**EPA Registration Division contact: Andrew Ertman**  **(703) 30**  **8**
**- 9367** 

**IR**
**- 4**  **PP# 1E7908**  EPA has received a pesticide petition **PP# 1E7908**  **from Interregional**  **Research Project Number 4 (IR**
**- 4)**  **, 500 College Road East,**  **Suite 201 W, Princeton, NJ 08540**  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: b **ean, succulent (0.02 ppm);**  **b rassica, leafy greens, subgroup 5B**  **(55 ppm) ;**  **t urnip,**  **greens (55 pm)**  **; v**  **egetable, fruiting, group 8**
**- 10**  **(3 .0**  **ppm) ;**  **f ruit, citrus, group 10** 
**- 10**  **(2.5 ppm)**  **; f**  **ruit, pome, group 11**
**- 10 (4.0 ppm);**  **p ersimmon (1.9 ppm); and**  **t ea**  **( 20**  **ppm)**
**.** The petition also proposes removing the existing tolerance for non

-bell pepper; fruiting vegetable group 8, except non

-bell pepper ; fruit, citrus, group 10; and fruit, pome, group 11 which will now be covered b y the newl y requested tolerances. EPA has determined that the petition c ontains 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 spect rometry 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 mi**  **nor 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, t** **race 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 dete**  **ction of residues by gas chromatography using nitrogen phosphorous detection.** 
3. Magnitude of residues. **Fi eld trials were conducted on**  **mustard greens 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. The highest average residue value for**  **mustard greens was**  **34 .9**  **parts per million (ppm)**
**. A tolerance on**  **Brassica, leafy greens, subgroup 5B is** 2

**b eing**  **proposed at 55 ppm .**  **The requested proposed**  **tolerance is**  **adequately supported.**  **The residue of buprofezin (the principal residue of concern)**  **on tea was evaluated**  **from studies cond ucted in China, Japan and India**  **. A tolerance on tea is being proposed**  **at 20 ppm. Th e data support the proposed tolerance.**  **A tolerance on persimmon**  **is requested to be**  **translated from established**  **tolerances on stone fruit, crop group 12 (except apricot and peach) at 1.9 ppm.**  **A tolerance on bean, succulent is requested to be established from data on snap**  **bean and is being**  **proposed at 0.02 ppm. The tolerance for snap bean**  **is currently**  **establ ished at**  **0.02 ppm**
**.**

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 cause**  **d 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 exte**  **nsive 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).** 3
**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 p**  **pm). 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 hydroxylati**  **on 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 residu**  **e 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 e ffects 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 en**  **docrine 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 blo od 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 con sidering the low levels of buprofezin to which humans are likely to**  **be exposed.** C. Aggregate Exposure4

1. Dietary exposure. **Acute and chronic dietary risk analyses were conducted by**  **the Agency to estimate the**  **potential buprofezin residues in/on the follo wing crops**  **with established tolerances :**  **almond, avocado, banana, bell and non** 
**- bell peppers,**  **Brassic a, head and stem, subgroup 5A [**  **broccoli; broccoli, Chinese; Brussels sprouts; cabbage; cabbage, Chinese (napa); cabbage, Chinese mustard; cauliflower;**  **cava lo**  **broccoli; kohlra bi**  **] ,**  **Brassica, leafy greens, subgroup 5B [broccoli raab;**  **cabbage, Chinese (bok choy); collards; kale; mizuna; mustard greens; mustard spinach; rape greens],**  **canistel, celery, coffee,**  **spinach, cotton, grape, grape raisin, longan, lychee,**  **ma mey sapote,**  **mango, papaya, persimmons,**  **pomegranates, Spanish**  **lime, head lettuce , leaf lettuce, snap bean, fruiting vegetables, cucurbit vegetables,**  **citrus fruits (crop group 10** 
**- 10)**  **, pome fruits (crop group 11** 
**- 10)**  **, stone fruits, almond, pistachio, olive,**  **and strawberry, tea**  **, turnip greens, and meat and milk,**  **using** DEEMTM (ver. 7.76) **. Residue estimates for water consumption were based on PRZM3/EXAMs and SCIGROW models and**  **incremental exposure assessments**  **for Brassica, leafy greens, persimmon, and tea**  **using LifeLine**  **TM version 5.0** 
**. Vegetable,**  **fruiting, gr oup 8** 
**- 10, except nonbell pepper;**  **Fruit, citrus, group 10** 
**- 10;**  **and Fruit, pome, group 11** 
**- 10 were modeled in the previous assessment** 
**.** 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 i nfants 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 resulta**  **nt safety factor used to establish the cPAD was 300. The cPAD was set at 0.0033 mg/kg/day.** 
**The acute dietary exposure was based on the following assumptions: residues at tolerance levels, 100% crop treated, and DEEMTM (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). 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).**5

**An incremental exposure assessment for the petitioned tolerances wa s performed**  **using LifeLineTM version 5.0. T olerance 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. T he resulting**  **incre mental**  **food exposure estimate for females 13**
**- 49 years old was**  **< 0. 1**  **% 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 incremental**  **chronic dietary exposure used 100**  **% crop treated for Brassica,**  **leafy greens, persimmons and tea. 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**  **6.3 % of the chronic population adjusted dose (cPAD)**  **and 5. 5**  **% for children 3** 
**- 5**  **years old. The total estimated risk from**  **chronic exposure does not exceed 8 6**  **% 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 monitorin**  **g 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 pe**  **sticide 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** 
**- e**  **nd 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 bas in.**  **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** 6

**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 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 surfa ce water and 0.09 ppb for**  **ground water (Federal Register V**  **ol .**  **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 buprofe zin 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 FF DCA 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 mechanis m 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 no**  **t 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 fro**  **m 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 at most 7.1**  **% of the acute referenc**  **e dose of females (13**
**- 49). This estimate is likely to be much less, as**  **mo re realistic data and models are developed**  **. Drinking water and other water consumption**  **scenarios were included in the dietary risk assessment modeling.**7

**ii. Chronic Risk. Based on the toxicology data base and**  **available information on anticipated residues, the chronic dietary exposure to the U.S. Pop**  **ulation (total) was estimated**  **to utilize no more than 86.3**  **% of the estimated chronic population adjusted dose (**  **cPAD). Drinking water and other potential water consumption scenarios 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 populat** **ion 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,**  **(85.5 % of the cPAD).**  **EP A 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 prote**  **ctive 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.**