iodotrifluoromethane

TOXICITY REVIEW

Subcommittee on Iodotrifluoromethane

Committee on Toxicology

Board on Environmental Studies and Toxicology

Division on Earth and Life Studies

NATIONAL RESEARCH COUNCIL OF THE NATIONAL ACADEMIES

THE NATIONAL ACADEMIES PRESS
Washington, D.C.
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Iodotrifluoromethane: Toxicity Review iodotrifluoromethane TOXICITY REVIEW Subcommittee on Iodotrifluoromethane Committee on Toxicology Board on Environmental Studies and Toxicology Division on Earth and Life Studies NATIONAL RESEARCH COUNCIL OF THE NATIONAL ACADEMIES THE NATIONAL ACADEMIES PRESS Washington, D.C. www.nap.edu

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Iodotrifluoromethane: Toxicity Review THE NATIONAL ACADEMIES PRESS 500 Fifth Street, NW Washington, DC 20001 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 project was supported by Contract No. DAMD17-99-C-9049 between the National Academy of Sciences and the U.S. Army. Any opinions, findings, conclusions, or recommendations expressed in this publication are those of the author(s) and do not necessarily reflect the view of the organizations or agencies that provided support for this project. International Standard Book Number 0-309-09307-4 (Book) International Standard Book Number 0-309-54550-1 (PDF) Additional copies of this report are available from: The National Academies Press 500 Fifth Street, NW Box 285 Washington, DC 20055 800-624-6242 202-334-3313 (in the Washington metropolitan area) http://www.nap.edu Copyright 2004 by the National Academy of Sciences. All rights reserved. Printed in the United States of America

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Iodotrifluoromethane: Toxicity Review THE NATIONAL ACADEMIES Advisers to the Nation on Science, Engineering, and 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 M. 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. Wm. A. Wulf 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. Harvey V. Fineberg 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 M. Alberts and Dr. Wm. A. Wulf are chair and vice chair, respectively, of the National Research Council. www.national-academies.org

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Iodotrifluoromethane: Toxicity Review SUBCOMMITTEE ON IODOTRIFLUOROMETHANE Members SAMUEL KACEW (Chair), University of Ottawa, Ottawa, ON H. TIM BORGES, Oak Ridge National Laboratory, Oak Ridge, TN KELLY J. DIX, Lovelace Respiratory Research Institute, Albuquerque, NM MARCIE FRANCIS, Battelle, Kensington, MD SIDNEY GREEN, JR., Howard University, Washington, DC ROBERT HAMLIN, Ohio State University, Columbus, OH DAVID KOTELCHUCK, Hunter College of the City University of New York GEORGE M. RUSCH, Honeywell Corporation, Morristown, NJ Staff ROBERTA M. WEDGE, Project Director NORMAN GROSSBLATT, Senior Editor JENNIFER E. SAUNDERS, Research Associate JENNIFER D. ROBERTS, Research Associate MIRSADA KARALIC-LONCAREVIC, Research Associate LUCY V. FUSCO, Senior Project Assistant JORDAN CRAGO, Senior Project Assistant SAMMY BARDLEY, Library Assistant Sponsor U.S. DEPARTMENT OF DEFENSE

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Iodotrifluoromethane: Toxicity Review COMMITTEE ON TOXICOLOGY BAILUS WALKER, JR. (Chair), Howard University Medical Center and American Public Health Association, Washington, DC MELVIN E. ANDERSEN, CIIT-Centers for Health Research, Research Triangle Park, NC EDWARD C. BISHOP, Parsons Corporation, Fairfax, VA GARY P. CARLSON, Purdue University, West Lafayette, IN JANICE E. CHAMBERS, Mississippi State University, Mississippi State LEONARD CHIAZZE, JR., Georgetown University, Washington, DC JUDITH A. GRAHAM, American Chemistry Council, Arlington, VA SIDNEY GREEN, Howard University, Washington, DC MERYL KAROL, University of Pittsburgh, Pittsburgh, PA STEPHEN U. LESTER, Center for Health Environment and Justice, Falls Church, VA DAVID H. MOORE, Battelle Memorial Institute, Bel Air, MD CALVIN C. WILLHITE, Department of Toxic Substances, State of California, Berkeley GERALD WOGAN, Massachusetts Institute of Technology, Cambridge Staff KULBIR S. BAKSHI, Program Director ROBERTA M. WEDGE, Senior Program Officer for Risk Analysis SUSAN N. J. MARTEL, Senior Program Officer ELLEN K. MANTUS, Senior Program Officer AIDA NEEL, Senior Program Assistant TAMARA DAWSON, Program Assistant

