R A 1231 I67 T6 1992 FUEL mm «'arw»: . l'rp‘ V“ Ni—vu‘utflf‘h .A ' BORON US. DEPARTMENT OF HEALTH & HUMAN SERVICES Public Health Service Agency for Toxic Substances and Disease Registry Fedora! Recycling Program" Printed on Recycled Paper ’ m HEALTH 1mm fill“ a m ‘ lIBRARY W or emu-0mm TOXICOLOGICAL PROFILE FOR BORON AND COMPOUNDS Prepared by: Life Systems, Inc. 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. MT- YO?,,,;¢KH vhf ‘ ‘ i i i , p, ' I FOREWORD l (a The Superfund Amendments and Reauthorization Act (SARA) of 1986 (Public Law 99-499) extended and amended the Comprehensive Environmental ( I 3 Response, Compensation, and Liability Act of 1980 (CERCLA or Superfund). r/L)t,L¢ 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 federal 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 l. l. l. P 1 l 1. l l UIDWNH 0‘ 7 WHAT IS BORON? CONTENTS UBLIC HEALTH STATEMENT . HOW MIGHT I BE EXPOSED TO BORON? HOW CAN BORON ENTER AND LEAVE MY BODY? HOW CAN BORON AFFECT MY HEALTH? IS THERE A MEDICAL TEST TO DETERMINE WHETHER I HAVE BEEN EXPOSED TO BORON? WHAT RECOMMENDATIONS HAS THE FEDERAL GOVERNMENT MADE TO. PROTECT HUMAN HEALTH? . WHERE CAN I GET MORE INFORMATION? 2. HEALTH EFFECTS 2. 2 l .3 INTRODUCTION . 2. 2 DISCUSSION OF HEALTH EFFECTS BY ROUTE OF EXPOSURE 2.2.1 Inhalation Exposure bWNH HrdpArdrahahaH mflO‘U‘L‘WNV-‘NWNO‘U‘ 2.2.2 r l E NM . . (D' . NMNNNNNNHNNNNNNNNO} NNNNNNNN 2.2.3 In PNNNNNNNUNNNNNNNNOMMNNMNNN wwwwwwwww NNNNNN mNO‘LflJ-‘WMH TOXICOKINETICS 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 2.3.1 Absorption iii ix xi WNNI—‘I—J DU.) vi 2.3.1.1 Inhalation Exposure 2.3.1.2 Oral Exposure 2.3.1.3 Dermal Exposure 2.3.2 Distribution . . . . 2. 3.2.1 Inhalation Exposure 2. 3. 2. 2 Oral Exposure . 2. 3. 2. 3 Dermal Exposure 2.3.3 Metabolism . 2.3.3.1 Inhalation Exposure 2. 3. 3. 2 Oral Exposure 2. 3. 3. 3 Dermal Exposure 2.3.4 Excretion . . 2. 3.4.1 Inhalation Exposure 2. 3. 4. 2 Oral Exposure 2. 3. 4. 3 Dermal Exposure 2. 3.4.4. Other Exposure 2.4 RELEVANCE TO PUBLIC HEALTH . . 2.5 BIOMARKERS OF EXPOSURE AND EFFECT . 2.5.1 Biomarkers Used to Identify and/or Quantify Exposure to Boron . 2. 5. 2 Biomarkers Used to Characterize Effects Caused by Boron . 2.6 INTERACTIONS WITH OTHER CHEMICALS . 2.7 POPULATIONS THAT ARE UNUSUALLY SUSCEPTIBLE . 2.8 MITIGATION OF EFFECTS 2.9 ADEQUACY OF THE DATABASE . 2.9.1 Existing Information on Health Effects of Boron 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 PRODUCTION, IMPORT, USE, AND DISPOSAL . 4.1 PRODUCTION . 4.2 IMPORT/EXPORT 4.3 USE . . . 4.4 DISPOSAL . POTENTIAL FOR HUMAN EXPOSURE 5.1 OVERVIEW . . 1 2 RELEASES TO THE ENVIRONMENT 5.2.1 Air 5.2. 2 Water 5. 2. 3 Soil . . 5.3 ENVIRONMENTAL FATE . . 5.3.1 Transport and Partitioning 5. 3. 2 Transformation and Degradation 5.3.2.1 Air 1 3. 2. 2 Water 5.3.2.3 Soil . . 5.4 LEVELS MONITORED OR ESTIMATED IN THE ENVIRONMENT 25 25 25 26 26 26 26 26 26 26 26 26 26 26 27 27 32 32 33 34 34 34 35 35 37 40 41 41 41 47 47 47 47 47 49 49 49 49 51 51 52 52 53 53 53 53 53 vii Air Water Soil Other Environmental Media U\U\U\U J-‘bbb bwmv—I POPULATIONS WITH POTENTIALLY HIGH EXPOSURES ADEQUACY OF THE DATABASE . 5.7.1 Data Needs 5.7.2 On- going Studies U‘U1U'I \IONUI 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 . GENERAL POPULATION AND OCCUPATIONAL EXPOSURE . S3 54 54 55 55 56 56 56 58 59 59 59 62 62 63 65 69 83 2-1 2-2 5-1 ix LIST OF FIGURES Levels of Significant Exposure to Boron and Compounds - Inhalation . Levels of Significant Exposure to Boron and Compounds - Oral Existing Information on Health Effects of Boron Frequency of NFL Sites with Boron Contamination 17 36 50 2-1 2-2 2-3 2-4 3-1 3-2 6-1 6-2 7-1 xi LIST OF TABLES Levels of Significant Exposure to Boron and Compounds - Inhalation . Levels of Significant Exposure to Boron and Compounds - Oral Dermal Levels of Significant Exposure to Boron and Compounds Genotoxicity of Boron In Vitro . Chemical Identity of Boron and Compounds Physical and Chemical Properties of Boron and Compounds Analytical Methods for Determining Boron in Biological Materials Analytical Methods for Determining Boron in Environmental Samples Regulations and Guidelines Applicable to Boron and Compounds 12 24 31 42 44 60 61 66 1. PUBLIC HEALTH STATEMENT This Statement was prepared to give you information about boron and to emphasize the human health effects that may result from exposure to it. The Environmental Protection Agency (EPA) has identified 1,177 sites on its National Priorities List (NPL). Boron has been found in at least 21 of these sites. However, we do not know how many of the 1,177 NPL sites have been evaluated for boron. As EPA evaluates more sites, the number of sites at which boron is found may change. This information is important for you to know because boron may cause harmful health effects and because these sites are potential or actual sources of human exposure to boron. 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 chemical such as boron, 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 BORON? Boron is a solid substance that widely occurs in nature. It usually does not occur alone, but is often found in the environment combined with other substances to form compounds called borates. Common borate compounds include boric acid, salts of borates, and boron oxide. Boron and salts of borate have been found at hazardous waste sites. Boron alone does not dissolve in water nor does it evaporate easily, but it does stick to soil particles. No information was found on whether common forms of boron evaporate easily or stick to soil particles; however, these forms do dissolve in water. Boron is present in air, water, and soil, but no information is available on how long it remains in these media. There is also no information available on the occurrence of borates in the env1ronment or on how long they persist in the environment. Borates are used mostly in the production of glass. They are also used in fire retardants, leather tanning and finishing industries, cosmetics, photographic materials, with certain metals, and for high-energy fuel. Pesticides for cockroach control and wood preservatives also contain borates. 2 1. PUBLIC HEALTH STATEMENT More information on the properties and uses of boron and boron compounds and how they behave in the environment may be found in Chapters 3, 4, and 5. 1.2 HOW MIGHT I BE EXPOSED T0 BORON? Boron occurs mainly in the environment through release into air, water, or soil after natural weathering processes. It can also be released from glass manufacturing, coal-burning power plants, copper smelters, and through its use in agricultural fertilizer and pesticides. It is estimated that releases from these sources are less than through natural weathering processes. You can be exposed to boron in food (mainly vegetables and fruits), water, air, and consumer products. Infants, in particular, can be exposed to borates in products used to control cockroaches. Since boron is taken up from the soil by plants, it can enter the food chain. Although boron has been found in animal tissue, it does not accumulate and it is not likely that eating fish or meat will increase the boron levels in your body. Boron has been found in groundwater at very low levels. Background levels of boron up to 5 parts of boron in 1 million parts (ppm) of surface water have been reported. However, in dry areas where there are natural boron-rich deposits, boron concentrations can be as high as 360 ppm. No data were found on the occurrence of boron compounds in surface or groundwater. While current drinking water surveys do not report any levels of boron, it has been found in tap water in the past. Levels reported in drinking water were less than l-3 ppm. There is potential for exposure to boron through contact with soil, since boron sticks to soil particles. Background levels up to 300 ppm have been reported. Exposure to air contaminated with boron is not likely to occur in the general population; however, there is risk of exposure to borate dust in the workplace. Concentrations from l—l4 milligrams of boron dust per cubic meter of air (mg/m3) have been reported in borax mining and refining plants and at sites where boric acid is manufactured. Exposure to boron may also occur from the use of consumer products, including cosmetics, topical medical preparations, and some laundry products. The average daily boron intake has been estimated to be 10—25 mg. Further information on how you might be exposed to boron is given in Chapter 5. 