Propene

Endpoint summary

Description of key information

Short description of key information on bioaccumulation potential result: 
A useful understanding of the toxicokinetics in rats, mice and humans has emerged.
Uptake of propene in the lung is controlled by the blood:air partition coefficient, the perfusion rate of the lungs and at high concentrations by saturable metabolism.  At concentrations of propene that do not result in saturation of metabolism, about 90% of inhaled propene was exhaled unchanged; this is due to the low uptake from the alveoli into blood.
Metabolism of propene to propene oxide is saturable.  Blood concentrations of propene oxide at steady state are low and not expected to increase substantially above the value reached at 3000 ppm (5,200 mg/m3).
Volunteer studies indicate that a similar situation, at least in part, exists in humans.
Exposure of both rats and humans to propene concentrations of approximately 25 ppm (43 mg/m3) results in similar concentrations of propene in blood however concentrations of propene oxide in human blood were approximately 60-fold lower than in rat blood.
PBPK modelling indicates that following exposure as described above, 35% of inhaled propene enters the blood and 20% of this is metabolised; this indicates that 7% of inhaled propene is metabolised, the remainder is exhaled unchanged.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Absorption rate - inhalation (%):

35

Additional information

Non-human information

Absorption

In mice, the rate of uptake of propene by inhalation was saturable exhibiting Michaelis-Menten kinetics. The maximum rate of uptake was 8±0.5 mg propene/kg bwt/h (Svensson and Osterman-Golkar, 1984). In Fischer 344 rats exposed by inhalation to 600 ppm (1,000 mg/m3) propene, blood concentrations of propene oxide were 740 ng/g within 5 minutes of the start of exposure; corresponding values during exposure to 6 ppm (10 mg/m3) propene were 160 ng/g after 5-12 minutes (Maples and Dahl, 1991). At exposure concentrations that do not saturate metabolism, uptake of propene by inhalation is controlled by the air concentration, the blood:air partition coefficient and the perfusion rate of the lung (Filser et al., 2000).

Distribution

Svensson et al., 1991 found that the levels of DNA adducts in liver, testes, lung, spleen and kidney were similar indicating an even dose distribution in the tissues studied. Following ip administration of propene oxide, liver had a somewhat higher dose than other tissues. 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 (Filser et al., 2000).

Metabolism and adduct formation

Two diastereomers of N-(2-hydroxypropyl) histidine were identified in the hydrolysate of haemoglobin from mice exposed by inhalation to propene (20,000 ppm) (34,400 mg/m³) showing that propene is metabolised to the epoxide and that the oxidation is not stereospecific. The amounts of alkylated products in DNA were below the detection limit (Svensson and Osterman-Golkar, 1984). The levels of adducts to N-terminal valine following exposure to propene oxide showed that the dose of propene oxide in blood was linearly related to the administered dose. The levels of adducts in propene-treated mice show that propene oxide is a major metabolite of propene (Svensson et al., 1991). The maximum rates of metabolism (Vmax) of propene were 110 and 50.4 µmol/h/kg for mouse and rat respectively; Vmax/2 was reached at 270 ppm and 400 ppm (460 and 690 mg/m³) in mice and rats respectively (Filser et al., 2000). Cytochrome P450 activity in both the liver and the nasal microsomes of rats were initially reduced during exposure to propene but had returned to approximately their initial values within 6h (Maples and Dahl, 1991). In Fischer 344 rats exposed to propene, concentrations of exhaled propene oxide decreased during exposure suggesting rapid inactivation of propene oxide producing cytochrome species. The saturation kinetics of the metabolism of propene is reflected by the propene oxide concentrations in blood (Filser et al., 2008) . In male and female rats exposed to propene by inhalation, the presence of HPVal adducts in systemic blood and N7-HPGua adducts in tissue from all treated groups demonstrated internal exposure to propene oxide. The number of adducts increased with exposure concentration up to 2,000 ppm (3,440 mg/m³) reaching a plateau above this concentration; this is likely to be due to saturation of the P450 mediated formation of propene oxide. The number of N7-HPGua adducts was similar in all tissues examined (Pottenger et al., 2007).

Elimination

Exhalation is the major route of elimination of propene. During exposure by inhalation to concentrations of propene that do not result in saturation of metabolism, 92% and 86% of inhaled propene was exhaled unchanged in rat and mouse respectively; this is due to the low uptake from the alveoli into blood (Filser et al., 2000).

Human Information

Following exposure of a healthy male volunteer to propene by inhalation, propene concentrations in exhaled air dropped rapidly. A physiological toxicokinetic model predicted that propene is eliminated so rapidly in humans that it cannot accumulate and that 35% of inhaled propene enters the blood, 20% of this is metabolised indicating that 7% of inhaled propene is metabolised, the remainder is exhaled unchanged (Filser et al., 2000)

In four male human volunteers exposed by inhalation to propene for 3 hours, the mean rate of metabolism was 30 µmol/h at an exposure concentration of 25 ppm (43 mg/m³); the majority of inhaled propene being exhaled unchanged. Mean blood concentrations of propene oxide calculated assuming a blood:air partition coefficient of 66 were 0.44 and 0.92 nmol/L at mean propene exposure concentrations of 9.82 and 23.4 ppm (17 and 40 mg/m³), respectively (Filser et al., 2008)