Fenamidone Human Health Risk Assessment DP No. 386359

Page 1 of 30 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 hu man health risk assessment for the proposed establishment of tolerances fo r inadvertent residues of fena midone in/on the cereal grains and forage, fodder and hay of cereal grai ns crop groups (CG 15 and 16, except rice).Fenamidone Human Health Risk Assessment D386359

Page 2 of 30 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 ................................................................. 30Fenamidone Human Health Risk Assessment D386359

Page 3 of 30 1.0 Executive Summary

Fenamidone is a broad-spectrum foliar fungicide currently registered for application to a variety of field crops includi ng, bulb vegetables, tuberous a nd corm vegetables, fruiting vegetables and leafy vegetables. The regist rant (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 da ta 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 rota tional crop tolerances in alfalfa.

HED has concluded there are sufficient data to support the requested establishment of rotational crop tolerances for additional comm odities in the cereal grains group based on submitted data. At this time, HED cannot re commend 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 fo r inadvertent residues of fena midone in/on the cereal grains crop group. Fenamidone has low acute toxicity via the oral, dermal, and inhalation routes. It produces moderate eye irrita tion, 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. De velopmental toxicity was observed in rats at the limit dose; no developmental toxicity wa s observed in rabbits. In the reproductive toxicity study in rats, decreased absolu te 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 spl een weights were observed. Reproductive toxicity was not observed. Based on the av ailable data and the selection of risk assessment endpoints that are pr otective of developmental eff ects, there are no residual uncertainties with regard to pre- and/or post-natal toxicit y. Therefore, the FQPA safety factor was reduced to 1X. An acceptable guide line immunotoxicity study in rats has been reviewed. While the study showed a poten tial immunosuppression at the highest dose tested, the existing risk assessment points of departure are lowe r and are therefore protective of this potential effect. Fenamidone is not likely to be a human carcinogen and studies indicate that th ere is no concern for mutagenicity for fenamidone.

Endpoint Selection Risk assessment endpoints were selected fo r 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 gaitFenamidone Human Health Risk Assessment D386359

Page 4 of 30 in female rats at a LOAEL of 500 mg/kg [NOAEL = 125 mg/kg]. The chronic PAD (cPAD) was derived from the combined chr onic toxicity/carcinogeni city 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 extrap olation, 10X for intraspecies variation, and the FQPA sa fety 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 i ssues with respect to international harmonization as a result of the proposed es tablishment of tolerances for inadvertent residues that are the subj ect of this petition.

Conservative acute and chr onic dietary risk assessments were conducted which used maximum field trial residue values, assume d 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 exis ting 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 th e existing and newly proposed uses of fenamidone.

Residential/Occupational Exposure There is no occupational or residential assessm ent 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 hum an subjects were intentionally exposed to a pesticide or other chemical.

Potential areas of environmental justice concer ns, to the extent possi ble, were considered in this human health risk assessment, in accordance with U.S. Executive Order 12898, "Federal Actions to Address Environmenta l Justice in Minority Populations and LowIncome Populations. 1 "

Regulatory Recommendations and Data Needs The following updated regulatory recommenda tion 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.pdfFenamidone Human Health Risk Assessment D386359

Page 5 of 30 risks of concern that would preclude the es tablishment 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 th e 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 a nd straw, group 16, forage...............................0.3 ppm Grain, cereal, forage, fodder and straw, group 16, hay..................................0.5 ppm Grain, cereal, forage, fodder a nd straw, group 16, stover ...............................0.5 ppm Grain, cereal, forage, fodder a nd straw, group 16, straw ...............................0.5 ppm

NOTE TO RD: The previously established rotational cr op 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 fo r residues of the fungicide fenamidone, including its metabolites and degrad ates, 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 recommendati on, 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 re quested rotational crop tolerances of dried shelled pea and bean (crop group 6C) and folia ge 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 numbe r of alfalfa trials for the establishment of rotational crop tolerances in alfalfa.Fenamidone Human Health Risk Assessment D386359

Page 6 of 30 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 includi ng, bulb vegetables, tuberous a nd 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 inadvert ent residues on wheat, sweet corn and field corn to support allowing ro tation to these commodities with a 30-day PBI.

