3 4. BEAD Chemical Profile (BCP) fo r Registration Review: Warf arin and Warfarin Sodium Salts (086002 and 086003) Amended. Colwell Cook. 10/14/2015.

5. Warfarin (086002) EFED Table 1 Report. 01/14/2015.

6. Warfarin (086002) HED Master Label Report. 01/14/2015.

7. Warfarin LUIS Report – EFED Labe l Date Report 1-14-15. 01/14/2015.

8. Warfarin (086002) General Chemi cal (Issues) Report. 01/14/2015.

These and other supporting documents for the warf arin and warfarin sodium salt registration review case may be found in the docket EPA-HQ-OPP-2015-0481 at http://www.regulations.gov

.4 OVERVIEW

The docket for warfarin and warfarin sodium sa lt is now open, initiating the first public comment period for this registration review (docke t number EPA-HQ-OPP-2015-0481). This registration

review case includes the followi ng active ingredients: warfarin (086002) an d warfarin sodium salt (086003). Warfarin and its so dium salt are anticoagu lant rodenticides. Th ey interfere with vitamin K synthesis, a vital component in the blood clotting pathway, thereby causing hemorrhaging in rodents. Warfar in and warfarin sodium salt were registered in 1950 and 1954, respectively, however there are currently no ac tive registrations for warfarin sodium salt. Warfarin was the first anticoagulant rodenticide to be developed and thus is considered a “firstgeneration” rodenticide. Warfarin is used to control mice, rats, voles and moles in and around homes and buildings, agricultural and animal premises, commercial and industrial sites, transport vehicles and sewage systems.

This Preliminary Work Plan (PWP) document expl ains what EPA's Office of Pesticide Programs knows about warfarin, highlights anticipated data and assessment needs, id entifies the types of information that would be especially useful to the Agency in conducting the review, and provides an anticipated timeline for completing the registration review for warfarin.

The registration review process was designed to include a publi c participation component to solicit input from interested stake holders. The Agency intends, by sharing this information in the docket, to inform the public of what it knows about warfarin and what types of new data or other information would be helpful for the Agency to receive as it moves toward a decision on warfarin. The Agency encourages all interested stakeholders to review the PWP and Appendix, and to provide comments and additional inform ation that will help the Agency’s decisionmaking process for this chemical. In addition to general areas on which persons may wish to comment, there are some areas identified in th e PWP and Appendix about which the Agency is specifically seeking comments and information. Interested stakehol ders could include: environmental non-profit or interest groups; pe sticide manufacturers; agricultural labor or commodity groups; commercial, institutional, reside ntial, and other users of pesticides; or the public at large.

The PWP begins by listing the anticipated data needs for warfarin and warfarin sodium salt. Next, it discusses the statutory and regulatory authority for registration review. Then the document provides chemical facts, use and usage in formation, recent actions, the anticipated risk assessments, and a projected registration review ti meline for warfarin and warfarin sodium salt. Finally, the Appendix to this document includes id entification and discussion of some areas that are considered generally in registration review along with some additional chemical case-specific

information.

A registration Standard for warfarin and its sodium salt was issued in August 1981. The Registration Standard summarized the available da ta supporting the registration of warfarin and its sodium salt and required additional data. Pursua nt to FIFRA section 4(g) (2) (A), the Agency issued the Reregistration Eligibility Document for Warfarin and its Sodium Salt in May 1991. The Agency is now initiating the Regist ration Review of Warf arin and its Sodium Salt. With this initial docket opening for the warfarin registration review, the Agency is also publishing an ecological problem fo rmulation for warfarin entitled, Registration Review –5 Preliminary Problem Formulati on for Ecological Risk, Environm ental Fate, and Drinking Water Assessments for Warfarin and a combined scoping document a nd qualitative human health risk

assessment for warfarin entitled Warfarin and Warfarin Sodium Salt. Human Health Assessment Scoping Document and Draft Human Health Risk Assessment in Support of Registration Review.

ANTICIPATED DATA NEEDS

Table 1 below summarizes anticipa ted data needs for warfarin. For additional discussion of the anticipated data needs, see the Registration Review – Preliminary Problem Formulation for Ecological Risk, Environmental Fate, and Dr inking Water Assessments for Warfarin and Warfarin and Warfarin Sodi um Salt. Human Health A ssessment Scoping Document and Draft

Human Health Risk Assessment in Support of Registration Review available in the public docket EPA-HQ-OPP-2015-0481, accessible at http://www.regulations.gov

.

