Registration Dossier

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 toxicity was predicted for 3,4,5,6-tetrachloro-2-(2,4,5,7-tetrabromo-3,6-dihydroxyxanthen-9-yl)benzoic acid, aluminium salt. The study assumed the use of male and female Wistar rats in Repeated Dose Toxicity Study for 13 weeks. Since no significant treatment related effects were observed, hence the No Observed Adverse Effect Level (NOAEL) for 3,4,5,6-tetrachloro-2-(2,4,5,7-tetrabromo-3,6-dihydroxyxanthen-9-yl)benzoic acid, aluminium salt is predicted to be 523.773681641 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

3,4,5,6-tetrachloro-2-(2,4,5,7-tetrabromo-3,6-dihydroxyxanthen-9-yl)benzoic acid, aluminium salt has very low vapor pressure (4.49E-018 Pa), so the potential for the generation of inhalable vapours 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 this end point was considered for waiver

Repeated dose toxicity: Dermal

The acute dermal toxicity value for 3,4,5,6-tetrachloro-2-(2,4,5,7-tetrabromo-3,6-dihydroxyxanthen-9-yl)benzoic acid, aluminium salt (as provided in section 7.2.3) is >2000 mg/kg body weight. The substance is also found to be not irritating to skin. Based on these considerations, the end point is considered as waiver.

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 3.3 and the supporting QMRF report has been attached

Qualifier:

according to guideline

Guideline:

other: Refer below principle

Principles of method if other than guideline:

This was a reproductive study performed in two parts. Haematology, clinical chemistry, and histopathology in males were reported in Mattie et al. 1995 and were not repeated as part of this study design. In the first part, males were treated for 70 to 90

Prediction is done using OECD QSAR Toolbox version 3.3, 2017

GLP compliance:

not specified

Specific details on test material used for the study:

- Name of the test material: 3,4,5,6-tetrachloro-2-(2,4,5,7-tetrabromo-3,6-dihydroxyxanthen-9-yl)benzoic acid, aluminium salt
- IUPAC name: 3,4,5,6-tetrachloro-2-(2,4,5,7-tetrabromo-3,6-dihydroxyxanthen-9-yl)benzoic acid, aluminium salt
- Molecular Formula: C20H4Br4Cl4O5.xAl
- Molecular Weight: 2387.0295 g/mol
- Substance type: Organic
- Smiles: c1c2c(c(c(c1Br)O)Br)Oc3c(cc(c(c3Br)O)Br)C2c4c(c(c(c(c4Cl)Cl)Cl)Cl)C(=O)[O-].c1c2c(c(c(c1Br)O)Br)Oc3c(cc(c(c3Br)O)Br)C2c4c(c(c(c(c4Cl)Cl)Cl)Cl)C(=O)[O-].c1c2c(c(c(c1Br)O)Br)Oc3c(cc(c(c3Br)O)Br)C2c4c(c(c(c(c4Cl)Cl)Cl)Cl)C(=O)[O-].[Al+3]

Species:

rat

Strain:

not specified

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:

13 weeks

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

Dose descriptor:

NOAEL

Effect level:

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

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 15 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 ( not "r") ) ) and "s" ) and "t" ) and "u" ) and ("v" and ( not "w") ) ) and ("x" and "y" ) )

Domain logical expression index: "a"

Referential boundary: The target chemical should be classified as Aromatic compound OR Aryl bromide OR Aryl chloride OR Aryl halide OR Carbonic acid derivative OR Carboxylic acid OR Carboxylic acid derivative OR Diarylether OR Ether OR Halogen derivative OR Heterocyclic compound OR Hydroxy compound OR No functional group found OR Phenol by Organic functional groups, Norbert Haider (checkmol) ONLY

Domain logical expression index: "b"

Referential boundary: The target chemical should be classified as Acid, aromatic attach [-COOH] OR Alcohol, olefinic attach [-OH] OR Aliphatic Carbon [CH] OR Aliphatic Carbon, two phenyl attach [-C-] OR Aliphatic Oxygen, two aromatic attach [-O-] OR Aluminium [Al] OR Aromatic Carbon [C] OR Bromine, aromatic attach [-Br] OR Bromine, olefinic attach [-Br] OR Carbonyl, olefinic attach [-C(=O)-] OR Carbonyl, one aromatic attach [-C(=O)-] OR Chlorine, aromatic attach [-Cl] OR Chlorine, olefinic attach [-Cl] OR Hydroxy, aromatic attach [-OH] OR Miscellaneous sulfide (=S) or oxide (=O) OR Olefinic carbon [=CH- or =C<] OR Oxygen, one aromatic attach [-O-] OR Oxygen, two olefinic attach [-O-] OR Tertiary Carbon by Organic functional groups (US EPA) ONLY

