Page 3 of 51

4.5.4 Summary of Points of Departure Used in Risk Assessment ............................... 20

5.0 DIETARY AND DRINKING WATER EXPOSURE AND RISK ASSESSMENT.... 22

5.1 Metabolite/Degradate Residue Profile......................................................................... 22

5.1.1 Summary of Plant Metabolism Studies................................................................. 22

5.1.2 Comparison of Metabolic Pathways...................................................................... 22

5.1.3 Environmental Fate and Transport ...................................................................... 23

5.1.4 Residues of Concern Summary and Rationale..................................................... 23

5.2 Food Residue Profile ..................................................................................................... 24

5.2.1 Residues in Crops.................................................................................................... 24

5.3 Water Residue Profile ................................................................................................... 25

5.3.1 Estimated Drinking Water Concentrations.......................................................... 25

5.4.1 Acute Dietary and Drinking Water Analysis ....................................................... 26

5.4.2 Chronic Dietary and Drinking Water Analysis ................................................... 26

6.0 RESIDENTIAL EXPOSURE AND RISK ASSESSMENT .......................................... 27

6.1 Residential Bystander Postapplication Inhalation Exposure .................................... 27

6.2 Spray Drift...................................................................................................................... 28

7.0 AGGREGATE EXPOSURE AND RISK ASSESSMENT............................................ 28

8.0 CUMULATIVE RISK...................................................................................................... 29

9.0 OCCUPATIONAL EXPOSURE/RISK CHARACTERIZATION.............................. 29

9.1 Exposure Scenarios....................................................................................................... 29

9.2 Handler Exposure.......................................................................................................... 29

9.2.1 Handler Exposure Scenarios.................................................................................. 29

9.2.2 Handler Exposure Data.......................................................................................... 30

9.2.3 Handler Exposure Assumptions............................................................................ 30

9.2.4 Handler Exposure and Risk Estimates................................................................. 32

9.3 Post Application Exposure............................................................................................ 35

9.3.1 Post Application Exposure Scenarios ................................................................... 35

9.3.2 Post Application Exposure Assumptions.............................................................. 35

9.3.3 Post-Application Exposure and Risk Estimates................................................... 37

9.3.4 Restricted Entry Interval ....................................................................................... 39

10. REFERENCES.................................................................................................................. 39

APPENDICES............................................................................................................................. 40

A TOXICOLOGY DATA SUMMARY.............................................................................. 40

A.1 Guideline Data Requirements................................................................................ 40
Page 4 of 51

A.2 Toxicity Profiles.......................................................................................................... 41

A.3 Toxicological Endpoints............................................................................................. 43

A.4 EXECUTIVE SUMMARIES .................................................................................... 47

APPENDIX B. Chemical Names And Structures Of Metabolites......................................... 49

APPENDIX C. Physical/Chemical Properties.......................................................................... 50

APPENDIX D. Studies Reviewed for Ethical Conduct.......................................................... 51
Page 5 of 51

1.0 EXECUTIVE SUMMARY

This document addresses the exposures and risks associated with exposures from currently 

registered uses and the proposed new uses of buprofezin. It also assesses potential enhanced 

sensitivity of infants and children from dietary and/or residential exposure as required under the 

Food Quality Protection Act (FQPA) of 1996.

Under PP#1F7905, Nichino America, Inc. is proposing a new use for buprofezin on tree nuts 

(including pistachio). Under PP#1E7908, Interregional Research Project Number 4 (IR-4), on 

behalf of the Agricultural Experiment Stations of CA, HI, NJ, NC, SC, TN, TX, and VA, and the 

tea industry, is proposing new uses for buprofezin on new members of a number of crop groups, 

leafy greens, subgroup 5B, turnip greens, succulent beans, persimmon, and tea (no U.S. 

Registration). 

Use Profile

Buprofezin is an insect growth regulator used for control of insects in the suborder Homoptera 

(cicadas, plant lice, scale insects). It is used on a variety of food/feed crops and ornamentals in 

the U.S. Buprofezin is registered to Nichino America, Inc. Established tolerances for residues 

of buprofezin range from 0.02-80 ppm in/on the registered crops (40 CFR 180.511). Tolerances 

have also been established for residues of buprofezin as a result of secondary residues, in milk 

(0.01 ppm) and meat (0.05 ppm). Buprofezin works by inhibiting chitin biosynthesis. It disrupts

molting, suppresses egg deposition, and reduces egg viability. Applications may be made using 

ground or aerial equipment. There are currently no buprofezin products registered for 

homeowner use and no products registered for application to residential areas.

Proposed New Uses

The buprofezin 3.6 lb/gal SC formulation (Courier 40SC, EPA Reg. No. 71711-20) is proposed 

for broadcast foliar applications to fruiting vegetables, group 8-10, leafy greens, subgroup 5B, 

turnip greens, and succulent beans. The buprofezin 70% dry flowable (DF) formulation 

(Applaud® 70DF Insect Growth Regulator; EPA Reg. No. 71711-21) is proposed for broadcast 

foliar applications to new members of the citrus and pome fruit groups, tree nuts, including 

pistachio, and persimmon. In addition, use directions were provided for multiple active 

ingredient products (MAI) containing buprofezin (EPA Registration Nos.: 71711-33, 71711-32); 

these products proposed lower rates of application for buprofezin and will not be discussed 

further.

The proposed use rate for pears and asian pears is higher than that originally proposed in 

connection with the current tolerance. The higher rate is acceptable only because the tolerance is 

being raised to harmonize with CODEX.
Page 6 of 51

The current citrus crop group use is not supported by adequate residue data (missing adequate 

lemon field trial data), so data are not available to support the expansion of the citrus crop group. 

A revised Section B is required, removing the new members of the citrus crop group.

Hazard Identification

The toxicology database for buprofezin is adequate for evaluating and characterizing buprofezin 

toxicity and selecting endpoints for purposes of this risk assessment except for a 28-day 

inhalation study and a developmental thyroid rat study. 

Buprofezin exhibits low acute toxicity. It falls within Toxicity Category III for acute oral toxicity

and Toxicity Category IV for acute dermal and inhalation toxicity, and eye and skin irritation. It 

is not a dermal sensitizer. 

The primary subchronic effects of concern in rat studies were increased microscopic lesions in liver 

and thyroid, increased liver weights, and increased thyroid weight in males. In chronic studies in the 

rat, increased incidence of follicular cell hyperplasia and hypertrophy in the thyroid of males were 

reported. A chronic dog study showed increased relative liver weights in female dogs. A rat dermal 

toxicity study showed liver and skin effects (increase in acanthosis and hyperkeratosis ) in females. 

Developmental and reproductive toxicity studies do not indicate concern for increased susceptibility 

in offspring. Toxicity in the offspring was found at dose levels that were also toxic to the parent and 

the effects observed in the offspring were not more severe, qualitatively, than the effects observed in 

the parent.

Buprofezin was classified by HED’s Cancer Assessment Review Committee (CARC) as having 

“Suggestive Evidence of Carcinogenicity, but not sufficient to assess human carcinogenic 

potential" in 1999 based on liver tumors in female mice. Buprofezin was not carcinogenic to 

male and female rats. 

No neurotoxic effects were observed at any dose in a subchronic neurotoxicity study in rats at 

the highest dietary doses of 5000 ppm. Acute neurotoxicity study was waived based on the lack 

of neurotoxicity findings in the subchronic neurotoxicity study and the general toxicity of 

buprofezin. An immunotoxicity study did not demonstrate immunotoxic effects by buprofezin. 

A special study is required to generate specific data on the thyroid to protect the developing 

nervous system from thyroid hormone disrupting chemicals. 

Dose Response Assessment

Toxicological endpoints were selected for dietary/drinking water and occupational exposure 

scenarios. Acute and chronic reference doses (RfDs) were selected for assessment of food and 

drinking water exposures. An acute RfD for females 13-49 was selected from a developmental 

toxicity study in rats. An acute RfD for the general population was not selected because no 

effect attributable to a single day oral exposure was observed in animal studies. A chronic RfD 

was selected from a two year chronic feeding study in rats. Short and intermediate-term 

occupational exposures via the dermal and inhalation routes may occur based on the use pattern 
Page 7 of 51

and label directions. A toxicological endpoint for dermal worker exposure was selected from 24 

day dermal toxicity studies in rat. A toxicological endpoint from a 90 day feeding study in rats

was selected for assessment of inhalation exposure for workers. An uncertainty factor of 100X 

was applied for acute dietary and dermal exposures (10x for interspecies extrapolation, 10x for 

intraspecies variation). An uncertainty factor of 300X was applied for chronic dietary exposures 

(10X for interspecies extrapolation, 3X for interspecies variation, and10x for incomplete data 

base due to the need for a thyroid assay in rats). Short - and intermediate term inhalation PODs 

were selected from a 90-day oral toxicity study in rats. An MOE of 1000 is required for the 

short- and intermediate-term scenarios for inhalation exposure based on a 10X for intraspecies 

extrapolation, a 10X for interspecies variation and a 10x for incomplete data base due to the need 

for a thyroid assay in rats and the need for a 28-day inhalation study.

Exposure/Risk Assessment and Risk Characterization

Risk assessments were conducted for dietary (food and water) and occupational exposure 

pathways based on registered uses and the request for a new uses of buprofezin on brassica, 

coffee and pomegranate. Worker exposures were assessed for handler and post-application 

activities. 

Screening level acute and refined chronic dietary and drinking water risk assessments for 

buprofezin show that the acute and chronic combined dietary and drinking water exposure 

estimates are below HED’s level of concern for the general population and all population 

subgroups. 

Exposure and risk estimates indicate that occupational handler and post-application exposures 

are not of concern at the maximum allowable use rates for the proposed new uses for all but one 

handler and one post-application exposure scenario. The occupational analysis indicates 

exposures of concern for the scenario of mixing/loading dry flowable formulation for aerial 

application assuming that gloves are worn in accordance with the label requirement. The worker 

assessment indicates exposures of concern for the post-application scenario of thinning 

pomegranates. Since mechanical harvesting/thinning is often used for this crop, however, this 

estimate should be considered conservative.

Use of Human Studies

This risk assessment relies in part on data from studies in which adult human subjects were 

intentionally exposed to a pesticide or other chemical. These studies, listed in Appendix 2.0, 

have been determined to require a review of their ethical conduct. Some of these studies are also 

subject to review by the Human Studies Review Board. All of the studies used have received the 

appropriate review.

Environmental Justice

Potential areas of environmental justice concerns, to the extent possible, were considered in this 

human health risk assessment, in accordance with U.S. Executive Order 12898, "Federal Actions 

to Address Environmental Justice in Minority Populations and Low-Income Populations," 

http://www.eh.doe.gov/oepa/guidance/justice/eo12898.pdf).
Page 8 of 51

As a part of every pesticide risk assessment, OPP considers a large variety of consumer 

subgroups according to well-established procedures. In line with OPP policy, HED estimates 

risks to population subgroups from pesticide exposures that are based on patterns of that 

subgroup’s food and water consumption, and activities in and around the home that involve 

pesticide use in a residential setting. Whenever appropriate, non-dietary exposures based on 

home use of pesticide products and associated risks for adult applicators and for toddlers, youths, 

and adults entering or playing on treated areas postapplication are evaluated. Further 

considerations are currently in development, as OPP has committed resources and expertise to 

the development of specialized software and models that consider exposure to bystanders and 

farm workers as well as lifestyle and traditional dietary patterns among specific subgroups. 

Tolerance Recommendations

Pending submission of revised Sections B and F, there are no residue chemistry issues that would 

preclude granting unconditional registration for the requested uses of buprofezin, except 

expanded citrus fruit uses. The proposed uses and the available data support the following 

tolerances under 40 CFR 180.511 for residues of buprofezin in/on the following raw agricultural 

commodities:

Bean, succulent ................................................................0.02 ppm 

Brassica, leafy greens, subgroup 5B......................................60 ppm

Fruit, pome, group 11-10 (except pear and pear, oriental).............3.0 ppm

Nut, tree group 14 ..........................................................0.05 ppm

Pear............................................................................6.0 ppm

Pear, oriental..................................................................6.0 ppm

Persimmon................................................................... 1.9 ppm

Pistachio......................................................................0.05 ppm

Tea.............................................................................20 ppm

Turnip, greens............................................................... 60 ppm

Vegetable, fruiting, group 8-10........................................... 2.0 ppm

Error Correction in Currently Established Tolerances

Ilama.........................................................................0.30 ppm

Longan.......................................................................0.30 ppm

In connection with the establishment of the proposed tolerances and error corrections, the 

following existing tolerances should be removed.

Almond

Bean, snap

Fruit, pome, group 11

Vegetable, Fruiting, group 8

Llama

Loganberry
Page 9 of 51

2.0 HED RECOMMENDATIONS

2.1 Data Deficiencies/Conditions of Registration 

The immunotoxicity study has been satisfied. A 28-day inhalation study and a developmental 

thyroid rat study is required.

The following residue chemistry data deficiencies are related to the subject petition.

- Revised Section B, lowering the proposed single application rate on persimmon to 1.5 lb 

ai/A (and lowering the registered application rate on stone fruit), prohibiting the use of 

adjuvants, except for Tree Nuts and Leafy Brassica Vegetables and Turnip Greens.

- Revised Section B, correcting the terminology for asian pear to “pear, oriental.” 

- Revised Section F, proposing a 60 ppm tolerance for Brassica leafy vegetables, subgroup 

5B, and turnip greens; changing the proposed tolerance for fruiting vegetables, group 8-

10 to 2.0 ppm, removing the proposed tolerance of 4.0 ppm for Fruit, pome, group 11-10 

and adding a proposed tolerance of 3.0 ppm for Fruit, pome, group 11-10 (except pear 

and pear, oriental), adding a proposed tolerance of 6.0 ppm for pear, and pear, oriental, 

adding a proposed tolerance of 0.05 ppm for residues of buprofezin on pistachio, and 

removing the proposed tolerance for Fruit, citrus, group 10-10.

-

An alternative to lowering the proposed rate for stone fruit is to submit residue data to support 

the 2.0 lb ai/A rate and a petition to raise the stone fruit tolerances.

The following residue chemistry data deficiencies remain outstanding from previous petitions.

●radiovalidation of the livestock enforcement method (DP328796, 5/28/2008, T. Bloem)

●lemon field trial data (conclusion 3; D328796, 5/28/2008, T. Bloem, originally from D296492, 

12/17/03, T. Bloem)

●apple and grape processing studies (conclusion 4; DP328796, 5/28/2008, T. Bloem). The 

processing studies should be conducted at 5x the labeled rate using the labeled RTI and PHI.

