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3
Ethylene Glycol

John T. James, Ph.D., DABT

Toxicology Group

Habitability and Environmental Factors Division

Johnson Space Center

National Aeronautics and Space Administration

Houston, Texas

PHYSICAL AND CHEMICAL PROPERTIES

Ethylene glycol (EG) (see Table 3-1) is a colorless, odorless, slightly viscous, hygroscopic liquid with a bittersweet taste (Cavender and Sowinski 1994).

TABLE 3-1 Physical and Chemical Properties of Ethylene Glycol

Formula

HO-CH2-CH2-OH

CAS registry no.

107-21-1

Synonyms

1,2-ethanediol, 1,2-dihydroxyethane, ethane-1,2-diol, ethylene alcohol, ethylene dehydrate

Molecular weight

62.07

Boiling point

197.4°C

Melting point

−13.4°C

Specific gravity

1.11 (at 25°C)

Solubility

Soluble in water and aliphatic alcohols, almost insoluble in Hydrocarbons

OCCURRENCE AND USE

EG has many uses. It is used as antifreeze in motor vehicles and in hydraulic fluids, heat-exchange fluids, inks, solvents, softening agents, and the synthesis of many useful chemicals. It was used in heat-exchange loops in early U.S. space capsules and was present in heat-exchange loops in the Russian Mir space station. Leakage of EG from coolant loops in Mir was a persistent problem during the past few years because the space station was used beyond its intended service life. Once EG escapes from a coolant loop into the atmosphere,



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3 Ethylene Glycol John T. James, Ph.D., DABT Toxicology Group Habitability and Environmental Factors Division Johnson Space Center National Aeronautics and Space Administration Houston, Texas PHYSICAL AND CHEMICAL PROPERTIES Ethylene glycol (EG) (see Table 3-1) is a colorless, odorless, slightly vis- cous, hygroscopic liquid with a bittersweet taste (Cavender and Sowinski 1994). TABLE 3-1 Physical and Chemical Properties of Ethylene Glycol Formula HO-CH2-CH2-OH CAS registry no. 107-21-1 Synonyms 1,2-ethanediol, 1,2-dihydroxyethane, ethane-1,2-diol, ethylene alcohol, ethylene dehydrate Molecular weight 62.07 197.4oC Boiling point –13.4oC Melting point 1.11 (at 25oC) Specific gravity Solubility Soluble in water and aliphatic alcohols, almost insoluble in Hydrocarbons OCCURRENCE AND USE EG has many uses. It is used as antifreeze in motor vehicles and in hy- draulic fluids, heat-exchange fluids, inks, solvents, softening agents, and the synthesis of many useful chemicals. It was used in heat-exchange loops in early U.S. space capsules and was present in heat-exchange loops in the Russian Mir space station. Leakage of EG from coolant loops in Mir was a persistent prob- lem during the past few years because the space station was used beyond its intended service life. Once EG escapes from a coolant loop into the atmosphere, 86

