4
Ethylenimine1
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 (min) to 8 h (h). Three levels—AEGL-1 and AEGL-2, and AEGL-3—will be developed for each of five exposure periods (10 and 30 min, 1 h, 4 h, and 8 h) and will be distinguished by varying degrees of severity of toxic effects. It is believed that the recommended exposure levels are applicable to the general population including infants and children, and other individuals who may be susceptible. The three AEGLs have been 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

1

This document was prepared by the AEGL Development Team composed of Kowetha Davidson (Oak Ridge National Laboratory) and Chemical Manager Ernest V. Falke (National Advisory Committee [NAC] on Acute Exposure Guideline Levels for Hazardous Substances). 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) Committee on Acute Exposure Guideline Levels. The NRC committee 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).



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4 Ethylenimine1 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 Guide- line Levels for Hazardous Substances (NAC/AEGL Committee) has been estab- lished 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 (min) to 8 h (h). Three levels—AEGL-1 and AEGL-2, and AEGL-3—will be developed for each of five exposure periods (10 and 30 min, 1 h, 4 h, and 8 h) and will be distin- guished by varying degrees of severity of toxic effects. It is believed that the recommended exposure levels are applicable to the general population including infants and children, and other individuals who may be susceptible. The three AEGLs have been 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 1 This document was prepared by the AEGL Development Team composed of Kowetha Davidson (Oak Ridge National Laboratory) and Chemical Manager Ernest V. Falke (National Advisory Committee [NAC] on Acute Exposure Guideline Levels for Hazardous Substances). 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) Committee on Acute Exposure Guideline Levels. The NRC committee 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). 186

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187 Ethylenimine 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 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 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 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 idiosyncratic responses, could experi- ence the effects described at concentrations below the corresponding AEGL. SUMMARY Ethylenimine is a volatile, clear, colorless, flammable explosive liquid that has an odor similar to that of ammonia and an odor threshold reported as 2 ppm in air; however an odor detection (OD50) was reported as 0.698. It is a very reac- tive direct-acting alkylating agent, the activity of which is similar to that of ni- trogen and sulfur mustards. It is also very caustic, attacking numerous sub- stances including plastics, metals, and glass that does not contain carbonate or borax. Estimates of annual U.S. production of ethylenimine range between 1.65 and 4.85 million pounds prior to 1994. Ethylenimine is used in the manufacture of products such as triethylenemelamine, paper, textile chemicals, adhesive binders, and petroleum refining chemicals. Ethylenimine is stored in 320-pound cylinders, but shipping quantities are unknown. Relevant data on ethylenimine consisted of only a few case reports in hu- mans and acute inhalation lethality studies in laboratory animals. Toxicity due to exposure to ethylenimine is generally delayed and includes irritation to contact organs (skin, eyes, oral cavity, and upper and lower respiratory tract), systemic toxicity, and death depending upon the concentration. At extremely high con- centrations, however, irritation to contact organs may occur during or soon after exposure. The time course of irritation caused by ethylenimine is different from that caused by primary irritants such as ammonia, which causes an immediate response upon exposure regardless of concentration.

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188 Acute Exposure Guideline Levels One person died after a brief exposure to a high, but unknown concentra- tion of ethylenimine. Soon after exposure he experienced eye irritation, saliva- tion, vomiting, and breathlessness. Pulmonary edema was diagnosed but was not considered the cause of death. Several people exposed to ethylenimine and N- ethylethylenimine for 1½ to 2 h suffered severe eye and respiratory tract irrita- tion and vomiting that were delayed 3 to 7½ h after exposure, followed by hemoconcentration (increased in hemoglobin concentration), eosinophilia, and albuminuria. Occupational exposure to ethylenimine has produced skin sensiti- zation, slow-healing dermatitis, rapidly reversible irritation to the eyes and respi- ratory tract, and blistering, reddening, and edema of the scrotum. Direct contact of liquid ethylenimine with the tongue caused delayed inflammation and edema- tous swelling in the mouth and inflammation of the eyes, and direct contact of liquid ethylenimine with the skin caused necrotizing painless burns. Ethylen- imine is genotoxic in all test systems investigated including bacteria, fungi, plants, insects, and cultured mammalian cells. It is clastogenic in cultured hu- man cells. Repeated subcutaneous injections of rats with ethylenimine produced sarcomas at the injection site, chronic oral administration produced pulmonary and liver tumors in mice, and a single subcutaneous injection of 7-day old mice produced pulmonary tumors. Acute inhalation LC50 values were 2558, 1407, 545, 268, 259, 58, and 35 ppm for rats exposed to ethylenimine for 5, 10, 15, 60, 120, 240, or 480 min, respectively; LC50 values were 2906, 2824, 1283, 364, 235, 158, 45, and 27 ppm for guinea pigs exposed for 5, 10, 15, 30, 60, 120, 240, or 480 min, respectively (Carpenter et al. 1948); and the LC50 value was 2236 ppm for mice exposed for 10 min. In all studies, the time to death and other signs of toxicity were delayed depending on exposure concentration. Signs of toxicity in these animals in- cluded eye irritation, respiratory tract irritation, respiratory difficulty, prostra- tion, complete loss of muscular coordination (mouse only), and convulsions (mouse only). Systemic effects included lung damage, congestion in lungs and all internal organs, damage to the kidney tubules, and albuminuria in rats and guinea pigs. Data were not available for deriving AEGL-1 values for ethylenimine. The absence of AEGL-1 values does not imply that exposure below the AEGL-2 is without adverse health effects. The level of distinct odor awareness (LOA) for ethylenimine is 10.9 ppm. The LOA represents the concentration above which it is predicted that more than one-half the exposed population will experience at least a distinct odor intensity and 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. Ethylen- imine may not have distinct AEGL-1 warning properties. No animal studies designed specifically to examine nonlethal toxicity due to acute inhalation exposure to ethylenimine were located in the search, and the human case report involved exposure to other substances that could have con- tributed to the observed toxic effects. Although the logical point of departure

