3
Cyclohexylamine1
Acute Exposure Guideline Levels

PREFACE

Under the authority of the Federal Advisory Committee Act (FACA) P.L. 92-463 of 1972, the National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances (NAC/ AEGL Committee) has been established to identify, review and interpret relevant toxicologic and other scientific data and develop 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 min to 8 h. Three levels—AEGL-1, AEGL-2, and AEGL-3—are developed

1

This document was prepared by the AEGL Development Team composed of Sylvia Milanez (Oak Ridge National Laboratory) and Mark McClanahan (National Advisory Committee (NAC) on Acute Exposure Guideline Levels for Hazardous Substances member (Chemical Manager)). The NAC reviewed and revised the document and AEGLs as deemed necessary. Both the document and the AEGL values were then reviewed by the National Research Council (NRC) Subcommittee on Acute Exposure Guideline Levels. The NRC subcommittee concludes 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 guidelines reports (NRC 1993; NRC 2001).



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Acute Exposure Guideline Levels for Selected Airborne Chemicals, Volume 5 3 Cyclohexylamine1 Acute Exposure Guideline Levels PREFACE Under the authority of the Federal Advisory Committee Act (FACA) P.L. 92-463 of 1972, the National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances (NAC/ AEGL Committee) has been established to identify, review and interpret relevant toxicologic and other scientific data and develop 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 min to 8 h. Three levels—AEGL-1, AEGL-2, and AEGL-3—are developed 1 This document was prepared by the AEGL Development Team composed of Sylvia Milanez (Oak Ridge National Laboratory) and Mark McClanahan (National Advisory Committee (NAC) on Acute Exposure Guideline Levels for Hazardous Substances member (Chemical Manager)). The NAC reviewed and revised the document and AEGLs as deemed necessary. Both the document and the AEGL values were then reviewed by the National Research Council (NRC) Subcommittee on Acute Exposure Guideline Levels. The NRC subcommittee concludes 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 guidelines reports (NRC 1993; NRC 2001).

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Acute Exposure Guideline Levels for Selected Airborne Chemicals, Volume 5 for each of five exposure periods (10 and 30 min, 1 h, 4 h, and 8 h) and are distinguished 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 or milligrams per cubic meter [ppm or mg/m3]) of a substance above which it is predicted that the general population, including susceptible individuals, could experience notable discomfort, irritation, or certain asymptomatic, non-sensory 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 susceptible 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 susceptible individuals, could experience life-threatening health effects or death. Airborne concentrations below the AEGL-1 represent exposure levels that could produce mild and progressively increasing but transient and nondisabling odor, taste, and sensory irritation or certain asymptomatic, non-sensory effects. With increasing airborne concentrations above each AEGL, there is a progressive 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 infants, 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 corresponding AEGL. EXECUTIVE SUMMARY Cyclohexylamine is a respiratory, eye, and skin irritant, as well as a strong base (pKa = 10.7) with a fishy, amine odor. It is used primarily for boiler water treatment (corrosion inhibition) as well as organic synthesis of rubber and agricultural chemicals. Occupational exposure to cyclohexylamine has been reported to cause headache, nausea, dizziness, vomiting, eye, nose and throat irritation, and rapid and irregular heart-

