### UNITED STATES ENVIRONMENTAL PROTECTION AGENCY WASHINGTON, D.C. 20460

OFFICE OF CHEMICAL SAFETY AND POLLUTION PREVENTION



### MEMORANDUM



### Date:

Subject:



### From:

Through:

To: 12-MAR-2015



### Bicyclopyrone: Hwnan Health Risk Assessment for the Section 3 Registration Action

on Corn and the Establishment of Permanent Tolerances for Residues in/on Corn and Imported Sugarcane.

PC Code: 018986 DP Barcode: 0421265

Decision No.: 470867 Re2istration Nos.: 100-RUAL and IOO-RUAA

Petition Nos.: 3F8225, 2F8097, and 2E8098 Reeulatory Action: Section 3 Re2istrations

Risk Assessment Tvoe: Single ChemicaVAs;is;ireJ?ate Case No.: NA

TXR No.: 0056613 and 0056911 CAS No.: 352010-68-5

MRIDNo: NA 40CFR: NA

Kelly M. Lowe, Senior Environmental Scientist

# ~**~** Anwar 

### Y. Dunbar, Ph.D.,

### Pharmacolo**gist ~;I--~~**  George 

### F. Kramer, Ph.D., Senior Chemist**~ ~~~:::..-** **-- ---::a~~~**  

### Ri s k Assessment Branch 

### 1 (RAB 

### 1)

Health Effects Division (HED; 7509P)

Charles 

### W. Smith III, Branch

# Chie~**~~** RABl/HED (7509P)**~**

Donna Davis, RARC Reviewer
Elissa Reaves, RARC Reviewer

Risk Assessment Review Committee (RARC)

Erik Kraft Shaja Joyner
Rachel Holloman, Branch Chief Registration Division (RD; 7505P)

HED of the Office of Pesticide Programs (OPP) is charged with estimating the risk 

### to hwnan

health from exposure to pesticides. RD of OPP 

### has requested that HED evaluate hazard and

exposure data and conduct dietary, occupational, residential, and aggregate exposure assessments, as needed, to estimate the risk to hwnan health that will result from the proposed

use of the new active ingredient, bicyclopyrone, [ 4-hydroxy-3-{2-[(2-methoxyethoxy)methyl]-6- (trifluoromethyl)-3-pyridylcarbonyl} bicyclo[3.2. l ]oct-3-en-2-one ].

A summary of the findings and an assessment of human risk resulting from the proposed uses are provided in this document. The risk assessment and occupational/residential exposure and risk

assessment were provided by Kelly Lowe (RAB I), the dietary risk assessment and residue chemistry review were provided by George Kramer (RAB 1 ), the hazard characterization was

Page 1of49Bicyclopyrone Human Health Risk Assessment D421265

Page 2 of 49 

### provided by Anwar Dunbar (RAB1), and the drin king water assessment was provided by Cheryl
Sutton of the Environmental Fate and Effects Division (EFED).Bicyclopyrone Human Health Risk Assessment D421265

Page 3 of 49 

### Table of Contents

1.0 Executive Summary ............................................................................................................. 5

2.0 Recommendations .......................................................................................................... .......... 8

2.1 Data Deficiencies/Data Needs ............................................................................................. 8
2.2 Tolerance Considerations.................................................................................................. ... 8 2.2.1 Enforcement Analytical Method ................................................................................... 8
2.2.2 Recommended Tolerances ............................................................................................ 9
2.2.3 Revisions to Petiti oned-For Tolerances ...................................................................... 10
2.2.4 International Harmonization ....................................................................................... 10
2.3 Label Recommendations .................................................................................................... 10

3.0 Ingredient Profile ............................................................................................................ .... 10

3.1 Chemical Identity ........................................................................................................... 1 0
3.2 Physical/Chemical Properties ......................................................................................... 11

3.3 Proposed Use Pattern ..................................................................................................... 11

3.4 Anticipated Exposure Pathways ..................................................................................... 12

3.5 Consideration of Environmental Justice ........................................................................ 12

4.0 Hazard Characterization and Dose-Response Assessment ................................................ 13

4.1 Toxicology Studies Available for Analysis ................................................................... 13

4.2 Absorption, Distribution, Metabolis m, & Elimination (ADME) ................................... 14

4.2.1 Dermal Absorption.................................................................................................. 15

4.3 Toxicological Effects ..................................................................................................... 15

4.4 Safety Factor for Infants and Children (FQPA SF) ........................................................ 16

4.4.1 Completeness of the Toxicology Database ............................................................. 16

4.4.2 Evidence of Neurotoxicity ...................................................................................... 16

4.4.3 Evidence of Sensitivity/Susceptibility in the Developing or Young Animal ......... 17

4.4.4 Residual Uncertainty in the Exposure Database ..................................................... 17

4.5 Toxicity Endpoint and Point of Departure Selections .................................................... 17

4.5.1 Dose-Response Assessment .................................................................................... 17
4.5.2 Recommendation for Combining Routes of Exposures for Risk Assessment ........ 18

4.5.3 Cancer Classification and Risk Assessment Recommendation .............................. 18

4.5.4 Summary of Points of Departure and T oxicity Endpoints Used in Human Risk

Assessment .................................................................................................................... ........ 18

5.0 Dietary Exposure and Risk Assessment ............................................................................. 20

5.1 Metabolite/Degradate Residue Profile ........................................................................... 20

5.1.1 Summary of Plant and Animal Metabolism Studies ............................................... 20

5.1.2 Summary of Environmental Degradation ............................................................... 20

5.1.3 Comparison of Metabolic Pathways ....................................................................... 21

5.1.4 Residues of Concern Summary and Rationale ........................................................ 21

5.2 Food Residue Profile ...................................................................................................... 22

5.3 Drinking Water Residue Profile ..................................................................................... 22

5.4 Dietary (Food + Drinking Water) Risk Assessment ...................................................... 22

6.0 Residential (Non-Occupational) E xposure/Risk Characterization ..................................... 23

6.1 Spray Drift ................................................................................................................... ... 23
6.2 Residential Bystander Post-Appli cation Inhalation Exposure ....................................... 24Bicyclopyrone Human Health Risk Assessment D421265

Page 4 of 49 

### 7.0 Aggregate Exposure/Risk Characterization ....................................................................... 24

8.0 Cumulative Exposure/Risk Characterization ..................................................................... 24

9.0 Occupational Exposure/Risk Characterization ................................................................... 25

9.1 Handler Risk Assessment ............................................................................................... 25

9.2 Post-Application Risk Assessment................................................................................. 27

9.2.1 Inhalation Post-Application Risk Assessment ........................................................ 27

9.2.2 Dermal Post-Application Risk Assessment ............................................................ 27

9.2.3 Restricted Entry Interval ......................................................................................... 29

Appendix A. Toxicology Prof ile and Executive Summaries ....................................................... 30

Appendix B. Metabolism Summary Table ................................................................................... 42

Appendix C. Physical / Chemical Properties of Bicyclopyrone .................................................. 48

Appendix D. Review of Human Research ................................................................................... 49Bicyclopyrone Human Health Risk Assessment D421265

Page 5 of 49 

### 1.0 Executive Summary

Bicyclopyrone, [4-hydroxy-3-{2-[(2-met hoxyethoxy)methyl]-6-(trifluoromethyl)-3- pyridylcarbonyl}bicyclo[3.2.1]oct-3-en -2-one], is a new herbicide currently undergoing joint review with the Pesticide Management Regul atory Agency (PMRA) in Canada, and the
Australian Pesticides and Vete rinary Medicines Authority in Australia (APVMA). It is a member of the 4-hydroxyphenylpyruvate dioxygenas e (HPPD) inhibitor cl ass of herbicides (Group 27) and belongs to the triketone subclass of chemistry. Syngenta has submitted a petition
for establishment of tolerances for the new ac tive ingredient (ai) bi cyclopyrone on corn and imported sugarcane. The proposed use on corn is fo r the selective contact a nd residual control of broadleaf weeds in field corn, seed corn, silage corn, yellow popcorn, and sweet corn. The maximum application rate for SYN-A16003 Herbicid e [a soluble concentr ate (SC) formulation containing 18.5% ai (1.67 lb ai/gal)] is 0.044 lb a i/A. One application (early post-emergence) is recommended, but the labels do allow for split applications (one post-emergent and one preemergent) as long as the maximum single applica tion rate is not exceeded for the season. The minimum retreatment interval (RTI) is 14 days; the preharvest interval (PHI), 45 days. For sugarcane in Australia, the maximum application ra te is 0.267 lb ai/A, but the labels do allow for split applications. The minimum RTI is 28 days; the PHI, 28 days.

Hazard Assessment: The effects in the bicyclopyrone hazard database are indicative of inhibition of HPPD. Plasma tyrosine levels were consistently elevated in rats, rabbits and dogs (levels in mice were not tested). Consistent with these elevated tyrosine levels, ocular effects (corneal opacity, keratitis) were observed for su bchronic and chronic dura tions through the oral and dermal routes in rats, which was the most se nsitive species tested (minor instances in dogs). There were also increased incidences of thyroid follicular hyperplasia, and a chronic progressive nephropathy.

Different effects were observed in dogs. For s ubchronic oral exposure, c linical signs (moderate hypoactivity, slightly unsteady gait, increased he art rate, regurgitation, and vomiting) were observed, and clinical pathological indicators of toxici ty occurred in the eye and the thymus. Following chronic exposure, there was a dose depe ndent increase in chromatolysis and swelling
of selected neurons in the dorsa l root ganglia, and de generation of nerve fibers in the spinal
nerve roots in both sexes. In one female dog at the high dose, corn eal opacity and light sensitivity were observed.

Across the database, there were decreased abso lute body weights (the onl y finding in mice for any duration) and food consumption. There were no signs of immunotoxicity or neurotoxicity in rodents. Bicyclopyrone treatment resulted in developmental toxicity in both rats and rabbits, and there was an increased quantitative fetal suscep tibility in both species tested. In the twogeneration reproductive study in rats , ocular toxicity occurred in parents and offspring and there was no increased offspring susceptibility of a ny kind. Reproductive eff ects included changes in sperm parameters, and a decrease of precoital interval.

In a specialized in vivo study, bicyclopyrone increased metabolism of thyroid hormones suggesting that disruption of the thyroid pituitary axis accounted for the t hyroid hyperplasia in the chronic/carcinogenicity study.

Food Quality Protection Act (FQPA) Safety Factor (SF) Decision: The bicyclopyrone risk assessment team recommends that the FQPA SF be retained at 10X for all exposure scenarios
based on use of a lowest-observable adverse-eff ect level (LOAEL) for th e points of departureBicyclopyrone Human Health Risk Assessment D421265

Page 6 of 49 

### (PODs). The toxicology database for bicyclopyro ne is adequate for characterizing toxicity and quantification of risk for f ood and non-food uses; however, a LOAEL from the New Zealand white rabbit developmental and chro nic/carcinogenicity ra t toxicity studies has been used as the
POD for several scenarios. There is no evidence of neurotoxicity in either of the neurotoxicity screening batteries, but there are effects in the chronic dog study. The level of concern is low, however, since the study and POD chosen for the ch ronic dietary exposure scenario is protective
of these effects. There is evidence of increase d quantitative fetal susceptibility following in utero exposure in both rats and rabbits; however , these effects are well characterized and the selected endpoints are protective of the observe d fetal effects. Las tly, there are no residual uncertainties in the exposure database.

Dose-Response Assessment: The rabbit developmental study (LOAEL = 10 mg/kg/day) was selected for assessment of acute dietary (femal es 13-49 years old only) and short-/intermediateterm occupational dermal/inhalation e xposures. The LOAEL is based upon skeletal variations (the appearance of the 27 th 

### presacral vertebrae). A dermal absorption factor of 20.44% will be applied to dermal exposure scenarios. No endpoint attributable to a sing le dose and appropriate for the U.S. general population wa s seen in the bicyclopyrone toxi cological database; therefore, an acute POD for the general U.S. population wa s not established. The carcinogenicity study in
the rat was selected for assessment of chroni c dietary exposure (LOAEL = 0.28 mg/kg/day). The LOAEL is based upon an increased incidence of opaque eyes and corneal damage in both sexes compared to controls, an increa sed incidence of thyroid follicul ar hyperplasia in males, and an increased incidence of chronic progressive nephr opathy in the kidneys of males. Bicyclopyrone was classified as “suggestive evidence of carcino genic potential” based on the presence of rare ocular tumors in male rats; however, the Cancer Assessment Review Committee (CARC) determined that quantification of carcinogenic potential was not re quired and that cancer risks are adequately addressed by the chronic RfD.

Dietary Exposure Assessment: The residue chemistry database is adequate to support the proposed uses/tolerances. Studies depicting the metabolism of bicy clopyrone radiolabeled in the bicyclooctenone and pyridine rings were submitted for corn, sugarcane, rotational crops, laying hens, and lactating goats. The metabolism of bicyclopyrone in plants and livestock is qualitatively similar, although much more extensive in plan ts. Based on the metabolism studies and on residue data from field trials, the re sidue definition for enforcement and for risk assessment in plants (primary and rotational crops) and livestock is bicyclopyrone and its structurally related metabolites determ ined as the common moieties SYN503780 and CSCD686480. Analytical methods suitable for en forcement and data gathering have been developed and validated. Crop fi eld trials with bicyclopyrone we re conducted according to the proposed label directions in the U.S. with corn a nd in Australia and Brazil w ith sugarcane. In all sugarcane and field corn grain samples, residue s were below the limit of quantitation (LOQ). Quantifiable residues were found in the other corn raw agricultural commodities (RACs). As no significant concentration was observed in any pr ocessed fraction in the corn and sugarcane processing studies, separate tolerances for residues in processed corn and sugarcane commodities will not be required. Limited field rotational crop studies showed that quantifiable residues are not expected at the minimum proposed plantback intervals (PBIs). In the ruminant feeding study, residues were found only in kidney and liver.

Dietary Risk Estimates (Food + Drinking Water ): Acute and chronic aggregate dietary (food and drinking water) exposure a nd risk assessments were conduct ed using the Dietary Exposure Evaluation Model - Food Consumption Intake Database (DEEM-FCID, ver. 3.16) which incorporates the food consumption data from the United States Department of AgricultureBicyclopyrone Human Health Risk Assessment D421265

Page 7 of 49 

### (USDA) National Health and Nutrition Exam ination Survey, What We Eat in America (NHANES/WWEIA; 2003-2008). The re sidues of concern (ROC) fo r dietary risk assessment (and tolerance assessment) is the sum of the common moieties SYN503780 and CSCD686480,
calculated as the stoichiometric equivalent of bicyclopyrone, while the ROC for drinking water is the parent only, bicyclopyrone. The acute and chronic analyses assumed tolerance-level residues or average field trial residues, 100% crop-treated (CT), and mode led drinking water estimates. Since adequate processing studies have been submitted, which indicate that residues do not concentrate in corn or sugarcane commodities, the DEEM (ver. 7.81) default processing factors for these commodities were reduced to 1. The resulting acute [ ≤ 2.9% acute population-adjusted dose (aPAD) for females 13-49 years old] and chronic [ ≤ 91% chronic populat ion-adjusted dose (cPAD); children (1-2 years old) were the most highly exposed subgroup] dietary risk estimates
are not of concern to HED.

Residential (Non-Occupational) Ex posure and Risk Assessment: There are no residential uses proposed for bicyclopyrone. Therefore, resident ial handler and post-application exposure/risk
were not assessed.

Aggregate-Risk Estimates: In accordance with FQPA, HED must consider and aggregate pesticide exposures and risks from three major sources: food, drinking water, and residential exposures. Because there are no uses for bicy clopyrone that result in residential (nonoccupational) exposures, the aggregate assessment need only consider food and drinking water. Since the dietary exposure analys is included both food and drinki ng water, the dietary exposure estimates represent aggregate acute and chronic exposure to bicyclopyrone and its structurally related metabolites, determined as the common moieties SYN503780 and CSCD686480. All aggregate bicyclopyrone risk estimates are not of concern to HED.

