600882002 'Jmwa Saw Offica of -»»!(.i ar-c sf A-3CO' 3-32-002 sr>vir-r!Ti«f!tiii Mi» .Vbj.-mgtcir OC :0 Health Assessment Document for 1,1,2- Trichioro-1,2,2 - Trifiuoroethane (Chiorcfluorocarbon FC-113) ------- EPA-600/8-82-002 Review Draft Draft Do not cite or quote HEALTH ASSESSMENT DOCUMENT FOR 1,1,2-TRICHLORO-1,2,2-TRIFLUOROETHANE (CHLOROFLUOROCARBON FC-113) NOTICE This document is a preliminary draft. It has not been formally released by EPA and should not at this stage be construed to represent Agency policy. It is being circulated for comment on its technical accuracy and policy implications. ,,«0j, ii)i,;c!3 GG"wG4 Environmental Criteria and Assessment Office Office of Research and Development U.S. Environmental Protection Agency Research Triangle Park, North Carolina 27711 Project Coordinator: Mark M. Greenberg ------- DISCLAIMER This report is an internal draft for review purposes only and does not constitute Agency policy. Mention of trade names or commercial products does not constitute endorsement or recommendation for use. ------- PREFACE The Office of Health and Environmental Assessment, in consultation with an Agency work group, has prepared this health assessment to serve as a "source document" for Agency-wide use. Originally the health assessment was developed for use by the Office of Air Quality Planning and Standards; however, at the request of the Agency's Work Group on Solvents the assessment scope was expanded to address multimedia aspects. This assessment will help insure consistency in the Agency's consideration of the relevant scientific health data associated with chlorof1uorocarbon FC-113. In the development of the assessment document, the scientific literature has been inventoried, key studies have been evaluated, and summary/conclusions have been prepared so that the chemical's toxicity and related characteristics are qualitatively identified. Observed-effect levels and dose-response relationships are discussed, where appropriate, so that the nature of the adverse health responses are placed in perspective with observed environmental levels. ------- TABLE OF CONTENTS Page LIST OF TABLES . LIST OF FIGURES 1. SUMMARY AND CONCLUSIONS 1-1 2. INTRODUCTION 2-1 2.1 REFERENCES 2-3 3. PHYSICO-CHEMICAL PROPERTIES, PRODUCTION AND ENVIRONMENTAL FATE 3-1 3.1 CHEMICAL AND PHYSICAL PROPERTIES 3-1 3.2 ANALYTICAL METHODOLOGY 3-2 3.3 PRODUCTION, USE, EMISSIONS, AND AMBIENT MIXING RATIOS . 3-3 3.3.1 PRODUCTION 3-3 3.3.2 USE 3-4 3.3.3 AMBIENT AIR MIXING RATIOS 3-6 3.3.4 OTHER MEDIA 3-6 3.4 ATMOSPHERIC FATE 3-6 3.4.1 Persistence Time and Stratospheric Reactions . 3-9 3.5 REFERENCES 3-14 4. MAMMALIAN FATE AND DISPOSITION 4-1 4.1 ABSORPTION AND ELIMINATION 4-1 4.2 DISTRIBUTION AND METABOLISM 4-2 4.3 REFERENCES 4-6 5. HEALTH EFFECTS 5-1 5.1 ANIMAL STUDIES 5-2 5.1.1 Acute Toxicity 5-2 5.1.2 Cardiovascular and Respiratory Effects 5-2 5.1.2.1 Mouse 5-2 5.1.2.2 Dog 5-3 5.1.2.2.1 In Vitro -. 5-3 5.1.2.2.2 In Vivo 5-7 5.1.2.3 Monkey 5-11 5.1.3 Neurological Effects 5-14 5.1.3.1 Frog 5-14 5.1.3.2 Dog 5-14 5.1.4 Hepatoxicity 5-17 5.1.5 Teratogenic Effects 5-17 5.1.6 Mutagenic Effects 5-20 5.1.6.1 Mouse 5-20 5.1.7 Carcinogenic Effects 5-21 5.1.7.1 Mouse 5-21 5.1.8 Synergistic Effects 5-23 5.1.8.1 Mouse 5-23 5.1.9 Dermal Effects 5-25 5.1.10 Inhalation and Ingestion 5-25 5.2 HUMAN STUDIES 5-34 5.2.1 Occupation Exposure Studies 5-34 5.2.2 Experimental Exposure Studies > . . . 5-36 5.2.2.1 Inhalation 5-36 5.2.2.2 Dermal 5-39 5.2.2.3 Ingestion 5-41 V ------- 5.2.2.4 Synergistic, Carcinogenic, Mutagenic, and Teratogenic. . • 5-41 5.3 SUMMARY OF ADVERSE HEALTH EFFECTS AND ASSOCIATED LOWEST OBSERVABLE EFFECTS LEVELS 5-42 5.4 REFERENCES 5-45 6. ECOLOGICAL EFFECTS 6-1 6.1 CLIMATE 6-1 6.2 AGRICULTURAL CROPS 6-2 6.3 DOMESTIC AND WILD ANIMALS 6-2 6.4 AQUATIC SPECIES AND ECOSYSTEMS 6-2 7. CURRENT REGULATIONS, GUIDELINES, AND STANDARDS 7-1 8. COLLATED BIBLIOGRAPHY 8-1 ------- LIST OF TABLES Table Page 3-1 Physical Properties of trichlorotrifluoroethane . 3-2 3-2 Tropospheric levels of FC-113 3-7 3-3 Efficiency of various halocarbons in destroying stratospheric ozone relative to the ozone destruction efficiency of CFCL, (FC-11) 3-11 3-4 Important atmospheric reactions that affect stratospheric ozone 3-13 4-1 Mean tissue concentrations of FC-113 from rats exposed to 2,000 ppm 4-3 5-1 Effects of FC-113 on the electrocardiogram of anesthetized mice 5-4 5-2 Effect of FC-113 on the canine heart-lung preparation .... 5-5 5-3 Effect of FC-113 on cardiac sensitization to epinephrine in the unanesthetized dog 5-8 5-4 Respiratory and circulatory effects of FC-113 upon anesthetized Rhesus monkeys 5-12 5-5 Respiratory and circulatory effect of FC-113 upon anesthetized Rhesus monkeys 5-13 5-6 Carcinogenic effects of FC-113 + PB in mice, alone and in combination 5-22 5-7 Combined toxicity of FC-113 + PB upon neonatal mice 5-23 5-8 Dermal effects of FC-113 in mammals 5-24 5-9 Inhalation and ingestion toxicities of FC-113 in mammals . . . 5-25 5-10 Post-inhalation mean tissue concentrations of FC-113 in rats . 5-34 5-11 Post-inhalation breath concentrations of FC-113 in man .... 5-37 5-12 Effects of dermal exposure to FC-113 in man 5-41 5-13 Lowest observable adverse direct exposure effect levels . . . 5-44 Vll ------- LIST OF FIGURES Figure Page 5-1 Ventricular function curves in canine heart-lung preparations 5-6 5-2 Effect of 2% FC-113 on preganglionic stimulation of canine spinal preparations 5-15 5-3 Effect of 2% FC-113 on postganglionic stimulation of canine spinal preparations 5-16 5-4 Human exposures to FC-113; timetable of experiment 5-38 5-5 Effect of FC-113 upon psychomotor performance in man 5-40 Vlll ------- AUTHORS AND REVIEWERS The authors of this document are: Dr. Richard Carchman, Department of Pharmacology, The Medical College of Virginia, Health Sciences Division, Virginia Commonwealth University, Richmond, Virginia. [Chapter 5, Health Effects] Mr. Mark M. Greenberg, Environmental Criteria and Assessment Office, U.S. Environmental Protection Agency, Research Triangle Park, North Carolina. [Chapter 3, Physico-chemical Properties; Chapter 4, Mammalian Fate and Disposition] Contributing authors: Dr. Jeff Beaubier, Health Effects Research Laboratory, U.S. Environmental Protection Agency, Research Triangle Park, North Carolina. Dr. Dagmar Cronn, Washington State University, Pullman, Washington. IX ------- The following individuals reviewed an early draft of this document and submitted valuable comments: Or. Joseph Borzelleca Department of Pharmacology The Medical College of Virginia Health Sciences Division Virginia Commonwealth University Richmond, Virginia 23298 Dr. Herbert Cornish Dept. of Environmental and Industrial Health University of Michigan Ypsilanti, Michigan 48197 Dr. I. W. F. Davidson Dept. of Physiology/Pharmacology The Bowman Gray School of Medicine 300 S. Hawthorne Road Winston-Sal em, North Carolina 27103 Dr. Lawrence Fishbein National Center for Toxicological Research Jefferson, Arkansas 72079 Dr. John G. Keller P.O. Box 12763 Research Triangle Park, North Carolina 27709 Or. Marvin Legator Professor and Director Dept. of Preventive Medicine and Community Health Div. of Environmental Toxicity and Epidemiology University of Texas Medical Branch Galveston, Texas 77550 Dr. Benjamin Van Duuren Institute of Environmental Medicine New York University Medical Center New York, New York 10016 Dr. Richard Ward E. I. duPont de Nemours and Company Wilmington, DL Dr. Herbert Wiser U.S. E.P.A. Washington, DC ------- Participating Members of The Carcinogen Assessment Group Roy E. Albert, M.D. (Chairman) Elizabeth L. Anderson, Ph.D. Larry D. Anderson, Ph.D. Steven Bayard, Ph.D. Chao W. Chen, Ph.D. Bernard H. Haberman, D.V.M, M.S. Charaligayya B. Hiremath, Ph.D. Chang S. Lao., Ph.D. Robert McGaughy, Ph.D. Dharm W. Singh, D.V.M. , Ph.D. Nancy A. Tanchel, B.A. Todd W. Thorslund, Sc.D. Participating Members of The Reproductive Effects Assessment Group Peter E. Voytek, Ph.D. (Chairman) John R. Fowle III, Ph.D. Carol Sakai, Ph.D. Members of the Agency Work Group on Solvents Elizabeth L. Anderson Charles H. Ris Jean Parker Mark Greenberg Cynthia Sonich Steve Lutkenhoff James A. Stewart Paul Price William Lappenbush Hugh Spitzer David R. Patrick Lois Jacob Arnold Edelman Josephine Brecher Mike Ruggiero Jan Jablonski Charles Delos Richard Johnson Priscilla Holtzclaw Office of Office of Office of Office of Office of Office of Office of Office of Office of Consumer Office of Office of Office of Office of Office of Office of Office of Office of Office of and and and and and and Environmental Environmental Environmental Environmental Environmental Environmental Assessment Assessment Assessment Assessment Assessment Assessment Health Health Health Health Health Health Toxic Substances Toxic Substances Drinking Water Product Safety Commission Air Quality Planning and Standards General Enforcement Toxic Integration Water Regulations Water Regulations Solid Waste Water Regulations and Standards Pesticide Programs Emergency and Remedial Response and and Standards Standards XI ------- 1. SUMMARY AND CONCLUSIONS Compared with other halogenated hydrocarbon solvents with similar usage in industry, relatively little information is available from the literature on FC-113 (1,1,2-trichloro, 1,2,2-trifluoroethane), particularly with regard to its effects on mammalian organ systems. Existing evidence suggests that FC-113 is poorly metabolized, although recent data suggest that it is a sub- strate for the cytochrome P-450 mixed function oxidase system. Animal exposure studies indicate that FC-113 is retained in lipid-rich tissues. At ambient air mixing ratios (e.g., 18 ppt; 0.14 x 10 mg/m ) found or expected in the general environment and probably even at the higher levels (<4,160 ppt; <0.032 mg/m ) observed in urban areas, its potential for causing adverse, direct health effects are, thus far, undocumented. The limited experimental data do not indicate adverse health effects in humans at a TL\r of 1,000 ppm (7,700 mg/m ) due to exposure to FC-113. At exposure levels greatly exceeding 1,000 ppm (7,700 mg/m ), impairment of neurological and cognitive functions (humans) and detrimental cardiovascular effects (animals) have been observed. Because of the lack of detailed studies in these health areas, a conclusive assessment of the human health risks posed by ambient levels of FC-113 cannot be made. Before conclusions concerning the effects of long-term exposure to FC-113 can be drawn, more studies involving chronic exposure of animals are needed. Chlorofluorocarbon 113 is primarily of concern as a pollutant of the atmos- phere; it has a high vapor pressure and is practically insoluble in water. Direct effects of FC-113 upon the ecosystem have not been reported in the scien- tific literature; however, the high volatility and the absence of measurable levels in water suggest that FC-113 poses a low risk to aquatic species. The known information concerning the health effects of FC-113 is des- cribed in sections below. 1-1 ------- STRATOSPHERIC POLLUTION AND OZONE DEPLETION In contradistinction to an absence of demonstrated adverse health effects at FC-113 exposure levels below 1,000 ppm (7,700 mg/m ), the present concern focuses mainly on the potential contribution of FC-113 to health effects pro- jected to result from the photocatalytic destruction of stratospheric ozone (0-). A thin shield of ozone is located in the stratosphere, 10 to 50 kilometers above the earth's surface. Because it effectively absorbs ultraviolet-B radiation (in the wavelength range 290 to 320 nm), any decrease in 03 concen- tration is expected to result in an increased amount of this radiation (incident at the earth's surface) and human health effects associated with such radiation. More specifically photochemical reactions involving a variety of halogenated organic compounds, principally chlorof1uorocarbons, appear to have the potential to destroy ozone in the stratosphere to the extent that an increased incidence in certain types of skin cancer would likely result. It is difficult to estimate with much certainty the rate of 0, depletion that may be associated with atmospheric loadings of FC-113. The destruction of 0, in the stratosphere has been theorized to be catalyzed by atomic chlorine, released during photodestruction of halogen-containing species (such as FC-113) that are transported to the stratosphere. Chlorof1uorocarbon 113, and other structurally-similar compounds, are very resistant to destruction in lower portions of the atmosphere, i.e., the troposphere. Because it is essentially inert in the troposphere, FC-113 slowly is transported to the stratosphere. Chlorofluorocarbons have exceedingly long atmospheric lifetimes relative to most other atmospheric pollutants. FC-113 is estimated to have a stratospheric lifetime in the range of 86 to 100 years. Taking this and other information into account, recent modeling estimates of steady-state 0- depletion, consid- ering only current releases of FC-113, project less than one percent depletion per about 100 years. 1-2 ------- CARCINOGENICITY AND MUTAGENICITY The carcinogenic potential of FC-113 is unknown. Aside from a few studies that examined this issue, there is inadequate information to assess the carcino- genic potential of FC-113. Chiorofluorocarbon 113 has been reported to be nonmutagenic in the Ames assay system, with or without metabolic activation, and was reported to be nonmutagenic in a dominant lethal assay in the mice. Further testing is needed before any conclusions can be drawn with regard to the mutagenic po- tential of FC-113. TERATOGENICITY AND REPRODUCTIVE EFFECTS No clinical cases associate human exposure to FC-113 with congenital malformations in children. No epidemiological studies are available. In addition, no published animal studies are available which adequately assess the teratogenic or adverse reproductive potential of FC-113. Unpublished data from two studies conducted for E. I. duPont de Nemours and Company indicate that FC-113 did not produce toxic effects unique to rabbit conceptus at levels which were maternally toxic. It should be noted that these studies have major inadequacies and should be considered as pilot evaluations only. Maternal and fetal death precluded evaluation of a sufficient number of litters to establish a teratogenic effect. It is suggested that an assessment of the full potential of FC-113 to cause adverse teratogenic or reproductive effects can only be made after data are generated that are in accordance with current teratologic and reproductive testing (U.S. EPA, 1978, 1979). NEUROLOGICAL EFFECTS A noticeable impairment of psychophysiological function (as measured by task performance) has been reported in humans exposed to 2,500 to 4,500 ppm 1-3 ------- (19,250 to 34,650 mg/m ) of FC-113 for 30 minutes to 1 hour. Effects dis- appeared within 15 minutes after cessation of exposure. No impairment of exposure levels of 500 and 1,000 ppm (3,850 and 7,700 mg/m ) were observed during two weeks of exposure. CARDIOVASCULAR EFFECTS Serious cardiovascular effects are unreported in humans. Various animal studies (non-human primates and dogs) have indicated that acute exposure to high concentrations of FC-113 (as low as 2,000 ppm or 15,400 mg/m in a 6-hour exposure period) induces cardiac arrhythmias by sensitizing the heart to epinephrine. The compound may also induce myocardial depression by a direct effect on cardiac muscle, decrease contractile performance, and lead to hypo- tension by decreasing cardiac output and directly affecting peripheral vasodi- lation. A more definitive assessment of cardiovascular health hazards of FC-113 depends on future research. HEPATOXICITY Alterations of the smooth endoplasmic reticulum in livers of rats exposed to 1,000 and 2,000 ppm (7,700 and 15,400 mg/m3) FC-113 for 1 to 2 weeks as well as changes in drug-metabolizing hepatic enzymes have been observed. Some limited evidence suggests that FC-113 may act synergistically with other compounds; an increased mortality of mice was observed when FC-113 was admin- istered in combination with a pesticide synergist. 1-4 ------- 2. INTRODUCTION The principal intent of this document is to evaluate the health hazards associated with exposure to chlorofluorocarbon - 113 (FC-113). Chlorofluro- carbon 113 is released to ambient air as a result of evaporative loss during production, storage, consumer, and, manufacturing uses. Since its atmospheric reactivity is sufficiently low to allow it to reach the stratosphere, FC-113 also is of concern with regard to health effects of an indirect nature. In recent years, a great deal of attention has been focused upon the role of chlorofluorocarbons, including FC-113, and related species in the destruc- tion of stratospheric ozone (Oo). Depletion of 0., would increase the level of biologically-damaging ultraviolet radiation incident at the earth's surface. As a result, an increase in the incidence of certain types skin cancers would be likely to occur. A comprehensive discussion of the role of chloroflurocarbons in the photocatalytic destruction of stratospheric 0., is beyond the scope of this document. This area of stratospheric chemistry is rapidly changing with regard to refinements of atmospheric models and reaction kinetics. For a more de- tailed discussion, the reader is referred to recent publications of The National Research Council (1979a, b; 1982) and The World Meteorological Organization (1982). This health assessment document, however, does summarize the major findings of these groups in relation to estimates of stratospheric 0., change associated with chlorofluorocarbons in general, and whenever possible, with FC-113 in particular. It should be noted that FC-113 is simply one member of a group of struc- turally and chemically - related compounds that have the potential to alter stratospheric 0- levels. Others include: trichlorof1uromethane (FC-11), 2-1 ------- dichlorodifluoromethane (FC-12), dichlorotetrafluoroethane (FC-114), chloropenta- fluoroethane (FC-115), chlorodifluoroethane (FC-1426), and 1,1,1-trichloroethane (methylchloroform). In addition to evaluating the spectrum of health effects associated with FC-113 release to the environment, this document also discusses analytical methods, production, sources and emissions, ambient concentrations, and effects of an ecological nature to place FC-113 in a real-world perspective. 