Docket Number EPA-HQ-OPP-2015-0770 www.regulations.go v



## Difethialone Preliminary Work Plan

Registration Review: Initial Docket Case Number 7603

March 2016

Approved by: Di rector P esticide Re

- evalua ti on D ivision

Date:

### Difethialone Preliminary Work Plan -Table of Contents

OVERVIEW

................................................................................................................................... 4 ANTICIPATED DATA NEEDS

................................................ . .................... . .. .. .... .. . .... . .. . .... .. . .. . . 5 STATUTORY AND REGULATORY AUTHO RITY

.. . ... .. .. .. ...... . ... . ... . ... . .... .. ....... .. . .. . .. . .. . ........... 6 CHEM I CAL FACTS

........... . .. .. ..... .. .. ... ... . .. .. .. .. ... . ....... .. .. .. ... . .... . .. .. . .. ................ . ............................ 6 USE AND USAGE INFORMATION

... .. .. .. .. ... .. . ... .. .. ... . .. .. .. ... . .. .. .. .. .. ............................................ 7 RECENT ACTIONS

....................................................................................................................... 8 ANTICI PA T ED RISK ASSESSMENTS FOR REGI STRATION REVIEW

................................ 8 TIMELIN E

..................................... .. .. .. .. .. .. .. .......... ... ...... .. .. .. ...... . ... . ............................................. 11 NEXT STEPS

............... . ... . .. . .. .. .. .. .. . .. .. .. ... . ... ...... ... ........... . ....... . .. .. . ... ..... .. . .. . .. .. . ........ . .. . .......... . .... 12 Appendix

- Additional Areas Considered in the Difethialone Registration Review

............... 13

References: This Preliminary Work Plan summarizes the Environmental Protection Agency's current position based on the following documents: 1. Problem Formulation for Registration Review of Difethialone. Jose Melend ez and Brian Montague. March 9 , 2016. 2. Difethialone. Human Health Scoping Document in Support of Registration Review

. Margarita Collantes and Jaime D 'Agostino. March 15 , 2016

. 3. Rodenticide: Tier I (Scoping) Review of Human Incidents and Epidemiology Assessment. Shanna Recore. November 24, 2015. 4. BE AD Chemical Profilefor Registration Review of the Second Generation Anticoagulant Rodenlicides. Colwell Cook and Elizabeth Hill. February 23 , 2016. 5. Label Data Report. April 7 , 2015

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26. HED Master Label Report. April 7. 2015 7. EFED Table 1 Report. April 7, 2015 8. Summary of Hazard and Science Pol icy Co unci l (HASPOC) Meetin g on October 1 , 2015: Recommendation s on Data Requirem ents fo r Rodenticides. Uma Habib a. December 15 , 2015. These and other supporting documents for the difethialone Registration Review case may be found in the docket EPA- HQ-OPP-2015-0770 at http: //www.regulations.gov

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### OVERVIEW The docket for difethialone (EPA-HQ-OPP-2015

-0770) is now open, initiating the first public comment period for this Registration Review. Difethialone is a second generation anticoagulant rodenticide (SGAR) which inhibits coagulation, resulting in bleeding and eventual death in target pests, such as rats and mice

. There are no registered food or agricultural uses , and difethialone products are intended for occupational/professional use only. This Preliminary Work Plan (PWP) document explains what EPA's Office of Pesticide Programs knows about difethialone , highlighting anticipated data and assessment needs , identifying the types of information that would be especially useful to the Agency in conducting the review , and providing an anticipated timeline for completing the Registration Review for difethialone

. The Registration Review process was designed to include a public participation component to solicit input from interested stakeholders. The Agency intends , by sharing this information in the docket , to inform the public of what it knows about difethialone, and what types of new data or other information would be helpful for the Agency to receive as it moves toward a decision on difethialone. The Agency encourages all interested stakeholders to review the PWP and Appendix, and to provide comments and additional infonnation that will help the Agency's decision-making process for this chemical. 

