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

              OFFICE OF CHEMICAL SAFETY AND POLLUTION PREVENTION 

MEMORANDUM

January 30, 2013
TXR # 0056527

SUBJECT:	Trifloxystrobin:  Summary of Hazard and Science Policy Council (HASPOC) Meeting of November 29, 2012:  Recommendations on waiver requests for a 28-day inhalation study 
		
PC Code:  129112
DP Barcode:   405845
Decision No.: N/A
Registration No.: N/A
Petition No.: N/A
Regulatory Action: N/A 
Risk Assessment Type: N/A
Case No.: N/A
TXR No.: 0056527
CAS No.: 141571-21-7
MRID No.: N/A
40 CFR: 180.555


FROM:	Kristin Rury, MPH
		Executive Secretary, HASPOC
		Health Effects Division (7509P)

THROUGH:	Jess Rowland, MS. Co-Chair
      Anna Lowit, Ph.D, Co-Chair
            HASPOC
		Health Effects Division (7509P)

TO:		Sheila Healy, Toxicologist 
      Jeff Dawson, Acting Chief
		Registration Action Branch 3
		Health Effects Division (7509P)
		              
			
MEETING ATTENDEES:  

HASPOC Members:  Anna Lowit, Elizabeth Mendez, Jeff Evans, Jess Rowland, John Kough, Jonathan Chen, Julie Van Alstine, Kristin Rury, Michael Metzger, PV Shah, Ray Kent
Presenters:  Nancy Tsaur and Sheila Healy

Other Attendees:  Danette Drew, Kelly Lowe, Linda Taylor, Matthew Lloyd, William Irwin

I.	PURPOSE OF MEETING:

The Hazard and Science Policy Council (HASPOC) met initially on December 8, 2011 to discuss the need for a subchronic inhalation toxicity study; the study was required based on low margins of exposure (MOEs), including for handgun applications to turf (MOE = 190).  Since then the Risk Assessment Branch III (RAB III) has received an inhalation toxicity study waiver request from Bayer CropScience (Bayer) specifically addressing a need for updated exposure scenarios and exposure assumptions.  HASPOC met again on November 29, 2012 to discuss Bayer's subchronic inhalation toxicity study waiver request.  

II.  	SUMMARY OF WAIVER REQUEST:

Bayer rebutted the previous HASPOC decision, noting that the lowest MOE was from an outdated assessment (S. Wang, DP258460, 08/09/1999).  The highest inhalation exposure and was from mixing/loading/applying with a handgun to turf and resulted in an MOE of 190.  

III.  	SUMMARY OF USE PROFILE & PREVIOUS RISK ASSESSMENT:

Trifloxystrobin is a broad spectrum fungicide (oximinoacetate) of the strobilurin class.  Tolerances are currently established for the combined residues of trifloxystrobin and its metabolite(s) in/on various crop and livestock commodities ranging from 0.02 ppm (milk) to 38 ppm (citrus oil) [40 CFR §180.555(a)].  Trifloxystrobin is registered for use via several application methods, including groundboom, aerial, chemigation and airblast equipment.  

In the most recent risk assessment (N. Tsaur, D385972, 08/02/11), a subchronic inhalation toxicity study in the rat was required as a condition of registration for further characterization of inhalation risk.  Due to the potential for repeated occupational inhalation exposure, including exposure in indoor environments during seed treatment, there is concern for toxicity by the inhalation route.  

Using the oral point of departure (POD) from the last risk assessment (N. Tsaur, D396514, 09/19/2012), and updated exposure estimates, some short- and intermediate-term MOEs are near or below HED's level of concern (LOC) of 100.  The highest inhalation exposure is from occupational mixing/loading/applying with a mechanically pressurized handgun in a greenhouse to (MOE = 54).  The second highest inhalation exposure results from mixing/loading liquids for aerial application to high acreage crops (MOE = 180).  As a seed treatment, sweet corn represents the seed with the highest potential occupational inhalation exposure (based on application rate and seed treatment throughput).  Activities related to treating seed and planting treated seed at baseline (no respirator) result in inhalation MOEs ranging from 3,700 to 90,000 (LOC = 100).  

Residential handler inhalation MOEs from application to turf and ornamentals range from 3,700 to 20,000,000.

III. STUDY WAIVER REQUESTS

   a. Inhalation Study
In the past, OPP has used a set of criteria when considering the scientific information available to waive (or not waive) an inhalation study including the chemical's: 1) severe irritation and corrosivity, 2) low volatility, 3) large aerosol particle size, and 4) Acute Toxicity Category IV and an extrapolated MOE (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 analysis was conducted on a comparison of oral and inhalation experimental toxicology studies.  In general, this analysis showed that the degree to which oral 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 sensitive.  At this time, OPP is currently developing a scientifically supportable approach for considering waiver requests for inhalation studies.  In the interim, OPP will be using a weight of the evidence (WOE) approach which builds upon experience using the previously used criteria listed above and informed by the 2009 SAP.  

