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Description of key information

Acute Oral Toxicity: 

In Acute oral toxicity ,LD50 value was predicted based on OECD QSAR toolbox for target substance4-methoxy-2-methyl-N-phenylaniline(41317-15-1)was estimated to be 7032.78 mg/kg bw,and for differentstudies available on the structurally similar read across substance 2-methoxynaphthalene (93-04-9) was considered to be >2000 mg/kg bw and >5000 mg/kg bw,for4-(anilino)phenol (122-37-2) was considered to be 3300 mg/kg bw and for 2-Ethoxynaphthalene (93-18-5) was considered to be 5000 mg/kg bw.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,4-methoxy-2-methyl-N-phenylaniline(41317-15-1) cannot be classified for acute oral toxicity.

Acute Inhalation Toxicity: 

4-methoxy-2-methyl-N-phenylaniline (41317-15-1)has very low vapour pressure (0.0136 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 substance4-methoxy-2-methyl-N-phenylaniline (41317-15-1)was estimated to be 3454.3 mg/kg bw,and for differentstudies available on structurally similar read across substance 2-methoxynaphthalene (93-04-9) was considered to be >2000 mg/kg bw and >5000 mg/kg bw,and for2-Ethoxynaphthalene (93-18-5) was considered to be >2000 mg/kg bw.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,4-methoxy-2-methyl-N-phenylaniline (41317-15-1)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:
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: 4-methoxy-2-methyl-N-phenylaniline
- IUPAC name: 4-methoxy-2-methyl-N-phenylaniline
- Molecular formula: C14H15NO
- Molecular weight: 213.279 g/mol
- Smiles: c1(c(cc(cc1)OC)C)Nc1ccccc1
- InChl: 1S/C14H15NO/c1-11-10-13(16-2)8-9-14(11)15-12-6-4-3-5-7-12/h3-10,15H,1-2H3
- Substance type: Organic
Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals or test system and environmental conditions:
No data available
Route of administration:
oral: gavage
Vehicle:
not specified
Details on oral exposure:
No data available
Doses:
7032.78 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/female
Dose descriptor:
LD50
Effect level:
7 032.78 mg/kg bw
Based on:
test mat.
Remarks on result:
other: 50% mortality was observed
Mortality:
No data available
Clinical signs:
No data available
Body weight:
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" or "d" )  and ("e" and ( not "f") )  )  and ("g" and ( not "h") )  )  and ("i" and ( not "j") )  )  and ("k" and ( not "l") )  )  and "m" )  and ("n" and ( not "o") )  )  and ("p" and ( not "q") )  )  and "r" )  and ("s" and ( not "t") )  )  and "u" )  and "v" )  and "w" )  and "x" )  and ("y" and "z" )  )

Domain logical expression index: "a"

Referential boundary: The target chemical should be classified as Alkylarylether OR Amine OR Aromatic compound OR Ether OR Secondary amine OR Secondary aromatic amine by Organic functional groups, Norbert Haider (checkmol) ONLY

Domain logical expression index: "b"

Referential boundary: The target chemical should be classified as Aliphatic Carbon [CH] OR Aliphatic Carbon [-CH2-] OR Aliphatic Carbon [-CH3] OR Aliphatic Nitrogen, two aromatic attach [-N-] OR Aromatic Carbon [C] OR Nitrogen, two or tree olefinic attach [>N-] OR Olefinic carbon [=CH- or =C<] OR Oxygen, one aromatic attach [-O-] by Organic functional groups (US EPA) ONLY

Domain logical expression index: "c"

Referential boundary: The target chemical should be classified as Alkyl arenes OR Aromatic amine OR Ether OR Overlapping groups OR Precursors quinoid compounds by Organic Functional groups (nested) ONLY

Domain logical expression index: "d"

Referential boundary: The target chemical should be classified as Alkyl arenes OR Aromatic amine OR Aryl OR Ether OR Precursors quinoid compounds by Organic Functional groups ONLY

Domain logical expression index: "e"

Referential boundary: The target chemical should be classified as No alert found by DNA binding by OASIS v.1.3

Domain logical expression index: "f"

