4-[(5-amino-3-methyl-1-phenyl-1H-pyrazol-4-yl)azo]-2,5-dichlorobenzenesulphonic acid

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Description of key information

 Toxicity to reproduction

The reproductive toxicity of 4-[(5-amino-3-methyl-1-phenyl-1H-pyrazol-4-yl)azo]-2,5-dichlorobenzenesulphonic acid (12239-15-5)was estimated by SSS (2017) using OECD QSAR toolbox v3.4with log kow as the primary descriptor and NOAEL was estimated to be 563.0mg/kg bw. When male and female Crj: CD(SD) rats were exposed with 4-[(5-amino-3-methyl-1-phenyl-1H-pyrazol-4-yl)azo]-2,5-dichlorobenzenesulphonic acid (12239-15-5)orally. Thus, based on the above predictions and experimental study of 4-[(5-amino-3-methyl-1-phenyl-1H-pyrazol-4-yl)azo]-2,5-dichlorobenzenesulphonic acid (12239-15-5)and its functionally similar read across substance, No Observed Adverse Effect Level (NOAEL) was considered to be 563.0mg/kg bw Thus, comparing this value with the criteria of CLP regulation 4-[(5-amino-3-methyl-1-phenyl-1H-pyrazol-4-yl)azo]-2,5-dichlorobenzenesulphonic acid (12239-15-5)cannot be classified as reproductive toxicant.

Link to relevant study records

Reference

Endpoint:

screening for reproductive / developmental toxicity

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 v3.3 and the QMRF report has been attached.

Qualifier:

equivalent or similar to guideline

Guideline:

other: As mentioned below

Principles of method if other than guideline:

Prediction was done using OECD QSAR toolbox v3.3, 2017

GLP compliance:

not specified

Limit test:

no

Justification for study design:

No data available

Specific details on test material used for the study:

- Name of test material: 4-[(5-amino-3-methyl-1-phenyl-1H-pyrazol-4-yl)azo]-2,5-dichlorobenzenesulphonic acid / Acid Yellow 49
- IUPAC name: 4-[(5-amino-3-methyl-1-phenyl-1H-pyrazol-4-yl)azo]-2,5-dichlorobenzenesulphonic acid
- Molecular formula: C16H13Cl2N5O3S
- Molecular weight: 426.283 g/mole
- Smiles :n1(c2ccccc2)c(c(\N=N\c2c(cc(S(O)(=O)=O)c(c2)Cl)Cl)c(n1)C)N
- Inchl: 1S/C16H13Cl2N5O3S/c1-9-15(16(19)23(22-9)10-5-3-2-4-6-10)21-20-13-7-12(18)14(8-11(13)17)27(24,25)26/h2-8H,19H2,1H3,(H,24,25,26)/b21-20+
- Substance type: Organic
- Physical state: Solid powder (yellow)

Species:

rat

Strain:

Crj: CD(SD)

Details on species / strain selection:

No data available

Sex:

male/female

Details on test animals or test system and environmental conditions:

No data available

Route of administration:

oral: gavage

Vehicle:

not specified

Details on exposure:

No data available

Details on mating procedure:

No data available

Analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

42 days

Frequency of treatment:

Daily

Details on study schedule:

No data available

Dose / conc.:

563.33 mg/kg bw/day (nominal)

No. of animals per sex per dose:

No data available

Control animals:

not specified

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

Reproductive indices:

No data available

Offspring viability indices:

No data available

Clinical signs:

not specified

Dermal irritation (if dermal study):

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

Histopathological findings: non-neoplastic:

not specified

Histopathological findings: neoplastic:

not specified

Other effects:

no effects observed

Reproductive function: oestrous cycle:

not specified

Reproductive function: sperm measures:

not specified

Reproductive performance:

no effects observed

Dose descriptor:

NOAEL

Effect level:

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

Based on:

test mat.

Sex:

male/female

Basis for effect level:

reproductive performance

Remarks on result:

other: No effects on reproductive parameters was 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:

not specified

Dermal irritation (if dermal study):

not specified

Mortality / viability:

no mortality observed

Body weight and weight changes:

no effects observed

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:

NOAEL

Generation:

F1

Effect level:

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

Based on:

test mat.

