UNITED STATES ENVIRONMENTAL PROTECTION AGENCY WASHINGTON, D.C. 20460

OFFICE O
OFFICE OF CHEMCICAL SAFETY AND
POLLUTION PREVENTION



### Environmental Fate and Eco logical Risk Assessment
Problem Formulation In Support of Registration Review of Cyclanilide

http://pubchem.ncbi.nlm.nih.gov/image/struct urefly.cgi?cid=86133&width=400&height=400



### February 2, 2010

Completed By: Reviewed By : Mohammed Ruhman, Agronomist Mah T. Shamim, Ph.D Justin Housenger, Biologist Branch Chief, Environmental Risk Branch 5
Environmental Risk Branch 5 Envi ronmental Fate and Effects Division
Environmental Fate a nd Effects Division2 

### Table of Contents

1. Purpose .................................................................................................................... .... 3
2. Problem Formulation .................................................................................................. 3 2.1 Nature of Regulatory Action ..................................................................................... 3
2.2 Previous Risk Assessments ....................................................................................... 3
3. Stressor Source and Distribution ................................................................................ 4
3.1 Mechanism of Action ................................................................................................ 5 3.2 Overview of Pesticide Usage .................................................................................... 5 3.3 Environmental Fate and Transport ............................................................................ 7 4. Ecological Effects ..................................................................................................... 11 4.1 Aquatic and Terrestrial Effects ............................................................................... 11
4.2 Incident Database Review ....................................................................................... 15 4.3 Ecosystems Potentially at Risk ............................................................................... 15 4.4 Assessment Endpoints ............................................................................................ 16 4.5 Conceptual Model ................................................................................................... 16 5. Analysis Plan ............................................................................................................ 19
5.1 Stressors of Concern ............................................................................................... 20 5.2 Measures of Exposure ............................................................................................. 20
5.3 Measures of Effect .................................................................................................. 20 5.4 Integration of Exposure and Effects ....................................................................... 23 5.5 Endangered Species Assessments ........................................................................... 23 5.6 Monitoring Data ...................................................................................................... 24
5.7 Clean Water Act ...................................................................................................... 24 5.8 Endocrine Disrupter Screening Program ................................................................ 24 5.9 Uncertainty and Preliminary Identification of Data Gaps ...................................... 25



### List of Tables Table 1. Summary of use information fo r Cyclanilide, based on LUIS Report EFED spread sheet dated 03/26/2010 and evaluation of all labels (note: assumed entries based on label language and crop gr owth characteristics) ............................................................ 5 Table 2 Summary of physicochemic al properties of cyclanilide

........................................ 7 Table 3. Summary of Fate Properties of Cyclanilide

......................................................... 9 Table 4. Test Species Evaluated for Assessi ng P otential Acute and Chronic Ecological Effects of Cyclanilide. ...................................................................................................... 13 Table 5. Measures of Ecological Effects and Exposure for Cyclanilide

......................... 21 Table 6. Ecological Effects Data Requirem ents for Cyclanilide ..................................... 28 

### List of Figures

Figure 1. Cotton acreage data compared to estimated usage data for cyclanilide .............. 7 Figure 2. Structures for parent cyclanilid e and main degradate ...................................... 11 Figure 3. A conceptual model for cyclan ilide effects on aquatic organism s. .................. 18 Figure 4. A conceptual model of cyclan ilide effects on terrestrial organism s ................. 193 

## 1. Purpose

The purpose of this problem formulation is to provide the foundation for the ecological risk assessment being conducted for the regist ered uses of cyclanilide. As such, it articulates the purpose and objectiv es of the risk assessment, evaluates the nature of the problem, and provides a plan for analyzing th e data and characterizing there ecological risk (EPA, 1998). Additionall y, this problem formulation is intended to identify data gaps, uncertainties, and potenti al assumptions needed to ad dress those uncertainties in characterizing the ecological risk associated wi th the registered uses of cyclanilide.

Cyclanilide is a plant growth regulator that inhibits the ac tivity of auxin. The chemical was initially registered in 1997 and currently has uses on cotton as a growth regulator and harvest aid, and on cut flowers, ornamentals, and non-bearing nursery trees as a plant growth regulator. It is available as a susp ension concentrate and can be applied, in liquid form, either as a ground or aerial spray.



## 2. Problem Formulation

2.1 Nature of Regulatory Action

The Food Quality Protection Act of 1996 mandated the EPA to implement a new program, i.e., registration review ( http://www.epa.gov/oppsrrd1/registration_review/ ). All pesticides distributed or sold in the United St ates generally must be registered by EPA. The decision to register a pesticide is base d on the consideration of scientific data and other factors showing that it will not cause unr easonable risks to human health, workers,
or the environment when used as directed on product labeling. The registration review program is intended to ensure that, as the abili ty to assess risk evolves and as policies and practices change, all registered pesticides co ntinue to meet the st atutory standard of no
unreasonable adverse effects to human health and the environment. Changes in science, public policy, and pesticide use practices will occur over time. Through the new registration review program, the Agency periodically reevaluate s pesticides to make sure that as change occurs, products in th e marketplace can be used safely.

As part of the implementation of the new Registration Review program pursuant to Section 3(g) of the Federal Insecticide, Fungicide and Rodenticide Act (FIFRA), the Agency is beginning its evaluation to determ ine whether cyclanilide continues to meet the FIFRA standard for regist ration. This problem formulati on for the environmental fate and ecological risk assessment chapter in suppo rt of the registration review is intended for the initial docket opening the pub lic phase of the review process.



### 2.2 Previous Risk Assessments

Cyclanilide has been registered since 1997, and has been subject to two main risk
assessments. Previous assessments serve as th e basis for this problem formulation and a summary of the two assessments are included hereunder:4 (1) EFED's chapter for the first registration of this chemical (dated November 1996) 1

. This registration was for the cyclanilide form ulated with ethephon as an emulsifiable
concentrate for use as a cotton defoliant ei ther aerially or by ground equipment. Risk to terrestrial and semi-aquatic plants was not completely assessed due to lack of acceptable data for the vegetative vigor tests and for phytotoxic symptoms from seedling emergence testing.

(2) EFED chapter covering the proposed new us e of cyclanilide to ornamentals, cut flower crops and non-bearing fruit tr ees (EFED, (DP# 323619, October 2006).

Previous risk assessments concluded Level of Concern (LOC) exceedances as follows:

- Terrestrial plants (dicots only) for listed and non-listed species

- Acute LOC is exceeded for listed birds that feed on insects and for small-tointermediate sized listed mammals that f eed on short grass for dose-based acute RQs

- Chronic LOC for listed and non-listed ma mmals is exceeded for both dose and dietary-based RQs

In the 2006 assessment, potential risk to liste d and non-listed terrestr ial plants could not be characterized quantitatively from exposure due to drift because vegetative vigor data was classified as invalid (MRID 43868323). However, a second study was submitted by the registrant and is currently in re view. This study (MRID 44518602) and how it impacts the risk to terrestrial plants will be further discusse d in this problem formulation.



## 3. Stressor Source and Distribution

Based on review of fate and transport data for cyclanilide, the stressor is considered to be parent plus main degradate 2, 4-dichloroanilin e. The source of the stressor is application of cyclanilide to cotton fields and to nurser y stock of some fruit trees and ornamentals. The chemical is a plant growth regulator form ulated as emulsifiable concentrate and as liquid to be foliar applied, in liquid form, by gr ound and/or aerial equipment. Cyclanilide is stable to hydrolysis and photo degradation in water or on soils is not an important. Biotic laboratory studies suggest that the chemical degradates rather slowly in the soil system (half-life of 95 days) and expected to be highly persistent in anaerobic aquatic water/sediment systems. The degradation prof ile of cyclanilide in aerobic soil systems suggests formation of a major degradate, 2, 4-dichloroaniline metabolite. Metabolite 2, 4- dichloroaniline contain its parent’s moiety and appears to be persistence in at least one of the two soil systems examined. Cyclanilide pa rent shows similar persistence in the field with half-lives ranging from 35 to 114 days.

1 EFED’s Registration chapter for cyclanilide use on cotton (DP Bar codes: D223580, D223583, D225001, D226430, D226431, and D2230465).5 Cyclanilide may partition into the air from dry or wet soil service based on reported vapor pressure (6.3 x 10 -8 torr at 50  ̊ C). Additionally, adsorption/desorption data suggest that cyclanilide and its metabolite are mobile and expected to reach both surface and ground water by run-off.



### 3.1 Mechanism of Action

Cyclanilide is an auxin inhibitor that enha nces lateral branchi ng. Auxin is a plant hormone that influences the way buds break during growth. Cyclanilide is formulated alone to regulate growth in selected fruit and ornamental trees. In this case, actively growing plants shoots, devel oping leaves produce auxin, which inhibits later buds in leaf axils from developing into lateral shoot. Auxin, will in turn, tend to grow the plant upwards rather than branching laterally. As a result, nursery plan ts (fruit trees or ornamentals) often need to be mechanically pruned. Cyclanilide can be used as an alternative to pruning, by forcing the plant to branch laterally. When applied to actively growing foliage, cyclanilide appears to i nduce a transient inhib ition of auxin activity without otherwise damaging the growing shoot tip. As a result, lateral buds tend to develop as lateral shoots. 2 Because of this mechanism of action, cyclanilide is most effective in plant species that exhibit strong apical dominance, that is, plants in which the main (upwardly growing) stem grow s more rapidly than side stems.

Additionally, cyclanilide is formulated with two other active ingredients where the use purpose and mode of action is modified as follows:

(1) With mepiqual-Cl: The formulation is used during cotton growth (the squaring period) to regulate cotton plant growth and manage the vegetative vigor; and

(2) With ethephon: The formulation is applied at the end of the co tton season, before boll-opening, to promote boll opening, defoliation and inhibition of terminal foliar re-growth (i.e., bring cotton to maturity for harvest).



