
                 UNITED STATES ENVIRONMENTAL PROTECTION AGENCY
                            WASHINGTON, D.C.  20460
                                                                      OFFICE OF
                                                            CHEMICAL SAFETY AND
\* MERGEFORMAT
                                                           POLLUTION PREVENTION

MEMORANDUM


Date: February 6, 2014

SUBJECT:	Fenamidone: Amended 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: D417654
Decision No.:  475185
Registration No.:  264-695
Petition No.:  3E8150
Regulatory Action:  Section 3 Registration
Risk Assessment Type:  Single Chemical
Case No.:  NA
TXR No.:  NA
CAS No.:  161326-34-7
MRID No.:  49052101, 49052102, and 49052103
40 CFR:  180.579


FROM:	Ideliz 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)

The risk previous risk assessment (D409835; 12/31/13) was amended to include additional information with regards to FQPA considerations.

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	21
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	36

1.0 Executive Summary

Fenamidone is a broad-spectrum foliar fungicide currently 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 Science) 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; rarely, the thyroid or spleen was also affected at the LOAEL.  In chronic 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 and neurotoxic effects, there are no residual uncertainties with regard to pre- and/or post-natal toxicity.  Therefore, the FQPA safety factor was reduced to 1X.  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 weights 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 points of departure are lower and are protective of this potential effect.  HED classified 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 eye irritant, 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 beans.  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 DEEM(TM) default processing factors for many processed commodities, and included modeled estimates for drinking water.  Parent fenamidone and the metabolites 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 only.  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.  The 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 currently 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	HED 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 HED.  However, 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, D410422.

2.2.1	Enforcement Analytical Method

The current tolerance enforcement method entitled, RPA 407213:  method 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 successful ILV (independent laboratory validation), as well as validation by the Agency on a number of commodities including potato, cucumber, cantaloupe, lettuce, onion, tomato (fruit, paste, and puree), spinach, and wheat (forage, hay, straw, grain, bran, flour, 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-Imidazol-4-one, 3,5-dihydro-5-methyl-2-(methylthio)-5-phenyl-3 (phenylamino)-,(S)-), in or on the commodities."

Table 2.2.2.  Tolerance Summary for Fenamidone.
Commodity
                     Established*/Proposed Tolerance (ppm)
                        HED-Recommended Tolerance (ppm)
                                   Comments 
                        (correct commodity definition)
Ginseng
                                      0.8
                                     0.80

Bean, succulent
                                      0.8
                                     0.80
Bean, succulent, except cowpea
Onion, bulb, subgroup 3-07A 
                                      0.2
                                     0.20

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

*Tolerances 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 feedstuffs. The dietary burden associated with uses on cowpea is not supported by an appropriate feeding study; therefore, uses on cowpea have to be excluded from succulent bean.  In addition, tolerances established in the 40 CFR 180.579 (see Table 2.2.2) for 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 by HED.

2.2.4	International Harmonization

Mexican and Codex MRLs have not been established for the commodities under consideration (Refer to Appendix C).  The recommended tolerance definition and levels for onion, bulb, subgroup 3-07A, and onion, green, subgroup 3-07B are harmonized with established Canadian Maximum Residue Limits (MRLs) for similar commodities.  Moreover, identical regulatory levels are being recommended by 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[(R)] 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 provided for the proposed new uses considered in this petition.


3.0	Introduction

3.1	Chemical Identity

Table 3.1  Test Compound Nomenclature
Chemical Structure

Empirical Formula
C17H17N3OS - 311.401
Common Name
Fenamidone
Company experimental name
RPA 407213
IUPAC name
(S)-l-anilino-4-methyl-2-methylthio-4-phenylimidazolin-5-one
CAS Name
5S)-3,5-dihydro-5-methyl-2-(methylthio)-5-phenyl-3-(phenylamino)-4H-imidazol-4-one
CAS Registry Number
161326-34-7
End-use product/EP
REASON[(R)] 500 SC fungicide, PCP# 27462
Chemical Class
Imidazole fungicide
Known Impurities of Concern
N/A


