UNITED STATES ENVIRONMENTAL PROTECTION AGENCY WASHINGTON, D.C. 20460

OFFICE OF CHEMICAL SAFETY AND POLLUTION PREVENTION

MEMORANDUM

December 12

, 20 13

SUBJECT: Diflubenzuron : Human Health Risk Assessment for an Amended Sectio n 3 Reg i stration for the Expanded C itrus Crop Group 10 -10.

PC Code: 1 0820 1 DP Barcode: 403078

, 403079

, & 403080

Decision No.: 465090

, 465087

, & 465092 Registration No.: 400-461

, 400-466

, 400-

48 7

Petition No.: 2F80 15 Regulatory Action: Section 3

Risk Assessment Type: Huma n Hea l t h Risk Case No.: 0144

Assessment

TXRNo.: NA CAS No: 35367-38-5

MRIDNo.: NA 40 CFR: 180

. 3 77 

# -ziAL



# -

. FROM

. Thurston G. Morton, Chem t s t

# ~ ;J

Sus an V. Hummel, Senior Scientist /

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# /1/ ) I/

James S Miller, Environmental Scien t {l 'st

·-

## ,-yt-a_~ / 

# /lf.L

--- ( A Ayaad Assad

, PhD., Toxicologist 

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### ;I 

## .il L/ '--

Risk Asses s ment Branch 4

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Health Effe c t s D i v ision ( 7509P)**~**

THRO U GH: E li ssa Reaves

, P h .D

. , Branch Chief

## ~**~** Risk Assessment Branch 4

, H E D (7509P)

## -~**.**

TO: Rita Kumar / John Hebert

Insec t icide/Rodenticide Branch/RD (7505P)

Thi s document provides the Hea l t h Effects Division's (HED's) risk assessment of the amended

Section 3 u s e of diflubenzuron on the expanded citrus fruit crop gro u p 10

- 10.

Pa g e 1 of661.0 EXECUTIVE SUMMARY

.................. . . . . .. .. . . . .. . ... . ... . ...... . .... . ....... . ... . ... . ... .. .. .. ....... .. .... . .. .. . 5

2.0 HED Recommendations

. . . .. . ............................... . ..... .. ................... .. . . .... . .... ...... .. ....... .. .. .. . •

. 9

2.1 Data Deficiencies/Conditions of Registration

.. .. ....... . ................ . . . . . ... . . . . ..... .. .. ... .. .. .. ... .. . 9

2

. 2 T olerance Considerations

.. . .. . ... . ....................................... . ........................ . ... . .............. 10

2.2.1 Enforcement Analytical Method

.......................................... .. ....... .. .. . ................... 10

2.2.2 International Harmonization

................ . .. . .... . .................. . .... . .. .. ....... . ........ . ........... 10

2

. 2.3 Recommended Tolerances

. .. .. .. ... . . ...... . ................. . ... .. . . ........ . ................ . ................ 10

2.2.4 Revisions to Petitioned-For Tolerances

.. .. .. ... . ... . ............ . ....... . ... . . ... ... .. .. .. ............ 12

2

. 3 Label Recommendations

... . .. .. . ....... . .. .. ... . .. .. ... . . ... .. ... . ... . .. ... . ... . ... . ....... .. .. . .... . . . . . ... .. . . . . ... . 12

3

. 0 Introduc

· tion ...•

. . . ... . .. . ... . . ... . .. ... . ......... . . . ... . .. .. .. . ... .. .. .. .. .. .. .. ... . .. . ....... . . . .. ... . •..

. . ... .. .. .. .... . ........ 12

3.1 Chemical Identity

... . .. . ........................... . . . . . ........... . ... . ................ . .. .. .. .. ....... . .. . . .... . ......... 12

3.2 Physical/Chemical Characteristics

.. . .... .. ............ .. ... . ............ . ....... . . . . . . ... .. . .. . . . .... . .. .. ... .. . 13

3.3 Pesticide U se Patter

· n

. . . .. ... . ............... . .. .... ... .. ....... . ....................... .. .. •.

....... . ....... . ............ 14

3

. 3.1 Registered Products

.. . .................•.

. .. . .... . .. . .... . ... . .................... . . . ..... . ... . ..... .. ...... .. ..... 14

3

. 3.2 Proposed New Uses

. .. .. .. .. . .......... .. ............ . ................................................. . ........... . 14

3.4 Anticipated Exposure Pathways

. . .. . ... .. . ... ... . .. .. .. ....... . ...... .. •.

.. .. .. .. .. ... . . .... ... . ... . .. . .... .. .. ... 15

3.5 Considerations of Environmental Justice

. .. . . .... . ... . ............ . .. . ... ... . .. .. . .... .. . ... ... . ............ 15

4.0 Hazard Characterization and Dose

- Response Assessment

. .................... . ... . .. . ............. . 15

4.1 Toxicology Studies Available for Analysis

..... . .. . .. .. . ..... . .. .. . .. ... .. ....... . ... .•

. •..

.. .. . .... .. . ..... 15

4

. 2 Absorption, Distribution, Metabolism and Excretion

.. . . . .. . .... .... .... . .... . . .. ... .. .. .. .. . . . . . .. . 16

4.2.1 Dermal Absorption

... . .. . ............ . ............................... .. ...... . . . . •....

..... . ....... . ... . ... .. .. .. ... .. . 16

4.3 Toxicological Effects

.. .. . .... •

.. .. .. .. .. .. .. •. •...........

.. .... .. .. .. .. .. .. ...... ... . .. .. .. .. ... . . .... . .... . .. ... •

. .. .... 16

4.4 Safety Factor for Infants and Children ( F QP A Safety F actor)

........ . .. . . . .. . . . . .. ... . ....... 17

4.4.1 Completeness of the Toxicology Database

. .. ......................................................... 17

4.4.2 Evidence of Neurotoxicity

.......... . ..... . . .. .......... . ............. . ............................ . ... . .. ... ... 18

4

. 4.3 Evidence of Sens i tivity/Susceptibility in the Developing or Young Animal •

... .. 18

4.4.4 Residual Uncertainty in the Exposure Database

.. . .. .. .. .. .. . ........ . .. .. .. . . . ... . ... .. ......... 18

4.5 Toxicity Endpoint and Point of Departure

. .. •..

. .. .. . ... ... . .. . ....... . . . .. •.

... . .. .. ... . .. . .. .. . . .. ... ... . 18

4

. 5

. 1 Dose-

_ Response Assessment

. . . .. . ...**~** .. . .. . .... . .. .. .. ... . .. ... . .. .. ..... . .. . . .. .... .. ....... . .. .. ...... . ....... 18

4.5.2 Recommendations for Combining Exposure Routes

........... . ............... . .... . ... . . .... . 19

4.5.3 Classification of Carcinogenic Potential

........................................................ . .... . . 1 9

4.5.4 Summary of Points of Departure Used in Risk Assessment

.. . ....... . ... . ........... ..... 20

5.0 Dietary Exposure and Risk Assessment

........ . . .. ... . .. .. ....... . ....... . ...... . .... •

.... . ................ .. .. . 23

5.1 Metabolite/Degradate Residue Profile

.. ... .. . .. ....... .. . .. ..... . .................. •

....... . ................ . . 23

Pa g e 2 of66Page 3 of 66

5.1.1 Summary of Plant and Animal Metabolism Studies

................................ ............... 23

5.1.2 Summary of Environmental Degradation

................................ ................................ 23

5.1.3 Comparison of Metabolic Pathways

................................ ................................ ......... 23

5.1.4 Residues of Concern Summary and Rationale

................................ ........................ 24

5.2 Food Residue Profile

................................ ................................ ................................ ..... 24

5.3 Water Residue Profile

................................ ................................ ................................ ... 26

5.4 Di etary Risk Assessment

................................ ................................ ............................... 27

5.4.1 Description of Residue Data Used in Dietary Assessment

................................ ...... 27

5.4.2 Percent Crop Treated Used in Dietary Assessment

................................ ................ 27

5.4.3 Acute Dietary Risk Assessment

................................ ................................ ................. 27

5.4.4 Chronic Dietary Risk Assessment

................................ ................................ ............. 27

5.4.5 Cancer Dietary Risk Assessment

................................ ................................ .............. 28

5.4.6 Summary Table

................................ ................................ ................................ .......... 28

6.0 Residential (Non

- Occupational) Exposure/Risk Characterization

.............................. 29

6.1 Residential Bystander Post

- application Inhalation Exposure

................................ ... 29

6.2 Spray Drift

................................ ................................ ................................ ...................... 29

7.0 Aggregate Exposure/Risk Characterization

................................ ................................ ... 30

7.1 Acute & Chronic Aggregate Risk

................................ ................................ ................. 30

7.2 Short

- and Intermediate

- Term Aggregate Risk

................................ ......................... 30

8.0 Cumulative Exposure/Risk Characterization

................................ ................................ 30

9.0 Occupational Exposure/Risk Characterization

................................ ............................. 31

9.1 Exposure Scenarios

................................ ................................ ................................ ....... 31

9.2 Hand ler Exposure

................................ ................................ ................................ .......... 31

9.2.1 Handler Exposure Scenarios

................................ ................................ .................. 31

9.2.2 Handler Exposure Data

................................ ................................ .......................... 32

9.2. 3 Handler Exposure Assumptions

................................ ................................ ............ 33

9.2.4 Handler Exposure and Risk Estimates

................................ ................................ . 35

9.3 Post Application Exposure

................................ ................................ ............................ 38

9.3.1 Post Application Inhalation Exposure Scenarios

................................ ................. 38

9.3.2 Post Application Dermal Exposure Assumptions

................................ ................ 39

9.3.3 Post

- Application Exposure and Risk Estimates

................................ ................... 41

10. REFERENCES

................................ ................................ ................................ .................. 43

APPENDIX A TOXICOLOGY DATA SUMMARY

................................ ........................... 44

A.1 Guideline Data Requirements

................................ ................................ ................ 44Page 4 of 66

A.2 Toxicity Profiles

................................ ................................ ................................ ............. 45

A.3 Toxicological Endpoints

................................ ................................ ................................ 45

A.4 Executive Summaries

................................ ................................ ................................ .... 53

APPENDIX B. Chemical Names And Structures Of Diflubenzuron and Metabolites

....... 65

APPENDIX C. Physical/Chemical Properties

................................ ................................ .......... 66

APPENDIX D. Studies Reviewed for Ethical Conduct

................................ .......................... 66Page 5 of 66

1.0 EXECUTIVE SUMMARY

This document addresses the exposures and risks associated with exposures from currently registered uses and the proposed amended use of diflubenzuron . It also assesses potential enhanced sensitivity of infants and children from dietary and/or residential exposure as required under the Food Quality Protection Act (FQPA) of 1996.

Under PP# 2F 8015

, Chemtura Corporation is proposing to expand the use of diflubenzuron to

include all members of the citrus crop group 10

- 10

. Chemtura also requests a decrease in the retreatment interval from 90 to 30 days, and a decrease in the pre

- harvest (PHI) interval from 21 to 7 days.

In addition to the petition, separate submissions were made for Diflubenzuron 90% Concentrate (EPA Reg No. 400

- 466) to allow formulation into products for use on citrus, including low volume application (D403089), and for Dimilin 2L (2 lb/gal Flowable; EPA Reg. No. 400

- 461; D403090) at the rate of 0.156 lb ai/A, not to exceed 0.47 lb ai/A/season. The same restrictions are on this label, as well as the recommendation to add a petroleum spray oil, except for the minimum aerial spray volume of 3 gal/A (10 gal/A in CA). A separate amendment request for Micromite 80 WGS (EPA Reg No 400

- 487), requests an aerial spray volume of 3 gal/A (D403088).

Use Profile

Diflubenzuron, ( N

- [((4

- chlorophenyl) amino) carbonyl]

- 2, 6

- difluorobenzimide), a member of

the urea

- derivative chemical family, is classified as an insect growth regulator and is used as

both an acar i cide and insecticide. It is currently registered in the U.S. for use as a chitin inhibitor, which promotes an inability of immature insects to synthesi ze chitin to form a hard exoskeleton prevents development from the immature to the juvenile and adult stages. The main agriculture pests targeted for control with diflubenzuron are the twig borer ; stink bug ; grasshopper ; beet

armyworm ; soybean looper ; rust mite ; artichoke plume moth ; citrus leafminer; citrus root weevil; asian citrus psyllid; katydids, and peanuts root know nematode. Tolerances for diflubenzuron, currently established under 40 CFR §180.377, range from 0.05

- 55 ppm.

The chemical stru cture and nomenclature of diflubenzuron and its regulated metabolites are presented in Appendix B . The physicochemical properties of the technical grade of diflubenzuron are presented in Appendix C

.

Occupational application methods include

, aerial; groun dboom; airblast; chemigation; and pressurized handguns used for low and high volume applications. (i.e., low

- pressure handwand, handgun sprayer, backpack sprayer). Also, it is applied by hand (granular), through bait stati ons, and feed through systems. Dif lubenzuron is applied to numerous crops across 16 EPA crop group categories, and to agricultural non

- crop sites including livestock barns; agricultural structures and equipment. Residential applications are made with handheld equipment , however

Chemtura C orp. has maintained that all residential uses are obsolete and to be removed from all

labels.Page 6 of 66

Proposed New Uses

Chemtura Corporation has submitted an application for the registration of products containing

diflubenzuron for an amended use on fruit citr us (crop group 10

- 10) . The products are manufactured by Chemtura Agro

- Solutions , Inc. under the trade name Micromite 80WG ®

Insecticide (EPA Reg. No. 400

- 487 ) , and Dimilin ® 2LInsecti cide (EPA Reg. No. 400

- 461 )

. Occupational application methods include ; aerial; airblast and chemigation

. Chemtura is amending the use by lowering the pr e

- harvest interval (PHI) from 90 to 7 days for fru it citrus, (crop group 10

- 09). REI is 12 hours. The amended use is not proposed for residential use and residential exposu res are not expected based on the proposed uses.

The acute oral, dermal and inhalation toxicity of diflubenzuron is low. It is a mild eye irritant and not a skin irritant in laboratory animals. It is negative for sensitization in the guinea pig. In

sub chronic and chronic feeding studies, the primary endpoint of concern was methemoglobinemia and/or sulfhemoglobinemia. These effects were evident in both sexes of mice, rats, and dogs and were produced by more than one route of administration in rats [i.e.

, oral, dermal and inhalation]. The general consequence of methemoglobinemia and/or sulfhemoglobinemia is the impairment of the oxygen transportation capacity of the blood, which is generally known to be caused by aromatic amines in both humans and animal s.

The overall toxicology database is sufficient for a determination of potential hazard to infants and children. The data provide no indication of an increased susceptibility to rats or to rabbits

from in utero or post

- natal exposure to diflubenzuron. Developmental and reproduction studies in rats and rabbits indicate a very low hazard potential for adverse effects. Developmental studies were tested at the limit dose of 1000 mg/kg/day without apparent effects in both dams and the fetuses. The reprodu ction study indicated that effects in offspring occurred at doses that were higher than the doses producing effects in parents. There was no indication of

abnormalities in fetal development in the prenatal developmental toxicity studies in either rats or rabbits at the maternal limit doses of 1000 mg/kg/day. In addition, there was no evidence of sensitivity following pre

- and/or post

- natal exposure in a two

- generation reproduction study in

rats. The acute and subchronic neurotoxicity studies were recentl y waived by HASPOC (TXR

0056309 ) based on a weight of evidence approach. The recently submitted immunotoxicity study has been reviewed and immunotoxicity was not observed above the limit dose.

Dose Response Assessment

Toxicological endpoints were selected for dietary/drinking water, occupational and residential exposure scenarios. Acute and chronic points of departure (PODs) were selected for assessment of food and drinking water exposures. No appropriate acute endpoi nt was identified in the hazard database to quantitate the risk to the general population or to females 13

- 50 years old from single dose administration of diflubenzuron. Therefore, there is no acute reference dose (aRfD) or acute population

- adjusted dose (aPAD). A chronic/cancer POD for the general population was selected from a chronic toxicity study in dog . Short and intermediate

- term occupational exposures via the dermal and inhalation routes may occur based on the use pattern

and label directions. T oxicological endpoint for the short

- term dermal scenario was selected

from a 21

- day rat dermal study and intermediate

- term dermal endpoint was selected from a 13

- week oral (capsule) study in the dog

. The short

- and intermediate

- term inhalation endpointsPage 7 of 66

w ere selected from a 28

- day rat inhalation toxicity study. An uncertainty factor of 100X was applied to endpoints selected for all exposure routes ( 10X for interspecies extrapolation, 10X for intraspecies variation).

The HED RfD/Peer Review Committee c lassified diflubenzuron as “ Group E ,” evidence of non

carcinogenicity for humans, based on lack of evidence of carcinogenicity in rats and mice (April 27, 1995). PCA, a metabolite of diflubenzuron, tested positive for splenic tumors in male rats and hepat ocellular adenomas/carcinomas in male mice in a National Toxicology Program (NTP) study. Therefore, the RfD/Peer Review Committee classified PCA as a “ Group B2 " probable human carcinogen. However, recently submitted acceptable rat metabolism studies show that

diflubenzuron was not metabolized to either PCA or CPU. On May 8, 2001 (D 272976 ) , the MARC reviewed the recently submitted metabolism studies, accepted the study findings, and

concluded that cancer risks for CPU and PCA should be assessed individual ly. However, the

non

- cancer toxicities of CPU and PCA are well understood. CPU is less toxic and does not cause methemoglobin formation while PCA is similar in potency as diflubenzuron. Therefore, including the metabolites in the assessment is health prot ective. Additional toxicity data on these metabolites are not required.

Exposure/Risk Assessment and Risk Characterization

The chronic assessment assumed that diflubenzuron residues are present in all commodities at

established/recommended tolerance levels except for orange, grapefruit, and lemon where average field trial residues were used and that 100% of all crops are treat ed. For the chronic non

cancer dietary exposure analysis, d rinking water was incorporated directly into the dietary assessment using the estimated drinking water concentration (EDWC) for surface water of 12.8 ppb generated by the Pesticide Root Zone Model/ Exposure Analysis Modeling System (PRZM/ EXAMS) with index reservoir (IR) scenarios and percent crop area (PCA) adjustment

factors. The highest annual mean EDWCs for diflubenzuron (0.26 μg /L ) and CPU (12.52 μg /L ) were combined (12.8 μg /L ) to assess chronic non

- cancer dietary risk For the CPU cancer dietary exposure analysis an EDWC of 8.81 ppb was incorporated.

The resulting chronic dietary

- exposure estimates for combined food and drinking water are below HED’s LOC (i.e., <100% of the cPAD of 0.02 mg/kg bw/day) for the overall U.S. population and all population subgroups. Using the Dietary Exposure Evaluation Model software with the Food Commodity Intake Database (DEEM

- FCID ) software, dietary exposure is estimated to be ≤37% of the cPAD for the U. S. population and all population subgroups, including children 1 to 2 years old, the population subgroup with the highest estimated exposure.

