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 

Anwar 

Kelly M. 

Y. 

Lowe, 

Dunbar, 

Senior 

Ph.D., 

Environmental 

Pharmacologist 

Scientist 

~;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 

Donna Davis, 

(7509P) 

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 1of49 
Bicyclopyrone Human Health Risk Assessment D421265

Page 2 of 49 

provided by Anwar Dunbar (RAB1), and the drinking water assessment was provided by Cheryl 

Sutton of the Environmental Fate and Effects Division (EFED). 
Bicyclopyrone Human Health Risk Assessment D421265

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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 Petitioned-For Tolerances ...................................................................... 10

2.2.4 International Harmonization ....................................................................................... 10

2.3 Label Recommendations .................................................................................................... 10

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

3.1 Chemical Identity ........................................................................................................... 10

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, Metabolism, & 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 Toxicity 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) Exposure/Risk Characterization ..................................... 23

6.1 Spray Drift ...................................................................................................................... 23

6.2 Residential Bystander Post-Application Inhalation Exposure ....................................... 24
Bicyclopyrone Human Health Risk Assessment D421265

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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 Profile and Executive Summaries ....................................................... 30

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

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

Appendix D. Review of Human Research ................................................................................... 49

 
Bicyclopyrone Human Health Risk Assessment D421265

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1.0 Executive Summary 

Bicyclopyrone, [4-hydroxy-3-{2-[(2-methoxyethoxy)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 Regulatory Agency (PMRA) in Canada, and the 

Australian Pesticides and Veterinary Medicines Authority in Australia (APVMA). It is a 

member of the 4-hydroxyphenylpyruvate dioxygenase (HPPD) inhibitor class of herbicides 

(Group 27) and belongs to the triketone subclass of chemistry. Syngenta has submitted a petition 

for establishment of tolerances for the new active ingredient (ai) bicyclopyrone on corn and 

imported sugarcane. The proposed use on corn is for the selective contact and residual control of 

broadleaf weeds in field corn, seed corn, silage corn, yellow popcorn, and sweet corn. The 

maximum application rate for SYN-A16003 Herbicide [a soluble concentrate (SC) formulation 

containing 18.5% ai (1.67 lb ai/gal)] is 0.044 lb ai/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 application 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 rate 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 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 hyperplasia, and a chronic progressive 

nephropathy. 

Different effects were observed in dogs. 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 occurred in the eye and the thymus. 

Following chronic exposure, there was a dose dependent increase 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 absolute 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 developmental toxicity in both rats and rabbits, and 

there was an increased quantitative fetal susceptibility 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 any kind. Reproductive effects 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 thyroid 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-effect level (LOAEL) for the points of departure 
Bicyclopyrone Human Health Risk Assessment D421265

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(PODs). The toxicology database for bicyclopyrone is adequate for characterizing toxicity and 

quantification of risk for food and non-food uses; however, a LOAEL from the New Zealand 

white rabbit developmental and chronic/carcinogenicity rat 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 chronic dietary exposure scenario is protective 

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 characterized and the 

selected endpoints are protective of the observed fetal effects. Lastly, 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 (females 13-49 years old only) and short-/intermediateterm occupational dermal/inhalation exposures. The LOAEL is based upon skeletal variations 

(the appearance of the 27th presacral vertebrae). A dermal absorption factor of 20.44% will be 

applied to dermal exposure scenarios. 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 POD for the general U.S. population was not established. The carcinogenicity study in 

the rat was selected for assessment of chronic 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 increased incidence of thyroid follicular hyperplasia in males, and an 

increased incidence of chronic progressive nephropathy in the kidneys of males. Bicyclopyrone 

was classified as “suggestive evidence of carcinogenic 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 required 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 bicyclopyrone 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 plants. Based on the metabolism studies 

and on residue data from field trials, the residue definition for enforcement and for risk 

assessment in plants (primary and rotational crops) and livestock is bicyclopyrone and its 

structurally related metabolites determined as the common moieties SYN503780 and 

CSCD686480. Analytical methods suitable for enforcement and data gathering have been 

developed and validated. Crop field trials with bicyclopyrone were conducted according to the 

proposed label directions in the U.S. with corn and in Australia and Brazil with sugarcane. In all 

sugarcane and field corn grain samples, residues 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 processed 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 and risk assessments were conducted 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 Agriculture 
Bicyclopyrone Human Health Risk Assessment D421265

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(USDA) National Health and Nutrition Examination Survey, What We Eat in America 

(NHANES/WWEIA; 2003-2008). The residues of concern (ROC) for 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 modeled 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 population-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) Exposure and Risk Assessment: There are no residential uses 

proposed for bicyclopyrone. Therefore, residential 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 bicyclopyrone that result in residential (nonoccupational) exposures, the aggregate assessment need only consider food and drinking water. 

Since the dietary exposure analysis included both food and drinking 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 intermediate-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 are 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 concern on Day 0 (12 hours following 

application), the restricted-entry interval (REI) is based on the acute toxicity of bicyclopyrone 

technical material. Bicyclopyrone has low acute toxicity via the oral, dermal and inhalation 

routes (Toxicity Category IV), and is not an eye 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 labels, 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 ingredients 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 occupational post-application 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 quantitative occupational post-application inhalation 

exposure assessment for bicyclopyrone. 

Environmental Justice Considerations: Potential areas of environmental justice concerns, to 

the extent possible, were considered in this human health risk assessment, in accordance with 
Bicyclopyrone Human Health Risk Assessment D421265

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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 Exposure Database Version 1.1 (PHED 1.1), the 

Agricultural Handler Exposure Task Force (AHETF) database, and the Agricultural Reentry Task 

Force (ARTF) database are (1) subject to ethics review pursuant to 40 CFR 26, (2) have received 

that review, and (3) are compliant with applicable ethics requirements. For certain studies, the ethics 

review may have included review by the Human Studies 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/pesticides/science/post-appexposure-data.html. 

