Document ID: EPA-HQ-OPP-2013-0011-0003
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2013-02-15T05:00Z

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, LLC

2F8104

	EPA has received a pesticide petition (2F8104) from KIM-C1, LLC, 2547 W. Shaw Ave., Suite 116, Fresno, CA 93711 requesting, pursuant to section 408(d) of the Federal Food, Drug, and Cosmetic Act (FFDCA), 21 U.S.C. 346a(d), to amend 40 CFR part 180 by establishing a tolerance for residues of forchlorfenuron (N-(2-chloro-4-pyridinyl)-N'-phenyl urea) in or on the raw agricultural commodities 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 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.  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 analytical methods, both based on high performance liquid chromatography (HPLC) 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 preferred 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:
      
      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 trials were 50, 69, and 62 days respectively.  The 2010 almond trial PHIs were a bit longer at 127 and 123 days 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 trials and one trial each in Michigan, Washington and Wisconsin.  Two trials were conducted in 2006, two in 2010 and four trials were conducted in 2011.  The use patterns utilized maximized potential residues.  Preharvest intervals were 6 and 7 days in 2006, 21 days in 2010 and 11, 19, 10 and 8 days 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 work, use patterns were used to create the maximum potential for residues.  Preharvest intervals for the 2006 trial work were 40 and 52 days respectively, with 2010 trial work conducted with PHI's of 66 days for fresh fig and 80 days for dried fig.  Residue levels 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 days for the 2010 trials, and 52, 84 and 96 days for the 2011 field trials.   All pear analytical data showed residues <0.01 ppm (i.e., ND). 
      
      
      Pistachio:  
      Three pistachio trials were conducted in three separate California counties.  Two trials in 2006 and one in 2010.  Use patterns utilized maximized potential residues.  Preharvest intervals for 2006 pistachio trials were 93 and 86 days and 112 days for the 2010 trial.  Analytical data showed that residue levels were below 0.01 ppm (i.e., ND).
      
      Dried Plum (Prune):  
      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 days respectively, with the 2010 trial work being very similar at 95, 97, 98, and 100 days.  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 synthesis test.  The test systems assayed 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, body weight gain, food 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 body weight 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 which 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 F2 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, respectively.

      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 lymphocytic cell infiltration in the kidneys.  The NOAEL 
      was 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 body 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. In a 104-week combined chronic/oncogenicity study in rats, forchlorfenuron was administered in the diet at dose levels of 0, 150, 2,000 and 7,500 ppm.  Findings were decreased body weight and body histopathological effects in the kidney.  No oncogenicity was found.  The NOAEL for this study was 150 ppm (7 mg/kg/day in males 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, body weight gain, food consumption, increased kidney weights and 
      incidence of chronic kidney histopathological lesions.  The NOAEL for both 
      sexes was 10 mg/kg/day.  No oncogenicity 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 body 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 hydroxylation of the phenyl ring.  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, feces and milk were analyzed 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 days (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 respectively.  Overall, tissue radioactivity 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 days was extremely small (0.3% of the dose).  The residues consisted of parent CPPU, its hydroxylated metabolite, hydroxyl-CPPU, CPPU-glucuronide and other minor components requiring release from tissue by hydrolysis.
      

      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, chronic, 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 effects.  The results of all of these studies show no evidence of any endocrine-mediated effects and no pathology of the endocrine organs.  Consequently, it is concluded that forchlorfenuron does not possess estrogenic or endocrine disrupting properties.

C. Aggregate Exposure

      1.  Dietary exposure. Maximum Residue Levels:  In general, 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 maturity.  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 analytical laboratory reported the apparent residues below the LOQ.  MRLs were calculated with the March 2011 release of the OECD MRL Calculator 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 MRL is 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 MRL Calculator warns that the MRL is estimated with high uncertainty due to small data sets and/or high level of censorship.  For that reason, an MRL of 0.04 ppm for all commodities, except almond hulls with the calculated MRL of 0.15 ppm, with no warnings, is recommended.  This 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 MRLs/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 rarely at 10%.  Based on the 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 residues 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-Limited 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 analyses 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 bodyweight/weight gain/food consumption 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 the 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 MRLs 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 empirical-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.  The 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 MRLs 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.

      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" concerning 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 any other substances and forchlorfenuron does not appear to produce a toxic metabolite produced by 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 Determination

      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 safety of the proposed uses under the proposed temporary tolerances for forchlorfenuron:
            
      "EPA has determined that reliable data show the safety of infants and children would be adequately protected if the FQPA SF were reduced 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 additional 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 and surface water modeling used to assess exposure to forchlorfenuron in drinking water.  EPA used similarly conservative assumptions to assess exposure to forchlorfenuron residues in food. These assessments will not underestimate the exposure and risks posed by forchlorfenuron.
      
      EPA determines whether acute and chronic pesticide exposures are safe by
            comparing aggregate exposure estimates to the aPAD and cPAD. The aPAD and cPAD represent the highest safe exposures, taking into account all appropriate SFs. EPA calculates the aPAD and cPAD by dividing the POD by all applicable UFs. For linear cancer risks, EPA calculates the probability of additional cancer cases given the estimated aggregate exposure. Short-term, intermediate-term, and chronic-term risks are evaluated by comparing the estimated aggregate food, water, and
      residential exposure to the POD to ensure that the margin of exposure
      (MOE) called for by 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 concluded 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 any 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 already 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 certainty 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:
      
      Australia: An MRL of 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.
      
      Israel: An MRL of 0.01 ppm has been established for table grapes, wine grapes and kiwifruit.
      
      Japan: An MRL of 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.