4
Ethylenediamine1
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 for each of five exposure periods (10 and 30 min, 1 h, 4 h, and 8 h) and

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 4 Ethylenediamine1 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 for each of five exposure periods (10 and 30 min, 1 h, 4 h, and 8 h) and 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 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 Ethylenediamine (EDA) is a hygroscopic, flammable liquid and a strong base (pKa1 = 10.7; pKa2 = 7.6). EDA is a high production volume chemical, and is used to stabilize rubber latex, as an inhibitor in anti-freeze solutions, and in the preparation of dyes, insecticides, and fungicides. EDA is an eye, mucous membrane, and respiratory irritant and a known respiratory and skin sensitizer. Occupational inhalation exposure

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Acute Exposure Guideline Levels for Selected Airborne Chemicals, Volume 5 has resulted in an asthmatic response (rhinitis, coughing, wheezing, shortness of breath, and bronchospasm). EDA-sensitized individuals may experience more severe and/or different effects at a given exposure concentration or duration than nonsensitized people. The qualitative and quantitative differences in the response of the two groups to EDA are undefined. The derived AEGL values are for a once-in-a lifetime exposure and do not consider previous sensitization. The level of distinct odor awareness (LOA) for EDA is 2.1 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 values were not recommended due to insufficient data. Absence of AEGL-1 values does not imply that exposure to concentrations below the AEGL-2 is without adverse effects. AEGL-2 values were based on a study in which rats and guinea pigs (6/group) were exposed to approximately 484 ppm EDA (1,000 ppm nominal) for 30 min to 8 h. Both species exposed for 8 h had bronchiolar edema of unspecified severity and “light cloudy swelling of the kidney” (Carpenter et al., 1948). [The same laboratory showed in another study that the analytical concentration was approximately 50% of the nominal concentration, 1,000 ppm nominal corresponding to 484 ppm analytical (Pozzani and Carpenter 1954).] This was the only single-exposure study adequate for AEGL-2 derivation. No data were available to determine the concentration-time relationship for EDA toxic effects. The concentration-time relationship for many irritant and systemically acting vapors and gases was described by ten Berge et al. (1986) with the equation Cn × t = k, where the exponent n ranged from 1 to 3 for 90% of the chemicals examined. To obtain AEGL-2 values, scaling from 8 h to 30, 60, and 240 min was performed using n = 3. The 30-min value was adopted as the 10-min value because scaling from 8 h to 10 min was associated with unacceptably large uncertainty. An uncertainty factor of 3 was used for interspecies variability because a similar response was seen in two species, and a modifying factor of 3 was used because the key study did not specify the severity of the bronchiolar edema. An intraspecies uncertainty factor of 10 was applied because the data were insufficient to determine the mode of lung and kidney lesions (or which was the more

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Acute Exposure Guideline Levels for Selected Airborne Chemicals, Volume 5 sensitive end point) in the key study and consequently the potential variability of the human response to EDA. The AEGL-2 values are supported by a study in which 1/26 rats had unspecified lesions but no mortality after 30 exposures to 132 ppm EDA for 7 h/day (Pozzani and Carpenter, 1954). AEGL-3 values were derived from a range-finding test (Smyth et al. 1951) in which 0/6 rats died from exposure for 8 h to ~1,000 ppm but 6/6 died from 8-h exposure to ~2,000 ppm (stated as 2000 ppm and 4,000 ppm nominal, respectively; analytical estimates based on Pozzani and Carpenter 1954). Toxic effects (other than death) were not described, and 1,000 ppm was considered to be the lethality threshold. This was the only single-exposure study adequate for AEGL-3 derivation. Data were not available to determine the concentration-time relationship, and scaling across time was performed using the equation Cn × t = k and n = 3, as was done for AEGL-2. A total uncertainty factor of 100 was applied: 10 for interspecies variability (cause of death was undefined and there were no studies using other species) and 10 for intraspecies variability (lack of toxicity data in key study precludes definition of the mode or variability of the toxic response in humans). Target organs (liver and kidneys) were identified in a study where rats received 225 ppm EDA 7 h/day for up to 30 days (first deaths on exposure day 4), although the mode of toxicity was unclear (Pozzani and Carpenter 1954). The values appear in Table 4-1. TABLE 4-1 Summary of AEGL Values for Ethylenediamine Classification 10 min 30 min 1 h 4 h 8 h End point (Reference) AEGL-1a (Nondisabling) Not recommended due to insufficient AEGL-2data. (Disabling) 12 ppm (30 mg/m3) 12 ppm (30 mg/m3) 9.7 ppm (24 mg/m3) 6.1 ppm (15 mg/m3) 4.8 ppm (12 mg/m3) Bronchiolar edema, kidney swelling (Carpenter et al. 1948) AEGL-3 (Lethal) 25 ppm (62 mg/m3) 25 ppm (62 mg/m3) 20 ppm (49 mg/m3) 13 ppm (32 mg/m3) 10 ppm (25 mg/m3) Lethality threshold (Smyth et al. 1951)