1.3 HOW CAN BORON ENTER AND LEAVE MY BODY? Boron can enter your body when you eat food (fruit and vegetables) breathe borate dust in the air, and when damaged skin comes in contact with it. Because very small amounts of boron are present in all drinking water, boron can enter your body when you drink water. When boron enters the body by mouth or when you breathe borate dust, it goes to the intestines where it is passed to various parts of the body including the liver, brain, and kidney. No information is available on what factors affect how fast boron enters the body. However, animal studies suggest boron readily enters the body after contact with damaged skin. Most of the boron leaves the body in urine 3 1. PUBLIC HEALTH STATEMENT primarily from food eaten. Over half of the boron taken by mouth can be found in urine within 24 hours and the other half can be detected for up to 4 days. Boron compounds can be found in urine up to 23 days if you are accidentally exposed to very large amounts. Further information on how boron enters and leaves the body is given in Chapter 2. 1.4 HOW CAN BORON AFFECT MY HEALTH? If humans eat large amounts of boron (4,161 ppm) over short periods of time, it can affect the stomach, intestines, liver, kidney, and brain and can eventually lead to death. Irritation of the nose and throat or eyes can occur if small amounts of boron (4.1 mg/m3) are breathed in. Boron can irritate the eyes if it comes in contact with them for long periods of time. Animal studies indicate that the male reproductive organs, especially the testes, are affected if large amounts of boron are eaten or drunk for short or long periods of time. Studies in animals also indicate delayed development and structural defects in offspring, primarily in the rib cage, from maternal exposure to boron during pregnancy. These effects have not been seen in humans. Irritation of the nose can occur in animals if large amounts of boron are breathed in for long periods of time. These effects have not been seen in humans. No information is available on whether boron is likely to cause cancer in humans. There is no evidence of cancer in animals exposed to boron for long periods of time. More information on the health effects of boron in humans and animals can be found in Chapter 2. 1.5 IS THERE A MEDICAL TEST TO DETERMINE WHETHER I HAVE BEEN EXPOSED TO BORON? There are reliable and accurate ways of measuring boron in the body. Blood and urine can be examined to determine if excessive exposure to boron has occurred. Boron and, to a limited extent, boron-related compounds can be measured in body fluids. However, special equipment is needed for detection and analysis. Tests are not routinely available in a doctor's office. It is not known whether boron levels measured in the body can be used to predict potential health effects. Further information on how boron can be measured in exposed humans is presented in Chapters 2 and 6. 1.6 WHAT RECOMMENDATIONS HAS THE FEDERAL GOVERNMENT MADE TO PROTECT HUMAN HEALTH? The federal government has set regulatory standards and guidelines to protect individuals from the effects that may occur if exposed to boron. The EPA has established tolerances for total boron of 30 ppm in or on cottonseed and 8 ppm in or on citrus fruits. The Food and Drug Administration has 4 1. PUBLIC HEALTH STATEMENT designated that borax and boric acid are generally recognized as safe (GRAS) as indirect food additives in adhesive components, components of paper, paperboard, sizing and coatings. The Occupational Safety and Health Administration (OSHA) has set a permissible exposure limit of 10 mg/m3 for boron oxide and sodium tetraborate in the workplace air for 8 hour/day exposures over a 40-hour work week. Limits of 10 mg/m3 for boron tribromide and 3 mg/m3 for boron trifluoride have been set. Additional information on governmental regulations regarding boron can be found in Chapter 7. 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 boron and compounds 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 boron 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 (365 days or more). Levels of significant exposure for each route and duration are presented in tables and illustrated in figures. The points in the figures showing no-observed—adverse-effect levels (NOAELs) or lowest-observed—adverse-effect levels (LOAELs) reflect the actual doses (levels of exposure) used in the studies. LOAELs have been classified into "less serious" or "serious" effects. These distinctions are intended to help the users of the document identify the levels of exposure at which adverse health effects start to appear. They should also help to determine whether or not the effects vary with dose and/or duration, and place into perspective the possible significance of these effects to human health. The significance of the exposure levels shown in the tables and figures may differ depending on the user's perspective. For example, physicians concerned with the interpretation of clinical findings in exposed persons may be interested in levels of exposure associated with "serious" effects. Public health officials and project managers concerned with appropriate actions to take at hazardous waste sites may want information on levels of exposure associated with more subtle effects in humans or animals (LOAEL) or exposure levels below which no adverse effects (NOAEL) have been observed. Estimates of levels posing minimal risk to humans (Minimal Risk Levels, MRLs) may be of interest to health professionals and citizens alike. Estimates of exposure levels posing minimal risk to humans (MRLs) have been made, where data were believed reliable, for the most sensitive noncancer effect for each exposure duration. MRLs include adjustments to reflect human variability from laboratory animal data to humans. Although methods have been established to derive these levels (Barnes et al. 1988; EPA 1989a), uncertainties are associated with these techniques. Furthermore, ATSDR acknowledges additional uncertainties inherent in the 6 2. HEALTH EFFECTS 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 2.2.1.1 Death No studies were located regarding death in humans or animals after inhalation exposure to boron. 