5
Crotonaldehyde, trans and cis + trans1
Acute Exposure Guideline Levels

PREFACE

Under the authority of the Federal Advisory Committee Act (P.L. 92-463) of 1972, the National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances has been established to identify, review, and interpret relevant toxicologic and other scientific data and develop acute exposure guideline levels (AEGLs) for high-priority, acutely toxic chemicals.

AEGLs represent threshold exposure limits for the general public and are applicable to emergency exposure periods ranging from 10 minutes (min) to 8 hours (h). Three levels—AEGL-1, AEGL-2, and AEGL-3—are developed for each of five exposure periods (10 min, 30 min, 1 h, 4 h, and 8 h) and are distinguished by varying degrees of severity of toxic effects. The three AEGLs are defined as follows:


AEGL-1 is the airborne concentration (expressed as parts per million [ppm] or milligrams per cubic meter [mg/m3]) of a substance above which it is predicted that the general population, including susceptible individuals, could experience notable discomfort, irritation, or certain asymptomatic nonsensory effects. However, the effects are not disabling and are transient and reversible upon cessation of exposure.

1

This document was prepared by the AEGL Development Team composed of Sylvia Milanez (Oak Ridge National Laboratory) and Doan Hansen (Chemical Reviewer) [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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5 Crotonaldehyde, trans and cis + trans1 Acute Exposure Guideline Levels PREFACE Under the authority of the Federal Advisory Committee Act (P.L. 92-463) of 1972, the National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances has been established to identify, review, and interpret relevant toxicologic and other scientific data and develop acute exposure guide- line levels (AEGLs) for high-priority, acutely toxic chemicals. AEGLs represent threshold exposure limits for the general public and are applicable to emergency exposure periods ranging from 10 minutes (min) to 8 hours (h). Three levels—AEGL-1, AEGL-2, and AEGL-3—are developed for each of five exposure periods (10 min, 30 min, 1 h, 4 h, and 8 h) and are distin- guished by varying degrees of severity of toxic effects. The three AEGLs are defined as follows: AEGL-1 is the airborne concentration (expressed as parts per million [ppm] or milligrams per cubic meter [mg/m3]) of a substance above which it is predicted that the general population, including susceptible individuals, could experience notable discomfort, irritation, or certain asymptomatic nonsensory effects. However, the effects are not disabling and are transient and reversible upon cessation of exposure. 1 This document was prepared by the AEGL Development Team composed of Sylvia Milanez (Oak Ridge National Laboratory) and Doan Hansen (Chemical Reviewer) [Na- tional Advisory Committee (NAC) on Acute Exposure Guideline Levels for Hazardous Substances]. The NAC reviewed and revised the document and AEGLs as deemed neces- sary. Both the document and the AEGL values were then reviewed by the National Re- search Council (NRC) Committee on Acute Exposure Guideline Levels. The NRC Com- mittee has concluded that the AEGLs developed in this document are scientifically valid conclusions based on the data reviewed by the NRC and are consistent with the NRC guideline reports (NRC 1993, 2001). 123

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124 Acute Exposure Guideline Levels AEGL-2 is the airborne concentration (expressed as ppm or mg/m3) of a substance above which it is predicted that the general population, including sus- ceptible individuals, could experience irreversible or other serious, long-lasting adverse health effects or an impaired ability to escape. AEGL-3 is the airborne concentration (expressed as ppm or mg/m3) of a substance above which it is predicted that the general population, including sus- ceptible individuals, could experience life-threatening health effects or death. Airborne concentrations below the AEGL-1 represent exposure levels that can produce mild and progressively increasing but transient and nondisabling odor, taste, and sensory irritation or certain asymptomatic nonsensory effects. With increasing airborne concentrations above each AEGL, there is a progres- sive increase in the likelihood of occurrence and the severity of effects described for each corresponding AEGL. Although the AEGL values represent threshold levels for the general public, including susceptible subpopulations, such as in- fants, children, the elderly, persons with asthma, and those with other illnesses, it is recognized that individuals, subject to unique or idiosyncratic responses, could experience the effects described at concentrations below the correspond- ing AEGL. SUMMARY Crotonaldehyde is a colorless, flammable liquid and a potent eye, skin, and respiratory irritant. Inhaled crotonaldehyde can cause a burning sensation in the nasal and upper respiratory tract, lacrimation, coughing, bronchoconstriction, pulmonary edema, and deep lung damage. Crotonaldehyde is used primarily for the manufacture of sorbic acid and other organic chemicals. It is found in to- bacco smoke and is a combustion product of diesel engines and wood but also occurs naturally in meat, fish, and many fruits and vegetables. Crotonaldehyde exists as the cis and the trans isomer; commercial croton- aldehyde is a mixture of the two isomers consisting of >95% trans isomer. Be- cause no in vivo exposure studies were located for the individual isomers (in- formation was for the commercial mixture), the AEGL values in this document apply to both trans-crotonaldehyde (123-73-9) and the cis-trans mixture (4170- 30-3). AEGL-1 values were derived from a Health Hazard Evaluation conducted by National Institute for Occupational Safety and Health (NIOSH) in which workers exposed to approximately 0.56 ppm of crotonaldehyde for <8h reported occasional minor eye irritation (Fannick 1982). The same exposure concentra- tion was adopted for 10 min to 8 h because the critical end point (minor eye irri- tation in humans) was mild and mild irritant effects do not vary greatly over time. A total uncertainty factor of 3 was applied to account for intraspecies vari- ability, because the eye irritation is a direct surface-contact effect not subject to pharmacokinetic differences between individuals.

