B9 Ethylene Glycol

King Lit Wong, Ph.D.

Johnson Space Center Toxicology Group

Biomedical Operations and Research Branch

National Aeronautics and Space Administration

Houston, Texas

PHYSICAL AND CHEMICAL PROPERTIES

Ethylene glycol is a clear, colorless, odorless, and viscous liquid (ACGIH, 1986).

Synonym:

1, 2-Ethanediol

Formula:

HOCH2CH2OH

CAS number:

107-21-1

Molecular weight:

62.1

Boiling point:

197.6°C

Melting point:

-13°C

Vapor pressure:

0.06 torr at 20°C

Saturated vapor concentration at 20°C:

204 mg/m3 or 79 ppm

Conversion factors at 25°C, 1 atm:

1 ppm = 2.54 mg/m3 1 mg/m3 = 0.39 ppm

OCCURRENCE AND USE

Ethylene glycol is used as an antifreeze, an industrial humectant, and a solvent in paint and in the plastics industry (ACGIH, 1986). In the U.S. space program, it was used as an antifreeze in a payload experiment in one shuttle mission (Lam, 1988), and it was a component inside lithium manganese dioxide batteries used in payload experiments in two



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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 3 B9 Ethylene Glycol King Lit Wong, Ph.D. Johnson Space Center Toxicology Group Biomedical Operations and Research Branch National Aeronautics and Space Administration Houston, Texas PHYSICAL AND CHEMICAL PROPERTIES Ethylene glycol is a clear, colorless, odorless, and viscous liquid (ACGIH, 1986). Synonym: 1, 2-Ethanediol Formula: HOCH2CH2OH CAS number: 107-21-1 Molecular weight: 62.1 Boiling point: 197.6°C Melting point: -13°C Vapor pressure: 0.06 torr at 20°C Saturated vapor concentration at 20°C: 204 mg/m3 or 79 ppm Conversion factors at 25°C, 1 atm: 1 ppm = 2.54 mg/m3 1 mg/m3 = 0.39 ppm OCCURRENCE AND USE Ethylene glycol is used as an antifreeze, an industrial humectant, and a solvent in paint and in the plastics industry (ACGIH, 1986). In the U.S. space program, it was used as an antifreeze in a payload experiment in one shuttle mission (Lam, 1988), and it was a component inside lithium manganese dioxide batteries used in payload experiments in two

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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 3 shuttle missions (Lam, 1990, 1991). Ethylene glycol has also been predicted to be found as an off-gas product in the space station, but only in relatively small amounts (Leban and Wagner, 1989). One of the possible reasons is that its vapor pressure is low compared with other organic compounds found in off-gassing. TOXICOKINETICS AND METABOLISM Absorption Marshall and Cheng (1983) exposed rats, nose only, to 14C-ethylene glycol vapor at 32 mg/m3 for 30 min and found that at least 60% of the chemical inhaled was absorbed. Immediately after exposure, the concentrations of 14C activity in various tissues were compared, and those in the nasal cavity and the trachea were the highest. On the basis of the initial body burden of the 14C activity, Marshall and Cheng (1983) calculated that the rats received a dose of 0.7 mg/kg in the 30-min inhalation exposure at 32 mg/m3. They also observed that the plasma concentration of 14C activity peaked 6 h after the 30-min inhalation exposure of rats to ethylene glycol at 32 mg/m3. Assuming that all the 14C activity was due to 14C-labeled ethylene glycol, Marshall and Cheng (1983) calculated that the peak plasma concentration of ethylene glycol was about 1 µg/mL. Metabolism Ethylene glycol is metabolized via oxidation. McChesney et al. (1971) found that, in monkeys exposed orally to ethylene glycol at 1 mL/kg (or 1.1 g/kg), the metabolites included glycolic acid, oxalic acid, CO2, and a small amount of hippuric acid. The metabolic pathway probably involves stepwise oxidation. McChesney et al. (1972) proposed that ethylene glycol is first oxidized to glycolaldehyde, which is then oxidized to glycolic acid. Oxidation of glycolic acid results in glyoxylic acid. Glyoxylic acid might undergo several reactions, one of which is oxidation by glycolic acid dehydrogenase to oxalic acid (Rich-