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Acute Exposure Guideline Levels for Selected Airborne Chemicals, Volume 5 1. INTRODUCTION Ethylenediamine (EDA) is a very basic, hygroscopic and fuming liquid (25% solution has a pH of 11.9 at 25°C; pKa1 = 10.7; pKa2 = 7.6). It has a low flash point (93°F; open cup) and is very flammable (Benya and Harbison 1994). EDA vapor is an eye, mucous membrane, and respiratory irritant and a well-known respiratory and skin sensitizer (Beard and Noe 1981). EDA liquid is corrosive and produces chemical burns in the skin and eyes (Carpenter and Smyth 1946; Smyth et al. 1951). The EDA odor threshold has been reported as 1.0 ppm (Verschueren 1996; Amoore and Hautala 1983) and 1-11 ppm (Ruth 1986). Occupational inhalation exposure has resulted in both immediate and delayed asthmatic symptoms including rhinitis, coughing, wheezing, shortness of breath, and bronchospasm. In animal studies, EDA vapor caused hair loss and lung, kidney, and liver damage. EDA is used to stabilize rubber latex, as an inhibitor in antifreeze solutions, as a pharmaceutic aid (aminophylline stabilizer), in the preparation of dyes, synthetic resins, insecticides, carbamate fungicides, and asphalt wetting agents (HSDB 2005). EDA vapor readily absorbs CO2 from the air to form a non-volatile carbonate (Budavari et al. 1996). EDA is manufactured mainly by reacting ethylene chloride with aqueous or liquid ammonia at about 100°C (HSDB 2005). EDA use in chemical synthesis is in closed systems (Cary et al. 1999). EDA is a high production volume chemical: U.S. production was >58 million pounds in 1993 (HSDB 2005). Some of the chemical and physical properties of EDA are listed in Table 4-2. 2. HUMAN TOXICITY DATA 2.1. Acute Lethality A 36-year-old worker in France was accidentally splashed on the chest with EDA liquid and also breathed in EDA vapors for a “few minutes” (Niveau and Painchaux 1973). The exposure concentration was not determined. The man quickly removed his clothes and washed up but, nevertheless, 4 h after exposure had red-brown generalized erythema, anuria, tachycardia (up to 100/min), and symptoms of hemolysis: increased blood potassium (275 mg/L), and lowered RBC count (5.16 × 106/mm3). Twelve hours after exposure, the man had elevated body tem-

