DRAFT TECHNICAL REPORT FOR ETHYLENE GLYCOL/PROPYLENE GLYCOL Prepared by: Clement International Corporation Under Contract No. 205-88-0608 Prepared for: U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES Public Health Service Agency for Toxic Substances and Disease Registry May 1993 ***DRAFT FOR PUBLIC COMMENT*** DISCLAIMER The use of company or product name(s) is for identification only and does not imply endorsement by the Agency for Toxic Substances and Disease Registry. *** DRAFT FOR PUBLIC COMMENT *** FOREWORD 94 3 The Superfund Amendments and Reauthorization Act (SARA) of 1986 (Public Law 99-499) amended [ QU KR » the Comprehensive Environmental Response, Compensation, and Liability Act (CERCLA or Superfund). Section - 211 of SARA also amended Title 10 of the U.S. Code, creating the Defense Environmental Restoration Program. Section 2704 (a) of Title 10 of the U.S. Code directs the Secretary of Defense to notify the Secretary of Health and Human Services of not less than 25 of the most commonly found unregulated hazardous substances at defense facilities. Section 2704(b) of Title 10 of the U.S. Code directs the Administrator of the Agency for Toxic Substances and Disease Registry (ATSDR) to prepare a technical report for each substance on the list provided by the Secretary of Defense under subsection (b). Each report must include the following: (A) The examination, summary, and interpretation of available toxicological information and epidemiological evaluations on a hazardous substance in order to ascertain the levels of significant human exposure for the substance and the associated acute, subacute, and chronic health effects. (B) A determination of whether adequate information on the health effects of each substance is available or in the process of development to determine levels of exposure which present a significant risk to human health of acute, subacute, and chronic health effects. (C) Where appropriate, identification of toxicological testing needed to identify the types or levels of exposure that may present significant risk of adverse health effects in humans. This technical report is prepared in accordance with guidelines developed by ATSDR and EPA. The original guidelines were published in the Federal Register on April 17, 1987. Each report will be revised and republished as necessary, but no less often than every three years, as required by SARA. The ATSDR technical report is intended to characterize succinctly the toxicological and adverse health effects information for the hazardous substance being described. Each report identifies and reviews the key literature (that has been peer-reviewed) that describes a hazardous substance’s toxicological properties. Other pertinent literature is also presented but described in less detail than the key studies. The report is not intended to be an exhaustive document; however, more comprehensive sources of specialty information are referenced. Each technical report begins with a public health statement, which describes in nontechnical language a substance’s relevant toxicological properties. Following the public health statement is information concerning levels of significant human exposure and, where known, significant health effects. The adequacy of information to determine a substance’s health effects is described in a health effects summary. Data needs that are of significance to protection of public health will be identified by ATSDR, the National Toxicology Program (NTP) of the Public Health Service, and EPA. The focus of the reports is on health and toxicological information; therefore, we have included this information in the beginning of the document. Foreword The principal audiences for the technical reports are health professionals at the Federal, state, and local levels, interested private sector organizations and groups, and members of the public. We plan to revise these documents in response to public comments and as additional data become available. Therefore, we encourage comments that will make the technical report series of the greatest use. Comments should be sent to: Agency for Toxic Substances and Disease Registry Division of Toxicology Mail Stop E-29 Atlanta, Georgia 30333 This report reflects our assessment of all relevant toxicological testing and information that has been peer reviewed. It has been reviewed by scientists from ATSDR, the Centers for Disease Control and Prevention (CDC), and other federal agencies. It has also been reviewed by a panel of nongovernment peer reviewers and is being made available for public review. Final responsibility for the contents and views expressed in this technical report resides with ATSDR. ", ™ (Mdm, a — William L. Roper. M.D.. M.P.H. Administrator Agency for Toxic Substances and Disease Registry CONTENTS FOREWORD ..uitiiitinnnnnnserssnssnssmnrsrrnsssssssanssssssuessmsssesssssssss iii JAST OER PRIGLIRES ...ouvnvrimsnsns enn ss ns sng omens sss smn mess hes sme ems wm mews vii LIST OF TABLES . sc tv tv truest ssisiasisstanneservosnsrnrsnramnmrmsnnsnsssussssnssss ix I. PUBLIC HEALTH STATEMENT . eee 1 1.1. WHAT ARE ETHYLENE GLYCOL AND PROPYLENE GLYCOL? ................ 1 1.2 WHAT HAPPENS TO ETHYLENE GLYCOL AND PROPYLENE GLYCOL WHEN THEY ENTER THE ENVIRONMENT? ...... iii 2 1.3 HOW MIGHT I BE EXPOSED TO ETHYLENE GLYCOL/PROPYLENE GLYCOL? ... 2 1.4 HOW CAN ETHYLENE GLYCOL/PROPYLENE GLYCOL ENTER AND LEAVE MY BODY? ou vvunnmmmnmnimnmesssnnmiassdsdsdsdsss dus onsssssnnescsnnersssn 2 1.5 HOW CAN ETHYLENE GLYCOL/PROPYLENE GLYCOL AFFECT MY HEALTH? ... 3 1.6 IS THERE A MEDICAL TEST TO DETERMINE WHETHER 1 HAVE BEEN EXPOSED TO ETHYLENE GLYCOL/PROPYLENE GLYCOL? .....ovi0ivun 3 1.7 WHAT RECOMMENDATIONS HAS THE FEDERAL GOVERNMENT MADE TO PROTECT HUMAN HEALTH? ..uuiuinciosinnnsmnnmnssssmannssnemnnesess 4 1.8 WHERE CAN [ GET MORE INFORMATION? ......... iii. 4 2. HEALTH BEPECTS |. poor rrr umm some som os moss sn mes a 6658 6 505 bo mm ot moe 000000 00 5 21 INTRODUCTION oui uvnnummssss os nnsnsnsnsesnsns sess esssesnesssss 5 22 RELEVANCETOPUBLICHEALTH ....... cc. 5 2.3 BIOMARKERS OF EXPOSURE AND EFFECT .. ....o.iiiii ieee 37 2.3.1 Biomarkers Used to Identify or Quantify Exposure to Ethylene Glycol OF PIOPYIENE GIYEOL +. ivi iisiuissisisvnbivsboosbmmmmn ns moenss ons wn 38 2.3.2 Biomarkers Used to Characterize Effects Caused by Ethylene Glycol or Propylene Glycol ....... 39 2.4 INTERACTIONS WITH OTHER CHEMICALS ............ iin... 39 2.5 POPULATIONS THAT ARE UNUSUALLY SUSCEPTIBLE ...................... 40 26 ONGOING STUDIES .... coco rarssisasissssnssassiotsssssssnsimmmmn sme wnens 41 3. CHEMICAL AND PHYSICAL INFORMATION . ....... iii 45 3.1 CHEMICAL IDENTITY eee 45 32 PHYSICAL AND CHEMICAL PROPERTIES . 2 vison vsssosunsnstssnsociosses 45 4. PRODUCTION, IMPORT, USE, AND DISPOSAL . .........iuiiiiitnnn... 49 5. POTENTIAL FOR HUMAN EXPOSURE .. ..... ieee ieee 53 5.1 OVERVIEW 53 52 RELEASES TO THE ENVIRONMENT .uvovnsanssssnsiinmmmnnonrecrenensesss 53 S21 AI uo rae nm om mn EE EEE TEES rom non wn ew nny vx sla EEE 8 53 522 WAST i vvcvvvmnmnnmmnnnmnnasnnmanmsnsnsnsssdeonssssssssnesen sesesesss 53 323 Soll. ciiininririmr ras asa EEE RE RE ERE Rey EE a 53 33 ENVIRONMENTAL FATE cour unsctr rr ra suas nasas as doas Snide sss ds edn oes 56 53.1 Transport and PArttoniNg ...cvcwsesssonsmsssmmnenasmsmensmesesnsesss 56 5.3.2 Transformation and Degradation ....................... iii... 56 S321 AIL 56 *** DRAFT FOR PUBLIC COMMENT *** vi 832.2 WALL vvvivmnmermnmm mmm mmm SAGER GE ERE DE 8, FE 56 BRZE SOU 5 vn mw 0 0 10 50 co 0b 0 ow sow oom wom mom mon hot FES BS EEE RP ER ER EEN AS 57 5.4 LEVELS MONITORED OR ESTIMATED IN THE ENVIRONMENT ............... 57 SAT AIT oe ee ee 57 SAT Wall vm ommm mss EBA REE A EER PEER REE ERT E EEE e ero a vse arnt sos 57 S43 SOU covummmmmmmmn ns nmn nw amami ddA FERRE RAED 2 54 5s E EF aE sass sans ono 57 5.4.4 Other Environmental Media ........... i 57 5.5 GENERAL POPULATION AND OCCUPATIONAL EXPOSURE .................. 58 5.6 POPULATIONS WITH POTENTIALLY HIGH EXPOSURES ..................... 58 6. ANALYTICAL METHODS vo inxumumammm saris sisi isi ts isi ts tssssssssrsassnsss numa 59 6.1 BIOLOGICAL MATERIALS . . ott ee ee ee ee ieee eee 59 6.2 ENVIRONMENTAL SAMPLES ee eee ees 60 Y. REGULATIONS AND ADVISORIES .. ccs nos sists sts ssa iissrsemene sesame man 69 B. REFERENCES i. itt i tttine in tasansanensensnsnssssasssssssssnssssmsnssenns ans 73 0. GLOSSARY © oo ee 99 APPENDICES A, USERS GUIDE coi 0585600 estas asus mmm ss ems assim osm ssese ss A-1 B. ACRONYMS, ABBREVIATIONS, AND SYMBOLS ............ ii B-1 C. PEER REVIEW ..ivivsmprensnnmunnssssmssmmnsmms fiiaSssey esmgsEEessssy ess C-1 *** DRAFT FOR PUBLIC COMMENT *** vil LIST OF FIGURES Metabolic Pathway for Oxidation of Ethylene Glycol ....................... unt. 7 Levels of Significant Exposure to Ethylene Glycol - Inhalation ......................... 11 Levels of Significant Exposure to Ethylene Glycol - Oral ...................... 00 19 Levels of Significant Exposure to Propylene Glycol - Inhalation ........................ 30 Levels of Significant Exposure to Propylene Glycol - Oral .................... one. 33 Existing Information on Health Effects of Ethylene Glycol .......................... 42 Existing Information on Health Effects of Propylene Glycol ........................... 43 *** DRAFT FOR PUBLIC COMMENT *** 4-1 5-1 6-1 6-2 7-1 7-2 LIST OF TABLES Levels of Significant Exposure to Ethylene Glycol - Inhalation ......................... Levels of Significant Exposure to Ethylene Glycol - Oral ............................. Gentoxicity of Ethylene Glycol In Vivo... Gentoxicity of Ethylene Glycol In Vitro ............... iii Levels of Significant Exposure to Propylene Glycol - Inhalation ........................ Levels of Significant Exposure to Propylene Glycol - Oral ............................ Levels of Significant Exposure to Propylene Glycol - Dermal .......................... Chemical Identity of Ethylene Glycol and Propylene Glycol ........................... Physical and Chemical Properties of Ethylene Glycol and Propylene Glycol ............... Facilities that Manufacture or Process Ethylene Glycol ............................... Releases to the Environment from Facilities that Manufacture or Process Ethylene Glycol . . . . Analytical Methods for Determining Ethylene Glycol and Propylene Glycol in Biological Materials ........... Analytical Methods for Determining Ethylene Glycol and Propylene Glycol in Environmental Samples . ....... Regulations and Guidelines Applicable to Ethylene Glycol ............................ Regulations and Guidelines Applicable to Propylene Glycol ........................... *** DRAFT FOR PUBLIC COMMENT *** 61 1. PUBLIC HEALTH STATEMENT This Statement was prepared to give you information about ethylene glycol/propylene glycol and to emphasize the human health effects that may result from exposure to it. The Environmental Protection Agency (EPA) has identified 1,300 sites on its National Priorities List (NPL). Ethylene glycol and propylene glycol have been found in at least 27 and 4 of these sites, respectively. However, we do not know how many of the 1,300 NPL sites have been evaluated for ethylene glycol/propylene glycol. As EPA evaluates more sites, the number of sites at which ethylene glycol/propylene glycol is found may change. This information is important for you to know because ethylene glycol/propylene glycol may cause harmful health effects and because these sites are potential or actual sources of human exposure to ethylene glycol/propylene glycol. When a chemical is released from a large source, such as an industrial plant, or from a container, such as a drum or bottle, it enters the environment as a chemical emission. This emission, which is also called a release, does not always lead to exposure. You can be exposed to a chemical only when you come into contact with the chemical. You may be exposed to it in the environment by breathing, eating, or drinking substances containing the chemical or from skin contact with it. If you are exposed to a hazardous chemical such as ethylene glycol/propylene glycol, several factors will determine whether harmful health effects will occur and what the type and severity of those health effects will be. These factors include the dose (how much), the duration (how long), the route or pathway by which you are exposed (breathing, eating, drinking, or skin contact), the other chemicals to which you are exposed, and your individual characteristics such as age, sex, nutritional status, family traits, life style, and state of health. 1.1 WHAT ARE ETHYLENE GLYCOL AND PROPYLENE GLYCOL? Ethylene glycol and propylene glycol are man-made liquid substances that absorb water. They are used to make antifreeze for cars, airplanes, and boats. Both ethylene glycol and propylene glycol are used to make polyester fibers. Propylene glycol is also used by the chemical and pharmaceutical industries to absorb extra water in certain medicines, cosmetics, or food products. Other names for ethylene glycol are 1,2-dihydroxyethane, 1,2-ethanediol, ethylene alcohol, glycol, and Dowtherm®. Other names for propylene glycol are 1,2- dihydroxypropane, 1,2-propanediol, methyl glycol, and trimethyl glycol. Ethylene glycol and propylene glycol are clear, colorless liquids at room temperature. Either compound may exist in air in the vapor form. They have no odor. In this report, ethylene glycol and propylene glycol are discussed together because they have very similar structures and physical properties. You can find more information on the sources, properties, and uses of ethylene glycol and propylene glycol in Chapters 3 and 4. *** DRAFT FOR PUBLIC COMMENT *** 2 1. PUBLIC HEALTH STATEMENT 1.2 WHAT HAPPENS TO ETHYLENE GLYCOL AND PROPYLENE GLYCOL WHEN THEY ENTER THE ENVIRONMENT? Waste streams from the manufacture of ethylene glycol and propylene glycol are primarily responsible for the releases of both compounds into the air, water, and soil. They can also enter the environment through the disposal of products that contain either ethylene glycol or propylene glycol. Neither compound is likely to exist in large amounts in the air. We have little information concerning what happens to ethylene glycol and propylene glycol in the air. The small amounts of ethylene glycol and propylene glycol that may enter the air are likely to break down quickly. If either chemical escapes into the air, it will take between 24 and 50 hours for one-half of the amount released to break down. Both compounds can mix completely with water and can stick to soil. Ethylene glycol and propylene glycol can break down slowly in surface water and in soil. Both compounds stay in water or soil for several days. Ethylene glycol and propylene glycol can travel from certain types of food packages into food products. See Chapters 4 and 5 for more information on ethylene glycol and propylene glycol in the environment. 1.3 HOW MIGHT | BE EXPOSED TO ETHYLENE GLYCOL/PROPYLENE GLYCOL? The general population can be exposed to ethylene glycol and propylene glycol because the compounds are in many common automotive, food, pharmaceutical, and photographic developing products. If you come in contact with automotive fluids such as antifreeze, coolants, and brake fluid, you may be exposed to ethylene glycol. If you eat food products, use cosmetics, or take medicines that contain propylene glycol, you will be exposed. People who work in industries that use ethylene glycol or propylene glycol may be exposed by touching these products or inhaling fumes from spraying these products. In areas where deicing fluids were sprayed, ethylene glycol vapor has been found in the air at low concentrations ranging between <0.05 milligram (mg) per cubic meter (m3) and 10.4 mg/m>. See Chapter 5 for more information on exposure to ethylene glycol and propylene glycol. 1.4 HOW CAN ETHYLENE GLYCOL/PROPYLENE GLYCOL ENTER AND LEAVE MY BODY? Ethylene glycol or propylene glycol can enter your bloodstream if you breathe air containing vapors from either compound. Both compounds can also enter your bloodstream through your skin if you come in direct contact with them. If you eat products that contain propylene glycol, it may enter your bloodstream. Exposure of the general population to ethylene glycol is limited to people who perform automotive maintenance or are using photographic developing solutions. Most of the ethylene glycol intoxication in humans and animals occur due to ingestion of improperly stored or disposed antifreeze solutions. Many of the humans exposed to ethylene glycol are exposed in their workplace or while changing *** DRAFT FOR PUBLIC COMMENT *** 3 1. PUBLIC HEALTH STATEMENT antifreeze, brake fluids, or coolants in their cars. However, other humans can accidentally be exposed when such products are not properly disposed. Exposure of the general population to propylene glycol is more likely since many foods, drugs, and cosmetics contain it. Studies in humans and animals show that ethylene glycol enters the body quickly and breaks down very quickly. These studies have shown that ethylene glycol is no longer found in urine or body tissues 48 hours after exposure. Propylene glycol breaks down at about the same rate as ethylene glycol. However, studies in humans and animals show that if you have repeated exposures to propylene glycol over a short time period, you may develop a sensitivity to it. 1.5 HOW CAN ETHYLENE GLYCOL/PROPYLENE GLYCOL AFFECT MY HEALTH? Exposure to ethylene glycol can remove water from the tissues in your body and cause loss of body water in the form of urine. If you drink ethylene glycol, within a few hours it will spread evenly throughout your body. Within 24-48 hours of drinking ethylene glycol, much of the compound will be excreted unchanged in the urine and the rest will completely break down and will no longer be detectable in your body as ethylene glycol. When ethylene glycol breaks down in the body, it forms chemicals that crystallize and that can collect in your body and prevent your kidneys from working. Death can occur after swallowing even a small amount of ethylene glycol. Additional studies show that effects in animals are very similar to those that occur in humans after swallowing ethylene glycol. Exposure to propylene glycol can also remove water from the tissues of your body. Propylene glycol breaks down at the same rate as ethylene glycol, although it does not form harmful crystals when it breaks down. If you are constantly exposed to propylene glycol, it may build up in your body and may leave your body in the urine without breaking down at all. Frequent skin exposure to propylene glycol can cause irritation to the skin. 1.6 IS THERE A MEDICAL TEST TO DETERMINE WHETHER | HAVE BEEN EXPOSED TO ETHYLENE GLYCOL/PROPYLENE GLYCOL? There are tests available to determine if you have been exposed to ethylene glycol or propylene glycol. These tests are only used on people who are showing symptoms of ethylene glycol poisoning (but could be used in other situations). Recently, tests have been developed that can detect ethylene glycol in blood in 30 minutes. Since both ethylene glycol and propylene glycol break down very quickly in the body, they are very difficult to detect even though the symptoms may be present. Refer to Chapters 2 and 6 for more information on these tests. *** DRAFT FOR PUBLIC COMMENT *** 4 1. PUBLIC HEALTH STATEMENT 1.7 WHAT RECOMMENDATIONS HAS THE FEDERAL GOVERNMENT MADE TO PROTECT HUMAN HEALTH? The government has developed regulations and guidelines for ethylene glycol and propylene glycol. These are designed to protect the public from potential adverse health ettects. The Occupational Safety and Health Administration (OSHA) regulates levels of ethylene glycol in the workplace. The maximum allowable amount of ethylene glycol in workroom air is 125 mg/m’. The average acceptable dietary intake of propylene glycol is about 23 mg of propylene glycol for every kilogram (kg) of body weight. More information on the regulations and guidelines that apply to ethylene glycol and propylene glycol is available in Chapter 7. 