2-methoxy-5-nitroanilinium chloride

Endpoint summary

Description of key information

Skin Irritation:

The dermal irritation potential of 2-methoxy-5-nitroanilinium chloride was estimated using OECD QSAR toolbox version 3.3 with logPow as the primary descriptor.

2-methoxy-5-nitroanilinium chloride was estimated to be not irritating to the skin of rabbits.

Based on the estimated result; 2-methoxy-5-nitroanilinium chloride can be considered 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-methoxy-5-nitroanilinium chloride was estimated using OECD QSAR toolbox version 3.3 with logPow as the primary descriptor.

2-methoxy-5-nitroanilinium chloride was estimated to be not irritating to the eyes of rabbits.

Based on the estimated results, 2-methoxy-5-nitroanilinium chloride can be considered 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 OEDC QSAR toolbox v3.3

GLP compliance:

not specified

Specific details on test material used for the study:

- Name of test material: 2-methoxy-5-nitroanilinium chloride
- IUPAC name: 2-methoxy-5-nitroanilinium chloride
- Molecular formula: C7H9ClN2O3
- Molecular weight: 204.6121g/mole
- Smiles: Cl.COc1ccc(cc1N)[N+](=O)[O-]
- Inchl: 1S/C7H8N2O3.ClH/c1-12-7-3-2-5(9(10)11)4-6(7)8;/h2-4H,8H2,1H3;1H
- Substance type: Organic
- Physical state: Solid powder

Species:

rabbit

Strain:

not specified

Details on test animals or test system and environmental conditions:

no data available

Type of coverage:

occlusive

Preparation of test site:

abraded

Vehicle:

not specified

Controls:

not specified

Amount / concentration applied:

0.4 g

Duration of treatment / exposure:

24 hours

Observation period:

72 hours

Number of animals:

3

Details on study design:

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 5 nearest neighbours
Domain  logical expression:Result: In Domain

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

Domain logical expression index: "a"

Referential boundary: The target chemical should be classified as Radical AND Radical >> Radical mechanism via ROS formation (indirect) AND Radical >> Radical mechanism via ROS formation (indirect) >> Nitrophenols, Nitrophenyl Ethers and Nitrobenzoic Acids AND SN1 AND SN1 >> Nucleophilic attack after reduction and nitrenium ion formation AND SN1 >> Nucleophilic attack after reduction and nitrenium ion formation >> Nitrophenols, Nitrophenyl Ethers and Nitrobenzoic Acids by DNA binding by OASIS v.1.3

Domain logical expression index: "b"

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

Domain logical expression index: "c"

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

Domain logical expression index: "d"

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

Domain logical expression index: "e"

Referential boundary: The target chemical should be classified as Michael addition 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 No alert found OR SN1 >> Iminium Ion Formation OR SN1 >> Iminium Ion Formation >> Aliphatic tertiary amines OR SN1 >> Nitrenium Ion formation >> Aromatic azo OR SN1 >> Nitrenium Ion formation >> Primary aromatic amine OR SN1 >> Nitrenium Ion formation >> Secondary aromatic amine OR SN1 >> Nitrenium Ion formation >> Tertiary aromatic amine OR SN1 >> Nitrenium Ion formation >> Unsaturated heterocyclic azo by DNA binding by OECD

Domain logical expression index: "f"

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

Domain logical expression index: "g"

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 >> Acetates OR Michael addition OR Michael addition >> Polarised Alkenes OR Michael addition >> Polarised Alkenes >> Polarised alkene - ketones OR Michael addition >> Quinones and Quinone-type Chemicals OR Michael addition >> Quinones and Quinone-type Chemicals >> Quinone-imine OR Schiff Base Formers OR Schiff Base Formers >> Direct Acting Schiff Base Formers OR Schiff Base Formers >> Direct Acting Schiff Base Formers >> Mono-carbonyls OR SN2 OR SN2 >> SN2 reaction at sp3 carbon atom OR SN2 >> SN2 reaction at sp3 carbon atom >> Allyl acetates and related chemicals OR SNAr OR SNAr >> Nucleophilic aromatic substitution OR SNAr >> Nucleophilic aromatic substitution >> Activated halo-benzenes OR SNAr >> Nucleophilic aromatic substitution >> Halo-triazines by Protein binding by OECD

