EPA REGISTRATION DIVISION COMPANY NOTICE OF FILING FOR

PESTICIDE PETITIONS PUBLISHED IN THE FEDERAL REGISTER EPA Registration Division contact: Cynthia Giles

- Parker

– Branch Chief, Fungicide Branch July 30, 2009 [ 9E7606 ] EPA has received a pesticide petiti on ( [ 9E7606 ]) from [Syngenta Crop Protection, Inc], [410 Swing Road, P.O. Box 18300, Greensboro, NC 27419

- 8300] proposing, 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. (Option s (pick one) 1. by establishing a tolerance for residues of “NA Remove” [isopyrazam (SYN520453)] in or on the raw agricultural commodity [banana] at [0.05] parts per million (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. [SYN520453 has been studied on wheat, grapes, and lettuce. The metabolic routes of SYN520453 in all three crops were the same and the parent molecule was the primary constituent of the total radioactive resi due (TRR) in all three matrices. The most significant metabolite identified in plant was the primary alcohol, the metabolites CSCD459488 and CSCD459489 (syn and anti 2 forms respectively). Based on the results of the metabolism studies conducted, it was co ncluded that the definition of the residue for tolerance enforcement purposes should be parent isopyrazam only (SYN534968 plus SYN534969); however the residue

- of

- concern for risk assessment purposes includes parent isopyrazam (SYN534968 plus SYN534969) plu s the metabolite CSCD459488.] 2. Analytical method. [An adequate, validated method (GRM006.01B) is available for enforcement purposes for the determination of residues of isopyrazam, analyzed as the isomers SYN534968 and SYN534969, in crop samples. The lim it of quantification has been set at 0.005 mg/kg for each isomer (0.01mg/kg for SYN520453 in total). Samples are extracted by homogenization with acetonitrile:water (80:20 v/v for most crops and 50:50 v/v for straw). Extracts are centrifuged and aliquots ( equivalent to 0.2 g) are diluted with methanol:water (50:50 v/v). Final determination is by LC

- MS/MS. An analytical method suitable for the determination of residues of the metabolites CSCD459488 and CSCD459489 (syn and anti forms respectively) in crop samples using an external standardization procedure is also available (GRM006.03A). The limit of quantification (LOQ) has been set at 0.005 mg/kg for both analytes. Samples are extracted by homogenization with acetonitrile:water (80:20 v/v). Extracts are cent rifuged and aliquots (equivalent to 0.09 g) are hydrolyzed with 0.1 M HCl at 60°C for 3 hours. Aliquots are then diluted with acetonitrile and ultra pure water. Final determination is by LCMS/MS. ]

3. Magnitude of residues. [Twelve residue trials were con ducted in Latin Am erica to determine the magnitude of the residue of SYN520453 in or on bananas. The targeted treatment regime consisted of five applications at a rate of 75 grams a.i./hectare with a 10

- day retreatment interval. Bananas were harvested afte r the last application was made (0

- day PHI). Banana peel, pulp and whole fruits were analyzed for residues of parent SYN520453 [analyzed as SYN534968 (anti ) and SYN534969 (syn )], and for residues of its metabolite [analyzed as CSCD459489 (anti ) and CSCD459 488 (syn )]. The limit of quantitation for each analyte was 0.005 ppm. Mean procedural recoveries of all analytes on all matrices were between the acceptable range of 70

- 110%. The maximum residue levels of SYN520453 (summed SYN534968 and SYN534969) were 0.0 84, 0.046 and 0.048 ppm in banana bagged peel, unbagged fruit and unbagged peel, respectively. The highest residue levels of CSCD459488 were 0.010, 0.014 and 0.016 ppm in banana bagged peel, unbagged fruit and unbagged peel, respectively.] B. Toxicological Profile 1. Acute toxicity. [SYN520453 is of low acute oral toxicity. Three (of the five) acute oral studies conducted focused on the isomeric proportions of SYN520453. 3 The LD 50 for isomeric mixtures containing more than 50% of the syn isomer of isopyraz am was >2000 mg/kg.] 2. Genotoxicty. [

In vitro , both specifications of SYN520453 (Tox Reserve and 70:30) were negative for bacterial reverse mutation, in vitro cytogenetics, and
ma mmalian cells gene mutation (L5178Y TK +/

- mouse lymphoma). The L5178 TK +/

- a ssay, which is also able to detect chromosomal damage, was negative for clastogenicity. In the in vitro cytogenetic assay using primary human lymphocyte cultures, neither specification of SYN520453 induced chromosomal aberrations. In vivo , SYN520453 (Tox Reserve specification) was found to be non

