|
||||||||||||||||
|
||||||||||||||||
The following HTML text is provided to enhance online readability. Many aspects of typography translate only awkwardly to HTML. Please use the page image as the authoritative form to ensure accuracy. 5
|
||||||||||||||||
 |
 |
Page 219 |
 |
 |
 |
|
| ||||||||||||||||||||||||||||||||
|
|
|||||||||||||||||||||||||||||||
Below are the first 10 and last 10 pages of uncorrected machine-read text (when available) of this chapter, followed by the top 30 algorithmically extracted key phrases from the chapter as a whole.
Intended to provide our own search engines and external engines with highly rich, chapter-representative searchable text on the opening pages of each chapter.
Because it is UNCORRECTED material, please consider the following text as a useful but insufficient proxy for the authoritative book pages.
Do not use for reproduction, copying, pasting, or reading; exclusively for search engines.
OCR for page 219
Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 9
5
Propylene Oxide1
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 have been 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 Claudia Troxel (Oak Ridge National Laboratory) and Chemical Manager Jim Holler (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).
OCR for page 220
Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 9
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
Propylene oxide is an extremely flammable, highly volatile, colorless liquid. Its odor has been described as sweet and alcoholic, and it has reported odor thresholds ranging from 10 to 200 ppm (Jacobson et al. 1956; Hellman and Small 1974; Amoore and Hautala 1983). The primary industrial uses of propylene oxide include in the production of polyurethane foams and resins, propylene glycol, functional fluids (such as hydraulic fluids, heat transfer fluids, and lubricants), and propylene oxide–based surfactants. It is also used as a food fumigant, soil sterilizer, and acid scavenger.
Data addressing inhalation toxicity of propylene oxide in humans were limited to one case report, general environmental work surveys, and molecular biomonitoring studies. Studies addressing lethal and nonlethal inhalation toxicity of propylene oxide in animals were available in monkeys, dogs, rats, mice, and guinea pigs. General signs of toxicity after acute exposure to propylene oxide vapor included nasal discharge, lacrimation, salivation, gasping, lethargy and hypoactivity, weakness, and incoordination. Repeated exposures resulted in similar but generally reversible signs of toxicity. Much of the toxicologic evidence suggests that propylene oxide reacts at the site of entry. Therefore, inhalation of propylene oxide results in respiratory tract irritation, eventually leading to death. Possible neurotoxic effects have also been observed in rodents and dogs after inhalation exposure to higher concentrations of propylene oxide.
Propylene oxide is a direct alkylating agent that covalently binds to DNA and proteins. Consequently, it has tested positive in a number of in vitro tests but has produced equivocal results in in vivo test systems. Data addressing the po-
OCR for page 221
Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 9
tential carcinogenicity of propylene oxide in animals is considered adequate for establishing propylene oxide as a carcinogen in experimental animals.
The AEGL-1 is based on a workplace survey that measured exposure concentrations of 380 ppm for 177 min, 525 ppm for 121 min, 392 ppm for 135 min, and 460 ppm for 116 min in the breathing zone of three workers during drumming operations (CMA 1998). Strong odor and irritation were noted in the survey. The nature of the irritation was not provided, but occasional eye irritation was noted as the reason for the monitoring program. Because the effects were considered mild irritation, the AEGL values would be set equal across time. Therefore, the four exposure concentrations can be averaged, resulting in a point of departure of 440 ppm. A total uncertainty factor and modifying factor of 6 is applied. An interspecies uncertainty factor was not needed, because the data were from human exposures. An intraspecies uncertainty factor of 3 was applied, because irritation is a point-of-contact effect and is not expected to vary greatly among individuals. A modifying factor of 2 is applied, because the defined effects are above an AEGL-1 (undefined irritation) but below an AEGL-2 end point.
No human data were available for deriving an AEGL-2. When considering animal data for deriving an AEGL-2, dyspnea in mice was the most sensitive end point consistent with the AEGL-2 definition, and mice were the most sensitive to the toxic effects of propylene oxide vapor. Therefore, the AEGL-2 values are based on data from the NTP (1985) study in which mice exposed to 387 ppm for 4 h exhibited dyspnea. Although a no-effect level was not established for dyspnea at this concentration, no other adverse effects were noted. In addition, compared with other studies investigating propylene oxide toxicity in mice, the NTP study reported toxic effects occurring at much lower concentrations than were observed in other studies. An interspecies uncertainty factor of 1 was applied, because mice are the most sensitive laboratory species in terms of the lethal effects of propylene oxide as well as clinical signs of toxicity, and available data indicate that mice are equally or slightly more sensitive than humans in the manifestation of clinical signs. The NTP (1985) study reported toxic effects at much lower concentrations than those observed in other studies. An intraspecies uncertainty factor of 3 was applied because the mechanism of toxicity— irritation—is a point-of-contact effect and is not expected to vary greatly among individuals. Therefore, a total uncertainty factor of 3 was applied.
Although the mechanism of action appears to be a direct irritant effect, it is not appropriate to set the values equally across time, because the irritation is no longer considered mild but is part of the continuum of respiratory tract irritation leading to death. The experimentally derived exposure value was therefore scaled to AEGL timeframes using the concentration-time relationship given by the equation Cn × t = k, where C is concentration, t is time, k is a constant, and n is 1.7 as calculated with the rat lethality data reported by Rowe et al. (1956) (ten Berge et al. 1986). The 10-min value was set equal to the 30-min value because of the uncertainty in extrapolating from the exposure duration of 4 h to 10 min.
