EPA-540/1-86-012 Agency Office of Emergency and Remedial Response Washington DC 20460 Off'ce of Research and Development Office of Health and Environmental Assessment Environmental Criteria and Assessment Office Cincinnati OH 45268 Superfund vvEPA 'HEALTH EFFECTS ASSESSMENT FOR SODIUM CYANIDE ------- EPA/540/1-86-012 September 1984 HEALTH EFFECTS ASSESSMENT FOR SODIUM CYANIDE U.S. Environmental Protection Agency Office of Research and Development Office of Health and Environmental Assessment Environmental Criteria and Assessment Office Cincinnati, OH 45268 U.S. Environmental Protection Agency Office of Emergency and Remedial Response Office of Solid Waste and Emergency Response Washington, DC 20460 ------- DISCLAIMER This report has been funded wholly or In part by the United States Environmental Protection Agency under Contract No. 68-03-3112 to Syracuse Research Corporation. It has been subject to the Agency's peer and adminis- trative review, and It has been approved for publication as an EPA document. Mention of trade names or commercial products does not constitute endorse- ment or recommendation for use. 11 ------- PREFACE This report summarizes and evaluates Information relevant to a prelimi- nary interim assessment of adverse health effects associated with sodium cyanide. All estimates of acceptable intakes and carcinogenic potency presented 1n this document should be considered as preliminary and reflect limited resources allocated to this project. Pertinent toxlcologic and environmental data were located through on-line literature searches of the Chemical Abstracts, TOXLINE, CANCERLINE and the CHEMFATE/DATALOG data bases. The basic literature searched supporting this document is current up to September, 1984. Secondary sources of Information have also been relied upon in the preparation of this report and represent large-scale health assessment efforts that entail extensive peer and Agency review. The following Office of Health and Environmental Assessment (OHEA) sources have been extensively utilized: U.S. EPA. 1980a. Ambient Water Quality Criteria for Cyanides, with Errata for Ambient Water Quality Criteria Documents dated June 9, 1981 (updated February 23, 1982). Prepared by the Environmental Criteria and Assessment Office, Cincinnati, OH, OHEA for the Office of Water Regulations and Standards, Criteria and Standards Divi- sion, Washington, DC. EPA 440/5-80-035. NTIS PB 81-117483. U.S. EPA. 1985. Drinking Water Criteria Document for Cyanide. Prepared by the Environmental Criteria and Assessment Office, Cincinnati, OH, OHEA for the Office of Drinking Water, Washington, DC. Final draft. The intent in these assessments 1s to suggest acceptable exposure levels whenever sufficient data were available. Values were not derived or larger uncertainty factors were employed when the variable data were limited in scope tending to generate conservative (I.e., protective) estimates. Never- theless, the interim values presented reflect the relative degree of hazard associated with exposure or risk to the chemical(s) addressed. Whenever possible, two categories of values have been estimated for sys- temic toxicants (toxicants for which cancer is not the endpoint of concern). The first, the AIS or acceptable intake subchronlc, is an estimate of an exposure level that would not be expected to cause adverse effects when exposure occurs during a limited time Interval (i.e., for an interval that does not constitute a significant portion of the Hfespan). This type of exposure estimate has not been extensively used or rigorously defined, as previous risk assessment efforts have been primarily directed towards exposures from toxicants in ambient air or water where lifetime exposure is assumed. Animal data used for AIS estimates generally include exposures with durations of 30-90 days. Subchronic human data are rarely available. Reported exposures are usually from chronic occupational exposure situations or from reports of acute accidental exposure. 111 ------- The AIC, acceptable Intake chronic, 1s similar 1n concept to the ADI (acceptable dally Intake). It 1s an estimate of an exposure level that would not be expected to cause adverse effects when exposure occurs for a significant portion of the Hfespan [see U.S. EPA (1980b) for a discussion of this concept]. The AIC Is route specific and estimates acceptable exposure for a given route with the Implicit assumption that exposure by other routes Is Insignificant. Composite scores (CSs) for noncarcinogens have also been calculated where data permitted. These values are used for ranking reportable quanti- ties; the methodology for their development 1s explained 1n U.S. EPA (1983). For compounds for which there 1s sufficient evidence of cardnogenlcHy, AIS and AIC values are not derived. For a discussion of risk assessment methodology for carcinogens refer to U.S. EPA (1980b). Since cancer 1s a process that 1s not characterized by a threshold, any exposure contributes an Increment of risk. Consequently, derivation of AIS and AIC values would be Inappropriate. For carcinogens, q-j*s have been computed based on oral and Inhalation data 1f available. 1v ------- ABSTRACT In order to place the risk assessment evaluation 1n proper context, refer to the preface of this document. The preface outlines limitations applicable to all documents of this series as well as the appropriate Inter- pretation and use of the quantitative estimates presented. Adequate data are available for experimental animals orally exposed to cyanide. The various studies agree well 1n terms of suggesting a NOEL. U.S. EPA (1985) has calculated a NOEL of 10.8 mg CNVkg for female rats exposed to cyanide 1n their food as a basis for estimating acceptable exposure levels (Howard and Hanzal, 1955). By analogy, an AIC for NaCN of 2.8 mg/day for a 70 kg human Is calculated. A CS of 11.4, based on CNS lesions 1n dogs treated by capsule with NaCN was calculated. Data for effects following Inhalation exposure to CN~ are extremely limited. An AIC has been estimated based on the TLV of 5 mg/m3 but should not be adopted because of presumed greater toxldty due to exposure by the Inhalation route. ------- ACKNOWLEDGEMENTS The Initial draft