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5 Propylene Oxide
Pages 219-292

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From page 219...
... Both the document and the AEGL values were then reviewed by the National Research Council (NRC) Committee on Acute Exposure Guideline Levels.
From page 220...
... 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.
From page 221...
... 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.
From page 222...
... 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.
From page 223...
... 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)
From page 224...
... 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)
From page 225...
... HUMAN TOXICITY DATA 2.1. Acute Lethality No data were found in the literature regarding lethality in humans after acute exposure to propylene oxide.
From page 226...
... 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)
From page 227...
... . Propylene oxide concentrations were also measured in the breathing zones of workers using Sipin personal sampler pumps over the 8-h work periods.
From page 228...
... 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 20min sampling period. Micronulei and chromosomal aberrations were measured; however, there was no control group with which to compare the results.
From page 229...
... 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.
From page 230...
... The propylene oxide vapor was generated by passing a stream of nitrogen through the liquid. Chamber air was sampled by drawing chamber air through a series of bubblers (the first containing a solution of CaCl2·2H2O in 0.1 N HCl, and the second containing water to trap any acid)
From page 231...
... TABLE 5-6 Mortality of Male Rats Exposed to Propylene Oxide Vapor for 4 Hours Concentration Mortality (%) [day of death]
From page 232...
... Propylene oxide vapor was generated by vaporizing propylene oxide at room temperature followed by dilution with air. Propylene oxide chamber air concentrations were measured 8 to 12 times per exposure period with a gas chromatograph.
From page 233...
... . In a repeated-exposure study, groups of three male and three female Wistar rats were exposed 6 h/day to air containing measured propylene oxide vapor concentrations of 0 or 997 ppm for 10 days or 1,940 ppm for 9 days (Shell Oil Company 1977)
From page 234...
... . TABLE 5-9 Mortality of Wistar Rats Exposed to Propylene Oxide for 4 Hours Mortality (%)
From page 235...
... In an acute inhalation exposure study by NTP (1985) , groups of five B6C3F1 mice of each sex were exposed to air containing measured concentrations of propylene oxide vapor -- generated by vaporizing propylene oxide at room temperature followed by dilution with air -- at 0, 387, 859, 1,102, 1,277, or 2,970 ppm for 4 h.
From page 236...
... (1956) exposed groups of female guinea pigs to nominal air concentrations of propylene oxide vapor at 2,000, 4,000, 8,000, or 16,000 ppm for various times (see Table 5-12)
From page 237...
... 3.2.3. Rats No mortalities occurred in groups of 10 white male rats exposed to measured concentrations of propylene oxide vapor at 945, 1,329, or 2,684 ppm for 4 h (see Section 3.1.2; Table 5-5; Jacobson et al.
From page 238...
... In a repeat-exposure study, groups of three male and three female Wistar rats survived exposure to propylene oxide vapor at 0 or 997 ppm for 6 h/day for 10 days (see Section 3.1.2; Shell Oil Company 1977)
From page 239...
... Five groups of 10 male and 10 female specific pathogen-free–reared rats were exposed to measured concentrations of propylene oxide vapor at 0, 76, 149, 298, or 600 ppm for 6 h/day, 5 days/week, for 13 weeks (Dow Chemical Company 1981)
From page 240...
... By 1 week postexposure, only rats from the 525-ppm exposure group still had olfactory epithelium degeneration and increased cell proliferation of the respiratory epithelium, both of which regressed to control levels by 4 weeks postexposure. A later study investigated the effects of propylene oxide vapor on nasal respiratory epithelial and hepatic cell proliferation in groups of six F344 rats exposed to propylene oxide vapor at 0, 5, 25, 50, 300, or 500 ppm for 6 h/day, 5 days/week, for 3 or 20 days (Ríos-Blanco et al.
From page 241...
... No histopathologic abnormalities were noted in rats exposed to ≤50 ppm for 20 days or in any group exposed to propylene oxide for 3 days. Cell proliferation as measured by BrdU incorporation was increased (p < 0.01)
From page 242...
... (1956) conducted several repeated-exposure experiments for 7 h/day, 5 days/week to various measured concentrations of propylene oxide vapor in male and female guinea pigs.
From page 243...
