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Suggested Citation:"B9: Ethylene glycol." National Research Council. 1996. Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 3. Washington, DC: The National Academies Press. doi: 10.17226/5435.
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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

Suggested Citation:"B9: Ethylene glycol." National Research Council. 1996. Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 3. Washington, DC: The National Academies Press. doi: 10.17226/5435.
×

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-

Suggested Citation:"B9: Ethylene glycol." National Research Council. 1996. Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 3. Washington, DC: The National Academies Press. doi: 10.17226/5435.
×

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

Suggested Citation:"B9: Ethylene glycol." National Research Council. 1996. Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 3. Washington, DC: The National Academies Press. doi: 10.17226/5435.
×

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

Suggested Citation:"B9: Ethylene glycol." National Research Council. 1996. Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 3. Washington, DC: The National Academies Press. doi: 10.17226/5435.
×

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.

Suggested Citation:"B9: Ethylene glycol." National Research Council. 1996. Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 3. Washington, DC: The National Academies Press. doi: 10.17226/5435.
×
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

Suggested Citation:"B9: Ethylene glycol." National Research Council. 1996. Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 3. Washington, DC: The National Academies Press. doi: 10.17226/5435.
×

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

Suggested Citation:"B9: Ethylene glycol." National Research Council. 1996. Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 3. Washington, DC: The National Academies Press. doi: 10.17226/5435.
×

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-

Suggested Citation:"B9: Ethylene glycol." National Research Council. 1996. Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 3. Washington, DC: The National Academies Press. doi: 10.17226/5435.
×

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

Suggested Citation:"B9: Ethylene glycol." National Research Council. 1996. Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 3. Washington, DC: The National Academies Press. doi: 10.17226/5435.
×

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

Suggested Citation:"B9: Ethylene glycol." National Research Council. 1996. Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 3. Washington, DC: The National Academies Press. doi: 10.17226/5435.
×

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-

Suggested Citation:"B9: Ethylene glycol." National Research Council. 1996. Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 3. Washington, DC: The National Academies Press. doi: 10.17226/5435.
×

sured diameters should be very close to the aerodynamic equivalent diameter given that the density of ethylene glycol is 1.1 (ACGIH, 1986; Hinds, 1982). Hinds found that these droplets were all in the inhalable range. The analytical method of Wills et al. (1974) could be used to measure ethylene glycol in either aerosol or vapor form. The exposure concentrations reported in the study of Wills et al. (1974) reflected the combined exposure concentration of aerosol and vapor. The weekly mean exposure concentrations were 29, 17, 23, 49, and 31 mg/m3, yielding a TWA concentration of 30 mg/m3 for the 30-d exposure. At the midpoint and the end of the exposure, the researchers subjected the men to a battery of psychometric tests designed to evaluate simple reaction time, reaction time with discrimination, visual-motor coordination, perception, and mental ability. No decrements in these neurological functions were detected; therefore, 30 mg/m 3 can be considered the NOAEL on the basis of the CNS effects resulting from a 30-d exposure to ethylene glycol.

Renal Toxicity

As discussed above, renal damage is one of the manifestations of acute intoxication with ethylene glycol. In the study of Wills et al. (1974), a nearly continuous exposure of 20 men to ethylene glycol at 30 mg/m3 for 30 d failed to produce any adverse changes in kidney functions, as measured by urine specific gravity, serum urea nitrogen, serum creatinine, and creatinine clearance.

Animal data on ethylene glycol's renal toxicity also were found in the literature. Felts (1969) reported that two chimpanzees exposed to aerosolized ethylene glycol at 256 mg/m3, with none of the aerosol droplets bigger than 5 µm, for 28 d had impaired ability to concentrate urine, which was indicative of distal tubular dysfunction. He then exposed four chimpanzees to the same concentration in a chamber held at an atmosphere of 5 psi, 68% oxygen, and 32% nitrogen for 28 d. No significant changes were detected in the blood urea nitrogen, serum creatinine, insulin clearance, and para-aminohippuric acid clearance; those findings suggest that no renal impairment developed in the four chimpanzees.

In the study by Coon et al. (1970), no histopathological changes

Suggested Citation:"B9: Ethylene glycol." National Research Council. 1996. Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 3. Washington, DC: The National Academies Press. doi: 10.17226/5435.
×

were found, and no changes occurred in the histochemical studies of lactate, isocitrate, succinate, glucose 6-phosphate, and b-hydroxybutyrate dehydrogenase in the kidneys and livers of rats, guinea pigs, and rabbits exposed to ethylene glycol continuously at 12 mg/m for 90 d or repeatedly at 57 mg/m3, 8 h/d, 5 d/w, for 30 d. Wiley et al. (1936) reported that repeated exposures to ethylene glycol at 398 mg/m3, 8 h/d, 5 d/w, for 16 w, killed 3 of 20 mice and 1 of 10 rats. The exposures, however, caused no histological changes in the surviving mice and rats. From the data on inhalation exposures summarized above, the NOAEL, based on ethylene glycol's renal toxicity in humans, is 30 mg/m3 for subchronic inhalation exposures.