The cancer assessment for PCA includes food only. For PCA, the cancer dietary exposure estimate for the U.S. pop ulation is 1 x 10 - 6

. The cancer assessment for CPU includes milk and water only. The cancer chronic EDWC in surface water for CPU is 8.81 ppb. For CPU, the cancer dietary exposure estimate for the U.S. population is 3 x 10 - 6

.

Although there are no regi stered homeowner uses, there are registered uses for professional applications to outdoor residential and recreational areas to control mosquitoes, moths, and otherPage 8 of 66

insects. However, the potential for post

- application residential exposure is expected to b e limited. Due to the low intermediate

- term dermal absorption rate (0.5%) of diflubenzuron, and since it is only applied to the tree canopy, minimal bystander contact is expected.

Based upon the proposed use patterns, short

- term (1

- 30 days) dermal and in halation exposures are typically expected for commercial and private (i.e., grower) pesticide mixers, loaders, and applicators. The toxicological endpoints for short

- term dermal and short

- term inhalation effects were derived from two different studies; ho wever, both studies indicate similar toxicological effects (i.e., methemoglobinemia). Since the results of the two studies indicate similar toxicological effects, the MOEs are shown as combined MOEs. HED’s level of concern (LOC) is a margin of exposure ( MOE) <100.

No chemical

- specific data were available with which to assess potential exposure to pesticide handlers. Therefore, the exposure and risk estimates presented in this document are based upon surrogate data in the Pesticide Handlers Exposure Data base (PHED) Ver. 1.1, Surrogate Exposure Guide (August 1998). Occupational exposures are assessed for pesticide handlers (i.e., mixers, loaders, applicators and flaggers) for agricultural workers. Intermediate

- term MOEs range from 460 for mixer/loader s u sing protective gloves to 7,200 for airblast mixer and loaders using protective gloves

. For occupational exposures, t he MOEs do not exceed HED’s LOC and

therefore not of concern.

A conservative, screening

- level assessment of intermediate

- term post

- appl ication exposure to agricultural workers y ields MOEs of 350 on “ Day after Treatment ( DAT ) 0” and 430 on “DAT 1” for hand harvesting citrus fruit. However a PHI of 7 day is stipulated on labels (EPA Reg

No.: 400

- 461, and 400

- 487). For the most conservative intermediate post

- application exposure scenario, MOEs at DAT 7 = 10,000; do not exceed HED's LOC and therefore not of concern.

Aggregate exposure risk assessments were assessed by incorporating the drinking water directly into the dietary

- exp osure assessment for the following scenario: chronic aggregate exposure (food + drinking water). Short

- , intermediate

- , and long

- term aggregate

- risk assessments were not performed because there are no registered or proposed uses of diflubenzuron which re sult in residential exposures. Acute and cancer aggregate

- risk assessments were not performed because no appropriate endpoint was available to determine the aRfD for the general population or any population subgroup and diflubenzuron is not carcinogenic.

Use of Human Studies

This risk assessment relies in part on data from studies in which adult human subjects were intentionally exposed to a pesticide or other chemical. These studies were determined to require a review of their ethical conduct, have received that review and have been determined to be

ethical.

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 12 898, "Federal Actions to Address Environmental Justice in Minority Populations and Low

- Income Populations,"Page 9 of 66

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

As a part of every pesticide risk assessment, OPP considers a large variety of consumer subgroups according to well

- established procedures. In line with OPP policy, HED estimates risks to population subgroups from pesticide exposures that are based on 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 post

- application are evaluated. Further considerations are currently in development, as OPP has committed resources and expertise to the development of specialized s oftware and models that consider exposure to bystanders and farm workers as well as lifestyle and traditional dietary patterns among specific subgroups.

Tolerance Recommendation

Pending submission of a revised Section F (see requirements under Proposed Tolerances), there are no residue chemistry issues that would preclude granting an amended Section 3 registration for the requested amended use of diflubenzuron on Crop Group 10

- 10 , or establishment of the following tolerances for residues of diflubenzuro n.

Fruit, c itrus

, g roup 10

- 10

................................ ..................... 3.0 ppm Citrus, oil

................................ ................................ ............... 32 ppm

The Codex Alimentarius has established maximum residue limits (MRL), expressed in terms of

diflubenzuron per se , for many commodities including: citrus fruits (0.5 ppm). As the U.S.

residue def

inition includes CPU and PCA, compatibility is not possible with the proposed tolerances. Numerical compatibility with CODEX is not possible as the Good Agricultural Practices ( GAP ) used for the CODEX MRL is different from the proposed use pattern in the US.

2.0 HED Recommendations

2.1 Data Deficiencies/Conditions of Registration

HED can recommend for registration and permanent tolerances for the proposed amended uses of diflubenzuron

.

The amendments for Micromite 80 WGS (EPA Reg No 400

- 487) and Dimilin 2L Concentrate (EPA Reg No. 400

- 461) are acceptable. The amendment for Diflubenzuron 90% Concentrate (EPA Reg No. 400

- 466) to allow formulation into products for use on citrus, including low volume application is acceptable, providing that the formulations to be used are limited to WDG and FlC formulations, at the same rates proposed here for the respective formulations.

Deficiencies are stated below. The specific tole rance recommendations are discussed in Section 2.2, and label modifications are discussed in Section 2.3.Page 10 of 66

Note to PM:

Revised Section F required. Analytical reference standard for diflubenzuron metabolite 13

- C

- PCA is expired (expired 11/7/2004), and must be replaced

.

2.2 Tolerance Considerations

2.2.1 Enforcement Analytical Method

Three enforcement methods for diflubenzuron are published in the Pesticide Analytical Manual (PAM, Vol. II) as Methods I, II, and III. Method I is a GC/ECD method that determines diflubenzuron in plants as derivatized PCA. Method II is a GC/ECD method th at can separately determine residues of diflubenzuron, CPU and PCA in eggs, milk, and livestock tissues, each as derivatized PCA. Method III is a high

- performance liquid chromatography/ultraviolet (HPLC/UV) method that determines diflubenzuron per se in e ggs, milk, and livestock tissues. All three methods have undergone successful Agency validations. The Diflubenzuron RED stated that Methods I and II are the preferred enforcement methods because they are easier to perform, have less interference, and are more sensitive.

In conjunction with PP#8F4925 on rice, a new analytical methodology for plant commodities was successfully validated by an independent laboratory as well as by Agency chemists at ACB/BEAD, and was forwarded to FDA for publication in PAM V ol. II as Roman Numeral Methods. These methods can separately determine residues of diflubenzuron by GC/ECD, CPU by GC/ECD, and PCA by GC/MS using an isotopically labeled internal standard and by summing the response of the two ions. The reported LOQ for diflubenzuron in/on rice grain, straw, and bran is 0.01 ppm, and is 0.05 ppm in/on rice hull. In rice straw, the LOQ for CPU is 0.01 ppm and 0.005 ppm for PCA.

2.2.2 International Harmonization

The Codex Alimentarius has established maximum residue limits (MRL), expressed in terms of

diflubenzuron per se , for many commodities including: citrus fruits (0.5 ppm). As the U.S. residue definition includes CPU and PCA, compatibility is not possible w ith the proposed tolerances. Numerical compatibility with CODEX is not possible as the GAP used for the CODEX MRL is different from the proposed use pattern in the US.

2.2.3 Recommended Tolerances

The tolerance expression for 40 CFR 180.377 (a)(1) shou ld read:

Tolerances are established for residues of d iflubenzuron , including its metabolites and degradates, in or on the commodities in the table below. Compliance with the tolerance levels specified below is to be determined by measuring only d iflubenz uron ( N

- [[(4

- chlorophenyl)amino]carbonyl]

- 2,6

- difluorobenzamide).Page 11 of 66

The tolerance expression for 40 CFR 180.377 (a)(2) should read:

Tolerances are established for residues of the insecticide d iflubenzuron ( N

- [[(4

- chlorophenyl)amino]carbonyl]

- 2,6

- difluorobenzamide) , in or on the commodities in the table below. Compliance with the tolerance levels specified below is to be determined by measuring only the sum of d iflubenzuron ( N

- [[(4

- chlorophenyl)amino]carbon yl]

- 2,6

- difluorobenzamide),

4

- chlorophenylyurea and 4

- chloroaniline , calculated as the stoichiometric equivalent of

diflubenzuron , in or on the commodity.

The tolerance expression for 40 CFR 180.377 (b) should read:

Time

- limited tolerances are established for of the insecticide diflubenzuron, (N

- [[(4

- chlorophenyl)amino]carbonyl]

- 2,6

- difluorobenzamide and its metabolites, in connection with use of the pesticide under section 18 emergency exemptions granted by EPA. Compliance with

the tolerance levels specified below is to be determined by measuring only the sum of diflubenzuron ( N

- [[(4

- chlorophenyl)amino]carbonyl]

- 2,6

- difluorobenzamide), 4

- chlorophenylyurea and 4

- chloroaniline, calculated as the stoichiometric equivalent of diflubenzuron, in or on the commodity. The tolerances are specified in the following table, and will expire and are revoked on the dates specified.

A revised Section F is needed to specify that the tolerances are to be set in 40 CFR 180.377 (a)(2). The proposed commoditie s and tolerance levels need to be revised to Pending submission of revised Section F, there are no residue chemistry issues that would preclude granting registration for the requested amended use of diflubenzuron

. Available data support the following tolerances under 40 CFR 180. 4 70 for residues of diflubenzuron in/on the following raw agricultural commodities:

Fruit, c itrus

, g roup 10

- 10 ........................................................3.0 ppm Citrus, oil...........................................................................32 ppm

Adequate c rop field trial data reflecting the proposed use patterns were submitted for purposes of establishing tolerances on the requested amended use. The Organization for Economic Cooperation and Development tolerance calculation procedures were utilized in dete rmining the appropriate tolerance level for the requested amended use . Changes in recommended tolerance are based on the use of these calculation procedures and are shown in Table 1.

The proposed and recommended tolerances for diflubenzuron as a result o f the subject action are presented in the table below

.Page 12 of 66

Table 2.2.3 . Tolerance Summary for Diflubenzuron.

Commodity Proposed Tolerance (ppm) Recommended

Tolerance (ppm) Comments;

[Correct Commodity Definition]

Tolerances Proposed in PP#2F8015

Citrus, Group 10

- 10 1.3 3.0 Fruit, citrus

, group 10

- 10

Recommended tolerance from OECD

calculator

Citrus Oil 39 32 Citrus, oil HAFT of 0.54 ppm multiplied by 55x

concentration factor.

2.2.4 Revisions to Petitioned

- For Tolerances

Revised Section F, proposing the following tolerances

Fruit, c itrus

, g roup 10

- 10

........................................................ 3.0 ppm Citrus, oil ...........................................................................32 ppm

2.3 Label Recommendations

A statement must be added to diflubenzuron labels stating “Not For Homeowner Use”

.

Flowable concentrates are considered comparable to a wettable granular formulation. Additionally, the proposed rate for the flowable formulation is lower than that for the WDG formulation. The petitioner/registrant should be reminded t hat each formulation to be used must be properly supported by residue data.

3 .0 Introduction

3.1 Chemical Identity

Structure and nomenclature are reported in Table 3.1

.Page 13 of 66

TABLE 3.1

. Diflubenzuron Nomenclature.
Compound

Common Name Diflubenzuron

Trade and other Names Dimilin, Vigilante, Micromite, Adept

IUPAC Name 1

- (4

- chlorophenyl)

- 3

- (2,6

- difluorobenzoyl)urea

CAS Name N

- [[(4

- chlorophenyl)amino]carbonyl]

- 2,6

- difluorobenzamide CAS Registry Number 35367

- 38

- 5

End

- Use Products (EP) 2 lb/gal FlC formulation; DIMILIN ® 2L (EPA Reg. No. 400

- 461); 25% WP formulation; DIMILIN ® 25W (EPA Reg. No. 400

- 465); 80% G formulation; Micromite ® 80WGS (EPA Reg. No. 400

- 487); Regulated Metabolite

Common name 4

- chlorophenylurea (CPU) Regulated Metabolite

Common Name 4

- chloroaniline (PCA)

3.2 Physical/Chemical Characteristics

The physicochemical properties of diflubenzuron are reported in Appendix C.

TABLE 3.2 Physicochemical Properties of Diflubenzuron.

Parameter Value Reference
Melting range 230

- 232 °C http://www.arsusda.gov/acsl/ services/ppdb/textfiles/DIFL

UBENZURON pH Not available Density Not available Water solubility (25 °C) 0.08 ppm Solvent solubility (25 °C) (ppm) 6.5 x 10 3 Acetone

2 x 10 3 Acetonitrile

2.4 x 10 4 Dioxane

1.04 x 10 5 Dimethylformamide

1.2 x 10 5 Dimethylsulfoxide

1 x 10 3 Methanol

6 x 10 2 Dichloromethane Vapor pressure (25 °C) 1.2 x 10
- 4 mPa Dissociation constant, pK

a Not available Octanol/water partition coefficient, Log(K OW ) 3.89Page 14 of 66

3.3 Pesticide Use Pattern

3.3.1 Registered Products

There are 78 active diflubenzuron registrations, 40 Section 3s

, 5 Section 18s, 9 EUPs

, and 24 SLNs (24(c)s )

.

3.3.2 Proposed New Uses

A summary of the proposed end

- use products and summary of proposed use patterns are listed

below.

Table 3.3.2.1 Summary of Proposed End

- Use Products

.

Trade Name Reg. No. % ai (formulation) Formulation

Type Target New

Crops Target Pests Label

Date

Micromite ®

80WGS 400

- 487 80% Water

dispersible granule Citrus Fruit

group (10

- 10) Citrus rust mite, Lepidopterous

miners, and citrus root weevil

complex Undated

specimen

label
Dimilin ® 2L 400

- 461 22% Flowable

Concentrate

Table 3.3.2.2 . Summary of Proposed Directions for Use of Diflubenzuron.

Applic. Timing, Type, Equipment. Formulation [EPA Reg. No.] Applic. Rate

(lb ai/A) Max. No. Applic.

per Season Max. Seasonal

Applic. Rate (lb ai/A) PHI

(days)

Citrus

Foliar Aerial (3

- 20 GPA) Ground (50

- 1,000 GPA) ( A irblast, and

C hemigation) Use Directions and Limitations: Maintain a minimum of 30 days between applications, except where split applications are used. Do not harvest cover crops for livestock feed or graze livestock in treated groves. The addition of a petroleum spray oil is recommended. Reentry

interval of 12 hours.

80% WGS [400

- 487] 0.3125 3 0.9375 (max yearly rate) 7

2 lb/gal FlC 0.156 3 0.47 7

Although not included in the petition, separate submissions were made for Diflubenzuron 90% Concentrate (EPA Reg No. 400

- 466) to allow formulation into products for use on citrus, and for Dimilin 2L (2 lb/gal Flowable) at the rate of 0.156 lb ai/A, not to exceed 0.47 lb ai/A/season. The same restrictions are on this label, as well as the recommendation to add a petroleum spray oil, except for the minimum aerial spray volume of 3 gal/A (10 gal/A in CA). A sepa rate amendment request for Micromite 80 WGS requests an aerial spray volume of 3 gal/A.

Conclusions . The submitted labels are adequate to allow evaluation of the residue data relative to the proposed uses. The additional amended uses will be acceptable once the tolerances are established. Flowable concentrates are considered comparable to a wettable granularPage 15 of 66

formulation. Additionally, the proposed rate for the flowable formulation is lower than that for the WDG formulation. The petitioner/registrant s hould be reminded that each formulation to be used must be properly supported by residue data.

3.4 Anticipated Exposure Pathways

The Registration Division has requested an assessment of human health risk to support the proposed amended use of diflubenzu ron on the remaining commodities in the citrus fruit subgroup . For domestic uses, humans may be exposed to diflubenzuron in food and drinking water, since diflubenzuron may be applied directly to growing crops and application may result

in diflubenzuron r eaching surface and ground water sources of drinking water. There are no residential uses of diflubenzuron

. In an occupational setting, applicators may be exposed while handling the pesticide prior to application, as well as during application. There is a potential for

post

- application exposure for workers re

- entering treated fields.

Risk assessments have be en previously prepared for the existing uses of diflubenzuron . This risk assessment considers all of the aforementioned exposure pathways based on the proposed new

uses of diflubenzuron , but also considers the existing uses as well, particularly for the d ietary

exposure assessment.

3.5 Considerations of Environmental Justice

Potential areas of environmental justice concerns, to the extent possible, were considered in this human health risk assessment, in accordance with U.S. Executive Order 12898, "Feder al Actions to Address Environmental Justice in Minority Populations and Low

- Income Populations," http://www.eh.doe.gov/oepa/guidance/justice/eo12898.pdf ).

As a part of every pesticide r isk assessment, OPP considers a large variety of consumer subgroups according to well

- established procedures. In line with OPP policy, HED estimates risks to population subgroups from pesticide exposures that are based on patterns of that subgroup’s food and water consumption, and activities in and around the home that involve pesticide use in a residential setting. Whenever appropriate, non

- dietary exposures based on home use of pesticide products and associated risks for adult applicators and for toddle rs, youths, and adults entering or playing on treated areas postapplication are evaluated. Further considerations are currently in development, as OPP has committed resources and expertise to the development of specialized software and models that conside r exposure to bystanders and farm workers as well as lifestyle and traditional dietary patterns among specific subgroups.

4.0 Hazard Characterization and Dose

- Response Assessment

4. 1 Toxicology Studies Available for Analysis

The overall toxicology database is sufficient for a determination of potential hazard to infants and children. The data provide no indication of an increased susceptibility to rats or to rabbits

from in utero or post

- natal exposure to diflubenzuron. Deve lopmental and reproduction studies in rats and rabbits indicate a very low hazard potential for adverse effects. DevelopmentalPage 16 of 66

studies were tested at the limit dose of 1000 mg/kg/day without apparent effects in both dams and the fetuses. The reproduction study indicated that effects in offspring occurred at doses that were higher than the doses producing effects in parents. There was no indication of abnormalities in the develop ing fet us in the prenatal developmental toxicity studies in either rats

or ra bbits at maternal limit doses of 1000 mg/kg/day. In addition, there was no evidence of sensitivity following pre

- and/or post

- natal exposure in a two

- generation reproduction rat study. The acute and subchronic neurotoxicity studies were recently waived by HASPOC (TXR

0056309 ) based on a weight of evidence approach. The recently submitted immunotoxicity study has been reviewed and immunotoxicity was not observed above the limit dose.

4.2 Absorption, Distribution, Metabolism and Excretion

R at metaboli sm data (MRID#s 44875501 and 44875502) indicate that diflubenzuron does not

metabolize to PCA or CPU nor is CPU converted to PCA. The HED MARC met several times (02/20/2001 and 05/8/2001), concurred with the study findings, and concluded that a 2% in vivo conversion factor for diflubenzuron to PCA or CPU should be dropped (MARC memo, 05/31/2001). Based on the toxicity observed only at higher doses in the NTP studies for both

CPU and PCA

, additional CPU and PCA toxicity data are not needed. The toxicity of CPA and PCA will be considered equal to diflubenzuron for the non

- cancer risk assessment. T he MARC

recommended that non

- carcinogenic risk assessment include parent, CPU and PCA.

