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Suggested Citation:"6 Propylene Glycol." National Research Council. 2008. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 3. Washington, DC: The National Academies Press. doi: 10.17226/12527.
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Suggested Citation:"6 Propylene Glycol." National Research Council. 2008. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 3. Washington, DC: The National Academies Press. doi: 10.17226/12527.
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Suggested Citation:"6 Propylene Glycol." National Research Council. 2008. Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 3. Washington, DC: The National Academies Press. doi: 10.17226/12527.
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6 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 NASA is planning to use propylene glycol (PG)-based coolant for the Orion crew exploration vehicle, which is part of the Constellation Program to send human explorers back to the Moon and then to Mars and other destinations in the solar system. Ethylene glycol (EG) was used as a coolant on the Russian Mir space station. In one incident on the Mir, several gallons of the coolant leaked out and EG was later found in high concentrations in the humidity con- densate. Since humidity condensate is used as a source of water for recycling in the International Space Station (ISS) program, all the humidity condensates col- lected from the Mir station after the spill had to be dumped and were not avail- able for water recovery through the test bed system. On the basis of extensive literature on the toxicity of EG (LaKind et al. 1999), its continued use is not recommended. Hence, PG is the choice to replace EG, as it is generally believed to be less toxic. The purpose of this document is to review the existing toxicology litera- ture on PG and develop spacecraft water exposure guidelines (SWEGs) for ac- ceptable concentrations (ACs) in the crew’s potable water for 1, 10, 100, and 1,000 d of potential exposure. STRUCTURE OF PROPYLENE GLYCOL 165

166 Spacecraft Water Exposure Guidelines PHYSICAL AND CHEMICAL PROPERTIES PG is a colorless, practically odorless, and rather viscous liquid. Unlike EG, it has no taste. Its physical and chemical properties are shown in Table 6-1. OCCURRENCE AND USE PG is commonly used as a food additive, in cosmetics, and in medicinal agents. It is thought to have low toxicity and is used as a vehicle for intravenous (IV) and topical medications, as well as for cosmetics. Some medications in which notable amounts of PG are present are lorazepam (Ativan), etomidate (Amidate), diazepam, esmolol, nitroglycerin (Tridil), pentobarbital, phenytoin, phenobarbital, and trimethoprim/sulfmethoxazole (Bactrim). The percentage of PG in many injectable forms generally ranges from 40% to 80% in single-dose units. For example, each single dose of a lorazepam solution of 2 milligrams per milliliter (mg/mL) contains 0.8 mL of PG (of a 1-mL dose) as the drug vehicle, whereas phenytoin (Dilantin) contains 40% PG (see Zar et al. 2007b). The Food and Drug Administration considers PG safe for use in medication and cosmetics. It is also antibacterial, 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 antifreeze. As the general weight of evidence in the toxicology literature supports the conclusion that PG-based fluids are preferable to EG- based fluids, the ISS program prefers to use PG rather than EG as a coolant. TABLE 6-1 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 Water solubility 100 g/100 g of H2O at 25ºC Specific gravity 1.04 Melting point –60°C Boiling point 187°C Vapor pressure 0.07 mm Hg at 20°C; 0.13 mm Hg at 25°C Concentration in air at 170 ppm at 25°C (calculated from vapor pressure at saturation that temperature) Conversion factor 1 ppm = 3.2 mg/m3, 1 mg/m3 = 0.31 ppm

Propylene Glycol 167 PHARMACOKINETICS AND METABOLISM PG is an alcohol of small molecular weight and is nonionic with high wa- ter solubility and without significant protein-binding capacity in vivo. These properties make it readily filtered and excreted by the kidneys. About 55% of PG is metabolized in the liver to lactic acid by alcohol dehydrogenase. The lactic acid is then converted through the gluconeogenic pathway to yield acetate and pyruvate, which is converted to glucose (Ruddick 1972, Morshed et al. 1989, Christopher et al. 1990). The remaining 45% of the PG dose is excreted un- changed by the kidneys. Yu et al. (1985) reported the pharmacokinetics of PG in humans (outpa- tients in a neurology clinic) during multiple dosing regimens after an oral dose of phenytoin containing either 20.7 g of PG, three times daily, or 41.2 g of PG, two times daily, for a minimum of 3 d as a part of a phenytoin bioavailability study. The oral formulation of phenytoin also contained 7.5 mL of ethanol in the first dose protocol and 15.0 mL per dose in the second protocol. The results in- dicated rapid absorption (peak concentrations reached in 1 h) and distribution, and dose-dependent clearance. An elimination half-life of 3.8 to 4.1 h, respec- tively, was observed for these two dose regimens, as well as rapid whole-body clearance of about 0.1 L/kg-h. Speth et al. (1987) determined the pharmacokinetics of PG administered as IV infusions as a part of a Phase I drug study in nine cancer patients with life expectancy of more than 2 mo. The formulation contained PG at 25 mg/mL and polyethylene glycol at 75 mg/mL in addition to the drug. In one protocol, the medication was infused for 4 h daily for 5 d at doses of 120 and 180 mg/m2. This corresponded to averages of 5.1 g and 7.7 g of PG per day. In another infu- sion protocol, 13 or 21 g/d once in 3 wk was also used. Blood samples were collected before, during, and at least eight times after infusion for up to 24 h. The results indicated that the clearance decreases with increasing dose, being 390 mL/min at a dose of 5.1 g/d, but only 144 mL/min at a dose of 21 g/d (Speth et al. 1987). The mean half-life was 2.3 h. The maximum plasma concentration of PG also increased nonlinearly with the total dose. As in the Yu et al. (1985) study, dose-dependent clearance was observed. Morshed et al. (1988) reported that in rats gavaged with PG at doses rang- ing from 0.368 to 5.881 g per kg of body weight, the time to peak in blood was dose related and ranged from 10 min at low doses to 2 h at high doses. Using the Michaelis-Menten rate equation, the authors determined that the maximum PG- metabolizing capacity was about 650 mg/kg/h in the rat, which is equivalent to 1.06 kg/d in a 70-kg human (Morshed et al. 1988). TOXICITY SUMMARY Clinical case studies report that giving critically ill patients high doses of certain medications in which PG is a vehicle for a prolonged time as an IV infu-

