Docket Number: EPA-HQ-OPP-2011-0153 www.regulations.gov



## Cyclanilide Final Work Plan Registration Review August 2011CYCLANILIDE FINAL WORK PLAN

Introduction

This is the Environmental Protection Agency’s (EPA’s) Final Work Plan for the registration review of cyclani lide. This work plan include s the anticipated registration review timeline. The work plan also addre sses public comments received concerning the Preliminary Work Plan in the Summary Document , which was posted in the cyclanilide registration review docket (EPA-HQ- OPP-2011-0153), and any other comments concerning the initial docket postings. The Summary Document provides information on what EPA knows about the pesticide and what additional risk analyses and data or information the Agency believes are needed to make a registration review decision.

The Agency is implementing the registration re view program pursuant to Section 3(g) of the Federal Insecticide, Fungicide, and Rode nticide Act (FIFRA), and will review each registered pesticide every 15 years to determ ine whether it continues to meet the FIFRA standard for registration. Ch anges in science, public polic y, and pesticide use practices will occur over time. The registration review program is intended to make sure that, as the ability to assess risk e volves and as policies and pract ices change, all registered pesticides continue to meet the statutory standard. Th e public phase of registration review begins when the initial docket is opened for each case. Information on this program is provided at: http://www.epa.gov/oppsrr d1/registration_review/

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Cyclanilide is a plant growth re gulator and defoliant. It is currently registered for use as a synergist or co-active ingredient on cott on as a harvest aid and for use to increase branching of trees, shrubs, and cut flower s in plant production facilities and outdoor nurseries; it is not registered for use in gr eenhouses. Cyclanilide products registered for use on cotton contain cyclanilide mixed with one other active ingred ient, either ethephon or mepiquat chloride. Non-agricultural or namental use sites include shade trees, herbaceous plants, non-flowering plants, and woody shrubs. Outdoor nursery use sites include nursery stock of apple, cherry, pear, and plum. There are no residential uses. Cyclanilide was first registered in the United States in 1997; therefor e, it was not subject to the reregistration re quirements of FIFRA.

Comments Received on Preliminary Work Plan

Multiple comments were received during the 60-day public comment period on the Preliminary Work Plan for cyclanilide. These comments are summarized in this

document. In the Preliminary Work Plan , EPA also solicited comments on three specific topics: environmental justice, wate r body impairment, and trade irritants. No

comments or information were received during the comment period concerning environmental justice, trade irritants, or water body impairment. No comments were received that change the work plan or anticipated data require ments for cyclanilide at this time. For further discussion on these comments please see the Summary of Comments and Agency Responses section below.

3Anticipated Risk Assessment and Data Needs

The Agency anticipates conducting a comp rehensive ecological risk assessment, including an endangered species risk assessment, for all uses of cyclanilide. The Agency anticipates needing data to conduct these assessments. The Agency also intends to require additional toxicological data and to update and revise the human health risk assessment for cyclanilide. Below is a summar y of the issues relevant to the registration review of cyclanilide and the an ticipated data requirements.

Ecological Risk:

• The most recent ecological risk assessments for cyclanilide were conducted in 1996 in support of the first registration of this chemical and in 2006 in support of the proposed new use of cyclanilide on or namentals, cut flower crops, and nonbearing fruit trees.

• The Agency has not conducted a risk assessment that supports a complete endangered species determination for cyclan ilide. The ecological risk assessment planned during registration review will a llow the Agency to determine whether cyclanilide’s use 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 Agency will consult with the U.S. Fish and Wildlife Service (USFWS) and/or National Marine Fisheries Service (NMFS) (the Services), as appropriate.

• On January 19, 2011, the Center for Biologi cal Diversity and the Pesticide Action

Network North America filed a lawsuit in th e United States District Court for the Northern District of California, agai nst the Environmental Protection Agency (EPA) for allegedly failing to undergo consultation with the USFWS and the NMFS regarding the effects of over 350 pe sticides, including cyclanilide, on over 200 endangered and threatened species throughout the Un ited States (Center for Biological Diversity, et al. v. EPA, et al., No. C 11-00293 (N.D.Cal.).

• The Agency anticipates needing the followi ng data in order to conduct a complete ecological risk assessment, including an endangered species assessment, for cyclanilide:

Environmental Fate

o Guideline No. 835.4100 – Aerobic Soil Metabolism

o Guideline No. 835.6100 (footnote 7) – Terre strial Field Dissipation (the environmental chemistry method and associated independent laboratory validation (ILV) of the submitted analytical method are expected to be required)

o Guideline No. 835.6200 (footnote 7) – Aquatic Field Dissipation (the environmental chemistry method and an associated independent laboratory

4validation (ILV) of the submitted analytical method are expected to be required)

Ecological Toxicity

o Guideline No. 850.1350 – Aquatic Invertebrate Life-cycle (saltwater)

o Guideline No. 850.1400 – Fish Early Life Stage (saltwater)

o Guideline No. 850.2100 – Avian Acute Oral Toxicity (passerine species)

o Guideline No. 850.4150 - Nontarget Area P hytotoxicity Tier II, Vegetative Vigor 1

• Please refer to EFED Registration Review Problem Formulation for Cyclanilide

, dated March 3, 2011, located in docket EPA-HQ-OPP-2011-0153 at www.regulations.gov, for a more detailed disc ussion of the antic ipated ecological

risk assessment and data needs.

