------- 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 ------- ------- EXECUTIVE SUMMARY AdlponHMle Is a colorless liquid at room temperature with no distinc- tive odor (Smiley, 1981). It Is soluble In many organic solvents and Is highly soluble 1n water (Smiley, 1981). It undergoes reactions typical of nltrlles, e.g., hydrolysis to adlpamlde and adlplc add and alcoholysls to substituted amides and esters (Smiley, 1981). AdlponltrUe can be produced commercially either by ammonlatlon of adlplc add, dlmerlzatlon of acrylo- nltrlle or hydrocyanatlon of butadiene (Smiley, 1981). Current domestic manufacturers are E.I. Dupont In Orange, TX and Victoria, TX and Monsanto Co. In Decatur, AL (SRI, 1986). As of January 1, 1986, the total adlpo- nltrlle production capacity of these plants was estimated to be 929 million pounds per year (SRI, 1986). The most Important use for this compound 1s as an Intermediate In the manufacturer of hexamethylened1am1ne, a precursor of Nylon 66 (Smiley, 1981). Ad1pon1tr1le may also be used In organic synthesis and as a solvent (Kuney, 1985; Hawley, 1981; Smiley, 1981). In the atmosphere, adlponltMle 1s expected to exist almost entirely In the vapor phase. Reaction with photochemically generated hydroxyl radical (estimated t./? -10 days) and physical removal by wet deposition are predicted to be Important fate processes. Ad1pon1tr1le Is not susceptible to reaction with ozone (U.S. EPA, 1987b). In water, aerobic blodegradatlon 1s the Important removal mechanism. Based on results of a blodegradatlon study, It appears that the blodegradatlon half-life of adlponUrlle 1n unaccllmated waters at 20°C Is -1 week (Ludzack et al., 1959a). Acclimation of microorganisms should Increase the rate of blodegradatlon and lower temperatures should decrease the rate of blodegradatlon (Ludzack et al., 1959a). Adsorption to suspended solids and sediments, bloaccumulatlon 1n 1v ------- aquatic organism and volatilization are not expected to be Important fate processes In water. In soil, aerobic blodegradatlon 1s expected to be the Important degradation mechanism. Adlponltrlle has the potential to undergo extensive leaching; however, blodegradatlon of the compound would limit the movement of this compound through soil. Volatilization 1s not expected to be significant 1n soil. Pertinent data regarding exposure to ad1pon1tr1le by Inhalation, dermal contact or 1ngest1on of food could not be located In the available litera- ture as cited 1n Appendix A. Adlponltrlle was tentatively Identified 1n the drinking water obtained from New Orleans, LA, 1n January 1976 (Lucas, 1984). Adlponltrlle was also detected 1n the effluent from a nylon manufacturing plant (Shackelford and Keith, 1980). There was little Information concerning toxldty of ad1pon1tr1le to aquatic organisms. The lowest reported acutely toxic concentration for freshwater fishes was 384 mg/i, an LC5Q for golden orfe (Knle et al., 1983). The lowest reported acutely toxic concentration for freshwater Invertebrates was 445 mg/i, an EC5Q for Immobilization of Daphnla magna (BMngmann and Kuehn. 1982). Data for saltwater species could not be located In the available literature as cited 1n Appendix A. Studies of the metabolism of ad1pon1tr1le Indicate that 1t Is absorbed by the gastrointestinal tract, metabolized to cyanide and excreted 1n the urine as thlocyanate (Svlrbely and Floyd, 1964; Gh1r1nghell1, 1955a; Tan 11 and Hashimoto. 1985). Tanll and Hashimoto (1985) found that the metabolism of adlponltrlle to cyanide In mice was greatly Inhibited by CC1. pretreat- ment, which Inhibits certain drug metabolizing enzymes In the liver. ------- Nylon workers exposed to adlponltrlle and hexamethylenedlamlne for 2-3 years showed a tendency for hyperchromlc anemia of the hemolytlc type and slight leukopenla (Ceresa, 1948a). Ceresa (1948b) attributed these effects to exposure to ad1pon1tr11e and hexamethylenedlamlne. Dogs fed adlponltrlle 1n the diet at levels <500 ppm had normal blood and urine values and tests for liver and kidney function (Svlrbely and Floyd, 1964). During the first week of the study, dogs fed 1000 ppm were not able to consume the entire dose. In a rat study (Svlrbely and Floyd, 1964), females treated with adlponltrlle 1n the drinking water at 0.5, 5.0 and 50 ppm and males at 50 ppm were found to have advanced adrenal degen- eration. Vomiting, tightness In the chest, headache, profound weakness with difficulty standing, vertigo, respiratory difficulty, tachycardia and low blood pressure were experienced by a human who consumed a few ml of adlpo- nltrlle (GhlrlnghelH, 1955b). Zeller et al. (1969) reported seven cases of skin Irritation 1n workers dermally exposed to adlponltrlle. Adlponltrlle rubbed on the backs of guinea pigs for 1 month resulted In weight loss, decreased calcium content of the blood, marked hyperchromlc hemolytlc anemia with leukopenla and lymphomonocytosls. Hlstologlcal examinations revealed swelling and congestion of nearly all Internal organs (Ceresa, 1948b). Rats exposed to adlponltrlle at 0.3 mg/8. for ten 6-hour exposures (5 days/week) showed Increases In blood glucose, urea nitrogen, creatlnlne and urine glucose, and decreases In erythrocyte count, hemoglobin, leukocyte count and urine osmolalHy. At 0.1 mg/l. Increases In urea nitrogen and lymphocytes and decreases 1n the number of eoslnophlls and neutrophlls were noted. No changes In clinical parameters were observed at 0.03 mg/8. (Smith and Kennedy, 1982). v1 ------- The oral ID™ In the rat was reported to be 960 mg/kg (Plokhova and Rubaklna, 1965) and 300 mg/kg (NIOSH, 1978). Mice, with an oral LD5Q of 172 mg/kg, may be somewhat more sensitive to the acute oral toxldty of adlponltrlle (Tan 11 and Hashimoto, 1985). The carclnogenlcHy of adlponltrlle following Inhalation, oral or other routes of exposure has not been studied. Ad1pon1tr1le tested negative for reverse mutation In S. typhlmurlum at concentrations <10,000 yg/plate, both with and without metabolic activation. Johannsen et al. (1986) orally dosed pregnant rats with adlponltrlle at 0, 30, 50 or 80 mg/kg/day on gestation days 6-19. Two rats at 80 mg/kg/day and one rat at 50 mg/kg/day died. Fetal body weights were significantly reduced at 80 mg/kg/day, but this observation was not attributed to treatment. No other changes were noted. No changes 1n fertility, gestation or viability were noted In two litters from rats exposed to adlponltrlle In the'r drinking water at 10, 100 or 500 ppm >jr 2 years (Svlrbely and Floyd, 1964). Chronic oral exposure to adlponltrlle resulted 1n a LOAEL of 0.5 ppm (0.07 mg/kg/day) that was associated with adrenal degeneration In the 2-year rat study (Svlrbely and Floyd, 1964). This study was unavailable for review and 1n addition appears to be an unpublished abstract. Data were considered Inadequate for estimation of either an RfD or an RQ. It Is recommended that comprehensive subchronlc oral testing be Initiated In the rat to determine a NOAEL. Data were Insufficient for derivation of cancer-based risk assessment values. Adlponltrlle was assigned to EPA Group 0, not classifiable as to human carclnogenldty. ------- TABLE OF CONTENTS 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 2 2. ENVIRONMENTAL FATE AND TRANSPORT. . . 