Toxicity of Alternatives to Chlorofluorocarbons : HFC-134a and HCFC-123 [1 ed.] 9780309572019
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Copyright © 1996. National Academies Press. All rights reserved.
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Toxicity of Alternatives to Chlorofluorocarbons: HFC-134a and HCFC-123
SUBCOMMITTEE TO REVIEW TOXICITY OF ALTERNATIVES TO CHLOROFLUOROCARBONS COMMITTEE ON TOXICOLOGY BOARD ON ENVIRONMENTAL STUDIES AND TOXICOLOGY COMMISSION ON LIFE SCIENCES NATIONAL RESEARCH COUNCIL
NATIONAL ACADEMY PRESS WASHINGTON, D.C. , 1996
Toxicity of Alternatives to Chlorofluorocarbons : HFC-134a and HCFC-123, National Academies Press, 1996. ProQuest Ebook
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ii NATIONAL ACADEMY PRESS 2101 Constitution Ave., N.W. Washington, D.C. 20418 NOTICE: The project that is the subject of this report was approved by the Governing Board of the National Research Council, whose members are drawn from the councils of the National Academy of Sciences, the National Academy of Engineering, and the Institute of Medicine. The members of the committee responsible for the report were chosen for their special competences and with regard for appropriate balance. This report has been reviewed by a group other than the authors according to procedures approved by a Report Review Committee consisting of members of the National Academy of Sciences, the National Academy of Engineering, and the Institute of Medicine. The National Academy of Sciences is a private, nonprofit, self-perpetuating society of distinguished scholars engaged in scientific and engineering research, dedicated to the furtherance of science and technology and to their use for the general welfare. Upon the authority of the charter granted to it by the Congress in 1863, the Academy has a mandate that requires it to advise the federal government on scientific and technical matters. Dr. Bruce Alberts is president of the National Academy of Sciences. The National Academy of Engineering was established in 1964, under the charter of the National Academy of Sciences, as a parallel organization of outstanding engineers. It is autonomous in its administration and in the selection of its members, sharing with the National Academy of Sciences the responsibility for advising the federal government. The National Academy of Engineering also sponsors engineering programs aimed at meeting national needs, encourages education and research, and recognizes the superior achievements of engineers. Dr. Harold Liebowitz is president of the National Academy of Engineering. The Institute of Medicine was established in 1970 by the National Academy of Sciences to secure the services of eminent members of appropriate professions in the examination of policy matters pertaining to the health of the public. The Institute acts under the responsibility given to the National Academy of Sciences by its congressional charter to be an adviser to the federal government and, upon its own initiative, to identify issues of medical care, research, and education. Dr. Kenneth I. Shine is president of the Institute of Medicine. The National Research Council was organized by the National Academy of Sciences in 1916 to associate the broad community of science and technology with the Academy's purposes of furthering knowledge and advising the federal government. Functioning in accordance with general policies determined by the Academy, the Council has become the principal operating agency of both the National Academy of Sciences and the National Academy of Engineering in providing services to the government, the public, and the scientific and engineering communities. The Council is administered jointly by both Academies and the Institute of Medicine. Dr. Bruce Alberts and Dr. Harold Liebowitz are chairman and vice chairman, respectively, of the National Research Council. The project was supported by the U.S. Department of Defense and the U.S. Environmental Protection Agency and administered by the U.S. Army under Contract No. DAMD 17-89-C-9086. Additional copies of this report are available from the Board on Environmental Studies and Toxicology, 2101 Constitution Avenue, N.W., Washington, D.C. 20418. Copyright 1996 by the National Academy of Sciences. All rights reserved. Printed in the United States of America
Toxicity of Alternatives to Chlorofluorocarbons : HFC-134a and HCFC-123, National Academies Press, 1996. ProQuest Ebook
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SUBCOMMITTEE TO REVIEW TOXICITY OF ALTERNATIVES TO CHLOROFLUOROCARBONS BERNARD M. WAGNER (Chair), Wagner Associates, Millburn, N.J. W. KENT ANGER, Oregon Health Sciences University, Portland, Oreg. CHARLES E. FEIGLEY, University of South Carolina, School of Public Health, Columbia, S.C. WALDERICO GENEROSO, Oak Ridge National Laboratory, Oak Ridge, Tenn. IAN GRAVES, University of Minnesota, Minneapolis, Minn. ROBERT SNYDER, Environmental & Occupational Health Sciences Institute, Piscataway, N.J. GERALD N. WOGAN, Massachusetts Institute of Technology, Cambridge, Mass. GAROLD S. YOST, University of Utah, Salt Lake City, Utah Staff KULBIR S. BAKSHI, Project Director RUTH E. CROSSGROVE, Editor CATHERINE M. KUBIK, Senior Program Assistant LUCY FUSCO, Project Assistant Sponsors U.S. Navy, U.S. Air Force, U.S. Environmental Protection Agency
Toxicity of Alternatives to Chlorofluorocarbons : HFC-134a and HCFC-123, National Academies Press, 1996. ProQuest Ebook
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COMMITTEE ON TOXICOLOGY ROGENE F. HENDERSON (Chair), Lovelace Biomedical and Environmental Research Institute, Albuquerque, N.Mex. DONALD E. GARDNER (Vice-Chair), Raleigh, N.C. DEBORAH A. CORY-SLECHTA, University of Rochester, Rochester, N.Y. ELAINE M. FAUSTMAN, University of Washington, Seattle, Wash. CHARLES E. FEIGLEY, University of South Carolina, Columbia, S.C. DAVID W. GAYLOR, U.S. Food and Drug Administration, Jefferson, Ark. WALDERICO M. GENEROSO, Oak Ridge National Laboratory, Oak Ridge, Tenn. IAN A. GREAVES, University of Minnesota, Minneapolis, Minn. SIDNEY GREEN, U.S. Food and Drug Administration, Laurel, Md. LOREN D. KOLLER, Oregon State University, Corvallis, Oreg. MICHELE A. MEDINSKY, Chemical Industry Institute of Toxicology, Research Triangle Park, N.C. JOHN L. O'DONOGHUE, Eastman Kodak Company, Rochester, N.Y. ROBERT SNYDER, Environmental and Occupational Health Sciences Institute, Piscataway, N.J. BAILUS WALKER, JR., Howard University, Washington, D.C. ANNETTA P. WATSON, Oak Ridge National Laboratory, Oak Ridge, Tenn. HANSPETER R. WITSCHI, University of California, Davis, Calif. GERALD N. WOGAN, Massachusetts Institute of Technology, Cambridge, Mass. GAROLD S. YOST, University of Utah, Salt Lake City, Utah
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Staff, Committee on Toxicology
KULBIR S. BAKSHI, Program Director MARVIN A. SCHNEIDERMAN, Senior Staff Scientist MARGARET E. MCVEY, Program Officer RUTH E. CROSSGROVE, Editor CATHERINE M. KUBIK, Senior Program Assistant LUCY FUSCO, Project Assistant
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BOARD ON ENVIRONMENTAL STUDIES AND TOXICOLOGY PAUL G. RISSER (Chair), Miami University, Oxford, Ohio MICHAEL J. BEAN, Environmental Defense Fund, Washington, D.C. EULA BINGHAM, University of Cincinnati, Cincinnati, Ohio PAUL BUSCH, Malcolm Pirnie, Inc., White Plains, N.Y. EDWIN H. CLARK, II, Clean Sites, Inc., Alexandria, Va. ALLAN H. CONNEY, Rutgers University, Piscataway, N.J. ELLIS COWLING, North Carolina State University, Raleigh, N.C. GEORGE P. DASTON, Procter & Gamble Co., Cincinnati, Ohio DIANA FRECKMAN, Colorado State University, Fort Collins, Colo. ROBERT A. FROSCH, Harvard University, Cambridge, Mass. RAYMOND C. LOEHR, University of Texas, Austin, Tex. GORDON ORIANS, University of Washington, Seattle, Wash. GEOFFREY PLACE, Hilton Head, S.C. DAVID P. RALL, Washington, D.C. LESLIE A. REAL, Indiana University, Bloomington, Ind. KRISTIN SHRADER-FRECHETTE, University of South Florida, Tampa, Fla. BURTON H. SINGER, Princeton University, Princeton, N.J. MARGARET STRAND, Bayh, Connaughton and Malone, Washington, D.C. GERALD VAN BELLE, University of Washington, Seattle, Wash. BAILUS WALKER, JR., Howard University, Washington, D.C. TERRY F. YOSIE, E. Bruce Harrison Co., Washington, D.C.
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Staff Program Directors, Board on Environmental Studies and Toxicology
JAMES J. REISA, Director DAVID J. POLICANSKY, Associate Director and Program Director for Natural Resources and Applied Ecology CAROL A. MACZKA, Program Director for Toxicology and Risk Assessment LEE R. PAULSON, Program Director for Information Systems and Statistics RAYMOND A. WASSEL, Program Director for Environmental Sciences and Engineering
Toxicity of Alternatives to Chlorofluorocarbons : HFC-134a and HCFC-123, National Academies Press, 1996. ProQuest Ebook
Toxicity of Alternatives to Chlorofluorocarbons : HFC-134a and HCFC-123, National Academies Press, 1996. ProQuest Ebook
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Copyright © 1996. National Academies Press. All rights reserved.
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COMMISSION ON LIFE SCIENCES THOMAS D. POLLARD (Chair), The Johns Hopkins University, Baltimore, Md. FREDERICK R. ANDERSON, Cadwalader, Wickersham & Taft, Washington, D.C. JOHN C. BAILAR III, University of Chicago, Chicago, III. JOHN E. BURRIS, Marine Biological Laboratory, Woods Hole, Mass. MICHAEL T. CLEGG, University of California, Riverside, Calif. GLENN A. CROSBY, Washington State University, Pullman, Wash. URSULA W. GOODENOUGH, Washington University, St. Louis, Mo. SUSAN E. LEEMAN, Boston University, Boston, Mass. RICHARD E. LENSKI, Michigan State University, East Lansing, Mich. THOMAS E. LOVEJOY, Smithsonian Institution, Washington, D.C. DONALD R. MATTISON, University of Pittsburgh, Pittsburgh, Pa. JOSEPH E. MURRAY, Wellesley Hills, Mass. EDWARD E. PENHOET, Chiron Corp., Emergyville, Calif. EMIL A. PFITZER, Research Institute for Fragrance Materials, Hackensack, N.J. MALCOLM C. PIKE, University of Southern California, Los Angeles, Calif. HENRY C. PITOT III, University of Wisconsin, Madison, Wisc. JONATHAN M. SAMET, The Johns Hopkins University, Baltimore, Md. HAROLD M. SCHMECK, JR., North Chatham, Mass. CARLA J. SHATZ, University of California, Berkeley, Calif. JOHN L. VANDEBERG, Southwestern Foundation for Biomedical Research, San Antonio, Tex. PAUL GILMAN, Executive Director
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OTHER RECENT REPORTS Board on Environmental Studies and Toxicology Upstream: Salmon and Society in the Pacific Northwest (1996) Science and the Endangered Species Act (1995) Wetlands: Characteristics and Boundaries (1995) Biologic Markers (Urinary Toxicology (1995), Immunotoxicology (1992), Environmental Neurotoxicology (1992), Pulmonary Toxicology (1989), Reproductive Toxicology (1989)) Review of EPA's Environmental Monitoring and Assessment Program (three reports, 1994-1995) Science and Judgment in Risk Assessment (1994) Ranking Hazardous Sites for Remedial Action (1994) Measuring Lead Exposure in Infants, Children, and Other Sensitive Populations (1993) Pesticides in the Diets of Infants and Children (1993) Issues in Risk Assessment (1993) Setting Priorities for Land Conservation (1993) Protecting Visibility in National Parks and Wilderness Areas (1993) Dolphins and the Tuna Industry (1992) Hazardous Materials on the Public Lands (1992) Science and the National Parks (1992) Animals as Sentinels of Environmental Health Hazards (1991) Assessment of the U.S. Outer Continental Shelf Environmental Studies Program, Volumes I-IV (1991-1993) Human Exposure Assessment for Airborne Pollutants (1991) Monitoring Human Tissues for Toxic Substances (1991) Rethinking the Ozone Problem in Urban and Regional Air Pollution (1991) Decline of the Sea Turtles (1990) Tracking Toxic Substances at Industrial Facilities (1990)
Toxicity of Alternatives to Chlorofluorocarbons : HFC-134a and HCFC-123, National Academies Press, 1996. ProQuest Ebook
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Committee on Toxicology Permissible Exposure Levels for Selected Military Fuel Vapors (1996) Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants, Volume 1 (1994) and Volume 2 (1996) Nitrate and Nitrite in Drinking Water (1995) Guidelines for Chemical Warfare Agents in Military Field Drinking Water (1995) Review of the U.S. Naval Medical Research Institute's Toxicology Program (1994) Health Effects of Permethrin-Impregnated Army Battle-Dress Uniforms (1994) Health Effects of Ingested Fluoride (1993) Guidelines for Developing Community Emergency Exposure Levels for Hazardous Substances (1993) Guidelines for Developing Spacecraft Maximum Allowable Concentrations for Space Station Contaminants (1992) Review of the U.S. Army Environmental Hygiene Agency Toxicology Division (1991) Permissible Exposure Levels and Emergency Exposure Guidance Levels for Selected Airborne Contaminants (1991) These reports may be ordered from the National Academy Press: (800) 624-6242 or (202) 334-3313
Toxicity of Alternatives to Chlorofluorocarbons : HFC-134a and HCFC-123, National Academies Press, 1996. ProQuest Ebook
Toxicity of Alternatives to Chlorofluorocarbons : HFC-134a and HCFC-123, National Academies Press, 1996. ProQuest Ebook
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PREFACE
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Preface
s part of the effort to phase out the use of stratospheric ozone-depleting substances, such as chlorofluorocarbons (CFCs) and Halon gases, the U.S. Navy is planning to substitute hydrofluorocarbon (HFC)-134a for the refrigerant CFC-12, and the Air Force is planning to substitute hydrochlorofluorocarbon (HCFC)-123 for the fire suppressant Halon 1211. The Navy asked the National Research Council (NRC) to review the toxicity data on HFC-134a and to recommend 1-hr and 24-hr emergency exposure guidance levels (EEGLs) and 90-day continuous exposure guidance levels (CEGLs). The Air Force requested the NRC to review the adequacy of the 1-min EEGL proposed by the Air Force for HCFC-123. In addition, the U.S. Environmental Protection Agency (EPA) requested the NRC to review the suitability of current methods for detecting and quantifying the risk of cardiac sensitization from exposure to CFCs and their substitutes. The NRC assigned these tasks to its Committee on Toxicology, which established the Subcommittee to Review Toxicity of Alternatives to
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PREFACE
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Chlorofluorocarbons. The subcommittee reviewed the toxicity data on the two CFC substitutes and the assessment protocol for cardiac sensitization. This report is intended to aid the Navy, the Air Force, and EPA in using CFC substitutes safely. Lieutenant Commander Kenneth Still, Commander Paul Gillooly, Captain David Macys, Dr. Robert Carpenter (all from the U.S. Navy), Dr. Jeffery Fisher (U.S. Air Force), Drs. Joseph Cotruvo and Rebecca Jones (both from EPA) are gratefully acknowledged for their interest and support of the project. Dr. James McDougal (formerly with the U.S. Air Force), Dr. George Rusch (Allied Signal Chemicals, Inc.), and Dr. Henry Trochimowicz (DuPont Chemical Company) are also thanked for providing valuable information. This report could not have been produced without the valuable efforts of the NRC staff, including Paul Gilman, executive director, Commission on Life Sciences; James J. Reisa, director, Board on Environmental Studies and Toxicology; Carol A. Maczka, director, Toxicology and Risk Assessment Program; Margaret McVey, program officer; Ruth E. Crossgrove, editor; Lucy Fusco, project assistant; and Catherine Kubik, senior program assistant. We especially acknowledge the subcommittee's great debt to Kulbir Bakshi, who not only ably fulfilled the role of project director but also contributed substantially to the drafting and revision of the report. Without his skills and input, our task could not have been completed in such a timely manner. Finally, we would like to thank all the members of the subcommittee for their expertise, input, and support throughout our deliberations. Bernard M Wagner, M.D. Chair, Subcommittee to Review the Toxicity of Alternatives to Chlorofluorocarbons Rogene F. Henderson, Ph.D. Chair, Committee on Toxicology
Toxicity of Alternatives to Chlorofluorocarbons : HFC-134a and HCFC-123, National Academies Press, 1996. ProQuest Ebook
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Contents
EXECUTIVE SUMMARY
Toxicity of Alternatives to Chlorofluorocarbons : HFC-134a and HCFC-123, National Academies Press, 1996. ProQuest Ebook
1
1 INTRODUCTION Statement of Task Definitions Structure of the Report 7 8 9 12
2 EVALUATION OF THE DOG CARDIAC SENSITIZATION TEST Introduction Mechanism of Action for Chemically Induced Arrhythmias Protocol for a Cardiac Sensitization Screening Study Cardiac Sensitization Experiments Involving Selected Halocarbons Conclusion References 13
13 14
15
18
20 21
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CONTENTS
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3
4
EXPOSURE GUIDANCE LEVELS FOR HYDROFLUOROCARBON-134a Introduction Background Information Toxicokinetics Toxicity Information Summary Recommendations for Exposure Guidance Levels References
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EXPOSURE GUIDANCE LEVELS FOR HYDROFLUOROCARBON-123 Introduction Recommendations for Exposure Guidance Levels References
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APPENDIX A Attachment 1: Attachment 2: Attachment 3: Attachment 4:
Supporting Documentation for the Exposure Guidance Level for Hydrofluorocarbon-123 Material Safety Data Sheet Halothane Summary of Toxicity Studies of HCFC-123 Summary of Acute Pharmacokinetic Study of HCFC-123 in Dogs by Inhalation
23 24 25 25 33 33 37
41 42 42 43 43 65 79 93 103
FIGURE Figure 2-1
Protocol for cardiac sensitization
17
TABLES Table 3-1 Table 3-2 Table 3-3
Acute Lethality of HFC-134a in Rats Summary of Non-cancer Toxicity Information for HCF-134a Summary of Carcinogenicity Information for HCF-134a
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27 34 35
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Toxicity of Alternatives to Chlorofluorocarbons: HFC-134a and HCFC-123
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Toxicity of Alternatives to Chlorofluorocarbons : HFC-134a and HCFC-123, National Academies Press, 1996. ProQuest Ebook
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EXECUTIVE SUMMARY
1
Executive Summary
n 1987, the Montreal Protocol on Substances That Deplete the Ozone Layer and its later versions called for phasing out chlorofluorocarbons (CFCs) (e.g., CFC-12, CFC-113, and CFC-114) and bromofluorocarbons (BFCs) (e.g., Halon gases). CFCs are still being used in large amounts in refrigeration, metal and electronics cleaning, mobile air conditioning, and sterilization. Until recently, Halon gases were the major components of fire extinguishants and were used extensively in fighting fires. Because CFCs and Halon gases have been produced and used in large quantities, any chemical that replaces them on a large scale must have relatively low risks associated with its production, use, and disposal, as well as minimal toxicity and impact on the environment. Two of the chemical classes under consideration for replacing CFCs are hydrochlorofluorocarbons (HCFCs) and hydrofluoro
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EXECUTIVE SUMMARY
2
carbons (HFCs). HCFCs break down more easily in the atmosphere than do CFCs. HCFCs have less stratospheric-ozone-depletion potential and less globalwarming potential. Use of HCFCs as transitional refrigerants will enable industry to phase out the production of CFCs and will offer environmental benefits over the continued use of CFCs. HFCs do not contain chlorine or contribute to destruction of stratospheric ozone. However, some HFCs might contribute to global warming. Although a few HFCs have been in use for some time, their potential use as replacements for CFCs has grown rapidly over the past several years. Concern has been raised that rapid expansion of the use of some HFCs might contribute to global warming. Nonetheless, use of HFCs not only offers lower overall risk to the environment than use of CFCs but also offers a reduction in the time needed to eliminate use of CFCs. The U.S. Department of Defense (DOD) needs exposure guidance levels for the alternatives to CFCs for emergencies and for continuous exposures of up to 90 days. Therefore, the Navy's Bureau of Medicine asked the National Research Council (NRC) to review the toxicity data on HFC-134a, a prime candidate for replacing CFC-12 (dichlorofluoromethane), which is used in refrigeration systems and medical aerosols. The Navy also asked the NRC to recommend 1-hr and 24-hr emergency exposure guidance levels (EEGLs) and a 90-day continuous exposure guidance level (CEGL) for HFC-134a and identify appropriate research to fill data gaps. Similarly, the Air Force requested that the NRC evaluate the adequacy of the 1-min EEGL proposed by Air Force toxicologists for exposure to HCFC-123. HCFC-123 is a proposed substitute for Halon 1211, the fire extinguishant currently used by the Air Force. In addition to the requests made by the Navy and the Air Force, the U.S. Environmental Protection Agency (EPA) asked the NRC to assess the suitability of current methods for detecting and quantifying the risk of cardiac sensitization from exposure to CFCs and their substitutes.