Referential boundary: The target chemical should be classified as AN2 OR AN2 >> Nucleophilic addition to alpha, beta-unsaturated carbonyl compounds OR AN2 >> Nucleophilic addition to alpha, beta-unsaturated carbonyl compounds >> alpha, beta-Unsaturated Aldehydes OR AN2 >> Schiff base formation OR AN2 >> Schiff base formation >> alpha, beta-Unsaturated Aldehydes OR Michael addition OR Michael addition >> Quinone type compounds OR Michael addition >> Quinone type compounds >> Quinone methides OR Radical OR Radical >> Radical mechanism via ROS formation (indirect) OR Radical >> Radical mechanism via ROS formation (indirect) >> Single-Ring Substituted Primary Aromatic Amines OR Radical >> ROS formation after GSH depletion OR Radical >> ROS formation after GSH depletion >> Quinone methides OR SN1 OR SN1 >> Alkylation after metabolically formed carbenium ion species OR SN1 >> Alkylation after metabolically formed carbenium ion species >> Polycyclic Aromatic Hydrocarbon Derivatives OR SN1 >> Nucleophilic attack after metabolic nitrenium ion formation OR SN1 >> Nucleophilic attack after metabolic nitrenium ion formation >> Single-Ring Substituted Primary Aromatic Amines OR SN2 OR SN2 >> Alkylation, direct acting epoxides and related OR SN2 >> Alkylation, direct acting epoxides and related >> Epoxides and Aziridines OR SN2 >> Alkylation, direct acting epoxides and related after P450-mediated metabolic activation OR SN2 >> Alkylation, direct acting epoxides and related after P450-mediated metabolic activation >> Polycyclic Aromatic Hydrocarbon Derivatives by DNA binding by OASIS v.1.3

Domain logical expression index: "g"

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

Domain logical expression index: "h"

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 Michael addition >> P450 Mediated Activation to Quinones and Quinone-type Chemicals >> Methylenedioxyphenyl OR Michael addition >> P450 Mediated Activation to Quinones and Quinone-type Chemicals >> Polycyclic (PAHs) and heterocyclic (HACs) aromatic hydrocarbons-Michael addition OR SN1 OR SN1 >> Nitrenium Ion formation OR SN1 >> Nitrenium Ion formation >> Primary aromatic amine OR SN1 >> Nitrenium Ion formation >> Secondary aromatic amine OR SN1 >> Nitrenium Ion formation >> Tertiary aromatic amine by DNA binding by OECD

Domain logical expression index: "i"

Referential boundary: The target chemical should be classified as Non binder, without OH or NH2 group by Estrogen Receptor Binding

Domain logical expression index: "j"

Referential boundary: The target chemical should be classified as Non binder, impaired OH or NH2 group OR Non binder, MW>500 OR Non binder, non cyclic structure by Estrogen Receptor Binding

Domain logical expression index: "k"

Referential boundary: The target chemical should be classified as No alert found by Protein binding by OASIS v1.3

Domain logical expression index: "l"

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 >> (Thio)Acyl and (thio)carbamoyl halides and cyanides  OR Michael Addition OR Michael Addition >> Michael addition on conjugated systems with electron withdrawing group OR Michael Addition >> Michael addition on conjugated systems with electron withdrawing group >> alpha,beta-Carbonyl compounds with polarized double bonds  OR Michael Addition >> Polarised Alkenes OR Michael Addition >> Polarised Alkenes >> Polarised Alkene - alkenyl pyridines, pyrazines, pyrimidines or triazines  OR Nucleophilic addition OR Nucleophilic addition >> Addition to carbon-hetero double bonds OR Nucleophilic addition >> Addition to carbon-hetero double bonds >> Ketones OR SN2 OR SN2 >> Interchange reaction with sulphur containing compounds OR SN2 >> Interchange reaction with sulphur containing compounds >> Thiols and disulfide compounds  by Protein binding by OASIS v1.3

Domain logical expression index: "m"

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

Domain logical expression index: "n"

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

Domain logical expression index: "o"

Referential boundary: The target chemical should be classified as Halogens OR Metalloids by Groups of elements

Domain logical expression index: "p"

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: "q"

