TOXICOLOGICAL PROFILE FOR 1,3-DICHLOROPROPENE Prepared by: Syracuse Research Corporation Under Subcontract to: Clement International Corporation Under Contract No. 205-88-0608 Prepared for: Agency for Toxic Substances and Disease Registry U.S. Public Health Service September 1992 Publ ii 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. il RA 12¢1 2. FOREWORD oo Debs The Superfund Amendments and Reauthorization Act (SARA) of 1986 } 671 (Public Law 99-499) extended and amended the Comprehensive Environmental | £47 Response, Compensation, and Liability Act of 1980 (CERCLA or Superfund). Co This public law directed the Agency for Toxic Substances and Disease PUBL Registry (ATSDR) to prepare toxicological profiles for hazardous substances which are most commonly found at facilities on the CERCLA National Priorities List and which pose the most significant potential threat to human health, as determined by ATSDR and the Environmental Protection Agency (EPA). The lists of the 250 most significant hazardous substances were published in the Federal Register on April 17, 1987; on October 20, 1988; on October 26, 1989; and on October 17, 1990. A revised list of 275 substances was published on October 17, 1991. Section 104(i)(3) of CERCLA, as amended, directs the Administrator of ATSDR to prepare a toxicological profile for each substance on the lists. Each profile must include the following content: (A) An examination, summary, and interpretation of available toxicological information and epidemiological evaluations on the 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, an 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 toxicological profile 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 profile will be revised and republished as necessary. The ATSDR toxicological profile is intended to characterize succinctly the toxicological and adverse health effects information for the hazardous substance being described. Each profile 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 profile is not intended to be an exhaustive document; however, more comprehensive sources of specialty information are referenced. iv Foreword Each toxicological profile 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 profiles is on health and toxicological information; therefore, we have included this information in the beginning of the document. The principal audiences for the toxicological profiles are health professionals at the federal, state, and local levels, interested private sector organizations and groups, and members of the public. This profile 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, the NTP, and other federa. agencies. It has also been reviewed by a panel of nongovernment peer reviewers. Final responsibility for the contents and views expressed in this toxicological profile resides with ATSDR. William L. Roper, M.D., M.P.H. Administrator Agency for Toxic Substances and Disease Registry CONTENTS FOREWORD LIST OF FIGURES LIST OF TABLES | UBLIC HEALTH STATEMENT z WHAT IS 1,3- DICHLOROPROPENE? HOW MIGHT I BE EXPOSED TO 1,3- DICHLOROPROPENE? HOW CAN 1,3-DICHLOROPROPENE ENTER AND LEAVE MY BODY? P 1 1. 1 : HOW CAN 1,3-DICHLOROPROPENE AFFECT MY HEALTH? 1 ue wn = EXPOSED TO 1,3-DICHLOROPROPENE? . WHAT RECOMMENDATIONS HAS THE FEDERAL GOVERNMENT MADE TO PROTECT HUMAN HEALTH? . 1.7 WHERE CAN I GET MORE INFORMATION? 1. a 2. HEALTH EFFECTS 2.1 INTRODUCTION . ‘ 2.2 DISCUSSION OF HEALTH EFFECTS BY ROUTE OF EXPOSURE 2.2.1 Inhalation Exposure 1. Death . Systemic Pffects Immunological Effects Neurological Effects Developmental Effects Reproductive Effects Genotoxic Effects Cancer posure Death . Systemic Rffects Immunological Effects Neurological Effects Developmental Effects Reproductive Effects Genotoxic Effects Cancer 1 Exposure Death Systemic Effects Immunological Effects Neurological Effects Developmental Effects Reproductive Effects Genotoxic Effects Cancer EE ee 2.2.2 ral E ONO UVLMP WRX ONO WVLE WN = 2.2.3 erm NNN NNNNNNNONMNNRNNNDNNNNNNONMNDNNNNNNDNDND NRO NNNPNONDNNE DNNNNDNNNNNDNNDNNDD ONNMNNNNNNNDNNNDND WWWWWWwWwWwWwDd MND NNNNDN oO HS WN IS THERE A MEDICAL TEST TO DETERMINE WHETHER I HAVE BEEN iii ix xi wv ww == O WO 00 J J 26 27 28 28 28 29 29 36 39 39 39 39 39 39 40 40 40 45 45 46 46 46 46 vi 2.3 TOXICOKINETICS 2.3.1 Absorption . ‘ 2.3.1.1 Iohaletion ENpeauLe 2.3.1.2 Oral Exposure 2.3.1.3 Dermal Exposure istribution . .1 Trhalation fuposure 2 Oral Exposure 3 Dermal Exposure lism . Co 1 Tobalation LRposuTe 2 Oral Exposure 3 io 1 2.3.2 2.3.3 bermal Exposure ret POF BW A FR 4b P ahalation Exposure 2 Oral Exposure 2.3.4.3 Dermal Exposure 2.4 RELEVANCE TO PUBLIC HEALTH 2.5 BIOMARKERS OF EXPOSURE AND EFFECT Dis 2.3.2 2.3.2. i Metabo 2.3.3. 2.3.3. 2.3.3. Excre 2.3.4. 2.3.4. 3. 2.5.1 Biomarkers Used to Identify and/or Quantify Enposure to 1,3-Dichloropropene 2.5.2 Biomarkers Used to Chasavterize Effects Caused uy 1,3-Dichloropropene . INTERACTIONS WITH OTHER CHEMICALS ; . POPULATIONS THAT ARE UNUSUALLY SUSCEPTIBLE . MITIGATION OF EFFECTS ADEQUACY OF THE DATABASE . 2.9.1 Existing Information on Health ‘Effects of 1,3-Dichloropropene 2 Data Needs . 3 On-going Studies NNN O 0 NO 2.9. 2.9. CHEMICAL AND PHYSICAL INFORMATION 3.1 CHEMICAL IDENTITY 3.2 PHYSICAL AND CHEMICAL PROPERTIES PRODUCTION, IMPORT, USE, AND DISPOSAL . 4.1 PRODUCTION 4.2 IMPORT/EXPORT 4.3 USE 4.4 DISPOSAL . POTENTIAL FOR HUMAN EXPOSURE 5.1 OVERVIEW . : 5.2 RELEASES TO THE ENVIRONMENT 5.2.1 Air 5.2.2 Water 5.2.3 Soil 5.3 ENVIRONMENTAL FATE . 5.3.1 Transport and Partitioning 5.3.2 Transformation and Degradation 46 46 46 47 47 47 47 47 48 48 48 50 50 50 50 50 52 52 62 63 63 63 64 64 65 65 67 75 77 77 77 81 81 81 81 81 85 85 87 87 87 88 88 88 90 vii 5.3.2.1 Air 5.3.2.2 Vater 5.3.2.3 Soil 5.4 LEVELS MONITORED OR ESTIMATED IN THE ENVIRONMENT 5.4.1 Air 5.4.2 Water 5.4.3 Soil . 5.4.4 Other Eonvizovmentl Media . . 5.5 GENERAL POPULATION AND OCCUPATIONAL EXPOSURE . 5.6 POPULATIONS WITH POTENTIALLY HIGH EXPOSURES 5.7 ADEQUACY OF THE DATABASE . 5.7.1 Data Needs . 5.7.2 On-going Studies 6. ANALYTICAL METHODS 6.1 BIOLOGICAL MATERIALS 6.2 ENVIRONMENTAL SAMPLES 6.3 ADEQUACY OF THE DATABASE 6.3.1 Data Needs . 6.3.2 On-going Studies 7. REGULATIONS AND ADVISORIES 8. REFERENCES 9. GLOSSARY APPENDICES A. USER'S GUIDE B. ACRONYMS, ABBREVIATIONS, AND SYMBOLS C. PEER REVIEW . 90 91 91 92 92 92 93 93 93 94 95 95 98 99 99 99 103 103 104 105 107 121 B-1 Cc-1 2-1 2-2 2-3 2<4 2-5 5-1 ix LIST OF FIGURES Levels of Significant Exposure to 1,3-Dichloropropene - Inhalation Levels of Significant Exposure to 1,3-Dichloropropene - Oral Correlation of Exposure to 1,3-Dichloropropane with Urinary Excretion of the N-Acetyl Cysteine Metabolite Proposed Metabolic Pathway for 1,3-Dichloropropene in the Rat Existing Information on Health Effects of 1,3-Dichloropropene Frequency of NPL Sites with 1,3-Dichloropropene Contamination 19 34 49 51 66 86 2-1 2-2 2-3 2-4 3-1 3-2 7-1 xi LIST OF TABLES Levels of Significant Exposure to 1,3-Dichloropropene - Inhalation . Levels of Significant Exposure to 1,3-Dichloropropene - Oral Levels of Significant Exposure to 1,3-Dichloropropene - Dermal Genotoxicity of 1,3-Dichloropropene In Vitro . Chemical Identity of the Isomers of 1,3-Dichloropropene Physical and Chemical Properties of the Isomers of 1,3-Dichloropropene Reported Compositions of Commercial Products Containing 1,3-Dichloropropene Analytical Methods for Determining cis- and trans-1,3-Dichloropropene in Biological Materials Analytical Methods for Determining 1,3-Dichloropropene in Environmental Samples Regulations and Guidelines Applicable to 1,3-Dichloropropene 10 30 41 59 78 79 82 100 102 106 1. PUBLIC HEALTH STATEMENT This Statement was prepared to give you information about 1,3-dichloro- propene and to emphasize the human health effects that may result from exposure to it. The Environmental Protection Agency (EPA) has identified 1,177 sites on its National Priorities List (NPL). 1,3-Dichloropropene has been found at 3 of these sites. However, we do not know how many of the 1,177 NPL sites have been evaluated for 1,3-dichloropropene. As EPA evaluates more sites, the number of sites at which 1,3-dichloropropene is found may change. The information is important for you because 1,3-dichloropropene may cause harmful effects and because these sites are potential or actual sources of human exposure to 1,3-dichloropropene. When a chemical is released from a large area 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 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 substance such as 1,3-dichloropropene, 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 IS 1,3-DICHLOROPROPENE? 1,3-Dichloropropene is a colorless liquid with a sweet smell. It dissolves in water and evaporates easily. There are two kinds of 1,3-dichloropropene, cis-1,3-dichloropropene and trans-1,3-dichloropropene, which are very closely related. These different forms of the same chemical behave very much alike and are usually combined in different amounts to form mixtures. The mixtures are mainly used in farming to kill tiny pests called nematodes that eat the roots of important crops. Sometimes, these mixtures also have small amounts of other chemicals that are very similar to 1,3-dichloropropene. When 1,3-dichloropropene is used in farm fields, it is sprayed into the ground. Once in the soil, some of it is likely to be broken down into smaller chemicals by either water or living things. These smaller chemicals may also pose a health hazard. Some of it may be carried deeper into the ground and may reach underground water supplies. However, in high crop-producing states like California where it has been used often, very little 1,3-dichloropropene has actually been found in groundwater. 