CYCLOATE (RO-NEET) RISK CHARACTERIZATION
CYCLOATE (RO-NEET)RISK CHARACTERIZATION DOCUMENTMedical Toxicology and Worker Health and Safety BranchesDepartment of Pesticide RegulationCalifornia Environmental Protection AgencyNovember 28, 1995
EXECUTIVE SUMMARYIntroductionCycloate, a thiocarbamate, is the active ingredient in Ro-Neet. It is a pre-plant useonly, herbicide, used to control weeds in fields for sugar beets, table beets, and spinach.Loss of cycloate from the soil is primarily via evaporation and bacterial breakdown. Resultsfrom field studies showed a half-life of 10-11 days for cycloate applied to sandy loam soil.Leaching potential to the groundwater is considered low. Cycloate is available as a liquidconcentrate and in granular form. However, only the liquid is registered in California.The current Risk Characterization Document addresses potential human exposuresfrom the California use of cycloate as an active ingredient in herbicides. The potential dietaryrisk to the general public from the possible consumption of foods containing the highest legalresidues of cycloate is also assessed.The Risk Assessment ProcessThe risk assessment process consists of four aspects: hazard identification, doseresponse assessment, exposure evaluation, and risk characterization.Hazard identification entails an evaluation of the toxicological properties of eachpesticide. The dose response assessment then considers the chemicals toxicologicalproperties and estimates the amount which could potentially cause an adverse effect. Thebasic principle of toxicology is that at a high enough dose, virtually all substances will causesome type of toxic manifestation. Although chemicals are often referred to as "dangerous"or "safe", as though these concepts were absolutes, in reality, these terms describe chemicalsthat require low or high doses, respectively, to cause toxic effects. Toxicological activity isdetermined in a battery of experimental studies which define the kinds of toxic effects that canbe caused, and the exposure levels (doses) at which the toxic effect is first seen. State andfederal testing requirements, including California's Birth Defect Prevention Act of 1984 (SB950, Petris), mandate that chemicals be tested at doses high enough to produce toxic effects,even if that testing requires dose levels many times higher than those to which people mightbe exposed.In addition to the intrinsic toxicological activity of the pesticide, the other parameterscritical to determining risk are the level, frequency and duration of exposure. The purpose ofthe exposure evaluation is to determine the potential amount of the pesticide likely to bedelivered though occupational, or dietary routes on an acute or chronic basis. The riskcharacterization then relates the toxic effects observed in the laboratory studies, conductedwith the high doses of pesticides, to potential human exposures to low doses of pesticides inthe diet, or work place. The potential for possible adverse health effects in human populationsis expressed as the margin of safety (MOS), which is the ratio of the dose which produces noeffect in laboratory studies to the theoretical human dose.Toxic Effects in Animal StudiesDamage to the nervous system is the major concern in the risk assessment ofcycloate. Toxic effects were present in both rats and dogs, after even a single treatment, andwhen cycloate was swallowed, inhaled, or came in contact with the skin.Animals given a single dose by mouth had brain damage (nerve cell death). Othertoxic effects identified in animals exposed to cycloate included decreased brain weight, an
undesirable increase in the number or size of cells of the lining of the nose, and irritation ofthe skin. Also detected was damage to nerves, muscle, liver, kidney, and heart. The dosesat which no toxic effects were observed were determined from the animal studies, or wereestimated when animal tests did not use doses low enough to determine no-effect levels.Potential Human ExposureA margin of safety of 100 is generally considered sufficient to be protective of humanhealth when the no-effect level is based on results from animal studies. The potentialexposure for consumers via dietary sources was ten thousand times lower than the dosewhich did not cause toxic effects in animals. Therefore, toxic effects are not expected inpeople from any cycloate in food. For farm workers, there was not always a margin of safetyof 100 for potential single or repeated-daily exposures during pre-plant use of the liquid formof cycloate. As continuous "chronic" worker exposure to cycloate is not expected to occur,margins of safety for potential chronic occupational exposure were not determined.A proposed exposure mitigation involving the use of an effective closed system formixing and loading emulsible cycloate concentrate, label-required Personal ProtectiveEquipment, and an enclosed cab would lower potential exposures considerably, producingMOSs of greater than 100. In lieu of using an enclosed cab, applicators could wear coverallsand a half-face respirator.An earlier review of the toxicity of cycloate was conducted for the United StatesEnvironmental Protection Agency by 2 experts in nervous system toxicity, Drs. Zoltan Annauof Johns Hopkins University and Mohamed Abou-Donia of Duke University. Drs. Annau andAbou-Donia agreed that the nervous system toxicity of cycloate in rat studies indicated thatpossibly serious effects could happen in people exposed to the chemical.Animal studies have also shown that cycloate causes brain damage at dose levelsbelow that of its other effects. The brain areas affected have been reported to be involvedwith learning and memory formation in both animals and humans. Thus, cycloate, unlikesome other nervous system toxins (e.g organophosphate insecticides) does not produceclinical signs of exposure, such as tremors or diarrhea, that would give warning ofcontamination and subsequent brain damage.The severity of the toxicity (i.e. brain cell damage) noted in the animal studies suggeststhat a higher MOS could be considered. However, the conservative estimation factors usedto determine potential no-effect levels from animal studies have already established anadditional safety margin.Tolerance AssessmentBased on the 95th percentile of the theoretical consumption of foods at the highestlegal residues (tolerances), the acute margins of safety were all greater than 22,000. Basedupon pesticide residue monitoring programs, the long-term consumption of foods containingresidues at tolerance levels was considered highly improbable. Therefore, an assessmentof the margins of safety from potential chronic exposure to foods with tolerance levels ofcycloate was not undertaken.ConclusionsThe risk from potential exposure to liquid cycloate, as present in herbicides, wasevaluated for farm workers, and for potential exposure in food to farm workers and the generalpublic. The potential risks to the general public from foods with the highest legal levels ofcycloate was also assessed.
