PAFT: Human Inhalation Studies on HFC

http://www.afeas.org/paft/tnostudy.html[20/07/2011 22:48:23]

"... the results are entirely consistent

with the extensive body of safety data

on the two HFCs ..."

"... government and industry

representatives agreed that the TNO

studies should be conducted."

Human Inhalation Studies on

HFC-134a and HFC-227ea

Summary of Studies

PAFT1, IPACT-I2 and IPACT-II3 recently completed double blind, ascending dose, clinical safety studies on HFC134a and HFC-227ea in healthy volunteers. (Emmen et al., 2000) The purpose of the studies was to provide data on

the effects of exposure to HFC-134a and HFC-227ea under carefully controlled conditions.

The studies were performed at TNO Food and Nutrition Institute in the Netherlands. The studies involved step-wise

exposure of subjects to HFC concentrations from 1000 to

8000 ppm, each for one hour. They also included air and

CFC-12 exposures. CFC-12 has been used for decades as a

propellant in pharmaceutical metered does inhalers. The

subjects were exposed individually in a whole-body

exposure chamber. The heart was monitored continuously

using electrocardiogram, while blood pressure and pulse

rate were monitored periodically before, during, and after

exposures. Lung function was monitored before and after each exposure. In addition, blood samples were collected at

designated intervals prior to, during, and after exposure, and were later analyzed for pharmacokinetics purposes.

The clinical phase of the studies was completed in late June 1998, and the results are entirely consistent with the

extensive body of safety data on the two HFCs. There were no treatment related effects of HFC exposure on any of the

parameters monitored, compared to air control and CFC-12 exposure.

Impetus for Studies

The TNO studies were commissioned primarily in response to a 1997 human inhalation study on Halon 1301, HFC134a, and HFC-227ea initiated at Wright-Patterson (W-P) Air Force Base in Ohio, USA. The W-P study was cosponsored by the U.S. Air Force and U.S. Environmental Protection Agency (EPA) for the purpose of monitoring

blood levels of these substances in human volunteers over a 30-minute inhalation period. The W-P study was not

designed to determine the safety of the gases (blood pressure and pulse rate were monitored during exposure, but not

continuously). The W-P investigators reported that two subjects exposed to 4000 ppm of HFC-134a and one subject

exposed to 6400 ppm of HFC-227ea experienced unexpected variations in blood pressure and pulse rate several

minutes into the exposure. One subject exposed to HFC-134a exhibited a decrease in blood pressure and pulse rate,

while two subsequent subjects (one exposed to HFC-134a and the other to HFC-227ea) exhibited increases in blood

pressure and pulse rate. The study was halted by investigators so that these findings could be properly assessed.

The W-P investigators met jointly with experts from key industry groups (PAFT, IPACT-I, and IPACT-II), the U.S.

Environmental Protection Agency (EPA), U.S. Department

of Defense, and the U.S. Food and Drug Administration to

address the events observed. The participants agreed that

the events were not consistent with the extensive body of

safety data on HFC-134a and HFC-227ea. For example,

IPACT-I & II human studies exposed subjects to HFC134a and HFC-227ea at blood levels greater than those in
PAFT: Human Inhalation Studies on HFC

http://www.afeas.org/paft/tnostudy.html[20/07/2011 22:48:23]

the W-P study, with no adverse effects. For several

reasons, however, including the fact that the W-P study was not blinded (e.g., the later subjects were aware of the

events of prior exposure), it was not possible to evaluate the incidents fully. For this reason, the government and

industry representatives agreed that the TNO studies should be conducted.

While starting at a lower exposure level (1000 ppm) than the W-P study, the TNO studies were designed to include a

higher exposure level (8000 ppm) than those used in the W-P study and over a much longer exposure period (1 hour).

As noted, these results of the TNO studies are entirely consistent with the extensive body of safety data on HFC-134a

and HFC-227ea (this body of data was developed not only prior to the W-P study, but also prior to any general usage

of the HFCs).

Publication of Results

The TNO reports have been filed with key regulatory agencies around the world to supplement and support existing

data files establishing the safety of these compounds for human use. In addition, the results have been published in the

scientific literature.

Citation: Human Safety and Pharmacokinetics of the CFC Alternative Propellants HFC 134a (1,1,1,2-Tetrafluoroethane) and HFC

227 (1,1,1,2,3,3,3-Heptafluoropropane) Following Whole-Body Exposure. H.H. Emmens, et al., Regulatory Toxicology and

Pharmacology, 32, 22-35 (2000).

1Programme for Alternative Fluorocarbon Toxicity Testing

2The International Pharmaceutical Aerosol Consortium for Toxicology Testing of HFA-134a

3The International Pharmaceutical Aerosol Consortium for Toxicology Testing of HFA-227

October 1998

Last updated February 19, 2001.