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

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Link to relevant study records

Reference

Endpoint:

screening for reproductive / developmental toxicity

Remarks:

based on test type (migrated information)

Type of information:

(Q)SAR

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Data is from QSAR Toolbox 3.4.0.17

Justification for type of information:

QSAR prediction: migrated from IUCLID 5.6

Qualifier:

according to guideline

Guideline:

OECD Guideline 421 (Reproduction / Developmental Toxicity Screening Test)

Principles of method if other than guideline:

Reproduction / Developmental Toxicity Screening Test of 5-oxo-1-(4-sulphophenyl)-2-pyrazoline-3-carboxylic acid in rats.

GLP compliance:

not specified

Limit test:

no

Species:

rat

Strain:

Wistar

Sex:

male/female

Details on test animals or test system and environmental conditions:

No data availabel

Route of administration:

oral: gavage

Vehicle:

water

Details on exposure:

No data availabel

Details on mating procedure:

No data availabel

Analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

40 to 55 days
males: 2 weeks prior to mating, mating and 5 weeks post mating
females: 2 weeks prior to mating, mating, pregnancy, 4 days lactation

Frequency of treatment:

Daily

Details on study schedule:

No data available

Remarks:

Doses / Concentrations:
860 mg/kg bw
Basis:

No. of animals per sex per dose:

No data available

Control animals:

yes

Details on study design:

No data available

Positive control:

No data available

Parental animals: Observations and examinations:

No data available

Oestrous cyclicity (parental animals):

No data available

Sperm parameters (parental animals):

No data available

Litter observations:

No data available

Postmortem examinations (parental animals):

No data available

Postmortem examinations (offspring):

No data available

Statistics:

No data available

Offspring viability indices:

No data available

Clinical signs:

no effects observed

Body weight and weight changes:

no effects observed

Food consumption and compound intake (if feeding study):

no effects observed

Organ weight findings including organ / body weight ratios:

not specified

Histopathological findings: non-neoplastic:

no effects observed

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:

860 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: No effect on systemic/reproductive performance/fertility

Clinical signs:

no effects observed

Mortality / viability:

no mortality observed

Body weight and weight changes:

no effects observed

Sexual maturation:

not specified

Organ weight findings including organ / body weight ratios:

not specified

Gross pathological findings:

no effects observed

Histopathological findings:

not specified

Remarks on result:

not measured/tested

Reproductive effects observed:

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" )  and ("d" and ( not "e") )  )  and "f" )  and ("g" and "h" )  )

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 >> 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 and Aminoalkylamine Side Chain OR Non-covalent interaction >> DNA intercalation >> N-Hydroxyethyl Lactams OR Non-covalent interaction >> DNA intercalation >> Polycyclic Aromatic Hydrocarbon and Naphthalenediimide Derivatives 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 >> Generation of ROS by glutathione depletion (indirect) OR Radical >> Generation of ROS by glutathione depletion (indirect) >> Haloalkanes Containing Heteroatom 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) >> 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 and Naphthalenediimide 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 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 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 after P450-mediated metabolic activation OR SN2 >> Alkylation, direct acting epoxides and related after P450-mediated metabolic activation >> Polycyclic Aromatic Hydrocarbon and Naphthalenediimide Derivatives OR SN2 >> Alkylation, nucleophilic substitution at sp3-carbon atom OR SN2 >> Alkylation, nucleophilic substitution at sp3-carbon atom >> Haloalkanes Containing Heteroatom OR SN2 >> Direct acting epoxides formed after metabolic activation OR SN2 >> Direct acting epoxides formed after metabolic activation >> Quinoline Derivatives OR SN2 >> Nucleophilic substitution at sp3 Carbon atom OR SN2 >> Nucleophilic substitution at sp3 Carbon atom >> Haloalkanes Containing Heteroatom OR SN2 >> Nucleophilic substitution at sp3 Carbon atom >> Specific Acetate Esters OR SN2 >> SN2 at an activated carbon atom OR SN2 >> SN2 at an activated carbon atom >> Quinoline Derivatives 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.1.4

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"

Parametric boundary:The target chemical should have a value of log Kow which is >= -1.91

Domain logical expression index: "h"

Parametric boundary:The target chemical should have a value of log Kow which is <= 1.82

Conclusions:

Estimated NOAEL was considered to be 860 mg/kg bw Wistar male and female rats were treated with 5-oxo-1-(4-sulphophenyl)-2-pyrazoline-3-carboxylic acid orally by gavage.

