Diflubenzuron ( 108201) Human H ea lth Ri sk Assessment

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON

, D.C

. 20460

OFFI C E O F C HEM I CAL SAF E TY AND POLLUTION PRE V ENTION

M E MORA N D U M

September 1 5, 20 15 DP # : 423328

SU B JECT : Diflubenzuron: Human H ea l th Risk As sess me n t fo r an Amended Section 3

R

egistration for Carrot

, Peach S u bgro u p 12- 1 2B, P lum S u bgro up l 2- l 2C,

P epper/Eggp l a n t Subgroup 8-1 OB

, Cottonseed Subgroup 20C

, A l fa l fa (Reg i o n a l

Re s triction s) a nd R 175 C r op Group Conver s i o n for Tree Nut Group 14-12.

P C Co d e : 108201 DP B a r c od e : 423328

D e ci s i o n N o .: 494116 R e gi s tration N o.: 400-461

P e titi o n N o .: 4E8306 Regulatory Action : Sec ti on 3 R egistra ti o n
Ri s k Assess m e nt T y p e: H u

m

a n H ealth Ri s k C a se N o .: 0144
Assessment

T XR No.: NA CAS No : 353 67-38- 5

MRlD No.: NA 40 CF R : § 180.3 77 I

F R O M: H annah Pope-Varsalona

, P



### ,

# TXsi)~s**k** Assessor / /,.,,,_

. Kell O ' Rourke

, ORE



### S umitra B ose Bi swas, 

# Ctlf!:;**~** y3 ·

# ~ Ri sk Assess ment Branch IV

Health Effec t s Di v ision (7509 P )

TH RO UG H: E l issa Reav es, PhD

, Branch C hi e f

Risk Assessment Branch I V

, HED (7509P)

T O: A Willis Ertman

, Risk Manager Review e r Barbara M ad d e n
, Risk Manager

Invertebra t e -V e rtebrate Branch II/RD (7505P) 

# 2-c-F

This d oc um e nt provide s th e Healt h Effect s Division 's ( H E O' s) ri s k assessment of the ame n ded

Section 3 fo r the ne w u se o f diflubenzuron o n carrot and alfalfa ( re g ional re s triction s), expand u se of peach S ub gro up 12-1 2 B

, plum Subgroup 1 2 -l 2C, pepper / egg plant Subgroup 8-1 OB

, cottonseed Subgroup 20C, and crop gro up expansion from for tree nut g r o up 14-12.

Page I of71Diflubenzuron (108201) Human Health Risk Assessment DP#: 4233 28

Page 2 of 71 1.0 Executive Summary

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

2.0 HED Recommendations

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

2.1 Da ta Deficiencies/Conditions of Registration

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

2.2 Tolerance Considerations

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

2.2.1 Enforcement Analytical Method

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

2.2.2 International Harmonization

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

2.2.3 Recommended Tolerances

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

2.2.4 Revisions to Petitioned

- For Tolerances

................................ ................................ 11

2.3 Label Recommendations

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

3.0 Introduction

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

3.1 Chemical Identity

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

3.2 Physical/Chemical Characteristics

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

3.3 Pesticide Use Pattern

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

3.3.1 Registered Products

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

3. 3.2 Proposed New Uses

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

3.4 Anticipated Exposure Pathways

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

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 Excreti on

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

4.2.1 Dermal Absorption

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

4.3 Toxicological Effects

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

4. 4 Safety Factor for Infants and Children (FQPA Safety Factor)

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

4.4.1 Completeness of the Toxicology Database

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

4.4.2 Evidence of Neurotoxicity

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

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

...... 18

4.4.4 Residual Uncertainty in the Exposure Database

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

4.5 Toxicity Endpoint an d Point of Departure

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

4.5.1 Dose

- Response Assessment

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

4.5.2 Recommendations for Combining Exposure Routes

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

4.5.3 Classification of Carcinogenic Potential

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

4.5.4 Summary of Points of Departure Used in Ris k Assessment

............................... 21

5.0 Dietary Exposure and Risk Assessment

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

5.1 Metabolite/Degradate Residue Profile

................................ ................................ ......... 23Diflubenzuron (108201) Human Health Risk Assessment DP#: 4233 28

Page 3 of 71 5.1.1 Summary of Plant and Animal Metabolism Studies

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

5.1.2 Summary of Environmental Degradation

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

5.1.3 Comparison of Metabolic Pathways

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

5.1.4 Residues of Concern Summary and Rationale

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

5.2 Food Residue Profile

................................ ................................ ................................ ..... 25

5.3 Water Residue Profile

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

5.4 Dietary Risk Assessment

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

5.4.1 Description of Residue Data Used in Dietary Assessment

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

5.4.2 Percent Crop Treated Used in Dietary Assessment

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

5.4.3 Acute Dietary Risk Assessment

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

5.4.4 Chronic Dietary Risk Assessment

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

5.4.5 Cancer Dietary Risk Assessment

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

5.4.6 Summary Table

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

6.0 Residential (Non

- Occupational) Exposure/Risk Characterization

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

6.1 Residential Bystander Post

- application Inhalation Exposure

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

6.2 Spray Drift

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

7.0 Aggregat e Exposure/Risk Characterization

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

7.1 Acute & Chronic Aggregate Risk

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

7.2 Short

- and Intermediate

- Term Aggregate Risk

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

8.0 Cumulative Exposure/Risk Characterization

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

9.0 Occupational Exposure/Risk Characterization

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

9.1 Exposure Scenarios

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

9.2 Handler Exposure

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

9.2.1 Handler Exposure Scenarios

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

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

................................ ................................ ............................ 37

9.3.1 Post Application Inhalation Exposure Scenarios

................................ ................. 37

9.3.2 Post Application Dermal Exposure Assumptions

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

9.3.3 Post

- Application Exposure and Risk Estimates

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

10.0 REFERENCES

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

APPENDIX A TOXICOLOGY DATA SUMMARY

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

A. Guideline Data Requirements

................................ ................................ ...................... 44Diflubenzuron (108201) Human Health Risk Assessment DP#: 4233 28

Page 4 of 71 B. Toxicity Profiles

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

C. Toxic ological Endpoints

................................ ................................ ................................ 50

D. Executive Summaries

................................ ................................ ................................ .... 56

APPENDIX B. Chemical Names and Structures of Diflubenzuron and Metabolites

......... 68

APPENDIX C. Physical/Chemical Properties

................................ ................................ .......... 69

APPENDIX D. International Residue Limits Table

................................ ................................ 70

APPENDIX E. Studies Reviewed for Ethical Conduct

................................ .......................... 71Diflubenzuron (108201) Human Health Risk Assessment DP#: 4233 28

Page 5 of 71 1.0 E xecutive S ummary

This document addresses the exposures and risks associated with currently registered uses and the proposed amended use s 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 IR

- 4 PP# 4E8306

, Chemtura Corporation is proposing to expand the use o f diflubenzuron

to include alfalfa, carrot, cottonseed Subgroup 20C, peach Subgroup 12

- 12B, plum Subgroup 12

- 12C, peppers/eggplant Subgroup 8

- 10B, and tree nuts G roup 14

- 12

. The petition also requests

increased tolerances for egg, poultry fat, and poultry meat byproducts to support the use on alfalfa. Additionally, a separate tolerance for residues on plum and dried prune was petitioned for.

Use Profile

Diflubenzuron, ( N

- [((4

- chlorophenyl) amino) carbonyl]

- 2, 6

- difluorobenzimide), a member of the

urea

- d erivative 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 synthesize chi tin to form a hard exoskeleton thereby preventing 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 peanut root

- knot nematode. Tolerances for diflubenzuron, currently established under 40 CFR §180.377 (1) and (2) , range from 0.0 2

- 55 ppm.

The chemical structure 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 inclu de

, aerial; groundboom; airblast; chemigation; and hand

held equipment

. (i.e., low

- pressure handwand, handgun sprayer, backpack sprayer). Diflubenzuron is applied to numerous crops across 21 EPA crop group categories , and to agricultural non

- crop sites inc luding livestock barns

, agricultural structures and equipment.

Proposed New Uses

Chemtura Corporation has submitted an application for a Section 3 registration for Dimilin® 2L (EPA Reg. No. 400

- 461) , an aqueous flowable formulation of diflubenzuron for use on alfalfa ( regionally restricted use) , carrot, cottonseeds Subgroup 20C, peach Subgroup 12

- 12B, plum Subgroup 12

- 12C, peppers/eggplant Subgroup 8

- 10B, and tree nuts G roup 14

- 12

. Occupational application methods include ground and aerial application

. The amended use is not proposed for residential use and residential exposures are not expected based on the proposed uses. The submitted labels are adequate for the proposed new uses.

Hazard CharacterizationDiflubenzuron (108201) Human Health Risk Assessment DP#: 4233 28

Page 6 of 71 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 methemoglobinem ia 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 sul fhemoglobinemia 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 animals.

The overall toxicology database is sufficient for a determination of potential haza rd 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 p otential 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 reproduction study indicated that effects in offspring occurred at doses that were higher than the doses producing effects in parents. The acute and subchronic neurotoxicity studies were waived by HASPOC (TXR 0056309 ) based on a weight of evidence approach. The recently submitted immunotoxicity study has been reviewed and immunotoxicity was not ob served above the lim it

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 an d drinking water exposures. 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 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 . Toxicological endpoint for the short

- and intermediate

- term
dermal scenario was selected from a 21

- day rat dermal study and both long

- term dermal and long

term inhalation endpoint s were selected from a 13

- week oral (capsule) study in the dog

. The short

and intermediate

- term inhalation endpoints were selected from a 28

- day rat in halation 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 classified diflubenzuron as “ Group E

, ” evidence of non

carcinogenicity for humans, based on lack of evidence of carcinogenicity in rats and mice (April 27, 1995 , TXR 0051295 ). PCA, a metabolite of diflubenzuron, tested positive for splenic tumors in male rats and hepatocellular adenomas/carc inomas 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 individually. 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 protect ive. Additional toxicity data on these metabolitesDiflubenzuron (108201) Human Health Risk Assessment DP#: 4233 28

Page 7 of 71 are not required.

Exposure/Risk Assessment and Risk Characterization

Dieta ry Assessment

A chronic non

- cancer and cancer dietary (food plus drinking water) exposure and risk assessments

were conducted us ing the Dietary Exposure Evaluation Model

- Food Consumption Intake Database (DEEM

- FCID), Version 3.16. The assessments were conducted for dietary exposure based on the existing and proposed uses. Drinking water estimates were directly incorporated into the analysis.

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

, however, a slightly refined chronic dietary risk assessment for diflubenzuron shows that chronic dietary risk estimates do not exceed H ED 's level of concern (i.e. < 100% chronic population adjusted doses (cPAD)) . C hronic 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 subgrou ps. The chronic dietary risk estimate for the highest reported exposed population subgroup, children 1

- 2 years old, is 39 % of the cPAD. The general US population

utilizes 10 % of the cPAD.

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 1 *s assigned to them. Individual cancer dietary exposure analyses

were conducted for ea ch metabolite.

The cancer assessment for PCA includes food only (not present in drinking water)

. For PCA, the cancer dietary exposure estim ate for the U.S. population is 1.3 x 10

- 6 . The cancer assessment for CPU includes milk and water only. For CPU, th e cancer dietary exposure estimate for the U.S. population is 2.8 x 10

- 6

.

Exposure Profile

Diflubenzuron is currently registered for use on numerous agricultural crops, as well as for use on agricultural non

- crop sites including livestock barns and agricultural structures. There are no registered residential uses for diflubenzuron and residential exposure is not anticipated for the proposed uses. Diflubenzuron is proposed for use on carrots, peach subgroup 12

- 12B, plum subgroup 12

- 12C, pepper/eggplant subgroup 8

- 10B, cottonseed subgroup 20C, alfalfa and a crop group conversion for tree nut group 14 to group 14

- 12 . The proposed formulated end

- use product is Dimilin® 2L, a flowable concentrate containing 22 % Diflubenzuron (EPA Reg. #400

- 4 61). The maximum single application rates range from 0.03 to 0.25 pounds active ingredient per acre (lb ai/A) and may be made to the fo liage via chemigation, aerial (pepper/eggplant, alfalfa, and cottonseed only), groundboom or airblast applications. The foliar applications are allowed for up to two to five times per season, depending on the crop, with retreatment intervals ranging from 7 to 14 days. The restricted entry interval for all the proposed uses is 12 hours. The proposed label

directs handlers to wear chemical

- resistant gloves in addition to baseline attire; further, mixers/loaders for aerial application are also required to wear a dust/mist filtering respirator. Based on the proposed use pattern, the potential exposure scenarios include short

- andDiflubenzuron (108201) Human Health Risk Assessment DP#: 4233 28

Page 8 of 71 intermediate

- term occupational exposures (handler and post

- application) , via the dermal and

inhalation routes

.

