Fenamidone Human Health Risk Assessment DP No. D417654

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UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C. 20460

OFFICE OF

CHEMICAL SAFETY AND

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.
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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
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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
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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 (% 
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CT) for all commodities, incorporated DEEMTM 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
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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 
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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®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)-4Himidazol-4-one

CAS Registry Number 161326-34-7

N

N

CH3

O S

CH3

N

H
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Table 3.1 Test Compound Nomenclature

End-use product/EP REASON®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)

1

and not likely to volatize due to low 

vapor pressure. Based on the octanol/water partition coefficient (Kow) fenamidone partitions to 

the lipophilic phase. However, it is soluble in both polar and non-polar solvents. Refer to 

Appendix B for the physicochemical properties of fenamidone. 

3.3 Pesticide Use Pattern

Fenamidone is proposed to be applied 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 preharvest 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®500 

SC fungicide, 

ground, aerial, 

chemigation

264-695 0.178-

0.267 Not Specified 0.80 14 14 day RTI

Succulent Beans

Reason®500 

SC fungicide, 

ground, aerial, 

chemigation

264-695 0.178-

0.267 Not Specified 0.80 3 7 day RTI

Bulb Vegetables

Reason®500 

SC fungicide, 

ground, aerial, 

chemigation

264-695 0.178 Not Specified 0.71 7 5-10 days RTI

 

1

FAO, 2000. Food and Agriculture Organization of the United Nations. FAO Pesticide Disposal Series 8. Assessing Soil 

Contamination: A Reference Manual. Appendix 2. Parameters of pesticides that influence processes in the soil. Editorial Group, 

FAO Information Division: Rome, 2000. http://www.fao.org/docrep/003/X2570E/X2570E00.htm. 
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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
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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.
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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 III2in 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 

 

2 Handbook of Pesticide Toxicology, Two-Volume Set: Principles and Agents, Volume 1 edited by Robert Krieger, 

p. 1207.
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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.
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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 preand/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 
Fenamidone Human Health Risk Assessment DP No. D417654

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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

IntermediateTerm

(1-6 months)

NOAEL = 5.45 

mg/kg/dayUFA= 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 

IntermediateTerm 

(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 LongTerm (>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.
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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

Carrot1Fenamidone 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®500 SC) on ginseng, and succulent beans (MRIDs 
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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 
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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, RPA412108, 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 207μg/L and the average concentration after 

breakthrough was 139 μg/L for the Central Sands Region of Wisconsin from 30 years of 

continuous use. These estimates represent potential exposure to private drinking water well in a 

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. 
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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 DEEMTM default 

processing factors for many processed commodities and included modeled drinking water 

estimates. The estimated exposure (food and water) to the U.S. population from the existing and 

proposed new uses of fenamidone resulted in an estimated risk equivalent to 3% of the acute 

population adjusted dose (aPAD) at the 95th percentile. The most highly exposed subpopulation 

was children 1 - 2 years with an estimated exposure equivalent to 5% of the aPAD at the 95th

percentile.

5.4.4 Chronic Dietary Risk Assessment

A chronic dietary risk assessment was conducted which used maximum field trial residue values, 

assumed 100 % CT for all commodities, incorporated DEEMTM default processing factors for 

many processed commodities and 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
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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

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 °C3). 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, 20104. 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 postapplication inhalation exposure into the Agency's risk assessments. If new policies or 

 

3 Reference: MRID 45385711

4 Available: http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html
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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/.
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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. 
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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 MOE5 Dose (mg/kg/day)6 MOE7 MOE8

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

1Exposure 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
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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 

Rate2

Amount 

Treated 3

Dermal Inhalation Total

baseline unit 

exposures

No respirator Dose 

(mg/kg/day)4 MOE5 Dose (mg/kg/day)6 MOE7 MOE8

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

1Exposure 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
Fenamidone Human Health Risk Assessment DP No. D417654

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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 

Coefficient1

(cm2/hr)

DAT2 DFRt

(μg/cm2)

3

Daily Dose 

(mg/kg/day)4

MOE5

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
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1 Transfer coefficient from Science Advisory Council for Exposure: Policy Memo #003 “Agricultural Transfer 

Coefficients”.