of this report was prepared by Syracuse Research Corporation under Contract No. 68-03-3112 for EPA's Environmental Criteria and Assessment Office, Cincinnati, OH. Dr. Christopher DeRosa and Karen Blackburn were the Technical Project Monitors and Helen Ball was ,the Project Officer. The final documents In this series were prepared for the Office of Emergency and Remedial Response, Washington, DC. Scientists from the following U.S. EPA offices provided review comments for this document series: Environmental Criteria and Assessment Office, Cincinnati, OH Carcinogen Assessment Group Office of A1r Quality Planning and Standards Office of Solid Waste Office of Toxic Substances Office of Drinking Water Editorial review for the document series was provided by: Judith Olsen and Erma Durden Environmental Criteria and Assessment Office Cincinnati, OH Technical support services for the document series was provided by: Bette Zwayer, Pat Daunt, Karen Mann and Jacky Bohanon Environmental Criteria and Assessment Office Cincinnati, OH v1 ------- TABLE OF CONTENTS 1. 2. 3. 4. 5. ENVIRONMENTAL CHEMISTRY AND FATE ABSORPTION FACTORS IN HUMANS AND EXPERIMENTAL ANIMALS . . . 2.1. 2.2. ORAL INHALATION TOXICITY IN HUMANS AND EXPERIMENTAL ANIMALS 3.1. 3.2. 3.3. 3.4. SUBCHRONIC 3.1.1. Oral 3.1.2. Inhalation CHRONIC 3.2.1. Oral 3.2.2. Inhalation TERATOGENICITY AND OTHER REPRODUCTIVE EFFECTS. . . . 3.3.1. Oral 3.3.2. Inhalation TOXICANT INTERACTIONS CARCINOGENICITY 4.1. 4.2. 4.3. 4.4. HUMAN DATA 4.1.1. Oral 4.1.2. Inhalation BIOASSAYS 4.2.1. Oral 4.2.2. Inhalation OTHER RELEVANT DATA WEIGHT OF EVIDENCE REGULATORY STANDARDS AND CRITERIA Page ... 1 ... 3 ... 3 ... 3 ... 4 ... 4 ... 4 ... 7 ... 8 ... 8 . . . . 11 ... 11 . . . . 11 ... 11 ... 11 ... 13 ... 13 ... 13 ... 13 ... 13 ... 13 ... 13 ... 13 ... 14 ... 15 V11 ------- TABLE OF CONTENTS (cont.) Page 6. RISK ASSESSMENT 17 6.1. ACCEPTABLE INTAKE SUBCHRONIC (AIS) 17 6.1.1. Oral 17 6.1.2. Inhalation 17 6.2. ACCEPTABLE INTAKE CHRONIC (AIC) 17 6.2.1. Oral 17 6.2.2. Inhalation 20 6.3. CARCINOGENIC POTENCY (q-j*) 21 6.3.1. Oral 21 6.3.2. Inhalation 21 7. REFERENCES 22 APPENDIX: Summary Table for Sodium Cyanide 32 ------- LIST OF TABLES No. Title Page 3-1 Subchronlc Tox1c1ty of Orally Administered Cyanide 5 3-2 Representative Control Studies of Occupational Exposure by Inhalation or Dermal Routes 9 3-3 Chronic Toxldty of Orally Administered Cyanide 10 5-1 Tolerances for Hydrogen Cyanide 1n Foodstuffs when Used as a Post-Harvest Fumlgant 16 1x ------- LIST OF ABBREVIATIONS ADI Acceptable dally Intake AIC Acceptable Intake chronic AIS Acceptable Intake subchronlc BCF B1oconcentrat1on factor bw Body weight CAS Chemical Abstract Service CNS Central nervous system CS Composite score GI Gastrointestinal Kow Octanol/water partition coefficient 1050 Dose lethal to 50% of recipients LOAEL Lowest-observed-adverse-effect level MED Minimum effective dose RNA Rlbonuclelc acid RV(j Dose-rating value RVe Effect-rating value TLV Threshold limit value TWA Time-weighted average UF Uncertainty factor ------- 1. ENVIRONMENTAL CHEMISTRY AND FATE The relevant physical and chemical properties for sodium cyanide are given below. Chemical class: Inorganic cyanide Molecular weight: 49.01 Vapor pressure: 0.76 mm Hg at 800°C (Towlll et al., 1978) Water solubility: 48 g/100 m«. at 10°C (Weast, 1980) Log octanol/water partition coefficient: 0.44 (estimated) BCF: 0.27 (estimated) The value for the K has been estimated by the method of Leo et al. (1971) from the value given by Hansch and Leo (1979). The value of 0.27 for the BCF has been estimated from the log K value given above and the equation of Velth et al. (1979). The atmospheric fate of sodium cyanide has not been comprehensively studied. The most likely chemical reaction for sodium cyanide In the atmosphere Is heterogenous reaction with OH» radicals. Considering the half-life of the homogenous hydrogen cyanide reaction with OH« radicals (Graedel, 1978), 1t appears unlikely that sodium cyanide will have any significant chemical loss mechanism In the troposphere. The primary removal process for atmospheric sodium cyanide appears to be physical. Both dry deposition and wet deposition may dominate the fate of sodium cyanide 1n the atmosphere, although, considering the aqueous solubility of sodium cyanide, the latter process appears to be more Important than the former process. -1- ------- Sodium cyanide may be lost from aquatic media primarily through the volatilization process (Callahan et al.. 1979). Sodium cyanide at low concentrations may undergo some blodegradatlon, but blodegradatlon 1s likely to be far less significant in determining the fate of sodium cyanide 1n aquatic media (Callahan et al., 1979). Similarly, because of Us low tendency to adsorb onto sediments, sorptlon may not be an Important process for sodium cyanide in aquatic media (Callahan et al., 1979). The fate of sodium cyanide In soil 1s Inadequately studied. To draw an analogy from its expected fate in water, 1t is likely that the fate of sodium cyanide in soil may be pH dependent. In acidic soils, the loss of hydrogen cyanide through volatilization may be the predominant mechanism from soil surfaces. In subsurface soil, sodium cyanide present in small concentrations (below the toxic levels for microorganisms) may undergo some mlcrobial degradation (Callahan et al., 1979), and a part may leach through the soil because of Us high water solubility and low soil sorptlon charac- teristics. In basic soils, the mobility of sodium is expected to be greatly restricted. The simple metal cyanides, such as sodium cyanide, are not expected to bioaccumulate 1n aquatic organisms (U.S. EPA, 1980a). As can be seen from the selected physical and chemical properties for sodium cyanide, the estimated value of 0.27 for the BCF for sodium cyanide 1s In conformity with the U.S. EPA (1980a) prediction. -2- ------- 2. ABSORPTION FACTORS IN HUMANS AND EXPERIMENTAL ANIMALS 2.1. ORAL Cyanide 1s readily absorbed by the 61 tract. Yamamoto et al. (1982) exposed rats orally by gavage to either 7 or 21 mg NaCN/kg bw. Following treatment and subsequent death (minutes later), levels of cyanide 1n the blood were 5.01+1.61 and 4.79+2.04 pg/ms, for the low-dose and high-dose, respectively. This Indicates that sodium cyanide 1s readily absorbed by the 61 tract. 