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

- ex posure 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 r esult 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 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 12898, "Federal Actions to Address Environmental Justice in Minority Populations and Lo w

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

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

acco rding 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 involv e pesticide use in a residential setting. Whenever appropriate, non

- dietary exposures based on home use of pesticide products and associated risks for adult applicators and for toddlers, youths, and adults entering or playing on treated areas post

- applica tion are evaluated. Further considerations are currently in development, as OPP has committed resources and expertise to the development of specialized software and models that consider exposure to bystanders and farm workers as well as lifestyle

and trad itional dietary patterns among specific subgroups.

Tolerance Recommendation

Pending submission of a revised Section F (see requirements under Proposed Tolerances , Table

2.2.3 ) and analytical standards for metabolite CPU and PCA, which have expired and must be replaced , there are no residue chemistry considerations that would preclude granting the requested use on peach and plum C S Gs, on carrots and regionally restricted use on alfalfa forage, hay and seed; as well as the necessary tolerances required to support those uses

. Additionally, there is no objection to the proposed expansions of the proposed use of diflubenzuron on peach ( Subgroup

12

- 12B) , plum ( Subgroup 12

- 12C)

, pepper /eggplant ( Subgroup 8

- 10B) , cotton seed ( Subgroup 20C), or conversion of the nut, tree, group 14 tolerance to nut, tree, group 14

- 12. Lastly, IR

- 4 has proposed new/increased livestock tolerances. The proposed tolerances are adequate to coverDiflubenzuron (108201) Human Health Risk Assessment DP#: 4233 28

Page 9 of 71 seconda ry residues in livestock. Listed are the recommended tolerances for each aforementioned commodity.

Cottonseed

, Subgroup 20C ..............................

...... .. 0

. 20 ppm

Egg ...............................................................

.. 0.07 ppm Poultry, fat ......................................................

.. 0.10 ppm Poultry, meat byp roducts .....................................

.. 0.08 ppm Carrots, roots ...................................................

.. 0.20 ppm Peach, Subgroup 12

- 12B ....................................

... 0.50 ppm Plum, Subgroup 12

- 12C .......................................

.. 0.50 ppm Nut, tree, group 14

- 12 ................................................ 0.20 ppm Pepper/Eggplant, Su bgroup 8

- 10B .............................. 1.0 ppm Alfalfa, forage ..................................................... 6.0 ppm Alfalfa, hay ......................................................... 20 ppm Alfalfa, seed ...................................................... 0.90 ppm

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

diflubenzuron per se , for many commodities including: peach CSG 12

- 12B (0.5 ppm), plum CSG

12

- 12C (including prunes) (0.5 ppm), nut tree (0.2 ppm), for chili pepper (3 ppm), dried chili pepper (20 ppm), sweet pepper (0.7 ppm), and for eggs (0.05 ppm). There are no Canadian or Mexican MRLs currently established.

2.0 HED Recommendations

2.1 Data Deficiencies/Conditions of Registration

None.

2.2 Tolerance Considerations

2.2.1 Enforcement Analytical Method

Adequate enforcement analytical methods are available for the enforcement of tolerances for residues of diflubenzuron and its metabolites in crop and livestock commodities. Three enforcement methods for diflubenzuron are published in PAM, Vol. II as Method s I, II, and III. Method I is a GC/ECD method that determines diflubenzuron in plants as derivatized 4

- chloroaniline ( PCA ) . Method II is a GC/ECD method that can separately determine residues of diflubenzuron, 4

- chlorophenylurea ( CPU ) and PCA in eggs, mi lk, and livestock tissues, each as derivatized PCA. Method III is an HPLC/UV method that determines diflubenzuron per se in eggs, milk, and livestock tissues. All three methods have undergone successful Agency

validations. The Diflubenzuron RED stated t hat 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 valid ated by an independent laboratory as well as by Agency chemists at ACB/BEAD, and was forwarded to FDA for publication in PAM Vol. II as Roman Numeral Methods. TheseDiflubenzuron (108201) Human Health Risk Assessment DP#: 4233 28

Page 10 of 71 methods can separately determine residues of diflubenzuron by GC/ECD, CPU by GC/ECD, and

P CA 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.

FDA multi

- residue method (MRM) testing data indicate that neither diflubenzuron, PCA, nor CPU are adequately recovered

.

2.2.2 International Harmonization

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

diflubenzuron per se , for many commodities including: peach CSG 12

- 12B (0.5 ppm), plum CSG

12

- 12C (including prunes) (0.5 ppm), nut tree (0.2 ppm), for chili peppe r (3 ppm), dried chili pepper (20 ppm), sweet pepper (0.7 ppm), and for eggs (0.05 ppm). There are no Canadian or Mexican MRLs currently established. The International Residue Limit (IRL) status sheet is

included as Appendix D to this memorandum.

The Age ncy is currently not harmonized with Codex with respect to the residue definition for plant

and livestock commodities in 40 CFR §180.377(a)(2)

. Since the Codex MRL is based on the same use pattern and data that EPA would rely on, HED recommends an increas e in the peach CSG 12

- 12B tolerance to 0.50 ppm, plum CSG 12

- 12C tolerance to 0.50 ppm, and nut, tree, group tolerance to 0.20 ppm to harmonize with the Codex MRL levels.

2.2.3 Recommended Tolerances

Tolerances are currently established under 40 CFR §180.377 comply with the HED Interim Guidance on Tolerance Expressions (S. Knizner, 5/27/09); therefore, no revisions are

recommended to the residue definition. Table 2.2.3, below summarizes the recommende d tolerance levels and commodity definitions required to support the proposed new and revised uses included in these petitions.

IR

- 4 is requested to submit a revised section F for the following reasons,

1) to remove the request for tolerance on plum, pru ne, dried. Based on a previously conducted processing study (MRID# 25252208) diflubenzuron residues are not found to concentrate on prunes (dried plum). Therefore, a separate tolerance for prunes is not required.

2) to increase the tolerances for poultr y egg, fat and meat byproducts. Based on the current dietary burden calculation, the anticipated residues in poultry fat, egg and meat byproducts are different than what was proposed.

Table 2.2.3 . Tolerance Summary for Diflubenzuron

. Commodity Proposed Tolerance (ppm) HED

- Recommended

Tolerance (ppm) Comments

( correct commodity definition )

40 CFR §180.377(a)(1) Tolerance for residues.

Cottonseed Subgroup 20C 0.2 0.20 Significant figures.Diflubenzuron (108201) Human Health Risk Assessment DP#: 4233 28

Page 11 of 71 Table 2.2.3 . Tolerance Summary for Diflubenzuron

. Commodity Proposed Tolerance (ppm) HED

- Recommended

Tolerance (ppm) Comments

( correct commodity definition )

Established tolerance for cotton,

undelinted seed can be removed from 40CFR and replaced by this Subgroup tolerance.
Egg 0.15 0.07 Current tolerance level is 0. 05 ppm; Increase to support the diflubenzuron

uses on alfalfa

.

Poultry, fat 0.15 0.10 Current tolerance level is 0.05 ppm; Increase to support the diflubenzuron

uses on alfalfa. Poultry, meat byproducts 0.06 0.08 Current tolerance level is 0.05 ppm; Increase to support the diflubenzuron

uses on alfalfa.
40 CFR §180.377(a)(2) Tolerance for residues.
Carrot, roots 0.2 0.20 Significant figures.

Peach Subgroup 12

- 12B 0.5 0.50 Significant figures. Established tolerance (0.07 ppm) for fruit, stone, group 12, except cherry

can be removed from 40CFR and replaced by this Subgroup tolerance.

Plum Subgroup 12

- 12 C 0. 5 0.50 Significant figures.

Established tolerance (0.07 ppm) for

f ruit, stone, group 12, except cherry

can be removed from 40CFR and replaced by this Subgroup tolerance

to harmonize with codex. Plum, prune, dried 0.5

-- A separate tolera nce is not required.

D iflubenzuron residues are not found to concentrate on prunes (dried

plum)

. Nut, tree, group 14

- 12 0.2 0.20 Significant figures.

Established tolerance for pistachio and nut, tree, group 14 can be

removed from 40CFR and replaced by this Subgroup tolerance to
harmonize with codex. Pepper/Eggplant Subgroup 8

- 10B 1.0 1.0 Established tolerance for pepper can be removed from 40CFR and replaced by this Subgroup tolerance.
40 CFR 7180.377(c) Tolerances with regional registrat ions. Alfalfa, forage 6 6.0 Significant figures. Alfalfa, hay 20 20
Alfalfa, seed 0.9 0.90 Significant figures.

2.2.4 Revisions to Petitioned

- For Tolerances

I R

- 4 is requested to submit a revised section F to remov e the request for tolerance on p lum, prune, dried and to revise the tolerance for poultry fat, meat byproduct as outlined in section 2.2.2. Based on a previously conducted processing study (MRID# 25252208) diflubenzuron residues are not found to concentrate on prunes (dried plum) a tolerance for prunes is not required. In addition, HED is recommending a number of changes in the numerical expression of the tolerance values inDiflubenzuron (108201) Human Health Risk Assessment DP#: 4233 28

Page 12 of 71 order to conform to current HED policy on significant figures.

2.3 Label Recommendations

None.

3.0 I ntroduction

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 acaricide and insecticide. It is currently registered in the U.S . for use as a chitin inhibitor, which promotes an inability of immature insects to synthesize 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 d iflubenzuron are twig borer, stink bug, grasshopper, beet armyworm, soybean looper, rust mite, artichoke plume moth, and peanuts root knot nematode. Tolerances for diflubenzuron, currently established under 40 CFR §180.377 (1) and (2) , range from 0.02

- 55 pp m.

3.1 Chemical Identity

The chemical structure and nomenclature of diflubenzuron and its metabolites is shown in Table

3.1.

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% W P 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)Diflubenzuron (108201) Human Health Risk Assessment DP#: 4233 28

Page 13 of 71 3.2 Physical/Chemical Characteristics

Diflubenzuron is a white crystalline solid, the technical material is off

- white to yellow crystals. Melting points of the technical material is 210

- 230°C, and the pure form of 230

- 232°C (both with decomposition). The compound is sparingly soluble in water. In polar solvent the solubility is moderate to good depending on the degree of polarity. It is a non

- volatile compound. The physicochemical properties of diflubenzuron are presented in Table 3.2.

TABLE 3.2 Physicochemical Properties of Diflubenzuron.

Parameter Value Reference
Melting range 230

- 232 °C http://www.arsusda.gov/a csl/services/ppdb/textfiles/

DIFLUBENZURON 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

3.3 Pesticide Use Pattern

3.3.1 Registered Products

There are 70 active diflubenzuron registrations, 26 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

ConcentrateDiflubenzuron (108201) Human Health Risk Assessment DP#: 4233 28

Page 14 of 71 Table 3

. 3.2.2 . Summary of Proposed Use Directions for Diflubenzuron.

Applic. Timing, Type, and

Equip. Formulation

[EPA Reg. No.] Application

Rate Max No.

Applications per Season Max

Seasonal Application

Rate Use Directions and

Limitations

Alfalfa

Apply up to one day before cutting of alfalfa forage or hay.

Chemigation, Groundboom, or

Aerial. Liquid ( 400

- 461 ) 0.016 to

0.031 lb

ai/A 3 apps/growing

season 0.094 lb ai/A REI = 12 hours. RTI = 14 days. PHI = 1 days

Carrots

Apply at first sign of larval

infestation.