Table 1: Anticipated Data Needs for the Warfarin Registration Review

Guideline

Number 1 Study Title 1 Test Material Estimated

Timeframe

(Months from receipt of DCI)

Anticipated Data Needs for the Parent Warfarin

850.6100 Environmental chemistry methods and associated independent laboratory validations for soil and

water TGAI 12

850.2100 Avian oral toxicity (with a passerine species) TGAI 12

850.2300 Avian reproduction toxicity (with an upland game bird species and a waterfowl species) TGAI 24

850.3100 Earthworm subchronic toxicity test TGAI 12

1 On June 27, 2012, EPA announced certain revisions in harmonized guideline series 850 – Ecological Effects Tests

– including renumbering and other designations or changes for some guideline studies. See “Final Test Guidelines; OCSPP 850 Series; Notice of Av ailability” 77 FR 38282 , June 27, 2012. http://www.regulations.gov/#!documen tDetail;D=EPA-HQ-OPPT-2009-0154-00286 STATUTORY AND REGULATORY AUTHORITY

The Food Quality Protection Act (FQPA) of 1996 mandated a registration review program. All pesticides distributed or sold in the United Stat es (U.S.) generally must be registered by the Environmental Protection Agency (EPA or the Ag ency), based on scientific data showing that they will not cause unreasonable ri sks to human health or the environment when used as directed on product labeling. The registration review program is intended to ma ke sure that, as the ability to assess risk evolves and as policies and practices change, all registered pesticides continue to meet the statutory standard of no unreasonabl e 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 pr ogram, the Agency periodically re-evaluates 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. 2

The Agency is implementing the registration revi ew program pursuant to Section 3(g) of the Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA), a nd will review each registered pesticide every 15 years to determine whether it continues to meet th e FIFRA standard for registration. The regulations governing regi stration 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 docke t during this initial comment period, the Agency will develop a Final Work Plan (FWP) and anticipated schedule for the registration review of warfarin.

CHEMICAL FACTS

Table 2 provides a summary of the chemical facts for warfarin.

Table 2: Chemical Facts for Warfarin

PC code 086002 (warfarin) 086003 (warfarin sodium salt)

Case Number 0011 CAS Number 81-81-2 (war farin) 129-06-6 (warfarin sodium salt) Year first registered 1950 (warfa rin) 1954 (warfarin sodium salt) Pesticide Type Rodenticide Chemical class Coumarin Anti-Coagulant Reregistration Eligibility Decision (RED) 1991 RED for Warfarin
1998 RED Rodenticide Cluster Cumulative group EPA has not made a common mechanism of toxicity finding as to warfarin and any other substances and warfarin does not appear to produce a toxic metabolite pr oduced by other substances.

40 CFR Citation There are no established tole rances for warfarin or its sodium salt.

2 http://www.epa.gov/oppsrrd1/registration_review/7 Table 2: Chemical Facts for Warfarin

Dual-use Warfarin and its sodium salt are registered for conventional pesticidal uses only and have no registered antimicrobial or biopesticidal uses. Non-pesticidal uses The sodium salt of warfarin is used as an anticoagulant in the

medical treatment of indivi duals with hyper-coagulation problems.

Pesticide Re-evaluation Division, Chemical Review Manager Caitlin Newcamp, newcamp.caitlin@epa.gov, 703-308-8043

Registration Division, Product Manager Marianne Lewis, lewis.marianne@epa.gov, 703-305-0120

USE AND USAGE INFORMATION

Table 3 summarizes the use and usage information for warfarin. Please see the BEAD Chemical Profile for Registration R eview: Warfarin and Warfarin Sodium Salts (086002 and 086003)

Amended available in the public docket EPA-HQ-OPP-2015-0481, accessible at http://www.regulations.gov

.

Table 3: Warfarin Use and Usage Information

Use Sites As a pesticide warfarin is re gistered for use in controlling rodents such as mice, rats, voles and mo les. Warfarin has both indoor and outdoor uses including in a nd surrounding homes, buildings, agricultural and animal premises, commercial/ industrial sites, transport vehicles, general and ornamental lawns and turf. In its capacity to control rodents, and th e potential diseases they vector,

warfarin is identified as a public health pesticide.

