m-(4,5-dihydro-5-imino-3-methyl-1H-pyrazol-1-yl)benzenesulphonic acid

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Description of key information

Toxicity to reproduction

The reproductive toxicity of 3-(5-imino-3-methyl-4,5-dihydro-1H-pyrazol-1-yl)benzene-1-sulfonic acid (68083-38-5)was estimated by SSS (2017) using OECD QSAR toolbox v3.4 with log kow as the primary descriptor and NOAEL was estimated to be 794.84 mg/kg bw. When male and female wistar rats were exposed with 3-(5-imino-3-methyl-4,5-dihydro-1H-pyrazol-1-yl)benzene-1-sulfonic acid (68083-38-5) orally.

Thus, based on the above predictions and experimental study of 3-(5-imino-3-methyl-4,5-dihydro-1H-pyrazol-1-yl)benzene-1-sulfonic acid (68083-38-5) and its structurally similar read across substance, No Observed Adverse Effect Level (NOAEL) was considered to be 794.84 mg/kg bw Thus, comparing this value with the criteria of CLP regulation 3-(5-imino-3-methyl-4,5-dihydro-1H-pyrazol-1-yl)benzene-1-sulfonic acid (68083-38-5)cannot be classified as reproductive toxicant.

 

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 from OECD QSAR toolbox v3.4 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 v3.4, 2018

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: m-(4,5-dihydro-5-imino-3-methyl-1H-pyrazol-1-yl)benzenesulphonic acid
- IUPAC name: 3-(5-imino-3-methyl-4,5-dihydro-1H-pyrazol-1-yl)benzene-1-sulfonic acid
- Molecular formula: C10H11N3O3S
- Molecular weight: 253.281 g/mole
- Smiles: O=S(=O)(O)c1cccc(N2N=C(CC2=N)C)c1
- Inchl: 1S/C10H11N3O3S/c1-7-5-10(11)13(12-7)8-3-2-4-9(6-8)17(14,15)16/h2-4,6,11H,5H2,1H3,(H,14,15,16)
- Substance type: Organic
- Physical state: Solid

Species:

rat

Strain:

Wistar

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

Type of inhalation exposure (if applicable):

other: NOT_SPECIFIED

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:

13 weeks

Frequency of treatment:

Daily

Details on study schedule:

No data available

Dose / conc.:

794.84 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:

no effects observed

Histopathological findings: non-neoplastic:

not specified

Histopathological findings: neoplastic:

not specified

Other effects:

not specified

Reproductive function: oestrous cycle:

not specified

Reproductive function: sperm measures:

not specified

Reproductive performance:

no effects observed

Dose descriptor:

NOAEL

Effect level:

794.84 mg/kg bw/day

Based on:

test mat.

Sex:

male/female

Basis for effect level:

reproductive performance

Remarks on result:

other: overall no effects on reproductive performance

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:

no mortality observed

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:

no effects observed

Histopathological findings:

not specified

Other effects:

not specified

Behaviour (functional findings):

not specified

Developmental immunotoxicity:

not specified

Dose descriptor:

NOAEL

Generation:

F1

Effect level:

794.84 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

clinical signs

mortality

gross pathology

Remarks on result:

other: overall no developmental toxic effects 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

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" )  and ("e" and ( not "f") )  )  and ("g" and ( not "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" )  and ("u" and ( not "v") )  )  and ("w" and ( not "x") )  )  and ("y" and ( not "z") )  )  and ("aa" and ( not "ab") )  )  and "ac" )  and ("ad" and ( not "ae") )  )  and ("af" and "ag" )  )

Domain logical expression index: "a"

Referential boundary: The target chemical should be classified as Aromatic compound OR Heterocyclic compound OR Sulfonic acid OR Sulfonic acid derivative by Organic functional groups, Norbert Haider (checkmol) ONLY

Domain logical expression index: "b"

