


                                       
                                       
                                       
                                       

                                       
                                       
Proposed Unconditional Registration of the New active ingredient Cyflumetofen for foliar application on Citrus (Crop Group 10-10), Pome Fruits (Crop Group 11-10), Grapes, Strawberries, Tomatoes, Tree Nuts (Crop Group 14-12) and Ornamentals

                                       
                                       
            
            
            
            
            
            
            
                                       
                                       
                     U.S. Environmental Protection Agency
                         Office of Pesticide Programs
                             Registration Division



                                       
                                       
                                       

                                       
                                       
                      Proposed Unconditional Registration
                   of the New Active Ingredient Cyflumetofen
                       for foliar application on Citrus
                        (Crop Group 10-10), Pome Fruits
                          (Crop Group 11-10), Grapes,
                            Strawberries, Tomatoes,
                         Tree Nuts (Crop Group 14-12)
                                and Ornamentals
                                       
                                       
                                       
                                       
                                       
                                       
                      Approved by: _____________________
                                       
									Lois Rossi, Director
									Registration Division
									Office of Pesticide Programs
                                       
                         Date: ______________________

Proposed Unconditional Registration of the New Active Ingredient Cyflumetofen for foliar application on tree nuts (crop group 14-12), pome fruits (crop group 11-10), citrus (crop group 10-10), grapes, strawberries, tomatoes and ornamentals

REGULATORY PROPOSAL

The U.S. Environmental Protection Agency referred to thereafter as EPA or the Agency, is proposing to grant the registrations for pesticide products containing the new active ingredient, cyflumetofen, a miticide formulated as a technical and two end use products.  Cyflumetofen belongs to the acrylonitrile class of chemicals and is a selective contact miticide that is effective on all mite life stages.  The proposed use sites for cyflumetofen are tree nuts (crop group 14-12), pome fruits (crop group 11-10), citrus (crop group 10-10), grapes, strawberries, tomatoes and ornamentals.   
Cyflumetofen is currently registered in Japan, Korea, Brazil, and in the European Union (ornamentals).   The present action was conducted as a joint review with Health Canada's Pesticide Management Regulatory Authority (PMRA) and Mexico's Federal Commission for the Protection against Sanitary Risk (COFEPRIS).

Three miticide products are under consideration, one technical and two end-use products (Sultan(TM) and Nealta(TM)).  Sultan is intended for use on ornamentals and Nealta(TM) for use on tree nuts, pome fruits, citrus, grapes, strawberries, and tomatoes.   

I.  CHEMICAL INFORMATION

Chemical Name: Cyflumetofen (2-methoxyethyl α-cyano-α-[4-(1,1-dimethylethyl)phenyl]-β-oxo-2-(trifluoromethyl)benzenepropanoate).

EPA PC Code: 138831

Chemical Abstracts Service (CAS) Number: 400882-07-7

Mode of Action: Cyflumetofen is a non-systemic, contact miticide that provides knockdown and residual control of tetranychid mites.  It has a novel insecticidal mode of action and acts as a mitochondria complex II electron transport inhibitor resulting in knockdown and residual control of the egg, nymph, and adult stages of tetranychid mites.

Registrant: BASF Corporation

Proposed Products: Cyflumetofen is proposed for registration as a technical product, and two end use products (Sultan and Nealta).  

The end-use products, formulated as suspension concentrates are to be applied as a foliar spray up via ground equipment.  Aerial applications are proposed for tomatoes only.  The proposed maximum single application rate and maximum application rate per crop cycle or year are 0.2 lb a.i. /A and 0.4 lb a.i. /A, respectively, corresponding to a maximum of 2 applications per crop cycle or year.  The proposed minimum application interval is 14 days.
II. HUMAN HEALTH RISK 

A summary of the human health effects and risk of cyflumetofen as assessed in the Agency document entitled "Cyflumetofen.  New Active Ingredient Human Health Risk Assessment to Support Uses on Citrus (Crop Group 10-10), Pome Fruits Crop Group 11-10), Tree Nuts (Crop Group 14-12), Grape, Strawberry, and Tomato" is provided below.

