Page 1 of 27 UNITED STATES ENVIRONMENTAL PROTECTION AGENCY WASHINGTON, D.C. 20460

OFFICE OF
CHEMICAL SAFETY AND

POLLUTION PREVENTION

MEMORANDUM

Date: November 8, 2010

SUBJECT: Tau-Fluvalinate. Human Health Assessment Scoping Document in Support of Registration Review.

PC Code: 109302 DP Barcode: D378275 Decision No.: 434039 Registration No.: NA Petition Nos.: NA Regulatory Action: NA Risk Assess Type: Single Chemical Aggregate (Registration Review Problem Formulation) Case No.: 2295

TXR No.: NA CAS No.: 102851-06-9

MRID No.: NA 40 CFR: 180.427

FROM: Danette Drew, Chemist Ideliz Negrón-Encarnación, Ph.D., Chemist Ana Rivera-Lupiáñez, Chemist William A. Irwin, Ph.D., Toxicologist

Risk Assessment Branch V Health Effects Division (7509P) Office of Pesticide Programs

THRU: Jack Arthur, Branch Chief

Risk Assessment Branch V Health Effects Division (7509P) Office of Pesticide Programs

TO: Molly Clayton, Chemical Review Manager

Pesticide Re-evalu ation Division (7508P) Office of Pesticide ProgramsPage 2 of 27 Executive Summary

Tau-fluvalinate, a type II class pyrethroid, is re gistered as a post-emergent insecticide/miticide for the control of a variety of insects in beeh ives and various outdoor or greenhouse settings. There are five EPA registered products: a techni cal grade for formulating end-use products, three liquid formulations and the impregnated plastic st rips used for beehives. Tau-fluvalinate has two special local needs (SLN) registrations for Calif ornia for use on carrots, brassica vegetables, and cole crops (non-food uses; crops are grown for s eed). There is a tolerance for residues of taufluvalinate on honey (0.02 ppm; 40 CFR 180.427), the only registered food use.

The last detailed human health risk a ssessment was completed in 2005 (S. Stanton et al.

, D321911, 9/29/05). The Re-registration Eligibility Decision (RED) was issued in September

2005.

The available toxicity data for tau-fluvalinate are adequate to assess the chemical’s hazard potential although there are severa l data gaps. An immunotoxicity study is required as a part of new data requirements for conventional pestic ide registration (40 CFR Part 158). An acute inhalation study is required as well as a 90-day/28-day inhala tion study. In addition, a 90-day dermal study is now required for non-food use app lications. An acute neur otoxicity study is also being required.

The developmental n eurotoxicity study ( DNT) was previously not reque sted for tau-fluvalinate. However, the Agency has new information regardi ng the potential for increased susceptibility in juveniles from pyrethroid exposures , and therefore, the guideline DNT requirement is maintained for all pyrethroids including tau-fluvalinate. De spite the existing DNT requirement, the Agency

has determined that conducti ng additional DNT studies on any pyrethroids is not likely to

contribute new information releva nt for risk assessment. EPA believes the existing DNTs on six pyrethroids (bifenthrin, cyfluthrin, cyhalothri n, cypermethrin, fenpropath rin and deltamethrin) provide sufficient information to determine th at the conclusions drawn from the DNTs, as combined, are applicable to all pyrethroids. Thus , EPA is hopeful that th e registrants with DNT requirements will elect to cite the existing database to satisfy the DNT requirement rather than devoting new substantial resources associated with performing and evaluating new DNT studies. Detailed considerations supporting th is conclusion can be found in “ Pyrethroids: Evaluation of Data from DNTs & Considerati on of Comparative Sensitivity” (E. Scollon, 1/20/10, D371723),

available at http://www.epa.gov/oppsrrd1/reevalua tion/pyrethroids-pyrethrins.html . In an effort to ensure the highest level of protection of infants and child ren, the Agency is continually reviewing scientific data rega rding the potentially increased susceptibility of pyrethroid pesticides as it becomes available. Therefore, the tau-fluvalinate risk as sessment may need to be revised to incorporate future findings.

Subsequent to the last risk assessment, the Ag ency has identified age- dependent pharmacokinetic factors associated with all pyrethr oid insecticides that may lead to uncertainty regarding effects

in children. Therefore, HED is recommending that th e toxicological points of departure and safety/uncertainty factors used for tau-flu valinate human health risk assessment be re-Page 3 of 27 evaluated during registration review. Once the outstanding data have been received, they will be evaluated for accepta bility and for suitability for use in the risk assessment.

The most recent acute and chronic dietary expos ure assessments were unrefined and used 100% crop treated assumptions and tolera nce-level residues in honey (the on ly registered food use is in beehives). An FQPA safety factor of 1X was used. Exposure from drinking water was incorporated in the acute and chronic risk as sessments using surface water estimated drinking water concentrations (EDWC). The acute and ch ronic dietary risk assessments (using DEEM) indicated that dietary risk estimates were below HED’s level of concern for the general population and all popula tion subgroups.

An updated dietary exposure assessment is recommended under registration review. If there are any changes to the toxicological points of departure or safety factors, or if EFED’s (Environmental Fate and Effects Divi sion) new drinking water assessment reflects changes in the estimated drinki ng water concentration, those should be incorporated into the new dietary assessment.

Current uses in residential settings include perimeter treatments, outside surfaces (crack and crevice), ant mound treatments (spot application) and use on roses, flowers, houseplants, ground covers, vines, ornamentals, shrubs and trees. Although tau-fluvalinate is labeled for use in residential areas, neither a residential handler assessment nor a residential post-application assessment has been performed to date. The reside ntial uses identified in 2005 were restricted to commercial applicators; therefore a residential handler (homeowner) assessment was not needed. However, since the 2005 assessment, two new EUPs have been registered for use on outdoor

residential areas. These new outdoor uses should be assessed for potential residential handler

exposure.

A post-application exposure assessmen t of the current resi dential uses of tau-fluvalinate is not necessary as it is HED’s standard practice not to assess post-applicati on residential exposures from treated ornamentals or from perimeter, s pot, and crack and crevice treatments to patios and

other outside surfaces.

The Agency is in the process of examining its policies and processes re garding inhalation risk assessment. The need for a bystander inhalati on risk assessment for tau-fluvalinate should be examined during registration review.

Aggregate risk estimates for tau-fluvalinate pr eviously only consider ed combined food and drinking water exposures because at that time no re sidential uses were exp ected to contribute to homeowner exposures of this chemical. Aggr egate acute and chronic dietary (food and water) exposures were below HED level of concern. Currently registered outdoor uses should be assessed for potential residential handler expo sures and an aggregate assessment should be performed, if necessary.

There is potential for short- and intermediate-term occupatio nal exposure to tau-fluvalinate during mixing, loading, application, and post-applic ation activities. HED has previously assessed

the use of tau-fluvalinate on ca rrots/brassica, outdoor /indoor ornamentals, outdoor perimeterPage 4 of 27 treatments (structures, buildings, etc), greenhouses and ant mounds for occupational inhalation exposures. Assessments of occupational handler s cenarios previously evaluated indicate that

short- and intermediate-term inhalation ri sks are not of concern to the Agency. It should be noted that the mix/load/application scenario for greenhouses should be assessed with low pressure hand wand equipment (assessed previo usly with high pressure hand wand).

There is no acceptable inhalation st udy available for tau-fluvalinate. An acute inhalation study and a 90-day/28-day inhalation study are required . Once these data have been received, they

will be evaluated for ac ceptability and for suitab ility for use in the inhalation assessments.

