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**EPA REGISTRATION DIVISION COMPANY NOTICE OF FILING FOR PESTICIDE PETITIONS PUBLISHED IN THE FEDERAL REGISTER**  **EPA Registration**  **Division contact: Cynthia Giles**  **- Parker; Acting Product Manager,**  **Team 20; (703) 305 -**  **7740 TEMPLATE:**  KIM
- C1, LL C 2F8104EPA has received a pesticide petition ( 2F 8104 ) from KIM
- C1, LLC, 2547 W. Shaw Ave., Suite 116, Fresno, CA 93711 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 by

establishing a tolerance for residues of forchlorfenuron (N

- (2

- chloro

- 4
- py ridinyl)

- N’
- phenyl urea) in or on the raw agricultural commodit ies almond, cherry (sweet), fig, pear, pistachio, plum/prune at 0.04 part per million (ppm) , and the processed commodity

almond, hulls, at 0.15 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 d ata 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. One plant metabolism study on each of three crops, including grapes, kiwi fruit and apple fruit, were conducted. Based on all three studies the residue of concern was defined as forchlorfenuron parent compound. 2. Analytical method
. Two anal yt ical methods, both based on high performance liquid chromatograph y (HPL C) procedures have been developed. The first method used a visible ultraviolet (UV) detector, while the second method used a mass spectrophotometer (MS) detector. Since the MS detector is capable of both qualitative as well as quantitative measurement, it is the pref erred method. The level of quantification (LOQ) in all of the crops (i.e., almond, cherry , fig, pear, pistachio and plum/prune) is 0.01 ppm. 3. Magnitude of residues
. Magnitude of residue field trials were conducted with CPPU on almond in 2005/06 and on cherry (sweet), fig, pear, pistachio and plum/prune in 2006. Additional residue field trials were conducted in 2010 for almond, fig and pistachio and in 2011 for sweet cherry and pear. Results are summarized hereafter:2

Almond: A total of five almond field trials were conducted in five separate California counties. Three trials were conducted in 2005 and two in 2010. In all almond trials, use patterns were used to maximize the potential for residues. Preharvest intervals (PHI) for the 2005 almond tri als were 50, 69, and 62 day s respectively
. The 2010 almond trial PHI s were a bit longer at 127 and 123 day s because later maturing varieties were used. In all cases, almond nut meat residues fell within the “non

- detectable” (ND) residue category . Almond hulls showed low levels of residue ranging from ND to 0.0841 ppm maximum. Sweet Cherry : Eight sweet cherry

field trials were conducted including three California trials, two Oregon trial s and one trial each in Michigan, Washington and Wisconsin. Two trials were conducted in 2006, two in 2010 and four tria ls were conducted in 2011. The u se patterns utilized maximized potential residues. Preharvest intervals were 6 and 7 days in 2006, 21 day s in 2010 and 11, 19, 10 and 8 day s in 2011. Residue data for sweet cherries were <0.01 ppm (i.e., ND). Fig: Residue trial work consisted of three trials conducted in three separate California counties. Two trials were conducted in 2006 and one additional trial was conducted in 2010. As with all the trial wor k, use patterns were used to create the maximum potential for residues. Preharvest intervals for the 2006 trial work were 40 and 52 day s respectively , with 2010 trial work conducted with PHI’s of 66 day s for fresh fig and 80 day s for dried fig. Residue l evels for the fig trial work were below 0.01 ppm (< Limit of Quantitation (LOQ) , i.e., ND. Pear: Eight pear trials were conducted in four states, three in California, two in Oregon, two in Washington and one in New York. Two trials were conducted in 2006 , three were conducted in 2010 and three were conducted in 2011. Use patterns maximized any

potential residues. Preharvest intervals were 47 and 63 days for the 2006 trials, 90, 94 and 107 day s for the 2010 trials, and 52, 84 and 96 day s for the 2011 fie ld trials. All pear anal yt ical data showed residues <0.01 ppm (i.e., ND).
Pistachio: Three pistachio trials were conducted in three separate California counties . T wo trials in 2006 and one in 2010. Use patterns utilized maximized potential residue s. Preharvest intervals for 2006 pistachio trials were 93 and 86 day s and 112 day s for the 2010 trial. Anal yt ical data showed that residue levels were below 0.01 ppm (i.e., ND). Dried Plum (Prune):3 Five dried plum or prune field trials were conducted in four California counties, including two trials in 2006 and three in 2010. Use patterns utilized maximized any possible residues. Preharvest intervals for the 2006 trial work were 90, 92, and 105 day s respectively , with the 2010 trial work being very s imilar at 95, 97, 98, and 100 day s. Residue data showed residue levels of <0.01 ppm (i.e., ND). In summary , the magnitude of residues in almond, cherry , fig, pear, pistachio and plum/prune are all at, or below, the LOQ (i.e., < 0.01 ppm). Non

