Docket Number EPA-HQ-OPP-2016-0031 www.regulations.gov

Flumethrin

Interim Registration Review Decision Case Number 7456

March 2020

Approved by: Elissa Reaves, Ph.D. Acting Director Pesticide Re-evaluation Division

Date: 03-17-2020 Docket Number EPA-HQ-OPP-2016-0031 www.regulations.gov

Table of Contents

I. INTRODUCTION ...... 3 A. Updates since the Proposed Interim Decision was Issued ...... 4 B. Summary of Flumethrin Registration Review ...... 4 C. Summary of Public Comments on the Proposed Interim Decision and Agency Responses ...... 6 II. USE AND USAGE ...... 8 III. SCIENTIFIC ASSESSMENTS ...... 8 A. Human Health Risks ...... 8 1. FQPA Safety Factor Determination ...... 9 2. Risk Summary and Characterization ...... 11 3. Human Incidents and Epidemiology ...... 13 4. Tolerances ...... 14 5. Human Health Data Needs ...... 14 B. Ecological Risks ...... 14 C. Pet Incidents ...... 15 D. Benefits Assessment ...... 15 IV. INTERIM REGISTRATION REVIEW DECISION...... 16 A. Risk Mitigation and Regulatory Rationale ...... 16 B. Interim Registration Review Decision ...... 16 C. Data Requirements ...... 17 V. NEXT STEPS AND TIMELINE ...... 17 A. Interim Registration Review Decision ...... 17 B. Implementation of Mitigation Measures ...... 17 APPENDICES ...... 18 Appendix A: Endangered Species Act Determination ...... 18 Appendix B: Endocrine Disruptor Screening Program ...... 19

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I. INTRODUCTION

This document is the Environmental Protection Agency’s (EPA or the agency) Interim Registration Review Decision (ID) for flumethrin (PC Code 036007 case 7456), and is being issued pursuant to 40 CFR §§ 155.56 and 155.58. A registration review decision is the agency's determination whether a pesticide continues to meet, or does not meet, the standard for registration in the Federal , Fungicide, and Rodenticide Act (FIFRA). The agency may issue, when it determines it to be appropriate, an interim registration review decision before completing a registration review. Among other things, the interim registration review decision may require new risk mitigation measures, impose interim risk mitigation measures, identify data or information required to complete the review, and include schedules for submitting the required data, conducting the new risk assessment and completing the registration review. Additional information on flumethrin can be found in the EPA’s public docket (EPA-HQ-OPP- 2016-0031) at www.regulations.gov.

FIFRA, as amended by the Food Quality Protection Act (FQPA) of 1996, mandates the continuous review of existing pesticides. All pesticides distributed or sold in the United States must be registered by the EPA based on scientific data showing that they will not cause unreasonable risks to human health or to the environment when used as directed on product labeling. The registration review program is intended to make sure that, as the ability to assess and reduce risk evolves and as policies and practices change, all registered pesticides continue to meet the statutory standard of no unreasonable adverse effects. Changes in science, public policy, and pesticide use practices will occur over time. Through the registration review program, the agency periodically re-evaluates pesticides to make sure that as these changes occur, products in the marketplace can continue to be used safely. Information on this program is provided at http://www.epa.gov/pesticide-reevaluation. In 2006, the agency implemented the registration review program pursuant to FIFRA § 3(g) and will review each registered pesticide every 15 years to determine whether it continues to meet the FIFRA standard for registration.

The EPA is issuing an ID for flumethrin so that it can move forward with aspects of the registration review that are complete. However, pursuant to the Federal Food, Drug, and Cosmetic Act (FFDCA) § 408(p), the agency will complete endocrine screening for flumethrin before completing registration review. See Appendix B for additional information on the endocrine screening for the flumethrin registration review.

Flumethrin (RS)-α-cyano-4-fluoro-3-phenoxybenzyl (1RS,3RS;1RS,3SR)-(EZ)-3-(β,4- dichlorostyryl)-2,2-dimethylcyclopropanecarboxylate; (CAS No. 69770-45-2) is a synthetic insecticide. Flumethrin (first registered in 2012) is contained in a technical grade active ingredient (TGAI) and in one end-use product registered for use as a pet collar (EPA Reg. No. 11556-155) which also includes the insecticide (CAS 138261- 41-3; PC Code 129099). Flumethrin was not subject to the reregistration requirements of FIFRA, because it was registered in 2012.

Flumethrin is contained in pet collars used for the prevention and treatment of ticks, fleas, and lice on dogs and cats. The collars are intended to be left in place for up to 8 months. Flumethrin is a member of the pyrethroids and class of , which share the same mode

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of action. The pyrethroids and pyrethrins work by altering nerve function, causing paralysis in target insect pests, eventually resulting in death of the target pest.

The agency has determined that the pyrethroids and pyrethrins share a common mechanism group (http://www.regulations.gov; EPA-HQ-OPP-2008-0489-0006). A screening-level cumulative risk assessment to assess human health risks was completed in 2011. This analysis did not identify cumulative risks of concern for children and adults. For further information, please see the cumulative risk assessment for the pyrethroids/pyrethrins, published on November 9, 2011 (USEPA, 2011a) (available at http://www.regulations.gov; EPA-HQ-OPP-2011-0746).