No occupational or residential dermal exposure or risk estimates were qu antitatively assessed as part of the 2005 RED. No toxi cological dermal endpoints were identified for tau-fluvalinate at that time; therefore, a quanti tative handler and post-applica tion dermal exposure and risk assessment was not performed . The mandatory 90-day dermal study will provide the necessary data to quantitatively assess potent ial occupational and residential handler and post-application dermal exposu re risk to tau-fluvalinate.

Tau-fluvalinate is a member of the pyrethroid cl ass of insecticides. This class also includes permethrin, cypermethrin, cyflut hrin, tau-fluvalinate, bifenthr in, fenpropathrin, and lambdacyhalothrin, among others. EPA developed a dr aft science policy document on the proposed common mechanism of toxicity for naturally-occurring pyrethri ns and synthetic pyrethroids (Proposed common mechanism grouping for the pyr ethrins and pyrethroids, draft, May 19, 2009; http://www.regulations.gov/search/R egs/home.html#documentDetail?R=09000064809a62df ). This document was supported by th e FIFRA Scientific Advisory Pa nel (SAP) and is available in

the docket ( http://www.regulations.gov/search/R egs/home.html#documentDetail?R=0900006480a1f8d7 ). EPA will finalize the policy document on the pyre throid common mechanism of toxicity taking

into account the SAP comments. Pesticides with a common mechan ism of toxicity are subject to

cumulative risk assessment under the FQPA. Research is on-goi ng by EPA’s Office of Research and Development (ORD) to make improvements to the Stochastic Human Exposure and Dose Simulation (SHEDS) probabilistic exposure model, which are important for the cumulative risk assessment. EPA ORD is also developing phys iologically-based pharmacokinetic models for several pyrethroids. The status of both of th ese research modeling efforts was reviewed by the FIFRA SAP in July, 2010 and meeting ma terials are available in the docket ( http://www.regulations. gov/search/Regs/home.html#doc ketDetail?R=EPA-HQ-OPP-2010-

0378 )

. For information regarding EPA’s efforts to evaluate the risk to pyrethroids, see http://www.epa.gov/oppsrrd1/reevalua tion/pyrethroids-pyrethrins.html.

Hazard Identification/Toxicology

Tau-fluvalinate, like other pyret hroid insecticides, causes neurot oxicity in insects and mammals by the modulation of nerve axon sodium channels. Pyrethroids interfere w ith the ability of the nervous system to relay nerve transmissions resulting in tremors, whole body convulsions, or excessive salivation, among other effects. The tau-fluvalinate mammalia n studies demonstrate typical clinical signs associat ed with pyrethroid neurotoxicit y, including excessive grooming, bulging eyes, abnormal stance, ruffled fur, hype ractivity, salivation, ataxia, muscle spasms,Page 5 of 27 tremors, gait abnormalities, startle response hype r reaction and more. Some evidence of nerve degeneration was seen at higher doses in the acute neurotoxicity study.

The available toxicity data for tau-fluvalinate are adequate to assess the chemical’s hazard potential although there are severa l data gaps. An immunotoxicity study is required as a part of new data requirements for conventional pestic ide registration (40 CFR Part 158). An acute inhalation study is required as well as a 90-day/28-day inhalati on. In addition, a 90-day dermal study is now required for non-food use applications . An acute neurotoxicity study is also being required. The developmental n eurotoxicity study ( DNT) was previously not requested. However, the Agency has new information regarding the poten tial for increased susceptibility in juveniles, and therefore, the DNT is curren tly required for all pyrethroids.

Tau-fluvalinate is moderately acute ly toxic, having been classified in Toxicity Category II by the oral route of exposure and Category III by the dermal route. It is not a primary irritant to either the eye (Toxicity Category III) or skin (Toxicity Category IV) a nd is not a dermal sensitization agent. The principle systemic effects observed in sub

- chronic and chronic studies include reductions in body weight/body weight gain (dogs a nd rats), liver weight changes (dogs and rats) and chronic nephritis (mouse).

No evidence of carcinogenicity was demonstrated in mice or rats, and there is no concern for mutagenicity. Tau -fluvalinate was negative for mutagenic effects in a battery of tests, including

reverse mutation in Salmonella typhimurium , sister chromatid exchange in CHO cells, mouse lymphoma mutagenic assay, mammalian cells in culture transformation assay and unscheduled DNA synthesis in rat hepatocytes.

The rat developmental toxicity study did not dem onstrate developmental t oxicity at the highest dose tested. The rabbit developmental toxicity dem onstrated some signs of skeletal variations (curved tibia and fibula) but at the same dose where maternal toxicity was seen. There were no effects of tau-fluvalinate on repr oductive performance. The offspri ng were noted to have tremors in one generation and to have sl ight body weight decrease in a nother generation, but these effects

occurred at a dose that was also toxic to the parents. There is no quantitative or qualitative evidence of increased susceptibility of rat or rabbit fetuses after in utero and/or postnatal exposure to tau-fluvalinate in the developmen tal and reproduction studies. Dose-response relationships are well-characterized and NOAELs/LOAELs have been identified for the critical effects. Despite the lack of quantita tive and qualitative susceptibility found in the guideline studies, new information (see web link below) gives the Agency cause for residual uncertainty for potential sensit ivity. The science supporting th is conclusion can be found in

“ Pyrethroids: Evaluation of Da ta from DNTs & Considerati on of Comparative Sensitivity” (E. Scollon, 1/20/10, D371723), available at http://www.epa.gov/oppsrrd1/re evaluation/pyrethroidspyrethrins.html . In an effort to ensure th e highest level of protection of infants and children, the Agency is continually reviewing scientific data regard ing the potentially increased susceptibility of pyrethroid pesticides as it b ecomes available. Therefore, th e tau-fluvalinate risk assessment may need to be revised to incorporate future findings.Page 6 of 27 Previously, the special FQPA safety factor wa s reduced to 1X, since there were no residualuncertainties for pre- and/or postnatal toxicity. However, during registration review, EPA will reevaluate all toxicological endpoint s and safety factors taking into consideration all available data.

Based on a weight-of-evidence approach, a conserva tive NOAEL for neurotox ic effects has been identified for tau-fluvalinate. This approach is based on the results of 2 studies: the rat chronic feeding study and the rat subchroni c neurotoxicity study. In the chr onic study in the rat, clinical signs of neurotoxicity in cluding: excessive salivation, pawing at bottom of the cage, lacrimation, abnormal stance, ruffling, and transient hyperactiv ity followed by hypoactivity were observed at 1.0 mg/kg/day; these effects were not seen at 0.5 mg/kg/day. These signs were observed during the first 3 hours after dosing and subsided within 6 hours. In th e subchronic study in the rat, excessive grooming and bulging eyes were noted in the animals at 2 mg/kg/day (the lowest dose tested).These two studies were evaluated in parallel because the clinical si gns of neurotoxicity in the rat chronic study are transi ent and mentioned in the re port but not well documented. However, HED believes that these early onset neurotoxic effects ar e consistent with the typical clinical signs associated with pyrethroids and are most likely th e result of preliminary nerve stimulation and/or agitation. At the next highest dose tested in the chronic rat study (2.5 mg/kg/day), the development of tr opic (plantar) ulcers could possi bly be indicative of amplified and prolonged nervous system stimulation/agita tion. Furthermore, the results of the 90-day subchronic neurotoxicity study are consistent with the results of the rat chronic feeding study, demonstrating marked evidence of neurotoxicity at a similar low dose. HED believes that the results of these 2 studies taken together form the basis for a clear NOAEL of 0.5 mg/kg/day for neurotoxic effects, with minimal effects beginni ng to be seen at 1.0 mg/kg/day in the chronic study, thus establishing a conservative LOAEL. The selection of this LOAEL is further supported by the increasingly severe neurotoxic effects seen at the higher doses of 2 mg/kg/day and 2.5 mg/kg/day, respectively, in the shorter- term subchronic study an d longer-term chronic feeding study. HED believes that this conservati ve determination is pr otective for all population subgroups. This NOAEL was applied to acute and ch ronic dietary exposures and short-term and intermediate- term inhalation exposures (s ee Appendix B for 2005 toxi cological dose and endpoint selections).

