Registration Dossier

Skin irritation:

The dermal irritation potential of 4-methoxy-2-methyl-N-phenylaniline was estimated using OECD QSAR toolbox v3.3 with logPow as the primary descriptor.

4-methoxy-2-methyl-N-phenylaniline was estimated to be irritating to the skin of New Zealand White rabbits.

Based on the estimated results, 4-methoxy-2-methyl-N-phenylaniline can be considered to be irritating to skin and can be classified under the category ”Category 2 “as per CLP regulation.

Eye Irritation:

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

4-methoxy-2-methyl-N-phenylaniline was estimated to be irritating to the eyes of New Zealand White rabbits.

Based on the estimated results, 4-methoxy-2-methyl-N-phenylaniline can be considered to be irritating to eyes and can be classified under the category “Category 2” as per CLP regulation.

Reference

Endpoint:

skin irritation: in vivo

Type of information:

(Q)SAR

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

results derived from a valid (Q)SAR model and falling into its applicability domain, with limited documentation / justification

Justification for type of information:

data is from OECD QSAR toolbox v3.3 and the QMRF report has been attached

Qualifier:

according to guideline

Guideline:

other: Estimated data

Principles of method if other than guideline:

Prediction was done using OECD QSAR toolbox v3.3

GLP compliance:

not specified

Specific details on test material used for the study:

- Name of 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
- Physical state: Solid dry powder

Species:

rabbit

Strain:

New Zealand White

Details on test animals or test system and environmental conditions:

no data available

Type of coverage:

semiocclusive

Preparation of test site:

shaved

Vehicle:

not specified

Controls:

not specified

Amount / concentration applied:

0.5 ml

Duration of treatment / exposure:

4 hours

Observation period:

21 days

Number of animals:

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:

positive indication of irritation

Irritant / corrosive response data:

signs of irritation observed

Estimation method: Takes mode value from the 12 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 ( not "n") ) ) and ("o" and ( not "p") ) ) and "q" ) and ("r" and ( not "s") ) ) and ("t" and ( not "u") ) ) and "v" ) and "w" ) and "x" ) and "y" ) and "z" ) and "aa" ) and ("ab" and ( not "ac") ) ) and ("ad" and ( not "ae") ) ) and ("af" and ( not "ag") ) ) and ("ah" and "ai" ) )

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 (!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: "f"

Referential boundary: The target chemical should be classified as Group CN log Kow > 4.5 OR Group CN log Kow > 5.5 OR Group CN Melting Point > 180 C by Skin irritation/corrosion Exclusion rules by BfR

Domain logical expression index: "g"

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: "h"

Referential boundary: The target chemical should be classified as Group CN Vapour Pressure < 0.001 Pa OR Group CNS Melting Point > 120 C OR Group CNS Melting Point > 50 C by Skin irritation/corrosion Exclusion rules by BfR

Domain logical expression index: "i"

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: "j"

Referential boundary: The target chemical should be classified as Group All log Kow > 9 by Skin irritation/corrosion Exclusion rules by BfR

Domain logical expression index: "k"

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: "l"

Referential boundary: The target chemical should be classified as Group C Aqueous Solubility < 0.0001 g/L by Skin irritation/corrosion Exclusion rules by BfR

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

Domain logical expression index: "n"

Referential boundary: The target chemical should be classified as Group C Melting Point > 55 C OR Group C Vapour Pressure < 0.0001 Pa by Skin irritation/corrosion Exclusion rules by BfR

Domain logical expression index: "o"

Referential boundary: The target chemical should be classified as Inclusion rules not met by Skin irritation/corrosion Inclusion rules by BfR

Domain logical expression index: "p"

Referential boundary: The target chemical should be classified as Aldehydes OR Aromatic amines OR Epoxides(=oxiranes) OR Ethylenglycolethers OR Ketones OR Phenols by Skin irritation/corrosion Inclusion rules by BfR

Domain logical expression index: "q"

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

Domain logical expression index: "r"

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

Domain logical expression index: "s"

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

Domain logical expression index: "t"

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: "u"

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

Domain logical expression index: "v"

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

Domain logical expression index: "w"