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EXECUTIVE SUMMARY
3
The NRC assigned the project to the Committee on Toxicology (COT), which established the Subcommittee to Review Toxicity of Alternatives to Chlorofluorocarbons. The subcommittee prepared this report. ASSESSMENT OF MODEL FOR CARDIAC SENSITIZATION Inhalation of some chlorinated hydrocarbons, such as CFCs and volatile anesthetics, can make the mammalian heart abnormally sensitive to epinephrine, resulting in cardiac arrhythmias and possibly death. The phenomenon is referred to as cardiac sensitization and can be experimentally induced by most halocarbons (e.g., carbon tetrachloride and chloroform) and some hydrocarbons (e.g., cyclopropane and n-hexane). The subcommittee evaluated the suitability of the available dog cardiacsensitization test developed by the DuPont Company for quantifying the risk of cardiac sensitization from exposure to CFCs and other related chemicals. In the cardiac-sensitization test, dogs are intravenously administered epinephrine at doses of 5-12 µg/kg and monitored for cardiac arrhythmias for 5 min. If no arrhythmias occur, the animals are exposed to the test chemical. After 5 min of exposure, the dog is given a second challenge injection of epinephrine, and the exposure to the test chemical is continued for an additional 5 min. The criterion for cardiac sensitization is the induction of ventricular fibrillation as monitored by an electrocardiogram. The test has been used to study the cardiacsensitization potential of many chemicals. The subcommittee concludes that the dog cardiac-sensitization test is effective in determining the potential of chemicals to sensitize the myocardium to epinephrine-induced arrhythmias. Although the dog cardiac-sensitization test is performed under conditions that are optimized for the induction of arrhythmias in animals, humans exposed to high concentrations of some halocarbons develop arrhythmias. Therefore, uncertainty factors are necessary when performing risk assess
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EXECUTIVE SUMMARY
4
ment for humans. The subcommittee recommends that the mechanism of cardiac sensitization be determined and that a more sensitive test be developed that permits adequate safety evaluation of halocarbons that will replace the currently used CFCs. This topic will be addressed in greater detail in 1996 in a workshop on toxicity of alternatives to CFCs, which is being organized by the NRC's Committee on Toxicology. EXPOSURE GUIDANCE LEVELS FOR HFC-134A The 1-hr EEGL recommended by the subcommittee for HFC-134a is 4,000 parts per million (ppm). This recommendation is based on a no-observedadverse-effect level (NOAEL) of 40,000 ppm, which was identified in cardiacsensitization tests of male beagles exposed to HFC-134a at concentrations of 40,000, 80,000, 160,000, and 320,000 ppm and simultaneously injected with epinephrine. Cardiac sensitization was observed in dogs exposed at the three highest concentrations but not at the lowest concentration of 40,000 ppm. Fetotoxic effects, such as a slight retardation of skeletal ossification, were observed in rats and rabbits at lower concentrations than those producing cardiac sensitization in dogs, but the NOAELs (20,000 ppm for rabbits exposed for 78 hr and 10,000 ppm for rats exposed for 240 hr) identified in the rat and rabbit tests cannot be used to establish a 1-hr EEGL because the animals were exposed to HFC-134a for much longer periods. (HFC-134a was not teratogenic or embryotoxic with exposures at concentrations up to 50,000 ppm.) Using the NOAEL of 40,000 ppm identified in dog cardiac-sensitization studies, the subcommittee determined the 1-hr EEGL to be 4,000 ppm (40,000 ppm divided by an uncertainty factor of 10 to allow for interspecies variability). Because blood concentrations of halogenated hydrocarbons are not likely to increase when exposure time is increased beyond 5-10 min, the NOAEL identified for cardiac sensitization following a 10-min exposure can be used without time extrapolation to set a 1-hr EEGL.
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EXECUTIVE SUMMARY
5
The recommended 24-hr EEGL is based on the fetotoxicity effects (slight retardation of skeletal ossification) observed in rats. Using a NOAEL of 10,000 ppm in rats, the subcommittee determined the 24-hr EEGL to be 1,000 ppm (10,000 ppm divided by an uncertainty factor of 10 to allow for interspecies variability). The maternal toxicity effects observed in rabbits were not used to determine the 24-hr EEGL because the effects observed were limited to bodyweight changes, which the subcommittee did not judge to be an important adverse effect. The recommended 90-day CEGL is based on a 2-year chronic toxicity study conducted in male rats exposed to HFC-134a at concentrations of 2,500, 10,000, or 50,000 ppm for 6 hr/day, 5 days/wk. The study identified 50,000 ppm as the NOAEL. An increase in testicular weight and benign Leydig tumors occurred at that dose. However, the subcommittee did not judge the increase in testicular weight to be an adverse effect. In addition, the increase in Leydig tumors is not applicable to humans because they are related to some unique aspect of rodent metabolism; therefore, the subcommittee identified 50,000 ppm as the NOAEL. Using the NOAEL of 50,000 ppm, the subcommittee determined the 90-day CEGL to be 900 ppm (50,000 ppm divided by an uncertainty factor of 10 to account for interspecies variability, a factor of 4 for a 24-hr/day exposure vs. a 6-hr/day exposure, and a factor of 5/7 for a 7-days/wk exposure vs. a 5-days/wk exposure). The subcommittee's proposed 1-hr and 24-hr EEGLs and the 90-day CEGL recommendations for HFC-134a are as follows: Proposed Recommendations for HFC-134a by the Subcommittee Exposure
Concentration, ppm
1-hr EEGL
4,000
24-hr EEGL
1,000
90-day CEGL
900
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EXECUTIVE SUMMARY
6
Although the recommended 24-hr EEGL of 1000 ppm and 90-day CEGL of 900 ppm are similar, they are based on different end points or target toxicities. The similarity of the exposure guidance levels recommended for 24hr and 90-day exposures is consistent with the fact that blood concentrations of CFCs or their substitutes reach maximal levels within minutes of the onset of exposure, and continued exposure for many hours or days does not increase blood concentrations further or lead to the buildup of the chemical in the body. EXPOSURE GUIDANCE LEVEL FOR HCFC-123 For HCFC-123, the end points of pharmacological or adverse effects considered for establishing an EEGL are cardiac sensitization, anesthesia or CNS-related effects, malignant hyperthermia, and hepatotoxicity. Cardiac sensitization was chosen as the most sensitive end point because of the potent sensitizing effect of this chemical and similar chemicals in epinephrine-challenged dogs. The EC50 (concentration required to produce cardiac sensitization in 50% of the animals) for HCFC-123 was determined in dog studies to be 1.9% (19,000 ppm) for a 5-min exposure. The Air Force toxicologists recommended that the EC50 of 19,000 ppm be the 1-min EEGL for HCFC-123. However, the subcommittee believes that 1,900 ppm (19,000 ppm divided by an uncertainty factor of 10 for interspecies variability) should be considered the human no-observed-effect level (NOEL) for a 1-min exposure to HCFC-123 on the basis of the dog cardiac-sensitization model. Therefore, the subcommittee recommends that the 1-min EEGL of 19,000 ppm proposed by the Air Force be lowered to 1,900 ppm.
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INTRODUCTION
7
1 Introduction
he 1987 Montreal Protocol on Substances that Deplete the zone Layer (and its later versions) called for the phasing out of both chlorofluorocarbons (CFCs) and bromofluorocarbons (BFCs). Specifically, the treaty called for the discontinuation of production of CFCs and some related compounds (e.g., carbon tetrachloride and methyl chloroform) by January 1, 1996. Production of the Halon gases was discontinued January 1, 1994. However, the protocol does not apply to the use of existing stocks of CFCs or Halon gases. CFCs continue to be used in large amounts in refrigeration, metal and electronics cleaning, mobile air conditioning, and sterilization. Until recently, the Halon gases were used extensively in fighting fires and were the major components of fire extinguishants. Because CFCs and Halon gases have been produced and used in such large quantities, any chemical that takes a substantial
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INTRODUCTION
8
portion of their market must have relatively low risk associated with its production, use, and disposal, as well as minimal or no toxicity and minimal impact on the environment. In response to current concerns over the release of CFCs and BFCs into the atmosphere, their effect on the ozone layer, and upcoming restrictions on their availability, industry has been searching for substitute chemicals that will perform the same functions as the CFCs and BFCs without adversely affecting human health or the environment. Two of the chemical classes under consideration for replacing CFCs are hydrochlorofluorocarbons (HCFCs) and hydrofluorocarbons (HFCs). HCFCs contribute to the destruction of stratospheric ozone, but to a much lesser extent than CFCs. Use of HCFCs as transitional refrigerants will allow industry to phase out the production of CFCs and will offer environmental benefits over the continued use of CFCs. Because they contain hydrogen, HCFCs break down more easily in the atmosphere than do CFCs. Therefore, HCFCs have less ozone depletion potential, in addition to less global-warming potential. HFCs do not contain chlorine and do not contribute to destruction of stratospheric ozone. However, some HFCs have a significant global-warming potential. Although a few HFCs have been in use for some time, the potential for HFCs as a replacement for CFCs has grown rapidly over the last several years. The U.S. Environmental Protection Agency (EPA) is concerned that rapid expansion of the use of some HFCs could contribute to global warming. Nonetheless, use of HFCs offers lower overall risk than use of CFCs as well as a reduction in the time needed to eliminate CFC use. STATEMENT OF TASK The U.S. Navy, as an extensive user of refrigeration equipment, is in the process of replacing CFC refrigerants used aboard ships
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INTRODUCTION
9
and submarines. Due to a concern for potential reproductive, developmental, and neurobehavioral effects from exposure to HFCs, the Navy's Bureau of Medicine asked the National Research Council (NRC) to review the toxicity data on HFC-134a, a prime candidate for the replacement of Freon 12 (dichlorofluoromethane). The Navy also asked the NRC to recommend 1-hr and 24-hr emergency exposure guidance levels (EEGLs) and a 90-day continuous exposure guidance level (CEGL) for HFC-134a and identify appropriate research to fill data gaps. Similarly, the Air Force has requested that the NRC evaluate the adequacy of the 1-min EEGL proposed by Air Force toxicologists for exposure to HCFC-123. HCFC-123 is a proposed substitute for Halon 1211, the fire extinguishant currently used by the Air Force. In addition to the requests made by the Navy and Air Force, the EPA asked the NRC to assess the suitability of current methods for detecting and quantifying the risk of cardiac sensitization from exposure to CFCs and their substitutes. The NRC assigned these tasks to the Committee on Toxicology (COT), which established the Subcommittee to Review Toxicity of Alternatives to Chlorofluorocarbons. The subcommittee reviewed applicable scientific documents, including reports prepared by EPA that assessed the toxicological data on potential CFC substitutes—HFCs and HCFCs. This report presents the subcommittee's assessment of (1) the toxicity of specific substitutes (1,1,1,2tetrafluoroethane (HFC-134a) and 1,1-dichloro-2,2,2-trifluoroethane (HCFC-123)), (2) the various methods used to quantify the toxicological effects of CFCs and their substitutes, including proposed EEGLs and CEGLs, and a model used to evaluate and quantify the risks of cardiac sensitization from exposure to CFCs and their substitutes, and (3) data gaps and future research needs. DEFINITIONS Emergency Exposure Guidance Level An EEGL is defined as a ceiling guidance level for single emer
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INTRODUCTION
10
gency exposures, usually lasting from 1 hr to 24 hr—an occurrence expected to be infrequent in the lifetime of a person. “Emergency” connotes a rare and unexpected situation with potential for significant loss of life, property, or mission accomplishment if not controlled. An EEGL can also be set for much shorter periods, such as 1-min or 5-min exposures. An EEGL, a single ceiling or upper number for a particular exposure period, specifies and reflects the subcommittee's interpretation of available information in the context of an emergency. An EEGL is acceptable only in an emergency, when some risks or some discomfort must be endured to prevent greater risks (such as fire, explosion, or massive release). Even in an emergency, exposure should be limited to a defined short period. Exposure at the EEGL might produce such effects as increased respiratory rate from increased carbon dioxide exposure, headache or mild centralnervous-system effects from carbon monoxide exposure, or respiratory-tract or eye irritation from ammonia, phosgene, or sulfur dioxide exposure. The EEGL is intended to prevent irreversible harm. Even though some reduction in performance is permissible, it should not prevent proper responses to the emergency (such as shutting off a valve, closing a hatch, removing a source of heat or ignition, or using a fire extinguisher). For example, in normal work situations, a degree of upper-respiratory-tract irritation or eye irritation causing discomfort would not be considered acceptable; during an emergency, it would be acceptable if it did not cause irreversible harm or seriously affect judgment or performance. The EEGL for a substance represents the subcommittee's judgment based on evaluation of experimental and epidemiological data, mechanisms of injury, and, when possible, operating conditions in which emergency exposure might occur, as well as consideration of DOD goals and objectives. Acute toxicity is the primary basis for establishing an EEGL. However, even brief exposure to some substances might have the potential to increase the risk of cancer or other delayed effects. If
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INTRODUCTION
11
the substance under consideration is carcinogenic, a cancer risk assessment is performed with the aim of providing an estimate of the exposure that would not lead to an excess risk of cancer greater than 1 in 10,000 exposed persons. The acceptable risk selected for military exposures is based on considerations of policy and objectives of DOD. In estimating the EEGL for a substance that has multiple biological effects, all end points—including reproductive (in both sexes), developmental, carcinogenic, neurotoxic, respiratory, and other organ-related effects—are evaluated, and the most important is selected. If confidence in the available data is low or if important data are missing, appropriate safety factors are used and the rationale for their selection is stated. Generally, EEGLs have been developed for exposure to single substances, although emergency exposures often involve complex mixtures of substances and thus have a potential for toxic synergism. In the absence of other information, guidance levels for complex mixtures can be developed from EEGLs by assuming as a first approximation that the toxic effects are simply additive—thus implying a proportional reduction in EEGLs for each of the constituents of a mixture. Continuous Exposure Guidance Level The CEGL is a ceiling guidance level set to avoid adverse health effects, either immediate or delayed, of prolonged exposures and to avoid degradation in crew performance that might endanger the objectives of a particular mission as a consequence of continuous exposure for up to 90 days. In contrast with EEGLs, which are intended to guide exposures during emergencies (exposures that, although not acceptable under normal operating conditions, should not cause serious or permanent effects), CEGLs are intended to provide guidance for operations lasting up to 90 days in closed environments such as in a submarine.