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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 3 ardson and Tolbert, 1961). Another reaction is the formation of formyl-S-CoA and CO2 (McChesney et al., 1972). According to Richardson and Tolbert (1961), alcohol dehydrogenase and glycolic acid dehydrogenase are involved in the catalysis of some of the reactions in the metabolic pathway. Excretion On the basis of data gathered in laboratory animals, ethylene glycol or its metabolites are excreted via three routes: urinary, expiratory, and fecal. In four monkeys given ethylene glycol orally at 1 mL/kg, about 44% of the dose was excreted in the urine within 24 h of the oral exposure, and very little was excreted in the urine in the 24-48 h period (McChesney et al., 1971). Half of the dose excreted in urine was unchanged ethylene glycol, and the balance was metabolites. Urinary metabolites collected for 48 h from one of those monkeys were analyzed. The results revealed that glycolic acid was the most abundant, accounting for 12% of the dose. Only 0.3% of the dose was excreted as oxalic acid in the urine of this monkey. Similar findings were reported by Wiley et al. (1938); in two dogs exposed to ethylene glycol at 5.5 g daily for 5 d, the conversion rate of ethylene glycol to urinary oxalic acid was 0.5%. There is evidence that the conversion rates of ethylene glycol to oxalic acid in rats and humans differ from the rates in the monkey and two dogs (Wiley et al., 1938; Levy, 1960). In addition to the monkey, McChesney et al. (1971) also studied the urinary excretion of ethylene glycol and its metabolites in six rats exposed orally to ethylene glycol at 1 mL/kg of body weight (or 1.1 g/kg). Rats excreted 56% of the dose in the urine within 24 h of oral exposure, and 32% of the dose was excreted as unchanged ethylene glycol. These rats excreted 2.5% of the dose as oxalic acid in the urine. The conversion rate to oxalic acid in rats is very similar to that in humans who have been found to convert about 2.3% of the ethylene glycol dose to oxalic acid in urine (Reif, 1950). In the inhalation study of rats conducted by Marshall and Cheng (1983), 63% of the body burden of ethylene glycol was expired as 14CO2 within 4 d of the exposure. Urinary excretion was the second most important route of ethylene glycol elimination. The researchers

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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 3 found that 20% of the initial body burden was excreted unchanged in the urine. Fecal excretion was the least important elimination route, because only 3% of the body burden was eliminated in the feces. The relative abundance of urinary elimination of ethylene glycol as the unchanged parent compound and metabolites versus CO2 in expired air is dose-dependent. When rats were injected intravenously with ethylene glycol at 20 or 200 mg/kg, 35 % of the dose was excreted in the urine and 39% of the dose was expired as CO2 (Marshall, 1982). When the dose was increased, however, urinary excretion became more important than CO2 expiration in eliminating ethylene glycol from the body. At a dose of 1000 or 2000 mg/kg, 56% of the dose was excreted in the urine, and only 26% was expired as CO2. Toxicokinetics Several toxicokinetics studies on ethylene glycol have been reported in the literature, but most of them involved a noninhalation route of exposure. Hewlett et al. (1989) compared the elimination half-lives of ethylene glycol in the plasma of rats and dogs. Rats were gavaged with ethylene glycol at 2 g/kg and the dose for dogs was 1 g/kg. Ethylene glycol was eliminated faster in the rats than the dogs; the half-life in the plasma was found to be only 1.7 h in rats versus 3.4 h in dogs. Comparison of the data of Hewlett et al. (1989) and McChesney et al. (1971) shows that rhesus monkeys tend to eliminate ethylene glycol at about the same rate as dogs. A half-life of 2.7-3.7 h in rhesus monkeys, which were given an oral dose of ethylene glycol at 1 mL/kg of body weight (or 1.1 g/kg), was found by McChesney et al. (1971). The elimination half-life of ethylene glycol appears to be dose-dependent. A review of the data shown in Table 9-1 indicates that the half-life lengthened when ethylene glycol was administered orally at a higher dose. The only toxicokinetics study with inhalation exposures to ethylene glycol was one conducted by Marshall and Cheng (1983). In that study, after reaching a peak 6 h following inhalation exposure of rats to 14C-ethylene glycol, the plasma concentration of 14C activity declined monoexponentially for the remaining 4 d, with a half-life of 39 h. Evidently, not all the 14C activity represented ethylene glycol. Hewlett et al. (1989) and Lenk et al. (1989) reported that the half-life of ethylene