- clastogenic in the rat bone marrow micronucleus assay and there was also no evidence for any indication of DNA damage or repair in the rat liver UDS (unscheduled DNA synthesis) assay.] 3. Reproductive and developmental toxicity. [SYN520453 was assessed for reproductive toxicity in a multi

- generation reproduction study in the rat at dietary inclusion levels of 0, 100, 500 or 3000 ppm SYN520453. The parental toxicity NOAEL was 100 ppm based on decreased body weight an d food consumption in females at 500 ppm, and increased liver weight and hepatocyte hypertrophy in F0 and F1 animals at 500 ppm. The offspring NOAEL was 100 ppm based on increased liver weights in F1 and F2 pups at 500 ppm. No treatment related reproductiv e parameters were affected due to treatment with SYN520453; thus the reproductive NOAEL was the top dose 3000 ppm, and a LOAEL was not established. There is no indication of increased sensitivity of offspring to SYN520453 in a multi

- generation reproduction study in rats. Two developmental toxicity studies were conducted in the rat: one with Tox Reserve
ma terial and the other with 70:30 material. In the study with Tox Reserve, rats were given oral doses of SYN520453 at 0, 20, 75 or 250 mg/kg/day on gestation days 5 to 21. The maternal NOAEL was 75 mg/kg/day based on mortality, decreasedbody weight gain and food consumption and clinical signs of toxicity at 250

mg/kg/day. The fetal NOAEL was 75 mg/kg/day based on increased postimplantation loss, a reduced number of live fetuses, decreased fetal weight and reduced ossification at 250 mg/kg/day. The fetal effects were considered to be secondary to maternal toxicity. In the rat developmental toxicity study with 70:30 material, rats were given oral doses of SYN520 453 at 0, 20, 75 or 200 mg/kg/day. The fetal and maternal NOAEL was 20 mg/kg/day based on decreased fetal body weight and delayed ossification; and decreases in maternal body weight gain at 75 and 200 mg/kg/day. The fetal effects were considered to be seco ndary to maternal toxicity. In rabbits, two preliminary developmental toxicity studies were conducted in the Himalayan rabbit and a preliminary and regulatory study were conducted in the New Zealand White (NZW) rabbit. All studies were conducted using the Tox Reserve material. 4 In the first preliminary study, Himalayan rabbits were given oral doses of 0, 100, 200 or 400 mg/kg/day. Mean maternal food consumption was decreased throughout treatment at 400 mg/kg/day. The only fetal effect possibly related to t reatment was the observation of 2 fetuses at 400 mg/kg/day with the variation of “eyes small, slight. ” In the second preliminary study, Himalayan rabbits were given oral doses of 0, 600, 800 or 1000 mg/kg/day. Maternal food consumption was slightly decreas ed at 1000 mg/kg/day. There was a small effect on male fetal body weights and a higher incidence of flexed or malrotated limbs at 1000 mg/kg/day. The main treatment related fetal finding was the observation, eyes of smaller than expected size, which
occurr ed either as an abnormality or variation. The combined incidence of small eyes (abnormality and variation) was increased in all dose groups, but not in a doserelated manner. It was concluded that administration of SYN520453 at 600

- 1000 mg/kg/day was associ ated with effects in the eye consistent with microphthalmia. A preliminary rabbit developmental toxicity study was conducted in NZW rabbits at doses of 0, 400, 700 or 1000 mg/kg/day. Maternal toxicity was noted at all dose levels tested, evident as decreas ed food consumption and decreased maternal weight gain throughout the treatment period. The effects were sufficient to produce
mo ribundity and/or abortion in animals from each dose group. Maternal liver weight was increased at all doses and hypertrophy and vacuolation were observed histopathologically. At 1000 mg/kg/day, there was an increase in the incidence of microphthalmia which was associated with the variations hemorrhagic ring around the iris and/or reddened or red areas around the eyes. In the regul atory developmental toxicity study, NZW rabbits were dosed at 0, 30, 150 or 500 mg/kg/day. The maternal NOAEL was 30 mg/kg/day based on clinical signs of toxicity (days 13

- 19), decreased food consumption, increased liver weights, and hepatocellular hypertr ophy and vacuolation at 150 and 500 mg/kg/day. The fetal NOAEL was 150 mg/kg/day based only on the single incidence of microphthalmia observed at 500 mg/kg/day. The single incidence of microphthalmia at 500 mg/kg/day was within the historical control range for the laboratory. However, based on the data from the NZW range

- finding study, which was conducted in the same laboratory, an association between treatment and thesingle incidence of microphthalmia at 500 mg/kg/day cannot be excluded.]