Chemigation or Groundboom

. Liquid ( 400

- 461 ) 0.1 25 lb

ai/A 2 apps/growing

season 0. 25 lb ai/A REI = 12 hours. RTI = 7 days. PHI = 7 days

Cotton seed Subgroup 20C

Depending on pest, apply before first bloom, first bloom through mid

- bloom, after mid

bloom, at pinhead stage, or when plant has reached full vegetative growth.

Chemigation, Groundboom

, or Aerial. Liquid ( 400

- 461 ) 0.031 to

0.1 25 lb

ai/A 6 app s /season 0. 75 lb ai/A REI = 12 hours. RTI = 5

to 14 days. PHI = 14 days.

Peach Subgroup 12

- 12B and Plum Subgroup 12

- 12C

Apply starting at early bloom.

Chemigation or Airblast. Liquid ( 400

- 461 ) 0.1 25 to

0.25 l b ai/A 2 apps/growing

season 0.5 lb ai/A REI = 12 hours. RTI =

14 days. PHI = 14 day.

Pepper/Eggplant Subgroup 8

- 10B

Apply starting at initial flowering..

Chemigation, Groundboom or Aerial. Liquid ( 400

- 461 ) 0. 063 to

0.125 lb

ai/A 5 apps/growing

season 0. 375 lb ai/A REI = 12 hours. RTI = 7 days. PHI = 7 days.

Tree Nuts group 14

- 12
Depending on pest, apply beginning at half shell hardening or at bud break.

Chemigation or Airblast

. Liquid ( 400

- 461 ) 0.125 to

0.25 lb ai/A 4 apps/growing

season 1.0 lb ai/A REI = 12 hours. RTI =

14 to 21 days. PHI = 28 day s

.

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 granular 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 PathwaysDiflubenzuron (108201) Human Health Risk Assessment DP#: 4233 28

Page 15 of 71 The Registration Division has requested an assessment of human health risk to support the proposed amended use of diflubenzuron t o include alfalfa, carrot, cottonseeds Subgroup 20C, peach Subgroup 12

- 12B, plum Subgroup 12

- 12C, peppers/eggplant Subgroup 8

- 10B, and tree nuts

crop g roup 14

- 12

. The petition also requests increased tolerances for egg, poultry fat, and poultry meat byproducts to support the use on alfalfa. Additionally, a separate tolerance for residues on plum and dried prune was petitioned for . 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 reaching 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 via the dermal and inhalation routes . There is a potential for post

- application dermal exposure for workers re

- entering treated fields.

Risk assessments have been 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 dietary

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

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

As a par t of every pesticide risk assessment, OPP considers a large variety of consumer Subgroup s according to well

- established procedures. In line with OPP policy, HED estimates risks to population Subgroup s 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 o f pesticide products and associated risks for adult 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 a nd expertise to the development of specialized software and models that consider exposure to bystanders and farm workers as well as lifestyle and traditional dietary patterns among specific Subgroup s.

4.0 Hazard Characterization and Dose

- Response Assessment

4.1 Toxicology Studies Available for Analysis

T he toxicology database for diflubenzuron is adequate for evaluating and characterizing toxicity and selecting endpoints for purposes of this risk assessment. A ll toxicity studies required in

accordance with new 40 CFR Part 158 data requirements have been submitted or waived by HASPOC (TXR 0056309 )

.Diflubenzuron (108201) Human Health Risk Assessment DP#: 4233 28

Page 16 of 71 4.2 Absorption, Distribution, Metabolism and Excretion

Rat metabolism 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. Th e 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.

In a metabolism study (MRID 44875502), [U

14 C

- anilino]

- diflubenzuron was administered to

male Fischer

- 344 rats at 104 mg/kg by a single gavage dose. Metabolites were characterized in urine and feces collected at 20, 48, 72 and 96 hrs post

- dosing. [ 14 C]

- diflubenzuron was well absorbed (at 96 hrs po st

- dosing, 2.22% of administered radioactivity was recovered in the urine and 87.4% in the feces). Most of the administered radioactivity (about 68%) was recovered within 20 hrs post

- dosing and an additional 15% was recovered between 20

- 48 hrs post

- dosing . Most of the administered diflubenzuron was excreted unchanged in the feces (87.4% of administered radioactivity); no other fecal metabolites were identified at detectable levels. In the urine, 9 metabolites were isolated and identified. The 2 major me tabolites in the urine were 4

- chloroaniline

- 2

- sulfate (0.9% of administered radioactivity; 45% of total recovered radioactivity in urine) and N

- (4

- chlorophenyl)oxamic acid (0.1 to 0.2% of administered radioactivity and 13%

of the total radioactive residues [ TRR ] ). The remaining 7 metabolites were recovered in very small

amou nts (0.1 to 1.3% of the TRR). Non

- metabolized CPU was not identified in the urine at detectable levels. The major metabolic pathway was hydroxylation of the anilino moiety to form

2'

- hydroxy diflubenzuron, which could be followed by dechlorination with or without substitution (N

- acetyl

- cysteine), hydrolysis followed by sulfation or N

- acetylation, or glucuronidation. Hydrolysis and acetylation followed by oxidation of the acetyl moiety was the major route of

formation for metabolite N

- (4

- chlorophenyl)oxamic acid. 4

- chloroaniline, CPU or their N

hydroxyl/hydroxylamine derivatives were not identified in either the urine or feces.

In a metabolism study for CPU (MRID 44875501), [U

14 C

- p henyl]

- chlorophenylurea was administered to male Fischer

- 344 rats at 198 mg/kg by a single gavage dose. Metabolites were characterized in urine and feces collected at 20 and 48 hrs and every 24 hrs thereafter to 144 hrs

post

- dosing. [ 14 C]

- CPU at 198 mg/k g was completely absorbed (at 144 hrs post

- dosing, 91% of administered radioactivity recovered in the urine, 7% in the feces and 1% each in the carcass and cage wash). Most of the administered radioactivity (about 70%) was recovered within 20 hrs post

dos ing and an additional 23% was recovered between 20

- 48 hrs post

- dosing. Five major metabolites (>5% of administered dose) and 7 minor metabolites were found; 10 were identified.

The 5 most abundant metabolites were: CPU

– 2

- sulfate (25.60% of administered d ose), phenylurea

- 4

- hydroxide (20.82%), CPU

- 2

- glucuronide (16.70%), CPU

- 3

- sulfate (7.93%) and phenylurea

- 4

- sulfate (6.65%). CPU was almost completely metabolized, with only 1.45% of the unchanged parent compound recovered in the urine plus feces. The majo r metabolic pathway was hydroxylation of the aromatic ring, followed by conjugation with glucuronic acid or sulfate. A second major pathway was oxidative dechlorination. Glutathione conjugation was presumed to occur (followed by further oxidative degrada tion or aliphatic amine substitution) and hydrolysisDiflubenzuron (108201) Human Health Risk Assessment DP#: 4233 28

Page 17 of 71 of the ureido moiety was a minor route. 4

- chloroaniline and N

- hydroxy metabolites of 4

- chloroaniline or CPU were not found in either the urine or feces of treated rats. All metabolites

were found in th e urine but only 4 were detected in the feces.

4.2.1 Dermal Absorption

Sprague

- Dawley rats were given 0.005 or 0.05 mg/cm 2 14 C

- 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 factor of 0.5 % was determined.

4.3 Toxicological Effects

For difl ubenzuron, t he hemopoietic system is the target site with effects including increased sulfhemoglobin and/or methemoglobin levels in rat and dog studies. In subchronic and chronic feeding studies, the primary endpoint of concern was methemoglobinemia and/o r sulfhemoglobinemia. However, no progression of toxicity was observed from short

- term studies

to chronic studies. The methemoglobinemia observed in the 13

- week dog study was also observed at the same dose in the chronic dog study. The effects on the he mopoietic system were evident in both sexes of mice, rats, and dogs and were evaluated 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 impa irment of the oxygen trans portation capacity of the blood

.

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 reproduction study indicated that effects in offspring occurred at doses that were higher than the doses producing effects in parents. The acute and subchronic neurotoxicity studies were waived by HASPOC (TXR 0056309 ) ba sed on a weight of evidence approach. I n addition, diflubenzuron was not immunotoxic at a dose exceeding the limit dose.

The acute oral, dermal and inhalation toxicity of diflubenzuron are toxicity categories III and IV

. It is a mild eye irritant and not a skin irritant in laboratory animals. It is negative for sensitization in the guinea pig.

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

carcinogenicity for humans, based on lack of evidence of carcinogeni city in rats and mice (04/27/1995 , TXR 0051295 ). PCA, a metabolite of diflubenzuron, tested positive for splenic tumors in male rats and 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 (TXR 0011539) . However, recently submitted acceptable rat metabolism studies show ed 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 ( Q 1 * ) for CPU and PCA should beDiflubenzuron (108201) Human Health Risk Assessment DP#: 4233 28

Page 18 of 71 assessed individually. Based on methemoglobinemia observed only at higher doses in NTP studies for both monuron, simila r 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 CPU and PCA will be considered equal to diflubenzuron for the non

- cancer risk assessment. The non

- carcinogenic risk assessment should include diflubenzuron, CPU and PCA. The Q 1 * for CPU is 1.52 x 10

- 2 and the Q 1 * for PCA is 1.12 x 10

- 1

.

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

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

The FQPA was reduced to 1x based on the 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 PCA. 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 weight of

evidence approach considering all the available diflubenzuron hazard and exposure information,

the HASPOC concluded that an acute and subchronic neurotoxicity studies are not required at this time (6/7/12, TXR #: 0056309). 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 sulfhemoglobi nemia 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 adequa te for FQPA assessment. Based on the available developmental toxicity studies in rats and rabbits, there is no increased susceptibility to fetuses exposed in utero

. There was no indication of abnormalities in fetal development in the 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 dietary food exposur e assessment uses conservative assumptions which result in protective estimates of dietary exposure. The dietary drinking water assessment uses values generated by model and associated modeling parameters which are designed to provide protective, high

- end estimates of water concentrations.

4.4.4 Residual Uncertainty in the Exposure DatabaseDiflubenzuron (108201) Human Health Risk Assessment DP#: 4233 28

Page 19 of 71 There are no residual uncertainties in the exposure database. The dietary risk assessment is conservative and will not underestimate dietary and/or non

- dietary residentia l exposure to

diflubenzuron

.

4.5 Toxicity Endpoint and Point of Departure

4.5.1 Dose

- Response Assessment

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

No appropriate toxicological endpoint attributable to a single exposure was identified in the hazard database, including oral developmental toxicity studies in rats and rabbits. A single oral dose of 1,000 mg/kg to mice and rats only resulted in marginal increases in methemoglobin suggesting that multiple doses are required to elicit methemoglobinemia. Therefore, an acute dietary risk

assessment is not warranted.

A chronic point of departure of 2 mg/kg/day (NOAEL) was selected from the chronic dog study.

The L OAEL of 10 mg/kg/day was based on methemoglobinemia and sulfhemoglobinemia. The standard 100x UF was applied to account for interspecies extrapolati on and intraspecies vari ation. The FQPA safety factor of 1x is applicable for chronic dietary risk assessment. Thus, the cPAD is 0.02 mg/kg/day.

Incidental oral endpoints were not selected since there are no registered or proposed uses of

diflubenzuron which result in residentia l exposure.

The short

- and intermediate

- term dermal scenarios are based on the 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). The 21

- day de rmal toxicity study

was selected for both the short

- and intermediate

- term scenarios since no progression in methemoglobinemia was observed in any of the oral studies. Furthermore, the dermal absorption is extremely low (0.5%) and also supports using the 21

- day dermal study for both short and

intermediate duration. This study is route

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

A long

- term dermal endpoint was selected from a chronic oral toxicity study in the dog. The NOAEL of 2.0 mg/kg/day was based on methemoglobinemia and sulfhemoglobinemia observed at 10 mg/kg/day (LOAEL). 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.

