TOXICOLOGICAL PROFILE FOR 2,4-DICHLOROPHENOL 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 July 1992 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. OR CAT TC ue No PUBL RAIS iii Cyc BY FOREWORD [447% The Superfund Amendments and Reauthorization Act (SARA) of 1986 pris (Public Law 99-499) extended and amended the Comprehensive Environmental Response, Compensation, and Liability Act of 1980 (CERCLA or Superfund) . This public law directed the Agency for Toxic Substances and Disease 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 FOREWORD LIST OF FIGURES LIST OF TABLES 1. 1. 1 2. HEALTH EFFECTS 2. 2.2 DISCUSSION OF HEALTH EFFECTS BY ROUTE OF EXPOSURE P 1 1 1. 1 1 us wn = aN .7 1 WHAT IS CONTENTS UBLIC HEALTH STATEMENT . . 2,4- DICHLOROPHENOL? . HOW MIGHT I BE EXPOSED TO 2,4- DICHLOROPHENOL? HOW CAN 2,4-DICHLOROPHENOL ENTER AND LEAVE MY BODY? HOW CAN 2,4-DICHLOROPHENOL AFFECT MY HEALTH? : IS THERE A MEDICAL TEST TO DETERMINE WHETHER I HAVE BEEN EXPOSED TO 2,4-DICHLOROPHENOL? WHAT RECOMMENDATIONS HAS THE FEDERAL GOVERNMENT "MADE TO PROTECT HUMAN HEALTH? WHERE CAN I GET MORE INFORMATION? INTRODUCTION . 2.2.1 Inhalation Exposure 2. 2. 2. 2. 2 3 NNO NNONNONNNONNONMNMNNNNONNNNNNNONNNDNNNNNNNDN NNO NNNDNDNNNDNNNRE NNN NNNNNNDND DNDN WWWWWWWWwWwbh MNNDDNNNNNDNDDNDN oN BFW al a a ONO UVLPWNREX oO UL Pw Death ; Systemic Effects Immunological Effects Neurological Effects Developmental Effects Reproductive Effects Genotoxic Effects Cancer posure Death . Systemic Effects 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 iis ix xi WN ~ wm WO WO WOW WOWWWOoWOoOWWN NN 2. No NN NN 3 O 00 NO vi TOXICOKINETICS 2.3.1 Absorption : 2.3.3.1 tahalation Exposure 2.3.1.2 Oral Exposure 1.3 Dermal Exposure 2.3.2 tribution . 3 2.1 Inhalation ERposute 2 Oral Exposure 3 Dermal Exposure 4 Other Routes of gErposure 2. Di 2. 2.3.2. 2.3.2. 2.3.2. abolism e 4 4. 4 3. is 2 3. 3. 3. t NN w Ww = ® rw retion . Pn koe 4 we .1 Inhalation Exposure 2 Oral Exposure 3 Dermal Exposure : 2.3.4.4 Other Routes of Exposure RELEVANCE TO PUBLIC HEALTH . oe BIOMARKERS OF EXPOSURE AND EFFECT c 3. 3. 3. 2.5.1 Biomarkers Used to Identify and/or ‘Quantify Exposuie to 2,4-Dichlorophenol 2.5.2 Biomarkers Used to Characterize Rffects Saved "vy 2,4-Dichlorophenol INTERACTIONS WITH OTHER CHEMICALS . POPULATIONS THAT ARE UNUSUALLY SUSCEPTIBLE . MITIGATION OF TOXICOLOGICAL EFFECTS ADEQUACY OF THE DATABASE . 2.9.1 Existing Information on Health Effects of 2,4-Dichlorophenol 2.9.2 Data Needs . 2.9.3 On-going Studies CHEMICAL AND PHYSICAL INFORMATION . 3.1 CHEMICAL IDENTITY 3.2 PHYSICAL AND CHEMICAL PROPERTIES PR 4. &. 4. 4. 0 1 2 3 4 DUCTION, IMPORT, USE, AND DISPOSAL . PRODUCTION Loa IMPORT/EXPORT USE 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 24 24 24 25 25 25 25 25 25 25 26 26 26 26 26 27 27 31 33 33 33 34 34 35 36 36 42 43 43 43 47 47 47 47 49 51 51 53 53 55 55 vii 5.3 ONMENTAL FATE . . Transport and Partitioning Transformation and Degradation 5.3.2.1 Air 5.3.2.2 Water 5.3.2.3 Soil ENVI 5.3. 5.3. No = 5.4 LEVELS MONITORED OR ESTIMATED IN THE ENVIRONMENT . 5.4.1 Air Water Soil Lo. . Other Eavitonuental Media . . GENERAL POPULATION AND OCCUPATIONAL EXPOSURE . POPULATIONS WITH POTENTIALLY HIGH EXPOSURE . ADEQUACY OF THE DATABASE . 5.7.1 Data Needs 5.7.2 On-going Studies 4. 4. 4. WEY An NW wv un ~N ovo 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 56 56 58 58 59 60 60 60 61 62 64 64 66 66 66 69 71 71 73 73 76 76 77 81 97 A-1 B-1 c-1 ix LIST OF FIGURES 2-1 Levels of Significant Exposure to 2,4-Dichlorophenol - Oral 2-2 Existing Information on Health Effects of 2,4-Dichlorophenol 5-1 Frequency of NPL Sites with 2,4-Dichlorophenol Contamination . 15 37 52 2-1 2-2 2-3 3-1 3-2 4-1 5-1 5-2 6-1 6-2 7-1 xi LIST OF TABLES Levels of Significant Exposure to 2,4-Dichlorophenol - Oral Levels of Significant Exposure to 2,4-Dichlorophenol - Dermal Genotoxicity of 2,4-Dichlorophenol In Vitro Chemical Identity of 2,4-Dichlorophenol Physical and Chemical Properties of 2,4-Dichlorophenol Facilities that Manufacture or Process 2,4-Dichlorophenol Releases to the Environment from Facilities that Manufacture or Process 2,4-Dichlorophenol Final Effluent 2,4-Dichlorophenol Concentrations in Industrial Waste Waters Analytical Methods for Determining 2,4-Dichlorophenol in Biological Materials Coe Analytical Methods for Determining 2,4-Dichlorophenol in Environmental Samples : Regulations and Guidelines Applicable to 2,4-Dichlorophenol 11 22 32 44 45 48 54 63 72 74 78 1. PUBLIC HEALTH STATEMENT This Statement was prepared to give you information about 2 ,4-dichlorophenol and to emphasize the human health effects that may result from exposure to it. The Environmental Protection Agency (EPA) has identified 1,300 National Priorities List (NPL) sites. 2,4-Dichlorophenol has been found at 9 of these sites. However, we do not know how many of the 1,300 NPL sites have been evaluated for 2,4-dichlorophenol. As EPA evaluates more sites, the number of sites at which 2,4-dichlorophenol is found may change. The information is important for you because 2,4-dichlorophenol may cause harmful health effects and because these sites are potential or actual sources of human exposure to 2,4-dichlorophenol. 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 to it in the environment by breathing, eating, or drinking substances containing the chemical, or from skin contact with it. If you are exposed to a hazardous substance such as 2 ,4-dichlorophenol, 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 2,4-DICHLOROPHENOL? 2,4-Dichlorophenol is a white solid, the form in which it is usually sold and used. Its smell has been described as medicinal. You can notice this smell if small amounts of this chemical are in water or in fish. 2,4-Dichlorophenol evaporates slightly faster than water, which evaporates slowly. It can also burn. This man-made chemical is produced and used at only a few places. It can be formed, however, in small amounts during the processes used to disinfect water for drinking or disposal. Most of the 2,4-dichlorophenol made is used directly to make other chemicals, especially chemicals that kill weeds and other plants. 2,4-Dichlorophenol also is used to kill germs. 2 ,4-Dichlorophenol might be found in the air, water, or soil near hazardous waste sites where it has not been properly disposed. However, it does not stay in the air, water, or soil for very long. In the air, 2,4-dichlorophenol changes to other chemicals within a few days or weeks. Small amounts of it dissolve in water. It usually sticks to soil on land and to soil at the bottom of rivers, ponds, and lakes. It also may travel through the soil to water that is below the soil. For more information about the use, 2 1. PUBLIC HEALTH STATEMENT disposal methods, and what happens to 2,4-dichlorophenol in the environment, please refer to Chapters 4 and 5 of this profile. 1.2 HOW MIGHT I BE EXPOSED TO 2,4-DICHLOROPHENOL? Small amounts of 2,4-dichlorophenol are sometimes present in air, water, and soil. You may be exposed to 2,4-dichlorophenol if you breathe air, drink water that contains it, or eat foods grown in soils that contain it. We do not know how much 2,4-dichlorophenol is in the general environment. The little that is known about its distribution indicates that 2,4-dichlorophenol will not be present very often, especially in air or soil. The amounts, if any, in air, water, and soil at most places will be very small. It is sometimes released to the environment when it is made and when it is used to make other chemicals. Certain situations can lead to higher than usual levels of exposure. If you live near a hazardous waste site where 2,4-dichlorophenol is not properly disposed, you could be exposed to the chemical by breathing air or drinking well water near these sites. We know of only a few waste sites that contain 2,4-dichlorophenol. Also, you could be exposed by breathing air if you live near places that make or use 2,4-dichlorophenol or that burn municipal trash or phenol chemicals. You may also be exposed to 2,4-dichlorophenol in drinking water as the result of the water disinfection process, which changes certain other phenol chemicals into 2,4-dichlorophenol. Workers who make or use the chemical may be exposed to higher levels of 2,4-dichlorophenol either by breathing it or having their skin come in contact with it, especially if some of it is spilled or there is an accident. For more information about the amounts of 2,4-dichlorophenol that are found in the environment and your chances of being exposed to it, see Chapter 5 of this profile. 1.3 HOW CAN 2,4-DICHLOROPHENOL ENTER AND LEAVE MY BODY? 2,4-Dichlorophenol enters your body quickly after you swallow it or substances that contain it. For example, if you swallow water containing 2,4-dichlorophenol, it will enter your bloodstream within minutes. 2,4-Dichlorophenol also can enter your body through your skin. If you spill 2,4-dichlorophenol on your skin or come into contact with water containing it, it will enter your body within minutes. If you breathe air containing 2,4-dichlorophenol, it can quickly enter your body through your lungs. The amount of 2,4-dichlorophenol that enters your body when you swallow, breathe, or come into skin contact with it depends on the amount you are exposed to and the length of time you are exposed. For example, more 2,4-dichlorophenol might enter your body if you drank one glass of water containing a large amount of it than if you drank water every day containing a small amount of it. The amount of 2,4-dichlorophenol that enters through your skin also depends on the amount of skin exposed. For example, more 3 1. PUBLIC HEALTH STATEMENT 2 ,4-dichlorophenol might enter through your skin if you bathed or swam in water containing it than if you washed your hands in the same water. 2,4-Dichlorophenol has been found at very few NPL waste sites. When it has been found at hazardous waste sites, it has been found in surface water, groundwater, and soil. Therefore, people living near waste sites and who get their water from wells near waste sites may be exposed to 2,4-dichlorophenol through drinking water. 2,4-Dichlorophenol may enter the skin of people who come into contact with surface water or soil at a waste site, especially children who play in the area. Children who play at a waste site where 2 ,4-dichlorophenol has been spilled could also be exposed if they eat the soil or lick their fingers or objects contaminated with the soil. Although air can be contaminated with 2,4-dichlorophenol, most spilled 2,4-dichlorophenol remains in the soil or water rather than evaporating into the air. Studies with animals suggest that most of 2,4-dichlorophenol that enters the body leaves within an hour in the urine, and all of it is likely to leave within 3 days. For more information on how 2,4-dichlorophenol can enter and leave your body, see Chapter 2. 1.4 HOW CAN 2,4-DICHLOROPHENOL AFFECT MY HEALTH? The severity of effects from exposure to harmful substances usually increases as both the level and length of time of exposure increase. Reports describing possible 2,4-dichlorophenol poisoning of factory workers suggest that if you breathe air containing 2,4-dichlorophenol for several years, you may damage your liver, skin, and possibly your kidneys. Skin contact with it over a long period may cause the same effects. If it is applied to animals in combination with other chemicals known to cause cancer, more cancer occurs than wher the other chemicals are applied alone, although 2,4-dichlorophenol alone does not cause cancer in animals when applied to the skin. Animals that drank 2,4-dichlorophenol for 2 years did not develop cancer. Neither did the offspring of animals whose mothers took it while they were pregnant. Even after these offspring took the chemical for another 2 years, they did not develop cancer. We do not know whether humans who eat or drink 2,4-dichlorophenol will develop cancer, nor do we know whether humans who have skin contact with cancer-causing agents would have more tumors if they also had 2,4-dichlorophenol on their skin. 2,4-Dichlorophenol has a bad taste and odor. At room temperature, it can be tasted at levels of about 8 parts per billion (ppb) and smelled at a levels of about 2 ppb in water. These are lower levels than those believed to affect your health. Results from animal studies show that skin contact with 2,4-dichlorophenol even for short periods of time can harm animals. Rabbits that had small amounts of it on their skin for only one day developed skin sores and became sluggish, and those that had small amounts in their eyes for 30 seconds were 4 1. PUBLIC HEALTH STATEMENT blinded. Rabbits that had large amounts of it on their skin for 1 day died. Animals that have eaten large amounts of 2,4-dichlorophenol in food immediately developed rapid breathing, muscle tremors, convulsions, weakness, hunched posture, loss of unconsciousness, and some even died. Animals that took smaller amounts of it in food or water over a long period of time had damaged livers, kidneys, spleens, bone marrow, and may also have damaged their respiratory tracts (although this may have been from breathing in the chemical rather than from swallowing it). Rats that drank water containing 2,4-dichlorophenol had some changes in the immune system, but the effects of 2,4-dichlorophenol on the immune system have not been fully studied. It is not known whether the same effects would happen in people if they were exposed in the same way. Some pregnant animals that drank water containing high levels of 2,4-dichlorophenol died, and those that drank enough to become sick had spontaneous abortions or gave birth to offspring that had low birth weights. Therefore, pregnant women who unknowingly eat or drink 2,4-dichlorophenol could harm themselves and their unborn babies. For more information on how 2,4-dichlorophenol can affect your health, see Chapter 2. 1.5 IS THERE A MEDICAL TEST TO DETERMINE WHETHER I HAVE BEEN EXPOSED TO 2,4-DICHLOROPHENOL? There are methods that are very specific for detecting the presence of 2,4-dichlorophenol in urine and blood, but these tests require special equipment that is not usually available at a doctor's office. It is not known exactly how long 2,4-dichlorophenol remains in body fluids of humans after they have been in contact with it, but tests can determine whether you have been exposed recently (within 1-3 days) to either 2,4-dichlorophenol or substances that are changed to 2,4-dichlorophenol in the body (for example, the pesticide lindane or the fumigant 1,3-dichlorobenzene). Exposure may not show up in urine samples collected more than 1-3 days after contact with 2,4-dichlorophenol because 2,4-dichlorophenol leaves the body quickly in the urine. 1.6 WHAT RECOMMENDATIONS HAS THE FEDERAL GOVERNMENT MADE TO PROTECT HUMAN HEALTH? The federal government has developed regulations and guidelines to protect individuals from the possible harmful health effects of exposure to 2,4-dichlorophenol. EPA has set a limit of 3 ppm (3 mg/L) in lakes and streams to protect human health from the possible effects of drinking 2,4-dichlorophenol-contaminated water or eating contaminated fish and shellfish. EPA also requires that any release of more than 100 pounds of 2,4-dichlorophenol to the environment be reported to the National Response Center. For more information on rules for criteria and standards for 2,4-dichlorophenol exposure, 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 2,4-dichlorophenol 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 2,4-dichlorophenol based on toxicological studies and epidemiological investigations. 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 (more than 364 days). 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. 8 2. HEALTH EFFECTS Although methods have been established to derive these levels (Barnes et al. 1988; EPA 1989a), 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 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 No studies were located regarding health effects in animals after inhalation exposure to 2,4-dichlorophenol. 2.2.1.1 Death No studies were located regarding death in humans or animals after inhalation exposure to 2,4-dichlorophenol. 2.2.1.2 Systemic Effects No studies were located regarding respiratory, cardiovascular, musculoskeletal, or renal effects in humans or animals after inhalation exposure to 2,4-dichlorophenol. Hematological Effects. Clinical assessment of two patients occupationally exposed during the manufacture of 2,4-dichlorophenol- and 2,4,5-trichlorophenol-based herbicides revealed hematology and blood chemistry parameters (blood counts, bleeding and clotting time, serum bilirubin, blood urea nitrogen, and others) within normal range (Bleiberg et al. 1964). These patients were diagnosed with porphyria or chloracne that may have been related to exposure to 2,4-trichlorophenol, 2,4,5-trichlorophenol, or intermediate chemicals including 2,4-dichlorophenol used in the production process. No studies were located regarding hematological effects in animals after inhalation exposure to 2,4-dichlorophenol. Hepatic Effects. Porphyria cutanea tarda has been reported in factory workers employed in the manufacture of 2,4-dichlorophenol and 2,4,5-trichlorophenol (Bleiberg et al. 1964). Their exposure to 2,4-dichlorophenol was probably through inhalation or dermal contact. Eleven cases of porphyria were identified, based on urinary porphyrin excretion, in a survey of 29 workers. Elevated serum transaminase levels and evidence of liver damage (e.g., regeneration and hemofuscin deposition) were detected from a liver biopsy in two cases that were studied in detail. Thus, the porphyria was probably related to liver injury. Definitive conclusions regarding the connection between the porphyria or liver injury and exposure to 9 2. HEALTH EFFECTS 2,4-dichlorophenol in this group of workers cannot be made, since the workers were exposed to a variety of chlorinated compounds; these included highly volatile substances formed during the manufacturing process (for example, dioxin). The data provide an alert for potential human risk, however. Information on exposure to other liver toxins, including alcohol, was not obtained. No studies were located regarding hepatic effects in animals after inhalation exposure to 2,4-dichlorophenol. Dermal/Ocular Effects. Chloracne, evidence of acquired porphyria, hyperpigmentation, and hirsutism have been observed in workers employed in the manufacture of 2,4-dichlorophenol- and 2,4,5-trichlorophenol-based herbicides (Bleiberg et al. 1964). As noted above in the discussion of hepatic effects, exposure to 2,4-dichlorophenol may have been through inhalation or dermal contact. Furthermore, the subjects were exposed to several chlorinated phenols in addition to 2,4-dichlorophenol (for example, dioxin); therefore, the cause of the chloracne cannot be ascribed specifically to 2,4-dichlorophenol. No studies were located regarding the following health effects in humans or animals after inhalation exposure to 2,4-dichlorophenol: Immunological Effects Neurological Effects Developmental Effects Reproductive Effects Genotoxic Effects NNN DN RRR RO oe ee Nous ow Genotoxicity studies are discussed in Section 2.4. 2.2.1.8 Cancer There is little evidence to link 2,4-dichlorophenol with cancer. Human cancer cases have been reported among factory workers engaged in the manufacture of 2,4-dichlorophenol- and trichlorophenol-based pesticides (Hardell 1981; Hardell et al. 1981; Honchar and Halperin 1981; Lynge 1985). Persons engaged in this work are exposed primarily by inhalation to many substances during the manufacture of these pesticides, including volatile compounds produced as intermediates in the manufacturing process. They may also be exposed dermally. Soft tissue sarcomas have been reported among agricultural, forestry, and horticultural workers exposed to phenoxy acids and chlorophenols (Eriksson et al. 1981). A problem with these data is that 2 ,4-dichlorophenol was probably not present to the extent of other chlorophenols. The data are further confounded by the presence of impurities (such as dioxins, which are known animal carcinogens) in the substances used by the workers. No increased risk for soft-tissue sarcoma or non-Hodgkin's lymphoma was found in another study of workers similarly exposed (Woods et al. 10 2. HEALTH EFFECTS by the workers. No increased risk for soft-tissue sarcoma or non-Hodgkin's lymphoma was found in another study of workers similarly exposed (Woods et al. 1987). It is not possible to draw conclusions from these data regarding cancer risk from 2,4-dichlorophenol. A possible link between malignant lymphoma and exposure to phenoxy acids, chlorophenols, and organic solvents, collectively, has been made (Hardell et al. 1981); apparently, combined exposure to these chemicals may increase cancer risk. No data regarding cancer in humans following inhalation exposure to 2,4-dichlorophenol, specifically and in the absence of other substances known to produce cancer, were located. No studies were located regarding cancer in animals after inhalation exposure to 2,4-dichlorophenol. 