Twentieth Interim Report of the Committee on
Acute Exposure Guideline Levels: Part A

Committee on Acute Exposure Guideline Levels

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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Twentieth Interim Report of the Committee on Acute Exposure Guideline Levels: Part A Committee on Acute Exposure Guideline Levels Committee on Toxicology Board on Environmental Studies and Toxicology Division on Earth and Life Studies

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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. W81K04-06-D-0023 and EP-W-09-007 between the National Academy of Sciences and the U.S. Department of Defense and the U.S. Environmental Protection Agency. Any opinions, findings, conclusions, or recommendations expressed in this publication are those of the authors and do not necessarily reflect the view of the organizations or agencies that provided support for this project. This report is available online from The National Academies Press at http://www.nap.edu. Copyright 2011 by the National Academy of Sciences. All rights reserved. Printed in the United States of America.

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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. Ralph J. Cicerone 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. Charles M. Vest 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. Ralph J. Cicerone and Dr. Charles M. Vest are chair and vice chair, respectively, of the National Research Council. www.national-academies.org

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COMMITTEE ON ACUTE EXPOSURE GUIDELINE LEVELS Members DONALD E. GARDNER (Chair), Inhalation Toxicology Associates, Savannah, GA EDWARD C. BISHOP, HDR Inc., Omaha, NE LUNG CHI CHEN, New York University, Tuxedo RAKESH DIXIT, MedImmune/AstraZeneca Biologics, Inc., Gaithersburg, MD KATHLEEN GABRIELSON, Johns Hopkins University, MD GUNNAR JOHANSON, Karolinska Institute, Stockholm, Sweden DAVID P. KELLY, Dupont Company, Newark, DE MARGARET MACDONELL, Argonne National Laboratory, Argonne, IL DAVID A. MACYS, U.S. Department of the Navy (retired), Oak Harbor, WA MARIA MORANDI, University of Montana, Missoula, MT FRANZ OESCH, University of Mainz, Mainz, Germany NU-MAY RUBY REED, California Environmental Protection Agency, Sacramento GEORGE RODGERS, University of Louisville, Louisville, KY RICHARD B. SCHLESINGER, Pace University, New York, NY ROBERT SNYDER, Rutgers University, Piscataway, NJ KENNETH STILL, Occupational Toxicology Associates, Hillsboro, OR Staff KEEGAN SAWYER, Project Director RUTH E. CROSSGROVE, Senior Editor MIRSADA KARALIC-LONCAREVIC, Manager, Technical Information Center RADIAH ROSE, Manager, Editorial Projects TAMARA DAWSON, Program Associate Sponsors U.S. ENVIRONMENTAL PROTECTION AGENCY U.S. DEPARTMENT OF DEFENSE v

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COMMITTEE ON TOXICOLOGY Members GARY P. CARLSON (Chair), Purdue University, West Lafayette, IN LAWRENCE S. BETTS, Eastern Virginia Medical School, Norfolk EDWARD C. BISHOP, HDR Engineering, Inc., Omaha, NE JAMES V. BRUCKNER, University of Georgia, Athens MARION F. EHRICH, Virginia Polytechnic Institute and State University, Blacksburg SIDNEY GREEN, Howard University, Washington, DC WILLIAM E. HALPERIN, UMDNJ–New Jersey Medical School, Newark MERYL H. KAROL, University of Pittsburgh, Pittsburgh, PA JAMES N. MCDOUGAL, Wright State University School of Medicine, Dayton, OH GERALD N. WOGAN, Massachusetts Institute of Technology, Cambridge Staff SUSAN N.J. MARTEL, Senior Program Officer for Toxicology KEEGAN SAWYER, Associate Program Officer RUTH E. CROSSGROVE, Senior Editor MIRSADA KARALIC-LONCAREVIC, Manager, Technical Information Center RADIAH ROSE, Manager, Editorial Projects TAMARA DAWSON, Program Associate vi

