Page 3 of 23

diflubenzuron, updates to its toxicity, exposure and usage databases, and current Agency science 

policies and risk assessment methods. 

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 

acarcide 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 know nematode. 

Tolerances for diflubenzuron, currently established under 40 CFR §180.377, range from 0.05-55 

ppm, and are tabulated in Table 6 of the Appendix along with international limits. 

The chemical structure and nomenclature of diflubenzuron and its regulated metabolites are 

presented in Table 1 of the Appendix. The physicochemical properties of the technical grade of 

diflubenzuron are presented in Table 2 of the Appendix.

Diflubenzuron, first registered in 1982, is available as a water dispersible granular, wettable 

powder, emulsifiable and soluble concentrate, ready-to-use solution and pellets. Pellets are 

unique to agricultural use sites as a feed-through for livestock fly control. As an acaricide and 

insecticide, diflubenzuron is applied with commercial spraying equipment such as; aircraft, 

groundboom, airblast, and handguns used for low and high volume applications. Also, it is 

applied by hand (granular), through bait stations, and feed through systems. Diflubenzuron is 

applied to numerous crops across 16 EPA crop group categories, and to agricultural non-crop 

sites including livestock barns; agricultural structures and equipment. Crop groups with the most 

label crop uses include root and tuber vegetables, citrus fruit, stone fruit, tree nuts and cereal 

grains. Non-agricultural use sites include: mosquito abatement on forest land and recreational 

areas (foliar treatment during periods of minimal use); and aquatic sties (standing water on tarps 

covering machinery) insect infestation and gypsy moth quarantine program scenarios; structural 

treatment for termites in soil, wall voids, and other structural parts (in bait stations), and 

commercial; industrial, and institutional maintenance areas. Some, but not all diflubenzuron 

labels indicate that the product is Restricted Use.

Hazard Identification/Toxicology

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, produced most likely 

by PCA, a metabolite of Diflubenzuron, 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 hemopoietic system is 

the target site with effects including increased sulfhemoglobin and/or methemoglobin levels in 

rat and dog studies. The general consequence of methemoglobinemia and/or 

sulfhemoglobinemia is the impairment of the oxygen transportation capacity of the blood, which 
Page 4 of 23

is generally known to be caused by aromatic amines in both humans and animals. Acute toxicity 

studies and endpoints used for risk assessment maybe found in Tables 3 and 4 of the Appendix, 

respectively.

Based on the most recent risk assessments (2006, 2008), the end points selected for dietary risk 

assessment are provided in Table 3 of the Appendix.

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). 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 did not produce either PCA or CPU in measurable amounts. On May 8, 2001, the 

MARC reviewed the recently submitted metabolism studies, accepted the study findings, and 

concluded that cancer risks for CPU and PCA should be assessed individually. The noncarcinogenic risk assessment should include diflubenzuron, CPU and CPA. Based on submitted 

plant and livestock metabolism studies, there are two sources for dietary exposure to PCA and 

CPU, residues in fungi (mushrooms) and residues in livestock commodities (milk and liver). 

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. There was no indication of abnormalities in 

the development of the fetal nervous system in the prenatal developmental toxicity studies in 

either rats or rabbits at the maternal limit doses of 1000 mg/kg/day. In addition, there was no 

evidence of effects on the nervous system following pre- and/or post-natal exposure in a twogeneration reproduction study in rats. There were no reports of treatment-related clinical 

observations indicative of central nervous system toxicity or histopathological changes in the 

central nervous system [non-perfused tissues] in the subchronic or the chronic studies. There are 

no indications of immunotoxicity in the available studies. There was no increased incidence of 

neoplastic lesions in either male or female rats or mice. However, an immunotoxicity study is 

required as a part of new data requirements in the 40 CFR Part 158 for conventional pesticide 

registration, and has recently been received and is under review. 

Data Required in the RED 

The data gaps identified in the diflubenzuron RED (21-day dermal toxicity study (MRID 

43954101; TXR 0050327, GLN 82-2) and a 28-day inhalation toxicity study (MRID 44950601; 

TXR 0050266, GLN 82-4) have been submitted, reviewed and found to be acceptable.

Data Requirements
Page 5 of 23

HED’s Hazard and Science Policy Council (HASPOC), based on a weight of evidence approach, 

considering all the available hazard and exposure information for diflubenzuron, concluded that 

the acute and subchronic neurotoxicity studies are not required at this time. This approach 

included the following exposure potential and hazard considerations: 1) no treatment-related 

evidence of neurotoxicity is seen in the diflubenzuron toxicity database (e.g., clinical signs, 

neuropathology, brain weight changes, functional/behavioral effects; 2) the target organ is the 

hematopoietic system and adverse outcome pathway are the formation of methemoglobinemia 

and/or sulfhemoglobinemia in the blood following oral, dermal and inhalation exposures; and 3) 

the PODs selected for dietary and non-dietary exposure risk assessments are based on 

methemoglobinemia and/or sulfhemoglobinemia; and 4) as such, HED has found through 

experience that neurotoxicity studies are not particularly sensitive studies for non-neurotoxic 

pesticides such a diflubenzuron. 

