4,5-dichloro-2-nitroaniline

Endpoint summary

Description of key information

Skin Irritation:

The dermal irritation potential of 4,5-dichloro-2-nitroaniline was estimated using OECD QSAR toolbox v3.3 with logPow as the primary descriptor.

4,5-dichloro-2-nitroaniline was estimated to be irritating to the skin of New Zealand White rabbits.

Based on the estimated results, 4,5-dichloro-2-nitroaniline 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 4,5-dichloro-2-nitroaniline was estimated using OECD QSAR toolbox v3.3 with logPow as the primary descriptor.

4,5-dichloro-2-nitroaniline was estimated to be not irritating to the eyes of Vienna White rabbits.

Based on the estimated results, 4,5-dichloro-2-nitroaniline can be considered to be not irritating to eyes and can be classified under the category “Not Classified” as per CLP regulation.

Key value for chemical safety assessment

Skin irritation / corrosion

Link to relevant study records

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: 4,5-dichloro-2-nitroaniline
Molecular formula: C6H4Cl2N2O2
Molecular weight: 207.016 g/mol
Smiles Notation: Nc1cc(Cl)c(Cl)cc1[N+]([O-])=O
InChI: 1S/C6H4Cl2N2O2/c7-3-1-5(9)6(10(11)12)2-4(3)8/h1-2H,9H2
Substance Type: Organic
Physical State: solid

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:

clipped

Vehicle:

unchanged (no vehicle)

Controls:

not specified

Amount / concentration applied:

500 mg

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 irritation observed

Estimation method: Takes mode value from the 6 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" )  )

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 Strong binder, NH2 group by Estrogen Receptor Binding

Domain logical expression index: "c"

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 ONLY

Domain logical expression index: "d"

Referential boundary: The target chemical should be classified as 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 ONLY

Domain logical expression index: "e"

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) >> Nitroaniline Derivatives OR Radical >> Radical mechanism via ROS formation (indirect) >> Nitroarenes with Other Active Groups OR SN1 OR SN1 >> Nucleophilic attack after diazonium or carbenium ion formation OR SN1 >> Nucleophilic attack after diazonium or carbenium ion formation >> Nitroarenes with Other Active Groups OR SN1 >> Nucleophilic attack after reduction and nitrenium ion formation OR SN1 >> Nucleophilic attack after reduction and nitrenium ion formation >> Nitroaniline Derivatives OR SN1 >> Nucleophilic attack after reduction and nitrenium ion formation >> Nitroarenes with Other Active Groups OR SN2 OR SN2 >> SN2 attack on activated carbon Csp3 or Csp2 OR SN2 >> SN2 attack on activated carbon Csp3 or Csp2 >> Nitroarenes with Other Active Groups by DNA binding by OASIS v.1.3 ONLY

Domain logical expression index: "f"

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

Domain logical expression index: "g"

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

Domain logical expression index: "h"

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

Domain logical expression index: "i"

Referential boundary: The target chemical should be classified as Class 3 (unspecific reactivity) by Acute aquatic toxicity classification by Verhaar (Modified) ONLY

Domain logical expression index: "j"

Parametric boundary:The target chemical should have a value of log Kow which is >= 0.526

Domain logical expression index: "k"

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

Interpretation of results:

other: not irritating

Conclusions:

4,5-dichloro-2-nitroaniline was estimated to be irritating to the skin of New Zealand White rabbits.

Executive summary:

The dermal irritation potential of 4,5-dichloro-2-nitroaniline was estimated using OECD QSAR toolbox v3.3 with logPow as the primary descriptor.

4,5-dichloro-2-nitroaniline was estimated to be irritating to the skin of New Zealand White rabbits.

Based on the estimated results, 4,5-dichloro-2-nitroaniline can be considered to be not irritating to skin and can be classified under the category “Not Classified” as per CLP regulation

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (not irritating)

Eye irritation

Link to relevant study records

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: 4,5-dichloro-2-nitroaniline
Molecular formula: C6H4Cl2N2O2
Molecular weight: 207.016 g/mol
Smiles Notation: Nc1cc(Cl)c(Cl)cc1[N+]([O-])=O
InChI: 1S/C6H4Cl2N2O2/c7-3-1-5(9)6(10(11)12)2-4(3)8/h1-2H,9H2
Substance Type: Organic
Physical State: solid

Species:

rabbit

Strain:

Vienna White

Details on test animals or tissues and environmental conditions:

no data available

Vehicle:

unchanged (no vehicle)

Controls:

not specified

Amount / concentration applied:

0.1g

Duration of treatment / exposure:

single exposure

Observation period (in vivo):

72 hours

Duration of post- treatment incubation (in vitro):

no data available

Number of animals or in vitro replicates:

2

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 irritation observed

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

(((((((("a" or "b" or "c" or "d" or "e" or "f") and "g") and("h" and(not "i")) ) and "j") and "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 Anilines (Acute toxicity) by US-EPA New Chemical Categories

Domain logical expression index: "b"

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

Domain logical expression index: "c"

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 ONLY

Domain logical expression index: "d"

Referential boundary:The target chemical should be classified as 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 ONLY

Domain logical expression index: "e"

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) >> Nitroaniline Derivatives OR Radical >> Radical mechanism via ROS formation (indirect) >> Nitroarenes with Other Active Groups OR SN1 OR SN1 >> Nucleophilic attack after diazonium or carbenium ion formation OR SN1 >> Nucleophilic attack after diazonium or carbenium ion formation >> Nitroarenes with Other Active Groups OR SN1 >> Nucleophilic attack after reduction and nitrenium ion formation OR SN1 >> Nucleophilic attack after reduction and nitrenium ion formation >> Nitroaniline Derivatives OR SN1 >> Nucleophilic attack after reduction and nitrenium ion formation >> Nitroarenes with Other Active Groups OR SN2 OR SN2 >> SN2 attack on activated carbon Csp3 or Csp2 OR SN2 >> SN2 attack on activated carbon Csp3 or Csp2 >> Nitroarenes with Other Active Groups by DNA binding by OASIS v.1.3 ONLY

Domain logical expression index: "f"

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

Domain logical expression index: "g"

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

Domain logical expression index: "h"

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

Domain logical expression index: "i"

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

Domain logical expression index: "j"

Referential boundary:The target chemical should be classified as No superfragment by Superfragments ONLY

Domain logical expression index: "k"

Referential boundary:The target chemical should be classified as Phenols and Anilines by Acute aquatic toxicity MOA by OASIS ONLY

Domain logical expression index: "l"

Referential boundary:The target chemical should be classified as H-acceptor-path3-H-acceptor AND Nitro-aromatic AND Primary aromatic amine, hydroxyl amine and its derived esters by in vivo mutagenicity (Micronucleus) alerts by ISS

Domain logical expression index: "m"

Referential boundary:The target chemical should be classified as 1-phenoxy-benzene by in vivo mutagenicity (Micronucleus) alerts by ISS

Domain logical expression index: "n"

Similarity boundary:Target: Nc1cc(Cl)c(Cl)cc1N(=O)=O
Threshold=20%,
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 Kow which is >= 1.86

Domain logical expression index: "p"

Parametric boundary:The target chemical should have a value of log Kow which is <= 4.33

Interpretation of results:

other: not irritating

Conclusions:

4,5-dichloro-2-nitroaniline was estimated to be not irritating to the eyes of Vienna White rabbits.

Executive summary:

The ocular irritation potential of 4,5-dichloro-2-nitroaniline was estimated using OECD QSAR toolbox v3.3 with logPow as the primary descriptor.

4,5-dichloro-2-nitroaniline was estimated to be not irritating to the eyes of Vienna White rabbits.

Based on the estimated results, 4,5-dichloro-2-nitroaniline can be considered to be not irritating to eyes and can be classified under the category “Not Classified” as per CLP regulation.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (not irritating)

Respiratory irritation

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

Skin Irritation:

In different studies, 4,5-dichloro-2-nitroaniline 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, 4-Chloro-2-nitroaniline[CAS: 89-63-4] and 1,2-Dichloro-4-nitrobenzene[CAS:99-54-7]. 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 dermal irritation potential was estimated for 4,5-dichloro-2-nitroaniline. 4,5 -dichloro-2-nitroaniline was estimated to be not irritating to the skin of New 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 4,5-dichloro-2-nitroaniline.Based on estimation,no severe skin irritation effects were known when 4,5-dichloro-2-nitroaniline was exposed to rabbit skin.Hence,4,5-dichloro-2-nitroaniline can be considered to be not irritating to skin.

Both the estimated studies are in agreement with each other indicating the possibility of 4,5-dichloro-2-nitroaniline being not irritating to skin.

These results are supported by the experimental study summarized in GESTIS, Institut für Arbeitsschutz der Deutschen Gesetzlichen Unfallversicherung (IFA) GESTIS-database on hazardous substance, 2017; for the structurally similar read across substance, 4-Chloro-2-nitroaniline[CAS: 89-63-4]. The test was performed according to FDA Guidelines. 4-Chloro-2 -nitroaniline was exposed to rabbits skin for 4 hours under occlusive conditions. The rabbits were observed for effects at 24 and 48 hours. Even after 24, 48 hours of contact, 4-Chloro-2 -nitroaniline did not cause any irritation to rabbit skin.

