2-[(4-amino-3-methoxyphenyl)sulphonyl]ethyl hydrogen sulphate

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Description of key information

NOAEL was estimated to be 525 mg/kg bw when rats were orally exposed with 2-[(4-amino-3-methoxyphenyl) sulphonyl] ethyl hydrogen sulphate.  

Thus, as per criteria of CLP regulation, 2-[(4-amino-3-methoxyphenyl) sulphonyl]ethyl hydrogen sulphate 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

Qualifier:

according to guideline

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

Specific details on test material used for the study:

Name: 2-[(4-amino-3-methoxyphenyl)sulphonyl]ethyl hydrogen sulphate
SMILES:COc1cc(S(=O)(=O)CCOS(O)(=O)=O)ccc1N
InChI:1S/C9H13NO7S2/c1-16-9-6-7(2-3-8(9)10)18(11,12)5-4-17-19(13,14)15/h2-3,6H,4-5,10H2,1H3,(H,13,14,15)
Molecular Formula:C9H13NO7S2
Molecular Weight:311.3337 g/mole

Species:

rat

Strain:

other: Crl:CD(SD)IGS BR VAF/Plus

Sex:

male

Route of administration:

oral: gavage

Type of inhalation exposure (if applicable):

not specified

Vehicle:

CMC (carboxymethyl cellulose)

Analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

63 days

Frequency of treatment:

Daily

Details on study schedule:

not specified

Dose / conc.:

525 mg/kg bw/day

No. of animals per sex per dose:

25 males

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:

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:

not specified

Reproductive function: oestrous cycle:

not specified

Reproductive function: sperm measures:

not specified

Reproductive performance:

not specified

Dose descriptor:

NOAEL

Effect level:

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

Based on:

test mat.

Sex:

male

Basis for effect level:

other: No effect observed

Remarks on result:

other: No effect 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:

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

Sexual maturation:

not specified

Organ weight findings including organ / body weight ratios:

not examined

Gross pathological findings:

not specified

Histopathological findings:

not examined

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: not specified

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" or "f" )  and ("g" and ( not "h") )  )  and ("i" and "j" )  )

Domain logical expression index: "a"

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

Domain logical expression index: "b"

Referential boundary: The target chemical should be classified as Radical AND Radical >> Radical mechanism via ROS formation (indirect) AND Radical >> Radical mechanism via ROS formation (indirect) >> Single-Ring Substituted Primary Aromatic Amines AND SN1 AND SN1 >> Nucleophilic attack after nitrenium ion formation AND SN1 >> Nucleophilic attack after nitrenium ion formation >> Single-Ring Substituted Primary Aromatic Amines by DNA binding by OASIS v.1.4

Domain logical expression index: "c"

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: "d"

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

Domain logical expression index: "e"

Referential boundary: The target chemical should be classified as AN2 AND AN2 >> Michael-type addition to quinoid structures  AND AN2 >> Michael-type addition to quinoid structures  >> Substituted Anilines by Protein binding by OASIS v1.4

Domain logical expression index: "f"

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

Domain logical expression index: "g"

Referential boundary: The target chemical should be classified as Radical AND Radical >> Radical mechanism via ROS formation (indirect) AND Radical >> Radical mechanism via ROS formation (indirect) >> Single-Ring Substituted Primary Aromatic Amines AND SN1 AND SN1 >> Nucleophilic attack after nitrenium ion formation AND SN1 >> Nucleophilic attack after nitrenium ion formation >> Single-Ring Substituted Primary Aromatic Amines by DNA binding by OASIS v.1.4

Domain logical expression index: "h"

Referential boundary: The target chemical should be classified as AN2 OR AN2 >>  Michael-type addition, quinoid structures OR AN2 >>  Michael-type addition, quinoid structures >> Quinones and Trihydroxybenzenes OR No alert found OR Non-covalent interaction OR Non-covalent interaction >> DNA intercalation OR Non-covalent interaction >> DNA intercalation >> Amino Anthraquinones OR Non-covalent interaction >> DNA intercalation >> Fused-Ring Primary Aromatic Amines OR Non-covalent interaction >> DNA intercalation >> Quinones and Trihydroxybenzenes OR Radical >> Radical mechanism via ROS formation (indirect) >> Amino Anthraquinones OR Radical >> Radical mechanism via ROS formation (indirect) >> Fused-Ring Primary Aromatic Amines OR Radical >> Radical mechanism via ROS formation (indirect) >> Nitroaniline Derivatives OR Radical >> Radical mechanism via ROS formation (indirect) >> Quinones and Trihydroxybenzenes OR SN1 >> Nucleophilic attack after metabolic nitrenium ion formation OR SN1 >> Nucleophilic attack after metabolic nitrenium ion formation >> Amino Anthraquinones OR SN1 >> Nucleophilic attack after metabolic nitrenium ion formation >> Fused-Ring Primary Aromatic Amines OR SN1 >> Nucleophilic attack after reduction and nitrenium ion formation OR SN1 >> Nucleophilic attack after reduction and nitrenium ion formation >> Nitroaniline Derivatives by DNA binding by OASIS v.1.4