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125 Crotonaldehyde, trans and cis + trans AEGL-2 values were based on a pulmonary function study in which rats were exposed for 5-240 min to 10-580 ppm of crotonaldehyde; individual expo- sure concentrations and durations were not given (Rinehart 1967). Rats had re- duced pulmonary gas uptake ability and, above 8,000 ppm-min, proliferative lesions of the respiratory bronchioles. Exposures above 16,000 ppm-min in- duced pulmonary edema and death. AEGL-2 values were calculated by dividing 8,000 ppm-min by 10, 30, 60, 240, or 480 min because concentration and time appeared to be equally important factors in altering the pulmonary uptake of CO and ether (supported by n = 1.2 derived from an LC50 study [a lethal concentra- tion in 50% of the rats] by Rinehart [1967]). A total uncertainty factor of 30 was used: 10 for interspecies uncertainty (because the actual exposure concentration and time were not known for the key study and there was a lack of supporting animal studies) and 3 for intraspecies uncertainty (although human variability to crotonaldehyde toxicity is not well-defined, a greater uncertainty factor was judged inappropriate because it yields 4- and 8-h AEGL-2 concentrations that caused only mild irritation in workers exposed for up to 8 h; Fannick 1982). The AEGL-3 was based on an LC50 study in which rats were exposed to crotonaldehyde vapor for 5 min to 4 h (Rinehart 1967). Most deaths occurred by 4 days after exposure. The animals had clear or slightly blood-tinged nasal exu- date; the rats that died within 1 day also had terminal convulsions. Necropsy showed that a few rats had pulmonary congestion. The 10-min, 30-min, 1-h, and 4-h AEGLs were obtained using the respective LC01 values calculated by probit analysis from the mortality data. The 8-h AEGLs were derived from the 4-h LC01 using the relationship Cn × t = k, where n = 1.2 was derived by ten Berge et al. (1986) from this study LC50 data. A total uncertainty factor of 10 was ap- plied: 3 for interspecies uncertainty because interspecies variability was small (LC50 values for rats, mice, and guinea pigs were within a factor of 2.5, and these studies yield similar or higher AEGL-3 values) and 3 for intraspecies un- certainty because great human variability is unlikely given the homogeneity of the animal data and a larger uncertainty factor yields 8-h AEGL-3 concentra- tions that caused only mild irritation in workers exposed for up to 8 h (Fannick 1982). A summary of AEGL values is shown in Table 5-1. A cancer inhalation slope factor was derived for crotonaldehyde and used to estimate the 10-4 excess cancer risk from a single 30-min to 8-h exposure, as shown in Appendix D. Crotonaldehyde concentrations associated with a 10-4 excess cancer risk were 25-fold greater than the toxicity-based AEGL-2 values for 30 to 480 min. The noncarcinogenic end points were considered to be more appropriate for AEGL-2 derivation because (1) there is insufficient evidence that inhalation is a route that results in crotonaldehyde-induced liver lesions or neo- plasia at concentrations comparable to the AEGL-2 values; (2) the data used to derive the cancer slope factor were very weak (the key study had only one dose group and one control group; the high dose was excluded due to lack of fit), and most of the neoplastic changes were benign; (3) AEGL values are applicable to rare events or single, once-in-a-lifetime exposures, and the data indicate that

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126 Acute Exposure Guideline Levels TABLE 5-1 Summary of AEGL Values for Crotonaldehyde End Point Classification 10 min 30 min 1h 4h 8h (Reference) AEGL-1a 0.19 ppm 0.19 ppm 0.19 ppm 0.19 ppm 0.19 ppm Mild eye (nondisabling) (0.55 (0.55 (0.55 (0.55 (0.55 irritation in mg/m3) mg/m3) mg/m3) mg/m3) mg/m3) humans (Fannick 1982) AEGL-2 27 ppm 8.9 ppm 4.4 ppm 1.1 ppm 0.56 ppm Impaired (disabling) (77 (26 (13 (3.2 (1.6 pulmonary mg/m3) mg/m3) mg/m3) mg/m3) mg/m3) function, NOAEL for bronchiole lesions (Rinehart 1967) AEGL-3 44 ppm 27 ppm 14 ppm 2.6 ppm 1.5 ppm Lethality NOEL (lethal) (130 (77 (40 (7.4 (4.3 (Rinehart 1967). mg/m3) mg/m3) mg/m3) mg/m3) mg/m3) a Odor threshold has been reported as 0.035-1.05 ppm. TNM neoplasms resulted from lifetime treatment; and (4) a direct comparison of estimated TNM cancer risk and AEGL values is not appropriate due to large differences in the methodologies used to obtain these numbers. 1. INTRODUCTION Crotonaldehyde (CH3CH = CHCHO) exists as a cis isomer (15798-64-8) and a trans isomer (123-73-9) or as a mixture of the two isomers (4170-30-3). Commercial crotonaldehyde (4170-30-3) consists of >95% trans isomer and <5% cis isomer (Budavari et al. 1996; IARC 1995). With the exception of one reported odor detection level, no physical or chemical data or human or animal studies were located for the cis or trans isomers individually; all available in- formation was for the commercial (cis-trans) mixture. Therefore, the AEGL values prepared in this document will apply to both trans-crotonaldehyde (123- 73-9) and the cis-trans mixture (4170-30-3). The Occupational Safety and Health Administration (OSHA), NIOSH, and the American Conference of Gov- ernmental Industrial Hygienists (ACGIH) have adopted the same occupational exposure limits (permissible exposure limit, recommended exposure limit, Threshold Limit Value) for both isomers. Crotonaldehyde is a potent lacrimator and an extreme eye, respiratory, and skin irritant. Exposures to sufficiently high concentrations have produced chok- ing, coughing, and a burning sensation on the face, in the nasal and oral pas- sages, and in the upper respiratory tract as well as bronchoconstriction and pul- monary edema (HSDB 2005). Its odor threshold has been reported as 0.035-0.2