1.8 WHERE CAN | GET MORE INFORMATION? If you have any more questions or concerns, please contact your community or state health or environmental quality department or: Agency for Toxic Substances and Disease Registry Division of Toxicology 1600 Clifton Road NE, E-29 Atlanta, Georgia 30333 This agency can also provide you with information on the location of the nearest occupational and environmental health clinic. These clinics specialize in the recognition, evaluation, and treatment of illnesses resulting from exposure to hazardous substances. *** DRAFT FOR PUBLIC COMMENT *** 2. HEALTH EFFECTS 2.1 INTRODUCTION The primary purpose of this chapter is to provide public health officials, physicians, toxicologists, and other interested individuals and groups with an overall perspective of the toxicology of ethylene glycol/propylene glycol and a depiction of significant exposure levels associated with various adverse health effects. It contains descriptions and evaluations of studies and presents levels of significant exposure for ethylene glycol/propylene glycol based on toxicological studies and epidemiological investigations. 2.2 RELEVANCE TO PUBLIC HEALTH Levels of significant exposure for each route and duration are presented in tables and illustrated in figures. The points in the figures showing no-observed-adverse-effect levels (NOAELSs) or lowest-observed-adverse- effect levels (LOAELS) reflect the actual doses (levels of exposure) used in the studies. LOAELs have been classified into "less serious" or "serious" effects. These distinctions are intended to help the users of this document identify the levels of exposure at which adverse health effects start to appear. They should also help to determine whether or not the effects vary with dose and/or duration, and place into perspective the possible significance of these differences to human health. The general population is likely to be exposed to both ethylene glycol and propylene glycol. The most frequent use of ethylene glycol is as antifreeze and deicer. Ethylene glycol is also used in polishes, cosmetics, hydraulic fluids, fat exchangers, solvents, color film processing solutions, and chemical intermediates (Wiener and Richardson 1988). Propylene glycol is also widely used and considered safe in commercial formulations of foods, drugs, and cosmetics (Morshed et al. 1988). Of the two glycols, ethylene glycol exhibits a much higher degree of toxicity than propylene glycol. Oral exposure to ethylene glycol and dermal exposure to propylene glycol are the two most likely exposure routes for these two glycols. The review of the literature focused on information generated in humans because the stages in oral ethylene glycol poisoning are well understood and documented, the knowledge of ethylene glycol metabolism is such that it permits successful treatment of ethylene glycol intoxication, and substantial information concerning pathology and pathophysiology of the organ systems involved is available. Although the majority of the studies in humans represent descriptions of case studies, they have been collected for a period of over 60 years. Animal studies corroborate human findings and were used to provide quantitative data to support observations made in humans. Propylene glycol induces substantially fewer adverse effects in humans than does ethylene glycol. Information on the effects that occur in humans after exposure to ethylene glycol and propylene glycol comes from case studies of accidental or intentional poisoning, and from studies of workers that are occupationally exposed in the manufacture of the two glycols. ETHYLENE GLYCOL Ethylene glycol is a colorless, odorless, water-soluble liquid with a sweet taste, most commonly used as an antifreeze fluid. The ready availability of antifreeze mixtures makes ethylene glycol intoxication a significant medical and veterinary problem. Antifreeze mixtures contain up to 95% ethylene glycol (Mallya et al. 1986; Siew et al. 1975a). The exposure route most commonly associated with adverse effects is oral ingestion. There are three stages of ethylene glycol toxicity in humans. They are well documented and occur within 72 hours after ingestion (Robinson and McCoy 1989; Vale 1979). The first stage involves central nervous system depression, metabolic changes, gastrointestinal upset, and spans the period of 30 minutes to 12 hours. During the second stage of ethylene glycol toxicity (12-24 hours after ingestion), the cardiopulmonary *** DRAFT FOR PUBLIC COMMENT *** 6 2. HEALTH EFFECTS symptoms (tachypnea, hyperpnea, and tachycardia) and severe serum hyperosmolarity become evident. These symptoms are largely due to metabolic acidosis. Renal involvement becomes evident during stage three which covers the period of 24-72 hours after ethylene glycol ingestion and is characterized by flank pain and polyuria. The histolopathological findings show renal tubular necrosis and deposition of calcium oxalate crystals (Vale 1979). One study defines the fourth stage as the late cerebral stage that occurs 6-13 days after ethylene glycol ingestion (Chung and Tuso 1989). The above-mentioned toxic effects will be discussed in detail below in the discussion of systemic effects. Once ingested, ethylene glycol is rapidly absorbed and evenly distributed throughout the body reaching peak blood levels 1-4 hours after ingestion (Winek et al. 1978). Approximately 24-48 hours later, it is difficult to detect ethylene glycol in either urine or tissues (Winek et al. 1978) indicating its relatively rapid biotransformation. The approximate serum half-life of ethylene glycol is 2.5 hours for children (Rothman et al. 1986), and 2.7 hours for adults during hemodialysis (Cheng et al. 1987). In untreated adults, the serum half-life has been estimated to be between 3.0 and 8.4 hours (Jacobsen et al. 1988; Peterson et al. 1981). Mechanism of Action. The mechanism of action of ethylene glycol can be best explained by describing the main effects that follow its ingestion: increased osmolal gap, metabolic acidosis, and formation of calcium oxalate crystals. The elucidation of ethylene glycol metabolism (Figure 2-1) can also help in the understanding of its mechanism of action. In the initial stages after the ingestion of ethylene glycol, its concentration in extracellular fluids increases leading to increased osmolality. This increased osmolality (hyperosmolarity) further leads to an increased osmolal gap, one of the hallmarks of ethylene glycol intoxication. Osmolal gap is defined as a difference between the measured and calculated osmolality. Serum osmolality (calculated) can be estimated from the formula that takes into account the concentrations of sodium, glucose, and blood urea nitrogen (BUN). This calculated osmolality is then compared to the osmolality measured following ethylene glycol ingestion, and if it is greater than 10 it indicates an increased osmolal gap (Fligner et al. 1985). The increased osmolal gap is not solely characteristic of ethylene glycol intoxication and can occur when there is a sufficient increase in serum osmolality. The second characteristic of ethylene glycol intoxication is metabolic acidosis. Ethylene glycol itself has low toxicity (Godolphin et al. 1980; Jacobsen and McMartin 1986), but it is metabolized to a variety of toxic metabolites such as glycolaldehyde, glycolic acid (glycolate), glyoxalic acid (glyoxylate), and oxalic acid (oxalate) (Jacobsen et al. 1988; Parry and Wallach 1974; Vale 1979; Wiener and Richardson 1988). In general, the accumulation of acids leads to acidosis, a state that is characterized by actual or relative decrease of alkali in body fluids in relation to the acid content. In the case of ethylene glycol, metabolic processes that follow ethylene glycol intoxication lead to the accumulation of glycolic and lactic acids resulting in metabolic acidosis. The assumption that ethylene glycol toxicity is due to its metabolic products is made because there is a latent period before the symptoms of acidosis appear, because there is no correlation between observed toxicity and ethylene glycol blood concentration, and because inhibition of oxidation prevents toxicity (Jacobsen and McMartin 1986). Furthermore, glycolic acid is the most abundant of all ethylene glycol metabolites (Jacobsen et al. 1984). Following ingestion of high doses of ethylene glycol glycolic acid tends to accumulate because it is a substrate for lactic dehydrogenase and/or glycolic acid oxidase. The metabolism of ethylene glycol is shown in Figure 2-1. Solid arrows represent the steps that are quantitatively most important while the broken arrows indicate minor metabolic conversions in humans. Knowledge of ethylene glycol metabolism helps one understand its mechanism of action, the pathogenesis of its toxicity, and the rationale for treatment of acute ethylene glycol intoxication. This knowledge comes from studies investigating oxidative biodegradation of ethylene glycol. *** DRAFT FOR PUBLIC COMMENT *** 7 2. HEALTH EFFECTS FIGURE 2-1. Metabolic Pathway for Oxidation of Ethylene Glycol* HO-CH,-CH,-OH adie Ethylene glycol Alcohol dehydrogenase J HO-CH,-C - a > ~ Syl Sa Citric / cycle Tso ~ 0, 0 Aldehyde C-C cencrogerase PL HO-CH,- 2 0 . Ml Glycolic a L’ v eon ~ = #00; 7’ ” ormate wt 2° o OH et - CoH CH, cence Oy RP ar” HO” 2 4 “OH H” “OH” o Gdé6-15 fetuses) 7 5000 (reduced litter 3 size; increased Bo) implantation hl loss) C 0 Oo 28 Mouse (GW) 10d 750 (9.45% reduced fetal 750 (increased skel- Price et al. a 1x/d body weight) etal malformations 1985 2 Gdé6- 15 in fetuses) 2 z Reproductive b4 29 Rat (F) Gd6-15 1000 Maronpot et al. * 1983 INTERMEDIATE EXPOSURE Death 30 Rat (F) 13wks 5000 (death in 4/10 Melnick 1984 males) Systemic 3 Rat (F) Renal 1000 (mild focal inter- DePass et al. stitial nephrit- 1986b is) Other 1000 32 Rat (F) 13uwks Renal 1250 2500 (oxalate nephrosis, Melnick 1984 renal failure) Other 2500 (13% decrease in body weight) St xxx INSJWWOD OIN8Nd HOS L4VHA xxx TABLE 2-2. Levels of Significant Exposure to Ethylene Glycol - Oral (continued) LOAEL (effect) S103443 HILTV3H 2 Exposure Key to duration/ NOAEL Less serious Serious figure” Species Route frequency System (mg/kg/day) (mg/kg/day) (mg/kg/day) Reference 33 Mouse (F) 13wks Hemato 5000 Melnick 1984 Hepatic 1250 2500 (hyaline degener- ation of centrilob- ular hepatocytes) Renal 1250 2500 (mild nephrosis) 34 Mouse (F) 13 wks Hemato 6500 NTP 1992 1 x/d Hepatic 3250 (hyaline degener- ation of centrilob- ular hepatocytes) Renal 3250 (tubular dilation, vacuolation, degenerative hy- perplasia) Other 1625 (7.2% lower body weight in males) Neurological 35 Rat (F) 13wks 5000 (calcium oxalate Melnick 1984 deposits in brain blood vessel walls) Reproductive 36 Rat (F) 1000 DePass et al. 1986b CHRONIC EXPOSURE Death 37 Rat (F) 12mo 1000 (26/26 males died DePass et al. by month 16) 1986a ol »xv INSWWNOD 018Nd HOH 14VHA sux TABLE 2-2. Levels of Significant Exposure to Ethylene Glycol - Oral (continued) Exposure LOAEL (effect) Key to duration/ NOAEL Less serious Serious figure® Species Route frequency System (mg/kg/day) (mg/kg/day) (mg/kg/day) Reference Systemic 38 Rat (F) 12mo Resp 1000 DePass et al. Gastro 1000 1986a Hemato 200 1000 (decreased hemato- crit) Hepatic 1000 (fatty metamorpho- sis) Renal 200° 1000 (oxalate nephrosis in males) 39 Mouse (F) 12mo Resp 1000 DePass et al. Cardio 1000 1986a Gastro 1000 Musc/skel 1000 Hepatic 1000 Renal 1000 40 Mouse (F) 2yrs Resp 6500 (pulmonary arter- NTP 1992 1 x/d ial medial hy- perplasia) Hepatic 6500 (hyaline degener- ation of centrilob- ular hepatocytes) Other 6500 41 Mouse (F) 2yrs Hepatic 1625 (hyaline degenera- NTP 1992 1 x/d ation of centrilob- ular hepatocytes) . Renal 3315 (oxalate nephrosis, urethra oxalate deposits) S103443 H1TV3H 2 Lb x»» INJWWOD 21M8Nd HOH L4VHA xxx TABLE 2-2. Levels of Significant Exposure to Ethylene Glycol - Oral (continued) Exposure LOAEL (effect) Key to duration/ NOAEL Less serious Serious figure’ Species Route frequency System (mg/kg/day) (mg/kg/day) (mg/kg/day) Reference Reproductive 42 Rat (F) 24mo 1000 DePass et al. 1986a 43 Mouse (F) 24mo 1000 DePass et al. 1986a “The number corresponds to entries in Figure 2-3. ®Used to derive a chronic oral Minimum Risk Level (MRL) of 2 mg/kg/day; administered dose (200 mg/kg/day) divided by an uncertainty factor of 100 (10 for extrapolation from animals to humans, and 10 for human variability). Cardio = cardiovascular; CNS = central nervous system; d = day(s); (F) = feed; (G) = gavage; Gastro = gastrointestinal; Gd = gestation days; (GW) = gavage in water; Hemato = hematological; hr = hour; LOAEL = lowest-observed-adverse-effect level; mo = month(s); Musc/skel = musculoskeletal; NOAEL = no-observed-adverse-effect level; Resp = respiratory; (W) = drinking water; wk = week(s); x = time(s); yr = years S103443 HLTV3H 2 81 xxx INFJWWOO OIN8Nd HOH 14VHA xxx FIGURE 2-3. Levels of Significant Exposure to Ethylene Glycol - Oral ACUTE (<14 Days) Systemic ¢ & 9 > & ; Bs & & & © & & & > & S$ > N s& $ 3 & & Ey & &F & 5 & &£ > & PF ® F Ff $F 365 Days) Systemic $ > > & S&F $F & © & & & A FJ » s & gh) & & & & ¥» E € &° & 100,000 - 10,000 @ 40m (¢ JT O4om @4m Q41m 1,000 @37r Qam Qs Q3m Q3amQO38 Pas Q3m Qazom @3sr Q3m @a3sr Q43m Q42r Ose Ose ' ! 100 L ~~ Key c Ca @ LOAEL for serious effects (animals) . d Dog 0 LOAEL for less serious effects (animals) Minimal risk level for m Mouse O NOAEL (snimehs) ) effects other than cancer r Ru A LOAEL for serious effects (humans) ~ A LOAEL for less serious effects (humans) The number next to each point corresponds to entries in Table 2-2. S103443 H1TVaH 2 (4 22 2. HEALTH EFFECTS The hematological parameters--white blood cells, red blood cells, hematocrit, and hemoglobin--were not affected in mice after acute oral ethylene glycol treatment, but hypocellularity and suppression of colony forming units were quite evident at a dose of 1,000 mg/kg/day (Hong et al. 1988). Male Fischer-344 rats treated with 1,000 mg/kg/day of ethylene glycol orally for 2 years had a reduced erythrocyte count, reduced hematocrit, and reduced hemoglobin (De Pass et al. 1986a). The information on ethylene glycol levels in bodily fluids has been scarce until recently because gas chromatography, which is most often used for ethylene glycol determination (see Chapter 6 for details), has not always been available to an emergency department physician. In general, ethylene glycol blood levels show no direct correlation with degree of toxicity (Jacobsen and McMartin 1986). Values in case reports have varied from 14.5 mg/dL (Underwood and Bennett 1973) to 650 mg/dL (Peterson et al. 1981). The great variation results from differences in the amounts of ethylene glycol consumed and in the times between ingestion and blood sampling. Because of the availability of ethylene glycol, accidental ingestion can occur and lead to adverse blood chemistry changes. However, such effects are unlikely to occur in populations living near hazardous waste sites since the ethylene glycol concentration necessary to cause such adverse effects is relatively high. Hepatic Effects. Studies in humans addressing whether adverse hepatic effects occur as a result of exposure to ethylene glycol have not been located. In mice exposed to an oral dose of 1,000 mg/kg of ethylene glycol, histopathology did not reveal any liver changes 1, 5, or 14 days after treatment (Hong et al. 1988). However, fatty change of the liver was seen in female Fischer-344 rats fed 200 and 1,000 mg/kg/day of ethylene glycol for 2 years (De Pass et al. 1986a). Although ethylene glycol is relatively quickly absorbed after ingestion and evenly distributed throughout the body, the liver is the main site of its oxidative degradation. Any impact on liver function after short-term exposure to ethylene glycol is expected to be quite minor. It is therefore reasonable to assume that liver function may be affected after exposure to ethylene glycol. Renal Effects. Adverse renal effects after ethylene glycol ingestion in humans can be observed during the third stage of ethylene glycol toxicity, 24-72 hours after acute exposure. The hallmark of renal toxicity is the presence of birefringent calcium oxalate monohydrate crystals deposited in renal tubules and their presence in urine after ingestion of relatively high amounts of ethylene glycol (Chung and Tuso 1989; Factor and Lava 1987; Godolphin et al. 1980; Heckerling 1987; MMWR 1987; Parry and Wallach 1974; Rothman et al. 1986; Siew et al. 1975a; Underwood and Bennett 1973). In addition to birefringent oxalate crystals in the tubular lumens other signs of nephrotoxicity can include focal tubular cell degeneration, atrophy, and tubular interstitial inflammation (Factor and Lava 1987). In a case study of a 38-year-old female who consumed 240 mL of antifreeze (3,454 mg ethylene glycol/kg/day), crystalluria was not present upon admission (about 12 hours after ingestion). Within 5 hours, excretion of calcium oxalate dihydrate crystals was evident, although monohydrate crystals became the primary form in the urine thereafter (2-3 hours) (Jacobsen et al. 1988). The presence of ethylene glycol metabolites--oxalic and glycolic acids--also contributes to nephrotoxicity. In the course of ethylene glycol intoxication, serum creatinine (Factor and Lava 1987; Spillane et al. 1991) and serum BUN (Chung and Tuso 1989; Factor and Lava 1987) levels may be increased. If untreated, the degree of renal damage caused by ethylene glycol progresses and leads to hematuria (MMWR 1987; Rothman et al. 1986; Underwood and Bennett 1973), proteinuria (Rothman et al. 1986), decreased renal function, anuria (Mallya et al. 1986; Parry and Wallach 1974; Spillane et al. 1991; Zeiss et al. 1989), and ultimately renal failure (Chung and Tuso 1989). These changes in the kidney are accompanied by acute tubular necrosis (Factor and Lava 1987), but normal or near normal renal function can return with adequate supportive therapy (Parry and Wallach 1974). In the majority of cases, the most effective therapy consists of hemodialysis and administration *** DRAFT FOR PUBLIC COMMENT *** 23 2. HEALTH EFFECTS of ethanol as a substrate competitor of ethylene glycol for oxidative enzymes which would decrease the formation of toxic metabolites. Similar observation of renal damage leading to oliguria and renal failure occurred in dogs (Beckett and Shields 1971) and cats (Penumarthy and Oehme 1975) after a single oral exposure to 4,880 mg/kg and 4,440 mg/kg of ethylene glycol, respectively. In monkeys receiving ethylene glycol in drinking water (0.25-10% for 6-13 days), five of seven animals given doses greater than 1,388 mg/kg/day had calcium oxalate crystals and evidence of necrosis in the kidney (Roberts and Siebold 1969). In dogs given a dose of 1,000-1,360 mg/kg/day, there were no increases in serum BUN or creatinine, suggesting normal renal function (Hewlett et al. 1989). In another study, no histopathological changes were observed in kidneys of mice after acute oral exposure to 1,000 mg/kg of ethylene glycol (Hong et al. 1988). These findings indicate that there may be dose-response. differences in the renal effects of ethylene glycol exposure. The results also show that the relationship between oxalate crystals in the kidney and nephrotoxicity is not causal, although the formation of oxalate crystals greatly contributes to renal toxicity. It seems reasonable to conclude from these studies that acute human exposure to relatively high doses of ethylene glycol leads to renal toxicity, but chronic exposure to low levels typically found in the vicinity of hazardous waste sites poses little risk of renal toxicity. A chronic-duration oral MRL of 2 mg/kg/day was derived from a NOAEL value of 200 mg/kg/day for the renal effects in rats (DePass et al. 1986a). The MRL was obtained by dividing the NOAEL value by 100 (10 for extrapolation from animals to humans, and 10 for human variability). No other data in support of this MRL were found. Metabolic Effects. One of the major adverse effects following acute oral exposure of humans to ethylene glycol concerns metabolic changes. These changes occur as early as 12 hours after ethylene glycol exposure. Ethylene glycol intoxication at doses as low as 1,628 mg/kg/day is accompanied by metabolic acidosis which is manifested by decreased pH and bicarbonate content in serum and other bodily fluids caused by accumulation of excess glycolic acid (Berger and Ayzar 1981; Cheng et al. 1987; Chung and Tuso 1989, Heckerling 1987; Jacobsen et al. 1988; MMWR 