The registrant is proposing to revise the fe namidone 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 inte rval (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 cer eal grains crop group (CG 15, except rice) and the forage, fodder and straw of the cerea l grains crop group (C G 16, except rice).

The registrant has also requested that the existing soybean rotational crop data be translated to establish rotational crop tolera nces 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 woul d like to establish rotational crop tolerances in alfalfa. The registrant has proposed to reduce the numbe r of alfalfa rotational trials from 12 to 10, based on an overlap analysis between growi ng regions of primary and rotational crops.

2.2 Structure and Nomenclature

Table 2.2, below contains a summary of th e test compound nomenclature. Additional fenamidone information, including stereoisomer structures and meta bolite nomenclature and structures is contained in Attachment 1.Fenamidone Human Health Risk Assessment D386359

Page 7 of 30 Table 2.2. Fenamidone Nomenclature.

Compound Chemical Structure

Common name fenamidone Company experimental name RPA 407213 IUPAC name ( S )-1-anilino-4-methyl-2-methylt hio-4-phenylimidazolin-5-one CAS name (5 S )-3,5-dihydro-5-methyl-2-(methylthio)-5-phenyl-3-(phenylamino)-4 H -imidazol-4-one CAS registry number 161326-34-7 End-use product (EP) Reason® 500 SC (44.4% S-fe namidone; 4.13 lb ai/gal; EPA Reg. No. 264-695)

2.3 Physical and Chemical Properties

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

Table 2.3. Physicochemical Properti es 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, pK
a Does not dissociate in the pH range of 1-13 MRID 45385714 Octanol/water partition coefficient, Log(K OW ) 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 pr ofile for fenamidone and the newly available immunotoxicity study (MRID 48321101) to determin e 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 CH 3

O S CH 3

N HFenamidone Human Health Risk Assessment D386359

Page 8 of 30 assay tests indicated that female rats were more sensitive to the parent than male rats.

The target organs in chronic studies in the m ouse 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 bot h sexes as the most se nsitive indicator of toxicity. At higher doses, follicular cells and th e liver were affected. The similarity in the systemic NOAELs and the type of toxicity obs erved (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 basi s, 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 studi es or the 2-generati on rat reproduction study. In rabbits, there were no devel opmental 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 reprodu ction study in rats), decreased absolute brain weight and pup body weight occurr ed at the same dose levels as decreased absolute brain weight and parental body weight, food consump tion, and increased liver and spleen weight. There were no effects on fertility and other meas ured 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 observe d only in high dose males. Additionally, decreased brain wei ght occurred in the rat reproduction study, as noted above.

The Agency previously required the registra nt to submit an abbreviated DNT in the Sprague Dawley rat with measurements of br ain weight and brain mo rphometric data to confirm findings in the full DNT conducted in th e Wistar rat as a condi tion of registration. Subsequent to this requirement, at th e 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 Agen cy’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 im munotoxicity 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 fo r technical fenamidone are included in this assessment as Attachment 2. The toxicity profile for fenamidone is summarized inFenamidone Human Health Risk Assessment D386359

Page 9 of 30 Attachment 3.

3.2 Cancer Classification and Risk Assessment Recommendation

Based on the negative carci nogenic potential of fenami done 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 nega tive 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 th e 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 pot ential pre-natal and/ or post-natal risks to infants and children.

