Sodium 4-(4-(2-hydroxynaphthalenylazo)phenylazo)benzenesulphonate

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Description of key information

The reproductive toxicity of Sodium 4-(4-(2-hydroxynaphthalenylazo)phenylazo)benzenesulphonate (6406-56-0)was estimated by SSS (2017) using OECD QSAR toolbox v3.4with log kow as the primary descriptor and NOAEL was estimated to be 620.00mg/kg bw.When male and female  Sprague-Dawley ratswere exposed with Sodium 4-(4-(2-hydroxynaphthalenylazo)phenylazo)benzenesulphonate (6406-56-0) orally.

Thus, based on the above predictions and experimental study on Sodium 4-(4-(2-hydroxynaphthalenylazo)phenylazo)benzenesulphonate (6406-56-0) and its structurally similar read across substance No Observed Adverse Effect Level (NOAEL) was considered to be between 500mg/kg bw to 1500mg/kg bw . Thus, comparing this value with the criteria of CLP regulation Sodium 4-(4-(2-hydroxynaphthalenylazo)phenylazo)benzenesulphonate (6406-56-0)

cannot be classified as reproductive toxicant.

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 v3.4and 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 v3.4, 2017

GLP compliance:

not specified

Limit test:

no

Justification for study design:

No data available

Specific details on test material used for the study:

- Name of test material (IUPAC name): Sodium 4-(4-(2-hydroxynaphthalenylazo)phenylazo)benzenesulphonate
- Common name: Acid Red 151
- Molecular formula: C22H15N4O4S.Na
- Molecular weight: 455.448 g/mol
- Smiles notation: c12c(\N=N\c3ccc(\N=N\c4ccc(S(O)(=O)=O)cc4)cc3)c(ccc1cccc2)O.[Na+]
- InChl: 1S/C22H16N4O4S.Na/c27-21-14-5-15-3-1-2-4-20(15)22(21)26-25-17-8-6-16(7-9-17)23-24-18-10-12-19(13-11-18)31(28,29)30;/h1-14,27H,(H,28,29,30);/q;+1/b24-23+,26-25+;
- Substance type: Organic

Species:

rat

Strain:

Sprague-Dawley

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

Vehicle:

not specified

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:

1. males:
- 15 days before mating,
- during the mating period (up to 13 days depending on the time taken to mate),
- until sacrifice (i.e. at least 5 weeks in total),
2. females:
- 15 days before mating,
- during the mating period (up to 13 days depending on the time taken to mate),
- during pregnancy,
- during lactation until day 4 post-partum inclusive,
- females with no delivery were treated until the day prior to sacrifice.
Day 1 corresponds to the first day of treatment period.

Frequency of treatment:

once a day, at approximately the same time each day, 7 days a week

Details on study schedule:

No data available

Dose / conc.:

620 mg/kg bw/day (nominal)

No. of animals per sex per dose:

10

Control animals:

not specified

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):

SACRIFICE
- Male animals: All surviving animals [describe when, e.g. as soon as possible after the last litters in each generation were produced.]
- Maternal animals: All surviving animals [describe when, e.g. after the last litter of each generation was weaned.]

GROSS NECROPSY: yes
- Gross necropsy consisted of [external and internal examinations including the cervical, thoracic, and abdominal viscera.]

HISTOPATHOLOGY / ORGAN WEIGHTS
The tissues indicated in Table [#] were prepared for microscopic examination and weighed, respectively.

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:

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:

no effects observed

Dose descriptor:

NOAEL

Effect level:

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

Based on:

test mat.

Sex:

male/female

Basis for effect level:

gross pathology

reproductive performance

Remarks on result:

other: No reproductive toxic effects was 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:

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:

no effects observed

Gross pathological findings:

no effects observed

Histopathological findings:

not specified

Other effects:

not specified

Behaviour (functional findings):

not specified

Developmental immunotoxicity:

not specified

Dose descriptor:

NOAEL

Generation:

F1

Effect level:

620 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

not specified

Basis for effect level:

viability

mortality

organ weights and organ / body weight ratios

gross pathology

Remarks on result:

other: overall no developmental toxic effects was 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 ( not "g") )  )  and ("h" and ( not "i") )  )  and ("j" and ( not "k") )  )  and ("l" and ( not "m") )  )  and ("n" and "o" )  )

Domain logical expression index: "a"

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

Domain logical expression index: "b"

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

Domain logical expression index: "c"

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

Domain logical expression index: "d"

Referential boundary: The target chemical should be classified as Not possible to classify according to these rules by DPRA Lysine peptide depletion

Domain logical expression index: "e"

Referential boundary: The target chemical should be classified as Low reactive OR Low reactive >> N-substituted aromatic amides by DPRA Lysine peptide depletion

