Registration Dossier

Skin Irritation:

The dermal irritation potential of 1,4-diamino-2,3-dichloroanthraquinone was estimated using OECD QSAR toolbox v3.3 with logPow as the primary descriptor.

1,4-diamino-2,3-dichloroanthraquinone was estimated to be not irritating to the skin of New Zealand White rabbits.

Based on the estimated results, 1,4-diamino-2,3-dichloroanthraquinone can be considered to be not irritating to skin and can be classified under the category “Not Classified” as per CLP regulation.

Eye Irritation:

The ocular irritation potential of 1,4-diamino-2,3-dichloroanthraquinone was estimated using OECD QSAR toolbox v3.3 with logPow as the primary descriptor.

1,4-diamino-2,3-dichloroanthraquinone was estimated to be irritating to the eyes of rabbits.

Based on the estimated results, 1,4-diamino-2,3-dichloroanthraquinone can be considered to be irritating to eyes and can be classified under the category “Category 2” as per CLP regulation.

Reference

Endpoint:

skin irritation: in vivo

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:

according to guideline

Guideline:

other: estimated data

Principles of method if other than guideline:

Prediction was done using OECD QSAR toolbox v3.3

GLP compliance:

not specified

Specific details on test material used for the study:

Name of the test chemical: 1,4-diamino-2,3-dichloroanthraquinone
Molecular formula: C14H8Cl2N2O2
Molecular weight: 307.135 g/mol
Smiles Notation: c1cc2c(cc1)C(=O)c1c(c(c(c(c1N)Cl)Cl)N)C2=O
InChI: 1S/C14H8Cl2N2O2/c15-9-10(16)12(18)8-7(11(9)17)13(19)5-3-1-2-4-6(5)14(8)20/h1-4H,17-18H2
Substance Type: Organic
Physical State: Solid crystal powder (purple-black)

Species:

rabbit

Strain:

New Zealand White

Details on test animals or test system and environmental conditions:

no data available

Type of coverage:

semiocclusive

Preparation of test site:

shaved

Vehicle:

unchanged (no vehicle)

Controls:

not specified

Amount / concentration applied:

no data available

Duration of treatment / exposure:

4 hours

Observation period:

72 hours

Number of animals:

3

Details on study design:

no data available

Other effects / acceptance of results:

no data available

Irritation parameter:

overall irritation score

Basis:

mean

Time point:

72 h

Reversibility:

not specified

Remarks on result:

no indication of irritation

Irritant / corrosive response data:

No signs of irritation observed

Estimation method: Takes mode value from the 9 nearest neighbours
Domain logical expression:Result: In Domain

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

Domain logical expression index: "a"

Referential boundary: The target chemical should be classified as Aminoaniline, para OR Anthracenone/ Antracendione OR Aryl halide OR Overlapping groups by Organic Functional groups (nested) ONLY

Domain logical expression index: "b"

Referential boundary: The target chemical should be classified as Amine OR Aromatic compound OR Aryl chloride OR Aryl halide OR Carbonyl compound OR Halogen derivative OR Ketone OR Primary amine OR Primary aromatic amine by Organic functional groups, Norbert Haider (checkmol) ONLY

Domain logical expression index: "c"

Referential boundary: The target chemical should be classified as Not possible to classify according to these rules by DPRA Lysine peptide depletion

Domain logical expression index: "d"

Referential boundary: The target chemical should be classified as High reactive OR High reactive >> Activated 1,3,5-triazine derivatives OR High reactive >> para-Quinones OR Low reactive OR Low reactive >> Activated haloarenes OR Low reactive >> Epoxides OR Low reactive >> Saturated di-ketones OR Low reactive >> Short-chain alpha-alkyl cinnamaldehyde derivatives OR Moderate reactive OR Moderate reactive >> Cinnamaldehyde type compounds by DPRA Lysine peptide depletion

Domain logical expression index: "e"

Referential boundary: The target chemical should be classified as Non binder, impaired OH or NH2 group by Estrogen Receptor Binding

Domain logical expression index: "f"

Referential boundary: The target chemical should be classified as Moderate binder, NH2 group OR Non binder, MW>500 OR Non binder, non cyclic structure OR Non binder, without OH or NH2 group OR Strong binder, NH2 group OR Weak binder, NH2 group by Estrogen Receptor Binding

Domain logical expression index: "g"

Parametric boundary:The target chemical should have a value of log Kow which is >= -0.388

Domain logical expression index: "h"

Parametric boundary:The target chemical should have a value of log Kow which is <= 7.63

Interpretation of results:

other: not irritating

Conclusions:

1,4-diamino-2,3-dichloroanthraquinone was estimated to be not irritating to the skin of New Zealand White rabbits.