No chronic inhalation study with ethylene glycol has been found in the literature. However, two chronic feeding studies were done. Blood et al. (1962) fed two male rhesus monkeys with a diet containing 0.2% ethylene glycol and a female rhesus monkey with a diet containing 0.5% for 3 y. Possible calcification of the urinary tract was monitored with x-rays before the exposure and once every 3 mo during the exposure, but no calcification was seen. When the monkeys were sacrificed after 3 y of ethylene glycol exposure, microscopic examination failed to reveal ethylene-glycol-related pathological changes in the kidney, ureter, urinary bladder, liver, esophagus, stomach, intestine, pancreas, heart, spleen, adrenal, pituitary, thyroids, parathyroids, lymph nodes, and bone marrow. Therefore, long-term feeding with a diet containing 0.2% ethylene glycol would have been devoid of any renal toxicity in the three monkeys studied by Blood et al. (1962). According to the National Institute of Occupational Safety and Health (NIOSH), a 1-ppm diet is equivalent to 0.05 mg/kg/d in monkeys (Sweet, 1987). As a result, a 0.2% diet is estimated to yield a daily dose of 100 mg/kg.

DePass et al. (1986a) performed a 2-y feeding study with ethylene glycol at concentrations of 1, 0.2, 0.04, or 0 g/kg/d in rats and mice. Ten animals of each species and sex in each group were sacrificed at 6, 12, and 18 mo into the exposure; the remaining animals were sacrificed at 24 mo. Renal lesions were detected only in male rats in the 1-g/kg/d group. The renal lesions included tubular hyperplasia, tubular dilation, peritubular nephritis, and oxalate crystalluria at 6 mo, chronic nephrosis and oxalate crystalluria at 12 mo, and tubular obstruction by oxalate crystals leading to secondary tubular degeneration and dilation at 18 mo. Because all the male rats in the 1-g/kg/d group died at 18 mo as a

Suggested Citation:"B9: Ethylene glycol." National Research Council. 1996. Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 3. Washington, DC: The National Academies Press. doi: 10.17226/5435.
×

result of oxalate nephrosis, no renal histological data were available at 24 mo. No renal injury was observed in any female rats or mice, as well as male rats in the lower dose groups.

Potential Effect on the Liver

Fatty liver changes have been reported in human victims who died from acute ethylene glycol ingestion. DePass et al. (1986a) also reported detecting mild fatty liver in female rats fed ethylene glycol at 1 g/kg/d for 24 mo. No hepatic histopathological changes were seen in female rats in the 1-g/kg/d group at 6, 12, or 18 mo. Similarly, the male rats were not inflicted with any hepatic histopathological changes. As discussed above, Blood et al. (1962) did not find any liver toxicity in two male monkeys fed a diet containing 0.2% ethylene glycol and 1 female monkey fed a diet with 0.5% for 3 y.

In contrast to the relatively heavy dietary exposures of ethylene glycol in the rat study of DePass et al. (1986a), no signs of liver injuries were found in animals or humans exposed subchronically to ethylene glycol's vapor or aerosol. Wills et al. (1974) found no changes in serum bilirubin, serum aspartate transaminase, alkaline phosphatase, and prothrombin time in 20 men exposed nearly continuously to 30 mg/m3, TWA. Similarly, Coon et al. (1970) failed to detect any abnormalities on the basis of the serum activities of aspartate transaminase, alanine transaminase, alkaline dehydrogenase, and lactate dehydrogenase in rats, guinea pigs, rabbits, and dogs exposed to ethylene glycol at either 12 mg/m3 for 90 d or 57 mg/m3, 8 h/d, 5 d/w, for 30 d. No histopathological changes in tissues, including the liver, that were examined were detected in rats, guinea pigs, and rabbits in the study of Coon et al. (1970) (12 mg/m3 continuously for 90 d or 57 mg/m3 repeatedly for 30 d) and in mice and rats in the study of Wiley et al. (1936) (398 mg/m3, 8 h/d, 5 d/w, for 16 w). Therefore, no evidence is found that inhaled ethylene glycol is hepatotoxic in long-term inhalation exposures.

Potential Hematological Effects

In the 2-y feeding study conducted by DePass et al. (1986a), certain

Suggested Citation:"B9: Ethylene glycol." National Research Council. 1996. Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 3. Washington, DC: The National Academies Press. doi: 10.17226/5435.
×

hematological changes were reported with an unusual time-dependency. Reduction in hematocrit, red-blood-cell counts, hemoglobin concentrations, and neutrophil counts were detected in male rats in the 1-g/kg/d group after 12 mo of oral administration but not after 6, 18, or 24 mo. No significant hematological changes were seen in female rats and mice of both sexes. Because the researchers failed to detect any hematological changes in male rats in the 1-g/kg/d group after the 12-mo result even though ethylene glycol continued to be fed to them for the next 12 mo, it is uncertain whether ethylene glycol is hematotoxic on the basis of that study alone.

