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Emergency and Continuous Exposure Limits for Selected Airborne Contaminants: Volume 2 FLUOROCARBON 12 BACKGROUND INFORMATION PHYSICAL AND CHEMICAL PROPERTIES Chemical formula: CCL2F2 Molecular weight: 120.92 Chemical name: Dichlorodifluoromethane Synonyms: FC-12, Freon 12 CAS number: 75–71–8 Melting point: −158 °C Boiling point: −29.8°C Specific gravity: 1.1834 (57°C) Vapor pressure: 5.7 atm (20°C) Solubility: Soluble in alcohol and ether; insoluble in water General characteristics: Nonflammable, colorless gas Conversion factors: 1 ppm=4.94 mg/m3 1 mg/m3 =0.2 ppm OCCURRENCE AND USE Fluorocarbon 12 (FC-12) has been used primarily as an aerosol propellant, refrigerant, and blowing agent for polymeric foams. Air conditioning is the suspected source of FC-12 contamination in submarines. SUMMARY OF TOXICITY INFORMATION EFFECTS ON HUMANS Of 34 cases of sudden death reported by the medical examiner of Dallas, Texas, to be due to abusive, deliberate use of products that can be inhaled, 16 involved fluorocarbons (Garriott and Petty, 1980). The victims were mainly white males aged 13–30 (mean, 18.4). FC-11 and FC-114 were used in addition to FC-12, and many products contained mixtures of FC-11 and FC-12. The sequence of events has been summarized by Aviado (1978) and others as follows: sensitization of the heart to prearrhythmic effects of epinephrine, depression of myocardial contractility, reduction in cardiac output, and irritation of mucosa in upper and lower respiratory tract that causes an increase in sympathetic and vagal impulses to the heart. Azar et al. (1972) exposed two human volunteers to FC-12 at 1,000 and 10,000 ppm for 2.5 h. Each volunteer was exposed twice at each concentration. Electrocardiographic monitoring and psychomotor performance tests revealed no adverse effects of exposure at 1,000 ppm. At 10,000 ppm, there was only a 7% reduction in psychomotor-test score. Rapid elimination from the lungs occurred when exposure stopped. The investigators concluded that a single brief exposure
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Emergency and Continuous Exposure Limits for Selected Airborne Contaminants: Volume 2 (up to 2.5 h) to FC-12 at 10,000 ppm could be tolerated without adverse health effects. Kehoe (1943) reported that exposure to FC-12 at up to 60,000 ppm was tolerated for 80 min by one human subject. When exposed at 40,000 ppm for 14 min and then at 20,000 ppm for 66 min, a second subject developed EEG changes and had slurred speech and decreased scores in psychologic tests. At 110,000 ppm, amnesia and cardiac arrhythmia occurred within about 10 min. Mergner et al. (1975) exposed a male and a female volunteer to radiolabeled FC-12 at 1,000 ppm for 7–17 min. Recovery of administered radioactivity in exhaled air was essentially complete. Radioactivity in urine and exhaled CO2 together amounted to less than 0.2% of administered radioactivity. EFFECTS ON ANIMALS FC-12 has not shown appreciable oral toxicity in laboratory animals in either acute or chronic exposures. These included 18-wk rat and dog feeding studies (fed at 160–379 mg/kg per day) and 2-yr rat feeding studies (up to 150 mg/kg per day) (Haskell Laboratory, 1955a; Hood, 1956; Sherman, 1974; Sherman and Barnes, 1966). No skin irritation was observed after contact of the gas with the skin of rats, rabbits, or guinea pigs. Transient eye irritation followed application of a 50% solution to rabbit eyes. Treated eyes were normal 24 h later. No eye irritation was seen after an aerosol mixture containing FC-12 was sprayed into the eyes of rabbits (Haskell Laboratory, 1955b; Hood, 1956). The lethal concentration of FC-12 for rats in a 3-h exposure was 620,000 ppm (Shugaev, 1963). Two-hour exposure at 600,000 ppm was lethal to rats, but not to guinea pigs (Scholz, 1962). Central nervous system effects were observed in all exposed species. In rats exposed for 30 min, there were no reactions at 200,000 ppm (Lester and Greenberg, 1950). At higher concentrations, the following effects were observed: muscular twitching and tremors