A.  Summary of Toxicological Effects

The toxicological database for cyflumetofen is considered complete.  A subchronic inhalation study was not available; however, the Agency determined that the requirement for this study is not needed at this time. The major target organ in rats, mice, and dogs following short-term and long-term oral administration of cyflumetofen is the adrenal glands characterized by increased organ weight and histopathology (vacuolation and hypertrophy of the adrenal cortical cells).  Cyflumetofen has low acute toxicity by oral, dermal, and inhalation routes of exposure. It is minimally irritating to the eyes but not to the skin.  It is a skin sensitizer.  Decreased serum hormone concentrations (FSH, progesterone, and 17 β-estradiol) were observed in the mid- and high-dose F1 females in a rat reproduction study while no hormonal effect was observed in the F1 male rats at any dose level.  However, there were no corresponding changes in reproductive performance at any dose level.  In the developmental toxicity study in rats, an increased incidence of wavy ribs was noted at the high- dose (1000 mg/kg/day), while an increased incidence of incompletely ossified sternal centra was observed at the mid- and high-dose levels.  These incidences occurred in the presence of maternal toxicity; no skeletal malformations were noted.  In the developmental toxicity study in rabbits, a downward flexion of the forepaws and/or hind paws was observed in the high-dose (1000 mg/kg/day) group pups and delays in skeletal ossification were observed in pups at the mid- and high-doses.  Maternal toxicity (adrenal effects) was also observed at the mid- and high- doses.   No evidence of neurotoxicity or immunotoxicity was observed in any of the submitted studies for cyflumetofen.
 
No acute reference dose (aRfD) was established to assess acute dietary risks since there was no evidence of toxicity attributable to a single dose for the general U.S. population, infants and children, or females 13-49 years of age in any studies.  For the chronic dietary risk assessment, a chronic reference dose (cRfD) of 0.17 mg/kg/day was established for assessments of all populations, with a no observed adverse effect level (NOAEL) of 16.5 mg/kg/day and a lowest observed adverse effect level (LOAEL) of 30.6 mg/kg/day based on effects on the adrenals (increased organ weight and histopathology), which is the target organ.  Three rat studies (90-day subchronic, chronic toxicity/carcinogenicity, and reproduction studies) were selected as co-critical studies for the chronic dietary endpoint. These studies are appropriate for the duration and populations of concern since there is no progression of toxicity over time. No dermal hazard was identified for cyflumetofen.  For short- and intermediate-term inhalation exposure, the NOAEL of 16.5 mg/kg/day with a LOAEL of 30.6 mg/kg/day based on effects on the adrenals was selected from the same co-critical studies chosen for the chronic reference dose. 

The risk assessments conducted for cyflumetofen were based on the most sensitive endpoints in the toxicity database, and the NOAELs selected for risk assessment are considered protective of potential developmental, neurotoxic, and immunotoxic effects for infants and children.  There is no evidence of increased qualitative or quantitative susceptibility in the developmental rat study or in the rat 2-generation reproduction study.  In the rabbit developmental toxicity study, a lower NOAEL was observed for the developmental effects compared to maternal effects.   However, the developmental effects have clearly defined NOAEL/LOAELs and NOAEL for such effects is more than 10-fold higher than the PODs.  Therefore, the PODs based on adrenal effects in rat are health protective of all lifestages.  There is no evidence of neurotoxicity in any of the submitted studies for cyflumetofen. 

The mutagenic potential of cyflumetofen, its metabolites, and an impurity was tested in in vitro and in vivo studies. There was no concern for mutagenicity for the parent, the metabolites or the impurity. Consequently, mutagenicity can be ruled out as a possible mode of action for tumor formation.  

In accordance with the EPA's Final Guidelines for Carcinogen Risk Assessment (March, 2005), the Cancer Assessment Review Committee (CARC) classified cyflumetofen as "Suggestive Evidence of Carcinogenic Potential". This classification is based on the presence of a single tumor type (thyroid c-cell) in one sex (male) and one species (rat), and the lack of concern for mutagenicity. When there is suggestive evidence of carcinogenicity, the Agency does not attempt a dose-response assessment as the nature of the data generally would not support one. Therefore, the Agency has determined that quantification of risk using a non-linear approach (i.e. the chronic reference dose) will adequately protect for all chronic toxicity, including carcinogenicity, likely to result from exposure to cyflumetofen.

B.  Food Quality Protection Act (FQPA) Safety Factor

EPA has determined that reliable data show that the safety of infants and children would be adequately protected if the FQPA safety factor (SF) were reduced to 1x for all exposure scenarios. That decision is based on the following findings:

   * The toxicity database for cyflumetofen is complete. 
      
   * There is no evidence of increased pre- and/or postnatal susceptibility for cyflumetofen.  

   * No evidence of Immunotoxicity.
      
   * There is no evidence of increased qualitative or quantitative susceptibility in the developmental rat and rabbit studies or in the rat 2-generation reproduction study.  These studies have clearly defined NOAEL/LOAELs.  There is no evidence of neurotoxicity in the acute and subchronic neurotoxicity studies for cyflumetofen, and a developmental neurotoxicity study is not required.  

   * There are no residual uncertainties in the exposure database.  Since the dietary and residential exposure estimates were based on conservative assumptions, EPA is confident that this assessment does not underestimate dietary (food and water) or residential exposure.  

