2,3,5-trimethylphenol

Endpoint summary

Description of key information

LD50 was estimated to be 2582 mg/kg bw when Gassner male and female rats were orally exposed with 2,3,5-trimethylphenol

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records

Reference

Endpoint:

acute toxicity: oral

Type of information:

(Q)SAR

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

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

Justification for type of information:

Data is predicted using OECD QSAR toolbox version 3.3 and the supporting QMRF report has been attached

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 401 (Acute Oral Toxicity)

Principles of method if other than guideline:

Prediction is done using QSAR Toolbox version 3.3

GLP compliance:

not specified

Test type:

acute toxic class method

Limit test:

no

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:

rat

Strain:

other: Gassner

Sex:

male/female

Details on test animals or test system and environmental conditions:

No data available

Route of administration:

oral: gavage

Vehicle:

other: aqueous Traganth

Details on oral exposure:

No data available

Doses:

2582 mg/kg bw

No. of animals per sex per dose:

10 male, 10 female

Control animals:

no

Details on study design:

No data available

Statistics:

No data available

Preliminary study:

No data available

Sex:

male/female

Dose descriptor:

LD50

Effect level:

2 582 mg/kg bw

Based on:

test mat.

Remarks on result:

other: 50% mortality observed

Mortality:

No data available

Clinical signs:

other: No data available

Gross pathology:

No data available

Other findings:

No data available

The prediction was based on dataset comprised from the following descriptors: LD50
Estimation method: Takes average value from the 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 "m" )  and ("n" and ( not "o") )  )  and ("p" and ( not "q") )  )  and ("r" and "s" )  )

Domain logical expression index: "a"

Referential boundary: The target chemical should be classified as Phenols (Acute toxicity) by US-EPA New Chemical Categories

Domain logical expression index: "b"

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

Domain logical expression index: "c"

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: "d"

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: "e"

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: "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 >>  Michael-type addition, quinoid structures OR AN2 >>  Michael-type addition, quinoid structures >> Quinoneimines OR Non-covalent interaction OR Non-covalent interaction >> DNA intercalation OR Non-covalent interaction >> DNA intercalation >> DNA Intercalators with Carboxamide Side Chain OR Non-covalent interaction >> DNA intercalation >> Fused-Ring Primary Aromatic Amines 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 >> Polynitroarenes OR Radical >> Radical mechanism via ROS formation (indirect) OR Radical >> Radical mechanism via ROS formation (indirect) >> Fused-Ring Primary Aromatic Amines 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) >> Nitrophenols, Nitrophenyl Ethers and Nitrobenzoic Acids OR Radical >> Radical mechanism via ROS formation (indirect) >> Single-Ring Substituted Primary Aromatic Amines OR Radical >> ROS formation after GSH depletion (indirect) OR Radical >> ROS formation after GSH depletion (indirect) >> Quinoneimines OR SN1 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 >> Fused-Ring Primary Aromatic Amines OR SN1 >> Nucleophilic attack after metabolic nitrenium ion formation >> Single-Ring Substituted Primary Aromatic Amines OR SN1 >> Nucleophilic attack after reduction and nitrenium ion formation 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 >> Nitrophenols, Nitrophenyl Ethers and Nitrobenzoic Acids OR SN1 >> Nucleophilic attack after reduction and nitrenium ion formation >> Polynitroarenes OR SN2 OR SN2 >> Alkylation, direct acting epoxides and related OR SN2 >> Alkylation, direct acting epoxides and related >> Epoxides and Aziridines 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 >> Alkylphosphates, Alkylthiophosphates and Alkylphosphonates OR SN2 >> Nucleophilic substitution at sp3 Carbon atom OR SN2 >> Nucleophilic substitution at sp3 Carbon atom >> Haloalkanes Containing Heteroatom OR SN2 >> SN2 at an activated carbon atom OR SN2 >> SN2 at an activated carbon atom >> Quinoline Derivatives 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.1.3

Domain logical expression index: "h"

Referential boundary: The target chemical should be classified as Michael addition AND Michael addition >> P450 Mediated Activation to Quinones and Quinone-type Chemicals AND Michael addition >> P450 Mediated Activation to Quinones and Quinone-type Chemicals >> Alkyl phenols by DNA binding by OECD

Domain logical expression index: "i"

Referential boundary: The target chemical should be classified as Acylation OR Acylation >> P450 Mediated Activation to Isocyanates or Isothiocyanates OR Acylation >> P450 Mediated Activation to Isocyanates or Isothiocyanates >> Benzylamines-Acylation 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 >> Polarised Alkenes-Michael addition OR Michael addition >> Polarised Alkenes-Michael addition >> Alpha, beta- unsaturated esters OR No alert found OR SN1 OR SN1 >> Carbenium Ion Formation OR SN1 >> Carbenium Ion Formation >> Allyl benzenes OR SN1 >> Iminium Ion Formation OR SN1 >> Iminium Ion Formation >> Aliphatic tertiary amines OR SN1 >> Nitrenium Ion formation OR SN1 >> Nitrenium Ion formation >> Aromatic azo OR SN1 >> Nitrenium Ion formation >> Aromatic nitro OR SN1 >> Nitrenium Ion formation >> Aromatic phenylureas OR SN1 >> Nitrenium Ion formation >> Primary aromatic amine OR SN1 >> Nitrenium Ion formation >> Tertiary aromatic amine by DNA binding by OECD

