Interim 1: 11/2007 INTERIM ACUTE EXPOSURE GUIDELINE LEVELS (AEGLs) FOR ADAMSITE (CAS Reg. No. 578-94-9) (DM) ETHYLDICHLOROARSINE (CAS Reg. No. 598-14-1) (ED) METHYLDICHLOROARSINE (CAS Reg. No. 593-89-5) (MD) PHENYLDICHLOROARSINE (CAS Reg. No. 696 -28-6) (PD) DIPHENYLCHLOROARSINE (CAS Reg. No. 712-48-1) (DA) Interim 1:11/2007 1 PREFACE 2 Under the authority of the Federal Advisory Committee Act (FACA) P. L. 92-463 of 1972, the 3 National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances 4 (NAC/AEGL Committee) has been established to identify, review and interpret relevant toxicologic and 5 other scientific data and develop AEGLs for high priority, acutely toxic chemicals. 6 AEGLs represent threshold exposure limits for the general public and are applicable to 7 emergency exposure periods ranging from 10 minutes to 8 hours. Three levels — AEGL-1, AEGL-2 and 8 AEGL-3 — are developed for each of five exposure periods (10 and 30 minutes, 1 hour, 4 hours, and 8 9 hours) and are distinguished by varying degrees of severity of toxic effects. The three AEGLs are defined 10 as follows: 11 AEGL-1 is the airborne concentration (expressed as parts per million or milligrams per cubic 12 meter [ppm or mg/m3]) of a substance above which it is predicted that the general population, including 13 susceptible individuals, could experience notable discomfort, irritation, or certain asymptomatic, 14 non-sensory effects. However, the effects are not disabling and are transient and reversible upon 15 cessation of exposure. 16 AEGL-2 is the airborne concentration (expressed as ppm or mg/m3) of a substance above 17 which it is predicted that the general population, including susceptible individuals, could experience 18 irreversible or other serious, long-lasting adverse health effects or an impaired ability to escape. 19 AEGL-3 is the airborne concentration (expressed as ppm or mg/m3) of a substance above which it 20 is predicted that the general population, including susceptible individuals, could experience 21 life-threatening health effects or death. 22 Airborne concentrations below the AEGL-1 represent exposure levels that could produce mild 23 and progressively increasing but transient and nondisabling odor, taste, and sensory irritation or certain 24 asymptomatic, non-sensory effects. With increasing airborne concentrations above each AEGL, there is a 25 progressive increase in the likelihood of occurrence and the severity of effects described for each 26 corresponding AEGL. Although the AEGL values represent threshold levels for the general public, 27 including susceptible subpopulations, such as infants, children, the elderly, persons with asthma, and 28 those with other illnesses, it is recognized that individuals, subject to unique or idiosyncratic responses, 29 could experience the effects described at concentrations below the corresponding AEGL. CHLOROARSENICALS Interim 1: 11/2007 1 TABLE OF CONTENTS 2 PREFACE ......................................................................... 3 3 LIST OF TABLES................................................................... 6 4 LIST OF FIGURES.................................................................. 5 5 EXECUTIVE SUMMARY............................................................ 8 6 1. INTRODUCTION ............................................................... 15 7 2. HUMAN TOXICITY DATA....................................................... 19 8 2.1. Acute Lethality .......................................................... 19 9 2.2. Nonlethal Toxicity ....................................................... 19 10 2.2.1. Case Reports .................................................... 19 11 2.2.2. Epidemiology Studies............................................. 25 12 2.2.3. Other.......................................................... 25 13 2.3. Developmental/Reproductive Effects ......................................... 25 14 2.4. Genotoxicity............................................................ 25 15 2.5. Carcinogenicity .......................................................... 25 16 2.6. Summary............................................................... 25 17 3. ANIMAL TOXICITY DATA....................................................... 26 18 3.1. Acute Lethality .......................................................... 26 19 3.1.1. Monkeys ....................................................... 26 20 3.1.2. Dogs .......................................................... 28 21 3.1.3. Rats........................................................... 31 22 3.1.4. Mice .......................................................... 32 23 3.1.5. Rabbits ........................................................ 