1,3-Dichloropropene, however, may be 2 1. PUBLIC HEALTH STATEMENT a problem at hazardous waste sites, where a variety of different chemicals are often buried in the ground together. These other chemicals can stop 1,3-dichloropropene from breaking down. Therefore, it is possible for 1,3-dichloropropene to reach groundwater from a hazardous waste site. Some of the 1,3-dichloropropene sprayed onto the ground will evaporate into the air. In the air, 1,3-dichloropropene will be broken down into smaller chemicals by sunlight. Some of the 1,3-dichloropropene in air may be washed down into the ground, lakes, or streams by rain. In water, 1,3-dichloropropene is expected to break down into small chemicals. Some of the 1,3-dichloropropene in water will also go back into the air. You will find more information on the chemical properties of 1,3-dichloropropene in Chapter 3. The uses of 1,3-dichloropropene are described in Chapter 4. More information on how 1,3-dichloropropene will behave in the environment is given in Chapter 5. 1.2 HOW MIGHT I BE EXPOSED TO 1,3-DICHLOROPROPENE? You can breathe 1,3-dichloropropene from the air. It can also get on your skin. The people most likely to breathe air containing 1,3-dichloropropene or to get it on their skin are workers who use it for farming or make it in factories. Small amounts of 1,3-dichloropropene can form in your drinking water when chlorine is added to the water supply. (Chlorine is added to kill germs in the water.) Crops that are grown in fields treated with 1,3-dichloropropene are most likely to contain it. However, food grown in 1,3-dichloropropene treated fields has not been shown to contain 1,3-dichloropropene. We do not know if this is because 1,3-dichloropropene is rapidly removed or broken down in the environment, or the treated crops break it down. Very small amounts of 1,3-dichloropropene from sewage treatment facilities, electrical power stations, and industrial facilities that use water to cool high-temperature furnaces may go into streams, rivers, and lakes. Some may go into the air. People who live near garbage dumps or places where chemicals are stored or buried, including hazardous waste sites, may breathe 1,3-dichloropropene if it escapes into the air or have 1,3-dichloropropene in their well water. They may drink some 1,3-dichloropropene in the tap water. They may also be exposed through skin contact with soil containing it. 1,3-Dichloropropene has been discovered at only three hazardous waste sites and in only a few underground water supplies. Again, we do not know if this is because 1,3-dichloropropene is not at other sites, or because it has not been looked for at other sites. In general, very little information is available about how much 1,3-dichloropropene is in the environment. We do not know the levels in soil, water, and air. 1. PUBLIC HEALTH STATEMENT You can find more information on how much 1,3-dichloropropene has been found in the environment and how you can be exposed to it in Chapter 5. 1.3 HOW CAN 1,3-DICHLOROPROPENE ENTER AND LEAVE MY BODY? 1,3-Dichloropropene can enter your body if you breathe air that contains it, if you drink water that is contaminated with it, or even if you touch it. Studies with animals have shown that if you breathe air that has 1,3-dichloropropene in it, most of the chemical will get into your bloodstream. Of course, the longer you breathe air with 1,3-dichloropropene in it, the more of it will enter your body. Also, the more water you drink with 1,3-dichloropropene in it, the more will pass into your bloodstream from your stomach or intestines. The longer 1,3-dichloropropene is in contact with your skin, the more of it will get into your body. If you live or work near a hazardous waste site where 1,3-dichloropropene is stored, you might breathe it if it escapes into the air. 1,3-Dichloropropene can get into the groundwater and into wells that supply drinking water, so you could drink water contaminated with it. You can also get 1,3-dichloropropene on your skin if you come into contact with soil contaminated with it. People who live in farming communities where 1,3-dichloropropene is used as a pesticide are also likely to come into contact with this chemical. Your body can get rid of 1,3-dichloropropene fairly quickly. Studies with animals have shown that most 1,3-dichloropropene leaves the body within 2 days. Most 1,3-dichloropropene leaves your body in urine, and smaller amounts leave in feces and the air you breathe out. For more information on how 1,3-dichloropropene gets into and leaves your body, see Chapter 2. 1.4 HOW CAN 1,3-DICHLOROPROPENE AFFECT MY HEALTH? The main health effects seen in humans who breathed 1,3-dichloropropene are: nausea; vomiting; irritation of the skin, eyes, nose, and throat; breathing difficulties; coughing; headache; and fatigue. Some people who breathed 1,3-dichloropropene could smell it when the amount reached 1 part 1,3-dichloropropene per million parts of air (ppm), but you may be able to smell it at even lower amounts. We do not know if 1,3-dichloropropene causes cancer in humans; however, three men who breathed 1,3-dichloropropene during the cleanup of a spill or during field spraying developed similar kinds of cancer, but we cannot be sure if 1,3-dichloropropene was the cause. Mice and rats that swallowed 1,3-dichloropropene got cancer. We do not know whether 1,3-dichloropropene can cause birth defects in humans. Although 1,3-dichloropropene did not cause birth defects in animals, pregnant rats that breathed it gave birth to fewer rat pups. Rats had lung damage and eye irritation and rabbits had difficulty getting on their feet and walking after they breathed high levels of 1,3-dichloropropene for short periods of time. Some rats even died. Rats and mice had damage to the lining of the nose, and mice had damage to the lining 4 1. PUBLIC HEALTH STATEMENT of the bladder after breathing lower levels of 1,3-dichloropropene for longer periods of time. Rats that swallowed single high doses of 1,3-dichloropropene had damage to the lining of the stomach, lung congestion, and difficulty walking. These effects were worse in rats that swallowed even higher doses, and included bleeding of the stomach, intestines, liver, and lungs. Some of the rats died. Rats had increased liver and kidney weights, which may indicate harmful effects in these organs, after swallowing lower doses every day for longer periods of time. Rats had damage to the lining of the stomach and some had cancer of the stomach and liver after swallowing low doses for most of their lives. Mice that swallowed low doses of 1,3-dichloropropene for most of their lives had stomach and kidney damage, and some had cancer of the stomach, urinary bladder, and lungs. Rabbits had irritated skin and hair loss, and guinea pigs had irritated skin and became allergic to 1,3-dichloropropene after a small amount was painted onto their backs. Rats that had large amounts of 1,3-dichloropropene painted onto their backs had skin irritation, difficulty breathing and walking, and bleeding from the lungs, stomach, and under the skin, and some even died. Rabbits had muscle bleeding, open sores and hair loss, and some even died after a large amount of 1,3-dichloropropene was painted onto their backs. You can find a more complete discussion of the health effects of 1,3-dichloropropene in humans and animals in Chapter 2. 1.5 IS THERE A MEDICAL TEST TO DETERMINE WHETHER I HAVE BEEN EXPOSED TO 1,3-DICHLOROPROPENE? It is possible to measure 1,3-dichloropropene or its breakdown products in blood and urine. The presence of 1,3-dichloropropene or its breakdown products in blood and urine, however, could also mean you were exposed to some other chemical that breaks down to 1,3-dichloropropene. In humans, the blood levels of breakdown products from 1,3-dichloropropene could be used to predict how much 1,3-dichloropropene has been breathed. However, tests for 1,3-dichloropropene in the blood and urine would only be useful for recent exposures, because 1,3-dichloropropene leaves the body within 1-2 days. You can find more information about these tests in Chapters 2 and 6. 1.6 WHAT RECOMMENDATIONS HAS THE FEDERAL GOVERNMENT MADE TO PROTECT HUMAN HEALTH? EPA has set 100 pounds as the limit of 1,3-dichloropropene that can be released into the environment at any particular site; releases of more than that must be reported. EPA has also set a limit of 87 micrograms 1,3-dichloropropene per liter of water (87 ug/L or 87 parts per billion [ppb]) for the amount of 1,3-dichloropropene that can be in lakes and streams. The Occupational Safety and Health Administration (OSHA) has set a limit of 1 ppm of 1,3-dichloropropene in the air you breathe at work. For more information on the regulations for 1,3-dichloropropene, see Chapter 7. 5 1. PUBLIC HEALTH STATEMENT 1.7 WHERE CAN I GET MORE INFORMATION? If you have any more questions or concerns not covered here, please contact your state health or environmental department or: Agency for Toxic Substances and Disease Registry Division of Toxicology 1600 Clifton Road, E-29 Atlanta, Georgia 30333 This agency can also provide you with information on the location of the nearest occupational and environmental health clinic. Such clinics specialize in recognizing, evaluating, and treating illnesses that result from exposure to hazardous substances. 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 1,3-dichloropropene 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 1,3-dichloropropene based on toxicological studies and epidemiological investigations. 1,3-Dichloropropene is widely used as a preplanting soil fumigant for the control of nematodes, and it has been available for agricultural use in many formulations. Formulations, instead of pure 1,3-dichloropropene, were used in most of the studies discussed here. The trade names and components of these formulation are listed below: Formulation Composition Telone® 40.2% cis, 38.3% trans (not otherwise specified) Telone C-17° 40%-41% cis, 38%-39% trans 19%-21% chloropicrin Telone I1I%a 48-53% cis, 42-45% trans 1% epichlorohydrin (not otherwise specified) Telone II®b 48%-53% cis, 42%-45% trans 2% epoxidized soybean oil DD® 25%-28% cis, 25%-27% trans 25%-29% 1,2-dichloropropane DD-92° 92% cis/trans (not otherwise specified) M-3993 48%-53% cis, 42%-45% trans 1% epichlorohydrin (not otherwise specified) In some studies, the investigation of the toxicity of 1,3-dichloropropene may have been confounded by other components in a formulation (e.g., chloropicrin and epichlorohydrin). This possibility is discussed in the appropriate sections of the text. Separate tables and figures for each formulation of 1,3-dichloropropene are not presented. Instead, the formulation used in each study is identified in the appropriate 8 2. HEALTH EFFECTS table. Further information on the formulations of 1,3-dichloropropene can be found in Chapter 4. 