The petitioner should be reminded that for import tolerance petitions, proposed use directions are 

required for the exporting countries, and residue data are needed for the areas in which 

buprofezin is used. 

2.2 Tolerance Considerations

2.2.1 Enforcement Analytical Method

Adequate enforcement methods are available in PAM I and PAM II for enforcement of 

buprofezin tolerances, including GC methods with nitrogen phosphorus detection (GC/NPD), 

and a GC/mass spectrometry (MS) method for confirmation of buprofezin residues in plant 

commodities. The GC/MS method utilizes three ions for identification of buprofezin. 
Page 10 of 51

The data collection methods were similar to the enforcement methods. One study used a newer 

LC/MS/MS method for data collection. Since adequate method validation and concurrent 

recovery data were attained in the field trial studies, HED concludes that the current enforcement 

methods are adequate for enforcement of the tolerances recommended as part of the current 

petition. 

A condition of registration requirement for radiovalidation of the livestock enforcement method 

has been outstanding since 12/17/2003 (T. Bloem, D296492).

2.2.2 International Harmonization

A tolerance of 0.05 ppm is recommended for tree nuts. This tolerance is harmonized with the 

CODEX almond MRL.

There is an established CODEX MRL of 2.0 ppm in/on pepper, which is based on the same US 

data as were referenced in the current petition. JMPR combined pepper and non-bell pepper into 

one data set for their MRL estimation. None of the residue data on fruiting vegetables exceeded 

2.0 ppm, so we are harmonizing with the CODEX MRL for peppers at 2.0 ppm. The CODEX 

MRL for tomato is 1.0 ppm, so the US will not be in harmony with this MRL by setting the crop 

group tolerance for fruiting vegetables.

For pome fruit, the CODEX MRLs are based on the same data and same GAP used to support 

the US tolerances, and the NAFTA calculator. As listed in Table 1, GAP is different for apple 

and pear; the number of applications and the application rate is higher on pear. The maximum 

residue in apple was 0.99 ppm. The maximum residue in pear was 3.64 ppm. Due to the 

difference in GAP, it makes sense to separate the pome fruit tolerance into “fruit, pome (exc pear 

and pear, oriental) at 3.0 ppm and pear and pear, oriental at 6.0 ppm. U.S. tolerances will be in 

harmony with CODEX.

For citrus fruit, we cannot harmonize with CODEX due to differences in GAP. For citrus, the 

US tolerance is based on a use rate of 2 applications at 2 lb ai/A with a 3 day PHI. The CODEX 

MRL is based on a use rate of 1 application at 0.025 kg ai/hL (0.5-0.9 kg ai/ha) with a 7 day PHI; 

residues in Spain were a maximum of 0.46 mg/kg, much lower than the residues from US trials.

There are currently no established Codex, Canadian, or Mexican maximum residue limits 

(MRLs) for buprofezin in/on the remainder of the proposed commodities. Therefore, 

harmonization is not an issue for buprofezin on those commodities. 
Page 11 of 51

2.2.3 Recommended Tolerances

Pending submission of revised Sections B and F, there are no residue chemistry issues that would 

preclude granting unconditional registration for the requested uses of buprofezin except Fruit, 

citrus, group 10-10. Available data support the following tolerances under 40 CFR 180.511 for 

residues of buprofezin in/on the following raw agricultural commodities:

Bean, succulent...............................................................0.02 ppm 

Brassica, leafy greens, subgroup 5B......................................60 ppm

Fruit, pome, group 11-10 (except pear and pear, oriental).............3.0 ppm

Nut, tree group 14 ..........................................................0.05 ppm

Pear..............................................................................6.0 ppm

Pear, oriental..................................................................6.0 ppm

Persimmon................................................................... 1.9 ppm

Tea.............................................................................20 ppm

Turnip, greens............................................................... 60 ppm

Vegetable, fruiting, group 8-10........................................... 2.0 ppm

Error Correction in Currently Established Tolerances

Ilama.........................................................................0.30 ppm

Longan.......................................................................0.30 ppm

In connection with the establishment of the proposed tolerances and error corrections, the 

following existing tolerances should be removed.

Almond

Bean, snap

Fruit, pome, group 11

Vegetable, Fruiting, group 8

Llama

Loganberry

2.2.4 Revisions to Petitioned-For Tolerances

Revised Section F, proposing a 60 ppm tolerance for Brassica leafy vegetables, subgroup 5B, 

and turnip greens; removing the proposed tolerance for fruiting vegetables, group 8-10, adding a 

proposed tolerance of 3.0 ppm for Fruit, pome, group 11-10 (except pear and pear, oriental), 

adding a proposed tolerance of 6.0 ppm for pear, and pear, oriental, and removing the proposed 

tolerance for Fruit, citrus, group 10-10.
Page 12 of 51

2.3 Label Recommendations

- Revised Section B, lowering the proposed single application rate on persimmon to 1.5 lb 

ai/A (and lowering the registered application rate on stone fruit), prohibiting the use of 

adjuvants, except for Tree Nuts and Leafy Brassica Vegetables and Turnip Greens.

- Revised Section B, correcting the terminology for asian pear to “pear, oriental.” 

3.0 INGREDIENT PROFILE 

3.1 Chemical Identity

Table 1. Buprofezin Nomenclature.

Compound

Common name Buprofezin

Company experimental name BF1

IUPAC name 2-tert-butylimino-3-isopropyl-5-phenyl-3,4,5,6-tetrahydro-3H-1,3,5-thiadiazin-4-

one

CAS name 2-[(1,1-dimethylethyl)imino]tetrahydro-3-(1-methylethyl)-5-phenyl-4H-1,3,5-

thiadiazin-4-one

CAS registry number 69327-76-0

End-use product (EP) 3.6 lb/gal FlC (Courier® 40SC Insect Growth Regulator; EPA Reg. No. 71711-

20)

70% DF (Applaud® 70DF Insect Growth Regulator; EPA Reg. No. 71711-21)

3.2 Physical/Chemical Characteristics 

A detailed description of the physicochemical properties of buprofezin is provided in Appendix 

C. 

3.3 Pesticide Use Pattern

3.3.1 Registered Products

There are 12 active buprofezin registrations, six Section 3s and 6 SLNs (24(c)s which are 

registered to Nichino America, Inc. 

N N

S

CH3

CH3

N

O

H3C CH3

CH3
Page 13 of 51

Table 2. Summary Report of Supported Registered Buprofezin Products

Reg # Name Company Name %AI

71711-15 Applaud 70WP Insect Growth Regulator Nichino America, Inc. 70

71711-16 Buprofezin Technical Nichino America, Inc. 99.1

71711-20 Buprofezin 40SC Nichino America, Inc. 40

71711-21 Applaud 70DF Insect Growth Regulator Nichino America, Inc. 70

71711-32 NNI-0871 SC Nichino America, Inc. 26.4

71711-33 NNI-0772 SC Nichino America, Inc. 25

CA050008 Courier 40SC Insect Growth Regulator Nichino America, Inc. 40

CA070010 Talus 40SC Insect Growth Regulator Nichino America, Inc. 40

CO070005 Talus 40SC Insect Growth Regulator Nichino America, Inc. 40

FL040012 Courier 40SC Insect Growth Regulator Nichino America, Inc. 40

PA070004 Talus 40SC Insect Growth Regulator Nichino America, Inc. 40

VA070001 Talus 40SC Insect Growth Regulator Nichino America, Inc. 40

3.3.2 Proposed New Uses 

There are currently three end-use products for buprofezin registered to Nichino America, Inc. for use 

on food/feed crops, including a 70% WP (APPLAUD® 70WP, EPA Reg. No. 71711-15), a 70% DF 

(APPLAUD® 70DF, EPA Reg. No. 71711-21), and a 3.6 lb/gal SC (Courier® 40SC, aka Centaur® 

WDG, EPA Reg. No. 71711-20). The 70% WP and/or 70% DF formulations are registered for uses 

on almonds, pistachios, bananas, pome fruits, stone fruit, citrus fruits, grapes, and various tropical 

fruits, and the 3.6 lb/gal SC formulation is registered for uses on cotton, cucurbit vegetables, lettuce, 

snap beans, and tomatoes. IR-4 is proposing the following: a new use for the 70% DF on 

persimmons, translated from stone fruit; a new use for the 3.6 lb/gal SC on Leafy Brassica 

Vegetables (subgroup 5B) and Turnip Greens; expanding the existing use for the 3.6 lb/gal SC on 

the new members of the fruiting vegetables (Crop Group 8-10), expansion of the current use on 

bean, snap, succulent to bean, succulent. The Buprofezin Technical label (EPA Reg. No. 71711-16) 

is being amended to state that uses on the new commodities are allowed.

In addition, several multiple active ingredient (MAI) products are available. VETICA® Insecticide 

(EPA Reg. No. 71711-32) contains 0.33 lb/gal flubendiamide and 2.33 lb/gal buprofezin. 

TOURISMO® Insecticide (EPA Reg. No. 71711-33) contains 1.17 lb/gal flubendiamide and 2.33 

lb/gal buprofezin. Labels were provided for this product in Section B; however, lower rates in terms 

of ai/A are proposed for these MAI products, so these uses are omitted from the use pattern table.

Proposed 70% DF and 3.6 lb/gal SC labels were provided. The labels indicate that application 

through irrigation equipment is prohibited and indicate the following rotational crop restrictions: (1) 

crop listed on the label may be planted at any time; (2) small grain crops and leafy vegetable may be 

planted 30 days after application; and (3) all other crops may be planted 60 days following 

application. Table 3 is a summary of the proposed use directions.
Page 14 of 51

Table 3. Summary of Directions for Use of Buprofezin.

App. Timing, Type, 

and Equip.

Formulation

[EPA Reg. No.]

App. Rate

(lb ai/A)

Max. No. 

App. Per 

Season

Max. Seasonal 

App. Rate (lb 

ai/A)

PHI

(days) Use Directions and Limitations

Persimmon, Translated from Stone Fruit

Broadcast foliar, during 

fruiting. Ground 

equipment.

70% DF

[71711-21] 1.5-2.0 2 4 14

Apply by ground equipment in 

>100 GPA1; a minimum RTI of 

14 days is specified

Tree Nuts

Broadcast foliar, during 

fruiting. Ground 

equipment.

70% DF

[71711-21] 1.5-2.0 1 2 60

Apply by ground equipment in 

>100 GPA1; a minimum RTI of 

14 days is specified

Pome Fruit (Crop Group 11-10), except Pear and Asian Pear

Broadcast foliar, during 

fruiting. Ground 

equipment.

70% DF

[71711-21] 0.4-1.5 1 1.5 14

Apply by ground equipment in 

>100 GPA1; a minimum RTI of 

14 days is specified

Citrus

Broadcast foliar, during 

fruiting. Ground 

equipment.

70% DF

[71711-21] 1.5-2.0 2 4 3

FL and TX only. Apply by 

ground equipment in >750 

GPA1; a minimum RTI of 60 

days is specified

Leafy Brassica Vegetables (subgroup 5B), Turnip Greens

Broadcast foliar, during 

vegetative development. 

Ground or air equipment.

3.6 lb/gal SC

[71711-20] 0.25-0.38 2/crop cycle4/year

0.76/crop

1.53/year 1

Apply by ground/air equipment 

in ≥20/≥5 GPA; a minimum 7-

day RTI is specified.

Pear, Asian Pear

Broadcast foliar, during 

fruit development. 

Ground equipment

70% DF

[71711-21] 1.5- 2.0 2 4 14

Apply by ground equipment in 

>80 GPA; >200 GPA for more 

mature trees a minimum 7-day 

RTI is specified.

Fruiting Vegetables (Crop Group 8-10)

Broadcast foliar; Ground 

or air equipment.

3.6 lb/gal SC

[71711-20] 0.25-0.38 2 0.76 1

Apply by ground/air equipment 

in ≥20/≥5 GPA; for 

greenhouse-grown tomatoes 

apply in a minimum of 20 

GPA; a minimum 5-day RTI is 

specified.

Bean, succulent

Broadcast foliar; Ground 

or air equipment.

3.6 lb/gal SC

[71711-20] 0.25-0.38 2 0.76 14

Apply by ground/air equipment 

in ≥20/≥5 GPA; for 

greenhouse-grown tomatoes 

apply in a minimum of 20 

GPA; a minimum 14-day RTI 

is specified.

1

 GPA = gallons per acre

3.4 Anticipated Exposure Pathways

Dietary (food and water) exposures are expected based on existing uses of buprofezin and the 

new use requests of buprofezin. A residential exposure assessment is not required for this 

assessment because there are no residential uses or exposures associated with the proposed new 

use or previously registered uses. 
Page 15 of 51

3.5 Considerations of Environmental Justice

Potential areas of environmental justice concerns, to the extent possible, were considered in this 

human health risk assessment, in accordance with U.S. Executive Order 12898, "Federal Actions 

to Address Environmental Justice in Minority Populations and Low-Income Populations," 

http://www.eh.doe.gov/oepa/guidance/justice/eo12898.pdf).

As a part of every pesticide risk assessment, OPP considers a large variety of consumer 

subgroups according to well-established procedures. In line with OPP policy, HED estimates 

risks to population subgroups from pesticide exposures that are based on patterns of that 

subgroup’s food and water consumption, and activities in and around the home that involve 

pesticide use in a residential setting. Whenever appropriate, non-dietary exposures based on 

home use of pesticide products and associated risks for adult applicators and for toddlers, youths, 

and adults entering or playing on treated areas postapplication are evaluated. Further 

considerations are currently in development, as OPP has committed resources and expertise to 

the development of specialized software and models that consider exposure to bystanders and 

farm workers as well as lifestyle and traditional dietary patterns among specific subgroups. 

4.0 HAZARD CHARACTERIZATION/ASSESSMENT

4.1 Toxicology Studies Available for Analysis

The toxicology database for buprofezin is adequate for evaluating and characterizing buprofezin

toxicity and selecting endpoints for purposes of this risk assessment except for a 28-day 

inhalation study and a developmental thyroid rat study. An acceptable immunotoxicity study 

required as part of new 40 CFR Part 158 data requirements for registration of a pesticide has 

been submitted and indicates no evidence of immunotoxicity.