6ettler and Balne (1938) exposed dogs to potassium cyanide equivalent to 1.57, 4.42 or 8.42 mg HCN/kg bw by gavage. Upon death (155, 21 and 8 minutes post-treatment), the amount of hydrogen cyanide remaining 1n the 61 tract was measured and subtracted from the amount administered; this was considered to be equivalent to the amount absorbed, and was 72, 24 and 16.6% for dogs receiving 1.57, 4.42 and 8.42 mg/kg, respectively. 2.2. INHALATION Pertinent data regarding the absorption of sodium cyanide by Inhalation could not be located 1n the available literature. -3- ------- 3. TOXICITY IN HUMANS AND EXPERIMENTAL ANIMALS 3.1. SUBCHRONIC 3.1.1. Oral. In evaluating studies regarding the oral toxldty of cyanide, factors affecting the rate of absorption may be as Important as the dose administered (U.S. EPA, 1985). Cyanide 1s metabolized rapidly by the liver to thlocyanate, an enzymatic rate-saturable reaction. Factors that enhance absorption may result 1n severe toxic manifestations from a dose that ordinarily would not cause toxldty, because the ability of the Hver to metabolize cyanide as a first pass phenomenon had been exceeded. The volume of the Intestinal contents and rate of peristalsis are factors that affect the rate of GI absorption. It may also be expected that toxldty would be more likely 1f cyanides are given as a bolus rather than 1n smaller allquots throughout the day. Another Important consideration regarding dietary studies 1s the propen- sity for cyanide to volatilize from treated foodstuffs, resulting 1n a lack of toxic manifestations at potentially dangerous levels (U.S. EPA, 1985). Also, animals (and presumeably humans) can successfully withstand higher doses of cyanide when administered 1n the diet rather than by Inhalation, because of the first pass conversion of orally administered cyanide to thlocyanate (detoxification) In the Hver when 1t 1s orally administered. Because of the expected similarities 1n the toxldty of sodium cyanide and other cyanides, studies with other cyanides are Included 1n the toxldty sections. Data regarding the subchronlc toxldty of orally administered cyanide are summarized 1n Table 3-1. Palmer and Olson (1979) reported significantly higher liver weights In adult rats exposed to 200 mg KCN/8. drinking water, but no effect on liver weight when potassium cyanide was administered as 200 -4- ------- TABLE 3-1 Subchronlc Toxlclty of Orally Administered Cyanide Species/ Number/Sex Height or Age Rat/70 g 7H/group 7H/group Rat/adult NR NR Rat/weanling BMW /group African giant rat/ 6N and 2F/ weanllng/~90 g group Plg/weanllng 1H and IF Dose of Compound 0 and 200 mg KCN/t drinking water 0 and 200 mg KCN/kg diet 0. 10 mg KCN/kg bw/day In diet 0-250 mg KCN/kg bw/day In diet 0, 1875 mg KCN/kg diet 0. 2500 mg KCN/kg diet 0, 1875 mg KCN/kg diet Dosea as CN- 0 and 80 mg/l (8 rog/kg bw/day) 0 and 80 tag/kg diet (4 mg/kg bw/day) 0. 4 mg/kg bw/day 0-100 mg/kg bw/day 0. 750 mg/kg diet (37.5 mg/kg bw/day) 0. 1000 mg/kg diet (36 mg/kg bw/day )b 0. 750 mg/kg d1et(~30 mg/kg bw/day )b Period of Exposure 21 days 21 days 25 days 90 days 56 days 84 days 56 days Effects Treated animals: significantly Increased (p<0.05) liver weights (15.8 g), compared with controls (13.5 g). No effect on body weight. Treated animals: no Increase In liver weights (13.7 g). compared with controls (13.5 g). No effect on body weight. No mortality. No mortality; this dose was 25 times the acute oral 1059 for rats. Animals tolerated CN~ better when It was mixed In feed. No effect on body weight, ratio of liver and kidney weight to body weight, food consumption, or protein efficiency ratio. Treated animals: slight reduction In food consumption and weight gain, compared with controls. No hlstopatho- loglcal changes In spleen, liver, kidney or thymus. Treated animals: small but significant reduction In food consumption (p<0.05), compared Reference Palmer and Olson. 1979 Hayes. 1967 Tewe and Haner. 1982 Tewe, 1982 Tewe and Haner. 1980 with controls. No effect on body weight, food efficiency ratio, protein efficiency ratio, or ratio of various organ weights (spleen, liver, kidney, heart, thyroid) to body weight. No hlstopathologlcal changes. ------- TABLE 3-1 (cont.) cr i Species/ Weight or Age Dog/7.6 kg Dog/NR Number/Sex 1 control, 3 treated (sex NR) 1 control, 3 treated (sex NR) Dose of Compound 0. 500 ppm NaCN In diet NaCN at 0, 0.5. 1.0 up to 2x2.0 ing/kg bu/day by capsule Dosea as CM- Period of Exposure 3 mg/kg bw/day 30-32 days 0. 0.27. 0.53 up 15 months to 2x1.1 ing/kg bw/day (average 3 mg/kg bw/day In high group) Effects No effects on food consumption, body weight gain, hematology, gross or microscopic pathology Toxlclty observed In high group: acute toxlclty Immediately after dosing, full recovery In <0.5 hours. All treated dogs: degeneration of ganglion and Purklnje cells of CNS Reference American Cyanamld Co., 1959 Her t ting et al., 1960 aValues In parentheses were calculated as follows: 1) For CN- In the diet, the dose In mg/kg/dlet Is multiplied by the fraction of body weight consumed by a rat/day (0.05). 2) For CN- In the water, the dose In mg/t Is multiplied by the average amount of t^O consumed by a rat/day (0.035 I/day), and divided by the weight of the rat (If unknown. It Is assumed to be 0.35 kg), e.g., rats assumed to drink water equivalent to 10X of their body weight/day. Calculated by U.S. EPA (1985) from body weight and food consumption data provided by Investigators. ------- mg/kg diet. Tewe (1982) and Tewe and Maner (1980, 1982) treated weanling pigs and rats with potassium cyanide, and observed only a slight reduction 1n food consumption with no other effects. Hayes (1967) reported that adult rats could tolerate 25 times the LD5Q dose of potassium cyanide when H was administered 1n the diet. When given 1n the diet, NaCN at 3 mg CN"/kg bw/day had no effect In dogs (American Cyanamld Co., 1959). The same dosage given by capsule led to signs of acute toxlclty 1n dogs from which recovery was complete within 0.5 hours (Herttlng et a!., 1960). When given by capsule to dogs for 15 months, 6 mg NaCN/kg bw/day was sufficient to cause cellular degeneration 1n the CNS. Although animals In this study were exposed to a range of potassium cyanide concentrations, these Investigators only reported mortality. 