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INTRODUCTION
12
STRUCTURE OF THE REPORT This report consists of the following: Chapter 2 contains an evaluation of the suitability of the current method for detecting and quantifying the risk of cardiac sensitization from exposure to CFCs and their substitutes. Chapter 3 reviews the toxicity data on HFC-134a and recommends 1-hr and 24-hr EEGLs and a 90-day CEGL. Chapter 4 evaluates the adequacy of the 1-min EEGL proposed by Air Force toxicologists for exposure to HCFC-123. Supporting documentation on HCFC-123 is contained in Appendix A and attachment 1, attachment 2, attachment 3 and attachment 4. That information was generated either by the Air Force toxicologists or the manufacturer of HCFC-123. The subcommittee reviewed but did not participate in the preparation of Appendix A and its attachments.
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EVALUATION OF THE DOG CARDIAC SENSITIZATION TEST
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2 Evaluation of the Dog Cardiac Sensitization Test
INTRODUCTION his chapter contains an evaluation of the suitability of the method used for detecting and quantifying the risk of cardiac sensitization from exposure to CFCs, their substitutes, and other hydrocarbons. The history of solvent-induced cardiac arrhythmia and the protocol used to evaluate the potential of volatile organic chemicals (VOCs) to cause this effect have been described by Reinhardt and co-workers (1971a). Since the early 1900s, it was known that inhalation of volatile anesthetics, such as cyclopropane and chloroform, can make the mammalian heart abnormally sensitive to epinephrine, resulting in cardiac arrhythmia and possibly death. This phenomenon is referred to as “cardiac sensitization” and can be induced experimentally by most halocarbon (e.g., carbon tetrachloride and chloroform) and hydrocarbon (e.g., cyclopropane, propane, iso-octane, and n-hexane) solvents and propellants.
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Deaths presumed to be due to cardiac arrest, as a result of the sensitization of the heart to epinephrine, have also been attributed to the intentional “sniffing” of aerosol propellants and from overexposure to VOCs in industrial settings. With respect to the former, in the 1960s, there were a series of deaths involving “sniffing” of aerosol propellants. This practice encompassed numerous aerosol products (e.g., fry-pan lubricant (PAM), hair spray, deodorant, antiseptic, and a product used to chill cocktail glasses) and involved spraying an aerosol product into a balloon or bag and then deeply inhaling the contents. Because the air in the balloon is displaced by the propellant, this procedure results in the inhalation of highly concentrated vapors. In all, from 1967 to 1969, 67 deaths were attributed to this practice. As stated above, other fatalities from overexposure to VOCs have been reported in industrial settings (NIOSH, 1989). Typically, they involved the use of volatile solvents in areas of poor ventilation. Estimates of the concentrations range from 37,000 to 130,000 ppm and even higher. The reported fatalities were somewhat surprising because the aerosol propellants typically involved—e.g., chlorofluorocarbon-12, chlorofluorocarbon-11, chlorofluorocarbon-113, iso-octane, propane, and vinyl chloride—are not acutely toxic even at high levels. MECHANISM OF ACTION FOR CHEMICALLY INDUCED ARRHYTHMIAS CFCs, their substitutes, and some other hydrocarbons decrease the threshold for epinephrine-induced arrhythmias by reducing the ability of the cardiovascular system to respond to stress. The major cardiac effects of epinephrine, which is produced by the adrenal gland, involve increasing the rate and force of cardiac contraction (Aviado and Belej, 1974). Normally, heart rate and force are precisely controlled by a balance between adrenergic and cholinergic innervation. Doses of epinephrine that are higher than physiological doses can increase the heart rate so that there is an
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imbalance between heart rate and force, leading to the induction of arrhythmias (Belej et al., 1974). Studies conducted by Starling and Evans (1962) using CFC-113 provide evidence that this compound appears to decrease the threshold for epinephrineinduced arrhythmias. In these studies, arrhythmias could be induced readily in dogs administered intravenous (i.v.) injections of epinephrine during exposure to CFC-113 at concentrations of 5,000 ppm. However, in the absence of epinephrine injections, no arrhythmias were induced when animals were exposed to CFC-113 at concentrations up to 12,000 ppm. That was the case even with external stimulation (Clark and Tinston, 1973; Hardy, 1991). Similarly, without the use of exogenous epinephrine, Aviado (1975) could not induce arrhythmias in mice administered CFC-113 at concentrations below 100,000 ppm or in monkeys at concentrations below 50,000 ppm. In earlier studies using loud noise to stimulate epinephrine release, arrhythmias occurred in animals exposed to CFCs at only very high concentrations (80% halocarbon, 20% oxygen) for 30 sec (Reinhardt et al., 1971a). In subsequent experiments where dogs were allowed to generate their own epinephrine by running on a treadmill, for example, cardiac sensitization could be induced by some CFCs, but only at concentrations 2 to 4 times those needed to induce sensitization in the preceding screening studies using injected epinephrine (Mullin et al., 1972). Therefore, administration of exogenous epinephrine following exposure to a test compound tends to overpredict the potential for a chemical to induce cardiac arrhythmia under normal or physiological levels of endogenous epinephrine. PROTOCOL FOR A CARDIAC SENSITIZATION SCREENING STUDY Before the start of the experiment, male dogs are fitted with a flow-through breathing mask that is designed to deliver the test
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vapor. They are conditioned to breathe through the face mask. Due to the anesthetic effect of the test vapor, dogs are also fitted and conditioned to stand in a sling that allows them to rest their feet on the ground. A canula for injecting epinephrine is implanted into the cephalic vein (Reinhardt et al., 1971a). Also, before the start of the experiment, the maximum i.v. dose of epinephrine that will not cause a serious or life-threatening arrhythmia, is determined. Clark and Tinston (1973) showed that injections of epinephrine at 5 µg/kg of body weight did not result in the development of serious arrhythmias. However, Hardy (1991) showed that the sensitivity to epinephrine could be improved by maximizing the dose of epinephrine for each dog. In this procedure, each dog is administered an i.v. injection of epinephrine at 4 µg/kg. If no serious arrhythmia develops, a second higher dose of epinephrine is administered. The injections are continued until either the dog develops a minimal response (defined as approximately 1-10 ectopic beats) or the maximum dose of 12 µg/kg is used. This dose is then administered with the test chemicals. The standard protocol that is followed in experimental studies is described below and depicted in Figure 2-1. As shown in Figure 2-1, at time zero, the dog is placed in the restraint, the breathing mask is attached, and the dog is allowed to breathe air for 2 min to acclimate. It should be noted that, although several species, including mice (White and Carlson, 1981), monkeys (Kawakami et al., 1990), rabbits (Reinhardt et al., 1973), and rats (Mullin et al., 1972), have been used to study the induction of cardiac arrhythmia, dogs are the species of choice in that they serve as a good cardiovascular model for humans, have a large heart size, and can be trained to calmly accept the experimental procedures. Following the acclimation period, the dog is administered an i.v. injection of epinephrine (5-12 µg/kg in 1 mL of saline) and monitored for cardiac arrhythmias. The dog continues breathing air for 5 min more and, if no arrhythmias occur, exposure to the test chemical is initiated at 7 min through the flow-through face mask. The cardiac response is continuously monitored by electrocardiography
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throughout the experiment. After 5 min of continuous exposure to the test compound, the dog is then given a second challenge injection of epinephrine. Exposure to the test chemical remains uninterrupted for an additional 5 min. The criterion for a cardiac sensitization response is the appearance of a burst of multifocal ventricular ectopic activity (MVEA) or ventricular fibrillation (VF) following the epinephrine challenge. Ventricular tachycardia alone is not considered definitive evidence of a positive response. In addition,
FIGURE 2-1 Protocol for cardiac sensitization. aDose of epinephrine (8 µg/kg) is approximately 10 times the levels of epinephrine seen in humans at times of stress. The total dose (8 µg/kg) contained in 1 mL of normal saline is infused in 9 sec by an automatic infusion pump. Source: Reinhardt et al., 1971a.
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EVALUATION OF THE DOG CARDIAC SENSITIZATION TEST
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isolated ectopic beats are not uncommon, are not lifethreatening, and are therefore not indicative of cardiac sensitization. The above protocol calls for a 5-min interval between the administration of the first i.v. injection of epinephrine and initiation of exposure to the test chemical. It also calls for a 5-min observation interval after the challenge injection of epinephrine. With respect to the former, the physiological response to an injection of epinephrine lasts for less than 60 sec. Thus, a period of 5 min between the first i.v. injection of epinephrine and exposure to the test chemical is adequate time to allow the dog to return to a normal cardiac rhythm. The decision to allow for 5-min intervals between exposures to concentrations of the test chemical is based on experiments of Mullin et al. (1979), who demonstrated that blood concentrations of the test chemical reached maximum levels within 5 min and equilibrium within the next 15 min of exposure. It is also important to note that the protocol as described above requires that i.v. injections of epinephrine be administered during the exposures to the test chemical. This is based on investigations of White and Carlson (1981) who exposed rabbits to trichloroethylene and found that chemically induced arrhythmias did not occur when epinephrine was administered 15-30 min after exposure to a sensitizing level of the solvents. CARDIAC SENSITIZATION EXPERIMENTS INVOLVING SELECTED HALOCARBONS The protocol described above has evolved from many experimental studies using a variety of techniques. CFC-113, a common solvent and degreasing agent, was evaluated in many of these studies. However, other fluorocarbons (e.g., CFC-11, CFC-12, HCFC-22, HCFC-123, and HFC-134a) have undergone similar testing (Aviado, 1975; Collins et al., 1992). Reinhardt et al. (1973) demonstrated that 10 of 29 dogs (34%) developed serious arrhythmias
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when exposed to CFC-113 at a concentration of 5,000 ppm for 5 min and then injected with epinephrine. Serious arrhythmias did not result in 12 dogs exposed to CFC-113 at 2,500 or 1,000 ppm for 5 min and then injected with epinephrine. Even when the exposures were continued for 6 hr at concentrations of 2,000 or 2,500 ppm, only one of six dogs developed a serious arrhythmia following the epinephrine injection. Furthermore, 12 dogs exposed five times to CFC-113 at 1,000 ppm for 6 hr per day and then injected with epinephrine showed no evidence of cardiac sensitization (Mullin, 1969). In an effort to study the effect of endogenous supraphysiological concentrations of epinephrine, dogs were exposed to CFC-113 at concentrations of 12,000 ppm and frightened by either a loud noise or an electric shock. The only effect observed on the electrocardiogram was an increase in heart rate. This suggests that the endogenous epinephrine levels generated under these conditions are not high enough to induce cardiac sensitization. In another series of studies, dogs were exposed to CFC-113 at 20,000 ppm while running on a treadmill (up to 300 ft per min for 20 min) (Mullin, 1969). No cardiac arrhythmias suggestive of sensitization were observed in any of the dogs. However, with other CFCs, tests involving endogenous epinephrine production did induce cardiac sensitization in dogs but only at exposure concentrations 2-4 times those needed to induce sensitization in the experimental screening studies using exogenous epinephrine. In the absence of any stimuli, spontaneous arrhythmias could not be induced in dogs even with CFC concentrations up to 100,000 ppm, clearly demonstrating that CFCs alone do not induce the arrhythmias. In a study involving humans, volunteers were exposed to CFC-113 at concentrations up to 1,000 ppm for 4 hr (Woollen et al., 1990). No significant effects were observed. In another study, volunteers were exposed to CFC-113 at concentrations of 500 ppm for 6 hr per day for 5 days during the first week and then at concentrations of 1,000 ppm for 6 hr per day for 5 days during the second week (Reinhardt et al., 1971b). The subjects did not partic
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ipate in any exercise. No cardiac abnormalities developed that could be associated with the exposure. In an earlier study, two male subjects were exposed for 2 3/4 hr to CFC-113 at concentrations as high as 4,500 ppm (Stopps and McLaughlin, 1967). With the exception of a slight decrement in the results of a series of psychomotor tests conducted during the exposures, there was no evidence of any adverse effect. Although these human studies involved a small number of subjects, the absence of cardiac effects supports the premise that the dog cardiac-sensitization model is a very sensitive test that can be used to evaluate the risk of cardiac arrhythmias in humans exposed to CFCs. The reason for the usefulness of the test in humans is because it is very sensitive and is optimized to cause cardiac arrhythmias through administration of epinephrine to dogs to the point that is just below the threshold for inducing cardiac sensitization. Because of the high sensitivity of the test, it was designed to screen chemicals for cardiac sensitization. It is a conservative test with built in safety factors. This test does not mimic human exposure scenarios. (Physiological levels of epinephrine are an order of magnitude below those used in the dog test.) Therefore, this test is not designed to set regulations for human health. A few fatalities have been reported from exposure to high concentrations of CFC-113. Estimates were made of the exposure concentrations in a few cases of the fatalities. Those estimates range from 37,000 ppm in a report by May and Blotzer (1984) to 120,000-300,000 ppm in a report by NIOSH (1989). Although these reports are only suggestive that high exposures to fluorocarbons can lead to death, these results are consistent with findings in dog studies. CONCLUSION In conclusion, the standard protocol, as outlined in Figure 2-1, has been shown to be effective in determining the potential of
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CFCs and their substitutes to sensitize the myocardium to epinephrine-induced arrhythmias. Although the dog cardiac sensitization test is performed under conditions which are optimized for the induction of arrhythmias in animals, humans exposed to high levels of some halocarbons develop arrhythmias. Therefore, uncertainty factors are necessary when performing risk assessment for humans. The subcommittee recommends that the mechanism of cardiac sensitization be determined and that a more sensitive test be developed that permits adequate safety evaluation of halocarbons that will replace the currently used CFCs. This topic will be addressed in greater detail in a workshop on toxicity of alternatives to CFCs that will be organized by the NRC's Committee on Toxicology in March 1996. REFERENCES Aviado, D.M. 1975. Toxicity of aerosol propellants in the respiratory and circulatory systems. X. Proposed Classification. Toxicology 3:321-332. Aviado, D.M. and M.A. Belej. 1974. Toxicity of aerosol propellants in the respiratory and circulatory systems. I. Cardiac arrhythmia in the mouse. Toxicology 2:31-42. Belej, M.A., D.G. Smith, and D.M. Aviado. 1974. Toxicity of aerosol propellants in the respiratory and circulatory systems. IV. Cardiotoxicity in the monkey. Toxicology 2:381-395. Clark, D.G., and D.J. Tinston. 1973. Correlation of the cardiac sensitizing potential of halogenated hydrocarbons with their physiochemical properties. Br. J. Pharmacol. 49:355-357. Collins, M.A., D.J. Tinston, and C.J. Hardy. 1992. Studies on the Acute Toxicity of Some Fluorocarbon Alternatives. Paper presented at the International Union of Toxicology Conference, Rome, Italy, June 28-July 3, 1992. Hardy, C. 1991. HCL-134a: Cardiac sensitization study in dogs. Rep. No. ISN 250/91169. Huntingdon Research Centre , Huntingdon, U.K. Kawakami, T., T. Takano, and R. Araki. 1990. Enhanced arrhythmo
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22
genicity of Freon 113 by hypoxia in the perfused rat heart. Toxicol. Ind. Health 6:493-506. May, D.C., and M.J. Blotzer. 1984. A report of occupational deaths attributed to fluorocarbon-113. Arch. Environ. Health 39:352-354. Mullin, L.S. 1969. Cardiac Sensitization: Fright/Treadmill Studies. HL-0325-69. Haskell Laboratory, E.I. du Pont de Nemours and Co., Wilmington, Del. Mullin, L.S., A. Azar, C.F. Reinhardt, P.E. Smith, and E. Fabryka. 1972. Halogenated hydrocarboninduced cardiac arrhythmias associated with release of endogenous epinephrine. Am. Ind. Hyg. Assoc. J. 33:389-396. Mullin, L.S., C.F. Reinhardt, and R. E. Hemingway. 1979. Cardiac arrhythmias and blood levels associated with inhalation of Halon 1301. Am. Ind. Hyg. Assoc. J. 40:653-658. NIOSH (National Institute of Occupational Safety and Health). 1989. NIOSH Alert: Preventing Death from Excessive Exposure to Chlorofluorocarbon 113. DHHS Publ. 89-109. Washington, D.C.: National Institute of Occupational Safety and Health. Reinhardt, C.F., A. Azar, M.E. Maxfield, P.E. Smith, Jr., L.S. Mullin. 1971a. Cardiac arrhythmias and aerosol sniffing. Arch. Environ. Health 22:265-279. Reinhardt, C.F., M. McLaughlin, M.E. Maxfield, L.S. Mullin, and P.E. Smith, Jr. 1971b. Human exposures to fluorocarbon 113 (1,1,2-trichloro-1,2,2-trifluoroethane). Am. Ind. Hyg. Assoc. J. 32:143-152. Reinhardt, C.F., L.S. Mullin, and M.E. Maxfield. 1973. Epinephrine-induced cardiac arrhythmia potential of some common industrial solvents. J. Occup. Med. 15:953-955. Starling, E.H., and L. Evans. 1962. P. 1413 in Principles of Human Psychology, 13th Ed., H. Davson and M.G. Eggleton, eds. Philadelphia: Lea & Febiger. Stopps, G.J., and M. McLaughlin. 1967. Psychophysiological testing of human subjects exposed to solvent vapors. Am. Ind. Hyg. Assoc. J. 28:43-50. White, J.F., and G.P. Carlson. 1981. Epinephrine-induced cardiac arrhythmias in rabbits exposed to trichloroethylene: Role of trichloroethylene metabolites. Toxicol. Appl. Pharmacol. 60:458-465. Woollen, B.H., E.A. Guest, W. Howe, J.R. March, H.K. Wilson, T.R. Auton, and P.G. Blain. 1990. Human inhalation pharmacokinetics of 1,1,2-trichloro-l,2,2-trifluoroethane (FC113). Int. Arch. Occup. Environ. Health 62:73-78.