Occupational Exposure and Risk Assessment: A quantitative assessment of occupational exposure has been conducted for the proposed uses . The occupational handler exposure and risk
estimates indicate that the short- and intermedia te-term dermal and inhalation combined margins of exposure (MOEs) are not of concern to HED (i.e., MOE ≥ 1000) with baseline attire (i.e., single layer of clothing, no gloves, and no respirator; all MOEs ≥ 1,700). The occupational postapplication dermal exposure and risk estimates ar e greater than the level of concern (LOC) of 1000 on the day of application, ranging from 1,800 to 49,000 depending on crop and activity. Since the post-application assessment is not a concer n on Day 0 (12 hours following application), the restricted-entry interval (REI) is based on the acute toxi city of bicyclopyrone technical material. Bicyclopyrone has low acute toxicity via the oral, dermal and inhalation routes (Toxicity Category IV), and is not an ey e or dermal irritant (Toxicity Category IV). Bicyclopyrone was not shown to be a skin sensitizer . Therefore, the acute toxicity categories for this chemical require a 12-hour REI under 40 CFR 156.208 (c)(2)(iii). The 12-hour REI, which currently appears on one of the proposed labe ls, is adequate for the proposed uses of bicyclopyrone. One of the labels has a longer REI of 24 hours, but has multiple active ingredients. Longer REIs may be necessary for the other active ingredie nts in the product and
would be addressed in the risk assessments for those active ingredients. Based on the Agency's current practices, a quantitative non-cancer oc cupational post-applica tion inhalation exposure assessment was not performed for bicyclopyrone. If new policies or procedures are put into place, the Agency may revisit the need for a qua ntitative occupational po st-application inhalation exposure assessment for bicyclopyrone.

Environmental Justice Considerations: Potential areas of environm ental justice concerns, to the extent possible, were considered in this hum an health risk assessment, in accordance withBicyclopyrone Human Health Risk Assessment D421265

Page 8 of 49 

### U.S. Executive Order 12898, “Federal Actions to Address Environmental Justice in Minority Populations and Low-Income Populations.”

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. These data, which
include studies from the Pesticide Handlers E xposure Database Version 1.1 (PHED 1.1), the Agricultural Handler Exposure Ta sk Force (AHETF) database, and the Agricultural Reentry Task Force (ARTF) database are (1) s ubject to ethics review pursuant to 40 CFR 26, (2) have received that review, and (3) are compliant wi th applicable ethics requirements. For certain studies, the ethics review may have included review by the Human St udies Review Board. Descriptions of data sources, as well as guidance on their use, can be found at the following Agency websites: http://www.epa.gov/pesticides/science/handler-exposure-data .html and http://www.epa.gov/pe sticides/science/post-appexposure-data.html.



### 2.0 Recommendations

HED concludes that the residue chemistry and toxicology data bases support registration of bicyclopyrone and the establishment of the perm anent tolerances listed in Section 2.2.2.

2.1 Data Deficiencies/Data Needs

ORE: In accordance with 40 CFR 158, dislodgeable-f oliar residue (DFR) da ta are required for all occupational (e.g., crop, nursery, greenhouse use sites) or residentia l (e.g., ornamental and vegetable gardens, pick your own farms, retail tree farms) uses that could result in postapplication exposure to foliage. The proposed uses for bicyclopyrone could result in postapplication exposure; however, chemical-specific DFR data are not availabl e. Since the highest estimated occupational post-applic ation exposure using default DFR values for bicyclopyrone is not minimal in comparison to the LOC (i.e., the calculated MOE is not greater than two times higher than the LOC, MOE = 1,800 compared to the LOC of 1000); EPA is requiring the 40 CFR DFR data to facilitate any necessary e xposure assessments refinements and to further EPA’s general understanding of the availability of dislodgeable foliar pest icide residues. These data should be submitted with any future uses of bicyclopyrone.

2.2 Tolerance Considerations

2.2.1 Enforcement Analytical Method

Suitable liquid chromatography-mass spectroscop y/mass spectroscopy (LC-MS/MS) methods for
tolerance enforcement have been developed and independently vali dated. For all matrices and analytes, the LOQ, defined as the lowest spik ing level where acceptable precision and accuracy data were obtained, was determined to be 0.01 ppm for each of the common moieties, SYN503780 and CSCD686480, for a combined LOQ of 0.02 ppm. HED has determined that these methods are suitable enforcement methods for plant and livestock commodities, respectively, as defined in Standard Opera ting Procedure (SOP) No. ACB-019 (9/15/08). The
FDA multi-residue methods are not suitable for detection and enforcement of bicyclopyrone
residues.

Plant Matrices: GRM030.05B is an LC-MS/MS method fo r field corn forage, ears, grain and stover, wheat forage, hay, straw and grain, radish roots and tops, and spinach leaves that is suitable for the determination of residues of bicy clopyrone and its structural ly related metabolitesBicyclopyrone Human Health Risk Assessment D421265

Page 9 of 49 

### determined as the common moieties, SYN 503780 and CSCD686480. This is achieved by cleaving the carbonyl bond in bicyclopyrone and st ructurally related metabolites using basic hydrogen peroxide. Residues of bicyclopyrone and structurally related metabolites were extracted from the sample matrices by homogenizing with an acetonitrile/water (80:20 v/v) solution. After centrifugation and filtration, basic hydrogen peroxide hydrolyzed bicyclopyrone and structurally related metabolites to SYN503780 or CSCD686480. Ultra-pure water was added to each sample before final determination by LC-MS/MS.

Livestock Matrices: GRM030.08B is an LC-MS/MS method for livestock matrices (milk, eggs, and bovine/poultry tissues) that is suitable for the determination of residues of bicyclopyrone and its structurally related metabolites determ ined as the common moieties SYN503780 and CSCD686480. Residues of bicyclopy rone and structurally relate d metabolites were extracted from the sample matrices by homogenizing with an acetonitrile/water (50: 50 v/v) solution. After centrifugation and filtration, basic hydrogen peroxi de hydrolyzed bicyclopyrone and structurally
related metabolites to SYN503780 or CSCD686480. Samples were passed through Phenomenex Strata-X solid-phase extraction (SPE) cartridges before final determination by LC-MS/MS.

2.2.2 Recommended Tolerances

HED has reviewed the available residue data and has determined the appropriate tolerance levels for residues of bicyclopyrone (Table 2.2.2). The recommended tolerance expression is as
follows:

(a) General. (1) Tolerances are established for residues of the he rbicide bicyclopyrone, including its metabolites and degradates, in or on the comm odities in the table below. Compliance with the tolerance levels specified below is to be determined by measuring only the sum of the common moieties SYN503780 (2-[(2-methoxyethoxy)methyl]-6- (trifluoromethyl)-3-pyridinecarboxy lic acid) and CSCD686480 (2-[(2- hydroxyethoxy)methyl]-6-(trifluoromethyl)-3-pyr idinecarboxylic acid), calculated as the stoichiometric equivalent of bicyclopyrone, in or on the commodities.

Table 2.2.2. Tolerance Summary for Bicyclopyrone.

Commodity Proposed Tolerance (ppm) HED-Recommended Tolerance (ppm) Comments ( correct commodity definition ) Field Corn, forage 0.40 0.30 Corn, field, forage Field Corn, grain 0.02 0.02 Corn, field, grain Field Corn, stover 0.50 0.40 Corn, field, stover Popcorn, grain 0.02 0.02 Corn, pop, grain Popcorn, stover 0.50 0.40 Corn, pop, stover Sweet Corn, forage 0.40 0.40 Corn, sweet, forage Sweet Corn, ears 0.02 0.03 Corn, sweet, kernel plus cob with
husks removed Sweet Corn, stover 0.50 0.70 Corn, sweet, stover Sugarcane, stalks 0.01 1 0.02 1 Sugarcane, cane Cattle, liver 0.06 1.5 Cattle, meat byproducts Goat, meat byproducts - 1.5 Sheep, meat byproducts - 1.5 Horse, meat byproducts - 1.5 Hog, meat byproducts - 0.15

1 No U.S. registration as of XXX.Bicyclopyrone Human Health Risk Assessment D421265

Page 10 of 49 

### 2.2.3 Revisions to Petitioned-For Tolerances

The proposed tolerance levels for most corn (f ield, pop, and sweet) RACs differ slightly from those being recommended by HED. Although both the petitioner and HED have used the OECD (Organization for Economic Cooperation and Deve lopment) calculation procedures to obtain tolerance levels, HED only included data from tr ials conducted according to the proposed label directions. The petitioner propos ed a tolerance level for sugar cane, cane below the method LOQ (0.01 ppm); the appropriate level is at the LOQ (0.02 ppm). HED’s proposed tolerance levels for livestock meat byproducts were based on the highes t tissue-to-feed ratio calculated from the dose closest to maximum dietary burdens. As residue s are expected in both liver and kidney, the appropriate RAC is "meat byproduc ts." Furthermore, per HED current policy, tolerances are recommended for all ruminants, not just catt le. In addition, HED is recommending numerous changes in the commodity definitions and for revi sions to the tolerance expression in order to conform to current Agency policy.

2.2.4 International Harmonization

There are no established Mexican or Codex maximum residue lim its (MRLs) for residues of bicyclopyrone. Therefore, issues of compatibility with respect to U.S. tolerances and Codex and/or Mexican MRLs do not exist. Bicyclopyrone is the subject of a jo int data review by the U.S. EPA, PMRA, and APVMA. At this time, the residue definitions and the recommended
tolerances and MRLs are harmonized among the joint review partners.

2.3 Label Recommendations

None.

3.0 Ingredient Profile

3.1 Chemical Identity

The chemical structure and nomenclature of bicyclopyrone and the common moieties, SYN503780 and CSCD686480, are presented in Table 3.1.1.

Table 3.1.1. Bicyclopyrone, SYN503780, and CSCD686480 Nomenclature. Compound: ai Chemical Structure

Common name Bicyclopyrone Company experimental name NOA449280 IUPAC name 4-hydroxy-3-{2-[(2-methoxyethoxy)methyl]-6-(trifluoromethyl)-3- pyridylcarbonyl}bicyclo[3.2.1]oct-3-en-2-one CAS name 4-hydroxy-3-[[2-[(2-methoxyethoxy)methyl]-6-(trifluoromethyl)-3- pyridinyl]carbonyl]bicyclo[3.2.1]oct-3-en-2-one

CAS # 352010-68-5 End-use product/EP SYN-A16003 Herbicide (100-RUAL) and A-19707 (100-RUAA) OH

O N O O

CF 3 OMeBicyclopyrone Human Health Risk Assessment D421265

Page 11 of 49 Table 3.1.1. Bicyclopyrone, SYN503780, and CSCD686480 Nomenclature. Compound: common moiety

O H N O O

CF 3 OMe

Company experimental name SYN503780 IUPAC name 2-(2-methoxy-ethoxymethyl)-6-trifluoromethyl-nicotinic acid CAS name 2-[(2-methoxy ethoxy)methyl]-6-(trif luoromethyl)-3-pyridinecarboxylic acid

CAS # 380355-55-5 Compound: common moiety

N O

O H

CF 3 O OH

Company experimental name CSCD686480 IUPAC name 2-(2-hydroxy-ethoxymethyl)-6-trifluoromethyl-nicotinic acid CAS name 2-[(2-hydroxyethoxy)methyl]-6-(trifluoromethyl)-3-pyridinecarboxylic acid



### 3.2 Physical/Chemical Properties

The physicochemical properties of bicyclopy rone are summarized in Appendix C. Bicyclopyrone is a solid under ambient conditions and is unlikely to vo latilize significantly based on its low vapor pressure (<3.75×10 -8 

### mm Hg at 20°C) and its Henry’s Law constant (1.7

x 10 -6 

### Pa m 3 

### /mol). Bicyclopyrone is a relatively solubl e, nonvolatile compound that is stable to hydrolysis across all environmental pH levels. W ith a pKa of 3.06, it will exist predominantly as an anion at environmental pHs. Bicyclopyrone is not expected to bioacc umulate in aquatic and terrestrial organisms based on its K ow 

### of -1.2 (pH 7).

3.3 Proposed Use Pattern

Bicyclopyrone is a new active ingr edient being proposed for use on field corn, seed corn, silage corn, yellow popcorn, and sweet corn. A petiti on has also been submitted for a tolerance on imported sugarcane. A summary of the proposed us e directions is included in Table 3.3.1 below. Table 3.3.2 provides a summar y of the proposed PBIs for bicyclopyrone.

Table 3.3.1. Summary of Proposed Use Directions for Bicyclopyrone.

Application Timing, Type,

and Equip. Formulation [EPA Reg. No.] Maximum Application

Rate Max No. Applications per Season Max Seasonal Application

Rate Use Directions and Limitations

Field Corn, Seed Corn, Silage Co rn, Yellow Popcorn, and Sweet Corn

Pre-plant, preemergence, or

early postemergence

Groundboom SC

SYN-A16003

Herbicide 1 [100-RUAL]

18.5% ai (1.67 lb ai/gal) 3.4 fl oz/A =
0.044 lb ai/A 2 (but not to
exceed the max

application rate) 0.044 lb ai/A  REI = 12 hours

 14-day RTI if 2 applications
are made.

 Do not apply via chemigation or aerial equipment.

 Corn may be treated up to 30 inches tall or up to the 8-leaf stage of corn growth.

 Do not feed or harvest forage
or sweet corn ears within 45Bicyclopyrone Human Health Risk Assessment D421265

Page 12 of 49 Table 3.3.1. Summary of Proposed Use Directions for Bicyclopyrone.

Application Timing, Type,

and Equip. Formulation [EPA Reg. No.] Maximum Application

Rate Max No. Applications per Season Max Seasonal Application

Rate Use Directions and Limitations

days after application.

Pre-plant, preemergence, or

early postemergence

Groundboom SC

SYN-A19707
Herbicide 2,3 [100-RUAA]

0.65% bicyclopyrone 3 qts/A =
0.023 lb bicyclopyrone
/A 2 (but not to
exceed the max

application rate) 3 qts/A =
0.023 lb bicyclopyrone
/A  REI = 24 hours

 Do not graze or feed forage from treated areas for 45 days following application.

 Do not harvest forage within 60 days after application.

 Corn (for grain, seed, or silage) may be treated up to
12 inches tall.

 Do not apply via chemigation or aerial equipment. Sugarcane (Australia only)

Broadcast spray up to the

3- to 4-leaf
crop stage, or as a directed spray in more

advanced

sugarcane SC

A16003E
HERBICIDE

200 g ai/L 1.5 L/ha = 300 g ai/ha 2 (but not to
exceed the max

application rate) 1.5 L/ha = 300 g ai/ha  4-week RTI if 2 applications
are made.

 Do not graze or cut for
livestock food for 4 weeks after application.

 Do not apply via chemigation or aerial equipment.

1. PPE = long-sleeved shirt and long pants, shoes plus socks, chemical-resistant gloves. 2. PPE = coveralls over short-sleeved shirt and short pants; ch emical-resistant gloves; chemical-resistant footwear plus socks ; chemical-resistant apron when mixing/loading, cleaning up spills, or cleaning equipment, or otherwise expos ed to the concentrate; chemical-resista nt headgear for overhead exposure. 3. Other active ingredients per gallon: atrazine 1.0 pound, bicyclopyrone 0.06 pounds , mesotrione 0.24 pounds and S-metolachl or 2.14 pounds. All application rates for chemicals other th an bicyclopyrone are equal to or below cu rrently approved labeled rates for these c hemicals.

Table 3.3.2. Interval Between SYN-A16003 Application and Planting of Rotational Crops. Crop PBI Field Corn, Seed Corn, Silage Corn, Sweet Corn, and Yellow Popcorn Anytime

Small Grain Cereals Including Wh eat, Barley, and Rye 4 Months Alfalfa, Cotton, Peanuts, Potato, Rice, Sorghum, and Soybeans 10 Months

All Other Crops 18 Months



### Conclusions: The proposed use directions are adequate to allow eval uation of the residue data relative to the proposed use.

3.4 Anticipated Exposure Pathways

Based on the proposed bicyclopyrone application scenarios, dietar y exposure is an anticipated exposure pathway as residues of bicyclopyr one may be found in/on crops, livestock commodities, and drinking water. Exposure in th e residential (non-occupational) setting is not anticipated. The current action is expected to result in short- and intermediate-term occupational exposures (handler and post-application).

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://epa.gov/complia nce/ej/resources/pol icy/exec_order_12898.pdf ). As a part of everyBicyclopyrone Human Health Risk Assessment D421265

Page 13 of 49 

### pesticide risk assessment, OPP considers a larg e variety of consumer subgroups according to well-established procedures. In line with OPP policy, HED estimates risks to population subgroups from pesticide exposures that are based on patterns of that subgroup’s food and water consumption, and activities in and around the home that involve pesticide use in a residential setting. Extensive data on food consumption pa tterns are compiled by the U.S. Department of Agriculture (USDA) under the NHANES/WWEIA; 2003-2008 and are used in pesticide risk assessments for all registered food uses of a pest icide. These data are analyzed and categorized by subgroups based on age, season of the year , ethnic group, and region of the country. Additionally, OPP is able to assess dietary e xposure to smaller, specialized subgroups and exposure assessments are performed when condi tions or circumstances warrant. Whenever appropriate, non-dietary exposures based on home use of pesticide products and associated risks for adult applicators and for t oddlers, youths, and adults enteri ng or playing on treated areas post-application are evaluated. Further considera tions are currently in development as OPP has committed resources and expertise to the developm ent of specialized software and models that consider exposure to bystanders and farm worker s as well as lifestyle and traditional dietary patterns among specific subgroups.

