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Page 2 of 69 Tralo pyril Registration Review Team

Human Health Timothy Dole Jonathan Chen
Zo e Layton

Environmental Fate and Effects Zoe Layton Srinivas Gowda James Breithaupt Siroos Mostaghimi

Risk Management Wanda Henson Rose Kyprianou Marshall Swindell

Office of Genera l Counsel Philip Ross

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Page 3 of 69 

### Table of Contents

1 Introduction

................................ ................................ ................................ ............................. 5 1.1 Statutory and Regulatory Authority

................................ ................................ ................. 5 1.2 Updates to the Work Plan

................................ ................................ ................................ . 7 1.3 Case Overview

................................ ................................ ................................ ................. 7 1.4 Chemical Identification and Properties

................................ ................................ ............ 8 1.5 Use/Usage Description

................................ ................................ ................................ ... 10 1.5.1 Registrations

................................ ................................ ................................ ........... 10 1.5.2 Usage Information

................................ ................................ ................................ .. 11 1.6 Regulatory History

................................ ................................ ................................ ......... 11 1.6.1 Recent/Pending Regulatory Actions

................................ ................................ ....... 12 1.6.2 Toleranc e Information

................................ ................................ ............................ 12 1.7 Incidents

................................ ................................ ................................ ......................... 12 1.7.1 Human Health

................................ ................................ ................................ ......... 12 1.7.2 Ecological

................................ ................................ ................................ ............... 12
2 Anticipated Data Needs

................................ ................................ ................................ ........ 12 3 Human Health Risk Assessment

................................ ................................ ........................... 15 3.1 Exis ting Toxicological Endpoints

................................ ................................ .................. 15 3.2 Dietary Exposure

................................ ................................ ................................ ............ 17 3.2.1 Food

................................ ................................ ................................ ............................ 17 3. 2.2 Drinking Water

................................ ................................ ................................ ........... 17 3.3 Occupational and Residential Exposures

................................ ................................ ....... 18 3.3.1 Occupational Handler Exposure

................................ ................................ ............. 18 3.3.2 Residential Handler Exposures

................................ ................................ ............... 20 3.3.3 Residential Post

- Application Exposures

................................ ................................ ...... 20 3.4 Aggregat e and Cumulative Exposure

................................ ................................ ............. 21 3.4.1 Aggregate Exposures

................................ ................................ .............................. 21 3.4.2 Cumulative Exposures

................................ ................................ ............................ 21
4 Environmental Risk Assessment

................................ ................................ ........................... 21 4.1 Environmental Fate and Exposure Pathways

................................ ................................ . 22 4.2 Ecological Effects Assessment

................................ ................................ ....................... 25 4.2.1 Mode of Action

................................ ................................ ................................ ....... 25 4.2.2 Measures of Effect (Ecotoxicology Assessment Endpoints)

................................ .. 25 4.3 Exposure Analysis Plan

................................ ................................ ................................ .. 30 4.3.1 Aquatic and Terrestrial Wildlife Exposure Estimates

................................ .................. 30 5 Endocrine Disruptor Scre ening Program (EDSP)

................................ ................................ . 31
6 Optional Label Changes

................................ ................................ ................................ ........ 32
7 Next Steps

................................ ................................ ................................ ............................. 32 8 Ref erences

................................ ................................ ................................ ............................. 32

Appendix A T oxicology Profile

................................ ................................ ............................... 40 Appendix B Environmental Fate

................................ ................................ ............................. 47 Appendix C Ecotoxicology Profile

................................ ................................ .......................... 55 Appendix D Comments Received Concerning the Preliminary Work Plan

............................ 65

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Page 4 of 69 List of Tables Table 1

– Summary of Anticipated Risk Assessments and Data Needs: Tralopyril

...................... 6 Table 2

– Anticipated Registration Review Schedule

................................ ................................ .... 7 Table 3

– Chemical Identification of Tralopyril

................................ ................................ ............. 8 Table 4

– Physical

- Chemical Properties for Tralopyril

................................ ................................ . 9 Table 5

– Chemical and Physical Properties of Tralopyril Degradates

................................ ........ 10 Table 6

– Distribution of Products by Specific Alkylbenzene Sulfonate

................................ ..... 11 Table 7

– Summary of Tralopyril Registered Uses

................................ ................................ ...... 11 Table 8

– Studies Anticipated as Needed for the Registration Review of Tralopyril

................... 13 Table 9

– Existing Toxicological Endpoints for Dietary Exposure to Tralopyril

......................... 16 Table 10

– Existing Toxicological Endpoints for Occupational/Residential Exposure to Tralopyril

................................ ................................ ................................ ................................ ...... 16 Table 11

– Occupational Handler Exposure Scenarios for Tralopyril

................................ .......... 19 Table 12

– Residential Handler Exposure Scenari os for tralopyril

................................ .............. 20 Table 13

– Selected Effects Endpoints for the Ecological Risk Assessment of Tralopyril

.......... 26 Table 14

– Selected Eff

ects Endpoints for the Ecological Risk Assessment of Tralopyril's Major Degradate CL322,250

