Docket Number EPA-HQ-OPP-2015-0401 

www.regulations.gov 

Difenoconazole Preliminary Work Plan 

Registration Review: Initial Docket 

Case Number 7014 

December 2015 

Approved by: 

Richard 

9:t-d:JQ-LcL

P. Keigwin, 

P ~~ Jr. 

Director 

Pesticide Re-evaluation Division 

Date: / ;;l_j C2 I I a. 0 Is 
Difenoconazole Preliminary Work Plan- Table of Contents 

OVERVIEW ................................................................................................................................... 4 

ANTICIPATED DATA NEEDS .................................................................................................... 5 

STATUTORY A D REGULATORY AUTHORITY ................................................................... 6 

CHEMICAL FACTS ...................................................................................................................... 7 

USE AND USAGE INFORMATION ............................................................................................ 8 

RECENT ACTIO S ....................................................................................................................... 9 

ANTICIPATED RISK ASSESSMENTS FOR REGISTRATION REVIEW ............................. 10 

TIMELINE .................................................................................................................................... 13 

EXT STEPS . . .. . .... .... ... . .. . . .. . ... . ... . ... . . .. . . ... . ... . . ... .. .. .. ... . .... . ... . ... . .. . . .. . .... .... .. . .... .. . . .. . .... ... . .. . ... . ... . .. 13 

Appendix - Additional Areas Considered in the Amicarbazone Registration Review ................ 13 

References: 

This Preliminary Work Plan summarizes the Environmental Protection Agency's current position 

based on the fo llowing documents: 

I. D{(enoconazole Preliminary Problem Formulation/or Environmental Fate, Ecological Risk, 

Endangered Species. and Drinking Water Exposure Assessments in Support of Registration 

Review. Michael Lowit, Faruque Khan, Sujatha Sankula. November 5, 20 15. 

2. Difenoconazole. Human Health Risk Scoping Document in Support of Registration Review. 

Ivan Nieves, Bonnie Cropp-Kohlligian, Thurston Morton, Abdallah KJ1asawinah. October 

I, 20 15. 

3. Difenoconazole: Tier I (Scoping) Review of Human Incidents and Epidemiology. Shanna 

Recore. September 15, 2015. 

-1. Common Triazole Metabolites: Updated Aggrega1e Human Health Risk Assessment to 

Address The New Section 3 Registrations For Use of Propiconazole on Tea, Dill, Mustard 

Greens, Radish, and 1Varercress; Use of Difenoconazole on Globe Artichoke, Ginseng and 

Greenhouse Grown Cucumbers and Conversion ofrhe Esrablished Foliar Uses/Tolerances 

2 
for Stone Fruit and Tree Nut Crop Groups to Fruit, Stone, Group 12-12 and the Nut, Tree, 

Group 1-1-12.: and Use ofF/utriafol on Hops. Thurston G. Morton. April9, 2015. 

5. Common Triazole Metabolites: Updated DietCIIy (Food + Wate1) Exposure and Risk 

Assessment to Address The New Section 3 Registrations For Use of Propiconazole on Tea, 

Dill, Mustard Greens, Radish, and Watercress; Use of Difenoconazole on Globe Artichoke, 

Ginseng and Greenhouse Grown Cucumbers and Conversion of the Established Foliar 

U-;es/Tolerancesfor Stone Fruit and Tree Nut Crop Groups to Fruit, Stone, Group 12-12 

and the N111. Tree, Group 1-1-12.; and Use ofF!utriq(ol on Hops. Thurston G. Morton. 

April 9, 2015. 

6. BEAD Che111ica/ Pn?file (BCP) .fhr Registration Review of Di{enoconazole ( 1288-17). 

Leonard Yourrnan. Rafael Prieto. Stephen Smcannan. December 2, 2015 

7. D((enoconazole (1288-1 7) Screening Level Usage Analysis (SLUA). October 2, 2014. 

8. Difenoconazole (1 288-17) EFED Table I Report. february 3, 2015. 

9. liED }vfaster Label Report: Difenoconazole (1 288-17). February 3, 2015. 

These and other supporting documents for the difenoconazole registration review case may 

be found in the docket EPA-HQ-OPP-20 15-040 I at http://www.rcgulations.gov. 