   * The chronic dietary exposure assessment used tolerance level residues for all commodities, 100% crop treated (% CT), and empirical processing estimates when available or DEEM(TM) default processing factors.  The drinking water assessment utilized water concentration values generated by models and associated modeling parameters which are designed to produce conservative, health protective, high-end estimates of water concentrations which are not likely to be exceeded.  For these reasons it can be concluded that the chronic dietary exposure analysis does not underestimate risk from chronic exposure to cyflumetofen.  Similarly, EPA does not believe that the residential exposure estimates are underestimated because they are also based on conservative assumptions including maximum application rates and standard values for unit exposures, acreage treated/amount handled.    Based on the use of conservative assumptions with respect to potential exposure from food, water and residential uses, the assessment will not underestimate children's exposure to cyflumetofen.   

C.  Cumulative Effects

Unlike other pesticides for which EPA has followed a cumulative risk approach based on a common mechanism of toxicity, EPA has not made a common mechanism of toxicity finding as to cyflumetofen and any other substances and cyflumetofen does not appear to produce a toxic metabolite produced by other substances. For the purposes of this tolerance action, therefore, EPA has not assumed that cyflumetofen has a common mechanism of toxicity with other substances. For information regarding EPA's efforts to determine which chemicals have a common mechanism of toxicity and to evaluate the cumulative effects of such chemicals, see the policy statements released by EPA's Office of Pesticide Programs concerning common mechanism determinations and procedures for cumulating effects from substances found to have a common mechanism on EPA's website at http://www.epa.gov/pesticides/cumulative/.  

D.  Aggregate Risk Assessment

1.  Dietary (Food + Drinking Water) Risk:

A chronic aggregate dietary food and drinking water exposure and risk assessment was conducted using the Dietary Exposure Evaluation Model software with the Food Commodity Intake Database DEEM-FCID(TM) (Version 3.16).  This software uses 2003-2008 food consumption data from the U.S. Department of Agriculture's (USDA's) National Health and Nutrition Examination Survey, What We Eat in America, (NHANES/WWEIA).  

Acute Dietary Risk: No acute dietary exposure and risk analysis was performed since there were no appropriate studies identified in the toxicology database that demonstrated evidence of toxicity attributable to a single dose.

Chronic Dietary Risk:  A partially refined chronic analysis was conducted that was based on tolerance-level residues, 100% crop treated (%CT) assumptions, and both empirically derived and default processing factors.  Using assumptions considered to be highly conservative, EPA has concluded that chronic risk estimates from exposure to cyflumetofen are below EPA's level of concern (<100% of the chronic population adjusted dose (cPAD)), and range from <1% of the cPAD for the general U.S. population to 2.3% of the cPAD for the highest exposed population subgroup of children 1-2 years old. 

2.  Residential Risk:

The proposed uses of cyflumetofen on ornamentals (i.e., residential settings), may result in adult residential handler and post-application exposure.  This exposure is expected to be only short-term in duration (i.e., 1 to 30 days) as intermediate- or long-term exposures are not likely based on the intermittent nature of applications by homeowners.  Since no dermal hazard was identified for cyflumetofen in the toxicological database, only inhalation exposure assessments were conducted.  The resulting inhalation margins of exposure (MOEs) for all scenarios are not of concern since they are above the level of concern (LOC) of 100 (MOEs >= 100).  

E.  Occupational Risk Assessment

   1. Handler Exposure and Risk:  

The occupational exposure and risk assessment addresses risks to workers exposed in an occupational setting via the dermal and inhalation routes of exposure.  Since no acute points of departure are identified, an acute aggregate risk assessment was not conducted.  EPA has conducted short-term and long-term (chronic) aggregate risk assessments for cyflumetofen.  Short-term aggregate MOEs are above the LOC of 100 and are not of concern (MOEs >= 100).  The long-term (chronic) aggregate assessment includes only dietary (food and water) exposure as long-term residential exposure is not expected.  

2.  Occupational Post-Application Exposure and Risk:  

 "Post-application" means exposures that occur when individuals are present in an environment that has been previously treated with a pesticide (also referred to as re-entry exposure).  Such exposures may occur when workers enter previously treated areas to perform job functions, including activities related to crop production, such as scouting for pests or harvesting.  Based on the proposed use pattern of cyflumetofen, short- and intermediate-term exposures are anticipated for handlers for the following reasons:  (1) the product can be applied twice per season (2) the product can be applied to multiple application sites, (3) there may be a large agribusiness and/or commercial applicators who may apply a product over a period of weeks, and (4) repeated use of miticides with similar modes of action can lead to build up therefore rotating miticides with different modes of action reduces the potential for developing mite resistance.  Long-term exposure is not expected for the proposed use patterns.

No dermal hazard has been identified for cyflumetofen; therefore occupational handler and post-application risks were assessed for the inhalation route of exposure only.  All estimated short- and intermediate-term handler inhalation risk estimates are above the Agency's level of concern (MOEs >= 100).  Based on the Agency's current practices, a quantitative post-application inhalation exposure assessment was not performed for cyflumetofen.


