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 Hand ler 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

AP PENDICES

................................ ................................ ................................ ............................. 40

A TOXICOLOGY DATA SUMMARY

................................ ................................ .............. 40

A.1 Guideline Data Requirements

................................ ................................ ................ 40Page 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

................................ .......................... 51Page 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.

Un der 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 t olerances for residues

of b uprofezin rang e 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 r esidues, in milk (0.01 ppm) and meat (0.05 pp m)

. Buprofezin works by inhibiting chitin biosynthesis . It disrupt s molting, suppress es egg deposition , and reduce s egg viability. Applications may be made using ground or aerial equipment. There are currently no buprofezin products registered for

home owner use and no products registered for application to residential areas

.

Proposed New Use s

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 p ome 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 rate s 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

T he 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

.

B uprofezin 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 ey e and skin irritation. It

is not a dermal sensitizer.

T he 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 i ncreased relative liver weights in female dogs. A rat dermal toxicity study showed liver and skin effects ( i ncrease in acanthosis and hyperkeratosis ) in females.

Developmental and reproductive toxicity studies do not indicate concern for increased susceptibility in offspring . T oxicity in the offspring was found at dose levels that were also toxic to the pare nt and

t he 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. B uprofezin was not carcinogenic to

male and female rats.

No neurotoxic effects were observed at any dose in a subchronic neurotoxicity study in rats a t 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 c hronic feeding study in rats

. Short and intermediate

- term occupational exposures via the dermal and inhalation routes may occur based on the use patternPage 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 endpoi nt 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 inhalat ion 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 f or 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 use s of buprofezin on brassica, coffee and pomegranate. Worker exposures were assessed for handler and post

- application

activities.

Screening level acute and refined chro nic 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 a nd risk estimates indicate that occupational handler and post

- application exposures

are not of concern at the maximum allowable use rate s for the proposed new uses for all but one handler and one post

- application exposure scenario. The occupational analys is 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 require ment. 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 w hich 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 . S ome 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 Lo w

- 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 pat terns 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 ad ult 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 so ftware 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 chemi stry 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 1 4

........................ .................................. 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 LoganberryPage 9 of 51

2.0 HED RECOMMENDATIONS

2.1 Data Deficiencies/Conditions of Re gistration

The immunotoxic i ty 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, correcti ng 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 (DP 328796, 5/28/2008, T. Bloem )

●lemon field tri al data (conclusion 3; D 328796, 5/28/2008, T. Bloem, originally from D296492, 12/17/03, T. Bloem ) ●apple and grape processing studies (conclusion 4; DP 328796, 5/28/2008, T. Bloem ). The processing studies should be conducted at 5x the labeled rate using th e 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 pla nt 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 a nd 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 almon d 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 o n 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 COD EX 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 Mexic an 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

residu es 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. 0 5 ppm

Pear

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

.................................................................. 6.0 ppm Persimmon

................................................................... 1.9 ppm

Tea

............................................................................. 20 ppm Turnip, greens

............................................................... 60 ppm Veg etable, 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 an d 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 pro posed 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 lo wering 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 INGREDI ENT 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

- 3 H

- 1,3,5

- thiadiazin

- 4

-

one

CAS name 2

- [(1,1

- dimethylethyl)imino]tetrahydro

- 3

- (1

- methylethyl)

- 5

- phenyl

- 4 H

- 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

- 2 1 )

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

.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

C A 0 5 000 8 Courier 40SC Insect Growth Regulator Nichino America, Inc. 4 0

C A 0 7 00 10 Talus 40SC Insect Growth Regulator Nichino America, Inc. 4 0

C O 0 7 00 05 Talus 40SC Insect Growth Regulator Nichino America, Inc. 4 0

FL 0 4 00 12 Courier 40SC Insect Growth Regulator Nichino America, Inc. 4 0

PA 0 7 000 4 Talus 40SC Insect Growth Regulator Nichino America, Inc. 4 0

VA0 7 0001 Talus 40SC Insect Growth Regulator Nichino America, Inc. 4 0

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 (Couri er® 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 formulat ion 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 Vegetabl es (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 p roducts, 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 veget able 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 GPA 1 ; 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 GPA 1 ; 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 GPA 1 ; 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

