UNITED STATES ENVIRONMENTAL PROTECTION AGENCY WASHINGTON, D.C. 20460 OFFICE OF CHEMICAL SAFETY AND POLLUTION PREVENTION

MEMORANDUM

Date: September 18, 2018

SUBJECT: Sodium Cyanide. Human Health Risk Assessment in Support of Registration Review.

PC Code: 045801 & 074002 DP Barcode: D447111 Decision No.: 541080 Registration No.: 6704-75, CA840006, etc. Petition No.: NA Regulatory Action: Registration Review Risk Assessment Type: Single Chemical, Aggregate Case No.: 3073 TXR No.: NA CAS No.: 74-90-8 & 143-33-9 MRID No.: NA 40 CFR: §180.130

FROM: Brian Van Deusen, Risk Assessor Janet Camp, Risk Assessor Thurston Morton, Dietary Assessor/Residue Chemist Minerva Mercado, Toxicologist Risk Assessment Branch 4 (RAB4) Health Effects Division (HED, 7509P)

THROUGH: Donald Wilbur, Branch Chief Risk Assessment Branch 4 (RAB4) Health Effects Division (HED) (7509P)

TO: Leigh Rimmer, Chemical Review Manager Nicole Zinn, Team Leader Risk Management and Implementation Branch 2 (RMIB2) Pesticide Re-evaluation Division (7508P) Office of Pesticide Programs

As part of Registration Review, PRD has requested that HED evaluate the hazard and exposure data and estimate the risks to human health that will result from the currently registered uses of sodium cyanide. The most recent human health risk assessment for sodium cyanide was performed in 2006 (B. Daiss, 7/10/2006, D318015). A Human Health Assessment Scoping Document in Support of Registration Review (B. Daiss, 9/8/2010, D373692) for sodium cyanide was completed in 2010. No risk assessment updates other than an updated acute dietary exposure assessment have been made in conjunction with registration review. This memorandum is an updated review of the previous risk assessment and serves as HED’s draft human health risk assessment for the registered uses of sodium cyanide.

Sodium Cyanide Human Health Risk Assessment DP No. 447111

Table of Contents Use Profile and Risk Assessment Conclusions ...... 3 Data Deficiencies ...... 3 Tolerance Considerations ...... 4 Label Recommendations ...... 4 Chemical Identity ...... 4 Hazard Characterization and Dose-Response Assessment ...... 5 Toxicology Studies Available for Analysis ...... 5 Toxicological Effects ...... 6 Safety Factor for Infants and Children (FQPA Safety Factor) ...... 8 Completeness of the Toxicology Database ...... 8 Evidence of Neurotoxicity ...... 8 Evidence of Sensitivity/Susceptibility in the Developing or Young Animal ...... 8 Toxicity Endpoint and Point of Departure (POD) Selections ...... 9 Cancer Classification and Risk Assessment Recommendation ...... 10 Dietary, Residential and Aggregate Exposure/Risk Characterization ...... 10 Dietary Exposure/Risk Characterization ...... 10 Residential and Bystander Exposure ...... 11 Aggregate Exposure ...... 11 Occupational Handler and Post-Application Exposure/Risk Characterization ...... 11 Incident and Epidemiological Data Review ...... 13 References ...... 13 Appendix A. Toxicology Profile and Executive Summaries ...... 17 A.1 Toxicology Data Requirements ...... 17 A.2 Toxicity Profiles ...... 18 A.3 Literature Search for Sodium Cyanide ...... 23 Appendix B. International Residue Limits ...... 24

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Use Profile and Risk Assessment Conclusions

Sodium cyanide is registered for use as a predacide and as an insecticide. As a predacide, it is used as an encapsulated single dose poison to control animals that are vectors of communicable disease or animals that prey upon livestock or threatened or endangered species. Individual capsules are loaded into an ejector device which is anchored to the ground. The capsule holder is treated with a scent used to attract predators to the unit. When an animal tugs at the capsule holder, a spring-driven plunger ejects the sodium cyanide capsule into its mouth. This product is limited to use only by trained and certified applicators under the direct supervision of a government agency. Occupational handler and post-application exposures for the use of sodium cyanide in these bait products are considered negligible based on use information, label restrictions, and the sodium cyanide being sealed within the ejector devices and placed in remote locations which effectively limits exposure.

As an insecticide, sodium cyanide is used as a source of hydrogen cyanide gas for quarantine fumigation of surface pests on citrus. There are two special local needs (SLN) food/feed use registrations for sodium cyanide as a fumigant in Arizona and California. However, active fumigation of citrus with hydrogen cyanide is limited to a single facility in California to control red scale on fresh market citrus bound for Arizona. The SLN end-use product is a granular formulation containing 98% sodium cyanide as the active ingredient. It is applied by professional applicators only. There are no products available for residential application. Dermal exposures are not expected based on the limited use pattern and were therefore not assessed. There is the potential for inhalation exposure to workers to hydrogen cyanide from its use in post-harvest fumigation of citrus contained in closed transport trailers.

Sodium cyanide is a restricted use pesticide that results in limited exposure to handlers. An acute dietary assessment resulted in no risks of concern. There are no registered residential uses so an aggregate exposure assessment is not needed. Even though sodium cyanide is restricted use and personal protective equipment (PPE) and extensive restrictions are required on the SLN label in order to decrease the likelihood of exposure, if inhalation exposures of hydrogen cyanide occur, there will be adverse effects. Based on potential occupational handler and post-application inhalation exposures to hydrogen cyanide from the post-harvest use on citrus, it may pose a human-health risk of concern. However, based on a review of the limited use pattern in California, the lack of incidents reported, and the requirement of handlers to wear personal hydrogen cyanide detector monitors, EPA concludes that the potential for exposure and risks is low.

Data Deficiencies

Residue chemistry deficiencies at the time of the RED are now satisfied except for the submittal of analytical standards. Analytical standards are not currently available in the EPA National Pesticide Standards Repository. Analytical reference standards must be supplied and replenished as necessary, as long as tolerances remain published in 40 CFR §180.130.

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Tolerance Considerations

In 2009 HED issued guidance on tolerance expressions (S. Knizner, 2009). We now conclude the tolerance expression should be revised as follows: Tolerances are established for residues of sodium cyanide, including its metabolites and degradates, in or on the commodities in the table below. Compliance with the tolerance levels specified below is to be determined by measuring only hydrogen cyanide in or on the commodity.

Table 1.2.1. Summary of Hydrogen Cyanide Established and Recommended Tolerances for Registration Review.

(a) General. Tolerances are established for residues of sodium cyanide, including its metabolites and degradates, in or on the commodities in the table below. Compliance with the tolerance levels specified below is to be determined by measuring only hydrogen cyanide in or on the commodity:

Established Revised Comments Commodity/Correct Commodity Definition Tolerance Tolerance (ppm) (ppm) Fruit, citrus, group 10-10 50 Commodity definition revision Fruit, citrus 50 Remove

The Codex Alimentarius and Canada have not established maximum residue limits (MRLs) for citrus fruit. Therefore, international harmonization is not an issue at this time.

Label Recommendations

There are no residue chemistry related label recommendations.

