UNITED STATES ENVIRONMENTAL PROTECTION AGENCY WASHINGTON, D.C. 20460 **OFFICE OF CHEMICA** **L SA FETY**  **AND POLLUTION PREVENTION**  **MEMORANDUM Date**  **:** April 22 , 201 4 **SUBJECT: Fluopicolide and its Metabolite, 2,6**  **- Dichlorobenzamide**  **( BAM).**  Human Health

Risk Assessment to Support a Petition for an Increased Tolerance on Tuberous and Corm Subgroup 1C Vegetables. **PC Code:** 027412 (Fluopicolide) & 027402 (BAM) **DP Barcode:** D 415186 **Decision No.:** 481092 **Registration No. :**  59639
- 139 **Petition No .:**  3F8191 **Regulatory Action:** Section 3 Registration **Risk A**  **ss essment Typ**  **e :**  Human Health **Case No.:** NA **T XR No.:**  NA **CAS No.:** 2008
- 54
- 4 **MRID No.:** 49177301 **40 CFR:** §180. 6 27 **FROM:** Peter Savoia, Chemist

Risk Assessment Branch V/VII Health Effects Division (7509P) **THROUGH:** Michael S. Metzger, Branch Chief

Matthew Lloyd , CIH; Industrial Hygienist Risk Assessment Branch V/VII Health Effects Division (7509P) **TO:** Tony

Kish, Risk Manager Dominic Schuler, Risk Manager Reviewer Fungicide Branch Registration Division (7505P) The Valent U.S.A. Corporation has submitted petition PP # 3F8191 which requests an increase in the tolerances on tuberous and corm subgroup 1C vegetables and potato processed waste established for the fungicide fluopicolide. This action is being sought to prevent the possible seizure of commodities for over tol erance residues which were legally treat ed with an earl y season soil application that has since been restricted
. This document is HED’s amended human health risk assessment incorporating the increased tolerances recommended for these commodities. Itcontains updated sections of the most recent HED Human Health Risk Assessment of December 201 3 completed for fluopicolide (D 416744 , A. Kamel , 1 2 / 18 /20 1 3 ). In doing so, the following sections which include residue chemistry , dietary exposure, and aggreg ate risk assessment have been updated to reflect the se amended tolerances
. Information contained in the December 20 1 3 risk assessment remains unchanged unless specificall y noted in this memorandum.Fluopicolide Human Health Risk Assessment DP No. D415186

Page 2 of 38 **1.0 Executive Summary** 
................................ ................................ ................................ ........... 4 **2.0 HED Recommendations** 
................................ ................................ ................................ .... 6 **2.1 Da**  **ta Deficiencies**
................................ ................................ ................................ ............ 6 **2.2 Tolerance Considerations** 
................................ ................................ .............................. 6 **2.2.1 Enforcement Analytical Method** 
................................ ................................ ............... 6 **2.2.2 Recommended Tolerances** 
................................ ................................ ......................... 7 **2.2.3 Revisions to Petitioned**  **- For Tolerances** 
................................ ................................ .... 7 **2.2.4 International Harmonization** 
................................ ................................ ..................... 7 **2.3 Label Recommendations** 
................................ ................................ ................................ 8 **2.3.1 Recommendations from Residue Reviews** 
................................ ................................ 8 **2.3. 2**  **Recommendations from Residential Assessment**
................................ ..................... 8 **3.0 Introduction** 
................................ ................................ ................................ ........................ 9 **3.1 Chemic**  **al Identity**
................................ ................................ ................................ ........... 9 **3.2 Physical/Chemical Characteristics** 
................................ ................................ ............. 10 **3.3 Pesticide Use Pattern** 
................................ ................................ ................................ .... 10 **3.4 Anticipated Exposure Pathways** 
................................ ................................ ................. 11 **3.5 Consideration of Environmental Justice** 
................................ ................................ .... 11 **4.0 Hazard Characterization and Dose**  **- Response Assessment** 
................................ .......... 12 **4.1 Toxicology Studies**  **Available for Analysis**
................................ ................................ . 12 **4. 2**  **Absorption, Distribution, Metabolism, & Elimination (ADME)**
............................. 12 **4.2 .1**  **Dermal Absorption**
................................ ................................ ................................ ....... 13 **4. 3**  **Toxicological Effects**
................................ ................................ ................................ . 13 **4. 4**  **Safety Factor for Infants and Children (FQPA Safety Factor)**
............................ 14 **4. 4.1**  **Completeness of the Toxicology Database**
................................ .............................. 14 **4. 4.**  **2 Evidence of Neurotoxicity** 
................................ ................................ ........................ 14 **4. 4.3**  **Evidence of Sensitivity/Susceptibility in the Developing Y oung Animal** 
................ 14 **4. 4.4**  **Residual Uncertainty in the Exposure Database**
................................ ....................... 1 4 **4. 5**  **Toxicity Endpoint and Point of Departure Selections**
................................ .............. 15 **4. 5.**  **1 Dose**  **- Response**  **Assessment**
................................ ................................ .......................... 15 **4. 5.2**  **Recommendations for Combining Routes of Exposures for Risk Assessment**
....... 1 5 **4. 5.3**  **Cancer Classification and Risk Assessment Recommendation**
................................ 16 **4. 5.4**  **Summary of points of Departure and Toxicity Endpoints**
................................ ....... 16 **4. 6**  **Endocrine Disruption**
................................ ................................ ................................ . 16 7 **5.0 Dietary Exposure and Risk Assessment** 
................................ ................................ ......... 18 **5.1 Metabolite/Degradate Residue Profi** **le**
................................ ................................ ....... 18 **5.1 .1**  **Summary of Plant and Animal Metabolism Studies**
................................ ................. 18 **5.1 .2**  **Summary of Environmental Degradation**
................................ ................................ 19 8 **5.1 .3**  **Comparison of Metabolic Pathways**
................................ ................................ ........... 19 **5.1 .4**  **Residues of Concern Summary and Rationale**
................................ .......................... 19 **5.2 Food Residue Profile** 
................................ ................................ ................................ .... 19 **5.3 Water Residue Profile** 
................................ ................................ ................................ .. 20 **5. 4**  **Dietary Risk Assessment**
................................ ................................ .............................. 21 **5.4.1 Description of Residue Data Used in Dietary Assessment** 
................................ .... 21 **5.4. 2**  **Percent Crop Treated Used in Dietary Assessment**
................................ .............. 2 1Fluopicolide Human Health Risk Assessment DP No. D415186

Page 3 of 38 **5.4.3 Acute Dietary Risk Assessment** 
................................ ................................ ............... 21 **5.4.4 Chronic Dietary Risk Assessment** 
................................ ................................ ........... 2 1 **5.4.5 Cancer Dietary Risk Assessment** 
................................ ................................ ............. 22 **5.4.6 Summary Table** 
................................ ................................ ................................ ......... 22 **6.0 Residential**  **(Non -**  **Occupational) Exposure/Risk Characterization**
............................. 2 2 **6.1 Residential Handler Exposure** 
................................ ................................ .................... 2 3 **6.2 Post**  **- Application Exposure** 
................................ ................................ .......................... 23 **6. 3**  **Residential Bystander Postapplication Inhalation Exposure**
................................ ... 2 5 **6. 4**  **Spray Drift**
................................ ................................ ................................ .................... 2 5 **7.0 Aggregate Exposure/Risk Characterization** 
................................ ................................ .. 2 6 **7.1 Acute Aggregate Risk** 
................................ ................................ ................................ ... 2 6 **7.2 Short** **- Term Aggregate Risk** 
................................ ................................ ........................ 2 6 **7.3 Intermediate**  **- Term Aggregate Risk** 
................................ ................................ ........... 2 7 **7.4 Chronic Aggregate R** **isk**
................................ ................................ .............................. 2 7 **8.0 Cumulative Exposure/Risk Characterization** 
................................ ............................... 2 7 **9.0 Occupational Exposure/Risk Characterization** 
................................ ............................ 2 7 **10.0 References** 
................................ ................................ ................................ ......................... 2 8 **Appendix A. Toxicology Profile and Executive Summaries**
................................ .................. 3 0 **A.1 Toxicology Data Requirements** 
................................ ................................ ................... 3 0 **A.2 Toxicity Profiles** 
................................ ................................ ................................ ............ 3 1 **Append ix B.**  **Review of Human Research**
................................ ................................ ................ 3 7 **Appendix C. Physical/Chemical Properties** 
................................ ................................ ............. 3 7 **Appendix D**  **. Major Fluopicolide Residues** 
................................ ................................ .............. 3 8Fluopicolide Human Health Risk Assessment DP No. D415186

Page 4 of 38 **1.0 Executive Summary**  The Health Effects Division (HED) has evaluated the toxicity and exposure databases to conduct a human health risk assessment for the fungicide active ingredient fluopicolide
. Itwas performed to support a petition to increase the tolerances on tuberous and corm subgroup 1C vegetables and potato processed waste. Fluopicolide share s a metabolite, 2 , 6
- dichlorobenzamide (BAM) with another active ingredient, dichlobenil ; s eparate toxicity data and endpoints have been selected for BAM
. However, sinc e increased tolerances on these commodities do not add significantl y to the BAM dietary exposure , the conclusions from the most recentl y conducted BAM human health risk assessment remain unchanged. The Agency will therefore rel y on that assessment to supp ort this use (D 354111 , D. Rate, 06 /19/08)
. This assessment addresses risks from the parent compound and its regulated metabolites, other than BAM. The principal registrant for fluopicolide is the Valent U.S.A. Corporation. Fluopicolide is a fungicide that controls a wide range of diseases including downy mildews, late blight, and some Pythium species
. Valent is proposing the following changes to the § 180.627 established tolerances 1 : **§ 180.627(a)**  **General. (1)** Vegetable, tuberous and corm subgroup 1C............................0.02 ppm Vegetable, tuberous and corm subgroup 1C............................0.3 ppm Potato, processed potato waste............................................0.05 ppm Potato, processed potato waste............................................0.3 ppm The toxicity

database for fluopicolide is complete and demonstrates it has low acute toxicity by the oral, dermal and inhalation routes. The subchronic and chronic toxicity studies showed that the primary effects of fluopicolide are in the liver. Developmental toxicity in the rabbit occurred onl y at doses that caused severe maternal toxicity (including death). In the rat, developmental effects were seen only at high dose levels in the presence of maternal toxicity . Toxicity endpoints and points of departure (PODs) are selected from the rabbit developmental and rat c hronic/cancer studies for all routes (dietary , incidental oral, dermal and inhalation) and durations of exposure (with the exception of acute exposures; there is no endpoint attributable to a single dose). The available data reveal that f luopicolide is not neurotoxic, carcinogenic, or mutagenic and does not appear to have immunotoxic potential. The Food Quality

Protection Act (FQPA) safety factor was reduced to 1 x because the toxicity database is complete , there is no evidence of quantitative susceptibili ty following in utero and/or postnatal exposure in the rabbit and rat developmental toxicity studies or in the 2
- generation rat reproduction study , and the exposure assessments are unlikel y to underestimate risk
. There is low concern for the qualitative susceptibility observed in the rat developmental toxicity study because the offspring effects (reduced growth and skeletal defects) and late
- term abortions are well characterized and accompanied b y maternal toxicity
. There has been no new toxicity data re ceived since the last human health risk assessment was carried out for fluopicolide in December 201 3
. The available toxicity data are adequate to assess the hazard
1 Tolerances shown with a strikethrough are currently established tolerances that would be deleted:Fluopicolide Human Health Risk Assessment DP No. D415186

