Emergency and Continuous Exposure Limits for Selected Airborne Contaminants: Volume 2 (1984)

Fluorocarbon 11 (FC-11) has been used primarily as an aerosol propellant, refrigerant, and blowing agent for polymeric foams. Its use is now banned because of its potential effects on the ozone layer.

It is prepared from carbon tetrachloride and antimony trifluoride (Stecher et al., 1968; ACGIH, 1980). FC-11 may be a contaminant of submarine atmospheres.

Inhalation of fluorocarbons during the years 1960–1970 was a prominent cause of abusive death among teen-agers. Severe cardiac arrhythmia—resulting from light plane anesthesia and intensified by hypercapnia, stress, or activity—was suggested as an explanation for 110 cases of sudden sniffing death (Bass, 1970). Typically, a person would spray the Freon into a paper bag from a commercial aerosol product and inhale it; after a few breaths and a short excitement period, death might occur. Fluorocarbons are thought to sensitize the heart to asphyxia-induced sinus bradycardia, atrioventricular block, and ventricular T-wave depression (Haj et al., 1980).

Accidental ingestion of FC-11 occurred when a healthy man mistook a bottle in a refrigerator for a bottle of plain water. This resulted in freezing, tissue necrosis, and multiple perforations of the

stomach. The patient recovered after surgery to remove the damaged tissue (Haj et al., 1980).

Labeled FC-11 administered to four healthy males by inhalation of a single breath held for 5 s was eliminated from the body rapidly. Results in humans appeared to parallel those in rats in more detailed studies (Williams et al., 1974). The investigators found rapid transfer of FC-11 to blood followed by distribution to fat, from which release was slow. Mergner et al. (1975) exposed a male and a female volunteer to radiolabeled FC-11 at 1,000 ppm for 7–17 min. Recovery of administered radioactivity in exhaled air was essentially complete (99% and 79%). Errors in collection of rapidly eliminated gases account for the differences from 100%. Only a very small fraction of the administered radioactivity (less than 0.2%) was exhaled as ¹⁴CO₂ or excreted as nonvolatile urinary activity. The impurities in FC-11—namely, chloroform and carbon tetrachloride—known to be metabolized could account for all the radioactivity found in urine and exhaled CO₂ after exposure to FC-11.

Cardiac effects have been studied in healthy subjects and patients with bronchopulmonary disease. None of the subjects exhibited cardiotoxic effects (Fabel et al., 1972).

Human volunteers were exposed to FC-113 (similar to FC-11) at 500 or 1,000 ppm for 6 h/d, 5 d/wk during a 2-wk period. No adverse changes were seen in performance of complex mental tasks, clinical status, or results of biochemical tests. Breath analysis did not reveal a significant buildup of FC-113 (Reinhardt et al., 1971).

FC-11 has not shown appreciable oral toxicity in rats and dogs in either acute or chronic studies (Haskell Laboratory, 1970; NCI, 1978). The chronic investigations include 1-mo, 90-d, and 2-yr studies. FC-11 was tested on the intact skin of mice. It was well tolerated by the skin, but retarded the recovery of wounds and burns and regrowth of hair (Quevauviller, 1960; Quevauviller et al., 1963). Dermal application of FC-11 to rabbit skin did not produce any lesions (Scholz, 1962). Transient conjunctival irritation was observed after application of FC-11 solution to the rabbit eye. No irreversible eye damage was seen (Haskell Laboratory, 1970; Kudo et al., 1971).

The LC₅₀ of FC-11 for rats in a 4-h exposure is 26,200 ppm (Haskell Laboratory, 1970). A 30-min exposure of rats at 50,000 ppm caused no signs of intoxication. Similar exposure at higher concentrations caused clinical signs of central nervous system depression. Concentrations of 100,000 ppm or more were fatal after less than 30 min (Lester and Greenberg, 1950). Acute exposure of other species of laboratory animals produced similar effects (Caujolle, 1964; Haskell Laboratory, 1970; Nuckolls, 1933; Scholz, 1962).

Rats, guinea pigs, monkeys, and dogs were continuously (24 h/d) exposed to FC-11 at approximately 1,000 ppm for 90 d. One monkey died on day 78, but its death was not definitely linked to exposure to FC-11. No other animals were affected. No compound-related pathologic changes were observed. Another group of animals was

exposed at 10,250 ppm, 8 h/d, 5 d/wk for 6 wk without adverse effects (Jenkins et al., 1970). In another study, dogs, cats, guinea pigs, and rats were exposed to FC-11 for 3.5 h/d, 5 d/wk for 4 wk; the dogs were exposed at 12,500 ppm, and the other animals at 25,000 ppm. No microscopic evidence of damage to the lungs, heart, spleen, liver, or kidneys was seen (Scholz, 1962).

Rats and mice exposed to FC-11 at 1,000 or 5,000 ppm for lifetime showed no evidence of carcinogenicity or other adverse health effects (C.Maltoni, unpublished).

