Tetrasodium 2,2'-[1,4-phenylenebis[carbonylimino[2-acetamido-4,1-phenylene]azo]]bis[5-[(4-sulphonatophenyl)azo]benzenesulphonate]

Endpoint summary

Description of key information

Repeated dose toxicity: Oral:

Based on the prediction done using the OECD QSAR toolbox version 3.3 with log kow as the primary descriptor and considering the five closest read across substances, repeated dose toxicity was predicted for Tetrasodium 2,2'-[1,4-phenylenebis [carbonylimino [2-acetamido-4,1-phenylene]azo]] bis[5-[(4-sulphonatophenyl)azo] benzenesulphonate]. The study assumed the use of male and female rats in a 28 days toxicity study. Since no significant treatment related effects were observed at the mentioned dose level, hence the No Observed Adverse Effect Level (NOAEL) for Tetrasodium 2,2'-[1,4-phenylenebis [carbonylimino [2-acetamido-4,1-phenylene]azo]] bis[5-[(4- sulphonatophenyl)azo] benzenesulphonate] is predicted to be 568.900024414 mg/Kg bw/day.

Based on this value it can be concluded that the substance is considered to not toxic as per the criteria mentioned in CLP regulation.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records

Reference

Endpoint:

repeated dose toxicity: oral

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 version 3.4 and the supporting QMRF report has been attached

Qualifier:

according to guideline

Guideline:

other: Refer below principle

Principles of method if other than guideline:

Prediction is done using OECD QSAR Toolbox version 3.4, 2018

GLP compliance:

not specified

Specific details on test material used for the study:

- Name of test material: Tetrasodium 2,2'-[1,4-phenylenebis[carbonylimino[2-acetamido-4,1-phenylene]azo]]bis[5-[(4-sulphonatophenyl)azo] benzenesulphonate]
- IUPAC name: tetrasodium 2-[(E)-2-{2-acetamido-4-[4-({3-acetamido-4-[(E)-2-{2-sulfonato-4-[(E)-2-(4-sulfonatophenyl)diazen-1-yl]phenyl} diazen-1-yl]phenyl}carbamoyl)benzamido]phenyl}diazen-1-yl]-5-[(E)-2-(4-sulfonatophenyl)diazen-1-yl]benzene-1-sulfonate
- Molecular formula: C48H34N12Na4O16S4
- Molecular weight: 1255.09 g/mole
- Smiles : [Na+].[Na+].[Na+].[Na+].c1(ccc(cc1)C(=O)Nc1cc(c(cc1)\N=N\c1c(cc(cc1)\N=N\c1ccc(cc1)S(=O)(=O)[O-])S(=O)(=O)[O-])NC(=O)C)C (=O)Nc1cc(c(cc1)\N=N\c1c(cc(cc1)\N=N\c1ccc(cc1)S(=O)(=O)[O-])S(=O)(=O)[O-])NC(=O)C
- Inchl: 1S/C48H38N12O16S4.4Na/c1-27(61)49-43-23-33(11-19-39(43)57-59-41-21-13-35(25-45(41)79(71,72)73)55-53-31-7-15-37(16-8-31) 77(65,66)67)51-47(63)29-3-5-30(6-4-29)48(64)52-34-12-20-40(44(24-34)50-28(2)62)58-60-42-22-14-36(26-46(42)80(74,75)76)56-54-32-9-17-38(18-10-32)78(68,69)70;;;;/h3-26H,1-2H3,(H,49,61)(H,50,62)(H,51,63)(H,52,64)(H,65,66,67)(H,68,69,70)(H,71,72,73)(H,74,75,76);;;;/q;4*+1/p-4/b55-53+,56-54+,59-57+,60-58+;;;;
- Substance type: Organic
- Physical state: Solid

Species:

rat

Strain:

CD-1

Details on species / strain selection:

No data

Sex:

male/female

Details on test animals or test system and environmental conditions:

No data

Route of administration:

oral: unspecified

Details on route of administration:

No data

Vehicle:

not specified

Details on oral exposure:

No data

Analytical verification of doses or concentrations:

not specified

Details on analytical verification of doses or concentrations:

No data

Duration of treatment / exposure:

3 months

Frequency of treatment:

Daily

Remarks:

No data

No. of animals per sex per dose:

No data

Control animals:

not specified

Details on study design:

No data

Positive control:

No data

Observations and examinations performed and frequency:

No data

Sacrifice and pathology:

No data

Other examinations:

No data

Statistics:

