MONOMETHYLAMINE INTERIM: 06/2008; Page 1 of 46 1 2 ACUTE EXPOSURE GUIDELINE 3 LEVELS (AEGLs) 4 FOR 5 MONOMETHYLAMINE 6 (CAS Reg. No. 74-89-5) 7 8 9 10 11 12 13 INTERIM 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 MONOMETHYLAMINE INTERIM: 06/2008; Page 2 of 46 1 PREFACE 2 3 Under the authority of the Federal Advisory Committee Act (FACA) P. L. 92-463 of 4 1972, the National Advisory Committee for Acute Exposure Guideline Levels for Hazardous 5 Substances (NAC/AEGL Committee) has been established to identify, review and interpret 6 relevant toxicologic and other scientific data and develop AEGLs for high priority, acutely toxic 7 chemicals. 8 9 AEGLs represent threshold exposure limits for the general public and are applicable to 10 emergency exposure periods ranging from 10 minutes to 8 hours. Three levels – AEGL-1, 11 AEGL-2 and AEGL-3 C are developed for each of five exposure periods (10 and 30 minutes, 1 12 hour, 4 hours, and 8 hours) and are distinguished by varying degrees of severity of toxic effects. 13 The three AEGLs are defined as follows: 14 15 AEGL-1 is the airborne concentration (expressed as parts per million or milligrams per 16 cubic meter [ppm or mg/m3]) of a substance above which it is predicted that the general 17 population, including susceptible individuals, could experience notable discomfort, irritation, or 18 certain asymptomatic, non-sensory effects. However, the effects are not disabling and are 19 transient and reversible upon cessation of exposure. 20 21 AEGL-2 is the airborne concentration (expressed as ppm or mg/m3) of a substance above 22 which it is predicted that the general population, including susceptible individuals, could 23 experience irreversible or other serious, long-lasting adverse health effects or an impaired ability 24 to escape. 25 26 AEGL-3 is the airborne concentration (expressed as ppm or mg/m3) of a substance above 27 which it is predicted that the general population, including susceptible individuals, could 28 experience life-threatening health effects or death. 29 30 Airborne concentrations below the AEGL-1 represent exposure levels that could produce 31 mild and progressively increasing but transient and nondisabling odor, taste, and sensory 32 irritation or certain asymptomatic, non-sensory effects. With increasing airborne concentrations 33 above each AEGL, there is a progressive increase in the likelihood of occurrence and the severity 34 of effects described for each corresponding AEGL. Although the AEGL values represent 35 threshold levels for the general public, including susceptible subpopulations, such as infants, 36 children, the elderly, persons with asthma, and those with other illnesses, it is recognized that 37 individuals, subject to unique or idiosyncratic responses, could experience the effects described 38 at concentrations below the corresponding AEGL. MONOMETHYLAMINE INTERIM: 06/2008; Page 3 of 46 1 TABLE OF CONTENTS 2 PREFACE.....................................................................................................................................................2 3 LIST OF TABLES........................................................................................................................................5 4 EXECUTIVE SUMMARY..........................................................................................................................6 5 1. INTRODUCTION................................................................................................................................8 6 2. HUMAN TOXICITY DATA...............................................................................................................9 7 2.1. Acute Lethality............................................................................................................................9 8 2.2. Nonlethal Toxicity.......................................................................................................................9 9 2.2.1. Odor Threshold/ Odor Awareness...........................................................................................9 10 2.2.2. Incidental or Occupational Exposure......................................................................................9 11 2.3. Neurotoxicity.............................................................................................................................10 12 2.4. Developmental and Reproductive Toxicity...............................................................................10 13 2.5. Genotoxicity..............................................................................................................................10 14 2.6. Carcinogenicity..........................................................................................................................10 