2.2.2 Oral Exposure 2.2.2.1 Death No data were located regarding deaths in humans following oral exposure to 2,4-dichlorophenol, but it is clear from animal studies that ingestion of large doses of 2,4-dichlorophenol can be fatal. LDsy, values were 3,670 mg/kg/day for rats (Kobayashi et al. 1972) and 1,276 and 1,630 mg/kg/day for mice (Borzelleca et al. 1985a, 1985b; Kobayashi et al. 1972). Five of a group of five Fischer 344 rats died when given a single gavage dose of 2,400 mg/kg, while 2,000 mg/kg had no effect on survival (Wil Research Laboratories, Inc. 1982). Another study by Hencke and Lockwood (1973) reported total mortality (two of two Sprague-Dawley rats) from single gavage administration of 5,000 mg/kg and no effect from 2,500 mg/kg. Although some differences between strains of rats may be expected, the very small sample size renders these data questionable. Four of 28 pregnant rats died after gavage dosing with 750 mg/kg/day for 3-6 days (Rodwell et al. 1989). Exposure of rats to concentrations as high as 2,000 mg/kg/day 2,4-dichlorophenol for up to 13 weeks did not cause mortality in either sex, while 2,600 mg/kg/day also did not affect survival of mice at this duration (NTP 1989). However, all mice died when exposed for 3 weeks to 5,200 mg/kg/day (NTP 1989). With chronic dietary exposure, no significant differences in survival were observed at any concentration tested in these species (levels as high as 440 mg/kg/day for rats and 1,300 mg/kg/day for mice) (NTP 1989). The LDs, values, highest NOAEL values, and all reliable LOAEL values for death in each species and duration category are recorded in Table 2-1 and plotted in Figure 2-1. » TABLE 2-1. Levels of Significant Exposure to 2,4-Dichlorophenol - Oral 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 ACUTE EXPOSURE Death 1 Rat (GO) 1d 2,000 2,400 (total mortality) Wil Research Laboratories, Inc. 1982 2 Rat (F) 14 d 2,000 NTP 1989 3 Rat (GO) 10 d 375 750 (four maternal Rodwell et al. 1x/d deaths) 1989 gd 6-15 4 Rat (GO) 18 hr 3,670 (LDgq) Kobayashi 2 doses et al. 1972 5 Mouse (GO) 1d 1,276 (LDsgq) Borzelleca et al.1985a, 1985b 6 Mouse (GO) 18 hr 1,630 (LDsgq) Kobayashi 2 doses et al. 1972 7 Mouse (F) 14 d 2,600 5,200 (1/10 deaths) NTP 1989 Systemic 8 Rat (F) 14 d Musc/skel 1,000 2,000 (hunched posture) NTP 1989 9 Rat (GO) 10 d Resp 750 (respiratory rales) Rodwell et al. 1x/d 1989 gd 6-15 10 Rat (GO) 1d Resp 2,400 (lung hemorrhage) Wil Research Laboratories, Inc. 1982 Neurological 11 Rat (GO) 1d 500 2,000 (lethargy, ataxia) 2,400 (severe ataxia, Wil Research prostration) Laboratories, Inc. 1982 12 Mouse (F) 14 d 5,200 NTP 1989 C S10d44d HITVHH TT TABLE 2-1 (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 Developmental 13 Rat (GO) 10d 375 750 (slightly decreased 750 (slightly increased Rodwell et al 1x/d fetal weight, early embryonic 1989 gd 6-15 delayed ossification) death) Reproductive 14 Rat (GO) 10d 750 Rodwell et al. 1x/d 1989 gd 6-15 INTERMEDIATE EXPOSURE Death 15 Rat (F) 13 wk 2,000 NTP 1989 16 Mouse (F) 3 wk 2,600 5,200 (100% mortality) NTP 1989 Systemic 17 Rat (W) 147 d Hepatic 30 (increased liver weight) Exon et al. Hemato 30 (increased spleen weight) 1984 18 Rat (F) 13 wk Resp 2,000 NTP 1989 Cardio 2,000 Gastro 2,000 Hemato 500 (bone marrow atrophy) Musc/skel 1,000 2,000 (hunched posture) Renal 2,000 Derm/Oc 2,000 18 Mouse (F) 13 wk Resp 2,600 NTP 1989 Cardio 2,600 Gastro 2,600 Hemato 2,600 Musc/skel 2,600 Hepatic 325 (necrosis) Derm/Oc 2,600 20 Mouse (F) 3 wk Renal 2,600 5,200 (tubular necrosis) NTP 1989 21 Mouse (F) 6 mo Hepatic 100 230 (hepatocellular Kobayashi hyperplasia) et al. 1972 C SIDH4AJd HLITVIH ct TABLE 2-1 (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 Systemic 22 Mouse (W) 90 d Other 491P Borzelleca et al. 1885a Immunological 23 Rat (W) 147 d 30 (increased serum Exon et al. antibodies) 1984 24 Rat (W) 147 d 0.3 3.0 (decreased delayed- Exon et al. type hypersensi- 1984 tivity response) Neurological 25 Rat (F) 13 wk 2,000 NTP 1988 26 Mouse (F) 13 wk 2,600 NTP 1989 Reproductive 27 Rat (W) 80 d 30 Exon et al. 1984 28 Mouse (W) 90 d 500 Seyler et al. 1984 CHRONIC EXPOSURE Death 23 Rat (F) 103 wk 440 NTP 1888 30 Mouse (F) 103 wk 1,300 NTP 1888 Systemic 3 Rat (F) 103 wk Resp 210 (nasal lesions) NTP 1989 Cardio 440 Gastro 440 Musc/skel 440 Hepatic 440 Renal 440 Derm/Oc 440 C S1D3A4d HLIVIH €1 TABLE 2-1 (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 32 Mouse (F) 103 wk Resp 1,300 NTP 1989 Cardio 1,300 Gastro 1,300 Hemato 1,300 Musc/skel 1,300 Renal 1,300 Derm/Oc 1,300 Neurological 33 Rat (F) 103 wk 440 NTP 1989 34 Mouse (F) 103 wk 1,300 NTP 1988 Reproductive 35 Rat (F) 103 wk 440 NTP 1989 36 Mouse (F) 103 wk 1,300 NTP 1989 8The number corresponds No effect on weight of Cardio = cardiovascular; (GO) = gavage oral; hr = to entries in Figure 2-1. spleen, thymus, or total body. d = days; Derm/oc = dermal ocular; (F) = food; Gastro = gastrointestinal; Gd = gestational day; hours; Hemato = hematological; LDgq = lethal dose (50% deaths); LOAEL = lowest-observed-adverse-effect level; Musc/skel = muscular/skeletal; NOAEL = no-observed-adverse-effect level; Resp = Respiratory; (W) = water; wk = weeks C S1Oddd4d HITVIH 71 FIGURE 2-1. Levels of Significant Exposure to 2,4-Dichiorophenol - Oral ACUTE (<14 Days) Systemic N 2 e 3) id & § s FF ¥F & & » (mg/kg/day) 10,000 p= @®nm He Qitam Sm Wen Ov 87 0x 0 Qu Que ® bid § ®x Qx OF , x @13 Qi Oa Ow Qi» 100 10 p= 1 - 01 0.01 pF 0.001 = Koy m Mouse B ox r Ra @ LOAEL for serous effects (animals) LOAEL for less senous eifects (animals) O NOAEL (anmais) The number next to each paint comesponds to entries in Table 2-1. C S10d444 HLIVAH ST (mg/kg/day) 10,000 1,000 100 0.1 0.01 0.001 FIGURE 2-1 (Continued) INTERMEDIATE (15-364 Days) Systemic @ & ® » » & Sg & £5 & & & & < iO & © RS Ng > ® 5 >" & F > $F § $ £ $ ¢ ¢& fF & J ® J oP F WN F ® c & ¥ & [ oer 19m 19m 19m 19m @ 20m On 01% O70 O01 O01 © Oa Om 160 O™ var O* 2s ~ Ow ® = 10m Ozm 21m = Qe O28m Qe Qe Qzr Oar Q2ar Qaar - Key m Mouse B ox r Rat @ LOAEL for serious effects (animals) @ LOAEL for less serious effects (animals) QO NOAEL (animals) The number next to each point corresponds to entries in Table 2-1. C S1O0d4d4d HITIVIH 91 17 2. HEALTH EFFECTS 2.2.2.2 Systemic Effects Respiratory Effects. No studies were located regarding respiratory effects in humans following oral exposure to 2,4-dichlorophenol. Labored breathing, as has been reported in mice fed lethal doses of 2,4-dichlorophenol (Borzelleca et al. 1985a, 1985b), probably reflects central nervous system depression. Lung hemorrhaging occurs in rats, but only with lethal doses administered by gavage (Wil Research Laboratories, Inc. 1982). No respiratory effects were noted in rats fed 2,000 mg/kg 2,4-dichlorophenol/day for 13 weeks. The nasal epithelium may be a target of long-term 2 ,4-dichlorophenol exposure. Nasal lesions were noted only in male rats exposed to 210 mg/kg/day for 103 weeks, and not in mice fed as much as 1,300 mg/kg/day for the same exposure period (NTP 1989). This effect may, therefore, be specific to the male rat and may have been due to aspiration while eating. No respiratory effects were seen in mice fed 2,600 mg/kg 2 ,4-dichlorophenol for 13 weeks. Cardiovascular Effects. No studies were located regarding cardiovascular effects in humans following oral exposure to 2,4-dichloro- phenol, but animal studies suggest that 2,4-dichlorophenol is not a cardiovascular toxicant. No cardiovascular effects were noted in rats fed 2,000 mg/kg 2,4-dichlorophenol/day or mice fed 5,200 mg/kg 2,4-dichlorophenol for 13 weeks. Studies with rats exposed to levels as high as 440 mg/kg/day and with mice exposed to as much as 1,300 mg/kg/day for durations of up to 103 weeks showed no effects on this system (NTP 1989). Gastrointestinal Effects. No studies were located regarding gastrointestinal effects in humans following oral exposure to 2 ,4-dichlorophenol. No treatment-related gastrointestinal effects were seen in rats fed 2,000 mg/kg 2,4-dichlorophenol/day or in mice fed 2,600 mg/kg/day for 13 weeks or in rats fed 440 mg/kg/day or mice fed 1,300 mg/kg/day for 103 weeks (NTP 1989). Possible mild catarrhal enteritis was observed in rats given single gavage dose of 316-5,000 mg/kg/day and sacrificed at 24 hours (Henck and Lockwood 1973). No pathology reports were available, however, for 7- or l4-day survivors. The very small sample size weakens the validity of these data. Hematological Effects. No studies were located regarding hematological effects in humans following oral exposure to 2,4-dichlorophenol. No hematological effects were seen in rats fed 2,000 mg/kg 2 ,4-dichlorophenol or in mice fed 2,600 mg/kg/day for 13 weeks. Hematological effects were observed in rats with protracted exposure. Elevated spleen weight was seen with exposure to 30 mg/kg/day for 21 weeks (Exon et al. 1984) and bone marrow atrophy with 500 mg/kg/day for 13 weeks (NTP 1989). Both erythroid and myelocytic elements were depleted. 18 2. HEALTH EFFECTS Musculoskeletal Effects. No studies were located regarding musculoskeletal effects in humans following oral exposure to 2,4-dichlorophenol. However, rats exposed to 2,4-dichlorophenol in food developed an abnormal hunched posture that may indicate a musculoskeletal or neurological effect. This effect has been observed in rats exposed to 2,000 mg/kg/day for 14 days or for 13 weeks (NTP 1989). Mice exposed to similar or higher levels for similar durations do not exhibit the effect; therefore, the phenomenon may be specific to the rat. Hepatic Effects. No studies were located regarding hepatic effects in humans following oral exposure to 2,4-dichlorophenol. Studies with animals suggest that 2,4-dichlorophenol is a hepatotoxicant with protracted exposure. Mice fed 325 mg 2,4-dichlorophenol/kg/day or more for 13 weeks dose-related increases in necrosis, but when fed 383 or 230 mg/kg/day for 90 days or 6 months, respectively, no effects were noted on serum glutamic-oxaloacetic transaminase and glutamic-pyruvic transaminase activity (Borzelleca et al. 1985a; Kobayashi et al. 1972). These enzymes are released in the bloodstream as a result of liver necrosis. These data may, in part, reflect differences in animal strains; these doses may more likely represent threshold levels for liver damage. Rats fed 30 mg/kg 2,4-dichlorophenol/day in drinking water had increased liver weights (Exon et al. 1984), an effect that could indicate hyperplasia or enzyme induction. Hepatocellular hyperplasia was seen in only one of 10 mice (Kobayashi et al. 1972). Diffuse syncytial alterations occurred in mice given 800 mg/kg 2,4-dichlorophenol/day for 103 weeks (NTP 1989). This evidence is suggestive but inconclusive for hepatotoxicity of 2,4-dichlorophenol. Renal Effects. No information was located regarding renal effects in humans following oral exposure to 2,4-dichlorophenol. Animal studies indicate that kidney damage is likely with intermediate or long-term oral exposure to high levels of 2,4-dichlorophenol. Table 2-1 shows that renal tubular necrosis has been found in mice fed very high levels (5,200 mg/kg/day) for 3 weeks, but no effect was seen in these animals with exposures of up to 2,600 mg/kg/day. No renal effects were seen in rats fed 2,000 mg/kg 2,4-dichlorophenol for 13 weeks. Urogenital staining of fur was seen in pregnant rats exposed to 200-750 mg/kg 2,4-dichlorophenol/day for 10 gestational days, but the toxicological significance of this effect is not known. Kidney pathology was not found in rats fed as much as 440 mg/kg/day or in mice fed up to 1,300 mg/kg/day for 103 weeks (NTP 1989). Dermal/Ocular Effects. No studies were located regarding dermal or ocular effects in humans following oral exposure to 2,4-dichlorophenol. Pregnant rats given 750 mg/kg 2,4-dichlorophenol by gavage experienced hair loss, but the toxicological significance of this is not known. No dermal/ocular effects were found in rats or mice given as much as 2,000 or 2,600 mg/kg/day, respectively, for up to 13 weeks nor for these same species fed up to 440 or 1,300 mg/kg/day for up to 103 weeks (NTP 1989). 19 2. HEALTH EFFECTS Other Systemic Effects. Other systemic effects in humans following oral exposure to 2,4-dichlorophenol were not located in the available literature. Pregnant rats administered 200-750 mg/kg/day 2,4-dichlorophenol by gavage on gestation days 6-15 showed decreased mean body weight gain (Rodwell et al. 1989). Studies with rats and mice fed 2,4-dichlorophenol for acute, intermediate, and chronic durations found dose-related decreases in food intake and body weight (NTP 1989). These later effects are believed to be due to the bad taste of 2,4-dichlorophenol. Since the validity of these data as NOAELs and LOAELs is questionable, the values are not recorded in Table 2-1 or plotted in Figure 2-1. 2.2.2.3 Immunological Effects No studies were located regarding immunological effects in humans after oral exposure to 2,4-dichlorophenol. Immune system effects have been reported in animals at low doses. Decreased delayed-type hypersensitivity occurred in rats during intermediate duration exposure to 3.0 mg/kg 2,4-dichlorophenol/ day, and increased serum antibodies were found in the blood of rats during similar exposures to 30 mg/kg/day. These preliminary findings suggest that the immune system may be especially sensitive to 2,4-dichlorophenol. No immune system effects occur with exposure to 0.3 mg/kg/day (Exon et al. 1984; Exon and Koller 1985). Bone marrow degenerates in rats fed 500 mg/kg 2 ,4-dichlorophenol/day for intermediate durations (NTP 1989). Both erythroid and myelocytic elements were depleted, but immunocompetence at this level has not been evaluated. The highest NOAEL value and all reliable LOAEL values for immunological effects in rats in the intermediate-duration category are recorded in Table 2-1 and plotted in Figure 2-1. 2.2.2.4 Neurological Effects No studies were located regarding neurological effects in humans following oral exposure to 2,4-dichlorophenol. However, central nervous system effects have been seen in mice fed acute lethal oral doses (Borzelleca et al. 1985a, 1985b; Deichmann 1943; Kobayashi et al. 1972; Wil Research Laboratories 1982). Typical effects include restlessness and increased respiratory rate, which appear quickly, followed shortly by tremors, convulsions, dyspnea, coma, and death. The hunched posture seen in rats fed high acute doses of 2,4-dichlorophenol was considered a musculoskeletal effect but could possibly be a neurological effect. The protocol of the NTP (1989) studies, however, included clinical observations that should have detected such gross neurological effects, yet none were reported in rats fed up to 2,000 mg/kg/day, in mice fed doses of up to 2,600 mg/kg/day for 13 weeks, or in rats or mice fed 440 and 1,300 mg/kg/day, respectively, for 103 weeks (NTP 1989). 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. 20 2. HEALTH EFFECTS 2.2.2.5 Developmental Effects No studies were located regarding developmental effects in humans following oral exposure to 2,4-dichlorophenol. Oral exposure of pregnant rats to 750 mg/kg 2,4-dichlorophenol/day for 10 gestational days induced slightly decreased fetal weight, delayed ossification of sternal and vertebral arches, and led to a slight increase in early embryonic deaths (Rodwell et al. 1989). Maternal death occurred at this dose level, indicating that 2,4-dichlorophenol was not, under these test conditions, selectively toxic to embryos or fetuses. The authors indicated that, although the deaths and fetal weights differed from that of concurrent controls, values were not different from historical control data from their laboratory. No evidence of malformations in the offspring was found in this study. No effects from exposure to 375 mg/kg/day were noted. In a 90-day oral exposure of female rats to 42 mg/kg 2,4-dichlorophenol/day in drinking water during the entire breeding and parturition period, no significant differences (p>0.05) were noted in developmental parameters, but some dose-related differences were seen (decreased litter size, increased percent stillborn) (Exon et al. 1984). No malformations were noted among the offspring at any dose tested. In a subsequent report of these same data by these authors, differences in the litter size and percent stillborn were considered to be statistically significant at the p<0.10 significance level (Exon and Koller 1985). The use of this unconventional level of significance, however, makes the statistical analysis questionable. The NOAEL value and LOAEL values for rats for developmental effects in the acute-duration category are recorded in Table 2-1 and plotted in Figure 2-1. 2.2.2.6 Reproductive Effects No information was located regarding reproductive effects in humans following oral exposure to 2,4-dichlorophenol. No reproductive effects were seen when female rats were fed up to lethal concentrations of 2,4-dichlorophenol for 10 gestational days (Rodwell et al. 1989). No reproductive effects were observed in female rats exposed to 2,4-dichlorophenol in drinking water for 10 weeks prebreeding and during gestation (Exon et al. 1984). No reproductive organ pathology was seen in rats or mice of either sex fed up to 2,000 or 5,200 mg/kg/day, respectively, for 103 weeks. Sperm from male mice fed 500 mg/kg 2,4-dichlorophenol/day for 90 days in drinking water were not impaired in their ability to penetrate ova (Seyler et al. 1984). All NOAEL values for each duration category are recorded in Table 2-1 and Figure 2-1. 21 2. HEALTH EFFECTS 2.2.2.7 Genotoxic Effects No studies regarding genotoxic effects in humans or animals following oral exposure to 2,4-dichlorophenol were located in the available literature. Genotoxicity studies are discussed in Section 2.4. 2.2.2.8 Cancer There are no data regarding cancer effects in humans following oral exposure to 2,4-dichlorophenol. Animal study data from two research groups have not yielded evidence of carcinogenicity from up to 107 weeks of oral exposure to 42 mg/kg 2,4-dichlorophenol/day (Exon and Koller 1985; NTP 1989). The study by Exon and Koller (1985) included prenatal and/or postnatal exposures. Feeding tests with rats and mice at doses up to 2,000 and 5,200 mg/kg/day, respectively, for periods of up to 103 weeks provided no evidence for carcinogenic activity due to 2,4-dichlorophenol (NTP 1989). 2.2.3 Dermal Exposure 2.2.3.1 Death No studies were located regarding lethality in humans after dermal exposure to 2,4-dichlorophenol. Studies with rabbits indicate that dermal exposure for no more than a day to 2,4-dichlorophenol may be lethal at high levels (1,414 mg/kg/day or above) to this species (Carreon et al. 1980a). This LOAEL value is recorded in Table 2-2. 2.2.3.2 Systemic Effects No studies were located regarding respiratory, cardiovascular, hematological, musculoskeletal, hepatic, or renal effects in humans or animals after dermal exposure to 2,4-dichlorophenol. The highest NOAEL values and all reliable LOAEL values for the following systemic effects in each species and duration category are recorded in Table 2-2. Gastrointestinal Effects. No studies were located regarding gastrointestinal effects in humans following dermal exposure to 2,4-dichlorophenol. A test with rabbits suggested that diarrhea may result from dermal exposure to 398 mg/kg/day (Hencke and Lockwood 1973). Very small numbers of test animals (two males/dose) severely limit interpretation of these data. Dermal/Ocular Effects. Studies that clearly indicate that dermal/ocular effects occur in humans dermally exposed to 2,4-dichlorophenol were not located in the available literature. Chloracne, evidence of acquired TABLE 2-2. Levels of Significant Exposure to 1,3-Dichlorophenol - Dermal Exposure LOAEL (effect) frequency/ Species duration System NOAEL Less Serious Serious Reference ACUTE EXPOSURE Death Rabbit 1d 4,000 mg/kg/day (estimated LD5q) Rabbit 1d 1,414 mg/kg/day (LDsp) Systemic Rabbit 1/30 seconds Ocular 0.1 mL (severe corneal damage) Rabbit 1d Gastro 398 mg/kg/day (diarrhea) Dermal 200 mg/kg/day (dermal lesions) Rabbit 1d Dermal 1,000 mg/kg/day (dermal lesions) Other 4,000 mg/kg/day? Neurological Rabbit 1d 250 mg/kg/day (lethargy) 2,000 mg/kg/day (anorexia) Carreon et al. 1980a Carreon et al. 1880b Hencke and Lockwood 1973 Hencke and Lockwood 1973 Carreon et al. 1880a Carreon et al. 1980b 2No effect on body weight d = day; Gastro = gastrointestinal; LDg = lethal dose (50% deaths); LOAEL = lowest-observed-adverse-effect level; NOAEL = no-observed-adverse-effect Yoves Z S1O0d4dd HITVIH cc 23 2. HEALTH EFFECTS porphyria, hyperpigmentation, and hirsutism have been observed in workers employed in the manufacture of 2,4-dichlorophenol- and 2,4,5-trichlorophenol- based herbicides (Bleiberg et al. 1964). These data are confounded by the facts that exposure probably occurred also through inhalation and that the subjects were exposed to several chlorinated phenols in addition to 2 ,4-dichlorophenol (for example, dioxin). The cause of these effects cannot be ascribed specifically to 2,4-dichlorophenol. Studies with rabbits clearly establish that 2,4-dichlorophenol damages the skin and cornea of this species. Dermal lesions were caused by a single direct application of as little as 200 mg/kg 2,4-dichlorophenol to bare abdominal skin (Carreon et al. 1980a, 1980b; Hencke and Lockwood 1973). No NOAEL values were identified by these studies. Severe corneal damage occurred in eyes of rabbits with a single direct application of 0.1 mL 2,4-dichloro- phenol (Hencke and Lockwood 1973). Careful washing of the eye 30 seconds after application did not prevent this damage. Other Systemic Effects. Studies reporting effects on body weight in humans following dermal exposure to 2,4-dichlorophenol were not located in the available literature. Studies with rabbits suggest that a single direct application of 4,000 mg/kg has no effect on body weight (Carreon et al. 1980b) . 