Page 5 of 38 potential of this chemical since the database for fluopicolide is complete and there are no datagaps noted. The relevant toxicity endpoints and uncertainty factors described in the prior risk assessment therefore remain appropriate for this evaluation. This memorandum incorporates those portions of the December 201 3 risk assessment which are p ertinent to this evaluation ( D416744, A. Kamel, 12/18/2013 ). The residue chemistry

database for both the parent compound and the BAM metabolite is complete and considered adequate to support all registered uses of fluopicolide
. No new residue chemistry d ata are required at this time
. Adequate metabolism (crops, livestock, and rotational crops), storage stability, and processing data are available. Adequate methods are also available for the enforcement of all currently

established tolerances. In regard to amending the tolerances on tuberous and corm subgroup 1C vegetables and potato processed waste , Valent has provided adequate modeling calculations to estimate residue concentrations while field trials are being completed (MRID No. 49177301). This action is being requested since there is a potential for fluopicolide limits to be exceeded because of an unintentional labeling error allowing for soil directed applications to be made on potatoes
. Upon submission of the completed field trial studies, th e Agency will evaluate these data and determine if it is necessary to either increase or decrease the se amended tolerances. There are no limits established on the use of fluopicolide by Codex or Mexico but there is a Canadian MRLof 0.02 ppm established on a number of tuberous and corm vegetables. In regard to potato processed waste, Canada does not establish tolerances on livestock feedstuffs. Consequently, upon amending the U.S. tolerance with this action, harmonization will not be possible with the Canadian MRLsince Canada has not yet established directed soil applications on potatoes for use. There are no other Codex, Canadian, or Mexican MRL s which have been established for the other uses which are the subject of this action. An acute dietary

e xposure and risk assessment was not conducted for fluopicolide because an endpoint attributable to a single dose was not identified from the available data. Further, a cancer dietary exposure and risk assessment was not conducted because f luopicolide is n ot likely

to be carcinogenic to humans
. A highl y conservative chronic dietary exposure and risk assessment was conducted using tolerance levels and highest field trial residues , 100% crop treated assumptions for most commodities, default processing factor s in the absence of empirical data , and modeled drinking water values. Chronic dietary (food and water) estimated risks were well below HED’s level of concern for the U.S. population and all population subgroups. There are no new residential uses assoc iated with this action; however, fluopicolide is registered on residential turf and recreational sites, such as golf courses. Exposure to fluopicolide from currentl y registered uses was assessed in 2013 . All short
- and intermediate
- term handler, post
- application and aggregate residential risks had margins of exposure ( MOE s) which were well above the level of concern of 100 , and are not of concern
. In accordance with the FQPA, an aggregate assessment was conducted which considered pesticide exposure and risk from the residential, food, and water pathway s. These exposures included adults applying fluopicolide in a residential setting (dermal and inhalation exposure), post
- application exposure to adults and children (dermal exposure), and post
- application oral exposure to children (byFluopicolide Human Health Risk Assessment DP No. D415186

Page 6 of 38 putting hands or objects in their mouth). The estimated aggregate short
- term risk estimates for all of the exposure scenarios were calculated and are not of concern
. There are no new occupational uses associated with this action; therefore, the o ccupational exposure and risk assessments which showed no risks of concern previously conducted in 2013 to establish fluopicolide tolerances on rotational corn remain unchanged. Potential areas of environmental justice con cerns, to the extent possible, were considered in this human health risk assessment, in accordance with U.S. Executive Order 12898, "Federal Actions to Address Environmental Justice in Minority Populations and L ow - Income Populations," http://www.eh.doe.gov/oepa/guidance/justice/eo12898.pdf ). This assessment relies in part on data from studies in which adult human subjects were intentionally exposed to a pesticide. These studies have received the appropriate ethical review. **2.0 HED**  **Recommendations** Pending the revision of Section F, there are no residue chemistry deficiencies that preclude establishing increased tolerances on tuberous and corm subgroup 1C vegetables and potato processed waste
. Additional data are needed as a condition of registration as outlined in section 2.1 below. The specific tolerance recommendations are presented below in section 2.2 along with the required label modifications which are discussed in section 2.3. **2.1 Data Deficiencies**  The residue chemistry

and toxicity

data bases are complete and sufficient for characterizing the residues, dietary

exposure , and hazard of fluopicolide. However, the registrant is required to submit a revised Section F amending the proposed tolerance for potato processed waste to 1.0 ppm as specified in Table 2.2.3
. In accordance with 40CFR158, EPA is also requiring turf transferable residue (TTR) data as part of the 2013 risk assessment made to establish fluopicolide tolerances on rotational corn. **2.2 Tolerance Considerations**  **2.2.1 Enforcement Analytical Method**  An acceptable LC/MS/MS enforcement method RM
- 43C
- 2 is available to enforce the tolerances established on tuberous and corm subgroup 1C vegetables as well as on other crop commodities. Briefly , homogenized plant matrices are mixed with acetone/water, and the mixture is acidified. An aqueous solution of L
- cy steine hydrochloride is added, and the sample is extracted. The extract is isolated by

gravity filtrati on and diluted to volume with acetone and water. An aliquot of the extract is concentrated to remove the acetone, and the concentrated extract is partitioned twice with methyl t- butyl ether (MTBE). The MTBE phases are combined, and an aliquot is evaporat ed to dry ness, re dissolved in acetonitrile/water, and then filtered for L C/MS/MS analy sis. For Method RM
- 43C
- 2, the primary

analy tical column is packed with reversed
- phase C18. In addition, the method providesFluopicolide Human Health Risk Assessment DP No. D415186

Page 7 of 38 for an alternative column packed with a mix ed phase of C18 plus a strong cation exchange packing material. The LC/MS/MS method has a limit of quantitation (L OQ) for fluopicolide of 0.01 ppm
. Adequate multi
- residue method testing data for fluopicolide and its metabolites were previously submitte d. Based on the results of the testing, the multi
- residue methods are not appropriate for determining residues of fluopicolide or its metabolites (D321209, A. Acierto , 0 1/23/2007). **2.2.2 Recommended Tolerances**  Tolerances for residues of fluopicolide are currently expressed in terms of the parent compound only when defining its uses. For this action, Valent is requesting to increase the tolerances on tuberous and corm subgroup 1C vegetables and potato processed waste. Pending the revision of Section F, there are no residue chemistry deficiencies that preclude increasing the permanent tolerances on tuberous and corm subgroup 1C vegetables and potato processed waste for fluopicolide. Tolerances are established for residues of the fungicide fluopicolide [2,6
- dichloro
-N
- [[3
- chloro
- 5
- (trifluoromethyl )
- 2
- py

ridinyl]methyl]benzamide], including its metabolites and degradates, in or on the commodities listed below. Compliance with the tolerance levels specified below is to be determined b y measuring only fluop icolide [2,6
- dichloro
-N
- [[3
- chloro
- 5
- (trifluoromethyl)
- 2
- py ridinyl]methyl]benzamide] in/on the commodities specified in Table 2.2.3 : **Table 2.2.3. Tolerance Summary for Fluopicolide.**  **Comm odity**  **Established**

**Tolerance (ppm)**  **Proposed**

**Tolerance (ppm)**  **Recommended**

**Tolerance (ppm) Comments** 

**Correct Commodity Definition** Potato, processed waste 0.05 0.3 1.0 Potato, processed waste Vegetable, tuberous and corm subgroup 1C 0.02 0.3 0.3 Vegetable, tuberous and corm subgroup 1C **2.2.3 Revisions to**  **Petitioned -**  **For Tolerances** Based on the maximum residue levels estimated in the modeling calculations provided by the registrant, an amended tolerance of 0.3 ppm is appropriate for tuberous and corm subgroup 1C vegetables (current tolerance is 0.02 ppm). In regard to potato processed waste , the registrant has proposed a tolerance of 0.3 ppm as well for this commodity . P rocessing data previousl y provided for potato indicate that residues of fluopicolide concentrate in wet peels . Based on the models provid ed b y Valent, residues of fluopicolide found in/on potato tubers are estimated to be in the range of 0.2 to 0.25 ppm following directed soil application. Using the highest estimated value of 0.25 ppm and the theoretical concentration factor of 4.0x, an am ended tolerance of 1.0 ppm is recommended for potato processed waste. **2.2.4 International Harmonization**  The modeling calculations provided for fluopicolide are adequate to support increased tolerances on tuberous and corm subgroup 1C vegetables proposed with this action (D417354, P. Savoia, 0 4 /22 /201 4 ). There are no MRL s established on the fluopicolide uses by Codex or Mexico.Fluopicolide Human Health Risk Assessment DP No. D415186

Page 8 of 38 However, the establishment of an increased U.S. tolerance will exceed the Canadian MRLof 0.02 ppm on various tuberous and corm vegetables. Harmonization with the Canadian MRL is not possible since Canada has not yet established directed soil applications on potatoes for use. In regard to potato processed waste, Canada does not establish tolerances on livestock feedstuff s. **2.3 Label Recommendations**  **2.3.1 Recommendations from Residue Reviews**  Valent has previously

submitted residue data to establish the foliar use of fluopicolide on tuberous and corm subgroup 1C vegetables. These data were reviewed b y the Agency and to lerances were set based on this proposed pattern of use. However, use directions for earl y s eason soil application to potatoes were also listed on the registered labels but the tolerance assessment that was conducted did not include treatments made in thi s manner. In response, the registrant submitted an amendment to temporaril y restrict the soil application use on potatoes. This action was followed by a petition request to increase these tolerances because there is a potential for fluopicolide limits to be exceeded. The revised tolerances proposed by Valent are based upon modeling calculations while additional field trial data are completed. The amendment of these tolerances will require that supporting residue studies must be submitted once completed and soil treatment uses will not appear on any registered labels. The soil directed use will remain restricted until field trial data are submitted and these data are evaluated to determine if it is necessary to either increase or decrease the amended tol erances. **2.3. 2**  **Recommendations f rom**  **Residential Assessment**  There are no new residential uses associated with this action , and therefore no recommendations for the residential exposure assessment are necessary
. Exposure to fluopicolide from the registered uses on residential turf and recreational sites, such as golf courses were assessed in the 2013 risk assessment. All short
- and intermediate
- term handler, post
- application and aggregate residential risks had margins of exposure ( MOE s) which were well above the level of concern of 100, and are not of concern.Fluopicolide Human Health Risk Assessment DP No. D415186

Page 9 of 38 **3.0 In**  **troduction 3.1**  **Chemical Identity**  **Table 3.1.1 Fluopicolide Nomenclature** 
. Chemical structure

Em pirical Formula C 14 H 8 Cl 3 F 3 N 2 O Common name Fluopicolide Com pany experimental name AE C638206 IUPAC name 2,6
- dichloro
-N
- [3
- chloro
- 5
- (trifluoromethyl)
- 2
-py ridylmethyl]benzamide CAS name 2,6
- dichloro
-N
- [[3
- chloro
- 5
- (trifluoromethyl)
- 2
-py ridinyl]methyl]benzamide CAS Registry Number 239110
- 15
- 7 End
- use products (EPs) V
- 10161 4SC Fungicide (39.5% fluopicolide; EPA File Symbol No. 59639
- RUN) V
- 10161 Premix Fungicide (5.54% fluopicolide and 55.4% propamocarb; EPA File Symbol No. 59639

–RUE) Chemical Class Fungicide Known Impurities of Concern None **Table 3.1.2 Chemical Names and Structures of Regulated Fluopicolide Metabolites.** Common name/code Chemical name Chemical structure **BAM** AE C653711 2,6
- dichlorobenzamide

**PCA** AE C657188 3
- chloro
- 5
- trifluoromethylpyridine
2
- carboxylic acid

**P1X** AE 1344122 3
- methylsulfinyl
- 5
- trifluoromethylpyridine
- 2
- carboxylic acid Cl

Cl N H N O Cl F 3 C

Cl

Cl N H 2 O

N Cl F 3 C

O H O

N F 3 C

O H O

S O C H 3Fluopicolide Human Health Risk Assessment DP No. D415186

Page 10 of 38 **3.2 Physical/Chemical Characteristics**  Fluopicolide is an active ingredient present in several registered fungicide products used to control p lant pathogens such as downy mildews, late blight, and some Pythium species
. The appearance of pure anal ytical grade fluopicolide is that of a fine cry stalline beige powder. The pure anal ytical grade fluopicolide is noted to have a weak phenol
- like odor while the technical grade product is noted to have no characteristic odor at all
. Fluopicolide is considered to be relativel y stable at ambient temperatures. It has an estimated vapor pressure of 8.03 x 10 - 7 Pa making volatilization an unlikely route of dissipation . Fluopicol ide has partition coefficients of Log P OW = 3.26 at pH 7.8 and 22 ± 1  C and L og P OW = 2.9 at pH 4.0, 7.3 and 9.1 and 40  C indicating l ittle potential for bioaccumulation. When fluopicolide is released into the environment its residues can be found in so il and surface water. F luopicolide may be transported off

- site to drinking water sources as entrained sediment or via spray drift during spray

applications. Fluopicolide is known to bind weakl y to soils, however, there is evidence that adsorption to soil may increase over time as the product is used. As a result, f luopicolide can be persistent in the environment because its residues can carry over into the following growing season. A detailed summary of the phy sical/chemical characteristics of fluopicol ide are presented in Appendix C for review. **3.3 Pesticide Use Pattern**  A label change will not be associated with the establishment of an increased tolerance for tuberous and corm subgroup 1C vegetables
. As previously noted, f ollowing the registration of fluopicolide for foliar use on tuberous and corm subgroup 1C vegetables, use directions for early season soil application to potatoes were also listed on the registered labels
. For the application to soil, the use directions n oted two directed soil treatments to be made at the maximum rate of 0.125 lb ai/A (140 g ai/ ha) following a 30
- day re - treatment interval (RTI) as depicted below in Table 3.3. However, the tolerance assessment that was made for the foliar use of fluopicol ide on these crops did not include directed treatments made to soil. As a result , the registrant was required to submit an amendment temporaril y restricting the soil application use on potatoes while field trial data are acquired. In the interim , the reg istrant has submitted th e current petition which requests to increase these tolerances b ecause there is a potential for fluopicolide limits to be exceeded on potatoes treated with soil directed applications
. Upon submission of the completed field trial studies, these data will be evaluated to determine if it is necessary to either increase or decrease the amended tolerances which will allow for the soil use label restriction to be removed.

