Diflubenzuron ( 108201) Human Health Risk Assessment 

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY 

WASHINGTON, D.C. 20460 

OFFICE OF CHEMICAL SAFETY AND POLLUTION PREVENTION 

MEMORANDUM 

September 15, 2015 

DP#: 423328 

SUBJECT: Diflubenzuron: Human Health Risk Assessment for an Amended Section 3 

Registration for Carrot, Peach Subgroup 12-12B, Plum Subgroup l 2- l 2C, 

Pepper/Eggplant Subgroup 8-1 OB, Cottonseed Subgroup 20C, Alfalfa (Regional 

Restrictions) and R 175 Crop Group Conversion for Tree Nut Group 14-12. 

PC Code: 108201 DP Ba rcode: 423328 

Decision No.: 494116 Registration No.: 400-461 

Petition No.: 4E8306 Regulatory Action: Section 3 Registration 

Risk Assessment Type: Human Health Risk Case No.: 0144 

Assessment 

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

MRlD No.: NA 40 CFR: § 180.377 I 

FR OM: Hannah Pope-Varsalona, P , TXsi)~sk Assessor/ /,.,,,_. 

Kell O'Rourke, ORE 

S

Ri

umitra 

sk Assess

Bose 

ment 

Biswas, 

Branch 

Ctlf!:; IV ~ y3 · ~ Health Effects Division (7509P) 

THROUGH: Elissa Reaves, PhD, Branch Chi ef 

Risk Assessment Branch IV, HED (7509P) 

TO: A Willis Ertman, Risk Manager Reviewer 

Barbara Madden, Risk Manager 

Invertebrate-Vertebrate Branch II/RD (7505P) 

2-c-F 

This document provides the Health Effects Division's (HEO's) risk assessment of the amended 

Section 3 for the new use of diflubenzuron on carrot and alfalfa (regional restrictions), expand use 

of peach Subgroup 12-1 2B, plum Subgroup 12-l 2C, pepper/eggplant Subgroup 8-1 OB, cottonseed 

Subgroup 20C, and crop group expansion from for tree nut group 14-12. 

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1.0 Executive Summary ............................................................................................................ 5

2.0 HED Recommendations ..................................................................................................... 9

2.1 Data 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 Excretion................................................ 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 and 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 Risk Assessment ............................... 21

5.0 Dietary Exposure and Risk Assessment.......................................................................... 23

5.1 Metabolite/Degradate Residue Profile......................................................................... 23
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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 Aggregate 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 ...................................................................................... 44
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B. Toxicity Profiles............................................................................................................. 45

C. Toxicological 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 .......................................................... 71
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1.0 Executive Summary

This document addresses the exposures and risks associated with currently registered uses and the 

proposed amended uses 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 of diflubenzuron 

to include alfalfa, carrot, cottonseed Subgroup 20C, peach Subgroup 12-12B, plum Subgroup 12-

12C, peppers/eggplant Subgroup 8-10B, and tree nuts Group 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-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 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 0.02-55 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 include, aerial; groundboom; airblast; chemigation; and handheld equipment. (i.e., low-pressure handwand, handgun sprayer, backpack sprayer). 

Diflubenzuron is applied to numerous crops across 21EPA crop group categories, and to 

agricultural non-crop sites including 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 Group 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 Characterization
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The acute oral, dermal and inhalation toxicity of diflubenzuron is low. It is a mild eye irritant and 

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

subchronic and chronic feeding studies, the primary endpoint of concern was methemoglobinemia 

and/or sulfhemoglobinemia. These effects were evident in both sexes of mice, rats, and dogs and 

were produced by more than one route of administration in rats [i.e., oral, dermal and inhalation]. 

The general consequence of methemoglobinemia and/or sulfhemoglobinemia is the impairment of 

the oxygen transportation capacity of the blood, which is generally known to be caused by aromatic 

amines in both humans and animals.

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) based on a weight of evidence approach. The recently submitted 

immunotoxicity study has been reviewed and immunotoxicity was not observed above the limit 

dose.

Dose Response Assessment

Toxicological endpoints were selected for dietary/drinking water, occupational and residential 

exposure scenarios. Acute and chronic points of departure (PODs) were selected for assessment 

of food and drinking water exposures. No appropriate acute 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 longterm inhalation endpoints were selected from a 13-week oral (capsule) study in the dog. The shortand intermediate-term inhalation endpoints were selected from a 28-day rat inhalation toxicity 

study. An uncertainty factor of 100X was applied to endpoints selected for all exposure routes 

(10X for interspecies extrapolation, 10X for intraspecies variation).

The HED RfD/Peer Review Committee classified diflubenzuron as “Group E,” evidence of noncarcinogenicity 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/carcinomas in male mice in a National Toxicology 

Program (NTP) study. Therefore, the RfD/Peer Review Committee classified PCA as a “Group 

B2" probable human carcinogen. However, recently submitted acceptable rat metabolism studies 

show that diflubenzuron was not metabolized to either PCA or CPU. On May 8, 2001 (D272976), 

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 noncancer 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 protective. Additional toxicity data on these metabolites 
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are not required.

Exposure/Risk Assessment and Risk Characterization

Dietary Assessment

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

were conducted using 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 HED's level of concern (i.e. <100% chronic population 

adjusted doses (cPAD)). Chronic risk from the dietary (food + drinking water) exposure to 

diflubenzuron will not exceed HED’s level of concern for the general U.S. population, and all 

population subgroups. The chronic dietary risk estimate for the highest reported exposed 

population subgroup, children 1-2 years old, is 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 Q1*s assigned to them. Individual cancer dietary exposure analyses 

were conducted for each metabolite.

The cancer assessment for PCA includes food only (not present in drinking water). For PCA, the 

cancer dietary exposure estimate 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.

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. #400-461). 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 foliage 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- and 
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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-exposure 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 result 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 Low-Income Populations," 

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

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

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

population subgroups from pesticide exposures that are based on patterns of that subgroup’s food 

and water consumption, and activities in and around the home that involve pesticide use in a 

residential setting. Whenever appropriate, non-dietary exposures based on home use of pesticide 

products and associated risks for adult applicators and for toddlers, youths, and adults entering or 

playing on treated areas post-application are evaluated. Further considerations are currently in 

development, as OPP has committed resources and expertise to the development of specialized 

software and models that consider exposure to bystanders and farm workers as well as lifestyle 

and traditional dietary patterns among specific subgroups. 

