Registration Dossier

Skin irritation:

The dermal irritation potential of 2-chlorobenzene-1,4-diammonium sulphate was estimated using OECD QSAR toolbox v3.3 with logPow as the primary descriptor. 2-chlorobenzene-1,4-diammonium sulphate was estimated to be not irritating to the skin of rabbits. Based on the estimated results, 2-chlorobenzene-1,4-diammonium sulphate 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 2-chlorobenzene-1,4-diammonium sulphate was estimated using OECD QSAR toolbox v3.3 with log Pow as the primary descriptor. 2-chlorobenzene-1,4-diammonium sulphate was estimated to be irritating to the eye of rabbits. Based on the estimated results, 2-chlorobenzene-1,4-diammonium sulphate can be considered to be irritating to eye and can be classified under the category “ Category 2 (irritating to eyes) based on GHS criteria” 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 predicted using OECD QSAR toolbox version 3.3 and QMRF report has been attached
Qualifier:: according to guideline
Guideline:: other: estimated data
Principles of method if other than guideline:: Prediction was done by using OECD QSAR toolbox v3.3
GLP compliance:: not specified
Specific details on test material used for the study:: IUPAC name: 2-chlorobenzene-1,4-diammonium sulphate
Molecular formula: C6H7ClN2.xH2O4S
Molecular weight:240.6661
substance type: organic
physical state: light grey colored solid powder.
InChI:1S/C6H7ClN2.H2O4S/c7-5-3-4(8)1-2-6(5)9;1-5(2,3)4/h1-3H,8-9H2;(H2,1,2,3,4)
Smiles:S(=O)(=O)(O)O.c1(c(ccc(c1)N)N)Cl
Species:: rabbit
Strain:: New Zealand White
Details on test animals or test system and environmental conditions:: No data available
Type of coverage:: not specified
Preparation of test site:: not specified
Vehicle:: not specified
Controls:: not specified
Amount / concentration applied:: Not specified
Duration of treatment / exposure:: Not specified
Observation period:: Not specified
Number of animals:: Not specified
Details on study design:: No data available
Irritation parameter:: overall irritation score
Basis:: mean
Time point:: other: Not specified
Reversibility:: not specified
Remarks on result:: no indication of irritation
Interpretation of results:: other: Not irritating
Conclusions:: 2-chlorobenzene-1,4-diammonium sulphate was considered to be not irritating to skin of rabbit.
Executive summary:: The dermal irritation potential of 2-chlorobenzene-1,4-diammonium sulphate was estimated using OECD QSAR toolbox v3.3 with logPow as the primary descriptor. 2-chlorobenzene-1,4-diammonium sulphate was estimated to be not irritating to the skin of rabbits. Based on the estimated results, 2-chlorobenzene-1,4-diammonium sulphate 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 predicted using OECD QSAR toolbox version 3.3 and QMRF report has been attached

Qualifier:

according to guideline

Guideline:

other: estimated data

Principles of method if other than guideline:

Prediction was done by using OECD QSAR toolbox v3.3

GLP compliance:

not specified

Specific details on test material used for the study:

IUPAC name: 2-chlorobenzene-1,4-diammonium sulphate
Molecular formula: C6H7ClN2.xH2O4S
Molecular weight:240.6661
substance type: organic
physical state: light grey colored solid powder.
InChI:1S/C6H7ClN2.H2O4S/c7-5-3-4(8)1-2-6(5)9;1-5(2,3)4/h1-3H,8-9H2;(H2,1,2,3,4)
Smiles:S(=O)(=O)(O)O.c1(c(ccc(c1)N)N)Cl

Species:

rabbit

Strain:

not specified

Details on test animals or tissues and environmental conditions:

No data available

Vehicle:

not specified

Controls:

not specified

Amount / concentration applied:

No data available

Duration of treatment / exposure:

No data available

Observation period (in vivo):

No data available

Number of animals or in vitro replicates:

No data available

Details on study design:

No data available

Irritation parameter:

overall irritation score

Basis:

mean

Time point:

other: Not specified

Reversibility:

not specified

Remarks on result:

positive indication of irritation

Estimation method: Takes mode 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 "i" ) and ("j" and ( not "k") ) ) and "l" ) and ("m" and ( not "n") ) ) and ("o" and ( not "p") ) ) and ("q" and ( not "r") ) ) and ("s" and ( not "t") ) ) and ("u" and ( not "v") ) ) and "w" ) and ("x" and ( not "y") ) ) and ("z" and ( not "aa") ) ) and "ab" ) and ("ac" and "ad" ) )