Chemical Identity Table 1.4.1. Test Compound Nomenclature.

Chemical Structure

Empirical Formula NaCN HCN Common Name Sodium cyanide Hydrogen cyanide IUPAC name Sodium cyanide Hydrogen cyanide cyanobrik, cyanogran, sodium Hydrocyanic acid, prussic acid, Other Names cyanide, hydrocyanic acid sodium formonitrile, formic anammonide, salt, cymag carbon hydride nitride, cyclon CAS Registry Number 143-33-9 74-90-8

Table 1.4.2. Physicochemical Properties of the Technical Grade Test Compound

Parameter Sodium Cyanide Hydrogen Cyanide

Molecular Weight 49.01 27.03

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Table 1.4.2. Physicochemical Properties of the Technical Grade Test Compound

Parameter Sodium Cyanide Hydrogen Cyanide

Boiling Point 1496°C at 760 mm Hg 26°C at 760 mm Hg

Melting Point 564 °C -13.4°C

Specific Gravity 1.7 0.7 at 20°C

Vapor Density 0.94

Vapor Pressure Negligible 620 mm Hg at 20°C

Solubility Soluble in water (37 g/100mL) Miscible with water and alcohol, slightly soluble in ether. Source: OSHA, 2004

Hazard Characterization and Dose-Response Assessment

Toxicology Studies Available for Analysis

The toxicological database for sodium cyanide (NaCN) is adequate for hazard characterization, and is mostly composed of open literature studies performed with various forms of cyanide compounds. The toxic moiety is the cyanide ion (CN-), which is released by all cyanides in biological media. Since all cyanides release the same toxic moiety, HED includes studies conducted using different cyanides in the sodium cyanide toxicology database. A list of cyanides in the sodium cyanide database, and their molar equivalencies, can be found in the notes to Appendix Table A.2.2.

The available toxicological studies applicable for risk assessment are summarized in Appendices A.1 and A.2, and include the following acceptable studies:

Guideline studies: • Acute oral toxicity study in rats; • Acute dermal toxicity study in rabbits; • Acute dermal irritation study in rabbits; • Prenatal developmental studies in rat

Non-guideline studies: • Subchronic studies via the oral route in rats and mice; • Subchronic studies via the inhalation route in rats and monkeys; • Reproduction and fertility effects studies via inhalation route in rats; • Chronic toxicity study in rats; • Genotoxicity and mutagenicity studies; • Subchronic neurotoxicity studies in male rats and in pigs; • Auditory function study in male rats; • Clinical trials in humans.

A specific absorption, distribution, metabolism and excretion (ADME) study is not available, however it is not needed because the wealth of literature studies describing the physiological effects of the different cyanides can be used to characterize the ADME of cyanides. As part of Page 5 of 24

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registration review for sodium cyanide, a broad survey of the literature was conducted to identify studies that report toxicity following exposure to sodium cyanide via exposure routes relevant to human health pesticide risk assessment not accounted for in the agency’s sodium cyanide toxicology database. The search strategy employed terms restricted to the name of the chemical plus any common synonyms, and common mammalian models to capture as broad a list of publications as possible for the chemical of interest. The search strategy returned 2,130 studies from the literature. During title/abstract and/or full text screening of these studies, 1 was identified as containing potentially relevant information (either quantitative or qualitative) for the sodium cyanide human health risk assessment. Following a full text review of the identified relevant study, it was determined that the study did not contain information that would impact the risk assessment and was not considered in the selection of endpoints or Points of Departure (PODs).

Toxicological Effects

The toxic moiety of sodium cyanide is the cyanide ion, which has high affinity for metals like trivalent iron. For sodium cyanide, as well as for other cyanides, the cyanide ion dissociates from the main molecule after entering the body. Cyanides are well absorbed via the gastrointestinal tract and rapidly absorbed via the respiratory tract. They are also absorbed through the skin. The permeability constant measured for the cyanide ion in aqueous solution was 3.5 × 10–4 cm/h, and that calculated for hydrogen cyanide was 1 × 10–4 cm/h (from in vitro human skin study by Dugard, 1987, as reviewed by Simeonova et al. 1984). Plant- based cyanides may be more effective when ingested orally than when dosed intravenously (Moertel et al. 1981), since the acidic environment of the stomach helps dissociate the cyanide ion from the glycoside. After absorption, cyanide quickly binds with the iron in key metabolic enzymes, preventing oxygen utilization and disrupting energy production at the cellular level. Cells are then forced into anaerobic metabolism, creating lactic acid and leading to acid-base imbalances and metabolic acidosis. High proportions of ingested cyanide will pass through the liver and be detoxified by the first-pass effect. Most of the absorbed cyanide is metabolized to thiocyanate in the liver. Minor pathways for detoxification are reaction with cystine and combination with hydroxycobalamin (vitamin B12a). All metabolites are excreted in the urine. Most of the cyanide in blood is sequestered in the erythrocytes, and a relatively small proportion is transported to target organs. Cyanide does not accumulate in tissues.

Most forms of cyanide are extremely toxic to mammals following acute exposure by the oral and inhalation routes. As described in numerous clinical cases from the open literature, the primary effects of acute cyanide exposure in humans are central nervous system symptoms, metabolic acidosis, and cardiovascular disturbances. Typical signs of acute cyanide poisoning include (in order of severity): weakness and confusion; headache; nausea; metabolic acidosis; gasping for air in a manner similar to asphyxiation, but with a more abrupt onset; difficulty breathing; respiratory arrest; loss of consciousness; seizures prior to death; cardiac arrest and death. Effects and symptoms associated with exposure to cyanides are similar via the oral, inhalation and dermal routes. However, the dermal rabbit LD50 (Toxicity Category I) is an order of magnitude higher than the rat oral LD50, suggesting that dermal doses, higher than those of oral, are required for toxicity to occur. One human case study from the literature reports severe eye damage after ocular exposure with a 5% sodium cyanide solution (Zhang et al. 2012).

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Via the inhalation route, a single dose of 0.079 mg hydrogen cyanide /L produced 30% mortality in rats (Blank and Ribelin 1985) (Toxicity Category I). The National Institute for Occupational Safety and Health (NIOSH) immediately dangerous to life or health (IDLH) level for humans is 0.025 mg/L in ambient air. This IDLH is similar to doses from literature studies that reported no effects after subchronic inhalation exposure in rats and monkeys (Blanke and Thanke 1984; Lewis et al. 1984a).

Via the oral route, the oral LD50 in rats is 7.5 mg sodium cyanide/kg/day (Toxicity Category I). The lowest reported oral lethal dose for humans is 0.54 mg HCN/kg body weight (Simeonova et al. 2004). Human studies with the cyanogenic glycoside amygdalin (laetrile) indicate that a single oral dose equivalent to 0.4 mg HCN/kg body weight is a lowest observed adverse effect level (LOAEL) based on clinical signs and elevated blood cyanide levels (Moertel et al. 1981 and 1982); however, a no adverse effect level (NOAEL) was not identified.

