2



### Zoxamide Preliminary Work Plan

– Table of Contents

OVERVIEW

................................ ................................ ................................ ................................ ... 4

ANTICIPATED DATA NEEDS

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

STATU TORY AND REGULATORY AUTHORITY

................................ ................................ ... 6

CHEMICAL FACTS

................................ ................................ ................................ ...................... 6

USE AND USAGE INFORMATION

................................ ................................ ............................ 7

RECENT ACTIONS

................................ ................................ ................................ ....................... 8

ANTICIPATED RISK ASSESSMENTS FOR REGISTRATION REVIEW

................................ 8

TIMELINE

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

NEXT STEPS

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

Appendix

– Additional Areas Considered in the Zoxamide Registration Review

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

References:

This Preliminary Work Plan summarize s the Environmental Protection Agency's current position based on the following documents:

1. Registration Review Problem Formulation for Zoxamide

. R. Sternberg and F. Khan

. May 20, 2014

.

2. Human Health Scoping Document in Support of Registration Review

. N. Tsaur , V. Chen, and M. Negussie

. June 4, 2014.

3. Zoxamide: Tier I Review of Human Incidents

. E. Evans and S. Recore

. February 11, 2014

.

4. BEAD Chemical Profile (BCP) for Registration Review: Zoxamide

. C. Chen , C. Paisley

Jones and A. Lee

. April 16, 2014

.

5. Zoxamide (101702) Screening Level Usage Analysis (SLUA). April 22, 2013

.

6. EFED Label Data Report. March 20, 20143

7. HED Master Label Report. March 20, 2014

These and other supporting documents for the zoxamide registration review case may be found in

the docket EPA

- HQ

- OPP

- 2014

- 0391 at http://www.regulations.gov

.4

OVERVIEW

The docket for zoxamide is now open , initiating the first public comment period for this registration review (docket number EPA

- HQ

- OPP

- 2014

- 0391 )

. Zoxamide is a non

- systemic

broad

- spectrum benzamide fungicide registered for use to control fungicidal disea ses ( e.g. , spot, downy mildew, rot, blight, mold, blotch) on select fruit and vegetable crops ; zoxamide is registered

for use on cucurbit vegetables (melons, pumpkin, squash, and watermelon), grapes, potatoes (white/Irish)

, and tomatoes. The proposed new use of zoxamide on onions (dry bulb), garlic, and

shallots is currently under review by the Agency

. Zoxamide products are used primarily in agricultural area s; zoxamide products have no registered residential uses. This Pr eliminary Work

Plan (PWP) document explains what EPA's Office of Pesticide Programs knows about zoxamide, highlighting anticipated data and assessment needs, identifying the types of information that would be especially useful to the Agency in conducting t he review , and providing an anticipated timeline for completing the registration review for zoxamide.

The registration review process was designed to include a public participation component to solicit input from interested stakeholders. The Agency inte nds, b y sharing this information in the docket,

to inform the public of what it knows about zoxamide and what types of new data or other information would be helpful for the Agency to receive as it moves toward a decision on zoxamide. 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 are some areas identified in the PWP and Appendix about which the Agency specifically seeks

comments and information. Interested stakeholders could include: environmental non

- profit or interest groups; pesticide manufacturers; agricultural labor or commo dity groups; commercial, institutional, residential, and other users of pesticides; or the public at large.

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

. Next, it discusses the statutory and regulatory authority for R egistration R eview. Then the document provides chemical facts, use and usage information, recent actions, the anticipated risk assessments, and a projected registration review timeline for zoxamide. Finally, the Appendix to this document includes identification and discussion of some areas that are considered generally

in R egistration R eview along with some additional chemical case

- specific information.5

ANTICIPATED DATA NEEDS

Table 1 below summari zes anticipated data needs for zoxamide . For additional discussion of the anticipated data needs, see the Registration Review Problem Formulation for Zoxamide and Human Health Scoping Document in Support of Registration Review

.