2 Day after treatment assuming REI of only 12 hours observed. 

3 DFR = derived from MRID 45386005; See ORE memo for additional detail 

4 Daily Dose = DFR (μg/cm2

) * Tc (cm2/hr) * (1 mg/1000 μg) * ET (8 hrs/day) * DA (10% dermal absorption) / 

body weight (80 kg)

5 MOE = PoD (NOAEL of 10.4 mg/kg/day) / Daily Dose (mg/kg/day)

Table 9.2.2 Intermediate-Term Occupational Post-application Dermal Exposures and Risks for 

Fenamidone

Crop Application 

Rate

(lb ai/A)

Exposure Potential: Work 

Activity

Transfer 

Coefficient1

(cm2/hr)

DAT2 DFRt

(μg/cm2)

3

Daily Dose 

(mg/kg/day)4

MOE5

Ginseng 0.27 Hand weeding 70

0 1.34

0.001 4,900

Scouting 210 0.003 1,600

Hand set irrigation 1,900 0.03 180

Succulent beans 0.27 Irrigate, scout, thin, weed 

immature plants

70

0 1.34

0.001 4,900

Irrigate, scout mature plants 210 0.003 1,600

Hand harvesting 1100 0.017 310

Hand set irrigation 1900 0.03 180

Bulb Vegetables 0.18 Scouting 1400

0

0.88 0.014 380

Hand set irrigation 1900 0.88 0.019 280

Hand weeding 4200 0.88 0.043 130

1 Transfer coefficient from Science Advisory Council for Exposure: Policy Memo #003 “Agricultural Transfer 

Coefficients”.

2 Day after treatment assuming REI of only 12 hours observed. 

3 DFR = derived from MRID 45386005; See ORE memo for additional detail

4 Daily Dose = DFR (μg/cm2

) * Tc (cm2/hr) * (1 mg/1000 μg) * ET (8 hrs/day) * DA (10% dermal absorption) / 

body weight (69 kg)

5 MOE = PoD (NOAEL of 5.45 mg/kg/day) / Daily Dose (mg/kg/day)

Restricted Entry Interval

The restricted entry interval (REI) is based on the acute toxicity of fenamidone, which is 

classified as Category III for acute dermal toxicity and for eye irritation potential, and Category

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.
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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 °C5). 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, 20106. 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 postapplication 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 postapplication 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®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

 

5 Reference: MRID 45385711

6 Available: http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html
Fenamidone Human Health Risk Assessment DP No. D417654

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M. Lloyd, 2013. D416497. Fenamidone. Occupational and Residential Exposure Assessment for 

a Proposed Use on Succulent Beans, Ginseng, and Bulb Vegetables. D416497.
Fenamidone Human Health Risk Assessment DP No. D417654

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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.
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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
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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
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Table A.2.2 Subchronic, Chronic, and Other Toxicity Profile a

Guideline No./Study 

Type

MRID No. (year)/ 

Classification /Doses Results

870.3700a

Prenatal developmental 

with parent - rat

45386106 (1997)

Acceptable, guideline

F: 0, 25, 150, or 1000 

mg/kg/day

Maternal NOAEL = 150 mg/kg/day

Maternal LOAEL = 1000 mg/kg/day based on decreased 

body weight gains and food consumption.

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 μg/plate 

(trial 1 +/-S9 and trial 2 

+S9) and 0, 10, 25, 50, 

100, 250, 500, or 1000 

μg/plate (trial 2 -S9).

There was no evidence of induced mutant colonies over 

background Salmonella typhimurium strains TA98, TA100, 

TA102, TA1535, and TA1537.
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Table A.2.2 Subchronic, Chronic, and Other Toxicity Profile a

Guideline No./Study 

Type

MRID No. (year)/ 

Classification /Doses Results

870.5100

Bacterial reverse 

mutation test with the 

RPA 412636 plant 

metabolite

45386115 (1999)

Acceptable, guideline

0, 8, 40, 200, 1000, or 

5000 μg/plate (trial 1) 

and 0, 312.5, 625, 

1250, 2500, or 5000 

μg/plate (trial 2) 

(+/-S9, both trials)

There was no evidence of induced mutant colonies over 

background in Salmonella typhimurium strains TA98, TA100, 

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 μg/plate (trial 1, 

+/- S9), 312.5, 625, 

1250, 2500, or 5000 

μg/plate (trial 2, -S9), 

and 62.5, 125, 250, 

500, 1000, or 2000 

μg/plate (trial 2, +S9).

There was no evidence of induced mutant colonies over 

background in Salmonella typhimurium strains TA98, TA100, 

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 μg/plate (trial 1) 

and 51.2, 128, 320, 

800, 2000, or 5000 

μg/plate (trial 2) 

(+/-S9, both trials)

There was no evidence of induced mutant colonies over 

background in Salmonella typhimurium strains TA98, TA100, 

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 μg/mL (Trial 1) 

and 400, 800, 1200, or 

1600 μg/mL (Trial 2)

(+/-S9, both trials)

RPA 412636 was non-mutagenic at doses up to the limit of 

solubility (1600 ug/mL) in both the presence and absence of 

S9 metabolic activation.