III. ENVIRONMENTAL RISK

A summary of the environmental fate and ecological effects and risks of cyflumetofen as assessed in the Agency document entitled "Cyflumetofen: New Chemical Ecological Risk Assessment for Section 3 New Use on Citrus, Pome Fruits, Grapes, Strawberries, Tomatoes, Tree Nuts, and Ornamentals" is provided below.

A.  Environmental Fate 

   1. Persistence:  

Cyflumetofen is not persistent in the environment and rapidly converts to degradates via abiotic hydrolysis reactions (DT50 = 9.75 hours at pH 7) and biotic reactions with (DT50 of less than 21 days).  Many of the degradates (e.g., A-2, A-18, AB-1, and B-1) are much more persistent than the parent.

For comparison, cyflumetofen has a comparatively low water solubility of 0.0277 mg/L at 20ºC and Koc of 131,826 L/kg-organic carbon.  Only degradates AB-11, AB-12, AB-1 dimer, AU16 (dimer), and AU17 (dimer) are predicted to have lower water solubility than the parent.  Similarly, only degradates AB-12, AB-1 dimer, and AU17 (dimer) are predicted to have higher Kocs than the parent.  Therefore, the vast majority of the degradates are expected to be more mobile than the parent.   

   2. Mobility:  

Since cyflumetofen is used by foliar application, residues may be deposited into soil via wash off from rainfall or irrigation activities as well as directly deposited onto soil during the application.  Cyflumetofen appears to be non-volatile.  This is supported by its water solubility (0.0277 mg/L at 20ºC) and low vapor pressure (< 4.43 x 10[-8] torr at 25ºC) and Henry's Law constant (< 9.3 x 10[-7] Pa*m[3]/mol at 20ºC).

   3. Bioaccumulation:  

The measured BCF (bio-accumulation in fish) is approximately 200x in whole fish (other tissues were not measured separately) based on TRR (total radioactive residues).  The BCF study is somewhat problematic in that the TRR were still increasing at the end of the accumulation phase.  The identity of radioactivity measured in the BCF study was not determined in the fish BCF study.  Therefore, it is unknown whether it is parent, degradate(s), or some combination of parent and degradate(s) that is accumulating in the fish.  However, the rate of accumulation appears to slow over the 21 day accumulation phase with concentrations only doubling from day 1 (approximately 100x) to day 21 (approximately 200x).  Therefore, given the high metabolism of Cyflumetofen evident in fish and high depuration rates of degradates, bioaccumulation in fish resulting from Cyflumetofen pesticide applications is not a concern.  



B.  Ecological Risk

Ecological risk characterization integrates the results of the exposure and ecotoxicity data to evaluate the likelihood of adverse ecological effects. The means of integrating the results of exposure and ecotoxicity data is called the risk quotient method. For this method, risk quotients (RQs) are calculated by dividing exposure estimates by ecotoxicity values, both acute and chronic (RQ = Exposure/Toxicity). RQs are then compared to EPA's levels of concern (LOCs). The LOCs are criteria used by the Agency to indicate potential risk to non-target organisms. The criteria indicate whether a pesticide, when used as directed, has the potential to cause adverse effects to non-target organisms. The ecological risk profile is described in detail below.

   1. Aquatic Organisms

Risk to Fish (Freshwater): The acute RQs calculated for freshwater fish represent risk based on the conservative assumption that the collective toxicity of parent cyflumetofen and all degradates are equivalent to the toxicity of the most toxic chemical among the parent and degradates for which data is available (i.e., degradate A-2).  Even under this conservative assumption, acute aquatic animal LOCs (>0.05) were not exceeded for freshwater fish regardless of use suggesting that the likelihood of adverse effects to freshwater fish from acute exposure as a result of the proposed uses of cyflumetofen is low.  
  
It should be noted that the freshwater fish acute toxicity study with A-2 yielded a NOAEC of <5.04 mg a.i./L.  This NOAEC is based on sublethal effects including unbalanced swimming, faulty respiratory function, loss of equilibrium, and non-typical pigmentation observed at the lowest concentration tested.  Overall, the likelihood of adverse effects to freshwater fish from acute exposure to A-2 is considered low because: 1) acute RQs calculated using the LC50 endpoint did not exceed LOCs; 2) no sublethal effects were observed in fish acute toxicity studies with parent cyflumetofen where the organisms were presumably exposed to A-2 as a result of rapid hydrolysis, and 3) TTR surface water EECs, which represent parent cyflumetofen and multiple degradates including A-2, are at least 3 orders of magnitude less than the observed NOAEC for A-2. 