### 3.2 Overview of Pesticide Usage

A summary of currently labeled agricultura l use patterns for cyclanilide is shown in
Table 1

1 Table 1. Summary of use information for Cycl anilide, based on LUIS Report EFED spread sheet dated 03/26/2010 and evaluation of all labels (note: assumed entries based on label language and crop growth characteristics)

Use Pattern Single Rates (lb

a.i./A) Number of Applications Maximum Yearly Rate (lb a.i./A) Application Interval (days) Application Method

& Timing of 1 st Application

Selected Pome & Stone Fruits Nursery Stock: (Apple, Pear, Cherry & Plum)* 0.1133 3 0.3400 14 (Assumed) Ground Spray; early Spring (both Assumed)

2 Elfving D.C., Visser D.B. 2003. Managing Grow th, Fruiting and Fruit Quality in Washington with Bioregulators. The Compact Fruit Tree. 36(3): 79-80.6 Use Pattern Single Rates (lb

a.i./A) Number of Applications Maximum Yearly Rate (lb a.i./A) Application Interval (days) Application Method

& Timing of 1 st Application

Selected Ornamentals Nursery Stock (Shade trees, Woody shrubs, Herbaceous & non-flowering plants)*

Cotton (Growth regulator) ** 0.0072
&
0.0115 3 0.0316 7 Aerial or Ground Spray; Pre-bloom (the 21-day squaring period)

Cotton (Harvest Aid)** * 0.2500 1 0.2500 NA Aerial or Ground Spray; before boll opening

* Use purpose: growth regulator (formulations contains only one active ingredient: cyclanilide)

** Use purpose: growth regulator (formulations contains two active ingredients: cyclanilide + mepiqual-Cl). The product is used during the crop growth (the squaring period) to regulate cotton plant growth and manage the vegetative vigor

*** Use purpose harvest aid (formulation contains two ac tive ingredients: cyclanilide + ethephon). The product is applied, at the end of the cotton season, before boll-open ing, to promote boll opening, defoliation and inhibition of terminal foliar re-growth (i.e., bring cotto n to maturity for harvest). Based on this information one application is assumed

Screening Level Usage Analysis (SLUA, date 06/22/2010) report for cyclanilide was provided by BEAD. Based on this report, the onl y usage data were for cotton and indicate the following:

• An average of 150,000 pounds of active in gredient was applied (values are calculated by merging pesticide usage data sources together; averaging across all observations, then rounding);

• An average of 10 percent of crop was tr eated (values are ca lculated by merging data sources together; averaging by year , averaging across all years, & rounding to the nearest multiple of 5); and

• A maximum of 20 percent of crop was trea ted (value is the single maximum value reported across all data sources, across a ll years, & rounded up to the nearest multiple of 5).

Figure 1 shows cotton acreage throughout the US (NASS data 2002) in addition to the U.S. Geological Survey (USGS) 3 pesticide use map. Comparison between the distribution of cotton acreage a nd the regional scale patterns in use intensity confirms that cotton is probably the main use pattern for cyclanilide with the exception of
Arizona. No use is shown for the cotton areas in Arizona.

3 The USGS pesticide maps are based on State level estimates of pesticide use rates for in dividual crops, which have been compiled by the National Center for Food and Agricu ltural Policy (NCFAP) for 1999 through 2004, and on the 2002 Census of Agriculture for county crop acreage crop. Please refer to (http://water.usgs.gov/nawqa/pnsp/usage/maps/compound_listing.php?year=02 ) for data limitation and to Method for Estimating Pesticide Use for a detailed discussion of how the pesticide use data were developed.7 1 Figure 1. Cotton acreage data compared to estimated usage data for cyclanilide

In California, the pesticide is used on cott on with a total use of nearly 2,000 to 2,100 lbs of active ingredient (California usage data from CA Department of Pesticide Regulation “CA DPR” form 2006 to 20080) 4

.


### 3.3 Environmental Fate and Transport

A summary of physicochemical properties of cy clanilide was obtained from previous risk
assessment and is included in Table 2

.

2 Table 2 Summary of physicochemical properties of cyclanilide

4 http://www.cdpr.ca.gov/docs/pur/purmain.htm8 PARAMETER VALUE(S) (units) SOURCE

CAS Chemical Name 1-[[(2,4- dichlorophenyl)amino]carb onyl]cyclopropanecarboxylic
acid Cyclanilide Fact Sheet May,

1997

http://www.epa.gov/opprd00 1/factsheets/cyclanilide.pdf IUPAC Chemical Name 1-(2,4- dichlorophenylaminocarbonyl)cyclopropanecarboxylic acid

Chemical Formula C 11 H 9 Cl 2 NO 3 From structure

PC Code 026201 OPP Databases

Chemical Structure

Smiles Code: c1cc(Cl)cc(Cl)c1NC(=O)C2CC2C(=O)O http://pubchem.ncbi.nlm.n ih.gov/image/structurefly. cgi?cid=86133&width=40 0&height=400

CAS Reg. No. 113136-77-9 Pesticide fact Sheet http://www.epa.gov/opprd00 1/factsheets/cyclanilide.pdf Molecular Weight 274.1 g/mole

Solubility ( 20 o C) 48 mg/L (ppm)

Vapor Pressure (VP @ 50 o C) 6.3 x 10 -8 torr MRID 433684-09

Henry’s Law Constant 4.73 x 10 -10 atm-m 3 -mol -1 Calculated @ 50 o C

Octanol-Water Partition Coefficient (21 o C) (log K OW and K OW ) 3.25, and 1,778 <7.52 x 10 -10 atm-m 3 -mol -1

Octanol-Air Partition
Coefficient

(log K O A and K OA ) 9.33 and 2.14 x 10 9 EPISuite v.4.0 Estimate

Bio-magnification Potential Presumption*: If log K OA > 5, log K OW >2 and the rate of chemical transformation is low, the chemical may bio-magnify in
terrestrial food chains ►

For cyclanilide, log K OA =9.33, log K OW =3.25 rate of transformation is relatively low; it appears that cyclanilide has a potential to bio-magnify in terrestrial food chains ► Gobas et al. 2003 5 support this presumption utilized here only as a broad
reference to determine the potential for biomagnification

5 Gobas, F.A.P.C., B.C. Kelly and J.A. Arnot. 2003. Quantitative structure activity relationships for predicting the bioaccumulati on of POPs in terrestrial food webs. QSAR
Comb. Sci. 22:329-336.9 Data in Table 2 indicate that cyclanilide has a mo lecular weight of 274.1 g/mol with a solubility of 48 ppm and an octanol/ water partition coefficient greater than 1,000 (K OW = 1,778), it appears that cyclanilide has the poten tial to bio-accumulate/ bio-concentrate in aquatic organisms such as fish.

For cyclanilide, the log K OA is 9.33 and the log K OW =3.25. For chemicals that are not readily metabolized in vivo, a log K OA and log K OW in this range (K OA > 5, log K OW >2) have been associated with bio-magnificati on in terrestrial-based food webs based on information presented in articles by Gobas et al. and Armitage & Gobas (2003 and 2007, respectively). However, this chemical may undergo substantial biotransformation in

vivo . Even though the EFED has not adopted an official reference to distinguish chemicals that bio-magnify, th eir presumption was utilized here as a general or broad reference to detect the bio-magnificati on potential in terrestrial food chains.

A summary of fate properties for cyclanilide fr om laboratory and field studies is listed in
Table 3

.

3 Table 3. Summary of Fate Properties of Cyclanilide

Property Value (Source Reference)

Hydrolysis Stable @ pH 5, 7 and 9 (MRID 433684-51) Direct Aqueous Photolysis (half-life, days) 44 days (MRID 438683-25) Soil Photolysis (half life, days) 151 days (MRID 438683-26) Aerobic Soil Metabolism (half-life, days) 95 days (MRID 438683-27) 62 days (MRID 4336844-52 & Amendment MR ID 438683-28) Anaerobic Aquatic Metabolism (half-life, days) Stable (MRID 438683-20)

K

ocs ( (milliliters/gram) 194 to 565 for sandy loam, loamy sand, silt loam, clay soil and sand sediment (MRID 433684-53& Amendment MR ID 445268- 01) Soil Dissipation (half-life, days) 73 day in Texas and 114 days in California (MRID 438683-30 and MRID 439694-01 for storage stability Fish Accumulation (BCF); concentration in tissue to exposure concentration in water 0.285X for edible, 2.7X for non-edible, and 1.28X for whole fish (wet weight). Depuration was rapid with approximately 75 % of accumulated residues depurating within 24 hours, and 100 % depurating within 14 days (MRIDs 440134-01 & 438683-33).10 Based on laboratory studies, cyclanilide is st able to hydrolysis and highly persistent to photolysis in water and on soil. In anaerobic aq uatic system, the chemical is expected to be stable. In contrast, the chemical appears to degrade slowly in aerobic soil systems (half-lives of approximate ly 62 to 95 days).

Mobility data suggest that pa rent and main metabolite are mobile to moderately mobile (K
ocs = 194 to 565 ml/g for parent cyclani lide and from 349 to 681 ml/g for 2, 4- dichloroanilide in soils and 883 ml/g for sediment (MRIDs: 43368453 & 43868329). Additionally, in a 30-day aged column leach ing study, <3% of the a pplied radioactivity
was detected in the leachates. After leachi ng, the majority of the applied radioactivity remained in the 0 to 6 cm (57-77%) and 6 to 12 cm (3-16%) segments of each soil column. RPA 90946 was the predominant compound in both the uppermost soil column segments (>98% of the extractable radio activity) and in the leachate (MRID 433684-54).

Four terrestrial field dissipation studies were conducted for cyclanilide in the main cotton producing areas (North Carolina, Mississippi, Ca lifornia, and Texas). Pa rent half-lives of 30 days was observed at North Carolina and Miss issippi site> In cont rast, the first-order
half-lives in Texas and California were 73 and 114 days; at both locations, residues declined until 2-3 months post-treatment, but then remained at a steady level until 6-8 months post-treatment; they declined rapidly ther eafter. At all four test sites, cyclanilide was found at greater than the Level of Quantitation (LOQ; 0.005 ppm) below the 0- to 15-cm soil depth only twice and was not found at > LOQ below 30 cm. It was detected down to 45 cm at < LOQ only twice. Information on the field behaviour of the cyclanilide degradate 2, 4-dichloaniline is incomplete at this time. The cyclanilide degradate, 2,4-dichloroaniline, was found at >0.005 ppm only twice.

Data on fish accumulation suggest that cyclanil ide is not likely to accumulate in fish.
Although the octanol-water partition coefficient is greater than 1,000 (K OW = 1,778 at

21 o C), a fish bio-concentrati on study suggests low bio-concen tration (0.285X for edible, 2.7X for non-edible, and 1.28X fo r whole fish on wet weight basis) and rapid/complete depuration evidenced by the fact that a pproximately 75 % of accumulated residues depurated within 24 hours, and 100 % depur ated within 14 days (MRIDs 440134-01 & 438683-33).