4.2.1 Dermal Absorption

Sprague

- Dawley rats were given 0.005 or 0.05 mg/cm. sq. of C

- 14 diflubenzuron technical in gum tragacanth [0.25%]. Systemic absorption was less than 0.5% at each time interval regardless of the dose. Approximately 4.7

- 6.2% diflubenzuron was bound to the skin at the application

site. A Dermal Absorption F actor of 0.5 % was determined.

4.3 Toxicological Effects

For diflubenzuron, t he hemopoietic system is the target site with effects including increased sulfhemoglobin and/or methemoglobin levels in rat and dog studies. The non

- cancer endpoints

from diflub enzuron are protective of the non

- cancer toxicity of the metabolites, CPU and PCA. The toxicity of CPA is well understood (WHO 2003) with the primary effect methemoglobin

formation. High doses in the NTP study with CPU did not show methemoglobin formatio n. Therefore, additional studies with CPU and PCA are not required.

The acute oral, dermal and inhalation toxicity of diflubenzuron is low. It is a mild eye irritant and not a skin irritant in laboratory animals. It is negative for sensitization in the guinea pig. In subchronic and chronic feeding studies, the primary endpoint of concern was methemoglobinemia and/or sulfhemoglobinemia. These effects were evident in both sexes of mice, rats, and dogs and were produced by more than one route of administr ation in rats [i.e., oral, dermal and inhalation]. The general consequence of methemoglobinemia and/or sulfhemoglobinemia is the impairment of the oxygen transportation capacity of the blood, which is generally known to be caused by aromatic amines in bot h humans and animals.Page 17 of 66

No appropriate acute endpoint was identified in the hazard database to quantitate the risk to the general population or to females 13

- 50 years old from single dose administration of diflubenzuron. Therefore, there is no aRfD or acute population

- adjusted d ose (aPAD). The

short

- term dermal endpoint was selected from a 21

- day rat dermal study with a NOAEL of 500 mg/kg/day based on a significant increase in methemoglobinemia observed at the lowest

observed

- adverse

- effect level (LOAEL) of 1000 mg/kg/day. The intermediate

- term dermal endpoint was selected from a 13

- week oral (capsule) study in the dog with a NOAEL of 2 mg/kg/day based on increased methemoglobinemia observed at the LOAEL 6.24 mg/kg/day.

The short

- , and intermediate

- term inhalation endpoints wer e selected from a 28

- day rat inhalation toxicity study with a NOAEL of 0.109 mg/L (highest dose tested, HDT), based on a statistically significant increase in methemoglobin levels observed at 0.12 mg/L (LOAEL). The chronic dietary, long

- term dermal and lo ng

- term inhalation endpoints were selected from a chronic dog study with a NOAEL of 2 mg/kg/day based on increased methemoglobin levels observed at 10 mg/kg/day (LOAEL). The cRfD is 0.02 mg/kg/day and the cPAD is 0.02 mg/kg/day.

The HED RfD/Peer Review Committee classified diflubenzuron as “Group E,” evidence of non

carcinogenicity for humans, based on lack of evidence of carcinogenicity in rats and mice (04/27/1995). PCA, a metabolite of diflubenzuron, tested positive for splenic tumors in male rats

a nd hepatocellular adenomas/carcinomas in male mice in a National Toxicology Program (NTP) study. Therefore, the RfD/Peer Review Committee classified PCA as a “Group B2" probable human carcinogen. However, recently submitted acceptable rat metabolism stud ies show that diflubenzuron was not metabolized to either PCA or CPU. On May 8, 2001, the MARC reviewed the recently submitted metabolism studies, accepted the study findings, and concluded that cancer risks for CPU and PCA should be assessed individually

. Based on

m ethemoglobinemia observed only at higher doses in NTP studies for both monuron, similar to CPU and PCA (6 and 18 mg/kg/day, NTP Report No. 351, July 1989 ), additional CPU and PCA toxicity data are not needed. The toxicity of CP U and PCA will be considered equal to

diflubenzuron for the non

- cancer risk assessment. The non

- carcinogenic risk assessment should include diflubenzuron, CPU and P C A.

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

4.4 Safety Factor for Inf ants and Children (FQPA Safety Factor)

The FQPA may be reduced to 1x based on recently waived neurotoxicity studies and the lack of sensitivity in the database.

4.4.1 Completeness of the Toxicology Database

The toxicological database for diflubenzuron is adequate for the purpose of this risk assessment. Adequate data are available for diflubenzuron as well as CPU and P C A. Specifically, the current

diflubenzuron non

- cancer endpoint for methemoglobinia is pr otective of the toxicity observed at higher doses in the NTP cancer studies conducted with either CPU or PCA. Based on a WOE approach considering all the available diflubenzuron hazard and exposure informati on, the

HASPOC concluded that an acute and subchr onic neurotoxicity study are not required at thisPage 18 of 66

time ( 6 / 7 /12

, TXR #: 00563 09 ). Furthermore, an acceptable immunotoxicity study has been submitted and reviewed by the Agency (TXR 0056396)

.

4.4. 2 Evidence of Neurotoxicity

There are no clear signs of neurotoxicity following subchronic or chronic dosing in multiple species in the diflubenzuron database. The toxicity profile of diflubenzuron shows that the principal toxic effects are the formation of methemoglobinemia and/or sulfhemoglobinemia in

the blood. Based on weight of evidence the acute and subchronic neurotoxicity studies are

waived (HASPOC, TXR 00563 09 ).

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

The toxicology database for diflubenzuron is adequate for FQPA assessment. Based on the available developmental toxicity studies in rats and rabbits, there is no increased susceptibility to fetuses exposed in utero

. The dietary food exposure assessment uses conservative assumptions which result in protectiv e estimates of dietary exposure. The dietary drinking water assessment uses values generated by model and associated modeling parameters which are designed to provide protective, high

- end estimates of water concentrations.

4.4.4 Residual Uncertainty in t he 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

diflu benzuron

.

4.5 Toxicity Endpoint and Point of Departure

4.5.1 Dose

- Response Assessment

Toxicity endpoints and points of departure (PODs) for dietary (food and water), and occupational exposure scenarios are summarized below. A detailed description of the studies used as a basis for the selected endpoints are presented in Appendix A.

No appropriate toxicological endpoint attributable to a single exposure was identified i n the hazard database, including oral developmental toxicity studies in rats and rabbits.

The chronic dog study was used to select the endpoint for establishing the cRfD of 0.02 mg/kg/day. The standard 100x UF was applied to account for interspecies extrapolation and intraspecies variation. The NOAEL of 2.0 mg/kg/day was based on methemoglobinemia and sulfhemoglobinemia seen at 10 mg/kg/day (LOAEL). The FQPA safety factor of 1x is applicab le for chronic dietary risk assessment. Thus, the cPAD is 0.02 mg/kg/day.

Incidental oral endpoints were not selected since t here are no registered or proposed uses of diflubenzuron which result in residential exposure.Page 19 of 66

A short

- term dermal endpoint was s elected from a 21

- day rat dermal toxicity study. The NOAEL of 500 mg/kg/day was based on the significant increase in methemoglobinemia observed at 1000 mg/kg/day (limit dose). This study is route

- specific, is of appropriate duration

and measures the effe cts of concern; i.e., methemoglobin and/or sulfhemoglobin.

An intermediate

- term dermal endpoint was selected from a subchronic oral toxicity dog study. The NOAEL of 2.0 mg/kg/day was based on increased methemoglobinemia at 6.24 mg/kg/day. This endpoint (methemoglobinemia/ sulfhemoglobinemia) was seen consistently in the 90

- day dog study and chronic toxicity studies in rats, mice and dogs at similar dosages and it is appropriate for this exposure period of concern. Since an oral NOAEL was selected for a

dermal

- exposure scenario, a dermal

- absorption factor of 0.5% should be used for this risk assessment when converting dermal exposure to oral equivalents.

A long

- term dermal endpoint was selected from a chronic oral toxicity study in the dog ( see section 3.5.2, above ) . An oral study was selected since no appropriate long

- term dermal study is

available in the database. A 0.5% dermal

- absorption factor should be used to convert to oral equivalents.

Inhalation endpoints were selected from a 28

- day rat inhal ation toxicity study. The NOAEL of 0.109 mg/L (HDT) in the study was based on no effect at highest dose tested

.

A long

- term inhalation endpoint was selected from a chronic oral toxicity dog study, see section 3.5.2, above. An oral study was selected sin ce no appropriate long

- term inhalation study is

available in the database. A 100% inhalation

- absorption factor should be used to convert to oral equivalents.

A MOE of 100 is adequa te for occupational exposure.

4.5.2 Recommendations for Combining Exposure Routes

Aggregate exposure risk assessments were assessed by incorporating the drinking water directly into the dietary

- exposure assessment for the following scenario: chronic aggregate exposure (food + drinking water). Short

- , intermediate

- , and long

- term aggreg ate

- risk assessments were not performed because there are no registered or proposed uses of diflubenzuron which result in residential exposures. Acute and cancer aggregate

- risk assessments were not performed because no appropriate endpoint was available t o determine the aRfD for the general population or any population subgroup and diflubenzuron is not carcinogenic.

4.5.3 Classification of Carcinogenic Potential

Based on the available evidence, w hich included adequate carcinogenicity studies in rats and mice, and battery of negative mutagenicity studies, diflubenzuron was classified as “Group E ,”

evidence of non

- carcinogenicity for humans, by the RfD Peer Review Committee (04/27/1995).

The fol lowing is excerpted from the HED Metabolism Committee Meeting Memorandum of 5/31/01 (D272976).Page 20 of 66

“CPU is the major degradate found in water and is a significant metabolite in milk. CPU is structurally related to monuron (N,N

- dimethyl

- CPU), a compound prod ucing tumors of the kidney and liver in male rats. Given that there is no accepted mechanism of carcinogenicity for monuron and that CPU is major metabolite of monuron in rats, there is still concern for the toxicity of CPU. Thus, a literature search was conducted for any toxicity studies for CPU. As no pertinent information was found (Personal Communication, Alberto Protzel, 5/8/01), risk from CPU will be assessed as follows: 1) for carcinogenic effects, a Q1* will be calculated for monuron and applied to CPU;

EFED has determined that PCA is only a minor metabolite of DFB in the environment (K. Costello, Personal Communication, 2/28/01). Drinking water will thus not be considered in the risk assessment for PCA. In summary, Cancer risks for CPU and PCA will be assessed individually. The tolerance expression should include parent, PCA and CPU. Although CPU is not of concern for the endpoints currently regulated for DFB, it is a major metabolite in milk and the major degradate found in water, with poten tial toxicity concerns.”

Therefore, a cancer assessment for CPU milk and water was conducted using a Q* of 1.52 x 10 - 2

. In addition, a cancer assessment for PCA food only was conducted using a Q* of 1.12 x 10 - 1

.

4.5.4 Summary of Points of Departure Used in Risk Assessment

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

Tables 4 .5.4.1 and 4.5.4.2

.Page 21 of 66

Table 4 .5.4.1 . Summary of Toxicological Doses and Endpoints for Diflubenzuron for Use in Dietary Human Health Risk

Assessments

Exposure/Scenario Point of

Departure Uncertainty/FQP

A Safety Factors RfD, PAD, LOC for Risk

Assessment Study and Toxicological Effects

Acute Dietary all populations Not

Applicable Not Applicable No appropriate endpoint attributable to single exposure was available

.

Chronic Dietary all populations NOAEL= 2

mg/kg/day UF A = 10X

UF H = 10X FQPA SF = 1x cPAD =

chronic RfD FQPA SF = 0.02 mg/kg/day Chronic Dog Study 0 0 146174 LOAEL = 10 mg/kg/day based on methemoglobinemia and sulfhemoglobinemia Cancer (all routes)

Diflubenzuron Classification: “Group E” evidence of non

- carcinogenicity for humans.

Cancer (oral,
dermal, inhalation) PCA “Group

B2"
probably

human
carcinogen

Q 1 * 1.12 x

10 - 1

(mg/kg/day) -

1 Not Applicable NTP Oral mouse study

Cancer (oral,
dermal, inhalation) CPU Q 1 *

based on

monuron a

structural
analog and

the Q 1 * 1.52

x 10 - 2 Not Applicable NTP Oral rat study

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 adver se effect level.

LOAE L = 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 extrapola te a NOAEL. UF S = use of a short

- term study for long

- term risk assessment. 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 = ref erence dose. MOE = margin of exposure. LOC = level

of concern. N/A = not applicabl ePage 22 of 66

Table 4.5.4.2 . Summary of Toxicological Doses and Endpoints for Diflubenzuron for Use in Residential and Occupational

Human Health Risk Assessments

Exposure/

Scenario Point of

Departure Uncertainty

Factors Level of Concern

for Risk

Assessment Study and Toxicological Effects

Short

- and

Intermediate

- Term

Incidental Oral (1 day

- 6 months) (Residential) Not applicable Not applicable Not applicable These endpoints were not evaluated. There are no registered uses of diflubenzuron which result in significant residential exposure.

Short

- Term Dermal (1

- 30 days) (Occupational) NOAEL = 500

mg/kg/day UF A = 10X

UF H = 10X LOC for MOE =

100 21

- Day rat dermal 43954101

LOAEL = 1000 mg/kg/day based on methemoglobinemia

Dermal Intermediate

Term (1

- 6 months) NOAEL = 2

mg/kg/day UF A = 10X

UF H = 10X

Dermal Absorption:

0.5% LOC for MOE =

100 13

- week oral dog 00038706

LOAEL = 6.4 mg/kg/day based on methemoglobinemia

Inhalation Short

Term (1

- 30 days) NOAEL =

0.109 mg/L

NOAEL =

20.30 1
mg/kg/day UF A = 10X

UF H = 10X LOC for MOE =

100 28

- day Inhalation rat Study

, 44950601

No effect at HDT 2 , 0.109 mg/L

Inhalation

Intermediate Term (1

- 6 months) NOAEL =

0.109 mg/L

NOAEL =

20.30 1
mg/kg/day UF A = 10X

UF H = 10X LOC for MOE =

100 28

- day Inhalation rat Study 44950601

No effect at HDT, 0.109 mg/L

Inhalation Long

Term (1

- 6 months) NOAEL = 2

mg/kg/day UF A = 10X

UF H = 10X LOC for MOE =

100 Chronic Dog Study

- 0 0146174

LOAEL = 10 mg/kg/day based on methemoglobinemia and sulfhemoglobinemia

Cancer (all routes) Classification: “Group E” evidence of non

- carcinogenicity for humans.

1 Conversion from mg/L to oral dose (mg/kg/day) = mg/L x absorption (1.0) x [Respiratory Volume (Sprague

- Dawley rats) for 6 hours/day] x Duration of Exposure (5 days/week)/body weight x 7 days/week = 0.109 mg/L x 1.0 x [0.26(RV) x 6 hrs] x 5 d/wk ÷ 0.236 kg x 7 d/wk = 20.3 mg/kg/day (TXR 0050503)

2 Hig hest Dose Tested

Based on the available toxicity database and the Agency's current practices, the short

- and

intermediate inhalation risk for diflubenzuron was assessed using a 28

- day inhalation toxicity study. The long

- term inhalation risk was assessed using a chronic toxicity study in dog. The Agency sought expert advice and input on issues related to this route to route extrapolation approach (i.e. the use of oral toxicity studies for inhalation risk assessment) from its Federal Insecticide, Fungicide , and Rodenticide Act Scientific Advisory Panel (SAP) in December 2009. The Agency received the SAP’s final report on March 2, 2010 ( http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html ). The Agency is in the process of evaluating the SAP report and may, as appropriate, reexamine and develop new policies and procedures for conducting inhalation risk assessments, including route to route extrapolation of toxicity data. If any new polici es or procedures are developed, the Agency may revisit the need for an inhalation toxicity study for diflubenzuron and/or a reexamination of the inhalation toxicity risk assessment.Page 23 of 66

5.0 Dietary Exposure and Risk Assessment

5.1 Metabolite/Degradate Resid ue Profile

5.1.1 Summary of Plant and Animal Metabolism Studies

The qualitative nature of the residue in plants and fungi is adequately understood based on data from citrus, mushroom, rice, and soybean metabolism studies. The metabolism of diflubenzuron in crops tested is similar, and the radioactive components are also similar to those found in soil. The nature of the residue in rotational crops is adequately understood. T he nature of the residue in livestock is also adequately understood based on acc eptable poultry and ruminant metabolism studies reflecting oral dosing. The HED Metabolism Assessment Review Committee (MARC) has concluded that the residues of concern, for the purpose of tolerance expression, are

diflubenzuron and its metabolites 4

- chlo rophenylurea (CPU) and 4

- chloroaniline (PCA).

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

5.1.2 Summary of Environmental Degradation

Under aerobic soil conditions, diflubenzuron appears to degrade to 4

- chlorophenyl urea (CPU) which reached a maximum concentration of 37% of applied at 14 days post

- treatment. The other major degradate, CO 2 , was reported to reach a maximum concentration of 26.3% of applied by 21 days post

- treatment. Three minor degradates, 2,6

- difluorob enzoic acid, 2,6

- difluorobenzamide, and p

- chloroaniline, each reaching a maximum concentration of <10% of applied, were identified in the aerobic soil metabolism study. These metabolites were detectable in an anaerobic soil metabolism study, as well. Due to the stability of diflubenzuron to abiotic processes, limited data are available on the persistence and mobility of diflubenzuron

metabolites.

5.1.3 Comparison of Metabolic Pathways

Rat metabolism data (MRID#s 44875501 and 44875502) indicate that diflu benzuron does not metabolize to PCA or CPU nor is CPU converted to PCA. In mushroom metabolism studies, residues of parent, CPU, DFBA and PCA were detected. Extracts from treated soybean leaves collected the day of the first application, leaves and pods collected the day of the second application, and leaves collected at harvest contained unchanged parent as >90% of the TRR (ppm values were not provided). No DFBA, CPU, or PCA was detected. Radioactive residues in citrus fruit consisted almost entirely of unchanged diflubenzuron; no detectable levels (<1 ppb) of PCA, CPU and DFBA were reported. Residues of diflubenzuron per se in apple fruit identified and residues of PCA, DFBA, and CPU were nondetectable (<1 ppb). Terminal residues identified in animal tissues, milk, and eggs include diflubenzuron, 2

- hydroxydiflubenzuron (2HDFB), 2,6

- difluorobenzamide (DFBAM), DFBA, CPU, and PCA.Page 24 of 66

5.1.4 Residues of Concern Summary and Rationale

The qu alitative nature of the residue in plants and fungi is adequately understood based on data from citrus, mushroom, rice, and soybean metabolism studies. The metabolism of diflubenzuron in crops tested is similar, and the radioactive components are also sim ilar to those found in soil.