4.2 Absorption, Distribution, Metabolism and Excretion

The absorption, distribution, metabolism, and excretion of buprofezin were studied in rats. The 

rat metabolism study indicated that 95% of the administered dose was excreted in urine and feces 

within 72 hours (feces - 79.1%; urine - 12.9%). In the feces, about 45% of the radioactivity was

recovered as parent compound, with the remainder as several metabolites. Buprofezin does not 

appear to bioaccumulate. 

In a metabolism study in rats, total recovery of administered test material was acceptable at 

95.6%. Metabolites in feces consisted primarily of unchanged parent (BF1; 45.4%) with lesser 

amounts of BF27 (2-tert-butylimino-5-(4-hydroxy-3-methoxyphenyl)-3-isopropyl-1,3,5-

thiadiazinan-4-one; 7.2% of dose) and BF28 (2-[3-isopropyl-3-

[methylsulfonylmethyl(phenyl)carbamoyl] ureido]-2-methylpropionic acid; 4.6% of dose). 

Hydrolysis of the extracted fecal fiber resulted in minor amounts (< 0.1% each) of BF9 (3-

isopropyl-5-phenyl-1,3,5-thiadiazinan-2,4-dione), BF10 (2-tertbutylimino-3-isopropyl-5-phenyl1,3,5-thiadiazinan-4-one-1-oxide), BF12(1-isopropyl-3-phenylurea), and BF13 (1-(4-

hydroxyphenyl)-3-isopropylurea). In urine, 12.9% of the administered dose was recovered. 

Polar conjugates released by sulfatase hydrolysis consisted of BF13 (0.5% of dose), BF23 (N-(4-
Page 16 of 51

hydroxyphenyl) acetamide; 2.5% of dose), and BF28 (0.3% of dose). A total of 60.7% of the 

administered dose was identified and no unknown metabolite or fiber bound residue exceeded 

3.7% of the dose.

There are no dermal absorption studies available with buprofezin.

 

4.3 Toxicological Effects

In subchronic toxicity studies, the primary effects of concern in the rat were increased 

microscopic lesions in liver and thyroid, increased liver weights, and increased thyroid weight in 

males. In chronic studies in the rat, an increased incidence of follicular cell hyperplasia and 

hypertrophy in the thyroid of males were reported. In chronic studies in the dog, increased 

relative liver weights were reported in females. Effects observed in a 24 day dermal toxicity 

study in rats included inflammatory infiltrate of the liver and an increase in acanthosis and 

hyperkeratosis of the skin in females. 

The developmental toxicity study in the rat showed reduced ossification and reduced pup weight

at maternally toxic doses (death, decreased pregnancy rates, increased resorption rates). No 

developmental toxicity was observed in the rabbit at or below maternally toxic dose levels. The 

reproductive toxicity study showed decreased pup body weights at dose levels where liver effects 

(increased relative and/or absolute liver weights) and decreased body weight gains were 

observed in the parental generations. These studies do not raise concern for increased 

susceptibility in offspring since toxicity in the offspring was found at dose levels that were also 

toxic to the parent(s) and the effects observed in the offspring were not more severe, 

qualitatively, than the effects observed in the parent(s). These data do not indicate a basis for 

concern for neurotoxicity. No neurotoxic effects were observed at any dose in a subchronic 

neurotoxicity study in rats at the highest dietary doses of 5000 ppm.

In an evaluation of buprofezin conducted in 1999 the CARC classified buprofezin as having 

“Suggestive Evidence of Carcinogenicity, but not sufficient to assess human carcinogenic 

potential" based on liver tumors in female mice. Buprofezin was negative in in vitro and in vivo

genotoxicity assays. The CARC noted findings from the published literature indicate that it 

causes cell transformation and induces micronuclei in vitro, but determined that, in the absence 

of a positive response in an in vivo micronucleus assay, buprofezin may have aneugenic potential 

which is not expressed in vivo.

The acute toxicity data indicate that buprofezin is in Toxicity Category III for acute oral toxicity 

and Toxicity Category IV for acute dermal toxicity, acute inhalation toxicity, eye irritation, and 

dermal irritation. It is not a dermal sensitizer.
Page 17 of 51

870.5100, 870-5300 Mutagenicity

Buprofezin was negative in five acceptable mutagenicity studies:

1. Reverse gene mutation, S. typhimurium (MRID 42873815)

2. Gene mutation: mouse lymphoma (MRID 42873816)

3. in vitro human cytogenetic assay (MRID 42873818)

4. Mutagenicity: mouse micronucleus assay (MRID 42873817)

 5. Mutagenicity: Unscheduled DNA synthesis (MRID 42873819)

The complete toxicity profile for buprofezin is provided in Appendix A. 

4.4 Safety Factor for Infants and Children (FQPA Safety Factor)

Pending the outcome of the comparative thyroid toxicity study, there is uncertainty with respect 

to the effect of buprofezin in developing offspring and a database uncertainty factor of 10X is 

retained. If the factor is applied to a point of departure (POD) based on thyroid effects in rats, 

the interspecies factor is reduced to 3X. Based on the lack of any neurotoxic effects in a 

subchronic neurotoxicty study at doses as high as 5000 ppm and the absence of neurotoxicity in 

subchronic and chronic tests, an acute meurotoxicity study was waived. 

4.4.1 Completeness of the Toxicology Database

The toxicity database for buprofezin is sufficient for a full hazard evaluation and is considered 

adequate to evaluate risks to infants and children. Acceptable developmental toxicity studies in 

the rat and rabbit, and acceptable multi- and single generation reproduction studies in the rat are 

available in the database. There was no evidence of neurotoxicity or immunotoxicity in the 

submitted studies. A developmental neurotoxicity study is not available but is not required at 

this time. Based on a preliminary review of a submitted immunotoxicity study, the study is 

acceptable and indicates no evidence of immunotoxicity. A special study on the thyroid is also 

required to protect the developing nervous system from thyroid hormone disrupting chemicals. 

An inhalation study is required based on Weight of the Evidence (WOE) by the Hazard and 

Science Policy Council (HASPOC) (TXR 0054073).

HASPOC RECOMMENDATIONS:

The HASPOC concludes based on a weight of evidence (WOE) approach that a 28-day 

inhalation toxicity study is required at this time. This approach considered all of the available 

hazard and exposure information for buprofezin, including: (1) the use of an oral POD that 

results in MOEs as low as 10-97 (the lowest MOEs) for risk via the inhalation route resulting 

from occupational exposures; (2) the physical/chemical properties and relatively high vapor 

pressure of buprofezin; and (3) the toxicological profile of buprofezin.
Page 18 of 51

4.4.2 Evidence of Neurotoxicity

There is evidence of thyroid toxicity following subchronic and chronic exposures to rats as well 

as chronic exposures to dogs characterized as decreases in serum thyroxine levels and increased 

thyroid weights in dogs and histopathological lesions in the subchronic and chronic toxicity 

studies in rats. As previously noted, disruption of thyroid homeostasis is the initial, critical effect 

that may lead to adverse effects on the developing nervous system. 

Normally, if a neurodevelopmental concern is raised by existing data on a pesticide, a rat 

developmental neurotoxicity (DNT) study is requested. However, a DNT study is not required 

for buprofezin since this study would not address thyroid toxicity concerns. Thus, in lieu of the 

rat DNT study, a special study is needed to further evaluate the hormonal responses associated 

with the developing fetal nervous system. OPP has developed guidance for thyroid assays in 

pregnant animals, fetuses and postnatal animals, and adult animals. The guidance is not intended 

to be prescriptive. The Agency recognizes that registrants may chose to propose an alternative 

approach that adequately addresses the issue of disruption of thyroid hormone homeostasis 

during development. Registrants are encouraged to consult with the Agency during development 

of any alternative study protocol or the implementation of the guidance.

4.4.3 Evidence of Sensitivity/Susceptibility in the Developing or Young Animal

The toxicology database for buprofezin is sufficient for FQPA assessment. Developmental 

toxicity studies in rats and rabbits and the reproduction studies in rats provided no indication of 

increased susceptibility of rats or rabbits following in utero exposure or of rats following 

pre/postnatal exposure to buprofezin. 

There is no concern for increased qualitative and/or quantitative susceptibility following in utero 

(rats and rabbits) and pre-and post-natal exposure (rats) to buprofezin. There are no residual 

uncertainties with regard to pre- and/or postnatal toxicity. The dietary food exposure assessment 

uses conservative assumptions which result in protective estimates of dietary exposure. The 

dietary drinking water assessment uses values generated by model and associated modeling 

parameters which are designed to provide protective, high-end estimates of water concentrations.

4.4.4 Residual Uncertainty in the Exposure Database 

There are no residual uncertainties in the exposure database. The dietary risk assessment is 

conservative and will not underestimate dietary and/or non-dietary residential exposure to 

buprofezin.

4.5 Toxicity Endpoint and Point of Departure

4.5.1 Dose-Response Assessment

Toxicity endpoints and points of departure (PODs) for dietary (food and water), occupational, 

and residential exposure scenarios are summarized below. A detailed description of the studies 

used as a basis for the selected endpoints are presented in Appendix A. 
Page 19 of 51

An acute POD for the general population was not selected for the lack of acute toxicity in the 

available studies including maternal toxicity in developmental studies. An acute POD of 200 

mg/kg (NOAEL) was selected for females age 13-49 years from a developmental study in rats 

based on incomplete ossification and reduced pup weight at 800 mg/kg/day. The developmental 

effects of concern are presumed to occur after a single exposure and are relevant only to females 

aged 13-49 years old since they occur in utero. Effects on the thyroid gland and related 

hormonal levels in the blood are related to the repeated exposure to buprofezin and therefore, are 

not appropriate for this acute endpoint. The acute exposure scenarios are not likely to result in 

toxicologically significant changes in thyroid hormonal levels because there is a normal daily 

fluctuation in the thyroid levels which may be indistinguishable from any single dose effects on 

hormone levels. An uncertainty factor (UF) of 100x (10x to account for intraspecies 

extrapolation and 10x for intraspecies variation) was applied to the NOAEL to obtain an acute 

reference dose (aRfD) of 2.0 mg/kg. Since the FQPA factor has been reduced to 1X, the acute 

population adjusted dose (aPAD) is equivalent to the aRfD.

A chronic POD of 1.0 mg/kg/day (NOAEL) was selected for the general population from a twoyear chronic feeding study in rats based on increased incidence of follicular cell hyperplasia and 

hypertrophy in the thyroid in males at the LOAEL of 8.7 mg/kg/day. A UF 300x (10x for 

intraspecies variation, 3x for interspecies extrapolation – reduced from 10X based on 

demonstrated evidence that rats are more susceptible to thyroid effects than humans – and a 10x 

for incomplete data base due to the need for a thyroid assay in rats) was applied to the dose to 

obtain a chronic reference dose (cRfD/cPAD) of 0.0033 mg/kg/day.

There are no residential uses for buprofezin. Therefore incidental oral exposure endpoints are 

not required and not selected for this assessment. 

Short - and intermediate term dermal PODs of 300 mg/kg/day were selected from 24-day dermal 

toxicity study in rats based on inflammatory infiltrate of the liver in females at the LOAEL of 

1000 mg/kg/day. An MOE of 100 is required for the short- and intermediate-term scenarios for 

dermal exposure. This includes 10X for interspecies extrapolation and 10X for intraspecies 

variation.

Short - and intermediate term inhalation PODs of 13 mg/kg/day were selected from a 90-day oral 

toxicity study in rats based on organ weight changes and microscopic finding in liver, thyroid 

and kidney at the LOAEL of 68.6 mg/kg/day. An MOE of 1000 is required for the short- and 

intermediate-term scenarios for inhalation exposure based on a 10X for intraspecies 

extrapolation, a 10X for interspecies variation and a 10x for incomplete data base due to the need 

for a thyroid assay in rats and the need for a 28-day inhalation study. 

4.5.2 Recommendations for Combining Exposure Routes

When there are potential residential exposures to the pesticide, aggregate risk assessment must 

consider exposures from three major sources: oral, dermal and inhalation exposures. Since there 

are no residential incidental oral exposures to buprofezin, aggregate exposure from food and 

non-food oral exposures is not required. Dermal and inhalation exposures to workers should be 
Page 20 of 51

aggregated for buprofezin, however, because the toxicity endpoints for these exposure routes are 

based on common target organ effect (i.e., liver toxicity). 

4.5.3 Classification of Carcinogenic Potential

In assessing the carcinogenic potential of buprofezin, HED’s Cancer Assessment Review 

Committee evaluated a 2-year combined chronic toxicity/carcinogenicity study in SpragueDawley rats and a 24-month carcinogenicity study in ICR-Cr mice. Based on the increased 

incidence of liver tumors in female mice only, no evidence of carcinogenicity in rats, and no 

evidence of genotoxicity in submitted guideline studies using in vitro and in vivo genotoxicity 

assays, the CARC (HED Doc. No. 0014045) classified buprofezin as having “Suggestive 

Evidence of Carcinogenicity, but not sufficient to assess human carcinogenic potential." No 

quantification of cancer risk is required. The CARC noted that although buprofezin was 

negative in in vitro and in vivo genotoxicity assays, the findings from the published literature 

indicate that it causes cell transformation and induces micronuclei in vitro; however, in the 

absence of a positive response in an in vivo micronucleus assay, the CARC concluded that 

buprofezin may have aneugenic potential which is not expressed in vivo. 

[Note: The cancer classification has not been updated based on the EPA’s 2005 Guidelines for 

Carcinogen Risk Assessment. However, any reclassification would not affect the conclusion that 

the cRfD is protective for carcinogenic effects and would therefore not affect the risk 

assessment.]

4.5.4 Summary of Points of Departure Used in Risk Assessment

Toxicological doses/endpoints selected for the buprofezin risk assessment are provided in Tables 

4 and 5.
Page 21 of 51

Table 4. Summary of Toxicological Doses and Endpoints for Buprofezin for Use in Dietary and Non-Occupational Human 

Health Risk Assessments

Exposure/Scenario Point of 

Departure

Uncertainty/FQPA 

Safety Factors

RfD, PAD, LOC

for Risk 

Assessment

Study and Toxicological Effects

Acute Dietary 

(General Population)

An acute RfD for the general population or any population subgroups was not selected because no effect 

attributable to a single (or few) day(s) oral exposure was observed in animal studies.

Acute Dietary

(Females 13-49 

years)

NOAEL = 

200 mg/kg

UFA= 10x

UFH=10x

FQPA SF= 1x

Acute RfD = 2.0 

mg/kg/day

aPAD = 2.0 

mg/kg

Developmental Toxicity Study - Rat (MRID 

42873813)

Developmental LOAEL = 800 mg/kg/day based on 

reduced ossification & decreased body weight in 

offspring. 