No toxicity endpoint was selected for dermal exposure to products containing tau-fluvalinate. Dermal exposure to products containing tau-fluva linate was previously e xpected to be largely self-limiting due to the irritation that occurs as a result of the “pyr ethroid reaction” (skin abrasions due to scratching). A 90-day derm al toxicity study is now being required.

Residue Chemistry

The name “fluvalinate” is currently the common name for the racemic mixture of the 4 isomers of cyano-(3-phenoxyphenyl)methyl N-[2-chlor o-4-(trifluoromethyl )phenyl]-valinate;

“tau-fluvalinate” is the te rm used for the half resolved mixtur e (2 of the 4 isomers). In the residue chemistry chapter of the 2005 RED, the ta u-fluvalinate name was used when it could be determined that the data were actually for the half resolved mixture; otherwise, the name fluvalinate was used (D300204, J.J. Morales, 2/22/ 05). The nomenclature, registration numbers, PC Code, chemical structure and physiochemical properties of tau-fluva linate are listed in Appendix C.Page 7 of 27 The nature of the residue for use of tau-fl uvalinate in beehives is understood (D300204, J.J. Morales, 2/22/05). The registered use does not in volve the direct application of tau-fluvalinate to honey, but involves the possible tr ansfer of secondary residues from tracking by the bee colony as they make contact with the insecticide strips. Therefore, HED determin ed that only the parent compound, tau-fluvalinate, is the residue of con cern. A tolerance of 0.02 ppm was established

for residues of tau-fluvalinate in honey. In addition, the produc t label restricted the use of beeswax (for human consumption) from bee comb s treated with tau-fluvalinate (EPA Reg. No. 2724-406). Currently, there are no re gistered uses of tau-fluvalinate on plant commodities (use on carrots, brassica vegetables, and cole crops grown for seed are non-food uses), neither in feedstuff commodities nor for direct animal treatments. However, acceptable metabolism studies of tau-fluvalinate in alfalfa, a pple, ruminant and poultry are ava ilable and the residue of concern

was established as tau-fluvalinate.

Acceptable enforcement methods for tau-fluvalinat e in honey are available. In addition, the FDA multi-residue methods published in the PAM Volume I, section 302 and 303, showed an acceptable recovery (>80%) for tau-fluvalinate.

In the product chemistry chapter of the 2005 RE D one deficiency was identified in the taufluvalinate database (D311824, J.J. Morales, 2/ 22/05), the UV/vis abso rption spectra of the Wellmark 87.2% test grade active ingredient of tau-fluvalinate (R eg. No. 2724-481) was not available. These studies were submitted by th e registrant and evaluated by OPP Technical

Review Branch. The studies were found to be acceptable according to OPPTS 830.7050 guidelines (D321133, S.B. Mathur, 9/7/05).

Dietary Exposure

Unrefined acute and chronic di etary exposure assessments were previously conducted with

DEEM-FCID TM and Lifeline TM software. The risk calculation s performed with both software were based on consumption data from the US DA’s Continuing Surveys of Food Intakes by Individuals (years 1994-1996 and 1998), 100% crop tr eated assumptions and tolerance-level residues of 0.02 ppm in honey (D300203, S. Stanton, 3/11/05). In addition, an FQPA safety factor of 1X was used. Exposure from drinking water was incorporated in the acute and chronic risk assessments using the 1 in 10 year’s annua l peak and average concentrations of surface water, respectively. Nearly all the estimated dietary exposure to tau-fluvalinate was from drinking water.

The acute and chronic dietary risk assessments indi cated that for all uses the risk estimates were below HED’s level of concern (<100% aPAD a nd < 100% cPAD) for the general population and all population subgroups. For the acute dietary ri sk assessment, the highest exposed population subgroup at the 95 th exposure percentile was infants (<1 year old) accounti ng for 5.1% of the

aPAD with DEEM-FCID TM and 3.9% of the aPAD with Lifeline TM . The chronic dietary risk assessment performed with both software also indicated that the highest exposed population subgroup were infants at <1% of the cPAD.Page 8 of 27 The last Drinking Water Assessment (DWA) of tau-fluvalinate was performed for the 2005 RED (D304067, M. Corbin, 2/3/05). A Tier II approach was used to estimate the surface water concentration. The average and peak estimated drinking water concentration of tau-fluvalinate in surface water was used for the chronic and acute dietary risk assessments, 0.065 ppb and 1.31 ppb, respectively.

A new drinking water assessment will be comple ted by EFED and will take into account any new data submitted to the EPA or published in th e literature. Input parameters will also be updated to reflect current input parameter guidance. It is an ticipated that tau-fluvalinate estimated drinking water concentrations (EDWCs ) in surface water resulting from registered uses will be calculated using PRZM and EXAM S models along with adjustments for percent cropped area (PCA). The SCI-GROW model will be used to determine ground water concentration resulting from use of tau-fluvalinate. This water assessment will include any monitoring data that ma y be available.

An updated dietary exposure assessment is r ecommended under registrati on review, to include any relevant changes to the toxicological points of departure and safety factors. If the new DWA reflect changes in the es timated drinking water concentration, those should also be incorporated into the new dietary assessment.

Residential Exposure

Current uses in residential settings include perimeter treatments, outside surfaces (crack and crevice), ant mound treatments (spot application) and use on roses, flowers, houseplants, ground covers, vines, ornamentals, shrubs and trees. Although tau-fluvalinate is labeled for use in residential areas, neither a residential handler assessment nor a residential post-application assessment has been performed to date. The reside ntial uses identified in 2005 were restricted to commercial applicators; therefore a residential handler (homeowner) assessment was not needed. However, since the 2005 assessment, two new EUPs have been registered for use on outdoor residential areas (roses, flowers, houseplants, ground covers, vines, ornamentals, shrubs and trees) which do not restrict the use to commerc ial applicators:1) Reg no. 72155-71 is a 3 in 1 combination product containing 0.014% tau-fl uvalinate (along with imidacloprid and tebuconazole). It is a ready- to- use (RTU) spray product. 2) Reg no. 72155-73 is a 3 in 1 combination product containing 0.61% tau-fl uvalinate (along with imidacloprid and tebuconazole). The label has instructions for mi xing and applying with a pump sprayer or hose end sprayer and a second part for use as a rea dy to spray RTU. These uses should be assessed for potential residential handler exposure.

No dermal exposure or risk estimates were quant itatively assessed as part of the 2005 RED since no toxicological dermal endpoints were identified fo r tau-fluvalinate at that time. The mandatory 90-day dermal study will provide th e necessary data to quantitativel y assess potential residential handler dermal exposure ri sk to tau-fluvalinate.

A post-application exposure assessmen t of the current resi dential uses of tau-fluvalinate is not necessary as it is HED’s standard practice not to assess post-applicati on residential exposures from treated ornamentals or from perimeter, s pot, and crack and crevice treatments to patios andPage 9 of 27 other outside surfaces. Additionally, the 2005 risk assessment concluded that the use of the taufluvalinate formulation as spot and perimeter tr eatment around structures and buildings were not wide area broadcast applications and would not likely result in significant post-application exposure of adults or children ( Tau- fluvalinate - RARC1 (2/9/05), therefore a post-application assessment was not performed for these uses and is not currently needed.