Domain logical expression index: "h"

Referential boundary: The target chemical should be classified as Class 5 (Not possible to classify according to these rules) by Acute aquatic toxicity classification by Verhaar (Modified) 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"

Similarity boundary:Target: COc1ccc(N(=O)=O)cc1N{+}.Cl{-}
Threshold=30%,
Dice(Atom centered fragments)
Atom type; Count H attached; Hybridization

Domain logical expression index: "k"

Referential boundary: The target chemical should be classified as Anilines (Hemolytic anemia with methemoglobinemia) Rank A AND Anilines (Hepatotoxicity) Rank C by Repeated dose (HESS)

Domain logical expression index: "l"

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

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 by Repeated dose (HESS)

Domain logical expression index: "n"

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

Domain logical expression index: "o"

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

Domain logical expression index: "p"

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

Domain logical expression index: "q"

Parametric boundary:The target chemical should have a value of log Kow which is >= -3.13

Domain logical expression index: "r"

Parametric boundary:The target chemical should have a value of log Kow which is <= -0.708

Interpretation of results:

other: not irritating

Conclusions:

2-methoxy-5-nitroanilinium chloride was estimated to be not irritating to the skin of rabbits.

Executive summary:

The dermal irritation potential of 2-methoxy-5-nitroanilinium chloride was estimated using OECD QSAR toolbox version 3.3 with logPow as the primary descriptor.

2-methoxy-5-nitroanilinium chloride was estimated to be not irritating to the skin of rabbits.

Based on the estimated result; 2-methoxy-5-nitroanilinium chloride can be considered 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 test material: 2-methoxy-5-nitroanilinium chloride
- IUPAC name: 2-methoxy-5-nitroanilinium chloride
- Molecular formula: C7H9ClN2O3
- Molecular weight: 204.6121g/mole
- Smiles: Cl.COc1ccc(cc1N)[N+](=O)[O-]
- Inchl: 1S/C7H8N2O3.ClH/c1-12-7-3-2-5(9(10)11)4-6(7)8;/h2-4H,8H2,1H3;1H
- Substance type: Organic
- Physical state: Solid powder

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:

39 mg

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

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 8 nearest neighbours
Domain  logical expression:Result: In Domain

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

Domain logical expression index: "a"

Referential boundary: The target chemical should be classified as Radical AND Radical >> Radical mechanism via ROS formation (indirect) AND Radical >> Radical mechanism via ROS formation (indirect) >> Nitrophenols, Nitrophenyl Ethers and Nitrobenzoic Acids AND SN1 AND SN1 >> Nucleophilic attack after reduction and nitrenium ion formation AND SN1 >> Nucleophilic attack after reduction and nitrenium ion formation >> Nitrophenols, Nitrophenyl Ethers and Nitrobenzoic Acids by DNA binding by OASIS v.1.3

Domain logical expression index: "b"

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

Domain logical expression index: "c"

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

Domain logical expression index: "d"

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

Domain logical expression index: "e"

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, 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 by Estrogen Receptor Binding

Domain logical expression index: "f"

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

Domain logical expression index: "g"

Referential boundary: The target chemical should be classified as Class 5 (Not possible to classify according to these rules) by Acute aquatic toxicity classification by Verhaar (Modified) ONLY

Domain logical expression index: "h"

Referential boundary: The target chemical should be classified as Anilines (Hemolytic anemia with methemoglobinemia) Rank A AND Anilines (Hepatotoxicity) Rank C by Repeated dose (HESS)

Domain logical expression index: "i"

Referential boundary: The target chemical should be classified as 4,4'-Methylenedianilines/benzidines (Hepatobiliary toxicity) Rank B  by Repeated dose (HESS)

Domain logical expression index: "j"

Referential boundary: The target chemical should be classified as Anilines (Hemolytic anemia with methemoglobinemia) Rank A AND Anilines (Hepatotoxicity) Rank C by Repeated dose (HESS)