Human Health Risk:

• The most recent human health risk a ssessment was conducted in 2007 in support of the use of cyclanilide on ornamentals, cut flowers, and non-bearing fruit trees.

• During registration review, the endpoints, doses, and uncertainty factors used in

the most recent human health risk asse ssment will be revisited based on current Agency policy, as well to incorporate any new data received and determined to be adequate.

• The cyclanilide tolerance expression will be reviewed during registration review to ensure that it appropriately covers the cyclanilide metabolites and degradates of risk concern and that it specifies the re sidues to be measured for each commodity.

• The current 40 CFR §180.506 listing for shee p, meat is incorrectly given as 0.20 ppm. This tolerance should be the same as that for the meat of cattle, goat, hog, and horse, at 0.02 ppm. The Agency anticipat es correcting this li sted tolerance in

advance of the draft risk assessment.

• During registration review, the Agency an ticipates conducting an updated dietary (food only) exposure risk assessment, including an updated aggregate risk assessment, to reflect current methodologies.

1 A Tier II study is expected to be required. The DCI expected to be issued will provide that a Tier I plant study may be conducted in lieu of a Tier II study with the understanding that any adverse effects observed by the Tier I study would necessitate conduct and submission of a Tier II study as well. The purpose of a Tier II study is to establish both a definitive No Observed Adverse Effect Concentration (NOAEC), or alternatively, a concentration at which ther e is a 5% observed inhibition effect (IC 05 ) to be used in a risk

assessment and effects determination for endangered or threatened species (listed species), and a definitive

IC 25 (concentration at which there is a 25% observed inhibition effect) for assessing risk to non-listed nontarget plants. If any adverse effects are observed in a Tier I study and neither a definitive NOAEC nor a

definitive IC 05 value is available, then the Agency may have to presume in its effects determination, that cyclanilide "may affect" and is “likely to adversely affect” listed plant species.

5• Based on current registered use patterns of cyclanilide and the current toxicological points of departure, the Agency does not anticipate conducting an updated drinking water exposure risk assessment at this time. If, in the future, any new uses are requested or if there is any reason for re-evaluation of the points of departure, a revised dietary (food + wa ter) risk assessment, including a revised aggregate risk assessment, may be needed.

• Currently, there are no registered uses for cyclanilide that would result in residential exposure. As such, risks fr om residential exposures have not been considered in previous assessments nor w ould they be considered at this time. However, residential bystander inhalati on exposures resulting from off-site transport (e.g., spray drift or volatilization) may occur as a result of applications of cyclanilide. The Agency is in th e process of examining its policies and refining the methods used to complete residential exposure assessments. Therefore, the potential need for a by stander inhalation risk assessment for cyclanilide will be examined during registration review.

• During registration review, the Agency anticipates conducting updated occupational and postapplication assessmen ts based on updated doses, endpoints, and procedures for dermal and inhalation risk assessment. The Agency anticipates including additional and more detailed review of the handler and postapplication exposure scenarios.

• The toxicity database for cyclanilide is complete except for the following studies, which the Agency anticipates requiring in order to conduct an updated human

health risk assessment:

o Guideline No. 870.3465 – 28-Day Inhalation Toxicity

o Guideline No. 870.7800 – Immunotoxicity

• Please refer to Cyclanilide. Human Health A ssessment Scoping Document in Support of Registration Review , dated January 18, 2011, available in docket EPAHQ-OPP-2011-0153 at www.regulations.gov, fo r a detailed discussion of the anticipated human health risk assessment and data needs.

Endocrine Disruptor Screening Program

As required by FIFRA and FFDCA, EPA review s numerous studies to assess potential adverse outcomes from exposure to chemicals. Collectively, these studies include acute,

subchronic and chronic toxici ty, including assessments of carcinogenicity, neurotoxicity, developmental, reproductive, and general or systemic toxicity. These studies include endpoints which may be susceptible to e ndocrine influence, including effects on endocrine target organ histopathology, organ weights, estrus cyclicity, sexual maturation, fertility, pregnancy rates, re productive loss, and sex ratios in offspring. For ecological hazard assessments, EPA evaluates acute test s and chronic studies that assess growth,

6developmental and reproductive effects in di fferent taxonomic groups. As part of its most recent cyclanilide registration decision, EP A reviewed these data and selected the most sensitive endpoints for relevant risk as sessment scenarios from the existing hazard database. However, as required by FFDCA s ection 408(p), cyclanilid e is subject to the endocrine screening part of the Endocrine Disruptor Screenin g Program (EDSP).