In addition to this flumethrin ID document, in September 2019 the EPA also published its Pyrethroids and Pyrethrins Ecological Risk Mitigation Proposal for 23 Chemicals, which summarizes the ecological risk assessment approach and outlines EPA’s mitigation to address potential ecological risks for pyrethroids as a whole. For specific information on the basis for the proposed ecological mitigation measures for the pyrethroids, please refer to the Pyrethroids and Pyrethrins Ecological Risk Mitigation Proposal for 23 Chemicals located in the Special Docket for Pyrethroids, Pyrethrins, and Synergists (located at http://www.regulations.gov; EPA-HQ- OPP-2008-0331). However, for flumethrin, there is no reasonable expectation for any registered use to cause direct or indirect adverse effects to federally listed threatened and endangered species. No adverse modification of critical habitat for federally listed species is expected from the use of flumethrin. Due to the nature of the product’s use and low likelihood of exposure for terrestrial and aquatic organisms, the EPA has made a “No Effect” (NE) finding and a “No Modification” (NM) of designated critical habitat determination under the Endangered Species Act (ESA), and is not proposing mitigation for flumethrin.

This document is organized in five sections: the Introduction, which includes this summary and a summary of public comments and the EPA’s responses; Use and Usage, which describes how and why flumethrin is used and summarizes data on its use; Scientific Assessments, which summarizes the EPA’s risk and benefits assessments, updates or revisions to previous risk assessments, and provides broader context with a discussion of risk characterization; the Interim Registration Review Decision, which describes the regulatory rationale for the EPA’s ID; and, lastly, the Next Steps and Timeline for completion of this registration review.

A. Updates since the Proposed Interim Decision was Issued

In November 2019, the EPA published the PID for flumethrin. In this ID, there are no updates to what was proposed in the PID.

B. Summary of Flumethrin Registration Review

Pursuant to 40 CFR § 155.50, the EPA formally initiated registration review for flumethrin with the opening of the registration review docket for the case. The following summary highlights the docket opening and other significant milestones that have occurred thus far during the registration review of flumethrin.

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• November 2016- The flumethrin Preliminary Work Plan (PWP), the Human Health Assessment Scoping Document in Support of Registration Review, and Flumethrin. Preliminary Problem Formulation and Ecological Risk Assessment and Effects Determination in Support of Registration Review were posted to the docket for a 60-day public comment period.

• November 2016- The agency announced the availability of the Preliminary Comparative Environmental Fate and Ecological Risk Assessment for the Registration Review of Eight Synthetic Pyrethroids and the Pyrethrins (referred to as the “Ecological Risk Assessment” hereafter), and the Ecological Risk Management Rationale for Pyrethroids in Registration Review (referred to as the “Rationale Document” hereafter), for a 60-day public comment period. The same FR Notice also announced the availability of the risk assessments for several other pyrethroids, and the Ecological Risk Assessment and Rationale Document, in the individual chemical dockets. o The comment period was extended for the Ecological Risk Assessment and the Rationale Document from January until July 2017. . During the public comment period, EPA received over 1,400 public comments across all the dockets of the pyrethroids. . These comments and the agency’s responses can be found in available at www.regulations.gov, docket number EPA-HQ-OPP-2008-0331. . None of the comments addressed flumethrin specifically, and none of the comments changed the ecological risk conclusions and effects determination for the flumethrin case.

• August 2017 - The Response to Public Comments on the Preliminary Problem Formulation and Ecological Risk Assessment in Support of the Registration Review of Flumethrin was published1. Several comments were received on the flumethrin-specific ecological risk assessment; however, they did not change the ecological risk conclusions and effects determination for the flumethrin case.

• September 2017 - The Final Work Plan (FWP) for flumethrin was posted. Several comments were received on the PWP; however, the comments did not change the schedule, risk assessment needs, or anticipated data requirements in the FWP.

• October 2017 - The Amended Final Work Plan for flumethrin was posted. In response to the Human Health Assessment Scoping Document, Bayer submitted several studies regarding pet transferable residues. The agency reviewed the submitted data and determined that they were sufficient to remove the anticipated need for a pet transferable residue study. All other elements of the agency’s 2017 FWP remained unchanged.

• A Generic Data Call-In (GDCI) was not issued for flumethrin as no new data were needed to conduct the registration review risk assessments.

1 https://www.regulations.gov/document?D=EPA-HQ-OPP-2016-0031-0017 5

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• May 2018 - The agency announced the availability of Flumethrin. Draft Human Health Risk Assessment for Registration Review for a 60-day public comment period. • No comments were received in the flumethrin docket during the comment period.

• July 2019 -The agency announced the availability of USEPA Office of Pesticide Programs’ Re-Evaluation of the FQPA Safety Factor for Pyrethroids: Updated Literature and CAPHRA Program Data Review, on the webpage https://www.epa.gov/sites/production/files/2019-08/documents/2019-pyrethroid-fqpa- caphra.pdf, which discusses the data and rationale underlying the agency’s decision to remove the 10X FQPA safety factor for the pyrethroids, including flumethrin.