### In addition to general areas on which persons may wish to comment, there are some areas identified in the PWP and Appendix about which the Agency specifically seeks comments and info1mation

. Interested stakeholders could include: environmental non-profit or interest groups; pesticide manufacturers; agricultural labor or commodity groups; commercial, inst i tutional, residential , and other users of pesticides ; or the public at large. The PWP begins b y listing the anticipated data needs for difethialone

. Next, it discusses the statutory and regulatory authority for Registration Review. Then the document provides chemical facts, use and usage information, recent actions, the anticipated risk assessments, and a projected Registration Review timeline for difethialone. Fina lly , the Appendix to this document includes identification and discuss ion of some areas that are considered generally in Registration Review along with some additional chemical case-specific information.

4A NTI C IPA T E D DATA NEE D S Table I be low summarizes antic i pated data need s for difethialone. For additional discussion of the anticipated data need s, see : Problem Formulation/or Registration Rev iew of Difethialone, and Difethialone. Human Health Scoping Document in Support of Registration Review. Table 1 : Anticipated Data Needs for th e Difethialone Regi stration Review Estimated Guideline Timeframe Number 1 St udy Title Test Material (Months from receipt ofDCI) 850.2100 Avian acute oral tox icity (passerine spec ies) 2 TGAI 24 850.2300 A vi an reproduction ( up land game s pec ies) TOAi 1 2 850.2300 A vian reproduction (waterfo wl species) TOAi 12 870.3200 21128-day dermal toxicity TOAI 24 870.3465 90-day inhalation study 3 TOA l 24 T GAI = technical grade active ingredient

1 On June 27 , 2012 , EPA announced certain revision s in harmonized g uidel ine ser i es 850

- Ecological Effects Tests

- including renumberin g and other designation s or changes for some guideline s tudie s. See " Final Test Guidelines; OCSPP 850 Series; Notice of Availabili ty" 77 FR 38282, June 27 , 20 12. http: //www.regulations.gov/# ! documentDetail; D= EPA-HO-O PPT-2009-0154-00 28 2 The observation period s hould be extended beyond that ofa s tandard 850.2100 s tudy (14 days) give n that effects from difethialone poi so nin g are not immediate (i.e., it shou ld be lon g enough to capture effec ts of difethialone poisoning and continue until evidence oftoxiciry has s ub sided) 3 Due to the expected short-term nature of occupational and commercial exposure , a s hort-term inhalation study (2 1 / 28 -day inhalation st udy) wou l d be acceptab l e. 

### 5STATUTORY AND REGULAT ORY AUTHORITY The Food Quality Protection Act (FQPA) of 1996 mandated a Registration Review program. All pesticides distributed or sold in the United States (U .S.) generally must be registered by the Environmental Protection Agency (EPA or the Agency) , based on scientific data showing that they will not cause unreasonable risks to human health or the environment when used as directed on product labeling. The Registration Review program is intended to make sure that, as the abilit y to assess risk evolves and as policies and practices change , all registered pesticides continue to meet the statutory standard of no unreasonable adverse effects to human health or the environment. Changes in science, public policy , and pesticide use practices will occur over time. Through the Registration Review program, the Agency periodically reevaluates pesticides to make sure that as change occurs , products in the marketplace can be used safely. Information on this program is provided on EPA's website. 4 The Agency is implementing the Registration Review program pursuant to Section 3(g) of the Federal Insecticide , Fungicide, and Rodenticide Act (FIFRA), and will review each registered pesticide every 15 years to determine whether it continues to meet the FIFRA standard for registration. The regulations governing Registration Review begin at 40 CFR 155.40. The Agency will consider benefits information and data as required by FIFRA. The public phase of Registration Review begins when the initial docket is opened for each case. The docket is the Agency ' s opportunity to state what it knows about the pesticide and what additional risk analyses and data or information it believes are needed to make a Registration Review decision. After reviewing and responding to comments and data received in the docket during this initial comment period, the Agency will develop a Final Work Plan (FWP) and anticipated schedule for the Registration Review of difethialone. CHEMICAL FACTS Table 2 provides a summary ofthe chemical facts for difethialone

. Table 2: Chemical Facts for Difethialone PC code 128967 Case Number 7603 CAS Number 104653-34-1 Year first registered 1995 Pesticide Type Rodenticide Chemical class SGAR Reregistration Eligibility Because it was registered after November 1984, difethialone was Decision (RED) not subject to reregistration. However it was included in the Risk Mitigation Decision for Ten Rodenticide s (May 2008). Tolerance Reassessment Not applicable Eligibility Decision (TRED) Cumulative group Not applicable