OCR for page 222
Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 9
The AEGL-3 derivation is based on the calculated 4-h BMCL05 (benchmark concentration, 95% lower confidence limit at the 5% response rate) of 1,161 ppm, the lowest BMCL05 value in rats (NTP 1985). Lethality data in the dog, a nonobligate nose breather, support use of the BMCL05 value in the rat, but the dog values should not be used as the basis for the AEGL-3 derivation because two of three animals in the high-dose group died before they were removed from the exposure chamber. Mouse data were not used because the mouse is overly sensitive to propylene oxide compared with the other species tested. The BMCL05 values in mice are 282 and 673 ppm (Jacobson et al. 1956; NTP 1985), compared with 1,161 to 3,328 ppm in rats (Jacobson et al. 1956; Shell Oil Co. 1977; NTP 1985) and 1,117 ppm in dogs (Jacobson et al. 1956). Other data demonstrating that the mouse BMCL05 values are unreasonably low include the studies in which only minimal effects were noted in monkeys exposed to 300 ppm for 6 h/day, 5 days/week, for 2 years (Sprinz et al. 1982; Lynch et al. 1983; Setzer et al. 1997), or to 457 ppm for 7 h/day for 154 days (Rowe et al. 1956), and the highest documented human exposure of 1,520 ppm for 171 min, which caused irritation that was not severe enough for the worker to cease working (CMA 1998). These data support the 4-h BMCL05 of 1,161 ppm in rats as a reasonable point of departure. An intraspecies uncertainty factor of 3 was applied, because the mechanism of toxicity—irritation—is a point-of-contact effect and is not expected to vary greatly among individuals. An interspecies uncertainty factor of 1 was applied because of the supporting data in dogs (similar 4-h BMCL05) and monkeys (2-year studies, which produced minimal effects). The 4-h AEGL-3 value using a total uncertainty factor of 3 is 387 ppm, which is conservative compared with the 300- or 457-ppm chronic exposure in monkeys producing minimal effects. Therefore, a total uncertainty factor of 3 was considered reasonable.
As for the AEGL-2 derivation, the point of departure for the AEGL-3 derivation was scaled to AEGL timeframes using the concentration-time relationship given by the equation Cn × t = k, where C is concentration, t is time, k is a constant, and n is 1.7 as calculated with the rat lethality data reported by Rowe et al. (1956) (ten Berge et al. 1986). The value was extrapolated across time, because the irritation is no longer considered mild; rather, the concentration represents the threshold for lethality. The 10-min value was set equal to the 30-min value because of the uncertainty in extrapolating from the exposure duration of 4 h to 10 min.
A level of distinct odor awareness (LOA) for propylene oxide of 21 ppm was derived on the basis of the odor detection threshold from the study of Hellman and Small (1974). The LOA represents the concentration above which it is predicted that more than half 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 the exposure due to odor perception.A quantitative carcinogenicity assessment for a single exposure to propylene oxide is not considered appropriate. Data indicate that propylene oxide is a threshold carcinogen
OCR for page 223
Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 9
that depends on increased cell proliferation and hyperplasia at the target site and would require repeated exposure to produce tumorigenesis. Therefore, a onetime exposure even to high concentrations of propylene oxide is not expected to result in tumor development. This conclusion is supported by the Sellakumar et al. (1987) study in which no tumors were observed when 12-week-old male Sprague-Dawley rats were exposed to propylene oxide at 433 or 864 ppm for 30 days or to 1,724 ppm for 8 days (exposures were for 6 h/day, 5 days/week) and allowed to die naturally.
The derived AEGL values are listed in Table 5-1.
1.
INTRODUCTION
Propylene oxide is an extremely flammable, highly volatile, colorless liquid, with a boiling point of 35ºC (Meylan et al. 1986; Budavari et al. 1996). The chemical has a high vapor pressure and limited solubility in water but is miscible with a number of organic solvents (ARCO 1983; Budavari et al. 1996). The odor of propylene oxide has been described as sweet and alcoholic, and it has reported odor thresholds ranging from 10 to 200 ppm (Jacobson et al. 1956; Hellman and Small 1974). The physicochemical data on propylene oxide are presented in Table 5-2.
TABLE 5-1 Summary of AEGL Values for Propylene Oxide
Classification
10 min
30 min
1 h
4 h
8 h
End Point (Reference)
AEGL-1 (Nondisabling)
73 ppm (170 mg/m3)
73 ppm (170 mg/m3)
73 ppm (170 mg/m3)
73 ppm (170 mg/m3)
73 ppm (170 mg/m3)
Humans: strong odor and irritation noted in monitoring study; average of four exposure concentrations and durations:380 ppm for 177 min, 525 ppm for 121 min, 392 ppm for 135 min, 460 ppm for 116 min (CMA 1998)
AEGL-2 (Disabling)
440 ppm (1,000 mg/m3)
440 ppm (1,000 mg/m3)
290 ppm (690 mg/m3)
130 ppm (310 mg/m3)
86 ppm (200 mg/m3)
Dyspnea in mice at 387 ppm for 4 h (NTP 1985)
AEGL-3 (Lethality)
1,300 ppm (3,100 mg/m3)
1,300 ppm (3,100 mg/m3)
870 ppm (2,100 mg/m3)
390 ppm (930 mg/m3)
260 ppm (620 mg/m3)
Calculated 4-h BMCL05 of 1,161 ppm in rats (NTP 1985)
Abbreviation: BMCL05, benchmark concentration, 95% lower confidence limit with 5% response.