**Table 3.3. Summary of Directions Envisioned**  **for the**  **Directed Soil Application of Fluopicolide.**Fluopicolide Human Health Risk Assessment DP No. D415186

Page 11 of 38 **Applic. Timing, Type,**  **and Equip. Form** **ulation**

**[EPA Reg. No.]**  **Applic.**

**Rate (lb**  **ai/A) Max. No.**  **Applic. per Season**  **Max.**

**Seasonal Applic. Rate**  **(lb ai/A) PHI** 

**(days) Use Directions and Limitations**  **Tuberous and Corm Subgroup 1C Vegetables**  Soil directed spray 59639
- 139

Fluopicolide Technical 0.125 lb

ai/A (140 g ai/ha) 2 0.250 lb ai/A

(280 g ai/ha) NA 1

Pre
-plant treatment RTI: 30 days

For early season soil application for controlling pink rot in potatoes. Follows one application at planting and the second at hilling. 1 NA
-Not Applicable **3.4 Anticipated Exposure Pathways**  The Registration Division has requested an assessment of human health risk to support an increased tolerance for fluopicolide on tuberous and corm subgroup 1C vegetables
. Potatoes treated with soil directed applications may expose humans to greater levels of this pesticide active ingredient in food and drinking water since more of it may reach growing crops. Fluopicolide is registered for use on agricultural crops as well as on turf (lawns, golf course, and recreational areas) . Exposure to fluopicolide may

occur from ingestion of residues in/on foods and in drinking water, and via the dermal and inhalation routes for adults using fluopicolide produ cts in residential settings. In addition, both adults and children may be exposed dermally

in post
- application scenarios on turf ; children may

also be exposed orall y in post
- application scenarios for turf . There is a potential for post - application dermal exposure for workers re
- entering treated fields as well as occupational handler inhalation exposure during mixing/loading/appl yi ng for agricultural and commercial handlers. **3.5 Consideration of Environmental Justice**  Potential areas of environmental ju stice concerns, to the extent possible, were considered in this human health risk assessment, in accordance with U.S. Executive Order 12898, "Federal Actions to Address Environmental Justice in Minority Populations and L ow - Income Populations," (http://www.eh.doe.gov/oepa/guidance/justice/eo12898.pdf
. As a part of every

pesticide risk assessment, OPP considers a large variety of consumer subgroups according to well
- established procedure s. In line with OPP policy, HED estimates risks to population subgroups from pesticide exposures that are based on patterns of that subgroup’s food and water consumption, and activities in and around the home that involve pesticide use in a residential setting. Extensive data on food consumption patterns are compiled by the U.S. Department of Agriculture’s (USDA’s) National Health and Nutrition Examination Survey /What We Eat in America, (NHANES/WWEIA) , are used in pesticide risk assessments for all registered food uses of a pesticide. These data are anal yz ed and categorized b y subgroups based on age, season of the year, ethnic group, and region of the country. Additionally , OPP is able to assess dietary exposure to smaller, specialized subgroups and exposure assessments are performed when conditions or circumstances warrant. Whenever appropriate, non
dietary exposures based on home use of pesticide products and associated risks for adult applicators an d for toddlers, youths, and adults entering or playing on treated areas post - application are evaluated. Further considerations are currentl y in development as OPP has committed resources andFluopicolide Human Health Risk Assessment DP No. D415186

Page 12 of 38 expertise to the development of specialized software and models that consider exposure to by standers and farm workers as well as lifestyle and traditional dietary patterns among specific subgroups. **4.0 Hazard Characterization and Dose**  **- Response Assessment**  Toxicological effects of fluopicolide were previously evaluated in the human health risk assessments conducted in 20 1 0 and 201 3 ( D384431, D. Davis, 12/9/2010 and D416744, A. Kamel, 12/18/2013 ). A registration review scoping document was released in 2013 (D405060, D. Drew, 02/10/2013). Subsequently , an immunotoxicity study was submitted and reviewed. The Hazard and Science Policy Council (HASPOC ; TXR. 0056544 ) met on December 19, 2012 to discuss the need for a 28
- day inhalation study
. The HASPOC has determined that, based on a weight of evidence (WOE) approach, a 2 8
- day

inhalation toxicity

study can be waived
. **4.1 Toxicology Studies Available for Analysis**  The toxicity

database for fluopicolide is complete and sufficient for characterizing the hazard of fluopicolide. The toxicity endpoints and points of departur e have not changed since the previous risk assessment ( D416744, A. Kamel, 12/18/2013 ). The immunotoxicity study submitted did not impact the endpoints selected for risk assessment purposes for fluopicolide. **4. 2**  **Absorption, Distribution, Metabolism ,**  **& Elimination (ADME)**  The results of rat metabolism studies (MRID No s . 46474226, 46474239, 46474241, 46474242, and 46474244) ), indicate that fluopicolide is readily absorbed and rapidly

excreted within 72 hours following a single oral dose of 10 mg/kg. Fe cal elimination accounted for 68.8
- 72.4% of the administered radioactivity whereas urinary excretion accounted for onl y 18.8
- 21.4% of the administered radioactivity. In the bile excretion study (MRID No. 46474244), 51.7% of the administered radioactive do se in both sexes was excreted by the cannulated bile duct indicating a significant portion of the radioactivity recovered in feces is derived from hepatic metabolism of fluopicolide. Time
- course blood/plasma and tissue studies revealed rapid absorption and distribution of administered radioactivity to all organs and tissues followed by moderatel y rapid excretion with reduction to background levels in most tissues and organs within 72 hours. Tissue concentrations peaked at 6
- 7 hours post
- dosing and about 96% of the peak tissue concentrations were dissipated between 6
- 7 hours and 168 hours post
- dose. Absorption and excretory patterns did not exhibit gender
- related variability, but blood/plasma kinetic studies (MRID No. 46474226) suggested a near
- saturation of absorption at the high dose (100 mg/kg bw). Based upon tissue burden data, neither fluopicolide nor its metabolites appear to undergo any significant tissue sequestration. With the exception of transiently higher levels in the liver, kidneys, and intestines during the elimination phase, radioactivity concentrations in any

given tissue consistently

represented considerabl y less than 1% of the administered dose within 24 hours ofFluopicolide Human Health Risk Assessment DP No. D415186

Page 13 of 38 administration of fluopicolide. The major urinary and fecal metabolite s were oxidative N
dealkyl ation cleavage products. **4.2.1 Dermal Absorption**  In a dermal penetration study , 14 C
- Fluopicolide in a commercial concentrate, or aqueous dilution of a concentrate for the low dose, was applied to the skin of 5 male Sprague
- Dawley rats/time point/dose (MRID No. 46708638)
. The dose ( 1.43 or 659 μg/cm2 skin) was applied to 12 cm2 skin and removed after 8 hours. The animals were sacrificed at 8, 24, 72, or 144 hours after application. Dermal absorption was found to range from 3
- 8% (high dose) to 22
- 37% (low dose). The most conservative value for risk assessment is a dermal absorption of 37% observed at 24 hours after application. In vitro dermal absorption data suggested that fluopicolide will penetrat e human skin at a substantially

lower rate (up to eight times less) than rat skin, providing confidence that a 37% dermal absorption factor is conservative for use in this risk assessment. **4. 3**  **Toxicological Effects** Fluopicolide is a fungicide intended fo r the control of plant diseases caused by Oomycetes
. Fluopicolide controls a wide range of Oomycete (Phycomyc ete) diseases including downy mildews ( Plasmopara , Pseudoperonospara , Peronospora , and Bremia ), late blight (Phytophthora ), and some Pythium speci es. Fluopicolide appears to interfere with mitosis and cell division resulting in the rapid destabilization of fungal cell structures; this pesticidal mode of action has been characterized as novel and unique and unlike the known modes of action of other registered fungicides. The toxic effects of fluopicolide have been examined in subchronic and chronic oral toxicity studies made in rats and mice which revealed liver toxicity in both species. Kidney

and thy roid toxicity were observed in rats only. Th e available data reveal that f luopicolide is not neurotoxic, carcinogenic, nor mutagenic. Fluopicolide does not exhibit immunotoxic potential. Developmental toxicity

in the rabbit occurred only at doses that caused severe maternal toxicity (including death). In the rat, developmental effects were seen onl y at high dose levels (700 mg/kg/day) in the presence of maternal toxicity . Similarly, offs pring effects (body weight, kidney) occurred onl y at levels causing toxicity in parents of the multi
- generation reproductive toxicity study
. There is no evidence of increased quantitative susceptibility of rat or rabbit fetuses to in utero or post - natal e xposure to fluopicolide. No toxic effects were observed in studies in which fluopicolide was administered by the dermal routes of exposure. For the dermal point of departure, the oral developmental rabbit study was selected because developmental effec ts were noted (qualitative susceptibility of the pups), which are not examined in dermal toxicity studies. In addition, dermal absorption is high ( i.e., 37% based on dermal penetration study). An inhalation toxicity study is not available. The Hazard an d Science Policy Council (HASPOC; TXR. 0056544) met on December 19, 2012 to discuss the need for this inhalation study
. The HASPOC has determined that, based on a weight of evidence (WOE) approach, a 28
- day

inhalation toxicity

study is not required at thi s time. This approach considered all of the available hazard and exposure information including (1) the physical/chemical propertiesFluopicolide Human Health Risk Assessment DP No. D415186

Page 14 of 38 of fluopicolide, including its potential to volatilize (8.03 x 10 - 7 Pa vapor pressure); (2) the low acute inhalation t oxic ity ; (3) the primary target organs of fluopicolide are the liver and hematopoietic sy stem following repeat oral exposure; (4) the use of an oral POD for fluopicolide results in screening level occupational/residential inhalation MOEs >40,000. Te chnical grade fluopicolide has low acute toxicity via oral, dermal and inhalation routes of exposure. Fluopicolide is not a dermal sensitizer, primary eye irritant, or primary

skin irritant. **4. 4**  **Safety factor for Infants and Children (FQPA Safety Factor)** The Agency

considers it appropriate to reduce the Food Quality Protection Act (FQPA) safety factor to 1 x because the toxicity database is complete. It shows there is no evidence of quantitative susceptibility

following in utero and/or postnatal exposure in the rabbit and rat developmental toxicity studies or in the 2
- generation rat reproduction study . These data also demonstrate there is low concern for the qualitative susceptibility observed in the rat developmental toxicity study because the offspring effects (reduced growth and skeletal defects) and late
- term abortions are well characterized and accompanied b y maternal toxicity (decreased maternal body weight) , and the exposure assessments are unlikely to underestimate risk
. **4. 4**  **.1 Completenes**  **s o**  **f the**  **Toxicology Database** The database is complete and adequate to characterize potential pre
- and/or post
- natal risk for infants and children. Developmental toxicity studies in rats and rabbits, and a rat reproduction study are available for FQPA assessment. **4. 4**  **.2 Evidence of N**  **eurotoxicity** Neurotoxicity

studies were conducted for fluopicolide
. No evidence of neurotoxicity was seen in the acute (CAN) or subchronic (SCN) oral rat neurotoxicity studies performed for fluopicolide. The only neurotoxic effect was a transient lowering of body temperature in the ACN study , but this was observed at a high dose (2000 mg/kg) and not seen in the SCN study
. **4. 4**  **.3 Evidence**  **o f Sensitivity/Su**  **sceptibility in the Developing o r Young Animal**  There is no evidence of quantitative susceptibility following in utero and/or postnatal exposure in the rabbit or rat developmental toxicity studies or in the 2
- generation rat reproduction study
. Q ualitative susceptibility observed in the rat developmental toxicity study included offspring effects (reduced growth and skeletal defects) and late
- term abortions which were accompanied b y maternal toxicity (i.e., mortality, abortion/premature delivery, decreased food consumption and bodyweight gain)
. . **4. 4**  **.4 Residual**  **Unc ertainty in the Exposure Datab**  **ase** The dietary

exposure assessment is based on an exaggerated exposure scenario which assumes that all commodities being consumed retain either tolerance level
- residues or highest field residuesFluopicolide Human Health Risk Assessment DP No. D415186