T he nature of the residue in livestock is also adequately understood based on acceptable poultry and ruminant metabolism studies reflecting oral dosing. The HED Metabolism Assessment Review Committee (MARC) has concluded that the residues of concern, for the purpose of tolerance expression, are diflubenzuron and its metabolites 4

- chlorophenylurea (CPU) and 4

- chloroaniline (PCA).

Table 5.1.4 . Summary of Metabolites and Degradates to be included in the Risk Assessment and Tolerance Expression.

Matrix For Risk Assessment  For Tolerance Expression

Plants diflubenzuron and its metabolites PCA and

CPU diflubenzuron and its metabolites PCA and

CPU

Rotational crop diflubenzuron and its metabolites PCA and

CPU diflubenzuron and its metabolites PCA and

CPU

Livestock: diflubenzuron and its metabolites PCA and

CPU diflubenzuron and its metabolites PCA and

CPU

Water diflubenzuron and its metabolite CPU N/A

5.2 Food Residue Profile

Chemtura Corporation has submitted field trial data for diflubenzuron on grapefruit, lemon, and orange, the representative crops of the citrus crop group. A total of 20 citrus field trials were conducted in the United States during the 2008 and 2009 growing seasons. Nine orange trials were conducted encompassing North American Free Trade Agreement (NAFTA) Growing Zones 3 (FL; 5 trials), 6 (TX; 1 trial), and 10 (CA; 3 trials). Six grapefruit trials were conducted encompassing NAFTA Growing Zones 3 (FL; 3 trials), 6 (TX; 1 trial) , and 10 (CA; 2 trials). Five lemon trials were conducted encompassing NAFTA Growing Zones 3 (FL; 1 trial) and 10 (CA; 4 trials). Although the petitioner reported that 23 trials were conducted on citrus fruits (12

– orange, 6

– grapefruit, and 5

– lemon) , HED has concluded that two of the orange trials conducted during 2008 constitute a single trial and three of orange trials conducted during 2009 constitute another single trial because the trial conditions at the respective sites were very

similar. For each year, the samples from these trial sites are considered replicate samples from a single trial for purposes of 860.1500 data requirements. The results from these studies are discussed in the appropriate data evaluation report (DER) and summarized in t he following

tables.Page 25 of 66

TABLE 5.2.1. Summary of Residue Data from Citrus Field Trials with Diflubenzuron.

Commodity Total Rate

lb a.i./A [Spray Vol 1 ] PHI

(days) Analyte 2 Residue Levels (ppm) 3

n Sample

Min. Sample

Max. LAFT 4 HAFT 4 Median Mean Std.

Dev.

Orange 0.9330

- 0.9588

[CONC+DIL] 7 DFB 9 0.096 0.730 0.104 0.565 0.256 0.332 0.163

CPU 9 <0.01 0.019 <0.01 <0.014 0.010 0.011 0.001

PCA 9 <0.005 <0.005 <0.005 <0.005 <0.005 <0.005 NA

CPU+PCA 9 <0.015 <0.024 <0.015 <0.019 0.015 0.016 0.001

Combined Residues 9 <0.111 <0.745 <0.123 <0.580 0.274 0.348 0.162

0.9443

- 1.0302
[ULV] 7 DFB 3 0.076 0.467 0.090 0.407 0.385 0.294 0.177

CPU 3 <0.01 <0.01 <0.01 <0.01 <0.01 <0.01 NA

PCA 3 <0.005 <0.005 <0.005 <0.005 <0.005 <0.005 NA

CPU+PCA 3 <0.015 <0.015 <0.015 <0.015 <0.015 <0.015 NA

Combined Residues 3 <0.091 <0.482 <0.105 <0.422 0.400 0.309 0.177

Grapefruit 0.9396

- 0.9609

[CONC+DIL] 7 DFB 6 0.073 0.571 0.105 0.476 0.170 0.233 0.152

CPU 6 <0.01 <0.01 <0.01 <0.01 <0.01 <0.01 NA

PCA 6 <0.005 <0.005 <0.005 <0.005 <0.005 <0.005 NA

CPU+PCA 6 <0.015 <0.015 <0.015 <0.015 <0.015 <0.015 NA

Combined Residues 6 <0.088 <0.586 <0.120 <0.491 <0.185 0.248 0.152

0.9510

- 0.9607
[ULV] 7 DFB 2 0.050 0.171 0.059 0.135 0.097 0.097 NA

CPU 2 <0.01 <0.01 <0.01 <0.01 <0.01 <0.01 NA

PCA 2 <0.005 <0.005 <0.005 <0.005 <0.005 <0.005 NA

CPU+PCA 2 <0.015 <0.015 <0.015 <0.015 <0.015 <0.015 NA

Combined Residues 2 <0.065 <0.186 <0.074 <0.150 0.112 0.112 NA

Lemon 0.9349

- 0.9469

[CONC+DIL] 7

- 8 DFB 5 0.186 1.242 0.227 1.068 0.593 0.636 0.385

CPU 5 <0.01 0.021 <0.01 <0.020 0.01 0.012 0.004

PCA 5 <0.005 <0.005 <0.005 <0.005 <0.005 <0.005 NA

CPU+PCA 5 <0.015 <0.026 <0.015 <0.025 0.015 0.017 0.004

Combined Residues 5 <0.201 <1.257 <0.242 <1.083 0.617 0.653 0.385

1 Application spray types: concentrate spray (CONC; 82

- 90 GPA); dilute spray (DIL; 158

- 170 GPA); ultra low volume spray (ULV; 3

- 4 GPA).

2 DFB = Diflubenzuron; CPU = 4

- chlorophenylurea; PCA = 4

- chloroaniline; Combined Residues = DFB + CPU + PCA.

3 Excep t for sample min/max, values reflect per trial averages; n = no. of field trials. For calculation of median, mean, and standard deviation, the LLMV ( 0.05 ppm for DFB, 0.01 ppm for CPU, and 0.005 ppm for PCA ) was used for any results reported as <LLMV in T able C.3. NA = not applicable.

4 LAFT = lowest average field trial; HAFT = highest average field trial.

Conclusions: The submitted residue data are scientifically adequate. Residue data for oranges are available from only 9 not the typically required 1 2 field trials. Although data from 12 orange field trials were included in the study, HED has concluded that two of the orange trials conducted during 2008 constitute a single field trial and three of the orange trials conducted during 2009 constitute ano ther single trial. The petitioner should be reminded to ad e quately separate field trials. ULV aerial application did not result in higher residues than the ground applications; residues in ULV trials were significantly lower than residues in ground appli cations.

The residue decline studies demonstrate that residues of diflubenzuron per se in/on orange, grapefruit, and lemon either declined gradually or remained steady at post

- treatment intervals outPage 26 of 66

to 21 days. With the exception of one orange sample with residues of CPU at 0.012 ppm (3 DALA), residues of CPU and PCA were below the LLMV (0.01 and 0.005 ppm, respectively) in/on all samples from the decline studies.

An acceptable method was used for residue quantitation, and adequate storage stability d ata are available to support sample storage intervals and conditions for all analytes.

The submitted orange processing study is adequate. Combined residues of diflubenzuron, CPU, and PCA were <1.091 ppm in/on orange fruit harvested 7 days following three broadcast foliar applications of diflubenzuron (80% WG) totaling 3.71 lb a.i./A (4.16 kg a.i./ha; 4x rate). Combined residues were <0.073, <0.973, and 59.78 ppm in orange juice, dried pulp and citrus oil, respectively. These data indicate that the combi ned residues did not concentrate in orange juice (0.07x processing factor) or dried pulp (0.89x processing factor), but did concentrate in orange citrus oil (55x processing factor).

5.3 Water Residue Profile

The drinking water residues used in the dietary risk assessment were provided by the Environmental Fate and Effects Division, summarized in the following memorandum: “Ecological Risk and Drinking Water Assessments for Proposed Label Amendments of

Diflubenz uron.” (DP #: 400093, F. Khan and S. Wente , 11/20/2012) and incorporated directly into this dietary assessment. Water residues were incorporated in the DEEM

- FCID into the food categories “water, direct, all sources” and “water, indirect, all sources.”

The estimated drinking water concentrations (EDWCs) for diflubenzuron use on citrus are higher than the previously recommended annual mean (chronic/non cancer) and 30 year average (chronic/cancer) concentrations for surface water. Therefore, the currentl y calculated EDWCs ( 3.47 μg /L for the peak (acute) concentration, 0.26 μg /L for the annual mean (chronic/non cancer) concentration, and 0.12 μg /L for the 30 year average concentration (chronic/cancer) are

recommended for diflubenzuron.

The current ED WCs of 4

- chlorophenyl urea (CPU) for surface water do not supersede the drinking water concentrations previously estimated ( US EPA, 2002: D279732 ) for drinking water. Therefore, the values ( 20.68 μg/L for the peak (acute) concentration, 12.52 μg /L for the annual mean (chronic/non

- cancer) concentration, and 8. 81 μg /L for the 36 year average concentration (chronic/cancer) from the previous drinking water assessment are recommended.

Since requested label modifications have no implication in ground water modeling, groundwater exposure for drinking water was not performed. Th e previous SCI

- GROW model estimated the concentrations of parent diflubenzuron and the degradate CPU in drinking water from shallow ground water sources to be 0.006 μg /L and 0.20 1 μg /L , respectively (US EPA, 2002). The above concentrations can be considered as both the acute and chronic value for the respective chemicals.Page 27 of 66

Table 5. 3. Summary of Estimated Surface Water and Groundwater Concentrations for Diflubenzuron

.
Scenario Surface Water Conc., pp b a Groundwater Conc., ppb b

Acute 24.2 0.207

Chronic (non

- cancer) 12.8 (parent 12.52 ppb+ CPU 0.26 ppb summed) 0.207

Chronic (cancer) 8.81 CPU

a From the Tier II PRZM

- EXAMS

- Index Reservoir model.

b From the SCI

- GROW model.

5.4 Dietary Risk Assessment

5.4.1 Description of Residue Data Used in Dietary Assessment

The chronic non

- cancer dietary exposure analys i s assumed diflubenzuron residues were present in all commodities at established/recommended tolerance levels for most commodities except orange (0.367 ppm), grapefruit (0.214 ppm) and lemon (0.653 ppm) which used average field

trial residues.

A residue va lue of 0.003 ppm was used for the PCA cancer assessment for all food commodities in DEEM. This represents 1⁄2 the LOQ. An average residue of 0.048 ppm was used for mushroom residue input value in the PCA cancer assessment. A residue value of 0.003 ppm was

used for the CPU cancer assessment for milk commodities.

5.4.2 Percent Crop Treated Used in Dietary Assessment

The chronic non

- cancer dietary exposure analys i s used 100% crop treated while the cancer dietary exposure analysis used the following average percent crop treated: soybeans (1%), peppers (1%), oranges (5%), tangerines (5%), grapefruit (15%), pear (5%), apricot (10%), peach (5%), almond, (10%), pecan (2.5%), rice (1%), wheat (1%), cotton (1%), artichoke (50%), and peanut (5%)

.

5.4.3 Acute Dieta ry Risk Assessment

No toxic effects attributable to a single (i.e., acute) exposure to diflubenzuron have been identified; therefore, an acute reference dose (RfD) has not been established for diflubenzuron and an acute dietary exposure assessment has not been conducted.

5.4.4 Chronic Dietary Risk Assessment

The slightly refined chronic dietary risk assessment for diflubenzuron shows that chronic dietary

risk estimates do not exceed HED's level of concern (i.e. <100% chronic population adjusted doses ( cPAD)) . The highest chronic drinking water concentration of 12.8 ppb was used in this analysis. The results of the analysis indicate that chronic risk from the dietary (food + drinking water) exposure to diflubenzuron will not exceed HED’s level of concern for the general U.S. population, and all population subgroups. The chronic dietary risk estimate for the highest reported exposed population subgroup, children 1

- 2 years old, is 3 8 % of the cPAD. The general US population utilizes 11 % of the cPAD.Page 28 of 66

5.4.5 Cancer Dietary Risk Assessment

Diflubenzuron is classified as “Group E,” evidence of non

- carcinogenicity for humans, therefore, a dietary cancer assessment is not required. However, metabolites CPU and PCA are considered probable carcinogens and have Q*s assigned to them. Individual cancer dietary exposure analyse s were conducted for each metabolite.

The cancer assessment for PCA includes food only. For PCA, the cancer dietary exposure estimate for the U.S. population is 1 x 10 - 6

. The cancer assessment for CPU includes milk and water only. The cancer chronic EDWC in surface water for CPU is 8.81 ppb. For CPU, the cancer dietary exposure estimate for the U.S. population is 3 x 10 - 6

.

5.4.6 Summary Table

Table 5.4.6. Summary of Dietary (Food and Drinking Water) Exposure and Risk for Diflubenzuron

Population Subgroup Acute Dietary ( 95 Percentile) Chronic Dietary Cancer

Dietary Exposure (mg/kg/day) % aPAD* Dietary Exposure (mg/kg/day) % cPAD* Dietary Exposure (mg/kg/day) Risk

General U.S. Population

No toxic effects attributable to a single (i.e., acute) exposure to
diflubenzuron have been identified; therefore, an

acute reference dose (RfD) has not been

established for

diflubenzuron and an acute dietary exposure

assessment has not been

conducted. 0. 002139 11

Diflubenzuron is classified as “Group E,”

evide nce of non

carcinogenicity for humans, therefore, a dietary cancer assessment is not required. All Infants (< 1 year old) 0.00 2615 13

Children 1

- 2 years old 0.007 606 3 8

Children 3

- 5 years old 0.00 5678 2 8

Children 6

- 12 years old 0.00 3006 1 5

Youth 13

- 19 years old 0.00 1800 9.0

Adults 20

- 49 years old 0.001 634 8.2

Adults 50

- 99 years old 0.001667 8.3

Females 13

- 49 years old 0.001 615 8.1

*The values for the highest exposed population for each type of risk assessment should be boldedPage 29 of 66

Table 5.4.7. Summary of Dietary ( Milk and Drinking Water) Exposure and Risk for Metabolite

CPU

Population Subgroup Acute Dietary ( 95 Percentile) Chronic Dietary Cancer

Dietary Exposure (mg/kg/day) % aPAD Dietary Exposure (mg/kg/day) % cPAD Dietary Exposure (mg/kg/day) Risk

General U.S. Population NA NA 0.000 204 3 x 10 - 6

Table 5.4.8. Summary of Dietary (Food Only ) Exposure and Risk for Metabolite PCA

Population Subgroup Acute Dietary ( 95 Percentile) Chronic Dietary Cancer

Dietary Exposure (mg/kg/day) % aPAD Dietary Exposure (mg/kg/day) % cPAD Dietary Exposure (mg/kg/day) Risk

General U.S. Population NA NA 0.000010 1 x 10 - 6

6 .0 Residential (Non

- Occupational) Exposure/Risk Characterization

A residential assessment is not required because there are no diflubenzuron products registered for homeowner use and there are no products registered for application to residential areas.

6.1 Residential Bystander Post

- application Inhalation Exposure

Based on the Agency's current practices, a quantitative post

- application inhalation exposure assessment was not performed for diflubenzuron at this time. However, volatilization of pesticides may be a potential source of post

- application inhalat ion 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 Decem ber 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 S AP report. The Agency may, as appropriate, develop policies 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 i nto place, the Agency may revisit the need for a quantitative post

- application inhalation exposure assessment for diflubenzuron

.

6.2 Spray Drift

Spray drift is always a potential source of exposure to residents nearby to spraying operations. This is particularly the case with aerial application, but, to a lesser extent, could also be a potential source of exposure from the ground application metho d employed for diflubenzuron

. The Agency has been working with the Spray Drift Task Force, EPA Regional Offices and StatePage 30 of 66

Lead Agencies for pesticide regulation and other parties to develop the best spray drift management practices (see the Agency’s Spray Drift website for more information at (http://www.epa.gov/opp00001/factsheets/spraydrift.htm) . On a chemical by chemical basis, the Agency is now requiring interim mitigation measures for aerial applications that must be placed on product labels/labeling . The Agency has completed its evaluation of the new database submitted by the Spray Drift Task Force, a membership of U.S. pesticide registrants, and is developing a policy on how to appropriately apply the data and the AgDRIFT computer model to

its risk assessments for pesticides applied by air, orchard airblast and ground hydraulic methods. After the policy is in place, the Agency may impose further refinements in spray drift management practices to reduce off

- target drift with specific products with s ignificant risks

associated with drift.

Although a quantitative residential post

- application inhalation exposure assessment was not performed as a result of pesticide drift from neighboring treated agricultural fields, an inhalation

exposure assessment wa s performed for flaggers. This exposure scenario is representative of a worse case inhalation (drift) exposure and may be considered protective of most outdoor agricultural and commercial post

- application inhalation exposure scenarios

.

7 .0 Aggregate Ex posure/Risk Characterization

In accord ance with the FQPA, HED must consider and aggregate (add) pesticide exposures and risks from three major sources: food, drinking water, and residential exposures (dermal and residential). In an aggregate assessment, exposures from relevant sources are added together and compared to quantitative estimates of hazard (e.g., a NOAEL or PAD), or the risks themselves can be aggregated. When aggregating exposures and risks from various sources, HED considers

both the route and duration of exposure.

7.1 Acute & Chronic Aggregate Risk

Acute and chronic aggregate exposures include food plus drinking water exposures. As

demonstrated under Section 5. 4, acute and chronic aggregate ri sks are not of concern.

7.2 Short

- and Intermediate

- Term Aggregate Risk

A Short

- and Intermediate

- Term Aggregate Risk assessment is not required because there are no diflubenzuron products regist ered for homeowner use and there are no products registered for application to residential areas.

8.0 Cumulative Exposure/Risk Characterization

Unlike other pesticides for which EPA has followed a cumulative risk approach based on a

common mechanism of toxicity, EPA has not made a common mechanism of toxicity finding as to diflubenzuron and any other substances and diflubenzuron does not appear to produce a toxic metabolite produced by other substances. For the purposes of this tolerance action, therefo re, EPA has not assumed that diflubenzuron has a common mechanism of toxicity with other

substances.Page 31 of 66

For information regarding EPA’s efforts to determine which chemicals have a common mechanism of toxicity and to evaluate the cumulative effects of such ch emicals, see the policy statements released by EPA’s Office of Pesticide Programs concerning common mechanism determinations and procedures for cumulating effects from substances found to have a common

mechanism on EPA’s website at http://www.epa.gov/pesticides/cumulative/.

9 .0 Occupational Exposure/Risk Characterization

9.1 Exposure Scenarios

Occupational handler and post

- application exposure scenarios were assessed for the proposed

amended use on lemons . Based on the product labels and information provided by the registrant,

short

- and intermediate

- term exposure is assessed for handlers and post

- application activities. Dermal and inhalation exposures are combined for diflubenzuron because the toxicity endpoints for these exposure routes are based on common toxicological endpoints. Labels for the

diflubenzuron proposed uses require that applicators and other handlers wear personal protectiv e equipment (PPE) consisting of; long

- sleeved shirt ; l ong pants and shoes with socks plus

chemical resistant gloves. Moreover, label (Dimilin® 2L) requires a respirator (MSHA/NIOSH approved TC

- 21C or any R, P, or HE filter) for mixing and loading for aerial fixed winged applications.