Domain logical expression index: "c"

Referential boundary: The target chemical should be classified as Aromatic perhalogencarbons OR Aryl halide OR Carboxylic acid OR No functional group found OR Overlapping groups OR Phenol OR Xanthene by Organic Functional groups (nested) ONLY

Domain logical expression index: "d"

Referential boundary: The target chemical should be classified as Aromatic perhalogencarbons OR Aryl OR Aryl halide OR Carboxylic acid OR Fused carbocyclic aromatic OR Fused saturated heterocycles OR No functional group found OR Phenol OR Xanthene by Organic Functional groups ONLY

Domain logical expression index: "e"

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

Domain logical expression index: "f"

Referential boundary: The target chemical should be classified as Michael addition OR Michael addition >> P450 Mediated Activation of Heterocyclic Ring Systems OR Michael addition >> P450 Mediated Activation of Heterocyclic Ring Systems >> Furans OR Michael addition >> P450 Mediated Activation to Quinones and Quinone-type Chemicals OR Michael addition >> P450 Mediated Activation to Quinones and Quinone-type Chemicals >> Alkyl phenols OR Michael addition >> P450 Mediated Activation to Quinones and Quinone-type Chemicals >> Arenes OR Michael addition >> P450 Mediated Activation to Quinones and Quinone-type Chemicals >> Hydroquinones OR Michael addition >> Polarised Alkenes-Michael addition OR Michael addition >> Polarised Alkenes-Michael addition >> Alpha, beta- unsaturated amides OR Michael addition >> Polarised Alkenes-Michael addition >> Alpha, beta- unsaturated esters OR Michael addition >> Polarised Alkenes-Michael addition >> Alpha, beta- unsaturated ketones OR SN1 OR SN1 >> Carbenium Ion Formation OR SN1 >> Carbenium Ion Formation >> Hydrazine OR SN1 >> Iminium Ion Formation OR SN1 >> Iminium Ion Formation >> Aliphatic tertiary amines OR SN1 >> Nitrenium Ion formation OR SN1 >> Nitrenium Ion formation >> Aromatic azo OR SN1 >> Nitrenium Ion formation >> Unsaturated heterocyclic azo OR SN2 OR SN2 >> Epoxidation of Aliphatic Alkenes OR SN2 >> Epoxidation of Aliphatic Alkenes >> Halogenated polarised alkenes by DNA binding by OECD

Domain logical expression index: "g"

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

Domain logical expression index: "h"

Referential boundary: The target chemical should be classified as AN2 OR AN2 >> Michael-type addition, quinoid structures OR AN2 >> Michael-type addition, quinoid structures >> Quinoneimines OR AN2 >> Carbamoylation after isocyanate formation OR AN2 >> Carbamoylation after isocyanate formation >> N-Hydroxylamines OR AN2 >> Nucleophilic addition to alpha, beta-unsaturated carbonyl compounds OR AN2 >> Nucleophilic addition to alpha, beta-unsaturated carbonyl compounds >> alpha, beta-Unsaturated Aldehydes OR AN2 >> Schiff base formation OR AN2 >> Schiff base formation >> alpha, beta-Unsaturated Aldehydes OR AN2 >> Shiff base formation after aldehyde release OR AN2 >> Shiff base formation after aldehyde release >> Specific Acetate Esters 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 by ROS formation (indirect) or direct radical attack on DNA OR Radical >> Radical mechanism by ROS formation (indirect) or direct radical attack on DNA >> Organic Peroxy Compounds OR Radical >> Radical mechanism via ROS formation (indirect) OR Radical >> Radical mechanism via ROS formation (indirect) >> N-Hydroxylamines OR Radical >> Radical mechanism via ROS formation (indirect) >> Specific Imine and Thione Derivatives OR Radical >> ROS formation after GSH depletion (indirect) OR Radical >> ROS formation after GSH depletion (indirect) >> Quinoneimines 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 >> Nucleophilic substitution at sp3 Carbon atom OR SN2 >> Nucleophilic substitution at sp3 Carbon atom >> Specific Acetate Esters by DNA binding by OASIS v.1.3

Domain logical expression index: "i"

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: "j"

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

Domain logical expression index: "k"

Referential boundary: The target chemical should be classified as No alert found AND SNAr AND SNAr >> Nucleophilic aromatic substitution AND SNAr >> Nucleophilic aromatic substitution >> Activated halo-benzenes by Protein binding by OECD

Domain logical expression index: "l"

