4-nitrotoluene-2-sulphonic acid

Endpoint summary

Key value for chemical safety assessment

Toxic effect type:

dose-dependent

Effects on fertility

Effect on fertility: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

700 mg/kg bw/day

Study duration:

subacute

Species:

rat

Effect on fertility: via inhalation route

Endpoint conclusion:

no study available

Effect on fertility: via dermal route

Endpoint conclusion:

no study available

Additional information

A Combined Repeat Dose Reproductive/Developmental Toxicity Screening Test according to OECD TG 422 in compliance with GLP is available to assess the reproductive toxicity of 4-nitrotoluene-2-sulphonic acid (GINC, Japan). In this study, the test substance was administered by gavage to 12 rats per sex and dose of 0, 175, 350 and 700 mg/kg.

In the test group of 700 mg/kg to male and female parents, there were no effects of the test substance on the estrous cycle, number of days required until copulation, as well as copulation rates. Additionally, there were neither histological changes in testes and epididymides nor abnormalities in staging of the seminiferous tubules, and there was no testicular toxicity to sperm production and development. In female animals, no abnormalities were found in the gestation period and parturition. There were no effects of the test substance on the numbers of corpora lutea and implantation sites, implantation rate, total number of live newborns, as well as birth and delivery rates. Further, no abnormalities were found in lactation behaviors after parturition. No effects on the fertilities of male and female parental animals were observed up to 700 mg/kg/day the highest dose tested. The NOEL for reproductive toxicity is considered to be 700 mg/kg/day, the highset dose tested, for parental males and females.

 

Furthermore, in the oral repeated dose toxicity study according to OECD 408 no test item-related effects were observed on testis.

Short description of key information:
4-nitrotoluene-2-sulphonic acid was tested in a Combined Repeat Dose Reproductive/Developmental Toxicity Screening Test by oral Administration in rats.
The NOELs for the reproductive/developmental toxicity are considered to be 700 mg/kg/day for parental males and females, and 350 mg/kg/day for pups. The NOAEL for maternal toxicity was determined to be 175 mg/kg/day.

Effects on developmental toxicity

Effect on developmental toxicity: via oral route

Endpoint conclusion:

adverse effect observed

Dose descriptor:

NOAEL

200 mg/kg bw/day

Study duration:

subacute

Species:

rat

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

A Dose Range Finding study on 4-nitrotoluene-2-sulphonic acid has been conducted for the subsequent Prenatal Developmental Toxicity study by oral gavage. No guidelines were applicable as this study was used for dose level selection purposes only. The folowing dose levels were applied: 500, 750 and 100 mg/kg bw/day. Based on mortality, severe clinical signs and body weight loss at 1000 and 750 mg/kg/day, selected dose levels for the Main study were 80, 200 and 500 mg/kg/day.

 

For the evaluation of the developmental toxicity of the substance a prenatal developmental study is available on the substance. It is performed as per the guideline OECD 414 and under GLP conditions.
The objectives of this study were to determine the potential of 4-nitrotoluene-2-sulphonic acid to induce developmental toxicity after maternal exposure during the critical period of organogenesis and to characterize maternal toxicity at the exposure levels tested when given orally by gavage to time-mated female Wistar Han rats from Days 6 to 20 post-coitum, inclusive. In addition, the No Observed Adverse Effect Levels (NOAELs) for maternal toxicity and developmental toxicity were evaluated.
The dose levels in this study were selected to be 0, 80, 200 and 500 mg/kg/day, based on the results of the Dose Range Finder.

A single female at 500 mg/kg/day was sacrificed before dosing on Day 15 post-coitum for humane reasons. Body weight loss, clinical signs (including labored breathing, hunched posture, erected fur and yellow feces), and low food consumption recorded for this animal were similar to the signs seen in the Dose Range Finding Study, in which  four females at 750 mg/kg/day and four females at 1000 mg/kg/day were euthanized before scheduled necropsy based on test item-related effects. Therefore, although these findings were recorded for a single high dose female only, the similarity of findings to those recorded in the Dose Range Finding Study made it conceivable that this preterm death was related to treatment with the test item. Therefore, this death was considered to represent an adverse effect of treatment with the test item.
In addition to the mortality observed at the high dose, 3/21 surviving females at 500 mg/kg/day were noted with abnormal breathing sounds. As this only occurred at the high dose and was in line with the results of the Dose Range Finding Study was considered test item-related. However, as this was a transient clinical sign, observed on single days only, this was considered to be non-adverse.

No test item-related changes were noted in any of the remaining maternal parameters investigated in this study (i.e., body weight, food consumption, thyroid hormone levels (triiodothyronine (T3), thyroxine (T4), thyroid-stimulating hormone (TSH)), thyroid gland weights, macroscopic evaluation, microscopic evaluation of the thyroid gland, uterine contents, corpora lutea, implantation sites and pre- and post-implantation loss).
No test item-related changes were noted in any of the developmental parameters investigated in this study (i.e. litter size, sex ratio, fetal body weights, anogenital distance, external, visceral and skeletal malformations, developmental variations and incidental findings).
In conclusion, based on the results of this prenatal developmental toxicity study in time-mated female Wistar Han rats the maternal No Observed Adverse Effect Levels (NOAELs) for 4-nitrotoluene-2-sulphonic acid was established as being 200 mg/kg/day. This was based on mortality of a single female at 500 mg/kg/day.
The developmental NOAEL for 4-nitrotoluene-2-sulphonic acid was established as being at least 500 mg/kg/day, in the absence of test item-related effects on the developmental parameters.

 

A second study, a combined Repeat Dose Reproductive/Developmental Toxicity Screening Test according to OECD TG 422 in compliance with GLP is available to assess the developmental toxicity of 4-nitrotoluene-2-sulphonic acid (GINC, Japan). In this study the test substance was administered by gavage to 12 rats per sex and dose of 0, 175, 350 and 700 mg/kg.

In the 700 mg/kg group no external anomalies were observed in pups. There were no effects of the test substance on the sex ratio, number of live pups, number of stillborns and live birth rate. However, in the 700 mg/kg group, there was a tendency towards low body weights in males and females, and towards low viability on day 4 of lactation. These changes were presumed to be secondary effects which arose from toxic changes during the gestation and lactation periods of the mother. The NOAEL for maternal toxicity was determined to be 175 mg/kg/day. 

 

 

Justification for classification or non-classification

Based on the available experimental data no classification as reproductive toxicant according to the CLP Regulation EC No.1272/2008 is proposed.