Referential boundary: The target chemical should be classified as Group 15 - Phosphorus P OR Group 16 - Sulfur S by Chemical elements

Domain logical expression index: "r"

Similarity boundary:Target: Cc1cc(OC)ccc1Nc1ccccc1
Threshold=40%,
Dice(Atom centered fragments)
Atom type; Count H attached; Hybridization

Domain logical expression index: "s"

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

Domain logical expression index: "t"

Referential boundary: The target chemical should be classified as 3-Methylcholantrene (Hepatotoxicity) Alert OR Aliphatic amines (Mucous membrane irritation) Rank C OR Amineptine (Hepatotoxicity) Alert OR Aromatic hydrocarbons (Liver enzyme induction) Rank C OR Tamoxifen (Hepatotoxicity) Alert by Repeated dose (HESS)

Domain logical expression index: "u"

Referential boundary: The target chemical should be classified as Aliphatic Carbon [CH] AND Aliphatic Carbon [-CH2-] AND Aliphatic Carbon [-CH3] AND Aliphatic Nitrogen, two aromatic attach [-N-] AND Aromatic Carbon [C] AND Nitrogen, two or tree olefinic attach [>N-] AND Olefinic carbon [=CH- or =C<] AND Oxygen, one aromatic attach [-O-] by Organic functional groups (US EPA) ONLY

Domain logical expression index: "v"

Referential boundary: The target chemical should be classified as Alkyl arenes AND Aromatic amine AND Ether AND Overlapping groups AND Precursors quinoid compounds by Organic Functional groups (nested) ONLY

Domain logical expression index: "w"

Referential boundary: The target chemical should be classified as Alkyl arenes AND Aromatic amine AND Ether AND Overlapping groups AND Precursors quinoid compounds by Organic Functional groups (nested) ONLY

Domain logical expression index: "x"

Referential boundary: The target chemical should be classified as Not calculated by Biodeg BioHC half-life (Biowin) ONLY

Domain logical expression index: "y"

Parametric boundary:The target chemical should have a value of log Kow which is >= 2.62

Domain logical expression index: "z"

Parametric boundary:The target chemical should have a value of log Kow which is <= 3.94

Interpretation of results:
other: not classified
Conclusions:
The LD50 value was estimated to be 7032.78 mg/kg bw,when male and female wistar rats were orally exposed with 4-methoxy-2-methyl-N-phenylaniline (41317-15-1) via gavage.
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 4-methoxy-2-methyl-N-phenylaniline (41317-15-1).The LD50 was estimated to be 7032.78 mg/kg bw,when male and female wistar rats were orally exposed with 4-methoxy-2-methyl-N-phenylaniline (41317-15-1) via gavage.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
Value:
7 032.78 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: 4-methoxy-2-methyl-N-phenylaniline
- IUPAC name: 4-methoxy-2-methyl-N-phenylaniline
- Molecular formula: C14H15NO
- Molecular weight: 213.279 g/mol
- Smiles: c1(c(cc(cc1)OC)C)Nc1ccccc1
- InChl: 1S/C14H15NO/c1-11-10-13(16-2)8-9-14(11)15-12-6-4-3-5-7-12/h3-10,15H,1-2H3
- Substance type: Organic
Species:
rabbit
Strain:
New Zealand White
Sex:
male/female
Details on test animals or test system and environmental conditions:
No data available
Type of coverage:
semiocclusive
Vehicle:
not specified
Details on dermal exposure:
No data available
Duration of exposure:
24 hours
Doses:
3454.3 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/female
Dose descriptor:
LD50
Effect level:
3 454.3 mg/kg bw
Based on:
test mat.
Remarks on result:
other: 50% Mortality was observed
Mortality:
No data available
Clinical signs:
No data available
Body weight:
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" or "d" )  and ("e" and ( not "f") )  )  and ("g" and ( not "h") )  )  and ("i" and ( not "j") )  )  and ("k" and ( not "l") )  )  and "m" )  and "n" )  and ("o" and ( not "p") )  )  and ("q" and ( not "r") )  )  and ("s" and "t" )  )

Domain logical expression index: "a"