Summary of Usage EPA has no avai lable usage data for warfarin. Formulation Type(s) Formulated as granules , pellets/tablets, microencapsulated pellets and solution (gel). Application Method(s) Applied in bait stations , by hand, orasyringe is used to apply the gel formulation into active underground mole burrows Technical Registrant(s) Reckitt Benckiser LLC, Bell Laboratories Inc., Hacco Inc., DuPont Chemoswed, Scimetrics Ltd. No. of Registrations 23 FIFRA Section 3 Registrations

Restricted Use No

Guidance for Commenters: Additional areas of informati on requested for this registration review, and of particular interest to EPA, are described below.8  The following information would improve th e Agency’s ability to assess potential ecological impacts from warfarin and other an ticoagulant rodenticides during registration

review:

o Acute, chronic and secondary toxicity data including data on retention of ingredients in liver, bl ood and other body tissues

o Studies on metabolism and retention times on warfarin in rode nts and non-target species

o Information on the number and species of birds and non-target mammals frequenting baited areas and the likelihood of their finding and consuming bait or poisoned primary consumers in the various use areas

o Methods to determine liver concentrations

o Total body burdens of rodentic ide that would corroborate death or even if such a cause-effect relationship is appropriate ( e.g., “threshold of toxicity”)

o The impacts of sub-lethal effects on reproduction and non-target mortality ( e.g., clotting abnormalities, hemorrhaging, stress factors including environmental

stressors such as adverse weather cond itions food shortages, predation, etc.)

o Information on bioaccumulation of repeated sub-lethal exposures to bait or poisoned rodents

o Any additional reports of incidents

o Additional toxicity data explor ing mode-of-action for warfarin

o Data on effects of long-term, low-do se exposure of warfarin on avian reproduction and survival, and data to asse ss toxicity of warfar in to terrestrial

invertebrates

 Confirmation of the following label information: sites of application; formulations; application methods and equipment; maxi mum application rates; frequency of application, application intervals, and maxi mum number of applica tions per season; and geographic limitations on use.

o Additionally, many of the labe ls for warfarin do not specify the maximum number of applications that can be applied pe r year. Some labels are missing a single maximum application rate.

 Use distribution ( e.g. , acreage and geographical distri bution of relevant use sites).

 Median and 90 th percentile reported use rates (lbs. a i/A) from usage data – national, state, and county.

 Use information by formulation, including typi cal amounts applied by use site, seasonally and annually; distances applied from buildings , amounts used in rural versus urban areas; use by Certified Applicators versus homeow ners and other non-certified applicators

 Typical application timing (date of first applic ation and application in tervals) – national, state, and county.

 Usage/use information for non-agricultural uses.

 Typical application interval (days).

 State or local use restrictions.

 Foreign technical registrants not listed above who supply tech nical warfarin to the U.S.

market.9 RECENT ACTIONS

 2011: An endangered species risk assessmen t was completed for San Francisco Bay Species.

 2013: A Notice of Intent to Cancel was releas ed which included warfarin-based products.

The details of this notice can be found at EPA-HQ-OPP-2013-0049 at www.regulations.gov.

ANTICIPATED RISK ASSESSMENT S FOR REGISTRATION REVIEW

The most recent ecological risk assessment was an endangered species risk assessment for San Francisco Bay Species. Completed in 2011. Findings and conclusions of all previous risk

assessments are summarized in the Warfarin and Warfarin Sodium Salt. Human Health Assessment Scoping Document and Draft Hum an Health Risk Assessment in Support of Registration Review and Registration Review – Preliminary Problem Formulation for Ecological Risk, Environmental Fate, and Drinking Water Assessments for Warfarin. These and other supporting documents for warfarin can be found at EPA-HQ-OPP-2015-0481 at www.regulations.gov

.

