UNITED STATES ENVIRONMENTAL PROTECTION AGENCY WASHINGTON, D.C. 20460



### MEMORANDUM DATE: January 30, 2013
TXR

### #: 0056523 OFFICE OF CHEMICAL SAFETY AND POLLUTION PREVENTION



### SUBJECT: Fluopyram: Summary ofHazard and Science Policy Council (HASPOC) Meeting ofNovember 29,2012: Recommendations on the Waiver Request for the Subchronic Inhalation Study Data Requirement. PC Code: 080302 Decision No.: N/ A 

### Petition No.: N/ A Risk Assessment Type: N/ A TXRNo.: 0056523 MRID 

### No.: N/ A 

### FROM: Kristin Rury, MPH 

# ¥-0--:x--. Executive Secretary

.... . (_) DP Barcode: N/A Registration No.: Nl 

### A Regulatory Action: N/ A Case No.: N/ 

### A CAS No.: NIA 

### 40CFR:N/A

Hazard and Science Policy Council (HASPOC) Health Effects Division (7509P)**Q~** 

### THROUGH: Jess Rowland, Co-Chair

# ~~~J_ Anna Lowit, Ph. D, Co-Chair 

## t/f Hazard and Science Policy Coun 1 ( SPOC) Health Effects Division (7509P) TO: Barry O'Keefe, Senior Biologist Myron Ottley, Ph. D., Senior Biologist JeffDawson, Acting Branch Chief Risk Assessment Branch III Health Effects Division (7509P) MEETING ATTENDEES
HASPOCMembers: 

### Anna Lowit, Elizabeth Mendez, JeffEvans, Jess Rowland, Jonathan Chen, Julie VanAlstine, Kristin Rury, Michael Metzger, PV Shah, Ray Kent
Presenters: 

### Barry O'Keefe, Myron Ottley
Page 1of5OtherAttendees: Cassi Walls, Danette Drew, JeffDawson, Mohsen Sahafeyan, Nancy Tsaur, William Irwin,
L PURPOSE OF MEETING Risk AssessmentBranch III (RAB III) received a waiver request from Bayer Crop Science for the required subchronic inhalationtoxicity study. Based oncurrentpolicies, a subchronic inhalationtoxicity study inrats is required to assess the potential for repeated handler inhalation exposure to fluopyram from use on agricultural crops. The HASPOC met onNovember 29, 2012 to discuss the need for a subchronic inhalation study in rats to support the registered uses of fluopyram. II. SUMMARY OF USE PROFILE & PREVIOUS RISK ASSESSMENT Fluopyram, (N-[2-[3-chloro-5-(trifluoromethyl)-2-pyridinyl]ethyl]-2- (trifluoromethyl)benzamide) is a newbroad-spectrum systemic fungicide ofthe pyridinyl-ethylbenzamide group registered for use on a variety ofagricultural crops, including apples, bananas (no US registration), cherries (sweet and tart), dried beans (selected), peanuts, potatoes, strawberries, sugar beets, tree nuts, watermelon, and wine grapes. The formulated end-use product is Fluopyram 500 SC Fungicide, a liquid formulation containing 41.5% ai (4.16lb/gal) fluopyram. Applications offluopyrammay be applied to agricultural crops using ground (chemigation, groundboom sprayers, airblast sprayers, low pressure hand wand sprayers, and backpack sprayers) or aerial equipment. Multiple applications may be made per season. Applications may also be made to strawberries and watermelon in greenhouses of 10 acres orlarger. Preharvest intervals (PHis) range from 0 to 14 days and the restricted entry interval (REI) is 12 hours. Exposure is expected to be ofshort- and intermediate-term durations.
In the mostrecent risk assessment (D385636, S. Healy, 11123/2011), anoral point ofdeparture (POD) of 14.5 mglkg/day was used for assessing risk for short- and intermediate-term inhalation exposures. The POD, derived from the ratreproductive toxicity study, was based onthe following effects inparents: clinical pathology changes, decreased spleen and thymus weights, increased liver weights, and centrilobular hypertrophy; and the following effects in offspring: decreased body weight and body weight gain, decreases in spleen and thymus weights, and slight delay in preputial separation atthe LOAEL of82.8 mglkg/day.
For all registered uses offluopyram, occupational non-cancer short- and intermediate-term inhalation margins ofexposure (MOEs) range from 8,800 to 1,400,000. The handler scenario resulting in the highest inhalation exposure was mixing/loading/applying liquids to watermelons and strawberries with high pressure handwands in greenhouses.
III. REGISTRANT'S RATIONALE FOR WAIVER
In the waiver request for the subchronic inhalation study submitted to EPA (MRID 48828301), the Registrantprovided the followingjustifications based onthe HED SOP 2002.01:

Page 2 of5• Low toxicity

- Acute skin and eye irritation studies showed fluopyram was not a skin or eye irritant (Toxicity Category IV for both). The acute inhalation study was also Toxicity Category IV, which indicates fluopyram is not expected to be a pulmonary irritant • LowVolatility

- The vapor pressure offluopyram is 2.3 X 1 0"8mm Hg which is significantly below HED's threshold of7.5x10"5 mm Hg for the indoor greenhouse uses and 7.5x104 mm Hg for outdoor uses. • MOEs That Exceed Level ofConcern

- As stated inthe most recentrisk assessment (D385636, S. Healy, 11123/2011) the oral POD (NOAEL

