Registration Dossier

Skin irritation:

The dermal irritation potential of 2-methylanisole was estimated using OECD QSAR toolbox v3.3 with logPow as the primary descriptor.

2-methylanisole was estimated to be not irritating to the skin of New Zealand White rabbits.

Based on the estimated results, 2-methylanisole can be considered to be not irritating to skin and can be classified under the category “Not Classified” as per CLP regulation.

Eye Irritation:

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

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

Based on the estimated results, 2-methylanisole can be considered to be not irritating to eyes and can be classified under the category “Not Classified” 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: 2-methylanisole
- IUPAC name: 1-methoxy-2-methylbenzene
- Molecular formula: C8H10O
- Molecular weight: 122.166 g/mole
- Smiles : COc1ccccc1C
- Inchl: 1S/C8H10O/c1-7-5-3-4-6-8(7)9-2/h3-6H,1-2H3
- Substance type: Organic
- Physical state: Liquid (Colorless)

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:

unchanged (no vehicle)

Controls:

not specified

Amount / concentration applied:

0.5ml

Duration of treatment / exposure:

4 hours

Observation period:

7 days

Number of animals:

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:

7 d

Reversibility:

not specified

Remarks on result:

no indication of irritation

Irritant / corrosive response data:

No signs of irritation were observed

Estimation method: Takes mode value from the 5 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 ( not "k") ) ) and ("l" and ( not "m") ) ) and "n" ) and ("o" and ( not "p") ) ) and ("q" and ( not "r") ) ) and "s" ) and ("t" and ( not "u") ) ) and "v" ) and ("w" and ( not "x") ) ) and ("y" and ( not "z") ) ) and ("aa" and ( not "ab") ) ) and ("ac" and ( not "ad") ) ) and ("ae" and ( not "af") ) ) and ("ag" and ( not "ah") ) ) and ("ai" and ( not "aj") ) ) and ("ak" and ( not "al") ) ) and ("am" and ( not "an") ) ) and ("ao" and ( not "ap") ) ) and ("aq" and "ar" ) )

Domain logical expression index: "a"

Referential boundary: The target chemical should be classified as Class 1 (narcosis or baseline toxicity) by Acute aquatic toxicity classification by Verhaar (Modified)

Domain logical expression index: "b"

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

Domain logical expression index: "c"

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

Domain logical expression index: "d"

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

Domain logical expression index: "e"

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

Domain logical expression index: "f"

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

Domain logical expression index: "g"

