Gases (petroleum), refinery blend

Basic toxicokinetics

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:

other: Non-GLP, non-guideline animal and human experimental studies, reported in peer reviewed literature, notable restrictions in design (human data only) but otherwise adequate for assessment.

Data source

Reference

Reference Type:

publication

Title:

Unnamed

Year:

2000

Materials and methods

Objective of study:

toxicokinetics

Test guideline

Qualifier:

no guideline followed

Principles of method if other than guideline:

Closed chamber uptake studies in mice & rats. 1 human exposed using a mask. PBPK model developed.

GLP compliance:

no

Test material

Test material information

Constituent 1

Reference substance name:

Propene

EC Number:

204-062-1

EC Name:

Propene

Cas Number:

115-07-1

Molecular formula:

C3H6

IUPAC Name:

prop-1-ene

Details on test material:

Propene, purity >99.9% ex Messer Greisheim (Krefield, Germany).

Radiolabelling:

no

Test animals

Species:

other: Mice, rats, human

Strain:

other: NMRI and B6C3F1 mice, Sprague-Dawley and Fischer 344/N rats

Sex:

male

Details on test animals or test system and environmental conditions:

- Male NMRI mice (30-45 g) and male Sprague-Dawley rats (300-500 g), were obtained from the breeding facility of GSF (Neuherberg, Germany).
- Male B6C3F1 mice (20-30 g) and male Fischer 344/N rats (210-290 g) were purchased from Charles River Wiga (Sulzfeld, Germany).
- Animals were fed with standard chow Nr 1324 from Altromin (Lage, Germany), had free access to tap water, and were maintained until experiments on a 12-h light/dark cycle in climate-controlled air (23°C, 60% relative humidity).
- A 48 year old male volunteer, 95 kg was exposed.

Administration / exposure

Route of administration:

inhalation

Vehicle:

other: air

Details on exposure:

- Mice and rats: closed chamber technique, whole body exposure, 2 rats or 5 mice/chamber.
- All glass chambers, 6.6 L volume (except for DDC pre-treated mice, 0.8 L).
- Exhaled CO2 trapped by soda lime and the chamber air was replenished automatically with the equivalent amount of O2. Chamber temperature was 19 -24ºC.
- Human exposure to constant propene concentrations via a two-valve breathing mask.

Duration and frequency of treatment / exposure:

Rats and mice: single, up to >24hr.
Human: single, up to 265 min.

Doses / concentrations

Remarks:

Doses / Concentrations:
Exposure of mice and rats to varying propene concentrations: initial concentrations of 10 - 10500ppm (17-18100 mg/m3) propene.
Exposure of rats to constant propene concentrations: concentrations of propene were 20.3, 62, 104, 253, 373, 496, 1000, 2020, 3000ppm (35-5200 mg/m3)
Human exposed to constant concentrations of 5 or 25ppm (9 or 43 mg/m3).

No. of animals per sex per dose / concentration:

2 rats or 5 mice per chamber. Human exposure (n=1).

Control animals:

no

Details on study design:

Liquid:air and tissue:air partition coefficients were determined in vitro using water and olive oil (liquid) and blood, kidney, liver, brain, lung, fat, and muscle of mouse, rat, and human. Tissues were obtained from NMRI mice, Sprague-Dawley rats and human blood from a volunteer, human tissue from an autopsy. Propene was analysed by gas chromatography.

Exposure of rats and mice to varying concentrations of propene: Usually, naive animals were exposed. Some animals were pre-treated with sodium diethyldithiocarbamate (DDC) in 0.9% saline solution (50 mg DDC/mL) in order to inhibit cytochrome P450-dependent metabolism. DDC was administered 0.5 to 6 h before exposure. Mice received DDC doses of 400 mg/kg and rats received doses of 200 mg/kg.

Statistics:

Toxicokinetic analysis: A physiological toxicokinetic model was used to simulate the inhalation of propene vapour, its distribution by the blood flow into several compartments, the metabolism, and the exhalation of the unchanged compound.

Results and discussion

Preliminary studies:

Tissue:air partition coefficients for propene measured in-vitro indicate a very low potential for accumulation in tissues; values for adipose were approximately 10x other tissues. The blood:air partition coefficient for propene for human tissue is approximately half that in rodents probably due to species differences in lipophilicity of haemoglobin.

