Hydrogen [4-[4-(diethylamino)-2',4'-disulphonatobenzhydrylidene]cyclohexa-2,5-dien-1-ylidene]diethylammonium, aluminium salt

Endpoint summary

Description of key information

Repeated dose toxicity: Oral

Based on the prediction done using the OECD QSAR toolbox version 3.4 with log kow as the primary descriptor and considering the five closest read across substances, repeated dose oral toxicity was predicted for the test compound Hydrogen [4-[4-(diethylamino)-2',4'-disulphonatobenzhydrylidene]cyclohexa- 2,5-dien -1-ylidene] diethylammonium, aluminium salt. The study assumed the use of male and female Wistar rats in a study of upto 28 days. No significant alterations were noted at the dose level of 525 mg/Kg bw/day. The predicted No Observed Adverse Effect Level (NOAEL) for Hydrogen [4-[4-(diethylamino)-2',4'-disulphonatobenzhydrylidene]cyclohexa-2,5-dien-1-ylidene]diethylammonium, aluminium salt is considered to be 525 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:

short-term 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:

equivalent or similar to guideline

Guideline:

other: Refer below principle

Principles of method if other than guideline:

Prediction is done using OECD QSAR Toolbox version 3.4, 2017

GLP compliance:

no

Specific details on test material used for the study:

- Name of the test chemical: Hydrogen [4-[4-(diethylamino)-2',4'-disulphonatobenzhydrylidene]cyclohexa-2,5-dien-1-ylidene]diethylammonium, aluminium salt
- Molecular formula: C27H32N2O6S2.1/3Al
- Molecular weight: 1658.0277 g/mol
Smiles Notation: CCN(CC)c1ccc(cc1)C(=C2C=CC(=[N+](CC)CC)C=C2)c3ccc(cc3S(=O)(=O)[O-])S(=O)(=O)[O-].CCN(CC)c1ccc(cc1)C(=C2C=CC(=[N+] (CC)CC)C=C2)c3ccc(cc3S(=O)(=O)[O-])S(=O)(=O)[O-].CCN(CC)c1ccc(cc1)C(=C2C=CC(=[N+](CC)CC)C=C2)c3ccc(cc3S(=O)(=O)[O-])S(=O)(=O)[O-].[Al+3]
InChI: 1S/3C27H32N2O6S2.Al/c3*1-5-28(6-2)22-13-9-20(10-14-22)27(21-11-15-23(16-12-21)29(7-3)8-4)25-18-17-24(36(30,31)32)19-26(25)37(33,34) 35;/h3*9-19H,5-8H2,1-4H3,(H-,30,31,32,33,34,35);/q;;;+3/p-3
- 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:

up to 28 days

Frequency of treatment:

No data

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:

525 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,NOEL
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 "g" )  )

Domain logical expression index: "a"

Referential boundary: The target chemical should be classified as Alkene AND Ammonium salt AND Aromatic amine AND Aryl AND Sulfonic acid by Organic Functional groups

Domain logical expression index: "b"

Referential boundary: The target chemical should be classified as Alkene AND Ammonium salt AND Aromatic amine AND Aryl AND Overlapping groups AND Sulfonic acid by Organic Functional groups (nested)

Domain logical expression index: "c"

Referential boundary: The target chemical should be classified as Aliphatic Carbon [CH] AND Aliphatic Carbon [-CH2-] AND Aliphatic Carbon [-CH3] AND Aliphatic Nitrogen, one aromatic attach [-N] AND Amino, aliphatic attach [-N<] AND Aromatic Carbon [C] AND Hydroxy, sulfur attach [-OH] AND Miscellaneous sulfide (=S) or oxide (=O) AND Olefinic carbon [=CH- or =C<] AND Suflur {v+4} or {v+6} AND Sulfinic acid [-S(=O)OH] AND Sulfonate, aromatic attach [-SO2-O] by Organic functional groups (US EPA)

Domain logical expression index: "d"

