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Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 8
1
Acrolein1
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, AEGL-2, and AEGL-3—are developed for each of five exposure periods (10 and 30 min and 1, 4, 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
1
This document was prepared by the AEGL Development Team composed of Cheryl B. Bast (Oak Ridge National Laboratory) and Chemical Managers Robert Snyder and Paul Tobin (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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Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 8
effects. However, the effects are not disabling and are transient and reversible upon cessation of exposure.
AEGL-2 is the airborne concentration (expressed as ppm or mg/m3) of a substance above which it is predicted that the general population, including susceptible individuals, could experience irreversible or other serious, long-lasting adverse health effects, or an impaired ability to escape.
AEGL-3 is the airborne concentration (expressed as ppm or mg/m3) of a substance above which it is predicted that the general population, including susceptible individuals, could experience life-threatening health effects or death.
Airborne concentrations below the AEGL-1 represent exposure levels that could produce mild and progressively increasing but transient and nondisabling odor, taste, and sensory irritation or certain asymptomatic, 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 AEGLs 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 idiosyncratic responses, could experience the effects described at concentrations below the corresponding AEGL.
SUMMARY
Acrolein is a colorless or yellowish liquid at ambient temperature and pressure. It has an acrid, pungent odor and is highly irritating to mucous membranes, especially the upper respiratory tract and eyes. The odor threshold is <0.1 ppm (Beauchamp et al. 1985). It is manufactured by air oxidation of propylene and is used as an intermediate in the production of acrylic acid. It is also used as a herbicide, algicide, and slimicide, in the cross-linking of protein collagen in leather tanning, as a fixative of histologic samples, and in the production of perfumes. Acrolein has also been used in military poison gas mixtures. The largest sources of human exposure to acrolein are from incomplete combustion of organic materials (such as in urban fires and forest fires), tobacco smoke, and the burning of fat-containing foods (Beauchamp et al. 1985).
The AEGL-1 values were based on very slight eye irritation and “annoyance” or discomfort observed in human subjects exposed to acrolein at 0.09 ppm (Weber-Tschopp et al. 1977). An intraspecies uncertainty factor of 3 was applied and is considered sufficient because minor ocular contact irritation is unlikely to vary greatly among humans. The values were held constant across time for the 10-min, 30-min, 1-h, 4-h, and 8-h time points because minor irritancy is generally a threshold effect, and prolonged exposure is not likely to result in a greatly enhanced effect.
The AEGL-2 was based on a 10-15% decrease in respiratory rate in healthy human subjects exposed to acrolein at 0.3 ppm for 1 h (Weber-Tschopp
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et al. 1977). According to ASTM (1991), decreases in respiratory rate in the range of 12% to 20% correspond to slight irritation, and decreases in respiratory rate in the range of 20% to 50% correspond to moderate irritation. Thus, the point-of-departure is considered a no-observed-adverse-effect level (NOAEL) for moderate irritation. An intraspecies uncertainty factor of 3 was applied and is considered sufficient because irritation is unlikely to vary greatly among humans. This uncertainty factor is further justified because of the sensitivity of the methods used, the fact that the point-of-departure effect was only a very small detectable decrease in respiration, the lack of evidence of marked variability across the study group, including women; and the fact that at twice the concentration, respiration was still only slightly decreased. Also, application of the default uncertainty factor of 10 would yield AEGL-2 values in the concentration range where only minor irritation was noted in controlled human studies. This value was back-extrapolated to the 10- and 30-min time points using the relationship Cn × t = k (ten Berge et al. 1986), where n = 1.2 (derived from lethality data in rats exposed to acrolein from 1 to 4 h). The 1-h exposure of 0.3 ppm was held constant for the 4- and 8-h AEGL-2 values since irritation is generally a threshold effect, and prolonged exposure is not likely to result in a greatly enhanced effect.
The 10-min, 30-min, and 1-h AEGL-3 values were based on the highest concentration causing no mortality in the rat after a 1-h exposure (14 ppm), and the 4-h and 8-h AEGL-3 values were based on the highest concentration causing no mortality in the rat after a 4-h exposure (4.8 ppm) (Ballantyne et al. 1989). Intraspecies and interspecies uncertainty factors (UFs) of 3 each were applied (total UF = 10) and are considered sufficient because irritation is not expected to vary greatly within or among species. Furthermore, application of either an intra- or interspecies uncertainty factor of 10 (total UF = 30) would yield values that are inconsistent with the total database. (For example, AEGL-3 values for acrolein would range from 2.1 to 0.09 ppm and only ocular, nasal, or throat irritation and decreased respiratory rates were observed in humans exposed to acrolein at concentrations of 0.09 to 0.6 ppm for up to 40 min (Weber-Tschopp, et al. 1977). People exposed to this range of acrolein for 10 min to 8 h probably would experience effects defined by AEGL-3. Values were extrapolated using the relationship Cn × t = k (ten Berge et al. 1986), where n = 1.2 (derived from lethality data in rats exposed to acrolein from 1 to 4 h).
The calculated values are listed in Table 1-1.
1.
INTRODUCTION
Acrolein is a colorless or yellowish liquid at ambient temperature and pressure. It has an acrid, pungent odor and is highly irritating to mucous membranes, especially the upper respiratory tract and eyes. The odor threshold is <0.1 ppm (Beauchamp et al. 1985).
