------- DISCLAIMER This report 1s an external draft for review purposes only and does not constitute Agency policy. Mention of "trade names or commercial products does not constitute endorsement or recommendation for use. 11 ------- PREFACE Health and Environmental Effects Documents (HEEDs) are prepared for the Office of Solid Waste and Emergency Response (OSWER). This document series Is Intended to support listings under the Resource Conservation and Recovery Act (RCRA) as well as to provide health-related limits and goals for emer- gency and remedial actions under the Comprehensive Environmental Response, Compensation and Liability Act (CERCLA). Both published literature and Information obtained for Agency Program Office files are evaluated as they pertain to potential human health, aquatic life and environmental effects of hazardous waste constituents. The literature searched for In this document and the dates searched are Included In "Appendix: Literature Searched." -Literature search material Is current up to 8 months previous to the final draft date listed on the front cover. Final draft document dates (front cover) reflect the date the document Is sent to the Program Officer (OSWER). Several quantitative estimates are presented provided sufficient data are available. For systemic toxicants, these Include Reference doses (RfOs) for chronic and subchronlc exposures for both the Inhalation and oral exposures. The subchronlc or partial lifetime RfD 1s an estimate of an exposure level that would not be expected to cause adverse effects when exposure occurs during a limited time Interval I.e., for an Interval that does not constitute a significant portion of the Hfespan. This type of exposure estimate has not been extensively used, or rigorously defined as-^ previous risk assessment efforts have focused primarily on lifetime exposure scenarios.. Animal data used for subchronlc estimates generally reflect exposure durations of 30-90 days. The general methodology for estimating subchronlc RfDs Is the same as traditionally employed for chronic estimates. except that subchronlc data are utilized when available. In the case of suspected carcinogens, RfDs are not estimated. Instead, a carcinogenic potency factor, or q-|* (U.S. EPA, 1980), Is provided. These potency estimates are derived for both oral and Inhalation exposures where possible. In addition, unit risk estimates for air and drinking water are presented based on Inhalation and oral data, respectively. Reportable quantities (RQs) based on both chronic toxlclty and cardno- genlclty are derived. The RQ 1s used to determine the quantity of a hazard- ous substance for which notification 1s required 1n the event of a release as specified under the Comprehensive Environmental Response, Compensation and Liability Act (CERCLA). These two RQs (chronic toxldty and carclno- genldty) represent two of six scores developed (the remaining four reflect IgnltabllUy, reactivity, aquatic toxlclty, and acute mammalian toxlclty). Chemical-specific RQs reflect the lowest of these six primary criteria. The methodology for chronic toxlclty and cancer based RQs are defined In U.S. EPA, 1984 and 1986a, respectively. 111 ------- EXECUTIVE SUMMARY Formic add 1s a colorless liquid at room temperature (Hawley, 1981). It Is a strong reducing agent, and may react as both an add and an aldehyde (Wagner, 1980). Formic acid Is produced as a coproduct during the manufac- ture of acetic add from the liquid-phase oxidation of butane (CMR, 1984). Celanese Corp In Pampa, TX, which has the capacity Jtp produce 25 million - ' t "" . , pounds/year of the refined product. Is the only current domestic manufac- turer of formic add. Union Carbide In Brownsville, TX, has a plant with a capacity of 60 million pounds/year that Is presently Idle; the company supplies this compound In the United States through Imports (CMR, 1984). Common uses for formic acid have been Identified as textile dyeing and finishing, Pharmaceuticals, rubber Intermediate, leather and tanning" treatment,-catalysts, and others [Including oil well acidizing (CMR, 1984)]. In the atmosphere, formic add Is expected to be removed by reaction with photochemlcally generated hydroxyl radicals and by wet deposition. Based on experimental data, the half-life for reaction with hydroxyl radicals was estimated to range between 29 and 50 days (Atkinson 1985). In water, blodegradatlon screening studies Indicate that formic add would blodegrade readily to CO- under aerobic conditions and to CO. and CH. under anaerobic conditions (P1ne, 1958; Flna et al., 1960). Numerous bio- degradation studies have been performed using standard BOO dilution water; 5-day BOO values ranging from 4.3-77.6% BOOT have been measured (Gaffney and Ingols, 1961; Heukeleklan and Rand, 1955; Price et al., 1974; Takemoto et al., 1981; Malaney and Gerhold, 1969; Placak and Ruchhoft, 1947). Chemical hydrolysis, oxidation, volatilization and adsorption to suspended solids and 1v ------- sediments are not expected to be significant fate processes In water. In soil, formic acid Is expected to be mobile. B1odegradat1on under aerobic and anaerobic conditions should be a significant fate process. ** - Formic acid has been Identified In surface water, sediment, groundwater, precipitation, ambient air, some fruits and beverages, and auto exhaust. This compound has also been Identified 1n emissions from forest fires, ' **-..' ' : ' dlesel fuel combustion, lacquer manufacturers, plastics combustion, refuse combustion', tobacco smoke and vegetation (Graedel, 1978; Graedel et al., 1986). Formic add Is a major constituent of precipitation In both urban and remote areas of the world, the combination of acetic and formic adds can constitute as much as 59% (w/v) of free add present 1n remote areas (Chapman et al., 1986). The mean concentration of formic add In unflltered samples of precipitation collected from sites 1n Wisconsin, Virginia and » Illinois was 0.78, 0.64 and 0.21 mg/l, respectively (Chapman et al., 1986; Keene and Galloway, 1984; Bachman and Peden, 1987). Unflltered rain samples collected from remote areas of the South Indian Ocean, Venezuela and Australia have been found to contain formic add at concentrations ranging from undetectable to 0.98 mg/l (Mazurek and S1mone1t, 1986). At various locations In California, the average and maximum concentrations of formic acid 1n ambient air by year are as follows: 1976 - 2 and 7 ppb, respec- tively; 1977 - 5 and 13 ppb, respectively; 1978 - 6 and 19 ppb, respec- tively; and 1980 - 4 and 10 ppb, respectively (Altshuller, 1983). Formic add has also been measured at several sites In the rural southwest United States at concentrations ranging between a few tenths of a ppb and 3.5 ppb (Altshuller, 1983). No data are available regarding the occurrence of formic add In drinking water. ------- Formic add occurs naturally In some fruits, vegetables, and leaves and roots of plants (Wagner, 1980). The natural level of formic add 1n various food and beverages such as fruit, fruit Juices, coffee, evaporated milk and cheese has been found to be on the order ,of several mg/kg (U.S. FDA, 1976). Dowden and Bennett (1965) reported a 24-hour TL of 175 mg/i for "" blueglll sunflsh, Lepomls macrochlrus. exposed to formic add. The 24-hour TLm for brine shrimp, Artemla sallna. exposed to formic add was 410 mg/l (Price et al., 1974). The 4-hour LC5Q of formic add to larvae of the mosquito, Aedes aeqyptl. was 0.04X (v/v) (Kramer et al., 1983). Wlldlsh et al. (1977) reported that herring, Clupea harengus. were neither attracted nor repelled by exposure to a 1.25 mg/l solution of 88% formic acid. An estimated BCF value of 0.23 for this compound suggests that formic acid will not bloaccumulate significantly 1n aquatic organisms. Bates .and Hurlbert (1970) reported a 0.08X survival rate after 30 minutes of exposure to a 0.012 M solution of formic add at a pH of 4.5 for the flagellate, Euqlena qradlls var. baclllarls. Schafer et al. (1983) estimated an oral LD5Q of >111 mg/kg for formic acid In the redwing black- bird, Aqelalus phoenlceus. based on food consumption over an 18-hour period. Absorption of formic add occurs by way of the gastrointestinal tract. lungs, skin and urinary bladder (Schultz, 1883; Lund, 1948a). Rapid gastrointestinal absorption of formic acid has been reported In humans (Halorny, 1969a). Widespread distribution of formic add to the blood, liver, kidney, brain, heart, spleen and testes 1n rabbits and mice has been reported (LelsvouM et al., 1987; Sperling et al., 1953). Formic acid undergoes oxidation to form CO- and water (von Oettlngen, 1959). The reaction can occur In the liver, kidney, spleen, lungs. Intestinal mucosa. gastrointestinal tract (by bacteria) and blood (Battelll, 1904; Flelg, 1907; Popoff, 1875; Hoppe-Seyler, 1876). The primary site of sodium formate v1 ------- oxidation 1s the liver (Malorny, 1969b). Rabbits and rats have been found ' to metabolize large amounts of formic add, whereas dogs appear to have a dose-11m1t1ng ability to metabolize formic add (Lund, 1948a,b; Halorny, 1969b; Pohl, 1893). Excretion of formic add 1n the urine 1s highly variable among species. In man, the half-life for formic acid excretion 1s 45-46 minutes (Malorny, 1969a). : -...- « ' - -: :-' U;- ' "- " '"-' No treatment-related effects were observed 1n men-Ingesting formic add T- -»rv--V ;; H? >t ".', -. ... ' --''-; ->' ..;K- ..".- :iJ,«" . . at 8 mg/kg/day for 4 weeks (Lebbln, 1916). Levels specified only as "higher" caused local actions. Several subchronlc studies where formic add was administered to rats In their diet or drinking water have been performed \ (Sporn et al., 1962; Solmann, 1921; Flelg, 1907). Slight, but not signifi- cant, growth Inhibition occurred at 0.5% 1n the diet (Sporn et al., 1962). Decreased food Intake and growth Inhibition occurred at 360 mg/kg/day (Solmann, 1921). A series of multlgeneratlon studies of rats given calcium formate 1n their drinking water have been reported by Malorny (1969b). Slightly Increased phagocytosis In moderately Increased ret1culoendothel1al and retlculohlstlocytic subcellular components 1n the lungs, spleen and abdom- inal lymph nodes occurred In rats at 200 mg/kg/day (equivalent to 160 mg/kg/day formic add). There was no effect on reproduction. A NOEL of 160 mg/kg/day was Identified 1n these studies. A variety of effects have been reported as a result of acute oral exposure In man (Rosewarne. 1983; Jefferys and Wlsenman, 1980; Rajan et al., 1985; Huhlendahl et al., 1978; Lambeth and Somasundaram, 1970; Mallzla et al., 1977; Slgurdsson et al., 1983; Jacques, 1982). These effects Include oral, pharyngeal, esophageal and gastrointestinal burns, mortality, Internal hemorrhaglng, hematologlc and cardiovascular anomalies, renal failure, liver damage, CNS depression, pylorlc obstruction and tracheal strictures. ------- Mortality has occurred In humans at an oral exposure range of 429-643 nig/kg formic acid (Jefferys and Wiseman, 1980). In guinea pigs, Inhalation of 0.34-13.5 ppm formic add resulted In a tt * - dose-related occurrence of Impaired respiratory function (Amdur, 1960). Acute oral and Inhalation data Indicate that mice, followed by rats, are the most sensitive species to formic add poisoning. * No carcinogenic response occurred 1n a 3-generat1on drinking water study In which Wlstar rats received 200 mg/kg/day calcium formate (Halorny, 1969b). Also, dermal exposure to 8% formic add 1n mice for up to 50 days produced no evidence of carclnogenldty (Fre1 and Stephens, 1968). Positive results occurred 1n three sex-linked lethality assays using D_. melanoqaster and 1n one forward mutation assay 1n E_. coll (Stumm-Tegethoff, 1969; Demerec et al., 1951). A negative result occurred 1n a ONA Inactlva- tlon assay 1n B_. subtnis (Freese et al., 1967). Data were Insufficient to evaluate the carcinogenic potential of formic add for humans; therefore, the compound was assigned to EPA group D, not classifiable as to carclnogenldty to humans. Quantitative cancer potencies, therefore, were not estimated. Data were Inadequate to derive RfD values for either subchronlc or chronic Inhalation exposure to formic add. An RfD of 2 mg/kg/day was derived for chronic oral exposure to formic add from the NOEL of 200 mg/kg/day calcium formate (equivalent to 160 mg/kg/day formic add) 1n the multlgeneratlon reproduction study by Malorny (1969b). The chronic RfD was adopted as the RfO for subchronlc oral exposure to formic add. An RQ of 1000 pounds was derived for the chronic toxldty of formic add based on reduced survival of offspring In rats In the study by Sporn et al. (1962). ------- TABLE OF CONTENTS Page 1. INTRODUCTION 1 1.1. STRUCTURE AND CAS NUMBER .."...... ." 1 1.2. PHYSICAL AND CHEMICAL PROPERTIES 1 1.3. PRODUCTION DATA 2 1.4. USE DATA . . . . 2 . 1.5. SUMMARY 3 \ - 2. ENVIRONMENTAL FATE AND TRANSPORT .1 . ...... 4 2.1. AIR ;'.". .;'-. . . 4 2.1.1. Reaction with Hydroxyl Radicals 4 2.1.2. Physical Removal Processes 4 2.2. WATER 4 2.2.1. Hydrolysis 4 2.2.2. Oxidation ........... 4 2.2.3. Photolysis 5 2.2.4. H1crob1al Degradation 5 2.2.5. Adsorption 6 - 2.2.6. Volatilization 6 2.3. SOIL 6 2.3.1. Chemical Degradation 6 2.3.2. Mlcroblal Degradation 6 2.3.3. Adsorption 6 2.4. SUMMARY 7 3. EXPOSURE 8 3.1. WATER 8 3.2. FOOD 8 3.3. AIR 9 3.4. DERMAL 10 3.5. SUMMARY 10 4. ENVIRONMENTAL TOXICOLOGY 12 4.1. AQUATIC TOXICOLOGY 12 4.1.1. Acute Toxic Effects on Fauna 12 4.1.2. Chronic Effects on Fauna 12 4.1.3. Effects on Flora 13 4.1.4. Effects on Bacteria and Other Microorganisms. . . 13 1x ------- TABLE OF CONTENTS (cont.) Page 4.2. TERRESTRIAL TOXICOLOGY 13 4.2.1. Effects on Fauna 13 4.2.2. Effects on Flora. - . ....... 14 4.3. FIELD STUDIES 14 4.4. AQUATIC RISK ASSESSMENT 14 4.5. SUMMARY i-V-t . .