United States Prevention, Pesticides EPA 738-R-00-005 Environmental Protection And Toxic Substances June 2000 Agency (7508C) oEPA Report on FQPA Tolerance Reassessment Progress and Interim Risk Management Decision Cadusafos ------- \ uj UNITED ENVIRONMENTAL PROTECTION AGENCY WASHINGTON D.C., OFFICE OF PREVENTION, PESTICIDES AND TOXIC SUBSTANCES MEMORANDUM DATE: July 31,2006 SUBJECT: Finalization of Interim Reregi strati on Eligibility Decisions (IREDs) and Interim Tolerance Reassessment and Risk Management Decisions (TREDs) for the Organophosphate Pesticides, and Completion of the Tolerance Reassessment and Reregi strati on Eligibility Process for the Organophosphate Pesticides FROM: Debra Edwards, Director Special Review and Reregi strati on Division Office of Pesticide Programs TO: Jim Jones, Director Office of Pesticide Programs As you know, EPA has completed its assessment of the cumulative risks from the Organophosphate (OP) class of pesticides as required by the Food Quality Protection Act of 1996. In addition, the individual OPs have also been subject to review through the individual- chemical review process. The Agency's review of individual OPs has resulted in the issuance of Interim Reregi strati on Eligibility Decisions (IREDs) for 22 OPs, interim Tolerance Reassessment and Risk Management Decisions (TREDs) for 8 OPs, and a Reregi strati on Eligibility Decision (RED) for one OP, malathion.l These 31 OPs are listed in Appendix A. EPA has concluded, after completing its assessment of the cumulative risks associated with exposures to all of the OPs, that: (1) the pesticides covered by the IREDs that were pending the results of the OP cumulative assessment (listed in Attachment A) are indeed eligible for reregistration; and Malathion is included in the OP cumulative assessment. However, the Agency has issued a RED for malathion, rather than an IRED, because the decision was signed on the same day as the completion of the OP cumulative assessment. Page 1 of 3 ------- (2) the pesticide tolerances covered by the IREDs and TREDs that were pending the results of the OP cumulative assessment (listed in Attachment A) meet the safety standard under Section 408(b)(2) of the FFDCA. Thus, with regard to the OPs, EPA has fulfilled its obligations as to FFDCA tolerance reassessment and FIFRA reregi strati on, other than product-specific reregi strati on. The Special Review and Reregi strati on Division will be issuing data call-in notices for confirmatory data on two OPs, methidathion and phorate, for the reasons described in detail in the OP cumulative assessment. The specific studies that will be required are: - 28-day repeated-dose toxicity study with methidathion oxon; and - Drinking water monitoring study for phorate, phorate sulfoxide, and phorate sulfone in both source water (at the intake) and treated water for five community water systems in Palm Beach County, Florida and two near Lake Okechobee, Florida. The cumulative risk assessment and supporting documents are available on the Agency's website at www.epa.gov/pesticides/cumulative and in the docket (EPA-HQ-OPP-2006-0618). Page 2 of 3 ------- Attachment A: Organophosphates included in the OP Cumulative Assessment Chemical Acephate Azinphos-methyl (AZM) Bensulide Cadusafos Chlorethoxyphos Chlorpyrifos Coumaphos DDVP (Dichlorvos) Diazinon Dicrotophos Dimethoate Disulfoton Ethoprop Fenitrothion Malathion Methamidophos Methidathion Methyl Parathion Naled Oxydemeton-methyl Phorate Phosalone Phosmet Phostebupirim Pirimiphos-methyl Profenofos Propetamphos Terbufos Tetrachlorvinphos Tribufos Trichlorfon Decision Document IRED IRED IRED TRED TRED IRED TRED IRED IRED IRED IRED IRED IRED TRED RED IRED IRED IRED IRED IRED IRED TRED IRED TRED IRED IRED IRED IRED TRED IRED TRED Status IRED completed 9/2001 IRED completed 10/2001 IRED completed 9/2000 TRED completed 9/2000 TRED completed 9/2000 IRED completed 9/2001 TRED completed 2/2000 IRED completed 6/2006 IRED completed 7/2002 IRED completed 4/2002 IRED completed 6/2006 IRED completed 3/2002 IRED completed 9/2001 IRED addendum completed 2/2006 TRED completed 10/2000 RED completed 8/2006 IRED completed 4/2002 IRED completed 4/2002 IRED completed 5/2003 IRED completed 1/2002 IRED completed 8/2002 IRED completed 3/2001 TRED completed 1/2001 IRED completed 10/2001 TRED completed 12/2000 IRED completed 6/2001 IRED completed 9/2000 IRED completed 12/2000 IRED completed 9/2001 TRED completed 12/2002 IRED completed 12/2000 TRED completed 9/2001 Page 3 of 3 ------- "^- % UNITED STATES ENVIRONMENTAL PROTECTION AGENCY # WASHINGTON, D.C. 20460 OFFICE OF PREVENTION, PESTICIDES AND TOXIC SUBSTANCES CERTIFIED MAIL Dear Registrant: This is to inform you that the Environmental Protection Agency (hereafter referred to as EPA or the Agency) has completed its review of the available data and public comments received related to the revised risk assessment for the organophosphate pesticide cadusafos. The public comment period on the revised risk assessment phase of the tolerance reassessment process is closed. The attached document summarizes the Agency's assessment of the dietary risk from cadusafos as part of the tolerance reassessment process for this chemical, presents a summary of the related food tolerance for this single chemical, and provides the Agency's current risk management decision based on the risk assessment. Cadusafos has no U.S. registrations and only one import tolerance on bananas, and the dietary risk analysis indicates that the risk is below the Agency's level of concern. Therefore, no mitigation is necessary at this time. A Notice of Availability for this "Report on FQPA Tolerance Reassessment Progress and Interim Risk Management Decision for Cadusafos" is published in the Federal Register. This document and the technical documents supporting it are available for viewing in the Office of Pesticide Programs' Public Docket and can also be found on the