------- DISCLAIMER This report Is 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 ------- ------- EXECUTIVE SUMMARY 4-Am1nopyr1d1ne Is an odorless, white crystalline compound that 1s stable to light. It 1s moderately soluble In water (Farm Chemicals Handbook, 1987). The compound Is manufactured by Rellly Tar & Chemical Corporation (Indianapolis, IN) by a synthetic process (SRI, 1987); recent production figures are not available. 4-Am1nopyr1d1ne, sold under the trade name Avltrol, Is used as a registered bird repellent (Farm Chemicals Handbook, 1987; Hadler, 1982). Ingestlon of 4-am1nopyr1d1ne-laden bait by birds results In aberrant behavior that frightens away other flock members (Hadler, 1982; Carlson, 1984). 4-Amlnopyrldlne can also be used as a chemical Intermediate (Hawley, 1981). When released to the atmosphere, 4-am1nopyr1d1ne can be expected to exist partly 1n the gas-phase where 1t will be degraded rapidly by reaction / with photochemlcally-produced hydroxyl radicals. Using the method of Atkinson (1987), the half-life for this reaction in a typical ambient atmo- sphere can be estimated to be 8 hours. Because 4-am1nopyr1d1ne has very low volatility from soil (Sims and Sommers, 1985,1986) or water, however, 1t Is not expected to partition significantly to air when released to soil or water. By analogy to aromatic amines as a chemical class (Mill and Mabey, 1985), 4-am1nopyr1d1ne may undergo significant degradation In sunlit natural water by reaction with photochemically-generated free radicals. Although 4-am1nopyr1d1ne 1s soluble 1n water, significant partitioning from the water column to suspended solids and sediment may occur because of a covalent binding reaction that has been observed 1n other aromatic amines (Parrls, 1980). Hydrolysis, direct photolysis and bVoconcentratlon may not be 1v ------- Important. The degradation of 4-am1nopyr1d1ne 1n soil has been studied by several Investigators (Na1k et al., 1972; Betts et al., 1976; Starr and Cunningham, 1975; Sims and Sommers, 1985, 1986).. Although the blodegradatlon 1n soil can vary greatly, their results Indicate that 4-am1nopyr1d1ne 1s generally resistant to blodegradatlon 1n soil. Soil half-lives ranging from 3 months to >22 months have been observed (Starr and Cunningham, 1975). Soil column leaching studies have shown that 4-am1no-pyr1d1ne Is not leached significantly In either alkaline or addle soils, although mobility 1n alkaline soils 1s slightly greater (Starr and Cunningham, 1975). 4-Am1nopyr1d1ne 1s released directly to the environment (primarily soil) through Us use as a bird repellent. Environmental releases from waste streams or fugitive emissions from the manufacture of 4-am1nopyr1d1ne or Us use as a chemical Intermediate may be minor In relation to Us use as a bird repellent. From a NIOSH survey (NOES) conducted between 1981 and 1983, It has been estimated that annually about 898 U.S. workers are potentially i exposed to 4-am1no-pyr1d1ne (NIOSH, 1985). Pertinent water, food, air or dermal monitoring data were not located In the available literature cited 1n Appendix A. Studies assessing the acute toxldty of 4-am1nopyr1d1ne to fish revealed that toxldty was not dependent on water temperature or hardness. The 96-hour LC5Qs for channel catfish and blueglll sunflsh exposed to 4-am1no- pyrldlne ranged from 2.43-7.56 mg/l (Schafer and Harking, 1975). The toxldty of 4-am1nopyr1d1ne to aquatic Invertebrates was assessed by Marking and Chandler (1981). Juvenile glass shrimp were the most sensitive spedes tested (96-hour LC5Q=0.37 mg/l), followed by mayfly nymphs (0.58 mg/l), crayfish (2.2 mg/l), frog larvae (2.4 mg/l), water fleas (3.2 ------- mg/l), caddlsfly larvae (15 mg/l), Asiatic clams (45 mg/l) and snails (62 mg/l). The NOEC for larval frogs appears to be <1 mg/l (Harking and Chandler, 1981). The tox1c1ty of 4-amlnopyrldlne to birds was studied extensively by a series of Investigators. Oral L05Q values ranged from 2.4-35 mg/kg for periods of exposure and observation of varying lengths. There was no evidence that reproduction among the progeny of 4-am1nopyr1d1ne-treated birds was affected by treatment of the parents (Schafer et al., 1975). There was no evidence of secondary hazard potential among predatory birds from the consumption of 4-am1nopyr1d1ne-k1lled birds (Holler and Schafer, 1982). Pharmacoklnetlc data 1n humans Indicate that 4-am1nopyr1d1ne 1s absorbed readily and nearly completely from the gastrointestinal tract (Uges et al., 1982). 4-Am1nopyr1d1ne appears to distribute widely throughout the tissues (Rupp et al., 1983), but excretion data (Uges et al., 1982) suggest that / bloaccumulatlon does not occur 1n humans. Metabolites have not been found In the urine of humans treated with 4-am1nopyr1d1ne, and blotransformatlon appears unlikely (Uges et al., 1982). In a study using volunteers (Uges et al., 1982), ~85X of an oral dose and 90% of an Intravenous dose of 4-am1no- pyrldlne was recovered 1n the urine, with an elimination half-life of 3.6 hours. 4-Am1nopyr1d1ne acts on the nervous system to Increase the release of acetylchollne. The compound has been used In humans for the reversal of residual neuromuscular blockade from some neuromuscular blocking agents and antibiotics. Experimental uses Include treatment of patients with Botullnus Intoxication, myoneural disorders and Alzheimer's disease. The clinical use of 4-am1nopyr1d1ne Is limited by Us narrow therapeutic Index; following a clinical dose of 0.15-0.3 mg/kg (route not specified), the only side effects v1 ------- noted were a slight Increase 1n systolic blood pressure and heart rate, while doses >0.5 mg/kg were Hkely to result 1n restlessness, confusion, nausea, weakness and ton1c-clon1c seizures (Agoston et al., 1985). A case report of an accidental oral exposure (Spyker et al., 1980} Indicated that a single dose of -0.6 mg/kg results In frank effects 1n humans. The only data concerning the subchronlc oral toxlclty of 4-am1nopyr1d1ne are two 90-day studies 1n the OPP CBI files summarized by U.S. EPA (1980b). Kohn (1968) observed hyper1rr1tab1l1ty 1n rats at dietary concentrations of 30 and 300 ppm 4-am1nopyr1d1ne, with no effects noted at 3 ppm. In dogs (Cervenka and Vega, 1968), salivation, muscular weakness and decreased bralnwelght were observed at a doses of >1.0 mg/kg/day. 4-Am1nopyr1d1ne has tested negative for reverse mutation 1n Salmonella typh1mur1um (Ogawa et al,, 1986; Wakabayshl et al., 1982). Data concerning the carclnogenlcUy, reproductive effects and toxlclty of 4-am1nopyr1d1ne following Inhalation or chronic oral exposure were not available 1n the / literature cited 1n Appendix A. No effects on reproduction or fetal development were reported 1n rats treated with 1-5 mg/kg/day by Intraperl- toneal Injection for 1 or 6 months (MHsov and Uzunov, 1972). The only available guideline or standard for 4-am1nopyr1d1ne Is an RQ of 1000 pounds (U.S. EPA, 1985). • Because of the lack of data concerning cardnogen1c1ty In humans and animals, 4-am1nopyr1d1ne can be classified as a CAG Group D chemical. The derivation of carcinogenic potency factors and a cancer-based RQ U pre- cluded by the lack of carclnogenldty data. Based on the 90-day rat study by Kohn (1968), subchronlc and chronic oral RfDs of 0.0002 mg/kg/day (0.01 mg/day) and 0.0002 mg/kg/day (0.001 mg/day) were calculated. These RfDs should be considered tentative because only limited Information concerning the CBI studies (Cervenka and Vega, 1968; Kohn, 1968) were available. ------- Based on low confidence In the study and the data base, confidence In these RfDs 1s low. Data were Insufficient for the development of freshwater and saltwater criteria for 4-am1nopyr1d1ne. A chronic toxic 1-ty. RQ for 4-amlno- pyrldlne of 100 pounds was calculated from the Kohn (1968) 90-day rat study. ------- 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. 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. M1crob1al Degradation ... 5 2.2.5. Volatilization 5 2.2.6. Adsorption. ... .... 5 2.2.7. . Bloconcentratlon. . 6 2.3. SOIL '. . 6 ./'•.• ,2.3.1. Adsorption 6 12.3.2. M1crob1al Degradation/Persistence 7 1 2.3.3. Volatilization 8 2.4. SUMMARY , 8 3. EXPOSURE 10 3.1. HATER 10 3.2. FOOD 10 3.3. AIR. 10 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 13 4.1.3. Effects on Flora 14 4.1.4. Effects on Bacteria 14 1x ------- TABLE OF CONTENTS (cont.) Page 4.2. TERRESTRIAL TOXICOLOGY . . . . . 14 4.2.1. Effects on Fauna. ...'.• .' 14 U4.2.2. Effects on Flora 22 4.3. FIELD STUDIES 22 4.4. SUMMARY 22 5. PHARMACOKINETCS 23 5.1. ABSORPTION . 23 5.2. DISTRIBUTION 23 5.3. METABOLISM 24 5.4. EXCRETION 24 5.5. SUMMARY 25 6. EFFECTS 27 6.1. SYSTEMIC TOXICITY . . . 27 6.1.1. Inhalation Exposure 27 6.1.2. Oral Exposure . 27 6.1.3. Other Relevant Information. . 28 6.2. CARCINOGENICITY 31 6.3. MUTAGENICITY 31 6.4. TERATOGENICITY 31 6.5. OTHER REPRODUCTIVE EFFECTS 31 6.6. SUMMARY , 31 7. EXISTING GUIDELINES AND STANDARDS ',• 34 7.1. HUMAN. 34 7.2., AQUATIC 34 8. RISK ASSESSMENT 35 8.1. CARCINOGENICITY. 35 8.1.1. Weight of Evidence , 35 8.1.2. Quantitative Risk Estimates . . . 35 8.2. SYSTEMIC TOXICITY 35 8.2.1. Inhalation Exposure ... 35 8.2.2. Oral Exposure . . . 35 8.3. AQUATIC 38 ------- TABLE OF CONTENTS (cont.) Page 9. REPORTABLE QUANTITIES ..... 40 9.1. BASED ON SYSTEMIC TOXICITY 40 9.2. BASED ON CARCINOGENICITY 40 10. REFERENCES 45 APPENDIX A: LITERATURE SEARCHED 55 APPENDIX B: SUMMARY TABLE FOR 4-AMINOPYRIDINE 58 x1 ------- LIST OF TABLES No. Title Page 4-1 Acute Toxldty of 4-AmlnopyMdlne to 36 Species of Birds. . . 15 6-1 Acute Toxldty of 4-Am1nopyr1d1ne to Mammals. . . '".:. 30 6-2 Hutagenlc Testing of 4-Am1nopyr1d1ne ." . 32 9-1 Oral Toxldty Data for 4-Am1nopyr1d1ne 41 9-2 Composite Scores for 4-Am1nopyr1d1ne Based on Oral Toxldty . 42 9-3 Minimum Effective Dose (MED) and Reportable Quantity (RQ) . . 