2.2.1.2 Systemic Effects No studies were located regarding cardiovascular, gastrointestinal, hematological, musculoskeletal, or renal effects in humans after inhalation exposure to boron. No studies were located regarding dermal/ocular effects after acute inhalation exposure in humans or animals for any duration category. Information on respiratory, cardiovascular, gastrointestinal, hematological, musculoskeletal, renal, and dermal/ocular effects is discussed below. The highest NOAEL values and all reliable LOAEL values for these systemic effects for each species and duration category are recorded in Table 2-1 and plotted in Figure 2—1. Respiratory Effects. Boron (as boron oxide and boric acid dusts) has been shown to cause irritation of the upper respiratory tract in humans. Based on a medical questionnaire from 113 workers (96% males, 4% females) employed in the borax industry for an average of 11 years, mean exposures of 4.1 mg/m3 to boron oxide and boric acid dusts were associated with dryness of the mouth, nose, or throat, sore throat, and productive cough (Garabrant et a1. 1984). While the authors reported differences between the test and control groups in age and numbers of smokers, no differences in symptoms were observed. Similarly, symptoms of acute respiratory irritation were related to exposures to borax dust at concentrations of 4 mg/m3 or more in a cross- sectional study of 629 borax workers actively employed for 11.4 years (Garabrant et al. 1985). Decreases in the forced expiratory volume (FEVI) were seen among smokers who had cumulative borax exposures of 80 mg/m3 or greater but were not seen among less exposed smokers or among nonsmokers. Radiographic abnormalities were not found. It was determined in a follow-up of the Garabrant et a1. 1985 study that the cumulative borax exposure effect HEALTH EFFECTS 2. Anvuaoh I uh ”Anvxoo> I x: "huouuuaAnuu I anom "Ho>oA uoowwouOnuo>vauvo>honnono: I qmoa noomwonUnuu>vwavo>h0n30uuno>oa I AH0uvunu I cavuuo “xduon I Kn “ovaxo canon I on .vaoq vuuon I \vn on 9:3; o: :3 .Né aux .N o>auosvouaom v\u£o onom .An uo xaxvn on 933:. a: :3 «Tc 5x n AuoanoAOHSUZ omon .Ha uo on 9:3; 3 330m :5 ma non N sh ouunno sh Aanvx uh auxn\0n=x up cavuao vxuno anma .A. we fiscauauauna 13\un on unavaas buouudnnuuv one 55 and“ x: «Nuo uam H ouEuunhm Mahmomxu maw ES 33 .18 33: 0.20220 WERE—ENE. 2252:. I wagon—=00 new :28 2 Eamonxm 235.55 3 £93 .5.“ mung... 9 2. HEALTH EFFECTS found previously was probably due to smoking workers with longer boron work histories and who smoke disproportionately more than those with shorter work histories. There was no indication that borax exposure at the levels studied (up to 15 mg/m3) impaired pulmonary function (Wegman et al. 1991). Direct irritation to mucous membranes of the nose and throat was also studied by Wegman et al. (1991) using an irritation scoring system together with real- time measurements of borax exposure concentrations. The study concluded that borates are mild irritants. However, these effects are likely to occur at concentrations exceeding 10 mg/m3 (OSHA Permissible Exposure Limit). Animal studies suggest that the respiratory tract is susceptible to boron toxicity. Rats exposed to 470 mg/m3 boron oxide aerosol for 10 weeks developed reddish exudates from their noses, but there were no deaths or signs of lung damage (Wilding et a1. 1959). No changes were observed in rats in the 77 mg/m3 dose group after 24 weeks of exposure, or in dogs exposed to a concentration of 57 mg/m3 for 23 weeks (Wilding et al. 1959). Cardiovascular Effects. Animal data are sparse. Rats exposed to aerosols of boron oxide at a concentration of 77 mg/m3 for 6 weeks showed no histopathological effects in the cardiovascular system (Wilding et al. 1959). Gastrointestinal Effects. Animal data are sparse. No changes were seen in the gastrointestinal tract of rats exposed to aerosols of boron oxide at a concentration of 77 mg/m3 for 6 weeks (Wilding et a1. 1959). Hematological Effects. Little is known concerning the effects of boron in animals. Rats exposed to aerosols of boron oxide for 10—24 weeks (up to 470 mg/m3) and dogs for 23 weeks (57 mg/m3) showed no significant changes in total red and white blood cell count, hemoglobin, hematocrit, and differential count (Wilding et al. 1959). Husculoskeletal Effects. Animal data are sparse. No histopathological effects of exposure were observed in the femur, rib, and muscle of rats exposed to aerosols of boron oxide at a concentration of 77 mg/m3 for 6 weeks (Wilding et al. 1959). Renal Effects. Data on the effects of boron in animals are sparse. No renal effects were observed in rats exposed to aerosols of boron oxide at a concentration of 77 mg/m3 for 6 weeks (Wilding et al. 1959). Dermal/Ocular Effects. Human occupational exposure to a mean concentration of 4.1 mg/m3 (as boron oxide and boric acid dust) produced eye irritation following chronic exposures in workers employed for an average of 11 years (Garabrant et al. 1984, 1985). 2.2.1.3 Immunological Effects No studies were located regarding immunological effects in humans or animals after inhalation exposure to boron. 10 2. HEALTH EFFECTS 2.2.1.4 Neurological Effects No studies were located regarding neurological effects in humans after inhalation exposure to boron. Adverse effects were not found on the brain of rats exposed to aerosols of boron oxide at a concentration of 77 mg/m3 for 6 weeks (Wilding et a1. 1959). 2.2.1.5 Developmental Effects No studies were located regarding developmental effects in humans or animals after inhalation exposure to boron. 2.2.1.6 Reproductive Effects Limited data were located regarding reproductive effects in humans after inhalation exposure to boron. One study was reported involving occupational exposure (10 years or greater) to boron aerosols (22-80 mg/m3) in males engaged in the production of boric acids (Tarasenko et a1. 1972). The study group was small, consisting of 28 men. Low sperm counts, reduced sperm motility and elevated fructose content of seminal fluids were observed. In animals, no effects were found on the ovary or testes of rats exposed to aerosols of boron oxide at a concentration of 77 mg/m3 for 6 weeks (Wilding et a1. 1959). 2.2.1.7 Genotoxic Effects No studies were located regarding the genotoxic effects in humans or animals after inhalation exposure to boron. Genotoxicity studies are discussed in Section 2.4. 2.2.1.8 Cancer No studies were located regarding cancer in humans or animals after inhalation exposure to boron. 2.2.2 Oral Exposure 2.2.2.1 Death Studies in humans, particularly infants, show that boron (as boric acid) can be lethal following ingestion. Infants who ingested formula accidentally prepared with 2.5% aqueous solution of boric acid died within 3 days after exposure (Wong et a1. 1964). It was estimated that the amount of boric acid consumed ranged from 4.51 to 14 g. Although 5 of 11 infants died, the authors provided histopathological data and weights for only 2 infants who had ingested 9.25 g (505 mg boron/kg/day) and 14 g (765 mg boron/kg/day) (Wong et a1. 