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 the test compound 2',4',5',7'-Tetrabromofluorescein aluminum salt. The study assumed the use of male and female Outbred Wistar in 90 days study. No significant alterations were noted at the mentioned dose level. The predicted No Observed Adverse Effect Level (NOAEL) for 2',4',5',7'-Tetrabromofluorescein aluminum salt is considered to be 1079 .5999 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: Dermal

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 dermal toxicity was predicted for the test compound 2',4',5',7'-Tetrabromofluorescein aluminum salt. The study assumed the use of male and female New Zealand White rabbits in 28 days study. No significant alterations were noted at the mentioned dose level. The predicted No Observed Adverse Effect Level (NOAEL) for 2',4',5',7'-Tetrabromofluorescein aluminum salt is considered to be 1500.0 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.

Toxic effect type:

dose-dependent

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:

Prediction is done using OECD QSAR Toolbox version 3.3, 2017

GLP compliance:

not specified

Limit test:

no

Specific details on test material used for the study:

- Name of the test material: 2',4',5',7'-Tetrabromofluorescein aluminum salt
- IUPAC name: 2-(2,4,5,7-tetrabromo-3,6-dihydroxy-9H-xanthen-9-yl)benzoic acid
- Molecular formula: C20H8Br4O5.2/3Al
- Molceular weight: 1991.5992 g/mol
- Substance type: Organic

Species:

rat

Strain:

Wistar

Remarks:

Outbred

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:

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:

1 079.6 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: No adverse effects were observed 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" or "e" ) and ("f" and ( not "g") ) ) and ("h" and ( not "i") ) ) and ("j" and ( not "k") ) ) and ("l" and ( not "m") ) ) and ("n" and ( not "o") ) ) and "p" ) and ("q" and ( not "r") ) ) and ("s" and ( not "t") ) ) and ("u" and "v" ) )

Domain logical expression index: "a"

Referential boundary: The target chemical should be classified as Phenols (Chronic toxicity) by US-EPA New Chemical Categories

Domain logical expression index: "b"

Referential boundary: The target chemical should be classified as Aryl OR Aryl halide OR Carboxylic acid OR Fused carbocyclic aromatic OR Fused saturated heterocycles OR Phenol OR Xanthene by Organic Functional groups ONLY

Domain logical expression index: "c"

Referential boundary: The target chemical should be classified as Aryl OR Aryl halide OR Carboxylic acid 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 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 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 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: "e"

Referential boundary: The target chemical should be classified as Aromatic compound OR Aryl bromide 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 Phenol by Organic functional groups, Norbert Haider (checkmol) ONLY

Domain logical expression index: "f"

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

Domain logical expression index: "g"

Referential boundary: The target chemical should be classified as AN2 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 Michael addition OR Michael addition >> Quinone type compounds OR Michael addition >> Quinone type compounds >> Quinone methides OR Non-covalent interaction OR Non-covalent interaction >> DNA intercalation OR Non-covalent interaction >> DNA intercalation >> DNA Intercalators with Carboxamide Side Chain 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 >> ROS formation after GSH depletion OR Radical >> ROS formation after GSH depletion >> Quinone methides 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 SN2 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 by DNA binding by OASIS v.1.3

Domain logical expression index: "h"

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

Domain logical expression index: "i"

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 SN1 OR SN1 >> Iminium Ion Formation OR SN1 >> Iminium Ion Formation >> Aliphatic tertiary amines 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: "j"

Referential boundary: The target chemical should be classified as No alert found by Protein binding alerts for Chromosomal aberration by OASIS v1.1

Domain logical expression index: "k"

Referential boundary: The target chemical should be classified as AN2 OR AN2 >> Michael addition to alpha, beta-unsaturated acids and esters OR AN2 >> Michael addition to alpha, beta-unsaturated acids and esters >> alpha, beta - Unsaturated Carboxylic Acids and Esters OR AN2 >> Michael-type addition to quinoid structures OR AN2 >> Michael-type addition to quinoid structures >> Phenols by Protein binding alerts for Chromosomal aberration by OASIS v1.1

Domain logical expression index: "l"

