Fenamidone Human Health Risk Assessment DP No. D409835

Page 1 of 36 UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C. 20460 **OFFICE OF CHEMICA** **L SA FETY**  **AND POLLUTION**  **PREVENTION MEMORANDUM**  **Date: December 31, 2013**  **SUBJECT: Fenamidone:**  Human Health Risk Assessment to Support the Section (3)

Registration and the Establishment of Tolerances for Uses on Ginseng, Succulent Beans (Except Cowpea), Bulb Onion (Subgroup 3 - 07A), and Green Onion (Subgroup 3 - 07B) . **PC Code:** 046679 **DP Barcode:** D409835 **Decision No.:** 475185 **Registration No. :**  264 - 695 **Petition No .:**  3E8150 **Regulatory Action:** Section 3 Registration **Risk Assessment Typ e**  **:** Single Chemical **Case No.:** NA **T XR No.:**  NA **CAS No.:** 161326 - 34 - 7 **MRID No.:** 49052101, 49052102, and 49052103 **40 CFR:** 180.579 **FROM:** Id eliz Negrón - Encarnación , Ph.D., Chemist

Matthew Lloyd, CIH, Industrial Hygienist Ronnie J. Bever, Jr., Ph.D., Toxicologist Risk Assessment Branch (RAB) V/VII Health Effects Division (HED; 7509P) and Karen Milians, Ph.D., Chemist Environmental Risk Branch IV Environmental Fate and Effects Division (EFED; 7507P) **THROUGH:** Danette Drew, Senior Chemist

Michael S. Metzger, Branch Chief RAB V/VII (HED; 7509P) **TO:** Laura Nollen/Barbara Madden

Risk Integration Minor Use, and Emergency Response Branch Registration Division (RD; 7505P) and Rosemary

Kearns/Tony Kish Fungicide Branch (RD; 7505P)Fenamidone Human Health Risk Assessment DP No. D409835

Page 2 of 36 **1.0 Executive Summary**  ................................ ................................ ................................ ........... 4 **2.0 HED Recommendations**  ................................ ................................ ................................ .... 5 **2.1 Data Deficiencies**  ................................ ................................ ................................ ............ 5 **2.2 Tolerance Considerations**  ................................ ................................ .............................. 5 **2.2.1 Enforcement Analytical Method**  ................................ ................................ ............... 6 **2.2.2 Recommended Tolerances**  ................................ ................................ ......................... 6 **2.2.3 Revisions to Petitioned**  **- For Tolerances**  ................................ ................................ .... 6 **2.2.4 International Harmonization**  ................................ ................................ ..................... 7 **2.3 Label Recommendations**  ................................ ................................ ................................ 7 **2.3.1 Recommendations from Residue Reviews**  ................................ ................................ 7 **2.3.2 Recommendations from Occupational/Residential Assessment**  ............................. 7 **3.0 Introduction**  ................................ ................................ ................................ ........................ 7 **3.1 Chemical Identity**  ................................ ................................ ................................ ........... 7 **3.2 Physical/Chemical Characteristics**  ................................ ................................ ............... 8 **3.3 Pesticide Use Pattern**  ................................ ................................ ................................ ...... 8 **3.4 Anticipated Exposure Pathways**  ................................ ................................ ................... 9 **3.5 Consideration of Environmental Justice**  ................................ ................................ ...... 9 **4.0 Hazard Characterization and Dose**  **- Response Assessment**  ................................ ............ 9 **4.1 Toxicology Studies Available for Analysis**  ................................ ................................ ... 9 **4.2 Absorption, Distribution, Metabolism, &**  **Elimination (ADME)** ............................. 10 **4.2.1 Dermal Absorption**  ................................ ................................ ................................ ... 10 **4.3 Toxicological Effects**  ................................ ................................ ................................ .... 11 **4.4 Safety Factor for Infants and Children (FQPA**  **Safety Factor)** ............................... 12 **4.4.1 Completeness of the Toxicology Database**  ................................ .............................. 12 **4.4.2 Evidence of Neurotoxicity**  ................................ ................................ ........................ 13 **4.4.3 Evidence of**  **Sensitivity/Susceptibility in the Developing or Young Animal** ........ 13 **4.4.4 Residual Uncertainty in the Exposure Database**  ................................ ................... 13 **4.5 Toxicity Endpoint and Point of Departure Selections**  ................................ .............. 13 **5.0 Dietary Exposure and Risk Assessment**  ................................ ................................ ......... 15 **5.1 Residues of Concern Summary and**  **Rationale** ................................ .......................... 15 **5.2 Food Residue Profile**  ................................ ................................ ................................ .... 15 **5.3 Water Residue Profile**  ................................ ................................ ................................ .. 17 **5.4 Dietary Risk Assessment**  ................................ ................................ .............................. 17 **5.4.1 Description of Residue Data Used in Dietary Assessment**  ................................ .... 17 **5.4.2 Percent Crop Treated Used in Dietary Assessment**  ................................ .............. 18 **5.4.3 Acute Dietary Risk Assessment**  ................................ ................................ ............... 18 **5.4.4 Chronic Dietary Risk Assessment**  ................................ ................................ ........... 18 **5.4.5 Cancer Dietary Risk Assessment**  ................................ ................................ ............. 18 **5.4.6 Summary Table**  ................................ ................................ ................................ ......... 18 **6.0 Residential (Non**  **- Occupational) Exposure/Risk Characterization**  ............................. 19 **6.1 Residential Bystander Post**  **- application Inhalation Exposure**  ................................ . 19 **6.2 Spray Drift**  ................................ ................................ ................................ .................... 20 **7.0 Aggregate Exposure/Risk Characterization**  ................................ ................................ .. 20 **8.0 Cumulative Exposure/Risk Characterization**  ................................ ............................... 20 **9.0 Occupational Exposure/Risk Characterization**  ................................ ............................ 21 **9.1 Short** **- /Intermediate**  **- Handler Risk**  ................................ ................................ ............ 21Fenamidone Human Health Risk Assessment DP No. D409835

Page 3 of 36 **9.2 Short** **- /Intermediate**  **- Post** **- Application Risk**  ................................ .............................. 24 **9.2.1 Dermal**  **Post -**  **application Risk**  ................................ ................................ .................. 24 **9.2.2 Inhalation**  **Post -**  **application Risk**  ................................ ................................ ............. 26 **10.0 References**  ................................ ................................ ................................ ......................... 26 **Appendix A. Toxicology Profile and Executive Summaries** ................................ .................. 28 **A.1 Toxicology Data Requirements**  ................................ ................................ ................... 28 **A.2 Toxicity Profiles**  ................................ ................................ ................................ ............ 29 **Appendix B. Physical/Chemical Properties** ................................ ................................ ............. 35 **Appendix C. International Residue Limits Table** ................................ ................................ .... 36Fenamidone Human Health Risk Assessment DP No. D409835

Page 4 of 36 **1.0 Executive**  **Summary** Fenamidone is a broad- spectrum foliar fungicide currentl y registered for application to a variety of field crops including, bulb vegetables, tuberous and corm vegetables, fruiting vegetables and leafy vegetables. The registrant (Bayer Crop Scienc e) proposed one action (PP# 3E8150) : a request to establish tolerances for residues of fenamidone on ginseng, succulent beans, bulb onion (subgroup 3 - 07A) , and green onions ( subgroup 3 - 07A) . **Hazard Characterization:** The toxicity database for fenamidone is considered adequate for characterization of the potential developmental, reproductive , carcinogenetic, mutagenic, neurotoxic, and immunotoxic effects of fenamidone . There are no outstanding data requirements for fenamidone. The current toxicological endpoints, points of departure ( PODs ) , and Food Quality Protection Act (FQPA) and other uncertainty factors reflect current policy . The target organ in fenamidone subchronic toxicity studies is generally

the liver; rarel y, the thy roid or spleen w as also affected at the LOAEL. Inchronic studies, the target organs were the liver in mouse and dog, and the liver and thyroid in rat. Increased susceptibility was not demonstrated in the rat or rabbit developmental studies , or the 2 - generation rat reproduction study . Reproductive toxicity was not observed in the rat. Based on the available data and the selection of risk assessment endpoints that are protective of developmental effects, there are no residual uncertainties with regard to pre - and/or post - natal toxicity . Therefore, the FQPA safety factor was reduced to 1 X. Clinical signs of neurotoxicity (such as urination and unsteady gait) were observed in the acute neurotoxicity study , and decreased brain weights were noted in the subchronic neurotoxicity

study . Additionally , decreased absolute brain weight s occurred in the rat reproduction study in adult F1 females and F2 female pups . An immunotoxicity study of fenamidone demonstrated immunosuppression at the highest dose tested; however, the existing risk assessment po ints of departure are lower and are protective of this potential effect. HED class ified fenamidone as “not likely to be a human carcinogen” by all relevant routes of exposure. Fenamidone has low acute toxicity via the oral, dermal, and inhalation routes based on lethality studies. It is a moderate e yeirritant, but is not a dermal irritant or a dermal sensitizer. **Residue Chemistry:** The residue chemistry database for fenamidone is considered complete. The current tolerance enforcement method, a liquid chromatographic method coupled with tandem mass spectrum detection (LC/MS/MS) is suitable to enforce the new plant tolerances proposed in this petition. The residue of concern for tolerance enforcement is parent fenamidone only . HED notes that since residues of fenamidone are detected through FDA Multi - Residue Method Protocol D, this protocol can also serve as an enforcement methodology . There are no issues with respect to international harmonization as a result of the proposed establishment of tolerances that are the subject of this petition. HED has concluded there are sufficient data to support the requested establishment of tolerances for all crops and crop groups , with the exception of succulent bean s. At this time, HED cannot recommend for tolerances on cowpea; therefore, a tolerance for succulent beans (except cowpea) is recommended. **Dietary Risk Assessment:** Conservative acute and chronic dietary risk assessments were conducted which used maximum field trial residue values, assumed 100 percent crop treated (% CT) for all commodities, incorporated DEEMTM default processing factors for many processedFenamidone Human Health Risk Assessment DP No. D409835

Page 5 of 36 commodities , and included modeled estimates for drinking water. Parent fenamidone and the metabolite s of concern for risk assessment were included in the dietary assessments. Acute and chronic dietary

(food and water) risks from the existing and proposed uses of fenamidone are not of concern to HED . **Residential Risk Assessment:**  Residential exposures are not quantitatively assessed in this document because, at this time, the proposed uses of fenamidone do not involve applications by homeowners or commercial applicators in residential settings. In addition, there are no currently registered non - agricultural (i.e., residential) uses of fenamidone. Therefore, residential exposure is not anticipated. **Aggregate Risk:** Since there are no registered or proposed residential uses for fenamidone, aggregate exposure estimates include food and drinking water onl y. Therefore, acute and chronic aggregate risks are not of concern for the existing and proposed uses of fenamidone. **Occupational Risk Assessment:**  An occupational risk assessment was conducted for the proposed uses of fenamidone. Th e occupational handler exposure and risk estimates indicate that the short - and intermediate - term combined (dermal and inhalation) margins of exposure (MOEs ) are not of concern to HED (i.e., MOE > 100) at the baseline level of exposure. The proposed label requires that occupational handlers wear chemical resistant gloves. With the label prescribed personal protection equipment (PPE ) , all the occupational handler exposure scenarios result in combined MOEs of 180 and greater. The occupational post - application dermal exposure and risk estimates are greater than the level of concern ( LOC ) of 100 on the day of application, ranging from 130 to 11,000 , depending on crop, activity , and exposure duration . The 12 - hour REI , which currentl y appears on the proposed label, is adequate for the proposed uses. Based on the Agency's current practices, a quantitative non - cancer occupational post - application inhalation exposure assessment was not performed for fenamidone at this time. **2.0 H**  **ED Recommendations**  HED has concluded there are sufficient data to support the requested establishment of tolerances for residues of fenamidone on ginseng , succulent beans (except cowpea) , bulb onion (subgroup 3 - 07A), and green onion (subgroup 3 - 07B) . The specific tolerance recommendations are discussed in Section 2.2 **2.1 Data Deficiencies**  No data deficiencies were identified to support the tolerances recommended by H ED. H owever, if the registrant wants to pursue uses on cowpeas an appropriate livestock feeding study must be submitted. **2.2 Tolerance Considerations**  K. Milians; and I. Encarnacion , D 410422 .Fenamidone Human Health Risk Assessment DP No. D409835