Laboratory and field degradat ion profile for cyclanilide suggest that the primary terrestrial dissipation mechanism for cyclanilide is aerobic microbial degradation to 2,4- dichloroaniline ( Figure 2 ) and presumably further degrad ation to cyclopropane-1,1- dicarboxylic acid. In one of the soils, 2, 4-dichloroaniline shows decline (MRID 4336844- 52 & Amendment MR ID 438683-28); however in another soil no decline was observed (MRID 438683-27)

.11 2 Figure 2. Structures for parent cy clanilide and main degradate

Parent cyclanilide Main degradate 2,4 dichloroaniline

Based on the degradation profile and the relative persistenc e of the main degradate 2,4 dichloroaniline (which contains the main moiety of the parent); the registration review risk assessment will consider parent plus degradate as the stressor.



## 4. Ecological Effects

4.1 Aquatic and Terrestrial Effects

As described in the Agency’s Overview Do cument (U.S EPA, 2004), the most sensitive endpoint for each taxonomic group will be used to calculate risk quotients (RQs). Assessment endpoints include direct toxic effects on the survival, reproduction, and growth of terrestrial and aquati c life as well as indirect effect s such as reduction in prey
base and/or modifi cation of habitat.

Acute and chronic toxicity da ta from studies submitted by pesticide registrants along with the available open literature are used to evaluate the potential direct effects of cyclanilide to the aquatic and terrestrial receptors identified in this section. This includes toxicity data on the technical grade active ingredient, degradates, and when available, formulated products. The open literature studies ar e identified through EPA’s ECOTOX database ( http://cfpub.epa.gov/ecotox/ ), which employs a literature search engine for locating chemical toxicity data for aquatic life, terres trial plants, and wildlife. The evaluation of both sources of data can also provide insight into the direct and indirect effects of cyclanilide on biotic communities from loss of sp ecies that are sensitive to the chemical and from changes in structure and functional ch aracteristics of the affected communities.

Other sources of information including the us e of acute probit dose response relationship to establish the probability of an individual e ffect and reviews of th e Ecological Incident Information System (EIIS) are conducted to further refine the characterization of12 potential ecological effects with exposure to cyclanilide. A summary of the available ecotoxicity information and the incident info rmation for cyclanilide are provided below.

Table 4 provides a summary of the taxonomic groups and the surrogate species tested to help understand potential acute a nd chronic ecological effects of cyclanilide. In addition, the table provides a preliminary overview of th e potential acute toxicity of cyclanilide by providing the acute toxic ity classifications.

Terrestrial Species

Technical grade cyclanilide is classified as moderately toxic to birds on an acute oral basis and slightly toxic to birds on an acute dietary basis. There were no submitted avian reproduction studies for cyclanilide. These st udies remain a requirement in order to
estimate risk to birds on a chr onic level. Although not an ec otoxicological requirement, a mammalian acute oral study with the rat showed th at cyclanilide is mode rately toxic. An acute contact toxicity study to the honey bee showed that cy clanilide is practically nontoxic to terrestrial insects.

Chronic effects on avian species, as previously mentioned could not be characterized due
to a lack of data. In a mammalian two generation study, reproductive toxicity was characterized as decreases in mean pup weights at the 300 and 1000 ppm dose levels. Mean pup weights were reduced by 10-32% at the 1000 ppm level throughout lactation for both generations. In the range finding study, reproductive eff ects seen at the 1400 ppm dose level included reduced mating indi ces, reduced gestation index, decreased mean implantation sites, increased pup mortality, and decreased pup weights.

Aquatic Species

Cyclanilide is classified as slightly toxi c to freshwater fish and invertebrates and
estuarine/marine fish on an acute basis. Ma rine mollusk endpoint were more sensitive than mysid shrimp endpoints and therefore cyclanilide is classified as moderately toxic to
marine/estuarine invertebra tes on an acute basis.

In a freshwater fish early life stage test, s ublethal effects to the fathead minnow included statistically significant reduced total length a nd wet weight in the two highest treatment levels (5 and 10 ppm). There were no sings of toxicity observed during the course of the
freshwater invertebrate life cycle test. There was no submitted study for chronic effect to a marine/estuarine fish species or a chronic study for marine/estuari ne invertebrates.

Terrestrial and Aquatic Plants

A seedling emergence/vegetative vigor study was submitted in support of cyclanilide (MRID 43868318) in 1995 that was classified a supplemental for all species for the seedling emergence but unacceptable for all species for the vegetative vigor. The seedling emergence data was classified as supplemental due to the phytotoxic effects observations data being unusable as the phytotoxic effects we re not rated. Furthermore,13 the study failed to determine an NOAEL for phytotoxic observations for several of the test species. For the vege tative vigor study, a spray volume of approximately 1000 gallons per acre was used which is much greater than the spray volume recommended for
the label as well as the fact that much of the volume would run off into the soil. These
studies were also conducte d using technical grade cyclanilide. 40 CFR Part 158 recommends Tier I and II terrestrial plant studies conducted with a typical end use (TEP) product.

A seedling emergence (MRID 43868323) was submitted in 1995 in support of cyclanilide as the typical end use product FINISH ® Harvest Aid. There was no accompanying vegetative vigor study. The study was classified as supplemental for all species due to the absence of a defined rating system when making phytotoxic observations. This was exemplified by cucumber in which the lowest three doses showed significant reductions and therefore endpoints could not be statistically calculated. Similarly in lettuce, since chlorosis was observed in a significant number of plants at all treatment levels, a NOAEL
could not be determined. Data for cucumber and lettuce could therefore not be upgraded to acceptable status even if observations on phytotoxicity were provided. The most sensitive endpoints observed in this species were not as sensitive as the previously submitted study MRID 43868318.

Previous assessments for cyclanilide did not account for a third set of seedling emergence/vegetative vigor studies be ing submitted in 1998 (MRID 44518602) which tested the TEP of cyclanilide on two speci es (lettuce and cucumber) for seedling emergence and all ten species for vegetative vigor. For seedling emergence, since MRID
43868323 was not able to calculate statistical endpoints for lettuce and cucumber, this study was submitted to provide these results. This study is currently in review.

Cyclanilide is classified as highly toxic to a ll tested aquatic plants with the exception of blue-green algae for which it was very highly toxic ( Table 4 ).

4 Table 4. Test Species Evaluated for Assessing Potential Acute and Chronic Ecological Effects of Cyclanilide.

Taxonomic Group Surrogate Species Acute Toxicity (LC 50 , EC 50 , LD 50, EC 25 )

-- Chronic Toxicity (NOAEC, LOAEC, NOAEL, LOAEL) MRID Acute Toxicity
Classification

Birds 1 Mallard duck ( Anas platyrhynchos ) LD 50 = Not determined

LC 50 = 1740 ppm

-- No Data 43368413

43368415

-- No Data --

Slightly toxic

--

Northern bobwhite

quail ( Colinus virginianus ) LD 50 = 240 ppm

LC 50 = 2580 ppm

-- No Data 43368414

43368416

-- No Data Moderately toxic

Slightly toxic

--14 Taxonomic Group Surrogate Species Acute Toxicity (LC 50 , EC 50 , LD 50, EC 25 )

-- Chronic Toxicity (NOAEC, LOAEC, NOAEL, LOAEL) MRID Acute Toxicity
Classification

Mammals Laboratory rat ( Rattus norvegicus ) LD 50 = 208 mg/kg bw

-- NOAEL = 30 ppm LOAEL = 300 ppm 43368424

43868313,
44073701 Moderately toxic

--

Insects Honey bee ( Apis mellifera ) LD 50 (contact) = > 100 ug/a.i/bee 43868324 Practically nontoxic

Freshwater Fish 2 Rainbow trout ( Oncorhynchus mykiss ) 96-hour LC 50 = > 11 mg/L 43368417 Slightly toxic

Bluegill sunfish ( Lepomis
macrochirus ) 96-hour LC 50 = > 16 mg/L 43368418 Slightly toxic

Fathead minnow NOAEC = 1.2 ppm LOAEC = 2.6 ppm 43868309 --

Freshwater
invertebrates Water Flea ( Daphnia

magna ) 48-hour EC 50 = >13

ppm

-- NOAEC = 12.6 ppm

LOAEC = >12.6 43368419

43876701 Slightly toxic

--

Estuarine/marine
fish Sheepshead minnow ( Cyprinodon variegatus ) 96-hour LC 50 = 49 ppm

-- No Data submitted 43368422

No data Slightly toxic

--

Estuarine/marine

invertebrates Mysid shrimp ( Americamyis bahia ) 96-hour EC 50 = 5 ppm 43368421 Moderately toxic

Eastern oyster ( Crassotrea virginica ) 96-hour EC 50 = 19 ppm 43368420 Slightly toxic

Terrestrial plants Multiple species Seedling Emergence 3 : Monocot EC 25 –

>0.25lb a.i/A

Monocot NOAEL -

0.0074 lb a.i/A
Dicot EC 25 – 0.017 lb
a.i/A
Dicot EC 05 4 -0.0011 lb
a.i/A Vegetative Vigor – Unacceptable study 43868318 --

Multiple Species Study in review 44518602 --

Aquatic plants Vascular Plant: Duckweed ( Lemna gibba ) Tier II: EC 50 = >0.22

ppm

-- NOAEC = 0.2 ppm 43868321 --

Non-vascular plants:
Marine Diatom

( Skeletonema

costatum ) Tier II: EC 50 = >0.27

ppm

-- NOAEC = 0.13 ppm 43868322 --

Blue-green algae Tier II: EC 50 = 0.080 43868320 --15 Taxonomic Group Surrogate Species Acute Toxicity (LC 50 , EC 50 , LD 50, EC 25 )

-- Chronic Toxicity (NOAEC, LOAEC, NOAEL, LOAEL) MRID Acute Toxicity
Classification

(Anabaena flosaquae ) ppm

-- NOAEC = 0.030 ppm

Freshwater diatom ( Navicula pelliculosa ) Tier II: EC 50 = >0.17

ppm

-- NOAEC = 0.023 ppm 43868319 --

Green Algae ( Selenastrum capricoruntum ) Tier II: EC 50 = 1.0 ppm

-- NOAEC = 0.0097 ppm 43368450 --

1 Birds represent surrogates for terrestrial-phase amphibians and reptiles

2 Freshwater fish represent surrog ates for aquatic-phase amphibians

3 The endpoints listed are endpoints other than phytotoxic observations. Phytotoxic observations were the most sensitive endpoints but did not yield valid results.

4 The EC 05 may be used in lieu of a NOAEL if the NOAEL is higher than the EC 25



### 4.2 Incident Database Review

A preliminary review on September 29, 2010 of the Ecological Incident Information System (EIIS, Version, 2.1) which is mainta ined by the Agency’s Office of Pesticide Programs, and the Avian Monitoring Information System (AIMS), which is maintained by the American Bird Conservancy, indicated no reported ecological in cident associated with the use of cyclanilide.