Conclusions

The toxicity database is adequate to support the existing registrations. The endpoints will be 

reevaluated during registration review. This process may trigger the need for a new norflurazon 

risk assessment.

Dietary and Drinking Water Exposure

The residue of concern for dietary exposure in plants, livestock, and fungi, determined by the 

HED Metabolism Assessment Review Committee (MARC) for the purpose of tolerance 

expression, is diflubenzuron and its metabolites PCA and CPU. The water residues of concern 

are the parent and the major degradate CPU. The most recent dietary exposure assessment was 

completed 8/25/2006, in support of new use on Peanuts, Okra, Small grains, Pummelo, Mustard 

Greens, Broccoli, Raab, Cabbage (bok choy), Collards, Kale, Mizuna, Mustard spinach, Rape, 

Greens and Turnip greens by A. Al-mudallal.

An acute dietary-exposure assessment was not performed because there were no toxic effects 

attributable to a single dose. Thus, an endpoint of concern was not identified to quantitate acute 

dietary risk to the general population or to any population subgroup.

A chronic dietary-exposure assessment was conducted using the established/recommended 

tolerances for all food commodities, 100% crop treated information for all proposed and existing 

uses, and DEEMTM Version 7.81 default processing factors for some processed commodities. 

Drinking water was incorporated directly into the dietary assessment using the EDWC generated 

by PRZM/EXAMS with IR scenarios and PCA adjustment factors.

Diflubenzuron chronic dietary (food + water) exposure estimates using the DEEM-FCIDTM 

software are below HED’s LOC for the U.S. population and each of the population subgroups. 

Using the DEEM-FCIDTM software, dietary exposure is estimated at 0.002285 mg/kg/day for the 

U.S. population (11% of the cPAD) and 0.007404 mg/kg/day (37% of the cPAD) for children 1 

to 2 years old, the population subgroup with the highest estimated chronic dietary exposure to 

diflubenzuron. 
Page 6 of 23

Cancer risk from consumption of PCA and CPU: Based on the submitted metabolism studies, 

there are two possible sources for dietary exposure to PCA and CPU- residues in fungi 

(mushrooms) and residues in livestock commodities (milk and liver). The estimated cancer 

dietary risk from PCA and CPU was not addressed in the most recent human health risk 

assessment because no new sources of residues of PCA and CPU were associated with the new 

uses included in that risk assessment.

Data Required in RED

860.1200 (171-3) Directions for Use - deletion of restrictions from all pertinent labels prohibiting 

the cutting of treated grass hay for livestock. All labels allowing repeated applications should be 

amended to list the minimum retreatment interval.

860.1380 (171-4(e)) Storage Stability - mushrooms, cottonseed, soybean seeds, grasses, walnuts. 

Metabolites PCA and CPU in milk and liver. Data on mushrooms were submitted in MRID 

45164001, awaiting review. Data on livestock commodities were submitted in MRID 45164002, 

awaiting review.

860.1500 (171-4(k)) Magnitude of Residue in Plants - grass (pasture, hay), cotton (gin 

byproducts), mushrooms. Data on mushrooms were submitted in MRID 44823701, 45164002. 

Data on cotton were submitted in MRID 45164003, awaiting review. Grass data submitted by 

IR-4.

860.1900 (165-2) Rotational Crops (field). MRID 44689703. D253043, reviewed 2/13/99 with 

PP# 8F4925 on rice, additional information is required.

860.1340b (171-4(d)) Due to Agency concerns about residues of PCA in plant and animal 

commodities, the registrant has been requested to develop data collection methods capable of 

determining PCA residues down to 1 ppb levels. MRID 44639101 has been submitted, and is 

awaiting review. (D264928)

Data Required in the RED, Currently in Review

The database for the dietary and drinking water assessment is complete. A number of residue 

chemistry studies are in-house awaiting review:

D356071 Residues on mushrooms, MRIDs 44823701 and -02

D263249 PCA method validation in meat, MRID 45013601

D264928 Analytical method in plants, MRID 44639101

D268446 Storage stability of PCA, CPU in mushrooms, MRID 45164002

D268447 Field trials in cotton, MRID 45164003

D268450 Field trials in soybeans, MRID 45164004

Conclusions

The dietary and drinking water exposure assessments are adequate based on current 

methodologies, but may need to be revised based on evaluation of unreviewed data and 
Page 7 of 23

reevaluation of PODs to ensure selected endpoints reflect current policy. The residue chemistry 

data requirements cannot be considered satisfied until the data have been reviewed and found to 

be acceptable. No new residue chemistry data are needed at this time.