2.2.3.3 Immunological Effects A possible immunological effect was noted in a study of 29 workers engaged in the manufacture of 2,4-dichlorophenol- and 2,4,5-trichlorophenol- based herbicides (Bleiberg et al. 1964). This effect, chloracne, was probably from tissue damage rather than of immunological origin, but this is uncertain, as were the route of exposure and exact chemical causing the effect (see Section 2.2.1.2). No studies were located regarding immunological effects in animals following dermal exposure to 2,4-dichlorophenol. 2.2.3.4 Neurological Effects No studies were located regarding neurological effects in humans after dermal exposure to 2,4-dichlorophenol. Rabbits given single applications of 240 mg/kg or more 2,4-dichlorophenol became lethargic (Carreon et al. 1980a, 1090b), and two rabbits in the 2,000 mg/kg group and one in the 4,000 mg/kg group became anorexic (Carreon et al. 1980b). This latter effect may be questionable because dermal exposure to as high as 4,000 mg/kg did not affect the body weight in this same species (Carreon et al. 1980a). Small sample sizes weaken the validity of these data, but the lethargy seen here is in keeping with signs of central nervous system depression seen in rats and mice orally exposed to 2,4-dichlorophenol. No NOAEL values were identified for 24 2. HEALTH EFFECTS neurological effects. The lowest LOAEL values for neurological effects in rabbits are recorded in Table 2-2. No studies were located regarding the following health effects in humans or animals after dermal exposure to 2,4-dichlorophenol. 2.2.3.5 Developmental Effects 2.2.3.6 Reproductive Effects 2.2.3.7 Genotoxic Effects Genotoxicity studies are discussed in Section 2.4. 2.2.3.8 Cancer No studies regarding cancer in humans following dermal exposure to 2,4-dichlorophenol alone were located. Several epidemiological studies of factory workers engaged in phenoxy herbicide manufacturing or of agricultural workers known to be exposed to phenoxy herbicides and chlorophenols noted an increased incidence of soft-tissue sarcoma (Eriksson et al. 1981; Hardell 1981; Honchar and Halperin 1981; Lynge 1985) and/or malignant lymphoma (Hardell 1981; Hardell et al. 1981). However, these persons were exposed, possibly by the dermal route, to several phenoxy acids, chlorophenols, and organic solvents, including volatile intermediates of the manufacturing process. Although it appears that combined exposure to these chemicals increases the risk of soft-tissue sarcoma and malignant lymphoma, no evidence has been located that links 2,4-dichlorophenol alone to cancer. A case- controlled study of the occupational exposure of men that may have included the dermal route to chlorinated phenols found no increased risk of developing soft-tissue sarcoma (Woods et al. 1987). In laboratory mice, 2,4-dichlorophenol has been found to promote tumors. Application of the known tumor initiator 9,10-dimethyl-1,2-benzanthracene (DMBA) to the mid-dorsal region, followed by dermal administration of about 0.005 mg 2,4-dichlorophenol for as little as twice weekly for 15 weeks, significantly increased the incidence of papillomas and carcinomas (Boutwell and Bosch 1959). No evidence has been located to suggest 2,4-dichlorophenol alone induces papillomas or carcinomas. 2.3 TOXICOKINETICS 2.3.1 Absorption 2.3.1.1 Inhalation Exposure No studies were located regarding absorption in humans or animals after inhalation exposure to 2,4-dichlorophenol. 25 2. HEALTH EFFECTS 2.3.1.2 Oral Exposure No studies were located regarding absorption in humans or animals after oral exposure to 2,4-dichlorophenol. Numerous toxicological studies show effects following oral administration, strongly indicating that absorption occurs. The lipophilic nature of this compound also predicts absorption, as noted by Somani and Khalique (1982). 2.3.1.3 Dermal Exposure No in vivo studies were located regarding absorption in humans after dermal exposure to 2,4-dichlorophenol. Data provided by in vitro studies of the permeability properties of human epidermis indicate that human skin is more permeable to 2,4-dichlorophenol than to phenol (Roberts et al. 1977, 1978), which is known to be absorbed across human skin (Piotrowski 1971). Thus, a reasonable assumption is that 2,4-dichlorophenol will be absorbed across human skin. Dermal absorption studies with rabbits indicate that 2,4-dichlorophenol may be absorbed across the skin of this species in lethal amounts (Carreon et al. 1980a; Hencke and Lockwood 1973). Animals were restrained from eating the substance by plastic sleeves covering the treated areas and a collar, thus clearly showing that 2,4-dichlorophenol was absorbed. No toxicokinetic measurements were made, however. Additional dermal toxicology studies with these animals yielded systemic effects that support these findings (Carreon et al. 1980b). The lipophilic nature of this compound also predicts absorption (Somani and Khalique 1982). 2.3.2 Distribution Although the observation of effects in several animal organs and tissues indicate that 2,4-dichlorophenol is widely distributed, no definitive studies were located regarding distribution in humans or animals after exposure to 2,4-dichlorophenol by the following routes: Inhalation Exposure Oral Exposure Dermal Exposure NNN www RNR wre 2.3.2.4 Other Routes of Exposure No studies were located regarding the distribution of 2,4-dichlorophenol in humans after exposure by other routes. However, a study in which laboratory animals were given 2,4-dichlorophenol intravenously provides some insight regarding distribution patterns anticipated in humans (Somani and Khalique 1982). Intravenously administered 2,4-dichlorophenol rapidly distributes to kidney, liver, fat, and brain in rats, with the highest 26 2. HEALTH EFFECTS concentrations in the kidney and liver. Elimination from these tissues is also rapid; elimination half-time for plasma is approximately 10 minutes (Somani and Khalique 1982). The results of in vitro binding studies of human serum proteins indicate that 2,4-dichlorophenol strongly binds to serum proteins, including albumin and globulin, and that the binding may be reversible (Judis 1982). 2.3.3 Metabolism No studies were located regarding metabolism in humans after exposure to 2,4-dichlorophenol. However, studies in rats and in vitro studies of rat tissues have identified the glucuronide conjugate as the major metabolite of 2,4-dichlorophenol (Somani and Khalique 1982). Two minor metabolites, dichloromethoxyphenols, have been detected in in vitro preparations; however, the extent to which they are formed in vivo has not been determined (Somani et al. 1984). The glucuronide conjugate of 2,4-dichlorophenol is formed in vivo in the kidney, liver, fat, and brain of the rat. Elimination of the conjugates from these tissues is rapid; elimination half-times were 4-10 minutes in brain and fat and about 30 minutes in kidney and liver (Somani and Khalique 1982). Based on the results of these studies, extensive biotransformation of 2,4-dichlorophenol to glucuronide conjugates and excretion of it in these forms occurs in rats and may also occur in humans. 2.3.4 Excretion 2.3.4.1 Inhalation Exposure No studies were located regarding excretion of 2,4-dichlorophenol by humans or animals after inhalation exposure. 2.3.4.2 Oral Exposure Studies regarding excretion in humans or animals after oral exposure to 2,4-dichlorophenol were not located. A study of rats quantified the halogenated phenols found in their urine after exposure to pesticides known to be metabolized to 2,4-dichlorophenol. Of 5,120 nmol of the pesticide VC 13 (dichlofenthion) fed to the animals, 3,470 nmol of 2,4-dichlorophenol was metabolized to 2,4-dichlorophenol. Excretion of 2,4-dichlorophenol was complete within 3 days (Shafik et al. 1973). It has not been determined whether administration of 2,4-dichlorophenol itself would yield the same results. 2.3.4.3 Dermal Exposure No studies were located regarding excretion of 2,4-dichlorophenol by humans or animals after dermal exposure. 27 2. HEALTH EFFECTS 2.3.4.4 Other Routes of Exposure Neither studies regarding excretion in humans after exposure by other routes nor quantitative data regarding excretion of 2,4-dichlorophenol by animals were located. However, a study with rats showed rapid clearance from the kidney, liver, fat, brain, and plasma of both the parent compound and metabolites after intravenous exposure to 2.5-3.0 mg 2,4-dichlorophenol in aqueous solution (Somani and Khalique 1982). Half-lives for 2,4-dichlorophenol and its conjugates ranged from 4 to 30 minutes in these tissues, with the highest values in kidney, followed by the liver, fat, plasma, and brain (Somani and Khalique 1982). No detectable amounts were found in the brain at 60 minutes, and no glucuronide conjugates were found in fat at any time. These data suggest that 2,4-dichlorophenol does not accumulate in body tissues but is quickly excreted. 2.4 RELEVANCE TO PUBLIC HEALTH Health effects in humans clearly attributable to exposure to 2,4-dichlorophenol were not located. Chloracne, porphyria cutanea tarda, elevated serum transaminase levels, and evidence of liver damage (regeneration and hemofuscin deposition) have been diagnosed in some factory workers, but concomitant exposure of these people to other toxic substances confounds these data. Liver necrosis has been observed in animals exposed to 2,4-dichlorophenol. Effects observed in animals but not reported in humans include death, respiratory failure, central nervous system depression, bone marrow atrophy, kidney and spleen damage, nasal lesions, developmental effects (decreased pup survival), reduced food intake, reduced body weight gain, and possibly impaired immune function. MRLs were not developed for acute-, intermediate-, or chronic-durations of exposure to 2,4-dichlorophenol by the inhalation or oral routes because data were inadequate to do so. An immunotoxicity study with rats found preliminary evidence of effects to this system from exposure to a low dose (30 mg/kg/day) for an intermediate-duration (Exon et al. 1984). These data are inappropriate for MRL derivation because insufficient supporting evidence is available to establish the certainty that 2,4-dichlorophenol is immunotoxic in animals, or for an assessment to be made regarding potential immunological effects in humans. An intermediate MRL based on a less sensitive end point; however, would not adequately protect the immune system should further tests validate the findings of the existing study. Acute-duration, intermediate- duration, and chronic-duration dermal MRLs were not derived for 2,4-dichlorophenol due to the lack of an appropriate methodology for the development of dermal MRLs. Death. Reported deaths of humans associated with 2,4-dichlorophenol were not located in the available literature. Differences in sensitivity are seen among animal species, and gavage administration kills animals at lower doses 28 2. HEALTH EFFECTS than does dietary exposure. We do not know which is the best model for humans for 2,4-dichlorophenol. Low numbers of mice died when they were fed 5,200 mg/kg/day for 14 days, while total lethality was seen when they were fed the same concentration for 13 weeks. Based on these animal data, 2,4-dichlorophenol could be expected to cause death in humans who eat large amounts of it for short periods of time (which is unlikely except in attempted suicides). Risk of death from long-term exposure could conceivably occur at lower dose levels. A characteristic sequence of signs precedes death in rats and mice: tremors, muscle weakness, loss of coordination, clonic convulsions (which pass quickly), dyspnea, coma, and respiratory arrest. These signs suggest central or peripheral nervous system toxicity as the cause of death (see discussion of Neurological Effects in this section). Other systemic or organ damage was not reported after acute oral exposure to lethal doses in animals. Rabbit studies indicate that dermal exposure to high levels of 2,4-dichlorophenol for only 1 day can be lethal. Central nervous system toxicity was also evident in these cases (severe ataxia, prostration, and tremors). This suggests that 2,4-dichlorophenol has the potential to induce these effects in humans exposed to high levels of 2,4-dichlorophenol, even though it has not been seen in humans. Systemic Effects Respiratory Effects. Respiratory effects in humans following exposure to 2,4-dichlorophenol have not been documented by the available data. Labored breathing and altered respiratory rates have been noted in rats and mice exposed to acute lethal oral doses of 2,4-dichlorophenol and in rats given acute lethal intraperitoneal doses. Acute lethal doses given dermally to rabbits led to respiratory rales and lung hemorrhage. It is possible that humans exposed to lethal doses of 2,4-dichlorophenol would exhibit these effects. The nasal lesions observed in rats may have been due to aspiration of 2,4-dichlorophenol while eating, rather than a systemic effect of this substance. It is possible that humans who breathe 2,4-dichlorophenol over long periods would develop nasal lesions, but this is uncertain. Gastrointestinal Effects. No gastrointestinal effects have been reported in humans following exposure to 2,4-dichlorophenol. Diarrhea and possible mild enteritis have been seen in rabbits exposed to 2,4-dichlorophenol, but the data were poorly supported. It is possible that these effects may occur in humans, but this has not been shown. Hematological Effects. Hematological effects in humans following exposure to 2,4-dichlorophenol have not been documented by available data. The elevated spleen weights and bone marrow atrophy seen in rats with protracted exposure to 2,4-dichlorophenol indicate that this system is at risk in this species. These effects could occur in humans exposed over long periods to 2,4-dichlorophenol, but this is uncertain. 29 2. HEALTH EFFECTS Musculoskeletal Effects. Musculoskeletal effects in humans following exposure to 2,4-dichlorophenol have not been documented. Hunched postures have been seen in rats, but not mice, with acute- or intermediate-duration exposures to high levels of 2,4-dichlorophenol. It is not known whether this is a musculoskeletal or neurological effect. This effect could occur in humans exposed to high levels of 2,4-dichlorophenol, but this is uncertain. Hepatic Effects. Hepatic effects in humans following exposure to 2,4-dichlorophenol have not been documented by available data. Mouse studies indicate that 2,4-dichlorophenol causes liver necrosis with protracted exposure. There is inconclusive evidence that the substance causes hepatocellular hyperplasia in rats and mice and diffuse syncytial alterations in mice exposed for long periods. It is, therefore, possible that liver effects could occur in humans exposed chronically to 2,4-dichlorophenol, even though they have not been seen in humans. A possible mechanism for the observed diffuse syncytial alterations was demonstrated by an in vitro study (Onfelt 1986) in which 2,4-dichlorophenol interfered with normal cell division by disrupting spindle formation. Interference of 2,4-dichlorophenol with oxidative phosphorylation, as demonstrated in in vitro studies with isolated mitochondria (Stockdale and Selwyn 1971), may be a mechanism for any or all of these liver effects, since it can deplete the energy stores available to affected cells. Renal Effects. Renal effects in humans following exposure to 2,4-dichlorophenol have not been documented by available data. Studies with mice indicate that exposure to very high levels of 2,4-dichlorophenol causes renal tubular necrosis. A toxicokinetic study in which rats were exposed intravenously to 2,4-dichlorophenol indicated that both the parent compound and conjugated metabolites have the greatest affinity for the kidney; although these substances are rapidly eliminated via urine, tissues of this organ may be especially at risk. It is possible that the human kidney would be affected by large amounts of 2,4-dichlorophenol, but this is uncertain. Dermal/Ocular Effects. Chloracne, evidence of acquired porphyria cutanea tarda, hyperpigmentation, and hirsutism have been observed in factory workers exposed to 2,4-dichlorophenol, but these people were concurrently exposed to phenoxy-based herbicides and other chlorinated phenols, preventing a clear establishment of effect due to 2,4-dichlorophenol exposure. The results of dermal studies with rabbits indicate that it is acutely toxic to skin and eyes. Dermal lesions result from exposure of skin to high concentrations of 2,4-dichlorophenol, and severe corneal damage is incurred with exposure to low levels. These data suggest that the above effects seen in factory workers may, in fact, have been caused by 2,4-dichlorophenol exposure over long periods and on a daily basis and that damage to skin and eyes may occur in humans acutely exposed by the dermal route. 30 2. HEALTH EFFECTS Immunological Effects. Immunological effects in humans following exposure to 2,4-dichlorophenol have not been documented, but immunological findings in animals suggest that the human immune system could be affected. One oral study in rats indicated that 2,4-dichlorophenol causes decreased cell-mediated immunity in that species. This finding is viewed as preliminary evidence of immune system dysfunction and needs further testing (such as host challenge assays). Although this has not been documented in humans, it appears to be the most sensitive end point in animals and, therefore, may have implications for humans. Neurological Effects. Evidence for neurological effects of 2,4-dichlorophenol in humans has not been reported. However, rats and mice fed acute lethal doses of 2,4-dichlorophenol demonstrated a common series of events that consisted of lethargy, tremors and muscle weakness, loss of coordination, clonic convulsions, dyspnea, coma, and respiratory arrest. This same sequence of events resulted partly from acute lethal dermal exposure. The mechanisms for these effects are not known, although interference with oxidative energy metabolism in the central nervous system has been suggested, based on in vitro studies with rat brain and nerve tissues (Farquharson et al. 1958). These severe neurological effects have been observed in animals only after oral or dermal exposure to high, lethal, or near-lethal levels; effects at nonlethal levels or more subtle neurological effects have not been reported. The occurrence of these effects in both test species lends credence to extrapolations to other mammalian species. 2,4-dichlorophenol may have the potential to induce these effects in humans at high doses, even though they have not been observed in humans. Developmental Effects. Developmental effects have not been observed in humans following exposure to 2,4-dichlorophenol. Results of teratology studies with rats indicate that 2,4-dichlorophenol may have the potential to cause decreased survival of offspring either in utero or after birth through a direct effect on the offspring or as a result of maternal toxicity. No evidence was found linking 2,4-dichlorophenol to malformations in offspring. Even though developmental effects have not been seen in humans, animal data suggest that 2,4-dichlorophenol may have the potential to cause abortions, but there does not appear to be cause for concern regarding teratogenicity. Reproductive Effects. Reproductive effects have not been observed in humans or animals following exposure to 2,4-dichlorophenol. Studies with pregnant rats revealed no significant effects on reproduction parameters although maternal toxicity (death, decreased body weight gain) was seen. There were also no effects on the ability of mouse sperm to penetrate ova. No reproductive organ pathology has been detected in either species, even after chronic exposure to high doses. This suggests that the possibility of effects on human reproductive function may be of low concern. 31 2. HEALTH EFFECTS Genotoxic Effects. Genotoxic effects have not been observed in humans following exposure to 2,4-dichlorophenol. Based on the equivocal results shown in Table 2-3 of tests with bacteria, yeasts, and mammalian cell systems, it is difficult to determine whether 2,4-dichlorophenol has the potential to cause genotoxicity in humans. 2,4-dichlorophenol lacks mutagenic activity in Salmonella typhimurium but exhibited a mixture of positive and negative activity in mammalian systems. This suggests that 2,4-dichlorophenol may have genotoxic potential in humans. Cancer. Cancer following exposure to 2,4-dichlorophenol alone has not been studied in humans. Oral chronic studies with rats and mice were negative, even with both pre- and postnatal exposure. However, the incidence of certain cancers among factory and agricultural workers suggests that 2,4-dichlorophenol might promote cancer in humans, especially in view of data that show that it promotes tumors in mice exposed via the dermal route. In that study, the dose on a per-body-weight basis was low (0.005 mg/kg/day), but the concentration at the site of application was high (20% solution). The study may have implications for industrial workers directly exposed to high concentrations of 2,4-dichlorophenol in combination with other compounds on a daily basis. Rabbit study data clearly indicate that 2,4-dichlorophenol is corrosive to skin and eyes, which may contribute to its cancer-promoting potential. 