Fenamidone Human Health Risk Assessment DP No. 386359 

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UNITED STATES ENVIRONMENTAL PROTECTION AGENCY 

WASHINGTON, D.C. 20460

OFFICE OF 

CHEMICAL SAFETY AND 

POLLUTION PREVENTION

MEMORANDUM

Date: July 20, 2011

SUBJECT: Fenamidone: Human Health Risk Assessment to Support the Label 

Amendment to Permit Rotation to All Cereal Grain, Except Rice and 

Establish Revised Tolerances for Inadvertent Residues. 

PC Code: 046679 DP Barcode: D386359 

Decision No.: NA Registration No.: 264-695 

Petition No.: NA Regulatory Action: Section 3 Registration 

Risk Assessment Type: NA Case No.: NA

TXR No.: NA CAS No.: 161326-34-7

MRID No.: NA 40 CFR: NA 

FROM: Matthew Lloyd, CIH; Industrial Hygienist 

 Alexandra LaMay, Biologist 

 Byong-Han Chin, Toxicologist 

 RAB VII 

 Health Effects Division (7509P) 

THROUGH: Kit Farwell, DVM

Michael S. Metzger, Chief 

 RAB VII 

 Health Effects Division (7509P) 

TO: Rosemary Kearns/Tony Kish (RM 22) 

 Fungicide Branch 

 Registration Division (7505P) 

Attached please find the most recent HED human health risk assessment for the proposed 

establishment of tolerances for inadvertent residues of fenamidone in/on the cereal grains 

and forage, fodder and hay of cereal grains crop groups (CG 15 and 16, except rice).
Fenamidone Human Health Risk Assessment D386359 

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Table of Contents 

1.0 Executive Summary ............................................................................................... 3

Regulatory Recommendations and Data Needs ......................................................... 4

2.0 Ingredient Profile ................................................................................................... 6

2.1 Summary of Proposed Uses ............................................................................... 6

2.2 Structure and Nomenclature ............................................................................. 6

2.3 Physical and Chemical Properties .................................................................... 7

3.0 Hazard Characterization ....................................................................................... 7

3.1 Hazard Profile .................................................................................................... 7

3.2 Cancer Classification and Risk Assessment Recommendation ..................... 9

3.3 Safety factor for Infants and Children (FQPA Safety Factor) ...................... 9

3.4 Summary of Points of Departure and Toxicity Endpoints Used in Human 

Risk Assessment .......................................................................................................... 10

3.5 Endocrine Disruption ........................................................................................... 10

4.0 Dietary Exposure/Risk Characterization .......................................................... 11

4.1 Metabolism and Environmental Degradation ............................................... 11

4.2 Analytical Methodology ................................................................................... 11

4.2.1 Data Collection Methodology................................................................... 11

4.2.2 Enforcement Methodology ....................................................................... 11

4.3 Drinking Water Residue Profile ..................................................................... 12

4.4 Food Residue Profile ........................................................................................ 12

4.5 Tolerances and International Residue Limits ............................................... 15

4.6 Dietary Exposure and Risk.............................................................................. 16

4.6.1. Acute Dietary Exposure/Risk ................................................................... 16

4.6.2 Chronic Dietary Exposure/Risk............................................................... 16

4.6.3 Cancer Dietary Risk ................................................................................. 16

4.6.4 Acute and Chronic Dietary Exposure and Risk Summary ................... 16

5.0 Residential Exposure/ Risk Pathway ................................................................. 17

6.0 Aggregate Risk Assessments and Risk Characterization ................................. 17

7.0 Cumulative Risk Characterization/Assessment ................................................ 17

8.0 Occupational Exposure ....................................................................................... 18

9.0 Data Needs and Label Recommendations ......................................................... 18

9.1 Toxicology ......................................................................................................... 18

9.2 Residue Chemistry ........................................................................................... 18

9.3 Occupational and Residential Exposure ........................................................ 18

10.0 Environmental Justice ......................................................................................... 18

References ........................................................................................................................ 20

Attachment 1. Chemical Structures ............................................................................. 22

Attachment 2. Acute Toxicity of Fenamidone ............................................................. 24

Attachment 3. Toxicity Profile for Fenamidone.......................................................... 25

Attachment 4. International Residue Limit Status Sheet........................................... 29

Attachment 5. Review of Human Research ................................................................. 30
Fenamidone Human Health Risk Assessment D386359 

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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 three 

actions– 1) a revision to the Reason® 500 SC label to use data submitted to support 

wheat and corn rotational crop tolerances to establish rotational crop tolerances for the 

remaining commodities except rice in the cereal grains crop group; 2) a request to 

translate the existing soybean rotational crop data to establish rotational crop tolerances 

for all crops in crop group 6C and 7 (dried shelled pea and bean [crop group 6C] and 

foliage of legume vegetables [crop group 7]) at a 30 day plant back interval; and 3) a 

request to reduce the number of required field trials to support rotational crop tolerances 

in alfalfa. 

HED has concluded there are sufficient data to support the requested establishment of 

rotational crop tolerances for additional commodities in the cereal grains group based on 

submitted data. At this time, HED cannot recommend for the requested rotational crop 

tolerances on crop groups 6C/7. HED has no objection to a reduction in the number of 

alfalfa trials based on submitted information. 

Hazard Identification 

The toxicity database for fenamidone is considered adequate for the proposed 

establishment of tolerances for inadvertent residues of fenamidone in/on the cereal grains 

crop group. Fenamidone has low acute toxicity via the oral, dermal, and inhalation routes. 

It produces moderate eye irritation, is not a dermal irritant, and is negative for dermal 

sensitization. Fenamidone systemic toxicity is primarily characterized by liver toxicity as 

indicated in studies on rats, mice, and dogs. Developmental toxicity was observed in rats 

at the limit dose; no developmental toxicity was observed in rabbits. In the reproductive 

toxicity study in rats, decreased absolute brain weights and pup body weights were 

observed in the pups at the same dose levels where decreased brain weights and parental 

body weights and increased liver and spleen weights were observed. Reproductive 

toxicity was not observed. Based on the available data and the selection of risk 

assessment endpoints that are protective of developmental effects, there are no residual 

uncertainties with regard to pre- and/or post-natal toxicity. Therefore, the FQPA safety 

factor was reduced to 1X. An acceptable guideline immunotoxicity study in rats has been 

reviewed. While the study showed a potential immunosuppression at the highest dose 

tested, the existing risk assessment points of departure are lower and are therefore 

protective of this potential effect. Fenamidone is not likely to be a human carcinogen and 

studies indicate that there is no concern for mutagenicity for fenamidone. 