2.2 DISCUSSION OF HEALTH EFFECTS BY ROUTE OF EXPOSURE To help public health professionals address the needs of persons living or working near hazardous waste sites, the information in this section is organized first by route of exposure--inhalation, oral, and dermal--and then by health effect--death, systemic, immunological, neurological, developmental, reproductive, genotoxic, and carcinogenic effects. These data are discussed in terms of three exposure periods--acute (less than 15 days), intermediate (15-364 days), and chronic (365 days or more). 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 (NOAELs) 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 the 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 effects to human health. The significance of the exposure levels shown in the tables and figures may differ depending on the user's perspective. For example, physicians concerned with the interpretation of clinical findings in exposed persons may be interested in levels of exposure associated with "serious" effects. Public health officials and project managers concerned with appropriate actions to take at hazardous waste sites may want information on levels of exposure associated with more subtle effects in humans or animals (LOAEL) or exposure levels below which no adverse effects (NOAEL) have been observed. Estimates of levels posing minimal risk to humans (Minimal Risk Levels, MRLs) may be of interest to health professionals and citizens alike. Estimates of exposure levels posing minimal risk to humans (MRLs) have been made, where data were believed reliable, for the most sensitive noncancer effect for each exposure duration. MRLs include adjustments to reflect human variability from laboratory animal data to humans. Although methods have been established to derive these levels (Barnes et al. 1988; EPA 1989), uncertainties are associated with these techniques. Furthermore, ATSDR acknowledges additional uncertainties inherent in the application of the procedures to derive less than lifetime MRLs. As an example, acute inhalation MRLs may not be protective for health effects that are delayed in development or are acquired following repeated acute insults, such as hypersensitivity reactions, asthma, or chronic bronchitis. As these 9 2. HEALTH EFFECTS kinds of health effects data become available and methods to assess levels of significant human exposure improve, these MRLs will be revised. 2.2.1 Inhalation Exposure 2.2.1.1 Death No studies were located regarding death in humans after inhalation exposure to 1,3-dichloropropene. LCs; values for inhalation exposure to 1,3-dichloropropene have been determined in rats (Streeter and Lomax 1988; Streeter et al. 1987). The LCs, for female rats exposed to Telone II®a for 4 hours was 904 ppm (95% confidence interval= 846-990 ppm) (Streeter et al. 1987). The LCs, for male rats could not be determined in this study but fell in the range 855-1035 ppm 1,3-dichloropropene. Telone C-17® appears to be more toxic than Telone 11%; the LCs, for rats after a l-hour exposure to Telone C-17® was 253 ppm (no range reported) (Streeter and Lomax 1988). Telone C-17® contains a relatively high proportion of chloropicrin, which may account for the enhanced toxicity. Six of 10 rats died after a 4-hour exposure to 676 ppm Telone II®a. In the same study, no rats died after a 4-hour exposure to 595 ppm or less of Telone II®a (Cracknell et al. 1987). Rabbits exposed to 300 ppm during gestation days 6-18 developed ataxia and died (Kloes et al. 1983). The cause of death was not determined, although lung congestion and edema were noted on necropsy. Intermediate- or chronic-duration exposures of mice, rats, guinea pigs, rabbits, and dogs to Telone II%a or Telome II®b (1-150 ppm for 4 weeks to 2 years) had no effect on survival rates compared to control groups that were untreated or exposed to filtered room air (Coate 1979a, 1979b; Linnett et al. 1988; Lomax et al. 1989; Stott et al. 1988; Torkelson and Oyen 1977). The LCs, values, the highest NOAEL values, and all reliable LOAELs for death in each species and duration category are recorded in Table 2-1 and plotted in Figure 2-1. 2.2.1.2 Systemic Effects The systemic effects observed in humans and animals after inhalation exposure to 1,3-dichloropropene are discussed below. The highest NOAEL values and all reliable LOAEL values for each systemic effect for each species and duration category are recorded in Table 2-1 and plotted in Figure 2-1. Respiratory Effects. Humans exposed to 1,3-dichloropropene (not otherwise specified) after a tank truck spill complained of mucous membrane TABLE 2-1. Levels of Significant Exposure to 1,3-Dichloropropene - Inhalation Exposure LOAEL (effect) Key to frequency/ NOAEL Less serious Serious figure? Species duration System (ppm) (ppm) (ppm) Reference Formulation ACUTE EXPOSURE Death 1 Rat 1d 253 (LCs) Streeter and T C17 1 hr/d Lomax 1988 2 Rat 1d 904 (LCgo females) Streeter et al. T Ila 4 hr/d 1987 3 Rat 1d 595 676 (6/10 died) Cracknell et al. T IIa 4 hr/d 1987 4 Rabbit 13 d 150 300 (6/7 died) Kloes et al. T Ila Gd 6-18 1983 6 hr/d Systemic 5 Rat 1d Resp 582 595 (swollen lungs) 676 (lung congestion) Cracknell et al. T Ila 4 hr/d Other 595 676 (adrenal 1987 congestion) 6 Rat 1d Resp 206 (atelectasis) Streeter and T C-17 1 hr/d Derm/oc 206 (eye irritation) Lomax 1988 7 Rat 1d Resp 1,035 (lung hemorrhage) Streeter et al. T Ila 4 hr/d Derm/oc 775 (eye irritation) 1987 8 Rat 1d Derm/oc 1,146 (eye irritation) Yakel and Kociba T Ila 1 hr/d 1977 Neurological 9 Rabbit 13d 150 300 (ataxia) Kloes et al. T Ila 6 hr/d 1983 Developmental 10 Rat 10d 150 300 (decreased litter Kloes et al. T Ila Gd 6-15 size) 1983 6 hr/d "g SLOdddd HLIVAH 01 TABLE 2-1 (Continued) LOAEL (effect) Exposure Key to frequency/ NOAEL Less serious Serious figure? Species duration System (ppm) (ppm) (ppm) Reference Formulation 11 Rabbit 13 d 150 Kloes et al. T Ila Gd 6-18 1983 6 hr/d INTERMEDIATE EXPOSURE Death 12 Rat 13 wk 150 Stott et al. T IIa 5 d/wk 1988 6 hr/d 13 Rabbit 6 mo 3 Torkelson and T IIa 5 d/wk Oyen 1977 0.5-4 hr/d 14 Gn pig 6 mo 3 Torkelson and T Ila 5 d/wk Oyen 1977 0.5-4 hr/d 15 Mouse 13 wk 150 Stott et al. T Ila 5 d/wk 1988 6 hr/d 16 Dog 6 mo 3 Torkelson and T IIa 5 d/wk Oyen 1977 0.5-4 hr/d Systemic 17 Rat 13 wk Resp 10 30 (nasal epithelial Coate 1979a T IIa 5 d/wk changes) 6 hr/d Cardio 90 Hepatic 90 Renal 80 18 Rat 10 wk Hemato 90 Linnett et al. pp® 5 d/wk Hepatic 90 1988 6 hr/d Renal 90 C S10d44d HLTVIH IT TABLE 2-1 (Continued) LOAEL (effect) Exposure Key to frequency/ NOAEL Less serious Serious figure? Species duration System (ppm) (ppm) (ppm) Reference Formulation 19 Rat 180 d Resp 30 90 (nasal lesions) Breslin et al. T IIb 5-7 d/wk Gastro 90 1989 6 hr/d Hepatic 30 Renal 30 20 Rat 13 wk Resp 30 80 (nasal Stott et al. T IIa 5 d/wk hyperplasia) 1988 6 hr/d Cardio 150 Gastro 150 Hemato 150 Musc/skel 150 Hepatic 150 Renal 150 Derm/oc 150 21 Rat 6 mo Resp 3 Torkelson and T IIa 5 d/wk Cardio 3 Oyen 1977 7 hr/d Hemato 3 Hepatic 3 22 Rabbit 6 mo Resp 3 Torkelson and T IIa 5 d/wk Cardio 3 Oyen 1977 0.5-4 hr/d Hemato 3 Hepatic 3 Renal 3 23 Gn pig 6 mo Resp 3 Torkelson and T Ila 5 d/wk Cardio 3 Oyen 1977 0.5-4 hr/d Hemato 3 Hepatic 3 Renal 3 C SLOdddd HITVAH Cl TABLE 2-1 (Continued) LOAEL (effect) Exposure Key to frequency/ NOAEL Less serious Serious figure? Species duration System (ppm) (ppm) (ppm) Reference Formulation 24 Mouse 13 wk Resp 30 90 (nasal Stott et al. T IIa 5 d/wk hyperplasia) 1988 6 hr/d Cardio 150 Gastro 150 Hemato 150 Musc/skel 150 Hepatic 150 Renal 30 80 (bladder hyperplasia) 25 Mouse 6-12 mo Resp 5 20 (hyperplasia) Lomax et al. T IIb 5 d/wk Cardio 60 1989 6 hr/d Gastro 60 Hemato 60 Musc/skel 60 Hepatic 60 Renal 20 60 (bladder hyperplasia) Derm/oc 60 26 Mouse 13 wk Resp 90 (nasal epithelial Coate 197%9a T Ila 5 d/wk changes) 6 hr/d Cardio 90 Hepatic 30 Renal 90 27 Dog 6 mo Resp 3 Torkelson and T Ila 5 d/wk Cardio 3 Oyen 1977 0.5-4 hr/d Gastro 3 Hemato 3 Musc/skel 3 Renal 3 Immunological 28 Rat 6-12 mo 60 Lomax et al. T IIb 5 d/wk 1989 6 hr/d C S10dd4dd HITVAH el TABLE 2-1 (Continued) LOAEL (effect) Exposure Key to frequency/ NOAEL Less serious Serious figure? Species duration System (ppm) (ppm) (ppm) Reference Formulation 23 Rat 13 wk 150 Stott et al. T Ila 5 d/wk 1988 6 hr/d 30 Rat 6-12 wk 50 Parker et al. pp° 5 d/wk 1982 6 hr/d 3 Mouse 13 wk 150 Stott et al. T Ila 5 d/wk 1988 6 hr/d > 32 Mouse 6-12 mo 60 Lomax et al. T 1Ib - 5 d/wk 1989 m > 6 hr/d = @ = 33 Mouse 6-12 wk 50 Parker et al. DD = 5 d/wk 1982 t= Tj 6 hr/d >] 53] Neurological 8 wn 34 Rat 6-12 mo 60 Lomax et al. T IIb 5 d/wk 1989 6 hr/d 35 Rat 13 wk 150 Stott et al. T 11a 5 d/wk 1988 6 hr/d 36 Rat 6-12 wk 50 Parker et al. op® 5 d/wk 1982 6 hr/d 37 Rabbit 6 mo 3 Torkelson and T Ila 5 d/wk Oyen 1977 0.5-4 hr/d KA! TABLE 2-1 (Continued) LOAEL (effect) Exposure Key to frequency/ NOAEL Less serious Serious figure? Species duration System (ppm) (ppm) (ppm) Reference Formulation 38 Gn pig 6 mo 3 Torkelson and T IIa 5 d/wk Oyen 1977 0.5-4 hr/d 39 Mouse 6-12 wk 50 Parker et al. op® 5 d/wk 1982 6 hr/d 40 Mouse 6-12 mo 60 Lomax et al. T IIb 5 d/wk 1989 6 hr/d 41 Mouse 13 wk 90 Coate 1979a T IIa 5 d/wk 6 hr/d 42 Mouse 13 wk 150 Stott et al. T IIa 5 d/wk 1988 6 hr/d 43 Dog 6 mo 3 Torkelson and T IIa 5 d/wk Oyen 1977 0.5-4 hr/d Developmental 44 Rat 180 d 90 Breslin et al. T IIb 5-7 d/wk 1989 6 hr/d Reproductive 45 Rat 6-12 mo 60 Lomax et al. T IIb 5 d/wk 1989 6 hr/d 46 Rat 180 d 90 Breslin et al. T IIb 5-7 d/wk 1989 6 hr/d C SLOdJddd HITVIH ST TABLE 2-1 (Continued) LOAEL (effect) Exposure Key to frequency/ NOAEL Less serious Serious figure® Species duration System (ppm) (ppm) (ppm) Reference Formulation 47 Rat 6-12 wk 50 Parker et al. pp*® 5 d/wk 1982 6 