- detectable to low levels of forchlorfenuron were found in almond hulls, with the highest level being 0.0841 ppm. B. Toxicological Profile 1. Acute toxicity. Acute toxicity endpoints for forchlorfenuron technical are as follows: **Guideline No./Study Type Results**  **Toxicity Category** 870.1100 Acute Oral

– Rat LD50 (mg/kg bw): M = 4904; F = 4899; Combined = 4918 III
870.1200 Acute Dermal

– Rabbit LD50 (mg/kg bw): M = >2000; F = >2000 III
870.1300 Acute Inhalation

– Rat LC50 (mg/L): M = >3.0; F = >3.0 IV 870.2400 Primary Eye Irritation

- Rabbit Mild eye irritant III 870.2500 Primary Skin Irritation

– Rabbit Non
- irritant IV 870.2600 Dermal Sensitization

– Guinea Pig Non
- sensitizer N/A

2. Genotoxicty. The genotoxic potential of forchlorfenuron was studied in vitro in bacteria and mammalian cells and in vivo in the unscheduled DNA sy nthesis test. The test sy stems assay ed did not show any evidence of genotoxicity

except in the bacterial mutagenicity assay , strain TA1535, without metabolic activation. The weight of evidence indicates that forchlorfenuron does not possess significant genotoxicity concerns.
3. Reproductive and developmental toxicity

. A developmental toxicity study was conducted with forchlorfenuron using rats gavaged with levels of 0, 100, 200 and 400 mg/kg/day . The maternal and developmental NOAELs were 200 mg/kg/day

based on reduced body weights, bod y weight gain, food4 consumption, and an increased incidence of alopecia in dams. There were no developmental effects. A developmental toxicity study was conducted with forchlorfenuron using rabbits gavaged with doses of 0, 25, 50 and 100 mg/kg/day . Maternal toxicity (decreased bod y wei ght and body weight gains) were observed at 50 mg/kg/day

and above. The maternal NOAEL was 25 mg/kg/day and the developmental NOAEL was 100 mg/kg/day . There were no developmental effects. A two generation reproduction study was conducted in rats in whic h forchlorfenuron was administered in the diet at levels of 0, 150, 2,000 and 7,500 ppm. There were no adverse effects of forchlorfenuron on reproductive success. Parental toxicity consisted of clinical signs, inhibition of body weight gain, reduced food consumption, and macroscopic and microscopic effects in the kidney . Reproductive toxicity in the highest dose consisted of slightly reduced live litter sizes in the F 2 litters. In the pups, body weights and survival (late lactation period) were reduced and at the high dose, pup mortality and emaciation were increased. The parental, pup and reproductive NOAELs were 150 ppm, 150 ppm and 2,000 ppm, respectivel y. 4. Subchronic toxicity

. Forchlorfenuron was tested in rats in a 3

- month study at dietary levels of 0, 200, 1,000 and 5,000 ppm Observations were decreased body weight, body weight gain and food efficiency. The NOAEL for males was 5,000 ppm (400 mg/kg/day) and in females was 1,000 ppm (84 mg/kg/day). Forchlorfenuron was tested in a 13

- week dietary toxicity study in mice conducted at dose levels of 0, 900, 1,800, 3,500 and 7,000 ppm. Effects included decreased body weight and food consumption, increased relative liver weight and l ymphocy tic cell infiltration in the kidneys. The NOAEL w as 3,500 ppm (609 mg/kg/day in males and 788 mg/kg/day in females). A 13
- week dietary

toxicity study was conducted with forchlorfenuron in beagle dogs at dose levels of 0, 50, 500 and 5,000 ppm. Effects included decreased bod y weight gain, food consumption, and food efficiency . The NOAEL for both sexes was 500 ppm (16.8 mg/kg/day in males and 19.1 mg/kg/day

in females).