Referential boundary: The target chemical should be classified as Amine AND Anion AND Aromatic compound AND Cation AND Sulfonic acid AND Sulfonic acid derivative AND Tertiary amine AND Tertiary mixed amine by Organic functional groups, Norbert Haider (checkmol)

Domain logical expression index: "e"

Similarity boundary:Target: CCN(CC)c1ccc(C(=C2C=CC(=N{+}(CC)CC)C=C2)c2ccc(S(=O)(=O)O{-})cc2S(O)(=O)=O)cc1
Threshold=50%,
Dice(Atom centered fragments)
Atom type; Count H attached; Hybridization

Domain logical expression index: "f"

Parametric boundary:The target chemical should have a value of log Kow which is >= 0.413

Domain logical expression index: "g"

Parametric boundary:The target chemical should have a value of log Kow which is <= 7.55

Conclusions:

The predicted No Observed Adverse Effect Level (NOAEL) for Hydrogen [4-[4-(diethylamino)-2',4'-disulphonatobenzhydrylidene]cyclohexa-2,5-dien-1-ylidene]diethylammonium, aluminium salt is considered to be 525 mg/Kg bw/day.

Executive summary:

Based on the prediction done using the OECD QSAR toolbox version 3.4 with log kow as the primary descriptor and considering the five closest read across substances, repeated dose oral toxicity was predicted for the test compound Hydrogen [4-[4-(diethylamino)-2',4'-disulphonatobenzhydrylidene]cyclohexa- 2,5-dien -1-ylidene] diethylammonium, aluminium salt. The study assumed the use of male and female Wistar rats in a study of upto 28 days. No significant alterations were noted at the dose level of 525 mg/Kg bw/day. The predicted No Observed Adverse Effect Level (NOAEL) for Hydrogen [4-[4-(diethylamino)-2',4'-disulphonatobenzhydrylidene]cyclohexa-2,5-dien-1-ylidene]diethylammonium, aluminium salt is considered to be 525 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

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

525 mg/kg bw/day

Study duration:

subacute

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

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 estimation and data from read across chemicals have been reviwed to determine the toxic nature of Hydrogen [4-[4-(diethylamino) -2',4'-disulphonatobenzhydrylidene]cyclohexa- 2,5-dien -1-ylidene] diethylammonium, aluminium salt pon repeated exposure by oral route. The studies are as mentioned below:

Based on the prediction done using the OECD QSAR toolbox version 3.4 with log kow as the primary descriptor and considering the five closest read across substances, repeated dose oral toxicity was predicted for the test compound Hydrogen [4-[4-(diethylamino)-2',4'-disulphonatobenzhydrylidene]cyclohexa- 2,5-dien -1-ylidene] diethylammonium, aluminium salt. The study assumed the use of male and female Wistar rats in a study of upto 28 days. No significant alterations were noted at the dose level of 525 mg/Kg bw/day. The predicted No Observed Adverse Effect Level (NOAEL) for Hydrogen [4-[4-(diethylamino)-2',4'-disulphonatobenzhydrylidene]cyclohexa-2,5-dien-1-ylidene]diethylammonium, aluminium salt is considered to be 525 mg/Kg bw/day.

In a study by Hall et al (Food and Cosmetic Toxicology, 1967) for >99% structurally and functionally similar read across chemical, Chronic repeated dose toxicity study of SPF Carworth Farm E male and female rats with Blue VRS (RA CAS no 129 -17 -9; IUPAC name: hydrogen [4-[4-(diethylamino)- 2',4'-disulphonato benzhydrylidene]cyclohexa-2,5-dien-1-ylidene]diethylammonium, sodium salt) at a concentration of 0.0, 0.3, 0.75, 1.5 and 3.0 % (0, 150, 375, 750 and 1500 mg/kg/day) orally was performed. Impairment of growth, Reduction in food consumption, compound intake and bluish-green and slightly more acid urine were observed in 1.5 and 3.0 % treated male and female as compared to control. In addition, Fatty changes in the liver of female rat and increase number of active acini in the thyroids of male rat of 1.5 and 3.0 % treated animals. Blue material in the lumen of convoluted tubules associated with a coloured line observed at the cortcomedullary junction of kidney in male of 3.0 % treated dose groups but this was not necessarily attributable to Blue VRS. Histological changes associated with acinal activity occur in response to stress of various kinds were noted. Therefore, the no observed adverse effect level (NOAEL) was considered to be 375 mg/kg/day (0.75 %) when SPF Carworth Farm E male and female rats were treated with Blue VRS orally for 90 days.