Page 15 of 38 found. The residential expos ure assessment assumes maximum label use rate as well as other conservative assumptions. Moreover, combining the residential incidental oral and dermal exposure scenarios is conservative. Therefore, there are no residual uncertainties in the exposure database and exposure s to fluopicolide will not be underestimated. Although EPA has required additional data on transferable residues from treated turf for fluopicolide, EPA is confident that it has not underestimated turf exposure due to the conservativeness of the default turf transfer value and conservative assumptions in the short
- term turf assessment procedures (e.g., assuming residues do not degrade over the thirty day assessment period and assuming high
- end activities on turf for every day of the assessment period). The additional data on transferable turf residues have been required in case refinement of exposure assessments is needed in the future and to further EPA’s general understanding of the availability of turf transferable pesticide resi dues. **4.5 Toxicity Endpoint and Point Departure Selections**  **4.5.1 Dose**  **- Response Assessment**  Details of the studies used for selecting toxicity endpoints and points of departure are presented in Appendix A of this assessment. An acute dietary

assessment was not conducted because an endpoint attributable to a single dose has not been identified for fluopicolide. For chronic dietary , incidental oral, dermal and inhalation exposures, the toxicity

endpoints and doses for risk assessment were selected from th e rabbit developmental and rat chronic/carcinogenicity studies which were considered co
- critical for endpoint selection. The toxicological profile for fluopicolide suggests that increased durations of exposure does not significantly increase the severity of observed effects. For the rabbit developmental study , the maternal LOAEL was 60 mg/kg/day b ased on death, abortions/premature deliveries (late
- term), decreased food consumption, and decreased body weight gain. The maternal NOAELwas 20 mg/kg/day . In the combined chronic toxicity /carcinogenicity study in rats the LOAEL was 109 mg/kg/day based on decreased body weight gain and increased thy roid weight and increased incidence of thyroid lesions with a NOAEL of 31.5 mg/kg/day. The NOAEL from the rabbit developmental study was used for the point of departure since it is protective of effects observed from similar dosing of the chronic/carcinogenicity rat study
. **4.5.2 Recommendations for Combining Routes of Exposure for Risk Assessment**  When there are potential residential and occupational exposures to a pesticide, a risk assessment must address all major sources of exposure (oral, dermal, and inhalation). In doing so, these exposures should be combined for risk assessment if they have the same toxicol ogical effects. For fluopicolide, the dermal , inhalation and incidental oral exposure routes share a common toxicological endpoint which enables risk estimates to be combined for th ese exposures .Fluopicolide Human Health Risk Assessment DP No. D415186

Page 16 of 38 **4.5.3 Cancer Classification and Risk Assessment**  **Recommendations** In accordance with the EPA’s Final Guidelines for Carcinogen Risk Assessment (March , 2005), the CARC classified Fluopicolide as **“Not Likely to be Carcinogenic to Humans” .**  This conclusion is based upon the evidence that a non
- genotoxic, mi togenic mode of action for liver tumors was established in the mouse and that the carcinogenic effects were not likely at doses that do not cause perturbations of the liver. Since all risk assessment points of departure were established at dose levels whi ch protect for any liver toxicity , people will not be exposed above these levels, and regulating at these levels will protect for any potential carcinogenic effects. There was no evidence of carcinogenicity in rats
. **4. 5.4**  **Summary of Points of Departure and Toxicity Endpoints Used in Human Risk**  **Assessment** A summary

of the toxicological endpoints and doses chosen for the relevant exposure scenarios for human risk assessment are found below in Table 4. 5 .4. **Table 4.5.4. Summary of Toxicological Doses and Endpoints for Fluopicolide for Use in Dietary and Occupational Human Health Risk Assessments**  **Exposure/ Scenario**  **Point of**

**Departure Uncertainty/** 

**FQPA Safety**  **Factors RfD, PAD, Level** 

**of Concern for Risk A**  **ssessment Study and Toxicological Effects** 

Ac ute Dietary (all populations) An endpoint attributable to a single dose was not identified from the available data. Chronic Dietary (all populations) Maternal

NOAEL=20 mg/kg/day UF A=10x

UF H=10x FQPA SF = 1X Chronic RfD =

0.2 mg/kg/day cPAD = 0.2 mg/kg/day **Developm ental Toxicity Study in Rabbits** 

LOAEL (maternal) = 60 mg/kg/day based on death, abortions/ premature deliveries, decreased food consumption and body weight gain. **Co -**  **critical: Chro nic/Oncogenicity Study in** 

**Rats** NOAEL = 31.5 mg/kg/day. LOAEL = 109.4 mg/kg/day based on decreased body weight gain and increased thyroid weight and increased incidence of thyroid lesions. Incidental Oral Short
- Term s Maternal

NOAEL = 20 mg/kg/day UF A=10x

UF H=10x FQPA SF = 1X MOE = 100

(residential) **Developm ental Toxicity Study in Rabbits** 

LOAEL (maternal) = 60 mg/kg/day based on death, abortions/ premature deliveries, decreased food consumption and body weight gain.Fluopicolide Human Health Risk Assessment DP No. D415186

Page 17 of 38 **Table 4.5.4. Summary of Toxicological Doses and Endpoints for Fluopicolide for Use in Dietary and Occupational Human Health Risk Assessments**  **Exposure/ Scenario**  **Point of**

**Departure Uncertainty/** 

**FQPA Safety**  **Factors RfD, PAD, Level** 

**of Concern for Risk A**  **ssessment Study and Toxicological Effects** 

Dermal Short
Term Maternal

NOAEL = 20 mg/kg/day UF A=10x

UF H=10x FQPA SF = 1X 37% dermal absorption MOE = 100

(residential) **Developm ental Toxicity Study in Rabbits** 

LOAEL (maternal) = 60 mg/kg/day based on death, abortions/ premature deliveries, decreased food consumption and body weight

gain. **Co -**  **critical: Chronic/Oncogenicity Study in**

**Rats** NOAEL = 31.5 mg/kg/day. LOAEL = 109.4 mg/kg/day based on decreased body weight gain and increased thyroid weight and increased incidence of thyroid lesions. Inhalation Short
and Intermediate
T erm (1
- 30 days, and 1
- 6 months) Maternal

NOAEL = 20 mg/kg/day UF A=10x

UF H=10x FQPA SF = 1X (inhalation and oral toxicity are assumed to be equivalent) MOE = 100

(residential) **Developm ental Toxicity Study in Rabbits** 

LOAEL (matern al) = 60 mg/kg/day based on death, abortions/ premature deliveries, decreased food consumption and body weight gain. **Co -**  **critical: Chronic/Oncogenicity Study in Rats**  NOAEL = 31.5 mg/kg/day. LOAEL = 109.4 mg/kg/day based on decreased body weight gain and increased thyroid weight and increased incidence of thyroid lesions. Cancer (oral, dermal, inhalation) Classification: **“Not Likely to be Carcinogenic to Hum ans”** 
. Point of Departure (POD) = A data point or an estimated point that is derived from observed dose
- response data and used to mark the beginning of extrapolation to determine risk associated with lower environmentally relevant human exposures. NOAEL = no observed adverse effect level. LOAEL = lowest observed adverse effect level. UF = uncertainty factor. UFA = extrapolation from animal to human (interspecies). UFH = potential variation in sensitivity among members of the human population (intraspecies). FQPA S F = FQPA Safety Factor. PAD = population adjusted dose (a = acute, c = chronic). RfD = reference dose. MOE = margin of exposure. LOC = level of concern. N/A = not applicable. **4. 6**  **Endocrine Disruption** As required under FFDCA section 408(p), EPA has devel oped the Endocrine Disruptor Screening Program (EDSP) to determine whether certain substances (including pesticide active and other ingredients) may

have an effect in humans or wildlife similar to an effect produced by a “naturall y occurring estrogen, or o ther such endocrine effects as the Administrator may designate.” The EDSP employ s a two - tiered approach to making the statutorily required determinations. Tier 1 consists of a battery of 11 screening assay s to identify the potential of a chemical substanc e to interact with the estrogen, androgen, or thyroid (E, A, or T) hormonal sy stems. Chemicals that go through Tier 1 screening and are found to have the potential to interact with E, A, or T hormonal sy stems will proceed to the next stage of the EDSP where EPA will determine which, if any , of the Tier 2 testsFluopicolide Human Health Risk Assessment DP No. D415186

Page 18 of 38 are necessary

based on the available data. Tier 2 testing is designed to identify any adverse endocrine related effects caused b y the substance, and establish a dose
- response relationship between the dose and the E, A, or T effect. Between October 2009 and February 2010, EPA issued test orders/data call
- ins for the first group of 67 chemicals, which contains 58 pesticide active ingredients and 9 inert ingredients. This list of chemicals was selec ted based on the potential for human exposure through pathway s such as food and water, residential activity, and certain post
- application agricultural scenarios. This list should not be construed as a list of known or likel y endocrine disruptors. Fluopic olide is not among the group of 58 pesticide active ingredients on the initial list to be screened under the EDSP. Under FFDCA sec. 408(p) the Agency must screen all pesticide chemicals. Accordingl y, EPA anticipates issuing future EDSP test orders/data c all
- ins for all pesticide active ingredients
. For further information on the status of the EDSP, the policies and procedures, the list of 67 chemicals, the test guidelines and the Tier 1 screening battery , please visit our website: http://www.epa.gov/endo/
. **5.0 Dietary Exposure and Risk Assessment**  **5.1 Metabolite/Degradate Residue Profile**  **5.1 .1**  **Summary of Plant and Animal Metabolism Studies** The qualitative nature of the residue for fluopicolide in primary crops is adequatel y understood b ased up on acceptable grape, lettuce, and potato metabolism studies
. HED has determined that the tolerance expression for all primary crops is fluopicolide (parent) only . For risk assessment purposes, the residue of concern for tuberous and corm subgroup 1C vegetables includes the parent compound, fluopicolide, and its metabolites, 3
- chloro
- 5
- trifluoromethylpy ridine
- 2
- carbox yl ic acid (PCA) and BAM. For all other primary crops, the residue of concern for risk assessment purposes includes the parent compound and the metabolite, BAM. With regard to rotational crops , confined rotational crop study data demonstrate the potential for quantifiable residues of fluopicolide and its metabolites at a 12 month PBI. The tolerance expression for rotational crops is fluopicolide (parent) only
. The residues of concern for the risk assessment for cereal grains as rotational crops are fluopicolide (parent), BAM, PCA, and P1 X in grain fo r human food, and fluopicolide (parent) and BAM in forage/hay

/straw and grain for livestock feed. For livestock, the nature of the residue for fluopicolide is also adequately understood based upon acceptable ruminant and poultry metabolism studies. The residue of concern for livestock commodities for tolerance setting purposes is fluopicolide (parent) only
. The residue of concern for risk assessment purposes in livestock commodities is fluopicolide and its BAM metabolite. **5.1 .2**  **Summary of Environmenta l Degradation**  Based upon two aerobic soil metabolism studies that were provided, the Agency has determined that the residues of concern in drinking water are parent fluopicolide and the degradate BAM ( D384431, D. S. Davis, 12/09/2010 ).Fluopicolide Human Health Risk Assessment DP No. D415186

Page 19 of 38 **5.1 .3**  **Comparison of Metabolic Pathways**  The metabolism of fluopicolide in rotational crops appeared to be more extensive than that observed in primary

crops (grapes, lettuce, and potato). Four rotational crop metabolites, 3
- OH
- BAM, P1 X , AE C653598, and AE B102859, were no t observed in the primary crop metabolism studies, but were found in the rotated crops. The metabolism of fluopicolide is qualitatively similar in primary plants. Inruminants and poultry , the metabolism proceeds in a similar fashion as in plants. Inrat s , fluopicolide was readily

absorbed and rapidl y excreted in the urine and feces. The major metabolites identified in rat were the same as the plant metabolites BAM, 3
- OH BAM, PCA and P1X indicating that the toxicity

of the metabolites consumed by humans in foods were evaluated (see Appendix D )
. **5.1.4 Residues of Concern Summary and Rationale**  The fluopicolide residues of concern for primary and rotational crops, livestock and drinking water are shown in Table 5.1.4. **Table 5.1.4**  **. Summary of Metabolites and Degradates to be included in the Risk Assessment and Tolerance**  **Expression for Fluopicolide.**  **Matrix Residues included in Risk**  **Assessment Residues included in**  **Tolerance Expression**