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Ethylene Glycol 87 it is removed into the humidity condensate or recondenses on cool surfaces only to revolatilize later when the surface warms up. Estimates made with detector tubes showed airborne concentrations up to 75 milligrams per cubic meter (mg/m3) in the Mir space station, and ground-based analyses of water samples from Mir showed concentrations up to 440 mg/liter (L) in the humidity conden- sate and 46 mg/L in the recycled water (Lizanna Pierre, Wyle Laboratories, per- sonal commun., 1999). Even though EG is not used in coolant loops in the In- ternational Space Station, it has been found in the U.S. laboratory humidity condensate at concentrations up to 11 mg/L; however, it has not been detected in the potable water (John R. Schultz, Wyle Laboratories, unpublished report, January 9, 2002). PHARMACOKINETICS AND METABOLISM The behavior of EG after it has been ingested into the body has been gen- erally understood for many years, but new discoveries have been reported in the past few years. The understanding of the behavior of EG has important implica- tions for treating acute poisonings and for understanding the metabolic path- ways that lead to detoxification or to production of more toxic metabolites. There are likely to be significant interindividual differences in the metabolism of EG because of genetic variations in the catalytic activity of key enzymes in the major metabolic pathway. Absorption Fasted rats given gavage doses of EG at 6 or 9 milliliters per kilogram (mL/kg) of body weight rapidly absorbed it into the body, where it reached peak blood concentrations in 1 to 4 h (Winek et al. 1978). At lower gavage doses of about 1 g/kg, serum concentrations of EG peaked in fasted rats and dogs 2 h after the dose was administered (Hewlett et al. 1989). Likewise, at an oral dose of 0.9 g/kg, female monkeys had peak plasma concentrations of EG of about 120 milligrams per deciliter (mg/dL) 2 h after dosing (McChesney et al. 1971). Rats and mice exposed orally at up to 1,000 mg/kg rapidly and completely ab- sorbed the dose (Frantz et al. 1996). Distribution Evidence from clinical cases of EG poisoning suggests that its volume of distribution is about 0.5 L/kg (Jacobsen et al. 1988), which indicates distribution into the total body water. The tissue distribution of 14C from [1,2- 14C]EG given orally was similar in female Sprague-Dawley rats and in CD-1 mice when the

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88 Spacecraft Water Exposure Guidelines same doses were given (Frantz et al. 1996). The species were tested at doses ranging from 10 to 1,000 mg/kg and tissues were assayed 96 h after dosing. In major organs from both species, the largest portion of the dose was found in the liver, followed by the kidney, lung, and brain. In terms of label found per gram of tissue, the largest amount was in the liver, followed by the lung and kidney, which were similar; the smallest amount of labeling was found in the brain. In another study, after an intravenous dose of [14C]EG (139 mg/kg) to monkeys, 15% was excreted in the urine by 4 h, but the remainder of the dose (label) was uniformly distributed to body tissues (McChesney et al. 1971). Metabolism Many investigators have studied EG metabolism in an effort to understand how its ingestion causes the range of toxic symptoms and metabolic distur- bances. The metabolism has been summarized as shown in Figure 3-1 (ATSDR 1997). EG is oxidized by alcohol dehydrogenase to glycoaldehyde, which is oxi- dized by aldehyde oxidase or aldehyde dehydrogenase to glycolic acid and gly- oxal. Lactate dehydrogenase appears to be involved in converting glyoxal to glycolic acid, glycolic acid to glyoxylic acid, and glyoxylic acid to oxalic acid, which is further oxidized to formic acid and carbon dioxide by a process involv- ing coenzyme A and flavin mononucleotides. Glyoxylic acid is metabolized to a number of other products, which have no apparent bearing on the toxicity of EG. The liver and kidney are believed to be the major sites where EG is metabo- lized. Alcohol dehydrogenase is a dimer with multiple molecular forms deter- mined by at least five gene loci (Agarwal and Goedde 1992). Certain subunits have a 20-fold higher metabolic capacity than others, so it is reasonable to ex- pect considerable interindividual variability in the metabolism of EG. Likewise, aldehyde dehydrogenase has a number of different molecular forms with differ- ent catalytic capabilities (Thomasson et al. 1993), which could further contrib- ute to interindividual variation in susceptibility to high oral doses of EG. Genetic polymorphisms in the human population can affect the suscepti- bility of individuals to xenobiotics such as EG when those polymorphisms con- trol the enzymatic capabilities of creating or eliminating toxic metabolites. The allelic variants of aldehyde dehydrogenase 2 (ALDH2) produce enzymes that have a wide range in their ability to catalyze the conversion of small aldehydes to organic acids. The nonfunctional allele is rare in most populations, but about 40% of Asians are heterozygous and 5% are homozygous for this allele. Be- cause astronauts are not screened for this genetic factor, one must assume that some individual astronauts are homozygous for the nonfunctional allele. De- pending on the mechanism of EG toxicity, they may be more or less susceptible to the toxic effects because of the accumulation of glycoaldehyde and reduced production of a downstream metabolite.

