7-acetamido-4-hydroxy-3-[[4-[[2-(sulphooxy)ethyl]sulphonyl]phenyl]azo]naphthalene-2-sulphonic acid

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Description of key information

Reproductive toxicity

NOAEL was estimated to be 353.95mg/kg bw when male and female wistar rats were exposed with 7-acetamido-4-hydroxy-3-[(E)-2-{4-[2-(sulfooxy) ethanesulfonyl]phenyl}diazen-1-yl]naphthalene-2-sulfonic acid (68189-39-9) orally.

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 v3.3 and the QMRF report has been attached.

Qualifier:

according to guideline

Guideline:

other: As mentioned below

Principles of method if other than guideline:

Prediction was done using OECD QSAR toolbox v3.3, 2017

GLP compliance:

not specified

Limit test:

no

Justification for study design:

not specified

Specific details on test material used for the study:

- Name of the test material: 7-acetamido-4-hydroxy-3-[(E)-2-{4-[2-(sulfooxy)ethanesulfonyl]phenyl}diazen-1-yl]naphthalene-2-sulfonic acid
- IUPAC name: 7-acetamido-4-hydroxy-3-[(E)-2-{4-[2-(sulfooxy)ethanesulfonyl]phenyl}diazen-1-yl]naphthalene-2-sulfonic acid
- Molecular formula: C20H19N3O11S3
- Molecular weight: 573.578 g/mol
- Smiles: c1c(c(c(c2ccc(cc12)NC(=O)C)O)\N=N\c1ccc(cc1)S(=O)(=O)CCOS(=O)(=O)O)S(=O)(=O)O
-InChI:1S/C20H19N3O11S3/c1-12(24)21-15-4-7-17-13(10-15)11-18(36(28,29)30)19(20(17)25)23-22-14-2-5-16(6-3-14)35(26,27)9-8-34-37(31,32)33/h2-7,10-11,25H,8-9H2,1H3,(H,21,24)(H,28,29,30)(H,31,32,33)/b23-22+
- 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:

water

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:

28 days

Frequency of treatment:

Daily

Details on study schedule:

No data available

Dose / conc.:

353.95 mg/kg bw/day (nominal)

No. of animals per sex per dose:

10

Control animals:

yes, concurrent vehicle

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:

effects observed, treatment-related

Food consumption and compound intake (if feeding study):

effects observed, treatment-related

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:

no effects observed

Dose descriptor:

NOAEL

Effect level:

353.95 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

reproductive performance

Remarks on result:

other: No effects observed on reproductive parameters

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 examined

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:

NOAEL

Generation:

F1

Effect level:

353.95 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

not specified

Basis for effect level:

clinical signs

mortality

other: teratogenic effects

Remarks on result:

other: overall no teratogenic effects were 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" or "d" )  and ("e" and ( not "f") )  )  and "g" )  and "h" )  and "i" )  and "j" )  and ("k" and "l" )  )

Domain logical expression index: "a"

Referential boundary: The target chemical should be classified as Vinyl Sulfones by US-EPA New Chemical Categories

Domain logical expression index: "b"

Referential boundary: The target chemical should be classified as Acylation AND Acylation >> Ester aminolysis AND Acylation >> Ester aminolysis >> Amides by Protein binding by OASIS v1.3

Domain logical expression index: "c"

Referential boundary: The target chemical should be classified as Acylation AND Acylation >> Direct Acylation Involving a Leaving group AND Acylation >> Direct Acylation Involving a Leaving group >> Acetates by Protein binding by OECD

Domain logical expression index: "d"

Referential boundary: The target chemical should be classified as Acid moiety AND Amides AND Phenol Amines AND Phenols by Aquatic toxicity classification by ECOSAR

Domain logical expression index: "e"

Referential boundary: The target chemical should be classified as No alert found by DNA binding by OASIS v.1.3

Domain logical expression index: "f"