5 2.1. AIR 5 2.1.1. Reaction with Hydroxyl Radicals 5 2.1.2. Reaction with Ozone 5 2.1.3. Physical Removal Processes 5 2.2. WATER 5 2.2.1. Hydrolysis. . . 5 2.2.2. Mlcroblal Degradation 6 2.2.3. Bloconcentratlon 6 2.2.4. Adsorption 6 2.2.5. Volatilization 7 2.3. SOIL 7 2.3.1. Hyd-olysls 7 2.3.2. M1crob1al Degradation 7 2.3.3. Adsorption 7 2.3.4. Volatilization 7 2.4. SUMMARY 8 3. EXPOSURE 9 4. AQUATIC TOXICITY 10 4.1. ACUTE TOXICITY 10 4.2. CHRONIC EFFECTS 10 4.3. PLANT EFFECTS 10 4.4. SUMMARY 11 5. PHARMACOKINETCS 12 5.1. ABSORPTION 12 5.2. DISTRIBUTION 12 5.3. METABOLISM 12 5.4. EXCRETION 13 5.5. SUMMARY 13 ------- TABLE OF CONTENTS (cont.) Page 6. EFFECTS 14 6.1. SYSTEMIC TOXICITY 14 6.1.1. Inhalation Exposures 14 6.1.2. Oral Exposures 14 6.1.3. Other Relevant Information 15 6.2. CARCINOGENICITY 18 6.2.1. Inhalation . 18 6.2.2. Oral 18 6.2.3. Other Relevant Information 18 6.3. MUTAGENICITY 18 6.4. TERATOGENICITY 18 6.5. OTHER REPRODUCTIVE EFFECTS 19 6.6. SUMMARY 19 7. EXISTING GUIDELINES AND STANDARDS 22 7.1. HUMAN 22 7.2. AQUATIC 22 8. RISK ASSESSMENT 23 8.1. CARCINOGENICITY 23 8.1.1. Weight of Evidence 23 8.1.2. Quantitative Risk Estimates 23 8.2. SYSTEMIC TOXICITY. . 23 8.2.1. Inhalation Exposure 23 8.2.2. Oral Exposure 24 9. REPORTABLE QUANTITIES 26 9.1. BASED ON SYSTEMIC TOXICITY 26 9.2. BASED ON CARCINOGENICITY 26 10. REFERENCES 29 APPENDIX A: LITERATURE SEARCHED 36 APPENDIX B: SUMMARY TABLE FOR ADIPONITRILE 39 1x ------- LIST OF TABLES No. TUIe Page 1-1 Current Domestic Manufacturers of AdiponHMle ........ 3 6-1 LD50 Values for Ad1pon1tr1le ................. 17 9-1 Oral Toxlclty Summary for AdlponHMTe Using Female Wlstar Rats ......................... 27 9-2 Ad1pon1tr1le: Minimum Effective Dose (MED) and Reportable Quantity (RQ) ................... 28 ------- LIST OF ABBREVIATIONS BCF B1oconcentrat1on factor BOD Biological oxygen demand CAS " Chemical Abstract Service CS Composite score EC5Q Concentration effective to 50% of recipients (and all other subscripted concentration levels) Koc Soil sorptlon coefficient standardized with respect to organic carbon Kow Octanol/uater partition coefficient LC5Q Concentration lethal to 50% of recipients (and all other subscripted dose levels) Dose lethal to 50% of recipients LOAEL Lowest-observed-adverse-effect level MED Minimum effective dose NOAEL No-observed-adverse-effect level ppm Parts per million RfD Reference dose RQ Reportable quantity RV,j Dose-rating value RVe Effect-rating value TWA Time-weighted average x1 ------- 1. INTRODUCTION 1.1. STRUCTURE AND CAS NUMBER AdlponHMle 1s also known as hexanedlnHMle, adlplc add nHrlle, tetramethyl cyanide and 1,4-d1cyanobutane (SANSS, 1987). The structure, empirical formula, molecular weight and CAS Registry number are as follows: N=C-CH2-CH2-CH2-CH2-CEN Empirical formula: C,H0N. o o e. Molecular weight: 108.14 CAS Registry number: 111-69-3 1.2. PHYSICAL AND CHEMICAL PROPERTIES Pure adlponltrlle Is a colorless liquid at room temperature with no distinctive odor (Smiley, 1981). It undergoes reactions typical of nltrlles, e.g., hydrolysis to adlpamlde and adlplc add and alcoholysls to substituted amides and esters (Smiley, 1981). Adlponltrlle Is soluble In methanol, ethanol, chloroalkane and aromatic solvents and has low solubility 1n carbon dlsulflde, ethyl ether and aliphatic hydrocarbons (Smiley, 1981). Selected physical properties are given below: Melting point, °C: 2.49 Smiley, 1981 Boiling point, °C: 295 Smiley, 1981 Vapor pressure at 20°C: 3.0xlO~3 mm Hg Neely and Blau, 1985 Water solubllHy, 20°C: 8xl04 mg/l Smiley, 1981 Log Kow: -0.32 Tanll and Hashimoto, 1985 -0.42 U.S. EPA, 1987a Density, 20°C: 0.965 g/cm3 Smiley, 1981 Refractive Index, njj : 1.4343 Smiley, 1981 Flashpoint, °C: 159 (closed cup) Smiley, 1981 0071d -1- 06/25/87 ------- 1.3. PRODUCTION DATA Adlponltrlle can be prepared commercially using either adlplc acid, acrylonltrlle or butadiene as feedstock (Smiley, 1981). In the adlplc add process, the feedstock Is allowed to react with ammonia over a catalyst to produce adiponltrlle. In one butadiene-based production process, butadiene 1s directly hydrocyanated 1n two successive steps to produce adiponltrlle. Another process Involves d1mer1zat1on of acrylonUrlle In an electrolyte cell to produce adiponltrlle (Smiley, 1981). Table 1-1 lists production Information concerning current domestic manufacturers of adiponltrlle. Although closed since 1980, the Monsanto plant In Pensacola, PL, has a yearly production capacity of 185 million pounds; this plant continues to hydrogenate adiponltrlle produced at other Monsanto locations to make hexamethylened1am1ne (SRI, 1986). 1.4. USE DATA The most Important commercial use for adlponltrlle 1s as an Intermediate In the manufacture of hexamethylenedlamlne, a p.^cursor of Nylon 66 (Smiley, 1981). Adiponltrlle may also be used In organic synthesis and as a solvent (Kuney, 1985; Hawley, 1981; Smiley, 1981). 1.5. SUMMARY Adiponltrlle 1s a colorless liquid at room temperature with no distinc- tive odor (Smiley, 1981). It Is soluble In many organic solvents and Is highly soluble In water (Smiley, 1981). It undergoes reactions typical of nUMles, e.g.. hydrolysis to adlpamlde and adlplc acid, and alcoholysls to substituted amides and esters (Smiley, 1981). Adiponltrlle can be produced commercially either by ammonlatlon of adlplc add, dlmeMzatlon of acrylo- nltrlle or hydrocyanatlon of butadiene (Smiley, 1981). Current domestic manufacturers are E.I. Dupont In Orange, TX and Victoria, TX and Monsanto 0071d -2- 06/25/87 ------- TABLE 1-1 Current Domestic Manufacturers of Ad1pon1tr1lea Company Location Annual Capacity0 (millions of pounds) E.I. Dupont E.I. Oupont Monsanto Co. Orange, TX Victoria, TX Decatur, AL 441 293 195 Total 929 aSource: SRI, 1986 ^Estimates as of January 1, 1986 0071d -3- 09/14/87 ------- Co. In Decatur, AL (SRI, 1986). As of January 1, 1986 the total adlpo- nHMle production capacity of these plants was estimated to be 929 million pounds per year (SRI, 1986). The most Important use for this compound Is as an Intermediate 1n the manufacturer of hexamethylenedlamlne, a precursor of Nylon 66 (Smiley, 1981). Adlponltrlle may also be used In organic synthesis and as a solvent (Kuney, 1985; Hawley, 1981; Smiley, 1981). 