Domain logical expression index: "f"

Referential boundary: The target chemical should be classified as Not known precedent reproductive and developmental toxic potential by DART scheme v.1.0

Domain logical expression index: "g"

Referential boundary: The target chemical should be classified as Known precedent reproductive and developmental toxic potential OR NO2-alkyl/NO2-benzene derivatives (8b) OR Non-steroid nucleus derived estrogen receptor (ER) and androgen receptor (AR) OR Non-steroid nucleus derived estrogen receptor (ER) and androgen receptor (AR) >> 4-alkylphenol-like derivatives (2b-3) OR Polyhalogenated benzene derivatives (8c) OR Toluene and small alkyl toluene derivatives (8a) by DART scheme v.1.0

Domain logical expression index: "h"

Referential boundary: The target chemical should be classified as Alkali Earth AND Non-Metals by Groups of elements

Domain logical expression index: "i"

Referential boundary: The target chemical should be classified as Halogens by Groups of elements

Domain logical expression index: "j"

Referential boundary: The target chemical should be classified as Aryl AND Azo AND Fused carbocyclic aromatic AND Naphtalene AND Phenol AND Sulfonic acid by Organic Functional groups

Domain logical expression index: "k"

Referential boundary: The target chemical should be classified as Isopropyl by Organic Functional groups

Domain logical expression index: "l"

Referential boundary: The target chemical should be classified as Aryl AND Azo AND Fused carbocyclic aromatic AND Naphtalene AND Overlapping groups AND Phenol AND Sulfonic acid by Organic Functional groups (nested)

Domain logical expression index: "m"

Referential boundary: The target chemical should be classified as Alkane, branched with tertiary carbon by Organic Functional groups (nested)

Domain logical expression index: "n"

Parametric boundary:The target chemical should have a value of log Kow which is >= -1.68

Domain logical expression index: "o"

Parametric boundary:The target chemical should have a value of log Kow which is <= 4.13

Conclusions:

In reproductive toxicity study, NOAEL was estimated to be 620.00mg/kg bw. When male and female Sprague-Dawley rats were exposed with Sodium 4-(4-(2-hydroxynaphthalenylazo)phenylazo)benzenesulphonate (6406-56-0) orally.

Executive summary:

The reproductive toxicity of Sodium 4-(4-(2-hydroxynaphthalenylazo)phenylazo)benzenesulphonate (6406-56-0)was estimated by SSS (2017) using OECD QSAR toolbox v3.4with log kow as the primary descriptor and NOAEL was estimated to be 620.00mg/kg bw.When male and female  Sprague-Dawley rats were exposed with Sodium 4-(4-(2-hydroxynaphthalenylazo)phenylazo)benzenesulphonate (6406-56-0) orally.

Effect on fertility: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

620 mg/kg bw/day

Study duration:

subchronic

Species:

rat

Quality of whole database:

Data is Klimicsh 2 and from QSAR Toolbox 3.4. (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 on Sodium 4-(4-(2-hydroxynaphthalenylazo)phenylazo)benzenesulphonate (6406-56-0)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 Sodium 4-(4-(2-hydroxynaphthalenylazo)phenylazo)benzenesulphonate (6406-56-0). The predicted data using the OECD QSAR toolbox has also been compared with the experimental studies performed on structurally similar read across substance.

The reproductive toxicity of Sodium 4-(4-(2-hydroxynaphthalenylazo)phenylazo)benzenesulphonate (6406-56-0)was estimated by SSS (2017) using OECD QSAR toolbox v3.4with log kow as the primary descriptor and NOAEL was estimated to be 620.00mg/kg bw.When male and female  Sprague-Dawley rats were exposed with Sodium 4-(4-(2-hydroxynaphthalenylazo)phenylazo)benzenesulphonate (6406-56-0) orally.

Further supported by   experimental study conducted byThe Joint FAO/WHO Expert Committee on Food Additives (JECFA)(Brilliant Black PN: Toxicological Evaluation of certain food additives (WHO Food additives Series 16- 1981)) on structurally similar read across substance with Brilliant Black PN (2519-30-4). A multigeneration reproductive toxicity study of Brilliant Black PN (2519-30-4) was performed on male and female wistar rats. The test material mixed with feed in dose concentration 0, 0.1, 1.0 or 3% (0, 50, 500, 1500 mg/kg bw per day) and administered orally for three successive generations. Each generation having 60 animals of each sex in the control and 40 animals of each sex in test animals. No adverse effects were observed with respect to fertility, litter size and weight, general condition, male/female ratio, growth during lactation, survival or maturation. Autopsy of parent rats and pups at weaning did not reveal any treatment related changes in organ weights other than caecal enlargement in the 3% dose group. Gross and microscopic examination of the F3 generation at weaning did not reveal any abnormalities due to treatment and no adverse effects were seen in the teratology study. It was concluded that Brilliant Black PN did not exert any adverse effects on reproductive function of Wistar rats when fed at dietary levels up to 3% (1500 mg/kg bw per day) for three successive generations. Therefore, NOAEL was considered to be at 3% (1500 mg/kg bw per day) for F0 F1 and F2 generation .When male and female wistar rats were treated with Brilliant Black PN (2519-30-4) orally.