Volatilization of pesticides may be a potential source of post-a pplication inhalation exposure to individuals (bystanders) nearby to pesticide applications. The Ag ency sought expert advice and input on issues related to volatilization of pe sticides from its Federal In secticide, Fungicide, and

Rodenticide Act Scientific Advi sory Panel (SAP) in December 2009. The Agency received the SAP’s final report on March 2, 2010 (http://www.epa.gov/scipoly/SA P/meetings/2009/120109meeting.html ). The Agency is in the process of evaluating the SAP report and may, as appropriate, develop policies and procedures to identify the need for and, subsequently, the way to incorporate post-application inhalation exposure into the Agency's risk assessments. If ne w policies or procedures are put into place, the Agency may revisit the need fo r a quantitative post -application inhalati on exposure assessment
for tau-fluvalinate.

Aggregate Exposure and Risk Assessment

In accordance with FQPA, HED considers and aggr egates pesticide exposures and risks from three major sources: food, drinking water, a nd residential exposures . In an aggregate assessment, exposures from dietary and residentia l sources are added together and compared to quantitative estimates of hazard (e.g., a NOAEL), or the risks themselves can be aggregated. When aggregating exposures and risks form va rious sources, HED considers both the route and duration of exposure.

In the case of tau-fluvalinate, the 2005 aggregat e risk estimates only considered combined food and drinking water exposures becaus e at that time no residential us es were expected to contribute to homeowner exposures of this chemical (D 321911, S. Stanton et al, 9/29/05 ). Acute and chronic dietary (food and water) exposures were below HED level of concern (<100% aPAD and <100% cPAD) for the general popul ation and all population subgroups.

Current residential uses include perimeter tr eatments/outside surfaces, ant mound treatments (spot application) and ready-to-use sprays for pe st control on roses, flowers, houseplants, ground covers, ornamentals, shrubs and trees, including a ready-to-use spray formulation that is not restricted to commercial applicators. These us es should be assessed fo r potential re sidential handler exposure and an aggregate assessmen t should be performed, if necessary. A postapplication exposure assessment of the current residential uses of tau-fluvalinate is not necessary as it is HED’s standard practice not to assess pos t-application residential exposures from treated ornamentals or from perimeter, spot, and crack and crevice treatm ents to patios and other outside

surfaces.Page 10 of 27 Occupational Exposure

Use Patterns

Tau-fluvalinate formulations curren tly include flowable concentrate, liquid, ready- to- use, and impregnated materials. This chemical may be applied as an outdoor general surface spray, perimeter treatment, crack and crevice treatme nt, and mound treatment around commercial and domestic dwellings. For treatment of landscape ornamentals and nursery uses, tau-fluvalinate may be applied using a broadcast spray, foliar sp ray, dip treatment, containerized treatment, and basal spray treatment. Greenhouse ap plications include broadcast, fogger, and bench treatments. For agricultural uses on carrots , and on brassica and cole crops (CA SLNs), tau-fluvalinate may be applied using aerial or ground equipment. Tau- fluvalinate is also labe led for use in the brood

chambers of bee hives. Treatments to bee hives ar e made using impregnated strips. The restricted entry interval (REI) for all crops is 12 hours.

The residential uses include perimeter treatme nts/outside surfaces, ant mound treatments (spot application) and ready-to-use sprays for pest control on roses, flowers, houseplants, ground covers, ornamentals, shrubs and trees.

There are five EPA registered products: a techni cal grade for formulating end-use products, one flowable formulation for commercial use only, tw o ready- to- use pump and hose-end sprays coformulated products (Imidacloprid + Tau-fluvalinate + Tebucon azole) for residential use only, and the impregnated plastic strips used for beeh ives. Appendix D lists th e currently registered tau-fluvalinate formulated products.

Maximum rates of application for occupational tau-fluvalinate use vary from 0.15 lb ai/A for application by aircraft and ground equipment for carrots, brassica a nd cole crops grown for seed, 0.011lb ai/gal for foliar spray a pplications on field and cont ainer-grown ornamentals, 0.0078 lb/100sq. ft. for broadcast/fog applications of commercial greenhouses (empty), 0.0783 lb ai/100 gal for dip treatment of foliage and flower cuttings, and 0.0078 lb/1000 sq. ft. for perimeter treatments/outside surfaces and perimete r outdoor crack and cr evice treatment of household/domestic dwellings, commercial/institu tional/industrial premises/equipment, paths and patios, and 0.0016 lb/ mound for ant m ound spot treatment applications.

The formulated end use product labels Pers onal Protective Equipment (PPE) include long sleeved shirt, long pants, shoes, so cks, and chemical resistant gloves.

Occupational Handler Risk Assessment

There is potential for short- and intermediate-term occupatio nal exposure to tau-fluvalinate during mixing, loading, application, and post-applic ation activities. HED has previously assessed

the use of tau-fluvalinate on ca rrots/brassica, outdoor /indoor ornamentals, outdoor perimeter treatments (structures, buildings, etc), greenhouses and ant mounds for occupational inhalation exposures (D319595, Travaglini, R., 07/25/2005). Assessments of occupational handler scenarios previously evaluated indi cate that short- and intermediate-term inhalation risks are notPage 11 of 27 of concern to the Agency (i.e., and MOE ≥ 100; MOEs range from 180 to 95,000) at either baseline or minimum level of personal protection. It should be noted that the mix/load/application scenario for greenhouses sh ould be assessed with low pressure hand wand equipment based on current HED practices (E xpoSac recommendation, 2010). The scenario was assessed previously with high pressure hand wan d. A new inhalation exposure assessment with the low pressure hand wand should result in higher MOE’s.

In the case of tau-fluvalinate, there is no acceptable inhalation study available. Inhalation exposures were assessed using oral toxicity e ndpoints (100% inhalation absorption assumed). An acute inhalation study was not prev iously required for tau- fluvalinate (2005 RED); however, according to the new Part 158 section 870 rules an acute inhalation study is now mandatory. A 90-day/28-day inhalation study is also require d due to exposure scenarios. The 90-day/28-day inhalation study (870.3465) was prev iously categorized as ‘reserved ’ in the 2005 RE D. Since only short- and intermediate-term exposure to workers is expected based on tau-fluvalinate use pattern, a 28-day repeated exposure study (instead of 90-day) will char acterize hazard and provide data for

a more refined inhalation risk assessment. Once these data have been received, they will be evaluated for acceptability and for suitability for use in the inhalation assessments.

Occupational exposure assessments of the tau-fl uvalinate impregnated strips for beehives, cut flower dipping treatments, and greenhouse fogge rs have not been previously performed. Occupational exposure resulting from use of the beehive strips is expected to be negligible, as the only potential times for worker contact ar e during application, when the beehive keeper removes the strips from the containers and plac es them in the hives, and during removal and disposal of the strips

. Since beehives are lo cated outdoors, and the vapor pressure of taufluvalinate is low (10 -7 torr) there is negligible potential fo r inhalation exposure. In order to mitigate any potential for dermal exposure, the label requires the use of protective gloves by applicators. Therefore, risk assessments for occupational exposure ar e not required for the

beehive use.

For the cut flowers dipping treatments, the Agen cy believes that the previously assessed high pressure hand wand greenhouse scen ario (the low pressure hand wand scenario was not assessed) would be a comparable, protective estimate of exposure to tau-fluvalinate from dipping

treatments.

