Fenbuc onazole Human Hea l th Risk Assessment DP No. 0403041

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON

, D

. C

. 20460

MEMORANDUM

Date : January 31, 2013 OFFICE OF CHEMICAL SAFETY AND POLLUTION PREVENTION

{ g SUBJECT: Fenbuconazole: Human Health Risk Assessment for an Increased To ler ance for Residues in Peppers, and a Label Amendment for the Enabl e® 2F Product.

PC Code: 1290 II DP Barcode: 0403041 Decision No.: 465307

, 468478 Petition No.: 2F8034 Registration No.: 62719-421; 62719-416

R isk Assessment Type: Single Chemical Aggregate TXRNo

. : NA Regula to ry Action: Section 3; Tolerance Amendment Case No

. : 7012 CAS No .: 1 14360-43- 6 MRIDNo.: NA 40 CFR: 180.480

FROM: 

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Linnea J. Hansen

, Ph.D

, Biologist and Ri sk

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Dennis McNeilly, Chemist 

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Risk Assessment Branch II 

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- Health Effects Divis ion (7509P)

THROUGH: Christina Swartz, Chief E lizabeth Holman

, Chemist**~ \~**  Risk Assessment Branch II Health Effects Division (7509P)

TO: Erin Malone Fungicide Branch Registration Division (7505P)

Page 

### 1 of43Fenbuconazole Human Health Risk Assessment DP No. D403041

Page 2 of 43 1.0 Executive Summary ........................................................................................................... 4 2.0 HED Recommendations .................................................................................................... 6 2.1 Data Deficiencies ............................................................................................................ 6 2.2 Tolerance Considerations .............................................................................................. 6 2.2.1 Enforcement Analytical Method ............................................................................... 7 2.2.2 Recommended Tolerances ......................................................................................... 7 2.2.3 Revisions to Petitioned-For Tolerances .................................................................... 7 None. ......................................................................................................................... .................. 7 2.2.4 International Harmonization ..................................................................................... 7 2.3 Label Recommendations ................................................................................................ 7 3.0 Introduction ........................................................................................................................ 8 3.1 Chemical Identity ........................................................................................................... 8 3.2 Physical/Chemical Characteristics ............................................................................... 9 3.3 Pesticide Use Pattern ...................................................................................................... 9 3.4 Anticipated Exposure Pathways ................................................................................. 10 3.5 Consideration of Environmental Justice .................................................................... 10 4.0 Hazard Characterization and Dose-Response Assessment .......................................... 11 4.1 Summary of Toxicological Effects .............................................................................. 11 4.2 Safety Factor for Infants and Children (FQPA Safety Factor) ............................... 13 4.2.1 Completeness of the Toxicology Database .............................................................. 13 4.2.2 Evidence of Neurotoxicity ........................................................................................ 13 4.2.3 Evidence of Sensitivity/Susceptibility in the Developing or Young Animal ........ 14 4.2.4 Residual Uncertainty in the Exposure Database ................................................... 14 4.3 Toxicity Endpoint and Point of Departure Selections .............................................. 14 5.0 Dietary Exposure and Risk Assessment ......................................................................... 16 5.1 Residues of Concern Summary and Rationale .......................................................... 16 5.2 Food Residue Profile .................................................................................................... 18 5.3 Water Residue Profile .................................................................................................. 21 5.4 Dietary Risk Assessment .............................................................................................. 22 5.4.1 Description of Residue Data Used in Dietary Assessment .................................... 22 5.4.2 Percent Crop Treated Used in Dietary Assessment .............................................. 23 5.4.3 Acute Dietary Risk Assessment ............................................................................... 23 5.4.4 Chronic Dietary Risk Assessment ........................................................................... 24 5.4.5 Cancer Dietary Risk Assessment ............................................................................. 24 5.4.6 Summary Table ......................................................................................................... 24 6.0 Residential (Non-Occupational) Exposure/Risk Characterization ............................. 25 6.5 Residential Bystander Post-application Inhalation Exposure ................................. 25 6.6 Spray Drift .................................................................................................................... 25 7.0 Aggregate Exposure/Risk Characterization .................................................................. 26 7.1 Acute & Chronic Aggregate Risk ............................................................................... 26 7.2 Short- and Intermediate-Term Aggregate Risk ........................................................ 26 8.0 Cumulative Exposure/Risk Characterization ............................................................... 26 9.0 Occupational Exposure/Risk Characterization ............................................................ 27 10.0 References ......................................................................................................................... 29 Appendix A. International Residue Limits .............................................................................. 31 Appendix B. Toxicology Profile ................................................................................................ 31Fenbuconazole Human Health Risk Assessment DP No. D403041

Page 3 of 43 B.1 Toxicology Data Requirements ................................................................................... 31 B.2 Toxicity Profiles ............................................................................................................ 33 Appendix C. Physica l/Chemical Properties ............................................................................. 42 Appendix D. Review of Human Research ................................................................................ 43Fenbuconazole Human Health Risk Assessment DP No. D403041

Page 4 of 43 1.0 Executive Summary

A human health risk assessment has been conduc ted to support a propose d increased tolerance for residues of the fungicide fenbuconazole on peppers. Fenbuconazole a broad spectrum triazole (conazole) fungi cide currently registered for us e on the following food/feed crops: almonds, apples, bananas, bushberries (subgroup 13- B), citrus fruits (group 10), cranberries, pecans, peanuts, peppers, stone fruits (group 12), sugar beets, and wheat. Tolerances are established for the combined residues of fenbucon azole and its lactone metabolites, expressed as parent, in/on plant commodities at levels rang ing from 0.05 ppm in/on almonds and pecans to 40 ppm in citrus oil [40 CFR §180.480(a)]. Toleran ces are also established at 0.05 ppm for the combined residues in livestock commodities.

Dow AgroSciences LLC is proposing to bridge fenbuconazole residue data for peppers from a product currently registered for use on peppers to a new product formulation. The tolerance for peppers was initially established based on field trial data submitted for the Indar ® 75 WSP formulation (EPA Reg. No. 62719-421). The regi strant then submitted a bridging study to translate residue data from Indar ® 75 WSP to the proposed new product Enable ® 2F (EPA Reg. No. 62719-416), a flowable, or suspension concen trate (SC) formulation of fenbuconazole. Indar ® 75 WSP is a wettable powder formulation p acked in water-soluble bags containing 75.0% active ingredient (ai), while Enable ® 2F is a liquid containing 23.5% ai (2 lb ai/gal). Although the use pattern for peppers is the same on the two labels, bridging residue da ta indicated that an increased tolerance for peppers would be needed to support the new formulation. Based on the existing residue data and HED’s review of the a dditional bridging data, a permanent tolerance of 1.0 on peppers is proposed for the combined residues of fenbuconazo le and its lactone metabolites, expressed as fenbuconazole.

The toxicology database for fenbuc onazole is largely complete, la cking only an immunotoxicity study. Although acute and subchronic neurotoxi city have not been submitted, HED’s Hazard Science Policy Council (HASPOC) concluded that these studies are not required, taking into consideration the lack of obser ved neurotoxic effects for fenbuc onazole as well as many other triazole fungicides. A route-specific rat inha lation study has not been submitted, but is also not required based on HED’s determination that fenbuc onazole shows no evidence of portal-of-entry effects, has low acute inhalation toxicity a nd very high MOEs for occupational inhalation exposure. Since the previous assessment, ra bbit developmental toxicity and rat metabolism studies were submitted; the findings of these studies are consistent with the existing data and do not affect the overall characteri zation of hazard or selection of doses and endpoints for risk assessment. The main target organ of fenbucon azole is the liver. Increased liver weight, hepatocellular hypertrophy and clin ical chemistry changes were observed in the rat, dog and mouse following subchronic and chronic exposure. In the rat, effects on the thyroid were also observed. Kidney and adrenal weights were in creased in dogs after chronic exposure. Fenbuconazole is classified as a “Group C, ” or possible human carcinogen, based on an increased incidence of liver tumors in male and female mice and thyroid tumors in male rats. A cancer potency factor has been used to estim ate potential cancer risk associated with fenbuconazole uses.Fenbuconazole Human Health Risk Assessment DP No. D403041

Page 5 of 43 The required 10x Food Quality Protection Act (FQPA) Safety Factor was reduced to 1x based on both toxicity and exposure considerations: 1) the toxicity database is largely complete, missing only the immunotoxicity study; 2) there was no evidence of qualitative or quantitative susceptibility in the developmental and reproductive toxicity studies; 3) there was no evidence of neurotoxicity, and a developmental neurotoxicity study is not required; 4) there was no evidence of immunotoxicity in the existi ng database; 5) the e xposure assessment was based on field trial residues and modeled drinking water estimates which will not underestimate dietary exposure and risk; and 6) there are no residential uses for the chemical.

For acute dietary exposure, the dose and endpoi nt for females age 13-49 were 30 mg/kg/day based on increased resorptions and decreased live fetuses per dam at the lowest observed adverse effects level (LOAEL) of 75 mg/kg/day. No haza rd was identified for acute dietary exposure and risk for the general population. For chronic dietary exposure to all populations, the dose and endpoint were 3 mg/kg/day based on decreased b ody weight gain and eff ects on the thyroid and liver at the LOAEL of 30.6 mg/kg/day. Inhalation exposure was assessed based on the no observed adverse effects level (NOAEL) of 5.1 mg/kg/day from the rat 90-day oral study, with decreased body weight and liver effects observed at the LOA EL of 25.3 mg/kg/day. This endpoint has changed since the prior assessment, which was based on effects observed in the rat chronic study. No hazard was identified for dermal exposure.

Adequate studies are available to characterize the me tabolism of fenbuconazole in plants and animals. Residues of concern in /on plants, including peppers, in rotational crops and in animal commodities are the parent fenbuconazole (RH- 7592) and its lactone metabolites, RH-9129 and RH-9130. For rotational crops other than the pr imary crop, plantback intervals specified on the existing labels and proposed supplemental labelin g obviate the need for limited field rotational crop trials and associated rotational crop tolerances.

HED used modeling to assess acute, chroni c and cancer aggregate dietary exposure to fenbuconazole. For acute dietary exposure, to lerance-level residues and 100% crop treated values were used. For chronic and cancer dietary exposure, a so mewhat refined analysis using average field trial residues, and 100% crop treate d values for the non-can cer dietary assessment. The cancer analysis is further refined in that it makes use of average percent crop treated estimates. Dietary non-cancer exposure and ri sk estimates are well below HED’s level of concern of 100% of the acute and chroni c population adjusted doses (aPAD and cPAD, respectively). Cancer risk is estimated at 2.2 x 10 -6 . Actual cancer risk is likely to be much lower, since the residue inputs ba sed on field trial data (as oppos ed to monitoring data) and the assumption of upper bound %CT estimates are expect ed to overestimate dietary exposure and risk.