2.5 BIOMARKERS OF EXPOSURE AND EFFECT Biomarkers are broadly defined as indicators signaling events in biologic systems or samples. They have been classified as markers of exposure, markers of effect, and markers of susceptibility (NAS/NRC 1989). A biomarker of exposure is a xenobiotic substance or its metabolite(s) or the product of an interaction between a xenobiotic agent and some target molecule(s) or cell(s) that is measured within a compartment of an organism (NAS/NRC 1989). The preferred biomarkers of exposure are generally the substance itself or substance-specific metabolites in readily obtainable body fluid(s) or excreta. However, several factors can confound the use and interpretation of biomarkers of exposure. The body burden of a substance may be the result of exposures from more than one source. The substance being measured may be a metabolite of another xenobiotic substance (e.g., high urinary levels of phenol can result from exposure to several different aromatic compounds). Depending on the properties of the substance (e.g., biologic half-life) and environmental conditions (e.g., duration and route of exposure), the substance and all of its metabolites may have left the body by the time biologic samples can be taken. It may be difficult to identify individuals exposed to hazardous substances that are commonly found in body tissues and fluids (e.g., essential mineral nutrients such as copper, zinc, and selenium). Biomarkers of exposure to 2,4-dichlorophenol are discussed in Section 2.5.1. TABLE 2-3. Genotoxicity of 2,4-Dichlorophenol In Vitro Results With Without Species (test system) End point activation activation Reference Prokaryotic organisms: Salmonella typhimurium TAS8, TA100, TA1535, TA1537 Gene mutation = = Rasanen et al. 1977 S. typhimurium TA1535, TA1537, TA1538, TA98, TA100 Gene mutation - - Simmon et al. 1977 S. typhimurium TA100 Gene mutation - - Rapson et al. 1980 S. typhimurium G46, TA1535, TA1000, C3076, TA1537, Gene mutation = = Probst et al. 1981 D3052, TA1538, TA98 S. typhimurium TA1535, TA1537, TAS8, TA100 Gene mutation (+) - Haworth et al. 1983; NTP 1989 Eukaryotic organisms: Mammalian cells: Rat hepatocytes DNA repair No data ie Probst et al. 1981 Mouse lymphoma cells L5178Y Gene mutation No data + NTP 1989 Chinese hamster ovary cells V78 Gene mutation No data - Jansson and Jansson 1989 Chinese hamster ovary cells V78 Gene mutation No data (+) Fiskesjo 1988 Chinese hamster ovary cells Spindle disturbance No data + Onfelt 1987 Chinese hamster ovary cells Sister chromatid exchange * % NTP 1989 CD-1 mouse cells Sister chromatid exchange = = Borzelleca 1983 Chinese hamster ovary cells Chromosomal aberrations - - NTP 1989 positive results negative results = weakly positive C S10d44d HLIVIH ce 33 2. HEALTH EFFECTS Biomarkers of effect are defined as any measurable biochemical, physiologic, or other alteration within an organism that, depending on magnitude, can be recognized as an established or potential health impairment or disease (NAS/NRC 1989). This definition encompasses biochemical or cellular signals of tissue dysfunction (e.g., increased liver enzyme activity or pathologic changes in female genital epithelial cells), as well as physiologic signs of dysfunction such as increased blood pressure or decreased lung capacity. Note that these markers are often not substance specific. They also may not be directly adverse, but can indicate potential health impairment (e.g., DNA adducts). Biomarkers of effects caused by 2,4-dichlorophenol are discussed in Section 2.5.2. A biomarker of susceptibility is an indicator of an inherent or acquired limitation of an organism's ability to respond to the challenge of exposure to a specific xenobiotic substance. It can be an intrinsic genetic or other characteristic or a preexisting disease that results in an increase in absorbed dose, biologically effective dose, or target tissue response. If biomarkers of susceptibility exist, they are discussed in Section 2.7, "POPULATIONS THAT ARE UNUSUALLY SUSCEPTIBLE." 2.5.1 Biomarkers Used to Identify and/or Quantify Exposure to 2,4-Dichlorophenol 2,4-Dichlorophenol and its conjugated metabolites are measurable in circulating plasma of rats within minutes to hours after intravenous injection with 2,4-dichlorophenol (Somani and Khalique 1982). These compounds are also measurable in the urine of animals within 3 days after exposure to some 2,4-dichlorophenol-based herbicides (Karapally et al. 1973; Shafik et al. 1973). Such quantitative data for humans were not located in the available literature. The animal data suggest that 2,4-dichlorophenol and its conjugated metabolites may be measurable in human plasma and urine within short periods after exposure to 2,4-dichlorophenol. The presence of 2,4-dichlorophenol or its metabolites in urine is not diagnostic for 2,4-dichlorophenol exposure because these compounds are also measurable in urine after exposure to certain other herbicides, such as lindane (Karapally et al. 1973) and VC-13 (Shafik et al. 1973). The presence of 2,4-dichlorophenol in the absence of other chlorinated phenol metabolites may be indicative of exposure to 2,4-dichlorophenol, but this is uncertain. For further information, see Section 2.3. 2.5.2 Biomarkers Used to Characterize Effects Caused by 2,4-Dichlorophenol There are no known biomarkers of effects caused by 2,4-dichlorophenol. 2.6 INTERACTIONS WITH OTHER CHEMICALS Exposure of mice to 2,4-dichlorophenol after exposure to chemicals that cause tumors, such as DMBA, may promote the development of more tumors 34 2. HEALTH EFFECTS (Boutwell and Bosch 1959). It is also possible (but not certain) that exposure to 2,4-dichlorophenol along with phenoxy-based herbicides will promote certain types of cancer (Hardwell et al. 1981). 2,4-Dichlorophenol interferes with oxidative energy metabolism in rats (Farquharson et al. 1958), so it may be expected that exposure to 2,4-dichlorophenol concurrently with other chemicals that are biotransformed by the mixed function oxygenase system (e.g., benzene, toluene, styrene, xylene, other chlorophenols) would alter their rate of metabolism and probably exacerbate their toxic effects. Another possibility is a decrease in toxicity, if administration is sequential rather than concurrent, due to enzyme induction and more rapid metabolism of 2,4-dichlorophenol. Furthermore, concurrent exposure to other substances that exert their toxic effects by uncoupling oxidative phosphorylation (e.g., tri-, tetra-, and pentachlorophenol) could be expected to lead to increased adverse responses. 2,4-Dichlorophenol is metabolized by the liver of rats to glucuronide conjugates (Somani and Khalique 1982), so it is possible that concurrent exposure to 2,4-dichlorophenol and other chemicals such as aliphatic and aromatic hydrocarbons, carboxyl acids, or other chemicals that are biotransformed in the liver to glucuronide conjugates will cause increased toxicity. 2.7 POPULATIONS THAT ARE UNUSUALLY SUSCEPTIBLE Studies with rats and mice have shown that 2,4-dichlorophenol seriously damages the liver, kidney, and bone marrow (NTP 1989), suggesting that persons with diseases of the liver, kidney, or bone marrow may be more susceptible to 2,4-dichlorophenol than are others. Based on findings for other chemicals, persons who are also exposed to other liver toxins, such as alcohol and barbiturates, may have heightened sensitivity. Evidence from rat studies (Exon et al. 1984) suggests that the immune system may be the most sensitive to 2,4-dichlorophenol. Persons with immune-system deficiencies may, therefore, be more susceptible to the effects of 2,4-dichlorophenol. 2.8 MITIGATION OF TOXICOLOGICAL EFFECTS This section will describe clinical practice and research concerning methods for reducing toxic effects of exposure to 2,4-dichlorophenol. This section is intended to inform the public of existing clinical practice and the status of research concerning such methods. However, because some of the treatments discussed may be experimental and unproven, this section should not be used as a guide for treatment of exposures to 2,4-dichlorophenol. When specific exposures have occurred, poison control centers and medical toxicologists should be consulted for medical advice. Specific methods for mitigating the effects of 2,4-dichlorophenol after its absorption have not been identified. Studies in animals have demonstrated that exposure to 2,4-dichlorophenol was associated with liver necrosis 35 2. HEALTH EFFECTS (Borzelleca et al. 1985a; Kobayashi et al. 1972) and diffuse syncytial alterations in the liver (NTP 1989). In vitro studies have shown that 2,4-dichlorophenol interferes with normal cell division by disrupting spindle formation (Onfelt 1986) and interferes with oxidative phosphorylation in isolated mitochondria (Stockdale and Selwyn 1971). Interference with oxidative energy metabolism in rat brain and nerve tissues in vitro (Farquharson et al. 1958) has also been suggested as a possible mechanism for neurological effects observed in animals after acute exposure to 2,4-dichlorophenol (Carreon et al. 1980b; Wil Research Laboratories, Inc. 1982). Administration of agents that block these mechanisms may mitigate the hepatotoxicity and neurotoxicity of 2,4-dichlorophenol. Renal tubular necrosis has also been found in animals exposed to 2,4-dichlorophenol (NTP 1989). Both 2,4-dichlorophenol and its glucuronide conjugates have a high affinity for the kidney. Depending upon whether 2,4-dichlorophenol or the conjugates are responsible for the kidney damage, agents that either inhibit the conjugation or enhance this pathway might mitigate renal effects. Although specific methods for mitigating effects of 2,4-dichlorophenol after absorption are not available, there are general recommendations for management and treatment of persons following acute, high-dose exposure. For example, methods to reduce absorption following dermal exposure to 2,4- dichlorophenol focus on decontaminating exposed areas of the body; contaminated clothing should be removed and the skin should be thoroughly washed with soapy water. If the eyes were exposed, they should be immediately flushed with water, followed as soon as possible with irrigation of each eye with normal saline. If oral exposure to 2,4-dichlorophenol occurs, water or milk may be administered to dilute the stomach contents, however, emesis should not be induced (Bronstein and Currance 1988; Stutz and Janusz 1988). In addition, administration of activated charcoal in water, although controversial, may decrease absorption if ingestion was recent (Stutz and Janusz 1988). Following acute, high-dose inhalation exposure to 2,4- dichlorophenol, administration of oxygen and ventilation assistance may be needed. For more comprehensive information on treatment of specific symptoms, refer to Bronstein and Currance (1988) and Stutz and Janusz (1988). 2.9 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 2,4-dichlorophenol is available. Where adequate information is not available, ATSDR, in conjunction with the National Toxicology Program (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 2,4-dichlorophenol. 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 36 2. HEALTH EFFECTS 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. 2.9.1 Existing Information on Health Effects of 2,4-Dichlorophenol The existing data on health effects of inhalation, oral, and dermal exposure of humans and animals to 2,4-dichlorophenol are summarized in Figure 2-2. The purpose of this figure is to illustrate the existing information concerning the health effects of 2,4-dichlorophenol. Each dot in the figure indicates that one or more studies provide information associated with that particular effect. The dot does not imply anything about the quality of the study or studies. Gaps in this figure should not be interpreted as "data needs" information (i.e., data gaps that must necessarily be filled). The available information on the effects of 2,4-dichlorophenol in humans was obtained from an epidemiological study that is limited in its use because exposure concentrations are unquantified. Furthermore, the subjects were simultaneously exposed to volatile intermediates and phenoxy herbicides that are, themselves, toxic. The predominant route of exposure in these cases is believed to be inhalation, but the possibility of some degree of dermal exposure cannot be ruled out. Figure 2-2 indicates that information exists for both the inhalation and dermal routes of exposure. The nature and the components of these exposures are different from those that would be likely to occur in the environment. Animal data are limited to oral and acute dermal/ocular exposures to 2,4-dichlorophenol. Animal studies of inhalation or long-term dermal exposure to 2,4-dichlorophenol are lacking. Such information would be particularly useful because most human environmental contact with 2,4-dichlorophenol would be via the respiratory tract and the skin. 2.9.2 Data Needs Acute-Duration Exposure. Information on acute-duration exposure to 2 ,4-dichlorophenol is limited to oral and dermal/ocular administration to animals. These data are limited to LDg, values (Borzelleca et al. 1985a; 1985b; Carreon et al. 1980a; 1980b; Kobayashi et al. 1972; Vernot et al. 1977), effects on body weight (NTP 1989; Rodwell et al. 1989), skin (Carreon et al. 1980a; 1980b; Hencke and Lockwood 1983), and eyes (Hencke and Lockwood 1973), developmental (Rodwell et al. 1989), possible neurological (Carreon et al. 1980a; 1980b; Kobayashi et al. 1972; Wil Research Laboratories, Inc. 1982) and gastrointestinal disorders (Henck and Lockwood 1973), and any effects that can be noted from gross necropsy (Wil Research Laboratories, Inc. 1982). Data are insufficient to derive MRLs for any route of acute exposure. 37 2. HEALTH EFFECTS FIGURE 2-2. Existing Information on Health Effects of 2,4-Dichlorophenol SYSTEMIC & S/o / & . & O WO £ © ¢ & & & 4 & = o Ey o S$ & & S/E/ E/E) E/E EP Inhalation ® © Oral Dermal ®| 0 ® HUMAN SYSTEMIC 0 2 ° » 8 & SS $2 S&S SS SS SSS ESS S/S E/E & E/) P/F Inhalation Oral eo/lo(o/oj0oj0o|0|0 Dermal oO ® ANIMAL @® Existing Studies 38 2. HEALTH EFFECTS Available data clearly indicate that 2,4-dichlorophenol can enter animal tissues by both oral and dermal routes of exposure and can be lethal. The cause of death is not clear, however, since death does not seem to be associated with pathology in any particular organ system (Borzelleca et al. 1985a; 1985b; Carreon et al. 1980a; 1980b; Hencke and Lockwood 1973; Kobayashi et al. 1972; NTP 1989; Rodwell et al. 1989; Wil Research Laboratories, Inc. 1982). Studies that could elucidate this would be useful. Pharmacokinetic data are limited to those from intravenous administration of 2,4-dichlorophenol (Somani and Khalique 1982; Somani et al. 1984). These show distribution to the kidney, liver, plasma, fat, and brain, but it is not known how much or how long it takes for the compound to be absorbed into the blood by any route of exposure. Additional kinetic studies may be useful for relating exposure levels, body and tissue burdens, and toxic effects across routes of exposure. Studies at low levels of exposure could identify blood or urine levels at which toxic effects occur. These data could serve to predict human risk levels, such as for those who live near hazardous waste sites and who might be exposed to this substance for brief periods. Intermediate-Duration Exposure. There are no data on intermediate- duration exposure of humans to 2,4-dichlorophenol, and animal data are limited to those for oral exposure through diet or drinking water. Damage to the liver and kidneys has been observed in both rats and mice (Exon et al. 1984; Kobayashi et al. 1972; NTP 1989), which is consistent with kinetics data derived via in vitro and intravenous-exposure studies (Somani and Khalique 1982; Somani et al. 1984). Preliminary immunological data in rats suggest that 2,4-dichlorophenol may be an immunotoxicant, and that this system may be most sensitive (Exon et al. 1984; Exon and Koller et al. 1985). Further studies, such as host challenge assays, or immunotoxicity assays by other routes of exposure, may provide information to resolve this issue. In vivo kinetic studies that include evaluation of absorption across the skin, respiratory, or gastrointestinal tissues would be useful in predicting the risk levels of people who live near hazardous waste sites containing 2,4-dichlorophenol or are exposed to it via drinking water. These studies could identify blood or urine levels at which toxic effects occur. Chronic-Duration Exposure and Cancer. Chronic-duration exposure data in humans are limited to epidemiological information from workers engaged in the manufacture of 2,4-dichlorophenol-based products and who work with herbicides and chlorophenols that may include some 2,4-dichlorophenol (Bleiberg et al. 1964; Eriksson et al. 1981; Hardell 1981; Hardell et al. 1981; Honchar and Halperin 1981; Lynge 1985; Woods et al. 1986). These data are of limited value because exposures were not quantified, and the workers were also exposed to other potentially harmful substances. Chronic feeding studies with rats and mice have found reduced body weight and food consumption in rats and mice and nasal lesions in rats (NTP 1989). These nasal lesions may have resulted from aspiration of the substance while eating rather than an effect induced by 39 2. HEALTH EFFECTS oral exposure. No other organ pathology was detected by these studies. Data were inadequate for derivation of MRLs. Chronic exposure is an important consideration with respect to 2,4-dichlorophenol because of groundwater and chlorinated drinking water contamination. Pharmacokinetiz studies would be useful to relate exposure levels, body and tissue burdens, and toxic effects. Inhalation studies aimed at delineating possible effects on the respiratory system would clarify whether respiratory tissues are targets of chronic exposure to airborne 2,4-dichlorophenol. They may also determine whether 2,4-dichlorophenol’s effect on food intake and body weight is systemic or merely the result of its foul taste and smell. There are no data regarding cancer in humans exposed to 2,4-dichlorophenol without concomitant exposure to other known carcinogenic compounds. Chronic feeding studies with rats and mice (NTP 1989) and drinking water studies with rats (Exon and Koller 1985) have not found evidence of cancer resulting from exposure to 2,4-dichlorophenol. In view of these data, it does not appear likely that chronic exposure by dermal or inhalation routes would yield substantially different results. One study demonstrated the promoting activity of 2,4-dichlorophenol in mice, but the concentration at the site of application was high (Boutwell and Bosch 1959). The study may have implications for persons living near hazardous waste sites if they are exposed to high levels of 2,4-dichlorophenol along with other cancer-causing agents. Kinetic studies for each route of exposure may help determine the need for more cancer studies and could determine the body burden associated with the promotion of cancer. Genotoxicity. In vivo genotoxicity data from human or animal studies have not been reported. Sister chromatid exchanges, spindle disturbances, and gene mutations have been noted in some in vitro studies with mammalian cells (Borzelleca 1983; Fiskesjo 1988; Haworth et al. 1983; Jansson and Jansson 1989; NTP 1989; Onfelt 1987; Probst et al. 1981; Rapson et al. 1980; Rasanen et al. 1977; Simmon et al. 1977), suggesting that it may be useful to conduct in vivo tests by the oral exposure route for mutagenicity in animals. Reproductive Toxicity. Reproductive toxicity of 2,4-dichlorophenol in humans has not been reported. Chronic oral studies with rats did not identify reproductive organ pathology in female rats (Exon et al. 1984) or male mice (Seyler et al. 1984), and oral exposure of female rats for 10 weeks prebreeding and during gestation did not lead to reproductive toxicity (Exon et al. 1984). Kinetic studies by all routes of exposure would determine whether exposure by routes other than oral might be expected to cause reproductive toxicity. Developmental Toxicity. Developmental toxicity of 2,4-dichlorophenol in humans has not been reported. Studies with rats have found no evidence that 40 2. HEALTH EFFECTS 2,4-dichlorophenol is teratogenic but have reported embryolethality and fetolethality from oral exposure during gestation (Rodwell et al. 1989). This toxicity was consistent with maternal toxicity, suggesting 2,4-dichlorophenol is not selective for developmental effects in these animals. Kinetic studies by all routes would be useful in determining blood and urine levels in dams associated with developmental effects in offspring. These data could serve as useful indicators of exposure of pregnant women who live near hazardous waste sites to potentially toxic levels of 2,4-dichlorophenol. Immunotoxicity. Studies regarding the immunotoxicity of 2,4-dichlorophenol to humans have not been reported. Oral exposure to high levels of 2,4-dichlorophenol has caused bone atrophy in rats (NTP 1989). At low levels, increased serum antibodies and decreased delayed-type hypersensitivity were noted in rats (Exon et al. 1984). The immunological findings may have the greatest significance for the general population, since it may be the most sensitive system in humans. Kinetic studies at low levels of exposure for each route may be useful in predicting toxic effects and may provide a useful index of the toxicity threshold for humans living near hazardous waste sites. Neurotoxicity. Neurotoxicity in humans from exposure to 2,4-dichlorophenol has not been reported. Acute oral- and dermal-exposure studies with rats and mice have noted a series of effects suggestive of central nervous system depression (lethargy, ataxia, tremors, short periods of clonic convulsions, dyspnea, coma) followed by death (Borzelleca et al. 1985a; 1985b; Kobayashi et al. 1972; NTP 1989; Wil Research Laboratories, Inc. 1982). In vitro data indicate interference with oxidative phosphorylation in rat brain and nerve tissue treated with 2,4-dichlorophenol (Onfelt 1986; Stockdale and Selwyn 1971). In vivo kinetic studies by all routes of exposure would be useful in relating exposure levels to the onset of these effects. Epidemiological and Human Dosimetry Studies. Present studies of human exposure to 2,4-dichlorophenol are limited to epidemiological accounts that imply exposure was by inhalation (although dermal exposure cannot be ruled out), and the data are confounded by concurrent exposures of the workers to other compounds that are known to have adverse effects (Bleiberg et al. 1964; Eriksson et al. 1981; Hardell 1981; Hardell et al. 1981; Honchar and Halperin 1981; Lynge 1985; Woods et al. 1986). Quantification of 2,4-dichlorophenol levels causing possible effects, such as chloracne, has not been done. Air concentration studies in factories where 2,4-dichlorophenol is used as an intermediate in manufacturing processes may be useful in determining whether workers are exposed to 2,4-dichlorophenol and to what extent they are exposed. This information could help clarify whether effects seen in workers could have been caused by 2,4-dichlorophenol. 