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189 Ethylenimine (POD) for deriving AEGL-2 values is the no-observed-effect level (NOEL) for extreme respiratory difficulty in guinea pigs exposed to 10 ppm ethylenimine for 480 min (Carpenter et al. 1948), this derivation would lead to AEGL-2 values close to or exceeding the life-threatening AEGL-3 concentrations. Therefore, AEGL-2 values were derived using the next shorter duration of 240 min, which also is a clear NOEL for respiratory difficulty in guinea pigs exposed to 10 ppm. The total uncertainty factor was 10. An uncertainty factor of 3 was applied for interspecies differences, because ethylenimine is a very reactive direct-acting alkylating agent, and the AEGL-2 effects would most likely be confined to the respiratory tract. Respiratory tract damage appears to be due to direct effect of an alkylating agent on the respiratory epithelium, and this mechanism is not ex- pected to be different among species. Humans and animals exhibit delays be- tween the time of exposure and the onset of symptoms, and the eyes and respira- tory tract were the most sensitive targets in rat, guinea pigs, and humans. An uncertainty factor of 3 was applied for intraspecies variability because the ef- fects appear to involve direct contact of the eyes or respiratory epithelium with a very reactive alkylating agent and the alkylating activity is not expected to vary appreciably among individuals in the population. Five male students responded similarly to an exposure to ethylenimine with respect to the time of onset of symptoms and the intensity of effects. Studies have shown that DNA damage is likely the initiating step in a cascade of events leading to cell damage and DNA damage can persist in lungs and systemic organs following inhalation exposure to alkylating agents. This mechanism is unlikely to be different among individu- als in the human population or among species. Scaling across the pertinent time frames was based on the equation C0.91 × t = k, where n = 0.91 was derived from the LC50 data for guinea pigs. The AEGL-2 values do not account for the poten- tial carcinogenicity of ethylenimine, because quantitative data were not available for deriving a unit risk value. AEGL-3 values were based on an acute inhalation study in rats (Carpenter et al. 1948). The LC01 (lethality threshold) of 15 ppm for the 8-h exposure dura- tion was estimated by probit analysis. The 8-h LC01 was selected because it had the smallest standard error. A total uncertainty factor of 10 was applied to the LC01. An uncertainty factor of 3 was applied for interspecies differences based on the same rationale as described for AEGL-2 derivation. In addition, the LC50 values for three test animal species were within a factor of 2 of each other, and like other effects of ethylenimine, death was delayed in all three species. Simi- larly, humans experienced a delay in the onset of life-threatening and/or very serious effects after exposure to ethylenimine. An uncertainty factor of 3, in- stead of the default of 10, was applied for intraspecies variability based on the same rationale described for the AEGL-2 derivation. Scaling across the pertinent time frames was based on the equation C1.1 × t = k, where n = 1.1 was derived from LC50 data for rats. AEGL values derived for ethylenimine are presented in Table 4-1.

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190 Acute Exposure Guideline Levels TABLE 4-1 Summary of AEGL Values for Ethyleniminea,b [ppm (mg/m3)] Classification 10- min 30-min 1-h 4-h 8-h End Point (Reference) Not recommendedc AEGL-1 (Nondisabling) AEGL-2 33 9.8 4.6 1.0 0.47 NOEL for extreme (Disabling) (59) (18) (8.2) (1.8) (0.84 ) respiratory difficulty (Carpenter et al. 1948) AEGL-3 51 19 9.9 2.8 1.5 Threshold for lethality (Lethal) (91) (34) (18) (5.0) (2.7) (Carpenter et al. 1948) a AEGL-2 and -3 values do not account for the potential cancer risk associated with expo- sure to ethylenimine, because quantitative data were not available for deriving a unit risk value. b Effects at these concentrations may be delayed following exposure. c The absence of AEGL-1 values does not imply that exposure below the AEGL-2 is without adverse health effects. 1. INTRODUCTION Ethylenimine is a volatile, clear, colorless, flammable, and explosive liq- uid. It readily polymerizes, and it behaves like a secondary amine (Trochi- mowicz et al. 1994). Ethylenimine is highly caustic, attacking materials such as cork, rubber, many plastics, metals, and glass except those without carbonate or borax (Gresham and West 1975), and it polymerizes explosively on contact with silver, aluminum, or acid (IARC 1999). Ethylenimine has a high vapor pressure; therefore, it readily vaporizes at room temperature. It has a strong ammonia-like odor detectable by humans at 1.5 to 2 ppm (Carpenter et al. 1948, Santodonato 1985). Van Doorn et al. (2002) reported an odor detection (OD50) of 0.698 ppm. Physical and chemical properties of ethylenimine are presented in Table 4-2. Ethylenimine is a direct-acting monofunctional alkylating agent. The alky- lating property is dependent on formation of an ethylenimonium ion, and the free base can be transported across the cell membrane (Ramel 1981). About 91% of ethylenimine is present as the imonium ion at pH 7. The activity of ethylenimine is similar to that of nitrogen and sulfur mustards. Ethylenimine is used as an intermediate in the production of triethylene- melamine; polymerized ethylenimine is used in paper, textile chemicals, adhe- sive binders, petroleum refining chemicals, fuels, lubricants, coating resins, var- nishes, lacquers, agricultural chemicals, cosmetics, ion-exchange resins, photographic chemicals, colloid flocculants, and surfactants (Trochimowicz et al. 1994). In 1964, 750 metric tons (1.65 million pounds) of ethylenimine were being produced annually in the United States and twice that rate was produced by 1978 (Ham 1981). Santodonato (1985) reported production in the United States as greater than 3.3 million pounds in 1978. World production in 1981 was about 12,500 tons (Ham 1981). In 1994, Trochimowicz et al. noted that there was only one domestic producer of ethylenimine, which had a production capac-

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191 Ethylenimine ity of 2.2 million kilograms (4.85 million pounds). Cordova Chemical Co. Mus- kegon, MI produced ethylenimine in the early 1980s, and announced that they would no longer permit shipping of the material off site as of January 1983 (Santodonato 1985), and are no longer producing the chemical (personal com- munication, March 25, 1997). Current producer(s) of ethylenimine are unknown, and no current information on shipping quantities was found in the literature. According to a NIOSH report, ethylenimine is stored in 320-pound cylinders (Ruhe 1982). The database on inhalation exposure to ethylenimine is limited to only a few human case reports and acute inhalation studies in animals. TABLE 4-2 Physical and Chemical Data for Ethylenimine Parameter Data Reference Chemical Name Ethylenimine Synonyms Ethyleneimine, aziridine, dimethylenimine, RTECS 2008 azacyclopropane, azirane, ENT-50324 CAS Reg. No. 151-56-4 RTECS 2008 Chemical Formula C2H5N RTECS 2008 Molecular Weight 43.08 RTECS 2008 Physical State Clear, colorless liquid Lewis 1993 mobile, colorless, very volatile fluid Trochimowicz et al. 1994 Odor Ammonia-like Carpenter et al. 1948 Melting Point -73.96°C O’Neil et al. 2001 -71°C Verschueren 1996 Boiling Point 56 to 57°C at 760 mm Hg O’Neil et al. 2001 55 to 56°C Verschueren 1996 Freezing Point -78°C Lewis 1993 Flash Point -11.1°C Lewis 1993 Density 0.8321 (24°C /4°C) O’Neil et al. 2001 Solubility Completely miscible in water Verschueren 1996 Soluble in alcohol O’Neil et al. 2001 Vapor Pressure 13.3 kPa (100 mm Hg) at 9.7°C Ham 1981 160 mm Hg at 20 °C O’Neil et al. 2001 250 mm Hg at 30°C Verschueren 1996 Vapor density 1.5 Verschueren 1996 Autoignition Temperature 322°C Lewis 1993 Flammability Limits in air 3.6 to 46% Lewis 1993 Explosive limit 3.6% (lower) to 4.6% (upper) Trochimowicz et al. 1994 375 g/m3 at 2°C 567 g/m3 at 30°C Saturated conc. in air Verschueren 1996 Alkalinity Strongly alkaline O’Neil et al. 2001 1 mg/m3 = 0.56 ppm; 1 ppm = 1.79 mg/m3 Conversion Verschueren 1996

