2,3,5-trimethylphenol

Endpoint summary

Description of key information

Skin Irritation:

Skin irritation effects were estimated by four different models i.e, Battery, Leadscope, SciQSAR and CASE Ultra used within Danish QSAR database for 2,3,5 –trimethyl phenol. Based on estimation, severe skin irritation effects were known when 2,3,5 –trimethyl phenol was exposed to rabbit skin

Eye Irritation:

The ocular irritation potential of 2,3,5-trimethyl phenol was estimated using OECD QSAR toolbox v3.3 with logPow as the primary descriptor.

2,3,5-trimethyl phenol was estimated to be severely irritating to the eyes of New Zealand White rabbits.

Based on the estimated results, 2,3,5-trimethyl phenol can be considered to be severely irritating to eyes and can be classified under the category “Eye 2” as per CLP regulation

Key value for chemical safety assessment

Skin irritation / corrosion

Link to relevant study records

Reference

Endpoint:

skin irritation: in vivo

Type of information:

calculation (if not (Q)SAR)

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

accepted calculation method

Justification for type of information:

data is from modelling databases

Qualifier:

according to guideline

Guideline:

other: estimated data

Principles of method if other than guideline:

To estimate the skin irritation potential of 2,3,5-trimethyl phenol in rabbits

GLP compliance:

not specified

Specific details on test material used for the study:

- Name of test material (as cited in study report): 2, 3, 5-Trimethylphenol
- Molecular formula: C9H12O
-Molecular weight: 136.193 g/mol
- Smiles notation: c1(c(cc(C)cc1O)C)C
- InChl : 1S/C9H12O/c1-6-4-7(2)8(3)9(10)5-6/h4-5,10H,1-3H3
- Substance type: Organic
- Physical state: Solid

Species:

rabbit

Strain:

not specified

Details on test animals or test system and environmental conditions:

no data available

Type of coverage:

not specified

Preparation of test site:

not specified

Vehicle:

not specified

Controls:

not specified

Amount / concentration applied:

no data available

Duration of treatment / exposure:

no data available

Observation period:

no data available

Number of animals:

no data available

Details on study design:

no data available

Other effects / acceptance of results:

no data available

Irritation parameter:

overall irritation score

Basis:

mean

Time point:

other: no data available

Reversibility:

not specified

Remarks on result:

positive indication of irritation

Irritant / corrosive response data:

Severe irritation was estimated in rabbits

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

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

 

Where,

IN = inside applicability domain

Interpretation of results:

Category 2 (irritant) based on GHS criteria

Conclusions:

Severe skin irritation effects of 2,3,5 –trimethyl phenol were estimated in rabbit skin by four different models i.e, Battery, Leadscope, SciQSAR and CASE Ultra used within Danish QSAR database.

Executive summary:

Skin irritation effects were estimated by four different models i.e, Battery, Leadscope, SciQSAR and CASE Ultra used within Danish QSAR database for 2,3,5 –trimethyl phenol. Based on estimation, severe skin irritation effects were known when 2,3,5 –trimethyl phenol was exposed to rabbit skin.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed (irritating)

Eye irritation

Link to relevant study records

Reference

Endpoint:

eye irritation: in vivo

Type of information:

(Q)SAR

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

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

Justification for type of information:

data is from OECD QSAR toolbox v3.4 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 v3.4

GLP compliance:

not specified

Specific details on test material used for the study:

- Name of test material (as cited in study report): 2, 3, 5-Trimethylphenol
- Molecular formula: C9H12O
-Molecular weight: 136.193 g/mol
- Smiles notation: c1(c(cc(C)cc1O)C)C
- InChl : 1S/C9H12O/c1-6-4-7(2)8(3)9(10)5-6/h4-5,10H,1-3H3
- Substance type: Organic
- Physical state: Solid

Species:

rabbit

Strain:

New Zealand White

Details on test animals or tissues and environmental conditions:

no data available

Vehicle:

unchanged (no vehicle)

Controls:

not specified

Amount / concentration applied:

100 mg

Duration of treatment / exposure:

single administration

Observation period (in vivo):

24,48,72 hours and 7 days post instillation

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:

other: 24,48, 72 h and 7 days

Reversibility:

not specified

Remarks on result:

probability of severe irritation

Irritant / corrosive response data:

Severe irritation was observed

Estimation method: Takes mode value from the 5 nearest neighbours
Domain  logical expression:Result: In Domain

((((((("a" or "b" or "c" or "d") and("e" and(not "f")) ) and(("g" or "h" or "i" or "j") and("k" and(not "l")) ) and(("m" or "n" or "o" or "p") and("q" and(not "r")) ) ) and("s" and(not "t")) ) and "u") and "v") and("w" and "x") )

Domain logical expression index: "a"

Referential boundary:The target chemical should be classified as Alkyl arenes AND Aryl AND Phenol by Organic Functional groups

Domain logical expression index: "b"

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

Domain logical expression index: "c"