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Acute Exposure Guideline Levels for Selected Airborne Chemicals, Volume 5 beat. Acute exposure of animals resulted in extreme mucous membrane irritation, gasping, tremors, clonic muscular spasms, lung hemorrhage, opaque corneas, vascular lesions, and hemolysis. The level of distinct odor awareness (LOA) for cyclohexylamine is 2.0 ppm (see Appendix B for LOA derivation). The 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 the public awareness of the exposure due to odor perception. AEGL-1, AEGL-2, and AEGL-3 values were derived from a study in which Sprague-Dawley rats (5/sex/dose) were exposed for 4 h to 54.2 ppm (Group III) or 567 ppm (Group II) cyclohexylamine vapor, or to a vapor/aerosol combination containing 542 ppm vapor and ~612 mg/m3 aerosol (Group I) (Bio/dynamics, Inc. 1990). This well-conducted study was the most comprehensive of the available acute exposure studies. At 54.2 ppm, rats developed labored breathing, partially closed eyes, and red nasal discharge. Rats exposed to the two higher concentrations also exhibited rales, gasping, dried red facial material, tremors, body weight loss, and ocular lesions (corneal opacity, ulceration). Corneal opacity and ulceration were irreversible in Groups I and II (i.e., still present 3 weeks after exposure), but most other effects were reversible in both Groups I and II or only in Group II. Two Group I rats died and developed alopecia and lesions in the nasal turbinates, lungs, and/or urinary bladder. AEGL-1 values were obtained by dividing 54.2 ppm by a modifying factor of 3, because the effects seen in rats at 54.2 ppm were more severe than prescribed by the AEGL-1 definition. Because mild sensory irritation is not expected to vary greatly over time, the same AEGL value was adopted for exposures of 10 min to 8 h. Uncertainty factors of 3 were applied for interspecies and intraspecies variability, respectively. Mild sensory irritation is not likely to vary greatly among humans or animals, and both human and additional animal data indicate that a greater UF was not warranted. The AEGL-1 is consistent with a study in which chemical workers exposed to 4-10 ppm for an undefined duration (<8 h) reported “no symptoms of any kind” (Watrous and Schulz 1950), but which was inappropriate for AEGL-1 derivation because effects were below AEGL-1 severity criteria. The AEGL-1 values are also consistent with two mouse respiratory irritation studies (Gagnaire et al. 1989; Nielsen and Yamagiwa 1989), from which it is predicted that 2.7 or 5.1 ppm

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Acute Exposure Guideline Levels for Selected Airborne Chemicals, Volume 5 should result in some sensory irritation in humans, whereas 0.27 or 0.51 ppm should cause no sensory irritation (Alarie 1981). AEGL-2 values were based on the Bio/dynamics, Inc. (1990) inhalation exposure of rats to cyclohexylamine for 4 h to 54.2 ppm. The rats had moderate respiratory effects and ocular irritation but no irreversible ocular lesions, consistent with an earlier study in which rats, a rabbit, and guinea pigs exposed to 150 ppm 7 h/day for up to 2 weeks had no eye lesions, but those exposed to 800 ppm had corneal opacity (Watrous and Schulz 1950). Data were not available to determine the concentration-time relationship for cyclohexylamine toxicity. The concentration-time relationship for many irritant and systemically acting vapors and gases may be described by Cn × t = k, where the exponent n ranges from 0.8 to 3.5 (ten Berge et al. 1986). To obtain protective AEGL-2 values, scaling across time was performed using n = 3 to extrapolate to exposure times <4 h (exposure duration in the key study), except for the 10-min values, and n = 1 to extrapolate to exposure times >4 h. The 30-min values were adopted as 10-min values due to unacceptably large uncertainty in extrapolating from ≥4 h to 10 min and to be protective of human health (NRC 2001). A total uncertainty factor of 10 was applied (3 for interspecies variability and 3 for intraspecies variability) because effects seen at 54.2 ppm were clearly reversible, and a larger uncertainty factor yields values at or below the AEGL-1. The AEGL-3 values were based on irreversible ocular lesions and an estimated lethality threshold in rats, from exposure for 4 h to 567 ppm. Data were not available to determine the concentration-time relationship, and scaling across time was performed using the ten Berge et al. (1986) equation Cn × t = k and n = 1 or n = 3, as for the AEGL-2 (NRC 2001). A total uncertainty factor of 30 was used: 10 for interspecies variability because, although tissue destruction caused by a severely corrosive agent is not expected to vary greatly among animals, the dose spacing in the key study failed to delineate the LOAEL for ocular lesions or the threshold for lethality in rats, and the set of animal studies was limited. An intraspecies uncertainty factor of 3 was applied because tissue destruction caused by a severely corrosive agent is not expected to vary greatly among humans; a greater uncertainty factor is not warranted because it yields concentrations comparable to AEGL-2 values in Table 3-1.