Although no incidents have been reported to the Agency, the absence of reported
incidents should not be construe d as the absence of incidents. Incident reports for nontarget organisms typically provide informa tion only on mortality events and plant damage incidents. Except for phytotoxic effects in terrestrial plants, sublethal effects for organisms such as reduced growth or impair ed reproduction are rarely reported. EPA’s changes in the registrant reporting require ments for incidents in 1998 may account for a reduced number of reported incidents. Re gistrants are now only required to submit detailed information on “major,” fish, wildlif e and plant incidents. Minor fish, wildlife, and plant incidents, as well as all other non-target incide nts, are generally reported aggregately and are not included in EIIS. In addition, there have been changes in state monitoring effects due to a lack of resources.



### 4.3 Ecosystems Potentially at Risk

The ecosystems at risk are often extensive in sc ope, and as a result it may not be possible to identify specific ecosystems during the deve lopment of a baseline risk assessment. However, in general terms, terrestrial ecosy stems potentially at ri sk could include the treated field and areas immediately adjacent to the treated field that may receive drift or runoff. Areas adjacent to the treated field could include cultivated fields, fencerows and16 hedgerows, meadows, fallow fields or grassla nds, woodlands, riparian habitats and other
uncultivated areas.

Aquatic ecosystems potentially at risk include water bodies adjacent to, or down stream from, the treated field and might include impounded bodies such as ponds, lakes and reservoirs, or flowing waterways such as str eams or rivers. For uses in coastal areas, aquatic habitat also includes marine ecosystems, including estuaries.

Cyclanilide is registered for use on cotton, or namentals, non-bearing fruit nursery trees,
and cut flowers. While the main harvest ar ea for cotton is limited to the southeastern United States, locations for the other uses of cyclanilide are more widespread.



### 4.4 Assessment Endpoints

Assessment endpoints represent the actual enviro nmental value that is to be protected, defined by an ecological entity (species, comm unity, or other entity) and its attribute or characteristics (EPA, 1998). For cyclanilid e, the ecological ent ities may include the following: birds, mammals, fr eshwater fish and invertebrate s, estuarine/marine fish and invertebrates, terrestrial plants , insects, and aquatic plants and algae. The attributes for each of these entities may include gr owth, reproduction, and survival.



### 4.5 Conceptual Model

For a pesticide to pose an ecological risk, it must reach ecological receptors in biologically significant concen trations. An exposure pathway is the means by which a pesticide moves in the environment from a source to an ecological receptor. For an ecological pathway to be complete, it must have a source, a release mechanism, an environmental transport medium, a point of exposure for ecological receptors, and a feasible route of exposure.

The conceptual model for cyclanilide pr ovides a written description and visual representation of the predicted relationships between cyclanilide, potential routes of exposure, and the predicted effects for the assessment endpoint. According to EPA’s ecological risk assessment guidelines (U.S EP A, 1998) a conceptual model consist of two major components: a risk hypothesi s and a conceptual diagram.

Risk Hypothesis A risk hypothesis describes the predicted re lationship among the stre ssor, exposure, and assessment endpoint response along with the rationa le for their selecti on. For cyclanilide, the following ecological risk hypothesis is be ing employed for this national-level risk

assessment:

Cyclanilide, when used in accordance with registered labels, will likely lead to off-site movement of the compound via runoff, spray drift, and eroded soil leading to exposure of non-target plants a nd animals. Based on information on environmental fate, mode of action, direct toxicity, and potentia l indirect effect,17 EFED assumes that registered uses of cyclanilide have the potential to cause reduced survival, growth, and reproducti on to non-target terrestrial and/or aquatic animals and plants.

Conceptual Diagram

The conceptual site model is a generic gr aphic depiction of the risk hypothesis, and assumes that cyclanilide, having outdoor uses only, is capable of affecting aquatic and terrestrial animals provided that environmental concentrations are sufficiently elevated as a result of proposed label uses. Based on an examination the physicochemical properties of cyclanilide, the fate and disposition n in the environmen t, and mode of application, a conceptual model was developed that repres ents the possible relationships between the stressors, ecological recept ors, and he assessment endpoints. Through a preliminary iterative process of examining availabl e data, the conceptu al model (i.e., the representation of the risk hypothesis) may be refined to reflect the likely exposure pathways and the organisms that are the most re levant and applicable to this assessment. It includes the potential pestic ide or stressor (cyclanilide), the sources and/or transport pathways, exposure media, exposure points, bi ological receptor type s, and attributes changes. The conceptu al model depicted in Figures 3 and 4, is similarly applicable to the urban outdoor uses of cyclanilide.

In order for a chemical to pose an ecologica l risk, it must reach ecological receptors in biologically significant concen trations. Exposure pathway is the means by which a pesticide movies in the environment from a source to an ecological receptor. For an ecological exposure pathway to be complete, it must have a source, a release mechanism, an environmental transport medium, a point of exposure for ecologi cal receptors, and a feasible route of exposure. In addition, the potential m echanisms of degradation/ transformation (i.e. which degradation/transformation products may form in the environment, in which media, and how much ) must be understood, especially if for the chemical, its metabolites/tran sformation products are of gr eater toxicological concern than the parent compound. The assessment of ecological exposure pathways, therefore, includes an examination of the source and pot ential migration pathways for constituents, and the determination of potential exposure routes.18 3 Figure 3. A conceptual model for cyclan ilide effects on aquatic organisms. 

### Stressor

Source

Receptors

Attribute Change Cyclanilide applied to use site and resul tant main degradate 2,4 dichloroaniline

Spray drift

Fish/aquatic-phase amphibians Eggs

Larvae
Juveniles / Adults

Individual organisms
Reduced survival Reduced growth Reduced reproduction Food chain Reduction in algae Reduction in prey Habitat integrity Reduction in primary productivity
Reduced cover Community change Surface water/

Sediment Runoff

Aquatic Animals
Invertebrates
Vertebrates 

### Exposure
Media

Uptake/gills or integument

Ingestion Ingestion Soil Ground water

Uptake/gills or integument

Aquatic Plants

N on-vascular
Vascular Uptake/cell, roots, leaves Riparian plant
terrestrial

exposure pathways see

Figure 219 4 Figure 4. A conceptual model of cycl anilide effects on terrestrial organisms



## 5. Analysis Plan

In order to address the risk hypothesis, the potential for adverse effect on the environment is estimated. The use, environmental fate , and ecological effects of cyclanilide are characterized and integrated to assess the risks. This is accomplished using a risk quotient (ratio of exposure concentration to effect concentrati on) approach. Although risk is often defined as the likelihood and magnitude of a dverse ecological effects, the risk-quotient based approach does not provide a quantitative estimate of likelihood and/or magnitude of an adverse effect. However, as outlined in the Over view Document (U.S EPA, 2004), the likelihood of effects to indi vidual organisms from particular uses of cyclanilide is estimated using the probit-dos e response slope and either the level of concern (discussed below) or actua l calculated risk quotient value.

This analysis plan will be revisited and may be revise d depending on the information submitted by the public in response to the openi ng of the Registration Review docket for cyclanilide. 

### Stressor

Source

Receptors

Attribute Change Cyclanilide applied to use site and resultant main degradate 2,4 dichloroaniline

Direct Application Spray drift

Birds / Terrestrialphase amphibians / reptiles /

mammals Terrestrial

Insects

Individual organisms
Reduced survival Reduced growth Reduced reproduction Food chain Reduction in prey Habitat integrity Reduction in primary productivity
Reduced cover Community change Terrestrial/riparian plants grasses/forbs, fruit, seeds (trees, shrubs) Runoff

Mammals 

### Exposure
Media Soil

Ingestion Ingestion

Ingestion Ingestion Dermal uptake/Ingestion

Root uptake

Terrestrial food
web Ingestion20 

### 5.1 Stressors of Concern

The stressor of concern for this assessment will include parent compound (cyclanilide) and its main degradate 2,4 dichloroaniline.



### 5.2 Measures of Exposure

In order to estimate risks of cyclanilide expos ures in aquatic and terrestrial environments, all exposure modeling and resulting risk conclusions will be based on maximum application rates for a given use. Meas ures of exposure are based on aquatic and terrestrial models that predict estimated environmental concentrations (EECs) of cyclanilide. The models that will be used to predict aquatic EECs are the Pesticide Root Zone Model coupled with the Exposure Anal ysis Model System (PRZM/EXAMS). The model used to predict terrestrial EECs on f ood items is T-REX. The model to derive
EECs relevant to terrestria l and wetland plants is TerrP lant. These models are parameterized using relevant reviewed registrant-submitted environmental fate data. Although the log Kow for cyclanil ide indicates that the chemi cal might have the potential to bioaccumulate, fish bioaccumulation studi es confirmed that cyclanilide is mostly
metabolized and that actual bi oaccumulation in fish is low. EFED currently does not plan to investigate the risk from bioaccumulation further.

Exposure estimates for terrestrial animals assumed to be in the target area or in an area exposed to spray drift are derived usi ng the T-REX model (version 1.3.1, 12/07/2006). This model incorporates the Kenega nomograph, as modified by Fletcher et al. (1994), which is based on a large set of actual field residue data. The upper limit values from the nomograph represented the 95 th percentile of residue values from actual field measurements (Hoerger and Kenega, 1972). The Fletcher et al. (1994) modifications to the Kenega nomograph are based on measured field residues from 249 published research papers, including information on 118 species of plants, 121 pesticides, and 17 chemical classes. EECs for terrestrial plants inhabi ting dry and wetland ar eas are derived using TerrPlant (version 1.2.2, 12/26/2006). This mode l uses estimates of pesticides in runoff and in spray drift to calculate EECs. EECs are based upon solubility, application rate and minimum incorporation depth.



### 5.3 Measures of Effect

Ecological effect data are used as measures of direct and indirect effects to biological receptors. Data were obtained from registrant-submitted studies or from literature studies identified by ECOTOX. The ECOTOXicol ogy database (ECOTOX) was searched on May 1, 2008 in order to provide mo re ecological effects data to bridge existing data gaps. ECOTOX is a source for locating single chemical toxicity data and potentially chemical mixture toxicity data for a quatic life, terrestrial plants, and wildlife. ECOTOX was created and is maintained by the USEPA, Office of Research and Development, and the
National Health and Environmental Effect s Research Laboratory's Mid-Continent Ecology Division (ECOTOX, 2006).21 Information on the potential effects of cyclanil ide on non-target animals is also collected from the Ecological Incident In formation System (EIIS; USEPA 2007 c ). The EIIS is a database containing adverse effect (typically mortality) reports on non-target organisms
where such effects have been associated w ith the use of pesticides. Where available,
sublethal effects observed in bot h registrant-submitted and open literature studies will be evaluated qualitatively. Such effects have included behavioral changes ( e.g. , lethargy, changes in coloration and effects olfaction). Quantitative assessments of risks, though, are limited to those endpoints that can be directly linked to the Agency’s assessment endpoints of impaired survival, growth and reproduction.