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Iodotrifluoromethane: Toxicity Review BOARD ON ENVIRONMENTAL STUDIES AND TOXICOLOGY1 Members JONATHAN M. SAMET (Chair), Johns Hopkins University, Baltimore, MD RAMON ALVAREZ, Environmental Defense, Austin, TX THOMAS BURKE, Johns Hopkins University, Baltimore, MD JUDITH C. CHOW, Desert Research Institute, Reno, NV RORY B. CONOLLY, CIIT Center for Health Research, Research Triangle Park, NC COSTEL D. DENSON, University of Delaware, Newark E. DONALD ELLIOTT, Willkie, Farr & Gallagher, LLP, Washington, DC CHRISTOPHER B. FIELD, Carnegie Institute of Washington, Stanford, CA WILLIAM H. GLAZE, Oregon Health and Science University, Beaverton SHERRI W. GOODMAN, Center for Naval Analyses, Alexandria, VA JUDITH A. GRAHAM, American Chemistry Council, Arlington, VA DANIEL S. GREENBAUM, Health Effects Institute, Cambridge, MA ROBERT HUGGETT, Michigan State University, East Lansing BARRY L. JOHNSON, Emory University, Atlanta, GA JAMES H. JOHNSON, Howard University, Washington, DC JUDITH L. MEYER, University of Georgia, Athens PATRICK Y. O’BRIEN, ChevronTexaco Energy Technology Company, Richmond, CA DOROTHY E. PATTON, International Life Sciences Institute, Washington, DC STEWARD T.A. PICKETT, Institute of Ecosystem Studies, Millbrook, NY JOSEPH V. RODRICKS, Environ Corp., Arlington, VA ARMISTEAD G. RUSSELL, Georgia Institute of Technology, Atlanta MITCHELL J. SMALL, Carnegie Mellon University, Pittsburgh, PA LISA SPEER, Natural Resources Defense Council, New York, NY KIMBERLY M. THOMPSON, Harvard School of Public Health, Boston MA G. DAVID TILMAN, University of Minnesota, St. Paul CHRIS G. WHIPPLE, Environ Incorporated, Emeryville, CA LAUREN A. ZEISE, California Environmental Protection Agency, Oakland Senior Staff JAMES J. REISA, Director DAVID J. POLICANSKY, Scholar RAYMOND A. WASSEL, Senior Program Officer for Environmental Sciences and Engineering KULBIR BAKSHI, Senior Program Officer for Toxicology ROBERTA M. WEDGE, Senior Program Officer for Risk Analysis K. JOHN HOLMES, Senior Program Officer SUSAN N.J. MARTEL, Senior Program Officer SUZANNE VAN DRUNICK, Senior Program Officer EILEEN N. ABT, Senior Program Officer ELLEN K. MANTUS, Senior Program Officer RUTH E. CROSSGROVE, Senior Editor 1   This study was planned, overseen, and supported by the Board on Environmental Studies and Toxicology.

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Iodotrifluoromethane: Toxicity Review OTHER REPORTS OF THE BOARD ON ENVIRONMENTAL STUDIES AND TOXICOLOGY Air Quality Management in the United States (2004) Endangered and Threatened Species of the Platte River (2004) Atlantic Salmon in Maine (2004) Endangered and Threatened Fishes in the Klamath River Basin (2004) Cumulative Environmental Effects of Alaska North Slope Oil and Gas Development (2003) Estimating the Public Health Benefits of Proposed Air Pollution Regulations (2002) Biosolids Applied to Land: Advancing Standards and Practices (2002) The Airliner Cabin Environment and Health of Passengers and Crew (2002) Arsenic in Drinking Water: 2001 Update (2001) Evaluating Vehicle Emissions Inspection and Maintenance Programs (2001) Compensating for Wetland Losses Under the Clean Water Act (2001) A Risk-Management Strategy for PCB-Contaminated Sediments (2001) Acute Exposure Guideline Levels for Selected Airborne Chemicals (4 volumes, 2000-2004) Toxicological Effects of Methylmercury (2000) Strengthening Science at the U.S. Environmental Protection Agency (2000) Scientific Frontiers in Developmental Toxicology and Risk Assessment (2000) Ecological Indicators for the Nation (2000) Waste Incineration and Public Health (1999) Hormonally Active Agents in the Environment (1999) Research Priorities for Airborne Particulate Matter (4 volumes, 1998-2004) The National Research Council’s Committee on Toxicology: The First 50 Years (1997) Carcinogens and Anticarcinogens in the Human Diet (1996) Upstream: Salmon and Society in the Pacific Northwest (1996) Science and the Endangered Species Act (1995) Wetlands: Characteristics and Boundaries (1995) Biologic Markers (5 volumes, 1989-1995) Review of EPA's Environmental Monitoring and Assessment Program (3 volumes, 1994-1995) Science and Judgment in Risk Assessment (1994) Pesticides in the Diets of Infants and Children (1993) Dolphins and the Tuna Industry (1992) Science and the National Parks (1992) Human Exposure Assessment for Airborne Pollutants (1991) Rethinking the Ozone Problem in Urban and Regional Air Pollution (1991) Decline of the Sea Turtles (1990) Copies of these reports may be ordered from the National Academies Press (800) 624-6242 or (202) 334-3313 www.nap.edu