2-2 ------- 2.1 REFERENCES National Research Council. National Academy of Sciences. Protection Against Depletion of Stratospheric Ozone by Chlorofluorocarbons, 1979a. National Research Council. National Academy of Sciences. Stratospheric Ozone Depletion by Halocarbons: Chemistry and Transport, 1979b. National Research Council. National Academy of Sciences. Causes and Effects of Stratospheric Ozone Reductions: An Update, 1982. World Meteorological Organization. WHO Global Ozone Research and Monitoring Project Report No. 11, May 1981. The Stratosphere 1981: Theory and Measurements, 1982. 2-3 ------- 3. PHYSICO-CHEMICAL PROPERTIES, PRODUCTION AND ENVIRONMENTAL FATE 3.1 CHEMICAL AND PHYSICAL PROPERTIES Chlorofluorocarbons, in general, are characterized by high density, low boiling point, low viscosity, low surface tension, and high thermal and photo- stability (Downing, 1966). They do not react with most metals below 200°C nor do they generally react with acids or oxidizing agents. However, specific and unusual applications should be carefully reviewed and tested. To a large degree, stability is attributed to the number of C-F bonds—bonds exhibiting high bond strength (Bower, 1971). Trichlorotrifluoroethane, CC12F-CC1F2 (FC-113), is a non-flammable, colorless liquid, characterized by a moderately high vapor pressure and a low boiling point (Table 3-1) and by high thermal and photolytic stability. It is practically insoluble in water, is heavier than water, and is extremely re- sistant to hydrolysis (E. I. duPont de Nemours, 1976). At equilibrium, with a partial pressure of one atmosphere and at 86°F, less than 0.005 grams of FC-113 per liter of water per year are hydrolyzed (E. I. duPont de Nemours, 1980). Its solubility in water, per atmosphere of partial pressure at 25°C, is 0.017 grams per 100 grams of water (E. I. duPont de Nemours, 1980). While FC-113, as others in this class, is relatively inert upon contact with common construction materials such as steel, copper, and aluminum, it has the po- tential to react violently with more reactive metals in their elemental state, e.g., sodium, potassium, and barium (E. I. duPont de Nemours, 1976). Zinc, magnesium, and aluminum alloys containing more than two percent magnesium are not recommended for use in systems where water may be present (Downing, 1966; E. I. duPont de Nemours, 1969). As a solvent, FC-113 is often used in azeo- tropic mixtures with acetone, methylene chloride, and ethyl and methyl alcohol (Ward, 1981). Blends of FC-113 and isopropyl alcohol are also used. 3-1 ------- TABLE 3-1. PHYSICAL PROPERTIES OF TRICHLOROTRIFLUOROETHANE* Molecular weight 187.4 Boiling point 47.6°C (760 mm) Vapor pressure 6.5 lb/m2 (25°C) Density 1.5 gin/cm Solubility 0.017 gm/100 gm H20 (0°C, 760 mm) Downing, 1966; E. I. duPont de Nemours, 1969,1976. 3.2 ANALYTICAL METHODOLOGY Detecting extremely low levels of FC-113 in ambient air requires so- phisticated analytical techniques. The two most commonly used systems, both of which have a lower limit of detection on the order of a few parts per trillion (ppt), are gas chromatography-mass spectrometry (GC-MS) and gas chromatography-electron capture detection (GC-ECD). To measure workplace concentrations, GC coupled with flame ionization or thermal conductivity detectors is satisfactory. 3.2.1 Sampling Because FC-113 levels in air are typically in the sub parts-per-billion (ppb) range, the sampling and analysis techniques have been designed to detect trace levels. Singh et al., (1979) have employed cryogenic trapping of air containing trace levels of FC-113. During sampling, traps are maintained at liquid oxygen temperature. Traps were made of stainless steel packed with a 4-inch bed of glass wool or glass beads. Aliquots are thermally desorbed and injected directly into the gas chromatograph. More recently, Singh et al., (1981b) collected air samples in precleaned, 1-liter electropolished stainless-steel canisters. Samples were then preconcentrated at liquid oxygen temperature in freezeout traps containing SE-30 or glass wool. 3-2 ------- Makide et al., (1980) used electropolished stainless-steel canisters, followed by preconcentration on a silicone OV-101 column at - 40°C. Column termperature was raised at a rate of 5°C per minute up to 70°C for separation of components. 3.2.2 Analysis Cronn and Harsch (1979) reported a detection limit of 12 ppt (at a mixing ratio of 50 ppt) with GC-MS. Precision was 10 percent. A lower detection limit (2 ppt) was found using GC-ECD (Harsch and Cronn, 1978). In this system, the FC-113 mixing ratio was 23 ppt and precision was again 10 percent. Cronn and coworkers have reported difficulties in measuring low levels of FC-113 in samples collected at high altitudes (Harsch and Cronn, 1978). Contamination resulted when the mixing ratio of FC-113 in the laboratory air was in the range of 15 to 20 ppb (0.116 to 0.154 mg/m ). Measurements of FC-113 in rural air samples by GC-ECD using a freezeout concentration technique resulted in a detection limit of 0.8 ppt with a precision of 1.8 percent at a mixing ratio of 21 ppt (Rasmussen et al., 1977). In a comparison of GC-ECD with GC-MS, Cronn et al. (Cronn and Harsch, 1979; Cronn et al., 1976a) judged GC-ECD to be superior in reproducibility and in yielding a lower limit of detection. Since the presence of water and oxygen in the EC detector may cause erroneous results for some compounds, oxygen should be eliminated during pre-concentration procedures while water can be removed through the use of drying tubes (Russell' and Shadoff, 1977). The lowest detection limit reported is that of Makide et al. , (1980), <0.05 ppt with a GC-ECD system. 3.2.3 Calibration Gas chromatographs have generally been calibrated with static dilutions of ppm-level standards (Harsch and Cronn, 1978; Rasmussen et al., 1977; Makide et al., 1980) and by use of permeation tubes (Singh et al., 1981b). 3-3 ------- Singh et al. (1977a) judged FEP Teflon tubing to be satisfactory in generating primary standards for FC-113. All tubing materials were either aluminum or glass. Errors in this approach were less than 10 percent. Similar results were recently reported by Singh et al., (1981b). Permeation rates were determined at 30 ± 0.05 °C. Error was < ± 10 percent. Cell per- meation tubes were conditioned for two weeks or longer. These investigators concluded that permeation tubes offer the most accurate means of generating primary standards. 3.3 PRODUCTION, USE, EMISSIONS, AND AMBIENT MIXING RATIOS 3.3.1 Production Chiorofluorocarbons typically are produced by displacing chlorine from chlorocarbons with hydrogen fluoride (HF). The starting material is normally tetrachloroethy1ene (Ward, 1981). Other chlorocarbons commonly used include carbon tetrachloride (CC1.), and hexachloroethane (C2Clg). A reaction sequence employing C-Cl. (tetrachloroethylene) to produce FC-113 is depicted as follows: C2C14 + 3 HF SbC15 C2C13F3 + 3 HC1 ci2 45-200°C In this method, chlorine gas (C12) maintains the antimony pentachloride (SbClg) catalyst in the pentavalent state (Ward, 1981). The reaction can proceed either in the liquid or vapor phase. Anhydrous hydrogen chloride (HC1) is the principal byproduct. Only two manufacturers currently produce FC-113 in the United States: Allied Chemical Corporation, Baton Rouge, Louisiana (SRI Inter., 1979) and E. I. duPont de Nemours and Company, Inc., at its Montague, Michigan and Corpus Christi, Texas plants (Ward, 1981). 3-4 ------- Accurate U.S. production data for FC-113 are not readily available. Production rates for 1979 are estimated to be about 59,000 metric tons (E. I. duPont, 1982). The RAND Corporation (USEPA, 1980a) estimated that production of FC-113 in 1977 amounted to about 37,000 metric tons (upper bound) of which solvent application accounted for 96 percent of the FC-113 available for use. In 1990, about 71,000 metric tons can be projected to be produced (USEPA, 1980a). The NRC (NRC, 1979a) projects that, based on extrapolation of histo- rical data, usage could increase by a factor of 2 or 3 by 1990. 3.3.2 Use Principal uses of FC-113 fall into several main categories (NRC, 1979a): (1) degreasing, cleaning, and drying applications; (2) removal of solder flux; (3) critical cleaning of electronic, electrical and mechanical assemblies; (4) application as a cutting fluid, carrier and reaction medium, and dry cleaning solvent. It is an alternative to tetrachloroethylene, currently the solvent of choice in the drycleaning industry (Fischer, 1980). It has not been used previously in aerosol formulations. In cleaning and drying operations, two types of solvent losses occur (USEPA, 1980b): (1) escape in vapor form and (2) in liquid form when tanks are emptied for cleaning. Although there are no identified reports that FC-113 has been detected in surface or drinking waters, this potential exists since FC-113 may be sealed in drums and buried. Because FC-113 has very limited solubility in water and is highly volatile, all releases of FC-113 can be expected to eventually be conveyed to the stratosphere. Estimates of the National Research Council (NRC, 1979a) suggest that FC-113 emissions during the period 1976-1977 were 30,000 metric tons. FC-113 was reported to account for over 15 percent of chlorofluorocarbon emissions (U.S. EPA, 1980a). The World Meterological Organization (WHO, 1982), 3-5 ------- citing figures supplied by E. I. duPont de Nemours and Company, reported a current global annual emissions rate of 91,000 metric tons. The National Research Council (1979a) estimated 1976-1977 emissions in the United States by use category as follows: (1) degreasing, cleaning, and drying, 5,909 metric tons; (2) solder flux removal, 6,818 metric tons; (3) critical cleaning and drying, 11,818 metric tons; and (4) miscellaneous, 5,454 metric tons (909 metric tons associated with dry cleaning applications). Substitution of alternative solvents was considered a possibility to somewhat reduce emissions of FC-113 in all use categories except (3), where no al- ternative solvent is available. In a recent RAND Corporation report (U.S. EPA, 1980a), all FC-113 pro- duced for nonaerosol end uses was estimated to "find its way into the ambient air." FC-113 accounts for less than one percent of the market for solvents to dryclean clothes (U.S. EPA, 1980a). In 1976, about 3 percent of FC-113 sold in the United States was used as an inert carrier (U.S. EPA, 1980a). Assuming prompt emissions, the RAND estimate for emissions is 35,000 metric tons (U.S. EPA, 1980b). 3.3.3 Ambient Air Mixing Ratios The extent to which emissions of FC-113 contribute to the loading of the atmosphere is indicated by recent measurements of ambient air mixing ratios (Table 3-2). Measurements made in the latter part of 1977 indicated a global average mixing ratio of 18 ppt (Singh ,et al., 1979a,b); no gradient was observed between the northern and southern hemispheres. In comparison, the two most dominant chlorof1uorocarbons (methane series), FC-11 and FC-12, were found at global average mixing ratios of 126 and 220 ppt, respectively. Singh et al. (1979) expected the stratosphere to be the major reservoir for FC-113; 3-6 ------- despite extensive study, tropospheric sinks for FC-11, FC-12, and FC-113 are uncommon, and there is now little expectation that they exist (NRC, 1979a,b.) The most recently reported mixing ratios for the northern and southern hemispheres are those of the World Meteorological Organization (WHO, 1982). Based upon the observations of Singh et al., (1981b) and Rasmussen et al., (1981), the WMO reported ranges of 12 to 25 ppt (northern hemisphere) and 11 to 22 ppt (southern hemisphere). The estimated limit of detection was 1 ppt with the estimated accuracy at 20 percent and the estimated precision at 10 percent. Singh et al., (1981b) reported an average atmospheric growth rate for FC-113 of 2 ppt per year, based on measurements made at Point Arena, California, a "clean" air site, from late 1979 to early 1981. In flights over the Pacific Northwest in March 1976, Cronn and coworkers (1976b) detected FC-113 in the upper troposphere at an average mixing ratio of 21 ± 4 ppt (0.17 ± 0.03 x 10"3 mg/m3). More recently, Cronn et al. (1977a,b) have detected FC-113 in whole-air samples collected during high altitude tropospheric flights over the Pacific Ocean west of San Francisco (37° N). An average northern hemisphere tropospheric background mixing ratio of 18 ± 2.3 ppt (0.14 ± 0.02 x 10 mg/m ) was measured (April 1977). 3.3.4 Other Media No information is available regarding levels of FC-113 in water or soil. 3.4 ATMOSPHERIC FATE The potential for ambient air mixing ratios of FC-113 to pose a hazard to human health is influenced by many processes. Of principal concern is trans- port to the stratosphere where it participates in ozone (OO destruction reactions. 3-7 ------- TABLE 3-2. TROPOSPHERIC LEVELS OF FC-113 OJ I 00 Location Arizona Phoenix Cal ifornia Badger Pass Los Angeles Point Reyes Mill Valley Oakland Palm Springs Point Arena Riverside San Jose Stanford Hills Yosemite Delaware Delaware City Kansas Jetmore Maryland Baltimore Nevada Reese River Date of measurement 4/23/79 5/5/77 4/9/79 4/28/76 12/1/75 1/11/77 6/28/79 5/5/76 5/23/77 8/30/78 12/8/79 4/25/77 8/21/78 11/23/75 5/12/76 7/8/74 6/1/78 7/11/74 5/14/77 - 5/6/79 - 5/13/77 - 4/21/79 - 5/4/76 - 12/12/75 - 1/12/77 - 7/10/79 - 5/11/76 - 5/30/77 - 9/5/78 - 2/18/81 - 5/4/77 - 8/27/78 - 11/30/75 - 5/18/76 - 7/10/74 - 6/7/78 - 7/12/74 - 5/20/77 Concentration (ppb) max 1.2513 0.255 4.1601 0.315 0.450 0.181 0.3088 0.105 0.042 0.027 0.137 0.144 0.365 0.157 0.031 <0.01 0.040 0.038 0.042 mm 0.0122 0.014 0.0488 0.029 0.012 0.027 0.0163 0.012 0.014 0.018 0.024 0.020 0.017 0.008 0.011 <0.01 0.012 <0.01 0.004 average 0.1513 0.027 0.3048 0.118 0.031 0.042 0.0494 0.037 0.023 0.022 0.025 0.099 0.076 0.031 0.020 0.023 0.03 0.019 ± ± ± ± + ± ± ± ± ± ± ± + ± ± ± 0.2247 0.026 0.6671 0.077 0.041 0.026 0.0591 0.013 0.006 0.002 0.166 0.068 0.030 0.003 0.005 0.006 Reference Singh et al. , Singh et al. , Singh et al. , Ibid IbTd TFTd Singh et. al. Singh et. al. Ibid Ibid Singh et. al. Ibid TFTd Ibid TbTd Lillian et al Singh et al. , Lillian et al Singh et al. , 1981a 1979 1981 , 1981 , 1979 , 1981b . , 1975 1979 . , 1975 1979 ------- TABLE 3-2. (continued) CO 1 UD Location New Jersey Bayonne Sandy Hook Seagirt New York New York City White Face Mtns. Ohio Wilmington Japan 9 rural sites Date of measurement 3/73 7/2/74 6/18/74 6/27/74 9/16/74 7/16/74 8/78 - 12/73 - 7/5/74 - 6/19/74 - 6/28/74 - 9/19/74 - 7/26/74 - 9/78 Concentration (ppb) max 38 0.56 <0.01 0.025 <0.01 0.075 0.027 mm <0.01 <0.01 <0.01 <0.01 <0.01 <0.01 0.021 • average 4.12 <0.08 <0.01 0.025 0.016 0.023 ± 0.016 Reference Lillian et al. , 1975 Ibid TbTd Ibid Ibid Ibid Makide et al., 1980 ------- 3.4.1 Persistence and Stratospheric Reactions It is generally accepted that the longer the tropospheric residence time for a chemical species, the greater the likelihood of diffusion into the stratosphere. Concern that FC-113 is destroying stratospheric 0., and thus may contribute to an increase in the incidence of skin cancer has intensified recently. Chi orof 1 uorocarbons are remarkably stable in the troposphere. However, they do undergo photodissociation in the stratosphere (NRC 1979a, b; NRC 1982; WMO, 1982). In a recent report prepared for the U. S. Environmental Protection Agency by the Rand Corporation (USEPA, 1980a), FC-113 was described as highly unreactive and may not decompose prior to entering the stratosphere. There are no known tropospheric sinks for FC-113. Japar et al. (unpub- Ifshed) and Hester et al. (1974) reported that no detectable loss of FC-113 occurs when it is irradiated, under simulated atmospheric conditions, in the presence of olefins and nitrogen oxides. The possibility that some decomposi- tion of chl orof 1 uorocarbons may occur upon contact with hot desert sands was examined by the National Research Council (1979a) and a small allowance in their estimate of 0- depletion was made. As shown in the following reaction sequence, release of atomic chlorine (Cl) leads to the photocatalytic destruction of 0,: hv - > CC1F - CC1F + Cl • Cl- + 03 - » CIO + 02 CIO + 0 - >• Cl- + 02 Atomic chlorine, produced in the first reaction, would react with 0^ to yield chlorine oxide (CIO) that, upon subsequent reaction, would form a chain re- action, resulting in a continual depletion of 0.,. 