1,2,4-trimethylbenzene

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics in vivo

Type of information:

migrated information: read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

supporting study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Non-guideline experimental study with clearly reported methods and results. Adequate for assessment.

Data source

Reference

Reference Type:

publication

Title:

Excretion of unchanged volatile organic compounds (toluene, ethylbenzene, xylene and mesitylene) in urine as result of experimental human volunteer exposure.

Author:

Janasik, B, Jakubowski, M, and Jalowiecki, P

Year:

2008

Bibliographic source:

Int. Arch. Occup. Environ. Health 81: 443-449.

Materials and methods

Objective of study:

excretion

Test guideline

Qualifier:

no guideline available

Principles of method if other than guideline:

The elimination kinetics of unchanged 1,3,5-trimethylbenzene in human urine was examined in six male volunteers exposed by inhalation to 1,3,5-trimethylbenzene. In addition, the relationship between air concentration of 1,3,5-trimethylbenzene and its concentration in urine and blood and the urinary concentration of its metabolite 3,5-dimethylbenzoic acid, was determined.

GLP compliance:

not specified

Test material

Test material information

Constituent 1

Reference substance name:

Mesitylene

EC Number:

203-604-4

EC Name:

Mesitylene

Cas Number:

108-67-8

Molecular formula:

C9H12

IUPAC Name:

1,3,5-trimethylbenzene

Constituent 2

Reference substance name:

1,3,5-Trimethylbenzene

IUPAC Name:

1,3,5-Trimethylbenzene

Details on test material:

- Name of test material (as cited in study report): Mesitylene
- Analytical purity: Not stated.

Test animals

Species:

human

Sex:

male

Details on test animals or test system and environmental conditions:

Age of volunteers was between 20 and 28 years.

Administration / exposure

Route of administration:

inhalation: vapour

Vehicle:

other: air

Details on exposure:

TYPE OF INHALATION EXPOSURE: whole body

GENERATION OF TEST ATMOSPHERE / CHAMPER DESCRIPTION
- Exposure apparatus: 117 cubic meter exposure chamber
- Air turnover rate: 350 m3/hr
- System of generating vapours: Vapour generation was based on continuous injection of liquid substance into the pressed air stream, with controlled speed.

Duration and frequency of treatment / exposure:

A single 4 or 8 hr exposure.

Doses / concentrations

Remarks:

Doses / Concentrations:
200 mg/m3 (25 ppm) for the 4-hr study; 20, 60 or 100 mg/m3 (5, 15, or 25 ppm) for the 8-hr study.

No. of animals per sex per dose / concentration:

6 male volunteers

Control animals:

no

Details on dosing and sampling:

4-HR EXPOSURE STUDY
Urine samples were collected at the following time points: before exposure, every 2 hr of exposure, and up to 24 hr from the onset of exposure.

8-HR EXPOSURE STUDY
Capillary blood samples obtained from the finger tips were collected before the start of exposure and at 30 min after termination of exposure. Urine samples were collected before exposure and for the last two hours of exposure.

Statistics:

Statistical analysis was carried out using StatGraphics Plus for Windows 4.1. Linear regression analysis was applied to examine the correlation between exposure parameters.

Results and discussion

Toxicokinetic / pharmacokinetic studies

Details on excretion:

The average percentage of the dose excreted as unchanged 1,3,5-trimethylbenzene in urine during the 4-hr exposure period and up to 24 hr post-exposure was 0.0012% (range: 0.00095% to 0.0047%). The elimination kinetics followed an open two-compartment model with half-life values of 0.45 hr and 6.68 hr for the first and second phases, respectively. When 1,3,5-trimethylbenzene was expressed quantitatively in different units, such as urine concentration (uncorrected and corrected for specific gravity or creatinine) and the excretion rate, uncorrected concentration provided the best results.

There was a linear relationship between the air concentration of 1,3,5-trimethylbenzene and the concentration of unchanged substance and its metabolite 3,5-dimethylbenzoic acid in urine samples collected during the last 2 hr of the 8-hr exposure period as well as the concentration of unchanged substance in blood samples collected 30 min after the termination of exposure. Unchanged 1,3,5-trimethylbenzene in urine was found to be a more precise method than the those based on the unchanged substance in blood or its metabolite in urine.

Applicant's summary and conclusion

Conclusions:

Interpretation of results (migrated information): other: Linear relationships were found between the air concentrations of 1,3,5-trimethylbenzene and the concentration of unchanged 1,3,5-trimethylbenzene and its metabolite 3,5-dimethylbenzoic acid as well as the unchanged substance in blood.
Linear relationships were found between the air concentrations of 1,3,5-trimethylbenzene and the concentration of unchanged 1,3,5-trimethylbenzene and its metabolite 3,5-dimethylbenzoic acid in urine as well as the unchanged substance in blood.

Executive summary:

Six male volunteers were exposed to 200 mg/m3 1,3,5 -trimethylbenzene vapours for 4 hours to determine the kinetics of elimination of unchanged 1,3,5 -trimethylbenzene in urine. Urine samples were collected before exposure, every 2 hours of exposure, and up to 24 hours from the start of exposure. In the subsequent study, six male volunteers were exposed to 20, 60, and 100 mg/m3 1,3,5 -trimethylbenzene vapours for 8 hours. Blood samples were collected before exposure and 30 minutes after the end of the exposure. Urine samples were collected before exposure and for the final two hours of the exposure period. The elimination kinetics of 1,3,5 -trimethylbenzene in urine followed an open two-compartment model with the half-life values of 0.45 and 6.68 hours for the first and second phases, respectively. There was a linear relationship between the air concentration of 1,3,5-trimethylbenzene and the concentration of unchanged substance and its metabolite 3,5-dimethylbenzoic acid in urine as well as the unchanged substance in blood. Unchanged 1,3,5-trimethylbenzene in urine was found to be a more precise method than those based on the unchanged substance in blood or its metabolite in urine.