0071d -4- 06/25/87 ------- 2. ENVIRONMENTAL FATE AND TRANSPORT Limited experimental data pertaining to the environmental fate and transport of adlponltrlle could be located In the available literature as cited 1n Appendix A. When possible, therefore, Information concerning the fate and transport of this compound was derived from physical property data or molecular structure. 2.1. AIR Based on the estimated vapor pressure of 3.0xlO~3 mm Hg at 20°C, adlponltrlle 1s expected to be present almost entirely 1n the vapor phase 1n the atmosphere (E1senre1ch et al., 1981). 2.1.1. Reaction with Hydroxyl Radicals. The estimated rate constant for the reaction of adlponltrlle with photochemically generated hydroxyl radicals Is ~10~10 cmVmolecule-sec at 25°C using the method of Atkinson (1985). Given the average hydroxyl radical concentration In air of 8xlOs molecules/cm3 (U.S. EPA, 1987b), the estimated half-life for this reaction Is -10 days (Atkinson, 1985). 2.1.2. Reaction with Ozone. Adlponltrlle 1s not susceptible to oxidation by ozone 1n the atmosphere (U.S. EPA, 1987b). 2.1.3. Physical Removal Processes. Based on a water solubility of 8x10* mg/i at 20°C (Smiley, 1981), 1t appears that significant amounts of adlponltrlle may be removed from the atmosphere by wet deposition. 2.2. HATER 2.2.1. Hydrolysis. In an abstract of a Russian study (Llnetskll and Serebryakov, 1965), the first-order hydrolysis rate constant for adlpo- n1tr1le 1n 2-5% NaOH solution at 100°C was reported as 1.18 mln'1. Under environmental conditions, however, adlponltrlle 1s not likely to hydrolyze significantly (U.S. EPA, 1986b). OOTld -5- 09/14/87 ------- 2.2.2. M1crob1al Degradation. Results of a blodegradatlon screening study, which used a natural water sample as seed, Indicate that blodegradatlon Is likely to be the most significant route of decomposition for adlponUrlle under aerobic conditions In water (Ludzack et al., 1959a). Incubation of 0.5-10 mg/i adiponltrlle In unaccllmated Ohio River water resulted In BOO values equivalent to theoretical oxygen demands of 0, 40 and >100X after 2, 5 and 12 days, respectively. Acclimation of microorganisms was examined by redoslng, and degradation occurred twice as fast after acclimation was achieved. The effect of temperature on blodegradatlon was also studied; blodegradatlon at 5°C required -3.5 times longer than at 20°C. Ludzack et al. (1959b) studied the blodegradatlon of adiponltrlle by activated sludge 1n a continuous feed test at 22-25°C; 93-98% BOD removal was measured with a mean aerator detention time of 7-13 hours at an Influent adiponltrlle concentration equivalent to a BOO of 275-350 mg/l. Adiponltrlle at 500 mg/l Incubated for 72 hours In three different activated sludge Inocula, was found to be resistant to biological oxidation (Lutln, 1970). Ludzack et al. (1959a) found that nltrlle oxidation proceeds by enzymatic hydrolysis leading to the formation of ammonia, followed by nitrification. 2.2.3. Bloconcentratlon. A BCF of 1 was estimated for adlponUrlle using a water solubility of 8.0x10* mg/l at 20°C (Smiley, 1981) and the following linear regression equation (Lyman et al., 1982): log BCF = 2.791 - 0.564 log S. This BCF value suggests that adiponltrlle will not bloaccumu- late significantly In aquatic organisms. 2.2.4. Adsorption. An estimated K value of 9 for adiponltrlle (Section 2.3.3.) suggests that adsorption to sediments or suspended solids In water would not be significant. 0071d -6- 09/14/87 ------- 2.2.5. Volatilization. Henry's Law constant for adlponHMle was esti- mated to be ~7xlO~9 atm-m3/mol at 25°C using a method of group contribu- tions to Intrinsic hydrophlUc character (Hlne and Mookerjee, 1975). This value of Henry's Law constant suggests that volatilization from water would not be an Important removal mechanism (Lyman et al., 1982). 2.3. SOIL 2.3.1. Hydrolysis. Because of the lack of experimental data the signifi- cance of this reaction cannot be determined. 2.3.2. H1crob1al Degradation. In the only study available regarding the blodegradatlon of ad1pon1tr1le by soil microorganisms, Kuwahara et al. (1980) found that Aeromonas sp. BN 7013 Isolated from soil 1s capable of using ad1pon1tr1le as Us sole source of nitrogen. Relatively rapid blodegradatlon of adlponUrlle 1n natural water samples and activated sludge Inocula suggests that blodegradatlon may also be the most Important removal mechanism 1n soil. 2.3.3. Adsorption. A K of 9 was estimated using a water solubility of 8.0x10* mg/l at 20°C (Smiley, 1981) and the following linear regres- sion equation (Lyman et al., 1982): log K = -0.55 log S * 3.64. This K value Indicates that adlponltrlle should be highly mobile In soil and susceptible to significant leaching (Swann et al., 1983). 2.3.4. Volatilization. Based on a vapor pressure of 3.0xlO~9 mm Hg at 20°C and a Henry's Law constant of 7xlO"9 atm-mVmol at 25°C, volatili- zation of ad1pon1tr1le from moist and dry soil surfaces 1s not expected to be a significant fate process. 007 Id -7- 09/14/87 ------- 2.4. SUMMARY In the atmosphere, adlponltrlle 1s expected to exist almost entirely In the vapor phase. Reaction with photochemically generated hydroxyl radical (estimated t,/2 -10 days) and physical removal by wet deposition are predicted to be Important fate processes. Ad1pon1tr1le Is not susceptible to reaction with ozone (U.S. EPA, 1987b). In water, aerobic blodegradatlon 1s the Important removal mechanism. Based on results of a blodegradatlon study, 1t appears that the blodegradatlon half-life of adlponltrlle In unaccllmated waters at 20°C 1s ~1 week (Ludzack et al., 1959a). Acclimation of microorganisms should Increase the rate of blodegradatlon and lower temperatures should decrease the rate of blodegradatlon (Ludzack et al., 1959a). Adsorption to suspended solids and sediments, bloaccumulatlon 1n aquatic organism and volatilization are not expected to be Important fate processes In water. In soil, aerobic blodegradatlon 1s expected to be the Important degradation mechanism. Adlponltrlle has the potential to undergo extensive leaching; however, blodegradatlon of the compound would limit the movement of this compound through soil. Volatilization Is not expected to be significant In soil. 0071d -8- 06/25/87 ------- 3. EXPOSURE Pertinent data regarding exposure to ad1pon1tr1le by Inhalation, dermal contact or Ingestlon of food could not be located 1n the available litera- ture as cited In Appendix A. Adlponltrlle was tentatively Identified In the drinking water obtained from New Orleans, LA, 1n January 1976 (Lucas, 1984). Adlponltrlle was also detected In the effluent from a nylon manufacturing plant (Shackelford and Keith, 1976). 