Page 1 of 4 **UNITED STATES ENVIRONMENTAL PROTECTION AGENCY**

**WASHINGTON, D.C. 20460**

**OFFICE OF CHEMICAL SAFETY AND POLLUTION**  **PREVENTION MEMORANDUM**  January 30 , 201 3 TXR # 0056527
**SUBJECT: Trifloxystrobin**  **:** Summary of Hazard and Science Policy Co uncil ( HASPOC ) Meeting of Novembe r 29 , 20 12 : 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 T **XR 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 (7509 P )
**THROUGH:** Jess Rowland, MS. Co

- Chair

Anna Lowit, Ph.D , Co

- Chair HASPOC Health Effects Division (7509P)
**TO:** Sheila Heal y , Toxicologist

Jeff Dawson , Acting Chief Registration Action Branch 3 Health Effects Division (7509P)

MEETING ATTENDEES : HASPOC Members: Anna L owit, Elizabeth Mendez, Jeff Evans, Jess Rowland, John Kough, Jonathan Chen, Julie Van Alstine, Kristin Rury , Michael Metzger, PV Shah, Ray Kent Presenter s : Nancy

Tsaur and Sheila Heal y Other Attendees: Danette Drew, Kell y Lowe, Li nda Taylor, Matthew Ll oy d, William IrwinPage 2 of 4

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 r equired 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 exposur e scenarios and exposure assumptions. HASPOC met again on November 29, 2012 to discuss Baye r’s subchronic inhalation toxicity study waiver request.
II. SUMMARY OF WAIVER REQUEST **:** Baye r rebutted the previous HASPOC decision , noting that the lowest MOE was from an outdated assessment ( S. Wang, DP258460, 08/0 9 /1999)

. The highest inhalation exposure and was from mixing/loading/applying with a handgun to turf and resulted in an MOE of 190.
II I

. SUMMARY OF USE PROFILE & PREVIOUS RI SK ASSESSMENT **:** T riflox ys trobin is a broad spectrum fungicide ( oximinoacetate) of the strobilurin class. Tolerances are currentl y established for the combined residues of triflox ys trobin 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)]. Triflox ys trobin is registered for use via several application methods, including groundboom, aerial, chemigation and airblast equipment. In the most recent risk assessment (N. Tsaur, D385972, 08/0 2/11), 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 environm ents 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 s hort

- and intermediate

- term MOEs are near or below HED’s level of concern (LOC) of 100. The highest inhalation exposure is from occupational m ixing/loading/appl yi ng with a mechanicall y pressurized handgun in a greenhouse to (MOE = 54 )

. T he second highest inhalation exposure results from mixing/loading liquids for aerial application to high acreage crops ( MOE = 180 )

. As a seed treatment, sweet corn represent s 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 an d ornamentals range from 3,700 to 20,000,000

. III. STUDY WAIVER REQUESTSPage 3 of 4

**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 i rritation 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 asse ssment approaches for semi

- volatile pesticides. As part of that issue paper, an anal ys is was conducted on a comparison of oral and inhalation experimental toxicology studies. In general, this analy sis showed that the degree to which oral PODs were protec tive of potential inhalation toxicity varied. In man y 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 consideri ng 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 t o vapors, droplets, and/or particles/dusts. The form of this exposure is determined b y a number of factors including physical

- chemical properties, use pattern, and exposure scenario. This interim WOE approach considers: 1) Phy sical

- chemical properties: Va por pressure and Henry ’s law constant are key considerations with respect to the volati li zation 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: An y application scenario that leads to inhalation exposure to droplets needs to be considered in the WOE analy sis 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, particularl y to droplets, and may contribute to contribute to spray drift. In the case of trifloxystrobin, mechanically pressurized hand gun 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 anal ys is for an inhalation toxicology

study waiver request. In the past, OPP has used MOEs of approximately 10 times higher than the level of concer n as a benchmark for granting waiver requests. The 2009 anal ys is 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 oth er factors discussed here. HASPOC agrees with Bayer that the updated calculation for th e 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 asPage 4 of 4

54 (handgun app to ornamentals, which is a use pattern not previousl y assess ed) and 180 (mixing/loading for aerial app licatio n to high acreage crops). **4)** Toxicity : Triflox ys trobin has relativel y 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 trifloxy strobin. Trifloxy strobin does not produce malformation s in either rat or rabbit developmental toxicity studie s and does not produce reproductive effects. Trifloxy strobin 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 cy totoxic 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

. Specificall y, 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, f or another strobilurin , py

raclostrobin, there were adverse respiratory effects obse rved in a 28 day inhalation study

(i.e., alveolar histiocy

tosis and olfactory

atroph y/necrosis in nasal tissue). Thus, the HASPOC cannot rule out the potential concern for inhalation toxicity for this class of chemicals.
IV

. HASPOC RECOMMENDATIONS : **B ased 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 trifloxy strobin , including: (1) the low vapor pressure of trifloxy strobin ( 3.4 x 10 - 6 Pa at 25  C ); (2) the low acute inhalation toxicity of trifloxy strobin (Toxicity Category IV); (3) a similar strobilurin chemical, p yraclostrobin, 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

. Be yond the guideline requirements, the inhalation t oxicity

study should include nasal histopathology (serial sections of the nasal passages) because of the nasal effects seen in the py raclostrobin subchronic inhalation toxicity study (olfactory

atroph y and necrosis) . The Agency requests a study

protocol b e 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 onl y to assess risks for inhalation exposure scenarios.