chronic toxicity study. Since no significant treatment related effects were observed at the mentioned dose level, hence the No Observed Adverse Effect Level (NOAEL) for trisodium 2-[(E)-2-(3-methyl-5-oxo-1-{4-[2-(sulfonatooxy)ethanesulfonyl]phenyl}-4,5-dihydro-1H-pyrazol-4-yl)diazen-1-yl] naphthalene-1,5-disulfonate is predicted to be 314.892852783 mg/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:
Data is from OECD QSAR Toolbox version 3.3 and the supporting QMRF report has been attached
Reference:
Composition 0
Qualifier:
according to
Guideline:
other: Refer below principle
Principles of method if other than guideline:
Predictin is done using OECD QSAR Toolbox version 3.3, 2017
GLP compliance:
not specified
Limit test:
no
Test material information:
Composition 1
Specific details on test material used for the study:
- Name of the test material: trisodium 2-[(E)-2-(3-methyl-5-oxo-1-{4-[2-(sulfonatooxy)ethanesulfonyl]phenyl}-4,5-dihydro-1H-pyrazol-4-yl)diazen-1-yl] naphthalene-1,5-disulfonate
- IUPAC name: trisodium 2-[(E)-2-(3-methyl-5-oxo-1-{4-[2-(sulfonatooxy)ethanesulfonyl]phenyl}-4,5-dihydro-1H-pyrazol-4-yl)diazen-1-yl]naphthalene-1,5-disulfonate
- Molecular formula: C22H20N4O13S4.3Na
- Molecular weight: 742.6253 g/mol
- Substance type: Organic
Species:
rat
Strain:
Wistar
Details on species / strain selection:
No data
Sex:
male/female
Details on test animals and environmental conditions:
No data
Route of administration:
oral: unspecified
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: for 14 days (during pre-mating and mating period), followed by treatment approx 3 weeks post-mating
Females: for 14 days (during pre-mating and mating period), throughout entire gestation and 4 days after littering, followed by an additional treatment until one day before sacrifice
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:
314.893 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: No signifcant alterations 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 7 nearest neighbours
Domain  logical expression:Result: In Domain

((((((((((("a" or "b" or "c" or "d" or "e" )  and ("f" and ( not "g") )  )  and ("h" and ( not "i") )  )  and ("j" and ( not "k") )  )  and ("l" and ( not "m") )  )  and ("n" and ( not "o") )  )  and ("p" and ( not "q") )  )  and ("r" and ( not "s") )  )  and "t" )  and ("u" and ( not "v") )  )  and ("w" and "x" )  )

Domain logical expression index: "a"

Referential boundary: The target chemical should be classified as Naphthalene sulfonic acids, condensates by OECD HPV Chemical Categories

Domain logical expression index: "b"

Referential boundary: The target chemical should be classified as Vinyl Sulfones by US-EPA New Chemical Categories

Domain logical expression index: "c"

Referential boundary: The target chemical should be classified as SN1 OR SN1 >> Nitrenium Ion formation OR SN1 >> Nitrenium Ion formation >> Aromatic azo OR SN1 >> Nitrenium Ion formation >> Unsaturated heterocyclic azo by DNA 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  by Protein binding by OASIS v1.3 ONLY

Domain logical expression index: "e"

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 by Protein 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

Domain logical expression index: "g"

Referential boundary: The target chemical should be classified as AN2 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 >> DNA Intercalators with Carboxamide 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) >> Nitroarenes with Other Active Groups OR Radical >> Radical mechanism via ROS formation (indirect) >> Single-Ring Substituted Primary Aromatic Amines OR Radical >> Radical mechanism via ROS formation (indirect) >> Specific Imine and Thione Derivatives OR SN1 OR SN1 >> Alkylation after metabolically formed carbenium ion species OR SN1 >> Alkylation after metabolically formed carbenium ion species >> Polycyclic Aromatic Hydrocarbon Derivatives OR SN1 >> Nucleophilic attack after carbenium ion formation OR SN1 >> Nucleophilic attack after carbenium ion formation >> Specific Acetate Esters OR SN1 >> Nucleophilic attack after diazonium or carbenium ion formation OR SN1 >> Nucleophilic attack after diazonium or carbenium ion formation >> Nitroarenes with Other Active Groups OR SN1 >> Nucleophilic attack after metabolic nitrenium ion formation OR SN1 >> Nucleophilic attack after metabolic 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 >> Nitroarenes with Other Active Groups OR SN1 >> Nucleophilic substitution on diazonium ions OR SN1 >> Nucleophilic substitution on diazonium ions >> Specific Imine and Thione Derivatives OR SN2 OR SN2 >> Acylation OR SN2 >> Acylation >> Specific Acetate Esters OR SN2 >> Alkylation, direct acting epoxides and related after P450-mediated metabolic activation OR SN2 >> Alkylation, direct acting epoxides and related after P450-mediated metabolic activation >> Polycyclic Aromatic Hydrocarbon Derivatives OR SN2 >> Alkylation, ring opening SN2 reaction OR SN2 >> Alkylation, ring opening SN2 reaction >> Four- and Five-Membered Lactones OR SN2 >> Nucleophilic substitution at sp3 Carbon atom OR SN2 >> Nucleophilic substitution at sp3 Carbon atom >> Specific Acetate Esters OR SN2 >> SN2 attack on activated carbon Csp3 or Csp2 OR SN2 >> SN2 attack on activated carbon Csp3 or Csp2 >> Nitroarenes with Other Active Groups by DNA binding by OASIS v.1.3