Short

- and intermediate

- term i nhalation endpoints were selected from a 28

- day rat inhalation toxicity study. The NOAEL of 0.109 mg/L (HDT) in the study was based on a no effect leve l at the highest concentration tested

. Although the erythrocyte count, hematocrit, and hemoglobin concentrations were decreased, the changes lacked histopathological correlates and were deemedDiflubenzuron (108201) Human Health Risk Assessment DP#: 4233 28

Page 20 of 71 biologically insignificant. At the termination, there were sl ight (

- 57%) decreases in erythrocyte counts, hemoglobin and hematocrit at the high dose when compared to controls. These changes, however, were not considered to be biologically significant due to lack of histopathological correlates

and there were no trea tment related effects on methemoglobin. However, the highest concentration is considered an inflection point and a slightly higher concentration or longer duration may have produced an adverse change in these parameters. Therefore the 28

- day inhalation s tudy is protective for the short

- and intermediate

- term durations. It is noted that the RfC methodology was not used to calculate a Human Equivalent Concentration (HEC) since the MAAD and GSD were not available from the inhalation study. Therefore, a n MOE of 100 is sufficient for the short

- and

intermediate

- term inhalation scenarios based on the conventional uncertainty factor of 100 ( 10x for interspecies extrapolation

, 10x for intraspecies variation , and 1x FQPA ).

A long

- term inhalation endpoint was sel ected from a chronic oral toxicity study in the dog. The NOAEL of 2.0 mg/kg/day was based on methemoglobinemia and sulfhemoglobinemia observed at 10 mg/kg/day (LOAEL). An oral study was selected since no appropriate long

- term inhalation study is available in the database. A 100% inhalation

- absorption factor should be used to convert to oral equivalents. An MOE 100 is sufficient for the short

- and intermediate

- term inhalation scenarios based on the conventional uncertainty factor of 100 ( 10x for interspecies extrapolation

, 10x for intraspecies variation , and 1x FQPA ).

4.5.2 Recommendations for Combining Exposure Routes

When there are potential residential exposures to the pesticide, aggregate risk assessment must consider exposures from three major sources: oral, dermal and inhalation exposures. Oral, d ermal and inhalation exposures to residents should be aggregated for diflubenzuron since the endpoints selected for these exposure routes are based on a common toxicological effect (i.e., methemoglobinemia).

4.5.3 Classification of Carcinogenic Potential

Based on the available evidence, which included adequate carcinogenicit y 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 following is excerpted from the HED Metabolism Committee Meeting Memorandum of 5/31/01 (D272976).

“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 producing tumors of the kidney

and liv er 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 studie s 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 Q 1 * 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,Diflubenzuron (108201) Human Health Risk Assessment DP#: 4233 28

Page 21 of 71 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 potential toxicity concerns.”

Therefo re, a cancer assessment for CPU milk and water was conducted using a Q 1 * of 1.52 x 10

- 2

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

- 1

.

Summary of Points of Departure Used in Risk Assessment

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

Tables 4 .5.4.1 and 4.5.4.2

.

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 MRID 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) 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 adverse effect level. LOAEL = lowest observed adverse effect level. UF = uncertainty factor. UF A = extrapolation from animal to human (i nterspecies). UF H = potential variation in sensitivity among members of the human population (intraspecies). UF L = use of a LOAEL to extrapolate a NOAEL. UF S = use of aDiflubenzuron (108201) Human Health Risk Assessment DP#: 4233 28

Page 22 of 71 short

- term study for long

- term risk assessment. UF DB = to account for the absence o f key date (i.e., lack of a critical study). FQPA SF = FQPA Safety Factor. PAD = population adjusted dose (a = acute, c = chronic). RfD = reference dose. MOE = margin of exposure. L OC = level of

concern. N/A = not applicabl eDiflubenzuron (108201) Human Health Risk Assessment DP#: 4233 28

Page 23 of 71 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

- , I ntermediate

- and Long

- Term

Incidental Oral (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

- and

Intermediate

- Term

Dermal NOAEL = 500

mg/kg/day UF A = 10X

UF H = 10X LOC for MOE =

100 21

- Day rat dermal MRID 43954101

LOAEL = 1000 mg/kg/day based on methemoglobinemia

Dermal Long

- Term NOAEL = 2

mg/kg/day

Dermal Absorption:

0.5% UF A = 10X

UF H =10X LOC for MOE =

100 Chronic Dog Study (oral)

- MRID 00146174

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

Short

- and

Intermediate

- Term

Inhalation Short NOAEL =

0.109 mg/L

NOAEL =

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

UF H = 10X LOC for M OE =

100 28

- day Inhalation rat Study

, MRID 44950601

No effect at HDT 2 , 0.109 mg/L

Inhalation Long

Term 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 Highest Dose Tested

5.0 Dietary Exposure and Risk Assessment

5.1 Metabolite/Degradate Residue Profile

5.1.1 Summary of Plant and Animal Metabolism Studies

The qualitative nature of the residue in plants 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 residues of concern for diflubenzuron for risk assessment and tolerance enforcement in plants and fungi, determined by HED Metabolism Assessment Review Committee ( MARC ) is diflubenzuron and

its metabolites 4

- chlorophenylurea ( CP U ) and 4

- chloroaniline ( PCA )

. The nature of the residue in plants has been adequately addressed and no additional data are required. Structures and names of diflubenzuron metabolites are provided in Appendix B

.

The nature of the residue in livestock is adequately understood based on acceptable poultry and ruminant metabolism studies reflecting oral dosing. The MARC has concluded that the residues of concern in livestock for the purpose of risk assessment and enforcement are diflubenzuron andDiflubenzuron (108201) Human Health Risk Assessment DP#: 4233 28

Page 24 of 71 its meta bolites PCA and CPU. The nature of the residue in livestock has been adequately addressed and no additional data are required.

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 o f 26.3% of applied by 21 days post

- treatment. Three minor degradates, 2,6

- difluorobenzoic acid, 2,6

- difluorobenzamide, and p

- chloroaniline, each reaching a maximum concentration of <10% of applied, were identified in the aerobic soil metabolism study. Th ese 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 Pa thways

Rat metabolism data (MRID#s 44875501 and 44875502) indicate that diflubenzuron 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 treat ed 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 w as 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), 2,6

- difluorobenzoic acid ( DFBA )

, p

- chlorophenyl urea ( CPU ) , and

p

- c hloroaniline ( PCA )

.

5.1.4 Residues of Concern Summary and Rationale

Although, the available confined rotational crop study was inadequate to fully satisfy the 860.1850 guideline, the nature of the residue in rotational crops is adequately understood for purpos es of this petition. The residues of concern in rotational crops are parent diflubenzuron, CPU, and PCA.

Conclusions: Although, available confined rotational crop study was not adequate, the nature of the residue in rotational crops has been adequately delineated. Additional confined rotational crop data are not required at this time.

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 . Only parent for some plants.

Rotational crop diflubenzuron and its metabolites PCA and

CPU diflubenzuron and its metabolites PCA and

CPUDiflubenzuron (108201) Human Health Risk Assessment DP#: 4233 28

Page 25 of 71 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

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 alfalfa

, carrot

, peach and plum

. The number, geographic representation, and the employed use patterns of the alfalfa, carrot, peach, and plum field trial data are adequate and support the requested use patterns. The residue data were generated using a validated data collection method, and are supported by adequate storage stability data. The maximum combined residues of diflubenzuron, CPU and PCA in/on alfalfa forage/hay/seed, carrot, peach, and plum were as follows, respectively: 3.60/13.3/0.48 ppm, 0.08 ppm, 0.48 ppm, and 0.23 ppm.

N o new field trial data were submitted to support expansion of the current uses to CSG 8

- 10B, CSG 20C and to support the conversion of CG 14 to 14

- 12. Since the requested expansions/conversion of the crop groups are for the identical formulation and use pa ttern, no new residue chemistry data, including processing studies, are required to support these requests.

TABLE 5

. 2.1. Summary of Residue Data from Crop Field Trials with Diflubenzuron.

Commodity Total

Applic. Rate (lb ai/A) PHI

(days) Diflubenzuron (ppm)

n Min. Max. HAFT 1 Median Mean Std. Dev.
Alfalfa Forage 2

0.10 1 18 0.82 2.9 2.5 1.8 1.8 0.50 Alfalfa Hay 2 18 2.6 9.1 8.2 5.2 5.3 1.8

Alfalfa Seed 10 0.056 0.43 0.43 0.18 0.23 0.15 TABLE 5.3.1.2. Summary of Residue Data from Crop Field Trials with Diflubenzuron.
Alfalfa Forage 0.1 1 6 0.0600 5.74 3.60 1.56 1.98 1.94

0.3

- 0.4 3.40 11.6 9.70 6.06 7.71 4.99 Alfalfa Hay 0.1 4.36 15.7 13.3 4.92 6.86 3.38

0.3

- 0.4 10.1 45.2 41.1 17.1 23.1 14.4

Alfalfa Seed 0.1 0.06 60.3 47.4 3 0.26 15.9 25.7

0.3 0.09 2.05 1.58 0.41 0.700 0.760

Table 5.3.1. 4

. Summary of Residue Data from Crop Field Trials with Diflubenzuron.

Carrot 0.243

- 0.255 3 2 0.06 0.06 0.06

- - - 6

- 7 18 0.06 0.08 0.07 0.06 0.06 0.004

10 2 0.06 0.06 0.06

- - - 14 2 0.06 0.06 0.06

- - - TABLE 5.3.1. 5

. Summary of Residue Data from Crop Field Trials with Diflubenzuron.

Peach 0.489

- 0.510 14 15 0.08 0.44 0.24 0.18 0.16 0.05

Plum 9 0.08 0.23 0.19 0.17 0.20 0.10

TABLE 5.3.1. 6

. Summary of Residue Data from Crop Field Trials with Diflubenzuron.

Peach 0.50 0 2 0.17 0.30 0.24 0.24 0.24 0.090

7 2 0.13 0.16 0.14 0.14 0.14 0.020

14

- 16 14 0.090 0.48 0.44 0.14 0.19 0.12

21 2 0.060 0.090 0.080 0.080 0.080 0.020

Plum 13

- 14 10 0.060 0.12 0.12 0.060 0.080 0.020Diflubenzuron (108201) Human Health Risk Assessment DP#: 4233 28

Page 26 of 71 Dried Plum 13 1 0.20 0.20 NA 3 NA NA NA

1 HAFT = Highest Average Field Trial

2 Alfalfa forage and hay 3 rd cutting

3 NA = Not applicable

There are ruminant and/or poultry feed items associated with the proposed uses of diflubenzuron on alfalfa (forage, hay, and seed) and carrot. Maximum reasonable dietary burdens (MRDBs) for diflubenzuron were calculated based on the proposed/registered us es. The MRDBs of diflubenzuron are 3.39 ppm for beef cattle, 19.34 ppm for dairy cattle, 1.05 ppm for poultry, and 1.0 ppm for hog.

TA BLE 5.2

. 2 Calculation of MRDBs.
Crop Commodity Type 1 Residue %Dry

Matter 2 %Diet Dietary Contribution 3

ppm input ppm

Beef Cattle

Alfalfa Hay R 20 HR 89 15 3.37

Wheat Grain CC 0.06 Median 89 20 0.01

Rice Bran CC 0.02 Median 90 15 0.003

Untreated feed NA NA NA NA NA 50 0

Total NA NA NA NA NA 100 3.39
Dairy Cattle

Peanut Hay R 55 HR 85 15 9.71

Grass Forage R 6 HR 25 30 7.20

Carrot Culls CC 0.2 HR 12 10 0.17

Wheat Grain CC 0.06 Median 89 20 0.01

Rice Bran CC 0.02 Median 90 15 0.003

Alfalfa Meal PC 20 HR 89 10 2.25

Total NA NA NA NA NA 100 19.34
Poultry

Wheat Grain CC 0.06 Median 89 75 0.05

Alfalfa Meal PC 20 HR 89 5 1.00

Untreated feed NA NA NA NA NA 20 0

Total NA NA NA NA NA 100 1.05

Swine

Rice Bran CC 0.02 Median 90 10 0.002

Alfalfa Meal PC 20 HR 89 5 1.00

Untreated feed NA NA NA NA NA 85 0

Total NA NA NA NA NA 100 1

The residue analytical methods used to generate alfalfa, carrot, peach and plum field trial data have been adequately validated and are acceptable for data collection purposes. Adequate storage stability data are available to support the storage conditions and intervals for sam ples fr om the

submitted field trials.