-. 14 5. PHARMACOKINETCS V . / . . V . . 17 .-, 5.1. ABSORPTION ;-...-. . ''?'.*'*'l'-"^-. 17 5.2. DISTRIBUTION 17 5.3. METABOLISM 19 5.4. EXCRETION 20 5.5. SUMMARY 23 6. EFFECTS . . . . '. . 24 6.1. SYSTEMIC TOXICITY. .;. .... 24 6.1.1. Inhalation Exposure 24 6.1.2. Oral Exposure 24 - 6.1.3. Other Relevant Information 26 6.2. CARCINOGENICITY 30 6.2.1. Inhalation 30 6.2.2. :ral. 30 6.2.3. 3ther Relevant Information. . 30 6.3. MUTAGENICITY 32 6.4. TERATOGENICITY 32 6.5. OTHER REPRODUCTIVE EFFECTS 32 6.6. SUMMARY 34 7. EXISTING GUIDELINES AND STANDARDS 36 7.1. HUMAN 36 7.2. AQUATIC 36 8. RISK ASSESSMENT 37 8.1. CARCINOGENICITY 37 8.1.1. Inhalation . 37 8.1.2. Oral 37 8.1.3. Other Routes 37 8.1.4. Weight of Evidence 37 8.1.5. Quantitative Risk Estimates 38 ------- TABLE OF CONTENTS (cont.) Page 8.2. SYSTEMIC TOXICITY. . 38 8.2.1. Inhalation Exposure 38 8.2.2. Oral Exposure . . ." 38 9. REPORTABLE QUANTITIES , . 41 9.1. BASED ON SYSTEMIC TOXICITY 41 9.2. BASED ON CARCINOGENICITY ..._... 44 10. REFERENCES . . 46 APPENDIX A: LITERATURE SEARCHED 61 APPENDIX B: SUMMARY TABLE FOR FORMIC ACID 64 APPENDIX C: DATA USED TO GENERATE DOSE/DURATION - RESPONSE GRAPHS FOR ORAL EXPOSURE TO FORMIC ACID 65 x1 ------- LIST OF TABLES No. Title Page 5-1 Formic Add Concentrations In Tissue Compartments After Five Dally Intravenous Doses 18 5-2 Urinary Excretion (Percent of Dose) of Formic Add 21 6-1 Effects of Acute Exposure to Formic Add In Humans 27 6-2 Oral LDsg Data for Formic Add. 29 6-3 LDso Values for Formic Add and Us Salts In the House. . . 31 6-4 Mutagenldty Data for Formic Acid ... '."'.' 33 9-1 Oral Toxldty Summary for Formic Add and Calcium Formate . . 42 9-2 Oral Composite Scores for Formic Add and Calcium Formate . . 43 9-3 Formic Acid: Minimum Effective Dose (MED) and Reportable Quantity (RQ) 45 ------- LIST OF ABBREVIATIONS AEL BCF BOD BOOT CAS CNS CS DNA PEL GMAV GMCV GRAS Koc Kow LC50 L°50 LOAEL MED NOAEL PEL pKa ppb ppm ppt RfD RQ RV TLV TWA v/v w/v Adverse effect level 81oconcentrat1on factor Biological oxygen demand Biological oxygen"demand, theoretical Chemical Abstract Service Central nervous system Composite score Deoxyr1bonucle1c add Frank effect level Genus mean acute values Genus mean chronic values Generally recognized as safe Soil sorptlon coefficient Octanol/water partition coefficient Concentration lethal to 50% of recipients Dose lethal to SOX of recipients Lowest-observed-adverse-effect level Minimum effective dose No-observed-adverse-effect level Permissible exposure level Negative log 10 add dissociation constant Parts per billion Parts per million Part per trillion Reference dose Reportable quantity Dose-rating value Effect-rating value Median tolerance level Threshold limit value Time-weighted average Volume per volume Weight per volume X111 ------- 1. INTRODUCTION 1.1. STRUCTURE AND CAS NUMBER Formic add 1s also known as amlnlc add, formyllc add, hydrogen carboxyllc add and methanolc acid (SANSS, 1988). The structure, empirical formula, molecular weight and CAS Registry number are as follows: 0 // . HC \ OH Empirical formula: CH.O- Molecular weight: 46.0 CAS Registry number: 64-18-6 1.2. PHYSICAL AND CHEMICAL PROPERTIES Formic add Is a colorless liquid with a.pungent odor (Hawley, 1981). It Is a strong reducing agent, and may react as both an add and an aldehyde, since the carboxyl group Is bound to a hydrogen atom rather than an alkyl group (Wagner, 1980). Formic acid decomposes readily by dehydra- tion, dehydrogenatlon or through a blmolecular redox reaction: HCOOH -» H20 * CO (dehydration) HCOOH -» H2 * C02 (dehydrogenatlon) 2 HCOOH -» H20 * C02 * HCHO (redox reaction) Even at room temperature, the rate of formic add decomposition Is measur- able; however, traces of water, Including the water formed by decomposition. Inhibit the reaction (Wagner, 1980). Formic add 1s mlsdble with ethanol, ethyl ether and glycerol (Wlndholz, 1983). Relevant physical and chemical properties are as follows: Melting point: 8.48C Wagner, 1980 Boiling point: 100.7°C Wagner, 1980 0136d -1- 03/14/89 ------- Vapor pressure (20°C): 34 mm Hg Boubllk et al., 1984 Water solubility: mlsdble Wlndholz, 1983 Log Kow: -0.54 Hansch and Leo, 1985 pKa (20°C): 3.75 Weast, 1985 Density (20°C): 1.220 g/cm3 Wagner, 1980 Flashpoint, open cup: 69°C Hawley, 1981 Odor threshold: A1r: 49 ppm (v/v) Amoore .and Hautala, 1983 Water: 1700 ppm (w/v) Amoore and Hautala, 1983 1.3. PRODUCTION DATA ' Celanese Corp. In Pampa, IX, Is the only domestic manufacturer currently producing formic add on a commercial scale (SRI, 1987). This plant has the capacity to produce 25 million pounds/year of refined formic add (CMR, 1984). Union Carbide 1n Brownsville, TX, has a plant with a capacity of 6Q_ million pounds/year, which 1s currently Idle; the company markets the . compound 1n the United States using a supply arrangement with overseas producers (CMR, 1984). Formic acid 1s obtained as a coproduct during acetic add production from the liquid-phase oxidation of butane (CMR, 1984). Based on an estimated 2.5% growth rate between 1983 and 1988, the U.S. demand for formic add during 1988 was projected to be 53 million pounds / (CMR. 1984). 1.4. USE DATA Common uses for formic add have been Identified as textile dyeing and finishing, Pharmaceuticals, rubber Intermediate, leather and tanning treatment, catalysts, and others [Including oil well acidizing (CMR, 1984)]. Other applications Include use In the manufacture of formates, oxalic add, organic esters, fumlgants, Insecticides, refrigerants, solvents 0136d -2- 04/12/89 ------- for perfumes and lacquers, and vinyl resin plastldzers, use In brewing (antiseptic), silvering glass and ore flotation and use as a food additive (U.S. FDA, 1988; Hawley, 1981). ** » 1.5. SUMMARY Formic add 1s a colorless liquid at room temperature (Hawley, 1981). It Is a strong reducing agent, and may react as both an add and an aldehyde (Wagner, 1980). Formic acid Is produced as a coproduct during the manufac- ture of acetic add from the liquid-phase oxidation of butane (CMR, 1984). Celanese Corp In Pampa, TX, which has the capacity to produce 25 million pounds/year of the refined product, 1s the only current domestic manufac- V . turer of formic add. Union Carbide 1n Brownsville, TX, has a plant with a capacity of 60 million pounds/year, which Is currently Idle; the company. supplies this compound 1n the United States through Imports (CMR. T984). -^ Common used for formic add have been Identified as textile dyeing and finishing, Pharmaceuticals, rubber Intermediate, leather and tanning treatment, catalysts, and others [Including oil well acidizing (CMR, 1984)]. 0136d -3- 04/12/89 ------- 2. ENVIRONMENTAL FATE AND TRANSPORT 2.1. AIR 2.1.1. Reaction with Hydroxyl Radicals. The rate constant for the reaction of formic add vapor with photochemlcally generated hydroxyl radicals 1n the atmosphere was experimentally determined to be 0.32xlO~la to 0.545xlO'12 cm3 molecule'1 sec'1 at 25°C (Atkinson, 1985). Using this range of values and assuming an average ambient hydroxyl radical concentration of 5.0x10* molecules/cm3 (Atkinson, 1985), the hydroxyl reaction half-life of formic add was estimated to range between 29 and 50 days. 2.1.2. Physical Removal Processes.. The complete water solubility of* formic add and Us pKa value of 3.75 suggest that significant amounts of this compound or Us anlons formed 1n the aerosol may be scavenged from thff atmosphere by wet deposition. The amount of formic add occurring In the atmosphere 1n partlculate form 1s expected to be negligible because of the relatively high vapor pressure of this compound (34 mm Hg at 25°C) (Boubllk et a!., 1984; E1senre1ch et a!., 1981). As a result, dry deposition of formic add Is not expected to be a significant removal process In the atmosphere. 2.2. WATER 2.2.1. Hydrolysis. Carboxyllc adds, such as formic add. are generally resistant to chemical hydrolysis under environmental conditions (Harris, 1982). 2.2.2. Oxidation. The rate constant for reaction of formic add with photochemlcally generated hydroxyl radicals In water was experimentally determined to be 1.4xl08 M"1 sec'1 at pH 5, 2.45xlO» to S.lxlO9 M"1 sec"1 at pH 7 and 4.0xlO» M'1 sec"1 at pH 9 (Anbar and Neta, 1967; Dorfman and Adams, 1973). Assuming an average hydroxyl radical 0136d -4- 04/07/89 ------- concentration of IxlO"17 mol/i 1n natural sunlH water (Mill et al., 1980), the respective oxidation half-lives of formic add at these pH levels were estimated to be 16 years, 259-327 days and 201 days. These values *« * suggest that oxidation by reaction with photochemlcally generated hydroxyl radicals 1n water would be too slow to be an environmentally significant fate process. -.; - 2.2.3. Photolysis. The absorption spectra of formic acid Indicate that 1t will not absorb light 1n the environmentally significant range (wave- length >290 nm) (Calvert and PUts, 1966). Therefore, photolysis of this compound Is probably not a significant fate process. 2.2.4. M1crob1al Degradation. In the standard BOD dilution technique. Incubation of 40 ppm formic acid for 3, 5, 10 and 20 days resulted 1n oxygen consumption equivalent to 2.9, 14.4, 38.8 and 34.5% BOOT, respectively, when ammonia was used as the nitrogen source of nutrient, and 2.1, 4.3, 38.8 and 38.8% BOOT, respectively, when nitrate was used as the nitrogen source (Gaffney and Ingols, 1961). Heukeleklan and Rand (1955) reported that In various blodegradatlon screening studies using standard BOD dilution water, formic add had 5-day BOD values ranging between 5.8 and 77.6% BOOT. Other experimenters have studied the blodegradatlon of formic add 1n standard BOO dilution water with the following results: 50-100% BOOT In 1 day (Malaney and Gerhold, 1969); 66% BOOT In 12 hours (McKlnney et al., 1956); 39.9% BOOT 1n 22-24 hours (Placak and Ruchhoft, 1947); 48-51% BOOT 1n 5 days and 60-68% BOOT In 20 days (Price et al., 1974); 62% BOOT in 5 days and 95% BOOT In 20 days In synthetic seawater (Price et al., 1974); 40.5% BOOT In 5 days (Takemoto et al., 1981); and 51.7% BOOT In 5 days In synthetic seawater (Takemoto et al., 1981). Formic add 1s also susceptible to blodegradatlon under anaerobic conditions (Brill et al., 1964; Speece, 1983; P1ne, 1958; 0136d -5- 03/14/89 ------- Flna et al., 1960). Formic acid 1s blodegraded to carbon dioxide under aerobic conditions, and to carbon dioxide and methane under anaerobic condi- tions (P1ne, 1958; Flna et al., I960). These data suggest that blodegrada- *» * tlon would be the dominant mechanism for the removal of formic add from environmental waters. ; . , .... . ..'-' 2.2.5. Adsorption. Considering the complete water solubility of formic acid and Us estimated K value of 12 (Section 2.3.3.), physical adsorp- tion to suspended solids and sediments In water 1s not expected to be an Important fate process. 2.2.6. Volatilization. The experimentally determined Henry's Law constant for formic acid of ,1.67xlO"7 atm-mVmol at 25°C (Gaffney et al., 1987} suggests that volatilization would not be a significant removal mechanism from surface water (Thomas, 1982). 2.3. SOIL 2.3.1. Chemical Degradation. Formic acid 1s not expected to undergo chemical hydrolysis under environmental conditions (Harris, 1982). Pertinent data regarding other chemical degradation processes were not located In the available literature dted 1n Appendix A. 2.3.2. H1crob1a1 Degradation. Based on the results of blodegradatlon studies 1n aqueous systems, It appears that soil microorganisms would readily blodegrade formic acid. Microbes capable of oxidizing formic acid under aerobic and anaerobic conditions have been Isolated from soil (Kung and Wagner, 1970; Pate! et al., 1978, 1979; Harada and Nagashlma, 1975; Brown et al., 1964). 2.3.3. Adsorption. In most natural soils with pH >5.0, formic add will be present In Its anlonlc form. The sorptlon of formate Ions on soils 1s 0136d -6- 03/14/89 ------- likely to depend on the Ion-exchange property, pH and particle size of the soil. Because of their high water solubility, formate Ions may leach readily from soils. .:.:»' - - 2.4. SUMMARY tt « In the atmosphere, formic acid 1s expected to be removed by reaction with photochemically generated hydroxyl radicals and by wet deposition. Based on experimental data, the half-life for reaction with hydroxyl radicals was estimated to range between 29 and 50 days (Atkinson, 1985). In water, blodegradatlon screening studies Indicate that formic add would blodegrade readily to C0_ under aerobic conditions and to CO. and CH under anaerobic conditions (P1ne, 1958; F1na et al., 1960). Numerous bio- degradation studies have been performed using standard BOO dilution water; 5-day BOD values ranging from 4.3-77.6% BOOT have been measured (Gaffney Ingols, 1961; Heukeleklan and Rand, 1955; Price et al., 1974; Takemoto et al., 1981; Malaney and Gerhold, 1969; Placak and Ruchhoft, 1947). Chemical hydrolysis, oxidation, volatilization and adsorption to suspended solids and sediments are not expected to be significant fate processes In water. In soil, formic add Is expected to be mobile. Blodegradatlon under aerobic and anaerobic conditions should be a significant fate process. 0136d -7- 04/07/89 ------- 3. EXPOSURE 3.1. WATER Levels of formic acid 1n water samples collected from various depths In Lake Klzakl, Japan, ranged from undetectable to 30 ygC/l (Hama and Handa, 1981). Formic acid was one of the most common organic acids found 1n sediments of Lake Bowa, Japan. This compound was not found In the Inter- ~> f i ..." '4 -' w . ' - - stltlal waters of the sediment, but was found In adsorbed form In and on the sediment particles. The concentration of formic add In whole sediment samples ranged between 0.5 and 9.5 ymol/g (23-437 yg/g) wet mud (Maeda and Kawal, 1986). Groundwater near a wood-preserving facility In Pensacola, PL, contained formic add at a concentration range of undetectable to 0.97 mg/l at various depths up to 18 m. Formic add may have been a product rendered from the wood during treatment or a blodegradatlon product of the solutes of creosote (GoerlUz et al., 1985). 