GPA 1 ; 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 cycle 4/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 request s 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, i n 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/j ustice/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 settin g. 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

considerati ons 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

T he 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 evidenc e 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

- phenyl

1,3,5

- t hiadiazinan

- 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 wit h 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 s tudies 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 to xic 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 wher e 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 neu rotoxic 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 Carcinogenici ty, 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 t ransformation 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 bupr ofezin 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 micronuc leus 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

retain ed . 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 absen ce 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 ev aluate 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 im munotoxicity 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 immunoto xicity. 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 (HA SPOC) (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 o f 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 adve rse 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 th is 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 g uidance for thyroid assa ys 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 disruptio n 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 De veloping 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 rabbi ts 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 assessm ent 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

- R esponse 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 yea rs 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 li kely 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 two

year 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 inter mediate

- 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 o n 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, agg regate exposure from food and

non

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

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

based on common target organ effec t (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 Sprague

Dawley rats and a 24

- month carcinogenicity study in ICR

- Cr mice. Based on the inc reased 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. 0 014045) classified buprofez in 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 assa ys, 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 aneuge nic 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 protec tive 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 T oxicological Effects

Ac ute 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 UF A = 10x

UF H =10x FQPA SF= 1x Acute RfD = 2.0

mg/kg/day

aPAD = 2. 0 mg/kg Developmental Toxicity Study

- R at (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 UF A = 3x

U F H =10x FQPA SF= 10x Chronic RfD =

0.0 33 mg/kg/day

cPAD = 0. 0033 mg/kg/day Two

- year C hronic T oxicity/ C arcinogenicity 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 Q 1 *). 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. UF A = extrapolation from animal to human (interspecies). UF H = potential variation in sensitivity among members of the human population (intraspecies). UF L = use of a LOAEL to extrapolate a NOAEL. UF S = use of a short

- term study for long

- term risk assessme nt. UF DB = 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 exposur e. LOC = level

of concern. N/A = not applic able.

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 UF A = 10x

UF H =10x Occupationa l 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 UF A = 10x

UF H = 10 x UF DB = 10x Occupationa l 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 Q 1 *). The cRfD is considered protective of the cancer effects.

UF = uncertainty factor. UF A = extrapolation from animal to human (interspecies). UF H = potential variation in sensitivity among members of the human population (intraspecies)

. UF DB = to account for the absence of key date (i.e., lack of a critical study ).Page 22 of 51

5.0 DIETARY AND DRINK ING 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 ma jor 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 tr eated 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 addit ion 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 bupr ofezin 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

Bupr ofezin 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 recovere d 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

- isopropyl

1,3,5

- thiadiazinan

- 4

- one; 7.2% of dos e) 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 li kely 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 pur poses 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 fo r 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 co ncern 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 : Sum m ary of Buprofezin Residues of Concern.

Matrix Residues of Concern

For Risk Assessment For Tolerance Expression

Crops with ≤7

- day PHI 1 Buprofezin

Buprofezin Crops with >7

- day PHI 1 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 crops 2 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 assessm ent 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 expo sure 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 an d 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 vegetab les, 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 toleran ces 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

ade quate 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 p roposed: 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; D P#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 use s on c offee 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

EDWC s below those previously determined. T he cof fee use yields the highest EDWC s to date.

The EDWCs f

or 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

Cranberries c 47.9 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 ass essment 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 adve rse 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 residue s 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 t o 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

, w hich 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 co ncern 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 indicat ed a 5x concentration of residues into milk cream and fat and a Log

K
ow 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 applica tion 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 sub groups.

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 colle ction methods but which may be estimated from metabolism data) were based on average field trial, average USDA Pesticide Data Program (PDP), or tolerance level r esidues 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 processedPage 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 i n/on the peel, the maximum theoretical concentration factor for peel was applied to residues in citrus peel.