2.0 Recommendations 

HED concludes that the residue chemistry and toxicology databases support registration of 

bicyclopyrone and the establishment of the permanent tolerances listed in Section 2.2.2. 

2.1 Data Deficiencies/Data Needs 

ORE: In accordance with 40 CFR 158, dislodgeable-foliar residue (DFR) data are required for 

all occupational (e.g., crop, nursery, greenhouse use sites) or residential (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 available. Since the highest 

estimated occupational post-application 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 exposure assessments refinements and to further 

EPA’s general understanding of the availability of dislodgeable foliar pesticide 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 spectroscopy/mass spectroscopy (LC-MS/MS) methods for 

tolerance enforcement have been developed and independently validated. For all matrices and 

analytes, the LOQ, defined as the lowest spiking 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 Operating 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 for 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 bicyclopyrone and its structurally related metabolites 
Bicyclopyrone Human Health Risk Assessment D421265

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determined as the common moieties, SYN503780 and CSCD686480. This is achieved by 

cleaving the carbonyl bond in bicyclopyrone and structurally 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 determined as the common moieties SYN503780 and 

CSCD686480. Residues of bicyclopyrone and structurally related metabolites were extracted 

from the sample matrices by homogenizing with an acetonitrile/water (50:50 v/v) solution. After 

centrifugation and filtration, basic hydrogen peroxide 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 herbicide bicyclopyrone, 

including its metabolites and degradates, in or on the commodities in the table below. 

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

only the sum of the common moieties SYN503780 (2-[(2-methoxyethoxy)methyl]-6-

(trifluoromethyl)-3-pyridinecarboxylic acid) and CSCD686480 (2-[(2-

hydroxyethoxy)methyl]-6-(trifluoromethyl)-3-pyridinecarboxylic 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 0.011 0.021 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

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2.2.3 Revisions to Petitioned-For Tolerances 

The proposed tolerance levels for most corn (field, 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 Development) calculation procedures to obtain 

tolerance levels, HED only included data from trials conducted according to the proposed label 

directions. The petitioner proposed a tolerance level for sugarcane, 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 highest tissue-to-feed ratio calculated from the dose 

closest to maximum dietary burdens. As residues are expected in both liver and kidney, the 

appropriate RAC is "meat byproducts." Furthermore, per HED current policy, tolerances are 

recommended for all ruminants, not just cattle. In addition, HED is recommending numerous 

changes in the commodity definitions and for revisions 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 limits (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 joint 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

CF3

OMe
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Table 3.1.1. Bicyclopyrone, SYN503780, and CSCD686480 Nomenclature. 

Compound: common moiety 

HO N

O

O

CF3

OMe

Company experimental name SYN503780 

IUPAC name 2-(2-methoxy-ethoxymethyl)-6-trifluoromethyl-nicotinic acid 

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

CAS # 380355-55-5 

Compound: common moiety 

N

O

HO

CF3

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 bicyclopyrone are summarized in Appendix C. 

Bicyclopyrone is a solid under ambient conditions and is unlikely to volatilize 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 m3/mol). Bicyclopyrone is a relatively soluble, nonvolatile compound that is stable to 

hydrolysis across all environmental pH levels. With a pKa of 3.06, it will exist predominantly as 

an anion at environmental pHs. Bicyclopyrone is not expected to bioaccumulate in aquatic and 

terrestrial organisms based on its Kow of -1.2 (pH 7). 

3.3 Proposed Use Pattern 

Bicyclopyrone is a new active ingredient being proposed for use on field corn, seed corn, silage 

corn, yellow popcorn, and sweet corn. A petition has also been submitted for a tolerance on 

imported sugarcane. A summary of the proposed use directions is included in Table 3.3.1 below. 

Table 3.3.2 provides a summary 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 Corn, Yellow Popcorn, and Sweet Corn

Pre-plant, preemergence, or 

early postemergence 

Groundboom 

SC 

SYN-A16003 

Herbicide1

[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 45 
Bicyclopyrone Human Health Risk Assessment D421265

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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 

Herbicide2,3 

[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; chemical-resistant gloves; chemical-resistant footwear plus socks; chemical-resistant 

apron when mixing/loading, cleaning up spills, or cleaning equipment, or otherwise exposed to the concentrate; chemical-resistant headgear for 

overhead exposure. 

3. Other active ingredients per gallon: atrazine 1.0 pound, bicyclopyrone 0.06 pounds, mesotrione 0.24 pounds and S-metolachlor 2.14 pounds. 

All application rates for chemicals other than bicyclopyrone are equal to or below currently approved labeled rates for these chemicals. 

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 Wheat, 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 evaluation of the residue data 

relative to the proposed use. 

3.4 Anticipated Exposure Pathways 

Based on the proposed bicyclopyrone application scenarios, dietary exposure is an anticipated 

exposure pathway as residues of bicyclopyrone may be found in/on crops, livestock 

commodities, and drinking water. Exposure in the 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 justice concerns, to the extent possible, were considered in this 

human health risk assessment, in accordance with U.S. Executive Order 12898, “Federal Actions 

to Address Environmental Justice in Minority Populations and Low-Income Populations,” 

(http://epa.gov/compliance/ej/resources/policy/exec_order_12898.pdf). As a part of every 
Bicyclopyrone Human Health Risk Assessment D421265

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pesticide risk assessment, OPP considers a large variety of consumer subgroups according to 

well-established procedures. In line with OPP policy, HED estimates risks to population 

subgroups from pesticide exposures that are based on patterns of that subgroup’s food and water 

consumption, and activities in and around the home that involve pesticide use in a residential 

setting. Extensive data on food consumption patterns 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 pesticide. These data are analyzed and categorized 

by subgroups based on age, season of the year, ethnic group, and region of the country. 