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

Domain logical expression index: "m"

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 >> Azlactones and unsaturated lactone derivatives OR Michael Addition OR Michael Addition >> Michael addition on conjugated systems with electron withdrawing group OR Michael Addition >> Michael addition on conjugated systems with electron withdrawing group >> alpha,beta-Carbonyl compounds with polarized double bonds OR Nucleophilic addition OR Nucleophilic addition >> Addition to carbon-hetero double bonds OR Nucleophilic addition >> Addition to carbon-hetero double bonds >> Ketones OR Schiff base formation OR Schiff base formation >> Benzoyl Schiff base formation OR Schiff base formation >> Benzoyl Schiff base formation >> Benzoyl phosphine oxides OR 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 alerts for skin sensitization by OASIS v1.3

Domain logical expression index: "n"

Referential boundary: The target chemical should be classified as No alert found by Respiratory sensitisation

Domain logical expression index: "o"

Referential boundary: The target chemical should be classified as Michael Addition OR Michael Addition >> Polarised alkenes OR Michael Addition >> Polarised alkenes >> Indigotine and related OR Pro-SN2 OR Pro-SN2 >> Pro-ring opening SN2 OR Pro-SN2 >> Pro-ring opening SN2 >> Vinyl benzenes by Respiratory sensitisation

Domain logical expression index: "p"

Referential boundary: The target chemical should be classified as Not bioavailable by Lipinski Rule Oasis ONLY

Domain logical expression index: "q"

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

Domain logical expression index: "r"

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

Domain logical expression index: "s"

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

Domain logical expression index: "t"

Referential boundary: The target chemical should be classified as Group 15 - Nitrogen N OR Group 15 - Phosphorus P by Chemical elements

Domain logical expression index: "u"

Parametric boundary:The target chemical should have a value of log Kow which is >= 5.14

Domain logical expression index: "v"

Parametric boundary:The target chemical should have a value of log Kow which is <= 9.91

Conclusions:

The predicted No Observed Adverse Effect Level (NOAEL) for 2',4',5',7'-Tetrabromofluorescein aluminum salt is considered to be 1079 .5999 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 the test compound 2',4',5',7'-Tetrabromofluorescein aluminum salt. The study assumed the use of male and female Outbred Wistar in 90 days study. No significant alterations were noted at the mentioned dose level. The predicted No Observed Adverse Effect Level (NOAEL) for 2',4',5',7'-Tetrabromofluorescein aluminum salt is considered to be 1079 .5999 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

1 079.6 mg/kg bw/day

Study duration:

chronic

Species:

rat

Quality of whole database:

Data is from OECD QSAR toolbox 3.3

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

Reference

Endpoint:

short-term repeated dose toxicity: dermal

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:

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 3.3, 2017

GLP compliance:

not specified

Limit test:

no

Specific details on test material used for the study:

- Name of the test material: 2',4',5',7'-Tetrabromofluorescein aluminum salt
- IUPAC name: 2-(2,4,5,7-tetrabromo-3,6-dihydroxy-9H-xanthen-9-yl)benzoic acid
- Molecular formula: C20H8Br4O5.2/3Al
- Molceular weight: 1991.5992 g/mol
- Substance type: Organic

Species:

rabbit

Strain:

New Zealand White

Details on species / strain selection:

No data

Sex:

male/female

Details on test animals or test system and environmental conditions:

No data

Type of coverage:

occlusive

Vehicle:

not specified

Details on 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:

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

Dermal irritation:

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:

1 500 mg/kg bw/day

Based on:

not specified

Sex:

male/female

Basis for effect level:

other: No adverse effects 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 8 nearest neighbours
Domain logical expression:Result: In Domain

(((("a" or "b" or "c" or "d" or "e" ) and ("f" and ( not "g") ) ) and ("h" and ( not "i") ) ) and ("j" and "k" ) )

Domain logical expression index: "a"

Referential boundary: The target chemical should be classified as Phenols (Chronic toxicity) by US-EPA New Chemical Categories

Domain logical expression index: "b"

