Interim 1: October/2007 ACUTE EXPOSURE GUIDELINE LEVELS (AEGLs) FOR TITANIUM TETRACHLORIDE (CAS Reg. No. 7550-45-0) TITANIUM TETRACHLORIDE Interim 1: October/2007 1 PREFACE 2 Under the authority of the Federal Advisory Committee Act (FACA) P. L. 92-463 of 1972, 3 the 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 5 and 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- 8 2 and AEGL-3 — are developed for each of five exposure periods (10 and 30 minutes, 1 hour, 4 9 hours, and 8 hours) and are distinguished by varying degrees of severity of toxic effects. The three 10 AEGLs are defined 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, 13 including susceptible individuals, could experience notable discomfort, irritation, or certain 14 asymptomatic, non-sensory effects. However, the effects are not disabling and are transient and 15 reversible upon 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 20 which it 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 23 mild and progressively increasing but transient and nondisabling odor, taste, and sensory irritation 24 or certain asymptomatic, non-sensory effects. With increasing airborne concentrations above each 25 AEGL, there is a progressive increase in the likelihood of occurrence and the severity of effects 26 described for each corresponding AEGL. Although the AEGL values represent threshold levels for 27 the general public, including susceptible subpopulations, such as infants, children, the elderly, 28 persons with asthma, and those with other illnesses, it is recognized that individuals, subject to 29 unique or idiosyncratic responses, could experience the effects described at concentrations below 30 the corresponding AEGL. ii TITANIUM TETRACHLORIDE Interim 1: October/2007 1 TABLE OF CONTENTS 2 PREFACE .................................................................. ii 3 LIST OF TABLES.............................................................v 4 EXECUTIVE SUMMARY..................................................... vi 5 1. INTRODUCTION ..........................................................1 6 2. HUMAN TOXICITY DATA .................................................2 7 2.1. Acute Lethality .........................................................2 8 2.2. Nonlethal Toxicity ......................................................2 9 2.2.1. Case Reports .....................................................2 10 2.2.2. Epidemiologic Studies ..............................................4 11 2.3. Developmental/Reproductive Toxicity ......................................4 12 2.4. Genotoxicity ...........................................................4 13 2.6. Carcinogenicity ........................................................4 14 2.7. Summary..............................................................5 15 3. ANIMAL TOXICITY DATA.................................................5 16 3.1. Acute Lethality .........................................................5 17 3.1.1. Dogs ............................................................5 18 3.1.2. Rats ............................................................6 19 3.2. Nonlethal Toxicity .....................................................10 20 3.2.1. Dogs ...........................................................10 21 3.2.2. Rats ...........................................................10 22 3.3. Developmental/Reproductive Toxicity .....................................12 23 3.4. Genotoxicity ..........................................................12 24 3.5. Chronic Toxicity/Carcinogenicity .........................................12 25 3.6. Summary.............................................................13 26 4. SPECIAL CONSIDERATIONS..............................................14 27 4.1. Metabolism and Disposition ..............................................14 28 4.2. Mechanism of Toxicity .................................................15 29 4.3. Structure Activity Relationships ..........................................15 30 4.4. Other Relevant Information ..............................................16 31 4.4.1. Species Variability ................................................16 32 4.4.2. Susceptible Populations ............................................16 33 4.4.3. Concentration-Exposure Duration Relationship .........................16 34 4.4.4. Concurrent Exposure Issues .........................................17 35 5. DATA ANALYSIS AND PROPOSED AEGL-1 .................................17 36 5.1. Summary of Human Data Relevant to AEGL-1 ...............................17 37 5.2. Summary of Animal Data Relevant to AEGL-1 ..............................17 38 5.3. Derivation of AEGL-1 ..................................................17 iii TITANIUM TETRACHLORIDE Interim 1: October/2007 1 6. DATA ANALYSIS AND PROPOSED AEGL-2 .................................18 2 6.1. Summary of Human Data Relevant to AEGL-2 ...............................18 3 6.2. Summary of Animal Data Relevant to AEGL-2 ..............................18 4 6.3. Derivation of AEGL-2 ..................................................18 5 7. DATA ANALYSIS AND PROPOSED AEGL-3 .................................19 6 7.1. Summary of Human Data Relevant to AEGL-3 ...............................19 7 7.2. Summary of Animal Data Relevant to AEGL-3 ..............................19 8 7.3. Derivation of AEGL-3 ..................................................19 9 8. SUMMARY OF PROPOSED AEGLS.........................................21 10 8.1. AEGL Values and Toxicity Endpoints ......................................21 11 8.2. Comparison with Other Standards and Guidelines ............................22 12 8.3. Data Adequacy and Research Needs .......................................24 13 9. REFERENCES ...........................................................25 14 APPENDIX A: Derivation of AEGL Values.......................................28 15 APPENDIX B: Time-Scaling Calculations ........................................32 16 APPENDIX C: Derivation Summary for Titanium Tetrachloride AEGLs ................35 iv TITANIUM TETRACHLORIDE Interim 1: October/2007 1 LIST OF TABLES 2 1. Chemical and Physical Data...................................................2 3 2. Summary of LC50 Values for Rats Exposed to Titanium Tetrachloride ..................7 4 3. Summary of Lethality Data for Rats Exposed to Titanium Tetrachloride ................8 5 4. Summary of Mortality of Rats Exposed to Titanium Tetrachloride for 4 Hours ...........9 6 5. Percentage of Respiratory Rate Decrease in Rats Exposed to Titanium Tetrachloride .....11 7 6. Comparative Toxicity of Titanium Tetrachloride Hydrolysis Products and of HCl .......16 8 7. AEGL-1 Values for Titanium Tetrachloride .....................................18 9 8. AEGL-2 Values for Titanium Tetrachloride .....................................19 10 9. Summary of Lethality Data Used for AEGL-3 Derivation ...........................20 11 10. AEGL-3 Values for Titanium Tetrachloride ....................................21 12 11. Summary of AEGL Values ..................................................21 13 12. Extant Standards and Guidelines for Titanium Tetrachloride .......................23 14 13. AEGL Values for Hydrogen Chloride .........................................24 v TITANIUM TETRACHLORIDE Interim 1: October/2007 1 EXECUTIVE SUMMARY 2 Titanium tetrachloride is a colorless liquid that fumes when in contact with moist air. The odor 3 of titanium tetrachloride has been described as penetrating, acrid, and irritating. The world-wide 4 production of titanium tetrachloride was estimated at 6 million tons in 1996. Titanium 5 tetrachloride is used in the manufacturing of titanium dioxide pigments, titanium metal, artificial 6 pearls, and iridescent glass; in the production of Ziegler-Natto catalysts; and as a military smoke 7 screen. 8 Titanium tetrachloride is highly corrosive. It hydrolyzes upon contact with moisture, releasing 9 heat, hydrochloric acid, and orthotitanic acids, thereby causing direct tissue damage in the lung. 10 Data indicate that the fine particulate oxychloride intermediates generated from titanium 11 tetrachloride hydrolysis are able to penetrate deep into the lung where hydrolysis is completed, 12 resulting in direct contact irritation and producing bronchitis or pneumonia. Skin (particularly 13 moist skin) and eye contact with liquid titanium tetrachloride can result in severe, deep burns. 14 Available data indicate that exposure to titanium tetrachloride