A non-dietary residential exposure assessment ha s not been performed because there are no registered residential uses of fenbuconazole. Consequently, dietary so urces (food plus drinking water) are the only sources of e xposure to fenbuconazole, and a separate aggregate assessment is not required. HED considered the potential for th e increased tolerance in peppers to affect the Agency’s conclusions regarding aggregate exposu re to free triazole and its conjugates. HED concluded that the increased to lerance does not have an impact on aggregate exposure to free triazole and its conjugates, and the risks are not of concern (D403618, T. Morton, 8/1/12).Fenbuconazole Human Health Risk Assessment DP No. D403041

Page 6 of 43 HED has determined that new occupational expos ure and risk assessments are not needed to ensure adequate protection of occupational workers mixing, loading and applying fenbuconazole to peppers, based on results of the previous ri sk assessment for peppers , and considering the identical use patterns for the two formula tions. Occupational exposure and risk for fenbuconazole were previously assessed using ba seline personal protective equipment (PPE). A quantitative non-cancer dermal exposure and ri sk assessment was not performed because no dermal hazard was identified. All non-cancer risks for inhalation exposure were below HED’s level of concern (MOE >100). Combined derm al and inhalation cancer risk for occupational handlers was at most 3.0 x 10 -7 for the Enable ® 2F formulation. Cancer risk associated with dermal exposure from harvesting and other activitie s occurring after application of the pesticide was estimated to be 1.4 x 10 -7

. This risk assessment relies in part on data from studies in which adult human subjects were intentionally exposed to a pest icide or other chemical. Thes e studies, listed in Appendix 2.0, have been determined to require a review of their ethical conduct. Some of these studies are also subject to review by the Human St udies Review Board. All of the studies used have received the appropriate review.

Potential areas of environmental justice concerns, to the extent possible, were considered in this human health risk assessment, in accordance wi th U.S. Executive Order 12898, “Federal Actions to Address Environmental Jus tice in Minority Populations an d Low-Income Populations,” http://www.eh.doe.gov/oepa/ guidance/justice/eo12898.pdf

.

2.0 HED Recommendations

HED recommends in favor of an increased tole rance for residues of fenbuconazole on peppers, and addition of the use on peppers to the label for Enable ® 2F. Additional data are needed, as outlined in Section 2.1. The specific tolerance recommendations are discussed in Section 2.2.

2.1 Data Deficiencies

There are no residue chemistry or expos ure data deficienci es for fenbuconazole.

An immunotoxicity study in the rat or mouse is required under the cu rrent 40 CRF Part 158. There are presently no other toxicology data defi ciencies for fenbuconazole. HED has concluded that a rat 28- or 90-day inhalati on toxicity, as well as acute and subchronic neurotoxicity studies, are not required based on consider ation of the available toxicity data, chemical properties and registered and proposed use patterns.

2.2 Tolerance Considerations

HED has examined the residue chemistry data base for fenbuconazole. There are no residue chemistry issues that would preclude increasi ng the tolerance for fenbuconazole on peppers. The HED-recommended tolerance is listed in Table 2.2.2.Fenbuconazole Human Health Risk Assessment DP No. D403041

Page 7 of 43 2.2.1 Enforcement Analytical Method

The available GC/NPD method, TR-34-90-47R, is considered adequate for tolerance enforcement and data collection purposes.

2.2.2 Recommended Tolerances

The tolerance expression proposed by the regist rant is appropriate a nd includes the required coverage and compliance statements; therefor e, the tolerance expression in 40 CFR §180.480 should be revised to reflect the proposed language as follows: “Tolerances are established for residues of the fungicide fenbuconazole, including its metabolites and degradates, in or on the commodities in the table below. Compliance with the tolerance levels specified below is to be determined by measuring only the sum of fe nbuconazole, alpha–[2–(4–c hlorophenyl)– ethyl]– alpha–phenyl–3–(1H–1,2,4–triazole)– 1–propanenitrile, and its metabolites RH–9129, cis–5–(4– chlorophenyl)– dihydro–3–phe nyl–3–(1H–1,2,4– triazole–1–ylmethyl)–2–3 H–furanone, and RH–9130, trans–5–(4– chlorophenyl)-dihydr o–3–phenyl–3– (1H–1,2,4–triazole–1–ylmethyl)–2– 3 H– furanone, calculated as the stoichiometric equivalent of fenbuconazole, in or on the following agricultural commodities.”

Table 2.2.2. Tolerance Summary for Fenbuconazole. Commodity Established/Proposed Tolerance (ppm) HED-Recommended Tolerance (ppm) Comments ( correct commodity definition ) Pepper 0.4 ppm 1.0 ppm Commodity definition: Pepper

2.2.3 Revisions to Petitioned-For Tolerances

None

2.2.4 International Harmonization

As summarized in Appendix A, maximum residue limits (MRLs) for residues of fenbuconazole have been established by Codex, Canada and Mexi co. The residue definition for both Codex and Mexico is parent fenbuconazole only, and the Canadi an residue definition is the same as the U.S. tolerance definition which includes the parent and 2 metabolites. The Codex MRL for pepper is 0.6 ppm and was most likely es tablished before the Enable ® 2F formulation was proposed for use on peppers, and includes only re sidues of the parent compound. This new formulation has higher residues values ranging up to 0.7 ppm, and the US tolera nce includes the two lactone metabolites. Harmonization with the 0.6 ppm tole rance is not feasible given the proposed new use pattern/formulation. No Canadian or Me xican MRLs are established for fenbuconazole on peppers, and thus there are no harmoni zation issues in North America.

2.3 Label Recommendations

NoneFenbuconazole Human Health Risk Assessment DP No. D403041

Page 8 of 43 3.0 Introduction

3.1 Chemical Identity

Table 3.1. Nomenclatu re of Fenbuconazole and its Regulated Metabolites Compound

Common name Fenbuconazole Company experimental names RH-7592 IUPAC name ( RS )-4-(4-chlorophenyl)-2-phenyl-2-(1 H -1,2,4-triazol-1-ylmethyl)butyronitrile

CAS name α -[2-(4-chlorophenyl)ethyl]- α -phenyl-1 H -1,2,4-triazole-1-propanenitrile Chemical class Conazoles (triazoles) Molecular weight 336.8 CAS registry number 114369-43-6 (119611-00-6, racemate) End-use products/EP 2 lb ai/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

Metabolite

Common name trans lactone metabolite Company experimental names RH-9130 N

N N Cl CN

O

N

N N O

Cl O

N

N N O

ClFenbuconazole Human Health Risk Assessment DP No. D403041

Page 9 of 43 Table 3.1. Nomenclatu re of Fenbuconazole and its Regulated Metabolites 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

3.2 Physical/Chemical Characteristics

Fenbuconazole is a triazole (conazole) fungi cide. The physico-chemical properties are summarized in Appendix Table C.1. The vapor pressure is rela tively low (0.37 x 10 -7 mm Hg). Water solubility of fenbuconazole is low (3.8 mg /L), and it has a high octanol/water partition coefficient [Log(K ow ) = 3.22]. Soil half-lives under both aerobic and anaerobic conditions are long (285 to 655 days), indicating th at fenbuconazole is moderately persistent in the environment and slightly mobile into groundwater.

3.3 Pesticide Use Pattern

Dow AgroSciences is proposing the first use of Enable ® 2F TM (2.0 lbs ai/gallon, EPA Reg. No. 62719-416) on peppers. The use dire ctions, as provided in the ex isting labels and proposed supplemental labeling, are summarized below in Table 3.3.

Table 3.3. Summary of Directio ns for Use of Fenbuconazole.

Applic. 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

Peppers (Including but not limited to: bell, chili, cooking, non-bell, pimento and sweet)
Broadcast foliar applications to peppers when disease first appears Ground or aerial equipment 75% WP [62719-421] 0.188 3 NS 0.75 7 Apply in a minimum of 30 gal/A, using ground equipment. The minimum RTI is 10-14 days. Do not make more than 2 consecutive applications.
Broadcast foliar applications to peppers when disease first appears Ground or aerial equipment 2.0 lbs ai/gal. SC [62719-416] 0.188 3 NS 0.75 7 Apply in a minimum of 30 gal/A, using ground equipment. The minimum RTI is 10-14 days. Do not make more than 2 consecutive applications.

1 Do not apply through any type of irrigation system. A lthough application using aerial equipment is permitted,

ground application is recommended.
2 RTI = re-treatment interval.
3 The maximum use rate is based on the use of 4 oz product/acre/application. NS = not specified.

Note that rotational crop restric tions indicate that the minimum pl ant-back interval is 35 days when the last application of the product is <0.188 lb ai/A, and 210 days when the last applicationFenbuconazole Human Health Risk Assessment DP No. D403041

Page 10 of 43 of the product is 0.188-1.0 lb ai /A; this language appears on th e proposed supplemental labeling for peppers, as well as on the main labels.

The personal protective equipment ( PPE) recommendations on the Indar ® 75WSP and Enable ® 2F labels indicate applic ators and other handlers should wear a long-sleeved shirt and long pants, shoes plus socks, chemical-resistant gloves, and chemical-resistant headgear for overhead exposure. The restricted entry in terval (REI) on the labe ls indicates workers may re-enter treated areas after 12 hours, which is appropriate based on the acute toxicity of technical fenbuconazole.

Conclusions: The use directions are adequate to allow for evaluation of the residue data relative to the proposed formulation. The available fiel d trial data and formulation bridging data on peppers are adequate and support the proposed use (4 oz product/A is eq uivalent to 0.188 lb ai/A). Although the single appl ication rates used in the field trials were ~0.167 lb ai/A (0.9x rate), the residue data from these tests are ad equate to support the 0.188 lb ai/A/application rate.

3.4 Anticipated Exposure Pathways

The Registration Division has requested an assess ment of human health risk to support the proposed revised tolerance for fenbuconazole on peppers, as well as addition of the use on peppers to the Enable ® 2F label. Humans may be exposed to fenbuconazole in food and drinking water, since it may be applied directly to growing crops and application may result in fenbuconazole reaching surface and ground water s ources of drinking water. There are no residential uses of fenbuconazole, so there is not likely to be exposur e in residential or nonoccupational settings. In an occupational setting, applicators may be e xposed while handling the pesticide prior to application, as well as duri ng application. There is a potential for postapplication exposure for workers re-entering treated fields.

Risk assessments have been previously conduc ted for fenbuconazole; toxicity data submitted prior to the last risk assessment but not incorporated into HED’s review have been evaluated in the current assessment, but did not affect HED’s conclusions with respect to hazard characterization and endpoint selection. A deta iled description of th e toxicity data and metabolism information may be found in th e risk assessment date d 6/12/2008 (D. Dotson, D344351). The current risk assessment considers all of the aforementioned exposure pathways based on the existing uses of fenbuconazole, and also considers the po tential for increased dietary exposure associated with the in creased tolerance for residues in peppers.

The dietary endpoints and doses for fenbuconazo le have not changed from the previous assessment. However, for occupational exposure assessment, the dose and endpoint selected for inhalation exposure and risk as sessment has been revised.