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 AN2 >> Schiff base formation by aldehyde formed after metabolic activation OR AN2 >> Schiff base formation by aldehyde formed after metabolic activation >> Geminal Polyhaloalkane Derivatives OR AN2 >> Shiff base formation for aldehydes OR AN2 >> Shiff base formation for aldehydes >> Geminal Polyhaloalkane Derivatives OR AN2 >> Thioacylation via nucleophilic addition after cysteine-mediated thioketene formation OR AN2 >> Thioacylation via nucleophilic addition after cysteine-mediated thioketene formation >> Haloalkenes with Electron-Withdrawing Groups OR Michael addition OR Michael addition >> Quinone type compounds OR Michael addition >> Quinone type compounds >> Quinone methides OR Radical OR Radical >> Generation of ROS by glutathione depletion (indirect) OR Radical >> Generation of ROS by glutathione depletion (indirect) >> Haloalkanes Containing Heteroatom OR Radical >> Radical mechanism by ROS formation (indirect) or direct radical attack on DNA OR Radical >> Radical mechanism by ROS formation (indirect) or direct radical attack on DNA >> Organic Peroxy Compounds OR Radical >> Radical mechanism via ROS formation (indirect) OR Radical >> Radical mechanism via ROS formation (indirect) >> Geminal Polyhaloalkane Derivatives 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 SN2 OR SN2 >> Acylation involving a leaving group OR SN2 >> Acylation involving a leaving group >> Geminal Polyhaloalkane Derivatives OR SN2 >> Acylation involving a leaving group after metabolic activation OR SN2 >> Acylation involving a leaving group after metabolic activation >> Geminal Polyhaloalkane Derivatives OR SN2 >> Alkylation by epoxide metabolically formed after E2 reaction OR SN2 >> Alkylation by epoxide metabolically formed after E2 reaction >> Monohaloalkanes 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 >> Haloalkenes with Electron-Withdrawing Groups OR SN2 >> Alkylation, direct acting epoxides and related after P450-mediated metabolic activation >> Polycyclic Aromatic Hydrocarbon Derivatives OR SN2 >> Alkylation, nucleophilic substitution at sp3-carbon atom OR SN2 >> Alkylation, nucleophilic substitution at sp3-carbon atom >> Monohaloalkanes OR SN2 >> Direct acting epoxides formed after metabolic activation OR SN2 >> Direct acting epoxides formed after metabolic activation >> Quinoline Derivatives OR SN2 >> Direct acylation involving a leaving group OR SN2 >> Direct acylation involving a leaving group >> Acyl Halides OR SN2 >> DNA alkylation OR SN2 >> DNA alkylation >> Vicinal Dihaloalkanes OR SN2 >> Internal SN2 reaction with aziridinium and/or cyclic sulfonium ion formation (enzymatic) OR SN2 >> Internal SN2 reaction with aziridinium and/or cyclic sulfonium ion formation (enzymatic) >> Vicinal Dihaloalkanes OR SN2 >> Nucleophilic substitution after carbenium ion formation OR SN2 >> Nucleophilic substitution after carbenium ion formation >> Monohaloalkanes OR SN2 >> Nucleophilic substitution at sp3 Carbon atom OR SN2 >> Nucleophilic substitution at sp3 Carbon atom >> Haloalkanes Containing Heteroatom OR SN2 >> Nucleophilic substitution at sp3 carbon atom after thiol (glutathione) conjugation OR SN2 >> Nucleophilic substitution at sp3 carbon atom after thiol (glutathione) conjugation >> Geminal Polyhaloalkane Derivatives OR SN2 >> SN2 at an activated carbon atom OR SN2 >> SN2 at an activated carbon atom >> Quinoline Derivatives by DNA binding by OASIS v.1.3

Domain logical expression index: "h"

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

Domain logical expression index: "i"

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 >> 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 >> Polycyclic (PAHs) and heterocyclic (HACs) aromatic hydrocarbons-Michael addition OR SN1 OR SN1 >> Iminium Ion Formation OR SN1 >> Iminium Ion Formation >> Aliphatic tertiary amines OR SN1 >> Nitrenium Ion formation OR SN1 >> Nitrenium Ion formation >> Secondary aromatic amine OR SN2 OR SN2 >> SN2 at an sp3 Carbon atom OR SN2 >> SN2 at an sp3 Carbon atom >> Aliphatic halides by DNA binding by OECD

Domain logical expression index: "j"

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

Domain logical expression index: "k"

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

Domain logical expression index: "l"

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

Domain logical expression index: "m"

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 OR SNAr OR SNAr >> Nucleophilic aromatic substitution on activated aryl and heteroaryl compounds OR SNAr >> Nucleophilic aromatic substitution on activated aryl and heteroaryl compounds >> Activated aryl and heteroaryl compounds by Protein binding by OASIS v1.3

Domain logical expression index: "n"

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

Domain logical expression index: "o"

Referential boundary: The target chemical should be classified as No alert found by Protein binding alerts for Chromosomal aberration by OASIS v1.1

Domain logical expression index: "p"

Referential boundary: The target chemical should be classified as AN2 OR AN2 >> Michael addition to the quinoid type structures OR AN2 >> Michael addition to the quinoid type structures >> N-Subsituted Aromatic Amines OR AN2 >> Nucleophilic addition to pyridonimine tautomer of aminopyridoindoles or aminopyridoimidazoles OR AN2 >> Nucleophilic addition to pyridonimine tautomer of aminopyridoindoles or aminopyridoimidazoles >> Heterocyclic Aromatic Amines OR Radical mechanism OR Radical mechanism >> ROS generation and direct attack of hydroxyl radical to the C8 position of nucleoside base OR Radical mechanism >> ROS generation and direct attack of hydroxyl radical to the C8 position of nucleoside base >> Heterocyclic Aromatic Amines OR SE reaction (CYP450-activated heterocyclic amines) OR SE reaction (CYP450-activated heterocyclic amines) >> Direct attack of arylnitrenium cation to the C8 position of nucleoside base OR SE reaction (CYP450-activated heterocyclic amines) >> Direct attack of arylnitrenium cation to the C8 position of nucleoside base >> Heterocyclic Aromatic Amines OR SR reaction (peroxidase-activated heterocyclic amines) OR SR reaction (peroxidase-activated heterocyclic amines) >> Direct attack of arylnitrenium radical to the C8 position of nucleoside base OR SR reaction (peroxidase-activated heterocyclic amines) >> Direct attack of arylnitrenium radical to the C8 position of nucleoside base >> Heterocyclic Aromatic Amines by Protein binding alerts for Chromosomal aberration by OASIS v1.1