1987; Parry and Wallach 1974; Siew et al. 1975a; Zeiss et al. 1989). There is an inverse relationship between the decreasing plasma pH and increasing plasma glycolic acid concentrations (Clay and Murphy 1977). The normal level of bicarbonate of 24 mmol/L can be depleted in cases of severe ethylene glycol intoxication to reach as low as 2 mmol/L (Jacobsen et al. 1984). This decrease in base concentration indicates that a similar quantity of acid has to be present to achieve such a depletion. Glycolic acid is the only acidic metabolite present in such quantities since humans highly intoxicated with ethylene glycol had glycolate concentrations from 17 to 29 mmol and <1 mmol of glyoxalate and oxalate (Jacobsen et al. 1984). Similar observations were made in animals. Metabolic acidosis due to glycolate accumulation was observed after acute oral exposure of dogs to 1,000-1,360 mg/kg of ethylene glycol (Hewlett et al. 1989), of rats to 1,000 mg/kg (Marshall 1982), and of monkeys to 3,000 mg/kg (Clay and Murphy 1977). These results indicate that glycolic acid is the major toxic metabolite causing metabolic acidosis and that its high serum levels are responsible for systemic toxicity after ethylene glycol exposure. Other characteristic metabolic effects of ethylene glycol poisoning are increased serum anion gap, increased osmolal gap, and hypocalcemia. Serum anion gap is calculated from concentrations of sodium, chloride, and bicarbonate and is elevated after ethylene glycol ingestion (Chung and Tuso 1989; Factor and Lava 1987, Heckerling 1987; Spillane et al. 1991; Zeiss et al. 1989). Osmolal gap represents the difference between the measured and calculated osmolalities and is also elevated during ethylene glycol intoxication. The amount of ethylene glycol causing these effects ranged from 1,628 to 12,840 mg/kg/day (Chung and Tuso 1989; Heckerling 1987; Spillane et al. 1991). The normal value for osmolal gap in humans is less than 10 (Fligner et al. 1985). *** DRAFT FOR PUBLIC COMMENT *** 24 2. HEALTH EFFECTS Hypocalcemia occurs when oxalate chelates with calcium ions forming insoluble calcium oxalate monohydrate crystals. This affects the overall ion concentration and can lead to an imbalance of divalent ion concentrations (Zeiss et al. 1989). Immunological Effects. No studies were located specifically addressing adverse immunological effects in humans or animals after inhalation exposure to ethylene glycol. Conflicting data were found regarding white blood cell counts, which were normal (Underwood and Bennett 1973) or elevated (Spillane et al. 1991) in two cases of oral ethylene glycol intoxication in humans. However, after intermediate inhalation exposure of 20 volunteers to 31 mg/m? ethylene glycol (range: 3-67 mg/m’; median: 30 mg/m3 mean: 31 mg/m? standard deviation: 11), no significant alterations in lymphocyte or monocyte counts were noted (Wills et al. 1974). The same observation was made in mice after acute oral exposure to ethylene glycol at 1,000 mg/kg (Hong et al. 1988). An increased neutrophil count was present in male but not female Fischer 344 rats orally exposed to 1,000 mg/kg/day of ethylene glycol for 2 years (DePass et al. 1986a). Currently, there is no evidence that acute exposure to high concentrations of ethylene glycol adversely affects immunological functions. Intermediate exposure to low concentrations of ethylene glycol possibly present in the vicinity of hazardous waste sites is not likely to produce adverse immunological effects in populations residing in the area. Neurological Effects. Adverse neurological reactions are among the first symptoms to appear in humans after ethylene glycol ingestion. These early neurotoxic effects are also the only symptoms attributed directly to ethylene glycol. Together with metabolic changes, they occur during the period of 30 minutes to 12 hours after exposure and are considered to be part of the first stage in ethylene glycol intoxication (Robinson and McCoy 1989; Vale 1979). In cases of acute intoxication, in which a large amount of ethylene glycol is ingested over a very short time period, there is a progression of neurological manifestations which, if not treated, may lead to convulsions and coma (Zeiss et al. 1989). Ataxia, slurred speech, and somnolence are common during the initial phase of ethylene glycol intoxication (MMWR 1987; Parry and Wallach 1974; Zeiss et al. 1989), as are irritation, restlessness, and disorientation (Cheng et al. 1987; Factor and Lava 1987; Rothman et al. 1986). In a fatal case of ethylene glycol poisoning, a 22-year-old man was admitted to the hospital in a state of stupor 6 hours after ingesting 4,071 mg/kg of ethylene glycol. He vomited several times prior to admission, lost consciousness, and became comatose (Siew et al. 1975a). Crystalline deposits of calcium oxalate in the walls of small blood vessels in the brain were found at autopsy in a man who died after acute ethylene glycol poisoning (Zeiss et al. 1989). Other neurological symptoms commonly encountered in cases of acute exposure to ethylene glycol are semiconsciousness (Underwood and Bennett 1973) and unresponsiveness (Chung and Tuso 1989; Spillane et al. 1991). More recently, several case reports described neurological symptoms associated with adverse effects of ethylene glycol on cranial nerves. These neurotoxic manifestations appear much later and according to some investigators constitute a fourth, late cerebral phase in ethylene glycol intoxication (Chung and Tuso 1989). Facial paralysis and bilateral optic nerve dysfunction were noted in a patient 13 days after ethylene glycol ingestion (Factor and Lava 1987). Delay in treatment may have contributed to the development of these symptoms; the patient was not treated until 3 days after ingesting ethylene glycol. Severe cranial nerve dysfunction including nerves VII, IX, and X was noted in a man 5 days after he ingested 12,840 mg/kg of ethylene glycol (Spillane et al. 1991). In another case of ethylene glycol poisoning, bilateral facial paralysis and peripheral neurosensory hearing loss were observed in a patient 18 days after ingestion of 2,714 mg/kg of ethylene glycol; this effect was only partially reversible (Mallya et al. 1986). Ethylene glycol neurotoxicity was also observed in cats given 4,440 mg/kg by gavage (Penumarthy and Oehme 1975). Neurological symptoms included abnormal gait, loss of reflexes, central nervous system depression (symptoms not specified), and convulsions. Similar signs of neurotoxicity were found in dogs after oral exposure to 4,880 mg/kg ethylene glycol (Beckett and Shields 1971). *** DRAFT FOR PUBLIC COMMENT *** 25 2. HEALTH EFFECTS Although the mechanism of ethylene glycol neurotoxicity is not completely understood, the available information in humans suggest that it occurs in two stages, an early one (30 minutes to 12 hours after exposure) and a late one (several days after exposure). The early stage symptoms are due to the direct toxicity of ethylene glycol, while the late stage neurotoxicity is due to metabolic acidosis caused by the accumulation of ethylene glycol metabolites, primarily glycolic acid. The evidence for this late neurotoxicity are crystalline deposits of calcium oxalate in the walls of small blood vessels found in the brain of the man who died of acute ethylene glycol poisoning (Zeiss et al. 1989). The role of calcium in ethylene glycol induced neurotoxicity is not known but the formation of calcium oxalate crystals may cause perturbation of intracellular calcium homeostasis causing membrane abnormalities generally associated with cell injury and cell death. Developmental Effects. Studies in humans have not addressed whether adverse developmental effects occur as a result of exposure to ethylene glycol. Dietary exposure of pregnant Fischer-344 rats to ethylene glycol (40-1,000 mg/kg/day) did not affect total implantation, fetal length, fetal weight, or litter size (Maronopot et al. 1983). Vertebral malformations and rib alterations were present in both treated and control animals, but ethylene glycol did not increase the incidence of these malformations. However, there were statistically significant increases in the incidences of poorly ossified and nonossified vertebral centers in fetuses of dams receiving 1,000 mg/kg/day of ethylene glycol; the authors did not consider these to be major malformations. These plus a number of external malformations were seen in Sprague-Dawley-derived rats and mice (Price et al. 1985) treated orally with doses up to 5,000 and 3,000 mg/kg/day, respectively, of ethylene glycol. The percentage of malformed live fetuses per litter and/or the percentage of litters with malformed fetuses were significantly elevated in all groups treated with ethylene glycol (Price et al. 1985). Although a NOAEL was not seen, there is insufficient evidence to suggest that exposure of pregnant women to ethylene glycol near hazardous waste sites may cause birth defects. Reproductive Effects. Studies in humans have not addressed whether adverse reproductive effects occur as a result of exposure to ethylene glycol. Results from a study done in mice are inconclusive. Histopathology done on testes from mice treated with 200, 400, and 1,000 mg/kg of ethylene glycol revealed marked loss of spermatogenic epithelium in a portion of the seminiferous tubules (Hong et al. 1988). The study does not indicate if one or all three doses of ethylene glycol induced this adverse effect. This effect was restricted to spermatogenic cells and did not involve Sertoli or interstitial cells. In a continuous breeding study done in CD-1 mice (Lamb et al. 1985), intermediate exposure to 1% ethylene glycol in drinking water slightly decreased the fertility of the exposed parental and F; generations. On the basis of these reports, the possibility of an adverse effect on fertility in males exposed to sufficiently high levels of ethylene glycol is likely. However, exposures expected in hazardous waste site areas are expected to pose minimal risk. Genotoxic Effects. Studies in humans did not address whether adverse genotoxic effects occur as a result of exposure to ethylene glycol. In Fischer-344 rats that received oral doses of 40, 200, and 1,000 mg/kg/day for three generations, there were no dominant lethal mutations or reproductive abnormalities (DePass et al. 1986b). The in vitro mutagenicity studies in Salmonella typhimurium gave uniformly negative results (Clark et al. 1979; McCann et al. 1975; Pfeiffer and Dunkelberg 1980; Zeiger et al. 1987). No growth inhibition due to deoxyribonucleic acid (DNA) damage by ethylene glycol was observed in a battery of Escherichia coli repair- deficient strains (McCarroll et al. 1981). Negative results were also obtained in two sets of studies when ethylene glycol was tested for gene mutation in the yeast, Schizosaccharomyces pombe (Abbondandolo et al. 1980), and for aneuploidy induction in the fungus, Neurospora crassa (Griffiths 1979, 1981). Because of the information available in humans and animals, it is reasonable to conclude that exposure to ethylene glycol poses minimal risk of causing genotoxic effects in exposed persons (see Tables 2-3 and 2-4). *** DRAFT FOR PUBLIC COMMENT *** xxx INFWWOO OIN8Nd HOH 14VHA xxx TABLE 2-3. Genotoxicity of Ethylene Glycol In Vivo Results With Without Species (test system) End point activation activation Reference Rat (in utero exposure) Dominant lethal NA - DePass et al. 1986b - = negative result; NA = not applicable S103443 H1ITV3H ¢ 92 xxx LINFWWOD O1M8Nd HOH 14VHA xxx TABLE 2-4. Genotoxicity of Ethylene Glycol In Vitro Results With Without Species (test system) End point activation activation Reference Prokaryotic organisms: Salmonella typhimurium Gene mutation - - Clark et al. 1979 Gene mutation - - McCann ct al. 1975 Gene mutation - - Pfeiffer and Dunkcelberg 1980 Gene mutation - - Zeiger ct al. 1987 Escherichia coli DNA damage - - McCarroll et al. 1981 Eukaryotic organisms: Schizosaccharomyces pombe Gene mutation - - Abbondandolo et al. 1980 Aneuploidy induction ~~ - - Griffiths 1979; 1981 Neurospora crassa No data - Griffiths 1979; 1981 S103443 H1TV3H ¢ 22 - = negative result; DNA = deoxyribonucleic acid 28 2. HEALTH EFFECTS Cancer. One epidemiologic study on renal cancer mortality examined the work and health histories of 1,666 employees of a chemical plant and found no elevation in the odds ratio for workers exposed to ethylene glycol (Bond et al. 1985), although the sample size was quite small. In addition, a 2-year oral exposure of mice and rats to 40, 200, and 1,000 mg/kg/day of ethylene glycol, produced no evidence of an oncogenic effect (De Pass 1986a). Furthermore, a recent 2-year dietary study in mice indicated a lack of carcinogenic effects (NTP 1992). Because of information available, it is reasonable to conclude that exposures to ethylene glycol incurred from waste site sources pose negligible risks of cancer. PROPYLENE GLYCOL Propylene glycol is a colorless, odorless, water-soluble liquid considered safe for use in commercial formulations of foods, drugs, and cosmetics. Propylene glycol is commonly used in the pharmaceutical industry as a solvent for drugs, as a stabilizer for vitamins, and in ointment for medicinal applications. This widespread use of propylene glycol stems from its low level of toxicity. There are two main reasons for that: (1) propylene glycol biodegradation proceeds via lactate to pyruvate in human metabolism, and (2) a significant amount of propylene glycol is excreted unchanged or as glucuronide conjugate via the renal pathway (Hannuksela and Forstrom 1978). It appears that adverse effects in humans and animals occur in two situations, either after acute exposure to very high propylene glycol levels or after prolonged chronic exposure to low levels of propylene glycol. The pharmacokinetic properties of propylene glycol are not completely understood, but absorption from the gastrointestinal tract is fairly rapid. The maximum plasma concentration of propylene glycol in humans is reached within 1 hour after oral exposure, while the elimination half-life is about 4 hours. The total body clearance is about 0.1 L/kg/hour and seems to be serum-concentration dependent (Yu et al. 1985). Dose- dependent elimination is seen in rats, with saturation of the pathways at doses above 5,880 mg/kg (Morshed et al. 1988). Death. No deaths have been reported as a result of exposure to propylene glycol in humans. LDs, values have been reported in rats (range: 22-26 g/kg) and mice (range: 18-20 g/kg) after acute oral exposure to propylene glycol (EPA 1987a). A fatal case of propylene glycol poisoning occurred in a horse given 3.8 L of propylene glycol instead of mineral oil. The horse died of respiratory arrest 28 hours after administration (Dorman and Haschek 1991). The acute oral LD, values of propylene glycol in rats, rabbits, and dogs are approximately 32, 18, and 9 mL/kg, respectively, (Andrews and Snyder 1986) and approximately 27 and 19 in mice and guinea pigs, respectively (EPA 1987a). It is unlikely that sufficient amounts of propylene glycol can be present or ingested near hazardous waste sites to cause death among people living in the area. The highest NOAEL values and all reliable LOAEL values for death in each species and duration category for propylene glycol after inhalation, oral, and dermal exposures are reported in Tables 2-5, 2-6, and 2-7, respectively, and plotted in Figures 2-4 (inhalation) and 2-5 (oral). Systemic Effects The highest NOAEL values and all reliable LOAEL values for systemic effects in each species and duration category for propylene glycol after inhalation, oral, and dermal exposures are reported in Tables 2-5, 2-6, and 2-7, respectively, and plotted in Figures 2-4 (inhalation) and 2-5 (oral). *** DRAFT FOR PUBLIC COMMENT *** xxx INFJWWOO OIN8Nd HOH 14VYHQA xxx TABLE 2-5. Levels of Significant Exposure to Propylene Glycol - Inhalation Exposure Key to duration/ NOAEL figure® Species frequency System (ppm) LOAEL (effect) Less serious (ppm) Serious (ppm) Reference INTERMEDIATE EXPOSURE Systemic 1 Rat 90d Resp 5d/wk 6hr/d Hemato Other 0.1 1.0 2.2 1.0 1.0 (nasal hemorrhag- ing) (increased goblet cells, thicken- ing of nasal respir- atory epithelium) (decreased hemo- globin, white blood cells, and lymphocytes in females) (decreased sorbit- ol dehydrogenase, gamma glutamyl transferase) (decreased kidney and body weight) Suber et al. 1989 ®The number corresponds to entries in Figure 2-4. d = day(s); Hemato = effect level; Resp = respiratory; wk = week(s) hematological; hr = hour(s); LOAEL = lowest-observed-adverse-effect level; NOAEL = no-observed-adverse- S103443 HITV3H 2 nN w 30 2. HEALTH EFFECTS FIGURE 2-4. Levels of Significant Exposure to Propylene Glycol - Inhalation INTERMEDIATE (15-364 Days) Systemic 2 S$ & &° & & wom 2° a 10 = Qr 1.0 p= QD Orr Dir orl Or Key r Rat Qo LOAEL for less serious effects (animals) The number next to each point corresponds to entries in Table 2-5. *** DRAFT FOR PUBLIC COMMENT *** xxx LINIGWNOD O118Nd HOH 14YHA xxx TABLE 2-6. Levels of Significant Exposure to Propylene Glycol - Oral LOAEL (effect) Exposure Key to duration/ NOAEL Less serious Serious figure’ Species Route frequency System (mg/kg/day) (mg/kg/day) (mg/kg/day) Reference ACUTE EXPOSURE Systemic 1 Human 24hr Derm/oc 29 (acute exanthema) Hannuksel la and 1x Forstrom 1978 Neurological 2 Human (W) 3d 1183 (severe mental Yu et al. 1985 2x/d symptoms) 3 Human 24hr 1200 (vertigo, curious Hannuksel la and 1x sensations) Forstrom 1978 4 Human (W) 3d 887 (severe mental Yu et al. 1985 3x/d symptoms) INTERMEDIATE EXPOSURE Systemic 5 Cat (F) 17wks Hemato 6000 (Heinz body Weiss et al. formation) 1990 6 Cat (F) Swks Hemato 1600 (Heinz body Christopher et formation) al. 1989%a Renal 1600 7 Cat (F) 3wks Hemato 8000 (hypercellular Christopher et bone marrow) al. 1989%9a Renal 8000 (polyuria, poly- dipsia) S103443 H1TV3H 2 Le xxx INTGWWOO 0IM8Nd HOH 14VHQA xxx TABLE 2-6. Levels of Significant Exposure to Propylene Glycol - Oral (continued) Exposure LOAEL (effect) Key to duration/ NOAEL Less serious Serious figure Species Route frequency System (mg/kg/day) (mg/kg/day) (mg/kg/day) Reference CHRONIC EXPOSURE Death 8 Rat (F) 2yr 2500 Gaunt et al. 1972 9 Dog (F) 2yr 5000 Weil et al. 1971 Systemic 10 Rat (F) 2yr Resp 2500 Gaunt et al. Cardio 2500 1972 Hemato 2500 Hepatic 2500 Renal 2500 Nn Dog (F) 2yr Hemato 5000 (decreased erythro- Weil et al. 1971 cytes, hemoglobin, hematocrit) Hepatic 5000 Renal 5000 Other 5000 Immunological 12 Dog (F) 2yr 5000 Weil et al. 1971 Neurological 13 Rat (F) 2yr 2500 Gaunt et al. 1972 “The number corresponds to entries in Figure 2-5. Cardio = cardiovascular; CNS = central nervous system; d = day(s); Derm/oc = dermal/ocular; (F) = feed; Hemato = hematological; hr = LOAEL = lowest-observed-adverse-effect level; NOAEL = no-observed-adverse-effect level; Resp = respiratory; (W) = drinking water; wk hour(s); week(s); x = time(s); yr = year(s) S103443 HITV3aH ¢ xxx INFJWWOO 21M8Nd HOS 14VHA xxx FIGURE 2-5. Levels of Significant Exposure to Propylene Glycol - Oral ACUTE INTERMEDIATE CHRONIC (<14 Days) (15-364 Days) (> 365 Days) Systemic Systemic Systemic » D KY 3» A & & & > > & $ & + > > © S (mg/kg/day) & & & & & & & & & & & & & 10,000 ®e Dre Bsc Quod Did O11d O1d Od O12d Qe Qtr Qior O1or Oo O1or Oar A Qsc Otc 3 1,000 A: A 100 |= Al 0 = Key Cat Dog Mouse Rat ~- 3 ao >rOe LOAEL for less serious effects (animals) NOAEL (animals) LOAEL for serious effects (humans) LOAEL for less serious effects (humans) he number next to each point corresponds to entries in Table 2-6. S103443 H1ITV3H ¢ © w TABLE 2-7. Levels of Significant Exposure to Propylene Glycol - Dermal Exposure LOAEL (effect) duration/ NOAEL Less serious Serious Species frequency System (mg/kg/day) (mg/kg/day) (mg/kg/day) Reference ACUTE EXPOSURE Systemic Human 48hrs Derm/oc 50 (skin edema and Kinnunen and 1x erythema) Hannuksela 1989 * > Human 48hr Derm/oc 15 ("basket weave" Willis et al. 0 1x pattern to stratum 1989 2 corneum) J n S 7 5 Human 48hr Derm/oc 15 30 (faint, patchy Willis et al. EF C 1x erythema with 1988 = & edema) m 6 1 0 Human 48hrs Derm/oc 0.2 (erythema and Kinnunen and m 2 1x edema) Hannuksela 1989 0 on = m Human 5d Hemato 6100 Commens 1990 Zz = 1x/d x * Human 70hr Resp 9000 (acute respiratory Fligner et al. >1x/d