Page 1 of 55 UNITED STATES ENVIRONMENTAL PROTECTION AGENCY WASHINGTON, D. C. 20460 OFFICE OF PREVENTION, PESTICIDES AND TOXIC SUBSTANCES August 3, 2006 MEMORANDUM Subject: Fenbuconazole: Human Health Risk Assessment for Proposed Uses on Almonds, Apples, Bananas, Bushberries, Citrus Fruit, Cranberries, Grapes, Peanuts, Pecans, Stone Fruits, Sugar Beets, and Wheat. PC Code: 129011, DP Barcode: D316607 Petition Nos. ( see below).

Regulatory Action: Section 3 Registration Action Risk Assessment Type: Single Chemical Aggregate From: Margarita Collantes, Risk Assessor, Biologist Michael Doherty, Chemist Kim Harper, Toxicologist Registration Action Branch 2 Health Effects Division ( 7509P)

Through: Richard Loranger, Branch Senior Scientist Registration Action Branch 2 Health Effects Division ( 7509P)

Christina Swartz, Branch Chief Registration Action Branch 2 Health Effects Division ( 7509P)

To: John Bazuin, PM25 Fungicide Branch Registration Division ( 7505P)

The following petition numbers are addressed within this risk assessment: 2F4127; 2F4135; 7F4887; 7F4900; 3H5663; 9F6024; 1F3989; 1F3995; 2F4154; 0E6208; 3F4194; 4H5689; 4F6879; 1F3989; 1E6252; 9E5041 Page 2 of 55 Table of Contents 1.0 Executive Summary ........................................................................................................ 4 2.0 Ingredient Profile ............................................................................................................ 7 2.1 Summary of Registered/ Proposed Uses........................................................................ 8 2.2 Structure and Nomenclature ...................................................................................... 11 2.3 Physical and Chemical Properties .............................................................................. 13 3.0 Metabolism Assessment ................................................................................................ 11 3.1 Comparative Metabolic Profile .................................................................................. 11 3.2 Nature of the Residue in Foods.................................................................................. 13 3.2.1. Description of Primary Crop Metabolism........................................................... 12 3.2.2 Description of Livestock Metabolism................................................................. 12 3.2.3 Description of Rotational Crop Metabolism....................................................... 13 3.3 Environmental Degradation....................................................................................... 13 3.4 Tabular Summary of Metabolites and Degradates...................................................... 13 3.5 Toxicity Profile of Major Metabolites and Degradates............................................... 15 3.6 Summary of Residues for Tolerance Expression and Risk Assessment ...................... 15 3.6.1 Tabular Summary .............................................................................................. 15 3.6.2 Rationale for Inclusion of Metabolites and Degradates....................................... 16 4.0 Hazard Characterization/ Assessment.................................................................................. 16 4.1 Hazard Characterization ............................................................................................ 17 4.2 FQPA Hazard Considerations .................................................................................... 28 4.2.1 Adequacy of the Toxicity Data Base .................................................................. 28 4.2.2 Evidence of Neurotoxicity ................................................................................. 28 4.2.3 Developmental Toxicity Studies ........................................................................ 28 4.2.4 Reproductive Toxicity Study.............................................................................. 28 4.2.5 Additional Information from Literature Sources................................................. 29 4.2.6 Pre and/ or Postnatal Toxicity............................................................................... 29 <IP_ADDRESS> Determination of Susceptibility...................................................................... 29 <IP_ADDRESS> Degree of Concern Analysis and Residual Uncertainties for Pre and/ or Postnatal Susceptibility ........................................................................................................ 29 4.3 Recommendation for a Developmental Neurotoxicity Study...................................... 29 4.4 Hazard Identification and Toxicity Endpoint Selection .............................................. 29 4.4.1 Acute Reference Dose ( aRfD)  Females age 13 49 ................................................ 29 4.4.2 Acute Reference Dose ( aRfD)  General Population 4.4.3 Chronic Reference Dose ( cRfD)......................................................................... 30 4.4.4 Incidental Oral Exposure ( Short and Intermediate Term) ................................... 30 4.4.5 Dermal Absorption ............................................................................................ 30 4.4.6 Dermal Exposure ( Short, Intermediate and Long Term) ..................................... 30 4.4.7 Inhalation Exposure ( Short, Intermediate and Long Term) ................................. 31 4.4.8 Margins of Exposure.......................................................................................... 31 4.4.9 Recommendation for Aggregate Exposure Risk Assessments ............................ 31 4.4.10 Classification of Carcinogenic Potential............................................................. 31 4.5 Special FQPA Safety Factor ...................................................................................... 34 4.6 Endocrine disruption ................................................................................................. 34 Page 3 of 55 5.0 Public Health Data ........................................................................................................ 32 5.1 Incident Reports ........................................................................................................ 32 6.0 Exposure Characterization/ Assessment .............................................................................. 32 6.1 Dietary Exposure/ Risk Pathway................................................................................. 32 6.1.1 Residue Profile .................................................................................................. 32 6.1.2 Acute and Chronic Dietary Exposure and Risk................................................... 36 6.2 Water Exposure/ Risk Pathway................................................................................... 35 6.3 Residential ( Non Occupational) Exposure/ Risk Pathway........................................... 36 6.3.1 Other ( Spray Drift, etc.) ..................................................................................... 36 7.0 Aggregate Risk Assessments and Risk Characterization ................................................ 36 7.1 Acute Aggregate Risk................................................................................................ 39 7.2 Short Term Aggregate Risk....................................................................................... 37 7.3 Intermediate Term Aggregate Risk............................................................................ 37 7.4 Long Term Aggregate Risk ....................................................................................... 37 7.5 Cancer Risk............................................................................................................... 38 8.0 Cumulative Risk Characterization/ Assessment .............................................................. 38 9.0 Occupational Exposure/ Risk Pathway ........................................................................... 39 9.1 Short/ Intermediate/ Long Term Handler Risk............................................................. 39 9.2 Short/ Intermediate/ Long Term Postapplication Risk.................................................. 49 10.0 Data Needs and Label Requirements ............................................................................. 52 10.1 Toxicology ................................................................................................................ 52 10.2 Residue Chemistry .................................................................................................... 52 10.3 Occupational and Residential Exposure ..................................................................... 53 References: ............................................................................................................................... 54 Appendices ............................................................................................................................... 55 Page 4 of 55 1.0 EXECUTIVE SUMMARY A human health risk assessment has been conducted to support the proposed new uses of fenbuconazole and associated tolerances submitted for a Section 3 registration on almonds, apples, bushberries, citrus, cranberries, grapes ( tolerance only), peanuts, pecans, stone fruit, sugar beets, and wheat. Fenbuconazole, ( alpha( 2( 4 chlorophenyl) ethyl) alpha phenyl 3( 1H 1,2,4 triazole) 1 propanenitrile), is a broad spectrum, triazole fungicide. It is formulated in wettable powder ( WP, 75% a. i.) and flowable concentrate ( FlC, 2 lb a. i./ gal) forms. Fenbuconazole may be applied by groundboom, airblast or aerial equipment. The application rates as specified on proposed registered labels vary from 0.062 to 0.19 lbs a. i./ acre depending on the crop.

Toxicology The Health Effects Division ( HED) has evaluated the toxicity data submitted by the petitioner and has found it to be of sufficient scope and quality to assess the human health hazards associated with fenbuconazole, including potential developmental, reproductive and neurotoxic effects. Fenbuconazole targets the liver and, to a lesser degree, the thyroid. Fenbuconazole is classified as " Group C" carcinogen based on increased incidence of liver and thyroid cancers in mice and rats, respectively. Developmental and reproductive studies show that there is no evidence of increased qualitative or quantitative susceptibility of the offspring to fenbuconazole. There is no evidence that fenbuconazole affects the endocrine system. There are no data gaps associated with the toxicological database.

Metabolic Profile Adequate studies are available depicting the metabolism of [ 14C] fenbuconazole in rats, primary crops ( peaches, peanuts, wheat, sugar beets), rotational crops ( collards, turnips, wheat), and livestock ( lactating goats, laying hens). Based on these studies, HED has determined that the residues of concern for risk assessment are fenbuconazole and the following metabolites: RH 9129, RH 9130, RH 4911( peanut only), and RH 7905 ( peanut only). The current analytical enforcement method has been validated for the analysis of fenbuconazole, RH 9129, and RH 9130, which are the residues of concern for tolerance enforcement. Additionally, the HED has identified the common triazole metabolites ( 1,2,4 triazole, triazolylalanine, and triazolylacetic acid) as residues of concern for risk assessment. Risks associated with exposure to these compounds have been addressed in a separate assessment ( M. Doherty, et al., D322215, 2/ 7/ 06).

Residue Chemistry, Environmental Fate and Drinking Water HED also evaluated the residue chemistry database for fenbuconazole. The residue chemistry data are sufficient to evaluate the nature and magnitude of residues in crops and livestock, although there are minor data gaps. To evaluate acute, chronic, and cancer dietary risks, HED used information in the residue chemistry database along with modeled estimates of fenbuconazole in drinking water to conduct dietary ( food + water) exposure assessments. Results of those analyses indicate that dietary exposures do not present risks of concern for the U. S. population or any population subgroups. There are minor data gaps associated with the residue chemistry database. Page 5 of 55 Residential Exposure: Currently there are no registered residential uses associated with fenbuconazole.

Aggregate Exposure: There are no residential uses associated with fenbuconazole. Consequently, dietary sources are the only sources of exposure to fenbuconazole and a separate aggregate assessment is not required.

Occupational Exposure:

Based on the number of seasonal applications indicated on this product label and information provided by the registrant, handler exposures for the proposed new uses are expected to be shortand intermediate term in duration. Both cancer and non cancer risks were estimated. All noncancer mixer/ loader, applicator and flagger inhalation MOEs were greater than the level of concern ( MOE > 100) at baseline.

EPA considers handler cancer risk estimates greater than one in ten thousand ( 1 x 10 4) to be of concern, and attempts to mitigate such exposures so that cancer risk estimates are reduced to one in one million ( 1 x 10 6) or less, where feasible. The cancer risk for private farmers ranged from 6.1 x 10 9 to 1.3 x 10 6 , while the cancer risk for commercial farmers ranged from 1.8 x 10 8 to 4.0E x 10 6 using either baseline or PPE ( single layer clothing and gloves) mitigation. HED does not consider any of these scenarios as a risk to workers.

Long term dermal exposure as a result of postapplication activities is not expected. Therefore a non cancer postapplication exposure assessment was not required. All cancer risks were lower than 1 x 10 6 and therefore were not a risk concern.

Restricted Entry Interval The restricted entry interval ( REI) is based on the acute toxicity of fenbuconazole technical material which is classified as Category III and IV. Acute toxicity Category III and IV chemicals require a 12 hour REI. Therefore the 12 hour REI which appears on the Enable 2F Fungicide and Indar 75WSP labels are adequate.

Environmental Justice Considerations:

Potential areas of environmental justice concerns, to the extent possible, were considered in this human health risk assessment, in accordance with U. S. Executive Order 12898, " Federal Actions to Address Environmental Justice in Minority Populations and Low Income Populations," http:// www. eh. doe. gov/ oepa/ guidance/ justice/ eo12898. pdf).

As a part of every pesticide risk assessment, OPP considers a large variety of consumer subgroups according to well established procedures. In line with OPP policy, HED estimates risks to population subgroups from pesticide exposures that are based on patterns of that subgroup's food and water consumption, and activities in and around the home that involve Page 6 of 55 pesticide use in a residential setting. Extensive data on food 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, nondietary 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.

Review of Human Research:

This risk assessment does not rely on any data from studies in which human subjects were intentionally exposed to a pesticide or other chemical.

Conclusion Based on our analysis of the available data and on estimates of risk, HED is recommending that a conditional registration for fenbuconazole be granted and that permanent tolerances be established for combined residues of fenbuconazole [  [ 2( 4 chlorophenyl) ethyl]   phenyl 3( 1H 1,2,4 triazole) 1 propanenitrile] and its metabolites, cis 5( 4 chlorophenyl) dihydro 3 phenyl 3( 1H 1,2,4 triazole 1 ylmethyl) 2 3H furanone ( RH 9129) and trans 5 ( 4 chlorophenyl) dihydro 3 phenyl 3( 1H 1,2,4 triazole 1 ylmethyl) 2 3H furanone ( RH 9130) as follows:

Almond                  . 0.05 Almond, hulls                 1.0 Apple                   . 0.4 Apple, wet pomace..             .. 1.0 Banana                  ... 0.3 Bushberry subgroup 13B           .. 0.3 Fruit, citrus, group 10             . 1.0 Citrus, oil                 . 40.0 Citrus, dried pulp               . 5.0 Cranberry                 .. 0.5 Grape*                   . 1.0 Peanut                    0.1 Pecan                   . 0.05 Fruit, stone, group 12              . 1.0 Beet, sugar, roots                 0.3 Beet, sugar, tops                . 9.0 Beet, sugar, dried pulp...            .. 1.0 Beet, sugar, molasses              . 0.4 Wheat, grain      ..          .. 0.1 Page 7 of 55 Wheat, forage                 4.0 Wheat, hay                 . 8.0 Wheat, straw                .. 8.0 Grain, aspirated fractions     ..       6.0 Meat byproducts of cattle, horses, goats, and sheep .. 0.05 * The CFR entry should indicate that there is no U. S. registration on grapes as of the date of the Federal Notice establishing the tolerance.