3-10 ------- As noted by the World Meteorological Organization (WMO, 1982), the efficiency of this cycling is closely coupled with other cycles, principally the nitrogen oxides and hydroxyl radical cycles. In addition, efficiency is, in part, determined by perturbations in atmospheric temperature such as the strato- spheric cooling resulting from increases in carbon dioxide levels in the troposphere (World Meteorological Organization, 1982; National Research Council, 1982). Wuebbles and Chang (1981) recently have evaluated the impact of FC-113 and other chlorofluorocarbons on stratospheric 0.,. through use of the 1-0 Lawrence Livermore National Laboratory Model. This model uses chemistry recommended by the NASA Panel on Laboratory Measurements (Hudson and Reed, 1979). If FC-113 were to be released at the same rate as FC-11 and FC-12 Wuebbles and Chang (1981) calculated an 0- loss, at steady-state, of 8.5 percent, due to FC-113. There are two processes for FC-113 destruction: direct photolysis and reaction with 0('D), excited atomic oxygen, the latter being produced upon photodissociation of 0,. Calculations made by Chou et al. (1978) indicate that photodissociation accounts for 84 to 89 percent of FC-113 removal. An atmospheric lifetime, based upon measured absorption coefficients, in the range of 63 to 122 years was estimated. An atmospheric lifetime of 86 years was recently estimated by Wuebbles (1981) using the one-dimensional (1-0) transport-kinetics model of The Lawrence Livermore National Laboratory. The wavelength region associated with the photodissociation of chloro- fluorocarbons is the range from 185 to 227 nm between the Schumann-Runge absorption band for 0- and the Hartley band for 03- Atkinson et al. (1976) concluded that chlorofluorocarbons with two or more chlorine atoms had suf- ficiently high ultraviolet absorption in this range that photodissociation was 3-11 ------- the predominant mode of decomposition in the critical region (30 kilometers) of the stratosphere. The absorption cross section for FC-113 over the 185 to 227 nm wavelength range indicates that FC-113 has approximately the same potential for photo- dissociation as dichlorodifluoromethane (FC-12), but less than that for tri- chlorofluoromethane (FC-11) (Chou et al., 1978). Upon complete photodis- sociation, each molecule of FC-113 and F-ll yield an equal number of Cl atoms. The absorption maxima of FC-113 and FC-12 in the near ultraviolet are 160 nm and 177 nm, respectively (Sandorfy, 1976); the absorption maximum of FC-11 is at a higher wavelength, 185 nm. In this narrow wavelength range, absorption of UV by 0- is at a minimum, thus allowing for absorption (consequently, destruction) by chlorofluorocarbons. Preliminary data in a modelling study using the Lawrence Livermore 1-0 model suggest that FC-113 has a calculated efficiency in reducing strato- spheric 03 comparable to that of FC-11 and FC-12 (Table 3-3) (Wuebbles, 1981). The World Meteorological Organization (WMO, 1982), assuming continued release at the 1979 estimated emissions rate for FC-113 and using the model of Wuebbles (1981) and revised reaction rate kinetics, calculated an estimated steady-state depletion of the total 0., column of 0.8 percent. The overall 03 depletion estimate for steady-state release of FC-11 and FC-12 (principal stratospheric contaminants) is in the range of 5 to 9 percent (World Meteoro- logical Organization, 1982; National Research Council, 1982). If other stra- tospherically - important halocarbons are considered (particularly FC-113, carbon tetrachloride, and methyl chloroform) at the current release rates, WMO estimates that the predicted column 0- depletion would be increased about 4 one-third. In scenarios more representative of real-time conditions, for example, considering the variations in carbon dioxide, and nitrogen oxides, the WMO derived other estimates of steady-state 0~ depletion. In each scenario, 3-12 ------- TABLE 3-3. EFFICIENCY OF VARIOUS HALOCARBONS IN DESTROYING STRATOSPHERIC OZONE RELATIVE TO THE OZONE DESTRUCTION EFFICIENCY OF CFC1, (FC-11) (Adapted from Wuebbles, 1981) J Compound FC-11 FC-12 FC-113 FC-114 FC-115 CH3CC13 FC-22 FC-21 FC-13 FC-112 FC-142b Relative Efficiency per Pound Emitted 1.00 0.85 0.80 0.60 0.32 0.14 0.05 0.04 0.45 0.96 0.05 Relative Efficiency per Molecule Emitted 1.00 0.75 1.09 0.75 0.36 0.13 0.03 0.03 0.34 1.42 0.04 Relative Efficiency per Chlorine Atom Emitted 1.00 1.12 1.09 1.13 1.08 0.13 0.10 0.05 1.02 1.07 0.12 a continued increase in upper stratosphere 0, depletion is predicted. As noted by the WMO (1982). the 5 to 9 percent depletion estimate due to FC-11 and FC-12, if correct, suggests that less than a 1 percent decrease in global average stratospheric 0- should have occurred to date. State-of-the-art instrumentation and statistical methodology indicate that detection of global average stratospheric 0- trends is limited to about a 2 percent change per decade. 3-13 ------- In addition to the uncertainties and limitations of the models used to estimate the impact of FC-113 upon CL, the complexity and rapidly changing knowledge of the atmospheric chemistry make it difficult to assess such impact in quantitative terms. Among the atmospheric reactions that can act to en- hance or restrict 0- depletion due to FC-113, the NRC (1979b) cited those described in Table 3-4 as important determinants. An evaluation of the impact of FC-113 upon stratospheric 0- must take into account these and other atmospheric processes if realistic estimates of 0, depletion are to be made. TABLE 3-4. IMPORTANT ATMOSPHERIC REACTIONS THAT AFFECT STRATOSPHERIC OZONE (NRC, 1979b) Cl -i CIO CIO Cl H HC1 CIO CIO CIO •°3 - + 0 - + NO KCH4 + OH + N02 N02 + + H02 — - CIO + 02 » Cl + 0- . Cl * N02 . MPT •+• PH . pi + U n + M •• C10N02 + M hv > Cl + N03 »• HOC! * 02 HOC! * hv > Cl + OH, CIO + H 3-14 ------- 3.5 REFERENCES Atkinson, R., G. M. Breuer, J. N. Pitts, Jr., and H. L. Sandoval. Tropo- spheric and stratospheric sinks for halocarbons: Photooxidation, 0('D) atom, and OH radical reactions. J. Geophy. Res. 81(33):5765-5770, 1976. Bower, F. A. Nomenclature and Chemistry of Fluorocarbon Compounds. Aerospace Medical Research Laboratory, Wright-Patterson Air Force Base, AD 751-423, December 1971. Chou, C. C., R. J. Milstein, W. S. Smith, H. Vera Ruiz, M. J. Molina, and F. S. Rowland. Stratospheric photodissociation of several saturated perhalo chlorofluorocarbon compounds in current technological use (Fluoro carbons-IB, -113, -114, and -115). J. Phys. Chem. 82(1):1-7, 1978. Cronn, D. R. , and D. E. Harsch. Determination of atmospheric halocarbon concentrations by gas chromatography - mass spectrometry. Anal. Lett. 12 (B14):1489-1496, 1979. "~ Cronn, D. R., R. A. Rasmussen, and E. Robinson. Phase I Report. Measure ment of Tropospheric Halocarbons by Gas Chromatography - Mass Spectrometry. Washington State University, August 1976a. Cronn, D. R. , R. A. Rasmussen, and E. Robinson. Measurement of Tropospheric Halocarbons by Gas Chromatography-Mass Spectrometry. Report for Phase I. Submitted to U.S. Environmental Protection Agency, Washington State University, Pullman, Washington, August 23, 1976b. Cronn, D. R. , R. A. Rasmussen, and E. Robinson. Measurement of Tropospheric Halocarbons by Gas Chromatography-Mass Spectrometry. Report for Phase II. Submitted to U.S. Environmental Protection Agency, Washington State University, Pullman, Washington, October, 1977a. Cronn, D. R. , R. A. Rasmussen, E. Robinson, and D. E. Harsch. Halogenated compound identification and measurement in the troposphere and lower stratosphere. J. Geophys. Res. 82:5935-5944, 1977b. Downing, R. C. Aliphatic Chlorofluorohydrocarbons. In: Kirk-Othmer1s Ency- clopedia of Chemical Technology, Volume 9, 2nd Edition, 1966. E. I. duPont de Nemours ^nd Company to U. S. Environmental Protection Agency. Addendum for Freon Products Division Bulletins B-2 and S-16, 1980. E. I. DuPont de Nemours and Company. Personal communication from D. Broughton, 17 March 1982. E. I. duPont de Nemours and Company. "Freon" fluorocarbons. Properties and Applications. Wilmington, DE, 1969. 3-15 ------- E. I. duPont de Nemours and Company. Thermodynamic Properties of "Freon" 113, Trichlorofluoroethane, CC12F-CC1F2 with addition of other physical proper- ties. Wilmington, DE, T-113A, 1976. Fischer William, personal communication, International Fabricare Institute, Rockville, Maryland, 1980. Harsch, D. E. , and D. R. Cronn. Low-pressure sample-transfer technique for analysis of stratospheric air samples. J. Chromat. Sci. 16:363-367, 1978. Hester, N. E. , E. R. Stephens, and 0. C. Taylor. Fluorocarbons in the Los Angeles Basin. J. Air Pollut. Control Assoc. 24(6):591-595, 1974. Japar, S. , J. N. Pitts, Jr., and A. H. Winer. The photostability of fluoro- carbons, unpublished. Lillian, D. , H. B. Singh, A. Appleby, L. Lobban, R. Arnts, R. Gumpert, R. Hague, J. Toomey, J. Kazan's, M. Antell, D. Hansen, and B. Scott. Atmospheric fates of halogenated compounds. Environ. Sci. Technol. 9(12):1042-1048, 1975 Makide, Y. , Y. Kanai, and T. Tominga. Background Atmospheric Concentrations of Halogenated Hydrocarbons in Japan. Bull. Chem. Soc. Japan 53:2681- 2682, 1980. McCarthy, 1963. Cited in: U.S. Environmental Protection Agency Environmental Hazard Assessment Report: Major one- and two-carbon saturated fluoro- carbons, review of data. EPA-560/8-76-003, August 1976. National Research Council. National Academy of Sciences. Protection Against Depletion of Stratospheric Ozone by Chloroflurocarbons, 1979a. National Research Council. National Academy of Sciences. Stratospheric Ozone Depletion by Halocarbons: Chemistry and Transport, 1979b. National Research Council. National Academy of Sciences. Causes and Effects of Stratospheric Ozone Reduction: An Update, 1982. Rasmussen, R. A., D. E. Harsch, P. H. Sweany, J. P. Krasnec, and D. R. Cronn. Determination of atmospheric halocarbons by a temperature programmed gas chromatographic freezeout concentration method. J. Air Poll. Cont. Assoc. 27(6):579-581, 1977. Russell, J. W. , and L. A. Shadoff. The sampling and determination of halo- carbons in ambient air using concentration on porous polymer. J. Chromat. 134:375-384, 1977. Sandorfy, C. Review Paper. UV absorption of fluorocarbons. Atmos. Environ. 10:343-351, 1976. Singh, H. B. , L. J. Salas, H. Shigeishi, and E. Scribner. Atmospheric halo- carbons, hydrocarbons, and sulfur herafloride. Global distributions, sources, and sinks. Science 203:899-903, 1979b. 3-16 ------- Singh, H. B. , L. J. Salas, H. Shigeishi, A. J. Smith, E. Scribner, and L. A. Cavanagh. U.S. Environmental Protection Agency. Atmospheric Distribu- tions, Sources, and Sinks of Selected Halocarbons, Hydrocarbons, SFfi and N20. EPA-600/3-79-107, November 1979. b Singh, H. B. , L. J. Salas, and R. Stiles. Trace chemicals in the "clean" trosphere. EPA-600/3-81-055. SRI International, Menlo Park, California, 1981b. Singh, H. B. , L. Salas, D. Lillian, R. R. Arnts, and A. Appleby. Generation of accurate halocarbon primary standards with permeation tubes. Environ. Sci. Techno!. 11(5):511-513, 1977. Singh, H. B. , L. J. Salas, A. J. Smith, and H. Shigeishi. Measurements of some potentially hazardous organic chemicals in urban environments. Atmos. Environ. 15:601-612, 1981a. SRI International. Directory of Chemical Producers, Menlo Park, California, 1979. U. S. Environmental Protection Agency. Economic Implications of Regulating Chlorofluorocarbon Emissions from Nonaerosol Applications. EPA 560/12-80- 001. Report prepared by RAND Corporation, October 1980a. U. S. Environmental Protection Agency. Environmental Hazard Assessment Report. Major one- and two-carbon saturated fluorocarbons, review of data. EPA-560/8-76-003, August 1976. U. S. Environmental Protection Agency. Regulating Chlorofluorocarbon Emissions: Effects on Chemical Production. EPA-560/12-80-001b. Report prepared by RAND Corp., October 1980b. U.S. Environmental Protection Agency. Proceedings of the Conference on Methyl Chloroform and Other Halocarbon Pollutants. EPA-600/9-80-003. January 1980c. U.S. Environmental Protection Agency. Unpublished data from modelling studies being conducted by the Lawrence Livermore Laboratory, 1980d. Ward, Richard B. E. I. duPont de Nemours and Company to Jean Parker, U. S. Environmental Protection Agency, 29 September 1980, and to Mark Green- berg, personal communication U.S. Environmental Protection Agency, March 6, 1981. Wuebbles, D. J. The relative efficiency of a number of halocarbons for des- troying stratospheric ozone. Lawrence Livermore National Laboratory. UCID 18924, 1981. Wuebbles, D. J. , and J. S. Chang. A study of the effectiveness of the C1X catalytic ozone loss mechanisms. J. Geophy. Res. 86(10):9869-9872, 1981. 3-17 ------- ------- 4. MAMMALIAN FATE AND DISPOSITION 4.1 ABSORPTION AND ELIMINATION Use of FC-113 as a solvent for degreasing fabricated metal parts and dry cleaning of fabrics suggests that workers will primarily be exposed through inhalation and contact with the skin. Little information has been published concerning the fate and disposition of FC-113 and related compounds. Most of the data was obtained through ex- perimentation on rodent species and at inhalation exposure levels well above ambient tropospheric levels. Chlorof1uorocarbons were judged to be absorbed by dogs through inhalation in the following descending order: FC-11 > FC-113 > FC-12 > FC-114 (Shargel and Koss, 1972). Levels were determined in arterial and venous blood of anesthetized male and female dogs following exposure to an aerosol mixture containing 25 percent (by weight) of each compound. Blood samples were ex- tracted with hexane prior to quantitation by gas chromatography-e1ectron capture detection. Peak arterial levels accounted for only a small percentage of total administered dose. In general, fluorocarbons and chlorof1uorocarbons exhibit biphasic ab- sorption patterns (Azar et al., 1973; Letkiewicz, 1976). A rapid initial increase in blood levels is followed by a slower increase to maximum concen- trations. Equilibrium is reached when arterial and venous blood concentra- tions are equal. During elimination, there is a rapid initial fall in blood levels followed by a slower decline to undetectable levels. During elimin- ation, venous concentrations exceed arterial concentrations, indicating that fluorocarbons are being released from tissues. 4-1 ------- Unpublished data from E. I. duPont de Nemours and Company (1979) indicate that FC-113 is absorbed upon skin exposure (hands, arms, and scalp). The scalp was particularly absorbent: after one individual's scalp was exposed for 15 minutes, the maximum FC-113 concentration in expired breath was 12.7 ppm (98 mg/m ) in 20 minutes; with another individual similarly treated, a maximum concentration of 7.4 ppm (57 mg/m ) was reached in 18.5 minutes. Ninety minutes after exposure, FC-113 concentrations were below 0.5 ppm (3.8 mg/m ) in all subjects. Administration of FC-12 and FC-114 to dogs by various routes of exposure indicate that chlorof1uorocarbons are eliminated solely via the respiratory tract (Matsumato et al., 1968). 4.2 DISTRIBUTION AND METABOLISM Chlorofluorocarbon 113 can be expected to be stored in lipid-rich tissues during continuous exposure. During the slow rise to maximal blood concentra- tion, arterial concentrations have been observed to be greater than venous concentrations (Azar et al., 1973). Blood levels of FC-113 and other fluoro- carbons were measured in beagle dogs during experiments reported by Trochi- mowicz et al. (1974). Animals were exposed for 10 minutes to 0.1 percent (1,000 ppm; 7,700 mg/m3), 0.5 percent (5,000 ppm; 38,500 mg/m3), and 1.0 per- cent (10,000 ppm; 77,000 mg/m ) FC-113. The investigators recorded higher levels in arterial blood during exposure and lower levels post exposure. The authors suggested that these observations reflect an uptake and release by body tissues. At exposure levels (5,000 ppm; 38,500 mg/m ) which have sensi- tized the heart to exogenous epinephrine, arterial blood levels of 12.5 pg/ml and venous blood levels of 4.9 ug/ml were observed (at 5 minutes of exposure). Carter et al. (1970) detected FC-113 in brain, liver, heart, and fat of rats exposed, via inhalation, for 7 to 14 days. Levels are shown in Table 4-1. Similar findings have recently been reported by Savolainen and Pfaffli 4-2 ------- TABLE 4-1. MEAN TISSUE CONCENTRATIONS OF FC-113 FROM RATS EXPOSED TO 2,000 PPM (Carter et al.t 1970) Exposure Tissue Brain Liver Heart (ug/gm) (ug/gm) (ug/gm) 22. 15. 16. 7 days 73 ± 77 ± 59 ± 1. 0. 2. 00 87 56 14 days 22. 16. 15. 65 ± 40 ± 03 ± 1. 1. 2. 33 72 51 Postexposure 24 hours 48 hours none none none none none none Fat (ug/gm) 722.48 ± 71.29 659.24 ± 21.17 108.45 ± 33.62 5.60 ± 2.94 Adrenal (ug) 8.39 ± 2.61 3.47 ± 0.34 none none Thyroid (ug) 1.09 ± 0.46 0.94 ± 2.00 none none (1980). Male Wistar rats exposed to 200, 1,000, and 2,000 ppm (1,540, 7,700, 15,400 mg/m ) FC-113 vapor for 2 weeks, 5 days per week, 6 hours daily exhibited a dose-dependent accumulation of the compound in peri renal fat and brain suggesting a long half-time of diminution from adipose tissue or organs with high lipid concentrations. The neurochemical effects of FC-113 exposure were examined by measuring levels of RNA, glutathione, and oxidative enzymes in brain tissue. After the second week of exposure to 1,000 ppm (7,700 mg/m ), cerebral RNA levels were 14.1 ±0.7 nmoles/mg protein. Corresponding controls were 12.8 ±1.0 nmoles/mg protein. This was statistically significant at p < 0.05. Glutathione levels, after one week of exposure of animals to 2,000 ppm, were lower than controls at p < 0.01 (2.4 ± 0.05 nmoles/mg protein compared to 2.6 ± 0.07 nmoles/mg protein. Glutathione peroxidase, an enzyme which protects cells from oxidative damage, was decreased (p < 0.01) compared to controls following the second week of exposure to 2,000 ppm (15,400 mg/m ). Exposed animals had a level of 17.5 ±1.0 nmoles/mg protein compared to 20.6 ±0.5 for controls. When rats were withdrawn from exposure to 2,000 ppm for 7 days, 4-3 ------- cerebral RNA decreased from a level of 13.1 ±0.4 nmoles/mg protein (controls) to 12.6 ± 0.2 (p < 0.05). Differences in levels for glutathione and glutathione peroxidase during this period were no longer observed. Vainio et al (1980) observed j_n vivo effects of FC-113 on a number of hepatic drug metabolizing enzymes. Male Wistar rats were exposed to 200, 1,000 or 2,000 ppm (1,540, 7,700, or 15,400 mg/m3) FC-113, 5 days per week, 6 hours daily for 1 or 2 weeks. NADPH cytochrome c reductase activity decreased 36 percent (p<0.01) and 19 percent (p<0.05) after 1 and 2 weeks of exposure, respectively, to 2,000 ppm. Microsomal cytochrome P-450 showed a statistic- ally significant decline after 1 week of exposure to 1,000 ppm (7,700 mg/m ) (p<0.01) and 2,000 ppm (15,400 mg/m ) (p<0.01). UDP glucuronosyl-transferase showed a dose-related increase in activity after 2 weeks of exposure of rats to 1,000 ppm (7,700 mg/m ) (p<0.01) and after 1 and 2 weeks of exposure to 2,000 ppm (15,400 mg/m ) (p<0.01 and <0.05, respectively). Glutathione content showed a statistically significant (p<0.05) after only 2 weeks of exposure at the 2,000 ppm (15,400 mg/m ) level. Evidence also was presented indicating that FC-113 was bound to cytochrome P-450 in the hepatic microsomes from uninduced and phenobarbital-induced rats. Phenobarbital treatment increased the affinity of FC-113 to cytochrome P-450, as judged from the decrease in the apparent spectral dissociation constant obtained from a type 1 difference spectrum. The observed binding does suggest that FC-113 may be a substrate for the mixed function oxidases. The authors suggested that FC-113 may have the potential to perturb microsomal membrane integrity. UOP glucuronosyltrans- ferase is a detoxification enzyme dependent on membrane integrity. IH vitro experiments with FC-11 (trichlorofluoromethane) suggest that some irreverible binding to phospholipids and protein occurs (Uehlehe and 4-4 ------- Werner, 1975). Minor amounts of urinary non-volatile metabolites have been demonstrated in man after exposure to FC-11 (Mergner et al., 1975). 