4-nitro-o-toluidine

Endpoint summary

Description of key information

Skin Irritation:

The dermal irritation potential of 2-methyl-4-nitroaniline (CAS No: 99-52-5) was estimated using OECD QSAR toolbox version 3.3 with logPow as the primary descriptor.

2-methyl-4-nitroaniline (CAS No: 99-52-5) was estimated to be not irritating to the skin of New Zealand White rabbits.

Based on the estimated result, 2-methyl-4-nitroaniline (CAS No: 99-52-5) can be considered to be not irritating to skin and can be classified under the category ˋnot classified’ as per CLP regulation.

Eye Irritation:

The ocular irritation potential of 2-methyl-4-nitroaniline (CAS No: 99-52-5) was estimated using OECD QSAR toolbox version 3.3 with logPow as the primary descriptor.

2-methyl-4-nitroaniline (CAS No: 99-52-5) was estimated to be not irritating to the eyes of New Zealand White rabbits.

Based on the estimated result, 2-methyl-4-nitroaniline (CAS No: 99-52-5) can be considered to be not irritating to eyes and can be classified under the category ˋnot 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:

calculation (if not (Q)SAR)

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

accepted calculation method

Justification for type of information:

data is from authoritative database

Qualifier:

according to guideline

Guideline:

other: estimated data

Principles of method if other than guideline:

To estimate the skin irritation potential of 2-methyl-4-nitroaniline

GLP compliance:

not specified

Specific details on test material used for the study:

- Name of test material (as cited in study report): 2-methyl-4-nitroaniline
- Molecular formula: C7H8N2O2
- Molecular weight: 152.152 g/mol
- Smiles notation: c1(cc(c(N)cc1)C)[N+](=O)[O-]
- InChI: 1S/C7H8N2O2/c1-5-4-6(9(10)11)2-3-7(5)8/h2-4H,8H2,1H3
- Substance type: Organic
- Physical state: Solid

Species:

rabbit

Strain:

not specified

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:

no data available

Duration of treatment / exposure:

no data available

Observation period:

no data available

Number of animals:

no data available

Details on study design:

no data available

Other effects / acceptance of results:

no data available

Irritation parameter:

overall irritation score

Basis:

mean

Time point:

other: not mentioned

Reversibility:

not specified

Remarks on result:

no indication of irritation

Irritant / corrosive response data:

No irritation observed

Table showing skin irritation estimation by three different models i.e, Leadscope, battery and SciQSAR &CASE Ultra,the average skin irritation results was given by the fourth model i.e, Battery model.

DK	Battery	SciQSAR	CASE Ultra	Leadscope
Skin irritation in rabbit	NEG	NEG	NEG	NEG
Domain	IN	IN	IN	IN

 

Where,

IN = inside applicability domain

Interpretation of results:

other: not irritating

Conclusions:

No Severe skin irritation effects of 2-methyl-4-nitroaniline were estimated in rabbit skin by four different models i.e, Battery, Leadscope, SciQSAR and CASE Ultra used within Danish QSAR database.

Executive summary:

Skin irritation effects were estimated by four different models i.e, Battery, Leadscope, SciQSAR and CASE Ultra used within Danish QSAR database for2-methyl-4-nitroaniline. Based on estimation, no severe skin irritation effects were known when 2-methyl-4-nitroaniline was exposed to rabbit skin.

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 OCD 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 (as cited in study report): 2-methyl-4-nitroaniline
- Molecular formula: C7 H8 N2 O2
- Molecular weight: 152.152 g/mol
- Smiles notation: c1(cc(c(N)cc1)C)[N+](=O)[O-]
- InChI: 1S/C7H8N2O2/c1-5-4-6(9(10)11)2-3-7(5)8/h2-4H,8H2,1H3
- Substance type: Organic
- Physical state: Solid

Species:

rabbit

Strain:

New Zealand White

Details on test animals or tissues and environmental conditions:

no data available

Vehicle:

unchanged (no vehicle)

Controls:

not specified

Amount / concentration applied:

100 mg undiluted test sample

Duration of treatment / exposure:

24 h

Observation period (in vivo):

24,48 and 72 h

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:

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 7 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(not "i")) ) and "j") and("k" and(not "l")) ) and "m") and("n" and(not "o")) ) and("p" and(not "q")) ) and("r" and(not "s")) ) and("t" and "u") )