The recommendation for a conditional registration is due to the residue chemistry data gaps associated with fenbuconazole as detailed in Section 10.2. In addition, as specified in HED's February 7, 2006 risk assessment ( M. Doherty et al, DP# 322215) for 1,2,4 triazole and its metabolites triazole alanine and triazole acetic acid, HED recommended that resolution of various issues be a condition of registration for new uses of triazole derivative fungicides and for new active ingredients which contain the 1,2,4 triazole ring. The requirement for a chronic toxicity/ oncogenicity study in male rats and female mice in the 2/ 7/ 2006 memo was later modified by HED to a 1 year chronic study in male and female rats ( Kit Farwell, DP# 321328, 5/ 10/ 2006). Therefore, HED recommends that the registration of the proposed new uses of fenbuconazole also be conditioned upon resolution of the following issues:

° Chemistry: Final two year storage stability study with 1,2,4 triazole; Resolution of concerns regarding the prevalence of conjugated residues of TA and the ability of the analytical method to quantify them. ° Toxicology: Free triazole:

  Developmental neurotoxicity study in rats;

  Chronic toxicity   1 year chronic rat study in males and females   Acute neurotoxicity study in rats [ This study, included in the original data requirements, was placed in reserve pending the results of the combined subchronic/ neurotoxicity study, in response to a previous waiver request. A new waiver request for this study was submitted in August 2005, and is under review.]; Triazole alanine:

  Developmental toxicity study in rabbits;

  Chronic toxicity study in rats, conducted according to current guidelines that include neurobehavioral assessments, with additional neuropathology evaluations conducted according to the neurotoxicity guidelines; Triazole acetic acid:

  Developmental toxicity study in rabbits;

  Combined 90 day feeding/ neurotoxicity study in rats. Page 8 of 55 2.0 INGREDIENT PROFILE Fenbuconazole is a broad spectrum, triazole type fungicide. It is formulated in wettable powder ( WP, 75% a. i.) and flowable concentrate ( FlC, 2 lb a. i./ gal) forms. The requested uses for fenbuconazole are summarized in Table 2.1.

2.1 Summary of Registered/ Proposed Uses Table 2.1. Summary of Directions for the Proposed/ Requested Uses of Fenbuconazole Application Timing, Type, and Equip. 1 Formulation [ EPA Reg. No.] Applic. Rate ( lb ai/ A) Max. No. Applic. per Season Max. Seasonal Applic. Rate ( lb ai/ A) PHI ( days) Use Directions and Limitations 2 Almond Broadcast foliar applications beginning at pink bud stage through petal fall. Ground or aerial equipment 2 lb/ gal FlC [ 62719 416]

75% WP [ 62719 421] 0.094 3 0.282 160 A minimum retreatment interval ( RTI) of 10 days is specified.

A non ionic surfactant should be used in the spray mix. Apple Broadcast foliar Unspecified equipment 2 lb/ gal FlC [ 62719 416] 0.12 4 0.5 14 A minimum retreatment interval of 7 days is specified. The grazing of livestock in treated areas is prohibited. The use of a non ionic surfactant in the spray mix is recommended. Banana Broadcast foliar applications beginning when leaves first appear Ground or aerial equipment 2 lb/ gal FlC [ 62719 416] 0.094 8 0.75 0 A minimum RTI of 14 days is specified. A non ionic surfactant should be used in the spray mix, and the use of an emulsifiable spray oil is recommended. Bushberry, Subgroup 13B Broadcast foliar applications beginning at bud break ( green tip) through fruit development. Ground or aerial equipment 75% WP [ 62719 421] 0.094 5 0.47 30 A minimum retreatment interval of 10 days specified. Do apply through any type of irrigation system. For ground and aerial applications, apply in a minimum volume of 10 and 20 gal/ A, respectively. A non ionic surfactant should be used in the spray mix. Citrus, Group 10 Broadcast foliar Unspecified equipment 2 lb/ gal FlC [ 62719 416] 0.125 3 0.375 0 A minimum retreatment interval is not specified. The grazing of livestock in treated areas is prohibited. The use Page 9 of 55 Table 2.1. Summary of Directions for the Proposed/ Requested Uses of Fenbuconazole Application Timing, Type, and Equip. 1 Formulation [ EPA Reg. No.] Applic. Rate ( lb ai/ A) Max. No. Applic. per Season Max. Seasonal Applic. Rate ( lb ai/ A) PHI ( days) Use Directions and Limitations 2 of a non ionic surfactant in the spray mix is recommended. Cranberry Broadcast foliar applications beginning when 50% of shoots show 3 inch of new growth, through fruit development. Ground or aerial equipment 75% WP [ 62719 421] 0.188 5 0.94 30 A minimum retreatment interval of 7 days is specified. Do apply through any type of irrigation system. For aerial applications, apply in a minimum volume of 10 gal/ A. A non ionic surfactant should be used in the spray mix. Grape ( Central and South America) Broadcast foliar application at flowering. Ground equipment 2 lb/ gal FlC 0.30 1 0.30 None Grapes ( Europe) Broadcast foliar applications beginning at 6 7 leaves unfolded through berry development. Ground equipment 50 g/ l EC 0.01 0.06 8 0.36 14 The supported minimum retreatment interval is 14 days.

Peanut Broadcast foliar beginning 4 weeks after planting or when disease first appears. Ground or aerial equipment 1 2 lb/ gal FlC [ 62719 416]

75% WP [ 62719 421] 0.125 8 1.0 14 A minimum retreatment interval of 10 days is specified. Do not feed hay or threshings or allow livestock to graze in treated areas. The minimum specified application volumes are 20 and 5 gal/ A for ground and aerial applications, respectively. A non ionic surfactant should be used in the spray mix. Pecan Broadcast foliar applications beginning at bud break up to shuck split. Ground or aerial equipment 2 lb/ gal FlC [ 62719 416]

75% WP [ 62719 421] [ 62719 443] 0.125 NS 0.75 28 Minimum RTIs are 10 days for applications between budbreak and pollination, and 14 days for cover sprays. Do not apply after shuck split or within 28 days of harvest. A non ionic surfactant should Page 10 of 55 Table 2.1. Summary of Directions for the Proposed/ Requested Uses of Fenbuconazole Application Timing, Type, and Equip. 1 Formulation [ EPA Reg. No.] Applic. Rate ( lb ai/ A) Max. No. Applic. per Season Max. Seasonal Applic. Rate ( lb ai/ A) PHI ( days) Use Directions and Limitations 2 be used in the spray mix. Stone Fruit, Group 12 Broadcast foliar applications beginning at early red bud stage through to crop maturity. Ground or aerial equipment 2 lb/ gal FlC [ 62719 416]

75% WP [ 62719 421] 0.094 4 0.75 ( 0.38) 3 0 A minimum RTI of 7 days is specified.

A non ionic surfactant should be used in the spray mix.

Sugar Beet Broadcast foliar applications when disease first appears. Ground or aerial equipment 4 2 lb/ gal FlC [ 62719 416] 0.125 4 0.5 14 A minimum retreatment interval of 10 days is specified. Do not feed treated tops to livestock. The minimum specified application volumes are 20 and 5 gal/ A for ground and aerial applications, respectively. A non ionic surfactant should be used in the spray mix. Wheat Broadcast foliar applications through heading ( Feekes growth stage 10.3 10.5) Ground or aerial equipment 4 2 lb/ gal FlC [ 62719 416]

75% WP [ 62719 421] 0.063 2 0.125 35 A minimum retreatment interval of 7 days is specified. Do not apply after completion of flowering ( Feekes growth stage 10.5) or within 35 days of harvest. Do not graze livestock in treated areas or cut the green crop for hay or silage. The minimum specified application volumes are 20 and 5 gal/ A for ground and aerial applications, respectively. A non ionic surfactant should be used in the spray mix. Seed treatment 5 2 lb/ gal FlC [ 62719 416]

75% WP [ 62719 421] 0.063 lb ai/ 100 lb seed ( 625 ppm) 1 NA NA Treated seed should be dyed and labeled to indicate that the seed have been treated with fenbuconazole, and must not be used for food or feed purposes 1 All use directions prohibit the grazing of livestock in treated areas and the feeding of cover crops grown in treated areas to livestock. Page 11 of 55 2 Applications should be made in a minimum of 10 gal/ A for aerial applications and 50 gal/ A for ground applications. 3 The most recently proposed use directions for stone fruits ( plums/ prunes) specifies a seasonal maximum of 0.38 lb ai/ A. 4 Ground applications can include the use of chemigation using the following types of irrigation systems: center pivot, lateral move, end tow, side ( wheel) roll, traveler, solid set, or hand move systems. 5 The seed treatment use is based on copies of proposed labels submitted in 1997.

2.2 Structure and Nomenclature Table 2.2. Nomenclature of Fenbuconazole and its Regulated Metabolites Compound N N N Cl CN Common name Fenbuconazole Company experimental names RH 7592 IUPAC name ( RS) 4( 4 chlorophenyl) 2 phenyl 2( 1H 1,2,4 triazol 1 ylmethyl) butyronitrile CAS name  [ 2( 4 chlorophenyl) ethyl]   phenyl 1H 1,2,4 triazole 1 propanenitrile Molecular weight 336.8 CAS registry number 114369 43 6 ( 119611 00 6, racemate)

End use products/ EP 2 lb/ gal FlC and 75% WPs Metabolite Common name cis lactone metabolite Company experimental names RH 9129 IUPAC names ( 3R, 5R) 5( 4 chlorophenyl) 3 phenyl 3( 1H 1,2,4 triazol 1 ylmethyl) dihydrofuran 2( 3H) one CAS names cis 5( 4 chlorophenyl) dihydro 3 phenyl 3( methyl 1 H, 2,4 triazole 1 yl 2( 3H) furanone Molecular weight 353.8 CAS registry number 146887 38 9 O N N N O Cl Page 12 of 55 Table 2.2. Nomenclature of Fenbuconazole and its Regulated Metabolites Metabolite O N N N O Cl Common name trans lactone metabolite Company experimental names RH 9130 IUPAC names ( 3S, 5R) 5( 4 chlorophenyl) 3 phenyl 3( 1H 1,2,4 triazol 1 ylmethyl) dihydrofuran 2( 3H) one CAS names trans 5( 4 chlorophenyl) dihydro 3 phenyl 3( methyl 1 H, 2,4 triazole 1 yl 2 ( 3H) furanone Molecular weight 353.8 CAS registry number 146887 37 8 2.3 Physical and Chemical Properties Table 2.3. Physicochemical Properties of the Technical Grade Fenbuconazole Parameter Value Reference Melting point 126.5  127.0 ° C pH Not available Bulk Density 0.50 g/ mL Water solubility at 22 ° C 3.8 mg/ L Solvent solubility ( g/ L) at 25 ° C Acetonitrile 231 Cyclohexanone 445 Ethyl alcohol 39 1 octanol 13 Aromatic 200 77 Ethyl acetate 159 Heptane 1.0 Vapor pressure at 25 ° C ( PAI) 0.37 × 10 7 mm Hg ( 4.9 × 10 6Pa)

Dissociation constant ( pKa) ( PAI) Not expected to dissociate in water Octanol/ water partition coefficient Log( KOW) 3.22 UV/ visible absorption spectrum   max ( nm) 196 262 268 275   ( L · mol 1 · cm 1) 53,000 750 740 480 PMRA Regulatory Note ( REG2003 03) on Fenbuconazole, 4/ 28/ 03 Page 13 of 55 3.0 METABOLISM ASSESSMENT 3.1 Comparative Metabolic Profile Adequate studies are available depicting the metabolism of [ 14C] fenbuconazole in rats, primary crops ( peaches, peanuts, wheat, sugar beets), rotational crops ( collards, turnips, wheat), and livestock ( lactating goats, laying hens). Major residues consistently noted in these studies include parent fenbuconazole and the lactone metabolites RH 9129, RH 9130, and RH 6467. The common triazole metabolites 1,2,4 triazole, triazolylalanine, and triazolylacetic acid were observed in all of the metabolism studies, with the degree of metabolite formation highly dependent on the species being studied.

In rats, fenbuconazole is rapidly absorbed and excreted within 96 hours following a single low or high dose or following repeated low doses. Low bioaccumulation of both the parent compound and metabolites was indicated by low levels in the tissues. Elimination occurred primarily by biliary excretion since the majority of the administered dose was recovered in the bile three days after exposure or in the feces four days after exposure. There were no sex or dose related differences in absorption, distribution, or elimination; these processes were also similar regardless of whether single or multiple exposure regimens were used. Extensive metabolism of fenbuconazole occurred, with sex and dose related differences. Very low ( 2 5%) parent compound was recovered in the feces following single or repeated low doses, but a higher percentage ( 21 37%) was found following a single high dose. More sulfate metabolites were found in female excreta compared to males, and more ketoacid metabolites were found in male urine compared to females.

Based on the peach and wheat studies, the Metabolism Committee ( N. Dodd and W. Wassell, 3/ 9/ 94) concluded that the residues of concern for uses on stone fruit, wheat, pecans, bananas, apples and almonds are fenbuconazole and its lactone metabolites, RH 9129 and RH 9130. This conclusion was contingent upon the petitioner providing data showing that RH 4911 is only a minor residue in these crops. The petitioner subsequently fulfilled this requirement by providing data from the wheat and peach metabolism studies showing that conjugates of RH 4911 accounted for < 5% of the TRR in peaches and wheat straw ( D200171, N. Dodd, 4/ 5/ 94). The Metabolism Committee also noted that the iminolactone metabolite ( RH 6468) would be included de facto in the residues of concern as this compound is converted to the lactones by the analytical methodology. After reviewing the sugar beet data, HED has also determined that fenbuconazole and it lactone metabolites are the residues of concern for uses on sugar beets ( D241864, PP# 7F4887). Metabolite studies with peanuts show that RH 7905 and RH 4911 are significant residues of concern in that crop.

