i

EPA REGISTRATION DIVISION COMPANY NOTICE OF FILING FOR 

PESTICIDE PETITIONS PUBLISHED IN THE FEDERAL REGISTER 

EPA Registration Division contact: Kathryn Montague, 703-305-1243

Syngenta Crop Protection, LLC

PP# [3F8225]

EPA has received a pesticide petition PP# [3F8225] 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: field corn, forage at 0.4 parts per million (ppm); field corn, grain, at 

0.02 ppm; field corn, stover at 0.5 ppm; popcorn, grain, at 0.02 ppm, popcorn, stover

at 0.5 ppm; sweet corn, forage at 0.40 ppm; sweet corn, ears at 0.04 ppm; sweet corn, 

stover at 0.50 ppm; and cattle liver at 0.06 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. Syngenta believes the studies supporting this bicyclopyrone

petition well characterize metabolism in plants. The metabolism and distribution of 

NOA449280 has been investigated in corn. The uptake, distribution and degradation 

of NOA449280 were investigated in corn by a pre-emergence treatment at 200 g ai/ha 

for one treatment group and by a pre-emergence treatment at 200 g ai/ha followed by

a post emergence treatment at 200 g ai/ha at the 8 – 9 leaf stage for a second 

treatment group. Samples were taken from each treatment group at early foliage (28 

days after the post emergence application; foliage only), forage (BBCH 75-79; foliage 

immature cobs and immature grain) and mature crop (BBCH 89; stover, cobs and 

grain). 

The total radioactive residues (TRR) of the harvested commodities and the 

percentages of the TRR (%TRR) are summarized below:
2

14C-Labeled Ring 

Test Substance

Relative 

Maturity

Sample/ 

Commodity

Pre-emergence 

Application

Pre- and postEmergence 

Application

TRR, 

mg/kg

% TRR

extracted

TRR, 

mg/kg

% TRR

extracted

Bicyclooctenone

Early foliage Foliage 0.033 77.7 0.354 83.2

Forage

Forage 0.023 78.3 0.459 84.0

Immature 

Cobs <0.010 NE 0.029 89.1

Immature 

Grain

<0.010 NE 0.037 91.9

Maturity

Stover 0.032 79.1 0.455 80.8

Cobs <0.010 NE 0.036 73.2

Grain <0.010 NE 0.058 76.6

Pyridine

Early foliage Foliage 0.042 83.5 0.440 93.1

Forage

Forage 0.083 88.1 0.925 90.6

Immature 

Cobs <0.010 NE 0.033 69.7

Immature 

Grain

<0.010 NE 0.020 88.8

Maturity

Stover 0.077 80.7 0.762 83.9

Cobs <0.010 NE 0.018 77.4

Grain <0.010 NE 0.025 78.8

NE – Not extracted as TRR of commodity <0.010 mg/kg 

Analysis of the harvested fractions show that NOA449280 was extensively

metabolized to a highly complex mixture of components with the principle 

biotransformations as follows:

 hydroxylation of the bicyclooctenone ring in at least two positions to

produce isomers of monohydroxylated and dihydroxylated NOA449280

 O-demethylation, and successive oxidation of the methoxyethoxymethylside

chain of NOA449280 to produce desmethyl, carboxyl and alcohol metabolites

 cleavage between the bicyclooctenone and pyridine ring systems of

NOA449280

 conjugation of some of the above metabolites to form their O-glycosides

The most significant metabolites contained both the bicyclooctenone and 

pyridine rings of NOA449280 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. 
3

Bicyclooctenone14C Pyridine -

14C

Corn Sample/

Commodity Metabolite % of 

TRR

Residue

(mg/kg)

% of

TRR

Residue

(mg/kg)

Forage

NOA449280 1.6 0.007 ND ND

CSAA806573 glycoside NA NA 4.6 0.042

CSCD686480 glycoside NA NA 1.8 0.017

CSCD686481 NA NA 3.0 0.027

CSAA589691 4.3 0.020 NA NA

Total desmethyl dihydroxy NOA449280 

isomers1 15.4 0.070 35.7 0.331

Total desmethyl monohydroxy 

NOA449280 isomers1 15.3 0.071 21.7 0.200

Total monohydroxy NO449280 isomers14.1 0.019 2.4 0.022

CSCD677694 ND ND 1.8 0.017

CSCD642512 2.0 0.009 ND ND

Stover

Total CSAA806573 (includes 

conjugates) NA NA 6.1 0.046

CSCD686480 glycoside NA NA 3.1 0.024

CSCD686481 NA NA 0.8 0.006

CSAA589691 3.8 0.017 NA NA

Total desmethyl dihydroxy NOA449280

isomers

1 11.3 0.051 21.4 0.163

Total desmethyl monohydroxy

NOA449280 isomers

1 11.0 0.050 11.7 0.089

Total monohydroxy NO449280 isomers12.1 0.010 4.5 0.034

CSCD677694 1.6 0.007 ND ND

CSCD642512 2.2 0.010 2.6 0.020

Mature Grain

CSAA589691 41.7 0.024 NA NA

Total desmethyl monohydroxy

NOA449280 isomers

ND ND 27.9 0.007

Total monohydroxy NO449280 ND ND 19.3 0.004

CSCD642512 ND ND 5.9 0.001

ND = not detected NA = not applicable

1

Total of all isomers with these structural characteristics including specific 

metabolites, metabolites of undefined substitution specificity, and conjugates

Comparison of the qualitative profile of metabolites present in samples from the

pre- emergence only application with those from the combined pre- and postemergence applications demonstrated a high degree of similarity. Metabolism 