Plants Primary Crops

All primary crops except Tuberous and Corm Vegetables Fluopicolide (parent) and BAM Fluopicolide Tuberous and Corm Vegetables Fluopicolide (parent), PCA, and BAM Rotational Crops All rotational crops except cereal grains Fluopicolide (parent) and BAM Fluopicolide Cereal grains
- grain for human food Fluopicolide (parent), PCA, P1X and BAM Cereal grains
- forage/hay/straw and grain for livestock feed Fluopicolide (parent) and BAM Livestock Fluopicolide (parent) and BAM Fluopicolide Drinking Water Fluopicolide (parent) and BAM Not applicable **5 .2**  **Food Residue**  **Profile** For this petition, Valent is requesting to increase the fluopicolide tolerances established on tuberous and corm subgroup 1C vegetables. The lower tolerances were initially set for a prior action which registered the foliar use of fluopicolide on these crops. This tolerance assessment was supported b y adequate field trial data acquired for potato and included an accompanying processing study
. To support th e current request to increase tolerances , Valent has provided adequate modeling calculations which estimate the concentration of fluopicolide that can occur in potato tubers through soil directed treatment (MRID No. 49177301).Fluopicolide Human Health Risk Assessment DP No. D415186

Page 20 of 38 BAM dietary

risks were not quantified as part of this assessment because the contribution of BAM from the use of fluopicolide is negligible compared to its contribution from the use of dichlobenil, another active ingredient sharing the same metabolite BAM. The Agency

previousl y concluded that the presence of residues of fluopicolide and BAM in milk, beef fat, kidney

and liver is not likely
. The Agency also concluded that residues are not likel y to be present in poultry

commodities as a result of feeding feedstuffs containing residues of fluopicolide and BAM. F or the increased tolerance now recommended for processed potato waste, the livestock dietary burden was recalculated and determined to be unaffected. Therefore, no modification to livestock tolerances is required, and dietary risk estimates for these commodities will be unchanged. **5.3 Water Residue Profile**  Estimated Drinking Water Concentrations (EDWCs) for the residues of fluopicolide were recently determined to support the establishment of tolerances on tuberous and corm subgrou p 1C vegetables for post
- emergence foliar applications. These analy ses were provided b y the Environmental Fate and Effects Division (EFED) in the memorandum “Tier II Drinking Water Exposure Assessment for Fluopicolide and its Major Degradate, 2,6
- Dichlorb enzamide (BAM) for Use on Potatoes, Carrots, Sugar Beets and Brassica (Cole) Leafy Vegetables ” (D370764, R. Miller, 07 /20/20 10)
. Fluopicolide is not included as an anal yt e monitored in U.S. surface and groundwater under the USGS’s National Water Quality Assessment (NAWQA) program. Since there is not adequate monitoring data available, surface water concentrations were estimated using the Tier II model PRZM version 3.12/ EXAMS version 2.98. Ground water concentrations were estimated using the Tier I SCI
- GROW model. The model and its description are available at the EPA internet site: http://www.epa.gov/oppefed1/models/water/
. The recommended estimated drinking water concentrations (EDWCs) for fluopicolide are summarized below in Table 5.3
. **Table 5.3**  **. Summ ary of Estimated Surface Water and Groundwater Concentrations for Fluopicolide**  **based on the Tuberous and Corm Vegetable Foliar Use Pattern**  **. Fluopicolide**  **Surface Water Conc., ppb 1**  **Groundwater Conc., ppb 2**  Ac ute 25.50 0.5 Chronic (non
- cancer) 24.14 Chronic (cancer) 22.36 1 From the Tier II PRZM
- EXAMS
- Index Reservoir model. Highest surface water EDWC assumed a maximum application rate of 0.125 lbs ai/A, a maximum number of 3 foliar applications and an RTI of 7 days. For the premix label a maximum application rate of 0.09 lbs ai/A, a maximum of 4 applications and a 10 day RTI were evaluated but did not lead to the highest EDWC values. The scenario that gave the maximum acut e and chronic (non
- cancer) EDWCs were aerial application to Florida Carrots. The scenario that gave the maximum cancer EDWC was aerial application to potatoes. 2 From the SCI
- GROW model assuming 3 applications of 0.125 lbs ai/A. Note: Since only a chronic dietary assessment was conducted, the value of 24.14 ppb is the value used to calculate exposure and risk.Fluopicolide Human Health Risk Assessment DP No. D415186

Page 21 of 38 **5.4 Dietary Risk Assessment**  **5.4.1 Description of Residue Data Used in Dietary Assessment**  For this dietary

assessment, tolerance level residu es were utilized for the established uses of fluopicolide except for rotational wheat commodities, and tuberous and corm vegetables. Maximum residue values were used for these crops since metabolite concentrations are required to be included for risk asse ssment . These residue values were carried forward from the previous dietary a ssessments made for fluopicolide (D381050, D. S. Davis, 08/19/2010 and D407936, A. Kamel, 04/08/2013). For tuberous and corm commodities, an appropriate residue value for risk a ssessment includes the parent compound and PCA metabolite. In order to estimate the level of fluopicolide that can occur from directed soil application, the registrant provided modeling calculations for tolerance setting purposes while field trials are completed
. This was represented b y modeling the maximum application rate for directed soil treatment to e stimate the percentage of fluopicolide residues which could be translocat ed to potato tubers
. To obtain a maximum residue value for risk assessment, a ratio was therefore determined for calculating a correlated level of the PCA metabolite. This was done by evaluating all of the available studies relevant for determining the residues of fluopicolide in root and tuber crops (potato metabolism study , pot ato field trial studies, and confined rotational crop study). Upon comparison, the 29 day plant
- back interval for radish roots which tested the py ridinyl label examined in the confined rotational crop study gave the most conservative ratio (82% PCA relati ve to parent). A maximum residue value of 0.54 ppm is therefore used for tuberous and corm vegetables which is determined by multiplying the modeled fluopicolide value recommended for tolerance (0.3 ppm) b y a factor of 1.8X Empirical data were u sed to determine appropriate values for all relevant processed commodities which are carried forward from the previous dietary assessments made for fluopicolide (D381050, D. S. Davis, 08/19/2010 and D407936, A. Kamel, 04/08/2013). **5.4.2 Percent Crop**  **Treated Used in Dietary Assessment** The dietary

assessment performed in support of this action is considered to be a highly conservative anal ys is. It includes tolerance level residues or maximum field trial residue levels for all crops, assumes 100% crop treated and uses empirical or default DEEM processing factors. **5.4.3 Acute Dietary Risk Assessment**  An acute dietary

exposure and risk assessment was not conducted because an endpoint attributable to a single dose has not been identified for fluopicolide. **5.4.4 Chronic Dietary Risk Assessment**  The chronic dietary

exposure anal ys is and risk assessment made is a highly conservative anal ys is that uses tolerance level residues or maximum field trial residues and a 100% crop treatedFluopicolide Human Health Risk Assessment DP No. D415186

Page 22 of 38 assumption (D417355, P. Savoia, 04/22/2014) . Dietary risk estimates were determined considering exposures from food and drinking water using EDWCs for all direct and indirect water sources provided b y EFED. The chronic risk estimates for fluopicolide are below the Agency ’s level of concern for the general U.S. population and all population subgroups ( i.e. , <100% of the chronic population adjusted dose) . The most highl y exposed population subgroup is children ages 1
- 2 with an estimate for fluopicolide for food and water of 1 3 % of the cPAD. **5.4.5 Cancer Dietary Risk Assessment**  A cancer dietary

exposure and risk assessment was not conducted since fluopicolide is not likely to be carcinogenic to humans. **5.4.6 Summary Table**  The established uses along with an increas ed tolerance on tuberous and corm subgroup 1C vegetables for fluopicolide will result in an estimated exposure to the U.S. Population which is equivalent to 7. 7 % of the cPAD. The most highl y exposed subgroup is children 1

– 2 years of age with an estimate d exposure equivalent to 1 3 % of the cPAD. Results for all subpopulations are shown in the table below. **Table 5.4.6. Summary of Dietary (Food and Drinking Water)**  **Exposure and Risk for Fluopicolide**  **Population Subgroup Acute Dietary**  **Chronic Dietary Cancer**  **Dietary Exposure**  **(m g/kg/day)**  **% aPAD*** **Dietary Exposure**  **(m g/kg/day)**  **% cPAD*** **Dietary Exposure**  **(m g/kg/day)**  **Risk** General U.S. Population

N/A 0.0 15484 7.7

N/A N/A All Infants (< 1 year old) 0.0 10881 5.4 Children 1
- 2 years old **0.0 25122**  **1 3**  Children 3
- 5 years old 0.0 23460 12 Children 6
- 12 years old 0.0 14866 7.4 Youth 13
- 19 years old 0.0 11526 5.8 Adults 20
- 49 years old 0.0 15214 7.6 Adults 50
- 99 years old 0.0 15629 7.8 Females 13
- 49 years old 0.0 15484 7.7 * %PADs are reported to 2 significant figures. **6.0 Residential (Non**  **- Occupational) Exposure/Risk Characterization**  There are no proposed residential uses associated with this petition . For this risk assessment there are existing residential uses that have been reassessed in this document to reflect updates to HED’sFluopicolide Human Health Risk Assessment DP No. D415186

Page 23 of 38 2012 Residential SOPs 2 along with policy changes for body

weight assumptions. The revision of residential exposures will impact the human health aggregate risk assessment for fluopicolide. There are products with uses on residential turf
- grass and recreational sites. The products may be applied to turf at rates up to 0.27 lb ai/A, for two applications at an interval of 14 day s. There are also uses on ornamental plants and trees with applicatio n rates up to 0.54 lb ai/A . Since the increased tolerances recommended do not add significantly to the BAM dietary

exposure, and there are no new residential uses, the conclusions from the most recently conducted BAM human health risk assessment remain un changed and a revised quantitative BAM risk assessment is not required

– aggregate risks for BAM are not of concern. **6. 1**  **Post -** **Application Exposure** There is the potential for short
- term post - application exposure f or individuals exposed as a result of being in an environment that has been previously treated with fluopicolide. These effects were previously

evaluated in the human health risk assessments conducted in 2010 and 2013 (D384431, D. Davis, 12/9/2010 and D416744, A. Kamel, 12/18/2013). All resi dential post
- application risk estimates for fluopicolide were found to be “not of concern” (MOEs > LOCs) for all exposure scenarios and all lifestages. **6. 2**  **Combined Exposure** Residential handler and post
- application scenarios should generall y not be combined. Although there is potential for the same individual (i.e., adult) to apply a pesticide in and around the home and be exposed by

reentering a treated area in the same day this is unlikely to occur day after day for 30 day s. Combining both of these exposure scenarios would also be inappropriate because of the unrealistically conservative nature of each individual assessment. B ecause of the conservative nature of the individual turf and ornamental plants/trees assessments, these scenarios were not comb ined. To depict the highest exposure and highest risk scenarios for the residential uses of fluopicolide, Table 6. 3 reflects the residential risk estimates for use in the aggregate assessment . These scenarios include;

 The recommended residential exposure for use in the adult aggregate assessment reflects dermal post
- application exposure to treated gardens.  The recommended residential exposure for use in the children (11 to < 16 years old) aggregate assessment reflects dermal post
- application expos ure from golfing.  The recommended residential exposure for use in the children (6 to < 11 ye ars old) aggregate assessment reflected dermal post
- application exposure to treated gardens.  The recommended residential exposure for use in the children (1 to <2 years old) aggregate assessment reflects dermal and hand
- to - mouth exposures from post
- application turf scenario (i.e., post
- application exposure to treated turf).