No significant chronic systemic or reproductive effects have been shown in mammals after repeated exposure to bolus doses below the rat LD50, or to dietary doses in the same order of magnitude as the LD50. A preliminary review of recent literature studies found that a few repeated dose animal studies indicate thyroid hormone effects or histopathological changes (Olusi et al. 1979; Tewe and Maner 1981; Daniel et al. 2014; Gotardo et al. 2015). The proposed thyroid effects of cyanides are likely due to internal exposure to the thiocyanate metabolite, a known inhibitor of iodine transport (reviewed by Simeonova et al. 2006). However other studies found no lesions in the thyroid gland in rodents (NTP 1993), no changes in thyroid hormone blood levels in rats or monkeys (Lewis et al. 1984), or no clear association of thyroid effects with human exposure to cyanides (reviewed by Simeonova et al. 2006). A repeat dose developmental study in rats that administered doses below but close to the LD50 to dams (using HCN equivalents: 3.0 mg repeat dose vs. 4.1 mg LD50) found no adverse maternal or developmental effects (IRDC 1982, 1983). However, adverse developmental malformations and/or variations are reported in the literature when golden hamsters were dosed with acutely toxic doses of cyanides, i.e. maternal animals show signs of toxicity (Willhite 1982; Frakes et al. 1985 and 1986), or when dosed subcutaneously thus bypassing detoxification by the liver that occurs after oral dose (in golden hamster; Doherty et al. 1982).

Neurological signs (confusion, headache, seizures) are hallmarks of acute cyanide poisoning, and are due to the high metabolic demand for oxygen in neurons. In a clinical trial of the cyanogenic glucoside amygdalin, cancer patients experience headaches, dizziness and mental obtundation after one dose (Moertel et al. 1982). However, such neurological effects occur rarely in repeated dose studies. It is unclear if in repeat dose studies neurological effects are due exclusively to cyanide exposure, or to interaction of cyanide exposure with other variables. Seizures and motor deficits were shown in rats after repeated cyanide exposure, but only in animals that were also fed diets deficient in sulfur amino acids, which are necessary for proper cyanide metabolism/detoxification (Kimani et al. 2014). These effects were not observed in rats fed regular diets and exposed to low levels of cyanide (one third of the LD50), indicating that neurological effects are secondary to the acute toxicity when the rat’s capacity to detoxify cyanide is compromised, and therefore not expected after repeat exposure in rats receiving a regular diet. In a developmental study where offspring were exposed (in utero and postnatally)

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to a dietary daily dose about 3X the bolus oral LD50 in the same species, pups showed mild delayed maturation of cerebellum (Malomo et al. 2004), however the study did not indicate if maternal animals showed acute poisoning symptoms. Lewis et al. (1984) reported behavioral effects in monkeys after repeated inhalation exposure, however the effect was marginally significant (p = 0.06, N = 5). Neurological effects have been observed in human populations with diets that rely mostly on cassava (known to contain cyanogenic glycosides). However, a direct link between the cyanide content of cassava and neurologic effects has not been proven since the same populations may also consume amino acid deficient diets (as reviewed by Kimani et al. 2014 and Simeonova et al. 2004), cassava may contain other components that are neurotoxic (as reviewed by U.S. DHHS 2006), and incidence neurological effects in humans often does not correlate with either exposure levels or serum thiocyanate levels (as reviewed by Simeonova et al. 2004).

Safety Factor for Infants and Children (FQPA Safety Factor)1

The toxicology database is adequate, no evidence of increased quantitative or qualitative susceptibility was identified, and the dietary assessments are based on reliable exposure data and will not underestimate exposure. However, the FQPA Safety Factor for sodium cyanide is 10X for acute dietary exposure scenarios because the POD was selected from a study in which a NOAEL was not observed (i.e. a 10X is added for LOAEL to NOAEL extrapolation). As indicated in the previous risk assessment (B. Daiss 7/10/2006, D318015), in selecting this safety factor, consideration was also given to the severity of effects from sodium cyanide, as well as the steep dose-response curve (i.e. a relatively small increase over the dose that shows no effects or mild effects leads to severe effects or lethality). The 10X FQPA safety factor is also protective of neurologic effects observed after acute exposure.

Completeness of the Toxicology Database

The existing toxicological database for sodium cyanide is complete and suitable for risk assessment. It includes a guideline rat developmental study (IRDC 1983), literature studies in golden hamsters and two rat reproductive effects studies from the open literature.

Evidence of Neurotoxicity

As explained in section 2.2 above, neurological effects are expected after acute exposure to cyanides.

Evidence of Sensitivity/Susceptibility in the Developing or Young Animal

There is no evidence of increased quantitative or qualitative offspring susceptibility to sodium cyanide. A repeat dose developmental study in rats showed no significant maternal or offspring effects (IRDC 1983). Additional literature studies in golden hamsters indicate adverse developmental outcomes occur only when maternal animals are dosed with acutely toxic doses

1 HED’s standard toxicological, exposure, and risk assessment approaches are consistent with the requirements of EPA’s children’s environmental health policy (https://www.epa.gov/children/epas-policy-evaluating-risk-children). Page 8 of 24

Sodium Cyanide Human Health Risk Assessment DP No. 447111 of cyanides (Willhite 1982; Frakes et al. 1985 and 1986). Literature studies found no reproductive effects in male or female rats (Kier et al. 1985a, 1985b).

Toxicity Endpoint and Point of Departure (POD) Selections

As explained in Section 2.2 above, repeat dose studies with cyanides do not show adverse effects when the dose is below that which would induce effects after a single dose (e.g. the LD50 in rat studies, acute symptoms/signs in other species including humans). Therefore, the toxicological database does not support progression of effects from acute to chronic exposures. Consequently, adverse effects are not expected after chronic exposure to sodium cyanide at levels that do not produce an acute response. Thus, a chronic dietary assessment is not needed and a chronic POD was not selected.

Using a Weight of Evidence (WOE) approach, the Agency previously selected an acute dietary endpoint based on two human studies using oral doses of amygdalin (laetrile), a cyanogenic glycoside that releases cyanide upon ingestion (R. Kent, W. Dykstra, 3/17/2006, TXR 0054130). These human studies were reviewed by the EPA Human Studies Review Board (HSRB), and were found to (1) meet the specific ethical standards prevalent at the time the research was conducted; (2) contain no evidence that the research was fundamentally unethical; and (3) contain no evidence of significant deficiencies in the ethical procedures (C. Fisher, 6/26/2006, EPA-HSRB-06-01; JM. Carley, 3/16/2006.) The studies identify a LOAEL equivalent to 0.4 mg HCN/kg/day based on clinical signs and elevated blood cyanide levels in humans after a single dose. Because the POD is derived from a human study, the uncertainty factor for interspecies variability (UFA) can be reduced to 1. A default uncertainty factor of 10 is applied to account for potential variation in sensitivity among members of the human population (UFH). An additional FQPA safety factor of 10 is also applied because a NOAEL was not identified (UFL), and to account for the severity of effects and the steep dose-response curve.

PODs were not selected for residential or occupational risk assessment. There are no residential uses. A quantitative occupational exposure assessment was not performed for sodium cyanide because the potential for exposure is low. Sodium cyanide is a restricted use pesticide and PPE (including personal hydrogen cyanide detector monitors) and extensive restrictions are required on the SLN label in order to decrease the likelihood of exposure (see Section 4.0). Since neither residential nor occupational quantitative assessments will be performed, PODs are not needed.