Domain logical expression index: "a"

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

Domain logical expression index: "b"

Referential boundary: The target chemical should be classified as Radical OR Radical >> Radical mechanism via ROS formation (indirect) OR Radical >> Radical mechanism via ROS formation (indirect) >> Single-Ring Substituted Primary Aromatic Amines OR SN1 OR SN1 >> Nucleophilic attack after metabolic nitrenium ion formation OR SN1 >> Nucleophilic attack after metabolic nitrenium ion formation >> Single-Ring Substituted Primary Aromatic Amines by DNA binding by OASIS v.1.3 ONLY

Domain logical expression index: "c"

Referential boundary: The target chemical should be classified as SN1 OR SN1 >> Nitrenium Ion formation OR SN1 >> Nitrenium Ion formation >> Primary aromatic amine by DNA binding by OECD ONLY

Domain logical expression index: "d"

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

Domain logical expression index: "e"

Referential boundary: The target chemical should be classified as Anilines (amino-para) OR Anilines (Unhindered) OR Inorganic Compound by Aquatic toxicity classification by ECOSAR ONLY

Domain logical expression index: "f"

Referential boundary: The target chemical should be classified as Non binder, non cyclic structure AND Weak binder, NH2 group by Estrogen Receptor Binding

Domain logical expression index: "g"

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

Domain logical expression index: "h"

Referential boundary: The target chemical should be classified as Not calculated by Hydrolysis half-life (Kb, pH 7)(Hydrowin) ONLY

Domain logical expression index: "i"

Referential boundary: The target chemical should be classified as Bioavailable by Lipinski Rule Oasis ONLY

Domain logical expression index: "j"

Referential boundary: The target chemical should be classified as Group 14 - Carbon C AND Group 15 - Nitrogen N AND Group 16 - Oxygen O AND Group 16 - Sulfur S AND Group 17 - Halogens Cl AND Group 17 - Halogens F,Cl,Br,I,At by Chemical elements

Domain logical expression index: "k"

Referential boundary: The target chemical should be classified as Group 15 - Phosphorus P OR Group 17 - Halogens Br OR Group 17 - Halogens F by Chemical elements

Domain logical expression index: "l"

Similarity boundary:Target: Nc1ccc(N)cc1Cl_OS(O)(=O)=O
Threshold=40%,
Dice(Atom centered fragments)
Atom type; Count H attached; Hybridization

Domain logical expression index: "m"

Referential boundary: The target chemical should be classified as Anilines (Hemolytic anemia with methemoglobinemia) Rank A AND Anilines (Hepatotoxicity) Rank C AND Not categorized by Repeated dose (HESS)

Domain logical expression index: "n"

Referential boundary: The target chemical should be classified as Aliphatic amines (Mucous membrane irritation) Rank C OR Chlorphentermine (Hepatotoxicity) Alert OR Nitrobenzenes (Hemolytic anemia with methemoglobinemia) Rank A OR Nitrobenzenes (Hepatotoxicity) Rank C OR Thiocarbamates/Sulfides (Hepatotoxicity) No rank by Repeated dose (HESS)

Domain logical expression index: "o"

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

Domain logical expression index: "p"

Referential boundary: The target chemical should be classified as Alkylarylether by Organic functional groups, Norbert Haider (checkmol)

Domain logical expression index: "q"

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

Domain logical expression index: "r"

Referential boundary: The target chemical should be classified as Carbonic acid derivative by Organic functional groups, Norbert Haider (checkmol)

Domain logical expression index: "s"

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

Domain logical expression index: "t"

Referential boundary: The target chemical should be classified as Hydroxylamine OR No functional group found by Organic functional groups, Norbert Haider (checkmol)

Domain logical expression index: "u"

Referential boundary: The target chemical should be classified as Aliphatic Nitrogen, one aromatic attach [-N] AND Aromatic Carbon [C] AND Chlorine, aromatic attach [-Cl] AND Chlorine, olefinic attach [-Cl] AND Hydroxy, sulfur attach [-OH] AND Miscellaneous sulfide (=S) or oxide (=O) AND Olefinic carbon [=CH- or =C<] AND Suflur {v+4} or {v+6} AND Sulfate, linear [-O-SO2-O-] AND Sulfinic acid [-S(=O)OH] AND Sulfite, linear [-OS(=O)O-] AND Sulfonic [SO2(-OH)-O] by Organic functional groups (US EPA)