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23
3 Exposure Guidance Levels for Hydrofluorocarbon-134a
INTRODUCTION ydrofluorocarbon (HFC)-134a or 1,1,1,2-tetrafluoroethane is a gaseous halocarbon that is being considered as a prime candidate for replacing other halocarbon materials, such as Freon 12 (dichlorodifluoromethane) and Freon 22, for use in air conditioning and refrigeration systems and possibly as an aerosol propellant or foam expansion agent. Due to a federal regulation that mandates switching from CFCs to other suitable compounds that either do not damage the ozone layer or damage the ozone layer less than CFCs, the U.S. Navy requested that the NRC review the toxicity data on HFC-134a and recommend 1-hr and 24-hr EEGLs. The Navy also requested that the NRC recommend a 90-day CEGL for HFC-134a and identify appropriate research to fill data gaps. The remainder of this chapter consists of the supporting documentation assembled and evaluated by the subcommittee in support of its recommendations.
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BACKGROUND INFORMATION Physical and Chemical Properties Common name:
FC-134a
Chemical name:
Ethane, 1,1,1,2-tetrafluoro
Synonyms:
HFC-134a; Norflurane; 1,1,1,2Tetrafluoroethane; HFA-134a; 1,2,2,2Tetrafluoroethane; F-134a; R134a; Refrigerant R134a
CAS number:
811-97-2
Chemical structure:
Description:
Colorless gas
Molecular weight:
102.03
Boiling point:
−26.5°C at 736 mm Hg
Melting point:
−101°C
Freezing point:
−101°C
Density and specific gravity:
1.21 g/mL (liquid under pressure at 77°F)
Vapor pressure:
96 psia at 25°C (77°C)
Flash point and flammability:
Nonflammable
Solubility:
0.15% in water; soluble in ether
Octanol and water partition coefficient:
Pow = 1.06
Conversion factors:
1 mg/L = 238 ppm; 1 ppm = 4.2 mg/m3
Occurrence and Use The major uses of HFC-134a are in mobile air conditioning and
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refrigeration; it may also be used as a propellant in medications, such as antiasthmatic preparations (Olson et al., 1990). TOXICOKINETICS Absorption of fluorocarbons and bromofluorocarbons via the inhalation route is rapid; the maximal blood concentrations of the substances develop within 5 min and equilibrium is achieved within the next 15 min of exposure (Azar et al., 1973; Trochimowicz et al., 1974; Mullin et al., 1979). Blood concentrations do not increase further with increasing durations of exposure for a given concentration of these substances. The time course of absorption of HFC-134a via the inhalation route is likely to be similar. Toxic effects observed in animals following oral and inhalation exposures to HFC-134a indicate that it is absorbed by the lungs and gastrointestinal (GI) tract (Salmon et al., 1980). Studies conducted in rats exposed to high concentrations of HFC-134a, either orally or via inhalation, indicate that it is rapidly excreted, mostly as the unchanged parent compound (Salmon et al., 1980). Analysis of the urine, feces, and expired air of rats exposed to HFC-134a at 10,000 ppm (1.0%) of HFC-134a for 1 hr showed that only 0.34-0.40% was metabolized. This study also provides evidence that some HFC-134a is retained in the liver and that relatively high amounts are retained in the adrenal gland. Studies with rat-liver microsomes show that HFC-134a is oxidized by the cytochrome-P-450 system; that implies that cytochrome-P-450-containing tissues, such as nasal mucosa, liver, and lungs, might convert HFC-134a to trifluoracetic acid, a toxic metabolite (Olson et al., 1990). TOXICITY INFORMATION No toxicity data are available on humans following exposure to
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26
HFC-134a. Animal studies indicate that HFC-134a has a low level of systemic toxicity following acute, subacute, subchronic, and chronic exposures. For example, neurotoxicity and cardiac sensitization occur after acute exposures to HCF-134a at high concentrations. HFC-134a at high concentrations appears to be a developmental toxicant (slight delays in skeletal ossification and lower body weights). The toxicity of HFC-134a in animals is discussed in more detail in the following discussion. Acute Toxicity HFC-134a has low acute toxicity via the inhalation route. Its approximate lethal concentration (ALC) in rats is 567,000 ppm following 4 hr of inhalation exposure. Silber and Kennedy (1979a) exposed six groups of rats (each group containing six animals) to HFC-134a at concentrations ranging from approximately 80,000 ppm to 653,000 ppm. Clinical signs of toxicity included lethargy, labored and rapid respiration, foaming at the nose, tearing, salivation, and weight loss. Rissolo and Zapp (1967) exposed rats to HFC-134a at concentrations of 750,000 ppm for 30 min. Two of four animals died. During exposure to the chemical, animals showed incoordination, pumping respiration, darkening of the eyes, unresponsiveness, cyanosis, convulsions, and death. Upon removal from exposure to HFC-134a, the surviving animals became coordinate within 5 min and appeared normal. Pulmonary congestion and edema were observed during necropsy of the two rats who died during exposure. Surviving rats were necropsied 14 days after exposure and showed no abnormalities. In summary, HFC-134a has very low acute toxicity. Lethal concentrations of HFC-134a range from 567,000 to 750,000 ppm in rats. Table 3-1 summarizes the acute toxicity information for HFC-134a.
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TABLE 3-1 Acute Lethality of HFC-134a in Rats Exposure Duration
Exposure Concentration, ppm
End Point
Reference
4 hr
567,000
Approximate lethal concentration
Siber and Kennedy, 1979a
30 min
750,000
2 of 4 died
Rissolo and Zapp, 1967
Cardiac Sensitization Mullin and Hartgrove (1979) evaluated the cardiac sensitization potential of HFC-134a in a standard epinephrine challenge test. Healthy male dogs were exposed to various concentrations of HFC-134a in the following manner. An intravenous control injection of epinephrine (8 µg/kg) was given before exposure. Following administration of the injection, the animals were exposed via inhalation for 5 min to HFC-134a at one of the following concentrations: 50,000, 75,000, or 100,000 ppm. A challenge dose of epinephrine (same as the pretest dose) was given immediately after cessation of exposure. Heart rate and wave dynamics were monitored with an electrocardiogram throughout the experiment. A “marked response” was scored when a life-threatening cardiac arrhythmia developed (multiple consecutive ventricular beats) or when ventricular fibrillation occurred and ended in cardiac arrest. No dogs exhibited “marked responses” (life-threatening cardiac arrhythmias such as multiple ventricular beats or ventricular fibrillation) at exposures of 50,000 ppm. Two of 10 dogs exhibited multiple ventricular beats upon exposure at 75,000 ppm of the test compound. Two of 4 dogs exposed at 100,000 ppm showed marked responses, one with multiple consecutive ventricular beats, the other with ventricular fibrillation leading to cardiac arrest. In summary, Mullin and Hartgrove's (1979) results indicate that HFC-134a is a weak cardiac sensitizer when tested in an epi
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nephrine challenge test in dogs. Epinephrine-induced cardiac arrhythmias were seen at doses of 75,000 ppm and greater. The noobserved-adverse-effect level (NOAEL) for this response was 50,000 ppm. Hardy et al. (1991) exposed beagle dogs to HFC-134a at concentrations of 40,000, 80,000, 160,000, and 320,000 ppm. The test involved intravenous injection of epinephrine before and during gas inhalation. The dose of epinephrine administered to each dog was adjusted to result in a few ectopic beats in the absence of the test chemical. Dogs were either administered 2, 4, or 8 µg/kg, depending on their individual sensitivity to epinephrine. Using this paradigm, no cardiac sensitization was observed in dogs at concentrations of 40,000 ppm, whereas concentrations of 80,000 ppm and higher induced cardiac sensitization. Therefore, the NOAEL for this study is 40,000 ppm. Subacute Toxicity Subacute toxicity studies in rats indicate that the only pathological changes following 14 days or 28 days of exposure (6 hr/day, 5 days/wk) to HFC-134a at 50,000 or 100,000 ppm were changes in the lung, indicative of focal interstitial pneumonitis (Silber and Kennedy, 1979b). Some changes in organ weights (liver, kidney, and gonads) were seen after 28 days of exposure at 50,000 ppm. Increased liver weight was also seen at an exposure concentration of 10,000 ppm in males. None of the organ-weight changes were associated with histological changes. Male albino rats exposed to HCF-134a by inhalation at approximately 100,000 ppm 10 times over a 2-week period for 6 hr/day, 5 days/ wk showed no compound-related hematological, blood chemistry, pathological, and urinary changes (Silber and Kennedy, 1979b). Urinary fluoride concentrations were increased after the ninth exposure, suggesting metabolic conversion of the retained halocarbon (Silber and Kennedy, 1979b). Groups of 16 male and 16 female rats were exposed
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to HCF-134a by inhalation at 1,000, 10,000, or 50,000 ppm 20 times in a 28day period for 6 hr/day (Riley et al., 1979). Changes in liver, kidney, and gonad weights were noted; these were confined to male rats exposed at 50,000 ppm except for a liver-weight increase, which was also seen at 10,000 ppm. There were no pathological changes in these tissues, and the liver- and kidney-weight increases are considered to be due to a physiological adaptation to treatment. The reduced testicular weight is not considered to be of toxicological importance. In summary, the only pathological change of possible relationship to treatment in these subacute tests was in the lungs of several male rats receiving 50,000 ppm. This lesion was a focal interstitial pneumonitis. The NOAEL for this study is 10,000 ppm (Silber and Kennedy, 1979b). Subchronic Toxicity Hext (1989) exposed groups of 20 male and 20 female Wistarderived albino rats to daily concentrations of HFC-134a at 0, 2,000, 10,000, or 49,500 ppm for 6 hr/day, 5 days/wk for 13 weeks. Half of the animals from each group were killed following termination of exposure and the remaining animals were killed following a 4-week “recovery” period. Body-weight gains, in general, tended to be lower in exposed groups than in controls; however, the differences were relatively small and were not doserelated. A few statistically significant changes in urine, blood chemistry, and hematological values and in the weights of the liver, lung, and heart did not appear to be either dose-related or consistent with repeated sampling. A statistically significant decrease in brain weights was reported; however, this change was not dose-related and was not accompanied by either positive histological findings or by transient central-nervoussystem (CNS) depression. Similar decreases in brain weight were not reported in animals allowed to recover after 4 weeks of sub
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chronic exposures to HFC-134a at up to 49,500 ppm or in animals sacrificed following 12 months of exposure to HFC-134a (Hext, 1989). In addition, histopathological findings were negative in animals allowed to recover following 4 weeks of exposure. Thus, the weight of evidence suggests that brain-weight decreases observed in female rats might be a statistical artifact. However, it is possible that brain lesions might be present in those areas of the brain that did not undergo histopathological examination. A decrease in brain weight could be representative of a significant loss of structure and function. In addition, cell loss within the CNS is often followed by replacement with connective tissue, minimizing the likelihood of measuring a decrease in overall brain weight. More specific information from ongoing studies is needed to evaluate fully the potential neurotoxicity of this compound. Developmental Toxicity Three inhalation studies (two in rats and one in rabbits) were conducted in animals to examine the developmental effects of HFC-134a. Lu and Staples (1981) exposed pregnant CD rats to HFC-134a at concentrations of 30,000, 100,000, and 300,000 ppm for 6 hr/day from days 6 to 15 of gestation. There was a significant reduction in fetal weight and significant increases in several skeletal variations following exposure of dams to HFC-134a at 300,000 ppm. Maternal toxicity was observed following exposure of dams at both 100,000 ppm (effects were reduced responses to noise stimuli and uncoordinated movements) and 300,000 ppm (effects were significant reductions in food consumption and body-weight gain, no responses to noise stimuli, severe tremors, and uncoordinated movements). No developmental effects were observed following exposure of dams at 30,000 or 100,000 ppm. Hodge et al. (1979a) exposed a group of pregnant rats (29-30 per group) to HFC-134a at concentrations of 0, 1,000, 10,000 or
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50,000 ppm for 6 hr/day on days 6-15 of gestation. No statistically significant evidence of maternal toxicity was observed following exposure of dams to concentrations of HFC-134a as high as 50,000 ppm. However, at this concentration, developmental toxicity was evident. Fetal body weight was significantly reduced, and skeletal ossification was significantly delayed. Wickramaratne (1989a,b) exposed pregnant New Zealand rabbits (18-23 per group) to HFC-134a at concentrations of 0, 2,500, 10,000, or 40,000 ppm, 6 hr/day on days 6-18 of gestation. Does were killed on day 29, and fetuses were weighed and examined for external, internal, and skeletal abnormalities. Inhalation exposure of rabbits in the 10,000- or 40,000-ppm group resulted in statistically significant increases in the fetal incidence of unossified seventhlumbar transverse processes. The incidence in control animals also increased with time. Therefore, the incidence was not considered a significant chemicalrelated effect. In addition, maternal toxicity was observed in rabbits exposed at both concentrations of HFC-134a. Specifically, there was a statistically significant reduction in food consumption and body-weight gains. There was also a dose-related increase in the incidence of gaseous distention of the stomach, which was statistically significant at 40,000 ppm. However, this increased incidence (12.7%) was only slightly outside the range for historical controls (2.3-11.5%). The reasons for the increase in gaseous distention is unclear, but it could be indicative of lung problems or nonrandom handling of the animals. No maternal or developmental effects were seen at 2,500 ppm. Reproductive Toxicity In a 28-day inhalation study, 16 male rats were exposed to HFC-134a at 0, 1,000, 10,000, 50,000 ppm for 6 hr/day, 5 days/wk (Riley et al., 1979). The rats exhibited decreased gonad weights at the 50,000-ppm exposure concentration. However, no effect was
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noted on the gonads of male rats exposed at 50,000 ppm (including organweight change) in a 90-day inhalation study; thus, the significance of this effect in the 28-day study is not clear. In a 2-year study conducted in male rats exposed to HFC-134a at 50,000 ppm for 6 hr/day, 5 days/wk, there was an increase in testicular weight (Hext and Parr-Dobrzanski, 1993). Leydig-cell hyperplasia and benign Leydig-cell tumors were also reported. The authors reported that none of these effects occurred following exposure of male rats at 10,000 ppm. Genotoxicity There is no evidence to suggest that HFC-134a induces either genetic or chromosomal mutations, and hence, there is no reason to suspect that HFC-134a might induce heritable effects in humans. HFC-134a is reported to be nonmutagenic when tested in the Ames assay (Litton Bionetics, 1976; Callandar and Priestley, 1990). It also did not alter DNA synthesis in rat hepatocytes (Trueman, 1990), induce chromosomal aberrations in human lymphocytes (Mackay, 1990), or alter micronucleus formation in the femoral bone marrow of exposed mice (Mueller and Hoffman, 1989). HFC-134a also appears to be nonmutagenic when tested in a dominant lethal assay (Hodge et al., 1979b). The results of the chromosomal aberrations in rat bone-marrow cells are inconclusive (Anderson and Richardson, 1979). Carcinogenicity Four groups of 85 male and 85 female rats were exposed to HFC-134a by inhalation at concentrations of 2,500, 10,000, and 50,000 ppm for 6 hr/day for up to 104 weeks (Hext and ParrDobrzanski, 1993). These exposures were whole-body exposures. No toxic effects were observed in the rats at concentrations of up
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to 10,000 ppm. At 50,000 ppm, there were increases in testicular weight, Leydig-cell hyperplasia, and Leydig-cell tumors. The Leydig-cell tumors are common in rats and are induced by a wide variety of chemicals in rats. They are usually induced in rats by epigenetic or secondary mechanisms and are related to some unique aspect of rodent metabolism. These tumors are not applicable to humans and thus not considered to be an adverse effect. Thus, the NOAEL or upper limit of animal exposure for nontoxic effects of HFC-134a is about 50,000 ppm. In a 52-week study, male and female rats were exposed to HFC-134a. The rats were exposed for 1 year by gavage 5 days/wk with HFC-134a dissolved in corn oil at a daily dose of 300 mg/kg of body weight. No carcinogenicity was observed in this investigation. However, only one concentration was used, and it is possible that the route of administration and the dose of the compound used were incapable of detecting a weak carcinogen (Longstaff et al., 1984). SUMMARY Table 3-2 summarizes the studies on HFC-134a for cardiac sensitization and subacute, developmental, and reproductive toxicity. Table 3-3 summarizes the studies on HFC-134a for genotoxicity and carcinogenicity. RECOMMENDATIONS FOR EXPOSURE GUIDANCE LEVELS The 1-hr EEGL recommended by the subcommittee is 4,000 ppm. This concentration is based on a NOAEL of 40,000 ppm identified in cardiac sensitization tests in which male beagles were exposed to HFC-134a at 40,000, 80,000, 160,000 and 320,000 ppm and simultaneously injected with epinephrine (Hardy et al.,
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Exposure Frequency and Duration
10 min
Dog
14-28 days for 6 hr/day, 5 days/wk
Gestation days 6-15, 6 hr/day
Gestation days 6-18, 6 hr/day
Rat
Rabbit
Toxicity of Alternatives to Chlorofluorocarbons : HFC-134a and HCFC-123, National Academies Press, 1996. ProQuest Ebook
104 days for 6 hr/day, 5 days/wk
Male rat
Increased testicular
weighta
50,000
50,000
50,000
10,000
Fetal toxicity Reduced gonad weighta
2,5000
10,000
Fetal toxicity Maternal toxicity
50,000
100,000
Fetal toxicity Maternal toxicity
30,000
10,000
40,000
50,000
NOAEL, ppm
Maternal toxicity
Interstitial pneumonitus
Cardiac sensitization
Cardiac sensitization
End Point
points were observed at the NOAEL, but are not considered adverse effects.