3.1.2. Inhalation. Only one animal study regarding the subchronlc toxldty of cyanide was located 1n the available literature. Hugod (1981) exposed rabbits (22/group) to either 0 or 0.55 mg/m3 hydrogen cyanide In air. After 28 days, the treated animals were not different from controls 1n myocardlal ultrastructure. In humans, exposure to cyanide by Inhalation and dermal routes has been reported In the metal Industry. Sandberg (1967) reported on a goldsmith apprentice who polished gold 5-10 times/day for 4 years. The polishing solution he used was prepared by adding 15 g of potassium cyanide to water, bringing 1t to a boll, then adding hydrogen peroxide; this process liberated hydrogen cyanide gas and splattered the skin. Symptoms of toxldty 1n this man Included headache, Ustlessness, numbness and partial paralysis of his left arm and leg, and partial loss of vision 1n his left eye. Other cases 1n which similar symptoms have been reported are summarized by NIOSH (1976). -7- ------- There have also been reports of goiter associated with occupational exposure to cyanide (Hardy et al., 1950). In addition, many case-control studies regarding exposure to cyanide have been reported. Several of these are summarized 1n Table 3-2. 3.2 CHRONIC 3.2.1. Oral. Data pertaining to the chronic toxldty of orally admin- istered cyanides are summarized 1n Table 3-3. Howard and Hanzal (1955) exposed rats to 0, 76, or 190 mg HCN/kg diet (equivalent to 0, 73, 183 mg CITVkg) for 104 weeks. Animals treated at any level had no signs of toxldty; no hlstopathologlcal changes 1n the heart, lungs, liver, spleen, stomach, Intestines, kidney, adrenals, thyroid, reproductive organs, cere- bellum or cerebrum; and no differences 1n growth rate compared with con- trols. The only effects of treatment were elevated levels of CfT1 In the erythrocytes and elevated thlocyanate 1n the blood, liver and kidneys. PhUbMck et al. (1979) treated groups of 10 male weanling rats with 0 or 1500 mg KCN/kg diet and reported signs of primary myelln degeneration 1n the spinal cord after 11.5 months treatment. Rats maintained on methlonlne and vitamin B.? deficient diet appeared to be affected more severely. With respect to humans, the high Incidence of amblyoplas, thyroid dis- orders and neuropathies seen in tropical regions of Africa has been associ- ated with chronic Ingestion of cassava, a dietary staple containing a cyano- genlc glycoslde that releases hydrogen cyanide when metabolized in vivo (Monekosso and Wilson, 1966; Osuntokun, 1968, 1972; Osuntokun et al., 1969, 1970; MacKenzie and Phillips, 1968; Makene and Wilson, 1972; Ermans et al., 1972; Delange and Ermans, 1971). Sufficient data to quantify dose and effects were not available in these studies. -8- ------- TABLE 3-2 Representative Control Studies of Occupational Exposure to Cyanide by Inhalation or Dermal Routes Study Population Control Population Period of Exposure Level of Exposure Effects Reference 36 male electro- platers from 3 factories, >30 years of age. all nonsmokers 13 HCN fumlgators who had suffered acute symptoms of HCN poisoning with loss of conscious- ness 31 men, 12 women In Romanian metal galvanizing oper- ation 20 males of com- parable age and socloeconomlc status: non- smokers not ex- posed to cyanide 4 HCN fumlgators who had not re- ported symptoms of acute HCN poisoning NR 5-15 years 1-27 years 0.25-16 years (mean: 5.4 years) mean concentration In the breathing zone: 7.1. 8.9 and 11.5 mg/m' for the three factories NR average exposure over 5' years: 0.26 mg/m« Exposed men: headache (29); weakness El Ghawabl (28); changes In smell and taste (28); et al.. 1975 giddiness (20); throat Irritation (16); vomiting (16); difficulty breathing (16); precordlal pain (7); difficulty focusing eyes (3); psychosis (2). Non- exposed workers had much lower inci- dences of these symptoms. Exposed workers also had significantly higher (p<0.001) hemoglobin to lymphocyte counts, and significantly higher (<0.001) uptake of »"I by the thyroid. 13 symptomatic men: high Incidence of Carmelo. 1955 nervous disorders; precordlal pain (9); EKG abnormalities (11); hypertroplc gastritis (11). 4 controls: no stomach or Intestinal disorders. Significantly reduced activity of cyto- Dlnca et al., chrome oxldase and other redox enzymes. 1972 NR = Not reported ------- TABLE 3-3 Chronic Toxlclty of Orally Administered Cyanide o I Species/ Starting Number Weight Rat/57 g 10F and lOM/group Weanling lOH/group rat/43 g Dose of Compound 0, 76, 190 mg HCN/kg diet 0, 1500 mg diet Dose as CN~ 0, 73, 183 mg/kg diet 0, 600 mg/kg diet (0.30 mg/kg bw/day)* Period of Exposure 104 weeks 11.5 months Effects No effects with regard to body weights or hls- topathologlcal changes of many organs. Treated rats: primary myelln degeneraton and vacuoles In spinal cord. Decreased plasma thyroxln levels at 4 months with recovery by 11 months. Reference Howard and Hanzal, 1955 Phllbrlck et al., 1979 *Assum1ng rats eat food equivalent to 554 of their body weight/day. ------- 3.2.2. Inhalation. Animal studies pertaining to the chronic toxlclty of Inhaled cyanide could not be located In the available literature. Exposure to cyanide In tobacco smoke, however, has been associated with tobacco amblyopla, Leber's hereditary optic atrophy, retrobulbar neuritis and optic atrophy (Wokes, 1958; Pettlgrew and Fell, 1972, 1973; Wilson and Matthews, 1966; Foulds et al., 1968; Wilson, 1983). These disorders Involve defective cyanide metabolism (the conversion of cyanide to thlocyanate by rhodanase 1s defective) and vitamin B,? deficiency. 3.3. TERATOGENICITY AND OTHER REPRODUCTIVE EFFECTS 3.3.1. Oral. The reproductive performance of rats fed 500 mg CN"/kg diet throughout gestation and lactation was unaffected (Tewe and Maner, 1981a). Furthermore, Utter size, weight of the pups at birth, and food consumption and growth rate of pups after birth were not significantly different from controls. In contrast, the fetuses of pigs (9/level) fed 276.6 or 520.7 mg CN~/kg diet throughout gestation to lactation had reduced organ to body weight ratios for thyroid, heart and spleen when compared with those born to pigs fed 30.6 mg CN~/kg diet. Sows treated at all levels had hyperplasia of the glomerull (Tewe and Maner, 1981b). Teratogenic affects per se were not reported 1n either of these studies. 