0071d -9- 09/14/87 ------- 4. AQUATIC TOXICITY 4.1. ACUTE TOXICITY Two available studies reported acute toxldty data for fish or aquatic Invertebrates exposed to adiponltrlle. Henderson et al. (1961) reported 96-hour LC5Q values of 820 and 1250 mg/l for fathead minnows, Plmephales promelas. 1n hard and soft water, respectively. These authors also reported 96-hour LC5_ values of 720 mg/l for bluegllls, Lepomls macrochlrus. and 775 mg/l for gupples, Leblstes retlculatus. both 1n soft water. Hardness 1n these studies was 20 mg/l for soft water and 380 mg/l for hard water. An LC,Q of 384 mg/l was reported for the golden orfe, Leudscus 1dus (Kn1e et al., 1983). The only Invertebrate species for which there was Information about adiponltrlle toxlclty was the cladoceran, Daphnla magna. Brlngmann and Kuehn (1982) reported a 24-hour EC,, for Immobilization of 445 mg/l, while Knle et al. (1983) reported an EC5Q of 1250 mg/l. 4.2. CHRONIC EFFECTS Pertinent data regarding chronic toxlclty of ad1pon1tr1le to aquatic organisms could not be located In the available literature as cited 1n Appendix A. 4.3. PLANT EFFECTS Knle et al. (1983) reported that 408 mg/l was a 30-mlnute EC... for Inhibition of culture growth of the bacterium Pseudomonas put Ida. Other data for aquatic plants or bacteria could not be located 1n the available literature as cited In Appendix A. 0071d -10- 09/14/87 ------- 4.4. SUMMARY There was little Information concerning toxldty of adlponltrUe to aquatic organisms. The lowest reported acutely toxic concentration for freshwater fishes was 384 mg/i, an LC5Q for the golden orfe (Knle et al., 1983). The lowest reported acutely toxic concentration for freshwater Invertebrates was 445 mg/l, an EC— for Immobilization of Daphnla magna (Brlngmann and Kuehn, 1982). Data for saltwater species could not be located 1n the available literature as cited 1n Appendix A. 0071d -11- 09/14/87 ------- 5. PHARHACOKINETICS 5.1. ABSORPTION Approximately 50% of the adlponltrlle consumed In the diet by mongrel female dogs was recovered 1n the urine as thlocyanate (Svlrbely and Floyd, 1964). Dietary concentrations ranged from 10-1000 ppm. 5.2. DISTRIBUTION Cyanide, an Important metabolite of ad1pon1tr1le, has been shown to cross the blood-brain barrier and locate 1n the brain. Tan 11 and Hashimoto (1985) measured cyanide at -0.71 wg/g of wet tissue In the brains of male ddY mice given an oral 4.8 mmol/kg (519 mg/kg) dose of adlponltrlle. The brains were harvested at the time of death, -83 minutes after treatment. In mice pretreated with CC1. to Inhibit the hepatic mixed function oxldase system (and presumably prevent degradation of adlponltrlle to cyanide), a 519 mg/kg dose of adlponltrlle did not cause death and cyanide was not found 1n the brain 83 ml.utes after treatment. 5.3. METABOLISM A number of studies Indicate that adlponltrlle Is metabolized to cyanide. Svlrbely and Floyd (1964) found that dogs fed adlponltrlle In the diet at 10-1000 ppm showed a dose-related Increase In thlocyanate excreted In the urine, which Is equivalent to -50% of the dose of adlponltrlle. The amount of thlocyanate In the bloodstream of guinea pigs Injected subcutaneously with adlponltrlle at 3-30 mg/kg was proportional to the administered dose (Gh1r1nghell1, 1955a). Tan11 and Hashimoto (1985) <• Identified cyanide In the brains of mice orally dosed with adlponltrlle. The metabolism of ad1pon1tr1le to cyanide was greatly Inhibited In mice pretreated with CC1., as evidenced by the fact that cyanide was not found 1n the brains of pretreated mice. OOTld -12- 11/17/87 ------- In an hi vitro study using mouse liver mlcrosomes, 6.23 ng cyan1de/mg protein/minute were formed from an ad1pon1tr1le concentration of 3.1 mM (Tan11 and Hashimoto, 1985). When mice were treated with CC1. before mlcrosomes were harvested, cyanide was not detected after adiponltrlle was added to the cultures. Tanll and Hashimoto (1985) stated that ad1pon1tr1le 1s probably hydroxylated at the a-carbon to form cyanohydMn, which degrades spontaneously 1n alkaline medium to form hydrogen cyanide. 5.4. EXCRETION Approximately 79% of the adiponltrlle (3-30 mg/kg) Injected subcuta- neously Into guinea pigs was accounted for as thlocyanate excreted 1n the urine (Gh1r1nghel11, 1955a). Dogs excreted -50% of an oral dose of adipo- nltrlle as urinary thlocyanate; negligible amounts of thlocyanate were found 1n the feces (Svlrbely and Floyd, 1964). 5.5. SUMMARY Studies of the metabolism of adiponltrlle Indicate that 1t 1s absorbed by the gastrointestinal tract, metabolized to cyanide and excreted 1n the urine as thlocyanate (Svlrbely and Floyd, 1964; Gh1r1nghell1, 1955a; Tanll and Hashimoto, 1985). Tan11 and Hashimoto (1985) found that the metabolism of adiponltrlle to cyanide In mice was greatly Inhibited by CC1. pretreat- ment, which Inhibits certain drug metabolizing enzymes 1n the liver. 0071d -13- 11/17/87 ------- 6. EFFECTS 6.1. SYSTEMIC TOXICITY 6.1.1. Inhalation Exposures. 6.1.1.1. SUBCHRONIC — Pertinent data regarding the toxldty of ad1pon1tr1le following subchronlc Inhalation exposure could not be located 1n the available literature as cited In Appendix A. 6.1.1.2. CHRONIC — Ceresa (1948a) reported that 27 Individuals who had worked In the nylon Industry, handling adiponltrlle and hexamethylene- dlamlne for 2-3 years, showed a definite tendency for hyperchromlc anemia of the hemolytlc type and slight leukopenla or lymphomonocytosls. 6.1.2. Oral Exposures. 6.1.2.1. SUBCHRONIC ~ Pertinent data regarding the toxldty of adiponltrlle following subchronlc oral exposure could not be located In the available literature as dted In Appendix A. 6.1.2.2. CHRONIC — NIOSH (1978) reviewed chronic oral studies of adiponltrlle In dogs and rats completed by Svlrbely and Floyd (1964). The original study report could not be obtained. However, the original report from the fourth portion of this series (SvUbely, n.d.) was located. Apparently each of the segments were only reported Vn abstract form. In the dog study, an unspecified number of female mongrel dogs were fed adiponltrlle In the diet at "the equivalent of" 10, 100, 500 and 1000 ppm for an unspecified period of time. Blood and urine values and tests for liver and kidney function were normal In dogs fed adiponltrlle at <500 ppm. During the first week, dogs fed 1000 ppm were not able to consume the entire dose; the dogs vomited or failed to eat a portion of H. In the rat study, an unspecified number of male and female Wlstar rats were provided with 0.5, 5.0 or 50 ppm adiponltrlle In their drinking water 0071d -14- 11/17/87 ------- for 2 years. Throughout the study, body weights remained normal and no hematologlc abnormalities were observed. At the end of the study, advanced adrenal degeneration was found In female rats at all three ad1pon1tr1le concentrations and 1n male rats exposed to 50 ppm. Degeneration of other organs was also noted, but was not considered to be compound-related. Determination of organ (spleen, liver, kidney) to body weight ratios revealed no significant differences. No effect on survival was reported. 