• September 2019 - The agency announced the availability of the flumethrin PID in the flumethrin registration review docket (EPA-HQ-OPP-2016-0031), for a 60-day public comment period. Along with the flumethrin PID the agency also announced the availability of the Pyrethroids and Pyrethrins Ecological Risk Mitigation Proposal for 23 Chemicals in the Special Docket for Pyrethroids, Pyrethrins, and Synergists (located at http://www.regulations.gov;EPA-HQ-OPP-2008-0331) for a 60-day public comment period. A Readers Guide - Instructions for Commenting on the Registration Review Documents in the Pyrethroids Group was also added to this chemical docket. Comments were submitted to the relevant docket to ensure timely consideration of comments (i.e., comments related to the ecological risk mitigation were submitted through the pyrethroids special docket, EPA-HQ-OPP-2008-0331). The following documents were also made available in the flumethrin registration review docket (EPA-HQ-OPP-2016- 0031): o Flumethrin: Updated Human Health Draft Risk Assessment in Support of Registration Review. New information was submitted since the previous risk assessment (Flumethrin: Human Health Draft Risk Assessment in Support of Registration Review) which allowed the database uncertainty factor to be reduced from 3X to 1X for children less than 6 years old. No risks of concern were identified in the previous DRA, and since the database uncertainty factor was removed, risk estimates were further reduced for children. There were no changes to the risk assessment endpoints or points of departure, exposure assessments (residential or occupational), aggregate, or cumulative assessments.

• March 2020 - The agency is completing the Flumethrin Interim Registration Review Decision.

C. Summary of Public Comments on the Proposed Interim Decision and Agency Responses

No comments were received on the flumethrin PID during the public comment period. However, the Bay Area Clean Water Agencies (BACWA) commented on the Pyrethroids and Pyrethrins Ecological Risk Mitigation Proposal for 23 Chemicals in the Special Docket for Pyrethroids, Pyrethrins, and Synergists about pet collars and down-the-drain exposure. Although this

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comment did not specifically mention flumethrin or cite any flumethrin-specific data, the agency addresses BACWA’s concern regarding pet collars below.

BACWA Comments on Down-the-Drain Exposure (Document ID: EPA-HQ-OPP-2008- 0331-0154): BACWA had concerns about potential underestimation of pyrethroid exposures as a result of the agency’s Publicly Owned Treatment Works (POTW) modeling methodology. BACWA cited monitoring data for that was higher than the agency’s modeled exposure estimates, illustrating this potential underestimation. BACWA disagreed with the agency’s conclusion that certain uses did not contribute substantially to down-the-drain exposures and advocated for the agency to include these uses in the down-the-drain assessment. These uses include pet spot-ons, collars, and indoor foggers, which BACWA has concluded contribute to POTW discharges. BACWA cited a growing body of data that pet spot-on treatments are discharged to sewer systems through direct transfer (pet washing) and indirect transfer (washing hands, fabric, and surfaces contacted by treated pets, and possibly through human waste) ); to support their claims, BACWA cited several studies. BACWA also cited scientific evidence connecting pet collars and indoor foggers to POTW discharges. BACWA asserts that these pyrethroids sources – particularly pet spot-ons – appear to be among the largest sources of insecticide discharges to the sewer system. BACWA also supported this claim by citing California Department of Pesticide Regulation (CDPR) studies showing that topical flea control formulations of (CAS No. 120068-37-3) could result in wastewater residues 2 to 29 days after treatment, as well as fipronil and pyrethroid studies showing that residues on treated pets could be transferred to human hands via petting, and subsequently down the drain from handwashing, weeks after application.

EPA Response: Uses that are not intended to have a direct pathway down the drain, such as pet collars and pet spot-ons, were not included in the EPA’s Ecological Risk Assessment for pyrethroids and pyrethrins. This is because their level of degradation, dissipation, and likelihood of contact with water transported down the drain is expected to be a small and currently unquantifiable fraction of the amount applied. As an example, pet spot-ons and the active ingredients in pet collars are not intended to be washed off the pet at the time of application. As a result, the actual contribution of a pet collar or pet spot-on to down-the-drain exposures is expected to be substantially lower than the amount applied. With regard to flumethrin specifically, the only registered product containing flumethrin is an end-use pet collar, which is expected to result in more limited residues than what is expected from pet spot-on treatments.

With regard to pet products generally, the agency is working with the Household and Commercial Products Association (HCPA) Pet Care Products Task Force to quantify household exposures from pet product uses and is also working to develop new Proposed Guidelines for Efficacy Testing of Topically Applied Pesticides Used Against Certain Ectoparasitic Pests on Pets. Additional information and materials from the agency’s June 11-14, 2019 Scientific Advisory Panel Meeting on the proposed efficacy guidelines are located in docket EPA-HQ- OPP-2019-0161. Both efforts may inform future work on the fate and transport of pesticides used in pet products. For additional details, see the Joint Response from OPP’s Environmental Fate and Effects Division and Pesticide Reevaluation Division to Comments on the Preliminary

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Risk Assessments for Pyrethroids and Pyrethrins Insecticides located on the Special Docket for Pyrethroids, Pyrethrins, and Synergists (EPA-HQ-OPP-2008-0331-0094).

II. USE AND USAGE

Flumethrin is an insecticide and miticide/acaricide. It is a synthetic pyrethroid insecticide which acts to prevents sodium channels in an organism’s neuronal membranes from closing, resulting in paralysis and eventual death. The Insecticide Resistance Action Committee categorizes flumethrin and other synthetic pyrethroids in “Mode of Action” (MOA) Group 3A (IRAC, 2018).

