2-methoxy-5-nitroanilinium chloride

Endpoint summary

Description of key information

Acute Oral Toxicity: 

In Acute oral toxicity ,LD50 value was predicted based on OECD QSAR toolbox for target substance 2-methoxy-5-nitroanilinium chloride (67827-72-9) was estimated to be 705.66 mg/kg bw,and for differentstudies available on the structurally similar read across substance 1-methoxy-2-methyl-4-nitrobenzene (99-53-6) was considered to be 390 mg/kg bw and for 3-nitrobenzoic acid (121-92-6) was considered to be 1820 mg/kg bw. All these studies concluded that the LD50 value is between 300-2000 mg/kg bw. Thus, comparing this value with the criteria of CLP regulation, 2-methoxy-5-nitroanilinium chloride (67827-72-9) can be classified as category IV of acute oral toxicity.

Acute Inhalation Toxicity: 

2-methoxy-5-nitroanilinium chloride (67827-72-9) has very low vapor pressure (1.63E-006 Pa.).So the potential for the generation of inhalable vapours is very low. Also the normal conditions of use of this substance will not result in aerosols, particles or droplets of an inhalable size, so exposure to humans via the inhalatory route will be highly unlikely and therefore the acute inhalation toxicity end point was considered for waiver.

Acute Dermal Toxicity:

In Acute dermal toxicity, LD50 value was predicted based on OECD QSAR toolbox for target substance 2-methoxy-5-nitroanilinium chloride (67827-72-9) was estimated to be 7228.03 mg/kg bw,and for differentstudies available on structurally similar read across substance 3'-Nitroacetophenone (121-89-1). All these studies concluded that the LD50 value is greater than 2000 mg/kg bw. Thus, comparing this value with the criteria of CLP regulation, 2-methoxy-5-nitroanilinium chloride (67827-72-9) cannot be classified for acute dermal toxicity.

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records

Reference

Endpoint:

acute toxicity: oral

Type of information:

(Q)SAR

Adequacy of study:

other information

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: as mentioned below

Principles of method if other than guideline:

Prediction was done by using OECD QSAR toolbox v3.3,2018

GLP compliance:

not specified

Test type:

other: estimated data

Limit test:

no

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/mol
- 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

Species:

rat

Strain:

Sprague-Dawley

Sex:

male

Details on test animals or test system and environmental conditions:

No data available

Route of administration:

oral: unspecified

Vehicle:

not specified

Details on oral exposure:

No data available

Doses:

705.66 mg/kg bw

No. of animals per sex per dose:

No data available

Control animals:

not specified

Details on study design:

No data available

Statistics:

No data available

Preliminary study:

No data available

Sex:

male

Dose descriptor:

LD50

Effect level:

705.66 mg/kg bw

Based on:

test mat.

Remarks on result:

other: 50% mortality was observed

Mortality:

No data available

Clinical signs:

other: No data available

Gross pathology:

No data available

Other findings:

No data available

The prediction was based on dataset comprised from the following descriptors: LD50
Estimation method: Takes average 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 ( not "j") )  )  and "k" )  and ("l" and ( not "m") )  )  and ("n" and ( not "o") )  )  and ("p" and ( not "q") )  )  and ("r" and ( not "s") )  )  and ("t" and ( not "u") )  )  and ("v" and ( not "w") )  )  and ("x" and "y" )  )

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 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: "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 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 by Protein binding by OECD

Domain logical expression index: "h"

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

Domain logical expression index: "i"

Referential boundary: The target chemical should be classified as Halogens AND Non-Metals by Groups of elements

Domain logical expression index: "j"

Referential boundary: The target chemical should be classified as Alkali Earth by Groups of elements

Domain logical expression index: "k"

Similarity boundary:Target: COc1ccc(N(=O)=O)cc1N{+}.Cl{-}
Threshold=20%,
Dice(Atom centered fragments)
Atom type; Count H attached; Hybridization

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 4,4'-Methylenedianilines/benzidines (Hepatobiliary toxicity) Rank B  OR Aliphatic amines (Mucous membrane irritation) Rank C by Repeated dose (HESS)