6.1.3. Other Relevant Information. NIOSH (1978) summarized a report by GhlMnghelH (1955b) concerning a case of acute poisoning In which an 18-year-old man consumed a few ml of ad1pon1tr1le. The man experienced vomiting, tightness 1n the chest, headache, profound weakness with diffi- culty standing, vertigo, respiratory difficulty, tachycardia and low blood pressure. The man recovered after being treated with sodium thlosulfate. As reviewed by NIOSH (1978), Zeller et al. (1969) reported seven cases of dermal exposure to adlponUrlle. Mild skin Irritation and Inflammation developed 1n six of the workers within 5-15 r.inutes of exposure. The seventh worker, whose shoe had been drenched with ad1pon1tr1le, had exten- sive destruction of the skin of the foot. The Injury required surgical treatment and the worker was Incapacitated for 117 days. To determine 1f the effects observed 1n humans occupatlonally exposed to ad1pon1tr1le and hexamethylenedlamlne (see Section 6.1.1.2.) could be attributed to ad1pon1tr1le, Ceresa (1948b) and Ceresa and De Blaslls (1950) examined the toxlclty of adlponUrlle and hexamethylenedlamlne 1n guinea pigs. An unspecified dose of ad1pon1tr1le was rubbed on the backs of guinea pigs dally for 1 month (Ceresa, 1948b). This treatment resulted In weight loss, decreased calcium content of the blood, marked hyperchromlc hemolytlc anemia with leukopenia and lymphomonocytosU. Hlstologlcal examinations revealed swelling and congestion of nearly all Internal organs. Because 0071d -15- 11/17/87 ------- hemolytlc anemia with leukopenla and degenerative changes In the liver and kidney were also noted 1n guinea pigs treated with subcutaneous Injections of hexamethylenedlamlne, Ceresa and De Blas11s (1950) concluded that both adlponltMle and hexamethylenedlamlne may contribute to the effects observed 1n humans. Smith and Kennedy (1982) exposed groups of 10 male Charles River CD rats to ad1pon1tr1le vapor at 0, 0.03, 0.1 or 0.3 mg/l (0, 30, 100 or 300 mg/m3) for ten 6-hour periods (5 days/week). After the ninth exposure, blood and urine analyses were completed. Following the tenth exposure, 5 rats/exposure group were sacrificed and comprehensive hlstologlcal examina- tions were conducted. The remaining rats were allowed to recover for 14 days when they were sacrificed for hlstologlcal examinations. During the exposures, the signs of toxlclty observed In all exposed groups Included Irregular breathing and mild salivation. Rats exposed at 0.3 mg/l showed weight loss during the first 5 exposures, and af.er 10 exposures had changes 1n clinical pa-ho-logy parameters Including. Increases 1n blood glucose, urea nitrogen, creatlnlne and urine glucose, and decreases 1n erythrocyte count, hemoglobin, leukocyte count and urine osmolalHy. At 0.1 mg/l, rats showed Increased blood urea nitrogen and lymphocytes and decreased numbers of eoslnophlls and neutrophlls. No changes 1n clinical chemistry parameters were observed at 0.03 mg/l. No hlstologlcal changes were noted at any exposure concentration. Fourteen days postexposure, clinical pathology parameters of all groups were normal and microscopic changes 1n the organs were not observed. LD-Q values for ad1pon1tr1le are presented 1n Table 6-1. Plokhova and Rubaklna (1965) reported effects of acute lethal oral doses of ad1pon1tr1le as excitation, convulsions, dyspnea, coma with death 1n 2-6 hours. H1sto- pathologlc changes Included hyperemla and dystrophlc changes In brain, 0071d -16- 11/17/87 ------- TABLE 6-1 Values for AdlponHMle Species Route of Administration 1050 Value Reference Rat Rat Rat Mouse3 House5 Guinea pig Rat House Inhalation oral oral oral oral subcutaneous subcutaneous Intraperltoneal 1.71 mg/l {1710 mg/m3) (4-hour LC5o) 960 mg/kg 300 mg/kg 1.59 mmol (-172 mg/kg) 2.65 mmol (-287 mg/kg) 50 mg/kg 200 mg/kg 40 mg/kg Smith and Kennedy. 1982 Plokhova and Rubaklna, 1965 NIOSH, 1978 Tan 11 and Hashimoto, 1985 Tan 11 and Hashimoto, 1985 Gh1r1nghell1, 1955b NIOSH, 1978 Plzak and Doull, 1969 aH1ce pretreated with an Intraperltoneal Injection of olive oil served as controls 1n an experiment with mice pretreated with CC14 (see Section 5.2). bH1ce were pretreated with an Intraperltoneal Injection of CC14. Mice appear to be somewhat more sensitive than rats to the acute oral tox1c1ty of adlponltrlle. 007 Id -17- 06/25/87 ------- liver, kidney and myocardium. Mice appear to be somewhat more sensitive than rats to the acute oral toxldty of ad1pon1tr1le. 6.2. CARCINOGENICITY 6.2.1. Inhalation. Pertinent data regarding the cardnogenlcHy of adiponltrlle following Inhalation exposure could not be located In the available literature as cited 1n Appendix A. 6.2.2. Oral. A NIOSH (1978) summary of a 2-year drinking water study of adiponltrlle 1n VHstar rats did not report carcinogenic effects. Additional Information concerning the cardnogenlcHy of adiponltrlle following oral exposure could not be located In the available literature as dted 1n Appendix A. The chemical 1s not currently scheduled for cancer testing by the NTP (1987). 6.2.3. Other Relevant Information. Pertinent data regarding the carclno- genldty of adiponltrlle by other routes of exposure could not be located In the available literature as cited In Appendix A. 6.3. MUTAGENICITY NIOSH (1978) reported that adiponltrlle was negative for reverse mutation 1n Salmonella typhlmurlum strains TA1536, TA1537, TA1538 and TA98 .at concentrations <10,000 yg/plate, both with and without metabolic activation. 6.4. TERATOGENICITY Johannsen et al. (1986) dosed groups of 25 mated Charles River, COBD CD rats by gavage with ad1pon1tr1le at 0, 30, 50 or 80 mg/kg/day on gestation days 6-19. The dams were sacrificed on gestation day 20 and the number and location of viable and nonvlable fetuses, early and late resorptlons, and the total number of Implants and corpora lutea were determined. The fetuses were examined for gross malformations and half were examined for visceral malformations while the remaining were examined for skeletal anomalies. 0071d -18- 11/17/87 ------- During the study, two 80 mg/kg/day rats and one 50 mg/kg/day rat died. No differences were found In uterine and fetal parameters measured at sacrifice. Fetal body weights were reduced significantly (p<0.05) at 80 mg/kg/day but not at 30 mg/kg/day, although the fetal body weights were essentially the same at these two dose levels. Because a dose-related change In fetal body weight was not observed, the Investigators concluded that there was no treatment-related effect on fetal body weight. Fetal examinations revealed no treatment-related malformations. 