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Ethylene Glycol 89 Free radical metabolites of EG have been found in bile and urine from male Sprague-Dawley rats given [13C2]EG (Kadiiska and Mason 2000). The free radical metabolites were demonstrated by the formation of adducts of an EG metabolite and a trapping agent, α-(4-pyridyl-1-oxide)-N-tert-butylnitrone. The formation of these adducts increased when 4-methylpyrazole, an alcohol dehy- drogenase inhibitor, was given concurrently with the EG dose, which suggests that more substrate is available for the free radical reaction when the primary metabolic pathway is blocked. Because blocking the major pathway also re- duces the toxicity of EG, the authors suggested that the free radicals do not con- tribute significantly to the acute toxicity of EG. There is an alternative interpretation of the above 4-methylpyrazole data that Kadiiska and Mason (2000) did not consider. Hepatic CYP2E1 can catalyze the conversion of EG to formaldehyde. Because the reaction proceeds through FIGURE 3-1 Metabolic pathways showing oxidation of EG. Source: ATSDR 1997.

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90 Spacecraft Water Exposure Guidelines the formation of H2O2 (Kukielka and Cederbaum 1995), it likely involves the formation of a reactive species and an EG radical intermediate. Thus, the protec- tive effect of 4-methylpyrazole on EG toxicity may also be the result of CYP2E1 inhibition and reduced EG radical formation, rather than inhibition of alcohol dehydrogenase. It has been recognized for some time that clinical management of EG poi- soning can be improved by measuring glycolic acid rather than EG in body flu- ids, especially if the ingestion occurred more than 24 h before hospital admis- sion (Fraser et al. 2002). Use of 4-methylpyrazole to block the activity of alcohol dehydrogenase in converting EG to more toxic metabolites has been recently recommended. For example, 10 patients treated with this antidote and having an initial blood concentration of less than 10 millimoles of glycolic acid per L did not develop renal symptoms (Fraser et al. 2002). The mechanism of EG-induced renal toxicity is not well understood at the cellular level. In vitro evidence from a study of human proximal tubule (HPT) cell death indicates that glycolic acid may not be the proximate metabolite caus- ing renal effects. Even though this metabolite is present at higher concentrations in the blood than oxalic acid, it appears to be the latter that causes the renal cell damage (McMartin and Cenac 2000). Dead and live cells were distinguished by the entry or exclusion of fluorescent dyes into the cultured cells. Oxalate pro- duced a concentration- and time-dependent entry of the red fluorescent dye into the cells with damaged membranes. Glycolic acid and glyoxylic acids failed to produce similar effects on the HPT cells at concentrations associated with renal effects in humans poisoned with EG. The authors concluded that oxalate (oxalic acid) in concentrations similar to urinary concentrations in EG-poisoned patients produces cytotoxicity in cultured HPT cells (McMartin and Cenac 2000). Another in vitro study of cell toxicity reached a different conclusion. Mouse proximal tubular segments (PTS) were incubated with EG or one of its metabolites (glycolate, glycoaldehyde, glyoxalate, or oxalate) for 15 to 60 min- utes (Poldelski et al. 2001). Cell injury was assessed by lactate dehydrogenase release, ATP depletion, or depletion of phospholipids in cell membranes. EG, glycolate, and oxalate did not produce overt injury to cells in the PTS. The au- thors concluded that glycoaldehyde and glyoxylate, because they produced pro- found ATP depletion and lactate dehydrogenase release in the PTS, are the pri- mary metabolites responsible for EG nephrotoxicity. One must simply conclude that there is no consensus on which EG me- tabolite is responsible for the toxic effects on the kidney. Metabolites and devel- opmental toxicity are discussed further in the developmental toxicity section. Elimination The half-life of EG in the blood depends on dose, route of administration, species, and strain. The estimated half-life in humans has been reported to be

