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**EPA REGISTRATION DIVISION COMPANY NOTICE OF FILING FOR PESTICIDE PETITIONS PUBLISHED IN THE FEDERAL REGISTER**  **EPA Registration**  **Division contact: Kathryn Montague**  **, 703 -**  **30 5**  **- 1243**  Sy ngenta Crop Protection, LLC PP# [ 3F8225 ] EPA has received a pesticide petition PP# [ 3F8225] from Sy ngenta 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 Bicyclop yrone : 4 - hydroxy- 3 - {2 - [(2 - methoxy ethoxy ) meth yl } - 6 - (trifluoromethyl) - 3 - py rid yl carbon yl } bicy clo [3.2.1]oct - 3 - en - 2 - one , in or o n 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. 4 0 ppm ; sweet corn, ears at 0. 0 4 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. Sy

ngenta believes the studies supporting this bicy clopy rone 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 b y a pre - emergence treatment at 200 g ai/ha for on e 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 earl y foliage (28 day s 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

**14 C**  **- Labeled Ring**  **Test Substance R**  **e l**  **a t**  **i ve**  **M a**  **tu r**  **i ty**  **S a**  **m**

**p l**  **e /**  **C o**  **mm od**  **i t**  **y P**  **r e** **- e**  **m e**  **r g**  **e n**  **c e** 

**A pp**  **li c**  **a ti**  **on P**  **r e** **- a**  **n d**  **p o**  **s t**  **** **E m**  **e r**  **g e**  **n c**  **e A**  **pp li**  **c a**  **ti on**  **T R**  **R ,**  **m g/k** **g %**  **T RR** 

**e x**  **t ra**  **c t**  **e d**  **T R** 

**R ,**  **m g/k** **g %**  **T RR** 

**e x**  **t ra**  **c t**  **e d** 

B i c y c l o o c t e none E ar ly f

o li a ge F o l i a ge 0 . 033 77 . 7 0 . 354 83 . 2 F o ra g e F o ra g e 0 . 023 78 . 3 0 . 459 84 . 0

Immature C obs <0 . 010 NE 0 . 029 89 . 1 Immature G ra in <0 . 010 NE 0 . 037 91 . 9 M a tu r i ty S t o v e

r 0 . 032 79 . 1 0 . 455 80 . 8 C obs <0 . 010 NE 0 . 036 73 . 2 G ra in <0 . 010 NE 0 . 058 76 . 6

P y r i dine E ar ly f

o li a ge F o l i a ge 0 . 042 83 . 5 0 . 440 93 . 1 F o ra g e F o ra g e 0 . 083 88 . 1 0 . 925 90 . 6

Immature C obs <0 . 010 NE 0 . 033 69 . 7 Immature G ra in <0 . 010 NE 0 . 020 88 . 8 M a tu r i ty S t o v e

r 0 . 077 80 . 7 0 . 762 83 . 9 C obs <0 . 010 NE 0 . 018 77 . 4 G ra in <0 . 010 NE 0 . 025 78 . 8 NE

– N o t extra c t e d a s T RR o f c o mm od it y <0 . 010 mg/k g Analy sis of the harvested fractions show that NOA449280 was extensively metabolized to a highly

complex mixture of components with the principle biotransformations as follows:
 h y dr o xyl at i o n o f t h e b i c yc loo c t e no n e r in g in at l e a s t t w o p o s i t i o ns to p ro duce i s o me r s o f mo no h y dr o xyl at ed and d ih y

dr o x y l at ed NOA449280
 O - d e me t hyl at i o n , and s ucc e s s ive o x i dat i o n o f t h e m e t h o x y e t h o xy m e t hyl s i de c h a in o f NOA449280 t o p ro duce de s me t hyl , carb o xyl a nd a l c o h o l m e t a b o l i t e s  c l e a vage be t ween t h e b i c y c loo c t e no n e and p y

r i d in e r in g s ys t e m s o f NOA449280
 c o n j ug at i o n o f s o me o f t h e ab o v e me t a b o l i te s t o f o r m t h e i r O - g l y c o s i d es The most significant metabolites contained both the bicyclooctenone and py ridine rings of NOA449280 and had undergone functional group biotransformation of mono - or dihydroxylation of the bicyclooctenone ring and/or O - demethylation of the methoxy ethoxymeth yl substituent side chain of the p yridine ring.3
**Bicyclooctenone**   ** 14** **C Pyridine**  **- 14**  **C Corn Sample/**  **Comm odity**  **Me tabolite**  **% of TRR**  **R es**  **i d**  **u e** 