studies conducted in corn and sugarcane have provided a detailed understanding 

of the biotransformation of NOA449280 in these crops. The metabolic 

pathways in these crops are similar. NOA449280 was found only in corn forage 

and was absent in all other samples examined. The majority of the metabolites 

were 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. 
4

Analytical method. For data submitted with this petition, the following analytical methods 

were utilized:

Substrate Analyte(s) Method Limit of 

Quantification

(mg/kg) as 

reported

Method/ Reference

(MRID#) 

Crops CSCD6864801

, 

SYN5037802, 

CSAA806573

LCMS/MS0.01

0.01

0.01

GRM030.05A

47841946

Crops CSAA5896913LCMS/MS0.01 GRM030.09A

47841972

Milk, eggs, 

tissues

NOA449280, 

SYN5037802, 

CSCD6864801

LCMS/MS0.01

0.010.01

GRM030.08A

47842046

1Residues are determined as CSCD686480 but reported as CSAA915194 equivalents 

(LOQ 0.01 mg/kg)

2 Residues are determined as SYN503780 but reported as NOA449280 equivalents (LOQ 

0.01 mg/kg)

3 Only corn grain samples were analysed with method GRM030.09A. 

The LOQ for the various crop and animal matrix methods is 0.01 mg/kg as either 

NOA449280 or CSAA915194 equivalents. Control samples were analyzed in duplicate 

and fortified samples were analyzed in quintuplet at the limit of quantification (LOQ, 

0.01 μg/L) for each analyte and in quintuplet at ten times the LOQ (0.1 mg/kg). 

Acceptable mean recoveries of between 70% and 120% with a relative standard deviation 

of <20% were found for all matrices. Analytical methods GRM030.03A, 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 NOA449280 

in crops and animal tissues. All study methods and validation reports will be submitted 

with this data package.

3. Magnitude of residues. A comprehensive program of residue field trials has been 

conducted to support the use of bicyclopyrone as a selective herbicide for the control of 

broad leaf weeds and annual grasses in corn. Bicyclopyrone is to be applied from preemergence through to early post-emergence using standard spraying equipment. 

Bicyclopyrone is generally to be applied once annually at a rate of 50 g bicyclopyrone/ha 

in corn. Additionally, a split application pre-emergent and early post emergent maybe 

used equating to the maximum recommended application/year. Twenty-nine corn cropfield trials (7 field corn/simulated sweet corn, 7 sweet corn, 12 field corn, and 3 popcorn) 

were successfully conducted in the United States to support the registration of a soluble 

concentrate (SL) formulation containing the active ingredient bicyclopyrone. When the 

corn was 30 inches tall or at the 8-leaf stage (V8), whichever occurred first, one over-the-
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top foliar broadcast spray application was made at a nominal rate of 0.045 lb ai/A (50 g 

ai/ha). The sample information is summarized in the following table. 

SAMPLE INFORMATION

FIELD CORN / SIMULATED SWEET CORN

Sample Type Sample Event

DAA1 

Range

Simulated Sweet Corn 

Forage Milk Stage 37-54

Simulated Sweet Corn 

Ears

(K+CWHR)2

Milk Stage 37-54

Field Corn Forage

45 ± 3 DALA 

or Late Dough/Early Dent 

Stage 

whichever comes first

41-47

Grain Maturity 79-113

Stover Maturity 80-113

SWEET CORN 

Forage Milk Stage 25-51

Ears (K+CWHR)2 Milk Stage 25-51

Stover 97-99 BBCH 48-96

POPCORN

Grain At Maturity 98-100

Stover At Maturity 98-100

1 DAA = Days After Application

2 K+CWHR = Kernels plus cob with husks removed.

The analytical phase was conducted at ABC Laboratories, Columbia, MO. The analytical 

methods used to determine bicyclopyrone-related residues in these samples are listed in 

the following table. 