acidosis) 1985 Cardio 9000 (cardiorespiratory arrest) Metab 9000 (increased osmolal gap) Neurological Human 70hr 9000 (hypoxic encephalo- Fligner et al. >1x/d pathy) 1985 Cardio = cardiovascular; d = day(s); Derm/oc = dermal/ocular; Hemato = hematological; hr = hour(s); LOAEL = level; NOAEL = no-observed-adverse-effect level; Resp = respiratory; x = time(s); yr = year(s) lowest-observed-adverse-effect ve 35 2. HEALTH EFFECTS Respiratory Effects. Acute respiratory acidosis and cardiorespiratory arrest occurred in an 8-month-old infant with second- and third-degree burns after acute dermal treatment with silver sulfadiazine containing a high amount of propylene glycol. The dose of propylene glycol was 9,000 mg/kg/day (Fligner et al. 1985). Serum propylene glycol reached the highest level of 1,059 mg/dL on day 14 causing hyperosmolarity with an osmolal gap of 130 mOsm/kg (Flinger et al. 1985). The normal value for osmolal gap in humans is less than 10 (Fligner et al. 1985). Study results regarding adverse respiratory effects after acute or intermediate inhalation exposure of animals to propylene glycol are inconclusive. The effects of acute inhalation exposure to 10% concentrations ofpropylene glycol for 20 and 120 minutes in rabbits showed an increased number of degenerated goblet cells in tracheal lining (Konradova et al. 1978). However, the observations made in rats after an intermediate inhalation exposure to propylene glycol did not support those findings. Rats who inhaled 1000 mg/m? of propylene glycol over 90 days had thickened respiratory epithelium with enlarged goblet cells (Suber et al. 1989). Nasal hemorrhaging was also present in rats exposed to a lower dose of 100 mg/m> propylene glycol, probably caused by dehydration. These studies do not indicate a basis for concern because comparable exposure conditions do not occur for the general population. Cardiovascular Effects. Very limited and conflicting information is available in humans and animals on cardiovascular effects after exposure to propylene glycol. An 8-month-old infant suffered cardiorespiratory arrest after four dermal exposures to propylene glycol in a silver sulfadiazine medication (Fligner et al. 1985). In animals, however, the heart histopathology of rats after a 2-year oral exposure to 2,500 mg/kg/day of propylene glycol revealed no changes (Gaunt et al. 1972). It appears that acute dermal exposure to very high levels of propylene glycol may cause adverse cardiovascular effects, but it is unlikely that such high levels would be present in the vicinity of hazardous waste sites. Hematological Effects. The clinical course of propylene glycol after acute exposure to sufficient amounts resembles that of acute ethylene glycol because of the similarity in biodegradation processes of the two glycols. Propylene glycol is oxidatively converted to lactic and pyruvic acids which, if present in sufficient amounts, contribute to metabolic acidosis and an increased osmolal gap. However, acidosis from propylene glycol is not as severe as that due to ethylene glycol. In a case of acute propylene glycol poisoning (the amount ingested not specified), the patient developed metabolic acidosis with an the osmolal gap of 51 mmol/kg (reference concentration is <10 mmol/kg) (Lolin et al. 1988). There is a possibility that this patient also ingested a large amount of ethanol since the serum ethanol level was 90 mg/dL. The level of propylene glycol was 400 mg/dL in the serum and 10 mg/dL in urine. To investigate the role of propylene glycol (used as a vehicle) in antipyrine metabolism, 10 healthy volunteers were given 5 mL propylene glycol every 4 hours for 48 hours (total amount of propylene glycol was 55 mL) (Nelson et al. 1987). No adverse effects were observed in any of the subjects. The limitation of this study is that results obtained after acute oral exposure to propylene glycol alone were not communicated; only those obtained after exposure to antipyrine alone, or antipyrine plus propylene glycol, were reported (Nelson et al. 1987). Increased osmolal gap was found in two cases of acute dermal and intravenous exposure to propylene glycol. An 8-month-old infant with a severe burn was topically treated with 9,000 mg/kg/day of propylene glycol used as a vehicle for silver sulfadiazine (Fligner et al. 1985). The osmolal gap reached a maximum of 130 mOsm/kg 14 days after the treatment started, while serum propylene glycol level peaked at 1,059 mg/dL. Another infant developed increased osmolality after being exposed intravenously to propylene glycol used as a vehicle for Enoximone (Huggon et al. 1990). However, in another study of acute dermal propylene glycol exposure of 12 adults to 6,100 mg/kg/day for 5 days, propylene glycol had no effect on either serum osmolality or lactic acid levels (Commens 1990). Increased serum propylene glycol levels, increased lactate, and increased total acid (serum lactate and pyruvate) were also found in a retrospective study of 35 human sera samples and 8 cerebrospinal fluid samples from *** DRAFT FOR PUBLIC COMMENT *** 36 2. HEALTH EFFECTS patients receiving intravenous medications with propylene glycol as the vehicle (Kelner and Baily 1985). The daily dose of propylene glycol ranged from 57 to 771 mg/kg. None of the sera samples were specifically collected for determination of propylene glycol levels; therefore, the time between propylene glycol administration and serum collection varied and was not specified in the report. However, statistically significant correlation was found between the lactate levels in serum and cerebrospinal fluid samples and the corresponding propylene glycol concentrations (Kelner and Baily 1985). Although the results of these studies are not conclusive, it seems that increased lactate levels leading to acidosis and increased osmolality may develop in humans after exposure to high levels of propylene glycol. The results from animal studies indicate that intermediate and chronic exposure to propylene glycol may lead to hemolysis of red blood cells. After intermediate inhalation exposure to 2,200 mg/m” of propylene glycol, female rats had decreased mean corpuscular hemoglobin concentrations and white blood cell counts, while no changes in red blood cells were observed in male rats under the same regimen (Suber et al. 1989). Similar observations were made in cats after intermediate oral exposure to propylene glycol. Increased numbers of Heinz bodies (sign of red blood cell degeneration) were observed in cats exposed to 1,600 and 6,000 mg/kg of propylene glycol for 5 and 17 weeks, respectively (Christopher et al. 1989a; Weiss et al. 1990). These findings are supported by results obtained in dogs after chronic oral exposure to 5,000 mg/kg/day (Weil et al. 1971). Red blood cell hemolysis was evidenced by decreased hemoglobin and hematocrit levels, and decreased total red blood cell counts. In rats, however, there were no changes in any of the hematological parameters after 2 years of chronic oral exposure to 2,500 mg/kg/day propylene glycol (Gaunt et al. 1972). These results indicate that there may be species differences with regard to the effect of propylene glycol on red blood cells. Hypocellularity of the bone marrow was observed in cats after intermediate oral exposure to 8,000 mg/kg/day of propylene glycol (Christopher et al. 1989a). Hepatic Effects. No studies were located addressing whether adverse hepatic effects occur in humans as a result of exposure to propylene glycol. The results from animal studies show that there are no adverse hepatic effects in rats after intermediate inhalation exposure to 2,200 mg/m? of propylene glycol (Suber et al. 1989). A similar observation was made in rats fed a diet containing 2,500 mg/kg/day of propylene glycol for 2 years (Gaunt et al. 1972). Based on these findings, it can be assumed that intermediate and chronic exposures to moderately high levels of propylene glycol will not have adverse hepatic effects in humans. It is not clear if hepatotoxicity would result after an acute exposure to a high level of propylene glycol. Since levels of propylene glycol in the vicinity of a hazardous waste site would probably be low, it is unlikely that adverse hepatic effects would occur in people living in the area. Renal Effects. No studies were located addressing nephrotoxicity in humans as a result of exposure to propylene glycol. Intermediate inhalation exposure of rats to 2,200 mg/m> did not cause adverse renal effects (Suber et al. 1989). The same observation was made in cats fed a diet delivering a dose of 1,600 mg/kg/day of propylene glycol for 5 weeks (Christopher et al. 1989a). In the same study, however, cats exposed to 8,000 mg/kg/day of propylene glycol for 3 weeks developed polyuria, considered a less serious adverse effect. Chronic exposure of both rats and dogs to 2,500 and 5,000 mg/kg/day, respectively, for 2 years, had no nephrotoxic effects in either species (Gaunt et al. 1972; Weil et al. 1971). These results indicate that exposure to low levels of propylene glycol possibly present at hazardous waste sites are not likely cause adverse renal effects in the human population living in the vicinity. Metabolic Effects. In an 8-month-old infant serum propylene glycol reached the highest level of 1,059 mg/dL causing hyperosmolarity with an osmolal gap of 130 mOsm/kg (Fligner et al. 1985). The normal value for osmolal gap in humans is less than 10. The infant had second- and third-degree burns and was treated with silver sulfadiazine containing a high amount of propylene glycol. The dose of propylene glycol was calculated *** DRAFT FOR PUBLIC COMMENT *** 37 2. HEALTH EFFECTS to be 9,000 mg/kg/day. Hyperosmolarity was due to the increased serum concentration of the osmotically active, low-molecular weight propylene glycol in the extracellular fluid. No other details were provided about the infant and its recovery. Immunological Effects. Since propylene glycol is widely used as a vehicle for dermally applied medications, several studies investigated its potential as both an irritant and contact allergen. Skin testing of 42 healthy volunteers showed that 100% propylene glycol caused faint, patchy erythema with edema in 40% of the tested subjects (Willis et al. 1988). In another study, an acute dermal exposure of eczema patients to 0.2 and 22.8 mg/cm? of propylene glycol caused skin edema and erythema in 3.8% of the 823 patients that were skin tested (Kinnunen and Hannuksela 1989). On the basis of the findings from these two studies, the authors concluded that propylene glycol has marginal irritant properties. The mechanism of the reaction is not understood, but electron microscopy revealed that propylene glycol causes hydration of corneal cells producing a characteristic "basket weave" pattern in the stratum corneum (Willis et al. 1989). In order to determine if propylene glycol can also evoke a hypersensitivity reaction, a total of 15 patients who had positive skin reactions to propylene glycol were exposed to an acute oral propylene glycol challenge (Hannuksela and Forstrom 1978). The hypersensitivity reaction that developed consisted of exanthem and cleared within 36-48 hours without any medications. These findings plus a long history of safe use in medicine indicate that prolonged dermal exposure to low levels of propylene glycol present at hazardous waste sites is very unlikely to cause hypersensitivity reactions in the human population living in the vicinity. Neurological Effects. Adverse neurological reactions were observed in patients who tested positive in a propylene glycol patch test after an acute oral challenge with 2-15 mL of propylene glycol (Hannuksela and Forstrom 1978). Although the observed neurotoxicity is attributed to propylene glycol, the study reports that this response was seen in allergic individuals. In a case of acute propylene glycol poisoning, neurotoxic symptoms included stupor and repetitive convulsions (Lolin et al. 1988). The study does not specify the amount of propylene glycol that caused neurotoxicity. Various degrees of propylene glycol neurotoxicity were also observed in a group of 16 outpatients of a neurology clinic after acute oral exposure to 887 mg/kg three times per day for at least 3 days (Yu et al. 1985). Very severe mental symptoms (not specified) were observed in one patient who had the highest overall propylene glycol plasma concentration, although patients with lower plasma propylene glycol levels showed similar neurotoxicity. The estimated half-life of propylene glycol is 3.8 hours. This means that there is a measurable accumulation of propylene glycol if it is ingested in the course of a multiple-dosing regimen (Yu et al. 1985). The limitation of the study is that it does not specify if the observed propylene glycol effects may have been associated with the neurological problems already present in those patients. No animal studies addressing possible neurotoxicity of propylene glycol were located. On the basis of this information, adverse neurological reactions due to exposure to low levels of propylene glycol possibly present at hazardous waste sites are very unlikely. Developmental Effects. Studies in humans or animals have not addressed whether adverse developmental effects can occur as a result of exposure to propylene glycol. Reproductive Effects. Studies in humans or animals have not addressed whether adverse reproductive effects can occur after exposure to propylene glycol. Genotoxic Effects. Studies in humans or animals have not addressed whether adverse genotoxic effects occur after exposure to propylene glycol. Propylene glycol was not mutagenic in Salmonella typhimurium strains TA98, TA100, TA1535, and TA1537 with and without metabolic activation (Pfeiffer and Dunkelberg 1980). *** DRAFT FOR PUBLIC COMMENT *** 38 2. HEALTH EFFECTS Cancer. There is no information regarding carcinogenicity of propylene glycol in humans. In a study of chronic oral exposure of rats to 2,500 mg/kg/day, there were no treatment-related increases in neoplasms (Gaunt et al. 1972). Based on this information, its long history of use in consumer products, and structural activity considerations, it is extremely unlikely that exposure to low levels of propylene glycol near hazardous waste sites would influence the incidence of cancer in the population living in the vicinity. 2.3 BIOMARKERS OF EXPOSURE AND EFFECT Biomarkers are broadly defined as indicators signaling events in biologic systems or samples. They have been classified as markers of exposure, markers of effect, and markers of susceptibility (NAS/NRC 1989). A biomarker of exposure is a xenobiotic substance or its metabolite(s) or the product of an interaction between a xenobiotic agent and some target molecule(s) or cell(s) that is measured within a compartment of an organism (NAS/NRC 1989). The preferred biomarkers of exposure are generally the substance itself or substance-specific metabolites in readily obtainable body fluid(s) or excreta. However, several factors can confound the use and interpretation of biomarkers of exposure. The body burden of a substance may be the result of exposures from more than one source. The substance being measured may be a metabolite of another xenobiotic substance (e.g., high urinary levels of phenol can result from exposure to several different aromatic compounds). Depending on the properties of the substance (e.g., biologic half-life) and environmental conditions (e.g., duration and route of exposure), the substance and all of its metabolites may have left the body by the time biologic samples can be taken. It may be difficult to identify individuals exposed to hazardous substances that are commonly found in body tissues and fluids (e.g., essential mineral nutrients such as copper, zinc, and selenium). Biomarkers of exposure to ethylene glycol/propylene glycol are discussed in Section 2.3.1. Biomarkers of effect are defined as any measurable biochemical, physiologic, or other alteration within an organism that, depending on magnitude, can be recognized as an established or potential health impairment or disease (NAS/NRC 1989). This definition encompasses biochemical or cellular signals of tissue dysfunction (e.g., increased liver enzyme activity or pathologic changes in female genital epithelial cells), as well as physiologic signs of dysfunction such as increased blood pressure or decreased lung capacity. Note that these markers are often not substance specific. They also may not be directly adverse, but can indicate potential health impairment (e.g., DNA adducts). Biomarkers of effects caused by ethylene glycol/propylene glycol are discussed in Section 2.3.2. A biomarker of susceptibility is an indicator of an inherent or acquired limitation of an organism’s ability to respond to the challenge of exposure to a specific xenobiotic substance. It can be an intrinsic genetic or other characteristic or a preexisting disease that results in an increase in absorbed dose, biologically effective dose, or target tissue response. If biomarkers of susceptibility exist, they are discussed in Section 2.5, "Populations That Are Unusually Susceptible." 2.3.1 Biomarkers Used to Identify or Quantify Exposure to Ethylene Glycol or Propylene Glycol Exposure to ethylene glycol and propylene glycol can be measured by determining the levels of ethylene glycol or propylene glycol in the blood. There are two difficulties associated with determining blood levels of these two glycols. The first is that both are absorbed and metabolized fairly rapidly in the body, which means that in most cases they are not present in the blood for more than a few hours after exposures. Second, the involved procedure needed for determination of the two glycols is not always readily available in emergency situations. *** DRAFT FOR PUBLIC COMMENT *** 39 2. HEALTH EFFECTS Presence of ethylene glycol or propylene glycol in the blood would indicate a very recent exposure. In humans, ethylene glycol and propylene glycol have a relatively short half-life in the body (about 3-4 hours) (Winek et al. 1978; Yu et al. 1985), and thus, only exposures that occurred 10-20 half-lives earlier would be detected in the blood. In dogs, the majority of ingested ethylene glycol is excreted unchanged in the urine (Grauer et al. 1984, 1987). Urine ethylene glycol concentrations are higher that serum ethylene glycol concentrations and remain detectable for a longer period. Because both ethylene glycol and propylene glycol are rapidly absorbed and biotransformed in the body, some of their metabolic products may be used to identify exposure to ethylene glycol or propylene glycol. Metabolic acidosis due to increased amounts of lactic acid occurs in cases of intoxication with ethylene glycol and sometimes with propylene glycol (Jacobsen et al. 1984). In cases of exposure to ethylene glycol, there is an increased amount of glycolic acid and a small increase in the amount of oxalic acid, both contributing to metabolic acidosis. As oxalic acid interacts with calcium from the body, it forms calcium oxalate crystals which can be detected in the urine (Jacobsen et al. 1988). Accumulation of glycolic acid primarily accounts for the acidosis of ethylene glycol intoxication; its presence can indicate significant exposure, even when the blood levels are very low (Hewlett et al. 1986; Jacobsen et al. 1984). Both serum glycolic acid and urinary calcium oxalate have been used to identify exposure to ethylene glycol. 