4.0 Hazard Characterization and Dose-Response Assessment

Bicyclopyrone is an effective inhibitor of th e enzyme HPPD and blocks the pathway of prenylquinone biosynthesis in plan ts. Bicyclopyrone shar es a structural and toxicological profile similar to mesotrione. For mesotrione, a wealth of mechanistic data are available both experimentally and in the litera ture which thoroughly characteri ze its molecular initiating event and adverse outcome pathway. In mammals, the amino acid tyrosine is catabolized by the tyrosine aminotransferase (TAT) enzyme to form the substrate 4-hydroxyphenylpyruvic acid (HPPA), which is then further catabolized by the HPPD enzyme for excretion. Inhibition of HPPD leads to the build-up of HPPA and this build-up results in el evated levels of tyrosine in the blood (tyrosinemia). Tyrosinemia in laborato ry animals results in ocular, developmental, liver, and kidney effects. TAT activity can vary depending on the species; therefore, the degree of tyrosine accumulation differs among species . Though extensive mechanistic data are not available for bicyclopyrone, there is strong evidence of tyrosinemia in its database.

4.1 Toxicology Studies Available for Analysis

The hazard database for bicyclopyrone is adeq uate for FQPA evaluation and for dose-response evaluation. Bicyclopyrone was evaluated for the following:

(1) Subchronic and chronic oral toxicity in rats, mice and dogs; (2) Subchronic dermal toxicity in rats; (3) Developmental toxicity in rats and rabbits; (4) Reproductive and postnatal toxicity in rats; (5) Carcinogenicity in mice and rats; (6) Neurotoxicity in rats; and (7) Immunotoxicity in mice.

Genetic toxicology studies were submitted by the re gistrant and consisted of a bacterial reverse gene mutation test, a micronucleus test, and an in vitro chromosome aberrati on test. In addition,
two mechanistic studies were submitted to eval uate the effect of bicyclopyrone on thyroid function. Appendix A includes a summary of th e bicyclopyrone toxicological database.Bicyclopyrone Human Health Risk Assessment D421265

Page 14 of 49 

### HED’s Hazard and Science Policy Council (HAS POC) evaluated all existing hazard and exposure data, and current use patterns for bicyclopyrone, and used a weight-of-evidence approach to waive the requirement for a develo pmental neurotoxicity and subchronic inhalation study at this time (TXR# 0056613 and 0056911).

4.2 Absorption, Distribution, Metab olism, & Elimination (ADME)

The absorption, distribution, metabolism and ex cretion of bicyclopyrone was characterized extensively in a series of st udies using both low- and high-do se, single and repeated dosing protocols. Bicyclopyrone was well absorbed from the gastro intestinal (GI) tract following administration of a single oral dose (2 or 200 mg/kg). Using bile-cannulation experiments, absorption from the GI tract was estimated to be 83-87% for the low dose in both sexes. The estimated absorption for the high dose was 86-90 % for both sexes. Maximum mean plasma concentrations (C max 

### ) were reached in both male and female rats within 1.3-2.3 hours (T max 

### ), indicating rapid abso rption kinetics. C max 

### values increased proportionally with dose suggesting nearly linear absorption. The levels of radioact ivity in plasma declined rapidly in a biphasic pattern. The mean plasma clearance ha lf-life values of the first phase ( α -phase) were estimated at 2.4-2.7 hours at 2 mg/kg bw in both sexes, and we re noted to increase m odestly to 3.2 hours at 200 mg/kg bw in males, but not in females. At the low dose, it was not possible to calculate a half-life value for the second phase ( β -phase) because the majority of samples were at or below
the limit of detection. At 200 mg/kg bw, the mean plasma β -phase half-life values were
estimated at 12.5 and 68.6 hours in males and female s, respectively. The highest levels of radioactivity were found in the liver (4% and 3% of the admini stered dose in males and females, respectively) and kidney (0.3% and 0.4% of th e administered dose in males and females, respectively). This pattern of tissue accumulation was independent of time, frequency of dosing and amount of dosing. All other tissues were ne ar or below the limit of detection (LOD). Radioactivity in the carcass accounted fo r <0.7% of the administered dose.

At both dose levels, the major radioactive comp onent in the urine of non-cannulated rats was parent compound, accounting for ca 40% and 80% of the dose in males and females, respectively, indicating greater metabolism in males. In bile duct cannulated rats, the metabolite profile in urine was similar to that obtained fr om intact rats. The metabolite profile obtained from rats administered multiple low doses of bicy clopyrone was similar to that obtained from the equivalent single dose.

There were no significant differences in the patterns of excret ion between the sexes. For the low dose, the major routes of excretion were the ur ine (64% and 85% of the administered dose in males and females, respectively) and feces (27% and 5% of the administered dose in males and females, respectively). For the high dose, the re sults were similar to those obtained for the low dose. The majority of the administered dose wa s eliminated within 24 hours of dosing for both the low and high dose groups, and fo r single and repeated dosing.Bicyclopyrone Human Health Risk Assessment D421265

Page 15 of 49 

### 4.2.1 Dermal Absorption

The dermal absorption of bicyclopyrone was evaluated in an in vivo dermal absorption study where rats were exposed for 6 hours to a 20% soluble liquid concentrate formulation and aqueous dilutions at 1/100 and 1/400 (0.005, 0.02, and 2 mg/cm 2 

### ). Based upon HED’s current policies, a dermal-absorption factor of 20.44% observed 24 hours post-exposure with the lowest dilution (1/400 concentration) was used to extrap olate oral doses to derm al-equivalent doses, for dermal exposure scenarios. This dermal absorp tion factor includes the absorbed and potentially
absorbed fractions derived from the sum of resi dues measured in the tissues/carcass, excreta, application site skin, and tape st rip 3 (chemical associated with ta pe strips 1 and 2 is considered non-penetrating). The application site was incl uded since data demonstrate ongoing depletion of the dose from the application s ite after washing and a corresp onding increase in tissues and excreta over time, which suggests the chemical at th e application site is bioavailable for further skin absorption.

4.3 Toxicological Effects

The effects in the bicyclopyrone hazard database are indicative of inhibition of HPPD. Plasma tyrosine levels were consisten tly elevated in rats, rabbits, an d dogs (levels in mice were not tested). Consistent with these elevated tyrosine levels, ocular effects (cor neal opacity, keratitis)
were observed for subchronic and chronic durations through the oral and dermal routes in rats, which was the most sensitive species tested (minor instances in dogs). There were also increased incidences of thyroid follicular hyperplasi a and a chronic progre ssive nephropathy.

While minor instances of ocular effects where obs erved in dogs; different toxicological effects were generally observed. For subchronic oral exposure, clinical signs (moderate hypoactivity, slightly unsteady gait, increased heart rate, regurgitation, and vomiting) were observed, and clinical pathological indicators of toxicity o ccurred in the eye and the thymus. Following chronic exposure, there was a dose-dependent incr ease in chromatolysis and swelling of selected neurons in the dorsal root ganglia , and degeneration of nerve fibers in the spinal nerve roots in both sexes. In one female dog at the high dose, corneal opacity and light sensitivity were
observed.

Across the database, there were decreased abso lute body weights (the only finding in mice for any duration) and food consumption. There were no signs of immunotoxicity or neurotoxicity in
rodents.

Bicyclopyrone treatment resulted in developmenta l toxicity in both rats and rabbits, and there was an increased quantitative fetal susceptibility in both species tested. In rats, maternal toxicity was not observed up to 1000 mg/kg/day. Fe tal effects occurred at all doses ( ≥ 100 mg/kg/day), and manifested as skeletal variations (increased incidences of full or rudimentary supernumerary ribs, pelvic girdle malpositioned caudal, cost al cartilage 11 long). In New Zealand White rabbits, maternal effects consisted of mortalit y/moribundity in conjunction with minimal food consumption at 200 mg/kg/day. Fetal effects once again occurred at all doses tested ( ≥ 10 mg/kg/day). The sole fetal e ffect at the lowest dose test ed was the appearance of the 27 th 

### presacral vertebrae. There were two studies in Himalayan rabbits. In both studies, maternal effects consisted of macroscopic findings in th e stomach wall and an increased incidence of postimplantation loss at the 250 mg/kg/day dose leve l. In the first study, fetal effects occurred starting at 50 mg/kg/day and cons isted of skeletal variations (increased incidence of the 27 thBicyclopyrone Human Health Risk Assessment D421265

Page 16 of 49 

### prepelvic vertebra and malpositioned pelvic girdle). In the se cond study, the increased quantitative fetal susceptibility was not observed due to a change in the dose selection. Fetal effects occurred at 250 mg/kg/day and consisted of external, visceral, and skeletal abnormalities, and visceral variations, skeletal , bone and cartilage variations. In total, the effects in these
studies are consistent with ot her chemicals in this class.

In the two-generation reproductive study in rats, ocular toxicity o ccurred in parents and offspring and there was no increased offspring susceptibi lity of any kind. Reproductive effects included changes in sperm parameters, and a decrease of precoital interval.

To determine the mechanism for the thyroid hyper plasia observed in the chronic/carcinogenicity study in rats, two mode-of-action st udies were performed. In the in vitro study, bicyclopyrone was negative for thyroid peroxidase inhibition. The results from the in vivo study suggested that the observed thyroid hyperplasia was the result of increased metabolism of thyroid hormones indicated by 1) decreased plasma T 3 

### and T 4 

### levels, 2) increased thyroid follicular cell hypertrophy, 3) increased liver weights associate d, and 4) increased hepatocellular centrilobular hypertrophy and increased hepatic uridine di phosphate glucuronyl transferase (UDPGT)
activities.

Bicyclopyrone is categorized as having low acute lethality via all routes of administration (Categories III and IV). Bicyclopyrone produ ces minimal eye irritation and mild acute inhalation toxicity (Toxi city Category IV).

4.4 Safety Factor for Infants and Children (FQPA SF)

The bicyclopyrone risk assessment team recommends that the 10X FQPA SF be retained in the form of the LOAEL to NOAEL factor for all expos ure scenarios. The toxicology database for bicyclopyrone is adequate for ch aracterizing toxicity and quantification of risk for food and nonfood uses; however, LOAELs from the New Zealand white rabbit developmental and chronic/carcinogenicity rat toxici ty studies have been used as the POD for several scenarios.
There is no evidence of neurotoxic ity in either of the neurotox icity screening batteries, though there are signs in the chronic dog study; the conc ern is low since the study and POD chosen for the chronic dietary exposure scenario is protec tive of these effects. There is evidence of increased quantitative fetal susceptibility following in utero exposure in both rats and rabbits; however, these effects are well ch aracterized and the selected e ndpoints and uncertainty factors are protective of the observed fetal effects. La stly, there are no residua l uncertainties in the exposure database.

4.4.1 Completeness of the Toxicology Database

The toxicology database for bi cyclopyrone is adequate for characterizing toxicity and quantification of risk for food and non-food uses . The following acceptable studies are available for evaluation: developmental toxicity studies in rats and rabbits, a two-generation reproduction study in rats, and acute and subchron ic neurotoxicity studies in rats.

4.4.2 Evidence of Neurotoxicity

There is no evidence of neurotoxicity in the rat in either of the neurotoxicity studies (acute or subchronic neurotoxicity). Both were tested at lower doses (4-20 mg/kg/day) and out to the limit dose or to half the limit dose (~500 – 1000 mg/kg/day) . Signs of neurotoxicity were noted in theBicyclopyrone Human Health Risk Assessment D421265

Page 17 of 49 

### chronic dog study (swelling of the dorsal root ganglion and nerv e fiber degeneration), but the concern is low since the study and POD chosen for the chronic dietary exposure scenario is protective of these effects.

4.4.3 Evidence of Sensitivity/Susceptibility in the Developing or Young Animal

There is evidence of an increased quantitative fetal susceptibility following in utero exposure to bicyclopyrone in both rats and rabbits (see Section 4.3). In al l developmental studies in the bicyclopyrone database, skeletal e ffects and cartilage variations ar e observed at doses below or at those which cause maternal toxicity. The level of concern is low because: (1) the effects are well characterized and (2) the selected endpoints a nd retention of FQPA f actor are protective of
the observed fetal effects.

4.4.4 Residual Uncertainty in the Exposure Database

There are no residual uncertainti es in the exposure database. The dietary assessment does not underestimate exposure. In addition, there are no currently proposed residential uses.

4.5 Toxicity Endpoint and Point of Departure Selections

4.5.1 Dose-Response Assessment

Acute Dietary Endpoint for the Ge neral Population: No endpoint attributable to a single dose and appropriate for the U.S. general populati on was seen in the bicy clopyrone toxicological database (i.e., acute neurotoxicity study); therefore, an acute di etary point of de parture was not established.

Acute Dietary Endpoint for Female s 13-49 Years of Age: The endpoi nt used for establishing the aPAD for females 13-49 years of age was selected from the prenatal developmental toxicity study in New Zealand White rabbits. An aP AD of 0.01 mg/kg/day was derived from a developmental LOAEL of 10 mg/kg/day and a 1000- fold factor that included a 10X for interspecies extrapolations, a 10X for intra- species variations, and a 10X FQPA SF/UF L. 

### The endpoint of concern is a developm ental effect characterized as an increased incidence of a 27 th 

### presacral vertebrate at the developmental LOA EL of 10 mg/kg/day. This endpoint could result from exposure to a single dose and is protective fo r the effects seen at higher doses in the other developmental toxicity studies in rats and rabbits with similar effects.

Chronic Dietary Endpoint for the General Popula tion: The endpoint used for deriving the cPAD was selected from a chronic/carcinogenicity to xicity study in rats. The cPAD, which is 0.00028 mg/kg/day, was derived from a LOAEL of 0.28 mg/kg/day and a 1000- fold factor that included a 10X for inter-species extrapolations, a 10X fo r intra-species varia tions, and a 10X FQPA
SF/UF L 

### . The LOAEL of 0.28 mg/kg/day is based on an increased incidence of opaque eyes and corneal damage in both sexes compared to contro ls, an increased incidence of thyroid follicular hyperplasia in males, and an increased incide nce of chronic progressi ve nephropathy in the kidneys of males. The endpoints of concern were seen following repeated oral exposure in the most sensitive species and are appropriate for assessing potential risk via chronic dietary exposure to bicyclopyrone. They are, thus, appropriate for the duration of exposure and protective of the general population, in cluding women of child-bearing age.

Short- (1-30 days) and Intermediate- (1-6 mont hs) Term Dermal and Inhalation Endpoints: ABicyclopyrone Human Health Risk Assessment D421265

Page 18 of 49 

### dermal toxicity study is available for bicyclopyro ne; however, there is qua ntitative su sceptibility seen in the toxicology database, and the route- specific dermal study did not assess the most sensitive life stage and endpoints in the database, particularly the in utero fetal skeletal effects.
The short- and intermediate-term dermal and inha lation endpoints for worker exposures are thus derived from the developmental New Zealand White rabbit study. The POD is based upon the developmental LOAEL of 10 mg/kg/day. The developmental LOAEL is 10 mg/kg/day based upon an increased incidence of a 27 th 

### presacral vertebrate. The rabbit developmental study is appropriate for the durations of exposure and is protective of the developing fetus of potentially pregnant female workers. The dermal equi valent LOAEL is 48.9 mg/ kg/day (10 mg/kg/day ÷ 20.44 % [dermal absorption factor] = 48.9 mg/kg/da y). The NOAEL for the route-specific 28- day dermal study is 50 mg/kg/day and the LOAE L is 250 mg/kg/day based on ocular lesions (keratitis or degeneration of corneal epithelium). The LOC for both dermal and inhalation exposure scenarios is 1000 based upon a 10X UF for inter-species extrapolations, a 10X UF for intra-species variations and a 10X FQPA SF/UF L 

### . This developmental study protects for the fetal effects, which occur in all four developmental studies in the bicyclopyrone hazard database. It is appropriate for the route as well as the durations of exposure in occupational settings.

4.5.2 Recommendation for Combining Routes of Exposures for Risk Assessment

The PODs for the dermal and inhalation routes are both based on the same prenatal developmental study where effects included skeletal variations; therefore, these routes can be combined into a total exposure.

4.5.3 Cancer Classification and Ri sk Assessment Recommendation

In accordance with the EPA’s Final Guidelines for Carcinogen Risk Assessment (March, 2005), the CARC classified bicyclopyrone as having “Sugge stive Evidence of Carcinogenic Potential.” The CARC considered the following factors in their weight-of-evidence deliberation on assessing the carcinogenic pot ential of bicyclopyrone:

1. The corneal tumors observed in male rats are treatment related and the doses tested were considered to be adequate and not ex cessive for assessing carcinogenicity.