43 ------- LIST OF ABBREVIATIONS ADI BCF CAS CNS CS GMAV HC1 LD50 LOAEL MED NOAEL NOEC NOEL NOES pKa ppm RBC RfO RQ RVd RVe TLC WBC Acceptable dally Intake Bloconcentratlon factor ; Chemical Abstract Service Central nervous system Composite score Frank effect level Genus mean acute value Hydrochlorlde salt Octanol/water partition coefficient Concentration lethal to 50% of recipients (and all other subscripted dose levels) Dose lethal to SOX of recipients Lowest-observed-adverse-effect level Minimum effect dose No-observed-adverse-effect level No-observed-effect concentration No-observed-effect level National Occupational Exposure Survey Negative log-|g of dissociation constant Parts per million Red blood cell Reference dose Reportable quantity Dose-rating value Effect-rating value Thin layer chromatography White blood cell ------- 1. INTRODUCTION 1.1. STRUCTURE AND CAS NUMBER 4-AmlnopyMdlne 1s a common chemical name for the compound currently referenced 'by CAS as 4-pyr1d1nam1ne (SANSS, 1988). Other synonyms for 4-am1nopyr1d1ne Include 4-AP, p-am1nopyr1d1ne, am1no-4-pyr1d1ne, gamma- pyrldylamlne and 4-pyr1dy1am1ne (SANSS, 1988). It 1s also known by the tradename Avltrol (Farm Chemicals Handbook, 1987). The structure, molecular weight, empirical formula and CAS Registry number for 4-am1nopyr1d1ne are as follows: Molecular weight: 94.12 Empirical formula: CrH,N? CAS Registry number: 504-24-5 1.2. PHYSICAL AND CHEMICAL PROPERTIES 4-Am1nopyr1d1ne 1s an odorless, white crystalline compound that 1s stable to light and moderately soluble 1n water (Farm Chemicals Handbook, 1987). It Is soluble In alcohol, ether and benzene (Weast, 1985). Selected physical properties are as follows: Melting point: < 158-9°C Weast, 1985 Boiling point: 273.5°C Hawley, 1981 Vapor pressure: at 180°C 13 mm Hg Weast, 1985 at 25°C (estimated) 0.00122 mm Hg U.S. EPA, 1987 Water solubility: at 25°C 76,600-83,000 ppm U.S. EPA/NIH. 1988 0124d -1- 09/19/88 ------- Log Kow: 0.26 Hansch and Leo, 1985 pKa at 25°C 9.11 Weast, 1985 A1r conversion mg/m3 = 3.9 ppm factors (25*C): ppm = 0.26 mg/m3 . In general, the aminopyMdines react with alkylatlng agents at the aromatic nitrogen to give derivatives (Goe, 1982). With a pKa of 9.11 at 25°C (Weast, 1985), 4-am1nopyr1d1ne Is a strong base 1n aqueous solution (U.S. EPA/NIH, 1988). 1.3. PRODUCTION DATA 4-Am1nopyr1d1ne Is manufactured by Rellly Tar & Chemical Corporation (Indianapolis, IN), which produces a wide range of pyrldlne compounds by synthetic processes (SRI, 1987). 4-Am1nopyr1d1ne can be produced by the hydrogenatlon of 4-n1tro pyr1d1ne-N-ox1de 1n the presence of a Raney-nlckel or palladium-carbon catalyst (Goe, 1982). Recent production figures for 4-am1nopyr1d1ne were not located. Rellly Tar & Chemical Corporation sells 4-am1nopyr1d1ne (97% minimum purity) 1n packages ranging from 1 kg cans to 55 gallon drums (Kuney, 1986). The U.S. EPA TSCA Production File for 1977 (U.S. EPA, ,1977) cites Rellly Tar & Chemical Corp. as the only U.S. manufacturer of 4-am1nopyr1d1ne; however, * • ( their 1977 production volume 1s listed as confidential. 1.4. USE DATA 4-Am1nopyr1d1ne, sold under the trade name AvHrol, Is used as a bird repellent (Farm Chemicals Handbook, 1987; Hadler, 1982). When Ingested from bait, 4-am1nopyr1d1ne acts as a soporific, causing birds to utter distress calls and fly In uncoordinated and spiral patterns. This aberrant behavior frightens other feeding flock members away from the crop area (Hadler, 1982; Carlson, 1984). Some or all applications of Avltrol may be classified by 0124d _2- 09/19/88 ------- the U.S. EPA as a registered pesticide. It Is used to control crows, pigeons, grackles, starlings, sparrows, cowblrds, gulls and blackbirds In and around structures and agricultures (sunflowers, field corn, sweet corn). It Is applied 1n grain baits that contain 0.5-3.0% 4-am1nopyr1d1ne or 25-50% powder concentrate (Farm Chemicals Handbook, 1987). 4-Am1nopyr1d1ne can also be used as an Intermediate (Hawley, 1981). 1.5. SUMMARY 4-Am1nopyr1d1ne Is an odorless, white crystalline compound that 1s stable to light. It Is moderately soluble 1n water (Farm Chemicals Hand- book, 1987). The compound 1s manufactured by Rellly Tar & Chemical Corpora- tion (Indianapolis, IN) by a synthetic process (SRI, 1987); recent produc- tion figures are not available. 4-Am1nopyr1d1ne, sold under the trade name Avltrol, 1s used as a registered bird repellent (Farm Chemicals Handbook, 1987; Hadler, 1982). Ingestlon of 4-am1nopyr1d1ne-laden bait by birds results 1n aberrant behavior that frlghtenfs away other flock members (Hadler, 1982; Carlson, 1984). 4-Am1nopyr1d1ne can also be used as an Intermediate (Hawley, 1981). 0124d -3- 09/19/88 ------- 2. ENVIRONMENTAL FATE AND TRANSPORT 2.1. AIR Organic compounds having vapor pressures >0.0001 mm Hg are expected to exist almost entirely In the vapor phase In the ambient atmosphere (E1senre1ch et al., 1981). Based on an estimated vapor pressure of 0.00122 mm Hg at 25°C (U.S. EPA, 1987), 4-am1nopyr1d1ne can be expected to exist 1n the vapor phase 1n ambient air. 2.1.1. Reaction with Hydroxyl Radicals. Using the method of Atkinson (1987), the rate constant for the vapor phase reaction of 4-am1nopyr1d1ne with photochemlcally produced hydroxyl radicals can be estimated to be 47.9xlO~12 cm3/molecule-sec at 25°C. Assuming a typical ambient atmospheric hydroxyl radical concentration of 5xlOf molecules/cm3 (Atkinson, 1985), the half-life for this reaction can be estimated to be -8 hours. Thus, reaction with hydroxyl radicals Is expected to cause rapid loss of 4-am1nopyr1d1ne 1n the atmosphere. 2.1.2. Physical Removal Processes. 4-Am1nopyr1d1ne Is soluble 1n water (Weast, 1985); therefore, removal of the free base or Its salts from the atmosphere by wet deposition processes (rainfall, etc.) may be possible. If the salts of this compound exist In participate form In the atmosphere, they may be partly removed by dry deposition. 2.2. HATER 2.2.1. Hydrolysis. Aromatic amines are generally resistant to aqueous environmental hydrolysis (Harris, 1982). Therefore, 4-am1nopyr1d1ne 1s not expected to hydrolyze significantly 1n water. t 2.2.2. Oxidation. As a chemical class, aromatic amines can react relatively rapidly 1n sunlit natural water by reaction with photochemical1y- geqerated free radicals such as hydroxyl radicals and peroxy radicals (Mill 0124d -4- 10/21/88 ------- and Mabey, 1985). Typical half-lives for the reaction of aromatic amines with hydroxyl and peroxy radicals on the surface of natural water are -30 and 19.2 hours, respectively, (Mill and Habey, 1985). Although photooxlda- tlon rate constants specifically for 4-am1nopyr1d1ne are not available, the data cited above suggest that photooxldatlon of 4-am1nopyr1d1ne In natural water may be an Important loss process. 2.2.3. Photolysis. 4-Am1nopyr1d1ne Is reported to be stable to light (Farm Chemicals Handbook, 1987); therefore, direct photolysis Is not expected to be significant 1n the environment. As noted above, however, 4-am1nopyr1d1ne may react relatively rapidly with oxldants formed by sunlight In natural water. 2.2.4. M1crob1al Degradation. Pertinent data, regarding the mlcroblal degradation of 4-am1nopyr1d1ne In water could not be located In the available literature as dted 1n Appendix A. Based on the soil degradation data presented In Section 2.3., however, 4-am1nopyr1d1ne may be resistant or only slowly biodegradable by microbes 1n water. 2.2.5. Volatilization. Using the chemical bond estimation method of H1ne and Mookerjee (1975), the Henry's Law constant for 4-am1nopyr1d1ne can be estimated to be 2.81x10"' atm-mVmol at 258C. This value of Henry's Law constant Indicates that volatilization from water Is not environmentally Important (Thomas, 1982). 2.2.6. Adsorption. Experimental data regarding the adsorption of 4-am1nopyr1d1ne to suspended solids and sediment 1n water could not be located 1n the available literature as dted 1n Appendix A. Although 4-am1nopyr1d1ne 1s soluble 1n water, the adsorption/leaching data presented In Section 2.3. suggest that some partitioning from the water column to humlc materials present 1n suspended solids and sediment may occur as a result of covalent binding. 0124d -5- 09/19/88 ------- 2.2.7. B1oconcentrat1on. The BCF of an organic chemical may be estimated from the equations (Bysshe, 1982), log BCF » 0.76 log Kow - 0.23 and ; (2-1) log BCF = 2.791 - 0.564 log water solubility (In ppm) (2-2) Based on a log K of 0.26 (Hansch and Leo, 1985) and a water solubility of -80,000 ppm at 25°C (U.S. EPA/NIH, 1988), the BCF for 4-am1nopyr1d1ne can be estimated from both equations to be ~1. This Indicates that bloconcen- tratlon 1n aquatic organisms may not be significant. 2.3. SOIL 2.3.1. Adsorption. Starr and Cunningham (1975) measured the leaching of 14C alpha-labeled 4-am1nopyr1d1ne In three alkaline soils (pH 7.6-7.8) and four acidic soils (pH 4.1-5.8). The leaching tests were conducted using 15 cm long soil columns that received an Initial surface application of the 4-am1nopyr1d1ne. Over a 20-day period, 1-7 Inches of simulated rainfall t were applied to each column. Sufficient water was applied every 2-3 days to produce an effluent from the bottom of each column. At the end of the 20-day period, only 0.02-0.18% of the applied radioactivity had been recovered In the effluents from the alkaline soils, while <0.01% was recovered In the effluents from the addle soils. Examination of the soil columns after the 20-day period Indicated that 95-99% of the radioactivity applied to the alkaline soils had remained 1n the upper 1-Inch layer of soil and that essentially all of radioactivity applied to the acidic soils was In the upper 1-Inch layer. These tests clearly demonstrated that 4-am1nopyr1- dlne may remain adsorbed strongly onto soil colloids; therefore, significant leaching 1s not expected to occur In most soils. 0124d -6- 10/21/88 ------- Aromatic amines have been observed to undergo rapid and reversible covalent binding with humlc materials In aqueous solution (Parrls, 1980). The Initial fast reaction of the amlne group with carbonyl of humate to form 1m1ne Unkoyd 1s followed by a slower and much less reversible reaction believed to represent the addition of the amlne to qulnoldal structures, followed by oxidation of the product to give an amlno-substUuted qulnone. These processes represent pathways by which aromatic amines may be converted to latent forms In the biosphere (Parrls, 1980). This covalent binding may account for the strong adsorption observed by Starr and Cunningham (1975) in their soil column leaching studies. 