3.2 Nature of the Residue in Foods 3.2.1. Description of Primary Crop Metabolism The degree of metabolism of fenbuconazole varies depending on the primary crop. Overall, three routes of metabolism appear to be important: ( i) initial cleavage of the triazole ring can Page 14 of 55 lead to terminal residues of triazolylalanine and/ or triazolylacetic acid; ( ii) hydroxylation of the chlorophenyl ring leads to glycoside conjugates of the parent molecule, seen primarily in peanut as the glucose conjugate of RH 4911; and ( iii) hydroxylation of the alkyl chain results in formation of the ketone ( RH 6467), lactone ( RH 9129 and RH 9130), and iminolactone ( RH 6468) metabolites. Relative amounts of these metabolites are summarized in Table 3.4.

3.2.2 Description of Livestock Metabolism Metabolism studies with lactating goats and laying hens show that the majority of the administered dose is excreted and only a small portion ( 1 2%) is absorbed. In the goat study,

0.4% of the administered dose was excreted in the milk. Overall, the metabolism of fenbuconazole in ruminants appears to proceed via three pathways involving either: ( i) oxidation at the unsubstituted phenyl ring to yield the 4 phenol metabolite ( RH 1311); ( ii) oxidation at the benzylic position of the chlorinated phenyl ring leading to the formation of the benzylic alcohol metabolite ( RH 6648) and the iminolactone ( RH 6468), lactones ( RH 9130 and RH 9129), keto acid ( RH 1745) metabolites and the benzylic conjugates ( sulfate and glucuronide conjugates of RH 6648); or ( iii) cleavage of the parent molecule eliminating the triazole ring to yield RH 7968, 1,2,4 triazole and lesser amounts of triazolylalanine. To date, the Agency has not received an acceptable poultry metabolism study. Based on the information available at this time, a 40 CFR 180.6( a)( 3) situation exists for poultry ( i. e., no expectation of finite residues); therefore, the lack of acceptable poultry metabolism data is not a significant data gap. If future new uses are sought for significant poultry feed items, then an acceptable poultry metabolism study will likely be required.

3.2.3 Description of Rotational Crop Metabolism Fenbuconazole appears to be extensively metabolized in the environment prior to uptake of residues by rotational crops. The major residues observed in rotational crops are triazolylalanine and triazolylacetic acid. Studies using radiolabeled fenbuconazole reveal that parent compound, RH 9129, RH 9130, and RH 6467 may be found in rotational crop matrices, but only in very small amounts.

3.3 Environmental Degradation Fenbuconazole is considered to be moderately persistent to persistent in the environment and slightly mobile to mobile in soils. Because of its adsorption to soil, the potential for fenbuconazole to leach to ground water appears to be slight. However, the potential to contaminate groundwater may be greater at vulnerable sites, i. e., where soils have low organic matter and where groundwater is relatively close to the surface. The long half lives of fenbuconazole in aerobic soil and terrestrial field dissipation studies indicate that when fenbuconazole is applied over multiple growing seasons, soil residue accumulation may result. These residues may be available for rotational crop uptake or may be transported with sediments during runoff events. For purposes of human health risk assessment, the residue of concern in water is fenbuconazole, per se. Page 15 of 55 3.4 Tabular Summary of Metabolites and Degradates Table 3.4. Summary of Metabolites and Degradates of Fenbuconazole. Common name/ code Chemical name Major Metabolite Minor Metabolite Chemical structure Fenbuconazole RH 7592  [ 2( 4 chlorophenyl) ethyl]   phenyl 1H 1,2,4 triazole 1 propanenitrile Peach Peanut Vine Sugar beet Wheat Ruminants Poultry Water Rotational Crops N N N Cl CN Iminolactone Metabolite RH 6468 5( 4 chlorophenyl) 3 phenyl 3( 1H 1,2,4 triazol 1 ylmethyl) dihydrofuran 2( 3H) imine   Ruminants Poultry O N N N N H Cl Lactone A and B Metabolites RH 9129 and RH 9130 trans or cis 5( 4 chlorophenyl) dihydro 3 phenyl 3( 1H 1,2,4 triazol 1 ylmethyl) 2( 3H) furanone Peach Poultry Ruminant Peanut Sugar beet Wheat Rotational Crops O N N N O Cl Benzylic Alcohol Metabolite RH 6648 4( 4 chlorophenyl) 4 hydroxy 2 phenyl 2 ( 1H 1,2,4 triazol 1 ylmethyl) butanenitrile   Poultry N N N Cl CN OH Ketone Metabolite RH 6467 4( 4 chlorophenyl) 4 oxo 2 phenyl 2( 1H 1,2,4 triazol 1 ylmethyl) butanenitrile Peanut Wheat Rotational Crops N N N Cl CN O 4 Phenol Metabolite RH 1311 4( 4 chlorophenyl) 2 ( 4 hydroxyphenyl) 2 ( 1H 1,2,4 triazol 1 ylmethyl) butanenitrile   Ruminants Poultry Egg N N N CN O H Page 16 of 55 Table 3.4. Summary of Metabolites and Degradates of Fenbuconazole. Common name/ code Chemical name Major Metabolite Minor Metabolite Chemical structure Glucosyl conjugate of RH 4911 RH 7905  [ 2[ 4 chloro 3( Dglucopyranosyloxy phenyl] ethyl]   phenyl 1H 1,2,4 triazole 1 propanenitrile Peanut Peach Wheat N N N O Cl CN O OH O H O H OH Cleaved Alcohol Metabolite RH 7968 4( 4 chlorophenyl) 2 ( hydroxymethyl) 2 phenylbutanenitrile   Ruminants Eggs Cl CN OH Triazole RH 0118 1H 1,2,4 triazole Eggs Poultry Rat Ruminant Milk NH N N Triazolylalanine TAA RH 3968 2 amino 3( 1H 1,2,4 triazol 1 yl) propanoic acid Peach Peanut Wheat Rotational Crops Milk N N N NH 2 HOOC Triazolylacetic acid TA RH 3779 RH 4098 1H 1,2,4 triazol 1 yl acetic acid Wheat Rotational Crops Peach N N N COOH 3.5 Toxicity Profile of Major Metabolites and Degradates Toxicological data specific to 1,2,4 triazole, triazolylalanine, and triazolylacetic acid have been submitted to the Agency. Risks associated with exposure to 1,2,4 triazole, triazolylalanine, and triazolylacetic acid are the subject of a separate risk assessment ( M. Doherty et al., D322215, 2/ 7/ 06). For major metabolites of fenbuconazole other than those three compounds, toxicological data are not available. Structural similarities between fenbuconazole and the metabolites RH 9129, RH 9130, and RH 4911 lead HED to believe that these compounds may have similar toxicity. HED also has concern regarding the potential toxicity of RH 7905 since cleavage of the labile sugar moiety results in the formation of RH 4911.

3.6 Summary of Residues for Tolerance Expression and Risk Assessment 3.6.1 Tabular Summary Table 3.6. Summary of Metabolites and Degradates to be included in the Risk Assessment and Tolerance Expression* Matrix Residues included in Risk Assessment Residues included in Tolerance Expression Page 17 of 55 Table 3.6. Summary of Metabolites and Degradates to be included in the Risk Assessment and Tolerance Expression* Matrix Residues included in Risk Assessment Residues included in Tolerance Expression Primary Crop Fenbuconazole + RH 9129 + RH 9130 + RH 7905 ( peanut only) + RH 4911 ( peanut only) Fenbuconazole + RH 9129 + RH 9130, expressed as fenbuconazole Plants Rotational Crop Not Applicable at this time Not Applicable at this time Ruminant Fenbuconazole + RH 9129 + RH 9130 Fenbuconazole + RH 9129 + RH 9130, expressed as fenbuconazole Livestock Poultry Not Applicable at this time Not Applicable at this time Drinking Water Fenbuconazole Not Applicable * The common triazole metabolites 1,2,4 triazole, triazolylalanine, and triazolylacetic acid have been identified as residues of concern for risk assessment. Separate assessments addressing these compounds have been conducted ( see. M. Doherty, et al., D322215, 2/ 7/ 06).

3.6.2 Rationale for Inclusion of Metabolites and Degradates HED has determined that the residues of concern for risk assessment are fenbuconazole and the following metabolites: RH 9129, RH 9130, RH 4911( peanut only), and RH 7905 ( peanut only). RH 9129 and RH 9130 are cis/ trans isomers of the lactone metabolite of fenbuconazole and may account for approximately one third of the total fenbuconazole residues. RH 9129 and RH 9130 are residues of concern for both risk assessment and tolerance enforcement purposes. RH 7905 is a minor metabolite except in peanut. In animals, the glucoside conjugate ( RH 7905) will be cleaved to yield RH 4911. Although RH 4911, being a hydroxy derivative of fenbuconazole, is likely to be less toxic than the parent, we have no specific toxicological information for this compound. Because it shares structural features with the parent, HED is assuming that it has the same toxicity as fenbuconazole. Therefore, RH 7905 and RH 4911 are being included as residues of concern for risk assessment ( peanuts only). The current analytical enforcement method has been validated for the analysis of fenbuconazole as well as RH 9129 and RH 9130.

4.0 HAZARD CHARACTERIZATION/ ASSESSMENT 4.1 Hazard Characterization Acute studies were conducted on both the technical material and end use product ( 25% a. i.). Technical grade fenbuconazole has low acute toxicity ( Category III for acute oral and inhalation exposures and Category IV for acute dermal exposure). The end use product also has low acute toxicity ( Category III for acute inhalation exposure and Category IV for acute oral and dermal exposures). Neither the technical material nor the end use product are skin or eye irritants ( Category IV), and neither are dermal sensitizers. Table 4.1a summarizes both the acute toxicity for the technical and end use product of fenbuconazole. Page 18 of 55 Table 4.1a  Acute Toxicity of Fenbuconazole  Technical and End Use Product Guideline No. Study Type MRID Results Toxicity Category 870.1100 Acute Oral  Rats 41031209 Oral LD50 ( M) > 2000 mg/ kg III 870.1100 Acute Oral  Rats 41031207 Oral LD50 ( M and F) > 2000 mg/ kg III 870.1100 Acute Oral  Rats 41031221 Oral LD50 ( M) > 5000 mg/ kg IV 870.1100 Acute Oral  Rats 41031222 Oral LD50 ( F) > 5000 mg/ kg IV 870.1200 Acute Dermal  Rats 41031208 LD50 ( M and F) > 5000 mg/ kg IV 870.1200 Acute Dermal  Rats 41031223 LD50 ( M) > 5000 mg/ kg IV 870.1200 Acute Dermal  Rats 41031224 LD50 ( F) > 5000 mg/ kg IV 870.1300 Acute Inhalation  Rats 41398201 LC50 ( M and F) > 2.1 mg/ L Particle size too large. Requirement was waived due to problem in generating respirable dust particles or liquid aerosol. III 870.1300 Acute Inhalation  Rats 41031225 LC50 ( M and F) > 2.1 mg/ L III 870.2400 Primary Eye Irritation Rabbits 41031211 Not irritating to unwashed eyes IV 870.2400 Primary Eye Irritation Rabbits 41031226 Not irritating to the eyes IV 870.2500 Primary Dermal Irritation Rabbits 41031212 Not irritating to the skin IV 870.2500 Primary Dermal Irritation Rabbits 41031227 Not irritating to the skin IV 870.2600 Dermal Sensitization Guinea pigs 41031213 Is not a sensitizer under conditions of study. N/ A 870.2600 Dermal Sensitization Guinea pigs 41031228 Is not a sensitizer under conditions of study. N/ A Subchronic and chronic feeding studies were conducted in the rat, mouse, and dog. In these studies, the liver was the main target of toxicity in all three species. At the LOAEL in the subchronic studies, there were changes in liver histopathology, predominantly hepatocellular hypertrophy. At doses higher than the LOAEL in the rat, the thyroid was a secondary target organ with increased follicular cell size. In the chronic studies, liver effects were seen ( including hepatocellular hypertrophy and vacuolization, changes in liver enzymes, and increased liver weights), as well as decreased body weight gains in all three species. Again, in the chronic rat study, the thyroid was a secondary target with increased thyroid and parathyroid weights and thyroid follicular cell hypertrophy. In addition, increased mean T4 and decreased TSH were Page 19 of 55 found in the high dose rats near the end of the study. In the chronic dog study, kidney and adrenal weights were also increased. Males and females throughout the studies appeared to be equally sensitive to fenbuconazole toxicity, except in the chronic mouse study, where male mice appeared to be more sensitive than the females.

In the rat and rabbit developmental toxicity studies and the two generation study in rats, all effects in the pups occurred in the presence of maternal toxicity, including changes in body weight and body weight gains in rats and decreased food consumption and clinical signs in rabbits. Developmental effects included increased post implantation loss and decreased fetuses per dam in the rat developmental study; increased early resorptions in the rabbit developmental study; and decreased mean pup body weight, increased number of stillborn pups, decreased number of total offspring delivered, and decreased viability index of pups in the two generation study in rats. No increased qualitative or quantitative susceptibility was observed in any of the studies. There was no evidence of neurotoxicity in any of the studies available in the toxicology database. Therefore, a developmental neurotoxicity study is not required at this time.