1964). Infants became lethargic and developed vomiting and diarrhea. ll 2. HEALTH EFFECTS Degenerative changes were seen in the liver, kidney, and brain. Acute exposure to dose levels of 895 mg boron/kg as boric acid was not lethal in one adult (Linden et al. 1986). In animals, boron (as boric acid and borax) is lethal following acute, intermediate, and chronic oral exposures. Estimates of oral LD5° in rats were 898 and 642 mg boron/kg (as boric acid and borax, respectively) (Smyth et al. 1969) and 510 and 550 mg boron/kg as borax and boric acid (Weir and Fisher 1972). No deaths were reported in dogs exposed to 696 mg boron/kg as boric acid and 738 mg boron/kg as borax (Weir and Fisher 1972). In a 14-day repeated—dose feeding study in male mice, doses of 2,251 and 3,671 mg boron/kg/day (as boric acid) were lethal in 20% and 60% of males, respectively (NTP 1987). The mice were lethargic and the spleen, liver, and renal medullae were discolored. Hyperplasia and dysplasia of the forestomach were also observed (NTP 1987). Survival was also reduced in mice following intermediate-duration exposure. Males (10%) died after exposure to a dose of 288 mg boron/kg/day (as boric acid) in the diet, while 80% of males and 60% of females died at 577 mg boron/kg/day (NTP 1987). Hyperkeratosis and/or acanthosis in the stomach and extramedullary hematopoiesis of the spleen in both sexes were observed at the highest dose tested (577 mg boron/kg/day). There was 100% mortality in rats fed 263 mg boron/kg/day for 90 days (Weir and Fisher 1972). Congestion of liver and kidneys, small gonads, and brain swelling were reported. When male mice consumed 48 and 96 mg boron/kg/day (as boric acid) for 103 weeks, mortality was 40% and 56%, respectively, compared to 18% in untreated controls (NTP 1987). No clinical signs were reported; however, boron caused increased incidence of testicular atrophy and interstitial hyperplasia. Mortality in female mice was 30% and 24% (48 and 96 mg boron/kg/day) compared to 34% in the untreated controls (NTP 1987). The LD50 values and the highest NOAEL values in animals and the lowest level at which death was reported in humans and the duration categories are recorded in Table 2-2 and plotted in Figure 2-2. 2.2.2.2 Systemic Effects No studies were located regarding respiratory effects in animals or cardiovascular or musculoskeletal effects in humans or animals after oral exposure to boron. Information on respiratory, gastrointestinal, hematological, hepatic, renal, and dermal/ocular effects is discussed below. The highest NOAEL values and all reliable LOAEL values for these systemic effects for each species and duration category are recorded in Table 2-2 and plotted in Figure 2-2. Respiratory Effects. Widespread vascular congestion and hemorrhages in the lungs were reported in one infant who ingested 505 mg boron/kg/day (Wong et al. 1964). 12 HEALTH EFFECTS 2. 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I w :1 or .1 Cor g 9 S a a a z F4 4 4 4 94 4 4 I a. m“ 80 20 I So; ESQ Em. l ooode gmubeEv oo/V «90 09,9 00,7 ~on «Ev $00 o; $0 4 a. o ,o 9 0/ x/ 0/. QO 9! 4 «9/ 0/2. A. 2:535 ES «3 thU< .80 I 358280 ucm cohom 2 2:8an EmoE=9m ho m_m>o._ .N.N mEDOE 18 HEALTH EFFECTS 2. .~-~ $32. 5 3E5 o. $832.8 Eon :03 o. :8: .353: 9:. 7.56:5 aucto 26:3 3.2 .2 ..m3. _ _ 5.0 u u . . n “.30 360 " ammo .VN so” .80 $9808.” 3» SN. .80 .20 .20 in awe . Ra Ra E3 8 END “$6 .8. am. Bantam-v Saw .8050 SN Ea Ema. . .9. .3. F. [V O O as 049 @94/ 99/0 90%, ofiy 299 000,. O/ 0/0 v 0?. 01$ 0. any ova / oo/ 7 00 au 0/. 0 /9/ / 4 2E2m>w ES 33: 353.255. Agsczcoov 3 mung”. IL 8.0 v.0 or SF 000% 000.9. A???“ 19 HEALTH EFFECTS 2. .me gawk E 3:25 2 uncoamwtoo «£0... 50% 2 :8: 596:: 9: 35:55 38% 39:8 $2 .2 d<9 < 35:55 58% “8:8 .2 d<9 4 33.553302 0 Eggs 38% 388 30:2 #29 0 So u I 8 o .8c8 :2. 55° 28% ‘m, 22.3 98% “8:8 .2 #29 I 882 E .2 .26. E. .2552 _ 80.. I am . I to >3. I F “$0 340 I or .90 .SO .80 500 .9. 5. .3. .RCEQO E8. .50 I 08 I 83 I 8o.2 amuaxaé 091V So 9 ¢ 01.. o 04% 3.8 3%. 0.20210 emaczcoov a.“ mung“. 20 2. HEALTH EFFECTS Gastrointestinal Effects. Ingestion of boron in humans can cause gastrointestinal effects. Nausea, persistent vomiting, diarrhea, and colicky abdominal pain in infants were associated with acute ingestion of a total of 184 mg boron/kg/day or greater (based on 1.9 kg body weight) as boric acid which was accidently incorporated in infant formula (Wong et a1. 1964). Vomiting was the only sign of boron toxicity in two adult females who had ingested 241 mg boron/kg/day as boric acid in a fungicide and 895 mg boron/kg of a boric acid-containing insecticide in a suicide attempt. The subjects were hospitalized for 24-96 hours and did not develop further symptoms following release (Linden et a1. 1986). Hematological Effects. Two male and three female dogs fed 44 mg boron/kg/day as borax had decreased packed cell volume and hemoglobin values. Erythrocyte count, total and differential leucocyte counts were comparable to control levels (Weir and Fisher 1972). Hepatic Effects. Case reports in humans suggest that the liver is susceptible to boron toxicity at high dose levels (Wong et a1. 1964). Jaundice has been reported, and there were mild alterations at histological examination in infants who ingested 505 or 765 mg boron/kg/day as boric acid (accidentally incorporated in infant formula) for 3-5 days (Wong et a1. 1964). In the same incident, congestion and fatty changes were observed, and there was parenchymatous degeneration in newborn infants who ingested 505 or 765 mg boron/kg as boric acid for 3-5 days (Wong et al. 1964). In rats given approximately 20.8 mg boron/kg/day as borax in drinking water, NADPH-cytochrome C reductase activity and cytochrome b5 content decreased in the liver microsomal fraction after 10 and 14 weeks (Settimi et a1. 1982). There was also a reduction in the cytochrome P-450 concentration detected at 14 weeks (Settimi et a1. 1982). Renal Effects. Human case reports involving high accidental ingestion levels show that boron can cause injury to the kidney. Degenerative changes in parenchymal cells with oliguria and albuminuria have been demonstrated in two newborn infants after ingestion of 505 and 765 mg boron/kg/day as boric acid in an evaporated milk formula over a period of 3-5 days (Wong et a1. 1964). Dermal/Ocular Effects. Skin effects can occur following ingestion of boron (as boric acid) in humans. Extensive exfoliative dermatitis began in infants as an erythema involving palms, soles, and buttocks. It eventually became generalized with subsequent bulbous formation, massive desquamation, and sloughing (Wong et a1. 1964). These changes were associated with ingestion of 505 mg boron/kg/day; however, skin lesions were lacking following ingestion of 765 mg boron/kg/day. Similarly, extensive erythema with desquamation was observed in an adult who ingested boric acid powder (Schillinger et a1. 1982). The exact amount ingested was not stated. However, 14 g (equivalent to 22.5 mg boron/kg based on 109 kg body weight) was measured as missing from a container from which the patient admitted consuming half its contents. 21 2. HEALTH EFFECTS In animals, rats fed 88 and 263 mg boron/kg/day as borax or boric acid had inflamed eyes and skin desquamations on the paws and tails (Weir and Fisher 1972). 2.2.2.3 Immunological Effects No studies were located regarding immunological effects in humans or animals after oral exposure to boron. 2.2.2.4 Neurological Effects Case reports in humans have indicated neurological effects after accidental ingestion of high levels of boron (as boric acid). Newborn infants who ingested 4.5-14 g boric acid showed central nervous system involvement manifested by headache, tremors, restlessness, and convulsions followed by weakness and coma (Wong et a1. 1964). Histological examination of 2 of 11 infants revealed congestion and edema of brain and meninges with perivascular hemorrhage and intravascular thrombosis at a dose 2505 mg boron/kg/day (Wong et a1. 1964). Seizure disorders have been associated with boron exposures (as borax) in infants who ingested 4-30 g borax for 4—10 weeks (O'Sullivan and Taylor 1983) and 9—125 g borax for 5-12 weeks (Gordon et al. 1973). Estimates of boron consumption could not be determined since the authors did not provide data on kilogram body weights. Blood boron levels in patients who ingested borax ranged from 2.6 to 8.5 pg/mL (O'Sullivan and Taylor 1983). In one infant with a seizure disorder who ingested borax for 3 months, the blood boron level was 1.64 mg/lOO mL (Gordon et al. 1973). In rats, exposure to approximately 20.8 mg boron/kg/day as borax (based on weight of 0.35 kg and average water consumption of 20.7 mL) in drinking water for up to 14 weeks caused increased cerebral succinate dehydrogenase activity after 10 and 14 weeks of exposure (Settimi et a1. 