3.5 Consideration of Environmental Justice

Potential areas of environmental ju stice concerns, to the extent possi ble, were considered in this human health risk assessment, in accordance w ith U.S. Executive Order 12898, "Federal Actions to Address Environmental Just ice in Minority Populations an d Low-Income Populations," ( http://www.eh.doe.gov/oepa/ guidance/justice/eo12898.pdf . As a part of every pesticide riskFenbuconazole Human Health Risk Assessment DP No. D403041

Page 11 of 43 assessment, OPP considers a large variety of c onsumer subgroups according to well-established procedures. In line with O PP policy, HED estimates risks to population subgroups from pesticide exposures that are ba sed on patterns of that subgrou p’s food and water consumption, and activities in and around th e home that involve pesticide use in a residential setting. Extensive data on food consumption patterns are compiled from the U.S. Department of Agriculture’s National Health and Nutrition Ex amination Survey, What We Eat in America, (NHANES/WWEIA) and are used in pesticide risk assessments for all registered food uses of a pesticide. These data are analyzed and categ orized by subgroups based on age, season of the year, ethnic group, and region of the country. Additionally, OPP is able to assess dietary exposure to smaller, specialized subgroups and exposure assessments are performed when conditions or circumstances warrant. Whenever appropriate, non-diet ary exposures based on home use of pesticide products and associated ri sks for adult applicators and for toddlers, youths, and adults entering or playing on treated ar eas 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 traditi onal dietary patterns am ong specific subgroups.

4.0 Hazard Characterization and Dose-Response Assessment

Comprehensive risk assessments for fenbucon azole were conducted in 2006 (D316607; M. Collantes) and 2008 (D344351; D. Dotson). There ar e no changes to the endpoints or points of departure (PODs) for dietary assessment for acute, chronic or cancer risk used in the previous evaluations. However, the endpoint and dose se lected for occupational inhalation exposure and risk assessment has been revi sed, reflecting changes in antic ipated exposure scenarios and reevaluation of the endpoints observed in th e rat 90-day study (see below, Section 4.3).

Since the previous assessment, a supplemen tal metabolism study in the rat and a second developmental toxicity study in the rabb it (MRIDs 46473401 and 45259401, respectively) have been reviewed. These studies have been consid ered in this assessment but do not affect the endpoints selected or the overall ev aluation of the toxicology findings.

4.1 Summary of Toxicological Effects

Subchronic and chronic feeding st udies were conducted in the rat, mouse and dog. In these studies, the liver was the main targ et of toxicity in all three speci es. At lower dose levels in the subchronic studies, there were changes in liver histopathology, predominantly hepatocellular hypertrophy, along with increased li ver weight. In the absence of other findings, these appeared to be adaptive liver changes, but at higher dos e levels, frank liver t oxicity was indicated by increases in liver enzymes (ALK, SGPT, SGOT). Increased hepatocellu lar vacuolization was observed at the higher dose levels as well, a nd in mice, hepatocellula r necrosis was observed with a low incidence at the highest dose. In th e rat, the thyroid was a secondary target organ with increased follicular cell size. In the chronic studies, liver effects were observed (including hepatocellular hypertrophy and v acuolization, changes in liver enzymes, and increased liver weights), as well as decreased body weight gains in all three specie s. Again, in the chronic rat study, the thyroid was a secondary target with increased thyroi d and parathyroid weights and thyroid follicular cell hypertr ophy. In addition, thyroid hormones were affected, with increasedFenbuconazole Human Health Risk Assessment DP No. D403041

Page 12 of 43 mean T4 (thyroxine) and decreased TSH (thyroi d stimulating hormone) being observed 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 app eared to be equally sensitive to fenbuconazole toxicity, except that male mice a ppeared to be more sensitive than the females after chronic exposure.

In the rat and rabbit developmental toxicity st udies 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 consum ption and clinical signs in rabbits. Developmental effects included increas ed 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, incr eased number of stillborn pups, decreased number of total offspring deliver ed, and decreased viability inde x of pups in the two generation study in rats. No increased qualitative or quant itative susceptibility was ob served in any of the studies. There was no evidence of neurotoxicity in any of the studi es available in the toxicology database. Therefore, a developmenta l neurotoxicity study is not required.

Fenbuconazole is classified as a Group C or possible human carcinogen under the 1986 Agency Guidelines for assessing carcinogenicity based on an increased incide nce of hepatocellular adenomas and carcinomas in male and female mice and thyroid follicular adenomas and combined adenomas/carcinomas in male rats. It has not been reevaluated under the current (2005) cancer guidelines, but may be reevaluated in the future as part of the ongoing Registration Review process. A cancer potency factor for qua ntification of risk was derived using combined hepatocellular adenomas/ carcinomas in female mice. The upper bound estimate of unit risk (Q 1 * (mg/kg/day) -1 ) is 3.59 x 10 -3 in human equivalents. Fen buconazole was not mutagenic in the available studies.

Although fenbuconazole has a relatively high octa nol:water coefficient and low solubility in water, dermal absorption was not significant and the majority of the radio-labeled compound could be recovered in a skin wash. Dermal pe netration in the rat, evaluated using a 23% ai formulation product, was ≤ 4.25% measured after a 10 hour expos ure. Consistent with these findings, no systemic toxicity was observed in the rat 28-day dermal toxicity study, and there was no dermal irritation at the application site.

Fenbuconazole is extensively metabolized (19 me tabolites identified or pr edicted) and rapidly excreted following single or repeat ed oral doses in the rat. Oxid ation on the chlorophenol ring or the phenol ring, cyclization of th e alcohol with the adjacent ni trile group and hydrolysis were observed. Glucuronide and sulfate conjugation of the hydroxyl groups also occurred. Cleavage of the triazole moiety was not a significant route of metabolism: very lo w levels of 1,2,4-triazole were observed in the urine (1.0 to 2.48% of dose) . Metabolism was qualitatively similar in both sexes and appears to become saturated at higher do se levels. Excretion was primarily via the bile and feces, with low levels of radioactivity in th e urine. Bioaccumulation was not observed.

As summarized in Appendix Table B.2.1, acute studies were conducted on both the technical material and end-use product (25% a.i.). Tech nical grade fenbuconazole has low acute toxicity (Category III for acute oral and inhalation exposures and Category IV for acute dermalFenbuconazole Human Health Risk Assessment DP No. D403041

Page 13 of 43 exposure), as does the end-use product (Categor y III for acute inhalation exposure and Category IV for acute oral and dermal exposures). Neither is a skin or eye irritant (Category IV), or a dermal sensitizer.

4.2 Safety Factor for Infants and Children (FQPA Safety Factor)

HED has determined that the re quired 10X FQPA Safety Factor should be reduced to 1x in assessing the risk posed by fenbuconazole. Th is recommendation was based on the following considerations:

• The toxicity data base is largely complete, wi th no data gaps for the assessment of the effects of fenbuconazole following in utero and/or postnatal exposure.

• An immunotoxicity study is required for fe nbuconazole, and is considered a data gap, however the existing database shows no evidence of immunotoxicity.

• There is no evidence of neurotoxicity in th e available database; acute and subchronic neurotoxicity studies are not available but were cons idered to be not required by HASPOC based on the lack of evidence of neurotoxicity in th e database, and a developmental neurotoxicity study is not required.

• There is no indication of quantit ative or qualitative susceptibil ity of rats or rabbits to in

utero and/or postnatal exposure to fenbuconazole.

• The dietary exposure assessment is based on mo dels and input parameters designed to be protective of human health. In additi on, the dietary assessments are based on conservative inputs.

• At this time, there are no registered resi dential uses for fenbucon azole. As a result, infants and children are not expected to be exposed through residential uses.

4.2.1 Completeness of the Toxicology Database

As summarized in Appendix Table B1, the toxico logy database is considered adequate for the purpose of assessing pre- and postnatal suscepti bility, lacking only an immunotoxicity study. However, no effects on the immune system were reported in the ava ilable studies and the conazole (triazoles), as a chem ical class, typically do not de monstrate immunotoxic effects. Therefore, no additional database uncertain ty factor for the lack of this study (UF DB ) was applied. Acceptable developmental toxicity stud ies in the rat and rabbi t and a rat reproductive toxicity study have been submitted. HED’s HASPOC (TXR #0056540) determined that acute and subchronic neurotoxicity stud ies in the rat are not required based on lack of evidence of neurotoxicity in th e available studies.

4.2.2 Evidence of Neurotoxicity

The available studies did not show potential for neurotoxicity. There is no evidence for neurotoxicity in the existing database for fenbuc onazole and the conazole fungicides as a group, which typically show either no evidence of ne urotoxicity, or neurotox icity at higher doses relative to the regulatory endpoint s. A developmental neurotoxi city study is not required.Fenbuconazole Human Health Risk Assessment DP No. D403041

Page 14 of 43 4.2.3 Evidence of Sensitivity/Susceptibility in the Developing or Young Animal

There is no evidence of increased qualitative or qu antitative susceptibility in the developing or young animal and there are no residual uncertainties wi th respect to pre- or postnatal exposure. There are currently no registered or proposed re sidential uses for fenbuconazole, so exposure is limited to dietary exposure.

4.2.4 Residual Uncertainty in the Exposure Database

There is no residual uncertainty in the exposure database. There are no exposure data gaps and the current dietary exposure assessment is base d on high-end assumptions such as field trial residue values and modeled estimates of drinking water residues. Therefore, the assessment is conservative and does not undere stimate dietary exposure.

4.3 Toxicity Endpoint and Point of Departure Selections

The toxicological endpoints and points of departure selected for dietary and occupational exposure and risk assessment are presented below in Tables 4.3.1 and 4.3.2. The complete toxicological profile for fenbuconazole is summar ized in Appendix Table B.2.2. There have been no changes to the dietary dose-response assessme nt or endpoints, the can cer classification/risk quantification or the occupati onal dermal assessment.

A revised occupational exposure and risk assessm ent has not been conducted for this assessment since the use pattern has not changed with the addition of peppers to the label for the new formulation. For future occupational inhalati on exposure assessments, the selected study and endpoint have changed. In the previous a ssessments, the rat comb ined chronic oral toxicity/carcinogenicity dietar y study, with a NOAEL of 3 mg/ kg/day, was selected as the critical study for all exposure durations, includ ing long-term. Currentl y, occupational exposure of only short- or intermediate-term durations is anticipated. A 28- or 90-day inhalation study is not required. Since long-term occupational exposur e is not anticipat ed, the oral studies of short or subchronic duration (rat, dog and mouse 90-da y dietary; rat reproduc tive toxicity; rat and rabbit developmental toxicity) were cons idered for inhalation exposure.