Referential boundary: The target chemical should be classified as Alkylarylether OR Amine OR Aromatic compound OR Ether OR Secondary amine OR Secondary aromatic amine by Organic functional groups, Norbert Haider (checkmol) ONLY

Domain logical expression index: "b"

Referential boundary: The target chemical should be classified as Aliphatic Carbon [CH] OR Aliphatic Carbon [-CH2-] OR Aliphatic Carbon [-CH3] OR Aliphatic Nitrogen, two aromatic attach [-N-] OR Aromatic Carbon [C] OR Nitrogen, two or tree olefinic attach [>N-] OR Olefinic carbon [=CH- or =C<] OR Oxygen, one aromatic attach [-O-] by Organic functional groups (US EPA) ONLY

Domain logical expression index: "c"

Referential boundary: The target chemical should be classified as Alkyl arenes OR Aromatic amine OR Ether OR Overlapping groups OR Precursors quinoid compounds by Organic Functional groups (nested) ONLY

Domain logical expression index: "d"

Referential boundary: The target chemical should be classified as Alkyl arenes OR Aromatic amine OR Aryl OR Ether OR Precursors quinoid compounds by Organic Functional groups ONLY

Domain logical expression index: "e"

Referential boundary: The target chemical should be classified as No alert found by DNA binding by OASIS v.1.3

Domain logical expression index: "f"

Referential boundary: The target chemical should be classified as AN2 OR AN2 >> Nucleophilic addition to alpha, beta-unsaturated carbonyl compounds OR AN2 >> Nucleophilic addition to alpha, beta-unsaturated carbonyl compounds >> alpha, beta-Unsaturated Aldehydes OR AN2 >> Schiff base formation OR AN2 >> Schiff base formation >> alpha, beta-Unsaturated Aldehydes OR Michael addition OR Michael addition >> Quinone type compounds OR Michael addition >> Quinone type compounds >> Quinone methides OR Radical OR Radical >> Radical mechanism via ROS formation (indirect) OR Radical >> Radical mechanism via ROS formation (indirect) >> Single-Ring Substituted Primary Aromatic Amines OR Radical >> ROS formation after GSH depletion OR Radical >> ROS formation after GSH depletion >> Quinone methides OR SN1 OR SN1 >> Alkylation after metabolically formed carbenium ion species OR SN1 >> Alkylation after metabolically formed carbenium ion species >> Polycyclic Aromatic Hydrocarbon Derivatives OR SN1 >> Nucleophilic attack after metabolic nitrenium ion formation OR SN1 >> Nucleophilic attack after metabolic nitrenium ion formation >> Single-Ring Substituted Primary Aromatic Amines OR SN2 OR SN2 >> Alkylation, direct acting epoxides and related OR SN2 >> Alkylation, direct acting epoxides and related >> Epoxides and Aziridines OR SN2 >> Alkylation, direct acting epoxides and related after P450-mediated metabolic activation OR SN2 >> Alkylation, direct acting epoxides and related after P450-mediated metabolic activation >> Polycyclic Aromatic Hydrocarbon Derivatives by DNA binding by OASIS v.1.3

Domain logical expression index: "g"

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

Domain logical expression index: "h"

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 SN1 OR SN1 >> Nitrenium Ion formation OR SN1 >> Nitrenium Ion formation >> Primary aromatic amine OR SN1 >> Nitrenium Ion formation >> Secondary aromatic amine OR SN1 >> Nitrenium Ion formation >> Tertiary aromatic amine by DNA binding by OECD

Domain logical expression index: "i"

Referential boundary: The target chemical should be classified as Non binder, without OH or NH2 group by Estrogen Receptor Binding

Domain logical expression index: "j"

Referential boundary: The target chemical should be classified as Non binder, MW>500 OR Non binder, non cyclic structure by Estrogen Receptor Binding

Domain logical expression index: "k"

Referential boundary: The target chemical should be classified as No alert found by Protein binding by OASIS v1.3

Domain logical expression index: "l"

