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Key value for chemical safety assessment

Effects on fertility

Description of key information

NOAEL was estimated to be 646 mg/kg bw when rats were orally exposed with 4,5-dihydro-5-oxo-4-[[4-[[2-(sulphooxy)ethyl]sulphonyl]phenyl]azo]-1-(4-sulphophenyl)-1H-pyrazole-3-carboxylic acid.  

Thus, as per criteria of CLP regulation, 4,5-dihydro-5-oxo-4-[[4-[[2-(sulphooxy)ethyl]sulphonyl]phenyl]azo]-1-(4-sulphophenyl)-1H-pyrazole-3-carboxylic acid 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 3.3 and the supporting QMRF report has been attached
Reference:
Composition 0
Qualifier:
according to
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
Test material information:
Composition 1
Specific details on test material used for the study:
- Name of test material (IUPAC name): 4,5-dihydro-5-oxo-4-[[4-[[2-(sulphooxy)ethyl]sulphonyl]phenyl]azo]-1-(4-sulphophenyl)-1H-pyrazole-3-carboxylic acid
- Molecular formula : C18H16N4O12S3
- Molecular weight : 576.538 g/mol
- Smiles notation : O=C(O)C1=NN(C(=O)[C@@H]1\N=N\c1ccc(S(=O)(=O)CCOS(=O)(=O)O)cc1)c1ccc(S(=O)(=O)O)cc1
- InChl : 1S/C18H16N4O12S3/c23-17-15(16(18(24)25)21-22(17)12-3-7-14(8-4-12)36(28,29)30)20-19-11-1-5-13(6-2-11)35(26,27)10-9-34-37(31,32)33/h1-8,15H,9-10H2,(H,24,25)(H,28,29,30)(H,31,32,33)/b20-19+
- Substance type: Organic
- Physical state: Solid
Species:
rat
Strain:
Wistar
Sex:
male/female
Route of administration:
oral: gavage
Type of inhalation exposure (if applicable):
not specified
Vehicle:
water
Details on exposure:
not specified
Details on mating procedure:
not specified
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
Approx 43 days
Frequency of treatment:
Daily
Details on study schedule:
not specified
Dose / conc.:
646 mg/kg bw/day
No. of animals per sex per dose:
12 animals/sex/group
Control animals:
yes, concurrent vehicle
Details on study design:
not specified
Positive control:
not specified
Parental animals: Observations and examinations:
not specified
Estrous 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:
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
Gross pathological findings:
not specified
Histopathological findings: non-neoplastic:
not specified
Histopathological findings: neoplastic:
not specified
Other effects:
not specified
Reproductive function: estrous cycle:
not specified
Reproductive function: sperm measures:
not specified
Reproductive performance:
not specified
Dose descriptor:
NOAEL
Effect level:
646 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: 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:
no effects observed
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 6 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 ("i" and ( not "j") )  )  and ("k" and ( not "l") )  )  and ("m" and ( not "n") )  )  and ("o" and ( not "p") )  )  and ("q" and ( not "r") )  )  and ("s" and "t" )  )

Domain logical expression index: "a"

Referential boundary: The target chemical should be classified as Vinyl Sulfones 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 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 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  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 >> Aromatic azo 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 Not possible to classify according to these rules by Keratinocyte gene expression

Domain logical expression index: "g"

Referential boundary: The target chemical should be classified as High gene expression OR High gene expression >> N-Acylamides by Keratinocyte gene expression

Domain logical expression index: "h"

Similarity boundary:Target: OC(=O)C1C(N=Nc2ccc(S(=O)(=O)CCOS(O)(=O)=O)cc2)C(=O)N(c2ccc(S(O)(=O)=O)cc2)N=1
Threshold=30%,
Dice(Atom centered fragments)
Atom type; Count H attached; Hybridization

Domain logical expression index: "i"

Referential boundary: The target chemical should be classified as Aromatic compound AND Carbonic acid derivative AND Carboxylic acid derivative AND Heterocyclic compound AND Sulfonic acid AND Sulfonic acid derivative AND Sulfuric acid derivative AND Sulfuric acid monoester by Organic functional groups, Norbert Haider (checkmol)

Domain logical expression index: "j"

Referential boundary: The target chemical should be classified as Carboxylic acid ester by Organic functional groups, Norbert Haider (checkmol)

Domain logical expression index: "k"

Referential boundary: The target chemical should be classified as Aromatic compound AND Carbonic acid derivative AND Carboxylic acid derivative AND Heterocyclic compound AND Sulfonic acid AND Sulfonic acid derivative AND Sulfuric acid derivative AND Sulfuric acid monoester by Organic functional groups, Norbert Haider (checkmol)

Domain logical expression index: "l"

Referential boundary: The target chemical should be classified as Secondary amine by Organic functional groups, Norbert Haider (checkmol)

Domain logical expression index: "m"

Referential boundary: The target chemical should be classified as Aryl AND Azo AND Carboxylic acid AND Pyrazolone AND Sulfate AND Sulfone AND Sulfonic acid AND Unsaturated heterocyclic amine AND Unsaturated heterocyclic fragment by Organic Functional groups