Referential boundary: The target chemical should be classified as Acylation OR Acylation >> Direct Acylation Involving a Leaving group OR Acylation >> Direct Acylation Involving a Leaving group >> Acetates OR Michael addition OR Michael addition >> Polarised Alkenes OR Michael addition >> Polarised Alkenes >> Polarised alkene - cyano by Protein binding by OECD

Domain logical expression index: "m"

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

Domain logical expression index: "n"

Referential boundary: The target chemical should be classified as Aliphatic nitriles (Hepatotoxicity) Rank B OR Aliphatic/Alicyclic hydrocarbons (Alpha 2u-globulin nephropathy) Rank C OR Carboxylic acids (Hepatotoxicity) No rank OR Ethionine (Hepatotoxicity) Alert OR Perhexiline (Hepatotoxicity) Alert OR Valproic acid (Hepatotoxicity) Alert by Repeated dose (HESS)

Domain logical expression index: "o"

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

Domain logical expression index: "p"

Referential boundary: The target chemical should be classified as Alkali Earth OR Alkaline Earth OR Metalloids OR Rare Earth OR Transition Metals by Groups of elements

Domain logical expression index: "q"

Referential boundary: The target chemical should be classified as Group 13 - Metals Al,Ga,In,Tl AND Group 14 - Carbon C AND Group 16 - Oxygen O AND Group 17 - Halogens Br AND Group 17 - Halogens Cl AND Group 17 - Halogens F,Cl,Br,I,At by Chemical elements

Domain logical expression index: "r"

Referential boundary: The target chemical should be classified as Group 14 - Metals Sn,Pb OR Group 15 - Nitrogen N OR Group 15 - Phosphorus P OR Group 16 - Sulfur S OR Group 17 - Halogens I by Chemical elements

Domain logical expression index: "s"

Referential boundary: The target chemical should be classified as Aromatic perhalogencarbons AND Aryl AND Aryl halide AND Carboxylic acid AND Fused carbocyclic aromatic AND Fused saturated heterocycles AND No functional group found AND Phenol AND Xanthene by Organic Functional groups ONLY

Domain logical expression index: "t"

Referential boundary: The target chemical should be classified as Aromatic compound AND Aryl bromide AND Aryl chloride AND Aryl halide AND Carbonic acid derivative AND Carboxylic acid AND Carboxylic acid derivative AND Diarylether AND Ether AND Halogen derivative AND Heterocyclic compound AND Hydroxy compound AND No functional group found AND Phenol by Organic functional groups, Norbert Haider (checkmol) ONLY

Domain logical expression index: "u"

Referential boundary: The target chemical should be classified as Moderate AND Very fast by Bioaccumulation - metabolism half-lives ONLY

Domain logical expression index: "v"

Referential boundary: The target chemical should be classified as No Data by Ultimate biodeg

Domain logical expression index: "w"

Referential boundary: The target chemical should be classified as > 100 days OR 1 to 10 days by Ultimate biodeg

Domain logical expression index: "x"

Parametric boundary:The target chemical should have a value of log Kow which is >= 3.78

Domain logical expression index: "y"

Parametric boundary:The target chemical should have a value of log Kow which is <= 5.74

Conclusions:

The No Observed Adverse Effect Level (NOAEL) for 3,4,5,6-tetrachloro-2-(2,4,5,7-tetrabromo-3,6-dihydroxyxanthen-9-yl)benzoic acid, aluminium salt is predicted to be 523.773681641 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 toxicity was predicted for 3,4,5,6-tetrachloro-2-(2,4,5,7-tetrabromo-3,6-dihydroxyxanthen-9-yl)benzoic acid, aluminium salt. The study assumed the use of male and female Wistar rats in Repeated Dose Toxicity Study for 13 weeks. Since no significant treatment related effects were observed, hence the No Observed Adverse Effect Level (NOAEL) for 3,4,5,6-tetrachloro-2-(2,4,5,7-tetrabromo-3,6-dihydroxyxanthen-9-yl)benzoic acid, aluminium salt is predicted to be 523.773681641 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

523.774 mg/kg bw/day

Study duration:

chronic

Species:

rat

Quality of whole database:

Data is from K2 prediction database

Reference

Endpoint:: repeated dose toxicity: inhalation, other
Data waiving:: other justification
Justification for data waiving:: other:

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

Prediction model based etimation and data from read across chemicals have been reviewed to determine the toxic nature of 3,4,5,6-tetrachloro

-2-(2,4,5,7-tetrabromo-3,6-dihydroxyxanthen-9-yl)benzoic acid, aluminium salt upon repeated exposure by oral route. The studies are as mentioned below:

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 toxicity was predicted for 3,4,5,6-tetrachloro-2-(2,4,5,7-tetrabromo-3,6-dihydroxyxanthen-9-yl)benzoic acid, aluminium salt. The study assumed the use of male and female Wistar rats in Repeated Dose Toxicity Study for 13 weeks. Since no significant treatment related effects were observed, hence the No Observed Adverse Effect Level (NOAEL) for 3,4,5,6-tetrachloro-2-(2,4,5,7-tetrabromo-3,6-dihydroxyxanthen-9-yl)benzoic acid, aluminium salt is predicted to be 523.773681641 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.