3.2	Physical/Chemical Characteristics

Fenamidone is moderately soluble in water (FAO, 2000) 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 by 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 (Refer to Table 3.3). The pre-harvest intervals (PHIs) 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.
                          Formulation [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[(R)] 500 SC fungicide, ground, aerial, chemigation
                                    264-695
                                  0.178-0.267
                                Not Specified 
                                     0.80
                                      14
                                  14 day RTI
                                Succulent Beans
Reason[(R)] 500 SC fungicide, ground, aerial, chemigation
                                    264-695
0.178-0.267
                                 Not Specified
                                     0.80
                                       3
                                   7 day RTI
                                Bulb Vegetables
Reason[(R)] 500 SC fungicide, ground, aerial, chemigation
                                    264-695
0.178
                                 Not Specified
                                     0.71
                                       7
                                 5-10 days RTI





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 fenamidone, 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 assessments have been previously 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 also considers the existing uses as well, particularly 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 assessment, 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/oepa/guidance/justice/eo12898.pdf.  As a part of every pesticide risk assessment, OPP considers a large variety of consumer subgroups according to well-established procedures.  In line with OPP policy, HED estimates risks to population subgroups from pesticide exposures that are based on patterns of that subgroup's food and water consumption, and activities in and around the home that involve pesticide use in a residential setting.  Extensive data on food consumption patterns are compiled by the 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 analyzed and categorized by subgroups based on age, season of the year, ethnic group, and region of the country.  Additionally, OPP is able to assess dietary exposure to smaller, specialized subgroups and exposure assessments are performed when conditions or circumstances warrant.  Whenever appropriate, non-dietary exposures based on home use of pesticide products and associated risks for adult applicators and for toddlers, youths, and adults entering or playing on treated areas post-application are evaluated.  Further considerations are currently 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

The toxicology database for fenamidone 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 by 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 rapidly 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 digestive system, the highest concentrations of radioactivity were found in the liver and/or thyroid at Tmax and in the thyroid at Tmax/10, regardless of sex or dose.  Fenamidone is extensively metabolized.  Phase 1 metabolism consisted predominantly of aromatic hydroxylation (RPA 409361) or N-oxidation of the N-phenyl ring (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 intermediates occurred.

4.2.1	Dermal Absorption

Dermal penetration was evaluated in MRID 45386111 and was determined to be approximately 10% using the EPA protocol for 10 hours of exposure. 


4.3	Toxicological Effects

Fenamidone is a fungicide that is absorbed by leaves and roots.  The exact mode of action has not yet been elucidated, but it is known that fenamidone inhibits mitochondrial cell respiration by blocking electron transport in Complex III in targeted fungi.  Generally, 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 thyroid 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 thyroid in rat.  In the chronic toxicity rat study, the systemic NOAEL was based on diffuse C-cell hyperplasia 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 systemic 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 policies.  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 supposedly toxicity was observed at the limit dose (1000 mg/kg/day) in males.  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 ossification 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 review for evaluation of these NOAELs as possible points of departure; however, the current points of departure are considerably lower and are considered protective.   

No carcinogenic potential was observed in chronic studies in rat, mice, and dog, and HED classified 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 colonies at the tk locus and increased chromosomal aberrations in human peripheral blood.

In the acute neurotoxicity study in rats, clinical signs 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 decreases in brain weights were observed only in high dose males.  Additionally, decreased brain weight occurred in the rat reproduction study.  As a condition of 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 analysis of the brain weight data addressed the Agency's concerns relative to dose difference, exposure duration, and strain difference.  Consequently, 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 decreased 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.  Immunosuppression 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, respectively).  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 Factor for Infants and Children (FQPA Safety Factor)

The fenamidone risk assessment team recommends 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 evidence of increased susceptibility in the Wistar rat.  For reasons that we have listed in Section 4.4.2, we believe that the risk assessment is protective of all populations.  Acute, subchronic, and developmental neurotoxicity studies are available, and all endpoints used in this risk assessment are protective of neurotoxic effects.  The dietary assessments are based on reliable data and will not underestimate children's exposure to fenamidone.  Residential assessment is not necessary 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 of the Toxicology Database

The toxicology database for fenamidone is complete.


