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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 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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AEGL-2 is the airborne concentration (expressed as ppm or mg/m3) of a substance above which it is predicted that the general population, including susceptible individuals, could experience irreversible or other serious, long-lasting adverse health effects or an impaired ability to escape.
AEGL-3 is the airborne concentration (expressed as ppm or mg/m3) of a substance above which it is predicted that the general population, including susceptible individuals, could experience life-threatening health effects or death.
Airborne concentrations below the AEGL-1 represent exposure levels that 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 progressive increase in the likelihood of occurrence and the severity of effects described for each corresponding AEGL. Although the AEGL values represent threshold levels for the general public, including susceptible subpopulations, such as infants, children, the elderly, persons with asthma, and those with other illnesses, it is recognized that individuals, subject to unique or idiosyncratic responses, could experience the effects described at concentrations below the corresponding AEGL.
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 tobacco 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 crotonaldehyde is a mixture of the two isomers consisting of >95% trans isomer. Because no in vivo exposure studies were located for the individual isomers (information 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 concentration was adopted for 10 min to 8 h because the critical end point (minor eye irritation 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 variability, because the eye irritation is a direct surface-contact effect not subject to pharmacokinetic differences between individuals.
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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 exposure concentrations and durations were not given (Rinehart 1967). Rats had reduced pulmonary gas uptake ability and, above 8,000 ppm-min, proliferative lesions of the respiratory bronchioles. Exposures above 16,000 ppm-min induced 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 concentration 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 exudate; 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 applied: 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 uncertainty because great human variability is unlikely given the homogeneity of the animal data and a larger uncertainty factor yields 8-h AEGL-3 concentrations 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 neoplasia 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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TABLE 5-1 Summary of AEGL Values for Crotonaldehyde
Classification
10 min
30 min
1 h
4 h
8 h
End Point (Reference)
AEGL-1a (nondisabling)
0.19 ppm
(0.55 mg/m3)
0.19 ppm
(0.55 mg/m3)
0.19 ppm
(0.55 mg/m3)
0.19 ppm
(0.55 mg/m3)
0.19 ppm
(0.55 mg/m3)
Mild eye irritation in humans (Fannick 1982)
AEGL-2 (disabling)
27 ppm
(77 mg/m3)
8.9 ppm
(26 mg/m3)
4.4 ppm
(13 mg/m3)
1.1 ppm
(3.2 mg/m3)
0.56 ppm
(1.6 mg/m3)
Impaired pulmonary function, NOAEL for bronchiole lesions (Rinehart 1967)
AEGL-3 (lethal)
44 ppm
(130 mg/m3)
27 ppm
(77 mg/m3)
14 ppm
(40 mg/m3)
2.6 ppm
(7.4 mg/m3)
1.5 ppm
(4.3 mg/m3)
Lethality NOEL (Rinehart 1967).
aOdor 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 information 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 Governmental 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 choking, coughing, and a burning sensation on the face, in the nasal and oral passages, and in the upper respiratory tract as well as bronchoconstriction and pulmonary edema (HSDB 2005). Its odor threshold has been reported as 0.035-0.2
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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 natural 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, cauliflower, 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). Crotonaldehyde 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 alcohol, butyraldehyde, quinaldine, thiophenes, pyridenes, dyes, pesticides, pharmaceuticals, 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; discrete 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 detection and irritation thresholds for crotonaldehyde, perhaps in some cases due
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TABLE 5-2 Chemical and Physical Data
Property
Descriptor or Value
Reference
Synonyms
4170-30-3: 2-butenal, crotonal, crotonic aldehyde, 1-formyl-propene, β-methylacrolein 123-73-9: (E)-2-butenal, (E)-crotonaldehyde, trans-2-butenal, trans-crotonaldehyde
IARC 1995
Chemical formula
CH3CH = CH − CHO
Budavari et al. 1996
Molecular weight
70.09
Budavari et al. 1996
CAS registry number
4170-30-3 (mixture of cis and trans isomers)
123-73-9 (trans isomer)
IARC 1995
Physical state
Liquid
Budavari et al. 1996
Color
White liquid; yellows on contact with air
NIOSH 2002
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
Melting point
−76.5°C
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
Conversion factors
1 mg/m3 = 0.349 ppm; 1 ppm = 2.87 mg/m3
Verschueren 1996, 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 repeatedly (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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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 concentration 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 confounding 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 crotonaldehyde 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 crotonaldehyde 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 (Sandoz Colors and Chemicals) in East Hanover, New Jersey, at the request of workers 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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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 personal 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 concentration 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 summary 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 reproductive effects resulting from acute exposure to crotonaldehyde.
