Registration Dossier

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 Aluminium, 3-hydroxy-4-[(4-sulfo-1-naphthalenyl)azo]-2,7- naphthalene disulfonic acid complex. The study assumed the use of male and female Wistar rats in a 90 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 Aluminium, 3-hydroxy-4-[(4-sulfo- 1-naphthalenyl)azo]-2,7-naphthalene disulfonic acid complex is predicted to be 1069.599975586 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.

Repeated dose toxicity: Inhalation

Aluminium, 3-hydroxy-4-[(4-sulfo-1-naphthalenyl)azo]-2,7-naphthalenedisulfonic acid complex has very low vapor pressure of 4.51E-23 mm Hg, so the potential for the generation of inhalable vapurs is very low, also the normal conditions of use of this substance will not result in aerosols, particles or droplets of an inhalable size, so exposure to humans via the inhalatory route will be highly unlikely and therefore is end point was considered for waiver

Repeated dose toxicity: Dermal

The acute dermal toxicity value for Aluminium, 3-hydroxy-4-[(4-sulfo-1-naphthalenyl)azo]-2,7- naphthalene disulfonic acid complex (as provided in section 7.2.3) based on the data available from the read across chemicals is >2000 mg/kg body weight. The substance was also considered to be not irritating and not sensitizing to the skin on the basis of read across data. Based on these considerations, the end point for repeated dermal toxicity is considered as waiver.

Reference

Endpoint:

repeated dose toxicity: oral

Type of information:

(Q)SAR

Adequacy of study:

key study

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 3.3 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 3.3, 2018

GLP compliance:

not specified

Limit test:

no

Specific details on test material used for the study:

- Name of test material : Aluminium, 3-hydroxy-4-[(4-sulfo-1-naphthalenyl)azo]-2,7-naphthalenedisulfonic acid complex
- IUPAC name: Aluminium, 3-hydroxy-4-[(4-sulfo-1-naphthalenyl)azo]-2,7-naphthalenedisulfonic acid complex
- Molecular formula: C20H14AlN2O10S3
- Molecular weight: 565.51 g/mol
- Substance type: Organic
- Physical state: Solid

Species:

rat

Strain:

Wistar

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:

90 days

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:

1 069.6 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: No significant alterations 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" ) and ("e" and ( not "f") ) ) and ("g" and ( not "h") ) ) and ("i" and ( not "j") ) ) and ("k" and ( not "l") ) ) and ("m" and ( not "n") ) ) and ("o" and ( not "p") ) ) and ("q" and "r" ) )

Domain logical expression index: "a"

Referential boundary: The target chemical should be classified as Naphthalene sulfonic acids, condensates by OECD HPV Chemical Categories

Domain logical expression index: "b"

Referential boundary: The target chemical should be classified as Cation by Substance Type

Domain logical expression index: "c"

Referential boundary: The target chemical should be classified as Acid moiety AND Not classified AND Phenols by Aquatic toxicity classification by ECOSAR

Domain logical expression index: "d"

Referential boundary: The target chemical should be classified as Acid moiety 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 Non-covalent interaction OR Non-covalent interaction >> DNA intercalation OR Non-covalent interaction >> DNA intercalation >> DNA Intercalators with Carboxamide Side Chain OR Non-covalent interaction >> DNA intercalation >> Fused-Ring Primary Aromatic Amines OR Radical OR Radical >> Radical mechanism via ROS formation (indirect) OR Radical >> Radical mechanism via ROS formation (indirect) >> Fused-Ring Primary Aromatic Amines OR SN1 OR SN1 >> Nucleophilic attack after metabolic nitrenium ion formation OR SN1 >> Nucleophilic attack after metabolic nitrenium ion formation >> Fused-Ring Primary Aromatic Amines by DNA binding by OASIS v.1.3

Domain logical expression index: "g"

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

Domain logical expression index: "h"

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

Domain logical expression index: "i"

Referential boundary: The target chemical should be classified as No alert found by Protein binding by OASIS v1.3

Domain logical expression index: "j"

Referential boundary: The target chemical should be classified as SNAr OR SNAr >> Nucleophilic aromatic substitution on activated aryl and heteroaryl compounds OR SNAr >> Nucleophilic aromatic substitution on activated aryl and heteroaryl compounds >> Activated aryl and heteroaryl compounds by Protein binding by OASIS v1.3

Domain logical expression index: "k"

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

Domain logical expression index: "l"

Referential boundary: The target chemical should be classified as Carboxylic acids (Hepatotoxicity) No rank by Repeated dose (HESS)

Domain logical expression index: "m"

Referential boundary: The target chemical should be classified as Aromatic compound AND Azo compound AND Cation AND Hydroxy compound AND Phenol AND Sulfonic acid AND Sulfonic acid derivative by Organic functional groups, Norbert Haider (checkmol)

Domain logical expression index: "n"

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

Domain logical expression index: "o"