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Acute Exposure Guideline Levels for Selected Airborne Chemicals, Volume 5 TABLE 3-1 Summary of AEGL Values for Cyclohexylamine Classification 10 min 30 min 1 h 4 h 8 h End point (Reference) AEGL-1a (Non-disabling) 1.8 ppm (7.3 mg/m3) 1.8 ppm (7.3 mg/m3) 1.8 ppm (7.3 mg/m3) 1.8 ppm (7.3 mg/m3) 1.8 ppm (7.3 mg/m3) Mild sensory and/or ocular irritation in rats (Bio/dynamics, Inc. 1990). AEGL-2 (Disabling) 11 ppm (45 mg/m3) 11 ppm (45 mg/m3) 8.6 ppm (35 mg/m3) 5.4 ppm (22 mg/m3) 2.7 ppm (11 mg/m3) Moderate respiratory effects and ocular irritation; NOAEL for irreversible ocular lesions (Bio/dynamics, Inc. 1990). AEGL-3 (Lethal) 38 ppm (150 mg/m3) 38 ppm (150 mg/m3) 30 ppm (120 mg/m3) 19 ppm (77 mg/m3) 9.5 ppm (39 mg/m3) Lethality threshold and irreversible ocular lesions (Bio/dynamics, Inc. 1990). aReported odor thresholds vary from 2.6 to 110 ppm. 1. INTRODUCTION Cyclohexylamine is a strong base (pKa = 10.6; HSDB 2002) and a flammable liquid. Cyclohexylamine occurs naturally, in the wood of the plant Toddalia asiatica (Tsai et al. 1998). Cyclohexylamine is produced by the catalytic hydrogenation of aniline at elevated temperatures and pressures, by the ammonolysis of cyclohexanol, or by the reduction of nitrocyclohexane (Sandridge and Staley 1978). Its uses include boiler water treatment (corrosion inhibition), synthesis of rubber chemicals, agricultural chemicals, plasticizers, and emulsifying agents (HSDB 2002). In the 1960s, a major use of cyclohexylamine was the production of cyclamate sweeteners for beverages and food products; this practice was banned by the U.S. Food and Drug Administration in 1970 (IARC 1980). U.S. demand for cyclohexylamine was estimated as 25 million lbs for 2002, which included exports up to 5 million pounds per year (HSDB 2002). As of 1994, the U.S. International Trade Commission listed only two U.S. producers, but the amounts produced or sold were not disclosed (USITC 1995).

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Acute Exposure Guideline Levels for Selected Airborne Chemicals, Volume 5 Cyclohexylamine is a respiratory, eye, and skin irritant. The marked corrosive, irritant properties and foul odor generally limit human exposure to airborne cyclohexylamine. Watrous and Schulz (1950) pointed out that “the strong, disagreeable smell of cyclohexylamine, and its intensely bitter taste provide good warning properties.” Reported odor thresholds vary widely, ranging from 2.6 ppm (Amoore and Hautala 1983) to 26-110 ppm (Ruth 1986). Occupational exposure to cyclohexylamine has caused symptoms including headache, nausea, dizziness, vomiting, eye, nose, and throat irritation, and rapid and irregular heartbeat. Acute exposure of animals resulted in extreme mucous membrane irritation, gasping, lung hemorrhage, opaque corneas, tremors, restlessness and clonic spasm of the trunk and paw muscles, hemolysis, and vascular lesions. The primary fate of cyclohexylamine in the atmosphere is reaction with hydroxyl radicals, with a half-life of approximately 1.82 days (EPA 1987). Chemical and physical properties of cyclohexylamine are listed in Table 3-2. TABLE 3-2 Chemical and Physical Data Parameter Value Reference Synonyms Cyclohexanamine, aminocyclohexane, aminohexahydrobenzene, cyclohexylamine, hexahydroaniline, hexahydrobenzenamine IARC 1980 Chemical formula C6H13N Budavari et al. 1996 Molecular weight 99.18 Budavari et al. 1996 CAS Registry Number 108-91-8 IARC 1980 Physical state Liquid IARC 1980 Color Colorless or yellow HSDB 2002 Solubility in water Completely miscible Budavari et al. 1996 Acid ionization constant, pKa 10.6 HSDB 2002 Vapor pressure 8.4 mm Hg at 20°C Eastman Kodak 1984 Vapor density (air = 1) 3.42 Verschueren 1996 Liquid density (water = 1) 0.8647 at 25/25°C Budavari et al. 1996 Melting point −17.7°C Budavari et al. 1996 Boiling point 134.5°C at 760 mm Budavari et al. 1996 Flammability/explosive limits 1.5-9.4% NIOSH 2005 Conversion factors 1 mg/m3 = 0.247ppm; 1ppm = 4.06 mg/m3 Verschueren 1996