The NOAELs previously identified for the subchr onic oral studies in ra ts, mice and dogs (M/F) were 1.3/1.5, 3.8/5/7 and 3.3/3.5 mg/kg/day, respec tively. However, effects at the stated LOAELS identified for the rat, mouse a nd dog 90-day studies (5.1/6.3, 11.1/17.6 and 13.3/14.0 mg/kg/day, respectively) were limited to liver hypertrophy and increased liver weight (in the dog, slight but not statistically si gnificant increases in ALK were also observed at Week 13; significant changes were seen at the high dose). Based on cu rrent HED science policy, these changes are suggestive of an ad aptive liver response and are not indicative of a clear adverse effect. At the next highest dose in each study (25.3/31.1, 28.6/50.4 and 50.4/53.3 mg/kg/day, respectively), altered liver enzymes indicated an adverse effect on the liver. Therefore, the NOAELs and LOAELs for these studie s were reassigned to the next highest dose. For short- and intermediate-term inhalation exposure, the ra t 90-day NOAEL of 5.1 mg/kg/day was selectedFenbuconazole Human Health Risk Assessment DP No. D403041

Page 15 of 43 based on liver hypertrophy and clinical chemis try changes observed at the LOAEL of 25.3 mg/kg/day. This endpoint is pr otective of developmental and reproductive effects, which were observed only at doses ≥ 40 mg/kg/day and for which NOAELs ranging from 4 to 30 mg/kg/day (developmental toxicity) were observed. Since an oral study was selected for assessing the inhalation route, toxicity via this route was considered to be equi valent to toxicity via the oral route, for the purpose of risk assessment.

For all of the relevant routes and durations of exposure, clear NOAELs and LOAELs were identified. In addition, the toxicity database is considered to be largely complete, and no database uncertainty factors (UFs) were needed to account for missing data. With the reduction of the FQPA SF to 1X, the standard uncertainty f actors of 100X (based on 10X for intraspecies variability and 10X for interspeci es extrapolation) were applied. For inhalation risk assessment, the level of concern (LOC) is a margin of expos ure (MOE) of 100. For dietary assessments, the combined UF of 100X was incorpor ated into the relevant refere nce doses (RfDs) and population adjusted doses (PADs).

Table 4.3.1 Summary of Toxicological Doses and Endpoints for Fenbuconazole for Use in Dietary Health Risk Assessments

Exposure/ Scenario Point of Departure Uncertainty/FQPA Safety Factors RfD, PAD, Level of Concern for Risk Assessment Study and Toxicological Effects

Acute Dietary (General Population, including Infants and Children) An appropriate dose and endpoint were not identified for this population group.

Acute Dietary (Females 13- 49 years of age) NOAEL = 30 mg/kg/day UF A = 10x UF H =10x FQPA SF= 1x Acute RfD = 0.3 mg/kg/day

Acute PAD= 0.3 mg/kg/day Developmental rat study

Developmental LOAEL = 75 mg/kg/day based on increased resorptions and decreased live fetuses per dam. Chronic Dietary (All Populations) NOAEL= 3 mg/kg/day UF A = 10x UF H =10x FQPA SF= 1x Chronic RfD = 0.03 mg/kg/day

cPAD = 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 Cancer (oral, dermal, inhalation) Classification: Group C, probable human carcinogen. This classification is based on increased incidence of hepatocellular adenomas and carc inomas in male and female mice and thyroid follicular adenomas and combined adenomas/carcinom as in male rats. Quantification of risk was derived using combined hepatocellular adenomas/carcinomas in female mice. The upper bound estimate of unit risk, Q 1 * (mg/kg/day) -1 is 3.59 x 10 -3 in human equivalents. Point of Departure (POD) = A data point or an estimated poin t that is derived from observed dose-response data and used to mark the beginning of extrapolation to determine risk associated with lower en vironmentally relevant human exposures. NOAEL = no observed adverse effect level. LOAEL = lowest observed adverse effect level. UF = uncertainty factor. UF A = extrapolation from animal to human (interspecies). UF H = potential variation inFenbuconazole Human Health Risk Assessment DP No. D403041

Page 16 of 43 sensitivity among members of the human population (intra species). FQPA SF = FQPA Safety Factor. PAD = population adjusted dose (a = acute, c = chronic). RfD = reference dose. N/A = not applicable.

Table 4.3.2 Summary of Toxicological Doses and Endpoints for Fenbuconazole for Use in Occupational Human Health Risk Assessments

Exposure/ Scenario Point of Departure Uncertainty Factors Level of Concern for Risk Assessment Study and Toxicological Effects

Dermal All Durations No endpoint of concer n was identified, based on a lack of hazard via the dermal route.

Inhalation Short-Term (1- 30 days) andIntermediateterm (1-6 months) Oral study NOAEL= 5.1 mg/kg/day

[Inhalation toxicity assumed equivalent to oral toxicity] UF A =10x UF H =10x Occupational LOC for MOE = 100 90-day oral toxicity - Rat

LOAEL = 25.3/31/1 (M/F) mg/kg/day based on decreased body weight gain, clinical chemistry changes, and histopathological lesions in the liver and thyroid gland. Cancer (oral, dermal, inhalation) Classification: Group C, probable human carcinogen. This classification is based on increased incidence of hepatocellular adenomas and carcinomas in male and female mice and thyroid follicular adenomas and combined adenomas /carcinomas in male rats. Quantification of risk was derived using combined hepatocellular adenomas/carcinomas in female mice. The upper bound estimate of unit risk, Q 1 * (mg/kg/day) -1 is 3.59 x 10 -3 in human equivalents. Point of Departure (POD) = A data point or an estimated poin t that is derived from observed dose-response data and used to mark the beginning of extrapolation to determine risk associated with lower en vironmentally relevant human exposures. NOAEL = no observed adverse effect level. LOAEL = lowest observed adverse effect level. UF = uncertainty factor. UF A = extrapolation from animal to human (interspecies). UF H = potential variation in sensitivity among members of the human population (intrasp ecies). MOE = margin of exposure. LOC = level of concern. N/A = not applicable.

5.0 Dietary Exposure and Risk Assessment

5.1 Residues of Concern Summary and Rationale

HED has previously considered the residues of concern for both risk assessment and tolerance enforcement, based on the results of acceptable metabolism studies. HED has determined that the residues of concern for risk assessment ar e fenbuconazole and the following metabolites: RH-9129, RH-9130, RH-4911(peanut only), and RH-7905 (peanut only). RH-9129 and RH9130 are cis/trans isomers of the lactone me tabolite of fenbuconazole and may account for approximately one third of the total fenbuconazo le residues. RH-9129 and RH-9130 are residues of concern for both risk-assessment and tolera nce-enforcement purposes. RH-7905 is a minor metabolite except in peanut. In animals, the gl ucoside conjugate (RH-7905) will be cleaved to yield RH-4911. Although RH-4911, a hydroxy-derivativ e of fenbuconazole, is likely to be less toxic than the parent, there is no specific toxi cological information for this compound. Because it shares structural features with the parent , HED has assumed it has the same toxicity as fenbuconazole. Therefore, RH-7905 and RH-4911 have been included as residues of concern for risk assessment (peanuts only). The current anal ytical enforcement method has been validated for the analysis of fenbuconazole as well as RH-9129 and RH-9130.Fenbuconazole Human Health Risk Assessment DP No. D403041

Page 17 of 43 Another metabolite, the iminolactone me tabolite (RH-6468) is also be included de facto in the residues of concern, because it is converted to the lactones by the anal ytical method, and would be included in the measured residues. Drinking Water

The estimated drinking water concentrations (EDWCs ) used in the dietary risk assessments were provided by the Environmental Fate and Effect s Division (EFED, D344352, J. Lin, 1/16/2008). The EDWCs were incorporated directly into th ese dietary assessments in the food categories “water, direct, all sources” a nd “water, indirect, all sources. ” The EDWCs for fenbuconazole were generated with the coupled models PR ZM and EXAMS for surface water and SCI-GROW for groundwater. Modeled surface water EDWCs are based on the maximum label application rate to peppers (acute value) or cherries (chronic and cancer va lues). The groundwater EDWC is based on the maximum label application rate to cherries. EDWCs reflect exposure to fenbuconazole. The common triazole metabolites 1,2,4-triazole, triazole al anine, and triazole acetic acid have been identified as residues of concern for risk assessment. A separate dietary exposure assessment has been performed for these metabolites (D403618, T. Morton). As a result, they are not being in cluded in this assessment.

The PRZM/EXAMS 1-in-10 year annual peak su rface water value of 24.1 ppb for peppers is greater than the SCI-GROW groundwater value of 0.031 ppb. As a result, the surface water value was used in the acute dietary analysis. The 1 in 10 year annual mean surface water value of 16.5 ppb for cherries is greater than the gr oundwater value of 0.031 ppb. As a result, the surface water value was used in the chronic dietar y analysis. Finally, the 30-year annual mean surface water value of 11.7 ppb for cherries is greater than the groundw ater value of 0.031 ppb. As a result, the surface water value was used in the cancer dietary analysis. The SCI-GROW Model and its description are available at the EPA internet site: http://www.epa.gov/oppefed/models/water/

.

Table 5.1. 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 ExpressionPlants Primary Crop Fenbuconazole + RH-9129 + RH9130 + RH-7905 (peanut only) + RH-4911 (peanut only) Fenbuconazole + RH-9129 + RH-9130, expressed as fenbuconazole

Rotational Crop Not Applicable Not ApplicableLivestock Ruminant Fenbuconazole + RH-9129 + RH9130 Fenbuconazole + RH-9129 + RH-9130, expressed as fenbuconazole Poultry Not Applicable Not Applicable Drinking Water Fenbuconazole Not Applicable

* The common triazole metabolites 1,2,4-triazole, triazolylala nine, and triazolylacetic acid have been identified as residues of concern for risk assessment. Separate asse ssments addressing these com pounds have been conducted (see. T. Morton, D403618).Fenbuconazole Human Health Risk Assessment DP No. D403041

Page 18 of 43 5.2 Food Residue Profile

The qualitative nature of fenbuconazole residues in plants and livestock is adequately understood Based on acceptable metabolism studies in peaches, peanuts, sugar beets, and wheat. In addition to the fenbuconazole residues of concern for ri sk assessment and tolerance enforcement, HED has considered the potential for exposure to the triazole meta bolites 1,2,4-triazole, triazole alanine, and triazole ace tic acid as a result of fenbuconazole use. The free triazole and its conjugates are considered to be residues of conc ern for risk assessment for all triazole-derivative fungicides. While HED does not set tolerances for these metabolites, a separate dietary and aggregate assessment is conducted when new uses of triazole-derivativ e fungicides have the potential to increase exposure to free triazole and its conjugates.

There are no livestock feedstuffs associated w ith the use on peppers and the proposed increased tolerance; therefore, data requirements for livestock meta bolism and feeding studies are not relevant to this tolerance petition. However, livestock tolerances have been established in conjunction with other crop uses of fenbuconazo le, and the data suppor ting the established livestock tolerances are adequate.

There are adequate data for risk assessment and to lerance assessment. There were finite residues of the parent compound in/on peppers in the brid ging study, and there were very low levels or non-detectable levels of the metabolite RH-9129 . Residue levels for the RH-9130 metabolite were all below the limit of detection (LOD). Re sidues of the parent compound tended to decline with increasing pre-harvest interval (PHI) with an estimated half-life of between 8 to 9 days. Residue data are summarized below.

5.2.1 Crop Field Trials (860.1500) D390352, S. Oonnithan, 9/8/2011
Bridging Data Dow AgroSciences has submitted a bridging study on pepper to translate residues from Indar ®
75WSP to Enable ® 2F, thereby obviating the need for a fu ll field trial data set for use of the Enable ® 2F formulation on peppers.