OCR for page 224
Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 9
Propylene oxide is produced primarily by one of two processes: from direct oxidation of propylene with air or oxygen or via the intermediate propylene chlorohydrin (Gardiner et al. 1993). The largest use of propylene oxide is in production of polyurethane foams and resins, followed by its use in production of propylene glycol resulting from its hydrolysis. Other common applications include its use in manufacturing functional fluids (such as hydraulic fluids, heat transfer fluids, and lubricants) and propylene oxide–based surfactants, and its use as a food fumigant and acid scavenger (ARCO 1983). The Chemical Economics Handbook (SRI International 1995) has estimated that 3,575 to 3,650 million pounds of propylene oxide were produced in the United States in 1998. Worldwide annual capacity for propylene oxide production was estimated at 8.8 billion pounds on Jan. 1, 1994 (SRI International 1995).
Data addressing the toxicity of propylene oxide in humans were limited to one case report, general environmental health surveys, and molecular biomonitoring studies. Studies addressing lethal and nonlethal toxicity of propylene oxide in several species of experimental animals were available.
TABLE 5-2 Chemical and Physical Data for Propylene Oxide
Parameter
Value
Reference
Chemical name
Propylene oxide
Synonyms
1,2-Epoxypropane, methyloxidrane, propene oxide, 1,2-propylene oxide
ACGIH 1996
CAS registry number
75-56-9
Molecular formula
C3H6O
Molecular weight
58.08
Budavari et al. 1996
Physical state
Liquid
Budavari et al. 1996
Color
Colorless
Budavari et al. 1996
Melting and boiling points
−112.13ºC and 34.23ºC
Budavari et al. 1996
Solubility
40.5% by wt in water at 20ºC; 59% by wt in water at 25ºC
Budavari et al. 1996; Gardiner et al. 1993
Specific gravity
0.8304 at 20ºC; 0.826 at 25ºC
Gardiner et al. 1993
Density (water = 1)
2.0
Gardiner et al. 1993
Vapor pressure
445 torr at 20ºC
ACGIH 1996
Conversion factors
1 ppm = 2.376 mg/m3 at 25ºC 1 mg/m3 = 0.421 ppm
Gardiner et al. 1993
OCR for page 225
Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 9
2.
HUMAN TOXICITY DATA
2.1.
Acute Lethality
No data were found in the literature regarding lethality in humans after acute exposure to propylene oxide.
2.2.
Nonlethal Toxicity
2.2.1.
Odor Threshold
Reported ranges of odor threshold vary widely. In one study, 14 subjects found the odor of propylene oxide to be “sweet, alcoholic, and like natural gas, ether, or benzene” (Jacobson et al. 1956). By using an osmoscope, median detectable concentrations were computed by the time-percent effect method of Litchfield, and the median detectable odor concentration was calculated to be 200 ppm (95% confidence interval [C.I.]: 114 to 353 ppm). Amoore and Hautala (1983) reported an odor threshold of 44 ppm; Hellman and Small (1974) reported a threshold of 10 ppm for odor detection and 35 ppm for odor recognition. Subjects classified the odor as neutral to pleasant. The American Industrial Hygiene Association (AIHA 1989) and the Environmental Protection Agency (EPA) (1992) have critiqued studies with odor threshold data, and both have classified the studies by Jacobson et al. (200 ppm) and Hellman and Small (10 and 35 ppm) as acceptable.
2.2.2.
Case Reports
One case report of acute exposure was reported in the Russian literature (Beliaev et al. 1971). A 43-year-old male worker was accidentally exposed to propylene oxide vapor for 10 to 15 min while cleaning up a spill. The exposure concentration was exceedingly high, 1,400 to 1,500 milligrams per liter (mg/L) (590,000 ppm), evoking doubt about the accuracy of the measurement. Shortly after exposure, he developed eye and lung irritation, burning behind the sternum, and restlessness. Headache, general weakness, and diarrhea followed 1.5 h later, and within 2 h he was cyanotic and had collapsed. He was given oxygen and antihistamines and was treated for shock. He regained consciousness but remained weak, had diarrhea, and vomited periodically. His pulse and blood pressure returned to normal 2 h later, and he was discharged from the hospital in satisfactory condition after 10 days.
2.2.3.
Workplace Exposures
An environmental health survey in 1949 measured propylene oxide levels over drums being filled with polypropylene glycol (1% to 8% free propylene
OCR for page 226
Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 9
oxide content) (CMA 1998). Two 30-min samples contained propylene oxide at 348 and 913 ppm (vol/vol). Another sample collected for 12 min over the opening to a polypropylene glycol mixing tank during purging contained 28 ppm. Workers complained of eye irritation after 2 weeks of steady operation. No fatalities in the 23 potentially exposed workers occurred within 5 months of the sampling.