Hence, 4-Chloro-2-nitroaniline can be considered to be not irritating to skin.

These results are further supported by the experimental study summarized in Hazardous Substance DataBank [HSDB], U S National Library of Medicine, last updated 2008; for the structurally similar read across substance, 1,2-Dichloro-4-nitrobenzene[CAS:99-54-7]. The test was performed according to OECD 404 Guidelines. 500 mg of 1,2-Dichloro-4-nitrobenzene moistened with physiological saline was applied under semi-occlusive conditions to 3 rabbits for 4 hours. The rabbits were observed and the reactions were scored 30 - 60 min and 24, 48 or 72 hours after removal of the patch. The mean scores (reading 30 - 60 min and 24, 48 or 72 hours after removal of the patch) for erythema/scabbing and edema were 0.2 and 0.0 respectively. The effects observed had disappeared at the 24-hour reading time point.

Since the effects were fully reversible within 24 hours, 1,2-Dichloro-4-nitrobenzene can be considered not irritating to skin.

Based on the available data for the target as well as read across chemicals and applying the weight of evidence approach, 4,5-dichloro-2-nitroaniline can be considered not irritating to skin.Comparing the above annotations with the criteria of CLP regulation, test chemical can be classified under the category “Not Classified” 

Eye Irritation:   

In different studies, 4,5-dichloro-2-nitroaniline 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, 1,2-Dichloro-4-nitrobenzene[CAS:99-54-7] and 1-chloro-3-nitrobenzene [CAS: 121-73-3].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 ocular irritation potential was estimated for 4,5-dichloro-2-nitroaniline. 4,5 -dichloro-2-nitroaniline was estimated to be irritating to the not eyes of Vienna White rabbits.

This result is supported by the experimental study summarized in Hazardous Substance DataBank [HSDB], U S National Library of Medicine, last updated 2008; for the structurally similar read across substance, 1,2-Dichloro-4-nitrobenzene[CAS:99-54-7]. Undiluted 0.1 ml 1,2-Dichloro-4-nitrobenzene was instilled in the conjunctival sac of the right eye of 3 albino rabbits (1 female and 2 males). The rabbit were observed for signs of irritation till 5 days. Signs of irritation observed in rabbits included moderate immediate discomfort, lacrimation together with moderate erythema and edema, and a slight cloudiness of the corneal area. A slight degree of inflammation was present in 1 rabbit after 72-hour.These effects were fully reversible in 5 days.

Since the observed effects were reversible in 5 days, 1,2-Dichloro-4-nitrobenzene can be considered to be not irritating to rabbit eyes.

These results are also supported by the experimental study summarized in BG Chemie InfoCenter TOXIKOLOGISCHE BEWERTUNGEN, last updated 11/2000; for the structurally similar read across substance, 1-chloro-3-nitrobenzene [CAS: 121-73-3]. 100 mg dose of the chemical (99% pure) was instilled into the conjunctival sac of the left eye of 3 New Zealand White rabbits. Twenty-four hours prior to the beginning of the experiment, and 72 hours after administration, one drop of sodium fluorescein solution was instilled into the treated eye of each animal, and damage to the cornea was assessed under ultraviolet light. Inspection of the treated eyes for signs of irritation was performed at 1, 24, 48 and 72 hours after instillation.

At 1 and 24 hours after treatment, mild to moderate swelling and severe reddening of the conjunctivae occurred. At 48 hours after treatment, one animal showed marked hyperaemia of the conjunctival blood vessels. At 72 hours after treatment, 2 animals were still observed to have marked hyperaemia of the conjunctival blood vessels. After 7 days, all signs of irritation were reversible. Since the effects were completely reversible by 7 days,1-chloro-3-nitrobenzene can be considered not irritating to eyes.

Based on the available data for the target as well as read across chemicals and applying the weight of evidence approach, 4,5-dichloro-2-nitroaniline can be considered not irritating to skin.Comparing the above annotations with the criteria of CLP regulation, test chemical can be classified under the category “Not Classified”.

Justification for classification or non-classification

Available studies for 4,5-dichloro-2-nitroaniline indicate that it is not likely to cause irritation to skin and eyes.

Hence, 4,5-dichloro-2-nitroaniline can be classified under the category “Not Classified” as per CLP regulation.