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Ethylene Glycol 91 3 to 6 h (Winek 1975, Peterson et al. 1981); however, in an untreated patient with renal failure the half-life for elimination from plasma was 8.4 h (Jacobsen et al. 1988). Hemodialysis of this patient 11 h after admission reduced the half- life in plasma to 3 h; conversely, later treatment with intravenous ethanol pro- longed the elimination of EG from the blood. In Sprague-Dawley rats given near-lethal doses (6 or 9 mL/kg) the half- life in blood was estimated to be 5 to 7 h, with the longer half-life associated with the lower dose (Winek et al. 1978). At less toxic doses, the elimination half-life seems to be somewhat shorter. In rats given EG at 2 g/kg, the half-life was only 1.7 h, whereas in dogs given EG at 1 to 1.4 g/kg, the half-life was 3.4 h (Hewlett et al. 1989). In CD-1 mice given [14C]EG at 0.01 to 1 g/kg, the amount of label eliminated in the breath and urine combined was 75% to 90% of the dose; however, at the lowest dose, 55% was eliminated in the breath and at the highest dose 56% was eliminated in the urine (Frantz et al. 1996). The route of elimination was dose dependent in F344 rats given an intravenous injection of EG. At 20 and 200 mg/kg, 39% of the dose was exhaled as CO2 and 2% was excreted by the kidney as glycolate; however, at 1,000 and 2,000 mg/kg, 26% of the dose was eliminated as CO2 from the respiratory system and 20% was ex- creted as glycolate in the urine (Marshall 1982). The renal toxicity occurs as the detoxification pathways are overwhelmed and more toxic metabolites are elimi- nated by the kidney rather than by exhalation of less toxic CO2. TOXICITY SUMMARY The toxicity of EG is well understood from fatal and near-fatal acute poi- sonings in humans as well as long-term studies in animals consuming EG in their water or food. There are three or four recognized stages in acute human poisonings. The long-term effects of EG ingestion in animals include adverse effects on the kidney, blood cells, and possibly the liver. There is some evidence that EG can cause reproductive and developmental toxicity in animals. Reviews of EG toxicity have been published (LaKind et al. 1999, Brukner and Warren 2001). Acute Toxicity (1- to 5-d Exposure) Stages of EG Poisoning Oral ingestion is by far the major route of exposure of humans to EG. In the United States, 6 to 60 deaths per year are attributed to ingestion of EG (ACGIH 1996). Life-threatening poisonings can occur as a result of deliberate or accidental ingestion of about 1.4 mL/kg (about 100 mL for a 70-kg person) (ATSDR 1997). On the basis of milligram per kilogram of body weight, humans