Normally, a margin of safety of 100 is considered sufficient for protection of humanhealth. All margins of safety for potential food exposures to the general population wereabove 100. For farm workers, some margins of safety to protect against toxic effects frompotential repeated-day work exposures were less than 100. A proposed exposure mitigationwould lower potential exposures considerably, producing MOSs of greater than 100.The margins of safety from the possible consumption of foods with the highest legallevels (tolerances) of cycloate were greater than 100.
CONTRIBUTORS AND ACKNOWLEDGMENTSPrincipal Author:Earl F. Meierhenry, DVM, Ph.D., ACVPStaff ToxicologistHealth Assessment SectionMedical Toxicology BranchToxicology Data Reviews:Joyce Gee, Ph.D.Senior ToxicologistMedical Toxicology BranchThomas P. Kellner, Ph.D., DABT,Staff ToxicologistMedical Toxicology BranchDietary Exposure:Carolyn Rech, B.S.Associate Pesticide Review ScientistHealth Assessment SectionMedical Toxicology BranchOccupational Exposure:Michael H. Dong, Ph.D.Staff ToxicologistWorker Health and Safety BranchPeer Review:Keith Pfeifer, Ph.D., DABTSenior ToxicologistMedical Toxicology BranchJay Schreider, Ph.D.Primary State ToxicologistMedical Toxicology BranchDPR acknowledges the review of this document by the Office of Environmental Health HazardAssessment.i
TABLE OF G.4444556III.IV.Chemical IdentificationRegulatory HistoryTechnical and Product FormulationsUsageIllness ReportsPhysical/Chemical PropertiesEnvironmental FateToxicology okinetics/MetabolismAcute ToxicitySubchronic ToxicityChronic Toxicity/OncogenicityGenotoxicityReproductive ToxicityDevelopmental ToxicityNeurotoxicityEpidemiological Surveys/Human StudiesRisk Assessment31A.B.C.313237Hazard IdentificationExposure AssessmentRisk CharacterizationV.Risk Appraisal40VI.Proposed Risk Mitigation46VII.Conclusion47VIII.Tolerance Assessment48IX.References50X.Appendices61A.Human Occupational Exposure AssessmentB.Proposed Mitigation of Cycloate Exposureii
LIST OF TABLESpage1.Summary of Acute Toxicity Observed in Animals Exposed toCycloate Liquid122.Incidence of Nasal Epithelial Hyperplasia/Hypertrophy in RatsExposed to Cycloate via Inhalation for 13 Weeks153.Incidence of Nasal Cavity Lesions in Rats Exposed to Cycloatefor 3 Weeks, or Exposed to Cycloate for 3 Weeks Followed by70 days Recovery194.Incidence of Treatment-Related Axonal Atrophy Observed inNervous Systems of Female Rats Fed Cycloate for Two Years215.Summary of Cycloate Neurotoxicity276.Residues of Cycloate in Spinach and Sugar Beets337.Potential Dietary Exposure to Cycloate358.Absorbed Daily Dosages for Workers Handling Cycloate inCalifornia, as Calculated from Biological Monitoring Data369.Neurotoxicity Margins of Safety for Potential Acute Short-TermOccupational Exposure to Cycloate Liquid3810.Margins of Safety Critical for Seasonal Exposure of Driver/Applicators Handling Cycloate and Their Seasonal Average DailyDosage46iii
I. SUMMARYCycloate, a thiocarbamate, is the active ingredient in Ro-Neet. It is a selectiveherbicide (pre-plant use only) used to control weeds in fields for sugar beets, table beets, andspinach. Dissipation of cycloate from the soil is primarily via volatilization and microbialdegradations. Results from field dissipation studies showed a half-life of 10-11 days forcycloate applied to sandy loam soil. Leaching potential to the groundwater is considered low.Cycloate is absorbed via oral, dermal, and inhalation routes. The absorption rate viathe dermal route for rats is approximately 19.3%, and that via the inhalation route is unknown.N-ethyl-cyclohexylamine is the major urinary metabolite in the rat, mouse, and monkey givencycloate. It is also one of the major degradation products found in the soil treated withcycloate or in plants grown in cycloate treated fields.Neurotoxicity is the major concern in the risk assessment of cycloate. Toxic effectshave been detected in both rats and dogs, after exposure periods as short as one dose, andby all exposure routes tested.Brain damage (neuronal necrosis) was present in rats receiving a single oral dose ofcycloate. An estimated No-Observed-Effect-Level (NOEL) of 20 mg/kg for neuronal necrosiswas calculated based on the default assumption that a NOEL is 1/10th of the LowestObserved-Effect-Level (LOEL). This estimated NOEL was selected for evaluating