3.3.2. Inhalation. Pertinent data regarding the teratogenldty of Inhaled cyanide could not be located 1n the available literature. 3.4. TOXICANT INTERACTIONS Since cyanide 1s a known Inhibitor of cytochrome oxldase, compounds such as sulflde or azlde, which also Inhibit cytochrome oxldase, may synerglze with cyanide (Nlcholls, 1975; Smith et al.. 1977). Vitamin C may also enhance the toxlclty of cyanide. Basu (1983) treated a group of guinea pigs -11- ------- first with vitamin C, then with potassium- cyanide, and another group only with potassium cyanide. Vitamin C-treated animals had a 100% Incidence of severe tremors, ataxla, muscle twitches, paralysis and convulsion. Animals exposed only to potassium cyanide had a 38% Incidence of these symptoms. It was hypothesized that vitamin C may tie up cystelne, a sulfur donor poten- tially Involved 1n the conversion of cyanide to thlocyanate, Its less harmful metabolite. Compounds that generate methemoglobln (sodium nitrate, amyl nitrate, hydroxylamlne or methylene blue) antagonize the toxic effects caused by cyanide, since methemoglobln competes with cytochrome oxldase for cyanide (Smith and Olson, 1973; Way, 1981). Cobalt-containing compounds also antagonize the toxldty of cyanide, since cobalt has an affinity for cyanide (Mushett et a!., 1952; FMedberg and Schwarzkopf, 1969; Davlson, 1969). -12- ------- 4. CARCINOGENICITY 4.1. HUMAN DATA 4.1.1. Oral. Pertinent data regarding the carc1nogen1c1ty of orally Ingested cyanide (hydrogen cyanide, potassium cyanide or sodium cyanide) could not be located 1n the available literature. 4.1.2. Inhalation. Pertinent data regarding the cardnogenldty of Inhaled cyanide could not be located In the available literature. 4.2. BIOASSAYS 4.2.1. Oral. Pertinent data regarding the cardnogenldty of orally administered cyanide could not be located In the available literature. 4.2.2. Inhalation. Pertinent data regarding the cardnogenldty of Inhaled cyanide could not be located 1n the available literature. 4.3. OTHER RELEVANT DATA Of the three mutagenldty studies located 1n the available literature, two were negative and one was marginally positive.. De Flora (1981) reported that potassium cyanide was not mutagenlc to five strains of Salmonella typhlmuMum, regardless of the presence or absence of S-9 (mammalian activa- tion system). Karube et al. (1981) also reported negative results from a rec-assay In Bacillus subtlHs. Kushl et al. (1983) reported that hydrogen cyanide gas was marginally mutagenlc to S. typhlmurlum strain TA100 In the absence of S-9, but not mutagenlc to strain TA98 1n the presence or absence of S-9. Tewe and Maner (1981a) reported that no teratogenlc effects were observed when Wlstar rats were exposed to 500 ppm of cyanide In the diet throughout pregnancy; however, Tewe and Maner (1981b) reported that fetuses of pigs fed 276.6 or 520.7 mg CN (as KCN)/kg diet throughout pregnancy had reduced ratios of organ weight to body weight. At these levels, sows had kidney hyperplasla and morphological changes In thyroid cells. -13- ------- 4.4. WEIGHT OF EVIDENCE IARC has not evaluated the risk to humans associated with oral or Inha- lation exposure to cyanide. Since data are lacking regarding the cardno- genlclty of cyanides to animals or humans, applying the criteria proposed by the Carcinogen Assessment Group of the U.S. EPA (Federal Register, 1984) for evaluating the overall weight of evidence of cardnogenlcity to humans, cyanide 1s most appropriately designated a Group D-Nqt Classified chemical. -14- ------- 5. REGULATORY STANDARDS AND CRITERIA FAO and WHO have established an Interim ADI for cyanide In food of 3.5 mg/man/day, assuming a 70 kg man (U.S. EPA, 1980a). In the June 9, 1981 Errata for Ambient Water Quality Criteria (U.S. EPA, 1980a), an Interim ADI of 7.56 mg CN~/day water was established, based on a NOAEL of 10.8 mg/kg/ day derived from the chronic study of Howard and Hanzal (1955) (see Section 3.2.1.). In the calculation of this value, an uncertainty factor of 100 was used. In addition, an average body weight of 70 kg and consumption of 2 H water/day and 6.5 g fish/day were assumed. The U.S. Public Health Service (1962) has recommended that levels of cyanide 1n water not exceed 0.2 mg/a. ACGIH (1983) has recommended a TWA-TLV of 5 mg/m3 for cyanides, with the Indication that dermal absorption may also be Involved. This value 1s based on Irritation to the respiratory system and 1s Intended to protect from the effects of chronic exposure to hydrogen cyanide (derived primarily from the report by El Ghawabl et al., 1975). NIOSH (1976) and OSHA (1981) have also adopted this value as a recommended standard Tolerances have been set for residues of hydrogen cyanide when used as a post-harvest Insecticide fumlgant. Those tolerances have been presented In Table 5-1 (Code of Federal Regulations, 1982). -15- ------- TABLE 5-1 Tolerances for Hydrogen Cyanide 1n Foodstuffs When Used as a Post-Harvest Fumigant* Foodstuff Tolerance (ppm) Cereal flours 125 Cereals cooked before eaten 90 Uncooked ham, bacon, sausage 50 Cocoa 200 Several spices 250 Several grains 75 Dried beans, peas, nuts 25 *Source: Code of Federal Regulations, 1982 -16- ------- 6. RISK ASSESSMENT 6.1. ACCEPTABLE INTAKE SUBCHRONIC (AIS) 6.1.1. Oral. Data from animal studies are Insufficient for the calcula- tion of an AIS for subchronlc oral exposure to sodium cyanide. In the studies by Palmer and Olson (1979), Tewe and Maner (1980, 1982) and Tewe (1982), animals were exposed to only one level of treatment In addition to the control level of exposure (0 mg KCN/kg diet). Furthermore, Palmer and Olson (1979) reported an Increase 1n liver weight In animals exposed to 4 mg/kg bw/day 1n the diet, but no effect on animals exposed to the same dose 1n drinking water. While Hayes (1967) exposed rats to a range of doses (0-250), he reported only mortality. Effect levels cannot be established from these studies. 