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Appendixes

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1 Allylamine1 Acute Exposure Guideline Levels PREFACE Under the authority of the Federal Advisory Committee Act (P.L. 92-463) of 1972, the National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances has been established to identify, review, and interpret relevant toxicologic and other scientific data and develop acute exposure guide- line levels (AEGLs) for high-priority, acutely toxic chemicals. AEGLs represent threshold exposure limits for the general public and are applicable to emergency exposure periods ranging from 10 minutes (min) to 8 hours (h). Three levels—AEGL-1, AEGL-2, and AEGL-3—are developed for each of five exposure periods (10 min, 30 min, 1 h, 4 h, and 8 h) and are distin- guished by varying degrees of severity of toxic effects. The three AEGLs are defined as follows: AEGL-1 is the airborne concentration (expressed as parts per million [ppm] or milligrams per cubic meter [mg/m3]) of a substance above which it is predicted that the general population, including susceptible individuals, could 1 This document was prepared by the AEGL Development Team composed of Sylvia Milanez (Oak Ridge National Laboratory) and Loren Koller, Chemical Manager (Na- tional Advisory Committee [NAC] on Acute Exposure Guideline Levels for Hazardous Substances). The NAC reviewed and revised the document and AEGLs as deemed neces- sary. Both the document and the AEGL values were then reviewed by the National Re- search Council (NRC) Committee on Acute Exposure Guideline Levels. The NRC com- mittee has concluded that the AEGLs developed in this document are scientifically valid conclusions based on the data reviewed by the NRC and are consistent with the NRC guideline reports (NRC 1993, 2001). 13

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14 Acute Exposure Guideline Levels experience notable discomfort, irritation, or certain asymptomatic nonsensory effects. However, the effects are not disabling and are transient and reversible upon cessation of exposure. AEGL-2 is the airborne concentration (expressed as ppm or mg/m3) of a substance above which it is predicted that the general population, including sus- ceptible individuals, could experience irreversible or other serious, long-lasting adverse health effects or an impaired ability to escape. AEGL-3 is the airborne concentration (expressed as ppm or mg/m3) of a substance above which it is predicted that the general population, including sus- ceptible individuals, could experience life-threatening health effects or death. Airborne concentrations below the AEGL-1 represent exposure levels that can produce mild and progressively increasing but transient and nondisabling odor, taste, and sensory irritation or certain asymptomatic nonsensory effects. With increasing airborne concentrations above each AEGL, there is a progres- sive increase in the likelihood of occurrence and the severity of effects described for each corresponding AEGL. Although the AEGL values represent threshold levels for the general public, including susceptible subpopulations, such as in- fants, children, the elderly, persons with asthma, and those with other illnesses, it is recognized that individuals, subject to unique or idiosyncratic responses, could experience the effects described at concentrations below the correspond- ing AEGL. SUMMARY Allylamine is a colorless or yellowish volatile liquid with a very sharp ammonia-like odor that is irritating to mucous membranes. It is highly flamma- ble and moderately reactive with oxidizing materials. Industrially, it is used in the vulcanization of rubber and in the synthesis of pharmaceuticals. In addition to being a severe respiratory, eye, and skin irritant, allylamine is a cardiovascu- lar toxin when administered at high doses orally, by injection, or by inhalation. Allylamine cardiotoxicity is proposed to be related to its metabolism to acrolein and hydrogen peroxide. AEGL-1 values were based on a study in which 35 young adult human volunteers were exposed for 5 min to 2.5, 5, or 10 ppm allylamine (10-14 per concentration; sex and age not specified; Hine et al. 1960). A group was also exposed briefly to 14 ppm, which was reported as intolerable and exposure was almost immediately terminated. The subjects graded their sensory responses for eye irritation, nose irritation, pulmonary discomfort, central nervous system (CNS) effects (headache, nausea), and olfactory cognition on a five-point scale (0 = absent; 1 = slight; 2 = moderate; 3 = severe; 4 = extreme or intolerable). All subjects detected the odor of allylamine, and there were dose-related increases in the incidence of slight or moderate eye irritation (21%, 15%, 50%), nose irrita- tion (50%, 54%, 100%), and pulmonary discomfort (29%, 46%, 50%) at 2.5, 5,