Domain logical expression index: "n"

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: "o"

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

Domain logical expression index: "p"

Referential boundary: The target chemical should be classified as Aliphatic Amine, primary AND Ether AND Nitrobenzene AND Overlapping groups by Organic Functional groups (nested)

Domain logical expression index: "q"

Referential boundary: The target chemical should be classified as Alkyl halide by Organic Functional groups (nested)

Domain logical expression index: "r"

Referential boundary: The target chemical should be classified as Aliphatic Amine, primary AND Ether AND Nitrobenzene AND Overlapping groups by Organic Functional groups (nested)

Domain logical expression index: "s"

Referential boundary: The target chemical should be classified as Alkoxy by Organic Functional groups (nested)

Domain logical expression index: "t"

Referential boundary: The target chemical should be classified as Aliphatic Amine, primary AND Ether AND Nitrobenzene AND Overlapping groups by Organic Functional groups (nested)

Domain logical expression index: "u"

Referential boundary: The target chemical should be classified as Sulfate by Organic Functional groups (nested)

Domain logical expression index: "v"

Referential boundary: The target chemical should be classified as Aliphatic Amine, primary AND Ether AND Nitrobenzene AND Overlapping groups by Organic Functional groups (nested)

Domain logical expression index: "w"

Referential boundary: The target chemical should be classified as Aryl halide OR Biphenyl by Organic Functional groups (nested)

Domain logical expression index: "x"

Parametric boundary:The target chemical should have a value of log Kow which is >= -2.8

Domain logical expression index: "y"

Parametric boundary:The target chemical should have a value of log Kow which is <= 0.553

Interpretation of results:

Category 4 based on GHS criteria

Conclusions:

The LD50 value was estimated to be 705.66 mg/kg bw,when male Sprague-Dawley rats were orally exposed with 2-methoxy-5-nitroanilinium chloride (67827-72-9).

Executive summary:

In a prediction done by SSS (2018) using the OECD QSAR toolbox with log kow as the primary descriptor, the acute oral toxicity was estimated for 2-methoxy-5-nitroanilinium chloride (67827-72-9).The LD50 was estimated to be 705.66 mg/kg bw,when male Sprague-Dawley rats were orally exposed with 2-methoxy-5-nitroanilinium chloride (67827-72-9).

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

705.66 mg/kg bw

Quality of whole database:

Data is Klimisch 2 and from QSAR toolbox 3.3

Acute toxicity: via inhalation route

Link to relevant study records

Reference

Endpoint:

acute toxicity: inhalation

Data waiving:

other justification

Justification for data waiving:

other:

Endpoint conclusion

Endpoint conclusion:

no study available

Quality of whole database:

Waiver

Acute toxicity: via dermal route

Link to relevant study records

Reference

Endpoint:

acute toxicity: dermal

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: as mentioned below

Principles of method if other than guideline:

Prediction was done by using OECD QSAR toolbox v3.3,2018

GLP compliance:

not specified

Test type:

other: estimated data

Limit test:

no

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/mol
- 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

Species:

rabbit

Strain:

New Zealand White

Sex:

not specified

Details on test animals or test system and environmental conditions:

no data available

Type of coverage:

occlusive

Vehicle:

not specified

Details on dermal exposure:

no data available

Duration of exposure:

24 hours

Doses:

3128.45 mg/kg bw

No. of animals per sex per dose:

no data available

Control animals:

not specified

Details on study design:

no data available

Statistics:

no data available

Preliminary study:

no data available

Sex:

not specified

Dose descriptor:

LD50

Effect level:

3 128.45 mg/kg bw

Based on:

test mat.