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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 3 TABLE 9-1 Elimination Half-life of Ethylene Glycol Oral Dose, g/kg Species Half-life Reference 1.1 Monkey 2.7-3.7 McChesney et al., 1971 2 Rat 1.7 Hewlett et al., 1989 3.3-5.5 Rat 4.1-4.5 Lenk et al., 1989 1 Dog 3.4 Hewlett et al., 1989 10.7 Dog 10.8 Grauer et al., 1987 glycol in plasma was only 1.7 h or 4.1-4.5 h in rats given an oral dose of ethylene glycol at 1-2 g/kg or 3.3-5.5 g/kg, respectively. The half-life of the plasma 14C activity measured by Marshall and Cheng (1983) was 10-20 times that of ethylene glycol reported by Hewlett et al. (1989) and Lenk et al. (1989). Therefore, the half-life of 39 h of the plasma 14C activity reflected the elimination of ethylene glycol's metabolites (Marshall and Cheng, 1983). Since Hewlett et al. (1989) reported that the elimination half-life of glycolic acid equaled that of ethylene glycol in rats, the half-life of 39 h of the plasma 14C activity found by Marshall and Cheng (1983) probably represented the elimination kinetics of metabolites other than glycolic acid. TOXICITY SUMMARY A review of the literature on the toxicity of ethylene glycol indicates that the three major toxic end points of ethylene glycol poisoning are mucosal irritation, central-nervous-system (CNS) effects, and renal toxicity. In very severe poisoning, ethylene glycol can be lethal. Details of these toxic effects of ethylene glycol are summarized below. Acute or Short-Term Exposures Relatively few data are available on the toxicity of ethylene glycol in acute or short-term inhalation exposures. Most of the information on its acute toxicity is derived from oral exposures.

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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 3 Lethality Ingestion of ethylene glycol has been known to be lethal in certain cases. The minimum oral lethal dose for average human adults has been estimated to be about 110 g (Scully et al., 1979). Evidence of species differences in ethylene glycol's lethality was presented by Laug et al. (1939). They exposed animals to ethylene glycol via gavage and found that the LD50 was 6.1, 8.1, and 14.4 g/kg in rats, guinea pigs, and mice, respectively. In rats and guinea pigs, ethylene glycol was discovered to be more deadly in large adults than small adults. However, body-weight dependency of the lethal effect was not found in mice. Their mortality data are summarized in Table 9-2. TABLE 9-2 Mortality Data of Laug et al.(1939) Species Dose, g/kg Body Weight, g Mortality Rats 5.0 214 3/10   5.0 380 7/10 Guinea pigs 6.6 268 1/10   6.6 558 9/9 Mice 13.8 14.6 7/10   13.8 27.1 6/10 CNS, Cardiopulmonary, and Renal Toxicity Berman et al. (1957) divided the responses to acute poisoning from ethylene glycol ingestion in humans into three stages. The first stage is characterized by CNS depression clinically similar to ethanol intoxication. This stage appears within half an hour to several days, depending on the amount ingested (Berman et al., 1957; Friedman et al., 1962; Moriarty and McDonald, 1974). Friedman et al. found that, if the dose is high (e.g., 90-120 g in a 17-y-old Caucasian girl), the victim can enter into a coma, convulse, and die. The urine might contain oxalate crystals and albumin. In an autopsy of a victim, Friedman et al. (1962) found oxalate crystals in multiple tissues, most notably in the lumen of

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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 3 renal proximal tubules, astrocytosis in the cerebral cortex, thalamus, globus pallidus, and the brain stem, together with a focal loss of cerebellar Purkinje cells and centrilobular fatty changes in the liver. The second stage involves cardiopulmonary dysfunctions. The studies of Berman et al. (1957) and Friedman et al. (1962) revealed that there could be tachypnea, cyanosis, pulmonary edema, bronchopneumonia, left ventricular hypertrophy, myositis resulting in muscle pain, and even death. The third stage consists primarily of progressive renal impairment. Both studies mentioned above showed that the victim can develop proteinuria, anuria, flank pain, and costovertebral angle tenderness. In a 14-y-old Caucasian boy who died from ingesting 120 g of ethylene glycol, renal biopsy showed focal hydropic degeneration of the proximal tubules with luminal obliteration of many of the tubules, glomeruli with increased density and cellularity, and numerous calcium oxalate crystals in tubular lumens and in some tubular epithelial cells (Friedman et al., 1962). The histopathological changes in the heart, lung, and kidney, which have been documented in ethylene-glycol poisoning cases in humans, most likely are due to massive doses. Hong et al. (1988) failed to detect any histopathological changes in mice given ethylene glycol at 0, 50, 100, or 250 mg/kg/d for 4 d by gavage. One day after the 4-d exposure, they examined the heart, lung, kidney, urinary bladder, adrenal glands, liver, thymus, spleen, stomach, intestines, uterus, and testes in the mice and found no change in those tissues. However, the researchers found a suppression of granulocyte-macrophage progenitor colony formation in the bone marrow of male mice 14 d after the mice were gavaged with ethylene glycol at 50 mg/kg/d for 4 d. They also reported that a similar gavage at 100 mg/kg/d reduced the cellularity in the bone marrow of the mice after 14 d of exposure, whereas gavage at 50 mg/kg/d had no such effect. Some investigators have studied the CNS effects of ethylene glycol in laboratory animals. Most of its CNS effects can be characterized as CNS depression. The administration of ethylene glycol by gavage in rats and guinea pigs at fatal or near-fatal doses produced ''no narcosis but varying degrees of sluggish depressed functioning'' (Smyth et al., 1941). Similarly, Bove (1966) exposed rats to ethylene glycol by oral gavage and found that a dose of 12 g/kg produced marked lethargy in 3