The previously submitted processed food and feed study on prune (dried plums) is adequate. Based on the study diflubenzuron residues do not concentrate in/on prunes.

Additionally, based on the submitted data

- c ombin ed residues of diflubenzuron, CPU and PCA inDiflubenzuron (108201) Human Health Risk Assessment DP#: 4233 28

Page 27 of 71 dried plu ms were 0.20 ppm (Table 5.3.3).

5.3 Water Residue Profile

The drinking water residues used in the dietary risk assessment were provided by the

Environmental Fate and Effects Division (EFED) , summarized in the following memorandum: “Ecological Risk and Drinking Water Assessments for Proposed Label Amendments of

Diflubenzuron.” (DP # 423330 , F. Khan, 04 /20/20 15 ) and incorporated directly into this dietary

assessment. The estimated drinking wat er concentrations ( EDWCs ) of diflubenzuron and CPU were generated using the Surface Water Concentration Calculator model (SWCC) for surface

water and the Pesticide Root Zone Model

- Groundwater (PRZM

- GW) model for ground water. Water residues were incorpora ted in the DEEM

- FCID into the food categories “water, direct, all

sources” and “w ater, indirect, all sources.”

The maximum application rate of 0.312 lbs a.i./A X 3 applications/year for citrus as well as 0.25 lbs a.i./A X 4 applicati ons/year for tree nut were modeled with the SWCC and PRZM

- GW models. Model input parameters were chosen according to current guidance (USEPA, 2009 and USEPA, 2013a). For surface water sources of drinking water, the recommended peak (acute) concentration of 4.61 μg/L, annual mean (non

- cancer chronic) concentration of 0.41 μg/L and the 30 year annual average concentration (cancer chronic) of 0.38 μg/L based on LV application of diflubenzuron for citrus use. For CPU, the recommended surface water concentrati ons are 6.83 μg/L for acute, 0.89 μg/L for non

- cancer chronic and 0.51 μg/L for cancer chronic also based on a e rial application representative of citrus use

.

For groundwater sources of drinking water, the maximum acute and chronic estimated

concentrations of CPU in shallow groundwater from PRZM

- GW model for applications to citrus

were 8.62 μg /L and 8.02 μg /L, respectively. However, the concentrations of diflubenzuron in groundwater were negligible. Recommended surface water and groundwater EDWCs for human

health are listed in Table 5.3.1

.Diflubenzuron (108201) Human Health Risk Assessment DP#: 4233 28

Page 28 of 71 Table 5.3.1 . Drinking Water Exposure Estimates for Diflubenzuron and its Major Degradate, CPU for Use on Various Crops.

Source Residue Peak Exposure ( μg /L) Annual

Mean Exposure ( μg /L) 30

- year

Average Exposure (μg/L)

Surface water 1 Diflubenzur

on 2 4.61 0.41 0.38

CPU 2 6.83 0.89 0.51

Total 11.44 1.3 0.89

Groundwater 1 Diflubenzur

on 0

--- 0

CPU 8.62

--- 8.02

Total 8.62 0 8.02

1 EDWCs generated using SWCC and PRZM

- GW models for aerial LV application of 0.312 lbs a.i./A X 3 applications for citrus use

2 Estimated in FL Citrus scenario

5.4 Dietary Risk Assessment

5.4.1 Description of Residue Data Used in Dietary Assessment

The chronic non

- cancer dietary exposure analysis 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 value 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 assessme nt. 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 (2.5%), oranges (10%), tangerines (10%), grapefruit (25%), pear (5%), apricot (10%), peach (5%), almond, (10%), pecan (2.5%), rice (2.5%), w heat (1%), cotton (1%), artichoke (45%), peanut (10%), lemon (1%), plum (5%), and walnut (2.5%)

.

5.4.3 Acute Dietary 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.Diflubenzuron (108201) Human Health Risk Assessment DP#: 4233 28

Page 29 of 71 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 results of th e 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 Subgroup s. The chronic dietary risk estimate for the highes t reported exposed population Subgroup , children 1

- 2 years old, is 39 % of the cPAD. The general US population utilizes 10 % of the cPAD.

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 1 *s assigned to them. Individual cancer dietary exposure analyses

were conducted for each metabolite.

The cancer asses sment for PCA includes food only (not present in drinking water) . For PCA, the cancer dietary exposure estim ate for the U.S. population is 1.3 x 10

- 6 . The cancer assessment for CPU includes milk and water only. For CPU, the cancer dietary exposure estimate for the U.S. population is 2.8 x 10

- 6

.

5.4.6 Summary Table

Table 4. 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. 002056 10

Diflubenzuron is classified as “Group E,”

evidence of non

carcinogenicity for humans, therefore, a dietary cancer assessment is not required. All Infants (< 1 year old) 0.00 2667 13

Children 1

- 2 years old 0.007 726 3 9

Children 3

- 5 years old 0.00 5705 2 9

Children 6

- 12 years old 0.00 2977 1 5

Youth 13

- 19 years old 0.00 1709 9

Adults 20

- 49 years old 0.001 509 8

Adults 50

- 99 years old 0.001584 8

Females 13

- 49 years old 0.00 1497 8

*The values for the highest exposed population for each type of risk assessment should be boldedDiflubenzuron (108201) Human Health Risk Assessment DP#: 4233 28

Page 30 of 71 Table 5. 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 0.000187 2.8 x 10

- 6

Table 6. 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 0.000011 1.3 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 inhalation exposu re to individuals nearby to pesticide applications. The Agency sought expert advice and input on issues related to volatilization of pesticides from its Federal Insecticide, Fungicide, and Rodenticide Act Scientific Advisory Panel (SAP) in December 2009. The Agency received the SAP’s final report on March 2, 2010 ( http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html ) and is in the process of evaluating the SAP report. The Agency may, as appropriate, develop policies and procedures to identify the need for and, subsequently, the way to incorporate post

- application inhalation exposure into the Agency's risk assessment s. If new policies or procedures are put into 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 near by to spraying operations. This is particularly the case with aerial application, but, to a lesser extent, could also be a potentialDiflubenzuron (108201) Human Health Risk Assessment DP#: 4233 28

Page 31 of 71 source of exposure from the ground application method employed for diflubenzuron . The Agency has been working with the Sp ray Drift Task Force, EPA Regional Offices and State Lead Agencies for pesticide regulation and other parties to develop the best spray drift management practices (see the Agency’s Spray Drift website for more information at (http://www.epa.gov/opp00001/fa ctsheets/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

submitt ed 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 groun d hydraulic methods. After the policy is in place, the Agency may impose further refinements in spray drift management practices to reduce off

- target drift with specific products with significant risks associated with

drift.

Although a quantitative resid ential post

- application inhalation exposure assessment was not performed as a result of pesticide drift from neighboring treated agricultural fields, an inhalation exposure assessment was performed for flaggers. This exposure scenario is representative of a worse case inhalation (drift) exposure and may be considered protective of most outdoor agricultural and commercial post

- application inhalation exposure scenarios

.

7.0 Aggregate Exposure/Risk Characterization

In accordance 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 source s 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 Acu te & Chronic Aggregate Risk

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

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

7.2 Short

- and Intermediate

- Term Aggregate Ris k

A Short

- and Intermediate

- Term Aggregate Risk 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.

8.0 Cumulative Exposure/Risk Charac terization

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 n ot appear to produce a toxic metabolite produced by other substances. For the purposes of this tolerance action, therefore, EPADiflubenzuron (108201) Human Health Risk Assessment DP#: 4233 28

Page 32 of 71 has not assumed that diflubenzuron has a common mechanism of toxicity with other substances.

For information regarding EPA’s ef forts to determine which chemicals have a common mechanism of toxicity and to evaluate the cumulative effects of such chemicals, see the policy statements released by EPA’s Office of Pesticide Programs concerning common mechanism determinations and procedu res 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
Occupational handler and post

- application exposures are anticipated from the proposed uses of

diflubenzuron.

9.1 Exposure Scenarios

Occupational handler and post

- application exposure scenarios were assessed for the proposed uses

. Based on the product labels and informat ion 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 to protect for the possibility of common toxicological endpoints

.

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 registration action, diflubenzuron products are applied using aerial, groundboom, airblast, and chemig ation equipment.

9.2.1 Handler Exposure Scenarios

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

1) Mixing/loading liquids for aerial, chemigation, groundboom, and airblast applications; 2) Applying sprays via aerial, airblast and groundboom equipment; and 3) Flagging for aerial applications.

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.Diflubenzuron (108201) Human Health Risk Assessment DP#: 4233 28

Page 33 of 71 Application Rate : The application rate s used in this assessment are provided in Table 3.3.2.2.

Unit Exposures: It is the policy of HED to use the best available data to assess handler exposure. Sources of generic handler data, used as surrogate data in the absence of chemical

- specific data, include 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 Exposur e 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,

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

- exposure

- data.html

.

9.2.3 Handler Exposure Assumptions

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

 1200 and 350 acres for aerial application to high and typical acreage crops, respectively

 200 and 80 acres for groundboom application to high and typical acreage crops, respectively

 40 a cres for airblast applications

 350 acres for flaggers

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 Because the short

- and intermedia te

- term dermal and inhalation PODs were based on route

specific toxicity studies, no absorption factors were necessary to estimate exposure.

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

- term and exposures 30 days to six months a s 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 large 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) Estimates of dermal and inhalation exposure were calculated for the baseline level of personal protective equipment (PPE), which is define d as a single layer of clothing consisting of a longDiflubenzuron (108201) Human Health Risk Assessment DP#: 4233 28

Page 34 of 71 sleeved shirt, long pants, shoes plus socks, no protective gloves, and no respirator. The diflubenzuron product label directs mixers, loaders, applicators and other handlers to wear long

sleeved shirt a nd long pants, shoes plus socks, and chemical

- resistant gloves ; further, mixers/loaders for aerial application are also required to wear a dust/mist filtering respirator.

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:

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/kg body weight/day), Daily Exposure = Amount (mg ai/day) deposited on the surface of the skin that is available for dermal absorption or amount inhaled that is available for inhalation absorption, Absorption Factor = A measure of the amount of chemical that crosses a biological boundary such as the skin or lungs, and Body Weight = Body weight determined to represent the population of interest in a

risk assessment.

Margin of Exposure (MOE):

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 val ues 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 the 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 exposure routes were similar. Dermal and inhalation risk estimates were combined using the following formula:Diflubenzuron (108201) Human Health Risk Assessment DP#: 4233 28

Page 35 of 71 Total MOE = 1/ (1/Dermal MOE) + (1/Inhalation MOE )

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. 4 . The combined dermal and inhalation e xposure risks are not of concern (i.e., MOEs >100) at baseline PPE, with estimates ranging from 1,200 to
420,000 . T he label also requires chemical resistant gloves to be worn during most mixing and loading activities

, and a respirator is included while mi xing and loading of a liquid for aerial applications.

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); per the Agency’s Worker Protection Standard stipulations for engineering controls, pilots are not required to wear protective gloves for the dura tion of the application. With this level of protection, there are no risk estimates of concern for applicators.