Referential boundary: The target chemical should be classified as Michael Addition OR Michael Addition >> Michael addition on conjugated systems with electron withdrawing group OR Michael Addition >> Michael addition on conjugated systems with electron withdrawing group >> alpha,beta-Carbonyl compounds with polarized double bonds  OR Michael Addition >> Polarised Alkenes OR Michael Addition >> Polarised Alkenes >> Polarised Alkene - alkenyl pyridines, pyrazines, pyrimidines or triazines  OR SN2 OR SN2 >> Interchange reaction with sulphur containing compounds OR SN2 >> Interchange reaction with sulphur containing compounds >> Thiols and disulfide compounds  by Protein binding by OASIS v1.3

Domain logical expression index: "m"

Referential boundary: The target chemical should be classified as High (Class III) by Toxic hazard classification by Cramer (original) ONLY

Domain logical expression index: "n"

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

Domain logical expression index: "o"

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

Domain logical expression index: "p"

Referential boundary: The target chemical should be classified as Halogens OR Metalloids by Groups of elements

Domain logical expression index: "q"

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 AND Group CN Aqueous Solubility < 0.1 g/L by Skin irritation/corrosion Exclusion rules by BfR

Domain logical expression index: "r"

Referential boundary: The target chemical should be classified as Group C Melting Point > 55 C by Skin irritation/corrosion Exclusion rules by BfR

Domain logical expression index: "s"

Parametric boundary:The target chemical should have a value of log Kow which is >= 0.796

Domain logical expression index: "t"

Parametric boundary:The target chemical should have a value of log Kow which is <= 4.47

Interpretation of results:
other: not classified
Conclusions:
The LD50 value was estimated to be 3454.3 mg/kg bw,when male and female new Zealand white rabbits were semiocclusively exposed with 4-methoxy-2-methyl-N-phenylaniline (41317-15-1) 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 4-methoxy-2-methyl-N-phenylaniline(68083-38-5).The LD50 was estimated to be 3454.3 mg/kg bw,when male and female new Zealand white rabbits were semiocclusively exposed with 4-methoxy-2-methyl-N-phenylaniline(41317-15-1) by dermal application for 24 hours. 

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
Value:
3 454.3 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,4-methoxy-2-methyl-N-phenylaniline(41317-15-1) 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 for4-methoxy-2-methyl-N-phenylaniline(41317-15-1) along with the study available on the structurally similar read across substance 2-methoxynaphthalene (93-04-9),4-(anilino)phenol (122-37-2) and 2-Ethoxynaphthalene (93-18-5).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 4-methoxy-2-methyl-N-phenylaniline (41317-15-1).The LD50 was estimated to be 7032.78 mg/kg bw,when male and female wistar rats were orally exposed with 4-methoxy-2-methyl-N-phenylaniline (41317-15-1) via gavage.

In another experimental study conducted bySustainability Support Services (Europe) AB(study number:14_49_057, 2014-06-25 )for the structurally similar read across substance 2-methoxynaphthalene (93-04-9). Acute Oral Toxicity Study of Methyl 2-naphthyl ether in Rats was performed as per OECD No. 423.Six female Wistar rats were selected for acute oral toxicity study.The test material was dissolved in corn oil and given in dose concentration 2000 mg/kg bw by oral gavage route.The animals were fasted for minimum 16-18 hours prior to dosing and for 4 hours post dosing, with food withheld but drinking water providedad libitum. The time intervals between dosing were determined by the onset, duration and severity of toxic signs. Three rats of group G1 were dosed with starting dose of 2000 mg/kg body weight and the animals showed no mortality post dosing, so another three rats of the same group were dosed with 2000 mg/kg weight and no mortality was observed. Hence, further dosing was stopped. Mean body weight of all six animals was observed with gain on day 7 and 14. Normal clinical signs were observed throughout the experimental period. No external and internal gross pathological examination were seen in all the six animals treated with 2000 mg/kg body weight during terminal sacrifice.Hence the LD50 value was considered to be >2000 mg/kg bw. When female Wistar rats were treated with Methyl 2-naphthyl ether (93-04-9) orally.