1982). Increased RNA concentration and increased acid proteinase activity in brain occurred after 14 weeks (Settimi et al. 1982). All LOAEL values for neurological effects in humans and animals are recorded in Table 2-2 and plotted in Figure 2-2. 2.2.2.5 Developmental Effects No studies were located regarding developmental effects in humans after oral exposure to boron. In animals, fetotoxicity was observed in rats and mice The average fetal body weight per litter in rats was reduced in pups of dams administered 13.6 mg boron/kg/day or greater (78 mg/kg/day boric acid) on gestation days 0 to 20 (Heindel et a1. 1991). Similarly, pups of mice administered 79 mg boron/kg/day (452 mg/kg/day boric acid) showed reduced body weight. Boron was also teratogenic in rats and mice. There was agenesis or shortening of rib XIII and the lateral ventricles of the brain were enlarged in rats at dose 22 2. HEALTH EFFECTS levels of 28.4 mg boron/kg/day (163 mg/kg/day boric acid) or greater (Heindel et a1. 1991). Skeletal effects were reported at the highest dose tested (175.3 mg boron/kg/day or 1,003 mg/kg/day boric acid) in mice. No effects were observed in the 43.4 mg boron/kg/day (248 mg/kg/day boric acid) dose group (Heindel et a1. 1991). Based on a value of 13.6 mg boron/kg/day, an intermediate oral MRL of 0.01 mg/kg/day was calculated as described in the footnote on Table 2-2. 2.2.2.6 Reproductive Effects No studies were located regarding reproductive effects in humans after oral exposure to boron. Animal studies demonstrated that boron can cause injury after intermediate and chronic exposure to the gonads in animals, especially the testes. Impaired spermatogenesis has been reported in rats administered 300 mg/boron/L as borax (44.7 mg boron/kg/day) in drinking water for 70 days (Seal and Weeth 1980), but no reproductive effects were evident in rats administered up to 6 mg boron/L of borax (0.6 mg boron/kg/day) in drinking water for 90 days (Dixon et a1. 1976). While severe testicular atrophy was seen in dogs fed up to 44 mg boron/kg/day (1,750 ppm boron, as borax or boric acid) for 90 days (Weir and Fisher 1972), partial testicular atrophy in rats occurred at a dose of 26 mg boron/kg/day (525 ppm boron) (Weir and Fisher 1972). Degeneration or atrophy of the seminiferous tubules was demonstrated in mice fed 144 mg boron/kg/day as boric acid (5,000 ppm boric acid) (NTP 1987). In rats fed at least 50 mg boron/kg/day (as borax) up to 60 days, there were reduced testicular weight and germinal aplasia at 60 days (Dixon et a1. 1979). In the same study, 250 mg boron/kg/day caused reduction in hyaluronidase, sorbitol dehydrogenase, and lactic acid dehydrogenase (isoenzyme-X) at 30 days and testicular and epididymal weights were reduced (Dixon et a1. 1979). In contrast, Lee et a1. (1978) did not find significant adverse effects in male rats fed 50 mg boron/kg/day (as borax) for 30 and 60 days. Dogs were fed 29 mg boron/kg/day as borax and boric acid (1,170 ppm), respectively in the diet for 38 weeks (Weir and Fisher 1972). Testicular atrophy and spermatogenic arrest were reported. When dogs were administered 8.8 mg boron/kg/day (350 ppm borax or boric acid) for 2 years, no reproductive effects were observed (Weir and Fisher 1972). Reproductive effects were reported in rats following chronic exposure. In rats fed up to 58.5 mg boron/kg/day (as borax or boric acid) for several generations, there was a lack of viable sperm in atrophied testes and ovulation decreased in females (Weir and Fisher 1972). There were testicular atrophy and interstitial hyperplasia in mice that consumed lethal doses (48 and 96 mg boron/kg/day) over a period of 103 weeks. However, the authors did not specify cause of death (NTP 1987). In a 2—generation reproduction mouse study using continuous breeding protocol, there was degeneration of the seminiferous tubules and spermatogenesis was impaired at dose levels of 111 mg boron/kg/day (636 mg/kg/day boric acid) or greater. No effects were observed in the 27 mg boron/kg/day (152 mg/kg/day boric acid) dose group (NIEHS 1990). 23 2. HEALTH EFFECTS The highest NOAEL values and all reliable LOAEL values for reproductive effects in animals and duration category are recorded in Table 2-2 and plotted in Figure 2-2. 2.2.2.7 Genotoxic Effects No studies were located regarding genotoxic effects in humans and animals after oral exposure to boron. Genotoxicity studies are discussed in Section 2.4. 2.2.2.8 Cancer No studies were located regarding cancer in humans after oral exposure to boron. In a life-time bioassay in which male and female B6C3F1 mice consumed 48 mg boron/kg/day or 96 mg boron/kg/day as boric acid in the diet, there was no evidence of carcinogenicity (NTP 1987). 2.2.3 Dermal Exposure 2.2.3.1 Death No studies were located regarding death in humans or animals after dermal exposure to boron. 2.2.3.2 Systemic Effects No studies were located regarding hematological and dermal/ocular effects in humans and respiratory, cardiovascular, gastrointestinal, musculoskeletal, hepatic, or renal effects in humans or animals after dermal exposure to boron. All reliable LOAEL values for systemic effects in each species and duration category are recorded in Table 2-3. Hematological Effects. Data are sparse in animals. It was reported in Draize and Kelley (1959) that the application of 25-200 mg/kg/day boric acid in aqueous solution did not produce hematological changes when rubbed onto intact skin during a 90-day rabbit study. No quantitative data were provided; therefore, these results could not be evaluated. Dermal/Ocular Effects. Animal studies show that boron oxide dust can affect the eye and skin. Instillation of boron oxide dust (50 mg) into the eyes of four rabbits produced conjunctivitis (Wilding et al. 1959). Application of l g boron oxide dust to a 25 cm2 area of the skin of four rabbits produced erythema that lasted for 2—3 days (Wilding et a1. 1959). 24 HEALTH EFFECTS 2. fio>0a uoommuuunuo>vu|u0>honno|0d I Amua uuumwou0nu0>vunvo>honnOIUno>Oa I qmoun vac: Aacanauo. onoa .aa an Aan£u5uov .H 00‘suun On mdavaun Anuua>auu:§mcouv ma uoxfiuon v fl uunnud 0«Eounhm mubmomxm MHDU< Each OUCOuuwom Ahav\w1\wfiv Ahuv\m¥\wfiv Ahav\mx\nfiv Eounhm ceauuusv noduonw macauom macauon nnoq Amhahoaaha ivkaivkafiv u:uau:u>o> Lanule Genotoxicity studies are discussed in Section 2.4. 2.2.3.8 Cancer No studies were located regarding cancer effects in humans or animals after dermal exposure to boron. 2.3 TOXICOKINETICS 2.3.1 Absorption 2.3.1.1 Inhalation Exposure No quantitative studies were located regarding absorption in humans or animals after inhalation exposure to boron. Reports of upper respiratory tract symptoms following exposure to boron oxide and boric acid dusts suggest boron can deposit in the upper airway (Garabrant et al. 1984, 1985). 2.3.1.2 Oral Exposure No quantitative studies were located regarding absorption in humans or animals after oral exposure to boron and compounds. Gastrointestinal absorption was indicated in humans as evident by the urinary recovery of 93.9% of the ingested dose of boric acid when urine samples were calculated over a 96 hour period (Jansen et al. 1984a). Neurological, kidney, and liver damage following ingestion further suggest that boron can be absorbed (Wong et al. 1964). 