2.3.2. Mlcroblal Degradation/Persistence. The degradation of 4-amlno- pyrldlne 1n soil has been studied by several Investigators (Na1k et al., 1972; Betts et al., 1976; Starr and Cunningham, 1975; S1ms and Sommers, 1985, 1986). Their results Indicate that 4-am1nopyr1d1ne 1s not rapidly destroyed 1n soil, and may be relatively persistent. Na1k et al. (1972) examined the degradation of 4-am1nopyr1d1ne 1n enrichment cultures using a 1 mM solution of the chemical and a 0.5% aqueous solution of fertile garden soil as the Inocula. The disappearance of applied 4-am1nopyr1d1ne required >170 days under both aerobic and anaerobic * conditions. The authors concluded that am1nopyr1d1ne Is resistant to mlcroblal attack. Betts et al. (1976) examined the degradation of 14C-labelled 4-am1no- i pyrldlne In three different soils and 1n pure cultures of five soil micro- organisms. In aerobic soil degradation experiments, a lag period of -20 days was required before a significant rate of 14CO_ evolution was observed In any of the soils. At the end of 60 days, 6-24% of the applied radioactivity had been recovered as 14CO_. In 60-day flooded soil 0124d -7- 09/19/88 ------- tests, 21-24% of applied radioactivity was lost; however, the loss may have been due to binding to the soil In an unextractable form rather than to actual degradation. Pure cultures of five microorganisms Isolated from soil were unable to metabolize 4-am1nopyr1d1ne In 5-6 days of Incubation. Starr and Cunningham (1975) studied the degradation of 14C-labeled 4-am1nopyr1d1ne In various alkaline and addle soils under varying conditions. Under anaerobic conditions, metabollzatlon to 14CO_ was negligible. Under aerobic conditions, a lag period of at least 1 week was required before significant conversion to "CO- was observed. Metaboll- zatlon rates varied significantly with soil type, temperature and moisture content. A 3-month C(L evolution rate at 30°C varied from 0.4% 1n an addle (pH 4.1} loam soil to >50% In a lighter textured, alkaline (pH 7.8) loamy sand. The metabollzatlon half-life of 4-am1nopyr1d1ne In the soils tested ranged from -3 months to >22 months. Sims and Sommers (1985,1986) found 4-amlnopyrldlne to be generally / resistant to degradation 1n soil decomposition studies using a silt loam soil. Only -6% degradation at an Initial concentration of 2 mmol/kg was observed In 64 days. The authors suggested that this resistance to blodegradatlon may have been due to toxlclty of the 4-am1nopyr1d1ne to the microorganisms. 'In the Belts et al. (1976) pure culture study mentioned above, 4-am1nopyr1d1ne was not toxic to the microorganisms, but also was not metabolized by the microorganisms. 2.3.3. Volatilization. Sims and Sommers (1985, 1986) reported that 4-am1nopyr1d1ne has very low volatility from soil. 2.4. SUMMARY When released to the atmosphere, 4-am1nopyr1d1ne can be expected to exist partly 1n the gas-phase where 1t will be degraded rapidly by reaction 0124d -8- 09/19/88 ------- with photochemically-produced hydroxyl radicals. Using the method of Atkinson (1987), the half-life for this reaction In a typical ambient atmosphere can be estimated to be 8 hours. Because 4-am1nopyr1d1ne has very low volatility from soil (S1ms and Sommers, 1985,1986) or water, however, It Is not expected to partition significantly to air when released to soil or water. By analogy to aromatic amines as a chemical class (Mill and Mabey, 1985), 4-am1nopyr1d1ne may undergo significant degradation In sunlit natural water by reaction with photochemically-generated free radicals. Although 4-am1nopyr1d1ne Is soluble 1n water, significant partitioning from .the water • column to suspended solids and sediment may occur because of a covalent binding reaction that has been observed In other aromatic amines (Parrls, 1980). Hydrolysis, direct photolysis and bloconcentratlon may not be Important. The degradation of 4-am1nopyr1d1ne 1n soil has been studied by several Investigators (Na1k et al., 1972; Betts et al., 1976; Starr and Cunningham, 1975; S1ms and Sommers, 1985, 1986). Although the blodegradatlon » In soil can vary greatly, their results Indicate that 4-am1nopyr1d1ne Is generally resistant to blodegradatlon In soil. Soil half-lives ranging from 3 months to >22 months have been observed (Starr and Cunningham, 1975). Soil column leaching studies have shown that 4-amlnopyrldlne 1s not leached significantly 1n either alkaline or addle soils, although mobility In alkaline soils 1s slightly greater (Starr and Cunningham, 1975). 0124d -9- 10/21/88 ------- 3. EXPOSURE 4-Am1nopyr1d1ne 1s released directly to the environment (primarily soil) through Us use as a bird repellent. It Is applied to crop fields 1n grain baits containing 0.5-3.0% 4-am1nopyr1d1ne or as a 25-50% powder concentrate (Farm Chemicals Handbook, 1987). Environmental releases from waste streams or fugitive emissions from the manufacture of 4-am1nopyr1d1ne or Us use as a chemical Intermediate may be minor In relation to Us use as a bird repellent. From the preliminary results of the NIOSH survey (NOES) conducted between 1981 and 1983, 1t has been estimated that 898 U.S. workers per year are potentially exposed to 4-am1nopyr1d1ne (NIOSH, 1985). 3.1. WATER Pertinent data regarding the monitoring of 4-am1nopyr1d1ne In water could not be located 1n the available literature as dted 1n Appendix A. 3.2. FOOD Pertinent data regarding the monitoring of 4-amlnopyrldlne 1n food could not be located 1n the available literature as cited 1n Appendix A. 3.3. AIR Pertinent data regarding the monitoring of 4-am1nopyr1d1ne In air could not be located In the available literature as cited 1n Appendix A. 3.4. DERMAL / Pertinent data regarding dermal monitoring of 4-am1nopyr1d1ne could not be located In the available literature as cited In Appendix A. 3.5. SUMMARY 4-Am1nopyr1d1ne Is released directly to the environment (primarily soil) through Us use as a bird repellent. Environmental releases from waste 0124d -10- 10/21/88 ------- streams or fugitive emissions from the manufacture of 4-am1nopyr1d1ne or Ususe as a chemical Intermediate may be minor 1n relation to Us use as a bird repellent. From a NIOSH survey (NOES) conducted between 1981 and 1983, It has been estimated that annually about 398 U.S. workers are potentially exposed to 4-am1nopyr1d1ne (NIOSH, 1985). Pertinent water, food, air or dermal monitoring data could not be located 1n the available literature as cited In Appendix A. 0124d -11- 10/21/88 ------- 4. ENVIRONMENTAL TOXICOLOGY 4.1. AQUATIC TOXICOLOGY 4.1.1. Acute Toxic Effects on Fauna. Schafer and Harking (1975) assessed * "i the acute toxlclty of 4-am1nopyr1d1ne to channel catfish, Ictalurus punc- tatus. and blueglll sunflsh, LepomVs macrochlrus. at various temperatures and water hardnesses. Water hardness concentrations ranged from 10-13, 40-48, 160-180 and 280-320 mg/l as CaCO, for very soft, soft, hard and very hard water, respectively. Toxdty of 4-am1nopyr1d1ne to catfish varied by <2-fo1d based on variations 1n water hardness and temperature. The static acute 3-, 6-, 24- and 96-hour LC5Qs (and 95X confidence limits) for channel catfish exposed to 4-am1nopyr1d1ne at 22°C 1n soft water were 13.8 (12.3-15.5),< 13.8 (12.3-15.5), 9.35 (8.3-10.6) and 5.B mg/l (5.2-6.4), respectively. Values for the 6-, 24- and 96-hour exposure periods for catfish 1n soft water at 17°C were 16.4 (13.8-19.4), 9.8 (8.6-11.2) and 4.36 mg/l (3.9-4.8), respectively. Toxldty of 4-am1nopyr1d1ne to catfish at 12°C ranged from 4.36 mg/l (LCCQ) ^n verv nard water to 8.74 mg/l (LC5Q) In soft water after 24 hours. The 96-hour LC5Qs ranged from 2.43 mg/l 1n very hard water to 4.00 mg/l 1n hard, soft and very soft water. The ;3-, 6-, 24- and 96-hour LC5Qs (and 95% confidence limits) for blueglll sunflsh exposed to 4-am1nopyr1d1ne at 22'C 1n soft water were 18.1 (15.3-21.4), 15.0 (13.0-17.3). 12.3 (10.7-14.1) and 7.56 mg/l (6.3-9.1), respectively. Values 1n soft water at 17°C were 18.1 (15.3-21.4), 16.2 (14.1-18.6), 11.8 (9.7-14.3) and 5.60 mg/l (4.8-6.5), respectively. The 3-hour LC.Q for sunflsh at 12°C was Identical 1n very soft and soft water (38.1 mg/l). The 6-hour LC5Qs 1n very soft, soft and hard water were 26, 23.2 and 38.1 mg/l, respectively. The 24-hour LC5Q ranged from 8.60 0124d -12- 09/19/88 ------- mg/l 1n very hard water to 12.3 mg/l 1n hard water. The 96-hour LC5Q ranged from 2.82 mg/l 1n hard water to 4.41 mg/l 1n soft water (Schafer and Marking, 1975). : Marking and Chandler (1981) assessed the acute toxldty of 4-am1nopyr1- dlne to a variety of aquatic Invertebrates 1n static tests. All studies were conducted In reconstituted water with a hardness of <40 mg/l as CaCO-. Tests with mayfly nymphs, Isonychla sp., were conducted at 12°C. Tests with water fleas, Daphnla magna. were conducted at 21°C. All other tests were conducted at 16°C. The 6-, 24- and 96-hour LC5Qs (and 95% confidence Intervals) for D_. magna were 24 (19-30), 17 (14-20) and 3.2 mg/l (2.3-4.5), respectively. Values for glass shrimp, Palaemonetes kadlakensls. were 47 (32-70), 3.3 (2.3-4..6) and 0.37 mg/l (0.25-0.56), respectively. Values for crayfish, Procambrus acutus acutus. were >60, 14 (11-18) and 2.2 mg/l (1.7-2.8), respectively. Values for mayflys were 24 (20-28), 5.3 (3.9-7.2) and 0.58 mg/l (0.45-0.74), respectively. Values for caddlsfly larvae, 'Hydropsvche sp., were 99 (78-130), 30 (21-41) and 15 mg/l (9.8-22), respectively. Values for frog larvae, Rana sphenocephala. were >30, 7.2 (6.6-7.8) and 2.4 mg/l (2.0-2.9), respectively. The 24- and 96-hour .lCcQs (and 95% confidence Intervals) for adult Asiatic clams, Corblcula manllensls. were 78 (69-88) and 45 mg/l (40-50), respectively. Values for adult river horn snail, Oxytrema catenarla. were >100 and 62 mg/l (53-73), respectively. 4.1.2. Chronic Effects on Fauna. 4.1.2.1. TOXICITY -- Marking and Chandler (1981) assessed hatching success and larval survival of the leopard frog, Rana sphenocephala. upon exposure to 4-am1nopyr1d1ne. Eggs were exposed to 4-am1nopyr1d1ne within 16 hours after deposition at a temperature of 16°C under static conditions. 