Tolerances and International Harmonization

U.S. tolerances, International maximum residue levels (MRLs), and Canadian MRLs for 

diflubenzuron are not compatible for a number of commodities for which tolerances have been 

established by each entity. A summary of US and international tolerances and maximum residue 

limits including commodities for which U.S. tolerances differ from Codex and Canadian MRLs 

is attached (Table 5 of the Appendix). HED will determine during Registration Review, if 

tolerances can be harmonized with CODEX MRLs. The tolerance expression for diflubenzuron 

needs to be reviewed and updated as necessary based on HED’s Interim Guidance on Tolerance 

Expressions (S. Knizner, 5/27/09). 

Residential Exposure

Applications to residential areas by homeowners and occupational handlers include; Koi ponds, 

water fountains, and other bodies of water around the home; mosquito abatement districts in 

intermittently flooded areas, but not for use where swimming occurs; tree, shrub and recreation 

areas (during periods of minimal use); insect infestation and gypsy moth quarantine program 

scenarios ; standing water (tire and storage tarp); outdoor forest lands backing up to residential 

areas (park- foliar treatment during periods of minimal use), and structural treatment for termites 

in soil, wall voids, and other structural parts (in bait stations). However, label language also 

states that these applications are to be applied by occupational handlers during periods of 

minimal residential use. Therefore, a residential handler and post-application assessment will be 

needed. 

Residential Handler

HED has determined that there is a potential for residential exposure based on current registered 

labels.

Based upon the current use patterns, potential residential exposure scenarios include:

1) Residential Handler: placing pellets into ponds, water fountains, and other bodies of water 

around the home. 

Residential Post-Application

A residential post-application assessment is needed. 

In accordance with the updated Part 158 data requirements (2007), one or more DFR studies are 

required when a pesticide has residential or occupational uses that could result in postapplication dermal exposure. As part of the recent revision to the Health Effects Division’s 2012 

Standard Operating Procedures for Residential Pesticide Exposure Assessment, 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 
Page 8 of 23

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 value 

would provide an adequate margin of safety for any potentially higher residues seen in a 

chemical-specific DFR study. A DFR study is not required for diflubenzuron at this time since 

the dermal residential post-application MOE for adults is 2,200, which is more than 4 times 

higher than the LOC of 100. 

Exposure 

Scenario Population TTRt(ug/cm2)

Transfer 

Coefficient 

(cm2/hr) 

Hours of 

Exposure 

(hr)

Exposure 

(mg/day)

Absorbed 

Dermal Dose 

(mg/kg/day) 

Dermal 

MOE 

(rounded)

High Contact 

Lawn 

Activities 

(Liquids)

Adults

0.035

180,000

1.5

9.38 0.12 4,200

1 to <2 

years

49,000 2.55 0.22 2,200

Mowing Turf 

(Liquids)

Adults 0.03473437

5

5,500

1

0.1910 0.002403007 210,000

1 to <2 

years

4,500 0.1563 0.002751843 180,000

Residential Bystander Post-application Inhalation Exposure: Based on the Agency's current 

practices, a quantitative residential bystander 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 FIFRA SAP in December 2009. The Agency is in the process of evaluating 

the SAP report and 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. 

Data Required in RED

Post-application reentry exposure (§132-1a, 133-3, and 133-4) for the application of 

diflubenzuron in residential locations.

Conclusions

HED has determined that there is a potential for residential handler exposure based on current 

registered labels, therefore an updated residential handler assessment is needed. Furthermore, an 

updated residential post-application exposure assessment is required for registration review and 

both residential assessments will be based upon revisions to HED’s Residential SOPs which 

were reviewed by the Scientific Advisory Panel (SAP) in October 2009. 

The Post-application reentry exposure data required in the RED are not needed, as an adequate 

MOE has been estimated, based on current residential SOPs and label rates.
Page 9 of 23

Aggregate Exposure

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

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

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

residential uses. The acute and chronic exposure estimates from the dietary exposure analyses 

represent aggregate risk for acute and chronic exposures and are not of concern. 

Short term aggregate exposure takes into account residential exposure plus average exposure 

levels to food and water (considered to be a background exposure level). There are no 

residential uses, so this aggregate assessment is not needed. The potential for residential 

exposure will be reconsidered during registration review, and an assessment will be conducted if 

needed.

Conclusions

An updated aggregate exposure assessment is needed to include the needed residential handler 

and post-application exposure assessment. 