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Acute Exposure Guideline Levels for Selected Airborne Chemicals, Volume 5 2. HUMAN TOXICITY DATA 2.1. Acute Lethality No reports of human lethality resulting from acute cyclohexylamine exposure were located. 2.2. Nonlethal Toxicity 2.2.1. Odor Threshold/Odor Awareness The odor detection threshold for cyclohexylamine was reported to be 2.6 ppm by Amoore and Hautala (1983). The value of 2.6 ppm was stated to be the geometric mean of all available literature data (not given), omitting extreme points and duplicate values, although the methods used to obtaining the individual odor thresholds were not described. Another secondary source listed the low and high reported odor detection thresholds for cyclohexylamine of 26 and 110 ppm, respectively (Ruth, 1986). It is possible that the low threshold in the latter source was a typographic error and should have been 2.6 ppm. 2.2.2. Occupational Exposure Watrous and Schulz (1950) described three cases of industrial cyclohexylamine exposure. A 42-year-old chemical operator, exposed for about an hour, noticed a strong, fishy smell, felt lightheaded and became very anxious. Later the same day, he reported loss of appetite, anxiety that prevented his falling asleep, burning in his throat, and a rapid heartbeat. Medical examination the following day revealed no abnormalities although the man still complained of anxiety. Air cyclohexylamine concentrations were not obtained at the time but were measured at a later time (not specified) and found to be 4-10 ppm. The location and number of operators involved were not given, though “this exposure caused no symptoms of any kind in the operators.” In the second case, a 27-year-old operator was splattered on the face with liquid cyclohexylamine dissolved in a caustic solution (not identified). The skin on his face became red and developed many small white spots characteristic of coagulative necrosis. The man became nau-

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Acute Exposure Guideline Levels for Selected Airborne Chemicals, Volume 5 seated and vomited an hour after the accident and twice more later. He had a normal pulse and blood pressure but became drowsy, had slurred speech and widely dilated pupils that responded poorly to light. The next day he apparently recovered except for some facial crusting. The third clinical case described by Watrous and Schulz (1950) was of a supervisor of the process that used cyclohexylamine. He was exposed to cyclohexylamine vapor on several occasions and said that he became nauseated, although he did not vomit (no further details were provided). NIOSH conducted a Health Hazard Evaluation of the Cincinnati Electronics Corp. (Hills and Lushniak 1989; Hills et al. 1990). Employees reported symptoms including headache, rapid and irregular heartbeat, nausea, dizziness, vomiting, and eye, nose and throat irritation that persisted for several hours to several days. They worked in an area humidified by a water boiler to which was added four times the normal amount of a corrosion inhibitor containing cyclohexylamine (and diethylaminoethanol). The odor was described as musty-acrid, ammonia-like, musty radiator, or pungent. Air samples were not collected during the incident. Samples collected by NIOSH several days later (2 h, 0.2 liters/min [LPM]) had cyclohexylamine concentrations below detectable limits (~0.08 ppm), likely due to the six boiler steam purgings and daily addition of clean replacement water to the boiler after the incident prior to the NIOSH investigation. 2.3. Neurotoxicity No descriptions of neurologic involvement other than the case descriptions by Watrous and Schulz (1950) were located. 2.4. Developmental/Reproductive Toxicity There are no confirmed reports of cyclohexylamine-induced reproductive or developmental toxicity in humans. Microgastria, a rare congenital anomaly arising from a defect in embryological development and resulting in effects including asplenia, upper limb hypoplasia, and intestinal malrotation, was reported in a 2.75-year old boy conceived as the result of insemination by donor following Clomid stimulation (Hanson et al. 1990). While this individual was in utero, his mother was ex-