Repeated dose oral toxicity study was performed by Davis et al (Toxicology and Applied Pharmacology, 1966) for the structurally and functionally similar read across chemical Ponceau SX (RA CAS no 4548 -53 -2; IUPAC name: disodium 3-[(2,4-dimethyl-5-sulfonatophenyl)diazenyl]-4-hydroxynaphthalene -1- sulfonate) using Osborne-Mendel male and female rats. The study was performed using 12 male and 12 female rats each at dose levels of 5.0, 2.0, 1.0, 0.5, or 0.0% (2500, 1000, 500, 250 and 0 mg/kg) for 2 years. The animals were subjected to hematology, gross and microscopic pathology. 104 of the 120 rats were received in the Pathology Laboratory for gross and microscopic examination (the remaining 16 rats were discarded because of advanced postmortem autolysis). Tissues sectioned include the following: liver, lung, heart, spleen, pancreas, stomach, small intestine, colon, kidney, adrenal, thyroid, testis (or ovary and uterus), leg muscles, leg bones with included marrow, and any tumor or other unusual condition. Of the 12 animals, examinations were made of urinary bladder of 11 animals, prostate of 6, and parathyroid of 6. During the study, growth effect was negligible, and there was no effect on survival. No effect of chemical were observed on weights of heart, liver, kidney, spleen, and testes at autopsy. Gross lesions most commonly seen were tumors and granular kidneys but none was related to Ponceau SX treatment. Non treatment related chronic pneumonia and testicular atrophy of moderate or greater degree were infrequent. Other gross lesions (some of which were examined microscopically) occurred at random in the following numbers of animals among the 104 rats examined: middle ear infection, 5; enlarged spleen, 4; mesenteric arteritis, 2; left tubo-ovarian abscess, 2; cataract, 2; distended urinary bladder (hydronephrosis with one), 2; one each of dilated mammary ducts, distended cecum and colon, enlarged right seminal vesicle, emaciation, and mouth infection from long teeth. No microscopic pathologic changes were attributed to Ponceau SX. The most commonly occurring tumors were pulmonary lymphosarcoma and various types of mammary tumors. The nephritis was of the usual chronic variety in all groups. The incidental microscopic pathological findings, again randomly distributed and not attributable to Ponceau SX treatment, included myelosis in the four enlarged spleens (all four animals had tumors, some ulcerated), arteritis in the kidneys of two rats (plus testis in one), and squamous metaplasia in the glandular stomach of one animal. Based on the observations made, the No Observed Adverse Effect Level (NOAEL) for Ponceau SX is considered to be 5% (2500 mg/kg/day) when Osborne-Mendel rats were exposed to the test chemical upon repeated exposure by oral route.

Based on the data available for the target chemical and its read across, Hydrogen [4-[4-(diethylamino)-2',4'-disulphonatobenzhydrylidene]cyclohexa- 2,5-dien -1-ylidene] diethylammonium, aluminium salt is not likely to be toxic upon repeated exposure by oral route.

Justification for classification or non-classification

Based on the data available for the target chemical and its read across, Hydrogen [4-[4-(diethylamino)-2',4'-disulphonatobenzhydrylidene]cyclohexa- 2,5-dien -1-ylidene] diethylammonium, aluminium salt (CAS no 15876 -40 -1) is not likely to be toxic upon repeated exposure by oral route.