................................ ................................ ................................ ................... 27 Table 15

– Selected Effects Endpoints for the Ecological Risk Assessment of Tralopyril's Major Degra date CL322,248

................................ ................................ ................................ ................... 29 Table 16

– Acute Toxicity Data for Tralopyril

................................ ................................ ............. 40 Table 17

– Summary of parent tralopyril half

- lives and degradate am ounts and half

- lives in environmental fate studies

................................ ................................ ................................ ............ 49 Table 18

– Sorption (Kf/Koc) of parent tralopyril and its main degradates

................................ . 50 Tab le 19

– Physical

- Chemical Properties for Tralopyril and its Primary Metabolites

................. 50 Table 20

– Reviewed and Accepted Paint Leaching Studies for Tralopyril in Seawater

............. 51 Table 21

– Toxicity Profile of Tralopyril Parent and Degradates to Birds

................................ ... 56 Table 22

– Toxicity Profile of Tralopyril Parent and Degradates to Freshwater Fish, Acute and Chronic

................................ ................................ ................................ ................................ .......... 57 Table 23

– Toxicity Profile of Tralopyril Parent and Degradates to Freshwater Invertebrates, Acute and Chronic

................................ ................................ ................................ ........................ 58 Table 24

– Toxicity Profile of Tralopyril Parent and Degradates to Estuarine and Marine Fish, Acute and Chronic

................................ ................................ ................................ ........................ 59 Table 25

– Toxicity Profile of Tralopyril Parent and Degradates to Estuarine an d Marine Invertebrates, Acute and Chronic

................................ ................................ ................................ . 60 Table 26

– Toxicity Profile of Tralopyril Parent and Degradates to Benthic Invertebrates, Freshwater and Estuarine/Marine

................................ ................................ ................................ . 62 Table 27

– Toxicity Profile of Tralopyril Parent and Degradates to Terristrial/Semi Aquatic Plants

................................ ................................ ................................ ................................ ............. 62 Table 28

– Toxicity Profile of Tralopyril Parent and Degr adates to Aquatic Plants

.................... 63

List of Figures Figure 1

– Conceptual Model for Ecological Exposure and Effects of Tralopyril to Aquatic Organisms from the Antifoulant Use

................................ ................................ ............................ 25

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Page 5 of 69 

# 1 Introduction

This document is the Environmental Protection Agency’s (EPA or “the Agency”) Preliminary Work Plan (PWP) for tralopyril

. This case was originally titled “econea” and has since been renamed “tralopyril” to replace the trade name with the generic active ingredient name. The PWP document explain ed what EPA's Office of Pesticide Programs knows about tralopyril

, highlighting anticipated data and assessment needs, identifying the types of information that would b e especially useful to the Agency in conducting the review, and providing an anticipated timeline for completing tralopyril ’s review. This work plan addresses public comments received concerning the PWP, which was posted in the t ralopyril registration rev iew docket (EPA

- HQ

OPP

- 2013

- 0217) on June 26, 2013

. A public comment period was initiated, which concluded on August 26, 2013. Further, this document makes final the work plan for the t ralopyril registration review process.



## 1.1 Statutory and Regulatory Author ity

The Food Quality Protection Act (FQPA) of 1996 mandated a registration review program. All pesticides distributed or sold in the United States generally must be registered by the U.S. Environmental Protection Agency (USEPA, EPA, or the Agency) based on scientific data showing that they will not cause unreasonable risks to human health or the environment when used as directed on product labeling. The registration review program is intended to make sure that, as the ability to assess risk evolves and as p olicies and practices change, all registered pesticides continue to meet the statutory standard of no unreasonable adverse effects to human health or the environment. Changes in science, public policy, and pesticide use practices will occur over time. Thro ugh the registration review program, the Agency periodically reevaluates pesticides to make sure that as change occurs, products in the marketplace can be used safely. Information on this program is provided at http://www.epa.gov/oppsrrd1/registration_review/

.
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 pesti cide every 15 years to determine whether it continues to meet the FIFRA standard for registration. The regulations governing registration review begin at 40 CFR 155.40. The Agency will consider benefits information and data as required by FIFRA. The public phase of registration review begins when the initial docket is opened for each case. The docket is the Agency’s opportunity to state what it knows about the pesticide and what additional risk analyses and data or information it believes are needed to make a registration review decision.

Documents associated with this registration review can be viewed at http://www.regulations.gov in docket EPA

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- 0217 . Below is a summary of the issues relevant to this registration review case.