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127 Crotonaldehyde, trans and cis + trans ppm (Verschueren 1996), 0.037-1.05 ppm (Ruth 1986), 0.038 ppm (Tepikina et al. 1997), and 0.12 ppm (trans isomer; Amoore and Hautala 1983). Human exposure to crotonaldehyde occurs from both man-made and natu- ral sources. Crotonaldehyde has been identified in exhaust from jet, gasoline; and diesel engines; from tobacco smoke; and from the combustion of polymers and wood (IARC 1995). Crotonaldehyde occurs naturally in meat, fish, many fruits (apples, grapes, strawberries, tomatoes) and vegetables (cabbage, cauli- flower, Brussel sprouts, carrots), bread, cheese, milk, beer, wine, and liquors (IARC 1995). It is emitted from volcanoes, from the Chinese arbor vitae plant, and from pine and deciduous forests (IARC 1995; HSDB 2005). Crotonalde- hyde has been detected in drinking water, wastewater, human milk, and expired air from nonsmokers. Crotonaldehyde is a very flammable liquid (Budavari et al. 1996). It is manufactured commercially by adding aldol to a boiling dilute acid solution and removing the crotonaldehyde by distillation. Crotonaldehyde is used primarily for the production of sorbic acid; it is also used for the synthesis of butyl alco- hol, butyraldehyde, quinaldine, thiophenes, pyridenes, dyes, pesticides, pharma- ceuticals, rubber antioxidants, and chemical warfare agents and as a warning agent in locating breaks and leaks in pipes (IARC 1995, Budavari et al. 1996; Verschueren 1996). Crotonaldehyde degrades in the atmosphere by reacting with photochemically produced hydroxyl radicals (half-life of about 11 h) or ozone (half-life of about 15.5 days; HSDB 2005). U.S. production of crotonaldehyde in 1975 was >2,000 pounds, and about 463 pounds was imported into the United States in 1984 (HSDB 2005). The chemical and physical properties of crotonaldehyde are listed in Table 5-2; dis- crete information was not available for the trans isomer of crotonaldehyde, and the information given is for the cis-trans mixture (except for synonyms and the CAS registry numbers). 2. HUMAN TOXICITY DATA 2.1. Acute Lethality Crotonaldehyde vapor “may be fatal” if inhaled or absorbed through the skin; no further information was provided (Eastman Chemical Co. 1998). 2.2. Nonlethal Toxicity 2.2.1. Odor Threshold and Odor Awareness A wide range of concentrations have been reported for the human odor de- tection and irritation thresholds for crotonaldehyde, perhaps in some cases due

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128 Acute Exposure Guideline Levels TABLE 5-2 Chemical and Physical Data Descriptor or Value Reference Property Synonyms 4170-30-3: 2-butenal, crotonal, IARC 1995 crotonic aldehyde, 1-formyl- propene, β-methylacrolein 123-73-9: (E)-2-butenal, (E)- crotonaldehyde, trans-2-butenal, trans-crotonaldehyde CH3CH = CH − CHO Chemical formula Budavari et al. 1996 Molecular weight 70.09 Budavari et al. 1996 CAS registry number 4170-30-3 (mixture of cis and IARC 1995 trans isomers) 123-73-9 (trans isomer) Physical state Liquid Budavari et al. 1996 Color White liquid; yellows on contact NIOSH 2002 with air Solubility in water 18.1 g/100 g at 20°C Budavari et al. 1996 Vapor pressure 19 mmHg at 20°C Verschueren 1996 Vapor density (air = 1) 2.41 Budavari et al. 1996 Liquid density (water = 1) 0.853 at 20/20°C Budavari et al. 1996 −76.5°C Melting point Budavari et al. 1996 Boiling point 104.0°C at 760 mm Budavari et al. 1996 Flammability/explosion limits 2.1-15.5% NIOSH 2002 1 mg/m3 = 0.349 ppm; 1 ppm = Conversion factors Verschueren 1996, 2.87 mg/m3 IARC 1995 to analytical measurement errors (Steinhagen and Barrow 1984). Amoore and Hautala (1983) reported the odor threshold to be 0.12 ppm for trans- crotonaldehyde, whereas the irritation threshold was 14 ppm and 19 ppm for the nose and eyes, respectively. In several secondary sources, the odor detection threshold for crotonaldehyde was given as 0.035-1.05 ppm and the irritation threshold was 8.0 ppm (Ruth 1986; Verschueren 1996). In a study in which 25 volunteers were exposed to 0.02-2.3 mg/m3 (0.007-0.8 ppm) of crotonaldehyde, the odor was detected by several persons at the lowest concentration tested, and roughly half the people were able to detect the odor at 0.11 mg/m3 (0.038 ppm; Tepikina et al. 1997). The test subjects were exposed to each concentration re- peatedly (about 2-4 times) to eliminate guessing and also to “pure air” to give a point of reference (i.e., incidence of false positives). An unpublished source (van Doorn et al. 2002) reported 0.069 ppm and 0.063-0.2 ppm as the trans- crotonaldehyde and cis-crotonaldehyde odor detection thresholds, respectively (OT50; i.e., concentration at which 50% of the odor panel observed an odor without necessarily recognizing it).