Occupational Exposure 

Diflubenzuron is registered for many agricultural uses and for use in non-crop areas. There is 

potential for short- and intermediate-term occupational exposure to diflubenzuron during 

handling (mixing, loading, and applying), or re-entry into previously treated areas. Based on the 

activity use pattern, the duration of exposure is expected to be short- term (ST; 1 to 30 days) and 

intermediate-term (IT; 1 to 6 months) for occupational scenarios; long-term exposures (greater 

than 6 months) are not anticipated based on the proposed use pattern. For the dermal and 

inhalation routes of exposure, the same points of departure were chosen for ST and IT exposures; 

therefore, risk estimates are protective for both durations of exposure. The level of concern 

(LOC) for risk estimates is a margin of exposure (MOE) of less than 100 for short- and 

intermediate-term exposure. Risk assessments were conducted for occupational handler and 

post-application exposure scenarios based on registered uses. The most recent ORE assessment 

was conducted 9/8/2010, by R. Daiss in support of a feed-through use on cattle. The last 

comprehensive ORE assessment was conducted 8/7/1996 by Jeff Evens for the RED. Estimated 

MOEs were not of concern for any of the handler and post-application exposure scenarios 

assessed. 

Handler exposures were assessed for mixing, loading, applying scenarios with aerial, ground, 

and handheld spray equipment. Standard HED unit exposure data were use to estimate risk to 

handlers and from post-application activities 

Occupational Handlers

Based upon the current use patterns, potential occupational exposure scenarios include: 

1. Mixer/loader using open-pour loading of wettable powder, water 

dispersible granule (solid soluble concentrate and water dispersible granules) for aerial 

application and ground applications.
Page 10 of 23

2. Mixer/loader using open-pour loading of emulsifiable and soluble 

concentrate for aerial application and ground applications.

3. Mixing/loading granules for ground and aerial application.

4. Aerial applicators (enclosed cockpit) of sprays and granules.

5. Applicator using open-cab groundboom spray equipment.

6. Applicator using airblast equipment.

7. Applicators applying granules

8. Mixer/Loader/Applicator (MLA) for backpack and mechanically 

pressurized handgun sprayer applications for ground and soil directed (drench 

treatments).

9. Flaggers supporting aerial application (sprays and granules) operations.

10. Mixing pellets into livestock feed for livestock feed-throughs.

For diflubenzuon, no chemical-specific data are available for exposure assessment to pesticide 

handlers; therefore, occupational handler assessments are based primarily on surrogate unit 

exposures from the Pesticide Handlers Exposure Database (PHED). Previous risk estimates 

were typically based on the maximum application rates and assuming maximum area treated per 

day or gallons handled. However, HED policies have since changed yielding updated acreage 

assumptions as well as updated unit exposures1. Consequently, occupational handler scenarios 

may need to be revised during registration review.

Occupational Post-Application

Post-application dermal and inhalation assessments were not conducted for diflubenzuron in the 

RED due to the low exposure potential and since no toxicological criteria had been triggered at 

that time. Since the time of the RED, post-application exposure assessments have been 

conducted for some scenarios.

EPA has determined that there is an exposure potential for persons entering treated sites after 

application is complete. Representative post-application exposure scenarios are as follows:

1. Harvesters reentering treated orchards and fields.

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

3. Harvesters and persons handling ornamentals in greenhouses.

4. Mushroom house workers handling treated compost and casing soil.

5. Mushroom harvesters.

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 

 

1
Page 11 of 23

default dislodged residue value would provide an adequate margin of safety for any potentially 

higher residues seen in a chemical-specific DFR study. A DFR study is not required for 

diflubenzuron at this time since the dermal occupational post-application MOE for adults is 

3,200,000, which is greater than 4 times higher than the LOC of 100. Therefore, using the default 

dislodged residue value would provide an adequate margin of safety for any potentially higher 

residues seen in a chemical-specific DFR study. See table 2 for specifics.

Table 2: Occupational Post-Application Exposure using Maximum Application Rate

DAT DFR Levels

Ug/cm2

Margin of Exposures (MOEs)

1 2 3 4 5 6

0 0.876 110,000,000 50,000,000 20,000,000 8,100,000 6,000,000 3,200,000

 

Scenario TC Activity

1 100 orchard maintenance, scouting, hand weeding

2 230 transplanting

3 580 scouting, hand pruning

4 1400 hand harvesting, pollination, hand pruning, bagging fruit

5 1900 Irrigation (hand set)

6 3600 thinning fruit

Restricted Entry Interval (REI):

The REI for diflubenzuron is 12 hours based on the acute toxicity classification of III for acute 

dermal and eye irritation routes of exposure. It is classified in Toxicity Category IV for acute 

inhalation toxicity and primary skin irritation. It is not a dermal sensitizer. Therefore the interim 

worker protection standard REI of 12 hours is adequate to protect agricultural workers from postapplication exposures. 

Data required in the RED 

Postapplication reentry exposure (§132-1a, 132-1b, 133-3, and 133-4) for citrus, 

chrysanthemums (greenhouse), cotton (or soybeans, and mushrooms). A waiver request 

(D252607) needs to be reviewed. 