2,4-Dichlorophenol has been found in the 41 2. HEALTH EFFECTS groundwater, surface water, and soil of some hazardous waste sites. Well- controlled epidemiological studies of people who live near these sites could supplement and clarify the database on 2,4-dichlorophenol-induced human health effects. Biomarkers of Exposure and Effect. Biomarkers of exposure in humans following exposure to 2,4-dichlorophenol have not been reported. The presence of the parent compound or its metabolites in tissues and urine indicates exposure either to 2,4-dichlorophenol or to other substances that yield it as a metabolite (e.g., 2,4-dichlorophenol-based herbicides) (Karapally et al. 1973; Shafik et al. 1973; Somani and Khalique 1982). Kinetic studies with rats indicate that these compounds are cleared from the blood and urine of rats 24 hours to 3 days after exposure to 2,4-dichlorophenol (Somani and Khalique 1982; Somani et al. 1984). Kinetic studies by all routes of exposure would provide information on body burden compared to blood and urine levels that could be useful in determining whether persons living near hazardous waste sites have been exposed to 2,4-dichlorophenol Biomarkers of effect in humans following exposure to 2,4-dichlorophenol have not been reported. The nature of effects seen in animals orally exposed to 2,4-dichlorophenol, along with known mechanisms of action (Onfelt 1986; Stockdale and Selwyn 1971), are such that biomarkers of effects peculiar to 2,4-dichlorophenol are unlikely to be identified. Similarly, rabbits that are dermally exposed to 2,4-dichlorophenol show dermal/ocular irritation and corrosion (Carreon et al. 1980a; 1980b; Hencke and Lockwood 1973), which are likely to be noticed in persons exposed by this route. However, these symptoms may be induced by many other compounds and are therefore not specific to 2,4-dichlorophenol. Kinetic studies at low levels of exposure by all routes that clearly delineate body burden as related to effect levels may be useful in identifying biomarkers of effect that could serve as guidelines for populations living at or near hazardous waste sites. Absorption, Distribution, Metabolism, and Excretion. The pharmacokinetics of 2,4-dichlorophenol in humans following exposure to 2,4-dichlorophenol have not been reported. The kinetics of absorption have not been studied for any route of exposure in any species. Quantitative data regarding distribution, metabolism, and excretion of 2,4-dichlorophenol were located in one intravenous exposure study with rats (Somani and Khalique 1982). Small amounts of this substance and its metabolites apparently distribute throughout the body but do not tend to accumulate. They are quickly excreted in urine. It is not known, however, whether large amounts might overload the metabolism or excretory sites. Kidney and liver lesions have been reported with high oral exposures (Exon et al. 1984; Kobayashi et al. 1972; NTP 1989), suggesting that these organs may be incapacitated under such conditions. Kinetic studies by all routes of exposure and for varied durations would be useful for relating exposure levels and body and tissue 42 2. HEALTH EFFECTS burdens to type of exposure. These data could serve as useful indicators of exposure for populations living at or near hazardous waste sites. Comparative Toxicokinetics. Toxicokinetic data for 2,4-dichlorophenol following exposure in humans have not been reported. Toxicokinetic data for 2,4-dichlorophenol are limited to one study in which it was intravenously injected into rats (Somani and Khalique 1982), and in vitro studies with the same species (Somani and Khalique 1982; Somani et al. 1984). Kinetic studies by all routes of exposure and for varied durations would be useful for relating exposure levels, body and tissue burdens, and toxic effects. Qualitatively, we may expect similar end points of toxicity, but the levels that cause the effects may be very different. These data could serve as useful predictors of toxicity for persons living near hazardous waste sites. Mitigation of Effects. In vitro studies aimed toward identification of drugs that would inhibit the action of 2,4-dichlorophenol as an uncoupler of oxidative phosphorylation and disrupter of spindle formation during cell division would be useful. Areas that could be addressed include elucidation of the relationship between uncoupling and disturbances of spindle function and identification of mechanisms for both decreasing the lipophilicity of 2,4-dichlorophenol, which allows its entry into the cells, and altering the acid-base gradient, which allows it to act as a protonophore during uncoupling. 2.9.3 On-going Studies No reports of on-going research pertaining to health effects in humans or animals exposed to 2,4-dichlorophenol were located in the available literature. 43 3. CHEMICAL AND PHYSICAL INFORMATION 3.1 CHEMICAL IDENTITY Data pertaining to the chemical identity of 2,4-dichlorophenol are listed in Table 3-1. 3.2 PHYSICAL AND CHEMICAL PROPERTIES The physical and chemical properties of 2,4-dichlorophenol are presented in Table 3-2. 44 3. CHEMICAL AND PHYSICAL INFORMATION TABLE 3-1. Chemical Identity of 2,4-Dichlorophenol Characteristic Information Reference Chemical name 2,4-Dichlorophenol CAS 1989 Synonyms 1,3-Dichloro-4-hydroxybenzene; CAS 1989; Trade name(s) Chemical formula Chemical structure Identification numbers: CAS registry NIOSH RTECS EPA hazardous waste OHM/TADS DOT/UN/NA/IMCO shipping HSDB NCI 2,4-DCP; 4,6-dichlorophenol No data CgH,C1,0 OH Cl Cl 120-83-2 SK8575000 U081 7217235 UN 2020 1139 C55345 OHM/TADS 1989 CAS 1989 CAS 1989 CAS 1989 RTECS 1989 RTECS 1989 OHM/TADS 1989 HSDB 1989 Chemline 1989 HSDB 1989 CAS = Chemical Abstracts Service DOT/UN/NA/IMCO = Department of Transportation/United Nations/North America/ International Maritime Dangerous Goods Code HSDB = Hazardous Substances Data Bank NCI = National Cancer Institute NIOSH = National Institute for Occupational Safety and Health OHM/TADS = Oil and Hazardous Materials/Technical Assistance Data System RTECS = Registry of Toxic Effects of Chemical Substances 3. 45 CHEMICAL AND PHYSICAL INFORMATION TABLE 3-2. Physical and Chemical Properties of 2,4-Dichlorophenol Property Information Reference Molecular weight 163.00 Weast 1972 Color White Hawley 1981 Physical state Solid Hawley 1981 Melting point 45°C Hawley 1981 Boiling point 210°C Hawley 1981 Density, 60/25°C 1.383 Sax 1984 Dissociation constant 7.892 Serjeant and Dempsey at 25°C (pKa) 1979 Odor Medicinal HSDB 1989 Odor threshold Water 0.0003-0.04 mg/L Verschueren 1983 Air 1.4007 mg/m? Ruth 1986 Solubility Water at 20°C Organic solvents Partition coefficients Log octanol/water Log K,. Vapor pressure Supercooled liquid at 25°CP Solid at 25°C° Henry's law constant at 25°C¢ Autoignition temperature Flashpoint, open cup Flashpoint, closed cup 4500 mg/L soluble in ethyl alcohol, carbon tetrachloride, ethyl ether, benzene, chloroform 2.92 2.10-3.782 0.116 mmHg 0.067 mmHg (estimated) 3.16x107® atm-m®/mol (calculated) No data 93.3°C (200°F) 113.8°C (237°F) Verschueren 1983 Hawley 1981; Weast 1972 Hansch and Leo 1985 Boyd 1982; Artiola- Fortuny and Fuller 1982 Bidleman and Renberg 1985 Bidleman and Renberg 1985 Thomas 1982 HSDB 1989 OHM/TADS 1989 46 3. CHEMICAL AND PHYSICAL INFORMATION TABLE 3-2 (Continued) Property Information Reference Flammability limits No data Conversion factors ppm (v/v) to mg/m’ 1 ppm (v/v) x 0.150 = mg/m? in air (20°C) mg/m> to ppm (v/v) 1 mg/m® x 6.67 = ppm (v/v) in air (20°C) Explosive limits No data *Log K,. can vary significantly with pH (Artiola-Fortuny and Fuller 1982; Seip et al. 1986). PMeasured vapor pressure for supercooled liquid phase (15.4 Pa at 25°C). ‘Vapor pressure for the solid calculated from the vapor pressure of the supercooled liquid at 25°C. dCalculated from vapor pressure and water solubility. 47 4, PRODUCTION, IMPORT, USE, AND DISPOSAL 4.1 PRODUCTION 2,4-Dichlorophenol is manufactured as an end-use product and as an intermediate in the production of end-use products, including herbicides and disinfectants. It is manufactured by the reaction of chlorine with phenol in liquid sulfur dioxide (Freiter 1979). Dow Chemical U.S.A., Midland, Michigan, and Vulcan Chemicals, Wichita, Kansas, are listed as current U.S. producers of 2,4-dichlorophenol in 1989 (SRI 1989; TRI 1989). Aldrich Chemical Co., Inc., Milwaukee, Wisconsin; Rhone-Poulenc Inc., Monmouth Junction, New Jersey; Monsanto Co., Sauget East St. Louis, Illinois; Diamond Shamrock Corp., Newark, New Jersey; and Chem South Corp., Childersburg, Alabama, have previously been listed as manufacturers of 2,4-dichlorophenol (EPA 1989b; HSDB 1989; OHM/TADS 1989). The 1977 U.S. production level of 2,4-dichlorophenol ranged from 22 to 120 million pounds (EPA 1989b). An estimated 48 million pounds were produced in 1974 (Freiter 1979). No further information regarding the recent U.S. production of 2,4-dichlorophenol was located. It is not possible, therefore, to conclude whether total production volume is increasing or decreasing or whether there are more or less producers than there used to be. Table 4-1 lists information contained in the SARA Section 313 TRI concerning the maximum amounts of 2,4-dichlorophenol on site at facilities that manufacture or process the chemical (TRI 1989). The TRI data should be used with caution since the 1989 data represent first-time reporting by these facilities. Only certain types of facilities were required to report. This is not an exhaustive list. 4.2 IMPORT/EXPORT The United States imported 2,399 pounds of 2,4-dichlorophenol in 1983 (USITC 1984). American Hoechst Corp., Bridgewater, New Jersey, was listed as one of two importers of 2,4-dichlorophenol in the United States in 1977. The name of the second importer was confidential. The U.S. import volume for 1977 was from 1 to 10 million pounds (EPA 1989b). No further information regarding the import or export of 2,4-dichlorophenol was located. 4.3 USE Nearly all of the 2,4-dichlorophenol produced is directly used to make other organic compounds. The largest single use for 2,4-dichlorophenol is as an intermediate in the production of herbicides including 2,4-dichlorophenoxy- acetic acid (2,4-D), and 2,4-D salts and esters. Bifenox and dichloroprop herbicides, and 4-(2,4-dichlorophenoxy)butyrate herbicide are a few of the other herbicides produced from 2,4-dichlorophenol (HSDB 1989; IARC 1986; Windholz 1983). 2,4-Dichlorophenol also is used in the production of pentachlorophenol, disinfectants, fungicides, miticides, bactericides, TABLE 4-1. Facilities That Manufacture or Process 2,4-Dichlorophenol? Maximum amount Facility Location on site Use (lbs) Helena Chemical Company Ka'u Agribusiness Co., Inc. Vulcan Chemicals The Dow Chemical Company Rhone-Poulenc Incorporated Ag Company Sandoz Crop Protection Corporation West Helena, AR Pahala, HI Wichita, KS Midland, MI Mount Pleasant, TN Beaumont, TX 100,000-999, 999 No data 10,000-99, 999 1,000,000-9,999,999 100,000-999, 999 100,000-999, 999 In re-packaging In ancillary or other uses Produce; for on-site use/processing; as a reactant Produce; for on-site use/processing; for sale/distribution; as a reactant; in ancillary or other uses As a reactant For on-site use/processing @Derived from TRI 1989 Y ‘NOILONao¥d TVSOdSIA ANV ‘ASN ‘I¥0dWI 8% 49 4. PRODUCTION, IMPORT, USE, AND DISPOSAL antiseptics, and mothproofing compounds (CESARS 1989; Chemline 1989; HSDB 1989). An insignificant amount of the total of 2,4-dichlorophenol produced is isolated for direct usage (Scow 1982). Alkali salts of 2,4-dichlorophenol are used as germicides and antiseptics (CESARS 1989), and in the production of pentachlorophenol (HSDB 1989). 4.4 DISPOSAL Before undertaking land disposal of waste residues (including waste sludge), environmental regulatory agencies should be consulted for guidance on acceptable disposal practices (HSDB 1989). Materials containing concentrated 2,4-dichlorophenol may be disposed of by rotary kiln incineration at 820°-1,600°C and residence times of seconds for liquids and hours for solids, or incineration after mixing with another combustible fuel. Care should be taken to prevent formation of phosgene by assuring complete combustion and removal of the hydrogen chloride formed by the use of scrubbers (HSDB 1989). Biological treatment can be used for 2,4-dichlorophenol-containing waste waters (HSDB 1989). 2,4-Dichlorophenol has been identified as a hazardous waste by the Environmental Protection Agency, and the disposal of this compound is regulated under the federal Resource Conservation and Recovery Act (RCRA). Specific information pertaining to federal regulations regarding the land disposal of 2,4-dichlorophenol are provided in the Code of Federal Regulations (EPA 1988a). Release of 2,4-dichlorophenol is regulated under the Clean Water Act by the National Pollutant Discharge Elimination System (NPDES). Information regarding pretreatment standards may be found in 40 CFR 403 and information regarding effluent guidelines and standards for 2,4-dichlorophenol are found in 40 CFR Parts 401.15, 413.02, 423, 433.11, 464.31, 464.41, 469.12, and 469.22. 51 5. POTENTIAL FOR HUMAN EXPOSURE 5.1 OVERVIEW There are no known natural sources of 2,4-dichlorophenol (Scow 1982). 2,4-Dichlorophenol is released primarily to water and air as a result of the manufacture and use of 2,4-dichlorophenol itself and of 2,4-dichlorophenoxy- based herbicides. An important source of release to water is via the formation of 2,4-dichlorophenol during the chlorination of phenol-containing process water, waste water, natural water, and drinking water. It is difficult to relate the small amount of data known to the potential for human exposure to 2,4-dichlorophenol. The data do indicate, however, that releases of the chemical are somewhat limited and that human exposure may occur primarily due to the formation of 2,4-dichlorophenol during chlorination processes. The predominant removal process for 2,4-dichlorophenol in ambient air may be the gas-phase reaction with photochemically-generated hydroxyl radicals, gas-phase reaction with nitrate radicals during the night, or direct photolysis. Direct photolysis is probably the predominant removal process for 2,4-dichlorophenol in many surface waters. The predominant removal process for 2,4-dichlorophenol in soil is probably biodegradation. 2,4-Dichlorophenol may adsorb to certain soils and may leach through other soils. Overall, 2,4-dichlorophenol is not expected to persist in ambient air, water, or soil. 2,4-Dichlorophenol has been found in the gas phase of ambient urban air and in rainwater of one U.S. city at very low concentrations. 2,4-Dichlorophenol has been found infrequently in surface water and sediment. The chemical was detected in 56 of 108 samples of finished drinking water in the National Organics Monitoring Survey (NOMS) and was detected, but not quantified, in 17.2% of the samples of drinking water systems in the United States that derived their water from groundwater supplies. EPA has identified 1,177 NPL sites. 2,4-Dichlorophenol has been found at nine of the sites evaluated for the presence of this chemical (View 1989). However, we do not know how many of the 1,177 NPL sites have been evaluated for this chemical. As more sites are evaluated by EPA, the number may change. The frequency of these sites within the United States can be seen in Figure 5-1. 2,4-Dichlorophenol has been found in 0.2% of 1,736 samples of effluent at a median concentration of 46 pg/L and at a range of 7.0-300 pg/L. The chemical has been found in the leachates or groundwater plumes from one or more chemical waste sites. These few data suggest that 2,4-dichlorophenol is not expected to be found very frequently in the environment, except when it is formed during chlorination of drinking water. Human exposure via contact with contaminated environmental media, therefore, is expected to occur mainly through ingestion of and dermal contact with contaminated drinking water. The general population may be exposed to 2,4-dichlorophenol through the ingestion of contaminated drinking water and food and the inhalation of contaminated air. The data do suggest that widespread exposure to high levels FIGURE 5-1. FREQUENCY OF NPL SITES WITH 2,4—-DICHLOROPHENOL CONTAMINATION * FREQUENCY EFF 1 sITEe EEF 2 sITES * Derived from View 1989 H 3 SITES 'S 4YNSOdXd NVWNH ¥0d TVILNILOd cS 53 5. POTENTIAL FOR HUMAN EXPOSURE of 2,4-dichlorophenol is unlikely. Populations with potentially unusually high exposure to 2,4-dichlorophenol generally include employees of establishments that manufacture or use 2,4-dichlorophenol, 2,4-dichloro- phenoxy-based herbicides, or 2,4-dichlorophenol-containing products, those who live in the vicinity of 2,4-dichlorophenol-containing waste disposal sites, and waste incinerators, and those whose drinking water is derived from phenol or 2,4-dichlorophenol-contaminated groundwater or surface water. 5.2 RELEASES TO THE ENVIRONMENT According to the SARA Section 313 TRI, an estimated total of 19,151 pounds of 2,4-dichlorophenol were released to the environment from manufacturing and processing facilities in the United States in 1987 (TRI 1989). The TRI data should be used with caution since the 1989 data represent first-time reporting by these facilities. Only certain types of facilities were required to report. This is not an exhaustive list. The estimated emission data reported by Scow (1982) listed below are uncertain and should be used with caution. These estimated emission rates were based upon an estimated production volume of 31 million pounds of 2,4-dichlorophenol for 1977, an assumption that all of the 2,4-dichlorophenol produced was used in the production of the herbicide 2,4-dichlorophenoxyacetic acid, and estimated emission factors (Scow 1982). 5.2.1 Air Releases of 2,4-dichlorophenol to the atmosphere may occur during its production mainly as an intermediate in the manufacture of end-use products, including herbicides and disinfectants (Scow 1982). Atmospheric emission sources during production and use as an intermediate include loss through vents in the reactor, dryer, and distillation apparatus (Scow 1982). EPA TRI estimates that 3 of 6 facilities listed that manufacture or process 2,4-dichlorophenol released a total of 2,321 pounds of 2,4-dichlorophenol into the air in 1987 (TRI 1989). The breakdown of the facilities and the amount of individual atmospheric emissions are shown in Table 5-1. 2,4-Dichlorophenol has been detected in the atmospheric emissions from the combustion of municipal solid waste, hazardous waste, coal, wood, and 2,4-dichlorophenoxy- based herbicides, such as 2,4-dichlorophenoxyacetic acid (Gomez et al. 1988; Junk et al. 1986; Oberg et al. 1987; Paasivirta et al. 1985). Since 2 4-dichlorophenol is a slightly volatile chemical (see Section 5.3.1), slow volatilization from contaminated environmental waters, effluents, and hazardous waste sites is a potential source of minor releases to the atmosphere. Recent estimates of the atmospheric loading rate of 2,4-dichlorophenol from sources in the United States were not located. The estimated 1977 airborne emissions of 2,4-dichlorophenol were 35,500 pounds: 30,900 pounds from production of 2,4-dichlorophenol and 4,600 pounds from its use in the production of 2,4-dichlorophenoxyacetic acid (Scow 1982). TABLE 5-1. Releases to the Environment from Facilities That Manufacture or Process 2,4-Dichlorophenol? Total (lbs) Underground POTW Off-site Facility Location Air injection Water Land Environment transfer transfer Helena Chemical Company West Helena, AR 250 0 0 0 250 0 0 Ka'u Agribusiness Co., Pahala, HI 0 0 0 12,000 12,000 0 0 Inc. Vulcan Chemicals Wichita, KS 0 4,330 0 0 4,330 0 0 The Dow Chemical Company Midland, MI 1,571 0 250 0 1,821 0 250 Rhone-Poulenc Mount Pleasant, TN 500 250 0 0 750 0 61,000 Incorporated Ag Company Sandoz Crop Protection Beaumont, TX 0 0 0 0 0 0 17,472 Corporation 3Derived from TRI 1989 POTW = publicly owned treatment works 'S HINSOdXT NVWNH ¥0d TVIINALOJ 7S 35 5. POTENTIAL FOR HUMAN EXPOSURE 5.2.2 Water EPA TRI estimates that only 250 pounds of 2,4-dichlorophenol were released to U.S. surface waters by one of six facilities that manufacture or process the chemical (TRI 1989). The breakdown of the facilities and the amount of individual emissions in water are shown in Table 5-1. There are no releases of 2,4-dichlorophenol into Publicly Owned Treatment Works (POTWs) from the manufacturing and processing facilities listed in the database (TRI 1989). The anthropogenic sources of 2,4-dichlorophenol in natural waters include waste water from industries that manufacture 2,4-dichlorophenol and products made from it, such as 2,4-dichlorophenoxyacetic acid (Scow 1982). Chlorination of phenol-containing process water, waste water, natural water, and drinking water has been shown to generate 2,4-dichlorophenol (Burttschel et al. 1959; Carlson and Caples 1975; Onodera et al. 1984; Paasivirta et al. 1985; Sithole and Williams 1986). 