2.3.1.3 Dermal Exposure No quantitative studies were located regarding boron absorption in humans or animals after dermal exposure. Urinary excretion studies in humans (Section 2.3.4.3) suggest there is very little absorption of boron through intact skin. Excretion studies (Section 2.3.4.3) in rabbits suggest that boron is readily absorbed following contact with damaged skin (Draize and Kelley 1959). 26 2. HEALTH EFFECTS 2.3.2 Distribution No quantitative studies were located regarding distribution in humans or animals after exposure to boron and compounds by the following routes: .3.2.1 Inhalation Exposure .3.2.2 Oral Exposure .3.2.3 Dermal Exposure NNN 2.3.3 Metabolism No studies were located regarding metabolism in humans or animals after exposure to boron or boron compounds by the following routes: 2.3 3.1 Inhalation Exposure 2.3 3.2 Oral Exposure 2.3 3.3 Dermal Exposure 2.3.4 Excretion 2.3.4.1 Inhalation Exposure No studies were located regarding excretion in humans after inhalation exposure to boron. In rats that inhaled average concentrations of 77 mg/m3 boron oxide aerosols over a 22 week period, an average of 11.90 mg boron/kg/day was detected in the urine compared to 0.24 mg/kg/day in untreated control groups (Wilding et al. 1959). 2.3.4.2 Oral Exposure Over 93% of the administered dose was excreted in the urine of six male human volunteers 96 hours after administration of a single oral dose of 1.9 mg boron/kg (as boric acid) (Jansen et al. 1984a). An analysis of nine cases involving boric acid poisoning revealed a mean half—life of 13.4 hours (4-27.8). There was no correlation between half-life and calculated serum boric acid level at to (r-0.08, p-O.84) (Litovitz et a1. 1988). Boric acid was detected in urine of patients 23 days after a single ingestion (Wong et a1. 1964). In rabbits, 50%—66% of the administered dose was recovered in urine after ingestion of l7.l—119.9 mg boron/kg/day as boric acid (Draize and Kelley 1959). 2.3.4.3 Dermal Exposure Limited data in humans suggest that very little absorption of boron occurs through intact skin. There was no increase in the urinary excretion of boron in one human subject following the application of 15 g boric acid (37.5 mg boron/kg bw) on the forearm for 4 hours (Draize and Kelley 1959). 27 2. HEALTH EFFECTS Animal studies support human findings. Draize and Kelley (1959) applied 200 mg/kg as boric acid to intact, abraded or burnt, and partially denuded skin of rabbits. Net urinary excretion of boric acid per 24 hours during 4 consecutive days of compound treatment was 1.4, 7.6 and 21.4 mg/kg, respectively (0.25, 1.3, and 3.7 mg boron/kg, respectively). 2.3.4.4. Other Exposure In eight adult volunteers administered a single dose of boric acid (562-611 mg) by intravenous infusion, 98.7% of the administered dose was recovered in urine 120 hours after injection (Jansen et al. 1984b). Renal blood clearance averaged 39.1 mL/min per 1.73 m2 surface area in eight adult human subjects administered intravenous injections of 35 mg boron/kg (as sodium pentaborate). Urine boron concentrations on the day of administration averaged 1.19 mg/mL (Farr and Konikowski 1963). 2.4 RELEVANCE TO PUBLIC HEALTH Estimates of levels of exposure to boron posing minimal risk to humans (MRLs) have been made. These are discussed in Section 2.2 and were based on data believed to be reliable for the most sensitive noncancer effect for each route and exposure duration. No data were located on effects of acute- duration inhalation exposure in humans or animals nor on intermediate-duration inhalation exposure to boron in humans. Available information on intermediate-duration inhalation exposure in animals and chronic-duration inhalation exposure in humans do not reliably identify the most sensitive target organ. No data on effects of acute-duration oral exposure to boron in humans or animals nor on intermediate exposure in humans were located. In animals, prenatal exposure of mice (79 mg boron/kg/day as boric acid) and rats (13.6 mg boron/kg/day as boric acid) during gestation days 0-17 and 0-20 caused developmental effects consisting of reduced fetal body weight or minor skeletal changes and possibly delay in maturation (Heindel et al. 1991). There was degeneration of the seminiferous tubules and impaired spermatogenesis in mice exposed to dose levels of 111 mg boron/kg/day as boric acid for 2 generations (NIEHS 1990). In other studies involving intermediate- duration exposure, gonadal damage, primarily in the testes, was evident at dose levels from 26 to 288 mg/kg/day (NTP, 1987; Weir and Fisher 1972), but not at dose levels of 0.6 and 25 mg/kg/day (Dixon et al. 1976, 1979). Exposure of dogs to boron (as boric acid or borax) in the diet for 38 weeks caused testicular atrophy and spermatogenic arrest at dose levels of 29 mg boron/kg/day (Weir and Fisher 1972). Based on a LOAEL value of 13.6 mg boron/kg/day for developmental toxicity, an intermediate oral MRL of 0.01 mg boron/kg/day was derived using an uncertainty factor of 1,000 (10 for use of a LOAEL, 10 for extrapolation from animals to humans and 10 for human variability). However, testicular effects were reversible within 25 days after compound treatment ceased. No effects were observed in rats fed diets containing doses up to 8.75 mg boron/kg/day) for 2 years (Weir and Fisher 1972). Because developmental toxicity occurred at dose levels less than those for reproductive toxicity, the intermediate MRL based on developmental toxicity should be protective against reproductive toxicity following chronic 28 2. HEALTH EFFECTS exposure. No data were located on effects of chronic-duration oral exposure in humans. A chronic MRL was not derived. Acute-duration, intermediate- duration, and chronic-duration dermal MRLs were not derived for boron due to the lack of an appropriate methodology for the development of dermal MRLs. No studies have been found regarding immunological effects of boron and compounds in humans or animals. Death. Human studies have shown that boron can be lethal following short-term exposure. The minimal lethal dose of ingested boron (as boric acid) was reported to be 2-3 g in infants, 5—6 g in children and 15-20 g in adults (Locatelli et a1. 1987; Wong et a1. 1964). No data were found on the potential for boron to cause death in humans after intermediate and chronic inhalation and oral exposures. Liver, kidney, brain damage, and skin lesions have been found in lethal cases following ingestion of boron, but death has been attributable to respiratory failure. In other studies, chronic dermal exposure to boron in neonates was fatal (Litovitz et al. 1988). There appears to be a differential susceptibility with regard to death in adults. It has been postulated that increased competence of the adult kidney accounts for adult tolerance to boron. Based on these findings, lethality may be an area of concern following neonate exposure to boron. Animal studies support human findings. Boron was lethal after ingestion for acute, intermediate, and chronic duration exposures (NTP 1987; Smyth et a1. 1969; Weir and Fisher 1972). Systemic Effects Respiratory Effects. Symptoms of acute irritation of the upper airway were observed at borax and boric acid levels of 4 mg/m3 or greater (Garabrant et al. 1984, 1985). No adverse respiratory effects were observed in humans following intermediate inhalation exposures. Chronic inhalation exposure caused irritation of the upper respiratory tract (Garabrant et al. 1984, 1985). There were no changes in the FEV1 and FVC in borax workers (Wegman et a1. 