Mixer/loader/applicator exposure data for ULV applications using ground equipment (§231 and 

232). (Not included in DCI)

Conclusions

The occupational exposure assessment is adequate but may need to be updated to reflect current 

policy. The occupational handler and post-application exposure scenarios may be reassessed or 

assessed during registration review. No additional data are required at this time.
Page 12 of 23

Public Health and Pesticide Epidemiology Data

The evaluation of the OPP Incident Data System (IDS), showed that, from January 1, 2007 to 

February 22, 2012, there was one reported incident involving diflubenzuron which was classified 

as moderate severity. Overall, there are few incidents involving diflubenzuron reported to IDS. 

Diflubenzuron is not included in the Agricultural Health Study (AHS), and therefore this study 

does not provide information for this report.

Based on the low frequency and severity of incident cases reported for diflubenzuron, there does 

not appear to be a concern at this time that would warrant further investigation. The Agency will 

continue to monitor the incident information and if a concern is triggered, additional analysis 

will be included in the risk assessment.

Endocrine Disruption

As required by FIFRA and FFDCA, EPA reviews numerous studies to assess potential adverse 

outcomes from exposure to chemicals. Collectively, these studies include acute, subchronic and 

chronic toxicity, including assessments of carcinogenicity, neurotoxicity, developmental, 

reproductive, and general or systemic toxicity. These studies include endpoints which may be 

susceptible to endocrine influence, including effects on endocrine target organ histopathology, 

organ weights, estrus cyclicity, sexual maturation, fertility, pregnancy rates, reproductive loss, 

and sex ratios in offspring. For ecological hazard assessments, EPA evaluates acute tests and 

chronic studies that assess growth, developmental and reproductive effects in different 

taxonomic groups. As part of its most recent registration decision, EPA reviewed these data and 

selected the most sensitive endpoints for relevant risk assessment scenarios from the existing 

hazard database. However, as required by FFDCA section 408(p), diflubenzuron is subject to the 

endocrine screening part of the Endocrine Disruptor Screening Program (EDSP). 

EPA has developed the EDSP to determine whether certain substances (including pesticide active 

and other ingredients) may have an effect in humans or wildlife similar to an effect produced by 

a “naturally occurring estrogen, or other such endocrine effects as the Administrator may 

designate.” The EDSP employs a two-tiered approach to making the statutorily required 

determinations. Tier 1 consists of a battery of 11 screening assays to identify the potential of a 

chemical substance to interact with the estrogen, androgen, or thyroid (E, A, or T) hormonal 

systems. Chemicals that go through Tier 1 screening and are found to have the potential to 

interact with E, A, or T hormonal systems will proceed to the next stage of the EDSP where EPA 

will determine which, if any, of the Tier 2 tests are necessary based on the available data. Tier 2 

testing is designed to identify any adverse endocrine-related effects caused by the substance, and 

establish a dose-response relationship between the dose and the E, A, or T effect. 

Under FFDCA section 408(p), the Agency must screen all pesticide chemicals. Between October 

2009 and February 2010, EPA issued test orders/data call-ins for the first group of 67 chemicals, 

which contains 58 pesticide active ingredients and 9 inert ingredients. Diflubenzuron is not 

among the group of 58 pesticide active ingredients on the initial list to be screened under the 

EDSP. Accordingly, as part of registration review, EPA will issue future EDSP orders/data callins, requiring the submission of EDSP screening assays for dilubenzuron. For further 
Page 13 of 23

information on the status of the EDSP, the policies and procedures, the list of 67 chemicals, 

future lists, the test guidelines and the Tier 1 screening battery, please visit our website: 

http://www.epa.gov/endo/.

Human Studies

The occupational exposure and risk assessment for diflubenzuron relied in part on data from 

studies in which adult human subjects were intentionally exposed to a pesticide or other 

chemical. Dermal absorption was examined in a series of special studies in which test material 

was applied dermally to adult male volunteers. These studies required a review of their ethical 

conduct and have received the appropriate review by the Human Studies Review Board (HSRB). 

Future occupational assessments conducted for registration review of diflubenzuron will use data 

contained in HED’s generic pesticide exposure databases such as Pesticide Handlers Exposure 

Database (PHED), the Agricultural Reentry Task Force (ARTF) Database and the Outdoor 

Residential Exposure Task Force (ORETF) Database). Recommended unit exposures for 

occupational handler assessments have generally been derived only from PHED. However, 

recently both the ORETF and AHETF have produced pesticide handler exposure monitoring data 

that the Agency is using in place of PHED (http://www.epa.gov/pesticides/science/handlerexposure-data.html). As more reliable data become available, the Agency will continue to 

replace existing data and new exposure monitoring data will be incorporated into HED’s 

Registration Review assessments as necessary. EPA has reviewed all the studies supporting 

these multi-pesticide generic exposure databases, and has found no clear and convincing 

evidence that the conduct of any of them was either fundamentally unethical or significantly 

deficient relative to the ethical standards prevailing at the time the research was conducted. All 

applicable requirements of EPA’s Rule for the Protection of Human Subjects of Research (40 

CFR Part 26) have been satisfied, and there is no regulatory barrier to continued reliance on 

these studies.