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Page 6 of 69 Table 1

– Summary of Anticipated Risk Assessments and Data Needs : Tralopyril

Risk Assessment Assessment Necessary to Support Registration Review Date of Most

Recent Assessment Type of

Assessment Required (New/Updated) Data Anticipated as Needed

(See Table 8 for more detail about anticipated data needs)

Dietary (food) No N/A None None

Dietary (drinking water) Yes 4/16/ 20 08 Updated Developmental Toxicity (non

- rodent) Reproductive Toxicity Chronic Or al Toxicity Cancer Study

Occupational Handler Yes 2/15/2007 Updated Dermal Exposure, Outdoor Inhalation Exposure , Outdoor

Residential Handler Yes 4/10/2008 Updated Dermal Exposure, Outdoor Inhalation Exposure , Outdoor
Aggregate Yes None New Non e

Cumulative No None None None

Tolerance Review No N/A None None

Ecological Yes 4/24/2007 Updated Leaching data in fresh water (special study) for parent tralopyril ( anticipated study will need to address CL 322,250)

Avian reproduction study with tralopyril

Acute zebra fish study or a rainbow trout fish early life stage study with tralopyril (data from the parent expected to be used as surrogate for major degradates)

Freshwater benthic invertebrate chronic reproduction study one with an amphipod and one with a chironomid for the parent (special study a )

Saltwater benthic invertebrate with an amphipod for CL 322,250 (special study a )

pKa values for CL 322,250 and CL 322,248

Log Kow values for CL 322,250, CL 322,248, and CL 325,195

N/A = Not appli cable

a The anticipated Data Call

- In Notice (DCI) will provide that protocols need to be required to be submitted for review prior to conduct of the study. Because of the photodegradation potential, The anticipated DCI will require that sediment in test v essels should be shielded to reduce bias from laboratory lighting and design.

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Page 7 of 69 Table 2

– Anticipated Registration Review Schedule

Anticipated Activity Target Date * Completion Date Phase 1: Opening the Docket Open Docket and 60

- Day Comment Period for Preli minary Work Plan 201 3

- 06 2013

- 06

- 26
Close Public Comment Period 2013

- 08 2013

- 08

- 26 Phase 2: Case Development
Issue Final Work Plan 2013

- 12
Issue Data Call

- In (DCI) 2014

- 12
Receive Data to be Considered in Risk As sessment 2017

- 12 Open 30

- Day Public Comment Period for Preliminary Risk Assessment(s) 2019

- 06
Close Public Comment Period 2019

- 07 Phase 3: Registration Review Decision and Implementation Open 60

- Day Public Comment Period for Pro posed Decision 2019

- 12
Close Public Comment Period 2020

- 02
Issue Final Decision 2020

- 06 Begin Post

- Decision Followup 2020 Total (years) 7

* The anticipated schedule will be revised as necessary ( e.g ., need arising under the Endocrine Disruptor Screening Prog ram with respect to the active ingredients in this case).



## 1.2 Updates to the Work Plan

Since the publication of the PWP, the agency has made the following updates:

Added this section “ Updates to the Work Plan. ” Updated the dates in Table 2. Removed study entit led “In vitro Salmonella typhimurium Reverse Mutation Assay” from Table 8. Updated Table 13 to include an additional acute toxicity study in the rat per response to public comments.
Removed the Guidance for Commenters Section

. Added Appendix D “Comments Re ceived Concerning the Preliminary Work Plan.”
Added other minor edits to the Final Work Plan

.
The Agency received fourteen comment s on the initial docket. The comment s received changed the data requirements (see above ) and timeline described in the PWP. A summary of the

comment s received and the Agency’s responses are presented in Appendix D

.



## 1.3 Case Overview

The docket for t ralopyril (Case 5114 ) has been established at http://www.regulations.gov in docket number EPA

- HQ

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- 2013

- 0 21 7.

Tralopyril is registered for use as antifoulant in paint for both recreational and commercial vessels in fresh and salt water. There are two technical products that contain 93.2 and 99 percent tralopyril and seven end use products that contain 2.9 to 7.28 percent tralopyril. One of the end use products contains only tralopyril and the other products also contain zinc pyrithione (ZPT).

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Page 8 of 69 The products can be applied by brush, roller and airless sprayer. Two or three coats are
recommended for best performance.

Some of the tralopyril end use products that contain ZPT prohibit airless sprayer application by residential (non

- commercial) users and require that residential users apply no more than one coat within a 24 hour time period. The se restrictions are based on the ZPT RED (not based on tralopyril). All products are antifouling paints registered for use on ships hulls and bottoms and are applied using an airless spray gun system.



## 1.4 Chemical Identification and Properties

Table 3 p resents the two active ingredients to be assessed in Case 4006: Sodium dodecylbenzene sulfonate (PC Code: 079010) and Dodecylbenzene sulfonic acid (PC Code: 098002). The major difference between these actives are the ions on the sulfonate groups which are sodium versus hydrogen respectively, both ionize. ABS product chemistry information relevant to risk assessment is summarized in Table 3

. Table 3

– Chemical Identification of T ralopyril

C ommon Name Tralopyril

C hemical Name s 1H

- Pyrrole

- 3

- c arbonitrile,4

- bromo

- 2

- (4

- chlorophenyl)

- 5

- (trifluoromethyl)