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Acute Exposure Guideline Levels for Selected Airborne Chemicals, Volume 5 TABLE 4-2 Chemical and Physical Data Parameter Value Reference Synonyms 1,2-ethanediamine; 1,2-diaminoethane Budavari et al. 1996 Chemical formula C2H8N2 Budavari et al. 1996 Molecular weight 60.10 Budavari et al. 1996 CAS Registry Number 107-15-3 Benya and Harbison 1994 Physical state Thick liquid Budavari et al. 1996 Color Colorless, clear Budavari et al. 1996 Solubility in water Freely soluble, forming a hydrate Budavari et al. 1996 Acid ionization constant, pKa pKa1 = 10.7; pKa2 = 7.6 HSDB 2005 Vapor pressure 10.7 mm Hg at 20°C Parmeggiani 1983   10 mm Hg at 21.5°C Benya and Harbison 1994   12.1 mm Hg at 25°C HSDB 2005 Vapor density (air = 1) 2.07 Benya and Harbison 1994 Liquid density (water = 1) 0.898 at 25°C Budavari et al. 1996 Melting point 8.5°C Benya and Harbison 1994 Boiling point 116-117°C at 760 mm Budavari et al. 1996 Flammability/explosive limits 2.5-12% (at 212°F) NIOSH 2005a Conversion factors 1 mg/m3 = 0.407 ppm; 1 ppm = 2.46 mg/m3 Benya and Harbison 1994 perature (39°C) and pulse (120/min), coughing with expectoration, abdominal cramps, diarrhea, blackish vomiting, and anuria resulting in an increased blood urea (0.8 g/L). His condition continued to worsen and he died from cardiac collapse 55 h after exposure. 2.2. Nonlethal Toxicity Studies were conducted with EDA-sensitized and non-sensitized individuals. In many cases there was incomplete information about the actual EDA exposure concentration or time that elicited the human responses. Studies in which quantitative data were provided for air EDA concentration and/or exposure duration are summarized in Table 4-3. Several secondary sources (Cary et al. 1999; IPCS 2005) list effects potentially caused in humans by EDA inhalation as irritation of the respiratory tract (a burning sensation, cough, dyspnea, a sore throat), lung edema, and an asthmatic response. It is noted that symptoms of lung edema often do not become manifest until a few hours after exposure,

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Acute Exposure Guideline Levels for Selected Airborne Chemicals, Volume 5 TABLE 4-3 Summary of Quantitative Human Ethylenediamine (EDA) Inhalation Studies Exposure Concentration Exposure Time End Point Reference 1.0-11 ppm Unknown Odor threshold Hellman and Small 1974a 100 ppm 5-10 sec Inoffensive Pozzani and Carpenter 1954 200 ppm 5-10 sec Slight tingling of face and nasal mucosa 400 ppm 5-10 sec Intolerably irritating to nasal mucosa   0.4 ppm Not specified (≤8 h) Background maximal concentration; effects on workers were not addressed. Hansen et al. 1984 <1 to >10 ppm <8 h Asthmatic symptoms in 38 EDA-sensitized workers Aldrich et al. 1987 Unknown (TLV=10 ppm) 20 min Delayed (2.5-4 h) asthmatic symptoms in 2 sensitized workers from workplace exposure Nakazawa and Matsui 1990 30 ppm 15 min Severe asthmatic reaction 3 and 12 h after exposure of sensitized worker (24-33% ↓ in FEV1) Ng et al. 1991 Not stated; in area had 4.8, 10.5 ppm <8 h Cough, phlegm, wheezing in 12 sensitized workers; diurnal expiratory flow rate variation Ng et al. 1995 0.804 mg/m3 (vapor/aerosol) 1 min Irritation threshold for the most“sensitive” individuals tested. Dubinina et al. 1997 aSame values were reported in Amoore and Hautala 1983, Verschueren 1996, and Ruth 1986.