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Table 2.4.1. Summary of Toxicological Doses and Endpoints for Sodium Cyanide for Use in Dietary Human Health Risk Assessments. Uncertainty/ RfD, PAD for Exposure/ POD FQPA Safety Risk Study and Toxicological Effects Scenario Factors Assessment Moertel et al (1981 and 1982) MRID 46769601 and 46769602 Acute Dietary Based on clinical signs (nausea (General UFA = 1X Population, Acute RfD = 30-31%, vomiting 17-25%, LOAEL = 0.4 mg UFH = 10X including Infants aPAD = 0.004 headaches 7-8%, dizziness 7- HCN/kg/day and Children, and FQPA SF = mg/kg/day 10%; mental obtundation 4-5% Females 13-49 UFL = 10X and dermatitis 2%) associated years of age) with elevated blood cyanide levels (2-3 µg/ml) observed after single oral dose. Point of departure (POD) = A data point or an estimated point that is derived from observed dose-response data and used to mark the beginning of extrapolation to determine risk associated with lower environmentally relevant human exposures. LOAEL = lowest-observed adverse-effect level. UF = uncertainty factor. UFA = extrapolation from animal to human (interspecies). UFH = potential variation in sensitivity among members of the human population (intraspecies). UFL = use of a LOAEL to extrapolate a NOAEL. UFS = use of a short-term study for long-term risk assessment. UFDB = to account for the absence of key data (i.e., lack of a critical study). FQPA SF = FQPA Safety Factor. aPAD = acute population-adjusted dose. RfD = reference dose.

Cancer Classification and Risk Assessment Recommendation

The agency has not assigned a cancer classification to sodium cyanide. However, there is no evidence in the toxicological database for sodium cyanide of any mutagenic, genotoxic or long term carcinogenic effects. Several in vitro mutagenicity studies from the literature, which include bacterial and mammalian cell systems, indicate cyanides are not mutagenic or genotoxic. A chronic toxicity study in rats did not find significant increases in tumor formation after exposure to cyanide. The relevant mutagenicity studies and the chronic toxicity study in rats are summarized in Appendix A.

In addition, the toxicological database for sodium cyanide does not support progression of effects from acute to chronic exposures. Because of the severe acute effects associated with cyanide exposure, which include death, the chronic effects that sometimes lead to cancer are not expected for sodium cyanide exposure. Consequently, carcinogenic effects after long-term exposure to cyanides are not expected.

Dietary, Residential and Aggregate Exposure/Risk Characterization

Dietary Exposure/Risk Characterization

A slightly refined acute probabilistic dietary exposure analysis was performed for sodium cyanide. The analysis was based on maximum pulp and peel residues of hydrogen cyanide from a citrus residue study and 100 percent crop treated (PCT). Tolerances for residues in livestock commodities are not established. DEEM default concentration factors were used for citrus juices. Drinking water was not included in the analysis since this is a post-harvest fumigation use. Risk estimates for food only are not of concern. At the 95th percentile of exposure, the subgroup with the highest exposure for the food only analysis was the children 1 to 2 years old Page 10 of 24

Sodium Cyanide Human Health Risk Assessment DP No. 447111 which had an exposure of 0.001667 mg/kg/day which utilizes 42% of the acute population- adjusted dose (aPAD).

Table 3.1.1. Results of Acute Dietary (Food Only) Exposure and Risk Analysis. Exposure (mg/kg/day) Population Subgroup aPAD (mg/kg/day) (95th Percentile of % aPAD Exposure) General U.S. Population 0.000463 12 All Infants (<1 year old) 0.000175 4.4 Children 1-2 years old* 0.001667 42 Children 3-5 years old 0.001254 31 Children 6-12 years old 0.004 0.000680 17 Youth 13-19 years old 0.000513 13 Adults 20-49 years old 0.000386 9.6 Adults 50-99 years old 0.000310 7.8 Females 13-49 years old 0.000388 9.7 *The subpopulation with the highest risk estimates.

Adverse effects are not expected after chronic exposure to sodium cyanide at levels that do not produce an acute response. Therefore, a chronic dietary assessment is not needed, and a chronic POD was not selected.

Residential and Bystander Exposure

There are no registered residential uses for sodium cyanide, therefore residential exposures and risks were not assessed.

Based on potential bystander inhalation exposures to hydrogen cyanide from the post-harvest use on citrus, it may pose a human-health risk of concern. However, based on a review of the limited use pattern and air monitoring data from the single facility in California at which hydrogen cyanide fumigation occurs, EPA concludes that the potential for bystander exposure and risks is low.

Aggregate Exposure

An aggregate exposure assessment from the combined food and non-food exposures is not required because there are no residential uses of sodium cyanide.

Occupational Handler and Post-Application Exposure/Risk Characterization

Occupational handler and post-application exposures for the use of sodium cyanide in bait products are considered negligible based on use information, label restrictions, and the sodium cyanide being sealed within the ejector devices and placed in remote locations which effectively limits exposure.

There are fumigation uses of sodium cyanide for the generation of hydrogen cyanide in Arizona as well as California to control red scale and other surface pests on fresh market citrus bound for

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Arizona under the restrictions of SLN labels. However, active fumigation of citrus with hydrogen cyanide is limited to a single facility in California. Dermal exposures to occupational handlers and post-application workers are not expected based on the limited use pattern and were therefore not assessed. Due to the acute toxicity of hydrogen cyanide via the inhalation route, PPE and extensive restrictions are required on the SLN label for handlers. The SLN label restrictions are as follows: • Handlers must wear personal hydrogen cyanide detector monitors set to alarm at 5 ppm HCN. • Handlers must wear required PPE including: cloth or disposable coveralls covering arms, legs, and body fully to neck, gloves, and goggles or faceshield during preparation and gas generation activities. • A restricted area boundary is established that extends a minimum of 20-feet around all sides of the fumigated trailer with appropriate warning signs posted during application and 50-feet during aeration. Only fumigation personnel are permitted within this restricted area during treatment and aeration. • Trailers are fumigated for 1-hour at 1-ounce sodium cyanide for each 100 ft3 of fumigated volume which results in 6 ounces of HCN per 1,000 ft3. • Circulation fans must be installed in the trailer with sufficient power to circulate the entire air volume of the trailer every 5 minutes. • Trailers are aerated for 30 minutes and only 1 trailer can be aerated during any 30-minute period. The aeration must exhaust at least 10 fumigated enclosure volumes within 30 minutes or aeration will continue until 10 fumigated volumes have been achieved. The trailer doors are then opened and allowed to passively aerate for 5 minutes to complete aeration. Handlers are not permitted to enter the trailers until air concentrations are below 5 ppm HCN. • Aeration exhaust discharge must extend above the top of the trailer and at least 20 feet above the ground. • Fumigation of trailers with roll-up doors is prohibited. Trailers must be equipped with one of the following combinations: front and rear vents, or rear vents with a side loading door. • Drivers are instructed to inform receiving personnel of the possible presence of low residual levels of HCN.