2. The corneal tumors observed in male rats ar e supported by structur e-activity relationship (SAR) data for the HPPD inhibitors pyra sulfotole, tembotrione, and mesotrione.

3. The lung tumors in mice are not considered treatment related.

4. There are no concerns for mu tagenicity or genotoxicity.

Quantification of bicyclopyrone’s carcinogen ic potential is not required. The CARC recommended using a non-linear approach (i.e., reference dose (RfD)) that will adequately account for all chronic toxicity, including carcinogenicity, that c ould result from exposure to bicyclopyrone.

4.5.4 Summary of Points of Departure and T oxicity Endpoints Used in Human Risk
AssessmentBicyclopyrone Human Health Risk Assessment D421265

Page 19 of 49 Table 4.5.4.1. Summary of Toxicological Doses and Endpoints for Bicyclopyrone for Use in Dietary Human
Health Risk Assessments.

Exposure/
Scenario POD Uncertainty/FQPA Safety Factors RfD, PAD,
LOC for Risk
Assessment Study and Toxicological Effects

Acute Dietary (General Population, including
Infants and Children) No endpoint attributable to a single dose and appropriate for the U.S. general population was seen in the bicyclopyrone toxicological database; therefore, an acute dietary point of departure for the general U.S. population was not established.

Acute Dietary (Females 13- 49 years of age) LOAEL =
10 mg/kg/day UF A = 10X

UF H = 10X FQPA SF /UF L = 10X Acute RfD =

0.01 mg/kg/day
aPAD = 0.01 mg/kg/day Prenatal Developmental Study (New Zealand White rabbits) Developmental LOAEL = 10 mg/kg bw based on skeletal variations (the appearance of the 27 th presacral vertebrae).

Chronic Dietary (All Populations) LOAEL =
0.28 mg/kg/day UF A = 10X

UF H = 10X FQPA SF/UF L = 10X Chronic RfD
= 0.00028 mg/kg/day

cPAD =
0.00028 mg/kg/day Carcinogenicity (rat) LOAEL = 0.28/0.35 mg/kg/day (M/F) based on a dose dependent increase in the incidence of opaque eyes and corneal damage in both sexes compared to controls, an increased incidence of thyroid follicular hyperplasia in males, and an
increased incidence of chronic progressive nephropathy in the kidneys of
males.

Cancer (oral, dermal, inhalation) Classification: “Suggestive evidence of cancer” base d on the presence of rare ocular tumors in male rats. Quantification of bicyclopyrone’s car cinogenic potential is not required. The CARC recommended using a non-linear approach (i.e., Rf D) that will adequately account for all chronic toxicity, including carcinogenicity that could result from exposure to bicyclopyrone. Point of departure (POD) = A data point or an estimated point that is derived from observed dose-response data and used to mark the beginning of extrapolation to determine risk associated with lower en vironmentally relevant human exposures. LOAEL = lowest-observed adverse-ef fect level. UF = uncertainty factor. UF A = extrapolation from animal to human (interspecies). UF H = potential variation in sensitivity among members of the human population (intraspecies). UF L = use of a LOAEL to extrapolate a NOAEL. FQPA SF = FQPA Safety Factor. PAD = population-adjusted dose (a = acute, c = chronic). RfD = reference dose.Bicyclopyrone Human Health Risk Assessment D421265

Page 20 of 49 Table 4.5.4.2. Summary of Toxicological Doses and Endpoints for Bicyclopyrone for Use in Occupational
Human Health Risk Assessments.
Exposure/
Scenario POD Uncertainty

Factors LOC for Risk

Assessment Study and Toxicological Effects

Dermal Short- (1-30 days)
and
IntermediateTerm (1-6 months) LOAEL =
10 mg/kg/day

DAF =
20.44% 1 UF A = 10X

UF H = 10X

UF L = 10X Occupational LOC
for MOE = 1000 Prenatal Developmental Study (New Zealand White rabbits) Developmental LOAEL = 10 mg/kg bw based on skeletal variations (the appearance of the 27 th presacral vertebrae).

Inhalation Short- (1-30 days) and
IntermediateTerm (1-6 months) LOAEL =
10 mg/kg/day UF A = 10X

UF H = 10X

UF L = 10X Occupational LOC
for MOE = 1000 Prenatal Developmental Study (New Zealand White rabbits) Developmental LOAEL = 10 mg/kg bw based on skeletal variations (the appearance of the 27 th presacral vertebrae).

Cancer (oral, dermal, inhalation) Classification: “Suggestive evidence of cancer” base d on the presence of rare ocular tumors in male rats. Quantification of bicyclopyrone’s car cinogenic potential is not required. The CARC recommended using a non-linear approach (i.e ., RfD) that will adequately account for all chronic toxicity, including carcinogenicity that could result from exposure to bicyclopyrone. Point of departure (POD) = A data point or an estimated point that is derived from observed dose-response data and used to mark the beginning of extrapolation to determine risk associated with lower en vironmentally relevant human exposures. LOAEL = lowest-observed adverse-ef fect level. UF = uncertainty factor. UF A = extrapolation from animal to human (interspecies). UF H = potential variation in sensitivity among members of the human population (intraspecies). UF L = use of a LOAEL to extrapolate a NOAEL. MOE = margin of exposure. LOC = level of

concern.

1 Dermal-absorption factor derived from MRID 47842239.



### 5.0 Dietary Exposure and Risk Assessment D409546, G. Kramer, 10-MAR-2015 (residue chemistry summary for the current action) D421267, G. Kramer, 10-MAR-2015 (dietary exposure analysis for the current action)



### 5.1 Metabolite/Degradate Residue Profile

5.1.1 Summary of Plant and Animal Metabolism Studies

The metabolism of bicyclopyrone in plants (rota tional crops, corn, and sugarcane) and animals (goat, hen, and rat) is qualitat ively similar, although much mo re extensive in plants (see Appendix B). In plants, bicyclopy rone was generally absent. The majority of the residue was comprised of metabolites formed by hydroxylation on one or more sites on the bicyclic ring or demethylation of the methoxyethoxymethyl si de chain followed by hydroxylation. Some conjugation to glycosides was observed with the hydroxyl derivatives and some cleavage between the two ring systems was also observed. In animals, bicycl opyrone was the major component of the residue. The primary metabol ic processes observed in clude demethylation of the methoxyethoxymethyl side chai n, hydroxylation on one or more sites of the bicyclooctenone ring, a minor amount of bridge cl eavage between the rings, and c onjugation to some extent.

5.1.2 Summary of Environmental Degradation

Microbial degradation in aerobic soil and photodeg radation in soil are likely to be the main environmental fate pathways by which the com pound transforms. Major transformation products of bicyclopyrone include: CSCC163768 [6-(tri fluoromethyl)pyridine-2,3-dicarboxylic acid], SYN503780, CSCD656832 [3-hydroxy- 6-(trifluoromethyl)pyr idine-2-carboxylic acid] CSCD642512 [2-[[3-(2,4-dioxobicyclo[3.2.1]octa ne-3-carbonyl)-6-(tri fluoromethyl)-2-Bicyclopyrone Human Health Risk Assessment D421265

Page 21 of 49 

### pyridyl]methoxy]acetic acid], CSAA589691 [(1S,3R)-cyc lopentane-1,3-dicarboxylic acid], and carbon dioxide. Minor transformation products of bicyclopyrone include: CSAA806573 (2- hydroxymethyl-6-trifluoromethyl-nicotinic acid) and CSAA915194 [4-hydroxy-3-[2-(2-hydroxyethoxymethyl)-6-trifluoromethyl-pyridine-3- carbonyl]-bicyclo[3.2.1]oct-3-en-2-one].

5.1.3 Comparison of Metabolic Pathways

The metabolism of bicyclopyrone in plants and animal s is qualitatively similar. The majority of the residue was comprised of metabolites form ed by hydroxylation on one or more sites on the bicyclic ring or demethylation of the methoxyethoxymethyl side chain followed by hydroxylation. The environmental fate pathways proceed via successive oxidation of the pyridinyl 2-methoxyethoxymethyl group and cleavage of the pyr idinyl and bicyclooctenone rings.

5.1.4 Residues of Concern Summary and Rationale

The Residues of Concern Knowledgebase S ubcommittee (ROCKS) me t on July 31, 2014 to discuss the residues of concern for bicyclopyrone in plant, livestock commodities, and drinking water. The proposed enforcement method for plant and livestock commodities converts the major residues (i.e., bicyclopyrone , CSAA915194, CSCD67 5162, CSCD677306, CSCD677692, CSCD677694, CSCD677693, CSCD675164, and CS CD686480) to one of two common moieties. The residues measured in the enforcement method for bicyclopyrone account for all the residues of concern (ROC) in plant and li vestock commodities; therefore, the ROC for tolerance assessment and dietary risk assessmen t is the sum of bicycl opyrone and its common moieties, SYN503780 and CSCD686480, calculated as the stoichiometric equivalent of bicyclopyrone.

The ROC for drinking water is the parent, bicyclopyrone. The si ngle-ring degradates (CSCC163768, CSCD656832, CSAA589691, and SYN503780) are not considered residues of toxicity concern due to the absence of the diketone enol moiety associated with the toxicity of bicyclopyrone. In addition, ther e is no specific toxicological c oncern associated with their structure. The degradate, CSCD642512, was obs erved in major quantities in soil aerobic metabolism; however, terrestrial field dissipatio n studies show its presence at low relative amounts. Based on the low exposure expected for CSCD642512 and the absence of additional toxicological concern with resp ect to parent, it is excluded as a ROC in drinking water.

Table 5.1.4. Summary of Metabolites and Degradates to be Included in the Risk Assessment and Tolerance Expression.

Matrix Residues Included in Risk

Assessment Residues Included in Tolerance Expression

Plants Primary Crop Bicyclopyrone and its structurally
related metabolites determined as
the common moieties SYN503780
and CSCD686480 Bicyclopyrone and its structurally
related metabolites determined as the
common moieties SYN503780 and

CSCD686480 Rotational Crop

Livestock Ruminant Poultry Drinking Water Bicyclopyrone Not Applicable SYN503780 = 2-[(2-methoxyetho xy)methyl]-6-(trifluoromethy l)-3-pyridinecarboxylic acid. CSCD686480 = 2-[(2-hydroxyethoxy )methyl]-6-(trifluoromethyl)-3 -pyridinecarboxylic acid.Bicyclopyrone Human Health Risk Assessment D421265

Page 22 of 49 

### 5.2 Food Residue Profile

Crop field trials with bicyclopyrone were conducted according to the proposed label directions in
the U.S. with corn and in Australia and Brazil wi th sugarcane. In all sugarcane and field corn grain samples, residues were below the LOQ. Qu antifiable residues were found in the other corn RACs; recommended tolerance levels were obtai ned using the OECD calculation procedures. As no significant concentration wa s observed in any processed frac tion in the corn and sugarcane processing studies, separate tolerances for residues in processed corn and sugarcane commodities will not be required. Limited field rotational crop studies showed that quantifiable residues are not expected at the minimum proposed PBIs. In the ruminant feeding study, residues were found only in kidney and liver with re sidue levels in these matrices not linearly related to the dose administered. The appropriate tolerance levels for meat byproducts were based on the tissue-tofeed ratio calculated from the dose closest to maximum dietary burde ns. All residue study results are supported by adequa te storage stability data.

5.3 Drinking Water Residue Profile

Drinking water residues pr ovided by EFED (Memo, C. Su tton, 30-SEP-2014; D421261) were incorporated directly into the acute and chronic dietary analyses as “water, direct, all sources” and “water, indirect, all sources.” The Su rface Water Concentrati on Calculator (SWCC) computer model was used to generate surface water Estimated Drinking Water Concentrations (EDWCs) for use in the human h ealth dietary risk assessment, while the Pesticide Root Zone Model for Groundwater (PRZM-GW) and the Scr eening Concentration in Ground Water (SCIGROW) models were used to generate groundwater EDWCs. As noted above, the ROC was determined to be parent bicyclopyrone only. The maximum acute and chronic surface water EDWCs associated with bicyclopy rone use on corn were 2.87 and 0.857 μg/L, respectively. For groundwater sources of drinking water, th e maximum acute and chronic EDWCs of bicyclopyrone in sha llow groundwater from PR ZM-GW were 3.76 and 3.23 μ g/L, respectively. These values represent 30 years of use at the maximum label rate for corn. While there were higher values associated with another scenario (Florida citr us) and with a longer simulation period (100 years, WI corn), the recommended valu es are representative of the proposed use on corn and correspond to an area (DE, MD, VA areas) in which corn is grown in the U.S. EDWCs of 0.00376 ppm and 0.00323 ppm were used in the acu te and chronic anal yses, respectively.

Table 5.3.1. Maximum EDWCs for Bicyclopyrone Use on Corn.

Drinking Water Source (Model Used) Use (rate modeled) Maximum EDWC

Acute (μg/L) Chronic (μg/L)

Surface water (SWCC; ND corn scenario) Corn 0.045 lbs ai/./A x 1 (0.05 kg/ha) 2.87 0.857

Groundwater (PRZM-GW) Corn 0.045 lbs ai/./A x 1 (0.05 kg/ha) 3.76 1 3.23

Groundwater (SCI-GROW) Corn 0.045 lbs ai/./A x 1 (0.05 kg/ha) 1.32 1.32

1 Values in bold are recommended for use in the human health risk assessment.



### 5.4 Dietary (Food + Drinking Water) Risk Assessment

For acute and chronic assessments, HED is con cerned when dietary risk exceeds 100% of the PAD. The DEEM-FCID analyses estimate the di etary exposure of the general U.S. population and various population subgroups. The results re ported in Table 5.4.1 are for the general U.S.Bicyclopyrone Human Health Risk Assessment D421265

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### population, all infants (<1 year old), children 1- 2 years old, children 3-5 years old, children 6-12 years old, youth 13-19 years old, females 13-49 year s old, adults 20-49 year s old, and adults 50- 99 years old.

The unrefined acute analysis assumed tolera nce-level residues for all commodities and 100% CT. Processing factors were set to "1" for all included commodities, based on empirical data that demonstrates that bicyclopyrone residues do not c oncentrate in corn or sugarcane commodities. The acute analysis also incorporated the most recent drinking water estimates provided by
EFED. There were no effects attributable to a single (i.e., acute) exposure for all populations excluding females 13-49 years old; therefore, an acute dietary assessment was only conducted for females 13-49 years old. The acute dietary risk estimate (food + drinking water) at the 95 th 

### percentile was 2.9% of the aPAD for the female s 13 to 49 years old population subgroup, and is thus below HED’s LOC (<100% aPAD).

The partially refined chronic analysis assumed average field trial residues for crops, tolerancelevel residues for livestock commodities, and 100% CT. Processing factors were set to "1" for all commodities, based on empirical data that de monstrates that bicyclopyrone residues do not concentrate in corn or sugarcane commodities. Th e chronic analysis also incorporated the most recent drinking water estimates provided by EFED . The resulting chronic risk estimates are below HED’s LOC (<100% of the cPAD) for th e general U.S. population and all population subgroups. The population subgroup with the grea test exposure and risk estimate was children 1-2 years old, which utilized 91% of the cPAD.

Table 5.4.1. Summary of Dietary (Food and Drinki ng Water) Exposure and Ri sk for Bicyclopyrone.

Population Subgroup Acute Dietary (95 th Percentile) Chronic Dietary

cPAD (mg/kg/day) Exposure (mg/kg/day) %cPAD aPAD (mg/kg/day) Dietary Exposure (mg/kg/day) % aPAD

General U.S. Population

N/A N/A N/A 0.00028 0.000123 44 All Infants (<1 year old) 0.000233 83 Children 1-2 years old* 0.000255 91 Children 3-5 years old 0.000223 80 Children 6-12 years old 0.000159 57 Youth 13-19 years old 0.000100 36 Adults 20-49 years old 0.000111 40 Adults 50-99 years old 0.000104 37 Females 13-49 years old* 0.01 0.000290 2.9 0.000105 37

* The populations with the greate st risk estimates are bolded.



### 6.0 Residential (Non-Occupational) Exposure/Risk Characterization

There are no currently proposed bicyclopyrone uses that result in residential (non-occupational) exposure. Therefore, residential handler and pos t-application exposure/ri sks were not assessed.