FC-11, like other chlorofluorocarbons and hydrocarbons, was capable of sensitizing the beagle heart to exogenous epinephrine in standard 5-min cardiac-sensitization screening studies. A 5-min cardiac-sensitization screening test consists of a control intravenous injection of epinephrine at 8 μg/kg, followed later by a 5-min exposure to fluorocarbon and then a challenge with 8 μg/kg intravenously. Manifestation of arrhythmia (multiple consecutive ventricular beats), which is considered to pose a serious threat to life, or cardiac arrest (ventricular fibrillation) constitutes a positive test. The lowest concentration that elicited a marked response in exposed dogs was 5,000 ppm. A concentration of 1,000 ppm was ineffective. Dogs exposed while running on a treadmill (to increase their circulating epinephrine) were not sensitized at concentrations up to 10,000 ppm (Mullin et al., 1972).

Azar et al. (1973) studied nonanesthetized dogs and reported that the average blood concentrations of FC-11 associated with cardiac sensitization were 28.6 μg/L in arterial and 19.7 μg/L in venous blood.

Belej and Aviado (1975) studied cardiopulmonary toxicity of propellants in anesthetized dogs. They concluded that FC-11, unlike eight other halocarbon propellants studied, produced bronchodilation, rather than bronchoconstriction. It also reduced pulmonary compliance and respiratory minute volume. FC-11 had the greatest tachycardiac effect of all compounds studied. Effects of FC-11 on the circulatory system were summarized by Aviado (1975, 1978).

In a bioassay supported by the National Cancer Institute (1978), oral FC-11 was not carcinogenic in rats or mice. No significant increase in tumor formation was seen in a study that used subcutaneous injection (Epstein et al., 1967). Additionally, FC-11 has not been shown to be mutagenic in the Salmonella typhimurium reverse-mutation bioassay (C.F.Reinhardt, Haskell Laboratory, personal communication). No embryotoxic, fetotoxic, or teratogenic effect of FC-11 was shown in a study with pregnant rats and rabbits; the animals were exposed for 2 h/d to a 200,000 ppm of a FC-11/FC-12 (1:9) mixture from day 4 to 16 of gestation for rats and from day 5 to 20 for rabbits (Paulet, 1976). Blake and Mergner (1974) studied the biotransformation of ¹⁴C-labelled FC-11 (8,000–12,000 ppm) in male and female beagles after a short (6–20 min) inhalation. Essentially all the inhaled fluorocarbon was recovered in the exhaled air within 1 h. Only traces of radioactivity were found in urine or exhaled CO₂. The investigators concluded that FC-11 is relatively refractory to biotransformation after a short inhalation exposure and that it is rapidly exhaled chemically unaltered.

The American Conference of Governmental Industrial Hygienists (1980, 1983) recommended a ceiling of 1,000 ppm. The Occupational Safety and Health Administration’s (1983) permissible exposure limit currently in effect for FC-11 is a ceiling of 1,000 ppm.

The previous EELs and CEL were established by the Committee on Toxicology in 1966. No adverse effects have been observed in dogs, monkeys, guinea pigs, or rats continuously exposed to FC-11 at 1,000 ppm for 90 d or in a similar group repeatedly exposed at 10,250 ppm, 8 h/d, 5 d/wk for 6 wk (Jenkins et al., 1970). Dogs exposed at 12,500 ppm and cats, guinea pigs, and rats at 25,000 ppm for 4 wk were not affected (Scholz, 1962). Human exposure to FC-113 (a compound similar to FC-11) at 1,500 ppm produced no adverse effects after 2.75 h. Signs of central nervous system involvement were seen after exposure to FC-113 at 2,500 ppm for 30 min. These effects were reversible, and the volunteers appeared normal 15 min after cessation of the experiment (C.F.Reinhardt, Haskell Laboratory, personal communication). FC-11 can sensitize the mammalian heart to epinephrine and result in serious cardiac arrhythmia. However, the possible combined effects of excitement-stimulated epinephrine release and FC-11 on the heart are not easy to predict. It would therefore be prudent to take a more cautious approach to EEL recommendations than was taken by the Committee in 1966, when it was not aware of the sudden-sniffing-death syndrome. The previous 60-min and 24-h EELs are too high, on the basis of experimental cardiac sensitization of dogs, which occurred when they were exposed at 5,000 ppm and given a large challenge injection of epinephrine. However, no sensitization occurred in resting dogs exposed at 1,000 ppm and given epinephrine or in exercising dogs exposed at 10,000 ppm (Mullin et al., 1972).

Based on the no-observed-adverse-effect concentration of FC-113 in humans (1,500 ppm for 2.5 h), the 10,000-ppm concentration (which did not cause cardiac arrhythmia in exercising dogs), and the results in standard 5-min cardiac-sensitization screening tests in dogs, the Committee recommends a 60-min EEL of 1,500 ppm. It bases its 24-h EEL on the finding in humans that repeated exposure to FC-113 at 500 or 1,000 ppm for 2 wk did not result in adverse effects. Finally, using the no-observed-effect concentration of 1,000 ppm in a continuous-exposure animal study and applying an uncertainty factor of 10, the Committee arrives at a recommended CEL of 100 ppm.

The present Committee’s recommended EELs and CEL for FC-11 and the limits proposed in 1966 are shown below.

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