Page 6 of 36 **2.2.1 Enforcement Analytical Method**  The current tolerance enforcement method entitled , RPA 407213: m ethod of Analysis for RPA 407213 and its Metabolites RPA 717879 (DADK -Fen), RPA 408056 (DA -Fen) and RPA 405862 (MRID No. 45385918), is a liquid chromatographic method coupled with tandem mass spectrum detection (LC/MS/MS) which has been radiovalidated. Further , the method has undergone succe ssful ILV (independent laboratory v alidation) , as well as validation by the Agency

o n a number of commodities including potato, cucumber, cantaloupe, lettuce, onion, tomato (fruit, paste, and puree), spinach, and wheat (forage, hay , straw, grain, bran, flo ur, shorts, germ, and middlings). The data acquisition method used for the commodities under consideration is similar to the enforcement method. Therefore, HED concludes that the enforcement method is also suitable to enforce the new plant tolerances proposed in this petition. **2.2. 2**  **Recommended Tolerances** HED recommends that 40 CFR § 180.579 be amended by establishing tolerances for the plant commodities listed in the **Table 2.2.**  **2** . The tolerance expression is: “ Tolerances are established for residues of the fungicide, fenamidone, including its metabolites and degradates, in or on the following commodities. Compliance with the tolerance levels is to be determined by measuring only fenamidone (4H - Im idazol - 4 - one, 3,5 - dihydro - 5 - methyl - 2 - (methylthio) - 5 -phenyl - 3 (phenyl amino) - ,(S) - ), in or on the commoditie s.” **Table 2.2.**  **2 . Tolerance Summary for**  **Fenam idone**  **. Comm** **odity Established**  ***** **/Proposed Tolerance (ppm)**  **HED -**  **Recommended Tolerance (ppm)**  **Comments**

**( correct commodity definition**  **)** Ginseng 0.8 0.8 0 Bean, succulent 0.8 0.8 0 Bean, succulent, except cowpea Onion, bulb, subgroup 3 - 07A 0.2 0.2 0 Onion, green, subgroup 3 - 07B 1.5 1.5 Garlic 0.20* Remove These commodities are covered under the proposed/ recommended onion, bulb, subgroup 3 - 07A and onion, green, subgroup 3 - 07B. Garlic, great headed 0.20* Remove Onion, dry bulb 0.20*/Remove Remove Onion, green 1.5*/Remove Remove Onion, welsh 1.5* Remove Shallot, bulb 0.20* Remove Shallot, fresh leaves 1.5* Remove *T olerances established under the 40 CFR 180.579. **2.2. 3**  **Revisions to Petitioned -**  **For Tolerances** The succulent bean definition includes cowpea which has forage and hay that are considered significant livestock feedstuff s. The dietary

burden associated with uses on cowpea is notFenamidone Human Health Risk Assessment DP No. D409835

Page 7 of 36 supported by

an appropriate feeding study ; therefore, uses on cowpea have to be excluded from succulent bean. In addition, tolerances establishe d in the 40 CFR 180.579 (see Table 2.2.2 ) fo r commodities covered under subgroups 3 - 07A and 3 - 07B should be removed. The registrant should submit a revised Section F in which the proposed tolerances are the same as those recommended b y HED. **2.2. 4**  **Interna tional Harmonization**  Mexican and Codex MRLs have not been established for the commodities under consideration (Refer to Appendix C) . The recommended tolerance definition and l evels for onion, bulb, subgroup 3 - 07A , and onion, green, subgroup 3 - 07B are har monized with established Canadian Maximum Residue Limits (M RL s) for similar commodities. Moreover, identical regulatory levels are being recommended b y EPA and PMRA reviewers for ginseng and commodities under the succulent bean definition as part of this joint review (Refer to Table 2.2. 2 ). **2.3 Label Recommendations**  **2.3.1 Recommendations from Residue Reviews**  The label of Reason ® 500 SC Fungicide (EPA Reg. No. 264 - 695) has to be modified to specify that application to succulent beans is limited to all bean commodities under that definition with the exception of cowpea (e.g. Succulent Bean, Except Cowpea) . **2.3.2 Recommendations**  **from Occupational /Residential**  **Assessment** No recommendations are provide d for the proposed new uses considered in this petition . **3.0 In**  **troduction 3.1**  **Chemical Identity Table 3.1 Test Compound Nom**  **enclature** Chemical Structure Em pirical Formula C 17 H 17N 3 OS - 311.401 Common Name Fenamidone Com pany experimental name RPA 407213 IUPAC name (S ) - l - anilino - 4 - methyl - 2 - methylthio - 4 -phenylimidazolin - 5 - one CAS Name 5 S ) - 3,5 - dihydro - 5 - methyl - 2 - (methylthio) - 5 -phenyl - 3 - (phenylamino) - 4Himidazol - 4 - one CAS Registry Number 161326 - 34 - 7 N N C H 3 O S C H 3 N HFenamidone Human Health Risk Assessment DP No. D409835

Page 8 of 36 **Table 3.1 Test Compound Nom enclature**  End - use product/EP REASON ® 500 SC fungicide, PCP# 27462 Chemical Class I midazole fungicide Known Impurities of Concern N/A **3.2 Physical/Chemical Characteristics**  Fenamidone is moderately soluble in water ( FAO, 2000 ) 1 and not likely to volatize due to low vapor pressure. Based on the octanol/water partition coefficient (Kow) fenamidone partitions to the lipophilic phase . However, it is soluble in both polar and non -polar solvents. Refer to **Appendix B** for the physicochemical properties of fenamidone. **3.3 Pesticide Use Pattern**  Fenamidone is proposed to be applied b y ground, aerial or chemigation on ginseng, succulent beans and bulb vegetables. The maximum seasonal application for these crops ranges from 0.71 - 0.80 lbs a.i./A and the application rate is 0.178 - 0.267 lbs a.i./A (Ref er to **Table 3.3**  ). The pre harvest interval s (PHI s ) are 14 days for ginseng , 3 days for succulent beans , and 7 days for bulb vegetables . **Table 3**  **. 3**  **. Summary of Directions for Use of Fenamidone**  **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** Ginseng Reason® 500 SC fungicide, ground, aerial, chemigation 264 - 695 0.178 - 0.267 Not Specified 0.80 14 14 day RTI

Succulent Beans Reason® 500 SC fungicide, ground, aerial, chemigation 264 - 695 0.178 - 0.267 Not Specified 0.80 3 7 day RTI

Bulb Vegetables Reason® 500 SC fungicide, ground, aerial, chemigation 264 - 695 0.178 Not Specified 0.71 7 5 - 10 days RTI

1 FAO, 2000. Food and Agriculture Organization of the United Nations. FAO Pesticide Disposal Series 8. Assessing Soil Contamin ation: A Reference Manual. Appendix 2. Parameters of pesticides that influence processes in the soil. Editorial Group, FAO Information Division: Rome, 2000. http://www.fao.org/docrep/003/X25 70E/X2570E00.htm .Fenamidone Human Health Risk Assessment DP No. D409835

Page 9 of 36 **3.4 Anticipated Exposure Pathways**  The Registration Division has requested an assessment of human health risk to support the proposed new use of fenamidone on ginseng, succulent beans, bulb onion (subgroup 3 - 07A) , and green onions ( subgroup 3 - 07A) . Humans may be exposed to fenamidone in food and drinking water, since fenamidone may be applied directly

to growing crops and application may result in fenamidone reaching surface and ground water sources of drinking water. There are no residential uses of fenamido ne, so exposure in residential or non - occupational settings is unlikely . In an occupational setting, applicators may be exposed while handling the pesticide prior to and during application, as well as from workers re - entering treated fields. Risk asses sments have been previousl y conducted for fenamidone and no new toxicity data have been received since the previous risk assessment. This risk assessment considers all of the potential exposure pathways based on the proposed new uses of fenamidone, but als o considers the existing uses as well, particularl y for the dietary exposure assessments. **3.5 Consideration of Environmental Justice**  Potential areas of environmental justice concerns, to the extent possible, were considered in this human health risk as sessment, in accordance with U.S. Executive Order 12898, "Federal Actions to Address Environmental Justice in Minority Populations and Low - Income Populations," (http://www.eh.doe.gov/o epa/guidance/justice/eo12898.pdf . As a part of every

pesticide risk assessment, OPP considers a large variety of consumer subgroups according to well - established procedures. In line with OPP policy, HED estimates risks to population subgroups from pestic ide 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 USDA under the National Health and Nutrition Examination Survey , What We Eat in America, (NHANES/WWEIA) and are used in pesticide risk assessments for all registered food uses of a pesticide. These data are anal yz ed and categorized by subgroups based on age, season o f 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 and 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 and expertise to the development of specialized software and models that consider exposure to bystanders and farm workers as well as lifestyle and traditional dietary patterns among specific subgroups. **4.0 Hazard**  **Characterization and Dose -**  **Response Assessment 4.1**  **Toxicology Studies Available for Analysis**Fenamidone Human Health Risk Assessment DP No. D409835

Page 10 of 36 The toxicology

database for f

enamidone is complete and sufficient for assessing the toxicity and characterizing the hazard of fenamidone . The toxicology studies for fenamidone are summarized in Appendix A. No new toxicity and/or metabolism data have been received since the last risk assessment. However, a data waiver for the subchronic inhalation toxicity study was granted b y the Hazard and Science Policy Council (HASPOC ; TXR # 0056828 ) . The database includes the following studies:

 Subchronic: 21 - day

dermal toxicity

(rabbit); 90 - day

oral toxicity

(rat, mouse, and dog)  Developmental toxicity : developmental toxicity (rat); developmental toxicity (rabbit)  Reproduction: 2 - generation reproduction study (rat)  Chronic: combined oral chronic toxicity /carcinogenicity

(rat); carcinogenicity

(mouse); chronic oral toxicity

(dog)  Neurotoxicity : acute neurotoxicity (rat); subchronic neurotoxicity (rat); developmental neurotoxicity

(rat)  Other: immunotoxicity study (rat); dermal penetration (rat); mutagenicity battery ; metabolism (rat) The studies available for consideration of fenamidone toxicity provide a comprehensive database, with routes of administration that are consistent with potential exposure scenarios. Additionally , there are 90 - day oral toxicity