5
. Chronic toxicity. Ina 104
- week combined chronic/oncogenicit y study in rats, forchlor fenuron was administered in the diet at dose levels of 0, 150, 2,000 and 7,500 ppm. Findings were decreased body weight and bod y histopathological effects in the kidney . No oncogenicity was found. The5 NOAEL for this stud y was 150 ppm (7 mg/kg/day in mal es and 9 mg/kg/day in females). Forchlorfenuron was administered in the diet to mice for 78

- weeks at dose levels of 0, 10, and 1,000 mg/kg/day . Observations were decreased body weight, bod y weight gain, food consumption, increased kidney weights and i ncidence of chronic kidney histopathological lesions. The NOAEL for both sexes was 10 mg/kg/day . No oncogenicit y was found. In a 12
- month study , forchlorfenuron was administered in the diet given to dogs at dose levels of 0, 150, 3,000 and 7,500 ppm. Observations included reduced bod y weight, body weight gain, food consumption, and various hematology

changes. The NOAEL for both sexes was 3,000 ppm (87 mg/kg/day

in males and 91 mg/kg/day in females).
6
. Animal metabolism. A rat metabolism study indicated that forchlorfenuron is almost completely

absorbed and most of the 14 C
- forchlorfenuron

- derived radioactivity

is rapidly eliminated primarily

via the urine. The majority of the metabolism of forchlorfenuron was via h ydrox yl ation of the phen ylring. The sulfate conjugate of the hydroxyl forchlrofenuron was the major metabolite excreted in the urine, accounting for as much as approximately 96% of the urinary radioactivity . Tissue residues accounted for less than 1% of the administered dose at 168 hours post

- dosing. In a goat metabolism study , a lactating dairy goat received capsules fortified with [ 14 C]
- CPPU for three consecutive days. The dose rate was equivalent to ~11 ppm CPPU in the diet. Dissected tissues, urine, fece s and milk were anal yz ed for total radioactive residues (TRR) by liquid scintillation counting techniques. Recovery

of [ 14 C]
- CPPU
- derived radioactivity is summarized hereafter. **Recovery of 14**  **C from a Goat Treated with [ 14**  **C] -**  **CPPU**

14 C in Urine (% of Dose) 14 C in Feces

(% of Dose) 14 C in Milk

(% of dose) 14 C in Bile

%of Dose 14 C in GIT

Contents (% of Dose) Total 14 C

Recovery (% of Dose) 31.89 46.18 0.95 0.22 19.74 98.99 The TRR in milk was highest in the first two day s (of four) of sampling. Maximum residue concentration (0.491 ppm) occurred on day 2 in the afternoon milking. Only

liver (0.207 ppm) and kidney (0.099 ppm) contained radioactive residues greater than 0.01ppm. Muscle and fat had 0.002 and 0.000 ppm respectivel y. Overall, tissue radioac tivity represented a very

small portion (aprox. 0.31%) of the administered dose. The amount of [ 14 C]
- CPPU
derived residues in dairy

goat tissues and milk after oral administration for 3 consecutive day s was extremel y small (0.3% of the dose). The residue s6 consisted of parent CPPU, its hydrox yl ated metabolite, hydrox yl

- CPPU, CPPU
- glucuronide and other minor components requiring release from tissue by hydrol ys is.
7. Metabolite toxicology
. Metabolites occur at levels below 0.1 ppm and, therefore, are below levels required to be assayed in animal testing. Nevertheless, the toxicity of sulfate conjugate (and any other animal metabolites) was assessed during the conduct of the CPPU required mammalian toxicity

studies.
8. Endocrine disruption
. No special studies to investigate the potential for endocrine effects of forchlorfenuron have been performed. However, a large, detailed toxicology

data base exists for the compound with studies in all required categories. Included are acute, sub

- chronic, c hronic, developmental and reproductive toxicology studies, with detailed histology and histopathology

of numerous tissues, including endocrine organs, following repeated or long

- term exposures. These studies are considered capable of revealing endocrine e ffects. The results of all of these studies show no evidence of an y endocrine

- mediated effects and no pathology of the endocrine organs. Consequentl y, it is concluded that forchlorfenuron does not possess estrogenic or endocrine disrupting properties.
C. Aggregate Exposure 1. Dietary exposure. Maximum Residue L evels: Ingeneral, CPPU was applied during the growing season at 10

– 11 grams of active ingredient per acre. The crops were harvested at varying post