Fenbuconazole is not mutagenic. On August 11, 1993, the Health Effects Division Carcinogenicity Peer Review Committee ( CPRC) determined that fenbuconazole should be classified as Group C  Possible Human Carcinogen and recommended that a low dose extrapolation model applied to the experimental animal tumor data should be used for quantification of human risk ( Q1*). The Q1* established for use in cancer risk analysis is 0.00359 ( mg/ kg/ day) 1 in human equivalents.

A dermal absorption study was conducted in rats. The majority of the radio labeled compound could be recovered in a skin wash. A value of 4.25% dermal absorption, measured 10 hours after exposure, has been selected for use in risk assessment.

In rats, fenbuconazole is rapidly absorbed and excreted within 96 hours following a single low or high dose or following repeated low doses. Low bioaccumulation of both the parent compound and metabolites was indicated by low levels in the tissues.

Table 4.1b summarizes the toxicity profile of fenbuconazole. Page 20 of 55 Table 4.1b  Toxicity Profile of Fenbuconazole Technical Guideline No. Study Type MRID Doses Results 870.3100 90 Day oral toxicity rodents  rats 41073502 0, 20, 80, 400, and 1600 ppm ( Males: 0, 1.3, 5.1, 25.3, and 103.0 mg/ kg/ day; Females: 0, 1.5, 6.3, 31.1, and 123.9 mg/ kg/ day) NOAEL = 1.3/ 1.5 mg/ kg/ day ( M/ F) LOAEL = 5.1/ 6.3 mg/ kg/ day ( M/ F) based on liver histopathology 870.3100 90 Day oral toxicity rodents  mice 41073503 0, 20, 60, 180, and 540 ppm ( Males: 0, 3.8, 11.1, 28.6, and 99.1 mg/ kg/ day; Females: 0, 5.7, 17.6, 50.4, and 139.2 mg/ kg/ day) NOAEL = 3.8/ 5.7 mg/ kg/ day ( M/ F) LOAEL = 11.1/ 17.6 mg/ kg/ day ( M/ F) based on liver histopathology 870.3150 90 Day oral toxicity in nonrodents  dogs 41073504 0, 30, 100, 400, and 1600 ppm ( Males: 0, 1.0, 3.3, 13.3, and 50.4 mg/ kg/ day; Females: 0, 1.1, 3.5, 14.0, and 53.3 mg/ kg/ day) NOAEL = 3.3/ 3.5 mg/ kg/ day ( M/ F) LOAEL = 13.3/ 14.0 mg/ kg/ day ( M/ F) based on liver histopathology 870.3200 21/ 28 Day dermal toxicity  rats 41875013 42882701 0, 250, 625, and 1000 mg/ kg/ day NOAEL = 1000 mg/ kg/ day ( HDT) LOAEL = > 1000 mg/ kg/ day 870.3250 90 Day dermal toxicity N/ A N/ A Not performed 870.3465 90 Day inhalation toxicity N/ A N/ A Not performed 870.3700 Prenatal developmental in rodents  rats 41031214 41073505 0, 30, 75, and 150 mg/ kg/ day Maternal NOAEL = 30 mg/ kg/ day Maternal LOAEL = 75 mg/ kg/ day based on decreased body weight and body weight gain Developmental NOAEL = 30 mg/ kg/ day Developmental LOAEL = 75 mg/ kg/ day based on increased postimplantation loss and a decrease in the number of live fetuses/ dam Page 21 of 55 Table 4.1b  Toxicity Profile of Fenbuconazole Technical Guideline No. Study Type MRID Doses Results 870.3700 Prenatal developmental in nonrodents  rabbits 41875014 42882701 0, 10, 30, and 60 mg/ kg/ day Maternal NOAEL = 10 mg/ kg/ day Maternal LOAEL = 30 mg/ kg/ day based on decreased food consumption and increased incidence of clinical signs ( soft/ scant/ no feces and red discharge) Developmental NOAEL = 30 mg/ kg/ day Developmental LOAEL = 60 mg/ kg/ day based on increased early resorptions 870.3800 Reproduction and fertility effects  rats 41875015 0, 8, 80, and 800 ppm ( 0, 0.4, 4, and 40 mg/ kg/ day) Parental systemic NOAEL = 4 mg/ kg/ day Parental systemic LOAEL = 40 mg/ kg/ day based on maternal death during delivery, decreased body weight and food consumption, increased number of dams not delivering viable or delivering nonviable offspring, and increased adrenal and thyroid/ parathyroid weights Reproductive NOAEL = 40 mg/ kg/ day ( HDT) Reproductive LOAEL = > 40 mg/ kg/ day Offspring systemic NOAEL = 4 Offspring systemic LOAEL = 40 mg/ kg/ day based on decreased mean pup body weight, increased number of stillborn pups, decreased number of total offspring delivered, and decreased viability index 870.4100 Chronic toxicity  rodents See 870.4300 870.4100 Chronic toxicity  dogs 41875049 0, 15, 150, and 1200 ppm ( 0, 0.38, 3.75, and 30 mg/ kg/ day) NOAEL = 3.75/ 0.38 mg/ kg/ day ( M/ F) LOAEL = 30/ 3.75 mg/ kg/ day ( M/ F) based on decreased body weight gain Note: dose related adaptive liver changes were observed in highdose males and females. Page 22 of 55 Table 4.1b  Toxicity Profile of Fenbuconazole Technical Guideline No. Study Type MRID Doses Results 870.4200 Carcinogenicity  rats See 870.4300 870.4200 Carcinogenicity  mice 41893301 41635303 Males: 0, 10, 200, and 650 ppm ( 0, 1.43, 28.6, and 92.9 mg/ kg/ day) Females: 0, 10, 650, and 1300 ppm ( 0, 1.43, 92.9, and 186 mg/ kg/ day) NOAEL = 1.43 mg/ kg/ day ( M & F) LOAEL = 28.6/ 92.9 mg/ kg/ day ( M/ F) based on decreased body weight, increased relative and absolute liver weight, and hepatocellular hypertrophy and vacuolization Evidence of carcinogenicity 870.4300 Combined chronic toxicity/ carcinogenicity  rat 41635301 41635302 Control  0 ppm Low  4 ppm ( weeks 1 & 2), 6 ppm ( weeks 3 & 4), and 8 ppm ( weeks 5 term)

Mid  40 ppm ( weeks 1 & 2), 60 ppm ( weeks 3 & 4), and 80 ppm ( weeks 5 term)

High  400 ppm ( weeks 1 & 2), 600 ppm ( weeks 3 & 4), and 800 ppm ( weeks 5 term)

( Males: 0, 0.31, 3.03, and 30.62 mg/ kg/ day; Females: 0, 0.4, 4.02, and 43.07 mg/ kg/ day) NOAEL = 3.0/ 4.0 mg/ kg/ day ( M/ F) LOAEL = 30.6/ 43.1 mg/ kg/ day ( M/ F) based on decreased body weight gain ( F), hepatocellular enlargement and vacuolization ( F), increased thyroid weight ( M& F), and histopathological lesions in the thyroid gland ( M)

Evidence of carcinogenicity 870.4300 Combined chronic toxicity/ carcinogenicity  rat 42021901 42055001 Control  0 ppm Low  400 ppm ( weeks 1 & 2), 600 ppm ( weeks 3 & 4), and 800 ppm ( weeks 5 term)

High  800 ppm ( weeks 1 & 2), 1200 ppm ( weeks 3 & 4), and 1600 ppm ( weeks 5 term)

( 0, 30.4, and 63.9 mg/ kg/ day) NOAEL = Not established LOAEL = 30.4 mg/ kg/ day ( M) based on decreased body weight gain, increased liver weight, and increased thyroid and parathyroid weights Note: only males were used in this study.

Insufficient evidence of carcinogenicity Page 23 of 55 Table 4.1b  Toxicity Profile of Fenbuconazole Technical Guideline No. Study Type MRID Doses Results 870.5100 Gene mutation  bacterial reverse mutation assay 41031216 TA1535  30 300 ug TA1537  30 300 ug TA98  0.2 20 ug TA100  160 1600 ug No mutagenic activity in bacteria ( Salmonella typhimurium) under conditions of this assay.

Note: only TA1535, TA1537, TA98, and TA100 were tested. This study is classified unacceptable.

870.5100 Gene mutation  bacterial reverse mutation assay 41031217 TA1535  30 300 ug TA1537  30 300 ug TA98  30 300 ug TA100  30 300 ug No mutagenic activity in bacteria ( Salmonella typhimurium) under conditions of this assay.

Note: only TA1535, TA1537, TA98, and TA100 were tested. This study is classified unacceptable.

870.5300 Cytogenetics  in vitro mammalian cell gene mutation test ( CHO Cells) 41031218 15 50 ug/ ml without S9 activation 35 60 ug/ ml with S9 activation No increase in mutant frequency at the HGPRT locus, in the presence or absence of S9 activation.

870.5385 Cytogenetics  mammalian bone marrow chromosomal aberration test ( rats) 41031219 0, 0.25, 1.25, and 2.5 g/ kg No increase in number of cells with aberrations or in aberrations per cell.

870.5550 Other effects  unscheduled DNA synthesis in mammalian cells in culture ( rats) 41031220 0, 7.5, 10.0, 12.5, and 15.0 ug/ ml No evidence ( or a dose related positive response) that unscheduled DNA synthesis was induced. Page 24 of 55 Table 4.1b  Toxicity Profile of Fenbuconazole Technical Guideline No. Study Type MRID Doses Results 870.7485 Metabolism and pharmacokinetics  rat 41875017 41875018 1) 1 mg/ kg radiolabelled, single dose by oral gavage 2) 100 mg/ kg radiolabelled, single dose by oral gavage 3) 1 mg/ kg unlabelled, 14 days in the diet, PLUS 1 mg/ kg radiolabelled, single dose by oral gavage 4) 1 mg/ kg radiolabelled, by i. v. injection The mean recovery of radioactivity 4 days after exposure was 82.6 93.0% following single or repeated oral doses and 88.2 99.2% following single i. v. doses, indicating rapid absorption, distribution, and elimination. Rapid elimination and low tissue levels indicate low bioaccumulation of the parent and metabolites.

Elimination occurred primarily by biliary excretion because recovery of radioactivity was mostly in the feces: 75.6 83.7% following oral exposure and 77.2 91.4% following i. v. exposure. In urine, radioactivity recovery was 5.5 12.6% for all dose scenarios. Peak radioactivity in the blood occurred 3 hours following a single low dose and 3 6 hours after a single high dose, indicating biphasic elimination.

Only 8.5 14.8% and 0.0 2.7% of the parent compound was recovered in the feces and urine, respectively, indicating extensive metabolism. A number of major metabolites were identified; however, 50% and 20% of metabolites in the feces and urine, respectively, were not identified. Sex related differences include a greater number of sulfate metabolites in female excreta compared to males, and a greater number of ketoacid metabolites in male urine compared to females. Page 25 of 55 Table 4.1b  Toxicity Profile of Fenbuconazole Technical Guideline No. Study Type MRID Doses Results 870.7485 Metabolism and pharmacokinetics  rat 42900801 1) 1 mg/ kg radiolabelled, single dose by oral gavage 2) 100 mg/ kg radiolabelled, single dose by oral gavage 3) 1 mg/ kg unlabelled, 14 days in the diet, PLUS 1 mg/ kg radiolabelled, single dose by oral gavage The mean recovery of radioactivity 3 4 days after exposure was 90.4 104.5% following single or repeated oral doses, indicating rapid absorption, distribution, and elimination. Bioaccumulation of the parent compound and metabolites is low. There were no major sex or doserelated differences in absorption, distribution, or elimination.

Elimination occurred primarily by biliary excretion: recovery of the administered dose occurred mainly in the bile ( 79.1 87.1%) 3 days after exposure and mostly in the feces ( 78.7 94.4%) 4 days after exposure. In contrast, radioactivity recovery in the urine was 3.2 11.5% at 3 and 4 days after exposure.

Extensive metabolism occurred; numerous metabolites were found in the feces and urine. There is a dose related difference in metabolism. A higher amount of parent compound was found in the feces following the single high dose compared to the single or repeated low dose( s), which suggests that saturation may be occurring at the high dose.

870.7600 Dermal penetration  rat 41875019 0, 0.125, 1.25, and 12.5 mg/ kg Note: End use product ( 23.1%) was tested Mean % of the dose absorbed ( sum of urine, feces, carcass, and skin) after 10 hrs of exposure:

0.125 mg/ kg: 4.25% 1.25 mg/ kg: 2.08% 12.5 mg/ kg: 0.45%

4.2 FQPA Hazard Considerations The FQPA safety factor was removed ( i. e., reduced to 1x) in assessing the risk posed by fenbuconazole. This recommendation was based on the following: Page 26 of 55   There are no data gaps for the assessment of the effects of fenbuconazole following in utero and/ or postnatal exposure; a developmental neurotoxicity study is not required.   There is no indication of quantitative or qualitative susceptibility of rats or rabbits to in utero and/ or postnatal exposure to fenbuconazole   The dietary exposure assessment is based on models and input parameters designed to be protective of human health.   At this time, there are no registered residential uses for fenbuconazole; therefore, this type of exposure to infants and children is not expected.

4.2.1 Adequacy of the Toxicity Data Base The toxicology database is complete and adequate for risk assessment.

4.2.2 Evidence of Neurotoxicity Acute and sub chronic neurotoxicity studies are not required for fenbuconazole. The available toxicology studies do not indicate that fenbuconazole is neurotoxic. Neither sub chronic nor chronic toxicity studies in rats and mice nor the developmental toxicity studies in rats or rabbits indicated that the nervous system was specifically affected by treatment with fenbuconazole.