The bridging study conducted on bell pepper consiste d of side-by-side trials in six locations, in which both formulations were applied to peppers. The submitted residue data (6 samples) for the WP and SC formulations were analyzed using the OECD MRL calculation procedures for the purpose of comparing the data sets from the previous ly reviewed field trials used to establish the existing tolerance and the new br idging data. The results of the comparison are shown below:Fenbuconazole Human Health Risk Assessment DP No. D403041

Page 19 of 43 Table 5.2.1a. Fenbuconazole Total Residue 1

Indar ® WSP

2008 Data Indar ® WSP Bridging Study Enable ® 2F Bridging Study Current or recommended tolerance 0.40 0.70 1.0 Lowest residue 0.05 0.029 0.044 Highest residue 0.22 0.465 0.668 Mean residue 0.136 0.142 0.189 No. of samples (avg. of 2 replicates) 18 6 6 1 See D390352, S. Oonnithan, 8 Sept 2011.

Conclusions: Although the submitted bridging resi due data on pepper using the WP (Indar ® ) and SC (Enable ® 2F) formulations of fenbuconazole are limited, the results summarized above indicate the potential for signi ficantly higher residues of fenbuc onazole than found in the earlier field trials, even for the existing formulation. Based on the submitted data, the current 0.40 ppm tolerance does not support the higher residues found on pepper with either the WP formulation or the SC formulation. Therefore, the existing to lerance should be increased to 1.0 ppm to support use of the SC formulation. HED notes that the re sidue values for bell and non-bell peppers in the original submission were very similar (MRID 47215801); therefore the us e of only bell peppers in the bridging study is not an issue.

Triazole Metabolites

Residues of 1,2,4-triazole and triazole acetic acid were non-detectable (<0.003 ppm) in all treated pepper samples. Triazole alanine residues ranged from 0.0187 to 0.158 ppm in treated peppers. Untreated control pepper samples also ha d triazole alanine residues which ranged from 0.0029 to 0.013 ppm. Table 5.2.1b lists the results from the triazole metabolite analyses and is taken directly from the study report.Fenbuconazole Human Health Risk Assessment DP No. D403041

Page 20 of 43 Table 5.2.1b. Bell Pepper Field Tria l Data for Fenbuconazole (Triazole Metabolites). Residue Found in PPM c Trial Identification (variety) Rate a Sampling Interval b (days) Test Substance Triazole Triazole alanine Triazole acetic acid

Tallassee, AL (King Arthur) 4 x 0.188 7 Enable ND ND 0.0191 0.0213 ND <LOD

Indar <LOD <LOD 0.0187 0.0195 <LOD ND

Shady Grove, FL (Aristotle) 4 x 0.188 7 Enable <LOD <LOD 0.0289 0.0265 <LOD <LOD

Indar <LOD <LOD 0.0228 0.0244 <LOD <LOD

Stewardson, IL (Better Bell) 4 x 0.188 7 Enable ND ND 0.0226 0.024 <LOD <LOD

Indar ND ND 0.0325 0.0309 <LOD <LOD

Uvalde, TX (Camelot) 4 x 0.188 7 Enable <LOD ND 0.0247 0.0244 ND ND

Indar ND ND 0.0268 0.0268 ND ND

Visalia (Cypress) 4 x 0.188 7 Enable <LOD ND 0.0297 0.0287 <LOD ND

Indar <LOD <LOD 0.0220 0.0237 ND <LOD

Sanger, CA (Cypress) 4 x 0.188 0 Enable <LOD <LOD 0.106 0.099 <LOD <LOD

Indar <LOD ND 0.136 0.144 <LOD <LOD

4 x 0.188 3 Enable ND ND 0.107 0.116 <LOD <LOD

Indar <LOD <LOD 0.158 0.149 <LOD <LOD

4 x 0.188 7 Enable ND ND 0.090 0.084 <LOD <LOD

Indar ND <LOD 0.130 0.102 <LOD <LOD

4 x 0.188 10 Enable ND ND 0.095 0.104 <LOD <LOD

Indar ND ND 0.147 0.143 <LOD <LOD

4 x 0.188 14 Enable ND ND 0.102 0.106 <LOD <LOD

Indar ND ND 0.126 0.128 <LOD <LOD (a) Four foliar broadcast applications were made at 0.188 lb a i/A each time for a total treatment rate of 0.752 lb ai/A. (b) Sampling Interval is the days from the last application. (c) Individual residue levels are shown for each of the two replicates samples collected from each treatment plot. The LOD is 0.00 3 ppm and the LOQ is 0.01 ppm. ND is no chromatographic response.
Conclusions: There were no significant differences in triazole metabolite residue level resulting from treatment with either formulation. Residue s of 1,2,4-triazole and tri azole acetic acid were all non-detectable. Residues of triazole al anine averaged 0.025 ppm, while the maximum observed residue for triazole alanine was 0.158 pp m. These triazole metabolites have been addressed in a separate risk assessment, but ultimately do not impact HED’s estimate of aggregate exposure and risk from free triazole, triazole alanine and triazole acetic acid.Fenbuconazole Human Health Risk Assessment DP No. D403041

Page 21 of 43 5.2.2 Field Rotational Crops (860.1900) D259204, S. Oonnithan, 7/25/06

An adequate confined rotational crop study is avai lable indicating that the metabolite profile for fenbuconazole in rotational crops is similar to the metabolism in primary crops. Limited rotational crop field trials and rotational crop tolera nces are not required pr ovided labels continue to specify a minimum PBI of 35 days followi ng the last application to peppers of ≤ 0.188 lb ai/A, and a minimum PBI of 210 days following a last application of 0.188 - 1.0 lb ai/A.

5.2.3 Processed Food and Feed (860.1520)

HED does not require residue data for any processed commodities associated with peppers. Therefore, data requirements for processed food and feed are not releva nt to the currently proposed increased tolerance.

5.3 Water Residue Profile Drinking Water Exposure Assessment for Fenbuconazole Use on Pepper, D344352, J. Lin, 1/16/2008

Fenbuconazole is considered to be moderately pe rsistent 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 groundwater appears to be slight. However, the potential to contaminate groundwater may be gr eater at vulnerable sites, i.e ., where soils have low organic matter and where groundwater is relatively close to the surface. For purposes of human health risk assessment, the residue of c oncern in water is fenbuconazole.

RH-9129, RH-9130, RH-6467, and RH- 0118 (1,2,4-triazole) are degradates of fenbuconazole. In the aerobic metabolism study, concentrations of the metabolites RH-9129, RH-9130, and RH6467 increased with time accounting for 2.5-9.6% of the applied radioactivity in both soils treated with both radiolabels (RH-9129 and RH-9130 are diastereomers). 1,2,4-Triazole accounted for 11.2-13.6% and for 6.5-6.6% of the applied 14 C-triazole-RH-7592 in the Lawrenceville and Pasquotank soils, respectivel y. In the anaerobic metabolism study, RH-9129 and combined RH-9130/RH-6467 accounted fo r 0.6% (day 0) to 7.33% (day 60).

Given that the use pattern for peppers has not changed, HED used the drinking water assessment used in the last risk assessment for peppers. The estimated drinking water concentrations (EDWCs) used in the dietary risk assessments were provided by the Environmental Fate and Effects Division (EFED, D344352, J. Lin, 1/16/2 008) and are summarized below in Table 5.3. The EDWCs were incorporated directly into th ese dietary assessments in the food categories “water, direct, all sources” a nd “water, indirect, all sources. ” The EDWCs for fenbuconazole were generated with the coupled models PR ZM and EXAMS for surface water and SCI-GROW for groundwater. Modeled surface water EDWCs are based on the maximum label application rate to peppers (acute value) or cherries (chronic and cancer va lues). The groundwater EDWC is based on the maximum label application rate to cherries. These EDWCs reflect concentrations of fenbuconazole-specific residu es. The common triazole meta bolites 1,2,4-triazo le, triazole alanine, and triazole acetic ac id have separate EDWCs and have been included in HED’s aggregate assessment for free triazole and its conjugates.Fenbuconazole Human Health Risk Assessment DP No. D403041

Page 22 of 43 The PRZM/EXAMS-generated drinking water estim ates for surface water sources of drinking water were all greater than those generated by the SCI-GROW model for groundwater sources of drinking water. Therefore, HED relied on surf ace water estimates, which are protective of exposure from both ground and surface water sour ces. The 1-in-10-year annual peak surface water value of 24.1 ppb was used in the acute assessment; the 1-in-10-year annual mean surface water value of 16.5 ppb used in the chronic non-ca ncer dietary analysis . The 30-year annual mean surface water value of 11.7 ppb was used in the cancer dietary analysis. The drinking water models and descriptions are available at the EPA internet site: http://www.epa.gov/oppefed/models/water/

.

Table 5.3 Summary of Estimated Surface Wa ter and Groundwater Concentrations for Fenbuconazole.
Scenario Surface Water Conc., ppb a Groundwater Conc., ppb b

Acute 24.1 0.031 Chronic (non-cancer) 16.5 0.031 Chronic (cancer) 11.7 0.031

a From the Tier II PRZM-EXAMS - Index Reservoir model. Input parameters are based on maximum label application rate to cherries fo r the chronic assessments, and for peppers for the acute assessment.
b From the SCI-GROW model. Data taken from EFED Drinking Water Assessment, D344352, J. Lin, 1/16/2008.

5.4 Dietary Risk Assessment

5.4.1 Description of Residue Data Used in Dietary Assessment

For peppers, the HED-recommended tolerance level of 1.0 ppm was used as the residue value in the acute dietary exposure analysis. The averag e field trial value of 0.19 ppm for peppers from the Enable ® 2F bridging study was used for the chroni c and cancer dietary exposure analyses. Residue values used for all other commodities ar e discussed in detail in the previous dietary exposure memo completed for fenbuconazole (D 350321, D. Dotson, 6/12/2008). Tolerances for fenbuconazole are listed in 40CFR§180.480. The acu te and chronic assessments are based on 100% crop treated assumptions for all commodities.

The residue estimates used in these assessments are directly from the field trial data and, by nature of the analytical methods, account for all of the fenbuconazole-specific residues of concern in crops and livestock. A separate dietary exposure a ssessment has been performed for the common triazole metabolites (D403618, T. Morton) . Crop field trials re sulted in measurable fenbuconazole residues of concern for all crops.

Acute Assessment. The acute dietary (food + water) assessme nt is a screening-level assessment. It is based on tolerance-level residues for a ll foods, assumes 100% crop treated, and the acute estimated drinking water concentration (EDWC) for fenbuconazole in surface water (24.1 ppb), which is a high-end estimate derived from the use pattern for peppers. The acute assessment includes DEEMTM Version 7.81 default processing f actors for those commodities that were notFenbuconazole Human Health Risk Assessment DP No. D403041

Page 23 of 43 addressed by the available processing studies. For commodities where there are data indicating that residues do not concentrate during processing, a factor of one was used to be protective.