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

Domain logical expression index: "d"

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

Domain logical expression index: "e"

Referential boundary:The target chemical should be classified as No alert found by DNA binding by OASIS v.1.4

Domain logical expression index: "f"

Referential boundary:The target chemical should be classified as AN2 OR AN2 >>  Michael-type addition, quinoid structures OR AN2 >>  Michael-type addition, quinoid structures >> Flavonoids OR AN2 >>  Michael-type addition, quinoid structures >> Quinoneimines OR AN2 >>  Michael-type addition, quinoid structures >> Quinones and Trihydroxybenzenes OR AN2 >> Carbamoylation after isocyanate formation OR AN2 >> Carbamoylation after isocyanate formation >> Hydroxamic Acids OR AN2 >> Carbamoylation after isocyanate formation >> N-Hydroxylamines OR AN2 >> Michael-type addition on alpha, beta-unsaturated carbonyl compounds OR AN2 >> Michael-type addition on alpha, beta-unsaturated carbonyl compounds >> Four- and Five-Membered Lactones OR AN2 >> Michael-type conjugate addition to activated alkene derivatives OR AN2 >> Michael-type conjugate addition to activated alkene derivatives >> Alpha-Beta Conjugated Alkene Derivatives with Geminal Electron-Withdrawing Groups OR AN2 >> Nucleophilic addition reaction with cycloisomerization OR AN2 >> Nucleophilic addition reaction with cycloisomerization >> Hydrazine Derivatives 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 >> Polarized Haloalkene Derivatives 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 after aldehyde release OR AN2 >> Shiff base formation after aldehyde release >> Specific Acetate Esters OR AN2 >> Shiff base formation for aldehydes OR AN2 >> Shiff base formation for aldehydes >> Haloalkane Derivatives with Labile Halogen 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 AN2 >> Thioacylation via nucleophilic addition after cysteine-mediated thioketene formation >> Polarized Haloalkene Derivatives OR Non-covalent interaction OR Non-covalent interaction >> DNA intercalation OR Non-covalent interaction >> DNA intercalation >> Acridone, Thioxanthone, Xanthone and Phenazine Derivatives OR Non-covalent interaction >> DNA intercalation >> Amino Anthraquinones OR Non-covalent interaction >> DNA intercalation >> Aminoacridine DNA Intercalators OR Non-covalent interaction >> DNA intercalation >> Coumarins OR Non-covalent interaction >> DNA intercalation >> DNA Intercalators with Carboxamide and Aminoalkylamine Side Chain OR Non-covalent interaction >> DNA intercalation >> Fused-Ring Nitroaromatics OR Non-covalent interaction >> DNA intercalation >> Fused-Ring Primary Aromatic Amines OR Non-covalent interaction >> DNA intercalation >> Organic Azides OR Non-covalent interaction >> DNA intercalation >> Polycyclic Aromatic Hydrocarbon and Naphthalenediimide Derivatives OR Non-covalent interaction >> DNA intercalation >> Quinolone Derivatives OR Non-covalent interaction >> DNA intercalation >> Quinones and Trihydroxybenzenes OR Non-covalent interaction >> DNA intercalation >> Triarylimidazole and Structurally Related DNA Intercalators OR Non-specific OR Non-specific >> Incorporation into DNA/RNA, due to structural analogy with  nucleoside bases    OR Non-specific >> Incorporation into DNA/RNA, due to structural analogy with  nucleoside bases    >> Specific Imine and Thione Derivatives 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 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 by ROS formation >> Five-Membered Aromatic Nitroheterocycles OR Radical >> Radical mechanism by ROS formation >> Organic Azides OR Radical >> Radical mechanism via ROS formation (indirect) OR Radical >> Radical mechanism via ROS formation (indirect) >> Acridone, Thioxanthone, Xanthone and Phenazine Derivatives OR Radical >> Radical mechanism via ROS formation (indirect) >> Amino Anthraquinones OR Radical >> Radical mechanism via ROS formation (indirect) >> Anthrones OR Radical >> Radical mechanism via ROS formation (indirect) >> C-Nitroso Compounds OR Radical >> Radical mechanism via ROS formation (indirect) >> Conjugated Nitro Compounds OR Radical >> Radical mechanism via ROS formation (indirect) >> Coumarins OR Radical >> Radical mechanism via ROS formation (indirect) >> Diazenes and Azoxyalkanes OR Radical >> Radical mechanism via ROS formation (indirect) >> Flavonoids OR Radical >> Radical mechanism via ROS formation (indirect) >> Fused-Ring Nitroaromatics OR Radical >> Radical mechanism via ROS formation (indirect) >> Fused-Ring Primary Aromatic Amines OR Radical >> Radical mechanism via ROS formation (indirect) >> Geminal Polyhaloalkane Derivatives OR Radical >> Radical mechanism via ROS formation (indirect) >> Hydrazine Derivatives OR Radical >> Radical mechanism via ROS formation (indirect) >> N-Hydroxylamines OR Radical >> Radical mechanism via ROS formation (indirect) >> Nitro Azoarenes OR Radical >> Radical mechanism via ROS formation (indirect) >> Nitroaniline Derivatives OR Radical >> Radical mechanism via ROS formation (indirect) >> Nitroarenes with Other Active Groups OR Radical >> Radical mechanism via ROS formation (indirect) >> Nitrobiphenyls and Bridged Nitrobiphenyls OR Radical >> Radical mechanism via ROS formation (indirect) >> Nitrophenols, Nitrophenyl Ethers and Nitrobenzoic Acids OR Radical >> Radical mechanism via ROS formation (indirect) >> p-Aminobiphenyl Analogs OR Radical >> Radical mechanism via ROS formation (indirect) >> Polynitroarenes OR Radical >> Radical mechanism via ROS formation (indirect) >> p-Substituted Mononitrobenzenes OR Radical >> Radical mechanism via ROS formation (indirect) >> Quinones and Trihydroxybenzenes OR Radical >> Radical mechanism via ROS formation (indirect) >> Single-Ring Substituted Primary Aromatic Amines OR Radical >> Radical mechanism via ROS formation (indirect) >> Specific Imine and Thione Derivatives OR