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15 Allylamine and 10 ppm, respectively. CNS effects were not dose related. The same AEGL-1 value was used for 10 min to 8 h because mild sensory irritation or discomfort does not generally vary greatly with time. The AEGL-1 point of departure was 1.25 ppm, which was obtained by applying a modifying factor (MF) of 2-2.5 ppm, which was the lowest effect level. The MF was used because exposure was for only 5 min, and it is unclear whether “moderate” irritation or discomfort is comparable to “notable” irritation or discomfort, which exceeds the scope of AEGL-1. An intraspecies uncertainty factor of 3 was applied because allylamine acts as a contact irritant, and the severity of its effects is not expected to vary greatly among humans. Also, use of a greater uncertainty factor would yield a concentration below 0.2 ppm, which was a no-effect level for workers exposed for up to 4 h (Shell Oil Co. 1992). The derived AEGL-1 value of 0.42 ppm for 10 min to 8 h is also consistent with two mouse respiratory irritation studies (Gagnaire et al. 1989, 1993), from which it is predicted that exposure for a few hours to 0.9 ppm would cause sensory irritation in humans but that 0.09 ppm would not (Alarie 1981). AEGL-2 values were based on two studies. The 10-, 30-, and 60-min AEGLs were developed from the Hine et al. (1960) human 5-min exposure study that was used to derive AEGL-1 values but using 10 ppm as the point of departure. Ten ppm caused slight or moderate eye and nose irritation and pul- monary discomfort and was the no-observed-adverse-effect level (NOAEL) for “intolerable” irritation that occurred at 14 ppm. The same value was adopted for 10-60 min because the degree of irritation or discomfort resulting from exposure to 10 ppm was not expected to increase over a 1-h period beyond the scope of AEGL-2. An intraspecies uncertainty factor of 3 was used because allylamine acts as a contact irritant and the severity of its effects is not expected to vary greatly among humans. The resulting AEGL-2 value of 3.3 ppm was not adopted for 4 or 8 h, however, because a rat study (Guzman et al. 1961) indi- cated that exposure to 3.3 ppm for 4 or 8 h may cause cardiotoxicity. In the latter study, exposure to 40 ppm for 16 h was a NOAEL for cardiovascular lesions, which were seen from exposure to 60 ppm for 14 h (myofibril fragment damage, perivascular edema, and cellular infiltration). Time-concentration scaling was performed using the ten Berge et al. (1986) equation Cn × t = k, where n = 1.7 was calculated from a linear regression of the Guzman et al. (1961) rat cardio- toxicity data. An interspecies uncertainty factor of 5 was applied because the mechanism of toxicity is similar among several mammalian species (and hu- mans) but differences in susceptibility are unknown, and an uncertainty factor of 3 yields values approaching the no-observed-effect level (NOEL) for lethality from pulmonary lesions for a 4- or 8-h exposure. An intraspecies uncertainty factor of 10 was used because the variability of the cardiotoxic response to al- lylamine among humans is undefined, and potentially sensitive populations exist (diabetics, persons with congestive heart failure). This yields 4- and 8-h AEGLs of 1.8 and 1.2 ppm, respectively, indicating that for these longer exposure dura- tions, cardiotoxicity is a more sensitive end point than eye and respiratory irritation.

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16 Acute Exposure Guideline Levels AEGL-3 values were derived from a study on rat inhalation with a lethal concentration in 50% of the sample (LC50) in which exposures were for 1, 4, or 8 h (Hine et al. 1960). All treated rats showed signs of eye and respiratory tract irritation, and some had lacrimation and red nasal discharge. Rats that died had stomachs distended with air, fluid-filled lungs, alveolar hemorrhage, and pulmo- nary edema. The NOEL for lethality, as represented by LC01 (1% lethality) val- ues calculated using probit analysis, was the AEGL-3 end point. The 1-h, 4-h, and 8-h AEGLs were obtained using the respective LC01 values. The 10- and 30- min AEGLs were derived from the 1-h LC01 using the relationship Cn × t = k , where n = 0.85 was calculated from the Hine et al.LC50 data. An uncertainty factor of 30 was applied: 10 to account for interspecies variability (lack of acute toxicity studies from other species with AEGL-3 level end points) and 3 for hu- man variability (the steep dose-response (~2-fold increase in concentration caused mortality to increase from 0 to 100%) indicates that the NOEL for lethal- ity due to direct destruction of lung tissue is not likely to vary greatly among humans). The derived AEGL-3 values, as well as the AEGL-1 and AEGL-2 values, are shown in Table 1-1. 1. INTRODUCTION Allylamine is a colorless or yellowish volatile liquid that is highly flam- mable and moderately reactive with oxidizing materials (HSDB 2003). It is completely soluble in water with a pKa of 9.7 and has a very sharp ammonia-like odor that is irritating to mucous membranes (Budavari et al. 1996; HSDB 2003; Boor and Hysmith 1987).2 Industrially, it is used in the vulcanization of rubber and in the synthesis of commercial products, including mercurial diuretics, seda- tives, and antiseptics (Benya and Harbison 1994). Allylamine is manufactured by the amination of alkyl halides (e.g., allyl chloride and ammonia) and is also a natural constituent of foodstuffs (Budavari et al. 1996; HSDB 2003). In addition to being a severe respiratory, eye, and skin irritant, allylamine is cardiotoxic when administered at high doses orally, by inhalation, or by injec- tion. It has been used to induce cardiac and vascular lesions in laboratory ani- mals to model human cardiovascular disease. Allylamine cardiotoxicity is pro- posed to be related to its metabolism to acrolein and hydrogen peroxide in cardiac and vascular tissues (Boor and Hysmith 1987; Ramos et al. 1988). Al- lylamine lethal inhalation toxicity has been examined in rats and mice and its nonlethal inhalation toxicity in single- and multiple-exposure studies using monkeys, rats, mice, and rabbits. Studies with human volunteers and exposures in the workplace have yielded limited information about the irritant and toxic effects of short-term inhalation exposure. The allylamine odor threshold is 2 pKa is the negative log of the acid dissociation constant.