90 days for 6 hr/day, 5 days/wk
Male rat
aEnd
28 days for 6 hr/day, 5 days/wk
Male rat
Reproductive toxicity
Gestation days 6-15, 6 hr/day
Rat
Developmental toxicity
Rat
Subacute toxicity
10 min
Dog
Acute toxicity
Species
TABLE 3-2 Summary of Non-cancer Toxicity Information for HCF-134a
10,000
50,000
300,000
100,000
50,000
80,000
75,000
LOAEL, ppm
Hext and Parr-Dobrzanski, 1993
Hext, 1989
Riley et al., 1979
Wickramaratne, 1989a,b
Hodge et al., 1979a
Lu and Staples, 1981
Silber and Kennedy, 1979b
Hardy et al., 1991
Mullin and Hartgrove, 1979
Reference
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1991). Cardiac sensitization was seen in dogs exposed at the highest concentrations but was not observed in dogs exposed at 40,000 ppm. Although fetotoxic effects were observed in rats and rabbits at lower exposure concentrations, the NOAELs (20,000 ppm for rabbits exposed for 78 hr and 10,000 ppm for rats exposed for 240 hr) identified in these tests cannot be used to establish a 1-hr EEGL because animals were exposed to HFC-134a for much longer periods than would be appropriate for setting 1-hr EEGLs. Using the NOAEL of 40,000 ppm identified in dog cardiac sensitization studies, the subcommittee determined the 1-hr EEGL to be 4,000 ppm (40,000 ppm divided by an uncertainty factor of 10 to account for interspecies variability). Because blood concentrations of halogenated hydrocarbons are not likely to increase with increasing duration of exposure beyond 5 min, the NOAEL identified for cardiac sensitization following a 10-min exposure can be used without time extrapolation to set a 1-hr EEGL. The subcommittee selected the lower NOAEL (40,000 ppm) from the Hardy et al. (1991) study rather than the higher NOAEL (50,000 ppm) from the Mullin and Hartgrove (1979) study of cardiac sensitization, because Hardy et al. (1991) adjusted the dose of epinephrine administered to each dog individually, whereas Mullin and TABLE 3-3 Summary of Carcinogenicity Information for HCF-134aa Species
Exposure Frequency and Duration
Tumors
Reference
Rat
Inhalation for 104 wk for 6 hr/day, 5 days/ wk
Lydig-cell tumorsb
Hext and ParrDobrzanski, 1993
Rat
Oral (gavage) for 52 wk, once per day
No tumors observed
Longstaff et al., 1984
aNo studies have shown any mutagenicity, unschedules DNA synthesis, or chromosomal aberrations. bLeydig-cell tumors are not considered indicative of adverse effects in humans because they are not applicable to humans.
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Hartgrove (1979) used the same dose of epinephrine for all dogs. Results from the cardiac-sensitization test using a 10-min exposure should not be used to set 24-hr EEGLs or 90-day CEGLS. Therefore, the 24-hr EEGL is based on the fetotoxicity effects observed in rats (Hodge et al., 1979a). Using a NOAEL of 10,000 ppm, the subcommitte determined the 24-hr EEGL to be 1,000 ppm (10,000 ppm divided by an uncertainty factor of 10 to account for interspecies variability). The maternal toxicity effects observed in rabbits were not used to determine the 24-hr EEGL because the effects observed were bodyweight changes, and the subcommittee did not consider those effects to be adverse. The 90-day CEGL is based on the 2-year chronic toxicity study conducted in male rats exposed to HFC-134a at 2,500, 10,000, or 50,000 ppm for 6 hr/day, 5 days/wk (Hext and Parr-Dobrzanski, 1993). The NOAEL identified in the study is 50,000 ppm. At that dose, increases in testicular weight and benign Leydig tumors were reported. However, the subcommittee does not consider the increase in testicular weight to be an adverse effect in itself, and the increase in Leydig tumors is not applicable to humans because those tumors are related to some unique aspect of rodent metabolism. Therefore, the subcommittee identified 50,000 ppm as the NOAEL. Using the NOAEL of 50,000 ppm, the subcommittee determined the 90-day CEGL to be 900 ppm (50,000 ppm divided by 10 to account for interspecies variability, a factor of 4 for a 24-hr/ day exposure (vs. a 6-hr/day exposure), and a factor of 5/7 for a 7-days/wk exposure (vs. a 5-days/wk exposure)). Although the recommended 24-hr EEGL (1,000 ppm) and 90-day CEGL (900 ppm) are similar, they are based on different end points or target toxicities. The fetotoxicity observed in rats during gestation was used to develop the 24-hr EEGL, whereas the 90-day CEGL was recommended on the basis of no adverse effects observed in rats chronically exposed to 50,000 ppm. The similarity of the exposure guidance levels recommended for 24-hr and 90-day exposures is consistent with the fact that blood concentrations of this class of compounds reach maximal levels within minutes of the onset of expo
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sure, and continuing exposure for many hours or days does not increase blood concentrations further (Mullin et al., 1979). Proposed Recommendations for HFC-134a Exposure
Concentration, ppm
1-hr EEGL
4,000
24-hr EEGL
1,000
90-day CEGL
900
REFERENCES Anderson, D., and C.R. Richardson. 1979. Arcton-134a: A Cytogenetic Study in the Rat. ICI Rep. No. CTL/P/444. Imperial Chemical Industries , Alderley Park, Macclesfield, Cheshire, U.K. Azar, A., H.J. Trochimowicz, J.B. Terrill, and L.S. Mullin. 1973. Blood levels of fluorocarbon related to cardiac sensitization. Am. Ind. Hyg. Assoc. J. 34:102-109. Callander, R.D., and K.P. Priestley. 1990. HFC-134a: An Evaluation Using the Salmonella Mutagenicity Assay. ICI Rep. No. CTL/P/2422. Central Toxicology Laboratory, Imperial Chemical Industries , Alderley Park, Macclesfield, Cheshire, U.K. Hardy, C.J., I.J. Sharman, and G.C. Clark. 1991. Assessment of Cardiac Sensitisation Potential in Dogs. Rep. No. CTL/C/ 2521. Huntingdon Research Centre , Huntingdon, Cambridgeshire, U.K. Hext, P.M. 1989. HFC 134a: 90-Day Inhalation Toxicity Study in the Rat. ICI Rep. No. CTL/ P/2466. Central Toxicology Laboratory, Imperial Chemical Industries , Alderley Park, Macclesfield, Cheshire, U.K. Hext, P.M., and R.J. Parr-Dobrzanski. 1993. HFC-134a: A 2-Year Inhalation Toxicity Study in the Rat. ICI Rep. No. CTL/P/3841. Central Toxicology Laboratory, Imperial Chemical Industries , Alderley Park, Macclesfield, Cheshire, U.K. Hodge, M.C.E., M. Kilmartin, R.A. Riley, T.M. Weight, and J. Wilson.
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1979a. Arcton 134a: Teratogenicity Study in the Rat. ICI Rep. No. CTL/P/417. Central Toxicology Laboratory, Imperial Chemical Industries , Alderley Park, Macclesfield, Cheshire, U.K. Hodge, M.C.E., D. Anderson, I.P. Bennett, and T.M. Weight. 1979b. Arcton-134a: Dominant Lethal Study in the Mouse. ICI Rep. No. CTL/P/437. Central Toxicology Laboratory, Imperial Chemical Industries , Alderley Park, Macclesfield, Cheshire, U.K. Litton Bionetics. 1976. Mutagenicity Evaluation of Genetron-134a. LBI Project No. 2683. Final Report. Prepared for Allied Chemical Corp. by Litton Bionetics, Kensington, Md. Longstaff, E., M. Robinson, C. Bradbrook, J.A. Styles, and I.F.H. Purchase. 1984. Genotoxicity and carcinogenicity of fluorocarbons: Assessment by short-term in vitro tests and chronic exposure in rats. Toxicol. Appl. Pharmacol. 72:15-31. Lu, M., and R. Staples. 1981. 1,1,1,2-Tetrafluoroethane (FC-134a): Embryo-fetal toxicity and teratogenicity study by inhalation in the rat. Report No. 317-81. Haskell Laboratory , Wilmington, Del. Mackay, J.M. 1990. HFC-134a: An Evaluation in the in Vitro Cytogenetic Assay in Human Lymphocytes. ICI Rep. No. CTL/P/2977. Central Toxicology Laboratory, Imperial Chemical Industries , Alderley Park, Macclesfield, Cheshire, U.K. Müller, W., and T. Hoffmann. 1989. CFC-134a Micronucleus Test in Male and Female Mice after Inhalation. Rep. No. 89.0015, Study No. 88.1244. Hoechst Aktiengesellschaft , Frankfurt, Germany. Mullin, L.S., and R.W. Hartgrove. 1979. Cardiac Sensitization. Rep. No. 42-79. Haskell Laboratory , Wilmington, Del. Mullin, L.S., C.F. Reinhardt, and R.E. Hemingway. 1979. Cardiac arrhythmias and blood levels associated with inhalation of Halon 1301. Am. Ind. Hyg. Assoc. J. 40:653-658. Olson, M.J., C.A. Reidy, J.T. Johnson, and T.C. Pederson. 1990. Oxidative defluorination of 1,1,1,2tetrafluoroethane by rat liver microsomes. Drug Metab. Dispos. 18:992-998. Riley, R.A., I.P. Bennett, I.S. Chart, C.W. Gore, M. Robinson, and T.M. Weight. 1979. Arcton-134a: Subacute Toxicity to the Rat by Inhalation. ICI Rep. No. CTL/P/463. Central Toxicology Laboratory, Imperial Chemical Industries , Alderley Park, Macclesfield, Cheshire, U.K. Rissolo, S.B., and J.A. Zapp. 1967. Acute Inhalation Toxicity. Rep. No. 190-67. Haskell Laboratory , Wilmington, Del.
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Salmon, A.G., J.A. Nash, M.F.S. Oliver, and A. Reeve. 1980. Arcton134a: Excretion, Tissue Distribution, and Metabolism in the Rat. ICI Rep. No. CTL/P/ 513. Central Toxicology Laboratory, Imperial Chemical Industries , Alderley Park, Macclesfield, Cheshire, U.K. Silber, L.S., and G.L. Kennedy. 1979a. Acute Inhalation Toxicity of Tetrafluoroethane. Rep. No. 422-79. Haskell Laboratory , Wilmington, Del. Silber, L.S., and G.L. Kennedy. 1979b. Subacute Inhalation Toxicity of Tetrafluoroethane (HFC 134a). Rep. No. 228-79. Haskell Laboratory , Wilmington, Del. Trochimowicz, H.J., A. Azar, J.B. Terrill, and L.S. Mullin. 1974. Blood levels of fluorocarbon related to cardiac sensitization: Part II. Am. Ind. Hyg. Assoc. J. 35:632-639. Trueman, R.W. 1990. HFC-134a: Assessment for the Induction of Unscheduled DNA Synthesis in Rat Hepatocytes In Vivo. ICI Rep. No. CTL/P/2550. Central Toxicology Laboratory, Imperial Chemical Industries , Alderley Park, Macclesfield, Cheshire, U.K. Wickramaratne, G.A. 1989a. HFC-134a: Teratogenicity Inhalation Study in the Rabbit. ICI Rep. No. CTL/P/2504. Central Toxicology Laboratory, Imperial Chemical Industries , Alderley Park, Macclesfield, Cheshire, U.K. Wickramaratne, G.A. 1989b. HFC-134a: Embryotoxicity Inhalation Study in the Rabbit. ICI Rep. No. CTL/P/2380. Central Toxicology Laboratory, Imperial Chemical Industries , Alderley Park, Macclesfield, Cheshire, U.K.
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4 Exposure Guidance Levels for Hydrochlorofluorocarbon-123
INTRODUCTION he U.S. Air Force requested that the NRC evaluate the adequacy of the 1min EEGL for hydrochlorofluorocarbon (HCFC)-123 that was proposed by toxicologists at Wright-Patterson Air Force Base. HCFC-123 is a proposed substitute for Halon 1211, the fire extinguisher currently used by the Air Force. Appendix A of this report contains the documentation prepared by Air Force toxicologists in support of the proposed 1-min EEGL for HCFC-123. This supporting documentation was submitted to the subcommittee for consideration. It contains the background information on HCFC-123, reviews the toxicokinetics, toxicity, and exposure information and provides recommendations for exposure guidance levels.