Tolerance 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 CSGs, 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), cottonseed (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 cover 
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secondary 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 byproducts ....................................... 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, Subgroup 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 Methods 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, milk, 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 that Methods I and II are the preferred enforcement 

methods because they are easier to perform, have less interference, and are more sensitive.

In conjunction with PP#8F4925 on rice, a new analytical methodology for plant commodities was 

successfully validated by an independent laboratory as well as by Agency chemists at ACB/BEAD, 

and was forwarded to FDA for publication in PAM Vol. II as Roman Numeral Methods. These 
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methods can separately determine residues of diflubenzuron by GC/ECD, CPU by GC/ECD, and 

PCA by GC/MS using an isotopically labeled internal standard and by summing the response of 

the two ions. The reported LOQ for diflubenzuron in/on rice grain, straw, and bran is 0.01 ppm, 

and is 0.05 ppm in/on rice hull. In rice straw, the LOQ for CPU is 0.01 ppm and 0.005 ppm for 

PCA. 

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 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. The International Residue Limit (IRL) status sheet is 

included as Appendix D to this memorandum. 

The Agency 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 increase 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 recommended 

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, prune, 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 poultry 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.
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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 12-12C 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

to harmonize with codex.

Plum, prune, dried 0.5 -- A separate tolerance is not required.

Diflubenzuron 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 registrations.

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

IR-4 is requested to submit a revised section F to remove the request for tolerance on plum, 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 in 
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order to conform to current HED policy on significant figures. 

2.3 Label Recommendations

None.

3.0 Introduction

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 diflubenzuron 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 ppm.

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% WP formulation; DIMILIN® 25W (EPA Reg. No. 400-465);

80% G formulation; Micromite® 80WGS (EPA Reg. No. 400-487);

Regulated Metabolite

Common name 4-chlorophenylurea (CPU)

Regulated Metabolite

Common Name 4-chloroaniline (PCA)

F

F O

N

H

O

N

H

Cl

O

N

H

Cl

H2N

Cl

H2N
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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 103 Acetone 

2 x 103 Acetonitrile 

2.4 x 104 Dioxane 

1.04 x 105 Dimethylformamide 

1.2 x 105 Dimethylsulfoxide 

1 x 103 Methanol 

6 x 102 Dichloromethane 

Vapor pressure (25 °C) 1.2 x 10- 4 mPa

Dissociation constant, pKa Not available

Octanol/water partition coefficient, Log(KOW) 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%

Waterdispersible 

granule Citrus Fruit 

group

(10-10)

Citrus rust mite, Lepidopterous 

miners, and citrus root weevil 

complex

Undated 

specimen 

label

Dimilin® 2L 400-461 22% Flowable

Concentrate
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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) 

0.125 lb 

ai/A

2 apps/growing 

season

0.25 lb ai/A REI = 12 hours. RTI = 7 

days. PHI = 7 days

Cottonseed Subgroup 20C

Depending on pest, apply 

before first bloom, first bloom 

through mid-bloom, after midbloom, at pinhead stage, or 

when plant has reached full 

vegetative growth.

Chemigation, Groundboom, or 

Aerial.

Liquid 

(400-461) 

0.031 to 

0.125 lb 

ai/A

6 apps/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) 

0.125 to 

0.25 lb 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

days.

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 should be reminded that each formulation to be used must 

be properly supported by residue data.

3.4 Anticipated Exposure Pathways
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The Registration Division has requested an assessment of human health risk to support the 

proposed amended use of diflubenzuron to include alfalfa, carrot, cottonseeds Subgroup 20C, 

peach Subgroup 12-12B, plum Subgroup 12-12C, peppers/eggplant Subgroup 8-10B, and tree nuts 

crop group 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 part of every pesticide risk assessment, OPP considers a large variety of consumer Subgroups 

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

population Subgroups from pesticide exposures that are based on patterns of that Subgroup’s food 

and water consumption, and activities in and around the home that involve pesticide use in a 

residential setting. Whenever appropriate, non-dietary exposures based on home use of pesticide 

products and associated risks for adult applicators and for toddlers, youths, and adults entering or 

playing on treated areas post-application are evaluated. Further considerations are currently in 

development, as OPP has committed resources and expertise to the development of specialized 

software and models that consider exposure to bystanders and farm workers as well as lifestyle 

and traditional dietary patterns among specific Subgroups. 

4.0 Hazard Characterization and Dose-Response Assessment

4.1 Toxicology Studies Available for Analysis

The toxicology database for diflubenzuron is adequate for evaluating and characterizing toxicity 

and selecting endpoints for purposes of this risk assessment. All toxicity studies required in 

accordance with new 40 CFR Part 158 data requirements have been submitted or waived by 

HASPOC (TXR 0056309).
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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. The toxicity of CPA and PCA 

will be considered equal to diflubenzuron for the non-cancer risk assessment. The MARC 

recommended that non-carcinogenic risk assessment include parent, CPU and PCA.

In a metabolism study (MRID 44875502), [U14C-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. [14C]-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). 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 metabolites 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 

amounts (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 Nhydroxyl/hydroxylamine derivatives were not identified in either the urine or feces. 

In a metabolism study for CPU (MRID 44875501), [U14C-phenyl]-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. [14C]-CPU at 198 mg/kg 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 postdosing 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 dose), 

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 major 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 degradation or aliphatic amine substitution) and hydrolysis 
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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 the 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/cm2 14C-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 diflubenzuron, the 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/or 

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 hemopoietic 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 impairment of the oxygen transportation 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) based on a weight of evidence approach. In 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 noncarcinogenicity for humans, based on lack of evidence of carcinogenicity 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 showed 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 (Q1

*

) for CPU and PCA should be 
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assessed individually. Based on methemoglobinemia observed only at higher doses in NTP studies 

for both monuron, similar to CPU and PCA (6 and 18 mg/kg/day, NTP Report No. 351, July 1989),

additional CPU and PCA toxicity data are not needed. The toxicity of 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 Q1

*

for CPU is 1.52 x 10-2and the 

Q1

*

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 protective 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 sulfhemoglobinemia in the 

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

(HASPOC, TXR 0056309).