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17 Allylamine TABLE 1-1 Summary of AEGL Values for Allylamine End Point Classification 10 min 30 min 1h 4h 8h (Reference) AEGL-1a 0.42 ppm 0.42 ppm 0.42 ppm 0.42 ppm 0.42 ppm Mild human irritation (nondisabling) (0.98 (0.98 (0.98 (0.98 (0.98 or discomfort (Hine mg/m3) mg/m3) mg/m3) mg/m3) mg/m3) et al. 1960) AEGL-2 3.3 ppm 3.3 ppm 3.3 ppm 1.8 ppm 1.2 ppm Human eye and (disabling) (7.7 (7.7 (7.7 (4.2 (2.8 respiratory irritation mg/m3) mg/m3) mg/m3) mg/m3) mg/m3) and NOAEL for severe irritation (≤1 h; Hine et al. 1960); NOAEL for cardiovascular lesions in rats (≥4 h; Guzman et al. 1961) AEGL-3 150 ppm 40 ppm 18 ppm 3.5 ppm 2.3 ppm Lethality NOEL in (lethal) (350 (93 (42 (8.2 (5.4 rats (Hine et al. 1960) mg/m3) mg/m3) mg/m3) mg/m3) mg/m3) a Odor threshold is ≤2.5 ppm. <2.5ppm based on the human study of Hine et al. (1960) and is reported as 6.2 ppm by Summer (1971). Allylamine chemical and physical properties are listed in Table 1-2. 2. HUMAN TOXICITY DATA 2.1. Acute Lethality No quantitative data were located regarding lethal allylamine exposure in humans. It was reported that allylamine inhalation may cause irregular respira- tion, cyanosis, excitement, convulsions, and death, although neither further de- tails nor the source of this information was provided (HSDB 2003). 2.2. Nonlethal Toxicity 2.2.1. Odor Threshold/Odor Awareness A published odor threshold was not found for allylamine. An unpublished source (van Doorn et al. 2002) reported 3.7 ppm as the odor detection threshold (OT50; that is, the concentration at which 50% of the odor panel observed an odor without necessarily recognizing it). A value of 3.7 conflicts with a sensory

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18 Acute Exposure Guideline Levels TABLE 1-2 Chemical and Physical Data Property Descriptor or Value Reference Synonyms Monoallylamine; 2- Budavari et al. 1996 propenamine; 3- aminopropylene Chemical formula CH2 = CHCH2 NH2 Budavari et al. 1996 Molecular weight 57.10 Budavari et al. 1996 CAS registry number 107-11-9 Benya and Harbison 1994 Physical state Liquid Budavari et al. 1996 Color Colorless or yellowish HSDB 2003 Solubility in water Completely miscible Budavari et al. 1996 Acid ionization constant, pKa 9.7 HSDB 2003 Vapor pressure 242 mm Hg at 25°C HSDB 2003 Vapor density (air = 1) 1.97 Benya and Harbison 1994 Liquid density (water = 1) 0.76 at 20/4°C Verschueren 1996 −88°C Melting point HSDB 2003 Boiling point 55-58°C Budavari et al. 1996 Flammability/explosive limits 2.2-22% HSDB 2003 1 mg/m3 = 0.428 ppm Conversion factors Verschueren 1996 1 ppm = 2.33 mg/m3 threshold experimental study, in which all 36 volunteers exposed to allylamine for 5 min reported “olfactory cognition” at the lowest concentration tested of 2.5 ppm (Hine et al. 1960; see Section 2.2.2). Additionally, if the methodology of van Doorn et al. (2002) is used to calculate an LOA (level of distinct odor awareness; see Appendix B), a value of 58 ppm is calculated, which exceeds a concentration (i.e., 14 ppm) found to be intolerable by humans (Hine et al. 1960). The method used to determine the 3.7-ppm odor threshold was not re- ported, which may explain its discrepancy with the Hine et al. study (e.g., a higher concentration may be needed for detection by sniffing for a few seconds than by inhalation for 5 min). 2.2.2. Experimental Studies The sensory threshold for detecting inhaled allylamine was examined in 35 young adult human volunteers exposed for 5 min to 2.5, 5, 10, or 14 ppm (10-14 per concentration; sex and age not specified; Hine et al. 1960). It was not specified whether the same persons were exposed to more than one concentra- tion. To compensate for the loss of allylamine upon the entrance of subjects into the 16,680-L chamber, the initial concentration of allylamine in the chamber