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Acute Exposure Guideline Levels for Selected Airborne Chemicals, Volume 5 posed to cyclohexylamine on pregnancy day 34 or 35. The boy was born a normal size (7.5 lbs) and had a normal karyotype. No details of the cyclohexylamine exposure were given. No causal relationship between the microgastria and cyclohexylamine exposure was asserted by the study authors. 2.5. Genotoxicity Cyclohexylamine did not induce cytogenetic changes (rings, dicentrics, chromatid breaks or aberrations) in human lymphocytes in vitro (Brewen et al. 1971). Cells were exposed at the G0, G1, S, or G2 stages of the cell cycle with up to 500 μg/mL cyclohexylamine. 2.6. Carcinogenicity No epidemiologic studies or case reports of carcinogenicity occurring from cyclohexylamine exposure by any route were located. IARC (1987) and the ACGIH (2004) concluded that there is inadequate evidence in humans and in experimental animals to establish the carcinogenicity of cyclohexylamine. IARC placed cyclohexylamine (with cyclamates) in carcinogenicity Group 3 and the ACGIH placed it in Group A4. The Environmental Protection Agency (EPA) has not provided a carcinogenicity weight-of-evidence classification for cyclohexylamine (EPA 2005). 2.7. Summary Several occupational studies described effects from acute inhalation exposure to unknown air concentrations of cyclohexylamine. Workers reported headache, rapid and irregular heartbeat, nausea, dizziness, vomiting, and eye, nose and throat irritation. Watrous and Schulz (1950) found that exposure during an unspecified fraction of a workday to 4-10 ppm cyclohexylamine “caused no symptoms of any kind,” but there was no indication whether the workers were able to detect the characteristic odor. Widely varying odor detection thresholds were reported for cyclohexylamine in two secondary sources (2.6 ppm and 26-110 ppm). There

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Acute Exposure Guideline Levels for Selected Airborne Chemicals, Volume 5 was no evidence in humans of cyclohexylamine inhalation causing carcinogenicity, reproductive or developmental effects, or genotoxicity. 3. ANIMAL TOXICITY DATA Only a small number of animal studies were located; these used rats, mice, guinea pigs, and rabbits. Unfortunately, most had incomplete reporting of the methods and/or results. The cyclohexylamine inhalation studies are summarized in Table 3-3. 3.1. Acute Lethality 3.1.1. Rats In a 4-h acute inhalation toxicity study conducted by Bio/dynamics, Inc. (1990), Sprague-Dawley rats (5/sex/dose) were administered nominal concentrations of 8.8 (Group I), 6.4 (Group II), or 0.57 mg/L (Group III) cyclohexylamine (determined using the test substance weight and delivered air volume). Exposure was in a 100-L Plexiglas chamber. The analytical concentrations of cyclohexylamine vapor were measured hourly, and for Groups I, II, and III were, respectively, 2.2, 2.3, and 0.22 mg/L (542 ppm, 567 ppm, and 54.2 ppm). The Group I atmosphere also contained cyclohexylamine aerosol (mean of 612 mg/m3 range of 5.5-1,500 mg/m3; mean mass median diameter [MMMD] of 11 μM, measured hourly). The aerosol appeared to have formed by reaction of the vapor with moisture from the animals, since aerosol was not seen during empty chamber trials at the same target concentration. Additional desiccation of the chamber air during exposure of Group II and III animals eliminated all but small amounts of aerosol (Group II: 0.00011-0.59 mg/m3, 12 μM MMMD; Group III: 0.88-54 mg/m3, 2.2 μM MMMD). Rats were observed for 2 weeks (Group III) or 3 weeks (Groups I, II) post exposure and were weighed on days 1 (preceding exposure), 2, 3, 5, 8, 15, and for Groups I and II, also on day 22. Necropsies were performed on all animals (no histopathology was performed). Two Group I rats died on day 2. They had alopecia and nasal, lung, and urinary bladder lesions. Groups I and II rats had dyspnea, gasping, tremors, partly or completely shut eyes, profuse lacrimation, corneal opacity and ulceration, red nasal discharge, dried red or brown stains on