4-5 ------- 4.3 REFERENCES Azar, A., H. J. Trochinowicz, J. B. Terrell, and L. S. Mull in. Blood levels of fluorocarbon related to cardiac sensitization. Amer. Ind. Hyg. Assoc. J. 34(3):102-109, 1973. E. I. duPont de Nemours and Company. Data submitted to the U.S. Environmental Protection Agency, Environmental Criteria and Assessment Office, August 20, 1979. letkiewicz, F. J. Environment Hazard Assessment Report: Major One- and Two-Carbon Saturated Flourocarbons, EPA-560/8-76-003, U.S. Environmental Protection Agency, Office of Toxic Substances, August 1976. Matsumato, T., K. C. Pani, J. J. Kovaris, and F. Hamit. Aerosol tissue adhe- sive spray. Fate of freons and their acute topical and systemic toxicity. Arch. Surg. 97:727-735, 1968. Mergner, G. W. , D. A. Blake, and M. Helrich. Biotransformation and elimina- tion of 14C-trichlorofluoromethane (FC-11) and 14C-dichlorodifluoro- methane (FC-12) in man. Anesthes. 42:345-351, 1975. Savolainen H. and P. Pfaffli. Dose-dependent neurochemical effects of 1,1,2- trichloro-l,2,2-trifluoroethane inhalation exposure in rats. Toxicol. Lett 6:43-49, 1980. Uehleke, J. , and Th. Werner. A comparative study of the irreversible binding of labelled halothane, trichlorof1uoromethane, chloroform, and carbon tetrachloride to hepatic protein and lipids in vitro and in vivo. Arch. Toxicol. 34:289:308, 1975. Vainio, H. , J. Nickels, and T. Heinonen. Dose-related hepatotoxicity of l,l,2-trichloro-l,2,2,-tr.fluoroethane in short-term intermittent inhala- tion exposure in rats. Toxicol. 18:17-25, 1980. 4-6 ------- 5. HEALTH EFFECTS The impact of FC-113 upon human health must be viewed from two separate perspectives: (1) potential effects resulting from direct exposure and (2) possible indirect adverse effects resulting from pertubations of stratospheric °3' INDIRECT EFFECTS As discussed in earlier chapters, FC-113 is transported to the strato- sphere where it is predicted to photocatalytically destroy 03 (Panofsky, 1978; Molina and Rowland, 1974). Depletion of stratospheric 03, in turn, allows more damaging ultraviolet (UV-B) radiation to reach the earth's surface. Such projected depletion of stratospheric 0, resulting in increased UV-B radiation has the potential to result in an increase in the incidence of certain types skin cancers as well in mortality (National Research Council, 1979a,b; 1982). Skin cancer is of two general types. It is the most common neoplasm in man and is increasing rapidly (Beaubier, 1980). One type of skin cancer, mel- anoma, arises in the pigment-producing melanocytes and/or in nevocytes (cells comprising moles). Unlike nonmelanomas (which arise in skin cells), melanomas metastasize readily to brain, heart, liver, and kidneys (Beaubier, 1980). Thus, melanoma is highly fatal. Whereas nonmelanoma occurs about 50 times more frequently than melanoma, melanoma is responsible for more lethality (Beaubier, 1980). Experimentally, UV-B radiation (wavelength range 290-320 nm) has been shown to cause mutations and cellular death (Smith, 1976,; Setlow, 1974), and produce nonmelanoma cancers in mice (Forbes and Urbach, 1975). In contrast, there are no reliable models for light - induced melanoma. Further- more, exposure to sunlight is only one of several factors associated with the occurrence of melanomas, making it difficult to estimate the relative contri- bution of UV-B radiation. 5-1 ------- The National Research Council (1979a) reported that recent epidemiologic studies of the National Cancer Institute have concluded that the biological amplification factor (fractional change in skin cancer incidence rates per fractional change in UV-8 radiation) is two, rather than one as previously presented. Also, when the fractional change in UV-8 radiation per fractional change in Og concentration is considered, the overall amplification factor (fractional change in skin cancer incidence rate per fractional change in 0, concentration) is four, rather than two as previously presented. Taking this and other information into account, the NRC (1982) estimated that there will be a 2 to 5 percent increase in basal cell skin cancer incidence per 1 percent decrease in stratospheric 0-; the increase in squamous cell skin cancer in- cidence will be about double that. Because of data limitations implicating UV-B as the only responsible wavelength region, the NRC (1982) did not make a prediction about the increase in incidence of malignant melanoma associated with a decrease in 0,. DIRECT EFFECTS 5.1 ANIMAL STUDIES 5.1.1 Acute Toxicity Acute inhalation exposures of various animal species to fluorocarbons at levels exceeding 25,000 ppm (192,500 mg/m ) in inhaled air results in adverse effects. Exposures to concentrations between 50,000 and 250,000 ppm (385,000 and 1.925 x 10 mg/m ) have been fatal. A characteristic feature of FC-113 exposure is tachycardia and hypertension at 25,000 and 50,000 ppm (192,500 and 385,000 mg/m ). High concentrations have induced cardiac arrhythmia in dog, sensitized the heart to the action of epinephrine in dog and mouse and caused depression of myocardial contractility in dog. 5.1.2 Cardiovascular and Respiratory Effects 5.1.2.1 Mouse—Aviado and Belej (1974) evaluated the ability of FC-113 to induce cardiac arrhythmias and to sensitize the heart to epinephrine. In this 5-2 ------- study male Swiss mice (25 to 35 grams) were anesthetized with sodium pentobar- bital (i.v., 0.7 mg/10 g). This dosage is equivalent to 70 mg/kg. A lead II electrocardiogram was used to monitor the cardiovascular response. There were three mice in each of four experimental groups. Group (1) inhaled 5 percent (50,000 ppm; 385,000 mg/m ) FC-113; group (2) inhaled 5 percent (50,000 ppm; 385,000 mg/m ) FC-113 plus a challenging dose of epinephrine 2 minutes prior to the initiation of inhalation; group (3) inhaled 10 percent (100,000 ppm; 770,000 mg/m ) FC-113; group (4) inhaled 10 percent (100,000 ppm; 770,000 mg/m ) FC-113 and a similar challenge schedule as described for (2). This dose of epinephrine (i.v., 60 ug/kg) was previously found to produce a tran- sient and moderate cardiac acceleration. The results of this study are presented in Table 5-1. FC-113 at 5 per- cent (50,000 ppm; 385,000 mg/m ) produced a response (ventricular ectopic beats) in the presence of a challenging dose of epinephrine while inhalation of 10 percent (100,000 ppm; 770,000 mg/m ) FC-113 resulted in cardiac abnorma- lities both with and without epinephrine. 5.1.2.2 003 5.1.2.2.1 J.n vitro. Aviado and Belej (1975) tested the ability of FC-113 to depress myocardial contractility in a canine heart-lung preparation. The dogs were anesthetized with sodium pentobarbital (i.v., 30 mg/kg). The force of myocardial contractility was measured by a Walton strain-gauge and was plotted as ventricular function curves. The experimental groups consisted of three dogs each: group 1 inhaled 2.5 percent (25,000 ppm; 192,500 mg/m ) FC-113; group 2 inhaled 5.0 percent (50,000 ppm; 385,000 mg/m ) FC-113. The results are presented in Table 5-2 and Figure 5-1. Both 2.5 percent (25,000 ppm; 192,500 mg/m3) and 5.0 percent (50,000; 385,000 mg/m3) FC-113 caused no decrease in myocardial contractility as measured by the strain-gauge while both ventricular function curves show a shift to the right. This shift indicates a decrease in ventricular output for the same filling pressure, or a 5-3 ------- TABLE 5-1. EFFECTS OF FC-113 ON THE ELECTROCARDIOGRAM OF ANESTHETIZED MICE Concentration % V/V 5 10 Exposure to FC-113 alone No. of Type of Arrhythmia Exposures (incidence) 3 none 3 inverted T wave (1) Exposure No. of Exposures 3 3 to FC-113 and Epinephrine Type of Arrhythmia (incidence) ventricular ectopics (1) ventricular bigeminy (3) Data from Aviado et al. (1974). en ------- TABLE 5-2. EFFECT OF FC-113 ON THE CANINE HEART-LUNG PREPARATION ADMINISTRATION OF 2.5 AND 5% PROPELLANTS TO HEART-LUNG PREPARATIONS FIXED AT 5 cm LEVEL OF VENOUS RESERVOIR (MEAN ± S.E.M.) Propellant f luorocarbon No. Trichlorotri- fluoroethane FC-113 Inhaled concen- tration 2.5 5.0 Number of prepar- ations 3 3 Heart rate Myocardial force (beats/min) Con- trol 147 ± 12.5 148 ± 13.1 Re- sponse 148 ± 10.6 150 ± 12.5 % A - 2 ± 1 - 1 ± 1 Con- trol 82 ± 1.5 90 ± 2.7 (g) Re- sponse 80 ± 0.6 86 ±2.1 Left atrial pressure Cardiac output (mm Hg) % A - 3 ± 1 - 4 ± 1 Con- trol 2.9 ± 0.2 2.9 ± 0.2 Re- % A sponse trol 3.0 + 2 ± 0.2 ± 3 3.0 + 3 ± 0.1 ± 3 (1/minl Con- 1.31 ± 0.17 1.27 ± 0.02 Re- sponse 1.28 ± 0.02 1.23 ± 0.02 % A - 3 ± 1 - 3 ±0.1 Data from Aviado and Belej (1975). en i en ------- 16 14 12 e I 5 10 & O a ac u 14 12 10 O CONTROL O PC 113 I 25% v/v O CONTROL 0 FC113 50%v/v I I 2468 LEFT ATRIAL PRESSURE, mm Hg Figure 5-1. Ventricular function curves in canine heart-lung preparations before and during inhal- ation of 2.5 or 5.0% propellant in air. Each point represents the mean and standard error of the mean in groups of 3 preparations. From Aviado and Belej. 1975. 5-6 ------- decrease in myocardial contraction indicating that the ventricular function curve is the more sensitive of the two measures. Both 2.5 percent (25,000 ppm; 192,500 mg/m ) and 5.0 percent (50,000 ppm; 385,000 mg/m ) FC-113 caused myocardial depression in the canine heart-lung preparation. 5.1.2.2.2 Li vivo. Reinhardt et al. (1973) tested the ability of FC-113 to sensitize the heart to exogenous epinepnrine. Unanesthetized male beagle dogs were exposed to FC-113 concentrations of 0.25 percent (2,500 ppm; 19,250 mg/m ), 0.50 per- 3 3 cent (5,000 ppm; 38,500 mg/m ) and 1.0 percent (10,000 ppm; 77,000 mg/m ). Electrocardiograph recordings monitored the cardiovascular response. A marked response (see Table 5-3) was defined as the development of a life-threatening arrhythmia (e.g., multiple consecutive ventricular beats) not present follow- ing the first (control) dose of epinephrine. Epinephrine was administered 5 minutes before and 5 minutes after the initiation of the 10 minute FC-113 inhalation period following a 7-minute period of inhalation of room air. It was previously shown that doses of epinephrine (i.v., 8 ug/kg) administered 10 minutes apart did not produce additive effects. No marked responses were observed in twelve exposures at 0.25 percent (2,500 ppm; 19,250 mg/m ) FC-113. The results are presented in Table 5-3. FC-113 causes cardiac sensitiza- tion to exogenous epinephrine at a concentration of 0.5 percent (5,000 ppm; 38,500 mg/m ). Autopsies performed on both dogs that developed fatal arrhyth- mias revealed no gross or microscopic abnormalities indictive of a pathological condition. In an earlier unpublished report, Reinhardt and coworkers cautioned that results obtained at exogenous epinephrine concentrations should not be extra- polated to humans at lower fluorocarbon exposure levels (Mullin et al., 1971). It was noted that a much higher concentration of fluorocarbon is needed to sensitize a dog's heart to the action of its own circulating level of epine- phrine, even when it is elevated through exercise. It was suggested that there is a considerable margin of safety between effect levels in dogs given 5-7 ------- TABLE 5-3. EFFECT OF FC-113 ON CARDIAC SENSITIZATION TO EPINEPHRINE IN THE UNANESTHETIZED DOG Concentration of FC-113 en i CO Nominal 0.25 0.50 1.0 Data from Numbers in % (U/V) Analytical (gas. chrom. ) 0.25 - 0.27 0.40 - 0.57 0.90 - 0.95 Reinhardt et al. (1973). parentheses indicate number of No. of No. Dog Exposures Marked 12 29 4 cases of ventricular fibri of Responses 0 10 (1) 3 (1) llation and % Marked Responses 0.0 34.5 75.0 cardiac arrest included in marked responses. ------- exogenous epinephrine and levels that humans would normally experience. The rate of epinephrine secretion from the human adrenal gland in time of stress was reported to reach a level of 0.004 mg/kg/min (as cited in Mullin et al., 1971). Exogenous epinephrine, as employed in the Haskell Laboratory experi- ments, was reported to yield a dose of about 0.050 mg/kg/min, or ten times higher than a human would be likely to secrete in time of stress. Clark and Tinston (1973) determined the EC5Q for the cardiac sensitizing effects of FC-113 using unanesthetized beagle dogs (10-13 kg). Lead II elec- trocardiograms were recorded to monitor the cardiovascular response. The experimental groups consisted of four to seven dogs each. The dogs inhaled FC-113 for 5 minutes, receiving equal doses of epinephrine (i.v. , 5 ug/kg) 30 seconds before the end of the inhalation period and 10 minutes post-exposure. Cardiac arrhythmias were never observed prior to the first or second injection of epinephrine even when it followed a challenge injection that had caused an arrhythmia. At 1.0 percent (10,000 ppm; 77,000 mg/m ) FC-113, 50 percent of the animals can be sensitized to the effects of epinephrine with a 95 percent confidence interval of 0.5 percent to 1.4 percent around this value. It should be pointed out that the above-mentioned cardiac sensitization studies are used to rank substances and, because exogenous epinephrine was administered, cannot be extrapolated to human situations in which epinephrine is endogenously released in certain situations. Blood levels of FC-113 and other fluorocarbons in beagle dogs that are associated with the cardiac sensitizing effect of FC-113 have been examined by Trochimowicz et al. (1974). Exogenous epinephrine was not administered to the animals. After recovery from surgery during which indwelling catheters were implanted, four dogs were exposed via face mask for 10 minutes to FC-113 at levels of 0.1 percent (1,000 ppm; 7,700 mg/m3), 0.5 percent (5,000 ppm; 38,500 3 3 mg/m ), and 1.0 percent (10,000 ppm; 77,000 mg/m ). The investigators recorded 5-9 ------- an arterial-venous difference during and after exposure. The authors suggested that this observation reflects an uptake by body tissues. After exposure, levels for all fluorocarbons were higher in venous blood. At the sensitizing level (5,000 ppm; 38,500 mg/m ), blood concentrations of 12.5 ug/ml arterial blood and 4.9 ug/ml venous blood were recorded (at 5 minutes of exposure). At the TLv (1,000 ppm; 7,700 mg/m ), blood concentrations were 2.6 ug/ml (arterial) and 1.5 ug/ml (venous). In a followup study, Trochimowicz et al. (1976) tested dogs with experi- mentally-induced myocardial infarctions to determine if heart damage might lower the apparent threshold for cardiac sensitization due to chlorofluoro- carbons. Although FC-113 was not used (methyl chloroform, trichlorofluoro- methane, and bromotrifluoromethane were the test substances), the test results were reported to indicate that the halocarbons had no greater potential for cardiac sensitization among dogs having recovered from myocardial infarction than normal, healthy dogs. Concentrations of the test chemicals ranged from 0.25 percent (V/V) for methyl chloroform to 10 percent (v/v) for bromotri- fl uoromethane. Test method involved exposure to test chemicals, followed by an intravenous dose (8 .ug/kg) of epinephrine. This dose of epinephrine was reported to cause only mild ECG alterations. Unpublished data of Mull in and coworkers (1971) suggest that, in beagle dogs trained to run on a treadmill while being exposed (up to 16 minutes) to FC-113, (8 dogs to 10,000 ppm; 77,000 mg/m3 and 4 dogs to 20,000 ppm; 154,000 mg/m ), endogenous epinephrine is not high enough to cause cardiac arrhythmias at FC-113 levels below 20,000 ppm (154,000 mg/m3). In cardiac sensitization studies conducted by E. I. duPont de Nemours and Company, it was concluded that FC-113 is capable of sensitizing a dog's heart to exogenous epinephrine following exposure to concentrations between 2,000 to 2,500 ppm (15,400 to 19,250 mg/m3) for periods of 0.5, 1, or 6 hours. One of six dogs exposed to 2,500 ppm (19,250 mg/m3) for both 0.5 and 1 hour gave a 5-10 ------- marked response. However, it was reported that exposures (12) of dogs to concentrations of 10,000 ppm (77,000 mg/m ) FC-113 for a duration of 5 minutes did not cause cardiac arrhythmias in dogs frightened by a loud noise or electric shock (Haskell Laboratory, 1979). 5.1.2.3 Monkey—Belej et al. (1974) tested the effects of FC-113 upon heart rate, myocardial force, aortic blood pressure, left atria! pressure, and pulmonary arterial pressure in anesthetized rhesus monkeys. The monkeys were anesthetized with sodium pentobarbital (i.v., 30 mg/kg), and their tracheas were cannulated for artificial respiration. A lead II EKG recorded cardio- vascular responses; myocardial contraction was measured with a strain-gauge. The experimental groups, which consisted of three animals each, inhaled either 2.5 percent (25,000 ppm; 2,500 mg/m ) or 5.0 percent (50,000 ppm; 385,000 mg/m ) FC-113 for 5 minutes alternating with inhalation of room air for 10 •t minutes. The results presented in Table 5-4 indicate that 2.5 percent (25,000 ppm; 192,500 mg/m ) FC-113 is capable of inducing both tachycardia and myocardial depression. The authors report that both concentrations caused cardiac arrhythmias. Aviado and Smith (1975) tested the effects of FC-113 upon respiration and circulation using rhesus monkeys anesthetized with sodium pentobarbital (i.v., 30 mg/kg). The tracheas were cannulated for artificial respiration. Lead II EKG and femoral arterial blood pressure were continuously recorded. The following parameters were determined: pulmonary resistance, pulmonary com- pliance, and respiratory minute volume. Each test group consisted of three monkeys. Each group inhaled either 2.5 percent (25,000 ppm; 192,500 mg/m ) or 5.0 percent (50,000 ppm; 385,000 mg/m ) FC-113 for 5 minutes, alternating with room air for 15 minutes. 5-11 ------- TABLE 5-4. RESPIRATORY AND CIRCULATORY EFFECTS OF FC-113 UPON ANESTHETIZED RHESUS MONKEYS en l FC-113 % Inhaled Concentration 2.5 5.0 FC-113 % Inhaled Concentration 2.5 5.0 FC-113 % Inhaled Concentration 2.5 5.0 Heart rate (beats/min) Monkey # Control 3 150.0 0.0 3 155.0 ± 2.9 Response 163.0 ± 8.8 185. Oa ±13.2 A % + 8.9 ± 5.9 19.8 ±10.8 Aortic blood pressure Control Monkey # mg/Hg 3 80.0 ± 2.9 3 80.7 ± 0.7 Pulmonary Monkey # Control 3 9.0 , 0.0 3 9.5 ±0.3 Response 76.7 ± 2.7 61. 