In 1968, air sampling was conducted in the breathing zone of three workers during typical drumming operations of propylene oxide (CMA 1998). The sampling was conducted to evaluate the effectiveness of local exhaust ventilation in response to worker complaints of occasional eye irritation. Samples were taken starting 5 min after overhead heater fans were turned on (providing additional ventilation) or starting 5 min after the overhead heater fans were off (when worker complaints were typically noted). Air samples were collected in airtight Saran® bags and analyzed by vapor-phase chromatography. Results of the sampling are presented in Table 5-3.
TABLE 5-3 Summary Results of Personal Exposure Monitoring for Propylene Oxide During Typical Drumming Operations
Sample Number
Description of Samples (taken in breathing zone of operators during drumming of propylene oxide)
Personnel Monitored
Sampling Duration (min)
TWA for Monitoring Period (ppm)
1
Sampling initiated 5 min after overhead heater fan turned on, heater fan on for duration of monitoring
Drumming operator 1
177
380
2
Sampling initiated 5 min after overhead heater fan turned off, heater fan off for duration of monitoring
Drumming operator 1
171
1520
3
Sampling initiated 5 min after overhead heater fan turned off, heater fan off for duration of monitoring
Drumming operator 2
124
1310
4
Sampling initiated 5 min after overhead heater fan turned off, heater fan off for duration of monitoring
Drumming operator 2
121
525
5
Sampling initiated 5 min after overhead heater fan turned on, heater fan on for duration of monitoring
Drumming operator 3
135
392
6
Sampling initiated 5 min after overhead heater fan turned on, heater fan on for duration of monitoring
Drumming operator 3
116
460
Abbreviation: TWA, time-weighted average.
Source: CMA 1998.
OCR for page 227
Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 9
Exposures were 1,520 ppm (vol/vol) for 171 min, 1,310 ppm for 124 min, and 525 ppm for 121 min with the overhead heater fan turned off and 380 ppm for 177 min, 392 ppm for 135 min, and 460 ppm for 116 min with the overhead heater fan turned on (CMA 1998). The industrial hygienist was in the drumming booth during the monitoring periods and stated that “the odor was quite strong during the sampling; however, the irritation was not intolerable.” Other observations noted by the hygienist included the following: “odor was quite obvious but not objectionable”; “pronounced odor, nonobjectionable”; and “general area in drumming room, about 10 feet from drumming station, odor was detectable but faint.” No fatalities in the 30 potentially exposed workers (including the hygienist) occurred within 5 months of sampling, indicating that the measured exposures to propylene oxide were not fatal.
Background propylene oxide concentrations were measured over three 8-h shifts in a plant in 1975 to perform baseline routine annual monitoring (CMA 1998). The concentration of the samples in ambient air ranged from none detected (<0.1 ppm) to 31.8 ppm (vol/vol). Propylene oxide concentrations were also measured in the breathing zones of workers using Sipin personal sampler pumps over the 8-h work periods. Measured concentrations ranged from 13.2 to 31.8 ppm as 8-h time-weighted averages (TWAs) measured over the 3-day sampling period (see Table 5-4). No worker complaints were noted in the report.
2.3.
Developmental and Reproductive Toxicity
No human developmental and reproductive toxicity data on propylene oxide were found in the literature.
2.4.
Genotoxicity
Unscheduled DNA synthesis after in vitro challenge with the carcinogen N-acetoxy-2-acetylaminofluorene was measured in lymphocytes of 23 process workers exposed to propylene oxide (Pero et al. 1982). The control population consisted of workers in a nearby mechanical industry factory. Five of the most exposed workers had an estimated TWA of 0.6 to 12 ppm during 5 working days, and some workers had short exposures to concentrations as high as 1,000 ppm. Exposed workers showed a decreased capacity for unscheduled DNA synthesis, a step in the enzymatic repair of DNA lesions. Osterman-Golkar et al. (1984) reported a good correlation between the estimated exposures of eight workers to propylene oxide vapor and hemoglobin adduction at the N-(2-hydroxypropyl)histidine residues. Workers exposed to the highest estimated concentration of approximately 10 ppm for 25% to 75% of their work time had adduct levels in the range of 4.5 to 13 nanomoles (nmol) per gram (g) of hemoglobin. Pero et al. (1985) also found a significant increase in the alkylation of histidine residues of hemoglobin in relation to propylene oxide exposure and a significant decrease in proficiency of DNA repair as measured by unscheduled
OCR for page 228
Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 9
DNA synthesis. Linear regression of the hemoglobin adducts versus DNA repair proficiency revealed a significant correlation (r = −0.64; p < 0.03).
Cytogenetic monitoring studies measuring chromosomal aberrations were carried out on groups of employees of the Shell petrochemical company (de Jong et al. 1988). From 1976 to 1981, these employees were potentially exposed to a number of genotoxic chemicals, including propylene oxide, with exposures occurring well below the occupational exposure limits. One group under investigation was limited in its exposure to propylene oxide alone, and the average air concentration of propylene oxide in the plant where the group worked was 0.042 ppm (geometric mean; range <0.042 to 2.74 ppm). The authors concluded that no correlation could be made between increased chromosomal aberrations and work exposure to low levels of propylene oxide or to any of the other genotoxic chemicals under investigation.
Högstedt et al. (1990) measured cytogenic end points in the blood of 20 male individuals exposed to propylene oxide for 1 to 20 years in a plant that produced alkylated starch. Average concentrations of propylene oxide measured in the breathing zones during 2- to 4-h measuring periods ranged from 0.33 to 11.4 ppm, with a peak concentration of 56 ppm measured during a shorter 20-min sampling period. Micronulei and chromosomal aberrations were measured; however, there was no control group with which to compare the results. A correlation was observed between measured propylene oxide air concentrations and the presence of the hemoglobin adduct hydroxypropylvaline in the exposed workers.