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19 Allylamine was about 10% greater than the target air allylamine concentration for the low concentrations and about 1% greater at the high allylamine concentrations (not specified which concentrations were considered low or high). The air allylamine concentration was continuously monitored by a recording infrared spectropho- tometer. The subjects graded their sensory responses for eye irritation, nose irri- tation, pulmonary discomfort, CNS effects, and olfactory cognition on a five- point scale, ranging from “absent” to “extreme” (intolerable); results are shown in Table 1-3. All test subjects detected the odor of allylamine at the lowest concentra- tion tested (2.5 ppm). At 2.5, 5, and 10 ppm, respectively, there were dose- related increases in the incidence of slight or moderate eye irritation (21%, 15%, and 50%), nose irritation (50%, 54%, 100%), and pulmonary discomfort (29%, 46%, 50%). The incidence of slight or mild CNS effects, such as slight headache or nausea, was not dose related (21%, 0%, and 10% at 2.5, 5.0, and 10 ppm). At 14 ppm “irritation of [the] eyes, nose, and throat and pulmonary discomfort were considered intolerable, and exposure was terminated almost at once.” The num- ber of subjects exposed to 14 ppm and their individual sensory evaluations were not given. Summer (1971) reported 6.2 ppm as the odor threshold for allylamine and 80 ppm as the concentration at which it becomes irritating to humans. It was not described in detail how these values were obtained (i.e. exposure duration, range of concentrations tested), although it appears that they may have been obtained by a panel of “sniffers,” and thus exposure was for a few seconds. These values are much higher than the concentration (2.5 ppm) found to be detected by all exposed human subjects (13/13) within 5 min, with some subjects even experi- encing mild respiratory irritation (Hine et al. 1960). The reason for the discrep- ancy between the two studies is unknown; it may be due to the different expo- sure durations. TABLE 1-3 Sensory Responses of Human Subjects to a 5-Min Allylamine Inhalation Exposurea Exposure Concentration and Grade of Response 10 ppm (n = 10) 2.5 ppm (n = 13 or 14) 5 ppm (n = 13) Effect 012340 1 2 3 4 01234 Olfactory cognition 391 4 9 253 Eye irritation 11 1 2 11 2 541 Nose irritation 7 5 2 6 6 1 55 Pulmonary discomfort 10 2 2 7 6 541 CNS effects 11 2 1 13 91 a Test subjects graded their responses as follows: 0 = absent; 1 = slight; 2 = moderate; 3 = severe; 4 = extreme (intolerable). Source: Data from Hine et al. 1960. Reprinted with permission; copyright 1960, Ameri- can Medical Association.

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20 Acute Exposure Guideline Levels 2.2.3. Case Reports Workers at a chemical manufacturing company exposed to mono-, di-, and tri-allylamine (simultaneously) occasionally reported symptoms, including tightness, congestion, and pain in the chest (especially on breathing or cough- ing), sore throat, runny nose, nausea, vomiting, red eyeballs, tightness in the jaw and behind the ears, and hurting teeth but had normal cardiac creatine phos- phokinase levels and electrocardiograms (EKGs) (Shell Oil Co. 1992). The symptoms were ameliorated by drinking Coca-Cola. Neither the exposure time (typically several minutes) nor air allylamine concentration was measured. Plant supervisors and the company’s industrial hygienist stated that symptoms were reported only when spills and leaks occurred, and 18 of 22 questionnaires filled out by workers (September-October 1981) checked “yes” for a question asking, “Was there was a spill or other unusual exposure at the time symptoms began?” The four people who checked “no” had numerous exposures and did not identify discrete incidents. To test a new stationary air sampler, ambient samples (no spills, etc.) were collected in five areas of the chemical plant (in September 1981) where workers could be present for up to 4 h on a typical day. In April 1982, personal monitoring was conducted by the company industrial hygienist. Workers were not evaluated. The air concentration was <0.1 to 0.2 ppm for monoallylamine, <0.01 to 0.3 ppm for diallylamine, and <0.01 to 0.6 ppm for triallylamine, all potential sources of product line leaks and of a maintenance procedure requiring opening of a product line. All air samples were below the limit of quantitation (LOQ) (0.5 or 5 ppm) for all three amines. People working in these areas wore protective clothing and/or respirators and were not exam- ined. It is unlikely that symptoms would have been experienced by workers in either monitoring situation since there were no unintentional spills or leaks. Guzman et al. (1961) carefully examined operators working with al- lylamine and did not find any cardiovascular effects, despite occasional com- plaints of irritation of the mucous membranes, nausea, and disagreeable odor. No experimental details or quantitative results were provided. 2.2.4. Accidents During the course of an acute inhalation study in mice, leaks developed in the apparatus and the workers fixing the leaks were exposed to an unknown concentration of allylamine vapors (Hart 1939). [The mice were exposed to 24,437-31,035 ppm allylamine in a 5-L bell jar connected to a flowmeter, and airflow was 750 mL/min.] The vapors initially caused severe irritation of the mucous membranes of the nose, mouth, and eyes, which developed into an in- tense burning with lacrimation, coryza, and sneezing. The symptoms disap- peared quickly (not specified) after exposure ceased.

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21 Allylamine 2.3. Neurotoxicity No human neurotoxicity studies were located with allylamine exposure by any route. 2.4. Developmental/Reproductive Toxicity No studies on the developmental or reproductive effects of allylamine in humans were located. 2.5. Genotoxicity No studies on the genotoxicity of allylamine in humans were located. 2.6. Carcinogenicity No studies on the carcinogenicity of allylamine in humans were located (nor of its proposed metabolite, acrolein). Neither the U.S. Environmental Pro- tection Agency (EPA) nor the International Agency for Research on Cancer (IARC) has classified allylamine as to its carcinogenic potential. 2.7. Summary No human data were located involving acute lethal exposure to allylamine. Sensory irritation was experienced by volunteers exposed to 2.5-10 ppm for 5 min, whereas exposure to about 14 ppm was immediately intolerable (Hine et al. 1960). There were several case reports and accidents involving occupational exposure to allylamine, in which workers experienced chest pain and respiratory irritation, although neither exposure durations nor concentrations were available. No studies were located describing developmental, reproductive, genotoxic, or carcinogenic effects in humans. 3. ANIMAL TOXICITY DATA 3.1. Acute Lethality Lethality as a toxic end point was described in several rat and mouse acute inhalation exposure studies. Kulagina (1975) reported an LC50 of 320 mg/m3 (137 ppm) for mammals, although no further experimental details were pro- vided.