3a ± 9.3 arterial Response 9.2 ± 0.4 9.6 ± 0.2 A % - 4.1 ± 2.5 -23.8 ± 7.0 Myocardial force (g) Control 47.5 ± 7.7 45.3 ± 5.1 Left Control 3.7 ± 0.4 3.8 ± 0.4 Response 38.4 ± 4.2 29.3 ± 7.5 atrial pressure Response 4.1 ± 0.8 4.9 ± 1.0 A % -17.1 ± 6.8 -35.8 ±12.6 A % 10.8 ± 1.0 37.2 ± 7.2 pressure (mm/Hg) A % + 3.3 ± 4.2 + 1.1 ± 1.1 Mean S.E.M. Mean S.E.M. p <0.05 compared with control Data from Belej et al. (1974) ------- TABLE 5-5. RESPIRATORY AND CIRCULATORY EFFECT OF FC-113 UPON ANESTHETIZED RHESUS MONKEYS tn l % Concentration FC-113 Monkey # 2.5 3 5.0 3 % Concentration FC-113 Monkey ft 2.5 3 5.0 3 Pulmonary resistance Control cm H20/l/sec 21.78 ± 3.49 21.58 ± 3.00 Respiratory Control ml/min. 1230 47.3 1292 ± 99 Response 19.69 ± 2.71 18.84 ± 2.47 minute Response 1250 ± 28.9 1302 ± 72 % A - 8.87 + 4.75 -12.07 ± 6.64 % A + 1.80 ± 1.80 + 1.10 ± 3.20 Pulmonary Control ul/cm H20 6.87 ± 0.43 6.67 ± 0.58 Control bpm 169 ± 13.65 173.33 ± 12.02 compliance Response % A 7.27 + 5.97 ±0.41 ± 2.30 7.50 ±13.95 ±0.25 ± 8.80 Heart rate Response % A 199 +18.07 ± 19.09 ± 8.14 221.67 +27.85a ±21.67 + 8.58 % Aortic bloodj>ressure Concentration FC-113 Monkey # 2.5 3 5.0 3 Control mm/Hg 101.67 ± 1.67 110.67 ± 5.78 Response 93.00 ± 3.05 82.33 ± 2.33 % A - 8.54a ± 2.36 -25.153 ± 4.75 p <0.05 Data from Aviado and Smith (1975). ------- The results are presented in Table 5-5: 2.5 percent (25,000 ppm; 192,500 mg/m ) and 5.0 percent (50,000 ppm; 385,000 mg/m ) FC-113 caused a decrease in pulmonary resistance, an increase in pulmonary compliance, no change in respira- tory minute volume, a significant increase in heart rate for the group that inhaled 5.0 percent (50,000 ppm; 385,000 mg/m3) FC-113, and a significant decrease in aortic blood pressure for both groups. 5.1.3 Neurological Effects 5.1.3.1 Frog—Young and Parker (1975) studied the effect of FC-113 on the activity of acetylcholinesterase, an enzyme required in the repolarization of nerve fibers. A vagal heart preparation of the leopard frog (Rana pipiens) was used. The heart was stimulated by a pair of platinum electrodes and was triply cannulated to allow for the introduction of the test compound. The specifics of the experimental procedure were not given. Their results indicated that the ED50 for an FC-113-induced increase in -4 acetylcholinesterase activity was 1.6 x 10 gm/ml, a level close to its saturation concentration in water. 5.1.3.2 DOCJ--Carter et al. (1970) studied the effects of FC-113 on neural transmission through autonomic ganglia. Spinal preparations of four female beagle dogs (8.0-13.7 kg) were tested using heart rate as an indicator of the cardiac response to pre- and postganglionic stimulation. Control reponses were determined prior to the administration of 2 percent (20,000 ppm; 154,000 mg/m ) FC-113 with and without atropine (0.05 mg/kg). The experimental values were determined at the end of the ten minute exposure period. The control values were then verified 15 minutes after the termination of the exposure. The results are presented in Figures 5-2 and 5-3. Approximately two percent (20,000 ppm; 154,000 mg/m3) FC-113 had no effect upon postganglionic stimulation though it did reduce an increase in the heart rate response to preganglionic stimulation and further decreased it when atropine was added. 5-14 ------- 160 140 s I 120 M •°. 100 K ! » K | 60 40 20 T T I I I I -O— CONTROL 100% OXYGEN -O—2% FC-113IN OXYGEN -•— 2% FC-113IN OXYGEN PLUS ATROP1NE 0.05 mg/kg STANDARD ERROR -I 0.1 0.3 1 36 10 20 40 FREQUENCY OF STIMULATION, stim/iec Figure 5-2. Effect of 2% FC-113 on preganglionic stimulation of canine spinal preparations. Source: Carter et al. (1970). 5-15 ------- 140 J IU ec UJ I I CONTROL (100% OXYGEN) O-2%FC-113IN OXYGEN 40 — 20 — 0.1 0.3 136 10 FREQUENCY OF STIMULATION, itim/jec Figure 5-3. Effect of 2% FC-113 on postganglionic stimulation of canine spinal preparations. Source: Carter et al. (1970). 5-16 ------- The authors believe that the further decrease in response in the presence of atropine, a muscarinic blocking agent, could be indicative of FC-113-induced nicotinic blockade in the stellate ganglion. Neurochemical effects in rats exposed to 1,000 and 2,000 ppm (7,700 and 15,400 mg/m ) FC-113 are described on page 4-3 and 4-4. 5.1.4 Hepatoxicity Proliferation and vacuolization of the smooth endoplasmic reticulum of the liver was observed when male Wistar rats were exposed to 1,000 and 2,000 ppm (7,700 and 15,400 mg/m3) FC-113 for 1 and 2 weeks (Vainio et al.t 1980). The rough endoplasmic reticulum showed no clear alteration. Hepatocyte microvilli were normal while some mitochondria showed condensations. No effects of exposure to 200 ppm (1,540 mg/m ) were noted. Effects of FC-113 exposure on hepatic enzymes are discussed in Chapter 4. 5.1.5 Teratogenic Effects The following discussion subscribes to the basic viewpoints and defini- tions of the terms "teratogenic" and "fetotoxic11 as summarized and stated by Chernoff (1980): Generally, the term "teratogenic" is defined as the tendency to produce physical and/or functional defects in offspring j_n utero. The term "fetotoxic" has traditionally been used to describe a wide variety of embryonic and/or fetal divergences from the normal which cannot be classified as gross terata (birth defects) ~ or which are of unknown or doubtful significance. Types of effects which fall under the very broad category of fetotoxic effects are death, reductions in fetal weight, enlarged renal pelvis edema, and increased incidence of supernumary ribs. It should be emphasized, however, that the phenomena of terata and fetal toxicity as currently defined are not separable into precise categories. Rather, the spectrum of adverse embryonic/fetal effects is continuous, and all deviations from the normal must be considered as examples of developmental toxicity. Gross morphological terata represent but one aspect of this spectrum, and while the significance of such structural changes is more readily evaluated, such effects are not necessarily more serious than certain effects which are ordinarily classified as fetotoxic— fetal death being the most obvious example. In view of the spectrum of effects at issue, the Agency suggests that it might be useful to consider developmental toxicity in terms of three basic subcategories. The first subcategory would be embryo or fetal lethality. This is, of course, an irreversible effect and may occur with or without the occurrence of gross terata. The second subcategory would be teratogenesis and 5-17 ------- would encompass those changes (structural and/or functional) which are induced prenatally, and which are irreversible. Teratogenesis includes structural defects apparent in the fetus, functional deficits which may become apparent only after birth, and any other long-term effects (such as carcinogenicity) which are attributable to HI utero exposure. The third category would be embryo or fetal toxicity as comprised of those effects which are potentially reversible. This subcategory would therefore include such effects as weight reductions, reduction in the degree of skeletal ossification, and delays in organ maturation. Two major problems with a definitional scheme of this nature must be pointed out, however. The first is that the reversiblity of any phenomenon is extremely difficult to prove. An organ such as the kidney, for example, may be delayed in development and then appear to "catch up". Unless a series of specific kidney function tests are performed on the neonate, however, no conclusion may be drawn concerning permanent organ function changes. This same uncertainty as to possible long-lasting after effects from developmental deviations is true for all examples of fetotoxicity. The second problem is that the reversible nature of an embryonic/ fetal effect in one species might, under a given agent, react in another species in a more serious and irrever- sible manner. Two unpublished studies in rabbits are available from E.I. duPont deNemours and Company, Inc. (Hazelton Laboratories, 1967). In both studies, the number of pregnant animals and fetuses evaluated were inadequate for use in assess- ing the teratogenic potential of FC-113. In both studies, the treatment period was shorter than those suggested for current teratogenicity testing. In both the inhalation and feeding studies, dosages administered produced signs of maternal toxicity. The first study, performed in 1967, exposed 12 rabbits per dosage group via inhalation to 0 (air), 2,000 or 20,000 ppm (15,400 or 154,000 mg/m of FC-113 for 2 hours daily on days 8 through 16 of presumed gestation (equivalent to days 6 through 14 of gestation when day 0 = day of insemination). Pregnancy occurred in 4, 4 and 7 rabbits in the respective dosage groups. Signs of maternal toxicity in rabbits exposed to 20,000 ppm (154,000 mg/m ) of FC-113 consisted of lowered body weight gain during the first week of exposure and eye irritation. One doe in the 20,000 ppm (154,000 mg/m ) dosage group died; another delivered prematurely on day 29. A total of 19/4 pups/litter, 8/4 pups/litter, and 24/5 pups/litter were evaluated in the control, low and high dosage groups, respectively. One pup 5-18 ------- in the low and two in the high dosage group were dead at examination. No remarkable variations were observed in external soft tissue or skeletal examina- tions of the fetuses. The second study, performed in 1967, evaluated 8 rabbits per dosage group, and 0, 1 and 5 gm/kg/day FC-113 was administered on days 8 through 11 of gestation (days 6 through 9 of gestation when day 0 = day of insemination). It is assumed that the agent was given orally, via stomach tube, since refer- ence was made to the possible toxic effect of the "dosing technique"; however, the method of agent administration was not cited in the report. One, 3 and 4 rabbits died in the groups administered 0, 1 and 5 gm/kg/day FC-113, respectively. In high dosage group rabbits, food and water consumption were reduced during the treatment period, and body weight loss (300 to 500 grams) occurred. Only 3, 6 and 4 rabbits in the respective dosage groups became pregnant. The three control rabbits delivered naturally 21 live and 3 dead pups. In low dosage group rabbits, one of the pregnant rabbits died following the third dose, another died during natural delivery, and the third rabbit survived to deliver pups. The remaining three rabbits in the lowest dosage groups that were pregnant were Caesarean-sectioned. A total of 32 live fetuses or pups were evaluated. Death in one rabbit in the high dosage group after the first dose pre- cluded evaluation for pregnancy in one rabbit. One rabbit died after the fourth dose and apparently had 9 live embryos jjn utero. One rabbit died on day 16 (day 14 when day 0 = insemination) of gestation and had nine dead fetuses i_n utero. Another rabbit aborted four dead fetuses on day 29 (day 27 when day 0 = insemination) of gestation. One rabbit was Caesarean-sectioned and had 10 fetuses in utero, 7 of which were dead. 5-19 ------- As a result of non-pregnancy, maternal death or i_n utero embryo/fetal death, only 21/3 pups/litter, 32/5 pups/litter, and 3/1 pups/litter delivered naturally or Caesarean delivered were evaluated for malformations. Eleven dead fetuses in two litters, either aborted or dead rn utero, were also evaluated for malformations. No remarkable anatomical changes were reported in the few fetuses which were examined. 5.1.6 Mutagenic Effects 5.1.6.1 Mouse—Using a dominant lethal assay, Epstein et al. (1972) tested the mutagenic effects of FC-113. Swiss mice (8-10 week old males and virgins) were used. The following criteria for determining mutagenicity were used: "(1) one or more weeks with a mean of 0.90 or more early fetal deaths per pregnancy regardless of the percent of pregnant females with early deaths; (2) one or more weeks with 55 percent or more of the pregnant females having early deaths; (3) one or more weeks with a mean of less than 9 total implants per pregnancy." There were two experimental groups of males injected i.p. with FC-113: group 1, 200 mg/kg (7 mice); group 2, 1000 mg/kg (9 mice). Each male was subsequently caged with three virgin females which were replaced weekly for eight weeks. The females were sacrificed and autopsied thirteen days after the midweek of the caging. Neither experimental group met the above criteria. The authors concluded that FC-113 was not mutagenic under the concentrations tested, route of admin- istration, strain and test system employed. Unpublished data of E. I. duPont de Nemours and Company indicate FC-113 was nonmutagenic in four strains (TA 1535, 1537, 98 and 100) of S. typhimurium (Haskell Laboratory, 1977). FC-113 was classified as non-mutagenic since the reversion frequency was less than two times the spontaneous frequency and since less than 0.02 revertants/ nmole were observed. FC-113 was nonmutagenic in the presence and absence of a rat-liver homogenate activation system. The 5-20 ------- experiment was carried out in 9-liter glass chambers with four concentrations of FC-113, 2 percent, 6 percent, 10 percent, and 19 percent. Chloroethylene served as the positive control. The cytotoxicity of the test sample in the • presence and absence of an activation system as measured in TA 1535 was the basis for selective concentrations for mutagenesis testing. The negative results obtained from the dominant lethal test and the Salmonella S-9 assay are not considered to provide sufficient evidence to classify FC-113 as non-mutagenic. The dominant lethal test is not considered to be a sensitive test because of the high background of spontaneously-occur- ring dominant lethals (Russell and Matler, 1980). The Ames test may not necessarily be effective in assessing the mutagenicity of certain halogenated hydrocarbons (Ames, 1979). Additional tests are needed to determine the mutagenic potential of FC-113. 5.1.7 Carcinogenic Effects 5.1.7.1 Mouse—The use of sprays containing a pesticide, a piperonyl syner- gist and a propel 1 ant prompted Epstein and coworkers (1967a) to evaluate the Id vivo interactions between FC-113 and piperonyl butoxide, a pesticide syner- gist. Incidence of hepatomas and lymphomas were used to indicate carcino- genicity. The number of mice and litters in each of the four test groups presented in Tables 5-6 and 5-7 is indicated in Table 5-7. Each group re- ceived the following subcutaneous injections into the neck: 0.1 ml on days 1 and 4 and 0.2 ml on days 14 and 21 after birth. The groups were differ- entiated according to the solution injected: (each group was injected subcutaneously with test material) (1) solvent controls (redistilled 5 3 tricaprylin); (2) 10 percent (100,000 ppm; 7.7 x 10 mg/m ) FC-113 in tricaprylin; (3) 5 percent piperonyl butoxide (PB) in tricaprylin; (4) FC-113 and PB as indicated in (2) and (3). 5-21 ------- TABLE 5-6. CARCINOGENIC EFFECTS OF FC-113 + PB IN MICE, ALONE AND IN COMBINATION Ul ro Hepatomas Treatment group Solvent controls FC-113 PB FC-113 and PB Sex M F M F M F M F # of mice autopsied, alive at week 51 (# at risk) 48 68 21 20 20 36 18 24 # of tumors as % of it of (number) 4 0 1 0 0 0 3 0 in each period mice at risk (percent) 8 0 5 0 0 0 17 0 Malignant ft of tumors as % of # of (number) 1 0 0 1 0 0 0 1 lymphomas in each period mice at risk (percent) 2 0 0 5 0 0 0 4 In addition, one mammary carcinoma occurred in one female of the FC-113 alone group. Data from Epstein et al. (1967a). ------- TABLE 5-7. COMBINED TOXICITY OF FC-113 + PB UPON NEONATAL MICE Treatment group Solvent controls 10% FC-113 5% PB 10% FC-113 + 5% PB # of mice Weaning Average wt. (g) (# of litters) mortality at 51 weeks 170 (16) 52 (4) 91 (8) 94 (8) 14 M F 2 M F 15 M F 46 M F 50,5 45.3 53.6 48.2 52.0 47.0 59.0 57.0 % Increase in weight over controls 6.1 6.4 3.0 3.8 16.8 25.8 Data from Epstein (1967b). The data are presented in Table 5-6. They indicate that 10 percent (100,000 ppm; 7.7 x 10 mg/m ) FC-113 did not alter the incidence of hepatomas beyond the control values though it did increase the incidence of malignant lymphomas. One case of a mammary carcinoma was also found among the females of group two. No mammary carcinomas were found in the control group. It is important to note that the statistical significance of these data was not evaluated. Conney et al. (1972) reported that environmental exposure to piperonyl butoxide is unlikely to inhibit human microsomal enzyme function. 5.1.8 Synergistic Effects 5.1.8.1 Mouse—Epstein et al. (1967a, 1967b) tested the synergistic toxicity and hepatotoxicity of FC-113 and piperonyl butoxide (PB). Neonatal Swiss mice were used in the study. Percent mortality prior to weaning was used to indi- cate the effects of FC-113 and PB alone or in combination. This study was part of the study discussed previously. 