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192 Acute Exposure Guideline Levels 2. HUMAN TOXICITY DATA 2.1. Acute Lethality Gresham and West (1975) described an accident in which a 57-year-old man was exposed to ethylenimine vapor for “probably not more than five min- utes” while dispensing the chemical into small containers. He showed signs of eye, nasal, and laryngeal irritation along with salivation, vomiting, and acute breathlessness. Clinical examination revealed that he had pulmonary edema. He required assisted respiration for several weeks and was dismissed from the hos- pital 5 weeks after admission. Three weeks later, he was readmitted to the hospi- tal as his condition suddenly deteriorated as he developed shortness of breath, a wheezy cough, bronchospasm, tracheal ulcerations, and stenosis. He died 2 weeks later (10 weeks after exposure). The autopsy showed collapsed and flabby trachea and bronchi and pulmonary edema. Histopathologic examination showed destruction of the cartilaginous structure of the tracheobronchial tree, i.e. the mucosa was replaced by granulation or occasionally fibrous tissue. Granulomatous polyps were found in the smaller bronchi along with emphysema and bronchopneumonia. There was some debate whether tracheal destruction was a direct effect of inhaling ethylenimine or if it was caused by the extensive delay in granulation resulting from the aggressive steroid therapy in the early stages of treatment. The authors concluded that the tracheal damage was likely due to delayed granulation of the trachea caused by steroid therapy; conse- quently, there was doubt that his death resulted from inhaling ethylenimine. The concentration of ethylenimine to which this worker was exposed was not known, but the severity of the initial symptoms suggested that exposure was intense. 2.2. Nonlethal Toxicity 2.2.1. Odor Threshold Carpenter et al. (1948) reported that 2 ppm was the lowest concentration at which eight subjects detected the odor of ethylenimine upon entering a room. The odor of ethylenimine is described as being similar to that of ammonia; therefore, the odor does not serve as a specific warning for the presence of ethylenimine in the air (Carpenter et al. 1948). The level of distinct odor awareness (LOA) for ethylenimine calculated based on an odor threshold (OT50) of 0.698 ppm and using the guidance pro- vided by van Doorn et al. (2002) is 10.9 ppm. The LOA calculation is presented in Appendix C. 2.2.2. Experimental Studies, Case Reports, and Anecdotal Data Carpenter et al. (1948) reported that eye and nose irritation does not occur in humans exposed to concentrations of ethylenimine vapor less than 100 ppm,

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193 Ethylenimine and that the onset of irritation is not “prompt” at this concentration. [This type of irritation appears to be different from that caused by a primary sensory irritant, which usually occurs immediately upon exposure.] No additional information was provided in this report to support the authors’conclusion. These are the only data reported by Carpenter et al. (1948), and no additional inferences or conclu- sions can be drawn from these data. Exposure to ethylenimine was associated with skin sensitization in two laboratory workers. Severe slow-healing dermatitis of the hand in one worker engaged in production of ethylenimine and conjunctivitis, nasal irritation, and throat irritation that persisted for about 1 day in two or three workers was re- ported by Carpenter et al. (1948). No additional information was provided in this report. In an attempt to force five male college students from a room, they were ex- posed successively to ammonia, isopentane, ethylenimine, and N-ethylethylenimine during a 2- to 3-h period (Weightman and Hoyle 1964). The men were exposed in a 10 × 14-foot ventilated room at a temperature of about 7 to 16°C. They were first exposed to 500 mL of household ammonia and 100 mL of isopentane; the odors were removed with a ventilation fan in about 5 to 10 min. One hour later, they were exposed to 20 g of ethylenimine and 100 g of N- ethylethylenimine. When the men left the room about 12 to 2 h later, they were aware of lacrimation and smarting of the eyes. However, it was not until 3 to 7 h later that symptoms of lacrimation, eye inflammation, photophobia, nausea, vomiting, and inflammation of the respiratory tract caused the men to seek medical attention. Profound hacking cough with normal chest findings devel- oped in the first 12 h. Clinical observations included fever, conjunctival irrita- tion, evidence of liver inflammation, transitory increase in hemoglobin concen- trations up to 20 g, eosinophilia (7 to 13%), mild albuminuria, and extensive respiratory irritation manifested by decreased respiratory (pulmonary) function. Ulceration of the posterior nasal cavity was reported for one student and an ab- normal electrocardiogram was noted in another. The students were released from the hospital within 11 to 25 days. Three students recovered completely in about 3 months, whereas two continued to show residual conjunctival inflamma- tion and reduced respiratory function. The effects experienced by the students cannot be attributed entirely to ethylenimine, because these exposures involved both ethylenimine and N-ethylethylenimine. However, some symptoms (lacri- mation, eye inflammation, photophobia, nausea, vomiting and extreme respira- tory tract irritation) are similar to those described after exposure to sulfur mus- tard, another alkylating agent (ATSDR 2003, NRC 2003). Ammonia causes irritation immediately upon exposure; the delayed onset of irritation to the eyes and respiratory tract of the students suggests that the eye and respiratory tract inflammation was not caused by exposure to ammonia. Isopentane is unlikely to cause damage to the respiratory tract. Concentrations up to 500 ppm are without effect in humans, and the LC50 for isopentane is ex- tremely high for the mouse (1,000,000 mg/m3 = 339,000 ppm) (Cavender 1994). Toxicity information on N-ethylethylenimine could not be found; it is possible