4 http: //www2.epa.gov / pesticide-reevaluat i on 

### 6Table 2: Ch emic a l F acts for Dif ethialon e 40 CFR C itation There are no established tolerances for difeth ialone. Dual-use Difethialone is registered for conventional pesticidal uses only and has no registered antimicrob ial or biopesticidal uses. Non-pestic ida l uses There are no identified non-pesticidal uses of difethialone. Pesticide Re-evaluation Nicole Zinn , zinn.nicole @ epa.gov , (703 ) 308- 7076 Division , Chemical Review Manager Registration Division, Marianne Lewis , lewi s .marianne @ epa.gov , 703-308-8043 Product Manager 

### U SE AND USAGE I NFORMATION Tab le 3 summarizes the use and usage information for difethialone. Please see the 

### BEAD Chemical Profile for Registration Review of the Second Generation Anticoagulant Rodenticides in the Registration Review docket for more details.
T a ble 3: Difethialone Us e a nd Us a ge Information Summary of Use Difethialone is a SGAR, developed as a result ofrodents developing resistance to warfarin and other first-generation anticoagulants. It is registered for the control of commensal rodents and work s by interfe ring with the b lood clotting mechanism. The primary use site for difethialone is in and near human habitats. Products must be in locations out of reach of children, pets , domestic animals , and non-target wildlife or in tamper-resistant bait station s . Bait stations are mandatory in outdoor above-ground use. Use Sites Difethialone is registered for use in and around agricu ltu ral /ind u strial/commercial /resident ial buildings, trans port vehicles (ships , trains , and aircraft) , food processi ng h and li ng and storage areas , around refuse/solid waste containers , and in sewers. Difethialone products require ba it stations for all outdoor and above-ground placements and for indoor placements where children , wild life or dome s tic animals may be exposed , and restrict application to within 50 to 100 feet of man-made structures. Burrow baiting is proh ibited. Summary of Usage Specific data on difethialone usage are not available

. Formu lation Type(s) Difethialone is formulated as pellets , read y-to-use (RTU) place packs , blocks , mini-b locks , meal , and paste. Application Method(s ) Consumer-use products containing difethialone are prohibited. Professional/ commercial uses of SGARs require bait stations for all outdoor and above-ground placements and for indoor placements where children , wildlife or domestic animals may be exposed. Furthermore , labels prohibit broadcast app lication. Technical Registrant(s) Liphatech Inc.
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### T able 3: Difethialone Use and Us ag e Information No. ofRegistrations 

## I 14 Section 3 products 5 and 1 Section 24c products Restricted Use 

## I No 

### G uidance for Co mm en ter s: Additional areas of use and usage related information requested for this Registration Review, and of particular interest to EPA, are described below.

• Information about preferences of applicators and what drives the selection of one SGAR over another, along with more details on when and why these SGARs are used would be helpful for future assessments. • Use distribution (e.g. , acreage and geographical distribution ofrelevant use s ites)

. • Median and 90 1 h percentile reported use rates (pounds active ingredient per acre) from usage data

- national, state, and county. • Typical application timing (date of first application and application intervals)

- national , state , and county. • Usag e /use information. • State or local use re s trictions. • Foreign technical registrants not listed above who supply technical difethialone to the U.S. market. 

### RECENT ACTIO NS In May 2008, the Agency issued the Risk Mitigation Decision for Ten Rodenticides , which included difethialone. Thi s final risk mitigation decision included components to minimize children ' s exposure to rodenticide products used in homes, and to reduce wildlife exposures and eco logical risks. More information on the 2008 decision case may be found in the docket EPAHQ-OPP- 2006-0955 at http: //www.regulations.gov . 

### ANTI CIPATED RI S K ASSESSMENT S F OR REGI STRATIO N RE VI EW The most recent human health assessment for difethialone was completed in 2008 for a proposed use on commensal rodents. In this 2008 assessment, occupational exposures were not quantified because the new product's formulation and use pattern were the same as a currently registered product. The most recent ecological and environmental fate risk assessment conducted for difethialone is the endangered species assessment for the risks of difethialone to the federally threatened Alameda whipsnake , and the federally endangered salt marsh harvest mouse and San Joaquin kit fox , which was issued in March 2012. Findings and conclusions from these risk assessments are summarized in the Difethialon e: Preliminary Problem Formulation/or Environmental Fate, Ecological Risk , Endangered Species, and Drinking Water Exposure Assessments in Suppo rt o/Registration Review, and Difethialone. Human Health Scoping Document in Support of Registration Review.