168 Spacecraft Water Exposure Guidelines sion leads to some changes in serum. Dose-effect relationships and factors that influence the toxicity of PG are not clearly described in the toxicology literature. Although PG is generally regarded as having low toxicity in adults after oral ingestion, there have been reports in humans and animals of CNS, renal, hema- tologic, and cardiac toxicity (LaKind et al. 1999). Case reports have described hyperosmolality, with or without lactic acido- sis, in patients when PG was used as a vehicle for IV infusion of nitroglycerin or etomidate (an imidazole compound and a nonbarbiturate hypnotic, respectively). In addition to the clinical information on these two medical compounds, a vast amount of literature exists on the accumulation of PG associated with the infu- sion of lorazepam (a benzodiazepine with considerable sedative properties used as an antianxiety agent and also as a hypnotic and anticonvulsant) in intensive care patients (see Zar et al. 2007b). Each milliliter dose of lorazepam injection (2 mg/mL) contained at least 828 mg of PG. Although the clinical significance of elevated PG concentrations and associated toxicity has not been well de- scribed or well documented in these cases, they all present metabolic evidence of PG toxicity (increased lactic acid, metabolic acidosis, hyperosmolality) with- out evidence of clinical deterioration (Wilson et al. 2005). Reports have also been published on nephrotoxicity associated with PG from lorazepam infusions (Yaucher et al. 2003) and from large doses of pheno- barbital and pentobarbital infusion in a 16-y-old boy (Yorgin et al. 1997). The mechanism of nephrotoxicity is unknown, though Morshed et al. (1994), using human proximal tubule cell culture, concluded that in PG-treated cells, the plasma membrane ruptured with increased lactate release, and PG caused cellu- lar swelling and vacuolation, perhaps due to the osmolality of fluid drawn into the vacuoles. These studies are described in detail below. Table 6-2 provides a summary of studies that have investigated the toxic- ity of orally administered PG. Acute Toxicity In all the case studies of acute accidental ingestion of PG, the subjects re- covered after medical intervention. When very high doses of PG were involved, acute effects primarily indicated CNS depression (Cavender and Sowinski 1994), lactic acidosis (Cate and Hendrick 1980), and hyperosmolality (Fligner et al. 1985). The CNS effects seem to be due to the parent compound. Lolin et al. (1988) reported stupor and repetitive convulsions in a case of human acute PG poisoning. The amount of PG ingested was unknown. A summary of acute PG toxicity in humans and animals is provided below.

TABLE 6-2 Toxicity Summary of PG Administered by Oral Route Mode of Dose Duration Dosing Species Effects Reference 3 g/kg Single dose Gavage New Zealand Elevated blood D-lactate and L-lactate (lactatemia). Morshed et al. white rabbit; n=4 1991a 3 g/kg/d Daily for Gavage Wister rat (M); Enhanced activities of some digestive enzymes and Morshed et al. 10, 20, and n=6/group enhanced absorption of some amino acids and 1991b 30 d calcium; no change in intestinal brush border membrane; NOAEL = 3 g/kg/d. 0 (0%), 1.6 (1.0%), 3.7 140 d Drinking Rat (sex and Mild vacuolization of central lobular cells of liver in Seidenfeld and (2.0%), 7.7 (5.0%), 13.2 water strain not 10% group; death in 25% and 50% groups by 70 d. Hanzlik 1932 (10.0%), 26 (25.0%), and known); n=5 No changes in several parameters measured; NOAEL 50 (50%) g/kg/d = 5% (7.7 g/kg/d). 5% or 10% Up to 9 mo Drinking Dog; n=4 No changes in liver or kidney function or in Van Winkle water histopathology of several organs. and Newman 1941 2 and 5 g/kg/d in diet 2y Feed Dog (M, F); n=5 5-g/kg dose group: increase in RBC hemolysis and Weil et al. slight increase in serum bilirubin noted; hemoglobin, 1971 packed cell volume, and RBC count were lower; no effects on organ weights, urine biochemical parameters, liver function tests, hepatotoxicity marker enzymes, water consumption, body weight, or histopathology in low–dose group; increased urine output in 5 g/kg/d PG-treated female groups; NOAEL = 2 g/kg/d. (Continued) 169

170 TABLE 6-2 Continued Mode of Dose Duration Dosing Species Effects Reference 1,225 (2.45%) and 2,450 2y Feed Rat, inbred strain; No effects (NOAEL = 1,225 mg/kg/d). Morris et al. (4.9%) mg/kg/d in diet n=20/group 1942 mg/kg/d (ppm): 200 2y Feed Rat (M); No changes in food consumption, hematology, urinary Gaunt et al. (6,250), 400 (12,500), n=30/group cell excretion, kidney function, or histopathology. No 1972 900 (25,000), 1700 tumor incidence in any tissue. (50,000) mg/kg/d (ppm): 300 2y Feed Rat (F); 30/group No changes in food consumption, hematology, urinary Gaunt et al. (6,250), 500 (12,500), cell excretion, kidney function, or histopathology. No 1972 1,000 (25,000), 2,100 tumor incidence in any tissue. (50,000) 10.1 g/kg/d (5.1% Continuous Drinking Swiss CD-1 Reproductive and developmental toxicity study; no Gulati et al. wt/vol) breeding water mouse (M, F); effect on fertility of males or females in first or 1985 study 20/group/sex second generation. 16, 74.3, 345, and 1,600 Gestation Oral Rat; 25/group No noticeable effect on nidation (implantation of FDRL 1973 mg/kg days 6 to intubation fertilized ovum in endometrium of the uterus in 15 pregnancy) or maternal or fetal survival; extent of skeletal tissue abnormalities was the same as in untreated controls. NOAEL = 1,600 mg/kg/d. 16, 74.3, 345, and 1,600 Gestation Oral Mouse; 25/group No noticeable effect on nidation or maternal or fetal FDRL 1973 mg/kg days 6 to intubation survival; extent of skeletal tissue abnormalities was 15 the same as in untreated controls. NOAEL = 1,600 mg/kg/d. 15.5, 72, 334.34, and Gestation Oral Hamster; No noticeable effect on nidation or maternal or fetal FDRL 1973 1,559 mg/kg/d days 6 to intubation 25/group survival; extent of skeletal tissue abnormalities was 10 the same as in untreated controls. NOAEL = 1,559 mg/kg/d.