2,4-Dichlorophenol has been detected in the final waste water from industries that manufacture iron and steel, electrical components, photographic equipment/supplies, pharmaceuticals, organic chemicals/plastics, paper pulp, and paperboard mills (EPA 1981; Leuenberger et al. 1985; Paasivirta et al. 1985). 2,4-Dichlorophenol may be present in the waste water of some of these industries as a result of its formation via the chlorination of phenol used or generated in processes, since there was no information located concerning the direct use of 2,4-dichlorophenol by some of these industries. 2,4-Dichlorophenol is formed via the sunlight photolysis of the nitrofen, a herbicide which is applied to rice paddy water for weed control (Nakagawa and Crosby 1974). Recent estimates of the aquatic discharge rates of 2,4-dichlorophenol from sources in the United States were not located. The estimated 1977 water emissions of 2,4-dichlorophenol were 741,000 pounds, including 648,000 pounds from production of 2,4-dichlorophenol and 93,000 pounds from its use in the production of 2,4-dichlorophenoxyacetic acid (Scow 1982). 2,4-Dichlorophenol was found in the surface water of 0.71% of the sites in the Contract Laboratory Program (CLP) Statistical Database at a geometric mean concentration of 61 ppb (ug/L) for those sites where the compound was found. The chemical was found in the groundwater at 1.4% of the sites at a geometric mean concentration of 47 ppb (CLPSD 1989). Note that the CLP Statistical Database includes data from both NPL and non-NPL sites. 5.2.3 Soil EPA TRI estimates that 12,000 pounds of 2,4-dichlorophenol were discharged directly to land in 1987 from facilities in the United States that manufacture or process this chemical that are listed in the database (TRI 1989); however, an estimated 78,700 pounds are disposed of in off-site facilities by these industries, and some of this material may be released to soil at these facilities (see Table 5-1). In addition, about 4,580 pounds are 56 5. POTENTIAL FOR HUMAN EXPOSURE disposed of by underground injection (see Table 5-1). Therefore, manufacturing and processing industries are sources of release in soils surrounding the disposal sites. Release of 2,4-dichlorophenol to soil may occur at wood preserving facilities and sawmills that use chlorophenolic fungicides (Kitunen et al. 1985, 1987; Valo et al. 1984). Soil disposal of solid waste containing 2,4-dichlorophenol is estimated as minimal (Scow 1982). 2,4-Dichlorophenol has been identified in the leachate or groundwater plume at industrial hazardous waste landfills, and leachate at municipal solid waste landfills (Artiola-Fortuny and Fuller 1982; Brown and Donnelly 1988; Johnson et al. 1985). Formation of 2,4-dichlorophenol in soil can result from the application of pesticides such as 2,4-dichlorophenoxyacetic acid, which may contain 2,4-dichlorophenol as an impurity, or from the soil metabolization of pesticides containing the 2,4-dichlorophenoxy structure (Royal Society of Chemistry 1983; Smith 1985). Soil contamination may result from atmospheric rainout since 2,4-dichlorophenol has been found in rainwater (Leuenberger et al. 1985). 2,4-Dichlorophenol was found in the soil of 0.928% of the sites in the CLP Statistical Database at a median concentration in positive samples of 1241 pg/kg (CLPSD 1989). Note that the CLP Statistical Database includes data from both NPL and non-NPL sites. Recent estimates of the soil discharge rates of 2,4-dichlorophenol from sources in the United States were not located. The estimated 1977 soil emissions from the production of 2,4-dichlorophenol and its use in the production of 2,4-dichlorophenoxyacetic acid were assumed to be negligible (Scow 1982). 5.3 ENVIRONMENTAL FATE Because the pK, of 2,4-dichlorophenol is 7.892 at 25°C, the pH of the environmental medium in which it is present will affect the degree to which the chemical is dissociated (Serjeant and Dempsey 1979). The degree of dissociation may have a significant effect upon the transport, partitioning, transformation, and degradation of 2,4-dichlorophenol in the environment. 5.3.1 Transport and Partitioning 2,4-Dichlorophenol is relatively reactive in the atmosphere (see Section 5.3.2.1); transport within the atmosphere then is expected to be limited. The vapor pressure of 2,4-dichlorophenol (see Table 3-2) suggests that this compound will not partition from the vapor phase to the particulate phase in the atmosphere (Eisenreich et al. 1981). Based upon its moderately high water solubility and moderate vapor pressure (see Table 3-2), atmospheric 2,4-dichlorophenol is likely to be removed by wet deposition. This is confirmed by its detection in rainwater. Probably, only limited amounts will wash out due to the relatively short atmospheric half-life of 2,4-dichlorophenol (0.8-3 hours) (see Section 5.3.2.1). 57 5. POTENTIAL FOR HUMAN EXPOSURE Volatilization of 2,4-dichlorophenol from water is expected to be a slow process and, therefore, not a major removal process in surface waters. Using the Henry's law constant, a half-life of 14.8 days was calculated for evaporation from a model river 1 m deep with a current of 1 m/sec and a wind velocity of 3 m/sec, and neglecting adsorption to sediment (Thomas 1982). A volatilization half-life of 213 days from a model pond can be estimated using a model that includes the effects of adsorption to sediment (EPA 1988b). The biological treatment of waste water containing 2,4-dichlorophenol has shown that none of the chemical is removed by stripping (Stover and Kincannon 1983). Volatilization from near-surface soil is also not expected to be a significant removal process. Volatilization will be even slower as the pH of the medium increases, thereby increasing the ionization of the 2,4-dichlorophenol. Freitag et al. (1984) measured BCFs of 100 and 260 for golden orfe fish, Leuciscus idus melanotus, and algae, Chlorella fusca, respectively. A 12-hour BCF of 34 was measured in goldfish, Carassius auratus (Kobayashi et al. 1979). These BCF values indicate that 2,4-dichlorophenol is not expected to bioconcentrate significantly in these aquatic organisms. The average annual concentrations of 2,4-dichlorophenol found in several species of leeches from an industrially polluted creek were 4x10“ times the average annual concentrations detected in the water from which the leeches were taken; one species of leech, Dina dubia, had 2x10° times more 2,4-dichlorophenol than did the water (Metcalfe et al. 1984). Therefore, the use of freshwater mussels, Anodonta piscinalis, and leeches, Erpobdella puncata, Glossiphonia complanata, and Helobdella stagnata, as bioindicators for the presence of 2,4-dichlorophenol in environmental waters has been suggested (Herve et al. 1988; Metcalfe et al. 1984). Small amounts of 2,4-dichlorophenol may be absorbed through the roots of plants growing in 2,4-dichlorophenol- contaminated soil and translocated to other parts of the plants (Isensee and Jones 1971). Tops of oat and soybean plants, grown to maturity in soil containing 0.07 ppm of 2,4-dichlorophenol, contained 0.010 and 0.020 ppm (dry tissue basis) 2,4-dichlorophenol. Experiments that measured absorption of 2,4-dichlorophenol from nutrient solutions indicated that the amounts translocated to plant tops were far smaller than the amounts found in the roots. After 14 days, the average amounts of 2,4-dichlorophenol in the roots and tops of soy beans were 87 and 0.13 ppb, respectively, and in the roots and tops of oats were 90 and 1.85 ppb, respectively (Isensee and Jones 1971). Despite the high concentrations found in certain species of leech, 2,4-dichlorophenol is not expected to bioconcentrate in animals or plants or to biomagnify in food chains. The partitioning of 2,4-dichlorophenol between water and sediment is expected to depend on the pH of the water. Two sorption mechanisms may be operative; one is the normal hydrophobic sorption that is common to hydrophobic organic compounds and can be correlated with organic carbon content of sediments, and the other is hydrogen bonding between the sediment and the chemical (Boyd 1982; Isaacson and Frink 1984). K,. values ranged from 3,130 to 3,990 at pH 6.21-6.35 in fine and course sediment from Lake Zoar, 58 5. POTENTIAL FOR HUMAN EXPOSURE Connecticut, with 30%-50% of the adsorbed chemical being irreversibly bound (Isaacson and Frink 1984). Average K,, values of 266, 654, and 715 were determined using lake sediment, river sediment, and aquifer material, respectively, over a pH range of 6.5-8.5 (Schellenberg et al. 1984). No adsorption onto sodium montmorillonite and sodium kaolinite clays in aqueous suspensions was observed at pH 2, 7, and 10 (Luh and Baker 1970). These observations indicate that adsorption of 2,4-dichlorophenol onto sediment and suspended particulate matter may be an important removal process in some environmental waters. The transport and partitioning of 2,4-dichlorophenol in soils will depend upon its sorption and volatilization characteristics. The sorption characteristics will be similar to those described in sediments. The adsorption of 2,4-dichlorophenol has been correlated with the pH of the soil, iron oxide, clay, and silt content of soils (Artiola-Fortuny and Fuller 1982). Adsorption generally decreases with increasing pH (Artiola-Fortuny and Fuller 1982; Isaacson and Frink 1984; Schellenberg et al. 1984; Seip et al. 1986). K,. values ranging from 244 to 6000 have been reported for five mineral soils in soil adsorption studies (Artiola-Fortuny and Fuller 1982). A K,, of 126 has been reported for a clay loam soil with a pH of 5.7 (Boyd 1982). These K,c values indicate that the mobility of 2,4-dichlorophenol in soil may vary considerably in soils of different composition and at different pHs. Leaching of 2,4-dichlorophenol to groundwater then may occur in the absence of significant degradation under certain conditions. This conclusion is confirmed by the observation of a K,. of approximately 0 for 2,4-dichlorophenol in soil with a pH of 10 (Johnson et al. 1985), and by the detection of 2,4-dichlorophenol in groundwater at industrial hazardous waste landfills and in leachate at municipal solid waste landfills (see Sections 5.2.2 and 5.2.3). 5.3.2 Transformation and Degradation 5.3.2.1 Air The predominant removal process for 2,4-dichlorophenol in ambient air may be direct photolysis or the gas-phase reaction with photochemically- generated hydroxyl radicals in the troposphere. An estimated half-life for 2,4-dichlorophenol for the reaction with atmospheric hydroxyl radicals is 5.3 days (Atkinson 1987). Direct photolysis may be predicted to be a contribute to the removal of 2,4-dichlorophenol from the atmosphere, based upon the fact that 2,4-dichlorophenol in the un-ionized form absorbs light at wavelengths greater than 290 nm (Sadtler 1966). This prediction is supported by the observed direct photolysis of 2,4-dichlorophenol in sunlit aqueous solutions (Hwang et al. 1986). The reaction of 2,4-dichlorophenol with nitrate radicals during the night may contribute to the removal of 2,4-dichlorophenol from polluted air, such as that in urban areas based upon the reactivity of phenol with nitrate radicals (Atkinson et al. 1987). 59 5. POTENTIAL FOR HUMAN EXPOSURE 5.3.2.2 Water Direct photolysis may be an important removal process for 2,4-dichlorophenol in near-surface water where attenuation of sunlight is usually minimal. Based upon the rates of photolysis of distilled water solutions of 2,4-dichlorophenol exposed to 4 hours of midday sunlight, the photolysis half-life has been estimated to be 0.8 and 3.0 hours for the summer and winter, respectively (Hwang et al. 1986). The rate of photolysis for 2,4-dichlorophenol may increase as the pH of the solution increases because the ionized form has an absorption maximum at 308 nm, which extends to greater than 330 nm, whereas the un-ionized form has an absorption maximum at 287 nm, which extends to approximately 310 nm (Sadtler 1966). The increased rate of photolysis for the ionized form of 2,4-dichlorophenol is supported by experiments using artificial light at wavelengths greater than 290 nm, which have determined that the quantum yield for the ionized form is 5-10 times higher than it is for the un-ionized form (Boule et al. 1984). The photoproducts of these reactions using artificial light include three of the isomers of chlorocyclopentadienoic acid (Boule et al. 1984). 2,4-Dichlorophenol may also be removed via reaction with photochemically produced singlet oxygen in natural waters. The estimated half-life for this reaction at pH 8 under midday sun (assuming a singlet oxygen concentration of 4x10-14 M) using experimentally determined rate constants is 62 hours (Scully and Hoigne 1987). The half-life for this process may be even shorter in certain natural waters based upon the following observation. The rate of reaction of singlet oxygen with 2,4-dichlorophenol increases significantly as the solution is raised from pH 5.5 to pH 9 (Scully and Hoigne 1987). 2,4-Dichlorophenol has been shown to readily biodegrade in natural waters and sediments under both aerobic and anaerobic conditions. Degradation of 97.5%-100% of 2,4-dichlorophenol has been observed in aerated and buffered (pH 7) lake water after 9-30 days incubation (Aly and Faust 1964). After 40 days, 84% of the 2,4-dichlorophenol initially present in stream water under aerobic conditions at 20°C had been degraded; 60% was degraded in sterilized stream water, however, suggesting that biodegradation was not the only process involved (Baker et al. 1980). Adaptation may affect the rate of biodegradation of 2,4-dichlorophenol in natural waters as evidenced by the observation of lag times of 2.5 and 8.3 days for degradation in river water from two different collections (Banerjee et al. 1984). No degradation of 2,4-dichlorophenol was observed in samples of reservoir water (Banerjee et al. 1984). In unaerated and unbuffered lake water (under predominately anaerobic conditions as indicated by the presence of hydrogen sulfide), 49.4%-80% degradation occurred in 43 days of incubation (Aly and Faust 1964). In stream sediment under aerobic conditions, 73% of the 2,4-dichlorophenol was degraded versus 21% degradation in sterile sediment at 20°C (Aly and Faust 1964). Complete degradation of 2,4-dichlorophenol has been observed in freshwater pond sediment under anaerobic conditions in two studies within approximately 15 and 28 days (Kohring et al. 1989; Rogers and Hale 1987). The major product of degradation in sediment under anaerobic conditions was 4-chlorophenol, 60 5. POTENTIAL FOR HUMAN EXPOSURE which was further degraded after an extended lag period (Kohring et al. 1989). Degradation of 2,4-dichlorophenol to nondetectable ranges was observed within 3-4 months in anaerobic and methanogenic groundwater aquifer material; only 39% degradation was observed after 3 months in sulfate-reducing aquifer material (Gibson and Sulfita 1986; Smith and Novak 1987). Dechlorination to chlorophenol was the pathway of degradation in the aquifer materials. Relatively rapid degradation of 2,4-dichlorophenol has also been reported in various sewage and water treatment processes. Based upon chemical oxygen demand determination using an activated sludge inoculum, 98% of initial 2,4-dichlorophenol was degraded in 5 days incubation following a 20-day acclimation period (Pitter 1976). Complete degradation of 2,4-dichlorophenol was observed in 28 days incubation using fresh, unacclimated sludge under anaerobic conditions (Boyd and Shelton 1984). 5.3.2.3 Soil The predominant removal process for 2,4-dichlorophenol in soil is probably biodegradation. In studies conducted in a clay loam soil at 0°C and 4°C under aerobic conditions, 79% and 82% of the 2,4-dichlorophenol was degraded in 14 and 12 days versus 1% and 0% in the sterile controls, respectively (Baker et al. 1980). A half-life of 1.5 days was determined for degradation of 2,4-dichlorophenol in a fine sandy loam soil at 20°C under aerobic conditions (Namkoong et al. 1989). In studies in clay, clay loam, and sandy loam soils, only 10%-40% of the added !“C-radiolabeled 2,4-dichlorophenol was extracted from the soil after 7 days incubation at 20°C; however, only 30%-60% of the added radiolabel was accounted for by 2,4-dichlorophenol and the two identified metabolites, 2,4-dichloroanisole and 14Cc0, (Smith 1985). The presence of other chemicals in soil may slow the rate of degradation of 2,4-dichlorophenol. This is based upon the observation that the presence of phenol and o-cresol reduced the rate of degradation of 2,4-dichlorophenol to approximately 13% of the rate observed when 2,4-dichlorophenol alone was present in the soil, apparently due to preferential removal of phenol and o-cresol (Namkoong et al. 1989). Even in the presence of phenol and o-cresol, biodegradation is probably the predominant removal process in soil. Hydrolysis is not expected to be a significant removal process in soil. 5.4 LEVELS MONITORED OR ESTIMATED IN THE ENVIRONMENT 5.4.1 Air Monitoring data concerning the presence of 2,4-dichlorophenol in ambient air are lacking. 2,4-Dichlorophenol was found at an average concentration of 1.5 ng/m® (range 0.60-2.3 ng/m®) in the atmospheric gas-phase during seven rainfalls in Portland, Oregon, during February and April 1984 (Leuenberger et al. 1985). The detection of 2,4-dichlorophenol in the rainwater in 61 5. POTENTIAL FOR HUMAN EXPOSURE Portland, Oregon (Leuenberger et al. 1985), confirms the presence of 2,4-dichlorophenol in ambient air. 5.4.2 Water 2,4-Dichlorophenol has been found in surface water, rainwater, sediment, drinking water, groundwater, industrial effluents, and surface water near hazardous waste sites. Information concerning background levels of 2,4-dichlorophenol was not located. Data from EPA STORET Data Base indicate that 2,4-dichlorophenol has a low frequency of occurrence in ambient surface water, sediment, groundwater, and waste water streams in the United States (STORET 1989; Staples 1985). 2,4-Dichlorophenol has been found in 1.7% of 2,728 samples of total surface water (dissolved and suspended chemical) at a median concentration of 1.24 pg/L and at a range of 0.004-65.0 ug/L. It has been found only in one sample of sediment at a concentration of 2,100 ug/kg (dry weight) (STORET 1989). Sheldon and Hites (1979) found several isomers of dichlorophenols in 1978 at a concentration of 0.4 ug/L in water from the Delaware River in Philadelphia, Pennsylvania, taken 2 miles upstream from the effluent discharge of a municipal waste treatment plant. 2,4-Dichlorophenol may be found in drinking water as a result of the chlorination of phenol-containing source water (Burttschell et al. 1959; Onodera et al. 1984; Sithole and Williams 1986). Its presence in groundwater is probably the result of release to soil, often leachate from waste dumps, and the subsequent leaching of 2,4-dichlorophenol through the soil to the groundwater. Although there are several reports of the qualitative detection of 2,4-dichlorophenol in drinking water in the United States, quantitative data are lacking (Dyksen and Hess 1982; Kim and Stone 1980; Kopfler et al. 1977; Scow 1982). 2,4-Dichlorophenol was detected in 56 of 108 samples of finished drinking water at a mean concentration of 0.18 pg/L in the National Organics Monitoring Survey (NOMS) (Scow 1982). Additional information from NOMS indicates that 2,4-dichlorophenol was found at a concentration of 0.04 pg/L in the drinking water of Waterford, New York in 1976 (Kim and Stone 1980). In federal studies of finished drinking waters, 2,4-dichlorophenol was detected, although not quantified, in 17.2% of the samples, which derived their water from groundwater supplies in the United States (Dyksen and Hess 1982). 2,4-Dichlorophenol has been identified, but not quantified, in drinking waters from three of seven cities studied. The cities include Cincinnati, Ohio, sampled in 1980, and New Orleans, Louisiana, and Philadelphia, Pennsylvania, both sampled in 1976 (Lucas 1984). More recent data concerning the frequency and concentration of 2,4-dichlorophenol contamination of drinking water in the United States were not located. Data from EPA STORET Data Base indicate that 2,4-dichlorophenol has been found in 0.71% of 3,113 samples of groundwater and spring water at a median concentration of 10 pg/L and at a range of 1.0-700 pg/L (STORET 1989). 62 5. POTENTIAL FOR HUMAN EXPOSURE 2,4-Dichlorophenol was detected during seven rainfalls in Portland, Oregon, between February and April 1984; concentration in rain ranged from 2.8 to 13 ng/L and averaged 5.9 ng/L (Leuenberger et al. 1985). 2,4-Dichlorophenol has been found in the effluent discharges from several industries. Table 5-2 lists data from industries that have been reported to release 2,4-dichlorophenol in the final effluents of treated waste water (EPA 1981). 