Chronic (Non-cancer) and Cancer Assessments. The chronic (non-can cer) and cancer dietary assessments include contributions from both food and water. The chronic estimated drinking water concentration (EDWC) for fenbuconazole is the 1-in-10-year annual mean surface water value of 16.5 ppb in surface water, which is a high-e nd estimate derived from the use on cherries. The cancer estimated drinking water concentratio n (EDWC) is the 30-year annual mean surface water value of 11.7 ppb for cherries, which is al so a high-end estimate derived from the use on cherries. For many crops average residue valu es were used. The chronic assessments use DEEMTM version 7.81 default processing factors fo r commodities that do not have empirical processing factors. The non-can cer assessment assumes 100% crop treated, whereas the cancer assessment makes use of average percent-crop-t reated estimates. The following percent crop treated estimates were used in the cancer dietar y risk assessment for the following crops that are currently registered for fenbuconazole: almonds : 5%, Apples: 5%, apricots: 5%, blueberries: 55%, cherries: 15%, grapefruit: 40%, nectarines : 5%, oranges: 5%, peaches: 15%, pecans: 10%, plums/prunes: 1%, sugar beets: 1% , tangelos: 10%, tangerines: 1%.

5.4.2 Percent Crop Treated Used in Dietary Assessment Screening Level Estimates of Agricultural Uses (SLUA) for the Fungicide Fenbuconazole (129011), Sepehr Haddad, 11 /13/2012.
The acute and non-cancer chronic dietary as sessments are based on 100% crop treated assumptions for all commodities.

The following average percent crop treated estimates ( Screening Level Estimates of Agricultural Uses (SLUA) for the Fungicide Fenbuconazole (129011), Sepehr Haddad, 11 /13/2012) were used in the cancer dietary risk assessment for th e following crops that are currently registered for fenbuconazole: almonds: 5%, apples: 5%, aprico ts: 5%, blueberries: 55%, cherries: 15%, grapefruit: 40%, nectarines: 5%, oranges: 5%, peaches: 15%, pecans: 10 %, plums/prunes: 1%, sugar beets: 1%, tangelo s: 10%, tangerines: 1%.

5.4.3 Acute Dietary Risk Assessment

Females Age 13-49 were assessed for acute dietar y risk; no endpoints of c oncern were identified for the general population including infants and child ren. No risks of concern were identified for acute dietary exposure. The results of the acu te dietary exposure analysis for females 13-49 years of age at the 95 th , 99 th , and 99.9 th percentiles of exposure are reported in Table 5.4.3. As percent crop treated estimates we re not used in the acute assessm ent, HED recommends that the 95 th percentile of exposure be used for re gulation. The population subgroup Females 13-49 utilizes 2.9% of the aPAD at the 95 th percentile of exposure.Fenbuconazole Human Health Risk Assessment DP No. D403041

Page 24 of 43 Table 5.4.3. Results of Acute Dietary Exposure Analysis (Food and Drinking Water)

Population Subgroup aPAD (mkd)* 95 th Percentile 99 th Percentile 99.9 th Percentile Exposure

(mkd) % aPAD Exposure (mkd) % aPAD Exposure (mkd) % aPAD Females 13-49 years old 0.30 0.008618 2.9 0.013971 4.66 0.026168 8.72 *mkd: milligram per kilogram body weight per day

5.4.4 Chronic Dietary Risk Assessment

All populations were evaluated for chronic dietary risk. No risks of concern were identified in the chronic dietary exposure analysis. The most highly exposed population subgroup is children 1-2 years old which utilizes 6.7% of the cP AD (Table 5.4.6). The general U.S. population utilizes 2.3% of the cPAD.

5.4.5 Cancer Dietary Risk Assessment

Cancer risk is determined for the general U.S. population only. Applying the Q 1 * value of 0.00359 (mg/kg/day) -1 to the exposure value of 0.000604 mg/kg/day yields a cancer risk estimate of 2.2 x 10 -6 (Table 5.4.6). Although the cancer risk a ssessment incorporated estimates of %CT and the use of average field tria l data, the cancer risk estimate c ould be further refined with the use of monitoring data, and actual cancer risk is e xpected to be lower than the value presented in the table below.

5.4.6 Summary Table

The results of the dietary exposure and risk anal yses for acute and chronic dietary exposures, and for cancer risk, are summarized below in Table 5.4.6.

Table 5.4.6. Summary of Dietary Exposure a nd Risk for Fenbuconazole (Food and Drinking Water)

Population Subgroup* Acute Dietary (95 th Percentile) Chronic Dietary Cancer Dietary Exposure (mg/kg/day) % aPAD Dietary Exposure (mg/kg/day) % cPAD Dietary Exposure (mg/kg/day) Risk General U.S. Population N/A N/A 0.000705 2.3

0.000604 2.2 x 10 -6 All Infants (< 1 year old) N/A N/A 0.001755 5.8 Children 1-2 years old N/A N/A 0.002018 6.7 Children 3-5 years old N/A N/A 0.001410 4.7 Children 6-12 years old N/A N/A 0.000796 2.7 Youth 13-19 years old N/A N/A 0.000458 1.5 Adults 20-49 years old N/A N/A 0.000587 2.0 Adults 50-99 years old N/A N/A 0.000652 2.2 Females 13-49 years old 0.008618 2.9 0.000602 2.0Fenbuconazole Human Health Risk Assessment DP No. D403041

Page 25 of 43 6.0 Residential (Non-Occupational) Exposure/Risk Characterization

There are presently no residential uses for fenbuconazole.

6.5 Residential Bystander Post-application Inhalation Exposure

Based on the Agency's current practices, a quant itative post-application inhalation exposure assessment was not performed for fenbuconazole at this time primarily be cause of the low acute inhalation toxicity (Toxicity Category III and IV), low vapor pressure (at 25 o C, 3.7 x10 -8 mm Hg at 25C), and the low proposed use rate (0.188 lb ai/A). However, volatilization of pesticides may be a source of post-application inhalati on exposure to individua ls nearby pesticide applications. The Agency sought expert advice an d input on issues relate d to volatilization of pesticides from its Federal Insecticide, Fungicide , and Rodenticide Act Scie ntific Advisory Panel (SAP) in December 2009, and received th e SAP’s final report on March 2, 2010 ( http://www.epa.gov/scipoly/sa p/meetings/2009/120109meeting.html ). The Agency is in the process of evaluating the SAP report and may, as appropriate, develop policies and procedures to identify the need for and, subsequently, the way to incorporate post-application inhalation exposure into the Agency's risk assessments. If new policies or procedures are developed, the Agency may revisit the need fo r a quantitative post -application inhalati on exposure assessment for fenbuconazole.

6.6 Spray Drift

Spray drift is always a potential source of expos ure to residents nearby to spraying operations. This is particularly the case with aerial appl ications allowed on fenbuconazole labels, but, to a lesser extent, could also be a potential source of exposure fr om ground application methods 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 practi ces (see the Agency’s Spray Drift website for more information at http://www.epa.gov/opp00001/fact sheets/spraydrift.htm). On a chemical by chemical basis, the Agency is now requiring inte rim mitigation measures for aerial applications that must be placed on product labels/labeling. Th e Agency has completed its evaluation of the new database submitted by the Spray Drift Task Force, a membership of U.S. pesticide registrants, and is developing a policy on how to appropriately apply the data and the AgDRIFT computer model to its risk assessments for pes ticides applied by air, or chard 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-targ et drift with specific products with significant risks associated with drift.

Although a quantitative residential post-applic ation inhalation exposure assessment was not performed as a result of pesticide drift from nei ghboring treated agricultural fields, an inhalation exposure assessment was performed for flaggers. Th is exposure scenario is representative of a worse case inhalation (drift) exposure and may be considered protective of most outdoor agricultural and commercial post-application inhalation exposure scenarios

.Fenbuconazole Human Health Risk Assessment DP No. D403041

Page 26 of 43 7.0 Aggregate Exposure/Risk Characterization

In accordance with the FQPA, HED must consider and aggregate (add) 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 th e risks themselves can be aggregated. When aggregating exposures and risks from various sources, HED consider s both the route and duration of exposure.
7.1 Acute & Chronic Aggregate Risk

Acute and chronic (both cancer and non-cancer) aggregate exposures include food plus drinking water exposures. As demonstrat ed under Section 5.4, acute and ch ronic aggregate risks are not of concern.

7.2 Short- and Intermediate-Term Aggregate Risk

Short-and intermediate-term aggr egate exposures take into acc ount residential exposure plus average exposure levels to food and water (consid ered to be a background exposure level). For fenbuconazole, there are no residential uses, and th erefore a short-term a ggregate risk assessment was not needed.

Updated Aggregate Assessment of Free Triazole & its Conjugates

Reference: Common Triazole Metabolites: Updated A ggregate Human Health Risk Assessment

to Address The Amended Propiconazole Sectio n 3 Registration to Add Use on Sugarcane. DP403619, T. Morton, 8/1/12.

The addition of the proposed amended use doe s not increase the aggregate exposure to free triazole and its conjugates. Therefore, the mo st recent aggregate human health risk assessment for free triazole and its conjugates, which indicated the aggregate estimates are below HED’s level of concern (D403619, T. Morto n, 8/1/12), is also protective of potential aggregate exposure and risk associated with this tolerance action for fenbuconazole.

8.0 Cumulative Exposure/Risk Characterization

Fenbuconazole is a member of the triazole-cont aining class of pesticid es. Although conazoles act similarly in fungi by inhibiti ng ergosterol biosynthesis, there is not necessarily a relationship between their pesticidal activity and their mech anism 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 esse ntially the same, sequen ce of major biochemical events (EPA, 2002). In conazoles, however, a variable pattern of toxi cological responses is found. Some conazoles are hepatotoxic and he patocarcinogenic in mice. Some induce thyroidFenbuconazole Human Health Risk Assessment DP No. D403041

Page 27 of 43 tumors in rats. Some induce developmental, repr oductive, and neurological effects in rodents. Furthermore, the conazoles produce a diverse ra nge of biochemical even ts including altered cholesterol levels, stress res ponses, and altered DNA methylati on. It is not clearly understood whether these biochemical events are directly co nnected to their 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 appr oach based on a common mechanism of toxicity for the conazoles. For information regardi ng EPA’s procedures for cumulating effects from substances found to have a common mechan ism of toxicity, see EPA’s website at http://www.epa.gov/pesticides/cumulative

. Fenbuconazole is a triazole-derived pesticide. This class of compounds can form the common metabolite 1,2,4-triazole and two tr iazole conjugates (triazolylalanine and triazolylacetic acid). To support existing tolerances and to establish ne w tolerances for triazole -derivative pesticides, including fenbuconazole, U.S. EPA conducted a huma n health risk assessment for exposure to 1,2,4-triazole, triazolylalanine, and triazolylacetic acid resulting fr om the use of all current and pending uses of any triazole-der ived fungicide. The risk asse ssment is a highly conservative, screening-level evaluation in te rms of hazards associated with common metabolites (e.g., use of a maximum combination of uncertainty factors) and potential dietary a nd non-dietary exposures (i.e., high end estimates of both dietary and non- dietary exposures). In addition, the Agency retained the additional 10X FQPA safety factor for the protection of infants and children. The assessment includes evaluations of risks for va rious subgroups, including those comprised of infants and children. The Agency’s complete risk assessment is found in the propiconazole reregistration docket at http://www.regulations.gov , Docket Identification (ID) Number EPAHQ-OPP-2005-0497.

