NAC\Interim1:11/2007 ACUTE EXPOSURE GUIDELINE LEVELS (AEGLs) FOR NITROGEN MUSTARDS (HN1 CAS Reg. No. 538-07-8) (HN2 CAS Reg. No. 51-75-2) (HN3 CAS Reg. No. 555-77-1) INTERIM NITROGEN MUSTARDS (HN-1, HN-2, HN-3) NAC/Interim1:11/2007 PREFACE 1 2 Under the authority of the Federal Advisory Committee Act (FACA) P. L. 92-463 of 3 1972, the National Advisory Committee for Acute Exposure Guideline Levels for Hazardous 4 Substances (NAC/AEGL Committee) has been established to identify, review and interpret 5 relevant toxicologic and other scientific data and develop AEGLs for high priority, acutely toxic 6 chemicals. 7 8 AEGLs represent threshold exposure limits for the general public and are applicable to 9 emergency exposure periods ranging from 10 minutes to 8 hours. Three levels — AEGL-1, 10 AEGL-2 and AEGL-3 — are developed for each of five exposure periods (10 and 30 minutes, 1 11 hour, 4 hours, and 8 hours) and are distinguished by varying degrees of severity of toxic effects. 12 The three AEGLs are defined as follows: 13 14 AEGL-1 is the airborne concentration (expressed as parts per million or milligrams per 15 cubic meter [ppm or mg/m3]) of a substance above which it is predicted that the general 16 population, including susceptible individuals, could experience notable discomfort, irritation, or 17 certain asymptomatic, non-sensory effects. However, the effects are not disabling and are 18 transient and reversible upon cessation of exposure. 19 20 AEGL-2 is the airborne concentration (expressed as ppm or mg/m3) of a substance above 21 which it is predicted that the general population, including susceptible individuals, could 22 experience irreversible or other serious, long-lasting adverse health effects or an impaired ability 23 to escape. 24 25 AEGL-3 is the airborne concentration (expressed as ppm or mg/m3) of a substance above 26 which it is predicted that the general population, including susceptible individuals, could 27 experience life-threatening health effects or death. 28 29 Airborne concentrations below the AEGL-1 represent exposure levels that could produce 30 mild and progressively increasing but transient and nondisabling odor, taste, and sensory 31 irritation or certain asymptomatic, non-sensory effects. With increasing airborne concentrations 32 above each AEGL, there is a progressive increase in the likelihood of occurrence and the 33 severity of effects described for each corresponding AEGL. Although the AEGL values 34 represent threshold levels for the general public, including susceptible subpopulations, such as 35 infants, children, the elderly, persons with asthma, and those with other illnesses, it is recognized 36 that individuals, subject to unique or idiosyncratic responses, could experience the effects 37 described at concentrations below the corresponding AEGL. 38 39 40 2 NITROGEN MUSTARDS (HN-1, HN-2, HN-3) NAC/Interim1:11/2007 1 TABLE OF CONTENTS 2 3 4 PREFACE ...................................................................2 5 6 LIST OF TABLES.............................................................4 7 8 SUMMARY..................................................................5 9 10 1. INTRODUCTION ..........................................................9 11 12 2. HUMAN TOXICITY DATA.................................................11 13 2.1. Acute Lethality ....................................................11 14 2.2. Nonlethal Toxicity ..................................................11 15 2.2.1. Dermal Effects .............................................11 16 2.2.2. Ocular Effects ..............................................14 17 2.3. Developmental/Reproductive Effects ...................................15 18 2.4. Genotoxicity .......................................................15 19 2.5. Carcinogenicity ....................................................15 20 2.6. Summary .........................................................15 21 22 3. ANIMAL TOXICITY DATA.................................................16 23 3.1. Acute Lethality ....................................................16 24 3.2. Nonlethal Toxicity ..................................................24 25 3.3. Developmental/Reproductive Effects ...................................24 26 3.4. Genotoxicity .......................................................24 27 3.5. Carcinogenicity ....................................................24 28 3.6. Summary .........................................................24 29 30 4. SPECIAL CONSIDERATIONS...............................................24 31 4.1. Metabolism and Disposition ..........................................24 32 4.2. Mechanism of Toxicity ..............................................24 33 4.3. Structure-Activity Relationships .......................................25 34 35 5. DATA ANALYSIS FOR AEGL-1 .............................................25 36 5.1. Human Data Relevant to AEGL-1 ......................................25 37 5.2. Animal Data Relevant to AEGL-1 ......................................25 38 5.3. Derivation of AEGL-1 ...............................................25 39 40 6. DATA ANALYSIS FOR AEGL-2 .............................................25 41 6.1. Human Data Relevant to AEGL-2 ......................................25 42 6.2. Animal Data Relevant to AEGL-2 ......................................26 43 6.3. Derivation of AEGL-2 ...............................................26 44 45 3 NITROGEN MUSTARDS (HN-1, HN-2, HN-3) NAC/Interim1:11/2007 1 7. DATA ANALYSIS FOR AEGL-3 .............................................28 2 7.1. Human Data Relevant to AEGL-3 ......................................28 3 7.2. Animal Data Relevant to AEGL-3 ......................................28 4 7.3. Derivation of AEGL-3 ...............................................28 5 6 8. SUMMARY OF AEGLs.....................................................30 7 8.1. AEGL Values and Toxicity Endpoints ..................................30 8 8.2. Comparisons with Other Standards and Guidelines ........................31 9 8.3. Data Adequacy and Research Needs ....................................32 10 11 9. REFERENCES............................................................32 12 13 APPENDIX A: Derivation of AEGL Values.......................................37 14 15 APPENDIX B: Time Scaling Calculations.........................................51 16 17 APPENDIX C: Derivation Summary for Nitrogen Mustard AEGLs .....................53 18 19 APPENDIX D: Category Plots for Nitrogen Mustard AEGLs..........................63 20 21 22 LIST OF TABLES 23 24 Table 1. Chemical and physical data for HN1 ......................................9 25 Table 2. Chemical and physical data for HN2 .....................................10 26 Table 3. Chemical and physical data for HN3 .....................................10 27 Table 4. Vesicant action of nitrogen mustard vapors on forearm skin of human volunteer 28 subjects following 10-min. or 20-min. exposures ........................12 29 Table 5. Vesicant action of nitrogen mustard vapors on forearm skin of human volunteer 30 subjects following 5-min. exposures ..................................14 31 Table 6. Response of human volunteer subjects to whole-body exposure to nitrogen mustards14 32 Table 7. Estimated effects thresholds in humans exposed to nitrogen mustard vapors ......16 33 Table 8. Lethal toxicity in laboratory species following inhalation exposure to HN1 .......17 34 Table 9. Lethal toxicity in laboratory species following inhalation exposure to HN2 .......19 35 Table10. Lethal toxicity in laboratory species following inhalation exposure to HN3 .......22 36 Table 11. AEGL-1 Values For HN1, HN2, and HN3 .................................25 37 Table 12. AEGL-2 Values For HN1, HN2, and HN3 .................................28 38 Table 13. AEGL-3 Values For HN1, HN2, and HN3 .................................30 39 Table 14. Summary of AEGL Values for Nitrogen Mustards ...........................31 40 Table 15. Extant standards and guidelines for HN1, HN2, and HN3 .....................31 41 42 43 4 NITROGEN MUSTARDS (HN-1, HN-2, HN-3) NAC/Interim1:11/2007 1 SUMMARY 2 3 Nitrogen mustards are tertiary bis(β-chloroethyl)amines with vesicant activity. All are active 4 alkylating agents and ocular injurants as well. Although HN2 and HN3 were specifically 5 developed as military agents, HN1 was originally developed as a pharmaceutical. HN2 6 (mechlorethamine) later found use as a pharmaceutical. Both HN1 and HN3 are among the 7 chemical agents found in Chemical Agent Identification Sets (CAIS) that are considered a 8 component of non-stockpiled material. Development of AEGL values is limited to the nitrogen 9 mustards referred to as HN1, HN2, and HN3. 10 11 Because of the nature of the chemicals under review, military literature is a major source of the 12 relevant toxicity data.. Consequently, much of the data sources possess “limited distribution”, 13 which is a separate issue from “classification”. For various reasons, sources may possess a 14 restricted distribution because of treaty restrictions on data access with allies, concerns regarding 15 distribution of engineering information characterizing agent dissemination or generation in other 16 sections of the same document, and related issues. To ensure public access to pertinent toxicity 17 data originating from “limited distribution” materials, pertinent data from those sources have 18 been incorporated into the technical support document. 19 20 All human exposure studies