3 
OVERVIEW 

The docket for difenoconazole is now open, initiating the first public comment period for this 

registration revi ew (docket number EPA-HQ-OPP-20 15-040 I). Di fenoconazole, 1-[2-[2-chloro4-( 4-chloro-phenoxy)-phenyl)-4-methyl-[ I ,3 )dioxolan-2-ylmethyl)-l /-1-( 1 ,2,4]triazole, is a 

broad-spectrum fungicide. with registered uses on many fruits, vegetables, cereals, field crops, 

and golf course turfgrass, and ornamental plants, including roses. 

This Preliminary Work Plan (PWP) document explains what EPA's Office of Pesticide Programs 

knows about difenoconazole, highlighting anticipated data and assessment needs, identifying the 

types of infom1ation that would be especially useful to the Agency in conducting the review, and 

providing an anticipated timeline for completing the registration review for difenoconazole. 

The registration review process was designed to include a public participation component to 

solicit input from interested stakeholders. The Agency intends, by sharing this information in the 

docket, to inform the public of what it knows about di fenoconazole and what types of new data 

or other information would be helpful for the Agency to receive as it moves toward a decision on 

difenoconazole. The Agency encourages all interested stakeholders to review the PWP and 

Appendix and to provide comments and additional information that will help the Agency's 

decision-making process for this chemical. In addition to general areas on which persons may 

wish to comment, there arc some areas identified in the PWP and Appendix about which the 

Agency specificall y seeks comments and information. Interested stakeholders could include: 

environmental non-profit or interest groups; pesticide manufacturers; agricultural labor or 

commodity groups; commerciill, institutional, residential. and other users of pesticides; or the 

public at large. 

The Preliminary Work Plan begins by listing the anticipated data needs for difenoconazole. 

ext. it discusses the statutory and regulatory authority for Registration Review. Then the 

document provides chemical facts, use and usage information, recent actions, the anticipated risk 

assessments, and a projected registration review timeline for difenoconazole. fina ll y, the 

Appendix to this document includes identification and discussion of some areas that are 

considered generally in registration review along with some additional chemical case-specific 

information. 

4 
ANTICIPATED DATA NEEDS 

Table I below summarizes an ticipated data needs for difenoconazole. For additional discussion 

of the anticipated data needs, see the Difenoconazole Prelimincuy Problem Formulation for 

Environmental Fate, Ecological Risk, Endangered Species. and Drinking Water Exposure 

Assessments in Support of Registration Review. 

Table 1: Anticipated Data Needs for the Difcnoconazole Registration Review 

Estimated 

Guideline Number Study Title2 

Test Material1 

Timeframe 

(Months from 

receipt of DCI) 

Anticipated Data Needs for Difenoconazole 

Non-GDL_N Tier I Honeybee adult acute oral exposure TGAI 12 

Non-GDLN Tier I Honeybee adult chronic oral exposure TGAI 12 

Non-GDLN Tier I Honeybee larval acute exposure TGAI 12 

Non-G DLN Tier I Honeybee larval chronic oral exposure TGAI 12 

Residue in pollen and nectar 

on-GDLN Tier II (recommendation pending risks identified in 

TEP 24 

Tier I studies) 

Semi-fie ld testing for pollinators (tunnel and 

feed ing studies) 

Non-GDLN Tier II TEP 24 

(recommendation pending risks identified in 

Tier I studies) 

Full-field testing for pollinators 

850.3040 Tier Ill (recommendation pending risks identified in 

TEP 24 

Tier II studies) 

Independent laboratoty validation report for 

850.6100 (!LV) ana lytical method in soil for difenoconazole TGAI 12 

and its metabolites (CGA-205375, CGA142856, and CGA-71019). 

Environmental chemistry method and 

independent laboratory validation for 

850.6100 (ECM/ILV) analytica l method in water for TGAI 12 

difenoconazole and its metabolites (CGA205375, CGA-1 42856, and CGA-71 0 19). - .. ~ 1

TGAI - techlllcal grade acuvc mgred1cnt: I EP = typ1cal end-use product 

!On June 27. 2012. EPA announced cenain revisions in harmonized guideline series 850 - Ecological Effects Tests- including 

renumbering and/or removal of the Tier designations for some guideline studies. cc "Final Test Guidelines: OCSPP 850 Series: 

Notice of 1\ vailabi lity" 77 FR 38282. June 27. 2012. http://,,.,, w.rcgulations.gov/11 !ducumcntDctaii:D EP/\- 110-0PPT-2009-

0 154-002S 

5 
STATUTORY AND REGULATORY AUTHORITY 

The Food Quality Protection Act (FQPA) of 1996 mandated a registration review program. All 

pesticides distributed or sold in the United States (U.S.) generally must be registered by the 

Environmental Protection Agency (EPA or the Agency), based on scientific data showing that 

they will not cause unreasonable risks to human health or the environment when used as directed 

on product labeling. The registration review program is intended to make sure that, as the ability 

to assess risk evolves and as policies and practices change, all registered pesticides continue to 

meet the statutory standard of no unreasonable adverse effects to human health or the 

environment. Changes in science, public policy, and pesticide use practices will occur over time. 