TABLE 5-4 Summary Results of Personal Exposure Monitoring
Job Classification
Number of Persons Monitored
Number of Samples
Propylene Oxide
Concentration Range (ppm)
Mean Job Class Concentrationa (ppm)
Mean
95% UCL
Maintenance personnel
5
8
14.9-18.9
17.4
18.30
Laboratory personnel
2
2
30.2-31.8
31.0
36.05
Engineer
1
1
30.2
30.2
N/A
Foreman
2
4
16.1-23.8
20.58
24.49
Operator
6
11
13.2-23.3
18.69
20.31
aCalculated arithmetic mean and 95% upper confidence level (UCL) for the associated job class. Job classes were identified and monitored by homogenous exposure groups rather than job titles.
Abbreviation: UCL, 95% upper confidence level; N/A, not applicable.
Source: CMA 1998.
OCR for page 229
Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 9
2.5.
Carcinogenicity
Data on the potential carcinogenicity of propylene oxide in humans are limited and no definitive conclusions can be drawn. A retrospective cohort study of alkylene oxide–exposed workers conducted by Thiess et al. (1982) and a mortality study by Egedahl et al. (1989) did not find increased mortality from cancer or any other cause, but the studies were confounded by exposure to multiple alkene oxides as well as other chemicals. A nested case-control study investigating cancer incidences in workers ever exposed to propylene oxide versus never exposed did not result in significant associations of specific cancers with exposure (Ott et al. 1989).
2.6.
Summary
Available data on human exposure to propylene oxide were limited. Odor detection threshold values for propylene oxide ranged from 10 to 200 ppm. The only case report of an occupational exposure was of a male worker accidentally exposed to a high concentration of propylene oxide for 10 to 15 min. Symptoms of exposure included eye and lung irritation, burning sensation in the chest, restlessness, headache, general weakness, diarrhea, and vomiting. The worker reportedly recovered. Other workplace exposure information was reported in environmental health surveys. Measured exposure concentrations of propylene oxide were as high as 1,520 ppm for 171 min with no reports of fatality. A strong odor and undefined irritation were noted at this concentration. In another report, 8-h TWAs measured over a 3-day sampling period indicated propylene oxide exposures ranging from 13.2 to 31.8 ppm. Ambient air concentrations of propylene oxide ranged from none detected to 41.8 ppm. The report noted no worker complaints.Molecular biomonitoring studies of workers exposed to low concentrations of propylene oxide have revealed a good correlation between hemoglobin adduction, decreased proficiency for DNA repair, and estimated exposure to propylene oxide. Cytogenetic studies have not found a significant correlation between in vivo propylene oxide exposure and micronuclei or chromosomal aberrations. Data on the potential carcinogenicity of propylene oxide in humans are limited and no definitive conclusions can be drawn.
3.
ANIMAL TOXICITY DATA
3.1.
Acute Lethality
3.1.1.
Dogs
Jacobson et al. (1956) exposed groups of three male beagle dogs to measured propylene oxide vapor concentrations of 1,363, 2,005, 2,030, or 2,481 ppm for 4 h. Animals were exposed in constant-flow gassing chambers with a capac-
OCR for page 282
Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 9
Chi square = 26.64
Degrees of freedom = 8
Probability model = 8.17E-04
Ln(likelihood) = –20.39
B 0 = –3.9364E+01
Student t test = –2.9553
B 1 = 3.8770E+00
Student t test = 3.2821
B 2 = 2.3053E+00
Student t test = 3.3066
Variance B 0 0 =
1.7742E+02
Covariance B 0 1 =
-1.5682E+01
Covariance B 0 2 =
-8.9312E+00
Variance B 1 1 =
1.3954E+00
Covariance B 1 2 =
7.7204E-01
Variance B 2 2 =
4.8607E-01
Estimation ratio between regression coefficients of ln(concentration) and ln (minutes)
Point estimate = 1.682
Lower limit (95% confidence limit) = 1.265
Upper limit (95% confidence limit) = 2.099
OCR for page 283
Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 9
APPENDIX C
BENCHMARK CALCULATIONS
Benchmark Calculations
The benchmark calculations are based on the study by NTP (1985) using a range of four concentrations in rats. For derivation of 10- and 30-min and 1-, 4-, and 8-h AEGL-3 values, a BMCL05 of 1,161 ppm, derived with the log-probit model, was used.
BMCL05 = 1,161 ppm
BMC01 = 1,845 ppm
Probit Model. (Version: 2.8; Date: 02/20/2007)
Input Data File: C:\BMDS\PO\RATNTP.(d)
Gnuplot Plotting File: C:\BMDS\PO\RATNTP.plt
Fri Nov 02 17:38:56 2007
BMDS model run:
The form of the probability function is
P[response] = background + (1 – background) × CumNorm(intercept + slope × log(dose)), where CumNorm(.) is the cumulative normal distribution function.
Dependent variable = mortality
Independent variable = concentration
Slope parameter is not restricted
Total number of observations = 5
Total number of records with missing values = 0
Maximum number of iterations = 250
Relative function convergence has been set to 1e-008
Parameter convergence has been set to 1e-008
User has chosen the log-transformed model.