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

were based on the f

eeding 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 K

ow 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 treat ed assumptions for a number of crops for

which data w ere 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 appr opriate, develop policiesPage 28 of 51

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

application inhalation exposure into the Agency's risk assessments. If new policies or procedures are put into place, the Agency may revisit t he 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 applica tion, 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 req uiring 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 res ult 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 mos t 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

reside ntial 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 vario us 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 re present 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 t hat 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 appro ach 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

comm on 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 mecha nism 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

O ccupational handler and post

- application exposure scenarios were assessed for th e r isk

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 describ e 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 che mical used in each application), the kinds of equipment used, the target beingPage 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 patter ns 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

follow ing 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), t he 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 Refere nce Table” (http://www.epa.gov/opp00001/science/handler

- exposure

table.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 mixi ng/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 ac re 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 Factor s 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 eq uivalent 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, lo ng 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 sleeve d 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 Fa ctor = 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)

Aver age 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

pesticid e, 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 estim ates 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 MOE 5

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

Grou ndboom (Soluble Concentrate) Crop Groups (5B) Leafy Brassica

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

Appl ying

Aerial (Enclosed Cockpit) 6

(Soluble Concentrate) Crop Groups (5B) Leafy Brassica

Greens 0.38 350 0.068 5 0.0001 0.0083 36,000 110,000Page 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 MOE 5

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 calc ulated 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 inha lation 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, suc h 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 Age ncy'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 perfor ming post

application 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 relate d 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/2009/1201 09meeting.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 identif y 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 occupationa l

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

handler s. 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 occupation al 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 r ow ing.

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 chemical

specific 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. ThePage 36 of 51

standard values recommended for use in predicting post

- application exposure that are used in this assessment, known as “transfer coefficient s”, 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/post

app

- exposure

- data.html

.

Note: 1) Duplicate post

- application activities with different transfer coefficients are noted within the

same crop group s (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 acti vities 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 esti mates 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 sh ort

- /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/cm 2 on day zero cr op group 5B; Brassica and Leafy Vegetables.

2). 5.6 ug/cm 2 on 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 post

application activities:

DFR t (μg/cm 2 ) = AR (lb ai/acre) x F x (1

- D) t x 4.54E8 μg/lb x 2.47E

- 8 acre/cm 2

Where:

DFR t = dislodgeable foliage residue on day "t" (μg/cm 2 ),

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) = DFR t (μg/cm 2 ) x 1E

- 3 mg/μg x TC (cm 2 /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),

DFR t = dislodgeable foliage residue on day "t" (μg/cm 2 ),

TC = transfer coefficient (cm 2 /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 rece ived 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 post

application exposure and risk calculations

, as sumptions, and results is provided in Table 1 1

.Page 38 of 51

Table 11 . Summary of Estimated Post

- application MOEs for Agricultural Crops

Crop Application

Rate
(lb ai/A) 1 DAT 2 DFR 3
(μg/cm 2 ) TC 4

(cm 2 /hr) Activity 4 Short

- /Int

Term 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 DAT 2 DFR 3
(μg/cm 2 ) TC 4

(cm 2 /hr) Activity 4 Short

- /Int

Term MOE 5

Persimmons
(Deciduous Trees) 2.0 0 5.609 100 Orchard Maintenance, Hand Weeding, Propping, Bird

Control 5,300Page 39 of 51

1. Maximum application rate from proposed label: Courier® 40SC Insect Growth Regulator (E PA 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/cm 2 ) = dislodgeable foliar residues co rresponding to DAT, based on 25 % of application rat e. 4. TC (cm 2 /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 I V 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 require d 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 , D 3 9 5215

, 7 /2 6 /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

, D 400883

, 07/26/2012

Buprofezin : Occupational Risk Asse ssment for the Request to Add Uses o n Crop Group 14 (tree nuts and pistachios), Crop Group 5B (brassica, and leafy greens), and (persimmons ). J.S. Miller, D 3 9 2675 , 8/23/2012