hr/d 48 Rat 10 wk 90 Linnett et al. op* 5 d/wk 1988 6 hr/d 49 Rat 13 wk 150 Stott et al. T IIa 5 d/wk 1988 6 hr/d 50 Mouse 6-12 mo 60 Lomax et al. TID 5 d/wk 1989 6 hr/d 51 Mouse 13 wk 150 Stott et al. T IIa 5 d/wk 1988 6 hr/d 52 Mouse 6-12 wk 50 Parker et al. pp® 5 d/wk 1982 6 hr/d CHRONIC EXPOSURE Death 53 Rat 2yr 60 Lomax et al. T IIb 5 d/wk 1989 6 hr/d 54 Mouse 2 yr 60 Lomax et al. T IIb 5 d/wk 1989 6 hr/d C S10dd4d4d HLTVIH 91 TABLE 2-1 (Continued) LOAEL (effect) Exposure Key to frequency/ NOAEL Less serious Serious figure? Species duration System (ppm) (ppm) (ppm) Reference Formulation Systemic 55 Rat 2 yr Resp 20 60 (epithelial Lomax et al. T IIb 5 d/wk degeneration) 1989 6 hr/d Cardio 60 Gastro 60 Hemato 60 Musc/skel 60 Hepatic 60 Renal 60 Derm/oc 60 56 Mouse 2 yr Resp 5¢ 20 (hyperplasia) Lomax et al. T IIb 5 d/wk Cardio 60 1989 6 hr/d Gastro 20 60 (hyperplasia) Hemato 60 Musc/skel 60 Hepatic 60 Renal 60 Derm/oc 60 Immunological 57 Rat 2 yr 60 Lomax et al. T IIb 5 d/wk 1989 6 hr/d Neurological 58 Rat 2 yr 60 Lomax et al. T IIb 5 d/wk 1989 6 hr/d 59 Mouse 2 yr 60 Lomax et al. T IIb 5 d/wk 1989 6 hr/d C S10d44d HLTVIH LT TABLE 2-1 (Continued) LOAEL (effect) Exposure Key to frequency/ NOAEL Less serious Serious figure? Species duration System (ppm) (ppm) (ppm) Reference Formulation Reproductive 60 Rat 2 yr 60 Lomax et al. T IIb 5 d/wk 1989 6 hr/d 61 Mouse 2 yr 60 Lomax et al. T IIb 5 d/wk 1989 6 hr/d 8The number corresponds to the entries in Figure 2-1. bysed to derive an intermediate inhalation minimal risk level (MRL) of 0.003 ppm; concentration adjusted for intermittent exposure, converted to a human equivalent concentration, and divided by an uncertainty factor of 100 (10 for extrapolation from animals to humans, and 10 for human variability). Used to derive a chronic inhalation MRL of 0.002 ppm; dose adjusted for intermittent exposure, converted to a human equivalent concentration, and divided by an uncertainty factor or 100 (10 for extrapolation from animals to humans, and 10 for human variability). Cardio = cardiovascular; d = day(s); pp® = (25% cis-1,3-dichloropropene, 27% trans-1,3-dichloropropene, 28% 1,2-dichloropropane); Derm/oc = dermal/ocular; Gastro = gastrointestinal; Gd = gestation day; Gn pig = guinea pig; Hemato = hematological; hr = hour(s); LCgy = lethal concentration, 50% kill; LOAEL = lowest-observed-adverse-effect level; mo = month(s); Musc/skel = musculoskeletal; NOAEL = no-observed-adverse-effect level; Resp = respiratory; T C-17 = Telone C-17 (40% cis-1,3-dichloropropene, 39% trans-1,3-dichloropropene, 21% chloropicrin); T IIa = Telone ir’ (53% cis-1,3-dichloropropene, 45% trans-1,3-dichloropropene, 1X epichlorohydrin); T IIb = Telone 1° (50% cis-1,3-dichloropropene, 43% trans-1,3-dichloropropene, 2X epoxidized soybean oil); wk = week(s); yr = year(s) 4 S1LOdJdd HLTVAH 81 FIGURE 2-1. Levels of Significant Exposure to 1,3-Dichloropropene - Inhalation (ppm) 10,000 100 10 0.1 ACUTE (<14 Days) Systemic "5, @ior Qtr Qin Key The number next to each point corresponds to entries in Table 2-1. Rat Rabbit oceeon LD50 LOAEL for serlous effects (animals) LOAEL for less serious effects (animals) NOAEL (animals) "g S10dd443 HLIVIH 61 FIGURE 2-1 (Continued) INTERMEDIATE (15-364 Days) Systemic » & a ¥ i & #F Nd & & & SF 5 & © + & 3° > > 2) & & & <&@ oF 8 & 3 (ppm) 10,000 p= 1,000 p OtsmOr Qaum Qeor Oram Qaor Oz4m Qzor OzumQzxr Qzem Q20r 100 (4m Gsm Gro Bor 26m (170 o 18r Bz 170 O18: Oror gn Oesn ©" Oesm© QO2sm 20 ond Fe 7 OQter O20 5m 10 = Qi Ozsm 0186014 Oran O27 Oza Ger Oem O2760m0 Oz Cen Ors OerOz Qe Oz Oar Ome Cen Oe 1} ! 1 1 1 01 Pp 1 1 1 I 0.01 1 Key 0.001 = r Rat LOAEL for less serious effects (animals) : Nirmal ik Yavel or m Mouse O NOAEL (animals) bo Tsk ov h Rabbit , effects other than cancer g Guinea pig / d Dog The number next to each point corresponds to entries in Table 2-1. “2 S103443 HLIVIH 0¢ (ppm) 10,000 1,000 100 0.1 0.01 0.001 FIGURE 2-1 (Continued) INTERMEDIATE (Continued) (15-364 Days) Systemic N > ¥ & J & Si F & > §& ¥ A 2 $ XC © P & £ & iF & 8 ® 9 & & 9 & - Q2or Qotm Qa 2m Qos Osim or ve 4m Oem Q17r Qe Oo im Oar 8 Oesm Oram nam Or por OuomOnsr One Osom som Cas Cure 4 om L ers O3g Oazn 0439 Cogg Cem 1 Key r Rat LOAEL for less serfous effects (animals) - m Mouse (OO NOAEL (animals) h Rabbit g Guinea pig d Dog The number next to each point corresponds 10 entries in Table 2-1. Z S10344d HITVIH 1¢ 100 10 0.1 0.001 FIGURE 2-1 (Continued) CHRONIC (> 365 Days) Systemic @ & * & & F&F FF S$ FoF $& & & F ¥ © > & 3 & £ & & 5 & $ ¢ $ & & & § * ® J ° L ¥ LF ® Ni € * ® Osam Osa @s OsemOsse PsemOsse Osem Osse Ossm Oss Oem Osse Osan Ose OsemOsse O57 Osom Ose Osim Or @sem Oss frramannnnensy Osem Key r Rat m Mouse ( LOAEL for less serious effects (animals) . 1 Minimal risk level for QO NOAEL (animals) ' 1 effects other than cancer rs The number next to each point corresponds to entries in Table 2-1. C S103443 HLIT1VIH [AA 23 2. HEALTH EFFECTS irritation, chest pain, cough, and breathing difficulties (Flessel et al. 1978; Markovitz and Crosby 1984). Acute-duration exposures of rats to various formulations of 1,3-dichloropropene caused respiratory effects. Gross pathological examination revealed atelectasis, emphysema, and/or edema in rats exposed to 206 ppm of Telone C-17® for 1 hour. Atelectasis was still present in animals surviving the 2-week observation period (Streeter and Lomax 1988). As noted for death in Section 2.2.1.1, Telone C-17® also appears to be more toxic than Telone II%a after acute-duration exposure. The presence of chloropicrin may enhance the toxicity of Telone C-17®. No respiratory effects were noted in rats after a 4-hour exposure to 582 ppm of Telone II®a, although swollen lungs were observed in rats after a 4-hour exposure to 595 ppm. This indicated a steep concentration-response curve (Cracknell et al. 1987). In the same study, rats exposed to 676 ppm had lung congestion, tracheal congestion, and fluid in the thoracic cavity (Cracknell et al. 1987). Multifocal lung hemorrhage was observed in rats exposed for 4 hours to 1,035 ppm of Telone II%a (Streeter et al. 1987). Intermediate-duration exposure studies indicate that effects on the upper respiratory tract appear to be concentration- and duration-related. Rats and mice had no respiratory lesions attributable to Telone I1I%a after exposure to 30 ppm or less for 4 weeks (Coate 1979b). Similarly, no respiratory lesions attributable to DD® were observed after gross and microscopic evaluation of rats exposed to 50 ppm or less for 6-12 weeks (Parker et al. 1982). No respiratory effects were observed in rats exposed to 10 ppm Telone II®a for 13 weeks (Coate 1979a). In contrast, rats exposed to 30 ppm Telone II%a or more for 13 weeks developed epithelial changes in the nasal turbinates that included loss of cytoplasm, nuclei disorganization, and occasional necrotic cells (Coate 1979a). Based on the NOAEL for respiratory effects from this study (Coate 1979a), an intermediate inhalation MRL of 0.003 ppm was calculated as described in the footnote to Table 2-1. The epithelial lesions were more severe in rats exposed to 90 ppm or more of Telone II%a for 13 weeks or more and included hyperplasia and focal necrosis (Breslin et al. 1989; Coate et al. 1979a; Stott et al. 1988). No significant respiratory effects were observed in rats exposed to 60 ppm Telone IIb, the highest concentration tested, for 6 or 12 months (Lomax et al. 1989). Mice also developed hyperplastic and/or degenerative lesions of the nasal epithelium after exposure to 90 ppm Telone II%a for 13 weeks (Stott et al. 1988) or to 20 or 60 ppm Telone II®b for 6-12 months. No respiratory effects were noted on gross and histopathological examinations after an intermediate inhalation exposure of rats, guinea pigs, rabbits, or dogs to 3 ppm Telone II®a for 6 months (Torkelson and Oyen 1977). Higher concentrations were not tested. Although exposure to 60 ppm of Telone II®b for 6-12 months did not result in respiratory effects in rats, exposure to the same concentration for 2 years caused olfactory epithelium degeneration (Lomax et al. 1989). A statistically 24 2. HEALTH EFFECTS significant increase in bronchioalveolar adenomas, benign lung tumors, was also noted in males exposed to 60 ppm but not in females. In mice exposed to 20 or 60 ppm Telone II®b, the epithelial hypertrophy/hyperplasia did not progress in severity or extent from 6 to 24 months. Degeneration of the olfactory epithelium, however, was noted in 48 of 50 male mice and 45 of 50 female mice exposed to 60 ppm, and in 1 of 50 males and 1 of 50 females exposed at 20 ppm (Lomax et al. 1989). Based on the NOAEL for respiratory effects in mice in this study, a chronic inhalation MRL of 0.002 ppm was calculated as described in the footnote in Table 2-1. These data indicate that acute exposure to 1,3-dichloropropene has effects on the lungs of rats, while intermediate or chronic inhalation exposure to 1,3-dichloropropene produces hyperplastic lesions of the upper respiratory tract in rats and mice and degeneration of the olfactory epithelium in mice. Cardiovascular Effects. No studies were located regarding cardiovascular effects in humans after inhalation exposure to 1,3-dichloropropene. No lesions attributable to Telone I1I%a were found upon histological evaluation of the heart and aorta from rats and mice exposed to 150 ppm or less for up to 13 weeks (Coate 1979a, 1979b; Stott et al. 1988), rats and mice exposed to 60 ppm Telone II®b for 6, 12, or 24 months (Lomax et al. 1989), or rats exposed to 50 ppm DD® for 6-12 weeks (Parker et al. 1982). Although other indices of cardiovascular toxicity were not examined, 1,3-dichloropropene does not appear to have cardiovascular effects. Gastrointestinal Effects. No studies were located regarding gastrointestinal effects in humans after inhalation exposure to 1,3-dichloropropene. No gastrointestinal effects were noted after gross and histologic examinations of the stomachs and intestines of rats exposed to 50 ppm or less of DD® for 6-12 weeks (Parker et al. 1982), rats or mice exposed to 150 ppm or less of Telone I1I%a for 13 weeks (Stott et al. 1988), or rats or mice exposed to 60 ppm of Telone II® for 6 or 12 months (Lomax et al. 1989). Similarly, no gastrointestinal lesions attributable to 1,3-dichloropropene were observed in rats exposed to 60 ppm of Telone II®b for 2 years (Lomax et al. 1989). In contrast, 8 of 50 male mice exposed to 60 ppm Telone II® for 2 years had hyperplasia and hyperkeratosis of the forestomach. The NOAEL for this effect was 20 ppm in the male mice. Female mice did not develop hyperplasia or hyperkeratosis of the forestomach (Lomax et al. 1989). Hematological Effects. No studies were located regarding hematological effects in humans after inhalation exposure to 1,3-dichloropropene. 