9.0 Occupational Exposure/Risk Characterization

Detailed occupational exposure and risk ch aracterizations for the use of both product formulations containing fenbuconazole have previously been conducted. Both product formulations were previously assessed for handler exposures, fo r similar scenarios. Indar ® 75 WSP was evaluated for use on pepper and other crops (S. Wan g, D345898, 5/28/2008) and Enable ® 2F was assessed for use on cranberry, pea nut, and other crops (D28908, M. Collantes, 6/26/2006). Both assessments used the same singl e application rates (0.1 9 lb ai/A), equipment (ground and aerial foliar), timing (10 day interval ), and number of applications (4) as are currently proposed for the labe l amendment for peppers.

HED has taken into consideration the findings of the previous risk assessment for peppers and the similarities between the use pattern of th e existing and proposed formulations, and has determined that new occupational exposure and risk assessments are not needed to ensure adequate protection of occupational workers mi xing, loading and applying the fungicide.

Comparison of Use Pattern Indar ® 75 WSP is registered for use on pepper (inc luding bell, chili, cooking, pimento, and sweet varieties) at single and s easonal maximum application ra tes of 0.188 and 0.75 lb ai/A, respectively. The label allows a maximum of 4 applications occurri ng at10 day intervals; however, the label prohibits more than 2 consecutive applications of fenbuconazole, in order toFenbuconazole Human Health Risk Assessment DP No. D403041

Page 28 of 43 prevent development of resistance . The pre-harvest interval (PHI) is 7 days after the last application. The registrant is propo sing the same use pattern for Enable ® 2F on pepper.

The personal protective equipmen t (PPE) specified on the Indar ® 75 WSP label includes baseline clothing (long sleeved shirt, l ong pants and shoes with socks), chemical resistant gloves, and chemical resistant head gear for overhead exposure. The same PPE recommendations are specified on the proposed label for Enable ® 2F.

Both labels have the same restri cted-entry interval (REI) of 12 hours, which is based on the acute toxicity of the technical active i ngredient. Exposure (dermal and i nhalation) is expected to be of short- or intermediate-term duration for all scen arios. Long-term occupa tional exposure is not anticipated, either from de rmal or inhalation routes.

Occupational Handler Assessments In the previous assessments, dermal risks were no t assessed quantitatively due to the lack of systemic toxicity via the dermal route, and in the absence of developmental or reproductive effects that would not have b een assessed in the dermal study.

For inhalation exposure, the previous assessment us ed the dose and endpoint from the rat chronic oral study (liver and thyroid eff ects), in the absence of a route- specific inhalation toxicity study. In conjunction with the current risk assessment, HED’s HASPOC determined that a subchronic inhalation toxicity study is not needed for fenbuconazole (TXR No. 0056540). For the current assessment, a new occupational inhalation exposu re assessment is not needed; however in the future, the dose and endpoint for inhalation expo sure will be taken from the 90-day rat study. Since the 90-day no-observed-adverse-effects- level (NOAEL) and lowest-observed-adverseeffects-level (LOAEL) are slightly higher than in the chronic study, HED’s risk estimates for inhalation exposure will be lower.

As stated previously, quantitative non-cancer derm al risk assessments were not needed due to the lack of toxicity via the dermal route. For Indar ® 75 WSP on pepper, the estimated short-term non-cancer inhalation risk for handlers was an MO E greater than or equal to 9,100 assuming the use of baseline PPE; the MOEs were greater than 100 and are therefor e not of concern. Combined dermal and inhalation cancer risk for occupational handlers was estimated to be at most 1.62 x 10 -7 . Given that the use patterns are similar, differences between risk estimates for the two formulations were driven by the unit ex posures for the various handler scenarios. The non-cancer inhalation MOE for Enable ® 2F was ≥ 2,600 assuming baseline PPE, and the estimated combined dermal and inhalation cancer risk was at most 3.0 x 10 -7

. Occupational Post-Application Assessments In the previous assessment, HED did not qua ntitatively assess non-can cer post-application dermal exposure and risk for Indar ® 75 WSP or Enable ® 2F due to the lack of systemic toxicity via the dermal route. Cancer risk for dermal post-application exposure was estimated to be at most 9.9 x 10 -8 . Since the use pattern has not cha nged, HED did not conduct an updated postapplication exposure assessment. A new assessme nt would address the following changes in the assumptions used: 1) increased body weight, fr om 70 to 80 kg; 2) increased life expectancy, from 70 to 78 years; and 3) increased transfer coefficient, from 1,000 to 1,900 cm 2 /hour for highFenbuconazole Human Health Risk Assessment DP No. D403041

Page 29 of 43 exposure activities. The use of these assumpti ons would increase estimated post-application cancer risk to approximately 1.4 x 10 -7

.

10.0 References

Fenbuconzole. Occupational Exposure Assessmen t to Support Use of a New Formulation on Peppers. D404874, C. Swartz, 1/31/13.

Fenbuconazole: Acute, Chronic and Cancer Aggregate Dietary (Food and Drinking Water) Exposure Analysis for the Section 3 Registratio n Action Increasing the Tolerance for Peppers. D403621, D. McNeilly, 1/8/2013.

Fenbuconazole. Petition for an Increased Toleran ce and the Registration of an SC formulation Use on Peppers: Summary of Analytical Chemistry and Residue Data. D403621, D. McNeilly, 12/8/2012.

Fenbuconazole: Bridging Residue Data on Pepper from Indar ® 75WSP to Enable ® 2F Formulation. D390352, S. Oonnithan, 9/8/2011.

Fenbuconazole: Human Health Risk Assessmen t for the Proposed Use on Peppers. D344351, D. Dotson, 6/12/2008.

Fenbuconazole: Summary of Hazard and Scie nce Policy Council (HASPOC) Meeting of December 20, 2012: Recommendation on the need for a 28-day inhalation study and acute/subchronic neurotoxicity stud ies in the rat (TXR # 0056540).

Fenbuconazole. Petition for Registration for Us e on Pepper, Bushberry Subgroup (13-B), and Cranberry. Summary of An alytical Chemistry and Re sidue Data, D313752, D. Dotson, 6/12/2008.

Occupational and Residential Exposure Assessment for Section 3 Registration for use of Fenbuconazole on Peppers, D345898, S. Wang, 5/28/2008.

Fenbuconazole. Acute, Chronic, and Cancer Aggregate Dietary (Food and Drinking Water) Exposure Analysis for the Section 3 Re gistration Action, D350321, D. Dotson, 6/12/2008.

Drinking Water Exposure Assessment for Fenbuconazole Use on Pepper, D344352, J. Lin, 1/16/2008.

Screening Level Estimates of Agricultural Us es (SLUA) for the Fungicide Fenbuconazole (129011), Sepehr Haddad, 11 /13/2012.

Fenbuconazole: Human Health Risk Assessment for Proposed Uses on Almonds, Apples, Bananas, Bushberries, Citrus Fruit, Cranberrie s, Grapes, Peanuts, Pecans, Stone Fruits, Sugar Beets, and Wheat. PC Code: 129011, DP Ba rcode: D316607, M. Collantes, et al, 8/3/2006.Fenbuconazole Human Health Risk Assessment DP No. D403041

Page 30 of 43 Common Triazole Metabolites: Updated Dietar y (Food + Water) Exposure and Risk Assessment to Address The Amended Propicon azole Section 3 Registration to Add Foliar Use on Sugarcane. T. Morton. D403618. 8/1/2012.

Common Triazole Metabolites: Updated Aggregat e Human Health Risk Assessment to Address The Amended Propiconazole Section 3 Registrati on to Add Use on Sugarcane. T. Morton. D403619. 8/1/2012.Fenbuconazole Human Health Risk Assessment DP No. D403041

Page 31 of 43 Appendix A. International Residue Limits

Fenbuconazole (129011; 10/10/2012) Summary of US and International Tolerances and Maximum Residue Limits Residue Definition : US Canada Mexico 2 Codex 3
40 CFR § 180.480

Plant/Livestock: combin ed residues of the fungicide fenbuconazole, alpha-[2-(4-chlorophenyl)- ethyl]-alpha-phenyl-3-(1H1,2,4-triazole)- 1-propanenitrile, and its metabolites RH-9129, cis-5-(4-chlorophenyl)- dihydro-3-phenyl-3-(1H1,2,4- triazole-1-ylmethyl)-2-3 H-furanone, and RH-9130, trans-5-(4- chlorophenyl)dihydro-3-phenyl-3- (1H-1,2,4- triazole-1-ylmethyl)-2-3 H- furanone, expressed as fenbuconazole α -[2-(4-chlorophenyl)ethyl]- α

phenyl-1 H -1,2,4- triazole-1-propanenitrile, including the metabolites cis -5-(4-chlorophenyl)-dihydro-3- phenyl-3-(1 H -1,2,4- triazol-1-ylmethyl)-2-3 H -furanone and trans -5-(4- chlorophenyl)-dihydro-3-phenyl-3- (1 H -1,2,4- triazol-1-ylmethyl)-2-3 H -furanone Fenbuconazole. The residue is fat-soluble.

Commodity 1 Tolerance (ppm) /Maximum Residue Limit (mg/kg) US Canada Mexico 2 Codex 3

Pepper 1.0 0.6 peppers 2 peppers Chili, dried (draft MRL awaiting ARfD evaluation)

Completed: M. Negussie; 10/12/2012

1 Includes only commodities of interest for th is action. Tolerance values should be th e HED recommendations and not those propo sed by the applicant. 2 Mexico adopts US tolerances and/or Codex MRLs for its export purposes. 3 * = absent at the limit of quantitation; Po = postharvest treatment, such as treatment of stored grains. PoP = processe d postharvest treated commodity, su ch as processing of treated st ored wheat. (fat) = to be measured on the fat portion of the sample. MRLs indicated as proposed have not been finalized by the CCPR and the CAC.