The study was further supported by Opdyke, D. L. J (Food and Cosmetics Toxicology. Vol. 13, Pg. 885, 1975) and IPCS (aliphatic and aromatic ethers (jecfa 52, 2004) ) for the structurally similar read across substance 2-methoxynaphthalene (93-04-9). The acute toxicity study was conducted to evaluate the toxic effects of administration of methyl 2-naphthyl ether in male and female rat by the oral route.No mortality was observed at dose concentration 5000mg/kg bw. Hence LD50 value was considered to be >5000 mg/kg of body weight. When rats were treated with methyl 2-naphthyl ether (93-04-9) orally.

This is further supported 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 substance4-(anilino)phenol (122-37-2).Acute oral toxicity study was done in rats using test material4-Hydroxydiphenylamine (122-37-2).50% mortality was observed at dose3300 mg/kg bw.In Autonomic Nervous System, direct Parasympathomimetic effect was observed. Behavioral changes such as general Anesthetic symptom was observed in treated animals.In hematological examination, methemoglobinemia-carboxyhemoglobin was observed.Hence,LD50 value was considered to be 3300 mg/kg bw,when rats were treated with 4-Hydroxydiphenylamine (122-37-2)orally.

Also these results are further supported by the experimental study conducted by Sustainability Support Services (Europe) AB (study number: 19168, 2017-08-11) for the structurally similar read across substance2-Ethoxynaphthalene (93-18-5).The acute oral toxicity profile of Ethyl 2-naphthyl ether (CAS No. 93-18-5) in Sprague Dawley rats. Corn oil was used as vehicle.Initially, three female animals were treated at the dose level of 300 mg/kg body weight of the test item (Step - I). Administration of the test item at 300 mg/kg did not result in any signs of toxicity and mortality at 24 hours after the dosing. As no mortality was observed at 24 hours after the dosing, three female animals were added to the study and treated with the same dose of 300 mg/kg of the test item (Step - II). Administration of the test item at 300 mg/kg did not result in any signs of toxicity and mortality after the dosing. No mortality was observed at 300 mg/kg dose group, hence additional three female animals were treated with the higher dose of 2000 mg/kg of the test item (Step - I). Administration of the test item at 2000 mg/kg resulted in polyurea, diarrhoea and ataxic gait with onset on day 2 after the dosing and no mortality after the dosing. As no mortality were observed at 24 hours after the dosing, additional three female animals were treated with the higher dose of 2000 mg/kg of the test item (Step - II). Administration of the test item at 2000 mg/kg resulted in polyurea, diarrhoea and ataxic gait with onset from day 1 to day 2 after the dosing and no mortality after the dosing. Gross pathological examination did not reveal any abnormalities in animals from 300 mg/kg and 2000 mg/kg dose groups. Hence,The lethal concentration (LD50) value for acute oral toxicity test was considered to be 5000mg/kg bw,when female Sprague Dawley rats were treated with Ethyl 2-naphthyl ether (CAS No. 93-18-5)orally via gavage according to OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method).

Thus, based on the above studies on4-methoxy-2-methyl-N-phenylaniline (41317-15-1)and it’s structurally similar read across substances 2-methoxynaphthalene (93-04-9),4-(anilino)phenol (122-37-2) and 2-Ethoxynaphthalene (93-18-5), it can be concluded that LD50 value is greater than 2000 mg/kg bw. Thus, comparing this value with the criteria of CLP regulation,4-methoxy-2-methyl-N-phenylaniline (41317-15-1)cannot be classified for acute oral toxicity.

Acute Inhalation Toxicity: 

4-methoxy-2-methyl-N-phenylaniline (41317-15-1)has very low vapour pressure (0.0136 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,4-methoxy-2-methyl-N-phenylaniline (41317-15-1)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 for4-methoxy-2-methyl-N-phenylaniline (41317-15-1)along with the study available on structurally similar read across substance 2-methoxynaphthalene (93-04-9) and2-Ethoxynaphthalene (93-18-5). 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 for4-methoxy-2-methyl-N-phenylaniline(68083-38-5).TheLD50 was estimated to be3454.3 mg/kg bw,whenmale and female new Zealand white rabbitswere semiocclusivelyexposed with4-methoxy-2-methyl-N-phenylaniline(41317-15-1) by dermal application for 24 hours. 

