8
Propylenimine1
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 minutes (min) to 8 hours (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 Managers Mark McClanahan and 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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8 Propylenimine1 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 minutes (min) to 8 hours (h). Three levels—AEGL-1 and AEGL-2, and AEGL-3—will be devel- oped 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 be- lieved that the recommended exposure levels are applicable to the general popu- lation including infants and children, and other individuals who may be suscep- tible. 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 Managers Mark McClanahan and Ernest V. Falke (National Advisory Committee [NAC] on Acute Expo- sure 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 Expo- sure 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). 368

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369 Propylenimine 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 Propylenimine is an aziridine compound used to modify latex surface coating resins to improve adhesion and to modify bonding properties of textiles, paper, and dyes. It is also used in photography, in the pharmaceutical industry, in gelatins, and organic syntheses. Propylenimine is a colorless oily liquid that has an odor similar to that of ammonia. It is flammable and is an explosion haz- ard. Propylenimine is similar in structure and toxicity to ethylenimine. No data were found concerning toxicity or the odor detection threshold for propylenimine in humans. A time-response study conducted in rats and guinea pigs showed that one of six guinea pigs died after exposure to 500 ppm for 60 min and none of the six died after exposure to the same concentration for 30 min. Five of six rats died after exposure to 500 ppm for 240 min and none of the six died after exposure to the same concentration for 120 min. No concentration- response data were available for deriving AEGL values from animal studies. Therefore, a relative potency approach was used to derive AEGL-2 values based on lethality data for propylenimine and ethylenimine. Propylenimine was 4 to 8 times less toxic than ethylenimine depending on the species: 4 or 5 times less toxic to the guinea pig and 8 times less toxic to the rat. Tumors developed at multiple sites in rats treated orally with propylenimine for 28 or 60 weeks; there- fore, IARC classified propylenimine as Group 2B (possibly carcinogenic to hu- mans). Propylenimine is mutagenic in Salmonella and Drosophila.

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370 Acute Exposure Guideline Levels Data are not available for deriving AEGL-1 values for propylenimine; therefore, no AEGL-1 values were recommended. The absence of AEGL-1 val- ues does not imply that exposures below AEGL-2 are without adverse health effects. In addition, data are not available for estimating the level of distinct odor awareness (LOA) for propylenimine. Data consistent with AEGL-2 end points were not available for propylen- imine; therefore, the AEGL-2 values were derived based on a relative toxicity approach in which the inhalation toxicity of propylenimine was compared with that of ethylenimine. A relative potency factor of 5, which is the geometric mean of the three relative toxicity values calculated from the inhalation studies in rats and guinea pigs exposed to the same concentrations and/or durations, was ap- plied to the AEGL-2 values for ethylenimine. Use of the geometric mean is common practice in toxicology when calculating means of values associated with risk assessments or other expressions of comparative toxicity. It is typically used because it does not give excessive weight to extreme values (“outliers”). It draws outliers toward the center of the distribution, decreasing the sensitivity of the parameter to undue influence of the outlier (Gad 2005). The geometric mean was used for the propylenimine AEGL-2 assessment because of the variability in relative potency values between ethyleneimine and propylenimine (relative potencies were 8-fold in a rat study and 4- and 5-fold in two guinea pig studies). The AEGL-2 values for ethylenimine based on a no-observed effect level (NOEL) for extreme respiratory difficulty in guinea pigs were 33, 9.8, 4.6, 1.0, and 0.47 ppm for 10 min, 30 min, 1 h, 4 h, and 8 h, respectively. In addition, a modifying factor of 2 was applied to account for the deficient database for pro- pylenimine. The resulting AEGL values for propylenimine are 83, 25, 12, 2.5, and 1.2 ppm for exposure durations of 10 min, 30 min, 1 h, 4 h, and 8 h, respec- tively. A single exposure of guinea pigs to 500 ppm of propylenimine for 30 min was a no-observed effect level (NOEL) for lethality and this concentration was used as the point of departure for deriving AEGL-3 values. An uncertainty fac- tor of 10 (3 for interspecies sensitivity and 3 for intraspecies variability) was applied to the NOEL for lethality. An interspecies uncertainty factor of 3 was selected because propylenimine is a reactive direct-acting alkylating agent, and the effects of acute toxicity are expected to be confined to the respiratory tract. Propylenimine-induced respiratory tract damage appears to be due to a direct effect of the alkylating agent on the respiratory epithelium; this mechanism is expected to be similar among species. An uncertainty factor of 3 was applied for intraspecies variability because the effects appear to involve direct contact of the eyes or respiratory epithelium with a very reactive alkylating agent and these effects are not expected to differ considerably among members of the popula- tion. Studies have shown that DNA damage is probably the initiating step in a cascade of events leading to cell damage after exposure to alkylating agents, and DNA damage persists in respiratory and systemic organs following inhalation exposure to these agents. This mechanism is not expected to be different among individuals in the population or among various species. Time scaling was based

