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Administrative data

Key value for chemical safety assessment

Effects on fertility

Description of key information

The NOAEL was estimated to be 605 mg/kg bw when Crl:CD(SD)IGS BR VAF/Plus female rats were orally exposed with 4-amino-N-(4-aminophenyl)benzene-1-sulfonamide.

Thus, as per criteria of CLP regulation, 4-amino-N-(4-aminophenyl)benzene-1-sulfonamide 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 3.4 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 3.4
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 : 4-amino-N-(4-aminophenyl)benzenesulphonamide
- Molecular formula : C12H13N3O2S
- Molecular weight : 263.32 g/mol
- Smiles notation : O=S(=O)(c1ccc(cc1)Nc1ccc(cc1)N)N
- InChl : 1S/C12H13N3O2S/c13-9-1-3-10(4-2-9)15-11-5-7-12(8-6-11)18(14,16)17/h1-8,15H,13H2,(H2,14,16,17)
- Substance type : Organic
- Physical state : Solid
Species:
rat
Strain:
other: Crl:CD(SD)IGS BR VAF/Plus
Sex:
female
Route of administration:
oral: gavage
Type of inhalation exposure (if applicable):
not specified
Vehicle:
CMC (carboxymethyl cellulose)
Remarks:
0.5%
Details on exposure:
not specified
Details on mating procedure:
not specified
Analytical verification of doses or concentrations:
not specified
Details on analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
15 days prior mating and for 17 days thereafter.
Frequency of treatment:
Daily
Details on study schedule:
not specified
Dose / conc.:
605 mg/kg bw/day (nominal)
No. of animals per sex per dose:
25 females
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:
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
Gross pathological findings:
not specified
Neuropathological findings:
not specified
Histopathological findings: non-neoplastic:
no effects observed
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:
605 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
histopathology: non-neoplastic
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:
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:
NOAEL
Generation:
F1
Effect level:
605 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
mortality
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 5 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" )  )

Domain logical expression index: "a"

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

Domain logical expression index: "b"

Referential boundary: The target chemical should be classified as SN1 AND SN1 >> Nitrenium Ion formation AND SN1 >> Nitrenium Ion formation >> Primary aromatic amine by DNA binding by OECD

Domain logical expression index: "c"

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

Domain logical expression index: "d"

Referential boundary: The target chemical should be classified as Acylation AND Acylation >> Acylation involving an activated (glucuronidated) sulfonamide group AND Acylation >> Acylation involving an activated (glucuronidated) sulfonamide group >> Arenesulfonamides AND AN2 AND AN2 >> Michael-type addition to quinoid structures  AND AN2 >> Michael-type addition to quinoid structures  >> Substituted Anilines AND AN2 >> Nucleophilic addition at polarized N-functional double bond AND AN2 >> Nucleophilic addition at polarized N-functional double bond >> Arenesulfonamides by Protein binding by OASIS v1.4

Domain logical expression index: "e"

Referential boundary: The target chemical should be classified as Amides AND Anilines (Unhindered) by Aquatic toxicity classification by ECOSAR

Domain logical expression index: "f"

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

Domain logical expression index: "g"

Referential boundary: The target chemical should be classified as Moderate binder, NH2 group OR Non binder, MW>500 OR Weak binder, NH2 group by Estrogen Receptor Binding

Domain logical expression index: "h"

Parametric boundary:The target chemical should have a value of log Kow which is >= -1.43

Domain logical expression index: "i"

Parametric boundary:The target chemical should have a value of log Kow which is <= 6.84

Conclusions:
NOAEL was estimated to be 605 mg/kg bw when Crl:CD(SD)IGS BR VAF/Plus female rats were orally exposed with 4-amino-N-(4-aminophenyl)benzene-1-sulfonamide.
Executive summary:

In a prediction done by SSS (2017) using the OECD QSAR toolbox with log kow as the primary descriptor, the acute oral toxicity was estimated for 4-amino-N-(4-aminophenyl)benzene-1-sulfonamide. The NOAEL was estimated to be 605 mg/kg bw when Crl:CD(SD)IGS BR VAF/Plus female rats were orally exposed with 4-amino-N-(4-aminophenyl)benzene-1-sulfonamide.

Effect on fertility: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
605 mg/kg bw/day
Study duration:
subchronic
Species:
rat
Quality of whole database:
Data is Klimisch 2 and OECD QSAR toolbox
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-amino-N-(4-aminophenyl) benzene-1-sulfonamide 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-amino-N-(4-aminophenyl)benzene-1-sulfonamide along with the study available on structurally similar read across substance 4,4'-Diamino-2,2'-stilbenedisulfonic acid (CAS no 81-11-8) and 1,3-Benzenediol (108-46-3). 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 acute oral toxicity was estimated for 4-amino-N-(4-aminophenyl)benzene-1-sulfonamide. The NOAEL was estimated to be 605 mg/kg bw when Crl:CD(SD)IGS BR VAF/Plus female rats were orally exposed with 4-amino-N-(4-aminophenyl)benzene-1-sulfonamide.