Additionally, OPP is able to assess dietary exposure to smaller, specialized subgroups and 

exposure assessments are performed when conditions or circumstances warrant. Whenever 

appropriate, non-dietary exposures based on home use of pesticide products and associated risks 

for adult applicators and for toddlers, youths, and adults entering or playing on treated areas 

post-application are evaluated. Further considerations are currently in development as OPP has 

committed resources and expertise to the development of specialized software and models that 

consider exposure to bystanders and farm workers as well as lifestyle and traditional dietary 

patterns among specific subgroups. 

4.0 Hazard Characterization and Dose-Response Assessment 

Bicyclopyrone is an effective inhibitor of the enzyme HPPD and blocks the pathway of 

prenylquinone biosynthesis in plants. Bicyclopyrone shares a structural and toxicological profile 

similar to mesotrione. For mesotrione, a wealth of mechanistic data are available both 

experimentally and in the literature which thoroughly characterize 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 elevated levels of tyrosine in 

the blood (tyrosinemia). Tyrosinemia in laboratory 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 adequate 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 registrant and consisted of a bacterial reverse 

gene mutation test, a micronucleus test, and an in vitro chromosome aberration test. In addition, 

two mechanistic studies were submitted to evaluate the effect of bicyclopyrone on thyroid 

function. Appendix A includes a summary of the bicyclopyrone toxicological database. 
Bicyclopyrone Human Health Risk Assessment D421265

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HED’s Hazard and Science Policy Council (HASPOC) 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 developmental neurotoxicity and subchronic inhalation 

study at this time (TXR# 0056613 and 0056911). 

4.2 Absorption, Distribution, Metabolism, & Elimination (ADME) 

The absorption, distribution, metabolism and excretion of bicyclopyrone was characterized 

extensively in a series of studies using both low- and high-dose, single and repeated dosing 

protocols. Bicyclopyrone was well absorbed from the gastrointestinal (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 (Cmax) were reached in both male and female rats within 1.3-2.3 hours (Tmax), 

indicating rapid absorption kinetics. 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 clearance 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 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 females, respectively. The highest levels of 

radioactivity were found in the liver (4% and 3% of the administered dose in males and females, 

respectively) and kidney (0.3% and 0.4% of the 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 near or below the limit of detection (LOD). 

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, indicating greater metabolism in males. 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 majority 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

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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/cm2

). 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 extrapolate oral doses to dermal-equivalent doses, for 

dermal exposure scenarios. This dermal absorption factor includes the absorbed and potentially 

absorbed fractions derived from the sum of residues measured in the tissues/carcass, excreta, 

application site skin, and tape strip 3 (chemical associated with tape strips 1 and 2 is considered 

non-penetrating). The application site was included since data demonstrate ongoing depletion of 

the dose from the application site after washing and a corresponding increase in tissues and 

excreta over time, which suggests the chemical at the 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 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 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 hyperplasia and a chronic progressive nephropathy. 

While minor instances of ocular effects where observed 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 occurred in the eye and the thymus. Following 

chronic exposure, there was a dose-dependent increase 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 absolute 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 developmental 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. Fetal 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, costal cartilage 11 long). In New Zealand White 

rabbits, maternal effects consisted of mortality/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 effect at the lowest dose tested was the appearance of the 27th

presacral vertebrae. There were two studies in Himalayan rabbits. In both studies, maternal 

effects consisted of macroscopic findings in the stomach wall and an increased incidence of postimplantation loss at the 250 mg/kg/day dose level. In the first study, fetal effects occurred 

starting at 50 mg/kg/day and consisted of skeletal variations (increased incidence of the 27th
Bicyclopyrone Human Health Risk Assessment D421265

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prepelvic vertebra and malpositioned pelvic girdle). In the second 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 other chemicals in this class. 

In the two-generation reproductive study in rats, ocular toxicity occurred in parents and offspring 

and there was no increased offspring susceptibility of any kind. Reproductive effects included 

changes in sperm parameters, and a decrease of precoital interval. 

To determine the mechanism for the thyroid hyperplasia observed in the chronic/carcinogenicity 

study in rats, two mode-of-action studies 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 T3 and T4 levels, 2) increased thyroid follicular cell 

hypertrophy, 3) increased liver weights associated, and 4) increased hepatocellular centrilobular 

hypertrophy and increased hepatic uridine diphosphate glucuronyl transferase (UDPGT) 

activities. 

Bicyclopyrone is categorized as having low acute lethality via all routes of administration 

(Categories III and IV). Bicyclopyrone produces minimal eye irritation and mild acute 

inhalation toxicity (Toxicity 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 exposure scenarios. The toxicology database for 

bicyclopyrone is adequate for characterizing toxicity and quantification of risk for food and nonfood uses; however, LOAELs from the New Zealand white rabbit developmental and 

chronic/carcinogenicity rat toxicity studies have been used as the POD for several scenarios. 

There is no evidence of neurotoxicity in either of the neurotoxicity screening batteries, though 

there are signs in the chronic dog study; the concern is low since the study and POD chosen for 

the chronic dietary exposure scenario is protective 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 characterized and the selected endpoints and uncertainty factors 

are protective of the observed fetal effects. Lastly, there are no residual uncertainties in the 

exposure database. 

4.4.1 Completeness of the Toxicology Database 

The toxicology database for bicyclopyrone 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 subchronic 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 the 
Bicyclopyrone Human Health Risk Assessment D421265

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chronic dog study (swelling of the dorsal root ganglion and nerve 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 all developmental studies in the 

bicyclopyrone database, skeletal effects and cartilage variations are 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 and retention of FQPA factor are protective of 

the observed fetal effects. 

4.4.4 Residual Uncertainty in the Exposure Database 

There are no residual uncertainties 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 General Population: No endpoint attributable to a single dose 

and appropriate for the U.S. general population was seen in the bicyclopyrone toxicological 

database (i.e., acute neurotoxicity study); therefore, an acute dietary point of departure was not 

established. 