12.3, 57.1, 267, and Gestation Oral Rabbit; 10/group No noticeable effect on nidation or maternal or fetal FDRL 1973 1,230 mg/kg/d days 6 to intubation survival; extent of skeletal tissue abnormalities was 18 the same as in untreated controls. NOAEL = 1,230 mg/kg/d. 0 (0%), 1,819 (1.0%), 1 wk prior Drinking Swiss CD-1 No adverse effect on reproduction: number of litters, Gulati et al. 4,796 (2.5%), and 10,118 to and water mouse (M, F); litter size, pup weight, or sex ratio; no effect on 1985 (5.0%) mg/kg/d based on continued 20/group/sex reproductive capacity of the offspring, even from the water consumption through 14 high-dose group. wk (continuous breeding schedule) Abbreviations: M, male; F, female. Note: LD50 values included in Table 6-1 are not included here. In addition, there are several studies that have used cats as experimental animals. In almost all of them, Heinz body formation due to PG administration and subsequent RBC lysis were reported. Heinz body formation seems to be unique to cats and they are not suitable models for human risk assessment. Therefore, it was decided not to include these toxicity studies in this summary table. 171

172 Spacecraft Water Exposure Guidelines Human Toxicology Studies of PG A vast amount of literature exists in the area of management of intensive care medications regarding the heightened awareness of the potential toxicity from PG being present as a vehicle solution in many IV medications. The au- thors of these investigations are aware that infusion of medications containing PG will administer a PG load faster than the patients can metabolize or eliminate PG, leading to accumulation in the system. In several cases, patients were treated with many medications at the same time. A few human case studies in which PG intoxication from PG accumulation has been described are briefly presented here. • Yu et al. (1985) studied the pharmacokinetics of orally ingested PG in patients who received boluses of phenytoin doses containing PG. In one pro- tocol, the patients (n = 16) ingested 20.7 g of PG three times daily (once in 8 h); in another protocol, the patients (n = 6) ingested 41.2 g of PG two times daily (once in 12 h). These preparations also contained 7.5 and 15 mL of ethanol, re- spectively, per dose. The patients were maintained on this formulation for at least 3 d. In addition to the pharmacokinetics, the authors included some state- ments about CNS toxicity, described only as “mental symptoms.” They reported no correlation between the peak plasma concentration of PG and the “severity of mental symptoms.” This finding may indicate that the parent compound may not be responsible for CNS toxicity. Our confidence in the reported CNS toxicity is low because of the lack of detail. The preparation also contained a significant amount of alcohol. Serum lactic acid, arterial pH, and other clinical parameters such as osmolality and anion gap were not measured. • In a short-term infusion pharmacokinetic Phase I study of a cytostatic agent containing PG, nine cancer patients were infused 4 h daily for 5 d at doses of 120 and 180 mg/m2, amounting to a PG dose of 5.1 or 7.5 g/d (Speth et al. 1987). The average peak blood concentrations in these groups ranged from 55 to 425 µg/mL (low to high dose), and it was reported that a steady state was not obtained at the end of the 4-h infusion. In another infusion protocol, some sub- jects received a PG dose of 13 or 21 g/d once in 3 wk. The authors also deter- mined venous pH, lactate, serum osmolality, and free hemoglobin before, dur- ing, and 12 h after infusion to monitor lactic acidosis, hyperosmolality, and hemolysis. Neither lactic acidosis nor hyperosmolality was observed, even in patients with the highest serum PG concentrations. Urine chemistry was not determined. • Yorgin et al. (1997) reported proximal tubular cell injury in a 16-y- old patient who had 14 d of treatment with high doses of phenobarbital (with 70% PG) and pentobarbital (with 41% PG), with some doses of phenytoin. The PG daily dose ranged from 23.4 to 90.3 g. Reported proximal tubular cell injury was based on renal biopsy findings of swollen epithelial cells with vacuolated cytoplasm and extensive dilation of renal tubules. An increased osmolal gap, which is the difference between measured serum osmolality and calculated se-

Propylene Glycol 173 rum osmolality, was seen only after 11 d of treatment and the serum creatinine increased above normal only after 9 d of treatment. The authors did not mention metabolic acidosis. As these medications are well known to induce liver metabo- lism of drugs and chemicals, including PG, it is uncertain how much confidence one can have in extrapolating to the state where PG leads to renal injury in healthy individuals. The patient in this study had also been using illicit drugs, which could have an affect on the interpretation of these results. • In a retrospective review of 128 patients who received continuous in- fusion of lorazepam for a long duration, Yaucher et al. (2003) studied the corre- lation between serum PG concentrations, osmolality, anion gap, and serum creatinine concentrations (as a marker for decreased renal function). Eight pa- tients with serum creatinine levels higher than baseline were identified. Most of these patients were admitted for respiratory failure requiring mechanical ventila- tion and some had end-stage liver disease, AIDS, and T-cell lymphomas. The duration of infusion in these eight subjects ranged from 7 to 75 d, the cumulative amount of PG ranged from 249 to 3,685 g, and the median time to serum creatinine increase was 9 d. The authors concluded that there was a weak to moderate correlation between the cumulative amount of PG and the increase in serum creatinine concentration and they interpreted this elevation to indicate acute renal toxicity by PG. The decrease in serum creatinine with the discon- tinuation of lorazepam supported the hypothesis/speculation that PG might be the causative factor. The authors also reported that serum was hyperosmolar with metabolic acidosis. Seven of 8 patients had elevated osmolal and anion gaps. • In a pilot case study, Wilson et al. (2005) evaluated the incidence of PG-mediated toxicity in medical intensive care unit patients receiving IV lorazepam or diazepam. The pilot study included 21 patients who received ben- zodiazepine in PG (lorazepam or diazepam) and 23 patients who received mida- zolam, another benzodiazepine, delivered in an alternative solvent. Four patients who received IV lorazepam or diazepam did not show signs of clinical deteriora- tion, but had metabolic evidence of PG toxicity (elevated anion gap, decreased serum bicarbonate, elevated serum osmolality). Only one subject who received PG-containing medication had serum lactic acid measured and it was found to be elevated. In subjects receiving IV midazolam, neither metabolic abnormality nor clinical deterioration was seen, suggesting that metabolic toxicity was caused only by PG. • In a prospective observational study of critically ill patients who re- ceived continuous infusions of lorazepam, Arroliga et al. (2004) investigated the accumulation of serum PG and its relationship to the osmolal gap by evaluating how early in the exposure period the accumulation of PG and the increased os- molal gap could be seen. They noted that hyperosmolar anion gap metabolic acidosis was observed when the continuous infusion of lorazepam (with PG) was equal to or more than 48 h, at which time the mean cumulative PG dose was 1,219 mg/kg/d and serum PG was about 200 mg/dL (range 94 to 359 mg/dL). Even though a high osmolal gap (mean 48.0 mmol/kg; normal range <12