No data

Clinical signs:

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

Gross pathological findings:

not specified

Neuropathological findings:

not specified

Histopathological findings: non-neoplastic:

not specified

Histopathological findings: neoplastic:

not specified

Other effects:

not specified

Details on results:

No data

Dose descriptor:

NOAEL

Effect level:

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

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: No significant effects were noted at the mentioned dose level

Critical effects observed:

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" )  and ("f" and ( not "g") )  )  and ("h" and ( not "i") )  )  and ("j" and ( not "k") )  )  and ("l" and ( not "m") )  )  and "n" )  and "o" )  and "p" )  and ("q" and ( not "r") )  )  and ("s" and "t" )  )

Domain logical expression index: "a"

Referential boundary: The target chemical should be classified as Non-covalent interaction AND Non-covalent interaction >> DNA intercalation AND Non-covalent interaction >> DNA intercalation >> DNA Intercalators with Carboxamide and Aminoalkylamine Side Chain by DNA binding by OASIS v.1.4

Domain logical expression index: "b"

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: "c"

Referential boundary: The target chemical should be classified as Acylation AND Acylation >> Acylation involving an activated (glucuronidated) carboxamide group AND Acylation >> Acylation involving an activated (glucuronidated) carboxamide group >> Carboxylic Acid Amides AND Acylation >> Direct acylation involving a leaving group AND Acylation >> Direct acylation involving a leaving group >> Carboxylic Acid Amides AND Acylation >> Ester aminolysis AND Acylation >> Ester aminolysis >> Amides AND AN2 AND AN2 >> Michael-type addition to quinoid structures  AND AN2 >> Michael-type addition to quinoid structures  >> Carboxylic Acid Amides by Protein binding by OASIS v1.4

Domain logical expression index: "d"

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: "e"

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

Domain logical expression index: "f"

Referential boundary: The target chemical should be classified as Non binder, MW>500 by Estrogen Receptor Binding

Domain logical expression index: "g"

Referential boundary: The target chemical should be classified as Moderate binder, NH2 group OR Non binder, impaired OH or NH2 group by Estrogen Receptor Binding

Domain logical expression index: "h"

Referential boundary: The target chemical should be classified as Non binder, MW>500 by Estrogen Receptor Binding

Domain logical expression index: "i"

Referential boundary: The target chemical should be classified as Non binder, without OH or NH2 group by Estrogen Receptor Binding

Domain logical expression index: "j"

Referential boundary: The target chemical should be classified as Non binder, MW>500 by Estrogen Receptor Binding

Domain logical expression index: "k"

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

Domain logical expression index: "l"

Referential boundary: The target chemical should be classified as Not categorized by Repeated dose (HESS)

Domain logical expression index: "m"

Referential boundary: The target chemical should be classified as Thiocarbamates/Sulfides (Hepatotoxicity) No rank OR Valproic acid (Hepatotoxicity) Alert by Repeated dose (HESS)

Domain logical expression index: "n"

Similarity boundary:Target: CC(=O)Nc1cc(NC(=O)c2ccc(C(=O)Nc3ccc(N=Nc4ccc(N=Nc5ccc(S(=O)(=O)O{-}.[Na]{+})cc5)cc4S(=O)(=O)O{-}.[Na]{+})c(NC(C)=O)c3)cc2)ccc1N=Nc1ccc(N=Nc2ccc(S(=O)(=O)O{-}.[Na]{+})cc2)cc1S(=O)(=O)O{-}.[Na]{+}
Threshold=20%,
Dice(Atom centered fragments)
Atom type; Count H attached; Hybridization

Domain logical expression index: "o"

Similarity boundary:Target: CC(=O)Nc1cc(NC(=O)c2ccc(C(=O)Nc3ccc(N=Nc4ccc(N=Nc5ccc(S(=O)(=O)O{-}.[Na]{+})cc5)cc4S(=O)(=O)O{-}.[Na]{+})c(NC(C)=O)c3)cc2)ccc1N=Nc1ccc(N=Nc2ccc(S(=O)(=O)O{-}.[Na]{+})cc2)cc1S(=O)(=O)O{-}.[Na]{+}
Threshold=30%,
Dice(Atom centered fragments)
Atom type; Count H attached; Hybridization

Domain logical expression index: "p"