Domain logical expression index: "n"

Referential boundary: The target chemical should be classified as Alkene by Organic Functional groups

Domain logical expression index: "o"

Referential boundary: The target chemical should be classified as Aryl AND Azo AND Carboxylic acid AND Pyrazolone AND Sulfate AND Sulfone AND Sulfonic acid AND Unsaturated heterocyclic amine AND Unsaturated heterocyclic fragment by Organic Functional groups

Domain logical expression index: "p"

Referential boundary: The target chemical should be classified as Alkoxy OR Alkyl arenes by Organic Functional groups

Domain logical expression index: "q"

Referential boundary: The target chemical should be classified as Aryl AND Azo AND Carboxylic acid AND Pyrazolone AND Sulfate AND Sulfone AND Sulfonic acid AND Unsaturated heterocyclic amine AND Unsaturated heterocyclic fragment by Organic Functional groups

Domain logical expression index: "r"

Referential boundary: The target chemical should be classified as Biphenyl by Organic Functional groups

Domain logical expression index: "s"

Parametric boundary:The target chemical should have a value of log Kow which is >= -5.49

Domain logical expression index: "t"

Parametric boundary:The target chemical should have a value of log Kow which is <= 4.09

Conclusions:
NOAEL was estimated to be 646 mg/kg bw when rats were orally exposed with 4,5-dihydro-5-oxo-4-[[4-[[2-(sulphooxy)ethyl]sulphonyl]phenyl]azo]-1-(4-sulphophenyl)-1H-pyrazole-3-carboxylic acid.
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 4,5-dihydro-5-oxo-4-[[4-[[2-(sulphooxy)ethyl]sulphonyl]phenyl]azo]-1-(4-sulphophenyl)-1H-pyrazole-3-carboxylic acid. The NOAEL was estimated to be 646 mg/kg bw when rats were orally exposed with 4,5-dihydro-5-oxo-4-[[4-[[2-(sulphooxy)ethyl]sulphonyl]phenyl]azo]-1-(4-sulphophenyl)-1H-pyrazole-3-carboxylic acid.  

Effect on fertility: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
646 mg/kg bw/day
Study duration:
subchronic
Species:
rat
Quality of whole database:
Data is Klimisch 2 and from OECD QSAR
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, 4,5-dihydro-5-oxo-4-[[4-[[2-(sulphooxy)ethyl]sulphonyl]phenyl]azo]-1-(4-sulphophenyl)-1H-pyrazole-3-carboxylic acid 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 4,5-dihydro-5-oxo-4-[[4-[[2-(sulphooxy)ethyl]sulphonyl]phenyl]azo]-1-(4-sulphophenyl)-1H-pyrazole-3-carboxylic acid 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) and Black PN (CAS no 2519-30-4). 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 4,5-dihydro-5-oxo-4-[[4-[[2-(sulphooxy)ethyl]sulphonyl]phenyl]azo]-1-(4-sulphophenyl)-1H-pyrazole-3-carboxylic acid. The NOAEL was estimated to be 646 mg/kg bw when rats were orally exposed with 4,5-dihydro-5-oxo-4-[[4-[[2-(sulphooxy)ethyl]sulphonyl]phenyl]azo]-1-(4-sulphophenyl)-1H-pyrazole-3-carboxylic acid.  

In another experimental study conducted by Colljnset al(Food Chem Toxic, Vol. 28, No. 12, pp. 821-827) 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 rats were treated with Tartrazine in the concentration of 0, 60, 100, 200, 400, 600 and 1000 mg/kg /day orally by gavage in water. One female in 60 mg/kg body weight/day died on day 13 of gestation of gavage difficulties unrelated to dosage. No clinical sign of toxicity were observed in treated female rats as compared to control. Significant increase in food consumption at 100 mg/kg body weight/day and no effect on body weight were observed in treated female rats as compared to control. No effect on reproductive parameters such as % of pregnant female, no of corpora, implantation, no of viable fetuses, 5 resorptions, early death or late deaths per litter and sex ratio of treated rats as compared to control. Similarly, no effect on fetus’s viability and body weight were observed in treated rats. In addition, three hydrocephalic pups in a single litter and isolated increase in the number of litters containing fetuses with at least two types of stemebral variations in fetuses at 200 mg/kg body weight/day, significant increase in haemorrhages at 600 mg/kg body weight/day and four fetuses from three litters at 1000 mg/kg body weight/day were observed but, The incidences of fetuses with visceral variations and of litters containing those fetuses were similar in all groups. Therefore, NOAEL was considered to be 1000 mg/kg bw/day for F0 and F1 generation when Osborne-Mendel female rats were treated with Tartrazine orally by gavage for 19 days.