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

Domain logical expression index: "x"

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

Domain logical expression index: "y"

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

Domain logical expression index: "z"

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: "aa"

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: "ab"

Referential boundary: The target chemical should be classified as No alert found by in vivo mutagenicity (Micronucleus) alerts by ISS

Domain logical expression index: "ac"

Referential boundary: The target chemical should be classified as H-acceptor-path3-H-acceptor by in vivo mutagenicity (Micronucleus) alerts by ISS

Domain logical expression index: "ad"

Referential boundary: The target chemical should be classified as Alkyl substituent on aromatic ring AND Aromatic amine [-NH2 or -NH-] AND Aromatic ether [-O-aromatic carbon] AND Aromatic-CH3 AND Aromatic-H AND Benzene AND Methyl [-CH3] AND Unsubstituted phenyl group (C6H5-) by Bioaccumulation - metabolism alerts

Domain logical expression index: "ae"

Referential boundary: The target chemical should be classified as Unsubstituted aromatic (3 or less rings) by Bioaccumulation - metabolism alerts

Domain logical expression index: "af"

Referential boundary: The target chemical should be classified as Basic [80,90) AND No pKa value by Ionization at pH = 1

Domain logical expression index: "ag"

Referential boundary: The target chemical should be classified as Basic [0,10) by Ionization at pH = 1

Domain logical expression index: "ah"

Parametric boundary:The target chemical should have a value of log Kow which is >= 2.54

Domain logical expression index: "ai"

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

Interpretation of results:

Category 2 (irritant) based on GHS criteria

Conclusions:

4-methoxy-2-methyl-N-phenylaniline was estimated to be irritating to the skin of New Zealand White rabbits.

Executive summary:

The dermal irritation potential of 4-methoxy-2-methyl-N-phenylaniline was estimated using OECD QSAR toolbox v3.3 with logPow as the primary descriptor.

4-methoxy-2-methyl-N-phenylaniline was estimated to be irritating to the skin of New Zealand White rabbits.

Based on the estimated results, 4-methoxy-2-methyl-N-phenylaniline can be considered to be irritating to skin and can be classified under the category ”Category 2 “as per CLP regulation.

Endpoint conclusion:

adverse effect observed (irritating)

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: 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
- Physical state: Solid dry powder

Species:

rabbit

Strain:

New Zealand White

Details on test animals or tissues and environmental conditions:

no data available

Vehicle:

not specified

Controls:

not specified

Amount / concentration applied:

100 microliters

Duration of treatment / exposure:

8 days

Observation period (in vivo):

8 days

Duration of post- treatment incubation (in vitro):

no data available

Number of animals or in vitro replicates:

6

Details on study design:

no data available

Irritation parameter:

overall irritation score

Basis:

mean

Time point:

other: 8 days

Reversibility:

not specified

Remarks on result:

positive indication of irritation

Irritant / corrosive response data:

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" or "d" ) and "e" ) and ("f" and ( not "g") ) ) and ("h" and ( not "i") ) ) and "j" ) and "k" ) and "l" ) and "m" ) and "n" ) and "o" ) and "p" ) and "q" ) and "r" ) and "s" ) and "t" ) and "u" ) and "v" ) and "w" ) and "x" ) and "y" ) and ("z" and ( not "aa") ) ) and ("ab" and ( not "ac") ) ) and "ad" ) and ("ae" and ( not "af") ) ) and ("ag" and ( not "ah") ) ) and ("ai" and "aj" ) )

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 Bioavailable by Lipinski Rule Oasis ONLY

Domain logical expression index: "f"

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

Domain logical expression index: "g"

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

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 15 - Phosphorus P OR Group 16 - Sulfur S by Chemical elements

Domain logical expression index: "j"

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

Domain logical expression index: "k"

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

Domain logical expression index: "l"

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

Domain logical expression index: "m"

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

Domain logical expression index: "n"

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

Domain logical expression index: "o"

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

Domain logical expression index: "p"

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

Domain logical expression index: "q"

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

Domain logical expression index: "r"

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: "s"

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: "t"

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: "u"

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: "v"

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

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

Domain logical expression index: "z"

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

Domain logical expression index: "aa"