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BOARD ON ENVIRONMENTAL STUDIES AND TOXICOLOGY1 Members ROGENE F. HENDERSON (Chair), Lovelace Respiratory Research Institute, Albuquerque, NM PRAVEEN AMAR, Northeast States for Coordinated Air Use Management, Boston, MA TINA BAHADORI, American Chemistry Council, Washington, DC MICHAEL J. BRADLEY, M.J. Bradley & Associates, Concord, MA DALLAS BURTRAW, Resources for the Future, Washington, DC JAMES S. BUS, Dow Chemical Company, Midland, MI JONATHAN Z. CANNON, University of Virginia, Charlottesville GAIL CHARNLEY, HealthRisk Strategies, Washington, DC FRANK W. DAVIS, University of California, Santa Barbara RICHARD A. DENISON, Environmental Defense Fund, Washington, DC H. CHRISTOPHER FREY, North Carolina State University, Raleigh J. PAUL GILMAN, Covanta Energy Corporation, Fairfield, NJ RICHARD M. GOLD, Holland & Knight, LLP, Washington, DC LYNN R. GOLDMAN, George Washington University, Washington, DC LINDA E. GREER, Natural Resources Defense Council, Washington, DC WILLIAM E. HALPERIN, University of Medicine and Dentistry of New Jersey, Newark PHILIP K. HOPKE, Clarkson University, Potsdam, NY HOWARD HU, University of Michigan, Ann Arbor ROGER E. KASPERSON, Clark University, Worcester, MA THOMAS E. MCKONE, University of California, Berkeley TERRY L. MEDLEY, E.I. du Pont de Nemours & Company, Wilmington, DE JANA MILFORD, University of Colorado at Boulder, Boulder FRANK O’DONNELL, Clean Air Watch, Washington, DC RICHARD L. POIROT, Vermont Department of Environmental Conservation, Waterbury DANNY D. REIBLE, University of Texas, Austin ROBERT F. SAWYER, University of California, Berkeley KATHRYN G. SESSIONS, Health and Environmental Funders Network, Bethesda, MD JOYCE S. TSUJI, Exponent Environmental Group, Bellevue, WA MARK J. UTELL, University of Rochester Medical Center, Rochester, NY Senior Staff JAMES J. REISA, Director DAVID J. POLICANSKY, Scholar RAYMOND A. WASSEL, Senior Program Officer for Environmental Studies SUSAN N.J. MARTEL, Senior Program Officer for Toxicology ELLEN K. MANTUS, Senior Program Officer for Risk Analysis EILEEN N. ABT, Senior Program Officer RUTH E. CROSSGROVE, Senior Editor MIRSADA KARALIC-LONCAREVIC, Manager, Technical Information Center RADIAH ROSE, Manager, Editorial Projects 1 This study was planned, overseen, and supported by the Board on Environmental Studies and Toxicology. vii

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OTHER REPORTS OF THE BOARD ON ENVIRONMENTAL STUDIES AND TOXICOLOGY A Risk-Characterization Framework for Decision-Making at the Food and Drug Administration (2011) Review of the Environmental Protection Agency’s Draft IRIS Assessment of Formaldehyde (2011) The Use of Title 42 Authority at the U.S. Environmental Protection Agency (2010) Review of the Environmental Protection Agency’s Draft IRIS Assessment of Tetrachloroethylene (2010) Hidden Costs of Energy: Unpriced Consequences of Energy Production and Use (2009) Contaminated Water Supplies at Camp Lejeune—Assessing Potential Health Effects (2009) Review of the Federal Strategy for Nanotechnology-Related Environmental, Health, and Safety Research (2009) Science and Decisions: Advancing Risk Assessment (2009) Phthalates and Cumulative Risk Assessment: The Tasks Ahead (2008) Estimating Mortality Risk Reduction and Economic Benefits from Controlling Ozone Air Pollution (2008) Respiratory Diseases Research at NIOSH (2008) Evaluating Research Efficiency in the U.S. Environmental Protection Agency (2008) Hydrology, Ecology, and Fishes of the Klamath River Basin (2008) Applications of Toxicogenomic Technologies to Predictive Toxicology and Risk Assessment (2007) Models in Environmental Regulatory Decision Making (2007) Toxicity Testing in the Twenty-first Century: A Vision and a Strategy (2007) Sediment Dredging at Superfund Megasites: Assessing the Effectiveness (2007) Environmental Impacts of Wind-Energy Projects (2007) Scientific Review of the Proposed Risk Assessment Bulletin from the Office of Management and Budget (2007) Assessing the Human Health Risks of Trichloroethylene: Key Scientific Issues (2006) New Source Review for Stationary Sources of Air Pollution (2006) Human Biomonitoring for Environmental Chemicals (2006) Health Risks from Dioxin and Related Compounds: Evaluation of the EPA Reassessment (2006) Fluoride in Drinking Water: A Scientific Review of EPA’s Standards (2006) State and Federal Standards for Mobile-Source Emissions (2006) Superfund and Mining Megasites—Lessons from the Coeur d’Alene River Basin (2005) Health Implications of Perchlorate Ingestion (2005) 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 (seven volumes, 2000-2009) 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) viii