Through the registration review program, the Agency periodically reevaluates pesticides to make 

sure that as change occurs, products in the marketplace can be used safely. Information on this 

program is provided on EPA's website. 1 

The Agency is implementing the registration review program pursuant to Section 3(g) of the 

Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA), and will review each registered 

pesticide every 15 years to determine whether it continues to meet the FIFRA standard for 

registration. The regulations governing registration review begin at 40 CFR 155.40. The 

Agency will consider benefits information and data as required by FIFRA. The public phase of 

registration review begins when the initial docket is opened for each case. The docket is the 

Agency"s opportunity to state what it knows about the pesticide and what additional risk analyses 

and data or information it believes are needed to make a registration review decision. After 

reviewing and responding to comments and data received in the docket during this initial 

comment period, the Agency will develop a Final Work Plan (fWP) and anti cipated schedule for 

the registration review of di fenoconazole. 

CHEMICAL FACTS 

Table 2 provides a summary of the chemical facts for difenoconazole. 

Table 2: Chemical Facts for Difcnoconazole 

PC code 128847 

Case Number 7014 

CAS Number 119446-68-3 

Year first registered 1994 

Pesticide Type Fungicide 

Chemical class Triazolc 

Reregistration Eligibility No Reregistration Eligibility Decision (RED) was issued for 

Decision difenoconazole. 

Tolerance Reassessment Difenoconazole was not subj ect to tolerance reassessment. 

Eligibility Decision (TRED) 

Cumulative group Difenoconazole has not been identified as a member of a 

cumulative group that shares a common mechanism of toxicity. 

40 CFR Citation Tolerances for difenoconazole are established in 40 CFR § 180.4 75. 

1 http://www2.cpa.gov/pcsticidc-rccvaluation 

6 
Table 2: Chemical Facts fot· Difenoconazolc 

Dual-use Difenoconazole is registered for conventional pesticidal uses only 

and has no registered antimicrobial or biopesticidal uses. 

Non-pesticidal uses There are no identified non-pesticidal uses of difenoconazole. 

Pesticide Re-evaluation Maria Rivera Piansay 

Division, Chemical Review Piansay.maria@epa.gov 

Manager (703 )308-8063 

Registration Division, Tony Kish 

Product Manager Kish.tonv(@cpa.gov 

(703)308-9443 

USE AND USAGE INFORMATION 

Table 3 summarizes the use and usage information for difenoconazole. Please see the BEAD 

Chemical Profile for Registration Review: Difenoconazole, 1288-17 in the registration review 

docket for more details. 

Summary of Use 

Use Sites 

Summary ofUsage 

Table 3: Difenoconazolc Use and Usage Information 

Difenoconazole is a broad-spectrum triazole fungicide that works 

by inhibiting demethylation and other processes in sterol 

biosynthesis. Difenoconazole is a penetrating systemic fungicide 

which is rapidly absorbed by leaves and is then distributed within 

plant tissue by translaminar movement. 

Agricultunl l Use S ites: Difenoconazole is registered for use on 

plants or seeds of a number of fruits, vegetables. cereals, and field 

crops. Crops include citrus, pome fruits, low growing berries, 

tuberous and corm vegetables, fruiting vegetables, cucurbit 

vegetables, stone fruits, tree nuts, and cole crops. More 

specifically, this chemical is registered for almonds, barley, 

canola, carrots, sweet corn, cotton, filbert (hazelnut), 

garbanzos/chick peas, garlic, grapes, leeks, oats, onions, pecan, 

pepper, pistachio, potatoes, rye, shallot, soybeans, sugar beets, 

tomatoes, triticale, and wheat. 

Non-agricultural Use S ites: Outdoor application to established 

ornamentals in landscaped areas, including (but not limited to) 

recreational parks, institutional sites, golf courses and residential 

properties by commercial and non-professional (i.e., homeowner) 

applicators. 