## = 14.5 mg/kg/day) results in occupational short- and intermediate-term inhalation MOEs ranging from 7,700 to 1

,300,000, whichexceed HED'sminimum MOE of 1,000. IV. INHALATION STUDY WAIVER DISCUSSION Previously, the Office ofPesticide Programs (OPP) used a set ofcriteriato determine whetheror not aninhalation study could be waived. These criteriaconsidered the scientific information available for the chemical, including its: 1) degree ofirritation and corrosivity; 2) volatility; 3) aerosol particle size; and 4) Acute Toxicity Category and extrapolated MOEs (e.g., MOEs 10 times higher than the target). In 2009, OPP developed an issue paper onrisk assessment approaches for semi-volatile pesticides. As part ofthat issue paper, an analytical comparison was conducted oforal and inhalation experimental toxicology studies. In general, this analysis showed thatthe degree to which oral points ofdeparture (PODs) were protective ofpotential inhalation toxicity varied. In many cases the oral POD was protective, but in some cases the inhalation PODs were significantly more protective. Currently, OPP uses a weight ofthe evidence (WOE) approach that builds upon OPP'sexperience using the criteria listed above and conclusions from the 2009 SAP. As approaches for route-to-route extrapolation continue to evolve and improve, OPP may incorporate additional considerations into the WOE analysis. Inhalation exposure can be to vapors, droplets, and/or particles/dusts. The form ofinhalation exposure is determined by a number offactors including physical-chemical properties, use pattern, and exposure scenarios. OPP's interim WOE approach considers: 1. 

### Physical-ChemicalProperties: Vapor pressure and Henry's law constant are key considerations with respect to volatilizationafter sprays have settled.**Flu~yram** has a vapor pressure of2.3 X 10"8mm Hg. The Henry's lawconstant is 2.98 X 10"5 Pa morI at 20

# oc (distilled water). However, lowvapor pressure and/or Henry's law constant do not preclude exposure to aerosolized droplets orparticles/dust.
2. 

### Use Pattern andExposure Scenarios: Any application scenario that leads to inhalation exposure to droplets needs to be considered in the WOE analysis for an inhalation toxicology study waiver request. HED acknowledges that airblast and aerial applications are more likely to lead to higher occupational handler inhalation exposure, particularly to droplets, and may contribute to spray drift. In the case offluopyram, the mixing/loading/applying ofliquids with high pressure handwands to strawberries and watermelons in greenhouses results in the highest inhalation exposures. 3. 

### Margins of Exposure (MOEs): TheMOEestimates for inhalation scenarios were calculated using an oral toxicity study and should be considered inthe WOE analysis for an inhalation
Page 3 of5toxicology study waiver request. Inthe past, OPPhas used MOEs ofapproximately 10 times higher than the level ofconcern as a benclunark for granting waiver requests. The 2009 analysis suggests this approach is appropriate for most pesticides but not all. Using 

### this interim WOE approach, MOEs from 10-100 times greaterthanthe level ofconcernwill be considered in combination with other factors discussed here. Inthe case offluopyram, the short- and intermediate-term occupational handler inhalation MOEs range from 8,000 (mixing/loading/applying liquids to strawberries and watermelons in greenhouses) to 1,400,000. 4. 

### Toxicological Effects: Fluopyram is a broad-spectrum systemic fungicide ofthe pyridinylethyl-benzamide group. It acts byinhibiting succinate dehydrogenase inthe cell respiration offungi. The mechanismoftoxicity in mammals is not clearly defined. Fluopyram has relatively lowacute toxicity via the oral (Toxicity Category III), dermal (Toxicity Category III), and inhalationroutes (Toxicity Category IV). It is notaneye or dermal irritant (Toxicity Category IV) or dermal sensitizer. The primary toxic effects of fluopyram toxicity seen in subchronic and chronic oral toxicity studies inrats, mice, and dogs are decreased body weight and liver effects. Livereffects were characterized byincreased liverweight, hepatocellular hypertrophy, hepatocellular vacuolation, increased mitosis and hepatocellular necrosis. Livereffects inrodents were seen at lower dose levels 

### than those in the dogs. Thyroid effects were found atdose levels similarto those that produced liver effects inrats and mice; effects consisted offollicular cell hypertrophy, increased thyroid weight and hyperplasia atdose levels 2::100 mg/k.g/day. Changes in thyroid hormone levels (T3& T4) and increased TSH were also seen in rats in a subchronic toxicity study where these parameters were measured. In male mice, there was an increased incidence ofthyroid adenomas. In the genotoxicity battery, fluopyram was shown to have no genotoxic potential. Inthe carcinogenicity study, increased liver tumors were also observed in female rats. The registrant is currently conducting mechanistic studies to demonstrate a mode ofaction for tumor formation. Fluopyram is not a developmental toxicant, nordid it adversely affect reproductive parameters.

. When considering a waiver request for an inhalationtoxicity study, the Agency will attempt to evaluate other pesticides which share the same mode ofaction (MOA) and/or are 

### in the same class. These pesticides canprovide important information with respect to potential inhalation toxicity. Specifically, ifother similar pesticides show inhalation toxicity studies to be more sensitive, an inhalationtoxicity study may be required regardless ofMOE, depending onthe exposure profile. Theriskassessment team conducted a data searchusing the Integrated Structure, Toxicology, Endpoints and Properties (ISTEP) database on benzamide fungicides to explore evidence ofportal ofentry effects on the respiratory system and anyresults ofinhalation toxicity for structurally related chemicals to fluopyram. No fluopyram analogs were found inthe !STEPdatabase.

Page4 of5IV. HASPOC RECOMMENDATIONS 

### Based on a WOE**approach~** 

### the HASPOC concluded that a subchronic inhalation toxicity study is not required at this time. This approach included all ofthe available hazard and exposure information for flupyram, including: (1) the low vapor pressure offluopyram (2.3 x 10· 8 

### mm Hg); (2) the low acute inhalation toxicity offluopyram (Toxicity Category IV); and 3) the use ofan oral POD established for the most sensitive endpoint/target organs resulting in screening-level MOEs ranging from 8,800 to 1,400,000.

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