(rat) studies for the plant metabolites, RPA 412636 and 410193, and mutagenicity studies for the plant metabolites and isomers, RPA 412636, RPA 412708, and RPA 410193. **4.2 Absorption, Distribution, Metabolism, & Elimination (ADME)**  Fenamidone is an imidazole fungicide that is well absorbed and rapidl y excreted . At 3 mg/kg (single and repeated dosing), excretion occurs primarily in the urine and bile ; however, 50 - 68% of the dose is found in the feces (biliary excretion not measured) at 300 mg/kg. The high and sustained levels of radioactivity in the plasma suggested a hepatic first pass effect. The area under the curve (AUC ) was more than double in females compared to males at 300 mg/kg; however, elimination was slightly more rapid in females than males in the repeated dose and high dose groups while the elimination rate was similar in the low dose groups . Excluding the diges tive s ys tem , the highest concentrations of radioactivity were found in the liver and/or thy roid at T max and in the thy roid at T max/10 , regardless of sex or dose. Fenamidone is extensively metabolized. Phase 1 metabolism consisted predominantly of aromati c hydroxyl ation (RPA 409361) or N - oxidation of the N -phenylring (RPA 409352) followed by N - oxidation of both metabolites at the nitrogen bridge (RPA 408056). During phase II metabolism, glucuronidation and sulfation of these metabolites and other interme diates occurred. **4.2.1 Dermal Absorption**  Dermal penetration was evaluated in MRID 45386111 and was determined to be approximate ly 10% using the EPA protocol for 10 hours of exposure.Fenamidone Human Health Risk Assessment DP No. D409835

Page 11 of 36 **4.3 Toxicological Effects**  F enamidone is a fungicide that is absorbed b y leaves and roots . The exact mode of action has not ye t been elucidated , but it is known that fenamidone inhibits mitochondrial cell respiration b y blocking electron transport in Complex III 2 in targeted fungi. Generall y, decreased body weight and/or hepatotoxicity

provided the most sensitive endpoints in studies on rats, mice, and dogs . The target organs in subchronic toxicity studies are generally

the liver; rarely , the thy

roid or spleen were also affected at the LOAEL. Target organs for chronic studies were the liver in the mouse and dog and the liver and thy roid in rat. In the chronic toxicity rat study, the systemic NOAEL was based on diffuse C - cell hy perplasia of the thyroid in both sexes as the most sensitive indicator of toxicity . At higher doses, follicular cells and the liver were affected. The similarity

in the s ys temic NOAELs and the type of toxicity observed (primarily

liver) for the 90 - day rat studies with the parent and plant metabolites (RPA 412636, RPA 412708, and RPA 410193) demonstrated that, on a subchronic basis, the plant metabolites were not more toxic than the parent. Since the 2011 fenamidone risk assessment, two data evaluation records were revised to reflect current Agency

p olicies. Previously , the Agency review of the dermal toxicity study (MRID 45386110) resulted in a classification of unacceptable, guideline, because only two doses were tested and supposedl y toxicity was observed at the limit dose (1000 mg/kg/day) in male s. However, the noted toxicity (decreased body weight, body weight gain, and food consumption) is based on very

conservative measures. This assessment was revised, classified as acceptable, and the NOAEL is now the limit dose. Similarly , developmental toxicity was noted in the rat study (MRID 45386106) based on decreased body weights and increased incidences of incomplete skeletal ossification; however, the decreased fetal weight was likely related to the decreased maternal weight, and the delayed ossifi cation was considered to be related to the delayed growth. Therefore, the NOAEL was revised for developmental toxicity to be the limit dose (1000 mg/kg/day). Due to these changes, it is expected that the ToxSAC will be consulted during registration revie w for evaluation of these NO AE Ls as possible points of departure ; however, the current points of departure are considerabl y lower and are considered protective . No carcinogenic potential was observed in chronic studies in rat, mice, and dog, and HED cl assified fenamidone as “not likely” to be a human carcinogen by all relevant routes of exposure. All mutagenicity studies were negative for both the parent and plant metabolites (RPA 412636, RPA 412708, and RPA 410193), except the parent induced mutant co lonies at the tk locus and increased chromosomal aberrations in human peripheral blood . In the acute neurotoxicity study in rats, clinical sign s on Day 1 included staining of the anogenital region ; mucous in the feces; hunched posture; and unsteady gait. Inthe subchronic neurotoxicity in rats , marginal decrease s in brain weights were observed only in high dose males. Additionally , decreased brain weight occurred in the rat reproduction study . As a condition of

2 Handbook of Pesticide Toxicology, T wo - Volume Set: Principles and Agents , Volume 1 edited by Robert Krieger, p. 1207.Fenamidone Human Health Risk Assessment DP No. D409835

Page 12 of 36 registration, the Agency

previously

required the registrant to submit an abbreviated developmental neurotoxicity (DNT) study

in the Sprague Dawley

rat with measurements of brain weight and brain morphometric data. The purpose of this requirement was to confirm findings in the full DNT conducted in the Wistar rat. However, Bayer CropScience provided additional information on the DNT study on June 11, 2009; the anal ys is of the brain weight data addressed the Agency ’s concerns relative to dose difference, exposure duration, and strain difference. C onsequently , additional DNT data are no longer required for fenamidone. Fenamidone did not demonstrate any qualitative or quantitative increased susceptibility in the rat and rabbit developmental toxicity studies or the 2 - generation rat reproduction study . In rabbits and rats , there were no developmental effects up to the highest dose tested and in the presence of maternal toxicity . In the reproduction study in rats, decreased absolute brain weight in F2 female pups occurred at the same dose levels as de creased absolute brain weight in F1 parental females. There were no effects on fertility and other measured reproductive parameters. As specified in the new 40 CFR Part 158 data requirements, an immunotoxicity study on fenamidone was conducted. Immunosu ppression was demonstrated at the highest dose tested in the immunotoxicity

study ; however, the existing risk assessment points of departure are lower and are protective of this potential effect. Fenamidone has low acute toxicity via the oral, dermal, and inhalation routes (Categories III, III, and IV, respectivel y) . It is a moderate eye irritant (Category III) , but is not a dermal irritant (Category IV) or a dermal sensitizer. The acute oral assay tests indicated that female rats were more sensitive than male rats. The results of the acute toxicity studies for fenamidone are included in this assessment as Attachment 2. The toxicity profile for fenamidone is summarized in Attachment 3. **4.4 Safety**  **F actor for Infants and Children (FQPA Safety Factor)**  The fenamidone risk assessment team recommend s that the FQPA Safety Factor be reduced to 1X because there is an adequate toxicity database for fenamidone and exposure data are complete , or are estimated based on data that reasonably account for potential exposures. There is no evidence of susceptibility and there are no residual uncertainties concerning pre - or post natal toxicity . Acute, subchronic, and developmental neurotoxicity studies are available, and all endpoints used in this risk assessment are protective of neurotoxic effects. The dietary assessment s are based on reliable data and will not underestimate children’s exposure to fenamidone. Residential assessment is not necess ary for fenamidone as there are no residential uses. Quantitative residential assessment for fenamidone is not required as there are no residential uses and residential exposure is not anticipated. **4.4.1 Completeness**  **o f**  **the Toxicology Database**  The toxic ology

database for fenamidone is complete .Fenamidone Human Health Risk Assessment DP No. D409835

Page 13 of 36 **4.4.2 Evidence of N**  **eurotoxicity** In the acute neurotoxicity study in rats, clinical sign s on Day 1 included staining of the anogenital region , mucous in the feces , hunched posture , and unsteady gait. In the subchronic neurotoxicity in rats , marginal decrease s in brain weights were observed onl y in high dose males. Additionally , decreased absolute brain weights occurred in the rat reproduction study in adult F1 females and F2 female pups. In the submitted DN T study in Wistar rats, no maternal toxicity was observed at doses up to 4700 ppm (429 mg/kg/day). The offspring s ys temic toxicity manifested as decreased body weight (9 - 11%) and body weight gain (8 - 20%) during pre - weaning and decreased body weight (4 - 6%) during post - weaning. The offspring NOAEL was 1000 ppm (92.3 mg/kg/day). **4.4.3 Evidence**  **o f Sensitivity/Su**  **sceptibility in the Developing o r Young Animal**  Fenamidone did not demonstrate any qualitative or quantitative increased susceptibility in the rat and rabbit developmental toxicity studies or the 2 - generation rat reproduction study . In rabbits and rats, there were no developmental effects up to the highest dose tested and in the presence of maternal toxicity . In the reproduction study in rats, decreased absolute brain weight in F2 female pups occurred at the same dose levels as decreased absolute brain weight in F1 parental females. There were no effects on fertility and other measured reproductive parameters. **4.4.4 Residual**  **Uncertainty in the Exposure Datab**  **ase** Based on the available data and the selection of risk assessment endpoints that are protective of developmental and neurotoxic effects, there are no residual uncertainties with regard to pre and/or post - natal toxicity . For dietary assessments, maximum field trial residue values and 100 percent crop treated (% CT) were used. Drinking water estimates were based on conservative modeling assumptions. Dietary assessments included parent fenamidone and all metabolites of toxicological c oncern. As noted above, quantitative residential assessment for fenamidone is not required as there are no residential uses and residential exposure is not anticipated. **4.5 Toxicity Endpoint and Point of**  **D eparture Selections**  Since the 2011 risk assessment, two data evaluation records (a 28 - day dermal rat and developmental rat toxicity studies) were revised to reflect current Agency policies. Due to these changes, it is expected that the Toxicology Scientific Advisory

Council (ToxSAC) will be consulted during registration review of fenamidone. Based on the outcome of the ToxSAC, the need for a dermal risk assessment and the overall impact on risk assessment endpoints, points of departure (PODs), and uncertainty factors/safety factors (UF/SFs) may need to be reevaluated during registration review ; however, current points of departure are considerabl y lower and are protective. There have been no other changes to the prior dose - response assessment , and there have been no changes to the prior recommendations for combining routes of exposure and/or cancer classification. Table 4. 5 .1 contains a summary of the fenamidone points of departure for use in dietary and occupational/residential risk as sessments .Fenamidone Human Health Risk Assessment DP No. D409835

Page 14 of 36 **Table 4.**  **5 .1**  **. Toxicological Doses and Endpoints**  **for Fenamidone for Use in Dietary and Non**  **- Dietary Human Health Risk Assessments**  **Exposure Scenario**  **Point of Departure Uncertainty**  **Factors /**  **FQPA S F**  **RfD/Level of**

**Concern for Risk Assess**  **me nt**  **Study and Toxicological Effects** Acute Dietary (All populations) NOAEL = 125

mg/kg/day UF A= 10x

UF H= 10x FQPA SF= 1 Acute RfD = 1.25

mg/kg/day Acute PAD = 1.25 mg/kg/day **Acute Neurotoxicity in Rats** : LOAEL =

500 mg/kg/day based on urination, staining/soiling of the anogenital region, mucous in the feces, and unsteady gait in the females Chronic Dietary (All populations) NOAEL= 2.83

mg/kg/day UF A= 10x

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

0.0283 mg/kg/day Chronic PAD = 0.0283 mg/kg/day **2 Year Chronic Toxicity/Carcinogenicity**