Agricultural Usage: From 2008 to 2013, annual usage of 

clifenoconazole averaged 140,000 pounds of active ingredient (A. I.) 

treating an annual average of 6.4 million acres, with an overall 

average application rate of 0.021 pounds A. I. per acre. Usage may 

be higher because our data sources do not capture all registered 

agricultural use sites such as leeks, shallot, triticale, etc. The use 

7 
Table 3 : Difcnoconazolc Usc and Usage Information 

of difenoconazole has steadily increased since 2008 as measured 

by pounds A. I. and total area treated. In additi on. as seed 

treatment data for various crops are not surveyed. their usage 

estimate is I ikcly an underestimate of actual percent crop treated. 

Non-agricultural Usage: There arc no available non-agricultural 

usage data for difenoconazole. 

Formulation Type(s) Difenoconazole is formulated as a tlowable concentrate, emulsion 

(oil) in water, emulsifiable concentrate, ready-to-use solution, and 

liquid soluble concentrate. 

Application Method(s) This herbicide is applied as a ground and aerial spray or as a seed 

treatment. It is also applied as broadcast spray and by 

chemigation. Other application methods include broadcast spray, 

chemigation, bin/truck drench or in-line dip/drench or flooder, 

and/or in-line aqueous or fruit coating spray application. 

Techni cal Registrant(s) Syngenta Crop, LLC 

Albaugh, LLC 

Nufarm Americas, Inc. 

Number of Registrations Thirty five Section 3 registrations 1 

Restricted Use No .. 1Secuon 3 product labels can b.: obtaan ed from the Pesucadc Product Label Systl.!m (PPLS) wcbsnt: 

(h ttr //oa puh.c pa. gov/pest hl ppl homc) 

Guidance for Commcntcrs: Additiona l areas of use and usage related information requested 

for this registration review, and of particular interest to EPA, are described below. 

• Certain difenoconazole labels are unclear with respect to application parameters such as 

maximum number of applications, minimum application intervals, and maximum application 

rates per acre (maximum lb ai/ A/year) for labels that refer only to per-crop or per-season 

rates (see Difenoconazole (1288-1 7) EFED Table 1 Report). 

• The Agency does not have non-agricultural usage data and infonnation on the use or usage of 

difenoconazole on golf course turfgrass, ornamental plants, either commercial or residential. 

Information that might clarify the relative importance of difenoconazole in comparison to 

alternati ves would be helpful if the Agency conducts benefits or impact assessments. 

• Usage data on seed treatment crops not surveyed by ava il able databases. 

• Pounds of active ingredient applied, percent crop treated, and application rates on registered 

use sites. 

• Additional information on the occurrence of resistance to difenoconazole would be useful in 

establishing benefits and developing resistance management language. 

8 
RECENT ACTIONS 

• Recently approved new uses on peas and beans, artichoke, post-harvest to pome fruits 

(May I 0, 20 15). 

• Recently approved new uses on gi nseng artichoke greenhouse cucumber conversions to 

crop groups 12- 12 stone fruits and tree nuts 14-1 2 (December 14, 20 15). 

• Data associated with new uses arc required as condition of registration with the exception 

of honey bee data. 

ANTICIPATED RISK ASSESSMENTS FOR REGISTRATION REVIEW 

The most recent ecological and environmental fa te risk assessments were conducted in 2014. 

Findings and conclusions from these risk assessments are summarized in Difenoconazole 

Preliminary Problem Formulation for Environmental Fate, Ecological Risk, Endangered 

Species. and Drinking Water Exposure Assessments in Support of Registration Review. 

During registration review, the Agency anti cipates the need to conduct a comprehensive 

ecological risk assessment, including an endangered species assessment, for all uses of 

difenoconazole. The Agency also anticipates the need to determine if additional data are needed 

to address possible concerns about bystander exposures to volatilized difenoconazole. If 

toxicological endpoints, points of departure, standard operating procedures, or default exposure 

assumptions are revised, new human health risk assessments may be needed. A dietary 

assessment for common tri azole degradates/metabolites may also be needed. 

Table 4 below summarizes the anticipated registration review risk assessments based on the 

EFED Problem Formulation and HED Scoping Document and Draft Human llealth Risk 

Assessment. 

9 
T able 4: Anticipa ted Risk Assessments for the Difenoconazole Registra tion Review 

Type of Risk Assessment Conduct'? Notes 

E cological and E nvironmenta l F ate 

Comprehensive ecological y The Agency will conduct a comprehensive 

(species to be assessed ecological risk assessment for the parent 

include terrestria l and di,fenoconazole, including an endangered 

aquatic organisms), species assessment. 

including endangered species 

Incidents Will check for updates For a discussion of reported ecological 

incidents for difenoconazole, see page 21 of 

the Problem formul ati on . 