Endpoint Selection 

Risk assessment endpoints were selected for dietary exposure scenarios. Acute and 

chronic reference doses (RfDs) and population adjusted doses (PADs) [PAD = 

RfD/FQPA SF] were selected for assessment of food exposures. The acute PAD (aPAD) 

was derived from an acute neurotoxicity study in rats based on the observation of 

urination, staining/soiling of the anogenital region, mucous in the feces, and unsteady gait 
Fenamidone Human Health Risk Assessment D386359 

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in female rats at a LOAEL of 500 mg/kg [NOAEL = 125 mg/kg]. The chronic PAD 

(cPAD) was derived from the combined chronic toxicity/carcinogenicity study in rats 

[increased severity of diffuse thyroid C-cell hyperplasia in both sexes of rats]; the 

NOAEL was 2.83 mg/kg/day. An uncertainty factor of 100X was applied to PODs 

selected for the dietary exposure route (10X for inter-species extrapolation, 10X for intraspecies variation, and the FQPA safety factor was reduced to 1X. 

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. 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 for inadvertent 

residues that are the subject of this petition. 

Conservative acute and chronic dietary risk assessments were conducted which used 

maximum field trial residue values, assumed 100 percent crop treated (% CT) for all 

commodities, incorporated DEEMTM default processing factors for many processed 

commodities and included modeled estimates for drinking water. Acute and chronic 

dietary (food and water) risks from the existing and proposed uses of fenamidone are not 

of concern. 

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 newly proposed uses of 

fenamidone. 

Residential/Occupational Exposure 

There is no occupational or residential assessment necessary in this risk assessment as 

there are no direct applications to crops addressed in the petition. This risk assessment 

does not rely on data from studies in which human subjects were intentionally exposed to 

a pesticide or other chemical. 

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 LowIncome Populations.1

" 

Regulatory Recommendations and Data Needs 

The following updated regulatory recommendation is appropriate for fenamidone. 

Provided the data needs summarized below are addressed, there are no human health 

 

1

 Available: http://www.eh.doe.gov/oepa/guidance/justice/eo12898.pdf 
Fenamidone Human Health Risk Assessment D386359 

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risks of concern that would preclude the establishment of the following tolerances for 

inadvertent residues of fenamidone in/on the cereal crop group (CG 15 and 16, except 

rice). 

Under 40 CFR §180.579(d) for residues of fenamidone: 

Provided the registrant submits a revised Section F reflecting the revised commodity 

definitions shown below, the available data support the following tolerances for indirect 

or inadvertent residues of fenamidone (4-H-imidazol-4-one, 3,5-dihydro-5-methyl-2-

(methylthio)-5-phenyl-3-(phenylamino, (S)-) and its metabolite RPA 717879 (2,4-

imidazolidinedione, 5-methyl-5-phenyl) in or on the following rotational crop 

commodities: 

Grain, cereal, group 15, except rice.........................................................0.1 ppm 

Grain, cereal, forage, fodder and straw, group 16, forage...............................0.3 ppm 

Grain, cereal, forage, fodder and straw, group 16, hay..................................0.5 ppm 

Grain, cereal, forage, fodder and straw, group 16, stover ...............................0.5 ppm 

Grain, cereal, forage, fodder and straw, group 16, straw ...............................0.5 ppm 

NOTE TO RD: The previously established rotational crop tolerances for the individual crops in the crop 

groups (sweet corn, field corn, and wheat) should be removed from the tolerance summary for fenamidone 

and replaced with the crop group tolerances above. According to HED’s Interim Guidance on Tolerance 

Expressions (5/27/09, S. Knizner), the tolerance expression for fenamidone should be revised as stated 

below [from HED’s “Fenamidone: Changes to Tolerance Expression; 07/20/11; D392064]:

Indirect or inadvertent residues. Tolerances are established for residues of the fungicide 

fenamidone, including its metabolites and degradates, in or on the commodities in the 

table below. Compliance with the tolerance levels specified below is to be determined by 

measuring fenamidone (4H-Imidazol-4-one, 3,5-dihydro-5-methyl-2-(methylthio)-5-

phenyl-3 (phenylamino)-, (S)-), and its metabolite RPA 717879 (2,4-imidazolidinedione, 

5-methyl-5-phenyl), in or on the following commodities when present therein as a result 

of application of fenamidone to the crops in paragraph (a)(1). 

Prior to a favorable recommendation, HED requests the following: 

 The petitioners should submit revised section Fs reflecting the commodity 

definitions and levels shown above. 

At this time, HED cannot recommend for the requested rotational crop tolerances of dried 

shelled pea and bean (crop group 6C) and foliage of legume vegetables (crop group 7) at 

a 30 day PBI to fields treated with fenamidone. 

HED has no objection to a reduction in the number of alfalfa trials for the establishment 

of rotational crop tolerances in alfalfa. 

 
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2.0 Ingredient Profile 

2.1 Summary of Proposed Uses 

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. Fenamidone is a chiral compound with the technical 

product consisting of 98.5% S-fenamidone. Tolerances are established for residues of 

fenamidone in raw agricultural commodities, animal commodities and for inadvertent 

residues under 40 CFR §180.579. 

There are currently tolerances for inadvertent residues on wheat, sweet corn and field 

corn to support allowing rotation to these commodities with a 30-day PBI. 

The registrant is proposing to revise the fenamidone label for the formulated product, 

Reason® 500 SC to allow rotation to all crops, except rice, in the cereal crop group (CG 

15, except rice and CG 16, except rice) with a 30-day plant back interval (PBI) after a 

maximum seasonal application of 0.8 lb ai/A to a primary crop. There are no direct uses 

of fenamidone on these crops. The registrant proposes to use data submitted to support 

wheat and corn rotational crop tolerances to establish rotational crop tolerances for the 

remaining commodities except rice in the cereal grains crop group (CG 15, except rice) 

and the forage, fodder and straw of the cereal grains crop group (CG 16, except rice). 

The registrant has also requested that the existing soybean rotational crop data be 

translated to establish rotational crop tolerances for dried shelled pea and bean (crop 

group 6C) and foliage of legume vegetables (crop group 7) at a 30 day PBI to fields 

treated with fenamidone. 