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Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 8
TABLE 1-1 Summary of AEGL Values for Acrolein
Classification
10 min
30 min
1 h
4 h
8 h
End Point (Reference)
AEGL-1 (Nondisabling)
0.030 ppm (0.070 mg/m3)
0.030 ppm (0.070 mg/m3)
0.030 ppm (0.070 mg/m3)
0.030 ppm (0.070 mg/m3)
0.030 ppm (0.070 mg/m3)
Very slight eye irritation, “annoyance” and discomfort in humans (Weber-Tschopp et al. 1977)
AEGL-2 (Disabling)
0.44 ppm (0.92 mg/m3)
0.18 ppm (0.41 mg/m3)
0.10 ppm (0.23 mg/m3)
0.10 ppm (0.23 mg/m3)
0.10 ppm (0.23 mg/m3)
10-15% decrease in respiratory rate in humans (Weber-Tschopp et al. 1977)
AEGL-3 (Lethal)
6.2 ppm (14 mg/m3)
2.5 ppm (5.7 mg/m3)
1.4 ppm (3.2 mg/m3)
0.48 ppm (1.1 mg/m3)
0.27 ppm (0.62 mg/m3)
1 h (10-min, 30-min and 1-h values) or 4 h (4-h and 8-h values) no-effect level for death in rats (Ballantyne et al. 1989)
Acrolein is manufactured by air oxidation of propylene and is used as an intermediate in the production of acrylic acid. It is also used as a herbicide, algicide, and slimicide, in the cross-linking of protein collagen in leather tanning, as a fixative of histologic samples, and in the production of perfumes. Acrolein has also been used in military poison-gas mixtures (ATSDR 2007). The production volume of acrolein in the United States was more than 100-500 million pounds in 1998 (ATSDR 2007).
The largest sources of human exposure to acrolein are from incomplete combustion of organic materials (such as in urban fires and forest fires), tobacco smoke, and the burning of fat-containing foods (Beauchamp et al. 1985).
The chemical structure is depicted below, and the physical and chemical properties of acrolein are presented in Table 1-2.
2.
HUMAN TOXICITY DATA
2.1.
Acute Lethality
Information concerning death in humans following inhalation exposure to acrolein is limited and anecdotal. Henderson and Haggard (1943) reported that exposure to acrolein at 150 ppm is fatal after 10 min. Gosselin et al. (1979) described the case of a 4-year-old boy exposed to smoke containing acrolein from an overheated fryer. Death occurred by “asphyxia” 24 h after the 2-h exposure to smoke. Autopsy indicated massive cellular desquamation of the bronchial lining, miscellaneous debris in the bronchial lumen, and multiple pulmonary infarcts. The boy’s 2-year-old brother also died, but no details were presented concerning his case. No acrolein concentration was reported, and smoke components in addition to the acrolein probably were partially responsible for the observed pathology.
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TABLE 1-2 Chemical and Physical Data for Acrolein
Parameter
Data
Reference
Common Name
Acrolein
ATSDR 2007
Synonyms
Acraldehyde, acrylaldehyde, allyl aldehyde, 2-propenal, propylene aldehyde
ATSDR 2007
CAS registry no.
107-02-8
ATSDR 2007
Chemical formula
C3H4O
ATSDR 2007
Molecular weight
56.06
O’Neil et al. 2001
Physical state
Liquid
O’Neil et al. 2001
Odor threshold
<0.1 ppm
Beauchamp et al. 1985
0.03-0.034 ppm: acrolein-sensitive persons
Beauchamp et al. 1985
ATSDR 2007
0.16 ppm
Melting, boiling, and flash points
−88°C/52.5°C/−18°C (open cup)
O’Neil et al. 2001
Density
0.8389 g/m3 at 20°C
O’Neil et al. 2001
Solubility
212,000 mg/L in water at 25°C; miscible with lower alcohols, ethers, hydrocarbons, acetone, benzene
ATSDR 2007
Vapor pressure
210 mm Hg at 20°C
O’Neil et al. 2001
1 ppm = 2.328 mg/m3
ATSDR 2007
1 mg/m3 = 0.43 ppm
2.2.
Nonlethal Toxicity
2.2.1.
Case Reports
Champeix et al. (1966) described high fever, dyspnea, cough, foamy ex-pectoration, cyanosis, and pulmonary edema in a 36-year-old man exposed to an undetermined concentration of acrolein in the course of one work day. Eighteen months after exposure, pneumonopathy, bronchitis, and emphysema were still present. Bauer et al. (1977) described similar respiratory effects in a 21-year-old man exposed to smoke from an overheated pan for 6 h. No other details were available, and components of the smoke in addition to acrolein may have contributed to the observed effects.
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2.2.2.
Experimental Studies
Lachrymation and marked eye, nose and throat irritation were observed within 20 seconds (s) in individuals exposed to acrolein at 0.81 ppm and within 5 s in those exposed at 1.22 ppm (Sim and Pattle 1957).
The effects of inhalation exposure to acrolein were evaluated in human volunteers in a series of three experiments as follows: (1) a “continuous” exposure at steadily increasing concentrations; (2) several exposures of short duration at continuously increasing concentrations; and (3) a longer exposure period (1 h) at a constant acrolein concentration (Weber-Tschopp et al. 1977). Subjectively perceived irritation and “annoyances” (the closest translation; another term might be “discomfort”) by means of a scaled questionnaire; eye-blinking rate; and respiratory rate via an elastic measurement tape that registered breath movements in the lower rib area were recorded during the exposures.
For the “continuous” exposure, 53 healthy students (31 men and 22 women) were divided into groups of three. Each volunteer was subjected to two experiments, one involving exposure to acrolein and the other without acrolein under identical conditions (control experiment). The duration of the experiments was 40 min, during which the acrolein concentration rose from 0 to 0.60 ppm in the first 35 min and remained constant during the last 5 min of the experiment. Each volunteer had to fill out the questionnaire every 5 min. Immediately after that, the blinking rate was measured for two subjects (of the groups of three). For the third subject, the respiratory rate was monitored continuously during the entire experimental period.
In the second of the series of experiments, 42 healthy students (17 men and 25 women) participated in an interrupted exposure experiment. Groups of four subjects were exposed to acrolein at 0, 0.15, 0.30, 0.45, and 0.60 ppm. Each individual was exposed to each concentration for 1.5 min five times with 8-min recovery periods in between. One minute into each exposure, they received the questionnaire.
Finally in the third of the series of experiments, 46 healthy students (21 men and 25 women) were exposed (in groups of three) to acrolein at 0.3 ppm for 60 min. Eye-blinking rate, respiratory rate, and subjective irritation determined immediately before exposure served as the control. The remainder of the protocol was identical to that for “continuous” exposure.
