


EPA Registration Division contact: Samantha Hulkower (703) 603-0683
IR-4
PP# 1F7905

	EPA has received a pesticide petition PP # 1F7905 from Nichino America, Inc.  4550 New Linden Hill Road, Suite 501, Wilmington, DE  91808 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. 511 by establishing a tolerance for residues of buprofezin in or on the raw agricultural commodities: nut, tree group 14 (including pistachios) (0.05 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. This summary has been prepared by Nichino America, Inc., Wilmington, DE 19808, the registrant.

A. Residue Chemistry
	1. Plant metabolism. The metabolic profile of buprofezin has been elucidated in a wide range of crops, including tomatoes, lettuce, cotton, and citrus.   In citrus, although buprofezin was a major component of the residue, a chromatographically well-defined region of radioactivity, clearly associated with polar conjugates, was observed. Mass spectrometry identified the principal polar residue as a hexose conjugate of BF4 (buprofezin hydroxylated in the t-butyl group). Although the conjugate was resistant to enzyme hydrolysis, acid hydrolysis of the polar fraction released predominantly BF26 with minor amounts of BF9 and BF12. The same compounds were observed following acid hydrolysis of a standard of BF4 clearly indicating that BF4 is the conjugated metabolite existing in citrus. Although only limited metabolism was observed in lettuce and cotton, trace levels of similar metabolites, including the conjugate BF4 were observed indicating that the metabolic pathway does not differ with plant species.

	2. Analytical method. The proposed analytical method involves extraction, partition, clean-up and detection of residues by liquid chromatography with tandem mass spectral detection (LC/MS/MS).

      3. Magnitude of residues. Field trials were conducted on pecans with buprofezin, the principal residue of concern, in the required geographic regions in the United States at the maximum rate and minimum application and the minimum pre-harvest interval.  Buprofezin residues for all samples in pecans were less than the limit of quantitation (LOQ) which was 0.01 mg/kg.   Based on these residue data and residue data previously submitted for almonds, a tolerance for the Tree Nut Crop Group 14 and Pistachios is being proposed at 0.05 ppm; the currently established tolerance for almonds (0.05 ppm) be revoked; and the currently established tolerance for Almond, hulls (2.0 ppm) remain as established. The requested proposed tolerance is adequately supported.

B. Toxicological Profile
	1. An extensive battery of toxicology studies has been conducted with buprofezin.  EPA has evaluated the available toxicity data and considered its validity, completeness, and reliability as well as the relationship of the results of the studies to human risk  The nature of the toxic effects caused by buprofezin is discussed in Unit III.A. of the Final Rule on Buprofezin Pesticide Tolerance published in the Federal Register on September 5, 2001 (66 FR 46381) (FRL-6796-6).   An assessment of toxic effects caused by buprofezin including the toxicological endpoints of concern is also discussed in Unit III.A. and Unit III B. of the Federal Register dated June 25, 2003   (FRL-7310-7) (68 FR 37765).
      2. Animal metabolism. The metabolism of buprofezin has been extensively studied in various species of animals and fish. Buprofezin has several groups that can metabolize in a variety of ways thus potentially producing a very large number of metabolites. Extensive metabolism to many minor metabolites was observed in all the animal species. Metabolism in fish was, however, much more limited and clearly defined. Although not all metabolic intermediates have been detected in all the species, the major routes of metabolism have been identified in animals and fish and a consistent pattern is observed throughout these species. The proposed metabolic pathway was provided in the tolerance petition, PP 0F6087. For convenience, degradates are referred to by an internal code: BF 1 through 13. Corresponding chemical structures were provided in the tolerance petition, PP 0F6087.