Inhalation exposure can be to vapors, droplets, and/or particles/dusts.  The form of this exposure is determined by a number of factors including physical-chemical properties, use pattern, and exposure scenario.  This interim WOE approach considers:

1) Physical-chemical properties:  Vapor pressure and Henry's law constant are key considerations with respect to the volatilization after sprays have settled. Trifloxystrobin (408.4 g/mol) has a low vapor pressure (3.4 x 10[-6] Pa at 25 C) and the Henry's law constant is 2.3 x 10-3 Pa m³ mol[-1] at 25°C.   However, low vapor pressure and/or Henry's law constant does not preclude exposure to aerosolized droplets or particles/dusts.
   
2) Use pattern & 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.  It is, however, acknowledged that air blast and aerial applications are more likely to lead to higher occupational handler inhalation exposure, particularly to droplets, and may contribute to contribute to spray drift.  In the case of trifloxystrobin, mechanically pressurized handgun applications in greenhouses result in the highest inhalation exposure.  
   
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 toxicology study waiver request.  In the past, OPP has used MOEs of approximately 10 times higher than the level of concern as a benchmark 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 10-100X over the level of concern will be considered in combination with other factors discussed here. 
   HASPOC agrees with Bayer that the updated calculation for the handgun scenario to turf would result in an MOE of 4,300 (using a body weight of 80 kg).  However, RAB III has reassessed all inhalation MOEs for registered scenarios with the latest occupational exposure calculation spreadsheet.  The new screening assessment results in inhalation MOEs as low as 54 (handgun app to ornamentals, which is a use pattern not previously assessed) and 180 (mixing/loading for aerial application to high acreage crops). 
   
4)  Toxicity:  Trifloxystrobin has relatively low acute toxicity via the oral (Toxicity Category IV), dermal (Toxicity Category IV), and inhalation (Toxicity Category IV) routes of exposure; it is a mild eye (Toxicity Category III) and dermal irritant (Toxicity Category IV), and is a dermal sensitizer.  With repeated dosing by either the oral or dermal route, the liver is consistently the target organ for trifloxystrobin.  Trifloxystrobin does not produce malformations in either rat or rabbit developmental toxicity studies and does not produce reproductive effects.  Trifloxystrobin was determined not to be carcinogenic in mice or rats following long-term dietary administration.  However, it is positive for mutagenicity in Chinese Hamster V79 cells at cytotoxic dose levels while testing negative in the remaining mutagenicity studies.
    For considering a waiver request for inhalation toxicity study, the Agency will evaluate other pesticides which share the same MOA and/or are in the same chemical class.  These pesticides may provide important information with respect to potential inhalation toxicity. Specifically, if other similar pesticides show inhalation toxicity studies to be more sensitive, and depending on the exposure profile, an inhalation toxicity study may be required regardless of MOE.  HASPOC has granted waivers for inhalation toxicity studies for two strobilurin fungicides, azoxystrobin and fluoxastrobin based on high MOEs.  However, for another strobilurin, pyraclostrobin, there were adverse respiratory effects observed in a 28 day inhalation study (i.e., alveolar histiocytosis and olfactory atrophy/necrosis in nasal tissue).  Thus, the HASPOC cannot rule out the potential concern for inhalation toxicity for this class of chemicals.  

IV.  HASPOC RECOMMENDATIONS:

Based on a WOE approach considering all the available hazard and exposure information for trifloxystrobin, the HASPOC determined that a 28-day inhalation toxicity study in the rat is required at this time.  This approach considered all the available hazard and exposure information for trifloxystrobin, including: (1) the low vapor pressure of trifloxystrobin (3.4 x 10[-6] Pa at 25 C); (2) the low acute inhalation toxicity of trifloxystrobin (Toxicity Category IV); (3) a similar strobilurin chemical, pyraclostrobin, demonstrated adverse respiratory effects in a subchronic inhalation toxicity study in rats at 0.030 mg/L/day or 6.9 mg/kg/day; and (4) the use of an oral POD resulting in MOEs as low as 54 and 180.  Beyond the guideline requirements, the inhalation toxicity study should include nasal histopathology (serial sections of the nasal passages) because of the nasal effects seen in the pyraclostrobin subchronic inhalation toxicity study (olfactory atrophy and necrosis).  The Agency requests a study protocol be submitted prior to beginning the study. In the absence of a route-specific inhalation study, the HASPOC recommends that a 10X database uncertainty factor be applied only to assess risks for inhalation exposure scenarios.    