**( mg**  **/ k**  **g )**  **% o**  **f**

**T RR**  **R e**  **s i**  **d u**  **e**

**( mg**  **/ k**  **g )** 

Forage NOA449280 1.6 0.007 ND ND

CSAA806573 glycoside N A N A 4 . 6 0 . 0 42 CSCD686480 glycoside N A N A 1 . 8 0 . 0 1 7 CSCD686481 N A N A 3 . 0 0 . 0 27 CSAA589691 4 . 3 0 . 0 2 0 NA N A Total desmethyl dihydroxy NOA449280 isomers 1 1 5 . 4 0 . 0 7 0 3 5 . 7 0 . 3 31 Total desmethyl monohydroxy NOA449280 isomers 1 1 5 . 3 0 . 0 7 1 2 1 . 7 0 . 2 00 Total monohydroxy NO449280 isomers 1 4 . 1 0 . 0 1 9 2 . 4 0 . 0 22 CSCD677694 N D N D 1 . 8 0 . 0 17 CSCD642512 2 . 0 0 . 0 0 9 ND N D

Stover To t a l C S AA 8 0 6 573 (includes

conjugates) NA NA 6 . 1 0 . 0 46 C S C D 6 8 6 48 0 g l yco s i de NA NA 3 . 1 0 . 0 2 4 C S CD 6 8 6 481 N A N A 0 . 8 0 . 0 06 C S AA 5 8 9 691 3 . 8 0 . 0 17 N A N A T o t a l d e s m

e th yl d i h yd

r o xy N OA4 4 9 28 0 i s o m e r s 1 1 1 . 3 0 . 0 5 1 2 1 . 4 0 . 1 6 3 T o t a l d e s m

e th yl m o n oh yd r o xy N OA4 4 9 28 0 i s o m e r s 1 11.0 0 . 0 50 1 1 . 7 0 . 0 89 Total monohydroxy NO449280 isomers 1 2.1 0.010 4.5 0.034 C S CD 6 7 7 694 1 . 6 0 . 0 07 N D N D C S CD 6 4 2 512 2 . 2 0 . 0 10 2 . 6 0 . 0 20 Mature Grain C S A A 589691 41 . 7 0 . 024 N A N A

T o t al de s me t hy

l monohydr oxy NOA4 49280 i s o m e r s ND ND 27.9 0.007 T o t al monohydr oxy NO 449 2 80 ND ND 19.3 0.004 C S C D 642512 N D N D 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 specificit y, and conjugates C o m p ar i s o n o f t h e qu a l i

t at ive p r o f

il e o f me t a

b o l i t e s p r e s e n t in s a m p l e s f r o m t h e p r e - e me r g e nc e o n l y ap p li c at i o n w i t h t h o s e f r o m t h e co m

b in e d p r e - and p o st e me r g e nc e a

p p li cat i o ns d e mo n s t r a

t e d a hi g h d e gr e e o f s imi l ar i t y. Metabolism studies conducted in corn and sugarcane have provided a detailed understanding of the biotransformation of NOA449280 in these crops. The metabolic pathway s in these crops are similar. NOA449280 was found onl y in corn forage and was absent in all other samples examined. The majority of the metabolites were formed b y h ydrox yl ation on one or more sites on the bicy clic ring or demethylat ion of the methoxyethox ym eth yl side chain followed b y hydrox yl ation. Some conjugation to glycosides was observed with the hydroxyl derivatives and some cleavage between the two ring s ys tems was also observed.4