In the case of greenhouse fog treatments, occu pational risks exposures were not previously assessed due to lack of inhalation exposure da ta for this use. However, a tau-fluvalinate greenhouse fogger study (MRID 47338007) has been submitted since the 2005 RED and inhalation exposure estimates should be asse ssed for greenhouse fog treatments.

Post –Application Risk Assessment

Inhalation Occupational post-applicati on exposure to tau-fluvalinate is an ticipated to occur based on the use pattern of tau-fluvalinate. With the exception of the greenhou se uses, post-application inhalation exposure to tau-fluvalinate is expected to be minimal. Based on the Agency's practices, a quantitative occupational post-application inhala tion exposure assessment was not performed for tau-fluvalinate. However, there are multiple potential sources of post-application inhalationPage 12 of 27 exposure to individuals performing post-application activit ies in previously treated fields. These potential sources include volatil ization of pesticides and re

- suspension of dusts and/or particulates that contain pestic ides. The Agency sought expert advice and input on issues related to volatilization of pesticides from its Fede ral Insecticide, Fungici de, and Rodenticide Act Scientific Advisory Panel (SAP) in December 2009. The Agency received the SAP’s final report on March 2, 2010 ( http://www.epa.gov/scipoly/SAP/ meetings/2009/120109meeting.html ). The Agency is in the process of evaluating the SAP report as well as available post-application inhalation exposure data gene rated by the Agricultural Re

- entry Task Force and may, as appropriate, develop policies and procedures, to identify the need for and, subsequently, the way to incorporate occupational pos t-application inhalation exposur e into the Agency's risk assessments. If new policies or procedur es are put into place, the Agency may re

- visit the need for a quantitative occupational post-application inhalation ex posure assessment for taufluvalinate.

Dermal No occupational post-application dermal exposure or risk estimates were quantitatively assessed as part of the 2005 RED. No toxicological dermal endpoints were identified for tau-fluvalinate at that time; therefore, a quantitative post-a pplication dermal exposure and risk assessment was not performed. The mandatory 90-day dermal study will pr ovide the necessary data to quantitatively assess potential occupati onal post-application dermal exposur e risk to tau-fluvalinate. The dermal study must be requested and occupati onal post-application dermal exposure risk scenarios quantitatively assessed for all tau-fluvalinate uses.

The toxicity categories of the active ingredient fo r acute dermal, eye irrita tion, and skin irritation potential are used to determine the interim REI (Restricted-entry Intervals). The tau-fluvalinate

technical material has been classified in Toxici ty Category III for acute dermal and primary eye

irritation. It is not a dermal irr itant (toxicity Category IV). Per the Worker Protection Standard (WPS), a 12-hr restricted entry in terval (REI) is required for chem icals classified under Toxicity Category III or IV. The registered labels indi cate an interim REI of 12 hrs, which is in compliance with the WPS.

Public Health and Pesticide Epidemiology Data

The OPP Incident Data System (IDS) a nd the Centers for Disease Control and Prevention/National Institute for Occupational Sa fety and Health (CDC/N IOSH) Sentinel Event Notification System for Occupational Risk-Pestic ides (SENSOR) database were consulted for pesticide incident data on th e active ingredient tau-fluvalinat e. Additionally, the Agency is looking to include findings from the Agricultur al Health Study (AHS), beginning with the problem formulation phase of registrati on review (K. Middleton, D378502, 8/10/2010).

For IDS aggregate summaries, from 2000 to May 25, 2010, there are 91case reported for taufluvalinate. Because it falls within the categ ories reported as counts (which includes minor, unknown or no effects), there is no unique report that provides details about the incident and single chemical incidents are not distinguished fr om multiple chemical incidents. For the main IDS from 2000 to May 25, 2010, there was one case reported for tau-fluvalinate in the databasePage 13 of 27 with moderate severity. In this case, an unknown age female, reported the following health effects: face swelling, hives, welts , and sores inside the mouth.

For NIOSH SENSOR from 1998 to 2007, seven cases were reported that involved the active ingredient tau-fluvalinate. Of these cases, fourwere reviewed because, in these cases, taufluvalinate was used as a single chemical only and had a certainty classification of definite, probable, or possible. The health effects reporte d included: gastrointestin al (75%), respiratory (50%), ocular (25%), neurologi cal (25%), and dermal (25%). Symptoms are not mutually exclusive; a patient may have many symptoms. Th ese cases were classified as low to moderate severity (three low, one moderate). Two cas es (one occupational and one non-occupational) were the result of drift exposure. One case involved a landscaper experiencing dermal symptoms while applying tau-fluvalinate. One case was exposed while spraying greenhouse ornamentals; he took off his respirator and the wind bl ew the product back in to his face.

Tau-fluvalinate is not included in the AHS, and therefore not c onsidered in this report.

Conclusions for Public Health and Pesticide Epidemiology Data

Based on the low frequency of inci dent cases, there does not appear to be a concern at this time that would warrant further investigation. The Ag ency will continue to monitor the incident information and if a concern is triggered, add itional analysis will be included in the risk

assessment.

Tolerance Assessment and International Harmonization

Where possible, EPA encourages the harmoni zation of the US Tolerances and Maximum Residue Limits (MRLs) in key export markets. A table with the US tolerances, the Canada MRLs, Mexico MRLs and Codex MRLs for tau-fl uvalinate in registered RACs is provided in Appendix E. These tolerances and MRLs are base d on the residue analysis of tau-fluvalinate.

The only US tolerance is estab lished for tau-fluvalinate resi dues in honey. Currently, Codex,

Canada and Mexico does not have MRLs established for the use of tau-fluvalinate. If necessary, the Agency will work to harmonize tolera nces/MRLs, during registration review.

On 5/27/2009 HED established interim guida nce on writing tolerance expressions for enforcement purposes. In order to add clarity to the language used to esta blish the coverage of the tolerance expression and measurement of the le vel of the residue in the RACs the text in the 40 CFR § 180.427 should read: “(a) General. (1) To lerances are establishe d for residues of taufluvalinate, including its metabolites and degradates, in or on the commodities in the table below. Compliance with the tolerance levels specified be low is to be determined by measuring only taufluvalinate [cyano-(3-phenoxyphenyl)methyl N-[2 -chloro-4-(trifluoro methyl)phenyl]-Dvalinate].”

Environmental JusticePage 14 of 27 There do not appear to be any particular soci oeconomic subgroups that may experience a higher degree of exposure to tau- fluvalinate. Potential areas of envi ronmental justice concerns, to the extent possible, will be considered in future hum an health risk assessments for tau-fluvalinate, in accordance with U.S. Executive Order 12898, "Fed eral Actions to Address Environmental Justice in Minority Populations and Low-Income Populations," http://www.epa.gov/compliance/resour ces/policies/ej/exec_order_12898.pdf . The Office of Pesticide Programs (OPP) typically considers the highest potential exposures from the legal use of a pesticide when conducting human health ri sk assessments, including, but not limited to, people who obtain drinking water fro m sources near agricultural ar eas, the variability of diets within the U.S., and people who may be exposed when harvesting crops. Should these highest exposures indicate potential risks of concern, OPP further refine s the risk assessments to ensure

that the risk estimates are based on the best available information.