Maternal LOAEL = 800 mg/kg/day based on 

mortality, decreased food consumption, weight loss, 

clinical signs, decreased pregnancy rates and 

increased resorption rates

Chronic Dietary 

(All Populations)

NOAEL = 1.0 

mg/kg/day

UFA= 3x

UFH=10x

FQPA SF= 10x

Chronic RfD = 

0.033

mg/kg/day

cPAD = 0.0033

mg/kg/day

Two-year Chronic Toxicity/Carcinogenicity Study -

Rat (MRID 42935202, 44394025)

LOAEL = 8.7 mg/kg/day based on increased 

incidence of follicular cell hyperplasia and 

hypertrophy in the thyroid of males.

Incidental Oral 

Dermal

Inhalation

There are no residential uses for or exposures to bufrofezin. Therefore exposure endpoints are not required 

and not selected for residential exposure assessment. 

Cancer (all routes) “C” Possible human carcinogen. (No Q1*). The cRfD is considered protective of the cancer effects.

Point of Departure (POD) = A data point or an estimated point that is derived from observed dose-response data and used to mark the beginning 

of extrapolation to determine risk associated with lower environmentally relevant human exposures. NOAEL = no observed adverse effect level. 

LOAEL = lowest observed adverse effect level. UF = uncertainty factor. UFA = extrapolation from animal to human (interspecies). UFH = 

potential variation in sensitivity among members of the human population (intraspecies). UFL = use of a LOAEL to extrapolate a NOAEL. UFS = 

use of a short-term study for long-term risk assessment. UFDB = to account for the absence of key date (i.e., lack of a critical study). FQPA SF = 

FQPA Safety Factor. PAD = population adjusted dose (a = acute, c = chronic). RfD = reference dose. MOE = margin of exposure. LOC = level 

of concern. N/A = not applicable.

Table 5. Summary of Toxicological Doses and Endpoints for Buprofezin for Use in Occupational Human Health Risk 

Assessments

Exposure/

Scenario

Point of 

Departure

Uncertainty 

Factors

Level of Concern 

for Risk 

Assessment

Study and Toxicological Effects

Dermal Short (1-30 days)

and Intermediate (1-6 

months) Term

NOAEL= 

300

mg/kg/day

UFA= 10x

UFH=10x

Occupational LOC 

for MOE = 100

24 Day Dermal Toxicity Study - Rats (MRID 

44394024)

LOAEL = 1000 mg/kg/day based on decreased 

body weight gain

Inhalation Short (1-30 

days) and Intermediate (1-

6 months) Term

NOAEL=

13.0 

mg/kg/day

UFA= 10x

UFH = 10x

UFDB = 10x

Occupational LOC 

for MOE = 1000

90 Day Oral Toxicity Study - Rat (MRID 

42935201)

LOAEL = 68.6 mg/kg/day based on organ weight 

changes and microscopic finding in liver, thyroid 

and kidney

Cancer (all routes) “C” Possible human carcinogen. (No Q1*). The cRfD is considered protective of the cancer effects.

UF = uncertainty factor. UFA = extrapolation from animal to human (interspecies). UFH = potential variation in sensitivity among members of 

the human population (intraspecies) . UFDB = to account for the absence of key date (i.e., lack of a critical study).
Page 22 of 51

5.0 DIETARY AND DRINKING WATER EXPOSURE AND RISK ASSESSMENT

5.1 Metabolite/Degradate Residue Profile

5.1.1 Summary of Plant Metabolism Studies

The qualitative nature of buprofezin residues in plants is understood based on the available 

lettuce, cotton, tomato, and lemon metabolism studies. A new lemon metabolism study was 

included in this submission and is discussed below. Buprofezin was the major residue identified 

in the lettuce, cotton, and tomato metabolism studies (all other identified residues were <10% 

total radioactive residues; TRR). The lemon metabolism study provided data for fruit treated 75 

and 14 days prior to harvest and fruit treated 75 days prior to harvest only. Buprofezin (66% 

TRR, PHI = 14 days; 18% TRR, PHI = 75 days) and BF 4 conjugate (6% TRR, PHI = 14 days; 

34% TRR, PHI = 75 days) were the major identified residues (all other identified residues were 

<10% TRR). In addition to determining that buprofezin is the residue of concern for tolerance 

setting and risk assessment in crops, the Metabolism Assessment Review Committee (MARC) 

has concluded that: (1) the residues of concern for risk assessment in grape juice are buprofezin 

and BF12; (2) residues of BF9 and BF12 should be monitored in all future processing studies and 

field trials; and (3) until the requested data on BF4 conjugate are available from the requested 

orange, apple and grape processing studies, residues of BF4 conjugate should be estimated for 

risk assessment purposes in/on crops with extended application to harvest intervals (≥50 days). 

The RAB4 risk assessment team determined that the buprofezin:BF4 conjugate residue ratio 

from the citrus metabolism study (1.8x) should be used with the buprofezin residue data from the 

field trials and should be applied to crops with PHIs > 7 days.

Structures and names of buprofezin metabolites are provided in Appendix B. 

5.1.2 Comparison of Metabolic Pathways

Buprofezin is the primary metabolite in plants, ruminants, poultry, and rats. Plant metabolism 

studies were conducted in lettuce, cotton, tomato, and and lemon. The predominant metabolite 

was buprofezin. Additional metabolites were BF9, BF12, and BF26. In ruminant studies, the 

primary metabolite was buprofezin. In milk, BF23 was also a significant metabolite. In 

ruminant tissues, buprofezin and BF2 were found. In rats, only feces and urine were 

investigated; 95% of the administered compound is recovered in the feces and urine within 72 

hours, and that 45% is recovered in feces as the parent compound, with the remainder as several 

metabolites, including BF27(2-tert-butylimino-5-(4-hydroxy-3-methoxyphenyl)-3-isopropyl1,3,5-thiadiazinan-4-one; 7.2% of dose) and BF28 (2-[3-isopropyl-3-

[methylsulfonylmethyl(phenyl)carbamoyl] ureido]-2-methylpropionic acid, BF9 (3-isopropyl-5-

phenyl-1,3,5-thiadiazinan-2,4-dione), BF10 (2-tertbutylimino-3-isopropyl-5-phenyl-1,3,5-

thiadiazinan-4-one-1-oxide), BF12(1-isopropyl-3-phenylurea), and BF13 (1-(4-hydroxyphenyl)-

3-isopropylurea). Smaller amounts of buprofezin and metabolites were recovered in urine. 
Page 23 of 51

5.1.3 Environmental Fate and Transport

Buprofezin may get into surface water via spray drift, in solution in runoff water, or attached to 

soil particles eroded during runoff events. If it reaches acidic water (pH 5), buprofezin is 

expected to slowly hydrolyze. In neutral or alkaline water (pH 7), buprofezin will likely remain 

bound to sediment or suspended particles (due to its high soil/water partitioning coefficients), 

and could persist for several months if the water is deep, static, and/or cloudy. However, 

buprofezin persistence may be reduced significantly by photolysis if the water is shallow and 

clear. Based on the Henry's Law constant, buprofezin loss to air is expected to be minor. 

Although moderately persistent in soils, the use rates and the mobility/leaching data indicated 

that buprofezin will have low propensity to leach into ground water. 

5.1.4 Residues of Concern Summary and Rationale

The qualitative nature of buprofezin residues in plants is understood based on the available 

lettuce, cotton, tomato, and lemon metabolism studies. Residues of concern for tolerance 

enforcement include only buprofezin. Residues of concern for risk assessment include 

buprofezin and BF 4 conjugates, including measurement of BF9, BF12, and BF26. Residues of 

BF4 conjugates should be estimated for risk assessment purposes in/on fruit crops and crops with 

longer pre-harvest intervals using the buprofezin:BF4 conjugate residue ratio from the citrus 

metabolism study (1.8x) and the buprofezin residue data from the field trials (please see the 

chemistry summary document for further explanation of this factor).

Adequate ruminant and poultry metabolism studies are available for buprofezin. The tolerance 

expression for milk and ruminant tissues will include only buprofezin; for purposes of risk 

assessment, the residues of concern in milk are buprofezin and BF23; for purposes of risk 

assessment, the residues of concern in ruminant tissues are buprofezin and BF2. There is no 

reasonable expectation of finite residues in poultry commodities at the present time.
Page 24 of 51

Table 6: Summary of Buprofezin Residues of Concern.

Matrix

Residues of Concern

For Risk Assessment For Tolerance 

Expression

Crops with ≤7-day PHI1 Buprofezin

Buprofezin

Crops with >7-day PHI1

Buprofezin and BF4 Conjugate

Grape juice Buprofezin, BF4 Conjugate, and BF12

Processed Commodities Based on the results of the grape processing study which indicate 

that BF9 and/or BF12 residues may concentrate to a greater 

degree than parent, default processing factors in DEEM should 

not be reduced based on buprofezin data alone. 

Rotational crops2 Buprofezin, BF9, and BF12

Ruminant tissue Buprofezin and BF2

Milk Buprofezin and BF23

Poultry and eggs

Due to the limited residues in egg and tissue samples collected from the poultry 

metabolism study, the MARC determined that a conclusion pertaining to the residues of 

concern in egg and poultry was not possible. 

Water Buprofezin Not Applicable

MARC Memos: D264546, T. Bloem, 4/20/00; D273214, T. Bloem, 3/13/01; TXR No. 0052261, T. Bloem, 12/10/03. 

1 Table updated with RAB4 decision concerning circumstances under which the BF4 Conjugate should be considered a residue 

of concern for the risk assessment and is based on information not available to the MARC. 

2 Residues of concern in rotational crops are buprofezin, BF9 and BF12. However, since there are no rotational crop tolerances, 

the BF9 and BF12 metabolites are not included in the dietary exposure analysis for rotational crops. 

5.2 Food Residue Profile

5.2.1 Residues in Crops

The submitted magnitude of the residue data for mustard greens and pecans are adequate and 

reflect the maximum proposed use pattern for Brassica leafy vegetables, subgroup 5B, turnip 

greens, and tree nuts. The number and locations of the field trials are sufficient, and the samples 

were analyzed using an adequately validated method. Adequate storage stability data are 

available to support the storage conditions and durations of samples from the field trials. Based 

on the submitted data, and the Organization for Economic Cooperation and Development 

(OECD) tolerance calculation procedures, HED concludes that a tolerance of 60 ppm is needed 

for Brassica leafy vegetables, subgroup 5B, and turnip greens. Since all buprofezin residues in 

pecans and almonds (previously reviewed) were non-quantifiable, a tolerance of 0.05 ppm is 

appropriate for tree nuts and pistachios.

The submitted magnitude of the residue data for tea are adequate to support a tolerance of 20 

ppm, provided the use pattern is 2 applications of 2.5 kg/ha with a 14 day PHI. The available 

data on stone fruits are adequate to support a tolerance of 1.9 ppm on persimmon, provided the 

single application rate for persimmon must be lowered to 1.5 lb ai/A to match the residue data 

translated from stone fruit (and the application rate for buprofezin on stone fruit must be 

similarly lowered).

A revised Section B is required.
Page 25 of 51

The remainder of the proposed tolerances constitute expansions of existing crop groups (fruiting 

vegetables, citrus, and pome fruit), and expansion of the tolerance for succulent snap beans to 

include all succulent beans. With the exception of citrus and pome fruit, the existing data are 

adequate to support those groups. A condition of registration requirement for residue data on 

lemon (N=3) has been outstanding since 12/17/2003 (T. Bloem, D296492). The pome fruit crop 

group tolerance is adequately supported for the use pattern originally proposed: 1 application to 

apples at 1.50 lb ai/A, 14 day PHI; 2 applications to pears at 1.58 lb ai/A, 14 day PHI 

(PP#3E6742). However, the use pattern proposed in the current petition for pears and oriental 

pears is 2 applications at 2.0 lb ai/A with a 14 day PHI. No residue data have been submitted to 

support the higher rate. The product jacket shows no amendment request was submitted to 

increase the rate. However, we will allow the higher rate, since the tolerance for pears will be 

harmonized with CODEX at 6.0 ppm buprofezin.

5.3 Water Residue Profile

5.3.1 Estimated Drinking Water Concentrations 

Drinking water residues were incorporated directly into the acute and chronic dietary analyses 

(“water, direct, all sources” and “water, indirect, all sources”) and were provided by the 

Environmental Fate and Effects Division (EFED; DP#s 395217 and 393932, R. Parker, 4/5/12). 

EFED generated the surface water and ground water estimates using the Pesticide Root Zone 

Model 3 (PRZM3; ver. 3.12.2; 2-May-2005)/Exposure Analysis Modeling System (EXAMS; 

ver. 2.98.04.06; 25-Apr-2005) and Screening Concentration in Ground Water (SCIGROW; Tier 

1) models, respectively. For the purposes of assessing drinking water risk, estimated drinking 

water exposure concentrations (EDWCs) are based on the use with the highest potential 

exposure. Based on Tier II exposure modeling, past assessments have found the maximum 

exposure to be from the uses on coffee and citrus (DP# 360583, M. Corbin, 1/8/09) based on the 

Puerto Rico Coffee and Florida Citrus scenarios. The proposed new and expanded uses yield 

EDWCs below those previously determined. The coffee use yields the highest EDWCs to date. 

The EDWCs for coffee are based on a maximum seasonal application rate of 4 lb ai/acre.

Updated EDWCs are provided in Table 7.

Table 7. Maximum EDWCs (μg/L) from registered and proposed uses of buprofezin.

Surface Water a Groundwater b

Use Acute

[1-in-10 year peak]

Chronic

[1-in-10 year average] 30-year average Acute and Chronic

Maximum Current Use

Citrus - Fl 57.4 12.5 9.1 0.09

Coffee - PR 58.2 18.6 13.6 0.09

Proposed Uses

Strawberry 11.2 3.8 2.9

N/A

Low-growing 

berries 13.1 4.2 2.6

Leafy vegetables 20.4 6.4 4.5

Cranberriesc47.9 N/A N/A

 a Generated using Tier II linked simulation models PRZM (3.12.2) /EXAMS (2.98.04.06).

 b Generated using Tier I model SCIGROW (2.3).

c Generated using Tier 1 Rice Model v. 1.0.
Page 26 of 51

5.4 Dietary and Drinking Water Exposure and Risk

Screening level acute and refined chronic dietary and drinking water exposure and risk 

assessments were conducted using the Dietary Exposure Evaluation Model with the Food 

Commodity Intake Database (DEEM-FCIDTM). Dietary risk assessment incorporates both 

exposure and toxicity of a given pesticide. For acute and chronic dietary assessments, the risk is 

expressed as a percentage of a maximum acceptable dose (i.e., the dose which HED has 

concluded will result in no unreasonable adverse health effects). This dose is referred to as the 

population adjusted dose (PAD). The PAD is equivalent to the reference dose (RfD) divided by 

the additional Safety Factor, if applied. For acute and non-cancer chronic exposures, HED is 

concerned when estimated dietary risk exceeds 100% of the PAD. 