0124d -13- 09/19/88 ------- The exposures were continued until eggs hatched or development ceased. Hatching of control eggs required 9-11 days. The Investigators reported a hatching success of <5X among eggs exposed to <10 mg/l. Larval survival was >95X at 1 mg/i but <5X at 2 mg/l. 4.1.2.2. BIOACCUMULATION/BIOCONCENTRATION — No measured steady-state BCF value for 4-am1nopyr1d1ne was found 1n the literature. Based on the regression equation, log BCF • 0.76 log K - 0.23 (Lyman et al., 1982) and a log K value of 0.26 (see Section 1.2.), a BCF value of 0.93 1s estimated for this compound. This value suggests that 4-am1nopyr1d1ne will not bloaccumulate significantly 1n aquatic organisms. 4.1.3. Effects on Flora. 4.1.3.1. TOXICITY — Pertinent data regarding the effects of chronic exposure of aquatic flora to 4-am1nopyr1d1ne could not be located In the available literature as cited In Appendix A. 4.1.3.2. BIOCONCENTRATION — Pertinent data regarding the bloconcen- tratlon of 4-am1nopyr1d1ne by aquatic flora could not be located In the available literature as cited 1n Appendix A. 4.1.4. Effects on Bacteria. Pertinent data regarding the effects of exposure of aquatic bacteria to 4-am1nopyr1dlne could not be located 1n the available literature as cited In Appendix A. 4.2. TERRESTRIAL TOXICOLOGY 4.2.1. Effects on Fauna. Schafer et al. (1973a) summarized the existing Information regarding the toxlclty of 4-am1nopyr1d1ne to birds (Table 4-1). Oral LDgQ values ranged from 2.4 mg/kg for several species to 35 mg/kg for the domestic chicken. Gall us gall us. Only one study reported an Intramuscu- lar LD5Q: 2.4 mg/kg for the red-winged blackbird, Aqelalus phoenlceus. Dermal LD5Qs reported for red-billed quelea, Quelea quelea. and sparrows, Passer domestlcus. were both >100 mg/kg. 0124d -14- 09/19/88 ------- TABLE 4-1 Acute Toxlclty of 4-Amlnopyrldlne to 36 Species of Birds* 1 tn 1 CD Species (mixed or unknown sex unless noted) — - Scaled dove .Scardafella squammata Ruddy-breasted seedeater Sporophlla rolnuta Brown-throated parakeet Aratlnga pertlnax Blue-black grassqult Volatina jacarlna Olckclssel Splza amerlcana Orange-fronted parakeet Aratlnga canlcularls Ruddy ground dove Columblgalllna talpacotl Shiny cowblrd Nolothrus bonarlensls Black-billed magpie Pica pica Route per os per os per os per os per os per os per os per os pef os •--.. Carrier LDso grain >4 grain <7.2 grain -10 grain 10 grain -10 grain -12 grain <25 propylene glycol , <1.0 propylene glycol 2.4 95X Confidence Limits (rag/kg) NR NR NR 5.6-18 NR NR NR NR NR GO 00 ------- TABLE 4-1 (cont.) o. 1 1 o VO Species (mixed or unknown sex unless noted) Common crow Corvus brachyrhynchos Yellow-billed magpie Pica nuttalll Common grackle Qulscalus qulscula Bronzed cowblrd Tangavlus aeneus Mallard Anas platyrhynchos Robin Turdus migrator lus Brown-headed cowblrd Molothrus ater Trlcolored blackbird Agelalus tricolor Sparrow hawk Falco sparverlus Budgerigar Route per os per os per os per os per os per os per os per os per os per os Carrier propylene glycol "propylene glycol propylene glycol propylene glycol propylene glycol propylene glycol propylene glycol propylene glycol propylene glycol propylene glycol LD50 2.4 2.4 2.4 3.2 4.2 4.2 4.2 4.2 5.6 5.6 95% Confidence Limits (rag/kg) NR NR NR 1.8-5.6 NR 2.4-7.5 NR NR . 4.2-7.5 NR Melopslttacus undulatus CD CO ------- TABLE 4-1 (cont.) 0 no Q. 1 _i ~J O tO V. Species (mixed or unknown sex unless noted) House finch Carpodacus mexlcanus Golden -crowned sparrow Zonotrlchla atrlcapllla White-crowned sparrow Zonotrlchla leucophrys Ring-necked pheasant Phaslanus colchlcus (4 weeks) (female) Coturnlx quail Coturnlx coturnlx (male, and female) Hour n Ing dove Zenaldura macroura Green jay Cyanocorax yncas White-winged dove Zenatda aslatlca Ring-billed gull Larus delawarensls Bobwhlte Route per per per per per per per per per per per per OS OS OS OS OS OS OS OS OS OS OS OS Carrier propylene propylene propylene propylene propylene propylene propylene propylene propylene propylene water water glycol glycol glycol glycol glycol glycol glycol glycol glycol glycol ' LD50 5 5 5 7 5 7 8 8 13 8 15 .6 .6 .6 .5 .6 .65 .05 .1 (HC1) (HC1) 95X Confidence Limits (rag/kg) NR 3.2-10 3.2-10 5.7-9.8 3.2-10 6.59-8.89 7.01-9.24 7.5-10 NR NR NR NR 00 Collnus vlrglnlanus ------- TABLE 4-1 (cont.) to o. CO Species (mixed or unknown sex unless noted) Route Carrier 95% Confidence Limits (rag/kg) Starling Sturnus vulgar Is Domestic chicken Gallus gallus (2-3 weeks) per os per os per os per os per os water pellet propylene glycol water water 14 (HC1) <6 4.9 35 (HC1) 15 (HC1) NR NR 3.6-6.6 NR NR Red-winged blackbird Agelalus phoenlceus L (male) CO 1 Common pigeon Columbia llvla House sparrow Passer domes tlcus Red-billed quelea Quelea quelea Boat-tailed grackle o Cassldlx mexlcanus to per os per os per os Intramuscular per os per os per os per os per os per os dermal per os dermal per os per os water , water propylene glycol propylene glycol water propylene glycol propylene glycol water water water acetone propylene glycol acetone propylene glycol water 8.5 3.2 (HC1) 2.4 2.4 20 (HC1) 7.5 7.5 4.0 3.8 3.6 >100 5.6 >100 3.2 1.7-7.1 NR NR 1.5-3.8 NR NR NR NR NR NR NR NR 3.2-10 NR 1.8-5.6 NR m *Source: Schafer et al., 1973a NR = Not reported ------- Schafer et al. (19735) reported the oral and dermal toxldty of 4-am1no- pyrldlne to quelea. Quelea quelea. house sparrows. Passer domestlcus. and red-winged blackbirds, Agelalus phoenlceus. Oral toxldty was determined by per os administration of propylene glycol solutions from a mlcrosyrlnge. Dermal toxldty was determined by applying acetone solutions to a sparsely feathered skin area. The acute oral LD~Qs were 5.6, 7.5 and 2.4 mg/kg, respectively. The dermal LD..S for quelea and sparrows were both >100 mg/kg. LD5Qs were based on a 4-day observation period following a single dose of 4-am1nopyr1d1ne. Schafer and Harking (1975) assessed the effects of long-term exposure of bobwhHe quail, Collnus v1rg1n1anus. mourning dove, Zenalda macroura. ring-necked pheasant, Phaslanus colchlcus. quail, Coturnlx coturnlx. and starling, Sturnus vulqarls. to 4-am1nopyr1d1ne. Acute oral LD5Qs for quail, dove and female pheasant offered 3% 4-am1nopyr1d1ne-contam1nated bait (cracked corn) for 7-35 days were 15.0, 8.1 and 7.5 mg/kg, respectively. The acute oral LD5Qs'for quail offered 4-am1nopyr1d1ne-contam1nated feed (<1,000 ppm) for 28-40 days were 7.65 mg/kg for males and 8.05 mg/kg for females. An L05Q for doves offered contaminated feed could not be calcu- lated because of an Insufficient level of mortality. Treatment of starlings by gavage dally for 25 days with a propylene glycol solution containing a dose of 1.78 mg/kg 4-am1nopyr1d1ne resulted In an acute oral LD5Q of 4.9 mg/kg. > Schafer et al. (1975) assessed the effects of 4-am1nopyr1d1ne on repro- duction and survival In quail, Coturnlx coturnlx. 1n three separate studies. In the Initial study, male and female birds were gavaged with a propylene glycol solution containing either 0 or 5.62 mg/kg 4-am1nopyr1d1ne, then paired with untreated mates. All birds treated with 4-am1nopyr1d1ne 0124d -19- 09/19/88 ------- exhibited hyperactlvlty, tremors and minor motor seizures within 4 hours of treatment, while two males died within 24 hours of treatment. Egg produc- tion by treated females was reduced significantly during the 3rd week of the study. Hatchab111ty of eggs was not affected. In a second study, breeding pairs were fed a diet that contained 0-1,000 ppm 4-am1nopyr1d1ne for 4 weeks. No effects were observed among birds fed <31.6 ppm 4-amlnopyrldlne. There were no significant reproductive effects among birds fed 100 and 316 ppm 4-am1nopyr1d1ne, although growth among males during the 4-week study was depressed and food consumption was reduced for the first 2 weeks In the 316 ppm dose group. All birds dosed with 1,000 ppm 4-amlnopyrldlne died within 3 weeks. The 28-day LC5Qs for male and female quail 1n this study were 447 and 562 ppm, respectively. In the third study, the F, progeny from the second study were mated when they reached sexual maturity; no effects on reproduction were observed among these birds. Garrison et al. (1982) assessed the lethal and sublethal effects of 4-am1nopyr1d1ne to three species of mannlklns, Lonchura punctulata. Lonchura leucogaster and Lonchura malacca. and one species of sparrow, Passer montanus. Birds were dosed with various concentrations of 4-am1nopyr1d1ne 1n propylene glycol. using a 50 ml syringe with 4 cm polyethylene tubing attached to the needle. Four to six birds per treatment {species dependent) received a dose volume of 10 yl/10 g bw. The Investigators reported L05Q values (and 95% confidence limits) of 7.94 (5.47-11.52), 3.11 (2.62-3.69), 4.45 (3.33-5.97) and 3.54 mg/kg (1.84-6.80) for L. punctulata. L_. leucogaster. L_. malacca and P. montanus. respectively. Garrison et al. (1982) reported that the average times from dosing with 5.0 mg/kg to the » first distress call emitted by dosed birds were 33.8, 21.3, 52.8 and 23.0 minutes, respectively. The Investigators also assessed the effects of 0124d -20- 09/19/88 ------- 4-am1nopyr1d1ne-treated grain on sparrows. Six birds were force-fed one kernel of Mce treated with either 0.5 (4.4 rag/kg) or l.OX (9.8 mg/kg) 4-am1nopyr1d1ne. All birds demonstrated effects from the treatments within 30 minutes. The average times to mortality were 90 and 26 minutes, respectively. Holler and Schafer (1982) assessed the hazards to sharp-shinned hawks, Acdpter strlatus. and American kestrels, Falco sparvelrus. from the consumption of blackbirds killed with 4-am1nopyr1d1ne. The food source for Isolated hawks and kestrels was obtained by feeding caged blackbirds a 1% 4-am1nopyr1d1ne bait diluted 1:1 or 1:9 or a 3% 4-am1nopyr1d1ne bait diluted 1:99. Dead blackbirds were frozen at -20°C until needed. Hawks were offered two dead blackbirds/day for 7 days, while kestrels were offered one dead blackbird/day for 7 days. The Investigators reported that there was no Indication of secondary hazard potential to either of these predatory birds from the consumption of 4-am1nopyr1d1ne-contam1nated blackbirds. Hudson et al.' (1984) reported acute oral LD5Qs for male mallard ducks, Anas platyrhynchos. offered products containing 95 and 99.9% 4-am1nopyr1- dlne. The oral LD5Qs (and 95% confidence limits) for 3- to 4-month-old ducks were 4.36 (3.36-5.66) and 5.19 mg/kg (4.00-6.73), respectively. Sultana et al. (1986) determined the acute oral LD5Q of 4-am1no- pyrldlne for rock dove, Columba 11v1a. rose-ringed parakeets, PsUtacula kramerl. house sparrows, Passer domestlcus. and white-backed munlas, Lonchura strlata. Birds were gavaged with propylene glycol solutions of 4-am1nopyr1d1ne by mlcrosyrlnge or ball-tipped gavage needle, then segre- gated one to a cage and monitored for mortality for 48 hours after treat- ment. The Investigators reported L05Q values (and 95% confidence limits) of 2.50 (3.73-1.68), 3.02 (3.02-3.02), 4.20 (7.14-4.28) and 2.97 mg/kg (4.26-2.08), respectively. 