25 2. HEALTH EFFECTS Hematological parameters have been examined in many studies of intermediate or chronic duration in which several species were exposed by inhalation to formulations of 1,3-dichloropropene. No exposure-related hematological effects were observed in rats, guinea pigs, rabbits, or dogs exposed to 3 ppm Telone II®a for 6 months (Torkelson and Oyen 1977), in rats and mice exposed to 150 ppm Telone II®a for 13 weeks (Stott et al. 1988), to 60 ppm Telone II®b for 6-24 months (Lomax et al. 1989), or in male or female rats exposed to DD® at concentrations up to 90 ppm for up to 10 weeks (Linnett et al. 1988; Parker et al. 1982). Histological examination of bone marrow also did not reveal any adverse effects in either intermediate or chronic duration exposure studies (Lomax et al. 1989; Stott et al. 1988). Musculoskeletal Effects. No studies were located regarding musculoskeletal effects in humans after inhalation exposure to 1,3-dichloropropene. Gross and histopathological examination of bone and skeletal muscle did not reveal any differences between exposed and control groups of rats and mice exposed to up to 50 ppm DD® for 6-12 weeks (Parker et al. 1982), 150 ppm Telone II%a for 13 weeks (Stott et al. 1988), or 60 ppm Telone II®b for 6-24 months (Lomax et al. 1989). Hepatic Effects. No studies were located regarding hepatic effects in humans after inhalation exposure to 1,3-dichloropropene. Gross and histopathological examination of livers did not reveal any differences between exposed and control groups of rats and mice after inhalation exposure to up to 150 ppm of Telone II®a for 13 weeks or less (Coate et al. 1979b; Stott et al. 1988), up to 50 ppm DD® for 6-12 weeks (Parker et al. 1982), or up to 60 ppm Telone II®b for 24 months or less (Lomax et al. 1989). Renal Effects. No studies were located regarding renal effects in humans after inhalation exposure to 1,3-dichloropropene. Male and female rats exposed to 3 ppm Telone II®a for 6 months developed reversible cloudy swelling of the renal tubular epithelium (Torkelson and Oyen 1977). No adverse renal effects were observed in rats allowed to recover for 3 months following the last exposure. The cloudy swelling observed in these rats was not confirmed in more recent studies, even at longer durations and/or higher concentrations. Exposure to 1 ppm in this study had no renal effects in the rats. Guinea pigs, rabbits, and dogs exposed to 3 ppm suffered no renal effects under the same exposure protocol (Torkelson and Oyen 1977). 26 2. HEALTH EFFECTS Gross and histological examination of the kidneys from rats and mice exposed to up to 150 ppm Telone II%a for 4-13 weeks (Coate et al. 1979b; Stott et al. 1988), to 50 ppm DD® for 6-12 weeks (Parker et al. 1982), or to 60 ppm Telone II®b for 6-24 months (Lomax et al. 1989) revealed no differences between exposed and control groups. Urinalysis also revealed no differences between exposed and control groups of rats and mice (Lomax et al. 1989; Parker et al. 1982; Stott et al. 1988). Moderate hyperplasia of the transitional epithelium of the urinary bladder was found in female mice exposed to 90 or 150 ppm Telone II®a for 13 weeks (Stott et al. 1988). Mice exposed to 30 ppm did not show hyperplasia of the urinary bladder. Similarly, mice exposed to up to 60 ppm Telone II®a for 6-24 months did not show hyperplasia of the urinary bladder (Lomax et al. 1989). Female mice administered Telone II®a in a 2-year gavage study also showed a dose-related increase in urinary bladder hyperplasia (Section 2.2.2.2) (NTP 1985). Dermal/Ocular Effects. No studies were located regarding dermal or ocular effects in humans after inhalation exposure to 1,3-dichloropropene. Gross and histological examination of the eyes and skin of rats and mice exposed to up to 150 ppm Telone II®a for 13 weeks (Stott et al. 1988) to 60 ppm for 6-24 months (Lomax et al. 1989) revealed no differences between exposed and control groups. 2.2.1.3 Immunological Effects No studies were located regarding immunological effects in humans after inhalation exposure to 1,3-dichloropropene. Gross and histological examination of the thymus and lymph nodes of rats and mice exposed to 150 ppm or less of Telone II®a for 13 weeks (Stott et al. 1982), to 60 ppm Telone II®b for 6-24 months (Lomax et al. 1989), or to 50 ppm of DD® for 6-12 weeks (Parker et al. 1982) revealed no lesions attributable to 1,3-dichloropropene exposure. However, more sensitive tests for immune system function were not used. The highest NOAEL values for each species and duration category are recorded in Table 2-1 and plotted in Figure 2-1. 2.2.1.4 Neurological Effects No neurological effects were observed in humans occupationally exposed to 1,3-dichloropropene at levels high enough to require medical attention (Markovitz and Crosby 1984). 27 2. HEALTH EFFECTS Ataxia of the hindlimbs and loss of the righting reflex was observed in pregnant rabbits exposed to 300 ppm of Telone II®a during gestation days 6-18. No neurological signs of toxicity were observed in rabbits exposed to 50 or 150 ppm nor in rats exposed to 300 ppm (Kloes et al. 1983). No clinical signs of neurotoxicity were observed in rats, guinea pigs, rabbits, or dogs after inhalation exposure to 3 ppm Telone II®a for 6 months (Torkelson and Oyen 1977), in rats or mice exposed to up to 150 ppm Telone II%a for 13 weeks (Coate 1979a; Stott et al. 1988), or to 60 ppm Telone II®b for 6-24 months (Lomax et al. 1989). The absence of clinical signs is supported by histological examinations of brain and spinal cords in rats and mice that revealed no lesions attributable to 1,3-dichloropropene exposure (Coate 1979a; Lomax et al. 1989; Stott et al. 1988). More sensitive tests for neurological effects, however, were not included in these studies. The acute LOAEL value in rabbits and the highest NOAEL values for neurological effects in each species and duration category are recorded in Table 2-1 and plotted in Figure 2-1. 2.2.1.5 Developmental Effects No studies were located regarding developmental effects in humans after inhalation exposure to 1,3-dichloropropene. No developmental effects were found in groups of rats exposed to 50 or 150 ppm Telone II®a during gestation days 6-15 (Kloes et al. 1983). In contrast, rats exposed to 300 ppm Telone II®a during gestation days 6-15 had fewer fetuses per litter, an increase in the incidence of litters totally resorbed, and an increase in the number of litters with resorptions. Rats exposed to 300 ppm Telone II®a had urine and fecal staining, nasal exudate, a red crusty material around the eyes, and significantly decreased food and water consumption and body weight. These observations indicate serious maternal toxicity in rats exposed to 300 ppm, which could account for the decreased litter size, increased resorptions, and increased number of litters with resorptions. Rabbits were evaluated for developmental effects after exposure to up to 300 ppm Telone II®a during gestation days 6-18 (Kloes et al. 1983). No developmental effects attributable to 1,3-dichloropropene exposure were observed in the 50 and 150 ppm groups. In contrast, marked maternal toxicity in the 300 ppm group precluded evaluation of developmental effects; signs of maternal toxicity included ataxia, loss of the righting reflex, significantly decreased body weight, and the death of six of seven rabbits. No developmental effects were observed in the progeny of groups of male and female rats exposed to 90 ppm or less Telone II®b for two generations (Breslin et al. 1989), or in pregnant rats and rabbits exposed to 120 ppm or less Telone II®a during gestation days 6-15 (Hanley et al. 1987). The parameters monitored included pup survival, pup body weight, pup crown-rump length, and gross pathology. Delayed ossification was noted in 14 rat pups of 28 2. HEALTH EFFECTS 21 litters exposed in utero to 120 ppm, but this may have been due to the decreased food and water consumption and body weight of the dams (Hanley et al. 1987). The LOAEL in rabbits and the highest NOAEL values for developmental effects are recorded in Table 2-1 and plotted in Figure 2-1. 2.2.1.6 Reproductive Effects No studies were located regarding reproductive effects in humans after inhalation exposure to 1,3-dichloropropene. No adverse reproductive effects and no histological changes in reproductive organs were observed in parental groups or progeny of male and female rats exposed to up to 90 ppm Telone II®b for two generations (Breslin et al. 1989). Male and female rats evaluated for libido, fertility, estrus cycling (females), and histological changes of reproductive organs showed no adverse effects after exposure to 90 ppm DD® for 10 weeks (Linnett et al. 1988). Gross and histological examination of reproductive organs and tissues of rats and mice exposed to 150 ppm of Telone II®a for 13 weeks (Stott et al. 1988), 60 ppm Telone II®a for 6-24 months (Lomax et al. 1989), or 50 ppm of DD® for 6-12 weeks (Parker et al. 1982) revealed no lesions attributable to 1,3-dichloropropene. More sensitive tests for reproductive effects, however, were not included in these studies. The highest NOAEL values for intermediate-duration reproductive effects in each species are recorded in Table 2-1 and plotted in Figure 2-1. 2.2.1.7 Genotoxic Effects No studies were located regarding genotoxicity in humans or animals after inhalation exposure to 1,3-dichloropropene. Other genotoxicity studies are discussed in Section 2.4. 