Analytical Method1 Matrices

Analyte 

Measured

Analyte 

Equivalent 

NOA449280 – Analytical Method (GRM030.05A) for the 

Determination of Residues of NOA449280 and Structurally Related 

Metabolites as the Moieties SYN503780 and CSCD686480 and for 

the Determination of CSAA806573 in Crop Matrices. Final 

Determination by LC-MS/MS (MRID: 47841946)

All

SYN503780 NOA449280

CSCD686480 CSAA915194

NOA449280 – Analytical Method GRM030.09A for the 

Determination of NOA412101 (CSAA589691) in Field Corn Grain 

(MRID: 47841972)

Grain 

Only

NOA412101

(CSAA589691)

Not 

Applicable

1

See Analytical Phase Report (Appendix 2) for method modifications.

The definition of residue (DoR) for tolerance enforcement in crop and animal 

commodities is parent NOA449280 and its structurally related metabolites determined as 

SYN503870 and CSCD686480 by a common moiety method.
6

Residues of SYN503780 and CSCD686480 were determined in or on all of the samples 

(via method GRM030.05A). The mean recoveries from concurrently fortified samples 

ranging from 0.01 to 0.5 ppm as NOA449280 and CSAA915194 equivalents were within 

70-128%. The relative standard deviation (RSD) was <20%. These data demonstrate 

acceptable performance of the analytical method during the conduct of this study. 

Residues of NOA412101 (CSAA589691) were determined in grain samples only (via 

method GRM030.09A). The mean recoveries from concurrently fortified samples (from 

0.01 to 0.5 ppm) were within 70-120%. The relative standard deviation (RSD) was 

<20%. These data demonstrate acceptable performance of the analytical method during 

the conduct of this study. 

Residues of NOA449280 and CSAA915194 (detected as SYN503780 and CSCD686480 

respectively) were not found in any non-treated control samples at levels above 0.01 

ppm. A summary of the residues (sum of the two common moiety analytes) found in 

corn matrices treated at a nominal application rate of 0.045 lb ai/A (50 g ai/ha) is 

presented in the following table.

Matrix n

1

Sum of NOA449280 Related Residues via GRM 030.05A (ppm)

2,3

Min Max HAFT4 Median Mean Std. Dev.

Sweet Corn Forage 28 ND 0.280 0.229 0.113 0.117 0.0694

Sweet Corn Ears

(K+CWHR)5 28 ND 0.0355 0.0346 <LOQ 0.0162 0.0056

Sweet Corn Stover 14 <LOQ 0.373 0.291 0.0889 0.143 0.119

Field Corn Forage 38 ND 0.229 0.178 0.0974 0.100 0.047

Field Corn & Popcorn 

Grain 44 ND <LOQ <LOQ <LOQ <LOQ 0.0019

Field Corn & Popcorn 

Stover 44 ND 0.277 0.270 0.0495 0.0731 0.0665

1

n = number of treated samples

2 The sum of SYN503780 and CSCD686480 expressed as NOA449280 and CSAA915194 equivalents respectively.

3 LOQ = 0.01 ppm for each analyte (0.02 ppm total). For statistical purposes an individual sample residue value of 

0.005 ppm (1/2 LOQ) was used for non-detectable (ND) residues and 0.01 ppm (LOQ) was used for sample residues 

<LOQ. 

4 HAFT = Highest Average Field Trial

5 K+CWHR = Kernels plus cob with husks removed.

Residues of NOA412101 (CSAA589691) were quantified in five of the non-treated 

control samples ranging from 0.011 to 0.017 ppm. At the time of study initiation the 

definition of residue had not yet been proposed. Therefore, analysis of NOA412101 

(CSAA589691) was included in this study. Since that time the Definition of the 

Residue (DoR) for tolerance enforcement and risk assessment was proposed to be 

parent NOA449280 and its structurally related metabolites, which are determined as 

SYN503780 and CSCD686480 by a common moiety method. NOA412101 was not 

part of the proposed Definition of Residue (DoR). It appears that NOA412101 

(CSAA589691) residues are not unique to bicyclopyrone. A summary of NOA412101 

(CSAA589691) residues found in corn grain treated with bicyclopyrone at a nominal 

application rate of 0.045 lb ai/A (50 g ai/ha) is presented in the following table:
7

Matrix n

1 Analyte

NOA412101 (CSAA589691) Residues 

via GRM 030.09A (ppm)2

Min Max HAFT3 Median Mean SD

Field Corn & 

Popcorn Grain 44 NOA412101

(CSAA589691) <LOQ 0.0258 0.0258 0.010 0.0123 0.0038

1

n = number of treated samples

2 LOQ = 0.01 ppm; for statistical purposes a value of 0.01 was used for <LOQ.

3 HAFT = Highest Average Field Trial

Results from this study support the registration of bicyclopyrone applied to corn at 0.045 

lb ai/A (50 g ai/ha).