**in Rats**  : LOAEL = 7.07/9.24 mg/kg/day (M/F) based on increase in severity of diffuse thyroid C - cell hyperplasia in both sexes Incidental Oral Short - Term (1 - 30 days) NOAEL = 10.4

mg/kg/day UF A= 10x

UF H= 10x FQPA SF= 1 Residential LOC

for MOE = 100 **90 -** **Day Feeding in Rats:** LOAEL = 68.27

mg/kg/day based on increased liver weights and incidences of ground glass appearance of the hepatocytes in males. Incidental Oral Intermediate Term (1 - 6 months) NOAEL = 5.45

mg/kg/dayUF A= 10x

UF H= 10x FQPA SF= 1 Residential LOC

for MOE <100 **2 -**  **Generation Reproduction Study in**

**Rats:** LOAEL = 89.2 mg/kg/day based on decreased absolute brain weight in female F1 adults and female F2 offspring. Dermal and Inhalation Short - Term (1 - 30 days) Oral NOAEL = 10.4

mg/kg/day 10% Dermal Absorption (DA) 100% Inhalation Absorption (IA) UF A= 10x

UF H= 10x FQPA SF= 1 Residential LOC

for MOE <100 Occupational LOC for MOE <100 **90 -** **Day Feeding in Rats:** LOAEL = 68.27

mg/kg/day based on increased liver weights and incidences of ground glass appearance of the hepatocytes in males. Dermal and Inhalation Intermediate Term (1

– 6 months) Oral NOAEL = 5.45

mg/kg/day 10% DA 100% IA UF A= 10x

UF H= 10x FQPA SF= 1 Residential LOC

for MOE <100 Occupational LOC for MOE <100 **2 -**  **Generation Reproduction Study in** 

**Rats** LOAEL = 89.2 mg/kg/day based on decreased absolute brain weight in female F1 adults and female F2 offspring. Dermal and Inhalation Long Term (>6 months) Oral NOAEL = 2.83

mg/kg/day 10% DA 100% IA UF A= 10x

UF H= 10x FQPA SF= 1 Residential LOC

for MOE <100 Occupational LOC for MOE <100 **2 -** **Year Chronic Toxicity/Carcinogenicity**

**in Rats:** LOAEL = 7.07/9.24 mg/kg/day [M/F] based on increase in severity of diffuse thyroid C - cell hyperplasia in both sexes. Cancer Based on the negative carcinogenic pot ential of fenamidone in rats and mice, HED classified fenamidone

as **“not likely”** to be a human carcinogen by all relevant routes of exposure. 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 ob served adverse effect level. LOAEL = lowest observed adverse effect level. UF = uncertainty factor. UFA = extrapolation from animal to human (intraspecies). UF H = potential variation in sensitivity among members of the human population (interspecies). FQPA SF = 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.Fenamidone Human Health Risk Assessment DP No. D409835

Page 15 of 36 **5.0 Dietary Exposure and Risk Assessment**  **5.1 Residues of**  **Concern Summary and Rationale** D3 91039 , A. LaMay, 7/07/11 , Residue Chemistry Chapter D314116, T. Bloem, 6/21/07, Human Health Risk Assessment D 410422 , K. Milian s, I. Negrón - Encarnación The nature of the residue in plants, animals, rotational crops and water is adequatel y understood based on previousl y submitted data detailed in the citation above. The residues of concern for tolerance setting and risk assessment purposes are summarized in **Table 5 .1**  . **Table 5 .1**  **Summary of Metabolites and Degradates to be included in the Risk Assessment and Tolerance Expression**  Matrix Residues included in Tolerance Expression Residues included in Risk Assessment

Plants Primary Crop

(excluding carrot) Fenamidone Fenamidone, RPA 717879 (DADK - Fen) , RP A 408056 (DA - Fen), and RPA 405862 Carrot 1 Fenamidone Fenamidone, and RP A 413255 Rotational Crop Fenamidone, RPA 717879 (DADK - Fen) Fenamidone, RPA 717879 (DADK - Fen) and RPA 408056 (DA - Fen) (free and conjugated) Livestock Ruminant Fenamidone, RPA 717879 (DADK - Fen) Fenamidone, RPA 717879 (DADK - Fen) and RPA 408056 (DA - Fen) (free and conjugated) Poultry Drinking Water Fenamidone, RP A - 412636, RPA - 412108, RPA - 411639, RPA - 413255, RPA - 409446, and RPA - 410995 1 For future field trials with the root vegetables, HED recommends that parent f enamidone, and the metabolites RPA 413255, RPA 717879 (DADK - Fen) and RPA 408056 (DA - Fen), and RPA 405862 are measured. **5 .2**  **Food Residue**  **Profile** D 410422 , K. Milians, I. Negrón - Encarnación Residue field trial studies were submitted to support the registration request for the use of fenamidone (formulated as Reason® 500 SC) on ginseng, and succulent beans (MRIDs 49052101, 49052102 and 49052103) . In addition, th e registrant proposed tolerances for bulb onion (subgroup 3 - 07A), and green onion (subgroup 3 - 07B) based on previously submitted data . Residues of fenamidone and /or its metabolites were quantifiable in/on all the proposed crops or representative commoditie s . Tolerances based on residues of parent fenamidone are recommended as 0.80 ppm for ginseng, 0.80 ppm for succulent bean (except cowpea), 0.20 ppmFenamidone Human Health Risk Assessment DP No. D409835

Page 16 of 36 for bulb onion (subgroup 3 - 07A) and 1.5 ppm for green onion (subgroup 3 - 07B). For dietary assessment, the residues of concern include parent fenamidone and the corresponding metabolites for each food matrix. The new residue levels that were included in the acute and chronic dietary

risk assessment and a description of how they were calculated are shown in **Tab le**  **5.2** . **Table 5.2**  **. Summ ary of New Residue Values Added to the Acute and Chronic Dietary Risk**  **Assessment Crop/Commodity**  ***** **Residue Value (ppm)**  **Comment**

Ginseng 1.19 The field crop studies monitored for residues of fenamidone and metabolites (RPA 717879, RPA 408056 and RPA 405862) in ginseng . RP A 413255 is included as a residue of concern for ginseng since it is in the same crop group as carrot, however, this analyte was not determined in the field trials for ginseng. Data from carrot was used to estimate a factor to account for RPA 413255 . The carrot metabolism study (469291101.der.doc) indicated that residues of RPA 413255 were 0.6x that of fenamidone (D314318, T. Bloem, 7 - Jun - 2007) . The ginseng field trials showed that residues of parent fenami done were 0.35 ppm, conjugated RPA 408056 were 0.024 ppm, RPA 717879 were <0.02 and RPA 405862 were 0.022 for combined residues of 0.98 ppm ( D409835 , K. Milians ). Using the 0.6x factor to account for RPA 413255 the combined residue level would be 1.19 pp m (0.98 ppm + 0.35 ppm x 0.21ppm). Snap Beans 0.52 The field crop studies monitored for residues of fenamidone and metabolites (RPA 717879, RPA 408056 and RPA 405862) in snap beans. Residues of fenamidone, RP A 405862 , RP A 717879, RPA 408056 in snap beans were 0.46, 0.02, 0.02 and 0.02 ppm, respectively, for a total residue of 0.52 ppm ( MRID 4905210 3; D409835 , K. Milians ) . Onion, bulb, subgroup 3 - 07A 0.186 Adequate data were previously submitted to establish tolerances on these subgroups based on residue data for bulb onions. A. LaMay (D391040, 07/7/11) Onion, bulb, subgroup 3 - 07 B 1.23 Adequate data were previously submitted to establish tolerances on this subgroup based on residue data for green onions. A. LaMay (D391040, 07/7/11) Tolerances are currentl y established for livestock commodities. The only feedstuffs associated with the proposed new uses are cowpea forage and hay which may

be fed to dairy

cattle consisting of up to 20% of the diet. Considering the residue levels of fenamidone, RPA 717879 and RPA 408056 in/on cowpea hay and forage a dietary

burden of 22.1 ppm is estimated which exceeds the highest dose tested in the lactating dairy cattle study

by 2.8 - fold. HED concludes that it is not possible to determine if revised milk and meat tolerances might be required as a result of feeding dairy

cattle cowpea forage and hay treated with fenamidone; therefore, HED does not consider the cowpea use adequately supported by residue data. A ruminant feeding study reflecting a concentration in the diet which brackets the newl y calculated dietary burden would be required to support a use on cowpeas. In the absence of an appropriate feeding study , HED recommend s to establish a tolerance for bean, succulent, except cowpea.Fenamidone Human Health Risk Assessment DP No. D409835

Page 17 of 36 **5.3 Water Residue Profile**  The drinking water estimate was provided b y the Environmental Fate and Effects Division (EFED) and was incorporated directly into the acute and chronic dietary risk assessments (James K. Wolf, D409837 , 09/18/13). Monitoring data are not available for residues of fenamidone and its metabolites in water; therefore , EFED has provided modeled values for ground and surface water. The modeled EDWCs (estimated drinking water concentrations) are reported for parent and its degradation products that were identified as residues of concern in drinking water, RPA - 41 2636, RPA 412108, RPA - 411639, RPA - 413255, RPA - 409446, and RPA - 410995 . The drinking water EDWCs recommended for use in the human health dietary risk assessment are those estimated for groundwater. The highest daily total fenamidone residue concentratio n in shallow groundwater estimated by PRZM - GW is 207μg/L and the average concentration after breakthrough was 139 μg/L for the Central Sands Region of Wisconsin from 30 years of continuous use. These estimates represent potential exposure to private drinking water well in a highl y vulnerable pesticide use area where numerous pesticide residues have been detected in groundwater. For both the acute and chronic dietary anal ys is, HED used the maximum ground water EDWC of 207 μg/L ( **0.207 ppm**), since it is the highest EDWC reported for fenamidone. **Table 5. 3**  **Summary of Estimated Surface Water and Groundwater Concentrations**

**for Fenamidone.**  Scenario Surface Water Conc., ppb a Groundwater Conc., ppb b Ac ute 41.7 207 Chronic (non - cancer) 11.9 Chronic (cancer) 5.99 a From the Tier II PRZM - EXAMS - Index Reservoir model. b From the PRZM - GW mo del. USEPA, 2013, J. Wolf, D409837 . **5.4 Dietary Risk Assessment**  K. Milians, D416496 **5.4.1 Description of Residue Data Used in Dietary Assessment**  The residues of concern for dietary assessment include parent fenamidone and the corresponding metabolites for each food matrix as specified in Table 5.1 . For the food commodities associated with proposed new uses, the residue levels that were included in the acute and chronic dietary risk assessment and a description of how they were calculated are shown in Table 5.2 .Fenamidone Human Health Risk Assessment DP No. D409835

Page 18 of 36 **5.4.2 Percent Crop Treated Used in Dietary Assessment**  For all commodities (existing and proposed uses) , 100 percent crop treated estimates were used in the acute and chronic dietary risk assessments . **5.4.3 Acute Dietary Risk Assessment**  An acute dietary

risk assessment was conducted which used maximum field trial residue values, assumed 100 percent crop treated (% CT) for all comm odities, incorporated DEEMTM default processing factors for many processed commodities and included modeled drinking water estimates. The estimated exposure (food and water) to the U.S. population from the existing and proposed new uses of fenamidone resulted in an estimated risk equivalent to 3% of the acute population adjusted dose (aPAD) at the 95 th percentile. The most highly exposed subpopulation was children 1 - 2 years with an estimated exposure equivalent to 5 % of the aPAD at the 95 th percentile. **5.4.4 Chronic Dietary Risk Assessment**  A chronic dietary

risk assessment was conducted which used maximum field trial residue values, assumed 100 % CT for all commodities, incorporated DEEMTM default processing factors for many processed commodities and inc luded modeled drinking water estimates. The estimated exposure (food and water) to the U.S. population from the existing and proposed new uses of fenamidone resulted in an estimated risk equivalent to 53 % of the chronic population adjusted dose (cPAD). The most highl y exposed subpopulation was children 1