Appendix B. Toxicology Profile

B.1 Toxicology Data Requirements

The requirements (40 CFR 158.340) for food uses of fenbuconazole are in Table B1. Use of the new guideline numbers does not imply that the ne w (1998) guideline protoc ols were used. The acute and chronic toxicity pr ofiles are shown in Tables B.2.1 and B.2.2, respectively.Fenbuconazole Human Health Risk Assessment DP No. D403041

Page 32 of 43 Study Technical
Required Satisfied 870.1100 Acute Oral Toxicity ....................................................... 870.1200 Acute Dermal Toxicity ..................................................
870.1300 Acute In halation Toxicity ..............................................
870.2400 Acut e Eye Irr itation

....................................................... 870.2500 Acute Dermal Irritation ................................................. 870.2600 Skin Sensitiza tion .......................................................... yes
yes
yes
yes
yes
yes yes
yes
yes
yes
yes
yes 870.3100 90-Day Oral Toxicity in Rodents .................................. 870.3150 90-Day Oral Toxicity in Nonrodents ............................. 870.3200 21/28-Da y Dermal Toxicity ........................................... 870.3250 90-Day Dermal Toxicity ................................................ 870.3465 28/90-Day Inhalation Toxicity ...................................... yes
yes
yes

no

no yes
yes
yes

-

- 870.3700a Prenatal Developm ental Toxicity (rodent) ..................... 870.3700b Prenatal Developmen tal Toxicity (nonrodent) .............. 870.3800 Reproductio n and Fertility Effects ................................. yes
yes
yes yes
yes
yes 870.4100a Chronic T oxicity (rodent) .............................................. 870.4100b Chronic Toxi city (nonrodent) ........................................ 870.4200a Carcinog enicity (rat) ...................................................... 870.4200b Carcinoge nicity (mouse) ................................................ 870.4300 Combined Chroni c Toxicity/Carci nogenicity ................ yes
yes
yes
yes
yes yes
yes
yes
yes
yes 870.5100 Mutagenicity—Bacterial Reverse Mutation Test .......... 870.5300 Mutagenicity—Mammalian Cell Gene Mutation Test .. 870.5385 Mutagenicity—Struc tural Chromosomal Aberrations ... 870.5550 Mutagenicity—O ther Genotoxic Effects ....................... yes
yes
yes
yes yes
yes
yes
yes 870.6200a Acute Neurotoxicity Screening Battery (rat) ................. 870.6200b 90-Day Neurotoxicity Screening Battery (rat) ............... 870.6300 Developm ental Neurot oxicity ........................................ no

no

no -

-

- 870.7485 Metabolism and Pharmacokinetics ................................
870.7600 Derm al Penetr ation ........................................................ 870.7800 Immunotoxicity ............................................................. yes
yes
yes yes
yes

noFenbuconazole Human Health Risk Assessment DP No. D403041

Page 33 of 43 B.2 Toxicity Profiles

Table B.2.1 - Acute Toxicity of Fenbuconazole - T echnical (shaded) and End-Use (2F, 24% ai) Product

Guideline No. Study Type MRID Results Toxicity Category

870.1100 Acute Oral - Rats 41031209 Oral LD 50 (M) > 2000 mg/kg III

870.1100 Acute Oral - Rats 41031207 Oral LD 50 (M and F) > 2000 mg/kg III

870.1100 Acute Oral - Rats 41031221 Oral LD 50 (M) > 5000 mg/kg IV

870.1100 Acute Oral - Rats 41031222 Oral LD 50 (F) > 5000 mg/kg IV

870.1200 Acute Dermal - Rats 41031208 LD 50 (M and F) > 5000 mg/kg IV

870.1200 Acute Dermal - Rats 41031223 LD 50 (M) > 5000 mg/kg IV

870.1200 Acute Dermal - Rats 41031224 LD 50 (F) > 5000 mg/kg IV

870.1300 Acute Inhalation - Rats 41398201 LC 50 (M and F) > 2.1 mg/L Particle size too large. Requirement was waived because of a problem in generating respirable dust particles or liquid aerosol. III

870.1300 Acute Inhalation - Rats 41031225 LC 50 (M and F) > 2.1 mg/L III

870.2400 Primary Eye IrritationRabbits 41031211 Not irritating to unwashed eyes IV

870.2400 Primary Eye IrritationRabbits 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 SensitizationGuinea pigs 41031213 Is not a sensitizer under conditions of study. N/A

870.2600 Dermal SensitizationGuinea pigs 41031228 Is not a sensitizer under conditions of study. N/A

Table B.2.2 - Toxicity Profile of Fenbuconazole Technical

Guideline No. Study Type MRID Doses ResultsFenbuconazole Human Health Risk Assessment DP No. D403041

Page 34 of 43 Table B.2.2 - 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 or 1600 ppm (Males: 0, 1.3, 5.1, 25.3 or 103.0 mg/kg/day; Females: 0, 1.5, 6.3, 31.1 or 123.9 mg/kg/day) NOAEL = 5.1/6.3 mg/kg/day (M/F) LOAEL = 25.3/31.1 mg/kg/day (M/F) based on decreased body weight, liver effects (histopathology, clinical chemistry effects and increased liver weight)

870.3100 90-Day oral toxicity rodents - mice 41073503 0, 20, 60, 180, and 540 ppm ( Males: 0, 3.8, 11.1, 28.6 or 99.1 mg/kg/day; Females: 0, 5.7, 17.6, 50.4 or 139.2 mg/kg/day) NOAEL = 11.1/17.6 mg/kg/day (M/F) LOAEL = 28.6/50.4 mg/kg/day (M/F) based on liver histopathology and clinical chemistry changes

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 or 50.4 mg/kg/day; Females: 0, 1.1, 3.5, 14.0 or 53.3 mg/kg/day) NOAEL = 13.3/14.0 mg/kg/day (M/F) LOAEL = 50.4/53/3 mg/kg/day (M/F) based on liver histopathology, clinical chemistry in females

870.3200 21/28-Day dermal toxicity -
rats 41875013 42882701 0, 250, 625 or 1000 mg/kg/day NOAEL = 1000 mg/kg/day (HDT) (systemic and local dermal irritation) LOAEL = >1000 mg/kg/day (systemic and local dermal irritation)

870.3250 90-Day dermal toxicity N/A N/A Not performed

870.3465 28 or 90-Day inhalation toxicity N/A N/A Not performed

870.3700 Prenatal developmental in rodents - rats 41031214 41073505 0, 30, 75 or 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 decreased implantations, increased post-implantation loss and a decrease in the number of live fetuses/damFenbuconazole Human Health Risk Assessment DP No. D403041

Page 35 of 43 Table B.2.2 - Toxicity Profile of Fenbuconazole Technical

Guideline No. Study Type MRID Doses Results

870.3700 Prenatal developmental in nonrodents - rabbits 41875014 42882701 0, 10, 30 or 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

870.3700 Prenatal developmental in nonrodents - rabbits 45259401 0, 15 or 45 mg/kg/day Maternal NOAEL = 15 mg/kg/day

Maternal LOAEL = 45 mg/kg/day, based on decreased food consumption and increased incidence of clinical signs (soft/scant/no feces) Developmental NOAEL = 15 mg/kg/day
Developmental LOAEL = 45 mg/kg/day based on decreased fetal body weightFenbuconazole Human Health Risk Assessment DP No. D403041

Page 36 of 43 Table B.2.2 - Toxicity Profile of Fenbuconazole Technical

Guideline No. Study Type MRID Doses Results

870.3800 Reproduction and fertility effects - rats 41875015 0, 8, 80 or 800 ppm (0, 0.4, 4 or 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 or 1200 ppm (0, 0.38, 3.75 or 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 liverchanges were observed in highdose males and females.

870.4200 Carcinogenicity -
rats See 870.4300

870.4200 Carcinogenicity - mice 41893301 41635303 Males: 0, 10, 200 or 650 ppm (0, 1.43, 28.6 or 92.9 mg/kg/day) Females: 0, 10, 650 or 1300 ppm (0, 1.43, 92.9 or 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 carcinogenicityFenbuconazole Human Health Risk Assessment DP No. D403041

Page 37 of 43 Table B.2.2 - Toxicity Profile of Fenbuconazole Technical

Guideline No. Study Type MRID Doses Results

870.4300 Combined chronic toxicity/ carcinogenicity -
rat 41635301 41635302 Control - 0 ppm

Low - 4 ppm (weeks 1 & 2), 6 ppm (weeks 3 & 4) or 8 ppm (weeks 5-term)

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

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

( Males: 0, 0.31, 3.03 or 30.62 mg/kg/day; Females: 0, 0.4, 4.02 or 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) or 800 ppm (weeks 5-term)

High - 800 ppm (weeks 1 & 2), 1200 ppm (weeks 3 & 4) or 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

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.Fenbuconazole Human Health Risk Assessment DP No. D403041

Page 38 of 43 Table B.2.2 - Toxicity Profile of Fenbuconazole Technical

Guideline No. Study Type MRID Doses Results

870.5300 Cytogenetics - in vitro mammalian cell gene mutation test (CHO Cells) 41031218 15-50 μg/mL without S9 activation

35-60 μg/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 or 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 or 15.0 μg/mL No evidence (or a dose-related positive response) that unscheduled DNA synthesis was induced.Fenbuconazole Human Health Risk Assessment DP No. D403041

Page 39 of 43 Table B.2.2 - 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 female urine.Fenbuconazole Human Health Risk Assessment DP No. D403041

Page 40 of 43 Table B.2.2 - 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 radiolabeled, 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 might be occurring at the high dose.

870.7485 Metabolism and pharmacokinetics
– rat (supplemental) 46473401 1) 1 mg/kg radiolabelled, single dose by oral gavage, urine and feces collection up to 48 hrs; 2) 100 mg/kg radiolabelled, single dose by oral gavage, urine and feces collection up to 72 hrs;
3) 100 mg/kg radiolabelled single dose by oral gavage, urine and feces collection 72-96 hrs. Evaluation of 1,2,4-triazole levels in urine and feces occurred at very low levels (2.48% AD, males and 1.0% AD, females). Alanine and acetic acid conjugates were not detected.Fenbuconazole Human Health Risk Assessment DP No. D403041

Page 41 of 43 Table B.2.2 - Toxicity Profile of Fenbuconazole Technical

Guideline No. Study Type MRID Doses Results

870.7600 Dermal penetration - rat 41875019 0, 0.125, 1.25 or 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%Fenbuconazole Human Health Risk Assessment DP No. D403041

Page 42 of 43 Appendix C. Physical/Chemical Properties

Table C.1. Physical and Chemical Proper ties of the Technical Grade Fenbuconazole

Parameter Value Reference Molecular weight 353.8

D310959, S. Oonnithan, 7/25/2008 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 -6 Pa) Dissociation constant (pK a ) (PAI) Not expected to dissociate in water Octanol/water partition coefficient Log(K OW ) Log(K OW ) = 3.22

UV/visible absorption spectrum λ max (nm) 196 262 268 275 ε (L·mol -1 ·cm -1 ) 53,000 750 740 480 Soil Half-life (t 1/2 in days) Aerobic : 285 and 367 days, silty clay loam and sandy loam soils, respectively Anaerobic : 451 and 655 days, silty clay loam and sandy loam soils, respectively D344352, J. Lin, 1/16/08Fenbuconazole Human Health Risk Assessment DP No. D403041

Page 43 of 43 Appendix D. Review of Human Research

This risk assessment relies in part on data from studies in which adult human subjects were intentionally exposed to a pesticide or other chemical. Thes e studies, listed below, have been reviewed for ethical conduct. The studies we re considered appropriate for use in risk
assessments.

The PHED Task Force, 1995. The Pesticide Handlers Exposure Database, Version 1.1. Task Force members Health Canada, U.S. Environmental Protection Agency, and the National Agricultural Chemicals Association, released February, 1995.

The Agricultural Handler Exposure Task Force (AHETF), 2011. The Occupational Handler Unit Exposure Surrogate Reference T able. U.S. Environmental Protection Agency. Released June 21, 2011.