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371 Propylenimine on the equation, Cn × t = k, where n = 0.91 was derived by probit analysis of LC50 data for guinea pigs exposed to ethylenimine. The AEGL values are sum- marized in Table 8-1. 1. INTRODUCTION Propylenimine is an aziridine compound similar to that of ethylenimine (Ham 1981). Propylenimine is the second most important aziridine, the first be- ing ethylenimine (Ham 1981). Propylenimine is a colorless oily liquid. One source stated that the odor of propylenimine is similar to that of aliphatic amines (fishy) (Trochimowicz et al. 1994), whereas other sources stated that propylen- imine has an odor similar to that of ammonia (Ham 1981; RTECS 2008). Pro- pylenimine is flammable, and it is an explosion hazard (Trochimowicz et al. 1994; HSDB 2006). Propylenimine is used to modify latex surface coating res- ins to improve adhesion, and propylenimine and its derivatives are used to mod- ify bonding properties of textiles, paper, and dyes. It is also used in photogra- phy, in pharmaceutical industries, as an oil additive, in gelatins, and in organic syntheses (IARC 1975; Lewis 1993, Trochimowicz et al. 1994). The data concerning the toxicity of propylenimine are very limited, neces- sitating a relative toxicity approach for deriving AEGL-values. Therefore, the AEGL values derived for ethylenimine served as the basis for deriving AEGLs for propylenimine. The physical and chemical properties of propylenimine are presented in Table 8-2. 2. HUMAN TOXICITY DATA 2.1. Acute Lethality No reports were found on the acute lethality due to exposure to propylen- imine. 2.2. Nonlethal Toxicity No epidemiologic or experimental studies, case reports, or anecdotal data concerning potential nonlethal toxicity, developmental/reproductive toxicity, cancer, or genotoxicity were located in the literature searched. However, the acute toxicity of propylenimine is likely to be similar to that of ethylenimine because of their similar chemical and physical properties. Humans exposed to ethylenimine in air experience skin, eye, and respiratory tract irritation, nausea, vomiting, headache, dizziness, and shortness of breath (Trochimowicz et al. 1994). However, concentrations, exposure durations, and specific routes of ex- posure were not presented in this report.

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372 Acute Exposure Guideline Levels TABLE 8-1 AEGL Values for Propyleniminea,b [ppm (mg/m3)] Classification 10 min 30 min 1 h 4h 8h End Point (Reference) AEGL-1c Not recommendedd (Nondisabling) AEGL-2c 83 25 12 2.5 1.2 NOEL for extreme (Disabling) (200) (58) (28) (5.8) (2.8) respiratory difficulty (Carpenter et al. 1948) AEGL-3c 170 50 23 5.1 2.4 Lethality threshold, (Lethal) (398) (120 ) (54 ) (12) (5.6 ) Carpenter et al. 1948 a AEGL-2 and -3 values do not account for the potential cancer risk due to inhalation exposure to propylenimine. b Effects including death, irritation to eyes, and irritation to the respiratory tract may be delayed until after cessation of exposure. c AEGL values for propylenimine = AEGL for ethylenimine H 5 (relative potency factor) ) 2 (modifying factor). d The absence of AEGL-1 values does not imply that exposures below the AEGL-2 levels are without adverse health effects. TABLE 8-2 Physical and Chemical Data for Propylenimine Parameter Data Reference Chemical Name Propylenimine HSDB 2006 Synonyms 2-Methylaziridine; propylene RTECS 2008 imine; methlyethylenimine CAS Registry No. 75-55-8 RTECS 2008 Chemical Formula C3 H7N RTECS 2008 Molecular Weight 57.11 RTECS 2008 Physical State Colorless oily liquid; colorless Trochimowicz et al. 1994; mobile liquid; water-white Ham 1981; Lewis 1993 liquid Odor Boiling/Freezing Point 66-67 ºC/-65 ºC Ham 1981; Lewis 1993 Density 0.812 at 16/4 ºC Lewis, 1993, HSDB 2006; 0.8039- 0.8070 at 25/25ºC IARC 1975 0.802 at 25/4 ºC Solubility Miscible or soluble in water; Lewis 1993; Trochimowicz et soluble in most organic al. 1994 solvents Vapor Pressure 112 mm Hg at 20.0 ºC Ham 1981 179 mm Hg at 30.0 ºC 269 mm Hg at 39.0 ºC 436 mm Hg at 51.0 ºC 760 mm Hg at 66.0 ºC Vapor Density 2.0 (air = 1) Trochimowicz et al. 1994 1 ppm = 2.34 mg/m3 Conversion NIOSH 2005 a Density of the liquid and the density of water at the temperature indicated.