In the study of DePass et al. (1986a), even if the hematological changes found in male rats after 12 mo (not at 6, 18, or 24 mo) of ethylene glycol exposure were chemically related, there is no evidence that ethylene glycol has hematological toxicity in primates. Blood et al. (1962) failed to discover any microscopic change in the bone marrow of two male rhesus monkeys fed 0.2% ethylene glycol and one female rhesus monkeys fed 0.5% ethylene glycol for 3 y. Similarly, no hematological changes have ever been demonstrated in humans exposed to ethylene glycol via inhalation. In the study by Wills et al. (1974) of 20 men exposed to ethylene glycol at 30 mg/m3, venous blood was sampled on d 0, 1, 3, 5, 8, 12, 19, 22, 26, and 29. No changes in hematocrit, hemoglobin concentration, neutrophil counts, and prothrombin time were detected. Therefore, the hematological findings of DePass et al. (1986a) and Hong et al. (1988) might be either peculiar to rodents or produced only by oral exposures at a relatively high dose.

Lethality

Inhalation exposures to ethylene glycol can be lethal. A continuous exposure of eight monkeys to aerosolized ethylene glycol at 500 mg/m 3 for up to 30 w killed six of them (Harris, 1969). Autopsies revealed impacted intestines and oxalate crystals in the kidneys and lungs.

Coon et al. (1970) reported that 30 repeated exposures, 8 h/d, 5 d/w, to ethylene glycol at 10 or 57 mg/m3 failed to kill any rats, guinea pigs, rabbits, dogs, and monkeys. However, a 90-d continuous exposure to ethylene glycol at 12 mg/m3 killed some guinea pigs, a rat, and a rabbit as shown in Table 9-4.

Suggested Citation:"B9: Ethylene glycol." National Research Council. 1996. Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 3. Washington, DC: The National Academies Press. doi: 10.17226/5435.
×

TABLE 9-4 Mortality Data from Inhalation Exposure to Ethylene Glycol Study (Coon et al., 1970)

Exposure

Concentration, mg/m3

Guinea

Rat

Pig

Rabbit

Dog

Monkey

Control

0

4/123

0/73

0/12

0/12

0/8

Repeated

10

0/15

0/15

0/3

0/2

0/2

Repeated

57

0/15

0/15

0/3

0/2

0/2

Continuous

12

1/15

3/15

1/3

0/2

0/3

The LC20 of 12 mg/m3 in guinea pigs is not used in setting SMACs because, in the study by Wills et al. (1974), no deaths occurred among 20 men exposed nearly continuously (20 to 22 h/d) for 30 d to 30 mg/m3, TWA.

Carcinogenesis

A search of the National Library of Medicine's database, Medline, failed to reveal any epidemiological data on tumor incidences associated with ethylene glycol exposures in humans. Only one cancer bioassay is known. The 2-y feeding study by DePass et al. (1986a) showed that ethylene glycol is not carcinogenic up to 1.0 g/kg/d in rats and mice.

Genotoxicity

The lack of carcinogenicity of ethylene glycol appears to be consistent with its lack of genotoxicity. In the studies of McCann et al. (1975), Pfeiffer and Dunkelberg (1980), and Zeiger et al. (1987), ethylene glycol failed to increase mutation frequency in Ames tests. Similarly, McGregor et al. (1991) reported that ethylene glycol tested negative in the L5178Y mouse lymphoma cell forward mutation assay. In the study of McCarrol et al. (1981), ethylene glycol did not appear to cause DNA damage because it did not inhibit the growth of several strains of Escherichia coli, which were deficient in DNA repair ability. According to Griffiths (1979), ethylene glycol did not produce aneuploidy in Neurospora crassa.

Suggested Citation:"B9: Ethylene glycol." National Research Council. 1996. Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 3. Washington, DC: The National Academies Press. doi: 10.17226/5435.
×
Reproductive Toxicity

Ethylene glycol's reproductive toxicity, or the lack thereof, has been studied using both conventional continuous breeding protocols for more than one mating period (Lamb et al., 1985; DePass et al., 1986b) and a new short-term screening protocol for only one mating period (Harris et al., 1992). In a study with mice, Lamb et al. (1985) found that ethylene glycol might cause reproductive toxicity. Mice were given ethylene glycol in drinking water at concentrations of 0.25%, 0.5%, or 1% for 18 w, starting at age 11 w. Starting 1 w after the beginning of ethylene glycol exposure, pairs of male and female mice were mated for 14 w and then separated for 3 w while still being exposed. In the 1%-dose group, the researchers observed reduced number of litters per mated pair, reduced number of live pups per litter, and reduced live pup weight. The offspring of female mice in the 1%-dose group exhibited unusual facial features, such as wide-set eyes and a short snout, and skeletal defects. The fertility of these offspring was lower than that of controls (61% vs. 80%), but the difference was not statistically significant. It should be noted that the effects found in the 1%-dose group might be related to the general toxicity of ethylene glycol in female mice, because the exposure decreased the body weight of the female mice by about 10% in w 10 (Lamb et al., 1985). Because the maternal weight loss in this study was severe, the presence of maternal toxicity lessened the value of the study in the detection of developmental toxicity. Therefore, the study of Lamb et al. (1985) is not as useful as the study of DePass et al. (1986b), which is described below.

