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Suggested Citation:"16 Propylene Glycol." National Research Council. 2008. Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 5. Washington, DC: The National Academies Press. doi: 10.17226/12529.
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Suggested Citation:"16 Propylene Glycol." National Research Council. 2008. Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 5. Washington, DC: The National Academies Press. doi: 10.17226/12529.
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Suggested Citation:"16 Propylene Glycol." National Research Council. 2008. Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 5. Washington, DC: The National Academies Press. doi: 10.17226/12529.
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Suggested Citation:"16 Propylene Glycol." National Research Council. 2008. Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 5. Washington, DC: The National Academies Press. doi: 10.17226/12529.
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Suggested Citation:"16 Propylene Glycol." National Research Council. 2008. Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 5. Washington, DC: The National Academies Press. doi: 10.17226/12529.
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Suggested Citation:"16 Propylene Glycol." National Research Council. 2008. Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 5. Washington, DC: The National Academies Press. doi: 10.17226/12529.
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Suggested Citation:"16 Propylene Glycol." National Research Council. 2008. Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 5. Washington, DC: The National Academies Press. doi: 10.17226/12529.
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Suggested Citation:"16 Propylene Glycol." National Research Council. 2008. Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 5. Washington, DC: The National Academies Press. doi: 10.17226/12529.
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Suggested Citation:"16 Propylene Glycol." National Research Council. 2008. Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 5. Washington, DC: The National Academies Press. doi: 10.17226/12529.
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Suggested Citation:"16 Propylene Glycol." National Research Council. 2008. Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 5. Washington, DC: The National Academies Press. doi: 10.17226/12529.
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Suggested Citation:"16 Propylene Glycol." National Research Council. 2008. Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 5. Washington, DC: The National Academies Press. doi: 10.17226/12529.
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Suggested Citation:"16 Propylene Glycol." National Research Council. 2008. Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 5. Washington, DC: The National Academies Press. doi: 10.17226/12529.
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Suggested Citation:"16 Propylene Glycol." National Research Council. 2008. Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 5. Washington, DC: The National Academies Press. doi: 10.17226/12529.
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Suggested Citation:"16 Propylene Glycol." National Research Council. 2008. Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 5. Washington, DC: The National Academies Press. doi: 10.17226/12529.
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Suggested Citation:"16 Propylene Glycol." National Research Council. 2008. Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 5. Washington, DC: The National Academies Press. doi: 10.17226/12529.
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16 Propylene Glycol Raghupathy Ramanathan, Ph.D. Toxicology Group Habitability and Environmental Factors Division Johnson Space Center National Aeronautics and Space Administration Houston, Texas BACKGROUND AND PURPOSE On the Mir space station, several gallons of ethylene glycol were used as a coolant. In one incident, gallons of coolant leaked out and ethylene glycol va- pors were detected in the air. A high concentration of ethylene glycol was also found in the humidity condensate that would be used as a source of water for recycling on the International Space Station. On the basis of extensive literature on the toxicity of ethylene glycol, its use was not recommended. Propylene gly- col (PG) is generally believed to be less toxic than ethylene glycol (LaKind et al. 1999). NASA is planning to use PG-based coolant for the Orion crew explora- tion vehicle, which is part of the Constellation Program to send human explorers back to the moon and onward to Mars and other destinations in the solar system. The purpose of this document is to review the existing inhalation toxicol- ogy literature on PG and develop maximum acceptable air concentrations for 1 h, 24 h, 7 d, 30 d, 180 d, and 1,000 d of potential exposure to vapors of PG. STRUCTURE OF PROPYLENE GLYCOL PG is a colorless, practically odorless and tasteless, and somewhat viscous liquid (see Table 6-1 for physical and chemical properties of propylene glycol). 314