Sex:

not specified

Basis for effect level:

mortality

body weight and weight gain

Remarks on result:

other: overall no developmental toxic effects was 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

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

Domain logical expression index: "a"

Referential boundary: The target chemical should be classified as Acid moiety OR Anilines (Unhindered) OR Pyrazoles/Pyrroles by Aquatic toxicity classification by ECOSAR ONLY

Domain logical expression index: "b"

Referential boundary: The target chemical should be classified as SNAr OR SNAr >> Nucleophilic aromatic substitution OR SNAr >> Nucleophilic aromatic substitution >> Activated halo-benzenes by Protein binding by OECD ONLY

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 >> Primary (unsaturated) heterocyclic amine 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 1,1-Diaminoalkene derivative [C=C(N)N]  AND Aliphatic Carbon [CH] AND Aliphatic Carbon [-CH2-] AND Aliphatic Carbon [-CH3] AND Aliphatic Nitrogen, one aromatic attach [-N] AND Aromatic Carbon [C] AND Aromatic Nitrogen, five-member ring AND Azo [-N=N-] AND Azomethine, aliphatic attach [-N=C] AND Chlorine, aromatic attach [-Cl] AND Chlorine, olefinic attach [-Cl] AND Hydrazine [>N-N<] AND Hydroxy, sulfur attach [-OH] AND Miscellaneous sulfide (=S) or oxide (=O) AND Nitrogen, two or tree olefinic attach [>N-] AND Olefinic carbon [=CH- or =C<] AND Suflur {v+4} or {v+6} AND Sulfinic acid [-S(=O)OH] AND Sulfonate, aromatic attach [-SO2-O] by Organic functional groups (US EPA)

Domain logical expression index: "e"

Referential boundary: The target chemical should be classified as Aliphatic Sulfur, two aromatic attach by Organic functional groups (US EPA)

Domain logical expression index: "f"

Parametric boundary:The target chemical should have a value of log Kow which is >= -2.08

Domain logical expression index: "g"

Parametric boundary:The target chemical should have a value of log Kow which is <= 2.02

Conclusions:

In reproductive toxicity study, NOAEL was estimated to be 563.0mg/kg bw. When male and female Crj: CD(SD) rats were exposed with 4-[(5-amino-3-methyl-1-phenyl-1H-pyrazol-4-yl)azo]-2,5-dichlorobenzenesulphonic acid (12239-15-5)orally.

Executive summary:

The reproductive toxicity of 4-[(5-amino-3-methyl-1-phenyl-1H-pyrazol-4-yl)azo]-2,5-dichlorobenzenesulphonic acid (12239-15-5)was estimated by SSS (2017) using OECD QSAR toolbox v3.4with log kow as the primary descriptor andNOAEL was estimated to be 563.0mg/kg bw. When male and female Crj: CD(SD) rats were exposed with 4-[(5-amino-3-methyl-1-phenyl-1H-pyrazol-4-yl)azo]-2,5-dichlorobenzenesulphonic acid (12239-15-5)orally.

Effect on fertility: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

563 mg/kg bw/day

Study duration:

subacute

Species:

rat

Quality of whole database:

Data is Klimicsh 2 and from QSAR Toolbox 3.3. (2017)

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-amino-3-methyl-1-phenyl-1H-pyrazol-4-yl)azo]-2,5-dichlorobenzenesulphonic acid (12239-15-5) 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-amino-3-methyl-1-phenyl-1H-pyrazol-4-yl)azo]-2,5-dichlorobenzenesulphonic acid (12239-15-5).The predicted data using the OECD QSAR toolbox has also been compared with the experimental studies performed on structurally similar read across substance.

The reproductive toxicity of 4-[(5-amino-3-methyl-1-phenyl-1H-pyrazol-4-yl)azo]-2,5-dichlorobenzenesulphonic acid (12239-15-5)was estimated by SSS (2017) using OECD QSAR toolbox v3.4with log kow as the primary descriptor and NOAEL was estimated to be 563.0mg/kg bw. When male and female Crj: CD(SD) rats were exposed with 4-[(5-amino-3-methyl-1-phenyl-1H-pyrazol-4-yl)azo]-2,5-dichlorobenzenesulphonic acid (12239-15-5)orally.

