                                                                               
                                                                               
    	  
  	 
                                         
                                     Amitraz
    
                                          
                   Interim Registration Review Decision 
                                Case Number 0234 
                                          
                                          
                                  December 2021 
                                          
                                          
                                          
                                       
                                       
                                                                               
                                                                               
                                                                   Approved by:
  


Mary Elissa Reaves, Ph.D.

Director

Pesticide Re-evaluation Division
                                                                          Date:
      12/06/2021
                                       
                                       
		
                                 Table of Contents 
I. 	INTRODUCTION	3
A.	Updates Since the Proposed Interim Decision was Issued	4
B.	Summary of Amitraz Registration Review	4
C.	Summary of Public Comments on the Proposed Interim Decision and Agency Responses	6
II. 	USE AND USAGE	7
III.	SCIENTIFIC ASSESSMENTS	7
A.	Human Health Risks	7
1.	Risk Summary	7
2.	Human Incidents and Epidemiology	8
3.	Tolerances	9
4.	Human Health Data Needs	10
B.	Ecological Risks	10
1.	Risk Summary	10
2.	Ecological Incidents	11
3.	Ecological and Environmental Fate Data Needs	11
C.	Pet Incidents	11
D.	Benefits Assessment	12
IV.   INTERIM REGISTRATION REVIEW DECISION	14
A.	Risk Mitigation and Regulatory Rationale	14
B.	Environmental Justice	15
C.	Tolerance Actions	16
D.	Interim Registration Review Decision	16
E.	Data Requirements	17
V. 	NEXT STEPS AND TIMELINE	17
A.	Interim Registration Review Decision	17
B.	Implementation of Mitigation Measures	17
VI.    REFERENCES	18
Appendix A:  Endangered Species Act Determination	20
Appendix B:  Endocrine Disruptor Screening Program	21

	

   I. 	INTRODUCTION 
    	 
   This document is the Environmental Protection Agency's (EPA or the Agency) Interim Registration Review Decision (ID) for amitraz (PC Code 106201; case 0234). In a registration review decision under the Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA), the Agency determines whether a pesticide continues to meet FIFRA's registration standard. Where appropriate, the Agency may issue an interim registration review decision before completing a registration review. Among other things, the interim registration review decision may determine that new risk mitigation measures are necessary, lay out 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. For more information on amitraz, see EPA's public docket (EPA-HQ-OPP-2009-1015) at www.regulations.gov.    
   
   FIFRA mandates the continuous review of existing pesticides. All pesticides distributed or sold in the United States must be registered by 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. In 2006, the Agency began implementing the registration review program. EPA will review each registered pesticide every 15 years. Through the registration review program, the Agency intends to verify that all registered pesticides continue to meet the registration standard as the ability to assess and reduce risk evolves and as policies and practices change. By periodically re-evaluating pesticides as science, public policy, and pesticide-use practices change, the Agency ensures that the public can continue to use products in the marketplace that do not present unreasonable adverse effects. For more information on the registration review program, see http://www.epa.gov/pesticide-reevaluation. 
   
   The Agency is issuing an ID for amitraz so that it can move forward with aspects of the registration review that are complete. EPA is currently working with the U.S. Fish and Wildlife Service and the National Marine Fisheries Service (the Services) to improve the consultation process for federally listed threatened and endangered (listed) species and their designated critical habitat for pesticides under the Endangered Species Act (ESA). The Agency has determined that the current registrations of amitraz present limited exposure potential to non-target organisms outside of beehives, including federally listed species. Therefore, a "No Effect" determination has been made for all federally listed species. However, pursuant to the Federal Food, Drug, and Cosmetic Act (FFDCA), the Agency will complete endocrine screening for amitraz, before completing registration review. For more information on the listed-species determination and the endocrine screening for amitraz registration review see Appendices A and B. 
   
   Amitraz is an insecticide/acaricide currently registered for use in pet collars for control of ticks on dogs and as impregnated strips for control of varroa mites in beehives. Amitraz is a member of the formamidine class of insecticides. There are two currently registered products with amitraz as the active ingredient (a.i.): Preventic Tick Collar for Dogs (EPA Reg. No. 2382-104) and Apivar (EPA Reg. No. 87243-1). Amitraz was registered for use as a pet spot-on product (Certifect for Dogs, EPA Reg. No. 65331-7); however, the registrant voluntarily cancelled the product, and a Federal Register notice (FRN) was issued on May 13, 2019 (84 FR 20882) announcing the final cancellation. As a result, this use was not included in the draft risk assessments (DRAs).  
   
   This document is organized in five sections:
          Introduction (summarizing the registration review milestones and responding to public comments).
          Use and Usage (discussing how and where amitraz is used).
          Scientific Assessments (summarizing EPA's risk and benefits assessments, updating or revising previous risk assessments, and discussing risk characterization).
          Interim Registration Review Decision (presenting EPA's interim decision, regulatory rationale, and any mitigation measures to address risks of concern); and
          Next Steps and Timeline (discussing how and when EPA intends to complete registration review).
    
 Updates Since the Proposed Interim Decision was Issued

In August 2021, the Agency published the Proposed Interim Decision (PID) for amitraz. Since the publication of the PID, the Agency has determined that additional data need to be submitted to address the post-natal day (PND) 5 thyroid hormone measurement data gap identified in the draft Human Health Risk Assessment. 

EPA has not updated the draft Human Health Risk Assessment or the draft Ecological Risk Assessment. This ID finalizes the Agency's risk mitigation and draft supporting documents (Amitraz: Draft Human Health Risk Assessments for Registration Review and Amitraz Draft Ecological Risk Assessment for Registration Review), which are available in EPA's public docket (EPA-HQ-OPP-2009-1015).
	