Referential boundary: The target chemical should be classified as Aryl OR Aryl halide OR Carboxylic acid OR Fused carbocyclic aromatic OR Fused saturated heterocycles OR Phenol OR Xanthene by Organic Functional groups ONLY

Domain logical expression index: "c"

Referential boundary: The target chemical should be classified as Aryl OR Aryl halide OR Carboxylic acid 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 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 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 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: "e"

Referential boundary: The target chemical should be classified as Aromatic compound OR Aryl bromide 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 Phenol by Organic functional groups, Norbert Haider (checkmol) ONLY

Domain logical expression index: "f"

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

Domain logical expression index: "g"

Referential boundary: The target chemical should be classified as SN1 OR SN1 >> Alkylation after metabolically formed carbenium ion species OR SN1 >> Alkylation after metabolically formed carbenium ion species >> Polycyclic Aromatic Hydrocarbon Derivatives OR SN2 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 by DNA binding by OASIS v.1.3

Domain logical expression index: "h"

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

Domain logical expression index: "i"

Referential boundary: The target chemical should be classified as Michael Addition OR Michael Addition >> Michael addition on conjugated systems with electron withdrawing group OR Michael Addition >> Michael addition on conjugated systems with electron withdrawing group >> alpha,beta-Carbonyl compounds with polarized double bonds OR SN2 OR SN2 >> SN2 Reaction at a sp3 carbon atom OR SN2 >> SN2 Reaction at a sp3 carbon atom >> Activated alkyl esters and thioesters OR 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: "j"

Parametric boundary:The target chemical should have a value of log BCF max which is >= 2.28 log(L/kg wet)

Domain logical expression index: "k"

Parametric boundary:The target chemical should have a value of log BCF max which is <= 4.39 log(L/kg wet)

Conclusions:

The predicted No Observed Adverse Effect Level (NOAEL) for 2',4',5',7'-Tetrabromofluorescein aluminum salt is considered to be 1500.0 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 dermal toxicity was predicted for the test compound 2',4',5',7'-Tetrabromofluorescein aluminum salt. The study assumed the use of male and female New Zealand White rabbits in 28 days study. No significant alterations were noted at the mentioned dose level. The predicted No Observed Adverse Effect Level (NOAEL) for 2',4',5',7'-Tetrabromofluorescein aluminum salt is considered to be 1500.0 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

1 500 mg/kg bw/day

Study duration:

chronic

Species:

mouse

Quality of whole database:

Data is from K2 OECD QSAR Toolbox 3.3

Endpoint conclusion:

no study available

Prediction model based estimation and data from read across chemicals have been reviewed to determine the toxic nature of 2',4',5',7'- Tetrabromofluorescein aluminum salt upon repeated exposure by oral and dermal route of exposure. The studies are as mentioned below:

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 the test compound 2',4',5',7'-Tetrabromofluorescein aluminum salt. The study assumed the use of male and female Outbred Wistar in 90 days study. No significant alterations were noted at the mentioned dose level. The predicted No Observed Adverse Effect Level (NOAEL) for 2',4',5',7'-Tetrabromofluorescein aluminum salt is considered to be 1079 .5999 mg/Kg bw/day.

Repeated dose oral toxicity study of structurally 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 ) was performed in rats. Fischer-344 (F-344) male rats were treated with D&C Red No. 28 orally in diet in the concentration of 500 mg/kg/day. The animals were observed for changes in body weight and excretion of the dye in urine of treated animals. Increase in body weight gain was observed in treated rats over the 14 days observation period. 8-week-old rats weighed 168 g±6 g and by 10 weeks they weighed 225 g±10 g. As there is no control in the study the effect were not supposed to be treatment related. Daily intake was observed to be 500 mg/kg for 14 days. Therefore, the No Observed Adverse Effect 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 repeated dose oral toxicity study performed as part of the evaluation of teratogenicity for structurally similar read across chemical, the toxicity of Phloxine (RA CAS no 6441 -77 -6; IUPAC name: Food Dye Red No. 104) was studied using female Wistar rats. The rats were orally exposed to Phloxine via their diet at a dosage of 0, 03, 1.0 or 3.0%. (0, 300, 1000and 3000 mg/kg bw/day). The animals were observed for clinical signs, body weight and food consumption changes, food efficiency and utrine weight. No signs of toxicity were noted during the period of pregnancy. At the highest dose level of 3000 mg/Kg, a slight depression of weight gain was noted. No marked changes in body weight were noted in 300 and 1000 mg/Kg groups. The net amounts of phloxine ingested daily during pregnancy were 2870 mg/kg for 3000 mg/Kg group, 920 mg/kg for 1000 mg/Kg group and 280 mg/kg for 300 mg/Kg group, respectively. At 3000 mg/Kg, a decrease in food efficiency were observed. No significant differences between the phloxine-treated and control groups were found in the uterus weight at the studied dose levels. Based on the observations made, the No Observed Adverse Effect Level (NOAEL) was considered to be 3000 mg/kgbw/day in the pregnant female Wistar rats when they were orally exposed to Phloxine (Food Red No. 104) during gestation.