4. Subchronic toxicity. [Subchronic testing was conducted in the mouse, rat, and dog via the oral route of exposure, including evaluation of the effect of isomer content of SYN520453. Three 28

- day studies conducted in rats showed similar findings and confirmed that the liver was the systemic target organ for SYN520453. Liver effects were evident at doses of 500 ppm and above, with no liver effects observed at 300 ppm (approximately 28.1 mg/kg/day). The only other evidence of systemic toxicity was the observed decrease in b ody weight gain compared to controls, which tended to occur at dose levels of 2000 ppm and above, and which were observed in conjunction with decreased food utilization. The study conducted with pure syn and anti

- isomers demonstrated equivalent toxicologic al properties 5 from both a qualitative and quantitative perspective. Two 90

- day dietary studies in rats demonstrated similar toxicological findings to the 28

- day studies. The NOAELs from the two 90

- day studies were similar: a NOAEL of 300 ppm (21.3 mg/kg/ day) in the Tox Reserve study, and a NOAEL of 250 ppm for both Tox Reserve and 70:30 specification materials in the comparative study, based on decreased body weight/weight gain, clinical chemistry changes, increased liver weight, and hepatocellular hypert rophy and vacuolation at 1500 and 2000 ppm respectively. The 90

- day dietary study in mice was conducted with Tox Reserve material at 0, 500, 2500 or 7000 ppm. The systemic toxicity findings in this study were decreased body weight/weight gain observed at 2 500 and 7000 ppm. Increased liver weight was seen at all dose levels and hepatocyte hypertrophy was seen in both sexes at 2500 and 7000 ppm. Minimal hypertrophy was seen in males at 500 ppm. Two 90

- day oral toxicity studies were conducted in dogs; one was conducted using Tox Reserve and the other with 70:30 material. In the first 90

- day study with Tox Reserve material, dogs were dosed orally at 0, 30, 100 or 300 mg/kg/day. In the second 90

- day study with 70:30 material, dogs were dosed orally at 0, 10, 30 o r 250 mg/kg/day. The findings were similar. An overall NOAEL of 30 mg/kg/day was based on initial body weight loss and/or decreased weight gain and decreased food consumption, and increased liver weights (males only) at 100 and 250 mg/kg/day. One male dog at the mid

- dose of 100 mg/kg/day also displayed abnormal clinical signs/behavior, some of which were evident throughout the study.] 5. Chronic toxicity. [SYN520453 was evaluated for chronic toxicity in the dog and rat, and for carcinogenic potential in the rat and the mouse. In the 1 year dog study with Tox Reserve, dogs were dosed orally by capsule at 0, 25, 100 or 250 mg/kg/day. The NOAEL was 25 mg/kg/day based on decreased body weight gain and minor changes in clinical chemistry, and increased liver weig ht (males only) at 100 and 250 mg/kg/day. No clinical signs of toxicity were observed in the 1 year dog study up to a dose level of 250 mg/kg/day. In a 2 year rat combined chronic toxicity/carcinogenicity study conducted at dietary inclusion levels of 0, 1 00, 500 or 3000 ppm, there were no treatment related effects on survival. The NOAEL for the chronic toxicity phase of the study was 100 ppm and the NOAEL for neoplastic findings was 500 ppm (27.6 and 34.9 mg/kg/day in males and females respectively) based on increased incidence of hepatocellular adenoma and uterine carcinoma observed as a consequence of excessive dosing infemales at 3000 ppm. The overall NOAEL was 100 ppm (5.5 and 6.9 mg/kg/day in

males and females respectively) based on decreased body wei ght/weight gain in females at 500 ppm, and minor changes in clinical chemistry and non

- neoplastic findings in the liver at 500. In a carcinogenicity study in the mouse, mice were fed diets containing 0, 70, 500 or 6 3500 ppm SYN520453 for a period of up to 80 weeks. There were no treatment related effects on survival. A part from an increased incidence of „discharge from the eye ‟ in males at 3500 ppm, there were no effects o n the clinical condition of the animals. There were no treatment

- related neoplastic micropathology findings. The NOAEL for this study was 70 ppm (7.8 mg/kg/day in males and 9.9 mg/kg/day in females) based on r educed food utilization in females at 500 ppm, and hepatocellular hypertrophy and increased liver weight at 500 ppm.] 6. Animal metabolism. [SYN520453 was extensively metabolized by rats via oxidation to give a range of hydroxy, dihydroxy, acid and hydroxy acid metabolites. Oxidation of the N