EPA has developed the EDSP to determine whether certain substances (including pesticide active and other ingred ients) may have an effect in humans or wildlife similar to an effect produced by a “natur ally occurring estrogen, or othe r such endocrine effects as the Administrator may designate.” The ED SP 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 substa nce 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 wher e EPA will determine which, if any, of the Tier 2 tests are necessary based on the availa ble data. Tier 2 te sting 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 orders/data call-ins for the first group of 67 chemicals, which contains 58 pesticide active ingredient s and 9 inert ingredients. Cyclanilide is not among the group of 58 pesticid e active ingredients on the initial list to be screened under the EDSP. Accordingly, as part of registration review, EPA will issue future EDSP orders/data call-ins, requiring the submission of EDSP screening assays for cyclanilide. For further information on th e status of the EDSP, the policies and procedures, the list of 67 chemicals, futu re lists, the test guide lines and the Tier 1 screening battery, please visit our website: http://www.epa.gov/endo/

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Timeline

The projected timeline for the completion of the cyclanilide registration review is presented in Table 1.

7Table 1. Projected Cyclanilide Registration Review Timeline Activity Estimated Date Opening the Docket Open Docket and Open Public Comment Period 2011 – March

Close Public Comment Period 2011 – May Case Development Develop Final Work Plan (FWP) 2011 – August Issue Data Call-In (DCI) 2012 – April - June

Data Submission 2014 – April - June Develop Preliminary Risk Assessments and Open Public Comment 2015 – Oct. - Dec.

Close Public Comment Period 2016 – Jan. - March Registration Review Decision Develop Proposed Registration Revi ew Decision and Open Public

Comment Period 2016 – April - June

Close Public Comment Pe riod 2016 – July - Sept. Issue Registration Review Deci sion and Begin Post-Decision Follow-up 2017

Total (years) 6

Summary of Comments and Agency Responses

The cyclanilide registration review docket was open for a 60-day public comment period beginning on March 30, 2011. During the co mment period, multiple comments were

received. None of the comments received prompted changes in the cyclanilide work plan. Comments received regarding data requirements are summarized below. Please

see Cyclanilide. Response to Comments on the Human Health Assessment Scoping Documents and Preliminary Work Plan , dated July 19, 2011 and EFED Response to Bayer CropScience Comments to PWP Comme nts on the Registration Review of Cyclanilide , dated November 23, 2010, located in docket EPA-HQ-OPP-2010-0228 on

the internet at www.regulations.gov , for EPA’s responses to other comments received.

This document finalizes the work plan for th e cyclanilide registrati on review process.

Comments by the FIFRA Endangered Species Task Force (FES TF) [EPA-HQ-OPP2011-0153-0010]

Comment 1: The FIFRA Endangered Species Task Force (FESTF) submitted a comment that the Agency should ensure that any co mpany who is a technical registrant for cyclanilide, but not a member of the FE STF (or a company having met its data compensation obligations) provide a formal “o ffer-to-pay” to FESTF in conjunction with their support of the active ingredient.

Response 1: The Agency thanks FESTF for its comment and will consider this information as it completes the endangered species assessment and makes its registration

review decisions.

8Comments by Bayer CropScience (BCS) [EPA-HQ-OPP-2011-0153-0011]

Comment 1: BCS provided information on current cyclanilide products, use sites, pending cancellations, and labels.

Response 1: The Agency will ensure that the assessments conducted for the registration review of cyclanilide will incorporate curre ntly registered produc ts and use sites and formulations. The Agency will review the mo st current registered labels and/or new proposed labels at the time when future risk assessments are conducted. The Agency thanks BCS for its assistance in clarifying that information.

Comment 2: BCS submitted comments on several st udies proposed to be required in the cyclanilide registration review DCI.

Response 2: A summary the comments submitted by BCS and EPA’s responses is presented in Table 2.

Table 2. Summary of BCS Comments on Anticipated Cyclanilide Data Requirements and EPA Response

Guideline Number BCS Comment EPA Response

835.4100 Aerobic Soil

Metabolism BCS commented that a new aerobic soil metabolism study for cyclanilide has been conducted,

and when combined with the extraction studies for 3,5-DCA, should be suitable for fulfilling this data requirement. The Agency thanks BCS for the comment. Prior to issuing the registration review DCI, the Agency will review the submitted study, along with

the additional data and literature referenced in the comments, to determine the adequacy of the data in fulfilling the data requirement. 835.6100 (footnote 7) –

Terrestrial Field Dissipation (the environmental chemistry

method and associated independent laboratory validation (ILV) of the submitted analytical method)

Submission of the final report for the storage stability study BCS commented that for the method development and ILVs for soil, the soil method referenced in

the EFED Problem Formulation for cyclanilide was performed by the registrant as indicated and that the method is a satisfactory

enforcement method . The report

cited in the EFED Problem

Formulation as the method is actually an independent laboratory validation. Together, these two reports satisfy the requirement for

an enforcement method for soils with an independent validation.