 Summary of Amitraz Registration Review 
   
   On March 31, 2010, the Agency formally initiated registration review for amitraz 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 amitraz.   
    
       ::   March 2010  -  EPA posted the Amitraz Preliminary Work Plan (PWP), dated March 16,  
        2010, the Amitraz Human Health Assessment Scoping Document in Support of Registration Review, and the Problem Formulation for the Environmental Fate and Ecological Risk, Endangered Species, and Drinking Water Assessments in Support of the Registration Review of Amitraz to the public docket for a 60-day public comment period. 
    
          September 2010  -  EPA posted the Amitraz Final Work Plan (FWP), dated September 13, 2010, to the public docket. The Agency received one public comment on the PWP. The comment did not change the schedule, risk assessment needs, or expected data requirements for registration review.    
    
 November 2011  -  EPA issued a generic data call-in (GDCI) for amitraz to obtain data needed to conduct the registration review risk assessments (GDCI-106201-1053) for amitraz. All data have been submitted and the GDCI has been satisfied. However, following EPA's review of the extended one-generation reproduction toxicity study (EOGRTS) study, EPA identified data deficiencies in the PND 5 thyroid hormone measurements which are considered a data gap.

 November 2018  - EPA posted the Amitraz: Draft Human Health Risk Assessment for Registration Review in Support of Registration Review and the Amitraz: Preliminary Ecological Risk Assessment and Endangered Species Assessment for Registration Review of the Conventional Use in Honey Bee Hives for a 60-day public comment period. EPA made a "No Effect" determination under the Endangered Species Act (ESA) for all federally listed species for all currently registered uses of amitraz. Seven comments were received during the comment period. The comments resulted in EPA's revision of the human health risk assessment but did not result in changes to the ecological risk assessment conclusions, the ESA determination, nor the registration review timeline for amitraz.   
         
 June 2021  -  EPA posted the Amitraz: Proposed Interim Registration Review Decision (PID), dated June 21, 2021, to the public docket for a 60-day public comment period. Along with the PID, the following documents were also posted in the amitraz registration review docket: 
 Amitraz: Revised Draft Human Health Risk Assessment for Registration Review dated May 4, 2021.
 Amitraz: Revised Occupational and Residential Exposure Assessment for Registration Review dated May 4, 2021.
 Amitraz: Data Evaluation Record for the Study "Torsion Study and Collar Placement Stimulations for the Preventic Tick Collar for Dogs (EPA Registration Number 2382-104)" dated May 4, 2021.
 Amitraz: Response to Comments on the Draft Human Health Risk 
               Assessment for Registration Review dated July 25, 2019. 
 Amitraz: Response to Public Comments on the Draft Ecological 
               Risk Assessment dated July 16, 2019.
 Amitraz: Transmittal of Updated Incident Data from the Ecological Fate and Effects Division, dated June 3, 2021.
               
 December 2021  -  The Agency completed the Amitraz: Interim Registration Review Decision (ID) and will post it to the public docket.

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

During the 60-day public comment period for the amitraz PID, which opened on August 3, 2021 and closed on October 4, 2021, the Agency received public comments from two sources. Comments were received from the United States Department of Agriculture (USDA), and the People for the Ethical Treatment of Animals (PETA). The Agency's responses to these comments are below. The Agency thanks USDA and PETA for their comments and has considered them in developing this ID. 
               
Comments submitted by USDA (Docket ID EPA-HQ-OPP-2009-1015-0034)

Comment: USDA recognizes amitraz as a high-benefit tool for beekeepers and is one of the few alternatives available that is safe, efficacious, and cost-effective. USDA appreciated EPA's recognition of the agricultural importance of amitraz for varroa control in honey bee hives, and that this benefit was characterized within the context of the Agency's risk concerns for bees themselves. USDA fully supported EPA's PID, including the proposal to maintain a 0.2 ppm amitraz tolerance for honey, to harmonize with the European Union's maximum residue level (MRL). USDA also supported EPA's "no effect" determination for consultation purposes under the Endangered Species Act.

EPA Response: The Agency thanks USDA for their comments and support.

Comments Submitted by People for the Ethical Treatment of Animals (PETA) (Docket ID: EPA-HQ-OPP-2009-1015-0035).	
    
   Comment: PETA applauded OPP's Health and Effects Division for relying on human in vitro data to update the human dermal absorption factor (DAF) in the revised draft human health risk assessment. PETA also requested that the Agency publish a policy allowing waivers for the rat in vivo and the rat in vitro dermal absorption test to ensure that registrants are aware of the Agency's willingness to accept only the relevant human in vitro data to allow for robust risk assessment and timely protection of human health and the environment that is not delayed by the conduct of tests not needed or used by the Agency.
   
   EPA Response: The Agency thanks PETA for its support of its use of human in vitro data in the revised draft human health risk assessment and appreciates the recommendations. The Agency is not currently developing a policy document regarding the use of human in vitro data; however, EPA is working on updating the Organisation for Economic Co-operation and Development (OECD) 156 dermal guidance, which will indicate that the United States and Canada have shifted to using in vitro studies alone. With respect to waivers, a waiver for the animal-based study is not necessary when a human in vitro study is submitted to the Agency instead. 
   