Propylene Glycol 315 TABLE 16-1 Physical and Chemical Properties of Propylene Glycol Chemical formula: CH3CHOHCH2OH or C3H8O2 Chemical name: Propylene glycol Synonyms: 1,2-propanediol, 1,2-dihydroxypropane, methyl glycol Molecular weight: 78 CAS number: 57-55-6 Boiling point: 187°C Vapor pressure: 0.07 mm Hg at 20°C; 0.13 mm Hg at 25°C Concentration in air at saturation: 170 ppma at 25°C Conversion factor: 1 ppm = 3.2 mg/m3, 1 mg/m3 = 0.31 ppm, 1 mg/L = 313 Ppm a Calculated from the vapor pressure at that temperature. Source: Data from Rowe and Wolf 1982. OCCURRENCE AND USE PG is commonly used as an additive in cosmetics and in medicinal agents. It is thought to have low toxicity and is used as a vehicle for intravenous (IV) medications, topical medications, and cosmetics. The Food and Drug Admini- stration considers it safe for use in medication and cosmetics. It is also antibacte- rial, which makes it useful as a preservative and disinfectant. PG is the principal component of aircraft deicing and anti-icing fluids and of motor vehicle anti- freeze. As the general weight of evidence in the toxicology literature supports the conclusion that PG will be less toxic than ethylene glycol, PG-based coolant is strongly considered for use in NASA Constellation Program transport vehi- cles. PHARMACOKINETICS AND METABOLISM No data, human or animal, describing the toxicokinetics of PG exposure through inhalation are available. Because the solubility of PG in water is high, one might expect that any inhaled vapor reaching the lungs would be very well absorbed by the lung and metabolized by the liver in a fashion similar to its me- tabolism from an ingested dose, although one might expect some quantitative differences. Cavender and Sowinski (1994) described a work in which humans were exposed to 10% PG in a mist tent with labeled deionized water. Less than 5% of the mist entered the body and, of this amount, 90% lodged in the naso- pharynx and disappeared in the stomach; very little was found in the lungs. It appears that most of the inhaled PG aerosol becomes trapped in the upper respi- ratory tract and does not reach the lungs. For orally administered PG, the metabolites are lactic acid and pyruvic acid, which the body uses as an energy source (either through oxidation by the

316 SMACs for Selected Airborne Contaminants tricarboxylic acid cycle or through the generation of glycogen and glucose by the glycolytic pathway) (Ruddick 1972). One-third of absorbed PG is excreted via the kidneys (Browning 1965a,b). GENERAL TOXICITY INFORMATION ON PG No reports of human toxicity from environmental or occupational expo- sure to PG vapors have been published. However, there are several clinical case reports of PG-associated toxicities, such as hyperlactatemia, metabolic acidosis, hyperosmolality, and renal toxicity occurring when patients received certain sedatives such as benzodiazepines (diazepam or lorazepam, etomidate) by con- tinuous IV infusion for several hours (LaKind et al. 1999, Zar et al. 2007). Sur- prisingly, almost all reports of PG-associated toxicity come from cases treated with lorazepam by IV infusion, although a long list of medications contain PG as a suspension medium. In all these medications, the solvent contained several milligrams to grams of PG (see Yaucher et al. 2003, Wilson et al. 2005, Zar et al. 2007), which amounted to moderate to high doses of PG, the concentrations one is least likely to receive via inhalation. These studies may not be directly relevant to an inhalation route of exposure; however, the observations indicate the toxicity potential of PG. ACUTE EXPOSURE Human case studies reporting death caused by exposure to PG (including exposure through industrial use) were not found in the scientific literature (Cavender and Sowinski 1994). Wieslander et al. (2001) studied the acute ocular and respiratory effects of experimental exposure to PG in an aviation emergency training simulator. Nonasthmatic volunteers (22 men and 5 women) were exposed in an aircraft simulator to PG mist over 1 min to concentrations ranging from 176 to 851 mil- ligrams per cubic meter (mg/m3) (geometric mean concentration of PG was 309 mg/m3). Tests conducted within 15 min after the exposures included an estimate of tear-film stability breakup time, nasal patency by acoustic rhinometry, dy- namic spirometry, and a symptom questionnaire with 23 yes-or-no questions for ocular and respiratory symptoms (nasal and throat irritation, difficulty in breath- ing); smell; dermal symptoms; and symptoms of headache, nausea, fatigue, diz- ziness, and intoxication. After exposure to PG mist for 1 min, tear-film stability decreased, ocular and throat symptoms increased, forced expiratory volume in 1 s per forced vital capacity was slightly reduced, and self-rated severity of dysp- nea was slightly increased. Subjects exposed to the higher concentrations had a more pronounced increase in throat symptoms and a more pronounced decrease in tear-film stability. The four subjects who reported developing an irritative cough during exposure to PG also had an increased perception of mild dyspnea (shortness of breath, difficult or labored breathing).