174 Spacecraft Water Exposure Guidelines mmol/kg) was noted in all patients, high anion gap acidosis was seen in only six patients. One criticism of this study was that serum lactate concentrations for five of nine patients were not available, and the lactate concentrations in the rest were low or near normal levels. Even with a cumulative dose of more than 1.2 g/kg/d, the mean serum creatinine concentrations did not change significantly from the baseline to the end of the infusion period of 2 d, indicating that there was no renal toxicity at this dose rate for this duration. This result is different from the observations in the Yaucher et al. report, mentioned earlier, in which the authors reported nephrotoxicity after 9 d of high doses of infusion of PG. • Zar et al. (2007a) reported a case history of one individual admitted for alcohol intoxication (with multiple admissions for alcohol intoxication in the past). This individual was infused with high doses of lorazepam and on the eighth day developed severe metabolic acidosis, a significant increase in serum creatinine (indication of acute kidney toxicity), and a marginal increase in blood urea nitrogen. The patient also showed a high osmolal gap (145 mmol/kg; nor- mal <12 mmol/kg). Until the eighth day, all the measurements were within ac- ceptable limits and the patient had received a cumulative amount of 1,699 g of PG over the 7 d of infusion of lorazepam. Animal Toxicology Studies of PG Toxicology data on PG were derived mostly from studies conducted in the 1930s and 1940s. Several investigators have determined the lethal doses of PG in animals and the results were summarized by Ruddick (1972) for various routes of administration. In a study in rats of oral 50% lethal doses (LD50) for PG, lethargy and coma were observed before death (Clark et al. 1979). The LD50 for PG by oral ingestion is summarized in Table 6-3. TABLE 6-3 LD50 of PG Administered by Oral Route Species LD50a Number per Group per Dose Rat (four studies) 30.0b 5 21.0 10 28.0 5 28.8 Not known Mouse 23.9 20 Rabbit 18.9 10 Guinea pig 18.9 10 Dog 20.0 Not known a Expressed as gram per kilogram of body weight. b LD40 only. Source: Ruddick 1972. Reprinted with permission; copyright 1972, Toxicology and Ap- plied Pharmacology.

Propylene Glycol 175 Short-Term Toxicity (1 to 10 d) In the literature, only one human and one animal study (besides the LD50 determination studies) could be found that investigated acute toxicity after oral exposure to PG. Yu et al. (1985) studied 22 subjects in an oral phenytoin bioavailability study during multiple doses in an outpatient clinic. PG was used as a formula- tion solvent. This study was described earlier in this document. PG at 38.66 mmol/kg (equal to 3 g/kg) was administered orally to rabbits (n = 4) and blood concentrations of PG and lactate were measured 0, 0.25, 1, and 3 h after the dose (Morshed et al. 1991a). PG administration elevated the concentrations of blood L-lactate, which plateaued at 0.25 h, to 2.45-fold higher than predose concentrations. Production of D-lactate in blood was also increased significantly at 3 h (about 30-fold increase over controls). The authors did not mention how long it took blood lactate concentrations to return to control levels. Subchronic Toxicity (11 to 100 d) No subchronic controlled human PG oral ingestion studies were found in the literature. Some long-term IV infusion studies in patients requiring pharma- cologic sedation were described byYaucher et al. (2003), who discussed studies in which the duration of infusion of lorazepam containing PG ranged from 7 to 75 d. Few animal studies were found. Morshed et al. (1991b) studied the effect of multiple oral doses of PG at 3 g/kg on the intestinal uptake of nutrients and enzymes involved in terminal digestion in the rat. The doses were administered daily for 10, 20, or 30 d. The authors showed that several enzymes involved in the terminal digestions—such as sucrase, lactase, and gamma-glutamyl transpeptidase—increased as did the absorption of some amino acids (glycine, L- aspartic acid, and L-lysine). The structural integrity of the jejunal surface was unaffected, which indicates that 3 g/kg can be considered a no-observed- adverse-effect level (NOAEL) in rats for any adverse gastrointestinal effects for at least 30 d. Bauer et al. (1992) conducted a 13-wk study in which they fed male and female cats a diet containing 0%, 6%, or 12% PG ( 0, 2,100, or 3,600 mg/kg) and measured changes in several hematologic parameters every 2 wk. Signifi- cant decreases in hemoglobin were noted, but they were not dose related. In Patty’s Industrial Hygiene book series, a Dow Chemical study was summarized in which cats were fed various concentrations of PG in their food (Rowe and Wolf 1982). It was reported that the primary treatment-related effect was on red blood cells (RBCs), which exhibited Heinz body formation (aggregates of dena- tured hemoglobin protein globin chains precipitated within the RBCs) followed by increased hemosiderin pigment in liver Kupffer cells and spleen endothelial cells. All these findings are consistent with PG-mediated destruction of RBCs. These changes were dose related.

176 Spacecraft Water Exposure Guidelines Another study reported that cats that consumed moist cat food containing 41% PG (dose rate 8,000 mg/kg/d) for 22 d showed decreased activity, mental depression (according to the author), and mild to moderate ataxia. These cats had much higher serum D-lactate concentrations than control cats (Christopher et al. 1990). However, cats that consumed diets containing 12% PG (dose rate 1,600 mg/kg/d) for 35 d did not exhibit such neurobehavioral symptoms (Chris- topher et al. 1990). Weiss et al. (1992) reported that, compared with control cats, those fed a diet containing 12% PG for 14 d developed reticulocytosis and increased Heinz body numbers and haptoglobin. The RBCs from these cats showed increased fragility to mechanical stress, which indicates reduced RBC life span. Cats are poor models for compounds such as PG because the literature in- dicates that they lack the enzymes for glucuronide conjugation of PG, making them the most sensitive species to PG poisoning. For this reason, these studies are included here for completeness, but are not appropriate for use in SWEG derivation. Chronic Exposures (>100 d) No human studies describing exposure to PG for this duration are avail- able in the toxicology literature. Rats given 10% PG in drinking water for 100 d showed no change in body weight after an initial loss during the first 10 d (Weatherby and Haag 1938). Seidenfeld and Hanzlik (1932) conducted a drink- ing water study in which rats (sex and strain not provided) were given water containing 0%,1%, 2%, 5%, 10%, 25%, and 50% PG, corresponding to 0, 1.6, 3.7, 7.7, 13.2, 26.0, and 50.0 g/kg/d, respectively, over 140 d. In addition to rou- tine body weight measurements, urine was microscopically examined and kid- ney, heart, spleen, and liver histology was evaluated. Animals that received 25% and 50% PG died at about 69 d. Rats who were part of the 1%, 2%, and 5%, dose groups appeared normal and histopathology of tissues revealed no abnor- malities; in particular, no renal lesions were found. The rats in the 10% group also appeared normal, with the exception of a moderate degree of vacuolization of the central lobular cells. The water intake of the animals in the 0% to 10% dosage groups was not affected. In this study, the authors mentioned that the 140-d NOAEL appears to be 5% PG or 7.7 g/kg/d in drinking water. Weil et al. (1971) conducted a study on groups of five male and five fe- male beagle dogs fed diets containing PG and dextrose for 2 y. Mortality, change in body weight, and food and water consumption data were collected. In addition, micropathology and organ weights for liver, kidney, and spleen were studied and blood, urine, and biochemical parameters were measured. Hematol- ogy was measured at 0, 6, 12, 23, and 23.5 mo. The results showed that no changes occurred in any of the above parameters in the group eating a diet that included 2 g/kg/d of PG; however, there were a number of changes in the group eating a diet that included PG at 5 g/kg/d. In this latter group, there was an in-