II. 	USE AND USAGE                     

   Amitraz is a contact acaricide classified by the Insecticide Resistance Action Committee (IRAC) as a Group 19 (an octopamine receptor agonist) chemical, which activates receptors in the central nervous system leading to hyperexcitation in ticks and mites (IRAC 2021). The distinct biochemical mechanism of amitraz is different from any of the other major classes of insecticides (Ahmed and Matsumura 2012). There are currently only two end-use amitraz products, one for impregnated strips for beehives and the other for impregnated dog collars. When dogs wear the collar impregnated with amitraz, they are protected from ticks for up to 90 days. In addition, upon exposure to amitraz, ticks already feeding on dogs detach and die (Hollingworth 1976, Dawkins and Gladney 1978). The strips to control varroa mites on honey bees in beehives exert control for up to 56 days.  

Impregnated Strips for Beehives Usage

The only survey of beehive chemical use known to EPA is a state-level survey for use in California for the years between 2013 and 2017. The survey indicates an annual average of 300 lbs of amitraz was reported for use in beehives (CDPR, 2018). 

Dog Collar Usage

According to non-agricultural market research data, 30% of respondents who owned dogs in a 2019 survey used a type of impregnated collar on dogs to target ticks (this includes all active ingredients with dog collar uses for ticks). Approximately 3,600 lbs of amitraz were reported to be used in dog collars in 2019 (NMRD, 2019b). 

III.	SCIENTIFIC ASSESSMENTS 
    
A.	Human Health Risks  
    
   The Agency has summarized the updated amitraz human health risk assessment below. The Agency used the most current science policies and risk assessment methodologies to prepare this risk assessment in support of the registration review of amitraz. For additional details on the human health assessments for amitraz, see Amitraz: Human Health Draft Risk Assessment for Registration Review, Amitraz: Response to Comments on the Draft Human Health Risk Assessment for Registration Review, and Amitraz: Revised Draft Human Health Risk Assessment for Registration Review, in EPA's public docket (EPA-HQ-OPP-2009-1015).
     
 Risk Summary  
   
   The 2018 Amitraz: Human Health Draft Risk Assessment for Registration Review identified potential human health risks of concern for the dog collar use, including residential handler risks, residential post-application risks, and occupational handler risks. 
   
Since the 2018 risk assessment, a revised human health risk assessment was completed in 2021. Numerous refinements were incorporated into this assessment based on comments received and additional data submissions. As a result of these refinements, Amitraz: Revised Draft Human Health Risk Assessment for Registration Review concluded that there are no human health risks of concern. Changes incorporated into the revised risk assessment included:
 The use of human in vitro dermal absorption data alone to derive the dermal absorption factor (DAF), resulting in a revised DAF of 1%.
 Additional brain morphometric data from the extended one-generation reproduction toxicity study (EOGRTS) were submitted, evaluated, and integrated into the revised risk assessment.
 The interspecies uncertainty factor (UFA) for chronic dietary, incidental oral, dermal, and inhalation exposures was reduced from 10X to 3X to account for interspecies extrapolation (reduced based on unique toxicodynamic differences in human versus rat with respect to thyroid homeostasis).
 In the previous DRA, a tolerance level of 0.1 ppm was recommended for amitraz in honey. Based on comments received from the registrant, EPA is retaining the current 0.2 ppm tolerance for honey.
 The acute and chronic dietary assessments have been revised to reflect the current tolerance level for honey. The chronic dietary assessment has been revised to reflect an updated chronic population adjusted dose (cPAD) (based on the updated UFA). 
 An updated pet collar assessment was completed that incorporated submitted data that allowed refinement of the liquid to dust ratio and a refined transferable residue factor from the existing transferable residue study.
 Updated residential and occupational dermal exposures reflecting an updated DAF of 1%. 
 Updated residential and occupational assessments reflecting a revised level of concern (LOC) of 300 (based on the updated UFA).
 An aggregate (residential plus dietary exposure) assessment was conducted. An aggregate assessment was not performed in the previous assessment. 
 Updated Tier 1 review of human health incidents. 
             
   Cumulative Risks 
   
EPA has not made a common-mechanism-of-toxicity-to-humans finding for amitraz and any other substance. Amitraz does not appear to produce a toxic metabolite produced by other substances. Therefore, EPA has premised this ID and the underlying risk assessments on the conclusion that amitraz does not have a common mechanism of toxicity with other substances.
   
 Human Incidents and Epidemiology 

EPA reviewed amitraz incidents reported to the Office of Pesticide Programs database. As of EPA's latest search on August 2, 2018, there were nine cases reported to the Main Incident Data System (IDS) from January 1, 2013 to March 1, 2018, that involved the active ingredient amitraz. Of these nine case reports, four incidents involved the single active ingredient amitraz (only). These incidents involved adults and were classified as moderate severity. Three of the cases involved contact with a dog collar and the fourth involved ingestion of "dog flea medication." Reported symptoms included headache, vomiting, malaise, ocular swelling, and respiratory distress. The other five amitraz incidents reported involved multiple active ingredients. A search was conducted in Aggregate IDS. From January 1, 2013 to March 1, 2018, there were 72 incidents reported involving amitraz. Seventy incidents were classified as minor severity and two incidents had no or unknown severity. 

