Registration Dossier

Skin Irritation:

The dermal irritation potential of sodium hydrogen 8-aminonaphthalene-1,6-disulfonate was estimated using OECD QSAR toolbox v3.4 with logPow as the primary descriptor.

Sodium hydrogen 8-aminonaphthalene-1,6-disulfonate was estimated to be not irritating to the skin of albino rabbits.

Based on the estimated results, sodium hydrogen 8-aminonaphthalene-1,6-disulfonate 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 sodium hydrogen 8-aminonaphthalene-1,6-disulfonate was estimated using OECD QSAR toolbox v3.4 with logPow as the primary descriptor.

Sodium hydrogen 8-aminonaphthalene-1,6-disulfonate was estimated to be not irritating to the eyes of rabbits.

Based on the estimated results, sodium hydrogen 8-aminonaphthalene-1,6-disulfonate can be considered to be not irritating to eyes and can be classified under the category “Not Classified” 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 v3.4 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 v3.4

GLP compliance:

not specified

Specific details on test material used for the study:

- Name of test material: sodium hydrogen 8-aminonaphthalene-1,6-disulfonate
- Molecular formula: C10H8NNaO6S2
- Molecular weight: 325.2962 g/mol
- Smiles notation: c1cc2cc(cc(c2c(c1)S(=O)(=O)O)N)S(=O)(=O)[O-].[Na+]
- InChl: 1S/C10H9NO6S2.Na/c11-8-5-7(18(12,13)14)4-6-2-1-3-9(10(6)8)19(15,16)17;/h1-5H,11H2,(H,12,13,14)(H,15,16,17);/q;+1/p-1
- Substance type: Organic
- Physical state: Solid

Species:

rabbit

Strain:

other: albino

Details on test animals or test system and environmental conditions:

no data available

Type of coverage:

occlusive

Preparation of test site:

shaved

Vehicle:

not specified

Controls:

not specified

Amount / concentration applied:

500 mg

Duration of treatment / exposure:

4 hours

Observation period:

14 days

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:

14 d

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

Domain logical expression index: "a"

Referential boundary: The target chemical should be classified as Naphthalene sulfonic acids, condensates by OECD HPV Chemical Categories

Domain logical expression index: "b"

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

Domain logical expression index: "c"

Referential boundary: The target chemical should be classified as Non-covalent interaction AND Non-covalent interaction >> DNA intercalation AND Non-covalent interaction >> DNA intercalation >> Fused-Ring Primary Aromatic Amines AND Radical AND Radical >> Radical mechanism via ROS formation (indirect) AND Radical >> Radical mechanism via ROS formation (indirect) >> Fused-Ring Primary Aromatic Amines AND SN1 AND SN1 >> Nucleophilic attack after metabolic nitrenium ion formation AND SN1 >> Nucleophilic attack after metabolic nitrenium ion formation >> Fused-Ring Primary Aromatic Amines by DNA binding by OASIS v.1.4

Domain logical expression index: "d"

Referential boundary: The target chemical should be classified as AN2 AND AN2 >> Michael-type addition to quinoid structures AND AN2 >> Michael-type addition to quinoid structures >> Substituted Anilines by Protein binding by OASIS v1.4

Domain logical expression index: "e"

Referential boundary: The target chemical should be classified as Strong binder, NH2 group by Estrogen Receptor Binding

Domain logical expression index: "f"

Referential boundary: The target chemical should be classified as Acid moiety AND Anilines (Unhindered) AND Salt by Aquatic toxicity classification by ECOSAR

Domain logical expression index: "g"

Referential boundary: The target chemical should be classified as Aromatic amines AND Sulfonic acids or their salts by Skin irritation/corrosion Inclusion rules by BfR

Domain logical expression index: "h"

Referential boundary: The target chemical should be classified as Activated N-heterocycles OR Esters of organic sulfonic or sulfuric esters OR Inclusion rules not met OR Ketones OR Phenols by Skin irritation/corrosion Inclusion rules by BfR

Domain logical expression index: "i"