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Iodotrifluoromethane: Toxicity Review OTHER REPORTS OF THE COMMITTEE ON TOXICOLOGY Spacecraft Water Exposure Guidelines for Selected Contaminants, Volume 1 (2004) Toxicologic Assessment of Jet-Propulsion Fuel 8 (2003) Review of Submarine Escape Action Levels for Selected Chemicals (2002) Standing Operating Procedures for Developing Acute Exposure Guideline Levels for Hazardous Chemicals (2001) Evaluating Chemical and Other Agent Exposures for Reproductive and Developmental Toxicity (2001) Acute Exposure Guideline Levels for Selected Airborne Contaminants, Volume 1 (2000), Volume 2 (2002), Volume 3 (2003), Volume 4 (2004) Review of the US Navy’s Human Health Risk Assessment of the Naval Air Facility at Atsugi, Japan (2000) Methods for Developing Spacecraft Water Exposure Guidelines (2000) Review of the U.S. Navy Environmental Health Center’s Health-Hazard Assessment Process (2000) Review of the U.S. Navy's Exposure Standard for Manufactured Vitreous Fibers (2000) Re-Evaluation of Drinking-Water Guidelines for Diisopropyl Methylphosphonate (2000) Submarine Exposure Guidance Levels for Selected Hydrofluorocarbons: HFC-236fa, HFC-23, and HFC-404a (2000) Review of the U.S. Army’s Health Risk Assessments for Oral Exposure to Six Chemical-Warfare Agents (1999) Toxicity of Military Smokes and Obscurants, Volume 1(1997), Volume 2 (1999), Volume 3 (1999) Assessment of Exposure-Response Functions for Rocket-Emission Toxicants (1998) Toxicity of Alternatives to Chlorofluorocarbons: HFC-134a and HCFC-123 (1996) Permissible Exposure Levels for Selected Military Fuel Vapors (1996) Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants, Volume 1 (1994), Volume 2 (1996), Volume 3 (1996), Volume 4 (2000)

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Iodotrifluoromethane: Toxicity Review Preface Chlorofluorobromines (halons) have been used in a variety of applications, including fire suppression. The U.S. Army uses halons as fire suppressants in several aircraft and ground vehicles. However, these substances have been associated with stratospheric ozone-layer depletion and, as required by international agreements, are being replaced. Iodotrifluoromethane (CF3I) is one compound under consideration by the U.S. Army (and others) as a halon replacement. The U. S. Army Center for Health Promotion and Preventive Medicine at Aberdeen Proving Ground, Maryland, prepared a toxicity review of CF3I in 1999 and updated it in 2002. The Office of the Surgeon General of the Army asked the Committee on Toxicology (COT) of the National Research Council to conduct an independent evaluation of the Army’s toxicity review for CF3I. In response to the Army’s request, the Research Council formed the Subcommittee on Iodotrifluoromethane, which prepared this report. This report has been reviewed in draft form by persons chosen for their diverse perspectives and technical expertise in accordance with procedures approved by the Research Council's Report Review Committee. The purpose of this independent review is to provide candid and critical comments that will assist the institution in making its published report as sound as possible and to ensure that the report meets institutional standards of objectivity, evidence, and responsiveness to the study charge. The review comments and draft manuscript remain confidential to protect the integrity of the deliberative process. We wish to thank the following for their review of this report: Kerry Dearfield, U.S. Environmental Protection Agency, Washington, DC; Paul Foster, National Institute of Environmental Health Sciences, Research Triangle Park, NC; Donald E. Gardner, Inhalation Toxicology Associates, Raleigh, NC; Michael Gargas, The Sapphire Group, Beavercreek, OH; Murray Mittleman, Beth Israel Deaconess Medical Center, Boston, MA; James F. O’Bryon, The O’Bryon Group, Bel Air, MD; Carol Rice, University of Cincinnati, OH; and Henry J. Trochimowicz, Delaware Toxicology Associates, Inc., Newark, DE. Although the reviewers listed above have provided many constructive comments and