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

utero exposure in the developmental t oxicity 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 we re 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 mi nimal. HED concludes that the acute and chronic exposure estimates in this analysis are unlikel y to underestimate actual exposure. The drinking water component of the dietary assessment utilizes water concentration values ge nerated 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 da ta gaps that would affect the FQPA safety factor.Fenamidone Human Health Risk Assessment D386359

Page 10 of 30 3.4 Summary of Points of Departure a nd 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 UF A = 10x
UF H = 10x FQPA SF= 1 Acute RfD = 1.25 mg/kg/day

Acute PAD = 1.25 mg/kg/day Acute Neurotoxicity in Rats : LOAEL = 500 mg/kg/day based on urination, staining/soiling of the anogenital region, mucous in the feces, and unsteady gait in the females

Chronic Dietary (All populations) NOAEL= 2.83 mg/kg/day UF A = 10x UF H = 10x FQPA SF= 1 Chronic RfD = 0.0283 mg/kg/day

Chronic PAD = 0.0283 mg/kg/day 2 Year Chronic Toxici ty/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 po tential of fenamidone in rats a nd mice, HED classi fied 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 obs erved dose-response data and used to mar k the beginning of extrapolation to determine risk associated with lower environmenta lly relevant human exposures. NOAEL = no observed adverse effect level. LOAEL = lowest observed adverse effect level. UF = uncertainty factor. UF A = extrapolation from animal to human (intraspecies). UF H = potential variation in sensitivity among member s of the human population (interspecies). UF L = use of a LOAEL to extrapolate a NOAEL. UF S = use of a short-term study for long-term risk assessment. UF DB = 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), EP A has developed the Endocrine Disruptor Screening Program (EDSP) to determine whet her 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 em ploys a two-tiered approach to making the statutorily required determinations. Tier 1 cons ists of a battery of 11 screening assays to identify the potential of a chemical substan ce to interact with th e estrogen, androgen, or thyroid (E, A, or T) hormona l 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. Ti er 2 testing is designed to identify any adverse endocrine related effects caused by th e substance, and esta blish a dose-response relationship between the dose a nd the E, A, or T effect.

Between October 2009 and February 2010, EPA issu ed 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 humanFenamidone Human Health Risk Assessment D386359

Page 11 of 30 exposure through pathways such as food and wa ter, residential activity, and certain postapplication agricultural s cenarios. This list should not be construed as a list of known or likely endocrine disruptors.

Fenamidone is not among the group of 58 pesticid e 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 anticip ates issuing future EDSP test orders/data call-ins for all pesticide active ingredients.

For further information on the status of the ED SP, 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, animal s, rotational crops and water is adequately understood based on previously submitted data deta iled in the citation above. The residues of concern for tolerance setting and risk asse ssment 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 fena midone 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 met hodology 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 forFenamidone Human Health Risk Assessment D386359

Page 12 of 30 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 radiovali dated. Further the method has undergone successful ILV (independent laboratory valida tion) as well as validation by the Agency on a number of commodities including pot ato, cucumber, cantaloupe, lettuce, onion, tomato (fruit, paste, and puree) , spinach, and wheat (forage, hay, straw, grain, bran, flour, shorts, germ, and middlings). HED concludes th at this method is also suitable to enforce the new plant tolerances proposed in this pe tition. HED notes th at since residues of fenamidone are detected through FDA Multi-Resi due 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 direct ly into the acute and chronic dietary risk

assessments.

Monitoring data are not availabl e for residues of fenamidone and its metabolites in water; therefore EFED has provided modeled va lues for ground and surface water. The modeled EDWCs (estimated drinking water c oncentrations) are repo rted for parent and its degradation products, RPA-41263 6, 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 m odel 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 pe rcent 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 μ g/L for the 1 in 10 year da ily peak concentration, 12.86

μ g/L for the 1 in 10 year annual average concentration, and 6.89 μ g/L for the 30 year annual average concentration. The maximum co ncentration of total fenamidone residues in shallow groundwater are not expected to exceed 178 μ g/L.