- ; Pyrrole

- 3

- carbonitrile, 4

- bromo

- 2

- (p

- chlorophenyl)

- 5

-

(trifluoromethyl) ; 2

- (p

- chlorophenyl)

- 3

- cyano

- 4

- bromo

- 5

- trifluoromethyl pyrrole ; Tralopyril

Classification Halogenated Pyrrole Nitrile

PC Co de 119093
CAS No. 122454

- 29

- 9
Molecular Formula C 12 

### H 5 

### BrClF 3 

### N 2 

### Molecular Weight 349.53 g/mol

Available B romine 45.72%

Available C hlorine 20.28%
Available F luorine 32.62%

Molecular Structure:

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Page 9 of 69 The parent tralopyril product chemistry information (so urce: MRIDs 45673902, 456739 03, 456739 06, 45673907 and 48596802) relevant to risk assessment is summarized in Table 4 and details of the environmental fate properties are discussed in Appendix B

.

Table 5 below co ntains the chemical and physical properties of the tralopyril degradates CL 322,250, CL 322,248, and CL 325,195.

Table 4

– Physical

- Chemical Properties for T ralopyr il

Guideline Number Physical and Chemical Properties Value

830.150 0 Product Identity and Composition Refer to Table 3
830.1650 Description of Formulation Process Confidential Business Information (CBI)
830.1800 Enforcement Analytical Method HPLC Method M

- 3408.01

830.6302 Color Pale yellow

- brown Beige White powder Off

- White powder

830.6303 Physical State Powder Solid at room temperature.
830.6304 Odor Slightly sweet, marzipan

- like odor

830.6313 Stability to normal and elevated

temperature, metals/metal ions The test substance was stable after incubation for 14 days a t 54 C and is stable in the presence of copper and iron.

830.6314 Oxidation/Reduction:

Chemical Incompatibility: Oxidizer. Materials to avoid: Strong Oxidizing Agents.
830.6315 Flammability The TGAI is not combustible/flammable.
830.7000 pH 5.16 (0.1% w /v dispersion in dist. water).

830.7050 UV/Visible Absorption The wavelengths of maximum absorbance are as follows: 281.4, 281.9, and 223.9 for acidic, neutral and alkaline conditions, respectively.

830.7200 Melting point Examination of the differential scanning calorimetry endotherms with programmed heating indicated that melting starts at 252.3 C (525.5 K), with a peak at
253.4 C (526.6 K). No decomposition was observed at temperatures below 400 C.
830.7220 Boiling point Not applicable (TGAI is solid)

. 830.7300 Density 1.714 g/cm 3 at 20oC
830.7370 Dissociation Constant in water pKa = 7.08 at 26 C

830.7550 Partition coefficient ( n

octanol/water) Log K

ow 3.5

830.7840 Solubility in water Water solubility by column elution at 20 C: 0.17 mg/L in unadjus ted water (nominal pH of 4.9) and 0.16 mg/L in seawater (nominal pH of 8.1).

830.7860 Solubility in Organic solvents at 20°C Acetone 300.5 g/L Ethyl acetate 236.0 g/L

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Page 10 of 69 Guideline Number Physical and Chemical Properties Value

n

- Heptane 7.2 g/L Methanol 109.1 g/L

n

- Octanol 85.2 g/L Xylene 5.6 g/L

830.7950 Vapor p ressure 1.42 x 10 - 10 mm Hg at 20 C
3.45 x 10 - 10 mm Hg at 25 C



### Table 5

– Chemical and Physical Properties of Tralopyril Degradates

Degradate Name CL 322,250 (parent compound minus three fluorines forming a carboxylic acid by hydrat ion) CL 325,195 (D ebrominated parent compound with hydration forming a ketone and an ortho hydroxylated trifluoromethyl

group) CL 322,248

( Debrominated C L 322,250 )

Inert PC Code 619094 619093 NA
Chemical Family Pyroles Pyroles Pyroles

Molecular Formula C 11 H 6 Br 1 CL 1 N 2 C 12 H 6 F 3 ClN 2 O 2 C 11 H 7 CLN 2 Molecular Weight g/ml 281.54 302.64 248.67

Molecular Structures:

Log P (Log Kow) 3.72 2 4.17 2 1.68 2

Solubility in water mg/l 5.63 17.95 476

Vapor pressure mm Hg at
25 C 7.62 x 10 - 7 3.45 x 10 - 9 7.0 x 10 - 11

Henry’s Law ( m 3 mol - 1 ) 5 x 10 - 8 7.65 x 10 - 11 4.8 x 10 - 14

References: EPI Suite 4.1;
1 Values used in Henry’s Law Calculations
2 These EPI

- Suite 4.1 values for Log P are questionable because the experimental log P value for parent traloyril with 3 fluorines a nd 1 bromine was 3.5 (MRID 45673906). The loss of halogens results in compounds that are more water soluble and therefore the log P is expected to be lower because of preferential partitioning into the water phase

.