Analytical method. For data submitted with this petition , the following analy tical methods were utilized: **Substrate Analyte(s)**  **Method Limit of**  **Quantification (mg/kg)**  **as reported**  **Method/ Reference**

**(MRID#) Crops**  CSCD686480 1 ,

SYN503780 2 , CSAA806573 LC MS/MS 0.0 1

0. 01 0.01 GRM030.05A

**47841946** Crops CSAA589691 3 LC MS/MS 0.01 GRM030.09A **47841972** Milk, eggs, tissues NOA449280,

SYN503780 2 , CSCD686480 1 LC MS/MS 0.01

0.0 1 0.0 1 GRM030.08A

**47842046** 1 Residues are determined as CSCD686480 but reported as CSAA915194 equivalents (LOQ 0.01 mg/kg) 2 Residue s are determined as SYN503780 but reported as NOA449280 equivalents (LOQ 0.01 mg/kg) 3 Only corn grain samples were anal ys ed 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 anal yz ed in duplicate and fortified samples were anal yz ed in quintuplet at the limit of quantification (LOQ, 0.01 μg/L) for each anal yte and in quintuplet at ten times the L OQ (0.1 mg/kg). Acceptable mean recoveries of between 70% and 120% with a relative standard deviation of <20% were found for all matrices. Anal yt ical 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 bicyclop yrone as a selective herbicide for the control of broad leaf weeds and annual grasses in corn. Bicyclopy rone is to be applied from pre emergence through to early post - emergence using standard spraying equipment. Bicyclop yrone is generally to be a pplied once annually

at a rate of 50 g bicyclopy rone/ha in corn. Additionally , a split application pre - emergent and early post emergent may

be used equating to the maximum recommended application/year. Twent y - nine corn crop field 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 bicy clop yrone. When the corn was 30 inches tall or at the 8 - leaf stage (V8), whichever occurred first, one over - the -5

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 INF ORMATION**  **FIELD CORN / SIMULATED SWEET CORN Sample Type**  **Sample Event DAA**  **1 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/Earl y 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 **PO PCORN** 

Grain At Maturity 98 - 100 Stover At Maturity 98 - 100 1 DAA = Day s After Application 2 K+CWHR = Kernels plus cob with husks removed. The anal yt ical phase was conducted at ABC Laboratories, Columbia, MO. The anal yt ical methods used to determine bicyclop yrone - related residues in these samples are listed in th e following table. **Analytical Method 1**  **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 concurrentl y 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 anal yt ical metho d 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 stand ard deviation (RSD) was <20%. These data demonstrate acceptable performance of the anal yt ical method during the conduct of this study . Residues of NOA449280 and CSAA915194 (detected as SYN503780 and CSCD686480 respectivel y) were not found in any non - tr eated control samples at levels above 0.01 ppm. A summary

of the residues (sum of the two common moiety analy tes) 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 Ma**  **x HAFT**  **4 Median**  **Mean Std. Dev.**  **Sw eet Corn Forage**  28 ND 0.280 0.229 0.113 0.117 0.0694 **Sw eet Corn Ears**  **(K+CWHR) 5**  28 ND 0.0355 0.0346 <LOQ 0.0162 0.0056 **Sw eet 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 y et been proposed. Therefore, anal ys is 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). Itappears that NOA412101 ( CSAA589691) residues are not unique to bicy clopy rone. A summary

of NOA412101 ( CSAA589691) residues found in corn grain treated with bicyclop yrone at a nom inal 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**  **Ma x**  **HAFT 3**  **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 bicyclop yr one 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 Exp osure 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 dai ry cattle feeding stud y (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 ey es or skin. Under conditions of a local l ymph 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 ey e. Itis 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 ey e. Itis 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 ey es or skin. Under conditions of a local ly mph 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 ey e. 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 moderately8 irritating to the skin and to the ey e. It is a sensitizer in the Buehler test in the guinea pig. A summary

of the a cute toxicity

studies are cited below:

**Hazard Indicator**  **(Guideline No.) Bicyclopyrone** 

**Technical (NOA449280)**  **SYNA16003 (SL)**  **SYNA19707**

**(ZC) Tox Category** 

**(respectively)**
Acute Oral LD 50 , 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. Genotoxic i ty. Bicyclopy rone has been examined in a range of in vitro and in vivo genotoxicity

assay s, 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 ly mphocy tes in vitro . It is not clastogenic and doe s 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 studie d in a multigeneration study

in the rat. Dose levels of 0, 25, 500 or 5000ppm, selected on the basis o f a preliminary range finding study , were administered in the diet to groups of 25 male and 25 female F0 generation9 rats. Treated diet was administered c ontinuously 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 m aintained until the F2 litters were weaned. NOA449280 had no toxicologically

significant effect on reproductive parameters in either generation. In adults, lower bod ywei ght and bod yweight gain were noted in F0 and F1 animals at 5000ppm and in F1 animals at 500ppm. Sy stemic toxicity was evident in adults at 500 ppm and above including corneal opacity , histopathological and weight changes in the thy roid reflecting minor perturbations in thyroid homeostasis and increased kidney weight accompanied b y histopatho logical changes in the kidney , pelvic dilatation , in F1 animals only . At 25 ppm ocular opacit y was noted in F0 males and in F1 males and females. The NOAEL for s ys temic 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 the se dose levels. The NOAEL for s ys temic 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 Himalay an. Groups of 24 bred female Wistar rats were administered NOA449280 b y oral gavage at dose levels of 0, 100, 500 or 1000 mg/kg/day on gestation day s 6 - 20, and cesarean section performed on gestation day 21. Effects on maternal bod y weight and weight gain were observed at all doses tested, and food consumption was depressed at the two highest doses teste d (500 and 1000 mg/kg/day). There was no evidence of a teratogenic response. Pelvic girdle mal - positioning (alternativel y 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 delay s in ossification that would not be expected to have an y long - term effects on survival and developm ent. 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 b y gavage on gestation day s 7 - 28, and cesarean section performed on gestation day 29. Significant maternal10 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 w ere 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 (13 th ) pair of ribs in all do se groups. Maternal t yrosine was elevated at all dose levels and skeletal effects of this nature have been shown to be associated with plasma ty rosine elevations, consistent with HPPD inhibition, the known mode of action of NOA449280. These effects are c onsidered to be of no toxicological significance. Two separate studies were conducted with the Himalay an 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 Ze aland White. Maternal toxicity

demonstrated in this strain was substantially less evident; a low incidence of maternal mortalit y and lower bod y 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 in cidence of caudal displacement of the pelvic girdle (27 pre sacral vertebrae) and supernumerary ribs were seen. These variations, which are commonly

observed in rabbits, have been shown to be associated with elevated plasma ty rosine and were likely

a refle ction of the increase in ty

rosine seen in the maternal plasma The flat dose - response in these changes parallels the plasma ty rosine levels measured in these rabbits, which rapidl y reached an apparent plateau. Similar skeletal changes were also observed i n the New Zealand White rabbit and were correlated with elevated tyrosine. The biological significance of these changes is questionable, and they are generall y regarded as of little or no toxicological significance. Superimposed on this background of t yros ine - related minor skeletal changes was an increase in the overall malformation rate at the high dose level (250 mg/kg/day) in both Himalay an rabbit studies. The malformations affected different organs/structures and were observed at visceral and skeletal examination. At 50 mg/kg/day , there was a slight11 (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

i n 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 clearl y identified as a no - observed - effect level (NOEL). 4. Subchronic toxicity. The short - term toxicity of bicy clop yr one has been evaluate d 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 - day s in two studies, one a preliminary stud y in the AlpkAPfSD r at (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, functiona l observational battery (FOB), haematology