The only registered product containing flumethrin is an end-use pet collar which also includes the neonicotinoid insecticide imidacloprid (CAS 138261-41-3; PC Code 129099). There are no other registered indoor residential or commercial uses, nor any outdoor or agricultural uses. Label directions instruct users to open the container only when the product needs to be used, to fasten the collar around the dog/cat neck, and to leave the collar in place for up to 8 months. In general, pet "spot-on" treatments and collars are designed to be stand-alone pet treatments; i.e., the products are designed to work alone without the need for other treatments. Shampoos by comparison are designed to be used in conjunction with other products as part of a treatment plan.

Nationally, residential consumers purchase around 410,000 pounds of active ingredient (lbs a.i.) of pyrethroid insecticides for use in the household2. This amount would include most pet products, but usage specific to flumethrin is not reported. Professional management companies use around 1.7 million lbs a.i. of pyrethroids for control of various household pests, both in and around residential and commercial buildings3 (NMRD, 2017b). Pet products, including products used by commercial groomers, however, would not be captured in these data.

Overall, the production of flumethrin has increased substantially since the first product containing flumethrin was registered in 2012.

III. SCIENTIFIC ASSESSMENTS

A. Human Health Risks

A summary of the agency’s human health risk assessment is presented below. The agency used the most current science policies and risk assessment methodologies to prepare a risk assessment in support of the registration review of flumethrin. For additional details on the human health assessment for flumethrin, see Flumethrin: Draft Human Health Risk Assessment for

2 NMRD. 2012-2016. Non-agricultural Research Market Data. [Accessed July 2019]. 2017a. Consumer Markets for Pesticides and Fertilizers 2016. 2012. Consumer Markets for Pesticides and Fertilizers 2012. 3 NMRD. 2012-2016. Non-agricultural Research Market Data. [Accessed July 2019]. 2017b. Professional Pest Management Markets for Pesticides 2016. 8

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Registration Review and Flumethrin: Updated Human Health Draft Risk Assessment in Support of Registration Review, which are available in the flumethrin registration review docket EPA- HQ-OPP-2016-0031.

1. Pyrethroids FQPA Safety Factor Determination

The Food Quality Protection Act (1996) requires EPA to apply a ten-fold margin of safety (10X FQPA safety factor) for infants, children, and women of child-bearing age to account for potential juvenile sensitivity to pesticides, unless there are reliable data to reduce this safety factor. The agency considers the FQPA safety factor as having two components: 3X assigned to pharmacokinetic (PK) differences and 3X to pharmacodynamic (PD) differences.4 The PK component depicts the process of chemicals being absorbed, distributed, metabolized, and excreted from and in the body. The PD component determines how a chemical brings about target tissue responses at a given dose.

For the pyrethroids that went through reregistration, which did not include flumethrin, EPA determined the toxicological database provided reliable information to reduce the 3X FQPA PD component of the safety factor for all populations to 1X5. While there was enough information to reduce the 3X FQPA PK safety factor for women of child-bearing age to 1X, some uncertainty remained for infants and children because available animal data indicated an increase in sensitivity to pyrethroids for juvenile rats compared to adult rats. EPA required developmental neurotoxicity studies (DNTs) with the intention of addressing this uncertainty; however, after a 2009 review of the pyrethroids toxicological database, which considered all the available reproductive and developmental studies, the agency determined that the DNT did not provide sufficient information related to the susceptibility of infants and children. Therefore, EPA notified registrants that they could satisfy outstanding DCI requirements for pyrethroids DNT studies by citing the previously-submitted DNT studies for six pyrethroids. In addition, in order to address the uncertainty of comparative life-stage sensitivity, EPA solicited protocols from all pyrethroid companies in 2010, requesting interested parties submit a protocol for a study designed to identify and quantify potential juvenile sensitivity. A majority of the pyrethroid registrants formed a group called the Pyrethroid and Pyrethrins Technical Working Group (PPTWG) and they were ultimately the only group to submit a protocol for review.

In July 2010, the FIFRA Scientific Advisory Panel (SAP) convened to review the PPTWG protocol, which proposed using a combination of in vitro studies, targeted in vivo studies, and physiologically-based pharmacokinetic (PBPK) models to evaluate the life-stage sensitivity of pyrethroids. The SAP supported PBPK modeling as an appropriate path forward for addressing juvenile sensitivity, and some elements of the proposal were modified following SAP and EPA

4 USEPA Office of Pesticide Programs’ Re-Evaluation of the FQPA Safety Factor for Pyrethroids: Updated Literature and CAPHRA Program Data Review July 2019 https://www.epa.gov/sites/production/files/2019- 08/documents/2019-pyrethroid-fqpa-caphra.pdf 5 USEPA Office of Pesticide Programs’ Re-Evaluation of the FQPA Safety Factor for Pyrethroids: Updated Literature and CAPHRA Program Data Review July 2019 https://www.epa.gov/sites/production/files/2019- 08/documents/2019-pyrethroid-fqpa-caphra.pdf

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recommendations6. The PPTWG was eventually expanded and became the Council for the Advancement of Pyrethroid Human Risk Assessment (CAPHRA).

Between late 2010 and early 2015, CAPHRA’s efforts were focused on development of the overall approach using data for and permethrin to first develop the PBPK model parameterized for these two active ingredients (Type II and Type I pyrethroids, respectively). By May 2015, the CAPHRA knowledge-base for deltamethrin and permethrin was robust enough for critical evaluation of the approach, including their intended use of the data for read-across along with computational approaches for modeling other pyrethroids7. The SAP encouraged the CAPHRA to address certain deficiencies in the dataset and PBPK model but were generally supportive of the PBPK approach.