Referential boundary: The target chemical should be classified as (!Undefined)Group All Lipid Solubility < 0.01 g/kg AND (!Undefined)Group CNS Surface Tension > 62 mN/m AND Group All log Kow < -3.1 AND Group All Melting Point > 200 C AND Group CNS log Kow < 0.5 AND Group CNS log Kow < -2 AND Group CNS Melting Point > 120 C AND Group CNS Melting Point > 50 C by Skin irritation/corrosion Exclusion rules by BfR

Domain logical expression index: "j"

Referential boundary: The target chemical should be classified as (!Undefined)Group CN Lipid Solubility < 0.4 g/kg OR (!Undefined)Group CNHal Lipid Solubility < 4 g/kg OR (!Undefined)Group CNHal Lipid Solubility < 400 g/kg OR Group CN Aqueous Solubility < 0.1 g/L OR Group CN Melting Point > 180 C OR Group CN Molecular Weight > 290 g/mol OR Group CN Vapour Pressure < 0.001 Pa OR Group CNHal Aqueous Solubility < 0.001 g/L OR Group CNHal Aqueous Solubility < 0.1 g/L OR Group CNHal log Kow > 3.8 OR Group CNHal Molecular Weight > 370 g/mol OR Group CNHal Molecular Weight > 380 g/mol by Skin irritation/corrosion Exclusion rules by BfR

Domain logical expression index: "k"

Similarity boundary:Target: Nc1cc(S(O)(=O)=O)cc2cccc(S(=O)(=O)O{-}.[Na]{+})c12
Threshold=20%,
Dice(Atom centered fragments)
Atom type; Count H attached; Hybridization

Domain logical expression index: "l"

Similarity boundary:Target: Nc1cc(S(O)(=O)=O)cc2cccc(S(=O)(=O)O{-}.[Na]{+})c12
Threshold=50%,
Dice(Atom centered fragments)
Atom type; Count H attached; Hybridization

Domain logical expression index: "m"

Similarity boundary:Target: Nc1cc(S(O)(=O)=O)cc2cccc(S(=O)(=O)O{-}.[Na]{+})c12
Threshold=80%,
Dice(Atom centered fragments)
Atom type; Count H attached; Hybridization

Domain logical expression index: "n"

Similarity boundary:Target: Nc1cc(S(O)(=O)=O)cc2cccc(S(=O)(=O)O{-}.[Na]{+})c12
Threshold=40%,
Dice(Atom centered fragments)
Atom type; Count H attached; Hybridization

Domain logical expression index: "o"

Parametric boundary:The target chemical should have a value of log BCF max which is >= 0.961 log(L/kg wet)

Domain logical expression index: "p"

Parametric boundary:The target chemical should have a value of log BCF max which is <= 1.54 log(L/kg wet)

Interpretation of results:

other: not irritating

Conclusions:

Sodium hydrogen 8-aminonaphthalene-1,6-disulfonate was estimated to be not irritating to the skin of albino rabbits.

Executive summary:

The dermal irritation potential of sodium hydrogen 8-aminonaphthalene-1,6-disulfonate was estimated using OECD QSAR toolbox v3.4 with logPow as the primary descriptor.

Sodium hydrogen 8-aminonaphthalene-1,6-disulfonate was estimated to be not irritating to the skin of albino rabbits.

Based on the estimated results, sodium hydrogen 8-aminonaphthalene-1,6-disulfonate 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 v3.4 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 v3.4

GLP compliance:

not specified

Specific details on test material used for the study:

- Name of test material: sodium hydrogen 8-aminonaphthalene-1,6-disulfonate
- Molecular formula: C10H8NNaO6S2
- Molecular weight: 325.2962 g/mol
- Smiles notation: c1cc2cc(cc(c2c(c1)S(=O)(=O)O)N)S(=O)(=O)[O-].[Na+]
- InChl: 1S/C10H9NO6S2.Na/c11-8-5-7(18(12,13)14)4-6-2-1-3-9(10(6)8)19(15,16)17;/h1-5H,11H2,(H,12,13,14)(H,15,16,17);/q;+1/p-1
- Substance type: Organic
- Physical state: Solid

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:

55mg

Duration of treatment / exposure:

24 hours

Observation period (in vivo):

21 days

Duration of post- treatment incubation (in vitro):

no data available

Number of animals or in vitro replicates:

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:

21 d

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 5 nearest neighbours
Domain logical expression:Result: In Domain