Referential boundary: The target chemical should be classified as Aromatic compound AND Azo compound AND Cation AND Hydroxy compound AND Phenol AND Sulfonic acid AND Sulfonic acid derivative by Organic functional groups, Norbert Haider (checkmol)

Domain logical expression index: "p"

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

Domain logical expression index: "q"

Parametric boundary:The target chemical should have a value of Molecular weight which is >= 65.1 Da

Domain logical expression index: "r"

Parametric boundary:The target chemical should have a value of Molecular weight which is <= 526 Da

Conclusions:

The No Observed Adverse Effect Level (NOAEL) for Aluminium, 3-hydroxy-4-[(4-sulfo- 1-naphthalenyl)azo]-2,7-naphthalene disulfonic acid complex is predicted to be 1069.599975586 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 Aluminium, 3-hydroxy-4-[(4-sulfo-1-naphthalenyl)azo]-2,7- naphthalene disulfonic acid complex. The study assumed the use of male and female Wistar rats in a 90 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 Aluminium, 3-hydroxy-4-[(4-sulfo- 1-naphthalenyl)azo]-2,7-naphthalene disulfonic acid complex is predicted to be 1069.599975586 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.

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

1 069.6 mg/kg bw/day

Study duration:

subchronic

Species:

rat

Quality of whole database:

Data is from K2 QSAR prediction database

Endpoint conclusion:

no study available

Quality of whole database:

Waiver

Endpoint conclusion:

no study available

Endpoint conclusion:

no study available

Quality of whole database:

Waiver

Endpoint conclusion:

no study available

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 Aluminium, 3-hydroxy-4-[(4-sulfo-1-naphthalenyl)azo]-2,7- naphthalene disulfonic acid complex. The study assumed the use of male and female Wistar rats in a 90 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 Aluminium, 3-hydroxy-4-[(4-sulfo- 1-naphthalenyl)azo]-2,7-naphthalene disulfonic acid complex is predicted to be 1069.599975586 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) 50 -60% structurally similar rread 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).

Gaunt et al (Food and Cosmetic Toxicology, 1974) performed repeated oral toxicity of another 50 -60% structurally 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.

Toxicity of 50 -60% structurally similar read across chemical FD & C Red No. 40 (Allura red AC; RA CAS no 25956 -17 -6; IUPAC name: disodium 6-hydroxy-5-[(2-methoxy-3-methyl-4-sulfonato phenyl) diazenyl]naphthalene-2-sulfonate) was assessed by Borzelleca et al (Food and Cosmetic Toxicology, 1989) in Sprague Dawley rats in life time study. 30 Sprague Dawley rats per sex per dose group were fed FD & C Red No. 40 (Allura Red AC) in diet at dose concentration ofMales: 0.37, 1.39 or 5.19% (0, 180, 701,2829 mg/kg bw/day), Females: 0.37, 1.39 or 5.19% (0, 228, 901, 3604 mg/kg bw/day), 1 wk before mating, throughout the 3-wk breeding period, and during the gestation and lactation periods. No significant compound related adverse effect were observed on mortality, clinical signs, body weight (except for a reduction in body weight in high-dose females at the end of the study), food consumption, hematology, clinical chemistry, gross and .The no adverse-effect level (NOAEL) in this study were 5.19% (2829 mg/kg/day) for male rats, and 1.39% (901 mg/kg/day) for female rats.

Repeated dose toxicity: Inhalation

Aluminium, 3-hydroxy-4-[(4-sulfo-1-naphthalenyl)azo]-2,7-naphthalenedisulfonic acid complex has very low vapor pressure of 4.51E-23 mm Hg, so the potential for the generation of inhalable vapurs is very low, also the normal conditions of use of this substance will not result in aerosols, particles or droplets of an inhalable size, so exposure to humans via the inhalatory route will be highly unlikely and therefore is end point was considered for waiver

Repeated dose toxicity: Dermal

The acute dermal toxicity value for Aluminium, 3-hydroxy-4-[(4-sulfo-1-naphthalenyl)azo]-2,7- naphthalene disulfonic acid complex (as provided in section 7.2.3) based on the data available from the read across chemicals is >2000 mg/kg body weight. The substance was also considered to be not irritating and not sensitizing to the skin on the basis of read across data. Based on these considerations, the end point for repeated dermal toxicity is considered as waiver.

Based on the available data for the functionally similar read across chemicals and the applying the weight of evidence approach, Aluminium, 3-hydroxy-4-[(4-sulfo-1-naphthalenyl)azo]-2,7-naphthalenedisulfonic acid complex is considered to be not likely to classify as a toxicant upon repeated exposure by oral route.

Based on the available data for the functionally similar read across chemicals and the applying the weight of evidence approach, Aluminium, 3-hydroxy-4-[(4-sulfo-1-naphthalenyl)azo]-2,7-naphthalenedisulfonic acid complex (CAS no 12227 -62 -2) is considered to be not likely to classify as a toxicant upon repeated exposure by oral route.