9.2 Handler Exposure

The term “handler” applies to individuals who mix, load, and apply the pesticide product. There is a potential for exposure to diflubenzuron during mixing, loading, and application activities through the dermal and inhalation routes. For this registrati on action, diflubenzuron products are applied using aeria l, airblast, and chemigation equipment.

9.2.1 Handler Exposure Scenarios

Based on the anticipated use patterns and current labeling, types of equipment and techniques that can potentially be use d, occupational handler exposure is expected from the proposed uses. The quantitative exposure/risk assessment developed for occupational handlers is based on the following scenarios:

1. Mixer/loader using open

- pour loading of a water dispersible granule for aerial, airblast, and chemigation applications.

2. Mixer/loader using open

- pour loading of flowable concentrate for aerial, airblast, and chemigation applications.

3. Appl icator aerial (enclosed cockpit) of sprays. 4. Appli cator using airblast equipment.

5. Flag gers supporting aerial application (spray) operations.

Note: Application for chemigation was not assessed, whereas this process is mechanicallyPage 32 of 66

9.2.2 Handler Exposure Data

HED uses the term handlers to describe those individuals who are involved in the pesticide application process. HED believes that there are distinct job functions or tasks related to applications and exposures can vary depending on the specifics of each t ask. Job requirements (amount of chemical used in each application), the kinds of equipment used, the target being treated, and the level of protection used by a handler can cause exposure levels to differ in a manner specific to each application event. Application Rate : The maximum application rate for all exposure scenarios is 0.3125 lb ai/Acre

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 i n the absence of chemical

- specific data, include PHED 1.1, the AHETF database, the Outdoor Residential Exposure Task Force (ORETF) database, or other registrant

- submitted occupational exposure studies. Some of these data are proprietary (e.g., AHETF data) , and subject to the data protection provisions of FIFRA. The standard values recommended for use in predicting handler exposure that are used in this assessment, known as “unit exposures”, are outlined in the “Occupational Pesticide Handler Unit Exposure Surrogate Reference Table” ( http://www.epa.gov/opp00001/science/handler

- exposure

table.pdf ), which, along with additional information on HED policy on use of surrogate data,

incl uding descriptions of the various sources, can be found at http://www.epa.gov/pesticides/science/handler

- exposure

- data.html

.

Estimates of dermal and inhalation exposure were ca lculated for various levels of personal protective equipment (PPE). Results are presented for “baseline,” defined as a single layer of clothing consisting of a long sleeved shirt, long pants, shoes plus socks, no protective gloves, and no respirator, as w ell as baseline with various levels of PPE as necessary (e.g., gloves, respirator, etc). The Dimilin ® 2L label instructs applicators and other handlers to wear ; long

- sleeved shirt, long pants, chemical resistant gloves and shoes plus socks. Mixers and loaders supporting fixed wing aircraft must wear long

- sleeved shirt, long pants, chemical resistant gloves, shoes plus socks and dust/mist filtering respirator wit h MSHA/NIOSH approval number prefix TC21C or a NIOSH approved respirator with R,P or HE filter.

HED’s HIARC met to discuss the adequacy of the toxicological database relative to diflubenzuron (Memo, G. Reddy, HED DOC. NO. 0050503, “DIFLUBENZURON

– 3 rd Rep ort of the Hazard Identification Assessment Review Committee, 03/06/2002). Diflubenzuron was classified in Acute Toxicity Category III for acute dermal toxicity and primary eye irritation. It was classified in Toxicity Category IV for acute inhalation an d primary skin irritation and it is not a dermal sensitizer. Relative to this assessment of handler exposure and risk, the HIARC

identified a short

- term (1

– 30 days) dermal toxicological endpoint (methemoglobinemia) with a NOAEL of 500 mg/kg bw/day. Th e dermal endpoint was identified from a 21 day dermal study

in the rat. The HIARC also identified a short

- term inhalation endpoint (methemoglobinemia) with a NOAEL of 20.3 mg/kg bw/day. The endpoint was identified from a 28

- day inhalation study in the ra t. See Table 9.2.2 for a summary of exposure and risk to occupational pesticide

handlers. The level of concern is for MOEs < 100.Page 33 of 66

9.2.3 Handler Exposure Assumptions

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

35 0 acres for mixing/loading to support aerial applications, 350 acres for mixing /loading chemigation applications. 40 acres for mixing /loading airblast applications,

350 acres for applying with aerial equipment,

4 0 ac res for applying with airblast equipme nt, and 350 acres for flagging to support aerial applications.

Body Weight The standard body weight for the general population (80 kg) was used for all exposure scenarios covered in this risk assessment since the endpoints selected were not developmental and/or fetal

effects

.

Absorption Factor s The intermediate

- term dermal absorption factor is 0.5%. No dermal absorption factor was needed

for short

- term exposure scenarios.

Exposure Duration: HED classifies exposures from 1 to 30 days as short

- term and exposures 30 days to six months

as intermediate

- term. Exposure duration is determined by many things, including the exposed population, the use site, the pest pressure triggering the use of the pesticide, and the cultural practices surrounding that use site. For most agricultural uses, it is reasonable to believe that occupational handlers will not apply the same chemical every day for more than a one

- month time frame; however, there may be a la rge agribusiness and/or commercial applicators who may apply a product over a period of weeks (e.g., completing multiple applications for multiple clients within a region).

Personal Protective Equipment (PPE) For pesticide handlers, this assessment pres ents “baseline” and “baseline with gloves PPE (i.e. workers wearing a single layer of work clothing consisting of a long sleeved shirt, long pants, shoes, plus socks and water resistant gloves ) calculations. See table 9.2.2 for specifics.

Note: For aeria l mixer and loading, label specific directions for Dimilin ® 2L instructs applicators

and other handlers to wear ; long

- sleeved shirt, long pants, chemical resistant gloves and shoes plus socks. Mixers and loaders supporting fixed wing aircraft must wear lo ng

- sleeved shirt, long pants, chemical resistant gloves, shoes plus socks and dust/mist filtering respirator with MSHA/NIOSH approval number prefix TC21C or a NIOSH approved respirator with R,P or HE

filter. Table 9.2.2 assesses baseline and label specifi c PPE.

Occupational Non

- Cancer Dermal Exposure and Risk Estimate Equations

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:Page 34 of 66

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

Where:

Average Daily Dose = Absorbed dose received from exposure to a pesticide in a given scenario (mg pesticide active ingredient/k g body weight/day), Daily Exposure = Amount (mg ai/day) deposited on the surface of the skin that is available for dermal absorption or amount inhaled that is available for inhalation absorption, Absorption Factor = A measure of the amount of che mical 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):

Non

- cancer risk estimates for each application handler scenario are calculated using a Margin of Exposure (MOE), which is a ratio of the toxicological endpoint to the daily dose of concern. The daily dermal and inhalation dose received by occupational handlers were compared to the appropriate POD (i.e . NOAEL) to assess the risk to occupational handlers for each exposure route. All MOE values were calculated using the following formula:

MOE = POD (typically a NOAEL in mg/kg/day) ADD (mg/kg/day)

where:

MOE = Margin of Exposure: value used by HED to represent risk or risk estimates

(unitless),

POD = Point of Departure,

NOAEL = No Observed Adverse Effect Level (mg/kg/day): Dose level in a toxicity

study, where no observed adverse effects occurred in t he study, and

ADD = Average Daily Dose (mg/kg/day): the absorbed dose received from

exposure to a pesticide in a given scenario.

Dermal and inhalation risk estimates were combined in this assessment, since the toxicological effects for these exposu re routes were similar. Dermal and inhalation risk estimates were combined using the following formula:

Total MOE = 1/ (1/Dermal MOE) + (1/Inhalation MOE )

Note: The Agency has evaluated scenarios that may be limited in nature such as flagging during aerial applications because engineering controls (i.e., Global Positioning Satellite technology) are now predominantly used as indicated by the 1998 National Agr icultural Aviation Association (NAAA) survey of their membership. It appears, however, flaggers are still used in approximately 10 to 15 percent of aerial application operations. In cases like these, the Agency strongly encourages the use of the engineer ing control system but will continue to evaluate risks for flaggers and any other population where a clear exposure pathway exists until the potential for exposure is eliminated. The Agency is aware that NAAA is conducting another survey onPage 35 of 66

exposure issue s and will consider those results as are timely and appropriate.

HED has no data to assess exposures to pilots using open cockpits. The only data available is for exposure to pilots in enclosed cockpits. Therefore, risks to pilots are assessed using the engineering control (enclosed cockpits) and baseline attire (long

- sleeve shirt, long pants, shoes, and socks); pilots are not required to wear protective gloves. With this level of protection, there are no risk estimates of concern for applicators.

9.2. 4 Handler Exposure and Risk Estimates

Summaries of the combined, dermal plus inhalation short

- , and intermediate

- term risks for each exposure scenario are presented in Table 9.2.2. The combined dermal and inhalation exposure

risks are not of concern (i.e., MOEs >100) at baseline PPE, however as directed on the label, chemical resistant gloves are to be worn during most mixing and loading activities , however a respirator is included while mixing and loading of a liquid for aerial applications.Page 36 of 66

Table 9.2.2. Occupational Handler Non

- Cancer Exposure and Risk Estimates for Diflubenzuron

.

Exposure

Scenario Crop or

Target Dermal Unit

Exposure
(μg/lb ai) 1 Inhalation

Unit Exposure
(μg/lb ai) 1 Max App.

Rate 2

Area

Treated

or

Amount

Handled Daily 3 Dermal

Intermediate

- Term Inhalation

Intermediate

- Term Total

MOE 8

Baseline Baseline /

Gloves

Or
Eng. Ctrl. Baseline lb ai/Acre Dose (mg/kg/day) 4 MOE 5

Baseline

or Eng. Ctrl. Dose

(mg/kg/day) 6 MOE 7

Baseline Short

Term Int.

- Term

BL BL Label

Specific

PPE

or Eng. Ctrl.

Mixer/Loader (WDG : water dispersible granular)

Aerial
Lemons

Group 10

- 10 227 51.6 8.96 0.3125 350 0. 0 01 5 1

, 3 0 0 0.01 23 1, 7 00 1 ,5 00 7 4 0 1 ,3 00

Airblast 40 0.0 0 01 78 1 1

, 00 0 0.001 4 1 5 ,000 1 5, 000 6 ,3 00 12

, 000

Chemigation 350 0.0 0 1 55 1

, 3 0 0 0.01 23 1, 7 00 1 ,7 00 7 4 0 1 ,3 00

Mixer/Loader ( Fl C : flowable concentrate)

Aerial
Lemons

Group 10

- 10 220 37.6 0.219 0.3125 350 0.0 0 1 5 1

, 3 0 0 0.000 3 68 ,000 56, 000 1 ,3 0 0 7,600

Airblast
220 37.6 0.219 0.3125 40 0.0 0 01 7 1 2

, 00 0 0.00003 4 590 ,000 49 0

, 000 1 2,00 0 6 1, 000

Chemigation 350 0.0 0 1 5 1

, 3 0 0 0.000 3 68 ,000 56, 000 1 ,300 7 ,0 00

Applicator (liquid)

Aerial Lemons

Group

10

- 10 NA 5 0.068

0.3125 350 0.00003 4 58 ,000 0.0000 93 2 2 0,000 NA NA 4 6 ,000 9

Airblast 1,770 1,590 4.71 40 0.0 0 1 3 8 1

, 4 0 0 0.000 736 28 ,000 2 6, 000 1 ,3 0 0 1 ,5 00

Flagger

Aerial Lemons

Group 10

- 0 11 12 0.35 0.3125 350 0.000 0 75 2 7

, 00 0 0.0004 79 4 2 ,000 4 2, 000 1 6, 000 1 5, 000

1 Based on the “Occupational Pesticide Handler Unit Exposure Surrogate Reference Table” ( 03/2013 ); Level of mitigation: Baseline, PPE, Eng. Controls.

2 Based on registered or proposed labels (Reg. No. 400

- 487; 400

- 461).

3 Expo sure Science Advisory Council Policy #9.1.

4 Dermal Dose = Dermal Unit Exposure ( μ g/lb ai) × Conversion Factor (0.001 mg/ μ g) × Application Rate (lb ai/acre or gal) × Area Treated or Amount Handled (A or gal/day) × DAF (%) ÷ BW (kg).

Intermediate

- Term is protective of short

- Term

5 Dermal MOE = Dermal NOAEL (mg/kg/day) ÷ Dermal Dose (mg/kg/day). Intermediate

- Term is protective of short

- TermPage 37 of 66

6 Inhalation Dose = Inhalation Unit Exposure ( μ g/lb ai) × Conversion Factor (0.001 mg/ μ g) × Appl ication Rate (lb ai/acre or gal) × Area Treated or Amount Handled (A or gal/day) ÷ BW ( kg).

Intermediate

- Term is protective of short

- Term

7 Inhalation MOE = Inhalation NOAEL (mg/kg/day) ÷ Inhalation Dose (mg/kg/day). Intermediate

- Term is protective of sho rt

- Term

8 Total MOE = NOAEL (mg/kg/day) ÷ Dermal Dose + Inhalation Dose OR Total MOE = 1 ÷ (1/Dermal MOE + 1/Inhalation MOE).

9 Engineering Control

.Page 38 of 66

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 prev iously treated areas to perform job functions, including activities related to crop production. In the case for

diflubenzuron , post

- application dermal exposure to field workers following aerial, airblast, and chemigation applications is probable.

9.3.1 Post Application Inhalation Exposure Scenarios

Based on the Agency's current practices, a quantitative post

- application inhalation exposure assessment was not performed for diflubenzuron at this time primarily because of the low acute inhalation toxicity (Toxicity Category III and IV), low vapor pressure (insert VP), and the low proposed use rate (0. 3125 lb ai/A). However, there are multiple potential sources of post

application inhalation exposure to individuals performing post

- application activities in previously treated fields. These potential sources include volatilization of pesticides and resuspension of dusts and/or particulates that contain pesticides. The Agency sought expert advice and input on issues related to volatilization of pesticides fro m its Federal Insecticide, Fungicide, and Rodenticide Act Scientific Advisory Panel (SAP) in December 2009, and received the SAP’s final report on March 2, 2010 ( http://www.epa.g ov/scipoly/SAP/meetings/2009/120109meeting.html ). The Agency is in the process of evaluating the SAP report as well as available post

- application inhalation exposure data generated by the ARTF and may, as appropriate, develop policies and procedures, to

i dentify 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 occup ational post

- application inhalation exposure assessment for diflubenzuron.

Although a quantitative occupational post

- application inhalation exposure assessment was not performed, an inhalation exposure assessment was performed for occupational/commercial handlers. Handler exposure resulting from application of pesticides outdoors is likely to result in higher exposure than post

- application exposure. Therefore, it is expected that these handler inhalation exposure estimates would be protective of most occ upational post

- application inhalation exposure scenarios.Page 39 of 66

9.3.2 Post Application Dermal Exposure Assumptions

A series of assumptions and exposure factors served as the basis for completing the occupational

post

- application risk assessments. Each assumption and factor is detailed below on an individual

basis. EPA has determined that there is an exposure potential for persons entering treated sites after application is complete. Representative post

- application exposure scenarios are as follows:

1. Harvesting by hand.

2. Scouts and other crop advisors reentering treated orchards and fields

3. Pruning by hand.

4. Weeding by hand

5. Transplanting

6. Baiting and trapping

7. Transplanting

8. Orchard maintenance

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. The 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

.

Body Weight The standard body weight for the general population (80 kg) was used for all exposure scenarios

covered in this risk assessment since the endpoints selected were not developmental and/or fetal

effects

Absorption Factor s The intermediate

- term dermal absorption factor is 0.5%. No dermal absorption factor was needed

for short

- term exposure scenarios.

Chemical

- specific dislodgeable foliar residue data have not been submitted for diflubenzuron. Therefore, this assessment uses HED’s default assumption that 25% of the application is available for transfer on day 0 following the application and the residues dissipate at a rate of

10% e ach following day.

The highest ( i.e ., most conservative) TC relative to the subject crop (lemon) is for hand harvesting with a TC of 1

, 4 00 cm2/hr. For risk assessment purposes, a TC of 1

, 4 00 cm2/hr is used in conjunction with the maximum rate of application (0.3125 lb a.i./A).Page 40 of 66

Occupational Post

- application Non

- Cancer Dermal Exposure and Risk Estimate Equations

Average Daily Dose (ADD): Potential daily exposures for occupational post

- application workers were calculated using the following form ulas:

DFR t (μg/cm 2 ) = AR (lb ai/A) * F * (1

- D) t * 4.54E8 μg/lb * 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 or 25% (unitless)

D = fraction of residue that dissipates daily or 10% (unitless)

t = number of days after application day (days)

Daily Exposure (mg ai /day) = TC (cm 2 /hr) * CF1 * DFR t (μg/cm 2 ) * ET (hrs /day) * 1E

- 3 mg/μg

where: Daily Exposure = Amount (mg ai/day) tha t is available for dermal absorption,

TC = Transfer coefficient (cm 2 /hr),

DFR t = Dislodgeable Foliar Residue on day “t” (μg/cm 2 ), and

ET = Exposure Time (hours /day).

The daily doses were calculated using the following formula:

Average Daily Dose (mg ai/kg/day) = [Daily Exposure (mg ai/day) * Absorption (%)] Body Weight (kg)

where: Average Daily Dose = Absorbed dose received from exposure to a pesticide in a given scenario (mg pesticide active ingredient/kg body wei ght/day), Daily Exposure = Amount (mg ai/day) that is available for dermal absorption, Absorption Factor = A measure of the amount of chemical that crosses a biological boundary such as the skin (%), and Body Weight = Body weight determined to repres ent the population of interest in a risk assessment (kg).

Margin of Exposure: Non

- cancer risk estimates for each application handler scenario are calculated using a Margin of Exposure (MOE), which is a ratio of the toxicological endpoint to the daily dose of concern. The daily dermal dose received by occupational post

- application workers was compared to the appropriate POD (i.e. NOAEL) to assess the risk to occupational

post

- application workers. All MOE values were calculated using the following formula:

MOE = POD (typically a NOAEL in mg/kg/day) ADD (mg/kg/day)Page 41 of 66

where:

M OE = Margin of Exposure: value used by HED to represent risk or risk estimates

(unitless),

POD = Point of Departure,

NOAEL = No Observed Adverse Effect Level (mg/kg/day): Dose level in a toxicity

study, where no observed adverse effects occurr ed in the study, and

ADD = Average Daily Dose (mg/kg/day): the absorbed dose received from

exposure to a pesticide in a given scenario.