Acute Dietary Endpoint for Females 13-49 Years of Age: The endpoint 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 aPAD 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/UFL. The 

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

presacral vertebrate at the developmental LOAEL of 10 mg/kg/day. This endpoint could result 

from exposure to a single dose and is protective for 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 Population: The endpoint 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 and a 1000-fold factor that included a 

10X for inter-species extrapolations, a 10X for intra-species variations, and a 10X FQPA 

SF/UFL. 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 controls, an increased incidence of thyroid follicular 

hyperplasia in males, and an increased incidence of chronic progressive 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, including women of child-bearing age. 

Short- (1-30 days) and Intermediate- (1-6 months) Term Dermal and Inhalation Endpoints: A 
Bicyclopyrone Human Health Risk Assessment D421265

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dermal toxicity study is available for bicyclopyrone; however, there is quantitative susceptibility 

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 inhalation 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 27th 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 equivalent LOAEL is 48.9 mg/kg/day (10 mg/kg/day ÷ 

20.44 % [dermal absorption factor] = 48.9 mg/kg/day). The NOAEL for the route-specific 28-

day dermal study is 50 mg/kg/day and the LOAEL 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/UFL. 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 Risk Assessment Recommendation 

In accordance with the EPA’s Final Guidelines for Carcinogen Risk Assessment (March, 2005), 

the CARC classified bicyclopyrone as having “Suggestive Evidence of Carcinogenic Potential.” 

The CARC considered the following factors in their weight-of-evidence deliberation on 

assessing the carcinogenic potential of bicyclopyrone: 

1. The corneal tumors observed in male rats are treatment related and the doses tested were 

considered to be adequate and not excessive for assessing carcinogenicity. 

2. The corneal tumors observed in male rats are supported by structure-activity relationship 

(SAR) data for the HPPD inhibitors pyrasulfotole, tembotrione, and mesotrione. 

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

4. There are no concerns for mutagenicity or genotoxicity. 

Quantification of bicyclopyrone’s carcinogenic 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 could result from exposure to 

bicyclopyrone. 

 

4.5.4 Summary of Points of Departure and Toxicity Endpoints Used in Human Risk 

Assessment 
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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 

UFA = 10X 

UFH = 10X 

FQPA SF /UFL = 

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 27th presacral 

vertebrae). 

Chronic 

Dietary (All 

Populations) 

LOAEL = 

0.28 

mg/kg/day 

UFA = 10X 

UFH = 10X 

FQPA SF/UFL= 

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” based on the presence of rare ocular tumors in 

male rats. Quantification of bicyclopyrone’s carcinogenic 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 environmentally relevant human 

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

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

(intraspecies). UFL = 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

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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 

UFA = 10X 

UFH = 10X 

UFL = 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 27th presacral 

vertebrae). 

Inhalation 

Short- (1-30 

days) and 

IntermediateTerm (1-6 

months) 

LOAEL = 

10 

mg/kg/day 

UFA = 10X 

UFH = 10X 

UFL = 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 27th presacral 

vertebrae). 

Cancer (oral, 

dermal, 

inhalation) 

Classification: “Suggestive evidence of cancer” based on the presence of rare ocular tumors in 

male rats. Quantification of bicyclopyrone’s carcinogenic 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 environmentally relevant human 

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

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

(intraspecies). UFL = 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 (rotational crops, corn, and sugarcane) and animals 

(goat, hen, and rat) is qualitatively similar, although much more extensive in plants (see 

Appendix B). In plants, bicyclopyrone 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 side 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, bicyclopyrone was the major 

component of the residue. The primary metabolic processes observed include demethylation of 

the methoxyethoxymethyl side chain, hydroxylation on one or more sites of the bicyclooctenone 

ring, a minor amount of bridge cleavage between the rings, and conjugation to some extent. 

5.1.2 Summary of Environmental Degradation 

Microbial degradation in aerobic soil and photodegradation in soil are likely to be the main 

environmental fate pathways by which the compound transforms. Major transformation products 

of bicyclopyrone include: CSCC163768 [6-(trifluoromethyl)pyridine-2,3-dicarboxylic acid], 

SYN503780, CSCD656832 [3-hydroxy-6-(trifluoromethyl)pyridine-2-carboxylic acid] 

CSCD642512 [2-[[3-(2,4-dioxobicyclo[3.2.1]octane-3-carbonyl)-6-(trifluoromethyl)-2-
Bicyclopyrone Human Health Risk Assessment D421265

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pyridyl]methoxy]acetic acid], CSAA589691 [(1S,3R)-cyclopentane-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 animals is qualitatively similar. 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 side chain followed by 

hydroxylation. The environmental fate pathways proceed via successive oxidation of the 

pyridinyl 2-methoxyethoxymethyl group and cleavage of the pyridinyl and bicyclooctenone 

rings. 

5.1.4 Residues of Concern Summary and Rationale 

The Residues of Concern Knowledgebase Subcommittee (ROCKS) met 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, CSCD675162, CSCD677306, CSCD677692, 

CSCD677694, CSCD677693, CSCD675164, and CSCD686480) 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 livestock commodities; therefore, the ROC for 

tolerance assessment and dietary risk assessment is the sum of bicyclopyrone and its common 

moieties, SYN503780 and CSCD686480, calculated as the stoichiometric equivalent of 

bicyclopyrone. 

The ROC for drinking water is the parent, bicyclopyrone. The single-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, there is no specific toxicological concern associated with their 

structure. The degradate, CSCD642512, was observed in major quantities in soil aerobic 

metabolism; however, terrestrial field dissipation studies show its presence at low relative 

amounts. Based on the low exposure expected for CSCD642512 and the absence of additional 

toxicological concern with respect 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-methoxyethoxy)methyl]-6-(trifluoromethyl)-3-pyridinecarboxylic acid. 