Agency's web page, "www.epa.gov/pesticides/op." This document is based on the updated technical information found in the cadusafos public docket. The docket not only includes background information and comments on the Agency's preliminary risk assessments, but also now includes the revised risk assessment for cadusafos, and a document summarizing the Agency's Response to Comments. The Response to Comments document addresses corrections to the preliminary risk assessment submitted by the chemical manufacturer, FMC Corporation, as well as comments submitted by the general public and stakeholders during the comment period on the risk assessment. This document and the process used to develop it are the results of a pilot process to facilitate greater public involvement and participation in the reregistration and /or FQPA tolerance reassessment decisions on pesticides. As part of the Agency's effort to involve the public in the implementation of the Food Quality Protection Act of 1996 (FQPA), the Agency is undertaking a special effort to maintain open public dockets on the organophosphate pesticides and to engage the public in the reregistration ------- and tolerance reassessment processes for these chemicals. The idea of using such an open process was developed by the Tolerance Reassessment Advisory Committee (TRAC), a large multi- stakeholder advisory body which advised the Agency on implementing the new provisions of the FQPA. The reregistration and tolerance reassessment reviews for the organophosphate pesticides are following this new process. Please note that the cadusafos risk assessment concerns only this particular organophosphate. Because the FQPA directs the Agency to consider available information on cumulative risk from substances sharing a common mechanism of toxicity, such as the toxicity expressed by the organophosphates through a common biochemical interaction with cholinesterase, the Agency will evaluate the cumulative risk posed by the entire organophosphate class of chemicals after completing risk assessments for the individual organophosphates. The Agency is working to complete a methodology to assess cumulative risk, and individual assessments of each organophosphate are likely to be necessary elements of any cumulative assessment. The Agency has decided to move forward with individual assessments and to identify mitigation measures, where necessary. The Agency will issue the final tolerance reassessment decision for cadusafos once the cumulative assessment for all of the organophosphates is complete. If you have questions on this document, please contact the Special Review and Reregistration Division representative, Jacqueline McQueen at (703) 308-8164. Sincerely yours, Lois A. Rossi, Director Special Review and Reregistration Division Attachment ------- Report on FQPA Tolerance Reassessment Progress and Interim Risk Management Decision for Cadusafos ------- ------- TABLE OF CONTENTS CADUSAFOS TEAM i GLOSSARY OF TERMS AND ABBREVIATIONS iii EXECUTIVE SUMMARY 1 I. INTRODUCTION 1 II. CHEMICAL OVERVIEW 3 A. Regulatory History 3 B. Chemical Identification 3 C. Use Profile 4 D. Estimated Usage of Pesticide 5 III. SUMMARY OF CADUSAFOS RISK ASSESSMENT 6 IV. FQPA TOLERANCE REASSESSMENT PROGRESS AND INTERIM RISK MANAGEMENT DECISION 9 A. Tolerance Reassessment Progress & Interim Risk Management Decision... 9 B. Summary of Phase 5 Comments 10 C. Regulatory Position 10 1. FQPA Assessment 10 a. "Risk Cup" Determination 10 b. Tolerance Summary 11 2. Endocrine Disrupters Effects 11 D. Regulatory Rationale 12 V. WHAT MANUFACTURERS MUST DO 12 A. Additional Data Requirements 12 B. Risk Mitigation Requirements 12 VI. RELATED DOCUMENTS AND HOW TO ACCESS THEM 13 BIBLIOGRAPHY 15 ------- ------- CADUSAFOS TEAM Office of Pesticide Programs: Health Effects Risk Assessment Richard Griffin JohnPunzi Nicole Paquette Use and Usage Analysis Michael Hennessey Stephen Smearman Registration Support Marylin Mautz Risk Management Angel Chiri Jacqueline McQueen ------- ------- GLOSSARY OF TERMS AND ABBREVIATIONS AE Acid Equivalent a.i. Active Ingredient AGDCI Agricultural Data Call-In ai Active Ingredient aPAD Acute Population Adjusted Dose AR Anticipated Residue ARC Anticipated Residue Contribution BCF Bioconcentration Factor CAS Chemical Abstracts Service CI Cation CNS Central Nervous System cPAD Chronic Population Adjusted Dose CSF Confidential Statement of Formula CFR Code of Federal Regulations CSFII USD A Continuing Surveys for Food Intake by Individuals DCI Data Call-in DEEM Dietary Exposure Evaluation Model DFR Dislodgeable Foliar Residue ORES Dietary Risk Evaluation System DWEL Drinking Water Equivalent Level (DWEL) The DWEL represents a medium specific (i.e., drinking water) lifetime exposure at which adverse, noncarcinogenic health effects are not anticipated to occur. DWLOC Drinking Water Level of Comparison. EC Emulsifiable Concentrate Formulation EEC Estimated Environmental Concentration. The estimated pesticide concentration in an environment, such as a terrestrial ecosystem. EP End-Use Product EPA U.S. Environmental Protection Agency FAO Food and Agriculture Organization FDA Food and Drug Administration FIFRA Federal Insecticide, Fungicide, and Rodenticide Act FFDCA Federal Food, Drug, and Cosmetic Act FQPA Food Quality Protection Act FOB Functional Observation Battery G Granular Formulation GENEEC Tier I Surface Water Computer Model GLC Gas Liquid Chromatography GLN Guideline Number 111 ------- GLOSSARY OF TERMS AND ABBREVIATIONS GM Geometric Mean GRAS Generally Recognized as Safe as Designated by FDA HA Health Advisory (HA). The HA values are used as informal guidance to municipalities and other organizations when emergency spills or contamination situations occur. HAFT Highest Average Field Trial HOT Highest Dose Tested IR Index Reservoir LC50 Median Lethal Concentration. A statistically derived concentration of a substance that can be expected