Table 1: Anticipated Data Needs for th e Zoxamide Registration Review

Guideline

Number 1 Study Title 1 Test Material Estimated

Timeframe

(Months from receipt of DCI)

Anticipated D ata Needs for the Parent Zoxamide

835. 4100 Aerobic soil metabolism (two soils) TGAI /PAIRA 2 24

835.4400 Anaerobic aquatic metabolism (two sediments) TGAI /PAIRA 2 24

850.1735 Whole sediment acute toxicity invertebrates

(freshwater)

– 2 species 3 TGAI 12

850.1740 Whole sediment acute toxicity invertebrates

(marine)

– 1 species 4 TGAI 12

850.2100 Avian acute oral toxicity test, passerine 5 TGAI 12

850.4100 Seedling emergence and seedling growth (two

species 6 ) TEP 12

Non

- GLN A cute honey bee larvae feeding study 5, 7 TGAI 12

Outstanding Data Requirements from Conditional Registration(s) 8

860.1380 Storage stability study 9 TGAI

-- TGAI = technical grade active ingredient; TEP = typical end

- use product ;

1 On June 27, 2012, EPA announced certain revisions in harmonized guideline series 850

– Ecological Effects Tests

– including renumbering and other designations or changes for some guideline studies. See “Final Test
Guidelines; OCSPP 850 Series; Notice of A vailability” 77 FR 38282, June 27, 2012. http://www.regulations.gov/#!documentDetail;D=EPA

- HQ

- OPPT

- 2009

- 0154

- 0028

2 Test substance should be technical grade or a pure active ingredient radiolabelled

3 Acute sediment tests with the midge Chironomus dilutus and freshwater amphipod Hyalella azteca

4 Acute sediment test with the estuarine/marine amphipod Leptocheirus plumulosus

5 The anticipated DCI will require submission of a protocol prior to study initiation

. 6 S eedling emergence testing is anticipated for corn and ryegrass only. For corn, a study that defines a NOAEC ( i.e.

, a concentration that is not statistically different from the negative control for a ll assessed endpoints) is needed

. For ryegrass, a Tier II test is anticipated to be needed

. 7 For reference material on the screening

- level risk assessment process for honey bees, see “White Paper in Support of the Proposed Risk Assessment Process for Bees” as submitted to the FIFRA Scientific Advisory Panel : http://www.regulations.gov/#!documentDetail;D=EPA

- HQ

- OPP

- 2012

- 0543

- 0004

8 The study listed in this section was previously required as a condition of registration and is still outstanding.

S torage stability data (Guideline 860.1380) for tomatoes were previously required as a condition of registration (T. Alston, DP274785, 08/30/2001). This study will not be included in the anticipated Registration Review DCI

because it is already required as a condition of registration.

9 Specifically for tomatoes and cucurbits6

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 envi ronment 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 marketpla ce can be used safely. Informatio n on this program is provided on EPA’s website

. 10

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

. T he Agency will consider benefits information and data as required b y 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 believ es 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 F inal W ork P lan (FWP) and anticipated schedule for the registrat ion review

of zoxamide.

CHEMICAL FACTS

Table 2 provides a summary of the chemical facts for zoxamide

.

Table 2: Chemical Facts for Zoxamide

PC code 101702

Case Number 7032

CAS Number 156052

- 68

- 5

Year first registered 2001 Pesticide Type Fungicide

Chemical class Non

- systemic, broad

- spectrum benzamide fungicide ; FRAC group 22 (low to medium risk for resistance development)

R eregistration Eligibility Decision (R E D) Because it was registered after November 1984, zoxamide was not subject to reregistrat ion.

Tolerance Reassessment Eligibility Decision (TRED) Not applicable . There is no record of a TRED.

10 http://www.epa.gov/oppsrrd1/registration_review/7

Table 2: Chemical Facts for Zoxamide

Cumulative group Not applicable. EPA has not assumed that zoxamide has a common mechanism of toxicity with other substances

. 40 CFR Citation Tolerances for zoxamide are established in 40 CFR §180.567.

Tolerances for zoxamide are established in grapes, grapes (raisins), tomato, and vegetable (cucurbit group 9). Tolerances for combined residues of zoxamide and metabolites are established in potato,

potato (granules/flakes), potato (wet peel) and proposed in onion (subgroup 3

- 07A)

. Dual

- use Zoxamide 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 zoxamide.

Pesticide Re

- evaluation Division, Chemical Review Manager Tanja Crk crk.tanja@epa.gov (703) 308

- 8202 Registration Division

, Product Manager Tony Kish kish.tony@epa.gov (703) 308

- 9443

USE AND USAGE INFORMATION

Table 3 summarizes the use and usage information for zoxamide. Please see the BEAD Chemical Profile (BCP) for Registration Review: Zoxamide in the registration review docket for more

details

.

Table 3 : Zoxamide Use and Usage Information

Summary of Use Broad

- spectrum fungicide registered for use on potatoes, tomatoes, cucurbits, and grapes.