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

Domain logical expression index: "a"

Referential boundary: The target chemical should be classified as Naphthalene sulfonic acids, condensates by OECD HPV Chemical Categories

Domain logical expression index: "b"

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

Domain logical expression index: "c"

Referential boundary: The target chemical should be classified as Non-covalent interaction AND Non-covalent interaction >> DNA intercalation AND Non-covalent interaction >> DNA intercalation >> Fused-Ring Primary Aromatic Amines AND Radical AND Radical >> Radical mechanism via ROS formation (indirect) AND Radical >> Radical mechanism via ROS formation (indirect) >> Fused-Ring Primary Aromatic Amines AND SN1 AND SN1 >> Nucleophilic attack after metabolic nitrenium ion formation AND SN1 >> Nucleophilic attack after metabolic nitrenium ion formation >> Fused-Ring Primary Aromatic Amines by DNA binding by OASIS v.1.4

Domain logical expression index: "d"

Referential boundary: The target chemical should be classified as AN2 AND AN2 >> Michael-type addition to quinoid structures AND AN2 >> Michael-type addition to quinoid structures >> Substituted Anilines by Protein binding by OASIS v1.4

Domain logical expression index: "e"

Referential boundary: The target chemical should be classified as Strong binder, NH2 group by Estrogen Receptor Binding

Domain logical expression index: "f"

Referential boundary: The target chemical should be classified as Acid moiety AND Anilines (Unhindered) AND Salt by Aquatic toxicity classification by ECOSAR

Domain logical expression index: "g"

Referential boundary: The target chemical should be classified as Amine AND Anion AND Aromatic compound AND Cation AND Primary amine AND Primary aromatic amine AND Sulfonic acid AND Sulfonic acid derivative by Organic functional groups, Norbert Haider (checkmol)

Domain logical expression index: "h"

Referential boundary: The target chemical should be classified as 1,2-diol OR Alcohol OR Alkyl fluoride OR Alkyl halide OR Alkylarylether OR Aryl chloride OR Aryl fluoride OR Aryl halide OR Aryl iodide OR Azo compound OR Carbamic acid halide OR Carbonic acid derivative OR Carbonic acid diester OR Carbonyl compound OR Carboxylic acid OR Carboxylic acid amide OR Carboxylic acid derivative OR Carboxylic acid ester OR Carboxylic acid prim. amide OR Carboxylic acid sec. amide OR CO2 derivative (general) OR Diarylether OR Ether OR Halogen derivative OR Heterocyclic compound OR Hydroxy compound OR Ketone OR Nitrile OR Nitro compound OR No functional group found OR Phenol OR Primary alcohol OR Primary aliphatic amine OR Secondary alcohol OR Secondary amine OR Secondary aromatic amine OR Secondary mixed amine (aryl, alkyl) OR Sulfenic acid derivative OR Sulfonamide OR Sulfone OR Sulfuric acid derivative OR Sulfuric acid monoester OR Thioether by Organic functional groups, Norbert Haider (checkmol)

Domain logical expression index: "i"

Similarity boundary:Target: Nc1cc(S(O)(=O)=O)cc2cccc(S(=O)(=O)O{-}.[Na]{+})c12
Threshold=20%,
Dice(Atom centered fragments)
Atom type; Count H attached; Hybridization

Domain logical expression index: "j"

Similarity boundary:Target: Nc1cc(S(O)(=O)=O)cc2cccc(S(=O)(=O)O{-}.[Na]{+})c12
Threshold=30%,
Dice(Atom centered fragments)
Atom type; Count H attached; Hybridization

Domain logical expression index: "k"

Similarity boundary:Target: Nc1cc(S(O)(=O)=O)cc2cccc(S(=O)(=O)O{-}.[Na]{+})c12
Threshold=40%,
Dice(Atom centered fragments)
Atom type; Count H attached; Hybridization

Domain logical expression index: "l"

Similarity boundary:Target: Nc1cc(S(O)(=O)=O)cc2cccc(S(=O)(=O)O{-}.[Na]{+})c12
Threshold=50%,
Dice(Atom centered fragments)
Atom type; Count H attached; Hybridization

Domain logical expression index: "m"

Parametric boundary:The target chemical should have a value of log BCF max which is >= 0.961 log(L/kg wet)

Domain logical expression index: "n"

Parametric boundary:The target chemical should have a value of log BCF max which is <= 0.963 log(L/kg wet)

Interpretation of results:

other: not irritating

Conclusions:

Sodium hydrogen 8-aminonaphthalene-1,6-disulfonate was estimated to be not irritating to the eyes of rabbits.