at 300,000–400,000 ppm, loss of postural reflex at 500,000 ppm, and loss of righting reflex at 600,000 ppm. Guinea pigs were similarly affected at 200,000–300,000 ppm (Nuckolls, 1933). Mice survived a 24-h exposure at 10,000 ppm, but microscopic examination revealed nonspecific lung changes (Quevauviller et al., 1963). Rats, guinea pigs, monkeys, rabbits, and dogs were exposed to FC-12 continuously at 810 ppm for 90 d (Prendergast et al., 1967). Although 2 of 15 rats and 1 of 15 guinea pigs died during exposure, there were no visible signs of toxicity. During the course of the experiment—which involved tests of several other chemicals, such as trichloroethylene, carbon tetrachloride, and other fluorocarbons—7 of 304 control rats and 2 of 34 control guinea pigs died. Pathologic examination revealed focal necrosis in the livers of the guinea pigs. This change was thought to be due to the continuous nature of the exposure or the high degree of susceptibility of the guinea pig. No pathologic changes were seen in the tissues of the other four species. In another experiment, test animals were exposed at 840 ppm for 8 h/d, 5 d/wk, for 6 wk (Nuckolls, 1933). No signs of toxicity were seen,
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Emergency and Continuous Exposure Limits for Selected Airborne Contaminants: Volume 2 and pathologic examination revealed changes similar to those seen in the continuous study (Nuckolls, 1933). At higher concentrations, toxic signs indicative of CNS effects were observed on repeated exposure (Sayers et al., 1930; Scholz, 1962; Watanabe and Aviado, 1975). In addition, rats and mice exposed to FC-12 at 1,000 and 5,000 ppm for 104 wk showed no evidence of carcinogenicity (C.Maltoni, unpublished). FC-12, like other chlorofluorocarbons and hydrocarbons, is capable of sensitizing the beagle heart to exogenous epinephrine in standard 5-min cardiac-sensitization screening studies. The concentration needed to elicit marked responses in 50% of exposed dogs is 80,000 ppm (Clark and Tinston, 1973). Dogs exposed to FC-12 while running on a treadmill to increase their own epinephrine concentration were sensitized at concentrations over 100,000 ppm (Mullin, 1970; Mullin et al., 1972). Lessard et al. (1978) reported that epinephrine perfusion induced cardiac arrhythmia in rabbits and dogs breathing gas mixtures of 79% FC-12 and 21% O2. After 5 min of inhalation, arterial blood contained FC-12 at 0.8 mg/L in rabbits and 0.7 mg/L in dogs. Blake and Mergner (1974) studied the biotransformation and elimination of FC-12 in beagles after exposure to radiolabeled FC-12 (8,000–12,000 ppm, v/v). Essentially all the inhaled air was recovered in the exhaled air within 1 h. Only traces of radioactivity were found in urine or exhaled CO2. All tissues contained measurable concentrations of nonvolatile radioactivity 24 h after exposure, but together represented less than 1% of the administered dose. It was not possible to determine whether this radioactivity was associated with metabolites of FC-12 or with unavoidable radiolabeled impurities present in the administered gas mixture. The investigators concluded that FC-12 is relatively refractory to biotransformation after a short inhalation exposure and that it is rapidly exhaled in its unaltered form. INHALATION EXPOSURE LIMITS The ACGIH TLV-TWA (1983) and the OSHA federal standard (1983) for FC-12 are both 1,000 ppm; ACGIH recommended a TLV-STEL for 15-min excursions of 1,250 ppm. COMMITTEE RECOMMENDATIONS The previous EELs and CEL were established by the Committee in 1966. On the basis of a small decrement in human psychomotor performance at 10,000 ppm and none at 1,000 ppm for 2.5 h and positive findings in dogs in the 5-min cardiac-sensitization screening test at 80,000 ppm and in exercising dogs at 100,000 ppm, the Committee recommends a 60-min EEL of 10,000 ppm for FC-12. Because FC-12 is rapidly eliminated in expired air, the Committee recommends a 24-h EEL of 1,000 ppm and a CEL of 100 ppm. The present Committee’s recommended EELs and CEL for FC-12 and the limits proposed in 1966 are shown below.