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

The toxicology database for diflubenzuron is adequate for FQPA assessment. Based on the 

available developmental toxicity studies in rats and rabbits, there is no increased susceptibility to 

fetuses exposed in utero. 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 exposure assessment 

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

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

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

4.4.4 Residual Uncertainty in the Exposure Database 
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There are no residual uncertainties in the exposure database. The dietary risk assessment is 

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

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 Appendix 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 LOAEL of 10 mg/kg/day was based on methemoglobinemia and sulfhemoglobinemia. The 

standard 100x UF was applied to account for interspecies extrapolation and intraspecies variation. 

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 residential 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 dermal 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 inhalation 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 level at 

the highest concentration tested. Although the erythrocyte count, hematocrit, and hemoglobin 

concentrations were decreased, the changes lacked histopathological correlates and were deemed 
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biologically insignificant. At the termination, there were slight (-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 treatment 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 study 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, an 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 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 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, dermal 

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 carcinogenicity studies in rats and mice, 

and battery of negative mutagenicity studies, diflubenzuron was classified as “Group E,” evidence 

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

The 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 liver in male rats. Given that there is no accepted mechanism of carcinogenicity for monuron 

and that CPU is major metabolite of monuron in rats, there is still concern for the toxicity of CPU. 

Thus, a literature search was conducted for any toxicity studies for CPU. As no pertinent 

information was found (Personal Communication, Alberto Protzel, 5/8/01), risk from CPU will be 

assessed as follows: 1) for carcinogenic effects, a Q1

* will be calculated for monuron and applied 

to CPU;

EFED has determined that PCA is only a minor metabolite of DFB in the environment (K. Costello, 
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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.”

Therefore, a cancer assessment for CPU milk and water was conducted using a Q1

*

of 1.52 x 10-2. 

In addition, a cancer assessment for PCA food only was conducted using a Q1

*

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 provided 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 

UFA= 10X

UFH=10X

FQPA SF = 1x 

cPAD = 

chronic RfD 

FQPA SF 

= 0.02 mg/kg/day 

Chronic Dog Study MRID 00146174

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

Q1

* 1.12 x 

10-1

(mg/kg/day)

Not Applicable NTP Oral mouse study

Cancer (oral, 

dermal, inhalation)

CPU Q1

*

based on 

monuron a 

structural 

analog and 

the Q1

*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. UFA = extrapolation from animal to human (interspecies). UFH = potential 

variation in sensitivity among members of the human population (intraspecies). UFL = use of a LOAEL to extrapolate a NOAEL. UFS = use of a 
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short-term study for long-term risk assessment. UFDB = to account for the absence of key date (i.e., lack of a critical study). FQPA SF = FQPA 

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

concern. N/A = not applicable
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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-, 

Intermediate- 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 

UFA= 10X

UFH=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% 

UFA= 10X

UFH=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 = 

20.301

mg/kg/day 

UFA= 10X

UFH=10X

LOC for MOE = 

100 

28-day Inhalation rat Study, MRID 44950601

No effect at HDT2, 0.109 mg/L

Inhalation Long

Term

NOAEL = 2 

mg/kg/day 

UFA= 10X

UFH=10X

LOC for MOE = 

100

Chronic Dog Study -00146174

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 (CPU) 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 and 
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its metabolites 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, CO2, was reported to reach a maximum concentration of 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. These metabolites were detectable in an anaerobic soil 

metabolism study, as well. Due to the stability of diflubenzuron to abiotic processes, limited data 

are available on the persistence and mobility of diflubenzuron metabolites.

5.1.3 Comparison of Metabolic Pathways

Rat metabolism data (MRID#s 44875501 and 44875502) indicate that 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 treated soybean leaves 

collected the day of the first application, leaves and pods collected the day of the second 

application, and leaves collected at harvest contained unchanged parent as >90% of the TRR (ppm 

values were not provided). No DFBA, CPU, or PCA was detected. Radioactive residues in citrus 

fruit consisted almost entirely of unchanged diflubenzuron; no detectable levels (<1 ppb) of PCA, 

CPU and DFBA were reported. Residues of diflubenzuron per se in apple fruit identified and 

residues of PCA, DFBA, and CPU were nondetectable (<1 ppb). Terminal residues identified in 

animal tissues, milk, and eggs include diflubenzuron, 2-hydroxydiflubenzuron (2HDFB), 2,6-

difluorobenzamide (DFBAM), 2,6-difluorobenzoic acid (DFBA), p-chlorophenyl urea (CPU), and 

p-chloroaniline (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 purposes 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 

CPU
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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. 

No 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 pattern, 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. HAFT1 Median Mean Std. Dev.

Alfalfa Forage2

0.10 1

18 0.82 2.9 2.5 1.8 1.8 0.50

Alfalfa Hay2 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 47.43 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 0.020
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Dried Plum 13 1 0.20 0.20 NA3 NA NA NA

1HAFT = Highest Average Field Trial

2Alfalfa forage and hay 3rd cutting

3NA = 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 uses. 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.

TABLE 5.2.2 Calculation of MRDBs.

Crop Commodity Type1 Residue %Dry

Matter2

%Diet Dietary Contribution3

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 samples from 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 -combined residues of diflubenzuron, CPU and PCA in 
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dried plums 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, 04/20/2015) and incorporated directly into this dietary 

assessment. The estimated drinking water 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 incorporated in the DEEM-FCID into the food categories “water, direct, all 

sources” and “water, 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 applications/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 concentrations 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 aerial 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.
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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 water1

Diflubenzur

on2 4.61 0.41 0.38

CPU2 6.83 0.89 0.51

Total 11.44 1.3 0.89

Groundwater1

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 assessment. A residue value of 0.003 ppm was used for the 

CPU cancer assessment for milk commodities.

5.4.2 Percent Crop Treated Used in Dietary Assessment

The chronic non-cancer dietary exposure analysis 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%), wheat (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. 
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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 the analysis indicate that chronic risk from the dietary (food + drinking 

water) exposure to diflubenzuron will not exceed HED’s level of concern for the general U.S. 

population, and all population Subgroups. The chronic dietary risk estimate for the highest 

reported exposed population Subgroup, children 1-2 years old, is 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 Q1*s assigned to them. Individual cancer dietary exposure analyses 

were conducted for each metabolite.

The cancer assessment for PCA includes food only (not present in drinking water). For PCA, the 

cancer dietary exposure estimate 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 noncarcinogenicity for 

humans, therefore, a 

dietary cancer assessment 

is not required.