For both the acute and chronic dietary anal ysis, HED will use the maximum ground water EDWC of 178 μ g/L (0.178 ppm), since it is the highe st 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 wh eat and corn support the establishment ofFenamidone 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) commoditie s with a 30-day plant back interval (PBI). The wheat, sweet corn a nd field corn residue results fr om the rotational crop trials were similar; there were no detectible residu es 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 conc urs 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 tole rance 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 diet ary risk assessment are show n in the table below.Fenamidone Human Health Risk Assessment D386359

Page 14 of 30 Table 4.4.2. Summary of New Residue Valu es 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 resi dues 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 swee t 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 tolera nces for the cereal grains, the residue data for corn were used in the dietary assessment since specific residue data are ava ilable for these crops. Residue data for wheat were used for all other cereal grains for th e 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 proces sing. Given that (1) th is request is for a rotational crop use and there were no detectib le 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 residue s 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

Page 15 of 30 Animal Commodities Approval of this action would permit rotation to the following feed items: barley grain, hay, and straw; popcorn grain and stover; mille t grain, forage, hay and straw; oat grain, forage, hay and straw; rye gr ain, forage, and straw, sorghum grain, forage, and stover. There are currently tolerances for inadvert ent residues on wheat, sweet corn and field corn. HED has previously calculated a di etary burden for lives tock which includes residues of fenamidone and its regulated metabol ites 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 likel y to result in residues in feed items which are higher than residues in feed items curren tly 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 rotati onal 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 ro tational crops of cerea l crops (CG 15 and 16, except rice). The existing wh eat and corn rotational crop da ta were used to support the establishment of tolerances in/on barley, buckwheat, millet, oats, popcorn, rye, sorghum, teosinte, and triticale based on simila r residue levels and use patterns.

There are no Codex, Canadian or Mexican MR Ls (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 petiti on. 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, strawFenamidone Human Health Risk Assessment D386359

Page 16 of 30 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 assessmen t 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 propos ed new uses of fenamidone resulted in an estimated risk equivalent to 3% of the acute population adjusted dose (aPAD) at the 95 th percentile. The most highly exposed subpop ulation was children 1 - 2 years with an estimated exposure equivalent to 5% of the aPAD at the 95 th percentile. There are no acute dietary risks of concern for the existi ng and newly proposed uses of fenamidone. Acute dietary results for all subgr oups are shown in Table 4.6.4, below.

4.6.2 Chronic Dietary Exposure/Risk

A conservative chronic dietary risk asse ssments 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 ne w uses of fenamidone resulted in an estimated risk equivalent to 52% of the ch ronic population adjust ed dose (cPAD). The most highly exposed subpopulation was childre n 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/AFenamidone Human Health Risk Assessment D386359

Page 17 of 30 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 w ith highest exposure are shown in bold. * PAD = population adjusted dose.

5.0 Residential Exposure/ Risk Pathway

There are no existing or proposed uses of fe namidone that result in residential exposure; therefore, residential handler and post application exposure an d risk assessments were not conducted for fenamidone.

6.0 Aggregate Risk Assessment s 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 bot h 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, respectivel y. There are no acute or chronic aggregate risks of concern for the existing and proposed uses of fenamidone.

7.0 Cumulative Risk Char acterization/Assessment

Unlike other pesticides for which EPA has fo llowed 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 subs tances 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 commonFenamidone 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 mech anism of toxicity and to evaluate the cumulative effects of such chemicals, see th e policy statements released by EPA’s Office of Pesticide Programs concer ning common mechanism determin ations 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 occupation al assessment was conducted for proposed rotational crops of all cereal grai ns (except rice), as there is no direct application to these crops and no uses that result in occupati onal exposure relevant to this assessment.

HED has completed several occupational expo sure 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). Ea rlier assessments incl ude uses on a number of agricultural crops, commercially grow n ornamentals, and seed treatments.