Main ADME results

Main ADME results 1

Type:

absorption

Results:

uptake of propene by inhalation is controlled by the air concentration, the blood:air partition coefficient and the perfusion rate of the lung and at high concentrations by saturable metabolism

Main ADME results 2

Type:

distribution

Results:

predicted steady state concentrations of propene in human tissues are approximately twice those in rodents for the same blood concentration

Main ADME results 3

Type:

excretion

Results:

elimination is via metabolism and exhalation of unchanged propene, for concentrations below saturation of metabolism, predicted percentage of the inhaled dose exhaled unchanged is 86%, 92% and 93% for mouse, rat and human respectively

Toxicokinetic / pharmacokinetic studies

Details on absorption:

Uptake of propene by inhalation is controlled by the air concentration, the blood:air partition coefficient and the perfusion rate of the lung and at high concentrations by saturable metabolism.

Details on distribution in tissues:

Predicted steady state concentrations of propene in human tissues are approximately twice those in rodents for the same blood concentration

Details on excretion:

Elimination of propene is via metabolism and exhalation of unchanged propene. For exposures below the concentration at which metabolism becomes saturated, the predicted percentage of the inhaled dose exhaled unchanged is 86%, 92% and 93% for mouse, rat and human respectively.

Toxicokinetic parameters

Toxicokinetic parameters 1

Toxicokinetic parameters:

other: mouse: Vmax=110 µmol/h/kg; Km=270 ppm

Toxicokinetic parameters 2

Toxicokinetic parameters:

other: rat: Vmax=50.4 µmol/h/kg; Km=400 ppm

Metabolite characterisation studies

Metabolites identified:

no

Details on metabolites:

The ability of sodium diethyldithiocarbamate (DDC) to inhibit propene metabolism indicates that most propene metabolism is oxidative.

Applicant's summary and conclusion

Conclusions:

Interpretation of results: no bioaccumulation potential based on study results
Uptake of propene by inhalation is controlled by diffusion kinetics and cardiac output. Species differences in the blood:air partition coefficient for propene (human approximately half rodent) are probably due to differences in lipophilicity of haemoglobin. Tissue:air partition coefficients for propene measured in-vitro indicate a very low potential for accumulation in tissues. Propene metabolism is predominantly oxidative. Elimination of propene is via metabolism and exhalation of unchanged propene. The maximum rates of metabolism (Vmax) of propene were 110 and 50.4 µmol/h/kg for mouse and rat, respectively; Km was 270 and 400 ppm in mice and rats, respectively. For exposures below the concentration at which metabolism becomes saturated, the predicted percentage of the inhaled dose exhaled unchanged is >86% in both rodents and humans.

Executive summary:

In this study, male NMRI mice, male B6C3F1 mice, male Sprague-Dawley rats and male Fischer rats as well as one male human volunteer were exposed to propene in order to develop a PBPK model. Mice and rats were exposed in a closed chamber, wholy body technique, while human exposure was performed using two-valve breathing mask.The initial exposure propene contrantration for mice and rats were 10 - 10500ppm (17-18100 mg/m3). The exposure of rats to constant propene concentrations were as follows: 20.3, 62, 104, 253, 373, 496, 1000, 2020, 3000ppm  (35-5200 mg/m3); while human volunteer was exposed to constant concentrations of 5 or 25ppm (9 or 43 mg/m3). Liquid:air and tissue:air partition coefficients were determined in vitro using water and olive oil (liquid) and myltiple tissues obtained from NMRI mice, Sprague-Dawley rats, human blood from a volunteer and human tissue from an autopsy. The results showed that propene has no bioaccumulation potential based on this study.

Uptake of propene by inhalation is controlled by diffusion kinetics and cardiac output. Tissue:air partition coefficients for propene measured in-vitro indicate a very low potential for accumulation in tissues. Propene metabolism is predominantly oxidative. Elimination of propene is via metabolism and exhalation of unchanged propene. The maximum rates of metabolism (Vmax) of propene were 110 and 50.4 µmol/h/kg for mouse and rat, respectively; Km was 270 and 400 ppm in mice and rats, respectively. For exposures below the concentration at which metabolism becomes saturated, the predicted percentage of the inhaled dose exhaled unchanged is >86% in both rodents and humans.