CSCD686480 = 2-[(2-hydroxyethoxy)methyl]-6-(trifluoromethyl)-3-pyridinecarboxylic acid. 
Bicyclopyrone Human Health Risk Assessment D421265

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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 with sugarcane. In all sugarcane and field corn 

grain samples, residues were below the LOQ. Quantifiable residues were found in the other corn 

RACs; recommended tolerance levels were obtained using the OECD calculation procedures. 

As no significant concentration was observed in any processed 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 PBIs. In the ruminant feeding study, residues were found 

only in kidney and liver with residue 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 burdens. All residue study 

results are supported by adequate storage stability data. 

5.3 Drinking Water Residue Profile 

Drinking water residues provided by EFED (Memo, C. Sutton, 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 Surface Water Concentration Calculator (SWCC) 

computer model was used to generate surface water Estimated Drinking Water Concentrations 

(EDWCs) for use in the human health dietary risk assessment, while the Pesticide Root Zone 

Model for Groundwater (PRZM-GW) and the Screening 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 bicyclopyrone use on corn were 2.87 and 0.857 μg/L, respectively. For 

groundwater sources of drinking water, the maximum acute and chronic EDWCs of 

bicyclopyrone in shallow groundwater from PRZM-GW were 3.76 and 3.23 μg/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 citrus) and with a longer simulation 

period (100 years, WI corn), the recommended values 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 acute and chronic analyses, 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) 3.761 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 concerned when dietary risk exceeds 100% of the 

PAD. The DEEM-FCID analyses estimate the dietary exposure of the general U.S. population 

and various population subgroups. The results reported 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 years old, adults 20-49 years old, and adults 50-

99 years old. 

The unrefined acute analysis assumed tolerance-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 concentrate 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 95th

percentile was 2.9% of the aPAD for the females 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 demonstrates that bicyclopyrone residues do not 

concentrate in corn or sugarcane commodities. The 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 the general U.S. population and all population 

subgroups. The population subgroup with the greatest 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 Drinking Water) Exposure and Risk for Bicyclopyrone. 

Population Subgroup

Acute Dietary 

(95th Percentile)

Chronic Dietary 

cPAD 

(mg/kg/day) 

Exposure 

(mg/kg/day) aPAD %cPAD 

(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 greatest 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 post-application exposure/risks were not assessed. 

6.1 Spray Drift 

 

Spray drift is a potential source of exposure to those nearby pesticide applications. This is 

particularly the case with aerial application, but, to a lesser extent, 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 Task 
Bicyclopyrone Human Health Risk Assessment D421265

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Force (a task force composed of various registrants which was developed as a result of a Data 

Call-In issued by EPA), EPA Regional Offices and State Lead Agencies for pesticide regulation 

and other parties to develop the best spray drift 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 drift as a potential source of exposure 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 for that pesticide will be considered 

concurrently. The approach is outlined in the revised (2012) Standard Operating Procedures 

For Residential Risk Assessment (SOPs) - Residential Exposure Assessment Standard Operating 

Procedures Addenda 1: Consideration of Spray Drift. This document outlines the quantification 

of indirect non-occupational exposure to drift. 

6.2 Residential Bystander Post-Application Inhalation Exposure 

Volatilization of pesticides may be a source of post-application inhalation exposure to 

individuals nearby pesticide applications. The agency sought expert advice and input on issues 

related to volatilization of pesticides from its Federal Insecticide, Fungicide, and Rodenticide Act 

(FIFRA) Scientific Advisory Panel (SAP) in December 2009, and 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 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., flux 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 residential exposures. Because there are no uses 

for bicyclopyrone that result in residential (non-occupational) exposures, the aggregate 

assessment need only consider food and water. Since the dietary exposure analysis included 

both food and water, the discussion and exposure estimates presented in Section 5.4 represent 

aggregate acute and chronic exposure to bicyclopyrone. All aggregate bicyclopyrone risk 

estimates are not of concern to HED. 

8.0 Cumulative Exposure/Risk Characterization 

The Hazard and Science Policy Council (HASPOC) met on June 28, 2007 to discuss the mode of 

action and human relevance of HPPD inhibiting herbicides. The following is a summary of their 

decision regarding the need for a cumulative risk assessment (HASPOC Memo, 17-DEC-2007). 

There are marked differences among species in the ocular toxicity associated with inhibition of 

HPPD. Ocular effects following treatment with HPPD inhibitor herbicides are seen in the rat but 

not in the mouse. Monkeys also seem to be recalcitrant to the ocular toxicity induced by HPPD 

inhibition. One explanation for this species-specific response in ocular 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 tyrosine aminotransferase (TAT). In contrast to 

rats where ocular toxicity is observed following exposure to HPPD-inhibiting herbicides, mice 

 

1

 Available: http://www.epa.gov/opp00001/factsheets/spraydrift.htm 
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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 starts in childhood but is 

often sustained throughout patient’s lifetime. The human experience indicates that a therapeutic 

dose (1 mg/kg/day dose) of nitisinone has an excellent safety record in infants, children, and 

adults and that serious adverse health outcomes have not been observed in a population followed 

for approximately a decade. Rarely, ocular effects 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 tyrosine levels and biological effects in various species. In the 

future, assessments of HPPD-inhibiting herbicides may consider more appropriate models and 

cross species extrapolation methods. Therefore, 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 determined 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 data protection provisions of FIFRA. Additional information on 

HED policy on use of surrogate data, including descriptions of the various sources, can be found 

at the Agency website (http://www.epa.gov/pesticides/science/handler-exposure-data.html). 

9.1 Handler Risk Assessment 

HED uses the term handlers to describe those individuals who are involved in the pesticide 

application process. Based on the anticipated use patterns, and the current labeling regarding 

types of equipment and techniques that can be used, occupational handler exposure is expected. 