5-23 ------- Table 5-7 illustrates the synergistic toxicity of FC-113 and PB. The mortality rate of FC-113 + PB (46 percent) was greater than either compound alone (2 percent and 15 percent). Table 5-6 shows that the combined presence of FC-113 and PB did not produce a synergistic lymphotoxicity while it did produce a synergistic hepatotoxicity. There was also an anomalous weight gain in all but the control mice. The gain was greatest in the FC-113 + PB treat- ment group, indicating that the effects were synergistic. The authors did not ascertain the nature of this weight gain. 5.1.9 Dermal Effects Table 5-8 summarizes the data found on the dermal effects of FC-113 in mammals. Few effects have been observed, other than a drying of the skin due to lipid removal. TABLE 5-8. DERMAL EFFECTS OF FC-113 IN MAMMALS Concentration Duration Effects Reference 40% in sesame seed oil 100% 100% 5 g/kg g/kg daily, No effect on shaved skin 12 days of rabbits 5 x/w, No visible effect on 20 w shaved back of rabbits Practically non- irritating to eye and paw of rabbit 1 x/d, Weight fluctuations, 5 d skin damage, liver changes (microscopic), no other systemic effects in rabbits Approximate Lethal Dose (rats). Dermal and tissue damage at site of appli- cation; no other systemic effects EPA, 1976 Desoille et al., 1968 DuPrat et al. 1976 Oesoille et al., 1968 Clayton, 1966 5-24 ------- 5.1.10 Inhalation and Ingestion Due to the amount and diversity of data on FC-113, this information is presented in tabular form (Tables 5-9 and 5-10). TABLE 5-9. INHALATION AND INGESTION TOXICITIES OF FC-113 IN MAMMALS Animal (Number) % ppm A/S* Duration Mice 5.7 57,000 A 30' 5-12 50,000- A 15' 120,000 9.5 95,000 A 2 h >10 >100,000 A 30' 15 150,000 A 15' (4Qrf) 0.2 2,000 S 2 w Guinea (12) 1.0 10,000 A 5' to to (9) 1.2 12,000 A h h (6) (512 A 1 h humidity, (3) 58°F) A 2 h 1.1 11,000 A 2 h Effects Anesthetic; delayed death with >6% Initial excitement and convulsions during anesthesia LC50 LC50 Anesthetic Hema to logical values; clinical chemistries; EEC; body weight; organ- to-body weight ratios; no change No adverse effects; recovered quickly Same Same Same Slight narcotic effect Reference Raventos and Lemon, 1965 Burn, 1959 Oesoille et al . , 1968 Raventos and Lemon, 1965 EPA, 1966 Carter et al . , 1970 Underwriters Laboratories, 1941 AIHAC, 1968 5-25 ------- TABLE 5-9. (continued) Animal (Number) % Guinea Pigs TTfy 2.5 to 2.9 (9) (6) (3) (12) 4.8 to 5.2 (9) ppm A/S* 25,000 A to 29,000 A (41* humidity; 67-68°F) A A 48,000 A to 52,000 A (67% humi di ty ; 58-70°F) Duration Effects Reference 5' No adverse effects; Underwriters recovered quickly Laboratories 1941 h h Slight tremors within 10'; rapid breathing; eyes partially closed; slight lachrymation; recovered quickly 1 h Same 2 h Same; recovered within 2 days 5' No adverse effects; Underwriters recovered quickly Laboratories 1941 h h Coordination loss; tremors; unable to stand within 10'; irregular breathing; eyes partially closed; lachrymation; recovered within one day (5) 1 h Semi-conscious; convulsive tremors; irregular breath- ing; deaths of 2 animals 4 and 5 days post-exposure; recovery within 8 days (3) (12) (9) 9.5 95,000 to to 11.3 113,000 (51% humidity; 70-72°F) A A A A A 2 h Same; deaths 2 and 3 days post-exposure 5' Coordination loss; tremors; unable to stand; recovery within 1 day h h Unconscious; convulsive tremors; lachrymation and nasal discharge; breathing fast and irregular; death of 2 animals 3 and 4 days post-exposure Underwriters Laboratories 1941 5-26 ------- TABLE 5-9. (continued) Animal (Number) % ppm A/S* Duration Effects Reference Guinea Pigs (6) A (3) A 12 120,000 A 1 h Same; deaths 1 post-exposure and 4 days 2 h Same; all animals dead within 1 day 2 h LC50 •JU post-exposure Desoille et al . , 1968 (12) (9) (2) 16.4 164,000 to to 16.6 166,000 5' (73°F) 1 h Coordination loss within I1 ; unable to stand; convulsive tremors; recovered within 1 day Unconscious; convulsive tremors; deaths; 5 animals within first 20'; 2 animals 1 and 2 days post-exposure Unconscious; deaths: 1 animal within first 45'; 1 animal 2 days post- exposure Underwriters Laboratories, 1941 •(109) 0.51 5,100 6 h/d, No change in growth rate, Steinberg 5 d/w, organ-to-body weight . et al., 4 w ratios, appearance upon 1969 necropsy (3) 2.5 25,000 S 3.5 h/d, 0/3 deaths; no changes in 20 d weight gain, rbc, wbc, differential white count, hemoglobin, urinary pro- tein and sediment, heart, lungs, liver, kidney, spleen; no signs of toxicity Clayton, 1966 5-27 ------- TABLE 5-9. (continued) Animal (Number) % Rats (5*) 1.14 (5*) 1.3 1.76 5.5 8.7 10.0 (5*) 10.0 11 15 20 22.2 (10* 0.21 and to 10?) 0.29 ppm 11,400 13,000 17,600 55,000 87,000 100,000 100,000 110,000 150,000 200,000 222,000 2,075 to 2,885 A/S* A A A A A A A A A A A S Duration 6 h 6 h 2 h 4 h 6 h 3 h 6 h 2 h 15' 45' 7 n/d, 30 d Effects Rotobar performance: no change 1 h: restlessness 2 h: quiet; rotobar test, no change Liver and kidney congestion ALC Convulsions; unresponsive- ness; respiratory impair- ment; microscopic exam: pulmonary edema; ALC Convulsions, rapid breath- ing, unresponsiveness, cyanosis, death in 2-3 hrs ALC LC50; some delayed mortality Anesthetic ALC 3-15': convulsions, rapid breathing, unresponsive- ness, cyanosis, death 0/20 deaths; body weights, gross and microscopic pathology: normal ; no signs of toxicity Reference Steinberg et al . , 196! AIHAC, 1968 EPA, 1966 Clayton, 1962 AIHAC, 1968 Clayton, 1966 Desoille et al . , 196£ Kuebler, 1964 EPA, 1966 AIHAC, 1968 Clayton, 1966 5-28 ------- TABLE 5-9. (continued) Animal (Number) % ppm A/S' Duration Effects Reference Rats 0.2 2,000 S 2 w 0/5 deaths; hematological values, clinical chemis- tries, EEC, body weight, organ-to-body weight ratios: no changes except in kidneys (wt >controls), no adverse symptomology Carter et al., 1970 (20) (12) (50*) (5*) (109 and 10*) 0.2 2,000 S 2 w 0.5 5,000 S 7 h/d, 5 d/w, 30 d 0.5 5,000 S 7 h/d, 30 d 0.51 5,100 S 6 h/d, 5 d/w, 4 w 0.51 5,100 S 6 h/d, 5 d/w, 4 w 0.51 5,100 S 6 h/d, 5 d/w, 4 w See Table 10 No deaths, no weight gain, slight liver damage 0/12 deaths, abnormal weight gain; 3 rats: slightly pale livers, others normal; kidneys normal Rotobar test: no change Voluntary movement (activity wheels) and necropsy: no changes Growth rate, organ-to- body weights, necropsy: no changes Clayton, 1962 Clayton, 1966 Steinberg et al . , 1969 Steinberg et al., 1969 2.5 25,000 3.5 h/d, 0/5 deaths; weight gain, 20 d rbc, wbc, differential white count, hemoglobin, urinary protein and sediment, heart, lungs, liver, kidney, spleen: no changes; no signs of toxicity Clayton, 1966 5-29 ------- TABLE 5-9. (continued) Animal (Number) % ppm A/S* Rats ~75) 6 60,000 S (4) 40 400,000 S 1.2 12,000 C (5*) 30 g/kg I Duration 1 h/d, 5 d 1 h/d, 5 d 2 h/d, 5 d/w, 365- 730 d undi 1 uted app 1 i ed orally, Ix Effects Deaths: 0/5; liver: 2 rats fair amounts of fat in Kupffer cells Deaths: 0/4; mild hepato- toxicity; moderate degree of mitotic activity in liver cells of one rat; others showed similar activity but to a lesser degree Deaths: 3/6 (3/6 Controls died also); sleepiness 0/5 deaths; lethargy; facial edema; abdominal distension; liquid fecal discharge: symptoms Reference Burn et al. , 1959 Desoille et al., 196 Michael son a Huntsman , 1964 disappeared after 24 h; ruffled coat; autopsies: no gross pathological changes; avg wt. change: +46 g (5*) (5*) (5*) 35 g/kg 50 g/kg 43 g/kg I I I Same Same Undiluted Same; avg. wt change: +41 g Same; avg wt. change: +19 g 43 ± 4.8 g/kg = LD,n Michael son a applied orally, Ix Huntsman, 1964 5-30 ------- TABLE 5-9. (continued) Animal (Number) % ppra A/S> Duration Effects Reference 45 g/kg I Same Lethargy; facial edema; abdominal distension; liquid fecal discharge: symptoms disappeared after 24 h; ruffled coat; deaths: 3/5, 5-24 h post- ingestion; avg wt. change of survivors +25 g; avg wt. change of dead animals: -12g; autopsy of dead animals: lung hemorrhaging, possibly due to contact with FC-113; livers: mottled surface, normal color; stomach and GI tract: abnormally distended with gas and fluid Michael son and Huntsman, 1964 (5*) 45 g/kg 50 g/kg I I Undiluted applied orally, Ix ALC Same effects as 45 g/kg; deaths: 4/5, days 1-7 post-exposure; avg. wt. change survivors: 31 g; avg. dead animals: -49 g Clayton, 1966 Michael son and Huntsman, 1964 55 g/kg I Same Same; deaths: 5/5, days 3-9 post-exposure; avg. wt. change: 0 g Rabbits 1.1 11,000 S 17 g/kg I Dogs (29 1.14 11,400 A and 2*) 2 h/d, Deaths: 0/6; no variation 5 d/w, 120 w Approximate lethal dose 6 h 2 hr: vomiting, lethargy, nervousness; 4 hr: stupor, lethargy; 5-6 hr: tremors; 15 minutes post-exposure: no signs Desoille et al., 1968 AIHAC, 1968 Steinberg et al . , 1969 5-31 ------- TABLE 5-9. (continued) Animal (Number) % ppm A/S* Duration Effects Reference Dogs (1<* 1.3 13,000 A 6 h 5 min: depressed placing Steinberg and reflex; 10 min: nervous- et al . , 19f 19) ness; 15': extreme pupil dilation, trembling; 30min: loss of muscle coordination; 1 hr: vomiting, trembling; 5 min. post-exposure: de- pressed front and rear hopping reflex; 15 min. post-exposure: no signs 0.2 2,000 S 2 w Hematological values; Carter et al. clinical chemistries; EEC; 1970 body weight; organ-to-body weight ratios: no changes; 0/8 deaths 0.51 5,100 S 6 h/d, Plasma LDH, amylase activ- Steinberg and 5 d/w, ity, BUN, hematocrit, et al., 1969 2<*) 4 w % neutrophils, % lympho- cytes checked weekly: no changes; organ-to-body weight ratios, food con- sumption, olfactory, hear- ing, following with eyes; blinking, facial skin sen- sation, tone of face and jaw muscles, gag reflex, tongue control, light-pupillary reflex, optic disc appear- ance, flexor, extensor postural thrust, placing, righting, hopping, knee jerk: no changes; no pathological changes • ••^•••••••^••••.••••^••••^••••••••^•••••••••••••^•••^^••^•••••^••••••^^••••••••••••••••••WMVWVHWVMBVlVMVMMVVMWVV (2) 1.25 12,500 S 3.5 h/d, 0/2 deaths; weight gain, Clayton, 1966 20 d rbc, wbc, differential white count, hemoglobin, urinary protein and sedi- ment, heart, lungs, liver, kidney, spleen: all normal; no signs of toxicity 5-32 ------- TABLE 5-9. (continued) Animal (Number) % ppm A/S* Duration Effects Reference Dogs it? and ) 200 ml. into exposed stomach 2 h Stomach exposed, cardiac and pyloric sphincters 11 gated, FC-113 added; 2 h: gastric juices measured; volume = 200 ml gross appearance gastric mucosa: normal Clayton, 1966 (2) 1.25 12,500 S Monkeys (49 ) 0.2 2,000 S 3.5 h/d, 0/2 deaths; weight gain, Ibid. 20 d rbc, wbc, differential white count, hemoglobin, urinary protein and sedi- ment, heart, lungs, liver, kidney, spleen: all normal; no signs of toxicity 2 w 0/4 deaths; hematological Carter et al., values, clinical chemis- tries, EEG, body weight: no changes; organ-to-body weight ratios: all monkeys, enlarged thyroids; control: monkeys: all thyroids normal 1970 *I = Ingested; A = acute; S = Subchronic; C = Chronic 5-33 ------- TABLE 5-10. POST-INHALATION MEAN TISSUE CONCENTRATIONS OF FC-113 IN RATS Tissue Brain ug/g Liver ug/g Heart |jg/g Fat |jg/g Adrenal ug Thyroid ug Exposure 7 day 22.73 (1.00) 15.77 (0.87) 16.59 (2.56) 722.48 (71. 29) 8.39 (2.61) 1.09 (0.46) 14 day 22.65 (1.33) 16.40 (1.72) 15.03 (2.51) 659.24 (21.17) 3.47 (0.34) 0.94 (2.00) Postexposure 24 hours None None None 108.45 (33.62) None None 48 hours None None None 5.60 (2.94) None None ( ) Standard Deviation Data from Carter et al. (1970), addendum. 5.2 HUMAN STUDIES Much of what is known is derived from instances in which individuals were accidentally or experimentally exposed to high concentrations of chlorofluoro- carbons. 5.2.1 Occupational Exposure Studies Triebig and Burkhardt (1978) observed the effects of occupational inha- lation exposures to FC-113. Ten women (25-54 years of age; length of exposure 1-14 years, average 8.7 years) and three men (27-43 years of age; length of 5-34 ------- exposure 6-21 years, average 11 years) were used in the study. Case histories, clinical chemistry (blood Hb, Hbg, erythrocytes, leukocytes, SCOT, SGPT, fasting blood sugar, urine protein, sugar, bile pigment, and sedimentation rate), and breath analyses were performed before the one-week exposure period. After the exposure period, blood chemistry, urinalysis, and breath analyses were performed again. The concentration of FC-113 in the workroom was deter- mined by infrared spectrometry. Room air measurements indicated average daily levels between 23.3 ±9.2 and 62.4 ± 29.5 ppm (180 ± 71 and 480 ± 227 mg/m ) during the exposure period. Prior to the commencement of this experiment, each of the women had worked at least one day in the workroom (concentration FC-113, 11 to 113 ppm; 85 to 870 mg/m ) and each of the men had worked 15 to 20 minutes/day for 2 to 3 days/week. During the one week observation period, each woman spent one day in the workroom (3.5 to 5.8 hours) while the men had irregular and brief periods of exposure. Analysis of blood and urine revealed no abnormalities. Breath analyses indicated a range of 3.6 to 9.75 mg FC-113/liter (average 6.33 mg/1) in the women and a range of 1.20 to 4.85 mg/1 (average 2.48 mg/1) in the men. Two of the women experienced headaches, dizziness, and nausea at the end of the exposure period. Another woman had similar complaints after only 3 hours of exposure. Imbus and Adkins (1972) also conducted studies of the effects of occupa- tional exposures to FC-113. Only males were observed. Clinical examination and blood chemistry (cholesterol, calcium, inorganic phosphorous, total bili- rubin, albumin, total protein, uric acid, BUN, glucose, lactate dehydrogenase, alkaline phosphatase, and SGOT) were used as an indication of adverse effects. There were fifty males in each of the two groups: (1) those unexposed to FC-113 (average age 37 years); (2) those exposed to FC-113 (average age 34 years; average exposure 2.77 years; exposure values determined from one day's 161 samplings: range 46 to 4,780 ppm (354 to 36,806 mg/m ), mean 699 ppm 5-35 ------- (5,382 mg/m ), 50th percentile estimate 521 ppm (4,012 mg/m3), median 425 ppm (3,272 mg/m3). The results indicated no adverse effects other than one case of FC-113- induced dermatitis. 5.2.2 Experimental Exposure Studies 5.2.2.1 Inhalati on—Rei nhardt et al. (1971) also conducted experiments on the effects of exposures to FC-113 using four healthy male volunteers (22-30 years of age). A broad base of responses was measured in terms of clinical tests (equilibrium, breath analysis, chest x-ray, urinalysis, and blood chemistries: alkaline phosphatase, cholesterol, total bilirubin, total protein, albumin, globulin, A/G ratio, total lipids, SGOT, LOH, creatinine, glucose, BUN, and uric acid), psychomotor tests and subjective impressions. The subjects were exposed to FC-113 for 3 hours in the morning and 3 hours in the afternoon, 5 days/week, for 2 weeks in an environmental chamber (61 x 6 1/2' x 10'). The concentration of FC-113 in the environmental chamber was determined by gas chromatography. During week 1, the concentration was 500 ppm (3,850 mg/m ). During week 2, the concentration was 1,000 ppm (7,700 mg/m). Psychomotor tests were administered to each individual prior to and after exposure at each level. The authors reported no evidence of a detrimental effect due to exposure to FC-113, based on test scores. Clinical testing, conducted before each exposure and three days after final exposure, indicated no abnormal findings regarding hematology, blood chemistry, or urinalysis. These findings were supported by no adverse subjective impressions or disturb- ances of equilibrium. The results of breath analyses performed after each exposure are shown in Table 5-11. As shown in Table 5-11, the morning samples obtained during the week of exposure to 1,000 ppm (7,700 mg/m ) indicates that not all of the FC-113 was eliminated overnight. Only one individual had a measurable breath level (1.5 ppm; 11.6 mg/m ), about 48 hours following the last exposure to 1,000 ppm (7,700 mg/m ). These data suggest that exposure 5-36 ------- over longer periods would be needed to determine if FC-113 is retained by tissues during repetitive exposures. Stopps and Mclaughlin (1967) tested the psychomotor effects of FC-113. Two healthy males were used in the study. Four different psychomotor tests performed by each subject were used to determine adverse effects. The sub- jects were exposed to FC-113 for two and three-quarter hours in an environ- mental chamber (2 1/2' x 3' x 5'). The timetable of the experiment is shown in Figure 5-4. The concentrations of FC-113 in the environmental chamber were TABLE 5-11. POST-INHALATION BREATH CONCENTRATIONS OF FC-113 IN MAN Summary of Breath Sampling Data (Chiorof1uorocarbon 113 Concentration (ppm) in Alveolar Air) Exposure Day of Subject Week I M T W T F II M T W T F III M T W T F IV M T W T F 500 a.m. < 1 < 1 < 1 < 1 < 1 < 1 < 1 2.0 < 1 < 1 < 1 < 1 1.5 < 1 3.0 < 1 < 1 < 1 1.0 < 1 ppm p.m. 60 65 59 57 51 61 56 51 49 55 45 27 18 18 31 47 44 35 35 41 1000 a.m. < 1 < 1 2.0 1.5 1.5 < 1 1.5 1.5 1.0 1.5 < 1 < 1 2.0 3.0 1.0 < 1 1.0 1.5 2.0 2.0 ppm p.m. 113 88 71 105 93 115 85 102 79 103 88 66 57 54 60 84 67 56 60 71 Post- expgsure a.m. < 1 < 1 - - - 1.5 < 1 - - - < 1 < 1 - - - < 1 < 1 - - ™ Note: (-) Indicates not measured. Reinhardt et al. (1971). 5-37 ------- on OJ CX> SUBJECT SUBJECT ENTERS LEAVES CHAMBER CHAMBER ^ ..„, PERIOD OF BUILDUP IN "F-113" CONCENTRATION IN CHAMBER •^- 45 mint. -^ 1 ^ ' lim» 46 n PERIOD OF EQUILIBRATION BETWEEN SUBJECT'S TISSUES AND ENVIRONMENT -^- 30 mini. «^ \ i FIRST BATTERY OF TESTS •^ 17 mini. •*»• 1 \ ' \ SECOND BATTERY OF TESTS r ' •^- It mini> r i r 1 hour 1 hour 2 houri 2 hour* 2 hour* lint. 16 mini. 32 mini. 10 mini. 27 mini. 45 mint. Figure 5-4. Human exposures to FC-113; timetable of experiment. and Mclaughlin, 1967. From Stopps ------- determined by gas chromatography and the concentrations tested were 1,500; 2,500; 3,500; 4,000; and 4,500 ppm (11,500; 19,250; 26,950; 30,800; and 34,650 3 mg/m ). The results are presented in Figure 5-5. Because the results of the first and second series of psychomotor tests during each exposure showed no consistent trends, the scores are presented as the average of the individual scores, expressed as the percentage change from control values. In general, the results indicate no adverse effects were apparent at 1,500 ppm (11,550 mg/m3). At concentrations of 2,500 ppm (19,250 mg/m ), an adverse effect is apparent. In addition to an impairment of psychomotor performance, both subjects reported the following effects after one half to one hour exposures at the three highest concentrations tested: loss of concentration on the task at hand, drowsiness, "heaviness" in the head with no actual headache, and dizziness upon lateral shaking of the head. These effects were gone fifteen minutes after having left the chamber. Post -exposure psychomotor testing, breath and blood analyses for FC-113 were not performed. 5.2.2.2 Dermal—Dermal absorption of FC-113 has been evaluated in man (Has- kell Laboratory, 1968). Three subjects were tested. Concentrations of FC-113 in alveolar air was used as an indication of FC-113 absorption. "The subjects had their hands and forearms exposed for thirty minutes, and portions of their scalps exposed for fifteen minutes. The concentration of FC-113 in their breath was then measured at various times after termination of the exposure. The data are presented in Table 5-12. At 90 minutes post-exposure, the concentrations of FC-113 in exhaled air in two of the three subjects had 3 3 decreased from a high of 12 ppm (92 mg/m ) to less than 0.5 ppm (3.8 mg/m ). In one of the subjects, a concentration of 0.1 ppm (0.7 mg/m ) remained 18 hours post-exposure. These data indicate that the human body absorbs FC-113 5-39 ------- MANUAL DEXTERITY A MANUAL DEXTERITY B 1500 2500 3500 ppm 4500 +10% H- CARD SORTING +10% 0 •10% •20% •30% -40% - CARD SORTING WITH AUXILIARY TASK J_ 1500 2500 3500 4500 ppm Figure 5-5. Effect of FC-113 upon psychomotor performance in man. From Stopps and Mclaughlin, 1967. 