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47 Allylamine APPENDIX A Derivation of AEGL-1 Values Key study: Hine et al. (1960). Thirty five young adult human volun- teers were exposed for 5 min to 2.5, 5, or 10 ppm of al- lylamine (10-14/concentration; sex and age not speci- fied). A group was also exposed briefly to 14 ppm, which was reported as intolerable, and exposure was al- most immediately terminated. All subjects detected the odor of allylamine, and there were dose-related in- creases in the incidence of slight or moderate eye irrita- tion (21%, 15%, 50%), nose irritation (50%, 54%, 100%), and pulmonary discomfort (29%, 46%, 50%) at 2.5, 5, and 10 ppm, respectively. The AEGL-1 point of departure was 1.25 ppm, which was obtained by apply- ing a modifying factor of 2 to the lowest effect level of 2.5 ppm. Toxicity end point: Mild sensory irritation or discomfort in humans exposed to 1.25 ppm for 10 min to 8 h. Scaling: None: The same AEGL-1 value was used for 10 min to 8 h because mild sensory irritation or discomfort does not vary greatly with time. Uncertainty Factors: Total uncertainty factor: 3. Interspecies: Not applicable. Intraspecies: 3; allylamine acts as a contact irritant, and the severity of its effects is not expected to vary greatly among hu- mans. Also, use of a greater uncertainty factor would yield a concentration below 0.2 ppm, which was a no- effect level for workers exposed for up to 4 h (Shell Oil Co. 1992). Modifying factor: 2, because exposure was for only 5 min and it is unclear whether “moderate” irritation or discomfort is compara- ble to “notable” irritation or discomfort, which exceeds the scope of AEGL-1.

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48 Acute Exposure Guideline Levels Calculations: 2.5 ppm/6 = 0.42 ppm (0.98 mg/m3) 10-min AEGL-1: 2.5 ppm/6 = 0.42 ppm (0.98 mg/m3) 30-min AEGL-1: 2.5 ppm/6 = 0.42 ppm (0.98 mg/m3) 1-h AEGL-1: 2.5 ppm/6 = 0.42 ppm (0.98 mg/m3) 4-h AEGL-1: 2.5 ppm/6 = 0.42 ppm (0.98 mg/m3) 8-h AEGL-1: Derivation of AEGL-2 Values 10, 30, and 60 min Key study: Hine et al. (1960); same study used to derive AEGL-1 values. Young adult human volunteers (35; sex and ages unknown) were exposed to 2.5, 5, 10, or 14 ppm. The AEGL-2 point of departure was 10 ppm, which caused slight or moderate eye and nose irritation and pulmonary discomfort and was the NOAEL for “intolerable” irrita- tion seen at 14 ppm. Toxicity end point: Human sensory irritation or discomfort; NOAEL for “intolerable” irritation. Scaling: None; the degree of irritation or discomfort resulting from exposure to 10 ppm was not expected to increase over a 1-h period beyond the scope of AEGL-2. Uncertainty factors: Total uncertainty factor: 3. Interspecies: Not applicable. Intraspecies: 3; used because allylamine acts as a contact irritant, and the severity of its effects is not expected to vary greatly among humans. Calculations for 10, 30, and 60 min: 10 ppm/3 = 3.3 ppm (7.7 mg/m3)

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49 Allylamine 4 and 8 h Key study: Guzman et al. (1961). Male Long-Evans rats exposed to 40 ppm for 16 h had heart morphology comparable to controls (NOAEL), but rats exposed to 60 ppm for 14 h had cardiovascular lesions consisting of scattered myo- fibril fragments with loss of striation, perivascular edema, and cellular infiltration (LOAEL). Toxicity end point: NOAEL for cardiovascular lesions. C1.7 × t = k (ten Berge et al. 1986); n = 1.7 was calcu- Scaling: lated from a linear regression of the Guzman et al. (1961) rat cardiotoxicity data. Uncertainty factors: Total uncertainty factor: 50. Interspecies: 5; the mechanism of toxicity is similar among several mammalian species (and humans), but differences in susceptibility are unknown; 3 yields values approaching NOEL for lethality from pulmonary lesions. Intraspecies: 10; the variability of cardiotoxic response among hu- mans is unknown, and potentially sensitive populations exist (diabetics, persons with congestive heart failure). Calculations for 4 and 8 h: Concentration 40 ppm1.7 × time (16 h) = k = 10.95 ppm1.7-h UF (50) C1.7 × 4 h = 10.95 ppm1.7-h 4-h AEGL-2: 4-h AEGL-2 = 1.8 ppm (4.2 mg/m3) C1.7 × 8 h = 10.95 ppm1.7-h 8-h AEGL-2: 8-h AEGL-2 = C = 1.2 ppm (2.8 mg/m3) Derivation of AEGL-3 Values Hine et al. 1960. Rat inhalation LC50 study. All treated Key study: rats showed signs of eye and respiratory tract irritation, and some had lacrimation and red nasal discharge. Rats dying from exposure had stomachs distended with air,