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92 Spacecraft Water Exposure Guidelines seem to be more susceptible than laboratory animals to the toxicity of orally ingested EG (ACGIH 1996, Table 3-2). Ingestion of a single large dose of EG leads to a three- to four-stage se- quence of clinical symptoms beginning with the central nervous system (CNS) (Cavender and Sowinski 1994). This stage typically begins soon after ingestion and can last up to 12 h. The symptoms resemble drunkenness and they can pro- gress to coma, convulsions, and death if the dose is large enough. These CNS effects are thought to be due primarily to unmetabolized EG or its aldehyde me- tabolites (Parry and Wallach 1974). The second stage lasts from 12 to 36 h after ingestion and involves car- diopulmonary effects. Clinical findings can include tachypnea, tachycardia, hy- potension, cyanosis, pulmonary edema, bronchopneumonia, and congestive heart failure. This stage is believed to be caused by metabolic acidosis (glycolic acid and lactic acid) and by hypocalcemia due to chelation of calcium with ox- alate to form insoluble crystals. If a person survives the initial stages, then a third stage involving renal failure may ensue. The renal injury may be reflected in a urinalysis by the pres- ence of protein, red and white blood cells (RBC and WBC), casts, and calcium oxalate crystals. Blood urea nitrogen (BUN) and creatinine may be elevated and the end result can be tubular necrosis, anuria, and death. The formation of cal- cium oxalate in the kidney plays a major role in this stage; however, there is also evidence that products of EG metabolism lead directly to tubular necrosis. According to some investigators, a fourth “cerebral stage” involving neu- rologic symptoms can appear approximately 2 wk after ingestion of EG (Chung and Tuso 1989). Cranial nerve dysfunction, facial paralysis, hearing loss, and optic nerve damage can be found at this time. These late symptoms are thought to be due to accumulated metabolites of EG that produce metabolic acidosis. Acute Toxicity Data The acute toxicity database consists almost entirely of lethality studies in animals and lethal, or near-lethal, ingestions in humans (see Table 3-2). These data, which involve a broad range of species, suggest that there is not more than a 6-fold interspecies variation in the amount (based on gram per kilogram of body weight) of EG required to cause death. Humans seem to be one of the more susceptible species; however, the conditions of human exposure differed greatly from the conditions used to expose animals. The circumstances surrounding the incidents of human ingestion of EG are important to understanding how to use these “data.” Walton (1978) reported details of six fatal EG poisonings from deliberate ingestion of antifreeze, with the intention of suicide. The suicide attempts followed publicity surrounding an

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TABLE 3-2 Summary of Toxic Effects Dose or Route or Concentration Exposure Species Effects Reference Acute Dosages (1-5 d) 8-15 g/kg Oral Mouse Cavender and LD50. Sowinski 1994 4-13 g/kg Oral Rat Cavender and LD50. Sowinski 1994, NTP 1993 7-11 g/kg Oral Guinea pig Cavender and LD50. Sowinski 1994 5 g/kg Oral Rabbit Cavender and LD50. Sowinski 1994 2-3 g/kg Oral Human, n=2 Lower lethal. Walton 1978 1.6 g/kg Oral Human Minimum lethal estimate.a Gessner et al. 1961 1.1 g/kg Oral Human, n=7 Minimum lethal estimate. Hunt 1932, as cited in Laug et al. 1939 1.1 g/kg over 3 d Oral Human, n=5 Serious, but not lethal. Moriarty and McDonald 1974 0.05-0.25 g/kg/d Oral B6C3F1 mouse, Bone marrow hypocellularity, suppression of progenitor colony Hong et al. 1988 for 4 d gavage M/F formation, and erythropoiesis. All reversible in females. (Continued) 93

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94 TABLE 3-2 Continued Dose or Route or Concentration Exposure Species Effects Reference Short-term Dosages (6-30 d) 0.25% 28 d DW Charles River rat, Renal lesions (weanlings). Gershoff and M, n=6 Andrus 1962 0.5%-4.0% 10 d DW SD rat, F, n=10 Increased incidence or severity of renal lesions, decreased RBC Robinson et al. indices and WBC count in 4% group NOAEL was 2%.a 1990 0.5%-4.0% 10 d DW SD rat, M, n =10 Increased incidence or severity of renal lesions at 2% and 4%; Robinson et al. NOAEL was 0.5%.a 1990 1.0% 21 d DW Porton rat, M Oxalate deposits in kidney. Rofe et al. 1986 0.25%-10% 6-13 d DW Macaque, n=2-7 Renal lesions, azotemia; no renal crystals at 0.25%. Roberts and Seibold 1969 Subchronic Dosages (31-180 d) 0.25%-10% 13-157 d Macaque, M, Anemia, azotemia. Roberts and DW n=2-7 Seibold 1969 0.25%-2% 90 d DW SD rat, M, n=10 2/10 died at high dose; renal lesions increased in severity or Robinson et al. incidence at all concentrations; LOAEL was 0.25%.a 1990 0.5%-4% 90 d DW SD rat, F, n=10 8/10 died at highest dose; renal lesions increased in severity Robinson et al. or incidence in 2% and 4% groups; decreased leukocytes in 1990 all groups except 1% group, which was taken as the NOAEL.a 1% 70 d DW Rat, M, n=5-13 Death due to renal failure, liver had centrilobular necrosis. Hanzlik et al. 1947 0.3%-5% 94 d feed B6C3F1 mouse, No clinical signs, no changes in clinical pathology values, Melnick 1984 M, n=10 nephrosis, and centrilobular degeneration in liver of 2.5% and NTP 1993 5% groups. NOAEL was 1.25% (3 g/kg/d)a for these effects.