Similarity boundary:Target: CC(=O)Nc1cc(NC(=O)c2ccc(C(=O)Nc3ccc(N=Nc4ccc(N=Nc5ccc(S(=O)(=O)O{-}.[Na]{+})cc5)cc4S(=O)(=O)O{-}.[Na]{+})c(NC(C)=O)c3)cc2)ccc1N=Nc1ccc(N=Nc2ccc(S(=O)(=O)O{-}.[Na]{+})cc2)cc1S(=O)(=O)O{-}.[Na]{+}
Threshold=40%,
Dice(Atom centered fragments)
Atom type; Count H attached; Hybridization

Domain logical expression index: "q"

Referential boundary: The target chemical should be classified as Anion AND Aromatic compound AND Azo compound AND Carbonic acid derivative AND Carboxylic acid derivative AND Carboxylic acid sec. amide AND Cation AND Sulfonic acid derivative by Organic functional groups, Norbert Haider (checkmol)

Domain logical expression index: "r"

Referential boundary: The target chemical should be classified as Aryl chloride by Organic functional groups, Norbert Haider (checkmol)

Domain logical expression index: "s"

Parametric boundary:The target chemical should have a value of log Kow which is >= 0.36

Domain logical expression index: "t"

Parametric boundary:The target chemical should have a value of log Kow which is <= 10

Conclusions:

The No Observed Adverse Effect Level (NOAEL) for Tetrasodium 2,2'-[1,4-phenylenebis [carbonylimino [2-acetamido-4,1-phenylene]azo]] bis[5-[(4- sulphonatophenyl)azo] benzenesulphonate] is predicted to be 568.900024414 mg/Kg bw/day.

Executive summary:

Based on the prediction done using the OECD QSAR toolbox version 3.3 with log kow as the primary descriptor and considering the five closest read across substances, repeated dose toxicity was predicted for Tetrasodium 2,2'-[1,4-phenylenebis [carbonylimino [2-acetamido-4,1-phenylene]azo]] bis[5-[(4-sulphonatophenyl)azo] benzenesulphonate]. The study assumed the use of male and female rats in a 28 days toxicity study. Since no significant treatment related effects were observed at the mentioned dose level, hence the No Observed Adverse Effect Level (NOAEL) for Tetrasodium 2,2'-[1,4-phenylenebis [carbonylimino [2-acetamido-4,1-phenylene]azo]] bis[5-[(4- sulphonatophenyl)azo] benzenesulphonate] is predicted to be 568.900024414 mg/Kg bw/day.

 

Based on this value it can be concluded that the substance is considered to be not toxic as per the criteria mentioned in CLP regulation.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

568.9 mg/kg bw/day

Study duration:

subchronic

Species:

rat

Quality of whole database:

Data is from K2 QSAR prediction database

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion

Endpoint conclusion:

no study available

Quality of whole database:

Waiver

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

Repeated dose toxicity: Oral:

Prediction model based estmation for the target chemical and data from read across chemicals has been reviewed to determine the toxic nature of the test chemical Aluminium, 3-hydroxy-4-[(4-sulfo-1-naphthalenyl)azo]-2,7-naphthalenedisulfonic acid complex. The studies are as summarized below:

Based on the prediction done using the OECD QSAR toolbox version 3.3 with log kow as the primary descriptor and considering the five closest read across substances, repeated dose toxicity was predicted for Tetrasodium 2,2'-[1,4-phenylenebis [carbonylimino [2-acetamido-4,1-phenylene]azo]] bis[5-[(4-sulphonatophenyl)azo] benzenesulphonate]. The study assumed the use of male and female rats in a 28 days toxicity study. Since no significant treatment related effects were observed at the mentioned dose level, hence the No Observed Adverse Effect Level (NOAEL) for Tetrasodium 2,2'-[1,4-phenylenebis [carbonylimino [2-acetamido-4,1-phenylene]azo]] bis[5-[(4- sulphonatophenyl)azo] benzenesulphonate] is predicted to be 568.900024414 mg/Kg bw/day.