The Agency matches quantitative occupational exposure assessment with appropriate characterization of exposure potential. While HED presents q uantitative risk estimates for human flaggers where appropriate, agricultural aviation has changed dramatically over the past two decades. According the 2012 National Agricultural Aviation Association (NAAA) survey of their membership, the use of GPS for s wath guidance in agricultural aviation has grown steadily from the mid 1990’s. Over the same time period, the use of human flaggers for aerial pesticide applications has decreased steadily from ~15% in the late 1990’s to only 1% in the most recent (2012) N AAA survey. The Agency will continue to monitor all available information sources to best assess and characterize the exposure potential for human flaggers in agricultural aerial applications.Diflubenzuron (108201) Human Health Risk Assessment DP#: 4233 28

Page 36 of 71 Table 9

. 2

. 4 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 Maximum

Application Rate (lb ai/A) 2 Area

Treated (acres) 3 Dermal

(LOC = 100) Inhalation

(LOC = 100) Total

(LOC = 100)

Baseline Baseline Dose (mg/kg/day) 4 MOE 5 Dose (mg/kg/day) 4 MOE 5 MOE 6

Mixer/Loader

Aerial/
chemigation application of liquid formulation Pepper/Eggplant Subgroup

220 0.219 0.125 350 0.12 4,200 0.00012 170,000 4,100

Alfalfa, Cottonseed 1200 0.413 1,200 0.00041 49,000 1,200

Groundboom/
chemigation application of liquid formulation Carrot, Pepper/Eggplant Subgroup 80 0.0275 18,000 0.000027 740,000 18,000

Cottonseed 200 0.0688 7,300 0.000069 300,000 7,100

Airblast/
chemigation application of liquid formulation Peach, Plum, Tree nuts 0.25 40 0.0275 18,000 0.000027 740,000 18,000

Applicator

Aerial spray application Pepper/Eggplant Subgroup 2.08
(engineering control) 0.0049

(engineering control)

0.125 350 0.00114 440,000 0.00000268 7,600,000 420,000

Alfalfa, Cottonseed 1200 0.0039 130,000 0.00000919 2,200,000 120,000

Groundboom spray application Carrot, Pepper/Eggplant Subgroup 78.6 0.34 80 0.00983 51,000 0.000043 480,000 46,000

Cottonseed 200 0.0246 20,000 0.00011 190,000 18,000

Airblast spray application Peach, Plum, Tree nuts 1770 4.71 0.25 40 0.221 2,300 0.00059 34,000 2,200

Flagger

Flagger for aerial spray application Pepper/Eggplant Subgroup

, Cottonseed 11 0.35 0.125 350 0.00601 83,000 0.00019 110,000 47,000

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

2 Based on proposed label (Reg. No. 400

- 461 ).

3 Exposure Science Advisory Council Policy #9.1. Note: Aerial application is proposed for alfalfa, cottonseed, and pepper/eggplant Subgroup only.

4 Dose = Unit Exposure ( μg /lb ai) × Conversion Factor (0.001 mg/ μg ) × Application Rate (lb ai/acre) × Area Treated (A/day) ÷ BW ( 80 kg).

5 MOE = NOAEL ÷ Dermal or Inhalation Dose (mg/kg/day); where dermal NOAEL = 500 mg/kg/day and inhalation NOAEL = 20.3 mg/kg/day

. 6 Total MOE = 1 ÷ [(1 ÷ Dermal MOE) + (1 ÷ Inhalation MOE)]Diflubenzuron (108201) Human Health Risk Assessment DP#: 4233 28

Page 37 of 71 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 re

- entry exposure). Such exposures may occur when workers enter previously treated areas to perform job functions, including activities related to crop production, such as scouting for pests or harvesting.

Post

- applicatio n exposure levels vary over time and depend on such things as the type of activity, the nature of the crop or target that was treated, the type of pesticide application, and the chemical’s degradation properties. In addition, the timing of pesticide appli cations, relative to harvest activities, can greatly reduce the potential for post

- application exposure.

9.3.1 Post Application Inhalation Exposure Scenarios

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 v olatilization of pesticides from 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.gov/scipoly/SAP/meetings/2009/120109meeting.html ). The agency has evaluated the SAP report and has developed a Volatilization Screening Tool and a subsequent Volatilization Screening Analysis ( http://www.regulations.g ov/#!docketDetail;D=EPA

- HQ

- OPP

2014

- 0219 ). During Registration Review, the agency will utilize this analysis to determine if data (i.e., flux studies, route

- specific inhalation toxicological studies) or further analysis is required for

diflubenzuron.

In addition, the Agency is continuing to evaluate the available post

- application inhalation exposure data generated by the Agricultural Reentry Task Force. Given these two efforts, the Agency will continue to identify the need for and, subsequently, the way to incorporate occupational post

application inhalation exposure into the agency's risk assessments.

Although a quantitative occupational post

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

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

- application inhalation exposure scenarios.

Furthermore, inhalation exposure during dusty mechanical activities such as shaking and mechanical harvesting is another potential source of post

- application inhalation ex posure. However, the airblast applicator scenario is believed to represent a reasonable worst case surrogate estimate of post

- application inhalation exposure during these dusty mechanical harvestingDiflubenzuron (108201) Human Health Risk Assessment DP#: 4233 28

Page 38 of 71 activities. The non

- cancer inhalation risk estimate for commercial airblast application is not of concern (i.e., MOE > 100).

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.

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

- term and exposures 30 days to six months as

intermediate

- term. For diflubenzuron, short

- and intermediate

- term exposures are expected for the following reasons: (1) diflubenzuron is an insect growth regulator that is recommended to be applied at various stages throughout the season; (2) up to 2 to 6 foliar applications can be made per season 5 to 21 days apart, depending on the crop; and (3) commercial applicators may apply this product at various locations within a region over a period of weeks. In addition, the short

- and

intermediate

- term PODs are the same; therefore, short

- term risk estimates are protective of longer

term exposures.

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 ARTF exposure monitoring studies, and, as proprietary data, are subject to the data protection provision s of FIFRA. The standard values recommended for use in predicting

post

- application exposure that are used in this assessment, kno wn as “transfer coefficients”, are presented in the 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 the Agency website ( http://www.epa.gov/pesticides/science/post

- app

- exposure

- data.html )

.

For this assessment, post

- application dermal exposure was assessed for the activity with the highest transfer coefficient for each crop/crop group, and is considered to be protective of all other activities within that crop/crop group.

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 dev elopmental and/or feta l

effects.

Absorption Factor

s Because the short

- and intermediate

- term dermal PODs were based on route

- specific toxicity studies, no absorption factors were necessary to estimate exposure.Diflubenzuron (108201) Human Health Risk Assessment DP#: 4233 28

Page 39 of 71 Application Rate The application rates used in this assessment are provided in Table 3.3.2.2

.

Exposure Time The average occupational workday is assumed to be 8 hours.

Residues

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% each following day.

In addition, no chemical

- specific data are a vailable for the amount of residue available on the cotton bolls; i.e., dislodgeable boll residue (DBR) data. However, surrogate data are available from a study with the active ingredient tribufos; (MRID 42701601). Note to RD: These data may trigger a d ata compensation issue between registrants. The residue data from this study were reviewed previously and found to be acceptable in risk assessment (Memo, B. Tarplee, 3/12/1997, D227007). The average DBR levels (μg/50 gram sample) were analyzed using lin ear regression to estimate the dissipation over time. For screening purposes, the Day 0 predicted cotton boll residue value, adjusted for the difference in application rate between the study and the proposed label, was used as a surrogate residue level fo r this assessment.

Occupational Post

- application Non

- Cancer Dermal Exposure and Risk Estimate Equations The algorithms used to estimate non

- cancer exposure and dose for occupational post

- application

workers are presented below:

Average Daily Dose (ADD)

P otential daily exposures for occupational post

- application workers were calculated using the following formulas:

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:Diflubenzuron (108201) Human Health Risk Assessment DP#: 4233 28

Page 40 of 71 Daily Exposure = Amount (mg ai/day) that 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 weight/day), Daily Exposure = Amount (mg ai/day) that is available for dermal absorption, Absorption Factor = A measure of the amount of ch emical that crosses a biological boundary such as the skin (%), and Body Weight = Body weight determined to represent 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)

where:

MOE = Margin of Exposure: value used by HED to represen t 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 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 EstimatesDiflubenzuron (108201) Human Health Risk Assessment DP#: 4233 28

Page 41 of 71 The short

- and intermediate

- term post

- application exposure scenarios associated with the proposed

uses for diflubenzuron are summarized in Table 9

. 3

. 3

. 1

. All scenarios resulted in MOEs greater than the LOC of 100 (ranging from 2,000 to 68,000) on day 0 (1 2 hours after application) and, therefore, are not of concern to HED.

Table 9

. 3

. 3

. 1. Occupational Post

- application Non

- Cancer Exposure and Risk Estimates for Diflubenzuron

.

Crop/Site Activities Transfer

Coefficient (cm 2 /hr) Proposed

Application Rate (lb ai/A) DFR

(μg/cm 2 ) 1 Dermal Dose

(mg/kg/day) 2 MOE 3

(LOC = 100)

Short

- and Intermediate

- term

Carrots Vegetable, root 1,900

0.125 0.35 0.067 7,500

Alfalfa Field / row crop, low

/ medium 210 0.007 68,000

Pepper/Eggplant Vegetable, fruiting 1,900 0.067 7,500

Cottonseed Field / row crop, low

/ medium 5050 (g cotton

boll/hr) 0.10 μg/g 0.051 9,900

Peach, Plum Tree, “fruiting”,

deciduous 3,600

0.25 0.70 0.252 2,000

Pecans (and other tree nuts) Tree, "nut" 580 0.041 12,000

1 DFR = Application Rate (lb ai/A) × F × (1

- D) t × 4.54E8 μg/lb × 2.47E

- 8 acre/cm 2 ; where F = 0.25 and D = 0.10 per day. Note: cotton harvesting dislodgeable boll residue (DBR) = (Best fit DBR at 0 days, MRID# 42701601 (75.55 μg/50g) x Proposed Application Ra te (0 .125 lb ai/A)) / Study Application Rate (1.88 lb ai/A) = 0.10 μg/g

2 Daily Dermal Dose = [DFR (μg/cm 2 ) × Transfer Coefficient × 0.001 mg/μg × 8 hrs/day  BW (80 kg).

3 MOE = POD (500 mg/kg/day) / Daily Dermal Dose.

Restricted Entry Interval (REI) The REI specified on the proposed label is based on the acute toxicity of diflubenzuron. Diflubenzuron has low acute toxicity via the dermal route (Toxicity Category III), is minimally irritating to the eyes (Toxicity Category III), and is not a dermal ir ritant (Toxicity Category IV).

Diflubenzuron was not shown to be a skin sensitizer. Short

- and intermediate

- term post

application risk estimates were not a concern on day 0 (12 hours following application) for all

post

- application activities. Under 40 C FR 156.208 (c) (2) (iii), a ctive i ngredient s classified as Acute III or IV for acute dermal, eye irritation and primary skin irrigation are assigned a 12

- hour REI. Therefore, the [156 subpart K] Worker Protection Statement interim REI of 12 hours is adequ ate to protect agricultural workers from post

- application exposures to diflubenzuron

.

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 25%. Of the analyzed DFR s tudies, 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 default dislodged residueDiflubenzuron (108201) Human Health Risk Assessment DP#: 4233 28

Page 42 of 71 valu e would provide an adequate margin of safety for any potentially higher residues seen in a

chemical

- specific DFR study. As shown in Table 9.3.3.1, a conservative, screening

- level

assessment of intermediate

- term post

- application exposure to agricultural workers yields MOEs

of 2,000 and greater on “DAT 0”, which are above the waiver criteria of 4x the LOC (400). Therefore, a DFR study is not required f or diflubenzuron at this time.Diflubenzuron (108201) Human Health Risk Assessment DP#: 4233 28

Page 43 of 71 10.0 REFERENCES

Diflubenzuron. Chronic Non

- Cancer and Cancer Dietary and Drinking Water Exposure and Risk Assessments in Support of the New Use Registration of Diflubenzuron Formulated Product on Alfalfa, Carrot, Cottonseeds Subgroup 20C, Peach Subgroup 12

- 12B, Plum Subgroup 12

- 12C Peppers/Eggplant Subgroup 8

- 10B and Conversion for Tree Nuts Group 14

- 12. S

. Bose Biswas

, D427147, 08/05 /15

Diflubenzuron: Occupational and Residential Exposure and Risk Assessment for Proposed Use on Alfalfa, Carrot, Peach, Plum, Pepper/Eggplant, Cottonseed, and Tree Nut

. K

. O’Rourke

, D 4 28151

, 8 /1 2 /201 5

.