5.4.1 Acute Dietary and Drinking Water Analysis

A screening level acute dietary analysis was conducted for this assessment assuming 100% crop 

treated for all commodities. Total residues of concern in crop commodities (i.e., buprofezin and 

the BF4 Conjugate which is not detectable by data collection methods but which may be estimated 

from metabolism data) were based on tolerance level residues of buprofezin and available 

metabolism data to estimate other residues of concern. Given the potential for BF9 and BF12 to 

concentrate to a greater degree than buprofezin in processed commodities, DEEM default 

processing factors were retained for all commodities, except for tomato paste and puree, which 

were reduced based on empirical data. Based on the submitted lemon metabolism data, which 

indicated that residues of concern are primarily found in/on the peel, the maximum theoretical 

concentration factor for peel was used to estimate residues of concern in citrus peel. Total residues 

of concern in meat (i.e., buprofezin and BF2) and milk (i.e., buprofezin and BF23) were based on 

the feeding study data which were used to establish meat and milk tolerances. Based on the 

submitted data, which indicated a 5x concentration of residues into milk cream and fat and a Log 

Kow of 4.31, a default 25x concentration factor was applied for milk fat. The acute analysis also 

incorporated the 1 in 10 year peak surface drinking water estimate resulting from application of 

buprofezin to coffee. The resulting acute exposure estimate for females 13-49 years old is not of 

concern to HED (5% acute population adjustment dose (aPAD)). No acute endpoint was identified 

for the remaining population subgroups. 

 

Table 8: Summary of Acute Dietary Exposure and Risk for Buprofezin.

Population Subgroup aPAD (mg/kg/day) Acute (95th Percentile)

Exposure (mg/kg/day) %aPAD

Females 13-49 years old 2 0.0987 5

5.4.2 Chronic Dietary and Drinking Water Analysis

A refined chronic dietary analysis was conducted for this assessment using percent crop treated 

estimates when available. Total residues of concern in crop commodities (i.e., buprofezin and the 

BF4 Conjugate which is not detectable by data collection methods but which may be estimated 

from metabolism data) were based on average field trial, average USDA Pesticide Data Program 

(PDP), or tolerance level residues to estimate anticipated residues of buprofezin and available 

metabolism/magnitude of the residue data to estimate other residues of concern. Given the 

potential for BF9 and BF12 to concentrate to a greater degree than buprofezin in processed 
Page 27 of 51

commodities, DEEM default processing factors were retained for all commodities, except for 

tomato paste and puree, which were reduced based on empirical data. Based on the submitted 

lemon metabolism data, which indicated that residues of concern are primarily found in/on the 

peel, the maximum theoretical concentration factor for peel was applied to residues in citrus peel. 

Total residues of concern in meat (i.e., buprofezin and BF2) and milk (i.e., buprofezin and BF23) 

were based on the feeding study data which were used to establish meat and milk tolerances. 

Based on the submitted data, which indicated a 5x concentration of residues into milk cream and 

fat and a Log Kow of 4.31, a default 25x concentration factor was applied for milk fat. The chronic 

analysis also incorporated the 1 in 10 year average surface drinking water estimate resulting from 

application of buprofezin to coffee. The resulting chronic exposure estimates indicate no risks of 

concern general population or other population subgroups. The chronic risk exposure estimate for 

children 1-2 years old, the most highly exposed population was 91% of the cPAD. 

The chronic exposure assessment is conservative and is likely to overestimate risks based on a 

number of factors including, use of 100% crop treated assumptions for a number of crops for 

which data were unavailable, use of a conservative factor to account for the BF4 Conjugate, use 

of default processing factors, and use of drinking water exposure estimates for application of 

buprofezin to coffee, which is grown in limited areas the U.S. (e.g., Puerto Rico, Hawaii). 

Table 9. Summary of Chronic Dietary and Drinking Water Exposure and Risk for Buprofezin

Table 13. Summary of Chronic Dietary and Drinking Water Exposure and Risk for Buprofezin

Table 13. Summary of Chronic Dietary and Drinking Water Exposure and Risk for Buprofezin

Table 13. Summary of Chronic Dietary and Drinking Water Exposure and Risk for Buprofezin

Table 13. Summary of Chronic Dietary and Drinking Water Exposure and Risk for Buprofezin

Population Subgroup cPAD (mg/kg/day) Chronic

Exposure (mg/kg/day) %cPAD

General U.S. Population

0.0033

0.0017 51

All Infants (< 1 year old) 0.0022 68

Children 1-2 years old 0.0030 91

Children 3-5 years old 0.0027 82

Children 6-12 years old 0.0015 47

Youth 13-19 years old 0.0014 42

Adults 20-49 years old 0.0014 43

Adults 50+ years old 0.0019 58

Females 13-49 years old 0.0014 43

6.0 RESIDENTIAL EXPOSURE AND RISK ASSESSMENT

Residential exposures and risk are not assessed in this document because the proposed uses of 

buprofezin do not involve applications by homeowners or commercial applicators in residential 

settings at this time. In addition, there are no existing residential uses.

 

6.1 Residential Bystander Postapplication Inhalation Exposure

Based on the Agency's current practices, a quantitative post-application inhalation exposure 

assessment was not performed for buprofezin at this time. However, volatilization of pesticides 

may be a potential source of post-application inhalation exposure to individuals nearby to 

pesticide applications. The Agency sought expert advice and input on issues related to 

volatilization of pesticides from its Federal Insecticide, Fungicide, and Rodenticide Act 

Scientific Advisory Panel (SAP) in December 2009. The Agency received the SAP’s final report 

on March 2, 2010 (http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html) and is 

in the process of evaluating the SAP report. The Agency may, as appropriate, develop policies 
Page 28 of 51

and procedures to identify the need for and, subsequently, the way to incorporate postapplication inhalation exposure into the Agency's risk assessments. If new policies or 

procedures are put into place, the Agency may revisit the need for a quantitative post-application 

inhalation exposure assessment for buprofezin.

6.2 Spray Drift

Spray drift is always a potential source of exposure to residents nearby to spraying operations. 

This is particularly the case with aerial application, but, to a lesser extent, could also be a 

potential source of exposure from the ground application method employed for Buprofezin. The 

Agency has been working with the Spray Drift Task Force, EPA Regional Offices and State 

Lead Agencies for pesticide regulation and other parties to develop the best spray drift 

management practices (see the Agency’s Spray Drift website for more information at 

http://www.epa.gov/opp00001/factsheets/spraydrift.htm). On a chemical by chemical basis, the 

Agency is now requiring interim mitigation measures for aerial applications that must be placed 

on product labels/labeling. The Agency has completed its evaluation of the new database 

submitted by the Spray Drift Task Force, a membership of U.S. pesticide registrants, and is 

developing a policy on how to appropriately apply the data and the AgDRIFT computer model to 

its risk assessments for pesticides applied by air, orchard airblast and ground hydraulic methods. 

After the policy is in place, the Agency may impose further refinements in spray drift 

management practices to reduce off-target drift with specific products with significant risks 

associated with drift.

Although a quantitative residential post-application inhalation exposure assessment was not 

performed as a result of pesticide drift from neighboring treated agricultural fields, an inhalation 

exposure assessment was performed for flaggers. This exposure scenario is representative of a 

worse case inhalation (drift) exposure and may be considered protective of most outdoor 

agricultural and commercial post-application inhalation exposure scenarios. 

7.0 AGGREGATE EXPOSURE AND RISK ASSESSMENT 

In accordance with the FQPA, when there are potential residential exposures to a pesticide, 

aggregate risk assessment must consider exposures from three major routes: oral, dermal, and 

inhalation. There are three sources for these types of exposures: food, drinking water, and 

residential uses. In an aggregate assessment, exposures from relevant sources are added together 

and compared to quantitative estimates of hazard (e.g., a NOAEL or PAD), or the risks 

themselves can be aggregated. When aggregating exposures and risks from various sources, 

HED considers both the route and duration of exposure. The proposed/registered buprofezin 

uses are not expected to result in residential exposure. Therefore, the acute and chronic exposure 

estimates provided in the Dietary Exposure Section represent aggregate exposure. Dermal and 

inhalation exposures to workers should be aggregated for buprofezin because the toxicity 

endpoints for these exposure routes are based on common target organ effect (i.e., liver toxicity).
Page 29 of 51

8.0 CUMULATIVE RISK

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 does not have, at this time, available data to determine whether buprofezin has a common 

mechanism of toxicity with other substances. 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 which 

have tolerances in the U. S. For the purposes of this tolerance reassessment 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 website at http://www.epa.gov/fedrgstr/EPA_PEST/2002/January/Day_16/.

9.0 OCCUPATIONAL EXPOSURE/RISK CHARACTERIZATION

9.1 Exposure Scenarios

Occupational handler and post-application exposure scenarios were assessed for the risk 

assessment of the proposed new uses. Based on the product labels and information provided by 

the registrant, short- and intermediate-term exposure is assessed for occupational handlers and

post-application activities. Dermal and inhalation exposures to workers are aggregated for 

buprofezin because the toxicity endpoints for these exposure routes are based on common 

toxicological effects.

9.2 Handler Exposure 

The term “handler” applies to individuals who mix, load, and apply the pesticide product. The 

following handler exposure scenarios were assessed for proposed new buprofezin uses.

9.2.1 Handler Exposure Scenarios

Occupational handler and post-application exposure scenarios were assessed for the proposed 

use of buprofezin on crop group 14 (tree nuts and pistachios), crop group 5B (brassica, and leafy 

greens), and (persimmons). 

HED uses the term handlers to describe those individuals who are involved in the pesticide 

application process. HED believes that there are distinct job functions or tasks related to 

applications and exposures can vary depending on the specifics of each task. Job requirements 

(amount of chemical used in each application), the kinds of equipment used, the target being 
Page 30 of 51

treated, and the level of protection used by a handler can cause exposure levels to differ in a 

manner specific to each application event. 

Based on the anticipated use patterns and current labeling, types of equipment and techniques 

that can potentially be used, occupational handler exposure is expected from the proposed uses. 

The quantitative exposure/risk assessment developed for occupational handlers is based on the 

following scenarios: 

MIXER/LOADER

1. Open mixing/loading liquids for aerial applications;

2. Open mixing/loading liquids and dry flowables for airblast applications;

3. Open mixing/loading liquids for groundboom applications;

APPLICATORS

1. Applying sprays with aerial equipment;

2. Applying sprays with airblast equipment;

3.Applying sprays with groundboom equipment; and

FLAGGERS

1. Flagging for aerial applications.

9.2.2 Handler Exposure Data

Unit Exposures: 

It is the policy of HED to use the best available data to assess handler exposure. Sources of 

generic handler data, used as surrogate data in the absence of chemical-specific data, include the 

Pesticide Handlers Exposure Database Version 1.1 (PHED 1.1), the Agricultural Handler 

Exposure Task Force (AHETF) database, the Outdoor Residential Exposure Task Force 

(ORETF) database, or other registrant-submitted occupational exposure studies. Some of these 

data are proprietary (e.g., AHETF data), and subject to the data protection provisions of FIFRA. 

The standard values recommended for use in predicting handler exposure that are used in this 

assessment, known as “unit exposures”, are outlined in the “Occupational Pesticide Handler Unit 

Exposure Surrogate Reference Table” (http://www.epa.gov/opp00001/science/handler-exposuretable.pdf), which, along with additional information on HED policy on use of surrogate data, 

including descriptions of the various sources, can be found at 

http://www.epa.gov/pesticides/science/handler-exposure-data.html.

9.2.3 Handler Exposure Assumptions

Area/Amount Treated

Based on HED ExpoSAC Policy No. 9.1, the area treated in a day was assumed to be:

350 acres for mixing/loading to support aerial applications,

40 acres for mixing/loading to support airblast applications,

80 acres for mixing/loading to support groundboom applications,

350 acres for applying with aerial equipment,

40 acres for applying with airblast equipment,

80 acres for applying with groundboom equipment, and

350 acres for flagging to support aerial applications.
Page 31 of 51

Application Rates

Courier® 40SC Insect Growth Regulator (EPA Reg. No. 71711-20) has a maximum application 

rate ranging from 9.0 to 13.6 fl. oz per acre or 0.25 to 0.38 lbs ai/acre. The label states that a 

maximum of 4 applications per year is allowed. 

Applaud® 70DF Insect Growth Regulator (EPA Reg. No. 71711-21) has a maximum application 

rate ranging from 34.5 to 46.0 oz. per acre or 1.5 to 2.0 lbs ai/acre. The label states that a 

maximum of 1 application per growing season is allowed. 

Vetica® Insecticide (EPA Reg No.71711-32) has a maximum application rate ranging from 10.0 

to 20.0 oz. per acre or 0.18 to 0.36 lbs ai/acre. The label states that a maximum of 2 applications 

per growing season is allowed. 

Tourismo® Insecticide (EPA Reg. No. 71711-32) has a maximum application rate ranging from 

10.0 to 14.0 oz. per acre or 0.18 to 0.25 lbs ai/acre. The label states that a maximum of 3 

applications per growing season is allowed. 

Body Weight

The average adult body weight of 80 kg was used for estimating short-term dermal and 

inhalation daily dose calculations. 

Absorption Factors

Since the short- and intermediate-term dermal POD was based on a route-specific toxicity study, 

no absorption factor was necessary to estimate exposure for short-and intermediate-term 

durations. Since no inhalation absorption data are available, toxicity by the inhalation route is 

considered to be equivalent to the estimated toxicity by the oral route of exposure.

Personal Protective Equipment (PPE)

For pesticide handlers, this assessment presents “baseline” (i.e. workers wearing a single layer of 

work clothing consisting of a long sleeved shirt, long pants, shoes, plus socks and no protective 

gloves or respirators) estimates for both dermal and inhalation exposure. However, label 

specifications state that applicators and handlers must wear a single layer of work clothing 

consisting of a long sleeved shirt, long pants, shoes plus socks, and chemical resistant gloves. 