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 C Surface Tension > 62 mN/m by Skin irritation/corrosion Exclusion rules by BfR

Domain logical expression index: "r"

Referential boundary: The target chemical should be classified as (!Undefined)Group CN Lipid Solubility < 0.4 g/kg OR (!Undefined)Group CNS Surface Tension > 62 mN/m OR Group All log Kow > 9 OR Group All Melting Point > 200 C OR Group C Aqueous Solubility < 0.0001 g/L OR Group C Melting Point > 55 C OR Group C Vapour Pressure < 0.0001 Pa OR Group CHal log Kow > 4.5 OR Group CHal Melting Point > 65 C OR Group CHal Molecular Weight > 280 g/mol OR Group CN Aqueous Solubility < 0.1 g/L OR Group CN log Kow > 4.5 OR Group CN Melting Point > 180 C OR Group CN Molecular Weight > 290 g/mol OR Group CN Vapour Pressure < 0.001 Pa OR Group CNS Melting Point > 50 C by Skin irritation/corrosion Exclusion rules by BfR

Domain logical expression index: "s"

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

Domain logical expression index: "t"

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

Domain logical expression index: "u"

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

Domain logical expression index: "v"

Similarity boundary:Target: Cc1ccccc1OC
Threshold=20%,
Dice(Atom centered fragments)
Atom type; Count H attached; Hybridization

Domain logical expression index: "w"

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

Domain logical expression index: "x"

Referential boundary: The target chemical should be classified as Aliphatic/Alicyclic hydrocarbons (Alpha 2u-globulin nephropathy) Rank C OR Aromatic hydrocarbons (Liver enzyme induction) Rank C OR Perhexiline (Hepatotoxicity) Alert OR Tamoxifen (Hepatotoxicity) Alert by Repeated dose (HESS)

Domain logical expression index: "y"

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: "z"

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

Domain logical expression index: "aa"

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

Domain logical expression index: "ab"

Referential boundary: The target chemical should be classified as alpha,beta-unsaturated aliphatic alkoxy group by in vivo mutagenicity (Micronucleus) alerts by ISS

Domain logical expression index: "ac"

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

Domain logical expression index: "ad"

Referential boundary: The target chemical should be classified as Oxolane by in vivo mutagenicity (Micronucleus) alerts by ISS

Domain logical expression index: "ae"

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

Domain logical expression index: "af"

Referential boundary: The target chemical should be classified as Aliphatic monoalcohols by Eye irritation/corrosion Inclusion rules by BfR

Domain logical expression index: "ag"

Referential boundary: The target chemical should be classified as Aromatic ether [-O-aromatic carbon] AND Aromatic-CH3 AND Aromatic-H AND Methyl [-CH3] by Biodegradation fragments (BioWIN MITI)

Domain logical expression index: "ah"

Referential boundary: The target chemical should be classified as Aliphatic ether [C-O-C] by Biodegradation fragments (BioWIN MITI)

Domain logical expression index: "ai"

Referential boundary: The target chemical should be classified as Aromatic ether [-O-aromatic carbon] AND Aromatic-CH3 AND Aromatic-H AND Methyl [-CH3] by Biodegradation fragments (BioWIN MITI)

Domain logical expression index: "aj"

Referential boundary: The target chemical should be classified as -CH2- [linear] by Biodegradation fragments (BioWIN MITI)

Domain logical expression index: "ak"

Referential boundary: The target chemical should be classified as Not categorized by US-EPA New Chemical Categories

Domain logical expression index: "al"

