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 1of4 
Page 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 Hazard and Science Policy Council (HASPOC) met on 

January 8, 2015 to discuss the need for a subchronic 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 toxicology study requirements: "No inhalation toxicity study, other 

than an acute inhalation toxicity study in rats, is available for famoxadone. The HIARC has 

determined that if the target Margin of Exposure (MOE) of 300 for 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 concern (cataracts) has not been observed in any of the studies in 

the rat. Alternatively, the registrant may provide evidence demonstrating that the cataract 

formation in dogs is, in fact, species-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, EXPOSURE, 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 has one end-use product, 

Tanos® Fungicide which is a water dispersible granule co-formulated with cymoxanil. Exposure 

is expected to be short- and intermediate-term for occupational handlers and post-application 

workers. 

The agency acknowledges that the hazard characterization and identification and uncertainty 

factors will be re-assessed in the future. Further, 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. Hansen, 347669 and 347672, 09/15/2008), an oral point of 

departure (POD) of 10 mg/kg/day was selected to assess risk from any inhalation exposure. The 
Page 3 of 4

POD was based on treatment-related 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 weeks); and hyperkalemia 

(first observed at 5 weeks). In addition, convulsions 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 (other than acute studies) 

available on famoxadone. Since an oral dose was selected, absorption via the inhalation route is 

assumed to be equivalent to oral absorption. 

Occupational handler inhalation exposures and risks have been updated and are presented herein. 

In previous famoxadone occupational assessments, 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 anticipated1

. 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 currently required by famoxadone labeling), increasing levels of 

respiratory protection, and engineering controls. For intermediate-term occupational inhalation 

exposures, MOEs range from 120 to 230,000 with consideration of no respirator, increasing 

levels of respiratory protection, and engineering controls. 

 

III. STUDY WAIVER REQUESTS 

A. Inhalation Study (90-days) 

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. Famoxadone has a 

low vapor pressure of 6.4 x 10-7 Pa. The Henry’s law constant is 4.6X10-8 atm-m3

/mol. 

However, low vapor pressure and/or Henry’s law constant do not preclude exposure to 

                                                            
Page 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 applications are more likely to lead 

to higher occupational handler inhalation 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 highest 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 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 10-100 times 

greater than the level of concern (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 MOEs 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 available 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 famoxadone, (3) using an oral POD and 100% absorption, short-term 

occupational handler were as low as 120. In the 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 registrant submit a protocol for review prior to the 

conduction of an inhalation study.