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

Domain logical expression index: "ab"

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

Domain logical expression index: "ac"

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

Domain logical expression index: "ad"

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: "ae"

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: "af"

Referential boundary: The target chemical should be classified as Group C Aqueous Solubility < 0.0001 g/L by Skin irritation/corrosion Exclusion rules by BfR

Domain logical expression index: "ag"

Referential boundary: The target chemical should be classified as Aromatic Amine Type Compounds by Oncologic Primary Classification

Domain logical expression index: "ah"

Referential boundary: The target chemical should be classified as Not classified by Oncologic Primary Classification

Domain logical expression index: "ai"

Parametric boundary:The target chemical should have a value of log Kow which is >= 2.06

Domain logical expression index: "aj"

Parametric boundary:The target chemical should have a value of log Kow which is <= 4.52

Interpretation of results:

Category 2 (irritating to eyes) based on GHS criteria

Conclusions:

4-methoxy-2-methyl-N-phenylaniline was estimated to be irritating to the eyes of New Zealand White rabbits.

Executive summary:

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

4-methoxy-2-methyl-N-phenylaniline was estimated to be irritating to the eyes of New Zealand White rabbits.

Based on the estimated results, 4-methoxy-2-methyl-N-phenylaniline can be considered to be irritating to eyes and can be classified under the category “Category 2” as per CLP regulation.

Endpoint conclusion:

adverse effect observed (irritating)

Endpoint conclusion:

no study available

Skin Irritation:

In different studies,4-methoxy-2-methyl-N-phenylaniline hasbeen investigated for potential for dermal irritation to a greater or lesser extent. The studies are based on in vivo experiments along with predicted data for target chemical and its structurally similar read across substances,Diphenylamine[CAS: 122-39-4] and 4-Hydroxydiphenylamine[CAS: 122-37-2]. The predicted data using the OECD QSAR toolbox has also been compared with the experimental data.

In a prediction done by SSS (2018) using the OECD QSAR toolbox v3.3 with log kow as the primary descriptor, the skin irritation potential was estimated for4-methoxy-2-methyl-N-phenylaniline. 4-methoxy-2-methyl-N-phenylaniline was irritating to New Zealand White rabbit skin.

This is supported by the experimental study summarized in Diphenylamine- PESTICIDE RESIDUES IN FOOD – 1984, Sponsored jointly by FAO and WHO; for the structurally similar read across substance,Diphenylamine[CAS: 122-39-4].Undiluted 0.5 g of diphenylamine was applied to the intact and abraded skin of rabbits and observed for signs of irritation (duration of application and observation period not mentioned). Slight irritation was observed when diphenylamine was applied to the skin of rabbits.

Hence, diphenylamine can be considered to be slightly irritating to skin.

The above studies are further supported by the experimental study summarized in OTS0571980, NTRL report, last updated 1992; for the structurally similar read across substance, 4 -Hydroxydiphenylamine[CAS: 122-37-2]. 4-Hydroxydiphenylamine was applied daily for 5 days to the uncovered skin of 10 guinea pigs and observed for signs of irritation.

Slight erythema was observed in 5 of 10 guinea pigs on day 1. On day 5, the entire area was hemorrhagic, necrotic or with eschar formation which led to death of all the treated animals. Repeated exposure of 4-Hydroxydiphenylamine can cause irritation to guinea pigs skin.

Hence, 4-Hydroxydiphenylamine can be considered to be highly irritating to skin.

Based on the available data for the target and read across substances and applying the weight of evidence approach, 4-methoxy-2-methyl-N-phenylaniline can be considered to be irritating to skin.Comparing the above annotations with the criteria of CLP regulation, it can be classified under the category “Category 2”.

Eye Irritation:

In various studies,4-methoxy-2-methyl-N-phenylaniline hasbeen investigated for potential for ocular irritation to a greater or lesser extent. The studies are based on in vivo experiments along with predicted data for target chemical and its structurally similar read across substances,Methyl 2-naphthyl ether [CAS: 93-04-9], 4-methoxyaniline[CAS: 104-94-9] and 4-Amino-2 -nitrodiphenylamine-2'-carboxylic Acid [CAS: 117907-43-4]. The predicted data using the OECD QSAR toolbox has also been compared with the experimental data.