## 1.5 Use/Usage Description

1.5.1 Registrations

Ther e are 11 registered products that contain tralopyril. The products are presented in Table 6

. Most of the products are powder and solid at room temperature

.

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Page 11 of 69 Table 6

– Distribution of Products by Specific Alk ylbenzene Sulfonate

Chemical
Name PC

Code % ai Formulations Registered Products

Tralopyril 119093 2.9

- 99% Soluble Concentrate; Ready to Use 577

- 570, 2693

- 220, 2693

- 230, 7313

- EA, 9339

- GG, 43813

- 27, 43813

- 52,44891

- 19, 60061

- 134, 60061

- 137, 74681

- 28



### A listing of the registered uses of tralopyril is included in Table 7

. Tralopyril is registered for use as antifoulant in paint for both recreational and commercial vessels in fresh and salt water. There are two technical product s that contain 93.2 and 99 percent tralopyril and nine end use products that contain 2.9 to 7.28 percent tralopyril. One of the end use products contains only tralopyril and the other end use products also contain zinc pyrithione (ZPT). The products can be applied by brush, roller and airless sprayer. Two or three coats are recommended for best performance.

Some of the tralopyril end use products that contain ZPT prohibit airless sprayer application by residential (non

- commercial) users and require th at residential users apply no more than one coat within a 24 hour time period. These restrictions are based on the ZPT RED (not based on tralopyril). All products are antifouling paints registered for use on ships hulls and bottoms and are applied using an airless spray gun system.

Table 7

– Summary of Tralopyril Registered Uses

Use Application Method Amount Ai in Paint Paint Coverage
Boats, ships, hull bottom Brush, Roller, Airless Sprayer 2.9 to 7.28 percent 267 to 528 ft 2 /ga llon



### 1.5.2 Usage Information

According to the Section Seven Tracking System (SSTS) database

, the production volume for tralopyril is less than 20,000 kg per year for the years 2008 to 2011.



## 1.6 Regulatory History

The first product containing t ralopyril (Econe a®)

, 4

- bromo

- 2

- (4

- chlorophenyl)

- 5

- (trifluoromethyl)

- 1H

- pyrrole

- 3

- carbonitrile , was received in May of 2002 as a technical product with approved uses to formulate a non

- copper based antifoulant coating. The first end use and
technical product s containing tr alopyril were registered in 2007. There are currently 2 technical
and 9 end use products with t ralopyril as an active ingredient. There are currently no outstanding
Data Call

- In data requirements for this active ingredient. There are no products containing this ingredient as an inert ingredient.

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Page 12 of 69 

### 1.6.1 Recent/Pending Regulatory Actions

There are currently no product s containing tralopyril awaiting a registration decision

.



### 1.6.2 Tolerance Information

There are no tolerances or exemptions from tolerances for tralopyri l because there are no currently registered uses for this active ingredient associated with food or feed.



## 1.7 Incidents

1.7.1 Human Health
The Incident Data System (IDS) of The Office of Pesticide Programs (OPP) of Environmental Protection Agency (EPA) contain s rep orts of incidents from various sources, including registrants, other federal and state health and environmental agencies and individual consumers, submitted to OPP since 1992. As of June 4, 2013, n o incident s have been reported in IDS associated with tral opyril use from 1992 to the present

.



### 1.7.2 Ecological
No tralopyril ecological incidents have been reported in the Agency’s Ecological Incident Information System (EISS) for the time period spanning 2005 to 2012.



# 2 Anticipated Data Needs

Table 8 presents a summary of the data anticipated as being needed to support this registration
review.

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Page 13 of 69 Table 8

– Studies Anticipated as Needed for the Registration Review of Tralopyril

GLN Study Name Test Substa nce Time Frame

(Measured in months from DCI Receipt) Risk Assessment(s)

Data Will Support Use Site(s)

Triggering Anticipated Data Requirement Applicable Exposure Scenario s

Studies Anticipated to be Required through the Registration Review DCI

875.12 00 887.1400 Outdoor Exposure, Dermal

Outdoor Exposure, Inhalation tralopyril 36 Occupational Handler Residential Handler Antifoulant Paint Airless Spray Application by Commercial Painters Brush/Roller Application by Do it Yourself Painters

870.3700 De velopmental T oxicity

(non

- rodent species) tralopyril 24 Drinking Water Antifoulant Paint (Fresh Water Uses) Oral exposures to drinking water

contaminated with tralopyril or its degradates.

870.3800 or OECD 443 5 Reproductive Toxicity tralopyril
24 Drinkin g Water Antifoulant Paint (Fresh Water Uses) Oral exposures to drinking water

contaminated with tralopyril or its degradates

.

870.4100 C hronic O ral Toxicity tralopyril
36 Drinking Water Antifoulant Paint (Fresh Water Uses) Oral exposures to drinking wate r

contaminated with tralopyril or its degradates

.

