Sulphur hexafluoride

Endpoint summary

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Additional information

Pharmacokinetics of SonoVue™ (BR1) was investigated in a clinical study with male and female human volunteers. SonoVue™, is an echo contrast agent based on stabilized sulfur hexafluoride (SF6) microbubbles. The blood kinetics and pulmonary elimination of SF6 after intravenous bolus injection of two dosage levels (0.03 and 0.3 mL/kg of SonoVue™ were evaluated in 12 healthy subjects (7 men, 5 women). In addition, safety and tolerability were evaluated by monitoring vital signs, adverse effects, discomfort, and physical examinatino and laboratory parameters associated with the SonoVue™ injection. The blood kinetics of SF6 was not dose dependent. SF6 was rapidly removed from the blood by the pulmonary route, with 40% to 50% of the injected dose eliminated within the first minute after administration and 80% to 90% eliminated by 11 minutes after administration; the elimination was similar in men and women and independent of dose. Both dosages were well tolerated. No adverse effects were observed immediately or during the 24-hour follow-up period. Based on the results of this study, it could be concluded that SF6 was rapidly removed from the blood. The route of SF6 elimination was as parent compound by means of the lungs in the expired air. The extremely rapid pulmonary elimination of the compound indicates that SF6 does not accumulate in healthy subjects, even with repeated administration.

In addition, the blood kinetics, pulmonary elimination, and possible renal elimination of SF6 was studied after a single intravenous injection of SonoVue™ (BR1) in rabbits. BR1 was administered at two dose levels, 0.3 ml/kg (12 µg SF6/kg) and 1.0 ml/kg (40 µg SF6/ kg), corresponding to approx. 10 and 30 times, respectively, the expected human imaging dose. SF6 in blood, urine and exhaled air was assayed using GC.

Results show that after administration of BR1, SF6 disappears very rapidly from the blood: about 80% of the injected dose is cleared after the first minute following administration of BR1, and blood levels of SF6 drop to trace levels 6 min after administration (<0.1 ng/ml blood). Total clearance of SF6 from blood is extremely rapid (218 to 231 ml/min/kg), and half-life elimination of blood SF6 is less than 1 minute. SF6 is eliminated almost exclusively via the pulmonary route following administration of BR1. More than 90% of the injected dose recovered is eliminated within 3 min. Only ultra trace quantities of SF6 (< 0.1 ng/g urine or less than 0.001% of the injected dose) were detected in urine contained in the bladder at 2 h, thus showing that renal elimination is not an elimination route for SF6. Results of this study demonstrate that the inert gas SF6, administered by intravenous injection is rapidly eliminated via the pulmonary route and does not accumulate in the rabbit.

SF6 accumulation, distribution and elimination were evaluated by Pashin et al. (1987) in a study with limitations. 45 male rats of not specified strains and 25 male Wistar rats were exposed via inhalation to SF6. The absorption and the distribution of SF6 in blood and in several tissues were studied after short-time and prolonged exposure. The concentration used and the length of exposure were not specified. SF6 was detected in blood and in several tissues. Perirenal fatty tissue showed the highest affinity to SF6. After 5 hour of exposure, SF6 reached the saturation value in perirenal fatty tissue. The elimination was studied by exposing animals to 70% SF6 for 1 hour and measuring the decreasing concentration in the body and in the exhaled air. 95% of SF6 was eliminated from perirenal fatty tissue within 4 hours after the end of the exposure. SF6 levels in exhaled air decreased with a comparable rate and the maximal concentration measured did not exceed 0.05%. SF6 is rapidly eliminated. Furthermore, the study suggests that SF6 is excreted as parent compound via exhaled air.

In the available 28 -day repeated dose toxicity study with reproductive and developmental screening, performed according to OECD guidelines and under GLP, the concentration of SF6 in blood of exposed rats was measured on day 28 of the study, approximately 4 hours after the start of the exposure to SF6. The amount detected in the blood samples of the animals exposed to the analytical concentration of 302687 mg/m3 SF6 (target concentration of 50000 ppm) ranged from 1.3-3.6 µg/ml blood (mean 2.3 + 0.7).