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50 Acute Exposure Guideline Levels fluid-filled lungs, alveolar hemorrhage, and pulmonary edema. Lethality NOELs, estimated from LC01 values obtained Toxicity end point: by probit analysis: 1-h LC01 = 533 ppm 4-h LC01 = 104 ppm 8-h LC01 = 69.2 ppm C0.85 × t = k (data from Hine et al. 1960; ten Berge et al. Scaling: 1986). Note: Only the 10- and 30-min AEGL-3 values required scal- ing (used the 1-h LC01). Uncertainty factors: Total uncertainty factor: 30. Interspecies: 10; to account for the lack of acute toxicity studies with AEGL-3 end points from other species. Intraspecies: 3; steep dose-response (~2-fold increase in concentra- tion caused mortality to increase from 0 to 100%) indi- cates the NOEL for lethality due to direct destruction of lung tissue is not likely to vary greatly among humans. Calculations for 10 and 30 min: Concentration 533 ppm0.85 × time (1 h) = k = 11.54 ppm0.85-h UF (30) C0.85 × 0.167 h = 11.54 ppm0.85-h 10-min AEGL-3: 10-min AEGL-3 = 150 ppm (350 mg/m3) C0.85 × 0.5 h = 11.54 ppm0.85-h 30-min AEGL-3: 30-min AEGL-3 = 40 ppm (93 mg/m3) Calculations for 1, 4, and 8 h: C = 533 ppm (= LC01) 1-h AEGL-3: 1-h AEGL-3 = 533 ppm/30 = 18 ppm (42 mg/m3) 4-h AEGL-3: C = 104 ppm (= LC01) 4-h AEGL-3 = 104 ppm/30 = 3.5 ppm (8.2 mg/m3)

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51 Allylamine 8-h AEGL-3: C = 69.2 ppm (= LC01) 8-h AEGL-3 = 69.2 ppm/30 = 2.3 ppm (5.4 mg/m3) APPENDIX B Derivation of the Level of Distinct Odor Awareness The level of distinct odor awareness (LOA) represents the concentration above which it is predicted that more than half of the exposed population will experience at least a distinct odor intensity; about 10% of the population will experience a strong odor intensity. The LOA should help chemical emergency responders in assessing public awareness of the exposure due to odor perception. The LOA derivation follows the guidance given by van Doorn et al. (2002). An odor detection threshold (OT50; i.e., the concentration at which 50% of the odor panel observed an odor without necessarily recognizing it) of 3.7 ppm was reported for allylamine by van Doorn et al (2002). This value conflicts with a sensory threshold experimental study in which all 36 volunteers exposed to allylamine for 5 min reported “olfactory cognition” at the lowest concentration tested of 2.5 ppm. Proceeding with the use of 3.7 ppm yields the following: The concentration (C) leading to an odor intensity (I) of distinct odor de- tection (I = 3) is derived using the Fechner function: I = kw × log (C/OT50) + 0.5. For the Fechner coefficient the default of kw = 2.33 will be used due to the lack of chemical-specific data: 3 = 2.33 × log (C/3.7) + 0.5, which can be rearranged to log (C/3.7) = (3 − 0.5) / 2.33 = 1.07 and results in C = (101.07) × 3.7 = 43.5 ppm. The resulting concentration is multiplied by an empirical field correction factor. It takes into account that in everyday life such factors as sex, age, sleep, smoking, upper-airway infections and allergies, and distraction increase the odor detection threshold by a factor of 4. In addition, it takes into account that odor perception is very fast (about 5 s), which leads to the perception of concentration peaks. Based on current knowledge, a factor of 1/3 is applied to adjust for peak exposure. Adjustment for distraction and peak exposure leads to a correction factor of 4/3 = 1.33. LOA = 43.5 × 1.33 = 58 ppm.

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52 Acute Exposure Guideline Levels The calculated LOA for allylamine is 58 ppm, which exceeds a concentra- tion (i.e., 14 ppm) found to be intolerable by humans (Hine et al. 1960). There- fore, the calculated LOA conflicts with human empirical data, as did the OT50, and neither the LOA nor the OT50 is considered valid. APPENDIX C Time-Scaling Calculations Allylamine: AEGL-2 n-Value Derivation Derivation of n for Cn × t = k, Based on Rat Cardiotoxicity Data (Guzman et al. 1961) Input Data: Regression Output: Log Time Log Concentration Concentration (h) Time Intercept 3.4443 −0.5845 100 2.0000 4 2.3802 Slope 60 1.7782 14 2.9243 R Squared 0.8922 −0.9446 50 1.6990 20 3.0792 Correlation 40 1.6021 32 3.2833 Degrees of freedom 3 20 1.3010 48 3.4594 Observations 5 n = 1.71. k = 781244.19. 2.2 2 Log Concentration 1.8 1.6 1.4 1.2 2.2 2.4 2.6 2.8 3 3.2 3.4 3.6 Log Time FIGURE 1-1 Best-fit concentration (ppm allylamine) × time (exposure dura- tion in hours) curve. Linear progression of rat lethality data.