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129 Crotonaldehyde, trans and cis + trans 2.2.2. Experimental Studies Twelve healthy males ages 18-45 were exposed for 10 or 15 min to 12 mg/m3 (about 4.1 ppm) in a 100-m3 chamber at 20-25°C with a wind velocity of 1 mph (exposure duration was unclear from the study text; Sim and Pattle 1957). Crotonaldehyde vapor was produced by bubbling air through a known volume of liquid until all of the liquid evaporated; air samples were analyzed for con- centration by using a bubbler containing hydroxylamine hydrochloride solution at pH 4.5 and noting the pH change. The men reported the crotonaldehyde vapor to be highly irritating to all mucosal surfaces, particularly the nose and upper respiratory tract (Sim and Pattle 1957). Lacrimation occurred after an average of 30 s, but eye irritation “did not increase after onset of lacrimation.” A confound- ing factor in the experiment was that there were no restrictions on the men’s activities, and they were allowed to smoke tobacco during exposure; smoking or activity levels were not provided. The threshold for crotonaldehyde irritation in humans was reported as 0.0005 mg/liter (L) (0.17 ppm; Trofimov 1962). In this experiment, volunteers inhaled crotonaldehyde vapor through a mask for 1 min; it was not specified how the vapor was generated or how the concentrations were measured. Factors taken into account were odor detection and irritation of the eyes and mucous membranes of the nose and trachea; it was not specified on which of these end points the estimated irritation threshold was actually based. Trofimov suggested that the maximum permissible concentration of crotonaldehyde in air should be limited to 0.0005-0.0007 mg/L (0.17-0.24 ppm) to prevent irritation. 2.2.3. Occupational and Other Exposures Laboratory personnel (two or three people) who “sniffed” 15 ppm of cro- tonaldehyde vapor for a few seconds (<30 s) during brief openings of animal chambers reported that the odor was very strong but not intolerable and that there was no eye discomfort. The personnel who “sniffed” 45-50 ppm of croton- aldehyde vapor only momentarily noted that the odor was “very strong, pungent, and disagreeable, but not particularly biting to nasal passages” (Rinehart 1967, 1998). Lacrimation was not induced in the subjects, although they experienced a burning sensation of the conjunctivae and a strong desire to blink repeatedly. NIOSH conducted a Health Hazard Evaluation in a chemical plant (San- doz Colors and Chemicals) in East Hanover, New Jersey, at the request of work- ers at the plant, some of whom complained of occasional minor eye irritation (Fannick 1982). NIOSH measured crotonaldehyde air concentrations using midget impingers; analysis was performed using gas chromatography with flame ionization detection. Eight air samplers were placed near the vats of chemicals and two were worn by the NIOSH industrial hygienist, who was near the vats most of the time. These measurements likely overestimated the actual exposure concentrations because workers were allowed to move about and were not near

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130 Acute Exposure Guideline Levels the vats during an entire 8-h work shift. NIOSH determined that the average crotonaldehyde concentration of general air samples was 1.6 mg/m3 (0.56 ppm; range, <0.35 to 1.1 ppm; 0.35 ppm was the limit of quantitation). The two per- sonal samples were 0.66 and 0.73 ppm. These workers were also simultaneously exposed to acetic acid and small amounts of acetaldehyde (which occasionally caused a perceptible sweet odor), 3-hydroxybutyraldehyde, and dimethoxane. Crotonaldehyde was probably the most potent irritant among these chemicals, based on its greater quantity and its much lower RD50 (reference dose—the con- centration that decreases the respiration rate of mice by 50% due to respiratory irritation [Schaper, 1993; Fannick 1982]). Fieldner et al. (1954) reported that inhalation exposure to crotonaldehyde at 3.5-14 ppm was sufficiently irritating to wake a sleeping person and that 3.8 ppm was irritating within 10 s. Dalla Vale and Dudley (1939) compiled a list of “threshold values” that produce a noticeable odor in the air. The list included crotonaldehyde at 7.3 ppm, which the authors characterized as an eye and a nose irritant. (Experimental details for these two studies were not available.) A sum- mary of the human studies is presented in Table 5-3. 2.3. Neurotoxicity No human neurotoxicity studies were located for crotonaldehyde exposure by any route. 2.4. Developmental and Reproductive Toxicity No human studies were located that described developmental or reproduc- tive effects resulting from acute exposure to crotonaldehyde. 2.5. Genotoxicity Crotonaldehyde (5-250 µM) induced sister chromatid exchanges, struc- tural (but not numerical) chromosome aberrations, and micronuclei in cultured human lymphocytes and Namalva cells (a permanent lymphoblastoid cell line; Dittberner et al. 1995). The micronuclei were centromere-negative by fluores- cence in situ hybridization using a human centromere-specific DNA probe, indi- cating crotonaldehyde was acting by a clastogenic mechanism. Nath et al. (1998) compared the levels of crotonaldehyde adducts in gingi- val tissue DNA from human smokers and nonsmokers using a 32P-postlabeling high-performance liquid chromatography method. Smokers had significantly higher levels of the DNA adducts than the nonsmokers (5.5- to 8.8-fold in- crease). Crotonaldehyde (without exogenous activation) also was shown to bind

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131 Crotonaldehyde, trans and cis + trans TABLE 5-3 Human Crotonaldehyde Exposure Data Exposure Exposure End Point and Concentration Time Confounding Factors Reference 0.035-0.2 ppm Undefined Odor thresholds from secondary Verschueren 1996; 0.037-1.05 ppm (a few sources; descriptions of most of the Ruth 1986; Amoore 0.12 ppm seconds) original studies were unavailable. and Hautala 1983 0.038 ppm Undefined Subjects were exposed multiple Tepikina et al. 1997 (few seconds) times. Roughly half detected odor at this air concentration. 0.17 ppm 1 min Odor detection and/or irritation; Trofimov 1962 exposure through mask; undefined analytical method. 0.56 ppm <8 h Occasional eye irritation; Fannick 1982 (up to 1.1 ppm) concentration up to 1.1 ppm; co- exposure to other chemicals. 4.1 ppm 15 min Marked respiratory irritation; Sim and Pattle 1957 (10 min) lacrimation in ~30 s; co-exposure to cigarette smoke. 3.5-14 ppm Undefined Irritation sufficient to wake a Fieldner et al. 1954 3.8 ppm 10 s sleeping person “Irritating within 10 s; no further details. 7.3 ppm Undefined Very sharp odor and strong Dalla Vale and (seconds?) irritation to the eye and nose; no Dudley 1939 experimental details. 8 ppm Undefined Irritation threshold; methods used Ruth 1986; Amoore 14 ppm (nose) (a few to determine or define “irritation” and Hautala 1983; 19 ppm (eyes) seconds) were not given. Amoore and Hautala 1983 15 ppm <30 s Lab workers “sniffed” Rinehart 1967 crotonaldehyde. Odor strong but not intolerable; no eye discomfort. 45-50 ppm <30 s Lab workers “sniffed” Rinehart 1967 crotonaldehyde. Odor strong, pungent, and disagreeable; burning sensation of conjunctivae but no lacrimation. the DNA of human fibroblasts in vitro (Wilson et al. 1991). Hecht et al. (2001) showed that deoxyguanosine and DNA Schiff-base adducts that formed after crotonaldehyde exposure were unstable at the nucleoside level but stable in DNA.