Buprofezin

, Drinking Water Exposure Assessment

– R. Parker , D 39 3932

, 4 / 5 /1 2 230 Transplanting 2,300

580 Scouting, Hand Pruning,

Training 920

1,400 Hand Harvesting 380

3,600 Thinning Fruit 150Page 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 y es

yes

yes

- N o 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 y es

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 -

- yes 2

yes

-

870.7485 General Metabolism

................................ ...................... 870.7600 Dermal Penetration

................................ ........................ 870.7800 Immunotoxicity

................................ ............................. yes

- Yes yes

- yes

1 HASPOC (TXR 005 4073 )

2 waived (TXR 0055414)Page 41 of 51

A .2 Toxicity Profiles

Table 2 Acute Toxicity Profile Buprofezin [PC 275100 1]

Guideline No./ Study Type MRID No. Results Toxicity Category

870.1100 Acute oral toxicity 42873806 LD 50 1635 mg/kg (M)

LD 50 2015 mg/kg (F) III

870.1200 Acute dermal toxicity 42873807 LD 50 >5000 mg/kg IV

870.1300 Acute inhalation toxicity 42873808 LC 50 >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 base d on reduced ossification, reduced pup weight, fetal edema.

870.3700b Developmental Toxicity in non

rodents (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 dog s 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 test ed 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 T oxicity in R ats (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 resu lt 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 ( c RfD)

- 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) 100Page 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 additio n, 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 stu dy 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 ( S hort

- and I ntermediate

- 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 ) = 0.0 033 mg/kg/day

3 00 (UF)Page 45 of 51

A

. 3

. 6 Dermal Exposure ( Short and Intermediate

- Term )

Selected Stud y: 24

- day Dermal Toxicity Study in Rats

In a subchronic dermal toxicity study (MRID 44394024) T75 Buprofezin 99.0% a.i. was

administered dermal ly 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 perio d 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 nec ropsy 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 1 000 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/d ay 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 eff ects 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 expos ure. This includes 10X fo r interspecies extrapolation and 10 X 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 Stud y : 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 decreasedPage 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) ; i ncreased thromboplastin time (119% of control ); decreased plasma cholinesterase level (76% of control, females), an d decreased glucose (75%) and triglyceride (50

- 81%) levels

. I ncreased 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. Hepatocyt e 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 drople ts 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 expos ure 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, a n inhalation absorption factor of 100% should be used

.Page 47 of 51

A.4 EXECUTIVE SUMMAR IES

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, uro genital 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 e xcept 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 differ ent 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 ossifi cation, and reduced pup weight.

In a prenatal developmental toxicity study (MRID 4 2873812) 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 we ight 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

corpo ra 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 histor ical control ranges. The m aternal NO A EL is 50 mg/kg /day. The maternal LO A EL is 250 mg/kg based on decreased body weight and food consumption and possibly increased fetal loss. The d evelopmental 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, a nd 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 n aturally. 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 sex es (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 b uprofezin 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 l iver and kidney weight increases observed in the first study were not observed in the second study. Offspring toxicit y 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). T he LOAEL is 81.5 mg/kg/day (1000 ppm) based on decreased body weight gain and organ weight changes. The NO A EL 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 repr oduction 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 thePage 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 g uidance 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 alternat ive 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 guida nce.

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

- phenylureaPage 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

- methylethyl

4

- phenyl

- allophanate

APPENDIX C. Physical/Chemical Properties

Physicochemical Properties of Buprofezin

. Parameter Value Reference

Molecular Weight 305.4 D P# 2 80879, 6/6 /2002 , B.

Kitchens Melting point/range 104

- 106 °C

pH 6.35

Density 1.18 g/cm 3

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 - 2 Pa at 52 °C

Dissociation constant, pK

a Does not disperse

Octanol/water partition coefficient, Log(K OW ) 4.31 at 20 °C

UV/visible absorption spectrum N ot availablePage 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)