Following the 2015 SAP, the EPA and the CAPHRA continued to meet regularly to work through technical issues, as well as discuss updates on the status of the research program. By spring 2018, the CAPHRA submitted the in vitro and in vivo studies, as well as the PBPK model code and a related white paper to EPA8. The CAPHRA white paper described the integration of multiple data streams and the modeling approach to determine the key contributors to age-related toxicokinetic difference. The October 2018 peer review noted deficiencies in the white paper as well as opportunities for further testing of the model parameters. In addition, the peer review panel requested full model documentation and recommended an independent quality assurance (QA) review9 after CAPHRA addressed these issues identified by the panel.

The EPA worked with the CAPHRA to discuss the white paper updates, model testing, and additional information necessary for EPA’s evaluation of the weight of evidence (WOE). CAPHRA completed this work in July 2019, and EPA determined it could proceed with its WOE determination, which included review of the open literature and well as data generated by CAPHRA.

EPA has concluded that no new information of suitable quality was available on the age-related PD properties of the pyrethroids. Therefore, the previous conclusion that the PD contribution to the FQPA safety factor is 1X remains the same.10 Regarding PK, recent data including human PBPK models, as well as in vivo and in vitro data on protein binding, enzyme ontogeny and metabolic clearance, support the conclusion that the PK contribution to the FQPA safety factor is 1X for all populations. Therefore, the agency concludes that the default 10X FQPA safety factor

6 Transmittal of the Meeting Minutes of the FIFRA SAP Meeting Held on July 23, 2010 on “Scientific Issues associated with the Comparative Adult and Juvenile Sensitivity Toxicity Protocols for Pyrethroid” October 9, 2010 https://www.regulations.gov/document?D=EPA-HQ-OPP-2010-0378-0015 7 Transmittal of Meeting Minutes of the FIFRA Scientific Advisory Panel Meeting held on “Research to Evaluate the Potential for Juvenile Sensitivity to Pyrethroids” August 19 2015 https://www.epa.gov/sites/production/files/2015- 08/documents/051915minutes.pdf 8 CAPHRA Responses to EPA’s External Peer Review, April 12, 2019. Revised August 28, 2019 9 TERA Cross Walk Review of CAPHRA’s Response to the EPA’s Contractor Led Peer Review Final Report, September 11, 2019 10 Re-Evaluation of the FQPA Safety Factor for Pyrethroid Pesticides June 27, 2011 https://www.regulations.gov/document?D=EPA-HQ-OPP-2011-0746-0011

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can be reduced to 1X for all populations for the pyrethroids pesticides. In December 2019, EPA determined that while the use of a PBPK model is appropriate to evaluate the potential for differential sensitivity of pyrethroids, as a class, between juveniles and adults, the model is not robust enough to be used for the development of chemical-specific uncertainty factors in the risk assessments for individual pyrethroids except those on which the model was conducted (deltamethrin and permethrin)11.

EPA’s full evaluation, USEPA Office of Pesticide Programs’ Re-Evaluation of the FQPA Safety Factor for Pyrethroids: Updated Literature and CAPHRA Program Data Review (July 2019), is available at www.regulations.gov (EPA-HQ-OPP-2008-0331).

2. Risk Summary and Characterization Flumethrin is contained within a collar which is affixed to a domesticated dog or cat. As such, the labeled use and application method of flumethrin limits human exposure to adults and children in residential settings and occupational handlers (professional applicators/groomers). Humans are not expected to be exposed to flumethrin in food and/or drinking water since there are no currently registered food uses of flumethrin and drinking water exposure is not expected from the registered pet collar uses. A quantitative spray drift assessment was also not conducted for the flumethrin pet collar since this use will not result in spray drift exposures. While there is potential for exposure to flumethrin vapors from the pet collar, the exposure is expected to be minimal given the chemical’s pet-only uses.

Due to the uncertainty associated with the physical form of pet collar products, the agency has begun efforts to reevaluate pet collar formulations to carefully consider whether pet collar product active ingredients are released as a liquid or solid form, and, if determined to be both, the relative fraction of each. In 2016, the flumethrin registrant submitted data to determine whether the chemical was released from the pet collar as a liquid or a dust. Based on this study, the human health risk assessment assumed that adults affixing the collars, as well as people exposed to flumethrin residues after the collar was placed on the pet, would be exposed to 99.71% liquid flumethrin and 0.29% solid flumethrin (i.e., as a dust). Based on existing data, liquid formulations exhibit a lower transfer value compared to solids/dust products, resulting in a lower potential exposure.

For more information on the human health risks conclusions for flumethrin, refer to the Flumethrin: Draft Human Health Risk Assessment for Registration Review, and the Flumethrin: Updated Human Health Draft Risk Assessment in Support of Registration Review which are available in the public docket.

11 Pyrethroids: Current Use and Potential Applications of a Generic Physiologically-Based Pharmacokinetic (PBPK) Model. December 17, 2019 https://www.regulations.gov/document?D=EPA-HQ-OPP-2008-0331-0141 11

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Dietary (Food + Water) Risks

Humans are not exposed to flumethrin in food and drinking water since there are no currently registered food uses of flumethrin and drinking water exposure is not expected from the registered pet collar uses. Thus, a dietary exposure and risk assessment was not conducted.