Remarks on result:

other: 50% Mortality was observed

Mortality:

no data available

Clinical signs:

other: no data available

Gross pathology:

no data available

Other findings:

no data available

The prediction was based on dataset comprised from the following descriptors: LD50
Estimation method: Takes average value from the 6 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 ( not "i") )  )  and ("j" and ( not "k") )  )  and ("l" and "m" )  )

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 Not possible to classify according to these rules by DPRA Cysteine peptide depletion

Domain logical expression index: "e"

Referential boundary: The target chemical should be classified as High reactive OR High reactive >> Activated haloarenes by DPRA Cysteine peptide depletion

Domain logical expression index: "f"

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

Domain logical expression index: "g"

Referential boundary: The target chemical should be classified as Moderate binder, OH grooup by Estrogen Receptor Binding

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 Thiocarbamates/Sulfides (Hepatotoxicity) No rank 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 Aliphatic amines (Mucous membrane irritation) Rank C by Repeated dose (HESS)

Domain logical expression index: "l"

Parametric boundary:The target chemical should have a value of OVERALL OH rate constant which is >= 1.22E-013 cm3/molecule-sec

Domain logical expression index: "m"

Parametric boundary:The target chemical should have a value of OVERALL OH rate constant which is <= 5E-011 cm3/molecule-sec

Interpretation of results:

other: not classified

Conclusions:

The LD50 value was estimated to be 3128.45 mg/kg bw,when new Zealand white rabbits were occlusively exposed with 2-methoxy-5-nitroanilinium chloride (67827-72-9) by dermal application for 24 hours.

Executive summary:

In a prediction done by SSS (2018) using the OECD QSAR toolbox with log kow as the primary descriptor, the acute dermal toxicity was estimated for 2-methoxy-5-nitroanilinium chloride (67827-72-9).The LD50 was estimated to be 3128.45 mg/kg bw,when new Zealand white rabbits were occlusively exposed with 2-methoxy-5-nitroanilinium chloride (67827-72-9)by dermal application for 24 hours. 

Endpoint conclusion

Endpoint conclusion:

no study available

Dose descriptor:

LD50

Value:

3 128.45 mg/kg bw

Quality of whole database:

Data is Klimisch 2 and from QSAR toolbox 3.3

Additional information

Acute Oral Toxicity: 

In different studies, 2-methoxy-5-nitroanilinium chloride (67827-72-9) has been investigated for acute oral toxicity to a greater or lesser extent. Often the studies are based on in vivo experiments and estimated data in rodents, i.e. most commonly in rats for 2-methoxy-5-nitroanilinium chloride (67827-72-9) along with the study available on the structurally similar read across substance 1-methoxy-2-methyl-4-nitrobenzene (99-53-6) and for 3-nitrobenzoic acid (121-92-6). The predicted data using the OECD QSAR toolbox has also been compared with the experimental studies. The studies are summarized as below –

In a prediction done by SSS (2018) using the OECD QSAR toolbox with log kow as the primary descriptor, the acute oral toxicity was estimated for 2-methoxy-5-nitroanilinium chloride (67827-72-9).The LD50 was estimated to be 705.66 mg/kg bw,when male Sprague-Dawley rats were orally exposed with 2-methoxy-5-nitroanilinium chloride (67827-72-9).

In experimental study conducted by U.S. National Library of Medicine (Chemidplus Database,U.S. National Library of Medicine,2017) and RTECS (RTECS (registry of toxic effect of chemical substance database), 2017) for the structurally similar read across substance 1-methoxy-2-methyl-4-nitrobenzene (99-53-6). Acute oral toxicity study was done in mouse using test material 1-methoxy-2-methyl-4-nitrobenzene (99-53-6).50% mortality was observed at dose 390 mg/kg bw. Hence,LD50 value was considered to be 390 mg/kg bw,when mouse was treated with 1-methoxy-2-methyl-4-nitrobenzene (99-53-6) orally.

Also these results are further supported by MAK Collection for Occupational Health and Safety (3-Nitrobenzoesäure [MAK Value Documentation in German Language, 2015] The MAK Collection for Occupational Health and Safety, 1–15,2015) and ENVIRONMENTAL HEALTH RESEARCH AND TESTING, INC. (National Toxicology Program National Institute of Environmental Health Sciences; .June, 1989) for the structurally similar read across substance 3-nitrobenzoic acid (121-92-6). An acute oral test was conducted on female wistar rats to determine its LD50.During the test, the animals were exposed to the chemical at concentration f1820 mg/kg body weight. The treated rats had developed symptoms of over-excitability, immobility, motor disturbances or aggressiveness occurred as symptoms of poisoning. No conspicuous findings were found in macroscopic examinations.Thus on the basis of observed effects, the LD50 of test chemical 3-nitrobenzoic acid (CAS No: 121-92-6) was estimated to be 1820 mg/kg body weight in female wistar rats.