9.3.3 Post

- Application Exposure and Risk Estimates

For all dermal post

- application exposure scenarios, risk estimates do not exceed HED’s LOC (Dermal LOC = 100) , therefore, are not of concern to HED.

In accordance with the updated Part 158 data requirements (2007), one or more DFR studies are required when a pesticide has occupational uses that could result in post

- application dermal exposure. HED analyzed a number of DFR studies and selected a new default value for the fraction of the application rate available to be dislodged after a foliar application (F AR ). This

default value is 2 5%. Of the analyzed DFR studies, the maximum F AR value seen was 89% or 3.6 times higher than the default residue transfer value. Therefore, a calculated MOE of approximately 4 times higher than the LOC (i.e., an MOE > 400 if the LOC = 100) using the

defa ult dislodged residue value would provide an adequate margin of safety for any potentially higher residues seen in a chemical

- specific DFR study. A conservative, screening

- level

assessment of intermediate

- term post

- application exposure to agricultural wo rkers yields MOEs

of 3

, 3 0 0 on “DAT 0” , which do es not exceed HED's LOC and above the waiver criteria of 4x the LOC (400). Therefore, a DFR study is not required for diflubenzuron at this time. See table 9.3.3 for specifics.Page 42 of 66

Table 9.3.3 Occupational Post

- application Non

- Cancer Exposure and Risk Estimates for Diflubenzuron

.

Crop/Site Activities Transfer Coefficient (cm 2 /hr) DFR/TTR 1 Dermal Dose (mg/kg/day) 2 MOE 3

Short

- term

Orchard Citrus: Crop Group

10

- 10 Hand Harvesting 1,400

0.876 0.000613 820,000

Scouting/Pruning 580 0.000254 20,000,00

Transplanting 230 0.000101 5,000,000

Baiting and Trapping Hand Weeding

Orchard maintenance 100 0.0000438 11,000,000

Intermediate

- term

Orchard Citrus: Crop Group

10

- 10 Hand Harvesting 1,400

0.876 0.000613 3,300

Scouting/Pruning 580 0.000254 7,900

Transplanting 230 0.000101 2 0, 000

Baiting and Trapping Hand Weeding

Orchard maintenance 100 0.0000438 46,000

1 DFR = Application Rate × F × (1

- D) t × 4.54E8 μg/lb × 2.47E

- 8 acre/cm 2 ; where F = 0.25 and D = 0.10 per day OR

TTR = Application Rate × F × (1

- D) t × 4.54E8 μg/lb × 2.47E

- 8 acre/cm 2 ; where F = 0.1 and D = 0.10 per day OR

cite chemical

- specific study

2 Daily Dermal Dose = [DFR (μg/cm 2 ) × Transfer Coefficient × 0.001 mg/μg × 8 hrs/day × dermal absorption (%)] BW (kg).

3 MOE = POD (mg/kg/day) / Daily Dermal Dose. Daily Dermal Dose = [DFR/TTR (μg/cm 2 ) × TC × 0.001 mg/μg × 8 hrs/day × dermal absorption

Restricted Entry Interval (REI) :

The REI for diflubenzuron is 12 hours based on the acute toxicity classification of III for acute dermal and eye irritation routes of exposure. It is classified in Toxicity Category IV for acute inhalation toxicity and primary skin irritation. It is not a dermal sensitizer. Therefore the interim worker protection standard REI of 12 hours is adequate to protect agricultural workers from post

application exposures.Page 43 of 66

10. REFERENCES

Diflubenzuron on Citrus, Group 10

- 10 . Summary of Analytical Chemistry and Residue Data

., S. Hummel

, D 403082

, 7/1 7 /2013

Diflubenzuron Chronic Non

- Cancer and Cancer Dietary and Drinking Water Exposure and Risk Assessments for the Amended Use on the Citrus Crop Group

, T. Morton

, D407784

, 12 / 12 /2013

Diflubenzuon : Occupational and Residential Assessment of Diflubenzuron Use in Citrus Crop Group 10

- 10

. J.S.

Miller

, D 403088 7/11/2013

IR

- 4/Section 3

- Local and New Uses Registration for Diflubenzuron Use on Peanuts, Okra, Small grains (Winter, Spring, Durum, Barley, and Oats), Pummelo, Mustard Greens, Broccoli, Raab, Cabbafe (bok choy), Collards, Kale, Mizuna, Mustard spinach, Rape, Greens and Turnip greens

. – A. Al

- mudallal

, D 321156

, 8 / 25 / 06

Diflubenzuron: Summary of Hazard and Science Policy Council (HASPOC) Meetings of April 26, 2012: Recommendations on the need for a neurotoxicity battery (acute and subchronic neurotoxicity studies)

, J. Van

Alstine

, TXR# 0056309

, 6/7/12

.

Health Effects Division (HED) Metabolism Assessment Review Committee (MARC) Meetings of 2/20/01 & 5/8/01.

Diflubenzuron . Residues of Concern for Cancer Risk Assessment. Chemical 108201. Barcode D272976. Case

239100. Submission S590172.Page 44 of 66

APPENDICES

A PPENDIX A TOXICOLOGY DATA SUMMARY

A .1 Guideline Data Requirements

Attachment 1 . Diflubenzuron Toxicology Data Requirements

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 21/28

- Day Dermal

................................ ........................ 870.3250 90

- Day Dermal

................................ ............................. 870.3465 28

- Day Inhalation

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

yes

yes

yes

yes yes

yes

yes

yes

yes

870.3700 Developmental Toxicity (rodent)

................................ . 870.3700 Developmental Toxicity (nonrodent)

........................... 870.3800 Reproduction

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

yes

yes yes

yes

yes

870.4100 Chronic Toxicity (rodent)

................................ ............. 870.4100 Chronic Toxicity (nonrodent)

................................ ....... 870.4200 Oncogenicity (rat)

................................ ......................... 870.4200 Oncogenicity (mouse)

................................ .................. 870.4300 Chronic/Oncogenicity (mouse)

................................ .... 870.4500 Chronic/Oncogenicity (rat)

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

yes

yes

yes

yes

yes yes

yes

yes

yes

yes

yes

870.5100 Mutagenicity

— Gene Mutation

- bacterial

.................... 870.5xxx Mutagenicity

— other genotoxic effects

........................ 870.5375 Mutagenicity

— Structural Chromosomal Aberrations

.. yes

yes

yes yes

yes

yes

870.6100 Acute Delayed Neurotox. (hen)

................................ .... 870.6100 90

- Day Neurotoxicity (hen)

................................ ......... 870.6200 Acute Neurotox. Screening Battery (rat)

...................... 870.6200 Chronic Neurotox. Screening Battery (rat)

................... 870.6300 Develop. Neurotox

................................ ....................... no

no

yes *

yes *

no ......

......

......

......

......

870.7485 General Metabolism

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

................................ ....................... 870.7800 Immunotoxicity yes

no

yes Yes

--- yes

*HASPOC waived the acute and subchronic neurotoxicity studies.Page 45 of 66

A .2 Toxicity Profiles

Table A.2 : Diflubenzuron Acute Toxicity Profile

Guideline

No

. Study Type MRID # Results Toxicity Category

870.1100 Acute Oral Toxicity

– rat 00157103 LD 50 =>5,000 mg/kg IV

870.1200 Acute Dermal Toxicity

- rabbit 00157104 LD 50 =>2000 mg/kg III

870.1300 Acute Inhalation Toxicity

– rat 00163311 LC 50 =>2.49 mg/L IV

870.2400 Acute Eye Irritation 00157105 mild irritant III

870.2500 Acute Dermal Irritation 00157106 no irritation IV

870.2600 Skin Sensitization 42251101 negative -

A.3 Toxicological Endpoints

Non

- Guideline Short

- Term Inhalation Exposure (1

- 30 Days)

Study Selected: Twenty

- eight day rat inhalation

MRID No .: 44950601

Executive Summary: In a subchronic inhalation toxicity study (MRID 44950601), dimilin technical (96.5% a.i., Batch FUX021000

- FUN91A10A) was administered to groups of 10 male and 10 female Sprague

- Dawley albino rats/concentration. Exposure was by nose

- only inhalation

at co ncentrations of 0, 12, 34, or 109 mg/m 3 (0. 0.012, 0.034, or 0.109 mg/L) for 6 hours/day, 5 days/week, for approximately 4 weeks (22

- 23 consecutive exposures, excluding weekends, over

a 30

- 31 day calendar period).

There was no test material

- related effect on mortality, body weight or weight gain, food consumption, clinical signs, ophthalmoscopy, urinalysis, organ weights, and gross or microscopic pathology. Slight but statistically significant decreases were seen in erythrocyte counts, hemoglobin, and hem atocrit in both sexes (93

- 95% of controls) and in serum bilirubin in males (increased from 0.1 to 0.2 mg/dL) administered 100 mg/m 3 . It is unclear whether these alterations were induced by treatment, however, they were too small to be biologically signifi cant and lacked microscopic correlates, and were thus considered toxicologically unimportant. Under the conditions of this study, therefore, a LOAEL was not established and the NOAEL is the highest dose tested, i.e., 109 mg/m 3 (0.109 mg/L).

This subchron ic inhalation toxicity study in the rat is Acceptable/Non

- Guideline . The study satisfies the guideline requirement for a subchronic inhalation toxicity study in rats as requested by the HIARC.Page 46 of 66

Dose and Endpoint for Risk Assessment: NOAEL = 20.30 mg/kg/d 1 (0.109 mg/L; HDT).

Comments about Study/Endpoint : The study is of appropriate for route and duration of exposure. The concentration selected for risk assessment did not elicit any adverse effect following 28 days of inhalation exposure. The HIARC, however, selected this dose based on methemoglobinemia which was consistently observed across species and studies even though it was not seen in the critical study.

Non

- Guideline Intermediate

- Term Inhalation Exposure (1

- 6 months)

Study Selected: Twenty

- eight day rat inhalation

MRID No .: 44950601

Executive Summary: see Short

- Term Inhalation

Dose and Endpoint for Risk Assessment: NOAEL = 20.30 mg/kg/d (0.109 mg/L; HDT).

Comments about Study/Endpoint : The study is of appropriate for route and duration of exposure.

The concentration sele cted for risk assessment did not elicit any adverse effect following 28 days of inhalation exposure. The HIARC, however, selected this dose based on methemoglobinemia which was consistently observed across species and studies even though it was not seen i n the critical study.

A.3.1 Acute Reference Dose (aRfD)

-

No appropriate endpoints (effects) attributable to a single exposure (dose) were identified in any of the oral studies; therefore, an acute RfD is not established for diflubenzuron and

acute die tary risk was not assessed.

A .3. 2 Chronic Reference Dose (cRfD)

- All Populations

This endpoint was established in 1986. It was reassessed by this Committee pursuant to the FQPA and is discussed below.

Study Selected: Chronic Toxicity

- Dog. §83

- 1a

MRID No. : 00146174

Executive Summary: In a 52

- week chronic oral study, technical grade diflubenzuron was administered in gelatin capsules to beagle dogs once each day (7 days/week) at dose levels of 0 (control), 2, 10, 50 or 250 mg/kg/day. Groups of 6 male and 6 female dogs were used for each treated group and 12 male and 12 female dogs were used for the control group. Mortality, clinical signs, food consumption and water consumption were not affected by treatment with diflubenzuron. Except for a s light decrease in mean bodyPage 47 of 66

weight gain observed in female dogs at 250 mg/kg/day, body weights were also not affected. Ophthalmoscopic examinations, clinical chemistries and urinalyses were negative. Statistically significant increases in methemoglobin a nd sulfhemoglobin were observed in male and female dogs at dose levels of ≥10 mg/kg/day. Heinz bodies were also observed in the erythrocytes of male dogs at 250 mg/kg/day and in those of female dogs at ≥50 mg/kg/day. At dose levels of 50 mg/kg/day and hi gher, signs of hemolytic anemia, destruction of erythrocytes and of compensatory regeneration of erythrocytes were observed. Increased platelet counts were also noted in females at ≥50 mg/kg/day. Absolute spleen and liver weights, but not relative organ body weight ratios, were increased in male dogs at 50 and 250 mg/kg/day. Organ weights were not increased in female dogs. The NOAEL in this study is 2 mg/kg/day and the LOAEL is 10 mg/kg/day, based on methemoglobinemia and sulfhemoglobinemia.

Dose and Endpoint for Establishing RFD : NOAEL = 2.0 mg/kg/d based on methemoglobinemia and sulfhemoglobinemia at 10 mg/kg/day (LOAEL).

Uncertainty Factor(s):

Chronic RfD = 2.0 mg/kg/day (NOAEL) = 0.02 mg/kg/day 100 (UF)

Comments about Study/En dpoint/Uncertainty Factor : The HIARC concurred with the dose, end point, and the uncertainty factor selected by the RFD Committee in 1986.

A .3. 3 Dermal Absorption

Dermal Absorption Factor: 0.5 percent.

Twenty four [24] male Sprague

- Dawley rats were divided into two groups of twelve [12] males each and given either 0.005 or 0.05 mg/cm.sq. of C

- 14 diflubenzuron technical in gum tragacanth [0.25%]. Four [4] animals per dose group were sacrificed after eithe r 1, 4, or 10 hours of exposure. The control group consisted of three [3] males with one [1] animal sacrificed at the end of 1,4, or 10 hours of exposure. Systemic absorption was less than 0.5% at each time interval regardless of the dose. Approximately 4. 7

- 6.2% diflubenzuron was bound to the skin at the application site.Page 48 of 66

A .3. 4 Dermal Exposure (Short and Intermediate

- Term)

Dermal Exposure (Short

- Term)

Study Selected: 21

- Day dermal toxicity study in rat.

MRID No.: 43954101

Executive Summary: In a subchronic, 21

- day dermal toxicity study (MRID 43954101), Dimilin (diflubenzuron tech. 96.7% a.i.) was administered to 10/sex/dose in 0.25% gum tragacanth in distilled, deionized water to the dorsal skin on the backs of the test animals
at 0, 20, 500, or 1,000 mg/kg/day for 6 hour period each day.

Dermal treatment for 21 days did not affect mortality, clinical signs, body weight changes, food consumption and/or organ weight changes. At 1,000 mg/kg/day, slight

dermal irritation and traces of acanthosis and hyperkeratosis were noted in males and females. Liver and kidney histopathology was remarkable. Males exhibited slight elevations in the white cell count in the mid and high dose groups. Males also had small reductions in hemoglobin and h ematocrit at 1000 mg/kg dose group. In females at the top two dose there were statistically significant (P < 0.05) decreases in RBC count, hemoglobin levels and hematocrit values. Hematological changes in males and females

were within in the historical r anges for this species and age of rat, and therefore, considered not biologically significant. Methemoglobin levels increased significantly (P < 0.05 & 0.01) in males and females at 1000 mg/kg dose. There was increased incidence of anisocytosis, hypochr omasia and polychromasia in males and females at the top dose. On August 14, 2001, the HED HIARC re

- evaluated the study and concluded that the increased methemoglobinemia in males and females at 1000 mg/kg should be considered as toxicity

- induced change. Therefore, the NOAEL is 500 mg/kg and LOAEL is 1000 mg/kg (Limit Dose), based on methemoglobinemia.

Dose and Endpoint for Risk Assessment: NOAEL = 500 mg/kg/day based on increased methemoglobinemia at 1000 mg/kg/day (Limit Dose).

Comments about Study/Endpoint: This dermal toxicity study in rats is route

- specific, is of appropriate duration and measures the effects of concern, i.e., methemoglobin and/or sulfhemoglobin. Previously, the end

- points for short

- term exposure was based on a 14

- day mous e feeding study. The HIARC re

- evaluated the 21

- day dermal study in rat and revised the NOAEL from 20 mg/kg/day to 500 mg/kg/day, since the methemoglobinemia seen at 500 mg/kg/day was within normal physiological parameters, but occurred at

adverse levels a t 1000 mg/kg/day (Limit Dose).Page 49 of 66

Dermal Exposure (Intermediate

- Term)

Study Selected: 13

- week oral [subchronic] feeding study in dogs. §82

- 1b

MRID No .: 00038706

Executive Summary: In a subchronic feeding study, technical grade diflubenzuron (batch # P7227) was administered in the diet to beagle dogs at dose levels of 0 (control), 10, 20, 40 and 160 ppm (equal to 0, 0.42, 0.84, 1.64 and 6.24 mg/kg/day). Groups of 3

male and 3 fem ale dogs were used for each treated and control group. Hematology and blood chemistries were performed at 2, 4, 6 and 12 weeks: methemoglobin, sulfhemoglobin and urinalyses were performed at 6 and 12 weeks. Ophthalmoscopic

examinations were conducted at 6 and 12 weeks. Gross necropsies were performed on all dogs. Organ weights were determined and histopathological examinations were performed at the terminal sacrifice at 13 weeks. Mortality, clinical signs, body weights and food consumption were not aff ected by treatment with diflubenzuron. Ophthalmoscopic examinations were negative. Methemoglobinemia was observed in the dogs at 160 ppm (after 6 weeks). No gross necropsy, organ weight or histopathological changes were reported at any level that could be related to treatment with diflubenzuron.

Endpoint and dose for use in risk assessment : NOAEL 2.0 mg/kg/day based on increased methemoglobinemia at 6.24 mg/kg/day. Corrected for 0.5% dermal absorption. See

discussion below.

Comments about studies a nd/or endpoint : In this 13

- week feeding study in dogs, a steady state for methemoglobinemia was observed to occur after 6 weeks. In both the rat study and the mouse study, a NOAEL of about 2 mg/kg/day was calculated by regression analysis. Considering all the available data (including data from chronic feeding studies in rats, dogs and mice in which the NOAEL for methemoglobinemia/sulfhemoglobinemia to be used to calculate the RfD also was 2 mg/kg/day), it was concluded that the NOAEL

for intermediate term risk assessments should be 2 mg/kg/day (rather than the slightly lower NOAEL of 1.64 mg/kg/day determined in the dog study above). However, since an oral NOAEL was selected for a dermal endpoint a dermal absorption factor of 0.5%

should be used for this risk assessment when converting dermal exposure to oral equivalents Therefore, the dermal equivalent dose derived from a NOAEL by the oral route is 400.0 mg/kg/day [i.e., 2.0 mg/kg/day ÷ 0.005 = 400.0 mg/kg/day).

Dermal Exposure (Intermediate

- Term)

Study Selected : Chronic Toxicity

- Dog. §83

- 1a

MRID No .: 00146174

Executive Summary : In a 52

- week chronic oral study, technical grade diflubenzuron was administered in gelatin capsules to beagle dogs once each day (7 days/week) at dosePage 50 of 66

levels of 0 (control), 2, 10, 50 or 250 mg/kg/day. Groups of 6 male and 6 female dogs were used for each treated group and 12 male and 12 female dogs were used for the control group. Mortality, clinical signs, food consumption and water consumption were

not affec ted by treatment with diflubenzuron. Except for a slight decrease in mean body weight gain observed in female dogs at 250 mg/kg/day, body weights were also not affected. Ophthalmoscopic examinations, clinical chemistries and urinalyses were negative. St atistically significant increases in methemoglobin and sulfhemoglobin were observed in male and female dogs at dose levels of ≥10 mg/kg/day. Heinz bodies were also observed in the erythrocytes of male dogs at 250 mg/kg/day and in those of female dogs at ≥ 50 mg/kg/day. At dose levels of 50 mg/kg/day and higher, signs of hemolytic anemia, destruction of erythrocytes and of compensatory regeneration of erythrocytes were observed. Increased platelet counts were also noted in females at ≥50 mg/kg/day.