2.5.
Genotoxicity
Crotonaldehyde (5-250 µM) induced sister chromatid exchanges, structural (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 fluorescence in situ hybridization using a human centromere-specific DNA probe, indicating crotonaldehyde was acting by a clastogenic mechanism.
Nath et al. (1998) compared the levels of crotonaldehyde adducts in gingival 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 increase). Crotonaldehyde (without exogenous activation) also was shown to bind
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TABLE 5-3 Human Crotonaldehyde Exposure Data
Exposure Concentration
Exposure Time
End Point and Confounding Factors
Reference
0.035-0.2 ppm
0.037-1.05 ppm
0.12 ppm
Undefined
(a few seconds)
Odor thresholds from secondary sources; descriptions of most of the original studies were unavailable.
Verschueren 1996; Ruth 1986; Amoore and Hautala 1983
0.038 ppm
Undefined
(few seconds)
Subjects were exposed multiple times. Roughly half detected odor at this air concentration.
Tepikina et al. 1997
0.17 ppm
1 min
Odor detection and/or irritation; exposure through mask; undefined analytical method.
Trofimov 1962
0.56 ppm (up to 1.1 ppm)
<8 h
Occasional eye irritation; concentration up to 1.1 ppm; co-exposure to other chemicals.
Fannick 1982
4.1 ppm
15 min
(10 min)
Marked respiratory irritation; lacrimation in ~30 s; co-exposure to cigarette smoke.
Sim and Pattle 1957
3.5-14 ppm
3.8 ppm
Undefined
10 s
Irritation sufficient to wake a sleeping person
“Irritating within 10 s; no further details.
Fieldner et al. 1954
7.3 ppm
Undefined
(seconds?)
Very sharp odor and strong irritation to the eye and nose; no experimental details.
Dalla Vale and Dudley 1939
8 ppm
14 ppm (nose)
19 ppm (eyes)
Undefined
(a few seconds)
Irritation threshold; methods used to determine or define “irritation” were not given.
Ruth 1986; Amoore and Hautala 1983; Amoore and Hautala 1983
15 ppm
<30 s
Lab workers “sniffed” crotonaldehyde. Odor strong but not intolerable; no eye discomfort.
Rinehart 1967
45-50 ppm
<30 s
Lab workers “sniffed” crotonaldehyde. Odor strong, pungent, and disagreeable; burning sensation of conjunctivae but no lacrimation.
Rinehart 1967
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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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 carcinogen; EPA 2002) based on limited animal data (Chung et al. 1986; see Section 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 conditions or analytical measurements of concentration, which were often not reported. For example, laboratory workers who intentionally “sniffed” crotonaldehyde 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 occasional 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 deoxyguanosine 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 summarized in Table 5-4.
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TABLE 5-4 Acute Lethality of Crotonaldehyde Inhalation Exposure in Animals
Species
Exposure Time
Concentration (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
10 min
“Saturated” (~40,000)
LC0; no other effects described.
LC100; no other effects described.
(Smyth and Carpenter 1944; Smyth 1966; Union Carbide Corp. 1992)
Rat
6 h
35-98
LC0; rats had pink extremities, nasal irritation, and labored breathing
6 h on days 1,2,4
94-108
LC≥75; rats gasped, had pink extremities, one death after day 1, two after day 4 (other killed on day 5). Lungs were congested.
6 h
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 h
2,094-16,229
907; 1,256
LC100; death within 2 hours; gasping, pink extremities, tremors, convulsions, salivation, and prostration (Eastman Kodak Corp. 1992).
Rat
5 min
10 min
15 min
30 min
60 min
4 h
1,920-4,640
800-2,050
550-1,290
370-890
370-640
50-200
LC50 = 3132
LC50 = 1480
LC50 = 809
LC50 = 593
LC50 = 391
LC50 = 88
All rats gasped, had lowered respiratory rate, lost weight; excitatory stage was seen at ≥1000 ppm; most deaths by day 4, some had clear or blood-stained nasal discharge; few rats had pulmonary congestion (Rinehart 1967; see Table 5-5).
Rat
4 h
~70 (not stated)
LC50 = 70 ppm; no other effects described (Voronii et al. 1982).
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APPENDIX A
Derivation of AEGL-1 Values
Key study:
Fannick 1982. Human occupational exposure to a mean concentration of 0.56 ppm crotonaldehyde during a workday caused occasional eye irritation; exposure time not given but was <8 h.