870.4200 Cancer Study tralopyril
36 Drinking Water Antifoulant Paint (Fresh Water Uses) Oral exposures to drinking water

contaminated with tralopyril or its degradates

. 850.1075 or 850.1400 Acute (zebra f ish) or Early

life Stage (rainbow trout) tralopyril 24 Ecological Antifoulant paint (Fresh water Uses) Exposure of aquatic organisms to tralopyril

or its degradates in surface water

Special Study 1 Whole sediment; chronic

invertebrates freshwater (2 specie s

— 1 amphipod and 1 chironomid) tralopyril 24 Ecological Antifoulant paint (Fresh and salt water uses) Exposure of aquatic organisms to tralopyril

or its degradates in sediment

Special Study 2 Whole sediment, chronic

marine invertebrate (1 species

- amphipo d) CL 322,250 24 Ecological Antifoulant paint (Salt water uses) Exposure of saltwater benthic organisms to

its degradates in sediment

850.2300 Avian Reproduction tralopryil 24 Ecological Antifoulant paint (Fresh water uses) Exposure of aquatic organisms t o tralopyril

or its degradates in surface water

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Page 14 of 69 GLN Study Name Test Substa nce Time Frame

(Measured in months from DCI Receipt) Risk Assessment(s)

Data Will Support Use Site(s)

Triggering Anticipated Data Requirement Applicable Exposure Scenario s

Special Study 3 Leaching from antifoulant

paint in freshwater EP (monitor tralopyril and degradates) 12 Ecological Antifoulant Paint (Fresh Water Uses) Oral exposures to drinking water

contaminated with tral opyril or its degradates

.

Exposure of aquatic organisms to tralopyril or its degradates in surface water.
830.7550 or 830.7560 or 830.7570 4 Log Kow CL 322,250 CL 322,248 CL 325,195 12 Ecological Antifoulant Paint (Fresh and salt water use) Exposure of aquatic organisms to tralopyril

degradates in surface water

1 Based on log P (Log Kow) of >3, Koc values of 5,571

- 23,150 ml/g, and a half

- life of >10 days.

2 Th e anticipated DCI requiring this special study will require the submission of a protocol for re view prior to conduct of the study.

3 The registrant has not submitted any data on leaching of tralopyril and its degradates in freshwater. All submitted leaching data employed artificial seawater and the Agency assumes that boats currently in ocean w ater can be transported and used in freshwater, creating exposure. Leaching data are anticipated to be needed for each registered paint.

4 The EPI

- Suite 4.1 values are questionable because the experimental log P value for parent tralopyril with 3 fluorine s and 1 bromine was 3.5 (MRID 45673906). The loss of halogens to form the degradates results in compounds that are more water soluble than the parent compound, and therefore are more likely to have a lower log P value than the parent compound

. 5 EPA consid ers the OECD Extended One

- Generation Reproductive Toxicity Study (OECD 443) to be an acceptable substitute for GLN 870.3800 Two

- Generation Reproduction.

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Page 15 of 69 

# 3 Human Health Risk Assessment

EPA anticipates the need to revise the existing toxicological endpo ints as part of this registration review. Table s 9 and 10 presents the endpoints used in EPA’s most recent human health risk

assessment s.



## 3.1 Existing Toxicological Endpoints

Several toxicological studies were identified as data gaps and as anticipated data needs for registration review based on currently registered uses. All available information including existing toxicology studies, valid scientific literature, and the studies that are expected to be required for registration review will be considered in e stablishing the endpoints to be used in the registration review risk assessment. The following issues regarding these endpoints will also need to be addressed:

The inhalation exposures were assessed in the initial registration decision using an endpoint o f 5.7 mg/kg/day that was converted from a 90 day inhalation toxicity study in rats where the LOAEL was 20 mg/m 3 

### based on portal of entry effects. This conversion was made so that the PHED unit exposure data, which are reported in terms of exposure

per am ount of ai handled, could be used. During registration review an inhalation exposure study, where the exposures are reported in terms of air concentration, will be used and these exposures will be assessed using a human equivalent concentration (HEC). It is estimated that the HEC would equal 24 mg/m 3 

### using the formula HEC= LOAEL * 6 hours/8 hours * RDDR where the RDDR = 1.57. It also estimated that the level of concern for the uncertainty factor would be 100 which would include the standard factors of 3 and 10 normally associated with an HEC and an additional factor of 3 for the lack of a NOAEL. Dividing the HEC of 24 mg/m 3 

### by the uncertainty factor of 100 yields an “RfC” of 0.24 mg/m 3 

### as an eight hour TWA. This Rfc value would most likely be used to assess inhalation exposures for occupational handlers. Dermal exposures were assessed in the initial registration decision using an endpoint of 1000 mg/kg/day for systemic effects from a dermal toxicity study. This endpoint will not be used during registr ation review because dermal exposures are not normally assessed when the NOAEL is at the limit dose. It will be necessary; however, to the assess irritation effects that are represented by the NOAEL of 100 mg/kg/day for the appearance of sores that were o bserved at the LOAEL of 300 mg/kg/day.