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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 3 h and death in less than 24 h. However, 9 g/kg caused only moderate lethargy. The only data on the CNS depression effect of inhaled ethylene glycol were gathered by Flury and Wirth (1934). They exposed cats to ethylene glycol at 500 mg/m3 for a total of 28 h in 5 d. The animals developed a slight narcosis from which they recovered after the exposure. Metabolic Acidosis and Miscellaneous Signs and Symptoms In 12 teenagers who drank an unknown amount of antifreeze containing ethylene glycol, leukocytosis and pleocytosis were detected (Moriarty and McDonald, 1974). Nausea, vomiting, and abdominal pain were found in 60% of the patients. Oxalate crystals in the urine and metabolic acidosis were present in 33% and 50%, respectively, of the patients. The investigators reported that the severity of the clinical picture was not correlated with the urinary and blood concentrations of ethylene glycol in these victims. Metabolic acidosis induced by ethylene glycol was also found in animals by Clay and Murphy (1977). They injected ethylene glycol at 3 or 4 g/kg intraperitoneally into pigtail monkeys. After the injection, a transient narcosis developed. The monkeys recovered from the narcosis for "a period of hours" but entered into comas later. A severe acidosis developed 12-24 h after the injection, with a drop in blood pH by a unit of 0.2-0.3. Hewlett et al. (1989) reported that an oral dose of ethylene glycol at 2 g/kg in rats or 1 g/kg in dogs caused mild acidosis with no sedation. The amount of oxalic acid formed from ethylene glycol metabolism could not entirely explain the degree of acidosis seen in victims of ethylene glycol poisoning; therefore, the acidosis might be partially due to other acidic metabolites of ethylene glycol (Friedman et al., 1962; Moriarty and McDonald, 1974). Clay and Murphy (1977) showed that a decrease in blood bicarbonate concentrations in pigtail monkeys was associated with an increase in the blood concentration of glycolic acid. They also showed that exposure of monkeys to 4-methylpyrazole, which is an inhibitor of alcohol dehydrogenase, 30 min after the intraperitoneal injection of ethylene glycol shortened the duration of metabolic acidosis induced by ethylene glycol. The evidence suggests that ethyl-

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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 3 ene glycol causes metabolic acidosis via formation of its metabolites. According to Jacobsen et al. (1984), glycolic acid is important in causing acidosis in ethylene glycol poisoning in humans. Mucosal Irritation Wills et al. (1974) exposed 20 men to a mixture of ethylene glycol aerosol and vapor at 30 mg/m3, time-weighted average (TWA), 20-22 h/d for 30 d. To determine which concentrations were irritating, the experimenters periodically increased the ethylene glycol concentration for up to 15 min (typically the increase occurred immediately after a lunch break when the volunteers returned to the exposure chamber). The responses of the volunteers to these spurts of relatively high exposures are summarized in Table 9-3. In what appears to be an interim report of that study, Harris (1969), one of the investigators, described the results of exposure of male volunteers to aerosolized ethylene glycol for up to 28 d. The data on mucosal irritation responses from that report are also included in Table 9-3. TABLE 9-3 Responses of Male Volunteers to Ethylene Glycol Exposure Concentration, mg/m3 Response Reference 64 Completely oblivious to the exposure Harris, 1969 127 Pharyngeal irritation Harris, 1969 40 Irritation became common Wills et al., 1974 188 Exposure tolerated for 15 min Wills et al., 1974 190 Exposure not tolerated when subjects awakened from sleep Harris, 1969 >200 Exposure not tolerated because of pain in the tracheobronchial tree Wills et al., 1974 244 Exposure not tolerated for more than 1-2 min Wills et al., 1974 308 Subjects rushed out of chamber after only one or two breaths Wills et al., 1974