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53 Allylamine Allylamine: AEGL-3 n-Value Derivation Derivation of n for Cn × t = k, Based on Rat LC50 Study Data of Hine et al. (1960) Input Data: Regression Output: Log Concentration Concentration Time (h) Log Time Intercept 3.2567 −1.1823 1,933 3.2862 1 0.0000 Slope R2 286 2.4564 4 0.6021 0.9798 −0.9898 177 2.2480 8 0.9031 Correlation Degrees of freedom 1 Observations 3 n = 0.8457765 k = 568.14929. 3.4 3.2 3 2.8 Log Concentration 2.6 2.4 2.2 2 0 0.2 0.4 0.6 0.8 1 Log Time FIGURE 1-2 Best-fit concentration (ppm allylamine) × time (exposure dura- tion in hours) curve. Linear progression of rat lethality data.

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54 APPENDIX D Category Plot for Allylamine Chemical Toxicity - TSD All Data Allylamine 100000.0 Human - No Effect Human - Discomfort 10000.0 Human - Disabling 1000.0 Animal - No Effect Animal - Discomfort 100.0 ppm Animal - Disabling AEGL-3 10.0 Animal - Some Lethality AEGL-2 1.0 Animal - Lethal AEGL-1 AEGL 0.1 0 60 120 180 240 300 360 420 480 Minutes FIGURE 1-3 Category plot of human and animal toxicity data compared with AEGL values.

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Allylamine 55 APPENDIX E Acute Exposure Guideline Levels for Allylamine Derivation Summary for Allylamine AEGLs (107-11-9) AEGL-1 VALUES 10 min 30 min 1h 4h 8h 0.42 ppm 0.42 ppm 0.42 ppm 0.42 ppm 0.42 ppm Key Reference: Hine, C.H., J.K. Kodama, R.J. Guzman, and G.S. Loquvam. 1960. The toxicity of allylamines. Arch. Environ. Health 1:343-352. Test Species/Strain/Number: Young adult human volunteers (age and sex not speci- fied), 10-14/concentration Exposure Route/Concentrations/Durations: Inhalation; 2.5, 5, or 10 ppm for 5 min; 14 ppm <1 min. Effects: All subjects detected the odor of allylamine. At 2.5, 5, and 10 ppm, respec- tively, there were dose-related increases in the incidence of slight or moderate eye irritation (21%, 15%, 50%), nose irritation (50%, 54%, 100%), and pulmonary dis- comfort (29%, 46%, 50%). The incidence of CNS effects was not dose related. The AEGL-1 point of departure was 1.25 ppm, which was obtained by applying a modi- fying factor of 2 to the lowest effect level of 2.5 ppm, to ensure that effects do not exceed AEGL-1 severity. End point/Concentration/Rationale: Mild sensory irritation or discomfort in humans exposed to 1.25 ppm for 10 min to 8 h. Uncertainty Factors/Rationale: Uncertainty Factors: Total uncertainty factor: 3. Interspecies: Not applicable. Intraspecies: 3; allylamine acts as a contact irritant, and the severity of its effects is not expected to vary greatly among humans. Also, use of a greater uncertainty factor would yield a concentration below 0.2 ppm, which was a no-effect level for workers exposed for up to 4 h (Shell Oil Co. 1992). Modifying Factor: 2; applied because exposure was for only 5 min and it is unclear whether “moderate” irritation or discomfort is comparable to “notable” irritation or discomfort, which exceeds the scope of AEGL-1. Animal to Human Dosimetric Adjustment: None. Time Scaling: None; same AEGL value is adopted for 10 min to 8 h because mild sensory irritation or discomfort is not expected to vary greatly over time. Data Adequacy: Dataset was adequate. A human experimental study was used to develop AEGL-1 values, which are supported by an occupational monitoring study indicating 0.2 ppm was a no-effect level in workers (Shell Oil Co. 1992) and by two mouse RD50 studies (Gagnaire et al. 1989, 1993) from which it is predicted that 0.9 ppm should result in some sensory irritation in humans, whereas 0.09 ppm should cause no sensory irritation (Alarie 1981).