4.2.3 Developmental Toxicity Studies No quantitative or qualitative susceptibility was observed in either of the developmental rat or rabbit studies. In the developmental rat study, increased post implantation loss and decreased live fetuses per dam were noted at a dose level in which decreased maternal body weight and body weight gain were observed. Since the developmental effects observed in the rat study were seen in the presence of maternal toxicity, they are not considered to be qualitatively more severe than the maternal effects. The maternal LOAEL in the rabbit study, which is based on decreased food consumption and increased clinical signs, is a lower dose level than the developmental LOAEL, which is based on increased early resorptions.

4.2.4 Reproductive Toxicity Study In the two generation reproduction study, a decrease in mean pup body weight, an increased number of stillborn pups, a decreased number of total offspring delivered, and a decreased viability index for pups were seen at the same dose level that produced maternal death and decreased maternal body weights. The same types of toxicity were seen in dams and in pups ( i. e., death and body weight changes), and these effects were seen at the same dose level; thus, there is no increase in qualitative or quantitative susceptibility in the two generation reproduction study.

4.2.5 Additional Information from Literature Sources A literature search was not conducted at this time. Page 27 of 55 4.2.6 Pre and/ or Postnatal Toxicity <IP_ADDRESS> Determination of Susceptibility The data provided no indication of increased susceptibility of rats or rabbits to in utero and/ or postnatal exposure to fenbuconazole. In the prenatal developmental study in rats and rabbits and the two generation study in rats, effects in the offspring were observed only at or above those treatment levels which resulted in maternal toxicity.

<IP_ADDRESS> Degree of Concern Analysis and Residual Uncertainties for Pre and/ or Post natal Susceptibility The degree of concern for infants and children exposed to fenbuconazole in utero and/ or postnatally is low; there are no residual uncertainties. The toxicology database for fenbuconazole is complete and adequate for risk assessment purposes. Acceptable developmental studies in rats and rabbits and the two generation reproduction study in rats did not show evidence of increased susceptibility in offspring exposed to fenbuconazole in utero and/ or postnatally. While the toxicology database does not have an appropriate endpoint for an acute dietary assessment for the general population, a NOAEL has been selected for the subpopulation Females 13 49 based on developmental effects ( increased resorptions and decreased live fetuses per dam) seen at the LOAEL in the developmental rat study. By regulating on the effect of concern for this subpopulation, the risk assessment is protective of potential effects to infants and children. There are currently no registered or proposed residential uses for fenbuconazole, so exposure to fenbuconazole is limited to dietary exposure.

4.3 Recommendation for a Developmental Neurotoxicity Study The available toxicology database does not indicate that fenbuconazole is neurotoxic to rats, rabbits, or dogs. In the acceptable rat and rabbit developmental studies and rat reproduction study, there was no evidence of increased quantitative or qualitative susceptibility resulting from in utero and/ or postnatal exposure to fenbuconazole. Therefore, a developmental neurotoxicity study is not required.

4.4 Hazard Identification and Toxicity Endpoint Selection 4.4.1 Acute Reference Dose ( aRfD)  Females age 13 49 The acute dietary endpoint for females 13 49 is based on increased resorptions and decreased live fetuses per dam observed at the LOAEL of 75 mg/ kg/ day in a developmental rat study. This endpoint is considered appropriate for this population subgroup because the observed developmental effects are presumed to occur following a single oral dose. The NOAEL was 30 mg/ kg/ day, resulting in an acute reference dose ( aRfD) of 0.3 mg/ kg/ day ( standard 10x intraspecies variation and 10x interspecies extrapolation safety factors were applied). Selection of this dose and endpoint is supported by the fact that the NOAEL in the developmental rat study Page 28 of 55 is equal to the NOAEL in the developmental rabbit study; the LOAEL in the developmental rabbit study is based on increased resorptions, which could also occur following a single oral dose.

4.4.2 Acute Reference Dose ( aRfD)  General Population The current toxicology database does not have a dose and endpoint suitable for acute dietary exposure assessment for the general population. None of the effects seen in the database ( excluding developmental effects) were considered to occur as the result of one oral dose.

4.4.3 Chronic Reference Dose ( cRfD)

The chronic dietary endpoint is based on effects in the combined chronic toxicity/ carcinogenicity study in the rat: decreased body weight gain, increased thyroid weight, and histopathological lesions in the liver and thyroid gland observed at the LOAEL of 30.6/ 43.1 mg/ kg/ day ( M/ F). Although a lower NOAEL is identified in the mouse carcinogenicity study based on liver effects, the mouse study was not chosen as a basis for the chronic dietary endpoint because it was compromised by a hepatitis infection which could have potentiated liver toxicity. A lower NOAEL was also identified for females in the chronic dog study based on decreased body weight gain; however, the rat study is considered more robust than the dog study. In addition, liver toxicity was seen at a similar dose in both the rat and dog studies. The NOAEL was 3 mg/ kg/ day, with a chronic reference dose ( cRfD) of 0.03 mg/ kg/ day ( standard 10x intra species variation and 10x interspecies extrapolation safety factors were applied).

4.4.4 Incidental Oral Exposure ( Short and Intermediate Term)

Currently, there are no proposed or registered residential uses for fenbuconazole; therefore, an incidental oral exposure risk assessment is not necessary at this time.

4.4.5 Dermal Absorption The 21 day dermal absorption study in rats indicated that fenbuconazole is poorly absorbed through the skin, as there was no dermal or systemic toxicity up to the limit dose. Therefore, a 4.25% ( at one hour) dermal absorption factor was selected from the dermal penetration study in rats and should be applied to dermal risk assessments.

4.4.6 Dermal Exposure ( Short, Intermediate and Long Term)

No dermal or systemic toxicity was seen in male and female Sprague Dawley rats following 15 repeated dermal applications of fenbuconazole up to the limit dose in the 21 day dermal toxicity study. Because toxicity was not seen following dermal exposure over this time frame and since there are no residential uses for fenbuconazole at this time, short and intermediate term dermal endpoints were not selected. Page 29 of 55 At this time, current and proposed uses will not result in long term dermal exposure. However, for future long term dermal risk assessments involving chronic ( non cancer) effects, the NOAEL of 3 mg/ kg/ day from the combined chronic toxicity/ carcinogenicity study in the rat should be used in conjunction with the 4.25% dermal absorption factor described in section 4.4.5. For long term dermal risk assessments involving carcinogenic effects, the Q1 * of 3.59 x 10 3 should be used since fenbuconazole has been classified as a Group C carcinogen.

4.4.7 Inhalation Exposure ( Short, Intermediate and Long Term)

In previous risk assessments, inhalation endpoints were not selected based on fenbuconazole's low inhalation toxicity and previous use patterns. However, due to the numerous new uses which require application of fenbuconazole by airblast, the RAB2 Risk Assessment Team selected an inhalation endpoint for risk assessment purposes. The dose and endpoint selected for all durations of inhalation risk assessment were chosen from the combined chronic toxicity/ carcinogenicity study in rats. The NOAEL is 3.0 mg/ kg/ day, based on decreased body weight gain, increased thyroid weights, and histopathological lesions in the liver and thyroid glands observed at the LOAEL. Body weight effects were evident after 4 weeks of treatment with fenbuconazole and continued throughout the study, making this endpoint suitable for all durations of exposure. A sub chronic inhalation toxicity study has not been submitted for this chemical; therefore the default inhalation absorption factor of 100% should be applied for risk assessment.

The chronic rat study is considered more robust than either the chronic mouse or dog studies ( see section 4.4.3 for more details) or than the sub chronic rat study for the purposes of risk assessment. Although a lower NOAEL was noted in the sub chronic rat toxicity study, based on histopathological changes in the liver, this dose was not selected for short or intermediate term endpoints. Liver histopathology was the basis for the LOAEL in both the sub chronic and chronic rat studies. Therefore, the chronic NOAEL ( 3 mg/ kg/ day) is protective of this effect, and the lower value of the subchronic rat NOAEL ( 1.3 mg/ kg/ day) is considered an artifact of dose selection.

4.4.8 Margins of Exposure All target margins of exposure are 100.

4.4.9 Recommendation for Aggregate Exposure Risk Assessments There are no registered or proposed residential uses for fenbuconazole; therefore, the aggregate exposure risk assessment should be based on dietary and drinking water exposure only.

4.4.10 Classification of Carcinogenic Potential Under the 1986 cancer classification scheme, fenbuconazole was classified as a Group C  Possible Human Carcinogen, with a low dose extrapolation model applied to the animal data for the quantification of human risk ( Q1*). This was based on increased incidence of hepatocellular Page 30 of 55 adenomas and carcinomas in male and female mice and of thyroid follicular adenomas and combined adenomas/ carcinomas in male rats. Based on mechanistic data, quantification of risk was derived using combined hepatocellular adenomas/ carcinomas in female mice. The upper bound estimate of unit risk, Q1* ( mg/ kg/ day) 1 is 3.59 x 10 3 in human equivalents.

Table 4.4 Summary of Toxicological Dose and Endpoints for Fenbuconazole for use in Human Risk Assessment Exposure Scenario Dose Used in Risk Assessment, UF Special FQPA SF* and Level of Concern for Risk Assessment Study and Toxicological Effects Acute Dietary ( Females 13 49 years of age) NOAEL = 30 mg/ kg/ day UF = 100a Acute RfD = 0.3 mg/ kg FQPA SF = 1 aPAD = acute RfD FQPA SF = 0.3 mg/ kg Developmental rat study Developmental LOAEL = 75 mg/ kg/ day based on increased resorptions and decreased live fetuses per dam.

Acute Dietary ( General population including infants and children) None None Not selected.

No appropriate dose and endpoint could be identified for these population groups.

Chronic Dietary ( All populations) NOAEL= 3 mg/ kg/ day UF = 100a Chronic RfD = 0.03 mg/ kg/ day FQPA SF = 1 cPAD = chronic RfD FQPA SF = 0.03 mg/ kg/ day Combined chronic toxicity/ carcinogenicity  Rat LOAEL = 30.6/ 43.1 ( M/ F) mg/ kg/ day based on decreased body weight gain, increased thyroid weight, and histopathological lesions in the liver and thyroid gland Incidental Oral ( All durations) None None Not selected.

No registered uses would result in residential exposure.

Long Term Dermal ( several months to lifetime) Oral study NOAEL= 3 mg/ kg/ day ( dermal absorption rate = 4.25%) Residential LOC for MOE = NA Occupational LOC for MOE = 100a Combined chronic toxicity/ carcinogenicity  Rat LOAEL = 30.6/ 43.1 ( M/ F) mg/ kg/ day based on decreased body weight gain, increased thyroid weight, and histopathological lesions in the liver and thyroid gland Page 31 of 55 Table 4.4 Summary of Toxicological Dose and Endpoints for Fenbuconazole for use in Human Risk Assessment Exposure Scenario Dose Used in Risk Assessment, UF Special FQPA SF* and Level of Concern for Risk Assessment Study and Toxicological Effects Inhalation ( All durations) Oral study NOAEL= 3 mg/ kg/ day Absorption factor = 100% Residential LOC for MOE = NA Occupational LOC for MOE = 100a Combined chronic toxicity/ carcinogenicity  Rat LOAEL = 30.6/ 43.1 ( M/ F) mg/ kg/ day based on decreased body weight gain, increased thyroid weight, and histopathological lesions in the liver and thyroid gland Cancer ( oral, dermal, inhalation) Classification: Under the 1986 cancer classification scheme, fenbuconazole was classified as a Group C  Possible Human Carcinogen with a low dose extrapolation model applied to the animal data for the quantification of human risk ( Q1*). This was based on increased incidence of hepatocellular adenomas and carcinomas in male and female mice and of thyroid follicular adenomas and combined adenomas/ carcinomas in male rats. Based on mechanistic data, quantification of risk was derived using combined hepatocellular adenomas/ carcinomas in female mice. The upper bound estimate of unit risk, Q1* ( mg/ kg/ day) 1 is 3.59 x 10 3 in human equivalents.

UF = uncertainty factor, FQPA SF = FQPA safety factor, NOAEL = no observed adverse effect level, LOAEL = lowest observed adverse effect level, PAD = population adjusted dose ( a = acute, c = chronic) RfD = reference dose, LOC = level of concern, NA = Not Applicable a Database uncertainty factor reduced to 1x.

4.5 FQPA Safety Factor The FQPA safety factor has been removed ( reduced to 1x) since: 1) the toxicology database is complete; 2) there is no indication of increased susceptibility of rat or rabbit fetuses to in utero and/ or postnatal exposure to fenbuconazole in acceptable developmental and reproductive toxicity studies; 3) the dietary exposure assessment is based on models and input parameters designed to be protective of human health; and 4) there are currently no registered residential uses for fenbuconazole; therefore, this type of exposure to infants and children is not expected.

4.6 Endocrine disruption EPA is required under the FFDCA, as amended by FQPA, to develop a screening program to determine whether certain substances ( including all pesticide active and other ingredients) " may have an effect in humans that is similar to an effect produced by a naturally occurring estrogen, or other such endocrine effects as the Administrator may designate." Following recommendations of its Endocrine Disruptor and Testing Advisory Committee ( EDSTAC), EPA determined that there was a scientific basis for including, as part of the program, the androgen and thyroid hormone systems, in addition to the estrogen hormone system. EPA also adopted EDSTAC's recommendation that the Program include evaluations of potential effects in wildlife. Page 32 of 55 For pesticide chemicals, EPA will use FIFRA and, to the extent that effects in wildlife may help determine whether a substance may have an effect in humans, FFDCA authority to require the wildlife evaluations. As the science develops and resources allow, screening of additional hormone systems may be added to the Endocrine Disruptor Screening Program ( EDSP).