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Waste Incineration and Public Health (2000) Hormonally Active Agents in the Environment (1999) Research Priorities for Airborne Particulate Matter (four 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 (five volumes, 1989-1995) 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 ix

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OTHER REPORTS OF THE COMMITTEE ON TOXICOLOGY Review of the Department of Defense Enhanced Particulate Matter Surveillance Program Report (2010) Evaluation of the Health and Safety Risks of the New USAMRIID High-Containment Facilities at Fort Detrick, Maryland (2010) Combined Exposures to Hydrogen Cyanide and Carbon Monoxide in Army Operations: Final Report (2008) Managing Health Effects of Beryllium Exposure (2008) Review of Toxicologic and Radiologic Risks to Military Personnel from Exposures to Depleted Uranium (2008) Emergency and Continuous Exposure Guidance Levels for Selected Submarine Contaminants, Volume 1 (2007), Volume 2 (2008) Review of the Department of Defense Research Program on Low-Level Exposures to Chemical Warfare Agents (2005) Review of the Army's Technical Guides on Assessing and Managing Chemical Hazards to Deployed Personnel (2004) Spacecraft Water Exposure Guidelines for Selected Contaminants, Volume 1 (2004), Volume 2 (2007), Volume 3 (2008) 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), Volume 5 (2007), Volume 6 (2008), Volume 7 (2009), Volume 8 (2010), Volume 9 (2010) Review of the U.S. 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), Volume 5 (2008) x

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Preface Extremely hazardous substances (EHSs)2 can be released accidentally as a result of chemical spills, industrial explosions, fires, or accidents involving railroad cars or trucks transporting EHSs, or they can be released intentionally through terrorist activities. These substances can also be released by improper storage or handling. Workers and residents in communities surrounding industrial facilities where EHSs are manufactured, used, or stored and in communities along the nation’s railways and highways are potentially at risk of being exposed to airborne EHSs during accidental or intentional releases. Pursuant to the Superfund Amendments and Reauthorization Act of 1986, the U.S. Environmental Protection Agency (EPA) has identified approximately 400 EHSs on the basis of acute lethality data in rodents. As part of its efforts to develop acute exposure guideline levels for EHSs, EPA and the Agency for Toxic Substances and Disease Registry (ATSDR) in 1991 requested that the National Research Council (NRC) develop guidelines for establishing such levels. In response to that request, the NRC published Guidelines for Developing Community Emergency Exposure Levels for Hazardous Substances in 1993. Subsequently, Standing Operating Procedures for Developing Acute Exposure Guideline Levels for Hazardous Substances was published in 2001. It provided updated procedures, methods, and other guidelines used by the National Advisory Committee (NAC) on Acute Exposure Guideline Levels for Hazardous Substances and the NRC Committee on Acute Exposure Guideline Levels (AEGLs) in considering acute adverse health effects to develop AEGL values. Using the 1993 and 2001 NRC guideline reports, the NAC—consisting of members from EPA, the Department of Defense (DOD), the Department of Energy (DOE), the Department of Transportation (DOT), other federal and state governments, the chemical industry, academia, and other organizations from the private sector—has developed AEGLs for approximately 200 EHSs. In 1998, EPA and DOD requested that the NRC independently review the AEGLs developed by NAC. In response to that request, the NRC organized within its Committee on Toxicology the Committee on Acute Exposure Guideline Levels, which prepared this report. At its meetings, the committee hears presentations from NAC staff and its contractor, Syracuse Research Cooperation, on draft AEGL documents. At some meetings, the committee also hears presentations from NAC’s collaborators from other countries. The committee provides comments and recommendations on those documents in its interim reports to NAC, and NAC uses those comments to make revisions. The revised documents are presented by NAC to the committee at subsequent meetings until the committee concurs with the final draft documents. The revised documents are then published as appendixes in the committee’s reports. The present report is the committee’s 20th interim report. It summarizes the committee’s conclusions and recommendations for improving NAC’s AEGL documents for the following chemicals and chemical classes: bromoacetone, butane, BZ (3-quinuclidinyl benzilate), chloroacetone, chloroacetyl chloride, dichloroacetyl chloride, epichlorohydrin, ethylphosphorochloridate, ethylene chlorohydrin (2- 2 As defined pursuant to the Superfund Amendments and Reauthorization Act of 1986. xi

