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Toxicological information

Basic toxicokinetics

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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-GLP, non-guideline, animal experimental study, published in peer reviewed literature, no restrictions, fully adequate for assessment.

Data source

Reference
Reference Type:
publication
Title:
Toxicokinetics and metabolism of pseudocumene (1, 2, 4-trimethylbenzene) after inhalation exposure in rats
Author:
Swiercz R, Rydzynski K, Wasowicz W, Majcherek W and Wesolowski W.
Year:
2002
Bibliographic source:
Int. J. Occup. Med. Environ. Health, 15, 37-42

Materials and methods

Objective of study:
toxicokinetics
Principles of method if other than guideline:
Dynamic inhalation chamber study in rats. Time course of 1,2,4-trimethylbenzene in blood and concentrations of dimethylbenzoic acid in urine determined.
GLP compliance:
not specified

Test material

Reference
Name:
Unnamed
Type:
Constituent
Type:
Constituent
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): pseudocumene
- Analytical purity: ≥97%
- Source: Fluka
- Conversion factors: 1 ppm≈ 4.92 mg/m3, 1 mg/m3 ≈ 0.20 ppm
Radiolabelling:
no

Test animals

Species:
rat
Strain:
other: Wistar Imp:DAK
Sex:
male
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: no data
- Weight at study initiation: 180-370 g
- no further details

ENVIRONMENTAL CONDITIONS
- Temperature: 20-23°C
- Humidity: 45-60%
- no further details

IN-LIFE DATES:
- no data

Administration / exposure

Route of administration:
inhalation: vapour
Vehicle:
unchanged (no vehicle)
Details on exposure:
TYPE OF INHALATION EXPOSURE: no data

TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: dynamic inhalation chambers (volume 250 dm3)
- Vapours of pseudocumene were generated by heating liquid solvents in a washer.
- The desired concentrations of vapours were obtained by diluting them with the air.
- Concentrations of solvent vapours in the exposure chamber were measured every 30 min by means of GC-FID.
Duration and frequency of treatment / exposure:
Single 6 hr
Doses / concentrations
Remarks:
Doses / Concentrations:
25, 100 or 250 ppm (nominal concentration)
No. of animals per sex per dose:
4
Control animals:
no
Details on dosing and sampling:
Blood was collected from the tail vein during the 1st, 2nd, 3rd, 4th, 5th and 6th h of exposure, as well as 3, 15, 30, 45 min and 1, 2, 3, 4, 5, 6 h after its termination
Urine samples were collected 18 h after the termination of exposure in metabolic cages.
Statistics:
The kinetic analysis of pseudocumene in blood was calculated on an open two-compartment model using Sigma Plot 4.0 (Jandel Corporation) for Windows. The Michaelis-Menten parameters (Km and Vmax) for pseudocumene metabolism were estimated by analyzing Lineweaver-Burk plots using Microsoft Excel 5.0.

Results and discussion

Toxicokinetic / pharmacokinetic studies

Details on absorption:
The absorption half life of pseudocumene in blood increased with increasing exposure concentration (38, 68 & 101 minutes at 25, 100 & 250ppm respectively)
Details on excretion:
The terminal half life for elimination of pseudocumene from blood increased with increasing exposure concentration (3.8, 5.3 & 17.3h at 25, 100 & 250ppm respectively)

Metabolite characterisation studies

Metabolites identified:
yes
Details on metabolites:
3,4-dimethylbenzoic acid (3,4-DMBA), 2,4-dimethylbenzoic acid (2,4-DMBA) and 2,5-dimethylbenzoic acid (2,5-DMBA) were measured in urine by GC after hydrolysis. 3,4-DMBA was present at the highest concentration.

Applicant's summary and conclusion

Conclusions:
Interpretation of results (migrated information): other:
The rates of uptake and elimination of pseudocumene from blood were dependant on the exposure concentration. All 3 isomers of DMBA were detected in urine, 3,4-DMBA was present at the highest concentration. A significant linear correlation was found between the level of exposure and the concentration of dimethylbenzoic acids. The enzyme kinetic parameters [Km (mg/l) & Vmax (mg/h/kg)] for pseudocumene biotransformation in rats were estimated (3,4-DMBA, Km = 28, Vmax = 96; 2,4-DMBA, Km = 7, Vmax = 25; 2,5-DMBA, Km = 7, Vmax = 23).
Executive summary:
Both the absorption half life and terminal elimination half life of pseudocumene from blood increased with increasing exposure concentration. The three isomers of dimethylbenzoic acid (3,4 -, 2,4- & 2,5 -) were all detected in urine following hydrolysis; the 3,4 - isomer was present at the highest concentration.