0124d -21- 09/19/88 ------- 4.2.2. Effects on Flora. Pertinent data regarding the effects of exposure of terrestrial flora to 4-am1nopyr1d1ne could not be located In the available literature as dted In Appendix A. '•;,. 4.3. FIELD STUDIES Pertinent data regarding the effects of 4-am1nopyr1d1ne on flora and fauna 1n the field could not be located In the available literature as cited In Appendix A. 4.4. SUMMARY Studies assessing the acute toxldty of 4-am1nopyr1d1ne to fish revealed that toxldty was not dependent on water temperature or hardness. The 96-hour LC5Qs for channel catfish and blueglll sunflsh exposed to 4-amlno- pyrldlne ranged from 2.43-7.56 mg/i (Schafer and Marking, 1975). The toxldty of 4-am1nopyr1d1ne to aquatic Invertebrates was assessed by Marking and Chandler (1981). Juvenile glass shrimp were the most sensitive spedes tested . (96-hour LC5Q=0.37 mg/SL), followed by mayfly nymphs (0.58 mg/l), crayfish (2.2 mg/i), frog larvae (2.4 mg/l), water fleas (3.2 mg/i), caddis fly larvae (15 mg/i), Asiatic clams (45 mg/l) and snails (62 mg/i). The NOEC for larval frogs appears to be <1 mg/l (Marking and Chandler, 1981). ; The toxldty of 4-am1nopyr1d1ne to birds was studied extensively by a series of Investigators. Oral LD5Q values ranged from 2.4-35 mg/kg for periods of exposure and observation of varying lengths. There was no i evidence that reproduction among the progeny of 4-am1nopyr1d1ne-treated birds was affected by treatment of the parents (Schafer et al., 1975). There was no evidence of secondary hazard potential among predatory birds from the consumption of 4-am1nopyr1d1ne-k1lled birds (Holler and Schafer, 1982). 0124d -22- 10/21/88 ------- 5. PHARHACOKINETICS 5.1. ABSORPTION In a study by Uges et al. (1982), six volunteers (60-81 kg) were treated < t orally with 20 mg 4-amlnopyMdlne (two 10 mg enteric-coated tablets). Concentrations of 4-am1nopyr1d1ne In the serum and urine were measured at varying Intervals for up to 9 and 36 hours, respectively. 4-Am1nopyr1d1ne was detected 1n the serum 128±38 minutes after Ingestlon of the coated tablets, and a maximum serum concentration of 62±15 yg/l was reached at 193i51 minutes after treatment. Based on urinary excretion data, the Inves- tigators .estimated that 98±8% of the dose was absorbed. The same subjects and three additional volunteers (one male, two females) were also treated with an Intravenous Injection of 20 mg 4-aro1nopyr1d1ne (at least 14 days ' between treatments). By comparing serum 4-am1nopyr1d1ne concentrations following oral and Intravenous dosing, the Investigators calculated that b1oavanab111ty was 95^29%. Coated capsules were required for oral treatment with 4-am1nopyr1d1ne because of the occurrence of gastric cramps 1n three of four persons treated with uncoated tablets (two 10 mg tablets). Following treatment with uncoated tablets, urine and saliva concentrations of 4-am1nopyr1d1ne were measured. 4-Am1nopyr1d1ne was found 1n the saliva -6 minutes after Ingestlon, with salivary concentrations higher than those In serum, and peaking at 25±30 minutes. The Investigators stated that the rapid absorp- tion of 4-am1nopyr1d1ne (beginning within 15 minutes of Ingestlon) Indicates that the compound 1s absorbed from the stomach. 5.2. DISTRIBUTION Following oral and Intravenous treatment of human volunteers (60-81 kg) with a 20 mg dose of 4-am1nopyr1d1ne, no difference was found In 4-am1no- pyrldlne concentrations 1n the serum before and after ultraflltratlon, 0124d -23- 09/19/88 ------- Indicating negligible binding to serum proteins (Uges et al., 1982). In a review of the pharmacoklnetlcs and side-effects of 4-am1nopyr1d1ne, Sohn and Uges (1981) stated that the compound readily crosses the blood-brain barrier. Supporting data were not provided. Rupp et al. (1983) treated seven fasted anesthetized mongrel dogs with an Intravenous Injection of 4-am1nopyr1d1ne (1 mg/kg). The volume of distribution was calculated to be 8.6 times the volume of the serum, suggesting extensive distribution to the tissues. 5.3. METABOLISM In the study by Uges et al. (1982), urine collected for 24 hours from persons treated with 4-am1nopyr1d1ne as described above (six oral, nine Intravenous) contained >85% of the administered dose. When urine was Incubated with beta-glucuronldase or hydrochloric add there was no Increase 1n the amount of detectable free 4-am1nopyr1d1ne In the urine, suggesting that 4-am1nopyr1d1ne did not undergo glucuronldatlon or sulfonatlon. Using a TLC technique, N-ace'tyl-4-am1nopyr1d1ne hydrochlprlde was not detected In the urine from volunteers treated with 4-am1nopyr1d1ne, Indicating that N-acetylat1on of 4-am1nopyr1d1ne had not occurred. The Investigators concluded that blotransformatlon of 4-am1nopyr1d1ne 1s unlikely. 5.4. EXCRETION In a study by Evenhuls et al. (1981), six volunteers anesthetized for 1 hour with a ketamlne-dlazepam anesthetic were treated with an Intravenous Injection of 4-am1nopyr1d1ne (a ketamlne-dlazepam antagonist) at a dose of 0.3 mg/kg. Blood and urine were sampled and analyzed for 4~am1nopyr1d1ne for varying periods up to 8 or 48 hours, respectively. In five of the six volunteers, a secondary Increase In plasma concentration was observed after the Initial decrease. The time of onset of the secondary Increase was 0124d -24- 09/19/88 ------- highly variable between Individuals, occurring 20-90 minutes after the Injection. 4-Am1nopyr1d1ne excreted 1n the urine accounted for 84.7% of the dose 12-14 hours after the Injection and 87.3X of the dose at 48 hours. In volunteers given an Intravenous Injection of 4-am1nopyr1d1ne (20 mg), Uges et al. (1982) reported that the elimination half-life In the serum was 3.6±0.9 hours. About 30 hours after six human volunteers were given an Intravenous Injection of 4-am1nopyr1d1ne, 90.6±7.8X of the compound was excreted In the urine. About 30 hours following an oral dose of 4-am1no- pyrldlne (20 mg) 1n enteric-coated tablets, 88.5+4.8% of the unchanged compound was excreted 1n the urine. Treatment of four volunteers wHh uncoated tablets of 4-am1nopyr1d1ne resulted In the recovery of 86.3^6.7% of the dose 1n the urine 1n -30 hours. The Investigators concluded that excretion was almost exclusively through the kidney. During 10 hours after dosing, Rupp et al. (1983) recovered from the urine of seven fasted anesthetized dogs 60±9X of a dose of 4-am1nopyr1d1ne / at 1 mg/kg. During the same period, only 0.QUO.01% of the administered compound was recovered In the bile. An elimination half-life of 125 minutes was calculated. The Investigators estimated renal clearance rate -4-fold greater than glomerular filtration rate and concluded that renal excretion Involved tubular secretion. 5.5. SUMMARY Pharmacok1net1c data 1n humans Indicate that 4-amlnopyrldlne 1s absorbed readily and nearly completely from the gastrointestinal tract (Uges et al., 1982). 4-Am1nopyr1d1ne appears to distribute widely throughout the tissues (Rupp et al., 1983), but excretion data (Uges et al., 1982) suggest that bloaccumulatlon does not occur 1n humans. Metabolites have not been found In the urine of humans treated with 4-am1nopyr1d1ne, and blotransformatlon 0124d -25- 09/19/88 ------- appears unlikely (Uges et al., 1982). In a study using human volunteers (Uges et al., 1982), -85% of an oral dose and 90% of an Intravenous dose of 4-am1nopyr1d1ne was recovered 1n the urine, with an elimination half-life of 3.6 hours. 0124d -26- 10/21/88 ------- 6. EFFECTS 6.1. SYSTEMIC TOXICITY : 6.1.1. Inhalation Exposures. Pertinent data regarding the toxlclty of 4-am1nopyr1d1ne following subchronlc or chronic Inhalation exposure could not be located In the available literature as cited 1n Appendix A. 6.1.2. Oral Exposure. 6.1.2.1. SUBCHRONIC — The only data regarding the subchronlc oral toxldty of 4-am1nopyr1d1ne are two studies In the OPP CBI files summarized by U.S. EPA (19805). Kohn (1968) fed rats (number not provided) 4-am1nopyr1d1ne hydrochlorlde In the diet at concentrations of 3, 30 or 300 ppm for 90 days. Information regarding controls was not provided. At 300 ppm, all surviving rats (specific survival data not provided) were hyperlrrKable to noise and touch. Brain weights of female rats and liver weights of male rats treated at 300 ppm were significantly (p<0.05) elevated.. No changes 1n blood and urlnalyses were noted. Gross and /• hlstopathologlc examinations also did not reveal any significant changes. Additional .data In the CBI version of the study Indicate that sporadic hyper1rr1tab1l1ty also occurred at 30 ppm, and that the 3 ppm dose was a NOEL (U.S. EPA, 1986a). In a study by Cervenka and Vega (1968), beagle dogs (number unspecified) were fed diets containing 4-am1nopyr1d1ne hydrochlorlde at concentrations that provided doses of 0.1, 1.0 or 2.0-3.25 mg 4-am1nopyr1d1ne/kg/day for 90 days. Information regarding controls was riot provided. At >2.0 mg/kg/day, dogs exhibited salivation and muscular weakness; no hlstopathologlcal lesions were observed. According to the summary, no dose-related trends In mean organ weights were observed, although at the two highest doses brain weights were slightly decreased. The review .from which these data were taken (U.S. EPA, 1980b) stated that "examination of the brain revealed no 0124d -27- 10/21/88 ------- abnormalities,* but the extent and protocol of that examination were not described. No changes 1n blood and uMnalyses were noted. 