5 Section 3 product label s can be obtained from the Pesticide Product Labe l System (PPLS) website

(http: //oaspub.epa.gov/pestlabl /ppl s.home). 8During Registration Review, the Agency anticipates the need to conduct a comprehensive ecological risk assessment, including an endangered species assessment, for all registered uses of difethialone. For human health, EPA anticipates the need to conduct an occupational handler risk assessment during Reg istration Re v iew. 

### Iftoxicological endpoints or points of departure are re v ised based on the data that are anticipated to be required for Registration Review , they will be con sidered in the new assessments, as well as any changes to the s tandard operating procedures or default ex posure assumptions. Table 4 s ummarizes the anticipated Registration Review risk assessments based on Problem Formulation for Registration Review of Difethialon e, and Difethialone

. Human Health Scoping Do cument in Support of Registration Re view.

9Table 4: Anticipated Risk Assessments for the Difethialone Registration Review Type of Risk Assessment Conduct? Notes Ecoloe:ical and Environmental Fate Comprehensive ecological , 

### y The potential for aquatic exposure is assumed to be including endangered species negligible based on the use pattern ; therefore , EPA doe s not anticipate conducting an aquatic risk assessment. Exposures of honey bees to difethialone res idues are not expected since they are unlikely to feed on bait blocks and residues are not expected to be present in pollen and nectar. Therefore , EPA is not requesting the full sui t e of poll inator protection studies as outlined in recent guidance 6
, at this time. Incidents Will check for For a discussion of reported ecolog ical incidents for updates difethialone , see page 15 ofthe Problem Formulation. Human Health Dietary Fo od N The registered use patterns fo r difethialone are not expected to result in dietary exposures from surface or ground drinking water, as all end-use products prohibit broadcasting difethialone or applying products directly to food or feed crops . Drinking water N See above Occupational Handlers (mixers , loaders, 

### y Short-term dermal and inhalation occupational applicators) handler exposure assessments are expected during Registration Review based on the potential exposure to handlers during the application of difethialone. Po s t-application N All post-application activities for difethialone include the requirement for personal protecti ve equipment that limits post-application exposure. R esidential Handlers N Con sumer-based products for difethialone are prohibited. Therefore , re s idential exposures are not expected

. Po s t-application N See (residential handlers) above Other Ag gregate N An aggregate risk assessment evaluates the combined ri sk from dietary and residential exposures. However, based on the difethialone use pattern , no dietary (food or drinking water) or residential exposures are expected. C umulati ve N EPA has not made a common mechanism of toxicity finding as to difeth ialone and any other substances.

10Tolerances N All uses ofdifethialone are classified as non-food uses; therefore, no tolerances are established

. Incidents Will check for For a discussion of reported human incidents for updates difethialone, see the Rodenticide: Tier I (Scoping) Review of Human Incident s and Epidemiology Assessment

. G uidance for C ommenters: Additional ecological information requested for this Registration Review, and ofparticular interest to EPA, is described below.

• Information on the amount of product or active ingredient that may be applied per unit area, the number of applications that can be made per unit time, and the minimum interval between applications. • Non-guideline data o n toxicity to terrestrial invertebrates other than the honeybee may be useful for reducing uncertainty in the risk assessment. • Eco logical incidents (avian, reptilian , amphibian and mammalian mortalities) not already reported to the Agency. • Water quality monitoring data (see Appendix for further details). Guidance for C ommenters : Additional human health information requested for this Registration Review, and of particular interest to EPA, is described below

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• For bulk pelleted and meal baits, labels lack sufficient information on the appropriate methods and containers that may be used to measure the label specified amount of bait per refillable station . Information on the specific methods and amounts is requested. • Labels lack directions to specify a maximum number of refillable mouse and/or rat bait stations to be used for perimeter treatments of agricultural or commercial buildings. I nformation on maximum amounts app lied or information on the amount of product that may be handled on a given day by each occupational user is requested. TIME LINE EPA has created the following estimated timeline for the completion of the difethialone Registration Review in Table 5 below.
T able 5 : Projected Difetbialone Regis tration Review Timeline Activities Estimated Date Opening the D ocket Open Docket and 60-day Public Comment Period 20 1 6