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373 Propylenimine 2.3. Summary No human toxicity data were available for propylenimine. However, be- cause of its structural and physical and chemical similarity to ethylenimine, pro- pylenimine is expected to cause damage to the eye, respiratory tract, and skin, with onset of effects being delayed depending on the exposure concentration and duration. 3. ANIMAL TOXICITY DATA 3.1. Acute Lethality 3.1.1. Rats Carpenter et al. (1948) exposed groups of six rats (weight range 90-120 g) to 500 ppm of propylenimine for 5, 10, 15, 30, 60, 120, or 240 min; only five rats were exposed for 30 min. Although the report did not state it specifically, the animals were probably observed for 14 days, as was reported for studies with ethylenimine. No mortality occurred in groups exposed ≤120 min. Five of six rats exposed to 500 ppm for 240 min died. Other manifestations of toxicity were not specifically described; nevertheless, the authors stated that toxicity of pro- pylenimine was similar to but only one-eighth as severe as that of ethylenimine. Toxicity of ethylenimine was manifested by extreme respiratory difficulty at all concentrations ≥25 ppm, but only after exposure for at least 3 h at 25 ppm. Pros- tration was observed at 250 ppm (3 h) or 500 ppm (2 h). Death was delayed in all cases with some animals dying more than 10 days after exposure. Gross ex- amination revealed lung congestion and hemorrhage and congestion of all inter- nal organs in animals that died. Microscopic examination of tissues and organs revealed necrosis of the renal tubular epithelium, congested lungs with leakage of fluid and blood into the bronchioles of animals that died. Cloudy swelling was observed in the kidneys of survivors. 3.1.2. Mouse The lethal concentration for propylenimine reported for mice exposed by inhalation was >2 g/m3 (856 ppm) for a 10-min exposure (RTECS 2008). No other details are known. 3.1.3. Guinea pig Groups of six guinea pigs (weight range 250-300 g) were exposed to 500 ppm of propylenimine for 5, 10, 30, 60, 120, or 240 min; only five guinea pigs were exposed for 120 min (Carpenter et al. (1948). Although the investigators did not state specifically, the animals were probably observed for 14 days, the

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374 Acute Exposure Guideline Levels same as reported for studies with ethylenimine. No mortality occurred in groups exposed for 30 min. One of six, three of five, and six of six guinea pigs died after exposure for 60, 120, or 240 min, respectively. Other manifestations of toxicity were not specifically described; nevertheless, the report stated that tox- icity of propylenimine was similar to but only one-fourth as potent as that of ethylenimine. Exposure to ethylenimine caused by extreme respiratory difficulty at all concentrations ≥25 ppm, but only after exposure for at least 3 h at 25 ppm. Prostration was observed after exposure to 250 ppm for 3 h or 500 ppm for 2 h. Deaths of guinea pigs exposed to ethylenimine were delayed in all cases with some animals dying more than 10 days after exposure. Gross examination re- vealed pulmonary congestion and hemorrhage and congestion of all internal organs in animals that died. Microscopic examination of tissues and organs re- vealed necrosis of the renal tubular epithelium, pulmonary congestion with leak- age of fluid and blood into the bronchioles of guinea pigs that died, and cloudy swelling in the kidneys of survivors. 3.2. Nonlethal Toxicity No additional data were available on nonlethal effects of exposure to pro- pylenimine other than discussed above. 3.3. Developmental and Reproductive Toxicity No data were available on potential developmental and reproductive toxic- ity after inhalation exposure to propylenimine in experimental animals. 3.4. Carcinogenicity The overall incidence of malignant tumors was markedly increased in groups of 26 male and 26 female Charles River CD rats (6 weeks of age) admin- istered propylenimine by gavage (Ulland et al. 1971). The animals were admin- istered doses of 20 or 10 mg/kg body weight twice weekly for 28 or 60 weeks, respectively; all animals were killed at week 60. At 20 mg/kg, 28 tumors were found in 22/52 (males and females combined) rats killed after 60 weeks: glio- mas, ear-duct squamous cell carcinomas, intestinal adenocarcinomas, and leu- kemia in males and mammary tumors (primarily adenocarcinomas), gliomas, and miscellaneous tumors in females. At 10 mg/kg, 45 tumors were found in 37/52 rats killed at the end of the treatment period: gliomas, ear-duct squamous cell carcinomas, intestinal adenocarcinomas, leukemia, and miscellaneous tu- mors in males and mammary tumors, gliomas, ear-duct squamous cell carcino- mas, and miscellaneous tumors in females. Six male and six females serving as controls were killed at 61 weeks; one pituitary adenoma was found. IARC (1975, 1999) evaluated the carcinogenicity data for propylenimine and con- cluded that the evidence for carcinogenicity was sufficient in experimental ani-