6.5. OTHER REPRODUCTIVE EFFECTS Svlrbely (n.d) reported In an unpublished abstract that exposure of Holtzman rats (number unspecified) to 10, 100 or 500 ppm ad1pon1tr1le for three generations (2 Utters/generation) did not result 1n any adverse effects. Endpolnts monitored Included fertility, gestation (NOS) and viability. 6.6. SUMMARY Nylon workers exposed to adlponUrlle and hexamethylened1am1ne for 2-3 years showed a tendency for hyperchromlc anemia of the hemolytlc type and slight leukopenla (Ceresa, 1948a). Ceresa (1948b) attributed these effects to exposure to ad1pon1tr1le and hexamethylenedlamlne. Dogs fed adlponUrlle In the diet at levels <500 ppm had normal blood and urine values and tests for liver and kidney function (Svlrbely and Floyd, 1964). During the first week of the study, dogs fed 1000 ppm were not able to consume the entire dose. In a rat study (Svlrbely and Floyd, 1964), females treated with ad1pon1tr1le In the drinking water at 0.5, 5.0 and 50 ppm and males at 50 ppm were found to have advanced adrenal degen- eration. Vomiting, tightness In the chest, headache, profound weakness with difficulty standing, vertigo, respiratory difficulty, tachycardia and low 0071d -19- 11/17/87 ------- blood pressure were experienced by a human who consumed a few ml of adlpo- nHMle (Gh1r1nghell1, 1955b). Zeller et al. (1969) reported seven cases of skin Irritation In workers dermally exposed to adlponltrlle. Adlponltrlle rubbed on the backs of guinea pigs for 1 month resulted 1n weight loss, decreased calcium content of the blood, marked hyperchromlc hemolytlc anemia with leukopenla and lymphomonocytosls. Hlstologlcal examinations revealed swelling and congestion of nearly all Internal organs (Ceresa, 1948b). Rats exposed to adlponUMle at 0.3 mg/j. for ten 6-hour exposures (5 days/week) showed Increases 1n blood glucose, urea nitrogen, creatlnlne and urine glucose, and decreases 1n erythrocyte count, hemoglobin, leukocyte count and urine osmolalHy. At 0.1 mg/i, Increases 1n urea nitrogen and lymphocytes and decreases In the number of eoslnophlls and neutrophlls were noted. No changes In clinical parameters were observed at 0.03 mg/i. (Smith and Kennedy, 1982). The oral LD.Q 1n the rat was reported to be 960 mg/kg (Plokhova and Rubaklna, 1965) and 300 mg/kg (NIOSH, 1978). Mice, with an oral LD5Q of 172 mg/kg, may be somewhat more sensitive to the acute oral toxldty of adlponltrlle (Tan11 and Hashimoto, 1985). The carclnogenlcHy of adlponltrlle following Inhalation, oral or other routes of exposure has not been studied. Adlponltrlle tested negative for reverse mutation 1n S. typhlmurlum at concentrations <10,000 yg/plate, both with and without metabolic activation. Johannsen et al. (1986) orally dosed pregnant rats with adlponltrUe at 0, 30, 50 or 80 mg/kg/day on gestation days 6-19. Two rats at 80 mg/kg/day and one rat at 50 mg/kg/day died. Fetal body weights were significantly 0071d -20- 09/14/87 ------- reduced at 80 mg/kg/day, but this observation was not attributed to treat- ment. No other changes were noted. No changes In fertility, gestation or viability were noted 1n two litters from rats exposed to adlponltrlle In their drinking water at 10, 100 or 500 ppm for 2 years (Svlrbely and Floyd, 1964). 0071d -21- 06/25/87 ------- 7. EXISTING GUIDELINES AND STANDARDS 7.1. HUMAN NIOSH (1978) recommended that employee exposure to adlponltrlle not exceed 4 ppm (18 mg/m3) as a TWA for up to a 10-hour work shift 1n a 40-hour workweek. This recommendation Is based on the comparative acute toxlclty of IsobutyronHrlle and adlponUrlle Injected subcutaneously 1n female rats. Other guidelines or standards could not be located In the available literature as dted In Appendix A. 7.2. AQUATIC Guidelines and standards for the protection of aquatic organisms from the effects of adlponltrlle could not be located In the available literature as cited In Appendix A. 0071d -22- 06/25/87 ------- 8. RISK ASSESSMENT 8.1. CARCINOGENICITY Pertinent data regarding the cardnogenlcHy of adlponltrlle by any route of exposure could not be located In the available literature as cited 1n Appendix A. 8.1.1. Weight of Evidence. Data were not located regarding the cardno- genldty of adlponltrlle 1n humans or experimental animals; therefore, ad1pon1tr1le 1s placed 1n EPA Group D (U.S. EPA, 1986c), not classifiable as to human carclnogenlclty. 8.1.2. Quantitative Risk Estimates. The lack of data concerning the carclnogenlclty of ad1pon1tr1le precludes the derivation of risk assessment values based on carclnogenlclty. 8.2. SYSTEMIC TOXICITY 8.2.1. Inhalation Exposure. 8.2.1.1. LESS THAN LIFETIME EXPOSURES (SUBCHRONIC) '— The lack of data concerning the toxlclty of adlponltrlle following subchronlc Inhalation exposure precludes the derivation of a subchronlc Inhalation RfD. 8.2.1.2. CHRONIC EXPOSURES -- Nylon workers exposed to adlponltrlle and hexamethylenedlamlne for 2-3 years showed a definite tendency for hyper- chromic anemia of the hemolytlc type and slight leukopenla (Ceresa, 1948a). The study 1s Inadequate for the derivation of an Inhalation RfD because exposure was to a mixture of chemicals and because of the lack of quantita- tive exposure data. The recommended occupational standard of 4 ppm (18 mg/m3) (NIOSH, 1978) based on acute subcutaneous toxlclty of ad1pon1tr1le compared with 1sobutyron1tr1le In female rats 1s not adequate for determina- tion of an RfD for Inhalation exposure. 0071d -23- 09/14/87 ------- 8.2.2. Oral Exposure. 8.2.2.1. LESS THAN LIFETIME EXPOSURES (SUBCHRONIC) — The toxUHy of adlponHMle following subchronlc oral exposure has not been studied. 8.2.2.2. CHRONIC EXPOSURES — In a study by Svlrbely and Floyd (1964), blood and urine values and tests for liver and kidney function were normal In dogs fed adlponltrlle at <500 ppm for an unspecified length of time. During the first week of the study, dogs fed 1000 ppm were not able to consume the entire dose. Female rats provided with adlponltrlle 1n their drinking water at 0.5, 5.0 or 50 ppm and males at 50 ppm for 2 years were found to have advanced adrenal degeneration (Svlrbely and Floyd, 1964). No changes In body weight, organ weights or hematologlcal values were noted and no Increase 1n mortality was reported. Advanced adrenal degeneration was observed 1n all treated groups of females, but 1n males only at 50 ppm. These observations suggest that 0.5 ppm may be near the threshold for adrenal effects In females. Increased mortality was not reported 1n any treatment group, which suggests that the effects on the adrenal were not life threatening. The drinking water concentration of 0.5 ppm, therefore, constitutes a NOAEL 1n male rats and may be considered a LOAEL In female rats. The fact that this study was not available for review and that 1t appears from the evaluation of other reports from this series that the report only existed as an unpublished abstract precludes use of these data for RfO development. It 1s known that adlponltrlle 1s metabolized to cyanide. Therefore, the possibility that an RfD for adlponltrlle could be derived by analogy to cyanide was Investigated. However, the effects on the adrenal gland reported by Svlrbely and Floyd (1964) are Inconsistent with the reported critical effects of cyanide which are predominately CNS lesions. In addition the dose of adlponltrlle causing these adrenal lesions Is much 0071d -24- , 11/17/87 ------- lower than reported effect levels for cyanide (ATSDR, 1988). As a result of discrepancy 1n both critical effects and effective doses for adlponltrlle compared with cyanide, an RfO based on analogy 1s not derived. Adlponltrlle has not been examined for carclnogenldty, and the one teratogenlclty study (Johannsen et a!., 1986) located did not find fetal effects at doses below those that caused maternal toxldty. 