or blood clinical chemistry

parameters. In common with other inhibitors of 4 - hydrox yphen yl py

ruvate dioxygenase (HPPD) , the rat is the most sensitive species and toxicity

noted in both studies in this case is attributable to significantl y el evated plasma ty rosine concentrations. Dose levels of 2500ppm bicy clop yrone and above resulted in reduced bod y weight and weight gain in both sexes. The characteristic sign of ty rosine toxicity , corneal opacit y/keratitis, was no ted 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 accompan yi ng histopathological chang e 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 b y an y 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, respectivel y). 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 of12 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 . Mouse NOA449280 was administered in the diet to mice for 90 day s at dose levels 100, 3500 or 7000ppm to establish suita ble dose levels for an 80 week carcinogenicity

study . Administration of 7000ppm (equivalent to > 1000mg/kg bwt/day), the limit dose for this study ty pe, to CD - 1 mice did not adversel y affect bod yweight or haematology parameters. Dose levels of 7000 and 350 0ppm resulted in increased liver weight accompanied by minimal hepatocy

te h yp ertrophy . At 100ppm minimal increase in liver weight in females onl y was not accompanied b y any change in liver histopathology

and was therefore considered not to be of toxicologi cal 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 stud y. 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 day s of dosing; the top dose group was therefore terminated. Treatment related clinical observations included hy poactivity , unsteady

gait, ny stagmus, opisthotonus, rapid heart rate and vomiting. No adverse pathology was noted in central or peripheral nervous sy stem. There were no adverse effects of treatment following 28 day s dosing at the lower dose levels of 100 and 10 mg/kg/day . Plasma t yrosine levels and increased levels of ty

rosine 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 day s dosing at a maximum of 125 mg/kg no adverse effects were noted on bod ywei ght, clinical observations, haematology or histopathology

of organs examined. A decrease in cholesterol was noted in both sexes at 125 mg/kg. An increase in l iver weight was noted in females only at 125 mg/kg but in the absence of an y histopathological changes or any similar change noted in the subsequent 1 y ear 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 y ear study at dose levels of 2.5, 25 or 125 mg/kg one male from the top dose group was found dead after 336 day s; there had been no prior clinical signs. Signs of toxic ity in all animals included corneal opacit y and keratitis in some males and females at 125 and 25 mg/kg and histopathological changes in the nervous s ys tem,13 chromatoly sis and swelling of selected neurones in the dorsal root ganglion and minimal fibre degen eration 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 ye ar dog stud y . Sy ngenta 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 opacit y 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 w eek 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 - hydroxy

phen yl - py

ruvate dioxygenase (HPPD) corneal opacity accompanied b y keratitis and regenerative h yperplasia of the cornea was evident from week 4 of dosing until the end of the treatment period in animal s 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. Si milar 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 hy perplasia of, the corneal epithelium in this most sensitive species. A c lear 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 s ys temic exposure to significantly elevated t yrosine are an increased incidence of th yroid hypertroph y and hy perplasia, indicative of a perturbation in thy roid function and an increased incidence of chronic glomerulonephropathy , accompanied b y elevated covariant kidney weights and chan ges 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 cardiom yopath y, had clear NOAEL at 500ppm.

Mouse14 N OA449280 was administered in the diet to CD - 1 mice for 80 weeks in an OECD 451 guideline study (Robertson and Perry

2012). In contra s t 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 body weight gain was noted in both sexes and an increased liver weight was accompanied in males only by an increased incidence of mild centrilobular hepatocy te hy pertrophy . There was a numericall y higher incidence of bronchio - a lveolar 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 numericall y 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 t yrosine levels resulting from HPPD inhibition in this most sensitive species. Although it is known that inhib ition of H P PD in humans can result in elevated ty rosine a detailed anal ys is of the mode of action and its relevance to humans against accepted scientific criteria has shown that humans are unlikel y 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 ty rosine seen in male rats and the consequent corneal damage is unlikel y to be seen in humans (Hazard Science Policy