Propylene Glycol 317 In an animal study, Konradova et al. (1978) exposed rabbits to 10% PG by aerosol inhalation for 20 and 120 min to examine its effect on tracheal epithe- lium. After 20 min of exposure, no noteworthy alterations in the epithelia were observed. After prolonged exposure, pathologic alteration of the cilial cells was noted. In addition, both exposure durations produced alterations in goblet cells (increased number of degenerated mucus-discharging goblet cells in the rabbits’ tracheal lining). Short-Term and Subchronic Inhalation Exposure Studies No human data on the effects of short-term or subchronic duration expo- sure to PG vapors were found in the literature. In a 90-d nose-only inhalation exposure animal study, the frequency of certain clinical signs was measured every week, so the results are used here as short-term study observations. Suber et al. (1989) conducted a subchronic nose- only inhalation exposure study of PG in male and female Sprague-Dawley rats. They exposed rats to PG aerosol for 6 h/d, 5 d/wk for 90 d at concentrations of 0.16, 1.01, and 2.18 mg per liter (L) (160, 1,000, and 2,200 mg/m3 or 50, 313, and 688 parts per million [ppm]). These levels were measured and were not tar- get concentrations. The mass median aerodynamic diameters of the diluted aero- sols were less than 2.22 and 1.96 micrometers for the medium- and high- concentration groups, with geometric standard deviations of 1.44 and 1.57, re- spectively. Statistically significant nasal hemorrhaging and ocular discharge were observed beginning the second week of exposure. The reported incidence of nasal hemorrhaging and ocular discharge in the second week of exposure to the lowest test concentration, 50 ppm, was only 3%. The authors attributed the observed nasal hemorrhaging and ocular discharge to dehydration of the nasal passages and eyes. In males the incidence of these symptoms remained essen- tially constant throughout the exposure (69.9% at 2 wk versus 65.8% at 13 wk), but in females the incidence dropped dramatically from 65.1% at 2 wk to 0.0% at 13 wk. Respiratory rates and tidal volumes were also measured in four rats per group per sex on day 7; measurements were repeated on days 42 and 84. The measured respiratory parameters were found to be unaltered. The authors also measured hematology and clinical chemistry before the experiment and before necropsy, but not during the weeks of exposure. Although statistically significant differences were reported between the control groups and the highest-dose group (2.18 mg/L or 688 ppm) for certain hematologic parameters, such as white blood cell count and lymphocyte count, and for the activity of serum enzymes such as serum sorbitol dehydrogenase (all decreases), no dose-dependent relationship was observed. The observed trend of decreases in aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, and gamma-glutamyl transferase were hard to interpret.

318 SMACs for Selected Airborne Contaminants Chronic Inhalation Exposure Studies No published toxicity data exist on humans exposed chronically to PG va- pors either occupationally or from environmental exposures. Data were available from only one rodent study. Robertson et al. (1947) exposed rats (for 18 months) and monkeys (for 12 months) to PG vapor (at various percentages of atmos- pheric saturation in the case of monkeys). They used the following concentra- tions: rats, 0.17 to 0.35 mg/L (53 to 110 ppm); monkeys, 0.23 to 0.35 mg/L (72 to 110 ppm). In rats, general behavior and appearance; body weight (growth rate) of males; and gross and microscopic examination of lungs, kidneys, liver, and spleen were determined. Kidney function was also evaluated. No significant PG- related adverse effects could be found in the rats. There was no sign of eye irri- tation in any of the exposed animals. Monkeys were exposed to 60% saturated or supersaturated PG concentra- tions for 12 months (Robertson et al. 1947). General behavior and appearance, eye irritation, appetite, blood counts and hemoglobin, gross and microscopic organ lesions, and kidney function were assessed. PG-related increases in num- bers of red blood cells and hemoglobin content of blood were the only changes reported. Kidney function was not affected. It was noted that monkeys (both treated and untreated) had infections, to a variable extent, with parasites (roundworms) and lung mites. Many had anemia and were sick or dying during the experiment. Because of these adverse health conditions, only limited confi- dence can be placed in these data (see Table 16-2). CARCINOGENICITY There is no reported incidence of cancer from occupational exposures to PG. Neither the International Agency for Research on Cancer nor the National Toxicology Program has reported that this chemical is a potential carcinogen (NTP 2004). No chronic inhalation exposure study exists in which the carcino- genic potential of PG was evaluated. In several chronic oral ingestion studies (2- y feed studies; see Gaunt et al. 1972), no evidence of tumor induction was found in any of the tissues. GENOTOXICITY No in vivo genotoxicity studies have been conducted in humans or ani- mals exposed to PG by inhalation. In vitro tests using various strains of Salmo-

TABLE 16-2 Toxicity Studies of Propylene Glycol (Inhalation Exposures) Form of Exposure Concentration Administration Species General Effects References Range, 176 ppm to 851 Aerosol spray Human Data on tear-film stability, rhinometry, lung Wieslander et mg/m3; geometric mean, volunteers function tests (dynamic spirometry), symptom al. 2001 309 mg/m3; 1- min assessments were collected; reported significant exposure at several ocular irritation and throat irritation; some different times breathing difficulty. 0.16 mg/L (50 ppm), Inhalation Rat Observations: a high incidence of nasal Suber et al. 1989 1.0 mg/L (313 ppm), (nose only) hemorrhaging and ocular discharge; significantly 2.18 mg/L (688 ppm); (aerosol) reduced body weights in medium- and high-dose exposures were for 6 females; reduced red blood cells in high-dose h/d, 5 d/wk for 90 d. females. No changes in respiratory rates, tidal volume, or minute volume; unremarkable gross pathology of tissues (at necropsy); thickening of respiratory epithelium with increased number of goblet cells in medium- and high-dose groups. 230 mg/m3 (72 ppm) Inhalation (vapor) Monkey No effects on any of the parameters measured for Robertson et for 12 to 18 months, systemic effects; high mortality in control and al. 1947 continuous exposure treated groups due to various infections. 170 mg/m3 (53 ppm) Inhalation (vapor) Rat No effects on any of the parameters measured for Robertson et for 12 to 18 months, systemic effects. al. 1947 continuous exposure 319