2 Available: http://www.epa.gov/pesticides/science/residential
- exposure - sop.htmlFluopicolide Human Health Risk Assessment DP No. D415186

Page 24 of 38 **Table 6**  **. 3**  **. Residential Exposures for the Fluopicolide Aggregate Assessment. 1**  **Lifestage Residential Handler**  **Residential Post -**  **application**

**Dose (mg/kg/day) 2**  **MOE 3**  **Dose (mg/kg/day) 4**  **MOE 5**  **Dermal Inhalation**  **Total Dermal**  **Inhalation Total**  **Dermal Inhalation**  **Oral Total**  **Dermal Inhalation**  **Oral Total**  **Short -**  **Term** Adult 0.01 0.00003 0.010
- - 1,900 0.161 N/A N/A 0.161 120 N/A N/A **120** Child (11 to < 16 years old) N/A 0.0034 N/A N/A 0.0034 5,800 N/A N/A **5,800** Child (6 to < 11 years old) 0.095 N/A N/A 0.095 210 N/A N/A **210** Child (1 to < 2 years old) 0.074 N/A 0.0041 0.078 270 N/A 4,900 **260** 1 Bolded risk estimates should contribute to the residential exposure portion of the aggregate assessment. 2 Residential Handler Dose = the highest handler dose for each applicable lifestage of all scenarios assessed. Total = dermal + inhalation. 3 Residential Handler MOE = the MOEs associated with the highest doses identified. Total = 1 ÷ (1/Dermal MOE) + (1/I nhalation MOE). 4 Residential Post
- appl ication Dose = the highest post
- application dose for each applicable lifestage of all scenarios assessed. Total = dermal + inhalation + incidental oral, where applicable. 5 Residential Post
- application MOE = the MOEs associated with the highest doses identified. Total = 1 ÷ (1/Dermal MOE) + (1/I nhalation MOE) + (1/Incidental oral MOE).Fluopicolide Human Health Risk Assessment DP No. D415186

Page 25 of 38 **6. 3**  **Residential Bystander Post -** **A pplication Inhalation Exposure**  Although there are no agricultural applications associated with this action, there are registered uses of fluopicolide on agricultural crops. Based on the Agency's current practices, a quantitative post
- application inhalation exposure assessment was not performed for fluopicolide at this time primarily because of the low acute inhalation toxicity

(Toxicity Category IV) and low vapor pressure (6 x 10 - 9 mm Hg at 25° C). However, volatilization of pesticides may be a source of post
- application inhalation e xposure to individuals nearb y pesticide applications. The Agency sought expert advice and input on issues related to volatilization of pesticides from its Federal Insecticide, Fungicide, and Rodenticide Act Scientific Advisory

Panel (SAP) in December 2009 , and received the SAP’s final report on March 2, 2010 Available at: http://www.epa.gov/scipoly /sap/meetings/2009/120109meeting.html . The Agency is in the process of evaluating the SAP report and may , as appropriate, develop policies and procedures to identify the need for and, subsequently , the way to incorporate post
- application inhalation exposure into the Agency's risk assessments. If new policies or procedures are develo ped, the Agency may revisit the need for a quantitative post
- application inhalation exposure assessment for fluopicolide. Although a quantitative residential post
- application inhalation exposure assessment was not performed, an inhalation exposure assessm ent was performed for handlers. This exposure scenario is representative of a wors t case inhalation exposure and should be considered protective of post
- application inhalation exposure scenarios for fluopicolide. **6. 4**  **Spray Drift** Although there are no a gricultural applications associated with this action, there are registered uses of fluopicolide on agricultural crops. Spray drift is alway s a potential source of exposure to residents nearby to spraying operations. This is particularly

the case with a erial application, but, to a lesser extent, could also be a potential source of exposure from the ground application method employed for fluopicolide. The Agency has been working with the Spray Drift Task Force, EPA Regional Offices and State Lead Agencie s for pesticide regulation and other parties to develop the best spray drift management practices (see the Agency ’s Spray Drift website for more information (Available: http://www.epa. gov/opp00001/factsheets/spraydrift.htm. Agenc y has completed its evaluation of the new database submitted by the Spray

Drift Task Force, a membership of U.S. pesticide registrants, and is developing a policy on how to appropriatel y appl y the data and the AgDRIFT computer model to its risk assessments for pesticides applied b y air, orchard airblast and ground hydraulic methods. After the policy is in place, the Agency

may impose further refinements in spray drift management practices to reduce off
- target drift with specific products with significant risk estimates associated with drift. It is noted that the 0.27 lb ai/acre application rate for turf was modeled to estimate post
application residential exposure of children. As this rate is equal to or higher than many ofFluopicolide Human Health Risk Assessment DP No. D415186

Page 26 of 38 agricultural application rates, this scenario is protective of any exposure of children via spray drift from agricultural fluopicolide applications. **7.0 Aggregate Exposure/Risk Characterization**  In compliance with FQPA, HED must aggregate (add) pesticide exposures and risks from three major sources: food, drinking water, and residential exposures. To perform this aggregate assessment, exposures from all relevant sources are added together and compared to quantitative estimates of hazard (e .g., a NOAEL or PAD), or the risks themselves can be aggregated. When aggregating exposures and risks from various sources, HED considers both the route and duration of exposure. Fluopicolide is registered for use in residential settings as well as for u se on food; therefore, an aggregate risk was conducted which combined average food residues with non - occupational estimates of exposure. **7.1 Acute Aggregate Risk**  An acute aggregate assessment was not conducted because an endpoint attributable to a single dose was not identified from the available data for fluopicolide. **7.2 Short** **- and Intermediate**  **- Term Aggregate Risk**  Short
- term aggregate assessments include exposures that will occur from one to thirty day s and include the most protective short
- term residential exposure scenarios along with chronic food and water exposures
. The exposure scenario used for adults and children was post
- application exposure to treated gardens. Table 7.2.1 presents the most app ropriate scenario for aggregate food and water as well as short
- term residential risk calculations. The short
- term aggregate risk estimates were not of concern for adults or children. **Table 7.2 .1**  **Short -**  **Term Aggregate Risk Calculations Population**  **Short -**  **Term Scenario**

**NOAEL mg/kg/d**  **ay LOC**  **1 Max** 

**Allowable Exposure**  **2 mg/kg/day**  **Average**

**Food and Water**  **Exposure mg/kg/day**  **Residential**

**Exposure mg/kg/day**  **3 Total** 

**Exposure mg/kg/day**  **4 Aggregate** 

**MOE (food, water, and**  **residential) 5**  Adult Male 20 100 0.2 0.015 629 0.161 0.176 629 110 Adult Female 0.015 484 0.161 0.176 484 110 Child (6
- <11yr) 6 0.014 866 0.095 0.109 866 18 0 1 For LOC calculation a 10 x standard inter
- species, 10 x intra
- species and 1 × FPQA uncertainty factors are included. 2 Maximum Allowable Exposure (mg/kg/day) = NOAEL/LOC 3 Residential Exposure = [Oral exposure + Dermal exposure + Inhalation Exposure]. Values from Table 6
. 3 4 Total Exposure = Avg Food & Water Exposure + Residential Exposure) 5 Aggregate MOE = [NOAEL / (Avg Food & Water Exposure + Residential Exposure)] 6 This age group represents the most rerpresentative of a high
- end exposure residential scenario amo ng children
. The average food and water exposure daily dose was selected for the corresponding age group (6
- 12 yr.) from Table 5.4.1.1.Fluopicolide Human Health Risk Assessment DP No. D415186

Page 27 of 38 **7.3 Intermediate**  **- Term Aggregate Risk**  Intermediate
- term exposures to fluopicolide are not likely because of the intermittent nature of applications by

homeowners and the exposure pattern to golfing
. **7.4 C**  **hronic Aggregate Risk** Chronic or long
- term aggregate assessments include exposures that will exceed six (6) months. Since there are no chronic non
- occupational (residential) exposures, the chro nic aggregate assessment only includes f ood and drinkin g water exposures . Refer to section 5.4. 1 for a detailed discussion of the chronic dietary assessment. **7.5 Cancer Aggregate Risk**  HED has considered fluopicolide to be classified as “not likely to be carcinogenic to humans” ; no quantification of cancer risks is required. **8.0 Cumulative Exposure/Risk Characterization**  Unlike other pesticides for which EPA has followed a cumulative risk approach based on a common mechanism of toxicity, EPA has not made a common mechanism of toxicity finding for fluopicolide or any other substance . Although fluopicolide shares a common metabolite, BAM, with dichlobenil, quantification of risks for residues of BAM resulting from fluopicolide was not done as part of this assessment since they contribute an insignificant amount to the total BAM exposure. Furthermore, aggregate risks to BAM are not of concern. For the purposes of this tolerance action, EPA has not assumed that fluopicolide has a common mechanism of toxicity with other substances. For information regarding EPA’s ef forts to determine which chemicals have a common mechanism of toxicity and to evaluate the cumulative effects of such chemicals, see the policy

statements released by

EPA’s Office of Pesticide Programs concerning common mechanism determinations and procedures for cumulating effects from substances found to have a common mechanism on EPA’s website at : http://www.epa.gov/pesticides/cumulative/. **9.0 Occupational Exposure/Risk Characterization**  There are no new agricultural or occupational applications associated with this action which requests to increase the tolerances on tuberous and corm subgroup 1C vegetables. Therefore, there is no potential occupational exposure associated with the proposed change in use pattern.Fluopicolide Human Health Risk Assessment DP No. D415186

Page 28 of 3 8 **10.0 References**  DP No.: D 416744 Subject: **Fluopicolide.** Revised Human Health Risk Assessment for the New Section 3

Tolerances on Rotation al Corn. From: A. Kamel, A. LaMay , and J. Liccione To: T. Kish and D. Schuler Date: 0 2 / 18 /20 13 MRIDs: None DP No.: D 3 54111 Subject: **2,6 -**  **Dichlorobenzamide (BAM) .**  2,6
- Dichlorobenzamide (BAM) as a

Metabolite/Degradate of Fluopicolide and Dichlobenil. Human Health Risk Assessment for Proposed Uses of Rhubarb, Dichlobenil on Caneberries (Subgroup 13
- 07A), and Bushberries (Subgroup 13
- 07B). From: D. Rate To: S. Stanton Date: 0 6 /19/2008 MRIDs: None MRID No. : 49177301 Allen, R. (2013) Fluopicolide: Proposal for a Revised Tolerance on

Potato. L aboratory

Project ID VP
- 38438. Unpublished study prep ared b y Valent Technical Center. 19 p. DP No.: D 3 21209 Subject: Fluopicolide. PP#5E6903; Petition for Tolerances on Imported Grapes and

Raisins. Summary

of Analy tical Chemistry

and Residue Data. From: A. Acierto To: J. Whitehurst and T. Kish Date: 0 1 /23 /200 7 MRIDs: 46474025
- 46474045 , 46474101
- 46474106, 46708525, and 46708542 DP No. : D417354 Sub ject: **Flu o**  **picolide.** Section 3 Registration of an Amended Tolerance on Tuberous and

Corm Subgroup 1C Vegetables and Potato Processed Waste for Fluopicolide. From: P. Savoia To: D. Schuler and T. Kish Dated: 0 4 /22 /201 4 MRID No. : 49177301Fluopicolide Human Health Risk Assessment DP No. D415186

Page 29 of 38 DP No.: D 384431 Subject: **Fluopicolide and its Metabolite, 2,6 -**  **Dichlorobenzamide (BAM).** Amended

Human Health Risk Assessment to Support New Section 3 Uses on Brassica Leafy Greens Subgroup 5B, Potatoes , Sugar Beets, Carrots and to Allow Rotation to Wheat. From: D. S. Davis and A. LaMay To: J. Whitehurst and T. Kish Date: 12 / 0 9 /201 0 MRIDs: None DP No.: D405060 Subject: **Fluopicolide** Human Health Risk Assessment Scoping Document in Support of

Registration Review. From: D. Drew, A. LaMay , and J. Liccione To: R. Wasem Date: 0 2 / 10 /20 13 MRIDs: None TXR No.: 0056544 Subject: Fluopicolide: Summary of Hazard and Science Policy Council (HASPOC) Meetings of December 19 , 2012: Recommendations on the Requirement of a Subchronic Inhalation Study
. From: K. Rury To: D. Drew, J. Liccione, and M. Metzger Date: 12 / 19 /2012 MRIDs: None DP No. : D370764 Sub ject: Tier II Drinking Water Exposure Assessment for Fluopicolide and its Major