Executive summary:

The dermal irritation potential of 1,4-diamino-2,3-dichloroanthraquinone was estimated using OECD QSAR toolbox v3.3 with logPow as the primary descriptor.

1,4-diamino-2,3-dichloroanthraquinone was estimated to be not irritating to the skin of New Zealand White rabbits.

Based on the estimated results, 1,4-diamino-2,3-dichloroanthraquinone can be considered to be not irritating to skin and can be classified under the category “Not Classified” as per CLP regulation.

Endpoint conclusion:

no adverse effect observed (not irritating)

Reference

Endpoint:

eye irritation: in vivo

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:

according to guideline

Guideline:

other: Estimated data

Principles of method if other than guideline:

Prediction was done using OECD QSAR toolbox v3.3

GLP compliance:

not specified

Specific details on test material used for the study:

Name of the test chemical: 1,4-diamino-2,3-dichloroanthraquinone
Molecular formula: C14H8Cl2N2O2
Molecular weight: 307.135 g/mol
Smiles Notation: c1cc2c(cc1)C(=O)c1c(c(c(c(c1N)Cl)Cl)N)C2=O
InChI: 1S/C14H8Cl2N2O2/c15-9-10(16)12(18)8-7(11(9)17)13(19)5-3-1-2-4-6(5)14(8)20/h1-4H,17-18H2
Substance Type: Organic
Physical State: Solid crystal powder (purple-black)

Species:

rabbit

Strain:

not specified

Details on test animals or tissues and environmental conditions:

no data available

Vehicle:

unchanged (no vehicle)

Controls:

not specified

Amount / concentration applied:

0.1 ml

Duration of treatment / exposure:

24 hours

Observation period (in vivo):

72 hours

Duration of post- treatment incubation (in vitro):

No data avaiaaa

Number of animals or in vitro replicates:

3

Details on study design:

no data available

Other effects / acceptance of results:

no data avialable

Irritation parameter:

overall irritation score

Basis:

mean

Remarks:

\

Time point:

72 h

Reversibility:

not specified

Remarks on result:

no indication of irritation

Irritant / corrosive response data:

Signs of irritation were observed

Estimation method: Takes mode value from the 6 nearest neighbours
Domain logical expression:Result: In Domain

((((((((((("a" or "b" ) or "c" ) and "d" ) and "e" ) and "f" ) and "g" ) and ("h" and ( not "i") ) ) and ("j" and ( not "k") ) ) and ("l" and ( not "m") ) ) and "n" ) and ("o" and "p" ) )

Domain logical expression index: "a"

Referential boundary: The target chemical should be classified as Aminoaniline, para OR Anthracenone/ Antracendione OR Aryl halide OR Overlapping groups by Organic Functional groups (nested) ONLY

Domain logical expression index: "b"

Referential boundary: The target chemical should be classified as Amine OR Aromatic compound OR Aryl chloride OR Aryl halide OR Carbonyl compound OR Halogen derivative OR Ketone OR Primary amine OR Primary aromatic amine by Organic functional groups, Norbert Haider (checkmol) ONLY

Domain logical expression index: "c"

Referential boundary: The target chemical should be classified as Aromatic amines OR Ketones by Skin irritation/corrosion Inclusion rules by BfR ONLY

Domain logical expression index: "d"

Referential boundary: The target chemical should be classified as Aminoaniline, para AND Aniline AND Anthracenone/ Antracendione AND Aryl AND Aryl halide AND Cycloketone AND Diketone AND Fused carbocyclic aromatic by Organic Functional groups ONLY

Domain logical expression index: "e"

Referential boundary: The target chemical should be classified as Aminoaniline, para AND Anthracenone/ Antracendione AND Aryl halide AND Overlapping groups by Organic Functional groups (nested) ONLY

Domain logical expression index: "f"

Referential boundary: The target chemical should be classified as Aliphatic Nitrogen, one aromatic attach [-N] AND Aromatic Carbon [C] AND Carbonyl, olefinic attach [-C(=O)-] AND Chlorine, aromatic attach [-Cl] AND Chlorine, olefinic attach [-Cl] AND Diarylketone AND Ketone in a ring, olefinic aromatic attach AND Miscellaneous sulfide (=S) or oxide (=O) AND Olefinic carbon [=CH- or =C<] by Organic functional groups (US EPA) ONLY