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375 Propylenimine mals and classified the chemical propylenimine as possibly carcinogenic to hu- mans (Group 2B). 3.5. Genotoxicity Speck and Rosenkranz (1976) demonstrated that propylenimine (1.5 μg/plate) was mutagenic in Salmonella typhimurium strain TA100 incubated under aerobic or anaerobic conditions. Vogel and Nivard (1997) determined that propylenimine was mutagenic in the sex-linked recessive lethal assay using re- pair-deficient Drosophila melanogaster. 3.6. Summary Propylenimine was lethal in rats after exposure to 500 ppm for 240 min, whereas it was lethal in guinea pigs after exposure to 500 ppm for 60, 120, or 240 min. The effects of propylenimine were similar to but less severe than those of ethylenimine. The data were not adequate for calculating LC50 values for ei- ther rats or guinea pigs. Propylenimine administered orally induces malignant tumors at multiple sites in rats exposed for 28 or 60 weeks. IARC (1975) classi- fied propylenimine as Group 2B (possibly carcinogenic to humans) based on sufficient evidence in animals. Propylenimine is genotoxic in a variety of in vitro assay systems, including Salmonella typhimurium and Drosophila. No studies were available on nonlethal, developmental toxicity, or reproductive toxicity in animals. 4. SPECIAL CONSIDERATIONS 4.1. Metabolism, Disposition, and Kinetics No data were available on absorption, tissue distribution, metabolism, or elimination of propylenimine in humans or experimental animals. However, ethylenimine is excreted primarily in urine after intraperitoneal injection of ra- diolabeled compound, with a small percentage eliminated in expired air (Wright and Rowe 1967). Ethylenimine showed a two-compartment elimination pattern; one compartment had a half-time of 16 h and the other had a half-time of 56 days. Tissue distribution showed uptake by all tissues with the greatest uptake (specific activity) in liver followed by cecum, spleen, kidneys, intestines, and bone marrow. Ethylenimine was metabolized to unknown substances primarily by a route that did not involve oxidation. In addition, either the parent com- pound or a metabolite that retained the aziridine ring reacted with tissue compo- nents (Wright and Rowe 1967). Absorption, distribution, and excretion of pro- pylenimine are expected to be qualitatively similar to that of ethylenimine because the two compounds have similar structures, physical/chemical proper- ties, and biological effects.

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376 Acute Exposure Guideline Levels 4.2. Mechanism of Toxicity No data were available on the mechanism of toxicity of propylenimine; however, because of its structural similarity to ethylenimine, propylenimine is likely a reactive alkylating agent, with signs of toxicity being delayed until after exposure is terminated (insidious) depending on the exposure concentration. The mechanism of toxicity of propylenimine is expected to be similar to that of ethylenimine and mustard compounds. 4.3. Structure–Activity Relationship Propylenimine is structurally similar to ethylenimine, and data for ethylen- imine have been summarized (see Chapter 4). Briefly these data showed that exposure of an individual to a high, but unknown concentration of ethylenimine for no more than 5 min caused eye irritation, respiratory tract irritation, saliva- tion, vomiting, breathlessness, pulmonary edema, and death (Gresham and West 1975). Exposure of humans to a nonlethal concentration for 1.5 to 2 h caused clinical signs that were delayed in onset: photophobia, very severe vomiting, and coughing. Clinical observations associated with acute exposure to ethylenimine included fever, conjunctival irritation, evidence of liver inflammation, transitory hemoconcentration, eosinophilia, mild albuminuria, extensive respiratory irrita- tion manifested by decreased respiratory function, and ulceration of the posterior nasal cavity (Weightman and Hoyle 1964). The effects in animals exposed to propylenimine by inhalation are similar to those described for ethylenimine. Morality results and LC50 values for rats and guinea pigs exposed to ethylenimine are presented in Table 8-3. Mice died after exposure to 1170 ppm ethylenimine for 10 min; the LC50 was 2236 ppm for a 10-min exposure (Silver and McGrath 1948). 4.4. Other Relevant Information 4.4.1. Species variability Data were not available to assess the sensitivity of different species ex- posed to propylenimine. However, data for ethylenimine showed very little dif- ference in response between rats and guinea pigs exposed to ethylenimine at similar concentrations and durations of exposure. Mice, rats, and guinea pigs showed the characteristic delayed mortality response after inhalation exposure to ethylenimine, and the clinical signs of toxicity in the three species were similar. Because of the chemical similar structure and physical properties of propylen- imine and ethylenimine, the toxicity of propylenimine is also expected to be similar across species.

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377 Propylenimine TABLE 8-3 Effects of Acute Exposure of Wistar Rats and Guinea Pigs to Ethylenimine Exposure Exposure Mortality LC50a(ppm) Duration (min) Species Concentration (ppm) Response 5 Rat 100 0/6 2558 250 0/6 500 1/6 1000 1/5 4000 4/6 Guinea pig 250 0/6 2906 500 0/6 1000 0/6 4000 4/6 10 Rat 500 2/6 1407 1000 4/6 2000 1/6 4000 5/6 Guinea pig 2000 1/12 2824 4000 6/6 Rat 100 15 0/6 545 250 1/6 500 3/6 1000 5/6 2000 5/6 4000 6/6 Guinea pig 250 0/6 1283 500 0/6 1000 0/6 2000 6/6 30 Rat 500 5/6 Not determined 1000 6/6 2000 5/5 Guinea pig 100 0/6 364 250 0/6 500 5/6 1000 6/6 60 Rat 100 0/6 268 250 2/6 500 6/6 Guinea pig 25 0/12 235 100 1/6 250 2/6 500 6/6 120 Rat 50 0/6 259 100 1/6 250 3/6 (Continued)