to cause death in 50% of test animals. It is usually expressed as the weight of substance per weight or volume of water, air or feed, e.g., mg/1, mg/kg or ppm. LD50 Median Lethal Dose. A statistically derived single dose that can be expected to cause death in 50% of the test animals when administered by the route indicated (oral, dermal, inhalation). It is expressed as a weight of substance per unit weight of animal, e.g., mg/kg. LEL Lowest Effect Level LOG Level of Concern LOD Limit of Detection LOAEL Lowest Observed Adverse Effect Level MATC Maximum Acceptable Toxicant Concentration MCLG Maximum Contaminant Level Goal (MCLG) The MCLG is used by the Agency to regulate contaminants in drinking water under the Safe Drinking Water Act. mg/kg/day Milligram Per Kilogram Per Day mg/L Milligrams Per Liter MOE Margin of Exposure MP Manufacturing-Use Product MPI Maximum Permissible Intake MRID Master Record Identification (number). EPA's system of recording and tracking studies submitted. NA Not Applicable N/A Not Applicable NAWQA USGS National Water Quality Assessment NOEC No Observable Effect Concentration NOEL No Observed Effect Level NOAEL No Observed Adverse Effect Level NPDES National Pollutant Discharge Elimination System NR Not Required OP Organophosphate IV ------- GLOSSARY OF TERMS AND ABBREVIATIONS OPP EPA Office of Pesticide Programs OPPTS EPA Office of Prevention, Pesticides and Toxic Substances Pa pascal, the pressure exerted by a force of one newton acting on an area of one square meter. PAD Population Adjusted Dose PADI Provisional Acceptable Daily Intake PAG Pesticide Assessment Guideline PAM Pesticide Analytical Method PCA Percent Crop Area PDF USDA Pesticide Data Program PHED Pesticide Handler's Exposure Data PHI Preharvest Interval ppb Parts Per Billion PPE Personal Protective Equipment ppm Parts Per Million PRN Pesticide Registration Notice PRZM7 EXAMS Tier H Surface Water Computer Model Q !* The Carcinogenic Potential of a Compound, Quantified by the EPA's Cancer Risk Model RAC Raw Agriculture Commodity RBC Red Blood Cell RED Reregistration Eligibility Decision REI Restricted Entry Interval RfD Reference Dose RQ Risk Quotient RS Registration Standard RUP Restricted Use Pesticide SAP Science Advisory Panel SCI-GROW Tier I Ground Water Computer Model SF Safety Factor SLC Single Layer Clothing SLN Special Local Need (Registrations Under Section 24(c) of FIFRA) TC Toxic Concentration. The concentration at which a substance produces a toxic effect. TD Toxic Dose. The dose at which a substance produces a toxic effect. TEP Typical End-Use Product TGAI Technical Grade Active Ingredient TLC Thin Layer Chromatography ------- GLOSSARY OF TERMS AND ABBREVIATIONS TMRC Theoretical Maximum Residue Contribution torr A unit of pressure needed to support a column of mercury 1 mm high under standard conditions. TRR Total Radioactive Residue UF Uncertainty Factor |ig/g Micrograms Per Gram |ig/L Micrograms Per Liter USD A United States Department of Agriculture USGS United States Geological Survey UV Ultraviolet VI ------- EXECUTIVE SUMMARY EPA has completed its review of public comments on the revised risk assessment for cadusafos, and is, in this document, issuing its interim decision on the risk mitigation for this chemical. The revised risk assessment is based on review of the required target data base supporting the single cadusafos import tolerance and information received during the public comment periods in the open process developed through the Tolerance Reassessment Advisory Committee (TRAC). Cadusafos is not registered under FIFRA and may not be sold, distributed, or used in the U.S. One import tolerance for cadusafos in/on bananas was established through a petition submitted by FMC Corporation, the manufacturer of this chemical, in 1986. EPA's revised risk assessment for cadusafos indicates that the dietary risk does not exceed the Agency's level of concern; therefore, no risk mitigation is necessary at this time. The tolerance reassessment decision for cadusafos will be issued once the cumulative assessment for all of the organophosphates is completed. The Agency may need to issue risk management measures for cadusafos at the time the organophosphate cumulative assessment is finalized. I. INTRODUCTION This report on the progress toward tolerance reassessment of cadusafos is the result of the pilot process developed through the TRAC to facilitate greater public involvement in the ongoing FIFRA reregistration and FQPA tolerance reassessment initiatives on pesticides. Cadusafos is subject only to FQPA because it has only an import tolerance and is not registered for use in the U.S. However, some history and background of FIFRA is included here for informational purposes and to provide a discussion of the existing laws requiring action on pesticides. The Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA) was amended in 1988 to accelerate the reregistration of products with active ingredients registered prior to November 1, 1984. The amended act calls for the development and submission of data to support the reregistration of an active ingredient, as well as a review of all submitted data by the U.S. Environmental Protection Agency (referred to as EPA or "the Agency"). Reregistration involves a thorough review of the scientific database underlying a pesticide's registration. The purpose of the Agency's review is to reassess the potential hazards arising from the currently registered uses of the pesticide; to determine the need for additional data on health and environmental effects; and to determine whether the pesticide meets the "no unreasonable adverse effects" criteria of FIFRA. On August 3, 1996, the Food Quality Protection Act of 1996 (FQPA) was signed into law. This Act amends FIFRA to require tolerance reassessment during reregistration. It also requires that by August 2006, EPA review all tolerances in effect on the day before