Cattle Liver

The corn residue data from the 50 g/ha rate residue study (MRID# 49227101) being 

submitted has an impact on the calculated cattle dietary burdens, the residues that could 

be found in animal commodities consuming these corn products, and the tolerances 

proposed for the animal commodities. Using the 100% Crop Treated (Acute Exposure 

model) and the Highest Average Field Trial (HAFT) residues from the 50 g/ha rate corn 

study, the dietary burdens for cattle were calculated to be 0.082 ppm (beef cattle) and 

0.34 ppm (dairy cattle). Applying the residue transfer factors from the dairy cattle 

feeding study (MRID# 47842154) to these dietary burdens the calculated residues that 

could be found in the various animal commodities showed that only cattle liver would 

exceed 0.01 ppm (0.057 ppm in dairy cow liver and 0.014 in beef cattle liver). The 

tolerance is proposed at 0.06 ppm to cover the higher residue in dairy cow liver.

B. Toxicological Profile

1. Acute toxicity. NOA449280 is of low acute toxicity by the oral, dermal 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 NOA449280 is not considered to have a sensitising

potential following contact with the skin. NOA449280 SL (A16003E) is of 

low acute toxicity by the oral, dermal and inhalation routes. It is not irritating 

to the skin and only slightly irritating to the eye. It is a sensitizer in the 

Buehler test in the guinea pig. NOA449280 ZC (A19707A) is of low acute 

toxicity by the oral, dermal and inhalation routes. It is moderately irritating to 

the skin and to the eye. It is a sensitizer in the Buehler test in the guinea pig.

NOA449280 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, NOA449280 is not considered to have a

sensitising potential following contact with the skin. NOA449280 SL

(A16003E) is of low acute toxicity by the oral, dermal and inhalation routes. It

is not irritating to the skin and only slightly irritating to the eye. It is a 

sensitizer in the Buehler test in the guinea pig. NOA449280 ZC (A19707A) is 

of low acute toxicity by the oral, dermal and inhalation routes. It is moderately
8

irritating to the skin and to the eye. It is a sensitizer in the Buehler test in the 

guinea pig. A summary of the acute toxicity studies are cited below:

Hazard Indicator

(Guideline No.)

Bicyclopyrone 

Technical

(NOA449280)

SYNA16003

(SL)

SYNA19707 

(ZC)

Tox Category 

(respectively)

Acute Oral LD50, Rat

(870.1100) LD50 >5000 mg/kg LD50 >5000mg/kg

LD50=

1750mg/kg IV , IV, III

Acute Dermal LD50, 

Rat

(870.1200)

LD50

>5000 mg/kg LD50

>5000mg/kg

LD50 

>5000 mg/kg

IV, IV, IV

Acute Inhalation 

LC50, Rat

(870.1300)

LC50 >5.21 mg/L

LC50 >5.08 mg/l

LC50 >2.59 mg/l IV,IV, IV

Eye Irritation, Rabbit

(870.2400) Not irritant

Slightly irritant

Moderately 

irritating IV, IV, III

Skin Irritation, Rabbit

(870.2500) Not irritant

Not irritant

Moderately 

irritating IV, IV, III

Skin Sensitization

(LLNA)

(870.2600)

Negative

Sensitizer

Sensitizer Not Applicable

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. NOA449280 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. NOA449280 shows no genotoxic potential either in vitro or in 

vivo.

3. Reproductive and developmental toxicity.

Reproductive

The potential reproductive toxicity of NOA449280 has been studied in a 

multigeneration study in the rat. Dose levels of 0, 25, 500 or 5000ppm, 

selected on the basis of a preliminary range finding study, were 

administered in the diet to groups of 25 male and 25 female F0 generation 
9

rats. Treated diet was administered continuously throughout pre-mating 

and mating in both sexes and to females throughout gestation and lactation 

until pups were weaned at day 21. Selected pups were then maintained on 

diet, forming the F1 generation, were mated at weeks old and females 

were maintained until the F2 litters were weaned. NOA449280 had no 

toxicologically significant effect on reproductive parameters in either 

generation. In adults, lower bodyweight and bodyweight gain were noted 

in F0 and F1 animals at 5000ppm and in F1 animals at 500ppm. Systemic 

toxicity was evident in adults at 500 ppm and above including corneal 

opacity, histopathological and weight changes in the thyroid reflecting 

minor perturbations in thyroid homeostasis and increased kidney weight 

accompanied by histopathological changes in the kidney, pelvic dilatation, 

in F1 animals only. At 25 ppm ocular opacity was noted in F0 males and 

in F1 males and females. 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. 

Developmental

A range of developmental toxicity studies have been conducted with 

NOA449280 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.

Groups of 24 bred female Wistar rats were administered NOA449280 by 

oral gavage at dose levels of 0, 100, 500 or 1000 mg/kg/day on gestation 

days 6-20, and cesarean section performed on gestation day 21. Effects on 

maternal body weight and weight gain were observed at all doses tested, 

and food consumption was depressed at the two highest doses tested (500 

and 1000 mg/kg/day). There was no evidence of a teratogenic response.