BCS commented that the final report for the storage stability study for terrestrial field dissipation has previously been

submitted. The Agency thanks BCS for the comments and references regarding the terrestrial field dissipation Environmental Chemistry Method (ECM) and associated ILV. Prior to issuing the registration review DCI, the Agency will review the comments and

references related to the ECM and ILV for cyclanilide in soil to determine the adequacy of these two reports for satisfying the requirement for an

enforcement method for soils with independent validation.

The Agency thanks BCS for the comment confirms that the storage stability study was submitted. Prior to issuing the registration review DCI, the Agency will review the storage stability studies to determine the adequacy of the data in fulfilling the data requirement.

9Guideline No. 835.6200 (footnote 7) – Aquatic Field Dissipation (the environmental chemistry

method and an associated independent laboratory validation (ILV) of the submitted analytical method are expected to be required) BCS commented that they agree to update the current analytical method for water as appropriate and provide an independent laboratory validation for the

revised method. The Agency thanks BCS for planning to

submit these data.

850.2300 Avian Reproduction Study BCS commented that they would be submitting an avian reproduction study with the northern bobwhite quail.

BCS also agreed to conduct a second avian reproduction study

with the Mallard duck in anticipation of the DCI. The Agency thanks BCS for the

comment and confirms that the avian reproduction study with the northern bobwhite quail was submitted. Prior to registration review DCI issuance, the Agency will review this study to determine the adequacy of the data in fulfilling the data requirement.

The Agency thanks BCS for planning to submit the avian reproduction study with

the Mallard duck.

N/A BCS commented that they would be submitting a non-guideline study that may be useful for risk assessment purposes. It is a Pseudokirchneriella subcapitata growth inhibition test with cyclanilide 2,4-dichloroaniline. The Agency thanks BCS for the

comment and confirms that the requested study was submitted. Prior to registration review DCI issuance, the Agency will review this study to determine the acceptability of the data

for inclusion in the risk assessment.

Next Steps

The Agency plans to issue a DCI for cyclanilide in 2012 for the data gaps listed under the

Risk Assessment and Data Needs section of th is document. The information received in response to this DCI will be used to conduc t the anticipated huma n health, ecological, and endangered species risk assessments for cyclanilide.

1011 Summary of Data Gaps

A summary of the anticipated data needs for the cyclanilide registration review is presented in Table 3.

Table 3. Summary of Data Needs for Cyclanilide

Guideline

Number Anticipated Data Requirement Test

Material Estimated

Timeframe

(Measured

in Months

from DCI Receipt)

835.4100 Aerobic Soil Metabolism TGAI 24

835.6100 Terrestrial Field Dissipation (the environmental chemistry method and associated laboratory validation (ILV) of the submitted analy tical method are expected to be required) TEP 24

835.6200 Aquatic Field Dissipation (the environmental chemistry method and associated laboratory validation (ILV) of the submitted analy tical method are expected to be required) TEP 24

850.1350 Aquatic Invertebrate Life-cycle (saltwater) TGAI 12

850.1400 Fish Early Life Stage (saltwater) TGAI 12

850.2100 Avian Acute Oral Toxic ity (passerine species) TGAI 12

850.4150 Nontarget Area Phytotoxicity Tier II, Vegetative Vigor 2 TEP 12

870.3465 28-Day Inhalation Toxicity TGAI 12

870.7800 Immunotoxicity TGAI 12

2 A Tier II study is expected to be required. The DCI expected to be issued will provide that a Tier I plant study may be conducted in lieu of a Tier II study with the understanding that any adverse effects observed by the Tier I study would necessitate conduct and submission of a Tier II study as well. The purpose of a Tier II study is to establish both a definitive No Observed Adverse Effect Concentration (NOAEC), or alternatively, a concentration at which ther e is a 5% observed inhibition effect (IC 05 ) to be used in a risk

assessment and effects determination for endangered or threatened species (listed species), and a definitive

IC 25 (concentration at which there is a 25% observed inhibition effect) for assessing risk to non-listed nontarget plants. If any adverse effects are observed in a Tier I study and neither a definitive NOAEC nor a

definitive IC 05 value is available, then the Agency may have to presume in its effects determination, that cyclanilide "may affect" and is “likely to adversely affect” listed plant species.