The assessment of risk for direct effects to non-target organisms makes the assumption that toxicity of cyclanilide to birds is similar to terrestria l-phase amphibians and reptiles. The same assumption is made for fish and aquatic-phase amphibians.

The acute measures of effect used for animals in this screening-level assessment are the

LD 50 , LC 50 and EC 50 . LD stands for "Lethal Dose", and LD 50 is the amount of a material, given all at once, that is estimated to cause the death of 50% of the test organisms. LC
stands for “Lethal Concentration” and LC 50 is the concentration of a chemical that is estimated to kill 50% of the test organisms. EC stands for “Effective Concentration” and
the EC 50 is the concentration of a chemical that is estimated to produce a specific effect in 50% of the test organisms. Endpoints for chronic measures of exposure for listed and
non-listed animals are the NOAEL/NOAEC an d NOEC. NOAEL stands for “No
Observed-Adverse-Effect-Level” and refers to the highest tested dose of a substance that has been reported to have no harmful (adve rse) effects on test organisms. The NOAEC (i.e., “No-Observed-Adverse-Effect-Concentrati on”) is the highest test concentration at
which none of the observed effects were statis tically different from the control. The
NOEC is the No-Observed-Effects-Concentra tion. For non-listed plants, only acute exposures are assessed (i.e., EC 25 for terrestrial plants and EC 50 for aquatic plants); for listed plants, either the NOAEC or EC 05 is used.

5 Table 5. Measures of Ecological Effects and Exposure for Cyclanilide22 Assessment Endpoint Surrogate Species and Measures of Ecological Effect 1 Measures of Exposure

Birds 2 Survival Bobwhite acute oral LD 50 Bobwhite and mallard subacute dietary LC 50

Maximum residues on food items (foliar) Reproduction and growth Bobwhite and mallard chronic reproduction NOAEC and LOAEC (no studies available)

Mammals Survival Laboratory rat acute oral LD 50
Reproduction and growth Laboratory rat oral reproduction
chronic NOAEC and

LOAEC

Freshwater fish 3 Survival Rainbow trout and bluegill
sunfish acute LC 50 (no valid study available) Peak EEC 4

Reproduction and growth Fathead minnow chronic (early life-stage)
NOAEC and LOAEC 60-day average EEC 4

Freshwater invertebrates Survival Water flea (and other freshwater invertebrates) acute EC 50 Peak EEC 4

Reproduction and growth Water flea chronic (life cycle)

LOAEC 21-day average EEC 4

Estuarine/marine fish Survival Sheepshead minnow acute LC 50 (no study available) Peak EEC 4

Reproduction and growth Sheepshead minnow chronic (early life-stage) NOAEC
and LOAEC 60-day average EEC 4

Estuarine/marine invertebrates Survival Eastern oyster acute EC 50 and mysid acute LC 50 Peak EEC 4

Reproduction and growth Mysid chronic NOAEC and

LOAEC 21-day average EEC 4

Terrestrial plants 5 Survival and growth Mo nocot and dicot seedling emergence and vegetative vigor EC 25, EC 05 , and
NOAEC values Estimates of runoff and spray drift to non-target areas

Insects Survival (not quantitatively assessed) Honeybee acute contact LD 50 (no study available) Maximum application rate

Aquatic plants and algae Survival and growth Algal and vascular plant (i.e., duckweed) EC 50 and NOAEC values for growth
rate and biomass

measurements Peak EEC

1 If species listed in this table represent most commonly en countered species from registrant-submitted studies, risk assessment guidance indicates most sensitive species tested within taxonomic group are to be used for baseline risk

assessments.

2 Birds represent surrogates for amphibian s (terrestrial phase) and reptiles.23 3 Freshwater fish may be surrogate s for amphibians (aquatic phase).

4 One in 10-year return frequency.

5 Four species of two families of monocots - one is corn, six species of at least four dico t families, of which one is soybeans. LD 50 = Lethal dose to 50% of the test population; NOAEC = No observed adverse effect concentration; LOAEC = Lowest observed adverse effect concentration; LC 50 = Lethal concentration to 50% of the test population;

EC 50 /EC 25 = Effect concentration to 50%/25% of the test population.



### 5.4 Integration of Exposure and Effects

Risk characterization is the integration of exposure and ecological e ffects characterization to determine the potential ecologi cal risk from the use of pe sticides and the likelihood of
direct and indirect effects to non-target organisms in aquatic and terrestrial habitats. The exposure and toxicity effects data are integrated in order to evaluate the risks of adverse ecological effects on non-target species. For the assessment of risks, the risk quotient (RQ) method is used to compare exposure and measured toxicity values. EECs are divided by acute and chronic toxicity values. The resulting RQs are then compared to the Agency’s Levels of Concerns (LOCs) (U.S EP A, 2004). These criteria will be used to indicate when cyclanilide’s uses, as directed o the label, have the potential to cause
adverse direct or indirect eff ects to non-target organisms. In addition, incident data from the EIIS will be considered as part of the risk characterization.



### 5.5 Endangered Species Assessments

Consistent with the Agency’s responsibility under the Endangered Species Act (ESA), the Agency will evaluate risks to Federally-listed threatened and/or endangered (listed) species from registered uses of cyclanilide. This assessment will be conducted in accordance with the Overview Document (USE PA 2004), provisions of the ESA, and the
Services’ Endangered Species C onsultation Handbook (USFWS/NMFS, 1998).

The assessment of effects associ ated with the registration of cyclanilide is based on an
action area. The action area is considered to be the area directly or indirectly affected by the federal action, as indicated by the exceedan ce of Agency Levels of Concern (LOCs)
used to evaluate direct or indirect effects. The Agency’s approach to defining the action area under the provisions of the Overview Do cument (USEPA 2004) considers the results of the risk assessment process to estab lish boundaries for that action area with the understanding that exposures below the Agency’s defined LOCs constitute a no-effect threshold. For the purposes of this assessmen t, attention will be focused on the footprint of the action (i.e., the area where cyclanilid e application occurs), plus all areas where offsite transport may result in potential e xposure that exceeds the Agency’s LOCs. Specific measures of ecological effect that de fine the action area for listed species include any direct and indirect effects and/ or pot ential modification of its critical habitat, including reduction in survival, growth, and reproduction as well as the full suite of sublethal effects available in the effects literature. Therefore, the action area extends to a point where environmental exposures are below any measured lethal or sub-lethal effect threshold for any biological entity at the whol e organism, organ, tissue, and/ or cellular level of organization. In situa tions where it is not possible to determine the threshold for an observed effect, the action ar ea is not spatially limited and is assumed to be the entire24 United States.



### 5.6 Monitoring Data

The USGS NAWQA 6 databases were searched, a nd no monitoring data on the concentration of cyclanilide in surface water, groundwater, or sediment were found at the present time. It appears that cyclanilid e was not included in the USGS NAWQA list of analytes.



### 5.7 Clean Water Act

Cyclanilide is not identified as a cause of impairment for any water bodies listed as impaired under section 303(d) of the Clean Water Act, based on information provided at http://iaspub.epa.gov/tmdl_waters10/attain s_nation_cy.cause_detail_303d? p_cause_grou p_id=885 . In addition, no Total Maximum Daily Loads (TMDL) has been developed for cyclanilide, based on information provided at http://iaspub.epa.gov/tmdl_waters10/attain s_nation.tm dl_pollutant _detail?p_pollutant_gr oup_id=885&p_pollutant_group_name=PESTICIDES . More information on impaired
water bodies and TMDLs can be found at http://www.epa.gov/owow/tmdl/

. The Agency invites submission of water quality data for this pesticide. To the extent possible, data should conform to the qua lity standards in Appendix A of the OPP Standard Operating Procedure: Inclusion of Impaired Water Body and Other Water Quality Data in OPP’s Registration Revi ew Risk Assessment and Management Process (see: http://www.epa.gov/oppfead1/cb/ppdc /2006/november06/session1-sop.pdf), in order to ensure they can be used quantit atively or qualitatively in pesticide risk

assessments.



### 5.8 Endocrine Disrupter 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 endocrine influence

, including effects on endocrine target organ histopathology, or gan weights, estrous cyclicity, sexual maturation, fertility, pregnancy rates, reproductiv e loss, and sex ratios in offspring. For ecological hazard assessments, EPA evaluates acute tests and chronic studies that assess growth, developmental and reproductive effect s in different taxonomic groups. As part of its reregistration decision

, EPA reviewed these data and selected the most sensitive endpoints for relevant risk assessment scenar ios from the existing hazard database. However, as required by FFDCA section 408(p) , cyclanilide is subject to the endocrine screening part of the Endocrine Di sruptor Screening Program (EDSP).

6 http://infotrek.er.usgs.gov/nawqa _queries/swmaster/index.jsp (visited October, 27, 2010)25 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 avai lable 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 th e 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 the stat us 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/

.


### 5.9 Uncertainty and Preliminary Identification of Data Gaps

Environmental Fate & Transport

Two previous assessments were executed for cyclanilide and no fate and transport data gaps or uncertainties were identified except for the terrestrial field dissipation data (TFD). The latter study was classified as up-gradable by submission of the complete report on storage stability. Such report a ppear not be submitted as of to date.

The list of studies that were submitted is included previously in Table 3. Based on
examination of the available data and its quality, EFED recommends the following:

- Submittal of the complete report on storage stability and required data to upgrade the already submitted terrestrial field di ssipation studies (MRIDs 440134-01 and

438683-33.

- Submittal of two new aerobic soil studies (Guideline No. 835.4100) in which representative soils are use d, degradation profile is determined (all degradates included), and extraction procedure is appr opriate (able to ex tract bound residue or bound residue is identified when >10%)

- Upgrade previously submitted environmental chemistry method (MRID 438683-34; Guideline No. 835.6100) for determination of cyclanilide in soils possibly by26 modifying the method to be a state-of- the-art with appropriate LOQ. In addition an independent laboratory validation (ILV) is re quired as per guidelin e. Validation is to be performed by an independent laboratory as per the guideline. Submitted validation study (MRID 438683-31) appears to be conducted by the registrant.

- Submit a new state-of-the art environmental chemistry method (ECM) for determination of cyclanilide in water with an appropriate LOQ and an independent laboratory validation (ILV) as per the ECM/ILV Guideline No. 835.6200.