Further supported by experimental study conducted byJ-check (Ministry of Health, Labour and Welfare", "Ministry of the Environment" and "National Institute of Technology and Evaluation, J-check- 2010)on functionally similar read across substance 4,4'-diamino-2,2'-stilbenedisulfonic acid (81-11-8). In a Preliminary Reproduction Toxicity Screening Test, Crj:CD (SD) male and female rat were treated with 4,4'-diamino-2,2'-stilbenedisulfonic acid in the concentration of 0 (vehicle), 40, 200, 1000 mg/kg/day orally by gavage in 0.5% Sodium Carboxymethyl Cellulose solution for 41 days in male and from 14 days before mating to Day 3 of lactation in female. one male rat died after the start of administration on the fourth day at 200 mg/kg bw, and as a result of necropsy, perforation was found in the lung, so it was judged to be death due to administration error. No clinical sign and body weight change were observed. Significant increase in food consumption of male rats was observed at 1000 mg/kg bw from the start of administration to the 14th day, but after that, the values were similar to those of the control group, and no significant difference was observed. In females, no significant change was observed throughout the entire period. Similarly, No effects on reproductive parameters including the number of estrous cycle, copulation index, fertility index, gestation length, number of corpora lutea or implantations, implantation index, gestation index, delivery index, parturition or maternal behaviour, numbers of offspring or live offspring, sex ratio and the live birth index were observed as compared to control. No significant effect on survival rat, clinical sign and body weight at day 0 and day 4 and weight gain of pups as compared to control. In addition, No effect on absolute and relative testis and epididymis weight of male rats were observed as compared to control. Miniaturization of bilateral testes was observed in each case of 40 and 1000 mg / kg male rats. Atrophy of seminiferous tubules in bilateral testes were observed in 1 male control and testis miniaturization of 2 males at 1000 mg/kg bw, but it was judged as random change from the expression frequency did. No histological changes were found in the epididymal, non-mating and non-pregnant animals ovaries. No abnormalities were observed in both surviving animals and dead pups. Therefore, NOAEL was considered to be 1000 mg/kg/day for P and F1 generation when Crj:CD (SD) male and female rats treated with 4,4'-diamino-2,2'-stilbenedisulfonic acid orally by gavage.

Further supported by   experimental study conducted by OECD SIDS(SIDS Initial Assessment Report For BARIUM BIS[2-CHLORO-5(HYDROXY-1-NAPHTHYL)AZOTOLUENE-4-SULPHONATE, 1999)on functionally similar read across substance D & C Red No. 9 (pigment red 53:1) (5160-02-1). In reproductive and developmental toxicity study, male and female charles river CD rats were treated with D & C Red No. 9 (pigment red 53:1) in dose concentration 0,1000mg/kg orally. The test material mixed with basal diets. The animals were 35 days of age when treatment was initiated. After nine weeks of treatment, the animals were mated by pairing for seven days. The effect of test material for the in-utero phase was evaluated via mortality, clinical observations, body weight, food consumption, sex ratio, pup viability data and gross necropsy observations on selected animals. Compound consumption was judged to cause orange discoloration of the animals and their feces and an enlargement of their spleens during the in-utero and chronic phases. The chronic phase revealed non-neoplastic compound related effects which included a significant decrease in the red blood cell parameters (red blood cell count, packed cell volume and haemoglobin per cent) and an increase in the reticulocyte count observed after 3, 6, 12, 18 and 24 months of treatment. Compound consumption was judged to be associated with a significant increase in spleen weight, and the following non-neoplastic lesions of the spleen; extramedullary haematopoiesis, congestion, fibrosis, haemosiderosis, mesothelial hyperplasia, mesothelial cyst formation, capsular fibrosis and multifocal cellular proliferations in the capsule. The accumulation of haemsiderin in some other organs of the treated rats also suggest a compound-related effect. The combination of decreased red cell parameters, reticulocytosis and haemosiderosis supports the hypothesis that there was a compound related decreased erythrocyte survival and a haematopoietic response to that decreased red cell survival. There was no evidence for an impairment of reproductive functions in animals. No effect on fertility indices, gestation anomalies, viability and survival of the pups were observed in treated rats as compared to control. Hence, NOAEL was considered to be 1000mg/kg bw/day as no effects on reproductive and developmental parameters were observed. When male and female charles river CD rats were treated with D & C Red No. 9 (pigment red 53:1)(5160-02-1)orally.

Thus, based on the above predictions and experimental study of 4-[(5-amino-3-methyl-1-phenyl-1H-pyrazol-4-yl)azo]-2,5-dichlorobenzenesulphonic acid (12239-15-5)and its functionally similar read across substance, No Observed Adverse Effect Level (NOAEL) was considered to be 563.0mg/kg bw Thus, comparing this value with the criteria of CLP regulation 4-[(5-amino-3-methyl-1-phenyl-1H-pyrazol-4-yl)azo]-2,5-dichlorobenzenesulphonic acid (12239-15-5)cannot be classified as reproductive toxicant.

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

Thus, comparing this value with the criteria of CLP regulation 4-[(5-amino-3-methyl-1-phenyl-1H-pyrazol-4-yl)azo]-2,5-dichlorobenzenesulphonic acid (12239-15-5)cannot be classified as reproductive toxicant.