All Infants (< 1 year old) 0.002667 13

Children 1-2 years old 0.007726 39

Children 3-5 years old 0.005705 29

Children 6-12 years old 0.002977 15

Youth 13-19 years old 0.001709 9

Adults 20-49 years old 0.001509 8

Adults 50-99 years old 0.001584 8

Females 13-49 years old 0.001497 8

*The values for the highest exposed population for each type of risk assessment should be bolded
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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 exposure to individuals nearby to pesticide 

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

pesticides from its Federal Insecticide, Fungicide, and Rodenticide Act Scientific Advisory Panel 

(SAP) in December 2009. The Agency received the SAP’s final report on March 2, 2010 

(http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html) and is in the process of 

evaluating the SAP report. The Agency may, as appropriate, develop policies and procedures to 

identify the need for and, subsequently, the way to incorporate post-application inhalation 

exposure into the Agency's risk assessments. If new policies or procedures are put into place, the 

Agency may revisit the need for a quantitative post-application inhalation exposure assessment for 

diflubenzuron.

6.2 Spray Drift

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

This is particularly the case with aerial application, but, to a lesser extent, could also be a potential 
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source of exposure from the ground application method employed for diflubenzuron. The Agency 

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

for pesticide regulation and other parties to develop the best spray drift management practices (see 

the Agency’s Spray Drift website for more information at 

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

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

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

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

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

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

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

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

drift.

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

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

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

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

agricultural and commercial post-application inhalation exposure scenarios. 

7.0 Aggregate Exposure/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 sources are added together and 

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

be aggregated. When aggregating exposures and risks from various sources, HED considers both 

the route and duration of exposure.

7.1 Acute & Chronic Aggregate Risk

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

demonstrated under Section 5.4, acute and chronic aggregate risks are not of concern.

7.2 Short- and Intermediate-Term Aggregate Risk

A Short- and Intermediate- Term Aggregate Risk assessment is not required because there are no 

diflubenzuron products registered for homeowner use and there are no products registered for 

application to residential areas. 

8.0 Cumulative Exposure/Risk Characterization

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

common mechanism of toxicity, EPA has not made a common mechanism of toxicity finding as 

to diflubenzuron and any other substances and diflubenzuron does not appear to produce a toxic 

metabolite produced by other substances. For the purposes of this tolerance action, therefore, EPA 
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has not assumed that diflubenzuron has a common mechanism of toxicity with other substances.

For information regarding EPA’s efforts to determine which chemicals have a common 

mechanism of toxicity and to evaluate the cumulative effects of such chemicals, see the policy 

statements released by EPA’s Office of Pesticide Programs concerning common mechanism 

determinations and procedures for cumulating effects from substances found to have a common 

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

9.0 Occupational Exposure/Risk Characterization

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 information provided by the registrant, short- and intermediateterm 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 chemigation 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 task. 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. 
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Application Rate: The application rates 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 

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

including descriptions of the various sources, can be found at 

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

9.2.3 Handler Exposure Assumptions

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 acres 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 Factors

Because the short- and intermediate-term dermal and inhalation PODs were based on routespecific 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 as 

intermediate-term. Exposure duration is determined by many things, including the exposed 

population, the use site, the pest pressure triggering the use of the pesticide, and the cultural 

practices surrounding that use site. For most agricultural uses, it is reasonable to believe that 

occupational handlers will not apply the same chemical every day for more than a one-month time 

frame; however, there may be a 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 defined as a single layer of clothing consisting of a long 
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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 longsleeved shirt and 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 values were calculated using the following formula:

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

ADD (mg/kg/day)

where:

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

(unitless),

POD = Point of Departure,

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

study, where no observed adverse effects occurred in 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:
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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 exposure 

risks are not of concern (i.e., MOEs >100) at baseline PPE, with estimates ranging from 1,200 to 

420,000. The label also requires chemical resistant gloves to be worn during most mixing and 

loading activities, and a respirator is included while mixing 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 duration 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 quantitative 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 swath 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) NAAA 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.
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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 MOE5 Dose (mg/kg/day)4 MOE5 MOE6

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)]
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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-application 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 applications, 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 volatilization 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.gov/#!docketDetail;D=EPA-HQ-OPP2014-0219). 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 postapplication 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 for occupational/commercial 

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

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

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

exposure scenarios.

Furthermore, inhalation exposure during dusty mechanical activities such as shaking and 

mechanical harvesting is another potential source of post-application inhalation exposure.

However, the airblast applicator scenario is believed to represent a reasonable worst case surrogate 

estimate of post-application inhalation exposure during these dusty mechanical harvesting 
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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 longerterm 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 provisions of FIFRA. The standard values recommended for use in predicting 

post-application exposure that are used in this assessment, known 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 developmental and/or fetal 

effects.

Absorption Factors

Because the short- and intermediate-term dermal PODs were based on route-specific toxicity 

studies, no absorption factors were necessary to estimate exposure. 
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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 available 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 data 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 linear 

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 for 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)

Potential daily exposures for occupational post-application workers were calculated using the 

following formulas:

DFRt (μg/cm2) = AR (lb ai/A) * F * (1-D)t* 4.54E8 μg/lb * 2.47E-8 acre/cm2

where:

DFRt = dislodgeable foliage residue on day "t" (μg/cm2),

AR = Application Rate (lb ai/acre)

F = fraction of ai retained on foliage 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 (cm2/hr) * CF1 * DFRt (μg/cm2) * ET (hrs /day) * 1E-3 mg/μg

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

TC = Transfer coefficient (cm2/hr),

DFRt = Dislodgeable Foliar Residue on day “t” (μg/cm2), 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 chemical 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 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.

9.3.3 Post-Application Exposure and Risk Estimates
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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 (12 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 

(cm2/hr)

Proposed 

Application 

Rate (lb ai/A)

DFR

(μg/cm2)

1

Dermal Dose 

(mg/kg/day)2

MOE3

(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/cm2; 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 Rate (0.125 

lb ai/A)) / Study Application Rate (1.88 lb ai/A) = 0.10 μg/g

2 Daily Dermal Dose = [DFR (μg/cm2) × 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 irritant (Toxicity Category IV). 

Diflubenzuron was not shown to be a skin sensitizer. Short- and intermediate-term postapplication risk estimates were not a concern on day 0 (12 hours following application) for all 

post-application activities. Under 40 CFR 156.208 (c) (2) (iii), active ingredients 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 

adequate 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 (FAR). This default value 

is 25%. Of the analyzed DFR studies, the maximum FAR 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 residue 
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value 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 for diflubenzuron at this time. 
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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, 

D428151, 8/12/2015.