3.2. FOOD Formic add occurs naturally In some fruits, vegetables, and leaves and roots of plants (Wagner. 1980). The natural formic add content found In some foods and beverages Is as follows (U.S. FOA. 1976): fruits, 0.2-0.4 mg/kg; fruit Juices, 0.3-1.0 mg/kg; fruit syrups, 6.5-16.3 mg/kg; honey, 0.2-20 mg/kg; wines 0.01-3.4 mg/kg; coffee, roasted 13.5-20.0 mg/kg; evaporated milk, 0.3-0.4 mg/kg; and cheese 0.2-3.0 mg/kg. Formic acid Is used as a food additive and as a constituent of paper and paperboard used In food packaging (U.S. FOA, 1988). Data from the early.1970s Indicate that the average dally Intake (by age group) of formic add used as a food additive Is as follows: 0-5 months, 0.01 mg; 6-11 months, 0.09 mg; 12-23 months, 0.18 mg; and 2-65 years, 0.43 mg (U.S. FDA, 1976). 0136d -8- 08/15/89 ------- 3.3. AIR The formation of formic add In the atmosphere 1s due primarily to reaction of formaldehyde with free radicals (HO-, HO-») formed as a result of photochemical reactions (Altshuller, 1983; Adewuyl et al., 1984). Therefore, the concentration of formic add In the atmosphere generally will be higher In urban areas than In rural areas and during summer than during winter months. The concentration of formic acid In "Los Angeles, CA, air samples collected between July and September 1984 ranged between 0.066 and 2.98 ppb (Kawamura et al., 1985). At various locations In California, the average and maximum concentrations of formic acid In ambient air by year are as follows: 1976 - 2 and 7 ppb, respectively; 1977 - 5 and 13 ppb, respec- tively; 1978 - 6 and 19 ppb, respectively; and 1980 - 4 and 10 ppb, respec- tively (Altshuller, 1983). Formic acid has also been measured at several sites 1n the rural southwest United States. At a site northwest of Tucson, AZ. concentrations of this compound ranging between 1.5 and 3.5 ppb were reported during December., 1979 (Altshuller, 1983). At a site southeast of Tucson, AZ, concentrations between a few tenths of a ppb and 3 ppb were detected during July-August 1981 (Altshuller. 1983). A1r samples collected at two remote sites In Arizona during January-February 1980 contained -0.5-1.5 ppb (Altshuller, 1983). Atmospheric aerosol collected 0.4 and 3.5 km above a wet tropical forest In Guyana during June 1984 contained formic acid at concentrations of <0.5 and 1 ng/m3 (0.27 and .0.53 ppt), respec- tively (Gregory et al., 1986). Exhaust from a gasoline-powered automobile was found to contain 9.3 ppb formic acid (Kawamura et al., 1985). Formic acid was also Identified In emissions from forest fires, dlesel fuel combus- tion, lacquer manufacturers, plastics combustion, refuse combustion, tobacco smoke and vegetation (Graedel, 1978; Graedel et al., 1986). 0136d -9- 08/15/89 ------- Formic add has been Identified as one of the major constituents of precipitation, particularly In remote areas of the world. The combination of acetic and formic acids can constitute as much as 59% (v/w) of free acid present In remote areas. The source of'thls chemical In these locations Is probably anthropogenic (Chapman et al., 1986). , Unflltered rain samples collected from remote areas of the South Indian Ocean, Venezuela and Australia during 1980 and 1981 have been found to contain formic acid at concentrations ranging from undetectable to 0.98 mg/i (Mazurek and SlmoneH, 1986). The volume-weighted mean concentration of formic acid In precipitation collected at two sites In Wisconsin between March 15 and June 1, 1984, was 0.78 mg/8, In samples containing visible sediments and 0.44 mg/l 1n samples without sediments (Chapman et al., 1986). Keene and Galloway (1984) found levels of formic acid ranging between 0.04 and 2.16 mg/i with a volume-weighted mean of 0.64 mg/i In 16 samples collected between April 25 and October 1, 1983, at a site In central Virginia. The mean concentration of formic and acetic acids 1n precipitation collected during early spring months In central Illinois was 0.21 mg/a. (Bachman and Peden, 1987). UnfUtered precipitation collected In Los Angeles, CA, between November 1978 and April 1979 contained formic add at concentra- tions of undetectable to 0.0055 mg/l (Mazurek and SlmoneH, 1986). 3.4. DERMAL Data regarding human exposure to formic add by dermal contact were not located In the available literature cited In Appendix A. 3.5. SUMMARY Formic add has been Identified In surface water, sediment, groundwater, precipitation, ambient air, some fruits and beverages, and auto exhaust. 0136d -10- 08/15/89 ------- This compound has also been Identified In emissions from forest fires, dlesel fuel combustion, lacquer manufacturers, plastics combustion, refuse combustion, tobacco smoke and vegetation (Graedel, 1978; Graedel et al.. ** * 1986). Formic acid Is a major constituent of precipitation In both urban and remote areas of the world. The combination of acetic and formic adds can constitute as much as 59X (w/v) of free acid present In remote areas (Chapman et al., 1986). The mean concentration of formic add In unflltered samples of precipitation collected from sites 1n Wisconsin, Virginia and Illinois was 0.78, 0.64 and 0.21 mg/l, respectively (Chapman et al., 1986; Keene and Galloway. 1984; Bachman and Peden, 1987). Unflltered rain samples collected from remote areas of the South Indian Ocean, Venezuela and Australia have been found to contain formic add at concentrations ranging from undetectable to 0.98 mg/l (Mazurek and Slmonelt, 1986). At various locations In California, the average and maximum concentrations of formic acid 1n ambient air by year are as follows: 1976 - 2 and 7 ppb, respec- tively; 1977 - 5 and 13 ppb, respectively; 1978 - 6 and 19 ppb, respec- tively; and 1980 - 4 and 10 ppb, respectively (Altshuller, 1983). Formic acid has also been measured at several sites In the rural southwest United States at concentrations ranging between a few tenths of a ppb and 3.5 ppb (Altshuller, 1983). No data are available regarding the occurrence of formic add In drinking water. Formic acid occurs naturally In some fruits, vegetables, and leaves and roots of plants (Wagner, 1980). The natural level of formic add In various food and beverages such as fruit, fruit juices, coffee, evaporated milk and cheese has been found to be on the order of several mg/kg (U.S. FDA, 1976). 0136d -11- 08/15/89 ------- 4. ENVIRONMENTAL TOXICOLOGY 4.1. AQUATIC TOXICOLOGY 4.1.1. Acute Toxic Effects on Fauna. Dowden and Bennett (1965) assessed the acute toxldty of formic add to blueglll sunflsh, Lepomls macrochlrus. Tests were conducted In reconstituted water of unspecified quality at an unspecified test temperature. The Investigators reported a 24-hour TL of 175 mg/i. . _ Price et al. (1974) assessed the acute toxIcHy of formic add to brine shrimp, Artemla sallna. Brine shrimp were exposed to formic add 1n 150 ml wide-mouth bottles at 24.5°C for 24 hours. The Investigators reported a 24-hour TLm of 410 mg/l. ._,. . Kramer et al. (1983) assessed the acute toxldty of formic add to larvae of the mosquito, Aedes aegyptl. Second-third Instar larvae were exposed to formic acid In glass beakers or small jars. Larvae (10-20) were exposed to 50 ml of test solution for 4 hours at 22-24°C. The Investi- gators reported an average 4-hour LC,. of 0.04X (v/v) from the results of three trials In which the results of the separate experiments differed by less than £lOX. 4.1.2. Chronic Effects on Fauna. 4.1.2.1. TOXICITY -- Pertinent data regarding the effects of chronic exposure of aquatic fauna to formic acid were not located In the available literature cited In Appendix A. 4.1.2.2. BIOACCUHULATION/BIOCONCENTRATION No measured steady-state BCF value for formic add was found In the literature. Based on the regression equation, log BCF = 0.76 log K - 0.23 (Lyman et al., 1982) and a log KQW value of -0.54 (see Section 1.2.), a BCF value of 0.23 Is estimated for this compound. This value suggests that formic add will not bloaccumulate significantly In aquatic organisms. 0136d -12- 03/14/89 ------- 4.1.2.3. OTHER EFFECTS WUdlsh et al. (1977) assessed the prefer- ence/avoidance response of herring, Clupea harenqus. to formic add 1n sea water, and reported that herring were neither attracted nor repelled by exposure to a 1.25 mg/l solution of 88% formic add. - . . , ..j . , j 4.1.3. Effects on Flora. 4.1.3.1. TOXICITY Pertinent data regarding the toxic effects of exposure of aquatic flora to formic add were not located 1n the available ^.'-.-.. ':.- -~- .': . -V.' ' literature dted In Appendix A. 4.1.3.2. BIOCONCENTRATION Pertinent data regarding the bloconcen- tratlon potential of formic add In aquatic flora were not located In the available literature cited In Appendix A. 4.1.4. Effects on Bacteria and Other Microorganisms. Bates and Hurlbert (1970) assessed the effect of formic acid on the viability of populations of the flagellate, Euqlena gradlls var. baclllarls. Tests were conducted at 27°C 1n 100 ml of media 1n 250 ma, Ehrlenmeyer flasks. All cultures were Inoculated with cells to give an Initial concentration of 2xl03 cells/ml. Changes 1n cell mass were determined colorImetMcally using a 540 y (green) filter. The Investigators reported a 0.08% survival rate after 30 minutes of exposure to a 0.012 M solution of formic add at a pH of 4.5. 4.2. TERRESTRIAL TOXICOLOGY 4.2.1. Effects on Fauna. Schafer et al. (1983) determined the acute oral toxlclty .of formic acid to the redwing blackbird, Agelalus phoenlceus. Birds were trapped In the wild and preconditioned to captivity for 2-6 weeks before the start of testing. The Investigators estimated an oral LD5Q of >111 mg/kg for formic add based on food consumption over an 18-hour period. 0136d -13- 03/14/89 ------- 4.2.2. Effects on Flora. Pertinent data regarding the effects of , exposure of terrestrial flora to formic add were not located In the available literature cited 1n Appendix A. 4.3. FIELD STUDIES Pertinent data regarding the effects of formic add on flora and fauna 1n the field were not located In the available literature cited In Appendix A. ' 4.4. AQUATIC RISK ASSESSMENT Insufficient data regarding the effects of exposure of aquatic fauna and flora to formic add prevented the development of a freshwater criterion by the method of U.S. EPA/OWRS (1986) (Figure 4-1). Development of a criterion for formic add In freshwater will require conducting acute assays with a salmonld, a fish (other than blueglll sunflsh) or an amphibian, benthlc an3~~ planktonlc crustaceans, an Insect, a representative from a non-Chordate/ Arthropod phylum, and an Insectan family or phylum not represented previ- ously. Development of a criterion will also require conducting at least two chronic assays with fauna, one assay with an alga or vascular plant and at least one bloconcentratlon study. No data were located regarding the effects of exposure of marine fauna and flora to formic add, preventing the development of a saltwater criterion by the method of U.S. EPA/OWRS (1986). 4.5. SUMMARY Dowden and Bennett (1965) reported a 24-hour TL of 175 mg/l for blueglll sunflsh, Lepomls macrochlrus. exposed to formic add. The 24-hour TL for brine shrimp, Artemla sallna. exposed to formic add was 410 mg/l (Price et al., 1974). The 4-hour LC5Q of formic acid to larvae of the mosquito, Aedes aegyptl. was 0.04X (v/v) (Kramer et al., 1983). Wlldlsh et al. (1977) reported that herring, Clupea harenqus. were neither attracted 0136d -14- 04/07/89 ------- Fami ly *i Chordate (Salmon id-fish) tti Chordate (warmwater fish) *i Uhordate (fish or amphibian) *<* ' Crustacean (planktonic) *b Crust acear. (bentnic) fct. Inceet an t!V non-fcr t h r o pod / -Ch or d ate *£; New Insect an or phylum represent at ive '#9 al gae *iO Vascular plant TEST TYPli Acute* Nft 175- NA NP Nft Nft Nft Nft Nft Nft Chronic* Nft Nft , Nfl Nft Nft Nft Nft Nft Nft Nft BCF* Nft Nft Nft Nft Nft Nft Nft Nft Nft Nft 'S4-hou" TL- for bluegill .unfi.h Leoorni FIGURE 4-1 Organization Chart for Listing GHAVs, GMCVs and BCFs Required to Derive Numerical Water Quality Criteria by the Method of U.S. EPA/OWRS (1986) for the Protection of Freshwater Aquatic Life from Exposure to Formic Acid 0136d . -15- 04/07/89 ------- nor repelled by exposure to a 1.25 mg/i solution of 88X formic add. An estimated BCF value of 0.23 for this compound suggests that formic acid will not bloaccumulate significantly 1n aquatic organisms. Bates and Hurlbert (1970) reported a 0.08% survival rate after 30 minutes of exposure to a 0.012 M solution of formic add at a pH of 4.5 for the flagellate, Euqlena qradlls var. badllarls. . Schafer et al. (1983) estimated an oral ID... of >111 mg/kg for formic add In the redwing black- bird, Age!a1 us phoenlceus. based on food consumption over an 18-hour period. 0136d -16- 04/07/89 ------- 5. PHARMACOKINETICS 5.1. ABSORPTION Absorption of formic add by way of the gastrointestinal tract, lungs, skin and urinary bladder has been repprted 1n several mammalian species (Schultz, 1883; Lund, 1948a). In addition, rapid absorption of formic add .- :/- -:"- " J-; ' ' ' : ' ' ' ; '" .-''. ' .£?', from the gastrointestinal tract has been reported to occur In humans. '".;"-%' .".A*.'* * Malorny (1969a) measured plasma levels of formic add of 11.8 mg/100 ml at '".'"> 10 minutes'after administration of a 4.44 g dose of sodium formate to a vli^t human, von Oettlngen (1959) speculated that some formic add may undergo m1crob1al degradation before absorption can occur. 