Environmental Justice

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

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.hss.energy.gov/nuclearsafety/env/guidance/justice/eo12898.pdf). The OPP typically 

considers the highest potential exposures from the legal use of a pesticide when conducting 

human-health risk assessments, including, but not limited to, people who obtain drinking water 

from sources near agricultural areas, the variability of diets within the U.S., and people who 

might be exposed when harvesting crops. Should these highest exposures indicate potential risks 

of concern, OPP further refines the risk assessments to ensure that the risk estimates are based on 

the best available information.

Conclusions/Future Actions Needed

The actions needed in the future Registration Review for diflubenzuron are listed in the 

executive summary at the top of this document.
Page 14 of 23

References

Al-mudallal, A. IR-4/Section 3-Local and New Uses Registration for Diflubenzuron Use on 

Peanuts, Okra, Small grains (Winter, Spring, Durum, Barley, and Oats), Pummelo, Mustard 

Greens, Broccoli, Raab, Cabbafe (bok choy), Collards, Kale, Mizuna, Mustard spinach, Rape, 

Greens and Turnip greens, D321156, EPA Memorandum dated 08/25/2006.

Austin, L., Diflubenzuron on Barley, Oats, Wheat, Brassica Leafy Greens (Crop Subgroup 5B), 

Turnip Greens, Eggplant, Okra, Peanut, and Pummelo (PP#s 5E6965, 5E6966, and 5E6967). 

Health Effects Division (HED) Risk Assessment, (D321152, D321155, D321158). EPA 

Memorandum dated 9/14/2006.

Daiss, R. Diflubenzuron: Occupational Exposure Assessment for New Diflubenzuron FeedThrough Use for Cattle, D381612, EPA Memorandum dated 9/8/2010.

EPA, Reregistration Eligibility Decision (RED) for Diflubenzuron, August 1997, 

Evans, J. Occupational And Residential Exposure Assessment For The Diflubenzuron 

Reregistration Eligibility Document (D22844), EPA Memorandum dated 8/7/1996.

Van Alstine, J., Diflubenzuron: Summary of Hazard and Science Policy Council (HASPOC) 

Meetings of April 26, 2012: Recommendations on the need for a neurotoxicity battery (acute 

and subchronic neurotoxicity studies). EPA Memorandum dated 6/7/2012.

Knizner, S. Interim Guidance on Tolerance Expressions, EPA Memorandum dated 5/27/09. 

Myers, T, The HED Chapter of the Reregistration Eligibility Decision Document (RED)

for Diflubenzuron, EPA Memorandum dated 7/10/1995.

Recore, S. Diflubenzuron: Review of Human Incidents. EPA memorandum dated 5/23/2012.

Redden, J., Diflubenzuron. Human Health Risk Assessment For The Proposed Use Of 

Diflubenzuron For Control Of Grasshoppers Infesting Alfalfa Grown For Hay, Mixed 

Grass/Alfalfa Hay, And Grasses Grown For Seed In Northeastern Oregon. EPA Memorandum

dated 9/15/2008.
Page 15 of 23

Appendix

Table.1. Diflubenzuron Nomenclature.

Compound

F

F O

N

H

O

N

H

Cl

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

O

N

H

Cl

H2N

Common name 4-chlorophenylurea (CPU)

Regulated Metabolite

Cl

H2N

Common Name 4-chloroaniline (PCA)
Page 16 of 23

Table 2. Physicochemical Properties of Diflubenzuron.

Parameter Value Reference

Melting range 230-232 °C http://www.arsusda.gov/acsl/s

ervices/ppdb/textfiles/DIFLU

BENZURON

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
Page 17 of 23

Table 3. 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

no

no 

no

......

......

......

......

......

870.7485 General Metabolism ........................................................................

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

870.7800 Immunotoxicity

yes

no

yes

Yes

---

no*

* Immunotoxicity Study has been received and is under review.
Page 18 of 23

Table 4: Diflubenzuron Acute Toxicity Studiesc: 

Guideline

No. Study Type MRID #(S). Results Toxicity Category

870.1100

(81-1)

Acute Oral

(rat 1a) 

00157103 LD50 =>5,000 mg/kg IV

870.1200

(81-2)

Acute Dermal

(rat 2-a) 

00157104 LD50 =>2000 mg/kg III

870.1300

(81-3)

Acute Inhalation 

(rat 3a)

00163311 LC50 =>2.49 mg/L IV

870.2400

(81-4)

Primary Eye Irritation

(rabbit 4-a) 

00157105 mild irritant III

870.2500

(81-5)

Primary Skin Irritation

(rabbit 5a)

00157106 no irritation IV

870.2600

(81-6)

Dermal Sensitization

[guinea pig 6-b]

42251101 negative n/a

1-6

 MRIDs 00157103, 00157104, 00163311, 00157105, 00157106 and 42251101.

a

 Test material was diflubenzuron VC-90 (90% diflubenzuron).

b

 Test material was technical grade diflubenzuron.