2.2.1.8 Cancer No studies were located that convincingly link inhalation exposure to 1,3-dichloropropene with the development of cancer in humans. A clinical report describing three cases of neoplasms that developed after exposure to 1,3-dichloropropene, however, suggests that there may be an association (Markovitz and Crosby 1984). Nine firemen were exposed to 1,3-dichloropropene during cleanup of a tank truck spill. Six years later, two of the men developed histiocytic lymphomas that were refractory to treatment. Both men soon died. In addition, a 52-year-old farmer who had been in good health developed pain in the right ear, nasal mucosa, and pharynx after being exposed 29 2. HEALTH EFFECTS to 1,3-dichloropropene (not otherwise specified) from his tractor for 30 days. The hose carrying the 1,3-dichloropropene had a small leak that sprayed the chemical near the right side of the man’s face. Over the next year, the man developed leukemia that was refractory to treatment. He died of pneumonia 5 weeks after hospital admission. In the only study regarding the carcinogenic potential of 1,3-dichloropropene in animals after inhalation exposure, a statistically significant increase in the incidence of bronchioalveolar adenomas was observed in male mice exposed to 60 ppm Telone II®b for 24 months (Lomax et al. 1989). An increased incidence of this benign lung tumor, however, was not observed in female mice nor in male or female rats exposed to Telone II®b under the same protocol. 2.2.2 Oral Exposure 2.2.2.1 Death No studies were located regarding death in humans after oral exposure to 1,3-dichloropropene. Several studies were located that reported oral LDs, values for 1,3-dichloropropene in various formulations. The oral LDs, for M-3993 was 713 mg/kg (no range calculable) in male rats and 470 mg/kg (95% confidence limits=337-636 mg/kg) in female rats (Lichy and Olson 1975). In a similar study, the oral LDs, for Telone C-17® was 519 mg/kg (95% confidence interval=305-1,009 mg/kg) in male rats and 304 mg/kg (95% confidence interval=147-516 mg/kg) in female rats (Mizell et al. 1988). These data indicate that female rats are more sensitive to 1,3-dichloropropene in its various formulations than male rats. A much lower LDgy value of 150 mg/kg (95% confidence interval=130-170 mg/kg) was reported for Telone II®a in CFY-strain Sprague-Dawley rats (Jones and Collier 1986a). Similarly, the LDs, value determined for the cis-isomer of 1,3-dichloropropene for male and female rats combined was 121 mg/kg (95% confidence interval=107-137 mg/kg); for male rats only, 126 mg/kg (95% confidence interval=108-148 mg/kg); and for female rats only, 117 mg/kg (95% confidence interval=96-142 mg/kg) (Jones 1988a). The variability in LDsy, values could result from different rat stocks or strains, or, more likely, from differences in the 1,3-dichloropropene formulations used. No deaths were reported among rats that received gavage doses of Telone® for 13 weeks (Til et al. 1973). No differences were observed in the survival rates of rats that received 0, 25, or 50 mg/kg, or of mice that received 0, 50, or 100 mg/kg Telone II®b by gavage in corn oil for 2 years (NTP 1985). The LDsy values in rats and the highest NOAEL values for death in each species and duration category are recorded in Table 2-2 and plotted in Figure 2-2. TABLE 2-2. Levels of Significant Exposure to 1,3-Dichloropropene - Oral Exposure LOAEL (effect) Key to frequency/ NOAEL Less serious Serious figure? Species Route duration System (mg/kg/day) (mg/kg/day) (mg/kg/day) Reference Formulation ACUTE EXPOSURE Death 1 Rat (GO) 1d 150 (LDggp) Jones and T Ila 1x/d Collier 1986a 2 Rat (GO) 1d 75 121 (LDggp) Jones 1988a cis 1x/d 3 Rat (G) 1d 713 (LDgg - males) Lichy and Olson M-3993 1x/d 470 (LDgy - females) 1975 4 Rat (GO) 1d 518 (LDgy - males) Mizzell et al. T C-17 1x/d 304 (LDgy - females) 1988a Systemic 5 Rat (GO) 1d Gastro 100 (hyperkeratosis) Mizell et al. T.C-17 1x/d 1988a 6 Rat (GO) 1d Resp 110 (lung hemorrhage) Jones 1988a cis 1x/d Gastro 110 (intestinal hemorrhage) Hepatic 110 (liver hemorrhage) 7 Rat (GO) 1d Resp 75 (lung congestion) 250 (lung hemorrhage) Jones and T Ila 1x/d Gastro 75 (multiple white 170 (stomach Collier 1986a raised areas in hemorrhage) nonglandular regions) Hepatic 110 170 (mottled, dark liver) Renal 110 170 (dark kidneys) Neurological 8 Rat (GO) 1d 75 (ataxia) Jones 1988a cis 1x/d C SLOdddd HILTIVIH 0€ TABLE 2-2 (Continued) LOAEL (effect) Exposure Key to frequency/ NOAEL Less serious Serious figure? Species Route duration System (mg/kg/day) (mg/kg/day) (mg/kg/day) Reference Formulation INTERMEDIATE EXPOSURE Death 9 Rat (GO) 13 wk 30 Til et al. 1973 T 6 d/wk 1x/d Systemic 10 Rat (GO) 9 mo Gastro 50 NTP 1985 T Ila 3 d/wk Hepatic 50 1x/d Renal 50 11 Rat (GO) 13 wk Resp 30 Til et al. 1973 T 6 d/wk Cardio 30 1x/d Gastro 30 Hemato 30 Musc/skel 30 Hepatic 30 Renal 30 CHRONIC EXPOSURE Death 12 Rat (GO) 2 yr 50 NTP 1985 T Ila 3 d/wk 1x/d 13 Mouse (GO) 2 yr 50 100 NTP 1985 T IIa 3 d/wk 1x/d "2 S10d444d HLTVAH 1¢ TABLE 2-2 (Continued) LOAEL (effect) Exposure Key to frequency/ NOAEL Less serious Serious figure? Species Route duration System (mg/kg/day) (mg/kg/day) (mg/kg/day) Reference Formulation Systemic 14 Rat (GO) 2 yr Resp 50 NTP 1985 T Ila 3 d/wk Cardio 50 1x/d Gastro 25 (basal cell hyperplasia) Hemato 50 Musc/skel 50 Hepatic 50 Renal 50 Derm/oc 50 Systemic 15 Mouse (GO) 2 yr Resp 100 NTP 1985 T Ila 3 d/wk Cardio 100 1x/d Gastro 50 (hyperplasia) Hemato 100 Musc/skel 100 Hepatic 100 Renal 50 (hydronephrosis) Derm/oc 100 Immunological 16 Rat (GO) 2 yr 50 NTP 1985 T Ila 3 d/wk 1x/d 17 Mouse (GO) 2 yr 100 NTP 1985 T Ila 3 d/wk 1x/d Neurological 18 Rat (GO) 2 yr 50 NTP 1985 T IIa 3 d/wk 1x/d C SILOdJ4d HLTVAH ¢¢ TABLE 2-2 (Continued) LOAEL (effect) Exposure Key to frequency/ NOAEL Less serious Serious figure? Species Route duration System (mg/kg/day) (mg/kg/day) (mg/kg/day) Reference Formulation 19 Mouse (GO) 2 yr 100 NTP 1985 T IIa 3 d/wk 1x/d Reproductive 20 Rat (GO) 2 yr 50 NTP 1985 T Ila 3 d/wk 1x/d 21 Mouse (GO) 2 yr 100 NTP 1985 T Ila 3 d/wk 1x/d Cancer 22 Rat (GO) 2 yr 25 (hepatic tumors, NTP 1985 T IIa 3 d/wk forestomach 1x/d tumors) 23 Mouse (GO) 2 yr 50 (bladder, NTP 1985 T IIa 3 d/wk forestomach 1x/d tumors) 8The number corresponds to the entries in Figure 2-2. Cardio = cardiovascular; d = day(s); Derm/oc = dermal/ocular; G = gavage - not specified; Gastro = gastrointestinal; GO = gavage - oil; Hemato = hematological; LDgy = lethal dose, 50% kill; LOAEL = lowest-observed-adverse-effect level; M-3993 = Telone 1%; mo = month(s); Musc/skel = musculoskeletal; NOAEL = no-observed-adverse-effect level; Resp = respiratory; T = Telone (40% cis-1,3-dichloropropene, 38% trans-1,3-dichloropropene); T C-17 = Telone c-17° (40% cis-1,3-dichloropropene, 39% trans-1,3-dichloropropene, 21% chloropicrin); T IIa = Telone II® (53% cis-1,3-dichloropropene, 45% trans-1,3-dichloropropene, 1% epichlorohydrin); wk = week(s); yr = year(s) x = time(s) C S10d44d HITVIH €€ FIGURE 2-2. Levels of Significant Exposure to 1,3-Dichloropropene - Oral (mg/kg/day) 1,000 100 10 ACUTE INTERMEDIATE (<14 Days) (15-364 Days) Systemic Systemic & ¢ & 5 8 FP 30 5§ . & & & & & ° . ¢ > > < ~~ 20 © NS § & & & & & & & ¢ SO J & & 8 & & & KE mx We me: @ 1r re @ . Bz ® @®sx On Orn Oar Qe ®er Q1or Qtor Qtor Qs Otte O1r Or Or Orr Pine - Or Mie Orie Key r Rat LD50 un @ LOAEL for serious effects (animals) (D LOAEL for less serious effects (animals) O NOAEL (animal) The number next to each point corresponds to entries in Table 2-2 C S10Z443 HITVIH we (mg/kg/day) 1,000 100 10 FIGURE 2-2 (Continued) CHRONIC (2 365 Days) Systemic & Vd ¢ 2 > é& & & 5 o & & & & & 5 i” 5 o 2 & 98 Leiber and Berk 1984 desorb (isooctane); inject aliquot Water Purge and trap GC/FID 5 ppb No data EPA 1988 GC/MS (EPA CLP Method) Water Purge and trap GC/MS 0.34 ppb 22-178 EPA 1986a (EPA Method 8010) Wastewater Purge and trap GC/MS 0.20 ppb 86.7(cis) EPA 1982 (EPA Method 601) 0.34 ppb 73.5(trans) Soil Add water, heat to 40°, GC/FID 5 ppb No data EPA 1988 purge and trap, thermal GC/MS desorption (EPA CLP Method) Sediment Add water, heat to 40°, GC/FID 10 ppb No data EPA 1988 purge and trap, thermal GC/MS desorption (EPA CLP Method) ECD = electron capture detector FID = flame ionization detector GC = gas chromatography MS = mass spectrometry ‘9 SAQOHLIW TVOILATVNV 01 103 6. ANALYTICAL METHODS 6.3 ADEQUACY OF THE DATABASE Section 104(i) (5) of CERCLA as amended directs the Administrator of ATSDR (in consultation with the Administrator of EPA and agencies and programs of the Public Health Service) to assess whether adequate information on the health effects of 1,3-dichloropropene is available. Where adequate information is not available, ATSDR, in conjunction with the NTP, is required to assure the initiation of a program of research designed to determine the health effects (and techniques for developing methods to determine such health effects) of 1,3-dichloropropene. The following categories of possible data needs have been identified by a joint team of scientists from ATSDR, NTP, and EPA. They are defined as substance-specific informational needs that, if met, would reduce or eliminate the uncertainties of human health assessment. In the future, the identified data needs will be evaluated and prioritized, and a substance-specific research agenda will be proposed. 