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EPA REGISTRATION DIVISION COMPANY NOTICE OF FILING FOR 

PESTICIDE PETITIONS PUBLISHED IN THE FEDERAL REGISTER 

EPA Registration Division contact: Shaja Joyner, 703-308-3194

Syngenta Crop Protection, LLC

PP# [Insert petition number]

EPA has received a pesticide petition PP# ([insert petition number]) from Syngenta 

Crop Protection, LLC, P.O. Box 18300, Greensboro, NC 27419-8300 requesting, 

pursuant to section 408(d) of the Federal Food, Drug, and Cosmetic Act (FFDCA), 21 

U.S.C. 346a(d), to amend 40 CFR part 180

1. by establishing a tolerance for residues of

Bicyclopyrone: 4-hydroxy-3-{2-[(2-methoxyethoxy) methyl}-6-(trifluoromethyl)-3-

pyridylcarbonyl} bicyclo [3.2.1]oct-3-en-2-one, in or on the raw agricultural 

commodities: wheat, forage at 0.50 parts per million (ppm); wheat, grain, at 0.04

ppm; wheat, hay at 0.9 ppm; wheat, straw at 0.50 ppm; wheat, bran at 0.15 ppm; 

wheat, germ at 0.10 ppm; wheat, aspirated grain fractions at 0.50 ppm; barley, grain,

at 0.07 ppm, barley, hay at 0.3 ppm; barley, straw at 0.50 ppm; barley, bran at 0.15 

ppm and barley, germ at 0.10 ppm. EPA has determined that the petition contains 

data or information regarding the elements set forth in section 408 (d) (2) of 

FDDCA; however, EPA has not fully evaluated the sufficiency of the submitted data 

at this time or whether the data supports granting of the petition. Additional data may 

be needed before EPA rules on the petition.

A. Residue Chemistry

1. Plant metabolism. The qualitative nature of residues in plants is understood based 

on corn metabolism studies. The most significant metabolites contained both the 

bicyclooctenone and pyridine rings of Bicyclopyrone and had undergone functional 

group biotransformation of mono- or dihydroxylation of the bicyclooctenone ring 

and/or O-demethylation of the methoxyethoxymethyl substituent side chain of the 

pyridine ring. 

Analytical method. Adequate analytical methodology is available for data collection 

enforcement of bicyclopyrone residues. Analytical methods GRM030.05A and 

GRM030.08A have also undergone independent laboratory validation (ILV) to 

demonstrate the suitability of the methods for the monitoring of residues of 

Bicyclopyrone in crops and animal tissues. All study methods and validation reports have 
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been found acceptable by the EPA.

3. Magnitude of residues.

Complete residue data to support the requested tolerances are submitted with this 

petition. The requested tolerances wheat, forage, wheat, grain, wheat, hay, wheat, straw, 

wheat, bran, wheat, germ, wheat, aspirated grain fractions, barley, grain, barley, hay

barley, straw, barley, bran, and barley, germ at 0.10 ppm) are adequately supported. The 

residue studies were conducted per EPA Test Guidelines 860.1000, 860.1500, and 

860.1520.

B. Toxicological Profile

1. Acute toxicity. Bicyclopyrone is of low acute toxicity by the oral, dermal and 

inhalation routes of exposure and is not irritating to the eyes or skin. Under conditions of 

a local lymph node assay in the mouse Bicyclopyrone is not considered to have a 

sensitising potential following contact with the skin. TalinorTM is of low acute toxicity 

by the oral, dermal and inhalation routes. It is slightly irritating to the skin and to the eye. 

It is a sensitizer in the Buehler test in the guinea pig. 

2. Genotoxicity. Bicyclopyrone has been examined in a range of in vitro and in vivo 

genotoxicity assays, including end points of gene mutation, chromosomal damage and 

DNA repair. is not mutagenic to bacterial or mammalian cells in vitro and is not 

clastogenic in human lymphocytes in vitro. It is not clastogenic and does not induce DNA 

repair in vivo. Bicyclopyrone shows no genotoxic potential either in vitro or in vivo.