Degradate, 2,6
- Dichlorbenzamide (BAM) for Uses on Potatoes, Carrots, Sugar Beets, and Brassica (Cole) Leafy Vegetables. From: R. Miller To: T. Kish and J. Whitehurst Dated: 07 /20 /201 0 MRID No. : None DP No. : D417355 Sub ject: **Fluopicolide.** Chronic Aggregate Dietary Exposure Assessment of Food and Drinking Water to Support a Petition for an Increased Tolerance on Tuberous and Corm Subgroup 1C Vegetables. From: P. Savoia To: D. Schuler and T. Kish Dated: 04 /22 /201 4 MRID No. : NoneFluopicolide Human Health Risk Assessment DP No. D415186

Page 30 of 38 **Appendix A. Toxicology Profile and Executive Summaries A.1**  **Toxicology Data Requirements Study**  **Technical Required**  **Satisfied** 870.1100 Acute Oral Toxicity
................................ ....................... 870.1200 Acute Dermal Toxicity
................................ .................. 870.1300 Acute Inhalation Toxicity
................................ .............. 870.2400 Primary Eye Irritation
................................ .................... 870.2500 Primary Dermal Irritation
................................ .............. 870.2600 Dermal Sensitization
................................ ...................... yes yes yes yes yes yes yes

yes yes yes yes yes 870.3100 Oral Subchronic (rodent)
................................ ............... 870.3150 Oral Subchronic (nonrodent)
................................ ......... 870.3200 21
- Day

Dermal
................................ .............................. 870.3250 90
- Day

Dermal
................................ .............................. 870.3465 90
- Day

Inhalation
................................ .......................... yes yes yes yes yes yes

yes yes yes yes 870.3700a Developmental Toxicity (rodent)
................................ ... 870.3700b Developmental Toxicity (nonrodent)
............................. 870.3800 Reproduction
................................ ................................ . yes yes yes yes

yes yes 870.4100a Chronic Toxicity (rodent)
................................ .............. 870.4100b Chronic Toxicity (nonrodent)
................................ ........ 870.4200a Oncogenicity (rat)
................................ .......................... 870.4200b Oncogenicity (mouse)
................................ .................... 870.4300 Chronic/Oncogenicity
................................ .................... yes yes yes yes yes yes

yes yes yes yes 870.5100 Mutagenicity

—Gene Mutation
- bacterial
..................... 870.5300 Mutagenicity

—Gene Mutation
- mammalian
................ 870.5xxx Mutagenicity

— Structural Chromosomal Aberrations
... 870.5xxx Mutagenicity

—Other Genotoxic Effects
....................... yes yes yes yes yes

yes yes yes 870.6100a Acute Delayed Neurotoxicity (hen)
............................... 870.6100b 90
- Day Neurotoxicity (hen)
................................ ........... 870.6200a Acute Neurotoxicity Screening Battery (rat)
................. 870.6200b 90
- Day

Neurotoxicity Screening Battery (rat)
............... 870.6300 Develop. Neurotoxicity
................................ ................. no no yes yes no -

- yes yes

- 870.7485 General Metabolism
................................ ...................... 870.7600 Dermal Penetration
................................ ........................ 870.7800 Immunotoxicity
................................ ............................. yes yes yes yes

yes yesFluopicolide Human Health Risk Assessment DP No. D415186

Page 31 of 38 **A.2 Toxicity Profiles**  **Table A.2.1 Acute Toxicity Profile**  **- Test Substance**  **Guideline No. Study Type**  **MRID(s) Results**  **Toxicity Category**  870.1100 Ac ute oral [rat] Fluopicolide

Technical 98.3% (AE C638206) Form ulation SC 40 (AE C638206) Form ulation SC61 (AE B066752) 46708601 46709903 46709803 LD50 ≥ 2000 mg/kg (f)

LD50 ≥ 2000 mg/kg (m/f) LD50 ≥ 2000 mg/kg (m/f) III III III 870.1200 Ac ute dermal [rat]

Technical 97.7% (AE C638206) Form ulation SC40 (AE C638206) Form ulation SC61 (AE B066752) 46708605 46709904 46709804 LD50 ≥ 5000 mg/kg

LD50 ≥ 4000 mg/kg LD50 ≥4000 mg/kg IV III III 870.1300 Ac ute inhalation [rat]

Technical (AE C638206) Form ulation SC40 (AE C638206) Form ulation SC61 (AE B066752) 46708606 46709905 46709805 LC50 ≥ 5.16 mg/L

LC50 ≥ 1.789 mg/L LC50 ≥ 3.195 mg/L IV III IV 870.2400 Ac ute eye irritation [rabbit]

Technical 97.7% (AE C638206) Form ulation SC40 (AE C638206) Form ulation SC61 (AE B066752) 46708607 46709906 46709806 slight conjuctival irritation

chemosis/corneal opacity in both studies IV III III 870.2500 Ac ute dermal irritation [rabbit]

Technical 97.7% (AE C638206) Form ulation SC40 (AE C638206) Form ulation SC61 (AE B066752) 46708650 46709907 46709807 None (PDII = 0.00)

slight (PDII = 0.08) slight (PDII = 0.25) IV IV IV

**Table A.2.2 Subchronic, Chronic and Other Toxicity Profile**  **Guideline No.**  **Study Type MRID No. (year)/**  **Classification /Doses Results**  870.3050 28
- day dietary

toxicity (mouse) 46708609 (2000)

Acceptable/Guideline M/F: 0/0, 0.95/1.19, 10.4/12.9, 100/129, 980/1242 mg/kg/day NOAEL = 980/1242 mg/kg/day; the limit dose). The LOAEL was not observed.

870.3050 28
- day dietary

toxicity (rat) 46708610 (2000)

Acceptable/Guideline M/F: 0/0, 1.8/1.8, 17.4/17.9, 174/184, and 1720/1820 mg/kg/day NOAEL = 17.4/17.9 mg/kg/day in males/females). The LOAEL = 174/184 mg/kg/day (M/F) based on decreased body weight gain and food conversion in females and nephrotoxicity in males. 870.3050 28
- day dietary

toxicity (rat) AE 1344122 (Fluopicolide metabolite) 46708611 (2003)

Acceptable/Guideline M/F: 0/0, 1.5/1.7, 14.9/16.8, 151.6/167.1, 1495.3/1615.5 mg/kg/day NOAEL = 151.6/167.1 mg/kg/day. LOAEL = 1495.3/1615.5 mg/kg/day based on decreased body weights and body weight gains in both sexes, and nephrotoxicity in females. 870.3050 28
- day dietary

toxicity (rat) AE C657378 (a Fluopicolide metabolite) 46708612 (2003)

Acceptable/Guideline M/F: 0/0, 1.6/2.1, 16.2/20.4, 159.2/230.6, and 1775.0/1930.8 mg/kg/day NOAEL = 159.2/230.6 mg/kg/day.

LOAEL = 1775.0/1930.8 mg/kg/day based on d ecreases in body weight and body weight gain (males); increased absolute (females) and relative liver weight (both sexes) and relative kidney weight (males); increased cholesterol (both sexes); and histopathological effects in the liver (females), theFluopicolide Human Health Risk Assessment DP No. D415186

Page 32 of 38 **Table A.2.2 Subchronic, Chronic and Other Toxicity Profile**  **Guideline No.**  **Study Type MRID No. (year)/**  **Classification /Doses Results**  kidn eys (males), and thyroid (both sexes).

870.3050 28
- day oral

toxicity (dog) 46708613 (2000)

Acceptable/Non
- guideline 0, 10, 100, 1000 mg/kg/day NOAEL = 1000 mg/kg/day (limit dose). LOAEL was not observed.
870.3100 90
- Day

oral toxicity (rat) 46474112 (2000)

Acceptable/guideline M: 0, 7.4, 109, 1668 mg/kg/d F: 0, 8.4, 119, 1673 mg/kg/day NOAEL = 109 mg/kg/day for males; 8.4 mg/kg/day for females LOAEL = 1668 mg/kg/day for males and 119 mg/kg/day for females based on hypertrophy of the zona glomerulosa in the adrenal gland (M/F), decreased cellularity of the bone marrow (M/F), and trabecular hyperostosis of the bone joint (M) 870.3100 90
- Day

oral toxicity (mouse) 46474114 (2000)

Acceptable/guideline M/F: 0, 5.5, 53, 545 or 1092 mg/kg/day NOAEL = 1092 mg/kg/day (M/F) LOAEL = not identified
870.3100 90
- Day

oral toxicity (mouse) 46474116 (2001)

Acceptable/guideline M: 0, 10.4, 37.8, 161, 770 mg/kg/d F: 0, 12.6, 52.8, 207, 965 mg/kg/day NOAEL = 770 mg/kg/day for males; 207 mg/kg/day for females LOAEL = not identified for males; 965 mg/kg/day for females based on increased incidence of liver

oval cell proliferation 870.3150 90
- Day

oral toxicity (dog) 46474118 (2000)

Acceptable/guideline M&F: 0, 5, 70, 1000 mg/kg/day NOAEL = 1000 mg/kg/day (M/F) LOAEL = not identified (M/F)
870.3200 21/28
- Day dermal

toxicity (species) 46708614 (2003)

Acceptable Guideline 0, 100, 250, 500, 1000 mg/kg/day NOAEL = 1000 mg/kg/day LOAEL > 1000 mg/kg/day No local or systemic toxicity observed 870.3700a Prenatal

developmental in (rat) Pilot study 46708615 (2000)

Acceptable/non
- guideline F: 500, 1000 mg/kg/day (GD 7
- 20) NOAEL/LOAEL not determined. Only four

animals/group. Purpose of study was to determine high
- dose level for 46474120. 870.3700a Prenatal

developmental in (rat) 46474120 (2001)

Acceptable/guideline F: 0, 5, 60, 700 mg/kg/day (GD 7
- 20) Maternal NOAEL = 60 mg/kg/day LOAEL = 700 mg/kg/day based on decreased body

weight gain Developmental NOAEL = 60 mg/kg/day LOAEL = 700 mg/kg/day based on delayed fetal grow th and delayed ossification 870.3700b Prenatal

developmental in (rabbit) Pilot study 46708616 (2000)

Acceptable/non
- guideline F: 25, 50, 100, 250, 500, or 1000 mg/kg bw/day (GD 6
- 28) Maternal NOAEL = 25 mg/kg/day LOAEL = 50 mg/kg/day based on reduced defecation and abortion in a single dose Developmental NOAEL = 1000 mg/kg/day LOAEL = not observed 870.3700b Prenatal

developmental in 46474122 (2001)

Acceptable/guideline Maternal NOAEL = 20 mg/kg/day LOAEL = 60 mg/kg/day based on death, late
- termFluopicolide Human Health Risk Assessment DP No. D415186

Page 33 of 38 **Table A.2.2 Subchronic, Chronic and Other Toxicity Profile**  **Guideline No.**  **Study Type MRID No. (year)/**  **Classification /Doses Results**  (rabbit) F: 0, 5, 20, 60 mg/kg/day

(GD 6
- 28) abortion/premature delivery, decreased food consumption and weight gain Developmental NOAEL = 20 mg/kg/day LOAEL = 60 mg/kg/day based on abortion/premature delivery, decreased fetal body weight and crown
- rum

p length 870.3800 Reproduction and

fertility effects (rat) 46474124 (2003)

46474125 (additional data, 2004) 46474126 (range
- finding, 2002) Acceptable/guideline M: 0, 7.4, 36.4, 144.6 mg/kg/d F: 0, 8.1, 41.0, 159.7 mg/kg/day Parental/Systemic NOAEL = 36.4/41.0 mg/kg/day (M/F) LOAEL = 144.6/159.7 mg/kg/day (M/F) based on kidney toxicity in males and females and decreased

weight gain in females. Reproductive NOAEL = _144.6/159.7 mg/kg/day

(M/F) LOAEL = not identified. Offspring NOAEL = 36.4/41.0 mg/kg/day (M/F) LOAEL = 144.6/159.7 mg/kg/day (M/F) based on decreased body weight and weight gain. 870.4100b Chronic toxicity

(dog) 44674128 (2002)

Acceptable/guideline M&F: 0, 70, 300, 1000 mg/kg/day NOAEL = 300 mg/kg/day (M); _1000 mg/kg/day (F) LOAEL = 1000 mg/kg/day based on decreased body weight gain (M); not identified (F) 870.4200b Carcinogenicity

(mouse) 46474130 (2003)

Acceptable/guideline M: 0, 7.9, 64.5, 551.0 mg/kg/d F: 0, 11.5, 91.9, 772.3 mg/kg/day NOAEL = 64.5/91.9 mg/kg/day (M/F)

LOAEL = 551.0/772.3 mg/kg/day (M/F) based on decreased body weight and weight gain and liver

lesions. no evidence of carcinogenicity 870.4300 Chronic/

Carcinogenicity (rat) 4647413 9 (2003)