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132 Acute Exposure Guideline Levels 2.6. Carcinogenicity No human data were located that described carcinogenicity associated with crotonaldehyde exposure. In 1991 the U.S. Environmental Protection Agency (EPA) classified crotonaldehyde as in group C (a possible human car- cinogen; EPA 2002) based on limited animal data (Chung et al. 1986; see Sec- tion 3.6). The International Agency for Research on Cancer (IARC) concluded that there was inadequate evidence for humans and in experimental animals to establish the carcinogenicity of crotonaldehyde and placed it in group 3 (not classifiable as to its carcinogenicity to humans; IARC 1995). 2.7. Summary No information concerning acute lethal human exposure to crotonaldehyde was located. Values reported for the odor detection and irritation thresholds in humans were quite variable, ranging from 0.035 to 1.05 ppm and 0.17 to 14 ppm, respectively. The variation may be due to differences in exposure condi- tions or analytical measurements of concentration, which were often not re- ported. For example, laboratory workers who intentionally “sniffed” crotonalde- hyde for a few seconds found 15 ppm strong but not intolerable, whereas in other studies 3.5-14 ppm (duration unknown) was sufficiently irritating to wake up a sleeping person, and volunteers exposed to 4.1 ppm for 15 min (and also possibly to tobacco smoke) experienced respiratory irritation and lacrimation after an average of 30 s. Workers exposed occupationally to concentrations up to 1.1 ppm crotonaldehyde (along with several other chemicals) reported occa- sional mild eye irritation. There are no data to indicate that crotonaldehyde is neurotoxic or a human carcinogen by any route of exposure. Crotonaldehyde was clastogenic in cultured human cells. Crotonaldehyde DNA adducts were detected in human buccal cells, in higher levels in smokers than nonsmokers. The chemistry of crotonaldehyde and its direct reactions with DNA and deoxy- guanosine have been characterized. 3. ANIMAL TOXICITY DATA 3.1. Acute Lethality Death resulting from acute inhalation exposure to crotonaldehyde has been reported in rats, mice, guinea pigs, and rabbits. The available studies are summa- rized in Table 5-4.

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TABLE 5-4 Acute Lethality of Crotonaldehyde Inhalation Exposure in Animals Concentration Species Exposure Time (ppm) End Point; Reference Rat 30 min 35-2450 LC50= 1400 ppm. Gasping, eyes tightly shut, lacrimation, nose secretion during treatment; hyperemia in lungs, heart, kidneys, liver, spleen, and brain (Skog 1950). Rat 1 min “Saturated” LC0; no other effects described. 10 min (~40,000) LC100; no other effects described. (Smyth and Carpenter 1944; Smyth 1966; Union Carbide Corp. 1992) Rat 6h 35-98 LC0; rats had pink extremities, nasal irritation, and labored breathing 6 h on days 94-108 LC≥75; rats gasped, had pink extremities, one death after day 1, two after day 4 (other 1,2,4 killed on day 5). Lungs were congested. 6h 133; 166; 359 LC100; all died within 2 days except for 1 rat inhaling 166 ppm; rats gasped, had nasal irritation, pink extremities, and weight loss. 30-43 min; 2,094-16,229 LC100; death within 2 hours; gasping, pink extremities, tremors, convulsions, salivation, 2h 907; 1,256 and prostration (Eastman Kodak Corp. 1992). Rat 5 min 1,920-4,640 All rats gasped, had lowered respiratory rate, lost weight; excitatory LC50 = 3132 10 min 800-2,050 stage was seen at ≥1000 ppm; most deaths by day 4, some had clear or LC50 = 1480 15 min 550-1,290 blood-stained nasal discharge; few rats had pulmonary congestion LC50 = 809 30 min 370-890 (Rinehart 1967; see Table 5-5). LC50 = 593 60 min 370-640 LC50 = 391 4h 50-200 LC50 = 88 Rat 4h ~70 (not stated) LC50 = 70 ppm; no other effects described (Voronii et al. 1982). (Continued) 133

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162 Acute Exposure Guideline Levels APPENDIX A Derivation of AEGL-1 Values Key study: Fannick 1982. Human occupational exposure to a mean concentration of 0.56 ppm crotonaldehyde dur- ing a workday caused occasional eye irritation; expo- sure time not given but was <8 h. Toxicity end point: Ocular irritation. Scaling: None: 0.56 ppm = k; the critical end point (eye irrita- tion) was mild, and mild irritant effects generally do not vary greatly over time. Uncertainty factors: Total uncertainty factor: 3 Interspecies: Not applicable Intraspecies: 3, for intraspecies variability because the eye irrita- tion is a direct surface-contact effect not subject to pharmacokinetic differences between individuals. Calculations: 0.56 ppm/3 = 0.19 ppm (0.55 mg/m3) 10-min AEGL-1: 0.56 ppm/3 = 0.19 ppm (0.55 mg/m3) 30-min AEGL-1: 0.56 ppm/3 = 0.19 ppm (0.55 mg/m3) 1-h AEGL-1: 0.56 ppm/3 = 0.19 ppm (0.55 mg/m3) 4-h AEGL-1: 0.56 ppm/3 = 0.19 ppm (0.55 mg/m3) 8-h AEGL-1: Derivation of AEGL-2 Values Key study: Rinehart 1967. Rat pulmonary function study. Rats had lower rates of ether and CO absorption and those exposed to >8,000 ppm-min (product of concentra- tion and time; individual concentrations and exposure times were not given) developed proliferative respira- tory bronchiole lesions.

