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basic toxicokinetics in vitro / ex vivo
Type of information:
experimental study
Adequacy of study:
key study
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: This study was selected as the key study because the information provided for the hazard endpoint is sufficient for the purpose of classification and labelling and/or risk assessment.

Data source

Reference Type:
Partition Coefficients of Low-Molecular-Weight Volatile Chemicals in Various Liquids and Tissues
Gargas ML, Burgess RJ, Voisard DE, Cason GH and Anderson ME
Bibliographic source:
Tocicol. Appl. Pharmacol., 98:87-99

Materials and methods

Objective of study:
other: determining partition coefficients
Principles of method if other than guideline:
Determination of the tissue to air and liquid to air partition coefficients of the test substance in human and rat blood and rat tissues.
GLP compliance:
not specified

Test material

Constituent 1
Chemical structure
Reference substance name:
EC Number:
EC Name:
Cas Number:
Molecular formula:
Details on test material:
- Purity: > 98%

Test animals

other: CDF [F-344] CrlBr
Details on test animals or test system and environmental conditions:
- Source: Charles River Breeding Laboratory, Kinston, NY
- Weight at study initiation: between 200 and 300 g
- Housing: portable laminar air flow enclosure system
- Individual metabolism cages: no
- Diet: commercial food (Purina), ad libitum
- Water: tap water, ad libitum

- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Route of administration:
other: tissues were removed from animals then combined with the test item
Details on study design:
The liquids and tissues utilized were: 0.9% NaCl (saline) solution, reagent-grade olive oil heparanised rat, and human blood, and rat liver, muscle and fat tissues. Tissues were prepared as homogenates in saline solution in a 1:3 tissue weight:saline volume ratio (assuming a tissue density of 1.0 g/mL). The saline:air partition coefficient determinations were necessary to account for the amount of partitioning due to saline in the tissue homogenates and the oil:air values were used for comparison with the fat & coefficients. The saline:air and oil:air partition coefficients were also used as independent variables for modeling the blood and tissue:air values in multiple linear regression analyses.
Details on dosing and sampling:
Liquid scintillation vials with a septum were used incubate the sample matrix with the test item. The test item was introduced into the vials as a vapour by injecting 1 mL of atmosphere from a gas sampling bag containing an air concentration of between 5000 and 10000 ppm. The concentration of the test item in the vials was 200 to 400 ppm. After heating (37°C) and vortexing at 200 to 300 rpm for 15 minutes, equilibrium in the test vial was reached. The headspace chemical concentrations were sampled then analysed by gas chromatography utilizing a flame ionization detector.

Results and discussion

Toxicokinetic / pharmacokinetic studies

Toxicokinetic parametersopen allclose all
Toxicokinetic parameters:
other: Human blood:air = 6.04±0.38
Toxicokinetic parameters:
other: Rat blood:air = 9.58±0.94
Toxicokinetic parameters:
other: Saline:air =1.41±0.04
Toxicokinetic parameters:
other: Olive oil:air = 178±6
Toxicokinetic parameters:
other: Rat fat:air = 148±11
Toxicokinetic parameters:
other: Rat liver:air = 8.96±0.61
Toxicokinetic parameters:
other: Rat muscle:air = 3.52±0.54

Metabolite characterisation studies

Metabolites identified:
not measured

Applicant's summary and conclusion

Interpretation of results (migrated information): other: partition coefficients were determined for rat blood/tissues and human blood
This study and the conclusions which are drawn from it fulfil the quality criteria (validity, reliability, repeatability).
The techniques presented in this study offer a method for determining liquid & and tissue:air partition coefficients for volatile chemicals such as the test item.
Executive summary:

A technique was developed to determine partition coefficients for low-molecular-weight, volatile compounds such as the test substance. The liquid:air and tissue:air partitions were determined in 0.9% saline, in olive oil, and in blood, liver, muscle, and fat tissues from rats. Human blood:air values were also determined. The test substance, as a vapour, was mixed with the matrix then incubated for 15 minutes to allow for equilibration. Samples of the headspace were analysed by gas chromatography and the partition coefficient determined. 


Values were:

Human blood:air = 6.04±0.38

Rat blood:air = 9.58±0.94

Saline:air =1.41±0.04

Olive oil:air = 178±6

Rat fat:air = 148±11

Rat liver:air = 8.96±0.61

Rat muscle:air = 3.52±0.54