In a three-generation reproduction study in which rats were fed ethylene glycol in the diet at 0.04, 0.2, or 1 g/kg/d, DePass et al. (1986b) reported that ethylene glycol had no reproductive toxicity at doses up to 1 g/kg/d. They also found ethylene glycol to be negative in a dominant lethal test in F2-generation male rats exposed to the compound in the diet at about 0.04, 0.2, or 1.0 g/kg/d for three generations. The data of Lamb et al. (1985) and DePass et al. (1986b) indicate that ethylene glycol has no specific reproductive toxicity. It might, however, affect the reproductive function in female mice by causing general toxicity.

Harris et al. (1992) developed a new short-term screen for reproductive and developmental toxicity and used it to test four compounds, including ethylene glycol. In part A of the screen, female mice were

Suggested Citation:"B9: Ethylene glycol." National Research Council. 1996. Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 3. Washington, DC: The National Academies Press. doi: 10.17226/5435.
×

gavaged with ethylene glycol in water at concentrations of 0, 250, 700, or 2500 mg/kg/d for 21 d, from study day 0 to 20. Male mice were similarly gavaged from study day 3 to 20. The doses were chosen with the highest dose being about one-third of the LD50. On study days 8 to 12, the exposed females cohabited with exposed males. The animals were sacrificed on study day 21. Microscopic examinations of the liver, kidney, testis, and epididymis in the male mice were essentially negative. It should be noted that the lack of histopathological changes found in the Harris et al. (1992) study supports a similar finding by Hong et al. (1988) in mice gavaged with ethylene glycol at concentrations of 0, 50, 100, or 250 mg/kg/d for 4 d. In the reproductive study by Harris et al. (1992), no significant changes in the testis weight, epididymis weight, number of sperm per gram cauda, and percentage of motile sperm were detected in the male mice. In the female mice, ethylene glycol caused no clinical signs and no change in the fertility index.

In part B of the screen, untreated female and male mice cohabited 3 d to produce time-mated females, which were gavaged with ethylene glycol at the same doses as in part A of the screen on gestational d 8-14 (Harris, et al., 1992). The litters were examined on postnatal d 0, 1, and 4. The exposures to ethylene glycol did not change the number of live pups per litter. However, the exposure at 2500 mg/kg/d reduced the total litter weight on postnatal d 1 and 4. In conclusion, the short-term screen shows that ethylene glycol is, at the most, only very weakly toxic to the reproductive systems in mice.

Developmental Toxicity

Price et al. (1985) studied the developmental toxicity of ethylene glycol by gavaging rats at concentrations of 1250, 2500, or 5000 mg/kg/d and mice at 750, 1500, or 3000 mg/kg/d on gestational d 6-15. They reported that ethylene glycol could cause severe developmental toxicity in rats and mice. Other than a slight retardation of weight gain in the dams, there were no clinical signs of maternal toxicity. In rats, 5000 mg/kg/d induced postimplantation losses. There were also findings indicative of fetal toxicity. Exposure at 5000 or 2500 mg/kg/d reduced fetal body weight in rats, and exposures at all doses had the same effect

Suggested Citation:"B9: Ethylene glycol." National Research Council. 1996. Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 3. Washington, DC: The National Academies Press. doi: 10.17226/5435.
×

in mice. All groups showed increases in the percentage of litters with malformed fetuses and in the percentage of malformed live fetuses per litter. Malformations produced included axial skeletal dysplasia, neural tube closure defects, and craniofacial defects.

In a similar study, Tyl et al. (1993) exposed female rabbits to ethylene glycol via gavage at 0, 100, 500, 1000, or 2000 mg/kg/d on gestational d 6 through 19. The highest dose caused serious maternal toxicity, as manifested by a 42% mortality, several early deliveries, and renal toxicity (a presence of oxalate crystals in the lumen of cortical renal tubules accompanied by tubular necrosis, degeneration, and dilation). The other doses did not cause maternal toxicity. No developmental toxicity was detected in any of the exposure groups. There were no changes in preimplantation loss, postimplantation loss, the number of fetuses, fetal body weight, and the fetal sex ratio per litter. In addition, no increased incidence of malformation was found.

In part A of the short-term screen conducted by Harris et al. (1992), female mice were gavaged with ethylene glycol for 8 d before a 5-d mating period, 5 d during the mating period, and 8 d after the mating; and male mice were gavaged for 5 d before the mating, during the mating period, and 8 d after the mating. The exposure failed to affect significantly the total number of implants per female. However, the ethylene glycol exposure at 2500 mg/kg/d reduced the number of live implants and raised the number of dead implants per female; two of six litters were totally resorbed. Similar exposures at 700 or 250 mg/kg/d had no such effects. Harris et al. (1992) concluded that their short-term screen succeeded in detecting ethylene glycol as a developmental toxicant in mice. Tyl et al. (1993) compared their data with the data in the literature and concluded that the maternal sensitivities of three species to ethylene glycol can be ranked in the following decreasing order: rabbits, mice, and rats. In terms of its developmental toxicity, the ranked order is mice, rats, and rabbits (Tyl et al., 1993).