2.3.2 Biomarkers Used to Characterize Effects Caused by Ethylene Glycol or Propylene Glycol Adverse neurological reactions that can culminate in convulsions and coma are among the first symptoms in humans after ethylene glycol intoxication (Zeiss et al. 1989). Some of the most common manifestations of ethylene glycol neurotoxicity include ataxia, slurred speech, semiconsciousness, unresponsiveness, and somnolence (Cheng et al. 1987; Chung and Tuso 1989; Factor and Lava 1987, MMWR 1987; Parry and Wallach 1974; Rothman et al. 1986; Spillane et al. 1991; Underwood and Bennett 1973). Several more recent studies described adverse effects of ethylene glycol on cranial nerves; the symptoms appear later and may involve facial paralysis, bilateral optic nerve dysfunction, and peripheral neurosensory hearing loss. The presence of calcium oxalate monohydrate crystals is the hallmark of ethylene glycol intoxication. The crystals can be deposited in renal tubules and/or excreted in urine after exposure to relatively high amounts of ethylene glycol (Chung and Tuso 1989; Factor and Lava 1987; Godolphin et al. 1980; Heckerling 1987; MMWR 1987; Parry and Wallach 1974; Rothman et al. 1986; Siew et al. 1975a; Underwood and Bennett 1973). In some cases, there is a brief period of calcium oxalate dihydrate crystalluria (Jacobsen et al. 1988). Renal toxicity can also be indicated by increased serum levels of BUN or creatinine (Grauer et al. 1987). Respiratory system involvement occurs 12-24 hours after ingestion of ethylene glycol. The symptoms include hyperventilation (Godolphin et al. 1980), shallow rapid breathing (Zeiss et al. 1989), and generalized pulmonary edema (Vale 1979). Cardiovascular system involvement occurs during the second phase of ethylene glycol poisoning, at the same time as the respiratory system involvement. The symptoms are tachycardia, ventricular gallop, and ventricular dilation (Parry and Wallach 1974; Siew et al. 1975a; Vale 1979). As in the case of respiratory effects, cardiovascular involvement occurs after exposure to relatively high levels of ethylene glycol. Both of these types of effects are not specific ethylene glycol intoxication. *** DRAFT FOR PUBLIC COMMENT *** 40 2. HEALTH EFFECTS 2.4 INTERACTIONS WITH OTHER CHEMICALS Information regarding the influence of other chemicals on the toxicity of ethylene glycol comes from case studies describing treatment after accidental or intentional ingestion of ethylene glycol. The toxic effects of ethylene glycol result from its metabolic conversion by alcohol dehydrogenase into glycolic acid which is further metabolized to oxalate. The formation of oxalate crystals is the apparent cause of renal toxicity encountered after exposure to ethylene glycol. Administration of ethanol, 4-methyl pyrazole (also used as antidotes in cases of propylene glycol poisoning), or 1,3-butanediol reduces or eliminates ethylene glycol toxicity. This is accomplished by the following mechanisms: (1) ethanol, which is also metabolized by alcohol dehydrogenase, competes with ethylene glycol, thus preventing the formation of potentially toxic ethylene glycol metabolites; (2) 4-methyl pyrazole inhibits the activity of alcohol dehydrogenase (Baud et al. 1987, 1988); and (3) 1,3-butanediol is also a competitive inhibitor of ethylene glycol biotransformation and reduces the formation of glycolic acid (Hewlett et al. 1983). Therefore, ethanol, 4-methyl pyrazole, and 1,3-butanediol reduce the toxicity of ethylene glycol by interacting with or inhibiting the activity of alcohol dehydrogenase, thus reducing the amount of glycolic acid and oxalate formed. Magnesium and vitamin B6 were found to affect the toxicity of ethylene glycol. Vitamin B6 accelerates the oxidation of glyoxylate to carbon dioxide rather than to oxalate. Therefore, vitamin B6 deficiency can cause inhibition of ethylene glycol’s oxidation to carbon dioxide. Magnesium may prevent renal deposition of calcium oxalate by altering solvent characteristics of urine (Browning 1965). The first step in biotransformation of propylene glycol is catalysis by alcohol dehydrogenase as in the case of ethylene glycol. 4-Methyl pyrazole is considered to be a inhibitor of propylene glycol metabolism (Morshed et al. 1988). As in the case of ethylene glycol, 4-methyl pyrazole reduces potential toxic effects of propylene glycol and acts as an antidote, interfering with the biodegradation of propylene glycol. Review of the literature regarding the interaction and influence of other chemicals on the toxicity of propylene glycol revealed that propylene glycol is often used as a vehicle for administration of certain medications such as Valium, Dilantin, Nembutal (Kelner and Baily 1985), dihydrotachysterol (DHT) (Arulanantham and Genel 1978), Ketoconazole cream (Eun and Kim 1989), and Enoximone (Huggon et al. 1990). Among the observed effects were seizures and cerebral irritability (DHT), increased serum lactate (Valium, Dilantin, and Nembutal), increased serum osmolality (Enoximone), and skin allergy (Ketoconazole cream). All these adverse effects are attributed to propylene glycol and associated with the prolonged administration of these medications using propylene glycol as the vehicle. However, the precise interaction between propylene glycol and these medications was not investigated. In rats, hexobarbital-induced sleeping time was prolonged in the presence of propylene glycol (Dean and Stock 1974), probably because of competition for drug-metabolizing enzymes. 2.5 POPULATIONS THAT ARE UNUSUALLY SUSCEPTIBLE A susceptible population will exhibit a different or enhanced response to ethylene glycol/propylene glycol than will most persons exposed to the same level of ethylene glycol/propylene glycol in the environment. Reasons include genetic make-up, developmental stage, health and nutritional status, and chemical exposure history. These parameters result in decreased function of the detoxification and excretory processes (mainly hepatic and renal) or the pre-existing compromised function of target organs. For these reasons we expect the elderly with declining organ function and the youngest of the population with immature and developing organs will *** DRAFT FOR PUBLIC COMMENT *** 41 2. HEALTH EFFECTS generally be more vulnerable to toxic substances than healthy adults. Populations who are at greater risk due to their unusually high exposure are discussed in Section 5.6, "Populations With Potentially High Exposure." The review of literature regarding toxic effects of ethylene glycol revealed that individuals deficient in vitamin B6 may be more sensitive to toxic effects of ethylene glycol because vitamin B6 may reduce the accumulation of toxic metabolites (Browning 1965). No information was found on populations with unusual sensitivity to propylene glycol. However, populations that may show increased sensitivity include very young children, who have immature hepatic detoxification systems, and individuals with impaired liver or Kidney function. 2.6 ON-GOING STUDIES One on-going study regarding the health effects of ethylene glycol and propylene glycol was reported in the Federal Research in Progress File (FEDRIP 1991) database: "Genetic and Reproductive Toxicity of Ethylene Glycol (Mice)." The principal investigator is William W. Au from the University of Texas at Galveston. Existing information on health effects of ethylene glycol is shown in Figure 2-6, and existing information on the health effects of propylene glycol is shown in Figure 2-7. *** DRAFT FOR PUBLIC COMMENT *** 42 2. HEALTH EFFECTS FIGURE 2-6. Existing Information on Health Effects of Ethylene Glycol SYSTEMIC & & & $S & © ry © o Q SF A > *® & & & & & & £ £ Q W/E O E/ & J & & of Inhalation ® oO ® @ Oral ® 0 ® Dermal ® ® HUMAN SYSTEMIC / / SS & $$ a &/ 2 & & SS S = & & & F/I / SF) /F/ P/E) FP) TF Inhalation Oral oo 000 ® 0/0060 Dermal ANIMAL @ Existing Studies *** DRAFT FOR PUBLIC COMMENT *** 43 2. HEALTH EFFECTS FIGURE 2-7. Existing Information on Health Effects of Propylene Glycol SYSTEMIC o/ Ne SS QD > > & &/ &/ © */ ° $$ SS & © & & & S PL NY & cc $$ F ® QL ® ow? Inhalation Oral ® @ Dermal W oO HUMAN AN SYSTEMIC SS ’ NS ON F/ ® & &£ & & = & & gt //F/8/ SES ES&S ESP Inhalation LA Oral » Oo 060 © & Dermal ANIMAL @® Existing Studies *** DRAFT FOR PUBLIC COMMENT *** 45 3. CHEMICAL AND PHYSICAL INFORMATION 3.1 CHEMICAL IDENTITY Information regarding the chemical identity of ethylene glycol and propylene glycol is located in Table 3-1. 3.2 PHYSICAL AND CHEMICAL PROPERTIES Information regarding the physical and chemical properties of ethylene glycol and propylene glycol is located in Table 3-2. *** DRAFT FOR PUBLIC COMMENT *** 3. CHEMICAL AND PHYSICAL INFORMATION 46 TABLE 3-1. Chemical Identity of Ethylene Glycol and Propylene Glycol Characteristic Ethylene glycol? Propylene glycol” Chemical name Ethylene glycol Propylene glycol Synonym(s) 1,2-Dihydroxyethane; 1,2-Dihydroxypropane; Registered trade name(s) Chemical formula Chemical structure Identification numbers: CAS registry NIOSH RTECS EPA hazardous waste OHM/TADS DOT/UN/NA/IMCO shipping HSDB NCI 1,2-ethandiol; 1,2-ethane- diol; 2-hydroxyethanol; ethane-1,2-diol; ethylene alcohol; ethylene dihydrate; glycol; monoethylene glycol; MEG. Dowtherm® C,H,0, CH, -OH® CH,-OH 107-21-1 KW29750000 No data 7216718°¢ No data 5012 C00920 1,2-propanediol; 1,2- propylene glycol; 2,3 propanediol; hydroxy- propanol; alpha- propylene glycol; methyl glycol; methylethyl glycol; monopropylene glycol; trimethyl glycol. No data C3Hg0, d i CH-OH CH, -OH 57-55-6 TY2000000 No data 7216877 No data 174 No data Unless otherwise noted, all references for Ethylene glycol are HSDB 1991a. ®Unless otherwise noted, all references for Propylene glycol are HSDB 1991b. ‘Ovrebo et al. 1987 JEPA 1987a ‘OHM /TADS 1985 CAS = Chemical Abstracts Services; DOT/UN/NA/IMCO = Department of Transportation/United Nations/North America/International Maritime Dangerous Goods Code; EPA = Environmental Protection Agency; HSDB = Hazardous Substances Data Bank; NCI = National Cancer Institute; NIOSH = National Institute for Occupational Safety and Health; OHM /TADS = Oil and Hazardous Materials / Technical Assistance Data System; RTECS = Registry of Toxic Effects of Chemical Substances *** DRAFT FOR PUBLIC COMMENT *** TABLE 3-2. 47 3. CHEMICAL AND PHYSICAL INFORMATION Physical and Chemical Properties of Ethylene Glycol and Propylene Glycol Property Ethylene glycol? Propylene glycol” Molecular weight Color Physical state Melting point Boiling point Density: at 20°C/4 at 30°C/4 Odor Odor threshold Solubility: Water at 20°C Organic solvent(s) Partition coefficients: Log Kw Log K,. Vapor pressure at 20°C Henry’s law constant: at 25°C Autoignition temperature Flashpoint Flammability limits Conversion factors Explosive limits 62.07 Clear, colorless Liquid -13°C 197.6°C 1.1135 1.1065¢ Odorless No data Miscible with water Slightly soluble in ether; practically insoluble in benzene, chlorinated hydrocar- bons, petroleum ether, oils -1.36 No data 0.06 mmHg 2.34x10°1° atm-m>/mole 412.93°C! 111.26°Ct 3.2-21.6%" 1 ppm = 2.54 mg/m>8; 1 mg/L = 365.0 ppm# No data 76.11 Colorless Liquid -60°C*¢ 189°C 1.0361 No data Odorless No data Miscible with water Soluble in alcohol, ether, benzene -0.92¢ 0.88° 0.07 mmHg 1.2x10°® atm-m>/mole 421.26°Ct 99.04°C! 2.6-12.5%' 1 ppm = 3.11 mg/m; 1 mg/L = 321.6 ppmé No data aUnless otherwise noted all references for ethylene glycol are HSDB 1991a. bUnless otherwise noted all references for propylene glycol are HSDB 1991b. ‘EPA 1979 dBudavari et al. 1989 °EPA 1987a {Daubert and Danner 1989 8Rowe and Wolf 1982 *** DRAFT FOR PUBLIC COMMENT *** 49 4. PRODUCTION, IMPORT, USE, AND DISPOSAL Both ethylene glycol and propylene glycol have been used extensively in many different industries since both chemicals have the ability to absorb water and prevent overheating or freezing (HSDB 1991a, 1991b). In the transportation industry, ethylene glycol has been used as an ingredient in hydraulic brake fluids and as the major component in automotive antifreeze/coolant (HSDB 1991a). Approximately 39% of all ethylene glycol produced is used as antifreeze (CMR 1987). Aqueous solutions of propylene glycol, in addition to corrosion inhibitors, prevent freezing in the freshwater plumbing systems of recreational vehicles and boats (HSDB 1991b). Propylene glycol and ethylene glycol are also components in aircraft deicing fluids (HSDB 1991a, 19910). The clothing industry has used propylene glycol as an intermediate in the manufacture of polyesters and hydroxylated polyesters (Rowe and Wolf 1982). In addition, propylene glycol is used as an intermediate in the synthesis of polyether polyols, plasticizers, and adipic acid. Approximately 46% of the propylene glycol produced is used for polyester production (HSDB 1991b). Ethylene glycol has been used as an intermediate in the synthesis of esters, ethers, and polyester fibers and resins (Rowe and Wolf 1982). Approximately 45% of all ethylene glycol produced is used to make polyester fibers and film (CMR 1987). As a solvent, ethylene glycol has been used in inks, stains, pesticides, and adhesives (HSDB 1991a). Propylene glycol is a solvent for various pharmaceutical, food, and tobacco products. Some food colors and flavors have contained propylene glycol as a solvent (HSDB 1991b). Propylene glycol has been used as an emollient in pharmaceutical and cosmetic creams because it readily absorbs water. Propylene glycol has even been utilized in a vapor form as an air sterilizer in hospitals and public buildings (Rowe and Wolf 1982). Both ethylene glycol and propylene glycol have been added to latex paints to provide stability (HSDB 1991a, 1991b). The facilities in the United States that manufactured ethylene glycol in 1988 are listed in Table 4-1. The data listed in Table 4-1 should be used with caution since only certain types of facilities are required to report. This is not an exhaustive list. There is no information on facilities that manufacture propylene glycol because this information is not required to be reported. *** DRAFT FOR PUBLIC COMMENT *** 50 4. PRODUCTION, IMPORT, USE, AND DISPOSAL TABLE 4-1. Facilities That Manufacture or Process Ethylene Glycol® Range of maximum No. of amounts on site facil- in thousands Activities State” ities of pounds® and uses® AK 1 10-99 13 AL 24 0.1-9,999 2,3,7,8,09, 11, 12, 13 AR 17 1-49,999 7, 8, 11, 12, 13 AZ 7 (1) 0.1-99 8, 10, 11, 12, 13 CA 76 (3)¢ 0-49,999 1, 2,3,4,5,7,8,9, 10, 11, 12, 13 co 9 0-9,999 1, 2, 5, 8, 12, 13 cT 13 (1)¢ 1-99 7, 8, 12, 13 DE 5 0.1-999 7, 8,9, 12, 13 FL 36 (1)¢ 0.1-49,999 2,3,7,8,09, 10, 11, 12, 13 GA 62 (1)°¢ 0-9,999 1,2,5,7,8,09, 11, 12, 13 IA 27 0-49,999 1, 3, 4, 5,7,8,9, 10, 11, 12, 13 ID 5 1-999 1, 2,3, 5,8, 9, 11, 12, 13 IL 122 (4) 0.1-49,999 1, 2,3,4,5,6,7,8,9, 10, 11, 12, 13 IN 48 (1)¢ 0.1-999 5,7, 8,9, 10, 11, 12, 13 KS 13 (2)° 1-999,999 8, 9, 10, 12, 13 KY 37 (2)° 1-999 1, 3, 4, 5,7, 8,9, 10, 11, 12, 13 LA 37 (3) 1-> Min 1, 2,3,4,5,7,8,9, 10, 11, 12, 13 MA 19 (2)° 0-999 2,3,4,7,8,9, 10, 11, 12, 13 MD 16 (1)° 0-9,999 5,7,8, 11, 12, 13 ME 4 1-999 8, 11, 12, 13 MI 77 (2)® 0-9,999 3,7,8,9, 10, 11, 12, 13 MN 18 0-999 1, 3,5,7,8,9, 11, 12, 13 MO 48 (1)° 0-49,999 1, 2, 3,4,5,7,8,09, 10, 11, 12, 13 MS 7 (1) 1-999 7. 8, 11. 22, 13 v - (n* : 999 2 y y i 5,6,7,8, 09,10, 11, 12, 13 ND 3 10-99 9, 12 NE 3 1-9,999 8, 9, 13 NH 4 0-99 3, 8, 10, 11 NJ 76 (9) 0-99,999 1, 3, 4, 5,6, 7,8,9, 10, 11, 12, 13 NM 4 1-99 2,3,4,7,8,9, 10, 11 NV 2 10-99 2, 12, 13 NY 37 (1)® 0.1-999 1, 2,3,4,5,7,8,9, 10, 11, 12, 13 OH 92 (3)° 0.1-9,999 1, 2,3,4,5,7,8,9, 10, 11, 12, 13 0K 21 (1)° 1-9,999 2,3,7,8,9, 10, 11, 12, 13 OR 10 1-999 7, 8,9, 10, 12, 13 PA 65 (3)° 0-999 1, 2, 3,4,5,7,8,9, 10, 11, 12, 13 PR 16 0-499,999 8,9, 12, 13 RI 6 1-99 1, 5, 8, 10, 12, 13 SC 48 (4)° 0-49,999 1, 3, 4, 5,7, 8,9, 10, 11, 12, 13 on a 2)° Fr 999 > 3 & 7,8, 9, 11, 12, 13 TX 115 (4)° 0-99,999 1, 2,3,4,5,6,7,8,9, 10, 11, 12, 13 ut 6 10-999 5,8, 10, 12, 13 VA 30 (2)° 1-9,999 1, 4, 5,7, 8, 9, 10, 11, 12, 13 VT 2 (1)* 10-99 12, 13 *** DRAFT FOR PUBLIC COMMENT *** 51 4. PRODUCTION, IMPORT, USE, AND DISPOSAL TABLE 4-1 (Continued) Range of maximum No. of amounts on site facil- in thousands Activities State” ities of pounds® and uses WA 13 1-999 8, 9, 10, 11, 12, 13 WI 35 (2) 0-999 2, 3,7, 8,9, 10, 11, 12, 13 WV 14 0.1-> Mill 1, 3, 4,5,6, 7, 8, 11, 12, 13 WY 4 (1) 10-99 2, 4, 8, 12, 13 “TRI88 (1990) Post office state abbreviations “Data in TRI are maximum amounts on site at each facility. Activities/Uses: 1. produce 8. as a formulation component 2. import 9. as an article component 3. for on-site use/processing 10. for repackaging only 4. for sale/distribution 11. as a chemical processing aid 5. as a byproduct 12. as a manufacturing aid 6. as an impurity 13. ancillary or other use 7. as a reactant *Number of facilities reporting "no data" regarding maximum amount of the substance on site. *** DRAFT FOR PUBLIC COMMENT *** 53 5. POTENTIAL FOR HUMAN EXPOSURE 5.1 OVERVIEW Ethylene glycol and propylene glycol are released to the environment in manufacturing and processing waste streams and as the result of disposal of industrial and consumer products containing the compounds. Upon release to the environment, the compounds are expected to partition to and be transported in surface water and groundwater. Biodegradation is the most important transformation process in surface waters and soils; aerosols or vapors released to the atmosphere undergo photochemical oxidation. Ethylene glycol and propylene glycol are rapidly degraded in environmental media; they do not persist or bioaccumulate. Little information could be found on concentrations of these compounds in environmental media. Propylene glycol is an approved food additive and is also used in pharmaceuticals and cosmetics. The most important routes of exposure to ethylene and propylene glycol for members of the general population are ingestion and dermal contact with products containing these compounds. Workers are exposed via dermal contact and possibly inhalation in applications involving the heating or spray application of fluids containing the compounds. 5.2 RELEASES TO THE ENVIRONMENT 5.2.1 Air Little information was found regarding the release of propylene glycol to the atmosphere. Propylene glycol used as a solvent in paints, inks, and coatings will slowly volatilize to the atmosphere (HSDB 1991b). Releases of ethylene glycol to the atmosphere accounted for about 64%, or 13.4 billion pounds, of the estimated total environmental releases from domestic manufacturing and processing facilities in 1988 (TRIS8 1990). These releases are listed in Table 5-1. The data listed in Table 5-1 should be used with caution since only certain types of facilities are required to report. This is not an exhaustive list. There is no information on releases of propylene glycol because they are not required to be reported. 5.2.2 Water Ethylene glycol and propylene glycol are released to surface waters in waste water from production and processing facilities (e.g, propylene glycol was qualitatively identified in the effluent from chemical manufacturing plant in Memphis, Tennessee; ethylene glycol was detected but not quantitated in a chemical plant effluent in Brandenburg, Kentucky), from spills, and in runoff (e.g., through the use of the compounds such as deicing fluids). Propylene glycol may also be released to surface waters as a metabolite of propylene glycol dinitrate, a military propellant found in waste-water streams from munitions facilities (EPA 1979, 1987a). According to the 1988 Toxics Release Inventory (TRI8S8), an estimated total of at least 3.7 billion pounds of ethylene glycol were released to surface waters in 1988 from domestic manufacturing and processing facilities; an additional 17 billion pounds were released in effluents from publicly owned treatment works (TRI88 1990). There is no information on propylene glycol in TRI88 because it is not required to be reported. 5.2.3 Soil The major sources of releases of ethylene glycol and propylene glycol to soil are the disposal of used antifreeze fluids, brake fluids, and deicing fluids containing the compounds (EPA 1979, 1987a). Ethylene glycol may also be released to soil by the metabolism of ethylene by plants (Blomstrom and Beyer 1980). *** DRAFT FOR PUBLIC COMMENT *** Releases to the Environment from Facilities TABLE 5-1. That Manufacture or Process Ethylene Glycol® b Range of reported amounts released in thousands of pounds Off-site waste of No. facil- POTW transfer transfer d Total Environment Underground injection Water Land Air ities State® 8-8 0.3-0.3 8.3-8.3 0-0 0-0 0-0 AK 0-6.8 0-219.9 0-24 0-219.9 54 5. POTENTIAL FOR HUMAN EXPOSURE 0-131.1 @ o DO ~N Oo — | o (i A | Oo oC oOoOooo << © [22] oD COND * [2] DAN NNO ~NDDOWOWoOD o DN TN A TN NM ODN EE ODO OO ODODODODODOODOOO OO ww on Yd * an < on on . ” hd = . CO WN ON — HO N~ ~~ NDT =H OM Uo en COO OD OMOODOODOOOOC OO o o~N wn ~N ® © -— NO ™Mm NO OMOOODOOOWN—~O WOO ooo ODO OOOO ODODODODOOOO OO — on co COO —~O0O VON ~~ MO oo or OCD O0OO0O OOD ODO ODODODODOO OO TNO ON 0-101.3 0 3 3 0 3 0 6 COO O0ODO0ODO0ODO0ODO0OO0ODODOOOO™mO Loo CO O0OODO0OO0OO0OCOO0ODODOODOC OO 8 2 4 6 6 0 1 0. 