# i

EPA REGISTRATION DIVISION COMPANY NOTICE OF FILING FOR
PESTICIDE PETITIONS PUBLISHED IN THE FEDERAL REGISTER

EPA Registration Division contact: Shaja Joyner , 703

- 30 8

- 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 request ing, 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 o n the raw agricultural
commodities: wheat , forage at 0. 5 0 parts per million (ppm ); wheat , grain

, at 0.0 4

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. 5 0 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 have2

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 c ontact with the skin. Talinor TM 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. Genotoxic i ty. 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 ly mphocytes 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 studie d 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, b ody 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 i n 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 chang es 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 evaluate d by3

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 fo r 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 l evels 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 h istopathology 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 wit hin 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 histopatholog ical 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 no t 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 thi s 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 note d 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 14

year study this finding was considered adaptive and of no t oxicological 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; the re 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 Advers e 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 e valuated 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 contra s t 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 wa s 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 i n 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 t he metabolism and distribution of bicyclopyrone has been investigated in livestock, using laying hens and lactating goats as representative species for poultry and ruminates, respectively5

The absorption, distribution, metabolism and excretion of [pyridinyl

14 C] NOA449280 and [bicyclooctenone

14 C] 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 follow ing 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

T he absorption, distribution, metabolism and excretion of [pyridinyl

14 C] NOA449280 and [bicyclooctenone

14 C] NOA449280 were investigated following repeated oral administration to the lactating goat

. Results from analysis of samples from both radiolabels provided the fol lowing 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 bi cyclooctenane 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 excr etion 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 tox icological significance.

8. Endocrine disruption

. T he 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 , and6

therefore, no need to conduct additional immunotoxicity assessments, specifically a natural killer cell (NKC) activity assay.

C. Aggregat e 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 Nut rition 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 f or 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 estima ted 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 th e 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 wit h 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 95 th %

- 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/kg

bw/day). Since the benchmark MOE for this assessment was 1,000 and since the EP A 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 re gistered 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/kg

bw/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

-7

species variations; an additional 10X FQPA safety/uncertainty factor for using a LOAEL to extrapolate to a NOAEL. For the pur pose 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 pestic ide 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 95 th %

- 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 r eference 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 su rface 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 water8

exposure to the U.S. population resulted in a MOE of 19,6 76 (5.1% of the cRfD of 0.00028 mg/kg

- bw/day). Chronic drinking water exposure to the most exposed sub

population (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 E PA 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 a nd 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 bicycl opyrone 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 wit h 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 certai nty 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 non

occupational exposures.

2. Infants and children

. The chro nic 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 a ll 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 anticipa ted dietary exposure from food, water, and all other types of non

- occupational exposures.9

F. International Tolerances

There are currently no Maximum Residue Limits (MRLs) set for bicyclopyrone for crops by the Codex Alimentarius Commission. Internation al 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.