In a prediction done by SSS (2018) using the OECD QSAR toolbox v3.3 with log kow as the primary descriptor, the eye irritation potential was estimated for4-methoxy-2-methyl-N-phenylaniline. 4-methoxy-2-methyl-N-phenylanilinewas irritating to New Zealand White rabbit eyes.

This is supported by the experimental study performed in an OECD GLP laboratory (Sustainability Support Services (Europe) has letter of access, 2014) to evaluate the eye irritation potential of thestructurally similar read across substances,Methyl 2-naphthyl ether [CAS: 93-04-9].The study was performed according to OECD 405 Guidelines.Rabbits free from injury of eye were selected for the study. The eyes of all the rabbits were examined 24 hours prior to treatment. One eye of each rabbit served as control and other as treated. Control eye was left untreated whereas; 0.1 g of test item was instilled in the other (treated) eye of each rabbit. The eye was observed at 1, 24, 48, 72 hour, day 7, day 14 and day 21 for all the three animals post test item instillation. Ophthalmoscope was used for scoring of eye lesions. In the initial test,100 mg of test item was instilled into the conjunctival sac of the right eye of animal no.1 whereas the left eye of the rabbit served as the control. As animal no. 1 showed no severe ocular lesions; hence a confirmatory test was conducted on additional two rabbits (animal no. 2 and 3); 100 mg of test item was instilled into the conjunctival sac of right eye of both the rabbits and left eye served as the control. All the animals were observed till day 21 post test item instillation. Untreated eye of all the three rabbits were normal throughout the experimental period. The following grading scores were observed in treated eye of tested rabbits.

Observation at 1 hour after instillation of test item revealed: Cornea-No ulceration or opacity was seen in all the animals; Area of Opacity-Zero in all the animals; Iris:Normal in all the animals; Conjunctivae - Some blood vessels definitely hyperaemic (injected) was seen in all the animals; Chemosis:Some swelling above normal (includes nictitating membranes) was seen in all the animals.

Observation at 24 hours after instillation of test item revealed: Cornea-Scattered or diffuse areas of opacity (other than slight dulling of normal lustre); details of iris clearly visible was seen in all the animals; Area of Opacity- One quarter (or less) but not zero was seen in all the animals; Iris:Normal in all the animals; Conjunctivae -Diffuse, crimson color; individual vessels not easily discernible was seen in all the animals; Chemosis:Some swelling above normal (includes nictitating membranes) was seen in animal no. 1 and 3 whereas obvious swelling with partial eversion of lids was seen in animal no 2.