Domain logical expression index: "h"

Referential boundary: The target chemical should be classified as Non binder, MW>500 by Estrogen Receptor Binding

Domain logical expression index: "i"

Referential boundary: The target chemical should be classified as Non binder, non cyclic structure by Estrogen Receptor Binding

Domain logical expression index: "j"

Referential boundary: The target chemical should be classified as Non binder, MW>500 by Estrogen Receptor Binding

Domain logical expression index: "k"

Referential boundary: The target chemical should be classified as Strong binder, OH group by Estrogen Receptor Binding

Domain logical expression index: "l"

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

Domain logical expression index: "m"

Referential boundary: The target chemical should be classified as Allyl esters (Hepatotoxicity) Rank A OR Thiocarbamates/Sulfides (Hepatotoxicity) No rank by Repeated dose (HESS)

Domain logical expression index: "n"

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 >> Shiff base formation with carbonyl compounds AND AN2 >> Shiff base formation with carbonyl compounds >> Pyrazolone and Pyrazolidine Derivatives by Protein binding alerts for Chromosomal aberration by OASIS v1.1

Domain logical expression index: "o"

Referential boundary: The target chemical should be classified as Ac-SN2 >> Acylation involving an activated (glucuronidated) carboxamide group >> Carboxylic Acid Amines by Protein binding alerts for Chromosomal aberration by OASIS v1.1

Domain logical expression index: "p"

Referential boundary: The target chemical should be classified as Not classified by Oncologic Primary Classification

Domain logical expression index: "q"

Referential boundary: The target chemical should be classified as Acrylamide Reactive Functional Groups OR Aromatic Amine Type Compounds OR Arylazo Type Compounds OR Halogenated Aromatic Hydrocarbon Type Compounds OR Lactone Type Reactive Functional Groups OR Phenol Type Compounds by Oncologic Primary Classification

Domain logical expression index: "r"

Referential boundary: The target chemical should be classified as Vinyl Sulfones by US-EPA New Chemical Categories

Domain logical expression index: "s"

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

Domain logical expression index: "t"

Referential boundary: The target chemical should be classified as months and longer by Biodeg ultimate (Biowin 3) ONLY

Domain logical expression index: "u"

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

Domain logical expression index: "v"

Referential boundary: The target chemical should be classified as Imidazoles by Aquatic toxicity classification by ECOSAR

Domain logical expression index: "w"

Parametric boundary:The target chemical should have a value of log Kow which is >= -8.29

Domain logical expression index: "x"

Parametric boundary:The target chemical should have a value of log Kow which is <= 5.31

Conclusions:
The No Observed Adverse Effect Level (NOAEL) for trisodium 2-[(E)-2-(3-methyl-5-oxo-1-{4-[2-(sulfonatooxy)ethanesulfonyl]phenyl}-4,5-dihydro-1H-pyrazol-4-yl)diazen-1-yl] naphthalene-1,5-disulfonate is predicted to be 314.892852783 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 trisodium 2-[(E)-2-(3-methyl-5-oxo-1-{4-[2-(sulfonatooxy)ethanesulfonyl]phenyl} -4,5-dihydro-1H- pyrazol-4-yl) diazen-1-yl] naphthalene-1,5-disulfonate. The study assumed the use of male and female Wistar rats in a sub-chronic toxicity study. Since no significant treatment related effects were observed at the mentioned dose level, hence the No Observed Adverse Effect Level (NOAEL) for trisodium 2-[(E)-2-(3-methyl-5-oxo-1-{4-[2-(sulfonatooxy)ethanesulfonyl]phenyl}-4,5-dihydro-1H-pyrazol-4-yl)diazen-1-yl] naphthalene-1,5-disulfonate is predicted to be 314.892852783 mg/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
314.893 mg/kg bw/day
Study duration:
subchronic
Species:
rat
Quality of whole database:
Data is from K2 QSAR prediction database