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194 Acute Exposure Guideline Levels that N-ethylethylenimine could be a weak alkylating agent similar to ethylen- imine, and it may have contributed to the effects observed in the students. Five maintenance workers in an ethylenimine plant experienced irritation and swelling of the scrotum after exposure to ethylenimine fumes (vapor) or in one case liquid ethylenimine (Thiess et al. 1971). Symptoms did not become noticeable until several hours after exposure or until the day after exposure. A burning sensation in the scrotal area, reddening and blistering of the scrotal skin, and painful swelling of the scrotum occurred in one worker after liquid ethylen- imine was spilled on his trousers. He recovered within 8 days. The other work- ers who wore protective clothing and respirators experienced no signs or symp- toms suggestive of exposure to the eyes or respiratory tract. Exposure to the scrotal area was believed to have occurred via the bottom opening of the pant legs of the rubber suits, which conducted the vapors like a chimney. One worker experienced superficial erosion and intense reddening of the scrotal area, an- other experienced severe swelling and blister formation on the scrotum, and two experienced “considerable” scrotal swelling. The skin lesions healed within a few days except for one worker who had edema that extended to the penis and preputium and aggravated a preexisting condition. He required surgery (circum- cision) and 4 weeks to recover. The swelling of the scrotum was caused by edema of the scrotal area. The authors noted that spermiogenesis was not af- fected suggesting that the effects were local involving only the skin. Danehy and Pflaum (1938) described a worker who inadvertently spilled one drop (about 50 μL) of ethylenimine on his tongue; he immediately rinsed his mouth with water. Two hours after the incident, vomiting occurred several times at about 30-min intervals followed by inflammation and edema of the epithelium in the mouth and throat, swelling of the uvula, and inflammation of the eyes. The symptoms resolved within 2 days after the incident. Inhalation exposure from this incident was possible, but would have been negligible. Danehy and Pflaum (1938) also reported that vapors (no concentration reported) inhaled for a short period of time (23 min) were “definitely toxic” to humans. 2.2.3. Epidemiologic Studies No epidemiologic studies on the toxicity of ethylenimine were located in the literature searched. 2.3. Developmental and Reproductive Toxicity No developmental or reproductive toxicity studies were located in the available literature.

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195 Ethylenimine 2.4. Carcinogenicity An unconfirmed report noted that no evidence of carcinogenicity was found among 144 ethylenimine workers after 40 years of experience (D.J. Kil- ian, Dow Chemical, personal communication, Oct. 17, 1973). No other informa- tion on the potential carcinogenicity of ethylenimine in humans was located in the available literature. 2.5. Genotoxicity There was no significant increase in chromosome aberrations in leuko- cytes of chemical workers exposed to <0.5 ppm of ethylenimine for a mean of 8 years (Gaeth and Thiess 1972). No other in vivo human genotoxicity data were located in the available literature. Significantly increased frequencies of chromatid breaks/gaps and ex- changes were induced in cultured human embryonic lung fibroblast cells (WI- 38) and in human leukocytes incubated with 10-4 M ethylenimine. Increased frequencies in chromatid breaks/gaps were observed in human fibroblast cells incubated with 10-5 M ethylenimine (Chang and Elequin 1967). 2.6. Occupational Exposure Occupational exposure to ethylenimine can occur during its production or use. Because ethylenimine is a suspect carcinogen, OSHA (29 CFR 1910.1003 [1999]) require that workers be protected against contact with and exposure to ethylenimine; therefore, occupational exposure is expected to be very low. Ruhe (1982) reported air concentrations ranging from 0.01 to 0.03 mg/m3 in an area where workers connect and disconnect ethylenimine cylinders. The air samples were collected by six lapel samplers worn by workers who wore full protective equipment including airline respirators (a type of supply air respirator) while carrying out these operations. The four workers handling the ethylenimine cyl- inders reported no health problems. The exposure to the workers were probably lower than the measured air concentrations. No other data on occupational expo- sure were located in the available literature. 2.7. Summary Although the odor threshold for ethylenimine is reported to be about 2 ppm, there is no specific warning of the presence of ethylenimine in air because the odor is similar to that of ammonia. Because individuals would not be able to distinguish the odor of ammonia and ethylenimine, they would not take steps to

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196 Acute Exposure Guideline Levels avoid or lessen exposure if they thought they were exposed to ammonia. In con- trast to ammonia, eye and respiratory tract inflammation or irritation may not be noticed during the actual exposure to ethylenimine. One human fatality occurred after a brief exposure to a high, but unknown concentration of ethylenimine. Irritation was noticed soon after exposure, probably because of the high exposure concentration. However, it is possible that the cause of death was due to the secondary effects of treatment (steroid therapy) rather than exposure to ethylenimine. Nonlethal effects due to inhalation exposure to ethylenimine are character- ized by irritation or damage to contact organs; the effects are delayed in onset depending on exposure concentration. Severe eye and respiratory tract inflam- mation, photophobia, nausea, vomiting, and coughing may develop several hours after exposure to ammonia, isopentane, ethylenimine, and N-ethylethylen- imine in succession. Hemoconcentration (markedly increased hemoglobin con- centration), eosinophilia, albuminuria, and evidence of liver inflammation were noted during clinical examination. Symptoms following exposure to ammonia or isopentane are different from those described in this report suggesting that these compounds did not cause the observed effects. Skin sensitization, severe slow- healing dermatitis, and rapidly reversible eye and respiratory tract irritation have been associated with occupational exposure to ethylenimine. Direct contact of liquid ethylenimine on the tongue resulted in delayed serious effects on the oral cavity and eyes, and direct contact of liquid on the skin caused necrotizing painless burns. No data were found on the developmental/reproductive toxicity of ethylenimine in humans. Ethylenimine is clastogenic in cultured human cells. An unconfirmed report noted that no evidence of carcinogenicity was found among 144 ethylenimine workers after 40 years of experience (D.J. Kilian, Dow Chemical, personal communication, 1973). Table 4-3 summarizes the lethal and nonlethal effects of ethylenimine in humans. 3. ANIMAL TOXICITY DATA 3.1. Acute Lethality 3.1.1. Rats Carpenter et al. (1948) conducted acute toxicity studies in Wistar rats ex- posed to ethylenimine by inhalation at concentrations ranging from 25 to 4000 ppm and exposure durations ranging from 5 to 480 min (8 h) (see Table 4-3). Each group consisted of five or six male rats. The concentration of ethylenimine in the exposure chamber was not determined analytically, but was verified by delivery rate, total volume of test material delivered, and consistent mortality response with increasing concentration. The age of the rats was not reported, but they weighed between 60 and 180 g at the time of exposure. The animals were