When additional appropriate screening and/ or testing protocols being considered under the Agency's EDSP have been developed, fenbuconazole may be subjected to further screening and/ or testing to better characterize effects related to endocrine disruption.

5.0 PUBLIC HEALTH DATA 5.1 Incident Reports There are no clinical acute poisoning cases reported in the literature at this time for fenbuconazole.

6.0 EXPOSURE CHARACTERIZATION/ ASSESSMENT 6.1 Dietary Exposure/ Risk Pathway 6.1.1 Residue Profile The petitioner has submitted adequate studies describing residues of fenbuconazole and its residues of concern in almond, apple, banana, bushberry, citrus, cranberry, grape, peanut, pecan, stone fruit, sugar beet, and wheat. No major deficiencies were noted in the residue chemistry database; however, a number of minor deficiencies should be resolved prior to establishing tolerances. These deficiencies are listed in Section 10.

Crop field trials with the above listed commodities resulted in measurable residues of concern for all crops, though the relative amounts of each residue of concern varies based on the crop.

Maximum residue limits ( MRLs) for residues of fenbuconazole have been established by Codex Alimentarius, Canada, and Mexico. The residue definition for both Codex and Mexico is fenbuconazole, per se, and the Canadian residue definition is the combined residues of fenbuconazole and its metabolites, RH 9129 and RH 9130, each expressed as parent ( i. e., the same as the U. S. tolerance definition). The recommended tolerance levels, international MRLs, and processing factors associated with these fenbuconazole petitions are summarized in Table 6.1. The NAFTA MRL calculator was not used to derive the recommended tolerance levels.

Table 6.1.1 Summary of Tolerances, International Maximum Residue Limits, and Processing Factors for Fenbuconazole. Crop Commodity Recommended U. S. Tolerance, ppm International Maximum Residue Limits, ppm Processing Factor Almond Almond 0.05     Page 33 of 55 Table 6.1.1 Summary of Tolerances, International Maximum Residue Limits, and Processing Factors for Fenbuconazole. Crop Commodity Recommended U. S. Tolerance, ppm International Maximum Residue Limits, ppm Processing Factor Hulls 1.0     Apple Fruit Juice Pomace ( wet) 0.4   1.0         0.06h 2.46h Banana Banana 0.3 0.3d, 0.05e   Bushberry Bushberrya 0.3     Citrus Fruit Oil Pulp, dried 1.0 40 5.0         61 6.9 Cranberry Cranberry 0.5     Grape Grape Juice Wine Raisin 1.0                 0.18 0.07 N/ Ai Peanut Peanut 0.1     Pecan Pecan 0.05 0.05e   Stone Fruit Fruit Plum, dried 1.0   Multiplef 0.5g   3.4 Sugar beet Root Top Pulp, dried Molasses 0.3 9.0 1.0 0.4             5.4 1.8 Wheat Grain Forage Hay Straw AGFb 0.1 4.0 8.0 8.0 6.0 0.1e     3.0e           69.2 Cattle, goats, horses, sheep Meat Fat MBPc None None 0.05             a Includes Juneberry, Lingonberry, and Salal b AGF = Aspirated Grain Fractions c MBP = Meat Byproducts d Mexican MRL on plantains. Residue definition is fenbuconazole e Codex MRL. Residue definition is fenbuconazole only. f Codex: Peach   0.5 ppm, Cherry   1.0 ppm; Canada: Peach   0.5 ppm, Cherry   0.8 ppm, Plum   0.1 ppm g Canadian MRL. Residue definition is fenbuconazole+ RH 9129+ RH 9130. h Draft values pending evaluation of the apple processing study currently under review. i Due to the low amount of imported grapes processed into raisins, a processing factor for raisins is not required for this petition.

6.1.2 Acute and Chronic Dietary Exposure and Risk Fenbuconazole Chronic Dietary Exposure Assessment for the Section 3 Registration Action. M. Doherty, D329595, June 2006.

Acute, chronic, and cancer dietary risk assessments were conducted using the Dietary Exposure Evaluation Model ( DEEM FCID, Version 2.03), which uses food consumption data from the USDA's Continuing Surveys of Food Intakes by Individuals ( CSFII) from 1994 1996 and 1998. Page 34 of 55 The analyses were performed to estimate the dietary exposures and risks associated with the uses of fenbuconazole on the subject listed commodities. All three analyses include estimates for residues of fenbuconazole in water.

The acute dietary ( food + water) assessment is a screening level, Tier 1 assessment. It is based on tolerance level residues and assumes 100% crop treated, and it uses the EDWC for fenbuconazole in surface water ( 20.3 ppb), which is worst case estimate that is derived from the requested use pattern for cherries. As such, it is highly conservative with respect to evaluating potential impacts of acute dietary exposure to fenbuconazole on human health. The only population subgroup that is relevant for this acute assessment is females of child bearing age ( 13 49 years old). The acute risk estimate that results from this analysis is 3% of the acute population adjusted dose ( aPAD). This risk estimate is much less than HED's level of concern ( 100% of the aPAD).

The chronic ( non cancer) dietary assessment includes contributions from both food and water. This analysis is more refined and uses average residues from field trials. Due to the manner in which these data were submitted and reviewed, multiple averages were calculated for many of the crops. For these crops, the highest average was used in the analysis. The non cancer dietary analysis assumes 100% crop treated and the annual average EDWC from the cherry use ( 16.5 ppb). The maximum chronic risk estimate is 7% of the chronic population adjusted dose ( cPAD) and is for the infant population subgroup. The risk estimates for all other population subgroups are less than that for infants. As with the acute assessment, these risk estimates are all well below HED's level of concern.

The cancer dietary analysis uses the same food residue inputs as those of the non cancer assessment. The cancer analysis is further refined in that it makes use of percent crop treated estimates and the EDWC from the 30 year average from cherry use ( 11.7 ppb). The cancer risk estimate using these food residue inputs and a worst case use pattern assumption for water is 1.61 x 10 6. For fenbuconazole, the food only risk estimate is 0.72 x 10 6.

Cancer risks presented in this assessment are expressed to one significant figure. However, it should be noted that, in general, the precision which can be assumed for cancer risk estimates is best described by rounding to the nearest integral order of magnitude on the log scale, e. g. 3.16 x 10 7 to 3.16 x 10 6, expressed as 10 6. Risks are generally reported to one significant figure in HED risk assessments to allow better characterization of changes in risk which might result from potential risk mitigation. This rounding procedure indicates that risks should generally not be assumed to exceed the benchmark level of concern of 10 6 until the calculated risks exceed approximately 3 x 10 6. Discretion should be used in interpreting the significance of these calculated risks with consideration given to the precision in the risk estimates.

Based on the assumptions used in the cancer analysis and the available information in the fenbuconazole residue chemistry database, HED does not believe that the food + water risk estimate represents an actual risk of concern for the U. S. population. Therefore, based on the information available at this time, there are no dietary exposure concerns that would preclude Page 35 of 55 establishing the uses of and tolerances for fenbuconazole associated with the subject listed commodities.

Table 6.1.2. Summary of Dietary Exposure and Risk Estimates for Fenbuconazole Acute Dietary ( 95th Percentile) Chronic Dietary Cancer Population Subgroup Exposure ( mg/ kg/ day) % aPAD Exposure ( mg/ kg/ day) % cPAD Exposure ( mg/ kg/ day) Risk General U. S. Pop. 0.000666 2 0.0004494 1.61 x 10 6 All Infants (< 1 year) 0.002016 7 Children ( 1 2 years) 0.001795 6 Children ( 3 5 years) 0.001408 5 Children ( 6 12 years) 0.000783 3 Youth ( 13 19 years) 0.000419 1 Adults ( 20 49 years) 0.000525 2 Adults ( 50+ years) Not Applicable 0.000612 2 Females ( 13 49 years) 0.009014 3 0.000539 2 Not Applicable 6.2 Water Exposure/ Risk Pathway ( Revised Tier II Drinking Water Assessment for Fenbuconazole, A. Al Mudallal, D330709, July 7, 2006)

A Tier 2 drinking water assessment was performed using PRZM 3.12/ EXAMS 2.7.97 modeling with index reservoir ( IR) scenarios and percent cropped area ( PCA) adjustment factors. The assessment was based on the registered use rate of fenbuconazole cherries. The Tier II modeling for cherries predicts that the concentrations of fenbuconazole in surface water are not likely to exceed 20.3 µ g/ L for the peak concentration, 16.5 µ g/ L for the annual average concentration, and 11.7 µ g/ L for the 30 year average concentration.

Groundwater concentrations were estimated using a Tier 1 SCI Grow model ( version 2.2, Nov. 1, 2001). The assessment was based on an annual use rate of 0.75 ai/ acre. The SCI GROW model predicts the acute and chronic concentrations of fenbuconazole in shallow ground water to be 0.031 µ g/ L.

Table 6.2. Summary of Estimated Surface and Ground Water Concentrations for Fenbuconazole. Fenbuconazole Exposure Duration Surface Water Conc., ppb a Ground Water Conc., ppb b Acute 20.3 Chronic ( non cancer) 16.5 0.031 Chronic ( cancer) 11.7 a From the Tier II PRZM EXAMS  Index Reservoir model. Input parameters are based on Michigan Cherry scenario with 8 aerial applications of 0.094 lbs a. i./ acre, 7 day intervals. A default PCA factor of 0.87 was used. b From the SCI GROW model assuming a maximum annual use rate of 0.75 lb ai/ A, a Koc of 2884 ml/ g, and a half life of 393 days. Page 36 of 55 6.3 Residential ( Non Occupational) Exposure/ Risk Pathway There are currently no registered residential uses associated with fenbuconazole.

6.3.1 Other ( Spray Drift, etc.)

Spray drift is always a potential source of exposure to residents nearby to spraying operations. This is particularly the case with aerial application, but, to a lesser extent, could also be a potential source of exposure from the ground application method employed for fenbuconazole. The Agency has been working with the Spray Drift Task Force, EPA Regional Offices and State Lead Agencies for pesticide regulation and other parties to develop the best spray drift management practices. On a chemical by chemical basis, the Agency is now requiring interim mitigation measures for aerial applications that must be placed on product labels/ labeling. The Agency has completed its evaluation of the new data base submitted by the Spray Drift Task Force, a membership of U. S. pesticide registrants, and is developing a policy on how to appropriately apply the data and the AgDRIFT computer model to its risk assessments for pesticides applied by air, orchard airblast and ground hydraulic methods. After the policy is in place, the Agency may impose further refinements in spray drift management practices to reduce off target drift with specific products with significant risks associated with drift.

7.0 AGGREGATE RISK ASSESSMENTS AND RISK CHARACTERIZATION In accordance with the FQPA, HED must consider and aggregate pesticide exposures and risks from three major sources: food, drinking water, and residential exposures. In an aggregate assessment, exposures from relevant sources are added together and compared to quantitative estimates of hazard ( e. g., a NOAEL or PAD), or the risks themselves can be aggregated. When aggregating exposures and risks from various sources, HED considers both the route and duration of exposure. There are no residential exposure uses associated with fenbuconazole. Therefore, for purposes of this assessment, only dietary ( food) and drinking water sources of exposure were combined to obtain an estimate of potential aggregate risk.

For most pesticide active ingredients, water monitoring data are considered inadequate to determine surface and ground water drinking water exposure estimates, so model estimates have been used to estimate residues in drinking water ( EDWCs). The Environmental Fate and Effects Division ( EFED) and HED have agreed that acute, chronic and cancer EDWCs can be used directly in dietary exposure assessments to calculate aggregate dietary ( food + water) risk. This is done by using the relevant PRZM EXAMS value as a residue for water ( all sources) in the dietary exposure assessment. The principal advantage of this approach is that the actual individual body weight and water consumption data from the CSFII are used, rather than assumed weights and consumption for broad age groups.

7.1 Acute Aggregate Risk Page 37 of 55 Dietary exposure ( food + water) is the only source of exposure to fenbuconazole that is expected to result in acute exposure. Therefore, the acute aggregate exposure and risk estimate is equivalent to the acute dietary exposure and risk estimates discussed in Sections 6.1.2 and 7.0. Due to the toxicology of fenbuconazole, the only population subgroup of concern for the acute assessment is females 13 49 years old. The data are shown again in Table 7.1 for convenience.

Table 7.1 Acute Aggregate Exposure and Risk for Fenbuconazole Acute Dietary ( 95th Percentile) Population Subgroup aPAD Exposure ( mg/ kg/ day) % aPAD General U. S. Pop.

All Infants (< 1 year)

Children ( 1 2 years)

Children ( 3 5 years)

Children ( 6 12 years)

Youth ( 13 19 years)

Adults ( 20 49 years)

Adults ( 50+ years) Not Applicable Females ( 13 49 years) 0.3 0.009014 3 7.2 Short and Intermediate Term Aggregate Risks There are no residential uses associated with fenbuconazole; therefore short and intermediateterm aggregate risk assessments are not required.

7.3 Long Term Aggregate Risk Dietary exposure ( food + water) is the only source of exposure to fenbuconazole that is expected to be long term ( 180 365 days). Therefore, the long term aggregate exposure and risk estimates are equivalent to the chronic dietary exposure and risk estimates discussed in Sections 6.1.2 and 7.0. The data are shown again in Table 7.3 for convenience.