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378 Acute Exposure Guideline Levels TABLE 8-3 Continued Exposure Exposure Mortality LC50a(ppm) Duration (min) Species Concentration (ppm) Response Guinea pig 50 0/6 158 100 1/6 250 5/6 500 6/6 240 Rat 25 0/6 58 50 2/5 100 6/6 250 6/6 Guinea pig 10 0/6 45 25 2/5 50 2/6 100 6/6 250 6/6 480 Rat 25 1/6 35 50 5/6 Guinea pig 10 0/6 27 25 2/6 50 6/6 a LC50 values calculated by probit analysis. Source: Carpenter et al. 1948. Reprinted with permission; copyright 1948, American Medical Association. 4.4.2. Susceptible Subpopulations No data are available to assess the toxicity of propylenimine in potentially susceptible subpopulations. 4.4.3. Concentration-Exposure Duration Relationship Data were not available for evaluating the concentration-exposure duration relationship for propylenimine. For ethylenimine, a linear relationship was ob- tained for the log-log plot of LC50 concentration versus exposure duration for rats and guinea pigs. Because propylenimine and ethylenimine have similar chemical structures and activity; the concentration-exposure duration relation- ship is expected to be similar. 4.4.4. Other Data The oral LD50 for propylenimine is 19 mg/kg body weight (12-30 mg/kg) for rats dosed by gavage (Carpenter et al. 1948). The approximate LD50 is 0.043 mL/kg body weight when applied to the skin of guinea pigs and 0.005 mL when instilled in the eye of rabbits (Trochimowicz et al. 1994).

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382 Acute Exposure Guideline Levels shown that DNA damage is probably the initiating step in a cascade of events leading to cell damage (Papirmeister et al. 1985) after exposure to alkylating agents, and DNA damage can persist in respiratory and systemic organs follow- ing inhalation exposure to these agents (Rao et al. 1999). The resulting value was scaled across the relevant exposure durations using the equation: Cn × t = k, where n = 0.91 derived by regression analysis of LC50 data for guinea pigs ex- posed to ethylenimine. AEGL-3 values are presented in Table 8-7. Propylen- imine is carcinogenic to animals exposed by the oral route; IARC (1975, 1999) classified propylenimine as Group 2B (possibly carcinogenic to humans). The AEGL-3 values do not take into consideration the potential carcinogenicity to humans. 8. SUMMARY OF AEGLs 8.1. AEGL Values and Toxicity End Points AEGL values for propylenimine are summarized in Table 8-8. Human data were not available for deriving AEGL values and animal data were avail- able only for AEGL-3 derivation. Data were not available for deriving AEGL-1 values for propylenimine; therefore, no values are recommended. The absence of AEGL-1 values does not imply that exposure below AEGL-2 is without adverse health effects. Data were not available for deriving AEGL-2 values. Propylenimine is structurally and toxicologically similar to ethylenimine, AEGL-2 values were derived based on the relative potency compared with the AEGL values for ethylenimine. The rela- tive potency factor was 5 was applied to the AEGL-2 values for ethylenimine, and then a modifying factor of 2 was applied to account for a limited database on propylenimine. The AEGL-3 values were derived from the concentration (500 ppm) of propylenimine and the longest exposure duration that resulted in no deaths to guinea pigs. Uncertainty factors of 3 each for interspecies differences and 3 for interspecies variability (total = 10) were applied to the no-effect level for mortal- ity. 8.2. Comparison of AEGLs with Other Standards and Criteria The recommended threshold limit value B time-weighted-average (TLV- TWA) for propylenimine is 2 ppm (ACGIH 2000). This value was based on the comparison of toxicity to ethylenimine (TLV-TWA = 0.5 ppm). A skin notation was also recommended because of its similarity to ethylenimine (ACGIH 2000). The IDLH recommended by the National Institute for Occupational Safety and Health (NIOSH 1996) is 100 ppm based on the data of Carpenter et al. (1948,

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383 Propylenimine 1949). The Occupational Safety and Health (29 CFR 1910.1000 [1997]) permis- sible exposure level (PEL) for propylenimine is 2 ppm (5 mg/m3) with a skin designation. Table 8-9 compares existing standards and guidelines with the de- rived AEGL values. No other standards or guidelines have been published for propylenimine. TABLE 8-7 AEGL-3 Values for Propylenimine [ppm (mg/m3)] Chemical 10 min 30 min 1h 4h 8h Propylenimine 170 (398) 50 (120) 23 (54) 5.1 (12) 2.4 (5.6) TABLE 8-8 AEGL Values for Propyleniminea,b [ppm (mg/m3)] Classification 10 min 30 min 1h 4h 8h End Point (Reference) AEGL-1c No data available for deriving AEGL-1 values AEGL-2c 83 25 12 2.5 1.2 NOEL for extreme respiratory (200) (58 ) (28 ) (5.8 ) (2.8) difficulty (Carpenter et al. 1948) AEGL-3c 170 50 23 5.1 2.4 Lethality threshold (398) (120 ) (58) (12 ) (5.6 ) (Carpenter et al. 1948) a AEGL-2 and -3 values do not account for the potential cancer risk due to inhalation of propylenimine. b Effects including death, irritation to eyes, and irritation to the respiratory tract may be delayed until after exposure is terminated. c AEGL values for propylenimine = AEGL for ethylenimine × 5 (relative potency factor) ) 2 (modifying factor). TABLE 8-9 Extant Standards and Guidelines for Propyleneimine Exposure Duration Guideline 10 min 30 min 1h 4h 8h AEGL-1 No values were derived AEGL-2 83 ppm 25 ppm 12 ppm 2.5 ppm 1.2 ppm AEGL-3 170 ppm 50 ppm 23 ppm 5.1 ppm 2.4 ppm IDLH (NIOSH)a NA 500 ppm NA NA NA REL-TWA (NIOSH)b 2 ppm (8-h TWA), skin designation PEL-TWA (NIOSH)b 2 ppm (8-h TWA); skin designation TLV-TWA (ACGIH)c 2 ppm (8-h), skin notation MAK (Germany)d No value (carcinogenicity category 2: shown to cause cancer in animals; skin absorption) MAC (the Netherlands)e 0.63 mg/m3 (8-h) a IDLH (Immediately Dangerous to Life and Health, National Institute of Occupational Safety and Health) (NIOSH 1996) represents the maximum concentration from which one could escape within 30 min without any escape-impairing symptoms, or any irre- versible health effects.