The quantitative exposure/risk assessment developed for occupational handlers is based on the 

following scenarios: (1) mixing/loading liquids for groundboom applications, and (2) applying 

sprays via groundboom equipment. Dermal and inhalation risk estimates were combined in this 

assessment, since the regulatory endpoints for assessing these routes of exposure are identical. 

The occupational handler exposure and 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. 
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Table 9.1.1. Occupational Handler Non-Cancer Exposure and Risk Estimates for Bicyclopyrone. 

Exposure Scenario Crop or Target 

Dermal Unit 

Exposure 

(μg/lb ai)1

Inhalation Unit 

Exposure 

(μg/lb ai)1

Maximum 

Application 

Rate (lb 

ai/A)2

Area 

Treated (acres)3

Dermal 

(LOC = 1000) 

Inh

(LOC 

Mitigation Level Mitigation Level Dose (mg/kg/day)4 MOE5 Dose (mg/kg/day

Mixer/Loader 

Groundboom application of 

liquid formulation Corn 220 (baseline) 0.219 (baseline) 0.044 80 0.00575 1,700 0.000028 

Applicator 

Groundboom spray 

application Corn 78.6 (baseline) 0.34 (baseline) 0.044 80 0.00205 4,900 0.0000433 

1 Based on the “Occupational Pesticide Handler Unit Exposure Surrogate Reference Table” (March 2013); Level of mitigation: Baseline. 2 Based 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 %

5 Dermal MOE = Dermal LOAEL (10 mg/kg/day) ÷ Dermal Dose (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 k

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). 
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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 that 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 perform job functions, including activities 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 nature of the crop or target that was treated, the 

type of pesticide application, and the chemical’s degradation properties. In addition, the timing 

of pesticide applications, relative to harvest activities, can greatly reduce the potential for postapplication exposure. 

9.2.1 Inhalation Post-Application Risk Assessment 

There are multiple potential sources of post-application inhalation exposure to individuals 

performing post-application activities in previously treated fields. These potential sources 

include volatilization of pesticides and resuspension of dusts and/or particulates that contain 

pesticides. The agency sought expert advice and input on issues related to volatilization of 

pesticides from its FIFRA SAP in December 2009, and 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 Volatilization Screening Tool and a subsequent 

Volatilization Screening Analysis (http://www.regulations.gov/#!docketDetail;D=EPA-HQOPP-2014-0219). During Registration Review, the agency 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 evaluate the available post-application inhalation 

exposure data generated by the ARTF. Given these two efforts, the Agency will continue to 

identify the need for and, subsequently, the way to incorporate occupational post-application 

inhalation exposure into the agency's risk assessments. 

Although a quantitative occupational post-application inhalation exposure assessment was not 

performed, an inhalation exposure assessment was performed for occupational/commercial 

handlers. Handler exposure resulting from application of pesticides outdoors is likely to result in 

higher exposure than post-application exposure. Therefore, it is expected that these handler 

inhalation exposure estimates would be protective of most occupational post-application 

inhalation exposure scenarios. 

9.2.2 Dermal Post-Application Risk Assessment 

Short- and intermediate post-application dermal exposure is anticipated for the proposed crops 

with expected scenarios and resulting exposures 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

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Table 9.2.2.1. Occupational Post-application Non-Cancer Exposure and Risk Estimates for Bicyclopyrone.

Crop/Site Activities Transfer Coefficient 

(cm2/hr) 

Proposed 

Application Rate 

(lb ai/A) 

DFR1 Dermal Dose 

(mg/kg/day)2

MOE3

(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/cm2; where F = 0.25 and D = 0.10 per day. 

2 Daily Dermal Dose = [DFR (μg/cm2

) × 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, greenhouse use sites) or residential (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 studies, which resulted in the selection of a 

revised default values for the fraction of the application rate available for transfer after a foliar 

application (FAR). 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 – Determination of Dermal and Inhalation Exposure to 

Reentry Workers During Chrysanthemum Pinching in a Greenhouse” (EPA MRID 45344501). 

As a result, the range of FAR values was revised from 2-89% to 2-7%. In these data, a large 

range of transferability is observed and this variability can potentially be attributable to many 

factors such as active ingredient, formulation, field conditions in the studies, weather conditions 

(e.g., humidity), and many other difficult-to-quantify factors. Although witnessed across 

multiple chemicals, this range in FAR values is not expected when considering DFR data for a 

single chemical. At this time, the ARTF submission did not alter the selection of 25% as the 

reasonable, high-end default value. Because DFR data are not available for bicyclopyrone, EPA 

is using the default value of 25%. Although there may be a small degree of uncertainty in the 

use of the default DFR value for bicyclopyrone (i.e., there is a small chance that the FAR value 

may exceed the applicable default value), it is likely that the health-protective aspects of EPA’s 

occupational post-application assessment methodology will more than compensate for this 

potential uncertainty. For example, when assessing residential and occupational post-application 

exposure to gardens and ornamentals, EPA assumes the following: exposures occur to zero-day 

(i.e., day of application ) residues every day of the assessed exposure duration (i.e., EPA assumes 

that no dissipation or degradation occurs, it doesn’t rain, etc); individuals perform the same postapplication activities performed in the transfer coefficient study day after day (e.g., weeding, 

harvesting, pruning, etc.); and individuals engage in these post-application activities for a highend amount of time every day (represented by data reflecting time spent gardening based on 

survey data). 

Given the conservatisms discussed above and the potential compounding nature of these 

conservatisms, EPA is able to rely upon the calculated exposure estimates with confidence that 

exposure is not being underestimated. Since the highest estimated occupational post-application 

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 
Bicyclopyrone Human Health Risk Assessment D421265

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compared to the LOC of 1000); EPA is requiring the 40 CFR DFR data to facilitate any 

necessary exposure assessments refinements and to further EPA’s general understanding of the 

availability of dislodgeable foliar pesticide residues. 

9.2.3 Restricted Entry Interval 

The REI specified on the proposed label is based on the acute toxicity of bicyclopyrone. 