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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 3 On the basis of the reports of the above two investigators, an exposure of humans to ethylene glycol at 64 mg/m3 is nonirritating, but it is irritating at 140 mg/m3 and could become intolerable extremely rapidly at 308 mg/m3. Animal data on the irritation effect of ethylene glycol were gathered in the experiment of Flury and Wirth (1934). Moderate mucosal irritation was discovered in cats exposed to ethylene glycol at 500 mg/m3 for a total of 28 h in 5 d. When comparing the findings of Flury and Wirth with that of Wills et al. and Harris, the cats appeared not to be affected by ethylene glycol's irritation as much as the humans subjects. It is not certain whether it was due to a species difference in sensitivity or due to a difference in the detection sensitivity of irritation in the two studies. Subchronic and Chronic Exposures Ethylene glycol's toxicity in long-term exposures somewhat resembles that in short-term exposures. The major toxic effects in long-term exposures are mucosal irritation, CNS effects, and renal toxicity. Mucosal Irritation and Eye Toxicity Mucosal irritation induced by ethylene glycol was studied in subchronic exposures, but the results were mixed. Within 8 d of a 90-d continuous exposure, Coon et al. (1970) detected moderate-to-severe corneal erythema, edema, and discharge in all three rabbits and corneal opacity, with apparent blindness, in 2 of 15 rats exposed at a concentration of 12 mg/m3. No mention was made of any effects on the eyes of similarly exposed guinea pigs and monkeys (Coon et al., 1970). MacEwen (1969) reported that a 47-d continuous exposure of 30 rats and 20 guinea pigs to ethylene glycol at 12.6 mg/m3 resulted in no corneal changes. According to MacEwen (1969), four rabbits also were exposed continuously for 17 d. Only minimal cloudiness of the corneal surface was seen in the first 3 d, but no changes occurred afterward. Coon et al. (1970) also reported that exposures of rats, guinea pigs, and rabbits to ethylene glycol at a higher concentration of 57 mg/m3, albeit only intermittently (8 h/d, 5 d/w, for 6 w), failed to produce any signs

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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 3 of eye irritation. The absence of positive corneal findings in the exposure at 57 mg/m3, together with MacEwen's negative findings, casts doubt on whether the signs of eye irritation observed by Coon et al. (1970) in the 12-mg/m3 groups were chemical-related. Because no eye irritation or corneal damage was reported in human subjects exposed at 30 mg/m3, TWA, for 30 d (Harris, 1969; Wills et al., 1974), the eye irritation findings of Coon et al. (1970) are not relied on in setting the SMACs. CNS Effects Troisi (1950) studied 38 young women workers exposed to a vapor generated by heating a mixture of 40% ethylene glycol, 55% boric acid, and 5% ammonia at 105°C on a table within their reach. Nine of the 38 workers suffered recurrent attacks of loss of consciousness after a few hours of continuous work at that location. The attacks lasted for only 5 to 10 min. These nine workers also developed nystagmus and five of them had lymphocytosis. Among the workers who did not suffer unconsciousness, five had nystagmus. Urinary examinations in all 38 workers were normal. After the installation of a ventilation system for the area, the CNS effects disappeared. Unfortunately, the investigator did not characterize the concentration or composition of the vapor in that study. The mixture was heated at a temperature below boric acid's melting point of 185 C (Sax, 1984); therefore, it is highly unlikely that these workers inhaled boric acid at any significant concentration. Ammonia is not known to cause CNS depression and nystagmus (Wong, 1993). So the CNS effects observed by Troisi were probably due to ethylene glycol alone. The no-observed-adverse-effect level (NOAEL) for the CNS toxicity of ethylene glycol can be determined from the data of a 30-d study of Wills et al. (1974). They exposed 20 men to ethylene glycol for 20 to 22 h/d for 30 d. The test atmosphere, to which 20 human subjects were exposed, was generated by forcing ethylene glycol aerosol into the cooled air stream of three air conditioners that supplied air to the exposure chamber. Ethylene glycol droplets were collected at various locations in the chamber. Their diameters were 1 to 5 µm as measured under a microscope. Assuming these droplets were all spherical, the mea-