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384 Acute Exposure Guideline Levels b REL-TWA (Recommended Exposure Limits, National Institute of Occupational Safety and Health) (NIOSH 1996) is defined analogous to the ACGIH TLV-TWA. c PEL-TWA (Permissible Exposure Limits - Time Weighted Average, Occupational Health and Safety Administration) (29 CFR 1910.1000 [1997]) is defined analogous to the ACGIH-TLV-TWA, but is for exposures of no more than 10 h/day, 40 h/week. d TLV-STEL (Threshold Limit Value - Short Term Exposure Limit, American Confer- ence of Governmental Industrial Hygienists) (ACGIH 2000) is defined as a 15 min TWA exposure which should not be exceeded at any time during the workday even if the 8-h TWA is within the TLV-TWA. Exposures above the TLV-TWA up to the STEL should not be longer than 15 min and should not occur more than 4 times per day. There should be at least 60 min between successive exposures in this range. e MAK (Maximale Argeitsplatzkonzentration [Maximum Workplace Concentration]) (Deutsche Forschungsgemeinschaft [German Research Association] (DFG 2000) is de- fined analogous to the ACGIH-TLV-TWA. f MAC (Maximaal Aanvaarde Concentratie [Maximal Accepted Concentration]) Dutch Expert Committee for Occupational Standards, The Netherlands) (MSZW 2004) is de- fined analogous to the ACGIH-TLV-TWA. 8.3. Data Quality and Research Needs Numerous data gaps exist concerning toxicity of propylenimine to humans and animals. Human studies are precluded because propylenimine is carcino- genic in animals and is, therefore, a suspect carcinogen in humans. Because the data set for deriving AEGL values for propylenimine was deficient, a relative toxicity approach was used to derive AEGL-2 values for propylenimine. The available data indicate that propylenimine is structurally and toxicologically similar to ethylenimine. Therefore, the relative potency approach was a reason- able approach for deriving the AEGL-2 values for propylenimine. Concentra- tion-response data were not available for propylenimine; therefore, a no-effect level for lethality from a time-response study (rats and guinea pigs were exposed to the same concentration for different time periods) was used to derive the AEGL-3 values. Standard acute inhalation studies for propylenimine would pro- vide definitive data for deriving AEGL-1, -2 and -3 values. A single-exposure carcinogenicity study would provide data for carcinogen risk assessment. 9. REFERENCES ACGIH (American Conference of Governmental Hygienists). 2000. P. 59 in Threshold Limit Values for Chemical Substances and Physical Agents and Biological Expo- sure Indices. American Conference of Governmental Hygienists, Cincinnati, OH. 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. Carpenter, C.P., H.F. Smyth, Jr., and U.C. Pozzani. 1949. The assay of acute vapor toxic- ity, and the grading and interpretation of results on 96 chemical compounds. J. Ind. Hyg. Toxicol. 31(6):343-346.

