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Diss Factsheets

Toxicological information

Basic toxicokinetics

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Administrative data

Endpoint:
basic toxicokinetics in vivo
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment

Data source

Referenceopen allclose all

Reference Type:
publication
Title:
Unnamed
Year:
1987
Reference Type:
review article or handbook
Title:
The biochemistry of foreign compounds, Internat. series of monographs in pure and applied biology 5
Author:
Parke DV
Year:
1968
Bibliographic source:
Oxford; Pergamon Press, p. 147-148

Materials and methods

Objective of study:
metabolism
Test guideline
Qualifier:
no guideline followed
Principles of method if other than guideline:
Thymol was dissolved in propylene glycol (1-2 ml) and given 6 male albino rats per stomach tube at a dose level of 1 mmol/kg bw (ca. 150 mg/kg bw). Similar animals receiving solvent only served as controls. Urine samples were collected at -10°C at 24 hours intervals and anaylsed by chromatography after conjugate hydrolysis.
GLP compliance:
not specified

Test material

Constituent 1
Chemical structure
Reference substance name:
Thymol
EC Number:
201-944-8
EC Name:
Thymol
Cas Number:
89-83-8
Molecular formula:
C10H14O
IUPAC Name:
5-methyl-2-(propan-2-yl)phenol
Test material form:
solid
Radiolabelling:
no

Test animals

Species:
rat
Strain:
Wistar
Sex:
male
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Mollegaards Breeding Centre Ltd., Ejby, Denmark
- Weight at study initiation: 250 - 350 g
- Diet (e.g. ad libitum): ad libitum. They were switched from a standard pellet diet to a purified diet two days before dosing and during the experiments in order to reduce the number of normal chromatographic peaks in the urine extracts.

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
propylene glycol
Details on exposure:
PREPARATION OF DOSING SOLUTIONS:
The test compounds was dissolved in propylene glycol (1-2 mL) and given by stomach tube at a dose level of 1 mmol/kg.
Duration and frequency of treatment / exposure:
Single application
Doses / concentrations
Dose / conc.:
150.22 mg/kg bw/day
Remarks:
1 mmol = 150.22 mg/kg bw
No. of animals per sex per dose / concentration:
6
Control animals:
yes, concurrent vehicle
Details on dosing and sampling:
METABOLITE CHARACTERISATION STUDIES
- Tissues and body fluids sampled: urine
- Time and frequency of sampling: 24 h intervals
- From how many animals (samples pooled or not) : 6 animals, not pooled
- Method type(s) for identification: GLC-MS

TREATMENT FOR CLEAVAGE OF CONJUGATES (if applicable): conjugate hydrolysis using a glucuronidase + sulphatase preparation

ANALYTICAL METHOD
- Complete description including: The capillary GLC columns employed were prepared in using SE-54 (bonded phase), OV-1701 (bonded phase), Pluronic 64 and Emulphor. TMS-derivatives were chromatographed using 20 m SE-54 column (0.32 mm x 20 m) at 100°C for 2 min., then increasing at 8°C/min to 260°C. Methyl ester-derivatives chromatographed using OV-1701 column (0.29 mm x 30 m) at 100°C, then increasing at 8°C/min to 250°C. Mass spectra recorded from > m/z 80 (TMS-derivatives) or > m/z 50 (methyl ester-derivatives).

Results and discussion

Main ADME results
Type:
metabolism
Results:
Oxidation of the methyl and isopropyl groups occurred. This resulted in the formation of derivatives of benzyl alcohol and 2-phenylpropanol and their corresponding carboxylic acids. In contrast, ring hydroxylation of the two phenols was a minor reaction.

Toxicokinetic / pharmacokinetic studies

Details on excretion:
The urinary excretion of metabolites were rapid. Only very small amounts were excreted after 24 h.

Metabolite characterisation studies

Metabolites identified:
yes
Details on metabolites:
In the 24 h rat urine the following metabolites were identified:
2.5-Dihydroxy-p-cymene, 2-(2-hydroxy-4-methylphenyl)propan-1-ol, 5-Hxdroxymethyl)-2-(1-methylethyl)phenol, 2-(4-Hydroxymethyl-2-hydroxyphenyl)propan-1-ol, 2-(2-Hydroxy-4-methylphenyl)propionic acid, 3-Hydroxy-4-(1-methylethyl)benzoic acid (please refer to attached figure)

Any other information on results incl. tables

The urinary excretion of metabolites were rapid. Only very small amounts were excreted after 24 h. Although large quantities of thymol was excreted unchanged (or as their glucuronide and sulfate conjugates), extensive oxidation of the methyl and isopropyl groups also occurred. This resulted in the formation of derivatives of benzyl alcohol and 2-phenylpropanol and their corresponding carboxylic acids. In contrast, ring hydroxylation of the two phenols was a minor reaction.

The following metabolites were identified: 2.5-Dihydroxy-p-cymene, 2-(2-hydroxy-4-methylphenyl)propan-1-ol, 5-Hxdroxymethyl)-2-(1-methylethyl)phenol, 2-(4-Hydroxymethyl-2-hydroxyphenyl)propan-1-ol, 2-(2-Hydroxy-4-methylphenyl)propionic acid, 3-Hydroxy-4-(1-methylethyl)benzoic acid (please refer to attached figure).

Applicant's summary and conclusion

Conclusions:
The urinary excretion of metabolites were rapid. Only very small amounts were excreted after 24 h. Although large quantities of thymol was excreted unchanged (or as their glucuronide and sulfate conjugates), extensive oxidation of the methyl and isopropyl groups also occurred. This resulted in the formation of derivatives of benzyl alcohol and 2-phenylpropanol and their corresponding carboxylic acids. In contrast, ring hydroxylation of the two phenols was a minor reaction.
Executive summary:

Thymol was dissolved in propylene glycol (1-2 mL) and given 6 male albino rats per stomach tube at a dose level of 1 mmol/kg bw (ca. 150 mg/kg bw). Similar animals receiving solvent only served as controls. Urine samples were collected at -10°C at 24 hours intervals and analysed by chromatography after conjugate hydrolysis.

The urinary excretion of metabolites were rapid. Only very small amounts were excreted after 24 h. Although large quantities of thymol was excreted unchanged (or as their glucuronide and sulfate conjugates), extensive oxidation of the methyl and isopropyl groups also occurred. This resulted in the formation of derivatives of benzyl alcohol and 2-phenylpropanol and their corresponding carboxylic acids. In contrast, ring hydroxylation of the two phenols was a minor reaction. The following metabolites were identified: 2.5-Dihydroxy-p-cymene, 2-(2-hydroxy-4-methylphenyl)propan-1-ol, 5-Hxdroxymethyl)-2-(1-methylethyl)phenol, 2-(4-Hydroxymethyl-2-hydroxyphenyl)propan-1-ol, 2-(2-Hydroxy-4-methylphenyl)propionic acid, 3-Hydroxy-4-(1-methylethyl)benzoic acid.