3. Reproductive and developmental toxicity.

The potential reproductive toxicity of Bicyclopyrone has been studied in a 

multigeneration study in the rat. The NOAEL for systemic toxicity in adults was 

considered to be < 25 ppm based on ocular effects. The relevance of such effects in rats 

on human risk assessment is recognized as being low. In pups, body weights gain was 

reduced in F1 and F2 pups at 5000ppm and in F1 pups at 500ppm. Treatment related 

ocular effects and kidney weight increase were also evident at these dose levels. The 

NOAEL for systemic toxicity and sexual development in the offspring was considered to 

be 25ppm. 

A range of developmental toxicity studies have been conducted with Bicyclopyrone

comprised of a dose range-finding study and guideline compliant study in the Wistar rat, 

and dose range-finding and guideline compliant studies in two strains of rabbit: New 

Zealand White and Himalayan. Overall, the NOAEL for maternal animals was 

considered to be 50 mg/kg/day in both strains of rabbit. At a dose level of 10 mg/kg/day, 

the only treatment-related foetal effects noted were minor changes which are considered 

non-adverse, or transient in nature; this dose represents a no-observed-adverse effect 

level (NOAEL) in both strains of rabbit. A dose of 1 mg/kg/day has been clearly 

identified as a no-observed-effect level (NOEL).

4. Subchronic toxicity. The short-term toxicity of bicyclopyrone has been evaluated by 
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the oral route of administration in rats, dogs and mice. In addition, dermal toxicity was 

evaluated in rats in a 28-day study.

Bicyclopyrone was administered in the diet to rats for 90-days in two studies, one a 

preliminary study in the AlpkAPfSD rat (Rattray 2003) at dose levels 500, 2000 or 

5000ppm and one OECD guideline study in the Han Wistar rat (Shearer 2009) at dose 

levels 2.5, 10, 2500 or 5000ppm. In neither study was there a clear treatment related 

effect on clinical observations, functional observational battery (FOB), haematology or 

blood clinical chemistry parameters The characteristic sign of tyrosine toxicity, corneal 

opacity/keratitis, was noted in both sexes at dose levels 500ppm and above. Increased 

kidney weights were noted in males at dose levels of 500ppm and above but despite a 

tenfold increase in dose level there was no clear dose relationship and no accompanying 

histopathological change in the kidney. Similarly an increase in liver weight was noted at 

dose levels of 500ppm and above in males and 2000ppm and above in females. As with 

the kidney there was no clear dose response and the change was not accompanied by any 

significant changes in clinical chemistry or histopathology of the liver. The NOAEL in 

the 90 day rat studies was 10ppm (equivalent to 0.72 /0.88g/kg bwt/day for males and 

females, respectively).

In a 28-day dermal toxicity study, histopathological effects in the cornea, keratitis and 

minimal degeneration of the corneal epithelium, were noted in a small number of animals 

of sexes at 1000 and 250 mg/kg/day. Minor increases in liver weights (< 120% of 

control) in dosed males were within the historical control range and in the absence of any 

associated differences in histopathology or clinical chemistry were concluded to be of no 

toxicological significance. Similarly minor increased in kidney weights in males were 

without histopathological correlates and were considered to be of no toxicological 

significance. The 28-day dermal NOAEL was concluded to be 50 mg/kg/day.

Bicyclopyrone was administered in the diet to mice for 90 days at dose levels 100, 3500 

or 7000ppm to establish suitable dose levels for an 80 week carcinogenicity study. 

