5-amino-2-methoxybenzenesulphonic acid

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Description of key information

The NOAEL was estimated to be 660.5 mg/kg bw when rats were orally exposed with 5-amino-2-methoxybenzene-1-sulfonic acid. 

Thus, as per criteria of CLP regulation, 5-amino-2-methoxybenzene-1-sulfonic acid 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 3.3 and the supporting QMRF report has been attached

Qualifier:

according to guideline

Guideline:

other: as below

Principles of method if other than guideline:

Prediction is done using QSAR Toolbox version 3.3

GLP compliance:

not specified

Limit test:

no

Specific details on test material used for the study:

Name: 5-amino-2-methoxybenzenesulphonic acid
SMILES:O=S(=O)(O)c1c(OC)ccc(N)c1
InChI:1S/C7H9NO4S/c1-12-6-3-2-5(8)4-7(6)13(9,10)11/h2-4H,8H2,1H3,(H,9,10,11)
Molecular Weight: 203.217 g/mole
Mol. formula: C7H9NO4S

Species:

rat

Strain:

Wistar

Sex:

male/female

Route of administration:

oral: gavage

Type of inhalation exposure (if applicable):

not specified

Vehicle:

water

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:

8-9 weeks

Frequency of treatment:

Daily

Details on study schedule:

not specified

Dose / conc.:

660.5 mg/kg bw/day

No. of animals per sex per dose:

12

Control animals:

yes, concurrent vehicle

Details on study design:

not specified

Positive control:

not specified

Parental animals: Observations and examinations:

not specified

Oestrous 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:

no effects observed

Food consumption and compound intake (if feeding study):

no effects observed

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:

no effects observed

Histopathological findings: neoplastic:

not specified

Other effects:

no effects observed

Reproductive function: oestrous cycle:

not specified

Reproductive function: sperm measures:

not specified

Reproductive performance:

not specified

Dose descriptor:

NOAEL

Effect level:

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

Based on:

test mat.

Sex:

male/female

Basis for effect level:

body weight and weight gain

food consumption and compound intake

organ weights and organ / body weight ratios

gross pathology

histopathology: non-neoplastic

other: No effect observed

Remarks on result:

other: No reprotoxicity 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:

no effects observed

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:

other: not specified

Generation:

other: not specified

Based on:

not specified

Sex:

not specified

Basis for effect level:

other: not specified

Remarks on result:

other: No reprotoxicity 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 5 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 Anilines (Acute toxicity) by US-EPA New Chemical Categories

Domain logical expression index: "b"

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

Domain logical expression index: "c"

Referential boundary: The target chemical should be classified as Acid moiety AND Anilines (Unhindered) 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 OECD

Domain logical expression index: "e"

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

Domain logical expression index: "f"

Parametric boundary:The target chemical should have a value of log Kow which is >= -2.09

Domain logical expression index: "g"

Parametric boundary:The target chemical should have a value of log Kow which is <= 4.11

Conclusions:

NOAEL was estimated to be 660.5 mg/kg bw when rats were orally exposed with 5-amino-2-methoxybenzene-1-sulfonic acid.

Executive summary:

In a prediction done by SSS (2017) using the OECD QSAR toolbox with log kow as the primary descriptor, the reproductive toxicity was estimated for 5-amino-2-methoxybenzene-1-sulfonic acid. The NOAEL was estimated to be 660.5 mg/kg bw when rats were orally exposed with 5-amino-2-methoxybenzene-1-sulfonic acid. 

Effect on fertility: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

660.5 mg/kg bw/day

Study duration:

subchronic

Species:

rat

Quality of whole database:

Data is from Klimisch 2 and from 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, 5-amino-2-methoxybenzene-1-sulfonic acid has been investigated for reproductive oral 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 5-amino-2-methoxybenzene-1-sulfonic acid along with the study available on structurally similar read across substance 2- Amino-5-Methylbenzenesulfonic Acid (CAS no 88-44-8) and 4,4'-diamino-2,2'-stilbenedisulfonic acid (CAS no 81-11-8 ). 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 reproductive toxicity was estimated for 5-amino-2-methoxybenzene-1-sulfonic acid. The NOAEL was estimated to be 660.5 mg/kg bw when rats were orally exposed with 5-amino-2-methoxybenzene-1-sulfonic acid. 

