Dialuminium tris[2-(2,4,5,7-tetrabromo-6-oxido-3-oxoxanthen-9-yl)-3,4,5,6-tetrachlorobenzoate]

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Description of key information

NOAEL was estimated to be 803 mg/kg bw when Wistar male and female rats were orally exposed with Di aluminium tris[2-(2,4,5,7-tetrabromo-6-oxido-3-oxoxanthen-9-yl)-3,4,5,6-tetrachlorobenzoate].

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 predicted using OECD QSAR toolbox version 3.4 and the supporting QMRF report has been attached

Qualifier:

according to guideline

Guideline:

other: as below

Principles of method if other than guideline:

Prediction is done using QSAR Toolbox version 3.4

GLP compliance:

not specified

Limit test:

no

Specific details on test material used for the study:

- Name of test material: 2',4',5',7'-tetrabromo-4,5,6,7-tetrachloro-3',6'-dihydroxy-3H-spiro[2-benzofuran-1,9'-xanthen]-3-one
-Common Name: D & C Red no. 27
- Molecular formula: C20H4Br4Cl4O5
- Molecular weight : 785.6746 g/mole
- SMILES:Oc1c(Br)cc2c(c1Br)Oc1c(cc(Br)c(O)c1Br)C21c2c(Cl)c(Cl)c(Cl)c(Cl)c2C(=O)O1
- Substance type: Organic
- Physical state: Solid

Species:

rat

Strain:

Wistar

Sex:

male/female

Route of administration:

oral: gavage

Type of inhalation exposure (if applicable):

not specified

Vehicle:

CMC (carboxymethyl cellulose)

Details on exposure:

not specified

Details on mating procedure:

not specified

Analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

Approx 47 days

Frequency of treatment:

Daily

Details on study schedule:

not specified

Dose / conc.:

803 mg/kg bw/day

No. of animals per sex per dose:

Total:30
Main groups : 10 males+10 females per group
Recovery groups : 5 males + 5 females per group

Control animals:

yes, concurrent vehicle

Details on study design:

not specified

Positive control:

not specified

Parental animals: Observations and examinations:

Body weight and food consumption were examined.

Oestrous cyclicity (parental animals):

Estrous cycle were examined.

Sperm parameters (parental animals):

not specified

Litter observations:

not specified

Postmortem examinations (parental animals):

Gross pathology and Histopathology were examined.

Postmortem examinations (offspring):

not specified

Statistics:

not specified

Reproductive indices:

not specified

Offspring viability indices:

not specified

Clinical signs:

not specified

Dermal irritation (if dermal study):

not specified

Mortality:

not specified

Body weight and weight changes:

no effects observed

Food consumption and compound intake (if feeding study):

no effects observed

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:

no effects observed

Histopathological findings: neoplastic:

not specified

Other effects:

not specified

Reproductive function: oestrous cycle:

no effects observed

Reproductive function: sperm measures:

not specified

Reproductive performance:

not specified

Dose descriptor:

NOAEL

Effect level:

803 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

body weight and weight gain

food consumption and compound intake

gross pathology

histopathology: non-neoplastic

reproductive function (oestrous cycle)

other: No effect observed

Remarks on result:

other: Generation not specified (migrated information)

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:

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

Reproductive function: oestrous cycle:

not specified

Reproductive function: sperm measures:

not specified

Reproductive performance:

not specified

Based on:

not specified

Sex:

not specified

Basis for effect level:

other: not specified

Remarks on result:

other: not specified

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:

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

Sexual maturation:

not specified

Organ weight findings including organ / body weight ratios:

not specified

Gross pathological findings:

not specified

Histopathological findings:

not specified

Other effects:

not specified

Behaviour (functional findings):

not specified

Developmental immunotoxicity:

not specified

Based on:

not specified

Sex:

not specified

Basis for effect level:

other: not specified

Remarks on result:

other: not specified

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:

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

Sexual maturation:

not specified

Organ weight findings including organ / body weight ratios:

not specified

Gross pathological findings:

not specified

Histopathological findings:

not specified

Other effects:

not specified

Behaviour (functional findings):

not specified

Developmental immunotoxicity:

not specified

Based on:

not specified

Sex:

not specified

Basis for effect level:

other: not specified

Remarks on result:

other: not specified

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" or "d" )  and ("e" and ( not "f") )  )  and ("g" and ( not "h") )  )  and ("i" and "j" )  )