Use Sites Agricultural use sites. There are no reg istered non

- agricultural

uses. Summary of Usage Zoxamide usage averaged approximately 11,000 pounds of a.i. annually on approximately 80,000 acres of surveyed agricultural land (2003

- 2012). Applications to potatoes account for the majority of usage across this time period.

The average a.i. rate for all agricultural crops from 2008

- 2012 was 0.16 lbs per acre. The top crops with the highest average a.i. rate ( i.e., 0.17 lbs per acre) are tomatoes and pumpkins. Formulation Type(s) Zoxamide is formulat ed as an 80% wettable powder in water soluble packets (Zoxium® 80WSP ; Reg. No. 10163

- 6413 ) , and an 8.3% water dispersible granule co

- formulated w ith mancozeb, 66.7% (Gavel ®75DF ; Reg. No. 10163

- 6414 ). Application Method(s) Zoxamide can be applied with ground equipment, including chemigation, or by air. In addition to foliar applications, seed treatment is possible with Gavel ®75DF.8

Table 3 : Zoxamide Use and Usage Information

Technical Registrant (s) Gowan No. of Registrations 3 Section 3 Products 11 : Reg. No. 10163

- 6413 (TEP)

, - 6414 (TEP)

,

- 6415 ( TGAI) 0 Section 24c Registrations

Restricted Use No

Additi onal areas of use and usage related information requested for this registration r eview

, and of particular interest to EPA, are described below.

 Any future use/usage data on crops such as grapes, which currently have no usage reported in Proprietary Data.

RECENT ACTIONS

A new use request on onions (dry bulb), garlic, and shallots is under review.

ANTICIPATED RISK ASSESSMENTS FOR REGISTRATION REVIEW

T he most recent comprehensive human health risk assessment was conducted based on current risk and exposure assessment policies and do not indicate risk estimates of concern. T he most recent ecological and environmental fate risk assessment was completed in 201 3 . Findi ngs and

conclusions from these risk assessments are summarized in the Registration Review Problem Formulation for Zoxamide and Human Health Scoping Document in Support of Registration

Review

.

During registration review, t he Agency anticipates the need to conduct a comprehensive ecological

risk assessment, including an endangered species assessment, for all uses of zoxamide. For human health, EPA does not anticipate the need to conduct revised dietary and occupational risk

assessment s during registration review

. An updated residential exposure assessment will be required if spray drift and volatilization risk assessments are deemed necessary for off

- site transport characterization of non

- residential uses of zoxamide. Furthermore, during the

R egistration Review process, HED will evaluate whether or not the U S is able to harmonize

tolerances with Codex

. If toxicological endpoints or points of departure are revised based on the

data that are anticipated to be required for registration review

, th ey will be considered in the new

assessment s
, as well as any changes to the standard operating p rocedures or default exposure assumptions

.

T able 4 below summarizes the anticipated registration review risk assessments based on the EFED

Problem Formulation and HED Scoping Document

.

11 Section 3 product labels can be obtained f rom the Pesticide Produ ct Label System (PPLS) website ( http://oaspub.epa.gov/pestlabl/ppls.home ).9

Table 4: Anticipated Risk Assessments for the Zoxamide Registration Review

Type of Risk Assessment Conduct ? Notes

Eco logical and Environmental Fate Comprehensive ecological including endangered species Yes Species to be assessed include terrestrial and aquatic organisms. The assessment will be quantitative, whereby all degradates will be included in the total toxic residues approach.

Incidents Will check for updates For a discussion of ecological incident databases see

page 17 of the Problem Formulation. Currently, there are no reported ecological incidents.

Human Health Dietary

Food No Dietary (food and drinking water) exposure

assessment did not exceed the level of concern for the general U.S. population, infants, and children. Updated drinking water and dietary exposure risk

assessments are not anticipated to be needed at this

time. Drinking water

Occupational Handlers (mixers, loaders, applicators) No Existing occupational handler dermal exposure and risk assessments reflect current policy and procedures for the existing agricultural uses. Updates are not anticipated to be needed at this time. Post

- application

Residential

Handlers No An updated residential exposure assessment may be required if spray drift and volatilization risk assessments are deemed necessary for off

- site transport characterization of non

- residential uses of

zoxamide Post

- application

Other Aggregate No E valuates the combined risk from dietary and residential exposures.

Cumulative No EPA has not determined that zoxamide has a common mechanism of toxicity with other substances

Tolerances No During the Registration Review process, HED will

evaluate whether or not the U S is able to harmonize

with Codex

. Incidents Will check for updates For a discussion of human incident information for

zoxamide

, see page 6 of the Scoping Document and

the Zoxamide: Tier I Review of Human Incidents

. Currently, there are no re ported human incidents.10

TIMELINE

EPA has created the following estimated timeline for the completion of the zoxamide registration

review in Table 5 below

.