A query of the Center for Disease Control's National Institute for Occupational Health (CDC/NIOSH) SENSOR-Pesticides database identified 27 cases involving amitraz from 1998 to 2014. Twenty-two cases were low in severity, four cases were moderate in severity, and one case was high in severity. The high severity case was a child who accidentally ingested a spoonful of flea dip mistaken by an adult for cough medicine. Of the 27 amitraz cases, sixteen cases were occupational, and eleven cases were non-occupational. The occupational and non-occupational case exposure scenarios are delineated in D448216. The majority of all amitraz cases (19 cases) involved the application of amitraz-containing products (including flea dips, collars, and spot-on products) onto pets. Eighty-one percent of amitraz cases reported in SENSOR were low in severity. Ocular symptoms, primarily eye pain/irritation/inflammation, were most frequently reported among cases. Dermal symptoms including skin rashes, skin redness and pain were also commonly reported. Gastrointestinal symptoms including nausea and vomiting were reported in seven cases. Additional details regarding these incidents are described in Amitraz: Tier I Update Review of Human Incidents and Epidemiology for Draft Risk Assessment from 2018, which is located in the amitraz registration review docket (www.regulations.gov, docket document number EPA-HQ-OPP-2009-1015-0015).
 
   In an updated search for human incidents from January 1, 2018 to April 20, 2021, in Main IDS there was one incident reported that involved the active ingredient amitraz. This incident was classified as moderate severity and involved multiple active ingredients (amitraz, fipronil, and s-methoprene). There were two amitraz incidents reported in Aggregate IDS. These incidents were classified as minor severity. From 2015 to 2017, the SENSOR-Pesticides analysis identified no incidents involving amitraz. 
   
   Based on the continued low frequency of amitraz incidents reported to both IDS and SENSOR-Pesticides, there does not appear to be a concern at this time. The Agency will continue to monitor the incident information. The Agency intends to monitor human incidents for amitraz and will conduct additional analyses if necessary.
   
 Tolerances  

Amitraz is registered for uses that result in residues in or on food. Generally, a tolerance or tolerance exemption -- and for some uses, Food and Drug Administration (FDA) regulations or food contact notifications -- must cover the residues or the affected food is considered adulterated.  EPA has concluded that all of the necessary tolerances, exemptions, and FDA clearances are in place to cover residues resulting from amitraz's legal use.

The Agency has established tolerances for amitraz under 40 C.F.R. §180.287 for livestock commodities. EPA determined that revocations of these tolerances are necessary because there are no longer registered uses on livestock (dermal treatment) and there are no uses on livestock feedstuffs. A summary of these anticipated revocations is presented in Section IV.C.

There are no Codex MRLs established for amitraz. The EU has established an MRL for amitraz residues in honey at 0.2 ppm. Canada has established an MRL of 0.1 ppm in honey, which is lower than the U.S. tolerance of 0.2 ppm. The Agency intends to maintain the current 0.2 ppm level to ensure harmonization with the EU MRL based on concerns expressed by Veto-pharma about reducing the tolerance to 0.1 ppm. Although the 0.2 ppm tolerance level is higher than the Canada MRL of 0.1 ppm, and Canada is a major honey trade partner with the U.S., it is unlikely that amitraz will be found in U.S. honey above the 0.1 ppm MRL based on available data. For more details, please see the Amitraz Response to Comments on the Draft Human Health Risk Assessment for Registration Review (dated July 25, 2019). 
   
 Human Health Data Needs 

The data needs identified in Section IIII of this document are already covered by GDCI- human health database for amitraz is mostly complete. There is the lack of thyroid hormone measurements in post-natal day 5 (PND 5) pups in the EOGRTS in rats to assess potential qualitative or quantitative susceptibility. The Agency is working with the amitraz registrants to determine a timeline for the submission of these data. The FQPA Safety Factor of 10X is retained as a database uncertainty factor. Until these data are submitted, a database uncertainty factor of 10X has been retained for all exposure scenarios being assessed for amitraz except for acute scenarios for which thyroid toxicity is not pertinent. 
   
B.	Ecological Risks 
    
   The Agency has summarized the 2018 ecological risk assessment 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 amitraz. For additional details on the ecological assessment for amitraz see the Amitraz: Draft Ecological Risk Assessment for Registration Review and Amitraz: Response to Comments on the Draft Ecological Risk Assessment for Registration Review, in EPA's public docket (EPA-HQ-OPP-2009-1015). 
                             
 Risk Summary
               
   The Agency has not identified any ecological risks of concern for amitraz with the exception of potential risk to honey bees from impregnated strips placed in beehives. The Agency concluded that there are no relevant environmental exposure pathways to consider for the dog collar use. The Agency has concluded that the current registrations of amitraz present limited exposure potential to non-target organisms outside of the hive, including federally listed species. Therefore, a "No Effect" determination is made for all federally listed species. However, since the product requires honey bees to contact the product strips, exposure to honey bees within the hive is expected and there may be risk associated with these exposures. There is no reasonable expectation for any registered use of amitraz 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 amitraz.  
   
 Ecological Incidents                                  

A search of the Incident Data System (IDS) for amitraz was conducted in support of risk assessment for reports between the time amitraz was first registered until January 2018. EPA's review of the Incident Data System (IDS) to support the 2018 ecological risk assessment yielded 88 incidents that associate use of amitraz with bee kills. Most of the incidents reported up to 2014 involved the legal use of the now cancelled in-hive "Muticum" product (Reg. No. 54382-5; an impregnated strip of amitraz). In addition, there are two recently reported incidents which involved the Apivar product (Reg. No. 87243-1). Where sufficient details are available for the two recent incidents, it appears that while Apivar was used in the hives as intended by the label, the presence of other highly toxic insecticides were detected (e.g., Incident ID# I029385-00001). The magnitude of effects reported in these incidents ranged from several hives to thousands of hives. 

The Incident Data System (IDS) was reviewed for amitraz incidents that may have occurred since the draft ecological risk assessment was completed. This search excluded incidents classified as `unlikely' or `unrelated' and only includes incidents with the certainty categories of `possible' or, `probable'. There were two incidents reported since January 1, 2018, both of which were associated with bee kills. Multiple pesticides were present; therefore, there is uncertainty that the incidents were due to amitraz exposure. Thus, these incidents are classified as "possible".  
   