Executive summary:

The ocular irritation potential of sodium hydrogen 8-aminonaphthalene-1,6-disulfonate was estimated using OECD QSAR toolbox v3.4 with logPow as the primary descriptor.

Sodium hydrogen 8-aminonaphthalene-1,6-disulfonate was estimated to be not irritating to the eyes of rabbits.

Based on the estimated results, sodium hydrogen 8-aminonaphthalene-1,6-disulfonate can be considered to be not irritating to eyes and can be classified under the category “Not Classified” as per CLP regulation.

Endpoint conclusion:

no adverse effect observed (not irritating)

Endpoint conclusion:

no study available

Skin Irritation:

Various studieshas been investigated for the test chemicalsodium hydrogen 8-aminonaphthalene-1,6-disulfonate (CAS No:74543-22-9)to observe the 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 sodium hydrogen 8-aminonaphthalene-1,6-disulfonate (CAS No:74543-22-9) and its structurally similar read across substances, 3-acetamido-5-amino-4-hydroxybenzenesulphonic acid [CAS: 40306-75-0] and 7-Amino-4-hydroxy-2-naphthalenesulfonic acid [CAS: 87-02-5]. 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 for sodium hydrogen 8-aminonaphthalene-1,6-disulfonate (CAS No:74543-22-9). The substance sodium hydrogen 8-aminonaphthalene-1,6-disulfonate (CAS No:74543-22-9) was not irritating to the skin of albino rabbits.

The above result is supported by the experimental study conducted in SSS sponsored lab(Sustainability Support Services (Europe) AB has letter of access, 2012), for the structurally similar read across substance, 3-acetamido-5-amino-4-hydroxybenzenesulphonic acid [CAS: 40306-75-0].The study was performed according to OECD 404. The animals were prepared 24 hrs prior to application of test product. The furs from the dorsal area of trunk of animals were removed with electric clippers exposing an area measuring approximately 6 cm2 of body surface area of animal. The care was taken such that abrasion penetrated the Stratum corneum only and not dermis. The Primary Dermal Irritation Index(PDII) after 14 days was 0.5. The result obtained from present study reveals that the test compound 3-acetamido-5-amino-4-hydroxybenzenesulphonic acid was not irritating to skin of the New Zealand white rabbits when applied to the shaven back intact skin.

These studies are also supported by the experimental study conducted by GREIM H., J. AHLERS, R. BIAS, B. BROECKER, H. HOLLANDER, H.P. GELBKE, H.-J. KLIMISCH, I. MANGELSDORF, A. PAETZ, N SCHGN, G. STROPP, R. VOGEL, C. WEBER, K. ZIEGLER-SKYLAKAKIS and E. BAYER in (1994) in 2 New Zealand White rabbits (male and female) of another structurally similar read across substance7-Amino-4-hydroxy-2-naphthalenesulfonic acid (CAS No: 87-02-5) for the observation period of 7 days. In this skin irritation study, approx. 500 mg 7-amino-4-hydroxy-2-naphthalenesulfonic acid (I acid) was applied to the inner surface of the ears of 2 rabbits. The test chemical was applied under an adhesive dressing for 24 hours. At the end of the exposure period, the test substance was washed off with water and soap/vegetable oil. The observation period was 7 days. No skin irritation was observed after 7 days. Hence the chemical 7-Amino-4-hydroxy-2-naphthalenesulfonic acid (CAS No: 87-02-5) can be considered non-irritant to rabbit skin.

Based on the available data for the target and read across substances and applying the weight of evidence approach,it can be concluded thatchemical sodium hydrogen 8-aminonaphthalene-1,6-disulfonate (CAS No:74543-22-9) is unable to cause skin irritation and considered as not irritating.Comparing the above annotations with the criteria of CLP regulation, it can be classified under the category “Not Classified”.

