3,4,5,6-tetrachloro-2-(2,4,5,7-tetrabromo-3,6-dihydroxyxanthen-9-yl)benzoic acid, aluminium salt

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Description of key information

Toxicity to reproduction

In a prediction done by SSS (2017) using the OECD QSAR toolbox with log kow as the primary descriptor, the reproductive toxicity was estimated 3,4,5,6-tetrachloro-2-(2,4,5,7-tetrabromo-3,6-dihydroxyxanthen-9-yl)benzoic acid, aluminium salt (84473-86-9). Male and female reproductive parameters were unaffected by test material administration. Hence, NOAEL was estimated to be 845.875mg/kg bw. When male and femalewistar ratswere exposed with 3,4,5,6-tetrachloro-2-(2,4,5,7-tetrabromo-3,6-dihydroxyxanthen-9-yl)benzoic acid, aluminium salt (84473-86-9) orally.

Thus, comparing this value with the criteria of CLP regulation 3,4,5,6-tetrachloro-2-(2,4,5,7-tetrabromo-3,6-dihydroxyxanthen-9-yl)benzoic acid, aluminium salt (84473-86-9) can be "Not classified" for reproductive toxicity.

 

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 from OECD QSAR toolbox v3.3 and the QMRF report has been attached.

Qualifier:

equivalent or similar to guideline

Guideline:

other: As mentioned below

Principles of method if other than guideline:

Prediction was done using OECD QSAR toolbox v3.3, 2017

GLP compliance:

not specified

Limit test:

no

Justification for study design:

No data available

Specific details on test material used for the study:

- Name of test material : 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
- Smiles notation : 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]
- InChl: 1S/3C20H6Br4Cl4O5.Al/c3*21-5-1-3-7(8-9(20(31)32)13(26)15(28)14(27)12(8)25)4-2-6(22)17(30)11(24)19(4)33-18(3)10(23)16(5)29;/h3*1-2,7,29-30H,(H,31,32);/q;;;+3/p-3
- Substance type:Organic
- Physical state:Solid

Species:

rat

Strain:

Wistar

Details on species / strain selection:

No data available

Sex:

male/female

Details on test animals or test system and environmental conditions:

No data available

Route of administration:

oral: gavage

Vehicle:

arachis oil

Details on exposure:

No data available

Details on mating procedure:

No data available

Analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

6 weeks

Frequency of treatment:

daily

Details on study schedule:

No data available

Dose / conc.:

845.875 mg/kg bw/day (nominal)

No. of animals per sex per dose:

12

Control animals:

yes, concurrent vehicle

Details on study design:

No data available

Positive control:

No data available

Parental animals: Observations and examinations:

No data available

Oestrous cyclicity (parental animals):

No data available

Sperm parameters (parental animals):

No data available

Litter observations:

No data available

Postmortem examinations (parental animals):

No data available

Postmortem examinations (offspring):

No data available

Statistics:

No data available

Reproductive indices:

No data available

Offspring viability indices:

No data available

Clinical signs:

not specified

Dermal irritation (if dermal study):

not specified

Mortality:

no mortality observed

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:

no effects observed

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:

no effects observed

Dose descriptor:

NOAEL

Effect level:

845.875 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

mortality

body weight and weight gain

food consumption and compound intake

organ weights and organ / body weight ratios

gross pathology

reproductive performance

Remarks on result:

other: No effects on reproductive performance

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:

no effects observed

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 examined

Organ weight findings including organ / body weight ratios:

not specified

Gross pathological findings:

no effects observed

Histopathological findings:

not examined

Other effects:

not specified

Behaviour (functional findings):

not specified

Developmental immunotoxicity:

not specified

Dose descriptor:

NOAEL

Generation:

F1

Effect level:

845.875 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

body weight and weight gain

gross pathology

other: overall developmental effects

Remarks on result:

other: no effects on overall development of offspring

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 10 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 ("p" and ( not "q") )  )  and ("r" and ( not "s") )  )  and ("t" and ( not "u") )  )  and ("v" and ( not "w") )  )  and "x" )  and ("y" and "z" )  )

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 OASIS v.1.3

Domain logical expression index: "f"

Referential boundary: The target chemical should be classified as AN2 OR AN2 >> Carbamoylation after isocyanate formation OR AN2 >> Carbamoylation after isocyanate formation >> N-Hydroxylamines OR AN2 >> Shiff base formation after aldehyde release OR AN2 >> Shiff base formation after aldehyde release >> Specific Acetate Esters 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 SN1 OR SN1 >> Alkylation after metabolically formed carbenium ion species OR SN1 >> Alkylation after metabolically formed carbenium ion species >> Polycyclic Aromatic Hydrocarbon Derivatives 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 SN2 OR SN2 >> Acylation OR SN2 >> Acylation >> Specific Acetate Esters OR SN2 >> Alkylation, direct acting epoxides and related OR SN2 >> Alkylation, direct acting epoxides and related >> Epoxides and Aziridines OR SN2 >> Alkylation, direct acting epoxides and related after P450-mediated metabolic activation OR SN2 >> Alkylation, direct acting epoxides and related after P450-mediated metabolic activation >> Polycyclic Aromatic Hydrocarbon Derivatives 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: "g"