Domain logical expression index: "k"

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

Domain logical expression index: "l"

Referential boundary: The target chemical should be classified as Anilines (Hemolytic anemia with methemoglobinemia) Rank A AND Anilines (Hepatotoxicity) Rank C by Repeated dose (HESS)

Domain logical expression index: "m"

Referential boundary: The target chemical should be classified as Thiocarbamates/Sulfides (Hepatotoxicity) No rank by Repeated dose (HESS)

Domain logical expression index: "n"

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

Domain logical expression index: "o"

Referential boundary: The target chemical should be classified as Phenols by Skin irritation/corrosion Inclusion rules by BfR

Domain logical expression index: "p"

Parametric boundary:The target chemical should have a value of log Kow which is >= -3.99

Domain logical expression index: "q"

Parametric boundary:The target chemical should have a value of log Kow which is <= -0.787

Interpretation of results:

other: not irritating

Conclusions:

2-methoxy-5-nitroanilinium chloride was estimated to be not irritating to the eyes of rabbits.

Executive summary:

The ocular irritation potential of 2-methoxy-5-nitroanilinium chloride was estimated using OECD QSAR toolbox version 3.3 with logPow as the primary descriptor.

2-methoxy-5-nitroanilinium chloride was estimated to be not irritating to the eyes of rabbits.

Based on the estimated results, 2-methoxy-5-nitroanilinium chloride can be considered 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:

Several studies were performed to ascertain the degree of dermal irritation caused by 2-methoxy-5-nitroanilinium chloridein living organisms. These studies include in vivo studies in rabbits as well as predicted data for the target chemical as well its structurally similar read across substances,4-nitro-o-phenylenediamine[CAS: 99-56-9] and 3-nitrobenzoic acid[CAS: 121-92-6]. 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 v3.3 with log kow as the primary descriptor, the skin irritation potential was estimated for2-methoxy-5-nitroanilinium chloride. 2-methoxy-5-nitroanilinium chloridewas not irritating to rabbit skin.

 

This is supported by the experimental study performed by G. K. LLOYD et.al (Food and Cosmetics Toxicology, Volume 15, Issue 6, December 1977, Pages 607-610), to assess the dermal irritation potential ofstructurally similar read across substance,4-nitro-o-phenylenediamine[CAS: 99-56-9]. The study was conducted as per Consumer Product Safety Commission of the USA (Code of Federal Regulations, Title 16, Sec. 1500.41).2.5% (w/v) Suspension of 4-nitro o-phenylenediamine in 0.5% aqueous gum tragacanth, containing 0.05% Na2SO3 was applied to the intact and abraded skin of 3 New Zealand White albino rabbits. The rabbits were observed for signs of irritation till 72 hours and the reactions were scored based on the definition of skin irritation given in the  (Code of Federal Regulations, Title 16, Sec.1500.41).

None of the rabbits treated with 4-nitro o-phenylenediamine showed any signs of irritation during the 72 hours observation period. The Primary Irritation Index was 0.0.

Based on the scores and observations, 4-nitro-o-phenylenediamine was considered to be not irritating to albino New Zealand White rabbit skin.

 

The above studies are further supported by the experimental study performed by Bret Berner et.al (Journal of Toxicology: Cutaneous and Ocular Toxicology, 8:4, 481-492,1989) to assess the dermal irritation potential of structurally similar read across substance, 3-nitrobenzoic acid[CAS: 121-92-6]. 3-nitrobenzoic acid was purchased from Eastman Chemicals, Rochester.

Sixteen female subjects ranging from 35 to 45 years of age consented to the study. Ten were of Hispanic origin with various degrees of olive-complected skin. Five were white with type II skin, and one was a white/Polynesian mixture with a slightly olive skin tone. All subjects had reasonably clear backs with no or few comedones, moles, or freckles. On day 1 the subjects acclimated for a half hour during which time the sites was marked on the back with a felt tip marker. The scapular regions of the upper back un-occluded by undergarments were tested. A column of five test sites were marked on each side, avoiding the midline. This accommodated two replicates per subject for 3-nitrobenzoic acid and a distilled water control. The position of each treatment within a side of the back was randomized. Baseline scoring and measurements were taken. The relative humidity and temperature were noted. The 12 loaded test discs were applied to the skin occluded with 3%ethylene vinyl acetate (EVA) membrane and secured with tape (Scanpore Norgeplaster 6, Oslo, Norway).