the date of the enactment of the 1 ------- FQPA. FQPA amends both FIFRA and the Federal Food, Drug, and Cosmetic Act (FFDCA), but does not amend any of the existing reregistration deadlines. Therefore, the Agency is continuing its reregistration program while it resolves the remaining issues associated with the implementation of FQPA. The Agency is also continuing its progress toward tolerance reassessment as required by FQPA for all of the organophosphate chemicals, whether or not they are subject to the reregistration process. While the methodology for completion of the cumulative assessment for all of the organophosphates is being developed, individual risk assessments and risk mitigation measures, where appropriate, are being conducted. Although not subject to the reregistration process, the individual dietary assessment for the organophosphate cadusafos has been completed, and will be used in the cumulative assessment of all of the organophosphate chemicals, to satisfy the requirements of FQPA. Cadusafos is not registered for use in the United States; however, there is one import tolerance on bananas for this chemical. Because it is not registered in the U.S., it is not subject to the reregistration process. It is subject to the requirements of FQPA; therefore, a dietary risk assessment was completed. This document presents the Agency's dietary risk assessment for cadusafos, as part of the tolerance reassessment process. Note that there is no comment period for this document. As part of the process developed by the TRAC, which sought to open up the process to interested parties, the Agency's risk assessment for cadusafos has already been subject to numerous public comment periods, and a further comment period was deemed unnecessary. A Notice of Availability for this document is published in the Federal Register. The Phase 6 of the pilot process did not include a public comment period; however, for some chemicals, the Agency may provide for another comment period, depending on the content of the risk management decision. The implementation of FQPA has required the Agency to revisit some of its existing policies relating to the determination and regulation of dietary risk, and has also raised a number of new issues for which policies need to be created. These issues were refined and developed through collaboration between the Agency and the Tolerance Reassessment Advisory Committee (TRAC), which was composed of representatives from industry, environmental groups, and other interested parties. The TRAC identified the following science policy issues it believed were key to the implementation of FQPA and tolerance reassessment: Applying the FQPA 10-Fold Safety Factor Whether and How to Use "Monte Carlo" Analyses in Dietary Exposure Assessments How to Interpret "No Detectable Residues" in Dietary Exposure Assessments Refining Dietary (Food) Exposure Estimates Refining Dietary (Drinking Water) Exposure Estimates Assessing Residential Exposure Aggregating Exposure from all Non-Occupational Sources ------- How to Conduct a Cumulative Risk Assessment for Organophosphate or Other Pesticides with a Common Mechanism of Toxicity Selection of Appropriate Toxicity Endpoints for Risk Assessments of Organophosphates Whether and How to Use Data Derived from Human Studies The process developed by the TRAC calls for EPA to provide one or more documents for public comment on each of the policy issues described above. Each of these issues is evolving and in a different stage of refinement. Some issue papers have already been published for comment in the Federal Register and others will be published shortly. This document consists of six sections. Section I contains the regulatory framework for reregistration/tolerance reassessment as well as a description of the process developed by TRAC for public comment on science policy issues for the organophosphate pesticides. Section n provides a profile of the usage of the chemical. Section m gives an overview of the dietary risk assessment for cadusafos, including a discussion of any revisions that were made to the preliminary assessment. Section IV presents the Agency's progress towards tolerance reassessment, its interim decision and the regulatory position on this chemical. Section V discusses what the manufacturer's obligations are with respect to further actions required, and finally, Section VI provides information on how to access related documents. The entire revised risk assessment is not included in this document, but is available on the Agency's web page (www.epa.gov/pesticides/op), and in the Public Docket. II. CHEMICAL OVERVIEW A. Regulatory History Cadusafos, a nematicide and soil insecticide, is not registered under FIFRA and may not be sold, distributed, or used in the United States. However, a permanent tolerance of 0.01 ppm has been established by the U.S. EPA under 40 CFR §180.461 for residues of cadusafos in/on bananas imported into this country. B. Chemical Identification CADUSAFOS: HX ------- Common Name: Cadusafos ! Chemical Name: ! Chemical Family: ! CAS Registry Number: ! OPP Chemical Code: Empirical Formula: Molecular Weight: O-ethyl S,S-bis (1-methylpropyl) phosphorodithioate Organophosphate 95465-99-9 128864 C10H2302PS2 270.39 Trade and Other Names: Rugby, Apache Basic Manufacturers: FMC Corporation A detailed discussion on the physical properties of cadusafos can be found in the EPA document entitled "Cadusafos: HED Risk Assessment for the Risk Management Proposal," dated December 17, 1998. C. Use Profile The following information is based on the current uses of cadusafos outside of the United States, and includes an overview of use sites and application methods. Type of Pesticide: Summary of Use Sites: Nematicide and soil insecticide. Cadusafos is registered in Ecuador, Costa Rica, Honduras, Guatemala, Columbia and Mexico for use in/on bananas. Cadusafos is not registered under FIFRA and