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

Domain logical expression index: "h"

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 by DNA binding by OECD

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 Non binder, impaired OH or NH2 group OR Non binder, without OH or NH2 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 Perhexiline (Hepatotoxicity) Alert by Repeated dose (HESS)

Domain logical expression index: "o"

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: "p"

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

Domain logical expression index: "q"

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

Domain logical expression index: "r"

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: "s"

Referential boundary: The target chemical should be classified as Group 14 - Metals Sn,Pb OR Group 15 - Nitrogen N by Chemical elements

Domain logical expression index: "t"

Referential boundary: The target chemical should be classified as Inclusion rules not met AND Phenols by Skin irritation/corrosion Inclusion rules by BfR

Domain logical expression index: "u"

Referential boundary: The target chemical should be classified as Aliphatic acids and (Met)acrylic acids by Skin irritation/corrosion Inclusion rules by BfR

Domain logical expression index: "v"

Referential boundary: The target chemical should be classified as (!Undefined)Group All Lipid Solubility < 0.01 g/kg AND Exclusion rules not met AND Group All Aqueous Solubility < 0.000005 g/L AND Group All Aqueous Solubility < 0.00002 g/L AND Group All log Kow > 9 AND Group All Melting Point > 200 C AND Group All Molecular Weight > 650 g/mol AND Group CHal log Kow > 4.5 AND Group CHal Melting Point > 65 C AND Group CHal Molecular Weight > 280 g/mol AND Group CHal Molecular Weight > 370 g/mol by Eye irritation/corrosion Exclusion rules by BfR

Domain logical expression index: "w"

Referential boundary: The target chemical should be classified as Group C Aqueous Solubility < 0.0001 g/L OR Group C Aqueous Solubility < 0.0005 g/L OR Group C Melting Point > 55 C OR Group C Molecular Weight > 380 g/mol by Eye irritation/corrosion Exclusion rules by BfR

Domain logical expression index: "x"

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

Domain logical expression index: "y"

Parametric boundary:The target chemical should have a value of log Kow which is >= 4.06

Domain logical expression index: "z"

Parametric boundary:The target chemical should have a value of log Kow which is <= 5.12

Conclusions:

In reproductive toxicity study, NOAEL was estimated to be 845.875mg/kg bw. When male and female wistar rats were exposed with 3,4,5,6-tetrachloro-2-(2,4,5,7-tetrabromo-3,6-dihydroxyxanthen-9-yl)benzoic acid, aluminium salt (84473-86-9) orally.

Executive summary:

In a prediction done by SSS (2017) using the OECD QSAR toolbox with log kow as the primary descriptor, the reproductive toxicity was estimated 3,4,5,6-tetrachloro-2-(2,4,5,7-tetrabromo-3,6-dihydroxyxanthen-9-yl)benzoic acid, aluminium salt (84473-86-9). Male and female reproductive parameters were unaffected by test material administration. Hence, NOAEL was estimated to be 845.875mg/kg bw. When male and femalewistar ratswere exposed with 3,4,5,6-tetrachloro-2-(2,4,5,7-tetrabromo-3,6-dihydroxyxanthen-9-yl)benzoic acid, aluminium salt (84473-86-9) orally.

Effect on fertility: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

845.875 mg/kg bw/day

Study duration:

subacute

Species:

rat

Quality of whole database:

Data is Klimicsh 2 and from QSAR Toolbox 3.3. (2017)

Effect on fertility: via inhalation route

Endpoint conclusion:

no study available

Effect on fertility: via dermal route

Endpoint conclusion:

no study available

Additional information

Reproductive toxicity

In different studies, 3,4,5,6-tetrachloro-2-(2,4,5,7-tetrabromo-3,6-dihydroxyxanthen-9-yl)benzoic acid, aluminium salt (84473-86-9) has been investigated 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 rats for 3,4,5,6-tetrachloro-2-(2,4,5,7-tetrabromo-3,6-dihydroxyxanthen-9-yl)benzoic acid, aluminium salt (84473-86-9).The predicted data using the OECD QSAR toolbox has also been compared with the experimental studies performed on structurally similar read across substance.

In a prediction done by SSS (2017) using the OECD QSAR toolbox with log kow as the primary descriptor, the reproductive toxicity was estimated 3,4,5,6-tetrachloro-2-(2,4,5,7-tetrabromo-3,6-dihydroxyxanthen-9-yl)benzoic acid, aluminium salt (84473-86-9). Male and female reproductive parameters were unaffected by test material administration. Hence, NOAEL was estimated to be 845.875mg/kg bw. When male and femalewistar ratswere exposed with 3,4,5,6-tetrachloro-2-(2,4,5,7-tetrabromo-3,6-dihydroxyxanthen-9-yl)benzoic acid, aluminium salt (84473-86-9) orally.