Pelvic girdle mal-positioning (alternatively diagnosed as the presence of 

27 pre-sacral vertebrae in other laboratories) along with extra rib(s) was 

observed in all dose group. Slight changes in the pattern of ossification 

were also observed in the foetuses. Effects seen in foetal rats were 

categorized as variations or slight delays in ossification that would not be 

expected to have any long-term effects on survival and development.

In the New Zealand White rabbit, dose levels of 0, 10, 50 or 200 

mg/kg/day were selected based on preliminary studies. Groups of 25 bred 

females were administered NOA449280 by gavage on gestation days 7-28, 

and cesarean section performed on gestation day 29. Significant maternal 
10

toxicity was noted at 200 mg/kg/day, with decreases in body weight gain 

and food consumption leading to the loss of approximately 28% of the 

animals at this dose level due to euthanasia, abortion and/or early deaths.

There were no treatment-related malformations noted at external or 

visceral examination. Despite having exceeded the MTD, minimal 

evidence of an increase in a single grouping of skeletal changes, that was 

considered a malformation in this strain, was noted. These changes, 

classified as costal cartilage anomalies, though seen at a low incidence, 

were outside the historical control range. At 50 mg/kg/day, a low 

incidence of costal cartilage anomalies was within the historical control, 

though an association with treatment could not be excluded. The only

statistically significant treatment-related changes observed in the New 

Zealand White rabbit foetuses were increased incidences of an extra 

vertebra (27 pre-sacral vertebrae) and an extra (13th) pair of ribs in all dose 

groups. Maternal tyrosine was elevated at all dose levels and skeletal 

effects of this nature have been shown to be associated with plasma 

tyrosine elevations, consistent with HPPD inhibition, the known mode of 

action of NOA449280. These effects are considered to be of no 

toxicological significance.

Two separate studies were conducted with the Himalayan rabbit over a 

range of dose levels from 1- 250 mg/kg/day. The data generated in this 

strain presented a different picture than that seen in the New Zealand 

White. Maternal toxicity demonstrated in this strain was substantially less 

evident; a low incidence of maternal mortality and lower body weight gain 

was observed at 250 mg/kg/day in one of the two studies.

Foetal examination produced profiles of two separate responses to 

treatment. At 10 mg/kg/day and above, minor skeletal changes consisting 

of an increase in the foetal incidence (but not the litter incidence) of 

supernumerary ribs was observed. At 50 mg/kg/day and above, increases 

in the litter incidence of caudal displacement of the pelvic girdle (27 presacral vertebrae) and supernumerary ribs were seen. These variations, 

which are commonly observed in rabbits, have been shown to be 

associated with elevated plasma tyrosine and were likely a reflection of 

the increase in tyrosine seen in the maternal plasma The flat dose-response 

in these changes parallels the plasma tyrosine levels measured in these 

rabbits, which rapidly reached an apparent plateau. Similar skeletal 

changes were also observed in the New Zealand White rabbit and were 

correlated with elevated tyrosine. The biological significance of these 

changes is questionable, and they are generally regarded as of little or no 

toxicological significance.

Superimposed on this background of tyrosine-related minor skeletal 

changes was an increase in the overall malformation rate at the high dose 

level (250 mg/kg/day) in both Himalayan rabbit studies. The 

malformations affected different organs/structures and were observed at 

visceral and skeletal examination. At 50 mg/kg/day, there was a slight 
11

(non-significant) increase in the incidence of skeletal malformations. 

These changes were considered to be effects of NOA449280.

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 noobserved-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 the oral route of administration in rats, dogs and mice. In 

addition, dermal toxicity was evaluated in rats in a 28-day study.

Rat

NOA449280 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. In common with other inhibitors of 4-

hydroxyphenyl pyruvate dioxygenase (HPPD), the rat is the most sensitive 

species and toxicity noted in both studies in this case is attributable to 

significantly elevated plasma tyrosine concentrations. Dose levels of 

2500ppm bicyclopyrone and above resulted in reduced body weight and 

weight gain in both sexes. 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 
12

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.

Mouse

NOA449280 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.

Dog

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

with 250 mg/kg bwt/day NOA449280 was killed for humane reasons after 

7 days of dosing; the top dose group was therefore terminated. Treatment 

related clinical observations included hypoactivity, unsteady gait, 

nystagmus, opisthotonus, rapid heart rate and vomiting. No adverse 

pathology was noted in central or peripheral nervous system. There were 

no adverse effects of treatment following 28 days dosing at the lower dose 

levels of 100 and 10 mg/kg/day. Plasma tyrosine levels and increased 

levels of tyrosine metabolites in the urine were noted at all dose levels and 

considered to reflect exposure toNOA449280. A dose level of 125 

mg/kg/day was selected as the top dose level for the 90 day study

Following 90 days dosing at a maximum of 125 mg/kg no adverse effects 

were noted on bodyweight, clinical observations, haematology or 

histopathology of organs examined. 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 year study this finding was 

considered adaptive and of no toxicological significance. A dose of 125 

mg/kg bwt/day NOA449280 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, 
13

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 NOA449280 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 

NOA449280 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.