Radical >> Radical mechanism via ROS formation (indirect) >> Thiols OR Radical >> ROS formation after GSH depletion (indirect) OR Radical >> ROS formation after GSH depletion (indirect) >> Haloalcohols OR Radical >> ROS formation after GSH depletion (indirect) >> Quinoneimines OR SN1 OR SN1 >> Alkylation after metabolically formed carbenium ion species OR SN1 >> Alkylation after metabolically formed carbenium ion species >> Polycyclic Aromatic Hydrocarbon and Naphthalenediimide Derivatives OR SN1 >> Alkylation by carbenium ion formed OR SN1 >> Alkylation by carbenium ion formed >> Diazoalkanes OR SN1 >> Direct nucleophilic attack on diazonium cation (DNA alkylation) OR SN1 >> Direct nucleophilic attack on diazonium cation (DNA alkylation) >> Diazenes and Azoxyalkanes OR SN1 >> Nitrenium ion formation OR SN1 >> Nitrenium ion formation >> Sulfonyl Azides OR SN1 >> Nucleophilic attack after carbenium ion formation OR SN1 >> Nucleophilic attack after carbenium ion formation >> N-Nitroso Compounds OR SN1 >> Nucleophilic attack after carbenium ion formation >> Specific Acetate Esters OR SN1 >> Nucleophilic attack after diazonium or carbenium ion formation OR SN1 >> Nucleophilic attack after diazonium or carbenium ion formation >> Nitroarenes with Other Active Groups OR SN1 >> Nucleophilic attack after metabolic nitrenium ion formation OR SN1 >> Nucleophilic attack after metabolic nitrenium ion formation >> Amino Anthraquinones OR SN1 >> Nucleophilic attack after metabolic nitrenium ion formation >> Fused-Ring Primary Aromatic Amines OR SN1 >> Nucleophilic attack after nitrene formation OR SN1 >> Nucleophilic attack after nitrene formation >> Organic Azides OR SN1 >> Nucleophilic attack after nitrenium ion formation OR SN1 >> Nucleophilic attack after nitrenium ion formation >> N-Hydroxylamines OR SN1 >> Nucleophilic attack after nitrenium ion formation >> p-Aminobiphenyl Analogs OR SN1 >> Nucleophilic attack after nitrenium ion formation >> Single-Ring Substituted Primary Aromatic Amines OR SN1 >> Nucleophilic attack after nitrosonium cation formation OR SN1 >> Nucleophilic attack after nitrosonium cation formation >> N-Nitroso Compounds OR SN1 >> Nucleophilic attack after reduction and nitrenium ion formation OR SN1 >> Nucleophilic attack after reduction and nitrenium ion formation >> Conjugated Nitro Compounds OR SN1 >> Nucleophilic attack after reduction and nitrenium ion formation >> Fused-Ring Nitroaromatics OR SN1 >> Nucleophilic attack after reduction and nitrenium ion formation >> Nitro Azoarenes OR SN1 >> Nucleophilic attack after reduction and nitrenium ion formation >> Nitroaniline Derivatives OR SN1 >> Nucleophilic attack after reduction and nitrenium ion formation >> Nitroarenes with Other Active Groups OR SN1 >> Nucleophilic attack after reduction and nitrenium ion formation >> Nitrobiphenyls and Bridged Nitrobiphenyls OR SN1 >> Nucleophilic attack after reduction and nitrenium ion formation >> Nitrophenols, Nitrophenyl Ethers and Nitrobenzoic Acids OR SN1 >> Nucleophilic attack after reduction and nitrenium ion formation >> Polynitroarenes OR SN1 >> Nucleophilic attack after reduction and nitrenium ion formation >> p-Substituted Mononitrobenzenes OR SN1 >> Nucleophilic substitution after glutathione-induced nitrenium ion formation OR SN1 >> Nucleophilic substitution after glutathione-induced nitrenium ion formation >> C-Nitroso Compounds OR SN1 >> Nucleophilic substitution on diazonium ion OR SN1 >> Nucleophilic substitution on diazonium ion >> Specific Imine and Thione Derivatives OR SN2 OR SN2 >> Acylation OR SN2 >> Acylation >> Hydroxamic Acids OR SN2 >> Acylation >> N-Hydroxylamines OR SN2 >> Acylation >> Specific Acetate Esters OR SN2 >> Acylation involving a leaving group  OR SN2 >> Acylation involving a leaving group  >> Haloalkane Derivatives with Labile Halogen 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 OR SN2 >> Alkylation >> Alkylphosphates, Alkylthiophosphates and Alkylphosphonates OR SN2 >> Alkylation by epoxide metabolically formed after E2 reaction OR SN2 >> Alkylation by epoxide metabolically formed after E2 reaction >> Haloalcohols 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 cyclization OR SN2 >> Alkylation, direct acting epoxides and related after cyclization >> Nitrogen and Sulfur Mustards 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 >> Polarized Haloalkene Derivatives OR SN2 >> Alkylation, direct acting epoxides and related after P450-mediated metabolic activation >> Polycyclic Aromatic Hydrocarbon and Naphthalenediimide Derivatives OR SN2 >> Alkylation, nucleophilic substitution at sp3-carbon atom OR SN2 >> Alkylation, nucleophilic substitution at sp3-carbon atom >> Haloalkane Derivatives with Labile Halogen OR SN2 >> Alkylation, nucleophilic substitution at sp3-carbon atom >> Haloalkanes Containing Heteroatom OR SN2 >> Alkylation, nucleophilic substitution at sp3-carbon atom >> Sulfonates and Sulfates OR SN2 >> Alkylation, ring opening SN2 reaction OR SN2 >> Alkylation, ring opening SN2 reaction >> Four- and Five-Membered Lactones OR SN2 >> Direct acting epoxides formed after metabolic activation OR SN2 >> Direct acting epoxides formed after metabolic activation >> Coumarins 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 >> Direct nucleophilic attack on diazonium cation OR SN2 >> Direct nucleophilic attack on diazonium cation >> Hydrazine Derivatives 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 >> Specific Acetate Esters 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 OR SN2 >> SN2 at sp3 and activated sp2 carbon atom OR SN2 >> SN2 at sp3 and activated sp2 carbon atom >> Polarized Haloalkene Derivatives OR SN2 >> SN2 at sulfur atom OR SN2 >> SN2 at sulfur atom >> Sulfonyl Halides OR SN2 >> SN2 attack on activated carbon Csp3 or Csp2 OR SN2 >> SN2 attack on activated carbon Csp3 or Csp2 >> Nitroarenes with Other Active Groups by DNA binding by OASIS v.1.4