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Acute Exposure Guideline Levels for Selected Airborne Chemicals, Volume 5 TABLE 3-3 Cyclohexylamine Inhalation Exposure Animal Studies Single-Exposure Studies Species Exposure Time Conc. (ppm) Time of Death Mortality Effects, Comments (Reference) Rat 6 h 1,000 (none) 0/3 No death or reported effects   6 h 12,000 48 h 2/3 Death; no other details (Eastman Kodak,1984) Rat 4 h 4,000 (none) 0/6 No death or reported effects   4 h 8,000 ? 6/6 Death; no other reported effects   ≤2 h ~15,000 (none) 0/6 No death, reported effects (Smyth, et al. 1969) Rat 4 h 54.2 (none) 0/10 Lacrimation, red nasal discharge (see Table 3) Corneal lesions, severe respiratory effects   4 h 567 (none) 0/10   4 h >542a Day 2 2/10 As above; 2/10 died (Bio/dynamics, Inc. 1990) Rat Not given 443 (none) LC0 Effects reported but not ascribed to a specific dose or species include irritation of mucous membranes, restlessness, muscle spasm, hemolysis, vascular lesions, organ weight changes. Mice given 2.5 ppm had changes in subthreshold impulse summation. (Lomonova 1965)   (<8 h ?) 1,059 Mainly on days LCLo     1,847 7-14 LC50     2,833   LC100 Mouse not given 2.5, 12.3 (none) LC0     (<8 h ?) 24.6 Mainly on days LCLo       264 1-5 LC50       1,059   LC100   Mouse 15 min 26-84 (none) 0/6 RD50 = 51 ppm (Gagnaire et al. 1989; 1993)   120 min 79-220 (none) 0/6 Tracheally cannulated RD50 = 51 ppm

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Acute Exposure Guideline Levels for Selected Airborne Chemicals, Volume 5 Uncertainty factors: Total Uncertainty Factor: 10 Interspecies: 3—Effects seen at 54.2 ppm were clearly reversible and a larger uncertainty factor yields values at or below the AEGL-1. Intraspecies: 3—Effects seen at 54.2 ppm were clearly reversible and a larger uncertainty factor yields values at or below the AEGL-1. Calculations for 10 and 30 min, and 1 h: Calculations for 4 h: Calculations for 8 h: Derivation of AEGL-3 Key study: Bio/dynamics, Inc. 1990. Rats were exposed for 4 h to 54.2 ppm, 567 ppm or a vapor/aerosol combination (542 ppm vapor + ~612 mg/m3

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Acute Exposure Guideline Levels for Selected Airborne Chemicals, Volume 5   aerosol). At 54.2 ppm, rats had labored breathing, red nasal discharge, ocular irritation. At the two higher doses, rats also displayed rales, gasping, dried red material on the facial area, tremors, weight loss, ocular irritation, and irreversible ocular lesions; 2/10 rats exposed to the aerosol/vapor mix died (had nasal, lung, and urogenital lesions). Toxicity end point: 567 ppm was considered the threshold for lethality and caused irreversible ocular lesions Scaling: Cn × t = k (ten Berge et al. 1986); no data were available to derive n, so used n = 3 to extrapolate to <4 h and n = 1 to extrapolate to >4 h, except the 30-min values were adopted as 10 min values to be protective of human health (NRC 2001; see Section 4.4.3.). Uncertainty factors: Total Uncertainty Factors: 30 Interspecies: 10—Although tissue destruction caused by a severely corrosive agent is not expected to vary greatly among animals, the dose spacing in the key study did not precisely delineate the LOAEL for ocular lesions or the threshold for lethality in rats, and the set of animal studies was limited. Intraspecies: 3—Tissue destruction caused by a severely corrosive agent is not expected to vary greatly among humans; a greater uncertainty factor is not warranted because it yields concentrations comparable to AEGL-2 values. Calculations for 10 and 30 min, and 1 h:

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Acute Exposure Guideline Levels for Selected Airborne Chemicals, Volume 5 Calculations for 4 h: 4 h AEGL-3 = 567/30 = 19 ppm [77 mg/m3] Calculations for 8 h:

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Acute Exposure Guideline Levels for Selected Airborne Chemicals, Volume 5 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 the 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 (OT; stated to be the geometric mean of all available literature data, omitting extreme points and duplicate values; method of obtaining values not stated) of 2.6 ppm was obtained for cyclohexylamine from Amoore and Hautala (1983). The same citation listed an odor detection threshold of 0.83 for n-butanol, as compared to the reference value of 0.04 ppm as the odor threshold provided by van Doorn et al (2002). Based on the differences in n-butanol values from the two sources, an “inter-laboratory” correction factor is applied to 0.83 ppm as follows: The concentration C leading to an odor intensity (I) of distinct odor detection (I=3) is derived using the Fechner function: For the Fechner coefficient, the default of kw = 2.33 will be used due to the lack of chemical-specific data: The resulting concentration is multiplied by an empirical field correction factor. It takes into account that in every day life, factors such as sex, age, sleep, smoking, upper airway infections and allergies, as well as distraction, increase the odor detection threshold by a factor of 4. In addi-