Acceptable/guideline M: 0, 2.1, 8.4, 31.5, 109.4 mg/kg/day F: 0, 2.8, 10.8, 41.0, 142.2 mg/kg/day NOAEL = 31.5/41.0 mg/kg/day (M/F) LOAEL = 109.4/142.2 mg/kg/day based on decreased body weight gain (M/F) and thyroid

toxicity (M). no evidence of carcinogenicity 870.5100 Gene Mutation

(Salmonella ty phimurium) 46474146 (2001)

Unacceptable/guideline 1.6
- 5000 μg/plate 46474202 (2001) Acceptable/guideline 1.6
- 5000 μg/plate 46474148 (2001) Acceptable/guideline 1.6
- 5000 μg/

plate 46474144 (2001) Acceptable/guideline 1.6
- 5000 μg/plate 46474142 (2004) Acceptable/guideline AE638206 (batch mixture of PP/241067/1 and PP/241024) 5
- 5000 μg/plate negative (non
- mutagenic) Upgradeable if purity for test material is given. negative (non
- mutagenic) negative (non
- mutagenic) negative (non
- mutagenic positive (mutagenic)Fluopicolide Human Health Risk Assessment DP No. D415186

Page 34 of 38 **Table A.2.2 Subchronic, Chronic and Other Toxicity Profile**  **Guideline No.**  **Study Type MRID No. (year)/**  **Classification /Doses Results**  870.5300 Gene mutation

(Chinese hamster lung cells) 46474204 (2000)

Acceptable/guideline AE638206 (batch mixture of PP/241067/1 and PP/241024) 1.2
- 38 20 μg/mL negative (non
- mutagenic)

870.5375 Cy

togenetics 46474208 (2001)

Acceptable/guideline 1.22 to 625 μg/mL 46474206 (2004) Acceptable/guideline AE638206 (batch mixture of PP/241067/1 and PP/241024) 3.2 to 100 μg/mL negative for chromosome aberrations positive for aberrations without S9

870.5395 Micronucleus

(mouse) 46474214 (2003)

Acceptable/guideline 150, 300 or 600 mg/kg/day 46474210 (2005) Acceptable/guideline AE638206 (batch mixture of PP/241067/1 and PP/241024) 200, 600 or 2000 mg/kg/day 46474212 (2005) Acceptable guideline AE C638206 (Batch No. OP 2050046 at 2000 mg/kg/day negative at doses up to 600 mg/kg negative at doses up to 2000 mg/kg negative at dose of 2000 mg/kg

870.5550 Unscheduled

DNA Synthesis (rat hepatocytes) 42169839 (1989)

Acceptable/guideline negative at concentration up to 300 μg/mL in cultured rat hepatocytes (no OPPTS no./ FIFRA test guideline 84
- 2) Other

Genotoxicity Unscheduled DNA synthesis (rat hepatocytes) 46474216 (2000)

Acceptable/guideline AE638206 (batch mixture of PP/241067/1 and PP/241024) 600 or 2000 mg/kg negative at concentrations up to 2000 mg/kg in hepatocytes from treated rats

870.6200a Ac ute

neurotoxicity screening battery (rat) 46474218 (2002)

46474219 (range
- finding, 2002) Acceptable/guideline M/F: 0, 10, 100, 2000 mg/kg NOAEL = 100 mg/kg (M/F)

LOAEL = 2000 mg/kg (M/F) based on transiently

lowered body temperature.

870.6200b Subchronic

neurotoxicity screening battery 46474221 (2002)

46474222 (positive control, 2002) Acceptable/guideline M: 0, 15.0, 106.6, 780.6 NOAEL = 106.6/18.0 mg/kg/day (M/F) LOAEL = 780.6/125.2 mg/kg/day based on decreased body weight gain, food consumption, and

food efficiency.Fluopicolide Human Health Risk Assessment DP No. D415186

Page 35 of 38 **Table A.2.2 Subchronic, Chronic and Other Toxicity Profile**  **Guideline No.**  **Study Type MRID No. (year)/**  **Classification /Doses Results**  mg/kg/day F: 0, 18.0, 125.2, 865.8 mg/kg/day 870.6300 Developmental

neurotoxicity None 870.7485 Metabolism and

pharmacokinetics (rat) 46474242 (2004)
- main

studies 46474241 (2001) 46474244 (2003) 46474226 (2003) 46474239 (2003) rapid absorption, metabolism and excretion; main

metabolites were oxidative N
- dealkylation cleavage products. Primary route of excretion is fecal and urinary with little accumulation in the tissues.
870.7485 Metabolism and

pharmacokinetics (rat) 46708632 (2002)

Acceptable Non
- guideline Most of the metabolites observed were derivatives of AE C638206 fitting well with the prior known metabolites, implying cysteine or N
- acetyl
- cysteine introduction on the phe nyl ring from gluthione conjugation, hydroxylation, or other conjugations. 870.7485 Metabolism and

pharmacokinetics (rat) AE C657188 (PCA) 46708636 (2002)

Acceptable Guideline AE C657188 (PCA) showed high (87%) absorption but low (14

– 21%) metabolism. Excretion is mainly through the urine, with a minor portion in

the feces. 870.7485 Metabolism and

pharmacokinetics (rat) AE C653711 (2,6
- dichloro
benzamide 46708633 (2003)

46708634 (2003) 46708635 (2003) Acceptable Guideline Absorption: 50
- 79%. Metabolized extensively to 18 identified compounds. The majority of the radioactivity was associated with a mercapturic acid conjugate of hydroxyl
- chlorobenzamide (15
- 5
- 26.2%), pre sent in the urine Excretion mainly

through urine and feces. 870.7600 Dermal

penetration (rat) 46708638 (2003)

Acceptable Guideline 1.43, 659 ug/cm2 skin In vivo study Dermal Penetration rate: 37% 870.7600 Dermal

penetration (comparative) 46708637 (2003)

Acceptable Non
- guideline 1.9, 744 ug/cm2 skin In vitro study Rat skin dermal penetration rate is 7.8 times greater

than human skin. **A.3 Hazard Identification and Endpoint Selection**  **A.3.1 Acute Reference Dose (aRfD)**  **- Females age**  **13 -**  **49 Study Selected:**  None. **Comments:** No appropriate endpoint attributable to a single exposure (dose) was identified from the database. **A.3. 2**  **Chronic Reference Dose (cRfD) Study Selected:**  Developmental Toxicity Study in Rabbits MRID No: 46474122 **Dose and Endpoint for Risk Assessment:** NOAEL= 20 mg/kg/day based on death, abortions/premature deliveries, decreased food consumption and body weight gain at 60 mg/kg/day
. **Uncertainty Factor:** 100x (10x interspecies extrapolation, 10x intraspecies variability , 1x FQPA)Fluopicolide Human Health Risk Assessment DP No. D415186

Page 36 of 38 **Comments on Study/Endpoint/Uncertainty Factors:** This study is considered to be the most appropriate for chronic dietary dose and endpoint selection with support of the chronic/oncogenicity

study in rats (co
- critical study). In the latter study, the NOAEL was 31.5 mg/kg/day

based on decreased body weight gain and increased thy roid weight and increased incidence of thyr oid lesions at 109.4 mg/kg/day
. **A.3.4 Incidental Oral Exposure (Short** **- and Intermediate**  **- Term)**  **Study Selected:** Devel opmental Toxicity Study in Rabbits MRID No: 46474122 **Dose and Endpoint for Risk Assessment:** NOAEL= 20 mg/kg/day based on death, abortions/premature deliveries, decreased food consumption and body weight gain at 60 mg/kg/day
. **Uncertainty Factor:** 100x (10x interspecies extrapolation, 10x intraspecies variability, 1x FQPA) **Comments on Study/Endpoint/Uncertainty Factors:** The endpoint of concern in this study is appropriate for the population (infant and children) and duration of concern. **A.3.5 Dermal Exposure (Short** **- , Intermediate**  **- and Long**  **- Term)**  **Study Selected:** Developmental Toxicity Study in Rabbits MRID No: 46474122 **Dose and Endpoint for Risk Assessment:** NOAEL= 20 mg/kg/day based on death, abortions/premature deliveries, decreased food consumption and body weight gain at 60 mg/kg/day
. **Uncertainty Factor:** 100x (10x interspecies extrapolation, 10x intraspecies variability , 1x FQPA) **Comments on Study/Endpoint/Uncertainty Factors:** The developmental study is selected since developmental endpoints are not examined in dermal toxicity studies. It is also protective of effects observed in the chronic toxicity studies, i.e., decreased body weight gain and increased thy

roid weight and increased incidence of thy roid lesions. **A.3.6 Inhalatio**  **n Exposure (Short -**  **, Intermediate -**  **and Long -**  **Term) Study Selected:**  Developmental Toxicity Study in Rabbits MRID No: 46474122 **Dose and Endpoint for Risk Assessment:** NOAEL= 20 mg/kg/day based on death, abortions/premature deliveries, decreased food consumption and body weight gain at 60 mg/kg/day
. **Uncertainty Factor:** 100x (10x interspecies extrapolation, 10x intraspecies variability , 1x FQPA) **Comments on Study/Endpoint/Uncertainty Factors:** Th e developmental toxicity study is protective of any potential developmental effects. It is also protective of effects observed in the chronic toxicity

studies, i.e. , decreased body weight gain and increa sed thyroid weight and increased incidence of thy roid lesions.Fluopicolide Human Health Risk Assessment DP No. D415186

Page 37 of 38 **Appendix B. Review of Human Research** This risk assessment relies in part on data from studies in which adult human subjects were intentionally

exposed to a pesticide or other chemical. These data, which include studies from Pesticide Handlers Exposure Database Version 1.1 (PHED 1.1); the Agricultural Handler Exposure Task Force (AHETF) database ; the ARTF database; and the Outdoor Residential Exposure Task Force (ORETF) database , are (1) subject to ethics review pursuant to 40 CFR 26, (2) have received that review, and (3) are compliant with applicable ethics requirements. For certain studies, the ethics review may have included review b y the Human Studies Review Board. Descriptions of data sources, as well as guidance on their use, can be found at the Agency website **Appendix C**  **. Physical/Chemical Properties Physicochemical Properties of Fluopicolide.**  **Parameter Value**  **Reference** Molecular Weight 383.59 * Melting point/range 149  C MRID 46474015 pH 6.5 at 22.0  C ( 1% suspension) MRID 46474013 Density 1.65 g/cm3 (30 °C) MRID 46474016 Water solubility (20  C) 2.86 mg/L at pH 4 2.80 mg/L at pH 7 2.80 mg/L at pH 9 MRID 46474021 Solvent solubility (g/L at 20  C) n - Hexane: 0.20 Ethanol: 19.2 Toluene: 20.5 Ethyl acetate: 37.7 Acetone: 74.7 Dichloromethane: 126 Dimethyl sulfoxide: 183 MRID 46474022

Vapor pressure (25  C) 8.03 x 10 - 7 Pa MRID 46474023 Dissociation constant (pKa) No evidence of ionization in the pH range of 1.9 to 9.8 MRID 46474017 Octanol/water partition coefficient Log(KOW) Log P OW = 3.26 at pH 7.8 and 22 ± 1  C MRID 46474018 Log P OW = 2.9 at pH 4.0, 7.3 and 9.1 and 40  C MRID 46474019 UV/visible absorption spectrum Absorption maxima wavelengths (nm): In methanol: 203 and 271 In methanol/HCl: 202 and 270 In methanol/NaOH: 219 and 271 MRID 46474014
*The molecular weight was calculated from the Periodic Table. **Appendix D. Major Fl**  **uopicolide Metabolites**Fluopicolide Human Health Risk Assessment DP No. D415186

Page 38 of 38 **Chemical Names and Structures of Major**  **Fluopicolide Metabolites.** Common name/code Chemical name Chemical structure **BAM** AE C653711 2,6
- dichlorobenzamide

**3 -**  **OH -**  **BAM or BAM -**  **OH** AE C657378 2,6
- dichloro
- 3
- hydroxybenzamide

**PCA** AE C657188 3
- chloro
- 5
- trifluoromethylpyridine
2
- carboxylic acid

**P1X** AE 1344122 3
- methylsulfinyl
- 5
- trifluoromethylpyridine
- 2
- carboxylic acid Cl

Cl N H 2 O
Cl

Cl N H 2 O O H

N Cl F 3 C

O H O

N F 3 C

O H O

S O C H 3