6.1 Spray Drift

Spray drift is a potential source of exposure to those nearby pest icide applications. This is particularly the case with aerial application, but, to a lesser exte nt, spray drift can also be a potential source of exposure from the ground application methods (e.g., groundboom and airblast) employed for bicyclopyrone. The agency has been working with the Spray Drift TaskBicyclopyrone Human Health Risk Assessment D421265

Page 24 of 49 

### Force (a task force composed of various regist rants which was developed as a result of a Data Call-In issued by EPA), EPA Regi onal Offices and State Lead Agencies for pesticide regulation and other parties to develop the best spray drif t management practices (see the agency’s Spray Drift website for more information). 1 

### The agency has also developed a policy on how to appropriately consider spray drif t as a potential source of expo sure in risk assessments for pesticides. The potential for spray drift will be quantitatively evaluated for each pesticide during
the Registration Review process, which ensures that all uses fo r that pesticide will be considered concurrently. The approach is outlined in the revised (2012) Standard Operating Procedures For Residential Risk Assessment (SOPs) - Resi dential Exposure Asse ssment Standard Operating Procedures Addenda 1: Consideration of Spray Drift. This document outlines the quantification of indirect non-occupati onal exposure to drift.

6.2 Residential Bystander Post-Application Inhalation Exposure

Volatilization of pes ticides may be a source of post-ap plication inhala tion exposure to individuals nearby pesticide app lications. The agency sought expert advice and input on issues
related to volatilization of pesticides from its Federal Insec ticide, Fungicide, and Rodenticide Act (FIFRA) Scientific Advisory Pa nel (SAP) in December 2009, and received the SAP’s final report on March 2, 2010 (http://www.epa.gov/scipoly/SA P/meetings/2009/120109meeting.html). The agency has evaluated the SAP report and has de veloped a Volatilization Screening Tool and a subsequent Volatilization Screening Analysis (http://www.regulations.gov/#! docketDetail;D=EPA-HQ-OPP-2014- 0219). During Registration Review, the agency will utilize this analysis to determine if data (i.e., fl ux studies, route-specific inhalation toxicological studies ) or further analysis is required for bicyclopyrone.

7.0 Aggregate Exposure/Risk Characterization

In accordance with FQPA, HED must consider and aggregate pesticide exposures and risks from three major sources: food, drinking water, and resi dential exposures. Becau se there are no uses for bicyclopyrone that result in residentia l (non-occupational) e xposures, the aggregate assessment need only consider food and water. Since the dietary expos ure analysis included both food and water, the discussion and exposure estimates presented in Section 5.4 represent aggregate acute and chronic exposure to bicy clopyrone. All aggreg ate bicyclopyrone risk
estimates are not of concern to HED.

8.0 Cumulative Exposure/Ri sk Characterization

The Hazard and Science Policy Council (HASPOC) met on June 28, 2007 to discuss the mode of
action and human relevance of HP PD inhibiting herbicides. The following is a summary of their decision regarding the need for a cumulativ e risk assessment (HASPOC Memo, 17-DEC-2007).

There are marked differences among species in the ocular toxicity associat ed with inhibition of HPPD. Ocular effects following tr eatment with HPPD inhibitor herb icides are seen in the rat but not in the mouse. Monkeys also seem to be reca lcitrant to the ocular toxicity induced by HPPD inhibition. One explanation for th is species-specific response in oc ular opacity may be related to species differences in the clearance of tyrosine. A metabolic pathway exists to remove tyrosine from the blood that involves the liver enzyme tyrosi ne aminotransferase (TAT). In contrast to rats where ocular toxicity is observed followi ng exposure to HPPD-inhibiting herbicides, mice

1 Available: http://www.epa.gov/opp00001/factsheets/spraydrift.htmBicyclopyrone Human Health Risk Assessment D421265

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### and humans are unlikely to achieve the levels of plasma tyrosine necessary to produce ocular opacities because the activity of TAT in these species is much greater compared to rats.

HPPD inhibitors (e.g., nitisinone) are used as an effective therapeutic agent to treat patients suffering from rare genetic diseases of tyrosine catabolism. Treatment st arts in childhood but is often sustained throughout patient’s lifetime. Th e human experience indicat es that a therapeutic dose (1 mg/kg/day dose) of nitisinone has an excellent safety record in infants, children, and
adults and that serious advers e health outcomes have not been observed in a population followed for approximately a decade. Rarely, ocular effect s are seen in patients with high plasma tyrosine levels; however, these effects are transient and can be readily reversed upon adherence to a restricted protein diet. This observation indicates that an HPPD inhibitor in it and of itself cannot easily overwhelm the tyrosine -clearance mechanism in humans.

Therefore, exposures to environmental residues of HPPD-inhibiting herbicides are unlikely to result in the high blood levels of tyrosine and ocular toxicity in humans due to an efficient metabolic process to handle excess tyrosine. The Agency continues to study the complex relationships between elevated tyro sine levels and biologi cal effects in various species. In the future, assessments of HPPD-inhibiting herbicides may consider more appropriate models and cross species extrapolation methods. Theref ore, EPA has not conducted cumulative risk
assessment with other HPPD inhibitors.

9.0 Occupational Exposure/ Risk Characterization D421266, K. Lowe, 04-MAR-2015



### Based on the proposed new uses, it has been dete rmined that the potential exposure scenarios
that will need to be assessed include short- and intermediate-term occupational exposures (handler and post-application).

It is HED policy to use the best available data to assess exposure. In the absence of chemicalspecific data for bicyclopyrone, several sources of generic data were used in this assessment including PHED 1.1, the AHETF database, and the ARTF database. Some of these data are proprietary and subject to the da ta protection provisions of FI FRA. Additional information on HED policy on use of surrogate data, including de scriptions of the various sources, can be found at the Agency website (http://www.epa.gov/pestic ides/science/handler-exposure-data.html).

9.1 Handler Risk Assessment

HED uses the term handlers to describe those individuals who are invo lved in the pesticide application process. Based on the anticipated use patterns, and the current labeling regarding types of equipment and techniques that can be us ed, occupational handler exposure is expected. The quantitative exposure/risk a ssessment developed for occupati onal handlers is based on the following scenarios: (1) mixing/loading liqui ds for groundboom applicat ions, and (2) applying sprays via groundboom equipment. Dermal and inha lation risk estimates we re combined in this assessment, since the regulatory endpoints for as sessing these routes of exposure are identical.

The occupational handler exposure a nd risk estimates indicate that the short- and intermediateterm dermal and inhalation combined MOEs are not of concern to HED (i.e., MOE ≥ 1000) with baseline attire (i.e., single layer of clothing, no gloves, and no respirator; all MOEs ≥ 1,700). Table 9.1.1 is a summary of the handler exposure and risk estimates.Bicyclopyrone Human Health Risk Assessment D421265Page 26 of 49Table 9.1.1. Occupational Handler Non-Cancer Exposure and RiskEstimates for Bicyclopyrone.Exposure Scenario Crop or TargetDermal UnitExposure(μg/lb ai)1Inhalation UnitExposure(μg/lb ai)1MaximumApplicationRate (lbai/A)2AreaTreated(acres)3Dermal(LOC = 1000)Inhalation(LOC = 1000)Total(LOC =1000)Mitigation LevelMitigationLevelDose(mg/kg/day)4MOE5Dose(mg/kg/day)6MOE7MOE8Mixer/LoaderGroundboom application ofliquid formulationCorn 220 (baseline)0.219(baseline)0.044 80 0.00575 1,700 0.000028 360,000 1,700ApplicatorGroundboom sprayapplicationCorn78.6(baseline)0.34(baseline)0.044 80 0.00205 4,900 0.0000433 230,0004,8001 Based on the “Occupational Pesticide HandlerUnit Exposure Surrogate Reference Table”(March 2013); Level of mitigation: Baseline.2Based on proposed labels (SYN-A16003 Herbicide [100-RUAL] and SYN-A19707 [100-RUAA]).3 Exposure Science Advisory Council Policy #9.4 Dermal Dose = Dermal Unit Exposure (μg/lb ai) × Conversion Factor (0.001 mg/μg) × Application Rate (lb ai/acre) × Area Treated (A/day) × DAF (20.44 %) ÷ BW (69 kg).5 Dermal MOE = Dermal LOAEL (10 mg/kg/day) ÷ DermalDose (mg/kg/day).6 Inhalation Dose = Inhalation Unit Exposure (μg/lb ai) × Conversion Factor (0.001 mg/μg) × Application Rate (lb ai/acre) × Area Treated (A/day) ÷ BW (69 kg).7 Inhalation MOE = Inhalation LOAEL (10 mg/kg/day) ÷ Inhalation Dose (mg/kg/day).8 Total MOE = LOAEL (10 mg/kg/day)÷ (Dermal Dose + Inhalation Dose).Bicyclopyrone Human Health Risk Assessment D421265

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### 9.2 Post-Application Risk Assessment

HED uses the term post-application to describe exposures (inhalation and dermal) that occur when individuals are present in an environment th at has been previously treated with a pesticide (also referred to as re-entry exposure). Such exposures may occur when workers enter previously treated areas to pe rform job functions, including ac tivities related to crop production, such as scouting for pests or harvesting. Post -application exposure levels vary over time and depend on such things as the type of activity, the na ture of the crop or targ et that was treated, the type of pesticide application, and the chemical’s degradation properties. In addition, the timing of pesticide applications, relative to harvest act ivities, can greatly reduce the potential for postapplication exposure.

9.2.1 Inhalation Post-Application Risk Assessment

There are multiple potential sources of post-app lication inhalation exposure to individuals performing post-applicati on activities in previously treated fields. These potential sources
include volatilization of pesticides and resuspension of dusts and/or particulat es that contain pesticides. The agency sought expert advice an d input on issues relate d to volatilization of pesticides from its FIFRA SAP in December 2009, a nd received the SAP’s final report on March 2, 2010 (http://www.epa.gov/scipoly/SAP/meetings /2009/120109meeting.html). The agency has evaluated the SAP report and has developed a Vo latilization Screening Tool and a subsequent Volatilization Screening Anal ysis (http://www.regulations .gov/#!docketDetail;D=EPA-HQOPP-2014-0219). During Registration Review, the agen cy will utilize this analysis to determine if data (i.e., flux studies, route-specific inhalation toxicological studies) or further analysis is required for bicyclopyrone.

In addition, the Agency is continuing to eval uate the available post- application inhalation exposure data generated by the ARTF. Given thes e two efforts, the Agency will continue to identify the need for and, subsequently, the wa y to incorporate occupational post-application inhalation exposure into the ag ency's risk assessments.

Although a quantitative occupational post-applic ation inhalation exposure assessment was not performed, an inhalation exposure assessment was performed for occupational/commercial handlers. Handler exposure resultin g from application of pesticides outdoors is likely to result in higher exposure than post -application exposure. Therefore, it is expect ed that these handler inhalation exposure estimates would be protec tive of most occupatio nal post-application inhalation exposure scenarios.

9.2.2 Dermal Post-Applicat ion Risk Assessment

Short- and intermediate post-ap plication dermal exposure is an ticipated for the proposed crops with expected scenarios and resulting exposur es and MOEs summarized in Table 9.2.2.1. All scenarios resulted in MOEs greater than the LOC of 1000 (ranging from 1,800 to 49,000) on day 0 (12 hours after application; proposed REI) and, therefore, are not of concern to HED.Bicyclopyrone Human Health Risk Assessment D421265

Page 28 of 49 Table 9.2.2.1. Occupational Post-application Non-Cancer Exposure and Risk Estimates for Bicyclopyrone.

Crop/Site Activities Transfer Coefficient (cm 2 /hr) Proposed Application Rate (lb ai/A) DFR 1 Dermal Dose (mg/kg/day) 2 MOE 3 (LOC =

1000)

Corn Hand weeding 70

0.044 0.12 0.0002 49,000

Scouting 210 0.001 16,000

Irrigation (hand set) 1,900 0.006 1,800

1 DFR = Application Rate × F × (1-D) t × 4.54E8 μg/lb × 2.47E-8 acre/cm 2 ; where F = 0.25 and D = 0.10 per day. 2 Daily Dermal Dose = [DFR (μg/cm 2 ) × Transfer Coefficient × 0.001 mg/μg × 8 hrs/day × dermal absorption (20.44%)]  BW (69 kg). 3 MOE = POD (10 mg/kg/day) / Daily Dermal Dose.



### In accordance with 40 CFR 158, dislodgeable-foliar residue (DFR) data are required for all occupational (e.g., crop, nursery, gr eenhouse use sites) or reside ntial (e.g., ornamental and vegetable gardens, pick your own farms, retail tree farms) uses that could result in postapplication exposure to foliage. In the absence of chemical-specific DFR data, EPA uses default
values. The 2012 Standard Operating Procedures for Residential Pesticide Exposure

Assessment includes an analysis of a number of DFR st udies, which resulted in the selection of a revised default values for the fraction of the appl ication rate available fo r transfer after a foliar application (F AR 

### ). These values are based on an analysis of 19 DFR studies. Since that time, the ARTF has submitted information (MRID 49299201) that corrects an application rate error made in the original submission of “ARF039 – Determ ination of Dermal and Inhalation Exposure to Reentry Workers During Chrysanthemum Pi nching in a Greenhouse” (EPA MRID 45344501). As a result, the range of F AR 

### values was revised from 2-89% to 2-7%. In these data, a large range of transferability is observed and this vari ability can potentially be attributable to many factors such as active ingredient, formulation, fi eld conditions in the studies, weather conditions (e.g., humidity), and many other difficult-to-qu antify factors. A lthough witnessed across multiple chemicals, this range in F AR 

### values is not expected when considering DFR data for a single chemical. At this time, the ARTF submis sion did not alter the se lection of 25% as the reasonable, high-end default value. Because DF R data are not available for bicyclopyrone, EPA is using the default value of 25%. Although there may be a sma ll degree of uncertainty in the use of the default DFR value for bicyclopyrone (i.e., there is a small chance that the F AR 

### value may exceed the applicable default value), it is lik ely that the health-protective aspects of EPA’s occupational post-application assessment meth odology will more than compensate for this potential uncertainty. For example, when assess ing residential and occupational post-application exposure to gardens and ornamentals, EPA assume s the following: exposures occur to zero-day (i.e., day of application ) residue s every day of the assessed e xposure duration (i.e., EPA assumes that no dissipation or degradation occurs, it doesn ’t rain, etc); individuals perform the same postapplication activities pe rformed in the transfer coeffici ent study day after day (e.g., weeding, harvesting, pruning, etc.); and indi viduals engage in these post-a pplication activit ies for a highend amount of time every day (represented by da ta reflecting time spent gardening based on survey data).

Given the conservatisms discussed above a nd the potential compounding nature of these conservatisms, EPA is able to re ly upon the calculated exposure estimates with confidence that exposure is not being underestimated. Since th e highest estimated occupational post-application exposure using default DFR values for bicyclopyr one is not minimal in comparison to the LOC (i.e., the calculated MOE is not greater than two times hi gher than the LOC, MOE = 1,800Bicyclopyrone Human Health Risk Assessment D421265

Page 29 of 49 

### compared to the LOC of 1000); EPA is requir ing the 40 CFR DFR data to facilitate any necessary exposure assessments refinements and to further EPA’s genera l understanding of the availability of dislodgeable foliar pesticide residues.

9.2.3 Restricted Entry Interval

The REI specified on the proposed label is base d on the acute toxicity of bicyclopyrone. Bicyclopyrone has low acute toxicity via the oral, dermal and inha lation routes (Toxicity Category IV). It is not an eye or dermal irritant (Toxicity Cate gory IV), and was not shown to be
a skin sensitizer. Short- and intermediate-term post-application risk esti mates were not a concern on day 0 (12 hours following application) for all post-application activities. Under 40 CFR 156.208 (c) (2) (iii), ai’s classified as Acute III or IV for acute dermal, eye irritation and primary skin irrigation are assigned a 12-hour REI. Th erefore, the [156 subpart K] Worker Protection Statement interim REI of 12 hours is adequate to protect agricultural workers from postapplication exposures to bicyclopy rone. The 12-hour REI, which currently appears on one of the proposed labels, is adequate for the proposed uses of bicyclopyr one. One of the labels has a longer REI of 24 hours, but has multiple active ingr edients. Longer REIs may be necessary for the other active ingredients in the product and would be addresse d in the risk assessments for those active ingredients.

Appendix A. Toxicology Profile and Executive Summaries Appendix B. Metabolism Summary Table Appendix C. Physical/Chemical Properties of Bicyclopyrone Appendix D. Review of Human Research

RDI: RAB1 (15-OCT-2014) Kelly Lowe:S10947:Potomac Yard 1:703-347-8989:7509P:RAB1Bicyclopyrone Human Health Risk Assessment D421265

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### Appendix A. Toxicology Prof ile and Executive Summaries

The requirements (40 CFR 158.340) for food and non- food uses for bicyclopyrone are in Table A.1. Use of the new guideline numbers does not imply that the new (1998) guideline protocols
were used.

Table A.1. Toxicological Data Requirements for Bicyclopyrone.