Absolu te spleen and liver weights, but not relative organ body weight ratios, were increased in male dogs at 50 and 250 mg/kg/day. Organ weights were not increased in female dogs.

Dose and Endpoint for Risk Assessment : NOAEL = 2 mg/kg/day based on methemoglob inemia and sulfhemoglobinemia at 10.0 mg/kg/day (LOAEL). Corrected for 0.5% dermal absorption.

Comments about Study/Endpoint: . Long term dermal studies are not available for diflubenzuron therefore a chronic feeding study was chosen. However, since an o ral NOAEL was selected for a dermal endpoint a dermal absorption factor of 0.5% should be used for this risk assessment when converting dermal exposure to oral equivalents. Therefore the dermal equivalent dose producing a NOAEL by the oral route is 400.0 mg/kg/d [i.e. 2.0 mg/kg/day ÷ 0.005 = 400.0 mg/kg/day.

This risk assessment is not required at this time since there does not appear to be any long term exposure scenarios associated with this use. However, if long term exposure is anticipated in the future based on the use pattern then this risk assessment will be required.

A .3. 5 Inhalation Exposure (Short and Intermediate

- Term)

Inhalation Exposure (Short

- Term)

Study Selected: Twenty

- eight day rat inhalation

MRID No .: 44950601

Executive Summary: In a subchronic inhalation toxicity study (MRID 44950601), dimilin technical (96.5% a.i., Batch FUX021000

- FUN91A10A) was administered to groups of 10 male and 10 female Sprague

- Dawley albino rats/concentration. Exposure was by nose

- only inhalat ion at concentrations of 0, 12, 34, or 109 mg/m 3 (0. 0.012, 0.034, or 0.109 mg/L) for 6 hours/day, 5 days/week, for approximately 4 weeks (22

- 23Page 51 of 66

consecutive exposures, excluding weekends, over a 30

- 31 day calendar period).

There was no test material

- relat ed effect on mortality, body weight or weight gain, food

con sumption, clinical signs, ophthalmoscopy, urinalysis, organ weights, and gross or microscopic pathology. Slight but statistically significant decreases were seen in erythrocyte counts, hemoglobi n, and hematocrit in both sexes (93

- 95% of controls) and in serum bilirubin in males (increased from 0.1 to 0.2 mg/ d L) administered 100 mg/m 3 . It is unclear whether these alterations were induced by treatment, however, they were too small to be biologically significant and lacked microscopic correlates, and were thus considered toxicologically unimportant. Under the conditions of this study, therefore, a LOAEL was not established and the NOAEL is the highest dose tested, i.e., 109 mg/m 3 (0.109 mg/L).

This subchronic inhalation toxicity study in the rat is Acceptable/Non

- Guideline . The study satisf

ies the guideline requirement for a subchroni c inhalation toxicity study in rats as requested by the HIARC.

Dose and Endpoint for Risk Assessment: : NOAEL = 20.30 mg/kg/d 1 (0.109 mg/L; HDT).

Comments about Study/Endpoint : The study is of appropriate for route and duration of exposure. The concentr ation selected for risk assessment did not elicit any adverse effect following 28 days of inhalation exposure. The HIARC, however, selected this dose based on methemoglobinemia which was consistently observed across species and studies even though it was not seen in the critical study.

____________________________________

1 Conversion of mg/L to oral dose (mg/kg/day) = mg/L X absorption (1.0) X [Respiratory Volume (Sprague

- Dawley rats) for 6 hours/day] X Duration of Exposure (5 days/wk)/ body weight X 7 days/week = 0.109 mg/L X 1.0 X [10.26(RV) X 6 hrs] X 5d/wk ÷ 0.236 kg X 7d/wk = 20.30 mg/kg/day

Inhalation Exposure (Intermediate

- Term)

Study Selected: Twenty

- eight day rat inhalation

MRID No .: 44950601

Executive Summary: see Short

- Term Inhalation

Dose and Endpoint for Risk Assessment: : NOAEL = 20.30 mg/kg/d (0.109 mg/L; HDT).

Comments about Study/Endpoint : The study is of appropriate for route and duration of exposure. The concentration selected for risk assessment did not elicit any adverse effect following 28 days of inhalation exposure. The HIARC, however, selected this dose based on methemoglobinemia which was consistently observed across species and studiesPage 52 of 66

even though it was not seen in the critical study.

Inhalation Exposure (Long

- Term)

Study Selected: Chronic Toxicity

- Dog

MRID No .: 00146174

Executive Summary: see Chronic RfD

Dose and Endpoint for Risk Assessment: NOAEL = 2.0 mg/kg/d based on methemoglobinemia and sulfhemoglobinemia at 10 mg/kg/day (LOAEL).

Comments about Study/Endpoint/Uncertainty Factor: An oral study was selected since no appropriate inhalation study is available in the database. This study is of appropriate duration of exposure. Assume that inhalation absorption is equivalent to oral absorption.

Margin of Exposure

A margin of exposure of 100 is adequate for dermal and inhalation occupational exposure risk assess ment. There are no residential uses at the present timePage 53 of 66

A.4 E xecutive Summaries

870.3100 Oral Subchronic Toxicity

- Rodent

Study Selected: 14 day subchronic oral toxicity study in mice.

MRID No.: 00099713

Executive Summary: In a 14

- day subchronic oral toxicity study, technical grade diflubenzuron was administered each day by gavage to 10 Swiss strain male mice at a dose level of 8, 40, 200, 1000 or 5000 mg/kg/day. The mice were fasted for 16 hours prior to the first dose of test

material. The test material was administered as a suspension in 1% tragacanth. Twenty control animals were treated similarly with a blank suspension. Blood was drawn from all animals at 15 days after the first dose and analyzed for methemoglob in, sulfhemoglobin and Heinz bodies in the erythrocytes. At day 15, the animals were sacrificed and those of the control and highest dose groups were autopsied. Significantly increased (p < 0.05) levels of methemoglobin were observed at 1000 and 5000 mg/kg /day. Significantly increased (p < 0.05) levels of sulfhemoglobinemia were observed at 200, 1000 and 5000 mg/kg/day. The percentage of erythrocytes containing Heinz bodies was highly increased at 1000 and 5000 mg/kg/day. No effect on body weights or on org ans and tissues examined at autopsy was observed.

Dose and Endpoint for Risk Assessment: NOEL = 40 mg/kg/day based on increased sulfhemoglobin at 200 mg/kg/day.

870.31050 Oral Subchronic Toxicity

- Nonrodent

Study Selected: 13 week oral [subchronic] feeding study in dogs.

MRID No.: 00038706

Executive Summary: In a subchronic feeding study, technical grade diflubenzuron (batch # P7227) was administered in the diet to beagle dogs at dose levels of 0 (control), 10, 20, 40 an d 160 ppm (equal to 0, 0.42, 0.84, 1.64 and 6.24 mg/kg/day). Groups of 3 male and 3 female dogs were used for each treated and control group. Hematology and blood chemistries were performed at 2, 4, 6 and 12 weeks: methemoglobin, sulfhemoglobin and urinaly ses were performed at 6 and 12 weeks. Ophthalmoscopic examinations were conducted at 6 and 12 weeks. Gross necropsies were performed on all dogs. Organ weights were determined and histopathological examinations were performed at the terminal sacrifice at 1 3 weeks. Mortality, clinical signs, body weights and food consumption were not affected by treatment with diflubenzuron. Ophthalmoscopic examinations were negative. Methemoglobinemia was observed in the dogs at 160 ppm (after 6 weeks). No gross necropsy, organ weight or histopathological changes were reported at any level that could be related to treatment with diflubenzuron.Page 54 of 66

Endpoint and dose for use in risk assessment: Calculated NOEL 2.0 mg/kg/day based on increased methemoglobinemia at 6.24 mg/kg/d ay.

Comments about studies and/or endpoint: In this 13

- week feeding study in dogs, a steady state for methemoglobinemia was observed to occur after 6 weeks. In both the rat study and the mouse study, a NOEL of about 2 mg/kg/day was calculated by regression analysis. Considering all the available data (including data from chronic feeding studies in rats, dogs and mice in which the NOEL for methemoglobinemia/sulfhemoglobinemia to be used to calculate the RfD also was 2 mg/kg/day), it was concluded t hat the NOEL for intermediate term risk assessments should be 2 mg/kg/day (rather than the slightly lower NOEL of 1.64 mg/kg/day determined in the dog study above).

870.3200 21

- Day Dermal Toxicity

– Rat

Study Selected: 21

- Day dermal toxicity study in rat

MRID No.: 43954101

Executive Summary: In a subchronic, 21

- day dermal toxicity study, Dimilin (diflubenzuron tech. 96.7% a.i.) was administered to 10/sex/dose in 0.25% gum tragacanth in distilled, deionized

water to the dorsal skin on the backs of the test animals at 0, 20, 500, or 1,000 mg/kg/day for 6 hour period each day.

Dermal treatment for 21 days did not affect mortality, clinical signs, body weight changes, food consumption and/or organ weight changes. At 1,000 mg/kg/day, slight d ermal irritation and traces of acanthosis and hyperkeratosis were noted in males and females. Liver and kidney histopathology was remarkable. Males exhibited slight elevations in the white cell count in the mid and high dose groups. Males also had small reductions in hemoglobin and hematocrit at 1000 mg/kg dose group. In females at the top two doses there were statistically significant (P < 0.05) decreases in RBC count, hemoglobin levels and hematocrit values. Hematological changes

in males and females were within in the historical ranges for this species and age of rat, and therefore, considered not biologically significant. Methemoglobin levels increased significantly (P < 0.05 & 0.01) in males and females at 1000 mg/kg dose. There was increased in cidence of anisocytosis, hypochromasia and polychromasia in males and females at the top dose. On August 14, 2001, the HED HIARC re

- evaluated the study and concluded that the increased methemoglobinemia in males and females at 1000 mg/kg should be conside red as toxicity

induced change. Therefore, the NOAEL is 500 mg/kg and LOAEL is 1000 mg/kg based on methemoglobinemia.

Dose and Endpoint for Risk Assessment : NOAEL = 500 mg/kg/day based on increased methemoglobinemia at 1000 mg/kg/day.Page 55 of 66

Comments about S tudy/Endpoint : This dermal toxicity study in rats is route

- specific, is of appropriate duration and measures the effects of concern, i.e., methemoglobin and/or sulfhemoglobin. Previously, the end

- points for short

- term exposure were based on a 14

- day

mou se feeding study. The HIARC re

- evaluated the 21

- day dermal study in rat and revised the NOAEL from 20 mg/kg/day to 500 mg/kg/day, since the methemoglobinemia seen at 500 mg/kg/day was within normal physiological parameters, but occurred at adverse levels a t 1000 mg/kg/day.

870.3250 Intermediate

- Term Dermal Toxicity

– Dog

Study Selected : Chronic Toxicity

- Dog.

MRID No .: 00146174

Executive Summary : See 870.4100b Chronic Toxicity

– Nonrodent, below.

Dose and Endpoint for Risk Assessment : NOAEL = 2 mg/kg/day based on methemoglobinemia and sulfhemoglobinemia at 10 mg/kg/day (LOAEL). Corrected for 0.5% dermal absorption.

Comments about Study/Endpoint: Long term dermal studies are not available for diflubenzuron therefore a chronic feeding s tudy was chosen. However, since an oral NOAEL was selected for a dermal endpoint a dermal absorption factor of 0.5% should be used for this risk assessment when converting dermal exposure to oral equivalents. Therefore the dermal equivalent dose producing a NOAEL by the oral route is 400.0 mg/kg/day [i.e. 2.0 mg/kg/day ÷ 0.005 = 400.0 mg/kg/day.]

870.3465 90

- Day Inhalation

– Rat

Study Selected: Chronic Toxicity

- Dog

MRID No .: 00146174

Executive Summary: See 870.4100b Chronic Toxicity

– Nonrodent, b elow

Dose and Endpoint for Risk Assessment: NOAEL = 2.0 mg/kg/d based on methemoglobinemia and sulfhemoglobinemia at 10 mg/kg/day (LOAEL).

Comments about Study/Endpoint/Uncertainty Factor: An oral study was selected since no appropriate inhalation stu dy is available in the database. This study is of appropriate duration of exposure. Assume that inhalation absorption is equivalent to oral absorption.

870.3700 Developmental Toxicity

870.3700a Prenatal Developmental Toxicity Study

– RodentPage 56 of 66

Study Selected: Developmental Toxicity

– Rat

MRID No.: 41703504

Executive Summary: In a developmental toxicity in rats, Technical grade diflubenzuron [97.6% pure] was administered in 1.0% gum tragacanth solution by oral gavage to 2 groups of 24 Sprague Dawley rats on days 6

- 15 of gestation at dose levels of either 0 or 1000 mg/kg/day [the limit dose]. No maternal or developmental toxicity was observed. For maternal and developmental toxicity, the NOAEL was 1000 mg/kg/day (Limit

- Dose); a LOAEL was not

ach ieved.

870.3700b Prenatal Developmental Toxicity Study

– Nonrodent

Study Selected: Developmental Toxicity

– Rabbit

MRID No.: 41703505

Executive Summary: In a developmental toxicity study with rabbits, Technical grade diflubenzuron [97.6% pure] was administered in 1.0% gum tragacanth solution by oral gavage to 2 groups of New Zealand White rabbits on days 7

- 19 of gestation at dose levels of either 0 or 1000 mg/kg/day [the limit dose]. No maternal or developmental toxicity was observed. For

maternal and developmental toxicity, the NOAEL was 1000 mg/kg/day (Limit

- Dose); a LOAEL

was not achieved.

870.3800 Reproduction and Fertility Effects

– Rat

Study Selected : 2

- Generation Reproduction Study

- Rats

MRID No. : 42700002

Executive Summary : In a 2

- generation reproduction study in rats (Sprague

- Dawley) complete in 1992, 30 rats/sex/dose received either 0, 10, 200, 2000, or 4000 ppm (0, 0.67, 13.3, 136, and 278 mg/kg/day for P0 males and 0, 0.76, 15.3, 152, and 3l1 mg/kg/day for P 0 females during th e premating growth periods, respectively) of CGA

- 152005 (99.1% a.i.) mixed in the feed. Note that organ weights were not obtained in this study.

The study is classified as Core Minimum Data and satisfies the guideline requirement for a reproduction study.

870.4100a

Study Selected : Carcinogenicity/Oncogenicity Study

- Rat

MRID No. 00145467Page 57 of 66

Executive Summary: See 870.4300 Carcinogenicity

- Rat, below.

The combined chronic oral toxicity/oncogenicity study in the rat is classified Acceptable/guideline a nd satisfies the guideline requirements for a chronic toxicity and oncogenicity study in rats.

Adequacy of Dose Levels Tested: Dosing was considered adequate since the highest dose level tested, 500 mg/kg/day, approached the limit dose of 1000 mg/kg/day for cacinogenicity studies and significant toxicity (particulary methemoglobinemia, sulfhemoglobinemia, erythrocyte

destruction , compensatory regeneration of erythrocytes and hemolytic anemia) was observed at

this dose level.

870.4100b Chronic Toxicity

– Nonrodent

Study Selected : Chronic Toxicity

- Dog

MRID No.: 00146174

Executive Summary: In a 52

- week chronic oral study, technical grade diflubenzuron was administered in gelatin capsules to beagle dogs once each day (7 days/week) at dose levels of 0 (control), 2, 10, 50 or 250 mg/kg/day. Groups of 6 male and 6 female dogs were used for each treated group and 12 male and 12 female dogs were used for the control group. Mortality, clinical signs, food consumption and water consumption were not affected by treatment with diflubenzuron. Except for a slight decrease in mean body weight gain observed in female dogs at 250 mg/kg/ day, body weights were also not affected. Ophthalmoscopic examinations, clinical chemistries and urinalyses were negative. Statistically significant increases in methemoglobin and sulfhemoglobin were observed in male and female dogs at dose levels of 310 mg/kg/day. Heinz bodies were also observed in the erythrocytes of male dogs at 250 mg/kg/day and in those of female dogs at 350 mg/kg/day. At dose levels of 50 mg/kg/day and higher, signs of hemolytic anemia, destruction of erythrocytes and of compensat ory regeneration of erythrocytes were observed. Increased platelet counts were also noted in females at 350 mg/kg/day. Absolute spleen and liver weights, but not relative organ body weight ratios, were increased in male dogs at 50 and 250 mg/kg/day. Org an weights were not increased in female dogs. The NOAEL in this study is 2 mg/kg/day and the LOAEL is 10 mg/kg/day, based on methemoglobinemia and sulfhemoglobinemia.

Dose and Endpoint for Establishing RFD : NOAEL = 2.0 mg/kg/day based on methemoglobinem ia and sulfhemoglobinemia at 10 mg/kg/day (LOAEL).

Uncertainty Factor(s):

Chronic RfD = 2.0 mg/kg/day (NOAEL) = 0.02 mg/kg/day 100 (UF)

Comments about Study/Endpoint/Uncertainty Factor : The HIARC concurred with the dose, endPage 58 of 66

point, and the uncertainty factor selected by the RFD Committee in 1986.

870.4200a Carcinogenicity

– Rat

Study Selected : Oncogenicity Study

- Rat

MRID No.: NTP Report No. 351, July 1989

Executive Summary: In a carcinogenicity study, p

- choloroaniline (> 99% purit y) was dissolved in equimolar equivalents of hydrochloric acid and administered by gavage (5 days/week) to F344/N rats at dose levels of 0, 2, 6, or 18 mg/kg/day for 24

- months. Groups of 50 male and 50 female rats were used for each treated groups and the control group. Hematology examinations and mehtemoglobin measurements were conducted on 15 rats/sex/group at 6, 12, 18, and 24 months. Increased survival was observed in male rats at 2 and 6 mg/kg/day and in female rats at 2, 6, and 18 mg/kg/day relativ e to control rats. The authors of the study attributed the increased survival in these treatment groups to a decreased incidence of mononuclear cell leukemia in the same groups. Mean body weights for treated male and female groups generally remained with in 5% of the control male and female weights throughout the study. Results of hematology examinations and methemoglobin measurements showed mild hemolytic anemia and dose

related increases in methemoglobin at dose levels of 6 and 18 mg/kg/day. Male rats at 6 and 18 mg/kg/day and female rats at 18 mg/kg/day had blue extremities indicative of cyanosis. Histopathological examinations indicated nonneoplastic treatment

- related effects in spleen, liver, bone marrow and adrenal gland. Treatment

- related increas ed incidence of uncommon sarcomas of the spleen was observed in male rats in this study. These sarcomas included fibrosarcomas, hemangiosarcomas, and osteosarcomas, many of which metastasized to other sites. The

combined incidence of these sarcomas in ma le rats was 0/49, 3/50, and 38/50 at dose levels of 0, 2, 6 and 18 mg/kg/day, respectively. In addition, in female rats, 1 fibrosarcoma was observed at a 6 mg/kg/day and 1 osteosarcoma at 18 mg/kg/day. No additional uncommon sarcomas of the spleen were o bserved in female rats in this study. A marginally increased incidence of pheochromocytomas was also observed in the adrenal gland of male and female rats at 18 mg/kg/day. For male rats, the incidence was 13/49, 14/48, 15/48 and 26/49 and for female rats was 2/50, 3/50, 1/50, and 6/50 at dose levels of 0, 2, 6 and 18 mg/kg/day, respectively. Decreased incidences of mononuclear cell leukemias and of malignant lymphomas were also noted in the treated male and female rats in this study.