Default initial (and specified) parameter values
Background = 0
Intercept = −15.8272
Slope = 1.96437.
OCR for page 284
Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 9
Asymptotic correlation matrix of parameter estimates:
Intercept
Slope
Intercept
1
−1
Slope
−1
1
(The model parameters backgrounds have been estimated at a boundary point or have been specified by the user and do not appear in the correlation matrix.)
Parameter estimates:
95.0% Wald Confidence Interval
Variable
Estimate
Standard Error
Lower Confidence Limit
Upper Confidence Limit
Background
0
NAa
Intercept
−31.3034
15.5575
−61.7955
−0.811365
Slope
3.85333
1.90441
0.12075
7.58591
aNA indicates that this parameter has hit a bound implied by some inequality constraint and thus has no standard error.
Analysis of deviance table:
Model
Log(likelihood)
No. of Parameters
Deviance
Test d.f.a
p Value
Full model
–17.8428
5
Fitted model
–18.5238
2
1.36197 3
3
0.7145
Reduced model
–32.0518
1
28.418
4
<0.000
ad.f., degrees of freedom.
Akaike information criterion: 41.0475
Goodness of Fit
Dose
Estimated Probability
Expected
Observed
Scaled Size
Residual
0.0000
0.0000
0.0000
0
10
0.0000
1,277.0000
0.0001
0.0001
0
10
–0.030
2,970.0000
0.3117
3.117
3
10
–0.080
3,794.0000
0.6746
6.746
8
10
0.847
3,900.0000
0.7118
7.118
6
10
–0.781
Chi square = 1.33, degrees of freedom = 3, p = 0.7211.
Benchmark dose computation:
Specified effect = 0.05
Risk type = extra risk
Confidence level = 0.95
BMD = 2201.43
BMDL = 1,160.91
OCR for page 285
Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 9
FIGURE C-1 Probit model with 95% confidence level.
OCR for page 286
Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 9
APPENDIX D
CARCINOGENICITY ASSESSMENT
Discussion of Cancer Assessment of Propylene Oxide
Propylene oxide appears to cause cancer in animals at the site of contact. Intragastric administration of propylene oxide to Sprague-Dawley rats resulted in tumors of the forestomach, subcutaneous injections in rats generated sarcomas at the injection site, and inhalation exposure caused nasal cavity tumors in mice and rats (Walpole 1958; Dunkelberg 1982; NTP 1985). The nasal cavity tumors (nasal submucosa hemangiomas and hemangiosarcomas) in male and female C57CL/6 × C3H mice resulted from whole-body inhalation exposure to propylene oxide at 400 ppm for 6 h/day, 5 days/week, for 103 weeks (NTP 1985; also reported by Renne et al. 1986). No evidence of carcinogenicity was found at 200 ppm. Nonneoplastic effects of propylene oxide on the nasal turbinates of mice included acute and chronic inflammation, suppurative inflammation, and serous inflammation. F344/N rats exposed to propylene oxide at 400 ppm had an increased incidence of nasal epithelial papillary adenomas, although statistical significance was not achieved (NTP 1985). The tumor incidence indicates some evidence of carcinogenicity at 400 ppm but no evidence of carcinogenicity was found at 200 ppm. Nonneoplastic effects of propylene oxide on the nasal turbinates of rats included suppurative inflammation, epithelial hyperplasia, and squamous metaplasia.
Studies investigating the mode of action of propylene-oxide-induced nasal cavity tumors support the hypothesis that propylene oxide is a threshold carcinogen dependent on increased cell proliferation and hyperplasia at the target site. Propylene oxide covalently binds to DNA by introducing a 2-hydroxypropyl group, and the primary DNA adduct formed in rats after inhalation exposure to propylene oxide is the N7-(2-hydroxypropyl)guanine (7-HPG), particularly in nasal tissue (Ríos-Blanco et al. 1997, 2000, 2003a). The accumulation of 7-HPG in nasal respiratory tissue increased linearly with propylene oxide exposure concentrations ranging from 5 up to 500 ppm (Ríos-Blanco et al. 2003a). The investigators concluded that adduct accumulation in the nasal respiratory tissue was not sufficient to induce tumor formation as it had a linear concentration response, while nasal tumor formation had a nonlinear concentration response. In contrast, cell proliferation in the nasal respiratory epithelium was nonlinear and correlated better with tumor formation (Eldridge et al. 1995; Ríos-Blanco et al. 2003b). Hyperplastic lesions were present in the same region where nasal tumors developed in the NTP (1985) cancer bioassay in rats. The cell proliferation may be a result of the depletion of NPSH (includes GSH) in the respiratory nasal mucosa of rats and mice, the levels of which were depleted significantly after exposure to propylene oxide at 300 and 500 ppm (Morris et al. 2004; Lee et al. 2005; Morris and Pottenger 2006). Lee et al. (2005) proposed that de-
OCR for page 287
Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 9
pletion of GSH as a cosubstrate for the conjugation reaction with propylene oxide (a detoxification pathway) results in continuous and severe perturbation of GSH in the respiratory nasal mucosa of rodents repeatedly exposed to high concentrations of propylene oxide, which leads to inflammatory lesions and cell proliferation.