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56 Acute Exposure Guideline Levels AEGL-2 VALUES 10 min 30 min 1h 4h 8h 3.3 ppm 3.3 ppm 3.3 ppm 1.8 ppm 1.2 ppm Key Reference: Hine, C.H., J.K. Ko- Key Reference: Guzman, R.J., G.S. Loqu- dama, R.J. Guzman, and G.S. Loqu- vam, J.K. Kodama, and C.H. Hine. 1961. vam. 1960. The toxicity of allylamines. Myocarditis produced by allylamines. Arch. Environ. Health 1:343-352. Arch. Environ. Health 2:62-73. Test Species/Strain/Sex/Number: Test Species/Strain/Sex/Number: Male Young adult humans (age and sex un- Long-Evans rats; 1-20/group, as shown in specified), 10-14/concentration Table 1-5 of Section 3.1.1. Exposure Route/Concentrations/ Exposure Route/Concentrations/Durations: Durations: Inhalation; exposure to 20-100 ppm for Inhalation; 2.5, 5, or 10 ppm for 5 min; 4-48 h, as shown in Table 1-5 of Section 14 ppm <1 min. 3.1.1. Rats within dose groups were killed for analysis 8 h to 14 days after the start of exposure. Effects: At 2.5, 5, and 10 ppm, respec- Effects: Depending on exposure scenario, tively, there were dose-related in- ranged from no noted cardiovascular effects creases in the incidence of slight or to severe myocardial and/or cardiovascular moderate eye irritation (21%, 15%, lesions; there were several deaths, as shown 50%), nose irritation (50%, 54%, in Table 1-5 of Section 3.1.1. The LOAEL 100%), and pulmonary discomfort for cardiovascular lesions was exposure to (29%, 46%, 50%); the point of depar- 60 ppm for 14 h, and the NOAEL was ex- ture was 10 ppm, which was NOAEL posure to 40 ppm for 16 h. for “intolerable” seen at 14 ppm. End point/Concentration/Rationale: End point/Concentration/Rationale: Expo- Sensory irritation or discomfort in hu- sure to 40 ppm for 16 h was the NOAEL mans and the NOAEL for “intolerable” for cardiovascular lesions. irritation. Uncertainty Factors/Rationale: Uncertainty Factors/Rationale: Total uncertainty factor: 3. Total uncertainty factor: 50. Interspecies: Not applicable. Interspecies: 5; mechanism of toxicity is Intraspecies: 3: Used because similar among several mammalian species allylamine is acting as a contact (and humans), but differences in suscepti- irritant, and the severity of its effects is bility are unknown; 3 yielded values ap- not expected to vary greatly among proaching the NOEL for lethality from humans. pulmonary lesions. Intraspecies: 10; variability of cardiotoxic response among humans is unknown, and potentially sensitive populations exist (dia- betics, persons with congestive heart fail- ure). Modifying Factor: None. Modifying Factor: None. Animal to Human Dosimetric Adjust- Animal to Human Dosimetric Adjustment: ment: None. None. (Continued)

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57 Allylamine AEGL-2 VALUES Continued 10 min 30 min 1h 4h 8h 3.3 ppm 3.3 ppm 3.3 ppm 1.8 ppm 1.2 ppm Time Scaling: Cn × t = k, where n = 1.7 Time Scaling: None, because the de- gree of irritation is expected to remain [n is based on regression analysis of within the scope of AEGL-2 for 60 Guzman et al. (1961) cardiotoxicity data]. min. Data Adequacy: Dataset was limited but adequate. All derived AEGL-2 values were well below 14 ppm, which was “intolerable” to human volunteers (Hine et al. 1960). AEGL-3 VALUES 10 min 30 min 1h 4h 8h 150 ppm 40 ppm 18 ppm 3.5 ppm 2.3 ppm Reference: Hine, C.H., J.K. Kodama, R.J. Guzman, and G.S. Loquvam. 1960. The toxicity of allylamines. Arch. Environ. Health 1:343-352. Test Species/Strain/Sex/Number: Long-Evans rats, five/dose group. Exposure Route/Concentrations/Durations: Inhalation for 1, 4, or 8 h; see below: Effects: All treated rats showed signs of eye and respiratory tract irritation, and some had lacrimation and red nasal discharge. Rats that died had stomachs distended with air, fluid-filled lungs, alveolar hemorrhage, and pulmonary edema. Mortality rates and calculated LC50 and LC01 values are as follows: 1-h exposure 4-h exposure 8-h exposure Concentration Mortality Concentration Mortality Concentration Mortality 1,000 ppm 1/5 133 ppm 0/5 89 ppm 0/5 1,500 ppm 1/5 200 ppm 0/5 133 ppm 0/5 2,250 ppm 3/5 300 ppm 3/5 200 ppm 4/5 3,380 ppm 5/5 450 ppm 5/5 300 ppm 5/5 LC50 = 1933 ppm LC50 = 286 ppm LC50 =177 ppm LC01 = 533 ppm LC01 = 104 ppm LC01 = 69.2 ppm End point/Concentration/Rationale: LC01 values, representing the lethality NOEL, were calculated by probit analysis using 1-, 4-, and 8-h exposure data from the key study. Uncertainty Factors/Rationale: Total uncertainty factor: 30. Uncertainty factors: Total uncertainty factor: 30. Interspecies: 10; to account for the lack of acute toxicity studies with AEGL-3 end points from other species. Intraspecies: 3; steep dose-response (~2-fold increase in concentration caused mor- tality to increase from 0 to 100%) indicates the NOEL for lethality due to direct de- struction of lung tissue is not likely to vary greatly among humans. Modifying Factor: Not applicable. Animal to Human Dosimetric Adjustment: Not applied. Time Scaling: Cn × t = k, where n = 0.85, based on regression analysis of key study. Time scaling was used only for derivation of the 10- and 30-min values, using the 1- h LC01. Data Adequacy: The dataset was limited but adequate. The key rat study was well conducted, and the data were internally consistent.