Effects

Uncertainties and data gaps from previ ous assessment include a lack of avian reproduction studies to characteri ze chronic risk to birds, no early life stage test for an estuarine/marine fish spices, and no chroni c life cycle test for an estuarine/marine invertebrate species.

Additionally, the previous seedling emer gence study (MRID 43868323), was classified Supplemental for all species due to the se verity of phytotoxic obs ervations being not measured with a defined rating system. Fu rthermore, for lettuce and cucumber, the EC 25 and NOAEL could not be established due to sign ificant reductions in all treatment groups precluded the ability to st atistically determine these endpoints. A new seedling emergence study for lettuce and cucumber and vegetative vigor study for all ten species (MRID 44518602) was submitted, reviewed, and is classified as acceptable. This data now makes it possible to estimate ri sk to terrestrial plants.

The primary degradate of concern, 2,4 dichloroaniline, was identified in both aerobic soil metabolism studies submitted reaching consistent levels of 7-11%. The un-extractable residues for one of the submitted studies reach 30%, creating uncertainty in exactly how much of the parent or degradate remains af ter the study. The degr adate of concern was shown to be very persistent as maximum concentrations reached 16% at day-30 but
remained at detectable levels throughout the 180-day study.

There are no submitted ecotoxicity studies in with 2,4 dichloroaniline. Toxicity to aquatic taxa can be estimat ed using the EPI WEB v 4 EC OSAR tool which provides structure activity relationship estimates. For fish (freshwater and marine/estuarine), the tool predicts a 96-h LC 50 of 61 mg/L. This is a less toxic value than acute studies submitted for cyclanilide for freshwater and estuarine/marine fish (LC 50s of >11 mg/L and 49 mg/L, respectively). The predicted 48-hour LC 50 for Daphnia magna representing freshwater invertebrate is 37 mg/L which is less toxic than the LC 50 of >13 mg/L value
for Daphnia magna from exposure to cyclanilide. The green algae predicted 96-hour

EC 50 value was 19 mg/L which is less toxic than the >0.22 mg/L EC 50 for the most sensitive aquatic plant study submitted for cy clanilide (duckweed). Predicted chronic values for fish, Daphnia magna , and green algae are 5.7, 3.6, and 7.2, respectively. The value for fish is less toxic than that of the study submitted for cyclanilide (only a freshwater fish study was submitted), yet this was a more toxic value than the life cycle study submitted for freshwater invertebrates with cyclanilide.27 Although there are uncertainties with thes e values, as well as these values not distinguishing between fish in freshwater and marine/estuarine environments, they provide an indication that the 2,4 dichloroaniline is less toxi c to aquatic organisms than parent cyclanilide. Again, there is uncertainty with this statement, and the only way to be sure of the toxicity of 2,4 dichloroaniline and the characterization of sublethal effects to aquatic taxa would be a submission of ecotoxi city studies, but the Ag ency feels at this time that these studies are not warranted, es pecially since the re sidues of the primary degradate in the aerobic metabolism studies is somewhat uncertain and will be until a new study is submitted.

Regarding toxicity to terrestrial taxa, the EC OSAR tool only predicts toxicity endpoints for aquatic organisms. It is unclear if th e primary degradate, 2,4 dichloroaniline would pose a greater toxic risk to birds, small mamm als, and terrestrial i nvertebrates, however for the same reasons listed as above with the aquatic taxa, the Agency at this time is not requesting terrestrial ecotoxicity studies with 2,4 dichloroaniline.

For registration review, the follo wing studies are being requeste d to fulfill any data gaps:

Guideline Number: 850.2100 – Pass erine Acute Avian Oral Although two acute avian oral studies were received for the mallard duck and bobwhite quail, the Agency updated its data require ments in 40 CFR Part 158 (October 26, 2007) to include an acute oral toxicity study for both a passerine species and either a waterfowl or an upland game species. Furthermore, an LD 50 was not achieved in the mallard acute oral study due to regurgitation issues. Prior to starting toxicity te sting, a protocol will need to be provided for review. It is lik ely that, for most pesticide use patterns, passerines are more likely to be exposed th an upland games species and waterfowl.
Passerines are smaller and have faster meta bolisms than the species commonly used in acute oral testing for birds which could impact their sensitivity to chemicals.

Guideline Number: 850.1400 – Fish Ea rly Life Stage (saltwater) Cyclanilide has the pote ntial to enter estuarine/marine water bodies base d on its current use patterns that have proximity to coastal ar eas in the southeastern United States. Use patterns for cyclanilide include heavy uses along the Mississippi River which, from spray drift or runoff, have the poten tial to enter estuarine/marine environments. Furthermore, hydrolysis studies have shown cyclanilide to persist in water for more than 50 days (significantly more than the cutoff outlined in 40 CFR Part 158 of this study being required when the half life is gr eater than or equal to 4 days.)

Guidelines Number 850.1350 – Aquatic Inve rtebrate Life-Cycle (saltwater) The acute toxicity of cyclani lide to estuarine/marine invert ebrates indicates the potential for chronic risk, especially si nce the potential for chronic ex posure exists. Cyclanilide has the potential to enter es tuarine/marine water bodies ba sed on its curren t use patterns that have proximity to coastal areas in the so utheastern United States. Use patterns for cyclanilide include heavy uses along the Mississippi River which, from spray drift or runoff, have the potential to enter estuarine/marine environments.28 Table 6 lists the status of the ecological effects data requirements for cyclanilide.

6 Table 6. Ecological Effects Data Requirements for Cyclanilide

Guideline Data Requirement Test Species MRID Preliminary Study
Classification More Data
Needed for
Risk
Assessment?

71-1 (850.2100) Avian Oral LD 50 Mallard duck

Bobwhite

quail

Passerine

species 43368413

43368414

No Data Supplemental

Acceptable

No Data No

No

Yes 1

71-2 (850.2100) Avian Dietary LC 50 Mallard duck

Bobwhite

quail 43368415

43368416 Acceptable

Acceptable No

71-4 (850.2300) Avian Reproduction Mallard duck

Bobwhite

quail No data

No data No data

No data Yes

72-1 (850.1075) Freshwater Fish

LC 50 Rainbow

trout

Bluegill
sunfish 43368417

43368418 Supplemental

Supplemental No

72-2 (850.1010) Freshwater
Invertebrate Acute

LC 50 Water flea 43368419 Supplemental No

72-3(a) (850.1075) Estuarine/Marine
Fish LC 50 Sheepshead
minnow 43368422 Acceptable No

72-3(b) (850.1025 or

850.1055) Estuarine/Marine
Mollusk EC 50 Eastern oyster 433688420 Acceptable No

72-3(c) (850.1035 or

850.1045) Estuarine/Marine
Invertebrate EC 50 Mysid shrimp 43368421 Acceptable No

72-4(a) (850.1400) Freshwater Fish Early Life Stage Fathead
minnow 43868309 Acceptable No

72-4(b) (850.1300) Freshwater
Invertebrate Life Cycle Water flea 43876701 Acceptable No

72-4(c)
850.1350 Estuarine/marine
Invertebrate Life Cycle Mysid Shrimp No Data No Data Yes 2

72-4(d) (850.1400) Estuarine/Marine Fish Early Life Stage Sheepshead
minnow No Data No Data Yes 2

122-1(a)

850.1400 Seed germination

test Multiple species 43868318 Acceptable No29 Guideline Data Requirement Test Species MRID Preliminary Study
Classification More Data
Needed for
Risk
Assessment? 122-1(b) (850.4100) Seedling Emergence (Tier I) Multiple species 43868318 Supplemental No

122-1(c) (850.4150) Vegetative Vigor (Tier I) Multiple species 43868318 Unacceptable No

123-1(a) (850.4100) Seedling Emergence (Tier II) Multiple species 43868318
43868323
44518602 Supplemental Supplemental
In review No

123-1(b) (850.4150) Vegetative Vigor (Tier II) Multiple species 44518602 Acceptable No

122-2(a) (850.4400) Aquatic vascular plants (Tiers I and II) Duckweed 4386832 1 Acceptable No

122-2(b) (850.5400) Aquatic Nonvascular (Tiers I and II) Marine
Diatom 43868322 Acceptable

No Blue-green algae 43868320 Acceptable

Freshwater

Diatom 43868319 Acceptable

Freshwater algae 43368450 Acceptable

141-1 (850.3020) Honey bee acute contact toxicity Honey bee 43868324 Acceptable No

1 Data are required for one passerine species and either one waterfowl or one upland game bird species. At this time, only an acute oral test for a game bird species has been submitted.

2 Data required based on cyclanilide use patterns near co astal and/r estuarine areas, as well as a persistence of water (half life ≥ 4 days)30 

### Bibliography

U.S. Environmental Protection Agency. 1998. Guidelines for Ecological Risk Assessment. Risk Assessment Forum, Office of Research and Development, Washington, D.C. EPA/630/R-95/002F. April 1998.

U.S. Environmental Protection Agency. 2000. Risk Characterization Handbook. Science Policy Council, U.S. Environm ental Protection Agency, Washington,
D.C. 20460. EPA 100-B-00-002. December 2000.

U.S. Environmental Protection Agency. 2004. Overview of the Ecological Risk Assessment Process in the Office of Pesticide Programs, U.S. Environmental Protection Agency. Endangered and Threat ened Species Effects Determinations. Office of Prevention, Pesticides and T oxic Substances, Office of Pesticide Programs, Washington, D.C. January 23, 2004.

U.S. Environmental Protection Agency. 2005. Generic Format and Guidance for the Level I Screening Ecological Risk Asse ssments Conducted in the Environmental
Fate and Effects Division. Office of Pesticide Programs, Washington, D.C. January 24, 2005.

U. S. Environmental Protection Agency. 2007c . Ecological Incident Information System. http://www.epa.gov/espp/consultation/ecorisk-overview.pdf



### Environmental Fate References

MRID 43368451. Feung, C. (1992) Hydrolysis of (carbon 14)-RPA 90946 in Aqueous Buffer Solutions at pH 5, 7, and 9: La b Project Number: EC-90-129: 40913. Unpublished study prepared by Rhone-Poulenc Ag Co. 33 p.

MRID 43868325. Corgier, M.; Plewa, A. (1994) (Carbon 14)-RPA 090946: Photodegradation in Water: Lab Pr oject Number: 92-38: R&D/CRLD/AN/941697. Unpublished study prepared by Rhone-Poulenc Secteur Agro. 136 p.

MRID 43868326. Concha, M.; Shepler, K. (1994 ) Photodegradation of (carbon 14)- RPA-90946 on Soil by Natural Sunlight: Lab Project Number: 462W-1: 462W: EC-94- 255. Unpublished study prepared by PTRL West, Inc. 88 p.