Interaction with Other Chemicals

Literature on ethylene glycol's interaction with other chemicals is available. Ethanol treatment of a patient who had ingested a large amount of ethylene glycol appeared to prevent organ damage (Stokes

Suggested Citation:"B9: Ethylene glycol." National Research Council. 1996. Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 3. Washington, DC: The National Academies Press. doi: 10.17226/5435.
×

and Aueron, 1980). Evidence indicates that ethanol's therapeutic effect on ethylene glycol poisoning is related to the competitive inhibition of ethylene glycol's metabolism. Jacobsen et al. (1982) reported that a blood ethanol concentration of 70 mg/dL almost completely inhibited ethylene glycol metabolism in a patient with ethylene glycol intoxication. Grauer et al. (1987) found that coadministered ethylene glycol and ethanol in dogs reduced the elimination half-life of ethylene glycol in the plasma from 10.8 h for ethylene glycol only to 6.8 h for ethylene glycol and ethanol.

Suggested Citation:"B9: Ethylene glycol." National Research Council. 1996. Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 3. Washington, DC: The National Academies Press. doi: 10.17226/5435.
×

TABLE 9-5 Toxicity Summary

Concentration, mg/m3

Exposure Duration

Species

Effects

Reference

30

22 h/d, 30 d

Human

No changes in serum and urininary chemistry; no reduction in psychomotor performance

Wills et al., 1974

64

NS

Human

No irritation

Harris, 1969

127

NS

Human

Pharyngeal irritation

Harris, 1969

140

NS

Human

Eye and respiratory irritation became common

Wills et al., 1974

188

NS

Human

Irritating and tolerated for only 15 min

Wills et al., 1974

190

NS

Human

Subjects awaken out of their sleep; not tolerated

Harris, 1969

244

NS

Human

Not tolerated more than I or 2 min

Wills et al., 1974

308

NS

Human

Intolerable after a breath or two

Wills et al., 1974

10 or 57

8 h/d, 5 d/w, 6 w

Rat, guinea pig, rabbit, dog, monkey

No adverse effects

Coon et al., 1970

12

24 h/d 90 d

Guinea pig

3/15 guinea pigs died (vs. 0/73 in the control group)

Coon et al., 1970

12

24 h/d 90 d

Rat, rabbit

Moderate-to-severe eye irritation (3 and 8 d into the exposure in rabbits and rats, respectively); no chemical-induced histological, hematological, or serum chemistry changes; 1/15 rats died (vs. 4/123 in controls) and 1/3 rabbits died (vs. 0/12 in controls)

Coon et al., 1970

256

24 h/d, 28 d

Chimpanzee (n=2)

Slight reduction in kidney's urine concentrating ability; oxalate crystals found in the kidney of one of two chimpanzees

Felts, 1969

350

8 h/d, 16 w

Rat, Mouse

Cecal ulceration, cysts of pericecal lymph nodes

Wiley et al., 1936

500

28 h in 5 d

Rat

Eye and respiratory irritation

Flury and Wirth, 1934

Suggested Citation:"B9: Ethylene glycol." National Research Council. 1996. Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 3. Washington, DC: The National Academies Press. doi: 10.17226/5435.
×

Concentration, mg/m3

Exposure Duration

Species

Effects

Reference

500 to 600

22 h/d, 2 to 3 w

Monkey

Tolerated

Wills et al., 1974

a Only the more important results were included.

NS, not specified.

TABLE 9-6 Results of Selected Oral and Parenteral Studies

 

Exposure

 

 

 

Dose, g/kg

Route

Species

Effects

Reference

14.5

Oral

Dogs

Muscular incoordination lasted for 51 h

Kersting and Nielsen, 1969

4.4

i.v.

Dogs

Transient incoordination lasted < 6 h

Kersting and Nielsen, 1969

6.6

i.v.

Chimpanzees

Ataxia, coma, and death

Felt, 1969

2.2

i.v.

Chimpanzees

Ataxia, coma

Felt, 1969

2.2

i.v.

Rhesus monkeys

Ataxia for 2 h, recovered afterward

Felt, 1969

1.1

i.v.

Chimpanzees

Ataxia

Felt, 1969

1.1

i.v.