Referential boundary: The target chemical should be classified as AN2 OR AN2 >> Carbamoylation after isocyanate formation OR AN2 >> Carbamoylation after isocyanate formation >> N-Hydroxylamines OR AN2 >> Michael-type addition on alpha, beta-unsaturated carbonyl compounds OR AN2 >> Michael-type addition on alpha, beta-unsaturated carbonyl compounds >> Four- and Five-Membered Lactones OR AN2 >> Schiff base formation by aldehyde formed after metabolic activation OR AN2 >> Schiff base formation by aldehyde formed after metabolic activation >> Geminal Polyhaloalkane Derivatives OR AN2 >> Shiff base formation after aldehyde release OR AN2 >> Shiff base formation after aldehyde release >> Specific Acetate Esters OR AN2 >> Shiff base formation for aldehydes OR AN2 >> Shiff base formation for aldehydes >> Geminal Polyhaloalkane Derivatives OR Non-covalent interaction OR Non-covalent interaction >> DNA intercalation OR Non-covalent interaction >> DNA intercalation >> Coumarins OR Non-covalent interaction >> DNA intercalation >> DNA Intercalators with Carboxamide Side Chain OR Non-specific OR Non-specific >> Incorporation into DNA/RNA, due to structural analogy with  nucleoside bases    OR Non-specific >> Incorporation into DNA/RNA, due to structural analogy with  nucleoside bases    >> Specific Imine and Thione Derivatives OR Radical OR Radical >> Radical mechanism via ROS formation (indirect) OR Radical >> Radical mechanism via ROS formation (indirect) >> Coumarins OR Radical >> Radical mechanism via ROS formation (indirect) >> Geminal Polyhaloalkane Derivatives OR Radical >> Radical mechanism via ROS formation (indirect) >> N-Hydroxylamines OR Radical >> Radical mechanism via ROS formation (indirect) >> Specific Imine and Thione Derivatives OR SN1 OR SN1 >> Nucleophilic attack after carbenium ion formation OR SN1 >> Nucleophilic attack after carbenium ion formation >> Specific Acetate Esters OR SN1 >> Nucleophilic attack after metabolic nitrenium ion formation OR SN1 >> Nucleophilic attack after metabolic nitrenium ion formation >> N-Hydroxylamines OR SN1 >> Nucleophilic substitution on diazonium ions OR SN1 >> Nucleophilic substitution on diazonium ions >> Specific Imine and Thione Derivatives OR SN2 OR SN2 >> Acylation OR SN2 >> Acylation >> Specific Acetate Esters OR SN2 >> Acylation involving a leaving group  OR SN2 >> Acylation involving a leaving group  >> Geminal Polyhaloalkane Derivatives OR SN2 >> Acylation involving a leaving group after metabolic activation OR SN2 >> Acylation involving a leaving group after metabolic activation >> Geminal Polyhaloalkane Derivatives OR SN2 >> Alkylation, ring opening SN2 reaction OR SN2 >> Alkylation, ring opening SN2 reaction >> Four- and Five-Membered Lactones OR SN2 >> Direct acting epoxides formed after metabolic activation OR SN2 >> Direct acting epoxides formed after metabolic activation >> Coumarins OR SN2 >> DNA alkylation OR SN2 >> DNA alkylation >> Alkylphosphates, Alkylthiophosphates and Alkylphosphonates OR SN2 >> Nucleophilic substitution at sp3 Carbon atom OR SN2 >> Nucleophilic substitution at sp3 Carbon atom >> Specific Acetate Esters OR SN2 >> Nucleophilic substitution at sp3 carbon atom after thiol (glutathione) conjugation OR SN2 >> Nucleophilic substitution at sp3 carbon atom after thiol (glutathione) conjugation >> Geminal Polyhaloalkane Derivatives by DNA binding by OASIS v.1.3

Domain logical expression index: "g"

Referential boundary: The target chemical should be classified as No alert found by DNA binding by OECD ONLY

Domain logical expression index: "h"

Referential boundary: The target chemical should be classified as Class 5 (Not possible to classify according to these rules) by Acute aquatic toxicity classification by Verhaar (Modified) ONLY

Domain logical expression index: "i"

Referential boundary: The target chemical should be classified as Reactive unspecified by Acute aquatic toxicity MOA by OASIS ONLY

Domain logical expression index: "j"

Referential boundary: The target chemical should be classified as Reactive unspecified by Acute aquatic toxicity MOA by OASIS ONLY

Domain logical expression index: "k"

Parametric boundary:The target chemical should have a value of log Kow which is >= -4.18

Domain logical expression index: "l"

Parametric boundary:The target chemical should have a value of log Kow which is <= 1.93

Conclusions:

NOAEL was estimated to be 353.95mg/kg bw when male and female wistar rats were exposed with 7-acetamido-4-hydroxy-3-[(E)-2-{4-[2-(sulfooxy) ethanesulfonyl]phenyl}diazen-1-yl]naphthalene-2-sulfonic acid (68189-39-9) orally.

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 7-acetamido-4-hydroxy-3-[(E)-2-{4-[2-(sulfooxy)ethanesulfonyl]phenyl}diazen-1-yl]naphthalene-2-sulfonic acid (68189-39-9) .No effect was observed on reproductive function. Hence, NOAEL was estimated to be 353.95mg/kg bw when male and female wistar rats were exposed with 7-acetamido-4-hydroxy-3-[(E)-2-{4-[2-(sulfooxy) ethanesulfonyl]phenyl}diazen-1-yl]naphthalene-2-sulfonic acid (68189-39-9) orally.