   Please see the Amitraz: Preliminary Ecological Risk Assessment and Endangered Species Assessment for Registration Review and Amitraz: Transmittal of Updated Incident Data for more information about reported ecological incidents for amitraz. EPA will continue to monitor ecological incident information as it is reported to the Agency. 
   
 Ecological and Environmental Fate Data Needs 

The environmental fate and ecological effects database for amitraz is complete. The Agency does not expect any further environmental fate and ecological effects data needs for amitraz.  
 
C.	Pet Incidents

A query of Aggregate Incident Data System (IDS) domestic animal incidents from January 1, 2016 to December 31, 2020 found a total of 109 reported domestic animal incidents for the amitraz pet product, Preventic Tick Collar for Dogs (Reg. No. 002382-00104). These domestic animal incidents included two animal deaths, three major severity incidents, 56 moderate severity incidents, 47 minor severity incident and one incident that had no or unknown effects (Table 1). The available aggregate incident data for this time period do not specify whether the domestic animal affected is a dog or another species. The Agency will continue to monitor domestic animal incident data as it is reported to the Agency.  
   In its efforts to protect pets under FIFRA, EPA proposed requesting enhanced incident reporting and sales data for pet products akin to what is already submitted for spot-on products (https://www.epa.gov/pets/epa-evaluation-pet-spot-products-analysis-and-plans-reducing-harmful-effects) as part of the amitraz PID. These data would allow the Agency to conduct a comparative assessment of pet incidents across registered pet products based on sales data to better determine whether any changes to the pet product registrations and labels are necessary. 
   
   During the public comment period for the amitraz PID, EPA did not receive feedback from stakeholders on this proposal, nor did it receive comments on the most efficient way these data can be provided to the Agency and types of analyses that could be submitted to expedite the Agency's assessment. The Agency also requested feedback through comment periods for other PIDs, including the pyrethrins, MGK-264, and piperonyl butoxide. EPA will respond to any comments received on this topic from the other comment periods and decide on a path forward as a separate action.

Table 1. Preventic Tick Collar (Reg. No. 002382-00104) Aggregate Incidents 2016-2020 (OPP Aggregate IDS)
                                     Years
                                     Animal
                                    Death[a]
                               Major Severity[b]
                              Moderate Severity[c]
                              Minor Severity[d] 
                            No or Unknown Effects[e]
                                     2016
                                       1
                                       0
                                       31
                                      28
                                       0
                                     2017
                                       0
                                       2
                                       16
                                      10
                                       1
                                     2018
                                       1
                                       1
                                       6
                                       5
                                       0
                                     2019
                                       0
                                       0
                                       3
                                       2
                                       0
                                     2020
                                       0
                                       0
                                       0
                                       2
                                       0
                                  Grand Total
                                       2
                                       3
                                       56
                                      47
                                       1

                                        
                                        
                                        
                                       
                                        
      a Death  -  if the domestic animal died or was euthanized 
      b Major  -  if the domestic animal exhibited or was alleged to have exhibited symptoms which may have been life-threatening or resulted in residual disability 
      c Moderate  -  if the domestic animal exhibited or was alleged to have exhibited symptoms which are more pronounced, more prolonged or of a more systemic nature than minor symptoms and included some treatment and return to pre-exposure state
      d Minor  -  if the domestic animal was alleged to have exhibited symptoms, but they were minimally bothersome and resolved rapidly
      e Unknown  -  if symptoms are unknown or not specified


 Benefits Assessment                 
         
   Benefits of impregnated strips to control varroa mite in honey bee hives

The varroa mite, Varroa destructor (hereafter varroa), is the only target pest of amitraz-impregnated strips for use in honey bee (Apis mellifera) hives. Varroa is a parasite that feeds destructively on fat bodies in pupae and adult honey bees. Varroa also transmits many viruses to its host, including deformed wing and black queen cell, both of which are closely associated with significant colony losses (Sinkevich 2020). Minimizing harm to honey bees is essential while simultaneously controlling varroa. Including amitraz-impregnated strips, chemical control products labelled for control of varroa in honey bee hives are synthetic pesticides (amitraz, tau-fluvalinate, and coumaphos), two organic acids (formic and oxalic acids), and two plant derivatives (thymol and hop beta acids).

Amitraz, tau-fluvalinate, and coumaphos were used early and widely after varroa's introduction into the United States. However, there is now widespread control failure due to high levels of resistance to tau-fluvalinate and coumaphos (DeGrandi-Hoffman et al. 2012, Rinkevich 2020, Peck 2021). In addition, wax absorbs and maintains high levels of tau-fluvalinate and coumaphos (both lipophilic chemicals), and varroa are constantly exposed to sub-lethal levels of pesticide residues (Rinkevich 2020), likely contributing to pesticide resistance issues. Constant presence of tau-fluvalinate and coumaphos in the wax may also harm developing bees (DeGrandi-Hoffman et al. 2012, Peck 2021). 

While organic acids and plant derivatives also provide effective control, there are limitations with each respective chemistry. Formic and oxalic acids and thymol are sensitive to ambient temperatures (DeGrandi-Hoffman et al. 2012, Peck 2021), and efficacy of thymol is also affected by humidity and colony size (DeGrandi-Hoffman et al. 2012). Higher temperatures with formic acid applications can harm bees and cause queen loss (DeGrandi-Hoffman et al. 2012). Thymol imparts a detectable odor to treatment equipment and in honey (Peck 2021). Impregnated strips with hop beta acids need to be reapplied more frequently, every 14 to 30 days, compared to amitraz-impregnated strips that last up to 56 days. 