	3. Metabolite toxicology. 
	i. Metabolism in rats.  The major metabolite found in rat excreta was parent buprofezin in addition to several compounds formed after extensive metabolism. Whereas plant metabolism appeared restricted mainly to oxidation of the tertiary butyl group, oxidation of the butyl group and hydroxylation of the phenyl ring were both observed in rats. Oxidation of the t-butyl group proceeded beyond an alcohol to an acid and was accompanied by ring opening. The most extensively metabolized compound identified in rats was BF23 (acetylated p-aminophenol).
	ii. Metabolism in ruminants and hens. Residue levels were low (0.05 ppm) in all ruminant and poultry tissues and commodities, following treatment at exaggerated rates (approximately 20x and 7,500x the anticipated dietary burden, respectively). The only exceptions were cow liver (1.21 ppm), cow kidney (0.41 ppm), hen liver (0.15 ppm), and egg yolk (0.11 ppm). Extensive metabolism was observed in both species with a large number of minor metabolites being produced.  The principal metabolites identified in the cow were BF2 and BF23, indicating that the major pathway of degradation in ruminants is hydroxylation of the phenyl ring followed by opening and degradation of the heterocyclic ring. The identification of trace levels of BF13 confirms this pathway. As in rats, BF23 was the most extensively metabolized compound identified. Trace levels of BF12 were also detected. This indicates that the parallel pathway of heterocyclic ring opening without hydroxylation of the phenyl ring is also in operation. Similarly in hens, the identified metabolites were derived from degradation of the heterocyclic ring either with (BF13) or without (BF9 and BF12) phenyl ring hydroxylation.  No single unidentified compound accounted for more than 6% of the total residue in any animal tissue or commodity, with the exception of a component comprising 8.7% of egg white. The total residue in egg white was, however, only 0.02 ppm even at this highly exaggerated dose rate.
	 iii. Metabolism in fish. Analysis of fish tissues, following a bioaccumulation study, found a much simpler metabolic profile. Buprofezin was present in both edible and non-edible tissues, but the principle metabolites were polar conjugates of BF4. Trace levels of BF12 were also detected.


	4. Endocrine disruption. No special studies have been conducted to investigate the potential of buprofezin to induce estrogenic or other endocrine effects. The standard battery of required toxicity studies has been completed. These studies include an evaluation of the potential effects on reproduction and development and an evaluation of the pathology of the endocrine organs following repeated or long-term exposure. These studies are generally considered to be sufficient to detect any endocrine effects. The only effect noted on endocrine organs was an increased incidence of follicular cell hypertrophy and C-cell hyperplasia of the thyroid gland in rats administered buprofezin.  Buprofezin also caused mild to moderate hepatotoxic effects at this dietary concentration.  The effect on the thyroid is consistent with an increased turnover of T3/T4 in the liver with a resultant rise in TSH secretion (due to the hepatotoxicity). The rat is known to be much more susceptible than humans to these effects due to the very rapid turnover of thyroxine in the blood in rats (12 hours vs. about 5-9 days in humans). Therefore, the thyroid pathological  changes which have been noted following administration of high doses of buprofezin are considered to be of minimal relevance to human risk assessment, particularly considering the low levels of buprofezin to which humans are likely to be exposed.

C. Aggregate Exposure

1. Dietary exposure. Acute and chronic dietary risk analyses were conducted by the Agency to estimate to potential buprofezin residues in/on the following crops with established tolerances: almond, avocado, banana, bell and non-bell peppers, Brassica, head and stem, subgroup 5A [broccoli; broccoli, Chinese; Brussels sprouts; cabbage; cabbage, Chinese (napa); cabbage, Chinese mustard; cauliflower; cavalo broccoli; kohlrabi], canistel, celery, coffee, spinach, cotton, grape, grape raisin, longan, lychee, mamey sapote, mango, papaya, pecan, pomegranates, Spanish lime, head lettuce, leaf lettuce, snap bean, fruiting vegetables, cucurbit vegetables, citrus fruits, pome fruits, stone fruits, almond, pistachio, olive, and strawberry and meat and milk, using DEEM(TM) (ver. 7.76).   Residue estimates for water consumption were based on PRZM3/EXAMs and SCIGROW models and incremental exposure assessments for nuts  using LifeLine[TM] version 5.0.  