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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 3 There are no data on the NOAEL for renal toxicity based on acute experiments. Because it is difficult to estimate a 1-h AC from a NOAEL derived from a 10-d drinking study, no 1-h AC is set for renal toxicity. As indicated above, the 7-d AC is derived from the 30-d NOAEL based on a human study of Wills et al. (1974). Due to the smaller difference in the lengths of exposure, it can be argued that the 7-d AC should be derived from the 10-d NOAEL based on the animal data of Robinson et al. (1990) instead of the 30-d NOAEL of Wills et al. (1974). However, the 30-d NOAEL of Wills et al. is a better starting point for two reasons. First, the 30-d NOAEL was derived from human subjects, and the 10-d NOAEL was from a study in rats. Second, if the 10-d NOAEL is used as the starting point, the 7-d AC would be 230 mg/m3, which is too close to the concentration of 256 mg/m3 that Felts (1969) found to be toxic to the kidney in two chimpanzees after a 28-d inhalation exposure. Although no evidence was found that continuous exposure of the two chimpanzees to ethylene glycol at 256 mg/m3 was toxic to the kidney in 7 d, 230 mg/m3 does not provide a sufficient safety margin for a 7-d AC. The mechanism of ethylene glycol's renal toxicity is unclear. On the one hand, calcium oxalate crystals, formed from the oxalic acid metabolite, have been postulated to cause ethylene glycol's renal toxicity (Levy, 1960). On the other hand, some evidence indicates that ethylene glycol injures the kidney via mechanisms other than calcium oxalate crystallization (Wiley et al., 1938; Frommer and Ayus, 1982; Tyl et al., 1993). If ethylene glycol does cause renal injuries via formation of calcium oxalate crystals, it can be argued that, because microgravity is known to increase the renal excretion of calcium (Whedon et al., 1977), an uncertainty factor for the calcium effect during spaceflight might be needed for an extra safety margin in deriving ACs for ethylene glycol's renal toxicity. However, such an uncertainty factor is not necessary considering the insignificant load of urinary oxalic acid potentially contributed by a daily exposure to the AC of 13 mg/m3 estimated below. Rats absorb about 60% of the inhaled ethylene glycol (Marshall and Cheng, 1983). Assuming that human subjects behave like rats in absorbing 60% of the amount of ethylene glycol inhaled and assuming that astronauts inhale 20 m3/d (NRC, 1992a), the daily dose of ethylene glycol can be calculated as follows:

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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 3 Daily dose of ethylene glycol to astronauts = 13 mg/m3 × daily respiratory volume × absorption fraction = 13 mg/m3 × 20 m3/d × 0.60 = 156 mg/d. Based on the findings of Reif (1950), humans convert 2.3% of the dose of ethylene glycol to oxalic acid in urine. Urinary output of oxalate due to ethylene glycol inhalation = daily dose of ethylene glycol × conversion factor = 156 mg/d × 0.023 = 4 mg/d. According to Pak et al. (1985), the daily urinary excretion of oxalate in normal human subjects is about 23-24 mg/d. They estimated that the daily urinary excretion of oxalate has to increase beyond 45 mg/d to increase the risk of oxalate crystallization in the kidney. The contribution of 4 mg/d to urinary oxalate excretion by ethylene glycol inhalation at the long-term ACs of 13 mg/m3 is too small to bring the daily urinary oxalate excretion above the threshold of 45 mg/d. Therefore, if ethylene glycol's renal toxicity is due to calcium oxalate crystallization, the ACs of 13 mg/m3 need not be adjusted downward for microgravity-induced increases in urinary calcium excretion. Finally, it should be noted that, because ethylene glycol might cause renal injuries via a mechanism other than calcium oxalate crystallization, one should not set an AC for renal toxicity by calculating the ethylene glycol exposure concentration required to bring the daily urinary oxalate excretion to the threshold of 45 mg/d. Establishment of SMAC Values The ACs for all the important toxic end points are tabulated below. The lowest AC for an exposure duration is selected to be the SMAC for that duration. As a result, 64 mg/m3 is chosen to be the 1-h and 24-h SMACs, and the 7-d, 30-d, and 180-d SMACs are set at 13 mg/m3. These SMACs are set with consideration of all spaceflight-induced physiological changes, so no further adjustments are necessary.

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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 3 RECOMMENDATIONS Although renal toxicity has been emphasized as ethylene glycol's major toxicity for a long time, the derivation of ACs for its renal toxicity, mucosal irritation, and CNS depression shows that mucosal irritation and CNS depression are more important than renal toxicity for the establishment of exposure limits. The reason is that it takes a lower AC to prevent mucosal irritation and CNS depression than renal toxicity. Comparing the data of mucosal irritation with those of CNS depression, the conclusion is that the data gap on ethylene glycol's propensity to irritate mucous membranes is larger than that on CNS depression. Currently, the ACs for mucosal irritation in short-term exposures are set using the data of Wills' study (Wills et al., 1974; Harris, 1969). Wills and co-workers exposed 20 men to ethylene glycol almost continuously for 30 d, during which the exposure concentration was periodically raised for about 15 min to test ethylene glycol's irritancy. A study is needed in testing its irritancy by exposing human subjects to it for 1 to 2 h.