4.4.2	Evidence of Neurotoxicity

In the acute neurotoxicity study in rats, clinical signs 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 decreases in brain weights were observed only 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 DNT study in Wistar rats, no maternal toxicity was observed at doses up to 4700 ppm (429 mg/kg/day).  The offspring systemic 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).  

These results indicated an increased susceptibility of offspring. The concern for the increased susceptibility observed in the DNT, however, is low because: 1) of the lack of  neurobehavioral or neuropathological changes in the offspring at any dose; 2) the endpoints used for the various risk assessment scenarios are much more sensitive than that of the decreased bodyweight of the offspring occurring at almost half the limit-dose (429 mg/kg/day); 3) the NOAELs of  10.4, 5.4 and 2.83 mg/kg/day used for short-, intermediate-and long term risk assessments, respectively, are considerably (9-45 fold) lower than the offspring NOAEL of 92.3 mg/kg/day in the DNT.

4.4.3	Evidence of Sensitivity/Susceptibility in the Developing or 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 Database

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 concern. 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 Departure 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 considerably 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 assessments.  
  

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 SF
                   RfD/Level of Concern for Risk Assessment
                        Study and Toxicological Effects
Acute Dietary
(All populations)
NOAEL = 125 mg/kg/day
UFA= 10x
UFH= 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
UFA= 10x
UFH= 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
UFA= 10x
UFH= 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/day-
UFA= 10x
UFH= 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)
UFA= 10x
UFH= 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
UFA= 10x
UFH= 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
UFA= 10x
UFH= 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 potential 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 observed adverse effect level.  LOAEL = lowest observed adverse effect level.  UF = uncertainty factor.  UFA = extrapolation from animal to human (intraspecies).  UFH = 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.


5.0	Dietary Exposure and Risk Assessment 

5.1	Residues of Concern Summary and Rationale
D391039, A. LaMay, 7/07/11, Residue Chemistry Chapter
D314116, T. Bloem, 6/21/07, Human Health Risk Assessment
D410422, K. Milians, I. Negrón-Encarnación

The nature of the residue in plants, animals, rotational crops and water is adequately understood based on previously 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), RPA 408056 (DA-Fen), and RPA 405862

Carrot[1]
Fenamidone
Fenamidone, and RPA  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, RPA-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 fenamidone, and the metabolites RPA 413255, RPA 717879 (DADK-Fen) and RPA 408056 (DA-Fen), and RPA 405862 are measured.


5.2	Food Residue Profile
D410422, K. Milians, I. Negrón-Encarnación

Residue field trial studies were submitted to support the registration request for the use of fenamidone (formulated as Reason[(R)] 500 SC) on ginseng, and succulent beans (MRIDs 49052101, 49052102 and 49052103). In addition, the 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 commodities.  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 ppm 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 Table 5.2.   

Table 5.2.  Summary 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.  RPA 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 fenamidone 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 ppm (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, RPA 405862, RPA 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 49052103; 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 3-07B
                                     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 currently 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 newly calculated dietary burden would be required to support a use on cowpeas.  In the absence of an appropriate feeding study, HED recommends to establish a tolerance for bean, succulent, except cowpea.


5.3	Water Residue Profile

The  drinking water estimate was provided by 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-412636, 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 concentration in shallow groundwater estimated by PRZM-GW is 207ug/L and the average concentration after breakthrough was 139 ug/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 highly vulnerable pesticide use area where numerous pesticide residues have been detected in groundwater.  For both the acute and chronic dietary analysis, 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
Acute
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 model.
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.   