Bicyclopyrone has low acute toxicity via the oral, dermal and inhalation routes (Toxicity 

Category IV). It is not an eye or dermal irritant (Toxicity Category IV), and was not shown to be 

a skin sensitizer. Short- and intermediate-term post-application risk estimates 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. Therefore, the [156 subpart K] Worker Protection 

Statement interim REI of 12 hours is adequate to protect agricultural workers from postapplication exposures to bicyclopyrone. The 12-hour REI, which currently appears on one of the 

proposed labels, 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 ingredients in the product and would be addressed 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:RAB1

 
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Appendix A. Toxicology Profile 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 

no1

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 

no1

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 LD50 females >5000 mg/kg bw (94.5% ai) IV 

870.1200 Acute dermal [rat] 47841967 LD50 (Combined) >5000 mg/kg (94.5% ai) IV 

870.1300 Acute inhalation [rat] 47841968 LC50 (Combined) >5.2 mg/L (94.5% ai) IV 

870.2400 Acute eye irritation 

[rabbit] 47841970 Based on the mean degree of eye irritation, no require classification. IV 
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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 parameters 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] 

Maternal 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. 

Developmental NOAEL was not observed. 

LOAEL = 10 mg/kg bw based on skeletal 

variations (the appearance of the 27th presacral 

vertebrae). 

870.3700b Prenatal 

developmental 

(Himalayan rabbits) 

47841998 (2012) 

acceptable/guideline 

0, 10, 50, and 250 

mg/kg/day [F] 

Maternal NOAEL = 50 mg/kg bw. 

LOAEL = 250 mg/kg bw based upon 

macroscopic findings in the stomach wall of 

females and an increased incidence of postimplantation loss. 

Developmental 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] 

Maternal 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). 

Developmental 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

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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 F1 males) and an increased incidence of 

pelvic dilation of the kidney (F0 and F1 males 

and F1 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 F1 and F2 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 this 

assay, bicyclopyrone gave a negative, i.e. nonmutagenic, response in S. typhimurium strains 

TA1535, TA1537, TA98, and TA100 and E. 

coli strainsWP2 (pKM101) and WP2urvA 

(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

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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 clearance 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 majority 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

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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/cm2

 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 T3 and T4, 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.: 47841996 
Bicyclopyrone Human Health Risk Assessment D421265

Page 37 of 49 

Executive Summary: In a prenatal developmental toxicity study in rabbits (MRID #47841996), 

bicyclopyrone (NOA449280, 94.5%), in the vehicle, 0.5% (w/v) aqueous high viscosity 

carboxymethylcellulose (CMC), was administered orally 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, and 200 mg/kg/day administered 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 comparable regimen. The females were approximately 

5.5 months of age at the initiation of dose administration. All animals were observed twice daily 

for mortality and moribundity. Clinical observations, body weights, and food consumption were 

recorded at appropriate intervals. Blood samples for plasma analysis of parent and tyrosine 

concentrations were collected from all surviving 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 uteri, 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 recorded, and net body weights and net body weight 

changes were calculated. The fetuses were weighed, sexed, and examined for external, visceral, 

and skeletal malformations and developmental variations. 

Maternal effects are as follows: 

There were no test substance-related effects on survival or clinical or macroscopic findings for 

maternal animals at 10 and 50 mg/kg/day. Mean maternal body weight and food consumption 

parameters were unaffected at 10 and 50 mg/kg/day. 

A 200 mg/kg/day bicyclopyrone, significant maternal toxicity was manifested with 7 females in 

this group found dead (including 1 female that was 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 losses (as much as 639 g from the gestation day 7 

body weight). An additional two females in the 200 mg/kg/day group delivered on gestation day 

29 following slight reductions in food consumption or body weight loss. There were not effects 

on absolute maternal body weights. Mean maternal body-weight gains for this group were lower 

(although not statistically significantly) than the control group during gestation days 13-21 and a 

mean body weight loss was noted during gestation 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 often occurred in conjunction with low food 

consumption and decreased defecation when evaluated on an individual animal 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-related 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 LOAEL 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 increases 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 presacral vertebrae, and an extra site of ossification 

ventral to cervical centrum no. 2. 

A low incidence of skeletal costal cartilage anomalies (fused, bifurcated, and/or malpositioned 

costal cartilage) was observed in the 200 mg/kg/day group (4 fetuses from 3 litters in the 200 

mg/kg/day group compared to 0 fetuses in the control group). In addition, 2 fetuses from 2 litters 

at 50 mg/kg/day also exhibited costal cartilage anomalies. Although these values were at the 

upper level of the historical control incidence, an association with the test substance cannot be 

excluded. 

Based on the effects in this study, the developmental LOAEL is 10 mg/kg/day based upon 

skeletal variations (the appearance the 27th presacral vertebrae). The developmental 

NOAEL was not observed. 

Dose and Endpoint for Risk Assessment: The NOAEL was not observed. The LOAEL is 10 

mg/kg/day based upon skeletal variations (the appearance of the 27th 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 prenatal developmental toxicity study in New Zealand 

White rabbits. An aPAD 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 inter-species extrapolations, a 10X for 

intra-species variations, and a 10X FQPA SF/UFL. The endpoint of concern is a developmental 

effect characterized as an increased incidence of a 27th presacral vertebrate at the developmental 

LOAEL of 10 mg/kg/day. This endpoint is considered 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 chronic/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 and 52 female Han Wistar rats were 

assigned to the carcinogenicity study and dosed with diets containing 0, 5, 500, 2500, or 5000 

ppm bicyclopyrone for at least 104 consecutive weeks. In addition, a toxicity study comprising 

an additional five groups of 12 males and 12 females was included and dosed in an identical 

fashion for a period of 52 consecutive weeks. The 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 doses 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, corneal opacity and damage, 5000-ppm male animals 

were fed control diet over a 9-day period during 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 toxicity study animals: clinical observations, body weight, food 

consumption, hematology, coagulation, and clinical chemistry. Additionally, selected 

carcinogenicity study animals had samples taken for urinalysis at predetermined intervals and all 

underwent ophthalmoscopy examinations prior to initiation of dosing and at Weeks 50 and 102. 