Amitraz is considered by beekeepers to be a highly effective miticide of choice (Peck 2021). However, resistance to amitraz was reported in Minnesota shortly after its initial use in the late 1990's (Elzen et al. 2000). In 2019, amitraz resistance was suspected and ultimately detected from among some of the sampled commercial apiaries in Louisiana, New York, and South Dakota. Apiaries had at least a three-year history of using amitraz, and despite a long history of amitraz use, five of the eleven apiaries had no or low levels of resistance (Rinkevich 2020). Despite significant variation in control of varroa across individual colonies in an apiary or apiaries within the larger operation, amitraz is still regarded as an effective varroa control option (Rinkevich 2020).

In conclusion, amitraz-impregnated strips are the preferred tool by apiarists for control of varroa (Peck 2021). Amitraz does not have temperature, humidity or colony size limitations when applied to beehives. With the exception of tau-fluvalinate, amitraz has the longest treatment duration of the available products. This provides a convenience to end users in limiting the number of times retreatment of colonies is needed. Overall, amitraz-impregnated strips provide end users with an application method and chemical properties that may be preferable to other available varroa control products, some of which have widespread resistance issues.

Benefits of impregnated dog collars to control ticks

Multiple species of ticks are targets of amitraz in impregnated dog collars. Amitraz is part of a suite of active ingredients that help to control tick species of public health concern, including the brown dog tick (Rhipicephalus sanguineus), American dog tick (Dermacentor variabilis), and blacklegged tick (Ixodes scapularis) on domestic dogs. Tick prevention not only protects dogs, but it also prevents the transport of ticks into the home. For dogs in the U.S. in 2020, there were almost 900,000 cases of tick-borne disease reported (CAPC, 2021). Some ticks carry pathogens that can lead to sixteen different human diseases (CDC, 2020). The blacklegged tick, for example, vectors the pathogen that causes Lyme disease in humans. Between 2017 and 2019, there was a national mean cumulative incidence of 49 Emergency Department (ED) tick bite visits per 100,000 ED visits overall, with the highest incidence of 110 tick bite visits per 100,000 visits to the ED in the Northeastern U.S. alone (Marx et al. 2021).

For controlling ticks on dogs, pet owners have multiple options, among which include the use of a collar impregnated with insecticide, spot-on treatments containing insecticides, or a prescribed veterinary medication. These three types of products were the most used among respondents in 2019 for controlling ticks on dogs (NMRD 2019a). All commercially available collars can be applied to dogs to provide three to eight months of protection against ticks. This is in contrast to spot-on treatments and some veterinary medicine (prescription only) chewable tablets that provide a single month of control against the same pests. The Agency's earlier review of pet products that are possible alternatives to the pet collars impregnated with the organophosphate tetrachlorvinphos concluded that pet spot-ons are less convenient because they must be reapplied every month (Atwood and Smearman 2017). Veterinary medicines require a prescription, with pet owners incurring the additional cost of an office visit, thus they tend to be less convenient to obtain and use (Atwood and Smearman 2017). Amitraz-impregnated collars may be more convenient than many likely alternative products, including more commonly used pet spot-ons and veterinary medicines, because the amitraz collar is applied for three months of control, and a prescription from a veterinarian is not required to obtain it. 

Collars containing insecticides other than amitraz are equally as convenient as those with amitraz and may cost less monthly than amitraz collars (Atwood and Smearman 2017). However, acaracide resistance is a concern with any tick species of public health importance. There is documented resistance to permethrin and tolerance to fipronil among populations of the brown dog tick in Florida and Texas (Eiden et al. 2015). These two active ingredients are found in many pet products. For areas where there is acaricide resistance, amitraz may provide another control option for ticks on dogs. 

In conclusion, amitraz-impregnated dog collars may be more convenient and/or cost-effective than many likely alternative products. Amitraz is important in tick control since it provides an additional mode of action when resistance occurs with other active ingredients.

IV.   INTERIM REGISTRATION REVIEW DECISION 
    
   Risk Mitigation and Regulatory Rationale 
          
   The Agency has reviewed the risks and benefits associated with the registered uses of amitraz in developing this Interim Registration Review Decision. The Agency has determined that there are no human health or ecological risks of concern except for potential risk to honey bees from impregnated strip use in beehives. The Agency has also determined that thyroid hormone measurements in PND 5 rat pups are needed to confirm the human health risk conclusions in the risk assessment and is working with the registrants to determine a timeline for the submission of these data. EPA has also made a "no effect" determination for currently registered uses of amitraz under the Endangered Species Act for all listed species and designated critical habitat for those species.
   
   While there are potential risks to honey bees from amitraz strip use, these risks are likely much lower than alternative chemistries that target varroa mites. Additionally, this use provides benefits to beekeepers because of amitraz's long duration of efficacy (and corresponding limited need for retreatment) as compared to many alternatives, an application method preferred by many beekeepers, and amitraz's lack of temperature, humidity or colony size limitations when applied to beehives. Based on the limited risk profile and the aforementioned benefits, the Agency is not requiring any mitigation and has concluded that the FIFRA registration standard is met for the use of amitraz-impregnated strips in beehives pending submission and evaluation of the aforementioned PND 5 data.
   