Thus, based on the above studies on 2-methoxy-5-nitroanilinium chloride (67827-72-9) and it’s structurally similar read across substances 1-methoxy-2-methyl-4-nitrobenzene (99-53-6) and 3-nitrobenzoic acid (121-92-6), it can be concluded that LD50 value is between 300-2000 mg/kg bw. Thus, comparing this value with the criteria of CLP regulation, 2-methoxy-5-nitroanilinium chloride (67827-72-9) can be classified as category IV of acute oral toxicity.

Acute Inhalation Toxicity: 

2-methoxy-5-nitroanilinium chloride (67827-72-9) has very low vapor pressure (1.63E-006 Pa.).So the potential for the generation of inhalable vapours is very low. Also the normal conditions of use of this substance will not result in aerosols, particles or droplets of an inhalable size, so exposure to humans via the inhalatory route will be highly unlikely and therefore the acute inhalation toxicity end point was considered for waiver.

Acute Dermal Toxicity:

In different studies, 2-methoxy-5-nitroanilinium chloride (67827-72-9) has been investigated for acute dermal toxicity to a greater or lesser extent. Often the studies are based on in vivo experiments and estimated data in rodents, i.e. most commonly in rabbits for 2-methoxy-5-nitroanilinium chloride (67827-72-9) along with the study available on structurally similar read across substance substance 3'-Nitroacetophenone (121-89-1).The predicted data using the OECD QSAR toolbox has also been compared with the experimental studies. The studies are summarized as below –

In a prediction done by SSS (2018) using the OECD QSAR toolbox with log kow as the primary descriptor, the acute dermal toxicity was estimated for 2-methoxy-5-nitroanilinium chloride (67827-72-9).The LD50 was estimated to be 3128.45 mg/kg bw,when new Zealand white rabbits were occlusively exposed with 2-methoxy-5-nitroanilinium chloride (67827-72-9)by dermal application for 24 hours. 

 

The above study was further supported by U.S. National Library of Medicine (Chemidplus Database,U.S. National Library of Medicine,2017) andRTECS(RTECS (registry of toxic effect of chemical substance database), 2017) for thestructurally similar read across substance substance 3'-Nitroacetophenone (121-89-1).In Acute dermal toxicity study, rabbits were treated with 3'-Nitroacetophenone (121-89-1) in the concentration of 3000 mg/kg bw by dermal application. 50% mortality was observed in treated rabbits at 3000 mg/kg bw. Therefore,LD50 was considered to be 3000 mg/kg bw,when rabbits were treated with 3'-Nitroacetophenone (121-89-1) by dermal application.

Thus, based on the above studies on 2-methoxy-5-nitroanilinium chloride (67827-72-9) and it’s structurally similar read across substances, it can be concluded that LD50 value is greater than 2000 mg/kg bw. Thus, comparing this value with the criteria of CLP regulation, 2-methoxy-5-nitroanilinium chloride (67827-72-9) cannot be classified for acute dermal toxicity.

Justification for classification or non-classification

Based on the above studies on 2-methoxy-5-nitroanilinium chloride (67827-72-9) and it’s structurally similar read across substance 1-methoxy-2-methyl-4-nitrobenzene (99-53-6); 3-nitrobenzoic acid (121-92-6) and 3'-Nitroacetophenone (121-89-1), it can be concluded that LD50 value is between 300-2000 mg/kg bw for acute oral toxicity and greater than 2000 mg/kg bw for acute dermal toxicity. Thus, comparing this value with the criteria of CLP regulation, 2-methoxy-5-nitroanilinium chloride (67827-72-9) can be classified as category IV for acute oral toxicity and cannot be classified for acute dermal toxicity. For Acute inhalation toxicity wavier was added so, not possible to classify.