Human Hea lth •• 1 ·or 

Dietary 

Food N A new dietary risk assessment for 

( difenoconazole difenoconazole residues of concern is not 

residues of concern) anticipated to be needed during registrati on 

review. 

y A dietary assessment for common triazole 

(common degradates/metabolites may be needed. 

degradates/metabolites) 

Drinking water y A drinking water assessment will be 

(difenoconazole conducted, if wan·anted, to support future 

residues of concern) human hea lth dietary risk assessments of 

difenoconazole. The residues of concern are 

anticipated to be difenoconazole and CGA205375 unless information becomes available 

that indicates that other degradates should be 

included. 

y Difenoconazole may be considered in an 

(common degradates) updated drinking water assessment for 

common triazole degradates. 

Occupational 

Handlers (mixers, loaders, N A new occupational handler risk assessment is 

applicators) not anticipated to be needed during 

registration review. 

Post-application N A ne\v occupational post-application exposure 

is not anticipated to be needed during 

registration review. 

Residential 

Handlers N A new residential handler risk assessment is 

not anticipated to be needed during 

registration review. 

10 
Table 4: Anticipated Risk Assessments for the Difenoconazole Regist..ation Review 

Type of Risl< Assessment Conduct? Notes 

Post-application y During registration review, the Agency wi ll 

determine if data (e.g. , nux studies) or further 

analysis is required for a bystander risk 

assessment. 

Other 

Aggregate y As part of registration review, updated 

aggregate risk assessments for difenoconazole 

residues of concern may be necessary to 

reflect revised dietary or residential exposure 

estimates. 

Additionally, a dietary assessment for 

common triazole degradates/metabolites may 

be needed. 

Cumulati ve N EPA has not made a common mechanism of 

toxicity finding for difenoconazole and any 

other substances. 

Tolerances y U.S. tolerances are harmonized with Codex 

and Canadian maximum residue limit (MRL) 

with regards to definition of residues as well 

as levels in/on a number of commodities. 

Additiona l harmonization of residue levels 

wi ll be considered under registration review. 

Incidents Will check for updates Based on the low frequency and severity of 

incident cases reported for difenoconazolc in 

both IDS and SENSOR-Pesticides there does 

not appear to be a concern at this time that 

would warrant further investigation. The 

Agency will continue to monitor incident 

information and if a concern is triggered, 

additional analysis will be included in the risk 

assessment; see page 9 of the Scoping 

Document/Draft Risk Assessment and 

Difenoconazole: Tier I (Scoping) Review of 

Human Incidents and Epidemiology. 

Guidance for Commentcrs: Additional ecological information requested for this registration 

review, and of particular interest to EPA, is described below. 

• Ecological incidents not already reported to the Agency. 

• Water quality monitoring data (see Appendix for further details). 

II 
TIMELINE 

EPA has created the following estimated timeline for the completion of the difenoconazole 

registration review in Table 5 below. 

Table 5: Projected Difcnoconazole Registration Review Timeline 

Activities Estimated Date 

Opening the Docket 

Open Docket and 60-day Public Comment Period 20 15- December 

Close Public Comment 20 16- February 

Case Development 

Final Work Plan 20 16- April- June 

Issue DCI 20 16- July- September 

Data Submission 20 18- July- September 

60-day Public Comment Period for Draft Risk 2020- January - March 

Assessments 1 

Registration Review Decision 

60-day Publi c Comment Period for Proposed 2020- October- December 

Registration Review Decision 

Registration Review Decision and Begin Post-Decision 202 1- April -June 

Follow-up 

Total (years) 6 

'The regulauons goveming registration review generally require the Agency to provide a public comment period of 111 lcust JO cnlcndar days lor 

drall risk assessments; sec 40 CFR Part 155.53(c). For conventional pesticides. the Agency plans to provide a 60 calendar day public comment 

period generally for draft risk assessments. 

NEXT STEPS 

After the 60-day public comment period closes, the Agency will review and respond to any 

comments received in a timely manner and then issue a Final Work Plan for the registration 

review of di fenoconazole. 

12 
Appendix - Additional Areas Considered in the Difenoconazole Registration 

Review 

PUBLIC COMMENTS AND FEEDBACK: 

Guidance for Commcnters: The areas below highlight topics of special interest to the Agency 

where your comments, data submissions, or reference to sources of additional information could 

be of particular use. 