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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 3 TABLE 9-9 Acceptable Concentrations     Uncertainty Factors     To NOAEL   Small na Conversion Factorb Absorption Factorc Acceptable Concentrations, mg/m3 Effect, Data, Reference Species Species 1 h 24 h 7 d 30 d 180 d Mucosal irritation   NOAEL, 64 mg/m, 15 min (Wills et al., 1974; Harris, 1969) Human (n = 20) - - - - - 64 64 - - - NOAEL, 64mg/m3, 15 min (Wills et al., 1974; Harris, 1969) Human (n = 20) - - 20 - - - - 28 28 28 CNS depression   LOAEL, 1.1 g/kg, iv (Felts, 1969) Chimpanzee, monkey 10 10 - 20/24 0.6 1500 - - - - LOAEL, 1.1 g/kg, iv (Felts, 1969) Chimpanzee, monkey 10 10 - 20 0.6 - 24 - - - NOAEL, 30 mg/m3, 24/d, 30 d (Wills et al., 1974) Human (n = 20) - - 20 - - - - 13 13 13 Renal toxicity   NOAEL, 0.65 g/kg in drinking water (Robinson et al., 1990) Rat - 10 - 20 0.6 - 380 - - -

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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 3     Uncertainty Factors     To NOAEL   Small na Conversion Factorb Absorption Factorc Acceptable Concentrations, mg/m3 Effect, Data, Reference Species Species 1 h 24 h 7d 30 d 180 d Renal toxicity (cont.)   NOAEL, 30 mg/m3, 24/d, 30 d (Wills et al., 1974) Human - - 20 - - - - 13 13 13 SMACs             64 64 13 13 13 a To correct for small number of human test subjects, the factor I √(n/100). b To convert an oral dose to an inhalation exposure concentration. It is usually equal to the respiratory volume. c To correct for the incomplete respiratory absorption of ethylene glycol. —, Data not considered applicable to the exposure time; HR, Haber's rule.

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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 3 REFERENCES ACGIH. 1986. Documentation of the Threshold Limit Values and Biological Exposure Indices, 5th Ed., American Conference of Governmental Industrial Hygienists, Cincinnati, Ohio. ACGIH. 1991. Documentation of the Threshold Limit Values and Biological Exposure Indices , 6th Ed., American Conference of Governmental Industrial Hygienists, Cincinnati, Ohio. Berman, L. B., G. E. Schreiner, and J. Feys. 1957. The nephrotoxic lesion of ethylene glycol. Ann. Intern. Med. 46:611-619. Blood, F. R., G. A. Elliott, and M. S. Wright. 1962. Chronic toxicity of ethylene glycol in the monkey. Toxicol. Appl. Pharmacol. 4:489-491. Bove, K. E. 1966. Ethylene glycol toxicity. Am. Clin. Pathol. 45:46-50. Clay, K. L., and R. C. Murphy. 1977. On the metabolic acidosis of ethylene glycol intoxication. Toxicol. Appl. Pharmacol. 39:39-49. Coon, R. A., R. A. Jones, L. J. Jenkins, Jr., and J. Siegel. 1970. Animal inhalation studies on ammonia, ethylene glycol, formaldehyde, dimethylamine, and ethanol. Toxicol. Appl. Pharmacol. 16:646-655. DePass, L. R., R. H. Garman, M. D. Woodside, W. E. Giddens, R. R. Maronpot, and C. S. Weil. 1986a. Chronic toxicity and oncogenicity studies of ethylene glycol in rats and mice. Fundam. Appl. Toxi col. 7:547-565. DePass, L. R., M. D. Woodside, R. R. Maronpot, and C. S. Weil. 1986b. Three-generation reproduction and dominant lethal mutagenesis studies of ethylene glycol in the rat. Fundam. Appl. Toxicol. 7:566-572. Felts, M. 1969. Effects of Exposure to Ethylene Glycol on Chimpanzees. Proceedings of the Fifth Annual Conference on Atmospheric Contamination in Confined Space. AMRL TR-69-130, Paper No. 9. Wright-Patterson Air Force Base, Ohio. Flury, F., and W. Wirth. 1934. Zur toxicologie der losungsmittel. (Verschiedene ester, aceton, methylalcohol). Arch. Gewerbepathol. Gewerbehyg. 5:1-90. Friedman, E. A., J. B. Greenberg, J. P. Merrill, and G. J. Dammin. 1962. Consequences of ethylene glycol poisoning. Reports of four cases and review of the literature. Am. J. Med. 32:891-902.

