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).



The National Academies | 500 Fifth St. N.W. | Washington, D.C. 20001
Copyright © National Academy of Sciences. All rights reserved.
Terms of Use and Privacy Statement



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
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 peri- ods (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 Sub- stances). 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 conclu- sions based on the data reviewed by the NRC and are consistent with the NRC guideline reports (NRC 1993, 2001). 219

OCR for page 219
220 Acute Exposure Guideline Levels AEGL-2 is the airborne concentration (expressed as ppm or mg/m3) of a substance above which it is predicted that the general population, including sus- ceptible individuals, could experience irreversible or other serious, long-lasting adverse health effects, or an impaired ability to escape. AEGL-3 is the airborne concentration (expressed as ppm or mg/m3) of a substance above which it is predicted that the general population, including sus- ceptible individuals, could experience life-threatening health effects or death. Airborne concentrations below the AEGL-1 represent exposure levels that 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 progres- sive 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 liq- uid. 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 propyl- ene oxide include in the production of polyurethane foams and resins, propylene glycol, functional fluids (such as hydraulic fluids, heat transfer fluids, and lubri- cants), 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 toxic- ity of propylene oxide in animals were available in monkeys, dogs, rats, mice, and guinea pigs. General signs of toxicity after acute exposure to propylene ox- ide 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 evi- dence suggests that propylene oxide reacts at the site of entry. Therefore, inhala- tion 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 219
221 Propylene Oxide 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 con- centrations 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 irrita- tion 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 ap- plied, 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 de- fined 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 sensi- tive 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 ap- plied, because mice are the most sensitive laboratory species in terms of the le- thal 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 irrita- tion 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 219
222 Acute Exposure Guideline Levels The AEGL-3 derivation is based on the calculated 4-h BMCL05 (bench- mark 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 be- cause two of three animals in the high-dose group died before they were re- moved 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 ex- posed 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 inter- species uncertainty factor of 1 was applied because of the supporting data in dogs (similar 4-h BMCL05) and monkeys (2-year studies, which produced mini- mal 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 expo- sure 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 rela- tionship 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 Hell- man 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 assess- ing public awareness of the exposure due to odor perception.A quantitative car- cinogenicity assessment for a single exposure to propylene oxide is not consid- ered appropriate. Data indicate that propylene oxide is a threshold carcinogen

OCR for page 219
223 Propylene Oxide that depends on increased cell proliferation and hyperplasia at the target site and would require repeated exposure to produce tumorigenesis. Therefore, a one- time 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 liq- uid, with a boiling point of 35°C (Meylan et al. 1986; Budavari et al. 1996). The chemical has a high vapor pressure and limited solubility in water but is misci- ble 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 1h 4h 8h End Point (Reference) AEGL-1 73 73 73 73 73 Humans: strong odor (Nondisabling) ppm ppm ppm ppm ppm and irritation noted in (170 (170 (170 (170 (170 monitoring study; mg/m3) mg/m3) mg/m3) mg/m3) mg/m3) 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-2 440 440 290 130 86 Dyspnea in mice at 387 (Disabling) ppm ppm ppm ppm ppm ppm for 4 h (NTP 1985) (1,000 (1,000 (690 (310 (200 mg/m3) mg/m3) mg/m3) mg/m3) mg/m3) AEGL-3 1,300 1,300 870 390 260 Calculated 4-h (Lethality) ppm ppm ppm ppm ppm BMCL05 of 1,161 ppm (3,100 (3,100 (2,100 (930 (620 in rats (NTP 1985) mg/m3) mg/m3) mg/m3) mg/m3) mg/m3) Abbreviation: BMCL05, benchmark concentration, 95% lower confidence limit with 5% response.

OCR for page 219
224 Acute Exposure Guideline Levels Propylene oxide is produced primarily by one of two processes: from di- rect 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 Eco- nomics 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 biomoni- toring studies. Studies addressing lethal and nonlethal toxicity of propylene ox- ide 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, ACGIH 1996 propene oxide, 1,2-propylene oxide 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 –112.13ºC and 34.23ºC Budavari et al. 1996 boiling points Solubility 40.5% by wt in water at 20ºC; Budavari et al. 1996; 59% by wt in water at 25ºC 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 3 Conversion factors 1 ppm = 2.376 mg/m at 25ºC Gardiner et al. 1993 1 mg/m3 = 0.421 ppm