Further supported by experimental study conducted by Colljnset al(Food Chem Toxic, Vol. 30, No. 4, pp. 263-268, 1992) 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 rats were treated with Tartrazine in the concentration of 67.4, 131.8, 292.4, 567.9 and 1064.3 mg/kg bw/day orally in water. No effect on survival and clinical sign were observed in treated rats as compared to control. No effects on body weight and food consumption of treated female rats were observed as compared to control. Nine litters were totally resorbed, but the resorptions were not related to dosage (67.4 mg/kg bw/day-1 litter; 131.8 mg/kg bw/day-3 litters; 567.9 mg/kg bw /day-2 litters and 1064.3 mg/kg bw/day-3 litters) as compared to control. Similarly, no effect on Implantation efficiency, fetal viability and fetal development were observed in treated rats. In addition, haemorrhages, one animal with exencephaly (0.05% group), one animal with an extra fetus body attached to the chest (1064.3 mg/kg bw/day) and two animals with reduced tails (0 and 131.8 mg/kg bw/day) were observed in fetuses of treated female rats. The abnormalities are not dose related and they are considered random. Significant increase in reduced ossification of the hyoid bone and two skeletal variations in 67.4 and 567.9 mg/kg bw/day are considered to be random because of the lack of dose response. Therefore, NOAEL was considered to be 1064.3 mg/kg bw/day for F0 and F1 generation when Osborne-Mendel female rats were treated with Tartrazine orally by drinking water for 19 days.

Again supported by experimental study conducted by Gauntet al(Food and Cosmetics Toxicology Volume 5, 1967, Pages 171-177) on structurally similar read across substance Black PN (CAS no 2519-30-4), male and female rats were treated with Black PN in the concentration of 0, 150, 500, 1000 mg/kg/day by oral in diet for 90 days. No change in Clinical sign, Hematology, clinical chemistry and urine analysis was observed in both treated male and female rats compare to control. Significant growth retardation was observed in males at the 1000mg/kg/day and it associated with a reduced food intake. There were significant increase in the relative weights of the testes and kidneys at the dose level of 1000 mg/kg/day in treated male as compare to control. The elevated relative kidney weights were not accompanied by changes in the kidney function tests or in organ pathology. Decrease liver weight was also observed in 150 and 1000 mg/kg/day in treated female compare to control. In addition, Significant change was observed in the foci of inflammatory cell infiltration of the myocardium in treated males at 1000 mg/kg/day .The foci of inflammatory cell infiltration of the myocardium which occurred occasionally in males of the 1000 mg/kg/day group were of spontaneous origin.  On the basis of results NOEAL was considered to be 500 mg/kg/day in male rats and 1000 mg/kg/day in female rats respectively, male and female rats were treated with Black PN for 90 days.

Further supported by experimental study conducted by Gauntet al(Food and Cosmetics Toxicology Volume 10, Issue 1, 1972, Pages 17-27) on structurally similar read across substance Black PN (CAS no 2519-30-4), CFE male and female rats were treated with 0, 50, 250 and 500 mg/kg bw by oral in feed for 2 years. The fur and faeces of the rats fed diets containing Black PN were coloured black. No statistically significant effect on mortality, body weight and food consumption were observed in treated rats as compared to control. Similarly, No adverse haematological changes were seen in either sex or at any dietary level up to 12 months. At week 82, the haemoglobin concentration and packed cell volume were reduced in females at 500 mg/kg bw. These effects were not found after 2 yr, although at this time this group showed a reduction in the total leucocyte count. The terminal haemoglobin concentration and packed cell volume of male rats were reduced at all dose levels. No effect on urine or of the renal concentration test was observed in treated rats as compared to control. There was no black colour in urine collected free of faecal or other contamination. In addition, there were no statistically significant differences between the absolute organ weights of control rats and those of rats treated with Black PN However, in male rats, the relative liver weights were significantly higher in all treated rat as compared to control. No effect was observed on reproductive gonads, thyroid and pituitary, both in male and female treated rats compare to control. No significant change were observed in  hitopathological value in treated group when compare to control group at all dose level. No carcinogenic effect was observed in treated animal as compare to control group. Therefore, NOAEL was considered to be 500 mg/kg bw when CFE male and female rats were treated with Black PN orally in feed for 2 years.

Thus, based on the above study and predictions on 4,5-dihydro-5-oxo-4-[[4-[[2-(sulphooxy)ethyl]sulphonyl]phenyl]azo]-1-(4-sulphophenyl)-1H-pyrazole-3-carboxylic acid and its read across substances, it can be concluded that NOAEL value is 646 mg/kg bw with no effect on reproduction. Thus, as per criteria of CLP regulation, 4,5-dihydro-5-oxo-4-[[4-[[2-(sulphooxy)ethyl]sulphonyl]phenyl]azo]-1-(4-sulphophenyl)-1H-pyrazole-3-carboxylic acid 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 4,5-dihydro-5-oxo-4-[[4-[[2-(sulphooxy)ethyl]sulphonyl]phenyl]azo]-1-(4-sulphophenyl)-1H-pyrazole-3-carboxylic acid and its read across substances, it can be concluded that NOAEL value is 646 mg/kg bw with no effect on reproduction. Thus, as per criteria of CLP regulation, 4,5-dihydro-5-oxo-4-[[4-[[2-(sulphooxy)ethyl]sulphonyl]phenyl]azo]-1-(4-sulphophenyl)-1H-pyrazole-3-carboxylic acid can be not classified for reproductive toxicity.