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 Alkyl arenes AND Aniline AND Aryl AND Nitrobenzene by Organic Functional groups

Domain logical expression index: "c"

Referential boundary:The target chemical should be classified as Alkyl arenes AND Aniline AND Nitrobenzene AND Overlapping groups by Organic Functional groups (nested)

Domain logical expression index: "d"

Referential boundary:The target chemical should be classified as Aliphatic Carbon [CH] AND Aliphatic Carbon [-CH2-] AND Aliphatic Carbon [-CH3] AND Aliphatic Nitrogen, one aromatic attach [-N] AND Aromatic Carbon [C] AND Miscellaneous sulfide (=S) or oxide (=O) AND Nitro, aromatic attach [-NO2] AND Olefinic carbon [=CH- or =C<] by Organic functional groups (US EPA)

Domain logical expression index: "e"

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

Domain logical expression index: "f"

Referential boundary:The target chemical should be classified as 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, non cyclic structure OR Non binder, without OH or NH2 group OR Strong binder, NH2 group OR Strong binder, OH 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 Group 14 - Carbon C AND Group 15 - Nitrogen N AND Group 16 - Oxygen O by Chemical elements

Domain logical expression index: "i"

Referential boundary:The target chemical should be classified as Group 17 - Halogens Cl OR Group 17 - Halogens F OR Group 17 - Halogens F,Cl,Br,I,At by Chemical elements

Domain logical expression index: "j"

Similarity boundary:Target: Cc1cc(N(=O)=O)ccc1N
Threshold=20%,
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 AND Nitrobenzenes (Hemolytic anemia with methemoglobinemia) Rank A AND Nitrobenzenes (Hepatotoxicity) Rank C by Repeated dose (HESS)

Domain logical expression index: "l"

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

Domain logical expression index: "m"

Referential boundary:The target chemical should be classified as (!Undefined)Group All Lipid Solubility < 0.01 g/kg AND (!Undefined)Group CN Lipid Solubility < 0.4 g/kg by Skin irritation/corrosion Exclusion rules by BfR ONLY

Domain logical expression index: "n"

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

Domain logical expression index: "o"

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

Domain logical expression index: "p"

Referential boundary:The target chemical should be classified as No alert found by Respiratory sensitisation

Domain logical expression index: "q"

Referential boundary:The target chemical should be classified as Pro-Michael Addition OR Pro-Michael Addition >> Pro-quinone and related OR Pro-Michael Addition >> Pro-quinone and related >> Phenylenediamines by Respiratory sensitisation

Domain logical expression index: "r"

Referential boundary:The target chemical should be classified as Basic [0,10) AND No pKa value by Ionization at pH = 9

Domain logical expression index: "s"

Referential boundary:The target chemical should be classified as Acidic [0,10) by Ionization at pH = 9

Domain logical expression index: "t"

Parametric boundary:The target chemical should have a value of log Kow which is >= 1.16

Domain logical expression index: "u"

Parametric boundary:The target chemical should have a value of log Kow which is <= 2.17

Interpretation of results:

other: not irritating

Conclusions:

 2-methyl-4-nitroaniline was estimated to be not irritating to the eyes of New Zealand White rabbits.

Executive summary:

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

 2-methyl-4-nitroaniline was estimated to be not irritating to the eyes of New Zealand White rabbits.

On the basis of the estimated results, 2-methyl-4-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,2-methyl-4-nitroanilinehas 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, 2-methylbenzene-1,4-diamine [Toluene-2,5-Diamine] (CAS: 95-70-5 ) and 2-nitro-4-methylaniline (CAS: 89-62-3).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 skin irritation potential was estimated for2-methyl-4-nitroaniline. 2-methyl-4 -nitroanilinewas 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 2 -methyl-4-nitroaniline. Based on estimation, No severe skin irritation effects were known when2-methyl-4-nitroanilinewas exposed to rabbit skin.

Results from both estimated data indicate a possibility of 2-methyl-4-nitroaniline being not irritating to skin.