- March

- completed Close Public Comment 2016

- May Case D evelopme nt Final Work P lan (FWP) 2016

- September Issue DCI 20 1 6 October

- D ecember Data Submission 2018 October

- December

6 https: //www .epa.gov /pollinator-protection /pollinator-risk-assessment-guidance 11Table 5 : Projected Dif ethialon e Registration Re v iew T im eline A ctivities Estim a te d Date 60-day Public Comment Period for Draft Risk 2020 April

- June Assessments 7 Registration Review Decision 60-day Public Comment Period for Proposed Interim 2021 January - March Registration Review Decision Interim Registration Review Decision and Begin Post- 2021 Decision Follow-up Total (years) 6 NEXT S T EP S After the 60-day publ ic comment period closes, the Agency will review and respond to any comments received in a timely manner and then issue a FWP for the Registration Review of difethialone.

7 The regulations governin g Registration Review generally require the Agency to provide a public comment period

of at least 30 calendar days for draft risk assessments; see 40 CFR Part l 55.53(c). For conventional pesticides , the Agency plans to provide a 60 calendar day public comment period generall y for draft risk assessments. 12

### Appendix - Additional Areas Considered in the Difethialone Registration Review PUBLIC COMMENT S AN D FEEDB AC K : Guid ance for C ommenters: The areas below highlight topics of special interest to the Agency where your comments, data submissions, or reference to sources of additional information could be of particular use. Trade Irritants: Through the Registration Review process , the Agency intends to solicit information on trade irritants and , to the extent feasible , take steps toward facilitating irritant resolution. The Agency will work to harmonize tolerances and international maximum res idue limits (MRLs) and may modify tolerance levels to do so, when possible. Growers and other stakeholders are asked to comment on any trade irritant issues resulting from lack ofMRL s or disparities between U.S. tolerances and MRLs in key export markets, providing as much specificity as possible regarding the nature of the concern. Because difethialone is not registered for food/feed uses in the U.S. , it has no U.S

. tolerances; therefore, the Agency does not anticipate any trade irritant issues for it. Water Quality: Difethialone is not identified as a cause ofimpairment for any water bodies listed as impaired under section 303(d) of the Clean Water Act. 8 In addition , no Total Maximum Daily Loads (TMDL) have been developed for difethialone. 9 More information on impaired water bodies and TMD L s can be found at the Agency ' s website. 10 The Agency invites submission of water quality data for this pesticide. To the extent possible , data should conform to the quality standards in Appendix A of the OPP Standard Operating Procedure: Inclusion of Impaired Water Body and Other Water Quality Data in OPP ' s Registration Review Risk Assessment and Management Process 11 in order to ensure they can be used quantitatively or qualitatively in pesticide risk assessments. Environmental Justice: E PA seeks to achieve environmental justice, the fair treatment and meaningful involvement of all people , regardless of race , color, national origin , or income , in the development, implementation, and enforcement of environmental laws , regulations , and policies. To help address potential environmental justice issues , the Agency seeks information on any groups or segments ofthe population who , as a result of their location, cultural practices , or other factors , may have atypical , unusually high exposure to difethialone compared to the general po pulation. Please

8 http: //iaspub.epa.gov/tmdl waters IO/attains nation cy .cause detail 303d?p cause group id= 885 9http :// iaspub.epa.gov/ tmdl waters IO/ attains nation.tmdl pollutant detail?p pollutant group id= 885&p pollutant group name =PESTICIDES 1 0 http: //www.epa.gov/ owow/tmdl/ 11 http: //www2.epa.gov/pesticide-reevaluation / opp- guidance-submission-state-and-tribal-water-quality-monitoringdata 13comment 