15 2.7. Summary....................................................................................................................................10 16 3. ANIMAL TOXICITY DATA............................................................................................................11 17 3.1. Acute Lethality..........................................................................................................................11 18 3.1.1. Rats........................................................................................................................................12 19 3.1.2. Mice......................................................................................................................................15 20 3.2. Non-Lethal Toxicity..................................................................................................................15 21 3.2.1. Rats........................................................................................................................................16 22 3.2.2. Mice......................................................................................................................................16 23 3.2.3. Rabbits...................................................................................................................................16 24 3.2.4. Cats........................................................................................................................................17 25 3.3. Subchronic and Chronic Toxicity..............................................................................................17 26 3.4 Neurotoxicity.............................................................................................................................17 27 3.5. Developmental and Reproductive Toxicity...............................................................................18 28 3.6. Genotoxicity..............................................................................................................................18 29 3.7. Carcinogenicity..........................................................................................................................19 30 3.8. Summary....................................................................................................................................19 31 4. SPECIAL CONSIDERATIONS........................................................................................................20 32 4.1. Metabolism and Distribution.....................................................................................................20 33 4.2. Toxicity Mechanisms................................................................................................................21 34 4.3. Structure-Activity Relationship.................................................................................................22 35 4.4. Other Relevant Information.......................................................................................................23 36 4.4.1. Species Variability................................................................................................................23 37 4.4.2. Susceptible Populations........................................................................................................23 38 4.4.3. Concentration-Exposure Duration Relationship...................................................................24 39 5. DATA ANALYSIS FOR AEGL-1....................................................................................................24 40 5.1. Summary of Human Data Relevant to AEGL-1........................................................................24 41 5.2. Summary of Animal Data Relevant to AEGL-1........................................................................24 42 5.3. Derivation of AEGL-1...............................................................................................................25 43 6. DATA ANALYSIS FOR AEGL-2....................................................................................................26 44 6.1. Human Data Relevant to AEGL-2.............................................................................................26 45 6.2. Animal Data Relevant to AEGL-2............................................................................................26 46 6.3. Derivation of AEGL-2...............................................................................................................27 MONOMETHYLAMINE INTERIM: 06/2008; Page 4 of 46 1 7. DATA ANALYSIS FOR AEGL-3....................................................................................................27 2 7.1. Summary of Human Data Relevant to