Docket Number: EPA-HQ-OPP-2011-0153 

www.regulations.gov

Cyclanilide Final Work Plan 

Registration Review 

August 2011 

CYCLANILIDE FINAL WORK PLAN 

Introduction

This is the Environmental Protection Agency’s (EPA’s) Final Work Plan for the 

registration review of cyclanilide. This work plan includes the anticipated registration 

review timeline. The work plan also addresses 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 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. Changes in science, public policy, and pesticide use practices 

will occur over time. 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. The 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/oppsrrd1/registration_review/. 

Cyclanilide is a plant growth regulator and defoliant. It is currently registered for use as 

a synergist or co-active ingredient on cotton as a harvest aid and for use to increase 

branching of trees, shrubs, and cut flowers in plant production facilities and outdoor 

nurseries; it is not registered for use in greenhouses. Cyclanilide products registered for 

use on cotton contain cyclanilide mixed with one other active ingredient, either ethephon 

or mepiquat chloride. Non-agricultural ornamental 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; therefore, it was not subject 

to the reregistration requirements 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, water 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 requirements for cyclanilide at this 

time. For further discussion on these comments please see the Summary of Comments 

and Agency Responses section below. 

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Anticipated Risk Assessment and Data Needs

The Agency anticipates conducting a comprehensive 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 summary of the issues relevant to the registration 

review of cyclanilide and the anticipated 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 ornamentals, cut flower crops, and nonbearing fruit trees. 

• The Agency has not conducted a risk assessment that supports a complete 

endangered species determination for cyclanilide. The ecological risk assessment 

planned during registration review will allow 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 Biological Diversity and the Pesticide Action 

Network North America filed a lawsuit in the United States District Court for the 

Northern District of California, against the Environmental Protection Agency 

(EPA) for allegedly failing to undergo consultation with the USFWS and the 

NMFS regarding the effects of over 350 pesticides, including cyclanilide, on over 

200 endangered and threatened species throughout the United States (Center for 

Biological Diversity, et al. v. EPA, et al., No. C 11-00293 (N.D.Cal.). 

• The Agency anticipates needing the following 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) – Terrestrial 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 

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validation (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 Phytotoxicity Tier II, Vegetative 

Vigor1

 

• 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 discussion of the anticipated ecological 

risk assessment and data needs.

Human Health Risk: 

• The most recent human health risk assessment 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 assessment 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 residues to be measured for each commodity. 

• The current 40 CFR §180.506 listing for sheep, 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 anticipates correcting this listed tolerance in 

advance of the draft risk assessment. 

• During registration review, the Agency anticipates conducting an updated dietary 

(food only) exposure risk assessment, including an updated aggregate risk 

assessment, to reflect current methodologies. 

 

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 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 there is a 5% observed inhibition effect (IC05) to be used in a risk 

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

IC25 (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 IC05 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. 

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• 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 + water) 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 from residential exposures have not been 

considered in previous assessments nor would they be considered at this time. 

However, residential bystander inhalation 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 the process of examining its policies and 

refining the methods used to complete residential exposure assessments. 

Therefore, the potential need for a bystander inhalation risk assessment for 

cyclanilide will be examined during registration review. 

 

• During registration review, the Agency anticipates conducting updated 

occupational and postapplication assessments 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 Assessment Scoping Document in 

Support of Registration Review, dated January 18, 2011, available in docket EPAHQ-OPP-2011-0153 at www.regulations.gov, for a detailed discussion of the 

anticipated human health risk assessment and data needs.

Endocrine Disruptor Screening Program

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

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

subchronic and chronic toxicity, including assessments of carcinogenicity, neurotoxicity, 

developmental, reproductive, and general or systemic toxicity. These studies include 

endpoints which may be susceptible to endocrine influence, including effects on 

endocrine target organ histopathology, organ weights, estrus cyclicity, sexual maturation, 

fertility, pregnancy rates, reproductive loss, and sex ratios in offspring. For ecological 

hazard assessments, EPA evaluates acute tests and chronic studies that assess growth, 

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developmental and reproductive effects in different taxonomic groups. As part of its 

most recent cyclanilide 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), cyclanilide is subject to the 

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

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

pesticide active and other ingredients) may have an effect in humans or wildlife similar to 

an effect produced by a “naturally occurring estrogen, or other such endocrine effects as 

the Administrator may designate.” The EDSP employs a two-tiered approach to making 

the statutorily required determinations. Tier 1 consists of a battery of 11 screening assays 

to identify the potential of a chemical substance to interact with the estrogen, androgen, 

or thyroid (E, A, or T) hormonal systems. Chemicals that go through Tier 1 screening 

and are found to have the potential to interact with E, A, or T hormonal systems will 

proceed to the next stage of the EDSP where EPA will determine which, if any, of the 

Tier 2 tests are necessary based on the available data. Tier 2 testing is designed to 

identify any adverse endocrine-related effects caused by the substance, and establish a 

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

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

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

of 67 chemicals, which contains 58 pesticide active ingredients and 9 inert ingredients. 

Cyclanilide is not among the group of 58 pesticide active ingredients on the initial list to 

be screened under the EDSP. Accordingly, as part of registration review, EPA will issue 

future EDSP orders/data call-ins, requiring the submission of EDSP screening assays for 

cyclanilide. For further information on the status of the EDSP, the policies and 

procedures, the list of 67 chemicals, future lists, the test guidelines and the Tier 1 

screening battery, please visit our website: http://www.epa.gov/endo/. 

Timeline 

The projected timeline for the completion of the cyclanilide registration review is 

presented in Table 1. 

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Table 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 Review Decision and Open Public 

Comment Period 

2016 – April - June 

Close Public Comment Period 2016 – July - Sept. 

Issue Registration Review Decision 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 comment 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 Comments 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 the cyclanilide registration review process. 

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

Comment 1: The FIFRA Endangered Species Task Force (FESTF) submitted a comment 

that the Agency should ensure that any company who is a technical registrant for 

cyclanilide, but not a member of the FESTF (or a company having met its data 

compensation obligations) provide a formal “offer-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. 

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Comments 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 currently registered products and use sites and 

formulations. The Agency will review the most 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 studies 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. 

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Guideline 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 this document. The information received in 

response to this DCI will be used to conduct the anticipated human health, ecological, 

and endangered species risk assessments for cyclanilide. 

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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 analytical 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 analytical 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 Toxicity (passerine species) TGAI 12 

850.4150 Nontarget Area Phytotoxicity Tier II, Vegetative 

Vigor2 TEP 12 

870.3465 28-Day Inhalation Toxicity TGAI 12 

870.7800 Immunotoxicity TGAI 12 

 

 

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 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 there is a 5% observed inhibition effect (IC05) to be used in a risk 

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

IC25 (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 IC05 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.