320 SMACs for Selected Airborne Contaminants nella typhimurium with and without metabolic activation were negative (Clark et al. 1979, Pfeiffer and Dunkelberg 1980). In vitro studies using mammalian cells (human fibroblasts, Chinese hamster ovary cells, and Chinese hamster lung cells) that measured chromosome aberrations and DNA damage in cells exposed to PG were negative (Swenberg et al. 1976, Sasaki et al. 1980 as cited in Abe and Sasaki 1982). IMMUNOTOXICITY There are no reports of immunotoxicity from inhalation of PG by humans. The published animal inhalation studies have not specifically looked at changes in immune system parameters. REPRODUCTIVE AND DEVELOPMENTAL TOXICITY There are no published reports of reproductive or developmental toxicity in humans from inhalation of PG vapors in either an occupational setting or by environmental exposure. There are also no published animal data on this subject. RATIONALE Acceptable concentrations (ACs) were determined following the guide- lines of the National Research Council (NRC 1992) Subcommittee on Guide- lines for Developing Spacecraft Maximum Allowable Concentrations (SMACs) for Space Station Contaminants 1992. In the following paragraphs, derivation of ACs for durations of 1 h, 24 h, 7 d, 30 d, 180 d, and 1,000 d are shown for vari- ous effects as available and the SMAC for each duration will be determined based on the lowest AC for that duration. As a part of this process, NASA will also review the existing proposed guidelines, advisories, and regulatory values from various organizations, both regulatory and nonregulatory. There are no standards or health values for PG. The U.S. Environmental Protection Agency reference dose/reference concentration work group did not derive an inhalation reference concentration for PG. The airborne exposure lim- its set by the American Industrial Hygiene Association (AIHA) workplace envi- ronmental exposure level (WEEL) (8-h time-weighted average workplace envi- ronmental exposure level) for PG are 50 ppm for vapor and aerosol, 10 mg/m3 for aerosol only, and 400 ppm for PG mist and PG vapors (AIHA 1985). The Agency for Toxic Substances and Disease Registry (ATSDR) did not derive an acute-duration inhalation minimal risk level (MRL) for PG because no adequate studies were found. ATSDR derived an intermediate-duration inhala- tion MRL of 0.009 ppm for nasal hemorrhaging (ATSDR 1997) based on obser- vations in rats in the Suber et al. (1989) study. Because details were lacking, the ATSDR did not derive a chronic-duration inhalation MRL for PG after review-

Propylene Glycol 321 ing the only data available from one animal study of chronic-duration exposure in monkeys and rats (Robertson et al. 1947). Table 16-3 summarizes SMACs for various durations. The principal stud- ies selected, the adverse end point chosen, the rationale, and detailed calcula- tions have been presented in the preceding paragraphs. Derivation of 1- and 24-h ACs for Inhalation of PG For deriving the 1-h AC, the human subject experiment by Wieslander et al. (2001) was considered. Nonasthmatic volunteers were exposed to PG mist during aviation emergency training and several measurements were collected after 1-min exposures to PG mist at a mean concentration of 309 mg/m3 (about 96 ppm). Data collected on symptoms (average ratings on 10 questions, data collected on visual analog scale of 1 to 100) indicated that ocular irritation and throat irritation were significantly higher than preexposure responses. Dyspnea was higher but only of marginal significance (P = 0.048). The ocular irritation was not from redness of the eye or swollen eyes. On the basis of this study, it was considered that the concentration of 309 mg/m3 is a minimal lowest- observed-adverse-effect level (LOAEL) (mild adverse effect). As such sensory effects are based on concentration, and the symptoms were minor, it was de- cided to use this value for 1 h. Because exposures were just for 1 min, it was decided to use an uncertainty factor of 3 (or LOAEL to NOAEL factor) to derive a 1-h AC as follows: 1-h AC (throat and ocular irritation) = 96 ppm (LOAEL) ×1/3 (LOAEL to NOAEL) = 32 ppm TABLE 16-3 Spacecraft Maximum Allowable Concentrations for PG SMAC, Duration ppm Target Toxicity Principal Study 1h 32.0 Eye, throat, and respiratory system Wieslander et al. 2001 irritation 24 h 17.0 Nasal hemorrhage and ocular Suber et al. 1989 discharge 7d 9.0 Nasal hemorrhage and ocular Suber et al. 1989 discharge 30 d 3.0 Nasal hemorrhage and ocular Suber et al. 1989 discharge 180 d 1.5 Thickening of respiratory epithelium Suber et al. 1989 with increased goblet cells and increased mucin 1,000 d 1.5 Thickening of respiratory epithelium Suber et al. 1989 with increased goblet cells and increased mucin