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Emergency and Continuous Exposure Limits for Selected Airborne Contaminants: Volume 2 1966 1984 60-min EEL 30,000 ppm 10,000 ppm 24-hr EEL 20,000 ppm 1,000 ppm 90-d CEL 1,000 ppm 100 ppm
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Emergency and Continuous Exposure Limits for Selected Airborne Contaminants: Volume 2 REFERENCES American Conference of Governmental Industrial Hygienists. 1983. TLVs(R): Threshold Limit Values for Chemical Substances and Physical Agents in the Work Environment with Intended Changes for 1983–1984. Cincinnati, Ohio: American Conference of Governmental Industrial Hygienists. 93 p. Aviado, D. 1978. Physiological and biochemical responses to specific group of inhalants: concluding remarks. Fed. Proc. Fed. Am. Soc. Exp. Biol. 37:2508–2509. Azar, A., Reinhardt, C.F., Maxfield, M.E., Smith, P.E., Jr., and Mullin, L.S. 1972. Experimental human exposures to fluorocarbon 12 (dichlorodifluoromethane). Am. Ind. Hyg. Assoc. J. 33:207–216. Blake, D.A. and Mergner, G.W. 1974. Inhalation studies on, the biotransformation and elimination of [14C]trichlorofluoromethane and [14C]dichlorofluoromethane in beagles. Toxicol. Appl. Pharmacol. 30:396–407. Clark, D.G., and Tinston, D.J. 1973. Correlation of the cardiac sensitizing potential of halogenated hydrocarbons with their physicochemical properties. Br. J. Pharmacol. 49:355–357. Garriott, J., and Petty, C.S. 1980. Death from inhalant abuse: lexicological and pathological evaluation of 34 cases. Clin. Toxicol. 16:305–315. Haskell Laboratory for Toxicology and Industrial Medicine. 1955a. Eye irritation of Freon 12 in rabbits. Newark, Delaware: E.I.du Pont de Nemours & Co. [Unpublished] Haskell Laboratory for Toxicology and Industrial Medicine. 1955b. Acute oral toxicity of Freon 12, dichlorodifluoromethane. Newark, Delaware: E.I.du Pont de Nemours & Co. [Unpublished] Hood, D.B. 1956. Skin and eye irritation tests with aerosol hair sprays. Newark, Delaware: E.I.du Pont de Nemours & Co., Haskell Laboratory for Toxicology and Industrial Medicine  p. [Unpublished] Kehoe, R.A. 1943. [Unpublished Data on Dichlorodifluoromethane]. Cincinnati, Ohio: University of Cincinnati, Kettering Laboratory of Applied Physiology, College of Medicine. 22 p. Lessard, Y., Desbrousses, S., and Paulet, G. 1978. Rôle de l’adrénaline endogène dans le déclenchement de l’arythmie cardiague par le dichlorodifluorométhane (FC 12) chez les mammifères. C.R. Seances Soc. Biol. Paris 172:337–347.
