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.
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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 preharvest 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.
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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 
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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 DEEMTM (ver. 7.76). Residue estimates for water 

consumption were based on PRZM3/EXAMs and SCIGROW models and

incremental exposure assessments for nuts using LifeLineTM 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 
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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 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). An incremental exposure assessment for the petitioned 

tolerances was performed using LifeLineTM 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. 
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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 
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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. 
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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.