Systemic toxicity N OAEL was 2 mg/kg/day based on mild hemolytic anemia, dose

- related increased in methemoglobin levels in males and females, cyanosis in females observed at 6 mg/kg/day (LOAEL)

.

This oncogenicity study in the rat is classified Acceptable/non

- guideline and d oes not satisfy the guideline requirements for a oncogenicity study in rats.

Discussion of Tumor Data: Treatment

- related increased incidence of uncommon sarcomas of the spleen was observed in male rats in this study. These sarcomas included fibrosarcoma s, hemangiosarcomas, and osteosarcomas, many of which metastasized to other sites. ThePage 59 of 66

combined incidence of these sarcomas in male rats was 0/49, 3/50, and 38/50 at dose levels of 0, 2, 6 and 18 mg/kg/day, respectively. In addition, in female rats, 1 fi brosarcoma was observed at a 6 mg/kg/day and 1 osteosarcoma at 18 mg/kg/day. No additional uncommon sarcomas of the spleen were observed in female rats in this study. A marginally increased incidence of pheochromocytomas was also observed in the adrenal gland of male and female rats at 18 mg/kg/day. For male rats, the incidence was 13/49, 14/48, 15/48 and 26/49 and for female rats was 2/50, 3/50, 1/50, and 6/50 at dose levels of 0, 2, 6 and 18 mg/kg/day, respectively.

Decreased incidences of mononuclear cell leukemias and of malignant lymphomas were also noted in the treated male and female rats in this study. There was no increased incidence neoplastic lesions in either male or female mice.

Adequacy of Dose Levels Tested: Dosing was considered adequate to test the carcinogenic potential of p

- chloroaniline. Systemic toxicity (LOAEL) was observed in males and females at 6 mg/kg/day as evidenced by mild hemolytic anemia, dose

- related increased in methemoglobin levels, and c yanosis in females. The NOAEL was 2 mg/kg/day.

870.4200b Carcinogenicity

– Mouse

1) Study Selected : Oncogenicity Study

- Mouse

MRID No. 00142490

Executive Summary : In a 91

- week carcinogenicity study, technical grade diflubenzuron was

administered in the diet to HC/CFLP strain mice at dose levels of 0, 16, 80, 400, 2000, or 10000 ppm (equivalent to 0, 2.4, 12, 60, 300, or 1500 mg/kg/day). Groups of 52 male and 52 female mice were used for each treated group and 104 male and 104 female mice were use d for the control group. Mortality, body weights and food consumption were not affected by treatment with diflubenzuron. Increases in methemoglobin and sulfhemoglobin were consistently observed in male and female mice throughout the study at dose levels of 12 mg/kg/day and higher. A blue/gray discoloration of the skin and extremities and dark eyes accompanied the increased methemoglobin and sulfhemoglobin. At higher dose levels (particularly > 300 mg/kg/day), signs of hemolytic anemia, erythrocyte destr uction and compensatory regeneration were observed as were histopathological effects in the liver. Treatment with diflubenzuron was not associated with an increased incidence of neoplastic lesions in either male or female mice. Dosing was considered adeq uate since the highest dose tested, 1500 mg/kg/day, exceeded the limit dose of 1000 mg/kg/day for carcinogenicity studies.

The systemic toxicity NOAEL is determined to be 2.4 mg/kg/day. The systemic toxicity LOAEL is 12 mg/kg/day based on increased methe moglobin and sulfhemoglobin levels consistently observed in male and female mice throughout the study

.

The study is classified Acceptable/guideline and it satisfies the guideline requirements for a carcinogenicity study in mice.

Discussion of Tumor Data: There was no increased incidence of neoplastic lesions in eitherPage 60 of 66

male or female mice.

Adequacy of Dose Levels Tested: Dosing was considered adequate since the highest dose level tested, 1500 mg/kg/day, exceeded the limit dose of 1000 mg/kg/day.

2) Stu dy Selected : Oncogenicity Study

- Mouse

MRID No. : NTP Study, Report No. 351, July 1989.

Executive Summary: In a carcinogenicity study, p

- choloroaniline (> 99% purity) was dissolved in equimolar equivalents of hydrochloric acid and administered by gavage (5 days/week) to B6C3F1 mice at dose levels of 0, 3, 10, or 30 mg/kg/day for 24

- months. Groups of 50 male and 50 female mice were used for each treated gro up and the control group. Increased mortality was observed in male mice at 10 mg/kg/day after 99 weeks, but not at 30 mg/kg/day. Treatment did not affect mortality in female mice. Mean body weights for treated male and female groups were not affected by treatment with the test material. At 24 months, hemosiderin was observed in the kupffer cells of the livers of male and female mice and in the renal tubules of female mice at 30 mg/kg/day. Proliferation of hematopoietic cells was noted in the livers of female mice at all treatment levels. Increased incidence of combined hepatocellular adenomas/carcinomas were observed in the male mice in this study. Incidences were 11/50, 21/49, 20/50 and 21/50 at dose levels of 0, 3, 10, and 30 mg/kg/day, respectively . The increase in combined tumors were primarily due to a dose

- related increase in hepatocellular carcinomas as follows: 3/50, 7/49, 11/50, and 17/50 at 0, 3, 10, and 30 mg/kg/day, respectively. Many of these carcinomas metastasized to the lungs (1/50, 1 /49, 2/50, and 9/50 at 0, 3, 10, and 30 mg/kg/day, respectively). Increased incidence of hemangiosarcomas in the spleen and/or liver were also observed in the male mice in this study at 30 mg/kg/day. Incidences were 4/50, 4/49, 1/50, and 10/50 at dose

le vels of 0, 3, 10, and 30 mg/kg/day, respectively. Incidences of malignant lymphomas were decreased in the treated male and female mice. No evidence of carcinogenicity was observed in the female mice in this study.

Systemic toxicity NOAEL was 10 mg/kg/da y based on hemosiderin accumulation in kupffer cells of the liver in male and female mice at 30 mg/kg/day (LOAEL)

.

This oncogenicity study in mice is classified Acceptable/non

- guideline and does not satisfy the guideline requirements for a oncogenicity st udy in mice.

Discussion of Tumor Data: Increased incidence of combined hepatocellular adenomas/carcinomas were observed in the male mice in this study. Incidences were 11/50, 21/49, 20/50 and 21/50 at dose levels of 0, 3, 10, and 30 mg/kg/day, respectiv ely. The increase in combined tumors were primarily due to a dose

- related increase in hepatocellular carcinomas as follows: 3/50, 7/49, 11/50, and 17/50 at 0, 3, 10, and 30 mg/kg/day, respectively. Many of these carcinomas metastasized to the lungs (1/50 , 1/49, 2/50, and 9/50 at 0, 3, 10, and 30 mg/kg/day, respectively). Increased incidence of hemangiosarcomas in the spleen and/or liver were also observed in the male mice in this study at 30 mg/kg/day. Incidences were 4/50, 4/49, 1/50, and 10/50 at dose levels of 0, 3, 10, and 30 mg/kg/day, respectively.Page 61 of 66

Adequacy of Dose Levels Tested: Dosing was considered adequate to test the carcinogenic potential of p

- chloroaniline. Systemic toxicity (LOAEL) was observed in male and female mice at 30 mg/kg/day as evidenced by hemosiderin accumulation in kupffer cells of the liver. The NOAEL was 10 mg/kg/day.

870.4300 Chronic/Oncogenicity

Study Selected : Carcinogenicity Study

- Rat

MRID No. 00145467

Executive Summary: In a 104

- week carcinogenicity study, tec hnical grade diflubenzuron was administered in the diet to Sprague

- Dawley strain rats at dose levels of 0, 156, 625, 2500 or 10,000 ppm (equivalent to 0, 7.8, 31, 125 or 500 mg/kg/day). Groups of 50 male and 50 female rats were used for each treated group and 100 male and 100 female rats were used for the control group. Mortality, clinical signs, body weights and food consumption were not affected by treatment with diflubenzuron. Increases in methemoglobin and sulfhemoglobin were observed at

all treatmen t levels. Histopathological signs of erythrocyte destruction and compensatory regeneration were observed at levels of > 7.8 mg/kg/day. Signs of hemolytic anemia, increased resticulocytes and increased spleen and liver weights were noted at > 125 mg/kg/day. Treatment with diflubenzuron was not associated with increased incidence of neoplastic lesions in either males or females. Dosing was considered adequate since the highest dose level tested, 500 mg/kg/day, approached the limit dose of 1000 mg/kg/day for cacinogenicity studies and significant toxicity (particulary methemoglobinemia, sulfhemoglobinemia, erythrocyte destruction, compensatory regeneration of erythrocytes and hemolytic anemia) was observed at

this dose level. Systemic Toxicity NOAEL was not establised. The LOAEL is the lowest dose tested 7.8 mg/kg/day based on signs of erythrocyte destruction and compensatory regeneration.

This combined chronic oral toxicity/oncogenicity study in the rat is classified Acceptable/guideline and satisfies the guideline requirements for a chronic toxicity and oncogenicity study in rats.

Discussion of Tumor Data: There was no increased incidence of neoplastic lesions in either male

or female rats.

Adequacy of Dose Levels Tested: Dosing was considered adequate since the highest dose level tested, 500 mg/kg/day, approached the limit dose of 1000 mg/kg/day for cacinogenicity studies and significant toxicity (particulary methemoglobinemia, sulfhemoglobinemia, erythrocyte

destruction , compensatory regeneration of erythrocytes and hemolytic anemia) was observed at

this dose level.

870.7485 Metabolism

– Rat

Study Selected : Metabolism Study

- RatPage 62 of 66

MRID No.: 44875501, 44875502

Recently submitted rat metabolism data indicate that diflubenzuron does not metabolize to PCA or CPU nor is CPU converted to PCA. The HEDMARC met several times (2/20/01 and 5/8/01), concurred with the findings and concluded that a 2% in vivo conversion fac tor for diflubenzuron to PCA or CPU should be dropped (MARC memo dated May 31, 2001). For risk assessment, the toxicity of the CPU and PCA will be considered equal to parent,

diflubenzuron. In conclusion, the MARC recommended that non

- carcinogenic risk

a ssessment should include parent, CPU and PCA; and cancer risk for CPU and PCA should be assessed individually.

870.7600 Dermal Absorption

– Rat

Dermal Absorption Factor: 0.5 percent.

Twenty four male Sprague

- Dawley rats were divided into two groups of 12 males each and given 0.005 or 0.05 mg/cm.sq. of C

- 14 diflubenzuron technical in gum tragacanth [0.25%]. Four 4 animals per dose group were sacrificed after 1, 4, or 10 hours of exposure. The control group

consisted of 3 males with 1 animal sacrificed at the end of 1, 4, or 10 hours of exposure. Systemic absorption was less than 0.5% at each time interval regardless of the dose. Approximately 4.7

- 6.2% diflubenzuron was bound to the skin at the application site.

870.6200b Subchronic Neurotoxicity

Waived by HASPOC TXR 0056309

870.5100, 870

- 5300 Mutagenicity

Mutagenicty

– Bacterial

MRID No.: 41703503

Executive Summary: In a Salmonella/mammalian microsome plate incorporation assay, strains TA98, TA100, TA1535, TA1537 and TA1538 were exposed to technical grade diflubenzuron with and without S9 metabolic activation at concentrations of 0, 8, 40, 200, or 1000 ·g/plate. The high dose was selected on the basis of slight compound precipitation at 1000 ·g/plaste. Preparations for metabolic S9 activation were made from Aroclor induced rat liver. The solvent used was DMSO. Diflubenzuron was not cytotoxic with or without S9 act ivation in any of the Salmonella strains in this assay. There was no evidence of induced mutant colonies over background levels at any of the evaluated concentrations.

Mutagenicty

– Structural Chromosomal AberrationsPage 63 of 66

MRID No.: 41703502

Executive Summa ry: In an in vitro chromosome damage assay, cultures of Chinese hamster ovary (CHO) cells were exposed to technical grade diflubenzuron with and without S9 metabolic activation. The test material was tested at concentrations up to cytotoxic/precipitating levels of

200

- 250 ·g/ml. Preparations for S9 metabolic activation were made from Aroclor 1254 induced

rat liver. The solvent used was DMSO. The test material did not induce an increase in structural chromosome aberrations over background levels at an y of the evaluated concentrations.

Mutagenicty

– Other

MRID No.: 41703501

Executive Summary: In an unscheduled DNA synthesis (UDS) assay, cultures of primary rat hepatocytes were exposed to technical grade diflubenzuron at concentrations ranging from 0.1 to 333 ·g/ml. At the high dose of 333 ·g/ml, cytotoxicity was oserved (36% cell survival in an initial assay and 8% cell survival in a confirmatory assay). The solvent used was DMSO. Positive controls were adequate. The test material did not cause an appreciable increase in net nuclear grain counts compared to the solvent control at any of th e evaluated concentrations. Diflubenzuron did not induce a gentoxic effect in this assay system.

870. 7 800 Immunotoxicity

28

- Day (Dietary) Immunotoxicity Study

– Mice

MRID No: 48760512, TXR 0056396

EXECUTIVE SUMMARY : In an immunotoxicity study (MRID48760512 ), Diflubenzuron (99.2 % a.i., lot # AM8L17D481 ) was administered to fe male CD

- 1 mice (10/dose) at dose levels of 0 (vehicle control group), 80, 400, 2,000 or 10,000 ppm (equivalent to 0, 15, 77, 365 or 1832 mg/kg/day, respectively) for 28 days. The positive control group consisting of 10 female mice was administered cyclophosphamide (25 m g/kg/day, dose volume 10 mL/kg) by intraperitoneal injection on Days 24

- 28. On Day 24, all animals in all groups received a single intravenous dose of sheep red blood cells (SRBC) 1 x10 8 /mL (dose volume 0.2 mL/animal) into

the tail vein. Parameters such as , clinical condition, body weight, food consumption, organ weights, and immunotoxicity related to the treatment were monitored. At necropsy on Day 29, the thymus, and spleen from animals were removed and weighed. The sheep red blood cell (SRBC) antibody r esponse was measured with an enzyme

- linked immunosorbent assay (ELISA).

There were no premature dead and no treatment related clinical signs and symptoms observed. Increased mean food consumption for the 80, 400 and 2,000 ppm diflubenzuron groups were

no ted at Week 3, but it was a transient effect and there were no comparable changes in the 10,000 ppm group. There were no treatment related effects on water consumption, weekly mean body weight and terminal mean body weight when compared to the vehicle cont rol group. There were statistically significantly increase (p<0.05) of absolute and relative spleen weights at 2,000 and 10,000 ppm, but no treatment related changes in thymus weights. Positive control groupPage 64 of 66

(cyclophosphamide) had statistically significant ly decrease (p<0.05) of absolute and relative spleen and thymus weights; but no cyclophosphamide

- related effects on body weights.

The systemic toxicity NOAEL is 400 ppm (equivalent to 77 mg/kg bw/day); the LOAEL is 2000 ppm (equivalent to 365 mg/kg/day) based on increased spleen weight which was a consistent finding in previous toxicity studies.

There were no statistically significant treatment

- related effects on the specific anti

- SRBC antibody response by ELISA test in all treated groups. A high inter

- individual variability was noted in all the treatment groups as well as in the control group. Evaluation of individual animal data of this study did not show any trend or distribution that would demonstrate significant suppression of anti

- SRBC IgM respon se. Animals in positive control group, showed a statistically significant (

p <0.05) decrease of the anti

- SRBC IgM response to a challenge with SRBCs. This confirmed the ability of the test system to detect immunosuppressive effects and

confirmed the validi ty of the study design.

The Natural Killer (NK) cells activity was not evaluated in this study. The toxicology database for Diflubenzuron does not reveal any evidence of treatment related effects on the immune system. The overall weight of evidence sugge sts that the chemical does not directly target the immune system. Under HED guidance a NK cell activity assay is not required at this time.

The immunotoxicity NOAEL is 10,000 ppm (equivalent to 1832 mg/kg/day), tested above

the limit dose. The immunot oxicity LOAEL is not established.

This immunotoxicity study is classified acceptable/guideline; and satisfies the guideline requirement for an immunotoxicity study (OPPTS 870.7800) in mice.Page 65 of 66

APPENDIX B. Chemical Names And Structures Of Diflubenzuron and Metabolites

Diflubenzuron

4

- chlorophenylurea: CPU

4

- chloroaniline: PCAPage 66 of 66

APPENDIX C. Physical/Chemical Properties

APPENDIX D. Studies Reviewed for Ethical Conduct

This risk assessment relies in part on data from studies in which adult human subjects were intentionally exposed to a pesticide or other chemical. These studies were determined to require a review of their ethical conduct, have received that review and have been determined to be ethical.

The PHED Task Force, 1995. The Pesticide Handlers Expos ure Database, Version 1.1. Task Force members Health Canada, U.S. Environmental Protection Agency, and the National Agricultural Chemicals Association, released February, 1995.

The Agricultural Handler Exposure Task Force (AHETF), 2011. The Occupational Handler Unit Exposure Surrogate Reference Table. U.S. Environmental Protection Agency. Released June 21, 2011. Physicochemical Properties of Diflubenzuron.

Parameter Value Reference Melting range 230

- 232 °C http://www.arsusda.gov/acsl/service s/ppdb/textfiles/DIFLUBENZURO

N pH Not available Density Not available Water solubility (25 °C) 0.08 ppm Solvent solubility (25 °C) (ppm) 6.5 x 10 3 Acetone

2 x 10 3 Acetonitrile

2.4 x 10 4 Dioxane

1.04 x 10 5 Dimethylformamide

1.2 x 10 5 Dimethylsulfoxide

1 x 10 3 Methanol

6 x 10 2 Dichloromethane Vapor pressure (25 °C) 1.2 x 10 - 4 mPa Dissociation constant, pK

a Not available Octanol/water partition coefficient, Log(K OW ) 3.89

UV/visible absorption spectrum Not available