Propylene Glycol 177 crease in the rate of RBC hemolysis and the incidence of anisocytosis (a condi- tion characterized by a considerable variation in the size of cells, especially RBCs), poikilocytosis (an increase in the number of abnormally shaped RBCs), and reticulocytosis (an increase in the number of circulating immature RBCs), indicative of RBC destruction with accelerated replacement from the bone mar- row. Hemoglobin concentration, hematocrit, and total RBC count were slightly low at 6, 12, and 23 mo, but were only statistically significantly different from the controls at 23 mo. Total bilirubin increased slightly. Urine output was sig- nificantly higher in the female dogs at 6 and 12 mo and in males at 23 mo. Lower water intake and lower specific gravity of urine was also noted. In the 2 and 5 g/kg/d dosage groups, liver, spleen, bone marrow and kidney pathology, as well as serum markers for hepatotoxicity, were unremarkable. Based on these results, a dietary PG at of 2 g/kg/d was identified as a NOAEL for hematologic changes in dogs. In a 9-mo study, Van Winkle and Newman (1941) investigated the effect in two groups of dogs of consuming PG in drinking water. One group of male and female dogs was given 5% PG in water two times a day and another group of only males was allowed to drink 600 mL of water containing 10% PG per day. Kidney function was assessed by phenosulfonaphthalein excretion and liver function was studied by measuring rose bengal (rose bengal test for liver function) in the blood and galactose and uric acid in the urine. These tests indi- cated that liver and kidney function were not affected. Pathology of these organs was also unremarkable. In a 2-y diet study by Gaunt et al. (1972), male and female Sprague- Dawley CD rats were exposed to PG at 0, 6,250, 12,500, 25,000, or 50,000 parts per million (ppm) (estimated dose rates of 0, 200, 400, 900, or 1,700 mg/kg/d for males and 300, 500, 1,000, or 2,100 mg/kg/d for females). Body weights, organ weights, and hematologic parameters were measured. In addition, organs were evaluated microscopically for potential lesions. Behavior was also ob- served. No significant compound-related differences between control and treated groups were discernible. In a 2-y study, Morris et al. (1942) reported that after administration to al- bino rats of PG reconstituted in the diet at 2.45% and 4.9% (1,225 mg/kg/d and 2,450 mg/kg/d, respectively), no differences compared with control rats were noted in growth rate, food or water consumption, survival, or gross or micro- scopic lesions in lung, heart, liver, spleen, kidney, adrenal, or testis. However, in a summary table on pathologic lesions, these authors noted “slight liver dam- age” for the 2,450 mg/kg/d group, but they did not describe the histopathology of the liver. The percent incidence was also not mentioned. No renal calculi were found. Based on these results, it appears that, for 2 y PG ingestion in rats, 2,450 mg/kg/d is a lowest-observed-adverse-effect level (LOAEL) for liver ef- fects and 1,225 mg/kg/d is a NOAEL for all end points.

178 Spacecraft Water Exposure Guidelines GENOTOXICITY No in vivo genotoxicity studies of PG in humans or animals have been re- ported. In vitro tests using various strains of Salmonella typhimurium with and without metabolic activation were negative (Clark et al. 1979, Pfeiffer and Dunkelberg 1980). In vitro studies with 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). CANCER PG has not been classified as a carcinogen by the National Toxicology Program (NTP), the International Agency for Research on Cancer, or the U.S. Environmental Protection Agency (EPA). Animal studies using male and female rats fed diets containing PG for 24 mo (Gaunt et al. 1972) also have not shown PG to be a carcinogen. REPRODUCTIVE AND DEVELOPMENTAL TOXICITY No human reproductive toxicity data on PG could be located. The NTP conducted a reproduction and fertility assessment in CD-1 mice administered PG in their drinking water (Gulati et al. 1985). In the NTP continuous breeding study, PG was administered to mice in the drinking water at up to 5% (wt/vol) (estimated dose of 10.1 g/kg/d). This dose had no effect on fertility in either males or females in the first or second generation. Thus, in mice, PG is not con- sidered a reproductive toxicant in males or females or in their progeny. Simi- larly, in late 1970, the Food and Drug Research Laboratories Inc. conducted a reproductive and developmental study in rats and mice orally intubated with PG at 16, 74.3, 345, and 1,600 mg/kg on gestation days 6 to 15; in hamsters at 15.5, 72, 334.34, and 1,559 mg/kg on gestation days 6 to 10; and in rabbits at 12.3, 57.1, 267, and 1,230 mg/kg on gestation days 6 to 18 (FDRL 1973). There was no evidence of adverse reproductive or developmental health effects in any of these species. No effects on maternal or fetal survival or on the number of ab- normalities in soft or skeletal tissues were reported. The NTP Center for the Evaluation of Risks to Human Reproduction expert committee reported a sum- mary of these data in 2003 (CERHR 2003). The panel concluded that there is adequate evidence in mice that PG does not cause reproductive toxicity in males and females at exposures up to 5% PG in drinking water over an 18-wk expo- sure period. They also concluded that although no human developmental toxic- ity data were identified, data are sufficient to conclude that PG is not a devel- opmental toxicant in CD-1 mice, Wistar rats, Golden hamsters, and Dutch-