8 0-881.1 0-31 0-61 37 19 CA co CT DE FL LA MA MD *** DRAFT FOR PUBLIC COMMENT *** 0-94.5 0-8.6 0-0.3 0-0.1 0-61 0-0 0.5-146.1 0-0 0-0 16 0-146.1 0-0.5 ME 0-340 MI 0-27.5 MN 1 | oO oo on wn —_—— Oo EE oO ow om — Oo Oo vo ooo oom am 0. — Oo Oo f Xn oO oo —OoO OmMmOo oOo | | | | 1 1 OOOO OOo OO Oooo or OO Oooo «) oO = [i oo co | 1 co oo [a oo oo [a [==] OO —— 1 oOo oo 1 | oOo oo on © oNOoO Ny 1 1 | 1 oOo oo oo am | | 1 oO oO oo oo oo Io oO Oo oo 0-102 0-115 37 92 NY OH 0-54.6 0-0 0-59.1 0-20.3 0-14.1 21 0-19.9 0K xxx INSWWOO OIN8Nd HOH 14VHQ »xx TABLE 5-1 (Continued) Range of reported amounts released in thousands of pounds No. of Off-site facil- Underground Total POTW waste State ities Air injection Water Land Environment? transfer transfer OR 10 0-0.5 0-0 0-0.3 0-0 0-0.8 0-12.8 0-9.4 PA 65 0-86.8 0-0 0-170.7 0-22 0-171.6 0-40.7 0-45.7 PR 16 0-1.9 0-0 0-4.1 0-0.3 0-4.6 0-119.3 0-15.3 RI 6 0-4.9 0-0 0-41.5 0-0 0-44.5 0-0 0-68.2 SC 48 0-343.2 0-0 0-53 0-2.8 0-365.2 0-143.1 0-301 SD 1 0-0 0-0 0-0 0-0 0-0 0-0 0.1-0.1 TN 36 0-1,112 0-0 0-300 0-130 0-1,412 0-32.1 0-85.4 TX 115 0-2,302 0-2,715 0-38 0-178.4 0-4,951 0-310.7 0-1,662 ut 6 0-0.3 0-0 0-0 0-12.2 0-12.5 0-0.7 0-0.8 VA 30 0-504.3 0-0 0-1.1 0-0.3 0-504.5 0-1,924 0-100 VT 2 0-0.3 0-0 0-0 0-0 0-0.3 0-0 0-0 WA 13 0-0.5 0-0 0-3.1 0-0.3 0-3.8 0-11 0-36.5 WI 35 0-113 0-0 0-20.7 0-0 0-113 0-304.6 0-85 wv 14 0-1,030 0-0 0-110 0-2.9 0.1-1,140 0-15.6 0-7,242 WY 4 0-0.1 0-71.1 0-0.1 0-0 0-71.1 0-0 0-0.1 ®TRI88 (1990) ®pata in TRI are maximum amounts released by each facility. Quantities reported here have been rounded to the nearest hundred pounds, except those quantities > 1 million pounds which have been rounded to the nearest thousand pounds. “Post office state abbreviation 9The sum of all releases of the chemical to air, land, water, and underground injection wells by a given facility. POTW = Publicly owned treatment works JHNSOdX3 NYWNH HOH VILN3LOd 'S SS 56 5. POTENTIAL FOR HUMAN EXPOSURE According to TRI8S, an estimated total of at least 897 million pounds of ethylene glycol were released to soils in 1988 from domestic manufacturing and processing facilities; an additional 2.9 billion pounds were released by underground injection (TRI88 1990). There is no information on propylene glycol in TRI88 because it is not required to be reported. 5.3 ENVIRONMENTAL FATE 5.3.1 Transport and Partitioning Ethylene glycol and propylene glycol have low vapor pressures and are miscible with water. Therefore, upon release to the environment, the compounds are expected to be transported primarily in aqueous media (EPA 1979). The low Henry's law constant values for the compounds (108 range; see Table 3-2) suggest that releases to surface water will not partition to the atmosphere via volatilization. Adsorption to sediment or soil particulates is also not expected to be significant on the basis of the log K_. value for both compounds (see Table 3-2). The low log K, values suggest that bioconcentration and bioaccumulation of the compounds will be limited. Laboratory testing with ethylene glycol confirms insignificant bioconcentration in crawfish (LDOTD 1990), algae, and fish (Freitag et al. 1985). If released to the atmosphere (e.g., as vapors generated at elevated temperatures), physical removal of the compounds in rainfall is possible. Ethylene glycol and propylene glycol are expected to be highly mobile in soils; they may leach to groundwater upon release to surface soils unless degraded (see Section 5.3.2). For example, in laboratory studies, ethylene glycol was found to rapidly percolate through soil columns with little or no adsorption (Abdelghani et al. 1990; Lokke 1984). The compounds may also volatilize from dry surface soils (EPA 1979, 1987a; Hine and Mookerjee 1975; Lyman et al. 1982; Simmons et al. 1976). 5.3.2 Transformation and Degradation 5.3.2.1 Air Ethylene glycol and propylene glycol released to the atmosphere are expected to undergo rapid photochemical oxidation via reaction with hydroxyl radicals. The half-lives for the photochemical oxidation of propylene glycol and ethylene glycol have been estimated to be 20-32 hours and 24-50 hours, respectively (EPA 1987, HSDB 1991a, 1991b). 5.3.2.2 Water Biodegradation by a variety of acclimated and unacclimated microorganisms, under both aerobic and anaerobic conditions, is the most important transformation process for ethylene glycol and propylene glycol in surface waters. For example, the half-lives for the biotransformation of propylene glycol generally range from 1 to 4 days under aerobic conditions and from 3 to 5 days under anaerobic conditions (EPA 1987). Ethylene glycol was rapidly metabolized in aqueous solutions, as measured using five different biodegradation tests (Means and Anderson 1981). Other reports of biotransformation of ethylene glycol include metabolism by activated sludge microorganisms (Bieszkiewicz et al. 1979), river water microbes (Evans and David 1974), and bacteria isolated from the Great Salt Lake (Gonzalez et al. 1972) and pond water (Willetts 1981). The glycols are not expected to undergo significant abiotic transformation in surface waters via hydrolysis or oxidation (EPA 1979, 1987; HSDB 1991a, 1991b). For example, the half-life for reaction of propylene glycol with hydroxyl radicals in aqueous solution has been estimated to be 1.3-2.3 years (HSDB 1991a). However, *** DRAFT FOR PUBLIC COMMENT *** 57 5. POTENTIAL FOR HUMAN EXPOSURE photolysis of ethylene glycol sorbed to goethite, a common natural constituent of surface water sediments, by near ultraviolet radiation has been demonstrated in the laboratory. Formaldehyde and glycolaldehyde were detected as degradation products (Cunningham et al. 1985). 5.3.2.3 Soil Biodegradation by a variety of microorganisms under both aerobic and anaerobic conditions is also the most important transformation process for ethylene glycol and propylene glycol in soils, with half-lives similar to or less than those in surface waters (EPA 1987). In a laboratory study, soil microbes of the genera Pseudomonas, Citrobacter, and Serratia degraded ethylene glycol, at solution concentrations of 1-3%, within 3 days; concentrations higher than 5% were toxic to the microbes (Abdelghani et al. 1990). The soil microbe Clostridium glycolicum degraded ethylene glycol and propylene glycol under anaerobic conditions to acid and alcohol end products (Gaston and Stadtman 1963). As in surface waters, abiotic transformation of ethylene glycol and propylene glycol is not expected to be significant (EPA 1987a, 1991a; HSDB 1991a). 5.4 LEVELS MONITORED OR ESTIMATED IN THE ENVIRONMENT 5.4.1 Air Ethylene glycol was detected in ambient air samples, at time-weighted average concentrations of <0.05-0.33 mg/m? as aerosol and <0.05-10.4 mg/m? as vapor, following spray application of deicing fluids containing 50% solutions of the compound to the surfaces of bridges. The ambient air samples were collected above the sprayed bridges (LDOTD 1990). No information was found on atmospheric levels of propylene glycol. 5.4.2 Water No information was found on surface water or groundwater monitoring studies for ethylene glycol or propylene glycol. 5.4.3 Soil No information was found on soil concentrations of ethylene glycol or propylene glycol. 5.4.4 Other Environmental Media Ethylene glycol and propylene glycol have been identified in negligible amounts in the water-soluble component of cigarette smoke (Schumacher et al. 1977). Propylene glycol is used in some cosmetic and oral drug formulations and is a Generally Recognized as Safe (GRAS) additive in foods, where it is used as an emulsifying and plasticizing agent, humectant, surfactant, and solvent. The compound is added to foods at concentrations ranging from <0.001% in eggs and soups to about 15% in seasonings and flavors (EPA 1979). ' *** DRAFT FOR PUBLIC COMMENT *** 58 5. POTENTIAL FOR HUMAN EXPOSURE Ethylene glycol has been found to migrate from polyethylene terephthalate bottles used in the packaging of carbonated beverages into food simulants. The compound was detected at a concentration of about 100 ppb in a 3% acetic acid solution used as a food simulant after 6 months of storage at 32°C (Kashtock and Breder 1980). Propylene glycol has also been found to migrate into a number of foods from regenerated cellulose films containing the compound as a softening agent. The compound was detected in chocolates at 20-1,460 mg/kg after 5.5 months of storage, in fruit cakes at 10-154 mg/kg after 84-336 days of storage, in meat pies at <10-118 mg/kg after 3-7 days of storage, and in toffee at <10-1,530 mg/kg after 168-450 days of storage (Castle et al. 1988a). 5.5 GENERAL POPULATION AND OCCUPATIONAL EXPOSURE The most important route of human exposure to ethylene glycol for members of the general population is dermal contact with fluids used in automobiles (e.g., antifreeze, coolants, and brake fluids) (HSDB 1991a). However, purposeful or accidental ingestion of antifreeze by children and adults has caused the most morbidity and mortality in the past. The general population is exposed to propylene glycol primarily through ingestion of food and pharmaceutical products and through dermal contact with cosmetic products containing the compound (EPA 1979, 1987; HSDB 1991b). The average daily dietary intake of propylene glycol in Japan, where the compound is used as a food additive stabilizer, was estimated to be 43 mg/person in 1982 (Louekari et al. 1990). NIOSH estimated that about 2.5 million individuals were potentially exposed to propylene glycol in the workplace in 1970; the estimate for 1980 was 80,200 workers (HSDB 1991b). Dermal contact is expected to be the main route of worker exposure; however, inhalation of vapors or mists may also occur when the compound is heated, agitated, or sprayed (e.g., in deicing formulations) (HSDB 1991b; Rowe and Wolf 1982). Contact with the skin and eyes is the most likely route of worker exposure to ethylene glycol. Inhalation may be important where the compound is heated or if mists are generated by heat or violent agitation (Rowe and Wolf 1982). Air samples taken from the breathing zones of workers applying deicing fluids (50% ethylene glycol) to bridge surfaces contained the compound at concentrations of <0.05-2.33 mg/m? as aerosol and <0.05-3.37 mg/m? as vapor (LDOTD 1990). 5.6 POPULATIONS WITH POTENTIALLY HIGH EXPOSURES Workers in industries involved in the manufacture or use of products containing high concentrations of ethylene glycol or propylene glycol (e.g., antifreeze, coolants, deicing fluids, brakes fluids, solvents) may be exposed to high concentrations of the compounds, particularly in operations involving heating or spraying of these materials. *** DRAFT FOR PUBLIC COMMENT *** 59 6. ANALYTICAL METHODS The purpose of this chapter is to describe the analytical methods that are available for detecting and/or measuring and monitoring ethylene glycol/propylene glycol in environmental media and in biological samples. The intent is not to provide an exhaustive list of analytical methods that could be used to detect and quantify ethylene glycol/propylene glycol. Rather, the intention is to identify well-established methods that are used as the standard methods of analysis. Many of the analytical methods used to detect ethylene glycol/propylene glycol in environmental samples are the methods approved by federal organizations such as EPA and the National Institute for Occupational Safety and Health (NIOSH). Other methods presented in this chapter are those that are approved by groups such as the Association of Official Analytical Chemists (AOAC) and the American Public Health Association (APHA). Additionally, analytical methods are included that refine previously used methods to obtain lower detection limits, and/or to improve accuracy and precision. 6.1 BIOLOGICAL MATERIALS The primary method for measuring propylene glycol and ethylene glycol in biological samples is gas chromatography (GC) using either a flame ionization detector (FID) or mass spectrometry (MS) for quantification. GC is the preferred analytical method because of the ease of sample preparation and the accuracy of the quantification of sample concentrations. Alkali flame ionization detectors have also been used and give a response ratio of 3:1 compared with FID (Bogusz et al. 1986). Capillary gas chromatography with a constant current *Ni electron capture detector (ECD) has been used successfully with propylene glycol (Needham et al. 1982). Thin-layer chromatography (TLC) with a chloroform solvent has been used to detect ethylene glycol and its metabolites. Sample preparation for GC is important and proceeds through several steps: acidification, esterification, and extraction into an organic solvent. The use of the internal standards is necessary for quantification. Variations in sample preparation include the choice of the ester derivizating agent, use of SE-30 rather than OV-17 as the column stationary phase, and ultrafiltration for 20 minutes. Detection of propylene glycol and ethylene glycol in biological samples using GC with either FID or MS is very sensitive with detection limits ranging from sub to low ppm. The coefficient of variation (CV) varies with the concentration of glycol used but typically ranges from 0.4% to 27% and is usually less than 10%. HPLC has also be used to identify ethylene glycol and its metabolites such as glycolate (Hewlett et al. 1983) and hippurate (Riley et al. 1982) in biological samples, particularly urine. For ultimate confirmation, positive results may be confirmed with GC/MS, making the latter system the preferred method since the HPLC step can be omitted. However, HPLC methods to measure plasma levels of glycolate have been used to aid in diagnosis and treatment of ethylene glycol poisoning (Hewlett et al. 1986; Jacobsen et al. 1988). High-resolution proton nuclear magnetic resonance spectroscopy has potential use in the identification and quantification of propylene glycol and other chemicals in cerebrospinal fluid and serum (CSF) (Petroff et al. 1986). The technique has the advantages of (1) requiring no pretreatment of the specimens prior to analysis and no advance knowledge of possible compounds present in fluids and (2) extreme rapidity of results. Propylene glycol was detected at 1 ppm in CSF. Microscopy can be used to identify metabolic products of ethylene glycol. Scanning electron microscopy (SEM) at 20 kilovolts will detect crystals of calcite, calcium oxalate monohydrate, and calcium oxalate dihydrate in kidney tissue (Siew et al 1975b). Phase-contrast polarizing with x-ray powder diffraction may be used to identify hippuric acid crystals in urine (Foit et al. 1985). *** DRAFT FOR PUBLIC COMMENT *** 60 6. ANALYTICAL METHODS The use of ethylene oxide to sterilize tissue for transplantation may result in the formation of ethylene glycol when ethylene oxide is in prolonged contact with tissue. To quantify the formation of ethylene glycol in tissue, an HPLC method using a Refracto Monitor detector has been developed. The HPLC system can be used to detect ppm levels of ethylene glycol with a sensitivity of 2x10 refractive index unit full scale. This procedure has the following advantages: (1) requires only 4 minutes for analysis, (2) simple sample preparation, and (3) good reproducibility (Wu and Malinin 1987). Techniques to detect and quantify propylene glycol and, more particularly, ethylene glycol in human blood have been developed for use in hospital laboratories to assist in the diagnosis of ethylene glycol poisoning (caused by drinking antifreeze containing ethylene glycol). Consequently, these techniques are quite rapid, usually less than 30 minutes, and do not require elaborate sample preparation. Table 6-1 is a summary of some of the most commonly used methods reported in the literature for detecting propylene glycol and ethylene glycol in biological samples. The specific techniques used for each analytical method are listed in the table if that information was provided by the author(s). An alternative method, developed in a hospital, for detecting ethylene glycol in blood is the use of the DuPont Automated Clinical Analyzer triglyceride assay pack. This method, while relatively simple, cannot be used when the triglyceride concentration of the serum exceeds 12 g/L. and requires that positive results for ethylene glycol be confirmed using another method (Ochs et al. 1988; Ryder et al. 1986). Metabolites of ethylene glycol in the blood may be detected by analytical isotachophoresis using an LKB 2127 Tachophor equipped with both a conductivity detector and an ultraviolet detector. Blood and serum samples should not have been previously treated with oxalate, citrate, or ethylene diamine tetracetic acid. This technique may be of value when ethylene glycol poisoning is suspected but sufficient time has elapsed for metabolism of the compound to have occurred (Ovrebo et al. 1987). No information was located on detecting ethylene glycol or propylene glycol in feces, adipose tissue, or human milk. 6.2 ENVIRONMENTAL SAMPLES As with biological samples, GC is the major technique used to determine ethylene and propylene glycol concentrations in environmental samples whether in air, water, food, drugs, or other substances. Capillary gas chromatography with FID or ECD, possibly followed by MS, generally gives good quantitative results down to the ppm range with recovery usually greater than 80%. The determination of ethylene glycol and propylene glycol in air requires adsorption onto a surface and subsequent extraction. Water samples may be analyzed without preparation. Detection of ethylene glycol and propylene glycol in foods and drugs may be accomplished by chromatography of the sample; for substances with a high fat content, extraction with hexane may be used. Table 6-2 is a summary of some of the most commonly used methods reported in the literature for detecting propylene glycol and ethylene glycol in environmental samples. The specific techniques used for each analytical method are listed in the table if that information was provided by the author(s). Air sampling for ethylene glycol is performed by adsorption onto a resin column such as Amberlite XAD-2. Although activated charcoal filters have some utility, recovery is greater with the Amberlite, and it is the preferred adsorption medium. Ethylene glycol is extracted with a solvent with recovery of 98%. If activated charcoal is used for adsorption, 5% methanol in dichloromethane is the best solvent, although the maximum recovery is only 84% (Andersson et al. 1982, 1984). An alternative method for sampling ethylene glycol passes air through a glass fiber filter with a silica gel tube. Ethylene glycol is then extracted in a 2-propanol:water *** DRAFT FOR PUBLIC COMMENT *** xx INIWWOO OIM8Nd HOH LIVHA xxx TABLE 6-1. Analytical Methods for Determining Ethylene Glycol and Propylene Glycol in Biological Materials Sample matrix Preparation method Analytical method Sample detection Percent limit recovery Reference Human plasma (EG and PG) Human serum (PG) Deproteinize sample with acetic acid; vortex; centrifuge; spike supernatant with 1,2-butanediol as internal standard; react with butane-boronic acid; neutralize with NH,OH, extract with dichloromethane; concentrate Add acetonitrile with internal standard (1,2-butanediol) to sample; centrifuge; concentrate; extract with p-bromophenyl boric acid in ethyl acetate HRGC/MS HRGC/ECD 5s ppm (EG); 94-106 1 ppm (PG) 0.38 ppm >90 Giachetti et al. 1989 Needham et al. 1982 SAOHL3W TVOILATVYNY 9 io xx INGWWOO 0118Nd HOS L4VYHO »xx TABLE 6-1 (Continued) Sample matrix Preparation method Analytical method Sample detection limit Percent recovery Reference Human serum (EG) Human blood (PG) Add internal standard (1,2-butanediol and acetic acid in acetonitrile) to sample; centrifuge to remove protein precipitate; esterify supernatant with butylboronic acid and 2,2-dimethoxypropane; neutralize with NH,OH in acetonitrile Deproteinize sample with HCIO,; centrifuge; adjust pH of supernatant with KOH; centrifuge; use supernatant for GC HRGC/FID GC/MS NR 0.6 ppm 95 NR Smith 1984 Sisfontes et al. 1986 SAOHL3NW TVYOLLATYNY 9 29 xxx INSJWWOO O1N8Nd HOH L3VHA xxx TABLE 6-1 (Continued) Sample matrix Preparation method