UNITED STATES ENVIRONMENT AL PROTECTION AGENCY WASHINGTON, D.C. 20460

OFFICE OF CHEMICAL SAFETY AND POLLUTION PREVENTION

MEMORANDUM

Date: March I 0, 2015

SUBJECT: Famoxadone: Summary of Hazard and Science Policy Council (HASPOC) Meeting of January 8, 2015: Recommendations on the need for a subchronic inhalation toxicity study.

PC Code: 113202 Decision No.: 496180 Petition No.: NI A Risk Assessment Type: NI A TXR No.: 0057104 MRID No.: NIA

FROM: UmaHabiba Executive Secretary, HASPOC Health Effects Division (7509P)

THROUGH: Jeff Dawson, Co-Chair Anna Lowit Ph.D., Co-Chair HASPOC DP Barcode: NIA Registration No.: NIA Regulatory Action: NIA Case No.: NIA CASNo.: 131807-57-3 40CFR: NIA

Health Effects Division (HED; 7509

TO: Stephen Dapson, Ph.D., Toxicologist Katelynn King, Biologist Ideliz Negron-Encarnacion, Ph.D., Risk Assessor Michael Metzger, Branch Chief Risk Assessment Branch V and VII Health Effects Division (HED) and Christina Scheltema, Chemical Review Manager Patricia Parrot, Branch Chief Pesticide Re-evaluation Division (7508P)

MEETING ATTENDEES:

HASPOC Members: Anna Lowit, Chris Schlosser, Elissa Reaves, Elizabeth Mendez, Jeff Dawson, Jonathan Chen, Jonathan Leshin, Michael Metzger, P.V. Shah, Uma Habiba

Presenters: ldeliz Negr6n-Encarnaci6n, Katelynn King, Stephen Dapson

Page 1of4Page 2 of 4 Other Attendees: Cassi Walls, Chris Olinger, Donna Davis, Kristin Rury, Monique Perron, Nancy McCarroll, Wade Britton

I. PURPOSE OF MEETING

Under the current 40 CFR Part 158 Toxicology Data Requirements, a subchronic inhalation study is required for famoxadone. The Hazar d and Science Policy Council (HASPOC) met on January 8, 2015 to discuss the need for a subc hronic inhalation toxicity study to support registration review of famoxadone.

The HIARC stated in a previous decision report dated January 22, 2003, (TXR No. 0051462), with respect to additional toxi cology study requiremen ts: "No inhalation t oxicity study, other than an acute inhalation toxicity study in ra ts, is available for fa moxadone. The HIARC has determined that if the target Margin of Exposure (MOE) of 300 fo r the intermediate-term (1 - 6 months) inhalation exposure risk assessment for occupational workers cannot be met, then a 90- day subchronic inhalation toxicity study in dogs (OPPTS 870.3465) will be required to be performed and submitted. This study will need to be performed in dogs, rather than in rats, because the hazard endpoint of c oncern (cataracts) has not been obs erved in any of the studies in the rat. Alternatively, the re gistrant may provide evidence de monstrating that the cataract formation in dogs is, in fact, spec ies-specific (i.e. not relevant to humans). In that event, a study in rats will suffice.”

The hazard identification and toxicology for famoxadone is based on Human Health Risk Assessment P.P. # OF06070 and # 7E04847 April 17, 2003, April 29, 2003, P.P. # 5E7001 # 6E7099 March 7, 2007, P.P. # 7E7280, # 7E7281 September 15, 2008 and January 26, 2009.

II. SUMMARY OF USE PROFILE, EXPOS URE, AND HAZARD CONSIDERATIONS

Famoxadone is a fungicide belonging to the oxazolidine-diones chemical group of quinone outside inhibitor (Qol) fungicides. It is registered for use on caneberries, and fruiting, cucurbit, and leafy vegetables, bulb and green onions, tomato, cilantro leaves, potatoes, hops, and grapes to control and/or manage fungal and bacterial disease. In addition, tolerances are established for ruminant livestock commodities. There are no registered residential uses currently associated with this active ingredient (ai). Famoxadone ha s one end-use product, Tanos® Fungicide which is a wate r dispersible granule co-formula ted with cymoxanil. Exposure is expected to be short- and intermediate-t erm for occupational handl ers and post-application workers.

The agency acknowledges that the hazard charac terization and identification and uncertainty factors will be re-assessed in the future. Furthe r, the human relevance of the cataracts in the dog need to be carefully evaluated. For purposes of the HASPOC evaluation, the previously selected endpoints have been used.