Co uncil 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 (a

pproximately

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 bicy clop yr one has been investigated in livestock, using laying hens and lactating goats as representative species for poultry and ruminates, respectivel y. In each study bicy clop yrone radiolabelled with 14 C in either p yri dinyl or bicyclooctenone ring was used.15 Poultry The absorption, distribution, metabolism and excretion of [py ridinyl 14 C] NOA449280 and [bicy clooctenone 14 C] NOA449280 were investigated following repeated oral administration to the laying hen **.** Excret ion balance and tissue distribution investigations were performed following repeated oral administrations for 10 consecutive day s at a nominal dose level of 20 mg NOA449280/kg of dry diet. The total radioactive recovery was 81% and 79% for the py ridinyl and bicy clooctenone labels respectivel y. The majority of the administered radioactivity was recovered in the excreta (py ridinyl label: 76%, bicyclooctenone label: 76%). The highest residues were found in liver (1.752 mg/kg and 1.776 mg/kg for p yridin yl and bicy clooctenone labels respectively) and accounted for only ca 0.3% of the administered dose. Residue levels in other commodities such as egg y olk, 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 day s. Each of the samples along with excreta was anal yzed for characterization and identification of metabolites and to elucidate the biotransformation of NOA449280 in laying hens. Results from analy sis of samples from both radiolabels provided th e 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 T he absorption, distribution, metabolism and excretion of [py ridinyl 14 C] NOA449280 and [bicy clooctenone 14 C] 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 py ridinyl and bicyclooctenone labels respectivel y. The majority of the administered radioactivity was recovered in the urine (py ridinyl label: 60%, bicyclooctenone label: 62%). The highest residues were found in liver (2.726 mg/kg and 2.965 mg/kg16 for p yridin yl and bicy clooctenone labels res pectively) 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 day s. Each of these samples along with the urine, faeces and bile were anal yz ed for characterization and identification of metabolites and to elucidat e the biotransformation of NOA449280 in lactating goats. Results from anal ys is of samples from both radiolabels provided the following observations:
 The principal components present in tissues and milk were unchanged parent and the desmeth yl metabolite CS AA915194. Other minor metabolites were found in liver  O - demeth yl ation produced the metabolite CSAA915194  Hydroxylation of the bicyclooctenane ring occurred in 2 or more positions.  Trace levels of a p yridine 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 (desmeth yl parent) and several very minor metabolites found in the liver for the goat and several samples for the laying hen. Anal ys is of the excreta and urine provide d a more detailed understanding of the biotransformation of NOA449280 in these animals and allowed for a comparison of the metabolic pathway s with that found in the rat. Both animals, goat and hen , show similar biotransformation pathway s for NOA449280. The primary metabolic processes observed include O - demeth yl ation, 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 pathway s have been assessed as part of the in vivo toxicological assessment of Bicyclop yr one. In addition, based on structural anal ys is, crop degradates are considered to have lower toxicity potential than parent Bicy clopy rone and to be of no toxicological significance. 8. Endocrine disruption . T he bicy clop yrone safety database does not contain an y indication of a potential for direct effects of the compo und on the mammalian endocrine sy stem. 9. Immunotoxicity . The purpose of this study is to provide information on suppression of the immune sy stem 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 day s did not result in suppression of the humoral component of the immune sy stem. The no - observed - effect level (NOEL) for immune suppression was 5000 ppm (equ ivalent 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 an y evidence of an effect of NOA449280 on the immune sy stem. Based on data from all relevant studies, Sy

nge nta concludes that there is no evidence of immunotoxicity associated with NOA449280, and therefore, no need to conduct additional immunotoxicity

assessments, specificall y a natural killer cell (NKC) activity assay . C. Aggregate Exposure