Domain logical expression index: "v"

Referential boundary: The target chemical should be classified as Sulfur, S=O attach [-S-] by Organic functional groups (US EPA)

Domain logical expression index: "w"

Similarity boundary:Target: Nc1ccc(N)cc1Cl_OS(O)(=O)=O
Threshold=20%,
Dice(Atom centered fragments)
Atom type; Count H attached; Hybridization

Domain logical expression index: "x"

Referential boundary: The target chemical should be classified as No alert found by rtER Expert System ver.1 - USEPA

Domain logical expression index: "y"

Referential boundary: The target chemical should be classified as 4-Alkylanilines by rtER Expert System ver.1 - USEPA

Domain logical expression index: "z"

Referential boundary: The target chemical should be classified as Aromatic amine [-NH2 or -NH-] AND Aromatic chloride [-CL] AND Aromatic-H AND Not calculated by Biodegradation fragments (BioWIN MITI)

Domain logical expression index: "aa"

Referential boundary: The target chemical should be classified as Aromatic-CH3 by Biodegradation fragments (BioWIN MITI)

Domain logical expression index: "ab"

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

Domain logical expression index: "ac"

Parametric boundary:The target chemical should have a value of log Kow which is >= -4.4

Domain logical expression index: "ad"

Parametric boundary:The target chemical should have a value of log Kow which is <= 1.09

Interpretation of results:

Category 2 (irritating to eyes) based on GHS criteria

Conclusions:

2-chlorobenzene-1,4-diammonium sulphate was considered to be irritating to eye of rabbit.

Executive summary:

The ocular irritation potential of 2-chlorobenzene-1,4-diammonium sulphate was estimated using OECD QSAR toolbox v3.3 with log Pow as the primary descriptor. 2-chlorobenzene-1,4-diammonium sulphate was estimated to be irritating to the eye of rabbits. Based on the estimated results, 2-chlorobenzene-1,4-diammonium sulphate can be considered to be irritating to eye and can be classified under the category “ Category 2 (irritating to eyes) based on GHS criteria” as per CLP regulation.

Endpoint conclusion:

adverse effect observed (irritating)

Endpoint conclusion:

no study available

Skin irritation:

In different studies, 2-chlorobenzene-1,4-diammonium sulphate 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 human data for target chemical 2-chlorobenzene-1,4-diammonium sulphate and its structurally similar read across substances 2-methyl-p-phenylenediamine sulphate (CAS:615-50-9 ) and 2-Chloro-1,4-phenylenediamine (CAS: 615-66-7). The predicted data using the OECD QSAR toolbox has also been compared with the experimental data.

The dermal irritation potential of 2-chlorobenzene-1,4-diammonium sulphate was estimated using OECD QSAR toolbox v3.3 with logPow as the primary descriptor. 2-chlorobenzene-1,4-diammonium sulphate was estimated to be not irritating to the skin of rabbits. Based on the estimated results, 2-chlorobenzene-1,4-diammonium sulphate can be considered to be not irritating to skin and can be classified under the category “ Not classified” as per CLP regulation.

The above predicted data was supported by experimental study conducted by Christina L. Burnett et.al in International Journal of Toxicology 29 ( supplement 2) 2010 for the structurally similar read across substance 2-methyl-p-phenylenediamine sulphate (CAS:615-50-9 )

2-methyl-p-phenylenediamine sulphate was used as a test material to evaluate skin irritation potential on 10 Hartley albino guinea pigs.

The test material was applied on the flanks of test animal in the concentrations of0.1%, 0.2%, 0.5%, 1%, 2%, 5% and 10% in petrolatum for 48 hrs under occlusion .

No skin reaction were observed in any of the test animals in any of the test concentrations. Hence,2-methyl-p-phenylenediamine sulphate was considered as not skin irritant.

The above experimental result was further supported by experimental study conducted by Lynn Willis in Journal of the American college of Toxicology Volume 11, Number 4,1992 for the structurally similar read across substance 2-Chloro-1,4-phenylenediamine (CAS: 615-66-7).

2-Chloro-1,4-phenylenediamine was used as a test material to evaluate skin irritation potential on 3 albino rabbits. The test material was applied on the clipped hair free skin of albino rabbits on one abraded and one intact site on each animal. The test material was used in the concentration 0.5 ml of 2.5% w/v in distilled water for 24 hrs exposure . The patches were removed and the test sites scored on a scale of 0 to 4 Sites were scored again 72 h after the application. No skin irritation reactions were observed. Hence,2-Chloro-1,4-phenylenediamine was considered to be not irritating to rabbit skin .