- application intervals reflecting normal crop maturit y. As noted above, the residue limit of quantitation (LOQ) was 0.01 ppm. With the exception of almond hulls, no residues above the LOQ were found. In some cases, the anal yt ical laboratory reported the apparent residues below the LOQ. MRL s w ere calculated with the March 2011 release of the OECD MRLCalculator Excel spreadsheet. Residue values listed as “ND” (nondetectable) were entered as the LOQ and flagged for censorship. Apparent residues <LOQ were entered as reported. For almonds with hulls, the use of all ND values results in a distribution of residues with no variance. Hence, the MRLis the ND value, in this case 0.01 ppm. When apparent residues were entered a residue distribution could be considered for setting a MRL , in this case 0.02 ppm. The use of apparent residues is the more conservative approach. In all cases except almond hulls, the MRLCalculator warns that the MRLis estimated with high uncertainty due to small data sets and/or high level of censorship. For that reason, an MRLof 0.04 ppm for all commodities, except almond hulls with the calculated MRL of 0.15 ppm, with no warnings, is recommended. This7 approach is protective of human health and should prevent the finding of violative residues. Except for almond hulls , none of the commodities with existing tolerances or proposed MRL s /tolerances are used in animal feed. Almond hulls are generated in California and used in dairy cow feed (roughage) in California, usually at 5% of the diet and rarel y at 10%. Based on th e lactating goat metabolism study , predicted ppm TRRs in meat and milk were both 0.0007 ppm or less. This assessment was conservative in that it was based on the TRRs which are greater than the CPPU

- containing moieties. Since none of the predicted residu es in dairy approach the LOQ of 0.01 ppm no meat or milk tolerances are proposed and no residue tolerances are required for these commodities i. Food & ii. Drinking water Aggregate Risk Assessments

. In the most recent forchlorfenuron Final Rule (USEPA, 2008. Forchlorfenuron: Permanent and Time

- Li mited Tolerances. Final Rule. Federal Register, Vol. 73, No. 159, pp 47841
- 47847, 8/15/08) , EPA noted that there were no acute toxicity endpoints attributable to a single exposure, therefore no acute dietary ana ly ses were needed. EPA selected a no observed adverse effect level (NOAEL) of 7 mg/kg/day from a chronic oral toxicity study in the rat. The lowest observed adverse effect level (LOAEL) was 93 mg/kg/day based on decreased bod yw eight/weight gain/food cons umption and kidney toxicity
. EPA assigned uncertainty factors of 10X intraspecies, 10X interspecies and 1X for FQPA. The level of concern was 100 and the chronic reference dose (RfD) was 0.07 mg/kg/day. For th e assessment of these six new crops , dietary and drinking water exposure and risk assessments were done with the Dietary Exposure Estimation Model (DEEM), Version 2.16. Existing permanent tolerance residue values along with the MRL s suggested in section C.1. above of this Petition were used to create the residue file. Potential residues in drinking water were taken from the Federal Register Final Rule noted above (namely , 0.003 ppb (=0.000003 ppm) ) . DEEM default processing factors were used for all commodities except raisins, for which the empiric al

- based tolerance was used . The percent crop treated (PCT) was assumed to be 100%. This approach is considered to be conservative in that it estimates theoretical maximum exposure and risk. Dietary and drinking water exposure reach a level of concern when exposure approaches and equals the RfD. T he exposure of the most highly exposed population (Children 1

– 2 years old) occupies 0.2% of the RfD and is not of concern. The existing tolerances and proposed MRL s are protective of human health, including the most sensitive population. EPA noted no other concerns regarding aggregate exposure or cumulative risk in the 8/15/08 Final Rule Federal Register notice.8 2. Non

- dietary exposure
. There are no residential uses for forchlorfenuron.
D. Cumulative Effects In the 8/15/08 Federal Register notice establishing permanent tolerances for forchlorfenuron in the Bushberry subgroup 13