The aquatic chronic LOC (=1) conducted using both parent and degradates, is not exceeded for freshwater fish regardless of use, suggesting that the likelihood of adverse effects to freshwater fish from chronic exposure as a result the proposed uses of cyflumetofen is low.
Risk to Aquatic Invertebrates (Freshwater):  Similar to fish, aquatic invertebrate acute and chronic toxicity studies with technical grade cyflumetofen were conducted as limit tests because of the low solubility of cyflumetofen (i.e., 28.1 ug/L at 20°C).  Mean-measured concentrations of 17.2 and 16.2 ug a.i./L for Daphnia magna (acute and chronic tests, respectively), 6.30 ug a.i./L  for Eastern oyster and 22.7 ug a.i./L for mysid shrimp were achieved using a saturator column and flow-through exposure.  An acute toxicity study with Daphnia magna was also conducted with a 20.4% formulation of cyflumetofen which results in a mean-measured concentration of 744 ug a.i. /L.  

 Based on studies with daphnids, Eastern oyster, and mysid shrimp, technical grade cyflumetofen is practically non-toxic to aquatic freshwater invertebrates up to the tested solubility limit on an acute basis.
 
 Daphnia toxicity tests were conducted with cyflumetofen degradates A-2, B-1, and B-2; tests with the latter two degradates were limit tests.  A-2 is slightly toxic to freshwater invertebrates with an EC50 of 10.52 mg a.i. /L; B-1 is practically non-toxic to freshwater invertebrates with an EC50 of >177 mg a.i./L; and B-2 is practically non-toxic up to the limit concentration (i.e., 0.020 mg a.i./L. The NOAEC for the study with A-2 was set at 3.83 mg a.i. /L based on immobility observed at higher concentrations.  In the studies with B-1 and B-2, since there was no statistically-significant immobility, the NOAEC was set at the highest treatment concentration (i.e., 177.5 mg a.i. /L and 0.020 mg a.i. /L, respectively).
 
The aquatic chronic LOC (=1) conducted using both parent and degradates, is not exceeded for aquatic freshwater invertebrates regardless of use, suggesting that the likelihood of adverse effects to freshwater fish from chronic exposure as a result the proposed uses of cyflumetofen is low.

Risk to Aquatic Invertebrates (Estuarine/marine):  Estuarine/marine fish and invertebrate RQs were not calculated because of the lack of appropriate toxicity endpoints.  Based on a comparison of acute toxicity endpoints between freshwater and estuarine/marine organisms, there is no indication that estuarine/marine fish/invertebrates are more sensitive to parent cyflumetofen than freshwater fish/invertebrates.  In addition, estuarine/marine fish/invertebrates would have to be several orders of magnitude more sensitive than freshwater fish/invertebrates to the most toxic degradate tested, A-2, to exceed Agency LOCs suggesting that the likelihood of adverse effects to estuarine/marine fish and invertebrates as a result of the proposed uses of cyflumetofen is low.
 
 Risks to Aquatic Plants: Aquatic plant Tier II studies were conducted with technical grade cyflumetofen.  In addition, a Tier I green algal study was conducted with a 20.4% formulation of cyflumetofen.  Toxicity endpoints for studies testing technical grade cyflumetofen are based on initial-measured concentrations because the rapid hydrolysis of cyflumetofen typically resulted in concentrations that were below the level of detection or quantification at study termination.  No effects were noted in any of the aquatic plant studies.
 
Toxicity tests with the green alga Pseudokirchneriella subcapitata were conducted with the cyflumetofen degradates AB-11 and B-1.  There were no effects in the limit test with AB-11.  In the test with B-1, the EC50 was non-definitive (i.e., >102.7 mg a.i. /L), and there was no NOAEC (i.e., <0.10 mg a.i. /L) due to statistically-significant effects at the lowest treatment concentration.  However, there is uncertainty associated with the latter study because of the lack of a clear concentration-response relationship.
 
 Risks to Benthic Invertebrates:  The aquatic acute and chronic LOCs were calculated using parent and degradates.  LOCs  (>0.05 and 1, respectively) are not exceeded for sediment-dwelling (benthic) invertebrates regardless of use suggesting that the likelihood of adverse effects to benthic invertebrates from acute or chronic exposure to cyflumetofen for all proposed uses is low. 
 
Chronic spiked sediment tests with Chironomus riparius were conducted with degradates AB-1 and AB-1 dimer.  Endpoints in the test with AB-1 were based on reduced emergence rates with NOAECs of 36.1 mg a.i./kg-dw, 34.2 mg a.i. /L, and 9.06 mg a.i. /L for sediment, pore water, and overlying water.  There were no statistically-significant effects on rates of emergence or development in the test with AB-1 resulting in the NOAEC being set at the highest treatment concentration: 75.3 mg a.i./kg-dw, 5.61 ug a.i. /L, and 27.4 ug a.i. /L for sediment, pore water, and overlying water.  
 