For this action of opening the warfarin regi stration review, the Agency has completed a qualitative human health risk assessment for warfarin in conjunction with its human health scoping document for warfarin. The Agency determ ined that no additional (human toxicity or exposure) data are needed at this time and a qualitative risk assessment for warfarin was warranted based upon the negligible exposure potential, lack of toxicity endpoints. A summary of anticipated risk assessments for the warfarin and warfarin sodium salt registration review are

below.10 Table 4: Anticipated Risk Assessments for the Warfarin and Warfarin Sodium Salt Registration Review

Type of Risk Assessment Conduct? Notes

Ecological and Environmental Fate Comprehensive ecological (species to be assessed include terrestrial and aquatic organisms), including endangered species Y

Incidents Will Check for Updates A summary of reported ecol ogical incidents can be

found in the Problem Formulation.

Human Health Dietary
Food N A qualitative dietary exposure was conducted (as part of this initial docket opening for warfarin and its sodium salt) because warfar in or its salt are not fooduse chemicals and end-use product packaging is expected to result in neg ligible dietary (food and/or drinking water) exposure. Drinking Water N

Occupational Handlers (mixers, loaders, applicators) N A qualitative occupation handler and post-application assessment was conducted (as part of this initial docket opening) because o ccupational exposures are anticipated to be negligible due to product packaging as a closed system. Post-application N

Residential Handlers N A qualitative residential exposure assessment was conducted (as part of this initial docket opening)

because residential bait a pplications are applied in bait stations or required to be packaged in tamperresistant packaging if children, domestic pets or wildlife may access. Therefore, the currently registered uses of warfarin are not expected to pose significant residential handl er or residential postapplication exposure. Post-application N

Other Aggregate N Because neither a qua ntitave dietary or quantitative residential assessment was completed for warfarin, a quantitative aggregate assessment for warfarin is not required at this time.11 TIMELINE

EPA has created the following estimated timeline fo r the completion of the warfarin and warfarin sodium salt registration re view in Table 5 below.

Table 5: Projected Warfarin and Warfarin So dium Salt Registrati on Review Timeline

Activities Estimated Date Opening the Docket Open Docket and 60-day Public Comment Period 2015 December Close Public Comment 2016 February Case Development Final Work Plan 2016 May Issue DCI 2016 July - September Data Submission 2018 July - September 60-day Public Comment Period for Draft Risk

Assessments 3 2020 January - March

Registration Review Decision 60-day Public Comment Period for Proposed Registration Review Decision 2020 October - December

Registration Review Decisi on and Begin Post-Decision Follow-up 2021

Total (years) 6

NEXT STEPS

After the 60-day public 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

warfarin and warfarin sodium salt.

3 The regulations governing 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 155.53(c). For conventional pesticides, the Agency plans to provide a 60 calendar day public comment period generally for draft risk assessments. Cumulative N EPA has not made a common mechanism of toxicity finding as to warfarin and any other substances and warfarin does not appe ar to produce a toxic metabolite produced by other substances. Tolerances N Because warfarin is not a food-use chemical, there are

no U.S. tolerances established

Incidents Will Check for Updates For a discussion of reported incidents, see the Warfarin and Warfarin Sodi um Salt. Human Health Assessment Scoping Document and Draft Human

Health Risk Assessment in Support of Registration

Review and Rodenticide: Tier I (Scoping) Review of Human Incidents and Epidemiology Assessment.12 Appendix – Additional Areas Considered in the Warfarin Registration Review

PUBLIC COMMENTS AND FEEDBACK:

Guidance for Commenters: The areas below highlight topics of special interest to the Agency where your comments, data submi ssions, or reference to sources of additional information could be of particular use.

Water Quality:

Warfarin and warfarin sodium salt are not identified as a cause of impairment for any water bodies listed as impaired under sec tion 303(d) of the Clean Water Act. 4 In addition, no Total Maximum Daily Loads (TMDL) have been de veloped for warfarin or its sodium salt. 5 More information on impaired water bodies and TM DLs can be found at the Agency’s website. 6 The Agency invites submission of wat er 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 Im paired Water Body and Other Water Quality Data in OPP’s Registration Review Risk A ssessment and Management Process 7 in order to ensure they can be used quantitatively or qualitativel y in pesticide risk assessments.