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RECOMMENDATIONS FOR EXPOSURE GUIDANCE LEVELS The documentation presented in Appendix A has been reviewed and revised in response to the subcommittee's comments. For HCFC-123, the end points of pharmacological or adverse effects considered for establishing an EEGL are cardiac sensitization, anesthesia or CNS-related effects, malignant hyperthermia, and hepatotoxicity. Cardiac sensitization was chosen as the most sensitive end point because of the sensitizing effect of this chemical and similar chemicals in the epinephrine-challenged dog model. The EC50 for HCFC-123 was determined to be 1.9% (19,000 ppm) for a 5-min exposure (Trochimowicz and Mullin, 1973). The Air Force toxicologists recommended that the EC50 of 19,000 ppm be the 1min EEGL for the HCFC-123. However, the subcommittee believes that 1,900 ppm (19,000 ppm divided by an uncertainty factor of 10 for interspecies variability) should be considered the human NOEL for a 1-min exposure to HCFC-123 in humans on the basis of the dog cardiac-sensitization model. Therefore, the subcommittee recommends that the 1-min EEGL of 19,000 ppm proposed by the Air Force be lowered to 1,900 ppm. The justification for using the LC50 for developing the 1-min EEGL is as follows: (1) actual duration of exposure for humans would be one-fifth the duration of the dog-test exposure; and (2) tissue concentrations in humans would be much less in a 1-min exposure than those in the 5-min exposure of dogs. REFERENCES Trochimowicz, H.J., and L.S. Mullin. 1973. Cardiac Sensitization Potential (EC50) of Trifluorodichloroethane. Haskell Laboratory Rep. 132-73. Haskell Laboratory for Toxicology and Industrial Medicine , Wilmington, Del.
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Appendix A
SUPPORTING DOCUMENTATION FOR THE EXPOSURE GUIDANCE LEVELS FOR HYDROCHLOROFLUOROCARBON-123 Prepared by
S. Channel, D. Dodd, J. Fisher, M. George, J. Lipscomb, J. McDougal, A. Vinegar, and J. Williams Armstrong Laboratory
Toxicology Division and Toxic Hazards Research Unit
Wright-Patterson Air Force Base
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APPENDIX A
44
BACKGROUND INFORMATION Physical and Chemical Properties1 Chemical name:
1,1-Dichloro-2,2,2-Trifluoroethane
Chemical formula:
CHCl2CF3
Molecular weight:
152.9
Synonym:
HCFC-123, Genetron-123
CAS no.:
306-83-2
Physical state:
Liquid at normal temperatures
Boiling point:
27.9°C @ 760 mm Hg
Freezing point:
−107°C
Vapor pressure:
11 psi (20°C)
Vapor density:
(Air = 1) 3.6
Solubility in water:
0.21% (wt) @ 70°F
Flash point:
N. A. - No flash point
Auto ignition:
Unknown, probably not applicable
Flame limits:
(In air, % by vol), none
Occurrence and Use Hydrochlorofluorocarbon (HCFC) 123 is used primarily as a foamblowing agent, as a refrigerant, and as an ingredient in cleaning solvents. The Air Force is considering the use of HCFC-123 as a fire extinguishant, replacing Halon 1211. Halon 1211 has been used as a fire extinguishant in streaming systems, where the extinguishant is manually discharged through a nozzle of small portable units that are commonly found in industry, military, and office settings. Jarabek et al. (1994) reviewed the process of searching for CFC substitutes with HCFC-123 as a specific example. Personnel with potential military occupational exposure to
1 Allied-Signal
Inc., Material Safety Data Sheet (Attachment 1).
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APPENDIX A
45
HCFC-123 as a fire extinguishant include maintenance personnel (crew chiefs) responding to aircraft fires on the flight line or in indoor structures, such as aircraft hangars, and trained fire fighters responding to alarms. The fire-fighterexposure scenario deals with military personnel who don appropriate firefighting gear, including respirators, immediately before fighting fire. Thus, the exposure scenario of concern in setting emergency exposure guidance levels (EEGLs) involves the emergency situation where maintenance personnel attempt to put out a fire without the appropriate fire-fighting equipment. The exposure duration of concern involves a 1-min period to simulate personnel discharging either the entire contents of a small (1- or 3-lb) extinguisher or the partial contents of a large (150-lb) extinguisher while attempting to put out an aircraft fire (usually an engine fire) from upwind of the fire (C. Kibert, Tyndall Air Force Base, Fla., personal commun., 1994). The potential for repeated exposures to a streaming agent such as Halon 1211 has been estimated to be minimal. According to D. Vickers (Tyndall Air Force Base, Fla., personal commun., 1994), there are about three aircraft fires per Air Force wing per year. An average wing has 60 crew chiefs assigned; therefore, the probability that a crew chief will experience a fire in any one year is 1 in 20 or 0.05. The probability of experiencing two fires in a 20-year career is 0.1887 or about 1 in 5, according to the multiplication rule:
The probability of experiencing three fires in a career is about 1 in 20. Probabilities of experiencing more than three fires are much less. The expectation of any crew chief for number of fires over a 20-year career is 1.
Toxicity of Alternatives to Chlorofluorocarbons : HFC-134a and HCFC-123, National Academies Press, 1996. ProQuest Ebook
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APPENDIX A
46
Probability of Aircraft Crew Chief Experiencing Multiple Fires in a 20-Year Career Fires, no.
Probability
2
0.1887
3
0.0596
4
0.0133
5
0.0022
6
0.0003
TOXICOKINETICS Brashear et al. (1992) exposed F344 and Sprague-Dawley rats to HCFC-123 and detected the metabolites 2-chloro-1,1,1-trifluoroethane (HCFC-133a) and 2-chloro-1,1-difluoroethylene in the liver immediately following exposure. The most abundant metabolite in the urine was TFA. Additionally, Harris et al. (1991) and Martin et al. (1992) exposed rats to 1% HCFC-123 and, via 19F nuclear magnetic resonance spectrometry, observed the formation of reactive TFA intermediates with liver proteins. These newly formed TFA proteins have been implicated in halothane-induced hepatitis (Harris et al., 1991; Owen and Van der Veen, 1986). (See Attachment 2 for toxicity information on halothane and a comparison of HCFC-123 and halothane.) Both oxidative and reductive pathways participate in the metabolism of HCFC-123. The reductive pathway occurs only under conditions of very low oxygen tension and would not be expected to be a common route in man (Dodd et al., 1993). It begins with reductive dehalogenation to produce a radical intermediate that either can accept a hydrogen atom from a protein or a phospholipid to form HCFC-133a or can lose a fluorine to yield chlorodifluoroethylene. The oxidative pathway catalyzed by cytochrome P-450 produces a dichloro geminal halohydrin, which is unstable, and releases HCl to form trifluoroacetylchloride, which is hydrolyzed to TFA. These pathways are similar to those for the structur
Toxicity of Alternatives to Chlorofluorocarbons : HFC-134a and HCFC-123, National Academies Press, 1996. ProQuest Ebook
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APPENDIX A
47
ally related compound halothane where TFA, HCFC-133a, and chlorodifluoroethylene have been detected as metabolites (Stier, 1964; Mukai et al., 1977; Sharp et al., 1979). It is unknown whether different isoforms of P-450 are responsible for differential metabolism of HCFC-123 or halothane via the oxidative or reductive pathways. The metabolism of halothane and several other halogenated hydrocarbons has been shown to be catalyzed primarily by the P-450IIE1 isoform. This isoform is expressed differentially in the sexes and is induced by such substances as ethanol, acetone, and isoniazid. The metabolism of HCFC-123 in vitro has been determined by using rat liver microsomes and aerobic conditions. Preliminary results of in vitro rat microsomal studies conducted at Wright-Patterson Air Force Base by C.S. Godin (personal commun.) indicate that the rate of formation of TFA from HCFC-123 is approximately 0.2 nmol/nmol P-450 per min. Urban and Dekant (1993) compared the metabolism of HCFC-123 and halothane in rat and human liver microsomes. For rat liver microsomes, the rate of formation of TFA from HCFC-123 was 3.1 nmol/mg per 20 min and the formation of TFA from halothane was 2.1 nmol/mg per 20 min. For human liver microsomes, rates of formation of TFA from HCFC-123 ranged from 5.4 to 41.9 nmol/mg per 20 min. TOXICITY INFORMATION Effects in Humans No literature citations were found of studies on HCFC-123 exposure to humans. Effects in Animals Single-Exposure Studies Attachment 3 of this supporting doumentation provides an out
Toxicity of Alternatives to Chlorofluorocarbons : HFC-134a and HCFC-123, National Academies Press, 1996. ProQuest Ebook
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APPENDIX A
48
line of acute-toxicity results for HCFC-123 and lists the references. Acute Toxicity and CNS Depression. Potential toxicity during acute exposure to HCFC-123 includes severe central nervous system (CNS) depression and cardiac sensitization. The liver might be a target organ of concern following acute exposure to HCFC-123. All animal species exposed to HCFC-123 show CNS depression, and in rodent LC50 studies, death is attributed to severe CNS depression. Rodent LC50 values are comparable across species and average 37,000 ppm for exposures of 4- to 6-hr durations (Darr, 1981; Hall and Moore, 1975; Coate, 1976; Waritz and Clayton, 1966). For exposures of ≤30 min duration in mice, concentrations of 74,000 ppm and higher produced mortality (Burns et al., 1982; Raventos and Lemon, 1965); 40,000 to 50,000 ppm was nonlethal. The lowest HCFC-123 concentration causing CNS depression (inactivity or altered response to auditory stimuli) in rats is 5,000 ppm (Mullin, 1976). A concentration of 1,000 ppm does not produce narcosis in rats or dogs (Mullin, 1976; Trochimowicz and Mullin, 1973). Cardiac Sensitization. The standard cardiac-sensitization protocol as defined by Reinhardt et al. (1971) has been applied to Halon and many of the Halon-replacement chemicals. [This protocol has been reviewed in detail in Chapter 2 of this report.] Briefly, the male beagle dogs are exposed to vapor concentrations of the test substance diluted in air via face mask following a “priming” dose of epinephrine (0.008 mg/kg given i.v. in 1 mL saline over 9 sec; rate = 50 µg/kg/min). After 5 min of exposure to the test agent, a “challenge” dose of epinephrine is administered under the same conditions as the priming dose. Cardiac activity is followed by electrocardiography and “marked” responses are tabulated. A “marked” response is defined as “those arrhythmias considered to pose a serious threat to life or which ended in cardiac arrest.” The only data available for HCFC-123 are reported by Trochimowicz and Mullin (1973). They used a “staircase-method” modifi
Toxicity of Alternatives to Chlorofluorocarbons : HFC-134a and HCFC-123, National Academies Press, 1996. ProQuest Ebook
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APPENDIX A
49
cation of the standard protocol to study vapor concentrations (% vol/vol in air) and obtained an estimate of the EC50. A summary of the results follows: Concentration (% vol/vol)
Marked Response
Percent
1.0
0/3
0
2.0
4/6a
67
4.0
3/3a
100
Statistical interpretation of the data indicated an EC50 of 1.9% with a 95% confidence interval of 1.29% ≤ EC50 ≤ 2.82%. These authors suggest that the unusually high percentage of fatal marked responses might reflect the nature of the staircase modification, which requires more test concentrations above the initial estimate of the EC50. Additionally, the extremely rapid onset of ventricular fibrillation, within 3 to 6 sec of the challenge dose, implies an effect that is specific to the compound itself. The table on the following page summarizes the cardiac-sensitization results for other chemicals under the same experimental conditions. Repeated exposures do not change the cardiac-sensitization effects of chemicals. Beck et al. (1973) studied the pharmacological actions, including cardiac arrhythmias and cardiac sensitization, of bromochlorodifluoromethane (BCF) in laboratory animals. BCF was selected as a prototype of halogenated hydrocarbons that produces CNS and cardiac effects. The authors (Beck et al., 1973) concluded from their results that cardiac sensitization occurred at the end of very brief exposures to BCF, but the concentration of BCF has to be high. Exposure (5 min/day, 3 days/week for 4 weeks) to BCF at a concentration that caused minimal cardiac sensitization did not make the heart more susceptible to epinephrine arrhythmias.
aSix
of seven marked responses ended in death.
Toxicity of Alternatives to Chlorofluorocarbons : HFC-134a and HCFC-123, National Academies Press, 1996. ProQuest Ebook
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APPENDIX A
50
Test Compound
Concentrationn (% vol/vol)
Marked Responses
Percent
Fluorocarbon 11
0.13 0.61 0.96
0/12 1/12 5/12
0 8.3 41.7
Fluorocarbon 12
2.5 5.0
0/12 5/12
0 41.7
Fluorocarbon 22
2.5 5.0
0/12 2/12
0 16
Fluorocarbon 114
2.5 5.0
1/12 7/12
8.3 58.3
Fluorocarbon 1301
5.0 7.5 15 20
0/62 1/18 8/69 2/7 8/13
0 5.5 11.6 28.6 61.5
Fluorocarbon 142b
2.5 5.0 10.0
0/6 5/12 12/12
0 41.7 100.0
Fluorocarbon 152a
5.0 15.0
0/12 3/12
0 25.0
Propane
5.0 10.0 20.0
0/6 2/12 7/12
0 16.7 58.3
Isobutane
2.5 5.0 10.0-20.0
0/12 4/12 6/6
0 33.3 100.0
Vinyl chloride
2.5 5.0 10.0
0/12 6/12 6/6
0 50.0 100.0
Dimethyl ether
10.0 20.0 30.0
0/6 2/12 2/6
0 16.7 33.3
Source: Adapted from Reinhardt et al. (1971) and Trochimowicz (1975).
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APPENDIX A
51
Malignant Hyperthermia. HCFC-123 has not been tested for its potential to produce malignant hyperthermia in the Pietrain malignant hyperthermiasusceptible pig model. Hepatotoxicity. The potential for acute HCFC-123 exposure to produce hepatotoxicity in the guinea pig has been evaluated recently at Wright-Patterson Air Force Base (G. Marit, A. Vinegar, and M. George, unpublished material, 1994). The use of a guinea pig model for examining the mechanisms of acute liver injury produced by halothane (Lunam et al., 1985; Lind et al., 1987) has received considerable attention, because the spectrum of liver injury observed in guinea pigs exposed to anesthetic concentrations (1%) of halothane resembles that observed in nonfatal halothane hepatitis in humans (Lunam et al., 1989). Exposure-related liver alterations were observed in guinea pigs exposed for 4 hr to HCFC-123-vapor concentrations of 3%, 2%, 1%, or 0.1%. In agreement with the results of Lunam et al. (1985, 1989) and Lind et al. (1987), there were wide variations in individual sensitivity based on lesion morphology, severity, and incidence. Liver lesions observed in guinea pigs exposed to 3% or 2% HCFC-123 included centrilobular necrosis and degeneration and were comparable to those observed in guinea pigs exposed to 1% halothane (G. Marit, A. Vinegar, and M. George, unpublished material, 1994). Hepatic lesions observed in guinea pigs exposed to 1% or 0.1% HCFC-123 were mild in severity (altered hepatocytes and lymphoid infiltrates) and multifocal or random in distribution. All liver lesions observed in guinea pigs exposed for 4 hr to HCFC-123 at concentrations of 0.1-3% were considered reversible. Repeat-Exposure Studies Attachment 3 of this supporting documentation provides an outline of repeat-exposure toxicity results for HCFC-123 and lists the references.