5.2. DISTRIBUTION . . ;- . Single dally doses of 100 mg/kg formic add, buffered to pH 7.4, were ,.; -administered Intravenously to 15 male New Zealand rabbits on 4 consecutlve'- days, followed by Intravenous administration. of 100 mg/kg l4C-form1c add on the 5th day (L1es1vuor1 et al., 1987). Formic add and 14C-formate were distributed by the blood to the brain, heart, liver, kidney and urine (Table 5-1). Peak concentrations In all compartments occurred within the first hour, except that peak concentrations In the brain occurred at 2 hours, suggesting that the blood-brain barrier slowed passage to this organ. Highest tissue levels of radlolabel were located In the liver and kidney, highly perfused organs of metabolism and excretion. Concentrations In the urine were higher than 1n any of the tissues. Sperling et al. (1953) reported that when 14C-labeled sodium formate was given by Intraperltoneal Injection to large Osborne-Hendel rats, the majority of the dose not excreted In the urine (-20%) was concentrated In the fat and/or protein fractions of the testes, lungs, spleen, heart, liver, stomach and kidneys. In this study, the highest concentrations of 14C-formate were found 1n the protein of the stomach and liver. 0136d -17- 04/07/89 ------- TABLE 5'-l Formic Acid Concentrations 1n Tissue Compartments After Five Dally . : ...Intravenous Doses* : ... -: a !ij i .-..:., Tissue Compartment Blood T Brain Heart Liver Kidney Urine ~ Time After the Fifth Dose (hours) 1 2 ,20 . -r -1 '->- : 2 20 ' 1 2 20 1 2 20 1 2 20 1 2 20 Total (vmol/g) 0.7*0.4 0.5>0.2 0.2*0.1; --1.1*0.4 1.3*0.6 . 0.7*0.4 0.8*0.3 0.7*0.3 0.5*0.2 1.5*0.5 1.1*0.4 0.3*0.05 1.7*0.7 1.0T0.6 0.4*0.1 44*22 32*~12 0.6*0.2 . - ... . 14C-Labeled (wmol/g) 0.3*0.1 0.2*0.1 0.1*0.05 0.4*0.2 "-'' 0.6T0.3 O.U0.05 0.6*0.3 0.4*0.2 O.H0.05 0.9*0.5 0.7*0.4 0.2*.0.05 0.8*0.5 0.7*0.2 0.2*.0.05 27*12 25*8 0.1*0.01 t .. Difference 0.4*0.1 0.2T0.1 ; 0.2*.0.05 ;:" 0.4*0. 2 - 0.5*0.2 0.4*0.1 0.6*0.2 0.3*0.1 0.3*0.1 0.4*0.2 0.5*0.2 O.U0.05 0.6*0.4 0.8*0.4 0.2*0.05 17f8 9*"6 o.sTo.i *Source: L1es1vuor1 et al., 1987 0136d -18- 04/07/89 ------- 5.3. METABOLISM Formic add 1s an endogenous compound Important 1n Intermediary metabo- lism (U.S. EPA, 1985). Upon absorption, formic add Is Immediately trans- formed Into formate (Malorny, 1969a). ..Although some formate 1s excreted unaltered, It Is also oxidized to form carbon dioxide and water (von Oettlngen, 19S9). Retained formate Is Incorporated Into proteins, I1p1ds and nucleic adds (Tracor-JUco, 1974). Oxidation of formate has been demonstrated \n_ vitro 1n liver, kidney, lung, spleen, Intestinal mucosa and In blood extracts (BatteTM, 1904; Flelg, 1907). Formic add has also been shown to be decomposed by bacteria 1n the gastrointestinal tract (Popoff, 1875; Hoppe-Seyler, 1876). At least 1n rat liver and Jejunum, formate oxidation Involves a catalase-hydrogen peroxide complex and enzymes such as xahthlne oxldase, uHcase, monoamlne oxldase and D-amlno add oxldase (Orcr~ and Rappoport, 1959). A study using rabbits Indicates that the liver appears to be the primary site of formate oxidation (Malorny. 1969b). The half-lives of formate (presumably administered Intravenously) In rabbits with excised livers vs. Intact rabbits were 130 and 25 minutes, respectively. Rabbits were found to oxidize large doses of formic add (Lund, 1948b; Bastrup, 1947). Dogs can oxidize completely only small doses of formic add (0.143 g/kg), and larger doses are excreted partially unchanged (Pohl, 1893; Grehant and Qulnquaud, 1887). Also, man can completely metabolize only limited doses of formic add; unaltered formic add Is excreted In the urine (Autenrleth, 1919; Welngarten, 1932). Malorny (1969b) reported biological half-lives of formic add following Intravenous Injection as follows: dog, 77 minutes; cat, 67 minutes; rabbit, 32 minutes; guinea pigs, 22 minutes; rats, 12 minutes. Malorny (1969b) generalized that the more rapid oxidation of formic acid by herbivores compared with 0136d -19- 04/07/89 ------- carnivores may reflect a greater supply of follc add 1n herbivores. Follc acid antagonists such as methotrexate Inhibited formic add oxidation. L1es1vuor1 et al. (1987) stated that the rat 1s a poor model for formic acid toxldty 1n humans because rats metabolize formic add through the follc *« * - acid cycle more efficiently than humans. They suggest that rabbits and dogs behave more closely to humans 1n this regard. . ,'; , When administered orally, the amount of Ingesta present In the gastro- intestinal tract and the concentration of the test material, as well as the magnitude of the dose, play a role In determining the rate of oxidation of formic add (von Oettlngen, 1959). 5.4. EXCRETION ,, Several studies that measured urinary excretion of" formic add In rabbits, rats, dogs and man are summarized In Table 5-2. The extent urlnary excretion of formic acid Is highly variable both within and between species, but appears to be generally dose-dependent 1n oral studies. Urinary excretion was -4 times higher In rats given a dose of 185 mg/day compared with rats given 19 mg sodium formate (Malorny, 1969b). Sperling et al. (1953), however, found little variation In urinary excretion 1n large male Osborne-Hendel rats given Intraperltoneal Injections of ~2 or 5 mg/kg / radlolabeled formate. Over an 8-day collection period, these rats excreted -82% of the Injected dose of radioactivity as expired 14C02 and -1.4% 1n the feces. The total radioactivity excreted averaged 88% of the dose; -78% of the dose was excreted within the first 24 hours. The Investigators estimated a half-life of ~7 days for radioactivity not excreted within the first 24 hours. 0136d -20- 04/07/89 ------- TABLF. 5-2 Urinary Excretion (Percent of Dose) of Formic Acid 0 o. Species/Strain Compound Route Oog/NR NR oral NR oral NR oral sodium Intravenous formate 7* sodium subcutaneous formate Rabbi t/NR NR oral sodium subcutaneous formate Rat calcium oral formate sodium oral formate Rat/Osborne- Na-14C- Intraper Honeal o Hendcl formate > -v Dose Percent of Dose 20 g 26 5 g 65 1 g 8-9 4 g 55 198 mg/kg 42 1 g/kg 14.2-19.3 303-317 mg/kg 2-8 185.4 ing/day 13.8 I -19 mg/day 3 NR 5.3 Reference Schotten, 1883 Grehant and Qulnquaud. 1887 Epplnger, 1913 Grehant and Qulnquaud, 1887 Lund, 1948a Epplnger, 1913 Lund, ]948b Nalorny, 1969b Malorny, 1969b Sperling et al., 1953 o - ' d ^ oo ------- TABLE 5-2 (cont.) CJ cr OL. Species/Strain Human Compound Route sodium oral formate sodium Intravenous formate Dose Percent of Dose 20 g 18 4 g 25-50 ' Reference Autenrleth, 1919 Uelngarten, 1932 NR = Not reported to I to us ------- 5.5. SUMMARY Absorption of formic add occurs by way of the gastrointestinal tract. lungs, skin and urinary bladder (Schultz, 1883; Lund, 1948a). Rapid gastro- intestinal absorption of formic add has been reported In humans (Malorny, 1969a). Widespread distribution of formic add to the blood, liver, kidney, brain, heart, spleen and testes 1n rabbits and mice has been reported (LelsvouM et al., 1987; Sperling et al., 1953). Formic add undergoes oxidation :to form, CO. and water (von Oettlngen, 1959).. The reaction can .occur In the liver, kidney, spleen, lungs. Intestinal mucosa, gastrointes- tinal tract (by bacteria) and blood (Battelll, 1904; Flelg, 1907; Popoff, 1875; Hoppe-SeyTer, 1876). The primary site of sodium formate oxidation Is the liver (Malorny, 1969b). Rabbits and rats have been found to metabolize .large amounts of formic add, whereas dogs appear to have a dose-Umltlng^- abllUy to metabolize formic acid (Lund, 1948a,b; Malorny, 1969b; Pohl, 1893). Excretion of formic add In the urine Is highly variable among species. In man, the half-life for formic add excretion Is 45-46 minutes (Malorny, 1969a). 0136d -23- 04/07/89 ------- 6. EFFECTS 6.1. SYSTEMIC TOXICITY 6.1.1. Inhalation Exposure. Completed studies regarding the subchronlc and chronic toxlclty of formic add as a result of Inhalation exposure were *» » not located; however, a subchronlc Inhalatton study of formic acid In rats and mice Is being conducted (NTP, 1988). ' ' 6.1.2. Oral Exposure. : ' ,". :-. 6.1.2.1. SUBCHRONIC No treatment-related effects occurred In an unspecified number of men given -8 mg/kg/day of formic add dally 1n lemonade for 4 weeks (Lebbln, 1916). At doses specified as "higher" than the Initial dose, however, "local actions" (presumably the effects of an acid Irritation) were observed. The duration of exposure at the higher dose was not specified. - " Groups of eight rats (sex and strain were not specified) were given casein-based diets containing 0.5 or 1.0% formic acid for 5-6 weeks to determine effects on growth and protein efficiency (Sporn et al., 1962). Control rats received basal diet without added formic add. Slight growth Inhibition was reported In both treated groups, but the extent was not statistically significant. Solmann (1921) administered formic acid In drinking water to groups of 3-6 rats at concentrations of 0.01, 0.01 and 0.1% for 11, 14 and 15 weeks, respectively. Additional groups were given 0.25X for 15 weeks (after 12 weeks at 0.01%) and 0.5% for 9 weeks (after 17 weeks at 0.1%). The use of controls was not reported. Variables measured Included food and water consumption and growth rate. Dosages estimated by the Investigators were 0136d -24- 04/07/89 ------- 8.1-10.25 mg/kg/day at 0.01X, 90.0 mg/kg/day at 0.1X, 160.0 mg/kg/day at 0.25X and 360 rag/kg/day at 0.5X. No effects were reported at 0.01-0.25X. At 0.5X, both food consumption and growth rate were depressed. Sporn et al. (1962) administered formic acid 1n drinking water at 0 or IX to 10 male and 50 female white rats grouped as follows: group I - untreated controls; group II - females on formic add throughout the experi- ment; group III - males on formic add throughout the.experiment; group IV - males and females on formic add throughout the experiment; group V - females on formic acid during lactation. Endpolnts evaluated were restricted to reproductive performance, hematologyi-^ver nitrogen content and adrenal ascorbic add content. Evaluations were conducted after 1, 3 and 7 months of exposure. The most significant observation was a marked reduction In survival of offspring on postpartum day 7 1n groups II, III and IV; however, survival data were not analyzed statistically (Section 6.5.). Hyperchromic anemia, basophlllc neutropenla, slight lymphocytosls and leuckocytosls were also observed 1n rats exposed to formic add. 6.1.2.2. CHRONIC The chronic oral toxldty of formic acid was Investigated over five generations (3 years) In Wlstar rats (Malorny, 1969b). The first generation consisted of 8 male and 24 female test rats and 8 control rats. The test rats received 0.2X (150-200 mg/kg/day, as determined by the author) calcium formate In their drinking water throughout the study. No treatment-related effects on reproduction, growth or organ function (not specified) were reported. Hlstopathologlc examination revealed slightly Increased phagocytosis In moderately Increased retlculo- endothellal and retlculohlstlocytlc elements In the lungs, spleen and abdominal lymph nodes; however, no tox1colog1cally significant effects could be attributed to chronic administration of calcium formate. 0136d -25- 08/15/89 ------- This study was repeated with a drinking water concentration of 0.4% , (300-400 rag/kg/day, as estimated by the author) calcium formate for two generations over 2 years (Malorny, 1969b). Hlstopathologlc examination of unspecified tissues revealed no treatment-related effects. 6.1.3. Other Relevant Information. Solmann (1921) reported that no effects occurred In men given 150 mg/kg/day for "some time.* Stern (1906) reported that vertigo, nausea, vomiting, albumlnurla, tenesmus, dyspnea and hypothermia occurred In men taking 2000-3000 mg formic acid several times/ day. The duration of exposure was not specified. Data regarding acute oral exposures of humans to mixtures containing formic add (for example, descaling compounds) are summarized In Table 6-1. Oral, pharyngeal, esophageal and gastrointestinal alteration and perforation are commonly reported effects of oral exposure to formic add. Additional effects'" Include mortality, Internal hemorrhaglng, hemolysls, hematologlc and cardiovascular effects, altered blood chemistry, metabolic addosls, renal failure, liver toxldty, CNS depression, pyloMc obstruction and tracheal strictures. One of six people died after Ingesting 30-45 g (429-643 mg/kg) of formic add; this level has been Identified as the threshold for mortality (Jefferys and Wiseman, 1980). Further, 14/16 humans died after Ingesting 45-200 g (643-2847 mg/kg) of formic add, and Jefferys and Wiseman (1980) concluded that consumption of 60 g (851 mg/kg) resulted 1n death In all cases. Dose-related Impaired respiratory function occurred 1n guinea pigs during 1-hour Inhalation exposures to 0.34-13.5 ppm formic add (Amdur, 1960). In addition, the Irritant effects of formic acid were found to be more potent than those of formaldehyde. Oral LDcQ values for formic add In dogs, rats, mice and rabbits are presented 1n Table 6-2. Mice, followed by rats, appear to be the most 0136d -26- 04/07/89 ------- o CO 0. TABLE 6-1 Effects of Acute Exposure to Formic Acid In Humans Route Age/Number/Sex Exposure Response Reference Oral 52 years/1/F NR/16/NR o -J \ CO NR/23/NR NR/6/NR 16-46 years (mean, 25 years)/ 30 M. 23 F 2 years/1/M unknown amount of SOX formic acid solution 45-200 g formic acid 5-30 g formic acid 30-45 g formic acid NR 50 100 ml of a solution con- taining >50X formic acid (decalclfter) Severe gastrointestinal and oral Irritation. CNS depression, Internal hemorrhaylng Mortality due to gastrointestinal hemorrhage In 14/16, acute renal failure, Intravascular coagula- tion, pneumonltls Oropharyngeal burns, gastro- intestinal ulceratlon and per- foration One mortality, severe gastro- intestinal homonhaying, intra vascular coagulation, renal Failure, liver toxlclty 15/53 mortalities, severe gastro- intestinal Irritation, facial/ oral burns, gastrointestinal hemorrhaglng, pneumonltls, cardiovascular effects, acute renal failure; lethal effect at >10 mi oral Death Rosewarne, 1983 Jefferys and Wiseman. 