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.
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APPENDICES

APPENDIX 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

yes

yes

yes

*HASPOC waived the acute and subchronic neurotoxicity studies (TXR 0056309).
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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 LD50 =>5,000 mg/kg IV

870.1200 Acute Dermal Toxicity-rabbit

00157104 LD50 =>2000 mg/kg III

870.1300 Acute Inhalation Toxicity– rat

00163311 LC50 =>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 Subchronic –

Mice (14-day study)

00099713 (1997) 

Acceptable/Non-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/Guideline

0 (control), 800, 4,000, 20,000 or 

100,000 ppm (equivalent to 0, 40, 

200, 1,000 or 5,000 mg/kg/day).

NOAEL= 40 mg/kg/day, 

LOAEL=200 mg/kg/day,

Increased methemoglobin 

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/Non-guideline

0, 160, 400, 2000, 10000 or 50000 

ppm (equivalent to 0, 8, 20, 100, 

500 or 2500 mg/kg/day).

NOAEL= not established

LOAEL=8 mg/kg/day, 

Increased methemoglobin 

and signs of hemolytic 

anemia, erythrocyte 

destruction 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 in 
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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/Guideline

0, 10, 20, 40 or 160 ppm (equal to 

0, 0.42, 0.84, 1.64 or 6.24 

mg/kg/day). 

NOAEL=1.64 mg/kg/day

LOAEL=6.24 mg/kg/day, 

based on increased 

Methemoglobinemia.

870.3200 21-day dermal study in 

rabbits.

00038716 (1975)

Acceptable/Guideline

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/Guideline

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.

LOAEL= 0.121 mg/L (of 

25% wettable powder

870.4100a 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 only. 

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 LOAEL = 5.83 

mg/kg/day in males and 

7.05 in females.

870.4100a 104-week rat chronic 

feeding study.

00145467 (1984)

Guideline (minimum)

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 was not 

established.

LOAEL= 7.8 mg/kg/day.
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870.4100b 52-week dog chronic 

feeding (gelatin capsules)

study.

00146174 (1985)

Acceptable/Guideline

0 (control), 2, 10, 50 or 250 

mg/kg/day.

NOAEL=2 mg/kg/day.

LOAEL=10 mg/kg/day,

Based on statistically 

significant increases in 

methemoglobin 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 limit dose of 1,000 

mg/kg/day for carcinogenicity studies 

and significant toxicity (particularly 

methemoglobinemia, 

sulfhemoglobinemia, erythrocyte 

destruction, compensatory regeneration 

of erythrocytes and hemolytic anemia) 

was observed 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 histopathological 

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/day 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-Chloroaniline 

(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 pchloroaniline (PCA). 

Acceptable/Non-guideline.

NOAEL was not established.

LOAEL=6 mg/kg/day based 

on showed mild hemolytic 

anemia and dose-related 

increases in methemoglobin

in both sexes.

Histopathological 

examinations indicated nonneoplastic treatment-related 

effects in the spleen, liver, 

bone marrow and adrenal 

gland. A treatment-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 proliferation of 

hematopoietic cells in the 
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24-month carcinogenicity 

gavage study in mice.

livers 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/Non-guideline

0 (control) or 1,000 mg/kg/day (limitdose study). The

NOEL for maternal toxicity is 1,000 

mg/kg/day and the NOEL for 

developmental toxicity is 1,000 

mg/kg/day.

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.

870.3700b Developmental toxicity 

study (gavage) in rabbits.

41703505 (1988)

Acceptable/Guideline

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 changes 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 body 
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weights in F1 pups from 

birth to 21 days post-partum.

870.5100 Salmonella/mammalian 

microsome plate 

incorporation assay

41703503 (1990)

Acceptable/Guideline

Concentrations 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

Concentrations up to 

cytotoxic/precipitating levels of 200-

250 μg/ml.

The test material did not 

induce an increase in 

structural chromosome 

aberrations over background 

levels at any of the evaluated 

concentrations.

870.5XXX Unscheduled DNA synthesis 

(UDS) assay

41703501 (1986)

Concentrations 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

14C 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 postdosing.

[

14C]-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 20-48 hrs postdosing. Most of the 

administered diflubenzuron 

was excreted in the feces 

(87.4%); no other fecal 

metabolites were identified 

at detectable levels. 9 

metabolites were isolated 

and identified in urine. The 

2 major metabolites in the 

urine were 4-chloroaniline2-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.

The half-life of radioactivity 

in blood was about 14 hours. 

By 7 days, over 98% of the

administered radioactivity 

was excreted.
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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 each treated group and 12 male and 12 female dogs were used for the control group. 

Mortality, clinical signs, food consumption and water consumption were not affected by 

treatment with diflubenzuron. Except for a slight decrease in mean body weight gain 

observed in female dogs at 250 mg/kg/day, body weights were also not affected. 

Ophthalmoscopic examinations, clinical chemistries and urinalyses were negative. 

Statistically significant increases in methemoglobin and sulfhemoglobin were observed in 

male and female dogs at dose levels of ≥10 mg/kg/day. Heinz bodies were also observed 

in the erythrocytes of male dogs at 250 mg/kg/day and in those of female dogs at ≥50 

mg/kg/day. At dose levels of 50 mg/kg/day and higher, signs of hemolytic anemia, 

destruction of erythrocytes and of compensatory regeneration of erythrocytes were 

observed. Increased platelet counts were also noted in females at ≥50 mg/kg/day. 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/day
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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/cm2 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-Term)

Dermal Exposure (Short-Term)

Study Selected: 21-Day dermal toxicity study in rat. 

MRID No.: 43954101

Executive Summary: In a subchronic, 21-day dermal toxicity study (MRID 43954101), 

Dimilin (diflubenzuron tech. 96.7% a.i.) was administered to 10/sex/dose in 0.25% gum 

tragacanth in distilled, deionized water to the dorsal skin on the backs of the test animals 

at 0, 20, 500, or 1,000 mg/kg/day for 6 hour period each day.

Dermal treatment for 21 days did not affect mortality, clinical signs, body weight changes, 

food consumption and/or organ weight changes. At 1,000 mg/kg/day, slight dermal 

irritation and traces of acanthosis and hyperkeratosis were noted in males and females. 