1991). Intermediate inhalation exposure in animals caused irritation of the nose (Wilding et al. 1959). Gastrointestinal Effects. Boron or boron compounds can result in gastrointestinal disorders in humans following acute and intermediate oral exposures. Most of the studies focused on clinical symptoms including vomiting and diarrhea. No data were found on biochemical changes and limited data were provided on histopathological effects. Infants appear to be particularly susceptible to boron toxicity, possibly due to the fact that their detoxifying enzyme systems are immature and there is greater gastrointestinal absorption. No studies were located in animals regarding gastrointestinal effects following boron exposure. 29 2. HEALTH EFFECTS Hepatic Effects. No adverse hepatic effects have been reported in humans or animals following inhalation or dermal exposure to boron or boron compounds. Acute oral exposure in humans caused congestion, fatty changes, and parenchymatous degeneration (Wong et a1. 1964). No data were available on biochemical changes. It is not clear how boron affects the liver; however, limited animal data suggest impaired electron transfer and macrometabolism. In studies with rats, boron interfered with flavin metabolism in flavoprotein- dependent pathways (Settimi et a1. 1982). It is not clear if similar effects will occur in humans. Renal Effects. No adverse renal effects have been reported in humans or animals following inhalation of boron oxide, boric acid dust, or boron oxide aerosol. Similarly, dermal exposure to boric acid in humans or animals did not adversely affect the kidneys. Renal tubular damage has been observed, and there was reduced urine output in infants who consumed 505 mg boron/kg in infant formula for 3-5 days (Wong et al. 1964). Since renal effects occurred in only a few cases and there is no confirming evidence in animals, the potential for boron to cause renal effects cannot be conclusively established. Dermal/Ocular Effects. Human occupational exposure to boron oxide and boric acid dusts in workplace air irritated the eyes (Garabrant et a1. 1984). Ingestion of large amounts of boron (505 mg boron/kg as boric acid) caused extensive exfoliative dermatitis in humans (Wong et a1. 1964). The application of boric acid on the forearm of human subjects did not affect the skin (Draize and Kelley 1959). Rabbits developed erythema when boron oxide dust was applied to the skin and conjunctivitis was observed following contact with boron oxide dust (Wilding et al. 1959). Immunological Effects. No studies were located regarding the effects of boron on the immune system in humans or animals after inhalation, oral, or dermal exposure. In the absence of effects on target organs and direct tests on immune function, the potential for boron to cause immunological effects in humans cannot be conclusively evaluated. Neurological Effects. No adverse neurological effects have been observed in humans or animals following inhalation or dermal exposure. Acute and intermediate oral exposures to boron and boron compounds caused various neurological responses in humans. Degenerative changes in brain neurons which may have been an agonal effect were reported in one infant who consumed 505 mg boron/kg as boric acid for 3 days (Wong et al. 1964). At a higher dose (765 mg boron/kg), there was extensive vascular congestion, widespread perivascular hemorrhage, and intravascular thrombosis in another infant who ingested infant formula containing boric acid for 5 days (Wong et al. 1964). Biochemical changes have also been found. Cerebral succinate dehydrogenase activity was increased in rats that ingested borate in drinking water for 10-14 weeks, suggesting alteration in electron-transfer in the mitochondrial respiratory chain (Settimi et al. 1982). Increased RNA concentration and increased acid proteinase activity in the brain also occurred (Settimi et al. 1982). Altered metabolism and brain tissue redox state suggest changes in protein metabolism. 3O 2. HEALTH EFFECTS Based on these considerations, neurological damage is an area of concern following exposure to boron at toxic levels. Developmental Effects. Developmental changes in rats and mice have been observed in offspring of dams exposed to 28.4 mg boron/kg/day and 175.3 mg boron/kg/day, respectively (Heindel et a1. 1991). These effects have been observed at dose levels in the same range as those producing changes in spermatogenesis. No epidemiological studies were located regarding the effects of boron on the developing fetus. Although human data are lacking and there are no direct quantitative studies regarding placental transfer of boron, positive responses in two animal species suggest that developmental toxicity may be an area of concern in humans following exposure to boron. The LOAEL value of 13.6 mg boron/kg/day (Heindel et a1. 1991) was used to calculate an intermediate oral MRL of 0.01 mg/kg/day as described in the footnote in Table 2-2. Reproductive Effects. A study of 28 male workers exposed to borate aerosols during the production of boric acid revealed low sperm counts in six of these workers (Tarasenko et a1. 1972). The authors reported exposure concentrations ranging from 22 to 80 mg/m3. The overall reliability of these data is reduced due to the small study group. It should also be noted that low sperm count is a naturally occurring phenomenon. No studies were located regarding reproductive effects in humans after oral or dermal exposure. In animals, boron affects gonads in dogs, rats, and mice. The testes are particularly susceptible after intermediate ingestion (44 and 29 mg boron/kg/day, respectively) (Seal and Weeth 1980; Weir and Fisher 1972). Following chronic oral exposure, no effects were observed at a dose of 8.75 mg boron/kg/day (Weir and Fisher 1972). In spite of the absence of reliable human data, limited evidence of reproductive effects in animals suggest that reproductive toxicity may be an area of concern following boron exposure in humans. Genotoxic Effects. No studies were located regarding genotoxic effects of boron by inhalation, oral, or dermal exposure in humans and animals. Results were negative in bacterial assays and in the in vitro (Table 2-4) mammalian assays, including tests for chromosomal aberrations and gene mutation. Existing data suggest that genotoxicity is not an area of concern following exposure to boron in humans. Cancer. No epidemiological studies were located associating cancer and boron exposure. In mice fed boron (as boric acid) for 103 weeks, the number of tumors observed did not differ significantly from untreated control levels (NTP 1987). In the absence of human data and studies from other animal species, and the lack of evidence of mutagenic activity, the carcinogenic potential of boron in humans cannot be determined conclusively. 31 HEALTH EFFECTS 2. uasnuu u>auamon I A nmoa ha: I I coduuuuonq aqEOnOEouSU hua>o hounENJ onodusu hood maz n . noduuuse 0:00 uEOSQEhH onsoz unaauo :aaanEEd: 3: «2.2 I n c0332: ucou adduDEEmNu .m Hnma .Aq uo ovuoEun u u Goduuusfi 0:00 «400 Nazcauononm amma .aa uo cannon u u acauause vcou Esauseasmuu .m nmou .Hn uo £uuo>um u u Goduuusfi 0:00 ESauJEan u afiaocoefinm nnEnacawno caucuuuxoum «vacuums: couuu>auua neuun>uuoq ucuon van AEounhn unouv noauunm uaonua3 Ava: unannou ouuub an Hanan Ho huuodnouaauo .clu n4n .ocoonncnm .oooooahnm cocoonnnom mum—Hm zmon uauoouncna nunnqnconz Nuomunona ‘muuanoaan snunuuuz m5 0 I "nuuaEzc M O O O acauaguducovm 093.. m o\ /n_v _ m__ M _ m 72: / / \ a a m \ /o\ /o\ /0 IO OI O vanaoaaaan yw uoz nonzuuaun 1.0.2:qu 3:: .6532 6a.: 6:. n 1258 1355 Quiz. oz nuav oz nulv oz .35. oz 081: 0—".an nonzaon Sac—Sn “Jun oanononuuo ovaxouuu—Suonav ”ouuuvhnaoov Ramon Slu- UAUMHOQ "uni—PAL:- UAHOQ Iuav oz ngcochm xnaom vauu canon uvqno coho: canon oaunuuuuuannnu 31.50900 1:. done: an hazy—.0“; #1043 .AIM NASH 43 CHEMICAL AND PHYSICAL INFORMATION 3. noodaunnam aauqfiosu uo nuuowwu catch mo huunuuum I wumhm Eounzm auun nonaunann< anUaC£OOHxnaaauuunz naounuuum vac duo I mocu I uvw nuuauunn< HaUuE0£U I m mumhz zmomz ~-so-~no~ .