Even though sodium cyanide is a restricted use pesticide and PPE/extensive restrictions are required on the SLN label in order to decrease the likelihood of exposure, if inhalation exposures of hydrogen cyanide occur, there will be adverse effects. Uncertainty exists around the occupational post-application inhalation exposures from the fumigant use of sodium cyanide based on no available off-gassing data for sodium cyanide or post-application worker air monitoring data for down-stream activities (i.e., workers unloading trailers upon delivery). Based on potential occupational handler and post-application inhalation exposures to hydrogen cyanide from the post-harvest use on citrus, it may pose a human-health risk of concern. However, based on a review of the limited use pattern in California, the lack of incidents reported, and the requirement of handlers to wear personal hydrogen cyanide detector monitors, EPA concludes that the potential for exposure and risks is low.

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Incident and Epidemiological Data Review

Sodium cyanide incidents were previously reviewed in 2010 (K. Oo, S. Recore, 5/20/2010, D373792). At that time, based on the low severity and frequency of cases reported to both Incident Data System (IDS) and NIOSH Sentinel Event Notification System for Occupational Risk (SENSOR)-Pesticides, there was not a risk of concern that warranted further analysis.

In the current five-year IDS analysis from January 1, 2013 to April 16, 2018, two incidents involving sodium cyanide were reported to Main IDS. Both incidents involved the use of Registration Number 6704-75 (M-44 Cyanide Capsules). There were no cases reported to Aggregate IDS. A query of SENSOR-Pesticides 1998-2014 identified no cases involving sodium cyanide.

The Agricultural Health Study (AHS) is a federally-funded study that evaluates associations between pesticide exposures and cancer and other health outcomes and represents a collaborative effort between the US National Cancer Institute (NCI), National Institute of Environmental Health Sciences (NIEHS), CDC’s National Institute of Occupational Safety and Health (NIOSH), and the US EPA. Sodium cyanide is not included in the AHS, and therefore this study does not provide information for this report.

Based on the continued low frequency of sodium cyanide incidents reported to both IDS and SENSOR-Pesticides, there does not appear to be a concern at this time (S. Recore, E. Evans, 8/23/2018, D448012). The Agency will continue to monitor the incident data and if a concern is triggered, additional analysis will be conducted.

References

T. Morton. Sodium Cyanide (074002): Acute Dietary (Food Only) Exposure and Risk Assessment for Registration Review. D447119. 9/11/2018

T. Morton. Sodium Cyanide: Residue Chemistry Summary in Support of Registration Review. D448534. 9/11/2018.

S. Recore, E. Evans. Sodium Cyanide: Tier I Update Review of Human Incidents and Epidemiology for Draft Risk Assessment. D448012. 8/23/2018

J.M Carley. 3/16/2006. Initial Ethics Review of Amygdalin Human Study. Attachment to EPA- HQ-ORD-2006-0187-0037. https://www.regulations.gov/document?D=EPA-HQ-ORD-2006- 0187-0037

C. Fisher. 6/26/2006. EPA-HSRB-06-01. April 4-6, 2006 Meeting EPA Human Studies Review Board Report. http://nepis.epa.gov

R. Kent and W. Dykstra. 3/17/2006, TXR 0054130. Human Studies Review Board: Final Weight of Evidence Comparison of Human and Animal Toxicology Studies and Endpoints for Hydrogen

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Cyanide Human Health Risk Assessment. D327266. EPA-HQ-ORD-2006-0187-0037. https://www.regulations.gov/document?D=EPA-HQ-ORD-2006-0187-0037

Simeonova FP, Fishbein L, World Health Organization & International Programme on Chemical Safety. (2004). Hydrogen cyanide and cyanides: human health aspects. Geneva: World Health Organization. http://www.who.int/iris/handle/10665/42942

U.S. Department of Health and Human Services (2006) Toxicological Profile for Cyanide. Public Health Service. Agency for Toxic Substances and Disease Registry. July 2006. https://www.atsdr.cdc.gov/toxprofiles/tp8.pdf

U.S. Environmental Protection Agency (2012) Guidance for Considering and Using Open Literature Toxicity Studies to Support Human Health Risk Assessment. Office of Pesticide Programs 8/28/2012. https://www.epa.gov/sites/production/files/2015-07/documents/lit- studies.pdf

Additional Toxicology References: Blank T.L, Ribelin W.E. (1985) One-Month Inhalation Toxicity of Acetone Cyanohydrin in Male and Female Sprague-Dawley Rats. Monsanto Company, Environmental Health Laboratory, St. Louis MO; Report No. MCL-4695. https://www.regulations.gov/document?D=EPA-HQ- OPPT-2002-0027-0006 Blank T.L, Thake D.C. (1984) Three-Month Inhalation Toxicity of Acetone Cyanohydrin in Male and Female Sprague-Dawley Rats. Monsanto Company, Environmental Health Laboratory, St. Louis MO; Report No. MSL-4423. https://www.regulations.gov/document?D=EPA-HQ- OPPT-2002-0027-0007 Daniel AT, Adekilekun TA, Adewale MA, Adekemi AT (2014) Cyanide-induced hyperthyroidism in male Wistar rats. Niger Med J. 55(3):246-9. doi: 10.4103/0300-1652.132060. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4089055/ De Flora S. (1981) Study of 106 organic and inorganic compounds in the Salmonella/microsometest. Carcinogenesis 2(4):283-298. De Flora S, Camoirano A, Zanacchi P, Bennicelli C. (1984) Mutagenicity testing with T A97 and TA 102 of 30 DNA-damaging compounds. negative with other Salmonella strains. Mutat Res 134: 159-165. https://doi.org/10.1016/0165-1110(84)90009-5 Doherty P.A., Ferm V.H, Smith R.P (1982) Congenital malformations induced by infusion of sodium cyanide in the golden hamster. Toxicology and Applied Pharmacology 64(3):456-464. https://doi.org/10.1016/0041-008X(82)90242-3 Dugard P.H. (1987) The absorption of cyanide through human skin in vitro from solutions of sodium cyanide and gaseous HCN. In: Ballantyne B, Marrs TC, eds. Clinical and experimental toxicology of cyanides. Wright, Bristol, IOP Publishing, pp. 127–137. Frakes R.A., Sharma R.P., Willhite CC. (1985) Developmental toxicity of the cyanogenic glycoside linamarin in the Golden Hamster. Teratology 31(2):241-246. https://doi.org/10.1002/tera.1420310209