may not be sold, distributed, or used in the U.S. Target Pests: Plant parasitic nematodes and soil insects. ------- Formulation Types: FMC Corporation produces a 10% granular formulation for use in banana-producing countries. Method and Rates of Application: Method and Rate - The established maximum seasonal rate is 6 grams of active ingredient (ai.) per mat per year, applied to the base of the plants. Timing - Cadusafos is applied at the beginning of the banana planting season. It may also be applied a second time, as needed. Use Classification: N/A - Not registered for use in the U. S. D. Estimated Usage of Pesticide This section summarizes the best estimates available for the pesticide uses of cadusafos. These estimates are derived from a variety of published and proprietary sources available to the Agency. The data, reported on an aggregate and site (crop) basis, reflect annual fluctuations in use patterns as well as the variability in using data from various sources. In the current risk assessment, the Agency estimated that cadusafos is used on about 10-15% of the annual banana imports into the U.S. The principal countries exporting bananas treated with cadusafos to the U.S. are Guatemala, Costa Rica, Ecuador, Columbia, Mexico and Honduras. Since the risk assessment was completed, more current information on the percent of imported bananas treated with cadusafos was submitted by the International Banana Association (IBA). This organization worked with banana growers to more accurately estimate the amount of cadusafos-treated bananas imported into the U.S. The estimates provided by the IBA range from a typical or average of 5.1% imported, to a high-end estimate of 7% for the years 1997 to 1998. These estimates are consistent with new information received by EPA from outside economic sources. Although the risk assessment was not updated again to include these figures, they will be considered for use in both the acute and chronic risk assessments at the time the cumulative assessment is conducted for all of the organophosphates. ------- III. SUMMARY OF CADUSAFOS RISK ASSESSMENT Following is a summary of EPA's revised human health risk findings and conclusions for the organophosphate pesticide cadusafos, as fully presented in the revised risk assessment document, "Cadusafos: Dietary Risk Assessment Update for FQPA Requirements," dated December 17, 1998. The risk assessment presented here forms the basis of the Agency's interim risk management decision for cadusafos only; the Agency must complete a cumulative assessment of the risks of all organophosphate pesticides before it can complete its reassessment of the cadusafos tolerance. Because cadusafos is not currently registered for use in the U.S., only a human health dietary assessment from exposure to this chemical through food was necessary. Human Health Risk Assessment During the comment period on the cadusafos preliminary risk assessment, FMC Corporation, the manufacturer, submitted comments noting that the decision to retain the 10X FQPA safety factor was based on the assumption that there were data gaps for all required neurotoxicity studies, although the company had previously submitted an acute delayed neurotoxicity study. FMC Corporation re- submitted this study and requested that the Agency evaluate the data and consider reducing the FQPA Factor. The Agency reviewed the study, and it was found to be acceptable and to show no delayed neurotoxicity and no evidence of neuropathology. Based on this information, the FQPA safety factor was reduced from 10X to 3X; the 3X was retained due to continuing data gaps for acute and subchronic neurotoxicity studies in rats. This was the only major revision to the risk assessment. Dietary Risk from Food Toxicity The Agency has reviewed all toxicity studies submitted and has determined that the toxicity database supports a dietary risk assessment for cadusafos as well as a future FQPA tolerance reassessment for the import tolerance on bananas. Further details on the toxicity of cadusafos can be found in the December 17, 1998 FLED Risk Assessment. A brief overview of the studies used for the dietary risk assessment is outlined in Table 1 of this document. FQPA Safety Factor The FQPA Safety Factor was reduced to 3X. As stated earlier in this document, the safety factor was initially 10X because of data gaps for three neurotoxicity studies: an acute delayed neurotoxicity study in hens, and acute and subchronic studies in rats. The acute delayed neurotoxicity study in hens was received and reviewed by the Agency, found to be acceptable, and to show no neurotoxicity and no delayed neuropathology in the treated animals. It was determined that adequate ------- actual data, surrogate data, and/or modeling outputs were available to satisfactorily assess exposure through food, and that the assumptions and models used in the assessments do not underestimate the potential risk for infants and children. Results of the study allowed for a reduction in the safety factor; however, because data gaps for the acute and subchronic rat neurotoxicity studies remain; an FQPA safety factor of 3X was retained. Population Adjusted Dose (PAD) The PAD is a relatively new term that characterizes the dietary risk of a chemical, and reflects the Reference Dose, either acute or chronic, that has been adjusted to account for the FQPA safety factor (i.e., RfD/FQPA safety factor). For the acute dietary assessment, risk is calculated considering what is eaten in one day (consumption) and maximum, high-end residue values in food. For chronic exposures, dietary risk is calculated by using the average consumption value for food and average residue value. In the case of cadusafos, the FQPA safety factor is 3X; therefore, the acute or chronic RfD / 3 = the acute or chronic PAD. A risk estimate that is less than 100% of the acute or chronic PAD does not exceed the Agency's risk concern. Exposure