The acrolein was introduced with a microliter syringe, evaporated, and blown into a 30-m3 climate chamber by means of a carrier gas stream. The acrolein concentrations were measured continually during the experiment with a Technicon air monitor IV system by reaction of acrolein with 4-hexylresorcin in an ethyl alcohol-trichloroacetic acid solution in the presence of mercury chloride. Measured concentrations were within 3.8% of target concentrations.
Annoyance increased with increasing acrolein concentration (from 0 to 0.6 ppm) for both continuous and interrupted exposure regimens. A significant dif-
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Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 8
ference between continuous and interrupted exposure was seen only at 0.15 ppm. Annoyance was significantly higher with the interrupted exposure to acrolein compared with the continuous exposure (p < 0.01 for opinion on air quality; p < 0.05 for wish to leave the room). During the 1-h exposure at 0.3 ppm, annoyance increased during the first 20-30 min and then remained constant. The authors assumed that during the first phase of exposure, an adaptation to the irritant took place, which disappeared at the higher concentrations and/or longer exposure durations.
In the continuous and the interrupted exposure experiments, ocular and nasal irritation increased significantly with increasing acrolein concentration; apparently, the eyes were more sensitive than the nose. Very slight ocular irritation was reported at 0.09 ppm, whereas nasal irritation was reported at 0.15 ppm. Throat irritation in both experiments was found to be a less sensitive criterion. In the continuous experiment, throat irritation increased significantly only at 0.43 ppm; in the interrupted experiment, there was no change. Ocular, nasal, and throat irritation also increased with increasing exposure duration during the 1-h exposure to acrolein at 0.3 ppm. The subjective irritation reached an intensity that remained constant after about 40 min.
When compared with the control experiment without acrolein where no effects on annoyance or irritation were observed, the differences between control and acrolein experiments were significant (p < 0.05).
In the continuous exposure regimen, the eye-blinking rate increased at concentrations from 0.17 ppm and greater in a concentration-dependent manner; the increase became significant (p < 0.01) once the acrolein concentration reached 0.26 ppm. The mean initial value of blinking rate was doubled at about 0.3 ppm. In the 1-h exposure (0.3 ppm), the blinking rate reached this point after only 10 min.
The respiratory rate decreased slightly with increasing acrolein concentration in the continuous exposure experiment. Compared with controls, the decrease was statistically significant at 0.6 ppm, with an average decrease of 25%. There was also a decrease in mean respiratory rate over the course of the 1-h exposure to acrolein at 0.3 ppm. An average decrease of 10-15% was observed after both 10 and 20 min of exposure, and the decrease was significant (p < 0.01) from 40 min on and fluctuated between 2.9 and 3.4 breaths/min (average 20% decrease).
Summarizing data from all the experiments conducted, thresholds for significant changes of the measured parameters are presented in Table 1-3, while effects at constant exposure of 0.3 ppm are presented in Table 1-4.
In another study, 36 students (26 male and 10 female) were exposed to acrolein at 0, 0.06, 1.3-1.6, or 2.0-2.3 ppm through an eye mask for 5 min (Darley et al. 1960). A 16-cubic-foot glass and aluminum fumigation chamber was constructed and operated as a stirred flow reactor. The chamber was set up in a greenhouse to study damage to plants from acrolein exposure. Three eye irrita-
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Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 8
TABLE 1-3 Effect Thresholds in Human Volunteers Exposed to Acrolein
Effect
Measurement
“Annoyance”
0.09 ppm
Very slight eye irritation
0.09 ppm
Nose irritation
0.15 ppm
Doubling of blinking rate
0.26 ppm
10% decrease in respiratory rate
0.3 ppm
Throat irritation
0.43 ppm
25% Decrease in respiratory rate
0.6 ppm
aValues combined from 1-h exposure and “continuous” exposure regimens.
TABLE 1-4 Effects Human in Subjects Exposed to Acrolein at 0.3 ppm
Effect
% of Subjects after 10 min
% of Subjects after 20 min
Wish to leave room
50
72
Moderate eye irritation
18
35
Severe eye irritation
3
18
Moderate Nose Irritation
7
19
Severe nose irritation
1
4
Moderate throat irritation
1
2
Severe throat irritation
0
1
Doubling of blinking rate
66
70
10-15% decrease in respiratory rate
47
60
tion booths were constructed adjacent to the plant exposure chamber. The exhaust air from the chamber was run in an all glass system to a manifold and then through three airflow lines, one to each eye exposure booth. The end of each line was connected to a loose-fitting plastic face mask. Acrolein was diluted in water and the mixture dispensed from a syringe into a stream of oxygen. Concentrations were determined by absorbing the vapors in a buffered semi-carbazide-hydrochloride solution and reading the absorbance on a spectrophotometer. During exposure, the subjects wore activated carbon respirators to breath clean air, and only the eyes were exposed to the acrolein. Each student recorded the degree of irritation every 30 s during the 5-min exposure. Irritation was rated as none (score 0), medium (score 1), or severe (score 2). The maximum value recorded by a subject during a test was used as the response for that experimental session. Average maximum irritation scores are as follows: 0 ppm = 0.361, 0.06 ppm = 0.471, 1.3-1.6 ppm = 1.182, and 2.0-2.3 ppm = 1.476. The filtered-air irritation score (0.361) and the 0.06-ppm acrolein score (0.471) are both <0.5, where 0 is defined as “no irritation” and 1 is defined as “medium irritation.”
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The conditions of this study did not allow distinguishing between slight irritation caused by other constituents of the greenhouse air, or even air movement in the eye mask, and that caused by acrolein at 0.06 ppm.
2.3.
Developmental and Reproductive Toxicity
Developmental and reproductive studies regarding acute human exposure to acrolein were not available.
2.4.
Genotoxicity
Genotoxic studies regarding acute human exposure to acrolein were not available.
2.5.
Carcinogenicity
Carcinogenicity studies regarding human exposure to acrolein were not available.
2.6.