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Frakes R.A., Sharma R.P., Willhite C.C., Gomez G. (1986) Effect of cyanogenic glycosides and protein content in cassava diets on hamster prenatal development. Fundam Appl Toxicol 7(2): 191-198. https://doi.org/10.1016/0272-0590(86)90147-8 Gotardo AT, Hueza IM, Manzano H, Maruo VM, Maiorka PC, Górniak SL. (2015) Intoxication by Cyanide in Pregnant Sows: Prenatal and Postnatal Evaluation. J Toxicol. 2015:407654. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4460237/ IRDC (International Research and Development Corporation) (1983) Range Finding teratology study in rats with test article acetone cyanohydrin with cover letter dates 042586. Lab Report IR- 83-094; Submitted under TSCA Section 8D: EPA Document No. 878216399; NTIS No. OTS0510327. IRDC (International Research and Development Corporation) (1984) Teratology study in rats with test article acetone cyanohydrin with cover letter dates 042586. Lab Report IR-83-105; Submitted under TSCA Section 8D: EPA Document No. 878216401; NTIS No. OTS0510329. Kier L.D., Blank T.L., Ribelin W.E. (1985a) Female Fertility Study of Sprague-Dawley Rats Exposed by the Inhalation Route to Acetone Cyanohydrin. Monsanto Company, Environmental Health Laboratory, St. Louis MO; Report No. MSL-5011. https://www.regulations.gov/document?D=EPA-HQ-OPPT-2002-0027-0005 Kier L.D., Blank T.L., Ribelin W.E. (1985b) Male Fertility Study of Sprague-Dawley Rats Exposed by the Inhalation Route to Acetone Cyanohydrin. Monsanto Company, Environmental Health Laboratory, St. Louis MO; Report No. MSL-5010. https://www.regulations.gov/document?D=EPA-HQ-OPPT-2002-0027-0004 Kimani S., Moterroso V., Morales P., Wagner J., Kipruto S., Bukachi F., Maitai C., Tshala- Katumbay D. (2014) Cross-species and tissue variations in cyanide detoxification rates in rodents and non-human primates on protein-restricted diet. Food Chem Tox. 66, 203-209. Lewis T.R., Anger W.K., Te Vault R.K. (1984) Toxicity evaluation of sub-chronic exposures to cyanogen in monkeys and rats. J Environ Pathol Toxicol Oncol. 5(4-5):151-63. Malomo A.O., Imosemi I.O., Osuagwu F.C., Oladejo O.W., Akang E.E.U., Shokunbi M.T. (2004) Histomorphometric studies on the effect of cyanide consumption of the developing cerebellum of wistar rat (Rattus Novergicus). West African Journal of Medicine 23 (4), 323-328. Moertel CG, Fleming TR, Rubin J, Kvols LK, Sarna G, Koch R, Currie VE, Young CW, Jones SE, Davignon JP. (1982). A Clinical Trial of Amygdalin (Laetrile) in the Treatment of Human Cancer. New England Journal of Medicine, 306(4): 201-206. MRID 46769602. Published. Moertel CG, Ames MM, Kovach JS, Moyer TP, Rubin JR, Tinker JH. (1981) A Pharmacologic and Toxicological Study of Amygdalin. JAMA 245(6)591-594, MRID 46769601. Published. National Toxicology Program (1993) Technical Report on Toxicity Studies of Sodium Cyanide (CAS No. 143-33-9) Administered in Drinking Water to F344/N Rats and B6C3F1 Mice. Charles D. Hébert, Study Scientist. NTP Toxicity Report Series No. 37. NIH Publication 94- 3386. https://ntp.niehs.nih.gov/ntp/htdocs/st_rpts/tox037.pdf Olusi S.O., Oke O.L., Odusote A. (1979) Effects of cyanogenic agents on reproduction and neonatal development in rats. Biology of the neonate, 36 (5-6): 233-243. https://doi.org/10.1159/000241234

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Tewe O.O., Maner J.H (1981) Performance and pathophysiological changes in pregnant pigs fed cassava diets containing different levels of cyanide. Research in Veterinary Science 30:147-151. Willhite CC (1982) Congenital Malformations Induced by Laetrile. Science 215:1513-1515. https://doi.org/10.1126/science.7063858

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Appendix A. Toxicology Profile and Executive Summaries

A.1 Toxicology Data Requirements The requirements (40 CFR 158.340) for non-food use of sodium cyanide are in the table below. Use of the new guideline numbers does not imply that the new (1998) guideline protocols were used.

Technical Study Required Satisfied 870.1100 Acute Oral Toxicity ...... yes yes 870.1200 Acute Dermal Toxicity ...... yes yes 870.1300 Acute Inhalation Toxicity ...... yes yes 870.2400 Acute Eye Irritation ...... no1,2 -- 870.2500 Acute Dermal Irritation ...... no1,2 yes 870.2600 Skin Sensitization ...... no1,2 -- 870.3100 90-Day Oral Toxicity in Rodents ...... yes yes 870.3150 90-Day Oral Toxicity in Nonrodents ...... no -- 870.3200 21/28-Day Dermal Toxicity ...... no2 -- 870.3250 90-Day Dermal Toxicity ...... no2 -- 870.3465 90-Day Inhalation Toxicity ...... yes yes 870.3700a Prenatal Developmental Toxicity (rodent) ...... yes yes 870.3700b Prenatal Developmental Toxicity (nonrodent) ...... no3 -- 870.3800 Reproduction and Fertility Effects ...... yes yes 870.4100a Chronic Toxicity (rodent) ...... yes yes 870.4100b Chronic Toxicity (nonrodent) ...... no -- 870.4200a Carcinogenicity (rat) ...... no2,4 -- 870.4200b Carcinogenicity (mouse) ...... no2,4 -- 870.4300 Combined Chronic Toxicity/Carcinogenicity ...... no -- 870.5100 Bacterial Reverse Mutation Test ...... yes yes 870.5500 Bacterial DNA Damage Test ...... yes yes 870.5550 Unscheduled DNA Synthesis Mammalian ...... yes yes Other DNA Breakage in Mammalian Cells ...... no yes 870.6200a Acute Neurotoxicity Screening Battery (rat) ...... no2 -- 870.6200b 90-Day Neurotoxicity Screening Battery (rat)...... no2 -- 870.6300 Developmental Neurotoxicity ...... no2 -- 870.7485 Metabolism and Pharmacokinetics ...... no2,5 -- 870.7600 Dermal Penetration ...... no2 -- 870.7800 Immunotoxicity ...... no2 -- 1 P. McLaughlin, Phase Four Review dated 6/4/1992. 2 Based on the current uses of sodium cyanide, these studies are not required. If different uses of sodium cyanide are proposed in the future, some or all of these studies may be required. 3 Development studies in two rodent species, rat and golden hamster, are available in the public literature. For sodium cyanide there is no need to test a non-rodent species because the mode of action of this chemical is the same in all mammalian species. 4 The chronic study in rats shows that cyanide is efficiently metabolize and not present in tissues when rats are dosed repeatedly at levels that do not cause acute effect. Therefore, long term internal exposure is not expected, and no effects would be observed in a carcinogenicity study. 5 Metabolism and pharmacokinetics of the cyanides are extensively reviewed in the public literature.

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A.2 Toxicity Profiles

Table A.2.1 Acute Toxicity Profile – Sodium Cyanide Guideline Study Type MRID(s)/ Results Toxicity No. TXR Category 870.1100 Acute oral rat 42610801/001 LD50 = 7.5 mg/kg males; 7.4 mg/kg I 0068 females; (4.1 mg HCN/kg) 870.1200 Acute dermal rabbit 41731201/001 LD50 = 41 mg/kg males; 50 mg/kg I 0866 females (23/28 mg HCN/kg) 870.1300 Acute inhalation rat Blank and 30% mortality after one exposure to I Ribelin 0.079 mg HCN/L (1985)1 870.2400 Acute eye irritation Not required (corrosive chemical)2 870.2500 Acute dermal irritation rabbit 42610802/001 Mortality (4/6) and severe irritation in NA 0068 surviving animals. 870.2600 Skin sensitization Not required (repeated exposure not expected) 1 Open literature study, no MRID or TXR available. 2 P. McLaughlin, Phase Four Review dated 6/4/1992.