34 24 3.1.6. Guinea Pigs..................................................... 36 25 3.1.7. Swine ......................................................... 38 26 3.1.8. Goats.......................................................... 39 27 3.1.9. Cats........................................................... 39 28 3.2. Nonlethal Toxicity ....................................................... 40 29 3.2.1. Monkeys ....................................................... 40 30 3.3. Developmental/Reproductive Effects ......................................... 42 31 3.4. Genotoxicity............................................................ 43 32 3.5. Carcinogenicity .......................................................... 43 33 3.6. Summary............................................................... 43 34 4. SPECIAL CONSIDERATIONS ..................................................... 45 35 4.1. Metabolism and Disposition ................................................ 45 36 4.2. Mechanism of Toxicity.................................................... 45 37 4.3. Structure-Activity Relationships............................................. 45 38 4.4. Other Relevant Information ................................................ 45 39 4.4.1. Species Variability .............................................. 45 40 4.4.2. Concentration-Exposure Duration Relationship ........................ 45 3 CHLOROARSENICALS Interim 1: 11/2007 1 5. DATA ANALYSIS FOR AEGL-1 ................................................... 45 2 5.1. Human Data Relevant to AEGL-1 ........................................... 45 3 5.2. Animal Data Relevant to AEGL-1 ........................................... 46 4 5.3. Derivation of AEGL-1 .................................................... 47 5 6. DATA ANALYSIS FOR AEGL-2 ................................................... 49 6 6.1. Human Data Relevant to AEGL-2 ........................................... 49 7 6.2. Animal Data Relevant to AEGL-2 ........................................... 49 8 6.3. Derivation of AEGL-2 .................................................... 50 9 7. DATA ANALYSIS FOR AEGL-3 ................................................... 52 10 7.1. Human Data Relevant to AEGL-3 ........................................... 52 11 7.2. Animal Data Relevant to AEGL-3 ........................................... 52 12 7.3. Derivation of AEGL-3 .................................................... 52 13 8. SUMMARY OF AEGLs........................................................... 56 14 8.1. AEGL Values and Toxicity Endpoints ........................................ 56 15 8.2. Comparisons with Other Standards and Guidelines.............................. 57 16 8.3. Data Adequacy and Research Needs .......................................... 59 17 9. REFERENCES .................................................................. 60 18 APPENDIX A: Derivation of AEGL Values ............................................. 65 19 APPENDIX B: Time Scaling Calculations ............................................... 88 20 APPENDIX C: Category Plots for Chloroarsenical AEGLs.................................. 92 21 APPENDIX D: Derivation Summary for Chloroarsenical AEGLs............................. 96 4 CHLOROARSENICALS Interim 1: 11/2007 1 LIST OF TABLES 2 Table 1. Nomenclature of Chloroarsenical Agents......................................... 16 3 Table 2. Chemical And Physical Data for Adamsite (DM)................................... 16 4 Table 3. Chemical And Physical Data for Diphenylchloroarsine (DA).......................... 17 5 Table 4. Chemical And Physical Data for Ethyldichloroarsine (ED) ........................... 17 6 Table 5. Chemical And Physical Data for Methyldichloroarsine (PD).......................... 18 7 Table 6. Chemical And Physical Data for Phenyldichloroarsine (PD) .......................... 18 8 Table 7. Response of Human Volunteers to Inhalation of DM................................ 20 9 Table 8. Estimation of Intolerable Exposure Concentrations for Adamsite (DM) ................. 21 10 Table 9. Response of Human Volunteers to Inhalation of DM................................ 22 11 Table 10. Results of Tolerance Studies on Human Volunteers Exposed to DM. .................. 23 12 Table 11. Effects of Acute Exposure of Monkeys to Adamsite (DM) Aerosols ................... 26 13 Table 12. Lethal Response in Monkeys Exposed to Adamsite (DM) Aerosol .................... 27 14 Table 13. Lethality in Monkeys Following Acute Inhalation Exposure to Adamsite (DM) .......... 27 15 Table 14. Acute Lethality of Dogs Following 30-Minute Inhalation 16 Exposure to Adamsite (DM) ............................................. 28 17 Table 15. Lethal Response in Dogs Exposed to Adamsite (DM) Aerosol.......................