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Acute Exposure Guideline Levels for Selected Airborne Chemicals, Volume 5 and may mask an asthmatic reaction. However, neither source cites specific studies from which this information was obtained. Cary et al. (1999) conclude that there is insufficient data to define the dose-response for an EDA-induced asthmatic response or an exposure level “without adverse effect.” 2.2.1. Odor Threshold/Odor Awareness The odor detection threshold for ethylenediamine was reported to be 1.0 ppm and the 50% and 100% odor recognition thresholds were given as 3.4 ppm and 11.2 ppm, respectively by Hellman and Small (1974). The same values were listed subsequently by Amoore and Hautala (1983), Verschueren (1996), and Ruth (1986). The latter also listed the odor detection threshold as 1-11 ppm and the human irritation threshold alternately as 250 and 500 mg/m3 (102 and 204 ppm). Union Carbide Corp. (1971) reported that “workers will not stay in concentrations of 2,000 ppm.” 2.2.2. Occupational Exposure Four laboratory personnel intentionally sniffed 100, 200, or 400 ppm EDA vapor for 5-10 sec (Pozzani and Carpenter 1954). It was not specified if these were nominal or analytical concentrations or how the test atmospheres were generated, although in another experiment described in the same study (rat 7-h exposure), EDA atmospheres were generated using liquid EDA and an evaporator. The test subjects indicated that 100 ppm was inoffensive, 200 ppm caused a slight tingling sensation in the face and slight irritation of the nasal mucosa, and 400 ppm was intolerably irritating to the nasal mucosa. Air EDA concentration in a Swedish petrochemical plant producing amines in a closed system was 0.4 ppm “only at a site for tanking” (Hansen et al. 1984). The number of samplings was not specified; presumably all other samples were below practical limits of detection (~0.04 ppm for same volume collected by impinger sampling method and analyzed by isotachophoreis). Air monitoring data was conducted in a manufacturing plant where 38/337 employees who worked with EDA became sensitized: they had rhinitis, coughing, and wheezing that cleared after removal from EDA

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Acute Exposure Guideline Levels for Selected Airborne Chemicals, Volume 5 exposure (Aldrich et al. 1987). EDA concentrations eliciting the worker responses were not provided. The vast majority of the 1,053 EDA monitoring measurements were <1 ppm (actual data were not given). The exposure period before sensitization occurred was shortest in current smokers (7.0 months) and longest for employees with no previous symptoms (37.3 months). Coater machine operators had the greatest incidence of EDA sensitization (14/54). Aldrich et al. (1987) concluded that “increased risk of EDA sensitization might be expected when workplace air concentrations of EDA exceed 1 ppm” and that perhaps the present 10 ppm EDA TLV should be reconsidered. Nakazawa and Matsui (1990) described two cases of occupational exposure to EDA in a Japanese chemical factory. An 18-year-old man with a history of urticaria and a 37-year-old man with a history of rhinitis developed symptoms of asthma after 4 and 7 months, respectively, of exposure to unspecified concentrations of EDA (Japanese workplace limits for EDA were 10 ppm at the time). Provocative exposure tests were done on these two men when they were symptom-free: they went to work as usual and after 20 min of exposure to EDA their reactions were monitored. Wheeze and rhonchi were audible in their lungs 2.5-4 h after the 20-min exposure, and both men had ~20-40% decreased FEV1 (forced expiratory volume in 1 sec) approximately 4 h after exposure. The 18-year-old additionally had cough, wheezing, and chronic dyspnea for ~7 days, and the 37-year-old man had additional symptoms 10-18 h after exposure. A non-sensitized subject did not develop any of these symptoms upon similar EDA exposure. Upon transfer to a new work environment, neither patient showed any asthmatic symptoms. Both men had elevated peripheral blood IgE antibodies to EDA but IgG and plasma histamine levels were unaffected. A 31-year-old non-smoking male chemical worker in Singapore without a history of asthma developed symptoms of bronchial asthma (frequent coughing, wheezing, and breathlessness) after approximately 3 months of EDA vapor exposure (Ng et al. 1991). He was also exposed to lesser amounts of other amines and organic chemicals. Measurement of his peak expiratory flow every 3 h while awake over 2 weeks showed reduced flow rates in the late mornings and afternoons (~17-24% lower FEV1), except on Saturdays and Sundays. In a bronchial provocation test, the worker inhaled 30 ppm EDA for 15 min from a respirator. He had no effects immediately after exposure, but 3 h later his peak flow rate fell by about 24% below baseline and he had chest tightness. Twelve hours after exposure, he had a severe bout of coughing, wheezing, and breathless-