Toxicity end point:
Ocular irritation.
Scaling:
None: 0.56 ppm = k; the critical end point (eye irritation) 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 irritation is a direct surface-contact effect not subject to pharmacokinetic differences between individuals.
Calculations:
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:
0.56 ppm/3 = 0.19 ppm (0.55 mg/m3)
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 concentration and time; individual concentrations and exposure times were not given) developed proliferative respiratory bronchiole lesions.
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Toxicity end point:
Moderate pulmonary impairment and NOAEL for proliferative lesions of the respiratory bronchioles.
Scaling:
C1 × t = k (concentration and time were approximately 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 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).
Calculations:
(Concentration)1 (30-480 min) = k = 8,000 ppm-min Apply the total UF of 30-8,000 ppm-min and get k = 267 ppm-min
10-min AEGL-2:
C1 × 10 min = 267 ppm-min
10 min AEGL-2 = 267 ppm-min/10 min = 27 ppm (77 mg/m3)
30-min AEGL-2:
C1 × 30 min = 267 ppm-min
30-min AEGL-2 = 267 ppm-min/30 min = 8.9 ppm (26 mg/m3)
1-h AEGL-2:
C1 × 60 min = 267 ppm-min
1 h AEGL-2 = 267 ppm-min/60 min = 4.4 ppm (13 mg/m3)
4-h AEGL-2:
C1 × 240 min = 267 ppm-min
4-h AEGL-2 = 267 ppm-min/240 min = 1.1 ppm (3.2 mg/m3)
8-h AEGL-2:
C1 × 480 min = 267 ppm-min
8-h AEGL-2 = 267 ppm-min/480 min = 0.56 ppm (1.6 mg/m3)
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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 exposure, 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.
Toxicity end point:
Lethality NOELs, estimated from LC01 values obtained 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 derive 8-h values
Scaling:
C1.2 × t = k (Rinehart 1967 LC50 data; ten Berge et al. 1986)
Uncertainty factors:
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; these studies yield similar or higher AEGL-3 values).
Intraspecies:
3, Great human variability is unlikely given the homogeneity of the animal data, and a larger uncertainty 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 AEGL-3:
10-min LC01 = 440 ppm
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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Calculations for 8 h:
8-h AEGL-3
C1.2 × 480 min = 755.4 ppm-min
8-h AEGL-3
C = 1.5 ppm (4.3 mg/m3)
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 crotonaldehyde. 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 detection (I = 3) is derived using the Fechner function:
For the Fechner coefficient, the default of kw = 2.33 will be used due to the lack of chemical-specific data:
The resulting concentration is multiplied by an empirical field correction factor. It takes into account that in 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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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.
The LOA for crotonaldehyde is 1.1 ppm.
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APPENDIX C
Category Plot for Crotonaldehyde
FIGURE 5-1 Category plot of human and animal toxicity data compared with AEGL values.
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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 carcinomas (combined) was 0/23, 11/27*, and 1/23 at 0, 0.6, and 6.0 mM, respectively (*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 calculation is performed as follows:
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 linearized multistage model (GLOBAL86 program; Howe et al. 1986), the inhalation 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 concentration 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:
An additional adjustment factor of 6 is applied to account for uncertainty regarding the stages of the carcinogenic process at which TNM or its metabolites may act (Crump and Howe 1984):
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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 unacceptably large inherent uncertainty; see Section 4.4.3.)
Exposure Duration
AEGL-2 Values (ppm) Based on Toxicity End Points
Crotonaldehyde Exposure Concentrations (ppm) with an Excess Cancer Risk of
10−4
10−5
10−6
½ h
8.9
221
22
2.2
1 h
4.4
110
11
1.1
4 h
1.1
28
2.8
0.28
8 h
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 factor, no reduction of exposure levels is applied to account for interspecies variability.
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 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 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 concentrations, 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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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. National 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 individuals.
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 concentrations 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 chemicals present.
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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 crotonaldehyde vapor. Am. Ind. Hyg. Assoc. J. 28:561-566.
Test species/Strain/Sex/Number: Male Sprague-Dawley rats; 12-16 per Ct (concentration × 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, although 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 crotonaldehyde vapor. Am. Ind. Hyg. Assoc. J. 28:561-566.
Test species/Strain/Sex/Number: Male Sprague-Dawley rats; 5-12/concentration (see below)
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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–mortality
10-min ppm–mortality
15-min ppm–mortality
30-min ppm–mortality
60 min ppm–mortality
240-min ppm–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 exponential 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 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: 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.