Summary
Information concerning human mortality from acrolein exposure is limited and anecdotal. Nonlethal case reports and experimental studies with healthy human volunteers suggest that low concentrations of acrolein are irritating to the eyes, nose, and throat and cause a decrease in respiratory rate. At higher concentrations, coughing, pulmonary edema (may be delayed in onset), bronchitis, or tracheobronchitis may occur. No information concerning effects in young, elderly, or asthmatic individuals was available. No information concerning reproductive and developmental toxicity, genotoxicity, or carcinogenicity was located.
3.
ANIMAL TOXICITY DATA
3.1.
Acute Lethality
3.1.1.
Nonhuman Primates
As the result of exposure to acrolein during an escape-performance test, one male baboon died 1.5 h after exposure to 2,780 ppm acrolein and another died 24 h after exposure to 1,025 ppm (Kaplan 1987). Both animals developed severe respiratory effects and died from pulmonary edema. This study is described in detail in section 3.2.1.
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3.1.2.
Rats
Ballantyne et al. (1989) exposed groups of five male and five female Sprague-Dawley rats to acrolein at 14, 22, 24, 31, or 81 ppm for 1 h or at 4.8, 7.0, 9.1, or 12.1 ppm for 4 h, followed by a 14-day observation period. Acrolein vapor was dynamically generated by metering pure liquid acrolein from a syringe pump into a heated glass evaporator. Glass beads were added to the evaporator to increase the surface area for vaporization. The vapor was then carried to the exposure chamber by a stream of air passing through the evaporator. The different concentrations of acrolein were obtained by varying the generation temperature, airflow rate through the generator, or airflow rate through the chamber. Chamber atmospheres were sampled four to six times during the 1-h exposures and 10 times during the 4-h exposures and were analyzed by gas chromatography. Lachrymation, perinasal, and periocular wetness, and mouth breathing were observed at all acrolein concentrations during exposure. After exposure, perinasal and perioral wetness and encrustation, mouth and audible breathing, decreased breathing rate, and hypoactivity were observed in all groups. Concentration-dependent signs of respiratory distress and hypoactivity were observed during post-exposure days 1 through 6. Body weights of surviving animals decreased during week 1 and recovered thereafter. Combined maleand female LC50 values (concentration with 50% lethality) of 26 ppm and 8.3 ppm were calculated for 1 h and 4 h, respectively. Necropsy of decedents revealed perinasal and perioral encrustation, mottled discoloration of the lungs and liver, clear fluid in the trachea and thoracic cavity, gas-filled stomach and intestine, and opaque or cloudy corneas. Histologically, pulmonary congestion and intraalveolar hemorrhage, fibrin deposition in the small airways, and necrosis and exfoliation of bronchiolar epithelia were observed in decedents. Mortality data are summarized in Table 1-5.
TABLE 1-5 Mortality of Rats Exposed to Acrolein for 1 or 4 Hours
Exposure Time
Concentration (ppm) Mean ± Standard Deviation
Mortality
Time to Death After Exposure
Males
Females
1-h
81 ± 1
5/5
5/5
3 h- 3 days
31 ± 2
5/5
5/5
3 h- 6 days
24 ± 1
2/5
1/5
1-3 days
22 ± 5
0/5
1/5
2 days
14 ± 7
0/5
0/5
—
4-h
12.1± 0.4
5/5
3/5
1-3 days
9.1 ± 1.4
3/5
4/5
1-13 days
7.0 ± 0.2
3/5
0/5
1-5 days
4.8 ± 0.2
0/5
0/5
—
Source: Ballantyne et al. 1989. Reprinted with permission; copyright 1989, Human & Experimental Toxicology.
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3.1.3.
Guinea Pigs
Male Dunkin-Hartley guinea pigs were exposed to acrolein at 0 or 1.6 ppm for 7.5 h on each of two consecutive days (Turner et al. 1993). There were no deaths in the control group, and 14% of the acrolein-exposed animals died. In another study, guinea pigs died 6 min into an exposure at 1,600 ppm (Davis et al. 1967). These studies and their nonlethal effects are described in section 3.2.4.
3.1.4.
Other Data
Acute lethality data were available for mice, rats, dogs, cats, hamsters, rabbits, and guinea pigs; however experimental details such as animal strains, exposure systems, and concentration-response data were unavailable. These data are summarized in Table 1-6.
3.2.
Nonlethal Toxicity
3.2.1.
Nonhuman Primates
Kaplan (1987) exposed juvenile male baboons (one per concentration) to acrolein at 12, 25, 95, 100, 250, 505 (two animals) 1,025, or 2,780 ppm for 5 min. The animals had been trained to perform an avoidance and escape test. After 5 min of exposure, the escape test was presented to the animal. If the animal did not exit within 10 s, shock was applied to the bars of the cage and maintained for 20 s. If the animal exited within 10 s, the response was designated “avoidance.” If the animal exited after 10 s but within 30 s, the response was designated “escape.” Avoidance and escape responses were both considered successful escape performance. Exposure to acrolein did not prevent the escape task: all acrolein-exposed animals made the avoidance response. Although not statistically significant, test escape times were slightly less during exposure when compared with pre-exposure times. Baboons exposed at 1,025 and 2,780 ppm developed severe respiratory complications and died from severe pulmonary edema 24 h and 1.5 h after exposure, respectively.
3.2.2.
Mice
Kane et al. (1979) exposed groups of four male Swiss-Webster mice to concentrations of aerosolized acrolein ranging from 0.1 to 100 ppm for 10 min to determine a reference dose (RD50). The mice were placed in a glass exposure chamber with the body of each animal in an airtight plethysmograph, and only the head extending into the exposure chamber. Each of the four plethysmographs of the mouse exposure chamber was connected to a pressure transducer to sense pressure changes created during inspiration and expiration. Each
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NIOSH immediately dangerous to life and health (IDLH) is defined by the NIOSH/OSHA Standard Completions Program only for the purpose of respirator selection and represents a maximum concentration from which, in the event of respiratory failure, one could escape within 30 min without experiencing any escape-impairing or irreversible health effects.