– 2 years with an estimated exposure equivalent to 89 % of the cPAD. **5.4.5 Cancer Dietary Risk Assessment**  Fenamidone is not likel y to be a human carcinogen; therefore a cancer dietary risk assessment is not required for this chemical. **5.4.6 Summary Table**  The results of the acute and chronic dietary exposure anal ys is are reported in the summary table below ( **Table 5.4.6**  ). **Table 5.4.6 . Summary of Dietary**  **(Food and Drinking Water) Exposure and Risk**  **for Fenam idone**  **Population Subgroup Acute Dietary**  **(95th Percentile) 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 0.042 3.4 0.015 53 N/A N/A All Infants (< 1 year old) 0.049 3.9 0.020 69 Female 13 - 50 years old 0.044 3.5 0.015 51Fenamidone Human Health Risk Assessment DP No. D409835

Page 19 of 36 **Table 5.4.6 . Summary of Dietary**  **(Food and Drinking Water) Exposure and Risk**  **for Fenam idone**  **Population Subgroup Acute Dietary**  **(95th Percentile) Chronic Dietary**  **Cancer Dietary**  **Exposure (m**  **g/kg/day) % aPAD** * **Dietary Exposure**  **(m g/kg/day)**  **% cPAD*** **Dietary Exposure**  **(m g/kg/day)**  **Risk** Children 1 - 2 years old **0.059 4.8**  **0.025 89**  Children 3 - 5 years old 0.058 4.7 0.023 80 Children 6 - 12 years old 0.035 2.8 0.015 52 Youth 13 - 19 years old 0.031 2.5 0.011 39 Adults 20 - 49 years old 0.042 3.4 0.014 51 Adults 50+ years old 0.044 3.5 0.015 52 Females 13 - 49 years old 0.044 3.5 0.015 51 N/A is “not applicable”. Populations with highest exposure are shown in bold. * PAD = population adjusted dose. **6.0 Residential (Non**  **- Occupational) Exposure/Risk Characterization**  Based on: M. Lloyd, **Fenamidone.** Occupational and Residential Exposure Assessment for a Proposed Use on Succulent Beans, Ginseng, and Bulb Vegetables. D416497 . There are no exi sting or proposed uses of fenamidone that result in residential exposure; therefore, quantitative residential handler and post - application exposure and risk assessments were not conducted for fenamidone. **6. 1**  **Residential Bystander Post**  **- application**  **Inhalation Exposure** Based on the Agency's current practices, a quantitative post - application inhalation exposure assessment was not performed for fenamidone at this time primarily because of the low acute inhalation toxicity

(Toxicity Category III and IV), and low vapor pressure (2.60 x 10 - 9 mm Hg at 20 °C 3 ). However, there are multiple potential sources of post- application inhalation exposure to individuals performing post - application activities in previously treated fields. These potential sources inc lude volatilization of pesticides and resuspension of dusts and/or particulates that contain pesticides. The Agency sought expert advice and input on issues related to volatilization of pesticides from its Federal Insecticide, Fungicide, and Rodenticide A ct Scientific Advisory Panel (SAP) in December 2009, and received the SAP’s final report on March 2, 2010 4 . The Agency is in the process of evaluating the SAP report as well as available post - application inhalation exposure data generated by the ARTF and m ay , as appropriate, develop policies and procedures, to identify

the need for and, subsequently , the way to incorporate occupational post application inhalation exposure into the Agency's risk assessments. If new policies or procedures are put into place, the Agency may revisit the need for a quantitative occupational post - application inhalation exposure assessment for fenamidone.

3 Reference: MRID 45385711 4 Available: http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.htmlFenamidone Human Health Risk Assessment DP No. D409835

Page 20 of 36 **6. 2**  **Spray Drift** Spray drift is always a potential source of exposure to residents nearby to spraying operations. This is particularly

the case with aerial application, but, to a lesser extent, could also be a potential source of exposure from the ground application method employed for fenamidone . The Agency has been working with the Spray Drift Task Force, EPA Regional Offices and State Lead Agencies for pesticide regulation and other parties to develop the best spray drift management practices (see the Agency ’s Spray Drift website for more information at http://www.epa.gov/opp00001/factsheets/spraydrift.htm). On a chemical by chemical basis, the Agency is now requiring interim mitigation measures for aerial applications that must be placed on product labels/labeling. The Agency has completed its evaluation of the new database submitted by

the Spray

Drift Task Force, a members hip of U.S. pesticide registrants, and is developing a policy

on how to appropriatel y apply 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 risks associated with drift. The potential for spray drift will be quantitatively evaluated for each pesticide during the Registration Review process which ensures that all uses for that pesticide will be considered concurrentl y. **7.0 Aggregate Exposure/Risk Characterization**  There are no existing or proposed uses which result in residential exposures; therefore, aggregate risk assessments should consider exposure from food and water only . Since the dietary exposure anal ys is included both food and drinking water estimates, the exposure and risk estimates presented in Sections 5.4.3 and 5.4.4 represent aggregate acute and aggregate chronic exposure and risk, respectivel y. There are no acute or chronic aggregate risks of concern for the existing and proposed uses of fenamidone. **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 as to fenamidone and any

other substances and fenamidone does not appear to produce a toxic metabolite produced b y other substances. For the purposes of this tolerance action, therefore, EPA has not assumed that fenamidone has a common mechanism of toxicity with other substances. For information regarding EPA’s efforts 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/.Fenamidone Human Health Risk Assessment DP No. D409835

Page 21 of 36 **9.0 Occupational Exposure/Risk Characterization**  Based on: M. Lloyd, **Fenamidone.** Occupational and Residential Exposure Assessment for a Proposed Use on Succulent Beans, Ginseng, and Bulb Vegetables. D416497 **9.1 Short** **- /Intermediate**  **- Handler Risk**  For fenamidone , based on the proposed use s , short - and intermediate - term exposures are expected for occupational handlers readying and applying foliar agricultural applications. The occupational handler exposure and risk estimates indicate that the short- and intermediate - term dermal and inhalation combined MOEs are not of concern to HED (i.e., MOE > 100 ) at the baseline level of exposure. For the purposes of this memo, a screening application rate of 0.267 lbs ai/A ( i.e., the maximum proposed single application rate) was used to quantitatively assess occupational handler risk estimates. The proposed lab el requires chemical resistant gloves be worn for occupational handlers. With the label prescribed PPE, all the occupational handler exposure scenarios result in combined dermal and inhalation MOE s of 180 or greater . Table s 9.1.1 and 9.1.2 present a summary of the short - and intermediate - term occupational handler risks for occupational handler scenarios involving the proposed uses of fenamidone .Fenamidone Human Health Risk Assessment DP No. D409835

Page 22 of 36 **Table 9.1.1 Short -**  **Term Occupational Exposure and Risk Estimates for Fenamidone** . **All estimates are based on PPE: Baseline or Single Layer with Gloves/No Respirator.**  Exposure Scenario Crop or Target Dermal Unit Exposure (ug/lb ai) 1 Inhalation Unit

Exposure (ug/lb ai) 1 Maximum

Application Rate (lb ai/A) 2 Amount

Treated (A) 3 Dermal Inhalation Total baseline unit exposures No respirator Dose (mg/kg/day) 4 MOE 5 Dose (mg/kg/day) 6 MOE 7 MOE 8 Mixer/Loader M/L liquids for aerial/chemigation Succulent beans/ginseng/ bulb vegetables 220 0.22 0.27 350 0.0258 400 0.000256 41,000 400 M/L for groundboom application Succulent beans/ginseng/ bulb vegetables 220 0.22 0.27 80 0.00588 1,800 0.0000585 180,000 1,800 Applicator Liquid sprays – aerial (EC) Succulent beans/ginseng/ bulb vegetables 2.08 0.0049 0.27 350 0.000243 43,000 0.00000573 1,800,000 42,000 Liquid sprays

– groundboom Succulent beans/ginseng/ bulb vegetables 78.6 0.34 0.27 80 0.0021 5,000 0.000090 110,000 4,800 Flagger Li quid, Flagger, Ag crops Succulent beans/ginseng/ bulb vegetables 11 0.35 0.27 350 0.00129 8,100 0.000409 25,000 6,100 1 Exposure Science Advisory Council Unit Exposure Surrogate Guide (level of mitigation: Baseline clothing, no respirator). 2 Based on proposed label (Reg. No. #M -445929 - 01 - 1 [to be included on EPA Reg. No. 264 - 695). 3 Exposure Science Advisory Council Policy #9. 4 Dermal Dose = Dermal Unit Exposure (ug/lb ai) x Conversion Factor (0.001 mg/ug) x Application Rate (lb ai/A) x Amount Treated (A/day) x DAF (10%) / BW (80 kg [ST] / 69 kg [IT). 5 Dermal MOE = Dermal NOAEL (10.4 (ST)/5.45 (IT) mg/kg/day)/Dermal Dose (mg/kg/day). LOC = 100 6 Inhalation Dose = I

nhalation Unit Exposure (ug/lb ai) x Conversion Factor (0.001 mg/ug) x A pplication Rate (lb ai/A) x Amount Treated (A/day) / BW (80 kg [ST] / 69 kg [IT]).). 7 Inhalation MOE = I

nhalation NOAEL (10.4 (ST)/5.45 (IT mg/kg/day)/ I nhalation Dose (mg/kg/day). LOC = 100 8 Total MOE = 1/(1/Dermal MOE + 1/I nhalation MOE). LOC = 100Fenamidone Human Health Risk Assessment DP No. D409835

Page 23 of 36 **Table 9.1.2 Intermediate -**  **Term Occupational Exposure and Risk Estimates for Fenamidone** . **All estimates are based on PPE: Baseline/No Respirator.**  Exposure Scenario Crop or Target Dermal Unit Exposure (ug/lb ai) 1 Inhalation Unit

Exposure (ug/lb ai) 1 Maximum

Application Rate 2 Amount

Treated 3 Dermal Inhalation Total baseline unit exposures No respirator Dose (mg/kg/day) 4 MOE 5 Dose (mg/kg/day) 6 MOE 7 MOE 8 Mixer/Loader M/L liquids for aerial/chemigation Succulent beans/ginseng/ bulb vegetables 220 0.22 0.27 350 0.299 18 0.0297 18000 180 M/L for groundboom application Succulent beans/ginseng/ bulb vegetables 220 0.22 0.27 80 0.00681 80 0.0000678 80000 800 Applicator Liquid sprays

– aerial (EC) Succulent beans/ginseng/ bulb vegetables 2.08 0.0049 0.27 350 0.00281 1900 0.00000664 820000 1900 Liquid sprays - groundboom Succulent beans/ginseng/ bulb vegetables 78.6 .34 0.27 80 0.0243 220 0.0000133 410000 220 Flagger Li quid, Flagger, Ag crops Succulent beans/ginseng/ bulb vegetables 11 .35 .27 350 0.0149 370 0.000474 11000 360 1 Exposure Science Advisory Council Unit Exposure Surrogate Guide (level of mitigation: Baseline clothing, no respirator). 2 Based on proposed label (Reg. No. #M - 445929 - 01 - 1 [to be included on EPA Reg. No. 264 - 695). 3 Exposure Science Advisory Council Policy #9. 4 Dermal Dose = Dermal Unit Exposure (ug/lb ai) x Conversion Factor (0.001 mg/ug) x Application Rate (lb ai/A) x DAF (10%) / BW (80 kg [ST] / 69 kg [IT]). 5 Dermal MOE = Dermal NOAEL (10.4 (ST)/5.45 (IT) mg/kg/day)/Dermal Dose (mg/kg/day). LOC = 100 6 Inhalation Dose = I

nhalation Unit Exposure (ug/lb ai) x Conversion Factor (0.001 mg/ug) x Application Rate (lb ai/A) / BW 80 kg [ST] / 69 kg [IT]). 7 Inhalation MOE = I

nhalation NOAEL (10.4 (ST)/5.45 (IT mg/kg/day)/ I nhalation Dose (mg/kg/day). LOC = 100 8 Total MOE = 1/(1/Dermal MOE + 1/I nhalation MOE). LOC = 100Fenamidone Human Health Risk Assessment DP No. D409835