Study Technical Required Satisfied 870.1100 Acute Oral Toxicity 870.1200 Acute Dermal Toxicity 870.1300 Acute Inhalation Toxicity 870.2400 Primary Eye Irritation 870.2500 Primary Dermal Irritation
870.2600 Dermal Sensitization yes

yes

yes

yes

yes

yes yes

yes

yes

yes

yes

yes 870.3100 Oral Subchronic (rodent) 870.3150 Oral Subchronic (nonrodent) 870.3200 21-Day Dermal 870.3250 90-Day Dermal 870.3465 90-Day Inhalation yes

yes

yes

yes

no 1 yes

yes

yes

yes

- 870.3700a Developmental Toxicity (rodent) 870.3700b Developmental Toxicity (nonrodent) 870.3800 Reproduction yes

yes

yes yes

yes

yes 870.4100a Chronic Toxicity (rodent) 870.4100b Chronic Toxicity (nonrodent) 870.4200a Oncogenicity (rat) 870.4200b Oncogenicity (mouse) 870.4300 Chronic/Oncogenicity (rat) yes

yes

yes

yes

yes yes

yes

yes

yes

yes 870.5100 Mutagenicity—Gene Mutation - bacterial 870.5100 Mutagenicity—Gene Reverse Mutation - bacterial 870.5300 Mutagenicity—Gene Mutation - mammalian 870. 5395 Mutagenicity—Micronucleus Assay in Bone Marrow 870. 5550 Mutagenicity—Unscheduled DNA Synthesis yes

yes

yes

yes

yes yes

yes

yes

yes

yes 870.6100a Acute Delayed Neurotoxicity (hen) 870.6100b 90-Day Neurotoxicity (hen) 870.6200a Acute Neurotoxicity Screening Battery (rat) 870.6200b 90-Day Neurotoxicity Screening Battery (rat) 870.6300 Develop. Neurotoxicity no

no

yes

yes

no 1 no

no

yes

yes

- 870.7485 General Metabolism
870.7600 Dermal Penetration 870.7800 Immunotoxicity yes

yes

yes yes

yes

yes 1 Studies are not required at this time based upon weight of evidence decisions by the HASPOC. Decisions are
discussed in detail in TXR#s 0056613 and 0056911

Table A.2.1. Acute Toxicity Profile - Bicyclopyrone.

Guideline

No. Study Type MRID Results Toxicity Category 870.1100 Acute oral [rat] 47841966 LD 50 females >5000 mg/kg bw (94.5% ai) IV 870.1200 Acute dermal [rat] 47841967 LD 50 (Combined) >5000 mg/kg (94.5% ai) IV 870.1300 Acute inhalation [rat] 47841968 LC 50 (Combined) >5.2 mg/L (94.5% ai) IV

870.2400 Acute eye irritation [rabbit] 47841970 Based on the mean degr ee of eye irritation, no require classification. IVBicyclopyrone Human Health Risk Assessment D421265

Page 31 of 49 Table A.2.1. Acute Toxicity Profile - Bicyclopyrone.

Guideline

No. Study Type MRID Results Toxicity Category

870.2500 Acute dermal irritation [rabbit] 47841969 No dermal irritation was observed. IV

870.2600 Skin sensitization [mice] 47841971 No dermal sensitization response in mice -

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

Guideline

No. Study Type MRID No. (year)/
Classification/Doses Results

870.3100 14-Day oral rangefinding toxicity (rat) 47841988 (2012) acceptable/non- guideline 0, 0.5 , 1, 2.5, 5, or 10

ppm (Actual test item intake/body weight/day was not calculated by the registrant) NOAEL = 10 ppm. LOAEL was not observed. Plasma tyrosine and bicyclopyrone concentrations were
elevated.

870.3150 28-Day oral toxicity (dog) 47841973 (2012) acceptable/non- guideline 0, 10, 100, and 250 mg/kg/day [M/F] (one M/F per sex, per dose) NOAEL = 100 mg/kg/day. LOAEL = 250 mg/kg/day based upon clinical signs (moderate hypoactivity, slightly unsteady gait, increased heart rate, regurgitation and vomiting), bodyweight loss and reduced food consumption for one male on day 7. Various clinical pathology parame ters were affected (a moderate retinopathy characterized by fluid effusion in the outer choroid of one eye, swelling and vacuolation of the retinal pigment epithelium, minimal inflammatory cell infiltration at the choroidal/retinal junction and partial retinal detachment. In addition there were reduced cortical lymphocytes in the thymus), and urine phenolic acid concentrations and plasma tyrosine and bicyclopyrone
concentrations were elevated.
Note: The 250-mg/kg/day dose group was terminated early because the highest dose tested
was considered to be in excess of the maximum
tolerable dose.

870.3100 90-Day oral toxicity (mouse) 47842172 (2012) acceptable/guideline 0, 100, 3500 and 7000 ppm (0, 15.4/20.8, 542.6/808.5, and 1127.4/1343.5 mg/kg/day [M/F]) NOAEL = 7000 ppm (1127.4/1343.5 mg/kg/day [M/F]).
LOAEL was not observed.

870.3100 90-Day oral toxicity (rat) 47841975 (2012) acceptable/guideline 0, 2.5, 10, 2500, and 5000

ppm M: 0, 0.18/0.22, 0.72/0.88, 183.07/228.8, and 363.12/442.3 [M/F]) mg/kg/day NOAEL = 0.72/0.88 mg/kg/day [M/F]. LOAEL = 183.07/228.82 mg/kg/day based upon an increased incidence of eye opacity in both sexes, decreased absolute body weights and food consumption in males, and an
increased incidence of ocular keratitis in both

sexes.Bicyclopyrone Human Health Risk Assessment D421265

Page 32 of 49 Table A.2.2. Subchronic, Chronic and Other Toxicity Profile.

Guideline

No. Study Type MRID No. (year)/
Classification/Doses Results

870.3150 90-Day oral toxicity (dog) 47841976 (2012) acceptable/guideline 0, 5, 25, 125 mg/kg/day [M/F] NOAEL = 125 mg/kg/day.
LOAEL was not observed.

870.3200 28-Day dermal toxicity (rat) 47841978 (2012) acceptable/guideline 0, 50, 250, 1000 mg/kg/day [M/F] NOAEL = 50 mg/kg/day. LOAEL = 250 mg/kg/day based on ocular keratitis in two males (moderate severity).

870.3700a Prenatal developmental (rats) 47841993 (2012) acceptable/guideline 0, 100, 500, 1000 mg/kg/day [F] Maternal NOAEL = 1000 mg/kg bw.
The maternal LOAEL was not observed. Developmental NOAEL was not observed. LOAEL = 100 mg/kg bw various skeletal variations (increased incidences of full or rudimentary supernumerary ribs, pelvic girdle malpositioned caudal, costal cartilage 11 long).

870.3700b Prenatal developmental (New
Zealand White rabbits) 47841996 (2012) acceptable/guideline 0, 10, 50, and 200 mg/kg/day [F] Materna l NOAEL = 50 mg/kg bw. LOAEL = 200 mg/kg bw based on mortality/moribundity in conjunction with minimal food consumption and effects on body weight changes. Developmenta l NOAEL was not observed. LOAEL = 10 mg/kg bw based on skeletal variations (the appearance of the 27 th presacral vertebrae).

870.3700b Prenatal developmental (Himalayan rabbits) 47841998 (2012) acceptable/guideline 0, 10, 50, and 250 mg/kg/day [F] Materna l NOAEL = 50 mg/kg bw. LOAEL = 250 mg/kg bw based upon macroscopic findings in the stomach wall offemales and an increased incidence of postimplantation loss. Developmenta l NOAEL = 10 mg/kg bw. LOAEL = 50 mg/kg bw based upon skeletal variations (27 prepelvic vertebra and malpositioned pelvic girdle).

870.3700b Prenatal developmental (Himalayan rabbits) 47841999 (2012) acceptable/guideline 0, 1, 10, 250 mg/kg/day [F] Materna l NOAEL = 10 mg/kg/day. LOAEL = 250 mg/kg/day based on 2 dams killed on day 22 post coitum due to general weak condition, decreased activity and prostrate position and at macroscopic examination had findings indicative of irritations in the stomach (red and dark red foci). Developmenta l NOAEL = 10 mg/kg bw. LOAEL = 250 mg/kg bw based external abnormalities, visceral abnormalities, visceral variations, skeletal abnormalities, skeletal variations, bone variations and cartilage
variations.Bicyclopyrone Human Health Risk Assessment D421265

Page 33 of 49 Table A.2.2. Subchronic, Chronic and Other Toxicity Profile.

Guideline

No. Study Type MRID No. (year)/
Classification/Doses Results

870.3800 Reproduction and fertility effects (rat) 47842127 (2012) acceptable/guideline 0, 25, 500, and 5000 ppm 0, 2.15/2.65, 43.65/52.7, 435.5/534 mg/kg/day [M/F] Parental/Systemic NOAEL was not
established. LOAEL = 2.15/2.65 (M/F) based upon ocular effects (corneal opacity and vascular keratitis P
and F 1 males) and an increased incidence of pelvic dilation of the kidney (F 0 and F 1 males
and F 1 females). Reproductive NOAEL = 43.65/52.7, mg/kg/day (M/F). LOAEL = 435.5/534 mg/kg/day (M/F) based upon changes in sperm parameters, and a decrease precoital interval Offspring NOAEL = 2.15/2.65 mg/kg/day (M/F). LOAEL = 43.65/52.7 mg/kg/day (M/F) based upon decreased absolute body weights, and an
increased incidence of litters with vascular
keratitis in the F 1 and F 2 generations.

870.4100b Chronic toxicity (dog) 47841977 (2012) acceptable/guideline 0, 2.5, 25, and 125 mg/kg/day [M/F] NOAEL was not observed. LOAEL = 2.5 mg/kg/day based upon an
increased incidence of chromatolysis and swelling of selected neurons in the dorsal root ganglia and degeneration of nerve fibers in the spinal nerve roots in both sexes (1-3 per sex/dose).

870.4200 Chronic/Carcinogeni city (rat) 47841985 (2012) acceptable/guideline 0, 5, 500, 2500, and 5000

ppm (0, 0.32/0.39, 32.6/41.6,
166/204 and 335/404 mg/kg/day [M/F]) NOAEL was not established. LOAEL = 0.28/0.35 mg/kg/day (M/F) based on a dose dependent increase in the incidence of opaque eyes and corneal damage in both sexes compared to controls, an increased incidence of thyroid follicular hyperplasia in males, and an increased incidence of chronic progressive nephropathy in the kidneys of males. Evidence of carcinogenicity (an increased occurrence of ocular squamous cell carcinomas and papillomas at 500, 2500, and 5000 ppm).

870.4300 Carcinogenicity (mouse) 47841987 (2012) acceptable/guideline 0, 70, 1700, 7000 ppm (0, 8.7/9.2, 233/242, 940/1027 mg/kg/day [M/F]) NOAEL = 1700 ppm (242 mg/kg/day [F])/ 7000 ppm (940 mg/kg/day [M]). LOAEL = 7000 ppm (1027 mg/kg/day [F]) = based upon decreased absolute body weights in
females. The LOAEL for males was not
established. No evidence of carcinogenicity (lung adenomas at 1700 ppm were not treatment related).Bicyclopyrone Human Health Risk Assessment D421265

Page 34 of 49 Table A.2.2. Subchronic, Chronic and Other Toxicity Profile.

Guideline

No. Study Type MRID No. (year)/
Classification/Doses Results

870.5100 Bacterial Mutation Assay In S. typhimurium And E
.coli 47841979 (2007) acceptable/guideline
Non-activated conditions: 5000, 2500, 1000, 500, 200 and 100 μg/plate
Activated conditions: 5000, 2500, 1000, 500, 200 and 100 μg/plate It is concluded that, under the conditions of thisassay, bicyclopyrone gave a negative, i.e. nonmutagenic, response in S. typhimurium strains TA1535, TA1537, TA98, and TA100 and E.
coli strainsWP2 (pKM101) and WP2 urvA (pKM101) in both the presence and absence of S9 -mix, and in strain TA1535 in the presence
of S9-mix.

870.5100 Salmonella typhimurium and
Escherichia coli
Reverse Mutation Assay 47841980 (2010) acceptable/guideline
Nonactivated conditions: 5000, 2500, 1000, 333, 100, and 33 μg/plate
Activated conditions: 5000, 2500, 1000, 333, 100, and 33 μg/plate During the described mutagenicity test and under the experimental conditions reported, bicyclopyrone did not induce gene mutations by base pair changes or frameshifts in the genome of the strains used. Bicyclopyrone is considered to be non-mutagenic in the Salmonella typhimurium and Escherichia coli reverse mutation assay.

870.5300 In Vitro Mammalian
Cell Gene Mutation

Test 47841981(1997) acceptable/guideline 0, 3994, 2995, 1997, 1497, 998, 499, 250, and 125 μg/mL (± S9) It is concluded that, under the conditions of this assay, bicyclopyrone is not mutagenic in
L5178Y TK+/- cells treated in vitro in either the presence or absence of S9-mix.

870.5395 Micronucleus Assay
in Bone Marrow
Cells of the Rat 47841984 (2008) acceptable/guideline 24 hr interval: 500, 1000, and 2000 mg/kg b.w.
48-hr interval: 2000 mg/kg b.w. In conclusion, it can be stated that under the experimental conditions reported, the test
substance did not induce micronuclei as determined by the micronucleus test with bone marrow cells of the rat. Therefore,bicyclopyrone is considered to be nonclastogenic in this micronucleus assay.

870.5550 In Vivo Rat Liver
Unscheduled DNA Synthesis Assay 47841983 (2007) acceptable/guideline 2000 mg/kg [M] Under the conditions of test, bicyclopyrone did not induce DNA repair, as measured by unscheduled DNA synthesis, in the rat liver in

vivo.

870.6200a Acute neurotoxicity screening battery (rats) 4782002 (2012) acceptable/guideline 0, 20, 200, 2000 mg/kg [M/F] Neurotoxicity NOAEL= 2000 mg/kg. Neurotoxicity LOAEL was not observed. Systemic NOAEL= 2000 mg/kg. Systemic LOAEL was not observed.

870.6200b 28- day preliminary
Subchronic neurotoxicity screening battery (rats) 47842140 (2012) acceptable/non- guideline 0, 500, 2500, and 5000

ppm M: 0, 50, 240, and 471 mg/kg/day F: 0, 53, 259, and 505 mg/kg/day Systemic NOAEL = 5000 ppm (471/505 mg/kg/day [M/F]). Systemic LOAEL was not observed. Neurotoxic NOAEL = 5000 ppm (471/505 mg/kg/day [M/F]).
Neurotoxic LOAEL was not observed.

870.6200b 90-day Subchronic neurotoxicity screening battery (rats) 4782004 (2012) acceptable/guideline 0, 50, 500, 5000 ppm (0, 4/4, 35/42, and 336/415 mg/kg/day [M/F]) Neurotoxicity NOAEL = 5000 ppm (336/415 mg/kg/day [M/F]). Neurotoxicity LOAEL was not observed. Systemic NOAEL was not observed. Systemic LOAEL is 50 ppm (4 mg/kg/day) based upon an increased incidence of unilateral keratitis in the eyes of males.Bicyclopyrone Human Health Risk Assessment D421265

Page 35 of 49 Table A.2.2. Subchronic, Chronic and Other Toxicity Profile.

Guideline

No. Study Type MRID No. (year)/
Classification/Doses Results

870.7465 Metabolism and pharmacokinetics (rat) 47841961, 47841962, 47841963, 47841964, 47841965, 47842110 (2010) acceptable/guideline 0, 2, and 200 mg/kg Using bile-cannulation experiments, absorption
from the GI-tract was estimated to be 83-87%
for the low dose in both sexes. The estimated absorption for the high dose was 86- 90% for both sexes. Maximum mean plasma concentrations (Cmax) were reached in both
male and female rats within 1.3-2.3 hours (Tmax), indicating rapid absorption kinetics for the low dose group. Cmax values increased proportionally with dose suggesting nearly linear absorption. The levels of radioactivity in plasma declined rapidly in a biphasic pattern. The mean plasma clearan ce half-life values of the first phase ( α -phase) were estimated at 2.4- 2.7 hours at 2 mg/kg bw in both sexes, and were noted to increase modestly at 200 mg/kg
bw to 3.2 hours in males but not in females. At the low dose, it was not possible to calculate a half-life value for the second ( β -phase) because the majority of samples were at or below the limit of detection. At 200 mg/kg bw, the mean plasma β half-life values were estimated at 12.5
and 68.6 hours in males and females respectively. The highest levels of radioactivity were found in the liver and kidney. This pattern of tissue accumulation was independent of time, frequency of dosing and amount of dosing. All other tissues were approaching or below the limit of detection. Radioactivity in the carcass accounted for
<0.7% of the administered dose. At both dose levels, the major radioactive component in the urine of non-cannulated rats was parent compound, accounting for ca 40% and 80% of the dose in males and females respectively. In bile duct cannulated rats, the metabolite profile
in urine was similar to that obtained from intact rats. The metabolite profile obtained from rats administered multiple low doses of bicyclopyrone was similar to that obtained from the equivalent single dose. There were no significant differences in the patterns of excretion between the sexes. For the low dose, the major routes of excretion were the urine (64% and 85% of the administered dose in males and females, respectively) and feces (27% and 5% of the administered dose in males and females, respectively) . For the high dose,
the results were similar to those obtained for the low dose. The major ity of the administered dose was eliminated within 24 hours of dosing for both the low and high dose groups and for single and repeated dosing.Bicyclopyrone Human Health Risk Assessment D421265

Page 36 of 49 Table A.2.2. Subchronic, Chronic and Other Toxicity Profile.