Administration of 7000ppm (equivalent to > 1000mg/kg bwt/day), the limit dose for this 

study type, to CD-1 mice did not adversely affect bodyweight or haematology 

parameters. Dose levels of 7000 and 3500ppm resulted in increased liver weight 

accompanied by minimal hepatocyte hypertrophy. At 100ppm minimal increase in liver 

weight in females only was not accompanied by any change in liver histopathology and 

was therefore considered not to be of toxicological significance. A dose level of 100ppm 

(equivalent to 15.4/20.8 mg/kg bwt/day in males and females respectively) was 

concluded to be the NOAEL for this study.

In a 28 day study at dose levels 10, 100 or 250 mg/kg the male dog dosed with 250 mg/kg 

bwt/day Bicyclopyrone was killed for humane reasons after 7 days of dosing; the top 

dose group was therefore terminated. A decrease in cholesterol was noted in both sexes at 

125 mg/kg. An increase in liver weight was noted in females only at 125 mg/kg but in the 

absence of any histopathological changes or any similar change noted in the subsequent 1 
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year study this finding was considered adaptive and of no toxicological significance. A 

dose of 125 mg/kg bwt/day Bicyclopyrone was concluded to be the NOAEL for the 90 

day study in dogs. In the 1 year study at dose levels of 2.5, 25 or 125 mg/kg one male 

from the top dose group was found dead after 336 days; there had been no prior clinical 

signs. Signs of toxicity in all animals included corneal opacity and keratitis in some 

males and females at 125 and 25 mg/kg and histopathological changes in the nervous 

system, chromatolysis and swelling of selected neurones in the dorsal root ganglion and 

minimal fibre degeneration in the sciatic nerve in some dogs from all dosed groups. A 

dose level of 2.5 mg/kg/wt Bicyclopyrone was reported to be the LOEL for the 1 year 

dog study. Syngenta concludes the No Observed Adverse Effect level (NOAEL) for the 

52-week toxicity study in dogs is 2.5 mg/kg based on an increase in corneal opacity in 

dogs treated with 25 mg/kg and above.

5. Chronic toxicity. The long-term toxicity and carcinogenic potential of Bicyclopyrone 

has been evaluated in a 104 week study in the rat which included a 52 week long-term 

toxicity phase and in an 80 week carcinogenicity study in the mouse.

The NOAEL for these findings was concluded to be 5ppm Bicyclopyrone. Other 

treatment related findings including an increased incidence of acinar atrophy of the 

pancreas in male rats and a decrease covariant heart weight, accompanied in male rats by 

a decreased incidence of cardiomyopathy, had clear NOAEL at 500ppm.

In contrast to the toxicities noted in the rat but consistent with findings noted for other 

HPPD inhibitors long-term dosing of up to the limit dose of Bicyclopyrone resulted in 

few adverse effects in the mouse. At the top dose of 7000ppm a slight reduction in 

bodyweight and bodyweight gain was noted in both sexes and an increased liver weight 

was accompanied in males only by an increased incidence of mild centrilobular 

hepatocyte hypertrophy. There was a numerically higher incidence of bronchio-alveolar 

adenomas in male mice receiving 7000 ppm Bicyclopyrone. However, no similar finding 

was noted in females and there were no other histopathological changes in the lung. 

Although higher than the study control, the incidence at 7000ppm was within the control 

range of studies running concurrently in the conducting laboratory. This numerically 

higher incidence of bronchio-alveolar adenomas in male mice at 7000ppm was concluded 

not to be related to treatment with Bicyclopyrone. A clear NOAEL for the 80 week 

study in the mouse was 1700ppm equivalent to 233 and 242 mg/kg bwt/day in male and 

female mice respectively. No treatment-related tumors were identified in the mouse 

following dietary dosing a limit dose (approximately 1000mg/kg bwt/day) for 80 weeks.

It is concluded that Bicyclopyrone does not present a carcinogenic hazard to humans.