Domain logical expression index: "g"

Referential boundary:The target chemical should be classified as Alkyl arenes AND Aryl AND Phenol by Organic Functional groups

Domain logical expression index: "h"

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

Domain logical expression index: "i"

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

Domain logical expression index: "j"

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

Domain logical expression index: "k"

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

Domain logical expression index: "l"

Referential boundary:The target chemical should be classified as Moderate binder, NH2 group OR Moderate binder, OH grooup OR Non binder, impaired OH or NH2 group OR Non binder, MW>500 OR Non binder, non cyclic structure OR Non binder, without OH or NH2 group OR Strong binder, NH2 group OR Strong binder, OH group OR Very strong binder, OH group OR Weak binder, NH2 group by Estrogen Receptor Binding

Domain logical expression index: "m"

Referential boundary:The target chemical should be classified as Alkyl arenes AND Aryl AND Phenol by Organic Functional groups

Domain logical expression index: "n"

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

Domain logical expression index: "o"

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

Domain logical expression index: "p"

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

Domain logical expression index: "q"

Referential boundary:The target chemical should be classified as AN2 AND AN2 >> Michael-type addition to quinoid structures  AND AN2 >> Michael-type addition to quinoid structures  >> Substituted Phenols by Protein binding by OASIS v1.4

Domain logical expression index: "r"