The predicted data is further supported by the data from read across chemicals.

In a study by Sweeta et al (Food and Chemical Toxicology, 2004) Repeated dose oral toxicity study was performed to determine the toxic nature of 93.37% structurally and functionally similar read across chemical D&C Red No. 28 (RA CAS no 18472 -87 -2; IUPAC name: 2',4',5',7'-tetrabromo-4,5,6,7-tetrachloro-3',6'-dihydroxy-3H-spiro[2-benzofuran-1,9'-xanthen]-3-one) using rats. Two groups of 8 week old 28 male Fischer-344 rats each were fed a diet containing blended rat chow (Teklad 4% Mouse-Rat Diet) mixed with Red 28 for 14 days such that their daily intake would be 500 mg/kg. Rats were weighed every other day. Food containers were also weighed every day to determine the amount of consumed diet. The diet was prepared and replaced every three days based on the actual food consumption and weight of the animals over the two-week period. On day 15, after a 12 h fasting period, one group was dosed by oral gavage with the dye (500 mg/kg; 2 ml/kg) in water while the other group was dosed with the vehicle (water, 2 ml/kg). To determine plasma kinetics and background levels of Red 28 from the diet, four rats from each group were killed by CO2 inhalation at 1, 2, 4, 8, 12, 24 and 48 h post dosing. At these times, blood (4–5 ml) was immediately collected from the posterior vena cava into a heparinized syringe and processed. An increase in body weight gain was observed in treated rats over the 14 days study period. 8-week-old rats at the start of the study weiged 168 g±6 g and by 10 weeks they weighed 225 g±10 g. As no control animals were included in the study, the effects were not supposed to be treatment related. No Red 28 dye was detected in the urine or cage rinse of treated rats. Based on the observations made, the No Observed Adverse Effdect level (NOAEL) was considered to be 500 mg/kg/day when Fischer-344 (F-344) male rats were treated with D&C Red No. 28.

In another study for 50 -60% structurally simlar read across chemical, repeated dose toxicity study was performed. Female Wistar rats were orally exposed to Phloxine (RA CAS no 6441 -77 -6; Regulatory name: Dipotassium 3,6-dichloro-2-(2,4,5,7-tetrabromo-6-oxido-3-oxoxanthen-9-yl)benzoate

) via their diet at a dosage of 0, 280, 920 and 2870 mg/kgbw/day. As seen by the results, an inhibition on maternal weight gain and a growth retardation in fetuses were observed in the highest dose level 2870 mg/kgbw/day of Phloxine. No evidence of increase in fetal death or no malformation to be related to dietary Phloxine administration was observed, and no teratogenicity was observed. Therefore, the no observed adverse effect level (NOAEL) was considered to be 2870mg/kgbw/day in the F0 generation and 920mg/kgbw/day in the F1 generation when female Wistar rats were orally exposed to Phloxine (Food Red No. 104) during gestation.

Repeated dose toxicity: Inhalation

3,4,5,6-tetrachloro-2-(2,4,5,7-tetrabromo-3,6-dihydroxyxanthen-9-yl)benzoic acid, aluminium salt has very low vapor pressure (4.49E-018 Pa), so the potential for the generation of inhalable vapours 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 this end point was considered for waiver

Repeated dose toxicity: Dermal

The acute dermal toxicity value for 3,4,5,6-tetrachloro-2-(2,4,5,7-tetrabromo-3,6-dihydroxyxanthen-9-yl)benzoic acid, aluminium salt (as provided in section 7.2.3) is >2000 mg/kg body weight. The substance is also found to be not irritating to skin. Based on these considerations, the end point is considered as waiver.

Based on the data available for the target chemical and its read across, 3,4,5,6-tetrachloro-2-(2,4,5,7-tetrabromo-3,6-dihydroxyxanthen-9-yl)benzoic acid, aluminium salt is not likely to classify as a toxicant upon repeated exposuure by oral route as per the criteria mentioned in CLP regulation.

Based on the data available for the target chemical and its read across, 3,4,5,6-tetrachloro-2-(2,4,5,7-tetrabromo-3,6-dihydroxyxanthen-9-yl)benzoic acid, aluminium salt (CAS no 84473 -86 -9) is not likely to classify as a toxicant upon repeated exposuure by oral route as per the criteria mentioned in CLP regulation.