6. Animal metabolism. Adequate data has been submitted to support the metabolism and 

distribution of bicyclopyrone has been investigated in livestock, using laying hens and 

lactating goats as representative species for poultry and ruminates, respectively
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The absorption, distribution, metabolism and excretion of [pyridinyl14C] NOA449280 

and [bicyclooctenone14C] NOA449280 were investigated following repeated oral 

administration to the laying hen. Each of the samples along with excreta was analyzed 

for characterization and identification of metabolites and to elucidate the 

biotransformation of bicyclopyrone in laying hens. Results from analysis of samples 

from both radiolabels provided the following observations:

 Radioactive residues in edible tissues consisted predominantly of 

NOA449280

 There was no appreciable difference in excretion profiles between the 

radiolabels

 Eggs contributed a minor route of excretion of the radioactivity

The absorption, distribution, metabolism and excretion of [pyridinyl14C] NOA449280 

and [bicyclooctenone14C] NOA449280 were investigated following repeated oral 

administration to the lactating goat. Results from analysis of samples from both 

radiolabels provided the following observations:

 The principal components present in tissues and milk were unchanged 

parent and the desmethyl metabolite CSAA915194. Other minor 

metabolites were found in liver

 O-demethylation produced the metabolite CSAA915194

 Hydroxylation of the bicyclooctenane ring occurred in 2 or more 

positions.

 Trace levels of a pyridine specific metabolite were observed indicating 

that cleavage of the rings was a very minor pathway

 Very little conjugation was observed

 There was no appreciable difference in excretion profiles between the 

radiolabels and distribution of residues was essentially the same for both 

labels

 Milk contributed a minor route of excretion of the radioactivity

7. Metabolite toxicology. Metabolites that are common to crop and mammalian metabolic 

pathways have been assessed as part of the in vivo toxicological assessment of 

Bicyclopyrone. In addition, based on structural analysis, crop degradates are considered 

to have lower toxicity potential than parent Bicyclopyrone and to be of no toxicological 

significance.

8. Endocrine disruption. The bicyclopyrone safety database does not contain any 

indication of a potential for direct effects of the compound on the mammalian endocrine 

system.

9. Immunotoxicity. Based on data from all relevant studies, Syngenta concludes that there 

is no evidence of immunotoxicity associated with NOA449280 Bicyclopyrone, and 
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therefore, no need to conduct additional immunotoxicity assessments, specifically a 

natural killer cell (NKC) activity assay. 

C. Aggregate Exposure

1. Dietary exposure. Tier I acute and Tier III chronic dietary exposure evaluations were 

performed for bicyclopyrone (NOA449280) using the Dietary Exposure Evaluation 

Model (DEEM-FCID Version 4.02) from EPA with 2005-2010 What We Eat in America 

(WWEIA), National Health and Nutrition Examination Survey (NHANES) consumption 

database. These bicyclopyrone exposure assessments included all current corn uses plus 

proposed uses on cereals (wheat and barley). In addition to the corn use, a sugarcane 

import tolerance was established for bicyclopyrone. Dietary exposure contribution from 

imported sugar was deemed negligible and imported sugar was not included in the risk 

assessments. The assessments utilized residue data from field trials where bicyclopyrone 

was applied at the maximum intended use rate and samples were harvested at the 

minimum pre-harvest interval (PHI) to obtain maximum residues. Projected percent crop 

treated values were estimated using the market leader approach. Secondary residues in 

animal commodities were estimated based on “maximum reasonably balanced diets” and

transfer factors were used to calculate the portion of the dietary burden transferred to 

animal tissues. Drinking water estimates were incorporated directly into the dietary 

exposure assessment using the higher of the estimated drinking water concentrations 

(EDWCs) for surface and ground water. 

Food. Acute Exposure.