   1. Terrestrial Organisms

Risk Concerns for Birds, Reptiles, and Terrestrial-Phase Amphibians:  Avian acute RQs were not calculated because avian acute oral and subacute-dietary toxicity studies for cyflumetofen have non-definitive endpoints.  Instead, the most sensitive, non-definitive acute dose- and dietary-based toxicity values for birds were compared directly to the highest avian acute dose- and dietary-based EECs for the proposed uses of cyflumetofen.  An acute oral study with bobwhite quail yielded the most sensitive, non-definitive avian dose-based toxicity endpoints, LD50 > 2000 mg a.i./kg-bw and NOAEL = 74 mg a.i./kg-bw based on the sublethal effect of hunched posture.  A sub-acute dietary study with bobwhite quail yielded the most sensitive, non-definitive avian dietary-based endpoints, LC50 > 5033 mg a.i./kg-diet and NOAEC = 1133 mg a.i./kg-diet based on the sublethal effect of reduced weight gain.  

The highest avian dose-based EECs correspond to those for small birds (20 g) and range from 1.33 (seeds) to 96.10 (short grass) mg/kg-bw.  Dietary-based EECs range from 5.27 fruits/pods/seeds) to 84.38 (short grass) mg/kg-diet.  These EECs are unlikely to cause avian mortality since they are roughly 2-3 orders of magnitude lower than test concentrations that caused no mortality in toxicity study.  Similarly, these EECs are unlikely to cause reduced weight gain since they are at least an order of magnitude greater than test concentrations that caused this sublethal effect in the bobwhite quail sub-acute dietary study.  However, the range of dose-based EECs does include test concentrations that were associated with sublethal effects (i.e., hunched posture) in the acute oral study with bobwhite quail.  Given that hunched posture was not observed in the sub-acute dietary or chronic, reproductive studies with bobwhite quail, the potential for cyflumetofen to cause this effect as a result of the proposed uses is low.  Therefore, this comparative analysis suggests that the likelihood of adverse effects to birds, reptiles and terrestrial-phase amphibians from acute exposure to cyflumetofen for all proposed uses is low.  

 Avian chronic, dietary-based RQs were calculated for the maximum application rate for each proposed use of cyflumetofen using the NOAEC from the bobwhite quail reproduction study (154 mg a.i./kg-diet).  Avian chronic, dietary-based RQs range from 0.03 to 0.55 across all uses and feeding categories.  Therefore, the avian chronic LOC of 1 is not exceeded for birds of any feeding categories regardless of the proposed use.  This suggests the likelihood of adverse effects to birds; reptiles and terrestrial-phase amphibians from chronic exposure to cyflumetofen for all proposed uses are low.

 Risk Concerns for Mammals: No mammalian acute dose-based RQs were calculated because the mammalian acute oral toxicity study for cyflumetofen has a non-definitive endpoint.  No mammalian acute dietary-based RQs were calculated because a mammalian acute dietary-based endpoint (i.e., LC50, mg/kg-diet) is not available.  
 
  An acute oral study with female Wistar rats yielded the non-definitive dose-based toxicity endpoint of LD50 > 2000 mg a.i./kg-bw.  The highest mammalian dose-based EECs correspond to those for small mammals (15 g) and range from 1.12 (seeds) to 80.45 (short grass) mg/kg-bw.  These EECs are unlikely to result in mammalian mortality or sublethal effects since they are roughly 2-3 orders of magnitude lower than test concentrations that caused no mortality or transitory sublethal effects in the acute oral toxicity study.  Therefore, this comparative analysis suggests that the likelihood of adverse effects to mammals from acute exposure to cyflumetofen for all proposed uses is low.
 
 Mammalian chronic dose- and dietary-based RQs were calculated for the maximum application rate for each proposed use of cyflumetofen using the NOAEC from a rat 2-generation reproduction study (150 mg/kg-diet, 9.21 mg/kg-bw/day).  Mammalian chronic dose- and dietary-based RQs range from 0.03 to 3.97 and 0.22 to 0.56, respectively, across all uses and feeding categories.  The mammalian chronic LOC of 1 is exceeded in small and medium mammals consuming short grass, tall grass, broadleaf plants, or arthropods and large mammals consuming short grass or tall grass.   In spite of these exceedances, EPA believes the actual risk of chronic effects is low for several reasons.  The chronic RQs reflect exposure at the site of application, following 2 applications at the maximum use rate. RQs would be expected to get closer to the no effect levels as the distance from the treated area increases, and when lower application rates or fewer applications are used.  Further, the RQs assume that mammals forage for food exclusively in the treated area.  Additionally, the models used to estimate concentrations of cyflumetofen in the environment are conservative screening models, designed to provide high-end exposure estimates, a more refined assessment would likely show further reduction in the likelihood of actual risk to mammals.  Typical use rates are expected to further reduce the levels of concern.  Although the risk of chronic effects on mammals is low, it cannot be entirely discounted.  To mitigate potential chronic risk to mammals, EPA proposes requiring labeling language intended to reduce the area of potential exposure to cyflumetofen residues by reducing inadvertent off-target exposure via drift and runoff.  (See Proposed Regulatory Decision section).