... However, no increases were noted in sperm head abnormalities. Groups of 25 mated female F344 rats were exposed to propylene oxide vapor at 0, 100, 300, or 500 ppm for 6 h/day during gestation days (GD)
From page 244...
... , ataxic gait, reduced body weight starting on day 7 of the premating period that continued throughout the study, inflammation and alveolar macrophage aggregates in the lung, and lesions in the upper and lower respiratory tract -- particularly in the respiratory and olfactory mucosa of the nasal cavity (respiratory epithelium showed regeneration with replacement squamous epithelium or that migrated to the cuboidal epithelium; olfactory epithelium exhibited necrosis, atrophy, and
From page 245...
... . No maternal or developmental effects were observed at propylene oxide exposure concentrations up to 500 ppm.
From page 246...
... . In an experiment assessing in vivo propylene oxide binding, male CBA mice were injected intraperitoneally with [14C]
From page 247...
... To assess concentration-dependent accumulation of 7-HPG in the nasal respiratory epithelium, lungs, and liver, groups of five male F344 rats were exposed to propylene oxide by inhalation of 0, 5, 25, 50, 300 or 500 ppm for 6
From page 248...
... A linear increase in the accumulation of 7-HPG in DNA was observed for all three tissues after exposure to propylene oxide for 3 days and for the nasal respiratory epithelium and lung after 20 days of propylene oxide exposure, while the liver exhibited a sublinear accumulation of 7-HPG after 20 days of propylene oxide exposure. Increased binding was present in nasal respiratory epithelium at the lowest concentration of 5 ppm.
From page 249...
... . F344/N rats exposed to propylene oxide at 400 ppm had an increased incidence of nasal epithelial papillary adenomas (statistical significance not achieved; see Table 5-19)
From page 250...
... 0/50, 0/50, 10/50* Hemangioma and hemangiosarcoma Nasal cavity: Squamous cell carcinoma, 0/50, 0/50, 2/50 papilloma F 50 0, 200, 400 ppm Nasal cavity: Hemangioma 0/50, 0/50, 3/50 6 h/d, 5 d/wk, 103 wk Hemangiosarcoma 0/50, 0/50, 2/50 Hemangioma and hemangiosarcoma 0/50, 0/50, 5/50*
From page 251...
... General signs of toxicity after acute exposure to propylene oxide vapor in dogs, rats, mice, and guinea pigs included nasal discharge (clear or bloody) , lacrimation, salivation, gasping, lethargy and hypoactivity, weakness, and incoordination (see Table 5-16)
From page 252...
... . Rats exposed to air containing propylene oxide at up to 3,000 ppm did not exhibit saturation kinetics, with 96% of the inhaled propylene oxide being metabolized and only 3% being exhaled unchanged.
From page 253...
... Shell Oil Co. 1977 3,450 No mortality Mouse 945 4 Lowest concentration causing death Jacobson et al.
From page 254...
... Abbreviations: M, male; F, female. TABLE 5-16 Summary of Propylene Oxide Nonlethal Inhalation Data in Laboratory Animals Concentration Species (ppm)
From page 255...
... 3,450 4h Highest concentration causing no mortality Shell Oil Co. 1977 Lacrimation, eye irritation, sedation, piloerection, mucous discharge from nose and mouth, respiratory difficulty Rat 600 6 h/d, 5 d/wk Transient restless behavior observed only during first 3 days of exposure; Dow Chemical occasional salivation and piloerection noted Company 1981 Mouse (M)
From page 256...
... Male F344/N rats exposed by nose only to propylene oxide vapor at 14 ppm for 60 min showed increasing blood propylene oxide concentrations during the first 10 min of exposure, with concentrations leveling off at 3 nanograms per g of blood for the remainder of the exposure (Maples and Dahl 1993)
From page 257...
... to 70%, 45%, 35%, and 15% of control values, respectively, while decreases in olfactory mucosal NPSH content did not follow a clear concentration response. Uptake efficiency in the URT was assessed during exposure to propylene oxide for 1 h at 0, 25, 50, 100, or 300 ppm at a flow rate of 50 mL/min (about one-half of the predicted minute volume)
From page 258...