Propylene Glycol 179 belted rabbits by daily oral intubation at doses stated in the studies outlined above. IMMUNOTOXICITY No reports of immunotoxicity of PG by oral ingestion in humans could be found in the literature (Table 6-2). Similarly, no animal studies that specifically looked at immune system parameters after oral administration of PG could be found in the literature. In the 2-y PG feeding study in dogs (Weil et al. 1971), as previously mentioned, pathology of bone marrow and spleen did not exhibit any compound-related effects in either the 2 or 5 g/kg/d dosage groups. RATIONALE The following paragraphs provide a rationale for proposing 1-, 10-, 100-, and 1,000-d SWEGs for PG in NASA’s spacecraft water. The values for SWEGs were based on ACs for each respective duration derived according to Methods for Developing Spacecraft Water Exposure Guidelines (NRC 2000). Approaches by Other Organizations No federal or state drinking water guidelines for PG exist. The health ef- fects data for PG were reviewed by the EPA reference dose (RfD)/reference concentration (RfC) work group and were determined to be inadequate for deri- vation of an inhalation RfC or an oral RfD. EPA did not propose a health advi- sory level for PG in drinking water. ATSDR (1997) did not derive an oral mini- mum risk level (MRL) for acute, intermediate, or chronic duration. According to the Food and Drug Administration, the acceptable daily intake is 25 mg/kg. The Joint FAO/WHO Expert Committee on Food Additives, the average daily intake of PG from food products in the United States has been estimated at 2,400 mg/d (34 mg/kg/d) for a 70-kg person (WHO 1974). An acceptable daily intake of 0 to 25 mg/kg was established for PG (or 1.8 g/d for a 75-kg male, when used as a food additive) by the Committee at its 17th meeting (published in WHO 1974). Derivation of ACs and SWEGS for Various Durations: A Note In our efforts to derive a SWEG for PG, two basic approaches were con- sidered. The author of this report favored using data from scientific studies with healthy animals exposed by oral ingestion as the most appropriate source of data. Such data always involve the limitation of extrapolating from one species

180 Spacecraft Water Exposure Guidelines to another, which has been extensively used by the risk-assessment community. The National Research Council (NRC) Subcommittee on SWEGs, however, recommended that patient data from infusion of drugs in which PG was the car- rier be used for derivation of a SWEG for PG. This approach has the limitations that the patients were seriously ill, other drugs were present, and the route of administration is not oral. The committee argued that the effects (hyperosmo- lality, osmolal gap, increased anion gap, and lactic acid acidosis) are not likely to have been caused by the medications such as lorazepam and diazepam used in the case studies. Also, discontinuation of the infusion of medications containing PG and hemodialysis to remove PG reversed the effects mentioned above, and thus PG is the most probable cause. Both approaches are described below, and, in the end, either approach yields results that differ by only a little more than a factor of 2. Derivation of 1-, 10-, 100-, and 1,000-d ACs Based on Clinical Case Studies (Human Subject Studies) A review by Zar et al. (2007b) described several case studies in which lorazepam, which contains about 80% PG as a vehicle, had been used for con- tinuous IV infusion. If one used the maximum recommended dose of lorazepam (0.1 mg/kg/h) for infusion, it would be equivalent to 168 mg/d for a 70-kg per- son. This in turn would equal 69 g/d of PG or about 1 g/kg/d. According to Zar et al., this amount would be considered safe, presumably extrapolating the guidelines proposed for the infusion of lorazepam. Furthermore, in the absence of any predisposed risk factors (such as liver disease, kidney disease, or respira- tory system infections), there would not be a need to further reduce the amount. Calculations by Wilson et al. (2005) also indicated that PG at 1 g/kg/d could be considered safe. As the data are from humans, no species factor will be applied. Using this value as a NOAEL, a 1-d AC for abnormal serum parameters (hy- perosmolality, osmolal gap, hyperlactatemia, and metabolic acidosis) can be calculated as follows: 1-d AC(abnormal serum parameters) = [1 g/kg/d(safe dose) × 70 kg(adult body weight)]/ (2.8 L/d)(water intake) = 25 g/L. The 10-d AC can be calculated after applying a safety factor of 3 to reduce the level for daily consumption for 10 d. This is justified as the review of case histories indicates that some of the adverse changes are seen after 8 to 10 d of infusion (Zar et al. 2007b). 10-d AC(abnormal serum parameters) = 25 g/L(1-d AC) × (1/3)(safety factor) = 8.33 g/L, rounded to 8 g/L. (This is equivalent to a dose of 0.32 g/kg/d.)

Propylene Glycol 181 The 100-d AC was derived by adopting the 10-d AC. The NRC subcom- mittee on SWEG directed NASA to use the 10-d AC without an additional safety factor, as it would not pose any risk of hyperosmolality or metabolic aci- dosis. A time factor is not needed to account for metabolic disturbances. 100-d AC(abnormal serum parameters) = 8 g/L(10-d AC). For calculating the 1,000-d AC, the NRC committee agreed with NASA’s use of animal data. The calculations are shown under the derivation of SWEGs using animal data. Table 6-4 presents the SWEGs that are based on the ACs derived for each exposure duration. The following controlled animal studies were considered for the derivation of ACs. 1-d AC for Ingestion (Animal Data) Several animal studies have been conducted to determine the LD50 values by the oral route. Derivation of a 1-d AC (acute-duration AC) from an LD50 is usually not done because there is too much uncertainty in the safety factors that need to be applied. Thus, it was decided to consider one study done in rabbits by Morshed et al. (1991a). In this study, a single oral bolus of PG at 3 g/kg (38.66 mmol/kg) was administered. Blood concentrations of L- and D-lactate peaked as early as 0.25 h and remained at this peak level through the last measurement, which was taken 3 h following PG administration. L-Lactate concentrations in- creased to 2.5-fold higher than those of controls and D-lactate increased to 30- fold higher than the controls. TABLE 6-4 SWEGs for PG Duration, d SWEG, g/L Toxicity End Point Principal Study 1 25 Hyperosmolality, osmolal gap, Clinical case studies hyperlactatemia, and metabolic (see Zar et al. 2007b) acidosis 10 8 Hyperosmolality, osmolal gap, Clinical case studies hyperlactatemia, and metabolic (see Zar et al. 2007b) acidosis 100 8 Hyperosmolality, osmolal gap, Clinical case studies hyperlactatemia, and metabolic (see Zar et al. 2007b) acidosis 1,000 1.7 Hematologic effects Weil et al. 1971