Rhesus monkeys

No behavioral changes

Felt, 1969

2.62 (daily for 10 d)

In drinking water

Rats (male)

No changes in blood urea nitrogen (BUN) and serum creatinine levels; renal histological changes included mild tubular dilatation, intratubular birefringent crystal, and acute inflammation

Robertson et al., 1990

1.34 (daily for 10 d)

In drinking water

Rats (male)

No changes in BUN, but serum creatinine levels increased; crystals in pelvis in 4/10 rats (0/10 in controls); no other renal changes

Robertson et al., 1990

0.65 (daily for 10 d)

In drinking water

Rats (male)

No changes in BUN or renal parameters studied

Robertson et al., 1990

Suggested Citation:"B9: Ethylene glycol." National Research Council. 1996. Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 3. Washington, DC: The National Academies Press. doi: 10.17226/5435.
×

TABLE 9-7 Exposure Limits Set or Recommended by Other Organizations

Agency or Organization

Exposure Limit, ppm

Reference

ACGIH's TLV

50

ACGIH, 1991

OSHA's PEL

50

ACGIH, 1991

NRC's 1-h EEGL

40

NRC, 1985

NRC's 24-h EEGL

20

NRC, 1985

NRC's 90-d CEGL

4

NRC, 1985

TLV, threshold limit value; PEL, permissible exposure limit; EEGL, emergency exposure guidance level; CEGL, continuous exposure guidance level.

TABLE 9-8 Spacecraft Maximum Allowable Concentrations

Exposure Duration

Concentration, ppm

Concentration, mg/m3

Target Toxicity

1 h

25

64

Mucosal irritation

24 h

25

64

CNS depression, mucosal irritation

7 da

5

13

CNS depression, renal toxicity

30 d

5

13

CNS depression, renal toxicity

180 d

5

13

CNS depression, renal toxicity

a The former 7-d SMAC is 50 ppm or 127 mg/m3.

RATIONALE FOR ACCEPTABLE CONCENTRATIONS

The SMACs are set with the assistance of guidelines provided by the National Research Council (NRC, 1992a). For each important toxic end point, acceptable concentrations (ACs) are established for the exposure durations of interest, i.e., 1-h, 24-h, 7-d, 30-d, and 180-d. These ACs are tabulated and the lowest AC for an exposure duration is selected to be the SMAC.

Suggested Citation:"B9: Ethylene glycol." National Research Council. 1996. Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 3. Washington, DC: The National Academies Press. doi: 10.17226/5435.
×
Mucosal Irritation

As discussed above, Harris (1969) reported that an exposure of men to ethylene glycol at 64 mg/m3 was nonirritating, and Wills et al. (1974) reported that mucosal irritation, of unspecified intensity, became common in 20 men at 140 mg/m3. A nonirritating concentration based on the experience of 20 men could still be slightly irritating in sensitive individuals. Nevertheless, because 1-h and 24-h SMACs are for emergencies, a potential for slight nose and throat irritation is acceptable. Consequently, the 1-h and 24-h ACs, based on mucosal irritation, are set at 64 mg/m3 without any correction for the small sample size. Even if mucosal irritation does occur in a small proportion of individuals at these ACs, it should only be sparse and mild because these ACs are much lower than 127 mg/m3, the lowest concentration that mucosal irritation has been reported in 20 men (Wills et al., 1974; Harris, 1969).

1-h and 24-h ACs for mucosal irritation

= short-term NOAEL

= 64 mg/m3.

For the longer-term exposures, however, the ACs should protect against any mucosal irritation. Harris (1969) reported that the 20 men were ''completely oblivious'' to the 64-mg/m3 exposure. Unfortunately, Harris did not specify the length of time these men were exposed at 64 mg/m3. Judging from the description of Wills et al. (1974), it appeared that these men were exposed at 64 mg/m3 for about 15 min. Because mucosal irritation resulting from ethylene glycol exposure is not expected to increase beyond 15 min, the 15-min NOAEL should also be nonirritating for an exposure lasting 7, 30, or 180 d. The 7-d, 30-d, and 180-d ACs for mucosal irritation are derived from the 15-min NOAEL.

The 15-min NOAEL is estimated from data gathered from only 20 men (Wills et al., 1974; Harris, 1969), so it is possible that some sensitive individuals could feel mucosal irritation at the 15-min NOAEL. The 15-min NOAEL, therefore, is adjusted for the small sample size in the derivation of the ACs by multiplying the NOAEL by the square root of 20 divided by 10.

Suggested Citation:"B9: Ethylene glycol." National Research Council. 1996. Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 3. Washington, DC: The National Academies Press. doi: 10.17226/5435.
×

7-d, 30-d, and 180-d ACs for mucosal irritation

= 15-min NOAEL × (√n)/10

= 64 mg/m3 × (√20)/10

= 28 mg/m3.

CNS Depression

CNS depression is the major CNS effect of ethylene glycol. Although nystagmus was reported in workers exposed to ethylene glycol, it was found in a co-exposure to other chemicals. Consequently, the acceptable concentrations to be derived here will aim at preventing CNS depression. No time adjustment is needed for the 7-d, 30-d, and 180-d ACs to prevent CNS depression. The reason is that the NOAEL in the study of Wills et al. (1974) was based on a 30-d exposure. CNS depression is believed to be dependent on blood concentration. The blood concentration of ethylene glycol should reach steady state before the midpoint of the 30-d exposure, when the psychometric tests were first used. A NOAEL from that study ought to be able to prevent CNS depression for 7, 30, or 180 d.

7-d, 30-d, and 180-d ACs for CNS depression

= 30-d NOAEL × (√n)/10

= 30 mg/m3 × (√20)/10

= 13 mg/m3.