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385 Propylenimine 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. Gad, S.C. 2005. Basic principles. Pp. 5-20 in Statistics and Experimental Design for Toxicologists and Pharmacologists, 4th Ed. Boca Raton: CRC Press. 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. HSDB (Hazardous Substance Data Bank). 2006. Propylenimine. TOXNET, Specialized Information Services, U.S. National Library of Medicine, Bethesda, MD [online]. Available: http://toxnet.nlm.nih.gov/cgi-bin/sis/search/f?./temp/~1vBki0:1 [accessed Nov. 18, 2008]. IARC (International Agency for Research on Cancer). 1975. 2-Methylaziridine. Pp. 61- 65 in Some Aziridines, N-, S- & O-Mustards and Selenium. IARC Monograph on the Evaluation of the Carcinogenic Risk of Chemicals to Man Vol. 9. Lyon, France: IARC. IARC (International Agency for Research on Cancer). 1999. 2-Methylazaridine. Pp. 1497-1502 in Re-evaluation of Some Organic Chemicals, Hydrazine and Hydro- gen Peroxide (Part 3). IARC Monograph on the Evaluation of Carcinogenic Risk to Humans Vol. 71. Lyon, France: IARC. Lewis, R.J., Jr. 1993. P. 971 in Hawley’s Condensed Chemical Dictionary, 12th Ed. New York: Van Nostrand Reinhold Co. MSZW (Ministerie van Sociale Zaken en Werkgelegenheid). 2004. Nationale MAC-lijst 2004:2-Methylaziridine. Den Haag: SDU Uitgevers [online]. Available: http:// www.lasrook.net/lasrookNL/maclijst2004.htm [accessed Oct. 24, 2008]. 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)- Propylene imine. U.S. Department of Health and Human Services, Centers for Disease Control and Prevention, National Institute of Occupational Safety and Health [online]. Available: http://www.cdc.gov/niosh/idlh/75558.html [accessed Nov. 18, 2008]. NIOSH (National Institute of Occupational Safety and Health). 2005. NIOSH Pocket Guide to Chemical Hazards: Propylene Imine. U.S. Department of Health and Human Services, Centers for Disease Control and Prevention, National Institute of Occupational Safety and Health, Cincinnati, OH. September 2005 [online]. Available: http://www.cdc.gov/niosh/npg/npgd0537.html [accessed Oct. 16, 2008]. NRC (National Research Council). 2003. Sulfur mustard (Agent HD). Pp. 301-383 in Acute Exposure for Selected Airborne Chemicals Vol. 3. Washington, DC: Na- tional 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.

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386 Acute Exposure Guideline Levels 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. 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. Aziridine, 2-methyl. RTECS No. CM8050000. National Institute for Occupational Safety and Health [online]. Available: http://www.cdc.gov/niosh/rtecs/cm7ad550.html [accessed Nov. 18, 2008]. 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. Speck, W.T., and H.S. Rosenkranz. 1976. Mutagenicity of azathioprine. Cancer Res. 36(1):108-109. Trochimowicz, H.J., G.L. Kennedy, Jr., N.D. Krivanek. 1994. Heterocyclic and miscella- neous nitrogen compounds. Pp. 3285-3521 in Patty’s Industrial Hygiene and Toxi- cology, Vol. IIB Toxicology, 4th Ed., G.D. Clayton, and F.E. Clayton, eds. New York: John Wiley & Sons, Inc. Ulland, B., M. Finkelstein, E.K. Weisburger, J.M. Rice, and J.H. Weisburger. 1971. Car- cinogenicity of industrial chemicals propylene imine and propane sultone. Nature 230(5294):460-461. Vogel, E.W., and M.J. Nivard. 1997. The response of germ cells to ethylene oxide, pro- pylene oxide, propylene imine and methyl methanesulfonate is a matter of cell stage-related DNA repair. Environ. Mol. Mutagen. 29(2):124-135. Weightman, J., and J.P. Hoyle. 1964. Accidental exposure to ethylenimine and N- ethylethylenimine vapors. JAMA 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.

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387 Propylenimine APPENDIX A Derivation of AEGL Values for Propylenimine DERIVATION OF AEGL-3 Key Study: Carpenter et al. 1948 Toxicity End Point: Lethality: NOEL for lethality: 500 ppm for 30 min Cn × t = k; n = 0.91 based on regression analysis of the guinea pig Time Scaling: data. C = 500 ppm/10 (uncertainty factor) = 50 ppm Cn × t = k; C = 50 ppm, t = 30 min, n = 0.91 k = 1054.8336 ppm minutes Uncertainty Factors: Total = 10: 3 for interspecies sensitivity, because propylenimine a reactive direct-acting alkylating agent, and the AEGL-2 effects are expected to be confined to the respiratory tract. Respiratory tract damage appears to be due to direct effect of an alkylating agent on the respiratory epithelium; this mechanism is expected to be similar among species. The time of onset of signs and symptoms of exposure on the eyes and respiratory tract is expected to be delayed in both humans and animals. 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 after exposure to alkylating agents, and DNA damage is persistent in respiratory and systemic organs following inhalation exposure to these agents. The alkylating activity of propylenimine is not expected to vary appreciably among individuals in the population Calculations: C = (k/t)1/0.91 = (1054.8 ppm minutes/10 min)1/0.91 = 170 ppm 10-min AEGL-3 C = (k/t)1/0.91 = (1054.8 ppm minutes/30 min)1/0.91 = 50 ppm 30-min AEGL-3 C = (k/t)1/0.91 = (1054.8 ppm minutes/60 min)1/0.91 = 23 ppm 1-h AEGL-3 C = (k/t)1/0.91 = (1054.8 ppm minutes/240 min)1/0.91 = 5.1 ppm 4-h AEGL-3 C = (k/t)1/0.91 = (1054.8 ppm minutes/480min)1/0.91 = 2.4 ppm 8-h AEGL-3

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388 Acute Exposure Guideline Levels APPENDIX B Carcinogenicity Assessment QUANTITATIVE CANCER ASSESSMENT FOR PROPYLENIMINE Only one carcinogenicity study (Ulland et al. 1971) was available for pro- pylenimine. In this study rats were administered propylenimine by gavage at two different doses for different time periods. The study author combined incidences of tumors at different anatomical sites but provided no data indicating that the incidence of each tumor type was related to administration of propylenimine. Therefore, these data are not suitable for a dose-response assessment of pro- pylenimine.