Residential Handler Risks

For the residential handler exposures, a total aggregated risk index (ARI) was used since the level of concern (LOCs) for dermal exposure (100) and inhalation exposure (30) are different. The residential handler exposures are not of concern for either the small- or large-sized collars as ARIs over 1 are not considered risks of concern. The ARIs range from 5.9 to 21.

Residential Post-Application Risks

The residential post-application exposures are not of concern for either the small- or large-sized collars. The residential post-application combined dermal exposure and risk estimates for adults are greater than the LOC for both sized collars (MOEs range from 2,100 to 17,000). MOEs above 100 are not of concern. The residential post-application combined dermal and incidental oral exposure and risk estimates for children (1 to < 2 years old) are also greater than the LOC for both sized collars (MOEs range from 1,800 to 5,200). MOEs above 100 are not of concern. Residential post-application inhalation exposure is expected to be negligible from pet collars; therefore, a quantitative assessment was not conducted.

Bystander Risks

A quantitative spray drift assessment was not conducted for the flumethrin pet collar since this use will not result in the potential for spray drift exposures.

Aggregate Risks

There are currently no registered food uses for flumethrin and drinking water exposure is not expected from the registered pet collar use of flumethrin. As a result, a quantitative aggregate risk assessment was not conducted.

Cumulative Risks

The agency is required to consider the cumulative risks of chemicals sharing a common mechanism of toxicity. The agency has determined that the pyrethroids and pyrethrins share a common mechanism group (http://www.regulations.gov; EPA-HQ-OPP-2008-0489-0006) with respect to human health. The members of this group share the ability to interact with voltage- gated sodium channels in the nervous system, which ultimately lead to neurotoxicity. The cumulative risk assessment for the pyrethroids/pyrethrins was published on Nov. 9, 2011 (USEPA, 2011a) and is available at http://www.regulations.gov; EPA-HQ-OPP-2011-0746. No cumulative risks of concern were identified at that time. For information regarding EPA’s efforts to evaluate the human health risk of exposure to pyrethroids, refer to

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http://www.epa.gov/oppsrrd1/reevaluation/pyrethroids-pyrethrins.html. After all of the chemical- specific interim decisions have been completed for the pyrethroids class of pesticides, an update of the cumulative risk assessment may be performed in association with registration review.

Occupational Handler Risks

Occupational handler exposure to the flumethrin pet collar may occur via the dermal and inhalation route when placed on a cat or dog by a professional applicator/groomer. The occupational handler exposure resulted in no risk estimates of concern (ARIs ≥ 1 are not of concern); ARIs ranged 1.7 to 6.2 for the small and large sized collars.

Occupational Post-Application Risks

Occupational post-application exposure could potentially occur; however, these types of exposures are not expected to be greater than residential post-application exposures. As a result, the agency did not conduct a quantitative occupational post-application exposure and risk assessment.

3. Human Incidents and Epidemiology Since the 2016 draft human health risk assessment, a new human health incident memo was posted to docket. From January 1, 2012 to February 4, 2016, there were 37 incidents reported to the Main Incident Data System (IDS) and 219 incidents reported to Aggregate IDS involving flumethrin (Seresto™ Collar, EPA Reg. No. 11556-155). Main IDS incidents involving only one pesticide are considered to provide more certain information about the potential effects of exposure from the pesticide. Thirteen of these incidents were classified as major severity, 124 incidents were classified as moderate severity and 219 incidents were classified as minor severity. Dermal symptoms were reported most often for the major severity incidents, including rash, pruritus and burning sensation.

From January 1, 2016 to August 27, 2019, in Main IDS there were 252 human health incidents reported that involved the active ingredient flumethrin. Of these 252 incidents, 19 were classified as major severity and 233 were classified as moderate severity. In Aggregate IDS, there were 374 human health incidents reported involving flumethrin. These incidents were classified as minor severity.

Of the 19 major severity incidents that were further reviewed, the symptoms most often reported were dermal (n=8) and neurological (n=7). However, a patient could exhibit multiple symptoms. Dermal symptoms reported include rash, redness, skin lesions, hives, and pruritus. Neurological symptoms reported include headaches, numbness, tingling and one person reported seizures. The total number of flumethrin incidents reported to IDS, from 2013 to 2018, appears to be increasing over time. However, the production of flumethrin has also increased substantially since the first product containing flumethrin was registered in 2012.

In addition, there was one minor severity incident reported to National Pesticide Information Center (NPIC), from January 1, 2011 to December 31, 2015, and three human health incidents

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classified as low severity reported in the Sentinel Event Notification System for Occupational Risks (SENSOR)-Pesticides analysis from 2013-2015. The agency will continue to monitor the incident data and if a concern is triggered, additional analysis will be conducted. Flumethrin is not included in the Agricultural Health Study; therefore, this study does not provide information specific for flumethrin on an individual chemical basis. The Agricultural Health Study (AHS) is a high quality, prospective epidemiology study evaluating the potential link between pesticide use and various health outcomes including cancer.

