1,2,4-trimethylbenzene

Direct observations: clinical cases, poisoning incidents and other

Administrative data

Endpoint:

direct observations: clinical cases, poisoning incidents and other

Type of information:

experimental study

Adequacy of study:

supporting study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Non-GLP, non-guideline human experimental study, published in peer reviewed literature, no restrictions, fully adequate for assessment.

Data source

Reference

Reference Type:

publication

Title:

Toxicokinetics of inhaled trimethylbenzenes in man

Author:

Järnberg J, Johanson G and Löf A

Year:

1996

Bibliographic source:

Toxicol Appl Pharmacol 140 (2): 281-8

Materials and methods

Endpoint addressed:

basic toxicokinetics

Principles of method if other than guideline:

Inhalation study in human volunteers. 1,2,4-trimethyl benzene was determined in blood, urine, and exhaled air.

GLP compliance:

not specified

Test material

Test material information

Constituent 1

Reference substance name:

1,2,4-trimethylbenzene

EC Number:

202-436-9

EC Name:

1,2,4-trimethylbenzene

Cas Number:

95-63-6

Molecular formula:

C9H12

IUPAC Name:

1,2,4-trimethylbenzene

Constituent 2

Reference substance name:

pseudocumene

IUPAC Name:

pseudocumene

Details on test material:

- Name of test material (as cited in study report): 1,2,4-Trimethylbenzene
- Analytical purity: >99%
- Source: Fluka, Buchs, Switzerland

Method

Type of population:

other: Healthy human volunteers

Subjects:

- Number of subjects exposed: 10
- Sex: male
- Age: average age 35 years (26-48 years)
- Race: Caucasian
- Demographic information: Not occupationally exposed to solvents
- Known diseases: All reported to be "healthy"

Ethical approval:

other: The study was approved by the Regional Ethical Committee at the Karolinska Institute, Solna, Sweden.

Route of exposure:

inhalation

Reason of exposure:

intentional

Exposure assessment:

measured

Details on exposure:

The subjects were exposed to 1,2,4-TMB for 2 hr in an exposure chamber at a constant work load of 50 W on an ergometer bicycle. The subjects were exposed to concentrations of 25 ppm (120 mg/m3) and 2 ppm (11 mg/m3) 1,2,4-TMB.
The volume of the chamber was 20 m3. The solvent was injected into the inflowing airstream by means of a high-performance liquid chromatography pump and completely vaporized before reaching the chamber. Vaporization was achieved by compressed air-mediated aerosol formation combined with evaporation of residual droplets by a metal plate heated to 130°C. The outlet airflow was 320 m3/hr giving an air exchange in the chamber of 16 times/hr. To prevent leakage of solvent the air pressure in the chamber was kept about 5 Pa lower than in the surrounding laboratory. Fans were operating near the ceiling and floor to achieve a uniform distribution of 1,2,4-TMB vapour.

Examinations:

- Urine analysis: All urine was collected from the onset of exposure until the next morning. Voiding times were before exposure and at 0, 2, 4, 11, and 20 hr post exposure. The total volume of urine was measured and an aliquot of 6 ml from each sample was immediately transferred to a head space vial for gas chromatographic analysis.
- Haematology: Capillary blood (200 µL) was sampled at selected intervals during exposure and until the next morning.
- Lung function: Pulmonary ventilation (L/min) was assessed at 0-2 and 2-6 hrs
- Other: The heart rate was recorded continuously during exposures with a heart rate meter .

Medical treatment:

None required

Results and discussion

Clinical signs:

No irritation or central nervous system effects were reported.

Results of examinations:

The respiratory uptake was approximately 64% and was independent of exposure concentration over the range studied.
Less than 0.002% of the respiratory uptake of 1,2,4-TMB was excreted unchanged in urine within 4 hr post-exposure.
Concentration of 1,2,4-TMB in arterial blood increased rapidly without reaching any plateau within the 2 hr exposure period.
Approximately 20% of the respiratory uptake of 1,2,4-TMB was exhaled unchanged during and after exposure.
The kinetics of 1,2,4-TMB were characterised by a large volume of distribution and long terminal elimination half life.

Any other information on results incl. tables

Summary of findings

(table based on Järnberg et al, 1996, Toxicol Appl Pharmacol 140 (2): 281-8 , Tables 1, 2 and 3)

Parameter measured	25 ppm 1,2,4-TMB	2 ppm 1,2,4-TMB
Heart rate (beats/min) 0-2 hr	80 ± 3	84 ± 3
Pulmonary ventilation (L/min) 0-2 hr	23 ± 2	24 ± 1
Pulmonary ventilation (L/min) 0-2 hr	11 ± 2	12 ± 1
Respiratory uptake (%)	64 ± 3	63 ± 2
Respiratory excretion (%)	20 ± 3	15 ± 5
Urinary excretion (%)	0.0010 ± 0.0004	0.0005 ± 0.0002
Volume of distribution (L/kg)	38±11	28±3
Total calculated blood clearance (L/hr/kg)	0.68 ± 13	0.87 ± 37
Half-life: 4^thphase (hr)	87 ± 27	65 ± 20

Applicant's summary and conclusion

Executive summary:

The respiratory uptake was approximately 64% and was independant of exposure concentration over the range studied. Less than 0.002% of the respiratory uptake of 1,2,4 -TMB was excreted unchanged in urine within 4 hr post-exposure. Concentration of 1,2,4-TMB in arterial blood increased rapidly without reaching any plateau within the 2 hr exposure period. Approximately 20% of the respiratory uptake of 1,2,4-TMB was exhaled unchanged during and after exposure. The kinetics of 1,2,4-TMB were characterised by a large volume of distribution and long terminal elimination half life indicative of distribution into lipid.