6.3.1 Data Needs Methods for Determining Biomarkers of Exposure and Effect. There are no known biomarkers of exposure that are unique to 1,3-dichloropropene. Therefore, standardized analytical methods for their determination are not warranted. There are no known biomarkers of effect that are unique to 1,3-dichloropropene. Therefore, standardized analytical methods for their determination are not warranted. Methods for Determining Parent Compounds and Degradation Products in Environmental Media. Methods for determining of 1,3-dichloropropene in environmental matrices have appeared in the literature. Of these, standardized methods exist only for the analysis of surface water, soil, or sediment samples (EPA 1982, 1986a, 1988). For sediments and soils, the levels of accuracy have not been reported. Both the accuracy and precision at which the trans-isomer can be measured in water is questionable. Therefore, refinement of the current procedures and establishing standardized methods for analyzing other media such as air will aid in determining levels of human exposure to 1,3-dichloropropene. A limited number of methods is available to determine 1,3-dichloro- propene in biological materials (Daft 1989; Kastl and Hermann 1983), and none of the methods have been standardized. The establishment of standardized methods for determining of 1,3-dichloropropene in biological materials, together with methods that are unique to 1,,3-dichloropropene exposure, would be helpful in determining the levels of and exposure to the general population. 104 6. ANALYTICAL METHODS 6.3.2 On-going Studies The Environmental Health Laboratory Sciences Division of the Center for Environmental Health and Injury Control, Centers for Disease Control, is developing methods for the analysis of 1,3-dichloropropene and other volatile organic compounds in blood. These methods use purge and trap methodology and magnetic mass spectrometry which gives detection limits in the low parts per trillion range. Other on-going studies developing new analytical methods for determining 1,3-dichloropropene in environmental matrices and/or biological materials were not located. 105 7. REGULATIONS AND ADVISORIES International, national, and state regulations and guidelines pertinent to human exposure to 1,3-dichloropropene are summarized in Table 7-1. 1,3-Dichloropropene is regulated by the Clean Water Effluent Guidelines for the following industrial point sources: electroplating, organic chemicals production, steam electricity power generation, asbestos product manufacturing, timber products processing, metal finishing, paving, roofing, paint formulating, ink formulating, gum and wood chemicals manufacturing, and carbon black manufacturing (EPA 1988). 106 7. REGULATIONS AND ADVISORIES TABLE 7-1. Regulations and Guidelines Applicable to 1,3-Dichloropropene Agency Description Information References INTERNATIONAL IARC Carcinogen classification Group 2B% IARC 1987 NATIONAL Regulations: a. Air: OSHA PEL TWA (skin) 1 ppm® OSHA 1989 (29 CFR 1810) b. Water: EPA OWRS Groundwater monitoring requirements Yes EPA 1987a (40 CFR 264) c. Other: EPA OTS Toxic chemical release reporting: Yes EPA 1987b commmunity right-to-know (proposed) (40 CFR 372.45) EPA OERR RQ 100 lbs EPA 1986b (40 CFR 302.4) Guidelines: a. Air: ACGIH TWA-TLV 1 ppm ACGIH 1989 EPA RfC (inhalation) 0.02 mg /m> IRIS 1991 b. Water: EPA OWRS Ambient water quality criteria for 87 ng/LC EPA 1980 protection of human health 14.1 mg /L4 c. Other: EPA RfD (oral) 0.0003 mg/kg/day IRIS 1991 Carcinogen classification Group B2°¢ STATE Regulations and Guidelines: a. Air: Acceptable ambient air concentrations NATICH 1988 Connecticut 100 ng/m’ Acceptable ambient limits Kentucky 10 mg/m’ State of Kentucky 1986 North Dakota 0.05 mg/m’ NATICH 1988 Nevada 0.009 mg/m’ NATICH 1988 Virginia 80 mg/m’ NATICH 1988 b. 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Telone C-17® soil fungicide and nematicide: Dermal sensitization potential in the Hartley albino guinea pig. Dow Chemical Company, Midland, Michigan. *Mizell M, Yano BL, Battjes JE. 1988a. Telone C-17® soil fungicide and nematicide: Acute oral toxicity study in Fischer 344 rats. Dow Chemical Company, Midland, MI. *Mizell M, Johnson K, Battjes J. 1988b. Telone C-17® soil fungicide and nematicide: Acute dermal toxicity study in New Zealand white rabbits. Dow Chemical Company, Midland, Michigan. *Morrill LG, Reed LW, Chinn KSK. 1985. Toxic chemicals in the soil environment. Vol. 2: Interactions of some toxic chemicals/chemical warfare agents and soils. Defense Technical Information Center Dugway Proving Ground, Utah. NTIS AD-A158 215. *Munnecke DE, Vangundy SD. 1979. Movement of fumigants in soil, dosage, responses, and differential effects. Ann Rev Phytopathol 17:405-429. *Nater JP, Gooskens VHJ. 1976. Occupational dermatosis due to a soil fumigant. Contact Dermatitis 2:227-229. *NAS/NRC. 1989. Biologic markers in reproductive toxicology. National Academy of Sciences/National Research Council. Washington, DC: National Academy Press, 15-35. *NATICH. 1988. National Air Toxics Information Clearinghouse. NATICH Data Base Report on State, Local and EPA Air Toxics Activities. Office of Air Quality Planning and Standards. Environmental Protection Agency. Research Triangle Park, NC. 115 8. REFERENCES *Neudecker T, Henschler D. 1986. Mutagenicity of chloroolefins in the Salmonella/mammalian microsome test. III. Metabolic activation of the allylic chloropropenes allyl chloride, 1,3-dichloropropene, 2,3-dichloro-l-propene, 1,2,3-trichloropropene, 1,1,2,3-tetrachloro-2-propene and hexachloropropene by S9 mix via two different metabolic pathways. Mutat Res 170:1-9. *Neudecker T, Stefani A, Henschler D. 1977. In vitro mutagenicity of the soil nematicide 1,3-dichloropropene. Experientia 33:1084-1085. *NIOSH. 1989. 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Subchronic inhalation toxicity of 1,3-dichloropropene/1,2-dichloropropane (DD?) in mice and rats. J Toxicol Environ Health 9:899-910. *Pellizzari ED, Hartwell TD, Harris BSH, et al. 1982. Purgeable organic compounds in mothers milk. Bull Environ Contam Toxicol 28:322-328. *Rawlings GD, Samfield M. 1979. Toxicity of secondary effluents from textile plants. U.S. Environmental Protection Agency, Washington, DC. EPA 600/7-78-168. *Roberts TR, Stoydin G. 1976. The degradation of (Z)- and (E)-1,3-dichloropropenes and 1,2-dichloropropane in soil. Pestic Science 7:325-335. *Rogers SE, Peterson DL, Lauer WC. 1987. Organic contaminants removal for potable reuse. J Water Pollut Control Fed 59:722-732. *Sabel GV, Clark TP. 1984. Volatile organic compounds as indicators of municipal solid waste leach contamination. Waste Management Res 2:119-130. *SANSS. 1989. Structure and Nomenclature Search System. 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GLOSSARY Acute Exposure -- Exposure to a chemical for a duration of 14 days or less, as specified in the Toxicological Profiles. 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 Toxicological Profiles. 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. 122 9. GLOSSARY 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 Toxicological Profiles. Immunologic Toxicity -- The occurrence of adverse effects on the immune system that may result from exposure to environmental agents such as chemicals. In Vitro -- Isolated from the living organism and artificially maintained, as in a test tube. In Vivo -- Occurring within the living organism. Lethal Concentration, (LC,) -- The lowest concentration of a chemical in air which has been reported to have caused death in humans or animals. Lethal Concentration sg) (LCs) -- A calculated concentration of a chemical in air to which exposure for a specific length of time is expected to cause death in 50% of a defined experimental animal population. Lethal Dose(,, (LD ,) -- 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 Dose soy (LDsp) -- The dose of a chemical which has been calculated to cause death in 50% of a defined experimental animal population. Lethal Time soy (LTs50) -- 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 chemical that is likely to be without an appreciable risk of deleterious effects (noncancerous) over a specified duration of exposure. 123 9. GLOSSARY 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,,) -- 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. q1* -- 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, the incremental excess cancer risk per unit of exposure (usually pg/L for water, mg/kg/day for food, and pg/m® for air). 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 1b 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. APPENDIX A USER'S GUIDE Chapter 1 Public Health Statement This chapter of the profile is a health effects summary written in nontechnical language. Its intended audience is the general public especially people living in the vicinity of a hazardous waste site or substance 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 substance. 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. 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 by duration of exposure and endpoint and to illustrate graphically levels of exposure associated with those effects. 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) for Less Serious and Serious health effects, or Cancer Effect Levels (CELs). In addition, these tables and figures illustrate differences in response by species, Minimal Risk Levels (MRLs) to humans for noncancer end points, 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. The LSE tables and figures can be used 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. The legends presented below demonstrate the application of these tables and figures. A representative example 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 exist, (2). (3). (4). (5). (6). (7). (8). {9}. A-2 APPENDIX A 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. Exposure Duration Three exposure periods: acute (1&4 days or less); intermediate (15 to 364 days); and chronic (365 days or more) are presented within each route of exposure. In this example, an inhalation study of intermediate duration exposure is reported. 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. 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 define a NOAEL and a Less Serious LOAEL (also see the two "18r" data points in Figure 2-1). Species The test species, whether animal or human, are identified in this column. 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 [substance x] via inhalation for 13 weeks, 5 days per week, for 6 hours per day. 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, one systemic effect (respiratory) was investigated in this study. 