Table 7.3 Aggregate for Long term Exposure to Fenbuconazole Chronic Dietary Population Subgroup cPAD Exposure ( mg/ kg/ day) % cPAD General U. S. Pop. 0.000666 2 All Infants (< 1 year) 0.002016 7 Children ( 1 2 years) 0.001795 6 Children ( 3 5 years) 0.001408 5 Children ( 6 12 years) 0.000783 3 Youth ( 13 19 years) 0.03 0.000419 1 Page 38 of 55 Table 7.3 Aggregate for Long term Exposure to Fenbuconazole Chronic Dietary Population Subgroup cPAD Exposure ( mg/ kg/ day) % cPAD Adults ( 20 49 years) 0.000525 2 Adults ( 50+ years) 0.000612 2 Females ( 13 49 years) 0.000539 2 7.4 Cancer Risk Dietary exposure ( food + water) is the only source of exposure to fenbuconazole that is expected to be chronic ( cancer  life time). Therefore, the chronic ( cancer) aggregate exposure and risk estimates are equivalent to the chronic ( cancer) dietary exposure and risk estimates discussed in Sections 6.1.2 and 7.0. The data are shown again in Table 7.4 for convenience.

Table 7.4 Aggregate for Chronic ( Cancer) Exposure to Fenbuconazole Population Q* Exposure ( mg/ kg/ day) Cancer Risk U. S. Population 3.59e 3 0.0004494 1.61 x 10 6 8.0 CUMULATIVE RISK CHARACTERIZATION/ ASSESSMENT Fenbuconazole is a member of the triazole containing class of pesticides. Although conazoles act similarly in plants ( fungi) by inhibiting ergosterol biosynthesis, there is not necessarily a relationship between this pesticidal activity and their mechanism of toxicity in mammals. Structural similarities do not constitute a common mechanism of toxicity. Evidence is needed to establish that the chemicals operate by the same, or essentially the same sequence of major biochemical events ( EPA, 2002). A variable pattern of toxicological responses are found for conazoles. Some are hepatotoxic and hepatocarcinogenic in mice. Some induce thyroid tumors in rats. Some induce developmental, reproductive, and neurological effects in rodents. Furthermore, the conazoles have a diverse range of biochemical events including altered cholesterol levels, stress responses, and altered DNA methylation. It is not clearly understood whether these biochemical events are directly connected to the toxicological outcomes. Thus, there is currently no evidence to indicate that conazoles share common mechanisms of toxicity and EPA is not following a cumulative risk approach based on a common mechanism of toxicity for the conazoles. For information regarding EPA's procedures for cumulating effects from substances found to have a common mechanism of toxicity, see EPA's website at http:// www. epa. gov/ pesticides/ cumulative/.

9.0 OCCUPATIONAL EXPOSURE/ RISK ASSESSMENT PATHWAY Page 39 of 55 ( Fenbuconazole: Occupational and Residential Exposure Assessment for Section 3 Registration for use of Fenbuconazole on Almonds, Apples, Bananas, Blueberries, Citrus Fruits, Cranberries, Pecans, Peanuts, Plums, Prunes, Sugar Beets, and Wheat; M. Collantes; DP Barcode 328908; June 2006)

9.1 Short/ Intermediate/ Long Term Handler Risk Fenbuconazole may be applied by groundboom, airblast and aerial equipment. Based on the number of seasonal applications indicated on this product label, and information provided by the registrant, handler exposures are expected to be short and intermediate term in duration.

Chemical specific data for assessing exposure during pesticide handling activities were not submitted to the Agency in support of this Section 3 application. It is HED policy to use data from the Pesticide Handlers Exposure Database ( PHED) Version 1.1 to assess handler exposures for regulatory actions when chemical specific data are not available ( HED Science Advisory Council for Exposure, SOP Number .007, January 1999).

9.1.1 Non Cancer Risk HED's level of concern for non cancer risks ( i. e., target level of Margins of Exposure ( MOE)) is defined by the uncertainty factors that are applied to the assessment. HED typically applies a 10X factor to account for inter species extrapolation and a 10X factor to account for intra species sensitivity. The total uncertainty factor that has been applied to the non cancer risk assessment for fenbuconazole is 100 for occupational exposure. For fenbuconazole, non cancer occupational exposure and risk estimates resulting in MOEs greater than or equal to 100 are not of concern to HED.

Summaries of the non cancer ( MOEs) risks for handlers are included in Table 9.1.1. All calculations used the maximum application rate to estimate worst case risk scenario for handler exposure and risk. All mixer/ loader, applicator, and flagger inhalation MOEs are greater than 100 at baseline, and therefore not of concern to HED. Since neither a short nor intermediateterm dermal endpoint was selected and long term dermal exposure to handlers is not expected, a handler dermal risk assessment was not required.

9.1.2 Cancer Exposure and Risk The Agency has defined a range of acceptable cancer risks for occupational carcinogenic risk (" Non Dietary Cancer Risk Policy", Dan Barolo, August 4, 1996). In summary, this policy memo indicates occupational carcinogenic risks that are 1 x 10 4 or lower require no risk management action. EPA considered occupational cancer risk estimates greater than one in ten thousand ( 1 x 10 4) to be of concern, and attempts to mitigate occupational exposures so that cancer risk estimates are one in one million ( 1 x 10 6) or less, where feasible.

To estimate the carcinogenic risk from absorbed average daily dose, the values were amortized over the working lifetime of occupational handlers. Current use patterns indicate that application can occur numerous times during a year. Based on use scenario and use patterns, it is anticipated that commercial applicators would apply fenbuconazole less than 30 days per year. It Page 40 of 55 was estimated that an individual farmer would handle fenbuconazole approximately 10 days per year. As a result, HED considered two handler populations ( small, medium, and large scale growers as well as commercial applicators) for the cancer risk assessment. Finally, a 35 year career and a 70 year lifespan were used to complete the calculations.

Table 9.1.2 summarizes the cancer risk for handler exposure. All cancer calculations use the maximum application rate to estimate risk. The cancer risk for private and commercial farmers ( i. e., mixer/ loaders, applicators and flaggers) were lower than 1 x 10 4 using either baseline or PPE ( single layer clothing and gloves) mitigation. The cancer risk for private farmers ranged from 6.1 x 10 9 to 1.3 x 10 6 , while the cancer risk for commercial farmers ranged from 1.8 x 10 8 to 4.0 x 10 6 .

Table 9.1.1: Non Cancer Short and Intermediate term Handler Risk Scenario Mitigation Crops Inhalation Unit Exposure ( mg/ lb) a Application Rate b ( lb ai/ acre) Acres Treated ( A/ day) c Inhalation Dose d ( mg/ kg/ day) Inhalation MOEe Mixer/ Loader 14,000 Wheat 0.062 200 0.00021 peanuts and sugar beets 0.12 0.00016 19,000 ENABLE 2F Groundboom cranberries 0.19 80 0.00026 12,000 Almonds, bananas, blueberries, plums, prunes, 0.094 0.000064 47,000 ENABLE 2F Airblast Baseline apples, citrus fruits, grapefruit, pecans, 0.12 40 0.000082 37,000 wheat 0.062 1200 0.0013 2,300 Almonds, bananas, blueberries, plums, prunes 0.094 0.00056 5,000 ENABLE 2F Aerial Baseline apples, citrus fruits, grapefruit, pecans, 0.0012 0.12 350 0.00072 4,200 Page 41 of 55 Table 9.1.1: Non Cancer Short and Intermediate term Handler Risk Scenario Mitigation Crops Inhalation Unit Exposure ( mg/ lb) a Application Rate b ( lb ai/ acre) Acres Treated ( A/ day) c Inhalation Dose d ( mg/ kg/ day) Inhalation MOEe cranberries 0.19 0.00114 2,600 Indar 75WSP Airblast Apricots, cherries, nectarines, peaches 0.00024 0.09 40 0.0000123 240,000 Page 42 of 55 Indar 75WSP Aerial 350 0.0001 30,000 Applicator Enable 2F wheat 0.00074 0.062 200 0.00013 23,000 Almonds, bananas, blueberries, plums, prunes 0.094 0.00024 13,000 Enable 2F airblast apples, citrus fruits, grapefruit, pecans, 0.0045 0.12 40 0.0003 10,000 wheat 0.062 1200 0.000072 42,000 Almonds, bananas, blueberries, plums, prunes 0.094 0.000032 94,000 apples, citrus fruits, grapefruit, pecans, 0.12 0.00004 75,000 Enable 2F aerial Cranberries 0.000068 0.19 350 0.000065 46,000 Indar 75 WSP Airblast 0.0045 40 0.0000034 880,000 Indar 75 WSP Aerial Baseline Apricots, cherries, nectarines, peaches 0.000068 0.09 350 0.00003 100,000 Flagger Enable 2F wheat 0.062 1200 0.00037 8100 Baseline Almonds, bananas, blueberries, plums, prunes 0.00035 0.094 350 0.000165 18,000 Page 43 of 55 apples, citrus fruits, grapefruit, pecans 0.12 0.00021 14,000 cranberry 0.19 0.00033 9100 Indar 75 WSP Apricots, cherries, nectarines, peaches 0.00035 0.09 350 0.00016 19,000 a. PHED Version 1.1 b. Application Rate based on proposed registered label for fenbuconazole products c. Acres Treated = Science Advisory Council Policy # 9.1 d. Short and Intermediate term Inhalation Dose ( mg/ kg/ day) = [ Rate ( lb ai/ A) x UE ( mg / lb ai ) x Acres Treated ( A/ day)] / BW ( 70 kg) e. Short and intermediate term Inhalation MOE = Inhalation NOAEL ( 3 mg/ kg/ day)/ Inhalation Dose ( mg/ kg/ day) Page 44 of 55 Table 9.1.2 Handler Cancer Risk for Fenbuconazole Scenario Mitigation Crop Dermal Dose a ( mg/ kg/ day) Inhalation Dose a ( mg/ kg/ day) Combined ADD b ( mg/ kg/ day) Private LADD c ( mg/ kg/ day) Private Cancer Risk d Commerical LADD e ( mg/ kg/ day) Commercial Cancer Risk f Mixer/ Loader wheat 0.02 0.00021 0.02 0.00027 9.9E 7 0.00083 3.0E 6 Peanuts,

sugar beets 0.017 0.00016 0.0172 0.000235 8.4E 7 0.0007 2.5E 6 Enable 2F Groundboom cranberries 0.027 0.00026 0.0273 0.00037 1.3E 6 0.0011 4.0E 6 Almonds,

bananas, blueberries,

plums,

prunes 0.0066 0.000064 0.0066 0.000091 3.3E 7 0.00027 9.8E 7 Enable 2F Airblast baseline Apples,

citrus fruits,

grapefruit,

pecans 0.0085 0.000082 0.0086 0.00118 4.2E 7 0.00035 1.3E 6 wheat 0.001 0.0013 0.0023 0.000032 1.1E 7 0.000095 3.4E 7 Enable 2F Aerial Baseline  Inhalation Single layer &

gloves

Dermal Almonds,

bananas, blueberries,

plums,

prunes 0.0005 0.00056 0.001 0.000015 5.2E 8 0.000044 1.6E 7 Page 45 of 55 Table 9.1.2 Handler Cancer Risk for Fenbuconazole Scenario Mitigation Crop Dermal Dose a ( mg/ kg/ day) Inhalation Dose a ( mg/ kg/ day) Combined ADD b ( mg/ kg/ day) Private LADD c ( mg/ kg/ day) Private Cancer Risk d Commerical LADD e ( mg/ kg/ day) Commercial Cancer Risk f Apples,

citrus fruits,

grapefruit,

pecans Peanuts and sugar beets 0.0006 0.00072 0.00132 0.000018 6.5E 8 0.000054 1.9E 7 cranberries 0.0009 0.00114 0.002 0.00003 9.9E 8 0.000084 3.0E 7 Indar 75WSP airblast 0.0004 0.00114 0.00154 0.00002 7.5E 8 0.000063 2.3E 7 Indar 75WSP aerial Apricots,

cherries, nectarines,

peaches 0.004 0.0000123 0.004 0.000055 1.9E 7 0.000165 5.9E 7 Applicator wheat 0.0001 0.00013 0.00023 0.0000031 1.1E 8 0.0000094 3.4E 8 Apples,

citrus fruits,

grapefruit,

pecans, peanuts, and sugar beets 0.000082 0.0001 0.00018 0.0000025 9E 9 0.0000074 2.7E 8 Enable 2F Groundboom baseline cranberries 0.00013 0.00016 0.00029 3.9E 6 1.4E 8 0.000012 4.3E 8 Page 46 of 55 Table 9.1.2 Handler Cancer Risk for Fenbuconazole Scenario Mitigation Crop Dermal Dose a ( mg/ kg/ day) Inhalation Dose a ( mg/ kg/ day) Combined ADD b ( mg/ kg/ day) Private LADD c ( mg/ kg/ day) Private Cancer Risk d Commerical LADD e ( mg/ kg/ day) Commercial Cancer Risk f Almonds,

bananas, blueberries,

plums,

prunes 0.00082 0.00024 0.001 0.000015 5.2E 8 0.000044 1.6E 7 Enable 2F airblast Apples,

citrus fruits,

grapefruit,

pecans 0.001 0.0003 0.0013 0.0000018 6.4E 8 0.000053 1.9E 7 wheat 0.00023 0.000072 0.0003 0.000004 1.5E 8 0.0000123 4.5E 8 Almonds,