potentialacute single-day human exposures. Other effects identified in animals exposed to cycloateincluded decreased brain weight, increases in the incidences of epithelial hyperplasia/hypertrophy of the nasal cavity, irritation of the skin, degeneration of nerve, muscle, testicular,heart, and kidney tissues; and adrenal hyperplasia/hypertrophy. For evaluation of thepotential repeated-daily exposures during pre-plant application of cycloate, potential braindamage following dermal and inhalation exposure was examined using a Combined MOS(Hazard Index) approach. A NOEL of 0.02 mg/kg/day was estimated for subchronic inhalationexposure based on the default assumption that a NOEL is 1/10th of the Lowest-ObservedEffect-Level (LOEL) for neurotoxicity (decreased brain weight) in a 15 exposure-day rat noseonly inhalation toxicity study. Potential subchronic dermal neurotoxicity (decreased brainweight) was assessed based on an estimated NOEL of 0.193 mg/kg/day in a 21 exposure-dayrat dermal toxicity study. For the effects on the nasal epithelium, a NOEL of 0.01 mg/kg/daywas calculated for the subchronic exposure also based on the default assumption that aNOEL is 1/10th of the Lowest-Observed-Effect-Level (LOEL). For potential chronic dietaryrisks to humans, a NOEL of 0.5 mg/kg/day was selected, and was based on nerve, liver,kidney, adrenal, and heart effects present in chronic dog and rat toxicity studies.Potential Human ExposureAn earlier review of the toxicity of cycloate was conducted for the US EPA by 2recognized experts in neurotoxicity, Drs. Zoltan Annau of Johns Hopkins University, andMohamed Abou-Donia of Duke University. Drs. Annau and Abou-Donia agreed that theneurotoxicity of cycloate observed in rat studies was indicative of possibly serious effects onhumans exposed to the compound.Animal studies have also shown that cycloate causes brain damage at dose levelsbelow that of its other effects. The brain areas affected have been reported to be involvedwith learning and memory formation in both animals and humans. Thus, cycloate, unlike1
some other nervous system toxins (e.g organophosphate insecticides) does not produceclinical signs of exposure, such as tremors or diarrhea, that would give warning ofcontamination and subsequent neural effects.A margin of safety (MOS) was calculated to assess the potential exposure to cycloatefor consumers via dietary sources or for workers via occupational exposure. A MOS is theratio of a NOEL identified in an appropriate study to the estimated potential exposure dosagefor humans. An MOS of at least 100 is generally considered sufficient to be protective ofhuman health when the NOEL is based on results from animal studies with a comparableduration of exposure for humans. The severity of the toxicity (i.e. brain cell damage) notedin the animal studies suggests that a higher MOS could be considered. However, theconservative estimation factors used to determine potential no-effect levels from animalstudies have already established an additional safety margin.The potential exposure for consumers via dietary sources all had MOSs of greater than49,000. For agricultural workers, the calculated single-day acute occupational brain damageMOSs were all greater than 230. The margins of safety for brain damage calculated forpotential repeated-daily exposure during the planting season ranged from 1-275. Thearithmetic mean of the MOSs was 8, while the geometric mean was 21. The margins ofsafety for damage to the nasal epithelium ranged from 1-234. The arithmetic mean of theMOSs was 8, while the geometric mean was 25.(geometric means presented forcomparison purposes only). As continuous "chronic" worker exposure to cycloate is notexpected to occur, margins of safety for potential chronic occupational exposure were notdetermined.Additional dietary exposure for workers was insignificant compared to the potentialoccupational exposure, and would not significantly affect the MOS estimates.Proposed MitigationA proposed mitigation involving an effective closed system for mixing and loadingcycloate emulsifiable concentrate, label-required Personal Protective Equipment (PPE), anduse of an enclosed cab would lower exposures considerably producing MOSs of greater than100. In lieu of using an enclosed cab, applicators could wear coveralls and a half-facerespiratorTolerance AssessmentBased on the 