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219 Ethylenimine and Biological Exposure Indices. American Conference of Governmental Indus- trial Hygienists, Cincinnati, OH. ATSDR (Agency for Toxic Substances Disease Registry). 2003. Toxicological Profile for Sulfur Mustard (Update). U.S. Department of Health and Human Services, Public Health Service, Agency for Toxic Substances and Disease Registry, Atlanta, GA [online]. Available: http://www.atsdr.cdc.gov/toxprofiles/tp49.pdf [accessed Oct. 29, 2008]. Axelsen, R.A. 1978. Experimental renal papillary necrosis in the rat: The selective vul- nerability of medullary structures to injury. Virchows. Arch. A Pathol. Anat. His- tol. 381(1):79-84. BRL (Bionetics Research Labs). 1968. Evaluation of Carcinogenic, Teratogenic, and Mutagenic Activities of Selected Pesticides and Industrial Chemicals, Vol. 1. Car- cinogenic Study. NCI-DCCP.CG-1973-1-1. NTIS PB-223-159. Prepared by Bio- netics Research Labs, Bethesda, MD, for the National Cancer Institute, Bethesda, MD. Brockman, H.E., C.Y. Hung, F.J. de Serres, and T.M. Ong. 1981. Mutagenicity of se- lected chemicals in Neurospora Crassa. Pp. 109-138 in Comparative Chemical Mutagenesis, F.J. De Serres, and M.D. Shelby, eds. Environmental Science Re- search Vol. 24. New York: Plenum Press. 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(1):2-6. Cavender, F. 1994. Aliphatic hydrocarbons. Pp. 1221-1266 in Patty’s Industrial Hygiene and Toxicology, Vol. II B, Toxicology, 4th Ed., G.D. Clayton, and F.E. Clayton, eds. New York: John Wiley and Sons. Chang, T.H., and F.T. Elequin. 1967. Induction of chromosome aberrations in cultured human cells by ethylenimine and its relation to cell cycle. Mutat. Res. 4(1):83-89. Danehy, J.P., and D.J. Pflaum. 1938. Toxicity of ethylene imine. Ind. Eng. Chem. 30(7):778. DFG (Deutsche Forschungsgemeinschaft). 2000. List of MAK and BAT Values 2000. Maximum Concentrations and Biological Tolerance Values at the Workplace Re- port No. 36. Weinheim, Federal Republic of Germany: Wiley VCH. Gaeth, V.J., and A.M. Thiess. 1972. Chromosome studies on chemical workers. Zbl. Arbeitsmed. Arbeischutz. 22:357-362 (as cited in Preston et al. 1981). Gresham, G.A., and I.E. West. 1975. Injury and repair of tracheobronchial cartilage fol- lowing accidental exposure to ethyleneimine. J. Clin. Pathol. 28(7):564-567. Ham, G.E. 1981. Imines, cyclic. Pp. 142-166 in Kirk-Othmer Encyclopedia of Chemical Technology, Vol 13, 3rd Ed. New York: John Wiley & Son. Haroun, L., and B.N. Ames. 1981. Mutagenicity of selected chemicals in the Salmo- nella/microsome mutagenicity test. Pp. 27-68 in Comparative Chemical Mutagene- sis, F.J. De Serres, and M.D. Shelby, eds. Environmental Science Research Vol. 24. New York: Plenum Press. Hemminki, K. 1994. DNA adducts of nitrogen mustard and ethylene imines. Pp. 313-321 in DNA Adducts: Identification and Biological Significance, K. Hemminki, A. Dipple, D.E.G. Shuker, F.F. Kadlubar, and H. Bartsch, eds. IARC Scientific Publi- cation No. 125. Lyon, France: International Agency for Research on Cancer. IARC (International Agency for Research on Cancer). 1999. Aziridine. Pp. 337-344 in Re-evaluation of Some Organic Chemicals, Hydrazine and Hydrogen Peroxide, Part II. IARC Monograph on the Evaluation of Carcinogenic Risk to Humans Vol. 71. Lyon, France: International Agency for Research on Cancer.

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220 Acute Exposure Guideline Levels Jackson, H., and R.M.V. James. 1965. Metabolic studies with certain ethyleneimine de- rivatives in relation to diuresis. Br. J. Pharmacol. Chemother. 25(1):223-227. Lewis, R.J., Jr. 1993. Pp. 490-491 in Hawley’s Condensed Chemical Dictionary, 12th Ed. New York: Van Nostrand Reinhold Co. Loprieno, N. 1981. Mutagenicity of selected chemicals in yeast: Mutation-induction at specific loci. Pp. 139-150 in Comparative Chemical Mutagenesis, F.J. De Serres, and M.D. Shelby, eds. Environmental Science Research Vol. 24. New York: Ple- num Press. Malashenko, A.M. 1968. Chemical mutagenesis in laboratory mammals [in Russian]. Sov. Genet. 4:538-543. Malashenko, A.M., and I.K. Egorov. 1968. Induction of dominant lethals in mice by ethylenimine and diethyl sulfate. Sov. Genet. 4:14-18. NIOSH (National Institute of Occupational Safety and Health). 1996. Documentation for Immediately Dangerous to Life or Health Concentrations (IDLH): NIOSH Chemical Listing and Documentation of Revised IDLH Values (as of 3/1/95)- Ethylenimine. U.S. Department of Health and Human Services, Centers for Dis- ease Control and Prevention, National Institute of Occupational Safety and Health [online]. Available: http://www.cdc.gov/niosh/idlh/151564.html [ac- cessed Oct. 30, 2008]. NRC (National Research Council). 2003. Sulfur Mustard (Agent HD). Pp. 301-383 in Acute Exposure Guideline Levels for Selected Airborne Chemicals, Vol. 3. Wash- ington, DC: National Academies Press. NRC (National Resource Council). 2001. Standing Operating Procedures for Developing Acute Exposure Guideline Levels for Hazardous Chemicals. Washington, DC: Na- tional Academy Press. NRC (National Research Council). 1993. Guidelines for Developing Community Emer- gency Exposure Levels for Hazardous Substances. Washington, DC: National Academy Press. O’Neil, M.J., A. Smith, P.E. Heckelman, J.R. Obenchain, Jr., J. Gallipeau, and M.A. D’Arecca. 2001. Ethylenimine. Pp. 676-677 in The Merck Index: An Encyclopedia of Chemicals, Drugs, and Biologicals, 13th Ed. Whitehouse Station, NJ: Merck. Papirmeister, B., C.L. Gross, H.L. Meier, J.P. Petrali, and J.B. Johnson. 1985. Molecular basis for mustard-induced vesication. Fundam. Appl. Toxicol. 5(6 Pt. 2):S134- S149. Pierce, J.O. 1993. Alkaline materials. Pp. 755-782 in Patty’s Industrial Hygiene and Toxicology, Vol. IIA Toxicology, 4th Ed., G.D. Clayton, and F.E. Clayton, eds. New York: John Wiley & Sons. Preston, R.J., I.D. Adler, A. Leonard, and M.F. Lyon. 1981. Mutagenicity of selected chemicals in in vivo cytogenetic assays. Pp. 549-631 in Comparative Chemical Mutagenesis, F.J. De Serres, and M.D. Shelby, eds. Environmental Science Re- search Vol. 24. New York: Plenum Press. Ramel, C. 1981. Comparative mutagenicity of triethylenemelamine, trenimon, and ethylenimine. Pp. 943-976 in Comparative Chemical Mutagenesis, F.J. De Serres, and M.D. Shelby, eds. Environmental Science Research Vol. 24. New York: Ple- num Press. Rao, P.V.L., R. Vijayaraghavan, and A.S. Bhaskar. 1999. Sulphur mustard induced DNA damage in mice after dermal and inhalation exposure. Toxicology 139(1-2):39-51. RTECS (Registry of Toxic Effects of Chemical Substances). 2008. Ethylenimine. RTECS No. KX5075000. National Institute for Occupational Safety and Health