6.1.2. Inhalation. Only one subchronlc animal study pertaining to cyanide exposure (Hugod, 1981) was located 1n the available literature. In this study, rabbits were exposed to a single level of hydrogen cyanide gas for only 28 days. Furthermore, the human occupational exposure studies are lacking 1n quantitative detail. Therefore, these studies cannot be used In quantitative risk assessment. 6.2. ACCEPTABLE INTAKE CHRONIC (AIC) 6.2.1. Oral. The U.S. EPA (1985) has recently reevaluated the data from the Howard and Hanzal (1955) 2-year experiment with HCN In rats and used these data to calculate an ADI for CN~. The Drinking Water Criteria Docu- ment for Cyanide (U.S. EPA, 1985) contains an 1n-depth discussion of the assumptions and calculations used 1n derivation of the ADI. This discussion 1s presented here In abbreviated form. The U.S. EPA (1985) chose to derive an ADI for CN~ rather than HCN because CN~ 1s presumed to be the toxic moiety 1n cyanide compounds. -17- ------- In determining the doses of CN~ to which the rats 1n this study were exposed on a mg/kg bw/day basis, the average body weights were estimated using the mean body weights at the beginning and end of the experiment and the growth charts provided by the Investigators. Average body weights arrived at by the U.S. EPA (1985) were 390 g and 394 g 1n low- and high-dose males and 232 g and 255 g 1n low- and high-dose females, respectively. Food consumption was measured by the Investigators and averaged 19.46 g and 18.50 g/rat/day 1n the low- and high-dose males and 14.69 g and 17.24 g/rat/day In the low- and high-dose females, respectively. The diets were prepared by fumigation and HCN was measured 1n the food offered to the rats. From these data, averaged over the entire treatment period, the U.S. EPA (1985) calcu- lated that the low-dose diet contained 73 ppm CN~ and the high-dose diet, 160 ppm CN~. From the above data, the U.S. EPA (1985) calculated the animal doses of CN~, expressed as mg/kg/day, for the male and female rats In the low- and high-dose groups as follows: low-dose male: 73 mg CN~/kg diet x 0.01946 kg diet/0.39 kg bw=3.6 mg CN~/kg bw/day high-dose male: 160 mg CN"/kg diet x 0.01850 kg diet/0.394 kg bw=7.5 mg CN~/kg bw/day low-dose female: 73 mg CN~/kg diet x 0.01469 kg diet/0.232 kg bw=4.6 mg CN~/kg bw/day high-dose female: 160 mg ClT/kg diet x 0.01724 kg diet/0.255 kg bw=10.8 mg CN~/kg bw/day -18- ------- Since effects were not observed 1n treated rats, the animal dose of 10.8 mg CN~/kg bw/day calculated for high dose females represents the highest NOEL. The U.S. EPA caluclated an ADI of 1.5 mg CN'/day for a 70 kg human by multiplying the animal dose, 10.8 CN~/kg bw/day by 70 kg and dividing by a UF of 500. This corresponds to an ADI for NaCN of 2.8 by multiplying the ADI for CN~ by the ratio of the formula weight of NaCN (49.01) to CN~ (26.02). A UF of 500 was chosen as follows: a factor of 10 to account for animal to human extrapolation, a factor of 10 to afford greater protection for unusually sensitive Individuals and a final factor of 5 because a criterion for drinking water was derived from a dietary study. Measurements by the Investigators demonstrated that HCN volatilized from the diet prepared by fumigation. It was believed that the final UF of 5 may adjust for the uncertainty associated with volatilization of HCN from the diet. The U.S. EPA (1985) also suggested that absorption of CN~ from drinking water might be facilitated but that absorption from the diet may be retarded by adsorption to food particles. The additional UF of 5 was also Intended to account for some of the uncertainty associated with this phenomenon. Since this ADI (2.8 mg NaCN/day for a 70 kg human) was derived by analogy from data processed by the U.S. EPA (1985) based on the most complete chronic data available and by a rationale that logically addressed the Issues Involved 1n risk assessment, this ADI Is adopted as the AIC for NaCN 1n this document. A CS was calculated for the effects observed (degeneration of ganglion cells 1n the CNS) 1n the study by Meriting et al. (1960) using dogs treated by capsule for 15 months with NaCN at 6 mg NaCN/kg bw/day. A human MED was calculated by multiplying the animal dose by the cube root of the ratio of the body weight of dogs (assumed: 14 kg) to that of humans (assumed: -19- ------- 70 kg) and multiplying the result by 70 kg to express the MED In mg/day for a 70 kg man. A human MED of 245.6 mg/day, corresponding to an RVd of 1.9, was calculated. The effects observed were assigned an RV of 6, because lesions were observed that were not reported to cause a decrement 1n organ function. A CS of 11.4 was calculated as the product of RV. and RVg. Although limited data using dogs (Herttlng et al., 1960) suggest a lower effect level, the dog has been questioned as an appropriate model (U.S. EPA, 1985). The dog 1s especially susceptible to CN~ poisoning, presumably due to low levels of hepatic rhodaneese, an enzyme Involved In the primary detoxification pathway for cyanide. 6.2.2. Inhalation. Only one subchronlc study pertaining to exposure to cyanide by Inhalation (Hugod, 1981) was located 1n the available literature. Since this study Involved exposure of rabbits for only 28 days, derivation of an AIC for chronic exposure from these data would be Imprudent. The TLV of 5 mg/m3 established by ACGIH (1983), however, can be used to derive an Interim ADI 1n the following manner. Assuming that a 70 kg man breathes a volume of 10 m3 a1r/8-hour workday and works 5 days/week, the TLV of 5 mg/m3 1s multiplied by the product of 10 mVday and 5/7 days/week to arrive at an Inhaled dose of 35.7 mg CN~/man/day. Dividing this value by an uncertainty factor of 10 to account for the range of sensitivities 1n the human population results 1n an Interim ADI of 3.57 mg CN~/man/day. This ADI (3.57 mg CN~/man/day) Is larger than the ADI derived for oral exposure to CN" by the U.S EPA (1985). Since cyanide Is readily absorbed by the pulmonary system and since the first pass effect of the liver (very Important 1n CN~ detoxification) Is bypassed by this route, It 1s strongly recommended that the ADI derived from the TLV not be adopted as an Inhala- tion ADI for CN". -20- ------- 6.3. CARCINOGENIC POTENCY (q.,*) 6.3.1. Oral. The lack of data regarding the carclnogenldty of Ingested cyanide precludes assessment of carcinogenic risk. 6.3.2. Inhalation. The lack of data regarding the carclnogenldty of Inhaled cyanide precludes assessment of carcinogenic risk. -21- ------- 7. REFERENCES ACGIH (American Conference of Governmental Industrial Hyglenlsts). 