... resulted in a linear increase in propylene oxide blood concentration only up to 300 ppm, with a steeper slope observed between exposure concentrations of 300 and 500 ppm. The repeated exposures to propylene oxide at ≤300 ppm resulted in lower propylene oxide blood levels than after a single exposure, suggesting possible induction of metabolic elimination of propylene oxide.
From page 259...
... Findings from repeat inhalation exposure studies in rodents revealed upper respiratory tract lesions, such as rhinitis and squamous metaplasia, hyperplasia, necrosis, and suppurative inflammation of the upper respiratory tract epithelium (Shell Oil Company 1977; Dow Chemical Company 1981; NTP 1985; Kuper et al. 1988; Eldridge et al.
From page 260...
... 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. In conclusion, data indicate that propylene oxide is a threshold carcinogen dependent on increased cell proliferation and hyperplasia at the target site and therefore would require repeated exposure to produce tumorigenesis.
From page 261...
... . The number of hemoglobin adducts formed in mice after exposure to propylene oxide has been estimated to be 4 times lower than the number formed by exposure to ethylene oxide (Farooqi et al.
From page 262...
... . In another workplace survey, measured propylene oxide exposure concentrations in the breathing zone of three workers during drumming operations were 1,520 ppm for 171 min, 1,310 ppm for 124 min, and 525 ppm for 121 min with the local heater fan turned off and 380 ppm for 177 min, 392 ppm for 135 min, and 460 ppm for 116 min with the heater fan turned on (CMA 1998)
From page 263...
... Dogs exposed to propylene oxide vapor at 1,363 ppm for 4 h exhibited lacrimation, salivation, and nasal discharge (Jacobson et al.
From page 264...
... In addition, compared with other studies investigating propylene oxide toxicity in mice, the NTP study reported toxic effects at much lower concentrations than those observed in other studies. An interspecies uncertainty factor of 1
From page 265...
... 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 no longer considered mild but is part of the continuum of respiratory tract irritation leading to lethality. The experimentally derived exposure value was therefore scaled to AEGL timeframes using the concentration-time relationship given by the equation Cn × t = k, where n was 1.7 as calculated with the rat lethality data reported by Rowe et al.
From page 266...
... . Lethality data on the dog, a nonobligate nose breather, support the 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.
From page 267...
... SUMMARY OF AEGLs 8.1. AEGL Values and Toxicity End Points The AEGL-1 values are based on the average of 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, or 460 ppm for 116 min)
From page 268...
... The graph in Figure 5-1 plots the propylene oxide AEGL values along with the existing acute human and animal toxicity data for propylene oxide in terms of the categories assigned to them. From this plot, one sees that the AEGL-1 values are below any exposure concentration resulting in any effects; the AEGL-2 values are below concentrations that produce discomfort; and the AEGL-3 values are in the range of concentrations that produce discomfort but below concentrations that produce disabling or lethal effects.
From page 269...
... The AEGL1 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.
From page 270...
... The ERPG-3 for propylene oxide is based on the following data: 1/10th the concentration not causing evident systemic toxicity in female guinea pigs exposed for 1 h; 1/3rd the concentration not producing systemic effects in female rats exposed for 2 h; about twice the concentration not causing effects in dogs, other than
From page 271...
... 1991. Genotoxic effects of ethylene oxide and propylene oxide: A com parative study.
From page 272...
... 1993. Genotoxic effects of ethylene oxide and propylene oxide in mouse bone marrow cells.
From page 273...
... 2005. Propylene oxide in blood and soluble nonprotein thiols in nasal mucosa and other tissues of male Fisher 344/N rats exposed to propylene oxide vapors - relevance of glutathione depletion for propylene oxide-induced nasal tu mors.
From page 274...
... 2001. Standing Operating Procedures for Developing Acute Exposure Guideline Levels for Hazardous Chemicals.
From page 275...
... 2003b. Effects of propylene oxide exposure on rat nasal respiratory cell proliferation.
From page 276...
... 1977. Initial submission: Toxicity Studies on Propylene Oxide: Acute Inhalation Toxicity Study and 10 Day Repeated Exposure Study (Final Re port)
From page 277...
... 1985. Propylene Oxide: As sessment of Neurotoxic Potential in Male Rats.
From page 278...