2,4-Dichlorophenol may be present in the waste water of some of these industries as a result of its formation via the chlorination of phenol used or generated in processes since there was no information located concerning the direct use of 2,4-dichlorophenol by some of these industries. The chemical has been detected in 30% of the samples of final effluents from 25 municipal sewage treatment plants at a concentration range of 0.1-10 ug/L (DeWalle et al. 1982). The low removal percentage observed for 2,4-dichlorophenol in these plants was reportedly due to its formation in the chlorination of the final effluent. Sheldon and Hites (1979) found several isomers of dichlorophenols in 1978 at a concentration of 0.4 pg/L in the final effluent from a publicly owned sewage treatment plant in Philadelphia, Pennsylvania. 2,4-Dichlorophenol has been found at a concentration of 0.01 mg/L in the leachate or groundwater plume from one or more unidentified industrial landfills (Brown and Donnelly 1988). The chemical has been found in groundwater samples taken in 1981-1983 near an abandoned creosote waste site in Conroe, Texas, at a concentration range from 3.2 to 79.7 pg/L; four of five samples from one well near a waste pit at the facility contained of 54.4 pg/L 2,4-dichlorophenol (Bedient et al. 1984). Data from EPA STORET Data Base indicate that 2,4-dichlorophenol has been found in 0.2% of 1,736 samples of effluent at a median concentration of 46 pg/L and at a range of 7.0-300 pg/L (STORET 1989). 2,4-Dichlorophenol was found at 9 of the 1,177 hazardous waste sites listed on the NPL (View 1989). Additionally, 2,4-dichlorophenol was found in the surface water of 0.71% of sites in the CLP Statistical Database at a positive geometric mean concentration of 61 ppb (ug/L) (CLPSD 1989). The chemical was also found in groundwater at 1.42% of the sites at a positive geometric mean concentration of 47.05 ppb (CLPSD 1989). 5.4.3 Soil 2,4-Dichlorophenol has been found in the leachates or groundwater plumes from one or more unidentified industrial landfills (Brown and Donnelly 1988). The chemical has also been found in groundwater samples taken near an abandoned creosote waste site in Conroe, Texas (Bedient et al. 1984). The presence of 2,4-dichlorophenol in the leachates and groundwater suggests that the compound was also present in the soil, although no soil monitoring data were reported in that study. 2,4-Dichlorophenol, which is formed as a result of biodegradation of the herbicide 2,4-dichlorophenoxyacetic acid in soil, is not expected to significantly contribute to soil contamination due to the relatively rapid biodegradation rates for 2,4-dichlorophenol itself in soil (see Section 5.3.2.3) (Baker et al. 1980; Namkoong et al. 1989; Smith 1985). 63 5. POTENTIAL FOR HUMAN EXPOSURE TABLE 5-2. Final Effluent 2,4-Dichlorophenol Concentrations in Industrial Waste Waters? Concentration in Final Effluent (ppm) Industry Mean Maximum Iron and steel 26 44 Photographic equipment/supplied Not applicable 10P Electrical/electrical components Not applicable 10° Foundries 33 220 Pharmaceuticals Not applicable 10° Organics/plastics manufacture 26 Not reported Pulp and paperboard mills 7.8 130 “Derived from EPA 1981 "Detected in only one sample 64 5. POTENTIAL FOR HUMAN EXPOSURE 5.4.4 Other Environmental Media The production of 2,4-dichlorophenol from degradation/metabolism of 2,4-dichlorophenoxy-based herbicides may result in the contamination of food crops following application of these herbicides. Cook et al. (1983) analyzed the free and total residues of 2,4-dichlorophenol in millet resulting from treatment with 2,4-dichlorophenoxyacetic acid. The residues of 2,4-dichlorophenol for seed ranged from not detected (less than 0.020 ppm detection limit) to 0.031 ppm for postemergence and preharvest treatment. The level in straw ranged from 0.027 to 0.033 ppm for postemergence treatment and 0.24-0.40 ppm for preharvest treatment. Only 15%-19% of the 2 ,4-dichlorophenol residues were in the free, unaltered, and acid extractable form and approximately 68%-71% of the residues dissipated within 4 weeks after postemergence treatment from millet forage. Chkanikov et al. (1976) studied the metabolism of 2,4-dichlorophenoxyacetic acid in various 2,4-dichlorophenoxy acid-treated plants and found that the glycoside of 2,4-dichlorophenol was the predominant metabolite in strawberry plants (Fragaria grandifora Ehrh.); this metabolite was either not detected or a very small percentage of 2,4-dichlorophenoxyacetic acid was absorbed in the wheat, grass, bean, soybean, and sunflower plants tested. Bristol et al. (1982) found that 2,4-dichlorophenol was an insignificant metabolite in potato tubers that were treated with 2,4-dichlorophenoxyacetic acid; no free residues and only small amounts of hydrolyzable residues of 2,4-dichlorophenol were found in the potato tubers. Exposure to 2,4-dichlorophenol via the ingestion of contaminated fish and possibly other foods may be limited by the pronounced taste imparted by the presence of 2,4-dichlorophenol (Persson 1984). 5.5 GENERAL POPULATION AND OCCUPATIONAL EXPOSURE The general population may be exposed to 2,4-dichlorophenol through the ingestion of contaminated drinking water and food, and the inhalation of contaminated air. Because of the lack of recent comprehensive monitoring data, the average daily intake of 2,4-dichlorophenol and the relative importance of each source of exposure cannot be determined. Since releases of 2,4-dichlorophenol to the environment are limited, widespread exposure to the chemical is unlikely (Scow 1982). Although limited air monitoring data are available, very low levels of 2,4-dichlorophenol are expected to be found in the air. Exposure to contaminated air may be expected to be highest near 2,4-dichlorophenol and 2,4-dichlorophenoxyacetic acid manufacturing facilities, waste incinerators, and 2,4-dichlorophenol-containing hazardous waste dumps. This follows from its possible release to the atmosphere during its manufacture and use and the manufacture and use of 2,4-dichlorophenoxyacetic acid and 2,4-dichlorophenoxyacetic acid-based herbicides, its presence in the atmospheric emissions from the combustion of municipal solid waste, hazardous waste, coal and wood, and its potential volatilization from contaminated environmental waters and effluent waters. Since chlorination is a widely used process in drinking water systems, 65 5. POTENTIAL FOR HUMAN EXPOSURE drinking water derived from source waters contaminated with phenol may lead to exposure to 2,4-dichlorophenol (Burttschell et al. 1959; Onodera et al. 1984; Sithole and Williams 1986). Although recent data concerning 2,4-dichlorophenol levels in finished drinking water are lacking, data from older studies suggest that exposure through the ingestion of contaminated drinking water may be a major contributor to general population exposure to 2,4-dichlorophenol (Scow 1982). Based upon older data from NOMS, which reported a mean concentration of 0.18 ug/L in finished drinking water, and assuming a daily consumption of 2 L of drinking water/day, an average daily intake of approximately 0.4 pg of 2,4-dichlorophenol has been estimated (Scow 1982). Exposure to 2,4-dichlorophenol via the ingestion of contaminated drinking water may be limited by the pronounced odor and taste imparted by the presence of 2,4-dichlorophenol at concentrations of 2 and 8 ug/L, respectively (Burttschell et al. 1959). Odor thresholds as low as 0.0003-0.04 mg/L in water have also been reported (Verschueren 1983). Exposure to 2,4-dichlorophenol due to ingestion of contaminated food may result from the production of 2,4-dichlorophenol via degradation/metabolism of 2,4-dichlorophenoxy-based herbicides applied to food crops. Although food monitoring data are lacking, exposure to 2,4-dichlorophenol through the ingestion of food is expected to be relatively minor. 2,4-Dichlorophenol was detected at levels up to 200 ppb in the urine of one-fourth of 197 children from two communities in Arkansas who lived near a herbicide manufacturing plant (Hill et al. 1989). The detection of 2,4-dichlorophenol in human urine may not be an accurate indicator of direct exposure to this compound as exposure to 2,4-dichlorophenoxy-based herbicides (or other metabolic precursors, such as 1,3-dichlorobenzene) may cause excretion of the compound in human urine (Hill et al. 1989). Dermal exposure to 2,4-dichlorophenol from surface water or drinking water is expected to be minimal due to the low concentrations observed and expected. Dermal exposure may be higher in occupational facilities where 2,4-dichlorophenol is made and/or used (Scow 1982). A National Occupational Exposure Survey (NOES) conducted by NIOSH from 1980-1983 estimated that 63 workers, including 23 female workers, were the potentially exposed to 2,4-dichlorophenol (NIOSH 1989). No report of actual measured exposure levels under any occupational situation in the United States was found in the literature. There is potential for inhalation and possibly dermal exposure to 2,4-dichlorophenol in occupations involving the manufacture and use of 2,4-dichlorophenol and 2,4-dichlorophenoxy-based herbicides, and occupations involving chlorination of phenol-containing water. The NOES database does not contain information on the frequency, concentration, or duration of exposure of workers to any of the chemicals listed therein. This survey provides only estimates of the number of workers potentially exposed to chemicals in the workplace. 66 5. POTENTIAL FOR HUMAN EXPOSURE 5.6 POPULATIONS WITH POTENTIALLY HIGH EXPOSURE Those involved in the manufacture or use of 2,4-dichlorophenol, 2 ,4-dichlorophenoxy-based herbicides, or 2,4-dichlorophenol-containing products may have the highest risk for exposure to 2,4-dichlorophenol, primarily via inhalation or dermal exposure. In addition, populations may be exposed via inhalation to higher than background levels at or near both identified and unidentified 2,4-dichlorophenol-containing waste disposal sites and landfills, and waste incinerators. Children playing in and around these sites may also be dermally exposed to 2,4-dichlorophenol. Persons whose drinking water is derived from phenol or 2,4-dichlorophenol-contaminated groundwater or surface water may be exposed to relatively high levels of 2,4-dichlorophenol over long periods of time. 5.7 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 2,4-dichlorophenol 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 2,4-dichlorophenol. 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. 5.7.1 Data Needs Physical and Chemical Properties. As shown in Table 3-2, the physical and chemical properties of 2,4-dichlorophenol have been characterized sufficiently to permit estimation of its environmental transport and partitioning (Artiola-Fortuny and Fuller 1982; Bidleman and Renberg 1985; Boyd 1982; Hansch and Leo 1985; Hawley 1981; HSDB 1989; OHM/TADS 1989; Ruth 1986; Sax 1984; Serjeant and Dempsey 1979; Verschueren 1983; Weast 1972). Production, Import/Export, Use, and Disposal. Data regarding the production methods for 2,4-dichlorophenol are available (Freiter 1979); however, data regarding current production, import and export volumes, use, and disposal patterns are lacking (Cesars 1989; Chemline 1989; EPA 1986b; Freiter 1979; HSDB 1989; IARC 1986; OHM/TADS 1989; Scow 1982; SRI 1989; TRI 1989; USITC 1984; Windholz 1983). Production data may be difficult to obtain, 67 5. POTENTIAL FOR HUMAN EXPOSURE since many companies desire to maintain the confidentiality of the data. Use, release, and disposal information is useful for determining where environmental exposure to 2,4-dichlorophenol may be high. Determining the percentage of 2,4-dichlorophenol captively used as an intermediate in the production of 2,4-dichlorophenoxy-based herbicides, the major use for 2,4-dichlorophenol, and release of 2,4-dichlorophenol from such production would be useful information for determining overall release of 2,4-dichlorophenol to the environment. Even if information on production, use, and disposal of 2,4-dichlorophenol were available, the amounts released would be difficult to estimate, since a contributing factor to its occurrence in the environment is its formation as a result of chlorination of phenol- containing process water, waste water, natural water, and drinking water (Burttschell et al. 1959; Carlson and Caple 1975; Onodera et al. 1984; Paasivirta et al. 1985; Sithole and Williams 1986). General disposal information is adequately described in the literature (EPA 1988a; HSDB 1989). Specific disposal information, obtainable by polling industries or industry organizations, may be useful for determining environmental burden and potential concentrations where environmental exposures may be high. According to the Emergency Planning and Community Right-to-Know Act of 1986, 42 U.S.C. Section 11023, industries are required to submit chemical release and off-site transfer information to EPA. The TRI, which contains this information for 1987, became available in May of 1989. This database will be updated yearly and should provide a list of industrial production facilities and emissions. Data are available on the methods of disposal of 2,4-dichlorophenol. Environmental Fate. Experimental data are available pertaining to most of the transport and partitioning properties of 2,4-dichlorophenol. Volatilization of 2,4-dichlorophenol from water and soil is expected to be a slow process but there were no experimental data located in the available literature (EPA 1988b; Stover and Kincannon 1983; Thomas 1982). Experimental data are available pertaining to many of the transformations of 2,4-dichlorophenol in the environment including biodegradation in water, soil, and sediment, and photodegradation in water (Aly and Faust 1964; Baker et al. 1980; Banerjee et al. 1984; Boule et al. 1984; Gibson and Suflita 1986; Hwang et al. 1986; Kohring et al. 1989; Namkoong et al. 1989; Rogers and Hale 1987; Sadtler 1966; Scully and Hoigne 1987; Smith 1985; Smith and Novak 1987). The photolytic fate of 2,4-dichlorophenol in air, however, is not known. Confirmation of the estimated slow rate of volatilization in addition to data regarding the overall half-life for 2,4-dichlorophenol in air would be helpful to estimate potential inhalation exposure near hazardous waste sites that contain 2,4-dichlorophenol. Data regarding the overall half-life in water and soil would also be helpful to estimate potential oral and dermal exposure to 2,4-dichlorophenol. Bioavailability from Environmental Media. Animal oral toxicity studies have shown that 2,4-dichlorophenol is absorbed through the gastrointestinal 68 5. POTENTIAL FOR HUMAN EXPOSURE tract (Borzelleca et al. 1985a, 1985b; Deichmann 1943; Exon and Koller 1985; Exon et al. 1984; Henke and Lockwood 1973; Kobayashi et al. 1972; NTP 1989; Rodwell et al. 1989; Seyler et al. 1984; Wil Research Laboratories, Inc. 1982). This indicates that 2,4-dichlorophenol may be absorbed through the ingestion of contaminated water and food. Exposure to 2,4-dichlorophenol via the ingestion of contaminated water, fish, and possibly other foods may be limited, however, by the pronounced taste imparted by the presence of 2,4-dichlorophenol. Absorption of 2,4-dichlorophenol may occur in the stomach following ingestion of contaminated soil because adsorption to the soil is expected to be minimized by the highly acidic pH present in the stomach. The limited information available concerning human dermal absorption suggests that 2,4-dichlorophenol may be absorbed by this route (Blaiberg et al. 1964; Boutwell and Bosch 1959; Carreon et al. 1980a, 1980b; Ericksson et al. 1981; Hardell 1981; Hardell et al. 1981; Henke and Lockwood 1978; Honchar and Halperin 1981; Lynge 1985). No information was available that indicated bioavailability via inhalation. Information regarding the potential for dermal or inhalation absorption or oral absorption via ingestion of contaminated soils might be helpful to characterize potential exposure to 2,4-dichlorophenol via these routes. Food Chain Bioaccumulation. Measured BCFs in fish and algae indicate that 2,4-dichlorophenol is not expected to bioconcentrate in aquatic organisms (Freitag et al. 1984; Kobayashi et al. 1979). The possible use of freshwater mussels and leeches as bioindicators of 2,4-dichlorophenol contamination in natural waters, however, suggests that bioaccumulation of 2,4-dichlorophenol is possible (Herve et al. 1988; Metcalfe et al. 1984). Small amounts of 2,4-dichlorophenol may be absorbed through the roots of plants growing in 2,4-dichlorophenol-contaminated soil, but the compound does not appear to bioconcentrate in plants (Isensee and Jones 1971). Further information concerning the possibility of aquatic bioconcentration and biomagnification of 2,4-dichlorophenol in organisms at other trophic levels might be useful since significant aquatic bioconcentration and food chain bioaccumulation might suggest significant human exposure of these chemicals from the consumption of aquatic and terrestrial foods. Exposure Levels in Environmental Media. Limited data were available regarding the concentrations of 2,4-dichlorophenol in the environment (Bedient et al. 1984; Brown and Donnelly 1988; Burttschell et al. 1959; CLPSD 1989; Cook et al. 1983; DeWalle et al. 1982; Dyksen and Hess 1982; EPA 1981; Kim and Stone 1980; Kopfler et al. 1977; Leuenberger et al. 1985; Lucas 1984; Onodera et al. 1984; Scow 1982; Sheldon and Hites 1979; Sithole and Williams 1986; Staples 1985; STORET 1989; View 1989). Current information on exposure levels would be helpful in assessing the potential general population exposure to 2,4-dichlorophenol. This might include information regarding exposure to 2,4-dichlorophenol in foods and in drinking water (especially drinking water derived from groundwater downgradient from hazardous waste disposal sites and 2,4-dichlorophenol- and phenol-contaminated surface waters), as well as in air 69 5. POTENTIAL FOR HUMAN EXPOSURE particularly near 2,4-dichlorophenol manufacturing facilities and hazardous waste sites. Exposure Levels in Humans. Data concerning exposure levels in humans are incomplete and not current (Hill et al. 1989; NIOSH 1989; Scow 1982). A detailed and recent database of exposure would be helpful in determining the current exposure levels because it would allow estimation of the average daily dose associated with various scenarios such as living near a hazardous waste disposal site, drinking contaminated water, or working in a contaminated workplace. 2,4-Dichlorophenol was detected in the urine of children from two communities in Arkansas (Hill et al. 1989); however, the detection of 2,4-dichlorophenol in human urine may not be an accurate indicator of direct exposure to this compound as exposure to 2,4-dichlorophenoxy-based herbicides (or other potential metabolic precursors, such as 1,3-dichlorobenzene) may cause excretion of 2,4-dichlorophenol in urine. Exposure Registries. No exposure registries for 2,4-dichlorophenol were located. This compound is not currently one of the compounds for which a subregistry has been established in the National Exposure Registry. The compound will be considered in the future when chemical selection is made for subregistries to be established. The information that is amassed in the National Exposure Registry facilitates the epidemiological research needed to assess adverse health outcomes that may be related to the exposure to the compound. 5:7:2 On-going Studies Remedial investigations and feasibility studies conducted at the nine NPL sites known to be contaminated with 2,4-dichlorophenol will add to the available database on exposure levels in environmental media, exposure levels in humans, and exposure registries, and will increase the current knowledge regarding the transport and transformation of 2,4-dichlorophenol in the environment. The U.S. Department of Agriculture is sponsoring a study of the chemistry and bioavailability of five phenolic waste constituents, including 2,4-dichlorophenol, in soil (Federal Research in Progress 1989). As part of the Third National Health and Nutrition Evaluation Survey (NHANES III), the Environmental Health Laboratory Sciences Division of the Center for Environmental Health and Injury Control, Centers for Disease Control, will be analyzing human urine samples for 2,4-dichlorophenol and other phenolic compounds. These data will give an indication of the frequency of occurrence and background levels of these compounds in the general population. No other on-going studies were located. 71 6. ANALYTICAL METHODS The purpose of this chapter is to describe the analytical methods that are available for detecting and/or measuring and monitoring 2,4-dichlorophenol in environmental media and in biological samples. The intent is not to provide an exhaustive list of analytical methods that could be used to detect and quantify 2,4-dichlorophenol. Rather, the intention is to identify well- established methods that are used as the standard methods of analysis. Many of the analytical methods used to detect 2,4-dichlorophenol in environmental samples are the methods approved by federal agencies such as EPA and the National Institute for Occupational Safety and Health (NIOSH). Other methods presented in this chapter are those that are approved by groups such as the Association of Official Analytical Chemists (AOAC) and the American Public Health Association (APHA). Additionally, analytical methods are included that refine previously used methods to obtain lower detection limits, and/or to improve accuracy and precision. 