Domain logical expression index: "a"

Referential boundary: The target chemical should be classified as Phenolphthaleins by US-EPA New Chemical Categories

Domain logical expression index: "b"

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 SNAr OR SNAr >> Nucleophilic aromatic substitution OR SNAr >> Nucleophilic aromatic substitution >> Activated halo-benzenes by Protein binding by OECD ONLY

Domain logical expression index: "c"

Referential boundary: The target chemical should be classified as High reactive AND High reactive >> Activated haloarenes by DPRA Cysteine peptide depletion

Domain logical expression index: "d"

Referential boundary: The target chemical should be classified as Low reactive AND Low reactive >> Activated haloarenes by DPRA Lysine peptide depletion

Domain logical expression index: "e"

Referential boundary: The target chemical should be classified as No alert found by DNA binding by OASIS v.1.4

Domain logical expression index: "f"

Referential boundary: The target chemical should be classified as AN2 OR AN2 >> Michael-type addition on alpha, beta-unsaturated carbonyl compounds OR AN2 >> Michael-type addition on alpha, beta-unsaturated carbonyl compounds >> Four- and Five-Membered Lactones OR AN2 >> Schiff base formation by aldehyde formed after metabolic activation OR AN2 >> Schiff base formation by aldehyde formed after metabolic activation >> Geminal Polyhaloalkane Derivatives OR AN2 >> Shiff base formation after aldehyde release OR AN2 >> Shiff base formation after aldehyde release >> Specific Acetate Esters OR Non-covalent interaction OR Non-covalent interaction >> DNA intercalation OR Non-covalent interaction >> DNA intercalation >> DNA Intercalators with Carboxamide and Aminoalkylamine Side Chain OR Non-covalent interaction >> DNA intercalation >> N-Hydroxyethyl Lactams 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 via ROS formation (indirect) OR Radical >> Radical mechanism via ROS formation (indirect) >> Geminal Polyhaloalkane Derivatives OR Radical >> Radical mechanism via ROS formation (indirect) >> Specific Imine and Thione Derivatives OR SN1 OR SN1 >> Nucleophilic attack after carbenium ion formation OR SN1 >> Nucleophilic attack after carbenium ion formation >> Specific Acetate Esters OR SN1 >> Nucleophilic substitution on diazonium ion OR SN1 >> Nucleophilic substitution on diazonium ion >> Specific Imine and Thione Derivatives OR SN2 OR SN2 >> Acylation OR SN2 >> Acylation >> Specific Acetate Esters OR SN2 >> Acylation involving a leaving group after metabolic activation OR SN2 >> Acylation involving a leaving group after metabolic activation >> Geminal Polyhaloalkane Derivatives OR SN2 >> Alkylation, ring opening SN2 reaction OR SN2 >> Alkylation, ring opening SN2 reaction >> Four- and Five-Membered Lactones OR SN2 >> Nucleophilic substitution at sp3 Carbon atom OR SN2 >> Nucleophilic substitution at sp3 Carbon atom >> Specific Acetate Esters OR SN2 >> Nucleophilic substitution at sp3 carbon atom after thiol (glutathione) conjugation OR SN2 >> Nucleophilic substitution at sp3 carbon atom after thiol (glutathione) conjugation >> Geminal Polyhaloalkane Derivatives by DNA binding by OASIS v.1.4

Domain logical expression index: "g"

Referential boundary: The target chemical should be classified as No alert found by Protein binding by OASIS v1.4

Domain logical expression index: "h"

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 >> Anhydrides (sulphur analogues of anhydrides)  OR Acylation >> Ester aminolysis OR Acylation >> Ester aminolysis >> Amides OR AN2 OR AN2 >> Michael-type addition to quinoid structures  OR AN2 >> Michael-type addition to quinoid structures  >> Substituted Phenols OR Radical reactions OR Radical reactions >> ROS Generation OR Radical reactions >> ROS Generation >> Sterically Hindered Piperidine Derivatives OR Schiff base formation OR Schiff base formation >> Direct acting Schiff base formers OR Schiff base formation >> Direct acting Schiff base formers >> 1,2-Dicarbonyls and 1,3-Dicarbonyls  by Protein binding by OASIS v1.4

Domain logical expression index: "i"

Parametric boundary:The target chemical should have a value of log Kow which is >= 3.32

Domain logical expression index: "j"

Parametric boundary:The target chemical should have a value of log Kow which is <= 13.2

Conclusions:

NOAEL was considered to be 803 mg/kg bw when Wistar male and female rats were orally exposed with Di aluminium tris[2-(2,4,5,7-tetrabromo-6-oxido-3-oxoxanthen-9-yl)-3,4,5,6-tetrachlorobenzoate].