Assumptions Residues of cadusafos in banana pulp were not detected in field trials conducted in seven sites. Further, no detections have been reported by the Food and Drug Administration, based on analysis of hundreds of samples from approximately a dozen countries. For this assessment, the Limit of Detection (LOD) of 0.001 ppm was used for the acute dietary assessment. For the chronic dietary assessment, l/2 of the LOD, or 0.0005, was used. The value of 0.001 ppm represents a probable upper-end estimate of cadusafos residues in banana pulp. Dietary risk analyses for cadusafos were conducted with the Dietary Exposure Evaluation Model (DEEM). DEEM incorporates consumption data generated in USDA's Continuing Surveys of Food Intakes by Individuals (CSFII), 1989-1992. ------- Table 1. Summary of Toxicological Endpoints and Other Factors Used in the Human Dietary Risk Assessment of Cadusafos. Assessment Acute Dietary Chronic Dietary Study 14-day (range finding) oral toxicity study in dogs (MRID 40017902) One-year feeding study in dogs (MRIDs 40017901/40017 902) Dose NOAEL= 0.02 mg/kg/day NOAEL= 0.001 mg/kg/day Endpoint Plasma ChE inhibition Plasma ChE inhibition UF 100 100 FQPA Safety Factor 3X 3X PAD 0.00007 mg/kg/ day 0.000003 mg/kg/ day Acute Food Risk An acute dietary assessment was conducted for cadusafos. The assessment used a residue estimate of 0.001 ppm, the LOD, and a distribution of consumption values. The acute risk estimates are considered upper-end estimates since the residue level assumed is a point estimate rather than a range, and because 100% of the crop treated is assumed. Based on the above parameters, DEEM estimates that the "Average U.S. Population" and the population subgroups of "All Infants (<1 year)" and "Children (1-6 years)" are exposed to cadusafos (per day) at a level less than the cadusafos acute PAD; that is, less than 100% of the aPAD is utilized. At the 99.9th percentile of exposure, the % acute PAD utilized is 21%, 31%, and 39%, respectively. Because these values are significantly lower than 100%, the acute dietary risk is not of concern to the Agency. The population group "All Infants" is noted since this group is typically estimated to be the most highly exposed group. This analysis satisfies the FQPA requirement for the special consideration of pesticide risk to children. Chronic Food Risk The chronic risk estimates are based on the residue level of 1A LOD (0.0005 ppm), the upper-end of the crop treated estimate (10-15%), and averaged food consumption estimates. The resultant risk estimate is not considered upper-end since the estimate is refined by the percent crop treated data. Based on these parameters, DEEM estimates that the "Average U.S. Population" and all population subgroups including "All Infants (<1 year)" are chronically exposed to cadusafos at a level less than the cadusafos chronic PAD. The percent of the chronic PAD utilized is less than 5% for all population groups; the % cPAD for infants less than 1 year and children 1-6 years were 4% and 2%, ------- respectively. Because these levels are significantly lower than 100%, the chronic dietary risk is not of concern. In summary, the potential acute and chronic dietary exposures to cadusafos-treated bananas are below the level of concern for all U.S. citizens, including infants and children. As discussed in the "Chemical Overview" section of this document, the Agency has recently received updated information on the percent of bananas imported into the United States. This information indicates that 5-7% is imported, not 10-15%, as the Agency's previous information indicated. This updated information will be considered for the acute and chronic risk assessments at the time that the cumulative assessment for all of the organophosphates is conducted. IV. FQPA TOLERANCE REASSESSMENT PROGRESS AND INTERIM RISK MANAGEMENT DECISION A. Tolerance Reassessment Progress & Interim Risk Management Decision The Agency has completed its assessment of the dietary risk of cadusafos but has not considered the cumulative effects of organophosphates as a class. Based on a review of these generic data and public comments on the Agency's revised risk assessment for the active ingredient cadusafos, EPA has sufficient information on the human health effects of cadusafos to make some interim decisions as part of the tolerance reassessment process under FQPA. Although the Agency has not yet completed its cumulative risk assessment for the organophosphates, the Agency has completed its assessment of risk from dietary exposure to cadusafos alone in order to determine whether any risk reduction measures are necessary to allow the continued importation of bananas containing this chemical, pending completion of the cumulative assessment. As a result of its assessment, EPA has determined that dietary risk from exposure to cadusafos does not exceed the Agency's level of concern. Therefore, no mitigation is necessary and no further actions are warranted at this time. The Agency may determine that action is necessary after assessing the cumulative risk of the organophosphate class. At that time, the Agency will also address any other outstanding risk concerns that may arise. Such an incremental approach to the tolerance reassessment process is consistent with the Agency's goal of improving the transparency of the implementation of FQPA. By evaluating each organophosphate in turn and identifying appropriate risk reduction measures, the Agency is addressing the risks from the organophosphates in as timely a manner as possible. Because the Agency has not yet completed the cumulative risk assessment for the organophosphates, this interim decision does not specifically address the reassessment of the existing cadusafos food residue import tolerance as called for by the FQPA. When the Agency has completed the cumulative assessment, the cadusafos tolerance will be reassessed in that light. At