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163 Crotonaldehyde, trans and cis + trans Toxicity end point: Moderate pulmonary impairment and NOAEL for proliferative lesions of the respiratory bronchioles. C1 × t = k (concentration and time were approxi- Scaling: mately equally important for toxicity) Uncertainty factors: Total uncertainty factor: 30 Interspecies: 10: The actual exposure concentration and time were not known for the key study, and there was a lack of supporting animal studies. Intraspecies: 3: Although human variability to crotonaldehyde toxicity is not well defined, a greater uncertainty fac- tor was judged inappropriate because it yields 4- and 8-h AEGL-2 concentrations that caused only mild ir- ritation in workers exposed for up to 8 h (Fannick 1982). (Concentration)1 (30-480 min) = k = 8,000 ppm-min Calculations: Apply the total UF of 30-8,000 ppm-min and get k = 267 ppm-min C1 × 10 min = 267 ppm-min 10-min AEGL-2: 10 min AEGL-2 = 267 ppm-min/10 min = 27 ppm (77 mg/m3) C1 × 30 min = 267 ppm-min 30-min AEGL-2: 30-min AEGL-2 = 267 ppm-min/30 min = 8.9 ppm (26 mg/m3) C1 × 60 min = 267 ppm-min 1-h AEGL-2: 1 h AEGL-2 = 267 ppm-min/60 min = 4.4 ppm (13 mg/m3) C1 × 240 min = 267 ppm-min 4-h AEGL-2: 4-h AEGL-2 = 267 ppm-min/240 min = 1.1 ppm (3.2 mg/m3) C1 × 480 min = 267 ppm-min 8-h AEGL-2: 8-h AEGL-2 = 267 ppm-min/480 min = 0.56 ppm (1.6 mg/m3)

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164 Acute Exposure Guideline Levels Derivation of AEGL-3 Values Key study: Rinehart 1967. Rat 5-min to 4-h exposure inhalation LC50 study. Most deaths occurred by 4 days after ex- posure, and the animals had clear or slightly blood- tinged nasal exudate; rats that died within 1 day also had terminal convulsions. Autopsy showed that a few rats had pulmonary congestion. Lethality NOELs, estimated from LC01 values ob- Toxicity end point: tained by probit analysis: 10-min LC01 = 440 ppm (standard error = 153) 30-min LC01 = 268 ppm (standard error = 50) 1-h LC01 = 138 ppm (standard error = 71) 4-h LC01 = 26 ppm (standard error = 7.8); used to de- rive 8-h values C1.2 × t = k (Rinehart 1967 LC50 data; ten Berge et Scaling: al. 1986) Uncertainty factors: Total uncertainty factor: 10 3, Interspecies variability was small (LC50 values for Interspecies: rats, mice, and guinea pigs were within a factor of 2.5; these studies yield similar or higher AEGL-3 values). Intraspecies: 3, Great human variability is unlikely given the ho- mogeneity of the animal data, and a larger uncer- tainty factor yields 8-h AEGL-3 concentrations that caused only mild irritation in workers exposed for up to 8 h (Fannick 1982). Calculations for 10, 30, 60, and 240 min: 10-min LC01 = 440 ppm 10-min AEGL-3: 10-min AEGL-3 = 440/10 = 44 ppm (130 mg/m3) 30-min AEGL-3: 30-min LC01 = 268 ppm 30-min AEGL-3 = 268/10 = 27 ppm (77 mg/m3) 1-h AEGL-3: 1-h LC01 = 138 ppm 1-h AEGL-3 = 138/10 = 14 ppm (40 mg/m3) 4-h AEGL-3: 4-h LC01 = 26 ppm 4-h AEGL-3 = 26/10 = 2.6 ppm (7.4 mg/m3)

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165 Crotonaldehyde, trans and cis + trans Calculations for 8 h: 26 ppm1.2 × time (240 min) = k = 755.4 ppm-min Concentration UF 10 C1.2 × 480 min = 755.4 ppm-min 8-h AEGL-3 C = 1.5 ppm (4.3 mg/m3) 8-h AEGL-3 APPENDIX B Derivation of the Level of Distinct Odor Awareness (LOA) The level of distinct odor awareness (LOA) represents the concentration above which it is predicted that more than half of the exposed population will experience at least a distinct odor intensity; about 10% of the population will experience a strong odor intensity. The LOA should help chemical emergency responders in assessing public awareness of exposure due to odor perception. The LOA derivation follows the guidance given by van Doorn et al. (2002). An odor detection threshold (OT50; i.e., concentration at which 50% of the odor panel observed an odor without necessarily recognizing it) of 0.069 ppm was reported for the trans isomer and 0.063-0.20 ppm for the cis isomer of cro- tonaldehyde. The value of 0.069 was used for the LOA calculations because commercial crotonaldehyde (tested in the animal studies) is a mixture of the two isomers consisting of >95% trans isomer. The concentration C leading to an odor intensity (I) of distinct odor detec- tion (I = 3) is derived using the Fechner function: I = kw × log (C /OT50) + 0.5 For the Fechner coefficient, the default of kw = 2.33 will be used due to the lack of chemical-specific data: 3 = 2.33 × log (C /0.069) + 0.5, which can be rearranged to log (C /0.069 = (3 − 0.5) / 2.33 = 1.07 and results in C = (101.07) × 0.069 = 0.81 ppm The resulting concentration is multiplied by an empirical field correction factor. It takes into account that in everyday life factors such as sex, age, sleep, smoking, upper-airway infections, and allergies, as well as distraction, increase the odor detection threshold by a factor of 4. In addition, it takes into account that odor perception is very fast (about 5 s), which leads to the perception of

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166 Acute Exposure Guideline Levels concentration peaks. Based on current knowledge, a factor of 1/3 is applied to adjust for peak exposure. Adjustment for distraction and peak exposure leads to a correction factor of 4/3 = 1.33. LOA = C × 1.33 = 0.81 ppm × 1.33 = 1.1 ppm The LOA for crotonaldehyde is 1.1 ppm.