Toxicity study animals received a detailed functional observation battery assessment once during 

treatment (Week 51/52). 

All surviving carcinogenicity and toxicity study animals were terminated and subjected to a 

detailed necropsy examination with a comprehensive histological evaluation after the completion 

of 104 or 52 weeks of treatment 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 incidence of opaque eyes and corneal 

damage in both sexes compared to the control group (0-2%). At 104 weeks in males, there was 

an increased incidence of thyroid follicular hyperplasia in males (19%) compared to the control 

group (4%). There was also an increase in the incidence of chronic progressive nephropathy in 

the kidneys of males (63%) compared to the control group (33%). 

At 500-ppm bicyclopyrone, there was a significant increase in the incidence of opaque eyes and 

corneal damage in both sexes (98-100%) compared 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 increase in the incidence of eye keratitis (88-100% for 

males and 87-100% for females) and the regenerative corneal hyperplasia (88-100% for males 

and 42-92% 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 (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 nephropathy in the kidneys of males (75%) compared to the control group 

(33%). In males, there was an increased incidence of squamous cell carcinoma and papilloma 

(4% and 2%) compared to the control group (0%). 

At 2500-ppm bicyclopyrone, there was a significant increase in the incidence of opaque eyes and 

corneal damage in both sexes compared to controls (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 no 
Bicyclopyrone 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 hyperplasia (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 incidence of thyroid follicular hyperplasia (23%) 

compared to the control group (4%). There was also an increase in the incidence of chronic 

progressive nephropathy in the kidneys of males (77%) compared to the control group (33%). 

There was a statistically significant 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 increase in the incidence 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 sexes there were significantly lower body weights (↓5-16% for males and 

↓5-20% for females), and a corresponding decrease 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 weights. 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 eye keratitis (88-100% for males and 73-92% for 

females) and the regenerative corneal hyperplasia (71-100% for males and 35-75% 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 (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 was a statistically significant 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 increased incidence of squamous cell carcinoma and 

papilloma (4% and 6%) compared to the control group (0%). 

Based upon the effects in this study, the 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: The 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 increased incidence of thyroid follicular hyperplasia in males, and an 

increased incidence of chronic progressive nephropathy in the kidneys of males. 
Bicyclopyrone Human Health Risk Assessment D421265

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Comments about Study/Endpoint/UFs: The endpoint 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 and a 1000-fold factor that included a 10X for 

inter-species extrapolations, a 10X for intra-species variations, and a 10X FQPA SF/UFL. 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 controls, an increased incidence of thyroid follicular 

hyperplasia in males, and an increased incidence of chronic progressive 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. 

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 susceptibility and the route specific dermal study did not assess the 

most sensitive endpoints in the database, particularly the in utero fetal skeletal effects. The 

short- and intermediate-term dermal and inhalation 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 27th presacral vertebrate. The developmental 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 equivalent LOAEL is 48.9 mg/kg/day (10 mg/kg/day ÷ 

20.44 = 48.9 mg/kg/day). The NOAEL for the route-specific 28-day dermal study is 50 

mg/kg/day and the LOAEL is 250 mg/kg/day based on ocular lesions (keratitis or degeneration 

of corneal epithelium) in a low number of animals therefore the dermal equivalent dose is more 

protective for this exposure scenario. The LOC for both dermal 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/UFL. This study protects for the fetal effects that 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. 

 
Bicyclopyrone Human Health Risk Assessment D421265

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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

O OH

CF3

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

CF3

OMe
Bicyclopyrone Human Health Risk Assessment D421265

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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

HO

CF3

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-pyridinecarboxylic acid) 

N

O

HO

CF3

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) 

HO

O

O HO

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 Photolysis 
Bicyclopyrone Human Health Risk Assessment D421265

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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 

HO

OH

O

O

N

O

OH

CF3

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

CF3

HO

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 

HO

OH

O

O

N

O

CF3

HO

OMe
Bicyclopyrone Human Health Risk Assessment D421265

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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

O OH

CF3

HO

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 

HO

OH

O

O

N

O

CF3

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 

HO

OH

O

O

N

O

OH

CF3

HO

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 

Water 
Bicyclopyrone Human Health Risk Assessment D421265

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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

HO

CF3

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

O OH

HO

CF3

Corn 

Sugarcane 

Rotational Crops Wheat Hay: 2 (0.004, 120-

day PBI) 

Ruminant 

Poultry 

Rat 

Water 

CSCC163768 

HO N

OH

O

O

CF3

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

O OH

CF3

O
Bicyclopyrone Human Health Risk Assessment D421265

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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 

HO

N

O OH

CF3

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) 

HO N

O

O

CF3

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

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Appendix C. Physical / Chemical Properties of Bicyclopyrone

Table C1. Physical / Chemical Properties of Bicyclopyrone. 

Property Results 

Molecular mass (molecular formula) 399.36 g/mole (C19H20F3NO5) 

Physical State (pure active substance) White Powder 

Melting Point (pure active substance) 65.3°C 

Relative Density (pure active substance) 1.503 g/cm3 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 Kow) 

At pH 5 log Kow = 0.25 

At pH 7 log Kow = -1.2 

At pH 9 log Kow = -1.9 

Dissociation Constant (pKa) at 20C 3.06 

 
Bicyclopyrone Human Health Risk Assessment D421265

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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. These 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 received that review, and (3) are compliant with applicable 

ethics requirements. For certain studies, the ethics review may have included review by the 

Human Studies Review Board. Descriptions of data sources, as well as guidance on their use, 

can be found at the Agency website2

. 

 

2

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

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