Executive summary:

Reproductive toxicity was estimated by using QSAR Toolbox version 3.4.0.17 in Wistar male and female rats trreated with 5-oxo-1-(4-sulphophenyl)-2-pyrazoline-3-carboxylic acid in the concentration of 860 mg/kg bw in water orally by gavage. No effect on systemic/reproductive performance/fertility was observed in treated male and femalerats. Therefore, estimated NOAEL was considered to be 860 mg/kg bw Wistar male and female rats were treated with 5-oxo-1-(4-sulphophenyl)-2-pyrazoline-3-carboxylic acid orally by gavage.   

Effect on fertility: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

860 mg/kg bw/day

Study duration:

subchronic

Species:

rat

Quality of whole database:

Data is Klimish 2 and from QSAR Toolbox version 3.4.0.17

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:

Data available for target 5-oxo-1-(4-sulphophenyl)-2-pyrazoline-3-carboxylic acid (118-47-8) and its read across Tartrazine (CAs no 1934-21-0) for reproductive toxicity are summarized as below 

Based on prediction done by using QSAR Toolbox version 3.4.0.17 (2016), reproductive toxicity was estimated in Wistar male and female rats by using 5-oxo-1-(4-sulphophenyl)-2-pyrazoline-3-carboxylic acid in the concentration of 860 mg/kg bw in water orally by gavage. No effect on systemic/reproductive performance/fertility was observed in treated male and female rats. Therefore, estimated NOAEL was considered to be 860 mg/kg bw Wistar male and female rats were treated with 5-oxo-1-(4-sulphophenyl)-2-pyrazoline-3-carboxylic acid orally by gavage.   

In a study conducted by Mehedi et al (2009), sub chronic toxicity was evaluated in male swiss albino mice by using Tartrazine in the concentration of 0, 0.1%, 1% and 2.5% (173.9 ±0.25, 1767.8±0.32and 5541.4±0.47 mg/kg/day ) by oral drinking water. Groups of Tartrazine treated mice, six males per dose group, were mated 1:1 with untreated females for 1 week. Females were then separated and allowed to gestate to term. For females that failed to deliver a litter, this was considered as a sign of male infertility whereas litter delivery indicated male fertility. Food and water consumption, body weight, reproductve fuction, Reproductive performance, organ weight and histopathology were observed. Decrase in food consumption and increase in water consumption were observed in 173.9, 1767.8 and 5541.4 mg/kg/day treated male rats as compared to control. Average (±SE) tartrazine intake calculated from liquid consumption, in mg kg^-1day^-1, was (173.9±0.25), (1767.8±0.32), (5541.4±0.47) for 0.1, 1 and 2.5% tartrazine groups, respectively. Significantly increased body weight gain was observed in 1767.8 mg/kg/day and decrease in relative testis and seminal vesicles weight in 173.9, 1767.8 and 5541.4 mg/kg/day treated male rats, but the effect were not statistically significant and no effect on absolute organ weight were observed in treated male rats as compared to control. Decreased in male mating index and body weight and litter sizes were observed in 5541.4 mg/kg/day treated male rats as compared to control. Similarly, significant decreased in Total number of spermatids count, Sperm concentration in epididymis reserves and percentage motility in 5541.4 mg/kg/day, percentage motility and Sperm concentration in epididymides in 1767.8 mg/kg/day and Sperm concentration in epididymides in 173.9 mg/kg/day treated male rats as compared to control. Sperm head (amorphous, macro-or microcephaly) and the sperm flagellum (entangled, twisted, coiled, with ANSA) morphological abnormalities and significantly affected percentage morphologically normal spermatozoa were observed in 5541.4 mg/kg/day treated male rats as compared to control. In addition, extensive disruption in semniferous tubules, widening of the interstitial spaces and loss leydig cells, Spermatogenic cells are affected and then depleted with absence of spermatozoa in the lumen at 5541.4 mg/kg/day, decreased intercellular connections and imperfect and dilation in some semniferous tubules of testis at 1767.8 mg/kg/day and emniferous tubules were not identical with conjunctive tissue dystrophy in testes at 173.9 mg/kg/day treated male rats as compared to control. Therefore NOAEL was considered to be173.9 mg/kg/day (0.1%) when swiss albino male mice treated with tartrazine orally by drinking water for 13 weeks.

