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Acetone Cyanohydrin 1 FINAL: 8/2005 2 ACETONE CYANOHYDRIN 3 (CAS Reg. No. 75-86-5) 4 ACUTE EXPOSURE GUIDELINE LEVELS 5 (AEGLs) 6 August 2005 ACETONE CYANOHYDRIN FINAL: 8/2005 7 PREFACE 8 Under the authority of the Federal Advisory Committee Act (FACA) P. L. 92-463 of 1972, the 9 National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances 10 (NAC/AEGL Committee) has been established to identify, review and interpret relevant toxicologic and 11 other scientific data and develop AEGLs for high priority, acutely toxic chemicals. 12 AEGLs represent threshold exposure limits for the general public and are applicable to 13 emergency exposure periods ranging from 10 minutes to 8 hours. AEGL-2 and AEGL-3 levels, and 14 AEGL-1 levels as appropriate, will be developed for each of five exposure periods (10 and 30 minutes, 1 15 hour, 4 hours, and 8 hours) and will be distinguished by varying degrees of severity of toxic effects. It is 16 believed that the recommended exposure levels are applicable to the general population including infants 17 and children, and other individuals who may be sensitive or susceptible. The three AEGLs have been 18 defined as follows: 19 AEGL-1 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 notable 21 discomfort, irritation, or certain asymptomatic, non-sensory effects. However, the effects are not disabling 22 and are transient and reversible upon cessation of exposure. 23 AEGL-2 is the airborne concentration (expressed as ppm or mg/m³) of a substance above which it 24 is predicted that the general population, including susceptible individuals, could experience irreversible or 25 other serious, long-lasting adverse health effects, or an impaired ability to escape. 26 AEGL-3 is the airborne concentration (expressed as ppm or mg/m³) of a substance above which it 27 is predicted that the general population, including susceptible individuals, could experience 28 life-threatening health effects or death. 29 Airborne concentrations below the AEGL-1 represent exposure levels that could produce mild 30 and progressively increasing odor, taste, and sensory irritation, or certain asymptomatic, non-sensory 31 effects. With increasing airborne concentrations above each AEGL level, there is a progressive increase in 32 the likelihood of occurrence and the severity of effects described for each corresponding AEGL level. 33 Although the AEGL values represent threshold levels for the general public, including sensitive 34 subpopulations, it is recognized that certain individuals, subject to unique or idiosyncratic responses, 35 could experience the effects described at concentrations below the corresponding AEGL level. ii ACETONE CYANOHYDRIN FINAL: 8/2005 36 TABLE OF CONTENTS 37 PREFACE ......................................................................... ii 38 EXECUTIVE SUMMARY............................................................vi 39 1. INTRODUCTION ............................................................ 1 40 2. HUMAN TOXICITY DATA ................................................... 3 41 2.1. Acute Lethality ......................................................... 3 42 2.2. Nonlethal Toxicity...................................................... 3 43 2.3. Developmental/Reproductive Toxicity ...................................... 3 44 2.4. Genotoxicity........................................................... 4 45 2.5. Carcinogenicity ........................................................ 4 46 2.6. Summary ............................................................. 4 47 3. ANIMAL TOXICITY DATA ................................................... 5 48 3.1. Acute Lethality ......................................................... 5 49 3.1.1. Rats........................................................... 5 50 3.1.2. Mice .......................................................... 6 51 3.2. Nonlethal Toxicity...................................................... 7 52 3.2.1 Rats........................................................... 7 53 3.3. Developmental/Reproductive Toxicity ...................................... 9 54 3.3.1 Rats........................................................... 9 55 3.4. Genotoxicity.......................................................... 10 56 3.5. Carcinogenicity ....................................................... 10 57 3.6. Summary ............................................................ 10 58 4. SPECIAL CONSIDERATIONS ............................................... 12 59 4.1. Stability, Metabolism and Disposition ...................................... 12 60 4.2. Mechanism of Toxicity ................................................. 