Equations and Calculations

Daily Dose:

Daily dose (dermal and inhalation) is calculated by normalizing the daily exposure (dermal or 

inhalation) value by body weight and accounting for absorption factors:

Average Daily Dose (mg/kg/day) = Daily Exposure (mg ai/day) x {Absorption Factor }

 Body Weight (kg)

Where:
Page 32 of 51

Average Daily Dose = Absorbed dose received from exposure to a pesticide in a 

given scenario (mg pesticide active ingredient/kg body 

weight/day),

Daily Exposure = Amount (mg ai/day) deposited on the surface of the skin 

that is available for dermal absorption or amount inhaled 

that is available for inhalation absorption,

Absorption Factor = A measure of the amount of chemical that crosses a 

biological boundary such as the skin or lungs, and

Body Weight = Body weight determined to represent the population of

interest in a risk assessment.

Margin of Exposure (MOE):

The daily dermal and inhalation dose received by occupational handlers was compared to the 

appropriate PoD (i.e. NOAELs) to assess the risk to occupational handlers. All MOE values 

were calculated using the following formula:

MOE = NOAEL (mg/kg/day)

Average Daily Dose (mg/kg/day)

Where:

MOE = Margin of exposure value used by HED to represent risk or how close 

a chemical exposure is to being a concern (unitless),

ADD = Average daily dose (ADD) is absorbed dose received from exposure to 

pesticide, and

NOAEL = Dose level in a toxicity study, where no observed adverse effects occurred 

in the study.

9.2.4 Handler Exposure and Risk Estimates

For all dermal and inhalation exposure scenarios, risk estimates do not exceed HED’s LOC 

(Dermal LOC = 100; Inhalation LOC = 1000) with label-specified PPE and, therefore, are not of 

concern to HED. Summaries of the short- and intermediate-term risk estimates for occupational 

handlers are included in Table 10.
Page 33 of 51

Table 10: Occupational Short and Intermediate-Term Risk Assessment/Amended Uses of Buprofezin

Exposure Scenario Crops

Application

Rate

Area 

Treated

Inhalation

Unit Exp.

Dermal

Unit Exp Inhalation

Daily Dose

Dermal

Daily Dose

MOE5

Short/Intermediate-Term

Baseline Baseline

(lb a.i/A)1(A/day)2

( g/lb ai)3( g/lb ai)3

(mg/kg/day)4(mg/kg/day)4

Dermal

(LOC = 

100)

Inhalation

(LOC = 1000)

Mixer/Loader

Aerial

(Soluble 

Concentrate)

Crop Groups

(5B) 

Leafy Brassica 

Greens

0.38 350 0.219 200 0.0004 0.37 820 35,700

Airblast

(Dry Flowable)

Crop Group 

(14)

Persimmons, and

Tree Nuts

2.0 40 8.96 227 0.009 0.23 1,300 1,450

Groundboom

(Soluble 

Concentrate)

Crop Groups 

(5B)

Leafy Brassica 

Greens

0.38 80 0.22 220 0.0001 0.084 3,600 160,000

Applying

Aerial

(Enclosed 

Cockpit)6

(Soluble 

Concentrate)

Crop Groups

(5B)

Leafy Brassica 

Greens 

0.38 350 0.068 5 0.0001 0.0083 36,000 110,000
Page 34 of 51

Table 10: Occupational Short and Intermediate-Term Risk Assessment/Amended Uses of Buprofezin

Exposure Scenario Crops

Application

Rate

Area 

Treated

Inhalation

Unit Exp.

Dermal

Unit Exp Inhalation

Daily Dose

Dermal

Daily Dose

MOE5

Short/Intermediate-Term

Baseline Baseline

(lb a.i/A)1(A/day)2

( g/lb ai)3( g/lb ai)3

(mg/kg/day)4(mg/kg/day)4

Dermal

(LOC = 

100)

Inhalation

(LOC = 1000)

Airblast

(Dry Flowable)

Crop Group 

(14)

Persimmons, and

Tree Nuts

2.0 40 4.71 1770 0.0047 1.78 170 2,800

Groundboom

(Open Cab)

(Soluble 

Concentrate)

Crop Groups 

(5B)

Leafy Brassica 

Greens, 

0.38 80 0.34 79 0.0001 0.03 10,000 100,000

Flagging

Flagging

Crop Groups 

(5B)

Leafy Brassica 

Greens

0.38 350 0.35 11.0 0.0006 0.018 16,000 22,000

1. Application rates are based on maximum values found in proposed labels: Courier® 40SC Insect Growth Regulator (EPA Reg. No.71711-20); Applaud® 70DF Insect Growth 

Regulator (EPA Reg. No. 71711-21); Vetica® Insecticide (EPA Reg No.71711-32), and Tourismo® Insecticide (EPA Reg. No. 71711-32).

2. Daily area treated is based on ExpoSAC Policy #9.

3. HED policies on use of surrogate data, including their sources, are presented in the “Occupational Pesticide Handler Unit Exposure 

 Surrogate Reference Table” (http://www.epa.gov/pesticides/science/handler-exposure-table.pdf) and (http://www.epa.gov/pesticides/science/handler-exposure-data.html)

4. Daily Dose (mg/kg/day) was calculated by: [(Unit Exposure * Appl. rate * Area treated) / 80 kg]. 

5. Short-/Intermediate-Term PODs are the same for each duration: Dermal [(NOAEL 300 mg/kg/day)], Inhalation [(NOAEL 13 mg/kg/day)], thus one column. The Dermal LOC 

 for the target MOE = 100. The inhalation LOC for the target MOE =1000.

6. Aerial: Enclosed Cockpit is an engineering control; therefore the unit exposures and MOEs reflect this.
Page 35 of 51

9.3 Post Application Exposure 

HED uses the term post-application to describe exposures that occur when individuals are 

present in an environment that has been previously treated with a pesticide (also referred to as a 

re-entry exposure). Such exposure may occur when workers enter previously treated areas to 

perform job functions, including activities related to crop production, such as orchard 

maintenance. In the case for buprofezin, post-application dermal exposure to field workers 

following ground and aerial applications is probable, since buprofezin is an insecticide that can 

be applied to all stages of growth.

Based on the Agency's current practices, a quantitative occupational post-application inhalation 

exposure assessment was not performed for buprofezin at this time. However, there are multiple 

potential sources of post-application inhalation exposure to individuals performing postapplication activities in previously treated fields. These potential sources include volatilization 

of pesticides and re-suspension of dusts and/or particulates that contain pesticides. The Agency 

sought expert advice and input on issues related to volatilization of pesticides from its Federal 

Insecticide, Fungicide, and Rodenticide Act Scientific Advisory Panel (SAP) in December 2009. 

The Agency received the SAP’s final report on March 2, 2010 

(http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html). The Agency is in the 

process of evaluating the SAP report as well as available post-application inhalation exposure 

data generated by the Agricultural Reentry Task Force and may, as appropriate, develop policies 

and procedures, to identify the need for and, subsequently, the way to incorporate occupational 

post-application inhalation exposure into the Agency's risk assessments. If new policies or 

procedures are put into place, the Agency may revisit the need for a quantitative occupational 

post-application inhalation exposure assessment for buprofezin. 

Although a quantitative occupational post-application inhalation exposure assessment was not 

performed, an inhalation exposure assessment was performed for occupational/commercial 

handlers. Handler exposure resulting from application of pesticides outdoors is likely to result in 

higher exposure than post-application exposure. Therefore, it is expected that these handler 

inhalation exposure estimates would be protective of most occupational post-application 

inhalation exposure scenarios.

9.3.1 Post Application Exposure Scenarios

Post-application exposure to buprofezin residues is expected for individuals involved in hand 

weeding; transplanting; scouting; thinning; hand harvesting; irrigation; orchard maintenance; 

poling; mechanical shaking; and hand pruning, sweeping, and wind rowing. 

9.3.2 Post Application Exposure Assumptions

Transfer Coefficients:

It is the policy of HED to use the best available data to assess post-application exposure. 

Sources of generic post-application data, used as surrogate data in the absence of chemicalspecific data, are derived from Agricultural Reentry Task Force (ARTF) exposure monitoring 

studies, and, as proprietary data, are subject to the data protection provisions of FIFRA. The 
Page 36 of 51

standard values recommended for use in predicting post-application exposure that are used in 

this assessment, known as “transfer coefficients”, are presented in the “Science Advisory 

Council for Exposure (ExpoSAC) Policy 3” 

(http://www.epa.gov/pesticides/science/exposac_policy3.pdf), which, along with additional 

information about the ARTF data, can be found at http://www.epa.gov/pesticides/science/postapp-exposure-data.html.

Note: 

1) Duplicate post-application activities with different transfer coefficients are noted within the 

same crop groups (Tree Nuts) in table 5. The reason for this is that crops in the same crop 

grouping might have minor differences in foliage density and structure. In these instances, 

different transfer coefficients were assigned to the same activity to accommodate these

differences

2) There are non-foliar activities associated with tree nuts (e.g., windrowing, sweeping, and 

hand pruning), but these have not been quantitatively assessed. It is HED’s belief that there 

will not be significant dermal and inhalation exposure from these activities due to (1) 

buprofezin’s aerobic soil metabolism Half-life of [(168 days (90% upper bound on mean) 

or 68.75 days (mean)] and the PHI of 60 days. In addition, the occupational handler 

“airblast” exposure scenario (which does not result in risk estimates of concern) serves as a 

surrogate for these activities due to the similarities concerning the respiration of dust 

In addition to the dermal TCs, the following assumptions were used in the post-application 

assessment:

Max Application Rates: 1) 0.38 lb ai/A for proposed new use on crop group 5B; 

Brassica and Leafy Vegetables. 

2) 2.0 lb ai/A for proposed new use on crop group 14; Tree 

Nuts, and Persimmons.

Exposure Duration = 8 hours per day,

Body Weight = 80 kg for average adult for short-/intermediate-term 

durations,

Dermal Abs. Factor = Since the short- and intermediate-term dermal POD was 

based on a route-specific toxicity study, no absorption factor 

was necessary to estimate exposure for short-and 

intermediate-term durations. 

Day “0” DFR estimates 1). 1.066 ug/cm2on day zero crop group 5B; Brassica and 

 Leafy Vegetables. 

2). 5.6 ug/cm2on day zero crop group 14; Tree Nuts, 

and persimmons.
Page 37 of 51

Equations/Calculations

The following equations were used to calculate risk estimates for workers performing postapplication activities:

DFRt (μg/cm2) = AR (lb ai/acre) x F x (1-D)tx 4.54E8 μg/lb x 2.47E-8 acre/cm2

Where:

DFRt = dislodgeable foliage residue on day "t" (μg/cm2),

AR = application rate (lb ai/acre),

F = fraction of ai retained on foliage (unitless), and

D = fraction of residue that dissipates daily (unitless).

DD t (mg/kg-day) = DFRt (μg/cm2) x 1E-3 mg/μg x TC (cm2/hr) x DA (%) x ET (hrs)

BW (kg)

Where:

DD t = daily dermal dose on day “t,”

t = number of days after application day (days),

DFRt = dislodgeable foliage residue on day "t" (μg/cm2),

TC = transfer coefficient (cm2/hr),

DA = dermal absorption factor (unitless),

ET = exposure time (hr/day), and

BW = body weight (kg).

Margin of Exposure (MOE) = NOAEL (mg/kg/day)

 Average Daily Dose (mg/kg/day)

Where:

MOE = Margin of exposure value used by HED to represent risk or how 

close a chemical exposure is to being a concern (unitless),

ADD = Average daily dose (ADD) is absorbed dose received from 

exposure to pesticide, and

NOAEL = Dose level in a toxicity study, where no observed adverse effects 

occurred in the study.

9.3.3 Post-Application Exposure and Risk Estimates

A target LOC or MOE of 100 is considered adequate for dermal exposure. Exposure and risk 

estimates indicate MOEs are not of concern (MOEs > 100) at the maximum use rate for 

occupational post-application exposure activities for the proposed new uses. A summary of postapplication exposure and risk calculations, assumptions, and results is provided in Table 11.
Page 38 of 51

Table 11. Summary of Estimated Post-application MOEs for Agricultural Crops

Crop

Application 

Rate

(lb ai/A) 1

DAT2 DFR 3

(μg/cm2)

TC 4

(cm2/hr) Activity 4 Short-/IntTerm MOE 5

Crop Group

(5B) 

Leafy Veg. Brassica 

Greens

0.38 0 1.066

70

Thinning plants 

Hand weeding 

40,000

210 Scouting 13,000

230 Transplanting 12,000

330 Scouting, Thinning 8,500

1,100 Hand harvesting 2,600

1,400 Hand harvesting, Scouting, 

Hand Weeding

2,000

1,900 Irrigation 1,500

4,200 Scouting, Hand weeding 670

Crop Group

(14) 

Tree Nuts

2.0 0 5.609

100 Orchard Maintenance, Hand 

Weeding, Sweeping 

5,300

190 Harvesting, Mechanical 

Shaking

2,800

230 Transplanting 2,300

580 Scouting, Hand Pruning 920

1,400 Hand harvesting 380

3,600 Thinning 150

Table 5. Summary of Estimated Post-application MOEs for Agricultural Crops

Crop

Application 

Rate

(lb ai/A) 1

DAT2 DFR 3

(μg/cm2)

TC 4

(cm2/hr) Activity 4 Short-/IntTerm MOE 5

Persimmons

(Deciduous Trees) 2.0 0 5.609 100

Orchard Maintenance, Hand 

Weeding, Propping, Bird 

Control

5,300
Page 39 of 51

1. Maximum application rate from proposed label: Courier® 40SC Insect Growth Regulator (EPA Reg. No. 71711-20); Applaud®

 70DF Insect Growth Regulator (EPA Reg. No. 71711-21); Vetica® Insecticide (EPA Reg No.71711-32), and Tourismo® Insecticide

 (EPA Reg. No. 71711-32)

2. DAT = Days after treatment needed to reach the LOC of 100; DAT 0 = the day of treatment/ assumed to be approx. 12 hours. 

3. DFR (μg/cm2) = dislodgeable foliar residues corresponding to DAT, based on 25% of application rate.

4. TC (cm2/hr) = transfer coefficients and associated activities from ExpoSAC Policy Number 3. 

(http://www.epa.gov/pesticides/science/exposac_policy3.pdf)

5. MOE = MOE on the corresponding DAT. MOE = NOAEL / Daily Dose. 

Daily Dose = [(DFR x TC x 100% Dermal absorption x 8-hr Exposure Time)] / [(CF: 1000 μg/mg) x (80-kg Body Weight) 

 Short-/intermediate-term NOAEL = 300 mg/kg/day. The LOC is 100.