In a study conducted by Colljns et al (1990), Teratogeninc potential was evaluated in Osborne-Mendel female rats by using 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 % of pregnant female, no of corpora, implantation, no of viable foetuses, 5 resorptions, early death or late deaths per litter and sex ratio of treated rats as compared to control. Similarly, no effect on foetuses 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 foetuses with at least two types of stemebral variations in foetuses at 200 mg/kg body weight/day, significant increase in haemorrhages at 600 mg/kg body weight/day and four foetuses from three litters at 1000 mg/kg body weight/day were observed but, The incidences of foetuses with visceral variations and of litters containing those foetuses 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.

In a study conducted by Colljns et al (1992), Teratogeninc potential was evaluated in Osborne-Mendel female rats by using 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/kgbw/day-1 litter; 131.8 mg/kg bw/day-3 litters; 567.9 mg/kg bw /day-2 litters and 1064.3 mg/kgbw/day-3 litters) as compared to control. Similarly, no effect on Implantation efficiency, foetal viability and foetal development were observed in treated rats. In addition, haemorrhages, one animal with exencephaly (67.4 mg/kg bw/day), one animal with an extra foetus body attached to the chest (1064.3 mg/kgbw/day) and two animals with reduced tails (0 and 131.8 mg/kg bw/day) were observed in foetuses 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/kgbw/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.

In a study conducted by Tanakaet al(2008), three-generation reproductive and neurobehavioral toxicity was evaluated in Crlj: CD1 male and female mice by using Tartrazine in the concentration of 0, 75, 225 and 675 mg/kg bw/day orally in feed. In F0 generation, No significant effect on body weight, food consumption and exploratory behaviour of treated mice were observed as compared to control. No significant effect on birth rate of offspring was observed as compared to control. In F1 generation, No significant adverse effect was observed on survival, litter size, litter weight, or sex ratio at birth. Significant increase in body weight was observed in 75, 225 and 675 mg/kg bw/day but not significant as compared to control. At 225 mg/kg bw/day, significantly accelerated swimming direction in male offspring and Surface righting in female offspring at PND 7 were observed. In male offspring, movement time (s), total distance (cm), average distance (cm) and number of turning were significantly affected at 3 weeks of age and no significant adverse effect was observed on movement activity and bodyweight of treated F1 offspring. In F2 generation, no significant adverse effects were observed on survival indices, litter size, litter weight, or sex ratio at birth as compared to control. At 75 mg/kg bw/day, significant increase in body weight of female offspring at PNDs 14 and 21, and in male offspring at PNDs 7, 14 and 21.Significant acceleration of swimming direction at PND 7 at 675 mg/kg bw/day and time taken of olfactory orientation at PND 14 and Surface righting at PND 7 in 225 mg/kg bw/day and time taken of olfactory orientation at PND 14 in 675 mg/kg bw/day were observed as compared to control. In male offspring, significant tendency to affected total distance (cm), average distance (cm) and average speed (cm/s) at 3 weeks and 8 week of age were observed at 675 mg/kg bw/day. No significant effects on reproduction were observed in treated male and female offspring were observed as compared to control. Few adverse effects on several behavioral parameters were observed in 675 mg/kg bw/day which is in excess of the ADI of tartrazine (0–7.5 mg/kg bw) unlikely to produce any adverse effects in humans. Therefore, NOAEL was considered to be 675 mg/kg bw/day for F0, F1 and F2 generation when Crlj: CD1 male and female mice were treated with Tartrazine orally in feed approx. 200 days.