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221 Ethylenimine [online]. Available: http://www.cdc.gov/niosh/rtecs/kx4d7038.html#L [accessed Oct. 31, 2008]. Ruhe, R.L. 1982. Health Hazard Evaluation Report: Hercules, Incorporated, Hopewell, Virginia. HETA 82-287-1240. PB84-172766. National Institute for Occupational Safety and Health, Cincinnati, OH. Santodonato, J. 1985. Monograph on Human Exposure to Chemicals in the Workplace: Aziridine. Final report. SRC TR 84-740. PB86-136587. Prepared by Syracuse Re- search Corporation for the National Cancer Institute, Bethesda, MD. Silver, S.D., and F.P. McGrath. 1948. A comparison of acute toxicities of ethylene imine and ammonia to mice. J. Ind. Hyg. Toxicol. 30(1):7-9. Thiess, A.M., W. Hey, and H.J. Ludewigs. 1971. Case reports on scrotal dermatitis fol- lowing exposure to ethylene imine vapors [in German]. Zentralbl. Arbeitsmed. 21(12):365-368. Todd and Taugher. 1918. Report 246 of the Pharmacological and Toxicological Division of the Chemical Warfare Service (as cited in Silver and McGrath 1948). Trochimowicz, H.J., G.L. Kennedy, Jr., and N.D. Krivanek. 1994. Heterocyclic and mis- cellaneous nitrogen compounds. Pp. 3285-3521 in Patty’s Industrial Hygiene and toxicology, Vol. IIB, Toxicology, 4th Ed., G.D. Clayton, and F.E. Clayton, eds. New York: John Wiley & Sons. van Doorn, R., M. Ruijten and T. Van Harreveld. 2002. Guidance for the Application of Odor in 22 Chemical Emergency Response, Version 2.1, August 29, 2002. Public Health Service of Rotterdam, The Netherlands. Velazquez, A., C. de Nava, R. Coutino, and I. Pulido. 1973. The relationship between gene and chromosome mutations in cultured chinese hamster cells exposed to afla- toxin B1. Mutat. Res. 21(4):241-242. Verschaeve, L., and M. Kirsch-Volders. 1990. Mutagenicity of ethyleneimine. Mutat. Res. 238(1):39-56. Verschueren, K. 1996. Pp. 975-978 in Handbook of Environmental Data on Organic Chemicals, 3rd Ed. New York: van Nostrand Reinhold. Vogel, E., A. Schalet, W.R. Lee, and F. Wuergler. 1981. Mutagenicity of selected chemi- cals in Drosophila. Pp. 175-256 in Comparative Chemical Mutagenesis, F.J. De Serres, and M.D. Shelby, eds. Environmental Science Research Vol. 24. New York: Plenum Press. Walpole, A.L., D.C. Roberts, F.L. Rose, J.A. Hendry, and R.F. Homer. 1954. Cytotoxic agents: IV. The carcinogenic actions of some monofunctional ethyleneimine de- rivatives. Br. J. Pharmacol. Chemother. 9(3):306-323. Watson, A.P., and G.D. Griffin. 1992. Toxicity of vesicant agents scheduled for destruc- tion by the chemical stockpile disposal program. Environ. Health Perspect. 98:259- 280. Weightman, J., and J.P. Hoyle. 1964. Accidental exposure to ethylenimine and N- ethylethylenimine vapors. J. Am. Med. Assoc. 189:543-545. Wright, G.J., and V.K. Rowe. 1967. Ethylenimine: Studies of the distribution and me- tabolism in the rat using carbon-14. Toxicol. Appl. Pharmacol. 11(3):575-584. Zimmermann, F.K. 1981. Mutagenicity of selected chemicals in yeast: Mitotic recombi- nation, gene conversion, and nondisjunction. Pp. 151-174 in Comparative Chemi- cal Mutagenesis, F.J. De Serres, and M.D. Shelby, eds. Environmental Science Re- search Vol. 24. New York: Plenum Press.

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222 Acute Exposure Guideline Levels APPENDIX A Derivation of AEGL Values for Ethylenimine Derivation of AEGL-2 Key study: Carpenter et al. 1948 Toxicity End Point: NOEL for extreme respiratory difficulty; 10 ppm for a 240-min exposure to guinea pigs Cn × t = k; n = 0.91 based on regression analysis of the guinea pig Time Scaling: data C = 10 ppm/10 (uncertainty factor) = 1.0 ppm Cn × t = k; C = 1.0 ppm, t = 240 min, n = 0.91 k = 240 ppm min Uncertainty Factors: Total = 10: 3 for interspecies differences, because ethylenimine is a very reactive direct-acting alkylating agent, and the AEGL-2 effects would be confined to the respiratory tract. Respiratory tract damage appears to be due to direct effect of an alkylating agent on the respiratory epithelium, and this mechanism is not expected to be different among species (NRC 2003). Humans and animals exhibit delays between the time of exposure and the onset of symptoms and the eyes and respiratory tract are the most sensitive targets in both species. 3 for intraspecies variability, because the effects appear to involve direct contact of the eyes or respiratory epithelium with a very reactive alkylating agent. Studies have shown that DNA damage is probably the initiating step in a cascade of events leading to cell damage and DNA damage is persistent in respiratory and systemic organs following inhalation exposure to alkylating agents. Alkylating activity of ethylenimine is not expected to vary appreciably among individuals in the population. Calculations: C = (k/t)1/0.91 = (240 ppm min/10 min)1/0.91 = 33 ppm 10-min AEGL-2 C = (k/t)1/0.91 = (240 ppm min/30 min)1/0.91 = 9.8 ppm 30-min AEGL-2 C =(k/t)1/0.91 = (240 ppm min/60 min)1/0.91 = 4.6 ppm 1-h AEGL-2 C = (k/t)1/0.91 = (240 ppm min/240 min)1/0.91 = 1.0 ppm 4-h AEGL-2 C =(k/t)1/0.91 = (240 ppm min/480 min)1/0.91 = 0.47 ppm 8-h AEGL-2