   In addition to the aforementioned PND 5 data, to determine whether the FIFRA registration standard is met for the dog collar use, EPA proposed requesting enhanced incident reporting and sales data for the Preventic collar akin to what is submitted for spot-on products (https://www.epa.gov/pets/epa-evaluation-pet-spot-products-analysis-and-plans-reducing-harmful-effects). These data would allow the Agency to conduct a comparative assessment of pet incidents across registered pet products based on sales data to better determine whether any changes to the pet product registrations and labels are necessary. The Agency also requested feedback through comment periods for other PIDs, including the pyrethrins, MGK-264, and piperonyl butoxide. EPA will respond to any comments received on this topic from the other comment periods and decide on a path forward as a separate action.

      B.	Environmental Justice 
   
EPA 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. EPA has conducted assessments of risks to individuals who handle amitraz products or may be exposed to them and found no risks of concern per Section III.A.1. Additionally, the Agency has considered that pet collars are a readily available and relatively inexpensive way of controlling pests on dogs, providing an affordable option for lower income populations. For example, ticks are important public health pests, and amitraz-impregnated dog collars may be more convenient and/or cost-effective for their control than other products (See Benefits Assessment Section III.D) that require veterinarian visits. While veterinary visits for prescription products may be less convenient and/or cost-effective than over-the-counter products such as the amitraz dog collar, data suggest that income is probably not a limiting factor in the availability of veterinary-supplied pest control products (Atwood and Smearman 2017).

The Agency sought information during the public comment period on any other groups or segments of the population who, as a result of their location, cultural practices, or other factors, may have atypical, unusually high exposure to amitraz compared to the general population or who may otherwise be disproportionately affected by the use of amitraz as a pesticide. EPA did not receive any comments concerning environmental justice.   
   
 Tolerance Actions	
   
The Agency determined that tolerances for residues of amitraz in livestock commodities should be revoked because there are no longer registered uses on livestock (dermal treatment) and there are no uses on livestock feedstuffs. The Agency therefore plans to exercise its FFDCA authority to revoke these tolerances for amitraz as summarized in Table 2, below.
   
Table 2.   Anticipated Changes to Tolerances for Amitraz: 40 CFR §180.287
   Commodity/Correct Definition
Established Tolerance (ppm)
   Anticipated
   Tolerance (ppm)
   Comments
   
   Cattle, fat
   0.1
                                    Revoke
   
               No U.S. registrations on livestock or feedstuffs

   Cattle, meat
   0.02
   
   
   Cattle, meat byproducts
   0.2
   
   
   Hog, fat
   0.1
   
   
   Hog, kidney
   0.1
   
   
   Hog, liver
   0.1
   
   
   Hog, meat
   0.05
   
   
   Hog, meat byproducts
   0.3
   
   
   Milk
   0.03
   
   
   Milk, fat
   0.2
   
   
     ppm=parts per million; equivalent to milligrams per kilogram [mg/kg].
   
D.	Interim Registration Review Decision  

	The Agency is issuing this ID in accordance with 40 CFR §§155.56 and 155.58. Except for the Endocrine Disruptor Screening Program (EDSP) the Agency has made the following interim decision: 1) EPA has determined that PND 5 thyroid hormone data are needed to support existing amitraz registrations; (2) EPA may require enhanced pet incident and sales data, which the Agency intends to address through a separate action; and 3) no changes to the affected registrations and their labeling are needed at this time, as described in Section IV. A of this document. 

EPA did not identify any human health or ecological risks of concern apart from potential adverse effects to honey bees from impregnated strip use in beehives. Risks to honey bees from this use are likely much lower than alternative chemistries that target varroa mites and provide cost, convenience, and flexibility benefits to beekeepers. Therefore, the Agency is not making any mitigation for this use and has concluded that the FIFRA registration standard is met for the use of amitraz-impregnated strips in beehives pending submission and evaluation of PND 5 thyroid hormone measurement data.

In addition to the aforementioned PND 5 data, to determine whether the dog collar use meets the FIFRA registration standard, EPA is considering requesting enhanced incident reporting and sales data that will help the Agency determine whether any changes to the dog collar registration and label are necessary. The Agency will make a decision regarding the possible data request as a separate action.

In this ID, the Agency is making no human health or environmental safety findings associated with the Endocrine Disruptor Screening Program (EDSP) screening of amitraz. The Agency's final registration review decision for amitraz will be dependent upon the result of the EDSP FFDCA § 408(p) determination. For more information, see Appendix B.

E.	Data Requirements  
         
   EPA has determined that PND 5 thyroid hormone measurement data in rats are needed, as EPA is considering requesting submission of enhanced pet incident and sales data as a separate action.  The Agency will work with the amitraz registrants to determine a timeline for the submission of PND 5 thyroid hormone measurement data in rats, which are considered a data gap, and may issue another DCI if needed. The Agency is also considering requesting submission of enhanced pet incident and sales data as a separate action.
   
V. 	NEXT STEPS AND TIMELINE  
    
 Interim Registration Review Decision 

    A Federal Register Notice will announce the availability of the amitraz ID. A final registration    review decision for amitraz will only be made after EPA completes (1) a FIFRA determination for the pet collar use and (2) an EDSP determination.
    
 Implementation of Mitigation Measures   
               
   Because the Agency has determined that mitigation measures and label language clarifications are not needed for the registration review of amitraz at this time, the Agency is not requesting submission of revised amitraz labels as part of this ID. 