 

In another experimental study conducted bySustainability Support Services (Europe) AB(study number:14_49_058,2014-06-25)for the structurally similar read across substance 2-methoxynaphthalene (93-04-9). Acute dermal toxicity study of Methyl 2-naphthyl etherin Rats was performed as per OECD No. 402. Five male and five female healthy young adult rats were randomly selected and used for conducting acute dermal toxicity study. Rats free from injury and irritation of skin were selected for the study. Twenty four hours prior to dermal application of test item, approximately 10% of body surface area of each rat was clipped. A limit dose of 2000 mg/ kg body weight of test item moistened with 0.2 ml distilled water was applied by single dermal application and observed for 14 days after treatment. On test day 0, an amount of test item moistened with 0.2 ml distilled water was applied directly on the intact skin of clipped area of rats; the porous gauze dressing was put on to the intact skin of clipped area.This porous gauze dressing was covered with a non-irritating tape.After the 24-hour application period, the dressings were removed and the skin was gently wiped with distilled water.The skin reactions were assessed. All the animals were observed for mortality, clinical signs, body weight and gross pathology. No mortality were observed in any animal, normal clinical signs were observed. Mean body weight of male and female was observed with increase on day 7 and 14, as compared to day 0. No pathological abnormality were observed. Thus the LD50 value was considered to be >2000 mg/kg bw. When male and female wistar rats were treated with Methyl 2-naphthyl ether (93-04-9) by dermal application .

The study was further supported by Opdyke, D. L. J (Food and Cosmetics Toxicology. Vol. 13, Pg. 885, 1975) for the structurally similar read across substance 2-methoxynaphthalene (93-04-9). The acute dermal toxicity study of Methyl 2-naphthyl ether was performed in rabbit by the dermal route. No mortality was observed at dose concentration 5000 mg/kg bw.Hence the lethal dose (LD50) value was considered to be  >5000 mg/kg of body weight.When rabbits were treated with  methyl 2-naphthyl ether (93-04-9) by dermal application.

This is further supported by Sustainability Support Services (Europe) AB (study number: 19169, 2017-08-11)for the structurally similar read across substance2-Ethoxynaphthalene (93-18-5).The acute dermal toxicity profile of Ethyl 2-naphthyl ether (CAS No. 93-18-5) in Sprague Dawley rats. Distilled water was used as vehicle.The test item was applied to shorn skin of 5 male and 5 female animals at 2000 mg/kg body weight. Administration of the test item at 2000 mg/kg did not result in any skin reaction at the site of application during the study period of 14 days. Administration of the test item did not result in any signs of toxicity and mortality during the study period of 14 days. Animals exhibited normal body weight gain through the study period of 14 days.Gross pathological examination did not reveal any abnormalities attributable to the treatment. Hence,The LD50 value was considered to be >2000 mg/kg bw,whenmale and female Sprague Dawley ratswere semiocclusively treated withEthyl 2-naphthyl ether (CAS No. 93-18-5)by dermal application following 14 days of observation period according to OECD Guideline 402 (Acute Dermal Toxicity).

Thus, based on the above studies on4-methoxy-2-methyl-N-phenylaniline (41317-15-1)and it’s structurally similar read across substances 2-methoxynaphthalene (93-04-9) and2-Ethoxynaphthalene (93-18-5), it can be concluded that LD50 value is greater than 2000 mg/kg bw. Thus, comparing this value with the criteria of CLP regulation,4-methoxy-2-methyl-N-phenylaniline (41317-15-1)cannot be classified for acute dermal toxicity.

Justification for classification or non-classification

Based on the above experimental studies and prediction on4-methoxy-2-methyl-N-phenylaniline (41317-15-1)and it’s structurally similar read across substances 2-methoxynaphthalene (93-04-9),4-(anilino)phenol (122-37-2) and 2-Ethoxynaphthalene (93-18-5), it can be concluded that LD50 value is greater than 2000 mg/kg bw. Thus, comparing this value with the criteria of CLP regulation,4-methoxy-2-methyl-N-phenylaniline (41317-15-1)cannot be classified for acute oral and dermal toxicity. For Acute inhalation toxicity wavier was added so, not possible to classify.