Page 24 of 36 HED has no data to assess exposures to pilots using open cockpits. The only data available is for exposure to pilots in enclose d cockpits. Therefore, risks to pilots are assessed using the engineering control (enclosed cockpits) and baseline attire (long - sleeve shirt, long pants, shoes, and socks); per the Agency ’s Worker Protection Standard stipulations for engineering controls, pilots are not required to wear protective gloves for the duration of the application. With this level of protection, there are no risk estimates of concern for applicators. **9.2 Short** **- /Intermediate**  **- Post** **- Application**  **Risk 9.2.1**  **Dermal Post -**  **application Risk**  Short - term post - application dermal MOEs (Table 9.2.1 ) range from 280 (hand weeding bulb vegetables) to 11,000 (hand weeding ginseng and succulent beans ). Intermediate - term MOEs (Table 9.2.2 ) range from 130 (hand weeding bulb vegetables) to 4,900 (h and weeding ginseng and succulent beans, and irrigating, scouting, thinning, weeding immature plants for succulent beans. Occupational post - application MOEs for the exposure scenario do not exceed HED’s level of concern (MOEs > 100) for both short - and intermediate - term exposures with baseline dermal PPE. Chemical - specific dislodgeable foliar residue data are available for fenamidone and w ere used to estimate the post - application risk . The available data are translated from a DFR study conducted on cantaloupe. The proposed application rate for bulb vegetables is identical to the one used in the cantaloupe DFR study . The proposed application rates for ginseng and succulent beans are 1.5x higher than the available DFR data. The effect of using a higher rate for each application (vs. 0.178 lb ai/A used in the study) on the DFR levels is not known. However, HED recommends the use of this DFR study to provide a Tier 1 screening level estimate of fendamidone DFR residues on the proposed crops . Tables 9 .2 . 1 and 9 .2. 2 present the short - and intermediate - term post - application dermal exposures and risk estimates for workers reentering treated fields. **Table 9.2.1. Short -**  **Term Occupational Post -**  **application Dermal Exposures and Risks for Fenamidone Crop**  **Application**

**Rate (lb ai/A)**  **Exposure Potential: Work**

**Activity Transfer** 

**Coefficient 1**  **(cm 2** **/hr) DAT**  **2 DFR** **t**

**(μg/cm 2**  **) 3**  **Daily Dose**

**(m g/kg/day)**  **4 MOE**  **5** Ginseng 0.27 Hand weeding 70 0 1.34 0.001 11,000 Scouting 210 0.003 3,700 Hand set irrigation 1,900 0.026 410 Succulent beans 0.27 Hand weeding 70 0 1.34 0.001 11,000 scout mature plants 210 0.003 3,700 Hand harvesting 1100 0.015 700 Hand set irrigation 1900 0.026 410 Bulb Vegetables 0.18 Scouting 1400 0 0.88 0.012 1400 Hand set irrigation 1900 0.88 0.017 620 Hand weeding 4200 0.88 0.037 280Fenamidone Human Health Risk Assessment DP No. D409835

Page 25 of 36 **1** Transfer coefficient from Science Advisory Council for Exposure: Policy Memo #003 “Agricultural Transfer Coefficients”. **2** Day after treatment assuming REI of only 12 hours observed. **3** DFR = derived from MRID 45386005; See ORE memo for additional detail **4** Daily Dose = DFR (μg/cm2 ) * Tc (cm2/hr) * (1 mg/1000 μg) * ET (8 hrs/day) * DA (10% dermal absorption) / body weight (80 kg) **5** MOE = PoD (NOAEL of 10.4 mg/kg/day) / Daily Dose (mg/kg/day) **Table 9.2.2 Intermediate -**  **Term Occupational Post -**  **application Dermal Exposures and Risks for Fenamidone**  **Crop Application** 

**Rate (lb ai/A)**  **Exposure Potential: Work**

**Activity Transfer** 

**Coefficient 1**  **(cm 2** **/hr) DAT**  **2 DFR** **t**

**(μg/cm 2**  **) 3**  **Daily Dose**

**(m g/kg/day)**  **4 MOE**  **5** Ginseng 0.27 Hand weeding 70 0 1.34 0.001 4,900 Scouting 210 0.003 1,600 Hand set irrigation 1,900 0.03 180 Succulent beans 0.27 Irrigate, scout, thin, weed immature plants 70 0 1.34 0.001 4,900 Irrigate, scout mature plants 210 0.003 1,600 Hand harvesting 1100 0.017 310 Hand set irrigation 1900 0.03 180 Bulb Vegetables 0.18 Scouting 1400 0 0.88 0.014 380 Hand set irrigation 1900 0.88 0.019 280 Hand weeding 4200 0.88 0.043 130 **1** Transfer coefficient from Science Advisory Council for Exposure: Policy Memo #003 “Agricultural Transfer Coefficients”. **2** Day after treatment assuming REI of only 12 hours observed. **3** DFR = derived from MRID 45386005; See ORE memo for additional detail **4** Daily Dose = DFR (μg/cm2 ) * Tc (cm2/hr) * (1 mg/1000 μg) * ET (8 hrs/day) * DA (10% dermal absorption) / body weight (69 kg) **5** MOE = PoD (NOAEL of 5.45 mg/kg/day) / Daily Dose (mg/kg/day) **Restricted Entry Interval** The restricted entry

interval (REI) is based on the acute toxicity of fenamidone, which is classified as Category

III for acute dermal toxicity and for eye irritation potential, and Category IVfor skin irritation potential. Fenamidone is not a dermal sensiti zer. Under the Worker Protection Standard (WPS) for Agricultural Pesticides, the default restricted- entry interval is 12 hours for active ingredients classified as acute toxicity categories III or IV for these routes of entry . Since the post - applicatio n risk is not a concern on Day 0 (12 hours following application), the restricted entry

interval (REI) is based on the acute toxicity of fenamidone technical material. Based on fenamidone’s classification as Toxicity Categories III/ IV, this chemical require s a 12 hour REIunder 40 CFR 156.208 (c) (2) (iii). The 12 - hour REI, which currently appears on the proposed label, is adequate for the proposed uses.Fenamidone Human Health Risk Assessment DP No. D409835

Page 26 of 36 **9.2.2 Inhalation**  **Post -**  **application Risk**  Based on the Agency's current practices, a quantitative post - application inhalation exposure assessment was not performed for fenamidone at this time primarily because of the low acute inhalation toxicity

(Toxicity Category III and IV), and low vapor pressure (2.60 x 10 - 9 mm Hg at 20 °C 5 ). However, there are multiple potential sources of post- application inhalation exposure to individuals performing post - application activities in previously treated fields. These potential sources include volatilization of pesticides and resuspension of dusts and/or particulates that contain pesticides. 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 6 . The Agency is in the process of evaluating the SAP report as well as available post - application inhalation exposure data generated by the ARTF and may , as appropriate, develop policies and procedures, to identify

the need for and, subsequently , the way to incorporate occupational post application inhalation exposure into the Agency's risk assessments. If new policies or procedures are put into place, the Agency may revisit the need for a quantitative occupational post - application inhalation exposure assessment for fenamidone. Although a quantitative occupational post - application inhalation exposure assessment was not performed, an inhalation exposure assessment was perfor med for occupational/commercial handlers. Handler exposure resulting from application of pesticides outdoors is likely to result in higher exposure than post - application exposure. Therefore, it is expected that these handler inhalation exposure estimates would be protective of most occupational post - application inhalation exposure scenarios . As a result, only dermal exposures were evaluated in the post application worker assessment. **10.0 References**  K. Milians, 2013. DP 416496 , Acute and Chronic Aggregate Dietary (Food and Drinking Water) Exposure and Risk Assessments to Support New Uses and Tolerances on Ginseng, Succulent Beans, Bulb Onion (Subgroup 3 - 07A), and Green Onion (Subgroup 3 - 07B). K. Milians, I . Negrón - Encarnación, 2013. DP 410422 . Residu e Chemistry Summary

Document to Support New Uses and Tolerances on Ginseng, Succulent Beans, Bulb Onion (Subgroup 3 - 07A), and Green Onion (Subgroup 3 - 07B). Summary of Analy tical Chemistry

and Residue Data. J. K. Wolf, 2013, D409837, D415146. Drinking Water Assessment for the Proposed New Use s on Potato Seed, Ginseng, Bulb Onion (Crop Subgroup 3 - 07A), Green Onion (Crop Subgroup 3 - 07B), and Succulent Beans for Reason ® 500 SC (44.4% fenamidone) (EPA Reg. No. 264 - 695) and Fenamidone Technical EPA Reg. No. 264 - 693) . CAS Name: ( 5 S ) - 3,5 - dihydro - 5 - methyl - 2 - (methylthio) - 5 -phenyl - 3 - (phenyl amino) - 4H - imidazol - 4 - one

5 Reference: MRID 45385711 6 Available: http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.htmlFenamidone Human Health Risk Assessment DP No. D409835

Page 27 of 36 M. Lloyd, 2013 . D416497. Fenamidone. Occupational and Residential Exposure Assessment for a Proposed Use on Succulent Beans, Ginseng, and Bulb Vegetables. D416497.Fenamidone Human Health Risk Assessment DP No. D409835

Page 28 of 36 **A ppendix**  **A .**  **Toxicology Profile and Executive Summaries A.1**  **Toxicology Data Requirements** The requirements (40 CFR 158.340) for food use for fenamidone are in Table 1. Use of the new guideline numbers does not imply that the ne w (1998) guideline protocols were used. **Study Technical**  **Required Satisfied**  870.1100 Acute Oral Toxicity ................................ ....................... 870.1200 Acute Dermal Toxicity ................................ .................. 870.1300 Acute Inhalation Toxicity ................................ .............. 870.2400 Acute Eye Irritation ................................ ....................... 870.2500 Acute Dermal Irritation ................................ ................. 870.2600 Skin Sensitization ................................ .......................... yes yes yes yes yes yes yes

yes yes yes yes yes 870.3100 90 - Day

Oral Toxicity in Rodents ................................ .. 870.3150 90 - Day

Oral Toxicity in Nonrodents ............................. 870.3200 21/28 - Day Dermal Toxicity ................................ ........... 870.3250 90 - Day