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223 Ethylenimine Derivation of AEGL-3 Key Study: Carpenter et al. 1948 Toxicity End Point: Threshold for lethality: the LC50 for a 480 min exposure was 35 ppm, the data was extrapolated to a LC01 (15 ppm) Cn × t = k; n = 1.1 based on regression analysis of the rat data Time Scaling: C = 15 ppm/10 (total uncertainty factor) = 1.5 ppm Cn × t = k; C = 1.5 ppm, t = 480 min, n = 1.1 k = 749.7934 ppm min Uncertainty Total = 10: 3 for interspecies differences, because ethylenimine is a Factors: very reactive direct-acting alkylating agent, and the AEGL-2 effects would be confined to the respiratory tract. Respiratory tract damage appears to be due to direct effect of an alkylating agent on the respiratory epithelium, and this mechanism is not expected to be different among species (NRC 2003). Humans and animals exhibit delays between the time of exposure and the onset of symptoms and the eyes and respiratory tract are the most sensitive targets in both species. In addition, the LC50 values for three species are within a factor of 2 and signs of very serious or life-threatening toxicity appear to be similar between animals and humans. 3 for intraspecies variability, because the effects appear to involve direct contact of the eyes or respiratory epithelium with a very reactive alkylating agent. Studies have shown that DNA damage is probably the initiating step in a cascade of events leading to cell damage and DNA damage is persistent in respiratory and systemic organs following inhalation exposure to alkylating agents. Alkylating activity of ethylenimine is not expected to vary appreciably among individuals in the population Calculations: C = (k/t)1/1.1 = (749.7934 ppm min/10 min)1/1.1 = 51 ppm 10-min AEGL-3 C = (k/t)1/1.1 = (749.7934 ppm min/30 min)1/1.1 = 19 ppm 30-min AEGL-3 C = (k/t)1/1.1 = (749.7934 ppm min/60 min)1/1.1 = 9.9 ppm 1-h AEGL-3 C = (k/t)1/1.1 = (749.7934 ppm min/240 min)1/1.1 = 2.8 ppm 4-h AEGL-3 C = (k/t)1/1.1 = (749.7934 ppm min/480 min)1/1.1 = 1.5 ppm 8-h AEGL-3

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224 Acute Exposure Guideline Levels APPENDIX B Quantitative Cancer Assessment for Ethylenimine Two reports were available for assessing the potential carcinogenicity of ethylenimine. In one study, 50% of rats injected subcutaneously with ethylen- imine in arachis oil developed sarcomas at the injection site, whereas no rats injected with arachis oil alone and only 17% injected with ethylenimine in water developed sarcomas (Walpole et al. 1954). The route or exposure for this study precludes deriving a risk value for comparison with AEGL values. Seven-day old male and female mice of two strains given a subcutaneous injection of ethylenimine (4.64 mg/kg body weight) and observed for 80 weeks caused an increase in the incidence of lung tumors in male mice of both strain and in the total incidence of tumors in male mice (BRL 1968). Although this is a single exposure study, it cannot be used to derive risk values for inhalation ex- posure, because the test material was administered subcutaneously. This study shows that ethylenimine can induce a carcinogenic response distant from the application site after only a single dose. In another study, two strains of male and female mice were administered ethylenimine by gavage for 3 weeks followed by ethylenimine in feed for up to 18 months (BRL 1968). All groups exposed to ethylenimine developed neo- plasms (pulmonary adenomas and/or hepatomas) by the end of the study. This study cannot be used to derive risk values because of the lack of an adequate dose term for the mouse. Ethylenimine was administered by gavage at a specific dose (4.64 mg/kg/day) from 7- to 28-days of age followed by administration in feed for up to 18 months at a concentration that delivered the gavage dose. The investigators stated that the concentration of ethylenimine in feed corresponded to the gavage dose, but the actual concentration of ethylenimine in the feed was not reported. The concentration was likely based on body weight and feed con- sumption of a 28-day old mouse, and this concentration was not adjusted during the course of the study to maintain a constant dose. Therefore, because body weight and food consumption change markedly with growth of the mouse, the dose received between day 28 of age until termination of the study also changes markedly and cannot be estimated. Consequently, without an estimate of the dose term, a quantitative assessment cannot be conducted for comparison with AEGL values. Further, only one experimental dose was used in this study, pre- cluding an adequate dose-response assessment.

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225 Ethylenimine APPENDIX C Derivation of the Level of Distinct Odor Awareness (LOA) for Ethylenimine The level of distinct odor awareness (LOA) represents the concentration above which it is predicted that more than one-half of the exposed population will experience at least a distinct odor intensity and about 10% of the population will experience a strong odor intensity. The LOA should help chemical emer- gency 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). The odor detection threshold (OT50) for ethylenimine is 0.6980 ppm (van Doorn et al. 2002). The concentration (C) leading to an odor intensity (I) of dis- tinct odor detection (I=3) is derived using the Fechner function: I = kw × log(C/OT50) + 0.5 For the Fechner coefficient, the default kw = 2.33 will be used because of the lack of chemical specific data: 3 = 2.33 × log (C/0.6980) + 0.5, which can be rearranged to log (C/0.6980) = (3 − 0.5)/2.33 = 1.07, and results in C = (101.07) × 0.6980 = 8.2008 ppm. 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 allergy, as well as 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 seconds), 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. Adjustments for distraction and peak exposure lead to a correction factor of 4/3 = 1.33. LOA = C × 1.33 = 8.20078 ppm × 1.33 = 10.907 (van Doorn et al. 2002) Therefore, the LOA for ethylenimine is 10.907 ppm.