- desmethyl metabolite of SYN520453 produced an equivalent range of N

- desmethyl metabolites. Incubation of SYN534969 (pure syn ) with rat liver microsomes resulted in oxidative biotransformation to the tertiary alcohol CS CD459488; quantities decreased with increased incubation time, demonstrating that the metabolite CSCD459488 is a short

- liver metabolite. The major routes of biotransformation appeared to be independent of dose level and sex and also appeared to be the same for both syn and anti isomers of the parent molecule. All metabolites accounting for >5% of the dose and the majority of minor metabolites were identified. Therefore in total, greater than 90% of the administered dose was accounted for by identified metab olites.] 7. Metabolite toxicology

. [Acute oral toxicity testing was performed with two metabolites, resulting in LD 50 >2000 mg/kg for both CSCD465008 and CSCD459488. Genotoxicity testing (bacterial reverse mutation, in vitro cytogenetics, and mammalian cell gene mutation (mouse lymphoma) with metabolites CSCD465008 and CSCD459488 indicated no genotoxicity. Subchronic toxicity studies (28 day dietary in the rat) were conducted with metabolites CSCD465008 and CSCD459488. CSCD465008 is toxicologically benign a nd is of lower toxicity than parent SYN520453. The metabolite CSCD459488 is considered to have equivalent toxicity to parent SYN520453, with both compounds having a NOAEL of 300 ppm (equivalent to approximately 27

- 28 mg/kg/day), and both compounds having a primary effect upon xenobiotic metabolizing enzymes in the liver with accompanying liver enlargement and centrilobular hypertrophy.] 8. Endocrine disruption

. The endocrine system includes the reproductive hormones estrogen and androgens as well as the thy roid hormone system. There is no evidence of any consistent treatment related effects with SYN520453 that could be considered as perturbation of endocrine homeostasis. There were no adverse affects related to female reproductive function or on reproduction in the multi

- generation reproductive toxicity study, and there were no micropathology changes in the organs that had altered weight effects. Overall, the database does not suggest that SYN520453 is an endocrine disruptor.C. Aggregate Exposure

1. Dietary exposure. [Tier I acute and chronic dietary exposure assessments 7 were performed for isopyrazam (a mixture of 3

- (difluoromethyl)

- 1

- methyl

-N

- [(1RS,4SR,9RS)

- 1,2,3,4

- tetrahydro

- 9

- isopropyl

- 1,4

- methanonaphthalen

- 5

- yl]pyrazole

- 4

- carboxamide (syn - isomer, also called SYN534968) and 3

- (difluoromethyl)

- 1

- methyl

-N

- [(1RS,4SR,9SR)

- 1,2,3,4

- tetrahydro

- 9

- isopropyl

- 1,4

- methanonaphthalen

- 5

-yl]pyrazole

- 4

- carboxamide (anti

- isomer, also called SYN534969)) using the Dietary Exposure Evaluation Model (DEEM

- FCID TM), version 2.16 from Exponent for a proposed use on imported bananas. There are no current or pending uses for isopyrazam. The definition of the residue for tolerance enforcement purposes is parent isopyrazam only (SYN534968 plus SYN534969); however the residue

- of

- co ncern for risk assessment purposes includes parent isopyrazam (SYN534968 plus SYN534969) plus the metabolite CSCD459488. An import tolerance for bananas of 0.05 ppm is proposed using the EPA/PMRA tolerance tool (PRO2008

- 02, ”Guidance for Setting Pesticide Maximum Residue Limits Based on Field Trial Data

- Rev ised,” PMRA , A pril 4, 2008), based upon residue field trial data on unbagged bananas treated at the maximum labeled application rate and harvested at the minimum pre

- harvest interval (PHI) of 0

- days. In these risk assessments, the EPA/PMRA tolerance tool was used to develop an upper- bound residue

- of

- concern estimate of 0.07 ppm from the same 0

- day PHI unbagged bananas to account for residues of both parent isopyrazam plus the metabolite CSCD459488. Defau lt DEEM processing factors were assumed for dried bananas (3.9X). Percent of crop treated (%CT) was conservatively assumed to be 100%. Since the proposed use on imported bananas will not result in transfer of residues to livestock via consumption of treate d feedstuffs, residues of isopyrazam in meat, milk, or egg commodities were not anticipated. Additionally, since there are no registered uses for isopyrazam in the United States, dietary exposures via drinking water (surface water and/or ground water) were also not considered. All consumption data for these assessments were taken from the USDA‟ s Continuing Survey of Food Intake by individuals (CSFII) with the 1994