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Acute Exposure Guideline Levels for Selected Airborne Chemicals, Volume 5 ness and his peak flow rate fell another 10%. (He was administered nebulized Ventolin and his peak flow improved.) A histamine challenge test (not described) showed he had a high degree of non-specific bronchial hyperreactivity. His chest x-ray and eosinophil counts were normal. His asthmatic attacks became less frequent and severe when he reduced his EDA exposure. Twelve men who worked in a Singapore factory manufacturing polyamide resin for a mean of 2.5 years and were exposed primarily to EDA vapor (also to other polyamines and organics) reported significantly more frequent symptoms of chronic cough, chronic phlegm, wheezing, and exertional breathlessness than unexposed workers (Ng et al. 1995). The EDA air concentration and exposure duration that elicited the stated symptoms were not specified. EDA analytical air concentrations of 10.5 and 4.8 ppm were measured in two air samples taken in areas where EDA was manually handled. The four workers who developed wheezing after beginning work at the factory had significantly greater diurnal variation in peak expiratory flow rates than the control group (DV-PEFR; measured every 3 waking hours for a week) but the FEV1, FVC, and FEV/FVC were unaffected. Dubinina et al. (1997) determined that the irritation threshold for a 1-min exposure in humans was 0.804 mg/m3 for the most sensitive individuals tested (not stated whether these were EDA-sensitized workers). The EDA vapor concentration is unknown because it was administered as a mixture of vapor and aerosol. Several other studies lacked sufficient EDA exposure information but provided useful descriptions of the effects of EDA exposure on humans. A 30-year-old male photography chemical mixer with late-onset asthma challenged for 15 min with an unknown concentration of EDA vapor developed asthmatic symptoms 4 h later (Lam and Chan-Yeung 1980). He had chest tightness, coughing, wheezing, and a 26% decrease in the FEV1 for 24 h after exposure. Results of a skin test (prick or intradermal with 1:100 EDA) were negative for immediate or type III reaction and precipitating antibodies to EDA were not found (Ouchterlony method). Plasma histamine levels in venous blood were not increased during bronchoconstriction. Dernehl (1951) and Lewinsohn and Ott (1991) examined medical records of approximately 200 workers exposed primarily to ethylene amines at a large chemical company (1947-1983). The concentration of EDA in the air was not reported. The employees had eye, skin, and respiratory symptoms, the latter consisting of rhinitis, congestion, coughing, wheezing, and dyspnea. The workers’ pulmonary

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Acute Exposure Guideline Levels for Selected Airborne Chemicals, Volume 5 function (FEV1 and FVC) was not related to EDA exposure duration or sensitization status after accounting for height, age, race, cigarette smoking, and examination date. Symptoms resolved in workers transferred from the amines unit. Grant (1986) reported that industrial exposure to EDA vapors for several hours at concentrations too low to cause discomfort or disability (exposure undefined) caused reversible edema of the corneal epithelium that was generally painless and caused colored halos to be seen around lights. Popa et al. (1969) found that 4/6 workers with EDA-induced bronchial asthma (no prior history of respiratory ailments) had bronchoconstriction immediately following a 5-min challenge with nebulized EDA. The EDA exposure concentration was 2 to 10-fold below concentrations that were non-irritating to control (non-sensitized) asthmatics, although no actual EDA concentrations were reported. The four workers had a 62% reduction in the FEV1 and a 44% increase in respiratory resistance compared to non-sensitized asthmatic controls when examined 30 or 60 min after exposure, a positive Prausnitz-Kustner IgE test, and eosinophilia in the sputum but no precipitating antibodies to EDA. The other two workers had dyspnea 1-2 h after exposure but all inhalation and immunological tests were negative. None of the workers reacted to common allergens, indicating that EDA induced a state of hypersensitivity in the airways that was specific to EDA. 2.3. Neurotoxicity No human neurotoxicity studies were located for EDA exposure by any route. 2.4. Developmental/Reproductive Toxicity No human developmental or reproductive EDA studies were found. 2.5. Genotoxicity No human genotoxicity data were located.