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0.3%-5% 94 d feed B6C3F1 mouse, F, NOAEL for all effects. Melnick 1984 n=10 NTP 1993 0.32%-5.0% 91 d feed F344 rat, M, n=10 1.25% NOAEL, 2.5% and 5.0% showed increased BUN, Melnick 1984 creatinine, and renal crystals. 0.32%-5.0% 91 d feed F344 rat, F, n=10 5.0% nephrosis, NOAEL other effects. Melnick 1984 Chronic Dosages (0.5-3 y) 0.2% 3 y feed Rhesus monkey, NOAEL for histopathology (2/2) of many organs including Blood et al. 1962 M, n=2 kidney. 0.5% 3 y feed Rhesus monkey, NOAEL for histopathology (1/1) of many organs including Blood et al. 1962 F, n=1 kidney. 0.2% 2 y feed SD rat, M, n=16 NOAEL for renal calcification, effects seen at 0.5%, 1%, and 4%. Blood 1965 Increased mortality in 1% and 4% groups. Normal hematology. 0.5% 2 y feed SD rat, F, n=16 NOAEL for renal calcification, effects seen at 1% and 4%. Blood 1965 Increased mortality in 4% group. Normal hematology. 1%-2% 2 y feed Albino rat, M/F, Renal oxalate crystals, atrophy, fibrosis. Liver centrilobular atro- Morris et al.1942 n =10 phy, bile duct proliferation, fatty changes, bladder stone in males. 0.04-1.0 g/kg/d 2 y feed F344 rat, F n=130 NOAEL 0.2 g/kg/da for mild fatty metamorphosis, monocyte DePass et al. infiltrate, and granulomas in liver; 1.0 g/kg/d was NOAEL for all 1986a other effects including neoplasia. 0.04-1.0 g/kg/d 2 y feed F344 rat, M, NOAEL 0.2 g/kg/da renal injury (creatinine, BUN, lesions) DePass et al. n=130 mineralization of heart, lung stomach, and for parathyroid 1986a hyperplasia. 80% of 1% group were dead by 15 months. Blood changes at 12-month sacrifice in 1.0% group: RBC, hematocrit, hemoglobin decreased 15%. WBC count increased 60%. NOAEL = 0.2 g/kg/d.a (Continued) 95

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96 TABLE 3-2 Continued Dose or Route or Concentration Exposure Species Effects Reference 1.0 g/kg/d 2 y feed CD1 mouse, M/F, NOAEL for clinical signs, histopathology, and neoplasia. DePass et al. n=80 1986a 0.62%-2.5% 2 y feed B6C3F1 mouse, NOAEL for clinical pathology in all groups. 1.5 g/kg/d NOAEL NTP 1993 (1.5-6 g/kg/d) M, n=50 for liver hyaline degeneration. NOAEL for neoplasms in all groups. Nephropathy in high-dose group at 15-month interim sacrifice. 1.25%-5% 2 y feed B6C3F1 mouse, NOAEL for clinical pathology in all groups 1.25%. LOAEL lung NTP 1993 (3-12 g/kg/d) F, n=50 arterial medial hyperplasia (10/50 versus 3/50 in controls). 1.25% NOAEL for liver hyaline degeneration. NOAEL for neoplasms in all groups. a Result was used as a basis for acceptable concentrations for the toxic effect described (see Table 3-9). Abbreviations: DW, drinking water; F, female; LD50, 50% lethal dose; M, male; SD, Sprague-Dawley.