1980 Jefferys and Ulseman, 1980 Jefferys and Wiseman, 1980 Rajan et al., 1985 NGhlcndahl ct al., 1978 ------- CJ o» Q. TABLE 6-1 (cont.) Route Age/Number/Sex Exposure Response Reference Oral chtldren/19/NR I ro 00 i 21 years/1/M 56 years/1/H 60 years/1/H Oral/ 35 years/1/H dermal Dermal 15/1/F unknown amount of decalclfters con- taining formic acid 1 cup formic acid 55* formic acid. 1.6% phosphoric acid, 4X qulnollne unknown quantity of formic acid sprayed In face with Jet of formic acid NR Esophageal and oral burns. gastrointestinal hemorrhaglng Oral esophageal and gastric burns, gastrointestinal hemor rhaglng, pylorlc obstruction Renal failure, heart failure. death Oropharyngeal burns, gastro- intestinal Irritation Gastrointestinal Irritation, burns on face and thorax Systemic effects Included meta- bolic acldosls, hemolysts. gastrointestinal Irritation, hemogloblnurla, leukocytosls, elevated blood urea; depressed. potassium and sodium levels. HQhlendahl et al., 1978 Lambeth and Somasundaram, 1970 Jacques, 1982 Hallzla et al., 1977 s Hallzla et al.. 1977 Stgurdsson et al., 1983 NR = Not reported ------- TABLE 6-2 Oral 1050 Data for Formic Add Species Dog Rat Mouse Rabbit L050 (mg/kg) 4000 1210 1830 1100 700 1100 >4000 Reference Sax, 1984 Sax, 1984 Guest et al.. NIOSH, 1988 NIOSH, 1988 Malorny, 1969b Guest et al., 1982 1982 0136d -29- 04/07/89 ------- sensitive species, and rabbits and dogs appear to be the least sensitive species to orally administered formic acid. For mice, LD5Q values of 142 and 940 mg/kg were reported for Intravenous and IntraperKoneal administra- tion, respectively (Guest et al., 1982). LD5Q values for several salts of formic add In mice are presented 1n Table 6-3. Sodium formate Is clearly the least toxic salt by either oral or Intravenous administration. Varia- tions In toxlclty probably reflect the toxlclty of the Individual cations. Inhalation LC.Q data were available only for rats'and mice. The !5-m1nute LC5Q values were 15,000 and 6200 mg/m3 for rats and mice, respectively (NIOSH, 1988); mice are more than 2 times as sensitive than rats to formic add vapor. ...... 6.2. CARCINOGENICITY 6.2.1. Inhalation. Pertinent data regarding the cardnogenlclty formlc add by Inhalation exposure were not located 1n the available literature cited In Appendix A. 6.2.2. Oral. In a 3-generat1on study, gross and hlstopathologlc examina- tions were performed on 250 Mlstar rats that were given a dosage of 200 mg/kg/day calcium formate In their drinking water for 2 years (Malorny, 1969b). Examination of the digestive tract, liver, kidneys and "other tissues" revealed no evidence of cardnogenlclty; however, whether this was a comprehensive examination of all organs and tissues 1s unclear from this translation. 6.2.3. Other Relevant Information. The epidermal carcinogenic potential of formic add was Investigated In a study where the ears of groups of 10 Inbred male Swiss mice were painted with 0 or 8% formic acid In distilled water, twice/week for 2, 5, 10, 20 or 50 days (Fre1 and Stephens, 1968). 0136d -30- 04/07/89 ------- TABLE 6-3 1050 Values for Formic Add and Its Salts 1 ft-the House* Substance L050 (mg/kg) 1050 Range { mg/kg) Calculated According to Formate Ion Equivalents Per os_ Formic add Sodium formate Potassium formate Ammonium formate Calcium formate 1100 11.200 5500 2250 1920 1000-1200 9600-12,800 5000-6000 2050-2460 1280-2560 1076 7410 2950 1606 1330 Intravenous Formic add Sodium formate Potassium formate Ammonium formate Calcium formate 145 807 95 410 154 138-151 800-813 93-97 408-412 150-158 142 534 51 293 107 *Source: Malorny, 1969b 0136d -31- 04/07/89 ------- There was no effect on the Incidence of hyperplasla, epidermal thickness, the presence of Inflammatory exudate or the hlstologlcal appearance of the tissues. 6.3. MUTA6ENICITY »* -. Limited mutagen1c1ty data were available for formic acid (Table 6-4). Positive results occurred In three sex-linked lethality assays using Droso- phlla melanogaster and In one forward mutation assay In Escherlchla coll (Stumm-Tegethoff, 1969; Demerec et al., 1951). Negative results were obtained In a ONA 1nact1vat1on assay 1n ONA donor strain Bacillus subtllls 60009 (Freese et al., 1967). Stumm-Tegethoff (1969) speculated that formic acid Inhibited catalase, allowing the accumulation of peroxides and free radicals that Interfere with correct DNA replication. 6.4. TERATOGENICITY - . - Malorny (1969b) reported that sodium formate Injected Into the air cell of chicken eggs at 48-96 hours of Incubation at 5, 10 or 20 mg/egg had no effect on embryo survival or body weight, and was "teratogenlcally unremark- able." Data were not located regarding the developmental toxldty of formic add In mammals. 6.5. OTHER REPRODUCTIVE EFFECTS In the drinking water study by Sporn et al. (1962) (see Section 6.1.2.1.). formic add administered to rats at IX 1n the water resulted 1n a marked decrease In neonatal survival at 7 days compared with untreated controls. In this experiment, female rats were exposed for 7 months, presumably Including the prematlng period through lactation. Decreased neonatal survival was not observed 1n the offspring of rats treated only during lactation. Survival data were not analyzed statistically. 0136d -32- 04/07/89 ------- o _J co Q. Assay Indicator/Organise DMA Bacillus subtil Is Inactlvatlon 60009 Reverse Escherlchta coll utatlon B/Sd-y/1. 3. 4. S; B/Sd 4/3. 4 ' Sex-linked Drosophjla co lethality *elanoqaster i 0. elanogaster D. elanoqaster TABLE 6-4 Hutagenlclty Data for Foralc Acid* Application Concentration Activating Response Cement or Dose Systea , liquid 10~> to 10~> H MR - NC suspension . ; plate 0. 0050-0. OQ70X MR » NC Incorporation . " . vapor exposure 0.1X NA » NC larval feeding 0.1X NA » NC larval feeding 0.1X NA » foralc acid stabilized at pH 7.5 lowered : Mitatton rate Reference freese et al.. 1967 Oenerec et al.. 1951 Stuan-Tegethoff. 1969 Stum-Tegethoff. 1969 Stuon-Tegethoff. 1969 *Purlty of the compound was not reported. NR . Not reported; NA . not applicable oo wD ------- Malorny (1969b) provided rats with drinking water containing 0.2% calcium formate that provided a dosage of calcium formate estimated by the Investigator at 150-200 mg/kg/day for five generations (see Section 6.1.2.2.). There was no effect on reproduction as determined by the number ** of offspring/litter or the body weight or length of the offspring. Without providing substantiating data, the Investigator reported that there was no effect on reproduction with calcium formate at 0.4% 1n studies that had progressed through two generations. 6.6. SUMMARY No treatment-related effects were observed 1n men Ingesting formic add at 8 mg/kg/day for 4 weeks (Lebbln. 1916). Levels specified only as "higher" caused local actions. Several subchronlc studies where formic add was administered to rats In their diet or drinking water have been performed (Sporn et al., 1962; Solmann, 1921; Flelg, 1907). Slight, but not signifi- cant, growth inhibition occurred at 0.5% In the diet (Sporn et al., 1962). Decreased food Intake and growth Inhibition occurred at 360 mg/kg/day (Solmann, 1921). A series of mult1generat1on studies of rats given calcium formate 1n their drinking water have been reported by Malorny (1969b). Slightly Increased phagocytosis In moderately Increased retlculoendotheHal and retlculohlstlocytic subcellular components 1n the lungs, spleen and abdominal lymph nodes occurred In rats at 200 mg/kg/day. There was no effect on reproduction. A NOEL of 200 mg/kg/day was Identified In these studies. Sporn et al. (1962) observed a decreased survlvabUHy In offspring during the first 7 days of life born to a first generation of rats exposed to 1.0% formic add 1n drinking water. 0136d -34- 07/03/90 ------- A variety of effects have been reported as a result of acute oral exposure 1n man (Rosewarne, 1983; Jefferys and Wlsenman, 1980; Rajan et * * al., 1985; MQhlendahl et al., 1978; Lambeth and Somasundaram, 1970; Mallzla et al., 1977; Slgurdsson et al., 1983; Jacques, 1982). These effects Include oral, pharyngeal, esophageal and gastrointestinal burns, mortality. Internal hemorrhaglng, hematologlc and cardiovascular anomalies, renal failure, liver damage, CNS depression, pylorlc obstruction and tracheal strictures. Mortality has occurred In humans at an oral exposure range of 429-643 mg/kg formic add (Jefferys and Wiseman, 1980). In guinea pigs, Inhalation of 0.34-13.5 ppm formic acid resulted In a ' ' . ' j '-',',' dose-related occurrence of Impaired respiratory function (Amdur, 1960). Acute oral and Inhalation data Indicate that mice, followed by rats, are the- most sensitive species to formic acid poisoning. No carcinogenic response occurred In a 3-generatlon drinking water study In which Wlstar rats received 200 mg/kg/day of calcium formate (Malorny, 1969b). Also, dermal exposure to 8% formic acid 1n mice for up to 50 days produced no evidence of cardnogenlclty (Fre1 and Stephens, 1968). Positive results occurred In three sex-linked lethality assays using 0. melanogaster and In one foward mutation assay In E.. coll (Stumm-Tegethoff, 1969; Oemerec et al., 1951). A negative result occurred In a DNA Inactlva- tlon assay In B_. sub tills (Freese et al., 1967). 0136d -35- 08/15/89 ------- 7. EXISTING GUIDELINES AND STANDARDS 7.1. HUMAN The OSHA (1985) PEL for occupational exposure . to formic add Is 9 mg/m3. ACGIH (1988) adopted an 8-hour TWA-TLV of 5 ppm (-9 mg/m3) and recommended that an STEL of 10 ppm (-18 mg/m3) be adopted. The TWA-TLV Is designed to protect humans from Irritating effects on the eyes, respiratory tract and possibly on the skin. The RQ for formic acid based on aquatic toxlclty Is currently 5000 (U.S. EPA, 1988). The U.S. EPA (1985) has verified an oral RfD of 2 mg/kg/day for formic add based on chronic and subchronk toxlclty 1n rats (see Section 8.2.2.2.). After a comprehensive safety review, the U.S. FDA (1980) affirmed the GRAS status of formic add as an Ingredient 1n human food. 7.2. AQUATIC Guidelines and standards for the protection of aquatic life from exposure to formic acid were not located In the available literature dted In Appendix A. 0136d -36- 08/15/89 ------- 8. RISK ASSESSMENT Statements concerning available literature 1n this document refer to published, quotable sources and are-In no way - meant to Imply that confidential business Information (CBI), which this document could not address, are not In existence. From examination of the bibliographies of the CBI data, however, It was determined that CBI data that would alter the approach to risk assessment or the risk assessment values presented herein do not exist. 8.1. CARCINOGENICITY 8.1.1. Inhalation. Studies of the Inhalation carclnogenldty of formic acid or Its formates were not located In the available literature; however, the NTP Is conducting a subchronlc Inhalation study of formic acid In rats and mice (NTP, 1988). 8.1.2. Oral. Malorny (1969b) exposed Wlstar rats to 200 mg/kg/day formic acid In their drinking water for three generations. No evidence of carclno- genldty was reported, although this study cannot be considered an adequate study of the carclnogenldty of formic add. 8.1.3. Other Routes. Frel and Stephens (1968) reported that mice exposed dermally (ear) to 8X formic add, twice/week for 2, 5, 10, 20 or 50 days showed no evidence of a carcinogenic response. 8.1.4. Weight of Evidence. The negative carclnogenldty results from the drinking water study reported by Malorny (1969b) provide Insufficient evidence to assess the carcinogenic potential of formic add or calcium formate In rats. In addition, the negative carclnogenldty results reported by Fre1 and Stephens (1968) are also Inadequate for the evaluation of the carcinogenic potential of formic add. Data were not located regarding the carcinogenic potency of formic add In humans. Therefore, using the U.S. 0136d -37- 04/07/89 ------- EPA (1986a) cancer assessment guidelines, formic add 1s classified as an EPA Group D carcinogen - not classifiable as to carcinogenic potential In humans. 8.1.5. Quantitative Risk Estimates. The lack of positive data precludes estimation of carcinogenic potencies for formic acid or Its formates for either Inhalation or oral exposure. ^.- ' . '*' " *" '-' ' 8.2. SYSTEMIC TOXICITY .-:.-..». :-:.