6.1.2.2. CHRONIC — Pertinent data regarding the toxldty of 4-am1nopyr1d1ne following chronic oral exposure could not be located 1n the available literature as dted In Appendix A. 6.1.3. Other Relevant Information. 4-Am1nopyr1d1ne acts at the motor nerve terminal to decrease membrane potassium conductance, which prolongs the action potential, causing an Influx of calcium and an Increase In the release of acetylchollne (Agoston et al., 1985). Because of this activity, 4-am1nopyr1d1ne has been used 1n humans to reverse residual neuromuscular blockade resulting from nondepolarlzlng neuromuscular blocking agents and certain antibiotics. Experimental uses of 4-am1nopyr1d1ne Include treatment of patients , with Botullnus Intoxication, myoneural disorders (e.g., myasthenla gravls, Eaton-Lambert syndrome) and Alzheimer's disease. The clinical use of 4-am1nopyr1d1ne Is limited by Its narrow therapeutic Index. t Agoston et al. (1985) reported that following a clinical dose of 0.15-0.3 mg/kg (route not specified), the only side effects noted were a slight Increase 1n systolic blood pressure and heart rate, while doses >0.5 mg/kg were likely to result 1n restlessness, confusion, nausea, weakness and ton1c-don1c seizures. Lundh et al. (1979) treated six myasthenla gravls patients with Intravenous Injections of 4-am1nopyr1d1ne at a dose of 10 mg Injected over a 10-m1nute period (body weights of patients were not provided). The treat- ment alleviated muscular weakness. Side effects reported Included paraes- thesla perlorally, a sensation of unsteadiness during walking, restlessness and pain In the arm of the Injection. Wessellng et al. (1984) found some Improvement 1n the mental capacity of 14 Alzheimer's patients treated with 4-am1nopyr1d1ne (10 mg twice a day) compared with treatment with placebos. 0124d -28- 09/19/88 ------- Spyker et al. (1980) reported that two men (100 kg) who accidentally Ingested a pinch (estimated to be -60 mg) of 4-am1nopyr1d1ne were admitted to the hospital and survived the poisoning. The symptoms observed 1n these men Included nausea, weakness, dizziness, profuse perspiration, altered mental status and hypertension. One man also experienced three tonlc-clonlc seizures. Schafer et al. (1973a) summarized the acute toxldty of 4-am1nopyr1d1ne 1n birds and mammals; LD~Q values for mammals are presented 1n Table 6-1. Dogs were the most sensitive mammal studied, with an oral LD5Q of 3.7 t mg/kg. Houston and Pleuvry (1984) reported gross ataxla 1n >40% of mice (Manchester strain) given an Intraperltoneal Injection of 4-am1nopyr1d1ne at 1.6 mg/kg. Convulsions were also noted 1n an unspecified number of mice. In a study by HUsov and Uzunov (1972), white rats of both sexes were treated with 4-am1nopyr1d1ne by Intraperltoneal Injection for 1 or 6 months. In the 1-month study, 'groups of 10 rats/sex were treated with 4-am1nopyr1- dlne at doses of 1 or 5 mg/kg/day, while 1n the 6-month study, similar groups of rats were treated at doses of 1 or 4 mg/kg/day. Control groups for both, studies were Injected with physiologic saline. H1stopatholog1c examination was limited to heart, liver, brain, lung, kidney and spleen. No effects on body weight, hemoglobin concentration and RBC or WBC counts were noted 1n either study. The only hlstopathologlc changes noted In the 1-month study were a dose-related "plethora of the capillaries" 1n the myocardlal 1nterst1t1um. and cerebral edema. In addition to the effects observed In the 1-month study, dose-related parenchymatous degeneration and fatty degeneration of the liver were observed In the 6-month study. 0124d -29- 01/11/89 ------- TABLE 6-1 Acute ToxIcHy of 4-Am1nopyr1d1ne to Mammals Species Rat Rat Mouse Mouse Mouse Mouse Mouse Dog Dog Rabbit Route oral Intraperltoneal Intraperltoneal Intraperltoneal Intraperltoneal subcutaneous Intravenous oral oral dermal Vehicle water water water water water water water capsule water water LD50 (rag/kg) 20 6.5 14.7 10 9 5 7 ; i 4 : 3.7 327 \ Reference Schafer et al., 1973a Schafer et al., 1973a ' Humphreys, 1962 Vohra et al., 1965 Pastier and Me Do wall, 1958 Lemelgnan and Lechat, 1967 Pastier and McDowall, 1958 Delchman and Gerarde, 1969 Schafer et al., 1973a Delchman and Gerarde, 1969 0124d -30- 10/21/88 ------- 6.2. CARCINOGENICITY Pertinent data regarding the cardnogenldty of 4-am1nopyr1d1ne could not be located 1n the available literature as dted 1n Appendix A. 6.3. MUTAGENICITY 4-Am1nopyr1d1ne has tested negative for reverse mutation In Salmonella typhlmuMum (Ogawa et al., 1986; Wakabayshl et al., 1982). Details of these studies are summarized 1n Table 6-2. Additional data concerning the mutagenldty of 4-am1nopyr1d1ne were not located. 6.4. TERATOGENICITY HUsov and Uzunov (1972) did not observe any malformations 1n offspring born to rats during 1- and 6-month Intraperltoneal Injection studies (see Section 6.1.3.). This study was limited; only 12 offspring from treated rats and 7 offspring from control rats were born from an unspecified number of pregnancies that "evolved normally." Additional data regarding the teratogenldty of 4-am1nopyr1d1ne were not located. 6.5. OTHER REPRODUCTIVE EFFECTS Pertinent data regarding reproductive effects of 4-am1nopyr1d1ne could not be located 1n the available literature as cited In Appendix A. 6.6. SUMMARY 4-Am1nopyr1d1ne acts on the nervous system to Increase the release of acetylchollne. The compound has been used 1n humans for the reversal of residual neuromuscular blockade from some neuromuscular blocking agents and antibiotics. Experimental uses Include treatment of patients with Botullnus Intoxication, myoneural disorders and Alzheimer's disease. The clinical use of 4-am1nopyr1d1ne 1s limited by Us narrow therapeutic Index; following a clinical dose of 0.15-0.3 mg/kg (route not specified), the only side effects noted were a slight Increase In systolic blood pressure and heart rate, 0124d -31- 09/19/88 ------- rs) TABLE 6-2 ( Hutagenlclty Testing of 4-Anlnopyrldlne Assay Indicator/ Organ Is* Purity Application Concentration or Dote Activating System Response CoMwnt Reference Reverse •utatlon 04 Reverse •utatlon Salmonella typhlmurlum TA1537. TA2637, TA98. TA100 S. typhlmurlua TA98. TA100 NR prelncubatlon plate Incor- poration >98X prelncubatlon NR none up to 2 mg/plate Also - when tested with Ogawa cobalt (II) chloride. et al.. 1986 which enhanced the muta- genlclty of other hetero- atomtc compounds (9-amlno- acrtdlne. 4-amlnoqulnollne and barman) Also - when tested with Uakabayashl norbarman, caused 3-amlno- et al.. 1982 pyrldlne and 2-amlno-3- methylpyrldlne to become mutagentc In the presence of S-9 NR - Not reported S CO oo ------- while doses >0.5 mg/kg were likely to result In restlessness, confusion, nausea, weakness and tonlc-clonlc seizures (Agoston et al., 1985). A case report of an accidental oral exposure (Spyker et al., 1980) Indicated that a single dose of -0.6 mg/kg results 1n frank effects In humans. The only data concerning the subchronlc oral toxlclty of 4-am1nopyr1d1ne are two 90-day studies In the OPP CBI files summarized by U.S. EPA (1980b). In a rat study (Kohn, 1968), hyper1rr1tab111ty was observed at dietary concentrations of 30 and 300 ppm 4-am1nopyr1d1ne, with no effects noted at 3 ppm. In dogs (Cervenka and Vega, 1968), salivation, muscular weakness and decreased brain weight were observed at doses of >1.0 mg/kg/day. *i 4-Am1nopyr1d1ne has tested negative for reverse mutation In Salmonella typhlmurlum (Ogawa et al., 1986; Wakabayshl et al., 1982). Data concerning the cardnogenldty, reproductive effects and toxlclty of 4-am1nopyr1d1ne following Inhalation or chronic oral exposure were not available In the literature dted In Appendix A. No effects on reproduction or fetal i t . development were reported 1n rats treated with 1-5 mg/kg/day by Intraperl- toneal Injection for 1 or 6 months (Mltsov and Uzunov, 1972). 0124d -33- 10/21/88 ------- 7. EXISTING GUIDELINES AND STANDARDS 7.1. HUMAN The RQ for 4-am1nopyr1d1ne 1s 1000 pounds (U.S. EPA, 1985). Additional guidelines and standards. Including EPA ambient water and air quality criteria, drinking water standards, FAO/WHO ADIs, EPA or FDA tolerances for raw agricultural commodities or foods, and ACGIH, NIOSH or OSHA occupational exposure limits could not be located 1n the available literature as dted 1n Appendix A. 7.2. AQUATIC Guidelines and standards for the protection of aquatic life from exposure to 4-am1nopyr1d1ne could not be located 1n the available literature as cited 1n Appendix A. 0124d -34- 02/08/89 ------- 8. RISK ASSESSMENT 8.1. CARCINOGENICITY Pertinent data regarding the carclnogenldty of 4-aro1nopyr1d1ne could not be located 1n the available literature as cited In Appendix A. 4-Amlno- pyrldlne has tested negative for reverse mutation In Salmonella typhlmurlum (Ogawa et al.t 1986; Wakabayshl et al., 1982). 8.1.1. Weight of Evidence. As a result of a lack of data concerning carclnogenldty In humans and animals, 4-am1nopyr1d1ne can be classified as an EPA Group D chemical (U.S. EPA, 1986b), not classifiable as to human carclnogenldty. 8.1.2. Quantitative Risk Estimates. The derivation of carcinogenic potency factors for 4-am1nopyr1d1ne 1s precluded by the lack of carclno- genldty data. 8.2. SYSTEMIC TOXICITY 8.2.1. Inhalation Exposure. The derivation of Inhalation risk assessment t values for 4-am1nopyr1d1ne 1s precluded by the lack of Inhalation data. 8.2.2. Oral Exposures. 