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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 3 Frommer, J. P., and J. C. Ayus. 1982. Acute ethylene glycol intoxication. Am. J. Nephrol. 2:1-5. Grauer, G. F., M. A. H. Thrall, B. A. Henre, and J. J. Hjelle. 1987. Comparison of the effects of ethanol and 4-methylpyrazole on the pharmacokinetics and toxicity of ethylene glycol in the dog. Toxicology 35:307-314. Griffiths, A. J. F. 1979. Neurospora prototroph selection system for studying aneuploid production. Environ. Health Perspec. 31:75-80. Harris, E. S. 1969. Inhalation Toxicity of Ethylene Glycol. Proceedings of the Fifth Annual Conference on Atmospheric Contamination in Confined Space. AMRL TR-69-130, Paper No. 8. Wright-Patterson Air Force Base, Ohio. Harris, M. W., R. E. Chapin, A. C. Lockhart, and M. P. Jokinen. 1992. Assessment of a short-term reproductive and developmental toxicity screen. Fundam. Appl. Toxicol. 19:186-196. Hewlett, T. P., D. Jacobsen, T. D. Collins, and K. E. McMartin. 1989. Ethylene glycol and glycolate kinetics in rats and dogs. Vet. Hum. Toxicol. 31:116-120. Hinds, W. C. 1982. Properties, behavior, and measurement of airborne particles. Pp. 49 and 227 in Aerosol Technology. New York: John Wiley & Sons. Hong, H. L., J. Canipe, C. W. Jameson, and G. A. Boorman. 1988. Comparative effects of ethylene glycol and ethylene glycol monomethyl ether exposure on hematopoiesis and histopathology in B6C3F1 mice. J. Environ. Pathol. Toxicol. Oncol. 8:27-38. Jacobsen, D., N. Osthy, and J. E. Bredesen. 1982. Studies on ethylene glycol poisoning. Acta Med. Scand. 212:11-15. Jacobsen, D., S. Ovrebo, J. Ostborg, and O. M. Sejersted. 1984. Glycolate causes the acidosis in ethylene glycol poisoning and is effectively removed by hemodialysis. Acta Med. Scand. 216:409-416. Kersting, E. J., and S. W. Nielsen. 1966. Experimental ethylene glycol poisoning in the dog. Am. J. Vet. Res. 27:574-582. Lam, C.-W. 1988. STS-26 payload experiments and chemicals and orbiter utility chemicals. P. 4 in Toxicologic Information and Risk Assessments. JSC No. 23072. Johnson Space Center, National Aeronautics and Space Administration, Houston, Tex. Lam, C.-W. 1990. STS-41 orbiter payload and inflight DSO chemicals. P. 18 in Toxicologic Information and Risk Assessments. JSC

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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 3 McChesney, E. W., L. Golberg, and E. S. Harris. 1972. Reappraisal of the toxicology of ethylene glycol. IV. The metabolism of labelled glycollic and glyoxylic acids in rhesus monkey. Food Cosmet. Toxicol. 10:655-670. MacEwen, J. D. 1969. Letter (dated 2/20/69) from J. D. MacEwen of SysteMed Corp. (Wright-Patterson Air Force Base, Ohio) to K. C. Back of Aerospace Medical Division, Wright-Patterson Air Force Base, Ohio. McGregor, D. B., A. G. Brown, S. Howgate, D. McBride, C. Riach, W. J. Caspary. 1991. Responses of the L5178Y mouse lymphoma cell forward mutation assay. 5.27 Coded chemicals. Environ. Mol. Mutagen. 17:196-219. Moriarty, R. W., and R. H. McDonald. 1974. The spectrum of ethylene glycol poisoning. Clin. Toxicol. 7:583-596. NRC. 1985. Emergency and Continuous Exposure Guidance Levels for Selected Airborne Contaminants, Vol. 4. Washington, D.C.: National Academy Press. NRC. 1992a. Guidelines for Developing Spacecraft Maximum Allowable Concentrations for Space Station Contaminants. Washington, D.C.: National Academy Press. NRC. 1992b. Appendix 3 in Guidelines for Developing Spacecraft Maximum Allowable Concentrations for Space Station Contaminants. Washington, D.C.: National Academy Press. Pak, C. Y. C., C. Skurla, and J. Harvey. 1985. Graphic display of urinary risk factors for renal stone formation. J. Urol. 134:867-870. 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. 18:115-118. Price, C. J., C. A. Kimmel, R. W. Tyl, and M. C. Marr. 1985. The developmental toxicity of ethylene glycol in rats and mice. Toxicol. Appl. Pharmacol. 81:113-127. Reif, G. 1950. Selbstversuche mit Athylenglykol. Pharmazie. 5:276. Richardson, K. E. and N. E. Tolbert. 1961. Oxidation of glyoxylic acid to oxalic acid by glycolic acid oxidase. J. Biol. Chem. 236: 1280-1284. Robinson, M., C. L. Pond, R. D. Laurie, J. P. Bercz, G. Henningsen, and L. W. Gondie. 1990. Subacute and subchronic toxicity of ethyl-

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