Additionally, the registrant would like to establish rotational crop tolerances in alfalfa. 

The registrant has proposed to reduce the number of alfalfa rotational trials from 12 to 10, 

based on an overlap analysis between growing regions of primary and rotational crops. 

2.2 Structure and Nomenclature 

Table 2.2, below contains a summary of the test compound nomenclature. Additional 

fenamidone information, including stereoisomer structures and metabolite nomenclature 

and structures is contained in Attachment 1. 
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Table 2.2. Fenamidone Nomenclature.

Compound Chemical Structure 

Common name fenamidone 

Company experimental name RPA 407213 

IUPAC name (S)-1-anilino-4-methyl-2-methylthio-4-phenylimidazolin-5-one 

CAS name (5S)-3,5-dihydro-5-methyl-2-(methylthio)-5-phenyl-3-(phenylamino)-4H-imidazol-4-one 

CAS registry number 161326-34-7 

End-use product (EP) Reason® 500 SC (44.4% S-fenamidone; 4.13 lb ai/gal; EPA Reg. No. 264-695) 

2.3 Physical and Chemical Properties 

 

Table 2.3, below contains a summary of the physicochemical properties of Fenamidone. 

Table 2.3. 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 

3.0 Hazard Characterization 

D314116, T. Bloem, 6/21/07

3.1 Hazard Profile

HED reviewed both the available toxicity profile for fenamidone and the newly available 

immunotoxicity study (MRID 48321101) to determine appropriate endpoints and points of 

departure for risk assessment. 

Fenamidone has low acute toxicity via the oral, dermal, and inhalation routes. It is a 

moderate eye irritant, but is not a dermal irritant or a dermal sensitizer. The acute oral 

N

N

CH3

O S

CH3

N H
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assay tests indicated that female rats were more sensitive to the parent than male rats. 

The target organs in chronic studies in the mouse and dog were the liver and in rat were the 

liver and thyroid. 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. Fenamidone is not likely to be a human carcinogen. All 

mutagenicity studies were negative for both the parent and plant metabolites (RPA 412636, 

RPA 412708, and RPA 410193). 

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, there were no developmental effects up to the highest dose tested and in the 

presence of maternal toxicity. In the rat, developmental findings and maternal findings 

both occurred at the limit dose. In the reproduction study in rats), decreased absolute brain 

weight and pup body weight occurred at the same dose levels as decreased absolute brain 

weight and parental body weight, food consumption, and increased liver and spleen weight. 

There were no effects on fertility and other measured reproductive parameters. 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 decrease in brain weights was observed only in high dose 

males. Additionally, decreased brain weight occurred in the rat reproduction study, as 

noted above. 

The Agency previously required the registrant to submit an abbreviated DNT in the 

Sprague Dawley rat with measurements of brain weight and brain morphometric data to 

confirm findings in the full DNT conducted in the Wistar rat as a condition of registration. 

Subsequent to this requirement, at the meeting of June 11, 2009, Bayer CropScience 

provided additional information on the DNT study. The registrant provided an analysis of 

the brain weight data which addressed the Agency’s concerns relative to dose difference, 

exposure duration and strain differences. Consequently, additional DNT data are no 

longer required for fenamidone. 

The dermal absorption factor for fenamidone is 10% based on the results of an acceptable 

dermal absorption study in rats. 

As specified in the new 40 CFR Part 158 data requirements, an immunotoxicity study on 

fenamidone was conducted. Although the immunotoxicity study showed potential 

immunosuppression at the highest dose tested, the existing risk assessment points of 

departure are lower and are therefore protective of this potential effect. 

The results of the acute toxicity studies for technical fenamidone are included in this 

assessment as Attachment 2. The toxicity profile for fenamidone is summarized in 
Fenamidone Human Health Risk Assessment D386359 

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Attachment 3. 

3.2 Cancer Classification and Risk Assessment Recommendation 

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. All mutagenicity studies were negative for both the parent and plant metabolites 

(RPA 412636, RPA 412708, and RPA 410193). 

3.3 Safety factor for Infants and Children (FQPA Safety Factor)

Based on available hazard information and the residue information used in the dietary 

risk assessments, HED concludes that the FQPA factor for fenamidone may be reduced to 

1X for the following reasons: 

 The toxicology database for fenamidone is complete for purposes of this risk 

assessment and the characterization of potential pre-natal and/or post-natal risks 

to infants and children. 

 No qualitative or quantitative increased susceptibility of rat or rabbit fetuses to in 

utero exposure in the developmental toxicity studies was observed. 

 No qualitative or quantitative increased susceptibility in the two generation 

reproduction study (rat). 

 Low concern for residual uncertainties in the DNT study (rat) since there is a 

well established offspring NOAEL which is 45x greater than the NOAEL used 

to establish the chronic dietary endpoint 

 Residue values used in the dietary risk assessments are unlikely to underestimate 

risk. Dietary exposure assessments were conducted using tolerance level 

residues and assumed 100% crop treated. Therefore, the acute and chronic 

dietary, food only, exposure is considered an upper bound conservative estimate. 

The contribution from drinking water is minimal. HED concludes that the acute 

and chronic exposure estimates in this analysis are unlikely to underestimate 

actual exposure. The drinking water component of the dietary assessment 

utilizes water concentration values generated by modeling parameters which are 

designed to provide conservative, health protective, high-end estimates of water 

concentrations which will not likely be exceeded. 

 There are no existing exposure-related data gaps that would affect the FQPA 

safety factor. 

 
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3.4 Summary of Points of Departure and Toxicity Endpoints Used in Human 

Risk Assessment 

Table 3.4, below, contains a summary of the fenamidone points of departure for use in 

dietary, and non-dietary risk assessments. 

Table 3.4. Summary of Toxicological Doses and Endpoints for Fenamidone for Use in 

Dietary Human Health Risk Assessments 

Exposure 

Scenario Point of Departure 

Uncertainty/ 

FQPA SF 

RfD, PAD or 

LOC 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 

Cancer Based on the negative carcinogenic potential of fenamidone in rats and mice, HED classified fenamidone 

as “not likely” to be a human carcinogen by all relevant routes of exposure. 