Executive summary:

In reproductive toxicity stiudy, No effects on body weight and food consumption were observed in treated male and female rats. Similarly, no effect on estrous cycle was observed in treated female rats. Therefore, NOAEL was considered to be 803 mg/kg bw when Wistar male and female rats were orally exposed with Di aluminium tris[2-(2,4,5,7-tetrabromo-6-oxido-3-oxoxanthen-9-yl)-3,4,5,6-tetrachlorobenzoate].

Effect on fertility: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

803 mg/kg bw/day

Study duration:

subchronic

Species:

rat

Quality of whole database:

The data is K2 level and from QSAR Toolbox version 3.4

Effect on fertility: via inhalation route

Endpoint conclusion:

no study available

Effect on fertility: via dermal route

Endpoint conclusion:

no study available

Additional information

Effect on fertility: via oral route

In different studies, Di aluminium tris[2-(2,4,5,7-tetrabromo-6-oxido-3-oxoxanthen-9-yl)-3,4,5,6-tetrachlorobenzoate] has been reviewed 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 rat for Di aluminium tris[2-(2,4,5,7-tetrabromo-6-oxido-3-oxoxanthen-9-yl)-3,4,5,6-tetrachlorobenzoate] along with the study available on structurally similar read across substance D&C Red No. 27 (CAS no 13473-26-2), Phloxine (Food Red No. 104) (CAs no 6441-77-6) and 2',4',5',7'-tetrabromo-4,5,6,7-tetrachloro-3',6'-dihydroxy-3H-spiro[2-benzofuran-1,9'-xanthen]-3-one (CAS no 18472-87-2). The predicted data using the OECD QSAR toolbox has also been compared with the experimental studies.

In a prediction done by SSS (2017) using the OECD QSAR toolbox with log kow as the primary descriptor, the reproductive toxicity was estimated for Di aluminium tris[2-(2,4,5,7-tetrabromo-6-oxido-3-oxoxanthen-9-yl)-3,4,5,6-tetrachlorobenzoate]. No effects on body weight and food consumption were observed in treated male and female rats. Similarly, no effect on estrous cycle was observed in treated female rats. Therefore, NOAEL was estimated to be 803 mg/kg bw when Wistar male and female rats were orally exposed with Di aluminium tris[2-(2,4,5,7-tetrabromo-6-oxido-3-oxoxanthen-9-yl)-3,4,5,6-tetrachlorobenzoate].

In another study summarized by NTP (NTP (National Toxicological Program) by Agency for Toxic Substances and Disease Registry, 2000) on structurally similar read across substance D&C Red No. 27 (CAS no 13473-26-2), CD male and female rats were orally exposed to D&C Red No. 27 in diet at a dosage of 0, 5, 50, 150 or 500 mg/kg/day. No effects were observed on body weight of pups, fertility, litter size and sex composition, viability or survival of treated male and female rats. Histopathological examination of tissues from generations F1 and F2 showed no treatment related effects. Therefore, NOAEL was considered to be 500 mg/kg/day for the F0, F1 and F2 generation when CD male and female rats were orally exposed to D&C Red No. 27 during three generations.

Further this is supported by experimental study conducted by Nakauraet al(J. Food Hyg. Soc. Vol. 16, No. 1, pg 34-40 (SHOKUHIN EISEIGAKU ZASSHI)) on structurally similar read across substance Phloxine (Food Red No. 104) (CAs no 6441-77-6), female Wistar rats were orally exposed to Phloxine via their diet at a dosage of 0,280, 920 and 2870 mg/kg bw . As seen by the results, a slight inhibition on maternal weight gain, water consumption and a growth retardation in fetuses were observed in the 2870 mg/kg bw of Phloxine. No evidence of increase in fetal death or no malformation to be related to dietary Phloxine administration was observed, and no teratogenicity except mentioned above. Therefore, NOAEL was considered to be 2870 mg/kg bw in the F0 generation and 920 mg/kg bw in the F1 generation when female Wistar rats were orally exposed to Phloxine (Food Red No. 104) during gestation for 22 days.