OSHA permissible exposure level (PEL) is a time-weighted average (8 h/d, 40 h/wk).
8.3.
Data Quality and Research Needs
Human data appropriate for derivation of AEGL-1 and AEGL-2 were available in a well-conducted study. However, no information was available concerning acrolein effects in young, elderly or asthmatic individuals. Animal data were available for derivation of AEGL-3 values. Although there are a plethora of acrolein studies, many are not appropriate for derivation of AEGL values. Well-conducted acute toxicity studies in animal species other than the rat might help support the derived AEGL values.
9.
REFERENCES
ACGIH (American Conference of Governmental Industrial Hygienists). 2003. TLVs and BEIs: Threshold Limit Values for Chemical Substances and Physical Agents and Biological Exposure Indices. American Conference of Governmental Industrial Hygienists, Cincinnati, OH.
AIHA (American Industrial Hygiene Association). 2004. Emergency Response Planning Guidelines and Workplace Environmental Exposure Level Guides Handbook. Fairfax ,VA: AIHA Press.
Alarie, Y., L. Kane, and C. Barrow. 1981. Sensory irritation: The use of an animal model to establish acceptable exposure to airborne chemical irritants. Pp. 48-92 in Toxicology: Principles and Practice, Vol. 1, A.L. Reeves, ed. New York: John Wiley and Sons.
Albin, T.B. 1962. Acrolein handling and toxicity. Pp. 234-239 in Acrolein, C.W. Smith, ed. New York: John Wiley and Sons.
Aranyi, C., W.J. O’Shea, J.A. Graham, and F.J. Miller. 1986. The effects of inhalation of organic chemical air contaminants on murine lung host defenses. Fundam. Appl. Toxicol. 6(4):713-720.
ASTM (American Society for Testing and Materials). 1991. Standard test method for estimating sensory irritancy of airborne chemicals, E981-84 Vol. 11.04. Pp. 610-618 in Annual Book of ASTM Standards, Vol. 11. Philadelphia: American Society for Testing and Materials.
Astry, C.L., and G.J. Jakab. 1983. The effects of acrolein exposure on pulmonary antibacterial defenses. Toxicol. Appl. Pharmacol. 67(1):49-54.
ATSDR (Agency for Toxic Substances and Disease Registry). 2007. Toxicological Profile for Acrolein. U.S. Department of Health and Human Services, Public Health Service, Agency for Toxic Substances and Disease Registry, Atlanta, GA. August
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2007[online]. Available: http://www.atsdr.cdc.gov/toxprofiles/tp124.pdf [accessed Oct. 21, 2008].
Ballantyne, B., D.E. Dodd, I.M. Pritts, D.J. Nachreiner, and E.H. Fowler. 1989. Acute vapour inhalation toxicity of acrolein and its influence as a trace contaminant in 2-methoxy-3,4-dihydro-2H-pyran. Hum. Toxicol. 8(3):229-235.
Bauer, K., K. Czech, and A. Porter. 1977. Severe accidental acrolein intoxication in the home [in German]. Wien Klin. Wochhenschr. 89(7):243-244.
Beauchamp, R.O., D.A. Andjelkovich, A.D. Klingerman, K.T. Morgan, and H.D. Heck. 1985. A critical review of the literature on acrolein toxicity. Crit. Rev. Toxicol. 14(4):309-380.
Bouley, G., A. Dubreuil, J. Godin, M. Boisset, and C. Boudène. 1976. Phenomena of adaptation in rats continuously exposed to low concentrations of acrolein. Ann. Occup. Hyg. 19(1):27-32.
Buckley, L.A., X.Z. Jiang, R.A. James, K.T. Morgan, and C.S. Barrow. 1984. Respiratory tract lesions induced by sensory irritants at the RD50 concentration. Toxicol. Appl. Pharmacol. 74(3):417-429.
Carpenter, C.P., H.F. Smyth, and U.C. Pozzani. 1949. The assay of acute vapor toxicity, and the grading and interpretation of results on 96 chemical compounds. J. Ind. Hyg. Toxicol. 31(6):343-346.
Catalina, P., L. Thieblot, and J. Champeix. 1966. Experimental respiratory lesions by inhalation of acrolein in the rat [in French]. Arch. Mal. Prof. 27(12):857-867.
Champeix, J., L. Courtial, E. Perche, and P. Catalina. 1966. Acute broncho-pneumopathy from acrolein vapors [in French]. Arch. Mal. Prof. 27(10):794-796.
Costa, M., A. Zhitkovich, M. Harris, D. Pastenbach, and M. Gargas. 1997. DNA-protein cross-links produced by various chemicals in cultured human lymphoma cells. J. Toxicol. Environ. Health 50(5):433-449.
Darley, E.F., J.T. Middleton, and M.J. Garber. 1960. Plant damage and eye irritation from ozone-hydrocarbon interactions. J. Agr. Food. Chem. 8(6):483-485.
Davis, T.R., S.P. Battista, and C.J. Kensler. 1967. Mechanism of respiratory effects during exposure of guinea pigs to irritants. Arch. Environ. Health 15(4):412-419.
Egle, J.L. 1972. Retention of inhaled formaldehyde, propionaldehyde, and acrolein in the dog. Arch. Environ. Health 25(2):119-124.
Feron, V.J., and A. Kruysse. 1977. Effects of exposure to acrolein vapor in hamsters simultaneously treated with benzo(a)pyrene or diethylnitrosamine. J. Toxicol. Environ. Health 3(3):379-394.
Gosselin, B., F. Wattel, C. Chopin, P. Degand, J.C. Fruchart, D. van der Loo, and O. Crasquin. 1979. A case of acute acrolein poisoning [in French]. Nouv. Presse. Med. 8(30):2469-2472.
Hales, C.A., P.W. Barkin, W. Jung, E. Trautman, D. Lamorghini, N. Herrig, and J. Burke. 1988. Synthetic smoke with acrolein but not HCl produces pulmonary edema. J. Appl. Physiol. 64(3):1121-1133.