9.3.4 Restricted Entry Interval

Buprofezin has been classified in Toxicity Category IV for acute dermal and eye irritation and 

Category IV for primary skin irritation. Per the Worker Protection Standard (WPS), a 12-hr 

restricted entry interval (REI) is required for chemicals classified under Toxicity Category III/IV. 

10. REFERENCES

Buprofezin. 1F7905: Tree Nuts (Including Pistchio); 1E7908: Bean, Succulent; Brassica, Leafy Greens, Subgroup 

5B; Turnip, Greens; Vegetable, Fruiting, group 8-10; Fruit, Citrus, Group 10-10; Fruit, Pome, Group 11-10; 

Persimmon; and Tea. Summary of Analytical Method and Residue Data., S. Hummel, D395215, 7/26/2012

Buprofezin – Acute and Chronic Dietary Risk Assessments for Tree Nuts (Including Pistachio); Succulent Beans; 

Brassica, Leafy Greens, Crop Subgroup 5B; Turnip Greens; Vegetable, Fruiting, Crop Group 8-10; Citrus Fruit, 

Crop Group 10-10; Pome Fruit, Crop Group 11-10; Persimmon; and Tea., B. Cropp-Kohlligian, D400883, 

07/26/2012

Buprofezin: Occupational Risk Assessment for the Request to Add Uses on Crop Group 14 (tree nuts and 

pistachios), Crop Group 5B (brassica, and leafy greens), and (persimmons). J.S. Miller, D392675, 8/23/2012

Buprofezin, Drinking Water Exposure Assessment – R. Parker, D393932, 4/5/12

230 Transplanting 2,300

580 Scouting, Hand Pruning, 

Training

920

1,400 Hand Harvesting 380

3,600 Thinning Fruit 150
Page 40 of 51

APPENDICES

A TOXICOLOGY DATA SUMMARY

A.1 Guideline Data Requirements

Table 1. Guideline Data Requirements for Buprofezin

Test Technical

Required Satisfied

870.1100 Acute Oral Toxicity.......................................................

870.1200 Acute Dermal Toxicity ..................................................

870.1300 Acute Inhalation Toxicity..............................................

870.2400 Primary Eye Irritation....................................................

870.2500 Primary Dermal Irritation ..............................................

870.2600 Dermal Sensitization......................................................

yes

yes

yes

yes

yes

yes

yes

yes

yes

yes

yes

yes

870.3100 Oral Subchronic (rodent)...............................................

870.3150 Oral Subchronic (nonrodent) .........................................

870.3200 21-Day Dermal ..............................................................

870.3250 90-Day Dermal ..............................................................

870.3465 90-Day Inhalation..........................................................

yes

yes

yes

no

yes

yes

yes

yes

-

No

1

870.3700a Developmental Toxicity (rodent)...................................

870.3700b Developmental Toxicity (nonrodent).............................

870.3800 Reproduction .................................................................

yes

yes

yes

yes

yes

yes

870.4100a Chronic Toxicity (rodent) ..............................................

870.4100b Chronic Toxicity (nonrodent)........................................

870.4200a Oncogenicity (rat)..........................................................

870.4200b Oncogenicity (mouse)....................................................

870.4300 Chronic/Oncogenicity....................................................

yes

yes

yes

yes

yes

yes

yes

yes

yes

yes

870.5100 Mutagenicity—Gene Mutation - bacterial.....................

870.5300 Mutagenicity—Gene Mutation - mammalian................

870.5375 Mutagenicity—Structural Chromosomal Aberrations...

870.5900 Mutagenicity—Other Genotoxic Effects.......................

yes

yes

yes

yes

yes

yes

yes

yes

870.6100a Acute Delayed Neurotox. (hen) .....................................

870.6100b 90-Day Neurotoxicity (hen)...........................................

870.6200a Acute Neurotox. Screening Battery (rat) .......................

870.6200b 90-Day Neuro. Screening Battery (rat)..........................

870.6300 Develop. Neuro..............................................................

no

no

yes

yes

no

-

-

yes2

yes

-

870.7485 General Metabolism ......................................................

870.7600 Dermal Penetration ........................................................

870.7800 Immunotoxicity .............................................................

yes

-

Yes

yes

-

yes

1 HASPOC (TXR 0054073)

2 waived (TXR 0055414)
Page 41 of 51

A.2 Toxicity Profiles

Table 2 Acute Toxicity Profile Buprofezin [PC 2751001]

Guideline No./

Study Type

MRID No. Results Toxicity 

Category

870.1100 Acute oral toxicity 42873806 LD50 1635 mg/kg (M)

LD50 2015 mg/kg (F)

III

870.1200 Acute dermal toxicity 42873807 LD50 >5000 mg/kg IV

870.1300 Acute inhalation toxicity 42873808 LC50 >4.21 mg/L estimated IV

870.2400 Acute eye irritation 44393201 mild IV

870.2500 Acute dermal irritation 44393202 slight IV

870.2600 Skin sensitization 42873826 negative NA

Table 3 Subchronic, Chronic and Other Toxicity Profile for Buprofezin

Guideline No.

Study Type

MRID No. (year)

Classification

Dose Levels

Results

870.3100

90-day oral toxicity 

rodents (rat)

42935201 (1986)

Acceptable/Guideline

NOAEL:13.0 mg/kg/day Males or M); 16.3 mg/kg/day 

(Females or F)

LOAEL:68.6 mg/kg/day (M); 81.8 mg/kg/day females based 

on incr. rel. thyroid wt–males, increased liver weights–M/F, 

incr. microscopic lesions in liver & thyroid–M/F

870.3200

24-day dermal toxicity 

(rat)

44394024 (1995)

Acceptable/non-guideline

Systemic NOAEL: 300 mg/kg/day

Dermal NOAEL: 300 mg/kg/day

Systemic LOAEL: 1000 mg/kg/day based on increased focal 

necrosis with an inflammatory infiltrate in liver(F)

Dermal LOAEL: 1000 mg/kg/day based on increased 

acanthosis and hyperkeratosis in skin (F)

870.3465 

28-Day Inhalation

Data Gap

870.3700a

Developmental 

Toxicity in rodents 

(rat)

42873813 (1987)

Acceptable/guideline

Maternal NOAEL 200 mg/kg/day

Developmental NOAEL 200 mg/kg/day

Maternal LOAEL 800 mg/kg/day based on mortality, 

decreased pregnancy rates, increased resorption rates

Developmental LOAEL 800 mg/kg/day based on reduced 

ossification, reduced pup weight, fetal edema.

870.3700b

Developmental 

Toxicity in nonrodents (rabbit)

42873812 (1986)

Acceptable/guideline

Maternal NOAEL 50 mg/kg/day

Developmental NOAEL 250 mg/kg/day

Maternal LOAEL 250 mg/kg/day based on decreased food 

consumption, decreased body weights.

Developmental LOAEL, not established (> 250 mg/kg/day)
Page 42 of 51

Table 3 Subchronic, Chronic and Other Toxicity Profile for Buprofezin

Guideline No.

Study Type

MRID No. (year)

Classification

Dose Levels

Results

870.3800

Reproduction and 

fertility effects in rats

42873814, 44394027 (1997)

Acceptable/guideline

Parental NOAEL 7.89 mg/kg/day

Reproductive/Developmental NOAEL 7.89 mg/kg/day

Parental LOAEL 81.47 mg/kg/day based on decreased body 

weight gain and on organ weight changes

Reproductive/Developmental LOAEL 81.47 mg/kg/day based 

on decreased pup weight.

870.4100

Chronic toxicity in 

dogs

42873810 (1994)

Acceptable/guideline

NOAEL 2 mg/kg/day

LOAEL 20 mg/kg/day based on increased bile duct 

hyperplasia M/F, increased serum alkaline phosphatase 

activity M/F, increased relative & absolute liver wts and 

decreased liver function in females.

870.4300

Chronic toxicity/ 

carcinogenicity in 

rodents (rat)

42935202, 44394025 (1997)

Acceptable/guideline

NOAEL 1.0 mg/kg/day

LOAEL 8.7 mg/kg/day based on increased incidence of 

follicular cell hyperplasia and hypertrophy in thyroid in males.

No evidence of carcinogenicity

870.4200

Carcinogenicity study 

in mice

42873811 (1992)

Acceptable/guideline

NOAEL 1.82 / 17.9 mg/kg/d (M/F)

LOAEL 17.40 / 191.0 mg/kg/d (M/F) based on increased 

absolute liver weights in males & females, increased 

hepatocellular adenomas in females, increased hepatocellular 

adenomas + carcinomas in females

870.5100

Mutagenicity: gene 

mutation

Salmonella

42873815 (1988)

Acceptable/guideline

not mutagenic, with or without activation tested up to 

cytotoxic levels

870-5300

Mutagenicity: gene 

mutation

mouse lymphoma

42873816 (1988)

Acceptable/guideline

not mutagenic, with or without activation tested up to 

cytotoxic levels

870.5300

Mutagenicity: in vitro 

human cytogenetic 

assay

42873818 (1988)

Acceptable/guideline

negative for chromosomal aberrations tested up to cytotoxic 

levels

870.5300

Mutagenicity: mouse 

micronucleus assay

42873817 (1983)

Acceptable/guideline

negative for micronucleus induction in bone marrow cells of 

males and females tested up to cytotoxic levels

870.5300

Mutagenicity: 

Unscheduled DNA 

synthesis

42873819 (1988)

Acceptable/guideline

negative for DNA repair tested up to cytotoxic levels

870.7485

Metabolism

42873820, 44394029 (1999)

Acceptable/guideline

79.1% recovered from feces, 12.9% from urine within 72 hr.

45.4% recovered as parent cpd, several metabolites identified.
Page 43 of 51

Table 3 Subchronic, Chronic and Other Toxicity Profile for Buprofezin

Guideline No.

Study Type

MRID No. (year)

Classification

Dose Levels

Results

870.6200

Subchronic 

neurotoxicity

48083902 (2005)

Acceptable/guideline

LOAEL > 5000 ppm, no neurotoxicity was observed

NOAEL = 5000 ppm (358.1/433.0 mg/kg/day in 

males/females, the highest dose tested)

870.7800

Immunotoxiciy

4844010 (2011) Not immunotoxic at doses tested.

A.3 Toxicological Endpoints

A.3.1 Acute Reference Dose (aRfD) - Females age 13-49

Selected Study: Developmental Toxicity in Rats (MRID 42873813). See Section 3.2.1

Dose and Endpoint for Establishing an aPAD: 200 mg/kg/day based on incomplete 

ossification and reduced pup weight at 800 mg/kg/day.

 

Uncertainty Factor (UF): 100 This includes 10x for interspecies extrapolation and 10x for 

intraspecies variation.

Comments about Study/Endpoint: The developmental effects of concern are presumed to 

occur after a single exposure and are relevant only to females aged 13-50 years old since they 

occur in utero. Effects on the thyroid gland and related hormonal levels in the blood are related 

to the repeated exposure to buprofezin and therefore, are not appropriate for this acute endpoint. 

The acute exposure scenarios are not likely to result in toxicologically significant changes in 

thyroid hormonal levels because there is a normal daily fluctuation in the thyroid levels which 

may be indistinguishable from any single dose effects on hormone levels. 

A.3.2 Acute Reference Dose (aRfD) - General Population

No appropriate endpoint was identified for the general population which might occur following a 

single dose or exposure, including maternal toxicity in developmental studies. 

A.3.3 Chronic Reference Dose (cRfD) - All Populations

Selected Study: Two-Year Chronic Feeding Study in Rats 

Acute RfD (females 13-49) = (NOAEL) 200 mg/kg = 2.0 mg/kg

 (UF) 100
Page 44 of 51

In a combined chronic toxicity/oncogenicity study (MRIDs 42935202, 44394025) buprofezin 

technical (>99% a.i.) was administered in the diet to 55 male and 55 female Sprague-Dawley rats 

for up to 24 months at levels of 0, 5, 20, 200, or 2000 ppm (approximate doses of 0 0.26, 0.90, 

8.7, or 90 mg/kg/day for males and 0, 0.33, 1.1, 11.2, or 115 mg/kg/day for females). Of these, 

5/sex/dose were sacrificed after six months and 10/sex/dose were sacrificed after 12 months. At 

2000 ppm, absolute and relative liver weights were significantly (p<0.05 or p<0.01) increased in 

both sexes and an increased incidence of enlarged hepatocytes, focal necrosis, and hyperplastic 

nodules was observed in livers of males and females. Both follicular cell hypertrophy and C-cell 

hyperplasia were significantly elevated in males and females, and absolute and relative thyroid 

weights were increased (statistically significant in males at 24 months and in females at six and 

12 months). In addition, body weight gains were reduced in males (-17%, p<0.01) at 24 months, 

and males had enlarged reticular cells of the spleen. At 200 ppm, follicular cell hypertrophy is 

elevated in males. No effects were noted in animals in the 20 ppm and 5 ppm groups. The 

LOAEL is 200 ppm (8.7 mg/kg/day), based on increased incidence of follicular cell hyperplasia 

and hypertrophy in the thyroid in males. The NOAEL is 20 ppm (1 mg/kg/day).

Dose and Endpoint for Establishing cRfD: 1.0 mg/kg/day based on increased incidence 

of follicular cell hyperplasia and hypertrophy in the thyroid in males at the LOAEL of 8.7 

mg/kg/day.

Uncertainty Factor(s): 300 This includes 10X for intraspecies variation, 3X for 

interspecies extrapolation – reduced from 10X based on demonstrated evidence that rats are 

more susceptible to thyroid effects than humans – and a 10X for incomplete data base due to the 

need for a thyroid assay in rats. 

Comments about Study/Endpoint/Uncertainty Factor: This study and the endpoint are 

appropriate for the route and duration of exposure. This study has the lowest definitive NOAEL 

of the available chronic studies in the rat, mouse and dog. 

A.3.4 Incidental Oral Exposure (Short- and Intermediate-Term)

There are no residential uses for buprofezin. Therefore incidental oral exposure endpoints are 

not required and not selected for this assessment. 

A.3.5 Dermal Absorption

There are no dermal absorption studies available with buprofezin.