Referential boundary: The target chemical should be classified as Neutral Organics by US-EPA New Chemical Categories

Domain logical expression index: "am"

Referential boundary: The target chemical should be classified as Phys-chem EPISUITE by Database Affiliation

Domain logical expression index: "an"

Referential boundary: The target chemical should be classified as Aquatic ECETOC by Database Affiliation

Domain logical expression index: "ao"

Referential boundary: The target chemical should be classified as Phys-chem EPISUITE by Database Affiliation

Domain logical expression index: "ap"

Referential boundary: The target chemical should be classified as Bioaccumulation Canada by Database Affiliation

Domain logical expression index: "aq"

Parametric boundary:The target chemical should have a value of log Kow which is >= 1.87

Domain logical expression index: "ar"

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

Interpretation of results:

other: not irritating

Conclusions:

2-methylanisole was estimated to be not irritating to the skin of New Zealand White rabbits.

Executive summary:

The dermal irritation potential of 2-methylanisole was estimated using OECD QSAR toolbox v3.3 with logPow as the primary descriptor.

2-methylanisole was estimated to be not irritating to the skin of New Zealand White rabbits.

Based on the estimated results, 2-methylanisole can be considered to be not irritating to skin and can be classified under the category “Not Classified” as per CLP regulation.

Endpoint conclusion:

no adverse effect observed (not 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: 2-methylanisole
- IUPAC name: 1-methoxy-2-methylbenzene
- Molecular formula: C8H10O
- Molecular weight: 122.166 g/mole
- Smiles : COc1ccccc1C
- Inchl: 1S/C8H10O/c1-7-5-3-4-6-8(7)9-2/h3-6H,1-2H3
- Substance type: Organic
- Physical state: Liquid (Colorless)

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:

no data available

Duration of treatment / exposure:

single exposure

Observation period (in vivo):

7 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

Other effects / acceptance of results:

no data available

Irritation parameter:

overall irritation score

Basis:

mean

Time point:

7 d

Reversibility:

not specified

Remarks on result:

no indication of irritation

Irritant / corrosive response data:

No signs of irritation observed

Estimation method: Takes mode value from the 5 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 ( not "k") ) ) and ("l" and ( not "m") ) ) and "n" ) and ("o" and ( not "p") ) ) and ("q" and ( not "r") ) ) and ("s" and ( not "t") ) ) and ("u" and ( not "v") ) ) and ("w" and ( not "x") ) ) and ("y" and ( not "z") ) ) and ("aa" and ( not "ab") ) ) and ("ac" and ( not "ad") ) ) and ("ae" and ( not "af") ) ) and "ag" ) and "ah" ) and ("ai" and "aj" ) )

Domain logical expression index: "a"

Referential boundary: The target chemical should be classified as Class 1 (narcosis or baseline toxicity) by Acute aquatic toxicity classification by Verhaar (Modified)

Domain logical expression index: "b"

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

Domain logical expression index: "c"

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

Domain logical expression index: "d"

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

Domain logical expression index: "e"

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

Domain logical expression index: "f"

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

Domain logical expression index: "g"