MRID 43368452. Feung, C.; Stillwell, D. (1994) Aerobic Soil Metabolism of RPA 090946: Lab Project Number: EC-93-248: 4439 1. Unpublished study prepared by RhonePoulenc Ag Co. 175 p.

MRID 43868327. Feung, C.; Stillwell, D. (1995) RP A 090946: Rate of Degradation in Soil Under Aerobic Conditions: Lab Proj ect Number: EC-94-280. Unpublished study prepared by Rhone-Poulenc Ag Co. and Agvise Labs. 156 p.31 MRID 43868328. Concha, M.; Shepler, K. (1995 ) Anaerobic Aquatic Metabolism of (carbon 14)-RPA-90946: Amended Report: Lab Project Number: 461W-1: 461W: EC94-254. Unpublished study prepared by PTRL West, Inc. 110 p.

MRID 43868320. Concha, M. and K. Shepler (1995) Anaerobic Aquati c Metabolism of 14C-RPA-90946. Laboratory Project No. EC 94-254. Unpublished Study Performed by PTRL West, Richmond, CA and Submitted by Rhone Poulenc Ag Co. RTP. NC (43868320, citation same as above).

MRID 43368453. Mislanker, S.; Estes, T. (1994) Adsorption/Desorption of (carbon 14)- RPA 090946: Lab Project Number: EC-94- 259. Unpublished study prepared by RhonePoulenc Ag Co. 93 p.

MRID 43368454. Mislanker, S. (1994) Aged Leaching Study of (carbon 14)-RPA 090946: Lab Project Number: EC-94-256. U npublished study prepared by RhonePoulenc Ag Co. 59 p.

MRID 43868329. Feung, C.; Stilwell, D. (1995) Soil Adsorption/Desorption of Cyclanilide Metabolite 2,4-Dichloroan iline: Lab Project Number: EC-94-290. Unpublished study prepared by Rhone-Poulen c Ag Co. and Agvise Labs. 147 p.

MRID 44526801. Mislankar, S.; Estes, T. (1994) Adsorption/Desorption of (carbon 14)-

RPA 090946: Amended Final Report: Lab Project Number: EC-94-259. Unpublished study prepared by Rhone-Poulenc Ag Co. 98 p.

MRID 43868330. Chancey, E. (1995) A terrestrial soil dissipation study with cyclanilide (RP 90946). Rhône-Poulenc Ag Company Proj ect Identification File Number 44805; Protocol and Study Nu mber US93I02R. Unpublished study performed by South Texas Ag Research, Inc., Levelland, TX; and Rhône-Poulenc Ag Company: Leland, MS; Clayton, NC; and San Juan Bautista, CA. Laboratory analyses performed by Agvise, Inc., Northwood, ND, and Rhône-Poulenc Ag Co mpany, Research Triangle Park, NC. Submitted by Rhône-Poulenc Ag Company, Research Triangle Park, NC. 621 p.

MRID 43969401. Hurst, K.M. (1996). Interim report - Storage stability of cyclanilide residues in soil. Rhône-Poulenc Ag Co mpany Study Number EC-95-311. Unpublished study performed and submitted by Rhône-Poulenc Ag Company, Research Triangle Park,

NC.

MRID 43368409. Cousin, J. (1993) RPA 090946 Ac tive Ingredient: Physical and Chemical Characteristics: Part F Vapour Pr essure: Lab Project Number: 91-48 PART F: R&D/CRLD/AN/9315944: 91-48. Unpublished study prepared by Rhone-Poulenc Secteur Agro. 44 p.

MRID 43868333. Wyness, L. (1995) Bioconcentration of (carbon 14)-RPA 090946 in Lepomis macrochirus Under Flow-Through Conditions: Amended Final Report: Lab Project Number: 198/79: 198/ 79-1018. Unpublished study prepared by Corning Hazleton32 (Europe). 79 p.

MRID 44013401. Jesudason, P.; Mackie, S. (1996) Cyclanilide--Bioconcentration, Metabolism, and Elimination of (carbon 14) Residues by Bluegill Sunfish (Lepomis macrochirus): Lab Project Numb er: EC-95-329: 10566- 0196-6386-140: 96-4-6446. Unpublished study prepared by Rhone-Poulenc Ag Co.; Springborn Labs, Inc.; and Lancaster Labs, Inc. 281 p.

MRID 43868301. Guyton, C. (1995) Rationale for S ite of (carbon 14)-Labeling of Cyclanilide in Environmental and Meta bolism Studies: Lab Project Number: 44814. Unpublished study prepared by Rhone-Poulenc Ag Co. 54 p.

MRID 43868331. Ibrahim, A. (1995) Validation of th e Method of Analysis for Residues of RPA 90946 and its Metabolite 2,4-Dichloroa niline in Soil: Final Report: Lab Project Number: EC-95-302: 44854. Unpublished study prepared by Rhone-Poulenc Ag Co. 221

p.

MRID 43868334. Schuster, L. (1995) Method Confirmation for RPA 90946 and its Metabolite 2,4-Dichloroaniline in Soil: Lab Project Number: 95469: EC-95-306. Unpublished study prepared by ABC Labs, Pan-Ag Division. 104 p.



### Ecological Effects References

MRID 43368413. C. A. Pendersen and A. M. Solatycki. RPA 90946: 14-day Acute
Oral LD 50 Study in Mallard Ducks. Study Comp letion Date: August 26, 1993. Laboratory: Bio-life Associat es, Ltd. Rhone-Poulenc Ag Company. Laboratory Report

ID: BLAL # 108-011-04.

MRID 43368414. C. A. Pendersen and D. W. Flet cher. RPA 90946: 14-day Acute Oral

LD 50 Study in Bobwhite Quail. Study Completio n Date: August 26, 1993. Laboratory: Bio-life Associates, Ltd. Sponsor: Rhone -Poulenc Ag Company. Laboratory Report ID: BLAL # 90 QD 150.

MRID 43368415. Carol A. Pedersen and Ann M. So latycki. RPA 90946: 8-Day Acute Dietary LC 50 Studying Mallard Ducklings. Stud y Completion Date: June 10, 1993. Laboratory: Bio-Life Asso ciates, Ltd. Sponsored by Rhone-Poulenc Ag Company Laboratory Report ID:B LAL NO. 108-010-02.

MRID 43368416. Carol A. Pedersen and Ann M. So latycki. RPA 90946: 8-Day Acute Dietary LC 50 Study in Bobwhite Quail. Study Completion Date: June 10, 1993. Laboratory: Bio-Life Associ ates, Ltd. Sponsored by Rhone-Poulenc Ag Company. Laboratory Report ID: BLAL No. 108-009-01.

MRID 43368417. Bowman, Jane and Reed Herzig. Acute Flow-Through Toxicity of
RPA 90946to Rainbow Trout (Onchorhynchus mykiss). Study Completion Date:33 September 17, 1993. Laboratory: ABC Laborat ory, Inc. Sponsored by Rhone-Poulenc Ag Company.Laboratory Report ID: 38989.

MRID 43368418. Bowman, Jane and Reed Herzig. Acute Flow-Through Toxicity of

RPA 90946 to Bluegill ( Lepomis macrochirus ). Study Completion Date: September 17, 1993. Laboratory: ABC Laboratories, Inc. Sponsored by: Rhone-Poulenc Ag Company Laboratory Report ID: 38990.

MRID 43368419. Burgess, David. Acute Flow-t hrough Toxicity of RPA 90946 to Daphnia magna . Study Completion Date: Sept ember 17, 1993. Laboratory: ABC Laboratories, Inc. Sponsored by: Rhone-P oulenc Ag Company. Laboratory Report ID:

38515.

MRID 43368420. Dionne, Emily. RPA 090946 - Acute Toxicity to Eastern Oyster (Crassostrea virginica) under Flow-Through Conditions. Study Completion Date: June 21, 1994. Laboratory: Springborn Laboratories, Inc. Sponsored: Rhone-Poulenc Ag Company. Laboratory Report ID: 94-6-5296.

MRID 43368421 . Bettencourt, Michael J. RPA 090946 - Acute Toxicity to Mysid Shrimp ( Mysidopsis bahia ) Under Flow-Through Conditions. Study Completion Date: June 28, 1994. Laboratory: Springborn Laboratories, Inc. Sponsored by Rhone-Poulenc Company. Laboratory Report ID: 94-6-5311.

MRID 43368422 . Bettencourt, Michael J. RPA 090946 - Acute Toxicity to Sheepshead Minnow ( Cyprinodon variegatus ) Under Flow-Through Conditions. Study Completion Date: July 21, 1994. Laboratory: Springborn Laboratories, Inc. Sponsored by RhonePoulenc Company. Laboratory Report ID: 94-7-5373.

MRID 43368450 . Hoberg, James R. Title: RPA 090946 - 5-day Toxicity to the Freshwater Green Alga, Selenastrum capricornutum . Study Completion Date: 29 March 1994. Laboratory: Springborn Laboratories, Inc. Sponsor: Rhone-Poulenc Ag Company Laboratory Report ID: 94-4-5250.

MRID 43868309. Machado, Mark W. RPA 090946 - Th e Toxicity to Fathead minnow (Pimephales promelas) during an Early Life-Stage E xposure. Study Completion Date: June 22, 1995

. Laboratory: Springborn Laboratories, Inc., Wareham, MA. Laboratory Report ID: 95-5-5884. Sponsored by Rhone -Poulenc Ag Company, Sophia Antipolis,

France.

MRID 43868318. Hoberg, James R. RPA 090946 - De termination of Effects on Seed Germination, Seedling Emergence and, Vegetati ve Vigor of Ten plant Species. Study Completion Date: January 19, 1995. Laborat ory: Springborn Labor atories, Inc., Wareham, MA. Sponsored by Rhone-Poulenc Ag Co mpany, Research Triangle Park, NC. Laboratory Report ID: 94-10-5490.34 MRID 43868319. Hoberg, James R. RPA 90946 - Toxi city to the Freshwater Diatom, Navicula pelliculosa . Study Completion Date: July 11, 1995. Laboratory: Springborn Laboratories, Inc., Wareham, MA. Spons or: Rhone-Poulenc Ag Company, Research Triangle Park, NC

. Laboratory Report ID: 95-6-5895.

MRID 43868320. Hoberg, James R. RPA- 090946 - T oxicity to the Freshwater - BlueGreen Alga, Anabaena flos-aquae . Study completion Date: July 11, 1995. Laboratory: Springborn Laboratories, Inc., Wareham, MA. Sponsored by Rhone-Poulenc Ag Company, Research Triangle Park, NC. Laboratory Report ID: 95-6-5883.