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Acute Exposure Guideline Levels for Selected Airborne Chemicals, Volume 5 tion, it takes into account that odor perception is very fast (about 5 sec) which leads to the perception of concentration peaks. Based on the current knowledge, a factor of 1/3 is applied to adjust for peak exposure. Adjustment for distraction and peak exposure lead to a correction factor of 4/3 = 1.33. The LOA for Cyclohexylamine is 2.0 ppm.

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Acute Exposure Guideline Levels for Selected Airborne Chemicals, Volume 5 APPENDIX C ACUTE EXPOSURE GUIDELINES FOR CYCLOHEXYLAMINE (108-91-8) DERIVATION SUMMARY AEGL-1 VALUES 10 min 30 min 1 h 4 h 8 h 1.8 ppm 1.8 ppm 1.8 ppm 1.8 ppm 1.8 ppm Key Reference: Bio/dynamics, Inc. 1990. An acute inhalation toxicity study of C-1388 in the rat. Final Report. Project no. 89-8214. December 4, 1990. Test Species/Strain/Sex/Number: Sprague-Dawley rats; 5/sex/dose. Exposure Route/Concentrations/Durations: Inhalation for 4 h of 54.2 ppm, 567 ppm, or a vapor/aerosol combination containing 542 ppm vapor and ~612 mg/m3 aerosol. Effects: At 54.2 ppm, rats had labored breathing, red nasal discharge, and partly closed eyes primarily during the 4-h exposure. Rats exposed to 567 ppm or the vapor/aerosol combination had severe respiratory effects and irreversible ocular lesions; 2/10 rats exposed to the aerosol-containing atmosphere died. End point/Concentration/Rationale: Mild respiratory and/or ocular irritation is expected to result from exposure to 18.1 ppm (obtained by dividing 54.2 ppm by the modifying factor of 3). Uncertainty Factors/Rationale: Total uncertainty factor: 10 Interspecies: 3—Mild sensory irritation from an alkaline irritant gas is not likely to vary greatly among animals. Supported by other animal (RD50) data. Intraspecies: 3—Mild sensory irritation from an alkaline irritant gas is not likely to vary greatly among humans. Supported by human (occupational) data. Modifying Factor: 3—Effects seen at 54.2 ppm are more severe than prescribed by the AEGL-1 definition. Animal to Human Dosimetric Adjustment: Not performed.

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Acute Exposure Guideline Levels for Selected Airborne Chemicals, Volume 5 Time Scaling: None; using the same value for 10 min to 8 h was considered appropriate because mild irritant effects do not vary greatly over time. Data Adequacy: The data set was small, but the key study was well-conducted (GLP). The derived AEGL-1 level (and appropriateness of the total UF) is supported by a human study (chemical workers exposed to 4-10 ppm for <8 h reported “no symptoms of any kind”; Watrous and Schulz 1950) and by two mouse respiratory depression (RD50) studies (Gagnaire et al. 1989; Nielsen and Yamagiwa 1989), from which it is predicted that 2.7 or 5.1 ppm should result in some sensory irritation in humans, whereas 0.27 or 0.51 ppm should cause no sensory irritation (Alarie 1981). AEGL-2 VALUES 10 min 30 min 1 h 4 h 8 h 11 ppm 11 ppm 8.6 ppm 5.4 ppm 2.7 ppm Key Reference: Bio/dynamics, Inc. 1990. An acute inhalation toxicity study of C-1388 in the rat. Final Report. Project no. 89-8214. December 4, 1990. Test Species/Strain/Sex/Number: Sprague-Dawley rats; 5/sex/dose. Exposure Route/Concentrations/Durations: Inhalation for 4 h of 54.2 ppm, 567 ppm, or a vapor/aerosol combination containing 542 ppm vapor and ~612 mg/m3 aerosol. Effects: At 54.2 ppm, rats had labored breathing, red nasal discharge, and partly closed eyes primarily during the 4-h exposure. Rats exposed to 567 ppm or the vapor/aerosol combination had severe respiratory effects and irreversible ocular lesions; 2/10 rats exposed to the aerosol-containing atmosphere died. End point/Concentration/Rationale: Exposure to 54.2 ppm for 4 h caused moderate respiratory effects and ocular irritation; is NOAEL for irreversible ocular lesions. Uncertainty Factors/Rationale: Total uncertainty factor: 10 Interspecies: 3—Effects seen at 54.2 ppm were clearly reversible and a larger uncertainty factor yields values at or below the AEGL-1. Intraspecies: 3—Effects seen at 54.2 ppm were clearly reversible and a larger uncertainty factor yields values at or below the AEGL-1. Modifying Factor: none.