An epidemiological report was developed to assess the association between exposure to the pyrethroids in humans and adverse carcinogenic and non-carcinogenic outcomes, as well as select individual pyrethroid chemicals, including flumethrin. Overall, the epidemiological report found little substantive evidence to suggest a clear, associative, or causal relationship between exposure to pyrethroids and cancer and non-cancer health endpoints studies, including the Agricultural Health Study publications reported. For further information, please see the Pyrethroids: Tier II Epidemiological Report12 dated April 30, 2019.

4. Tolerances There are no tolerances for flumethrin, as it is not registered for use on food crops. 5. Human Health Data Needs There are no data deficiencies for registration review in regard to the toxicology, residue chemistry, and occupational and residential exposure data requirements.

B. Ecological Risks

Flumethrin is classified as moderately toxic to terrestrial mammals on an acute oral, inhalation and dermal exposure basis (Toxicity Category II) and it is not considered an eye or dermal irritant (Toxicity Category IV). There are currently no toxicity data to assess the potential risk to other terrestrial or aquatic organisms from the registered use of flumethrin; however, given the exclusive use of flumethrin in pet collars (that are typically applied to domesticated animals that spend a large proportion of their time indoors), the use of flumethrin is considered to be primarily a use with de minimus exposure for non‐target organisms. RQs have not been calculated for flumethrin because the use in pet collars is not expected to lead to direct outdoor exposure, or through transport down the drain.

Due to low (de minimis) exposure potential associated with its flumethrin’s current use pattern, flumethrin is not anticipated to pose potential ecological risks of concern to aquatic invertebrates (freshwater or estuarine/marine), fish (freshwater or estuarine/marine), plants (terrestrial or aquatic), or terrestrial wildlife, including terrestrial invertebrates.

There is also no reasonable expectation for any registered use of flumethrin to cause direct or indirect adverse effects to federally listed threatened and endangered species. No adverse modification of critical habitat for federally listed species is expected from the use of flumethrin.

12 https://www.epa.gov/sites/production/files/2019-08/documents/tier-ii-epidemiology-report.pdf 14

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Because of the predominantly indoor use of the product and low likelihood of exposure for terrestrial and aquatic organisms the EPA has made “No Effect” (NE) and No Modification (NM) of designated critical habitat determinations under the Endangered Species Act (ESA).

Although flumethrin does not have ecological risks of concern, it is one of the 23 pyrethroids noted in the Ecological Risk Management Rationale for Pyrethroids in Registration Review, a companion piece to the 2016 Preliminary Comparative Environmental Fate and Ecological Risk Assessment for Registration Review of Eight Synthetic Pyrethroids and the Pyrethrins. This rationale document summarized potential risk concerns for the pyrethroids excluded from the quantitative ecological assessment. Chemicals noted in the Rationale Document include: , d‐, , flumethrin, , momfluorothrin, , tau‐fluvalinate, , and . RQ’s have not been calculated for flumethrin because the use in pet collars is not expected to lead to direct outdoor exposure, or through transport down the drain.

For additional details on the flumethrin-specific ecological risk assessment, see the 2016 Preliminary Problem Formulation and Ecological Risk Assessment and Effects Determination in Support of Registration Review, which is available in the flumethrin registration review docket (EPA-HQ-OPP-2016-0031). For additional details on the ecological assessment for the pyrethroids, see the Preliminary Comparative Environmental Fate and Ecological Risk Assessment for Registration Review of Eight Synthetic Pyrethroids and the Pyrethrins and the Ecological Risk Management Rationale for Pyrethroids in Registration Review, which are available in the pyrethroid-specific docket (EPA-HQ-OPP-2008-0331).

C. Pet Incidents

The EPA has received and evaluated numerous pet incidents since flumethrin’s registration in 2012; however, a comparative assessment of pet incidents across all registered pet products based on usage data is not available. The agency is conducting similar analyses on other pesticides registered for direct treatments to pets, such as spot-ons, and may consider conducting such analyses for other active ingredients with products registered for direct treatments to pets, such as collars. EPA has been engaged with stakeholders on a variety of different actions to address potential risks to pets from the use of pet spot-on products; additional information on this project can be found here: https://www.epa.gov/pets/epa-evaluation-pet-spot-products-analysis- and-plans-reducing-harmful-effects. As additional information is gathered through this project, EPA will be evaluating the use of pet products generally, including those that contain pyrethroids, to determine if additional changes are needed to pet product registrations.

D. Benefits Assessment

The pests targeted by the pet collars containing flumethrin can be serious problems in that they can cause anemia and can transmit various disease pathogens that affect both animals and humans. In this context, flumethrin offers benefits in terms of protection from pests of public health concern. Several alternatives in various forms that also offer such protection are also available in the U.S. marketplace. Pest control products for pets often contain other synthetic pyrethroids such as permethrin, as well as pyrethrins. 15

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The primary alternatives to the pyrethroid pet shampoos are insecticide-impregnated pet collars and direct-applied “spot-on” treatments. Registered non-pyrethroid pet collars include products containing tetrachlorovinphos (an ), (a ), insect growth regulators (such as ), or . These pet collars sometimes also contain pyrethroids (other than flumethrin) as co-formulated active ingredients. Non-pyrethroid active ingredients in “spot-on” treatments include fipronil, , or imidacloprid. These active ingredients are often co-formulated with insect growth regulators (e.g., or s- methoprene), which provide specific efficacy against flea eggs and larvae.