Thus base on the weight of evidence for target 5-oxo-1-(4-sulphophenyl)-2-pyrazoline-3-carboxylic acid (118-47-8) and its structurally similar read across Tartrazine (CAs no 1934-21-0) is likely to classified as non hazardous as per the criteria of CLP regulation.

Short description of key information:
Estimated NOAEL was considered to be 860 mg/kg bw Wistar male and female rats

Justification for selection of Effect on fertility via oral route:
Estimated NOAEL was considered to be 860 mg/kg bw Wistar male and female rats were treated with 5-oxo-1-(4-sulphophenyl)-2-pyrazoline-3-carboxylic acid orally by gavage

Effects on developmental toxicity

Description of key information

Estimated NOAEL was considered to be 930 mg/kg bw Sprague-Dawley rats were treated with 5-oxo-1-(4-sulphophenyl)-2-pyrazoline-3-carboxylic acid orally 

Link to relevant study records

Reference

Endpoint:

developmental toxicity

Type of information:

(Q)SAR

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Data is from QSAR Toolbox 3.4.0.17

Justification for type of information:

QSAR prediction: migrated from IUCLID 5.6

Qualifier:

equivalent or similar to guideline

Guideline:

other: as below

Principles of method if other than guideline:

Prediction is done using QSAR Toolbox version 33.4.0.17

GLP compliance:

not specified

Limit test:

no

Species:

rat

Strain:

Sprague-Dawley

Details on test animals or test system and environmental conditions:

No data available

Route of administration:

oral: gavage

Type of inhalation exposure (if applicable):

other: not applicable

Vehicle:

water

Details on exposure:

No data available

Analytical verification of doses or concentrations:

not specified

Details on analytical verification of doses or concentrations:

No data available

Details on mating procedure:

No data available

Duration of treatment / exposure:

11 days

Frequency of treatment:

Daily

Duration of test:

until gestation day 20

No. of animals per sex per dose:

25 male and female

Control animals:

yes

Details on study design:

No data available

Maternal examinations:

No data available

Ovaries and uterine content:

No data available

Fetal examinations:

No data available

Statistics:

No data available

Indices:

No data available

Historical control data:

No data available

Details on maternal toxic effects:

Maternal toxic effects:no data

Details on maternal toxic effects:
No data available

Remarks on result:

not measured/tested

Details on embryotoxic / teratogenic effects:

Embryotoxic / teratogenic effects:no data

Details on embryotoxic / teratogenic effects:
No data available

Dose descriptor:

NOAEL

Effect level:

930.167 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: No effect on development

Abnormalities:

not specified

Developmental effects observed:

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

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 on alpha, beta-unsaturated carbonyl compounds OR AN2 >> Michael-type addition on alpha, beta-unsaturated carbonyl compounds >> Four- and Five-Membered Lactones 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 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 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) >> Geminal Polyhaloalkane Derivatives OR SN1 OR SN1 >> Nucleophilic attack after carbenium ion formation OR SN1 >> Nucleophilic attack after carbenium ion formation >> Specific Acetate Esters OR SN2 OR SN2 >> Acylation OR SN2 >> Acylation >> Specific Acetate Esters 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 >> 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 >> Direct acting epoxides formed after metabolic activation >> Quinoline Derivatives OR SN2 >> Nucleophilic substitution at sp3 Carbon atom OR SN2 >> Nucleophilic substitution at sp3 Carbon atom >> Specific Acetate Esters 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 OR SN2 >> SN2 at an activated carbon atom OR SN2 >> SN2 at an activated carbon atom >> Quinoline Derivatives by DNA binding by OASIS v.1.4

Domain logical expression index: "f"

Referential boundary: The target chemical should be classified as No alert found by DNA binding by OECD

Domain logical expression index: "g"

Referential boundary: The target chemical should be classified as SN1 OR SN1 >> Iminium Ion Formation OR SN1 >> Iminium Ion Formation >> Aliphatic tertiary amines OR SN1 >> Nitrenium Ion formation OR SN1 >> Nitrenium Ion formation >> Aromatic azo OR SN1 >> Nitrenium Ion formation >> Aromatic nitro OR SN1 >> Nitrenium Ion formation >> Tertiary aromatic amine OR SN1 >> Nitrenium Ion formation >> Unsaturated heterocyclic azo by DNA binding by OECD