95th percentile of the potential consumption of foods with an establishedlegal residues for cycloate, the acute margins of safety at the highest legal residue levels(tolerances) were all greater than 22,000. Based upon pesticide residue monitoring programs,the long-term consumption of foods containing residues at tolerance levels was consideredhighly improbable. Therefore, an assessment of the margins of safety from theoretical chronicexposure to foods with tolerance levels of cycloate was not undertaken.ConclusionsThe toxicological risk from potential exposure to technical cycloate, as present in liquidherbicide formulations, was evaluated for job-related and dietary exposure for agriculturalworkers, and for the general population from anticipated dietary exposure. The potential risksfrom consumption of foods containing the highest legal residues (tolerance) of cycloate werealso assessed.2
The margins of safety for potential dietary exposures to the general population wereall greater than 100. For potential occupational exposures, the neurotoxicity margins of safetyvaried from 1-275, with arithmetic and geometric means of 8 and 21 respectively. Themargins of safety for damage to the nasal epithelium ranged from 1-234, with arithmetic andgeometric means of 8 and 25 respectively. A proposed exposure mitigation would lowerpotential exposure considerably, producing MOSs of greater than 100.The additional dietary exposure for workers was insignificant compared to theoccupational exposure, and would not affect the MOS estimates. A risk assessment of thecycloate granular formulation was not conducted, as it is not registered for use in California.The margins of safety from the potential consumption of foods with the highest legalresidues (tolerance) of cycloate were greater than 100.3
II. INTRODUCTIONA.CHEMICAL IDENTIFICATIONCycloate (S-ethyl cyclohexylethylthiocarbamate) is a selective herbicide for pre-plantuse only. It is used to control many broadleaf weeds, annual grasses, and nutsedge in fieldsfor sugar beets, table beets, and spinach. Cycloate controls weeds by interfering with normalseed germination and seedling development.It does not control established weeds.Thiocarbamates interfere with cuticle formation by inhibiting the biosynthesis of very longchain fatty acids, and thereby, aldehydes, alcohols, and wax esters (Corbett, et al., 1984).The possible main site of action is the inhibition of the incorporation of acetate into fatty acidduring the chain elongation process. The cholinergic signs (salivation, tremors, etc.) observedin animals given high doses of cycloate are assumed to be attributable to the inhibition ofcholinesterase.B.REGULATORY HISTORYThe United States Environmental Protection Agency (US EPA) has not set a ReferenceDose (Acceptable Daily Intake) for cycloate, stating that neurotoxicity considerationsprecluded establishment of a reference level. Reviews of the toxicity of cycloate byrecognized experts in neurotoxicity yielded concerns about possibly serious effects onhumans exposed to the pesticide. Cycloate was nominated for Special Review process of theUS EPA, based on neurotoxicity observed in laboratory studies of rats and dogs (US EPA,1993c).As part of the ongoing reregistration process for pesticides, the US EPA has publisheda list of outstanding data requirements for products containing cycloate as the activeingredient (EPA, 1991a). Specifically, additional information was requested concerning theeffects of cycloate in the following areas: avian acute dietary and reproductive toxicity,mammalian 21-day dermal toxicity, oncogenicity in mice, teratogenicity in rabbits, generalmetabolism, photodegradation in water, anaerobic soil metabolism, anaerobic aquaticmetabolism, leaching and adsorption/desorption, laboratory volatility, a confined rotationalcrop study, accumulation in fish, nature of residue in plants, nature of residue in livestock,residue analytical method (animals), magnitude of residue in meat/milk/poultry/eggs(feeding/dermal treatment), crop field trials, and the magnit
Nov 28, 1995 · Cycloate, a thiocarbamate, is the active ingredient in Ro-Neet. It is a selective herbicide (pre-plant use only) used to control weeds in fields for sugar beets, table beets, and spinach. Dissipation of cycloate from the soil is
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