Eye Irritation:

In different studies, sodium hydrogen 8-aminonaphthalene-1,6-disulfonate (CAS No:74543-22-9)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 sodium hydrogen 8-aminonaphthalene-1,6-disulfonate (CAS No:74543-22-9)and its structurally similar read across substances, 3-acetamido-5-amino-4-hydroxybenzenesulphonic acid [CAS: 40306-75-0] and 7-Amino-4-hydroxy-2-naphthalenesulfonic acid [CAS: 87-02-5]. 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 eye irritation potential was estimated for sodium hydrogen 8-aminonaphthalene-1,6-disulfonate (CAS No:74543-22-9). The substance sodium hydrogen 8-aminonaphthalene-1,6-disulfonate (CAS No:74543-22-9) was not irritating to the eyes of rabbits.

The above result is supported by the experimental study conducted in SSS sponsored lab(Sustainability Support Services (Europe) AB has letter of access, 2012), for the structurally similar read across substance, 3-acetamido-5-amino-4-hydroxybenzenesulphonic acid [CAS: 40306-75-0].The study was performed according to OECD 405. 3 female New Zealand White rabbits were used for the ocular irritation study. 0.1 gm of the test chemical was moistened with water was instilled in the conjunctival sac of rabbits after gently pulling the lower lid away from the eyeball. The other eye which remained untreated served as a control. The ocular lesions were evaluated at 1, 24, 48 and 72 hours after the treatment. The grades of ocular reactions (conjunctiva, cornea and iris) were recorded at each observation. To determine the reversibility of the effect the animals were observed normally for 21 days. Any other lesions in the eye viz pannus, staining were observed and scored accordingly. Examination of reactions was facilitated by use of biomicroscope and hand slit lamp. Individual animal weights before and during the study was observed. The overall irritation index of 3-acetamido-5-amino-4-hydroxybenzenesulphonic acid was 1.25 after 72 hours. Also 3-acetamido-5-amino-4-hydroxybenzenesulphonic acid did not produce any clinical signs of toxicity throughout the examination period of 21 days. Hence, under the test conditions, 3-acetamido-5-amino-4-hydroxybenzenesulphonic acid [CAS: 40306-75-0] can be concluded to be not irritating to New Zealand White rabbit eyes.

The above results are further supported by experimental study conducted by GREIM H., J. AHLERS, R. BIAS, B. BROECKER, H. HOLLANDER, H.P. GELBKE, H.-J. KLIMISCH, I. MANGELSDORF, A. PAETZ, N SCHGN, G. STROPP, R. VOGEL, C. WEBER, K. ZIEGLER-SKYLAKAKIS and E. BAYER in 1994 for structurally similar read across substance7-Amino-4-hydroxy-2-naphthalenesulfonic acid (CAS No: 87-02-5) in rabbits. In this study, 50 mg 7-amino-4-hydroxy-2-naphthalenesulfonic acid (I acid) was instilled into the conjunctival sac of 2 animals and each were observed for 7 days. No eye irritation was observed after 7 days. Hence the chemical 7-amino-4-hydroxy-2-naphthalenesulfonic acid (CAS No: 87-02-5) can be considered non-irritant to rabbit eyes.

Based on the available data for the target and read across substances and applying the weight of evidence approach,it can be concluded thatchemical sodium hydrogen 8-aminonaphthalene-1,6-disulfonate (CAS No:74543-22-9) is unable to cause ocular lesions and considered as not irritating.Comparing the above annotations with the criteria of CLP regulation, it can be classified under the category “Not Classified”.

The skin and eye irritation potential of test chemicalsodium hydrogen 8-aminonaphthalene-1,6-disulfonate (CAS No:74543-22-9)and its structurally similar read across substances, 3-acetamido-5-amino-4-hydroxybenzenesulphonic acid [CAS: 40306-75-0] and 7-Amino-4-hydroxy-2-naphthalenesulfonic acid [CAS: 87-02-5]were observed in various studies. The results obtained from these studies indicates that the chemicalsodium hydrogen 8-aminonaphthalene-1,6-disulfonate is unlikely to cause skin and eye irritation. Hencesodium hydrogen 8-aminonaphthalene-1,6-disulfonate (CAS No:74543-22-9)can be classified under the category “Not Classified” for skin and eye as per CLP.