0071d -25- 11/17/87 ------- 9. REPORTABLE QUANTITIES 9.1. BASED ON SYSTEMIC TOXICITY The toxldty of adlponltrUe was discussed 1n Chapter 6. The only data potentially suitable for the derivation of an RQ are summarized In Table 9-1. In the 2-year rat study (Svlrbely and Floyd, 1964), advanced adrenal degeneration was observed In female rats provided with ad1pon1tr1le In the drinking water at 0.5 ppm. Due to reporting deficiencies as discussed 1n Sections 6.1.2. and 8.2.2., these data are not used to estimate an RQ (Table 9-2). 9.2. BASED ON CARCINOGENICITY Data were not located regarding the carclnogenldty of ad1pon1tr1le 1n humans or animals and the compound was assigned to EPA Group D, not classi- fiable as to human carclnogenldty. Hazard ranking based on carclnogen- Iclty, therefore. Is not possible. OOVld -26- 11/17/87 ------- TABLE 9-1 Oral Toxldty Summary for AdlponHrlle Using Female Wlstar Ratsa»b Average Vehicle/ Transformed Equivalent Weight Physical Exposure Animal Dosec Human Dose^ (kg) State (mg/kg/day) (mg/kg/day) Response 0..356 drinking water 0.5 ppm In 0.07 the drinking water for 2 years 0.01 advanced adrenal degeneration aSo.urce: Svlrbely and Floyd, 1964; NIOSH, 1978 ^Number of animals at start of experiment and purity of compound were not reported.^ cCalculated by multiplying the 0.5 ppm drinking water level by 0.049 I/day, the reference water Intake for a 0.35 kg rat (U.S. EPA, 1985) and by dividing by the rat body weight. ^Calculated by multiplying the animal transformed dose by the cube root of the ratio' of" the animal body weight to the reference human body weight (70 kg). Reference rat body weight (U.S. EPA, 1985) 0071d -27- 06/25/87 ------- TABLE 9-2 AdlponHMle Minimum Effective Dose (MED) and Reportable Quantity (RQ) Route: Dose*: Effect: Reference: Data are Insufficient to evaluate an RQ. RVd: RVe: Composite Score: RQ: 'Equivalent human dose 0071d -28- 11/17/87 ------- 10. REFERENCES Atkinson, R. 1985. Kinetics and mechanisms of the gas-phase reaction of the hydroxyl radical with organic compounds under atmospheric conditions. Chem. Rev. 85: 69-201. ATSDR (Agency for Toxic Substance and Disease Registry). 1987. lexicological Profile on Cyanide. Atlanta, GA. BMngmann, G. and R. Kuehn. 1982.. Results of toxic action of water pollu- tants on Daphnla magna Straus tested by an Improved standardized procedure. Z. Wasser Abwasser Forsch. 15(1): 1-16. Ceresa, C. 1948a. The blood picture of certain workers 1n the nylon Industry. Med. Lavoro. 39: 162-165. (Hal.) Ceresa, C. 1948b. Experimental research on adiponltrlle poisoning. Med. Lavoro. 39: 274-281. (Hal.) Ceresa, C. and M. DeBlaslls. 1950. Poisoning with hexamethylenedlamlne. Med. Lavoro. 41: 78-85. (CA 44:8530e) E1senre1ch, S.J., B.B. Looney and J.O. Thornton. 1981. Airborne organic contaminants of the Great Lakes ecosystem. Environ. Scl. Technol. 15(1): 30-38. 0071d -29- 11/17/87 ------- Gh1r1nghell1, L. 1955a. ToxIcHy of adlplc nUrlle. II. Study of Influ- ence exercised on blood constituents by continuous supply and possibility of absorption through skin. Hed. Lavoro. 46: 229-234. (CA 49:15093fg) Gh1r1nghell1, L. 1955b. ToxIcHy of adlplc n1tr1le. CUnlcalplcture and mechanism of poisoning. Med. Lavoro. 46: 221-28. (Cited In NIOSH, 1978) Hawley, G.G. 1981. The Condensed Chemical Dictionary, 10th ed. Van Nostrand Relnhold Co., New York. p. 21. Henderson, C., Q.H. Pickering and A.E. Lemke. 1961. The effect of some organic cyanides (nltrlles) on fish. Proc. Fifteenth Ind. Waste Conf., Eng. Bull. Purdue Univ., Ser. No. 106. 65(2): 120-130. H1ne, J. and P.K. HookerJee. 1975. The Intrinsic hydrophlUc character oi organic compounds. Correlations 1n terms of structural Contributions. J. Org. Chem. 40(3): 292-298. Johannsen, F.R., G.J. Levlnskas, P.E. Berteau and D.E. Rodwell. 1986. Evaluation of the teratogenlc potential of three aliphatic nltrlles 1n the rat. Fund. Appl. Toxlcol. 7(1): 33-40. Kn1e, J., A. Haelke, I. Juhnke and W. Schiller. 1983. Results of studies of chemical substances using four blotests. Dtsch. Gewaesserkd. HHt. 27(3): 77-79. Kuney, J.E., Ed. 1985. Chemcyclopedla 1986. Vol. 4. American Chemical Society, Washington, DC. 0071d -30- 11/17/87 ------- Kuwahara, M., H. Yanase, Y. Klkuchl and K. Okuzuml. 1980. Metabolism of sucdnonltrlle 1n Aeromonas sp. Hakkokogaku Ka1sh1. 58: 441-448. L1netsk11, V.A. and B.R. Serebryakov. 1965. Alkaline hydrolysis of nltrlles as a method of detoxification of wastes. Izv. Vysshlrh Uchebn: Zavedenll, Neft 1 Gaz. 8: 72. (CA 62:11521c) Lucas, S.V. 1984. GC/MS analysis of organlcs In drinking water concentrates and advanced waste treatment concentrates. Vol. 2. Computer-printed tabula- tions of compound Identification results for large-volume concentrates. Columbus Labs. Health Eff. Res. Lab., Columbus, OH. EPA 600/1-84-0208. NTIS PB85-128239. Ludzack, F.J.. R.B. Schaffer, R.N. Bloomhuff and M.B. Ettlnger. 1959a. Biochemical oxidation of some commercially Important organic cyanides. Sewage Ind. Wastes. 31: 33-44. Ludzack, F.3., R.B. Schaffer and R.N. Bloomhuff. 1959b. Experimental treatment of organic cyanides by conventional sewage disposal processes. In: Proc. of the 14th Ind. Waste Con., Engineering Ext. Series No. 104: 547-565. Lutln, P.A. 1970. Removal of organic nltrlles from wastewater systems. J. Water Pollut. Control Fed. 42: 1632-1642. Lyman, W.J., W.F. Reehl and D.H. Rosenblatt. 1982. Handbook of Chemical Property Estimation Methods. McGraw Hill Book Co., New York. p. 4-9, 5-5, 7-5, 15-27. 0071d -31- 11/17/87 ------- Neely, W.B. and G.E. Blau. 1985. Environmental Exposure from Chemicals. Vol. 1. CRC Press Inc., Boca Raton, FL. p. 31. NIOSH (National Institute for Occupational Safety and Health). 