### ifyou are aware of any sub-populations that may have atypical, unusually high exposure compared to the general population. END ANGE RED S PEC IES: A risk assessment that supports a comp lete endangered species determination has not been conducted for difethialone. The ecological risk assessment planned during Registration Review will allow the Agency to determine whether use of difethialone has " no effect " or "may affect" federally listed threatened or endangered species (listed species) or their designated critical habitats. When an assessment concludes that a pesticide ' s use "may affect" a listed spec ies or its designated critical habitat, the Agency will consult with the U.S. Fish and Wildlife Service (FWS) and /or National Marine Fisheries Service (NMFS) (together, the Services), as appropriate. A previous endangered species assessment was conducted for difethialone in 2012, for the risks of difethialone to the federally threatened Alameda whipsnake , and the federally endangered salt marsh harvest mouse and San Joaquin kit fox. The assessment resulted in a determination that the use of difethialone " may affect" and is " likely to adversely affect" the subject species

. As a result, the Agency requested initiation of formal consultation with the FWS. ENDO C RINE DIS R UPTOR S CREENI NG PROGRAM : As required by FIFRA and FFDCA, EPA reviews numerous studies to assess potential adverse outcomes from exposure to chemicals. Collectively , these studies include acute, subchronic and chronic toxicity , including assessments of carcinogenicity , neurotoxicity, developmental, reproductive , and general or systemic toxic ity
. These studies include endpoints which may be susceptible to endocrine influence , including effects on endocrine target organ hi stopathology , organ weights , estrus cyclicity , sexual maturation , fertility , pregnancy rates, reproductive loss , and sex ratio s in offspring. For ecological hazard assessments, E PA evaluates acute tests and chronic studies that assess growth , developmental and reproductive effects in different taxonomic groups. As part of its reregistration decision for difethialone , EPA reviewed these data and selected the most sensitive endpoints for relevant risk assessment scenarios from the existing hazard database. However, as required by FFDCA section 408(p) , difethialone is subject to the endocrine screening part of the Endocrine Disruptor Screening Program (EDSP). EPA has developed the EDSP to determine whether certain substances (including pesticide active and other ingredients) may have an effect in humans or wildlife similar to an effect produced by a "naturally occurring estrogen , or other such endocrine effects as the Administrator may designate. " The EDSP employs a two-tiered approach to making the statutorily required determinations. Tier 1 consists of a battery of 11 screening assays to identify the potential of a chemical substance to interact with the estrogen , androgen, or thyroid (E, A, or T) hormonal systems. Chemicals that go through Tier 1 screening and are found to have the potential to interact with E, A , or T hormonal systems will proceed to the next stage of the EDSP where EPA will determine which , if any , of the Tier 2 tests are necessary based on the available data. Tier 2 testing is designed to identify any adverse endocrine-related effects caused by the substance , and establish a dose-response relationship between the dose and the E, A, or T effect.

14Under FFDCA section 408(p) , the Agency must screen all pesticide chemicals. Between October 2009 and February 2010, E PA issued test orders/data call-ins for the first group of 67 chemicals, which contains 58 pesticide active ingredients and 9 inert ingredients. A second list of chemicals identified for EDSP screening was published on June 14, 2013 12 and includes some pesticides scheduled for Registration Review and chemicals found in water. Difethialone is not on either list. Neither of these lists should be construed as a list of known or likely endocrine disruptors. Fo r further information on the status ofthe EDSP , the policies and procedures, the lists of chemicals , future lists, the test guidelines and the Tier 1 screening battery , please visit our website.'3 HUMAN STUDIES: Occupational and Residential The risk assessments EPA anticipates conducting during Registration Review will rely in part on data from studies in which adult human subjects were intentionally exposed to a pesticide to determine their dermal and inhalation exposure. Many such studies , involving exposure to many different pesticides , comprise generic pesticide exposure databases such as the Pesticide Handlers Exposure Database (PHED), the Agricultural Reentry Task Force (ARTF) Database , and the Outdoor Residential Exposure Task Force (ORETF) Database. EPA has reviewed all the studies supporting these multi-pesticide generic exposure databases , and has found no clear and convincing evidence that the conduct of any of them was either fundamentally unethical or significantly deficient relative to the ethical standards prevailing at the time the research was conducted. A ll applicable requirements ofEPA' s Rule for the Protection of Human Subjects of Research (40 CFR Part 26) have been satisfied , and there is no regulatory barrier to continued reliance on these studies.

12 See http: //www.regulations.gov /# !documentDetail;D= EPA-HO-OPPT-2009

-0477

- 0074 for the final second list of chemicals. 13 http: //www2.epa

.gov/endocrine-disruption

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