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 of Hazard and Science Policy Council (HASPOC) Meeting 

of November 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 

TXR No.: 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 

Jeff Dawson, Acting Branch Chief 

Risk Assessment Branch III 

Health Effects Division (7509P) 

MEETING ATTENDEES 

HASPOC Members: Anna Lowit, Elizabeth Mendez, Jeff Evans, Jess Rowland, Jonathan Chen, 

Julie Van Alstine, Kristin Rury, Michael Metzger, PV Shah, Ray Kent 

Presenters: Barry O'Keefe, Myron Ottley 

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Other Attendees: Cassi Walls, Danette Drew, Jeff Dawson, Mohsen Sahafeyan, Nancy 

Tsaur, William Irwin, 

L PURPOSE OF MEETING 

Risk Assessment Branch III (RAB III) received a waiver request from Bayer Crop Science for 

the required subchronic inhalation toxicity study. Based on current policies, a subchronic 

inhalation toxicity study in rats is required to assess the potential for repeated handler inhalation 

exposure to fluopyram from use on agricultural crops. The HASPOC met on November 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 new broad-spectrum systemic fungicide of the pyridinyl-ethylbenzamide group registered for use on a variety of agricultural 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 offluopyram may be applied to agricultural 

crops using ground ( chemigation, ground boom 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 or larger. Preharvest intervals (PHis) range from 0 to 14 days and the restricted entry 

interval (REI) is 12 hours. Exposure is expected to be of short- and intermediate-term durations. 

In the most recent risk assessment (D385636, S. Healy, 11123/2011), an oral point of departure 

(POD) of 14.5 mglkg/day was used for assessing risk for short- and intermediate-term inhalation 

exposures. The POD, derived from the rat reproductive toxicity study, was based on the 

following effects in parents: 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 at the LOAEL of 82.8 mglkg/day. 

For all registered uses offluopyram, occupational non-cancer short- and intermediate-term 

inhalation margins of exposure (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 Registrant provided the following justifications based on the HED SOP 2002.01: 

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• 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 

• Low Volatility - The vapor pressure of fluopyram is 2.3 X 1 0"8 mm 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 of Concern - As stated in the most recent risk 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, which exceed HED's minimum MOE of 1 ,000. 

IV. INHALATION STUDY WAIVER DISCUSSION 

Previously, the Office of Pesticide Programs (OPP) used a set of criteria to determine whether or 

not an inhalation study could be waived. These criteria considered the scientific information 

available for the chemical, including its: 1) degree of irritation 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 on risk assessment 

approaches for semi-volatile pesticides. As part of that issue paper, an analytical comparison 

was conducted of oral and inhalation experimental toxicology studies. In general, this analysis 

showed that the degree to which oral points of departure (PODs) were protective of potential 

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 of the 

evidence (WOE) approach that builds upon OPP's experience 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 of inhalation 

exposure is determined by a number of factors including physical-chemical properties, use 

pattern, and exposure scenarios. OPP's interim WOE approach considers: 

1. Physical-Chemical Properties: Vapor pressure and Henry's law constant are key 

considerations with respect to volatilization after sprays have settled. Flu~yram has a vapor 

pressure of 2.3 X 10"8 mm Hg. The Henry's law constant is 2. 98 X 10"5 Pa mor I at 20 oc 

(distilled water). However, low vapor pressure and/or Henry's law constant do not preclude 

exposure to aerosolized droplets or particles/dust. 

2. Use Pattern and Exposure 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 of fluopyram, the mixing/loading/applying of liquids 

with high pressure handwands to strawberries and watermelons in greenhouses results in the 

highest inhalation exposures. 

3. Margins of Exposure (MOEs): The MOE estimates for inhalation scenarios were calculated 

using an oral toxicity study and should be considered in the WOE analysis for an inhalation 

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toxicology study waiver request. In the past, OPP has used MOEs of approximately 10 times 

higher than the level of concern 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 greater than the level of concern will be 

considered in combination with other factors discussed here. In the case of fluopyram, 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 of the pyridinylethyl-benzamide group. It acts by inhibiting succinate dehydrogenase in the cell respiration 

of fungi. The mechanism of toxicity in mammals is not clearly defined. 

Fluopyram has relatively low acute toxicity via the oral (Toxicity Category III), dermal 

(Toxicity Category III), and inhalation routes (Toxicity Category IV). It is not an eye or 

dermal irritant (Toxicity Category IV) or dermal sensitizer. The primary toxic effects of 

fluopyram toxicity seen in subchronic and chronic oral toxicity studies in rats, mice, and dogs 

are decreased body weight and liver effects. Liver effects were characterized by increased 

liver weight, hepatocellular hypertrophy, hepatocellular vacuolation, increased mitosis and 

hepatocellular necrosis. Liver effects in rodents were seen at lower dose levels than those in 

the dogs. Thyroid effects were found at dose levels similar to those that produced liver 

effects in rats and mice; effects consisted of follicular cell hypertrophy, increased thyroid 

weight and hyperplasia at dose 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 of thyroid 

adenomas. In the genotoxicity battery, fluopyram was shown to have no genotoxic potential. 

In the carcinogenicity study, increased liver tumors were also observed in female rats. The 

registrant is currently conducting mechanistic studies to demonstrate a mode of action for 

tumor formation. Fluopyram is not a developmental toxicant, nor did it adversely affect 

reproductive parameters. . 

When considering a waiver request for an inhalation toxicity study, the Agency will attempt 

to evaluate other pesticides which share the same mode of action (MOA) and/or are in the 

same class. These pesticides can provide important information with respect to potential 

inhalation toxicity. Specifically, if other similar pesticides show inhalation toxicity studies to 

be more sensitive, an inhalation toxicity study may be required regardless of MOE, 

depending on the exposure profile. The risk assessment team conducted a data search using 

the Integrated Structure, Toxicology, Endpoints and Properties (ISTEP) database on 

benzamide fungicides to explore evidence of portal of entry effects on the respiratory system 

and any results of inhalation toxicity for structurally related chemicals to fluopyram. No 

fluopyram analogs were found in the !STEP database. 

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IV. 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 of the available hazard and 

exposure information for flupyram, including: (1) the low vapor pressure of fluopyram (2.3 x 10· 

8 mm Hg); (2) the low acute inhalation toxicity of fluopyram (Toxicity Category IV); and 3) the 

use of an 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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