Liver and kidney histopathology was remarkable. Males exhibited slight elevations in the 

white cell count in the mid and high dose groups. Males also had small reductions in 

hemoglobin and hematocrit at 1000 mg/kg dose group. In females at the top two dose there 

were statistically significant (P < 0.05) decreases in RBC count, hemoglobin levels and 

hematocrit values. Hematological changes in males and females were within in the 

historical 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, 
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hypochromasia and polychromasia in males and females at the top dose. On August 14, 

2001, the HED HIARC re-evaluated the study and concluded that the increased 

methemoglobinemia in males and females at 1000 mg/kg should be considered as toxicityinduced change. Therefore, the NOAEL is 500 mg/kg and LOAEL is 1000 mg/kg (Limit 

Dose), based on methemoglobinemia.

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

methemoglobinemia at 1000 mg/kg/day (Limit Dose). 

Comments about Study/Endpoint: This dermal toxicity study in rats is route- specific, is of 

appropriate duration and measures the effects of concern, i.e., methemoglobin and/or 

sulfhemoglobin. Previously, the end-points for short-term exposure was based on a 14-

day 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 (Limit Dose).

Dermal Exposure (Intermediate-Term)

Study Selected: 13-week oral [subchronic] feeding study in dogs. §82-1b

MRID No.: 00038706

Executive Summary: In a subchronic feeding study, technical grade diflubenzuron (batch 

# P7227) was administered in the diet to beagle dogs at dose levels of 0 (control), 10, 20, 

40 and 160 ppm (equal to 0, 0.42, 0.84, 1.64 and 6.24 mg/kg/day). Groups of 3 male and 

3 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. Ophthalmoscopic examinations were 

conducted at 6 and 12 weeks. Gross necropsies were performed on all dogs. Organ weights 

were determined and histopathological examinations were performed at the terminal 

sacrifice at 13 weeks. Mortality, clinical signs, body weights and food consumption were 

not affected by treatment with diflubenzuron. Ophthalmoscopic examinations were 

negative. Methemoglobinemia was observed in the dogs at 160 ppm (after 6 weeks). No 

gross necropsy, organ weight or histopathological changes were reported at any level that 

could be related to treatment with diflubenzuron. 

Endpoint and dose for use in risk assessment: NOAEL 2.0 mg/kg/day based on increased 

methemoglobinemia at 6.24 mg/kg/day. Corrected for 0.5% dermal absorption. See 

discussion below. 

Comments about studies 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 
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and the mouse study, a NOAEL of about 2 mg/kg/day was calculated by regression 

analysis. Considering all the available data (including data from chronic feeding studies in 

rats, dogs and mice in which the NOAEL for methemoglobinemia/sulfhemoglobinemia to 

be used to calculate the RfD also was 2 mg/kg/day), it was concluded that the NOAEL for 

intermediate term risk assessments should be 2 mg/kg/day (rather than the slightly lower 

NOAEL of 1.64 mg/kg/day determined in the dog study above). However, since an oral 

NOAEL was selected for a dermal endpoint a dermal absorption factor of 0.5% should be 

used for this risk assessment when converting dermal exposure to oral equivalents 

Therefore, the dermal equivalent dose derived from a NOAEL by the oral route is 400.0 

mg/kg/day [i.e., 2.0 mg/kg/day ÷ 0.005 = 400.0 mg/kg/day).

Dermal Exposure (Intermediate-Term)

Study Selected: Chronic Toxicity - Dog. §83-1a

MRID No.: 00146174

Executive Summary: In a 52-week chronic oral study, technical grade diflubenzuron was 

administered in gelatin capsules to beagle dogs once each day (7 days/week) at dose levels 

of 0 (control), 2, 10, 50 or 250 mg/kg/day. Groups of 6 male and 6 female dogs were used 

for each treated group and 12 male and 12 female dogs were used for the control group. 

Mortality, clinical signs, food consumption and water consumption were not affected by 

treatment with diflubenzuron. Except for a slight decrease in mean body weight gain 

observed in female dogs at 250 mg/kg/day, body weights were also not affected. 

Ophthalmoscopic examinations, clinical chemistries and urinalyses were negative. 

Statistically significant increases in methemoglobin and sulfhemoglobin were observed in 

male and female dogs at dose levels of ≥10 mg/kg/day. Heinz bodies were also observed 

in the erythrocytes of male dogs at 250 mg/kg/day and in those of female dogs at ≥50 

mg/kg/day. At dose levels of 50 mg/kg/day and higher, signs of hemolytic anemia, 

destruction of erythrocytes and of compensatory regeneration of erythrocytes were 

observed. Increased platelet counts were also noted in females at ≥50 mg/kg/day. 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.

Dose and Endpoint for Risk Assessment: NOAEL = 2 mg/kg/day based on 

methemoglobinemia and sulfhemoglobinemia at 10.0 mg/kg/day (LOAEL). Corrected for 

0.5% dermal absorption.

Comments about Study/Endpoint:. Long term dermal studies are not available for 

diflubenzuron therefore a chronic feeding study was chosen. However, since an oral 

NOAEL was selected for a dermal endpoint a dermal absorption factor of 0.5% should be 

used for this risk assessment when converting dermal exposure to oral equivalents. 

Therefore the dermal equivalent dose producing a NOAEL by the oral route is 400.0 
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mg/kg/d [i.e. 2.0 mg/kg/day ÷ 0.005 = 400.0 mg/kg/day.

This risk assessment is not required at this time since there does not appear to be any 

long term exposure scenarios associated with this use. However, if long term exposure 

is anticipated in the future based on the use pattern then this risk assessment will be 

required.

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 noseonly inhalation at concentrations of 0, 12, 34, or 109 mg/m3

(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 hematocrit 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/m3. It is 

unclear whether these alterations were induced by treatment, however, they were too small 

to be biologically significant and lacked microscopic correlates, and were thus considered 

toxicologically unimportant. Under the conditions of this study, therefore, a LOAEL was 

not established and the NOAEL is the highest dose tested, i.e., 109 mg/m3(0.109 

mg/L).

This subchronic 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/d1(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 
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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-Term Inhalation

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

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

exposure. The concentration selected for risk assessment did not elicit any adverse effect 

following 28 days of inhalation exposure. The HIARC, however, selected this dose based 

on methemoglobinemia which was consistently observed across species and 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 time
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D. Executive Summaries

870.3100 Oral Subchronic Toxicity - Rodent 

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

MRID No.: 00099713

Executive Summary: In a 14-day subchronic oral toxicity study, technical grade diflubenzuron 

was administered each day by gavage to 10 Swiss strain male mice at a dose level of 8, 40, 200, 

1000 or 5000 mg/kg/day. The mice were fasted for 16 hours prior to the first dose of test material. 