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 commodities, incorporated DEEM(TM) 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 DEEM(TM) 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 53% of the chronic population adjusted dose (cPAD).  The most highly 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 likely 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 analysis 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 Fenamidone
                              Population Subgroup
                                 Acute Dietary
                               (95th Percentile)
                                Chronic Dietary
                                     Cancer
                                        
                          Dietary Exposure (mg/kg/day)
                                    % aPAD*
                                Dietary Exposure
                                  (mg/kg/day)
                                    % cPAD*
                                Dietary Exposure
                                  (mg/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
                                       51
                                        
                                        
 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 existing 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).  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. 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.

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 membership of U.S. pesticide registrants, and is developing a policy on how to appropriately apply the data and the AgDRIFT computer model to its risk assessments for pesticides applied by 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 concurrently.  


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 analysis 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, respectively.  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 by 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/.



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 uses, 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 label 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 MOEs of 180 or greater.

Tables 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.  


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
Liquid, 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 = Inhalation Unit Exposure (ug/lb ai) x Conversion Factor (0.001 mg/ug) x Application Rate (lb ai/A) x Amount Treated (A/day) / BW (80 kg [ST] / 69 kg [IT]).).
[7] Inhalation MOE = Inhalation NOAEL (10.4 (ST)/5.45 (IT mg/kg/day)/ Inhalation Dose (mg/kg/day).  LOC = 100
[8] Total MOE = 1/(1/Dermal MOE  +  1/Inhalation MOE).  LOC = 100





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
Liquid, 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 = Inhalation 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 = Inhalation NOAEL (10.4 (ST)/5.45 (IT mg/kg/day)/ Inhalation Dose (mg/kg/day).  LOC = 100
[8] Total MOE = 1/(1/Dermal MOE  +  1/Inhalation MOE).  LOC = 100



HED has no data to assess exposures to pilots using open cockpits.  The only data available is for exposure to pilots in enclosed 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 (hand 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 were 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]
                              DFRt (ug/cm[2])[3]
                           Daily Dose (mg/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
                                      280
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 (ug/cm[2]) * Tc (cm[2]/hr) * (1 mg/1000 ug) * 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]
                              DFRt (ug/cm[2])[3]
                           Daily Dose (mg/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 (ug/cm[2]) * Tc (cm[2]/hr) * (1 mg/1000 ug) * 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 IV for skin irritation potential.  Fenamidone is not a dermal sensitizer.  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-application 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 requires a 12 hour REI under 40 CFR 156.208 (c) (2) (iii).  The 12-hour REI, which currently appears on the proposed label, is adequate for the proposed uses.



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).  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. 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 performed 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. DP416496, 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. DP410422. Residue 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 Analytical Chemistry and Residue Data.

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

M. Lloyd, 2013. D416497. Fenamidone.  Occupational and Residential Exposure Assessment for a Proposed Use on Succulent Beans, Ginseng, and Bulb Vegetables. D416497.Appendix 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 new (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
870.5395    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.
A.2	Toxicity Profiles

Table A.2.1.  Acute Toxicity Profile - Fenamidone
                                   Guideline
                                      No.
                                  Study Type
                                    MRID #
                                    Results
                               Toxicity Category
                                   870.1100
                                  Acute oral
                                   45386011
                             LD50 = 2028 mg/kg (F)
                           LD50 > 5000 mg/kg (M)
                                      III
                                   870.1200
                                 Acute dermal
                                   45386012
                             LD50 > 2000 mg/kg
                                      III
                                   870.1300
                               Acute inhalation
                                   45386013
                               LC50 > 2.1 m/L
                                      IV
                                   870.2400
                             Acute eye irritation
                                   45386015
                               moderate irritant
                                      III
                                   870.2500
                            Acute dermal irritation
                                   45386014
                                non-irritating
                                      IV
                                   870.2600
                             Dermal sensitization
                                   45386016
                               not a sensitizer
                                not applicable
                                       
                                       

                                       
                                       