... Scaling: Values were set equal across time because end point is mild irritation Uncertainty factors: 1 for interspecies variability 3 for intraspecies variability Modifying factor: 2 Combined uncertainty factors and modifying factor: 6 Calculations: C/(uncertainty factor) = 440 ppm/3 = 73 ppm 10-min, 30-min, 1-h, 4-h, 8-h AEGL-1 values set equal across time: 73 ppm Derivation of AEGL-2 Key study: NTP 1985 Toxicity end point: Dyspnea in mice exposed to 387 ppm for 4 h C1.7 × t = k where n of 1.7 was derived from rat Scaling: lethality data reported by Rowe et al.
From page 279...
... /3] 1.7 × 4 h = 15,490.4 ppm-h 10-min AEGL-2 The 10-min value was set equal to the 30-min value of 440 ppm because of the uncertainty in extrapolating from the exposure duration of 4 h to 10 min Cn × 0.5 h = 15,490.4 ppm-h 30-min AEGL-2 C1.7 = 30,980.8 ppm C = 438.4 ppm = 440 ppm Cn × 1 h = 15,490.4 ppm-h 1-h AEGL-2 C1.7 = 15,490.4 ppm C = 291.6 ppm = 290 ppm Cn × 4 h = 15,490.4 ppm-h 4-h AEGL-2 C1.7 = 3,872.6 ppm C = 129.00 ppm = 130 ppm Cn × 8 hr = 15,490.4 ppm-h 8-h AEGL-2 C1.7 = 1,936.3 ppm C = 85.8 ppm = 86 ppm Derivation of AEGL-3 Key study: NTP 1985 Calculated 4-h BMCL05 of 1,161 ppm using rat Toxicity end point: lethality data C1.7 × t = k where n of 1.7 was derived from rat Scaling: lethality data reported by Rowe et al.
From page 280...
... /31.7 ×4 h = 100,269.4 ppm-h 10-min AEGL-3 The 10-min value was set equal to the 30-min value of 1,300 ppm because of the uncertainty in extrapolating from the exposure duration of 4 h to 10 min Cn × 0.5 h = 100,269.4 ppm-h 30-min AEGL-3 C1.7 = 200,538.8 ppm C = 1,315.0 ppm = 1,300 ppm Cn × 1 h = 100,269.4 ppm-h 1-h AEGL-3 C1.7 = 100,269.4 ppm C = 874.7 ppm = 870 ppm Cn × 4 h = 100,269.4 ppm-h 4-h AEGL-3 C1.7 = 25,067.4 ppm C = 387.0 ppm = 390 ppm Cn × 8 h = 100,269.4 ppm-h 8-h AEGL-3 C1.7 = 12,533.7 ppm C = 257.4 ppm = 260 ppm
From page 281...
... 281 Propylene Oxide APPENDIX B TIME-SCALING CALCULATIONS Filename: PO for Log Probit Model Date: 05 November 2007 Time: 09:30:11 Sequence Conentration Number ppm Minutes Exposed Responded 1 2,000 420 10 0 2 4,000 420 10 10 3 4,000 240 10 4 4 4,000 120 10 4 5 4,000 60 5 0 6 8,000 120 10 10 7 8,000 60 10 5 8 8,000 30 10 2 9 8,000 15 10 0 10 16,000 30 10 10 11 16,000 15 15 0 Observations 1 through 11 considered Sequence Concentration Number (ppm) Minutes Exposed Responded 1 2,000 420 10 0 2 4,000 420 10 10 3 4,000 240 10 4 4 4,000 120 10 4 5 4,000 60 5 0 6 8,000 120 10 10 7 8,000 60 10 5 8 8,000 30 10 2 9 8,000 15 10 0 10 16,000 30 10 10 11 16,000 15 15 0 Used probit equation: Y = B0 + B1  X1 + B2  X2 X1 = concentration ppm, ln-transformed X2 = minutes, ln-transformed
From page 282...
... and ln (minutes) Point estimate = 1.682 Lower limit (95% confidence limit)
From page 283...
... 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.
From page 284...
... 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.
From page 285...
... FIGURE C-1 Probit model with 95% confidence level.
From page 286...
... 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.
From page 287...
... 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.
From page 288...
... 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.
From page 289...
... 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.
From page 290...
... 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.
From page 291...
... 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 concentrationtime 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.
From page 292...
... 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.


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