The experimental data for the read across chemicals is as mentioned below:

Repeated dose toxicity test were performed by Drake et al (Food and Cosmetic Toxicology, 1977) on mice with different concentrations from 0.1, 0.25, 0.5 or 1.0% (130, 325, 650, 1300 mg/kg bw/d) 60 -70% structurally and functionally similar read across chemical Black PN (RA CAS no 2519 -30 -4; IUPAC name: Tetra sodium 1-acetamido-2-hydroxy-3- (4-((4-sulphonato phenylazo) -7-sulphonato-1-naphthylazo))naphthalene-4,6-disulphonate) for 80 wk. 30 males and 30 females was used for the treatment and group of 60 mice of each sex as control. During the study period the animals were observed for clinical signs, mortality, hematology, urine analysis was performed and the animals were subjected to gross and histopathology. The general condition and behaviour of the animals were observed frequently and any mouse that showed signs of ill-health was isolated, to be returned to its cage on recovery or to be killed if its condition deteriorated. The mice were weighed at the start of the experiment, at wk 3 and then at intervals of 2 wk until wk 73 of the experiment. Blood sample were taken at wk 28 and 55. At 80 wk, blood samples were collected from the aorta of all surviving mice during the autopsy. For haematology blood samples were collected and for urine sample from 6-hr period from three groups of five mice of each sex from the controls and the groups on the two highest dietary levels of Black PN. Histopathology was also conducted. The ingestion of Black PN had no effect on the condition or behaviour and mortality of the animals. The haematological examinations revealed only inconsistent isolated changes of statistical significance. At wk 28 the haemoglobin concentrations and red blood cell counts were lower in female mice fed diet containing if 0.5 or 1.0% Black PN than in the controls. There were no comparable findings in the males. The total white cell count of the male animals fed 1.0% Black PN in the diet was higher than that of the controls at this time, but there was no comparable change in this measurement in the females, or in either sex at any other time. At wk 55, the haemoglobin concentrations of male animals fed 0.5% of the coiouring in the diet were significantly (P < 0.05) lower than the control values. However, the corresponding value at the higher dietary level was not affected and there were no differences from the control value in the females. Also at wk 55, the erythrocyte counts of females fed 1.0% Black PN were lower (P < 0.01) than those of the controls, but this finding was again isolated. There were no statistically significant differences between the control and test samples taken at wk 80. There were only scattered differences in mean organ weights between treated and control animals. A lower brain weight in females, compared with the control value, was the only difference affecting animals fed 1% Black PN. This difference, which did not occur in the males, was only marginally significant and there was no significant difference when the weights were expressed relative to body weight By contrast, the relative brain weight of females fed 0.25% Black PN was higher than the control figure. Liver weights of female but not of male mice fed 0.25% Black PN were lower than control values, but again this was an isolated finding and there were no significant differences in relative liver weights. Kidney weights of male animals only were significantly lower than control values at the two lowest levels of treatment (0.1 and 0.25%), but a significant difference in relative kidney weights of males occurred only at the 0.5% level, at which a higher value was recorded for the treated mice. The only other significant differences occurred in the relative heart weights, which were raised in male mice fed 0.5% and in females fed 0.25% Black PN. The incidence of histological findings was similar in all groups of mice, including the controls. Most of the tumours in the study occurred with either a comparable or a greater incidence in the control groups than in the treated mice. Several isolated tumours were identified in mice given the lower levels of Black PN, without comparable findings in the controls or in the highest dose group. They were a mammary fibroadenoma (in a female on 0.1%), a uterine fibromyoma (0.19%) and a squamous-cell carcinoma of the skin (female, 0.5%). The only tumour found at the highest dietary level without comparable control findings was a squamous- cell carcinoma of the skin in a male mouse fed 1% Black PN. Based on these considerations, the no observed adverse effect level (NOAEL) for Black PN in mice is considered to be 1 % (1300 mg/kg/day).