- 96 consumption database and the Supplemental CSFII children ‟ s survey (1998) consumption databa se.] i. Food. [Acute dietary (food only) risk assessments for parent isopyrazam plus metabolite CSCD459488 were performed for all population sub

- groups using an acute reference dose (aRfD) of 0.30 mg/kg

- bw/day, based upon a 90

- day study in dogs with a no o bserved adverse effect level (NOAEL) of 30 mg/kg

- bw/day and an uncertainty factor of 100X. The 100X safety factor includes intra

- and inter

- species variations; no additional FQPA safety factor was applied. For the purpose of aggregate risk assessment, the 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 expressed as a percent of the acute reference dose (%aRfD). At the 95 th percentile, acute (food only) exposure to the U.S. population resulted in a MOE of 210,328 (0.1% of the RfD of 0.30 mg/kgbw/ day). The most exposed sub

- population was all infants <1 year old, with a MOE of 43,765 (0.2% of the RfD of 0.30 mg/kg

- bw/day). Sin ce the benchmark MOE forthis assessment was 100 and since the EPA generally has no concern for exposures

above the benchmark or below 100% of the reference dose, Syngenta believes that 8 there is a reasonable certainty that no harm will result from dietary (food only) exposure to residues arising from the proposed use on imported bananas. Chronic dietary (food only) risk assessments for parent isopyrazam plus metabolite CSCD459488 were performed for all population sub

- groups using a chronic reference dose of 0.055 mg/kg

- bw/day, based upon a 2

-year study in rats with a no observed adverse effect level (NOAEL) of 5.5 mg/kg

- bw/day and an uncertainty factor of 100X. The 100X safety factor includes intra

- and inter

- species variations; no additional FQPA safety f actor was applied. For the purpose of aggregate risk assessment, the 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 exp ressed as a percent of the chronic reference dose (%cRfD). Chronic (food only) exposure to the U.S. population resulted in a MOE of 218,995 (0.0% of the cRfD of 0.055 mg/kg

- bw/day). The most exposed sub

- population was children (1

- 2 years old) with a MOE of 42,933 (0.2% of the cRfD of 0.055 mg/kg

- bw/day). Since the benchmark MOE for this assessment was 100 and since the EPA generally has no concern for exposures above the benchmark or below 100% of the reference dose, Syngenta believes that there is
a reason able certainty that no harm will result from dietary (food only) exposure to residues arising from the proposed use on imported bananas. A cancer dietary assessment was not conducted.] ii. Drinking water. [Since the proposed use on imported bananas will no t result in contributions of SYN520453 or its metabolite(s) to surface or ground water in the United States, a drinking water exposure assessment was not conducted.] 2. Non

- dietary exposure

. [There are no currently registered residential uses for SYN520453 , so a non - dietary residential exposure assessment was not conducted.] 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 esta blish, modify , or re voke 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 ”. Sy ngenta did not perform a cumulative risk assessment as part of this tolerance action for isopyrazam because HED has not yet determined that there are any other chemical substanc es that have a mechanism of toxicity common with that of isopyrazam.] E. Safety Determination 1. U.S. population. [Using the conservative assumptions described above, and based on the completeness and reliability of the toxicity data, the acute aggregate 9 (food only) exposure calculation for the proposed use of isopyrazam on imported bananas resulted in a MOE of 210,328 for the U.S. population. The chronic aggregate (food only) exposure analysis showed that exposure from the proposeduse of isopyrazam on i mported bananas resulted in a MOE of 218,995 for the U.S.

population. Since the worst case aggregate MOE of 210,328 (acute aggregate exposure) exceeds the benchmark MOE of 100, Syngenta believes that there is a reasonable certainty that no harm will occur to the U.S. Population from acute and chronic aggregate exposures arising from the proposed use of isopyrazam on imported bananas.] 2. Infants and children

. [Using the conservative assumptions described above, and based on the completeness and reliability of the toxicity data, the acute aggregate (food only) exposure calculation for the proposed use of isopyrazam on imported bananas resulted in a MOE of 43,765 for infants <1 year old. The chronic aggregate (food only) exposure analysis showed that exposure from the proposed use of isopyrazam on imported bananas resulted in a MOE of 42,933 for children 1

- 2 years old. Since the worst case aggregate MOE of 42,933 (chronic aggregate exposure) exceeds the benchmark M OE of 100, Syngenta believes that there is a reasonable certainty that no harm will occur to infants and children from acute and chronic aggregate exposures arising from the proposed use of isopyrazam on imported bananas.] F. International Tolerances [Ther e are no Codex Alimentarius MRLs set for isopyrazam.]