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389 Propylenimine APPENDIX C Derivation Summary of AEGL Values for Propylenimine AEGL-1 VALUES 30 min 1h 4h 8h Not recommended. 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: Not applicable. Interspecies: Not applicable. Intraspecies: Not applicable. Modifying Factor: Not applicable. Animal to Human Dosimetric Adjustment: Not applicable. Time Scaling: Not applicable. Data Quality and Support for AEGL Values: No data are available. AEGL-2 VALUES 10 min 30 min 1h 4h 8h 83 (200) 25 (58) 12 (28) 2.5 (5.8) 1.2 (2.8) 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 (see Chapter 4). Test Species/Strain/Number: Ethylenimine: male guinea pigs, 6 per group. Exposure Route/Concentration/Durations: Ethylenimine: inhalation; 10, 25, 50, 100, or 250 ppm for 240 min. Effects: Ethylenimine: 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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390 Acute Exposure Guideline Levels AEGL-2 VALUES Continued 10 min 30 min 1h 4h 8h 83 (200) 25 (58) 12 (28) 2.5 (5.8) 1.2 (2.8) End Point/Concentration/Rationale: Ethylenimine: No-effect-level for lethality in the guinea pig, 10 ppm exposure for 4 h; effects at 25 ppm and higher were above the definition for AEGL 2. The AEGL-2 values for propylenimine were derived based on the relative potency approach. Ethylenimine is five times more toxic than propylenimine. Uncertainty Factors/Rationale: Ethylenimine 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 the 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. Studies have shown that DNA damage is likely 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: 2 because of a deficient database. Animal to Human Dosimetric Adjustment: 1 Time Scaling: Ethylenimine: 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: No acute toxicity data for propylenimine were available for deriving AEGL-2 values. Therefore, AEGL-2 values for propylenimine were derived by the relative potency method; a relative potency of 5 was selected for propylenimine (based on lethality data, propylenimine was considered to be 5 times less toxic than ethylenimine). The resulting AEGL values were reduced by a factor of 2 because of a deficient database. The AEGL 2 values for ethylenimine were 33, 9.8, 4.6, 1.0, and 0.47 for 30 min, 1 h, 4 h, and 8 h, respectively. AEGL-3 VALUES 10 min 30 min 1h 4h 8h 170 (398) 50 (120) 23 (54) 5.1 (12) 2.4 (5.6) 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: guinea pig/6 per group. Exposure Route/Concentration/Durations: inhalation/500 ppm for 5, 10, 30, 60, 120, or 240 min. Effects: lethality, 1/6, 3/5, 6/6 at 60, 120, and 240 min, respectively; no deaths after exposures ≤30 min. (Continued)

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391 Propylenimine AEGL-3 VALUES Continued 10 min 30 min 1h 4h 8h 170 (398) 50 (120) 23 (54) 5.1 (12) 2.4 (5.6) End Point/Concentration/Rationale: no effect level for lethality Uncertainty Factors/Rationale: Total uncertainty factor: 10 Interspecies: 3 - propylenimine is a reactive direct-acting alkylating agent, and the AEGL-3 effects are expected to be confined to the respiratory tract. Respiratory tract damage appears to be due to the direct effect of an alkylating agent on the respiratory epithelium; this mechanism is expected to be similar among species. The time of onset of signs and symptoms of exposure on the eyes and respiratory tract is expected to be delayed in both humans and animals. Intraspecies: 3 - 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 after exposure to alkylating agents, and DNA damage is persistent in respiratory and systemic organs following inhalation exposure to these agents. Modifying Factor: 1 Animal to Human Dosimetric Adjustment: None applied. Time Scaling: Cn × k = t, where n = 0.91 derived empirically from LC50 data in which guinea pigs were exposed to ethylenimine for times ranging from 5 min to 480 min. Data Adequacy: Very few data were available for deriving AEGL-3 values for propylenimine. A standard acute lethality study has not been conducted for propylenimine; therefore, the time-response study in which rats and guinea pigs were exposed to 500 ppm for different time periods was used to derive AEGL-3 values. The data for the guinea pig showed that this species is more sensitive to propylenimine exposure than the rats; lethality occurred after exposure of guinea pigs to 500 ppm for 60 min and after exposure of rats to 500 ppm for 240 min.

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APPENDIX D 392 Category Plot for Propylenimine Chemical Toxicity - TSD All Data Propylenimine 1000.0 Human - No Effect Human - Discomfort Human - Disabling 100.0 Animal - No Effect Animal - Discomfort ppm Animal - Disabling 10.0 Animal - Some Lethality AEGL-3 AEGL-2 Animal - Lethal AEGL 1.0 0 60 120 180 240 300 360 420 480 Minutes FIGURE D-1 Category plot for propylenimine.