9.0 Data Needs and Label Recommendations

9.1 Toxicology

 None

9.2 Residue Chemistry

Prior to a favorable recommendati on, 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 concer ns, to the extent possi ble, were considered in this human health risk assessment, in accordance with U.S. Executive Order 12898, "Federal Actions to Address Environmenta l 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-es tablished 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 re sidential setting. Ex tensive data on foodFenamidone Human Health Risk Assessment D386359

Page 19 of 30 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 re gion of the country. Additionally, OPP is able to assess dietary exposure to sma ller, specialized subgr oups and exposure assessments are performed when conditions or circumstances warrant. Whenever appropriate, non-dietary expos ures based on home use of pesticide products and associated risks for adult applicators and fo r toddlers, youths, and adults entering or playing on treated areas postapplication are evaluated. Further considerations are currently in development as OPP has co mmitted resources and expertise to the development of specialized software and mode ls that consider exposure to bystanders and farm workers as well as lifestyle and tr aditional dietary patterns among specific subgroups.Fenamidone Human Health Risk Assessment D386359

Page 20 of 30 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 th e 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 Ve getable Subgroup 1B (except radish), Okra, Turnip Greens, Cilantro Leaves, Grape s 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) - Hu man-Health Risk Assessme nt 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: 3 rd 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 Docu ment 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 Docume nt 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 Tota l 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 th e Label Amendment to Permit Rotation to All Cereal Grain, Except Rice and Establis h 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 Ac tions 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 Asse ssment 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, 2/24/09Fenamidone Human Health Risk Assessment D386359

Page 22 of 30 Attachment 1. Chemical Structures

Structure and Nomenclature Informati on for Fenamidone and its Metabolites

Name Structure

Fenamidone ; RPA 407213

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

N O S CH 3

N H

*

14 C-N-phenyl-fenamidone CH 3 N

N O S CH 3

N H *

14 C-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

(5 S )-5-methyl-2-(methylthio)-3-[(2-nitrophenyl)amino]-5- phenyl-3,5-dihydro-4 H -imidazol-4-one

RPA 410914 (racemic mixture) N

N CH 3

O S CH 3

N H

N

N CH 3

O S CH 3

H

N H

N CH 3

O O

N H

N H

N CH 3

O O

HFenamidone Human Health Risk Assessment D386359

Page 23 of 30 Structure and Nomenclature Informati on for Fenamidone and its Metabolites

Name Structure

RPA 411639

(5 S )-5-methyl-2-(methylthio)-3-[(4-nitrophenyl)amino]-5- phenyl-3,5-dihydro-4 H -imidazol-4-one

RPA 406012 (racemic mixture)

RPA 410995

(5 S )-5-methyl-3-[(2-nitrophenyl)amino]-5- phenylimidazolidine-2,4-dione

RPA 409446

(5 S )-5-methyl-3-[(4-nitrophenyl)amino]-5- phenylimidazolidine-2,4-dione

RPA 407213-dimer

(5 S ,5' S )-3,3'-(1,2-diphenylhydrazine-1,2-diyl)bis[5- methyl-2-(methylthio)-5-phenyl-3,5-dihydro-4 H

imidazol-4-one]

anilineFenamidone Human Health Risk Assessment D386359

Page 24 of 30 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 LD 50 = 2028 mg/kg (F)
LD 50 > 5000 mg/kg (M) III

870.1200 Acute Dermal 45386012 LD 50 > 2000 mg/kg III

870.1300 Acute Inhalation 45386013 LC 50 > 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 applicableFenamidone Human Health Risk Assessment D386359

Page 25 of 30 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 withthe 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 liv er 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 hepatotoxi city 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

Page 26 of 30 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 pr oliferation 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 dose s 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 aber rations 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 f eces, 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, primaril y 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 incl uded RPA 408056 (racemic fo rm 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 Mexico 2 Codex 3

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

one None None

Commodity 1 Tolerance (ppm) /Maximum Residue Limit (mg/kg) US Canada Mexico 2 Codex 3 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 comm odity, such as processing of treat ed 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.