Referential boundary: The target chemical should be classified as Aliphatic Carbon [CH] OR Aliphatic Carbon [-CH2-] OR Aliphatic Carbon [-CH3] OR Aliphatic Nitrogen, one aromatic attach [-N] OR Aromatic Carbon [C] OR Azomethine, aliphatic attach [-N=C] OR Hydrazine [>N-N<] OR Hydroxy, sulfur attach [-OH] OR Miscellaneous sulfide (=S) or oxide (=O) OR Nitrogen, two or tree olefinic attach [>N-] OR Olefinic carbon [=CH- or =C<] OR Suflur {v+4} or {v+6} OR Sulfinic acid [-S(=O)OH] OR Sulfonate, aromatic attach [-SO2-O] by Organic functional groups (US EPA) ONLY

Domain logical expression index: "c"

Referential boundary: The target chemical should be classified as Amidine OR Aryl OR Overlapping groups OR Sulfonic acid OR Unsaturated heterocyclic amine OR Unsaturated heterocyclic fragment by Organic Functional groups (nested) ONLY

Domain logical expression index: "d"

Referential boundary: The target chemical should be classified as Amidine OR Aryl OR Sulfonic acid OR Unsaturated heterocyclic amine OR Unsaturated heterocyclic fragment by Organic Functional groups ONLY

Domain logical expression index: "e"

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

Domain logical expression index: "f"

Referential boundary: The target chemical should be classified as Non binder, impaired OH or NH2 group by Estrogen Receptor Binding

Domain logical expression index: "g"

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

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, without OH or NH2 group by Estrogen Receptor Binding

Domain logical expression index: "j"

Referential boundary: The target chemical should be classified as Weak binder, NH2 group by Estrogen Receptor Binding

Domain logical expression index: "k"

Referential boundary: The target chemical should be classified as Benzene/ Naphthalene sulfonic acids (Less susceptible) Rank C by Repeated dose (HESS)

Domain logical expression index: "l"

Referential boundary: The target chemical should be classified as 3-Methylcholantrene (Hepatotoxicity) Alert by Repeated dose (HESS)

Domain logical expression index: "m"

Referential boundary: The target chemical should be classified as Benzene/ Naphthalene sulfonic acids (Less susceptible) Rank C by Repeated dose (HESS)

Domain logical expression index: "n"

Referential boundary: The target chemical should be classified as Aromatic hydrocarbons (Liver enzyme induction) Rank C by Repeated dose (HESS)

Domain logical expression index: "o"

Referential boundary: The target chemical should be classified as Benzene/ Naphthalene sulfonic acids (Less susceptible) Rank C by Repeated dose (HESS)

Domain logical expression index: "p"

Referential boundary: The target chemical should be classified as Chlorphentermine (Hepatotoxicity) Alert by Repeated dose (HESS)

Domain logical expression index: "q"

Referential boundary: The target chemical should be classified as Benzene/ Naphthalene sulfonic acids (Less susceptible) Rank C by Repeated dose (HESS)

Domain logical expression index: "r"

Referential boundary: The target chemical should be classified as Perhexiline (Hepatotoxicity) Alert OR Tamoxifen (Hepatotoxicity) Alert by Repeated dose (HESS)

Domain logical expression index: "s"

Similarity boundary:Target: CC1CC(=N)N(c2cccc(S(O)(=O)=O)c2)N=1
Threshold=30%,
Dice(Atom centered fragments)
Atom type; Count H attached; Hybridization

Domain logical expression index: "t"

Similarity boundary:Target: CC1CC(=N)N(c2cccc(S(O)(=O)=O)c2)N=1
Threshold=20%,
Dice(Atom centered fragments)
Atom type; Count H attached; Hybridization

Domain logical expression index: "u"

Referential boundary: The target chemical should be classified as (!Undefined)Group All Lipid Solubility < 0.01 g/kg AND (!Undefined)Group CNS Surface Tension > 62 mN/m AND Group All Melting Point > 200 C AND Group CNS log Kow < 0.5 AND Group CNS Melting Point > 120 C AND Group CNS Melting Point > 50 C by Skin irritation/corrosion Exclusion rules by BfR

Domain logical expression index: "v"