Diflubenzuron. Petition for the Establishment of Permanent Tolerances and Registration for New uses on Alfalfa and Carrot; and Crop group Expansion for Peach Subgroup 12

- 12B; Plum Subgroup 12

- 12C; Nut, Tree, Group 14; and Pepper/Eggplant Subgroup 8

- 10B. Summary of Analytical Chemistry and Residue Data. S

. Bose Biswas , D423328, 08/05/15

Ecological Risk and Drinking Water Assessments for Proposed Label Amendments of Diflubenzuron. F. Khan, D423330, 04/20/2015

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.Diflubenzuron (108201) Human Health Risk Assessment DP#: 4233 28

Page 44 of 71 APPENDICES

A PPENDIX A TOXICOLOGY DATA SUMMARY

A. 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

yes

yes y es

yes

yes

*HASPOC waived the acute and subchronic neurotoxicity studies (TXR 0056309)

.Diflubenzuron (108201) Human Health Risk Assessment DP#: 4233 28

Page 45 of 71 B. 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 -

Table A.2. Subchronic, Chronic and Other Toxicity Profile

– Diflubenzuron

Guideline No. Study Type MRID No. (year)/ Classification

/Doses Results

870.3100 Gavage S ubchronic

–

Mice ( 14

- day study ) 00099713 (1997) Acceptable/N on

- guideline

0. 8, 40, 200, 1000 or 5000 mg/kg/day NAOEL = 40 mg/kg/day LOAEL=200 mg/kg/day.

based on increased sulfhemoglobin and erythrocytes containing

Heinz bodies

870.3100 Feeding Subchronic, (28

-

day) study in rats. 00070018 (1977) Acceptable/ G uideline 0 (control) , 800, 4,000, 20,000 or
100,000 ppm (equivalent to 0, 40, 200, 1,000 or 5,000 mg/kg/day). NOA EL= 40 mg/kg/day,

L OAEL=200 mg/kg/day,

I ncreased me themoglobin in males, increased sulfhemoglobin in males and females, increased spleen weights in males

and females.

870.3100 13

- week feeding study in

rats 00064550, 00074534 (1980) Acceptable / N on

- guideline

0 , 160, 400, 2000, 10000 or 50000

ppm (equivalent to 0, 8, 20, 100, 500 or 2500 mg/kg/day). NO AEL= not established

L OAEL=8 mg/kg/day, Increased methemoglobin

and signs of hemolytic anemia, erythrocyte

destruct ion in the spleen

and liver and regeneration of erythrocytes in the

bone marrow.

870.3100 13

- week feeding study in

Mice. 00142490 ( 1984 ) Acceptable/ Guideline 0 (control), 16, 80, 400, 2,000 or 10,000 ppm (equivalent to 0, 2.4, 12, 60, 300 or 1,500 mg/kg/day). NOAEL=2.4 mg/kg/day LOAEL=12 mg/kg/day.

Dose

- related, statistically significant increases in methemoglobin and sulfhemoglobin were consistently observed inDiflubenzuron (108201) Human Health Risk Assessment DP#: 4233 28

Page 46 of 71 male and female mice throughout the study at dose levels of 12 mg/kg/day and higher.

870

- 3150 13

- week feeding in dogs 00038706 (1974) Acceptable /G uideline

0 , 10, 20, 40 or 160 ppm (equal to
0, 0.42, 0.84, 1.64 or 6.24 mg/kg/day). NO AEL= 1.64 mg/kg/day

L OAE L = 6.24 mg/kg/day,

based on increased Methemoglobinemia.

870.3200 21

- day dermal study in

rabbits. 00038716 (1975) Acceptable/G uideline 21.5%, 10% or 4.64% suspensions of technical grade diflubenzuron were applied 5 days/week at the rate

of 1.5 mL/kg/day

. NOAEL was not

observed.

LOAEL= 69 mg/kg/day (based on increased methemoglobin at 4.64% suspension applied at the rate of 1.5 mL/kg/day).

780.3465 21

- day inhalation study in

rats. 00044325 (1975) Acceptable /G uideline 0 (control), 0.121, 0.866 or 1.85 mg/liter of Diflubenzuron 25% Wettable Powder. Exposures were for 1 hour/day, 5 days/week for 3

weeks. Methemoglobin and sulfhemoglobinemia were

observed in all treated

groups.

NOAEL= not observed.

LOA EL= 0.121 mg/L (of 25% wettable powder

870.4100 a 104

- week rat chronic

feeding study

. 00044329 (1975), 00099712 (1977) Unacceptable 0 (control), 10, 20, 40 or 160 ppm (equivalent to 0, 0.35, 0.70, 1.43 or 5.83 mg/kg/day in males and
to 0, 0.43, 0.88, 1.73 or 7.05 mg/kg/day in females). Blood testing at weeks 13, 26, 52, 78 and 102. Sulfhemoglobin and methemoglobin formation were assayed for the control, 40 and 160 ppm groups onl y. Sulfhemoglobin

formation was not
detected

. The NOAEL for methemoglobinemia =1.43 mg/kg/day in males

and 1.73 mg/kg/day in

females.

The L OAEL = 5.83 mg/kg/ day in males and

7.05 in females.

870.4100 a 104

- week rat chronic

feeding study

. 00145467 (1984)

Guideline (m inimum ) 0 (control), 156, 625, 2,500 or 10,000 ppm (equivalent to 0, 7.8, 31, 125 or 500 mg/kg/day ). A dose

- dependent, statistically significant

increases in methemoglobin and sulfhemoglobin in male

and female rats at 52

weeks and 104 weeks at

all treatment levels tested.

NOAEL w as not
established.

LOAEL= 7.8 mg/kg/day

.Diflubenzuron (108201) Human Health Risk Assessment DP#: 4233 28

Page 47 of 71 870.4100b 52

- week dog chronic

feeding ( gelatin capsules ) study

. 00146174 (1985) Acceptable/Guideline

0 (control), 2, 10, 50 or 250 mg/kg/day

. NO AEL= 2 mg/kg/day

. L OAEL= 10 mg/kg/day,

Based on s tatistically significant increases in

methe moglobin and sulfhemoglobin observed in male and female dogs.

870.4100b Carcinogenicity study in

rats (104 weeks). 00145467 (1984) Acceptable (minimum)/Guideline 0 (control), 156, 625, 2,500 or 10,000 ppm (equivalent to 0, 7.8, 31, 125 or 500 mg/kg/day

. Dosing was adequate since the highest dose level tested, 500 mg/kg/day, approached the li mit dose of 1,000 mg/kg/day for carcinogenicity studies and significant toxicity ( particularly methemoglobinemia, sulfhemoglobinemia, er ythrocyte

destructio n, compensatory regeneration

of erythrocytes and hemolytic anemia)

was observe d at this dose level. Increases in methemoglobin and sulfhemoglobin were

observed at all treatment

levels.
NOAEL was not

observed. LOAEL= 7.8 mg/kg/day

based on h istopathological signs of erythrocyte

destruction and compensatory regeneration

. Treatment with

diflubenzuron was not

associated with an increased

incidence of neoplastic

lesions in either males or

females.

870.4100b 91

- week carcinogenicity

study in rats. 00142490 (1984) Acceptable /Guideline 0 (control), 16, 80, 400, 2,000 or 10,000 ppm (equivalent to 0, 2.4, 12, 60, 300 or 1,500 mg/kg/day). Dosing was adequate since the highest dose tested, 1,500 mg/kg/day, exceeded

the limit dose of 1,000 mg/kg/d ay for carcinogenicity studies. NOAEL= 12 mg/mg/day. LOAEL = 2.4 mg/kg/day

based on consistent increases

in methemoglobin and sulfhemoglobin in both sexes throughout the study.

Literature study Carcinogenicity Studies on

p

- Chl oroaniline (Metabolite of Diflubenzuron)

24

- month carcinogenicity

gavage study in rats. National Toxicology Program (NTP) Report No. 351; July, 1989)

. 0 (vehicle control), 2, 6 or 18 mg/kg/day of p

chloroaniline (PCA). Acceptable /N on

- guideline. NOAEL was not established. LOAEL=6 mg/kg/day based

on showed mild hemolytic

anemia and dose

- related

increases in m ethemoglobin

in both sexes. Histopathological

examinations indicated non

neoplastic t reatment

- related

effects in the spleen, liver,

bone marrow and adrenal gland. A treatm ent

- related

increased incidence of

uncommon sarcomas of the spleen was observed in the male rats in this study.

Literature study Carcinogenicity Studies on

p

- Chloroaniline (Metabolite of Diflubenzuron) (National Toxicology Program (NTP) Report No. 351; July, 1989). 0 (vehicle control), 3, 10 or 30 mg/kg/day of p

- chloroaniline. NOAEL was not established. LOAEL=3 mg/kg/day based

on p roliferation of hematopoietic cells in theDiflubenzuron (108201) Human Health Risk Assessment DP#: 4233 28

Page 48 of 71 24

- month carcinogenicity gavage study in mice. live rs of female mice at all

treatment levels

. Increased

incidences of combined Hepato

- cellular adenomas/

carcinomas in male mice

.

870.3700 Developmental toxicity

study (gavage) in rats 41703504 (1988) Acceptable /N on

- guideline 0 (control) or 1,000 mg/kg/day (limit

dose study). The NOEL for maternal toxicity is 1,000 mg/kg/day and the N OEL for developmental to xicity is 1,000 mg/kg/day. NOAEL (maternal & developmental) =1000 mg/kg/day. LOAEL (maternal & developmental) was not

observed. No ma ternal toxicity or toxicity to the developing fetus was

observed in this study.

870.3700b Developmental toxicity

study (gavage) in rabbits. 41703505 (1988) Acceptable /G uideline 0 (control) or 1,000 mg/kg/day (limit

dose study ). NOAEL (maternal & developmental) =1000 mg/kg/day. LOAEL (maternal & developmental) was not

observed. No maternal toxicity or toxicity to the developing fetus was

observed in this study.

870.3800 2

- generation reproduction

study in rats (diet) 43578301 (1995)
Acceptable/ Guideline 0 (control), 500, 5,000 or 50,000 ppm (equivalent to about 0, 25, 250 or 2,500 mg/kg/day). NOAEL ( maternal ) was

not identified. LOAEL=25 mg/kg/day

based on methemoglobinemia, hemolytic anemia,

destruction of erythrocytes, and pathological chan ges in the spleen and liver.

NOAEL=2500 mg/kg/day ( reproductive )

LOAEL was not

identified.

NOAEL= 250 mg/kg/day ( Reproductive effects in the

progeny )

LOAEL= 2,500 mg/kg/day,

based on decreased bodyDiflubenzuron (108201) Human Health Risk Assessment DP#: 4233 28

Page 49 of 71 weights in F1 pups from birth to 21 days post

- partum.

870.5100 Salmonella/mammalian

microsome plate incorporation assay 41703503 (1990) Acceptable /Guideline

C oncentra tions of 0, 8, 40, 200 or 1,000 μg/plate. No evidence of induced

mutant colonies over background levels at any of

the evaluated concentrations.

870.5XXX in vitro chromosome damage

assay 41703501 (1990) Acceptable/Guideline

C oncentrations up to cytotoxic/ precipitating levels of 200

- 250 μ g/ml. The test material did not

i nduce an increase in

structural chromosome aberrations over background

levels at any of the evaluated

concentrations.

870.5XXX Unscheduled DNA synthesis

(UDS) assay 41703501 (1986)

C oncentrations of 0.1 to 333 μg/ml. At the high dose of 333 μg/ml, cytotoxicity was

observed. The test material

did not cause an appreciable

increase in net nuclear grain counts compared to the

solvent control at any of the

evaluated concentrations.

870.7485 General metabolism (rats) 41919001 (1990) Supplementary

, 44875502 (1999) Acceptable/Non

- guideline

14 C diflubenzuron ( by gavage) at single

dose level of 104 mg/kg

. Metabolites

were characterized in urine and feces collected at 20, 48, 72 and 96 hrs post

dosing. [ 14 C]

- diflubenzuron was

well

- absorbed (at 96 hrs

post

- dosing, 2.22% of administered radioactivity

was recovered in the urine and 87.4% in the feces).

About 68% administered radioactivity was recovered within 20 hrs post

- dosing

and 15% was recovered

between 2 0

- 48 hrs post

dosing. Most of the

administered diflubenzuron

was excreted in the feces (87.4%); no other fecal

metabolites were identified

at de tectable levels. 9

metabolites were isolated

and identified in urine. The 2 major metabolites in the

urine we re 4

- chloroaniline

2

- sulfate (0.9% of administered radioactivity;

45% of total recovered radioactivity in urine) and N

- (4

- chlorophenyl)oxamic acid (0.1 to 0.2% of administered radioactivity and 13% of the TRR). Radioactivity in expired air was negligible.