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Acute Exposure Guideline Levels for Selected Airborne Chemicals, Volume 5 APPENDIX A Derivation of AEGL Values Derivation of AEGL-1 AEGL-1 values are not recommended due to insufficient data. Absence of AEGL-1 values does not imply that exposure to concentrations below the AEGL-2 is without adverse effects. Derivation of AEGL-2 Key study: Carpenter et al. 1948. Rats and guinea pigs (6/group) were exposed for 30 min to 8 h to approximately 484 ppm EDA (1,000 ppm nominal). Rats exposed for 8 h had bronchiolar edema of unspecified severity and “light cloudy swelling of the kidney.” Toxicity end point: Bronchiolar edema and kidney swelling. (Note that EDA-sensitized individuals may experience more severe effects at a given exposure concentration and/or duration.) Scaling: Cn × t = k (ten Berge et al. 1986); no data were available to derive n; used n = 3 to extrapolate to <8 h to obtain protective AEGL values, except the 30-min value was adopted as the 10-min value because extrapolating from 8 h to 10 min is associated with unacceptably large inherent uncertainty. Total uncertainty factor: 30 Interspecies: 3: A similar response was seen in two species in the key study. Intraspecies: 10: Data were insufficient to determine the mode of lung and kidney lesions (or which was the more sensitive end point)

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Acute Exposure Guideline Levels for Selected Airborne Chemicals, Volume 5 in the key study and consequently the potential variability of the human response to EDA. Modifying factor: 3: The key study did not specify the severity of the bronchiolar edema. Calculations for <8 h: Calculations for 8 h: Derivation of AEGL-3 Key study: Smyth et al. (1951). No rats (0/6) died after an 8-h exposure to 1,000 ppm (2,000 ppm nominal) but 6/6 died at 2,000 ppm (4,000 ppm nominal). Toxic effects (other than death) were not described. Toxicity end point: Lethality threshold at 1,000 ppm. (Note that EDA-sensitized individuals may experience more severe effects at a given exposure concentration and/or duration.)

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Acute Exposure Guideline Levels for Selected Airborne Chemicals, Volume 5 Scaling: Cn × t = k (ten Berge et al. 1986); no data were available to derive n; used n = 3 to extrapolate to <8 h to obtain protective AEGL values, except the 30-min value was adopted as the 10-min value because extrapolating from 8 h to 10 min is associated with unacceptably large inherent uncertainty. Total uncertainty factor: 100 Interspecies: 10: The cause of death was not defined in the key study, and there were no supporting data with AEGL-3 end points from other species. Intraspecies: 10: Lack of toxicity data in key study precludes definition of the mode or variability of the toxic response in humans. Calculations for <8 h: Calculations for 8 h: 8-h AEGL-3 = 1,000 ppm / 100 = 10 ppm [25 mg/m3]

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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 (OT50, i.e., concentration at which 50% of the odor panel observed an odor without necessarily recognizing it) of 1.0 ppm was obtained for EDA from Hellman and Small (1974). The same citation listed an OT50 of 0.30 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 EDA 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 EDA is 2.1 ppm.

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Acute Exposure Guideline Levels for Selected Airborne Chemicals, Volume 5 APPENDIX C ACUTE EXPOSURE GUIDELINES FOR ETHYLENEDIAMINE (107-15-3) DERIVATION SUMMARY AEGL-1 VALUES 10 min 30 min 1 h 4 h 8 h Not recommended due to insufficient data. Key Reference: Not applicable. Test Species/Strain/Number: Not applicable. Exposure Route/Concentrations/Durations: Not applicable. Effects: Not applicable. End point/Concentration/Rationale: Not applicable. Uncertainty Factors/Rationale: Total uncertainty factor: Not applicable. Interspecies: Intraspecies: Modifying Factor: Not applicable. Animal to Human Dosimetric Adjustment: Not applicable. Time Scaling: Not applicable. Data Adequacy: AEGL-1 values were not recommended because none of the available human or animal data were considered adequate. Absence of AEGL-1 values does not imply that exposure to concentrations below the AEGL-2 is without adverse effects. AEGL-2 VALUES 10 min 30 min 1 h 4 h 8 h 12 ppm 12 ppm 9.7 ppm 6.1 ppm 4.8 ppm Key Reference: Carpenter, C.P., H.F. Smyth, Jr., and C.B. Shaffer. 1948. The acute toxicity of ethylene imine to small animals. J. Ind. Hyg. Toxicol. 30: 2-6. Test Species/Strain/Sex/Number: Rats and guinea pigs, 6/group, sex unspecified. Exposure Route/Concentrations/Durations: Rats and guinea pigs were exposed to 0 or to approximately 484 ppm EDA (1,000 ppm nominal) for 1/2, 1, 2, 4, or 8 h.