AEGL-3........................................................................27 3 7.2. Summary of Animal Data Relevant to AEGL-3........................................................................27 4 7.3. Derivation of AEGL-3...............................................................................................................28 5 8. SUMMARY OF AEGLs....................................................................................................................29 6 8.1. AEGL Values and Toxicity Endpoints......................................................................................29 7 8.2. Comparison with Other Standards and Guidelines....................................................................30 8 8.3. Data Adequacy and Research Needs.........................................................................................31 9 9. REFERENCES...................................................................................................................................32 10 APPENDIX А: Derivation of the Level of Distinct Odor Awareness (LOA)...........................................37 11 APPENDIX B: Derivation of AEGL Values.............................................................................................38 12 APPENDIX C: Category Plot for Methylamine (MMA)..........................................................................42 13 APPENDIX D: Derivation Summary of Acute Exposure Guideline Levels for Methylamine.................44 14 MONOMETHYLAMINE INTERIM: 06/2008; Page 5 of 46 1 LIST OF TABLES 2 3 TABLE 1.Summary of AEGL Values for Monoethylamine........................................................................7 4 TABLE 2. Physical and Chemical Properties of Monomethylamine...........................................................8 5 TABLE 3. Monoethylamine Acute Lethality Animal Studies...................................................................11 6 TABLE 4. Summary of Lethality Data in Rats Following Exposure to Monomethylamine.....................14 7 TABLE 5. Non-lethal Inhalation Toxicity Studies for Monomethylamine...............................................15 8 TABLE 6. AEGL-1 Values for Monomethylamine..................................................................................26 9 TABLE 7. AEGL-2 Values for Monomethylamine...................................................................................27 10 TABLE 8. AEGL-3 Values for Monomethylamine...................................................................................28 11 TABLE 9. Summary of AEGL Values for Monomethylamine.................................................................29 12 TABLE 10. Extant Standards and Guidelines for Monomethylamine.......................................................30 13 14 MONOMETHYLAMINE INTERIM: 06/2008; Page 6 of 46 1 EXECUTIVE SUMMARY 2 3 Methylamine (monomethylamine; MMA) is a primary aliphatic amine which has an 4 offensive fishy odor. It is a degradation product of alkaloids and proteins in many species, and is 5 an endogenous metabolite of epinephrine, sarcosine, and creatine in humans. MMA is a high 6 production volume chemical in the U.S. with a wide range of industrial applications as a 7 compressed gas and as a 40% aqueous solution. MMA is a potent eye and mucous membrane 8 irritant, which largely determines the clinical picture of MMA vapor intoxication. In both 9 humans and animals, MMA causes respiratory system toxicity (impaired breathing, lung 10 congestion and edema) that can lead to death, as well as corneal opacity. Animal studies have 11 also shown MMA-induced toxicity to the liver, brain, and hematopoietic and nervous systems. 12 13 MMA is metabolized in mammals by semicarbazide-sensitive amine oxidase (SSAO), to 14 form formaldehyde, hydrogen peroxide, and ammonia. Elevated levels of endogenous MMA 15 and/or increased SSAO activity, and the increased levels of the MMA metabolites, are believed 16 to cause vascular endothelial damage, and are associated with a number of disease states 17 (diabetes, heart disease, non-diabetic obesity, Alzheimer’s disease, cerebral arteriopathy, 18 inflammatory liver disease, atherosclerosis, and congestive heart failure). Individuals with 19 increased SSAO activity may therefore be a sensitive sub-population. Several studies indicate 20 that SSAO activity is greater in human than rodent tissues (Lewinsohn et al. 1978; Boomsma et 21 al. 2000). 22 23 The level of distinct odor awareness (LOA) for MMA is 0.56 ppm. The LOA represents 24 the concentration above which it is predicted that more than half of the exposed population will 25 experience at least a distinct odor intensity, and about 10% of the population will experience 26 strong odor intensity. The LOA should help chemical emergency responders in assessing the 27 public awareness of the exposure due to odor perception. 