Guideline

No. Study Type MRID No. (year)/
Classification/Doses Results

870.7600 In vivo dermal absorption (rat) 47842239 (2009) acceptable/guideline 0, 0.005, 0.02, and 2 mg/cm 2 bicyclopyrone Following a 6-hour dermal exposure to bicyclopyrone soluble liquid (SL) formulation concentrate (A16003E) and to 1/100 and 1/400 spray strength dilutions thereof, most of the applied dose was readily removed from the skin surface by mild skin washing. In all dose groups, residues remained in the skin after washing and thereafter declined in
concentration over the 120-hour assessment period. Absorption of bicyclopyrone over a time course of 6 hours accounted for 23.49, 21.71, and 24.01% of the 3 respective applied doses. Absorption of bicyclopyrone over a time course of 24 hours accounted for 9.58, 14.29, and 20.44 of the 3 respective applied doses. A dermal absorption factor of 20.44%
for risk assessment. 870.7800 Immunotoxicity (mice) 47842008 (2012) acceptable/guideline 0, 50, 500, and 5000 ppm (0, 10.6, 107.2, and 1192 mg/kg/day [F]) Immunotoxicity NOAEL = 5000 ppm. Immunotoxicity LOAEL was not observed. Systemic NOAEL = 5000 ppm. Systemic LOAEL was not observed.

NonGuideline Effect on Rat Thyroid Peroxidase Activity in vitro 47841989 (2012) acceptable/non- guideline 0, 0.1, 10, and 100 μM Bicyclopyrone is not an inhibitor of rat thyroid peroxidase activity in vitro.

NonGuideline Bicyclopyrone: 28 day dietary thyroid mode of action study
in rats 47841990 (2012) acceptable/non- guideline 0, 5, 500 or 5000 ppm (0, 0.5, 41.5, and 399.5 mg/kg/day [M]) This study has demonstrated that dietary
treatment of male Han Wistar rats with bicyclopyrone results in increased tyrosine,
decreased T 3 and T 4 , increased thyroid follicular cell hypertrophy and increased liver weight associated with increased hepatocellular centrilobular hypertrophy and increased hepatic UDPGT activity. These data can be used as part of a weight-of-the-evidence approach to explain the mode of action for the increased incidence of thyroid follicular cell hyperplasia observed in male Han Wistar rats in a 2-year carcinogenicity study.



### A.4 Executive Summaries

A.4.1 Acute Dietary Endpoint for the General Population: There were no effects up the HDT in the acute neurotoxicity study, and there were no other studies appropriate for this exposure scenario. Thus, no study will be chosen for this exposure scenario.

A.4.2 Acute Dietary Endpoint for Females 13-49 years of age

Study Selected: Prenatal Developmental Toxicity in Rabbits

MRID No.: 47841996Bicyclopyrone Human Health Risk Assessment D421265

Page 37 of 49 

### Executive Summary: In a prenatal developm ental toxicity study in rabbits (MRID #47841996), bicyclopyrone (NOA449280, 94.5%), in the vehi cle, 0.5% (w/v) aqueous high viscosity carboxymethylcellulose (CMC), was administered or ally by gavage to 3 groups of 25 time-mated young adult, female New Zealand White [Hra:( NZW)SPF] rabbits once daily from gestation days 7 through 28. Dose levels were 10, 50, a nd 200 mg/kg/day administ ered at a dose volume of 10 mL/kg. A concurrent control group composed of 25 time-mated females received the vehicle (0.5% high viscosity CMC) on a comparab le regimen. The females were approximately 5.5 months of age at the initiation of dose admini stration. All animals were observed twice daily for mortality and moribundity. Clinical observations, body weight s, and food consumption were recorded at appropriate interval s. Blood samples for plasma analysis of parent and tyrosine
concentrations were collected from all surv iving females at approximately 6 hours following dose administration on gestation day 28. A laparohysterectomy was performed on each surviving female on gestation day 29. The uter i, placenta, and ovaries were examined, and the numbers of fetuses, early and late resorptions, total implantations, and corpora lutea were recorded. Gravid uterine weights were reco rded, and net body wei ghts and net body weight changes were calculated. The fetuses were weig hed, sexed, and examined for external, visceral,
and skeletal malformations a nd developmental variations.

Maternal effects are as follows:
There were no test substance-related effects on su rvival or clinical or macroscopic findings for maternal animals at 10 and 50 mg/kg/day. M ean maternal body weight and food consumption parameters were unaffected at 10 and 50 mg/kg/day.

A 200 mg/kg/day bicyclopyrone, signif icant maternal toxicity was ma nifested with 7 females in this group found dead (including 1 female that wa s found dead following an abortion) or killed in

extremis from gestation day 22 to 28 following food consumption of ≤ 10 g/day for at least 4 days prior to death or euthanasia and body weight lo sses (as much as 639 g from the gestation day 7 body weight). An additional two females in th e 200 mg/kg/day group deli vered on gestation day 29 following slight reductions in food consumpti on or body weight loss. There were not effects on absolute maternal body weights. Mean matern al body-weight gains for this group were lower (although not statistical ly significantly) than th e control group during gestation days 13-21 and a mean body weight loss was noted during ge station days 21-29. Although mean food consumption values and mean body weights were not remarkably different from control group values, the effects on body-weight gains of ten occurred in conjunction with low food consumption and decreased defecation when evalua ted on an individual an imal basis. Mean gravid uterine weight, net body weight, and net body-weight gain for surviving females were
unaffected at this dose level. There were no test substance-relate d macroscopic findings observed in the 200 mg/kg/day group.

Based on mortality/moribundity in conjunction with minimal food consumption and effects on body weight changes, the maternal LO AEL is 200 mg/kg/day group. The maternal NOAEL is 50 mg/kg/day.

Fetal effects are as follows:Bicyclopyrone Human Health Risk Assessment D421265

Page 38 of 49 

### Test substance-related, statistically significant incr eases in a number of skeletal variations were
observed in all test substance- treated groups compared to the control group. These included increased incidences of 13th full rib(s), 27 presacra l vertebrae, and an extra site of ossification
ventral to cervical centrum no. 2.

A low incidence of skeletal costal cartilage an omalies (fused, bifurcated, and/or malpositioned costal cartilage) was observed in the 200 mg/kg/day group (4 fetu ses from 3 litters in the 200 mg/kg/day group compared to 0 fetuses in the cont rol group). In addition, 2 fetuses from 2 litters at 50 mg/kg/day also exhibited co stal cartilage anomalies. Al though these values were at the upper level of the historical cont rol incidence, an association w ith the test substance cannot be
excluded.

Based on the effects in this study, the deve lopmental LOAEL is 10 mg/kg/day based upon skeletal variations (the appearance the 27 th 

### presacral vertebrae). The developmental
NOAEL was not observed.

Dose and Endpoint for Risk Assessment: Th e NOAEL was not observed. The LOAEL is 10 mg/kg/day based upon skeletal varia tions (the appearance of the 27 th 

### presacral vertebrae).

Comments about Study/Endpoint/UFs: The endpoint used for establishing the aPAD for females 13-49 years of age was selected from the prenat al developmental toxic ity study in New Zealand White rabbits. An aPAD of 0.01 mg/kg/day wa s derived from a developmental LOAEL of 10 mg/kg/day and a 1000-fold factor that included a 10X for inter-spe cies extrapolations, a 10X for intra-species variations , and a 10X FQPA SF/UF L 

### . The endpoint of concern is a developmental
effect characterized as an increased incidence of a 27 th 

### presacral vertebrate at the developmental LOAEL of 10 mg/kg/day. This endpoint is c onsidered the result of a single dose, and is protective for the effects seen at higher doses in the other developmental toxicity studies in rats
and rabbits.

A.4.3 Chronic Dietary Endpoint for the General Population:

MRID No.: 47841996

Executive Summary: In a combined 52 week ch ronic/104 week rat dietary carcinogenicity study (MRID #47841985), bicyclopyrone (94.5% purity) was administered to groups of Han Wistar (CrL:WI(Han)) rats in the diet. Five groups of 52 male a nd 52 female Han Wistar rats were assigned to the carcinogenicity study and dos ed with diets containing 0, 5, 500, 2500, or 5000 ppm bicyclopyrone for at least 104 consecutive weeks. In add ition, a toxicity study comprising an additional five groups of 12 males and 12 fe males was included and dosed in an identical fashion for a period of 52 consecutive weeks. Th e equivalent doses for the carcinogenicity phase of the study were 0, 0.28/0.35, 28.4/35.8, 141/178 and 280/368 mg/kg/day (M/F). The equivalent doses for the toxicity phase of the study were 0, 0.32/0.39, 32.6/41.6, 166/204, and 335/404 mg/kg/day (M/F). Since the achieved do ses are similar between the two phases, the doses from the carcinogenicity phase will be used for risk assessment purposes.Bicyclopyrone Human Health Risk Assessment D421265

Page 39 of 49 

### Due to observation of severe eye lesions, corn eal opacity and damage, 5000-ppm male animals were fed control diet over a 9-day period durin g Weeks 4 and 5. Dosing recommenced after this period and was continuous to the end of the study.

The following were assessed at pre-determined intervals from pre-trial until study completion from carcinogenicity and toxi city study animals: clinical observations, body weight, food consumption, hematology, coagulation, and clin ical chemistry. Additionally, selected carcinogenicity study animals had samples taken for urinalysis at predeter mined intervals and all underwent ophthalmoscopy examina tions prior to initiation of dosing and at Weeks 50 and 102. Toxicity study animals received a detailed f unctional observation battery assessment once during treatment (Week 51/52).

All surviving carcinogenicity and toxicity study animals were te rminated and subjected to a detailed necropsy examination with a comprehens ive histological evaluation after the completion
of 104 or 52 weeks of tr eatment respectively.

The effects are as follows: There were no statistically significant differences in mortality between the controls and any groups treated with bicyclopyrone.

At 5-ppm bicyclopyrone, there was a 2-6% increase in the incide nce of opaque eyes and corneal damage in both sexes compared to the control gr oup (0-2%). At 104 weeks in males, there was an increased incidence of thyroid follicular hype rplasia in males (19%) co mpared to the control group (4%). There was also an increase in the incidence of chronic progressive nephropathy in the kidneys of males (63%) compar ed to the control group (33%).

At 500-ppm bicyclopyrone, there wa s a significant increase in the incidence of opaque eyes and corneal damage in both sexes (98-100%) compar ed to controls (0-2%). There was a minor
decrease in the absolute brain weights of males and females ( ↓ 3-7%), and a dose dependent increase in the adjusted weight of the kidneys ( ↑ 13%), though there was no correlation with the absolute kidney weights. There was an increas e in the incidence of eye keratitis (88-100% for males and 87-100% for females) and the regene rative corneal hyperplasia (88-100% for males and 42-92% for females) from 52 weeks to 104 w eeks compared to the control group (2%). In males, there was an increased incidence of thyroid follicular hypertrophy (75%) at 52 weeks compared to the control group (0%). At 104 weeks in males, there was an increased incidence of thyroid follicular hyperplasia ( 23%) compared to the control group (19%). This effect occurred
in females as well but there was not dose response. There was also an increase in the incidence of chronic progressive nephropat hy in the kidneys of males (75 %) compared to the control group (33%). In males, there was an increased inci dence of squamous cell carcinoma and papilloma (4% and 2%) compared to the control group (0%).

At 2500-ppm bicyclopyrone, there was a significant in crease in the incidenc e of opaque eyes and corneal damage in both sexes compared to cont rols (98-100%) compared to the control group (0- 2%). Relative to the control group, there was a minor decrease in the absolute brain weights of males and females ( ↓ 3-7%), and heart weights of females ( ↓ 7%). There was a dose dependent increase in the adjusted weight of the liver ( ↑ 12%) and the kidneys ( ↑ 15%), though there was noBicyclopyrone Human Health Risk Assessment D421265

Page 40 of 49 

### correlation with the absolute kidney weights. There was a dose dependent decrease in the adjusted weights of the hearts of males ( ↓ 7%) and the brains of females ( ↓ 3%). There was an increase in the incidence of eye keratitis ( 83% for males and 87-92% for females) and the regenerative corneal hyp erplasia (58-63% for males and 58% for females) from 52 weeks to 104 weeks compared to the control group (2%). In males, there was an increased incidence of thyroid follicular hypertrophy ( 83%) at 52 weeks compared to the control group (0%). At 104 weeks in males, there was an increased inci dence of thyroid folli cular hyperplasia (23%) compared to the control group (4%). There was al so an increase in th e incidence of chronic progressive nephropathy in the ki dneys of males (77%) compared to the control group (33%). There was a statistically signifi cant increase in the incidence of acinar cell atrophy in the pancreas of male animals (50%) compared to the control group (27%). In males, there was an increased incidence of squamous cell carcinoma and papilloma (4% and 2%) compared to the control group (0%).

At 5000-ppm bicyclopyrone, there was a significant in crease in the incidenc e of opaque eyes and corneal damage in both sexes (98-100%) compared to the control group (0 -2%). Relative to the control group, in both sexe s there were significan tly lower body weights ( ↓ 5-16% for males and ↓ 5-20% for females), and a corresponding d ecrease in body-weight gain in both ( ↓ 10-26% for
males and ↓ 6-36% for females). There were also minor changes in food consumption and
utilization. There was a minor decrease in the absolute brain weights of males and females ( ↓ 5- 8%), and heart weights of females ( ↓ 7%) at 104 weeks. There was a dose dependent increase in the adjusted weight of the liver ( ↑ 12%) and the kidneys ( ↑ 15%) at 104 weeks, though there was no correlation with the absolute kidney weight s. There was a dose dependent decrease in the adjusted weights of the hearts of males ( ↓ 8%) and the brains of females ( ↓ 4%) at 104 weeks. There was an increase in the incidence of ey e keratitis (88-100% for males and 73-92% for females) and the regenerative corneal hyperpla sia (71-100% for males and 35-75% for females) from 52 weeks to 104 weeks compared to the co ntrol group (2%). In males, there was an increased incidence of thyroid follicular hypertrophy ( 66%) at 52 weeks compared to the control group (0%). At 104 weeks in males, there was an increased incidence of thyroid follicular hyperplasia (33%) compared to the control group (4%). There was also an increase in the incidence of chronic progressive nephropathy in the kidneys of males (69%) at 104 weeks compared to the control group (33%). There wa s a statistically signifi cant increase in the incidence of acinar cell atrophy in the pancreas of male animals (58%) compared to the control group (27%). In males, there was an increa sed incidence of squamous cell carcinoma and papilloma (4% and 6%) compared to the control group (0%).

Based upon the effects in this study, th e LOAEL is 5 ppm (0.28/0.35 mg/kg/day [M/F]) based on a dose dependent increase in the incidence of opaque eyes and corneal damage in both sexes compared to controls, an increased incidence of thyroid follicular hyperplasia in males, and an increased incidence of chronic progressive nephropathy in the kidneys of
males. The NOAEL was not established.

Dose and Endpoint for Risk Assessment: Th e NOAEL was not observed. The LOAEL is 0.28 mg/kg/day based upon an increased incidence of opaque eyes and corneal damage in both sexes compared to controls, an increa sed incidence of thyroid follicul ar hyperplasia in males, and an increased incidence of chronic progressive nephropathy in the ki dneys of males.Bicyclopyrone Human Health Risk Assessment D421265

Page 41 of 49 

### Comments about Study/Endpoint/UFs: The endpoi nt used for deriving the cPAD was selected from a chronic/carcinogenicity toxicity study in rats. The cPAD, which is 0.00028 mg/kg/day, was derived from a LOAEL of 0.28 mg/kg/day a nd a 1000-fold factor that included a 10X for inter-species extrapolations, a 10X for intr a-species variations, and a 10X FQPA SF/UF L 

### . The LOAEL of 0.28 mg /kg/day is based on an incr eased incidence of opaque eyes and corneal damage in both sexes compared to controls, an increased incidence of thyroid follicular hyperplasia in males, and an increased incide nce of chronic progressi ve nephropathy in the kidneys of males. The endpoints of concern were seen following repeated oral exposure in the most sensitive species and are appropriate for assessing potential risk via chronic dietary exposure to bicyclopyrone. They are thus approp riate for the duration of exposure and protective of the general population.