Henderson, Y., and H.W. Haggard. 1943. Noxious Gases. New York: Reinhold Publishing Co.
ITII (International Technical Information Institute). 1975. Acrolein. Pp. 13-14 in Toxic and Hazardous Industrial Chemical Safety Manual for Handling and Disposal with Toxicity and Hazard Data. International Technical Information Institute, Tokyo, Japan (as cited in Beauchamp et al. 1985).
Iwanoff, N. 1910. Experimentelle Studien uber den Einfluss technisch und hygienisch wichtiger Gase und Dampfe auf den Organismus. XVI, XVII, XVIII. Uber einige
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praktisch wichtige Aldehyde (Formaldehyd, Acetaldehyd, Akrolein). Arch. Hyg. 73:307-340 (as cited in Beauchamp et al. 1985).
Kane, L.E., C.S. Barrow, and Y. Alarie. 1979. A short-term test to predict acceptable levels of exposure to airborne sensory irritants. Am. Ind. Hyg. Assoc. J. 40(3):207-229.
Kaplan, H.L. 1987. Effects of irritant gases on avoidance/escape performance and respiratory response in the baboon. Toxicology 47(1-2):165-179.
Kruysse, A. 1971. Acute Inhalation Toxicity of Acrolein in Hamsters. Report R 3516. Zeist,The Netherlands: Central Institute for Nutrition and Food Research (as cited in Feron and Kruysse 1977).
Kutzman, R.S., E.A. Popenoe, M. Schmaeler, and R.T. Drew. 1981. Changes in rat lung structure and composition as a result of subchronic exposure to acrolein. Toxicology 34(2):139-151.
Le Bouffant, L., J.C. Martin, H. Daniel, J.P. Henin, and C. Normand. 1980. Action of intensive cigarette smoke inhalation on the rat lung. Role of particulate and gaseous cofactors. J. Natl. Cancer Inst. 64(2):273-284.
Li, L., R.F. Hamilton, D.E. Taylor, and A. Holian. 1997. Acrolein-induced cell death in human alveolar macrophages. Toxicol. Appl. Pharmacol. 145(2):331-339.
MSZW (Ministerie van Sociale Zaken en Werkgelegenheid). 2004. Nationale MAC-lijst 2004: Acrylaldehyde. Den Haag: SDU Uitgevers [online]. Available: http://www.lasrook.net/lasrookNL/maclijst2004.htm [accessed Oct. 24, 2008].
Murphy, S.D., D.A. Klingshirn, and C.E. Ulrich. 1963. Respiratory response of guinea pigs during acrolein inhalation and its modification by drugs. J. Pharmacol. Exp. Therap. 141:79-83.
Murphy, S.D., H.V. Davis, and V.L. Zaratzian. 1964. Biochemical effects in rats from irritating air contaminants. Toxicol. Appl. Pharmacol. 6:520-528.
Nielsen, G.D., J.C. Bakbo, and E. Holst. 1984. Sensory irritation and pulmonary irritation by airborne allyl acetate, allyl alcohol, and allyl ether compared to acrolein. Acta Pharmacol. Toxicol. 54(4):292-298.
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)-Acrolein. U.S. Department of Health and Human Services, Centers for Disease Control and Prevention, National Institute of Occupational Safety and Health. August 1996 [online]. Available: http://www.cdc.gov/niosh/idlh/107028.html [accessed Oct. 16, 2008].
NIOSH (National Institute of Occupational Safety and Health). 2005. NIOSH Pocket Guide to Chemical Hazards: Acrolein. 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/npgd0011.html [accessed Oct. 16, 2008].
NRC (National Research Council). 1993. Guidance for Developing Community Emergency Exposure Levels for Hazardous Substances. Washington, DC: National Academy Press.
NRC (National Research Council). 2001. Standing Operating Procedures for Developing Acute Exposure Guideline Levels for Hazardous Chemicals. Washington, DC: National Academy Press.
O’Neil, M.J., A. Smith, P.E. Heckelman, J.R. Obenchain, Jr., J. Gallipeau, and M.A. D’Arecca. 2001. Acrolein. Pp. 24 in The Merck Index: An Encyclopedia of Chemicals, Drugs, and Biologicals, 13th Ed. Whitehouse Station, NJ: Merck.
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Patel, J.M., J.C. Wood, and K.C. Leibman. 1980. The biotransformation of allyl alcohol and acrolein in rat liver and lung preparations. Drug. Metab. Dispos. 8(5):305-308.
Pattle, R.E., and H. Cullumbine. 1956. Toxicity of some atmospheric pollutants. Br. Med. J. 2(4998):913-916.
Phillippin, C., A. Gilgen, and E. Grandjean. 1970. Toxicological and physiological investigation on acrolein inhalation in the mouse. Int. Arch. Arbeitsmed. 26(4):281-305.
Sim, V.M., and R.E. Pattle. 1957. Effect of possible smog irritants on human subjects. JAMA 165(15): 1908-1913.
Skog, E. 1950. A toxicological investigation of lower aliphatic aldehydes. I. Toxicity of formaldehyde, acetaldehyde, propionaldehyde and butyraldehyde, as well as acrolein and crotonaldehyde. Acta Pharmacol. Toxicol. 6(4):299-318.
Springall, D.R., J.A. Edginton, P.N. Price, D.W. Swanston, C. Noel, S.R. Bloom, and J.M. Polak. 1990. Acrolein depletes the neuropeptides CGRP and substance P in sensory nerves in rat respiratory tract. Environ. Health Perspect. 85:151-157.
Steinhagen, W.H., and C.S. Barrow. 1984. Sensory irritation structure-activity study of inhaled aldehydes in B6C3F1 and Swiss-Webster mice. Toxicol. Appl. Pharmacol. 72(3):495-503.
Swedish Work Environment Authority. 2005. Occupational Exposure Limit Value and Measures against Air Contaminants. AFS 2005:17 [online]. Available: http://www.av.se/dokument/inenglish/legislations/eng0517.pdf [accessed Oct. 21, 2008].
ten Berge, W.F., A. Zwart, and L.M. Appelman. 1986. Concentration-time mortality response relationship of irritant and systemically acting vapours and gases. J. Hazard. Mater. 13(3):301-309.