	i. Food. The Hazard Identification Assessment Review Committee (HIARC) met on 15-February-2000 and determined the endpoint selection for buprofezin (HED Doc. No. 014093) and subsequently on 22-October-2002 to evaluate the potential for increased susceptibility of infants and children from exposure to buprofezin.  Based on toxicological considerations, the special FQPA safety factor was set at 1X when assessing acute and chronic dietary exposures.  The acute dietary aPAD (acute population adjusted dose) was set at 2.0 mg/kg/day for females aged 13-50 years old based on a developmental toxicity study in rats that had an oral NOEL of 200 mg/kg/day.  The chronic dietary cPAD (chronic Population Adjusted Dose) was determined to be 0.01 mg/kg/day for the general population based on a oral NOAEL of 1.0 mg/kg/day in the two-year rat chronic/oncogenicity study.  The uncertainty factor of 30 was used to account for interspecies and intraspecies variations.  An additional 10x database uncertainty factor was applied.  The resultant safety factor used to establish the cPAD was 300.  The cPAD was set at 0.0033 mg/kg/day.   Since the only evidence of carcinogenicity was `suggestive', this endpoint was not deemed relevant to this assessment. 

The acute dietary exposure was based on the following assumptions: residues at tolerance levels, 100% crop treated, and DEEM(TM) (ver. 7.76) default processing factors for all registered/proposed commodities (Tier 1). For all currently registered crops and commodities, the acute risk was assessed as 7% of the aPAD for the population group females 13-49 years old.  No other population groups were identified based on the lack of adverse effects resulting from a single exposure  (Federal Register vol 74 No. 131 p 33157, July 19, 2009). An incremental exposure assessment for the petitioned tolerances was performed using LifeLine(TM) version 5.0.  Tolerance values were used for exposure and a default value of 100% crop treated. Expanded crops in the citrus and pome crop groupings were already modeled in the Agency's previous assessments.  The resulting incremental food exposure estimate for females 13-49 years old was approximately 0.0001% of the acute RfD bringing the total acute risk to 7% of the aPAD. No acute endpoint was identified for the remaining population subgroups.  

The chronic dietary exposure assessment for all currently registered crops for food and water resulted in a risk estimate of  80% of the cPAD of 80% for the population groups receiving the greatest exposure (all infants <1 year old and children 1-2 years old) (Federal Register vol 74 No. 131 p 33157, July 19, 2009). 
The incremental chronic dietary exposure used 100% crop treated for Nut, Tree Group 14. Proposed tolerance values were assumed for all crop residues. The food exposure estimates from residues of buprofezin for the U.S. population for the petitioned crops was 0.04% of the chronic population adjusted dose (cPAD) and 0.05% for children 3-5 years old. The total estimated risk from chronic exposure does not exceed 80% of the cPAD for the most sensitive population group, children 3-5 years old.  These can be considered conservative values.  

Since the only evidence of carcinogenicity was `suggestive', EPA regards the carcinogenic potential as very low.  Therefore, an exposure assessment for evaluating cancer risk was not deemed relevant to this assessment and was not conducted. 
	
	ii. Drinking water. The residue of concern in drinking water was determined to be buprofezin.  There are no established maximum contaminant levels or health advisory levels for residues of buprofezin in drinking water.  In the absence of comprehensive water monitoring data, the Agency uses the FQPA Index Reservoir Screening Tool or the Pesticide Root ZoneModel/Exposure Analysis Modeling System (PRZM/EXAMS) to produce estimates of pesticide concentrations in an index resevoir.   The SCI-GROW model is used to predict pesticide concentrations in shallow ground water. For a screening-level assessment for surface water EPA will use FIRST (a tier 1 model) before using PRZM/EXAMS (a tier 2 model). The FIRST model is a subset of the PRZM/EXAMS model that uses a specific high-end runoff scenario for pesticides. Both FIRST and PRZM/EXAMS incorporate an index reservoir environment, and both models include a percent crop area factor as an adjustment to account for the maximum percent crop coverage within a watershed or drainage basin.
	None of these models include consideration of the impact processing (mixing, dilution, or treatment) of raw water for distribution as drinking water would likely have on the removal of pesticides from the source water. The primary use of these models by the Agency at this stage is to provide a screen for sorting out pesticides for which it is unlikely that drinking water concentrations would exceed human health levels of concern.
	The estimated drinking water concentrations (EDWCs) in surface water were determined using the Tier II PRZM (Pesticide Root Zone Model) and EXAMS (Exposure Analysis Modeling System (PE4-PL, version 01).  PRZM is used to simulate pesticide transport as a result of runoff and erosion and spray drift from an agricultural field and EXAMS estimates environmental fate and transport of pesticides in surface water.  The EPA estimated that based on the maximum use pattern of two applications to Florida citrus for the acute and long-term estimates. The acute EDWCs estimated for buprofezin acute exposure are 57.4 ppb for surface water and 0.09 ppb for ground water.  The chronic EECs are estimated to be 18.6 ppb for surface water and 0.09 ppb for ground water (Federal Register Vol. 74 No. 131 p 33157, July 19, 2009). 