bananas, blueberries,

plums,

prunes 0.0001 0.000032 0.000132 0.0000018 6.5E 9 0.0000054 1.9E 8 Apples,

citrus fruits,

grapefruit,

pecans, peanuts,

sugar beets 0.00013 0.00004 0.00017 0.0000023 8.4E 9 0.000007 2.5E 8 Enable 2F aerial cranberries 0.0002 0.000065 0.00027 0.0000036 1.3E 8 0.000011 4E 8 Indar 75 WSP Airblast Baseline Apricots,

cherries, nectarines, 0.0069 0.0000034 0.007 0.000095 3.4E 7 0.0003 1E 6 Page 47 of 55 Table 9.1.2 Handler Cancer Risk for Fenbuconazole Scenario Mitigation Crop Dermal Dose a ( mg/ kg/ day) Inhalation Dose a ( mg/ kg/ day) Combined ADD b ( mg/ kg/ day) Private LADD c ( mg/ kg/ day) Private Cancer Risk d Commerical LADD e ( mg/ kg/ day) Commercial Cancer Risk f Indar 75 WSP Aerial peaches 0.000095 0.00003 0.000125 0.0000017 6E 9 0.000005 1.8E 8 Flagger Wheat 0.00049 0.00037 0.00086 0.000012 4.2E 8 0.000035 1.3E 7 Almonds,

bananas, blueberries,

plums,

prunes 0.00022 0.000165 0.00038 0.00000513 1.8E 8 0.0000156 5.6E 8 Apples,

citrus fruits,

grapefruit,

pecans, peanuts,

sugar beets 0.00028 0.00021 0.00049 0.0000066 2.4E 8 0.00002 7.2E 8 Enable 2F cranberry 0.00044 0.00033 0.00077 0.00001 3.7E 8 0.000032 1.1E 7 Indar 75 WSP Baseline Apricots,

cherries, nectarines,

peaches 0.00021 0.00016 0.00037 0.000005 1.8E 8 0.000015 5.5E 8 Notes:

a. See Table 5.1.2 of June 2006 M. Collantes Occupational Risk Assessment ( D328908)

b. ADD ( mg/ kg/ day) = [ Dermal Dose ( mg/ kg/ day) x 4.25% DA]+ Inhalation Dose ( mg/ kg/ day)

c. Private Farmer LADD ( mg/ kg/ day) = ADD x [( 10 days/ yr)/ ( 365 days/ yr)] x ( 35 yrs/ 70yrs) Page 48 of 55 d Private Farmer Cancer Risk = LADD x Q* ( 3.59 x 10 3 mg/ kg/ day) 1 e. Commercial Applicator LADD ( mg/ kg/ day) = ADD x [( 30 days/ yr)/ ( 365 days/ yr)] x ( 35 yrs/ 70yrs)

f. Private Applicator Cancer Risk = LADD x Q* ( 3.59 x 10 3 mg/ kg/ day) 1 Page 49 of 55 9.2 Non Cancer Short/ Intermediate/ Long Term Postapplication Risk Neither short nor intermediate term dermal endpoints were selected for fenbuconazole. Longterm dermal exposure as a result of postapplication activities is not expected. Therefore a noncancer postapplication exposure assessment was not required 9.2.1 Cancer Postapplication Risk No postapplication data were submitted in support of this registration action. Cancer risk and exposures resulting from postapplication activities were estimated using dermal transfer coefficients from the Science Advisory Council For Exposure Policy Number 3.1: Agricultural Transfer Coefficients, August 2000. The following assumptions, data and default values were also used:

Assumptions:   Application Rate = ranges from 0.064 lb ai/ A for wheat to cranberries at 0.19 lb ai/ A   Exposure Duration= 8 hours per day   Body Weight = 70 kg   Dermal Absorption= 4.25% for long term exposure   Fraction of a. i. retained on foliage is assumed to be 20% ( 0.2) on day zero (=% dislodgeable foliar residue, DFR, after initial treatment). This fraction is assumed to further dissipate at the rate of 10% ( 0.1) per day on following days. These are default values established by HED's Science Advisory Council ( SAC) for Exposure.

The Agency has defined a range of acceptable cancer risks for occupational carcinogenic risk Occupational carcinogenic risks that are 1 x 10 4 or lower require no risk management action. EPA considered occupational cancer risk estimates greater than one in ten thousand ( 1 x 10 4) to be of concern, and attempts to mitigate occupational exposures so that cancer risk estimates are one in one million ( 1 x 10 6) or less, where feasible.

In determining carcinogenic risk related to postapplication exposure, the values were amortized over the working lifetime of occupational workers. Furthermore, HED considered the following assumptions and data: 1.) the time interval between reapplication of fenbuconazole varies between 7 days and 30 or more days for the proposed uses, 2.) residues are assumed to decrease over time and 3.) it is unlikely that workers will be exposed to Day 0 residues 30 days a year. Therefore, HED used the average residue over 30 days to estimate cancer risk. All cancer risk estimates are lower than 1 x 10 6 and therefore are not a risk concern. Cancer risk estimates are summarized in Table 9.2.

Restricted Entry Interval The restricted entry interval ( REI) is based on the acute toxicity of fenbuconazole technical material which is classified as Category III and IV. Acute toxicity Category III and IV chemicals require a 12 hour REI. Therefore the 12 hour REI which appears on the Enable 2F Fungicide and Indar 75WSP labels is adequate. Page 50 of 55 Table 9.2: Postapplication Cancer Risk and Exposure for Fenbuconazole Transfer Coefficient c ( cm2/ hr) Daily Dose d ( mg/ kg/ day) LADD e Cancer Risk f Crop DAT a DFR b ( ug/ cm2) Low High Low High Low High Low High cranberry, Avg 0.136 2.6E 4 1.1E 5 3.9E 8 blueberry Avg 0.067 400 NA 1.3E 4 NA 5.4E 6 NA 2.0E 8 NA wheat Avg 0.044 2.2E 5 3.2E 4 8.8E 7 1.3E 5 3.2E 9 4.8E 8 sugar beet,

and peanut Avg 0.086 100 1500 4.2E 5 6.2 4 1.74E 6 2.6E 5 6.0E 9 9.2E 8 apples Avg 0.086 4.2E 5 1.2E 3 1.7E 6 5.17E 5 6.1E 9 1.8E 7 prunes and plums Avg 0.064 3.1E 5 9.4E 4 1.3E 6 3.8E 5 4.6E 9 1.4E 7 apricots, nectarines,

peaches and cherries Avg 0.067 100 3000 3.3E 5 9.3E 4 1.3E 6 4.0E 5 4.8E 9 1.4E 7 grapefruits,

oranges Avg 0.086 6.2E 4 1.2E 3 2.6E 5 5.1E 5 9.2E 8 1.8E 7 bananas Avg 1500 3000 4.9E 4 9.8E 4 2.0E 5 4.0E 5 7.2E 8 1.4E 7 almonds Avg 0.067 1.6E 4 8.2E 4 6.7E 6 3.4E 5 2.3E 8 1.2E 7 Pecans Avg 0.086 500 2500 2.1E 4 1.0E 3 8.6E 6 4.34E 5 3.1E 8 1.5E 7 a. DAT= 30 day residue average b. DFRt ( µ g/ cm2) = Application Rate ( lb ai/ A) x F x[[ 1( 1 D) 30 ]/[ 1( 1 D)]}/ t x 4.54E8 µ g/ lb x 24.7E 9 A/ cm2 c. Transfer Coefficients selected in accordance with SAC for Exposure Policy 3.1 ( August 2000)

d. Daily Dose ( mg/ kg/ day) = DFR ( ug/ cm2) x 0.001 mg/ ug x Tc ( cm2/ hr) x DA ( 4.25%) x ET ( 8 hrs/ day)/ 70 kg Page 51 of 55 e. LADD ( mg/ kg/ day) = DD x [( 30 days/ yr)/ ( 365 days/ yr)] x ( 35 yrs/ 70yrs)

f. Cancer Risk = LADD x Q* ( 3.59 x 10 3 mg/ kg/ day) 1 Page 52 of 55 10. DATA NEEDS AND LABEL REQUIREMENTS 10.1 Toxicology  None 10.2 Residue Chemistry The registrant has requested a large number of new uses for fenbuconazole. Data needs and label requirements are presented below and should be resolved prior to establishing tolerances, except where items are noted as being a condition of registration.

General ( All Petitions)   The petitioner must amend Section B of the petitions to specify whether application is to be made using ground and/ or aerial equipment, and to specify the application volumes to be used for application. These Sections B need to be modified to be consistent with proposed labels ( i. e., Enable 2F and Indar 75WSP) which state, " for aerial application apply a minimum of 5 gallons of water per acre on annual crops and 10 gallons of water per acre on perennial tree fruits and nuts" and " for aerial application apply in a minimum of 10 gallons of water per acre", respectively.

  The analytical reference standards for the two fenbuconazole metabolites, RH 9129 and RH 9130, are present in insufficient quantities at the Agency's Analytical Chemistry Branch repository. The registrant must submit one gram each of the reference standards for the two fenbuconazole metabolites, RH 9129 and RH 9130.

  Prior to being accepted as an enforcement method, the GC/ NPD method ( TR 34 94 142, MRID 43524907) for determining residues in livestock commodities must undergo a Tolerance Method Validation ( TMV). HED will initiate the TMV.

7F4900/ 4F6879 ( Citrus)   The petitioner must amend the proposed label to specify a minimum retreatment interval; the available data will support a minimum retreatment interval of 21 days.

  The petitioner must conduct another citrus processing study. Samples from the processing study must be analyzed within the intervals that fenbuconazole and metabolite residues have been shown to be stable ( 30 months for fruit and 12 months for oil and dried pulp). The required study does not need to include the analysis of juice samples; the current study is adequate to demonstrate that residues of fenbuconazole and its metabolites RH 9129 and RH 9130 do not concentrate in citrus juice. Granting of a registration should be made conditional upon resolution of this issue.

2F4135 ( Apple)   The petitioner must submit a revised Section F to specify a tolerance expression for the combined residues of fenbuconazole and its metabolites RH 9129 and RH 9130 Page 53 of 55 in terms of parent equivalents. In addition, the entry for apple juice, for which a tolerance level of " not required" is listed, should be deleted from Section F.

  The Agency has not reviewed an acceptable apple processing study for fenbuconazole. Granting of a registration should be made conditional upon resolution of this issue. We note that MRID 43621001 is under review.

7F4887 ( Sugar Beet)   The proposed label must be amended to remove the prohibition against the feeding of sugar beet tops to livestock, as the Agency does not allow the restriction of feeding of sugar beet tops.

1F3989, 1F3995, 2F4154 and 3F4194 ( Stone Fruits, Pecans, Bananas and Almonds)   None 9E5041 ( Bushberries)   As a condition of registration, two additional field trials are required for blueberries, one each from Regions 2 and 5.

1E6252 ( Cranberries)   The proposed use pattern for cranberries should be amended to specify a minimum retreatment interval of 10 days.

2F4127 ( Wheat)   Label directions for uses on wheat should be amended to: ( i) remove the prohibition against the grazing or feeding of forage or hay to livestock; ( ii) specify a minimum PHI for forage and hay; and ( iii) specify rotational crop restrictions. Although limited, the available data indicate that a 14 day PHI would be acceptable for wheat forage and hay, while the additional field trial data are being generated. For crops without primary label uses ( i. e., rotational crops), minimum plantback intervals ( PBIs) should be 35 days following applications totaling   0.188 lb ai/ A and 210 days following applications totaling 0.2 1.0 lb ai/ A.

  If the petitioner is continuing to support seed treatment use for fenbuconazole on wheat, then copies of new labels must be submitted with directions for that use.

  A complete set of 20 field trials are required on wheat forage and an additional 12 tests are required on wheat hay. These tests should be conducted using the currently proposed use pattern, which reflects one application on forage and up to two applications on hay at 0.063 lb ai/ A/ application. Although conditions will vary between test sites, the sampling intervals for forage and hay should be consistent enough for the Agency to be able to compare residues and assess an appropriate PHI. Granting of a registration should be made conditional upon resolution of this issue.

10.3 Occupational and Residential Exposure  None Page 54 of 55 REFERENCES 1. Revised Tier II Drinking Water Assessment for Fenbuconazole, A. Al Mudallal, D330709, July 7, 2006 2. Fenbuconazole Acute, Chronic and Cancer Dietary Exposure Assessment for the Section 3 Registration Action for New Uses. M. Doherty, D329595, June 2006. 3. Occupational and Residential Exposure Assessment for Section 3 Registration for use of Fenbuconazole on Almonds, Apples, Bananas, Blueberries, Citrus Fruits, Cranberries, Pecans, Peanuts, Plums, Prunes, Sugar Beets, and Wheat. M. Collantes; DP Barcode 328908; June 2006 4. Fenbuconazole Report of the Hazard Identification Assessment Review Committee, February 26, 1998 5. Carcinogenicity Peer Review of Fenbuconazole. S. Williams Foy and E. Rinde; March 15, 1996; TXR 0011894 6. HIARC Report for Fenbuconazole. S. Williams Foy; November 17, 1998; TXR 0012971 Page 55 of 55 APPENDICES 1.0 TOXICOLOGY DATA REQUIREMENTS HED is in the process of converting existing DERs to an electronically available format for inclusion into subsequent risk assessments.

2.0 NON CRITICAL TOXICOLOGY STUDIES HED is in the process of converting existing DERs to an electronically available format for inclusion into subsequent risk assessments.

3.0 METABOLISM CONSIDERATIONS Since fenbuconazole is not a new active ingredient and there is not additional information other then what has already been stated in the risk assessment, this section was not applicable.