- 07B and temporary tolerances in almond, cherry

(sweet), fig, pear, pistachio and plum/prune, EPA stated the following relative to “Cumulative effects from substances with a common mechanism of toxicity”: “Section 408(b)(2)(D)(v) of FFDCA requires that, when considering whether to establish, modify , or revoke a tolerance, the Agency consider “available information” concer

ning the cumulative effects of a particular pesticide’s residues and “other substances that have a common mechanism of toxicity .” “EPA has not made a common mechanism of toxicity finding as to forchlorfenuron and an y other substances and forchlorfenuron does not appear to produce a toxic metabolite produced b y other substances. For the purposes of this tolerance action, therefore, EPA has not assumed that forchlorfenuron has a common mechanism of toxicity with other substances.” E. Safety Determinatio n 1. U.S. population & 2. Infants and children EPA noted the following in FR Vol. 73, No. 159, 8/15/08 in the notice establishing prior temporary tolerances under PP 7F7246 in almond, sweet cherry , fig, pear, pistachio and plum/prune relative to the Agency ’s conclusions regarding the safet y of the proposed uses under the proposed temporary tolerances for forchlorfenuron:

“ EPA has determined that reliable data show the safet y of infants and children would be adequatel y protected if the FQPA SF were re duced to 1X. That decision is based on the following findings: i. The toxicity

database for forchlorfenuron is complete. ii. There is no indication that forchlorfenuron is a neurotoxic chemical and there is no need for a developmental neurotoxicity study or add itional UFs to account for neurotoxicity
. iii. There is no evidence that forchlorfenuron results in increased susceptibility

in in utero rats or rabbits in the prenatal developmental studies or in young rats in the 2

–generation reproduction study
. iv. There are no residual uncertainties identified in the exposure databases. EPA made conservative (protective) assumptions in the ground and9 surface water modeling used to assess exposure to forchlorfenuron in drinking water. EPA used similarly conservative assumpti ons to assess exposure to forchlorfenuron residues in food. These assessments will not underestimate the exposure and risks posed b y forchlorfenuron. EPA determines whether acute and chronic pesticide exposures are safe b y comparing aggregate exposure estimates to the aPAD and cPAD. The aPAD and cPAD represent the highest safe exposures, taking into account all a ppropriate SFs. EPA calculates the aPAD and cPAD by dividing the POD by all applicable UFs. For linear cancer risks, EPA calculates the probabi lity

of additional cancer cases given the estimated aggregate exposure. Short

- term, intermediate

- term, and chronic

- term risks are evaluated b y comparing the estimated aggregate food, water, and residential exposure to the POD to ensure that the margin of e xposure (MOE) called for b y the product of all applicable UFs is not exceeded. 1. Acute risk. An acute aggregate risk assessment takes into account exposure estimates from acute dietary consumption of food and drinking water. No adverse effect resulting from a single

- oral exposure was identified and no acute dietary endpoint was selected. Therefore, forchlorfenuron is not expected to pose an acute risk. 2. Chronic risk . Using the exposure assumptions described in this unit for chronic exposure, EPA has con cluded that chronic exposure to forchlorfenuron from food and water will utilize <1% of the cPAD for the general U.S. population and all subpopulations. There are no residential uses for forchlorfenuron. 3. Short

- term and intermediate

- term risk . Short

- term and Intermediate

term aggregate exposure takes into account short

- term and intermediate

term residential exposure plus chronic exposure to food and water (considered to be a background exposure level). Forchlorfenuron is not registered for an y use patterns that would result in short

- term and intermediate

- term residential exposure. Therefore, the short

- term and intermediate

- term aggregate risk, individually is the sum of the risk from exposure to forchlorfenuron through food and water, which has alre ad y been addressed, and will not be greater than the chronic aggregate risk. 4. Aggregate cancer risk for U.S. population . Since forchlorfenuron has been classified as not likely to be carcinogenic, aggregate cancer risk is not a concern. 5. Determination of safety

- U.S. population and Infants &Children. Based on these risk assessments, EPA concludes that there is a reasonable certaint y that no harm will result to the general population or to infants and children from aggregate exposure to forchlorfenuron residues.
F. International Tolerances The following international tolerances exist for forchlorfenuron:10

Australia: An MRLof 0.01 ppm has been established for grapes and as a temporary

MRL level for blueberries, mango and plum/prune. European Union: Forchlorfenuron MRLs are set for table grapes and kiwifruit at 0.05 ppm. However, a new EU MRL of 0.01 ppm is proposed because sufficient trials are available showing residues below 0.01 ppm. Is rael: An MRL of 0.01 ppm has been established for table grap es, wine grapes and kiwifruit. Japan: An MRLof 0.01 has been set for almonds. Mexico: Has deferred to the U.S. Tolerances. Therefore, all forchlorfenuron tolerances established in the U.S. apply to Mexico.