C

 HIARC TXR NO: 0050503 (March 6, 2002)
Page 19 of 23

Table 5. Summary of Toxicological Dose and Endpoints for Diflubenzuron for Use in Human Risk 

Assessment1.

Exposure

Scenario

Dose Used in Risk 

Assessment, UF 

FQPA SF and 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 in oral 

studies. Therefore, a risk assessment is 

not required.

Chronic Dietary

all populations

NOAEL= 2 

mg/kg/day

UF = 100

Chronic RfD = 

0.02 mg/kg/day

FQPA SF = 1x

cPAD = 

chronic RfD

FQPA SF

= 0.02 mg/kg/day

Chronic Toxicity Study - Dog

LOAEL = 10 mg/kg/day based on 

methemoglobinemia and 

sulfhemoglobinemia

Short- and 

Intermediate-Term 

Incidental Oral

(1 day - 6 months)

(Residential)

Not applicable Not applicable These endpoints were not evaluated. 

There are no registered uses of 

diflubenzuron which result in significant 

residential exposure.

Short-Term Dermal 

(1 - 30 days)

(Occupational)

NOAEL = 500 

mg/kg/day

LOC for MOE = 100 21-Day dermal rat

LOAEL = 1000 mg/kg/day based on 

methemoglobinemia

Intermediate-Term 

Dermal (1 - 6 

months)

(Occupational)

NOAEL = 2 

mg/kg/day

LOC for MOE = 100 13 - week oral dog 

LOAEL = 6.4 mg/kg/day based on 

methemoglobinemia 

Short-Term 

Inhalation (1 - 30 

days)

(Occupational)

NOAEL = 20.302

mg/kg/day

LOC for MOE = 100 28-day Inhalation Toxicity Study - Rat/

21-day Inhalation Toxicity Study - Rat

LOAEL = 0.12 mg/L based on 

methemoglobinemia (21-day study)

Intermediate-Term 

Inhalation (1 - 6 

months)

(Occupational)

NOAEL = 20.302

mg/kg/day

LOC for MOE = 100 28-day Inhalation Toxicity Study - Rat/

21-day Inhalation Toxicity Study - Rat

LOAEL = 0.12 mg/L based on 

methemoglobinemia (21-day study)

Cancer (oral, 

dermal, inhalation)

Diflubenzuron

Not Required

Not Applicable Acceptable oral rat and mouse 

carcinogenicity studies; no evidence of 

carcinogenic or mutagenic potential. 

“Group E” evidence of noncarcinogenicity for humans.

 1. UF = uncertainty factor, FQPA SF = FQPA safety factor, NOAEL = no-observed-adverse-effect level, LOAEL = lowestobserved-adverse-effect level, cPAD = chronic population- adjusted dose, RfD = reference dose, MOE = margin of exposure, 

LOC = level of concern.

2. Conversion from mg/L to oral dose (mg/kg/day)

3.
Page 20 of 23

Table 6: Summary of Chronic Dietary-Exposure Analysis and Risk for Diflubenzuron

Age Group cPAD (mg/kg/day) Exposure (mg/kg/day) % cPAD 

All Infants (<1 year old) 0.02 0.002299 12 

Children 1-2 years old 0.02 0.007404 37 

Children 3-5 years old 0.02 0.005714 29 

Children 6-12 years old 0.02 0.003419 17 

Youth 13-19 years old 0.02 0.002246 11 

Adults 20-49 years old 0.02 0.001599 8 

Adults 50+ years old 0.02 0.001784 9 

Females 13-49 years old 0.02 0.001668 8 

Table extracted from page 20, RA September 14, 2006 (DP 328204) 

Dietary Exposure to diflubenzuron was evaluated in connection with a Section 18 Risk 

assessment for use of diflubenzuron on alfalfa (9/15/2008) using the established/recommended 

tolerances for all food commodities, 100% crop treated information for all proposed and existing 

uses, and DEEMTM Version 7.81 default processing factors for some processed commodities. 

Drinking water was incorporated directly into the dietary assessment using the EDWC generated 

by PRZM/EXAMS with IR scenarios and PCA adjustment factors. 

Diflubenzuron chronic dietary (food + water) exposure estimates using the DEEM-FCIDTM 

software are below HED’s LOC for the U.S. population and each of the population subgroups. 