Environmental Justice:

EPA seeks to achieve environmenta l justice, the fair tr eatment and meaningful involvement of all people, regardless of race, color, national origi n, or income, in the deve lopment, implementation, and enforcement of environmental laws, regulati ons, and policies. To help address potential environmental justice issues, the Agency seeks information on any groups or segments of the population who, as a result of thei r location, cultural practices, or other factors, may have atypical, unusually high exposure to warfarin or its sodium salt compared to the general population. Please comment if you are aware of any sub-populations that may have atypical, unusually high exposure compared to the general population.

ENDANGERED SPECIES:

A risk assessment that supports a complete endangered species determination has not been

conducted for warfarin or its sodium salt. The ecological risk assessment planned during registration review will allow the Agency to determine whether use of warfarin or its sodium salt has a “no effect” or “may affect” federally li sted threatened or endangered species (listed species) or their designated critic al habitats. When an assessment concludes that a pesticide’s use “may affect” a listed species or its designated critical habitat, the Ag ency will consult with

the U.S. Fish and Wildlife Service and/or Nation al Marine Fisheries Service (the Services), as appropriate.

4 http://iaspub.epa.gov/tmdl_waters10/attains_nation_cy.cause_detail_303d?p_cause_group_id=885

5 http://iaspub.epa.gov/tmdl_waters10/attains_nation.tmdl _pollutant_detail?p_pollutant_group_id=885&p_pollutant_

group_name=PESTICIDES

6 http://www.epa.gov/owow/tmdl/

7 http://www.epa.gov/oppsrrd1/registration_review/water_quality_sop.htm13 A previous endangered species a ssessment was conducted for the San Francisco Bay Species in 2011 to address potential risk to the salt mars h harvest mouse and the Alameda whipsnake. Based on the best available information at the time of the risk assessment, the Agency made a “May Affect and Likely to Adversely Affect” de termination for the two species from the use of warfarin or its sodium salt. The Agency also dete rmined that there is the potential for effects to the Alameda whipsnake designated critical habitat from the use of warfarin.

ENDOCRINE DISRUPTOR SCREENING PROGRAM:

As required by FIFRA and FFDCA, EPA reviews num erous studies to asse ss potential adverse outcomes from exposure to chemicals. Collectiv ely, these studies includ e acute, subchronic and chronic toxicity, including asse ssments of carcinogenicity, ne urotoxicity, developmental, reproductive, and general or systemic toxicity. These studies include e ndpoints which may be susceptible to endocrine influe nce, including effects on endocri ne target organ histopathology, organ weights, estrus cyclicity, sexual maturatio n, fertility, pregnancy rates, reproductive loss, and sex ratios in offspring. For ecological hazard assessments, EPA evaluates acute tests and chronic studies that assess gr owth, developmental and reprod uctive effects in different taxonomic groups. As part of its most recent registration decision for warfarin and warfarin sodium salt, EPA reviewed these data and selected the mo st sensitive endpoints for relevant risk assessment scenarios from the existing hazard database. However, as required by FFDCA section 408(p), warfarin and its sodium salt are su bject to the endocrine screening part of the Endocrine Disruptor Screening Program (EDSP).

EPA has developed the EDSP to determine whet her 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 ot her such endocrine effect s as the Administrator may designate.” The EDSP employs a two-tiered approach to making th e 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 estrog en, androgen, or thyroid (E, A, or T) hormonal systems. Chemicals that go th rough Tier 1 screening and are found to have the potential to interact with E, A, or T hormonal systems will proceed to the next stag e of the EDSP where EPA will determine which, if any, of th e Tier 2 tests are necessary base d on the available data. Tier 2 testing is designed to identify a ny adverse endocrine-related eff ects caused by the substance, and establish a dose-response relationship between the dose and the E, A, or T effect.

Under FFDCA section 408(p), the Agency must screen all pesticide chemicals. Between October 2009 and February 2010, EPA issued test orders/data call-ins for the first group of 67 chemicals, which contains 58 pest icide active ingredient s and 9 inert ingredients. A second list

of chemicals identified for EDSP sc reening was published on June 14, 2013 8 and includes some pesticides scheduled for registration review and chemicals found in water

. Neither of these lists

should be construed as a list of known or likely endocrine disruptor s. Warfarin is not included on

either list.

8 See http://www.regulations.gov/#!documentDetail;D=EPA-HQ-OPPT-2009-0477-0074 for the final second list of

chemicals.