In another experimental study conducted by J-Check (Ministry of Health, Labour and Welfare", "Ministry of the Environment" and "National Institute of Technology and Evaluation, J-Check, 2010) on structurally similar read across substance 4,4'-Diamino-2,2'-stilbenedisulfonic acid (CAS no 81-11-8), Crj:CD (SD) male and female rats 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. At 200 mg / kg, one male died after the start of administration on the fourth day. At necropsy, perforation was found in the lung, so it was judged to be death due to administration error. No change was observed in general condition and body weight and weight gain were observed in treated rats as compared to control. In male rat at 1000 mg / kg, from the start of administration to the 14th day a significant increase in food consumption were observed, 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 effect was observed on estrous cycle, copulation index, fertility index, gestation length, number of corpora lutea or implantations, implantation index, gestation index, delivery index, parturition or maternal behavior were observed as compared to control of P generation. No significant change in both the actual weight and the body weight ratio in testis and epididymis were observed. Miniaturization of bilateral testes was observed in each case of 40 and 1000 mg / kg, 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 animal ovaries of p generation rats were observed as compared to control. In addition, No significant differences in numbers of offspring or live offspring, sex ratio, live birth index, viability index and body weight of pups were observed as compared to control. No abnormalities were observed in both surviving animals and dead animals as compared to control. 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 another experimental study given by United States Environmental Protection Agency (High Production Volume Information System (HPVIS)| OPPT | US EPA, 2017) on structurally similar read across substance 1,3-Benzenediol (108-46-3), Crj:CD (SD) male and female rats were treated with1,3-Benzenediolin the concentration of 0,12, 36, 100 and 300 mg/kg orally in drinking water. No mortality and change in general condition of P, F1 and F2 rats were observed as compared to control. Decreased in mean cumulative body weight gains were observed in P female during the pre-mating period or the entire generation in males at 300 mg/kg. There were no clear trends in mean weekly body weight gains in these males and females; however, mean body weights were decreased by up to 6.3% in P females from study day 56 through 70. Mean body weights in the 300 mg/kg P females were also decreased during the first week of gestation (up to 5.5%), throughout lactation (up to 8.4%) and after the lactation period ended (6.3%). Decreased mean cumulative body weight gains were observed in F1 males during the entire generation at 300 mg/kg. While there were no clear trends for weekly mean body weight gains, mean body weights in these males were decreased by up to 7.1% during the entire generation. Mean body weights were also reduced in the 300 mg/kg F1 females during lactation (up to 6.1%) and after the lactation period ended (up to 7.0%). Mean body weights and body weight gains were unaffected in the 12, 36 and 100 mg/kg P and F1 males and females. Similarly, Decreased mean water consumption was observed at 300 mg/kg F0 and F1 parental animals during the pre-mating period in females or the entire generation in males. Decreased mean water consumption of F1 pups gang housed by litter from PND 21 28. Water consumption was also often decreased in the 100 mg/kg males and females, although the decreases were less severe and the onset was later in the 300 mg/kg group. Mean water consumption in the 100 mg/kg was consistently reduced compared to the control beginning on study days 21-24; however, slight decreases were also noted inconsistently earlier in the pre-mating period. The decreased water consumption in the 100 mg/kg continued through the first week of gestation while the decreased water consumption in the 300 mg/kg females continued throughout gestation and lactation. Decreases in water consumption were not considered an adverse change due to the lack of associated effects on food intake and food utilization. No statistically significant effects on concentrations of T3, T4 or TSH were observed in P and F1 parental animals. No statistically significant effects on concentrations of T3, T4 or TSH were observed in F1 and F2 pups (PND 4 or PND 21). The higher TSH values were observed in the P males at the scheduled necropsy were not considered test article-related in the absence of effects on T3 or T4, organ weights or adverse macroscopic or microscopic findings. Test article-related decreased colloid within the thyroid glands of the 300 mg/kg P males was not considered adverse due to the lack of associated functional effects. In addition, no reproductive toxic effect were observed in P and F1 parental animals such as on estrous cycle, mean testicular and epididymal sperm numbers and sperm production rate, motility, progressive motility and morphology, mating and fertility indices, number of days between pairing and coitus, gestation length and parturition of treated rats were observed as compared to control. No significant change in organ weight of P and F1 parental animals. No gross pathological changes were observed in treated P, F1 and F2 male and female rats as compared to control. No histological changes were observed in treated male and female P and F1 rats. Therefore, NOAEL was considered to be 300 mg/kg for P, F1 and F2 generation when Crj:CD (SD) male and female rats treated with 1,3-Benzenediolorally in drinking water for 70 Days.

Thus, based on the above studies and predictions on 4-amino-N-(4-aminophenyl)benzene-1-sulfonamide and its read across substances, it can be concluded that NOAEL value is 605 mg/kg bw with no effect on reproduction. Thus, as per criteria of CLP regulation, 4-amino-N-(4-aminophenyl)benzene-1-sulfonamide 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 studies and predictions on 4-amino-N-(4-aminophenyl)benzene-1-sulfonamide and its read across substances, it can be concluded that NOAEL value is 605 mg/kg bw with no effect on reproduction. Thus, as per criteria of CLP regulation, 4-amino-N-(4-aminophenyl)benzene-1-sulfonamide can be Not classified for reproductive toxicity.