8.2.2.1. LESS THAN LIFETIME EXPOSURES (SUBCHRONIC) -- 4-Am1nopyr1d1ne has been used 1n humans to reverse neurornuscular blockade resulting from nondepolarlzlng neuromuscular blocking agents and certain antibiotics, and as an experimental treatment for Botullnus Intoxication, myoneural disorders and Alzheimer's1 disease (Agoston et al., 1985). Human experience Indicates that the compound has a very narrow therapeutic Index, with a dose of 0.15-3 mg/kg resulting 1n a slight Increase 1n systolic blood pressure and heart rate, and a dose >0.5 mg/kg resulting 1n restlessness, confusion, nausea, weakness and ton1c-clon1c seizures {Agoston et al., 1985). The report by Spyker et al. (1980), In which two 100 kg men who accidentally Ingested -60 0124d -35- 09/19/88 ------- mg of 4-am1nopyr1d1ne developed nausea, weakness, dizziness, altered mental status, and In one case tonlc-clonlc seizures, Indicates that a dose of -0.6 rag/kg 1s a PEL 1n humans. The available acute human data are not sufficient for risk assessment, but Indicate that a subchronlc RfD for 4-am1nopyr1d1ne should be <0.15 mg/kg/day. In a study by Cervenka and Vega (1968), dogs were fed diets containing 4-am1nopyr1d1ne at concentrations that provided doses of 0.1, 1.0 or 2.0-3.25 mg/kg/day for 90 days. At >2.0 mg/kg/day, dogs exhibited saliva- tion and muscular weakness; no compound-related hlstopathologlc lesions were observed. No dose-related trends 1n mean organ weights were observed, although brain weights were decreased at the two highest dosages. This study Indicates that >2.0 mg/kg/day 1s an adverse effect level, but from the Information available, 1t 1s not clear whether the slight and nondose- related decrease 1n brain weight at 1.0 mg/kg/day should be considered an adverse effect. In a 90-day study (Kohn, 1968), rats fed 4-am1nopyr1d1ne 1n the diet at 300 ppm were hyperlrrltable to noise and touch; males had Increased liver weights and females had Increased brain weights. Additional Information In the CBI files Indicates that sporadic hyper1rr1tab1lHy also occurred at 30 ppm. No effects were observed 1n rats fed 4-am1nopyr1d1ne In the diet at 3 ppm. Assuming rats consume food equivalent to 5% of their body weight/day (U.S. EPA, 1986c), the dietary concentrations of 4-am1nopyr1d1ne of 3, 30 and 300 ppm correspond to dosages of 0.15, 1.5 and 15 mg/kg/day, respectively. Although the Information concerning the Kohn (1968) study 1s also very limited, 1t 1s the only data available from which a subchronlc RfD can be estimated. Application of an uncertainty factor of 1000 [10 for species-to- species extrapolation, 10 to protect sensitive Individuals and 10 to reflect 0124d -36- 02/08/89 ------- deficiencies 1n the data base (U.S. EPA, 1988)] to the rat NOAEL of 0.15 mg/kg/day yields a subchronlc oral RfD of 0.0002 mg/kg/day or 0.01 mg/day for a 70 kg human. This subchronlc RfD 1s well below the acute human effect level of 0.5 mg/kg/day. Confidence 1n the RfD 1s low, based on low confidence In the study and data base. Few details were available concerning the CBI study. The validity of the study (Kohn, 1968) completed at Industrial BloTest Labora- tories 1s unknown. The supporting data are limited to a subchronlc study In dogs (Cervenka and Vega, 1968), for which few details were available. This RfD should be considered preliminary and should be reviewed when additional data are available. The RfD Is currently under review by the Agency's RfD Work Group (U.S. EPA, 1989). 8.2.2.2. CHRONIC EXPOSURE ~ Chronic oral studies of 4-am1nopyr1d1ne were not available. As mentioned 1n Section 8.2.2.1., an oral RfD for 4-am1nopyr1d1ne Is under review by the Reference Dose Work Group (U.S. EPA, 1989). A tentative RfD of 0.00002 mg/kg/day or 0.001 mg/day for a 70 kg human can be derived by dividing the subchronlc oral RfD [derived from the Kohn (1968) rat study] by an additional uncertainty factor of 10 to extrapolate from chronic to subchronlc data. Confidence 1n this RfD 1s low, based on low confidence In the study and data base. Because the basis of this RfD 1s not defensible,, verification of an RfD for 4-am1nopyr1d1ne should be deferred until the details of the Cervenka and Vega (1968) and Kohn (1968) studies are available or until additional studies are completed. 8.3. AQUATIC Insufficient data prevented the development of a criterion for the protection of freshwater life exposed to 4-am1nopyr1d1ne (Figure 8-1). The data base lacked an acute LCgQ with a representative species from the 0124d -37- 02/08/89 ------- Farni ly «tl Chords! c < £a 1 rnc-n id-fish) *rl Chordate (wferrnwster fish) «i Chordate (fish or amphibian) «t4 Crustacean (planktonic) lib Crustacean (benthic) *L Insect an ¥.7 non-Art hropod /-Chordat e *fc New Insect an or phylum represent at i ve «'3 algae «ilO Vascular plant TEST TYPE Acute* •» N(H 3. 972« 4. £30* 0.37- £.£' « 0.56* AS. 0" 15.0« Nfl NP Chronic* NP NA NA NA NA NA NA NA NA NA ECF« NA NA NA NA NA NA NA NA NA NA aNA « Not'available bAll values represent 96-hour cChannel catfish, Ictalurus punctatus dBlueg111 sunflsh, Lepotnls —^macrochlrus eGlass shrimp, Palaemonetes kadlakensls ^Crayfish, Procambrus acutus acutus QMayfly, Isonychla sp. ^Asiatic clam, Corblcula manllensls kaddlsfly, Hydropsyche sp. FIGURE 8-1 Organization chart for listing GHAVs required to derive numerical water quality criteria by the method of EPA/OWRS (1986) for the protection of freshwater aquatic life exposed to 4-am1nopyr1d1ne 0124d -38- 02/08/89 ------- Salmon1d family and the results of chronic tests either with freshwater algae or vascular plants. The data base also lacked acceptable chronic tests with fish or Invertebrates and results from studies assessing the bloaccumulatlon or bloconcentration of 4-am1nopyr1d1ne In aquatic organisms. No data were available regarding the effects of exposure of marine fauna and flora to 4-am1nopyr1d1ne, preventing the development of a saltwater criterion. 0124d -39- 02/08/89 ------- 9. REPORTABLE QUANTITIES 9.1. BASED ON SYSTEMIC TOXICITY The toxlclty of 4-am1nopyr1d1ne was discussed In Chapter 6. The only data suitable for the derivation of an RQ are the 90-day dog studies (Cervenka and Vega, 1968) rat study (Kohn, 1968). Table 9-1 summarizes these studies and Table 9-2 presents the derivation of CSs and RQs. In the study by Cervenka and Vega (1968), muscular weakness, salivation and a decrease In brain weight was observed In dogs treated at >2.0 mg/kg/day and a slight decrease 1n brain weight was observed at 1 mg/kg/day. From the limited Information available, H 1s not clear If the 1.0 mg/kg/day dose was a NOAEL or LOAEL; therefore, only the >2.0 mg/kg/day dose, corresponding to an RV. of 4.2, will be considered for CS derivation. Kohn (1968) reported sporadic hyper1rr1tabH1ty to noise and touch In rats treated orally with 4-am1nopyr1d1ne 1n the diet at a dose of -1.5 mg/kg/day, or an RV. of 5.1. Effects In both dogs and rats correspond to an RV of 7. Multiplying the larger RVd of 5.1 from the rat study by the RVg of 7, a CS of 35.7 Is calculated. The CS of 35.7 calculated from the rat study (Kohn, 1968), corresponding to an RQ of 100 pounds, Is selected to represent the toxldty of 4-amlno- pyrldlne and 1s presented 1n Table 9-3. 9.2. BASED ON CARCINOGENICITY No data were available concerning the carclnogenlclty of 4-am1nopyr1- dlne. 4-Am1nopyr1d1ne has tested negative for reverse mutation In Salmonella typhlmurlum (Ogawa et al., 1986; Wakabayshl et al., 1982) (see Section 6.3.). The lack of data concerning the carclnogenlcHy of 4-am1no- pyrldlne In either humans or animals Indicates that the compound should be 0124d -40- 10/21/88 ------- o IV* o 00 00 vD - TABLE 9-1 Oral Toxlclty Data for 4-Amlnopyrldlne4 Species/ Strain* Sex Dog/NR NR Rit/NR Ntf Average Body Weight* (kg) 12 0.35 Vehicle/ Physical State diet diet Exposure 2 mg/kg/day In the diet for 90 days 300 ppm In the diet For 90 days ., Animal Dosage (mg/kg/day) 2* 1.5' Equivalent Hunan Dosage0* (•g/kg/day) 0.1 0.026 Effect Salivation. muscular weak- ness Sporadic hyper- Irritability to noise and touch Reference Cervenka and Vega, 1968 Kohn. 1968 3Pur1ty not reported DNumber of animals/group not reported (Reference dog body weight (12 kg), reference rat body weight (0.35 kg) (U.S. EPA. 1986c) dAnlmal dose Multiplied by the cube root of the ratio of the antMl to reference human body weight (70 kg) and by 70 kg to express human MED In mg/day. and divided by an uncertainty factor of 10 to expand from subchronlc to chronic exposure 'Estimated by Investigators 'Reference food factor for rats - 0.05 (U.S. EPA. 1980b) NR • Not reported ------- 10 O. .. TABLE 9-2 Composite Scores for 4-Amlnopyrldlne Based on Oral Toxlclty Chronic Species Animal Dose Human MEDa RVd Effect RVe CSb RQ (mg/kg/day) (mg/day) : 5 Dog 2 7.0 4.2 CMS effect 7 29.4 100 Rat 1.5 1.8 5.1 CNS effect 7 35.7 100 Reference Cervenka and Vega. 1968 Kohn. 1968 Equivalent human dosage (mg/kg/day) multiplied by 70 kg bRVd multiplied by RVe GO 03 ------- TABLE 9-3 4-Amlnopyrldtne Minimum Effective Dose (MED) and Reportable Quantity (RQ) Route: Dose*: Effect: Reference: RVd: RVe: CS: RQ: oral 1.8 CNS Kohn 5.1 7 ' 35.7 100 mg/kg effects , 1968 pounds *Equ1valent human dose 0124d -43- 09/19/88 ------- classified as an EPA Group D chemical (U.S. EPA, 1986b). not classifiable as to human cardnogenldty. Hazard ranking based on carclnogenlclty 1s not possible for EPA Group D compounds. 0124d -44- 09/19/88 ------- 10. REFERENCES Agoston, S., D. Langreher and D.E. Newton. 1985. Pharmacology and possible clinical applications of 4-amlnopyrldlne. Semln. Anesth. 4(1): 81-86. 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Ninety-day subacute oral toxIcUy of compound 1861 (4-am1nopyr1d1ne) — Beagle dogs. Project Number 777 (unpub- lished study). Prepared by Llfestream Laboratories, Inc. under IF 1013. Submitted by Phillips Petroleum Co., Bartelsvllle, OK. CDU091756-G. (Cited In U.S. EPA, 1980b) Oelchman, W.B. and H.W. Gerarde. 1969. Toxicology of Drugs and Chemicals. Academic Press, New York. p. 93. (Cited In Schafer et al., 1973a) 9 * E1senre1ch, S.J., B.B. Looney and D.J. Thornton. 1981. Airborne organic contaminants In the Great Lakes ecosystem. Environ. Sd.. Technol. 15: 30-38. EPA/OWRS. (Environmental Protection Agency/Office of Water Regulations and Standards). 1986. Guidelines for Deriving Numerical National Water Quality r Criteria for the Protection of Aquatic Organisms and their uses. EPA/OWRS Washington, DC. 106 p. Evenhuls, J., S. Agoston, P.J. Salt, A.R. DeLange, W. Wouthuyzen and W. Erdmann. 1981. Pharmacok1net1cs of 4-am1nopyr1d1ne In human volunteers. Br. 0. Anaest. 53: 567-570. 