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APPENDIX C Category Plot for Crotonaldehyde Chemical Toxicity - TSD All Data Crotonaldehyde 100000.0 Human - No Effect Human - Discomfort 10000.0 Human - Disabling 1000.0 Animal - No Effect Animal - Discomfort 100.0 ppm Animal - Disabling AEGL-3 10.0 Animal - Some Lethality AEGL-2 1.0 Animal - Lethal AEGL-1 AEGL 0.1 0 60 120 180 240 300 360 420 480 Minutes FIGURE 5-1 Category plot of human and animal toxicity data compared with AEGL values. 167

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168 Acute Exposure Guideline Levels APPENDIX D CARCINOGENICITY ASSESSMENT Preliminary Cancer Assessment of Crotonaldehyde A preliminary cancer assessment of crotonaldehyde was performed using data from Chung et al. (1986). In this study, male F344 rats were treated with 0, 0.6, or 6.0 mM of crotonaldehyde in their drinking water for 113 weeks. The high-dose group had approximately 10% lower body weight gain starting at week 8. The incidence of hepatic neoplastic nodules and hepatocellular carci- nomas (combined) was 0/23, 11/27*, and 1/23 at 0, 0.6, and 6.0 mM, respec- tively (*p < .01; carcinoma: 0/23, 2/27, 0/23, respectively). The oral dose can be extrapolated to an air concentration that results in an equivalent human inhaled dose when assuming 100% lung absorption (NRC 1993). The extrapolation uses a rat intake of 2.06 mg of crotonaldehyde/day from the drinking water at the low dose (0.049 L/day (default) × 0.6 mmol/L × 70.09 g/mol crotonaldehyde), default body weights (BW) of 70 kg for humans and 0.35 kg for rats, and an inhalation rate of 20 m3/day for humans. The calcu- lation is performed as follows: Human equivalent concentration = 2.06 mg crotonaldehyde/day × 70 kg body weight = 20.6 mg/m3. 20 m3 air/day × 0.35 kg of body weight This yields air concentrations of 20.6 mg/m3 (7.2 ppm) and 206 mg/m3 (72 ppm), respectively, for 0.6 and 6.0 mM crotonaldehyde in water. Using the lin- earized multistage model (GLOBAL86 program; Howe et al. 1986), the inhala- tion unit risk (or slope factor; i.e., q1*) was calculated to be 0.0327 per (mg/m3). Note that the high dose was excluded from the unit risk calculation by the GLOBAL86 program due to lack of fit. For a lifetime theoretical cancer risk of 10−4, crotonaldehyde air concentra- tion is 10−4/0.0327 (mg/m3)−1 = 3.06 × 10-3 mg/m3. To convert a 70-year exposure to a 24-h exposure: (3.06 × 10-3 mg/m3) 25,600 days = 78.34 mg/m3 (risk) 70-year life. An additional adjustment factor of 6 is applied to account for uncertainty regard- ing the stages of the carcinogenic process at which TNM or its metabolites may act (Crump and Howe 1984):

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169 Crotonaldehyde, trans and cis + trans 78.34 mg/m3 ÷ 6 = 13.1 mg/m3 or 4.6 ppm. For exposures of less than 24 h, the fractional exposure (f) becomes 1/f × 24 h (NRC 1985). (Extrapolation to 10 min was not calculated due to unac- ceptably large inherent uncertainty; see Section 4.4.3.) AEGL-2 Values Crotonaldehyde Exposure Concentrations (ppm) (ppm) Based on with an Excess Cancer Risk of Exposure Toxicity End 10−4 10−5 10−6 Duration Points ½h 8.9 221 22 2.2 1h 4.4 110 11 1.1 4h 1.1 28 2.8 0.28 8h 0.56 14 1.4 0.14 Because animal doses were converted to an air concentration that results in an equivalent human inhaled dose for the derivation of the cancer slope fac- tor, no reduction of exposure levels is applied to account for interspecies vari- ability. Crotonaldehyde concentrations associated with a 10−4 excess cancer risk for a single 30- to 480-min exposure were 25-fold greater than the toxicity-based AEGL-2 values for 30-480 min. The noncarcinogenic end points were consid- ered to be more appropriate for AEGL-2 derivation because (1) there is insuffi- cient evidence that inhalation is a route that results in crotonaldehyde-induced liver lesions or neoplasia at concentrations comparable to the AEGL-2 values (liver effects were mentioned in two inhalation studies: Skog (1950) reported hyperemia in multiple organs, including the liver, at unspecified exposure con- centrations, and Salem and Cullumbine (1960) found that livers appeared enlarged in animals exposed to concentrations that killed all animals within 86 min); (2) the data used to derive the cancer slope factor were very weak (the key study had only one dose and one control group; the high dose was excluded due to lack of fit), and most of the neoplastic changes were benign; (3) multiple worst-case assumptions were made in extrapolating from the oral route to the inhalation route and in the derivation of the cancer slope factor; and (4) AEGL values are applicable to rare events or single, once-in-a-lifetime exposures and the neoplasms resulted from lifetime treatment.

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170 Acute Exposure Guideline Levels APPENDIX E ACUTE EXPOSURE GUIDELINE LEVELS FOR CROTONALDEHYDE Derivation Summary for Crotonaldehyde AEGLS (CAS Nos. 123-73-9 and 4170-30-3) AEGL-1 VALUES 10-min 30-min 1-h 4-h 8-h 0.19 ppm 0.19 ppm 0.19 ppm 0.19 ppm 0.19 ppm Key reference: Fannick, N. 1982. Sandoz Colors and Chemicals, East Hanover, New Jersey. Health Hazard Evaluation Report No. HETA-81-102-1244. Na- tional Institute for Occupational Safety and Health, Hazard Evaluations and Technical Assistance Branch, Cincinnati, OH. Test species/Strain/Sex/Number: Humans; number not specified but likely <10. Exposure route/Concentrations/Durations: Inhalation for <8 h to 0.56 ppm; highest measured air concentration was 1.1 ppm. Effects: Slight eye irritation. End point/Concentration/Rationale: Workers exposed to 0.56 ppm for a portion of their 8-h work shift occasionally had mild eye irritation. Uncertainty factors/Rationale: Uncertainty factors: Total uncertainty factor: 3 Interspecies: Not applicable Intraspecies: 3: for intraspecies variability because the eye irritation is a direct surface-contact effect not subject to pharmacokinetic differences between indi- viduals. Modifying factor: None. Animal to human dosimetric adjustment: Not necessary Time scaling: The same value is adopted for 10-min to 8-h exposures because the critical end point (eye irritation) was mild and mild irritant effects generally do not vary greatly over time. Human exposure studies suggested that scaling across time was not appropriate (the degree of irritation was much greater at shorter time periods than at longer time periods for the same Ct). Data adequacy: Database of appropriate studies was limited but included human data. The key study was conducted by NIOSH, and crotonaldehyde concentra- tions were measured analytically. A possible confounding factor was co- exposure of the workers to several other airborne chemicals, although mouse irritation data indicate that crotonaldehyde was the most irritating of the chemi- cals present.