Domain logical expression index: "h"

Referential boundary: The target chemical should be classified as Non binder, without OH or NH2 group by Estrogen Receptor Binding

Domain logical expression index: "i"

Referential boundary: The target chemical should be classified as Non binder, impaired OH or NH2 group OR Non binder, non cyclic structure OR Strong binder, OH group OR Very strong binder, OH group by Estrogen Receptor Binding

Domain logical expression index: "j"

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: "k"

Referential boundary: The target chemical should be classified as Acylation >> Direct Acylation Involving a Leaving group >> Anhydrides OR Michael addition OR Michael addition >> Acid imides OR Michael addition >> Acid imides >> Acid imides-MA OR SNAr OR SNAr >> Nucleophilic aromatic substitution OR SNAr >> Nucleophilic aromatic substitution >> Activated halo-benzenes by Protein binding by OECD

Domain logical expression index: "l"

Referential boundary: The target chemical should be classified as Not possible to classify according to these rules (GSH) by Protein binding potency

Domain logical expression index: "m"

Referential boundary: The target chemical should be classified as Moderately reactive (GSH) OR Moderately reactive (GSH) >> Substituted 1-Alken-3-ones (MA) by Protein binding potency

Domain logical expression index: "n"

Parametric boundary:The target chemical should have a value of log Kow which is >= -4.46

Domain logical expression index: "o"

Parametric boundary:The target chemical should have a value of log Kow which is <= 3.62

Conclusions:

Estimated NOAEL was considered to be 930 mg/kg bw Sprague-Dawley rats were treated with 5-oxo-1-(4-sulphophenyl)-2-pyrazoline-3-carboxylic acid orally by gavage for 11 day

Executive summary:

Developmental toxicity was estimated by using QSAR Toolbox version 3.4.0.17 in Sprague-Dawley rats by using 5-oxo-1-(4-sulphophenyl)-2-pyrazoline-3-carboxylic acid in the concentration of 930 mg/kg bw in water orally by gavage. No effect on development was observed in treated rats. Therefore, estimated NOAEL was considered to be 930 mg/kg bw Sprague-Dawley rats were treated with 5-oxo-1-(4-sulphophenyl)-2-pyrazoline-3-carboxylic acid orally by gavage for 11 day.

Effect on developmental toxicity: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

930 mg/kg bw/day

Study duration:

subacute

Species:

rat

Quality of whole database:

Data is Kilmish 2 and from QSAR Toolbox version 3.4.0.17

Effect on developmental toxicity: via inhalation route

Endpoint conclusion:

no study available

Effect on developmental toxicity: via dermal route

Endpoint conclusion:

no study available

Additional information

Developmental toxicity:

Data available for target 5-oxo-1-(4-sulphophenyl)-2-pyrazoline-3-carboxylic acid (118-47-8) and its read across Tartrazine (CAs no 1934-21-0) for developmental toxicity are summarized as below 

Based on prediction done by using QSAR Toolbox version 3.4.0.17 (2016), developmental toxicity was estimated in Sprague-Dawley rats by using 5-oxo-1-(4-sulphophenyl)-2-pyrazoline-3-carboxylic acid in the concentration of 930 mg/kg bw in water orally by gavage. No effect on development was observed in treated rats. Therefore, estimated NOAEL was considered to be 930 mg/kg bw Sprague-Dawley rats were treated with 5-oxo-1-(4-sulphophenyl)-2-pyrazoline-3-carboxylic acid orally by gavage for 11 day.