The 24-h AC to prevent CNS depression is set using CNS data gathered in animals with acute exposures to ethylene glycol. Kersting and Nielsen (1966) orally administered ethylene glycol to dogs by using ethylene glycol to moisten dry feed. They found that an oral dose of 14.5 g/kg caused muscular incoordination, which lasted as long as 51 h. An oral dose of 4.4 g/kg produced a transient incoordination, which lasted for less than 6 h, in the dogs. Felts (1969) injected primates intravenously with ethylene glycol once.

According to the data of Kersting and Nielsen (1966) in dogs and the data of Felts (1969) in monkeys and chimpanzees, 1.1 g/kg is the lowest dose known to cause CNS depression effects in acute ethylene glycol poisoning. The acute NOAEL is estimated from the LOAEL by applying an uncertainty factor of 10.

Suggested Citation:"B9: Ethylene glycol." National Research Council. 1996. Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 3. Washington, DC: The National Academies Press. doi: 10.17226/5435.
×

NOAEL for acute CNS depression

= LOAEL × 1/NOAEL factor

= 1.1 g/kg × 1/10

= 110mg/kg.

The 24-h AC for CNS depression is estimated by calculating the inhalation exposure concentration that would yield the acute NOAEL of 110 mg/kg in a 70-kg person breathing 20 m3 of air in 24 h (NRC, 1992b). Because Marshall and Cheng (1983) reported that rats absorbed about 60% of the inhaled ethylene glycol, that exposure concentration is corrected by the fraction absorbed. An interspecies extrapolation factor of 10 is also applied.

24-h AC for CNS depression

= acute NOAEL x body weight × 1/daily respiratory volume

× 1/absorption fraction × 1/species factor

= 110 mg/kg × 70 kg × 1/20 m3 × 1/0.60 × 1/10

= 64 mg/m3.

Similarly, the 1-h AC for CNS depression is set using the acute NOAEL of 110 mg/kg, assuming that a 70-kg person breathes 20 m3 of air in 24 h (NRC, 1992b).

1-h AC for CNS depression

= acute NOAEL × body weight × time adjustment

× 1/daily respiratory volume × 1/absorption fraction

× 1/species factor

= 110 mg/kg × 70 kg × (24 h/1 h) × 1/20 m3 × 1/0.60

× 1/10

= 1500 mg/m3.

Renal Toxicity

The exposure of 20 men to ethylene glycol at 30 mg/m3, TWA, for 30 d caused no changes in urinary creatinine clearance, serum urea nitrogen, and the urinary specific gravity (Wills et al., 1974). A concentration that did not produce any renal toxicity in 30 d should not be toxic to the kidney for a 7-d exposure. It also should not be toxic to

Suggested Citation:"B9: Ethylene glycol." National Research Council. 1996. Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 3. Washington, DC: The National Academies Press. doi: 10.17226/5435.
×

the kidney for a 180-d exposure, because the body should reach an equilibrium before 30 d in a continuous exposure. Consequently, the ACs for 7, 30, or 180 d can be set at the same concentration.

7-d, 30-d, and 180-d ACs for renal toxicity

= 30-d NOAEL × (√n)/10

= 30 mg/m3 × (√20)/10

= 13 mg/3.

To check the validity of these ACs, the renal toxicity data from the 2-y bioassay of DePass et al. (1986a) are used. Although mice were not affected in that study, rats given ethylene glycol orally at 1 g/kg/d for 2 y developed histological renal injuries. In contrast, a dose of 0.2 g/kg/d was not toxic to the kidney. An airborne concentration of ethylene glycol that will yield the same dose as a daily oral administration of 0.2 g/kg can be calculated by assuming that a 70-kg person breathes 20 m3/d (NRC, 1992a). Such calculations require a knowledge of the fraction absorbed via ingestion versus that via inhalation. Lenk et al. (1989) showed that rats given ethylene glycol orally at 3 or 5 mL/kg excreted 90-95% of the dose as ethylene glycol and glycolate in the urine in 48 h. According to McChesney et al. (1971), rats are known to excrete 2.5% of an oral dose of ethylene glycol in the urine as oxalic acid (Reif, 1950). The excretion data of Lenk et al. (1989) and McChesney et al. (1971) together indicate that orally administered ethylene glycol is essentially completely absorbed in rats. However, Marshall and Cheng (1983) showed that rats absorbed only 60% of inhaled ethylene glycol. As a result, the calculated airborne exposure concentration of ethylene glycol equivalent to an oral dose needs to be adjusted for the incomplete inhalation absorption.

Theoretical 7-d, 30-d, and 180-d ACs for renal toxicity

= 2-y NOAEL × body weight × 1/species factor × 1/daily respiratory volume × 1/absorption fraction

= 0.2 g/kg/d × 70 kg × 1/10 × 1/20 m3/d × 1/0.6

= 110 mg/m3.

The theoretical long-term ACs derived from the animal data, which were based on histopathological results, are much higher than those derived from the inhalation results in men gathered by Wills et al. (1974).