Turner, C.R., R.B. Stow, S.D. Talerico, E.P. Christian, and J.C. Williams. 1993. Protective role for neuropeptides in acute pulmonary response to acrolein in guinea pigs. J. Appl. Physiol. 75(6): 2456-2465.
Weber-Tschopp, A., T. Fischer, R. Gierer, and E. Grandjean. 1977. Experimentally induced irritating effects of acrolein on men [in German]. Int. Arch. Occup. Environ. Health 40(2):117-130.
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Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 8
APPENDIX A
Derivation of AEGL Values for Acrolein
Derivation of AEGL-1
Key study:
Weber-Tschopp et al. 1977
Toxicity end point:
Very slight eye irritation and “annoyance” or discomfort in healthy humans.
Scaling:
None
Uncertainty factor:
3 for intraspecies variability.
AEGL-1: (all time periods)
0.09 ppm ÷ 3 = 0.030 ppm
Derivation of AEGL-2
Key study:
Weber-Tschopp et al. 1977.
Toxicity end point:
10-15% decrease in respiratory rate in healthy humans
Scaling:
C1.2 × t = k for extrapolation to 10 and 30 min
(0.3 ppm) C1.2 × 1 h = 0.236 ppm-h
The 1-h exposure of 0.3 ppm was held constant for the 1-h, 4-h, and 8-h. AEGL-2 values since irritation is generally a threshold effect and a prolonged exposure is not likely to result in a greatly enhanced effect.
Uncertainty factor:
3 for intraspecies variability.
Calculations:
10-min AEGL-2
C1.2 × 0.167 h = 0.236 ppm-h
C1.2 = 1.41 ppm
C = 1.33 ppm
10-min AEGL-2 = 1.33 ÷ 3 = 0.44 ppm
30-min AEGL-2
C1.2 × 0.5 h = 0.236 ppm-h
C1.2 = 0.472 ppm
C = 0.535 ppm
30-min AEGL-2 = 0.535 ÷ 3 = 0.18 ppm
1-, 4-, and 8-h AEGL-2
0.3 ppm ÷ 3 = 0.10 ppm
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Derivation of AEGL-3
Key study:
Ballantyne et al. 1989
Toxicity end points:
Concentration causing no death in rats for a 1-h exposure (10 min, 30 min, 1 h).
Concentration causing no death in rats for a 4-h exposure (4 h, 8 h).
Scaling:
(14 ppm)1.2 × 1 h = 23.7 ppm-h
(4.8 ppm)1.2 × 4 h = 26.27 ppm-h
Uncertainty factors:
3 for interspecies variability.
3 for intraspecies variability.
Calculations:
10-min AEGL-3
C1.2 × 0.167 h = 23.7 ppm-h
C1.2 = 141.9 ppm
C = 62.1 ppm
10-min AEGL-3 = 62.1 ÷ 10 = 6.2 ppm
30-min AEGL-3
C1.2 × 0.5 h = 23.7 ppm·h
C1.2 = 47.4 ppm
C = 24.9 ppm
30-min AEGL-3 = 24.9 ÷ 10 = 2.5 ppm
1-h AEGL-3
14 ppm ÷ 10 = 1.4 ppm
4-h AEGL-3
C1.2 × 4 h = 26.27 ppm-h
C1.2 = 6.57 ppm
C = 4.79 ppm
1-h AEGL-3 = 4.79 ÷ 10 = 0.48 ppm
8-h AEGL-3
C1.2 × 8 h = 26.27 ppm-h
C1.2 = 3.28 ppm
C = 2.69 ppm
1-h AEGL-3 = 2.69 ÷ 10 = 0.27 ppm
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Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 8
APPENDIX B
Derivation Summary of AEGL Values for Acrolein
AEGL-1 VALUES
10 min
30 min
1 h
4 h
8 h
0.030 ppm
0.030 ppm
0.030 ppm
0.030 ppm
0.030 ppm
Key Reference: Weber-Tschopp, A., T. Fischer, R. Gierer, et al. 1977. Experimentally induced irritating effects of acrolein on men. Int. Arch. Occup. Environ. Health 40: 117-130.
Test Species/Strain/Number: Human/31 males and 25 females/young adults.
Exposure Route/Concentrations/Durations:
Inhalation/0 to 0.6 ppm with concentration increasing for 35 min, then constant at 0.6 ppm for 5 min; 0, 0.15, 0.30, 0.45, and 0.60 ppm for several 1.5-min exposures with a recovery period of 8 min between exposures; or 0.3 ppm for 60 min.
Effects: At 0.09 ppm, “annoyance”/discomfort and very slight eye irritation; at 0.15 ppm, nose irritation; at 0.26 ppm, doubling of blinking rate; at 0.3 ppm, 10% decrease in respiratory rate; at 0.43 ppm, throat irritation; and at 0.6 ppm, 25% decrease in respiratory rate. Effects are reported as threshold effects. (0.09 ppm determinant for AEGL-1).
End Point/Concentration/Rationale: eye irritation, annoyance/discomfort in humans at 0.09-ppm threshold.
Uncertainty Factors/Rationale:
Interspecies: 1, subjects were humans.
Intraspecies: 3, considered sufficient because minor ocular contact irritation is not likely to vary greatly between individuals; also, derived values are 2-fold below a no-observed-effect level (NOEL) for irritation in another human study (0.06 ppm, 5 min) (Darley et al. 1960).
Modifying Factor: Not applicable.
Animal to Human Dosimetric Adjustment: Not applicable.
Time Scaling: Values were held constant because minor irritation is generally a threshold effect and prolonged exposure is not likely to result in a greatly enhanced effect.
Data Adequacy: Well-conducted human study.
AEGL-2 VALUES
10 min
30 min
1 h
4 h
8 h
0.44 ppm
0.18 ppm
0.10 ppm
0.10 ppm
0.10 ppm
Key Reference: Weber-Tschopp, A., Fischer, T., Gierer, R. et al. 1977. Experimentally induced irritating effects of acrolein on men. Int. Arch. Occup. Environ. Health 40:117-130.