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Emergency and Continuous Exposure Limits for Selected Airborne Contaminants: Volume 2 Lester, D., and Greenberg, L.A. 1950. Acute and chronic toxicity of some halogenated derivatives of methane and ethane. AMA Arch. Ind. Hyg. Occup. Med. 2:335–344. Mergner, G.W., Blake. D.A., and Helrich, M. 1975. Biotransformation and elimination of 14C-trichlorofluoromethane (FC-11) and 14C-dichlorodifluoromethane (FC-12) in man. Anesthesiology 42:345–351. Mullin, L.S. 1970. Cardiac sensitization—fright exposures. Report No. 81–70. Newark, Delaware: E.I.du Pont de Nemours & Co., Haskell Laboratory for Toxicology and Industrial Medicine.  p. [Unpublished] Mullin, L.S., Azar, A., Reinhardt, C.F., Smith, P.E., Jr., and Fabryka, E.F. 1972. Halogenated hydrocarbon-induced cardiac arrhythmias associated with release of endogenous epinephrine. Am. Ind. Hyg. Assoc. J. 33:389–396. Nuckolls, A.H. 1933. The comparative life, fire, and explosion hazards of common refrigerants. Chicago, Illinois: National Board of Fire Underwriters, Underwriters’ Laboratories. [Misc. Hazard No. 2375]. 119 p. Occupational Safety and Health Administration. 1983. Toxic and Hazardous Substances. Air contaminants. 29 CFR 1910.1000. Prendergast, J.A., Jones, R.A., Jenkins, L.J., Jr., and Siegel, J. 1967. Effects on experimental animals of long-term inhalation of trichloroethylene, carbon tetrachloride, 1,1,1-trichloroethane, dichlorodifluoromethane, and 1,1-dichloroethylene. Toxicol. Appl. Pharmacol. 10:270–289. Quevauviller, A., Chaigneau, M., and Schrenzel, M. 1963. [Experimental studies with mice on tolerance of lungs to chlorofluorinated hydrocarbons.] Ann. Pharm. Franc. 21:727–734. (in French) Sayers, R.R., Yant, W.P., Chornyak, J., and Shoaf, H.W. 1930. Toxicity of dichloro-difluoro methane, a new refrigerant. U.S. Bureau of Mines. Report of Investigations, R.I. 3013. Washington, D.C.: U.S. Bureau of Mines, Department of Commerce. 15 p. Scholz, J. 1962. New toxicologic investigations of freons used as propellants for aerosols and sprays. Translation of: Fortschr. Biol. Aerosol-Forsch. Jahren 1957–1961, Ber. Aerosol-Kongr. 4:420–429. Sherman, H., and Barnes, J.R. 1966. Feeding studies with dichlorodifluoromethane (Freon-12(R) food freezant). Report No. 12–66. Newark, Delaware: E.I.du Pont de Nemours & Co., Haskell Laboratory for Toxicology and Industrial Medicine.  p. [Unpublished]
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Emergency and Continuous Exposure Limits for Selected Airborne Contaminants: Volume 2 Sherman, H. 1974. Long-term feeding studies in rats and dogs with dichlorodifluoromethane (Freon(R) 12 food freezant). Report No. 24–74. Newark, Delaware: E.I.du Pont de Nemours & Co., Haskell Laboratory for Toxicology and Industrial Medicine.  p. [Unpublished] Shugaev, V.A. 1963. The toxicology of refrigerant Freon-12. In: Levine, B.S., ed. U.S.S.R. Literature on Air Pollution and Related Occupational Diseases. Vol. 12. A survey. 1966. p. 161–163. [Translation of: Gig. Sanit. 28(6):95–97, 1963]. Available from Natl. Technical Information Service, Springfield, VA as TT 66–61429. Stecher, P.G., Windholz, M., and Heahy, D.S., es. 2968. The Merck Index: An Encylopedia of Chemicals and Drugs. 8th ed. Rahway, New Jersey: Merck & Co., Inc. p. 351–352. Watanabe, T., and Aviado, D.M. 1975. Subacute inhalational toxicity of aerosol propellants. Pharmacologist 17:192, abstr. 097.
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