Point of Departure (POD) = A data point or an estimated point that is derived from observed dose-response data and used to mark the 

beginning of extrapolation to determine risk associated with lower environmentally relevant human exposures. NOAEL = no 

observed adverse effect level. LOAEL = lowest observed adverse effect level. UF = uncertainty factor. UFA = extrapolation from 

animal to human (intraspecies). UFH = potential variation in sensitivity among members of the human population (interspecies). UFL

= use of a LOAEL to extrapolate a NOAEL. UFS = use of a short-term study for long-term risk assessment. UFDB = to account for the 

absence of key date (i.e., lack of a critical study). 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. 

3.5 Endocrine Disruption 

As required under FFDCA section 408(p), EPA has developed the Endocrine Disruptor 

Screening Program (EDSP) to determine whether certain substances (including pesticide 

active and other ingredients) may have an effect in humans or wildlife similar to an effect 

produced by a “naturally occurring estrogen, or other such endocrine effects as the 

Administrator may designate.” The EDSP employs a two-tiered approach to making the 

statutorily required determinations. Tier 1 consists of a battery of 11 screening assays to 

identify the potential of a chemical substance to interact with the estrogen, androgen, or 

thyroid (E, A, or T) hormonal systems. Chemicals that go through Tier 1 screening and 

are found to have the potential to interact with E, A, or T hormonal systems will proceed 

to the next stage of the EDSP where EPA will determine which, if any, of the Tier 2 tests 

are necessary based on the available data. Tier 2 testing is designed to identify any 

adverse endocrine related effects caused by the substance, and establish a dose-response 

relationship between the dose and the E, A, or T effect. 

Between October 2009 and February 2010, EPA issued test orders/data call-ins for the 

first group of 67 chemicals, which contains 58 pesticide active ingredients and 9 inert 

ingredients. This list of chemicals was selected based on the potential for human 
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exposure through pathways such as food and water, residential activity, and certain postapplication agricultural scenarios. This list should not be construed as a list of known or 

likely endocrine disruptors. 

Fenamidone is not among the group of 58 pesticide active ingredients on the initial list to 

be screened under the EDSP. Under FFDCA sec. 408(p) the Agency must screen all 

pesticide chemicals. Accordingly, EPA anticipates issuing future EDSP test orders/data 

call-ins for all pesticide active ingredients. 

For further information on the status of the EDSP, the policies and procedures, the list of 

67 chemicals, the test guidelines and the Tier 1 screening battery, please visit our website 

http:/www.epa.gov/endo/. 

4.0 Dietary Exposure/Risk Characterization 

4.1 Metabolism and Environmental Degradation 

D391039, A. LaMay, 7/07/11, Residue Chemistry Chapter 

D314116, T. Bloem, 6/21/07, Human Health Risk Assessment

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 4.1, 

below. 

Table 4.1. Summary of Metabolites and Degradates to be included in the Fenamidone 

Risk Assessment and Tolerance Expression

Matrix Tolerance Expression Residues for Risk Assessment 

Registered/proposed primary crops 

excluding root vegetables fenamidone fenamidone, RPA 717879 (DADK-Fen), RPA 408056 

(DA-Fen), RPA 405862 

Root vegetables fenamidone fenamidone, RPA 413255 

Animal commodities fenamidone, RPA 717879 

(DADK-Fen) 

fenamidone, RPA 717879 (DADK-Fen), RPA 408056 

(DA-Fen) 

Rotational Crops fenamidone, RPA 717879 

(DADK-Fen) 

fenamidone, RPA 717879 (DADK-Fen), and RPA 

408056 (DA-Fen) (free and conjugated) 

Water N/A Fenamidone, RPA 412636, RPA 412708, RPA 411639, 

RPA 413255, RPA 409446, and RPA 410995 

4.2 Analytical Methodology 

4.2.1 Data Collection Methodology 

There have been no new data submitted for this request on rotational crops; therefore, no 

data collection methodology is required. 

4.2.2 Enforcement Methodology 

D391039, A. LaMay, 7/07/11, Residue Chemistry Chapter 

D357372, A. LaMay, 2/24/09, Residue Chemistry Chapter 

The current tolerance enforcement method entitled RPA407213: method of Analysis for 
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RPA 407213 and its Metabolites RPA 717879, RPA 408056 and RPA 405862 (MRID No. 

45385918), a liquid chromatographic method coupled with tandem mass spectrum 

detection (LC/MS/MS) 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). HED concludes that this method is also suitable to enforce 

the new plant tolerances proposed in this petition. 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. 

4.3 Drinking Water Residue Profile 

D352807, J. Hetrick, 10/9/08, Drinking Water Assessment

The 2008 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. 

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, RPA-412636, RPA-412108, RPA-411639, RPA-413255, RPA409446, and RPA- 410995. These are the residues of concern in drinking water, as 

determined by the Metabolite Assessment Committee (MARC, 05/25/04). Surface water 

EDWCs were calculated using a Tier II model for surface water PRZM (Version 3.122) 

and EXAMS (Version 2.98.04) using the PE5 platform. The EDWC in ground water 

were estimated using SCI-GROW (Version 2.3). EDWCs in surface source water were 

corrected using the default percent crop area factor (0.87). The default PCA was applied 

because fenamidone can be used on numerous crops. No water treatment effects were 

considered in this assessment. These models and their descriptions are available at the 

EPA internet site: http://www.epa.gov/oppefed1/models/water/. 

The maximum Tier II EDWCs of total fenamidone residues in surface source water are 

not expected to exceed 47.88 μg/L for the 1 in 10 year daily peak concentration, 12.86 

μg/L for the 1 in 10 year annual average concentration, and 6.89 μg/L for the 30 year 

annual average concentration. The maximum concentration of total fenamidone residues 

in shallow groundwater are not expected to exceed 178 μg/L. 

For both the acute and chronic dietary analysis, HED will use the maximum ground water 

EDWC of 178 μg/L (0.178 ppm), since it is the highest EDWC reported for fenamidone. 