6.1 BIOLOGICAL MATERIALS The analytical methods for the determination of 2,4-dichlorophenol in biological samples are presented in Table 6-1. The methods for handling biological samples are presented by Fatiadi (1984). No official method approved by either federal or private trade groups could be found for 2,4-dichlorophenol. All methods presented in Table 6-1 are for the determination of 2,4-dichlorophenol in urine. No methods were located for the analysis of 2,4-dichlorophenol in human blood or tissue. The lack of methods probably results from the very quick excretion of 2,4-dichlorophenol from the body; this is indicated by its short half-life in urine (Somani and Khalique 1982; Somani et al. 1984). Most of the common methods for urine analysis involve the initial hydrolysis followed by gas chromatographic analysis with electron capture detection (GC-ECD). The hydrolysis enables the quantitation of total 2,4-dichlorophenol (free and conjugated compound). Combined analysis of hydrolyzed and unhydrolyzed urine samples would provide a measure of the conjugated and unconjugated (free) compound. Although electron capture detection is highly sensitive, its use has been criticized due to its nonspecificity (Hargesheimer and Coutts 1983). The most specific and, therefore, the most reliable technique, especially for trace analysis, utilizes gas chromatography, followed by a technique that confirms the identities of the GC peaks. The use of gas chromatography with mass spectrometry with selected ion monitoring has been suggested as a highly sensitive and specific method for the simultaneous quantification and identification of low levels of 2,4-dichlorophenol (Hargesheimer and Coutts 1983). Lores et al. (1981) support the use of GC-ECD and high-pressure liquid chromatography-electrochemical detection (HPLC-ED). Other methods include the use of porous, polymeric resins as 2,4-dichlorophenol sorbing agents for preconcentrating prior to quantification with GC (Edgerton et al. 1980) and HPLC with electrochemical detection (Fatiadi 1984). TABLE 6-1. Analytical Methods for Determining 2,4-Dichlorophenol in Biological Materials Sample detection Percent Sample matrix Preparation method Analytical method limit recovery Reference Urine Acid hydrolysis extraction, deriva- GC-ECD 8.3 ug/L 105% at Angerer et al. 1981 tization with acetic acid (total 194 ug/L 2,4-DCP) Distilled with H,S0,, extracted with GC-FID 1 ug/L No data Van Roosmalen et al. 1980 isopropyl ether (total 2,4-DCP) Acid hydrolysis, elution through GC-ECD 1 ug/L 847-897 at Edgerton et al. 1980 XAD-4 resin with 2-propanol-hexane 50-1,000 ug/L (total 2,4-DCP) Acid hydrolysis, elution through HPLC-MS No data No data Wright et al. 1981 XAD-4 resin with 2-propanol-hexane (total 2,4-DCP) Acid hydrolysis, extration with GC-MS-MS 1 ug/L 80% at 10 ug/L Holler et al. 1889 benzene, derivatization with fresh diozoethane Acid hydrolysis, elution through HPLC-ED No data No data? Lores et al. 1981 XAD-4 resin with 2-propanol-hexane (total 2,4-DCP) 8Recovery reported to be the same as that reported by Edgerton et al. 2,4-DCP = 2,4-dichlorophenol ECD = electron capture detector ED = electrochemical detection FID = flam ionization detector; GC = gas chromatography HPLC = high pressure liquid chromatography MS = mass spectrometry 1880 9 SAOHLYW TVDILATVNV CL 73 6. ANALYTICAL METHODS Although there were no corresponding methods for human blood or tissue, there are methods for rat blood plasma and liver, kidney, fat, and brain tissues (Somani and Khalique 1982). Blood plasma or tissue homogenates were extracted with methylene chloride, and the extracts were analyzed by GC-ECD. Acid hydrolysis of samples can be performed to give total 2,4-dichlorophenol. This method might be applicable to human blood and tissue with any necessary modifications. 6.2 ENVIRONMENTAL SAMPLES The analytical methods for the determination of 2,4-dichlorophenol in environmental samples are presented in Table 6-2. The sample handling methods are presented in EPA (1982). 2,4-Dichlorophenol probably exists predominantly in the vapor phase in the atmosphere, but small amounts of other phenols have been detected in the particulate phase (Leuenberger et al. 1985). The best method for the collection of 2,4-dichlorophenol may be to use an air sampler that uses glass-fiber filters to collect particulates, followed by gas adsorption cartridges for collecting volatile 2,4-dichlorophenol (Leuenberger et al. 1985). Multicomponent analyses generally use samples extraction with organic solvents under both acidic and basic conditions. Being acidic, 2,4-dichlorophenol is found in the acidic extract (Valkenburg et al. 1989). Among the commonly used methods, electron capture detection of the acetic acid derivative provides the best sensitivity. The mass spectrometric method, however, is better suited for multicomponent analysis. Several less common methods are available for the determination of 2,4-dichlorophenol in environmental samples. These include spectrophotometric measurement in the presence of 4-amino-antipyrine and potassium ferricyanide (APHA/AWWA/WPCF 1985), GC with mass sensitive detection of derivatives including cvanoethyldimethylsilyl ether derivatives (Bertrand et al. 1986), and spectrophotometric measurements of the 3-methylbenzothiazolin-2-one hydrazone derivative (Buckman et al. 1983). 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 2,4-dichlorophenol 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 2,4-dichlorophenol. 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 TABLE 6-2. Analytical Methods for Determining 2,4-Dichlorophenol in Environmental Samples Sample detection Percent Sample matrix Preparation method Analytical method limit recovery Reference Air Thermal desorption of cartridge GC-MS No data No data Leuenberger et al. 1985 Waste water Acidic extration with methylene GC-ECD (EPA method 0.68 ug/L 74% EPA 1982 chloride, clean extract if 604) necessary, derivatization with pentafluorobenzyl bromide Acidic extraction with methylene GC-MS (EPA method 2.7 ug/L 80% EPA 1982 chloride, concentration of 625) extract Water Acidic extraction with methylene GC-MS (EPA CLP 10 ug/L No data EPA 1988c chloride, concentration of method) extract Acidic extraction, cleanup, GC-ECD 0.22 ug/L 71x Bengtsson 1985 derivatization with heptafluoro- butyric anhydride Water, aqueous Extraction, concentration HPLC-UV 2.5 pg/L No data Baldwin and leachate Deboswki 1988 Extraction, concentration HPLC-PAD 0.020 ug/L No data Baldwin and Deboswki 1988 Drinking water, Distill sample directly, solvent- Spectrophotometric 1 ug/L for No data APHA/AWWA /WPCF waste water, extract (if necessary) at acidic 500 mL sample 1985 natural water pH, react with 4-amino-antipyrine and potassium ferricyanide at pH 8, extract in chloroform Water, waste None HPLC-ED 0.5 ug/L No data Armentrout water et al. 1979 Fresh water, Derivatization with acetic acid, GC-ECD 2 ug/L for 100 100% at 0.20 Abrahamsson and sea water extraction mL sample ug/L (drinking Xie 1983 water) and 2.0 ug/L (sea water) Potable water Sample acetylated in situ by HRGC-ECD <50 ug/L for 65%-104% (penta- Sithole et al. and raw source addition of acetic anhydride, (pentafluorobenzyl both deriva- fluorobenzyl 1986 water solvent extracted and concen- derivative) tives derivative) trated; alternately, extracted HRGC-MS (acetyl 842-115% (acetyl acidic sample is derivatized by derivative) derivative) pentafluorobenzyl bromide and column chromatographed 9 SAOHLIW TVDILATVNV YL TABLE 6-2 (Continued) Sample detection Percent Sample matrix Preparation method Analytical method limit recovery Reference Waste water, Acid extraction, concentration, GC-ECD No data 86% at 10 ug/L Buisson et al. sludge derivatization with pentafluoro- 1984 benzoyl chloride Soil Steam distillation of acidified GC-ECD No data 40% Narang et al. soil/water slurry, extraction 1983 Soil/sediment Acidic extraction of dried sample GC-M (EPA CLP method) 330 ug/g (wet No data EPA 1988c with methylene chloride concen- weight) tration of extract Sediment Soxhlet extraction of acidified GC-MSD 0.2 ug/g (50 g 88% at 1 ug/g Lee et al. 1987 water sediment slurry, deriva- sample) tized with acetic anhydride, extracted and concentrated Soxhlet extraction of acidified GC-ECD No data 80-82% at Lee et al. 1987 water sediment slurry, deriva- 10-100 ug/s tized with acetic anhydride, extracted and concentrated Steam distillation with iso- GC-ECD No data 74%-75% Kan et al. 1981 octane, heat with metallic mercury Pretreatment for heavily GC-ECD ~0.1 ug/g with 85%-102% at Xie 1983 polluted samples: extraction 1 g (dry weight) 40-400 ug/g of basified slurry, organic sample (without extract discarded; simultaneous pretreatment) extraction and derivatization of 83% at 200 ug/g of remaining slurry with acetic (with pretreatment) anhydride in hexane CLP = Contract Laboratory Program ECD = electron capture detector ED = electrochemical detection GC = gas chromatography HPLC = high pressure liquid chromatography HRGC = high resolution gas chromatography MS = mass spectrometry MSD = mass sensitive detection PAD = pulse amperometric detection UV = ultraviolet detection ‘9 SAOHIIW TVOILATVNV GL 76 6. ANALYTICAL METHODS 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. No biomarker other than the measurement of 2,4-dichlorophenol itself and its conjugates can be associated with exposure of 2,4-dichlorophenol (Karapally et al. 1973; Shafik et al. 1973; Somani and Khalique 1982) (see Section 2.5). Exposure methods are available for the determination of 2,4-dichlorophenol and its metabolic conjugates in urine (Angerer et al. 1981; Edgerton et al. 1980; Holler et al. 1989; Lores et al. 1981; Van Roosmalen et al. 1980; Wright et al. 1981). No analytical methods for their quantification in human blood or tissue were located, although methods exist for quantification in rat blood and tissues (Judis 1982; Somani and Khalique 1982). Analytical methods for the determination of 2,4-dichlorophenol in human blood and tissue might be useful in case of acute exposure. Since there are no known biomarkers of effects caused by 2,4-dichlorophenol, there is no need for analytical methods at this time. Methods for Determining Parent Compounds and Degradation Products in Environmental Media. Analytical methods with high sensitivity for the determination of 2,4-dichlorophenol in water and sediment are available (Abrahamson and Xie 1983; APHA/AWWA/WPCF 1985; Armentrout et al. 1979; Baldwin and Debowski 1988; Bengtsson 1985; Buisson et al. 1984; EPA 1982, 1988c; Kan et al. 1981; Lee et al. 1987; Sithole et al. 1986; Xie 1983). Methods with increased sensitivity for 2,4-dichlorophenol in soil and methods with measured recoveries in air might be helpful to estimate the extent of contamination in these media and the resultant potential of human exposure (EPA 1988c; Narang et al. 1983). Analytical methods for the determination of degradation products of 2,4-dichlorophenol are available (Boyd and Shelton 1984; Gibson and Sulfita 1986; Hwang et al. 1986; Kohring et al. 1989; Namkoong et al. 1989; Smith 1985; Smith and Novak 1987). 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 2,4-dichlorophenol and other phenolic compounds in urine. These methods involve urine hydrolysis, extraction, derivatization, and measurement using capillary gas chromatography/mass spectrometry/mass spectrometry. No on-going study regarding the determination of the 2,4-dichlorophenol in biological or environmental media was located in the available literature. 77 7. REGULATIONS AND ADVISORIES International, national, and state regulations and advisories are presented in Table 7-1. 2,4-Dichlorophenol is regulated by the Clean Water Effluent Guidelines for the following industrial point sources: steam electric, asbestos, timber products processing, metal finishing, paving and roofing, paint formulating, ink formulating, gum and wood, carbon black, metal molding and casting, aluminum forming, electrical and electronic components (EPA 1988d). 78 7. REGULATIONS AND ADVISORIES TABLE 7-1. Regulations and Guidelines Applicable to 2,4-Dichlorophenol Agency Description Information References INTERNATIONAL IARC Carcinogenic classification Group 2B2 IARC 1986; 1987 NATIONAL Regulations: a. Water: EPA OWRS General permits under the NPDES Yes EPA 1988e (40 CFR 122 APP D) Pesticide Chemicals Category EPA 1988f (40 CFR Effluent Limitations Guidelines, 414.91) Pretreatment Standards, and New Source Performance Standards Priority pollutant effluent limitations for BAT and NSPS Maximum for 1 day 112 ug/L Monthly average shall not exceed 39 ug L b. Food: FDA Tolerance for pesticides in food Yes EPA 1988g (40 CFR administered by EPA 180.142) c. Other: EPA OERR Reportable quantity 100 pounds EPA 1985 (40 CFR 302.4) EPA OSW Listing as hazardous waste Yes EPA 1988g (40 CFR 302.4) Listing as hazardous waste Yes EPA 1988h (40 CFR constituent 261, App VII) Listing as a toxic pollutant Yes EPA 1988i (40 CFR 403, App B) Groundwater monitoring requirement Yes EPA 1990 (40 CFR 264, App 1XER 161:2050.41) Guidelines: a. Water: EPA OWRS Ambient Water Quality Criteria EPA 1980 for Protection of Human Health Ingesting organisms only 3.09 mg/L Water and fish consumption 3.09 mg/L NAS SNARL for lifetime exposure 0.7 mg/L NRC 1980 b. Other: EPA RED (oral) 0.003 mg/kg/day EPA 1990 STATE Regulations and Guidelines: a. Air: Acceptable ambient air concentrations NATICH 1988 Michigan 77 ug/md (annual avg) 79 7. REGULATIONS AND ADVISORIES TABLE 7-1 (Continued) Agency Description Information References STATE (Continued) b. Water: Drinking water standards and guidelines FSTRAC 1988 Kansas 700 ug/L Maine 200 ug/L aGroup 2B: Limited evidence for human carcinogenicity. This classification was derived for the class of compounds, chlorophenols, and is based on data for mixtures containing a probable human carcinogen, 2,4,5- trichlorophenol (EPA 1989d), chlorophenol-based herbicides, or other possible carcinogens. No assessment has been made for 2,4-dichlorophenol alone. 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Biomed Mass Spectrom 8:475-479. %*Xie T. 1983. Determination of trace amounts of chlorophenols and chloroguaiacols in sediment. Chemosphere 12:1183-1191. 97 9. 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. 98 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 Concentrationg,, (LC) -- The lowest concentration of a chemical in air which has been reported to have caused death in humans or animals. Lethal Concentrationgsyy (LCsy) -- 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 (LDsy) -- The dose of a chemical which has been calculated to cause death in 50% of a defined experimental animal population. Lethal Time soy (LTs) -- A calculated period of time within which a specific concentration of a chemical is expected to cause death in 50% of a defined experimental animal population. Lowest-Observed-Adverse-Effect Level (LOAEL) -- The lowest dose of chemical in a study, or group of studies, that produces statistically or biologically significant increases in frequency or severity of adverse effects between the exposed population and its appropriate control. Malformations -- Permanent structural changes that may adversely affect survival, development, or function. Minimal Risk Level -- An estimate of daily human exposure to a chemical that is likely to be without an appreciable risk of deleterious effects (noncancerous) over a specified duration of exposure. Mutagen -- A substance that causes mutations. A mutation is a change in the genetic material in a body cell. Mutations can lead to birth defects, miscarriages, or cancer. 99 9. GLOSSARY 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. q.* -- The upper-bound estimate of the low-dose slope of the dose-response curve as determined by the multistage procedure. The q;* can be used to calculate an estimate of carcinogenic potency, 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. 100 9. GLOSSARY Short-Term Exposure Limit (STEL) -- The maximum concentration to which workers can be exposed for up to 15 min continually. No more than four excursions are allowed per day, and there must be at least 60 min between exposure periods. The daily TLV-TWA may not be exceeded. Target Organ Toxicity -- This term covers a broad range of adverse effects on target organs or physiological systems (e.g., renal, cardiovascular) extending from those arising through a single limited exposure to those assumed over a lifetime of exposure to a chemical. Teratogen -- A chemical that causes structural defects that affect the development of an organism. Threshold Limit Value (TLV) -- A concentration of a substance to which most workers can be exposed without adverse effect. The TLV may be expressed as a TWA, as a STEL, or as a CL. Time-Weighted Average (TWA) -- An allowable exposure concentration averaged over a normal 8-hour workday or 40-hour workweek. Toxic Dose (TDsy) -- A calculated dose of a chemical, introduced by a route other than inhalation, which is expected to cause a specific toxic effect in 50% of a defined experimental animal population. Uncertainty Factor (UF) -- A factor used in operationally deriving the RfD from experimental data. UFs are intended to account for (1) the variation in sensitivity among the members of the human population, (2) the uncertainty in extrapolating animal data to the case of human, (3) the uncertainty in extrapolating from data obtained in a study that is of less than lifetime exposure, and (4) the uncertainty in using LOAEL data rather than NOAEL data. Usually each of these factors is set equal to 10. 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 (14 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 {q,™) Key to LSE Figure The Key explains the abbreviations and symbols used in the figure. [1] TABLE 2-1. Levels of Significant Exposure to [Chemical x] - Inhalation Exposure LOAEL (effect) Key to frequency/ NOAEL Less serious Serious figure Species duration System (ppm) (ppm) (ppm) Reference [2}— INTERMEDIATE EXPOSURE owe © 0 ; [¢}— 18 Rat 13 wk Resp 3° 10 (hyperplasia) Nitschke et al. 5d/wk 1981 6hr/d CHRONIC EXPOSURE > Cancer d rd : 2 38 Rat 18 mo 20 (CEL, multiple Wong et al. 1982 > 5d/wk organs) 9 > 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) et eee eter [33] — + INTERMEDIATE CHRONIC (15-364 Days) (>365 Days) Systomis > 3 J yd / f--- & £ gS / £4 + a] —— — — —— 10,000 1.000 1° lg Ong. Bose On Gg GuuO> on On Owe Bre Psa Dron Bow - wl (04a YR De @= On Om Om On Om O% Om Gu po . fa [16] — —- ees Sei > Qw Ow "I ' 01 : 0 ‘ Estimaied Upper- —H4] 00 } : 0 s : Canoes Risk ooor | 3 Koy oa v A © 10AEL tor sedcus afiects (ardmaks) . 0 coor f- n Noss @ 10AEL tor less sarioun often fardmais) VM dh ve tr 10-7 [LT] O wOAEL jerimeny 3 ollecks ether han cancer 000001 L ’ — @ Cel Conow EfeciLovel — il he number nes lo each pain cor sspandd te entries In Table 2 | : Doses represent he ivwes! 6050 tasied por shudy ral produced 8 henedgenic rospanse and Go ast Imply The salstence of 8 Sveshald fer he cancer end pet FIGURE 2-1. Levels of Significant Exposure to [Chemical X]-Inhalation V XIAN3ddV 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 HPLC hr IDLH IARC ILO in Kd kg oC ow LC LC, LCs, LD; LD, LOAEL B-1 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 lowest-observed-adverse-effect level 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 RfD RTECS sec SCE SIC SMR STEL STORET TLV TSCA TRI TWA U.S. B-2 APPENDIX B Levels of Significant Exposure meter milligram minute milliliter millimeters millimole millions of particles per cubic foot Minimal Risk Level mass spectrometry National Institute of Environmental Health Sciences National Institute for Occupational Safety and Health NIOSH's Computerized Information Retrieval System 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 UF uncertainty factor WHO World Health Organization > greater than > greater than or equal to = equal to < less than < less than or equal to % percent a alpha B beta 5 delta ¥ gamma pm micron 73:4 microgram Cc-1 APPENDIX C PEER REVIEW A peer review panel was assembled for 2,4-dichlorophenol. The panel consisted of the following members: Dr. Christine Eccles, University of Maryland; Dr. Norbert Page, Private Consultant, Gaithersburg, MD; and Dr. Joseph Borzelleca, Medical College of Virginia. These experts collectively have knowledge of 2,4-dichlorophenol’s physical and chemical properties, toxicokinetics, key health end points, mechanisms of action, human and animal exposure, and quantification of risk to humans. All reviewers were selected in conformity with the conditions for peer review specified in Section 104(i) (13) of the Comprehensive Environmental Response, Compensation, and Liability Act as amended. Scientists from the Agency for Toxic Substances and Disease Registry (ATSDR) have reviewed the peer reviewers’ comments and determined which comments will be included in the profile. A listing of the peer reviewers’ comments not incorporated in the profile, with a brief explanation of the rationale for their exclusion, exists as part of the administrative record for this compound. A list of databases reviewed and a list of unpublished documents cited are also included in the administrative record. The citation of the peer review panel should not be understood to imply its approval of the profile’s final content. The responsibility for the content of this profile lies with the ATSDR. “U.S. Government Printing Office: 1992 — 636-281 UC. SERELEY LBRARES C0357671683