Trade lrriwnts: 

Through the registration review process, the Agency intends to solicit information on trade 

initants and, to the extent feasible, take steps toward facili tating irritant resolution. The Agency 

will work to harmonize tolerances and international maximum residue limits (MRLs) and may 

modify tolerance levels to do so, when possible. Growers and other stakeholders are asked to 

comment on any trade irritant issues resulting from lack of MRLs or disparities between U.S. 

tolerances and MRLs in key export markets, providing as much specificity as possible regarding 

the nature of the concern. 

Water Quality: 

Difenoconazole is not identified as a cause of impairment for any water bodies listed as impaired 

under section 303(d) of the Clean Water Act. 2 In addition, no Total Maximum Daily Loads 

(TMDL) have been developed for difenoconazole. More information on impaired water bodies 

and TMDLs can be found at the Agency's website.3 The Agency invites submission of water 

quality data for this pesticide. To the extent possible, data should conform to the quality 

standards in Appendix A of the OP P Standard Operating Procedure: inclusion of impaired 

Water Body and Other Water Quality Data in OPP 's Registration Review Risk Assessment and 

Management Process"' in order to ensure they can be used quantitatively or qualitatively in 

pesticide risk assessments. 

Environmental Justice: 

EPA seeks to achieve environmental justice, the fair treatment and meaningful involvement of all 

people, regardless of race, color, national origin, or income, in the development, implementation, 

and enforcement of environmental laws, regulations, and poli cies. To help address potential 

environmental justice issues, the Agency seeks information on any groups or segments of the 

population who, as a result of their location, cultural practices, or other factors, may have 

atypical. unusually high exposure to difenoconazole compared to the general population. Please 

comment if you arc aware of any sub-populations that may have atypical, unusually high 

exposure compared to the general population. 

1 hup://iaspub.epa.govltmdl waters I 0/auains nation cy.cause detail 303d?p cause group id=885 3 http://www.epa.gov/owow/tmd II 

·• hnp://www2.cpa. gov/ pest ic icle-rccva luation/opp-gu idance-subm iss ion- tate-and-triba 1-watcr-g ua I ity-monitoringdata 

13 
ENDANGERE D SPECIES: 

A risk assessment that supporis a complete endangered species determination has not been 

conducted for difenoconazole. The ecological risk assessment planned during registration 

review wi ll allow the Agency to determine whether use of difenoconazolc has "no effect" or 

··may affect" federally listed tlu·eatened or endangered species (listed species) or their designated 

critical habitats. When an assessment concludes that a pesticide's use "may affect" a listed 

species or its designated critical habitat, the Agency wi ll consult with the U.S. Fish and Wildlife 

Service and/or National Marine Fisheries Service (the Services), as appropriate. 

ENDOCRINE DlSRUPTOR SCREENING PROGRAM: 

As required by FTFRA and FFOCA, EPA revi ews 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 \veights, 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. /\s part of its most recent registration decision for difenoconazole, 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), 

amicarbazone 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 II screening assays to identify the potential of a 

chemical substance to interact with the estrogen, androgen, or thyroid (E, /\, 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 theE, 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. A second list 

of chemicals identified for EDSP screening was published on June 14, 20 135 and includes some 

pesticides scheduled for registration review and chemicals found in water. Neither of these lists 

s Sec b.!.!Q://www.regulntions. gov/#!documentDetai i;D=EPA-HQ-OPPT-2009-0477-0074 for the final second list of 

chem ica Is. 

14 
should be construed as a list of known or likely endocrine disruptors. Difenoconazo le does not 

appear on either list. 

For further information on the status of the EDSP, the policies and procedures, the lists of 

chemicals, future lists, the test guidelines and the Tier I screening battery, please visit our 

website. 1 

HUMAN STUDIES: 

Occupational and Residential 

Past difcnoconazole risk assessments rely in part on data from studies in which adult human 

subjects were intentionall y exposed to a pesti cide to determine their dermal and inhalation 

exposure. Many such studies, involving exposure to many different pesticides, comprise generic 

pesticide exposure databases such as the Pesticide Handlers Exposure Database (PHED), the 

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

Force (ORETF) Database. EPA has reviewed all the studies supporting these multi-pesticide 

generi c exposure databases, and has found no clear and convincing evidence that the conduct of 

any of them was either fundamentall y 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 ofResearch (40 CFR Part 26) have been 

satisfied. and there is no regulatory barrier to continued reliance on these studies. 

1

h!lp://www2.epa.gov/endocrinc-disruplion 

15