Effect on fertility: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

353.95 mg/kg bw/day

Study duration:

subacute

Species:

rat

Quality of whole database:

Data is Klimicsh 2 and from QSAR Toolbox 3.3. (2017)

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,7-acetamido-4-hydroxy-3-[(E)-2-{4-[2-(sulfooxy)ethanesulfonyl]phenyl}diazen-1-yl]naphthalene-2-sulfonic acid (68189-39-9)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 7-acetamido-4-hydroxy-3-[(E)-2-{4-[2-(sulfooxy)ethanesulfonyl]phenyl}diazen-1-yl]naphthalene-2-sulfonic acid (68189-39-9) 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 7-acetamido-4-hydroxy-3-[(E)-2-{4-[2-(sulfooxy)ethanesulfonyl]phenyl}diazen-1-yl]naphthalene-2-sulfonic acid (68189-39-9) .No effect was observed on reproductive function. Hence, NOAEL was estimated to be 353.95mg/kg bw when male and female wistar rats were exposed with 7-acetamido-4-hydroxy-3-[(E)-2-{4-[2-(sulfooxy) ethanesulfonyl]phenyl}diazen-1-yl]naphthalene-2-sulfonic acid (68189-39-9) orally.

 It is supported by experimental study conducted by WHO (Who Food Additives Series No. 12, International Programme on Chemical Safety World Health Organization, 18-27 April 1977) on structurally similar read across substance RED 2G (3734 -67-6) .In a repeated dose oral toxicity study, male and female rats were treated with RED 2G (3734 -67-6) in the concentration of 0, 24 or 114 ppm in cooked sausage. No effect on growth of treated rats was observed. Loss of hair in many treated rats was observed. No effect on liver function test (bromosulfthale in retention test) was observed in treated rats as compared to control. Similarly, no effect on spleen, kidneys, liver, heart or testes weight were observed in treated rats as compared to control. Increased erythropoiesis, increased splenic red pulp haemosider in and increased splenic red pulp reticular impregnation with iron were observed in treated rats as compared to control. In addition, no effect was observed on testes weight of male rats. Therefore, NOAEL was considered to be 114 ppm for male rats when male and female rats were treated with RED 2G orally in diet for 13 weeks.

It is supported by experimental study conducted by I.F. Gaunt, Madge Farmer, P. Grasso, S.D. Gangolli (Food and Cosmetics Toxicology Volume 5, 1967, Pages 171-177) on structurally similar read across substance Black PN (2519 -30-4). Reproductive toxicity study for Black PN (2519 -30-4) was conducted on male and female rats for 90 days by administrating in diet. When they were exposed at concentration of 0, 150, 500, 1000 mg/kg/day by oral diet for 90 days. Clinical sign, body weight, food consumption, , Haematology, clinical chemistry, urine analysis , organ weight and histopathology was observed . No significant change was observed at any dose level in both treated male and female rats compare to control. Significant growth retardation was observed in males at the 1000mg/kg/day level and it associated with a reduced food intake. There were significant increase in the relative weights of the testes and kidneys at the dose level of 1000 mg/kg/day in treated male was observed compare to control. The elevated relative kidney weights were not accompanied by changes in the kidney function tests or in organ pathology. Decrease liver weight was also observed in 150 and 1000 mg/kg/day in treated female compare to control. Significant change was observed in the foci of inflammatory cell infiltration of the myocardium in treated males at 1000 mg/kg/day .The foci of inflammatory cell infiltration of the myocardium which occurred occasionally in males of the 1000 mg/kg/day group were of spontaneous origin.  On the basis of results NOEL was considered to be 500 mg/kg/day in male rats and 1000 mg/kg/day in female rats respectively, for 90 days reproductive toxicity study.

So, based on the above mentioned studies for target substance 7-acetamido-4-hydroxy-3-[(E)-2-{4-[2-(sulfooxy)ethanesulfonyl]phenyl}diazen-1-yl]naphthalene-2-sulfonic acid (68189-39-9)and to its read across substance, it was considered that no adverse effects on reproductive parameter were observed. Therefore, according to CLP criteria, the substance 7-acetamido-4-hydroxy-3-[(E)-2-{4-[2-(sulfooxy)ethanesulfonyl]phenyl}diazen-1-yl]naphthalene-2-sulfonic acid (68189-39-9) 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

Therefore, according to CLP criteria, the substance 7-acetamido-4-hydroxy-3-[(E)-2-{4-[2-(sulfooxy)ethanesulfonyl]phenyl}diazen-1-yl]naphthalene-2-sulfonic acid (68189-39-9) cannot be classified as reproductive toxicant.