In addition, the U.S. Food and Drug Administration also regulates pet medications that control fleas and ticks. These include the non-pyrethroid active ingredients , , cythiolate, , selamectin, , milbemycin oxime, s-methoprene, and . Some of these products require veterinary licensing for use and some products may not be stand-alone treatments, i.e., they require the use of additional treatments or pest exclusion tactics to be fully effective.

For additional information on the benefits of pyrethroids in general, refer to the Pyrethroids and Pyrethrins Ecological Risk Mitigation Proposal for 23 Chemicals, also available in the public docket (EPA-HQ-OPP-2008-0331).

IV. INTERIM REGISTRATION REVIEW DECISION

A. Risk Mitigation and Regulatory Rationale

The agency has determined that there are no risks of concern associated with the registered use of flumethrin. As a result, the agency is not requiring any mitigation.

In addition, EPA is working to develop new Proposed Guidelines for Efficacy Testing of Topically Applied Pesticides Used Against Certain Ectoparasitic Pests on Pets. Current products containing flumethrin are formulated as pet collars targeting pests of public health concern and could be impacted by this larger effort. Additional information and materials from the agency’s (June 11-14, 2019) Scientific Advisory Panel Meeting are located at www.regulations.gov, docket number EPA-HQ-OPP-2019-0161.

B. Interim Registration Review Decision

In accordance with 40 CFR §§ 155.56 and 155.58, the agency is issuing this ID. Except for the Endocrine Disruptor Screening Program (EDSP) the agency has made the following interim decision: (1) no additional data are required at this time; and (2) no changes to the affected registrations and their labeling are needed at this time, as described in Section IV. A, as well the Pyrethroids and Pyrethrins Ecological Risk Mitigation Proposal for 23 Chemicals (EPA-HQ- OPP-2008-0331).

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In this ID, the agency is making no human health or environmental safety findings associated with the EDSP screening of flumethrin. The EPA has made a “no effect” determination under the Endangered Species Act (ESA) for all listed species and a “no modification (NM)” determination for designated critical habitat for such species and has therefore concluded that consultation with the U.S. Fish and Wildlife Service and the National Marine Fisheries Service under ESA § 7(a)(2) is not required.

The agency’s final registration review decision for flumethrin will be dependent upon the result of the EDSP FFDCA § 408(p) determination.

C. Data Requirements

The agency does not anticipate calling in additional data for the registration review of flumethrin at this time.

V. NEXT STEPS AND TIMELINE

A. Interim Registration Review Decision

A Federal Register Notice will announce the availability of this ID for flumethrin. However, a final decision for flumethrin may be issued without the agency having previously issued an interim decision. A final decision on the flumethrin registration review case will occur after an EDSP FFDCA § 408(p) determination.

B. Implementation of Mitigation Measures

Because the agency it not requiring mitigation measures for registration review of flumethrin, the agency does not need amended flumethrin labels.

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APPENDICES

Appendix A: Endangered Species Act Determination

There is no reasonable expectation for any registered use of flumethrin to cause direct or indirect adverse effects to threatened and endangered species. No adverse modification of critical habitat is expected from the use of flumethrin. Because of the predominantly indoor use of the product and low likelihood of exposure for terrestrial and aquatic organisms the EPA has made a “no effect” determination under the Endangered Species Act (ESA) for all listed species and No Habitat Modification for designated critical habitat for such species and has therefore concluded that consultation with the U.S. Fish and Wildlife Service and the National Marine Fisheries Service under ESA § 7(a)(2) is not required.

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Appendix B: Endocrine Disruptor Screening Program

As required by FIFRA and FFDCA, the EPA reviews numerous studies to assess potential adverse outcomes from exposure to chemicals. Collectively, these studies include acute, sub- chronic and chronic toxicity, including assessments of carcinogenicity, neurotoxicity, developmental, reproductive, and general or systemic toxicity. These studies include endpoints which may be susceptible to endocrine influence, including effects on endocrine target organ histopathology, organ weights, estrus cyclicity, sexual maturation, fertility, pregnancy rates, reproductive loss, and sex ratios in offspring. For ecological hazard assessments, the EPA evaluates acute tests and chronic studies that assess growth, developmental and reproductive effects in different taxonomic groups. As part of its most recent registration decision for flumethrin, the 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 § 408(p), flumethrin is subject to the endocrine screening part of the Endocrine Disruptor Screening Program (EDSP).

The 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 the 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.

Under FFDCA § 408(p), the agency must screen all pesticide chemicals. Between October 2009 and February 2010, the EPA issued test orders/data call-ins for the first group of 67 chemicals, which contains 58 pesticide active ingredients and 9 inert ingredients. The agency has reviewed all of the assay data received for the List 1 chemicals and the conclusions of those reviews are available in the chemical-specific public dockets. A second list of chemicals identified for EDSP screening was published on June 14, 2013,13 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 disruptors. Flumethrin is not on either list. For further information on the status of the EDSP, the policies and procedures, the lists of chemicals, future lists, the test guidelines and the Tier 1 screening battery, please visit the EPA website.14

In this ID, the EPA is making no human health or environmental safety findings associated with the EDSP screening of flumethrin. Before completing this registration review, the agency will make an EDSP FFDCA § 408(p) determination.

13 See http://www.regulations.gov/#!documentDetail;D=EPA-HQ-OPPT-2009-0477-0074 for the final second list of chemicals. 14 https://www.epa.gov/endocrine-disruption 19