Referential boundary:The target chemical should be classified as Acylation OR Acylation >> (Tio)carbamoylation of protein nucleophiles OR Acylation >> (Tio)carbamoylation of protein nucleophiles >> Isothiocyanates, Isocyanates OR Acylation >> Acylation involving an activated (glucuronidated) carboxamide group OR Acylation >> Acylation involving an activated (glucuronidated) carboxamide group >> Carboxylic Acid Amides OR Acylation >> Acylation involving an activated (glucuronidated) ester group OR Acylation >> Acylation involving an activated (glucuronidated) ester group >> Arenecarboxylic Acid Esters OR Acylation >> Acylation involving an activated (glucuronidated) sulfonamide group OR Acylation >> Acylation involving an activated (glucuronidated) sulfonamide group >> Arenesulfonamides OR Acylation >> Direct acylation involving a leaving group OR Acylation >> Direct acylation involving a leaving group >> (Thio)Acetates  OR Acylation >> Direct acylation involving a leaving group >> (Thio)Acyl and (thio)carbamoyl halides and cyanides  OR Acylation >> Direct acylation involving a leaving group >> Anhydrides (sulphur analogues of anhydrides)  OR Acylation >> Direct acylation involving a leaving group >> Azlactones and unsaturated lactone derivatives  OR Acylation >> Direct acylation involving a leaving group >> Carbamates  OR Acylation >> Direct acylation involving a leaving group >> Carboxylic Acid Amides OR Acylation >> Direct acylation involving a leaving group >> N-Carbonyl heteroaryl amines OR Acylation >> Direct acylation involving a leaving group >> N-Carbonylsulfonamides OR Acylation >> Direct acylation involving a leaving group >> Sulphonyl halides or cyanides  OR Acylation >> Ester aminolysis OR Acylation >> Ester aminolysis >> Amides OR Acylation >> Ester aminolysis >> Dithiocarbamates OR Acylation >> Ester aminolysis >> Dithioesters  OR Acylation >> Ester aminolysis or thiolysis OR Acylation >> Ester aminolysis or thiolysis >> Activated aryl esters  OR Acylation >> Ester aminolysis or thiolysis >> Carbamates  OR Acylation >> Ring opening acylation OR Acylation >> Ring opening acylation >> Active cyclic agents  OR Acylation >> Ring opening acylation >> beta-Lactams  OR AN2 >> Michael addition to activated double bonds OR AN2 >> Michael addition to activated double bonds >> alpha,beta-Unsaturated Carbonyls and Related Compounds OR AN2 >> Michael addition to activated double bonds in heterocyclic ring systems OR AN2 >> Michael addition to activated double bonds in heterocyclic ring systems >> Pyrazolone and Pyrazolidine Derivatives OR AN2 >> Michael addition to alpha, beta-unsaturated acids and esters OR AN2 >> Michael addition to alpha, beta-unsaturated acids and esters >> alpha,beta-Unsaturated Carboxylic Acids and Esters OR AN2 >> Michael type addition to activated double bond of pyrimidine bases OR AN2 >> Michael type addition to activated double bond of pyrimidine bases >> Pyrimidines and Purines OR AN2 >> Michael-type addition to activated double bonds in vinyl pyridines OR AN2 >> Michael-type addition to activated double bonds in vinyl pyridines >> Ethenyl Pyridines OR AN2 >> Michael-type addition to quinoid structures  >> Carboxylic Acid Amides OR AN2 >> Michael-type addition to quinoid structures  >> Gallic Acid Esters OR AN2 >> Michael-type addition to quinoid structures  >> Hydroxylated Phenols OR AN2 >> Michael-type addition to quinoid structures  >> N-Substituted Aromatic Amines OR AN2 >> Michael-type addition to quinoid structures  >> Quinoneimine OR AN2 >> Michael-type addition to quinoid structures  >> Substituted Anilines OR AN2 >> Nucleophilic addition at polarized N-functional double bond OR AN2 >> Nucleophilic addition at polarized N-functional double bond >> Arenesulfonamides OR AN2 >> Nucleophilic addition to pyridonimine tautomer of aminopyridoindoles or aminopyridoimidazoles (hypothesized) OR AN2 >> Nucleophilic addition to pyridonimine tautomer of aminopyridoindoles or aminopyridoimidazoles (hypothesized) >> Heterocyclic Aromatic Amines OR AN2 >> Schiff base formation with carbonyl compounds (AN2) OR AN2 >> Schiff base formation with carbonyl compounds (AN2) >> Pyrazolone and Pyrazolidine Derivatives OR AN2 >> Schiff base formation with carbonyl group of pyrimidine and purine bases OR AN2 >> Schiff base formation with carbonyl group of pyrimidine and purine bases >> Pyrimidines and Purines OR AN2 >> Thiocarbamoylation of protein nucleophiles OR AN2 >> Thiocarbamoylation of protein nucleophiles >> Isothiocyanates OR AR OR AR >>  Radical-type addition to imino tautomer of aminoacridines OR AR >>  Radical-type addition to imino tautomer of aminoacridines >> Benzoquinoline and Аcridine derivatives OR Ionic interaction OR Ionic interaction >> Electrostatic interaction of tetraalkylamonium ion with protein carboxylates OR Ionic interaction >> Electrostatic interaction of tetraalkylamonium ion with protein carboxylates >> Tetraalkylammonium ions OR Michael addition OR Michael addition >> Michae addition on quinoide type compounds OR Michael addition >> Michae addition on quinoide type compounds >> Quinone methide(s)/imines; Quinoide oxime structure; Nitroquinones, Naphthoquinone(s)/imines  OR Michael addition >> Michael addition on alpha,beta-Unsaturated carbonyl compounds OR Michael addition >> Michael addition on alpha,beta-Unsaturated carbonyl compounds >> alpha,beta-Aldehydes  OR Michael addition >> Michael addition on conjugated systems with electron withdrawing group OR Michael addition >> Michael addition on conjugated systems with electron withdrawing group >> Activated electrophilic ethenylarenes  OR Michael addition >> Michael addition on conjugated systems with electron withdrawing group >> alpha,beta-Carbonyl compounds with polarized double bonds  OR Michael addition >> Michael addition on conjugated