Cumulative Risk Assessment

Tau-fluvalinate is a member of the pyrethroid cl ass of insecticides. This class also includes permethrin, cypermethrin, cyfl uthrin, bifenthrin, fenpropathri n, and lambda-cyhalothrin, among others. EPA developed a draft science policy document on the proposed common mechanism of toxicity for naturally-occurri ng pyrethrins and synthetic pyr ethroids (Proposed common mechanism grouping for the pyrethrins and pyrethroids, draft, May 19, 2009; http://www.regulations.gov/search/R egs/home.html#documentDetail?R=09000064809a62df ). This document was supported by th e FIFRA Scientific Advisory Pa nel (SAP) and is available in

the docket ( http://www.regulations.gov/search/R egs/home.html#documentDetail?R=0900006480a1f8d7 ). EPA will finalize the policy document on the pyre throid common mechanism of toxicity taking

into account the SAP comments. Pesticides with a common mechan ism of toxicity are subject to

cumulative risk assessment under the FQPA. Research is on-goi ng by EPA’s Office of Research and Development (ORD) to make improvements to the Stochastic Human Exposure and Dose Simulation (SHEDS) probabilistic exposure model, which are important for the cumulative risk assessment. EPA ORD is also developing phys iologically-based pharmacokinetic models for several pyrethroids. The status of both of th ese research modeling efforts was reviewed by the FIFRA SAP in July, 2010 and meeting ma terials are available in the docket ( http://www.regulations. gov/search/Regs/home.html#doc ketDetail?R=EPA-HQ-OPP-2010-

0378 )

. For information regarding EPA’s efforts to evaluate the risk to pyrethroids, see http://www.epa.gov/oppsrrd1/reevalua tion/pyrethroids-pyrethrins.html.

Endocrine Disruptor Screening Program

As required under FFDCA section 408(p), EP A has developed the Endocrine Disruptor Screening Program (EDSP) to determine whether certain substances (inc luding pesticide active and other ingredients) may have an effect in humans or wildlife si milar 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 ap proach 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 estrog en, androgen, or thyroid (E, A, or T) hormonal systems. Chemicals that go th rough Tier 1 screening and are found to have the potential toPage 15 of 27 interact with E, A, or T hormonal systems will proceed to the next stag e of the EDSP where EPA will determine which, if any, of th e Tier 2 tests are necessary base d on the available data. Tier 2 testing is designed to identify a ny adverse endocrine related eff ects caused by the substance, and establish a dose-response relationship between the dose and the E, A, or T effect.

Between October 2009 and February 2010, EPA issued test orders/data call-ins for the first group of 67 chemicals, which contains 58 pesticid e active ingredients and 9 inert ingredients.

This list of chemicals was selected based on th e potential for human exposure through pathways such as food and water, residen tial activity, and certain post-applic ation agricultural scenarios.

This list should not be construed as a lis t of known or likely endocrine disruptors.

Tau-fluvalinate is not among the group of 58 pesticid e active ingredients on th e initial list to be

screened under the EDSP. Under FFDCA sec. 408(p) the Agency must screen all pesticide chemicals. Accordingly, EPA anticipates issuin g future EDSP test orders/data call-ins for all pesticide active ingredients.

For further information on the status of the ED SP, the policies and procedures, the list of 67 chemicals, the test guidelines and the Tier 1 screening battery, pleas e visit our website: http://www.epa.gov/endo/.

Human Studies

Past tau-fluvalinate risk assessments rely in part on data in generic databases from studies in which adult human subjects were intentionally ex posed to a pesticide to determine their dermal and inhalation exposure. Many su ch studies, involving exposure to many different pesticides, comprise generic pesticide exposure databases su ch as the Outdoor Residential Exposure Task

Force database and the Pesticid e Handler Exposure Database. EP A has reviewed all the studies supporting these multi-pesticide generic expos ure databases, and has found no clear and convincing evidence that the conduct of any of them was either fundame ntally unethical or significantly deficient relative to the ethical st andards prevailing at the time the research was conducted. There is no regulator y barrier to continued relian ce on these studies, and all applicable requirements of EPA’s Rule for the Protection of Human Subjects of Research (40 CFR Part 26) have been satisfied.

Data Requirements

Toxicology (See Appendix A for data requirement rationales.)

• Guideline 870.1300 - Acute Inhalation Toxicity

• Guideline 870.3250 - 90-Day Dermal Toxicity

• Guideline 870.3465 - 90-Day/28- Day Inhalation Toxicity

• Guideline 870.6200a- Acute Neurotoxicity Battery

• Guideline 870.6300 - Developmental Neurotoxicity Study

• Guideline 870.7800 – ImmunotoxicityPage 16 of 27 Residue Chemistry No data gaps currently identified.

Occupational and Residential No data gaps currently identified.Page 17 of 27 Appendix A: Rationales for Toxicology Data Requirements

Guideline Number: 870.1300 Study Title: Acute Inhalation Toxicity Rationale for Requiring the Data The Agency needs an acute inhalation study due to 40 CFR 870.1300 requir ements and because acute inhalation exposure to workers is expected based on tau-fluvalinate's use pattern. The study design simulates the route of acute human exposure via inhalati on to tau-fluvalinate. In this study, animals are exposed (nose/whole body) to aerosol concentrations of the test material for 6 hours in a single day. A detailed toxicological examination including the histopa thology of the respiratory system is conducted. This route-specific study would provide data for ass essing potential risks via the inhalation route. Practical Utility of the Data

How will the data be used?

This study will identify hazard (i.e. provide a dose and endpoint) following acute inhalation exposures. The results will be used in ri sk assessments as appropriate.

How could the data impact the Agency’s decision-making?

A sub-chronic inhalation study provides critical scientif ic information needed to characterize potential hazard to the human respiratory system from tau-fluvalin ate exposure. In the case of tau-fluvalinate, there is no acceptable acute inhalation study available. An acute exposure study that follows the Test Guidelines (870.1300) will characterize hazard and pr ovide data for a more refined inhalation risk assessment. This requirement is pending resolution of inhalation exposure for existing and possible future

uses.

Guideline Number: 870.3250 Study Title: 90-Day Dermal Toxicity Rationale for Requiring the Data The sub-chronic (90-day) dermal toxicity study is a new data requirement under 40 CFR Part 158 as a part of the data requirements for registration of a pesticide for non-food use.

The dermal toxicity Test Guidelines (OPPTS.870.3250) is intended to evaluate the toxic effects associated with continuous or repeated exposures to a test substance for a period of 90-days.

The Agency needs a 90-day dermal toxicity study for non-food use pesticides because the dermal route will be the primary route of exposures for chemicals designated with this use pattern (i.e., non-food). The Agency believes that this study is required becau se the longer term oral studies (i.e., chronic or carcinogenicity studies) which are required for food-u se pesticides are usually not required for non-food use pesticides. A 21/28 day dermal toxicity test is insufficient to identify potential hazards for non-food use pesticides because of the con cern for the longer duration exposure associated with this use pattern. For example, professional applicators may be subjected to repeated exposure during the 3 month period of peak summer infestation. For this type of increased exposure, professional applicators may not be adequately protected using data from a 21/28-day study. Practical Utility of the Data

How will the data be used?

A route specific (i.e., dermal) study will provide critic al scientific information needed to characterize potential hazard to the human population exposed to tau -fluvalinate by the dermal route. This study will provide a dose and a toxicological endpoint of concer n for quantification of risks for dermal exposures.Page 18 of 27 This study would eliminate the uncertainties associated w ith the use of an oral study with a default (100% oral equivalent) dermal absorption factor.

In many cases, toxicity observed via the dermal route will be different than toxicity observed via oral exposure, due to absorption and distribution of the toxic agent after exposure or differences in metabolism (i.e., systemic versus local). This means that the route-to-route extrapolation (i.e., use of an oral dose/endpoint) in risk assessment could result in under or over estimation of risks from the dermal

route.

How could the data impact the Agency’s future decision-making?