322 SMACs for Selected Airborne Contaminants For deriving the 24-h AC, the preceding study could not be used, primarily because of the very brief duration of exposure (1 min). Although the discomfort of ocular irritation and throat dryness at 32 ppm may be acceptable for 1 h, these symptoms may not be appropriate for extending the 1-min exposure data to 24 h. Therefore, on the recommendation of the NRC Spacecraft Exposure Guidelines (SEG) committee, the ten Berge method (ten Berge et al. 1986) of extrapolation from the 7-d AC (168 h) to 24 h was used as follows (see below for details of the 7-d AC derivation): 8.93 × 168 h = C3 × 24 h, where 8.9 ppm is the 7-d AC, 3 is a default factor for the chemical-specific exponent, and C is the concentration to be determined for 24 h, which can be calculated as 17 ppm. Thus, the 24-h AC = 17 ppm Derivation of 7-d AC for Inhalation of PG Suber et al. (1989) conducted a 90-d subchronic nose-only inhalation ex- posure study of PG in male and female Sprague-Dawley rats (19 males and 19 females each). In this study, the rats were exposed 6 h/d, 5 d/wk for 90 d to PG as an aerosol at concentrations of 0.16, 1.01, and 2.18 mg/L (160, 1,000, and 2,200 mg/m3 equivalent to 50, 313, and 688 ppm, respectively). During this study, the frequency of certain clinical signs was measured every week. Statisti- cally significant nasal hemorrhaging (all exposed groups) and ocular discharge were seen beginning with the second week of exposure. By the end of the first week of exposure to the lowest test concentration, 50 ppm, the incidence of these effects was only 3% (males). The authors attributed the observed nasal hemorrhaging and ocular discharge to dehydration by PG of the nasal passages and eyes. Regardless of the mechanism of action, ACs have been calculated on the basis of such end points. Based of these data, a no-observed-adverse-effect level (NOAEL) of 50 ppm for up to 1 wk can be identified. The review of the effects clearly shows that by the second week, 69% of the animals had nasal hemorrhaging and ocular discharge, even in the 50-ppm group. Thus, it appears that with longer exposure times, the incidence rate will increase for at least up to 2 wk (as the percent incidence did not change from 2 wk to 13 wk). Therefore, the exposure concentration has to be adjusted with a factor for discontinuous-to-continuous exposure. As far as the use of a species factor is concerned, it was considered that these effects may be due to the dehy- drating effect of PG aerosol (physicochemical effect). Known differences be- tween rats and humans in the structure of the nasal region may be important when considering effects on the respiratory tract and lung or when the metabo- lite of a compound affects the nasal mucosa. As this (dehydration) is a localized effect, the severity of the effect for a particular exposure concentration can be

Propylene Glycol 323 expected to be similar for rodents and humans. Therefore, a species factor is not needed. Thus, the 7-d AC can be calculated as follows: 7-d AC (nasal hemorrhaging) = 50 ppm (NOAEL) × [6 h/24 h × 5 d/7 d] (discontin. to contin.) = 8.9 ppm, rounded to 9 ppm Thus, the 7-d AC for effects on the nasal region is 9 ppm. Derivation of 30-d AC for Inhalation of PG The same adverse end points of nasal hemorrhaging and ocular discharge from the Suber et al. study were used to derive a 30-d AC, as no other data were presented in this study that could be used. From weeks 2 to 14, the average inci- dence of these effects in males, as stated in the body of the text of the authors’ document, was <1% in controls and 65%, 74%, and 75% in low-, medium-, and high-concentration exposure groups. As significant effects were noted at 2 wk, 50 ppm is the LOAEL for 2 wk. Because the data reflect the increased frequency of occurrence and not the severity of the effects, a factor of 3 from LOAEL to NOAEL for these sensory effects would be justifiable. As these effects are pri- marily due to the dehydrating effect of the chemical rather than to progressive tissue injury, a factor of 10 from LOAEL to NOAEL is not needed. In addition, it must be pointed out that, in a study by Robertson et al. (1947), described ear- lier under “Chronic Inhalation Exposure Studies,” no nasal hemorrhaging, ocu- lar discharge, or systemic toxicity was reported in rats or monkeys during a 12- to 18-month continuous whole-body exposure to at least 53 and 72 ppm of PG vapor, respectively (note that this study was not used to derive the AC for sub- chronic and chronic durations). The concentrations of PG in the Robertson et al. study (described earlier in this document) are comparable to that used in the Suber et al. study, but the exposure methods used in these studies were different. No species factor is used, as explained earlier. The 30-d AC is calculated as shown below. 30-d AC (nasal hemorrhaging) = 50 ppm (LOAEL) × 1/3 (LOAEL to NOAEL) × [6 h/24 h × 5 d/7 d] (discontin. to contin.) = 2.98 ppm, rounded to 3 ppm Thus, the 30-d AC for nasal hemorrhaging is 3 ppm. Derivation of 180-d AC for Inhalation of PG For derivation of the 180-d AC, the same 90-d nose-only subchronic study by Suber et al. (1989) was used. At the end of the 90-d exposure, body weight changes, food consumption, organ weight changes (especially of the kidneys), and other variables were also determined. According to NRC guidelines (NRC 1992, 2000), in general, changes in such variables are not to be considered in the