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chloroethanol), isocyanates (methyl, phenyl, and cyclohexyl), mercaptans (ethyl, methyl, phenyl, and tert- octyl), methacrylonitrile, methanesulfonyl chloride, methyl bromide, methyl chloride, methyl isothiocyanate, piperidine, nitrogen mustards (HN-1, HN-2, and HN-3), perchloryl fluoride, tetramethoxy silane, trimethoxy silane, and trimethylacetyl chloride This report has been reviewed in draft form by individuals chosen for their diverse perspectives and technical expertise in accordance with procedures approved by the NRC 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 ensuring that the report meets institutional standards for 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 individuals for their review of this report: Dr. Jeffrey W. Fisher, National Center for Toxicological Research, Food and Drug Administration; Dr. A. Wallace Hayes, Harvard University, School of Public Health; and Dr. Samuel Kacew, University of Ottowa. Although the reviewers listed above have provided many constructive comments and 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 Dr. Robert Goyer, Professor Emeritus, University of Western Ontario. Appointed by the NRC, Dr. Goyer 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 NRC. The committee gratefully acknowledges the valuable assistance provided by the following individuals: Iris Camacho and Ernest Falke (EPA); Gary Diamond, Mark Follansbee, Lisa Ingerman, and Julie Klotzbach (Syracuse Research Corporation); and George Rusch (Risk Assessment and Toxicology Services). The committee acknowledges James J. Reisa, director of the Board on Environmental Studies and Toxicology, for his helpful guidance. Keegan Sawyer, project director, for her work in this project. Other staff members who contributed to this effort are Susan Martel (senior program officer), Ruth Crossgrove (senior editor), Mirsada Karalic-Loncarevic (manager of the Technical Information Center), Radiah Rose (manager of editorial projects), and Tamara Dawson (senior program assistant). Finally, we would like to thank all members of the committee for their expertise and dedicated effort throughout the development of this report. Donald E. Gardner, Chair Committee on Acute Exposure Guideline Levels xii

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Contents BACKGROUND .........................................................................................................................................1 THE CHARGE TO THE COMMITTEE.....................................................................................................2 ACID CHLORIDES ....................................................................................................................................2 Chloroacetyl and dichloroacetyl chloride, 2 Methanesulfonyl chloride, 9 Trimethylacetyl chloride, 10 BROMOACETONE ................................................................................................................................. 12 BUTANE .................................................................................................................................................. 13 BZ (3-QUINUCLIDINYL BENZILATE) ............................................................................................... 14 CHLOROACETONE ............................................................................................................................... 17 EPICHLOROHYDRIN............................................................................................................................. 18 ETHYL PHOSPHORODICHLORIDATE ............................................................................................... 23 ETHYLENE CHLOROHYDRIN (2-CHLOROETHANOL)................................................................... 24 ISOCYANATES....................................................................................................................................... 29 n-Butyl isocyanate, 29 Cyclohexyl isocyanate, 29 Ethyl isocyanate, 30 Phenyl isocyanate, 31 MERCAPTANS........................................................................................................................................ 33 Ethyl mercaptan, 33 Methyl mercaptan, 34 Phenyl mercaptan, 35 tert-Octyl mercaptan, 36 xiii

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METHACRYLONITRILE ....................................................................................................................... 38 METHYL BROMIDE .............................................................................................................................. 39 METHYL CHLORIDE............................................................................................................................. 40 METHYLISOTHIOCYANATE............................................................................................................... 40 NITROGEN MUSTARDS (HN1, HN2, and HN3).................................................................................. 43 PERCHLORYL FLUORIDE.................................................................................................................... 47 PIPERIDINE............................................................................................................................................. 48 PROPANE ................................................................................................................................................ 48 TRIMETHOXYSILANE AND TETRAMETHOXYSILANE ................................................................ 49 COMMENTS PERTAINING TO ALL TECHNICAL SUPPORT DOCUMENTS ................................ 50 STANDING OPERATING PROCEDURES............................................................................................ 51 ABBREVIATIONS .................................................................................................................................. 52 xiv