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 AN2 >> Schiff base formation by aldehyde formed after metabolic activation OR AN2 >> Schiff base formation by aldehyde formed after metabolic activation >> Geminal Polyhaloalkane Derivatives OR AN2 >> Shiff base formation for aldehydes OR AN2 >> Shiff base formation for aldehydes >> Geminal Polyhaloalkane Derivatives OR Michael addition OR Michael addition >> Quinone type compounds OR Michael addition >> Quinone type compounds >> Quinone methides OR Radical OR Radical >> Generation of ROS by glutathione depletion (indirect) OR Radical >> Generation of ROS by glutathione depletion (indirect) >> Haloalkanes Containing Heteroatom OR Radical >> Radical mechanism by ROS formation (indirect) or direct radical attack on DNA OR Radical >> Radical mechanism by ROS formation (indirect) or direct radical attack on DNA >> Organic Peroxy Compounds OR Radical >> Radical mechanism via ROS formation (indirect) OR Radical >> Radical mechanism via ROS formation (indirect) >> Geminal Polyhaloalkane Derivatives 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 SN2 OR SN2 >> Acylation involving a leaving group OR SN2 >> Acylation involving a leaving group >> Geminal Polyhaloalkane Derivatives OR SN2 >> Acylation involving a leaving group after metabolic activation OR SN2 >> Acylation involving a leaving group after metabolic activation >> Geminal Polyhaloalkane Derivatives OR SN2 >> Alkylation by epoxide metabolically formed after E2 reaction OR SN2 >> Alkylation by epoxide metabolically formed after E2 reaction >> Monohaloalkanes 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 OR SN2 >> Alkylation, nucleophilic substitution at sp3-carbon atom OR SN2 >> Alkylation, nucleophilic substitution at sp3-carbon atom >> Monohaloalkanes OR SN2 >> Direct acting epoxides formed after metabolic activation OR SN2 >> Direct acting epoxides formed after metabolic activation >> Quinoline Derivatives OR SN2 >> DNA alkylation OR SN2 >> DNA alkylation >> Vicinal Dihaloalkanes OR SN2 >> Internal SN2 reaction with aziridinium and/or cyclic sulfonium ion formation (enzymatic) OR SN2 >> Internal SN2 reaction with aziridinium and/or cyclic sulfonium ion formation (enzymatic) >> Vicinal Dihaloalkanes OR SN2 >> Nucleophilic substitution after carbenium ion formation OR SN2 >> Nucleophilic substitution after carbenium ion formation >> Monohaloalkanes OR SN2 >> Nucleophilic substitution at sp3 Carbon atom OR SN2 >> Nucleophilic substitution at sp3 Carbon atom >> Haloalkanes Containing Heteroatom OR SN2 >> Nucleophilic substitution at sp3 carbon atom after thiol (glutathione) conjugation OR SN2 >> Nucleophilic substitution at sp3 carbon atom after thiol (glutathione) conjugation >> Geminal Polyhaloalkane Derivatives OR SN2 >> SN2 at an activated carbon atom OR SN2 >> SN2 at an activated carbon atom >> Quinoline Derivatives by DNA binding by OASIS v.1.3

Domain logical expression index: "h"

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

Domain logical expression index: "i"

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 >> 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 >> Polycyclic (PAHs) and heterocyclic (HACs) aromatic hydrocarbons-Michael addition OR Michael addition >> Polarised Alkenes-Michael addition OR Michael addition >> Polarised Alkenes-Michael addition >> Alpha, beta- unsaturated ketones OR SN1 OR SN1 >> Iminium Ion Formation OR SN1 >> Iminium Ion Formation >> Aliphatic tertiary amines OR SN1 >> Nitrenium Ion formation OR SN1 >> Nitrenium Ion formation >> Secondary aromatic amine OR SN2 OR SN2 >> SN2 at an sp3 Carbon atom OR SN2 >> SN2 at an sp3 Carbon atom >> Aliphatic halides by DNA binding by OECD

Domain logical expression index: "j"

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

Domain logical expression index: "k"

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 OR Strong binder, OH group OR Very strong binder, OH group OR Weak binder, OH group by Estrogen Receptor Binding

Domain logical expression index: "l"

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

Domain logical expression index: "m"

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 OR SNAr OR SNAr >> Nucleophilic aromatic substitution on activated aryl and heteroaryl compounds OR SNAr >> Nucleophilic aromatic substitution on activated aryl and heteroaryl compounds >> Activated aryl and heteroaryl compounds by Protein binding by OASIS v1.3

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 Group 14 - Carbon C AND Group 16 - Oxygen O by Chemical elements

Domain logical expression index: "r"

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

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/Alicyclic hydrocarbons (Alpha 2u-globulin nephropathy) Rank C OR Aromatic hydrocarbons (Liver enzyme induction) Rank C OR Perhexiline (Hepatotoxicity) Alert OR Tamoxifen (Hepatotoxicity) Alert by Repeated dose (HESS)

Domain logical expression index: "u"

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

Domain logical expression index: "v"

Referential boundary: The target chemical should be classified as Multi Cyclic Hydrocarbons by rtER Expert System ver.1 - USEPA

Domain logical expression index: "w"

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

Domain logical expression index: "x"

Referential boundary: The target chemical should be classified as Lactone Type Reactive Functional Groups by Oncologic Primary Classification