On day 2 the patches were removed and the sites marked again. Thirty minutes later, the measurements were repeated. Erythema and edema were scored by standard 0-4 visual scales, with an additional scale at 0.5 to signify borderline reaction. Blood flow assessed by laser Doppler velocimetry (LDV Med Pacific LD5000,Seattle, WA) and color (reflected light color analyzer by Minolta Chroma Meter CR-100) were measured. On day 3 the procedure of day 2 was repeated.

Primary irritation index (PII) was calculated as the average for the two time points of the sum of the erythema and edema scores. The average PII of 24 and 48 hours scores for 3 -nitrobenzoic acid was 1.0±1.3.

It can be considered that 3-nitrobenzoic acid was not irritating to human skin.

 

Based on the available data for the target as well as its structurally similar read across substances and applying the weight of evidence approach,2-methoxy-5-nitroanilinium chloride can be considered to be not irritating to skin. Hence, 2-methoxy-5-nitroanilinium chloride can be classified under the category “Not Classified” as per CLP Regulation.

 

 

Eye Irritation:

Several studies were performed to ascertain the degree of ocular irritation caused by 2-methoxy-5-nitroanilinium chloridein living organisms. These studies include in vivo studies in rabbits as well as predicted data for the target chemical as well its structurally similar read across substances,4-nitro-o-phenylenediamine[CAS: 99-56-9] and 3- nitroacetophenone [CAS: 121-89-1]. 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 v3.3 with log kow as the primary descriptor, the eye irritation potential was estimated for2-methoxy-5-nitroanilinium chloride. 2-methoxy-5-nitroanilinium chloridewas not irritating to rabbit eyes.

 

This is supported by the experimental study summarized in HSDB (Hazardous Substances Data Bank); US National Library of Medicine reviewed by SRC;last updated 2002; for the structurally similar substance,3- nitroacetophenone [CAS: 121-89-1]. The test chemical was instilled into rabbit eyes and effects were observed for 24 hours. The effects were graded on a scale 1-10 after 24 hours. 3- nitroacetophenone was rated 1 on scale of 1 to 10 according to degree of injury observed after 24 hr. The most severe injuries have been rated 10.

Therefore, 3- nitroacetophenone can be considered to be not irritating to rabbit eyes.

These results are supported by the experimental study summarized in JOURNAL OF THE AMERICAN COLLEGE OF TOXICOLOGY. Volume 4, Number 3, 1985; for the structurally similar read across substance,4-nitro-o-phenylenediamine[CAS: 99-56-9]. 2.5% (w/v) Suspension of 4-nitro o-phenylenediamine in 0.5% aqueous gum tragacanth, (containing 0.05% Na2SO3 pH adjusted to 7) was instilled into the eyes of 3 rabbits. The treated eyes were rinsed with50 ml of lukewarm water (37°C) 10 seconds after instillation of the test chemical. The eyes were observed for signs of irritation till 24 hours.

Occasional, transient mild conjunctival inflammation was observed in the rabbit eyes that did not persist for more than 24 hours.

Hence, 4-nitro-o-phenylenediamine can be considered to be not irritating to rabbit eyes.

 

Based on the available data for the target as well as its structurally similar read across substances and applying the weight of evidence approach,2-methoxy-5-nitroanilinium chloride can be considered to be not irritating to eyes. Hence, 2-methoxy-5-nitroanilinium chloride can be classified under the category “Not Classified” as per CLP Regulation.

Justification for classification or non-classification

Available data for 2-methoxy-5-nitroanilinium chloride indicates that it is not likely to cause any irritation or corrosion to skin and eyes.

Hence, 2-methoxy-5-nitroanilinium chloride can be classified under the category “Not Classified” as per CLP regulation.