1983. Threshold Limit Values for Chemical Substances and Physical Agents 1n the the Workroom Environment with Intended Changes for 1983-1984. Cincinnati, OH. p. 16. American Cyanamld Co. 1959. Report on sodium cyanide 30 day repeated feed- Ing to dogs. Central Med. Dept. Report Number 59-14. (Cited In U.S. EPA, 1985) Basu, T.K. 1983. High-dose ascorbic add decreases detoxification of cyanide derived from amygdalln (laetMle): Studies In guinea pigs. Can. J. Physlol. Pharmacol. 61(11): 1426-1430. (Cited In U.S. EPA, 1985) Callahan, M.A., M.W. SUmak, N.W. Gabel, et al. 1979. Water-Related Environmental Fate of 129 Priority Pollutants, Vol. 1. U.S. EPA, Office of Water Planning and Standards, Office of Water and Waste Management, Washing- ton, DC. EPA 440/4-79-02923. Carmelo, S. 1955. New contributions to the study of subacute-chronlc hydrocyanic add Intoxication 1n man. Rass Med. Ind. 24: 254-271. (Cited In U.S. EPA, 1985) Carson, B.L., L.H. Baker, B.L. Herndon, H.V. Ellis and E.M. Horn. 1981. Hydrogen Cyanide Health Effects. Prepared by Midwest Research Inst., Kansas City, MO. EPA 460/3-81-026. NTIS PB 82-116039. -22- ------- Code of Federal Regulations. 1982. Hydrogen cyanide. 21 CR1 93.236. Davlson, V. 1969. Cyanide poisoning. Occup. Health. 21: 306-308. (Cited In U.S. EPA, 1985) De Flora, S. 1981. Study of 106 organic and Inorganic compounds 1n the Sa Imone 11 a/micros ome test. Cardnogenesls J. (London). 2(4): 283-298. (Cited 1n U.S. EPA, 1985) Oelange, F. and A.M. Ermans. 1971. Role of a dietary goltrogen 1n the etiology of endemic goiter on Idjwl Island. Am. J. CUn. Nutr. 24: 1354-1360. (Cited 1n U.S. EPA, 1985) D1nca, C., L. Pod and I. GaletaMu. 1972. Considerations on leukocytlc oxldatlve enzyme changes 1n subjects exposed to prolonged action of cyan- hydrlc add 1n Industry. Med. Int. 24: 1385-1395. (CHed In U.S. EPA, 1985) El Ghawabl, S.H., M.A. Goofar, A.A. El-Sahart1, S.H. Aimed, K.K. Malash and R. Fares. 1975. Chronic cyanide exposure: a clinical, radlolsotope and laboratory study. Br. J. Ind. Med. 32: 215-219. (CHed 1n U.S. EPA, 1985) Ermans, A.M., F. Delange, M. Van der Velden and J. Klnthaert. 1972. Possible role of cyanide and thlocyanate in the etiology of endemic cretinism. Adv. Exp. Med. B1ol. 30: 455-486. (CHed 1n U.S. EPA, 1985) -23- ------- Federal Register. 1984. Environmental Protection Agency. Proposed guide- lines for carcinogenic risk assessment. 49 FR 46294-46299. Foulds, W.S., J.S. Cant, I.A. Chlsholm, J. Bronte-Stewart and J. WHson. 1968. Hydroxocobalamln 1n the treatment of Leber's hereditary optic atrophy. Lancet. (Great Britain). 1: 896-897. (Cited In U.S. EPA, 1985) Frledberg, K.D. and H.A. Schwarzkopf. 1969. Blausaureexhalatlon be1 der cyanldverglftung (The exhalation of hydrocyanic add 1n cyanide poisoning) Arch. Toxlcol. 24: 235-248. (Cited 1n U.S. EPA, 1985) Gettler, A.O. and 0.0. Balne. 1938. The toxicology of cyanide. Am. J. Med. Sci. 195: 182-198. (Cited In U.S. EPA, 1985) Graedel, T.E. 1978. Chemical Compounds 1n the Atmosphere. Academic Press, NY. p. 282-286. Hansch, C. and A-J. Leo. 1979. SubstHuent Constants for Correlation Analysis 1n Chemistry and Biology. John WHey and Sons, Inc. NY. p. 172. Hardy, H.L. W.M. Jeffries, M.M. Wesserman and W.R. Waddell. 1950. Th1o- cyanate effect following Industrial cyanide exposure—report of two cases. N. Engl. J. Med. 242: 968-972. (Cited 1n U.S. EPA, 1985) Hayes, W.T., Jr. 1967. The 90-dose LD5Q and a chronlcHy factor as measures of toxldty. Toxlcol. Appl. Pharmacol. 11: 327-335. (Cited 1n U.S. EPA, 1985) -24- ------- Hertting, G., 0. Kraupp, E. Schnetz and S. Wleketlch. 1960. Untersuchungen uber die Folgen elner chronlschen Verabrelchung akut toxlscher Dosen von Natrium cyanld an Hunden. Acta Pharmacol. Toxlcol. 17: 27-43. (Ger.) (Cited 1n U.S. EPA, 1985} Howard, J.W. and R.F. Hanzal. 1955. Chronic toxldty for rats of food treated with hydrogen cyanide. J. Agrlc. Food Chem. 3: 325-329. (Cited 1n U.S. EPA, 1985) Hugod, C. 1981. Myocardlal morphology 1n rabbits exposed to various gas- phase constituents of tobacco smoke - an ultrastructural study. Athero- sclerosis (Shannon, Ireland). 4(2): 181-190. (Cited In U.S. EPA, 1985) Karube, I., T. Matsunaga, T. Nakahara, S. Suzuki and T. Kada. 1981. Preli- minary screening of mutagens. with a mlcroblal sensor. Anal. Chem. 53(7): 1024-1026. (Cited 1n U.S. EPA, 1985) Kushl, A., T. Matsumoto and D. Yoshlda. 1983. Mutagen from the gaseous phase of protein pyrolyzate. Agrlc. B1ol. Chem. 47(9): 1979-1982. (Cited In U.S. EPA, 1985) Leo, A., C. Hansch and D.A. Elklns. 1971. Partition coefficients and their uses. Chem. Rev. 6: 525-616. MacKenzle, A.D. and C.I. Phillips. 1968. West Indian amblyopla. Brain (Great Britain). 91: 249-260. (Cited 1n U.S. EPA, 1985) -25- ------- Makene, W.J. and J. Wilson. 1972. Biochemical studies 1n Tanzanlan patients with ataxlc tropical neuropathy. J. Neurol. Neurosurg. Psychiatry (Great Britain). 35: 31-35. (Cited In U.S. EPA, 1985) Monekosso, G.L. and J. Wilson. 1966. Plasma thlocyanate and vitamin B,_ In Nigerian patients with degenerative neurological disease. Lancet (Great Britain). 1: 1062-1064. (Cited In U.S. EPA, 1985) Mushett, C.W., K.L. Kelley, G.E. Boxer and J.C. Rlckards. 1952. Antidotal efficacy of vitamin B,? (hydroxo-cobalamln) 1n experimental cyanide poisoning. Proc. Soc. Exp. Biol. Med. 81: 234-237. (Cited In U.S. EPA, 1985) Nlchplls, P. 1975. The effect of sulflde on cytochrome aa«. IsosteMc and allosterlc shifts of the reduced peak. Blochem. Blophys. Acta. 396: 24-35. (Cited In U.S. EPA, 1985) NIOSH (National Institute for Occupational Safety and Health). 1976. Criteria for a Recommended Standard...Occupational Exposure to Hydrogen Cyanide and Cyanide Salts (NaCN, KCN and Ca(CN)2). U.S. DHEW. U.S. GPO, Washington, DC. NIOSH Publ. No. 77-108. (Cited In U.S. EPA, 1985) OSHA (Occupational Safety and Health Administration). 