Repeated dose toxicity: Inhalation

The melting point 2',4',5',7'- Tetrabromofluorescein aluminum salt is >300 C. This suggests that dialuminium tris[2-(2,4,5,7-tetrabromo-6-oxido- 3-oxoxanthen-9-yl)benzoate] decomposes between 334.5 °C -338 °C at 972.1hPa without melting and does not exhibit very high vapour pressure. Inhalation is therefore not the likely route of exposure and hence this end point is considered for waiver.

Repeated dose toxicity: Dermal

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 dermal toxicity was predicted for the test compound 2',4',5',7'-Tetrabromofluorescein aluminum salt. The study assumed the use of male and female New Zealand White rabbits in 28 days study. No significant alterations were noted at the mentioned dose level. The predicted No Observed Adverse Effect Level (NOAEL) for 2',4',5',7'-Tetrabromofluorescein aluminum salt is considered to be 1500.0 mg/Kg bw/day.

Combined repeated dose & carcinogenicity by the dermal route was performed to determine the dermal toxic nature of structurally similar read across chemical 2',4',5',7'-Tetrabromofluorescein (RA CAS no 15086 -94 -9) upon repeated application. The test chemical was applied to the clipped dorsal area mice. The animals were observed for mortality, clinical signs and gross pathology and histopathology was performed. The percent survival of the treated mice changed with the duration of the treatment. The survival was 97% in 4 months, 93% in 10 months, 68% in 12 months and 50% in 18 months respectively. The incidence of extramedullary hematopoesis of the spleen (5 male and 5 females: 10%) in the test group was consistent with that found in the distilled water vehicle control groups. The incidence in the three distilled water control groups was 13 % , 18 % , and 22 % for a mean of 17.7 % . The test group did not show a greater incidence than a control group. The incidence of ectoparasitism was greater in the dye treated group than found in the vehicle controls. This increase in skin mite infestation may have contributed to the increase in epidermal change dermatitis, acanthosis, and hyperkeratosis observed in the dye treated groups. Although the number of neoplasias involving the mammary glands or internal organs was noted in the test group, there was, however, no apparent change in their pattern which could be attributed to the dermal application of the test dye compound. The incidence and severity of lesions of interstitial nephritis, cystitis, amyloidosis, and bronchopneumonia though observed in the test groups but there were no significant variations that could be attributed to application of the test compound. Based on the observations made, the No Observed Adverse Effect Level (NOAEL) for the test compound 2',4',5',7'-Tetrabromofluorescein is considered to be 140.1 mg when ICR mice were exposed with the test compound for 473 days.

Based on the data available for the target chemical and its read across, 2',4',5',7'-Tetrabromofluorescein aluminum salt does not exhibit toxicity upon repeated exposure by oral and dermal route of exposure and hence it is not likely to classify as toxic as per the criteria mentioned in CLP regulation.

Based on the data available for the target chemical and its read across, 2',4',5',7'-Tetrabromofluorescein aluminum salt (CAS no 15876 -39 -8) does not exhibit toxicity upon repeated exposure by oral and dermal route of exposure and hence it is not likely to classify as toxic as per the criteria mentioned in CLP regulation.