Sulphur hexafluoride

Direct observations: clinical cases, poisoning incidents and other

Administrative data

Endpoint:

direct observations: clinical cases, poisoning incidents and other

Type of information:

experimental study

Adequacy of study:

key study

Study period:

1999

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: Clinical study, acceptable for assessment of SF6 kinetics.

Data source

Reference

Reference Type:

publication

Title:

Human pharmacokinetics and safety evaluation of SonoVue, a new contrast agent for ultrasound imaging

Author:

Morel DR

Year:

2000

Bibliographic source:

Investigative Radiology 35 (1): 80-5

Materials and methods

Study type:

clinical case study

Endpoint addressed:

basic toxicokinetics

Test material

Test material information

Constituent 1

Reference substance name:

Sulphur hexafluoride

EC Number:

219-854-2

EC Name:

Sulphur hexafluoride

Cas Number:

2551-62-4

Molecular formula:

F6S

IUPAC Name:

sulphur hexafluoride

Test material form:

solid - liquid: suspension

Method

Type of population:

general

Subjects:

- Number of subjects exposed: 12
- Sex: 7 males / 5 females.
- Age: for the men, ages ranged from 24 to 36 years; for the women, ages ranged from 20 to 26 years.
- Body weight: men, 67 to 82 kg; women 56 to 69 kg.
- Height: men, 173-188 cm; women, 168-176 cm.
- Known diseases: none - healthy

Ethical approval:

confirmed and informed consent free of coercion received

Route of exposure:

other: Intravenous administration

Reason of exposure:

intentional

Exposure assessment:

measured

Details on exposure:

SonoVue™ is a suspension of stabilized SF6 microbubbles in saline (0.9% sodium chloride). SonoVue™ was supplied as a sterile lyophilized powder (25 mg) in a gaseous atmosphere (SF6) in 10-mL vials. The SonoVue™ preparation was reconstituted just before administration by adding 5 mL sterile saline to the vial using standard clinical aseptic techniques. The bubble concentration is between 100 and 500 million per ml. Each milliliter contains approximately 13 μL of SF6 of which approximately 8 μL is encapsulated in the microbubbles and the remaining 5 μL is dissolved in the aqueous phase of the suspension.
SonoVue™ was administered intravenously as a bolus dose of 0.03 or 0.3 mL/kg in a large antecubital vein through a 20-gauge catheter.
Each of the 12 subjects received two injections of SonoVue™, with a minimum of 3 days and a maximum of 14 days in between. The two dosage levels, 0.03 and 0.3 mL/kg, were randomly ordered..

Examinations:

Clinical observations
pulse, blood pressure, electrocardiogram, lung function

Blood Sampling
Blood samples were collected predose and 0.5, 1, 2, 3, 4, 6, 8, 12, 16, 20, 60, and 90 minutes after administration. Samples were collected using an indwelling catheter in a large forearm vein opposite to that used for SonoVue™ administration. Samples (3 mL) were collected anaerobically into K3EDTA-treated Vacutainer tubes (Becton Dickinson, Meylan, France) and were stored in the dark at room temperature before analysis.

Collection of Exhaled Air
Exhaled air samples were collected predose (-2–-1 minutes) and 0 to 0.5, 0.5 to 1, 1 to 2, 2 to 3, 3 to 4, 4 to 6, 6 to 8, 8 to 11, 11 to 15, 15 to 20, 20 to 30, 45 to 55, and 80 to 90 minutes after administration. Exhaled air was collected through a respiratory mask and a pulmonary monitoring system (Spirobank, MIR Srl, Rome, Italy) into Tedlar bags (SKC Inc., PA). The pulmonary monitoring system recorded the volume of air exhaled during each sampling period. Subjects were asked to exhale normally and continuously into plastic bags, which were changed at intervals. Sampling bags were connected to a two-way valve system to allow instantaneous switching from one bag to another; therefore, at no time were subjects asked to hold their breath. After collection of all samples for an individual subject, the bags containing expired air were stored at room temperature before analysis, which was carried out within 1 to 4 days.

Results and discussion

Clinical signs:

No clinically significant changes were observed in vital signs, clinical laboratory parameters, or physical examination during the study. No adverse effects were observed or reported immediately or during the 24-hour follow-up period. Four subjects (33.3%) reported six local heat or pain sensations at the injection site immediately after the injection. No subjects reported local heat or pain 5 minutes after the injection.

Results of examinations:

Details on absorption: Median blood concentrations of SF6 peaked 1 to 2 minutes after injection of both dosage levels in both men and women. After reaching the maximum blood concentration, SF6 rapidly declined.
Details on excretion: Pulmonary elimination of SF6 was extremely rapid. Within 1 minute after administration, approximately 39% to 45% (men) and 43% to 47% (women) of the administered doses (0.03 and 0.3 mL/kg, respectively) was eliminated with the exhaled air

Any other information on results incl. tables

Details on absorption:

Median blood concentrations of SF6 peaked 1 to 2 minutes after injection of both dosage levels in both men and women. After reaching the maximum blood concentration (Cmax), SF6 rapidly declined. The decline was monophasic for the 0.03-mL/kg dose and biphasic for the 0.3-mL/kg dose. For the 0.03-mL/kg dose, median blood concentrations of SF6 were approximately 20% and 13% of Cmax at 4 minutes after administration for men and women, respectively. For the 0.3-mL/kg dose, median blood levels of SF6 were approximately 6% and 16% of Cmax at 6 minutes after administration for men and women, respectively. Blood levels of SF6 were not detected or were below the lower limit of quantification at 12 minutes after administration for most of the subjects receiving the 0.03-mL/kg dose and at 60 minutes after administration for those receiving the 0.3-mL/kg dose.

Details on excretion:

Pulmonary elimination of SF6 was extremely rapid. Within 1 minute after administration, approximately 39% to 45% (men) and 43% to 47% (women) of the administered doses (0.03 and 0.3 mL/kg, respectively) was eliminated with the exhaled air. By 11 minutes after administration, 81% to 84% (men) and 78% to 89% (women) of the administered doses was eliminated by the pulmonary route for both dosage levels. The fraction of the administered dose eliminated in the expired air was thus similar for men and women and was independent of dose. Within 90 minutes, SF6 could no longer be detected in the expired air in most of the subjects for both dosage levels.

Applicant's summary and conclusion

Conclusions:

It was concluded that, under the test conditions, human exposure to SF6 did not result in any adverse effects. No clinically significant changes were observed in vital signs, clinical laboratory parameters, or physical examination during the study. 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 would indicate that SF6 does not accumulate in healthy subjects, even with repeated administration.

Executive summary:

A clinical study was conducted in 12 healthy subjects (7 men, 5 women) to evaluate the blood kinetics and pulmonary elimination of sulphur hexafluoride after intravenous bolus injection of two dosage levels (0.03 and 0.3 mL/kg) of SonoVue™. In addition, safety and tolerability were evaluated by monitoring vital signs, adverse effects, discomfort, and physical examination 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 would indicate that SF6 does not accumulate in healthy subjects, even with repeated administration.