Important Notes for Table A.2.2 (below): a The Agency determine that the available human study for sodium cyanide was the most relevant study for hazard characterization. LOAEL/NOAELs for non-human studies via the oral route have not been updated since the last risk assessment (B. Daiss 7/10/2006, D318015), because changes to those studies would not result in more relevant points of departure and do not change the endpoints used for risk assessment. b All studies in this table are either from the public literature or were submitted to other EPA offices (not to OPP) therefore neither MRID nor TXR numbers are available. See references list after table A.2.2. c The toxicology database for sodium cyanide (NaCN) relies on studies conducted with other cyanides because the toxic moiety is the cyanide ion (CN-), which is released by all cyanides in biological media. NaCN and potassium cyanide (KCN) are ionic compounds with the same molar fraction of CN-. Hydrogen cyanide (HCN) is a gas with the same molar fraction of CN- as NaCN and KCN. Acetone cyanohydrin (C4H7NO; also known as ACH) is an organic compound that reacts with water to release + HCN at a rate of one HCN molecule per ACH molecule (C4H7NO + H2O  HCN + C3H6O + 2H ). Amygdalin, prunasin and linamarin are cyanogenic glycosides found in plants, which release a maximum of 59.1, 91.5 and 109.3 mg HCN/g, respectively, when hydrolyzed (FAO/WHO 2012). Cyanogen ((CN)2) is a gas that consist of two cyanide groups. Laetrile is a semisynthetic cyanogenic glucuronide. For simplicity, NaCN, KCN and ACH doses are often expressed as HCN equivalents. Additional note: Air concentrations were converted to mg/L using equations in Understanding Units of Measurement by T.K. Boguski (https://cfpub.epa.gov/ncer_abstracts/index.cfm/fuseaction/display.files/fileID/14285); 0.1 mg/L = 100 mg/m3.

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Table A.2.2. Subchronic, Chronic, and Other Toxicity Profile – Sodium Cyanide (NaCN) a Guideline No./ Reference (year) b / Results Study Type Classification/Doses expressed in HCN equivalents c 870.3100 National Toxicology Program Male rats dose with 4.7 mg HCN/kg/day had 9% 90-Day Oral (1993) decrease weight of cauda epididymis and 2% Toxicity in Acceptable/non-guideline decreased sperm motility in male rats. At a higher dose, cauda epididymis weight was decreased 13%, Rodents 0, 3, 10, 30, 100 or 300 ppm in sperm motility 4%, and the number of (rats and mice) drinking water spermatids/testis 14% (without a change in number of Rat males: 0, 0.3, 0.9, 2.7, 8.5 or spermatids per gram of testis). 23.6 mg NaCN/kg/day No adverse effects in mice or in female rats. Equivalent to 0, 0.2, 0.06, 1.5, 4.7 or 13 mg HCN/kg/day 870.3465 Blank and Ribelin (1985) 30% mortality (3/10) in rats after one exposure to 28-Day Inhalation Acceptable/non-guideline 0.079 mg HCN/L. Irritation of the eyes and/or nose and breathing difficulties in the mid and high Toxicity (rat) 0, 9.3, 29.9 or 59.6 ppm ACH (0, exposure groups and hypoactivity in the high exposure 0.039, 0.125 or 0.249 mg ACH/L) group were observed during exposure. Sings for 6 hours/day, 5 days/week. associated with anoxia/hypoxia, such as respiratory Equivalent to 0, 0.012, 0.040 or distress, tremors and/or convulsions, foaming at the 0.079 mg HCN/L mouth, and prostrate posture were observed following the first exposure in four high exposure males. Three of these animals subsequently died. Chromo rhinorrhea and signs of irritation about the ear were also observed at pre- and post-exposure periods. Hematological, biochemical and relative organ weight changes were within the biological variation of the rat. Serum and urine thiocyanate levels were elevated in all exposure groups. No gross or microscopic lesions attributable to treatment were observed. 870.3465 Blank and Thake (1984) No significant adverse effects were observed. 90-day Inhalation Acceptable/non-guideline Thiocyanate levels were only elevated in the low and mid exposure level groups. Toxicity (rat) 0, 10.1, 28.6 or 57.7 ppm ACH (0, 0.035, 0.100 or 0.200 mg ACH/L) for 6 hours/day, 5 days/week. Equivalent to 0, 0.011, 0.032 or 0.064 mg HCN/L 870.3465 Lewis et al (1984a) At the high dose of 0.055 mg HCN/L, changes in 6-month Acceptable/non-guideline behavioral testing (doubling rate of lever-pressing response per hour compared to same group pre- Inhalation 0, 11 or 25 ppm (CN)2 (0, 0.023 or exposure rate) and decreased lung moisture in Toxicity (male 0.053 mg (CN)2 /L) for 6 monkeys and decreased body weight in rats were monkey and male hours/day, 5 days/week. rat) observed. Equivalent to 0, 0.024 or 0.055 mg HCN/L

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Table A.2.2. Subchronic, Chronic, and Other Toxicity Profile – Sodium Cyanide (NaCN) a Guideline No./ Reference (year) b / Results Study Type Classification/Doses expressed in HCN equivalents c 870.3700a IRDC (1982, 1983) Maternal NOAEL = 0.3 mg HCN/kg/day Prenatal Acceptable/guideline LOAEL = 1.0 mg HCN/kg/day based on slight developmental in Main study: 0, 1, 3, 10 mg acetone reductions in weight gain rodents (rat) cyanohydrin/kg during days 6-15 Developmental NOAEL = 3.0 mg HCN/kg/day of gestation LOAEL was not observed Equivalent to 0, 0.3, 1.0, or 3.0 mg HCN/kg BW/day 870.3800 Kier et al. (1985a) No significant general toxicity or reproductive effects Reproduction and Acceptable/non-guideline were detected in male rats. Females and offspring were not evaluated. Fertility Effects 0, 10, 29 or 57 ppm acetone (male rat cyanohydrin (0, 0.035, 0.101 or inhalation) 0.198 mg/L) Equivalent to 0, 0.011, 0.032, or 0.063 mg HCN/L Exposure: 6 hours/day, 5 days/week, for 10 weeks. 870.3800 Kier et al. (1985b) No significant general toxicity or reproductive effects Reproduction and Acceptable/non-guideline were detected in male rats. Males and offspring were not evaluated. Fertility Effects 0, 11, 30 or 59 ppm acetone (female rat cyanohydrin (0.038, 0.104, or inhalation) 0.205 mg /L) Equivalent to 0, 0.012, 0.033, or 0.065 mg HCN/L Exposure: 6 hours/day, 7 days/week up to day of mating (34- 36 exposures).