1. Dietary exposure. Tier III acute and chronic dietary exposure evaluation was completed for bicy clopy rone (NOA449280) using the Dietary Exposure Evaluation Model (DEEM - FCID TM ), 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 bicyclopy rone. 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 bicyclop yr one was applied at the maximum intended use rate and samples18 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 “max imum reasonabl y balanced diets” and transfer information from feeding studies. Drinking water estimates were incorporated directl y 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 ye ars 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 obser

ved adverse effect level (NOAEL) of 10 mg/kg/day and an uncertaint y 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 y ears old resulted in a MOE o f 290,215 (<0.1% of the acute RfD of 0.1 mg/kg - bw/day). The acute dietary (food onl y) 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 matern al toxicity study with a no observed adverse effect level (NOAEL) of 50 mg/kg/day and an uncertaint y factor (UF) of 100X for intra - and inter - species variations; no additional FQPA safety

factor was applied. The most sensitive sub population within the in fants and children population subgroups was children 1 - 2 y ears 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 ab ove the Benchmark MOE or below 100% of the reference dose, Sy ngenta 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 bicy clopy rone. Chronic Exposure. The bicyclop yr one chronic dietary (food onl y) 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/d ay and an uncertaint y 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 ca lculated 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 sub population was children (3 - 5 y ears old) with a MOE of 20,338 (4.9% of the chronic RfD). Since the benchmark MOE for this assessment was 10019 and since the EPA has no concern for exposures resulti ng in a MOE above the Benchmark MOE or below 100% of the reference dose, S yn genta believes that there is a reasonable certaint y that no harm will result from dietary (food onl y) exposure to residues arising from the proposed uses for bicyclop yr one. Cancer. Bicyclop yr one is considered “not likely to be a human carcinogen”. Therefore, no cancer dietary risk assessment was performed for bicyclop yrone. ii. Drinking water. The Estimated Drinking Water Concentrations (EDWCs) of NOA449280 from proposed use on corn were determined using Tier I F IR ST and Tier II PRZM/EXAMS which estimate pesticide concentration in surface water; Tier l SCI - GROW and data from NOA449280 field stud ies 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, respectivel y. 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 wi ll be considered protective for an y ground water concentration concerns. Acute Exposure from Drinking W ater. 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 b y taking the difference between the aggregate (food + drinking water) exposures and the food (alone) exposures for each population subgroup. Acute dr inking water exposure U.S. population resulted in a MOE of 139,276 (0.1% of the acute RfD of 0.5 mg/kg bw/day). The most exposed sub - population was females 13 - 49 y ears 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, Sy ngenta believes that there is a reasonable certaint y that no harm will result from acute drinking water exposure to residues arising from the current uses for NOA449280. Chronic Exposure from Drinking W ater . 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/kg bw/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 generall y has no concern for exposures below 100% of the chronic RfD, Sy ngenta believes that there is a reasonable certaint y that no harm will r esult 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 bicyclop yr one that would result in residential handler (mixer/loader/applicator) or post - a pplication exposure. A nondietary exposure risk assessment is therefore was not performed for bicyclop yr one. 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 do es not have, at this time, available data to determine whether bicyclopy rone 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 bicyclop yro ne has a common mechanism of toxicity with other substances. E. Safety Determination

1. U.S. population. The acute dietary exposure analy sis (food plus water) showed that exposure from the proposed bicy clopy rone crop uses resu lted 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 y ears 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 anal ys is (food plus water) showed that exposure from proposed bicy clop yrone 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 reliabilit y of the toxicity

data supporting these petitions, Sy ngenta believes that there is a reasonable certaint y that no harm will result from aggregate exposure to residues arising from all proposed bicyclop yr one uses, including anticipated dietary

exposure from food, water, and all other ty pes of non occupational exposures.21 2. Infants and children . The acute dietary exposure anal ys is (food plus water) showed that exposure from all proposed bicyclop yro ne 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 anal ys is (food plus water) showed that exposure from all proposed bicy clop yrone uses woul d 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 y ear old (the most sensitive population subgroup). Since all aggregate MOEs exceed the benchmark MOE of 100, Sy ngenta 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 bicyclop yrone uses, including anticipated dietary exposure from food, water and all other ty pes of non - occupational exposures. F. International Tolerances There are currently

no Maximum Residue L imits (MRL s) set for bicyclop yr one for crops by the Codex Alimentarius Commission and international MRL s for the herbicide bicy clop yro ne have not been established.