Test Species/Strain/Number: Human/31 males and 25 females/young adults.
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Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 8
10 min
30 min
1 h
4 h
8 h
0.44 ppm
0.18 ppm
0.10 ppm
0.10 ppm
0.10 ppm
Exposure Route/Concentrations/Durations:
Inhalation/0 to 0.6 ppm with concentration increasing for 35 min, then constant at 0.6 ppm for 5 min; 0, 0.15, 0.30, 0.45, and 0.60 ppm for several 1.5-min exposures with a recovery period of 8 min between exposures; or 0.3 ppm for 60 min.
Effects: At 0.09 ppm, annoyance/discomfort and very slight eye irritation; at 0.15 ppm, nose irritation; at 0.26 ppm, doubling of blinking rate; at 0.3 ppm, 10-15% decrease in respiratory rate; at 0.43 ppm, throat irritation; at 0.6 ppm, 25% decrease in respiratory rate. Effects are threshold effects (0.3 ppm determinant for AEGL-2).
End Point/Concentration/Rationale: 10-15% decrease in respiratory rate in humans/0.3 ppm/NOAEL for moderate irritation; decreases in respiratory rate in the range of 12% to 20% correspond to slight irritation, and decreases in respiratory rate in the range of 20% to 50% correspond to moderate irritation (ASTM 1991).
Uncertainty Factors/Rationale:
Interspecies: 1, subjects were human.
Intraspecies: 3, considered sufficient because irritation is unlikely to vary greatly among individuals. This uncertainty factor is further justified because of the sensitivity of the methods used, the fact that the point-of-departure effect was only a very small detectable decrease in respiration, the lack of evidence of marked variability across the study group, including women, and the fact that at twice the concentration, respiration was still only slightly decreased. Also, application of the default uncertainty factor of 10 yields AEGL-2 values in the range of concentrations where only minor irritation was noted in controlled human studies.
Modifying Factor: Not applicable.
Animal to Human Dosimetric Adjustment: Not applicable.
Time Scaling: The 1-h exposure of 0.3 ppm was adjusted by temporal scaling to obtain the 10- and 30-min AEGL-2 values using the relationship Cn × t = k, where n = 1.2 (derived from lethality data in rats exposed to acrolein from 1 to 4 h). The 1-h exposure of 0.3 ppm was held constant for the 4- and 8-h AEGL-2 values because irritation is generally a threshold effect and prolonged exposure is not likely to result in a greatly enhanced effect.
Data Adequacy: A well-conducted study in healthy humans was available. Irritative effects remained constant after approximately 40 min.
AEGL-3 VALUES
10 min
30 min
1 h
4 h
8 h
6.2 ppm
2.5 ppm
1.4 ppm
0.48 ppm
0.27 ppm
Key Reference: Ballantyne, B., Dodd, D.E., Pritts, D.J., et al. 1989. Acute vapor inhalation toxicity of acrolein and its influence as a trace contaminant in 2-methoxy-3,4-dihydro-2H-pyran. Human Toxicol. 8:229-235.
Test Species/Strain/Sex/Number: Sprague-Dawley rats/5 males and 5 females per concentration.
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Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 8
10 min
30 min
1 h
4 h
8 h
6.2 ppm
2.5 ppm
1.4 ppm
0.48 ppm
0.27 ppm
Exposure Route/Concentrations/Durations:
Rats/Inhalation: 14, 22, 24, 31, or 81 ppm for 1 h or 4.8, 7.0, 9.1, or 12.1 ppm for 4 h
End Point/Concentration/Rationale: No deaths in rats/14 ppm/threshold for death for 1-h exposure (determinant for 10-min, 30-min, and 1-h AEGL-3 values); no deaths in rats/4.8 ppm/threshold for death for 4-h exposure in rats (determinant for 4-h and 8-h AEGL-3 values).
Uncertainty Factors/Rationale: Total uncertainty factor: 10
Interspecies: 3
Intraspecies: 3
Intraspecies and interspecies uncertainty factors of 3 each are considered sufficient because irritation is not expected to vary greatly within or among species. Furthermore, application of either an intra- or interspecies uncertainty factor of 10 (total UF = 30) would yield values that are inconsistent with the total database. (For example, AEGL-3 values for acrolein would range from 2.1 to 0.09 ppm, and only ocular, nasal, or throat irritation and decreased respiratory rates were observed in humans exposed to acrolein at 0.09 to 0.6 ppm for up to 40 min (Weber-Tschopp, et al. 1977)). It is unlikely that people exposed to this range of acrolein for 10-min to 8-h would experience effects defined by AEGL-3.
Modifying Factor: Not applicable.
Animal to Human Dosimetric Adjustment: Insufficient data.
Time Scaling: Cn × t = k, where n = 1.2, derived from lethality data in rats exposed to acrolein from 1 to 4 h. Data point used for 10-min, 30-min and 1-h AEGL-3 derivation was 1 h. Data point used for 4-h and 8-h AEGL-3 derivation was 4 h (Appendix D).
Data Adequacy: Well-conducted study with appropriate end point for AEGL-3.
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APPENDIX C
Category Plot for Acrolein
FIGURE C-1 Category plot for acrolein.
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Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 8
APPENDIX D
Temporal Extrapolation for Acrolein
FIGURE D-1 Best fit concentration × time curve.
Log
Log
Time
Conc.
Time
Conc.
Regression Output:
1
26
0.0000
1.4150
Intercept
1.3857
2
12
0.3010
1.0792
Slope
−0.8237
4
8.3
0.6021
0.9191
R Squared
0.9598
Correlation
−0.9797
Degrees of Freedom
1
Observations
3
n =
1.21
k =
48.12
Minutes
Conc.
Hours
Conc.
30
1.48
0.5
43.02
60
0.83
1.0
24.30
240
0.27
4.0
7.76
480
0.15
8.0
4.38