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Table A.2.2. Subchronic, Chronic, and Other Toxicity Profile – Sodium Cyanide (NaCN) a Guideline No./ Reference (year) b / Results Study Type Classification/Doses expressed in HCN equivalents c 870.4100a Howard and Hanzal (1955) The investigators indicate that HCN produced no Chronic Toxicity Acceptable/non-guideline, signs of cyanide toxicity during a 2-year feeding period. However, according to data from Table IV in (rat) 0, 106 or 301 ppm HCN in diet the original manuscript, at the end of the study female 0, 2.6 or 5.6 mg HCN/kg/day mean body weight was reduced 31% at the low dose males and 16% at the high dose (248 g and 303 g 0, 4.4 or 5.2 mg HCN/kg/day respectively compared to 361 g control); male mean females body weight was reduced 7% at the low dose and 10% at the high dose (446 g and 436 g respectively, compared to 482 g control). No standard deviations or statistical analysis was provided. There were no significant differences in mortality, organ weights or histology between treatment groups and controls. Hematological values, determined initially and at termination of the study, were within normal limits. It is indicated that in the latter stages of the study a number of the rats were unthrifty in appearance, with alopecia, emaciation, skin tumors, and sores on their bodies; however, it is not indicated if these findings occurred with comparable incidence in controls and treated rats. 870.5100 De Flora et al (1981) Negative with and without metabolic activation in Bacterial Reverse KCN strains TA98, TA100, TA1535, TAI537 and TA1538. Mutation Test De Flora et al (1984) Negative with metabolic activation (not tested without (Salmonella) KCN metabolic activation) in strains TA82 and TA102. Kushi et al (1983) Negative and weakly positive with metabolic HCN activation. Negative and positive without metabolic activation. In strains TA98 and TA100. NTP (1993) Negative with and without metabolic activation in NaCN strains TA97, TA98, TA100 and TA1535. Kubo et al. (2002) Negative with and without metabolic activation in KCN strains TA98 and TA100. 870.5500 De Flora 1984 Negative with and without metabolic activation in Bacterial DNA KCN strains WP67, CM871 and WP2. Damage or Repair Tests (E. coli) 870.5550 Painter and Howard (1982) Negative with and without metabolic activation. Unscheduled KCN DNA Synthesis (HeLa cells) DNA Breakage Storer et al (1996) Negative with metabolic activation. Positive but (rat hepatocytes) KCN associated with cytotoxicity without metabolic activation.

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Table A.2.2. Subchronic, Chronic, and Other Toxicity Profile – Sodium Cyanide (NaCN) a Guideline No./ Reference (year) b / Results Study Type Classification/Doses expressed in HCN equivalents c DNA Breakage Bhattachrva et al (1997) Negative with metabolic activation. Positive but (rat thvmocytes KCN associated with cytotoxicity without metabolic and BHK-21 activation. hamster cells) DNA Breakage Vock et al (1998) Negative with metabolic activation. Positive but (A549 human KCN associated with cytotoxicity without metabolic lung carcinoma activation. cells) DNA Breakage Henderson et al (1998) Negative with metabolic activation. Positive but (TK6 human KCN associated with cytotoxicity without metabolic lymphoblastoma activation. cells) DNA Breakage Yamamoto (2002) Negative with metabolic activation. Positive without (mice brain KCN metabolic activation. mitochondrial fraction) Small clinical and Moertel et al (1981) IV dose was largely excreted unchanged in urine and ADME study in MRID 46769601 produced no clinical or laboratory evidence of toxic advance cancer reaction. Oral dose produced significant blood cyanide 4.5 g amygdalin/day intravenous patients – unknow levels to 2.1 microgram/mL but no clinical or (IV) or 0.5 g amygdalin 3 times per duration laboratory evidence of toxicity. One patient, day oral challenged with a large intake of raw almonds (a rich source of β-glucosidase), had transient symptoms of cyanide toxicity with escalating blood cyanide levels. Clinical trial in Moertel et al (1982) Oral NOAEL was not observed cancer patients – MRID 46769602 Oral LOAEL = 0.4 mg HCN/kg/day based on clinical 21 days Standard dose: 4.5 g amygdalin/m2 signs (nausea 30-31%, vomiting 17-25%, headaches body surface area/day IV; followed 7-8%, dizziness 7-10%; mental obtundation 4-5% and by 0.5 g amygdalin oral 3 dermatitis 2%) associated with elevated blood cyanide times/day. levels (2-3 µg/ml) observed after single oral dose. High dose: 7 g amygdalin/m2 body surface area/day IV; followed by 0.5 g amygdalin oral 4 times/day. Oral dose is equivalent to 0.4 mg HCN/kg/day Demonstration of Lehman (1956) This study was cited in the previous risk assessment. thiocyanate in Unacceptable However, it is unacceptable for risk assessment human saliva purposes. NaCN administered to an unknown number 20 to 30 mg NaCN without apparent of individuals. HED was unable to obtain additional effect Equivalent to 0.2, 11.0 or 16.5 mg details of the study, and therefore, neither the HCN/kg scientific validity nor the ethics of the study can be evaluated.

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A.3 Literature Search for Sodium Cyanide

Date and Time of Search: 05/04/2017; 13:15 pm Search Details: ((Sodium cyanide)) AND (rat OR mouse OR dog OR rabbit OR monkey OR mammal) PubMed hits: 2130 Number of Swift Articles: 1838 for Animal Number of Swift Articles: 738 for Human Number of Swift Articles: 0 for No Tag

All studies identified in the PubMed search were screened when the citation list was <100. Screening of larger citations lists (>100 citations) was conducted after prioritization in SWIFT- Review and focused on studies identified with the “Animal” and/or “Human” tag.

Number of Articles Identified as Relevant for Risk Assessment: 1 Citations of Articles Identified as Relevant for Risk Assessment:

Zhang B., Pan F and Yao YF. " Spontaneous resolution of extensive descemet membrane detachment caused by sodium cyanide injury to the eye." Cornea Series 31. 11 (2012): 1344- 1347.

Conclusion of Literature Search: Following a full text review, no studies were identified that contained relevant information (either quantitative or qualitative) that would impact the risk assessment or that would be considered in the selection of Points of Departure (PODs) for the sodium cyanide human health registration review risk assessment.

*PubMed is a freely available search engine that provides access to life science and biomedical references predominantly using the MEDLINE database. **SWIFT-Review is a freely available software tool created by Sciome LLC that assists with literature prioritization. SWIFT-Review was used to prioritize citations lists that were larger than 100. Studies identified in the PubMed search were tagged and grouped based on the model of interest in the study (e.g. human, animal, in vitro, etc.).

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Appendix B. International Residue Limits

Hydrogen Cyanide Summary of US and International Tolerances and Maximum Residue Limits Residue Definition: US Canada Codex3 40 CFR 180.130: Tolerances are established for residues of sodium cyanide, including its metabolites and degradates, in or on the commodities in the table below. Compliance with the tolerance levels specified below is to be determined by measuring only hydrogen cyanide. Tolerance (ppm) /Maximum Residue Limit (mg/kg) Commodity1 US Canada Codex Fruit, citrus, group 10-10 50 -- --

Completed: T. Morton; 07/12/18

1 Includes only commodities of interest for this action. Tolerance values should be the HED recommendations and not those proposed by the applicant.

2 Mexico adopts US tolerances and/or Codex MRLs for its export purposes.

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