--: .:';: ' -., ' . ---' ' '' " " *: ' *; ''b~'-VV 3 8.211. Inhalation Exposure. Pertinent data regarding the subchronlc or chronic Inhalation exposure to formic add or Us formates were not located In the available literature cited In Appendix A. 8.2.2. Oral Exposure. , :\ * ..." . » - 8.2.2.1. LESS THAN LIFETIME EXPOSURE (SUBCHRONIC) Formic add Is an endogenous substance Involved In Intermediary metabolism (U.S. EPA~ 1985). which has been granted GRAS status by the U.S. FDA (1980). Therefore, U 1s reasonable to expect that the toxic potency of formic acid should be low. The available toxldty data are confusing. In humans, the critical effect associated with acute 1ngest1on appears to be oropharyngeal add /' burns and gastrointestinal Irritation, which were reported at a dose range of 5-30 g (Jefferys and Wiseman, 1960). A dose range of 34-45 g was considered the threshold for mortality. Solmann (1921), however, reported that there were no adverse effects In men given 150 mg/kg/day (10.5 g/day for 70 kg man) for "some time." Lebbln (1916) reported no effects In men given 8 mg/kg/day (0.56 g/day) for 4 weeks; unspecified higher doses resulted In "local actions." The human data are Insufficient to estimate a reliable NOAEL that may serve as the basis for an RfD. 0136d -38- 04/07/89 ------- Three subchronlc oral studies using rats with formic add were considered. Sporn et al. (1962) reported a slight and not statistically *. * significant reduction 1n growth rate 1n rats fed diets containing 0.5 or 1.0% formic acid. Assuming a food factor for rats of 0.05 (U.S. EPA, 1986b), these dietary concentrations are equivalent to dosages of 250 and 500 mg/kg/day, respectively. In a drinking water study, formic add at 1% for 7 months was associated with neonatal mortality and hematologlc changes 1n the adult rats (Sporn et al., 1962). Assuming rats weigh 0.35 kg and Ingest 0.049 i of drinking water/day (U.S. EPA, 1986b). an equivalent dosage of 1400 mg/kg/day can be estimated. In another drinking water study, - Solmann (1921) reported reduced food consumption and growth rate 1n rats at 0.5% formic add. The Investigators estimated the dosage at 360 mg/kg/day^ «. No effects were observed at 0.25%. The animal studies discussed above were largely limited to evaluating effects on rates of food and water Intake and growth. In addition, the study by Sporn et al. (1962) evaluated reproductive performance and limited hematologlc endpolnts. No study, however, Included hlstopathologlc examina- tions. Therefore, these studies are Insufficient for derivation of an oral RfO for subchronlc exposure, and the chronic RfD of 1.6 mg/kg/day (rounded to 2 mg/kg/day) based on the Halorny (1969b) study (Section 8.2.2.2.), Is adopted as being protective for subchronlc oral exposure as well. 8.2.2.2. CHRONIC EXPOSURE -- Chronic oral data are restricted to the mult1generat1on study 1n rats In which caldum formate was administered In drinking water. A slight Increase 1n phagocytosis 1n lungs, spleen and abdominal lymph nodes (but no effects on reproduction) were observed 1n rats maintained for over five generations on drinking water containing 0.2% calcium formate (Malorny, 1969b). The Investigators estimated the dosage of calcium formate at 150-200 mg/kg/day. In a later study with 0.4% caldum 0136d -39- 07/03/90 ------- formate (300-400 mg/kg/day). which was still 1n progress, no hlstopathologU lesions were reported after 2 years (two generations). These data support the selection of 200 mg/kg/day for calcium formate as a chronic NOEL In rats. U.S. EPA (1985) applied an uncertainty factor of 100 (10 for extrapo- i - : latlon from animals to humans and 10 to protect unusually sensitive 1nd1- :. " " vlduals) to derive a verified oral RfD for formic add of 2 mg/kg/day. This derivation Implies that calcium formate dissociates to formate 1n biological systems, and the RfD for formic acid Is derived by analogy to formate. In the derivation of this RfD, correction has been made for the ratio of the molecular weight of formic acid to calcium formate, and 200 mg/kg/day should be considered a NOEL for calcium formate. The equivalent dosage of formic acid would be 160 mg/kg/day. The NOEL for formic add of 160 mg/kg/day, equivalent to 9.9 g/day for a 70 kg human, 1s above the lower dosage of 5 g associated with oropharyngeal burns and gastrointestinal Irritation In humans acutely exposed to the add Uself (Jefferys and Wiseman, 1980). Because the Irritation reported by Jefferys and Wiseman (1980) can be attributed to acute exposure to the add at levels not expected to be encountered 1n the environment, the rat NOEL of 160 mg/kg/day can serve as the basis for an RfD. Furthermore, Solmann (1921) reported no adverse effects In humans exposed to formic add at 150 mg/kg/day for "some time." Application of an uncertainty factor of 100 results 1n an RfD for formic add of 1.6 mg/kg/day, which would be rounded to 2 mg/kg/day. Confidence In the key study Is medium because of Us long length and because hlstopathologU examination was performed. Confidence In the data base Is low, therefore confidence 1n the RfD 1s also low. 0136d -40- 07/03/90 ------- 9. REPORTABLE QUANTITIES 9.1. BASED ON SYSTEMIC TOXICITY The toxIcUy of formic acid to humans and animals 1s discussed In Chapter 6. Subchronlc and chronic oral studies 1n laboratory animals with formic add and calcium formate reported sufficiently for evaluation and consideration are summarized 1n Table 9-1. In Chapter 8, a chronic RfD for formic acid was calculated given the assumption that at physiologic pH calcium formate exists primarily as the formate anlon. In Table 9-1, the dosage of formic add or calcium formate 1s expressed In terms of formic acid equivalents In mg/kg/day, and the equivalent human dose Is expressed as mg formic acld/kg/day. Effects In rats associated with prolonged exposure to formic acid 4MB Include depressed growth rate (Sporn et a!., 1962; Solmann, 1921), reduced survival of offspring (Sporn et a!., 1962) and slightly decreased phagocyto- sis In lung, spleen and lymph nodes (Halorny, 1969b). The Inhibition of growth reported 1n rats fed diets containing formic add (Sporn et al., 1962), however, was not statistically significant, and the Inhibition In growth In rats fed formic add In the drinking water (Solmann, 1921) was accompanied by decreased food Intake and 1s not considered a toxlcologlc effect of the chemical. Therefore, CSs are not calculated for growth Inhi- bition In these studies. Although the quality of the Sporn et al. (1962) and Malorny (1969b) reports Is marginal at best, CSs for reduced survival of offspring and for Increased phagocytosis are calculated 1n Table 9-2. The RV for both effects Is 1, Indicating that both effects were associated with high dosages, and the CSs derived therefore reflect only the severity of the effect observed. Therefore, the higher CS 1s calculated for reduced neonatal survival reported by Sporn et al. (1962). Although the 0136d -41- 04/07/89 ------- CO o» ex TABLE 9-1 Oral Toxtctty Sunnary for Formic Average Species/ Weight* Strain (kg) Rat/NR 0.35 Rat/NR 0.35 £ Rat/NR 0.35 i Rat/Wlstar 0.35 Compound/ Vehicle formic acid/ diet formic acid/ water formic acid/ water calcium formate/water Exposure O.SX of diet for 5-6 weeks O.SX In drinking for 9 weeks IX In drinking water for up to 7 months 0.2X In drinking water for five generations Transformed Animal Dose Expressed as Formic Add (mg/kg/day) 250 360 1400 160 Acid and Calcium Formate Equivalent Human Dose Expressed as Formic Ac1d>> (mg/kg/day) 43 62 239 27 tt'. Response ' t- Slight growth Inhibition . Decreased appetite and growth Inhibition Reduced survival of offspring Increased phagocytosis. Increased retlculoendothellal and rettculohlstlocytlc cells.. Reference Sporn et 1962 Solmann, Sporn et 1962 > Nalorny. »!.. 1921 1.. 1969b 'Reference value from U.S. EPA (1980) used. Calculated by multiplying the animal dose expressed as mg/kg/day formate by the cube root of the ratio of the animal body weight to the reference body weight for man of 70 kg. cThe weight of calcium formate Is converted to the weight of formic add by multiplying the weight of calcium formate by the ratio of the molecular weight of formic acid divided by the molecular weight of calcium formate and dividing by 2: (2 x 46.02/130.12) 0.707 NR - Not reported . o to ------- TABLE 9-2 Oral Composite Scores for Formic Add and Calcium Formate Compound Formic add Calcium formate Spedes/ Strain rat/NR rat/ Wlstar Animal Dose Expressed as Formic Add (mg/kg/day) 1400 160 Chronic Human MED Expressed as Formic Add* (mg/kg/day) 16,730 1.915 RVd Effect RVe CS 1 Reduced survival 8 8 of offspring 1 Slightly Increased 2 2 phagocytosis RQ Reference 1000 Sporn et al., 5000 Halorny, 1969b i 1962 'Equivalent human dose as mg/kg/day In Table 9-1 multiplied by 70 kg to express the HEO In ing/day for a 70 kg human. NR = Not reported ------- survival data cannot be analyzed statistically, the data do suggest that .w. neonatal survival was reduced. Therefore, the CS of 8, equivalent to an RQ of 1000, Is selected for the chronic toxldty of formic add (Table 9-3). 9.2. BASED ON CARCINOGENICITY Carclnogenldty data, summarized In Section 6.2., consist of an Inade- quate negative study using Wlstar rats exposed to 200 mg/kg/day of calcium formate 1n their drinking water for five generations (Malorny, 1969b). Since formic add was classified as EPA Group 0 - not classifiable as to human cardnogen1c1ty, an F factor could not be derived and formic add 1s not placed In a Potency Group. Hazard ranking for formic add, therefore, cannot be based on cardnogenldty. 0136d -44- 04/07/89 ' ------- TABLE 9-3 Formic Acid Minimum Effective Dose (MED) and Reportable Quantity (RQ) Route: oral i. " s ' ' ' :' * Species/sex: rats/M, F Duration: <7 months MED*: 16,730 mg/day Effect: reduced neonatal survival Reference: Sporn et al., 1962 RVd: 1 RVe: 8 Composite Score: 8 RQ: 1000 'Equivalent human dose 0136d -45- 04/07/89 ------- 10. REFERENCES ACGIH (American Conference of Governmental Industrial Hyglenlsts). 1988. *« - Threshold Limit values and Biological Exposure Indices for 1988-1989. Cincinnati, OH. p. 22, 39. Adewuyl, Y.G., A.S. Cho, R.P. Tsay and G.R. Carmlchael. 1984. Importance of formaldehyde In cloud chemistry. Atmos. Environ. 18: 2413-2420. Altshuller, A.P. 1983. Measurements of the products of atmospheric photo- chemical reactions In laboratory studies and 1n ambient air - Relationships between ozone and other products. Atmos. Environ. 17: 2383-2427. Amdur, M.O. 1960. The response of guinea pigs to Inhalation of formalde- hyde and formic add alone and with a sodium chloride aerosol. Int. J. A1r Pollut. 3(4): 201-220. Amoore, J.E. and E. Hautala. 1983. Odor as an aid to chemical safety: Odor threshold compared with threshold limit values and volatilities for 214 Industrial chemicals 1n air and water dilution. J. Appl. Toxlcol. 3: 272-290. Anbar, M. and P. Neta. 1967. A compilation of specific blmolecular rate constant for the reactions of hydrated electrons, hydrogen atoms and hydroxyl radical with Inorganic and organic compounds In aqueous solution. Int. J. Appl. Rad. Isotopes. 18: 493-523. 0136d -46- 04/07/89 ------- Atkinson. R. 1985. Kinetics and mechanisms of the gas-phase reactions of the hydroxyl radical with organic compounds under atmospheric conditions. Chem. Rev. 85: 69-201. Autenrelth. W. 1919. No title provided. Munch. Med. Wchnschr. 66: 862. (Cited In von Oettlngen, 1959} Bachman, S.R. and M.E. Peden. 1987. Determination of organic acid anlons 1n precipitation by 1on chromatography exclusion. Water Air Soil Pollut. 33: 191-198. Bastrup, J.T. 1947. On the excretion of formic add In experimental * poisoning with methyl alcohol. Acta. Pharmacol. Toxlcol. 3: 312. (Cited 1n von Oettlngen, 1959) Bates, R.C. and R.E. Hurlbert. 1970. Effect of acetate on Euqlena gradlls var. baclllarls as a function of environmental conditions. J. Protozool. 17(1}": 134-138. BattelH, F. 1904. Oxydatlon de 1'aclde formlque par les extralts des tlssus anlmaux en presence de peroxyde d'hydroqene. Compt. Rend. Acad. Scl. (Cited In von Oettlngen, 1959} Boubllk, T., V. Fried and E. Hala. 1984. The Vapor Pressures of Pure Substances: Selected Values of the Temperature Dependence of the Vapour Pressures of Some Pure Substances 1n the Normal and Low Pressure Region. Vol. 17. Elsevler Scl. Publ., Amsterdam, Netherlands, p. 45. 0136d -47- 04/07/89 ------- Brill, W.J., E.A. Wolln and R.S. Wolfe. 1964. Anaerobic formate oxidation: A ferredoxln-dependent reaction. Science. 144: 297-298. Brown, L.R., R.J. Strawlnsk! and C.S. McCleskey. 1964. The Isolation and characterization of Methanomonas methanooxldans. Can. J. Mlcroblol. 10: 791-799. Calvert, J.G. and J.N. PHts, Jr. 1966. Photochemistry. John Wiley and Sons, Inc., New York. p. 428-430. Chapman, E.G., D.S. Sklarew and J.S. FUcklnger. 1986. Organic adds 1n springtime Wisconsin precipitation samples. Atmos. Environ. 20: 1717-1725. CMR (Chemical Marketing Reporter). 1984. Chemical Profile: Formic Add. Schnell Publishing Co., New York. December 31, 1984. Crockett, P.W., B. K1l1an, K.S. Crump and R.B. Howe. 1985. Descriptive methods for using data from dissimilar experiments to locate a no-adverse- tox1c-effects region In the dose-duration plane. Prepared by K.S. Crump and Company, Inc., under Contract No. 68-01-6807 for the Environmental Criteria and Assessment Office, U.S. EPA, Cincinnati, OH. Demerec, M., G. Bertanl and J. Flint. 1951. Survey of chemicals for mutagenlc action on E_. coll. Am. Natural. 85(821): 119-136. Dorfman, L.M. and G.E. Adams. 1973. Reactivity of the hydroxyl radical In aqueous solution. National Bureau of Standards, Washington, DC. NSRD-NBS-46. NTIS COH-73-50623. p. 17-20, 24-31. 0136d -48- 04/07/89 ------- Dowden, B.F. and H.F. Bennett. . 1965. Toxldty of selected chemicals to certain animals. J. Mater Pollut. Control Fed. 37(9): 1308-1316. *» * Durkln, P. and W. Meylan. 1988. User's Guide for D2PLOT: A program for dose/duration graphs. Prepared by Chemical Hazard Assessment Division. Syracuse Research Corporation under Contract No. 68-C8-0004 for Environ- mental Criteria and Assessment Office, U.S. EPA, Cincinnati, OH. Elsenrelch, S.J., B.B. Looney and J.D. Thornton. 1981. Airborne organic contaminants of the Great Lakes ecosystem. Environ. Scl. Techno!. 15(1): 30-38. Epplnger, H. 1913. No title provided. W1en. Klin. Rundschau. 27: 49. (Cited 1n von Oettlngeni 1959) Flna, L.R., H.J. Slncher and D.F. Oecou. 1960. Evidence for the production of methane from formic acid by direct reduction. Arch. Blochem. Blophys. 91: 159-162. Flelg, C. 1907. Etude physlologlque de quelques composes formlques. Int. Pharmaco. 17: 147. (Cited In von Oettlngen, 1959) Freese, E.B., J. Gerson, H. Taber, H.J. Rhaese and E. Freese. 