In another study by Gaunt et al (Food and Cosmetic Toxicology, 1972) for the same read across chemical, repeated dose oral toxicity test was performed on the male and female rats at different concentrations 0, 1000, 5000 or 10,000 ppm (0, 50, 250 or 500 mg/Kg/day) for 2 yrs to determine the toxic nature of 60 -70% structurally and functionally similar read across chemical Brilliant Black 1 (RA CAS no 2519 -30 -4; IUPAC name: Tetra sodium 1-acetamido-2-hydroxy-3- (4-((4-sulphonato phenylazo) -7-sulphonato-1-naphthylazo))naphthalene-4,6-disulphonate). The rats were obtained from SPF colony and Spillers' Laboratory Small Animal Diet and water availablead lib. Animals were maintained at controlled temperature and humidity atmosphere. Groups of 24 male (body weight 115-140 g) and 24 female (body weight 115-130 g) rats housed four to a cage were fed on diets Black PN for up to 2 yr. Body-weight gain, food intake, haematology, serum chemistry, renal concentration tests, organ weights or incidence of pathological findings, including tumours were performed. Some effects were observed but no effects attributable to treatment. The fur and faeces of the rats fed diets containing Black PN were coloured black. Mortality : Many rats died or were killed during the course of the study but at no time were the numbers of deaths in the Black PN-treated animals significantly greater than those of the controls. The majority of the deaths occurred in the last 6 months of treatment. There were no significant differences between treated and control rats in body-weight gain and food consumption. No effects was observed in the mean daily intakes of Black PN were approximately 40, 180 and 360 mg/kg/day in males and 45, 240 and 470 mg/kg/day in females at the three dietary levels. No adverse haematological changes were seen in either sex or at any dietary level up to 12 months. At wk 82, the haemoglobin concentration and packed cell volume were reduced in females fed a diet containing 10,000 ppm Black PN. These effects were not found after 2 yr, although at this time this group showed a reduction in the total leucocyte count. There was no black colour in urine collected free of faecal or other contamination. There were no statistically significant differences between the absolute organ weights of control rats and those of rats fed diets containing Black PN .However, in male rats, the relative liver weights were significantly higher in all treated groups than in the controls. Chronic rat nephropathy was found in many of the animals. This consisted of renal tubular dilation, protein casts and foci of round-cell infiltration. Chronic lung changes encountered consisted of peribronchial and perivascular lymphocyte cuffing. The incidence of these findings did not vary significantly between treated and control groups. Based on the observations made, the No observed adverse effect level (NOAEL) for Brilliant Black 1 is considered to be 500 mg/Kg/day when exposed by oral route of exposure to male and female rats for 2 years.

Gaunt et al (Food and Cosmetic Toxicology, 1974) performed repeated oral toxicity of another functionally similar read across chemical Sunset Yellow FCF (RA CAS no 2783 -94 -0; IUPAC name: disodium 6-hydroxy-5-[(4-sulfonatophenyl)diazenyl]naphthalene-2-sulfonate) by performing a 80 weeks repeated dose toxicity study using Charles River CD mouse (male and female) at dose levels of 0, 100, 200, 400 or 800 mg/Kg (0.2, 0.4, 0.8 or 1.6% respectively) by oral diet route. The animals were observed for clinical signs, mortality, body weight changes, hematology and were subjected to gross and histopathology. The feeding of Sunset Yellow FCF did not adversely affect the death rate within the groups, the rate of body-weight gain, the organ weights or the haematological findings. The incidence and severity of the histopathological findings were similar in treated and control mice and there was no evidence of an increased incidence of tumours in the mice given Sunset Yellow FCF. Distension of the bladder, frequently associated with hydroureter and hydronephosis was noted. Pus and hard protein deposits were found in the bladders of many of the mice and in a number of cases it was possible to show that an obstruction had occurred in the urethra in the region of the bulbo-urethral complex. After the male mice were put into individual cages, there was a marked reduction in the number showing this syndrome, although isolated cases of urinary retention were seen throughout the study. Of the malignant tumours found, lymphomas and reticulum-cell neoplasms occurred in treated and control mice. In addition a splenic haemangiosarcoma and a mammary carcinoma were found in the female mice fed on the diet containing the lowest level of Sunset Yellow FCF (100 mg/Kg). A single tumour of the Harderian gland was found in a female from the group given the 1.6% level. The commonest benign tumours were pulmonary adenomas and benign cysts in the ovary, found with a similar frequency in treated and control mice. The only other tumour occurring in treated mice without a similar finding in the controls was a granulosa-cell tumour of the ovary in a mouse given 800 mg/Kg Sunset Yellow FCF. Thus, on the basis of above results the NOAEL (no observed adverse effect level) for Sunset Yellow FCF was considered to be 800 mg/kg diet.

Based on the available data for the functionally similar read across chemicals and the applying the weight of evidence approach, Benzenesulfonic acid, 2,2'-(1,4-phenylenebis(carbonylimino (2-(acetylamino)-4,1-phenylene)-2,1- diazenediyl))bis(5-(2-(4-sulfophenyl)diazenyl)-, sodium salt (1:4) is considered to be not likely to classify as a toxicant upon repeated exposure by oral route.

Justification for classification or non-classification

Based on the available data for the functionally similar read across chemicals and the applying the weight of evidence approach, Benzenesulfonic acid, 2,2'-(1,4-phenylenebis(carbonylimino (2-(acetylamino)-4,1-phenylene)-2,1- diazenediyl))bis(5-(2-(4-sulfophenyl)diazenyl)-, sodium salt (1:4) (CAS no 70210 -30 -9) is considered to be not likely to classify as a toxicant upon repeated exposure by oral route