5-40 ------- as a result of dermal exposure, and that the amount of FC-113 absorbed does not immediately disappear when the exposure ends. TABLE 5-12. EFFECTS OF DERMAL EXPOSURE TO FC-113 IN MAN Area exposed Portions of scalp Portions of scalp Hands and forearms Hands and forearms Duration of exposure 15 min. 15 min. 30 min. 30 min. Time of peak* 20.5 min. 18.5 min. 11.5 min. 23 min. Value of peak 12.7 ppm 7.4 ppm 9.6 ppm 1.7 ppm ^Expressed in minutes after termination of exposure Data from Haskell Laboratory, 1968 The results of unpublished dermatological experiments with FC-113 con- ducted for E.I. duPont de Nemours and Company suggested that human scalp and forehead were not adversely affected when FC-113 was applied over a 30-day period (Betro Research Laboratory, 1967). Twenty volunteers received applica- tions to entire scalp and most of forehead according to the following sche- dule: (1) For first five days, FC-113 was applied three times daily for 30 seconds, (2) the 6th day exposure consisted of a single 30-second application; (3) thereafter, FC-113 was applied for 1.5 minutes, once daily. Tests included: permeability, eccrine sweat secretion, sebum production, UV response, response to chemical irritants, and determination of bacterial flora. 5.2.2.3 Ingesti'on—Only one report on the effects of human ingestion of FC-113 has been found. Approximately one liter of cold FC-113 was accidental- ly delivered into the stomach of an anesthetized patient, producing immediate but transient cyanosis. The patient survived and reported only severe rectal irritation and diarrhea for 3 days thereafter (Clayton, 1966). 5.2.2.4 Synergistic, Carcinogenic, Mutagenic. and Teratogem'c--No information pertaining to any of these categories of effects of direct exposure to FC-113 in man have been found. 5-41 ------- 5.3 SUMMARY OF ADVERSE HEALTH EFFECTS AND ASSOCIATED LOWEST OBSERVABLE EFFECTS LEVELS Levels of FC-113 above 2,000 ppm (15,400 mg/m ) have been reported to result in cardiac sensitization of dogs after the administration of exogenuos epinephrine. No evidence of cardiac sensitization of animals in the absence of exogenous epinephrine at FC-113 levels below 10,000 ppm (77,000 mg/m ) has been reported. Animal studies with mice, rats, dogs and monkeys that had been exposed to levels exceeding 5,000 ppm (38,500 mg/m ) have shown that arrhythmias, tachycar- dia, hypotension, and depression of myocardial contractility could be elicited. Inhalation studies have shown the between 2,000 to 19,000 ppm (15,400 to 146,300 mg/m ) FC-113, in guinea pigs, rats, dogs, and monkeys, can result in a slight narcotic effect, liver and kidney congestion, and kidney and thyroid enlargement. Often these effects are not revealed by the usual hematological or clinical tests, indicating that these tests do not always show the full extent of damage induced by FC-113. The direct effect of FC-113 exposures upon humans, particularly at ambient concentrations found or expected, is unknown. No conclusions can be drawn, at this time, with regard to the carcinogenic, mutagenic, or teratogenic potential of FC-113 until more extensive testing is initiated. Because of the limited amount of data concerning human chronic exposure situations, it is difficult to estimate, with confidence, the lowest observed adverse effect level (LOAEL). The LOAEL is defined as the lowest dose in a study or group of studies producing functional impairment, behavioral abnorm- ality, and/or pathological lesions which hinder the performance of the whole organism. Inhalation studies with animals and the acute human exposure data of Stopps and McLaughlin suggest that the LOAEL may be in the range of 2,000 to 2,500 ppm (15,400 to 19,250 mg/m ). However, this level should be regarded with caution until additional chronic testing, using sensitive parameters of liver, kidney, and CNS damage, is performed. 5-42 ------- The data of Reinhardt et al. (1971), Triebig and Burkhardt (1978), and Imbus and Adkins (1972) suggest a no-observed adverse-effect level (NOAEL), for short-term exposure situations, in the range of 500 to 1,000 ppm (3,850 to 7,700 mg/m ). The NOAEL is defined as that dose which produces observed effects which do not in themselves represent known functional impairment, behavioral abnormality, and/or pathological lesions which hinder the perform- ance of the whole organism. Of concern, however, is the role of FC-113 in the possible depletion of stratospheric ozone. Photochemical reactions involving FC-113 have the poten- tial to destroy ozone in the stratosphere and one result would be an increase in the incidence of certain types of skin cancers. 5-43 ------- TABLE 5-13. LOWEST OBSERVABLE ADVERSE DIRECT EXPOSURE EFFECT LEVELS No. of Duration Criteria Species Mode of Treatment Subjects of Exposure Concentration Response Reference (ppm) Cardiac Sensitization beagle dog 8 ug/kg epinephrine 1/6 given i.v. prior to FC-113 and again after exposure 8 ug/kg epinephrine 1/6 i.v. prior to exposure and again after exposure Liver damage rat £ rat 12 Thyroid monkey 4 Psychomotor ability human inhalation 2 i 0.5 hour 6 hours 7 hr/day 5 day/wk 30 days 7 hr/day 5 day/wk 30 days 2 weeks 0.5 to 1 hour 2,500 cardiac sen- sitization to exogenous epi- nephrine 2,000 cardiac sen- si tizati on to exogenous epi- nephrine 5,000 slight liver damage 5,000 abnormal weight gain, 3 rats pale livers 2,000 enlarged thyroid 2,500 loss of con- centration, drowsiness, Haskell Laboratory, Oct. 1969 Ibid Clayton 1962 Clayton 1966 Carter, et al. , 1970 Stopps and McLaughlin 1967 dizziness (reversible upon cessation of exposure) ------- 5.4 REFERENCES Amer. Conf. Govern. Ind. Hyg. Threshold Limit Values for Chemical Substances in Workroom Air Adopted by ACGIH for 1979. Amer. Conf. Govern. Ind. Hyg. Documentation of the Threshold Limit Values for Substances in Workroom Air, 3rd Edition, 1971. Amer. Ind. Hyg. Assn. Comm. l,l,2-Trichloro-l,2,2-trifluoroethane, Am. Ind. Hyg. Assn. J. 29:521-525, 1968. Ames, B. N. Identifying environmental chemicals causing mutation and cancer. Science 204:587-593, 1979. Aviado, D. M., and M. A. Belej. Toxicity of Aerosol Propellants on the Res- piratory and Circulatory Systems. I. Cardiac Arrhythmia in the Mouse. Toxicology 2:31-42, 1974. Aviado, D. M., and D. G. Smith. Toxicity of Aerosol Propellents in the Res- piratory and Circulatory Systems. VIII. Respiration and Circulation in Primates. Toxicology 3:241-252, 1975. Aviado, O.M. Toxicity of Aerosol Propellents in the Respiratory and Circula- tory Systems. X. Proposed Classification. Toxicology 3: 321-332, 1975. Aviado, D. M., and M. A. Belej. Toxicity of Aerosol Propellants in the Res- piratory and Circulatory Systems. V. Ventricular Function in the Dog. Toxicology 3:79-86, 1975. Beaubier, J. The Skin Problem. Proceedings of the Quadrennial International Ozone Symposium, Boulder, CO. August 4-9, 1980. Belej, M. A., D. G. Smith, and D. M. Aviado. Toxicity of Aerosol Propellents in the Respiratory and Circulatory Systems. IV. Cardiotoxicity in the Monkey. Toxicology 2:381-395, 1974. Betro Research Laboratories, Inc. Unpublished data of E.I. duPont de Nemours and Company. HLO-0260-67, MRO-0916-001 (1967). Submitted to U.S. En- vironmental Protection Agency, 20 August 1979. Burn, J. H., H. G. Epstein, and P. J. Goodford. The Properties of the Anaes- thetic Substance 1,1,2-Trifluro- 1,2-Oichloroethane. Brit. J. Anaesth. 31:518-529, 1959. Burn, J. H. Pharmacological Testing of Anesthetics. Proc. Royal Soc. Med. 52:95-98, 1959. Carter, V. L. , P. M. Chikos, J. D. MacEwen, and K. C. Back. Effects of Inhal- ation of Freon 113 on Laboratory Animals. U.S. Nat. Tech. Info. Service Report AD727524, 1970. Clark, D. G. , and D. J. Tinston. Correlation of the Cardiac Sensitizing Potential of Halogenated Hydrocarbons with their Physiochemical Proper- ties. Brit. J. Pharm. 49:355-357, 1973. 5-45 ------- Clayton, J. W., Jr. The Toxicity of Fluorocarbons with Special Reference to Chemical Constitution. J. Occup. Med. 4(5):262-273, 1962. Clayton, J. W. Fluorine. The Mammalian Toxicology of Organic Compounds Containing Handbuch Exp. Pharmakol. 20:459-500, 1966. Conney, A. H., R. Chang, W. M. Levin, A. Garbut, A. D. Moore-Faure, A. W. Peck, and A. Bye. Effects of piperonyl butoxide on drug metabolism in rodents and man. Arch. Environ. Health 24:97-106, 1972. Desoille, H., L. Truffert, A. Bourguignon, P. Delavierre, M. Philbert, and C. Girard-Wallon. Experimental Study on the Toxicity of trichlorotrifluoro- ethane (Freon 113). Archives des Maladies Professionnelles de Medicine de Travail et de Securite Sociale 29:381-388, 1968. Duprat, P., L. Delsuat, and D. Gradiski. Pouvoir Irritant des Principaux Solvants Chlores Aliphatiques sur la Peau et les Muqueuses Oculaires du Lapi. Eur. J. of Tox. 9(3):171-177. Epstein, S. S., J. Andrea, P. Clapp, D. Mackintosh, and N. Mantel. Enhancement by piperonyl butoxide of acute toxicity due to Freons, Benzo ( a ) pyrene, and Griseofulvin in infant mice. Tox. and Appl Pharm. 11:442-448 1976b. Epstein, S. S., E. Arnold, J. Andrea, W. Bass, and Y. Bishop. Detection of Chemical Mutagens by the Dominant Lethal Assay in the Mouse. Tox. and App. Pharm. 23:288-325, 1972. Epstein, S. S., S. Joshi, J. Andrea, P. Clapp, H. Falk, and N. Mantel. Syner- gistic toxicity and carcinogenicity of 'Freons' and piperonyl butoxide. Nature 214:526-528, 1967a. Forbes, P. D. and F. Urbach. Experimental Modification of Photocarcinogenesis. I. Food Cosmet. Toxicol. 13:335, 1975. Haskell Laboratory. Unpublished data of E.I. duPont de Nemours and Company. MR-2363-001, HL-0325-69 (1969). Submitted to U.S. Environmental Protec- tion Agency, 20 August 1979. Haskell Laboratory. Unpublished data of E.I. duPont de Nemours and Company. MRO-1015-001, HL-0242-67 (1967). Submitted to U.S. Environmental Protec- tion Agency, 20 August 1979. Haskell Laboratory. Unpublished data of E.I. duPont de Nemours and Company. MR-1127-001, HL-0325-69 (1969). Submitted to U.S. Environmental Protec- tion Agency 20, August 1979. Haskell Laboratory. Unpublished data of E.I. duPont de Nemours and Company. MR-2627-001, HL-915-77 (1977). Submitted to U.S. Environmental Protec- tion Agency, 20 August 1979. 5-46 ------- Haskell Laboratory. Human Skin Absorption Studies with Trichlorofluoroethane. Medical Research Project No. MR-1014 (1968), submitted by E. I. Dupont de Nemours & Co.to U.S. Environmental Protection Agency, August 1979. Hazleton Laboratories, Inc. Unpublished data of E.I. duPont de Nemours and Company. MRO-1962-001, HLO-0258-67 (1967). Reproduction Study in Rab- bits. Submitted to U.S. Environmental Protection Agency, 20 August 1979. Hazleton Laboratories, Inc. Unpublished data of E. I. DuPont de Nemours and Company. MRO-1015, HLO-242 (1967). Final Report. Teratology Study in Rabbits. Submitted to U.S. Environmental Protection Agency, 20 August 1979. Huempfner, K. H. The Toxicity of Frigen 113 TR-T. Zentralblatt fuer Arbeits- medizin and Arbeitsschutz 4:118-119, 1974. Imbus, H. R. and C. Adkins. Physical Examinations of Workers Exposed to Tri- chlorotrifluoroethane. Arch. Environ. Health 24:257-261, 1972. Kuebler, H. The physiological properties of aerosol propellants. Aerosol Age 9:44, 1964. Michaelson, J. B., and D. J. Huntsman. Oral Toxicity of 1,2,2-trichloro-l, 1,2-trifluoroethane. J. Med. Chem. 7:378-379, 1964. Molina, M. J. , and F. S. Rowland. Stratospheric Sink for Chlorof1uoromethanes: Chlorine Atom-Catalyzed Destruction of Ozone. Nature 249:810-812, 1974. Mullin, L. S. , A. Azar, C. F. Reinhardt, P. E. Smith, and E. F. Fabryka. Halogenated hydrocarbon induced cardiac arrhythmias associated with release of endogenous epinephrine. Unpublished report of Haskell Labora- tory, E.I. duPont de Nemours and Company, MR1262, HL 279-71, (1971). Submitted to U.S. Environmental Protection Agency. National Research Council. National Academy of Sciences. Protection Against Depletion of Stratospheric Ozone by Chlorofluorocarbons, 1979a. National Research Council. National Academy of Sciences. Stratospheric Ozone Depletion by Halocarbons: Chemistry and Transport, 1979b. National Research Council. National Academy of Sciences. Causes and Effects of Stratospheric Ozone Reduction: An Update, 1982. Panofsky, N. A. Earth's endangered ozone. Environ. 20(3):17-40, 1978. Raventos, J., and P. G. Lemon. The impurities in Fluorthane: Their bio- logical properties. Brit. J. Anesthesia. 37:716-737, 1965. Reinhardt, C. F., M McLaughlin, M. E. Maxfield, L. S. Mullin, and P. E. Smith, Jr. Human Exposures to Fluorocarbon 113. Amer. Ind. Hgy. Assn. J. 32:143-152, 1971. Reinhardt, C. F., L. S. Mullin, and M. E. Macfield. Epinephrine-Induced Cardiac Arrhythmia Potential of Some Common Industrial Solvents. J. Occup. Med. 15(12):953-955, 1973. 5-47 ------- Setlow, R. 8. The Wavelengths in Sunlight Effective in Producing Skin Cancer: A Theoretical Analysis. Proc. National Academy of Sciences 71:3363-3366, 1974. Shargel, L., and R. Koss. Determination of Fluorinated Hydrocarbon Propellents in Blood of Dogs after Aerosol Administration. J. of Pharm. Sci. 61(9): 1445-1449, 1972. Smith, K. C. Molecular Changes in the Nucleic Acids Produced by Ultraviolet and Visible Radiation: In: Sunlight and Man. T. B. Fitzgerald et al., eds. Smith, K. C. Radiation-induced Cross-Linkings of DNA and Protein in Bacteria. j.n: Aging, Carcinogenesis, and Radiation Biology, K. C. Smith, ed. Plenum Press, 1976. Steinberg, M. B., R. E. Boldt, R. A. Renne, and M. H. Weeks. Inhalation Toxicity of l,l,2-Trichloro-l,2,l-trifluoroethane (TCTFE), U.S. Army Environmental Hygiene Agency, Study No. 33-18-68/69, 1969. Stopps, G. J., and M. Mclaughlin. Psychophysiological Testing of Human Sub- jects Exposed to Solvent Vapors. Amer. Ind. Hyg. Assn. J. 28: 43-50, 1967. Triebig, G., and K. Burkhardt. Studies on Persons Occupationally Exposed to l,l,2-Trichloro-l,2,2-Trifluoroethane. Int. Arch. Occup. Environ. Health 42:129-135, 1978. Trochimowicz, H. J., A. Azar, J. B. Ten-ill, and L. S. Mullin. Blood Levels of Fluorocarbon Related to Cardiac Sensitiration: Part II. Am. Ind. Hyg. Assn. J. 35:632-639, 1974. Trochimowicz, H. J., C. F. Reinhardt, L. S. Mullin, A. Azar, and B. W. Karrh. The effect of myocardial infarction on the cardiac sensitization poten- tial of certain halocarbons. J. Occup. Med. 18(1):26-30, 1976. Underwriters' Laboratories, Inc. The Comparative Life, Fire, and Explosion Hazards of Trifluorotrichloroethane ("Freon-113"), 1941. Vainio, H., J. Nickels, and T. Heinonen. Dose-related hepatoxicity of l,l,2-trichloro-l,2,2,-trifluoroethane in short-term intermittent inhala- tion exposure in rats. Toxicol. 18:17-25, 1980. Young, W., and J. A. Parker. Effect of Fluorocarbons on Acetylcholinesterase Activity and Some Counter Measures. Combust. Toxicology 2:286-297, 1975. 5-48 ------- 6. ECOLOGICAL EFFECTS The effects of FC-113 upon the environment must be viewed in terms of the role of this compound and other halocarbons in the destruction of strato- spheric ozone (0.,). The effects of 0, depletion upon the environment have recently been examined by the National Research Council (1982). (See Section 5.4). Among the conclusions of the NRC (1982) are: 1. The adaptability of plant species appears to be sufficient, under current ambient levels of UV-B, to maintain food crop yields. The potential for further adaptation to predicted increases in ambient UV-B is not known. 2. There is no information from which to predict the magnitude of adverse effects of enhanced UV-B on aquatic organisms. Natural populations of aquatic organisms have adapted to current UV-B levels so as to maximize repro- duction potential. 3. Although different species of both plants and animals have different sensitivities to increases in UV-B above current levels, the data currently available are not complete enough to predict population dynamics or the dis- placement of an individual species under current environmental conditions. 4. Only minor effects of increased UV-B levels are predicted for animals used for human food. 6.1 CLIMATE As discussed in detail in the 1979 NRC report (National Research Council, 1979a), the climatic effects of an increase in the atmospheric burden of chlorofluorocarbons are twofold: (1) they can contribute to the "greenhouse" effect; (2) perturb climate by altering the amount or distribution of 0-, which will then affect the radiation balance. 6-1 ------- 6.2 AGRICULTURAL CROPS Of 82 species tested, about 60 percent exhibited intermediate degrees of sensitivity to UV-B radiation. Radiation affected plant dry weight of yield and proportion of plant material represented in roots, shoots, and leaves (National Research Council, 1979a). The NRC (National Research Council, 1979a) concluded that "even though a reduction of atmospheric ozone of the magnitude now envisaged could have significant effects on crop yields in certain plant varieties, the proportion of general agricultural crops in various parts of the world that might be affected, and the degree to which yields might be reduced, cannot be meaningfully surmised at this time." 6.3 DOMESTIC AND WILD ANIMALS The NRC (National Research Council, 1979a; 1982) concluded that the impact of increased UV-B radiation would have no serious impact. The most likely impact would be an increased incidence of "cancer eye," a carcinoma of the conjunctiva in certain cattle varieties. 6.4 AQUATIC SPECIES AND ECOSYSTEMS The NRC (National Research Council, 1979a) concluded that "any ozone- layer reduction will lead to an increase in DUV (damaging ultraviolet) at all depths in the water column...we must accept the possibility that ozone deple- tion could seriously affect the aquatic biosphere." The impacts of 0- deple- tion on fishery species raise a concern for supplies of human food derived from aquaculture. However, there has not been any experimental work to explore this potential problem (National Research Council, 1979a). The NRC (1982) recently concluded that the magnitude of adverse effects of enhanced UV-B radiation on aquatic organisms cannot be predicted. It should be noted that the high volatility of FC-113, absence of measured levels in water, and low toxicity indicate that FC-113 presents a low direct risk to aquatic organisms (U.S. E.P.A. , 1981). 