1967. Inactivating DNA alterations Induced by peroxides and peroxide-containing agents. Hutat. Res. 4: 517-531. 0136d -49- 04/07/89 ------- Frel, J.V. and P. Stephens. 1968. The correlation of promotion of tumor growth and Induction of hyperplagla In epidermal two-stage cardnogenesU. Br. J. Cancer. 22: 88-92. (Cited 1n Tracor-JHco, 1974) Gaffney, P.E. and R.S. Ingols. 1961. Nitrate as the nitrogen source In BOD dilution water. Water Sewage Works. 108: 91-95. Gaffney, J.S., G.E. StreH, W.D. Spall and J.H. Hall. 1987. Beyond add rain. Environ. Scl. Techno!. 21(6): 519-524. - 4 GoerlHz, O.F., D.E. Troutman, E.M. Godsy and B.J. Franks. 1985. Migration of wood preserving chemicals 1n contaminated groundwater 1n a sand aquifer at Pensacola, Florida. Environ. Sc1. Techno!. 19: 955-961. Graedel, T.E. 1978. Chemical Compounds In the Atmosphere. Academic Press, New York. p. 211. Graedel, T.E., D.T. Hawkins and L.D. Claxton. 1986. Atmospheric Chemical / Compounds. Sources, Occurrence and Bloassays. Academic Press, New York. p. 345. Gregory, G.L., R.C. Harrlss, R.W. Talbot, et al. 1986. A1r chemistry over the tropical forest of Guyana. J. Geophys. Res. 91: 8603-8612. Grehant, N. and Qulnquaud. 1887. Que devlennent lesformlates IntroduUs dans 1'organlsme? Compt. Rend. Acad. Sc1. 104: 437. (Cited 1n von Oettlngen, 1959) 0136d -50- 04/07/89 ------- Guest, 0., G.V. Katz and B.O. AstHl. 1982. Saturated monocarboxyllc adds. In.: Patty's Industrial Hygiene and Toxicology, Vol. 2C, 3rd ed., G.D. Clayton and F.E. Clayton, Ed. Jotin Wiley and'Sons, Inc., New York. p. 4902-4987. Hama, T. and N. Handa. 1981. Volatile organic acids.. In lake water; their gas chromatographlc determination and ecological significance. Rlkuslugaku Zasshl. 42: 8-19. Hansch, C. and A.J. Leo. 1985. Medchem Project. Issue No. 26. Pomona College, Claremont, CA. -^i Harada, T. and Y. Nagashlma. 1975. Utilization of alkylether compounds by soil bacteria. J. Ferment. Techno!. 53: 218-222. Harris, J.C. 1982. Rate of hydrolysis. In.: Handbook of Chemical Property Estimation Methods, W.J. Lyman, W.F. Reehl and D.H. Rosenblatt, Ed. McGraw H111 Book Co., New York. p. 7-1 to 7-48. Hawley, G.G. 1981. The Condensed Chemical Dictionary, 10th ed. Van Nostrand Relnhold Co., New York. p. 476. Heukeleklan, H. and M.C. Rand. 1955. Biochemical oxygen demand of pure organic compounds. J. Water Pollut. Control Assoc. 29: 1040-1053. Hoppe-Seyler, F. 1876. Ueber die Processe der Gahrungen und Ihre Bezlehung zum Leben der Orgalnlsmen. Pfluger's Arch. ges. Physlol. 7: 1. (Cited In von Oettlngen, 1959) 0136d -51- 04/07/89 ------- Jacques, S. 1982. Acute renal failure following 1ngest1on of formic add. Nurs. Times. 78(31): 1312-1315. *» * '. Jefferys, D.B. and H.M. Wiseman. 1980. Formic add poisoning. Postgrad, Hed. J. 46(661): 761-762. Kawamura, K., L. Ng and I.R. Kaplan. 1985. Determination of organic adds ::- f -.:- --'ov-' ? . »vf , -fin-" ^ ' *< ' "- "'^ "''* '-''* (C1-C10) 1n the atmosphere, motor exhausts and engine oils. Environ. Scl. Techno!. 19: 1082-1086. Keene, W.C. and J.N. Galloway. 1984. Organic acidity In precipitation of North America. Atmos. Environ. 18: 2491-2497. Kramer, V.C., D.J. Schnell and K.W. Nlckerson. 1983. Relative toxldty of organic solvents to Aedes aegvptl larvae. 3. Invertebr. Pathol. 42(2): 285-287. Kung, H. and C. Wagner. 1970. Oxidation of C, compounds by Pseudomonas Sp. MS. Blochem. J. 116: 357-365. Lambeth, J. and K. Somasundaram. 1970. Pylorlc obstruction due to formic add Ingestlon. Hed. J. Malaysia. 24(3): 187-189. Lebbln. 1916. No title provided. Blochem Centralbl. p. v1, 83. (Cited 1n Solmann, 1921) 0136d -52- 04/07/89 ------- UeslvuoM, J., V.M. Kosma, Q. Naukkarlnen and H. Savolalnen. 1987. Kinetics and toxic effects of repeated Intravenous dosage of formic add 1n rabbits. Br. J. Exp. Pathol. 68: 853-861. Lund, A. 1948a. Metabolism of methanol and formic add In dogs. Acta Pharmacol. Toxlcol. 4: 108. (Cited 1n Tracor-JUco, 1974) Lund, A. 1948b. Metabolism of methanol and formic add 1n rabbits. Acta. Pharmacol. Toxlcol. 4: 99-107. (Cited 1n Tracor-JHco, 1974) Lyman, W.J., W.F. Reehl and D.H. Rosenblatt. 1982. Handbook of Chemical Property Estimation Methods. McGraw-Hill Book Co., New York. p. 5-5. ^ Maeda, H. and A. Kawal. 1986. Determination of organic adds In the lake sediment. Nippon Sulsan Gakka1sh1. 52: 1205-1208. Malaney, G.W. and R.M. Gerhold. 1969. Structural determinants In the oxidation of aliphatic compounds by activated sludge. JJK Ind. Waste Conf., Purdue Univ. Ext. Serv. 112: 249-257. Mallzla, E., C. Reale, P. P1etropaol1 and G.C. De RH1s. 1977. Formic acid Intoxication. Acta Pharmacol. Toxlcol. 41(2): 342-347. Malorny, G. 1969a. Metabolism studies with sodium formate and formic add 1n man. Z. Ernaehrungswlss. 9(4): 340-348. (In German with English trans- lation) (Cited In Tracor-JUco, 1974) 0136d -53- 04/07/89 ------- Malorny, G. 19695. Acute and chronic toxldty of formic add and Us formlates. Z. Ernahrungswlss. 9(4): 332-339. {In German with English translation) > » Mantel, N. and M.A. Schnelderman. 1975. Estimating "safe" levels, a hazardous undertaking. Cancer Res. 35: 1379-1386. Hazurek, M.A. and B.R.T. Slmonelt. 1986. Organic components In bulk and wet-only precipitation. CRC Cr1t. Rev. Environ. Contam. 16: 73. McKlnney, R.E., H.D. Tomllnson and R.L. Wllcox. 1956. Metabolism of aromatic compounds by activated sludge. Sewage Ind. Wastes. 28: 547-557. Mill, T., D.G. Hendry and H. Richardson. 1980. Free-radical oxldants In natural waters. Science. 207: 886-887. Muhlendahl, D.E., U. Oberdlsse and E.G. Krlenke. 1978. Local Injuries by accidental Ingestlon of corrosive substances by children. Arch. Toxlcol. 39: 299-314. NIOSH (National Institute for Occupational Safety and Health). 1988. RTECS (Registry of Toxic Effects of Chemical Substances). Online. CAS No. 64-18-6. NTP (National Toxicology Program). 1988. Chemical Status Report. 10/06/88. 0136d -54- 04/07/89 ------- Oro, J. and O.A. Rappoport. 1959. Formate metabolism In animal tissues. II. The mechanism of formate oxidation. J. B1o1. Chem. 234(7): 1661-1665. (Cited In Tracor-JUco, 1974) OSHA (Occupational Safety and Health Administration). 1985. Occupational Standards. Permissible Exposure Limits. 29 CMR 1910.10.00. p. 655-659. Patel, R.N., C.T. Hou and A. Felix. 1978. Mlcroblal oxidation of methane and methanol: Isolation of methane-utilizing bacteria and characterization of a facultative methane-utilizing Isolate. J. Bacterlol. 136: 352-358. Patel, R.M., S.L. Hoare and D.S. Hoare. 1979. Acetate-l-14C assimilation -~mv by Obligate methylotrophs. Pseudomonas. Hethanlca and Hethyloslnus trlcho- sporlum. Antonle Van Leeuwenhoek. 45: 499-511. P1ne, M.J. 1958. Methane fermentation of formate by Methanobacnius omel1ansk11. J. Bacterlol. 75: 356-359. Placak, O.R. and C.C. Ruchhoft. 1947. Studies of sewage purification. XVII. The utilization of organic substrates by activated sludge. Sewage Works J. 19: 423-440. Pohl, J. 1893. No title provided. Exper. Path. U. Pharmakol. 31: 281. (CHed In von Oettlngen, 1959) Popoff, L. 1875. Uber die sumpfgahrung. Arch Ges. Physlol. 10: 113. (Cited In von Oettlngen, 1959) 0136d -55- 04/07/89 ------- Price, K.S., G.T. Uaggy and R.A. Conway. 1974. Brine shrimp bloassay and seawater BOD of petrochemicals. J. Water Pollut. Control Fed. 46: 63-77. *« * Raj an, N., R. Rahlm and S. Krishna Kumar. 1985. Formic add poisoning with suicidal Intent: A report of 53 cases. Postgrad Med. J. 61(711): 35-36. *" Rosewarne, F.A. 1983. Self poisoning with formic add [letter]. Anaesthesia. 38(110): 1104-1105. SANSS (Structure and Nomenclature Search System). 1988. Chemical Informa- tion System (CIS) computer data base. On-line: May 5, 1988. Sax, N.I. 1984. Dangerous Properties of Industrial Materials, 6th ed. Vatr- Nostrand Relnhold Co., New York. p. 1453. Schafer, E.W., Jr., W.A. Bowles, Jr. and J. Hurlbut. 1983. The acute oral toxldty, repellency, and hazard potential of 998 chemicals to one or more species of wild and domestic birds. Arch. Environ. Cont. Toxlcol. 12(3): 355-382. Schotten. 1883. Ueber die fluchtlgen Savren des Pferdeharns und das Verholten der fluchten Fettauven In Organlsmus. Chem. 7: 375. (Cited In von Oettlngen, 1959) Schultz, L. 1883. No title provided. Arch. Exper. Path. U. Pharmakol. 16: 305. (Cited 1n von Oettlngen, 1959) 0136d -56- 04/07/89 ------- Slgurdsson, J., A. Bjornsson and S.T. Gudmundsson. 1983. Formic acid burn Local and systemic effects. Report of a case. Burns Incl. Therm. InJ. 9(5): 358-361. Solmann, T. 1921. Studies of chronic Intoxication of albino rats. III. Acetic and formic acids. J. Pharmacol. Exp. Ther. 16:1.463-474. Speece, R.E. 1983. Anaerobic biotechnology for Industrial wastewater treatment. Environ. Sc1. Technol. 17: 416A-427A. Sperling, F., E.S. Maxwell and VI.F. von Oettlngen. 1953. Comparative excretion and distribution of C14-labeled carbonate and formate 1n large albino rats. Am. J. Physlol. 174: 33-38. (Cited 1n Tracor-Oltco, 1974) Sporn, A., V. Paris and M.V. Shoebesch. 1962. Toxldty of formic add. Iglena, Bucharest. 11: 507-515. (Cited In Tracor-JHco, 1974) SRI (Stanford Research Institute). 1987. 1987 Directory of Chemical Producers: United States of America. SRI International, Menlo Park, CA. p. 681. Stern, M. 1906. Sixteen years of experience with formic acid as a thera- peutic agent. J. Am. Med. Assoc. 46: 1258-1262. (Cited In Tracor-JHco, 1974) Stumm-Tegethoff, B.F.A. 1969. Formaldehyde-Induced mutations In DrosophUa melanogaster In dependence of the presence of adds. Ther. Appl. Genet. 39: 330-334. 0136d -57- 04/07/89 ------- Takemoto, S., Y. Kuge and M. Nakamoto. 1981. The measurement of BOD In sea water. Su1sh1tsu Odaku Kenkyu. 4: 80-90. Thomas, R.G. 1982. Volatilization fro"m water. In.: Handbook of Chemical Property Estimation Methods, W.J. Lyman, W.F. Reehl and D.H. Rosenblatt, Ed. McGraw H111 Book Co.1, New York! p. 15-1 to 15-34. '" ''' *> -i - -' ' / Tracor-Jltco. 1974. Scientific Literature Reviews on Generally Recognized as Safe (GRAS) Food Ingredients - Formic Acid and Derivatives. NTIS PB228-558. U.S. EPA. 1980. Guidelines and Methodology Used 1n the Preparation of Health Effect Assessment Chapters of the Consent Decree Water Criteria^- Documents.^ Federal Register. 45(231): 79347-79357. U.S. EPA. 1984. Methodology and Guidelines for Ranking Chemicals Based on Chronic Toxlclty Data. Prepared by the Office of Health and Environmental Assessment, Environmental Criteria and Assessment Office, Cincinnati, OH for the Office of Emergency and Remedial Response, Washington, DC. U.S. EPA. 1985. Integrated Risk Information System (IRIS): Reference Dose (RfD) for Oral Exposure for Formic Add. Online. (Verification date 8/19/85). Office of Health and Environmental Assessment, Environmental Criteria and Assessment Office, Cincinnati, OH. U.S. EPA. 1986a. Guidelines for Carcinogen Risk Assessment. Federal Register. 51(185): 33992-34003. 0136d -58- 04/07/89 ------- U.S. EPA. 1986b. Reference Values for Risk Assessment. Prepared by the Office of Health and Environmental Assessment, Environmental Criteria and Assessment Office, Cincinnati, OM for the Office of Solid Waste, Washington, DC. . . * ' U.S. EPA. 1988. Integrated Risk Information Syslem (IRIS). Online. Chemical File for Formic Add. Office of Health and Environmental Assess- ment, Environmental Criteria and Assessment Office, Cincinnati, OH. U.S.- -ffA/OWRS (Office of Water Regulations and Standards). 1986. Guide- lines for Deriving Numerical Water Quality Criteria for the Protection of Aquatic Organisms and Their Uses. Office of Research and Development^ Washington, DC. NTIS PB85-227049/XAB. U.S. FDA (Food and Drug Administration). 1976. Evaluation of the Health Aspects of Formic Add, Sodium Formate, and Ethyl Formate as Food Ingre- dients. FDA Contract #223-75-2004, prepared for the U.S. FDA, Washington, DC. U.S. FDA (Food and Drug Administration). 1980. Affirmation of GRAS Status for Ethyl Formate, Formic Add, and Sodium Formate as Direct and Indirect Human Food Ingredients. Federal Register. 45(67): 22914-22915. U.S. FDA (Food and Drug Administration). 1988. Part 186 - Indirect Food Substances Affirmed as Generally Recognized as Safe. 21 CFR 186.1, 21 CFR 186.1316. 0136d -59- 08/15/89 ------- von Oettlngen, W.F. 1959. The aliphatic acids and their esters - Toxlclty and potential dangers. Am. Hed. Assoc. Arch. Ind. Health. 20: 517-531. Wagner, F.S. 1980. Formic acid and derivatives {formic add). In: K1rk- Othmer Encyclopedia of Chemical Technology, Vol. 11, 3rd ed., M. Grayson and D. Eckroth, Ed. John Wiley and Sons, Inc., New York. p. 251-258. Weast, R.C. 1985. CRC Handbook of Chemistry and Physics, 66th ed. CRC Press, Inc., Boca Raton, FL. p. 162. Welngarten, R. 1932. No title provided. Hed. Wchnschr. 79: 1043. (CHed 1n von Oettlngen, 1959) W1ld1sh, D.J., H. Akagl and N.J. Poole. 1977. Avoidance by herring of dissolved components In pulp mill effluents. Bull. Environ. Cont. Toxlcol. 18(5): 521-525. Wlndholz, M., Ed. 1983. The Merck Index, 10th ed. Merck and Co., Rahway, NJ. p. 605. 0136d -60- 04/07/89 ------- APPENDIX A .LITERATURE SEARCHED , * * This HEED Is based on data Identified by computerized literature searches of the following: * CHEMLINE TSCATS ' . . , CASR online (U.S. EPA Chemical Activities Status Report) TOXLINE TOXLIT TOXLIT 65 RTECS OHM TADS STORET SRC Environmental Fate Data Bases .. - , .. - SANSS . . ' AQUIRE TSCAPP NTIS Federal Register CAS ONLINE (Chemistry and Aquatic) HSDB SCISEARCH Federal Research In Progress These searches were conducted In Hay, 1988, and the following secondary sources were reviewed: ACGIH (American Conference of Governmental Industrial Hyglenlsts). 