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Washington, DC. p. 12. t Humphreys, S.R.. 1962. Toxldty and antlleukemlc effectiveness of pyrldlne derivatives and 1,2,4-thladlazol derivatives 1n mice — Relation to nlcotln- amlde antagonism. Cancer Res. Suppl. 22(2):483-550. (CHed In Schafer et al., 1973a) Kohn, F.E. ' 1968. Four-week subacute oral toxldty of compound 1861 Hydrochlorlde — Albino rats. (Unpublished study),. Prepared by Industrial t • Blotest Laboratories, Inc. under 224-12. Submitted by Phillips Petroleum Co., Bartlesvllle, OK. CDL: 229844-E. (Cited In U.S. EPA, 1980b) / Kuney, J.H., Ed. 1986. Chemcyclopedla 1987. Volume 5. American Chemical Society, Washington, DC. p. 51. Lemelgnan, M and P. Lechat. 1967. Antlcurare action of am1nopyr1d1nes. C.R. Acad. Sc1. Ser. D. 264: 169-172. (CHed 1n Schafer et al., 1973a) 0124d -48- 10/21/88 ------- Lundh, H., 0 Nllsson and I. Rosen. 1979. Effects of 4-am1nopyr1d1ne In myasthenla gravls. J. Neurol. Neurosurg. Psychlat. 42(2): 171-175. Lyman, W.J., M.F. Reehl and D.H. Rosenblatt. 1982. Handbook of Chemical Property Estimation Methods. Environmental Behavior of Organic Compounds. McGraw-Hill Book Co., New York, NY. 5-5. Marking, L.L. and J.H. Chandler. 1981. Toxlclty of six bird control chemicals to aquatic organisms. Bull. Environ. Contam. Toxlcol. 26(6): 705-716. Mill, T. and W. Mabey. 1985. Photochemical transformations.' In: Environ- mental Exposure From Chemicals, Volume I, W.B. Neely and G.E. Blau, Ed. CRC Press, Inc., Boca Raton, FL. p. 206-210. MHzov, V. and P. Uzunov. 1972. ToxIcUy of the compound VMI-10-3. EK. sp. Med. No. .ful. 11(3): 162-165. (Bulgarian with English translation) Na1k, M.N., R.B. Jackson, 0. Stokes and R.J. Swaby. 1972. Mlcroblal degradation and phytotoxldty of plcloram and other substituted pyrldlnes. Soil B1ol. Blochem. 4: 313-323. I / NIOSH (National Institute for Occupational Safety and Health). 1985. National Occupational Exposure Survey (NOES). Computer printout of survey as of 9/20/85. 0124d -49- 10/21/88 ------- Ogawa, H.I., K. Sakata, T. Inouye, et al. 1986. Combined mutagenlcUy of cobalt(II) salt and heteroaromatlc compounds In Salmonella typhlmurlum. Mutat. Res. 172(2): 97-104. Parrls, G.E. 1980. Covalent binding of aromatic amines to humates. 1. Reactions with carbonyls and qulnones. Environ. Scl. Techno!. 14: 1099-1106. X Rupp, S.M., Y. Shlnohara, O.M. Fisher, R.D. Miller and N.J. Castagnoll. 1983. Pharmacok1net1cs and pharmacodynamlcs of 4-am1nopyr1d1ne In anesthe- tized dogs. J. Pharmacol. Exp. Ther. 225(2): 351-354. SANSS. (Structure and Nomenclature Search System). 1988. Chemical Informa- tion System (CIS) computer data base. Schafer, E.W., Jr. and L.L. Marking. 1975. Long-term, effects of 4-amlno- pyrldlne exposure to birds and fish. J. Wild!. Manage. 39(4): 807-811. Schafer, E.W., Jr., R.B. Brunton and D.J. Cunningham. 1973a. A summary of the acute toxlclty of 4-am1nopyr1d1ne to birds and mammals. Toxlcol. Appl. Pharmacol. 26(4): 532-538. / Schafer, E.W., Jr., R.B. Bunton, N.H. Lockyer and J.F. DeGrazlo. 19735. Comparative toxlclty of seventeen pesticides to the quelea, house sparrow and red-winged blackbird. Toxlcol. Appl. Pharmacol. 26(1): 154-157. 0124d -50- 09/19/88 ------- Schafer, E.W., Jr., R.B. Brunton and N.F. Lockyer. 1975. The effects of subacute and chronic exposure to 4-am1nopyr1d1ne on reproduction 1n coturnlx quail. Bull. Environ. Contain. Toxlcol. 13(6): 758-764. S1ms, G.K. and I.E. Sommers. 1985. Degradation of pyrldlne derivatives In soil. J. Environ. Qual. 14: 580-584. S1ms, G.K. and I.E. Sommers. 1986. B1odegradat1on of pyrldlne derivatives In soil suspensions. Environ. Toxlcol. Chem. 5: 503-509. Sohn, Y.J. and D.R.A. Uges. 1981. Pharmacok1net1cs and side-effects of 4-am1nopyr1d1ne. Int. Congr. Ser. - Excerpta Med. 538: 224-228. Spyker, D.A., C. Lynch, J. ShabanowHz and J.A. S1nn. 1980. Poisoning with 4-am1nopyr1d1ne: Report of three cases. Cl1n. Toxlcol. 16(4): 487-497. / i SRI (Stanford Research Institute International). 1987. 1987 Directory of Chemical Producers. United States of America. SRI International, Menlo Park, CA. p. 325, 459. Starr, R.I. and D.J. Cunningham. 1975. Leaching and degradation of carbon-14 labeled 4-am1nopyr1d1ne 1n several soil systems. Arch. Environ. I Contam. Toxlcol1 3: 72-83. Sultana, P., J.E. Brooke and R.L. Bruggers. 1986. Repellency and toxldty of bird control chemicals to pest birds In Bangladesh. Trop. Pest. Manage. 32(3): 246-248. 0124d -51- 10/21/88 ------- Thomas, R.G. 1982. Volatilization from water. in: Handbook of Chemical Property Estimation Methods, W.J. Lyman, W.F. Reehl and O.H. Rosenblatt, Ed. McGraw-Hill Book Co., NY. p. 15-15, 15-16. Uges, D.R.A., Y.J. Sohn, B. Greljdanus, A.H.J. Scaf and S. Agoston. 1982. 4-Am1nopyr1d1ne kinetics. CUn. Pharmacol. 31: 587-593. U.S. EPA. 1977. Computer print-out of non-confidential .production data from the TSCA Production File for 1977. U.S. EPA, Washington, DC. U.S. EPA. 1980a. Guidelines and Methodology used 1n the Preparation of Health Effects Assessment Chapters of the Consent Decree 'Water Criteria Documents. Federal Register. 45(231): 79347-79357. U.S. EPA. 1980b. 4-Am1nopyr1d1ne. .AvHrol Pesticide Registration Standard. OPTS, U.S. EPA, Washington, DC. NTIS PB84-209907. U.S. EPA. 1984. Methodology and Guidelines for Ranking Chemicals Based on Chronic ToxicUy Data. Prepared by the Office of Health and Environmental Assessment, Environmental Criteria and Assessment Office, Cincinnati, OH for the Office of Solid Waste and Emergency Response, Washington, DC. U.S. EPA. 1985. Notification Requirements; reportable quantity adjust- ments; final rule and proposed rule. Federal Register. 50(65): 13456-13522. 0124d -52- 02/08/89 ------- U.S. EPA. 1986a. CBI Appendix for Review and Evaluation of ADI for: POOS 4-Amlnopyrldlne. Prepared by SRC under Contract No. 68-03-3228 for Environ- mental Criteria and Assessment Office, Cincinnati, OH. U.S. EPA. 1986b. Guidelines for Carcinogen Risk Assessment. Federal Register. 51(185): 33992-34003. U.S. EPA. 1986c. Reference Values for Risk Assessment. Prepared by the Office of Health and Environmental Assessment, Environmental Criteria and Assessment Office, Cincinnati, OH for the Office of Solid Waste, Washington, DC. U.S. EPA. 1987. Graphical Exposure Modeling System (GEMS). PCCHEM. Version April T987. U.S. EPA. 1988. Reference Dose (RfD): Description and Use In Health Risk Assessments. Integrated Risk Information System (IRIS). Online. Intra-Agency Reference Dose (RfD) Work Group, Office of Health and Environmental Assessment, Environmental Criteria and Assessment Office, Cincinnati, OH, February. U.S. EPA. 1989. Integrated Risk Information System (IRIS). Online. i Office of Health and Environmental Assessment, Environmental Criteria and Assessment Office, Cincinnati, OH. U.S. EPA/NIH (Environmental Protection Agency/National Institute of Health). 1988. OHM-TADS (011 and Hazardous Materials-Technical Assistance Data System). Online: May, 1988. 0124d -53- 02/08/89 ------- Vohra, M.H., S.N. Pradhan, P.C. Jain, S.K. Chatterlee and N. Anand. 1965. Synthesis and structure-activity relations of some amlnopyrldlne - Imldazo pyrldlnes and trlazole pyrldlnes. J. Hed. Chem. 8: 296-304. (CUed In Schafer et al., 1973a) Wakabayashl, K., T. Yahagl, M. Nagao and T. Suglmura. 1982. Comutagenlc effect of norharman with amlnopyrldlne derivatives. Hutat. Res. 105(4): 205-210. • Weast, R.C., Ed. 1985. CRC Handbook of Chemistry and Physics, 66th ed. CRC Press, Inc., Boca Raton, PL. p. C-462, D-160. Hessellng, H., S. Agoston, G.B.P. van Dam, et al. 1984. Effects of 4-am1nopyr1d1ne 1n elderly patients with Alzhemlers disease. N. Engl. J. Hed. 310: 988-989. 0124d -54- 10/21/88 ------- APPENDIX A LITERATURE SEARCHED This HEED 1s based on data Identified by computerized literature searches of the following: CHEHLINE 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 These searches were conducted 1n Hay 1988, and the following secondary sources were reviewed: ACGIH (American Conference of Governmental Industrial Hyg1en1sts). 1986. Documentation of the Threshold Limit Values and Biological Exposure Indices, 5th ed. Cincinnati, OH. ACGIH (American Conference of Governmental Industrial Hyg1en1sts). 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. I 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. 28. John WHey and Sons, NY. p. 2879-3816. Clayton, G.O. and F.E. Clayton, Ed. 1982. Patty's Industrial Hygiene and Toxicology, 3rd rev. ed., Vol. 2C. John Wiley and Sons, NY. p. 3817-5112. 0124d -55- 09/19/88 ------- Grayson, H. and D. Eckroth, Ed. 1978-1984. Klrk-Othmer 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 of Chemicals to Humans. IARC, WHO, Lyons, France. Jaber, H.H., 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 In the Special Review Program, Registration Standards Program and the Data Call 1n Programs. Registration Standards and the Data Call 1n 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. Worthing. C.R. and S.B. Walker, Ed. 1983. The Pesticide Manual. British Crop Protection Council. 695 p. Wlndholz, M., Ed. 1983. The Merck Index, 10th ed. Merck and Co., Inc., Rahway, NJ. 0124d -56- 09/19/88 ------- In addition, approximately 30 compendia of aquatic toxldty 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. Johnson, W.W. and H.T. Flnley. 1980. Handbook of Acute Toxldty of Chemicals to Fish and Aquatic Invertebrates. Summaries of Toxldty Tests Conducted at Columbia National Fisheries Research Laboratory. 1965-1978. U.S. Dept. 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. 0124d -57- 09/19/88 ------- IS) APPENDIX B Summary Table for 4-Amlnopyrldlne Species Exposure Effect RfD or q-|* Reference in CO Inhalation Exposure Subchronlc Chronic Carclnogenlclty Oral Exposure Subchronlc Chronic Carclnogenlclty rat 0.15 mg/kg/day NOAEL for CNS effects rat 0.15 mg/kg/day NOAEL for CNS effects ID ID ID 0.0002 mg/kg/day or 0.01 ng/day for a 70 kg human* 0.00002 mg/kg/day or 0.001 mg/day for a 70 kg human* ID Kohn, 1968 Kohn. 1968 REPORTABLE QUANTITIES Based on chronic toxlclty 100 Based on Carclnogenlclty ID VO CD CO Kohn. 1968 tThese RfDs should be considered tentative and should be reviewed when additional data are available. ID » Insufficient data ------- |