Domain logical expression index: "i"

Parametric boundary:The target chemical should have a value of Molecular weight which is >= 107 Da

Domain logical expression index: "j"

Parametric boundary:The target chemical should have a value of Molecular weight which is <= 418 Da

Conclusions:

The NOAEL was estimated to be 525 mg/kg bw when rats were orally exposed with 2-[(4-amino-3-methoxyphenyl)sulphonyl]ethyl hydrogen sulphate.

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 2-[(4-amino-3-methoxyphenyl)sulphonyl]ethyl hydrogen sulphate. The NOAEL was estimated to be 525 mg/kg bw when rats were orally exposed with 2-[(4-amino-3-methoxyphenyl)sulphonyl]ethyl hydrogen sulphate.  

Effect on fertility: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

525 mg/kg bw/day

Study duration:

subchronic

Species:

rat

Quality of whole database:

Data is 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, 2-[(4-amino-3-methoxyphenyl)sulphonyl]ethyl hydrogen sulphate 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 2-[(4-amino-3-methoxyphenyl)sulphonyl]ethyl hydrogen sulphate along with the study available on structurally similar read across substance 2-Amino-5-methylbenzenesulfonic acid (CAS no 88-44-8). 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 2-[(4-amino-3-methoxyphenyl) sulphonyl] ethyl hydrogen sulphate. The NOAEL was estimated to be 525 mg/kg bw when rats were orally exposed with 2-[(4-amino-3-methoxyphenyl) sulphonyl] ethyl hydrogen sulphate.  

In another experimental study conducted by J-check (Toxicity Testing Reports of Environmental Chemicals, vol.7 p163-171) and OECD SIDS (SIDS Initial Assessment Report For SIAM 16 Paris, 27-30 May 2003) on structurally similar read across substance 2-Amino-5-methylbenzenesulfonic acid (CAS no 88-44-8), Crj: CD(SD) male and female rats were treated with 2-Amino-5-methylbenzenesulfonic acid in the concentration of 0 (vehicle), 100, 300, 1000 mg/kg/day orally by gavage in Sesame oil. Ocular secretion in 100 mh/kg bw, hair loss in 300 and 1000 mg/kg bw were observed in male rats and hair removal was observed in the 100 mg / kg group through pregnancy and nursing periods, and in the control group of female rats. No change due to administration of the test substance was observed. No mortality and change in body weight were observed as compared to control. Statistically significant increase in food consumption from 1 to 15 days of administration in male rats at 1000 mg/kg bw and no effect on female rats were observed. In addition, statistically significant decrease in epididymis weight was observed at 300 mg/kg bw but there was no difference in the relative weight, and a similar change was observed in the 1000 mg / kg group There was not. There was no difference between the control group and each test substance administered group as testicular weight. No gross pathological change was observed in treated rats. Seminiferous tubular atrophy of the teste, testicular and epididymal atrophy, stromal cell proliferation, spermatogenesis of the epididymis were observed at 300 mg/kg bw and cell infiltration of the epididymis at 1000 mg / kg However, since it is low frequency expression, it was not considered to be influence of the test substance. Similarly, No effect on estrous cycle, copulation index, fertility index, gestation length, number of corpora lutea or implantations, implantation index, gestation index, delivery index, purturition or maternal behavior in treated rats. No clinical signs, mortality and change in body weight were observed as compared to control. Therefore, NOAEL was considered to be 1000 mg/kg bw when Crj: CD (SD) male and female rats were treated with 2-Amino-5-methylbenzenesulfonic acid orally by gavage for 48 days.

Thus, based on the above study and predictions on 2-[(4-amino-3-methoxyphenyl) sulphonyl]ethyl hydrogen sulphate and its read across substances, it can be concluded that NOAEL value is 525 mg/kg bw with no effect on reproduction. Thus, as per criteria of CLP regulation, 2-[(4-amino-3-methoxyphenyl) sulphonyl]ethyl hydrogen sulphate 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 2-[(4-amino-3-methoxyphenyl) sulphonyl]ethyl hydrogen sulphate and its read across substances, it can be concluded that NOAEL value is 525 mg/kg bw with no effect on reproduction. Thus, as per criteria of CLP regulation, 2-[(4-amino-3-methoxyphenyl) sulphonyl]ethyl hydrogen sulphate can be not classified for reproductive toxicity.