It is supported by experimental study conducted by M. SENO, S. FUKUDA and H. UMISA (Fd Chem. Toxic. Vol. 22, No. 1 pp. 55-60, 1984)on structurally similar read across substance Phloxine B(18472 -87-2).In a reproductive and developmental toxicity study, Jcl:ICR female mice treated with Phloxine B(18472 -87-2). 84 females mice were used in the study. The female were caged with male in pairs overnight. The next morning female with vaginal plugs were considered to be in day 0 of pregnancy and were housed individually. The test material administered in the concentration of 0, 2000,6000 and 10000 mg/kg/day (0, 1.0, 3.0 and 5.0 %)from the morning of day 6 through day 16 of pregnancy by oral feed. Animals were observed daily, beginning on day 6 of pregnancy, and were weighed on days 6, 12, 16 and 18. Food consumption and spillage were measured at regular intervals beginning on day 6 of pregnancy, and net amounts of food ingested were calculated. On day 18, the mice were killed under ether anaesthesia, and the maternal liver weight was recorded. Their reproductive status was determined. Corpora lutea were counted under a dissecting microscope. Implantation sites in each uterine horn were counted and the general condition of each conceptus was recorded. The live foetuses were removed, weighed, sexed and examined for external malformations. A third of the foetuses in each litter (selected randomly) were fixed in Bouin's solution and examined for soft-tissue abnormalities by a modified razor-section technique.The remainder were fixed in 95%ethanol, cleared with 1% KOH, stained with Alizarin Red S (Dawson, 1926) and examined for skeletal alteration.2 dams died on days 16 and 17. Another female in this group aborted on day 17.Significantly decreased in Maternal body-weight gains for days 6-16 of gestation were observed in 2000, 6000 and 10,000 mg/kg bw/day treated dams as compared to control. Similarly, the numbers of corpora lutea, implantations or live foetuses in all of the treated groups were slightly decreased, but not significantly in comparison with those of the control. Absolute and relative liver weight was significantly increased in 2000 mg/kg bw/day dose group as compared to control in F0 generation. In addition, Foetuses with open eyelids were observed in all treated dams. Exencephaly, significantly increased incidence of cleft palate and Significantly decreased numbers of ossified caudal vertebrae and phalanges, slightly reduced incidence of accessory sternebrae and significantly increased numbers of foetuses with a fourteenth rib or with an extra rib (at least one fourteenth rib that was half or greater than half the length of the preceding rib) were observed in 10,000 mg/kgbw/day treated fetuses as compared to control. Slight retardation of ossification was observed in 6000 mg/kgbw/day treated foetuses as compared to control. Splitting of the cervical vertebral arches was observed in 1000 mg/kg bw/day treated foetuses as compared to control. Hence, dose response was seen in the total incidence of skeletal abnormalities, suggested a teratogenic effect. Therefore, NOAEL was considered to be 2000 mg/kg body weight/day (1%) for F0 generation and LOAEL was considered to be 2000 mg/kg body weight/day (1%) for F1 generation when Jcl:ICR female mice were treated with Phloxine B orally by feed from day 6 to 16 of gestation.

It is supported by experimental study conducted by Pierce EC; Agersborg Hk Jr; Borzelleca Jf; Burnett CM; Eagle E; Ebert Ag; Kirschman JC; Scala RA (TOXICOL APPL PHARMACOL 29:121-122, 1974)on structurally similar read across substance D & C Red no. 27 (13473-26-2). Multi-generation reproduction studies with D & C Red no. 27 (13473-26-2) were performed in rats. Test material in dose concentration not excess 1000mg/kg was given in diet. Dose was calculated on the bases of previous long term feeding study in rats and dog.Data through the parental generation and F2b Litter give no indication of adverse effects on reproductive performance. Hence NOAEL was considered to be 1000mg/kg bw. When Multi-generation reproduction studies withD & C Red no. 27 were performed in rats orally.

Thus based on the above results it can be concluded that the substance 3,4,5,6-tetrachloro-2-(2,4,5,7-tetrabromo-3,6-dihydroxyxanthen-9-yl)benzoic acid, aluminium salt (84473-86-9) is expected to show the similar toxicological effect based on the effects observed in structurally similar read across substance . Thus, comparing this value with the criteria of CLP regulation 3,4,5,6-tetrachloro-2-(2,4,5,7-tetrabromo-3,6-dihydroxyxanthen-9-yl)benzoic acid, aluminium salt (84473-86-9) can be "Not classified" for reproductive 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

Thus, comparing this value with the criteria of CLP regulation 3,4,5,6-tetrachloro-2-(2,4,5,7-tetrabromo-3,6-dihydroxyxanthen-9-yl)benzoic acid, aluminium salt (84473-86-9) can be "Not classified" for reproductive toxicity.