that time, the ------- Agency will reassess cadusafos along with the other organophosphate pesticides to complete the FQPA requirements. Nothing in this report will preclude the Agency from making further FQPA determinations and tolerance-related rulemaking that may be required on this pesticide or any other in the future. If the Agency determines, before fmalization of the FQPA assessment for cadusafos, that any of the determinations described in this document are no longer appropriate, the Agency will pursue appropriate action, including but not limited to, reconsideration of any portion of this document. B. Summary of Phase 5 Comments EPA released its revised risk assessment for cadusafos to the public in July, 1999 and provided a 60 day comment period for interested parties to submit information, including risk mitigation suggestions or proposals. No comments were received. C. Regulatory Position 1. FQPA Assessment a. "Risk Cup" Determination As part of the FQPA tolerance reassessment process, EPA assessed the risks associated with this individual organophosphate. FQPA also requires the Agency to consider available information on cumulative risk from substances sharing a common mechanism of toxicity, such as the toxicity expressed by the organophosphates through a common biochemical interaction with cholinesterase enzyme. The Agency will evaluate the cumulative risk posed by the entire class of organophosphates once the methodology is developed and the policy concerning cumulative assessments is resolved. EPA has determined that risk from exposure to cadusafos is within its own "risk cup." In other words, if cadusafos did not share a common mechanism of toxicity with other chemicals, EPA would be able to conclude today that the import tolerance for cadusafos on bananas meets the FQPA safety standards. In reaching this determination, EPA has considered the available information on the special sensitivity of infants and children, as well as chronic and acute food exposure. An aggregate assessment was not conducted for cadusafos, because there are no domestic uses. But, results of the acute and chronic food assessments indicate that exposures are within acceptable levels; that is, risk from exposure to cadusafos "fits" within the individual risk cup. Therefore, the import tolerance remains in effect and unchanged until a full reassessment of the cumulative risk from all organophosphates is completed. 10 ------- b. Tolerance Summary The established tolerance for residues of cadusafos in/on plant commodities is currently expressed in terms of residues of cadusafos per se (O-ethyl S,S-di-sec-butyl phosphorodithioate) [40 CFR § 180.461]. It should be noted, however, that the preferred chemical name for cadusafos is O- ethyl S,S-bis(l-methylpropyl) phosphorodithioate. Sufficient residue field trial data are available to assess the established import tolerance on bananas. These trials were conducted in the Ivory Coast, Costa Rica, the Philippines, Guatemala, and Honduras using the granular formulation according to the maximum use patterns registered to foreign countries which export bananas to the United States. The tolerance for residues of cadusafos in/on imported bananas is 0.01 ppm, as shown in Table 2. Table 2. Tolerance Summary for Cadusafos Commodity Bananas Tolerance Listed Under 40 CFR § 180.461 0.01 ppm Reassessed Tolerance* 0.01 ppm Comment Banana, whole fruit * The term "reassessed" here is not meant to imply that the tolerance has been reassessed as required by FQPA, since this tolerance may be reassessed only upon completion of the cumulative risk assessment of all organophosphates, as required by this law. Rather, it provides a tolerance level for this single chemical, if no cumulative assessment was required, that is supported by all of the submitted residue data. 2. Endocrine Disrupter Effects EPA is required under the FFDCA, as amended by FQPA, to develop a screening program to determine whether certain substances (including all pesticide active and other ingredients) "may have an effect in humans that is similar to an effect produced by a naturally occurring estrogen, or other such endocrine effects as the Administrator may designate." Following the recommendations of its Endocrine Disrupter Screening and Testing Advisory Committee (EDSTAC), EPA determined that there was scientific bases for including, as part of the program, the androgen and thyroid hormone systems, in addition to the estrogen hormone system. EPA also adopted EDSTAC's recommendation that the Program include evaluations of potential effects in wildlife. For pesticide chemicals, EPA will use FIFRA and, to the extent that effects in wildlife may help determine whether a substance may have an effect in humans, FFDCA authority to require the wildlife evaluations. As the science develops and resources allow, screening of additional hormone systems may be added to the Endocrine Disrupter Screening Program (EDSP). When the appropriate screening and/or testing protocols being considered under the Agency's EDSP have been developed, cadusafos may be subjected to additional screening and/or testing to better characterize effects related to endocrine disruption. 