1978. Criteria for a Recommended Standard...Occupational Exposure to Nltrlles. Equitable Environ. Health, Inc., Rockvllle, MD. p. 166. NTP (National Toxicology Program). 1987. Management Status Report. Dated 1/9/87. Plokhova, E.I. and A.P. Rubaklna. 1965. lexicological characteristics of the dlnltnie of adlplc acid. G1g1ena Truda 1 Prof. Zabolevanlya. 9(9): 56-58. (CA 64:2650h) Plzak, V. and J. Ooull. 1969. A further survey of compounds for radiation protection, SAM-7R-69-1. Brooks Air Force Base. TX, USAF School of Aerospace Medicine, Aerospace medical Division (AFSC). p. 33-39. (Cited In NIOSH, 1978) SANSS (Structure and Nomenclature Search System). 1987. Chemical Informa- tion System (CIS) computer data base. Online: February, 1987. Shackelford, W.M. and L.H. Keith. 1980. Frequency of organic compound Identified In water. U.S. EPA, Athens, GA. EPA 600/4-76-062. Smiley, R.A. 1981. NltrHes. In: K1rk-0thmer Encyclopedia of Chemical Technology, 3rd ed., Vol. 15, M. Grayson and D. Eckroth, Ed. John WHey and Sons, New York. p. 897-901. 0071d -32- 09/14/87 ------- Smith, L.W. and G.L. Kennedy, Jr. 1982. Inhalation toxlclty of adlpo- nltrlle 1n rats. Toxlcol. Appl. Pharmacol. 65(2): 257-263. SRI (Stanford Research Institute). 1986. 1986 Directory of Chemical Producers: United States of America. SRI International, Menlo Park, CA. Svlrbely, J.L. n.d. Chronic studies of adiponltrlle, acrylonltrlle and B,Bi-oxyprop1on1tr1le. IV. Reproduction studies In rats and metabolic studies In rats and dogs. Sanitary Engineering Center, U.S. PHS, Cincinnati, OH. Svlrbely, J.L. and E.P. Floyd. 1964. Toxlcologlc studies of acrylonltrlle, adiponltrlle and B, Bl-oxyd1prop1on1tr1le — II. Chronic studies. Cincin- nati, U.S. Dept. of Health. Education and Welfare. Public Health Service, Bureau of State Services, Robert A. Taft Sanitary Engineering Center. p. 100. (Cited 1n NIOSH, 1978) Swann, R.L., D.A. Laskowskl, P.J. McCall, K. Vander Kuy and H.J. Dlshburger. 1983. A rapid method for the estimation of the environmental parameters octanol/water partition coefficient, soil sorptlon constant, water to air ratlio and water solubility. Res. Rev. 85: 17-28. Tan1i1, H. and K. Hashimoto. 1985. Structure-acute toxlclty relationship of dlnUrlles 1n mice. Arch. Toxlcol. 57(2): 88-93. Tullar, P.E. 1947. Final report on the pharmacology and toxicology of acrylonltrlle and acrylon. Kalusowskl Memorial Research Laboratories, George Washington University. 0071d -33- 11/18/87 ------- U.S. EPA. 1980. Guidelines and Methodology Used In the Preparation of Health Effect Assessment Chapters of the Consent Decree Water Criteria Documents. Federal Register. 45(231): 49347-49357. U.S. EPA. 1984. Methodology and Guidelines for Reportable Quantity Determinations 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 Solid Waste and Emergency Response, Washington, DC. U.S. EPA. 1985. 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. 1986a. Methodology for Evaluating Potential Cardnogenlclty In Support of Reportable Quantity Adjustments Pursuant to CERCLA Section 102. Prepared by the Office of Health and Environmental Assessment, Cancer Assessment Group for the Office of Solid Waste and Emergency Response, Washington, DC. U.S. EPA. 1986b. OHMTADS (Oil and Hazardous Materials Technical Assistance Data Systems). On-Hne: February, 1987. U.S. EPA. 1986c. Guidelines for Carcinogen Risk Assessment. Federal Register. 51(185): 33992-34003. 0071d -34- 11/17/87 ------- U.S. EPA. 1987a. Graphical Exposure Modeling System (GEMS). CLOGP computer program. Office of Toxic Substances, U.S. EPA, Washington, DC. U.S. EPA. 19875. Graphical Exposure Modeling System (GEMS). Fate of Atmo- spheric Pollutants (FAP). Office of Toxic Substances, U.S. EPA, Washington, DC. Zeller, H.V., H.T. Hofmann, A.M. Thless and W. Hey. 1969. Toxlclty of nUMles. Zentralbl. ArbeHsmed. ArbeUsschutz. 19: 225-238. (CUed 1n NIOSH, 1978) 0071d -35- 11/17/87 ------- APPENDIX A LITERATURE SEARCHED This HEED 1s based on data Identified by computerized literature searches of the following: TSCATS CASR online (U.S. EPA Chemical Activities Status Report) TOXLINE TOXBACK 76 TOXBACK 65 RTECS OHM TADS STORET SRC Environmental Fate Data Bases SANSS AQUIRE TSCAPP NTIS Federal Register These searches were conducted In February, 1987. In addition, hand searches were made of Chemical Abstracts (Collective Indices J5-9), and the following secondary sources should be reviewed: ACGIH (American Conference of Governmental Industrial Hyglenlsts). 1986. Documentation of the Threshold L1mVt Values and Biological Exposure Indices, 5th ed. Cincinnati, OH. ACGIH (American Conference of Governmental Industrial Hyglenlsts). 1986-1987. TLVs: Threshold Limit Values for Chemical Substances In the Work Environment adopted by ACGIH with Intended Changes for 1986-1987. Cincinnati, OH. Ill 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. 28. John Wiley and Sons, NY. p. 2879-3816. Clayton, G.D. 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. 007 Id -36- 09/14/87 ------- Grayson, H. and D. Eckroth, Ed. 1978-1984. Klrk-Othmer Encyclo- pedia of Chemical Technology, 3rd ed. John WHey and Sons, NY. 23 Volumes. ^ Hamilton, A. and H.L.'. Hardy. 1974. Industrial Toxicology, 3rd ed. Publishing Sciences Group, Inc., Littleton, MA. 575 p. IARC (International Agency for Research on Cancer). IARC Mono- graphs on the Evaluation of Carcinogenic Risk of Chemicals to Humans. WHO, IARC, Lyons, France. Jaber, H.M., W.R. Mabey, A.T. Lieu, 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. SRI International, Menlo Park, CA. EPA 600/6-84-010. NTIS PB84-243906. NTP (National Toxicology Program). 1986. 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). 1986. 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 1n Programs. Office of Pesticide Programs, Washington, DC. U.S. EPA. 1985. CSB Existing Chemical Assessment Tracking System. Name and CAS Number Ordered Indexes. Office of Toxic Substances, Washington. DC. USITC (U.S. International Trade Commission). 1985. Synthetic Organic Chemicals. U.S. Production and Sales, 1984, USITC Publ. 1422, 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. 0071d -37- 09/14/87 ------- In addition, approximately 30 compendia of aquatic toxiclty 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. Oohnson, W.H. 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, Fish and Wildlife Serv. Res. Publ. 137, Washington, DC. HcKee, 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. 0071d -38- 09/14/87 ------- o o APPENDIX B Summary Table for Adlponltrlle Species Exposure Effect RfD or qj* Reference I 01 Inhalation Exposure Subchrontc Chronic Carclnogentclty Oral Exposure Subchronlc ID ID ID ID Chronic ID Carctnogenlclty ID REPORTABLE QUANTITIES Based on Chronic Toxlctty: Based on Carclnogenlclty: ID ID oo ID = Insufficient Data ------- |