### Page 3 of 23

diflubenzuron, updates to its toxicity, exposure and usage databases, and current Agency science policies and risk as sessment 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 agricultur e 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 §180.37 7, 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 physicochemic al 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 solu tion 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 includin g 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 fores t 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 v oids, 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, de rmal 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, p roduced 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, der mal 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, respectivel y.

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 non

carcinogenici ty 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 am ounts. 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 non

carcinogenic risk assessment should include diflubenzu ron, 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 databas e 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 studi es 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 o ffspring 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 two

generation reproduction study in rats. There were no reports of treatment

- related clinical

obser vations 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 wa s 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 rec eived 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) ha ve 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 s tudies 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 pr ocess 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 Pe anuts, 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 establis hed/recommended tolerances for all food commodities, 100% crop treated information for all proposed and existing uses, and DEEM TM 

### Version 7.81 default processing factors for some processed commodities. Drinking water was incorporated directly into the diet ary 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 p opulation subgroups. Using the DEEM

- FCID TM 

### 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 high est 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 resid ues 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 include d 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

amen ded 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, MRID s 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 endpoint s 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 Harmonizati on

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 an d 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 toleran ce 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 i nfestation 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, wal l 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

- applicatio n 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) Reside ntial 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 post

application dermal exposure. As part of the recent revision to the Health Effects Division’s 2012 Standard Operating Procedures for Resi dential 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 (F AR 

### ). This default value is 25%. Of the

### Page 8 of 23

analyzed D FR studies, the maximum F AR 

### value seen was 89% or 3.6 times higher than the default residue transfer value. Therefore, a calculated MOE of approximately 4 times higher than the LOC (i.e., an MOE > 400 if the LOC = 100) using the 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, w hich is more than 4 times higher than the LOC of 100.

Exposure

Scenario Population TTR t (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

- applic ation 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

pote ntial 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 pr ocess 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 pro cedures 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

d iflubenzuron 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 b ased upon revisions to HED’s Residential SOPs which were reviewed by the Scientific Advisory Panel (SAP) in October 2009.

The P ost

- 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 expos ures 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 (consider ed 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.

Con clusions

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 expect ed 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 exposu re, 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

inte rmediate

- 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 cattl e. 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 occup ational 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 appl icators (enclosed cockpit) of sprays and granules

. 5. Appli cator using open

- cab groundboom s pray equipment.

6. Appli cator 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 ae rial 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 ass essments 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. How ever, HED policies have since changed yielding updated acreage assumptions as well as updated unit exposures 1 

### . 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 wit h 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 t he fraction of the application rate available to be dislodged after a foliar application (F AR 

### ). This default value is 25%. Of the analyzed DFR studies, the maximum F AR 

### value seen was 89% or 3.6 times higher than the default residue transfer value. There fore, 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 D FR 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 valu e 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/cm 2 Mar gin 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 sco uting, 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 post

application 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 mushroo ms). 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 t o 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 Dat a

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 diflubenz uron, 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.

E ndocrine 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 carcino genicity, 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 cycli city, 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

t axonomic 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), d iflubenzuron 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 human s 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

inte ract 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 eff ects 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 orde rs/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. Accor dingly, as part of registration review, EPA will issue future EDSP orders/data call

ins, 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 che micals, 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. T hese 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/handler

exposure

- 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 o r 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 1289 8, “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 lega l 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 harvest ing 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 i n 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, Wh eat, 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. Di flubenzuron: Occupational Exposure Assessment for New Diflubenzuron Feed

Through Use for Cattle, D381612, EPA Memorandum dated 9/8/2010.

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

Evans, J. Occupational And Residenti al 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 o n 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 Eli gibility 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

Difl ubenzuron 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

Common Name D iflubenzuron

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 Metab olite

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.g ov/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 10 3 Acetone

2 x 10 3 Acetonitrile

2.4 x 10 4 Dioxane

1.04 x 10 5 Dimethylformamide

1.2 x 10 5 Dimethylsulfoxide

1 x 10 3 Methanol

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

a Not available Octanol/water part ition coefficient, Log(K OW ) 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 I nhalation 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 Chroni c 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 Mu tagenicity

— 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 Ac ute 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

---

n o*

* Immunotoxicity Study has been received and is under review.

### Page 18 of 23

Table 4: Diflubenzuron Acute Toxicity Studies c :

Guideline

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

870.1100

(81

- 1) Acute Oral

(rat 1a) 00157103 LD 50 =>5,000 mg/kg IV

870.1200

(81

- 2) Acute Dermal

(rat 2

- a) 00157104 LD 50 =>2000 mg/kg III

870.1300

(81

- 3) Acute Inhalation

(rat 3a) 00163311 LC 50 =>2.49 mg/L IV

870.2400

(81

- 4) Primary Eye Irritation

(rabbit 4

- a) 00157105 mild irritant III

870.2500

(81

- 5) Primary Ski n 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% diflub enzuron).

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

Assessment 1

. Exposure

Scenario Dose Used in Risk

As sessment, 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 assess ment 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

sul fhemoglobinemia

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 exposu re.

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 = 20.30 2

mg/kg/day LOC for MOE = 100 28

- day Inhalation Toxicity Study

- Rat/

21

- day I nhalation Toxicity Study

- Rat LOAEL = 0.12 mg/L based on methemoglobinemia (21

- day study)

Intermediate

- Term Inhalation (1

- 6 months) (Occupational) NOAEL = 20.30 2

mg/kg/day LOC for MOE = 100 28

- day Inhalation Toxicity Study

- Rat/

21

- day Inhalation Toxi city 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 potent ial. “Group E” evidence of non

carcinogenicity for humans.
1. UF = uncertainty factor, FQPA SF = FQPA safety factor, NOAEL = no

- observed

- adverse

- effect level, LOAEL = lowest

observed

- 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 ol d 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 DEEM TM 

### 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 th e DEEM

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

- FCID TM 

### 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

T able 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 Mexico 1 

### Codex 2



### 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 Mexico 1 

### Codex 2

Artichoke, globe 6.0
Cattle, fat 0.05

Cat tle, 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

H og, 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 Mexico 1 

### Codex 2

### Page 22 of 23

Summary of US and International Tolerances and Maximum Residue Limits Residue Definition : US Canada Mexico 1 

### Codex 2



### 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 Mexico 1 

### Codex 2

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 (*) E dible 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 1 Mexico adopts US tolerances and/or Codex MRLs for its export purposes.

2 * = absent at the limit of quantitation; Po = postharvest trea tment, 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 a nd 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 conne ction 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

Alfa lfa, forage 6.0 12/31/14

Alfalfa, hay 6.0 12/31/14

Lemon 0.8 12/31/10