Rat

NOA449280 was administered in the diet to Han Wistar rats for 104 week 

in an OECD 453 guideline study (Robertson and Perry 2012) at dose 

levels of 0, 5, 500, 2500 and 500ppm. In common with other inhibitors of 

4-hydroxyphenyl-pyruvate dioxygenase (HPPD) corneal opacity

accompanied by keratitis and regenerative hyperplasia of the cornea was 

evident from week 4 of dosing until the end of the treatment period in 

animals given diets containing 500ppm NOA449280 and above. The 

findings were noted to be more severe in male rats and towards the end of 

the 104 week period a low incidence of squamous cell carcinomas and 

papillomas were noted in male rats at 50ppm and above. Similar tumours 

have been noted with other HPPD inhibitors in 104 week studies in the rat 

and are considered to be attributable to the continued damage to, and 

consequent regenerative hyperplasia of, the corneal epithelium in this most 

sensitive species. A clear No Observed Adverse Effect Level (NOAEL) 

for toxicity to the cornea was identified as 5ppm. Other toxicities 

identified in the NOA449280 chronic/carcinogenicity study in the rat and 

identified as resulting from chronic systemic exposure to significantly

elevated tyrosine are an increased incidence of thyroid hypertrophy and 

hyperplasia, indicative of a perturbation in thyroid function and an 

increased incidence of chronic glomerulonephropathy, accompanied by 

elevated covariant kidney weights and changes in urinary proteins, in 

males rats. The NOAEL for these findings was concluded to be 5ppm 

NOA449280. 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.

Mouse
14

NOA449280 was administered in the diet to CD-1 mice for 80 weeks in an 

OECD 451 guideline study (Robertson and Perry 2012). In contrast to the 

toxicities noted in the rat but consistent with findings noted for other 

HPPD inhibitors (Lewis and Botham 2012) long-term dosing of up to the 

limit dose of NOA449280 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 

NOA449280. 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 

NOA449280. 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. Dietary dosing of NOA449280 for 104 weeks to rats 

has been shown to result in squamous cell tumors of the cornea which are 

associated with constant damage and repair of the corneal epithelium and 

can be attributed to the significantly elevated tyrosine levels resulting from 

HPPD inhibition in this most sensitive species. Although it is known that 

inhibition of HPPD in humans can result in elevated tyrosine a detailed 

analysis of the mode of action and its relevance to humans against 

accepted scientific criteria has shown that humans are unlikely to exhibit 

the toxicities seen in the rat (Lewis and Botham 2012). In addition, the US

EPA have recognized that data available for HPPD inhibitors support the 

view that the high levels of plasma tyrosine seen in male rats and the 

consequent corneal damage is unlikely to be seen in humans (Hazard 

Science Policy Council Memo D 341612 dated 07/02/2007). Therefore, 

the tumors noted in male rats are considered to be rat specific and not 

relevant for human risk assessment.

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 NOA449280 does not present a carcinogenic 

hazard to humans.

6. Animal metabolism. 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. In each 

study bicyclopyrone radiolabelled with 14C in either pyridinyl or 

bicyclooctenone ring was used. 
15

Poultry

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

NOA449280 and [bicyclooctenone14C] NOA449280 were investigated 

following repeated oral administration to the laying hen. Excretion 

balance and tissue distribution investigations were performed following 

repeated oral administrations for 10 consecutive days at a nominal dose 

level of 20 mg NOA449280/kg of dry diet. The total radioactive recovery

was 81% and 79% for the pyridinyl and bicyclooctenone labels 

respectively. The majority of the administered radioactivity was 

recovered in the excreta (pyridinyl label: 76%, bicyclooctenone label: 

76%).

The highest residues were found in liver (1.752 mg/kg and 1.776 mg/kg 

for pyridinyl and bicyclooctenone labels respectively) and accounted for 

only ca 0.3% of the administered dose. Residue levels in other 

commodities such as egg yolk, egg white, muscle, peritoneal fat and skin 

and subcutaneous fat were low and in total accounted for <0.25% of the 

administered dose for both radiolabels. Radioactive residues in eggs 

(mean for a 24 hour period) reached a plateau of 0.10 mg/kg in both labels 

at approximately 6 to 8 days.

Each of the samples along with excreta was analyzed for characterization 

and identification of metabolites and to elucidate the biotransformation of 

NOA449280 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

Lactating Ruminants

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

NOA449280 and [bicyclooctenone14C] NOA449280 were investigated 

following repeated oral administration to the lactating goat. Excretion 

balance and tissue distribution investigations were performed following 

repeated oral administrations for 7 consecutive days at a nominal dose 

level of 30 mg NOA449280/kg of dry diet. The total radioactive recovery

was 87% and 82% for the pyridinyl and bicyclooctenone labels

respectively. The majority of the administered radioactivity was 

recovered in the urine (pyridinyl label: 60%, bicyclooctenone label: 62%).