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, respectively 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, 6.42, 32.86, or 162.18 mg/kg/day
F: 0, 7.73, 39.11, or 196.07 mg/kg/day
NOAEL = 6.42/7.73 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 rodents with parent -mouse
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/day 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 1000 mg/kg/day
NOAEL = 1000 mg/kg/day
LOAEL = not determined 
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.
Developmental NOAEL = 1000 mg/kg/day 
Developmental 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.
Developmental NOAEL = 100 mg/kg/day
Developmental 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/Systemic NOAEL = 4.04/5.45 mg/kg/day in males and in females
Parental/Systemic 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 1000 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-cell 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 ug/plate (trial 1 +/-S9 and trial 2 +S9) and 0, 10, 25, 50, 100, 250, 500, or 1000 ug/plate (trial 2 -S9).
There was no evidence of induced mutant colonies over background Salmonella typhimurium strains TA98, TA100, TA102, TA1535, and TA1537.
870.5100
Bacterial reverse mutation test with the RPA 412636 plant metabolite
45386115 (1999)
Acceptable, guideline
0, 8, 40, 200, 1000, or 5000 ug/plate (trial 1) and 0, 312.5, 625, 1250, 2500, or 5000 ug/plate (trial 2) 
(+/-S9, both trials)
There was no evidence of induced mutant colonies over background in Salmonella typhimurium strains TA98, TA100, TA1535, 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 ug/plate (trial 1, +/- S9), 312.5, 625, 1250, 2500, or 5000 ug/plate (trial 2, -S9), and 62.5, 125, 250, 500, 1000, or 2000 ug/plate (trial 2, +S9).
There was no evidence of induced mutant colonies over background in Salmonella typhimurium strains TA98, TA100, TA1535, 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 ug/plate (trial 1) and 51.2, 128, 320, 800, 2000, or 5000 ug/plate (trial 2) 
(+/-S9, both trials)
There was no evidence of induced mutant colonies over background in Salmonella typhimurium strains TA98, TA100, TA1535, 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 ug/mL (Trial 1) and 400, 800, 1200, or 1600 ug/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 ug/mL (Trial 1) and 100, 200, 400, or 800 ug/mL (Trial 2) 
(+/-S9, both trials)
RPA 410193 was non-mutagenic at doses up to the limit of solubility (800 ug/mL) in both the presence and absence of S9 metabolic activation.
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 ug/mL (Trial 1 -S9); 50, 75, 100, 125, 150, 175, or 200 ug/mL (Trial 2 -S9); 3.125, 6.25, 12.5, 25, 37.5, or 50 ug/mL (Trial 1 +S9); and 6.25, 12.5, 18.75, 25, 31.25, 37.5, or 43.75 ug/mL (Trial 2 +S9)
There was increased mutation frequency observed at >=12.5 ug/mL in the presence of S9-activation.
870.5375
In vitro mammalian cytogenetics (Chromosomal aberration assay in human peripheral blood) with parent
45386030 (1999)
Acceptable, guideline
2.9-300 ug/mL with S9-activation or 0.95-300 ug/mL without S9-activation
There was evidence of increased chromosome aberrations at 5.9 ug/mL or higher (-S9) or 147 ug/mL or higher (+S9).
870.5395
In vivo mouse 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 cytogenetic assay when administered to CD-1 mice up to the limit dose.
870.5395
In vivo mouse micronucleus
with RPA 412636
45386117 (1999)
Acceptable, guideline
M: 0, 75, 150, 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 mouse 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 mouse 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 ug/mL (Trial 1) and 1.25, 2.5, 5, 10, 20, or 30 ug/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 exposed up to cytotoxic levels.
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 (nuclear silver grain counts), in rat primary hepatocyte cultures exposed up to cytotoxic levels.
870.6200a
Acute 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 battery 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 gains, 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 x 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 717879 (racemic mixture of RPA 412636).
870.7600
Dermal penetration - 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.
Appendix B.  Physical/Chemical Properties

Table B.1.  Physicochemical 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 45385709


Appendix C. International Residue Limits Table

Table C.  Summary of US and International Tolerances and Maximum Residue 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)
(5S)-3,5-dihydro-5-methyl-2-(methylthio)-5-phenyl-3-
(phenylamino)-4H-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 cowpea
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, subgroup 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







Completed: 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).