1986. Documentation of the Threshold Limit Values and Biological Exposure Indices, 5th ed. Cincinnati, OH. ACGIH (American Conference of Governmental Industrial Hyglenlsts). 1987. TLVs: Threshold Limit Values for Chemical Substances In the Work Environment adopted by ACGIH with Intended Changes for 1987-1988. Cincinnati, OH. 114 p. Clayton, G.D. and F.E. Clayton, Ed. 1981. Patty's Industrial Hygiene and Toxicology, 3rd rev. ed., Vol. 2A. John Wiley and Sons, NY. 2878 p. Clayton, G.D. and F.E. Clayton, Ed. 1981. Patty's Industrial Hygiene and Toxicology, 3rd rev. ed.. Vol. 2B. John Wiley and Sons, NY. p. 2879-3816. 0136d -61- 04/07/89 ------- Clayton, 6.D. and F.E. Clayton, Ed. 1982. Patty's Industrial Hygiene and Toxicology, 3rd rev. ed., Vol. 2C. John WHey and Sons, NY. p. 3817-5112. Grayson, H. and D. Eckroth, Ed. 1978-1984. K1rk-0thmer Encyclo- pedia of Chemical Technology, 3rd ed,. John Wiley, and Sons, NY. 23 Volumes. Hamilton, A. and H.L. Hardy. 1974. Industrial Toxicology, 3rd ed. Publishing Sciences Group, Inc., Littleton, HA. 575 p. IARC (International Agency for Research on Cancer). IARC Mono- graphs on the Evaluation of Carcinogenic Risk *t>f Chemicals to Humans. IARC, WHO, Lyons, France. ,. : r. .,/... Jaber, H.M., W.R. Mabey, A.T. L1eu, T.W. Chou and H.L. Johnson. 1984. Data acquisition for environmental transport and fate screening for compounds of Interest to the Office of Solid Waste. EPA 600/6-84-010. NTIS PB84-243906. SRI International, Menlo Park, CA. ; NTP (National Toxicology Program). 1987. Toxicology Research and Testing Program. Chemicals on Standard Protocol. Management Status. Ouellette, R.P. and J.A. King. 1977. Chemical Week Pesticide Register. McGraw-Hill Book Co., NY. Sax, I.N. 1984. Dangerous Properties of Industrial Materials, 6th ed. Van Nostrand Relnhold Co., NY. SRI (Stanford Research Institute). 1987. Directory of Chemical Producers. Menlo Park, CA. U.S. EPA. 1986. Report on Status Report 1n the Special Review Program, Registration Standards Program and the Data Call In Programs. Registration Standards and the Data Call In Programs. Office of Pesticide Programs, Washington, DC. USITC (U.S. International Trade Commission). 1986. Synthetic Organic Chemicals. U.S. Production and Sales, 1985, USITC Publ. 1892. Washington, DC. Verschueren, K. 1983. Handbook of Environmental Data on Organic Chemicals, 2nd ed. Van Nostrand Relnhold Co., NY. Wlndholz, M., Ed. 1983. The Merck Index, 10th ed. Merck and Co., Inc., Rahway, NJ. Worthing, C.R. and S.B. Walker, Ed. 1983. The Pesticide Manual. British Crop Protection Council. 695 p. 0136d -62- 04/07/89 ------- In addition, approximately 30 compendia of aquatic toxlclty data were reviewed, Including the Following: Battelle's Columbus Laboratories. 1971. Water Quality Criteria Data Book. Volume 3. Effects of Chemicals on Aquatic Life. Selected Data from the Literature through 1968. Prepared for the U.S. EPA under Contract No. 68-01-0007. Washington, DC. f Johnson, W.W. and M.T. Flnley. 1980. Handbook of Acute Toxlclty of Chemicals to Fish and Aquatic Invertebrates! Summaries of Toxlclty Tests Conducted at Columbia National Fisheries Research Laboratory. 1965-1978. U.S. Oept. Interior, F1sh and Wildlife Serv. Res. Publ. 137, Washington, DC. McKee, J.E. and H.W. Wolf. 1963. Water Quality Criteria, 2nd ed. Prepared for the Resources Agency of California, State Water Quality Control Board. Publ. No. 3-A. Plmental, D. 1971. Ecological Effects of Pesticides on Non-Target Species. Prepared for the U.S. EPA, Washington, DC. PB-269605. Schneider, B.A. 1979. Toxicology Handbook. Mammalian and Aquatic - Data. Book 1: Toxicology Data. Office of Pesticide Programs, U.S. EPA, Washington, DC. EPA 540/9-79-003. NTIS PB 80-196876. 0136d -63- 04/07/89 ------- to o< Q. APPENDIX B Summary Table for formic Acid I a* Species Inhalation Exposure Subchronlc ID Chronic ID Carcinogenic I ty 10 Oral Exposure Subchronlc rat Chronic rat Carcinogenic Ity ID gtPORTABy_9yAjT ini s Based on chronic toxic Ity: Based on carclnogenlclty: Exposure ID ID ID 150-200 mq calcliM formate/ kg/day In Miltlgeneratlon study (200 ag/kg/day dosage equivalent to foratc acid at 141 ag/kg/day) 150-200 ag ca Ideal formate/ kg/day In Miltlgeneratlon study (200 ag/kg/day dosage equivalent to formic acid at 141 ag/kg/day) ID 1000 NO Effect RfD or q|* Reference * ID NO NA ID NO > NA ID ND NA slightly Increased phagocytosis 1 ag/kg/day Nalorny. 19696 In some tissues; no effects on - reproduction (NOAEL) t, slightly Increased phagocytosis 1 ag/kg/day Nalorny. 1969b In some tissues; no effects on reproduction (NOAEL) ID 10 , NA 1 > Sporn et al., 1962 NA ID - Insufficient data; NO -- not derived; NA ~ not applicable oo ID ------- .APPENDIX C DOSE/DURATION RESPONSE GRAPH(S) FOR EXPOSURE TO FORMIC ACID C.I. DISCUSSION Dose/duration-response graphs for oral exposure to formic add generated by the method of Crockett et al. (1985) using the computer software by Durkln and Meylan (1988) under contract to ECAO-C1nc1nnat1 are presented In Figures C-1 and C-2. Data used to generate these graphs are presented 1n Section C.2. In the generation of these figures all responses are classified as adverse (PEL, AEL or LOAEL) or nonadverse (NOEL or NOAEL) for plotting. If data are available for Inhalation exposure: The ordlnate expresses concentration 1n either of two ways. In flgure(s) {---), the experimental concentration expressed as mg/m3 was multiplied by the time parameters of the exposure protocol (e.g., hours/day and days/week) and Is presented as expanded experimental concentration [expanded exp cone (mg/m3)]. In f1gure(s) (), the expanded experimental concentration was multiplied by the cube root of the ratio of the animal :human body weight to estimate an equivalent human or scaled concentration [scaled cone (mg/m3)] (U.S. EPA, 1980; Mantel and Schnelderman, 1975). The boundary for adverse effects (solid line) Is drawn by Identifying the lowest-adverse-effect dose or concentration at the shortest duration of exposure at which an adverse effect occurred. From this point an Infinite line 1s extended upward parallel to the dose axis. The starting point. 1s then connected to the lowest-adverse-effect dose or concentration at the next longer duration of exposure that has an adverse-effect dose or concentration equal to or lower than the previous one. This process 1s continued to the lowest-adverse-effect dose or concentration. From this point a line Is extended to the right parallel to the duration axis. The region of adverse effects lies above the adverse effects boundary. 0136d -65- 04/07/89 ------- 9 t H It 100088 r IM 9 Z 1800 -r 108 t i iii iiiiiii i iiiiiii 0.00001 0.0001 0.001 0.01 0.1 HUNAN EQUIV MIRATION (fraction lifcspan) "*» ^ \ I ' 1 2 Key: N n F A o NOEL NOAEL PEL AEL NOCEL FIGURE C-l Dose/Duration Response Graph - Oral Exposure to Formic Acid Equivalents Using the Envelope Method 0136d -66- 04/07/89 ------- 1888888 91 01 H 18 188888 T I Z a z 18888 T 1888 T 188 F F o.aaeei N 4- 8.0001 O.OO1 8.81 8.1 HUMAN EQUIU MIRATION (fraction lifcspan) 1 2 Key: N n F A o NOEL NOAEL FEL AEL NOCEL FIGURE C-2 Dose/Duration Response Graph - Oral Exposure to Formic Add Equivalents Using the Censored Data Method 0136d -67- 04/07/89 ------- Using the envelope method, the boundary for no adverse effects (dashed line) 1s drawn by Identifying the highest no-adverse-effects dose or concentration. From this point a line parallel to the duration axis 1s extended to the dose or concentration axis. The starting point 1s then connected to the next highest or equal no-adverse-effect dose or ' -';v'/ concentration at a longer duration of exposure. When this process can no longer be continued, a line Is dropped parallel to the dose or concentration axis to the duration axis. The region of no adverse effects lies below the no-adverse-effects boundary. At both ends of the graph between the adverse-effects and no-adverse-effects boundaries are regions of ambiguity. The area (1f any) resulting from Intersection of the adverse-effects and no-adverse-effects boundaries Is defined as the region of contradiction. In the censored data method, all no-adverse-effect points located In the" region of contradiction are dropped from consideration and the no-adverse-effect boundary 1s redrawn so that 1t does not Intersect the adverse-effects boundary and no region of contradiction Is generated. This method results In the most conservative definition of the no-adverse-effects region. The data, a total of 15 records. Include several LD~Q values and effect levels from 1-day to 3-year studies In several species. The three human studies reported local Irritation or mortality from 1-day exposures. Little area of contradiction 1s apparent (see Figure C-l). Figure C-2 clearly delineates a boundary for no adverse effects that Is well above the recommended oral RfO of 1 mg/kg/day (70 mg/day for a 70 kg human). 0136d -68- 04/07/89 ------- ------- RECORD #3: Comment: Citation: RECORD #4: Comment: Citation: RECORD #5: Comment: Citation: Species: Rats Sex: NR Effect: PEL Route: Oral (NOS) Number Exposed: NR Number Responses: NR Type of Effect: DEATH Site of Effect: BODY Severity Effect: 9 1050 value; details not av< Guest et al., 1982 Species: Rats Sex: NR Effect: PEL Route: Oral (NOS) Number Exposed: NR Number Responses: NR Type of Effect: DEATH Site of Effect: BODY Severity Effect: 9 1050; details of study not NIOSH. 1988 Species: Mice Sex: NR Effect: PEL Route: Oral (NOS) Number Exposed: NR Number Responses: NR Type of Effect: DEATH Site of Effect: BODY Severity Effect: 9 Dose: Duration Exposure: Duration Observation: ** Ulable. % . Dose: Duration Exposure: Duration Observation: available. Dose: Duration Exposure: Duration Observation: 1830.000 1.0 days 1.0 days - .. . . . _ . .. 1100.000 1.0 days 1.0 days 700.000 1.0 days 1.0 days 1050 value; details not available. NIOSH, 1988 0136d -70- 04/07/89 ------- RECORD #6: Comment: Citation: RECORD #7: Comment: Citation: RECORD #8: Comment: Citation: Species: Mice Dose: Sex: NR Duration Effect: PEL Duration Route: Oral (NOS) *i Number Exposed: NR Number Responses: NR Type of Effect: DEATH Site of Effect: " BODY Severity Effect: 9 1050 value; details not available. Malorny. 1969b Species: Rabbits Dose: Sex: NR Duration Effect: FEL Duration Route: Oral (NOS) Number Exposed: NR Number Responses: NR Type of Effect: DEATH Site of Effect: BODY Severity Effect: 9 Details not available. Guest et al., 1982 Species: Humans Dose: Sex: NR Duration Effect: FEL Duration Route: Oral (NOS) Number Exposed: 6 Number Responses: 1 Type of Effect: DEATH Site of Effect: BODY Severity Effect: 9 This level has been Identified as mor Jefferys and Wiseman, 1980 1100.000 Exposure: 1.0 days Observation: 1.0 days 4000.000 Exposure: 1.0 days Observation: 1 .0 days 429.000 Exposure: 1 .0 days Observation: 1 .0 days talHy threshold. 0136d -71- 04/07/89 ------- RECORD #9: Comment: Citation: RECORD #10: Species: Rats Sex: Both Effect: NOCEL Route: -Water Number Exposed: Number Responses Type of Effect: SHe of Effect: Severity Effect: Unclear whether Malorny, 1969b Species: Human Sex: NR Effect: AEL Route: Oral Number Exposed: Number Responses Type of Effect: Site of Effect: Severity Effect: NR " : NR CANCR COLON 3 all organs s (NOS) 23 : NR IRRIT MOUTH 6 Dose: 200.000 Duration Exposure: 2.0 years Duration Observation: 2.0 years NR NR NR NR CANCR CANCR LIVER KIDNY 3 3 and tissues were examined Dose: 71.400 Duration Exposure: 1.0 days Duration Observation: 1.0 days 3 NR IRRIT COLON 6 Comment: Citation: RECORD #11: Oropharyngeal and gastrointestinal burns are the most commonly reported effects from oral exposure. Jefferys Species: Sex: Effect: Route: and Wiseman, 1980 Humans Hale NOEL Food Dose: 8.000 Duration Exposure: 4.0 weeks Duration Observation: 4.0 weeks Comment: Citation: Number Exposed: NR Number Responses: NR Type of Effect: IRRIT Site of Effect: MOUTH Severity Effect: 6 Formic acid was administered dally In lemonade. At "higher dose", "local actions" (presumably burns) were observed. Lebbln, 1916 0136d -72- 04/07/89 ------- RECORD #12: Species: Sex: Effect: Route: Rats NR AEL Food Dose: 250.000 Duration Exposure: 6.0 weeks Duration Observation: 6.0 weeks Number Exposed: 0 Number Responses: NR Type of Effect: WGTIN Site of Effect: BODY Severity Effect: 3 Comment: Citation: RECORD #13: Slight growth Inhibition, not statistically significant. Sporn et al., 1962 Species: Rats Sex: Both Effect: AEL Route: Water Number Exposed: Number Responses: Type of Effect: SHe of Effect: Severity Effect: 70 0 HE MAT BLOOD 3 Dose: Duration Exposure: Duration Observation: 70 NR DEATH FETUS 9 1400.000 7.0 months 7.0 months Comment: Endpolnts examined were reproductive performance, hematology, liver nitrogen content, adrenal ascorbic acid content. 1% formic add administered continuously for 7 months. Citation: Sporn et al., 1962 RECORD #14: Species: Rats Sex: Both Effect: NOAEL Route: Water Number Exposed: Number Responses: Type of Effect: SHe of Effect: Severity Effect: 8 NR FUNR. TESTE 3 Dose: Duration Exposure: Duration Observation: 24 32 NR NR FUNR WGTIN OVARY BODY 3 3 200.000 3.0 years 3.0 years Comment: Citation: No reproductive function, growth or organ function effects noted. Slight changes In lung, spleen, abdominal lymph nodes could not be attributed to administration of 0.2% calcium formate 1n water. Malorny, 1969b 0136d -73- 04/07/89 ------- RECORD #15; Comment: Citation: Species; Sex: Effect: Route: Rats Both NOAEL Water Number Exposed: Number Responses; Type of Effect: Site of Effect: Severity Effect: fi NR NR HISTO BODY 3 Dose: 400.000 Duration Exposure: 2.0 years Duration Observation: 2.0 years 300-400 mg/kg/day (0.4% calcium formate In drinking water Induced no hlstopathologlc lesions. No further details reported. Malorny, 1969b NR = Not reported 0136d -74- 04/07/89 ------- |