Acute Exposure. The acute dietary (food only) risk assessment for females 13 to 49 year 

old (the only population group of concern) was performed using an acute reference dose 

(aRfD) of 0.1 mg/kg-bw/day, based upon a rabbit developmental toxicity study with a 

lowest observed adverse effect level (LOAEL) of 10 mg/kg/day and an uncertainty factor 

(UF) of 100X for intra- and inter-species variations; an additional 10X FQPA 

safety/uncertainty factor for using a LOAEL to extrapolate to a NOAEL. For the purpose 

of the acute risk assessment, exposure values were expressed in terms of margin of 

exposure (MOE), which was calculated by dividing the LOAEL by the exposure for each 

population subgroup. In addition, exposure was also expressed as a percent of the acute 

reference dose (%aRfD). Acute (food only) exposure at the 95th%-ile of exposures to the 

females 13 to 49 years old resulted in a MOE of 38,873 (2.6% of the aRfD of 0.1 mg/kgbw/day). Since the benchmark MOE for this assessment was 1,000 and since the EPA 

has no concern for exposures resulting in a MOE above the Benchmark MOE or below 

100% of the reference dose, Syngenta believes that there is a reasonable certainty that no 

harm will result from dietary (food only) exposure to residues arising from the registered 

and proposed uses for bicyclopyrone.

Chronic Exposure. The bicyclopyrone chronic dietary (food only) risk assessment was 

performed for all population subgroups with a chronic reference dose of 0.00028 mg/kgbw/day based on a chronic rat chronic study a lowest observed adverse effect level 

(LOAEL) of 0.28 mg/kg-bw/day and an uncertainty factor of 100X for intra- and inter-
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species variations; an additional 10X FQPA safety/uncertainty factor for using a LOAEL 

to extrapolate to a NOAEL. For the purpose of the chronic risk assessment, exposure 

values were expressed in terms of margin of exposure (MOE), which was calculated by 

dividing the LOAEL by the exposure for each population subgroup. In addition, 

exposure was also expressed as a percent of the chronic reference dose (%cRfD). 

Chronic (food only) exposure to the U.S. population resulted in a MOE of 45,561 (2.2% 

of the cRfD of 0.00028 mg/kg-bw/day). The most sensitive sub-population was children 

(1-2 years old) with a MOE of 18,348 (5.5% of the cRfD). Since the benchmark MOE 

for this assessment was 1,000 and since the EPA has no concern for exposures resulting 

in a MOE above the Benchmark MOE or below 100% of the reference dose, Syngenta 

believes that there is a reasonable certainty that no harm will result from dietary (food 

only) exposure to residues arising from the registered and proposed uses for 

bicyclopyrone.

Cancer. Bicyclopyrone is considered “not likely to be a human carcinogen”. Therefore, 

no cancer dietary risk assessment was performed for bicyclopyrone.

ii. Drinking water. The Estimated Drinking Water Concentrations (EDWCs) of 

bicyclopyrone from proposed uses on wheat and barley were determined using Tier II 

Surface Water Concentration Calculator (SWCC) which estimates pesticide concentration 

in surface water, Tier l Screening Concentration in Ground Water (SCI-GROW), Tier II 

Pesticide Root Zone Model for Ground Water (PRZM-GW), and data from 

bicyclopyrone field monitoring studies which are appropriate for estimating potential

pesticide concentrations in ground water. The surface water EDWCs resulting from 

SWCC modeling were 3.263 ppb and 0.927 ppb for acute and chronic, respectively. The 

ground water EDWCs determined from bicyclopyrone small scale field monitoring 

studies were 1.475 ppb and 0.875 ppb for acute (peak) and chronic (annual average), 

respectively. Since the surface water EDWCs exceed the ground water EDWCs, the 

surface water values were used for risk assessment purposes and will be considered 

protective for any ground water concentration concerns.

Acute Exposure from Drinking Water. The acute surface water EDWC of 3.263 ppb was 

input directly into the DEEM-FCID software as “water, direct” and “indirect, all sources” 

to model the acute drinking water exposures. Exposure contributions at the 95th%-ile of 

exposures were determined by taking the difference between the aggregate (food + 

drinking water) exposures and the food (only) exposures for each population subgroup. 