MRID 4386832. Hoberg, James R. RPA 090946 - Toxicity- to Duckweed, Lemna gibba . Study Completion Date: July 13, 1995. Laboratory: Springborn Laboratories, Inc., Wareham, MA. Sponsored by Rhone-Poulenc Ag Company, Research Triangle Park, NC. Laboratory Report ID: 95-6-5922.

MRID 43868322. Hoberg, James R. RPA 090946. Toxi city to the Marine Diatom,
Skeletonema costatum . Study completion Date: July 14, 1995. Laboratory: Springborn Laboratories., Wareham, MA. Sponsored by: Rhone-Poul enc Ag Company, Research Triangle Park, NC. Labora tory. Report ID: 95-6-5913.

MRID 43868323. Hoberg, James R. EXP-31039B - Determination of Effects on Seedling Emergence and Vegetative Vigor of Ten Plant Species. Study Completion Date: July 17
, 1995

. Laboratory: Springborn Laborator ies, Inc., Wareham, MA. Sponsored by Rhone-Poulenc Ag Company, Re search Triangle Park, NC. Laboratory Report ID: 95-5-5867.

MRID 43868324. Petto, Ralf. Laboratory Testing for Toxicity (Acute Contact and Oral

LD 50 ) of RPA 090946 to Honeybees ( Apis mellifera L.)(Hymenoptera, Apidae). Study Completion Date: July 28, 1994. Laborator y: RCC Umweltchemie GmbH & Co KG, Rossdorf, Germany. Laboratory Report ID: 463700. Sponsored by Rhone-Poulenc Agro, Lyon Cedex, France.

MRID 43876701. Mc Elligott, A.:RPA 090946 - Daphnia magna Life Cycle (21-Day Static Renewal) Chronic Toxicity Study. Study Completion Date: July 7, 1995. Laboratory: Rhone-Poulenc Agrochimie. Centre de Recherche, Sophia Antipolis, France. Sponsored by Rhone-Poulenc Ag Company. Re search Triangle Park, NC. Laboratory Report ID: SA 95206.

MRID 44518602. Teixeira, D. EXP-31039C - Determination of Effects on Seedling Emergence of Two Plant Species and Vegeta tive Vigor of Ten Plant species. Study Completion Date: March 10, 1998. Laboratory: Springborn Labor atories, Inc., Wareham, MA. Sponsored Rhone-Poulenc Ag Company, Research Triangle Park, NC. Laboratory Report ID: 97-12-7199.35 

### Appendix A. PRD Data Reques t Justification Tables
(1) Ecological Data

Guideline Number: 850.2100 Study Title: Passerine Acute Avian Oral Rationale for Requiring the Data Although an acute avian oral study was received for the bobwhite quail, the Agency updated its data requirements in 40 CFR Part 158 (October 26, 2007) to include an acute oral toxicity study for both a passerine species and either a waterfowl or an upland game species. Furthermore, the submitted mallard acute oral study did not achieve an LD 50 due to regurgitation issues. Prior to starting toxicity testing, a protocol will need to be provided for review.

o Many passerine species utili ze agricultural fields, fo rests, residential areas and surrounding areas, and, therefore, ha ve the potential to be exposed to pesticides used in agricultural, forest, and residential settings

 It is likely that, for most pesticid e use patterns, passerines are more likely to be exposed to pesticid es than upland game species and
waterfowl

o Passerines are smaller and have faster metabolisms than the waterfowl and upland game bird species traditionally used in avian toxicity tests which could impact their sensitivity to chemicals. Practical Utility of the Data How did the Agency make its registr ation decision without these data? Since this is a new requirement, EPA was using th e results from the toxicity tests for the upland gamebird species (Note: A study on a waterfo wl species was submitted but did not achieve an

LD 50 ).

How will the data be used? Data from passerine toxicity studies will be used to estimate potential risks to birds associated with uses of cyclanilide. The data will reduce uncertainties associated w ith the current risk assessment for passerine species and will improve our understanding of the potential effects of cyclanilide.

How could the data impact the Agency’s future decision-making? Because birds significantly contribute to overall environmental quality, a solid understanding of the potential risks to birds, including passerine species, is essential for sound environmental management. Without acceptable data for cyclanili de, the Agency cannot determine the levels of cyclanilide that result in effects to passerine species. The lack of these data will limit the flexibility the Agency and registrants have in coming into compliance with the Endangered Species Act, and could result in use restrictions for cyclanilide which may otherwise be avoided, or which are unnecessarily severe.36 Guideline Number: 850.1400 Study Title: Fish Early Life Stage (saltwater) Rationale for Requiring the Data Cyclanilide has the potential to enter estuarine/marin e water bodies based on current usage patterns that include coastal areas. As cotton is grown mostly in the southeastern United States and in many areas along the Mississippi River, the potential for cyclanilide to enter estuarine/marine water bodies via spray drift or run exists. Furthermore, hydrolysis studies have shown cyclanilide to pe rsist in water for more than 50 days which is far greater than the ≥ 4 days half-life requirement of necessitating the study in 40 CFR Part

158.

Practical Utility of the Data How did the Agency make its re-registrat ion decision without this data? Previous risk assessments noted that the extremely lo w (ppb) concentrations of cyclanilide in the water based on current use patterns yielded RQs several magnitudes of order below the chronic LOC for freshwater species. Chronic risk to marine/estuarine remained un-estimated.

How will the data be used? The estuarine/marine fish early life stage study would allow the Agency to an alyze chronic effects, including effects on reproductive success and growth, to estuarine/marine fish. The effects data would be
used to determine the likelihood that the chronic ri sks can potentially impact aq uatic communities, either by direct effects on fish or by indirect effects via invertebrates by reducing their food sources.

How could the data impact the Agency’s future decision-making? If future endangered species risk assessments are perfo rmed without these data, the Agency would have to assume that cyclanilide "may affect" endangered fish directly (and endangered species from other taxa indirectly), and use of cyclanilide might need to be restricted in areas where endangered species could be exposed. The lack of these data will limit the flexibility the Agency and registrants have in coming into compliance with the Endangered Species Act and could r esult in use restrictions for cyclanilide which are unnecessarily severe.

Guideline Number: 850.1350 Study Title: Aquatic Invertebrate Life-Cycle (saltwater) Rationale for Requiring the Data The acute toxicity of cyclanilide to estuarine/marine i nvertebrates indicates the potential for chronic risk to animals in this taxon, and the potential for chronic ex posure exists. Cyclanilide has the potential to enter estuarine/marine water bodies based on current usage pa tterns that include coastal areas. Furthermore, hydrolysis studies have shown cyclanilide to persist in water for more than 50 days which is far greater
than the ≥ 4 days half-life requirement of necessitating the study in 40 CFR Part 158. Practical Utility of the Data How did the Agency make its re-registrat ion decision without this data? Previous risk assessments noted that the extremely lo w (ppb) concentrations of cyclanilide in the water based on current use patterns yielded RQs several magnitudes of order below the chronic LOC for freshwater species. Chronic risk to marine/estuarine remained un-estimated.

How will the data be used? The aquatic invertebrate life-cycle study would allow the Agency to analyze chronic effects, including effects on reproductive success and growth, to saltwater inve rtebrates. The effects data would be used to determine the likelihood that the chronic risks can poten tially impact aquatic communities, either by direct effects on invertebrates or by indirect effects on fish by reducing their food sources.

How could the data impact the Agency’s future decision-making?37 If future endangered species risk assessments are perfo rmed without these data, the Agency would have to assume that cyclanilide "may affect" endangered inve rtebrates directly (and endangered species from other taxa indirectly), and use of cyclanilide might need to be restricted in areas where endangered species could be exposed. The lack of these data will limit the flexib ility the Agency and registrants have in coming into compliance with the Endangered Species Act and could r esult in use restrictions for cyclanilide which are unnecessarily severe. (2) Fate & Transport Data

Guideline Number: 835.6100 Study Title: Environmental Chemistry Method and Associated Independent Laboratory Validation
for soil Rationale for Requiring the Data Previously submitted study needed to be upgraded for determining this chemical and major degradate in
soils. Practical Utility of the Data

How will the data be used? Data will be used to determine levels of cyclanilide and its major degradate in soils with high precision, accuracy, and appropriate detection/ quantification limits. In addition, the method should be validated by an independe nt laboratory. State- of the-art and validated analytical method is required in order to have it available for the pu blic to be used in dete rmining the concentration of the chemical and its major degradate in soils . Also the method is to be used in fate and transport studies to determine cyclanilide and/or major degradate following application to soil in
addition to monitori ng and/or spills.

Guideline Number: 835.6200 Study Title: Environmental Chemistry Method and Associated Independent Laboratory Validation
for water Rationale for Requiring the Data No method or validation was submitted for determining this chemical and major degradate in water. Practical Utility of the Data

How will the data be used? Data will be used to determine levels of cyclan ilide and its major degradate in water with high precision, accuracy, and appropriate detection/ quantification limits. In addition, the method should be validated by an independe nt laboratory. State- of the-art and validated analytical method is required in order to have it available for the pu blic to be used in dete rmining the concentration of the chemical and its major degradate in water. Also the method is to be used in fate and transport studies to determine cyclanilide and/or major degradate following application to soil in
addition to monitori ng and/or spills.

Guideline Number: 835.4100 Study Title: Aerobic soil metabolism Rationale for Requiring the Data In the registration review risk assessment, the Agency will consider parent plus degradate as the stressor. However, current data on the degradation profile of cyclanilide in aerobic soil systems suggests formation of a major degradate, 2, 4-dichloroaniline metabolite. Metabolite 2, 4- dichloroaniline contain its parent’s moiety and appears to be persistence in at least one of the two soil systems examined. Data is needed to c onfirm persistence/non-pers istence of the main degradate and confirm complete ex traction of residues left in th e soil and considered to be bound
residue. Practical Utility of the Data

How will the data be used?38 Additional aerobic soil metabolism data will facilitate a better understanding of the fate of cyclanilide and the degradation profile in the most important compar tment of the environment (the soil system). The soil system is expected to eventua lly receive applied pesticide.

How could the data change the Agency’s decision or impact the Agency’s future decision-making? In the absence of the required data, cyclanilide degrad ation profile will be assumed, conservatively, to include the major soil degradate in addition to the assumption that it is as toxic as the parent. Therefore, the expected environmental concentration will be muchhigher because it will be based on the total residue of concern (parent + degradate) and consequently Risk quotient will be higher resulting in possibly conclusions of higher risk.