6-2 ------- 7. CURRENT REGULATIONS, GUIDELINES, AND STANDARDS In March 1978, both the U.S. Environmental Protection Agency and the Food and Drug Administration banned CFCs as propel 1 ants in nonessential aerosol uses (Fed. Reg., 1978). It should be noted that while this ban applied to FC-113, FC-113 previously had been used in nonaerosol applications, applica- tions not covered by the ban. The concentration of FC-113 in the workplace to which nearly all workers may be repeatedly exposed without adverse effect is 1,000 ppm (7,700 mg/m ). This Threshold Limit Value has been proposed by the American Conference of Governmental and Industrial Hygienists (ACGIH, 1979). This value was recom- mended as a limit of good hygiene control for vapors of low toxicity (ACGIH, 1971). References are cited in Section 5.4, Chapter 5. 7-1 ------- 8. COLLATED BIBLIOGRAPHY Amer. Conf. Govern. Ind. Hyg. Threshold Limit Values for Chemical Substnaces in Workroom Air Adopted by ACGIH for 1979. Amer. Conf. Govern. Ind. Hyg. Documentation of the Threshold Limit Values for Substances in Workroom Air, 3rd Edition, 1971. Amer. Ind. Hyg. Assn. Comm. l,l,2-Trichloro-l,2,2-trifluoroethane, Am. Ind. Hyg. Assn. J. 29:521-525, 1968. Ames, B. N. Identifying environmental chemicals causing mutation and cancer. Science 204:587-593, 1979. Atkinson, R., G. M. Breuer, J. N. Pitts, Jr., and H. L. Sandoval. Tropo- spheric and stratospheric sinks for halocarbons: Photooxidation, 0('D) atom, and OH radical reactions. J. Geophy. Res. 81(33):5765-5770, 1976. Aviado, D. M., and D. G. Smith. Toxicity of Aerosol Propellants in the Res- piratory and Circulatory Systems. VIII. Respiration and Circulation in Primates. Toxicology 3_: 241-252, 1975. Aviado, D. M., and M. A. Belej. Toxicity of Aerosol Propellants on the Res- piratory and Circulatory Systems. I. Cardiac Arrhythmia in the Mouse. Toxicology 2:31-42, 1974. Aviado, D. M., and M. A. Belej. Toxicity of Aerosol Propellents in the Res- piratory and Circulatory Systems. V. Ventricular Function in the Dog. Toxicology 3:79-86, 1975. Aviado, D.M. Toxicity of Aerosol Propellants in the Respiratory and Circula- tory Systems. X. Proposed Classification. Toxicology 3: 321-332, 1975. Azar, A., H. J. Trochinowicz, J. B. Terrell, and L. S. Mullin. Blood levels of fluorocarbon related to cardiac sensitization. Amer. Ind. Hyg. Assoc. J. 34(3):102-109, 1973. Beaubier, J. The Skin Cancer Problem. Proceedings of the Quadrennial International Ozone Symposium, Boulder, CO, August 4-9, 1980. Belej, M. A., D. G. Smith, and D. M. Aviado. Toxicity of Aerosol Propellents in the Respiratory and Circulatory Systems. IV. Cardiotoxicity in the Monkey. Toxicology 2:381-395, 1974. Betro Research Laboratories, Inc. Unpublished data of E.I. duPont de Nemours and Company. HLO-0260-67, MRO-0916-001 (1967). Submitted to U.S. En- vironmental Protection Agency, 20 August 1979. Bower, F. A. Nomenclature and Chemistry of Fluorocarbon Compounds. Aerospace Medical Research Laboratory, Wright-Patterson Air Force Base, AD 751-423, December 1971. Burn, J. H. Pharmacological Testing of Anesthetics. Proc. Royal Soc. Med. 52:95-98, 1959. 8-1 ------- Burn, J. H., H. G. Epstein, and P. J. Goodford. The Properties of the Anaes- thetic Substance 1,1,2-Trifluro- 1,2-Dichloroethane. Brit. J. Anaesth. 31:518-529, 1959. Carter, V. L., P. M. Chikos, J. D. MacEwen, and K. C. Back. Effects of Inhal- ation of Freon 113 on Laboratory Animals. U.S. Nat. Tech. Info. Service Report AD727524, 1970. Chou, C. C., R. J. Milstein, W. S. Smith, H. Vera Ruiz, M. J. Molina, and F. S. Rowland. Stratospheric photodissociation of several saturated perhalo chlorofluorocarbon compounds in current technological use (Fluoro carbons-IB, -113, -114, and -115). J. Phys. Chem. 82(1):1-7, 1978. Clark, D. G. , and D. J. Tinston. Correlation of the Cardiac Sensitizing Potential of Halogenated Hydrocarbons with their Physiochemical Proper- ties. Brit. J. Pharm. 49:355-357, 1973. Clayton, J. W. The Mammalian Toxicology of Organic Compounds Containing Fluorine. Handbuch Exp. Pharmakol. 20:459-500, 1966. Clayton, J. W., Jr. The Toxicity of Fluorocarbons with Special Reference to Chemical Constitution. J. Occup. Med. 4(5):262-273, 1962. Cohen, E. N., J. R. Trudell, H. N. Edmunds, and E. Watson. Urinary metabolites of halothane in man. Anesth. 43:392-401, 1975. Conney, A. H., R. Chang, W. M. Levin, A. Garbut, A. D. Moore-Faure, A. W. Peck, and A. Bye. Effects of piperonyl butoxide on drug metabolism in rodents and man. Arch. Environ. Health 24:97-106, 1972. Cronn, D. R., and D. E. Harsch. Determination of atmospheric halocarbon concentrations by gas chromatography - mass spectrometry. Anal. Lett. 12 (B14):1489-1496, 1979. Cronn, 0. R., R. A. Rasmussen, and E. Robinson. Phase I Report. Measure ment of Tropospheric Halocarbons by Gas Chromatography - Mass Spectro- metry. Washington State University, August 1976a. Cronn, D. R., R. A. Rasmussen, and E. Robinson. Measurement of Tropo- spheric Halocarbons by Gas Chromatography-Mass Spectrometry. Report for Phase I. Submitted to U.S. Environmental Protection Agency, Washington State University, Pullman, Washington, August 23, 1976b. Cronn, D. R., R. A. Rasmussen, and E. Robinson. Measurement of Tropo- spheric Halocarbons by Gas Chromatography-Mass Spectrometry. Report for Phase II. Submitted to U.S. Environmental Protection Agency, Washington State University, Pullman, Washington, October, 1977a. Cronn, D. R., R. A. Rasmussen, E. Robinson, and D. E. Harsch. Halo- genated compound identification and measurement in the troposphere and lower stratosphere. J. Geophys. Res. 82:5935-5944, 1977b. 8-2 ------- Desoille, H. , L. Truffert, A. Bourguignon, P. Delavierre, M. Philbert, and C. Girard-Wallon. Experimental Study on the Toxicity of trichlorotrifluoro- ethane (Freon 113). Archives des Maladies Professionnelles de Medicine de Travail et de Securite Sociale 29:381-388, 1968. Downing, R. C. Aliphatic Chlorofluorohydrocarbons. In: Kirk-Othmer's Encyclopedia of Chemical Technology, Volume 9, 2nd Edition, 1966. Duprat, P., L. Delsuat, and D. Gradiski. Pouvoir Irritant des Principaux Solvants Chlores Aliphatiques sur la Peau et les Muqueuses Oculaires du Lapi. Eur. J. of Tox. 9(3):171-177. E. I. duPont de Nemours and Company. Personal communication from D. Broughton, 17 March 1982. E. I. duPont de Nemours and Company. "Freon" fluorocarbons. Properties and Applications. Wilmington, DE, 1969. E. I. duPont de Nemours and Company. Data submitted to the U.S. Environ- mental Protection Agency, Environmental Criteria and Assessment Office, August 20, 1979. E. I. duPont de Nemours and Company, Submission to to U. S. Environmental Protection Agency. Addendum for Freon" Products Division Bulletins B-2 and S-16, 1980. E. I. duPont de Nemours and Company. Thermodynamic Properties of "Freon" 113, Trichlorofluoroethane, CCI^F-CCIF, with addition of other physical properties. Wilmington, DE, T-EL3A, 19/6. Epstein, S. S. , E. Arnold, J. Andrea, W. Bass, and Y. Bishop. Detection of chemical mutagens by the dominant lethal assay in the mouse. Tox. and App. Pharm. 23:288-325, 1972. Epstein, S. S., J. Andrea, P. Clapp, D. Mackintosh, and N. Mantel. Enhancement by piperonyl butoxide of acute toxicity due to Freons, Benzo ( a ) pyrene, and Griseofulvin in infant mice. Tox. and Appl Pharm. 11:442-448, 1967b. Epstein, S. S., S. Joshi, J. Andrea, P. Clapp, H. Falk, and N. Mantel. Syner- gistic toxicity and carcinogenicity of 'Freons' and piperonyl butoxide. Nature 214:526-528, 1967a. Federal Register 43:11502, March 1978. Fischer, W. Personal communication, International Fabricare Insti- tute, Rockville, Maryland, 1980. Forbes, P. D., and F. Urbach. Experimental modification of photocarcinogenesis. I. Food Cosmet. Toxicol. 13:335, 1975. 8-3 ------- Harsch, D. E., and D. R. Cronn. Low-pressure sample-transfer technique for analysis of stratospheric air samples. J. Chromat. Sci. 16:363-367, 1978. ~~ Haskell Laboratory. Human Skin Absorption Studies with Trichlorofluoroethane. Medical Research Project No. MR-1014 (1968), submitted by E. I. Dupont de Nemours & Co.to U.S. Environmental Protection Agency, August 1979. Haskell Laboratory. Unpublished data of E.I. duPont de Nemours and Company. MR-2363-001, HL-0325-69 (1969). Submitted to U.S. Environmental Protec- tion Agency, 20 August 1979. Haskell Laboratory. Unpublished data of E.I. duPont de Nemours and Company. MRO-1015-001, HL-0242-67 (1967). Submitted to U.S. Environmental Protec- tion Agency, 20 August 1979. Haskell Laboratory. Unpublished data of E.I. duPont de Nemours and Company. MR-1127-001, HL-0325-69 (1969). Submitted to U.S. Environmental Protec- tion Agency 20, August 1979. Haskell Laboratory. Unpublished data of E.I. duPont de Nemours and Company. MR-2627-001, HL-915-77 (1977). Submitted to U.S. Environmental Protec- tion Agency, 20 August 1979. Hazleton Laboratories, Inc. Unpublished data of E.I. duPont de Nemours and Company. MRO-1962-001, HLO-0258-67 (1967). Reproduction Study in Rab- bits. Submitted to U.S. Environmental Protection Agency, 20 August 1979. Hazleton Laboratories, Inc. Unpublished data of E. I. OuPont de Nemours and Company. MRO-1015, HLO-242 (1967). Final Report. Teratology Study in Rabbits. Submitted to U.S. Environmental Protection Agency, 20 August 1979. Hester, N. E. , E. R. Stephens, and 0. C. Taylor. Fluorocarbons in the Los Angeles Basin. J. Air Pollut. Control Assoc. 24(6):591-595, 1974. Huempfner, K. H. The Toxicity of Frigen 113 TR-T. Zentralblatt fuer Arbeits- medizin and Arbeitsschutz 4:118-119, 1974. Imbus, H. R. and C. Adkins. Physical Examinations of Workers Exposed to Tri- chlorotrifluoroethane. Arch. Environ. Health 24:257-261, 1972. Japar, S., J. N. Pitts, Jr., and A. H. Winer. The photostability of fluorocarbons, unpublished. Kuebler, H. The physiological properties of aerosol propellants. Aerosol Age 9:44, 1964. Letkiewicz, F. J. Environment Hazard Assessment Report: Major One- and Two-Carbon Saturated Flourocarbons, EPA-560/8-76-003, U.S. Environmental Protection Agency, Office of Toxic Substances, August 1976. 8-4 ------- Lillian, D. , H. B. Singh, A. Appleby, L Lobban, R. Arnts, R. Gumpert, R. Hague, J. Toomey, J. Kazan's, M. Antell, 0. Hansen, and B. Scott. Atmosphere fates of halogenated compounds. Environ. Sci. Techno!. 9(12):1042-1048, 1975. Matsumato, T., K. C. Pani, J. J. Kovaris, and F. Hamit. Aerosol tissue adhe- sive spray. Fate of freons and their acute topical and systemic toxicity. Arch. Surg. 97:727-735, 1968. Mergner, G. W.. D. A. Blake, and M. Helrich. Biotragsformation and elimina- tion of C-tri chl orof "luoromethane (FC-11) and C-dichlorodifluoromethane (FC-12) in man. Anesthes. 42:345-351, 1975. Michaelson, J. B. , and D. J. Huntsman. Oral Toxicity of 1,2,2-trichloro-l, 1,2-trifluoroethane. J. Med. Chem. 7:378-379, 1964. Molina, M. J., and F. S. Rowland. Stratospheric sink for chlorof1uoromethanes: chlorine atom - catalyzed destruction of ozone. Nature 299:810-812, 1974. Mullin, L. S., A. Azar, C. F. Reinhardt, P. E. Smith, and E. F. Fabryka. Halogenated hydrocarbon induced cardiac arrhythmias associated with release of endogenous epinephrine. Unpublished report of Haskell Labora- tory, E.I. duPont de Nemours and Company, MR1262, HL 279-71, (1971). Submitted to U.S. Environmental Protection Agency. National Research Council. Halocarbons: Effects on stratospheric ozone. National Academy of Sciences, Washington, DC, 1976. National Research Council. National Academy of Sciences. Protection Against Depletion of Stratospheric Ozone by Chlorofluorocarbons, 1979a. National Research Council. National Academy of Sciences. Stratospheric Ozone Depletion by Halocarbons: Chemistry and Transport, 1979b. National Research Council. National Academy of Sciences. Causes and Effects of Stratospheric Ozone Reduction: An Update, 1982. Panofsky, N. A. Earth's endangered ozone. Environ. 20(3):17-40, 1978. Rasmussen, R. A., D. E. Harsch, P. H. Sweany, J. P. Krasnec, and D. R. Cronn. Determination of atmospheric halocarbons by a temperature programmed gas chromatographic freezeout concentration method. J. Air Poll. Cont. Assoc. 27(6):579-581, 1977. Reinhardt, C. F., L. S. Mullin, and M. E. Macfield. Epinephrine-Induced Cardiac Arrhythmia Potential of Some Common Industrial Solvents. J. Occup. Med. 15(12):953-955, 1973. Reinhardt, C. F. , M McLaughlin, M. E. Maxfield, L. S. Mullin, and P. E. Smith, Jr. Human Exposures to Fluorocarbon 113. Amer. Ind. Hgy. Assn. J. 32:143-152, 1971. Russell, L. B., and B. E. Matter. Whole mammal mutagenicity tests; evaluation of five methods. Mut. Res. 75:279-302, 1980. 8-5 ------- Russell, J. W., and L. A. Shadoff. The sampling and determination of halo- carbons in ambient air using concentration on porous polymer. J. Chromat. 134:375-384, 1977. Sandorfy, C. Review Paper. UV absorption of fluorocarbons. Atmos. Environ. 10:343-351, 1976. Savolainen H. and P. Pfaffli. Dose-dependent neurochemical effects of l,l,2-trichloro-l,2,2-trifluoroethane inhalation exposure in rats. Toxi- col. Lett 6:43-49, 1980. Setlow, R. B. The wavelengths in sunlight effective in producing skin cancer: A theoretical analysis. Proc. National Academy of Sciences 71:3363-3366, 1974. "~~ Shargel, L., and R. Koss. Determination of Fluorinated Hydrocarbon Propellants in Blood of Dogs after Aerosol Administration. J. of Pharm. Sci. 61(9): 1445-1449, 1972. Singh, H. B., L. J. Salas, and R. Stiles. Trace chemicals in the "clean" trosphere. EPA 600/3-81-055. SRI International, Menlo Park, California, 1981b. Singh, H. B., L. J. Salas, H. Shigeishi, and E. Scribner. Atmospheric halo- carbons, hydrocarbons, and sulfur hexafluoride: Global distributions, sources, and sinks. Science 203:899-903, 1979b. Singh, H. B., L. J. Salas, H. Shigeishi, A. J. Smith, E. Schribner, and L. A. Cavanagh. U.S. Environmental Protection Agency Atmospheric Distributions, Sources, and Sinks of Selected Halocarbons, Hydrocarbons, SFfi and N~0. EPA-600/3-79-107, November 1979a. ° i Singh, H. B., L. Salas, D. Lillian, R. R. Arnts, and A. Appleby. Generation of accurate halocarbon primary standards with permeation tubes. Environ. Sci. Techno!. 11(5):511-513, 1977. Singh, H. B., L. J. Salas, A. J. Smith, and H. Shigeishi. Measurements of some potentially hazardous chemicals in urban environments. Atmos. Environ. 15:601-612, 1981a. Smith, K. C. Molecular Changes in the Nucleic Acids Produced by Ultraviolet and Visible Radiation. In: Sunlight and Man. T. B. Fitzgerald et a!., eds. Smith, K. C, Radiation-Induced Cross-Linking of DNA and Protein in Bacteria. In: Aging, Carcinogenesis and Radiation Biology. K. C. Smith, ed., Plenum Press, 1976. SRI International. Directory of Chemical Producers, Menlo Park, California, 1979. Steinberg, M. B., R. E. Boldt, R. A. Renne, and M. H. Weeks. Inhalation Toxicity of l,l,2-Trichloro-l,2,l-trifluoroethane (TCTFE), U.S. Army Environmental Hygiene Agency, Study No. 33-18-68/69, 1969. 8-6 ------- Stopps, G. J. , and M. Mclaughlin. Psychophysiological Testing of Human Sub- jects Exposed to Solvent Vapors. Amer. Ind. Hyg. Assn. J. 28: 43-50, 1967. Triebig, G., and K. Burkhardt. Studies on Persons Qccupationally Exposed to l,l,2-Trich1oro-l,2,2-Trifluoroethane. Int. Arch. Occup. Environ. Health 42:129-135, 1978. Trochimowicz, H. J., A. Azar, J. B. Terrill, and L. S. MuTlin. Blood Levels of Fluorocarbon Related to Cardiac Sensitization: Part II. Am. Ind. Hyg. Assn. J. 35:632-639, 1974. Trochimowicz, H. J., C. F. Reinhardt, L. S. MuTlin, A. Azar, and B. W. Karrh. The effect of myocardia! infarction on the cardiac sensitization poten- tial of certain halocarbons. J. Occup. Med. 18(1):26-30, 1976. U. S. Environmental Protection Agency. Economic Implications of Regulating Chlorofluorocarbon Emissions from Nonaerosol Applications. EPA 560/ 12-80-001. Report prepared by RAND Corporation, October 1980a. U. S. Environmental Protection Agency. Environmental Hazard Assessment Report. Major one- and two-carbon saturated fluorocarbons, review of data. EPA-560/8-76-003, August 1976. U. S. Environmental Protection Agency. Regulating Chlorofluorocarbon Emissions: Effects on Chemical Production. EPA-560/12-80-001b. Report prepared by RAND Corp., October 1980b. U. S. Environmental Protection Agency. Proposed Guidelines for Registering Pesticides in the United States. 43 FR #163, August 22, 1978. pp. 37382-37388. U. S. Environmental Protection Agency. Proposed Health Effects Test Standards for Toxic Substances Control Act Test Rules and Proposed Good Laboratory Practice Standards for Health Effects. 44 FR (#145), July 26, 1979. pp. 44089-44092. U. S. Environmental Protection Agency. Draft Environmental Risk Assessment Document for Trichlorotrifluoroethane. Office of Toxic Substances, 14 September 1981. Underwriters' Laboratories, Inc. The Comparative Life, Fire, and Explosion Hazards of Trifluorotrichloroethane ("Freon-113"), 1941. Underwriters' Laboratories, Inc., 1941. The Comparative Life, Fire, and Explosion Hazards of Trifluorotrichloroethane (Freon-113). Ward, R. B. E. I. duPont de Nemours and Company. Personal communication to Dr. Jean Parker, U. S. Environmental Protection Agency, 29 September 1980. Ward, R. B. E. I. duPont de Nemours and Company. Personal communication to Dr. Jean Parker, U. S. Environmental Protection Agency, 29 September 1980, and to Mark Greenberg, U.S. Environmental Protection Agency, March 6, 1981. 8-7 ------- World Meteorological Organization. The Stratosphere 1981: Theory and Measure- ments. WHO Global Ozone Research and Monitoring Project Report No. 11, May 1981. The Stratosphere 1981: Theory and Measurements, 1982. Wuebbles, D. J. The relative efficiency of a number of halocarbons for des- troying stratospheric ozone. Lawrence Livermore National Laboratory, UCID 18924., 1981. Wuebbles, D. J. , and J. S. Chang. A study of the effectiveness of the C1X catalytic ozone loss mechanisms. J. Geophy. Res. 86(CIO):9869-9872, 1981. Young, W. , and J. A. Parker. Effect of Fluorocarbons on Acetylcholinesterase Activity and Some Counter Measures. Combust. Toxicology 2:286-297, 1975. Illinois 60604 8-8 ------- |