TESTING FOR INHALATION TOXICITY 293 In addition to all of this, it has been shown that the blood half-life of P-11 is between 0.3 and 1.5 rain, while the maximum blood concentration measured after two consecutive puffs from a nebulizer was •2.6 ptg/ml (4•2). It is known that at least 10 times this level is required to cause cardiac sensitization in nonanesthetized dogs when challenged with intravenous epinephrine (43, 44). We can safely conclude, then, that the propellants were not the culprits in the increase in asthma deaths. Just as a point of information, it has been re- ported (45) that this increase coincided with an increase in sales of one brand of nebulizer which contained 5 times the concentration of isoproterenol as was present in the other brands in addition, this more potent formula was not licensed for sale in this country, but was sold in the countries which experi- enced the epidemic of sudden asthma deaths. The myocardium of the dog has been shown to be particularly sensitive to isoproterenol when arterial oxygen tension is low (46), as would be the ease in a severe attack of asthma. Although the aerosol propellants were not implicated after all in these deaths, there is still a great deal of concern over their safety as a result of the findings of several investigations which may have been stimulated by the orig- inal, unfounded charges. One of the first such studies which supplied critical data on this problem was conducted by Reinhardt and his group (47). Briefly stated, they found that conscious dogs breathing a minimum of 0.35% P-11, or about 10 times as much p-19., experienced serious cardiac arrhythmias when challenged with an intravenous injection of epinephrine the concentra- tion of epinephrine approximated the amount thought to be released under conditions of stress. Additionally, they found that when the animal breathed 80% P-ll for 30 see, and was then frightened by a loud noise to stimulate en- dogenous epinephrine release, serious disturbances in heart rhythm could be produced in some of the dogs. Using barbiturate-anesthetized dogs, Flowers and Horan (48) have reported similar findings when the animals breathed the propellant gases from a plastic bag and were also given oxygen supple- mentation to prevent anoxia. A second study by Taylor et al. (49), better planned than the first, subject- ed monkeys to inhalation through an endotraeheal tube of an air mixture con- taining 30% P-19. and 9% P-114. They reported several different types of arrhythmias in response, without the use of injected ep'nephrine. Further work has also been done by Reinhardt's group (50). Using conscious beagle dogs which were running on a treadmill, they exposed the animals to atmos- pheres containing P-11, P-19., or P-114. Up to 1.0% P-11 produced no cardiac arrhythmias. At a level of 5.0% P-114, and 10.0% P-l•2, ventricular arrhythmias were produced in one of the dogs. For purposes of comparison, to return again to the calculation for propel- lant released by total discharge of a can of deodorant, we find that even the lowest level of P-19. which had an adverse effect on the heart in the above ex-

294 JOURNAL OF THE SOCIETY OF COSMETIC CHEMISTS periments (i.e., 10.0%) is about 100 times higher than the total amount of P-12 available in such a can when discharged into an 8 x 8 x 8-foot room, and the effective level of P-11 is at least 10 times that available. Use conditions for this aerosol deodorant would mean about 10-15 see (at most) of propellant discharge, producing a 0.005% concentration of P-12 in this room. Multiple use of several different aerosol products would not even begin to generate propel- lant levels such as are necessary for, or even close to, producing cardiac arrhythmias. It has been known for more than 60 years that halogenated hydrocarbons, such as chloroform, are capable of sensitizing the heart to epinephrine. Origi- nally intended for use as refrigerants, and then utilized in aerosol devices, the fiuorinated hydrocarbons were carefully tested for their toxic effects after inhalation of concentrations that were thought to be far in excess of any pos- sible perversions of use. As it turns out, however, it was not contemplated that they would be sprayed into a bag and then inhaled at a concentration of up- wards of 80%. Abuse of this type is impossible to control and diffleult to pre- vent. However, it must be kept in mind that this is an unintended misuse of the product, practiced by an extremely small percentage of the people who use aerosols. Fortunately, it appears that this fad may have run its course (or that the word may have spread about the inherent dangers), because the fre- quency of reports in the literature has declined greatly since the peak in 1969-71. We must admit, then, that as our aerosol products are made today, there is a possibility for abuse. However, there is absolutely no evidence yet to show that the fiuor:nated hydrocarbon propellants, at levels that would be encoun- tered during normal, or even exaggerated, use, have any deleterious effects on the user of a cosmetic aerosol. The cosmetic industry, fi•rough the CTFA and CSMA, has taken a very responsible position on the issue of propellant tox!eity anti has commissioned several studies into the effects of these propel- lants on both animals and humans. In addition, they have instituted an educa- tional program in which school-age children are shown a film dealing with the dangers in propellant abuse. While the last word has yet to be spoken on the ultimate safety of fi•e aero- sol propellants, this author hopes that when it is, it will be based on scientific evidence and n,•t on purely emotional considerations. The difference between conditions of use and those of gross abuse are great, and must be taken into account when any statements are made about propellant safety. (Received July 11, 1973 ) REFERENCES (1) Vogin, E. E., Goldhamer, R. E., Scheimberg, J., and Carson, S., Teratology studies in rats and rabbits exposed to an isoproterenol aerosol, Toxicol. Appl. Pharmacol., 16, 374-81 (1970).