4.4 Food Residue Profile 

D391039, A. LaMay, 7/07/11, Residue Chemistry Chapter 

D357372, A. LaMay, 2/24/09, Residue Chemistry Chapter 

Plant Commodities

The rotational crop field trial data for wheat and corn support the establishment of 
Fenamidone Human Health Risk Assessment D386359 

Page 13 of 30 

tolerances for residues of fenamidone and its regulated metabolites in the cereal crop 

group (CG 15 and 16, excluding rice) commodities with a 30-day plant back interval 

(PBI). The wheat, sweet corn and field corn residue results from the rotational crop trials 

were similar; there were no detectible residues in grain of field corn, sweet corn and 

wheat; and there were low residues in the forage commodities. The representative 

commodities for CG 15 are sweet corn, field corn, rice, sorghum and wheat. Since a 

tolerance on rice is not requested, HED concurs that the rotational crop data for wheat 

and corn can be translated to all small grains in the cereal crop group (CG 15 and 16, 

except rice) and support the proposed tolerance levels (see D357372, 2/24/09, A. LaMay 

for corn data; see D297216, 5/25/04, T. Bloem and D315563, 5/24/05, T. Bloem for 

wheat data). 

Residues to be used in dietary risk assessment are shown in the table below. 

 
Fenamidone Human Health Risk Assessment D386359 

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Table 4.4.2. Summary of New Residue Values Added to the Acute and Chronic 

Dietary Risk Assessment 

Crop/Commodity* Residue Value 

(ppm) Comment 

Cereal grains, Crop Group 

15 and 16 (except rice) 

which includes: barley, 

buckwheat, corn [pop], 

millet, oats, rye, sorghum, 

teosinte, triticale, wheat. 

0.594 

Translated from wheat data. The field rotational crop 

studies monitored for residues of fenamidone, RPA 717879, 

and free RPA 408056 with a highest combined residues in 

wheat grain of 0.075 ppm; residues of conjugated RPA 

408056 were estimated in wheat grain using the conjugated 

RPA 408056:RPA 717879 residue ratio for wheat grain 

from the confined rotational crop study (30-day PBI ratio = 

8.5) and the max RPA 717879 residue (0.061 ppm) from the 

field rotational crop studies (0.075 + 0.061 x 8.5 = 0.594 

ppm; D281887, T. Bloem, 18-Jul-2002) 

Field Corn and processed 

commodities 0.218 

 Maximum rotational crop field corn residue data reported 

<0.02 ppm for fenamidone and <0.02 ppm for combined 

residues of RPA 717879 and RPA 405862 (free). Residues 

of conjugated RPA 405862 were not reported, but are a 

residue of concern in rotational crops. Residues of RPA 

405862 were 8.5x residues of RPA 717879 from the wheat 

confined rotational crop study. Total residue of concern for 

field corn and processed commodities is calculated as 0.02 

ppm (fenamidone) + 0.02 ppm (RPA 717879 and free RPA 

405862) + 0.02 x 8.9 (ratio to yield conjugated RPA 

405862) = 0.218 (D357372, A. LaMay, 2/24/09). 

Sweet Corn (K + CWHR) 0.218 

Maximum rotational crop sweet corn (K+CWHR) residue 

data reported <0.02 ppm for fenamidone and <0.02 ppm for 

combined residues of RPA 717879 and RPA 405862 (free). 

Residues of conjugated RPA 405862 were not reported, but 

are a residue of concern in rotational crops. Residues of 

RPA 405862 were 8.5x residues of RPA 717879 from the 

wheat confined rotational crop study. Total residue of 

concern for sweet corn (K+CWHR) is calculated as 0.02 

ppm (fenamidone) + 0.02 ppm (RPA 717879 and free RPA 

405862) + 0.02 x 8.9 (ratio to yield conjugated RPA 

405862) = 0.218 (D357372, A. LaMay, 2/24/09). 

*Although there are not separate tolerances for the cereal grains, the residue data for corn were used in the 

dietary assessment since specific residue data are available for these crops. Residue data for wheat were 

used for all other cereal grains for the purposes of the dietary assessment. 

Processed Commodities

The only new processed commodities associated with this petition are those associated 

with barley grain, oats, and rye grain processing. Given that (1) this request is for a 

rotational crop use and there were no detectible residues in grain of field corn, sweet 

corn, and wheat; (2) no detectable residues were seen in field corn grain from a 30-day 

PBI with a 5X soil application rate; and (3) no detectable residues were seen in wheat 

processed commodities from a 30-day PBI with a 5X soil application rate, except for 

wheat germ which had no detectible residues of fenamidone but had residues near the 

LOQ for metabolite RPA 717879, however total residues were below the tolerance for 

the RAC; HED concludes that no additional processing data are required. Detectable 

residues of fenamidone are not expected in these processed commodities and tolerances 

for processed commodities of crop group 15 and 16 are not required. 
Fenamidone Human Health Risk Assessment D386359 

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Animal Commodities

Approval of this action would permit rotation to the following feed items: barley grain, 

hay, and straw; popcorn grain and stover; millet grain, forage, hay and straw; oat grain, 

forage, hay and straw; rye grain, forage, and straw, sorghum grain, forage, and stover. 

There are currently tolerances for inadvertent residues on wheat, sweet corn and field 

corn. HED has previously calculated a dietary burden for livestock which includes 

residues of fenamidone and its regulated metabolites in wheat, sunflower, and cottonseed 

animal feed items (D314318, T. Bloem, 2007). HED has determined that the animal feed 

items associated with this action are not likely to result in residues in feed items which 

are higher than residues in feed items currently used to calculated dietary burden. The 

new feed items are not likely to be additional items to the burden, but would replace 

items already considered and since the residues would not be higher, the dietary burden is 

not increased by the addition of these rotational crops. Therefore, no new or revised 

animal commodity tolerances are required to support the requested label amendment to 

allow rotation to all cereal grains except rice with a 30-day PBI. 

4.5 Tolerances and International Residue Limits 

Below is a summary of the proposed and HED-recommended tolerances and commodity 

definitions for residues of fenamidone for rotational crops of cereal crops (CG 15 and 16, 

except rice). The existing wheat and corn rotational crop data were used to support the 

establishment of tolerances in/on barley, buckwheat, millet, oats, popcorn, rye, sorghum, 

teosinte, and triticale based on similar residue levels and use patterns. 

There are no Codex, Canadian or Mexican MRLs (maximum residue levels) for residues 

of fenamidone in cereal crops (CG 15 and 16, except rice) (see Attachment 1). There are 

no issues with respect to international harmonization as a result of the proposed 

tolerances that are the subject of this petition. The registrant must revise the requested 

tolerances to reflect the revised commodity definitions shown below. 

Table 4.5. Tolerance Summary for Fenamidone. 