324 SMACs for Selected Airborne Contaminants AC derivations. The important measurements that will reflect the systemic ef- fects of PG are the changes in hematologic and clinical biochemistry variables. Hemoglobin concentration, white blood cell count and lymphocyte numbers, serum sorbitol dehydrogenase and gamma-glutamyl transferase activity, and total serum protein were measured in the study. However, these changes did not follow a definite dose-dependent pattern. There were no histopathologic changes. However, light microscopy of the respiratory epithelium showed thick- ening reflected in an increased number of goblet cells and an increase in their mucin content in both female and male animals with medium- and high-dose treatment groups. Because the authors reported that there were no histologic changes in the trachea, lungs, or larynx and minute volume, tidal volume, and respiratory rate were not significantly altered, the epithelial changes are consid- ered mild adverse effects, and thus one could identify 50 ppm as the NOAEL for these effects. For deriving the AC for 180 d, a factor for adjusting the exposure duration will be used. Although a species factor was not used for the nasal hemorrhaging end point earlier, a species factor of 3 will be used in this case. The factor is for the uncertainty in the severity of effects due to the differences between humans and rats in the nasal passage respiratory epithelium and the nature of the goblet cells. Because the AC is calculated for 180 d with data from a 90-d study, a time extrapolation factor of 180 d/90 d is used; 50 ppm is a NOAEL for this effect. 180-d AC (histologic changes) = 50 ppm (NOAEL) × [6 h/24 h × 5 d/7 d] (discontin. to contin.) × 1/3 (species factor) × 90 d/180 d (time extrapolation) = 1.49 ppm, rounded to 1.50 ppm Thus, the 180-d AC for histologic changes in the nasal passages is 1.5 ppm. The chronic whole-body exposure study of Robertson et al. (1947), de- scribed in detail earlier in this document, was also evaluated. Briefly, in the Robertson et al. study, monkeys and rats were continuously exposed to PG su- persaturated vapor in chambers for 12 to 18 months at the following concentra- tions: rats, 0.17 to 0.35 mg/L (53 to 110 ppm) for 18 months; monkeys, 0.23 to 0.35 mg/L (72 to 110 ppm) for 12 months. During the exposure period, there were no differences between the unexposed and the exposed groups in the gen- eral condition of the animals or in their general activity or behavior. There was no sign of eye irritation in any of the exposed animals. There was also no im- pairment of kidney function. The red blood cell counts and hematocrit values were greater than those of untreated controls. Several of the exposed female rats bore normal-sized litters; all the offspring appeared to be normal. However, in the study, the author reported that the overall health of the monkeys was unde- sirable, and they had a high mortality rate. In the rats, although PG had caused no generalized or localized inflammation of the bronchi or lungs, microscopic examination of the lungs revealed a localized infectious process. This was also noted in 25% of the control rats. Even though this effect was seen only in rats

Propylene Glycol 325 kept 8 months or longer (18 months), the NRC SEG committee recommended that this study not be used for AC derivation because of the high incidence of infection in control rats, as evidenced by the microscopic changes in the lungs. Derivation of 1,000-d AC for Inhalation of PG Although in the Robertson et al. (1947) study an 18-month chronic expo- sure to PG vapors did not lead to any overt systemic effects after rats were ex- posed to 53 to 100 ppm of PG, the study could not be considered for 1,000-d AC derivation because of reported infectious activity (small to large areas of intra- alveolar accumulation of polymorphonuclear leukocytes) in the lungs of 25% of the controls and in exposed rats. To arrive at a 1,000-d AC, it was decided to use the 180-d AC derived from the Suber et al. (1989) study. As the nature of the effects (epithelial changes in the nasal passages) seemed to be adaptive, the NRC SEG committee recommended using the 180-d AC without any time extrapolation factors from 180 to 1,000 d. Thus, the 1,000-d AC for nasal morphology change is 1.5 ppm Table 16-4 summarizes the ACs derived for various end points for various durations from 1 h to 1,000 d and the SMACs for each of these durations. .