13 61 4.3. Structure-Activity Relationships.......................................... 14 62 4.4. Other Relevant Information.............................................. 14 63 4.4.1. Effects of Cyanides and Acetone in Humans.......................... 14 64 4.4.2. Lethality of hydrogen cyanide in animals ............................. 16 65 4.4.3. Species Variability .............................................. 17 66 4.4.4. Intraspecies Variability ........................................... 17 67 5. DATA ANALYSIS FOR AEGL-1 ............................................. 19 68 5.1. Human Data Relevant to AEGL-1......................................... 19 69 5.2. Animal Data Relevant to AEGL-1......................................... 19 70 5.3. Derivation of AEGL-1.................................................. 19 71 iii ACETONE CYANOHYDRIN FINAL: 8/2005 72 6. DATA ANALYSIS FOR AEGL-2 ............................................. 21 73 6.1. Human Data Relevant to AEGL-2......................................... 21 74 6.2. Animal Data Relevant to AEGL-2......................................... 21 75 6.3. Derivation of AEGL-2.................................................. 21 76 7. DATA ANALYSIS FOR AEGL-3 ............................................. 22 77 7.1. Human Data Relevant to AEGL-3......................................... 22 78 7.2. Animal Data Relevant to AEGL-3 ........................................ 22 79 7.3. Derivation of AEGL-3.................................................. 22 80 8. SUMMARY OF AEGLs ...................................................... 23 81 8.1. AEGL Values and Toxicity Endpoints ..................................... 23 82 8.2. Comparison with Other Standards and Criteria............................... 25 83 8.3. Data Adequacy and Research Needs ....................................... 25 84 9. REFERENCES ............................................................. 27 85 APPENDIX A 86 Derivation Summary for Acetone Cyanohydrin AEGLs .............................. 31 87 AEGL-1.................................................................... 32 88 AEGL-2.................................................................... 34 89 AEGL-3.................................................................... 35 iv ACETONE CYANOHYDRIN FINAL: 8/2005 90 LIST OF TABLES 91 SUMMARY TABLE OF AEGL VALUES FOR ACETONE CYANOHYDRIN .................viii 92 TABLE 1: CHEMICAL AND PHYSICAL DATA .......................................... 1 93 TABLE 2: SUMMARY OF ACUTE LETHAL INHALATION DATA IN LABORATORY 94 ANIMALS .................................................................. 6 95 TABLE 3: SUMMARY OF NON-LETHAL SIGNS OF ACETONE CYANOHYDRIN 96 EXPOSURE IN LABORATORY ANIMALS....................................... 8 97 TABLE 4: SUMMARY OF ORAL LD50 DATA FOR ACETONE CYANOHYDRIN ............. 17 98 TABLE 5: AEGL-1 VALUES FOR ACETONE CYANOHYDRIN ........................... 20 99 TABLE 6: AEGL-2 VALUES FOR ACETONE CYANOHYDRIN ........................... 21 100 TABLE 7: AEGL-3 VALUES FOR ACETONE CYANOHYDRIN ........................... 23 101 TABLE 8: SUMMARY/RELATIONSHIP OF AEGL VALUES FOR ACETONE CYANOHYDRIN 23 102 TABLE 9. EXTANT STANDARDS AND GUIDELINES FOR ACETONE CYANOHYDRIN ..... 25 103 LIST OF FIGURES 104 FIGURE 1: CATEGORICAL REPRESENTATION OF ACETONE CYANOHYDRIN 105 INHALATION DATA ........................................................ 24 v ACETONE CYANOHYDRIN FINAL: 8/2005 106 EXECUTIVE SUMMARY 107 Acetone cyanohydrin is a colorless to yellowish liquid with a characteristic bitter almond odor 108 due to the presence of free HCN. The major use of acetone cyanohydrin is in the production of α- 109 methacrylic acid and its esters; the latter are used for the production of plexiglass. Further uses of acetone 110 cyanohydrin are in the production of acrylic esters, polyacrylic plastics and synthetic resins as well as in 111 the manufacture of insecticides, pharmaceuticals, fragrances and perfumes. Acetone cyanohydrin 112 decomposes spontaneously in the presence of water to acetone and hydrogen cyanide. 113 Fatalities and life-threatening occupational intoxication have been described after accidental 114 inhalation, skin contact and ingestion. Initial symptoms following mild exposure to acetone cyanohydrin 115 range from cardiac palpitation, headache, weakness, dizziness, nausea, vomiting to nose, eye, throat and 116 skin irritation. Acetone cyanohydrin behaves as its molar equivalent in cyanide both in vitro and in vivo. 117 All of the pharmacological actions of cyanide result from cyanide's reversible complex with the ferric 118 (+3) state of mitochondrial cytochrome c oxidase also known as ferrocytochrome c-oxygen 119 oxidoreductase. Cessation of electron transport
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