Commodity 

Proposed 

Tolerance (ppm)

Recommended 

Tolerance (ppm) 

Comments; Correct 

Commodity Definition

40 CFR §180.579(d)

Grain, cereal, group 15 

(except rice) 0.1 0.1 Grain, cereal, group 15, except 

rice 

Grain, forage, group 

16 0.3 0.3 Grain, cereal, forage, fodder 

and straw, group 16, forage 

Grain, hay, group 16 0.5 0.5 Grain, cereal, forage, fodder 

and straw, group 16, hay 

Grain, stover, group 16 0.5 0.5 Grain, cereal, forage, fodder 

and straw, group 16, stover 

Grain, straw, group 16 0.5 0.5 Grain, cereal, forage, fodder 

and straw, group 16, straw 
Fenamidone Human Health Risk Assessment D386359 

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4.6 Dietary Exposure and Risk 

D391040, A. Lamay, 7/07/11, Dietary Exposure and Risk Memorandum

4.6.1. Acute Dietary Exposure/Risk 

A conservative 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. There are no 

acute dietary risks of concern for the existing and newly proposed uses of fenamidone. 

Acute dietary results for all subgroups are shown in Table 4.6.4, below. 

4.6.2 Chronic Dietary Exposure/Risk 

A conservative chronic dietary risk assessments 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 52% of the chronic population adjusted dose (cPAD). The 

most highly exposed subpopulation was children 1 – 2 years with an estimated exposure 

equivalent to 90% of the cPAD. There are no chronic dietary risks of concern associated 

with the existing and newly proposed uses of fenamidone. Chronic dietary results for all 

subgroups are shown in Table 4.6.4, below. 

4.6.3 Cancer Dietary Risk 

Fenamidone is not likely to be a human carcinogen; therefore a cancer dietary risk 

assessment is not required for this chemical. 

4.6.4 Acute and Chronic Dietary Exposure and Risk Summary 

Table 4.6.4. 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 0.041808 3 0.014569 52 N/A N/A 
Fenamidone Human Health Risk Assessment D386359 

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Table 4.6.4. 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 

All Infants (< 1 year old) 0.049304 4 0.021887 77 

N/A N/A 

Children 1-2 years old 0.062898 5 0.025420 90 

Children 3-5 years old 0.057048 5 0.022859 81 

Children 6-12 years old 0.043157 3 0.015630 55 

Youth 13-19 years old 0.035613 3 0.011796 42 

Adults 20-49 years old 0.038559 3 0.013340 47 

Adults 50+ years old 0.041256 3 0.014109 50 

Females 13-49 years old 0.040734 3 0.013388 47 

N/A is “not applicable”. Populations with highest exposure are shown in bold. 

* PAD = population adjusted dose.

5.0 Residential Exposure/ Risk Pathway 

There are no existing or proposed uses of fenamidone that result in residential exposure; 

therefore, residential handler and post application exposure and risk assessments were not 

conducted for fenamidone. 

6.0 Aggregate Risk Assessments and 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 4.6.1 and 4.6.2 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. 

7.0 Cumulative Risk Characterization/Assessment 

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 
Fenamidone Human Health Risk Assessment D386359 

Page 18 of 30 

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/.

8.0 Occupational Exposure 

In this risk assessment, no occupational assessment was conducted for proposed 

rotational crops of all cereal grains (except rice), as there is no direct application to these 

crops and no uses that result in occupational exposure relevant to this assessment.

HED has completed several occupational exposure assessments on fenamidone; the most 

recent being a 2009 assessment for new uses on root vegetables, okra, turnip greens, 

cilantro and grapes (D352806, A. LaMay). Earlier assessments include uses on a number 

of agricultural crops, commercially grown ornamentals, and seed treatments. 

9.0 Data Needs and Label Recommendations 

9.1 Toxicology 

 None 

9.2 Residue Chemistry 

Prior to a favorable recommendation, HED requests the following: 

 The petitioners should submit revised section Fs reflecting the commodity 

definitions and levels shown in Table 4.5.

9.3 Occupational and Residential Exposure 

 None 

10.0 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 LowIncome 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 
Fenamidone Human Health Risk Assessment D386359 

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consumption patterns are compiled by the USDA under the Continuing Survey of Food 

Intake by Individuals (CSFII) 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 postapplication 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. 

 
Fenamidone Human Health Risk Assessment D386359 

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References 

Fenamidone. Human Health Risk Assessment to Support Section 3 Proposals to Add 

New Uses on the Root Vegetable Subgroup 1B (except radish), Okra, Turnip Greens, 

Cilantro Leaves, Grapes Grown East of the Rocky Mountains and Rotational Crop Uses 

for Field Corn, Sweet Corn and Soybeans. D353909, D. Davis, 3/02/09 

Fenamidone – Addendum to 3/2/2009 Human Health Risk Assessment to Support Section 

3 Proposals to Add New Uses on the Root Vegetable Subgroup 1B (except radish), Okra, 

Turnip Greens, Cilantro Leaves, Grapes Grown East of the Rocky Mountains and 

Rotational Crop Uses for Field Corn, Sweet Corn and Soybeans. D364699, D. Davis, 

6/16/09 

Fenamidone (PC Code 046679) - Human-Health Risk Assessment for Proposed Uses on 

Cotton, Tobacco, Carrot, Sunflower, Brassica Vegetables (group 5), Leafy (except 

Brassica) Vegetables (group 4), Fruiting Vegetables (group 8) and Strawberry 

(rotational crop). D314116, T. Bloem, 6/21/07. 

Fenamidone: 3rd HIARC Report, TXR # 0052379, W. Dykstra, 2/19/04. 

Fenamidone HASPOC Report, TXR # 0054626, R. Mitkus, 6/19/07. 

Fenamidone MARC Memorandum, TXR # 0052287, T. Bloem, 5/25/04. 

Fenamidone: Residue Chemistry Summary Document to Support Label Amendment to 

Permit Rotation to All Cereal Grains, Except Rice and Establishment of Revised 

Tolerances for Inadvertent Residues. D391039, A. LaMay, 07/07/11. 

Fenamidone: Residue Chemistry Summary Document to Support New Uses and 

Tolerances on the Root Vegetable Subgroup 1B (except radish), Okra, Turnip Greens, 

Cilantro Leaves and Grapes Grown East of the Rocky Mountains. D352806, D. Davis, 

12/18/08. 