28 29 The AEGL-1 is based on two studies. The point of departure in the Kinney et al. (1990) 30 study was a single 6-hour exposure of male CD rats to 75 ppm. Exposures were actually 31 repeated for two-weeks (10 exposures) and resulted in mild irritation of the nasal turbinates. 32 Repeat exposure to higher concentrations (250 and/or 750 ppm) caused more severe nasal lesions 33 and /or systemic toxicity and mortality. A single 6-hour exposure to 75 ppm is expected to cause 34 no more than mild sensory irritation. In the second study, exposure of male Wistar rats to 465 35 ppm for 30 minutes was a NOAEL for notable signs of discomfort, but resulted in interstitial 36 pneumonitis progressing to fibrosis (Jeevaratnam and Sriramachari 1994; Sriramachari and 37 Jeevaratnam 1994). A total UF of 10 was applied to the point of departure in both studies, 38 including 3 for interspecies uncertainty and 3 for human variability, because mild nasal irritation 39 from an alkaline irritant gas is a direct surface-contact effect not involving metabolism, and is 40 not likely to vary greatly between species or among humans (NRC 2001). Because the well- 41 conducted study of Kinney et al. (1990) was a repeat exposure study and the effect was 42 essentially a NOAEL, a modifying factor of 0.5 was applied. The study of Sriramachari and 43 Jeevaratnam (1994) used only one exposure, the description of the study results lacked details, 44 and the endpoint was above the definition of an AEGL-1. In the absence of robustness and in 45 light of the seriousness of the endpoint, a modifying factor of 3 was applied to the 465 ppm value 46 for a combined uncertainty and modifying factor of 30. Application of these uncertainty and 47 modifying factors to the respective studies yields an AEGL-1 value of 15 ppm. The resulting 48 AEGL-1 value of 15 ppm was adopted for 10 minutes to 8 hours because mild sensory irritation 49 is not expected to vary greatly over time. MONOMETHYLAMINE INTERIM: 06/2008; Page 7 of 46 1 AEGL-2 values were derived from the Kinney et al. (1990) repeat exposure study. Ten 2 exposures of male CD rats to 250 ppm, 6 hours/day, caused reversible lesions of the anterior 3 respiratory tract. The severity of the lesions (focal erosion and ulceration of the nasal turbinate 4 mucosa) was attributed to the repeat exposure scenario, i.e., repeated local irritation. Lesions did 5 not extend into the trachea or lungs. Lesions following a single exposure would be less severe 6 and also reversible. A total uncertainty factor of 10 was applied, including 3 for interspecies 7 uncertainty and 3 for human variability, because nasal irritation from an alkaline irritant gas is a 8 direct surface-contact effect not involving metabolism, and is not likely to vary greatly between 9 species or among humans (NRC 2001). Time scaling, Cn x t = k where n = 1.9, was based on rat 10 lethality data ranging from 6 to 60 minutes (data set of IRDC 1992a). Lethality data were used 11 to time-scale the AEGL-2 values because local irritation is considered the first step leading to 12 pulmonary irritation and death. 13 14 The AEGL-3 was based on the study provided by the International Research and 15 Development Corporation (IRDC 1992a) in which rats were exposed to concentrations of 16 17,600-35,300 ppm for 6 minutes, 10,600-17,400 ppm for 20 minutes, or 4100-8670 ppm for 17 60 minutes. The mortality response data of IRDC (1992a) were used in the probit-analysis based 18 dose-response program of ten Berge (2006) to calculate the LC at each AEGL-3 exposure 01 19 duration. The program incorporated all of the data at the 6-, 20-, and 60-minute time points. The 20 data indicated a time-scaling value of 1.9 (C1.9 x t = k). A total uncertainty factor of 10 was 21 applied, including 3 for interspecies uncertainty and 3 for human variability, because lethality 22 from an alkaline irritant gas is a direct surface-contact effect not involving metabolism, and is 23 not likely to vary greatly between species or among humans (NRC 2001). 24 25 AEGL values for MMA are presented in Table 1. 