Analytical method Sample detection limit Percent recovery Reference Human blood/ tissue (EG) Urine (EG) Urine (sodium fluorescein) (EG) Dog urine (glycolic acid) (EG) Grind anhydrous Na,SO, with sample; derivatize with n-butylboronic acid in acetone containing 1,3-butanediol as internal standard; centrifuge or filter Acidify sample with HCI; extract with CHCl; concentrate; spot on TLC; develop as for kidney tissue Untreated samples read in borosilicate tubes Dilute sample; add NaCl and acidify with HCl; extract in MEK; evaporate; dissolve residue in ethylacetate; derivatize with PNBDI; assay with solvent of methylacetate in isooctane GC/FID/AFID TLC Fluorescence (Wood's lamps) HPLC/UV NR NR NR 1-2 ng 70 NR NR 96 Bogusz et al. 1986 Riley ct al. 1982 Winter et al. 1990 Hewlett et al. 1983 SAOHL3W TVOLLATVYNY 9 €9 xxx INFWWNOD OIN8Nd HOH 14VHA xxx TABLE 6-1 (Continued) Sample matrix Preparation method Analytical method Sample detection limit Percent recovery Reference Human serum (EG) Human blood (PG) Add internal standard (1,2-butanediol and acetic acid in acetonitrile) to sample; centrifuge to remove protein precipitate; esterify supernatant with butylboronic acid and 2,2-dimethoxypropane; neutralize with NH,OH in acetonitrile Deproteinize sample with HCIO; centrifuge; adjust pH of supernatant with KOH; centrifuge; inject supernatant into GC HRGC/FID GC/MS NR 0.6 ppm 95 NR Smith 1984 Sisfontes et al. 1986 SAOHL13N TVOILATYNY 9 v9 xxx INFWWOO OIM8Nd HOH 14VHA xxx TABLE 6-1 (Continued) Sample detection Percent Sample matrix Preparation method Analytical method limit recovery Reference Kidney tissue dog Grind tissue with acidic TLC NR NR Riley et al. 1982 (hippurate) methanol; filter (EG) methylate; concentrate; spot on 254 nm TLC plate; develop twice with CHCl;/CH;0H; use fluorescent quenching with shortwave light Human tissue Extract samples in HPLC/RI S ppm NR Wu and Malinin 1987 (EG) HPLC grade water for 24 hours; filter supernatant; analyze on reverse-phase column AFID = alkali flame ionization detector; ATP = adenosine triphosphate; CHCl; = chloroform; CH;0OH = methanol; ECD = electron capture detector; EG = ethylene glycol; FID = flame ionization detector; GC = gas chromatography; HCI = hydrochloric acid; HClO, = chloroform; HPLC = high-performance liquid chromatography; HRGC = high resolution gas chromatography; KOH = potassium hydroxide; MEK = methylethyl ketone; MgSO, = magnesium sulfate; MS = mass spectrometry; NaCl = sodium chloride; NAD = nicotinamide adenine dinucleotide; Na,SO, = sodium sulfate; NH;OH = ammonium hydroxide; NR = not reported; PG = propylene glycol; PNBDI = O-p-nitrobenzyl-N,N’-diisopropylisourea; RI = refractive index detector; TLC = thin- layer chromatography; UV = ultraviolet detector SAOHL3N TVOILATVYNY 9 S9 *+x INIWWOO 0178nd Ho4 14VHA xxx TABLE 6-2. Analytical Methods for Determining Ethylene Glycol and Propylene Glycol in Environmental Samples Sample detection Percent Sample matrix Preparation method Analytical method limit recovery Reference Air? Collect sample on glass GC/FID 2 ppm 81-111 NIOSH 1984 fiber filters and silica gel; extract with 2- propanol:water Air Absorb sample to GC/FID NR 75-98 Andersson et al. 1982 Amberlite® XAD-2 with personal sampling pump; extract with diethyl ether Plastics Extract sample from GC/FID 16.5 ng 58-61 Muzeni 1985 plastic with carbon disulfide Concentrate sample then GC/FID 50 ppb 97-103 Kashtock and Breder Aqueous solution dilute with water; concentrate with helium gas; redilute 1980 SAOH13W TVOILATYNY ‘9 99 xx» INFWWOD O178Nd HOH 14YHA xxx TABLE 6-2 (Continued) Sample detection Percent Sample matrix Preparation method Analytical method limit recovery Reference Plastics Extract sample with GC/FID 2 ppm NR DeRudder et al. 1986 solvent of ethylacetate- water-methanol Food Add hot water to sample HRGC/FID 10 ppm 78-107 Castle et al. 1988b to obtain slurry; defat GC/MS with hexane; precipitate sugars with calcium hydroxide; concentrate; derivatize with BSTFA For ethylene glycol only. BSTFA = bis (trimethylsilyl)trifluoroacetamide; FID = flame ionization detector; GC = gas chromatography; HRCG = high resolution gas chromatography; MS = mass spectrometry SAOHLIN TVOILATYNY 9 19 68 6. ANALYTICAL METHODS solvent and injected into the gas chromatograph (Tucker and Deye 1981). The sensitivity of this method can be increased by use of a hot on-column injection technique using methanol as the solvent (Lang 1986). A portable, automated, photoionization gas chromatograph has been used to detect ethylene glycol in industrial facilities at levels as low as 0.05 ppm (Adams and Collins 1988). Ethylene glycol may be detected by a colorimetric reaction with 3-methyl-2-benzothiazolinone hydrazone hydrochloride. The solution is read at 630 nm in a spectrophotometer. This method may be used for ethylene glycol in water (Evans and Dennis 1973) or to detect ethylene oxide in air (Kring et al. 1984); however, this method is not quantitative and is relatively nonsensitive when compared with GC/MS. The migration of ethylene glycol from plastics into solution can be studied with GC. Sample preparation methods include extraction in hydrochloric acid (Ball 1984), distilled water (Spitz and Weinberger 1971), carbon disulfide (Muzeni 1985), dimethylformamide (Danielson et al. 1990), and a mixture of ethyl acetate, water, and methanol (DeRudder et al. 1986). Other methods for detecting ethylene glycol in industrial products include HPLC (Aboul-Enein and Islam 1989) and a periodate flow-through ion-selective electrode (Diamandis et al. 1980). The presence of ethylene glycol and propylene glycol in foods packaged with plastic films containing the compounds has been studied as have ethylene glycol levels in drugs sterilized with ethylene oxide. Sample preparation is important as different procedures vary depending on the fat content of the food sample. Foods with low fat content can be extracted with ethyl acetate, derivatized to a trimethyl silyl ether, and then injected into the gas chromatograph. For foods with a high fat content, hexane is used as the defatting agent prior to derivatization. Quantifying ethylene glycol or propylene glycol in wines requires no preparation of the samples prior to analysis (Kaiser and Rieder 1987; Klaus and Fischer 1987). Drugs in aqueous solutions may be analyzed directly, water insoluble drugs should be extracted in water, and ointments may be dissolved in hexane and then extracted with water. Recovery is between 80% and 114% with detection limits in the low-ppm range (Hartman and Bowman 1977; Manius 1979). The use of ion exchange chromatography with sulfuric acid as the mobile phase has also given good recovery (98-101%) with a detection limit of 5 pg/mL propylene glycol from pharmaceuticals (Iwinski and Jenke 1987). Although the use of TLC (Ballarin 1980) has been recommended, it has been superseded by GC. Propylene glycol in cigarette smoke has been detected using electrostatic precipitation or filter pad, with extraction and separation with capillary gas chromatography (Borgerding et al. 1990). No information was located on techniques for detecting and analyzing ethylene glycol and propylene glycol in soil. *** DRAFT FOR PUBLIC COMMENT *** 69 7. REGULATIONS AND ADVISORIES The international, national, and state regulations and guidelines regarding ethylene glycol and propylene glycol in air, water, and other media are summarized in Table 7-1 and Table 7-2. EPA (IRIS 1991) assigned ethylene glycol a reference dose (RfD) of 2.0 mg/kg/day with an uncertainty factor of 100 based on kidney toxicity in rats (DePass 1986). Ethylene glycol is on the list of chemicals appearing in "Toxic Chemicals Subject to Section 313 of the Emergency Planning and Community Right-to-Know Act of 1986" (EPA 1987b, 1988c). *** DRAFT FOR PUBLIC COMMENT *** 70 7. REGULATIONS AND ADVISORIES TABLE 7-1. Regulations and Guidelines Applicable to Ethylene Glycol Agency Description Information References INTERNATIONAL Guidelines: WHO Acceptable daily intake 25 mg/kg FAO/WHO 1974 NATIONAL Regulations: a. Air: OSHA Ceiling limit 125 mg/m3 OSHA 198%a (29 CFR (ethylene glycol) (50 ppm) 1910.1000); OSHA 1989b OSHA Meets criteria for medical Yes OSHA 1987 (29 CFR records (ethylene glycol) 1910.20); OSHA 1988 b. Food: FDA Indirect food additive for use only as Yes FDA 1977a (21 CFR as a component of adhesives. 175.105); FDA (ethylene glycol) 19776 c. Other: EPA OTS Toxic Chemical Release; Community Yes EPA 1987b (40 CFR Right to Know (ethylene glycol) 372); EPA 1988c Guidelines: a. Air: ACGIH Ceiling limit (ethylene glycol) 127 mg/m3 ACGIH 1990 (50 ppm) EPA Drinking water quality guidelines 7,000 pg/L FSTRAC 1988 (ethylene glycol) c. Other: RfD (oral) 2.0 mg/kg/day IRIS 1991 Carcinogenic classification No data Unit risk (air) No data Unit risk (water) No data STATE Regulations and Guidelines: a. Air: Acceptable ambient air concentrations NATICH 1991 (ethylene glycol) California-Montana 0.00 Florida-Pinellas Florida-Pinellas (8 hours) (24 hours) 1.25x103 pg/m3 3.00x102 pg/m3 *** DRAFT FOR PUBLIC COMMENT *** 71 7. REGULATIONS AND ADVISORIES TABLE 7-1 (Continued) Agency Description Information References STATE (Cont.) Massachusettes (24 hours) 3.45x10 ug/ m3 Massachusettes (Annual) 3 45x10] pLg/m Maryland 0.00 North Dakota (1 hours) 1.27 mg/m> Nevada (8 hours) 2.98 mg/m Oklahoma (24 hours) 1.27x10%ug/m> Texas (30 minutes) 1.27x103ug/m> Texas (Annual) 1.27x10%g/m> Maryland 0.00 Texas (30 minutes) 4.00x103g/m> Texas (Annual) 4.00x10%g/m Kentucky Signifigant emission levels of 2.240x10" Zpounds/hour NREPC 1986 toxic air pollutants (401 KAR 31:040) (ethylene glycol) b. Water: Drinking water quality guidelines and FSTRAC 1988 standards (ethylene glycol) Arizona 5500 ng/L Connecticut 100 ng/L Maine 5500 ng/L Vermont Primary groundwater quality standards: VANR 1988 Enforcement standard 7.0mg/L Preventive action limit 3.5mg/L ACGIH = American Conference of Governmental Industrial Hygienists; EPA = Environmental Protection Agency; FDA = Food and Drug Administration; OTS = Office of Toxic Substances; OSHA = Occupational Safety and Health Administration; RfD = Reference Dose; WHO = World Health Organization *** DRAFT FOR PUBLIC COMMENT *** 72 7. REGULATIONS AND ADVISORIES TABLE 7-2. Regulations and Guidelines Applicable to Propylene Glycol Agency Description Information References NATIONAL a. Other: EPA OWRS Pesticide subject to registration and Yes EPA 1989b (40 CFR reregistration (propylene glycol) STATE Regulations and Guidelines: a. 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Morphological changes in the liver and kidneys in ethylene glycol poisoning. Arkh Patol 39(2):51-58. *** DRAFT FOR PUBLIC COMMENT *** 99 9. GLOSSARY Acute Exposure -- Exposure to a chemical for a duration of 14 days or less, as specified in the Technical Reports. Adsorption Coefficient (K ) -- The ratio of the amount of a chemical adsorbed per unit weight of organic carbon in the soil or sediment to the concentration of the chemical in solution at equilibrium. Adsorption Ratio (Kd) -- The amount of a chemical adsorbed by a sediment or soil (i.e., the solid phase) divided by the amount of chemical in the solution phase, which is in equilibrium with the solid phase, at a fixed solid/solution ratio. It is generally expressed in micrograms of chemical sorbed per gram of soil or sediment. Bioconcentration Factor (BCF) -- The quotient of the concentration of a chemical in aquatic organisms at a specific time or during a discrete time period of exposure divided by the concentration in the surrounding water at the same time or during the same period. Cancer Effect Level (CEL) -- The lowest dose of chemical in a study, or group of studies, that produces significant increases in the incidence of cancer (or tumors) between the exposed population and its appropriate control. Carcinogen -- A chemical capable of inducing cancer. Ceiling Value -- A concentration of a substance that should not be exceeded, even instantaneously. Chronic Exposure -- Exposure to a chemical for 365 days or more, as specified in the Technical Reports. Developmental Toxicity -- The occurrence of adverse effects on the developing organism that may result from exposure to a chemical prior to conception (either parent), during prenatal development, or postnatally to the time of sexual maturation. Adverse developmental effects may be detected at any point in the life span of the organism. Embryotoxicity and Fetotoxicity -- Any toxic effect on the conceptus as a result of prenatal exposure to a chemical; the distinguishing feature between the two terms is the stage of development during which the insult occurred. The terms, as used here, include malformations and variations, altered growth, and in utero death. EPA Health Advisory -- An estimate of acceptable drinking water levels for a chemical substance based on health effects information. A health advisory is not a legally enforceable federal standard, but serves as technical guidance to assist federal, state, and local officials. Immediately Dangerous to Life or Health (IDLH) -- The maximum environmental concentration of a contaminant from which one could escape within 30 min without any escape-impairing symptoms or irreversible health effects. Intermediate Exposure -- Exposure to a chemical for a duration of 15-364 days, as specified in the Technical Reports. Immunologic Toxicity -- The occurrence of adverse effects on the immune system that may result from exposure to environmental agents such as chemicals. *** DRAFT FOR PUBLIC COMMENT *** 100 9. GLOSSARY In Vitro -- Isolated from the living organism and artificially maintained, as in a test tube. In Vivo -- Occurring within the living organism. Lethal Concentration; i) (LC) -- The lowest concentration of a chemical in air which has been reported to have caused death in humans or animals. Lethal Concentration (50) (LCs) -- A calculated concentration of a chemical in air to which exposure for a specific length of i is expected to cause death in 50% of a defined experimental animal population. Lethal Dose; (LD; o) -- The lowest dose of a chemical introduced by a route other than inhalation that is expected to have caused death in humans or animals. Lethal Doses, (LDgy) -- The dose of a chemical which has been calculated to cause death in 50% of a defined experimental animal population. Lethal Times, (LTs,) -- A calculated period of time within which a specific concentration of a chemical is expected to cause death in 50% of a defined experimental animal population. Lowest-Observed-Adverse-Effect Level (LOAEL) -- The lowest dose of chemical in a study, or group of studies, that produces statistically or biologically significant increases in frequency or severity of adverse effects between the exposed population and its appropriate control. Malformations -- Permanent structural changes that may adversely affect survival, development, or function. Minimal Risk Level -- An estimate of daily human exposure to a dose of a chemical that is likely to be without an appreciable risk of adverse noncancerous effects over a specified duration of exposure. Mutagen -- A substance that causes mutations. A mutation is a change in the genetic material in a body cell. Mutations can lead to birth defects, miscarriages, or cancer. Neurotoxicity -- The occurrence of adverse effects on the nervous system following exposure to chemical. No-Observed-Adverse-Effect Level (NOAEL) -- The dose of chemical at which there were no statistically or biologically significant increases in frequency or severity of adverse effects seen between the exposed population and its appropriate control. Effects may be produced at this dose, but they are not considered to be adverse. Octanol-Water Partition Coefficient (K ow) -- The equilibrium ratio of the concentrations of a chemical in n- octanol and water, in dilute solution. Permissible Exposure Limit (PEL) -- An allowable exposure level in workplace air averaged over an 8-hour shift. q,* -- The upper-bound estimate of the low-dose slope of the dose-response curve as determined by the multistage procedure. The q;* can be used to calculate an estimate of carcinogenic potency, he incremental excess cancer risk per unit of exposure (usually pg/L for water, mg/kg/day for food, and pg/m? for air). *** DRAFT FOR PUBLIC COMMENT *** 101 9. GLOSSARY Reference Dose (RfD) -- An estimate (with uncertainty spanning perhaps an order of magnitude) of the daily exposure of the human population to a potential hazard that is likely to be without risk of deleterious effects during a lifetime. The RfD is operationally derived from the NOAEL (from animal and human studies) by a consistent application of uncertainty factors that reflect various types of data used to estimate RfDs and an additional modifying factor, which is based on a professional judgment of the entire database on the chemical. The RfDs are not applicable to nonthreshold effects such as cancer. Reportable Quantity (RQ) -- The quantity of a hazardous substance that is considered reportable under CERCLA. Reportable quantities are (1) 1 pound or greater or (2) for selected substances, an amount established by regulation either under CERCLA or under Sect. 311 of the Clean Water Act. Quantities are measured over a 24-hour period. Reproductive Toxicity -- The occurrence of adverse effects on the reproductive system that may result from exposure to a chemical. The toxicity may be directed to the reproductive organs and/or the related endocrine system. The manifestation of such toxicity may be noted as alterations in sexual behavior, fertility, pregnancy outcomes, or modifications in other functions that are dependent on the integrity of this system. Short-Term Exposure Limit (STEL) -- The maximum concentration to which workers can be exposed for up to 15 min continually. No more than four excursions are allowed per day, and there must be at least 60 min between exposure periods. The daily TLV-TWA may not be exceeded. Target Organ Toxicity -- This term covers a broad range of adverse effects on target organs or physiological systems (e.g., renal, cardiovascular) extending from those arising through a single limited exposure to those assumed over a lifetime of exposure to a chemical. Teratogen -- A chemical that causes structural defects that affect the development of an organism. Threshold Limit Value (TLV) -- A concentration of a substance to which most workers can be exposed without adverse effect. The TLV may be expressed as a TWA, as a STEL, or as a CL. Time-Weighted Average (TWA) -- An allowable exposure concentration averaged over a normal 8-hour workday or 40-hour workweek. Toxic Dose (TDs) -- A calculated dose of a chemical, introduced by a route other than inhalation, which is expected to cause a specific toxic effect in 50% of a defined experimental animal population. Uncertainty Factor (UF) -- A factor used in operationally deriving the RfD from experimental data. UFs are intended to account for (1) the variation in sensitivity among the members of the human population, (2) the uncertainty in extrapolating animal data to the case of human, (3) the uncertainty in extrapolating from data obtained in a study that is of less than lifetime exposure, and (4) the uncertainty in using LOAEL data rather than NOAEL data. Usually each of these factors is set equal to 10. *** DRAFT FOR PUBLIC COMMENT *** A-1 APPENDIX A USER’S GUIDE Chapter 1 Public Health Statement This chapter of the profile is a health effects summary written in non-technical language. Its intended audience is the general public especially people living in the vicinity of a hazardous waste site or chemical release. If the Public Health Statement were removed from the rest of the document, it would still communicate to the lay public essential information about the chemical. The major headings in the Public Health Statement are useful to find specific topics of concern. The topics are written in a question and answer format. The answer to each question includes a sentence that will direct the reader to chapters in the profile that will provide more information on the given topic. The descriptive sentences (bullets) at the end of section 1.4 can be used to link significant health effects seen in humans and animals to chemical concentration and duration of