In the most recent risk assessment (B. Ha nsen, 347669 and 347672, 09/15/2008), an oral point of departure (POD) of 10 mg/kg/day wa s selected to assess risk from any inhalation exposure. ThePage 3 of 4 POD was based on treatment-re lated myotonic twitches observed in male and female dogs starting on study day 21. Other effects observed in male and female dogs at 23.8/23.3 mg/kg/day during the first 36 days of the study were decreased body weight, body weight gain, food consumption, and food efficiency; slight anemia (first observed at 5 w eeks); and hyperkalemia (first observed at 5 weeks). In addition, convul sions were observed in one female dog on day 34. None of these effects were observed in any male or female dog at 10.0/10.1 (M/F) mg/kg/day at any time during the study. There is no inhalation study of any duration (oth er than acute studies) available on famoxadone. Since an oral dose was se lected, absorption via the inhalation route is assumed to be equivalent to oral absorption.

Occupational handler inhalation e xposures and risks have been upda ted and are presented herein. In previous famoxadone occupational assessmen ts, only the short-term exposure duration was assessed. However, based on a reevaluation of the use pattern of famoxadone, both short- and intermediate-term inhalation exposures are anticipated 1 . For short-term occupational handler inhalation exposures, MOEs range from 880 to 1.6 million with consideration of exposures from use of no respirator (as is cu rrently required by famoxadone la beling), increasing levels of respiratory protection, and engine ering controls. For intermedia te-term occupational inhalation exposures, MOEs range from 120 to 230,000 with consideration of no respirator, increasing levels of respiratory protecti on, and engineering controls.

III. STUDY WAIVER REQUESTS

A. Inhalation Study (90-days)

Previously, the Office of Pesticid e Programs (OPP) used a set of cr iteria to determine whether or not an inhalation study could be waived. These cr iteria considered the scientific information available for the chemical, including its: 1) degr ee of irritation and corrosivity; 2) volatility; 3) aerosol particle size; and 4) Acute Toxicity Category a nd 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 inhalati on 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 significantl y more protective. Currentl y, OPP uses a weight of the evidence (WOE) approach that builds upon OPP’s e xperience using the criter ia listed above and conclusions from the 2009 SAP. As approaches for route-to-route extrap olation continue to evolve and improve, OPP may inco rporate additional considerations into the WOE analysis. Inhalation exposure can be to vapor s, droplets, and/or particles/ dusts. The form of inhalation exposure is determined by a number of factor s including physical-chem ical properties, use pattern, and exposure scenarios. OPP’ s interim WOE approach considers:

1. Physical-chemical properties: Vapor pressure and Henr y’s law constant are key considerations with re spect to volatilization after sprays have sett led. Famoxadone has a low vapor pressure of 6.4 x 10 -7 Pa. The Henry’s law constant is 4.6X10 -8 atm-m 3 /mol. However, low vapor pressure and/or Henry’s law constant do not preclude exposure toPage 4 of 4 aerosolized droplets or particles/dust.

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. Airblast and aerial applicati ons are more likely to lead to higher occupational handler i nhalation exposure, particularly to droplets, and may also contribute to spray drift. In the case of famoxadone, mixing/loading/applying DF/WDG for aerial application to leafy vegetables , peppers, caneberries, cucurbits, and bulb vegetables results in the hi ghest inhalation exposures [i .e., short-term, MOE = 880 (no respirator per current label); intermediate -term, MOE = 120 (no respirator per current label)].

3. Margins of Exposure (MOEs): MOE estimates for inhalation scenarios were calculated using an oral toxic ity 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 leve l of concern as a benchmark for granting waiver requests. The 2009 analysis suggest s this approach is appropriate for most pesticides but not all. Using this in terim WOE approach, MOEs from 10-100 times greater than the level of c oncern (LOC) will be considered in combination with other factors discussed here. In the case of famoxadone and using an oral POD and 100% absorption, the short-term inhalation MO Es for occupational handlers are 880 to 1.6 million; intermediate-term inhalation MOEs range from 120 to 230,000.

V. HASPOC CONCLUSIONS

The HASPOC acknowledges that the hazard identification, hazard characterization, and uncertainty factors will be re-assessed in the future. Based on the information provided the Council and using a weight of evidence (WOE) approach, the HASPOC recommends that a subchronic inhalation toxicity study is required for famoxadone at this time. This approach considered all of the availabl e hazard and exposure information for famoxadone, including (1) the physical/chemical properties and low volatility (6.4 x 10 -7 Pa) of famoxadone; (2) the low acute inhalation toxicity of fa moxadone, (3) using an oral POD and 100% absorption, short-term occupational handler were as low as 120. In th e absence of the inhalation study, a 10X database uncertainty factor will be applied for assessing for inhalation scenarios until the data need is fulfilled. The Agency recommends that the registra nt submit a protocol for review prior to the conduction of an inhalation study.