Based on the available data for the target as well as it read across substances;and applying the weight of evidence approach, it can be concluded that 2-chlorobenzene-1,4-diammonium sulphate was not irritating to skin. Itcan be classified under the category “Not Classified” as per CLP regulation.

Eye irritation:

In different studies, 2-chlorobenzene-1,4-diammonium sulphate 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 human data for target chemical 2-chlorobenzene-1,4-diammonium sulphate and its structurally similar read across substances 2-methylbenzene-1,4-diamine (CAS: 95-70-5 ) and 2-(2,4-diaminophenoxy)ethanol dihydrochloride (CAS: 66422-95-5). The predicted data using the OECD QSAR toolbox has also been compared with the experimental data.

The ocular irritation potential of 2-chlorobenzene-1,4-diammonium sulphate was estimated using OECD QSAR toolbox v3.3 with log Pow as the primary descriptor. 2-chlorobenzene-1,4-diammonium sulphate was estimated to be irritating to the eye of rabbits. Based on the estimated results, 2-chlorobenzene-1,4-diammonium sulphate can be considered to be irritating to eye and can be classified under the category “ Category 2 (irritating to eyes) based on GHS criteria” as per CLP regulation.

The above predicted data was supported by experimental study summarized in Hazardous Substances Data Bank (HSDB) for 2-METHYL-1,4-BENZENEDIAMINE U.S National Library of Medicine 2017 for the structurally similar read across substance 2-methylbenzene-1,4-diamine (CAS: 95-70-5 )

2,5-Diaminotoluene was used as a test material to evaluate ocular irritation potential on three rabbits. The test material was installed onto the eyes of rabbits in the concentration 0.1 mL of a 2.5% w/v in aqueous sodium sulphite (pH 7.0) for 10 sec. After 10 seconds the eye was rinsed with 50 mL of lukewarm water.eyes were evaluated and scored by Draize scoring system at 1 hr and then at Days 1, 2, 3, 4, and 7.

Mild conjuctival irritation was observed in 2 animals on day 1 and 3 respectively . No data regarding reversibility of the irritation was stated. Under the conditions of this test, toluene-2,5-diamine solution caused slight irritation to rabbit eyes.

The above experimental result was further supported by experimental data summarized in Opinion on: 2,4-diaminophenoxyethanol and its Salts European Commission (EC) - Scientific Committee on Consumer Products (SCCP) 2006 and Human Health tier II assessment for Ethanol, 2-(2,4- diaminophenoxy)-, dihydrochloride INVENTORY MULTI-TIERED ASSESSMENT AND PRIORITISATION (IMAP) - the National Industrial Chemicals Notification and Assessment Scheme (NICNAS) 2017 for the structurally similar read across substance2-(2,4-diaminophenoxy)ethanol dihydrochloride (CAS: 66422-95-5)

2-(2,4-diaminophenoxy)ethanol dihydrochloride was used as a test material to evaluate its eye irritation potential on three female New Zealand white rabbits according to guideline OECD 405. The test material was installed in the conjunctival sac of the left eye of the animals. The right eye was served as control . The eyes were not rinsed following instillation of the test item. Ocular reactions were assessed 1, 24, 48 and 72 hours after instillation, as well as on day 8 and day 15. The ocular reactions such as moderate to marked chemosis and slight to moderate redness of conjunctivae, slight to moderate corneal opacification and slight iridal lesions were observed.

At day 15 , similar though less marked ocular reactions were observed. Hence, 2-(2,4-diaminophenoxy)ethanol dihydrochloride was considered to be irritating to rabbit eye.

Based on the available data for the target as well as it read across substances;and applying the weight of evidence approach, it can be concluded that 2-chlorobenzene-1,4-diammonium sulphate was irritating to eye. It can be classified under the category “Category 2 (irritating to eyes) based on GHS criteria” as per CLP regulation.

Based on the available data for the target as well as it read across substances;and applying the weight of evidence approach, it can be concluded that 2-chlorobenzene-1,4-diammonium sulphate was not irritating to skin. Itcan be classified under the category “Not Classified” as per CLP regulation .

Whereas, on the basis of available data for the target as well as it read across substances;and applying the weight of evidence approach, it can be concluded that 2-chlorobenzene-1,4-diammonium sulphate was irritating to eye. It can be classified under the category “Category 2 (irritating to eyes) based on GHS criteria” as per CLP regulation.