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Acute Exposure Guideline Levels for Selected Airborne Chemicals, Volume 5 Animal to Human Dosimetric Adjustment: Not performed. Time Scaling: Cn × t = k (ten Berge et al. 1986); no data were available to derive n, so used n = 3 to extrapolate to <4 h and n = 1 to extrapolate to >4 h, except the 30-min values were adopted as 10-min values to be protective of human health (NRC 2001; see Section 4.4.3.). Data Adequacy: The data set was small but the key study was well-conducted (GLP guidelines used). There were no data to determine the value of n for time scaling. The NOAEL for corneal opacity was supported by another study with several species. AEGL-3 VALUES 10 min 30 min 1 h 4 h 8 h 38 ppm 38 ppm 30 ppm 19 ppm 9.5 ppm Key Reference: Bio/dynamics, Inc. 1990. An acute inhalation toxicity study of C-1388 in the rat. Final Report. Project no. 89-8214. December 4, 1990. Test Species/Strain/Sex/Number: Sprague-Dawley rats; 5/sex/dose Exposure Route/Concentrations/Durations: Inhalation; 4 h; 54.2 ppm, 567 ppm, or a vapor/aerosol combination containing 542 ppm vapor and ~612 mg/m3 aerosol. Effects: At 54.2 ppm, rats had labored breathing, red nasal discharge, and partly closed eyes primarily during the 4-h exposure. Rats exposed to 567 ppm or the vapor/aerosol combination had labored breathing, rales, gasping, dried red material on the facial area, tremors, weight loss, irreversible ocular lesions, and 1/5 males and 1/5 females exposed to the aerosol-containing atmosphere died and had nasal, lung, and urogenital tissue damage. End point/Concentration/Rationale: Exposure to 567 ppm for 4 h caused irreversible ocular lesions and was the lethality threshold. Uncertainty Factors/Rationale: Total uncertainty factor: 30 Interspecies: 10—Although tissue destruction caused by a severely corrosive agent is not expected to vary greatly among animals, the dose spacing in the key study did not precisely delineate the LOAEL for ocular lesions or the threshold for lethality in rats, and the set of animal studies was limited.

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Acute Exposure Guideline Levels for Selected Airborne Chemicals, Volume 5 Intraspecies: 3—Tissue destruction caused by a severely corrosive agent is not expected to vary greatly among humans; a greater uncertainty factor is not warranted because it yields concentrations comparable to AEGL-2 values. Modifying Factor: None. Animal to Human Dosimetric Adjustment: No data. Time Scaling: Cn × t = k (ten Berge et al. 1986); no data were available to derive n, so used n = 3 to extrapolate to <4 h and n = 1 to extrapolate to >4 h, except the 30-min values were adopted as 10-min values to be protective of human health (NRC 2001; see Section 4.4.3.). Data Adequacy: The data set was small but the key study was well-conducted (GLP guidelines used). There were no data to determine the value of n for time scaling. Supporting studies with lethality as an end point were limited.

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Acute Exposure Guideline Levels for Selected Airborne Chemicals, Volume 5 APPENDIX D Category Plot for Cyclohexylamine

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Acute Exposure Guideline Levels for Selected Airborne Chemicals, Volume 5 FIGURE D-1 Chemical toxicity—TSD all data, cyclohexylamine. Note that multiple-exposure studies were input as single exposures.