Referential boundary: The target chemical should be classified as Group C Aqueous Solubility < 0.0001 g/L by Skin irritation/corrosion Exclusion rules by BfR

Domain logical expression index: "w"

Referential boundary: The target chemical should be classified as Inclusion rules not met by Eye irritation/corrosion Inclusion rules by BfR

Domain logical expression index: "x"

Referential boundary: The target chemical should be classified as Subststituted pyrazoles by Eye irritation/corrosion Inclusion rules by BfR

Domain logical expression index: "y"

Referential boundary: The target chemical should be classified as (!Undefined)Group All Lipid Solubility < 0.01 g/kg AND Group All Melting Point > 200 C AND Group CNS Melting Point > 200 C AND Group CNS Melting Point > 50 C by Eye irritation/corrosion Exclusion rules by BfR

Domain logical expression index: "z"

Referential boundary: The target chemical should be classified as Group C Aqueous Solubility < 0.0005 g/L by Eye irritation/corrosion Exclusion rules by BfR

Domain logical expression index: "aa"

Referential boundary: The target chemical should be classified as (!Undefined)Group All Lipid Solubility < 0.01 g/kg AND Group All Melting Point > 200 C AND Group CNS Melting Point > 200 C AND Group CNS Melting Point > 50 C by Eye irritation/corrosion Exclusion rules by BfR

Domain logical expression index: "ab"

Referential boundary: The target chemical should be classified as Exclusion rules not met by Eye irritation/corrosion Exclusion rules by BfR

Domain logical expression index: "ac"

Referential boundary: The target chemical should be classified as Very fast by Bioaccumulation - metabolism half-lives ONLY

Domain logical expression index: "ad"

Referential boundary: The target chemical should be classified as No Data by Ultimate biodeg

Domain logical expression index: "ae"

Referential boundary: The target chemical should be classified as 10 to 100 days by Ultimate biodeg

Domain logical expression index: "af"

Parametric boundary:The target chemical should have a value of log Kow which is >= -4.28

Domain logical expression index: "ag"

Parametric boundary:The target chemical should have a value of log Kow which is <= 5.26

Conclusions:

In reproductive toxicity study, NOAEL was estimated to be 794.84 mg/kg bw. When male and female wistar rats were exposed with 3-(5-imino-3-methyl-4,5-dihydro-1H-pyrazol-1-yl)benzene-1-sulfonic acid (68083-38-5)orally.

Executive summary:

The reproductive toxicity of 3-(5-imino-3-methyl-4,5-dihydro-1H-pyrazol-1-yl)benzene-1-sulfonic acid (68083-38-5) was estimated by SSS (2017) using OECD QSAR toolbox v3.4 with log kow as the primary descriptor and NOAEL was estimated to be 794.84 mg/kg bw. When male and female wistar rats were exposed with 3-(5-imino-3-methyl-4,5-dihydro-1H-pyrazol-1-yl)benzene-1-sulfonic acid (68083-38-5)orally.

Effect on fertility: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

794.84 mg/kg bw/day

Study duration:

subchronic

Species:

rat

Quality of whole database:

Data is Klimicsh 2 and from QSAR Toolbox 3.4. (2018)

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 3-(5-imino-3-methyl-4,5-dihydro-1H-pyrazol-1-yl)benzene-1-sulfonic acid (68083-38-5) 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 3-(5-imino-3-methyl-4,5-dihydro-1H-pyrazol-1-yl)benzene-1-sulfonic acid (68083-38-5).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 3-(5-imino-3-methyl-4,5-dihydro-1H-pyrazol-1-yl)benzene-1-sulfonic acid (68083-38-5)was estimated by SSS (2017) using OECD QSAR toolbox v3.4 with log kow as the primary descriptor and NOAEL was estimated to be 794.84 mg/kg bw. When male and female wistar rats were exposed with 3-(5-imino-3-methyl-4,5-dihydro-1H-pyrazol-1-yl)benzene-1-sulfonic acid (68083-38-5) orally.