11 ------- D. Regulatory Rationale Cadusafos has only one import tolerance, and no U.S. registrations; therefore, only a dietary risk assessment for food was conducted. Based on analyses of both acute and chronic dietary risk, the Agency has determined that the risk estimates are below the Agency's level of concern; therefore, no mitigation measures are necessary at this time. V. WHAT MANUFACTURERS MUST DO A. Additional Data Requirements EPA is requiring acute, subchronic, and developmental neurotoxicity studies for all organophosphates, including those with no domestic registrations (i.e., tolerances are established only to allow treated commodities to be imported into the U.S.). These chemicals are not subject to Data Call-In (DCI) requirements under FIFRA. Although cadusafos has no U.S. registrations and therefore is not subject to a FIFRA DCI, it does have a tolerance for bananas that are imported into the U.S. EPA is currently working to require the submission of acute, subchronic, and developmental neurotoxicity studies under the authority of FFDCA. Results of these studies may further refine the risk assessments. B. Risk Mitigation Requirements As discussed in this document, the acute and chronic food risk from the use of cadusafos on imported bananas is not of concern to the Agency; therefore, no mitigation is necessary at this time. The Agency may need to pursue risk management measures for cadusafos once the cumulative assessment is finalized. 12 ------- VI. RELATED DOCUMENTS AND HOW TO ACCESS THEM This report is supported by documents that are presently maintained in the OPP docket. The OPP docket is located in Room 119, Crystal Mall #2, 1921 Jefferson Davis Highway, Arlington, VA. It is open Monday through Friday, excluding legal holidays from 8:30 am to 4 pm. The docket initially contained preliminary risk assessments and related documents as of September 10, 1998. Sixty days later the first public comment period closed. The EPA then considered comments, revised the risk assessment, and added the formal "Response to Comments" document and the revised risk assessment to the docket on July 7, 1999. All documents, in hard copy form, may be viewed in the OPP docket room or downloaded or viewed via the Internet at the following site: "http://www.epa.gov/pesticides/op." 13 ------- 14 ------- BIBLIOGRAPHY MRID CITATION 00146347 FMC Corp. (19??) Toxicology: For FMC 67825 20G. Unpublished summaries. 18 P- 00146348 Freeman, C. (1983) Acute Dermal Toxicity of FMC 67825 Technical in Rabbits: Study No. A83-916. Unpublished study prepared by FMC Toxicology Laboratories. 64 p. 00146349 Roberts, N.; Phillips, C.; Gopinath, C.; Fish, C. (1984) Acute Delayed Neuroroxicity Study With FMC 67825 Tecnical In The Domestic Hen: FMC Study No. A84-1246. Unpublished study prepared by Huntingdon Research Centre pic. 55 p. 00146350 Freeman, C. (1984) Acute Oral Toxicity Of FMC 67825 206 In Rats: Study No. A84-1233. Unpublished study prepared by FMC Toxicology Laboratory. 48 p. 00146351 Putman, D. (1984) Morphological Transformation Of BALB/3T3 Mouse Embryo Cells In The Presence And Absence Of Exogenous Metabolic Activation: Final Report: Study No. T2199.304. Unpublished study prepared by Microbiological Association, Inc. 19 p. 00147538 Freeman, C. (1983) Acute Oral Toxicity of FMC 67825 Technical in Mice: Study No. A83-915. Unpublished study prepared by FMC Toxicology Laboratory. 62 p. 00147539 Freeman, C. (1984) Acute Oral Toxicity of FMC 67825 Technical in Rats: Study No. A83-1164. Unpublished study prepared by FMC Toxicology Laboratory. 55 p. 00147540 Dudek, R. (1984) Four Hour Acute Aerosol Inhalation Toxicity Study in Rats of FMC 67825 Technical: Study No. A84-1231. Unpublished study prepared by Toxigenics, Inc. 67 p. 00147541 Freeman, C. (1984) Primary Eye Irritation of FMC 67825 Technical in Rabbits: Study No. A83-1154. Unpublished study prepared by FMC Toxicology Laboratory. 34 p. 00147542 Freeman, C. (1984) Primary Skin Irritation of FMC 67825 Technical in Rabbits: Study No. A84-1238. Unpublished study prepared by FMC Toxicology Laboratory. 32 p. 15 ------- BIBLIOGRAPHY MRID CITATION 00147543 Freeman, C. (1984) Skin Sensitization of FMC 67825 Technical in Guinea Pigs: Study No. A84-1271. Unpublished study prepared by FMC Toxicology Laboratory. 37 p. 00147544 Freeman, C. (1984) Acute Dermal Toxicity of FMC 67825 20G in Rabbits: Study No. A84-1235. Unpublished study prepared by FMC Toxicology Laboratory. 50 p. 00147545 Freeman, C. (1984) Primary Eye Irritation of FMC 67825 20G in Rabbits: Study Number A84-1236. Unpublished study prepared by FMC Laboratory. 37 p. 00147546 Freeman, C. (1984) Primary Skin Irritation of FMC 67825 20G in Rabbits: Study No. A84-1234. Unpublished study prepared by FMC Toxicology Laboratory. 3 p. 00147547 Freeman, C. (1984) Skin Sensitization of FMC 67825 20G in Guinea pigs: Study No. A84-1237. Unpublished study prepared by FMC Toxicology Laboratory. 39 p. 00147548 Haworth, S. (1984) Salmonella/Mammalian-microsome Plate Incorporation Mutagenicity Assay (Ames Test): Study No. T2199.501. Unpublished study prepared by Microbiological Associates. 35 p. 00147549 Thilagar, A. (1984) Chromosome Aberrations in Chinese Hamster Ovary (CHO) Cells: Final Report: Study No. T2199.337. Unpublished study prepared by Microbiological Associates. 57 p. 00147550 Thilagar, A. (1984) Unscheduled DNA Synthesis in Rat Primary Hepatocytes: Final Report: Study No. T2199-380. Unpublished study prepared by Microbiological Associates. 26 p. 00255690 See MRIDs 146347, 146348, and 147538 to 147543 00255691 See MRIDs 146349 to 146351, and 147544 to 147550 16 ------- BIBLIOGRAPHY MRID CITATION 00152019 Roberts, N.; Phillips, C; Gopinath, C; et al. (1984) Acute Delayed Neurotoxicity Study with FMC 67825 Technical in the Domestic Hen: Retp. No. FCC 59/84738/1: Study No. A84-1246. Unpublished study prepared by Huntingdon Research Centre, pic. 62 p. 40017901 Nolan, T.; Shellenberger, T.; Billups, L. (1986) One-year Oral Toxicity Study in the Dog with FMC 67825: Revised Final Report: Tegeris Report No. 8432: FMC Study No. A84-1538. Unpublished study prepared by Tegeris Laboratories, Inc. 640 p. 40017902 Mann, R; Seely, I; Shellenberger, T. (1985) 14-Day Range Finding Oral Toxicity Study in the Dog with FMC 67825: Tegeris Report No. 8406: FMC Study No. A84-1203. Unpublished study prepared by Tegeris Laboratories, Inc. 113 p. 41441803 De Prospo, I; Seaman, L.; Van Ness, M.; et al. (1987) Multi-generation Reproduction Study with FMC 67825 Technical in Rats: Lab Project Number: A85-1731. Unpublished study prepared by FMC Corp. and Hazleton Laboratories, Inc. 1459 p. 17 ------- |