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APPENDIX A
52
For evaluating general toxicity due to repeated exposure to HCFC-123, the 90-day (Malley, 1990a) and 1-year (Malley, 1990b) studies in rats are thorough and well documented. The exposure concentrations used in these studies were 0 (control), 300, 1,000, and 5,000 ppm. Malley states that a no-observed-effect level (NOEL) was not established in these studies owing to exposurerelated changes in select serum chemistry values and hepatic betaoxidation enzyme activity at all HCFC-123 concentrations. The liver is a target organ of toxicity following HCFC-123 exposure. Hepatic degenerative changes, including hypertrophy, clear cytoplasm, and necrosis with inflammatory cell infiltrates, were observed in the 90-day dog study at an exposure concentration of 10,000 ppm (Crowe, 1978). However, rats exposed to the same HCFC-123 concentration for 90 days (Crowe, 1978), or even higher concentrations for shorter exposure periods (Lewis, 1990; Kelly, 1989), did not produce similar hepatic effects, although some indexes of liver toxicity (liver weight, hepatocellular hypertrophy and fatty vacuolation, and hepatic peroxisomal activity) were observed to be of greater magnitude or incidence when compared with control values. For a no-observed-adverse-effect level (NOAEL), dogs exposed to 1,000 ppm for 90 days did not have liver damage. A study on the oncogenic potential of HCFC-123 in rats has been completed recently (Malley, 1992). Exposure concentrations were 5,000, 1,000, 300, and 0 (control) ppm. Consistent with the 90-day and 1-year studies (Malley, 1990a,b), exposure-related changes were observed in select serum chemistry values (e.g., triglyceride, glucose, and cholesterol) and in hepatic beta-oxidation enzyme activity at all HCFC-123 concentrations. In this study, a NOEL was not achieved using clinical chemical values—lower body weight and body-weight gain, increased incidence of neoplastic and non-neoplastic morphological changes, and higher hepatic betaoxidation activity—at all concentrations. The tumor incidences of concern were increases in benign hepatocellular adenomas or hepatic cholangiofibromas or both, increases in benign pancreatic acinar cell adenomas, and increases in interstitial cell adenoma in
Toxicity of Alternatives to Chlorofluorocarbons : HFC-134a and HCFC-123, National Academies Press, 1996. ProQuest Ebook
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APPENDIX A
53
the testes. Diffuse retinal atrophy was increased in all test groups of both males and females. Also noteworthy was the observation that the survival index was higher in HCFC-123-exposed rats in comparison to control rats. The potential for HCFC-123 to produce developmental toxicity or reproductive toxicity has not been evaluated fully. Developmental toxicity studies in rabbits (Bio-Dynamics, 1989a,b) and rats (Culik and Kelly, 1976; IBT, 1977) indicate that a concentration of 5,000 ppm is a NOAEL for the development of terata, but maternal toxicity effects were not studied in dogs exposed to HCFC-123 at 500 ppm. Only minimal toxicity was observed at 500 ppm in the Cullick and Kelly (1976) study. No evidence for maternal or fetal toxicity was seen in the IBT (1977) study. Testicular effects were observed in rats exposed to HCFC-123 at 20,000 ppm for 4 weeks (Kelly, 1989), although testicular lesions have not been observed in rats exposed to lower HCFC-123 concentrations (Kelly, 1976, 1989; Crowe, 1978; IBT, 1977; Malley et al., 1990a,b). The observation of benign testicular tumors in the rat 2-year bioassay might be coincidental. EXPOSURE ASSESSMENT Fire training exercises have been performed routinely by Air Force personnel. In 1991, the Air Force directed the Midwest Research Institute (MRI) to assess the hazards associated with the inhalation of selected Halonreplacement compounds and determine the fate and effects of the Halonreplacement-chemical and jet-fuel combustion products. To accomplish this directive, a detailed air-monitoring survey of representative training-exercise test burns was conducted by using Halon-replacement candidates, including HCFC-123, and by burning jet fuel. This fire-fighter training scenario differs from anticipated flight-line exposures to the crew chief in two ways: (1) fire fighters wore protective gear and used respirators, and (2) they applied the firefighting agent at a
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APPENDIX A
54
slow rate to avoid putting out the fire immediately. Selected results from this study (Midwest Research Institute, 1992) follow. Training exercises of test burns with HCFC-123 as the extinguishant involved the use of either 130 lb of HCFC-123 applied at a flow rate of 2.5 lb/ sec to an approximate 4-min (fire duration) 75-ft3 fuel fire (extinguishment not achieved) or 99 lb of HCFC-123 applied at a flow rate of 4.7 lb/sec to an approximate 30-sec (fire duration) fuel fire (extinguishment achieved). Analysis of the air samples in the breathing area of the fire fighter indicated that concentrations of HCFC-123 ranged from 0.2 to 5.4 ppm. Ground (ankle-height) concentrations of HCFC-123 were approximately 10-fold higher than head-height concentrations. Of comparative interest, plume-air-sample concentrations of HCFC-123 ranged from 0.18 to 180 ppm, and downwind-airsample concentrations of HCFC-123 ranged from 0.17 to 129 ppm. In the MRI study, risks to fire fighters were examined with respect to the generation of toxic-fuel and extinguishant combustion products (e.g., the acid gases HCl, HBr, HF, and COF2) that were analyzed in the test burns, but occupational risks were not calculated from measured concentrations of HCFC-123 per se. Using acid gases as an index for HCFC-123 and jet-fuel combustion products, the MRI investigators found that the limits in the model of immediately dangerous to life or health (IDLH) set for the individual acid gases were exceeded up to 50 meters downwind of the fire, and the IDLH limit for the combined acid gases was exceeded up to 100 meters downwind of the fire. Recently, the U.S. Environmental Protection Agency contracted with Meridian Research, Inc., to assess occupational exposures to Halon substitutes used for fire protection (Meridian Research Inc., 1992). HCFC-123 was selected for analysis in this assessment. The purpose of these studies was to assess the concentrations of the agents from an indoor release. Noteworthy results from this analysis follow. Three scenarios that represented worst-case exposure situations were considered for modeling:
Toxicity of Alternatives to Chlorofluorocarbons : HFC-134a and HCFC-123, National Academies Press, 1996. ProQuest Ebook
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APPENDIX A
55
1. Use of a 1-lb extinguisher in a single-person office. 2. Use of a 3-lb extinguisher in a two- or three-person office. 3. Use of a 150-lb extinguisher inside a large enclosed area (e.g., aircraft hangar). Occupational exposures were expressed as instantaneous peak concentrations, 30-min-average concentrations, and 8-hr time-weighted-average (TWA) concentrations. Meridian Research used a gas volume equivalent value of 1.97 for the modeling of HCFC-123 concentrations; thus, the concentration of HCFC-123 calculated to be needed to fight a fire was twice as much as that of Halon 1211. In the single-person office scenario where 1 lb of HCFC-123 was discharged in 10 sec in a 960-ft3 area, the peak concentration was 4,827 ppm, the 30-min average was 161 ppm, and the 8-hr TWA was 10 ppm. In the two- or three-person office scenario where 3 lb of HCFC-123 was discharged in a 1,780 ft3 area, the peak concentration was 1,970 ppm, the 30-min average was 66 ppm, and the 8-hr TWA was 4.1 ppm. The third exposure scenario included two hangar sizes (336,000 and 3,000,000 ft3) and two air-exchange rates (one-half or three air changes per hour (ACH)) for the 3-min discharge of approximately 128 lb of HCFC-123. To account for the differences between exposures near the fire and away from the fire, additional analyses were done. Depending on area size and ACH, the HCFC-123 peak concentrations near the fire ranged from 920 to 25,472 ppm and the 30-min averages ranged from 92 to 2,516 ppm. Away from the fire, the HCFC-123 peak concentrations ranged from 99 to 912 ppm and the 8-hr TWAs ranged from 6.2 to 373 ppm. In this example, the 8-hr TWA was redefined to account for a 2-hr absence of the worker soon after the discharge of the HCFC-123 cylinder. RECOMMENDATIONS FOR EXPOSURE GUIDANCE LEVEL As indicated previously, potential occupational military expo
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APPENDIX A
56
sure to HCFC-123 as a fire extinguishant is expected to be brief with low probability of repeated exposures. The selection of a 1-min exposure for establishing an EEGL is appropriate and represents a “typical” emergency exposure scenario outdoors or indoors where the area can be evacuated after use of a fire extinguisher. For HCFC-123, the end points of pharmacological or adverse effects considered for establishing an EEGL are cardiac sensitization, anesthesia or CNS-related effects, malignant hyperthermia, and hepatotoxicity. Cardiac sensitization was chosen as the most sensitive end point because of the potent sensitizing effect of this chemical and similar chemicals in the epinephrine-challenged dog model. The EC50 for HCFC-123 was determined to be 1.9% for a 5-min exposure (Trochimowicz and Mullin, 1973). We believe that 1.9% should be considered the human NOEL for a 1-min exposure to HCFC-123 in humans on the basis of the dog cardiac-sensitization model. We believe that this concentration is very unlikely to cause arrhythmias under the proposed-use scenario for the following reasons: • Actual duration of exposure for humans would be one-fifth the duration of the dog-test exposure. • Tissue concentrations in humans would be much less in a 1-min exposure than those in the 5-min exposure of dogs. • Arrhythmia-producing concentrations in humans would be much less than those in the dog exposure because an actual exposure scenario would not be in the presence of a supraphysiological i.v. bolus of epinephrine (i.e., a dose that is about 10 times that of a adrenal release in humans during times of stress). The dog cardiac-sensitization test is very conservative. It incorporates priming and supraphysiological challenge doses of epinephrine. The original purpose of this test was to rank chemicals that might be cardiac sensitizers and not to set regulatory limits for humans. In this test, the epinephrine dose is maximized to be just below the point where it causes arrhythmias by itself. There
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APPENDIX A
57
fore, the 1-min EEGL of 1.9% derived on the basis of the dog cardiacsensitization test is considered conservative. A recent study sponsored by the Air Force provides additional support for the recommendation for the 1-min EEGL to be 1.9% for HCFC-123 (Vinegar et al., 1995). Using this study to extrapolate assumes that the blood concentration at the NOEL (1% for 5 min) would be safe (Attachment 4). Using the slope of the relationship between blood concentration and exposure concentration for a 1-min exposure (Figure 1), the NOEL blood concentration (9.0 mg/L, range 2.7-18) would be equivalent to a 1-min exposure to 1.9% HCFC-123 in the atmosphere. Because 1.9% is the 5-min EC50 in the dog assay (a very conservative test) and because it can be extrapolated from the 5-min NOEL, 1.9% is suggested as the most appropriate 1-min EEGL. .
FIGURE 1 Extrapolation from the measured blood concentration at the NOEL. The 1-min line connects blood concentrations measured after a 1-min exposure to 1% and 5% HCFC-123.
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APPENDIX A
58
Studies in laboratory animals indicate that HCFC-123 is approximately three times less potent than halothane for producing anesthesia. Concentrations of approximately 1% halothane produce anesthesia. A subanesthetic halothane exposure of 4,000 ppm for 30 min causes transient impairment in mental performance in humans. In HCFC-123 inhalation studies, mild CNS depression is observed in rats exposed (for 6 hr) to 5,000 ppm, but these effects are rapidly reversible upon cessation of exposure. Dogs exposed to HCFC-123 at 10,000 ppm for 5 min show signs of CNS depression. In studies performed by Clark and Tinston (1982) involving acute exposure of rats and dogs to a series of halogenated hydrocarbons, CNS effects and cardiac sensitization occur at the same concentration, and the more potent the chemical was in producing CNS effects, the more potent it was in producing cardiac sensitization. For selected halogenated hydrocarbons, it would be difficult to choose one of these biological end points over the other as the most sensitive measure of pharmacological or toxicological effect. For the purposes of the EEGL, it was assumed that anesthetic effects would occur at the concentration that could cause cardiac sensitization. Malignant hyperthermia (MH) was ruled out as an end point because there is no evidence that HCFC-123 causes it, and halothane causes MH in only a very small portion of the population. If HCFC-123 caused MH and the incidence was similar that caused by halothane (1 in 50,000), it would not be as much of a concern as cardiac sensitization. Hepatotoxicity due to HCFC-123 was observed in guinea pigs exposed once for 4 hr to HCFC-123 concentrations of 3%, 2%, 1%, or 0.1%. However, the selection of cardiac sensitization as the most sensitive end point for a 1-min EEGL is still considered appropriate on the basis of the following rationales: • The guinea pig appears to be a sensitive model when compared with other species, such as the rat and human, for inducing hepatotoxicity with halothane (and presumably HCFC-123). The
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APPENDIX A
59
guinea-pig model's relevancy in assessing the health hazard to humans has not been evaluated fully. • The liver lesions produced by HCFC-123 were considered reversible and showed no indication of producing permanent damage morphologically or functionally. • The proposed mechanism that causes halothane to produce hepatitis is immunologically based. Although an association between TFA-protein adducts and liver toxicity exists, a dose-response relationship between formation of TFA-protein adduct and induction of immune responses in sensitized individuals does not exist. Without dose-response relationships, risk assessments of immune-mediated hepatitis for humans are not possible. • No information is available on the potential for HCFC-123 to produce liver toxicity in guinea pigs at short (2,000 mg/kg (24-hr occlusion; 2,000 mg/kg was the only dose tested) Source: Brock, 1988a CNS depression during exposure at concentrations of 5,000 ppm and higher (1 hr) No CNS depression at 1,000 ppm (1 hr) Source: Mullin, 1976 D. Rabbit LD50 (dermal): >2,000 mg/kg (24-hr occlusion; 2,000 mg/kg was the only dose tested) Source: Brock, 1988b E. Dog CNS depression:
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CNS depression during exposure at 10,000 ppm No CNS depression at 1,000 ppm Cardiac sensitization EC50: 19,000 ppm (5 min; includes epinephrine, 0.008 mg/kg, iv, challenge immediately before test chemical exposure) No reaction: 10,000 ppm (3/3) Marked reaction: 20,000 ppm (4/6) (3 died) Marked reaction: 40,000 ppm (3/3) (all died) Source: Trochimowicz and Mullin, 1973 II. ANIMAL STUDIES: REPEAT EXPOSURE A. General Toxicity 1. Rat 2-wk 10,000 ppm × 6 hr/day × 5 days/wk No toxicity, but CNS depression during exposure Source: Kelly, 1976 4-wk 1,000, 5,000, 10,000,20,000 ppm × 6 hr/day × 5 days/wk Dose-related effects: CNS depression during exposure (males and females at 5,000 ppm and above); body-weight-gain decrease (males at 10,000 and 20,000 ppm); relative liver-weight increase (males at 20,000 ppm; females at all doses); cytochrome-P-450 decrease (males at 10,000 and 20,000 ppm; females at all doses); urinary-fluoride increase (males at 20,000 ppm; females at 10,000 and 20,000 ppm); testicular degeneration and hypospermia (6 of 10 males at 20,000 ppm) Source: Kelly, 1989
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97
4-wk (males only) 1,000, 5,000, 20,000 ppm × 6 hr/day × 5 days/wk Dose-related effects: CNS depression during exposure (at 20,000 ppm); body-weight decrease (at all doses); absolute and relative liver-weight increase (at 20,000 ppm); relative testesweight increase (at all doses); cholesterol decrease (44% at 5,000 ppm; 51% at 20,000 ppm); serum alkaline phosphatase increase (79% at 20,000 ppm); hepatocellular hypertrophy and fatty vacuolation (at all doses); hepatic peroxisome increase (126% at 5,000 ppm; 242% at 20,000 ppm) Source: Lewis, 1990 90-day 1,000/10,000 ppm × 6 hr/day × 5 days/wk for 90 days Dose-related effects: CNS depression during exposure (10,000 ppm); body-weight-gain decrease (males and females at all doses); relative liver-weight-increase (males and females at all doses); relative testis- (males), adrenal- (males), kidney- (females), and stomach-(females) weight increases; tracheal lesion (3 of 21 females at 10,000 ppm) Source: Crowe, 1978 90-day 500, 1,000, 5,000 ppm × 6 hr/day × 5 days/wk for 94 days plus a 30-day recovery period after exposure Dose-related effects: body-weight-gain decrease (males at 5,000 ppm; females at 1,000 and 5,000 ppm—reversible); relative liverweight increase (in the high exposure level males and in all three HCFC-123 exposure level females; these increases were doserelated—reversible); initial diagnosis of liver lesions (reversible); diagnosis review indicated incidental lesions Source: IBT, 1977