At 24 hours observation the rabbits were examined for corneal epithelium cell damage using sodium fluorescein strips and noticed 40%, 50% and 40% damage in animal no. 1, 2 and 3 respectively. Observation at 48 hours after instillation of test item revealed: Cornea- Scattered or diffuse areas of opacity (other than slight dulling of normal lustre); details of iris clearly visible was seen in all the animals; Area of Opacity-One quarter (or less) but not zero was seen inall the animals; Iris:Normal in all the animals; Conjunctivae - Diffuse, crimson color; individual vessels not easily discernible in animal no. 3;Chemosis:Some swelling above normal (includes nictitating membranes) was seen in animal no. 1 and 2 whereas obvious swelling with partial eversion of lids in animal no. 3.Observation at 72 hours after instillation of test item revealed: Cornea- Scattered or diffuse areas of opacity (other than slight dulling of normal lustre); details of iris clearly visible was seen in all the animals; Area of Opacity-One quarter (or less) but not zero was seen in all the animals; Iris:Normal in all the animals; Conjunctivae - Diffuse, crimson color; individual vessels not easily discernible in all the animals; Chemosis:Some swelling above normal (includes nictitating membranes) was seen in all the animals. Observation on day 7 after instillation of test item revealed: Cornea- Scattered or diffuse areas of opacity (other than slight dulling of normal lustre); details of iris clearly visible was seen in all the animals; Area of Opacity-One quarter (or less) but not zero was seen in all the animals; Iris:Normal in all the animals; Conjunctivae-Some blood vessels definitely hyperaemic (injected) was seen in animal no.1 and diffuse, crimson color; individual vessels not easily discernible was observed in animal no. 2 and 3;Chemosis:Some swelling above normal (includes nictitating membranes) was seen in all the animals. Observation on day 14 after instillation of test item revealed: Cornea- Scattered or diffuse areas of opacity (other than slight dulling of normal lustre); details of iris clearly visible was seen in animal no. 1 and 2 whereas no ulceration or opacity was seen in animal no. 3;Area of Opacity-One quarter (or less) but not zero was seen in animals no. 1 and 2 whereas zero was seen in animal no. 3;Iris:Normal in all the animals; Conjunctivae -Some blood vessels definitely hyperaemic (injected) was seen in all the animals; Chemosis: Some swelling above normal (includes nictitating membranes) was seen in all the animals. Observation on day 21 after instillation of test item revealed: Cornea-No ulceration or opacity in all the animals; Area of Opacity-Zero in all the animals; Iris:Normal in all the animals; Conjunctivae -Blood vessels normal in all the animals; Chemosis: No swelling (Normal) in all the animals. The individual mean score for animal nos. 1, 2 and 3 at 24, 48, 72 hours for corneal opacity, iris, conjunctiva and chemosis were found 1.00, 0.00, 2.00, 1.00; 1.00, 0.00, 2.00, 1.33, and 1.00, 0.00, 2.00, 1.33, respectively. The effects observed in all the animals were fully reversible within an observation period of 21 days.

Under the experimental test conditions, “Methyl 2-naphthyl ether (CAS No: 93-04-9)” was “An Eye Irritant (Irritating to Eyes)” to New Zealand White Female rabbit eyes.

These results are supported by the experimental study summarized in The MAK Collection for Occupational Health and Safety, 1–10, 2012; for the structurally similar read across substance, 4-methoxyaniline[CAS: 104-94-9]. The study was conducted according to OECD guideline 405 in rabbits

4-methoxyaniline was applied to rabbit eyes and after 24 hours of dosing effects was observed.

4-methoxyaniline after 24 hours of exposure was irritating to the rabbit eye without irreversible effects.

The above results are further supported by the experimental study summarized in Opinion on 4-Amino-2-nitrodiphenylamine-2'-carboxylic acid, COLIPA n° B87, SCCS, last updated 11 December 2012; for the structurally similar read across substance, 4-Amino-2-nitrodiphenylamine-2'-carboxylic acid[CAS: 117907-43-4].The study was performed as per OECD 405 Guidelines.0.1 g of undiluted test chemical was instilled in the right eye of 4 male Albino rabbits, Kleinrusse strain (Chbb:HM)/Fa. The eyes remained unrinsed throughout the study. The left eye served as control.Ocular reactions were recorded at 1 and 6 hours and 1, 2, 3, 7, 10, 14, 17 and 21 days after instillation. The cornea was investigated further using fluorescein at 24 hours and 7 and 21 days.

Instillation of 4-amino-2-nitrodiphenylamine-2'-carboxylic acid affected the cornea and conjunctivae of the test rabbits. Slightly increased opacity of the cornea was seen in 2/4 rabbits eyes, resolving in one animal by day 4, but persisting to the end of the study in the other animal. These observations were supported by the fluorescein examination which revealed slight corneal epithelial damage in these two animals. Mild to moderate irritation of the conjunctivae was seen in 4/4 animals and persisted to the end of the study period in one.

Hence, undiluted 4-amino-2-nitrodiphenylamine-2'-carboxylic acid can be considered to be severely irritating to rabbit eyes.

Based on the available data for the target and read across substances and applying the weight of evidence approach, 4-methoxy-2-methyl-N-phenylaniline can be considered to be irritating to eyes.Comparing the above annotations with the criteria of CLP regulation, it can be classified under the category “Category 2”.

Based on the available information, 4-methoxy-2-methyl-N-phenylaniline is likely to irritation to eyes and skin.

Hence,4-methoxy-2-methyl-N-phenylaniline can be classified under the category “Category 2” as per CLP regulation.