1981. General Industry OSHA Safety and Health Standards (29 CFR 1910). U.S. Dept. Labor. OSHA 2206, Washington, DC. p. 633. (Cited In U.S. EPA, 1985) -26- ------- Osuntokun, B.O. 1968. An ataxlc neuropathy 1n Nigeria. Brain. 91: 215-248. (Cited in U.S. EPA, 1985) Osuntokun, B.O. 1972. Chronic cyanide neurotoxldty and neuropathy 1n Nigerians. Plant Foods Hum. Nutr. (Great Britain). 2: 215-266. (Cited 1n U.S. EPA, 1985) Osuntokun, B.O., F.L. Monekosso and J. Wilson. 1969. Relationship of a degenerative tropical neuropathy to diet, report of a field study. Br. Med. J. (Great Britain). 1: 547-550. (Cited In U.S. EPA, 1985) Osuntokun, B.O., A. Aladetoylnbo and A.O.G. Adeuja. 1970. Free-cyanide levels 1n tropical atoxic neuropathy. Lancet (Great Britain). 2: 372-373. (Cited 1n U.S. EPA, 1985) Palmer, I.S. and O.E. Olson. 1979. Partial prevention by cyanide of sele- nium poisoning 1n rats. Blochem. Blophys. Res. Commun. 90(4): 1379-1386. (Cited 1n U.S. EPA, 1985) Pettlgrew, A.R. and G.S. Fell. 1972. Simplified coloMmetMc determination of thlocyanate 1n biological fluid and Us application to Investigation of toxic amblyoplas. Clln. Chem. 18: 996-1000. (Cited 1n U.S. EPA, 1985) Pettlgrew, A.R. and G.S. Fell. 1973. M1crod1ffus1on method for estimation of cyanide in whole blood and Us application to the study of conversion of cyanide to thlocyanate. Clin. Chem. 19: 466-471. (Cited In U.S. EPA, 1985) -27- ------- PhllbMck, D.J., J.B. Hopkins, O.C. Hill, J.C. Alexander and R.G. Thomson. 1979. Effect of prolonged cyanide and thlocyanate feeding 1n rats. J. Toxlcol. Environ. Health. 5: 579-592. (Cited In U.S. EPA, 1985) Sandberg, C.G. 1967. A case of chronic poisoning with potassium cyanide. Acta Med. Scand. 181: 233-236. (Cited In U.S. EPA, 1985) Smith, L., H. Kruszyna and R.P. Smith. 1977. The effect of methemoglobln on the Inhibition of cytochrome c oxldase by cyanide, sulflde or azlde. Blochem. Pharmacol. 26: 2247-2250. (Cited 1n U.S. EPA, 1985) Smith, R.P. and M.V. Olson. 1973. Drug-Induced methemogloblnemla. Semin. Hematol. 10: 253-268. (Cited In U.S. EPA, 1985) Tewe, 0.0. 1982. Effect of dietary cyanide on the performance, metabolism and pathology of the African rat (Crlcetomys gamblanus Waterhouse). Nutr. Rep. Int. 26(4): 529-536. (Cited 1n U.S. EPA, 1985) Tewe, 0.0. and J.H. Maner. 1980. Cyanide, protein and Iodine Interactions 1n the performance, metabolism and pathology of pigs. Res. Vet. Sd. 29(3): 271-276. (Cited In U.S. EPA, 1985) Tewe, 0.0. and J.H. Maner. 1981a. Long-term and carry-over effect of dietary 1nogran1c cyanide (KCN) 1n the life cycle performance and metabolism of rats. Toxlcol. Appl. Pharmacol. 58(1): 1-7. (Cited 1n U.S. EPA, 1985) -28- ------- Tewe, 0.0. and J.H. Maner. 19815. Performance and pathophyslologlcal changes 1n pregnant pigs fed cassava diets containing different levels of cyanide. Res. Vet. Sc1. 30(2): 147-151. (Cited In U.S. EPA, 1985) Tewe, 0.0. and J.H. Maner. 1982. Cyanide, protein and Iodine Interaction 1n the physiology and metabolism of rats. Food Chem. 9(3): 195-204. (Cited 1n U.S. EPA, 1985) Towlll, I.E., J.S. Drury, B.L. WhHMeld, E.B. Lewis, E.L. Galyan and A.S. Mammons. 1978. Reviews of the Environmental Effects of Pollutants. V. Cyanide. U.S. EPA, HERL, ORD, Cincinnati, OH. EPA-600/1-78-027. NTIS PB 289920. U.S. EPA. 1980a. Ambient Water Quality Criteria for Cyanides, with Errata for Ambient- Water Quality Criteria Documents dated June 9, 1981 (Updated: February 23, 1982). Prepared by the Environmental Criteria and Assessment Office, Cincinnati, OH, OHEA for the Office of Water Regulations and Stan- dards, Criteria and Standards Division, Washington, DC. EPA 440/5-80-035. NTIS PB 81-117483. U.S. EPA. 1980b. Guidelines and Methodology Used 1n the Preparation of Health Effects Assessment Chapters of the Consent Decree Water Quality Criteria. Federal Register. 45: 79347-79357. U.S. EPA. 1983. Methodology and Guidelines for Reportable Quantity Deter- minations Based on Chronic Tox1c1ty Data. Prepared by the Environmental Criteria and Assessment Office, Cincinnati, OH, OHEA for the Office of Solid Waste and Emergency Response, Washington, DC. -29- ------- U.S. EPA. 1985. Drinking Water Criteria Document for Cyanide. Prepared by the Environmental Criteria and Assessment Office, Cincinnati, OH, OHEA for the Office of Drinking Water, Washington, DC. Final draft. U.S. Public Health Service. 1962. Drinking Water Standards. U.S. Gov. Printing Off., Washington, D.C. PHS Publ. No. 956. (Cited in U.S. EPA, 1985) VeHh, G.D., D.L. DeFoe and B.V. Bergstedt. 1979. Measuring and estimating the bloconcentratlon factor of chemicals 1n fish. J. Fish Res. Board Can. 36: 1040-1048. Way, J.L. 1981. Pharmacologlc aspects of cyanide and Its antagonism. lr\_: Cyanide Biology, B. Vennesland, E.E. Conn and C. Knowles, Ed. Academic, London, England, p. 29-49. (Cited 1n U.S. EPA, 1985) Weast, R.C., Ed. 1980. CRC Handbook of Chemistry and Physics, 61st ed. CRC Press, Boca Raton, FL. p. B-98, B-133, B-147. Wilson, J. 1983. Cyanide In human disease: A review of clinical and laboratory evidence. Fundam. Appl. Toxlcol. 3(5): 397-399. (Cited 1n U.S. EPA, 1985) Wilson, J. and D.M. Matthews. 1966. Metabolic Interrelationships between cyanide, thlocyanate and vitamin B,,, in smokers and non smokers. Clin. Sci. 31: 1-7. (Cited 1n U.S. EPA, 1985) -30- ------- Wokes, F. 1958. Tobacco amblyopla. Lancet. 2: 526-527. (Cited 1n U.S. EPA, 1985) Yamamoto, K., Y. Yamamoto, H. Hatlorl and T. Samori. 1982. Effects of routes of administration on the cyanide concentration distribution In the various organs of cyanide Intoxicated rats. Tohoku J. Exp. Med. 137(1): 73-78. (Cited In U.S. EPA, 1985) -31- ------- APPENDIX Summary Table for Sodium Cyanide CO ro I Inhalation AIS AIC Oral AIS AIC Species Experimental Effect Dose/Exposure NA NA NA NA NA NA rat NOEL - 10.8 mg NA CN-/kg/day Acceptable Intake Reference (AIS or AIC) NA NA ND ND NA 2.8 NaCN Howard and mg/day Hanzal, 1955; Maximum composite score dog 6 mg/kg bw/day for 15 months (RVd=1.9) degeneration of ganglion cells In CNS (RVe=6) 11.4 U.S. EPA, 1985 Herttlng et al.. 1960 NA = Not applicable; ND = not derived ------- |