Domain logical expression index: "g"

Similarity boundary:Target: Nc1c(Cl)c(Cl)c(N)c2c1C(=O)c1ccccc1C2=O
Threshold=50%,
Dice(Atom centered fragments)
Atom type; Count H attached; Hybridization

Domain logical expression index: "h"

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

Domain logical expression index: "i"

Referential boundary: The target chemical should be classified as Halobenzenes (Hepatotoxicity) Rank A by Repeated dose (HESS)

Domain logical expression index: "j"

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

Domain logical expression index: "k"

Referential boundary: The target chemical should be classified as Chlorphentermine (Hepatotoxicity) Alert by Repeated dose (HESS)

Domain logical expression index: "l"

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

Domain logical expression index: "m"

Referential boundary: The target chemical should be classified as SNAr OR SNAr >> Nucleophilic aromatic substitution OR SNAr >> Nucleophilic aromatic substitution >> Activated halo-benzenes by Protein binding by OECD

Domain logical expression index: "n"

Referential boundary: The target chemical should be classified as Does NOT Biodegrade Fast by Biodeg probability (Biowin 6) ONLY

Domain logical expression index: "o"

Parametric boundary:The target chemical should have a value of log Kow which is >= 1.08

Domain logical expression index: "p"

Parametric boundary:The target chemical should have a value of log Kow which is <= 4.74

Interpretation of results:

Category 2 (irritating to eyes) based on GHS criteria

Conclusions:

1,4-diamino-2,3-dichloroanthraquinone was estimated to be irritating to the eyes of rabbits.

Executive summary:

The ocular irritation potential of 1,4-diamino-2,3-dichloroanthraquinone was estimated using OECD QSAR toolbox v3.3 with logPow as the primary descriptor.

1,4-diamino-2,3-dichloroanthraquinone was estimated to be irritating to the eyes of rabbits.

Based on the estimated results, 1,4-diamino-2,3-dichloroanthraquinone can be considered to be irritating to eyes and can be classified under the category “Category 2” as per CLP regulation

Endpoint conclusion:

adverse effect observed (irritating)

Endpoint conclusion:

no study available

Skin Irritation:

In different studies, 1,4-diamino-2,3-dichloroanthraquinone has been investigated for potential for dermal irritation to a greater or lesser extent. The studies are based on in vivo experiments in rabbits along with predicted data for target chemical and its structurally similar read across substances, 2-ethylanthraquinone [CAS: 84-51-5], 1,4-diamino-9,10 -anthraquinone [CAS: 128-95-0] and 1-anilino-4-hydroxyanthraquinone [CAS: 19286-75-0]. The predicted data using the OECD QSAR toolbox has also been compared with the experimental data.

In a prediction done by SSS (2017) using the OECD QSAR toolbox with log kow as the primary descriptor, the skin irritation potential was estimated for1,4-diamino-2,3 -dichloroanthraquinone. 1,4-diamino-2,3-dichloroanthraquinonewas not irritating to the skin ofNew Zealand White rabbits.

Skin irritation effects were also estimated by four different models i.e, Battery, Leadscope, SciQSAR and CASE Ultra used within Danish QSAR database for 1,4-Diamino-2,3 -dichloroanthraquinone. Based on estimation, no severe skin irritation effects were known when1,4-Diamino-2,3-dichloroanthraquinone was exposed to rabbit skin. Hence, 1,4-Diamino-2,3-dichloroanthraquinone can be considered not irritating to skin.

Results from both the estimations indicate a possibility of 1,4-Diamino-2,3-dichloroanthraquinone being not irritating to skin.

These results are supported by the experimental study summarized in NTRL Report: OTS0534314; last updated 1991; for the structurally similar read across substance, 2 -ethylanthraquinone [CAS: 84-51-5]. The study was performed according to according to the Draize method. 6 albino New Zealand rabbits (3/sex) were used for the study. 0.5 ml (0.5 g) of the test material was applied to clipped areas of intact and abraded skin. The abrasions were longitudinal epidermal incisions sufficiently deep to penetrate the stratum corneum, but not so deep as to destroy the integrity of the derma. Applications were made under occlusive patches (1" x 1" gauze, covered by adhesive tape). Following application of 2-ethylanthraquinone the entire trunk of each animal was covered with an impermeable occlusive wrapping. The animals were then immobilized. The wrapping and test material were removed 24 hours following application. The sites were individually examined and scored separately for erythema and edema at 24 and 72 hours. The mean scores for 24 and 72 hours grading were averaged to determine final irritation indices. The Primary Irritation Index after 24, 72 hours for 2-ethylanthraquinone was 0.15.