Further supported by experimental study conducted by Senoet al(Food Chem. Toxic. Vol. 22, No. 1 pp. 55-60, 1984) on structurally similar read across substance 2',4',5',7'-tetrabromo-4,5,6,7-tetrachloro-3',6'-dihydroxy-3H-spiro[2-benzofuran-1,9'-xanthen]-3-one (CAS no 18472-87-2), Jcl: ICR female mice were treated with 2',4',5',7'-tetrabromo-4,5,6,7-tetrachloro-3',6'-dihydroxy-3H-spiro[2-benzofuran-1,9'-xanthen]-3-one in the concentration of 0, 1500, 4500 and 12000 mg/kg bw orally in feed from day 6 until 16 of gestation. Two of 21 dams in the 5% group died, one on each of days 16 and 17. Another female in this group aborted on day 17. These three animals were excluded from all computations. Otherwise, no overt signs of toxicity were observed in dams from any of the experimental groups. Maternal body-weight gains for days 6--16 of gestation were significantly decreased in all of the treated groups as compared to control. Average food intakes of the groups were approximately equal in all the treated mice. The maternal liver weight was significantly increased among dams in 12000 mg/kg bw group, but not among those receiving the 1500 and 4500 mg/kg bw doses as compared with the control. Similarly, the numbers of corpora lutea, implantations or live fetuses in all of the treated groups were slightly decreased, but not significantly in comparison with those of the control. No effects of treatment on the numbers of resorptions or dead fetuses were observed. Nor did the percentage of resorptions, the numbers of male and female fetuses or the mean fetal body weight show any changes due to treatment. In addition, the number of live fetuses decreased slightly at 1500, 4500 and 12000 mg/kg bw but not significantly as compared to control. Mean fetal body weight showed no changes due to treatment. Fetuses with open eyelids were found in 1500, 4500 and 12000 mg/kg bw groups. Exencephaly occurred in the control and 12000 mg/kg bw. Incidence of cleft palate in the 12000 mg/kg bw was significantly increased in comparison with the control. No dose-response was evident in the total incidence of external anomalies. None of the fetuses examined showed any soft-tissue anomalies. The numbers of ossified caudal vertebrae and phalanges were significantly decreased at the 12000 mg/kg bw dose level when compared with the control. The incidence of accessory sternebrae was slightly reduced at 12000 mg/kg bw, but not significantly as comparison to control. There was no dose-related effect on the incidence of cervical ribs. A significant increase in the total incidence of skeletal anomalies was observed at 4500 and 12000 mg/kg bw levels, where a dose-response was evident in the total incidence of skeletal anomalies as compared to control. Therefore, NOAEL for P generation and LOAEL for F1 generation was considered to be 1500 mg/kg bw when Jcl: ICR female mice were treated with 2',4',5',7'-tetrabromo-4,5,6,7-tetrachloro-3',6'-dihydroxy-3H-spiro[2-benzofuran-1,9'-xanthen]-3-one orally in feed from day 6 until 16 of gestation.

Thus, based on the above studies and predictions on Di aluminium tris[2-(2,4,5,7-tetrabromo-6-oxido-3-oxoxanthen-9-yl)-3,4,5,6-tetrachlorobenzoate] and its read across substances, it can be concluded that NOAEL 805 value. Thus, comparing this value with the criteria of CLP regulation, Di aluminium tris[2-(2,4,5,7-tetrabromo-6-oxido-3-oxoxanthen-9-yl)-3,4,5,6-tetrachlorobenzoate] can be Not classified for repeated dose toxicity.

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

Based on the above studies and predictions on Di aluminium tris[2-(2,4,5,7-tetrabromo-6-oxido-3-oxoxanthen-9-yl)-3,4,5,6-tetrachlorobenzoate] and its read across substances, it can be concluded that NOAEL 805 value. Thus, comparing this value with the criteria of CLP regulation, Di aluminium tris[2-(2,4,5,7-tetrabromo-6-oxido-3-oxoxanthen-9-yl)-3,4,5,6-tetrachlorobenzoate] can be Not classified for repeated dose toxicity.