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171 Crotonaldehyde, trans and cis + trans AEGL-2 VALUES 10-min 30-min 1-h 4-h 8-h 27 ppm 8.9 ppm 4.4 ppm 1.1 ppm 0.56 ppm Key reference: Rinehart, W. 1967. The effect on rats of single exposures to cro- tonaldehyde vapor. Am. Ind. Hyg. Assoc. J. 28:561-566. Test species/Strain/Sex/Number: Male Sprague-Dawley rats; 12-16 per Ct (con- centration × time) range Exposure route/Concentrations/Durations: Inhalation for 5 min to 4 h of 10-580 ppm; individual concentrations and exposure times were not given. Effects: Decreased pulmonary function at ≥ 2,000 ppm-min, manifest as a 5- 50% reduction in CO and ether uptake rates compared to preexposure values. Proliferative lesions of the respiratory bronchioles occurred at >8,000 ppm-min. End point/Concentration/Rationale: Decreased pulmonary function and NOAEL for proliferative lesions of the respiratory bronchioles at 8,000 ppm-min. Uncertainty factors/Rationale: Total uncertainty factor: 30 Interspecies: 10: The actual exposure concentration and time were not known for the key study, and there was a lack of supporting animal studies. Intraspecies: 3: Although human variability to crotonaldehyde toxicity is not well defined, a greater uncertainty factor was judged inappropriate because it yields 4- and 8-h AEGL-2 concentrations that caused only mild irritation in workers exposed for up to 8 h (Fannick 1982). Modifying factor: None. Animal to human dosimetric adjustment: Not applied Time scaling: Concentration and time appeared to be roughly equally important for toxicity; i.e., C1 × t = k, which is also supported by n = 1.2 derived from an LC50 study by Rinehart (1967). AEGL-2 values were calculated by dividing 8,000 ppm-min by 10, 30, 60, 240, or 480 min. Data adequacy: The database of appropriate studies was small. The key study was well conducted and crotonaldehyde air concentrations were measured, al- though the actual concentrations and exposure times were not given (only Ct values). AEGL-3 VALUES 10-min 30-min 1-h 4-h 8-h 44 ppm 27 ppm 14 ppm 2.6 ppm 1.5 ppm Key reference: Rinehart, W. 1967. The effect on rats of single exposures to cro- tonaldehyde vapor. Am. Ind. Hyg. Assoc. J. 28:561-566. Test species/Strain/Sex/Number: Male Sprague-Dawley rats; 5-12/concentration (see below) (Continued)

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172 Acute Exposure Guideline Levels AEGL-3 VALUES Continued 10-min 30-min 1-h 4-h 8-h 44 ppm 27 ppm 14 ppm 2.6 ppm 1.5 ppm Exposure route/Concentrations/Durations: Inhalation: see below for exposure times and concentrations. Effects: Most deaths occurred by 4 days after exposure, and the animals had clear or slightly blood-tinged nasal exudate (rats that died within 1 day also had terminal convulsions); some had pulmonary congestion. 5-min ppm– 10-min ppm– 15-min ppm– 30-min ppm– 60 min ppm– 240-min ppm– mortality mortality mortality mortality mortality mortality 1,920 – 0/5 800 – 1/12 550 – 0/10 370 – 0/10 370 – 4/10 50 – 1/10 2,420 – 1/5 1,110 – 4/12 680 – 2/10 420 – 2/10 400 – 6/10 60 – 2/10 2,680 – 1/5 1,380 – 6/12 750 – 5/10 530 – 4/10 490 – 7/10 70 – 4/10 3,180 – 3/5 1,820 – 7/12 850 – 7/10 675 – 6/10 590 – 7/10 100 – 6/10 4,160 – 4/5 2,050 – 9/12 980 – 7/10 800 – 8/10 640 – 10/10 120 – 8/10 4,640 – 5/5 LC50 = 1480 1,090 – 8/10 890 – 9/10 LC50 = 391 200 – 9/10 LC50 = 3132 LC01 = 440 1,290 – 10/10 LC50 = 593 LC01 = 138 LC50 = 88 LC01 = 1492 LC50 = 809 LC01 = 268 LC01 = 26 LC01 = 419 End point/Concentration/Rationale: LC01 values, representing the NOEL for lethality, were obtained by probit analysis and used to obtain the 10-, 30-, 1-h, and 4-h AEGL-3 values. The 8-h values were derived from the 4-h LC01 by ex- ponential time scaling and using n = 1.2. Uncertainty factors/Rationale: Total uncertainty factor: 10 Interspecies: 3: Interspecies variability was small (LC50 values for rats, mice, and guinea pigs were within a factor of 2.5, and these studies yielded similar or higher AEGL-3 values). Intraspecies: 3: Great human variability in unlikely given the homogeneity of the animal data, and a larger uncertainty factor yields 8-h AEGL-3 concentra- tions that caused only mild irritation in workers exposed for up to 8 h (Fannick 1982). Modifying factor: None. Animal to human dosimetric adjustment: Not applied Time scaling: Performed only for 8-h time point by exponential scaling; i.e., Cn × t = k, where n = 1.2 was derived by ten Berge et al. (1986) from the Rinehart (1967) rat LC50 data. Data adequacy: Database quality was considered adequate, and the key study was well conducted: 30-60 animals were tested per exposure time at five to seven crotonaldehyde concentrations, and a clear dose-response was obtained. Similar or higher AEGL-3 values could be obtained with mice, rats, and guinea pigs.