Chronic RfD = 1.0 mg/kg/day (NOAEL) = 0.0033 mg/kg/day

 300 (UF)
Page 45 of 51

A.3.6 Dermal Exposure (Short and Intermediate-Term)

Selected Study: 24-day Dermal Toxicity Study in Rats 

In a subchronic dermal toxicity study (MRID 44394024) T75 Buprofezin 99.0% a.i. was 

administered dermally to 5 CD rats/sex/dose in 2% (w/v) aqueous gum arabic solution at dose 

levels of 0, 100, 300 or 1000 mg/kg/day for 24-days followed by a recovery period lasting 2 

weeks. No mortality occurred and there were no clinical signs of toxicity. Food consumption 

was decreased (4-10%) in the animals in the treated groups when compared to control, however, 

a dose-response relationship was not evident. Gross necropsy revealed encrustation around the 

test site for 1 female in the 1000 mg/kg/day group and for 1 male and 1 female in the 300 

mg/kg/day group. Microscopic examination of the tissues showed hyperkeratosis and acanthosis 

of the skin in 4/5 males in the 1000 mg/kg/day group, compared to 2/5 animals in the control 

group. Males in all treated groups had a higher incidence (4/5) of basal epithelial cell vacuolar 

degenerative changes of the skin when compared to controls (2/5). One female in the 1000 

mg/kg/day group had a combination of histopathological changes indicative of a mild 

inflammatory response at the test site. There was a higher incidence of focal necrosis with 

inflammatory infiltrate of the liver in females in the 1000 mg/kg/day group (3/5) when compared 

to controls (1/5). The systemic dermal LOAEL is 1000 mg/kg/day based on an increase of focal 

necrosis with an inflammatory infiltrate of the liver in females. The systemic dermal NOAEL is 

300 mg/kg/day. The dermal LOAEL for local or topical effects is 1000 mg/kg/day based on an 

increase in acanthosis and hyperkeratosis of the skin in females and because one female showed 

a “full spectrum inflammatory response” of the skin. The local dermal NOAEL is 300 

mg/kg/day.

Dose and Endpoint for Risk Assessment: 300 mg/kg/day based on inflammatory infiltrate 

of the liver in females at the LOAEL of 1000 mg/kg/day.

Uncertainty Factor (UF): An MOE of 100 is required for the short- and intermediate-term 

scenarios for dermal exposure. This includes 10X for interspecies extrapolation and 10X for 

intraspecies variation.

Comments about Study/Endpoint: The endpoint of concern was seen following the 

appropriate route (dermal) and duration (1 - 30 days) of concern, and the experimental conditions 

simulate an actual worker exposure scenario. 

A.3.7 Inhalation Exposure (Short and Intermediate-Term)

Selected Study: 90-day Oral Toxicity Study in Rats

In a subchronic study (MRID 42935201), Jcl:SD rats were fed buprofezin (>99% a.i.) daily for 

90 days at dietary levels of 0, 40, 200, 1000, and 5000 ppm (approximately 0, 3.4, 13.0, 68.6 and 

316.2 mg/kg/day for males, and 0, 4.1, 16.3, 81.8, and 362.2 mg/kg/day for females, 

respectively). At 5000 ppm compound-related effects observed in both sexes included decreased 
Page 46 of 51

body weight and weight gain (74% - 94% of control); increased organ weights (liver: 132 - 152% 

of control; thyroid: 200 - 267% of control); increased incidence of gross lesions (thyroid 

enlargement); increased incidence of microscopic lesions in the liver and thyroid; increased 

levels of cholesterol (125 - 164% of control), BUN (119% of control), and protein (115 - 122% 

of control); increased thromboplastin time (119% of control); decreased plasma cholinesterase 

level (76% of control, females), and decreased glucose (75%) and triglyceride (50 - 81%) levels. 

Increased incidence of microscopic lesions (fat loaded hepatocytes in males and focal infiltration 

of small round cells were observed in females. Additional toxic effects were observed in the 

kidney (weight decrease, hyaline droplets and eosinophilic bodies). At 1000 ppm, the thyroid to 

body weight ration was increased to 125% of control in males (p<0.05) in males and follicular 

epithelial hyperplasia was seen in nearly all animals. Hepatocyte enlargement was seen in two of 

10 males and liver weights were increased significantly in females. Increased microscopic 

lesions in the liver and thyroid were observed in both sexes). Additional toxic effects were 

observed in the kidney (hyaline droplets and basophilic bodies). No significant adverse effects 

were noted at 200 and 40 ppm.

The LOAEL for this study is 1000 ppm (68.6 mg/kg/day) based on organ weight changes 

and microscopic findings in the liver and thyroid of both males and females, and in the kidney of 

males. The NOAEL is 200 ppm (13.0 mg/kg/day).

Dose and Endpoint for Risk Assessment: 13.0 mg/kg/day based on organ weight changes 

and microscopic finding in liver, thyroid and kidney at the LOAEL of 68.6 mg/kg/day

Uncertainty Factor (UF): An MOE of 300 is required for the short- and intermediate-term 

scenarios for inhalation exposure based on a 10X for interspecies extrapolation, a 3X for 

interspecies variation – reduced from 10x based on demonstrated evidence that more susceptible 

to thyroid effects than humans – and a 10x for incomplete data base due to the need for a thyroid 

assay in rats and the need for a 28 day inhalation study. 

Comments about Study/Endpoint: Since an oral NOAEL was selected for inhalation risk 

assessment, an inhalation absorption factor of 100% should be used.
Page 47 of 51

A.4 EXECUTIVE SUMMARIES

870.3700 Developmental Toxicity

In a developmental toxicity study (MRID 42873813) groups of 21 pregnant female CD rats were 

administered buprofezin by gavage at doses of 0, 50, 200 or 800 mg/kg/day from days five to 15 

of pregnancy. At 800 mg/kg/day toxic signs included loose feces, urogenital staining, hunched 

positions, lethargy, weight loss (70.5% of controls on gestation day 12, p<0.01), decreased food 

consumption (81.3% of controls on GD 12, p<0.01) and increased water consumption (131% of 

controls on GD 12, p<0.01). One female was sacrificed in extremis on gestational day 12. Of 

the 20 other females, three were not pregnant, and one totally resorbed the fetuses. The others in 

this group showed increased implantation losses. The 200 mg/kg/day group animals appeared to 

be normal except for intermittent food consumption changes and increased urine output. One 

female was not pregnant. The 50 mg/kg/day group females were similar to controls. None of 

the pups from any of the treatment groups showed morphological abnormalities different from 

concurrent or historical controls. In the 800 mg/kg/day dose group, the fetuses showed 

decreased fetal weights (89.4% of controls, p<0.001), fetal edema in five to 10 fetuses per litter 

(p<0.01), and reduced ossification in interparietal bones (p<0.001). At 200 mg/kg/day, reduced 

ossification was also observed (p<0.01), but was within the range of historical controls. At 50 

mg/kg/day, fetal findings were similar to controls. The NOAEL for maternal toxicity is 200 

mg/kg/day. The LOAEL is 800 mg/kg/day based on mortality, decreased food consumption, 

weight loss, clinical signs, decreased pregnancy rates and increased resorption rates. The 

NOAEL for developmental toxicity is 200 mg/kg/day, and the LOAEL is 800 mg/kg/day based 

on incomplete ossification, and reduced pup weight.

In a prenatal developmental toxicity study (MRID 42873812) New Zealand White rabbits 

(17/dose group) were given buprofezin (99% a.i.) in 2% aqueous gum arabic mucilage (w/v) by 

gavage during GD 6 to 19 at dosages of 0, 10, 50 and 250 mg/kg. Control animals were gavaged 

only with the gum arabic vehicle. There were no clinical toxic signs in any test groups. 

Decreased food consumption and body weights were seen in the high dose females early in the 

dosing period. The body weight reductions in the high dose females persisted during the 

remainder of gestation while the food consumption improved. Two females from the 10 

mg/kg/day dose group died but the deaths were not attributable to buprofezin treatment. One 

female in 50 mg/kg/day group aborted on GD 25, an abortion rate of 5.9%. Two females in the 

high dose group experienced total litter loss, a rate of 14.3%. These losses were within historical 

control ranges of 0.0 to 33.3%. There were no other compound related effects on the number of 

corpora lutea, implantations, resorptions or percent of pre- or post-implantation losses. There 

were no agent related changes in soft and skeletal tissues. Soft tissue variations and skeletal 

deviations were either absent or within historical control ranges. The maternal NOAEL is 50 

mg/kg/day. The maternal LOAEL is 250 mg/kg based on decreased body weight and food 

consumption and possibly increased fetal loss. The developmental toxicity NOEL is 250 

mg/kg/day, the highest dose tested.
Page 48 of 51

870.7600 Dermal Toxicity Studies

There are no dermal absorption studies available with buprofezin.

870.3800 Reproduction

In a two generation reproduction study with two litters per generation (MRID 42873814 with 

supplemental data provided in MRID 44394027) Wistar-Imamichi rats (30 per group) received 

buprofezin in the diet at target levels of 0, 10, 100, or 1000 ppm (approximately 0, 0.82, 7.99, 

and 84.40 mg/kg/day for males and 0, 0.81, 7.89, and 81.47 mg/kg/day for females). In both 

generations following the second mating, 10 dams per group were sacrificed on GD 21 and their 

fetuses were processed for teratological evaluation. The remaining dams were allowed to deliver 

and rear their pups naturally. Parental toxicity was observed at 1000 ppm manifested as slight 

but significantly decreased body weight gain in F1 males (82-94% of control) and females (88-

96%) during premating and in F2 males (80-93%) and females (80-96%). Liver and kidney 

weights were also increased at this dose level but not histopathology was performed precluding 

interpretation of these organ weight increases. Offspring toxicity was observed at 1000 ppm as 

evidenced by significantly decreased pup body weight in both sexes (83-93% of controls). 

In a second supplemental one-generation reproduction study with two litters per generation

(MRIDs 42873814 & 44394027) Wistar-Imamichi rats (25 per group) received buprofezin in the 

diet at dose levels of 0, 10, 100, or 1000 ppm (approximately 0, 0.82, 7.99, or 84.4 mg/kg/day in 

males and 0, 0.81, 7.89, or 81.47 mg/kg/day for females). The parental toxicity and liver and 

kidney weight increases observed in the first study were not observed in the second study. 

Offspring toxicity was observed in the second study at 1000 ppm as evidenced by significantly 

decreased pup body weight in both sexes (83-93% of controls).

Based on the combined results of the two rat reproduction studies, the parental NOAEL is 7.9 

mg/kg/day (100 ppm). The LOAEL is 81.5 mg/kg/day (1000 ppm) based on decreased body 

weight gain and organ weight changes. The NOAEL for offspring toxicity is 7.9 mg/kg/day (100 

ppm). The LOAEL is 81.5 mg/kg/day (1000 ppm) based on decreased pup weight. Data from 

the two reproduction studies show no evidence of reproductive toxicity at any dose. 

870.6200b Subchronic Neurotoxicity

There is evidence of thyroid toxicity following subchronic and chronic exposures to rats as well 

as chronic exposures to dogs characterized as decreases in serum thyroxine levels and increased 

thyroid weights in dogs and histopathological lesions in the subchronic and chronic toxicity 

studies in rats. As previously noted, disruption of thyroid homeostasis is the initial, critical effect 

that may lead to adverse effects on the developing nervous system. 

Normally, if a neurodevelopmental concern is raised by existing data on a pesticide, a rat 

developmental neurotoxicity (DNT) study is requested. However, a DNT study is not required 

for buprofezin since this study would not address thyroid toxicity concerns. Thus, in lieu of the 
Page 49 of 51

rat DNT study, a special study is needed to further evaluate the hormonal responses associated 

with the developing fetal nervous system. OPP has developed guidance for thyroid assays in 

pregnant animals, fetuses and postnatal animals, and adult animals (Appendix 3.0). The 

guidance is not intended to be prescriptive. The Agency recognizes that registrants may chose to 

propose an alternative approach that adequately addresses the issue of disruption of thyroid 

hormone homeostasis during development. Registrants are encouraged to consult with the 

Agency during development of any alternative study protocol or the implementation of the 

guidance. 

870.5100, 870-5300 Mutagenicity

Buprofezin was negative in five acceptable mutagenicity studies:

1. Reverse gene mutation, S. typhimurium (MRID 42873815)

2. Gene mutation: mouse lymphoma (MRID 42873816)

3. in vitro human cytogenetic assay (MRID 42873818)

4. Mutagenicity: mouse micronucleus assay (MRID 42873817)

 5. Mutagenicity: Unscheduled DNA synthesis (MRID 42873819)

The complete toxicity profile for buprofezin is provided in Appendix A. 

APPENDIX B. Chemical Names And Structures Of Metabolites

Chemical Names and Structures of Buprofezin and Metabolites. 

Common name;

Company code

Chemical name Chemical structure

BF9 3-isopropyl-5-phenyl-1,3,5-

thiadiazinan-2,4-dione

BF12 1-isopropyl-3-phenylurea

N N

S

CH3

CH3

O

O

N

H

N

H

O

CH3

CH3
Page 50 of 51

Chemical Names and Structures of Buprofezin and Metabolites. 

Common name;

Company code

Chemical name Chemical structure

BF4 2-(2-hydroxy-1,1-

dimethylethylimino)-3-isopropyl-5-

phenyl-1,3,5-thiadiazinan-4-one

BF26 2-amino-2-methylpropyl-2-methylethyl4-phenyl-allophanate

APPENDIX C. Physical/Chemical Properties

Physicochemical Properties of Buprofezin.

Parameter Value Reference

Molecular Weight 305.4 DP# 280879, 6/6/2002, B. 

Kitchens Melting point/range 104-106 °C

pH 6.35

Density 1.18 g/cm3

Water solubility (25 oC) 0.382 g/liter at 25 °C

Solvent solubility (25 oC) 520 g/liter - chloroform; 320 g/liter -

toluene; 240 g/liter acetone; 20 g/liter 

hexane

Vapor pressure (25 oC) 1.68 x 10-2Pa at 52 °C

Dissociation constant, pKa Does not disperse

Octanol/water partition coefficient, 

Log(KOW)

4.31 at 20 °C

UV/visible absorption spectrum Not available

N N

S

CH3

CH3

N

O

H3C CH3

OH

N

H

N

O

O

CH2

H3C CH3

NH2

CH

CH3

3
Page 51 of 51

APPENDIX D. Studies Reviewed for Ethical Conduct

The PHED Task Force, 1995. The Pesticide Handlers Exposure Database, Version 1.1. Task 

Force members Health Canada, U.S. Environmental Protection Agency, and the National 

Agricultural Chemicals Association, released February, 1995.

Agricultural Re-entry Task Force (ARTF) data base (SOP #3.1)