systems with electron withdrawing group >> Conjugated systems with electron withdrawing groups  OR Michael addition >> Michael addition on conjugated systems with electron withdrawing group >> Cyanoalkenes OR Michael addition >> Michael addition on conjugated systems with electron withdrawing group >> Nitroalkenes OR Michael addition >> Michael addition on polarised Alkenes OR Michael addition >> Michael addition on polarised Alkenes >> Polarised Alkene - alkenyl pyridines, pyrazines, pyrimidines or triazines  OR Michael addition >> Michael addition on polarised Alkenes >> Polarised Alkenes - sulfonates  OR Michael addition >> Michael addition on polarised Alkenes >> Polarised Alkenes - sulfones  OR No alert found OR Nucleophilic addition OR Nucleophilic addition >> Addition to carbon-hetero double bonds OR Nucleophilic addition >> Addition to carbon-hetero double bonds >> Ketones OR Nucleophilic addition >> Nucleophilic addition reaction at polarized N-functional double bond OR Nucleophilic addition >> Nucleophilic addition reaction at polarized N-functional double bond >> C-Nitroso compounds  OR Radical reactions OR Radical reactions >> Free radical formation OR Radical reactions >> Free radical formation >> Organic peroxy compounds OR Radical reactions >> ROS Generation OR Radical reactions >> ROS Generation >> Sterically Hindered Piperidine Derivatives OR Radical reactions >> ROS generation and direct attack of hydroxyl radical to the C8 position of nucleoside base OR Radical reactions >> ROS generation and direct attack of hydroxyl radical to the C8 position of nucleoside base >> Heterocyclic Aromatic Amines OR Schiff base formation OR Schiff base formation >> Direct acting Schiff base formers OR Schiff base formation >> Direct acting Schiff base formers >> 1,2-Dicarbonyls and 1,3-Dicarbonyls  OR Schiff base formation >> Schiff base formation with carbonyl compounds OR Schiff base formation >> Schiff base formation with carbonyl compounds >> Aldehydes OR Schiff base formation >> Schiff base formation with carbonyl compounds >> Aromatic carbonyl compounds OR Schiff base formation >> Schiff base on pyrazolones and pyrazolidinones OR Schiff base formation >> Schiff base on pyrazolones and pyrazolidinones >> Pyrazolones and Pyrazolidinones 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 SN1 OR SN1 >> Carbenium ion formation (enzymatic) OR SN1 >> Carbenium ion formation (enzymatic) >> Carbenium ion OR SN1 >> DNA and protein alkylation via the formation of alkyldiazonium ion OR SN1 >> DNA and protein alkylation via the formation of alkyldiazonium ion >> N-Nitrosoamine  Derivatives OR SN1 >> Nucleophilic substitution (SN1) on alkyl (aryl) mercury cations OR SN1 >> Nucleophilic substitution (SN1) on alkyl (aryl) mercury cations >> Mercury compounds  OR SN2 OR SN2 >> Cyanoalkylation of proteins via the nucleophilic substitution at sp3-carbon atom of cyanohydrins OR SN2 >> Cyanoalkylation of proteins via the nucleophilic substitution at sp3-carbon atom of cyanohydrins >> Cyanohydrins OR SN2 >> DNA and protein alkylation via the formation of alkyldiazonium ion OR SN2 >> DNA and protein alkylation via the formation of alkyldiazonium ion >> N-Nitrosoamine  Derivatives OR SN2 >> Interchange reaction with sulphur containing compounds OR SN2 >> Interchange reaction with sulphur containing compounds >> Thiols and disulfide compounds  OR SN2 >> Nucleophilic substitution at a Nitrogen atom OR SN2 >> Nucleophilic substitution at a Nitrogen atom >> N-Nitroso compounds  OR SN2 >> Nucleophilic substitution at sp3 carbon atom OR SN2 >> Nucleophilic substitution at sp3 carbon atom >> Alkyl halides  OR SN2 >> Nucleophilic substitution at sp3 carbon atom >> alpha-Activated haloalkanes  OR SN2 >> Nucleophilic substitution at sp3 carbon atom >> N-Nitroso compounds  OR SN2 >> Nucleophilic substitution at sp3 carbon atom >> Phosphonates OR SN2 >> Nucleophilic substitution at the central carbon atom of N-nitroso compounds OR SN2 >> Nucleophilic substitution at the central carbon atom of N-nitroso compounds >> N-Nitroso_compounds  OR SN2 >> Nucleophilic substitution on benzilyc carbon atom OR SN2 >> Nucleophilic substitution on benzilyc carbon atom >> alpha-Activated benzyls  OR SN2 >> Protein and/or DNA alkylation OR SN2 >> Protein and/or DNA alkylation >> Dialkyl Alkylphosphonates OR SN2 >> Protein azidation via an SN2-like reaction OR SN2 >> Protein azidation via an SN2-like reaction >> Organic sulfonyl azides  OR SN2 >> Ring opening nucleophilic substitution involving arene oxide derivatives and proteins OR SN2 >> Ring opening nucleophilic substitution involving arene oxide derivatives and proteins >> Benzoquinoline and Аcridine derivatives OR SN2 >> Ring opening SN2 reaction OR SN2 >> Ring opening SN2 reaction >> Epoxides, Aziridines and Sulfuranes  OR SN2 >> Ring opening SN2 reaction >> Mustard compounds  OR SN2 >> SN2 Reaction at a sp3 carbon atom OR SN2 >> SN2 Reaction at a sp3 carbon atom >> Activated alkyl esters and thioesters  OR SN2 >> SN2 reaction at a sulfur atom OR SN2 >> SN2 reaction at a sulfur atom >> Thiocyanates OR SN2 >> Thiocyanate formation via the nucleophilic-type substitution at the disulfide bond of proteins and enzymes OR SN2 >> Thiocyanate formation via the nucleophilic-type substitution at the disulfide bond of proteins and enzymes >> Cyanohydrins 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 OR SNAr >> Nucleophilic substitution on activated Csp2-atoms in quinolines OR SNAr >> Nucleophilic substitution on activated Csp2-atoms in quinolines >> Benzoquinoline and Аcridine derivatives OR SNVinyl OR SNVinyl >> SNVinyl at a vinylic (sp2) carbon atom OR SNVinyl >> SNVinyl at a vinylic (sp2) carbon atom >> Vinyl type compounds with electron withdrawing groups  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 by OASIS v1.4