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Page 16 of 69 Table 9

– Existing Toxicological Endpoints for Dietary Exposure to Tralopyril

Exposure Scenario Dose Used

for Endpoint Uncertainty Factors for Risk Assessment Study and Toxicological Effe cts

Acute Dietary 6.3 mg/kg/day

(LOAEL, Females) 10X intraspecies,

10X intraspecies, 3X conversion of the LOAEL to a NOAEL

Acute RfD = 6.3 mg/kg/day

10 x 10 x 3

= 0.021 mg/kg/day Subchronic (90) Day Oral LOAEL = 6.3 mg/kg/day (LDT) for females based on microscopic findings of the brain and spinal cord. NOAEL could not be determined in the females. LOAEL = 16.2 mg/kg/day in males. NOAEL = 5.2 mg/kg/day
Chronic Dietary (general

popu lation) 6.3 mg/kg/day

(LOAEL, Females) 10X intraspecies,

10X intraspecies, 3X conversion of the LOAEL to a NOAEL 10X data base uncertainty (missing chronic study and a neurotoxicity study)

Chronic RfD = 6.3 mg/kg/day

10 x 10 x 10 x 3

= 0.0021 mg/kg/day Subchronic (90) Day Oral LOAEL = 6.3 mg/kg/day (LDT) for females based on microscopic findings of the brain and spinal cord. NOAEL could not be determined in the females.
LOA EL = 16.2 mg/kg/day in males. NOAEL = 5.2 mg/kg/day



### Table 10

– Existing Toxicological Endpoints for Occupational/Residential Exposure to Tralopyril

Exposure Scenario Dose Used in Risk Assessment Target MOE for

Risk Assessment Stu dy and Toxicological Effects
Dermal* Short

- Term (1

- 30 days) and Intermediate

- Term (1

– 6 months) NOAEL = 100mg/kg/day Target MOE = 100 (10x interspecies extrapolation, 10x intraspecies variation+. Subchronic (90 Day) Dermal LOAEL = 300 mg/kg/day ba sed on the appearance of

sores

Dermal* Long

- Term (6 months

– lifetime) Risk assessment was not required based for this use pattern because long term exposures are not anticipated.

Inhalation

Short

- Term (1

- 30 days) and Intermediate Term (1

– 6 months) NOAEL could not be calculated ( <20mg/m 3 ) (LDT). Target MOE = 300

10x interspecies extrapolation, 10x intraspecies variation, 3x conversion of LOAEL to NOAEL Subchronic (90 Day) Inhalation Toxicity (Phase I)

LOAEL is 20

- mg/m 3 based chronic and subacute inflammation, ulcerations, exudates, epithelial hyperplasia, hyperkeratosis and de

generation of the olfactory epithelium in the nasal section
N1 to N3

. Decreased body weight gain was also seen at this dose level.
Inhalation Risk assessment not required based for this use pattern

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Page 17 of 69 Long

- Term (6 months

– lifet ime)
Cancer No cancer data available
*Note

- The toxicological endpoint for dermal systemic effects will not be used for registration review because it was based on a NOAEL of 1000 mg/kg/day which was the highest dose tested.



## 3.2 Dietary Exposure

3. 2 .1 Food
There are no food uses for tralopyril . T herefore

, EPA does not anticipate the need to conduct a dietary (food) risk assessment.



### 3. 2 .2 Drinking Water

The U.S. EPA conducted a drinking water asse ssment in 2008 and results were summarized in a memorandum dated April 16, 2008 1 

### . The results of both acute and chronic assessments for all subpopulations were below 20% of the aPAD or cPAD. Drinking water exposures to water containing tralopyril residue s from the antifouling paint uses were not considered of concern at that time. After reviewing the 2008 risk assessment

, the Agency has concluded that it is necessary to update the previous drinking water assessment. This is due to advances in the scient ific tools and models available to the Agency since conducting the 2008 assessment . A summary of planned revisions to the drinking water assessment are as follows:

More recent version of DEEM

- FCIDTM: The 2008 memo states that the risk assessment was conducted using the Dietary Exposure Evaluation Model (DEEM

FCIDTM, Version 2.02) DEEM

- FCIDTM which uses food and drinking water consumption data from the U.S. Depar tm ent o f Agriculture’s Continuing Surveys of Food Intakes by Individuals (CSFII) for 1994

- 1996 and 1998. A newer version (3.18) of DEEM

- FCIDTM is currently available 2

, 3 

### that contains more recent food commodity consumption data derived from the National Health and Nutrition Examination Survey/”What We Eat in America” for 2003

- 2008 4



### .

A newer version of MAM

- PEC (3.0) 5 

### is currently available. The most recent version will be used to estimate refined drinking water residue values.

Drinking water residue values wi ll be further updated based on the development of a freshwater lake scenario in MAM

- PEC . The 2008 memo states that the drinking water residue estimate used as an input into DEEM

- FCIDTM was determined using Version 1.6 of the Marine Antifoulant Model to Predict Environmental Concentrations (MAM

- PEC) for the primary degradation products of tra lopyril, CL 322,250 and CL

1 U.S. EPA (United States Environmental Protection Agency). 2008. An AD Memo from Talia Lindheimer to Marshall Swindell on “Acute and Chronic Drinking Water Exposure and Risk Assessment for the Registration Action of tralopyril (EP A Reg. #2693

- 200)”, April 16, 2008.