TABLE 16-4 Summary of Acceptable Concentrations and SMACs for Various Durations 326 Species and Acceptable Concentrations, ppm Adverse End Point Exposure Data Reference LOAEL/NOAEL 1h 24 h 7d 30 d 180 d 1,000 d Ocular and throat irritation Inhalation of PG; 1 min; Human, LOAEL = 96 ppm 32 — — — — — and slight dyspnea mean concentration = 309 Wieslander et al. mg/m3 (~ 96 ppm) 2001 Nasal hemorrhage and Inhalation of PG; 6 h/d, 5 Sprague-Dawley NOAEL for 1 wk — 17 — — — — ocular discharge d/wk; 0.16, 1.01, 2.18 mg/L rat, Suber et al. = 50 ppm; ten (160, 1,000, 2,200 mg/m3 1989 Berge method or 50, 313, 688 ppm) used Nasal hemorrhage and Inhalation of PG; 6 h/d, 5 Sprague- NOAEL for 1 wk — — 9 — — — ocular discharge d/wk; 0.16, 1.01, 2.18 mg/L Dawley rat, = 50 ppm (160, 1,000, 2,200 mg/m3 Suber et al. or 50, 313, 688 ppm) 1989 Nasal hemorrhage and Inhalation of PG; 6 h/d, 5 Sprague- LOAEL for 2 wk — — — 3 — — ocular discharge d/wk; 0.16, 1.01, 2.18 mg/L Dawley rat, = 50 ppm (160, 1,000, 2,200 mg/m3 Suber et al. or 50, 313, 688 ppm) 1989 Thickening of respiratory Inhalation of PG; 6 h/d, 5 Sprague- NOAEL = — — — — 1.5 1.5 epithelium with increased d/wk; 0.16, 1.01, 2.18 mg/L Dawley rat, 50 ppm goblet cells and their mucin (160, 1,000, 2,200 mg/m3 Suber et al. or 50, 313, 688 ppm) 1989 SMACs 32 17 9 3 1.5 1.5 Abbreviations: LOAEL, lowest-observed-adverse-effect level; NOAEL, no-observed-adverse-effect level; —, not calculated.

Propylene Glycol 327 REFERENCES AIHA (American Industrial Hygiene Association). 1985. Workplace Environmental Ex- posure Level (WEEL) Guide for Propylene Glycol. Fairfax (VA): American Indus- trial Hygiene Association. ATSDR (Agency for Toxic Substances and Disease Registry). 1997. Toxicological Pro- file for Ethylene Glycol and Propylene Glycol. U.S. Department of Health and Human Services, Public Health Service, Agency for Toxic Substances and Disease Registry, Atlanta, GA. September 1997. Abe, S., and M. Sasaki. 1982. SCE as an index of mutagenesis and/or carcinogenesis. Pp. 461-514 in Sister Chromatid Exchange. Progress and Topics in Cytogenetics Vol. 2, A.A. Sandberg, ed. New York: A.R. Liss. Browning, E. 1965a. Ethylene glycol. Pp. 594-600 in Toxicity and Metabolism of Indus- trial Solvents. New York: Elsevier. Browning, E. 1965b. Propylene glycol. Pp. 642-644 in Toxicity and Metabolism of In- dustrial Solvents. New York: Elsevier. Cavender, F.L., and E.J. Sowinski. 1994. Glycols. Pp. 4645-4719 in Patty’s Industrial Hygiene and Toxicology, Vol. 2F. Toxicology, 4th Ed., G.D. Clayton, and F.E. Clayton, eds. New York: Wiley. Clark, C.R., T.C. Marshall, B.S. Merickel, A. Sanchez, D.G. Brownstein, and C.H. Hobbs. 1979. Toxicological assessment of heat transfer fluids proposed for use in solar energy applications. Toxicol. Appl. Pharmacol. 51(3):529-535. Gaunt, I.F., F.M. Carpanini, P. Grasso, and A.B. Landsdown. 1972. Long-term toxicity of propylene glycol in rats. Food Cosmet. Toxicol. 10(2):151-162. Konradova, V., V. Vavrova, and J. Janota. 1978. Effect of the inhalation of a surface tension-reducing substance (propylene glycol) on the ultrastructure of epithelium of the respiratory passages in rabbits. Folia Morphol. (Praha) 26(1):28-34. LaKind, J.S., E.A. McKenna, R.P. Hubner, and R.G. Tardiff. 1999. A review of the com- parative mammalian toxicity of ethylene glycol and propylene glycol. Crit. Rev. Toxicol. 29(4):331-365. NRC (National Research Council). 1992. Guidelines for Developing Spacecraft Maxi- mum Allowable Concentrations for Space Station Contaminants. Washington, DC: National Academy Press. NRC (National Research Council). 2000. Methods for Developing Spacecraft Water Ex- posure Guidelines. Washington, DC: National Academy Press. NTP (National Toxicology Program). 2004. NTP-CERHR Expert Panel report on the reproductive and developmental toxicity of propylene glycol. Reprod. Toxicol. 18(4):533-579. Pfeiffer, E.H, and H. Dunkelberg. 1980. Mutagenicity of ethylene oxide and propylene oxide and of the glycols and halohydrins formed from them during the fumigation of foodstuffs. Food Cosmet. Toxicol. 18(2):115-118. Robertson, O.H., C.G. Loosli, T.T. Puck, H. Wise, H.M. Lemon, and W. Lester. 1947. Test for the chronic toxicity of propylene glycol and triethylene glycol on monkeys and rats by vapor inhalation and oral administration. J. Pharmacol. Exper. Therap. 91(1):52-76. Rowe, V.K., and M.A. Wolf. 1982. Glycols. Pp. 3817-3908 in Patty’s Industrial Hygiene and Toxicology, Vol. IIC. Toxicology, 3rd rev. Ed., G.G. Clayton, and F.E. Clay- ton, eds. New York: John Wiley & Sons.