On the basis of these data, propylene oxide is a threshold carcinogen, and repeated exposure would be required to produce tumorigenesis. Therefore, it is inappropriate to conduct a carcinogen assessment for a single exposure to propylene oxide, because a one-time exposure even to a high concentration of propylene oxide is not be expected to result in tumor development. This conclusion is supported by the Sellakumar et al. (1987) study in which no tumors were observed when 12-week-old male Sprague-Dawley rats were exposed to propylene oxide 433 or 864 ppm for 30 days or at 1,724 ppm for 8 days (exposures were for 6 h/day, 5 days/week) and allowed to die naturally.
OCR for page 288
Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 9
APPENDIX E
CALCULATION OF LEVEL OF DISTINCT ODOR AWARENESS FOR PROPYLENE OXIDE
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 the exposed population will experience at least a distinct odor intensity, and about 10% of the population will experience a strong odor intensity. The LOA should help chemical emergency responders in assessing the public awareness of the exposure due to odor perception. The LOA derivation follows the guidance given by van Doorn et al. (2002). For derivation of the odor detection threshold (OT50), a study is available in which the odor threshold for the reference chemical n-butanol (odor detection threshold 0.04 ppm) has also been determined:Hellman and Small (1974):Odor detection threshold for propylene oxide: 9.9 ppmOdor detection threshold for n-butanol: 0.3 ppmCorrected odor detection threshold (OT50) for propylene oxide: 9.9 ppm × 0.04 ppm/0.3 ppm = 1.32 ppmThe concentration (C) leading to an odor intensity (I) of distinct odor detection (I = 3) is derived by using the Fechner function:I = kw × log(C/OT50) + 0.5For the Fechner coefficient, the default of kw = 2.33 is used because of the lack of chemical-specific data:3 = 2.33 × log(C /1.32) + 0.5which can be rearranged tolog(C/1.32) = (3 – 0.5)/2.33 = 1.07 and results inC = (101.07) ×1.32 = 11.8 × 1.32 = 15.576 ppmThe resulting concentration is multiplied by an empirical field correction factor. It takes into account that everyday life factors—such as sex, age, sleep, smoking, upper air-way infections, and allergy as well as distraction—increase the odor detection threshold by a factor of 4. In addition, it takes into account that odor perception is very fast (about 5 s), which leads to the perception of concentration peaks. On the basis of current knowledge, a factor of 1/3 is applied to adjust for peak exposure. Adjustment for distraction and peak exposure lead to a correction factor of 4/3 = 1.33.LOA = C ×1.33 = 15.576 ppm × 1.33 = 20.7 ppm = 21 ppm. The LOA for propylene oxide is 21 ppm.
OCR for page 289
Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 9
APPENDIX F
ACUTE EXPOSURE GUIDELINE LEVELS FORPROPYLENE OXIDE
Derivation Summary for Propylene Oxide
AEGL-1 VALUES
10 min
30 min
1 h
4 h
8 h
73 ppm
73 ppm
73 ppm
73 ppm
73 ppm
Reference: Chemical Manufacturers Association (CMA 1998). Human Experience with Propylene Oxide. Prepared by Chemical Manufacturers Association for National Advisory Committee, (NAC)/AEGLs, October 16, 1998.
Test Species/Strain/Number: 3 male workers
Exposure Route/Concentrations/Durations: Inhalation: four propylene oxide exposure concentrations measured in the breathing zone of three workers: 380 ppm for 177 min, 525 ppm for 121 min, 392 ppm for 135 min, and 460 ppm for 116 min
Effects: A notation was made by the hygienist that a strong odor was present during sampling; however, the irritation was not intolerable. The nature of the irritation, other than the strong odor, was not provided, but occasional eye irritation was noted in the report as the reason for the monitoring program.
End Point/Concentration/Rationale: The AEGL-1 values are based on the average of four propylene oxide exposure concentrations measured in the breathing zone of the three workers, 440 ppm.
Uncertainty Factors/Rationale:
Total uncertainty factor: 3
Interspecies: Not applicable
Intraspecies: 3, the mechanism of toxicity, irritation, is not expected to differ greatly among individuals
Modifying Factor: 2, because the defined effects are above an AEGL-1 tier (undefined irritation), but below an AEGL-2 end point
Animal to Human Dosimetric Adjustment: Not applicable
Time-Scaling: Mild irritant effects are set equal across time
Data Adequacy: The AEGL-1 derivation would be improved if additional data on the degree of human irritation after exposure to propylene oxide were available. Animal studies reporting the severity of clinical signs at each respective exposure in multiple species would also be beneficial.
OCR for page 290
Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 9
AEGL-2 VALUES
10 min
30 min
1 h
4 h
8 h
440 ppm
440 ppm
290 ppm
130 ppm
86 ppm
Reference: National Toxicology Program (NTP 1985). Toxicology and Carcinogenesis Studies of Propylene Oxide (CAS No. 75-56-9) in F344/N Rats and B6C3F1 Mice (Inhalation Studies). NTP TR 267, NIH 85-2527, U.S. Department of Health and Human Services, Public Health Service, National Institute of Health, National Toxicology Program, Research Triangle Park, NC.
Test Species/Strain/Sex/Number: five B6C3F1 mice/sex/group
Exposure Route/Concentrations/Durations: Inhaled 0, 387, 859, 1,102, 1,277, or 2,970 ppm for 4 h
Effects:
Conc.