Domain logical expression index: "s"

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

Domain logical expression index: "t"

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

Domain logical expression index: "u"

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

Domain logical expression index: "v"

Similarity boundary:Target: Cc1cc(C)cc(O)c1C
Threshold=30%,
Dice(Atom centered fragments)
Atom type; Count H attached; Hybridization

Domain logical expression index: "w"

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

Domain logical expression index: "x"

Parametric boundary:The target chemical should have a value of log Kow which is <= 3.97

Interpretation of results:

Category 2 (irritating to eyes) based on GHS criteria

Conclusions:

2,3,5-trimethyl phenol was estimated to be severely irritating to the eyes of New Zealand White rabbits.

Executive summary:

The ocular irritation potential of 2,3,5-trimethyl phenol was estimated using OECD QSAR toolbox v3.3 with logPow as the primary descriptor.

2,3,5-trimethyl phenol was estimated to be severely irritating to the eyes of New Zealand White rabbits.

Based on the estimated results, 2,3,5-trimethyl phenol can be considered to be severely irritating to eyes and can be classified under the category “Eye 2” as per CLP regulation

Endpoint conclusion

Endpoint conclusion:

adverse effect observed (irritating)

Respiratory irritation

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

Skin Irritation:

In different studies, 2,3,5-trimethyl phenol 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 2,3,5-trimethyl phenol and its functionally similar read across substances p-nonylphenol (CAS: 104-40-5) and o-cresol (CAS:95-48-7). The predicted data using the OECD QSAR toolbox has also been compared with the experimental data.

 

Skin irritation effects were estimated by four different models i.e, Battery, Leadscope, SciQSAR and CASE Ultra used within Danish QSAR database for 2,3,5 –trimethyl phenol. Based on estimation, severe skin irritation effects were known when 2,3,5 –trimethyl phenol was exposed to rabbit skin.

In a prediction done by SSS (2017) using the OECD QSAR toolbox with log kow as the primary descriptor, the skin irritation potential was estimated for 2,3,5-trimethyl phenol. 2,3,5-trimethyl phenol was estimated to be severely irritating to the skin of rabbits.

These results are further supported by the experimental study conducted by Union Carbide Corp (OTS0573384, submitted by UNION CARBIDE CORP, last updated 09/10/82) for the functionally similar read across substance p-nonyl phenol (CAS: 104-40-5). The study was conducted according to DOT regulation 173.1300 Appendix A – Method of Testing Corrosion to Skin (46 FR 49889, October 8. 1981, and effective July 1, 1982) Guidelines in 6 young adult New Zealand White albino rabbits to assess the skin corrosive potential of 4-nonyl phenol. On the day before dosing the hair of each rabbit was closely clipped from the back with an electric clipper, so as to expose the back from the scapular to the lumbar region. The skin at the site remained intact; no abrasions were made.