328 SMACs for Selected Airborne Contaminants Ruddick, J.A. 1972. Toxicology, metabolism, and biochemistry of 1, 2-propanediol. Toxicol. Appl. Pharmacol. 21(1):102-111. Sasaki, M., K. Sugimura, M.A. Yoshida, and S. Abe. 1980. Cytogenetic effects of 60 chemicals on cultured human and Chinese hamster cells. Kromosomo II. 20:574- 584. Suber, R.L., R. Deskin, I. Nikiforov, X. Fouillet, C.R. Coggins. 1989. Subchronic nose- only inhalation study of propylene glycol in Sprague-Dawley rats. Food Chem. Toxicol. 27(9):573-583. Swenberg, J.A., G.L. Petzold, and P.R. Harbach. 1976. In vitro DNA damage/alkaline elution assay for predicting carcinogenic potential. Biochem. Biophys. Res. Com- mun. 72(2):732-738. Ten Berge, W.F., A. Zwart, and L.M. Appelman. 1986. Concentration-time mortality response relationship of irritant and systematically acting vapours and gases. J. Hazard. Mater. 13(3):301-309. Wieslander, G., D. Norbeck, and T. Lindgren. 2001. Experimental exposure to propylene glycol mist in aviation emergency training: Acute ocular and respiratory effects. Occup. Environ. Med. 58(10):649-655. Wilson, K.C., C. Reardon, A.C. Theodore, and H.W. Farber. 2005. Propylene glycol toxicity: A severe iatrogenic illness in ICU patients receiving IV benzodiazepines: A case series and prospective, observational pilot study. Chest 128(3):1674-1681. Yaucher, N.E., J.T. Fish, H.W. Smith, and J.A. Wells. 2003. Propylene glycol-associated renal toxicity from lorazepam infusion. Pharmacotherapy 23(9):1094-1099. Zar, T., C. Graeber, and M.A. Perazella. 2007. Recognition, treatment, and prevention of propylene glycol toxicity. Semin. Dial 20(3):217-219.

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NASA is aware of the potential toxicologic hazards to crew that might be associated with prolonged spacecraft missions. Despite major engineering advances in controlling the atmosphere within spacecraft, some contamination of the air appears inevitable. NASA has measured numerous airborne contaminants during space missions. As the missions increase in duration and complexity, ensuring the health and well-being of astronauts traveling and working in this unique environment becomes increasingly difficult. As part of its efforts to promote safe conditions aboard spacecraft, NASA requested the National Research Council to develop guidelines for establishing spacecraft maximum allowable concentrations (SMACs) for contaminants and to review SMACs for various spacecraft contaminants to determine whether NASA's recommended exposure limits are consistent with the guidelines recommended by the committee.

This book is the fifth volume in the series Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants, and presents SMACs for acrolein, C3 to C8 aliphatic saturated aldehydes, C2 to C9 alkanes, ammonia, benzene, carbon dioxide, carbon monoxide, 1,2-dichloroethane, dimethylhydrazine, ethanol, formaldehyde, limonene, methanol, methylene dichloride, n-butanol, propylene glycol, toluene, trimethylsilanol, and xylenes.

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