Fenamidone: Residue Chemistry Summary Document to Support New Rotational Crop 

Uses and Tolerances on Field Corn, Sweet Corn and Soybean. D357372, A. LaMay, 

2/24/09. 

Fenamidone Drinking Water Assessment for Total Residues in Surface and Water for 

Uses on Root vegetables (except sugar beets; Subgroup 1B, except radishes), okra, turnip 

greens, cilantro, and grapes East of the Rockies. D352807, J. Hetrick, 10/9/08. 

Fenamidone – Acute and Chronic Aggregate Dietary (Food and Drinking Water) 

Exposure and Risk Assessments to Support the Label Amendment to Permit Rotation to 

All Cereal Grain, Except Rice and Establish Revised Tolerances for Inadvertent 

Residues. D391040, A. LaMay, 07/07/11. 
Fenamidone Human Health Risk Assessment D386359 

Page 21 of 30 

Fenamidone – Acute and Chronic Aggregate Dietary (Food and Drinking Water) 

Exposure and Risk Assessments for Section 3 Registration Actions to Add New Uses on 

the Root Vegetable Subgroup 1B (except radish), Okra, Turnip Greens, Cilantro Leaves, 

Grapes Grown East of the Rocky Mountains and Rotational Crop Uses for Field Corn, 

Sweet Corn and Soybeans. D362172, D. Davis, 2/23/09. 

Fenamidone: Occupational Exposure/Risk Assessment for Proposed New Use of 

Fenamidone on Root vegetables (except sugar beet, subgroup 1B, except radish), okra, 

turnip greens, cilantro, and grapes east of the Rocky Mountains. D352806, A. LaMay, 

2/24/09 
Fenamidone Human Health Risk Assessment D386359 

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Attachment 1. Chemical Structures 

Structure and Nomenclature Information for Fenamidone and its Metabolites 

Name Structure 

Fenamidone; RPA 407213 

(5S)-3,5-dihydro-5-methyl-2-(methylthio)-5-phenyl-3-

(phenylamino)-4H-imidazol-4-one 

CH3

N

O N S

CH3

HN

*

14C-N-phenyl-fenamidone 

CH3

N

O N S

CH3

HN

*

14C-C-phenyl-fenamidone 

DA-Fen; RPA 408056 (racemic mixture) 

5-methyl-2-methylthio-5-phenyl-3,5-dihydroimidazol-4-

one 

RPA 405862 (racemic mixture) 

RPA 410193 (S enantiomer) 

5-methyl-5-phenyl-3-phenylamino-imidazolidin-2,4-dione 

DADK-Fen; RPA 717879 (racemic mixture) 

5-methyl-5-phenylimidazolidine-2,4-dione 

RPA 413255 

(5S)-5-methyl-2-(methylthio)-3-[(2-nitrophenyl)amino]-5-

phenyl-3,5-dihydro-4H-imidazol-4-one 

RPA 410914 (racemic mixture) 

N

N

CH3

O S

CH3

N

H

N

N

CH3

O S

CH3

H

N

H

N

CH3

O O

N

H

N

H

N

CH3

O O

H
Fenamidone Human Health Risk Assessment D386359 

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Structure and Nomenclature Information for Fenamidone and its Metabolites 

Name Structure 

RPA 411639 

(5S)-5-methyl-2-(methylthio)-3-[(4-nitrophenyl)amino]-5-

phenyl-3,5-dihydro-4H-imidazol-4-one 

RPA 406012 (racemic mixture) 

RPA 410995 

(5S)-5-methyl-3-[(2-nitrophenyl)amino]-5-

phenylimidazolidine-2,4-dione 

RPA 409446 

(5S)-5-methyl-3-[(4-nitrophenyl)amino]-5-

phenylimidazolidine-2,4-dione 

RPA 407213-dimer 

(5S,5'S)-3,3'-(1,2-diphenylhydrazine-1,2-diyl)bis[5-

methyl-2-(methylthio)-5-phenyl-3,5-dihydro-4Himidazol-4-one] 

aniline 

 
Fenamidone Human Health Risk Assessment D386359 

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Attachment 2. Acute Toxicity of Fenamidone 

Table 4: 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 Primary Eye Irritation 45386015 moderate irritant III 

870.2500 Primary Skin Irritation 45386014 non-irritating IV 

870.2600 Dermal Sensitization 45386016 not a sensitizer not applicable
Fenamidone Human Health Risk Assessment D386359 

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Attachment 3. Toxicity Profile for Fenamidone 

Guideline No./Study Type Results

870.3100a 

90-Day oral toxicity rodents with 

parent- rat 

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 

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 metaboliterat. 

NOAEL = 6.419/7.725 mg/kg/day in males and females, respectively. 

LOAEL = 32.860/39.111 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 

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-mice 

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 toxicity non-rodents 

with parent-dogs 

NOAEL =500 mg/kg/day for males and females (HDT) 

LOAEL = not determined

870.3200 

21-Day dermal toxicity- rat 

NOAEL = 1000 mg/kg/day in females. Not established in males. 

LOAEL = 1000 mg/kg/day in males based on decreased body weight, body 

weight gain and food consumption. The LOAEL was not observed in 

females. 

870.3700a 

Prenatal developmental with 

parent-rats 

Maternal NOAEL = 150 mg/kg/day 

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

gains, and decreased food consumption. 

Developmental NOAEL = 150 mg/kg/day 

Developmental LOAEL = 1000 mg/kg/day based on decreased fetal 

weights and incomplete ossification. 

870.3700b 

Prenatal developmental with 

parent-rabbits 

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.
Fenamidone Human Health Risk Assessment D386359 

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Guideline No./Study Type Results

870.3800 

Reproduction and fertility effects 

with parent- rat 

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)-dogs 

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 - rats 

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 - mice 

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. 

870.5265 

Gene Mutation 

with parent 

Fenamidone was non-mutagenic when tested up to or cytotoxic levels, in 

presence and absence of activation, in S. typhimurium strains TA98, 

TA100, TA102, TA1535 and TA1537. 

870.5265 

Gene Mutation 

with RPA 410193 

RPA 410193 was non-mutagenic when tested up to 5,000 ug/plate or 

cytotoxic levels, in presence and absence of activation, in S. typhimurium 

strains TA98, TA100, TA1535, and TA1537 and E. coli strain WP2uvA. 