182 Spacecraft Water Exposure Guidelines Because an increase in lactic acid is generally considered a metabolic change rather than an adverse clinical outcome, the change in this study is con- sidered a minimal LOAEL. It could be considered a serious effect when the con- centration in blood rises to the extent that it changes the pH of the blood. In this study, blood pH did not change. The medical literature has numerous cases of hyperlactatemia connected with case histories involving PG poisoning and com- plications involving administration of medications containing PG as the me- dium. All these data are from IV studies. Persistent high levels of blood lactate can lead to an increased osmolal gap. Increased lactate, especially D-lactate, in the blood has been correlated with the development of depression and with ataxia in cats (Christopher et al. 1990). The limitation of the Morshed et al. (1991a) study is that only one dose was used and the clinical relevance of this magnitude of change is not apparent. Because the pH of the blood did not change (no evidence of metabolic acidosis), NASA decided not to use these data to derive an AC for 1 d. 10-d AC for Ingestion (Animal Data) One animal study considered for the 10-d AC was that of Morshed et al. (1991b), who studied the intestinal uptake of nutrients and brush-border mem- brane enzymes in the rat after oral doses of PG at 3 g/kg/d for 10, 20, or 30 d. The treatment did not adversely affect the enzymes responsible for terminal di- gestion or absorption of certain amino acids and the structural integrity of the jejunal surface was unaffected. The toxicologic implications are not very clear; hence, an AC was not derived from these data. As cats are not an appropriate toxicology models for humans, data from cat studies cited in this document (Christopher et al. 1990, Weiss et al. 1992) and in the literature will not be used to derive an AC. 100-d AC for Ingestion (Animal Data) Sidenfeld and Hanzlik (1932) reported that when rats (strain and sex not specified, n = 5 per dose group) received PG in drinking water at 0%, 1.0%, 2.0%, 5.0%, and 10.0% (equal to 0, 1.6, 3.7, 7.7, and 13.2 g/kg/d) for 140 d, the liver of the rats exposed to 10% PG in water showed a moderate degree of cen- trilobular vacuolization. The two higher-dose groups are not included here be- cause of mortality in those groups. For all animals in the 0% to 10% PG groups, histopathology of heart, spleen, and kidney was unremarkable and urine was free of casts, cells, and albumin. A NOAEL for hepatotoxicity appears to be 5%, which corresponds to 7.7 g/kg/d. Though the authors used various doses, the histopathology observations are not in the form of data that can be used for benchmark dose methodology. Thus, the default LOAEL-NOAEL approach is used.

Propylene Glycol 183 A 100-d AC can be calculated based on hepatotoxicity using this NOAEL of 7.7 g/kg/d as follows: 100-d AC(hepatotoxicity) = [7.7 g/kg/d(NOAEL) × 70 kg(adult body weight) × (1/10)(species)]/2.8 L/d(water consumption) = 19.3 g/L, rounded to 19.0 g/L. Because 140-d data are being used for 100 d, a time factor is not needed. 1,000-d AC for Ingestion (Animal Data) For derivation of the 1,000-d AC, three animal chronic-duration exposure studies were considered since no suitable human exposure data could be found. The first study considered was by van Winkle and Newman (1941), who investigated the effect of 5% and 10% PG in the drinking water of male and female dogs after 9 mo of treatment. Kidney function and liver function were examined and no functional deficits were noted. Histopathology of these tissues was unremarkable. The second study is a 2-y PG feed study in male and female CD-1 mice (Gaunt et al. 1972). In this study, the mice consumed a diet containing PG at 0, 6,250, 12,500, 25,000, or 50,000 ppm for 2 y (approximately 0, 200, 400, 900, or 1,700 mg/kg/d in male mice and 0, 300, 500, 1,000, or 2,100 mg/kg/d in fe- male mice). Body weight and organ weight changes, hematologic parameters, and microscopic examination of organs were evaluated. No compound-related abnormal findings were discernible. Taking the conservative value for the dose of the male rats, 1,700 mg/kg/d for 2 y appears to be a NOAEL. The third study considered is a 2-y dog study by Weil et al. (1971). Groups of five male and five female beagle dogs were fed diets containing PG at concentrations of 2.0 and 5.0 g/kg/d. In dogs consuming a diet containing PG at 5 g/kg/d, increases in the the rate of RBC hemolysis and in the the incidence of anisocytosis, poikilocytosis, and reticulocytosis (which indicate RBC destruc- tion with accelerated replacement from the bone marrow) were noted. Compared to control dogs not receiving PG in the diet, hemoglobin and hematocrit values and total RBC count were slightly low, while total bilirubin was slightly in- creased. Urine output was significantly higher in the female dogs at 6 and 12 mo and in males at 23 mo. Lower water intake and lower specific gravity of urine was also noted. Serum markers for hepatotoxicity were unremarkable and pa- thology of the spleen, bone marrow, and kidney showed no treatment-related changes. Female dogs appeared to be more sensitive than males to the effects of PG. The results showed no changes in any of these parameters with PG at 2 g/kg/d. Based on the changes noted in the group receiving 5 g/kg/d, 2 g/kg/d could be identified as a NOAEL in dogs. The fourth study considered for deriving a 1,000-d AC is a 2-y study by Morris et al. (1942) in which an inbred strain of male and female albino rats

184 Spacecraft Water Exposure Guidelines (strain not mentioned) were fed a diet containing 2.45% or 4.9% PG. The esti- mated doses were 1,225 mg/kg/d or 2,450 mg/kg/d, respectively. No changes were seen in many general parameters. Gross microscopic lesions in lung, heart, liver, spleen, kidney, adrenal, and testes were evaluated. There were no renal calculi. The authors reported some slight pathologic lesions in the liver of the 2,450 mg/kg/d group (including diffuse centrilobular atrophy, bile-duct prolif- eration, and fatty degeneration). Thus, 2,450 mg/kg/d could be identified as a LOAEL for liver effects and 1,225 mg/kg/d is a NOAEL for all the effects for rats from PG ingestion for 2 y. Since there are no chronic drinking water studies available, the 2-y chronic exposure studies reviewed above were considered for deriving the 1,000-d AC. A comprehensive look at these studies seems to indicate that the kidney is not a target organ for PG toxicity in animals. However, the hematologic system ap- pears to be affected more than any other tissues, followed by affects to the liver. On the basis of these observations, the 1,000-d AC was calculated using the dog study of Weil et al. (1971), in which some disturbances in the hematologic sys- tem were evident. Because spaceflight also has some hematologic effects, this study is of particular interest in deriving the 1,000-d AC. Thus, a 1,000-d AC was calculated for hematologic effects using a NOAEL of 2 g/kg/d. 1,000-d AC(hematology) = [2 g/kg/d(NOAEL) × 70 kg(adult body weight) × (1/10)(species) × (1/3)(spaceflight)]/2.8 L/d(water consumption) = 1.67 g/L, rounded to 1.7 g/L. A summary of the ACs derived for PG for various durations of exposure (1-d, 10-d, 100-d, and 1,000-d) is shown in Table 6-5.