Mode of Action Analysis / Human Relevance Framework

Additional information

Repeated dose toxicity: Oral

Prediction model based estimation and data from read across chemicals have been reviewed to determine the toxic nature of

trisodium 2-[(E)-2-(3-methyl-5-oxo-1-{4-[2-(sulfonatooxy)ethanesulfonyl]phenyl} -4,5-dihydro-1H- pyrazol-4-yl) diazen-1-yl] naphthalene-1,5-disulfonate. 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 trisodium 2-[(E)-2-(3-methyl-5-oxo-1-{4-[2-(sulfonatooxy)ethanesulfonyl]phenyl} -4,5-dihydro-1H- pyrazol-4-yl) diazen-1-yl] naphthalene-1,5-disulfonate. The study assumed the use of male and female Wistar rats in a sub-chronic toxicity study. Since no significant treatment related effects were observed at the mentioned dose level, hence the No Observed Adverse Effect Level (NOAEL) for trisodium 2-[(E)-2-(3-methyl-5-oxo-1-{4-[2-(sulfonatooxy)ethanesulfonyl]phenyl}-4,5-dihydro-1H-pyrazol-4-yl)diazen-1-yl] naphthalene-1,5-disulfonate is predicted to be 314.892852783 mg/Kg bw/day.

This is further supported by the data provided by Gaunt et al (Food and cosmetic toxicology, 1974). Repeated oral toxicity of 50 -60% structurally and functionally similar read across chemical Sunset Yellow FCF (RA CAS no 2783 -94 -0; IUPAC name: disodium 6-hydroxy-5-[(4-sulfonatophenyl) diazenyl]naphthalene-2- sulfonate) was determined by performing a 80 weeks repeated dose toxicity study usiing Charles River CD mouse (male and female) at dose levels of 0, 100, 200, 400 or 800 mg/Kg (0.2, 0.4, 0.8 or 1.6% respectively) by oral diet route. The animals were observed for clinical signs, mortality, body weight changes, hematology and were subjected to gross and histopathology. The feeding of Sunset Yellow FCF did not adversely affect the death rate within the groups, the rate of body-weight gain, the organ weights or the haematological findings. The incidence and severity of the histopathological findings were similar in treated and control mice and there was no evidence of an increased incidence of tumours in the mice given Sunset Yellow FCF. Distension of the bladder, frequently associated with hydroureter and hydronephosis was noted. Pus and hard protein deposits were found in the bladders of many of the mice and in a number of cases it was possible to show that an obstruction had occurred in the urethra in the region of the bulbo-urethral complex. After the male mice were put into individual cages, there was a marked reduction in the number showing this syndrome, although isolated cases of urinary retention were seen throughout the study. Of the malignant tumours found, lymphomas and reticulum-cell neoplasms occurred in treated and control mice. In addition a splenic haemangiosarcoma and a mammary carcinoma were found in the female mice fed on the diet containing the lowest level of Sunset Yellow FCF (100 mg/Kg). A single tumour of the Harderian gland was found in a female from the group given the 1.6% level. The commonest benign tumours were pulmonary adenomas and benign cysts in the ovary, found with a similar frequency in treated and control mice. The only other tumour occurring in treated mice without a similar finding in the controls was a granulosa-cell tumour of the ovary in a mouse given 800 mg/Kg Sunset Yellow FCF. Thus, on the basis of above results the NOAEL (no observed adverse effect level) for Sunset Yellow FCF was considered to be 800 mg/kg diet.

13 week subchronic toxicity study was conducted by Maekawa (Food and chemical toxicology, 1987) to evaluate the toxic nature of 50 -60% structurally and functionally similar read across chemical tartrazine (RA CAS no 1934 -21 -0; IUPAC name: trisodium 5-hydroxy-1-(4-sulphophenyl)-4-(4-sulphophenylazo) pyrazole-3-carboxylate). 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.

Based on the data available for the target chemical and its read across, trisodium 2-[(E)-2-(3-methyl-5-oxo-1-{4-[2-(sulfonatooxy) ethanesulfonyl]phenyl} -4,5-dihydro-1H- pyrazol-4-yl) diazen-1-yl] naphthalene-1,5-disulfonate is not likely to be toxic upon repeated exposure by oral route. Hence it can be considered to be not 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, trisodium 2-[(E)-2-(3-methyl-5-oxo-1-{4-[2-(sulfonatooxy) ethanesulfonyl]phenyl} -4,5-dihydro-1H- pyrazol-4-yl) diazen-1-yl] naphthalene-1,5-disulfonate (CAS no 20298 -05 -9) is not likely to be toxic upon repeated exposure by oral route. Hence it can be considered to be not toxic as per the criteria mentioned in CLP regulation.