In another experimental study conducted by Ministry of Health, Labour, Welfare and Environment J-CHECK - (2016) for read across substance 2- Amino-5-Methylbenzenesulfonic Acid (CAS no 88-44-8),Crj: CD (SD) male and female rats by using2- Amino-5-Methylbenzenesulfonic Acid in the concentration of 0, 100, 300 and 1000 mg/kg/bw/day orally by gavage in Sesame oil. No effect on survival of treated male and female rats were observed. In amle rats, ocular secretion in 1 rat at 100 mg /kg, hair loss in 1 rat at 300 mg /kg and Crust and hair loss were observed in 1 in case at 1000 mg/kg. In female rats, hair removal was observed in 100 mg/kg group through pregnancy and nursing periods, and in the control group, all the dead animals were found in 2 cases. No clinical signs were observed in treated male and female rats due to treatment as compared to control.In female rats, at 100 and 1000 mg / kg, statistically significant decrease in body weight only at 4th day of nursing was observed as compared to the control. However, since there was no obvious difference on the other measurement days and it was a change only for 1 day, and since there was no obvious change in body weight gain during the nursing period, the influence of administration of the test substance It was not thought to be an accidental change.In male rats, statistically significant increase in food consumption from 8 to 15 days cumulative food intake from 1 to 15 days were observed at 1000 mg / kg bw and in female rats, no significant effect was observed as compared to control. Similarly, no reproductive toxic effect were observed onestrous cycle, corpus luteums, number of implantation traces, number of births and number of stillborn, gestation index, implantation rate, delivery rate, livebirth rate and mating rate of treated rats as compared to control. In addition,statistically significant decrease in absolute weights of epididymiswere observedin male rats but no effect on relative weight of epididymis were observed at 300 and 1000 mg/kg bw as compared to contorl.No significant changes were observed intesticular weigth of treated male rats as compared to control. In male rats, black lesions on lung in 1 animal, red spots of the liver, testis, epididymis and thinning of the coat in 1 case of the same individual gropue were observed at 300 mg/kg bw and thinning of the coat 1 case of the same individual gropue were observed at 1000 mg/kg bw. In female rats, black spots in lung stomach ulcers and white spots of the adrenal glands in 1 case each at 1000 mg/kg bw and ovary cyst and coat thinning were observed in 1 case each at 100 mg/kg bw. No findings that could be attributed to administration of the test substance were observed in any of the animals. In male rats, one case skin erosion and squamous epithelium hyperplasia and cell infiltration of epididymis at 1000 mg / kg, seminiferous tubular, testicular and epididymal atrophy of testes, stromal cell proliferation, spermatozoa of epididymis, lung inflammation and liver necrosis at 300 mg / kg were observed. However, since it is low frequency expression, it was not considered to be influence of the test substance. In female rats, 1 case of the lung inflammation, 1 case of the stomach ulcer, 1 part of the adrenal cortex and atrophy of the thymus at 1000 mg/kg bw, 1 case of atrophy of the thymus at 300 mg/kg bw and Young yolk sac cysts in one case, inflammatory infiltration of the skin and squamous epithelium proliferation were observed in one at 100 mg/kg bw, spontaneously delivered, so it was considered that there was no effect on the ovaries of the test substance. Atrophy of the thymus and purulent inflammation of the uterus were observed in one case in all the dead animals. No abnormal findings were observed in the other case. Therefore, NOAEL was considered to be 1000 mg/kg bw for P and F1 generation when Crj: CD (SD) male and female rats were treated with2- Amino-5-Methylbenzenesulfonic Acid orally by gavage inSesame oil for 28 days.

Further in a similar source study given for read across substance 2- Amino-5-Methylbenzenesulfonic Acid (CAS no 88-44-8), Crj: CD (SD) male and female rats by using 2- Amino-5-Methylbenzenesulfonic Acid in the concentration of 0, 100, 300 and 1000 mg/kg/bw/day orally by gavage in Sesame oil for 28 days. No effect on survival and clinical signs were observed in treated male and female rats as compared to control. No significant effects on body weight and body weight gain and food consumption were observed in treated male and female rats as compared to control. Significant decrease in white blood cell count was observed in males as compared to control. Decrease in white blood cell count was mainly due to the decrease in lymphocytes in view of the percentage of white blood cells at 1000 mg/kg bw. Significant decrease in total cholesterol in male, and significant increase in GPT and significant decreases in blood glucose were observed in female at 1000 mg/kg bw and significant decreases in blood glucose were observed in female rats at 100 mg/kg bw. Reduction in blood glucose was not observed in the 300 mg / kg bw and was a lack of dose correlation, but the value in the 1000 mg / kg group was clearly lower than that in the control group. Significant increase in specific gravity and decrease in pH were observed in male rats at 1000 mg/kg bw as compared to control. No significant change in hematology, clinical chemistry and Urinanalysis was observed in recovery group at 1000 mg/kg bw. Similarly, significant decrease in absolute and relative weights of thymus and significant increase in relative weight of spleen were observed in female rats at 100 mg/kg bw and significant increase in relative weight of spleen were observed in female rats at 300 and 1000 mg/kg bw, but the observed effects were dose dependent and considered as non significant. No significant changes were observed in testis, epididymis, and prostate and ovaries weigth of treated male and femlae rats as compared to control. In addition, Mild dilatation due to cecal contents retention was observed in each male and female rats but in recovery, no change in the cecum were observed at 1000 mg/kg bw. Mild changes in the lung, liver, pancreas, kidney and prostate were observed in the control group and 1000 mg / kg bw group, but findings that were sporadic and did not show dose correlation and were judged to be accidental changes. No gross pathological and histopathological changes were observed in testicle, epididymis, seminal vesicle, ovary and vagina of 1000 mg/kg bw treated male and female rats were observed as compared to control. Therefore, NOAEL was considered to be 1000 mg/kg bw for P generation when Crj: CD (SD) male and female rats were treated with 2- Amino-5-Methylbenzenesulfonic Acid orally by gavage in Sesame oil for 28 days.

Again supported by 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 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 behavior, 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.

Thus, based on the above study and predictions on 5-amino-2-methoxybenzene-1-sulfonic acid and its read across substances, it can be concluded that NOAEL value is 660.5 mg/kg bw with no effect on reproduction. Thus, as per criteria of CLP regulation, 5-amino-2-methoxybenzene-1-sulfonic acid 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 study and predictions on 5-amino-2-methoxybenzene-1-sulfonic acid and its read across substances, it can be concluded that NOAEL value is 660.5 mg/kg bw with no effect on reproduction. Thus, as per criteria of CLP regulation, 5-amino-2-methoxybenzene-1-sulfonic acid can be not classified for reproductive toxicity.