Th e half

- life of radioactivity

in blood was about 14 hours. By 7 days, over 98% of the administered radioactivity

was excreted.Diflubenzuron (108201) Human Health Risk Assessment DP#: 4233 28

Page 50 of 71 C. Toxicological Endpoints

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 dietary risk was not assessed.

Chronic Reference Dose (cRfD)

- All Populations

This endpoint was established in 1986. It was reassessed by HIARC 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 ea ch 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

ob served 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 an d 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,

destructi on 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).

Chronic RfD = 2.0 mg/kg/day (NOAEL) = 0.02 mg/kg/dayDiflubenzuron (108201) Human Health Risk Assessment DP#: 4233 28

Page 51 of 71 100 (UF)

Comments about Study/Endpoint/Uncertainty Factor : The HIARC (08/14/2001)

concurred with the dose, endpoint, and the uncertainty factor selected by the RFD

Committee in 1986.

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 2 C 14

- diflubenzuron technical in gum tragacanth [0.25%]. Four [4] animals per dose group were sacrificed after either 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.

Dermal Exposure (Short and Intermediate

- Te rm)

Dermal Exposure (Short

- Term)

Study Selected: 21

- Day derm al 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/s ex/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 wei ght 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 e levations 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 dose there were statistically significant (P < 0.05) decreases in RBC coun t, 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 significa ntly (P < 0.05 & 0.01) in males and females at 1000 mg/kg dose. There was increased incidence of anisocytosis,Diflubenzuron (108201) Human Health Risk Assessment DP#: 4233 28

Page 52 of 71 hypochromasia and polychromasia in males and females at the top dose. On August 14, 2001, the HED HIARC re

- evaluated the study and concluded th at 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 Assessme nt: 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., me themoglobin and/or sulfhemoglobin. Previously, the end

- points for short

- term exposure was based on a 14

- day mouse 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 meth emoglobinemia seen at 500 mg/kg/day was within normal physiological parameters, but occurred at adverse levels at 1000 mg/kg/day (Limit Dose).

Dermal Exposure (Intermediate

- Term)

Study Selected: 13

- week oral [sub chronic] 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 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 urinalyses were performed at 6 and 12 weeks. Ophthalmos copic 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 weig hts 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 w ere 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

discussio n below.

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 studyDiflubenzuron (108201) Human Health Risk Assessment DP#: 4233 28

Page 53 of 71 and the mouse study, a NOAEL of about 2 mg/kg/day was calculated by regression analysis. Considering all the available d ata (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 assessment s 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 dose levels of 0 (control), 2, 10, 50 o r 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 dif

lubenzuron. 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 i ncreases 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 le vels 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. Absolute spleen and liver weigh ts, 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 methemoglobinemia and sulfhemoglobine mia 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 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 400.0Diflubenzuron (108201) Human Health Risk Assessment DP#: 4233 28

Page 54 of 71 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 patter n then this risk assessment will be required.

Inhalation Exposure (Short

- , Intermediate

- , and Long 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 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.

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 evenDiflubenzuron (108201) Human Health Risk Assessment DP#: 4233 28

Page 55 of 71 though it was not seen in the critical study.

Inhalation Exposure (Intermediate

- Term)

Study Selected: Twenty

- eight day rat inhalation

MRID No .: 44950601

Executive Summary: see Short

- Ter m 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 studies 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 assessment. There are no residential uses at the present timeDiflubenzuron (108201) Human Health Risk Assessment DP#: 4233 28

Page 56 of 71 D. E xecutive Summaries

870.3100 Oral Subchronic Toxicity

- R odent

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 methemoglobin, sul fhemoglobin 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 organs 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.

870.31 50 Oral Subchronic Toxicity

- Nonrodent

Study Selected: 13 week oral [subchronic] feedin g 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 and 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 urinalyses were performed at 6 and 12

we eks. 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 sign s, 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 histopathologica l changes were reported at any level that could

be related to treatment with diflubenzuron.

Endpoint and dose for use in risk assessment: Calculated NOEL 2.0 mg/kg/day based on increasedDiflubenzuron (108201) Human Health Risk Assessment DP#: 4233 28

Page 57 of 71 methemoglobinemia at 6.24 mg/kg/day.

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 th e 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 that 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 deter mined 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 1,0 00 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 h yperkeratosis 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 100 0 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 incidence of anisocytosis, hypochromasia and polyc hromasia 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 based on methemoglobinemia.

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

Comments about Study/Endpoint : This dermal toxicity study in rat s 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

- dayDiflubenzuron (108201) Human Health Risk Assessment DP#: 4233 28

Page 58 of 71 mouse 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 at 1000 mg/kg/day.

870.3250 Intermediate

- Term D ermal 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 study was chosen. However, since an oral NOAEL was s elected 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 below

.

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 a ppropriate duration of exposure. Assume that inhalation absorption is equivalent to oral absorption.

870.3700 Developmental Toxicity

870.3700a Prenatal Developmental Toxicity Study

– Rodent

Study Selected: Developmental Toxicity

– Rat

MRID No.: 41703504Diflubenzuron (108201) Human Health Risk Assessment DP#: 4233 28

Page 59 of 71 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 achieved.

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 t oxicity, 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 the premating g rowth 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. 00145467

Executive Summary: See 870.4300 Carcinogenicit y

- Rat below.

The combined chronic oral toxicity/oncogenicity study in the rat is classified Acceptable/guideline

and satisfies th e guideline requirements for a chronic toxicity and oncogenicity study in rats.Diflubenzuron (108201) Human Health Risk Assessment DP#: 4233 28

Page 60 of 71 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 ( particularly methemoglobinemia, sulfhemoglobinemia, erythrocyte

destructio n, 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 ea ch 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 ob served 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 an d 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,

destructi on of erythrocytes and of compensatory 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. 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/day 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/Endpoint/Uncertainty Factor : The HIARC concurred with the dose, end point, and the uncertainty factor selected by the RFD Committee in 1986.

870.4200a Carcinogenicity

– RatDiflubenzuron (108201) Human Health Risk Assessment DP#: 4233 28

Page 61 of 71 Study Selected : Oncogenicity Study

- Rat

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

Executive Summary: In a carcinogenicity stud y, p

- choloroaniline (> 99% purity) 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 a t 2, 6, and 18 mg/kg/day relative 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 femal e groups generally remained within 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 g land. Treatment

- related increased 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 i ncidence 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 fibrosarcoma was observed at a 6 mg/kg/day and 1 osteosarcoma at 18 mg/kg/day. No additional uncomm on 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.

Systemic toxicity NOAEL 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 classifie d Acceptable/non

- guideline and does not satisfy the guideline requirements for an 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. The se sarcomas included fibrosarcomas, hemangiosarcomas, and osteosarcomas, many of which metastasized to other sites. The 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, one fibrosarcoma was observed at a 6 mg/kg/day and 1 osteosarcoma at 18 mg/kg/day. No additional uncommon sarcomas of the spleenDiflubenzuron (108201) Human Health Risk Assessment DP#: 4233 28

Page 62 of 71 were observed in female rats in this study. A marginally increased incidence of pheochromocytoma s 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

incidenc es of mononuclear cell leukemia and of malignant lymphoma 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 cyanosis 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

adminis tered 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 we re used 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 l evels 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 destruction 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 considere d adequate 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 methemoglobin 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 either male

or female mice.Diflubenzuron (108201) Human Health Risk Assessment DP#: 4233 28

Page 63 of 71 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) Study 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 an oncogenicity s tudy 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, respecti vely. 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 (1/5 0, 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 dos e levels of 0, 3, 10, and 30 mg/kg/day, respectively.Diflubenzuron (108201) Human Health Risk Assessment DP#: 4233 28

Page 64 of 71 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 ( particularly methemoglobinemia, sulfhemoglobinemia, erythrocyte destruction, compensatory regeneration of erythrocytes and hemolytic anemia) was observed at this dose level. Systemic Toxicity NOAEL

was not established . 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 th e 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 carcinogenicity studies and significant toxicity ( particularly methemoglobinemia, sulfhemoglobinemia, erythrocyte

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

this dose level.

870.7485 Metabolism

– RatDiflubenzuron (108201) Human Health Risk Assessment DP#: 4233 28

Page 65 of 71 Study Selected : Metabolism Study

- Rat

MRID No.: 44875501, 44875502

Recently submitted rat metabolism data indicate that diflubenzuron does not metabolize to 4

- chloroaniline ( PCA ) or 4

- chlorophenylurea ( CPU ) nor is CPU converted to PCA. The HEDMARC met several times (2/20/01 and 5/8/01), concurred with the findings and con cluded that a 2% in

vivo conversion factor 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 r ecommended that non

- carcinogenic risk assessment 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 2 . 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

Mutagenic i ty

– 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/pla te. 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 activ ation 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.

Mutagenicity

– Structural Chromosomal AberrationsDiflubenzuron (108201) Human Health Risk Assessment DP#: 4233 28

Page 66 of 71 MRID No.: 41703502

Executive Summary: 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/precipit ating 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 any of the evaluated concentrations.

Mutagenicity

– 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 o b served (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 the evaluated concentrations. Diflubenzuron did not induce a gen o toxic effect in this assay system.

870. 7 800 Immunotoxicity

Selected Study : 28

- Day (Diet ary) 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 noted 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 control group. There wereDiflubenzuron (108201) Human Health Risk Assessment DP#: 4233 28

Page 67 of 71 statistically significantly increase (p<0.05) of abs olute and relative spleen weights at 2,000 and 10,000 ppm, but no treatment related changes in thymus weights. Positive control group (cyclophosphamide) had statistically significantly decrease (p<0.05) of absolute and relative spleen and thymus weights; b ut 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 previou s 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 i n 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 response. 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 validity of the study design.

The Natural Killer (NK) cells activity was not e valuated 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 suggests that the chemical does not directly target the immune system. Under H ED 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 immunotoxicity 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.Diflubenzuron (108201) Human Health Risk Assessment DP#: 4233 28

Page 68 of 71 APPENDIX B. Chemical Names and Structures of Diflubenzuron and Metabolites

Diflubenzuron

4

- chlorophenylurea: CPU

4

- chloroaniline: PCADiflubenzuron (108201) Human Health Risk Assessment DP#: 4233 28

Page 69 of 71 APPENDIX C. Physical/Chemical Properties

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 availableDiflubenzuron (108201) Human Health Risk Assessment DP#: 4233 28

Page 70 of 71 APPENDIX D

. International Residue Limits Table

International Residue Limits

Diflubenzuron (PC Code 108201; 6/16/2015)

Summary of US and International Tolerances and Maximum Residue Limits Residue Definition :
US Canada Mexico 2 Codex 3

40 CFR §180.377: Plant: diflubenzuron (N

- [[(4

- chlorophenyl)amino]carbonyl]

- 2,6

- difluorobenzamide)

Livestock: diflubenzuron None Diflubenzuron (fat

soluble).

Commodity 1 Tolerance (ppm) /Maximum Residue Limit (mg/kg)

US Canada Mexico 2 Codex 3

Carrot, roots 0.2 0

Peach subgroup 12

- 12B 0.5 0 0.5 peach, nectarine
Plum subgroup 12

- 12C 0.5 0 0.5 plums (including prunes)

Nut, tree, group 14

- 12 0. 20 0.2 tree nuts
Pepper/Eggplant subgroup

8

- 10B 1.0 3 peppers, chili 20 peppers, chili, dried 0.7 peppers, sweet
Carrot, roots 0.2 0

Alfalfa, forage 6 .0

Alfalfa, hay 20

Alfalfa, seed 0.9 0

Cottonseed subgroup 20C 0.2 0

Egg 0. 07 0.05 (*)
Poultry, fat 0. 10

Poultry, meat byproducts 0.0 8

Completed by: M. Negussie; 06/29/15Diflubenzuron (108201) Human Health Risk Assessment DP#: 4233 28

Page 71 of 71 APPENDIX E . 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 Exposure Database, Version 1.1. Task Force members Health Canada, U.S. Environmental Protection Agency, and the Na tional 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, 201 1.