Risk Concerns for Terrestrial (Upland and Semi-Aquatic) Plants:  RQs for dicots were calculated for the maximum application rate and application method (ground) for each proposed use.  For non listed dicots, RQs were below 1.  However, for listed dicots, RQs are greater than 1.  These RQs were generated using the EC25 and NOAEC for the most sensitive dicot from the seedling emergence study (tomato, EC25/NOAEC = 0.0393/0.000706 lb a.i. /A) and dicot NOAEC from the vegetative vigor study (NOAEC = 0.273 lb a.i. /A).  RQs for monocots were not calculated due to a lack of appropriate seedling emergence endpoints in the most sensitive species, oats.  Doses in this study did produce effects that were observed at levels to approximate a 25% inhibition of shoot weight and length.  The EC25 (i.e., seedling emergence) was calculated for the other 3 monocots studies (onion, corn, and ryegrass).  

Overall, adverse effects to terrestrial plants (listed dicots and all monocots) from exposure to cyflumetofen as a result of the proposed uses are possible.  The Agency reviewed 10 terrestrial plants studies (4 monocots and 6 dicots) to assess the effects of cyflumetofen.  The results of the tests on all the dicots and most monocots were deemed acceptable.  Of the 4 monocots tested (i.e., oat, onion, corn, ryegrass), only the study with oat was deemed supplemental.  No effects were noted in the adult plants.  Therefore, a NOAEC for monocots was not established.  RQs were all less than 1, and the LOC was not exceeded for the other tested monocots (i.e., onion, corn, and ryegrass).  Because of the uncertainties in the oat study, the Agency is proposing to add an additional buffer zone of 15 feet to further protect against any potential effects of emerging non listed plants.  This additional measure is also similar to how the chemical has been proposed to be labeled in Canada.  If the registrant wishes to have the 15 foot buffer reexamined, they could repeat the oat study and see if a clearer dose response relationship is achieved.  Additionally, label language is being added with the intent to alert the users to spray drift exposure concerns when emerging seedlings are present.  Therefore, the Agency believes the potential risks are acceptable in light of the benefits.  (See Proposed Regulatory Decision section).  

Risk Concerns for Beneficial Invertebrates: While exposure potential exists via pathways such as spray drift, available toxicity data for cyflumetofen indicate that it is practically non-toxic to honeybees and other beneficial invertebrates on an acute contact and an acute oral basis.   Acute limit tests with two beneficial terrestrial arthropods  -  the parasitic wasp (A. rhopalosiphi) and the predatory mite (T. pyri)  -  using a 20.3% formulation of cyflumetofen both yielded a LR50 of >1.2 lb a.i./A  and a NOAEC of 1.2 lb a.i./A which are greater than the single maximum application rate of 0.2 lb a.i./A for cyflumetofen.

IV. PROPOSED REGULATORY DECISION

Under Section 3(c)(5) of the Federal Insecticide, Fungicide and Rodenticide Act (FIFRA), the Agency is proposing unconditional registration for pesticide products containing the new active ingredient cyflumetofen for use on tree nuts (crop group 14-12), pome fruits (crop group 11-10), citrus (crop group 10-10), grapes, strawberries, tomatoes and ornamentals.  The products under consideration for the new uses are:
      
         * Cyflumetofen Technical
         * Sultan(TM) miticide
         * Nealta(TM) miticide