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 0.005 ppm (see footnote "c"). LOAEL A Lowest-Observed-Adverse-Effect Level (LOAEL) is the lowest exposure level 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 end point used to A-3 APPENDIX A quantify the adverse effect accompanies the LOAEL. The "Less Serious" respiratory effect reported in key number 18 (hyperplasia) occurred at a LOAEL of 10 ppm. (10). Reference The complete reference citation is given in Chapter 8 of the profile. (11). CEL A Cancer Effect Level (CEL) is the lowest exposure level associated with the onset of carcinogenesis in experimental or epidemiological studies. CELs are always considered serious effects. The LSE tables and figures do not contain NOAELs for cancer, but the text may report doses which did not cause a measurable increase in cancer. (12). 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 0.005 ppm. LEGEND See LSE 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 levels for particular exposure duration. (13). Exposure Duration The same exposure periods appear as in the LSE table. In this example, health effects observed within the intermediate and chronic exposure periods are illustrated. (14). Health Effect These are the categories of health effects for which reliable quantitative data exist. The same health effects appear in the LSE table. (15). Levels of Exposure Exposure levels for each health effect in the LSE tables are graphically displayed in the LSE figures. Exposure levels are reported on the log scale "y" axis. Inhalation exposure is reported in mg/m> or ppm and oral exposure is reported in mg/kg/day. (16). NOAEL In this example, 18r NOAEL is the critical end point for which an intermediate inhalation exposure MRL is based. As you can see from the LSE figure key, the open-circle symbol indicates 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 0.005 ppm (see footnote "b" in the LSE table). (17). CEL Key number 38r is one of three studies for which Cancer Effect Levels (CELs) were derived. The diamond symbol refers to a CEL for the test species (rat). The number 38 corresponds to the entry in the LSE table. (18). (19). A-4 APPENDIX A 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 EPA's Human Health Assessment Group's upper-bound estimates of the slope of the cancer dose response curve at low dose levels (ay). Key to LSE Figure The Key explains the abbreviations and symbols used in the figure. [1] > TABLE 2-1. Levels © ©0000 088000 00 20% 0 es 0 ee ee se 0 0 0s 0 00 os of Significant Exposure to [Chemical x] - Inhalation LOAEL (effect) Exposure Key to frequency/ NOAEL Less serious Serious figure? Species duration System (ppm) (ppm) (ppm) Reference [2}— intermen1ATE EXPOSURE 5 7 [«}— 18 Rat 13 wk Resp P 10 (hyperplasia) Nitschke et al. 5d/wk 1981 6hr/d CHRONIC EXPOSURE 2 Cancer a ro = 38 Rat 18 mo 20 (CEL, multiple Wong et al. 1982 2 »~ 5d/wk / Wl! organs) > 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 8 The number corresponds to entries in Figure 2-1. [12}— b Used to derive an intermediate inhalation Minimal Risk Level (MRL) of 5 x 1073 ppm; dose adjusted for intermittent exposure and divided by an uncertainty factor of 100 (10 for extrapolation from animal to humans, 10 for human variability). CEL = cancer effect level; d = day(s); hr = hour(s); LOAEL = lowest-observed-adverse-effect level; mo = month(s); NOAEL = no- observed-adverse-effect level; Resp = respiratory; wk = week(s) S-V CHRONIC [3] - INTERMEDIATE (15-364 Days) (2365 Days) Systems — 1.000 100 } @ re OP Ge Pam 0 "ow » [¢] — »> Qe Ow 1} : ! eo ’ . oor | : ’ soot | 3 00001 | 000001 © FIGURE 2-1. On (hey GeO» or ° One Pre Pre Drea Poa - wr re @n= On OPre= Ose Os Oss O On ond 10 4 — 10 -s | Bound Human Canow Risk Levels Key 1049- ¢ Ra @ (104EL tor sorters sfocts jardmais) : -~ Mose @ 10AEL tur teas satens ohacs fara) | ed eh tov 10-7 & Ruan NOAEL (wine) | ofech ether han concer 8 Odneapy @ cel Concw Elect Lovet — & Madey he mumber nest te each paint Coe eapands te entries bv Teble 2 1 "Dosen represent he imwost dose tested por shally Pel odund o Aemedgenic 1enpErac and do no imply the sein innce of & Preshadt le Be sence ond paint Levels of Significant Bxposure to [Chemical X]-Inhalation V XIANdddV 9-v A-7 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 toxicological, epidemiological, and toxicokinetic information. This summary is designed to present interpretive, weight-of-evidence discussions for human health end points 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 discusses health effects by end point. Human data are presented first, then animal data. Both are organized by route of exposure (inhalation, oral, and dermal) and by duration (acute, intermediate, and 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. MRLs for noncancer end points if derived, and the end points from which they were derived are indicated and discussed in the appropriate section(s). Limitations to existing scientific literature that prevent a satisfactory evaluation of the relevance to public health are identified in the Identification of Data Needs section. Interpretation of Minimal Risk Levels Where sufficient toxicologic information was available, MRLs were derived. MRLs are specific for route (inhalation or oral) and duration (acute, intermediate, or chronic) of exposure. Ideally, MRLs can be derived from all six exposure scenarios (e.g., Inhalation - acute, -intermediate, -chronic; Oral - acute, - intermediate, - chronic). These MRLs are not meant to support regulatory action, but to aquaint 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 substance emission, given the concentration of a contaminant in air or the estimated daily dose received via food or water. MRLs are based largely on toxicological studies in animals and on reports of human occupational exposure. A-8 APPENDIX A MRL users should be familiar with the toxicological information on which the number is based. Section 2.4, "Relevance to Public Health," contains basic information known about the substance. Other sections such as 2.6, "Interactions with Other Chemicals" and 2.7, "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 used by the Environmental Protection Agency (EPA) (Barnes and Dourson, 1988; EPA 1989a) to derive reference doses (RfDs) for lifetime exposure. To derive an MRL, ATSDR generally selects the end point 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 effects (e.g., systemic, neurological, and developmental). In order to compare NOAELs and LOAELs for specific end points, all inhalation exposure levels are adjusted for 24hr exposures and all intermittent exposures for inhalation and oral routes of intermediate and chronic duration are adjusted for continous exposure (i.e., 7 days/week). If the information and reliable quantitative data on the chosen end point 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. The NOAEL is the most suitable end point for deriving an MRL. When a NOAEL is not available, a Less Serious LOAEL can be used to derive an MRL, and an uncertainty factor (UF) of 10 is employed. MRLs are not derived from Serious LOAELs. Additional uncertainty factors of 10 each are used 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 adjusted 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. ACGIH ADME ATSDR BCF BSC CDC CEL CERCLA CFR CLP cm CNS DHEW DHHS DOL ECG EEG EPA EKG FAO FEMA FIFRA fpm ft FR GC HPLC IDLH APPENDIX B ACRONYMS, ABBREVIATIONS, AND SYMBOLS American Conference of Governmental Industrial Hygienists Absorption, Distribution, Metabolism, and Excretion Agency for Toxic Substances and Disease Registry bioconcentration factor Board of Scientific Counselors 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 Department of Health, Education, and Welfare Department of Health and Human Services Department of Labor electrocardiogram electroencephalogram Environmental Protection Agency see ECG Food and Agricultural Organization of the United Nations Federal Emergency Management Agency Federal Insecticide, Fungicide, and Rodenticide Act first generation feet per minute foot Federal Register gram gas chromatography high performance liquid chromatography hour Immediately Dangerous to Life and Health International Agency for Research on Cancer International Labor Organization inch adsorption ratio kilogram octanol-soil partition coefficient octanol-water partition coefficient liter liquid chromatography lethal concentration low lethal concentration 50 percent kill lethal dose low lethal dose 50 percent kill LOAEL LSE m mg min mL mm mmo 1 mppcf MRL MS NIEHS NIOSH NIOSHTIC nm ng NHANES nmol NOAEL NOES NOHS NPL NRC NTIS NTP OSHA PEL Pg pmol PHS PMR ppb ppm ppt REL RED RTECS sec SCE SIC SMR STEL STORET TLV TSCA TRI TWA u.s. B-2 APPENDIX B lowest-observed-adverse-effect level Levels of Significant Exposure meter milligram minute milliliter millimeters millimole millions of particles per cubic foot Minimal Risk Level mass spectroscopy National Institute of Environmental Health Sciences National Institute for Occupational Safety and Health NIOSH's Computerized Information Retrieval System nanometer nanogram 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 proportional 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 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 B-3 APPENDIX B uncertainty factor 0 World Health Organization 2 5 greater than greater than or equal to equal to less than less than or equal to percent alpha beta delta gamma pm micron ug microgram pmol micromole =X OS®™WR RIAA ILIV V c-1 APPENDIX C PEER REVIEW A peer review panel was assembled for 1,3-dichloropropene. The panel consisted of the following members: Dr. Nancy Tooney, Polytechnic University, Brooklyn, New York; Dr. Michael Norvell, Private Consultant, Ringoes, New Jersey; and Dr. Ronny Woodruff, Bowling Green State University, Bowling Green, Ohio. These experts collectively have knowledge of 1,3-dichloropropene’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 the Comprehensive Environmental Response, Compensation, and Liability Act of 1986, Section 104. 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. “U.S. Government Printing Office: 1992 — 638-236 C. BERKELEY LIBRARIES Wim CD8L&a5053 = ——— e———