If the dermal toxicity study indicates that tau-fluvalin ate poses either a greater or lesser risk than that calculated using an oral dose, (as used in the inte rim decision), the risk assessment would be revised to reflect the magnitude of potential risk derived from the new data. Also, the requested data would allow the Agency to determine if the risks were over-est imated or under-estimated. If the risks were underestimated, additional risk mitigation measures could be required. If the risks were over-estimated, risk mitigation measures could be reduced.

Guideline Number: 870.3465 Study Title: 90-Day/28-Day Inhalation Toxicity Rationale for Requiring the Data Instead of conducting the inhalation study for 90-days, the Agency only needs a 28-day inhalation study because only short- and intermediate-term (but not lo ng-term) exposure to workers is expected based on tau-fluvalinate's use pattern. A longer-term inhalation st udy is required in situations in which a specific concern exists for increased hazard related to exposur e via the inhalation route. The 28-day inhalation toxicity study evaluates the potential hazard of a pesticide chemical following repeated inhalation exposures. This study is critical for pesticides with use patterns in which there is potential for repeated human exposures (e.g., professional applicators, green house use, etc.). The study design simulates the route of human exposure (inhalation). In this study, animals are exposed (nose/whole body) to aerosol concentrations of the test material for 6 hours/day, 5 days/week for 28 days. A detailed toxicological examination including the histopathology of the respirat ory system is conducted. This route-specific study would provide data for hazard characterization, do se response assessment, and a dose and endpoint for assessing potential risks via the inhalation route. Practical Utility of the Data

How will the data be used?

This study will identify hazard (i.e., provide a dose and endpoint) following repeated inhalation exposures to tau-fluvalinate. The results will be used in risk assessments as appropriate.

How could the data impact the Agency’s decision-making? A sub-chronic inhalation study provides critical scientif ic information needed to characterize potential hazard to the human respiratory system from tau-fluvalin ate exposure. In the case of tau-fluvalinate, there is no acceptable inhalation study available. A 28-da y repeated exposure study that follows the Test Guidelines (870.3465) will characterize hazard and pr ovide data for a more refined inhalation risk assessment. Exposure time may be reduced 28 days pendi ng exposure patterns, plateauing of effects and considering the overall toxicity potential of tau-fluva linate. This requirement is pending resolution of inhalation exposure for existing and possible future uses.Page 19 of 27 Guideline Number: 870.6200a Study Title : Acute Neurotoxicity Battery Rationale for Requiring the Data

This is a new data requirement under 40 CFR Part 158 as a part of the data requirements for registration of a pesticide (food and non-food uses).

The Neurotoxicity Screening Batte ry (OPPTS 870.6200) is designed to evaluate the potential adverse effects on the nervous system from exposure to pes ticide chemicals. The Ag ency believes that the guideline studies are inadequate in their assessment of behavioral effects and do not use optimal methods to evaluate the potential toxicity to the nervous tissue structure and function. To detect and characterize these potential effects more fully, a battery of more sensitive testing is required. The objective of this neurotoxicity battery testing is to evaluate the inci dence and severity of the functional and/or behavioral effects, the level of motor activity, and the histopathology of the nervous system. The acute neurotoxicity study is required to detect possible effects resulting from a single exposure. The sub-chronic neurotoxicity study is intended to detect possible effects resulting from repeated or long-term exposures.

Practical Utility of the Data

How will the data be used?

The acute and sub-chronic neurotoxicity studies pr ovide critical scientific information needed to characterize potential hazard to the human popul ation on the nervous system from tau-fluvalinate exposure. These studies can provide data on a wide range of functional tests for evaluating neurotoxicity including sensory effects, neuromuscular effects, le arning and memory and histopathology of the nervous system For example, animal studies with organophos phorous chemicals have shown neurotoxicity to be the primary toxic endpoints (e.g., cholinesterase inhib ition) of concern in rodents and non-rodents. These animal studies can be used to select endpoints a nd doses for use in risk asse ssment of all exposure scenarios and are considered a primary data source for reliable reference dose calculation. The Agency has established an oral reference dose (RfD) for assess ing dietary risks for a number of chemicals (e.g., organophoshates and carbamates) where neurotoxicity was the most sensitive endpoint of concern.

How could the data impact the Agency's future decision-making?

If the acute or sub-chronic neurotoxicity studies show that tau-fluvalinate poses either a greater or a diminished risk than that given in the interim decision’s conclusion, the risk assessment for taufluvalinate may need to be revised to reflect the ma gnitude of potential risk derived from the new data.

If the Agency does not have this data, a 10X database uncertainty factor may be applied when conducting a risk assessment using the currently available studies.

Guideline Number: 870.6300 Study Title: Developmental Neurotoxicity Study Rationale for Requiring the Data

Criteria have been developed for determining the n eed for a Developmental Neurotoxicity (DNT) study through extensive peer review, including revi ew by the FIFRA Scientific Advisory Panel ( http://www.epa.gov/scipoly/sap ). The requirement for a DNT study typically is conditional, but the study may be required if acute oral, dermal, or i nhalation studies showed neuropathy or neurotoxicity. For tau-fluvalinate, clinical signs of neurotoxicity and evidence of neuropathology have been observedPage 20 of 27 in the guideline studies (i.e. tremors and ataxia).

The reproduction study did not include an assessment of effects on the development of the nervous system. The required DNT study must be designed to evaluate the developing organism for functional

and behavioral deficiencies and structural altera tions to the nervous system, as may result from taufluvalinate exposure in utero or during early postnatal life. Practical Utility of the Data

How did the Agency make its reregis tration decision without these data? In part due to the absence of DNT data for tau-fl uvalinate, the Agency may consider retaining a10X FQPA (Food Quality Protection Act) database uncer tainty factor for the risk assessment. The uncertainty factor is expected to be prot ective for the sensitive population subgroups.

How will the data be used and how could the data impact the Agency’s future decision-making?

The DNT data will be used to characterize the neurot oxicity potential to infants and children, who may

be more sensitive to the neurotoxic effects of tau-fl uvalinate than adults. If review of the DNT study indicates that it is appropriate, and if other uncer tainties are adequately addressed, the 10X database uncertainty factor, if applied, could be removed; therefore effectively reducing human health risk estimates by an order of magnitude. If the data indi cate that infants and children are adversely affected by in utero exposure to tau-fluvalinate, or are more sens itive to tau-fluvalinate exposure in general, the Agency will consider choosing a new endpoint (fro m the DNT study) for the human health risk

assessment of tau-fluvalinate. Results from the study will allow the Agency to make the necessary adjustments (if any) to risk mitigation measu res resulting from the re-registration decision.

Guideline Number: 870.7800 Study Title : Immunotoxicity Rationale for Requiring the Data

This is a new data requirement under 40 CFR Part 158 as a part of the data requirements for registration of a pesticide (food and non-food uses).

The Immunotoxicity Test Guideline (OPPTS 870.7800) prescribes functional immunotoxicity testing and is designed to evaluate the potential of a repeated chemical exposure to produce adverse effects (i.e., suppression) on the immune system. Immuno-suppression is a deficit in the ability of the immune system to respond to a challenge of bacterial or viral infections such as tuberculosis (TB), Severe Acquired Respiratory Syndrome (SARS), or neoplasia. Because the immune system is highly complex, studies assessing functional immunotoxic endpoints are helpful in fully characterizing a pesticide’s potential immunotoxicity. These data will be used in combin ation with data from hematology, lymphoid organ weights, and histopathology in routine chronic or sub-chronic toxicity studies to characterize potential

immunotoxic effects. Practical Utility of the Data

How will the data be used?