A.4.4 Short- (1-30 days) and Intermediate- (1 -6 months) Term Dermal and Inhalation

MRID: Same as for Acute Females 13-49 years of age.

Executive Summary: Same as for Acute Females 13-49 years of age.

Dose and Endpoint for Risk Assessment: Same as for Acute Females 13-49 years of age.

Comments about Study/Endpoint/UFs: A dermal toxicity study is available for bicyclopyrone; however, there is quantitative sus ceptibility and the route specific dermal study did not assess the most sensitive endpoints in th e database, particularly the in utero fetal skeletal effects. The
short- and intermediate-term dermal and i nhalation endpoints are thus derived from the developmental New Zealand White rabbit study. The POD is based upon the developmental LOAEL of 10 mg/kg/day. The developmental LOAEL is 10 mg/kg/day based upon an increased
incidence of a 27 th 

### presacral vertebrate. The developmenta l study is appropriate for the durations of exposure and is protective of fetuses in utero who may be exposed when mothers are exposed in occupational settings. The dermal equivale nt LOAEL is 48.9 mg/ kg/day (10 mg/kg/day ÷ 20.44 = 48.9 mg/kg/day). The NOAEL for the rout e-specific 28-day dermal study is 50 mg/kg/day and the LOAEL is 250 mg/kg/day based on ocular lesions (kerat itis or degeneration of corneal epithelium) in a low number of animals therefore the dermal equivalent dose is more protective for this exposure s cenario. The LOC for both de rmal and inhalation exposure scenarios is 1000 based upon a 10X UF for inter- species extrapolations, a 10X UF for intraspecies variations and a 10X FQPA SF/UF L 

### . This study protects for th e fetal effects that occur in all four developmental studies in the bicyclopyrone hazard databa se. It is appropriate for the
route as well as the durations of exposure in occupational settings.Bicyclopyrone Human Health Risk Assessment D421265

Page 42 of 49 

### Appendix B. Metabolism Summary Table

Table B1. Tabular Summary of Metabolites and Degradates.

Chemical Name (Other Names in Parenthesis) and Structure Matrix Percent TRR (PPM) 1 Matrices - Major Residue (>10% TRR) Matrices - Minor Residue (<10% TRR) Bicyclopyrone (NOA449280) Corn Forage: 2 (0.007) Sugarcane Rotational Crops Spinach Foliage: 70 (0.03) Wheat Forage: 4 (0.002) Turnip Foliage: 4 (0.001) Ruminant Milk: 23-27 (0.003-0.004) Liver: 16-22 (0.44-0.66) Kidney: 44-50 (0.57-0.64) Muscle: 39-41 (0.009- 0.01) Fat: 41-44 (0.012-0.013) Poultry Egg Yolk: 76-79 (0.08) Egg White: 95-98 (0.08- 0.12) Liver: 74-86 (1.3-1.5) Muscle: 83 (0.07-0.11) Fat: 92-93 (0.15-0.17) Skin: 86-89 (0.37-0.46)

Rat Urine: 40-82% AD
Plasma: 49-94% of Total
Identified Feces: 2% AD

Water Aerobic Soil Metab., Anaerobic Soil Metab., Aerobic Aquatic Metab., Anaerobic Aquatic Metab., Soil Photodeg., Hydrolysis, Aqueous Photolysis Terrestrial Field Dissipation

CSAA915194 (4-hydroxy-3-[[2-[(2- hydroxyethyoxy)methyl]-6- (trifluoromethyl)-3-pyridinyl]carbonyl]- bicyclo[3.2.1]oct-3-en-2-one)

OH

O N O OH O

CF 3 Corn Sugarcane Rotational Crops Ruminant Milk: 57-60 (0.01) Liver: 60-70 (1.8-1.9) Kidney: 47-50 (0.61-0.66) Muscle: 43-46 (0.011- 0.012) Fat: 40-42 (0.011-0.013) Poultry Egg Yolk: 1 (0.001) Egg White: 2 (0.003) Muscle: 3 (0.004) Fat: 2 (0.004)

Rat Urine: 2-11% AD
Feces: <1-2% AD
Plasma: <1-3% of Total
Identified Water Aerobic Aquatic Metab., Anaerobic Aquatic Metab. OH

O N O O

CF 3 OMeBicyclopyrone Human Health Risk Assessment D421265

Page 43 of 49 Table B1. Tabular Summary of Metabolites and Degradates.

Chemical Name (Other Names in Parenthesis) and Structure Matrix Percent TRR (PPM) 1 Matrices - Major Residue (>10% TRR) Matrices - Minor Residue (<10% TRR)

CSCD686480 (2-[(2-hydroxyethoxy)methyl]-6- (trifluoromethyl)-3-pyridinecarboxylic acid)

N O

O H

CF 3 O OH Corn Forage: 2 (0.02, includes glycoside) Stover: 3 (0.02, includes glycoside) Sugarcane 20 (0.18, includes glycoside) Rotational Crops Wheat Forage: 17 (0.016, includes glycoside) Wheat Hay: 22 (0.11, includes glycoside) Wheat Straw: 15 (0.07, includes glycoside) Wheat Grain: 10 (0.02, includes glycoside)

Ruminant Liver: 1.1 (0.03) Poultry

Rat

Water

CSAA806573 (2-(hydroxymethyl)-6-(trifluoromethyl)- 3-pyridinecarb oxylic acid)

N O

O H

CF 3 OH Corn Forage: 5 (0.04, includes glycoside) Stover: 6 (0.05, includes glycoside) Sugarcane Rotational Crops Wheat Forage: 10 (0.005) Wheat Hay: 4 (0.02, includes glycoside) Wheat Straw: 7 (0.03, includes glycoside) Wheat Grain: 4 (0.007, includes glycoside)

Ruminant Poultry

Rat Feces: <1% AD Water Aqueous Photolysis, Anaerobic Soil Metab., Anaerobic Aquatic Metab.,
Terrestrial Field Dissipation

CSAA589691 ((1S, 3R)-cyclopentane dicarboxylic acid)

O H O O O H Corn Grain: 42 (0.04) Forage: 4 (0.02) Stover: 4 (0.02, includes glycoside) Sugarcane Rotational Crops

Ruminant Poultry

Rat Water Aqueous Photolysis Soil PhotolysisBicyclopyrone Human Health Risk Assessment D421265

Page 44 of 49 Table B1. Tabular Summary of Metabolites and Degradates.

Chemical Name (Other Names in Parenthesis) and Structure Matrix Percent TRR (PPM) 1 Matrices - Major Residue (>10% TRR) Matrices - Minor Residue (<10% TRR)

CSCD677694 Corn Forage: 2 (0.04) Stover: 2 (0.01) Sugarcane 8-9 (0.07) Rotational Crops Wheat Straw: 8-13 (0.04- 0.06) Wheat Forage: 5-8 (0.003- 0.007) Wheat Hay: 4-9 (0.02- 0.03) Wheat Grain: 3-4 (0.005- 0.006)

Ruminant Poultry

Rat

Water

CSCD677693

O H OH

O O

N O OH

CF 3 Corn Forage: 5-8 (0.02-0.07) Stover: 3-4 (0.02, includes glycoside) Grain: 5 (0.01) Sugarcane 24 (0.19-0.21, includes glycoside) Rotational Crops Ruminant Liver: 1.6-2.5 (0.04-0.07) Poultry

Rat Urine: 1% AD
Feces: 1% AD

Water

CSCD675164

OH

O N O O

CF 3

O H OMe Corn Sugarcane Trace of glycoside Rotational Crops Wheat Forage: 21-24 (0.016-0.020, includes CSCD677306) Turnip Foliage: 44 (0.009, includes CSCD677306) Turnip Roots: 33 (0.005)

Ruminant Poultry Liver: 2 (0.03)

Rat Urine: 2-8% AD
Feces: 2-8% AD
Plasma: 1% of Total
Identified

Water O H OH

O O

N O

CF 3

O H OMeBicyclopyrone Human Health Risk Assessment D421265

Page 45 of 49 Table B1. Tabular Summary of Metabolites and Degradates.

Chemical Name (Other Names in Parenthesis) and Structure Matrix Percent TRR (PPM) 1 Matrices - Major Residue (>10% TRR) Matrices - Minor Residue (<10% TRR)

CSCD675162

OH

O N O OH O

CF 3

O H Corn Forage: 10-15 (0.05-0.13, includes glycoside) Grain: 28 (0.01) Stover: 8-9 (0.03-0.07, includes glycoside)

Sugarcane 10-13 (0.09-0.10) Rotational Crops Wheat Forage: 23-27 (0.015-0.026, includes CSCD677693) Wheat Hay: 16-21 (0.067- 0.079, includes CSCD677693)
Wheat Straw: 16-24 (0.076-0.11, includes CSCD677693) Wheat Grain: 5-6 (0.009- 0.01, includes CSCD677693) Turnip Foliage: 6 (0.002, includes CSCD677693)

Ruminant Liver: 1.4-1.6 (0.04-0.05) Poultry Egg Yolk: 2 (0.002) Fat: 5 (0.01)

Rat Urine: 3% AD
Feces: 2% AD

Water

CSCD677306

O H OH

O O

N O

CF 3 OMe Corn Grain: 18 (0.007, includes glycoside, isomers) Sugarcane 16-18 (0.14-0.15, includes glycoside) Rotational Crops

Ruminant Poultry Liver: 2 (0.04)

Rat Urine: 1-4% AD
Feces: 1-3% AD
Plasma: <1% of Total
Identified

Water

CSCD677692

O H OH

O O

N O OH

CF 3

O H Corn Forage: 15-36 (0.07-0.33, includes isomers) Stover: 11-21 (0.05-0.16, includes isomers) Sugarcane 5-7 (0.04-0.06) Rotational Crops Wheat Forage: 1-2 (0.001) Wheat Grain: 1 (0.002)

Ruminant Poultry

Rat

WaterBicyclopyrone Human Health Risk Assessment D421265

Page 46 of 49 Table B1. Tabular Summary of Metabolites and Degradates.

Chemical Name (Other Names in Parenthesis) and Structure Matrix Percent TRR (PPM) 1 Matrices - Major Residue (>10% TRR) Matrices - Minor Residue (<10% TRR)

CSCD686481

N O

O H

CF 3 O OH O Corn Forage: 3 (0.03) Stover: 1 (0.01, includes glycoside) Sugarcane 6 (0.06) Rotational Crops Wheat Hay: 4 (0.02) Wheat Straw: 4 (0.02)

Ruminant Poultry

Rat

Water

CSCD642512 Corn Forage: 2 (0.01) Stover: 2-3 (0.01-0.02) Grain: 6 (0.001) Sugarcane Rotational Crops Wheat Hay: 1-3 (0.005- 0.008) Wheat Straw: 2-4 (0.009- 0.02)

Ruminant Poultry

Rat Water Aerobic Soil Metabolism Soil Photolysis, Anaerobic Soil Metab., Terrestrial Field Dissipation

CSAA757083

N OH O

O H

CF 3 Corn Sugarcane Rotational Crops Wheat Hay: 2 (0.004, 120- day PBI)

Ruminant Poultry

Rat

Water

CSCC163768

O H N OH O O

CF 3 Corn Sugarcane Rotational Crops Wheat Straw: 2 (0.006, 120-day PBI) Wheat Forage: 5 (0.002, 270-day PBI)

Ruminant Poultry

Rat Water Aqueous Photolysis, Soil Photolysis Anaerobic Soil Metab., Aerobic Aquatic Metab., Aerobic Soil Metab., Anaerobic Aquatic Metab.,
Terrestrial Field Dissipation OH

O N O OH O

CF 3 OBicyclopyrone Human Health Risk Assessment D421265

Page 47 of 49 Table B1. Tabular Summary of Metabolites and Degradates.

Chemical Name (Other Names in Parenthesis) and Structure Matrix Percent TRR (PPM) 1 Matrices - Major Residue (>10% TRR) Matrices - Minor Residue (<10% TRR)

CSCD656832

O H N OH O

CF 3 Corn Sugarcane Rotational Crops Wheat Forage: 39 (0.02, includes glycoside, isomers, 270-day PBI) Wheat Hay: 41 (0.06, includes glycoside, isomers, 270-day PBI) Wheat Straw: 35 (0.06, includes glycoside, isomers, 270-day PBI) Wheat Grain: 16 (0.009, includes glycoside, isomers, 270-day PBI) Turnip Foliage: 71 (0.012, includes glycoside, isomers, 270-day PBI)

Ruminant Poultry

Rat Water Aerobic Soil Metab.,
Terrestrial Field Dissipation Soil Photolysis

SYN503780 (2-[(2-methoxyethoxy)methyl]-6- (trifluoromethyl)-3-pyridinecarboxylic acid)

O H N O O

CF 3 OMe Corn Sugarcane Rotational Crops

Ruminant Poultry

Rat Feces: <1% AD Water Soil Photolysis, Terrestrial Field Dissipation Aqueous Photolysis, Aerobic Soil Metab., Anaerobic Soil Metab., Aerobic Aquatic Metab., Anaerobic Aquatic Metab.

CSAA456156 Corn Sugarcane Rotational Crops

Ruminant Poultry

Rat Water Aer. Aquatic Metab. + Photodeg. Sugarcane, 47842010; 0.27 lb ai/A; 1X rate; immature leaves; 42-day PHI. Corn, 47842011, pre-emergence spray at 0.27 lb ai/A + post-emergent spray at the 8- to 9-leaf growth stage at 0.27 lb ai/A; 8X; harvest at maturity. Goats; 47842014; 30 ppm; 130X MTDB; 7 days; 11-hour PSI. Laying Hen; 47842013; 20 ppm; 1200X MTDB; 10 days; 11-hour PSI. Rotational Crops; 47842023; 7X, applied to bare soil; 30- (wheat), 60- (turnip), 120-day (spinach) PBI. Rat Metabolism; 47841962; 200 mg gavage dose; Han Wistar rats, 1-day depuration.Bicyclopyrone Human Health Risk Assessment D421265

Page 48 of 49 

### Appendix C. Physical / Chemic al Properties of Bicyclopyrone

Table C1. Physical / Chemical Properties of Bicyclopyrone. Property Results Molecular mass (molecular formula) 399.36 g/mole (C 19 H 20 F 3 NO 5 ) Physical State (pure active substance) White Powder Melting Point (pure active substance) 65.3°C Relative Density (pure active substance) 1.503 g/cm 3 at 20.5°C Aqueous Solubility (at 25  C) Pure water: 1.2 g/L (a pH of about 3 was recorded) Aqueous sol.: 38 g/L at pH 4.9 Aqueous sol.: 119 g/L at pH 7.2 Aqueous sol.: 119 g/L at pH 9.2 Solubility in various solvents at 25  C Acetone >500 g/L Dichloromethane >500 g/L Ethyl acetate >500 g/L Hexane 8.9 g/L Methanol >500 g/L Octanol 91 g/L Toluene >500 g/L Vapour Pressure at 20  C <3.75 x 10 -8 mm Hg
Henry’s Law Constant at 25  C <1.7 x 10 -6 Pa m3 / mol (pure water; pH ~3)
<5.3 x 10 -8 Pa m3 / mol (pH 4.9)

<1.7 x 10 -8 Pa m3 / mol (pH 7.2)

<1.7 x 10 -8 Pa m3 / mol (pH 9.2)

Octanol/Water Partition Coefficient at 25°C (Log K
ow ) At pH 5 log K
ow = 0.25 At pH 7 log K
ow = -1.2 At pH 9 log K
ow = -1.9 Dissociation Constant (pK
a ) at 20  C 3.06Bicyclopyrone Human Health Risk Assessment D421265

Page 49 of 49 

### 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 data, which include studies from the PHED 1.1, the AHETF database, and the ARTF database are (1) subject to ethics review pursuant to 40 CFR 26, (2) have re ceived that review, and (3) ar e compliant with applicable ethics requirements. For certain studies, the ethics review may have included review by the
Human Studies Review Bo ard. Descriptions of data sources , as well as guidance on their use, can be found at the Agency website 2



### .

2 http://www.epa.gov/pesticides/science/handler-exposure-data.html and http://www.epa.gov/pesticides/science/post-app-exposure-data.html