The test material was administered as a suspension in 1% tragacanth. Twenty control animals were 

treated similarly with a blank suspension. Blood was drawn from all animals at 15 days after the 

first dose and analyzed for methemoglobin, sulfhemoglobin and Heinz bodies in the erythrocytes. 

At day 15, the animals were sacrificed and those of the control and highest dose groups were 

autopsied. Significantly increased (p < 0.05) levels of methemoglobin were observed at 1000 and 

5000 mg/kg/day. Significantly increased (p < 0.05) levels of sulfhemoglobinemia were observed 

at 200, 1000 and 5000 mg/kg/day. The percentage of erythrocytes containing Heinz bodies was 

highly increased at 1000 and 5000 mg/kg/day. No effect on body weights or on 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.

870.3150 Oral Subchronic Toxicity - Nonrodent 

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

MRID No.: 00038706

Executive Summary: In a subchronic feeding study, technical grade diflubenzuron (batch # 

P7227) was administered in the diet to beagle dogs at dose levels of 0 (control), 10, 20, 40 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. Ophthalmoscopic examinations were conducted at 6 and 12 weeks. Gross necropsies were 

performed on all dogs. Organ weights were determined and histopathological examinations were 

performed at the terminal sacrifice at 13 weeks. Mortality, clinical signs, body weights and food 

consumption were not affected by treatment with diflubenzuron. Ophthalmoscopic examinations 

were negative. Methemoglobinemia was observed in the dogs at 160 ppm (after 6 weeks). No 

gross necropsy, organ weight or histopathological changes were reported at any level that could 

be related to treatment with diflubenzuron. 

Endpoint and dose for use in risk assessment: Calculated NOEL 2.0 mg/kg/day based on increased 
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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 the 

available data (including data from chronic feeding studies in rats, dogs and mice in which the 

NOEL for methemoglobinemia/sulfhemoglobinemia to be used to calculate the RfD also was 2 

mg/kg/day), it was concluded 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 determined in the dog study 

above).

870.3200 21-Day Dermal Toxicity – Rat

Study Selected: 21-Day dermal toxicity study in rat

MRID No.: 43954101

Executive Summary: In a subchronic, 21-day dermal toxicity study, Dimilin (diflubenzuron tech. 

96.7% a.i.) was administered to 10/sex/dose in 0.25% gum tragacanth in distilled, deionized water 

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

period each day.

Dermal treatment for 21 days did not affect mortality, clinical signs, body weight changes, food 

consumption and/or organ weight changes. At 1,000 mg/kg/day, slight dermal irritation and traces 

of acanthosis and hyperkeratosis were noted in males and females. Liver and kidney 

histopathology was remarkable. Males exhibited slight elevations in the white cell count in the 

mid and high dose groups. Males also had small reductions in hemoglobin and hematocrit at 1000 

mg/kg dose group. In females at the top two doses there were statistically significant (P < 0.05) 

decreases in RBC count, hemoglobin levels and hematocrit values. Hematological changes in 

males and females were within in the historical ranges for this species and age of rat, and therefore, 

considered not biologically significant. Methemoglobin levels increased significantly (P < 0.05 & 

0.01) in males and females at 1000 mg/kg dose. There was increased incidence of anisocytosis, 

hypochromasia and polychromasia in males and females at the top dose. On August 14, 2001, the 

HED HIARC re-evaluated the study and concluded that the increased methemoglobinemia in 

males and females at 1000 mg/kg should be 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 rats is route- specific, is of 

appropriate duration and measures the effects of concern, i.e., methemoglobin and/or 

sulfhemoglobin. Previously, the end-points for short-term exposure were based on a 14- day 
Diflubenzuron (108201) Human Health Risk Assessment DP#: 423328

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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 Dermal Toxicity – Dog

Study Selected: Chronic Toxicity - Dog

MRID No.: 00146174

Executive Summary: See 870.4100b Chronic Toxicity – Nonrodent, below. 

Dose and Endpoint for Risk Assessment: NOAEL = 2 mg/kg/day based on methemoglobinemia 

and sulfhemoglobinemia at 10 mg/kg/day (LOAEL). Corrected for 0.5% dermal absorption.

Comments about Study/Endpoint: Long term dermal studies are not available for diflubenzuron 

therefore a chronic feeding 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 400.0 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 appropriate 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.: 41703504
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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 toxicity, the NOAEL was 1000 mg/kg/day (Limit-Dose); a LOAEL was not 

achieved.

870.3800 Reproduction and Fertility Effects – Rat

Study Selected: 2-Generation Reproduction Study - Rats

MRID No.: 42700002

Executive Summary: In a 2-generation reproduction study in rats (Sprague-Dawley) complete in 

1992, 30 rats/sex/dose received either 0, 10, 200, 2000, or 4000 ppm (0, 0.67, 13.3, 136, and 278 

mg/kg/day for P0 males and 0, 0.76, 15.3, 152, and 3l1 mg/kg/day for P0 females during the 

premating growth periods, respectively) of CGA-152005 (99.1% a.i.) mixed in the feed. Note that 

organ weights were not obtained in this study.

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

reproduction study.

870.4100a

Study Selected: Carcinogenicity/Oncogenicity Study - Rat

MRID No. 00145467

Executive Summary: See 870.4300 Carcinogenicity - Rat below.

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

and satisfies the guideline requirements for a chronic toxicity and oncogenicity study in rats.
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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 

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

this dose level.