870.5300

Mouse lymphoma 

cell/mammalian 

activation gene forward 

mutation assay (L5178Y 

hgprt) with RPA 

410193 (S-enantiomer 

of RPA 405862)

45386121 (1999)

Acceptable, guideline

50, 100, 200, 400, or 

800 μg/mL (Trial 1) 

and 100, 200, 400, or 

800 μg/mL (Trial 2)

(+/-S9, both trials)

RPA 410193 was non-mutagenic at doses up to the limit of 

solubility (800 ug/mL) in both the presence and absence of S9 

metabolic activation.
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Table A.2.2 Subchronic, Chronic, and Other Toxicity Profile a

Guideline No./Study 

Type

MRID No. (year)/ 

Classification /Doses Results

870.5300

Mouse lymphoma 

cell/mammalian 

activation gene forward 

mutation assay (tk

locus) with parent

45386101 (1999)

Acceptable, guideline

12.5, 25, 50, 75, 100, 

125, or 150 μg/mL 

(Trial 1 -S9); 50, 75, 

100, 125, 150, 175, or 

200 μg/mL (Trial 2 -

S9); 3.125, 6.25, 12.5, 

25, 37.5, or 50 μg/mL 

(Trial 1 +S9); and 6.25, 

12.5, 18.75, 25, 31.25, 

37.5, or 43.75 μg/mL 

(Trial 2 +S9)

There was increased mutation frequency observed at ≥12.5 

μg/mL in the presence of S9-activation.

870.5375

In vitro mammalian 

cytogenetics 

(Chromosomal 

aberration assay in 

human peripheral blood) 

with parent

45386030 (1999)

Acceptable, guideline

2.9-300 μg/mL with 

S9-activation or 

0.95-300 μg/mL 

without S9-activation

There was evidence of increased chromosome aberrations at 

5.9 μg/mL or higher (-S9) or 147 μg/mL or higher (+S9).

870.5395

In vivo 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 

μg/mL (Trial 1) and 

1.25, 2.5, 5, 10, 20, or 

30 μg/mL (Trial 2)

Fenamidone did not produce any evidence of unscheduled 

DNA synthesis, as determined by radioactive tracer 

procedures (nuclear silver grain counts), in rat primary 

hepatocyte cultures exposed up to cytotoxic levels.
Fenamidone Human Health Risk Assessment DP No. D417654

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Table A.2.2 Subchronic, Chronic, and Other Toxicity Profile a

Guideline No./Study 

Type

MRID No. (year)/ 

Classification /Doses Results

870.5550

Unscheduled DNA 

synthesis

with parent

45386103 (1999)

Acceptable, guideline

M: 800 or 2000 mg/kg

Fenamidone did not produce any evidence of unscheduled 

DNA synthesis, as determined by radioactive tracer 

procedures (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 preweaning and decreased body weight (4-6%) during postweaning

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 14C-labeled fenamidone, 

Sprague-Dawley rats received doses of 3 mg/kg (single, low 

dose), 3 mg/kg × 14 days (repeated low dose) and 300 mg/kg 

(high dose). Fenamidone was well absorbed and rapidly 

excreted, primarily in the urine and bile, at the low dose and 

repeated low dose. At 300 mg/kg, biliary excretion was not 

measured, although fecal excretion was 50-68% of the dose. 

Tissue levels of radioactivity were primarily found in the liver 

at the single low dose and in the thyroid in the repeated and 

high dose studies. Metabolite identification included RPA 

408056 (racemic form of RPA 412708) and RPA 717879 

(racemic mixture of RPA 412636).

870.7600

Dermal penetration - rat

45386111 (1999)

Acceptable, guideline

M: 0, 2.7, 29, or 269 ug 

ai/cm2

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 antiSRBC 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.
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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
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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 Mexico2 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-dihydro5-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-Himidazol-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-methyl5-phenyl)

(5S)-3,5-dihydro-5-

methyl-2-

(methylthio)-5-

phenyl-3-

(phenylamino)-4Himidazol-4-one

None

Commodity1 Tolerance (ppm) /Maximum Residue Limit (mg/kg)

US Canada Mexico2 Codex

Ginseng 0.8 0.15 ginseng roots3

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).