870.5265 

Gene Mutation 

with RPA 412708 

RPA 412708 was non-mutagenic when tested up to 5,000 ug/plate or 

cytotoxic levels, in presence and absence of activation, in S. typhimurium 

strains TA98, TA100, TA1535, and TA1537 and E. coli strain WP2uvrA. 

870.5265 

Gene Mutation 

with RPA 412636 

RPA 412636 was non-mutagenic when tested up to 5,000 ug/plate or 

cytotoxic levels, in presence and absence of activation, in S. typhimurium 

strains TA98, TA100, TA1535, and TA1537 and E. coli strain WP2uvrA. 

870.5300 

Mouse lymphoma cell/mammalian 

activation gene forward mutation 

assay (L5178Y hgprt) with parent 

Fenamidone 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 

412636. 

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. 

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. 
Fenamidone Human Health Risk Assessment D386359 

Page 27 of 30 

Guideline No./Study Type Results

870.5375

In vitro mammalian cytogenetics 

(Chromosomal aberration assay in 

human peripheral blood) with 

parent. 

There was evidence of chromosome aberrations both in the presence and 

absence of S-9 activation. 

870.5395 

In vivo Mouse Micronucleus 

with parent. 

Fenamidone was negative for chromosomal aberrations in the cytogenetic 

assay when administered singly or for 2 days to CD-1 mice up to 2000 

mg/kg/day. 

870.5395 

In vivo mouse micronucleus 

with RPA 412636 

RPA 412636 was not clastogenic in the mouse micronucleus test up to 350 

mg/kg (HDT). 

870.5395 

In vivo mouse micronucleus with 

RPA 412708 

RPA 412708 was not clastogenic in the mouse micronucleus assay when 

tested once daily for 2 days up to cytotoxic levels of 150 mg/kg. 

870.5395 

In vivo mouse micronucleus with 

RPA 410193 

RPA 410193 was not clastogenic in the mouse micronucleus assay when 

tested once daily for 2 days up to cytotoxic levels of 2000 mg/kg. 

870.5550 

Unscheduled DNA synthesis 

with parent 

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-rat 

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-rat 

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 

maternal NOAEL ≥ 429 mg/kg/day 

maternal LOAEL not established 

offpsring NOAEL = 92.3 mg/kg/day 

offspring LOAEL = 429 mg/kg/day based on decreased body weight (9-

11%) and body weight gain (8-20%) during pre-weaning and decreased 

body weight (4-6%) during post-weaning 

870.7485 

Metabolism and pharmacokinetics 

- rat 

In a rat metabolism study with C14- labeled fenamidone, Sprague-Dawley 

rats received doses of 3 mg/kg (single, low dose), 3 mg/kg x 14 days 

(repeated low dose) and 300 mg/kg (high dose). Fenamidone was well 

absorbed and rapidly excreted, primarily in the urine and bile, at the low 

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

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

of radioactivity were primarily found in the liver at the single low dose and 

in the thyroid in the repeated and high dose studies. Metabolite 

identification included RPA 408056 (racemic form of RPA 412708) and 

RPA 717879 (racemic mixture of RPA 412636) 

870.7600 

Dermal Penetration-rat 

Dermal penetration approximated 10% using the EPA protocol for 10 hours 

of exposure. 
Fenamidone Human Health Risk Assessment D386359 

Page 28 of 30 

Guideline No./Study Type Results

870.7800 Immunotoxicity 

Immunotoxicity study in rats showed a potential immunosuppression at the 

high dose. The LOAEL for immunotoxicity was 5000 ppm (387.4 

mg/kg/day) based on lower anti-SRBC IgM response and decreased 

thymus weights; the NOAEL is 1500 ppm (117.8 mg/kg/day). The 

systemic toxicity LOAEL was 5000 ppm (387.4 mg/kg/day) based on 

decreased body weights, body weight gains, and food consumption; the 

NOAEL is 1500 ppm (117.8 mg/kg/day). 
Fenamidone Human Health Risk Assessment D386359 

Page 29 of 30 

Attachment 4. International Residue Limit Status Sheet 

Fenamidone (PC Code 046679; 05/03/2011) 

Summary of US and International Tolerances and Maximum Residue Limits 

Residue Definition: 

US Canada Mexico2 Codex3

40 CFR 180.579: 

Plants: fenamidone (4H-Imidazol-4-one, 3,5-

dihydro-5-methyl-2-(methylthio)-5-phenyl-3 

(phenylamino)-, (S)-) 

Livestock: fenamidone (4H-imidazol-4-one, 

3,5-dihydro-5-methyl-2-(methylthio)-5-

phenyl-3-(phenylamino), (S)-) and its 

metabolite RPA 717879 (2,4-

imidazolidinedione, 5-methyl-5-phenyl), 

expressed as parent compound 

Indirect or inadvertent residues:. fenamidone 

(4-H-imidazol-4-one, 3,5-dihydro-5-methyl-2-

(methylthio)-5-phenyl-3-(phenylamino, (S)-) 

and its metabolite RPA 717879 (2,4-

imidazolidinedione, 5-methyl-5-phenyl)

Plants/Livestock 

(5S)-3,5-dihydro-5-methyl-2-

(methylthio)-5-phenyl-3- 

(phenylamino)-4H-imidazol-4-

one 

None None 

Commodity1 

Tolerance (ppm) /Maximum Residue Limit 

(mg/kg) 

US Canada Mexico2 Codex3

Grain, cereal, group 15, except rice 0.1 None None None 

Grain, cereal, forage, fodder and straw, group 

16, forage 0.3 None None None 

Grain, cereal, forage, fodder and straw, group 

16, hay 0.5 None None None 

Grain, cereal, forage, fodder and straw, group 

16, stover 0.5 None None None 

Grain, cereal, forage, fodder and straw, group 

16, straw 0.5 None None None 

Completed: M. Negussie; 05/03/2011 

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 * = absent at the limit of quantitation; Po = postharvest treatment, such as treatment of stored grains. PoP 

= processed postharvest treated commodity, such as processing of treated stored wheat. (fat) = to be 

measured on the fat portion of the sample. MRLs indicated as proposed have not been finalized by the 

CCPR and the CAC. 

 
Fenamidone Human Health Risk Assessment D386359 

Page 30 of 30 

Attachment 5. Review of Human Research 

This risk assessment does not rely on data from studies in which human subjects were 

intentionally exposed to a pesticide or other chemicals.