 

Also in another experimental study conducted byU.S. National Library of Medicine(HSDB (Hazardous Substances Data Bank); US national Library of Medicine reviewed by SRC, 2017.)on structurally similar read across substance with 2-Naphthalenesulfonic acid, 6-hydroxy-5-[(4-sulfophenyl)azo]-, disodium salt (2783-94-0).Three generation reproductive study of 2-Naphthalenesulfonic acid, 6-hydroxy-5-[(4-sulfophenyl)azo]-, disodium salt (2783-94-0) was performed on male and female Charles River CD rats. Animals were housed individually and fed the test diet ad libitum. The test material mixed with food in dose concentration 0, 5, 50, 150 or 500 mg/kg bw/day and 10 males and 20 females/group/generation were used .Pre-Mating Exposure / Males and Females were 60 days. Clinical observations were recorded twice daily with at least 5 hours between observations. Detailed physical examinations and palpation for masses were performed weekly. Body weights and food consumption were determined weekly for the first fourteen weeks, bi-weekly for the next 12 weeks and every 4 weeks thereafter until the end of the study. The intake of the test substance was determined from body weight, food consumption and dietary concentration. Haematology tests, including haemoglobin, haematocrit, erythrocyte and total and differential leukocyte counts, and erythrocyte morphology, were conducted on ten randomly selected animals at months 3, 6, 12, 18 and 24 of the study. Necropsies were conducted on all animals dying prior to study termination, killed in a moribund condition or killed on schedule. Histological examinations were conducted on all animals from both control groups, the highest dose group (2.0 or 5.0%) from each study and also on 10 rats randomly selected from each group for an interim sacrifice at 12 months. Histology was also performed on any animal with gross lesions or masses. Also tissues examined included adrenal glands, aorta, blood smear, brain, cecum, colon, duodenum, epididymus or uterus, esophagus, eyes, femur including marrow, tissue masses, gallbladder, heart, ileum, jejunum, duodenum, kidneys, liver, lungs and bronchi, mammary gland, nerves (sciatic), ovaries, lymph nodes, pancreas, parathyroids, pituitary gland, prostrate, rectum, skin, spleen, seminal vesicles, skeletal muscle, testes with epididymides, stomach, thymus, thyroid gland including parathyroid, trachea, urinary bladder, uterus.

 At the end of study, no treatment-related effects were reported on survival. No treatment-related changes were reported at gross necropsy. Histological evaluation revealed a variety of lesions, including neoplasms, present at similar incidences in control and treated animals. The authors considered the lesions to be spontaneous and not related to administration of the test material. There were no compound related effects on fertility, gestation, pup viability or lactation indices, on reproductive organs of females, or on organ weights among parents and offspring. There were no compound related lesions in any tissue examined histologically, including kidneys and adrenal glands from parental rats or from offspring. There was no toxicity to either the F1 or F2 generation. Food consumption was similar for control and treated animals at the lower dietary levels, but was slightly higher in the high-dose study, although not statistically significant. Haematological, clinical chemistry and urinalysis parameters did not differ significantly from the controls. Necropsies at one year did not reveal any treatment-related gross or microscopic changes. Hence NOAEL was considered to be 500mg/kg bw/day for F0, F1 and F2 generation. When male and female Charles River CD rats were treated with 2-Naphthalenesulfonic acid, 6-hydroxy-5-[(4-sulfophenyl)azo]-, disodium salt (2783-94-0) orally.

  

  Thus, based on the above predictions and experimental study on Sodium 4-(4-(2-hydroxynaphthalenylazo)phenylazo)benzenesulphonate (6406-56-0) and its structurally similar read across substance No Observed Adverse Effect Level (NOAEL) was considered to be between 500mg/kg bw to 1500mg/kg bw .

Thus, comparing this value with the criteria of CLP regulation Sodium 4-(4-(2-hydroxynaphthalenylazo)phenylazo)benzenesulphonate (6406-56-0) 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

Thus, comparing this value with the criteria of CLP regulation Sodium 4-(4-(2-hydroxynaphthalenylazo)phenylazo)benzenesulphonate (6406-56-0)cannot be classified as reproductive toxicant.