Domain logical expression index: "y"

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

Domain logical expression index: "z"

Referential boundary: The target chemical should be classified as alpha,beta-unsaturated aliphatic alkoxy group OR H-acceptor-path3-H-acceptor OR Oxolane by in vivo mutagenicity (Micronucleus) alerts by ISS

Domain logical expression index: "aa"

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

Domain logical expression index: "ab"

Referential boundary: The target chemical should be classified as Aliphatic monoalcohols by Eye irritation/corrosion Inclusion rules by BfR

Domain logical expression index: "ac"

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

Domain logical expression index: "ad"

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

Domain logical expression index: "ae"

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: "af"

Referential boundary: The target chemical should be classified as Acidic [0,10) OR No pKb value by Ionization at pH = 9

Domain logical expression index: "ag"

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

Domain logical expression index: "ah"

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

Domain logical expression index: "ai"

Parametric boundary:The target chemical should have a value of log Kow which is >= 2.07

Domain logical expression index: "aj"

Parametric boundary:The target chemical should have a value of log Kow which is <= 3.39

Interpretation of results:

other: not irritating

Conclusions:

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

Executive summary:

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

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

Based on the estimated results, 2-methylanisole can be considered to be not irritating to eyes and can be classified under the category “Not Classified” as per CLP regulation.

Endpoint conclusion:

no adverse effect observed (not irritating)

Endpoint conclusion:

no study available

Skin irritation:

In different studies, test chemical has 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 functionally similar read across substances. 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 dermal irritation potential was estimated for test chemical was 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 test chemical. Based on estimation, no severe skin irritation effects were known when test chemical was exposed to rabbit skin.

Results from both the estimations indicate a possibility of 2-methylanisole being not irritating to skin.

These results are further supported by the experimental study performed in an OECD GLP laboratory (Sustainability Support Services has letter of access) for the functionally similar read across substance. The study was conducted as per OECD guideline No. 404.Three healthy young adult male rabbits were used for the study. The hairs of all the rabbits were clipped at contralateral sites, approximately 24 hours prior to treatment. A dose of 500 mgof test item (moistened with 0.5 ml distilled water) was applied to the skin, over an area of approximately 6 x 6 cm clipped of hair on one side of rabbits. The other untreated side was kept as control area and 0.5 ml of distilled water was applied at this site. At the end of 4 hours, the gauze patch was removed and test item application site was wiped with water. Initially, the test item was applied to the clipped area of skin of one rabbit. The test site was covered with gauze patch. After 4 hours of exposure in animal no. 1, very slight erythema (barely perceptible) and no oedema observed at 1 hour of observation. At 24, 48 and 72 hours observation no erythema and oedema was observed in animal no 1.Hence the confirmatory test was conducted on additional two rabbits (No. 2 and 3)to confirm the non irritant nature of the test item. The patch was removed after 4 hours and rabbits were observed for erythema and oedema at 1, 24, 48 and 72 hours after patch removal, evaluated and graded as per Draize method. In animal no. 2 and 3 at 1 hour observation post patch removal, revealed very slight erythema (barely perceptible) and no oedema. At 24 hour animal no. 2 showed no erythema and oedema whereas animal no. 3 revealed very slight erythema (barely perceptible) and no oedema, At 48 and 72 hour post patch removal, both the animals recovered to normal. The individual mean score at 24, 48 and 72 hours for animal nos. 1, 2 and 3 were 0.00, 0.00, 0.33 and 0.00, 0.00, 0.00, for erythema and oedema formation, respectively.

Hence, it was concluded that test chemical was Non-Irritating to the skin of male New Zealand White rabbits under the experimental conditions tested and classified as "Not Classified" as per CLP criteria.

These results are further supported by the experimental study summarized in American Industrial Hygiene Association Journal, Volume 30, 1969 - Issue 5, Pages 470-476; for the functionally similar read across substance. Primary skin irritation on rabbits was recorded in a 10-grade ordinal series and was based upon the severest reaction that develops on the clipped abdominal skin of each of five albino rabbits within 24 hours of the uncovered application of 0.01 ml of undiluted sample or of solutions in water, propylene glycol, or acetone.