Mortality
(ppm)
Males
Females
Other Effects
387
0/5
1/5
Dyspnea
859
0/5
0/5
Dyspnea1
102
2/5
4/5
Dyspnea1
277
2/5
5/5
Dyspnea, sedation
2,970
5/5
5/5
Dyspnea, sedation, lacrimation
End Point/Concentration/Rationale: 387 ppm for 4 h based on dyspnea; dyspnea in mice is the most sensitive end point, and mice are the most susceptible species. Although a no-effect level was not established at this concentration, no other adverse effects were noted. This NTP (1985) study reported toxic effects at much lower concentrations than those observed in other studies. The death of a mouse at 387 ppm did not appear to be exposure related.
Uncertainty Factors/Rationale:
Total uncertainty factor: 3
Interspecies: 1, mice are the most sensitive species tested in terms of lethality and clinical signs of toxicity, and available data indicate that mice are equally or slightly more sensitive than humans in manifesting clinical signs. The clinical sign of dyspnea was by far the most sensitive end point. This NTP (1985) study reported toxic effects at much lower concentrations than those observed in other studies.
Intraspecies: 3, The mechanism of toxicity, irritation, is a point-of-contact effect and is not expected to differ greatly among individuals.
Modifying Factor: Not applicable
Animal to Human Dosimetric Adjustment: Not applicable
Time-Scaling: Although the mechanism of action appears to be a direct irritant effect, it is not appropriate to set the values equal across time because the irritation is part of the continuum of respiratory tract irritation leading to death. The experimentally derived exposure value was therefore scaled to AEGL timeframes by using the concentration-time relationship given by the equation Cn × t = k, where C is concentration, t is time, k is a constant, and n is 1.7 as calculated by using the rat lethality data reported by Rowe et al. (1956) (ten Berge et al. 1986). The 10-min value was set equal to the 30-min value because of the uncertainty in extrapolating from the exposure duration of 4 h to 10 min.
OCR for page 291
Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 9
10 min
30 min
1 h
4 h
8 h
440 ppm
440 ppm
290 ppm
130 ppm
86 ppm
Data Adequacy: Limited data consistent with a defined AEGL-2 end point were available. Animal studies reporting clinical signs often did not report the severity of the signs at each exposure concentration but rather gave only a general statement. Additional data consistent with a defined AEGL-2 end point in multiple species would be helpful in further defining the AEGL-2 levels.
AEGL-3 VALUES
10 min
30 min
1 h
4 h
8 h
1,300 ppm
1,300 ppm
870 ppm
390 ppm
260 ppm
Reference: NTP 1985. Toxicology and Carcinogenesis Studies of Propylene Oxide (CAS No. 75-56-9) in F344/N Rats and B6C3F1 Mice (Inhalation Studies). NTP TR 267, NIH 85-2527, U.S. Department of Health and Human Services, Public Health Service, National Institute of Health, National Toxicology Program, Research Triangle Park, NC.
Test Species/Strain/Sex/Number: five F344/N rats/sex/group
Exposure Route/Concentrations/Durations: inhaled 0, 1,277, 2,970, 3,794, or 3,900 ppm for 4 h
Effects:
Conc.
Mortality
(ppm)
Males
Females
Other Effects
1,277
0/5
0/5
None observed
2,970
1/5
2/5
Dyspnea, red nasal discharge
3,794
4/5
4/5
Dyspnea, red nasal discharge
3,900
3/5
3/5
Dyspnea, red nasal discharge
Calculated BMCL05: 1,161 pm
End Point/Concentration/Rationale: The 4-h BMCL05 of 1,161 ppm was used as the point of departure.
Uncertainty Factors/Rationale:
Total uncertainty factor: 3
Interspecies: 1, based on supporting data in dogs (similar 4-h BMCL05 of 1,116 ppm) and a 2-year study in primates that demonstrated no mortality at 300 ppm for 6 h/day, 5 days/week
Intraspecies: 3, the mechanism of toxicity, irritation, is a point of contact effect and is not expected to differ greatly among individuals.
Modifying Factor: NA
Animal to Human Dosimetric Adjustment: Not applicable
Time-Scaling: As for the AEGL-2 derivation, the experimentally derived exposure value for the AEGL-3 derivation was scaled to AEGL timeframes by using the concentration-time relationship given by the equation Cn × t = k, where C is concentration, t is time, k is a constant, and n is 1.7 as calculated by using the rat lethality data reported by Rowe et al. (1956) (ten Berge et al. 1986). The value was extrapolated across time because the
OCR for page 292
Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 9
10 min
30 min
1 h
4 h
8 h
1,300 ppm
1,300 ppm
870 ppm
390 ppm
260 ppm
irritation is no longer considered mild; the concentration represents the threshold for lethality. The 10-min value was set equal to the 30-min value because of the uncertainty in extrapolating from the exposure duration of 4 h to 10 min.
Data Adequacy: Data were adequate for derivation of an AEGL-3. The resulting values were supported by dog data (similar no-effect level of mortality in a nonobligate nose breather; Jacobson et al. 1956); monkey data, 300 ppm 6 h/day for 2 years not lethal (Sprinz et al. 1982; Lynch et al. 1983; Setzer et al. 1997); 457 ppm for 7 h/day for 154 days not lethal (Rowe et al. 1956); and human data (exposure to 1,520 ppm for 171 min not lethal) (CMA 1998).