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90-day 300, 1,000, 5,000 ppm × 6 hr/day × 5 days/wk for 90 days Dose-related effects: CNS depression during exposure (at 5,000 ppm); serum glucose and triglyceride decreases (males and females at all doses); cholesterol decrease (females at 1,000 and 5,000 ppm); lymphocyte decrease (females at 5,000 ppm); relative liverweight increase (males and females at 1,000 and 5,000 ppm); absolute liver-weight increase (males at 5,000 ppm); hepatic betaoxidation-enzyme increase (two- to four-fold increase in males and females at 1,000 and 5,000 ppm) Source: Malley, 1990a 1-yr 300, 1,000, 5,000 ppm × 6 hr/day × 5 days/wk for 1 yr Dose-related effects: CNS depression during exposure (at 5,000 ppm); body-weight-gain and food-consumption decreases (males at 5,000 ppm; females at 1,000 and 5,000 ppm); serum glucose and triglyceride decreases (males and females at all doses); cholesterol decrease (males at 5,000 ppm; females at 1,000 and 5,000 ppm); relative liver-weight increase (males and females at 5,000 ppm); hepatic beta-oxidation-enzyme increase (two- to four-fold increase in males at all doses and females at 1,000 and 5,000 ppm) with no change in hepatic cell-proliferation rate; urinary-fluoride increase (males and females at all doses) Source: Malley, 1990b 2. Dog 90-day (males only and organ weights were not determined)
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99
1,000, 10,000 ppm × 6 hr/day × 5 days/wk for 90 days Dose-related effects: CNS depression during exposure (at 10,000 ppm); hematology alterations (at 10,000 ppm); serum SGOT and SGPT increases (at 10,000 ppm); alkaline phosphatase increase (at 1,000 and 10,000 ppm); hepatic degenerative changes including hypertrophy, clear cytoplasm, and necrosis with inflammatory cell infiltration (at 10,000 ppm) Source: Crowe, 1978 B. Oncogenicity 1. Rat 2-year 300, 1,000, 5,000 ppm × 6 h/day × 5 days/wk for 2 yr Dose-related effects: Survival-index increase: Males
HCFC-123
Females
26%
0 ppm
23%
31%
300 ppm
34%
40%
1,000 ppm
46%
43%
5,000 ppm
59%
Select serum chemical increases (e.g., triglyceride, glucose, and cholesterol) and hepatic beta-oxidationenzyme increase (at all doses); NOEL not achieved on the basis lower body weight and body-weight-gain decrease (at all doses), relative liver-weight increase (at 5,000 ppm); increased incidence of neoplastic and nonneoplastic morphological changes and hepatic peroxisomal betaoxidation increases (at all doses); increased tumor incidences of concern: benign hepatocellular adenomas and/or hepatic cholangiofibromas, benign pancreatic acinar cell adenomas, and interstitial cell adenoma in the testes
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100
Source: Malley, 1992 C. Developmental Toxicity 1. Rat (impregnated females) 10,000 ppm × 6 hr/day × 10 gestation days (gestation days 6-15) CNS depression during exposure, equivocal fetal toxicity, and no terata Source: Culik and Kelly, 1976 5,000 ppm × 6 hr/day × 10 gestation days (gestation days 6-15) Maternal body-weight-gain decrease, no fetal toxicity Source: IBT, 1977 2. Rabbit (impregnated females) 1,000, 5,000,10,000, 20,000 ppm × 6 hr/day × 13 gestation days (gestation days 6-18) “range-finder study” Dose-related effects: maternal body-weight-gain and foodconsumption decreases (at all doses); fetal body-weight decrease (at all doses); tail defects (13% at 20,000 ppm) Litter-size decrease: Mean litter size
Dose, ppm
8.3
0
7.3
1,000
7.4
5,000
5.5
10,000
5.8
20,000
Source: Bio-Dynamics, 1989a 3. Rabbit (impregnated females) 500, 1,500, 5,000 ppm × 6 hr/day × 13 gestation days (gestation days 6-18) “definitive study”
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101
Dose-related effects: maternal body-weight-gain and foodconsumption decreases (at all doses) and no terata; increased number of resorptions: Relative incidence
Dose, ppm
1
0
3×
500
4×
1,500
5×
5,000
Source: Bio-Dynamics, 1989b III. REFERENCES Bio-Dynamics, Inc. 1989a. An Inhalation Range-Finding Study to Evaluate the Toxicity of CFC 123 in the Pregnant Rabbit. Project No. 88-3303. Bio-Dynamics. Bio-Dynamics, Inc. 1989b. An Inhalation Developmental Toxicity Study in Rabbits with HCFC 123. Project No. 88-3304. Bio-Dynamics. Brock, W.J. 1988a. Acute dermal toxicity study of HCFC-123 in rats. Report No. 577-88. Haskell Laboratory. Brock, W.J. 1988b. Acute dermal toxicity study of HCFC-123 in rabbits. Report No. 578-88. Haskell Laboratory. Burns, T.H.S., J.M. Hall, A. Bracken, and G. Gouldstone. 1982. Fluorine compounds in anaesthesia (9). Examination of six aliphatic compounds and four ethers. Anaesthesia 37:278-284. Coate, W.B. 1976. LC50 of G123 in Rats. Final Report. Project No. M165-162. Hazleton Laboratories America. Crowe, C.D. 1978. Ninety-Day Inhalation Exposure of Rats and Dogs to Vapors of 2,2Dichloro-1,1,1-Trifluoroethane (FC-123). Report No. 229-78. Haskell Laboratory. Culik, R., and D.P. Kelly. 1976. Embryotoxic and Teratogenic Studies in Rats with Inhaled Dichlorofluoroethane (Freon 21) and 2,2-Dichloro-1,1,1-Trifluoroethane (FC-123). Report No. 227-76. Haskell Laboratory. Darr, R.W. 1981. An acute inhalation toxicity study of fluorocarbon 123 in the Chinese hamster. Report No. MA-25-78-15. Allied Corp. , Morristown, N.J. Hall, G.T., and B.L. Moore. 1975. 1,1-Dichloro-2,2,2-Triflu
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APPENDIX A
102
oroethane. Acute Inhalation Toxicity. Report No. 426-75. Haskell Laboratory. Henry, J.E., and A.M. Kaplan. 1975. 1,1-Dichloro-2,2,2 trifluoroethane. Acute oral test. Report No. 638-75. Haskell Laboratory. IBT (Industrial Bio-test Laboratories). 1977. Ninety-Day Inhalation Study and Teratology Study with Genetron 123 in Rats. Report No. 8562-09344. Industrial Bio-test Laboratories , Decatur, Ill. Kelly, D.P. 1976. Two-Week Inhalation Toxicity Studies (FC-21 and FC-123). Report No. 149-76. Haskell Laboratory. Kelly, D.P. 1989. Four-Week Inhalation Study with HCFC-123 in Rats. Report No. 229-89. Haskell Laboratory. Lewis, R.W. 1990. HCFC 123: 28-Day Inhalation Study to Assess Changes in Rat Liver and Plasma. Report No. CTL/T2706. Central Toxicology Laboratory, Imperial Chemical Industries. Malley, L.A. 1990a. Subchronic Inhalation Toxicity: 90-Day Study with HCFC-123 in Rats. Report No. 594-89. Haskell Laboratory. Malley, L.A. 1990b. Combined Chronic Toxicity/Oncogenicity Study with HCFC-123. Two-Year Inhalation Toxicity Study in Rats (One-Year Interim Report). Report No. 260-90. Haskell Laboratory. Malley, L.A. 1992. Combined Chronic Toxicity/Oncogenicity Study with HCFC-123. Two-Year Inhalation Toxicity Study in Rats. Report No. 669-91. Haskell Laboratory. Müller, W., and T. Hofmann. 1988. HCFC 123 micronucleus test in male and female NMRI mice after inhalation. Report No. 88.1340. Pharma Research Toxicology and Pathology, Hoechst , Hattersheim, Germany. Mullin, L.S. 1976. Behavioral Toxicity Testing. Fluorocarbon 123. Report No. 941-76. Haskell Laboratory. Raventos, J., and P.G. Lemon. 1965. The impurities in fluothane: Their biological properties. Br. J. Anaesth. 37:716-737. Trochimowicz, H.J., and L.S. Mullin. 1973. Cardiac sensitization potential (EC50) of trifluorodichloroethane. Report No. 132-73. Haskell Laboratory. Waritz, R.S., and J.W. Clayton. 1966. Acute Inhalation Toxicity(FC-123). Report No. 16-66. Haskell Laboratory.
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103
ATTACHMENT 4 SUMMARY OF ACUTE PHARMACOKINETIC STUDY OF HCFC-123 IN DOGS BY INHALATION1 OBJECTIVE The objective of this study was to evaluate the pharmacokinetic behavior of HCFC-123 in an exposure scenario that mimics the cardiac-sensitization test in dogs and to use the data to support the development of a physiologically based pharmocokinetics model. Specific emphasis was placed on the measurement of blood and tissue samples following exposure of 1% or 5% HCFC-123 for 1-5 min. MATERIALS AND METHODS Two male beagle dogs per time-point were exposed to HCFC-123 at either 1% or 5% for various exposure durations (Table 1).
1 Vinegar,
A., D. Dodd, D. Pollard, R. Williams, and J. McDougal. 1995. Pharmacokinetics of HCFC-123 in Dogs. Technical Report No. AL/OETR-1995-0025, Armstrong Laboratory, Wright-Patterson Air Force Base, Ohio.
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104
Exposure was “nose-only” via a specially adapted canine anesthesia mask equipped with a two-way non-rebreathing valve. The exposure system was designed to provide instantaneous exposure of the dogs to the target concentrations and permit the drawing of blood samples. Blood samples were collected (as applicable) at 0 (pre-exposure), 1, 2, 3, 4, 5, 7.5, 10, 15, 30, 45, and 60 min during exposure and 1, 3, 6, 16, and 31 min after exposure and analyzed for HCFC-123. At the end of the exposure periods, animals were euthanized and samples from selected tissues (heart, liver, fat, and skeletal muscle) were collected as rapidly as possible for analysis of HCFC-123. TABLE 1 Experimental Design Number of Dogs
Dog I.D. Number
Exposure Concentration
Exposure Time
After Exposure
2
1974 1999
1%
1 min
na
2
1975 1986
1%
5 min
na
2
1992 1995
1%
60 min
na
2
1993 1994
1%
60 min
30 min
2
1979 1990
5%
1 min
na
2
1983 1997
5%
5 min
na
na = not applicable.
Exposure System The dog nose-only exposure system set up is presented schematically in Figure 1. Liquid HCFC-123 was evaporated by heating a glass reservoir while air passed across the test article surface. The HCFC-123 was first brought to target concentrations in a 500-liter NYU-type inhalation chamber, then supplied to the animal via a sideport. Concentrations in the exposure chamber were monitored with a Miran 1A gas analyzer. Chamber air flow, temperature, relative humidity, and oxygen were monitored as well. Each animal
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FIGURE 1 Dog nose-only exposure system setup.
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106
was exposed individually. The animal was first secured in a sling, and the snout placed in a modified dog anesthesia mask. The snout went through a small hole in a rubber diaphragm to provide a seal. The animal breathed either chamber atmosphere or room air via a valve on the exposure line sideport (Figure 1). The animal breathed the HCFC-123 through a two-way nonrebreathing valve to maintain a unidirectional flow of chemical. Blood and Tissue Sampling A 5.0-cm over-the-needle Teflon catheter was inserted into a saphenous vein. The catheter was attached to a three-way valve so that heparinized saline could be used to flush the catheter. A 3-mL glass syringe was used to draw blood samples. Three ≈ 100-µL samples were place into preweighed headspace vials and reweighed for analysis of HCFC-123 concentration. For tissue sampling, animals were euthanized by lethal injection. The dead animals were transferred as rapidly as possible to a necropsy suite to harvest tissues for HCFC-123 analysis. The intact heart was removed first, followed by samples of fat (perirenal), liver, and skeletal muscle. For each tissue, three subsamples of ≈ 500 mg were weighed and sealed in headspace vials. In general, the entire necropsy procedure was completed in less than 5 min. Analysis of Blood and Tissue Samples Blood and tissue samples were stored in a 80°C freezer until analysis. Headspace vials containing blood or standards were loaded onto a Tekmar 7050 static headspace sampler for injection onto a Varian 3700 gas chromatograph. The gas chromatograph was equipped with a 0.53-mm 25-m PoraPlot Q column and an electron capture detector. Tissue samples were first digested with sodium hydroxide solution to release the HCFC-123 into the head
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107
space. The digestion process occurred within the headspace vial. The digested samples were analyzed in the same manner as the blood. Sample headspace HCFC-123 concentrations were calculated from a standard curve. RESULTS The blood and tissue (heart, muscle, liver, and fat) concentrations for all exposure scenarios are given in Table 2 and Table 3, respectively. In animals exposed for 60 min (n = 4), the maximum venous blood concentrations (mean values) were attained within 30 min, with less than a 3% increase over the next 30 min (Figure 2 and Table 2). Animals allowed to recover for 30 min (n = 2) had rapid decreases in the venous blood concentrations within the first 16 min with concentrations approaching the limits of detection by 31 min after exposure (Figure 3 and Table 2). Figure 4 and Figure 5 are graphs of the triplicate blood concentrations at the early time points for all animals exposed to 1% and 5% HCFC-123, respectively. The experimental design allowed for the sampling of eight animals at 1.0-min during the 1% exposure concentrations. Due to problems in sampling, half of the 1.0-min samples were not available for analysis. The plot of data was tightly clustered, with a gradual increase in the blood concentrations during the first 5-6 min of the 1% exposure. This was not the case for the 5% exposure. The plot of data showed two parallel groupings of data (each a different dog) that increased in concentration from 1 to 5 min. More than two dogs would be required to know the blood concentrations with greater certainty. Difference in behavioral reaction to the 5% exposure concentration between dogs is the most plausible reason for differences in blood concentration. The rise and fall in tissue concentrations paralleled that of blood. Heart, liver, and muscle tissue appeared to take up HCFC-123 much quicker than fat tissue (Table 3). It should be noted that the concentration of chemical in fat, in animals exposed for 60
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109
TABLE 3 Tissue Concentrations in Dogs Exposed by Inhalation to HCFC-123 Tissue Concentrations (mg/L) Exposure Concentration and Exposure Time
Heart
Muscle
Liver
Fat
Animal I.D.
1% for 1 min
14.7 6.7
13.8 7
12.9 5.1
2.1 0.6
1999 1974
1% for 5 min
15.8 18.6
5.5 7.2
14.6 19.5
15.9 13.9
1975 1986
1% for 60 min
39.4 37.9
34.7 66.6
51.1 46
199.1 182.2
1992 1995
1% for 30 min after 60-min exposure
2.5 2.6
5.3 10.2
2.2 3.6
118.5 195.3
1993 1994
5% for 1 min
107.4 94.8
24.9 29.1
75.8 48.2
3.9 9.7
1979 1990
5% for 5 min
141 179.8
39.5 36.4
81.8 174.9
78.3 46.2
1997 1983
FIGURE 2 1% HCFC-123 dog blood levels for 60-min exposure.
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FIGURE 3 1% HCFC-123 dog blood levels after 60-min exposure.
FIGURE 4 1% HCFC-123 dog blood levels for all exposed animals.
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111
min, was two- to three-fold higher than the other tissues as expected. The solubility of HCFC-123 in fat (partition coefficient = 52.9) is approximately 25 times greater than muscle (2.3), liver (1.9), or heart (2.5) tissues. Subsequently, the washout of chemical in fat tissue was much slower than any other tissue. In general, the blood and tissue concentrations of HCFC-123 both increased with exposure time and increasing concentration.
FIGURE 5 5% HCFC-123 dog blood levels for all exposed animals. DISCUSSION Analysis of the pharmacokinetics from this study facilitates extrapolating the 5-min cardiac-sensitization level to the 1-min level. As expected, both blood and tissue concentrations increased with exposure time and increasing concentration. See Table 4. Blood and tissue concentrations of HCFC-123 after a 5-min exposure to 1% HCFC-123 (the no-effect level) can be assumed to be the con
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centrations at which there would be no cardiac arrhythmias. Blood and hearttissue concentrations are considered to be most relevant to the end point of cardiac sensitization. This table shows that Haber's law is not appropriate for this situation because, according to Haber's law, 1% HCFC-123 for 5 min should be equivalent to 5% HCFC-123 for 1 min. The results of this study were that the blood concentration of 5% HCFC-123 for 1 min was approximately 2.5 times greater than that of 1% HCFC-123 for 5 min, and the heart-tissue concentration of 5% HCFC-123 for 1 min was approximately 6 times greater than that of 1% HCFC-123 for 5 min. TABLE 4 Blood and Tissue Concentrationsa in Dogs Exposed by Inhalation to 1% or 5% HCFC-123 1% HCFC-123
5% HCFC-123
Sample
1 min
5 min
1 min
5 min
Blood
5.2 (4.1-7.6)b
9.0 (2.7-18.4)c
21.4 (5.8-43.2)b
114.9 (84.4-145.4)
Heart
10.7 (6.7-14.7)
17.2 (15.8-18.6)
101.1 (94.9-107.4)
160.4 (141.0-179.8)
Muscle
10.4 (7.0-13.8)
6.4 (5.5-7.2)
27.0 (24.9-29.1)
38.0 (36.4-39.5)
Liver
9.0 (5.1-12.9)
16.8 (14.4-19.2)
62.0 (48.2-75.8)
128.3 (81.8-174.9)
Fat
1.36 (0.6-2.1)
14.9 (13.9-15.9)
6.8 (3.9-9.7)
62.3 (46.2-78.3)
a c
Concentrations in milligrams per liter expressed as mean (range). b Four dogs. Five dogs.
Note: Number of dogs was two unless noted otherwise.
Toxicity of Alternatives to Chlorofluorocarbons : HFC-134a and HCFC-123, National Academies Press, 1996. ProQuest Ebook