Grade 1 indicates no irritation and Grade 2 the least visible capillary injection from the undiluted chemical. Grade 6 indicates necrosis when undiluted and Grade 10 indicates necrosis from a 0.01% solution. Primary Irritation score after 24 hours for alpha methylbenzyl ether was Grade 1.

Based on this grade, test chemical can be considered not irritating to rabbit skin.

The dermal irritation potential of test article was determined according to the OECD 439 test guideline for this study. The MatTek EpiDerm™ model was used to assess the potential dermal irritation of the test article by determining the viability of the tissues following exposure to the test article via MTT. Tissues were exposed to the test article and controls for ~one hour, followed by a 42 hour post-exposure recovery period. The viability of each tissue was determined by MTT assay. The MTT data show the assay quality controls were met and passed the acceptance of criteria. The mean of OD for test chemical was determined to be 0.039.The standard deviation of viabilities for test chemical were calculated to be 0.08.The Mean % tissue viability compared to negative control (n=3) of the test chemical was determined to be 2.3%.Hence, under the current experimental test conditions it was concluded that test chemical was considered to be irritating to human skin and can thus be classified as “ Irritating to eyes in Category 2'' as per CLP Regulation.

Based on the available data for the target as well as read across chemicals and applying the weight of evidence approach, test chemical can be considered 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, test chemical has 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 functionally similar read across substances. 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 for test chemical was estimated to be not irritating to the eyes of New Zealand White rabbits.

This results is supported by the experimental study summarized in American Industrial Hygiene Association Journal, Volume 30, 1969 - Issue 5, Pages 470-476; for the functionally similar read across substance. Eye injury in rabbits is recorded in a 10- grade ordinal series and is based upon the degree of corneal necrosis that results from instillation of various volumes and concentrations of chemical. Grade 1 indicates at most a very small area of necrosis resulting from 0.5 ml of undiluted chemical in the eye. Grade 5 indicates a so-called severe burn from 0.005 ml, and Grade 10 indicates a severe burn from 0.5 ml of a 1% solution in water or propylene glycol. Primary Irritation score after 24 hours for alpha methylbenzyl ether was Grade 1.

In the acute eye irritation study conducted in albino rabbits, test chemical was considered to be not irritating to rabbit eyes.

These results are further supported by the experimental study summarized in American Industrial Hygiene Association Journal, Volume 30, 1969 - Issue 5, Pages 470-476; for the functionally similar read across substance. Eye injury in rabbits is recorded in a 10- grade ordinal series and is based upon the degree of corneal necrosis that results from instillation of various volumes and concentrations of chemical. Grade 1 indicates at most a very small area of necrosis resulting from 0.5 ml of undiluted chemical in the eye. Grade 5 indicates a so-called severe burn from 0.005 ml, and Grade 10 indicates a severe burn from 0.5 ml of a 1% solution in water or propylene glycol. Primary Irritation score after 24 hours for Ethyl vinyl ether was Grade 1.

In the acute eye irritation study conducted in albino rabbits, test chemical was considered to be not irritating to rabbit eyes.

The ocular irritation potential of test article was determined according to the OECD 492 test guideline for this study. The MatTek EpiOcular™ model was used to assess the potential ocular irritation of the test articles by determining the viability of the tissues following exposure to the test article via MTT. Tissues were exposed to liquid test articles and controls for ~30 minutes, followed by a ~12 minute post-soak and approximately 2 hour recovery after the post-soak. The viability of each tissue was determined by MTT assay. The MTT data show the assay quality controls were met, passing the acceptance criteria. The mean of OD for test chemical was determined to be 0.865.The mean % tissue viability of test chemical was determined to be 30.8%. Hence, under the experimental test conditions it was concluded that test chemical was considered to be irritating to the human eyes and and can thus be classified as “ Irritating to eyes in Category 2’’ as per CLP Regulation.

Based on the available data for the target as well as read across chemicals and applying the weight of evidence approach, test chemical can be considered not irritating to eyes.Comparing the above annotations with the criteria of CLP regulation, test chemical can be classified under the category “Not Classified”.

Based on the available information, test chemical is not likely to cause any irritation to eyes and skin. Hence, test chemical can be classified under the category “Not Classified” as per CLP regulation.