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Ethylene Glycol 115 TABLE 3-7 Lesions Found in Male Rats Ingesting EG-Contaminated Water for 90 d Dose, Number Number Number Number Dose, % mg/kg/d of Rats with RTD with IC with SI 0 0 10 3 0 5 0.25 200 10 5 0 3 0.5 410 10 5 0 7 1.0 950 10 8 8 7 2.0 3,130 9 9 9 9 Abbreviations: IC, intratubular crystal; RTD, renal tubular degeneration; SI, subacute inflammation. TABLE 3-8 BMD Analysis for Lesions Seen in Rats Ingesting EG- Contaminated Water for 90 da Parameter/Lesion RTD IC SI BMD10 300 mg/kg/d 780 mg/kg/d 320 mg/kg/d (0.39%) (0.37%) (0.96%) 27b mg/kg/d BMDL10 390 mg/kg/d 46 mg/kg/d (0.06%) (0.03%) (0.48%) BMD01 120 mg/kg/d 680 mg/kg/d 115 mg/kg/d (0.14%) (0.15%) (0.84%) BMDL01 2.5 mg/kg/d 210 mg/kg/d 4 mg/kg/d (0.005%) (0.003%) (0.26%) P value (Pearson χ2) 0.68 1 0.25 AIC 56.83 12.008 59.56 a The appendix presents curve fittings for RTD (Figure 3-2), IC (Figure 3-3), and SI (Fig- ure 3-4). b Point of departure. Abbreviations: AIC, Akaike Information Criterion; BMD10, the maximum-likelihood dose expected to give a 10% response; BMD01, the maximum-likelihood dose expected to give a 1% response; BMDL10, the 95% lower confidence limit of the BMD10; BMDL01, the 95% lower confidence limit of the BMD01; IC, intratubular crystal; RTD, renal tubular degeneration; SI, subacute inflammation. response reversal between the control and low-dose groups. The low BMDL10 was selected as the point of departure for calculation of the AC for renal effects. 100-d AC(renal effects) = 27 mg/kg/d(BMDL10) × 1/10(species) × 1/3(interindividual variability) × 90 d/100 d(time extrapolation) × 70 kg(adult body weight)/2.8 L/d(water consumption) = 20 mg/L.

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116 Spacecraft Water Exposure Guidelines This result is well below the result (51 mg/L) if we begin with the lowest dose 0.25% (205 mg/kg/d) as a LOAEL and use it as the point of departure (see guideline for 100 d). Application of BMD Analyses to Predict a 1,000-d AC for Kidney Injury Comparing the third columns in Tables 3-6 and 3-8 reveals that the inci- dence of IC does not increase with increasing exposure time. The comparable benchmark estimates are roughly within a factor of 2. If this were the only ad- verse effect in the kidney, then the 1,000-d AC would be the same as the 10-d AC. However, inspection of the second columns in Tables 3-6 and 3-8 shows that the risk of RTD does increase with time of exposure. On the basis of the central estimates for a 10% risk (BMD10) for 10 and 90 d, we note that the value drops 5-fold from 1,410 to 300 as the time of exposure increases almost 10-fold from 10 to 90 d. To estimate the AC for 1,000 d (a 10-fold increase in ingestion time), we divide the 100-d AC of 20 mg/L by 5 as follows: 1,000-d AC(renal injury) = 20 mg/L(10-d AC) × 1/5(increased exposure time) = 4 mg/L. The summary of AC calculations and final SWEGs are given in Table 3-9.