Section 3(c)(5) of FIFRA authorizes the Agency to approve the registration of a pesticide without condition, if the Administrator determines that (i) its composition is such as to warrant the proposed claims for it, (ii) its labeling and other material required to be submitted comply with the requirements of this Act, (iii) it will perform its intended function without unreasonable adverse effects on the environment, and (iv) when used in accordance with widespread and commonly recognized practice it will not generally cause unreasonable adverse effects on the environment.
In reference to the first and second determinations above, the compositions of the pesticides are such that the proposed claims are warranted and the Agency received satisfactory data to conduct risk assessments for the uses proposed.
In reference to the third determination above, the Agency believes that the use of cyflumetofen will not cause any unreasonable adverse human health or ecological effects.  This determination is based on the findings in the Agency's conservative human health and environmental risk assessments.  
As explained earlier (see section III. B.2), the proposed uses of cyflumetofen may pose adverse effects to terrestrial plants (listed dicots and all monocots).  Additionally, potential chronic risks to small and medium mammals consuming short grass, tall grass, broadleaf plants, or arthropods and large mammals consuming short grass or tall grass may be expected as a result of the proposed cyflumetofen uses.  EPA believes the actual risk of chronic effects is low for several reasons.  The chronic RQs reflect exposure at the site of application, following 2 applications at the maximum use rate. RQs would be expected to get closer to the no effect level as the distance from the treated area increases, and when lower application rates or fewer applications are used.   Further, the RQs assume that all mammals forage for food exclusively in the treated area.  Additionally, the models used to estimate concentrations of cyflumetofen in the environment are conservative screening models, designed to provide high-end exposure estimates, a more refined assessment would likely show further reduction in the likelihood of actual risk to mammals.  Although the risk of chronic effects on mammals is low, it cannot be entirely discounted.   Moreover, a buffer zone of 15 feet from the edge of the treated fields will significantly reduce RQs and LOCs for terrestrial plants from exposure via spray drift.  Therefore to mitigate potential chronic risk to mammals and terrestrial plants (listed dicots and all monocots), the applicant has agreed to add the following labeling language intended to reduce the area of potential exposure to cyflumetofen residues by reducing inadvertent off-target exposure via drift and runoff:

   * Removal of aerial application from the label 
   * Inserting the following section: To ensure the protection of threatened or endangered species, it is important to maintain spray drift loadings below levels of concern for any area adjacent to the application site that is not excluded as possible habitat for these organisms, the following restrictions apply:

       o          Buffer distance: 15 feet 
       o          Release Height: 20 inches 
       o          Droplet Size: A combination of spray nozzles and appropriate pressure must be selected to provide ASABE standard S571.1 droplet size category of fine (DV0.5 of >= 180 microns) or coarser than fine. 
       o          Maximum ground wind speed: 15 mph 

The Agency believes that with the revised labeling as described above, 1) their composition are such as to warrant the proposed claims for them, (ii) the labeling and other material required to be submitted comply with the requirements of this Act, (iii) these pesticides will perform their intended function without unreasonable adverse effects on the environment, and (iv) when used in accordance with widespread and commonly recognized practice these pesticides will not generally cause unreasonable adverse effects on the environment.  Therefore, the Agency proposes to grant these unconditional registrations and establish permanent tolerances as summarized below.

Commodity
                           Proposed Tolerance (ppm)
                        EPA-Recommended Tolerance (ppm)
Almond, hulls
                                      4.0
                                      4.0
Citrus, oil
                                     16.0
                                      16
Fruit, citrus, group 10-10
                                      0.3
                                     0.30
Fruit, pome, group 11-10
                                      0.3
                                     0.30
Grape
                                      0.6
                                     0.60
Grape, raisin
                                      0.9
                                     N/A*
Nut, tree, group 14-12
                                     0.01
                                     0.01
Strawberry
                                      0.6
                                     0.60
Tomato
                                      0.2
                                    0.40**
            *Not required, raisin is covered by RAC grape tolerance
            ** EPA is establishing a tolerance for tomato at 0.40 ppm to fully account for residue loss from the field trial samples during freezer storage from the time of harvest to the time of analysis.
            
As stated earlier, this present action was conducted as a joint review with Health Canada's Pesticide Management Regulatory Authority (PMRA) and Mexico's Federal Commission for the Protection against Sanitary Risk (COFEPRIS).  Harmonization of tolerance expression and levels for plant commodities was achieved during the review process.

As required by FIFRA, the Agency published a notice of receipt (NOR) of this application in the Federal Register (77 FR 65878, 10/31/2012) to register pesticide products containing the new active ingredient cyflumetofen.  A notice of filling (NOF) was also published to announce the filling of a petition requesting the establishment of regulation for residues of cyflumetofen in or on various commodities (77 FR 30481, 05/23/2012).  No comments were received on either notice.

A.  Data Requirements

There are no outstanding data requirements for cyflumetofen.

B. Labeling Requirements

In order to mitigate potential chronic risk to mammals and terrestrial plants (listed dicots and all monocots), the applicant has agreed to add the following labeling language intended to reduce the area of potential exposure to cyflumetofen residues by reducing inadvertent off-target exposure via drift and runoff:





   * Do not apply via aerial application
   * Inserting the following section: To ensure the protection of threatened or endangered species, it is important to maintain spray drift loadings below levels of concern for any area adjacent to the application site that is not excluded as possible habitat for these organisms, following restrictions apply:

       o          Buffer distance: 15 feet 
       o          Release Height: 20 inches 
       o          Droplet Size: A combination of spray nozzles and appropriate pressure must be selected to provide ASABE standard S571.1 droplet size category of fine (DV0.5 of >= 180 microns) or coarser than fine. 
       o          Maximum ground wind speed: 15 mph 