There was one test site per animal, on the left side of the spinal column. Five-tenths milliliter (0.5 ml) of p-nonyl phenol applied beneath a surgical gauze square, 1inch*1inch was placed directly on the test site and held in place with tape. Plastic sheeting was then wrapped around the animals and secured with tape to retard evaporation and keep the test substance in contact with the skin without undue pressure. Following approximately 4 hours of exposure, the wrappings and gauze squares were removed and the test si tes wiped free of excess test material with castille soap and water. Observations were made for erythema and edema or other evidence of dermal irritation or injury 30 minutes after removal of the occlusive wrapping. i.e., approximately 4.5 hours. Irritation generally consisted of slight or very slight erythema and edema at 4 hours. At termination of the study (48 hours), however all animals exhibited evidence of corrosivity and tissue damage {necrotic skin). The Primary Irritation Index after 48 hours was 4.9.

Based on the score and observations, 4-nonylphenol was considered to be corrosive to skin.

The above results are also supported by the experimental study summarized in International Journal of Toxicology; Volume: 25 issue: 1_suppl, page(s): 29-127; 2006, for the functionally similar read across substance, o-cresol (CAS: 95-48-7). Undiluted o-cresol (volume not specified) was applied to the intact and abraded skin of 6 albino rabbits and effects were observed till 72 hours. Erythema and edema were scored at 24 and 72 hours. Erythema and edema was observed in all rabbits. The Primary dermal irritation score of o-cresol was 8.0(maximum score = 8.0).

Based on the scores and observations, o-cresol can be considered severely irritating to albino rabbit skin.

Based on the available data for the target as well as read across substances and applying the weight of evidence approach,2,3,5-trimethyl phenol was irritating to skin.Comparing the above annotations with the criteria of CLP regulation, test chemical can be classified under the category “Skin 2”.

 

Eye Irritation:

In different studies, 2,3,5-trimethyl phenol 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 human data for target chemical 2,3,5-trimethyl phenol and its functionally similar read across substances p-nonylphenol (CAS: 104-40-5) and o-cresol (CAS:95-48-7). 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 2,3,5-trimethyl phenol. 2,3,5-trimethyl phenol was estimated to be severely irritating to the eyes of New Zealand White rabbits.

This result is supported by the experimental study conducted by MONSANTO CO (OTS0538590, submitted by MONSANTO CO, last updated August 1992) for the functionally similar read across substance p-nonyl phenol (CAS: 104-40-5). The study was performed according to F.H.S.A guidelines.

0.1 ml undiluted p-nonylphenol was instilled into the eyes of 6 New Zealand Albino rabbits for 24 hours. The rabbits were observed for damage to cornea, iris and conjunctivae till 21 days and scored. The following observations were noted till 21 days of observation after instillation of p-nonyl phenol. At 10 minutes, moderate erythema, copious discharge. 1 hour: iris congestion, severe erythema, slight edema , copious discharge. 24 hours: Areas of slight corneal cloudiness, iris showed little or no reaction to light, severe erythema (necrosis), slight to moderate edema . 48- 168 hr: copious discharge with whitish exudates 10 days; slight ulceration in 5 rabbits and 21 days: slight ulceration in 2 rabbits, four scored zero. The mean irritation score for p-nonylphenol at 1, 24, 48, 72, 120 and 168 hours of observation were 21.0, 65.5, 64.8, 44.3, 40.1 and 33.6 respectively. The average irritation score after 72 hours was 58.2.

Based on the scores, p-nonyl phenol was considered to be moderately irritating to rabbit eyes.

The above results are also supported by the experimental study summarized in International Journal of Toxicology; Volume: 25 issue: 1_suppl, page(s): 29-127; 2006, for the functionally similar read across substance, o-cresol (CAS: 95-48-7). Undiluted, 0.1 ml o-cresol was instilled in to the eyes of 9 albino rabbits. Group I had 6 albino rabbits whose eyes remained unwashed throughout the test and Group II had 3 rabbits whose eyes were rinsed 4 seconds after instillation of test chemical.The eyes were scored for damage to cornea, iris and conjunctivae upto 72 hours post instillation. Corneal, iridial and conjunctival effects were observed in all animals (group I and II) throughout the 72 hours observation period.

Hence, o-cresol was considered to be severely irritating to rabbit eyes with or without 4 second washing after instillation.

 

Based on the available data for the target as well as read across substances and applying the weight of evidence approach,2,3,5-trimethyl phenol was irritating to eyes.Comparing the above annotations with the criteria of CLP regulation, test chemical can be classified under the category “Eye 2”.

Justification for classification or non-classification

Available data for2,3,5-trimethyl phenol suggests that it is likely to cause moderate to severe irritation to eyes and skin.

2,3,5-trimethyl phenol can be classified under the category “Skin 2” and “Eye 2” as per CLP regulation.