Table 5: Projected Zoxamide Registration Review Timeline

Activities Estimated Date
Opening the Docket
Open Docket and 60

- day Public Comment Period 2014

– June

Close Public Comment 2014

– August
Case Development

Final Work Plan 2014

– November

Issue DCI 2015 Jan.

- March

Data Submission 2017 Jan.

- March

60

- day Public Comment Period for Draft Risk

Assessments [1] 2018 July

– Sept.

Registration Review Decision

60

- day Public Comment Period for Proposed
Registration Review Decision 2019 April

- June

Registration Review Decision and Begin Post

- Decision

Follow

- up 2020

Total (years) 6

NEXT STEPS

After the 6 0

- 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 zoxamide.

[1] The regulations governing Registration Review generally require the Agency to provide a public comment period of at least 30 calendar days for draft risk assessments; see 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.11



### Appendix

– Additional Areas Considere d in the Zoxamide Registration Review

PUBLIC COMMENTS AND FEEDBACK :

Guidance for C ommenters: The areas below highlight topics of special interest to the Agency where your comments, data submissions, or reference to sou rces of additional information c ould be of particular use.

Trade Irritants:

Through the registration review process, the Agency intends to solicit information on trade irritants and, to the extent feasible, take steps toward facilitating irritant resolution. The Agency will work

to harmonize tolerances and international maximum residue limits (MRL s ) 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 betwe en U.S. tolerances and MRLs in key export markets, providing as much specificity as possible regarding

the nature of the concern.

Water Quality:

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

section 303(d) of the Clean Water Act

. 12 In addition, n o Total Maximum Daily Load s (TMDL) have been developed for zoxamide

. 13 More information on impaired water bodies and TMDLs

can be found at the Agency’s website

. 14 The Agency invites submission of water quality data for this pesticide. To the extent possible, submissions should include the key data elements noted

in the OPP Guidance for Submission of State and Tribal Water Quality Monitoring Data 15 in order to ensure they can be used quantitatively or qualitative ly 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 policies. 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 o ther factors, may have atypi cal, unusually high exposure to zoxamide compared to the general population. Please comment if you are aware of any sub

- populations that may have atypical, unusually high exposure compared to the general population.

ENDANGERED SPECIES :

12 http://iaspub.epa.gov/tmdl_waters10/attains_nation_cy.cause_detail_303d?p_cause_group_id=885

13 http://iaspub.epa.gov/tmdl_waters10/attains_nation.tmdl_pollutant_detail?p_pollutant_group_id=885&p_pollutant _group_name=PESTICIDES

14 http://www.epa.gov/owow/tmdl/

15 http://www.epa.gov/oppsrrd1/registration_review/water_quality_sop.htm12

A risk assessment that supports a complete endangered species determina tion has not been

conducted for zoxamide. The ecological risk assessment planned during registration review will

allow the Agency to determine whether use of zoxamide has “no effect” or “may affect” federally listed threatened 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 Ag ency will consult with the U.S. Fish and Wildlife Service and/or National Marine Fisheries Service (the Services), as appropriate.

ENDOCRINE DISRUPTOR SCREENING PROGRAM :

As required by FIFRA and FFDCA, EPA reviews numerous studies to assess potential ad verse 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 in clude 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. Fo r 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 for zoxamide

, 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), zoxamide 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 estr ogen, 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 ef fect.

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 iner t ingredients. A second list of chemicals identified for EDSP screening was published on June 14, 2013 16 and includes some pesticides scheduled for registration review and chemicals found in water

. Neither of these lists

should be construed as a list of kn own or likely endocrine disruptors.

16 See ht tp://www.regulations.gov/#!documentDetail;D=EPA

- HQ

- OPPT

- 2009

- 0477

- 0074 for the final second list of

chemicals.13

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 1 screening battery, please visit our

website. 17

HUMAN STUDIES :

Oc cupational

Past zoxamide risk assessments rely in part on data from studies in which adult human subjects were intentionally exposed to a pesticide 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 Ha ndlers Exposure Database (PHED) and the Agricultural Reentry Task Force (ARTF) Database

. 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 ethi cal standards prevailing at the time the research was conducted. A ll applicable requirements of EPA’s Rule for the Protection of Human Subjects of Research (40 CFR Part 26) have been satisfied , and

t here is no regulatory barrier to continued reliance on t hese studies

.

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