-nn-ca~od e-oo-non~ uuundoox mm ovuMOSawanu canon ovAEOMAauu canon n30hfih£fl4 .quon Daunauouuannso Avoflldufloov HIM Mdn:ou nuaEau huaaupnfllizm uouonsnuah unauuuonaou CoauaCUuoua< unduncoo >Ia n.5hoam unannoum nono> an .3 nou1>\qo:duuo uoq ”unavauawwoou Goduuuuom nuco>~on cacauuo o.o u. 4‘» H.o~ .on u. qzu n.no .uuuaa yo: no ofipagom «amazonuH usu.: "nuafianaaom IuIv oz Iuav oz iuuv oz lu-v oz na< Iuov oz ouov oz nuov oz Iuov oz Maui: ”UHOSHOMn—U hog unnOAMOB annflauog .u‘fi 02 IUIV 02 M08 n5.” com” a. nna.H u<.N .n.~ u.o~ u. hudncon uooun .337 9.2: 64.5. 6.83 9.22 £53 9:33 coco gwmm- .oens «on: cu nu fl«u.mou cowacna o.oom~ union nadugu: vuaom vazom oaaom vaaom uuaun Aquanhnm nuUaanou nnOHNOAoU anoauoaou nioun uo xuuum neaou hm.Hmn mm.Ho uw.ao “9.0“ unmaou undauodoz Knuon vans canon ov«xo canon :ouom huuonoum auvasonlou and nouon Ho nuuuuumouh aIOuIGJU 1:! alouahdh .Nln NAn€°0 nuueda uuudannanadm undonnnlah uuauauonfiou noduuCuaou5< ucaunuoo idH n.5ucuz unannoum non¢> xx no; uoua>\aocduoo noq ”nuCOuoaumooo couuuuuum nuau>a0n can-duo chN u. 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X \W ax. aflfigmw it... .38 .8». .18 :3: 0.2058 53335:: .l'u‘ll mm ..................... ooooooooooooooooooooooooooooooooooooooo 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 (Rst) for lifetime exposure. To derive an MRL, ATSDR generally selects the end point which, in its best judgement, represents the most sensitive human health effect for a given exposure route and duration. ATSDR cannot make this judgement or derive an MRL unless information (quantitative or qualitative) is available for all potential effects (e.g., systemic, neurological, and developmental). In order to compare NOAELs and LOAELS for specific end points, all inhalation exposure levels are adjusted for 24hr exposures and all intermittent exposures for inhalation and oral routes of intermediate and chronic duration are adjusted for continous exposure (i.e., 7 days/week). If the information and reliable quantitative data on the chosen end point are available, ATSDR derives an MRL using the most sensitive species (when information from multiple species is available) with the highest NOAEL that does not exceed any adverse effect levels. The NOAEL is the most suitable end point for deriving an MRL. When a NOAEL is not available, a Less Serious LOAEL can be used to derive an MRL, and an uncertainty factor (UF) of 10 is employed. MRLs are not derived from Serious LOAELs. Additional uncertainty factors of 10 each are used for human variability to protect sensitive subpopulations (people who are most susceptible to the health effects caused by the substance) and for interspecies variability (extrapolation from animals to humans). In deriving an MRL, these individual uncertainty factors are multiplied together. The product is then divided into the adjusted inhalation concentration or oral dosage selected from the study. Uncertainty factors used in developing a substance-specific MRL are provided in the footnotes of the LSE Tables. ACGIH ADME ATSDR BCF BSC CDC CEL CERCLA CFR CLP cm CNS DHEW DHHS DOL ECG EEG EPA EKG FAO FEMA FIFRA fpm ft GC HPLC hr IDLH IARC ILO in Kd kg Koc Kow LC LCLo LC50 Lo LDSO LOAEL LSE B-l APPENDIX B ACRONYMS, ABBREVIATIONS, AND SYMBOLS USED IN TEXT 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 Levels of Significant Exposure meter mg min mL mm mmol mppcf MRL MS NIEHS NIOSH NIOSHTIC nm “8 NHANES nmol NOAEL NOES NOHS NPL NRC NTIS NTP OSHA PEL P8 pmol PHS PMR ppb PPm PPt REL RfD RTECS sec SCE SIC SMR STEL STORET TLV TSCA TRI TWA U.S. UF WHO > 2 3-2 APPENDIX B milligram minute milliliter millimeters millimole millions of particles per cubic foot Minimal Risk Level mass spectroscopy National Institute of Environmental Health Sciences National Institute for Occupational Safety and Health NIOSH's Computerized Information Retrieval System nanometer nanogram National Health and Nutrition Examination Survey nanomole no-observed-adverse-effect level National Occupational Exposure Survey National Occupational Hazard Survey National Priorities List National Research Council National Technical Information Service National Toxicology Program Occupational Safety and Health Administration permissible exposure limit picogram picomole Public Health Service proportional mortality ratio parts per billion parts per million parts per trillion recommended exposure limit Reference Dose Registry of Toxic Effects of Chemical Substances second sister chromatid exchange Standard Industrial Classification standard mortality ratio short-term exposure limit STORAGE and RETRIEVAL threshold limit value Toxic Substances Control Act Toxic Release Inventory time-weighted average United States uncertainty factor World Health Organization greater than greater than or equal to QM‘QDdPIAAI 1‘: (NE equal to less than less than or equal to percent alpha beta delta gamma micron microgram B-3 APPENDIX B C-l APPENDIX C PEER REVIEW A peer review panel was assembled for boron. The panel consisted of the following members: Dr. Rajender Abraham, a private consultant; Dr. Hugh Evans, Associate Professor of Chemistry, Institute of Environmental Medicine, New York Unversity Medical Center; Dr. Ernest Foulkes, Director, Department of Environmental Health, University of Cincinnati; and Dr. William Buck, Professor of Toxicology, College of Veterinary Medicine, University of Illinois. These experts collectively have knowledge of boron's physical and chemical properties, toxicokinetics, key health end points, mechanisms of action, human and animal exposure, and quantification of risk to humans. A second panel of reviewers was assembled to review the sections on mitigation of effects. This panel consisted of: Dr. Brent Burton, Medical Director, Oregon Poison Center, Oregon Health Sciences University, Portland, Oregon; Dr. Alan Hall, Private Consultant, Evergreen, Colorado; and Dr. Alan Woolf, Director of Clinical Pharmacology and Toxicology, Massachusetts Poison Control System, The Children's Hospital, Boston, Massachusetts. All reviewers were selected in conformity with the conditions for peer review specified in the Comprehensive Environmental Response, Compensation, and Liability Act of 1986, Section 104. Scientists from the Agency for Toxic Substances and Disease Registry (ATSDR) have reviewed the peer reviewers' comments and determined which comments will be included in the profile. A listing of the peer reviewers’ comments not incorporated in the profile, with a brief explanation of the rationale for their exclusion, exists as part of the administrative record for this compound. A list of databases reviewed and a list of unpublished documents cited are also included in the administrative record. The citation of the peer review panel should not be understood to imply its approval of the profile’s final content. The responsibility for the content of this profile lies with the ATSDR. Us. Government Priming Office: 1992 — 623-281 m HEALTH UBRARV W II 1952 W" "7"???" 44“ =—-— __.—_q_._—‘_._ . aw" ll“ .C. BERKELEY LIBRARIES cnfisunaua