Based on the score and scale of interpretation of PII scores, 2-Ethylanthraquinone can be considered not irritating to skin.

These results are also supported by the experimental study summarized in JOURNAL OF THE AMERICAN COLLEGE OF TOXICOLOGY, Volume 10, Number 1,pp 103-111, 1991; for the structurally similar read across substance, 1,4-diamino-9,10-anthraquinone [CAS: 128-95-0]. 5% solution of Disperse Violet 1 was applied to the upper arm of 7 human volunteers for 3 hours. The test area was observed 24 hours after patch removal.5% solution of Disperse Violet 1 did not cause any irritation to the skin of 7 human volunteers after 3 hours exposure.

Hence, Disperse Violet 1 can be considered not irritating to skin.

The above results are further supported by the experimental study summarized in Scientific Committee on Cosmetology (seventh series), 1988; for the structurally similar read across substance, 1-anilino-4-hydroxyanthraquinone [CAS: 19286-75-0]. 0.5g of the test chemical mixed with water was applied to the intact and abraded skin of 6 rabbits under occlusion (duration not specified). The rabbits were observed for signs of irritation. Slight to very slight edema was observed in 3/6 rabbits. Hence, 1-anilino-4-hydroxyanthraquinone can be considered to be not irritating to rabbit skin.

Based on the available data for the target and read across substances and applying the weight of evidence approach, 1,4-diamino-2,3-dichloroanthraquinone can be considered to be not irritating to skin.Comparing the above annotations with the criteria of CLP regulation, it can be classified under the category “Not Classified”.

Eye Irritation:

In different studies, 1,4-diamino-2,3-dichloroanthraquinone has been investigated for potential for ocular irritation to a greater or lesser extent. The studies are based on in vivo experiments in rabbits along with predicted data for target chemical and its structurally similar read across substances, 1,4-diamino-9,10-anthraquinone [CAS: 128-95-0] and 1,2,4 -trihydroxy-9,10-dihydroanthracene-9,10-dione [CAS: 81-54-9]. The predicted data using the OECD QSAR toolbox has also been compared with the experimental data.

In a prediction done by SSS (2017) using the OECD QSAR toolbox with log kow as the primary descriptor, the skin irritation potential was estimated for1,4-diamino-2,3 -dichloroanthraquinone. 1,4-diamino-2,3-dichloroanthraquinonewas irritating to the eyes ofrabbits.

This result is supported by the experimental study summarized in JOURNAL OF THE AMERICAN COLLEGE OF TOXICOLOGY, Volume 10, Number 1,pp 103-111, 1991; for the structurally similar read across substance, 1,4-diamino-9,10-anthraquinone [CAS: 128-95-0]. 500 mg of Disperse Violet 1 was instilled into the conjunctival sac of rabbits (number not specified) and the eyes were examined 24 hours later. Disperse Violet 1 was moderately irritating to rabbit eyes after 24 hours of exposure.

Hence, Disperse Violet 1 can be considered to be an eye irritant.

The above results are further supported by the experimental study summarized in Sax's Handbook of Dangerous Industrial Materials, 12th Edition, 2012; for the structurally similar read across substance, 1,2,4-trihydroxy-9,10-dihydroanthracene-9,10-dione [CAS: 81-54-9]. 500 mg of 1,2,4-trihydroxyanthraquinone was instilled into rabbit eyes and observed for signs of irritation till 24 hours. 1,2,4-trihydroxyanthraquinone was mildly irritating to rabbit eyes after 24 hours of exposure. Hence, 1,2,4-trihydroxyanthraquinone can be considered to be an eye irritant.

Based on the available data for the target and read across substances and applying the weight of evidence approach, 1,4-diamino-2,3-dichloroanthraquinone can be considered to be irritating to eyes.Comparing the above annotations with the criteria of CLP regulation, it can be classified under the category “Category 2”.

Based on the available information, 1,4-diamino-2,3-dichloroanthraquinone is not likely to cause any irritation to skin but is irritating to eyes. Hence, 1,4-diamino-2,3-dichloroanthraquinone can be classified under the category “Not Classified” for skin irritation and “Category 2” for eye irritation as per CLP regulation.