VI.    REFERENCES 

   Ahmed, M.A.I. and F. Matsumura. 2014. Synergistic actions of formamidine insecticides on the activity of pyrethroids and neonicotinoids against Aedes aegypti (Diptera: Culicidae). Journal of Medical Entomology. 49: 1405-1410. Available online: https://doi.org/10.1603/ME12030
   
   Atwood, D., and S. Smearman. 2017. Alternatives Assessment for Tetrachlorvinphos (TCVP) (PC Code 083702) Impregnated Flea and Tick Collars on Dogs and Cats. Biological and Economic Analysis Division, Office of Pesticide Programs, U.S. EPA. 27 pp. Available online: https://www.regulations.gov/docket?D=EPA-HQ-OPP-2008-0316.
   
   [CAPC] Companion Animal Parasite Council. 2021 Parasite prevalence maps. Available online: https://www.petsandparasites.org/parasite-prevalence-maps#/2018/all/lyme-disease/dog/united-states/ (Accessed April 2021).
   
   California Department of Pesticide Regulation California (CDPR) Pesticide Use Reports (PUR). 2018. Data Files: 2013-2017. [Accessed April 2021].
   
   [CDC] Centers for Disease Control. 2020. Diseases transmitted by ticks in the U.S. Available online: https://www.cdc.gov/ticks/diseases/index.html. (Accessed April 2021).
   
   Dawkins, C.C., and W.J. Gladney. 1978. Detachment of four species of ticks (Acari: Ixodidae) Exposed to selected formamidine compounds. Journal of Economic Entomology. 71: 657-660. Abstract available: https://doi.org/10.1093/jee/71.4.657
   
   DeGrandi-Hoffman, G., F. Ahumada, G. Probasco, and L. Schantz. 2012. The effects of beta acids from hops (Humulus lupulus) on mortality of Varroa destructor (Acari: Varroidae). Experimental and Applied Acarology. 58: 407-421. Available online: https://link.springer.com/content/pdf/10.1007%2Fs10493-012-9593-2.pdf
   
   Eiden, A.L., P.E. Kaufman, F.M. Oi, S.S. Allan, and R.J. Miller. 2015. Detection of permethrin resistance and fipronil tolerance in Rhipicephalus sanguineus (Acari: Ixodidae) in the United States. Journal of Medical Entomology. 53: 429-436. Available online: https://doi.org/10.1093/jme/tjv005
   
   Elzen, P.J., J.R. Baxter, M. Spivak, and W.T. Wilson. 2000. Control of Varroa jacobsoni Oud. Resistant to fluvalinate and amitraz using coumaphos. Apidologie. 31: 437-441. Available online: https://www.apidologie.org/articles/apido/pdf/2000/03/m0312.pdf
   Hollingworth, R.M. 1976. Chemistry, biological activity, and uses of formamidine pesticides. Environmental Health Perspectives. 14: 57-69. Available online: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1475108/pdf/envhper00489-0059.pdf
   
   IRAC. 2021. Insecticide Resistance Action Committee Modes of Action. Available online: https://irac-online.org/modes-of-action/. Accessed March 2021.
   Marx, G.E., M. Spillane, A. Beck, Z. Stein, A.K. Powell, A.F. Hinckley. 2021. Emergency department visits for tick bite  -  United States, January 2017  -  December 2019. Morbidity and Mortality Weekly Report. U.S. Department of Health and Human Services/Centers for Disease Control and Prevention. 70: 612-616. Available online: https://www.cdc.gov/mmwr/volumes/70/wr/pdfs/mm7017a2-H.pdf
   
   Nonagricultural Market Research Data (NMRD). 2019a. Study on consumer markets for pesticides and fertilizers.  [Accessed March 2021]
   
   Nonagricultural Market Research Data (NMRD). 2019b. Study on consumer markets for pesticides and fertilizers.  Personal communication with C. Doucoure. Email dated March 23, 2021.
   
   Peck, D.T. 2021. The parasitic mite Varroa destructor: History, biology, monitoring, and management. pp. 235-252. In C.M. Faux and T.R. Kane (eds). Honey Bee Medicine for the Veterinary Practitioner, John Wiley, and Sons.
   
   Rinkevich, F.D. 2020. Detection of amitraz resistance reduced treatment efficacy in the varroa mite, Varroa destructor, within commercial beekeeping operations. PLOS ONE 15. Available online: https://doi.org/10.1371/journal.pone.0227264
   
   USEPA. 2007. Exposure and Fate Assessment Screening Tool (E-FAST) (ver 2.0). USEPA, Office of Pollution Prevention and Toxics Exposure Assessment Branch. October 2007. 174 pp. https://www.epa.gov/sites/production/files/2015-04/documents/efast2man.pdf
   
   USEPA. 2016. Preliminary Comparative Environmental Fate and Ecological Risk Assessment for the Registration Review of Eight Synthetic Pyrethroids and Pyrethrins: Part I. Assessing Pyrethroid Releases to POTWs. Office of Pesticides Program, Environmental Fate and Effects Division. DP 425791. 
   
   



Appendix A:  Endangered Species Act Determination 

  There is no reasonable expectation for any registered use of amitraz to cause direct or indirect adverse effects to threatened and endangered species. No adverse modification of critical habitat is expected from the use of amitraz. This is because of lack of exposure to listed species from currently registered amitraz uses. EPA has made a "no effect" determination under the Endangered Species Act (ESA) for all listed species and 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.


Appendix B:  Endocrine Disruptor Screening 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, 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, 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 amitraz, 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), amitraz 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.  
   
  Under FFDCA § 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 pesticide active ingredients and 9 inert ingredients. The Agency has reviewed all 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, 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. Amitraz 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 EPA website.  
  
  In this ID, EPA is making no human health or environmental safety findings associated with the EDSP screening of amitraz. Before completing this registration review, the Agency will make an EDSP FFDCA § 408(p) determination. 