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Iodotrifluoromethane: Toxicity Review suggestions, they were not asked to endorse the conclusions or recommendations, nor did they see the final draft of the report before its release. The review of this report was overseen by Roger O. McClellan, consultant, Albuquerque, NM. Appointed by the Research Council, he was responsible for making certain that an independent examination of this report was carried out in accordance with institutional procedures and that all review comments were carefully considered. Responsibility for the final content of this report rests entirely with the author committee and the institution. The subcommittee also gratefully acknowledges the following for making presentations or providing information: Glenn Leach, U.S. Army; Leslie Chaney, Therimmune Research Corporation; Gary Jepson, Dupont Company; Charles Reinhardt, consultant; Samuel Dudley, Emory University; Reva Rubenstein, consultant; and Juan Vitali, Georgia Tech Research Institute. The subcommittee is grateful for the assistance of the Research Council staff in preparing this report: Roberta Wedge, project director and program director for risk assessment; James Reisa, director of the Board on Environmental Studies and Toxicology; Kulbir Bakshi, program director for toxicology; Jennifer Saunders, research associate; Jennifer Roberts, research associate; Mirsada Karalic-Loncarevic, research associate; Norman Grossblatt, senior editor, Ruth E. Crossgrove, senior editor; Lucy Fusco, senior project assistant; and Jordan Crago, senior project assistant. Finally, I thank the members of the subcommittee for their dedicated efforts throughout the development of this report. Samuel Kacew, PhD Chair, Subcommittee on Iodotrifluoromethane

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Iodotrifluoromethane: Toxicity Review Abbreviations ACGIH American Conference of Governmental Industrial Hygienists AIHA American Industrial Hygiene Association CAA Clean Air Act CF3I iodotrifluoromethane, trifluoroiodomethane, trifluoromethyl iodide, trifluoroiodide, FIC-1311 CFC chlorofluorocarbon COF2 carbonyl fluoride COT Committee on Toxicology ECG electrocardiograph EPA U.S. Environmental Protection Agency FVF fatal ventricular fibrillation HCFC hydrochlorofluorocarbon HF hydrogen fluoride HFC hydrofluorocarbon HI hydrogen iodide LC50 lethal concentration, 50% of exposed population LOAEL lowest-observed-adverse-effect level NFPA National Fire Protection Association NOAEL no-observed-adverse-effect level OSHA U.S. Occupational Safety and Health Administration PBPK physiologically based pharmacokinetic model ppm parts per million SNAP EPA Significant New Alternatives Policy RBC red blood cell rT3 reverse triiodothyronine STEL short-term exposure limit T3 triiodothyronine T4 thyroxine TLV Threshold Limit Value TSH thyroid-stimulating hormone TWA time-weighted average USACHPPM U.S. Army Center for Health Promotion and Preventive Medicine WBC white blood cell

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Iodotrifluoromethane: Toxicity Review Contents     SUMMARY   3 1   INTRODUCTION   11      The Subcommittee’s Charge,   13      Organization of Report,   14 2   PHYSICAL AND CHEMICAL PROPERTIES AND EFFICACY   15      Physical and Chemical Properties,   15      Efficacy,   16 3   HEALTH EFFECTS: TOXICITY STUDIES   18      Animal Studies,   18      Human Studies,   27 4   CARDIAC SENSITIZATION   28      Development of Cardiac-Sensitization Studies,   28      Methods for Studying Cardiac Sensitization,   30      Blood and Tissue Pharmacokinetics,   36      Validity of the Cardiac-Sensitization Protocol,   40      Conclusions,   45      Army Concerns,   48 5   PHYSIOLOGICALLY BASED PHARMACOKINETIC MODELING   49      PBPK Modeling of Exposure to Fire Suppressants,   49      Model Simulations to Determine Safe Exposures,   53      Army Concerns,   56 6   HUMAN EXPOSURE   58      CF3I and Its Decomposition Products,   58      Uses of CF3I,   59

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Iodotrifluoromethane: Toxicity Review      Recommended Standards for CF3I and Its Decomposition Products,   61      Exposure to CF3I and Its Decomposition Products,   64     REFERENCES   68 APPENDIX A:   Biographical Information on Subcommittee on Iodotrifluoromethane   74 APPENDIX B:   Toxicity Review for Iodotrifluoromethane (CF3I): 2002 Update   77