These animal studies can be used to select endpoints and doses for use in risk assessment of all exposure scenarios and are considered a primary data source fo r reliable reference dose calculation. For example,

animal studies have demonstrated that immunotoxi city in rodents is one of the more sensitive manifestations of TCDD (2,3,7,8-tetrachlorodibenzo- p-dioxin) among developmental, reproductive, and endocrinologic toxicities. Additionally, the EPA has established an oral reference dose (RfD) for tributyltin oxide (TBTO) based on observed immunotoxicity in animal studies (IRIS, 1997).Page 21 of 27 How could the data impact the Agency's future decision-making?

If the immunotoxicity study shows that tau-fluvalinate poses either a greater or a diminished risk than that given in the interim decision’s conclusion, the risk assessments for tau-fluvalinate may need to be revised to reflect the magnitude of potential risk derived from the new data.

If the Agency does not have this data, a 10X database uncertainty factor may be applied for conducting a

risk assessment from the available studies.Page 22 of 27 Appendix B: Tau-fluvalinate Toxicology

Toxicological Doses and Endpoints used previously in the 2005 Tau-fluvalinate Human Risk

Assessments

Exposure

Scenario Dose, Uncertaint y Factors (UFs), and Safety Factors (SFs) Population Adjusted Dose (PAD) or Target Margin of Exposure (MOE) Study and Toxicological Effects

Tau-fluvalinate Dietary Exposures

Acute Dietary (general population) NOAEL = 0.5 mg/kg/day

UF = 100X (inter and intra

species) FQPA SF = 1X (currently determined to be a 10x)

Total UF = 100X

Acute RfD = 0.005 mg/kg/day aPAD = Acute RfD FQPA SF

aPAD = 0.005 mg/kg/day LOAEL = 1 mg/kg/day. Clinical signs in the rat chronic feeding study coupled with a LOAEL of 2 mg/kg/day based on excessive grooming and bulging eyes in the subchronic neurotoxicity study.

Chronic Dietary (general population) NOAEL = 0.5 mg/kg/day

UF = 100X (inter and intra

species) FQPA SF = 1X (currently determined to be a 10x)

Total UF = 100X

cRfD = 0.005 mg/kg/day cPAD = Chronic RfD FQPA SF

cPAD = 0.005 mg/kg/day LOAEL = 1 mg/kg/day. Clinical signs in the rat chronic feeding study coupled with a LOAEL of 2 mg/kg/day based on excessive grooming and bulging eyes in the

sub

- chronic neurotoxicity study.

Tau-fluvalinate Dermal Exposures

Dermal - all

intervals No endpoint selection.Page 23 of 27 Toxicological Doses and Endpoints used previously in the 2005 Tau-fluvalinate Human Risk

Assessments

Exposure

Scenario Dose, Uncertaint y Factors (UFs), and Safety Factors (SFs) Population Adjusted Dose (PAD) or Target Margin of Exposure (MOE) Study and Toxicological Effects

Tau-fluvalinate Inhalation Exposures

Inhalation (Short- and

IntermediateTerm ) NOAEL = 0.5 mg/kg/day

UF = 100X (inter and intra

species)

Total UF = 100X

100% inhalation absorption

assumed Occupational MOE =

100 LOAEL = 1 mg/kg/day. Clinical signs in the rat chronic feeding study coupled with a LOAEL of 2 mg/kg/day based on excessive grooming and bulging eyes in the subchronic neurotoxicity study.Page 24 of 27 Appendix C: Chemistry

Tau-Fluvalinate Residue of Concern.

Chemical structure

Common name Tau-fluvalinate

Molecular Formula C 26 H 22 ClF 3 N 2 O 3
Molecular Weight 502.93

IUPAC name ( RS )- α -cyano-3-phenoxybenzyl N -(2-chloro- α , α , α -trifluoro- p -tolyl)-D-valinate

CAS name cyano-(3-phenoxyphenyl)methyl N -[2-chloro-4-(trifluoromethyl)phenyl]-D-valinate

CAS registry number 102851-06-9 (tau-fluvalinate) 69409-94-5 (unresolved fluvalinate)

PC Code 109302

Physiochemical Properties of Tau-Fluvalinate

Parameter Value Reference

Boiling point 164 °C at 0.07 mm Hg D165590, 3/4/92, F. Toghrol

pH Not applicable; fluvalinate is practically

insoluble in water

Density, bulk density, or specific gravity 1.262 g/mL at 25 °C D165590, 3/4/92, F. Toghrol

Water solubility 2.4 ppb at 25 °C D272832 and D273228, 3/21/01,

K. Dockter

Solvent solubility at 25 °C 55.31 g/100 mL, methanol 24.05 g/100 mL, octanol

Miscible at all levels in isooctane, toluene, acetonitrile, 2-propanol, dimethylformamide,

and 1-octanol D272832 and D273228, 3/21/01,

K. Dockter

D165590, 3/4/92, F. Toghrol

Vapor pressure <1.0 x 10 -5 Pa, 25 °C D272832 and D273228, 3/21/01,

K. Dockter

Dissociation constant, pK

a Not applicable due to the instability of fluvalinate under acidic and basic conditions, and its extremely low water solubility. Phase 4 Review, 1/16/91

Octanol/water partition

coefficient P OW >10 6 , 25 °C D272832 and D273228, 3/21/01,

K. DockterPage 25 of 27 Physiochemical Properties of Tau-Fluvalinate

Parameter Value Reference

UV/visible absorption spectrum Acidic Methanol Medium:

255.5 nm ( ε 19410 L/(mol

• cm))

Neutral Methanol Medium:

255.5 nm ( ε 18597 L/(mol

• cm))

Basic Methanol Medium:

254.5 ( ε 27732 L/(mol

• cm))

297.5 ( ε 5566 L/(mol

• cm)) D321133, S.B. Mathur, 9/7/05Page 26 of 27 Appendix D: Tau-fluvalinate Products

Tau-fluvalinate Formulated Products

Product EPA Reg. Number % Active Ingredient (tau-fluvalinate)
Technical (MUP) 2724-481 93.7 %
Impregnated strip 2724-406 10.25 %

Flowable concentrate 2724-478 22.3 % Co-formulated Product (Imidacloprid + Tau-fluvalinate + Tebuconazole) Ready to Use Liquid Concentrate 72155-71

0.0143 % Co-formulated Product (Imidacloprid + Tau-fluvalinate + Tebuconazole) Ready to Use Spray 72155-73

0.61 %

Flowable concentrate CA04002200 22.3 %

Flowable concentrate CA96001000 22.3 %Page 27 of 27 Appendix E: International Residue Limits

Summary of US and International Tolerances and Maximum Residue Limits Residue Definition :

US Canada Mexico 2 Codex 3

40 CFR 180.427:

Plant: Tau-fluvalinate [cyano-(3- phenoxyphenyl)methyl N-[2-chloro-4- (trifluoromethyl)phenyl]-D-valinate] None None

Tolerance (ppm) /Maximum Residue Limit (mg/kg) Commodity 1 US Canada Mexico 2 Codex Honey 0.02

Completed: M. Ne gussie; 09/07/2010

1 Includes only commodities of interest for this action. Tolerance values should be the HED recommendations and not those proposed by the applicant.

2 Mexico adopts US tolerances and/or Codex MRLs for its export purposes.

3 * = absent at the limit of quantitation; Po = postharvest treatment, such as treatment of stored grains. PoP = processed postharvest treated co mmodity, such as processing of treated stored wheat. (fat) = to be measured on the fat portion of the sample. MRLs indicated as proposed have not been finalized by the CCPR and the CAC.