TABLE 6-5 Summary of ACs and SWEGs for PG NOAEL/ Uncertainty Factor AC, g/L of water LOAEL, To Species Time Other Safety Reference Toxicity End Point g/kg/d Species NOAEL Factor Factor Factors 1d 10 d 100 d 1,000 d study Hyperosmolality, 1 Human 1 1 1 3 for 10 d 25 8 8 — Zar et al. osmolal gap, 2007b hyperlactatemia, and metabolic acidosis Hepatotoxicity NOAEL Rat 1 10 1 1 — — 19 — Sidenfeld and =7 Hanzlik 1932 Hematologic effects NOAEL Dog 1 10 1 3a — — — 1.7 Weil et al. =2 1971 SWEG 25 8 8 1.7 a 3 = spaceflight safety factor for abnormal hematology. Abbreviation: —, none derived. 185

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Propylene Glycol 187 Lolin, Y., D.A. Francis, R.J. Flanagan, P. Little, and P.T. Lascelles. 1988. Cerebral de- pression due to propylene glycol in a patient with chronic epilepsy--the value of the plasma osmolal gap in diagnosis. Postgrad. Med. J. 64(754):610-613. Morris, H.J., A.A. Nelson, and H.O. Calvery. 1942. Observations on the chronic toxici- ties of propylene glycol, ethylene glycol, diethylene glycol, ethylene glycol mono- ethyl-ether, and diethylene glycol mono-ethyl-ether. J. Pharmacol. Exp. Therap. 74:266-273. Morshed, K.M., J.P. Nagpaul, S. Majumdar, and M.K. Amma. 1988. Kinetics of propyl- ene glycol elimination and metabolism in rat. Biochem. Med. Metab. Biol. 39(1):90-97. Morshed, K.M., J.P. Nagpaul, S. Majumdar, and M.K. Amma. 1989. Kinetics of oral propylene glycol-induced acute hyperlactatemia. Biochem. Med. Metab. Biol. 42(2):87-94. Morshed, K.M., A. L'Helgoualch, J.P. Nagpaul, M.K. Amma, and J.F. Desjeux. 1991a. The role of propylene glycol metabolism in lactatemia in the rabbit. Biochem. Med. Metab. Biol. 46(2):145-151. Morshed, K.M., J.F. Desjeux, J.P. Nagpaul, S. Majumdar, and M.K. Amma. 1991b. The effect of propane-diols on the intestinal uptake of nutrients and brush border mem- brane enzymes in the rat. Biochem. Med. Metab. Biol. 45(2):161-170. Morshed, K.M., S.K. Jain, and K.E. McMartin. 1994. Acute toxicity of propylene glycol: An assessment using cultured proximal tubule cells of human origin. Fundam. Appl. Toxicol. 23(1):38-43. NRC (National Research Council). 2000. Methods for Developing Spacecraft Water Ex- posure Guidelines. Washington, DC: National Academy Press. 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. Rowe, V.K., and M.A. Wolf. 1982. Propylene glycol. Pp. 3852–3861 in Patty’s Industrial Hygiene and Toxicology, Vol. 2C. Toxicology, 3rd rev. Ed., G.D. Clayton, and F.E. Clayton, eds. New York: Wiley. 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. La Kromosoma 20:574- 584. Seidenfeld, M.A., and P.J. Hanzlik. 1932. The general properties, actions, and toxicity of propylene glycol. J. Pharmacol. 44:109-121. Speth, P.A., T.B. Vree, N.F. Neilen, P.H. de Mulder, D.R. Newell, M.E. Gore, and B.E. de Pauw. 1987. Propylene glycol pharmacokinetics and effects after intravenous infusion in humans. Ther. Drug Monit. 9(3):225-258. 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. van Winkle, W., Jr., and H.W. Newman. 1941. Further results of continued administra- tion of propylene glycol. J. Food Sci. 6(5):509-516. Weatherby, J.H., and H.B. Haag. 1938. Toxicity of propylene glycol. J. Am. Pharm. Assoc. 27:466-471. Weil, C.S., M.D. Woodside, H.F. Smyth, Jr., and C.P. Carpenter. 1971. Results of feed- ing propylene glycol in the diet to dogs for two years. Food Cosmet. Toxicol. 9(4):479-490.

188 Spacecraft Water Exposure Guidelines Weiss, D.J., M.C. Bauer, M.J. Murphy, and V. Perman. 1992. Increased mechanical fra- gility and intravascular lysis of erythrocytes in cats fed a propylene glycol- containing diet. Comp. Haematol. Int. 2(3):157-161. WHO (World Health Organization). 1974. Toxicological Evaluation of Certain Food Additives with a Review of General Principles and of Specifications: 17th Report of the Joint FAO/WHO Expert Committee on Food Additives. Technical Report 539. Geneva: World Health Organization. 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. Yorgin, P.D., A.A. Theodorou, A. Al-Uzri, K. Davenport, L.V. Boyer-Hassen, and M.I. Johnson. 1997. Propylene glycol-induced proximal renal tubular cell injury. Am. J. Kidney Dis. 30(1):134-139. Yu, D.K., W.F. Elmquist, and R.J. Sawchuk. 1985. Pharmacokinetics of propylene glycol in humans during multiple dosing regimens. J. Pharm. Sci. 74(8):876-879. Zar, T., I. Yusufzai, A. Sullivan, and C. Graeber. 2007a. Acute kidney injury, hyperos- molality and metabolic acidosis associated with lorazepam. Nat. Clin. Pract. Nephrol. 3(9):515-520. Zar, T., C. Graeber, and M.A. Perazella. 2007b. Recognition, treatment, and prevention of propylene glycol toxicity. Semin. Dial 20(3):217-219.

Spacecraft Water Exposure Guidelines for Selected Contaminants: Volume 3 Get This Book
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NASA maintains an active interest in the environmental conditions associated with living and working in spacecraft and identifying hazards that might adversely affect the health and well-being of crew members. Despite major engineering advances in controlling the spacecraft environment, some water and air contamination is inevitable. Several hundred chemical species are likely to be found in the closed environment of the spacecraft, and as the frequency, complexity, and duration of human space flight increase, identifying and understanding significant health hazards will become more complicated and more critical for the success of the missions.

To protect space crews from contaminants in potable and hygiene water, NASA requested that the National Research Council NRC provide guidance on how to develop water exposure guidelines and subsequently review NASA's development of the exposure guidelines for specific chemicals. This book presents spacecraft water exposure guidelines (SWEGs) for antimony, benzene, ethylene glycol, methanol, methyl ethyl ketone, and propylene glycol.

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