26 TABLE 1.Summary of AEGL Values for Monomethylamine Endpoint Classification 10-min 30-min 1-h 4-h 8-h (Reference) Mild sensory (nasal) irritation in rats AEGL–11 15 ppm 15 ppm 15 ppm 15 ppm 15 ppm (Kinney et al. 1990; (Non-disabling) (19 mg/m3) (19 mg/m3) (19 mg/m3) (19 mg/m3) (19 mg/m3) Sriramachari and Jeevaratnam and 1994) Reversible nasal AEGL–2 160 ppm 92 ppm 64 ppm 31 ppm 21 ppm lesions in rats (Disabling) (200 mg/m3) (120 mg/m3) (80 mg/m3) (39 mg/m3) (27 mg/m3) (Kinney et al. 1990) AEGL–3 910 ppm 510 ppm 350 ppm 170 ppm 110 ppm LC in rats (IRDC 01 (Lethal) (1200 mg/m3) (650 mg/m3) (440 mg/m3) (220 mg/m3) (140 mg/m3) 1992a) 27 1 A Level of Distinct Odor Awareness (LOA) of 0.56 ppm was calculated for MMA based on the odor threshold of 28 0.035 ppm provided by Ruijten (2005). The LOA is defined as the concentration above which it is predicted that 29 more than half of the exposed population will experience at least a distinct odor intensity, and about 10% of the 30 population will experience a strong odor intensity (Van Doorn et al. 2002). MONOMETHYLAMINE INTERIM: 06/2008; Page 8 of 46 1 1. INTRODUCTION 2 3 Methylamine (monomethylamine; MMA) is a primary aliphatic amine which has an 4 offensive fishy odor. It is a natural degradation product of alkaloids and proteins in many 5 vegetable and animal species. Human endogenous sources of MMA also include epinephrine, 6 sarcosine, and creatine (Dar et al. 1985). MMA is a potent eye and mucous membrane irritant, 7 which largely determines the clinical picture of MMA vapor intoxication. In both humans and 8 animals, MMA at sufficiently high concentrations has caused severe toxicity to the respiratory 9 system (impaired breathing, lung congestion and edema) leading to death, as well as corneal 10 opacity. Animal studies have also shown MMA-induced toxicity to the liver, brain, and 11 hematopoietic system, as well as behavioral changes. 12 13 MMA is a colorless, easily liquefiable gas that is soluble in water, alcohol, acetone, and 14 benzene. It has a wide range of industrial applications as a compressed gas and as a 40% 15 aqueous solution. MMA is used in organic synthesis, as a fuel additive, in manufacture of 16 pharmaceutical preparations, insecticides, surfactants, explosives, plastic monomers, ion 17 exchange resins, rubber accelerates, cellulose acetate, rayon, photographic developers, and in the 18 tanning and dyeing industries (HSDB 2006). MMA is manufactured by several methods, 19 including heating methanol, ammonium chloride, and zinc chloride to approximately 300°C; 20 reacting ammonia and methanol at high temperature and pressure in the presence of silica- 21 alumina catalyst; and by the reductive amination of formaldehyde (Cavender 2001). In the U.S., 22 MMA is a high production volume chemical with an annual production volume of over 50 23 million pounds in 1985 (HSDB 2006). In 1997, the demand for the methylamines (MMA, 24 dimethylamine [DMA], and trimethylamine [TMA]) was estimated as 318 million lbs (Chemical 25 Marketing Reporter 1997). Selected physical and chemical properties of MMA are listed in 26 Table 2. 27 TABLE 2. Physical and Chemical Properties of Monomethylamine Parameter Value Reference Monomethylamine; MMA; amino- Synonyms O’Neil et al. 2001 methane; methanamine; Chemical Formula CH NH NIOSH 2006a 3 2 Molecular Weight 31.06 O’Neil et al. 2001 CAS Registration Number 74-89-5 O’Neil et al. 2001 Physical State Colorless gas NIOSH 2006a Water Solubility Very soluble Cavender 2001 Acid ionization constant, pK 10.65 at 25°C Cavender 2001 a Vapor Pressure 2 atm at 25°C Cavender 2001 Vapor Density (Air =1) 1.07 Cavender 2001 Liquid Density (water =1) 0.7691 Cavender 2001 Melting Point -93.5°C O’Neil et al. 2001 Boiling Point -6.3°C at 760 torr O’Neil et al. 2001 Explosive Limits 4.9 to 20.7 vol% in air NIOSH 2006a Conversion Factors 1 ppm = 1.27 mg/m3; 1 mg/l=783 ppm NIOSH 2006a 28 MONOMETHYLAMINE INTERIM: 06/2008; Page 9 of 46 1 2. HUMAN TOXICITY DATA 2 2.1. Acute Lethality 3 4 No quantitative human acute exposure studies were located. Yang et al. (1995) described 5 the care and treatment of 35 people accidentally exposed to MMA vapor that leaked from an 6 overturned truck carrying liquid MMA through a residential area in China. The exposure 7 duration was unknown, but was certainly no more than a few hours. The exposed group of 18 8 males and 17 females were 7-71 years old, and were hospitalized within 7-8 hours of exposure. 9 All had varying degrees of respiratory toxicity, including difficulty breathing, hoarse voice, dry 10 hurting throat, pink saliva, and chemical burns that led to edema and tissue damage of the nose, 11 mouth, and lungs. Many had lesions of the eyes (lids stuck together and painful, cloudy cornea, 12 impaired eyesight) and painful burns on exposed skin, with drainage and bleeding. Other 13 symptoms included coma, fainting, dizziness, headache, nausea, vomiting, stomach ache, black 14 stool, high body temperature (up to 39.5°C), rapid heart rate, circulatory failure, and seizures. 15 The patients were treated with oxygen and various antibiotics and rinses (boric acid, sodium 16 bicarbonate, hydrogen peroxide), and every effort was made to keep their respiratory systems 17 clear of the viscous mucous lumps of tissue that obstructed breathing. No one lost their eyesight, 18 but 6 of the 35 people died within 10 days of exposure. The period of highest mortality was 1-4 19 days after exposure, the major cause being chemical burns and tissue death of the lungs. 