OCR for page 219
225 Propylene Oxide 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 de- tectable 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) re- ported a threshold of 10 ppm for odor detection and 35 ppm for odor recogni- tion. 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 re- mained weak, had diarrhea, and vomited periodically. His pulse and blood pres- sure 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 219
226 Acute Exposure Guideline Levels 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 open- ing to a polypropylene glycol mixing tank during purging contained 28 ppm. Workers complained of eye irritation after 2 weeks of steady operation. No fa- talities 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 work- ers during typical drumming operations of propylene oxide (CMA 1998). The sampling was conducted to evaluate the effectiveness of local exhaust ventila- tion in response to worker complaints of occasional eye irritation. Samples were taken starting 5 min after overhead heater fans were turned on (providing addi- tional 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 TWA for Description of Samples (taken in Sampling Monitoring Period Sample breathing zone of operators during Personnel Duration Number drumming of propylene oxide) (min) (ppm) Monitored 1 Sampling initiated 5 min after overhead Drumming 177 380 heater fan turned on, heater fan on for operator 1 duration of monitoring 2 Sampling initiated 5 min after overhead Drumming 171 1520 heater fan turned off, heater fan off for operator 1 duration of monitoring 3 Sampling initiated 5 min after overhead Drumming 124 1310 heater fan turned off, heater fan off for operator 2 duration of monitoring 4 Sampling initiated 5 min after overhead Drumming 121 525 heater fan turned off, heater fan off for operator 2 duration of monitoring 5 Sampling initiated 5 min after overhead Drumming 135 392 heater fan turned on, heater fan on for operator 3 duration of monitoring 6 Sampling initiated 5 min after overhead Drumming 116 460 heater fan turned on, heater fan on for operator 3 duration of monitoring Abbreviation: TWA, time-weighted average. Source: CMA 1998.

OCR for page 219
227 Propylene Oxide 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 observa- tions 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 hygien- ist) occurred within 5 months of sampling, indicating that the measured expo- sures 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 de- tected (<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 sam- pling 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 ox- ide 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 syn- thesis, 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 hemo- globin. 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 219
228 Acute Exposure Guideline Levels 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 inves- tigation 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 corre- lation 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 Propylene Oxide Mean Job Class Number Concentrationa (ppm) of Persons Number of Concentration Job Classification Monitored Range (ppm) Samples Mean 95% UCL Maintenance 5 8 14.9-18.9 17.4 18.30 personnel Laboratory 2 2 30.2-31.8 31.0 36.05 personnel 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 a Calculated 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 219
229 Propylene Oxide 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 mor- tality 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 investigat- ing cancer incidences in workers ever exposed to propylene oxide versus never exposed did not result in significant associations of specific cancers with expo- sure (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, rest- lessness, headache, general weakness, diarrhea, and vomiting. The worker re- portedly recovered. Other workplace exposure information was reported in envi- ronmental 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 expo- sures 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 com- plaints.Molecular biomonitoring studies of workers exposed to low concentra- tions 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 meas- ured 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 219
282 Acute Exposure Guideline Levels 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 219
283 Propylene Oxide 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 219
284 Acute Exposure Guideline Levels 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 Lower Upper Variable Estimate Standard Error Confidence Limit Confidence Limit NAa Background 0 Intercept -31.3034 15.5575 -61.7955 -0.811365 Slope 3.85333 1.90441 0.12075 7.58591 a NA indicates that this parameter has hit a bound implied by some inequality constraint and thus has no standard error. Analysis of deviance table: No. of Test d.f.a Model Log(likelihood) Parameters Deviance 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 a d.f., degrees of freedom. Akaike information criterion: 41.0475 Goodness of Fit Estimated Dose Expected Observed Scaled Size Residual Probability 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 219
FIGURE C-1 Probit model with 95% confidence level. 285

OCR for page 219
286 Acute Exposure Guideline Levels 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 sarco- mas 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 turbi- nates of mice included acute and chronic inflammation, suppurative inflamma- tion, 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 indi- cates some evidence of carcinogenicity at 400 ppm but no evidence of carcino- genicity was found at 200 ppm. Nonneoplastic effects of propylene oxide on the nasal turbinates of rats included suppurative inflammation, epithelial hyperpla- sia, 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 car- cinogen 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 inhala- tion exposure to propylene oxide is the N7-(2-hydroxypropyl)guanine (7-HPG), particularly in nasal tissue (Ríos-Blanco et al. 1997, 2000, 2003a). The accumu- lation 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 respi- ratory tissue was not sufficient to induce tumor formation as it had a linear con- centration 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 pro- liferation may be a result of the depletion of NPSH (includes GSH) in the respi- ratory nasal mucosa of rats and mice, the levels of which were depleted signifi- cantly 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 219
287 Propylene Oxide pletion of GSH as a cosubstrate for the conjugation reaction with propylene ox- ide (a detoxification pathway) results in continuous and severe perturbation of GSH in the respiratory nasal mucosa of rodents repeatedly exposed to high con- centrations 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 pro- pylene oxide, because a one-time exposure even to a high concentration of pro- pylene 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 ob- served 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 219
288 Acute Exposure Guideline Levels 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 ex- perience 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 percep- tion. 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 de- fault 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 expo- sure. 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 219
289 Propylene Oxide APPENDIX F ACUTE EXPOSURE GUIDELINE LEVELS FORPROPYLENE OXIDE Derivation Summary for Propylene Oxide AEGL-1 VALUES 10 min 30 min 1h 4h 8h 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 219
290 Acute Exposure Guideline Levels AEGL-2 VALUES 10 min 30 min 1h 4h 8h 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. (Continued)

OCR for page 219
291 Propylene Oxide AEGL-2 VALUES Continued 10 min 30 min 1h 4h 8h 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 1h 4h 8h 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 (Continued)

OCR for page 219
292 Acute Exposure Guideline Levels AEGL-3 VALUES Continued 10 min 30 min 1h 4h 8h 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).