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226 Acute Exposure Guideline Levels APPENDIX D Derivation Summary for Ethylenimine AEGL Values AEGL -1 VALUES 10 min 30 min 1h 4h 8h Not recommended Key Reference: Not applicable. Test Species/Strain/Number: Not applicable. Exposure Route/Concentration/Durations: Not applicable. Effects: Not applicable. End Point/Concentration/Rationale: Not applicable. Uncertainty Factors/Rationale: Not applicable. Total uncertainty factor: Interspecies: Not applicable. Intraspecies: Not applicable. Modifying Factor: Not applicable. Animal to Human Dosimetric Adjustment: Not applicable. Time Scaling: Not applicable. Data Adequacy: Data were not available for deriving AEGL-1 values. AEGL -2 VALUES 10 min 30 min 1h 4h 8h 33 ppm 9.8 ppm 4.6 ppm 1.0 ppm 0.47 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(1):2-6. Test Species/Strain/Number: male guinea pigs, 6 per group Exposure Route/Concentration/Durations: Inhalation; 10, 25, 50, 100, or 250 ppm for 240 min Effects: Guinea pigs were exposed for 240 min. Clinical signs: eye and respiratory irritation, and extreme respiratory difficulty at 25-250 ppm; prostration at 250 ppm; no effects at 10 ppm Gross pathologic effects: congestion and hemorrhage in the lungs, congestion in all internal organs at 25-250 ppm; no effects at 10 ppm Microscopic effects: lung congestion leakage of fluid and red blood cells into bronchioles, tubular necrosis and cloudy swelling in the kidneys at 25-250 ppm; no effects at 10 ppm Mortality: 10 ppm, (0/6), 25 ppm (2/6), 50 ppm (2/6), 100 ppm (6/6), and 250 ppm (6/6) (Continued)

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227 Ethylenimine AEGL -2 VALUES Continued 10 min 30 min 1h 4h 8h 33 ppm 9.8 ppm 4.6 ppm 1.0 ppm 0.47 ppm End Point/Concentration/Rationale: No-effect-level for lethality in the guinea pig: 10 ppm exposure for 4 h; effects at 25 ppm and higher were more severe than those defined for AEGL 2. The logical point of departure (POD) is 10 ppm for 480 min, but this POD would lead to AEGL-2 values close to or exceeding the life-threatening AEGL-3 concentrations. Uncertainty Factors/Rationale: Total uncertainty factor: 10 Interspecies: 3 - Ethylenimine is a very reactive direct-acting alkylating agent, and the AEGL-2 effects would be confined to the respiratory tract. Respiratory tract damage appears to be due to direct effect of an alkylating agent on the respiratory epithelium, and this mechanism is not expected to be different among species. Humans and animals exhibit delays between the time of exposure and the onset of symptoms and the eyes and respiratory tract are the most sensitive targets in both species. Intraspecies: 3 - The effects appear to involve direct contact of the eyes or respiratory epithelium with a very reactive alkylating agent, and the alkylating activity of ethylenimine is not expected to vary appreciably among individuals in the population. Studies have shown that DNA damage is probably the initiating step in a cascade of events leading to cell damage and DNA damage is persistent in respiratory and systemic organs following inhalation exposure to alkylating agents. Modifying Factor: 1 Animal to Human Dosimetric Adjustment: 1 Time Scaling: Cn × k = t, where n = 0.91 derived empirically from guinea pig LC50 data with exposure times ranging from 5 min to 480 min. Data Adequacy: The only studies available for deriving AEGL-2 values were the acute lethality studies in rats and guinea pigs. The AEGL-2 values were, therefore, derived from a no-effect-level for extreme respiratory difficulty determined from the guinea pig study. Ethylenimine has carcinogenic activity; but these values do not take into consideration the potential excess lifetime cancer risk due to a single exposure. AEGL -3 VALUES 10 min 30 min 1h 4h 8h 51 ppm 19 ppm 9.9 ppm 2.8 ppm 1.5 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(1):2-6. Test Species/Strain/Number: Male Wistar rats, 6 per group. Exposure Route/Concentration/Durations: Inhalation, 25 or 50 ppm for 480 min. (Continued)

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228 Acute Exposure Guideline Levels AEGL -3 VALUES Continued 10 min 30 min 1h 4h 8h 51 ppm 19 ppm 9.9 ppm 2.8 ppm 1.5 ppm Effects: Exposure was for 480 min. Effects occurred at both concentrations. Clinical signs: eye and respiratory irritation, and extreme respiratory difficulty Gross pathologic effects: congestion and hemorrhage in the lungs, congestion in all internal organs. Microscopic effects: lung congestion leakage of fluid and red blood cells into bronchioles, tubular necrosis and cloudy swelling in the kidneys. Mortality: 25 ppm (1/6) and 50 ppm (5/6) End Point/Concentration/Rationale: The threshold for lethality in rats exposed for 480 min exposure was 15 ppm (LC01), derived by probit analysis of the data. Uncertainty Factors/Rationale: Total uncertainty factor: 10 Interspecies: 3 - ethylenimine is a very reactive direct-acting alkylating agent, and the AEGL-2 effects would be confined to the respiratory tract. Respiratory tract damage appears to be due to direct effect of an alkylating agent on the respiratory epithelium, and this mechanism is not expected to be different among species. Humans and animals exhibit delays between the time of exposure and the onset of symptoms and the eyes and respiratory tract are the most sensitive targets in both species. In addition, LC50 values for three species did not vary by more than twofold and signs of very serious or life- threatening toxicity appear to be similar between animals and humans. Intraspecies: 3 - the effects appear to involve direct contact of the eyes or respiratory epithelium with a very reactive alkylating agent, and the alkylating activity of ethylenimine is not expected to vary appreciably among individuals in the population. Studies have shown that DNA damage is probably the initiating step in a cascade of events leading to cell damage, and DNA damage is persistent in respiratory and systemic organs following inhalation exposure to alkylating agents. Modifying Factor: 1 Animal to Human Dosimetric Adjustment:1 Time Scaling: Cn × k = t, where n = 1.1 derived empirically from rat LC50 data for exposures from 5 min to 480 min. The 480 min value gave the LC01 with the smallest standard error. All other values were calculated from 480 min. Data Adequacy: Acute lethality studies were available for three laboratory species, two of which were exposed to varying concentration of ethylenimine for duration ranging from 5 to 480 min. The log concentration versus log time plot showed a linear relationship of the LC50 values for the entire range of exposure durations. Therefore, the data set available for deriving AEGL-3 values was robust and it could be extrapolated over the full range of relevant time periods (10 to 480 min). Ethylenimine has potential carcinogenic activity; however, data were not available for deriving cancer risk values. The AEGL values do not take into consideration the potential excess lifetime cancer risk due to a single exposure.

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APPENDIX E Category Plot for Ethylenimine Chemical Toxicity - TSD All Data Ethylenimine 10000.0 Human - No Effect Human - Discomfort 1000.0 Human - Disabling Animal - No Effect 100.0 Animal - Discomfort ppm 10.0 Animal - Disabling AEGL-3 Animal - Some Lethality AEGL-2 1.0 Animal - Lethal AEGL 0.1 0 60 120 180 240 300 360 420 480 Minutes FIGURE E-1 Category plot for ethylenimine. 229