In a study conducted by Tanakaet al(2008), three-generation reproductive and neurobehavioral toxicity was evaluated in Crlj: CD1 male and female mice by using Tartrazine in the concentration of 0, 75, 225 and 675 mg/kg bw/day orally in feed. In F0 generation, No significant effect on body weight, food consumption and exploratory behaviour of treated mice were observed as compared to control. No significant effect on birth rate of offspring was observed as compared to control. In F1 generation, No significant adverse effect was observed on survival, litter size, litter weight, or sex ratio at birth. Significant increase in body weight was observed in 75, 225 and 675 mg/kg bw/day but not significant as compared to control. At 225 mg/kg bw/day, significantly accelerated swimming direction in male offspring and Surface righting in female offspring at PND 7 were observed.

In male offspring, movement time (s), total distance (cm), average distance (cm) and number of turning were significantly affected at 3 weeks of age and no significant adverse effect was observed on movement activity and bodyweight of treated F1 offspring. In F2 generation, no significant adverse effects were observed on survival indices, litter size, litter weight, or sex ratio at birth as compared to control. At 75 mg/kg bw/day, significant increase in body weight of female offspring at PNDs 14 and 21, and in male offspring at PNDs 7, 14 and 21. Significant acceleration of swimming direction at PND 7 at 675 mg/kg bw/day and time taken of olfactory orientation at PND 14 and Surface righting at PND 7 in 225 mg/kg bw/day and time taken of olfactory orientation at PND 14 in 675 mg/kg bw/day were observed as compared to control. In male offspring, significant tendency to affected total distance (cm), average distance (cm) and average speed (cm/s) at 3 weeks and 8 week of age were observed at 675 mg/kg bw/day. No significant effects on reproduction were observed in treated male and female offspring were observed as compared to control. Few adverse effects on several behavioral parameters were observed in 675 mg/kg bw/day which is in excess of the ADI of tartrazine (0–7.5 mg/kg bw) unlikely to produce any adverse effects in humans. Therefore, NOAEL was considered to be 675 mg/kg bw/day for F0, F1 and F2 generation when Crlj: CD1 male and female mice were treated with Tartrazine orally in feed approx. 200 days.

In a study conducted by Colljns et al (1990), Teratogeninc potential was evaluated in Osborne-Mendel female rats by using 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 % of pregnant female, no of corpora, implantation, no of viable foetuses, 5 resorptions, early death or late deaths per litter and sex ratio of treated rats as compared to control. Similarly, no effect on foetuses 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 foetuses with at least two types of stemebral variations in foetuses at 200 mg/kg body weight/day, significant increase in haemorrhages at 600 mg/kg body weight/day and four foetuses from three litters at 1000 mg/kg body weight/day were observed but, The incidences of foetuses with visceral variations and of litters containing those foetuses 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.

In a study conducted by Colljns et al (1992), Teratogeninc potential was evaluated in Osborne-Mendel female rats by using 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/kgbw/day-1 litter; 131.8 mg/kg bw/day-3 litters; 567.9 mg/kg bw /day-2 litters and 1064.3 mg/kgbw/day-3 litters) as compared to control. Similarly, no effect on Implantation efficiency, foetal viability and foetal development were observed in treated rats. In addition, haemorrhages, one animal with exencephaly (67.4 mg/kg bw/day), one animal with an extra foetus body attached to the chest (1064.3 mg/kgbw/day) and two animals with reduced tails (0 and 131.8 mg/kg bw/day) were observed in foetuses 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/kgbw/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.

Thus base on the weight of evidence for target 5-oxo-1-(4-sulphophenyl)-2-pyrazoline-3-carboxylic acid (118-47-8) and its structurally similar read across Tartrazine (CAs no 1934-21-0) is likely to classified as non hazardous as per the criteria of CLP regulation.

Justification for selection of Effect on developmental toxicity: via oral route:
Estimated NOAEL was considered to be 930 mg/kg bw Sprague-Dawley rats were treated with 5-oxo-1-(4-sulphophenyl)-2-pyrazoline-3-carboxylic acid orally by gavage for 11 day.

Justification for classification or non-classification

Base on the weight of evidence for target 5-oxo-1-(4-sulphophenyl)-2-pyrazoline-3-carboxylic acid (118-47-8) and its structurally similar read across Tartrazine (CAs no 1934-21-0) is likely to classified as non hazardous for reproduction and development toxicant as per the criteria of CLP regulation.

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