The highest residues were found in liver (2.726 mg/kg and 2.965 mg/kg 
16

for pyridinyl and bicyclooctenone labels respectively) and accounted for 

only ca 0.7% of the administered dose. Residue levels in other 

commodities such as kidney, muscle and fat were low and in total 

accounted for <0.1% of the administered dose for both radiolabels. 

Radioactive residues in milk (mean for a 24 hour period) reached a plateau 

of about 0.008 mg/kg for both labels at approximately 2 to 3 days.

Each of these samples along with the urine, faeces and bile were analyzed 

for characterization and identification of metabolites and to elucidate the 

biotransformation of NOA449280 in lactating goats. 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

Metabolism studies conducted in laying hens and lactating goats have 

provided a detailed understanding of the biotransformation of 

NOA449280 in livestock. The metabolic pathways in these species are 

similar. Tissue residues in both animals consisted primarily of parent 

NOA449280 and CSAA915194 (desmethyl parent) and several very minor 

metabolites found in the liver for the goat and several samples for the 

laying hen. Analysis of the excreta and urine provided a more detailed 

understanding of the biotransformation of NOA449280 in these animals 

and allowed for a comparison of the metabolic pathways with that found 

in the rat. Both animals, goat and hen, show similar biotransformation 

pathways for NOA449280. The primary metabolic processes observed 

include O-demethylation, oxidation on one or more sites of the 

bicyclooctenone ring, a minor amount of bridge cleavage between the 

rings, and conjugation to some extent. Eggs and milk were minor routes 

of excretion for NOA449280.
17

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. The purpose of this study is to provide information on 

suppression of the immune system which might occur as a result of 

repeated exposure to a test chemical. Based on the results of this study, 

treatment of female Crl:CD-1(ICR) mice with NOA449280 in the diet for 

a minimum of 28 consecutive days did not result in suppression of the 

humoral component of the immune system. The no-observed-effect level 

(NOEL) for immune suppression was 5000 ppm (equivalent to 1192.3 

mg/kg/day). The only effect attributed to NOA449280 was higher liver 

weights noted for the 50, 500, and 5000 ppm groups; this effect was not 

considered to be adverse. There were no indications in this study that 

NOA449280 was immunotoxic. Similarly, data from subchronic, chronic, 

and reproductive toxicity studies of NOA449280 in the rat, mouse and 

dog, as appropriate, did not provide any evidence of an effect of 

NOA449280 on the immune system. Based on data from all relevant 

studies, Syngenta concludes that there is no evidence of immunotoxicity

associated with NOA449280, and therefore, no need to conduct additional 

immunotoxicity assessments, specifically a natural killer cell (NKC) 

activity assay. 

C. Aggregate Exposure

1. Dietary exposure. Tier III acute and chronic dietary exposure evaluation 

was completed for bicyclopyrone (NOA449280) using the Dietary

Exposure Evaluation Model (DEEM-FCIDTM), version 3.16 from 

Exponent. DEEM-FCID software incorporates food consumption data 

from the National Health and Nutrition Examination Survey)/ “What We 

Eat in America” (NHANES/WWEIA) dietary survey conducted in 2003-

2008. These exposure assessments included the proposed use on corn 

(including field corn, sweet corn and popcorn). In addition to the corn 

use, a sugarcane import tolerance was proposed for bicyclopyrone. All 

residues were below the LOQ (0.01 ppm) at the 1X label rate and no 

residues in sugarcane stalks were found even at exaggerated label rates of 

3X and 5X. As such, dietary exposure contribution from imported sugar 

considered 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
18

were harvested at the minimum pre-harvest interval (PHI) to obtain 

maximum residues. Percent of crop treated values were estimated based 

upon economic, pest and competitive pressures. Secondary residues in 

animal commodities were estimated based on “maximum reasonably 

balanced diets” and transfer information from feeding studies. 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. 

i. Food. Acute Exposure. The acute dietary (food only) risk assessment for 

females 13 to 49 years old was performed using an acute reference dose 

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

study with a no observed adverse effect level (NOAEL) of 10 mg/kg/day

and an uncertainty factor (UF) of 100X for intra- and inter-species 

variations; no additional FQPA safety factor was applied. Acute (food 

only) exposure to the females 13 to 49 years old resulted in a MOE of 

290,215 (<0.1% of the acute RfD of 0.1 mg/kg-bw/day). The acute 

dietary (food only) risk assessment for all general population subgroups 

was performed using an acute reference dose (aRfD) of 0.5 mg/kg-bw/day, 

based upon a New Zealand white rabbit maternal toxicity study with a no 

observed adverse effect level (NOAEL) of 50 mg/kg/day and an 

uncertainty factor (UF) of 100X for intra- and inter-species variations; no 

additional FQPA safety factor was applied. The most sensitive subpopulation within the infants and children population subgroups was 