	2. Non-dietary exposure. The term residential exposure is used in this document to refer to non-occupational, non-dietary exposure (e.g. for lawn and garden pest control, indoor pest control, termiticides, and flea and tick control on pets). Buprofezin is not registered for use on any sites that would result in residential exposure. 

D. Cumulative Effects
	A determination has not been made that buprofezin has a common mechanism of toxicity with other substances. Buprofezin does not appear to produce a common toxic metabolite with other substances. A cumulative risk assessment was, therefore, not performed for this analysis. 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.'' Unlike other pesticides for which EPA has followed a cumulative risk approach based on a common mechanism of toxicity, EPA has not made a common mechanism of toxicity finding as to buprofezin and any other substances and buprofezin 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 buprofezin has a common mechanism of toxicity with other substances. For information regarding EPA's efforts to determine which chemicals have a common mechanism of toxicity and to evaluate the cumulative effects of such chemicals, see the policy statements released by EPA's OPP concerning common mechanism determinations and procedures for cumulating effects from substances found to have a common mechanism on EPA's web site at  http://www.epa.gov/ pesticides/cumulative/. 

E. Safety Determination

	1. U.S. population. 
i. Acute risk.  Using the conservative assumptions discussed above, based on the completeness and reliability of the toxicity data, it is concluded that aggregate exposure to the proposed uses of buprofezin are estimated to utilize at most 
7% of the acute reference dose of females (13-49).  This estimate is likely to be much less, as more realistic data and models are developed.  Drinking water and other water consumption (EDWC of 57.4 ppb) scenarios were included in the dietary risk assessment modeling.  

ii. Chronic Risk.  Based on the toxicology data base and available information on anticipated residues, the chronic dietary exposure to the U.S. Population (total) was estimated to utilize no more than 80.0 % of the estimated chronic population adjusted dose (cPAD). Drinking water and other potential water consumption scenarios (EDWC of 12.5 ppb) were included in the dietary risk assessment modeling. Based on these assessments, it can be concluded that there is reasonable certainty of no harm to the U.S. Population or any population subgroup from exposure to buprofezin.  
   
	2. Infants and children. Chronic exposure to food and water to children ages 3-5, the highest exposed population subgroup, was 80.0 % of the cPAD).  EPA has determined that reliable data support the uncertainty factor (300 for combined interspecies and intraspecies variability and a data base uncertainty factor) for buprofezin.  EPA deemed an additional FQPA safety factor is not necessary to be protective of infants and children.  EPA generally has no concern for exposures below 100% of the cPAD. The Agency has considered the potential aggregate exposure from food, water and non-occupational exposure routes and has concluded aggregate exposure is not expected to exceed 100% of the chronic reference dose, and consequently, has determined there is a reasonable certainty that no harm will occur to infants and children from aggregate exposure to residues of buprofezin.

F. International Tolerances
Canada, Codex, and Mexico do not have maximum residue limits for residues of buprofezin in/on the proposed crops.  Therefore, harmonization is not an issue.  