Domain logical expression index: "j"

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

Domain logical expression index: "k"

Referential boundary: The target chemical should be classified as Acylation OR Acylation >> Ester aminolysis OR Acylation >> Ester aminolysis >> Amides by Protein binding by OASIS v1.3

Domain logical expression index: "l"

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

Domain logical expression index: "m"

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

Domain logical expression index: "n"

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

Domain logical expression index: "o"

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

Domain logical expression index: "p"

Referential boundary: The target chemical should be classified as Known precedent reproductive and developmental toxic potential AND Toluene and small alkyl toluene derivatives (8a) by DART scheme v.1.0

Domain logical expression index: "q"

Referential boundary: The target chemical should be classified as Not known precedent reproductive and developmental toxic potential by DART scheme v.1.0

Domain logical expression index: "r"

Parametric boundary:The target chemical should have a value of log Kow which is >= 2.53

Domain logical expression index: "s"

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

Interpretation of results:

Category 5 based on GHS criteria

Conclusions:

LD50 was estimated to be 2582 mg/kg bw when Gassner male and female rats were orally exposed with 2,3,5-trimethylphenol.

Executive summary:

In a prediction done by SSS (2017) using the OECD QSAR toolbox with log kow as the primary descriptor, the acute oral toxicity was estimated for 2,3,5-trimethylphenol. The LD50 was estimated to be 2582 mg/kg bw when Gassner male and female rats were orally exposed with 2,3,5-trimethylphenol.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

2 582 mg/kg bw

Quality of whole database:

Data is Klimisch 2 and from OECD QSAR toolbox

Acute toxicity: via inhalation route

Endpoint conclusion

Endpoint conclusion:

no study available

Acute toxicity: via dermal route

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

Acute oral toxicity:

In different studies, 2,3,5-trimethylphenol has been investigated for acute oral toxicity to a greater or lesser extent. Often are the studies based on in vivo experiments and estimated data in rodents, i.e. most commonly in rats for 2,3,5-trimethylphenol along with the study available on structurally similar read across substance 2,4,6-trimethylphenol (527-60-6) and 2,3-dimethylphenol (526-75-0). The predicted data using the OECD QSAR toolbox has also been compared with the experimental studies.

In a prediction done by SSS (2017) using the OECD QSAR toolbox with log kow as the primary descriptor, the acute oral toxicity was estimated for 2,3,5-trimethylphenol. The LD50 was estimated to be 2582 mg/kg bw when Gassner male and female rats were orally exposed with 2,3,5-trimethylphenol.

In another experimental study given United States Environmental Protection Agency (High Production Volume Information System (HPVIS)| OPPT | US EPA) on structurally similar read across substance2,4,6-trimethylphenol (527-60-6), rattus norvegicus male and female rats were treated with Phenol, 2,4,6-trimethyl- in the concentration of 2000 mg/kg bw orally by gavage and observed for 14 days. No mortality was observed in treated male and female rat. Piloerection was observed in all test animals for the first day of the study. All signs of piloerection were resolved by Day 3 of the study in all but one animal, which was resolved by Day 4 of the study. No unusual clinical observations were observed for the rest of the study. All animals gained weight during the 14-day post-dose observation period. No unusual lesions were observed in treated male and female rat. Therefore, LD50 was estimated to > 2000 mg/kg bw when rattus norvegicus male and female rats were treated with Phenol, 2,4,6-trimethyl-orally by gavage.

Also it is further supported by experimental study given by EFSA Panel on Food Contact Materials, Enzymes, Flavourings and Processing Aids (CEF) (EFSA Journal 2011; 9(5):1990) on structurally similar read across substance 2,3-dimethylphenol (CAS no 526-75-0), rats were treated with 2,3-dimethylphenol in the concentration of 5000 mg/kg bw. More than 50 % mortality was observed in rats at 5000 mg/kg bw. Therefore, LD50 was considered to be < 5000 mg/kg bw when rats were treated with 2,3-dimethylphenol orally by gavage.

Thus, based on the above studies and predictions on 2,3,5-trimethylphenol and its read across substances, it can be concluded that LD50 value is greater than 2000 mg/kg bw. Thus, comparing this value with the criteria of CLP regulation, 2,3,5-trimethylphenol can be “Not classified” for acute oral toxicity.

Justification for classification or non-classification

Based on the above studies and predictions on 2,3,5-trimethylphenol and its read across substances, it can be concluded that LD50 value is greater than 2000 mg/kg bw. Thus, comparing this value with the criteria of CLP regulation, 2,3,5-trimethylphenol can be “Not classified” for acute oral toxicity.