children 1-2 years old with a MOE of 442,131 (<0.1% of the acute RfD of 

0.5 mg/kg-bw/day). Since the benchmark MOE for this assessment was 

100 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 

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 0.0028 mg/kg-bw/day based on a chronic rat chronic 

study a no observed adverse effect level (NOAEL) of 0.28 mg/kg-bw/day

and an uncertainty factor of 100X for intra- and inter-species variations; 

no additional FQPA safety factor was applied. For the purpose of the 

aggregate risk assessment, exposure values were expressed in terms of 

margin of exposure (MOE), which was calculated by dividing the NOAEL 

by the exposure for each population subgroup. In addition, exposure was 

also expressed as a percent of the reference dose (%RfD). Chronic (food 

only) exposure to the U.S. population resulted in a MOE of 48,182 (2.1% 

of the chronic RfD of 0.0028 mg/kg-bw/day). The most sensitive subpopulation was children (3-5 years old) with a MOE of 20,338 (4.9% of 

the chronic RfD). Since the benchmark MOE for this assessment was 100 
19

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 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 NOA449280 from proposed use on corn were determined 

using Tier I FIRST and Tier II PRZM/EXAMS which estimate pesticide 

concentration in surface water; Tier l SCI-GROW and data from 

NOA449280 field studies which are appropriate for estimating potential 

pesticide concentrations in ground water. The surface water EDWCs 

resulting from PRZM/EXAMS modeling were 2.365 ppb and 0.689 ppb 

for acute and chronic, respectively. The ground water EDWCs determined 

from NOA449280 small scale field studies were 0.35 ppb and 0.22 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 

2.365 ppb was input directly into the DEEM-FCIDTM software as “water, 

direct and indirect, all sources” to model the acute drinking water 

exposures. Exposure contributions at the 99%-ile of exposures were 

determined by taking the difference between the aggregate (food + 

drinking water) exposures and the food (alone) exposures for each 

population subgroup. Acute drinking water exposure U.S. population 

resulted in a MOE of 139,276 (0.1% of the acute RfD of 0.5 mg/kgbw/day). The most exposed sub-population was females 13-49 years old 

with a MOE of 42,194 (0.2% of the aRfD of 0.1 mg/kg/day). Since the 

benchmark MOE for this assessment was 100 and since EPA generally has 

no concern for exposures below 100% of the acute RfD, Syngenta believes 

that there is a reasonable certainty that no harm will result from acute 

drinking water exposure to residues arising from the current uses for 

NOA449280.

Chronic Exposure from Drinking Water. The chronic surface water 

EDWC of 0.689 ppb was input directly into the DEEM-FCIDTM software 

as “water, direct and indirect, all sources” to model the chronic drinking 

water exposures. Chronic drinking water exposure to the U.S. population 

resulted in a MOE of 19,408 (0.5% of the chronic RfD of 0.012 mg/kgbw/day). Chronic drinking water exposure to the most exposed sub-
20

population (infants, <1 year old) resulted in a MOE of 7,527 (1.3% of the 

chronic RfD of 0.0028 mg/kg-bw/day). Since the Benchmark MOE for 

this assessment was 100 and since EPA generally has no concern for 

exposures below 100% of the chronic RfD, Syngenta believes that there is 

a reasonable certainty that no harm will result from chronic drinking water 

exposure to residues arising from the current uses for NOA449280.

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. The acute dietary exposure analysis (food plus water) 

showed that exposure from the proposed bicyclopyrone crop uses resulted 

in a MOE of 119,073 (0.1% of the acute RfD of 0.5 mg/kg-bw/day) for the 

general U.S. population. For the acute aggregate assessments, females 13-

49 years old were the most sensitive subgroup with an acute aggregate 

MOE of 36,917 or 0.3% of the aRfD (Benchmark MOE = 100; aRfD = 0.1 

mg/kg/day). The chronic dietary exposure analysis (food plus water) 

showed that exposure from proposed bicyclopyrone crop uses result in a 

MOE of 13,835 (2.6% of the chronic RfD of 0.0028 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. 
21

2. Infants and children. The acute dietary exposure analysis (food plus 

water) showed that exposure from all proposed bicyclopyrone uses would 

result in a MOE of 61,997 (0.2% of the acute RfD of 0.5 mg/kg-bw/day) 

for infants less than one year old population subgroup. The chronic 

dietary exposure analysis (food plus water) showed that exposure from all 

proposed bicyclopyrone uses would result in a MOE of 5,840 (5.1% of the 

chronic RfD of 0.0028 mg/kg-bw/day) for infants less than one year old 

(the most sensitive population subgroup). Since all aggregate MOEs 

exceed the benchmark MOE of 100, 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.

F. International Tolerances

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

bicyclopyrone for crops by the Codex Alimentarius Commission and 

international MRLs for the herbicide bicyclopyrone have not been 

established.