These results are further supported by the experimental study summarized in JOURNAL OF THE AMERICAN COLLEGE OF TOXICOLOGY; Volume 11, Number 4,1992; for the structurally similar read across substance, 2-methylbenzene-1,4-diamine [Toluene-2,5-Diamine] (CAS: 95-70-5 ).The study was performedaccording to the procedure prescribed in Code of Federal Regulations (CFR, Title 16, Sec. 1500.42). 2-methylbenzene-1, 4-diamine as applied as a 2.5% (w/v) preparation to the intact and abraded skin of 3 New Zealand White rabbits and skin reactions were noted after 72 hours. One rabbit had very slight erythema at the abraded site. The primary irritation index of 2-methylbenzene-1, 4-diamine (CAS No: - 95-70-5) was 0.3 and no signs of irritation were observed after 72h. 2-methylbenzene-1, 4-diamine can be considered not irritating to the skin of New Zealand White rabbits.

The above results are also supported by the experimental study summarized in BG Chemie InfoCenter TOXIKOLOGISCHE BEWERTUNGEN; 06/2000;for the structurally similar read across substance, 2-nitro-4-methylaniline (CAS: 89-62-3).The study was performedin accordance with OECD guideline No. 404. 3 albino New Zealand rabbits were subjected to a single semi-occlusive 4-hour exposure of the mechanically depilated dorsal skin to 500 mg of the test substance (mixed into a paste with 0.45 ml of 0.9-percent saline solution). The skin was assessed 30 to 60 minutes as well as 24, 48 and 72 hours after removal of the patch. The surface of the skin only showed yellowish discoloration.

During the entire observation period, no signs of irritation were seen. Hence, 2-nitro-p-toluidine (CAS No:- 89-62-3 ) was considered to be not irritating to the skin of albino New Zealand rabbits.

Based on the available data for the target as well as read across substances and applying the weight of evidence approach,2-methyl-4-nitroanilinewas 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,2-methyl-4-nitroanilinehas 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, 2-methylbenzene-1,4-diamine [Toluene-2,5-Diamine] (CAS: 95-70-5 ) and 2-nitro-4-methylaniline (CAS: 89-62-3).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 for2-methyl-4-nitroaniline. 2-methyl-4-nitroanilinewas estimated to be not irritating to the eyes of New Zealand White rabbits. 

This result is supported by the experimental study summarizedin JOURNAL OF THE AMERICAN COLLEGE OF TOXICOLOGY; Volume 11, Number 4,1992; for the structurally similar read across substance, 2-methylbenzene-1,4-diamine [Toluene-2,5-Diamine] (CAS: 95-70-5 ).The study was performed according to the procedure prescribed in Code of Federal Regulations (CFR, Title 16, Sec. 1500.42).2-methylbenzene-1,4-diaminewas instilled into the conjunctival sacs of three rabbits. After 10 seconds of exposure, the eyes were rinsed with water. Mild conjunctival inflammation was observed; however, these reactions did not persist for more than 24 h.Since the effects observed were reversible after 24 hours,2-methylbenzene-1,4-diamine(CAS No:-95-70-5) was considered to be not irritating to the eyes of New Zealand White rabbits.

The above results are also supported by the experimental study summarized in BG Chemie InfoCenter TOXIKOLOGISCHE BEWERTUNGEN; 06/2000;for the structurally similar read across substance, 2-nitro-4-methylaniline (CAS: 89-62-3).The study was performedin accordance with OECD guideline No. 405. 3 albino New Zealand rabbits received a single dose of 100 mg into the conjunctival sac of the eye. Assessment of the eyes was carried out 1 hour, 24, 48 and 72 hours following application. After one hour to 2 days the conjunctivae showed marked hyperaemia to the extent of a diffuse crimson-red colour and slight to marked swelling. In addition, in all 3 animals ocular discharge was observed which was discoloured on account of the test substance. The findings cleared up as of day 3 after instillation.The average numerical values were 0.33 for reddening of the conjunctiva and 0.0 for conjunctival swelling, iritis and clouding of the cornea. No known signs of ocular lesions were observed after 3 days of application. Hence, 2-nitro-p-toluidine (CAS No:- 89-62-3)was considered to be not irritating to the eyes of albino New Zealand rabbits.

Based on the available data for the target as well as read across substances and applying the weight of evidence approach,2-methyl-4-nitroanilinewas not irritating to eyes.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 data for 2-methyl-4-nitroaniline suggests that it is not likely to cause any irritation to eyes and skin.

2-methyl-4-nitroaniline was considered to be not irritating to skin and eyes, and can be classified under the category “Not Classified” as per CLP regulation.