exposure. These bullets give the reader a capsule understanding of the essential exposure-duration-effect relationships that have been developed in greater details throughout the rest of the profile. Significant effects at low and high doses are presented wherever the data permit. Chapter 2 Tables and Figures for Levels of Significant Exposure (LSE) Tables (2-1, 2-2, and 2-3) and figures (2-1 and 2-2) are used to summarize health effects and illustrate graphically levels of exposure associated with those effects. These levels cover health effects observed at increasing dose concentrations and durations, differences in response by species, minimal risk levels (MRLs) to humans for noncancer endpoints, and EPA's estimated range associated with an upper-bound individual lifetime cancer risk of 1 in 10,000 to 1 in 10,000,000. Use the LSE tables and figures for a quick review of the health effects and to locate data for a specific exposure scenario. The LSE tables and figures should always be used in conjunction with the text. All entries in these tables and figures represent studies that provide reliable, quantitative estimates of No-Observed-Adverse-Effect Levels (NOAELs), Lowest-Observed- Adverse-Effect Levels (LOAELs), or Cancer Effect Levels (CELs). The legends presented below demonstrate the application of these tables and figures. Representative examples of LSE Table 2-1 and Figure 2-1 are shown. The numbers in the left column of the legends correspond to the numbers in the example table and figure. LEGEND See LSE Table 2-1 (1) Route of Exposure One of the first considerations when reviewing the toxicity of a substance using these tables and figures should be the relevant and appropriate route of exposure. When sufficient data exists, three LSE tables and two LSE figures are presented in the document. The three LSE tables present data on the three principal routes of exposure, i.e., inhalation, oral, and dermal (LSE Table 2-1, 2-2, and 2-3, respectively). LSE figures are limited to the inhalation (LSE Figure 2-1) and oral (LSE Figure 2-2) routes. *** DRAFT FOR PUBLIC COMMENT *** 2) ©) 4) ©) (6) (7) ®) ©) (10) A-2 APPENDIX A Not all substances will have data on each route of exposure and will not therefore have all five of the tables and figures. Exposure Period Three exposure periods - acute (less than 15 days), intermediate (15 to 364 days), and chronic (365 days or more) are presented within each relevant route of exposure. In this example, an inhalation study of intermediate exposure duration is reported. For quick reference to health effects occurring from a known length of exposure, locate the applicable exposure period within the LSE table and figure. Health Effect The major categories of health effects included in LSE tables and figures are death, systemic, immunological, neurological, developmental, reproductive, and cancer. NOAELs and LOAELs can be reported in the tables and figures for all effects but cancer. Systemic effects are further defined in the "System" column of the LSE table (see key number 18). Key to Figure Each key number in the LSE table links study information to one or more data points using the same key number in the corresponding LSE figure. In this example, the study represented by key number 18 has been used to derive a NOAEL and a Less Serious LOAEL (also see the 2 "18r" data points in Figure 2-1). Species The test species, whether animal or human, are identified in this column. Section 2.4," Relevance to Public Health," covers the relevance of animal data to human toxicity and Section 2.3, "Toxicokinetics," contains any available information on comparative toxicokinetics. Although NOAELs and LOAELSs are species specific, the levels are extrapolated to equivalent human doses to derive an MRL. Exposure Frequency/Duration The duration of the study and the weekly and daily exposure regimen are provided in this column. This permits comparison of NOAELs and LOAELs from different studies. In this case (key number 18), rats were exposed to ethylene glycol /propylene glycol via inhalation for 6 hours per day, 5 days per week, for 3 weeks. For a more complete review of the dosing regimen refer to the appropriate sections of the text or the original reference paper, i.e., Nitschke et al. 1981. System This column further defines the systemic effects. These systems include: respiratory, cardiovascular, gastrointestinal, hematological, musculoskeletal, hepatic, renal, and dermal/ocular. "Other" refers to any systemic effect (e.g., a decrease in body weight) not covered in these systems. In the example of key number 18, 1 systemic effect (respiratory) was investigated. NOAEL A No-Observed-Adverse-Effect Level (NOAEL) is the highest exposure level at which no harmful effects were seen in the organ system studied. Key number 18 reports a NOAEL of 3 ppm for the respiratory system which was used to derive an intermediate exposure, inhalation MRL of 0.0006 ppm (see footnote "c" LOAEL A Lowest-Observed-Adverse-Effect Level (LOAEL) is the lowest dose used in the study that caused a harmful health effect. LOAELs have been classified into "Less Serious’ and "Serious" effects. These distinctions help readers identify the levels of exposure at which adverse health effects first appear and the gradation of effects with increasing dose. A brief description of the specific endpoint used to quantify the adverse effect accompanies the LOAEL. The respiratory effect reported in key number 18 (hyperplasia) is a Less serious LOAEL of 10 ppm. MRLs are not derived from Serious LOAELSs. Reference The complete reference citation is given in chapter 8 of the profile. *** DRAFT FOR PUBLIC COMMENT *** (11) (12) A-3 APPENDIX A CEL A Cancer Effect Level (CEL) is the lowest exposure level associated with the onset of carcinogenesis in experimental or epidemiologic studies. CELs are always considered serious effects. The LSE tables and figures do not contain NOAELSs for cancer, but the text may report doses not causing measurable cancer increases. Footnotes Explanations of abbreviations or reference notes for data in the LSE tables are found in the footnotes. Footnote "c" indicates the NOAEL of 3 ppm in key number 18 was used to derive an MRL of 0.0006 ppm. LEGEND See Figure 2-1 LSE figures graphically illustrate the data presented in the corresponding LSE tables. Figures help the reader quickly compare health effects according to exposure concentrations for particular exposure periods. (13) Exposure Period The same exposure periods appear as in the LSE table. In this example, health effects (14) observed within the intermediate and chronic exposure periods are illustrated. Health Effect These are the categories of health effects for which reliable quantitative data exists. The same health effects appear in the LSE table. (15) Levels of Exposure Exposure concentrations or doses for each health effect in the LSE tables are (16) (17) (18) graphically displayed in the LSE figures. Exposure concentration or dose is measured on the log scale "y" axis. Inhalation exposure is reported in mg/m> or ppm and oral exposure is reported in mg/kg/day. NOAEL In this example, 18r NOAEL is the critical endpoint for which an intermediate inhalation exposure MRL is based. As you can see from the LSE figure key, the open-circle symbol indicates to a NOAEL for the test species-rat. The key number 18 corresponds to the entry in the LSE table. The dashed descending arrow indicates the extrapolation from the exposure level of 3 ppm (see entry 18 in the Table) to the MRL of 0.0006 ppm (see footnote "c" in the LSE table). CEL Key number 38r is 1 of 3 studies for which Cancer Effect Levels were derived. The diamond symbol refers to a Cancer Effect Level for the test species-mouse. The number 38 corresponds to the entry in the LSE table. Estimated Upper-Bound Human Cancer Risk Levels This is the range associated with the upper-bound for lifetime cancer risk of 1 in 10,000 to 1 in 10,000,000. These risk levels are derived from the EPA's Human Health Assessment Group's upper-bound estimates of the slope of the cancer dose response curve at low dose levels (q'*). (19) Key to LSE Figure The Key explains the abbreviations and symbols used in the figure. *** DRAFT FOR PUBLIC COMMENT *** xxx INGWIWOO O1M8Nd HOH L4VHQA xxx [ } » TABLE 2-1. Levels of Significant Exposure to [Chemical x] - Inhalation Exposure LOAEL (effect) Key to frequency/ NOAEL Less serious Serious figure? Species duration System (ppm) (ppm) (ppm) Reference [2 J INTERMEDIATE EXPOSURE 7 10 [fr se I] 4 7 v v v v v v — 18 Rat 13 wk Resp 3° 10 (hyperplasia) Nitschke et al. 5d/wk 1981 6hr/d CHRONIC EXPOSURE Cancer 3 v he m Zz 38 Rat 18 mo 20° (CEL, multiple Wong et al. 1982 o 5d/wk organs) 2 7hr/d 39 Rat 89-104 wk 10 (CEL, lung tumors, NTP 1982 5d/wk nasal tumors) 6hr/d 40 Mouse 79-103 wk 10° (CEL, lung tumors, NTP 1982 5d/wk hemangiosarcomas) 6hr/d 2The number corresponds to entries in Figure 2-1. PPresented in Section 1.4. “Used to derive an intermediate inhalation minimal risk level (MRL) of 4 x 10-3 mg/m3; concentration was converted to an equivalent concentration in humans; concentration was adjusted for intermittent exposure and divided by an uncertainty factor of 100 (10 for extrapolation from animal to humans, 10 for human variability). This MRL is converted into 6 x 10°? ppm and is presented in Section 1.4. CEL = cancer effect level; d = day; Derm/oc = dermal/ocular; Gd '= gestation day; Gn pig = guinea pig; Hemato = hematological: hr = hour; LOAEL = lowest-observed-adverse-effect level; LCgo = lethal concentration, 50% kill; mo = month; NOAEL = no- observed-adverse-effect level; Resp = respiratory; wk = week vv xxx INFWINOD OI78Nd HOA 14VHA xxx [8 ——— —— INTERMEDIATE CHRONIC (15-364 Days) (2365 Days) Systemic Systemic 4 SF ; 0 # Sf / s LL gd 8 & # > lpm) — —_——— —,—— a —_— 10.000 J 1.000 “18 8 gue = Ot Buse BuO w» Om Ox On Brn Ose of 0". 0 o=35 om On Om Om On On wm $2 (i Que On 1 ’ ' 01 : 104 : ' Estimated Upper. +18] oor ' 10 -S | Bound Human ' Cancer Risk 0001 9 Key 106 Hw ¢ Ru © LOAEL for serious effects (animals) : 00001 | "Mouse OD LOAEL for less serious eftects farms) | Mima rat loved fr 10-7 ® Retox NOAEL (animate) § oflecks other han cancer I ' Sssre @ CEL. Cancer ENect Love ~ [#® FIGURE 2-1. The umber nes! to each paint con espands te entries in Table 2 1 "Doses represent he lowes! dose issied per $hudy rat produced 8 hamedgenic reapense and @e net buply he existence of 8 Sveshsld lw the cancer end paint. Levels of Significant Exposure to [Chemical X]-Inhalation V XION3ddV S-v A-6 APPENDIX A Chapter 2 (Section 2.4) Relevance to Public Health The Relevance to Public Health section provides a health effects summary based on evaluations of existing toxicologic, epidemiologic, and toxicokinetic information. This summary is designed to present interpretive, weight-of-evidence discussions for human health endpoints by addressing the following questions. 1. What effects are known to occur in humans? 2. What effects observed in animals are likely to be of concern to humans? 3. What exposure conditions are likely to be of concern to humans, especially around hazardous waste sites? The section covers endpoints in the same order they appear within the Discussion of Health Effects by Route of Exposure section, by route (inhalation, oral, dermal) and within route by effect. Human data are presented first, then animal data. Both are organized by duration (acute, intermediate, chronic). In vitro data and data from parenteral routes (intramuscular, intravenous, subcutaneous, etc.) are also considered in this section. If data are located in the scientific literature, a table of genotoxicity information is included. The carcinogenic potential of the profiled substance is qualitatively evaluated, when appropriate, using existing toxicokinetic, genotoxic, and carcinogenic data. ATSDR does not currently assess cancer potency or perform cancer risk assessments. Minimal risk levels (MRLs) for noncancer endpoints (if derived) and the endpoints from which they were derived are indicated and discussed. Limitations to existing scientific literature that prevent a satisfactory evaluation of the relevance to public health are identified in the Data Needs section. Interpretation of Minimal Risk Levels Where sufficient toxicologic information is available, we have derived minimal risk levels (MRLs) for inhalation and oral routes of entry at each duration of exposure (acute, intermediate, and chronic). These MRLs are not meant to support regulatory action; but to acquaint health professionals with exposure levels at which adverse health effects are not expected to occur in humans. They should help physicians and public health officials determine the safety of a community living near a chemical emission, given the concentration of a contaminant in air or the estimated daily dose in water. MRLs are based largely on toxicological studies in animals and on reports of human occupational exposure. MRL users should be familiar with the toxicologic information on which the number is based. Chapter 2.4, "Relevance to Public Health," contains basic information known about the substance. Other sections such as 2.7, "Interactions with Other Chemicals’, and 2.8, "Populations that are Unusually Susceptible’ provide important supplemental information. MRL users should also understand the MRL derivation methodology. MRLs are derived using a modified version of the risk assessment methodology the Environmental Protection Agency (EPA) provides (Barnes and Dourson, 1988) to determine reference doses for lifetime exposure (RfDs). The most suitable endpoint for deriving a minimal risk level is the no-observed-adverse-effect-level (NOAEL). The calculation is as follows: *** DRAFT FOR PUBLIC COMMENT *** A-7 APPENDIX A MRL = NOAEL/UF where: NOAEL = no-observed-adverse-effect-level UF = uncertainty factor To derive an MRL, ATSDR generally selects the most sensitive endpoint which, in its best judgement, represents the most sensitive human health effect for a given exposure route and duration. ATSDR cannot make this judgement or derive an MRL unless information (quantitative or qualitative) is available for all potential systemic, neurological, and developmental effects. If this information and reliable quantitative data on the chosen endpoint are available, ATSDR derives an MRL using the most sensitive species (when information from multiple species is available) with the highest NOAEL that does not exceed any adverse effect levels. When a NOAEL is not available, a lowest-observed-adverse-effect level (LOAEL) can be used to derive an MRL, and an uncertainty factor (UF) of 10 must be employed. Additional uncertainty factors of 10 must be used both for human variability to protect sensitive subpopulations (people who are most susceptible to the health effects caused by the substance) and for interspecies variability (extrapolation from animals to humans). In deriving an MRL, these individual uncertainty factors are multiplied together. The product is then divided into the inhalation concentration or oral dosage selected from the study. Uncertainty factors used in developing a substance-specific MRL are provided in the footnotes of the LSE Tables. *** DRAFT FOR PUBLIC COMMENT *** ACGIH ADME atm ATSDR BCF BSC C CDC CEL CERCLA CFR CLP cm CNS d DHEW DHHS dL DOL ECG EEG EPA EKG F Fy FAO FEMA FIFRA fpm ft FR g GC gen HPLC hr IDLH IARC ILO in Kd kkg oC Kow B-1 APPENDIX B ACRONYMS, ABBREVIATIONS, AND SYMBOLS American Conference of Governmental Industrial Hygienists Absorption, Distribution, Metabolism, and Excretion atmosphere Agency for Toxic Substances and Disease Registry bioconcentration factor Board of Scientific Counselors Centigrade Centers for Disease Control Cancer Effect Level Comprehensive Environmental Response, Compensation, and Liability Act Code of Federal Regulations Contract Laboratory Program centimeter central nervous system day Department of Health, Education, and Welfare Department of Health and Human Services deciliter Department of Labor electrocardiogram electroencephalogram Environmental Protection Agency see ECG Fahrenheit first filial generation Food and Agricultural Organization of the United Nations Federal Emergency Management Agency Federal Insecticide, Fungicide, and Rodenticide Act feet per minute foot Federal Register gram gas chromatography generation high-performance liquid chromatography hour Immediately Dangerous to Life and Health International Agency for Research on Cancer International Labor Organization inch adsorption ratio kilogram metric ton organic carbon partition coefficient octanol-water partition coefficient *** DRAFT FOR PUBLIC COMMENT *** L LC LC, LCs LD, LDs, LOAEL LSE m mg min mL mm mmHg mmol mo mOsm mppcf MRL MS NIEHS NIOSH NIOSHTIC ng nm NHANES nmol NOAEL NOES NOHS NPL NRC NTIS NTP OSHA PEL pg pmol PHS PMR ppb ppm ppt REL RfD RTECS sec SCE B-2 APPENDIX B liter liquid chromatography lethal concentration, low lethal concentration, 50% kill lethal dose, low lethal dose, 50% kill lowest-observed-adverse-effect level Levels of Significant Exposure meter milligram minute milliliter millimeter millimeters of mercury millimole month milliosmolal millions of particles per cubic foot Minimal Risk Level mass spectrometry National Institute of Environmental Health Sciences National Institute for Occupational Safety and Health NIOSH's Computerized Information Retrieval System nanogram nanometer National Health and Nutrition Examination Survey nanomole no-observed-adverse-effect level National Occupational Exposure Survey National Occupational Hazard Survey National Priorities List National Research Council National Technical Information Service National Toxicology Program Occupational Safety and Health Administration permissible exposure limit picogram picomole Public Health Service proportionate mortality ratio parts per billion parts per million parts per trillion recommended exposure limit Reference Dose Registry of Toxic Effects of Chemical Substances second sister chromatid exchange *** DRAFT FOR PUBLIC COMMENT *** SIC SMR STEL STORET TLV TSCA TRI TWA U.S. UF yr WHO wk EE RR KIA A VV = ae B-3 APPENDIX B Standard Industrial Classification standard mortality ratio short term exposure limit STORAGE and RETRIEVAL threshold limit value Toxic Substances Control Act Toxics Release Inventory time-weighted average United States uncertainty factor year World Health Organization week greater than greater than or equal to equal to less than less than or equal to percent alpha beta delta gamma micron microgram *** DRAFT FOR PUBLIC COMMENT *** APPENDIX C PEER REVIEW A peer review panel was assembled for ethylene glycol /propylene glycol. The panel consisted of the following members: Dr. Gregory Grauer, Associate Professor, Department of Clinical Sciences, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins, Colorado; Dr. Philip Leber, Private Consultant, Chem-Tox Consulting, Akron, Ohio; Dr. Kenneth McMartin, Professor, Department of Pharmacology and Therapeutics, Section of Toxicology, Louisiana State University Medical Center, Shreveport, Louisiana. These experts collectively have knowledge of ethylene glycol /propylene glycol’s physical and chemical properties, toxicokinetics, key health end points, mechanisms of action, human and animal exposure, and quantification of risk to humans. All reviewers were selected in conformity with the conditions for peer review specified in Section 104(i)(13) of the Comprehensive Environmental Response, Compensation, and Liability Act, as amended. Scientists from the Agency for Toxic Substances and Disease Registry (ATSDR) have reviewed the peer reviewers’ comments and determined which comments will be included in the profile. A listing of the peer reviewers’ comments not incorporated in the profile, with a brief explanation of the rationale for their exclusion, exists as part of the administrative record for this compound. A list of databases reviewed and a list of unpublished documents cited are also included in the administrative record. The citation of the peer review panel should not be understood to imply its approval of the profile’s final content. The responsibility for the content of this profile lies with the ATSDR. *** DRAFT FOR PUBLIC COMMENT *** U. C. BERKELEY LIBRARIES CO41LbL53504