Further supported by experimental study conducted byU. S. Environmental Protection Agency (EPA) Office of Pollution Prevention and Toxic Substances (OPPTS)(U. S. Environmental Protection Agency, Hazard Characterization Document, March, 2015) on structurally similar read across substance Sulfanilic acid (121-57-3). In a Reproduction Toxicity Screening Test, wistar male and female rat were treated with Sulfanilic acid (121-57-3)in the dose concentration of0 (water), 62.5 (50), 250 and 1000 mg/kg-bw orally by gavage in water .12 males and 12 females were placed in each dose group. Males were dosed daily for a minimum of four weeks, including a minimum of two weeks prior to mating and continued throughout the mating period until the study was terminated. Females were dosed two weeks prior to mating, until conception, throughout pregnancy and at least four days after delivery. Females showing no evidence of copulation were re-grouped with proven sires for a second mating phase. All the animals were observed for Survival, general condition, body weights, food and water consumption. At the end of the in-life phase, gross necropsy was performed, with organ mass recorded, tissues and organs preserved and processed histologically. A histopathological examination was conducted on samples from the 1000mg/kg-bw/day dose groups and the vehicle groups. No mortality was observed in treated male and female rats as compared to control. Rats at the1000mg/kg-bw/day dose showed oronasal bleeding during the first week and occasionally throughout the study. No effects were seen on body mass as well as food and water consumption was noted. at gross necropsy, No changes in organ weights of reproductive organs were noted. Noteworthy were the statistically insignificant, mild effects on litter mass of the high dose group and on pre-implantation loss of the 250mg/kg-bw/day and 1000 mg/kg-bw/day dose group. Similarly there was a mild tendency of relatively low total numbers of pups born with increasing test item dosage and a low mean number of live pups per dam at day 4 post-partum. Hence NOAEL was considered to be 1000 mg/kg/day for P generation and LOAEL was considered to be 250 mg/kg bw /day for F1 generation, when male and female wistar rats treated with Sulfanilic acid (121-57-3) orally by gavage.

Further supported by experimental study conducted byHealth and Consumer Protection Directorate General(Opinion on Phenylbenzimidazole Sulfonic Acid and its Salts- Sccp/1056/06)on structurally similar read across substance2-Phenylbenzimidazole-5-sulfonic acid (CAS No.- 27503-81-7). The study was conducted to determine the reproductive toxicity potential of 2-Phenylbenzimidazole-5-sulfonic acid (CAS No.- 27503-81-7) when administered orally to rats. Virgin female rats were used for the study. Two dose groups (25 animals each) were used, one test- (1000 mg/kg bw) and one control group (0 mg/kg bw). They were dosed from day 6-15 post coitum and kept off-dose from day 16-19. There were no signs of toxicity in dams. Animals were sacrificed on day 20 and necropsied. Reproductive parameters were examined [viz.no. of corpora lutea, no. of implantations and resorptions (complete, early and late)]. Foetuses were weighed, inspected macroscopically for external malformations and prepared for inspection for visceral and skeletal malformations (by transverse section and double staining respectively). They did not show any such malformations. Skeletal variations were the same (nature and frequency) in test- and control group. No effect was observed on numbers of corpora lutea, implantation sites, and viable fetuses were found. Therefore, under the condition of this study, the no-observed-adverse-effect level (NOAEL) for dams and foetuses was considered to be 1000 mg/kg bw.

Thus, based on the above predictions and experimental study of 3-(5-imino-3-methyl-4,5-dihydro-1H-pyrazol-1-yl)benzene-1-sulfonic acid (68083-38-5) and its structurally similar read across substance, No Observed Adverse Effect Level (NOAEL) was considered to be 794.84 mg/kg bw Thus, comparing this value with the criteria of CLP regulation 3-(5-imino-3-methyl-4,5-dihydro-1H-pyrazol-1-yl)benzene-1-sulfonic acid (68083-38-5)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 3-(5-imino-3-methyl-4,5-dihydro-1H-pyrazol-1-yl)benzene-1-sulfonic acid (68083-38-5) cannot be classified as reproductive toxicant.