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TABLE 3-9 Acceptable Concentrations of EG in Drinking Water to Prevent Adverse Effects Uncertainty Factors Acceptable Concentrations, mg/L Data/ Sex/ Micro- Inter- Exposure Reference Species NOAEL Species gravity individual Time 1d 10 d 100 d 1,000 d Reference Kidney Minimum lethal estimate M/F 50 1 1 3 1 270 — — — Gessner et 1.6 g/kg (apply to CNS also) al. 1961 Human 10-d NOAEL renal lesions, M/SD 1 10 3 3 1 — 180 — — Robinson et 0.5% in drinking water al. 1990 rats M/SD 1 10 3 3 1 — 140 — — Robinson et 10-d BMDL10 = 520 mg/kg/d (IC) rats al. 1990 90-d LOAEL renal lesions, M/SD 3 10 1 3 1.1 — — 51 — Robinson et 0.25 % in drinking water al. 1990 rats M/SD 1 10 1 3 1.1 — — 20 4 Robinson et 90-d BMDL10 = 27 mg/kg/d (IC) al. 1990 rats 730-d NOAEL renal lesions, M/F344 1 10 1 3 1 — — — 170 DePass et al. 1986a 0.2 g/kg/d feed rats Liver 91-d NOAEL centrilobular M/F344 1 10 1 3 1.1 — — 2,300 — Melnick 1984 necrosis, 3 g/kg/d feed rats NTP 1993 730-d NOAEL fatty change, F/F344 1 10 1 3 1 — — — 170 DePass et al. 1986a monocyte infil., granulomas, rats 0.2 g/kg/d feed (Continued) 117

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TABLE 3-9 Continued 118 Data/ Uncertainty Factors Acceptable Concentrations, mg/L Reference Sex/ Micro- Inter- Exposure Species NOAEL Species gravity individual Time 1d 10 d 100 d 1,000 d Reference Liver (Continued) 10-d NOAEL on RBC/WBC F/SD 1 10 3 3 1 — 820 — — Robinson indices, 2.0% (22 g/L) rats et al. 1990 drinking water 90-d NOAEL on WBC count, F/SD 1 10 3 3 1.1 — 290 — Robinson et al. 1990 1.0% (11 g/L) drinking water rats 730-d NOAEL RBC/WBC M/F344 1 10 3 3 1 — — — 55 DePass et al. 1986a indices, 0.2 g/kg/d feed rats 270 140 20 SWEG 4 Abbreviations: F, female; M, male; SD, Sprague-Dawley; —, not calculated.

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124 Spacecraft Water Exposure Guidelines APPENDIX Log-Logistic Model with 0.95 Confidence Level Log-Logistic 1 0.8 Fraction Affected 0.6 0.4 0.2 0 1000 1500 2000 2500 3000 0 500 BMDL BMD Dose 12:09 04/19 2007 FIGURE 3-2 Curve for 90-d renal tubular degeneration. P-value = 0.675 Specified effect = 0.1 Risk Type = Extra risk BMD = 302 BMDL = 27.4 Log-Logistic Model with 0.95 Confidence Level Log-Logistic 1 0.8 Fraction Affected 0.6 0.4 0.2 0 1000 1500 2000 2500 3000 0 500 BMDL BMD Dose 12:14 04/19 2007 FIGURE 3-3 Curve for 90-d tubular crystal formation. P-value = 1.0000 Specified effect = 0.1 Risk Type = Extra risk BMD = 779 BMDL = 391

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Ethylene Glycol 125 Log-Logistic Model with 0.95 Confidence Level Log-Logistic 1 0.8 Fraction Affected 0.6 0.4 0.2 0 1000 1500 0 2000 2500 3000 500 BMDL BMD Dose 12:04 04/19 2007 FIGURE 3-4 Curve for 90-d subacute inflammation. p value = 0.248 Specified effect = 0.1 Risk Type = Extra risk BMD = 317 BMDL = 46.5