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Acute Exposure Guideline Levels for Selected Airborne Chemicals, Volume 5 Effects: Animals exposed for 8 h had bronchiolar edema of unspecified severity and “light cloudy swelling of the kidney” but none died. Effects for shorter exposure durations were not specified. End point/Concentration/Rationale: Bronchiolar edema and kidney swelling from 8-h exposure to approximately 484 ppm EDA. Note that persons previously sensitized to EDA may experience more severe effects at a given exposure concentration and/or duration. Uncertainty Factors/Rationale: Total uncertainty factor: 30 Interspecies: 3: A similar response was seen in two species in the key study. Intraspecies: 10: Data were insufficient to determine the mode of lung and kidney lesions and consequently the potential variability of the human response to EDA. Modifying Factor: 3: The key study did not specify the severity of the organ lesions. Animal to Human Dosimetric Adjustment: Not performed. Time Scaling: Cn × t = k; no data were available to derive n, so used n = 3 to extrapolate to <8 h to obtain protective AEGL values, 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: Key study tested only one EDA concentration but at a number of time intervals. AEGL values are supported by a study in which 1/26 rats had unspecified lesions after 30 exposures of 7 h/day but none died (Pozzani and Carpenter, 1954). AEGL-3 VALUES 10 min 30 min 1 h 4 h 8 h 25 ppm 25 ppm 20 ppm 13 ppm 10 ppm Key Reference: Smyth, H.F., C.P. Carpenter, and C.S. Weil. 1951. Range-finding toxicity data: List IV. AMA Arch. Ind. Hyg. Occup. Med. 4: 119-122. Test Species/Strain/Sex/Number: Sprague-Dawley rats; 6/concentration (sex not specified). Exposure Route/Concentrations/Duration: Inhalation for 8 h to ~1,000 ppm (2,000 ppm nominal). Effects: Death was the only stated effect: 0/6 deaths at 2,000 ppm; 6/6 deaths at 4,000 ppm.

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Acute Exposure Guideline Levels for Selected Airborne Chemicals, Volume 5 End point/Concentration/Rationale: 1,000 ppm (2,000 ppm nominal) is the estimated lethality threshold for an 8-h exposure in rats. Note that EDA-sensitized persons may experience more severe and/or different effects at a given exposure concentration and/or duration. Uncertainty Factors/Rationale: Total uncertainty factor: 100 Interspecies: 10: The cause of death was not defined in the key study, and there were no supporting data with AEGL-3 end points from other species. Intraspecies: 10: Lack of toxicity data in key study precludes definition of the mode or variability of the toxic response in humans. Modifying Factor: None. Animal to Human Dosimetric Adjustment: Not performed. Time Scaling: Cn × t = k; no data were available to derive n, so used n = 3 to extrapolate to <8 h to obtain protective AEGL values, 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: Key study lacked a description of toxic effects other than death. An uncertainty factor of 100 is intended to account for the lack of supporting data from other species and an unknown mode of toxicity. Target organs (liver and kidneys) are identified in another rat study in which fractional mortality resulted from 30 exposures of 7 h/day to 225 ppm (first deaths on exposure day 4; Pozzani and Carpenter, 1954).

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

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Acute Exposure Guideline Levels for Selected Airborne Chemicals, Volume 5 FIGURE D-1 Chemical Toxicity—TSD all data, ethylenediamine