20 21 2.2. Nonlethal Toxicity 22 2.2.1. Odor Threshold/ Odor Awareness 23 24 MMA has a pungent, fishy odor. The MMA odor awareness threshold in humans was 25 reported as 0.021 ppm (Leonardos et al. 1969), 0.02-9.4 ppm (Ruth 1986), 0.0009-4.7 ppm 26 (AIHA 1989), and 3.2 ppm (Amoore and Hautala 1983). An odor awareness threshold (Lim ) olf 27 of 0.008 ppm was determined in 31 volunteers aged 18 to 50 by Dabaev (1981). Olfactory 28 fatigue to MA occurs readily (Sutton 1963). 29 30 A level of distinct odor awareness (LOA) of 0.56 ppm was calculated for MMA based on 31 an odor threshold of 0.035 ppm (Ruijten 2005). The LOA represents the concentration above 32 which it is predicted that more than half of the exposed population will experience at least a 33 distinct odor intensity, and about 10 % of the population will experience a strong odor intensity. 34 Calculations for the LOA are in Appendix A. 35 36 2.2.2. Incidental or Occupational Exposure 37 38 No studies were located in which the MMA air concentration, duration of exposure, and 39 resulting effects were all quantified. The concentration of MMA, DMA (dimethylamine), and 40 ammonia in workroom air and in the workers’ urine were measured over a 24-hour period in a 41 German factory processing DMA (Bittersohl and Heberer 1980). Air measurements taken at 14 42 locations in the factory (30-minute sampling time) revealed MMA levels of 0.55-29 ppm (13/14 43 were <3 ppm), DMA levels of 0.65-18 ppm (10/14 were <7 ppm), and ammonia levels of 1.4-50 44 ppm (9/14 ≤12 ppm). It was not noted whether the workers experienced any adverse effect from 45 the exposures. The results of the excretion study are described in Section 4.1. MONOMETHYLAMINE INTERIM: 06/2008; Page 10 of 46 1 Secondary sources reported the irritation threshold of MMA as 7.9 ppm (Izmerov et al. 2 1982) and 18 ppm (Ruth 1986). Exposure to 10 ppm MMA for a prolonged period was 3 reportedly not irritating, possibly due to olfactory fatigue, which is caused by aliphatic amines 4 (Sutton 1963). A worker exposed to 25 ppm MA reported “some irritation,” whereas 2-60 ppm 5 caused “allergic or chemical bronchitis,” but no other exposure details were provided (ACGIH 6 1992). 7 8 A secondary source reports that “methylamines” (defined as MMA, TMA, and DMA) 9 have a pungent, fishy odor below 100 ppm, but at air concentrations “somewhere in the range of 10 100-500 ppm,” their odor is indistinguishable from that of ammonia (Deichmann and Gerarde 11 1969). Short exposures (unknown duration) to 20-100 ppm MMA were reported to cause 12 irritation of the eyes, nose, and throat, whereas at >100 ppm, MMA vapors are “intolerably 13 ammoniacal,” and caused irritation of the nose and throat, violent sneezing, coughing, a burning 14 sensation of the throat, larynx constriction, difficulty breathing, pulmonary congestion, and lung 15 edema (Sutton 1963; Deichmann and Gerarde 1969). 16 17 2.3. Neurotoxicity 18 19 The only report of MMA neurotoxic effects to humans was made by Yang et al. (1995) in 20 their description of the accidental exposure to MMA vapor of 35 people who were hospitalized. 21 In addition to severe respiratory and ocular effects, symptoms included coma, fainting, dizziness, 22 headache, nausea, vomiting, and seizures. The exposure concentration and duration were not 23 reported but were certainly a small fraction of a day. 24 25 2.4. Developmental and Reproductive Toxicity 26 27 No human data regarding MMA reproductive or developmental toxicity were located. 28 29 2.5. Genotoxicity 30 31 No data were found on the genotoxic potential of MMA in humans. 32 33 2.6. Carcinogenicity 34 35 No human carcinogenicity studies were found for MMA, and no regulatory bodies have 36 evaluated its carcinogenic potential. 37 38 2.7. Summary 39 40 MMA has a pungent, fishy odor with an odor awareness threshold of 0.0009-4.7 ppm and 41 an irritation threshold of 7.9-18 ppm. Olfactory fatigue to MMA occurs readily. Secondary 42 source reports indicate that exposure to 20-100 ppm irritates the eyes, nose, and throat, and 43 concentrations >100 ppm are “intolerably ammoniacal,” causing irritation of the nose and throat, 44 burning throat, larynx constriction, difficulty breathing, pulmonary congestion, and lung edema. 45 No studies were located that evaluated MMA developmental or reproductive toxicity, 46 genotoxicity, or carcinogenicity to humans. The accidental poisoning (undefined exposure time 47 or concentration) of 35 people was described in which six people died within 10 days of 48 exposure, mainly due to lung chemical burns and tissue death. Other effects included difficulty