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

Inhalation Toxicity ................................ ........... yes yes yes no no yes

yes yes NA NA 870.3700a Prenatal Developmental Toxicity (rodent) ..................... 870.3700b Prenatal Developmental Toxicity (nonrodent) ............... 870.3800 Reproduction and Fertility Effects ................................ . yes yes yes yes

yes yes 870.4100a Chronic Toxicity (rodent) ................................ .............. 870.4100b Chronic Toxicity (nonrodent) ................................ ........ 870.4200a Carcinogenicity (rat) ................................ ...................... 870.4200b Carcinogenicity (mouse) ................................ ................ yes yes yes yes yes

yes yes yes 870.5100 Mutagenicity

—Bacterial Reverse Mutation Test .......... 870.5300 Mutagenicity

—Mammalian Cell Gene Mutation Test .. 870.5375 Mutagenicity

— Structural Chromosomal Aberrations ... 870.5385 Mutagenicity

—Mammalian bone marrow chromosomal aberration test 870.53 9 5 Mutagenicity

—Mammalian erythrocyte micronucleus test yes yes yes yes yes yes

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

Neurotoxicity Screening Battery (rat) ............... 870.6300 Developmental Neurotoxicity ................................ ........ yes yes yes yes

yes yes 870.7485 Metabolism and Pharmacokinetics ................................ 870.7600 Dermal Penetration ................................ ........................ 870.7800 Immunotoxicity ................................ ............................. yes yes yes yes

yes yes a Although there were no guideline 870.5385 or 870.5300 studies submitted, there are mutagenicity studies which evaluate both somatic and germinal cells, which is considered sufficient to satisfy CFR requirements. Mutagenicity guideline studies included 870.5550, in addition to those listed above.Fenamidone Human Health Risk Assessment DP No. D409835

Page 29 of 36 **A.2 Toxicity Profiles**  **Table A.2.1. Acute Toxicity Profile**  **- Fenamidone**  **Guideline No.**  **Study Type MRID #**  **Results Toxicity**  **Category** 870.1100 Ac ute o ral 45386011 LD 50 = 2028 mg/kg (F) LD 50 > 5000 mg/kg (M) III 870.1200 Ac ute d ermal 45386012 LD 50 > 2000 mg/kg III 870.1300 Ac ute i nhalation 45386013 LC 50 > 2.1 m/L IV 870.2400 Ac ute eye irritation 45386015 mo derate irritant III 870.2500 Ac ute dermal irritation 45386014 non - irritating IV 870.2600 Dermal s ensitization 45386016 not a sensitizer not applicableFenamidone Human Health Risk Assessment DP No. D409835

Page 30 of 36 **Table A.2.2 Subchronic, Chronic**  **, and Other Toxicity Profile**  **a Guideline No./Study**  **Type MRID No. (year)/** 

**Classification /Doses Results**  870.3100a 90 - Day oral toxicity rodents with parent - rat 45386025 (1995) Acceptable, guideline M: 0, 2.94, 8.95, 29.68 , or 305.48 mg/kg/day F: 0, 3.40, 10.55, 35.39, or 337.19 mg/kg/day NOAEL = **29.68/35.39** mg/kg/day in males and females, respectively. LOAEL = **305.48/337.19** mg/kg/day in males and females, respec tively based on decreased body weights, body weight gains, and food consumption in males and females, enlargement and prominent germinal centers in the spleen in males, and periportal vacuolation and bile duct hyperplasia in the liver of males. 870.3100a 90 - Day oral toxicity rodents with parent - rat 45386026 (1997) Acceptable, guideline M: 0, 4.05, 10.41, 68.27, or 343.93 mg/kg/day F: 0, 4.81, 12.00, 83.33, or 380.68 mg/kg/day NOAEL = **10.41/12.00** mg/kg/day in males and females, respectively. LOAEL = **68.27 /83.33**  mg/kg/day in males and females, respectively based on increased liver weights and incidence of ground glass appearance of the hepatocytes (mostly centrilobular) in the males. 870.3100a 90 - Day oral toxicity rodents with the RPA 412636 plant metabolite

- rat 45386114 (1999) Acceptable, guideline M: 0, 6.4 2 , 32.86, or 162.18 mg/kg/day F: 0, 7.7 3 , 39.11, or 196.07 mg/kg/day NOAEL = **6.4 2**  **/7.7 3**  mg/kg/day in males and females, respectively. LOAEL = **32.86/39.11** mg/kg/day in the males and females, respectively based on increased liver weights, liver enlargement, centrilobular hepatocyte hypertrophy and vacuolation, and follicular epithelial height of the thyroid in males. 870.3100a 90 - Day oral toxicity rodents with RPA 410193 plant metabolite

- rat 45386119 (1999) Acceptable, guideline M: 0, 9.4, 93.3, or 977.9 mg/kg/day F: 0 , 11.5, 114.9, or 1089.7 mg/kg/day NOAEL = **9.4/11.5** mg/kg/day in males and females, respectively. LOAEL = **93.3/114.9** mg/kg/day in males and females, respectively based on liver enlargement and increased liver weights and cholesterol in the males and on incidences of centrilobular hepatocellular hypertrophy in the males and females. 870.3100b 90 - Day oral toxicity rodent s with parent - mo use 45386027 (1997) Acceptable, guideline M: 0, 11.31, 44.49, 220.17, or 1064.25 mg/kg/day F: 0, 13.70, 54.13, 273.86, or 1375.17 mg/kg/day NOAEL = **44.49/54.13** mg/kg/day in the males and females, respectively. LOAEL = **220.17/273.86** mg/kg/d ay in the males and females, respectively based on mild hepatotoxicity as evidenced by increased liver weights and incidences of pale liver and hepatic microvacuolation in the males and decreased cholesterol and increased incidence of prominent lobulation of the liver in the females. 870.3150b 90 - Day oral (capsule) toxicity non - rodents with parent

- dog 45386028 (1999) Acceptable, guideline M & F : 0, 10, 100, or 500 mg/kg/day NOAEL = **500** mg/kg/day for males and females (HDT) LOAEL = **not determined**

870.3200 28 - Day dermal toxicity with parent - rat 45386110 (1999) Acceptable, guideline M & F: 0 or 10 00 mg/kg/day NOAEL = **1000** mg/kg/day LOAEL = **not determined**Fenamidone Human Health Risk Assessment DP No. D409835

Page 31 of 36 **Table A.2.2 Subchronic, Chronic**  **, and Other Toxicity Profile**  **a Guideline No./Study**  **Type MRID No. (year)/** 

**Classification /Doses Results**  870.3700a Prenatal developmental with parent - rat 45386106 (1997) Acceptable, guideline F: 0, 25, 150, or 1000 mg/kg/day **Maternal** NOAEL = **150** mg/kg/day **Maternal** LOAEL = **1000** mg/kg/day based on decreased body weight gains and food consumption. **Developm ental**  NOAEL = **100 0**  mg/kg/day **Developm ental**  LOAEL = **not observed** 870.3700b Prenatal developmental with parent - rabbit 45386107 (1999) Acceptable, guideline F: 0, 10, 30, or 100 mg/kg/day **Maternal** NOAEL = **10** mg/kg/day **Maternal** LOAEL = **30** mg/kg/day based on increased liver weights. **Developm ental**  NOAEL = **100** mg/kg/day **Developm ental**  LOAEL = **not observed.** 870.3800 Reproduction and fertility effects with parent - rat 45400014 (1999) Acceptable, guideline M & F: 0, 60, 1000, or 5000 ppm M: 0, 4.04 , 68.6, or 343 mg/kg/day F: 0, 5.45, 89.2, or 446 mg/kg/day **Parental/System ic**  NOAEL = **4.04/5.45** mg/kg/day in males and in females **Parental/System ic**  LOAEL = **68.6/89.2** mg/kg/day in males and females based on decreased absolute brain weight in F1 females. **Reproductive/Offspring** NOAEL = **4.04/5.45** mg/kg/day in males and females. **Reproductive/Offspring** LOAEL = **68.6/89.2** based on decreased absolute brain weight in F2 female pups. 870.4100b Chronic toxicity (1 year) with parent - dog 45400012 (1999) Acceptable, guideline M & F: 0, 10, 100, or 10 00 mg/kg/day NOAEL = **100** mg/kg/day in males and females LOAEL = **1000** mg/kg/day in males and females based on increased liver weight, triglycerides, and biliary proliferation in males, and alkaline phosphatase activity in both sexes. 870.4300 Chronic/Carcinogenicity with parent - rat 45400011, 45400010, and 45386105 (1999) Acceptable, guideline M: 0, 2.83, 7.07, 47.68 , or 260.13 mg/kg/day F: 0, 3.63, 9.24, 60.93 , or 335.10 mg/kg/day NOAEL = **2.83/3.63** mg/kg/day in males and females, respectively. LOAEL = **7.07/9.24** mg/kg/day in males and females based on an increase in severity of diffuse thyroid C - c ell hyperplasia in both sexes. **Carcinogenic potential is considered negative.** 870.4200b Carcinogenicity with parent - mouse 45400013 (1999) Acceptable, guideline M: 0, 9.5, 47.5, 525.5, or 1100.2 mg/kg/day F: 0, 12.6, 63.8, 690.5, or 1393.2 mg/kg/day NOAEL = **47.5/63.8** mg/kg/day in males and in females, respectively LOAEL = **525.5/690.5** mg/kg/day in males and in females based on decreased body weight, weight gain, food efficiency, increased food consumption and absolute and relative (to body) liver weights and liver nuclear pleomorphism in both sexes. **Carcinogenic potential is considered negative.** 870.5100 Bacterial reverse mutation test with parent 45386029 (1996) Acceptable, guideline 0, 50, 100, 250, 500, 1000, or 2500 μg/plate (trial 1 +/- S9 and trial 2 +S9) and 0, 10, 25, 50, 100, 250, 500, or 1000 μg/plate (trial 2 - S9). There was no evidence of induced mutant colonies over background Salmonella typhimurium strains TA98, TA100, TA 102, TA1535, and TA1537 .Fenamidone Human Health Risk Assessment DP No. D409835

Page 32 of 36 **Table A.2.2 Subchronic, Chronic**  **, and Other Toxicity Profile**  **a Guideline No./Study**  **Type MRID No. (year)/** 

**Classification /Doses Results**  870.5100 Bacterial reverse mutation test with the RPA 412636 plant metabolite 45386115 (1999) Acceptable, guideline 0, 8, 40, 200, 1000, or 5000 μg/plate (trial 1) and 0, 312.5, 625, 1250, 2 500, or 5000 μg/plate (trial 2) ( +/ - S9 , both trials ) There was no evidence of induced mutant colonies over background in Salmonella typhimurium strains TA98, TA100, TA 1535, and TA1537 and Escherichia coli strain WP2 uvrA .

870.5100 Bacterial reverse mutation test with RPA 410193 plant metabolite 45386120 (1999) Acceptable, guideline 8, 40, 200, 1000, or 5000 μg/plate (trial 1, +/ - S9), 312.5, 625, 1250, 2500, or 5000 μg/plate (trial 2, - S9), and 62.5, 125, 250, 500, 1000, or 2000 μg/plate (trial 2, +S9). There was no evidence of induced mutant colonies over background in Salmonella typhimurium strains TA98, TA100, TA 1535, and TA1537 and Escherichia coli strain WP2 uvrA .

870.5100 Bacterial reverse mutation test (RPA 412708, S - enantiomer of RPA 408056 ) 45386124 (1999) Acceptable, guideline 8, 40, 200, 1000, or 5000 μg/plate (trial 1) and 51.2, 128, 320, 800, 2000, or 5000 μg/plate (trial 2) (+/- S9 , both trials ) There was no evidence of induced mutant colonies over background in Salmonella typhimurium strains TA98, TA100, TA 1535, and TA1537 and Escherichia coli strain WP2 uvrA .