Suggested Citation:"B9: Ethylene glycol." National Research Council. 1996. Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 3. Washington, DC: The National Academies Press. doi: 10.17226/5435.
×

Therefore, the long-term ACs derived from the human inhalation data offer sufficient protection against renal toxicity, notwithstanding the relatively nonsensitive detection methods used by Wills et al. (1974) for renal toxicity.

To derive the 24-h ACs for renal toxicity, the 30-d NOAEL of Wills et al. is not used. It is not used because, theoretically, the 24-h AC should be higher than the 30-d NOAEL determined in a human study, but how much higher is unknown. As a result, the data of Robinson et al. (1990) are used. They reported that male rats given ethylene glycol in drinking water at a concentration of 2620 mg/kg/d for 10 d had no changes in blood urea nitrogen and serum creatinine levels, but the exposure significantly increased the following renal histological changes: mild tubular dilatation, minimal tubular necrosis, intratubular birefringent crystals, and acute inflammation. A similar exposure at 1340 mg/kg/d produced no change in the blood urea nitrogen level, but it increased the serum creatinine level. It did not produce significant increases in histological renal injuries, but birefringent crystals were seen in the renal pelvis of 4 of 10 animals (vs. 0/10 in the control group). However, ethylene glycol given to 10 male rats in a continuous exposure at 650 mg/kg/d for 10 d did not cause any change in the blood urea nitrogen and serum creatinine levels. It did not cause any significant increase in renal histological changes. There were also no birefringent crystals in the kidney in the 650-mg/kg group (Robinson et al., 1990). Therefore, a dose of 650 mg/kg given in 24 h should be devoid of any renal toxicity. To calculate a 24-h AC for renal toxicity from the 1-d NOAEL of 650 mg/kg, an inhalation exposure concentration yielding a dose of 650 mg/kg is calculated as follows.

24-h exposure concentration to yield a NOAEL of 650 mg/kg

= 1-d NOAEL × body weight × 1/daily respiratory volume

× 1/absorption fraction

= 650 mg/kg × 70 kg × 1/20 m3 × 1/0.60

= 3800 mg/m3.

24-h AC for renal toxicity

= 3800 mg/m3 × 1/species factor

= 3800 mg/m3 × 1/10

= 380 mg/m3.

Suggested Citation:"B9: Ethylene glycol." National Research Council. 1996. Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 3. Washington, DC: The National Academies Press. doi: 10.17226/5435.
×

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:

Suggested Citation:"B9: Ethylene glycol." National Research Council. 1996. Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 3. Washington, DC: The National Academies Press. doi: 10.17226/5435.
×

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.

Suggested Citation:"B9: Ethylene glycol." National Research Council. 1996. Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 3. Washington, DC: The National Academies Press. doi: 10.17226/5435.
×

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.

Suggested Citation:"B9: Ethylene glycol." National Research Council. 1996. Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 3. Washington, DC: The National Academies Press. doi: 10.17226/5435.
×

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

-

-

-

Suggested Citation:"B9: Ethylene glycol." National Research Council. 1996. Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 3. Washington, DC: The National Academies Press. doi: 10.17226/5435.
×

 

 

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.

Suggested Citation:"B9: Ethylene glycol." National Research Council. 1996. Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 3. Washington, DC: The National Academies Press. doi: 10.17226/5435.
×

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×

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Suggested Citation:"B9: Ethylene glycol." National Research Council. 1996. Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 3. Washington, DC: The National Academies Press. doi: 10.17226/5435.
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Suggested Citation:"B9: Ethylene glycol." National Research Council. 1996. Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 3. Washington, DC: The National Academies Press. doi: 10.17226/5435.
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Suggested Citation:"B9: Ethylene glycol." National Research Council. 1996. Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 3. Washington, DC: The National Academies Press. doi: 10.17226/5435.
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Suggested Citation:"B9: Ethylene glycol." National Research Council. 1996. Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 3. Washington, DC: The National Academies Press. doi: 10.17226/5435.
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Suggested Citation:"B9: Ethylene glycol." National Research Council. 1996. Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 3. Washington, DC: The National Academies Press. doi: 10.17226/5435.
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Suggested Citation:"B9: Ethylene glycol." National Research Council. 1996. Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 3. Washington, DC: The National Academies Press. doi: 10.17226/5435.
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Suggested Citation:"B9: Ethylene glycol." National Research Council. 1996. Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 3. Washington, DC: The National Academies Press. doi: 10.17226/5435.
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Suggested Citation:"B9: Ethylene glycol." National Research Council. 1996. Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 3. Washington, DC: The National Academies Press. doi: 10.17226/5435.
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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 3 Get This Book
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The National Aeronautics and Space Administration (NASA) has measured numerous airborne contaminants in spacecraft during space missions because of the potential toxicological hazards to humans that might be associated with prolonged spacecraft missions.

This volume reviews the spacecraft maximum allowable concentrations (SMACs) for various contaminants to determine whether NASA's recommended exposure limits are consistent with recommendations in the National Research Council's 1992 volume Guidelines for Developing Spacecraft Maximum Allowable Concentrations for Space Station Contaminants.

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