Acute drinking water exposure to the females 13 to 49 years old resulted in a MOE of 

105,263 (1.0% of the aRfD of 0.01 mg/kg-bw/day). Since the benchmark MOE for this 

assessment was 1,000 and since the EPA has no concern for exposures resulting in a 

MOE above the Benchmark MOE or below 100% of the reference dose, Syngenta 

believes that there is a reasonable certainty that no harm will result from drinking water 

exposure to residues arising from the registered and proposed uses for bicyclopyrone.

Chronic Exposure from Drinking Water. The chronic surface water EDWC of 0.927 ppb 

was input directly into the DEEM-FCID software as “water, direct tap” and “indirect, all 

sources” to model the chronic drinking water exposures. Chronic drinking water 
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exposure to the U.S. population resulted in a MOE of 19,676 (5.1% of the cRfD of 

0.00028 mg/kg-bw/day). Chronic drinking water exposure to the most exposed subpopulation (infants, <1 year old) resulted in a MOE of 4,143 (24.1% of the cRfD). Since 

the benchmark MOE for this assessment was 1,000 and since the EPA has no concern for 

exposures resulting in a MOE above the Benchmark MOE or below 100% of the 

reference dose, Syngenta believes that there is a reasonable certainty that no harm will 

result from drinking exposure to residues arising from the registered and proposed uses 

for bicyclopyrone.

2. Non-dietary exposure. There are currently no planned uses for bicyclopyrone that 

would result in residential handler (mixer/loader/applicator) or post-application exposure. 

A nondietary exposure risk assessment is therefore was not performed for bicyclopyrone.

D. Cumulative Effects

Cumulative Exposure to Substances with a Common Mechanism of Toxicity. Section 

408(b)(2)(D)(v) requires that, when considering whether to establish, modify, or revoke a 

tolerance, the Agency consider “available information” concerning the cumulative effects 

of a particular pesticide’s residues and “other substances that have a common mechanism 

of toxicity”. The EPA does not have, at this time, available data to determine whether 

bicyclopyrone has a common mechanism of toxicity with other substances or how to 

include this pesticide in a cumulative risk assessment. For the purposes of this tolerance 

action, the EPA has not assumed that bicyclopyrone has a common mechanism of 

toxicity with other substances.

E. Safety Determination

 1. U.S. population. An acute toxicological endpoint has not been established for the 

U.S. population; therefore, an acute exposure assessment was not performed for the U.S. 

population. The chronic aggregate dietary exposure analysis (food plus water) showed 

that exposure from registered and proposed bicyclopyrone crop uses would result in a 

MOE of 13,742 (7.3% of the cRfD of 0.00028 mg/kg-bw/day) for the general U.S. 

population. Based on the completeness and reliability of the toxicity data supporting 

these petitions, Syngenta believes that there is a reasonable certainty that no harm will 

result from aggregate exposure to residues arising from all proposed bicyclopyrone uses, 

including anticipated dietary exposure from food, water, and all other types of nonoccupational exposures. 

2. Infants and children. The chronic dietary exposure analysis (food plus water) 

showed that exposure from all proposed bicyclopyrone uses would result in a MOE of 

3,658 (27.3% of the cRfD of 0.00028 mg/kg-bw/day) for the most sensitive population 

subgroup, infants (<1 year old). Since all aggregate MOEs exceed the benchmark MOE 

of 1,000, Syngenta believes that there is a reasonable certainty that no harm will occur to 

infants and children from aggregate exposure to residues arising from all proposed 

bicyclopyrone uses, including anticipated dietary exposure from food, water, and all other 

types of non-occupational exposures.
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F. International Tolerances

There are currently no Maximum Residue Limits (MRLs) set for bicyclopyrone for crops 

by the Codex Alimentarius Commission. International MRLs for the herbicide 

bicyclopyrone have been established in Australia, Brazil, Canada and the United States 

for residues of bicyclopyrone in a variety of commodities.