870.5300 Mouse lymphoma cell/mammalian activation gene forward mutation assay (L5178Y hgprt) with RPA 412636 45386116 (1999) Acceptable, guideline 100, 200, 400, 800, or 1600 μg/mL (Trial 1) and 400, 800, 1200, or 1600 μg/mL (Trial 2) (+/- S9, both trials) RPA 412636 was non - mutagenic at doses up to the limit of solubility (1600 ug/mL) in both the presence and absence of S9 metabolic activation.

870.5300 Mouse lymphoma cell/mammalian activation gene forward mutation assay (L5178Y hgprt) with RPA 410193 (S - enantiomer of RPA 405862 ) 45386121 (1999) Acceptable, guideline 50, 100, 200, 400, or 800 μg/mL (Trial 1) and 100, 200, 400, or 800 μg/mL (Trial 2) (+/- S9, both trials) RPA 410193 was non - mutagenic at dos es up to the limit of solubility (800 ug/mL) in both the presence and absence of S9 metabolic activation.Fenamidone Human Health Risk Assessment DP No. D409835

Page 33 of 36 **Table A.2.2 Subchronic, Chronic**  **, and Other Toxicity Profile**  **a Guideline No./Study**  **Type MRID No. (year)/** 

**Classification /Doses Results**  870.5300 Mouse lymphoma cell/mammalian activation gene forward mutation assay ( tk locus ) with parent 45386101 (1999) Acceptable, guideline 12.5, 25, 50, 75, 100, 125, or 150 μg/mL (Trial 1 - S9); 50, 75, 100, 125, 150, 175, or 200 μg/mL (Trial 2 - S9); 3.125, 6.25, 12.5, 25, 37.5, or 50 μg/mL (Trial 1 +S9); and 6.25, 12.5, 18.75, 25, 31.25, 37.5, or 43.75 μg/mL (Trial 2 +S9) There was increased mutation frequency observed at ≥12.5 μg/mL in the presence of S9 - activation .

870.5375 In vitro mammalian cy togenetics (Chromosomal aberration assay in human peripheral blood) with parent 45386030 (1999) Acceptable, guideline 2.9 - 300 μg/mL with S9 - activation or 0.95 - 300 μg/mL without S9 - activation There was evidence of increased chromosome aberrations at 5.9 μg/mL or higher ( - S9) or 147 μg/mL or higher (+S9).

870.5395 In vivo mo use micronucleus with parent 45386104 (1999) Acceptable, guideline M & F: 0, 500, 1000, or 2000 mg/kg/day Fenamidone was negative for chromosomal aberrations in the cy togenetic assay when administered to CD - 1 mice up to the limit dose . 870.5395 In vivo mo use micronucleus with RPA 412636 45386117 (1999) Acceptable, guideline M: 0, 75, 1 50 , or 300 mg/kg/day RPA 412636 was not clastogenic in the mouse micronucleus test up to levels inducing bone marrow toxicity. 870.5395 In vivo mo use micronucleus with RPA 412708 45386125 (1999) Acceptable, guideline M: 0, 37.5, 75, or 150 mg/kg/day RPA 412708 was not clastogenic in the mouse micronucleus assay up to levels inducing bone marrow toxicity , clinical signs of toxicity, and mortality . 870.5395 In vivo mo use micronucleus with RPA 410193 45386122 (1999) Acceptable, guideline M: 0, 500, 1000 , or 2000 mg/kg/day RPA 410193 was not clastogenic in the mouse micronucleus assay when tested in CD - 1 mice up to the limit dose . 870.5550 Unscheduled DNA synthesis with parent 45386102 (1999) Acceptable, guideline 0.064, 0.32, 1.6, 8, 40, 200, 1000, or 5000 μg/mL (Trial 1) and 1.25, 2.5, 5, 10, 20, or 30 μg/mL (Trial 2) Fenamidone did not produce any evidence of unscheduled DNA synthesis, as determined by radioactive tracer procedures (nuclear silver grain counts), in rat primary hepatocyte cultures expo sed up to cytotoxic levels.Fenamidone Human Health Risk Assessment DP No. D409835

Page 34 of 36 **Table A.2.2 Subchronic, Chronic**  **, and Other Toxicity Profile**  **a Guideline No./Study**  **Type MRID No. (year)/** 

**Classification /Doses Results**  870.5550 Unscheduled DNA synthesis with parent 45386103 (1999) Acceptable, guideline M: 800 or 2000 mg/kg Fenamidone did not produce any evidence of unscheduled DNA synthesis, as determined by radioactive tracer procedures (nuc lear silver grain counts), in rat primary hepatocyte cultures exposed up to cytotoxic levels. 870.6200a Ac ute Neurotoxicity with parent - rat 45386108 (1999) Acceptable, guideline M & F: 0, 125, 500, or 2000 mg/kg NOAEL = **125** mg/kg/day LOAEL = **500** mg/kg/day based on urination, staining/soiling of the anogenital region, mucous in the feces, and unsteady gait in females. 870.6200b Subchronic neurotoxicity screening b attery with parent - rat 45386109 (2001) Acceptable, guideline M: 0 , 11.2, 73.5, and 392.3 mg/kg/day F: 0 , 12.7, 83.4, and 414.2 mg/kg/day NOAEL = **73.5/83.4** mg/kg/day in males and females, respectively. LOAEL = **392.3/414.2** mg/kg/day in males and females based on decreased absolute brain weight in males, and decreased body weight, weight g ains, and food consumption in both sexes. 870.6300 Developmental neurotoxicity study with parent - rat 46590001 (2005) Acceptable, guideline F: 0, 5.5, 23.2, 92.3, or 429 mg/kg/day **maternal** NOAEL ≥ **429** mg/kg/day **maternal** LOAEL **not determined offpsring**  NOAEL = **92.3** mg/kg/day **offspring** LOAEL = **429** mg/kg/day based on decreased body weight (9 - 11%) and body weight gain (8 - 20%) during pre weaning and decreased body weight (4 - 6%) during post weaning 870.7485 Metabolism and pharmacokinetics with parent - rat 45386112 (1999) Acceptable, guideline M & F: 3 or 300 mg/kg (single dose) or 3 mg/kg/day

(repeated dose) In a rat metabolism study with 14 C - labeled fenamidone, Sprague - Dawley rats received doses of 3 mg/kg (single, low dose), 3 mg/kg × 14 days (repeated low dose) and 300 mg/kg (high dose). Fenamidone was well absorbed and rapidly excreted, primarily in the urine and bile, at the low dose and repeated low

dose. At 300 mg/kg, biliary excretion was not measured, although fecal excretion was 50 - 68% of the dose. Tissue levels of radioactivity were primarily found in the liver at the single low

dose and in the thyroid in the repeated and high dose studies. Metabolite identification included RPA 408056 (racemic form of RPA 412708) and RPA 717 879 (racemic mixture of RPA 412636) . 870.7600 Dermal p enetration - rat 45386111 (1999) Acceptable, guideline M: 0, 2.7, 29, or 269 ug ai/cm 2 Dermal penetration approximated 10% using the EPA

protocol for 10 hours of exposure. 870.7800 Immunotoxicity - rat 48321101 (2010) Acceptable, guideline M: 0, 39.2, 117.8, or 387.4 mg/kg/day **systemic** NOAEL = **117.8** mg/kg/day **systemic** LOAEL = **387.4** mg/kg/day based on lower anti SRBC IgM response and decreased thymus weights **immunotoxicity** NOAEL = **117.8** mg/kg/day **immunotoxicity** LOAEL = **387.4** mg/kg/day based on lower anti - SRBC IgM response and decreased thymus weights; the NOAEL is 1500 ppm . a MRID 45424101 (OPPTS 870.3100a) was submitted, but a review could not be located. A study for OPPTS 870.5300 was submitted , but the MRID # and review could not be located. However, acceptable, guideline studies were available for each of these types of studies.Fenamidone Human Health Risk Assessment DP No. D409835

Page 35 of 36 **Appendix B**  **. Physical/Chemical Properties**  **Table B.1. Physicochem ical Properties of Technical Grade Fenamidone.**  Parameter Value Reference Melting point/range Pure: 137 °C, Technical: 135.5 °C MRID 45385708 pH 5.7 MRID 45385714 Density Pure: 1.290 g/mL MRID 45385708 Water solubility 0.0078 g/L at 20 °C MRID 45385712 Solvent solubility (under ambient conditions) 330 g/L in methylene chloride 250 g/L in acetone 106 g/L in ethyl acetate 86 g/L in acetonitrile 43 g/L in methanol 40 g/L in toluene 0.3 g/L in heptane MRID 45385712 Vapor pressure 2.60 x 10 - 9 mm Hg at 20 °C MRID 45385711 Dissociation constant, pKa Does not dissociate in the pH range of 1 - 13 MRID 45385714 Octanol/water partition coefficient, Log(KOW) 631 (2.8) MRID 45385713 UV/visible absorption spectrum Primary absorbance: 203 nm Secondary absorbance: 230 nm MRID 45385709Fenamidone Human Health Risk Assessment DP No. D409835

Page 36 of 36 **Appendix C. International Residue Limits Table** Table C . Summary of US and International Tolerances and Maximum Res idue Limits for Fenamidone (PC Code: 046679 ) Residue Definition : US Canada Mexico 2 Codex 40 CFR 180.579: Plants: fenamidone (4H - Imidazol - 4 - one, 3,5 - dihydro - 5 - methyl - 2 - (methylthio) - 5 -phenyl - 3 (phenylamino) - , (S) - ) Livestock: fenamidone (4H - imidazol - 4 - one, 3,5 - dihydro 5 - methyl - 2 - (methylthio) - 5 -phenyl - 3 - (phenylamino), (S) - ) and its metabolite RPA 717879 (DADK - Fen) ( 2,4 - imidazolidinedione, 5 - methyl - 5 -phenyl), expressed as parent compound Indirect or inadvertent residues: . fenamidone (4 - H imidazol - 4 - one, 3,5 - dihydro - 5 - methyl - 2 - (methlthio) - 5 - phenyl - 3 - (phenylamino, (S) - ) and its metabolite RPA 717879 (DADK- Fen) (2,4 - imidazolidinedione, 5 - methyl 5 -phenyl) (5 S ) - 3,5 - dihydro - 5 - methyl - 2 - (methylthio) - 5 - phenyl - 3 - (phenylamino) - 4 H imidazol - 4 - one None

Commodity 1 Tolerance (ppm) /Maximum Residue Limit (mg/kg) US Canada Mexico 2 Codex Ginseng 0. 8 0.15 ginseng roots 3 Beans, Succulent , except cow pea 0.8 Onion, bulb, subgroup 03 - 07A 0.20 0.2 Chinese, onions; Daylilies; dry bulb onions; fritillaria, bulbs; garlic; great - headed garlic; lilies; pearl onions, potato onions; serpent garlic, shallot bulbs onion, green, subgrou

p 03 - 07B 1.5 1.5 Beltsville bunching onions,

elegans hosta, fresh (Chinese chive leaves, chive leaves), fresh onions, fritillaria leaves, green onions, kurrats, lady's leek, leeks, macrostem onions, shallot leaves, tree onion tops, Welsh onion tops, wild leeks Com pleted: M. Negussie; 09/16/2013 1 Includes only commodities of interest for this action. Tolerance values should be the HED recommendations and not those proposed by the applicant. 2 Mexico adopts US tolerances and/or Codex MRLs for its export purposes. 3 Identical regulatory levels are recommended by EPA and PMRA as part of this joint review (0.08 ppm).