Using the DEEM-FCIDTM software, dietary exposure is estimated at 0.002285 mg/kg/day for the 

U.S. population (11% of the cPAD) and 0.007404 mg/kg/day (37% of the cPAD) for children 1 

to 2 years old, the population subgroup with the highest estimated chronic dietary exposure to 

diflubenzuron. The estimated exposures/risks for combined food and water are summarized in in 

the table below for all populations.
Page 21 of 23

Table 7 International Residue Limits 

Diflubenzuron (PC Code 108201; Date of Request 4/12/12)

Summary of US and International Tolerances and Maximum Residue Limits 

Residue Definition:

US Canada Mexico1 Codex2

40 CFR 180.377

Plant: diflubenzuron (N -[[(4-

chlorophenyl)amino]carbonyl]-2,6-

difluorobenzamide) 

Livestock: diflubenzuron

None Diflubenzuron (fat-soluble).

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

US Canada Mexico1 Codex2

Artichoke, globe 6.0

Cattle, fat 0.05

Cattle, meat 0.05 0.1 (fat) meat from mammals other 

than marine mammals)

Cotton, undelinted seed 0.2

Egg 0.05 0.05 (*)

Goat, fat 0.05

Goat, meat 0.05 0.1 (fat) meat from mammals other 

than marine mammals)

Grapefruit 0.5 0.5 citrus fruits

Hog, fat 0.05

Hog, meat 0.05 0.1 (fat) meat from mammals other 

than marine mammals)

Horse, fat 0.05

Horse, meat 0.05 0.1 (fat) meat from mammals other 

than marine mammals)

Milk 0.05 0.02 (*) milks F

Mushroom 0.2 0.3

Orange, sweet 0.5 0.5 citrus fruits

Poultry, fat 0.05

Poultry, meat byproducts 0.05

Poultry, meat 0.05 0.05 (*) (fat)

Sheep, fat 0.05 0.1 (fat) meat from mammals other 

than marine mammals)

Sheep, meat 0.05

Soybean 0.05

Soybean, hulls 0.5

Tangerine 0.5 0.5 citrus fruits

US [40 CFR §180.377(a)(2)] Canada Mexico1 Codex2
Page 22 of 23

Summary of US and International Tolerances and Maximum Residue Limits 

Residue Definition:

US Canada Mexico1 Codex2

40 CFR 180.377

Plant/Livestock:

2) combined residues of 

diflubenzuron and its 

metabolites 4-

chlorophenlyurea and 4-

chloroaniline 

None None Diflubenzuron (fat-soluble).

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

US Canada Mexico1 Codex2

Almond, hulls 6.0

Barley, grain 0.06

Barley, hay 3.0

Barley, straw 1.8

Brassica, leafy greens, 

subgroup 5B

9.0

Cattle, meat byproducts 0.15 0.1 (*) Edible offal (mammalian)

Fruit, stone, group 12, except 

cherry

0.07

Goat, meat byproducts 0.15 0.1 (*) Edible offal (mammalian)

Grain, aspirated fractions 11

Grass, forage, fodder, and 

hay, group 17

6.0

Hog, meat byproducts 0.15 0.1 (*) Edible offal (mammalian)

Horse, meat byproducts 0.15 0.1 (*) Edible offal (mammalian)

Nut, tree, group 14 0.06

Oat, forage 7.0

Oat, grain 0.06

Oat, hay 6.0

Oat, straw 3.5

Peanut 0.10

Peanut, hay 55

Peanut, refined oil 0.20

Pear 0.50 5 pome fruits

Pepper 1.0

Pistachio 0.06

Pummelo 0.50

Rice, grain 0.02 0.01 (*) rice

Rice, straw 0.8 0.7 rice straw and fodder, dry

Sheep, meat byproducts 0.15 0.1 (*) Edible offal (mammalian)

Turnip greens 9.0

Wheat, forage 7.0

Wheat, grain 0.06

Wheat, hay 6.0

Wheat, straw 3.5

Completed: : M. 

Negussie; 04/13/2011
Page 23 of 23

1Mexico adopts US tolerances and/or Codex MRLs for its export purposes.

2 * = absent at the limit of quantitation; Po = postharvest treatment, such as treatment of stored grains. PoP = 

processed postharvest treated commodity, such as processing of treated stored wheat. (fat) = to be measured on the 

fat portion of the sample. MRLs indicated as proposed have not been finalized by the CCPR and the CAC.

(b) Section 18 emergency exemptions . Time-limited tolerances are established for of the insecticide diflubenzuron, 

(N-[[(4-chlorophenyl)amino]carbonyl]-2,6- difluorobenzamide and its metabolites 4-chlorophenylurea and 4-

chloroaniline, in connection with use of the pesticide under section 18 emergency exemptions granted by EPA. The 

tolerances are specified in the following table, and will expire and are revoked on the dates specified.

Commodity Parts per million Expiration/revocation date

Alfalfa, forage 6.0 12/31/14

Alfalfa, hay 6.0 12/31/14

Lemon 0.8 12/31/10