870.4100b Chronic Toxicity – Nonrodent

Study Selected: Chronic Toxicity - Dog

MRID No.: 00146174

Executive Summary: In a 52-week chronic oral study, technical grade diflubenzuron was 

administered in gelatin capsules to beagle dogs once each day (7 days/week) at dose levels of 0 

(control), 2, 10, 50 or 250 mg/kg/day. Groups of 6 male and 6 female dogs were used for each 

treated group and 12 male and 12 female dogs were used for the control group. Mortality, clinical 

signs, food consumption and water consumption were not affected by treatment with 

diflubenzuron. Except for a slight decrease in mean body weight gain observed in female dogs at 

250 mg/kg/day, body weights were also not affected. Ophthalmoscopic examinations, clinical 

chemistries and urinalyses were negative. Statistically significant increases in methemoglobin and 

sulfhemoglobin were observed in male and female dogs at dose levels of 310 mg/kg/day. Heinz 

bodies were also observed in the erythrocytes of male dogs at 250 mg/kg/day and in those of female 

dogs at 350 mg/kg/day. At dose levels of 50 mg/kg/day and higher, signs of hemolytic anemia, 

destruction of erythrocytes and of 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 – Rat
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Study Selected: Oncogenicity Study - Rat

MRID No.: NTP 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 

F344/N rats at dose levels of 0, 2, 6, or 18 mg/kg/day for 24-months. Groups of 50 male and 50 

female rats were used for each treated groups and the control group. Hematology examinations 

and mehtemoglobin measurements were conducted on 15 rats/sex/group at 6, 12, 18, and 24 

months. Increased survival was observed in male rats at 2 and 6 mg/kg/day and in female rats at 

2, 6, and 18 mg/kg/day 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 female 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 gland. 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 incidence of these 

sarcomas in male rats was 0/49, 3/50, and 38/50 at dose levels of 0, 2, 6 and 18 mg/kg/day, 

respectively. In addition, in female rats, 1 fibrosarcoma was observed at a 6 mg/kg/day and 1 

osteosarcoma at 18 mg/kg/day. No additional uncommon sarcomas of the spleen were 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 classified 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. These 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 spleen 
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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 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 

administered in the diet to HC/CFLP strain mice at dose levels of 0, 16, 80, 400, 2000, or 10000 

ppm (equivalent to 0, 2.4, 12, 60, 300, or 1500 mg/kg/day). Groups of 52 male and 52 female 

mice were used for each treated group and 104 male and 104 female mice were 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 levels of 12 mg/kg/day and higher. A blue/gray 

discoloration of the skin and extremities and dark eyes accompanied the increased methemoglobin 

and sulfhemoglobin. At higher dose levels (particularly > 300 mg/kg/day), signs of hemolytic 

anemia, erythrocyte 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 considered 

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.
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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 group 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 levels 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/day 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 study 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, 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 levels of 0, 3, 10, 

and 30 mg/kg/day, respectively.
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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, technical 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 treatment 

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 the guideline requirements for a chronic toxicity and oncogenicity study in rats.

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

or female rats.

Adequacy of Dose Levels Tested: Dosing was considered adequate since the highest dose level 

tested, 500 mg/kg/day, approached the limit dose of 1000 mg/kg/day for carcinogenicity studies 

and significant toxicity (particularly methemoglobinemia, sulfhemoglobinemia, erythrocyte 

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

this dose level.

870.7485 Metabolism – Rat
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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 concluded 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 recommended 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/cm2. 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

Mutagenicity – 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/plate. 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 activation 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 Aberrations
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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/precipitating levels of 

200 - 250 ·g/ml. Preparations for S9 metabolic activation were made from Aroclor 1254 induced 

rat liver. The solvent used was DMSO. The test material did not induce an increase in structural 

chromosome aberrations over background levels at 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 observed (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 genotoxic effect in this assay system.

870.7800 Immunotoxicity

Selected Study: 28-Day (Dietary) Immunotoxicity Study – Mice

MRID No: 48760512, TXR 0056396

EXECUTIVE SUMMARY: In an immunotoxicity study (MRID48760512), Diflubenzuron (99.2 

% a.i., lot # AM8L17D481) was administered to female 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 mg/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 x108/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 

response 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 were 
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statistically significantly increase (p<0.05) of absolute and relative spleen weights at 2,000 and 

10,000 ppm, but no treatment related changes in thymus weights. Positive control group 

(cyclophosphamide) had statistically significantly decrease (p<0.05) of absolute and relative 

spleen and thymus weights; but no cyclophosphamide-related effects on body weights. 

The systemic toxicity NOAEL is 400 ppm (equivalent to 77 mg/kg bw/day); the LOAEL is 

2000 ppm (equivalent to 365 mg/kg/day) based on increased spleen weight which was a 

consistent finding in previous toxicity studies. 

There were no statistically significant treatment-related effects on the specific anti-SRBC antibody 

response by ELISA test in all treated groups. A high inter-individual variability was noted in all 

the treatment groups as well as in the control group. Evaluation of individual animal data of this 

study did not show any trend or distribution that would demonstrate significant suppression of 

anti-SRBC IgM 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 evaluated in this study. The toxicology database for 

Diflubenzuron does not reveal any evidence of treatment related effects on the immune system. 

The overall weight of evidence suggests that the chemical does not directly target the immune 

system. Under HED guidance a NK cell activity assay is not required at this time. 

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

limit dose. The 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. 
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APPENDIX B. Chemical Names and Structures of Diflubenzuron and Metabolites

Diflubenzuron

F

F O

N

H

N

H

O

Cl

4-chlorophenylurea: CPU

Cl

N

H

H2N

O

4-chloroaniline: PCA

Cl

H2N
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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 103 Acetone 

2 x 103 Acetonitrile 

2.4 x 104 Dioxane 

1.04 x 105 Dimethylformamide 

1.2 x 105 Dimethylsulfoxide 

1 x 103 Methanol 

6 x 102 Dichloromethane 

Vapor pressure (25 °C) 1.2 x 10- 4 mPa

Dissociation constant, pKa Not available

Octanol/water partition coefficient, 

Log(KOW)

3.89

UV/visible absorption spectrum Not available
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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 Mexico2 Codex3

40 CFR §180.377:

Plant: diflubenzuron (N -[[(4-

chlorophenyl)amino]carbonyl]-2,6-

difluorobenzamide) 

Livestock: diflubenzuron

None Diflubenzuron (fatsoluble).

Commodity1

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

US Canada Mexico2 Codex3

Carrot, roots 0.20

Peach subgroup 12-12B 0.50 0.5 peach, nectarine

Plum subgroup 12-12C 0.50 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 0.20

Alfalfa, forage 6.0

Alfalfa, hay 20

Alfalfa, seed 0.90

Cottonseed subgroup 20C 0.20

Egg 0.07 0.05 (*)

Poultry, fat 0.10

Poultry, meat byproducts 0.08

Completed by: M. Negussie; 06/29/15
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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 National Agricultural 

Chemicals Association, released February, 1995.

The Agricultural Handler Exposure Task Force (AHETF), 2011. The Occupational Handler Unit 

Exposure Surrogate Reference Table. U.S. Environmental Protection Agency. Released June 21, 2011.