2 http://www.epa.gov/opp00001/science/deem/

3 http://www.epa.gov/oppfead1/cb/csb_pa ge/updates/2012/deem

- fcid.hl

4 http://www.cdc.gov/nchs/nhanes.h

5 http://www.deltares.nl/en/software/1039844/mampec/1232321

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Page 18 of 69 322,248. MAM

- PEC is an integrated hydrodynamic and chemical fate model that provides predictions of environmental concentrations of antifouling products in various aquatic environments. The model has traditionally focused on si x “typical” marine environments, which were used in the 2007 ecological risk assessment and 2008 drinking water assessment. However, the Agency is in the process of developing a fresh water lake scenario which will allow the Agency to update the drinking water residue values as appropriate.

Availability of freshwater leaching data : due to the development of a fresh water lake scenario in MAM

- PEC, the Agency expects to refine the MAM

- PEC model estimations using freshwater leaching data. It has been dete rmined that in order to properly address the potential freshwater risk, leaching data in fresh water are anticipated to be required for parent tralopyril as well as its two primary degradates (CL 322,250 and CL 322,248). Once received and reviewed, the fr eshwater leaching data will be used to estimate refined drinking water residue values.

Availability of anticipated chronic/cancer study will further allow for a refined drinking water assessment.

The fate properties of tralopyril used in the drinking wat er assessment are summarized in a 2008 memorandum 6



### .



## 3.3 Occupational and Residential Exposures

Occupational and residential exposures are anticipated during the application of tralopyril containing antifoulant paints to commercial vessels and pleasure craft. The Agency assessed these exposures in 2007 prior to the registration of these paints

. H owever, t he Agency anticipates the need to revise the se assessments because they relied upon use assumptions , unit exposure values and toxicological endpoints that need to be updated. These assessments will need to be reassessed using the updated values . Outdoor Dermal (875.1200) and Inhalation (875.1400) Exposure studies are anticipated as being needed to supply the updated unit exposure values.



### 3.3.1 Occupational Hand ler Exposure
Occupational handler dermal and inhalation ex posures to tralopyril were assessed for handlers spraying antifoulant paint products onto ships 7 

### . This assessment was based on a product (Sigma Nexxum 20) which contained 3.4 percent tralopyril and had coverage of 220 feet ft 2 

### /gallon at 4 mils dry thickness. The inhalation and dermal exposures were assessed using PHED unit exposure data for the airless sprayer scenario. The inhalation unit exposures were adjusted using protection factors of 10, 50 and 100 for half face air purifying respirators, full face powered air purifying respirators (PAPR) and full face supplied air respirators. The dermal unit exposures

6 U.S. EPA (United States Environmental Protection Agency). 2008. An AD Memo from James Breithaupt to Marshall Swindell entitled, “Environmental Fate Assessment of EconeaTM Technical for New Registration as Antifoulant in Fresh Water”, April 1, 2008.

7 Tralopyril Occupational Exposure Re

- Assessment Using a Revised Dermal Toxicity Endpoint: Update of November 15, 2006 Review for a New Active Ingredient, 1H

- Pyrrole

- 3

- carbonitrile, 4

- bromo

- 2

- (4

- chlorophenyl)

- 5

- (trifluoromethyl)

, (a.k.a., tralopyril ), Proposed as an An tifoulant D295928, D327535, D327536 & D330452, 2/15/2007.

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Page 19 of 69 were adjusted using factor of 2 to account for the use of tyvek coveralls. The amount o f paint handled was assumed to be either 14 gallons based on a submitted assessment or 50 gallons based on generic information from the ACC. The dermal MOEs ranged from 87 to 830 and exceeded the target 100 for both use estimates (i.e. 14 or 50 gallons) i f gloves were worn. The inhalation MOEs ranged from 7 to 6000 and exceeded 100 only if the two highest levels of respiratory protection (Full face PAPR or full face SAR) were worn.

The labels generally require dermal PPE (i.e. gloves) that yield dermal MOEs of 100 but they do not require respiratory protection that yields MOEs of 100. Some labels do not require any respiratory protection even though they allow spray application. Some labels only specify that a “mask” should be worn while others have th e statement “commercial users must wear a respirator with an organic vapor removing cartridge with a pre

- filter approved for pesticides (MSHA/NIOSH APPROVAL NUMBER TC

- 14G) or a NIOSH approved full face respirator with an organic removing cartridge with a P

- 100 prefilter”. Because the general phrase “a respirator” does not itself specify the type of respirator, a worker could wear a half face respirator which yields an MOE of 60, and still be in compliance with certain labels. It is recommended that the la bels be revised to state that full face respirators with organic vapor cartridges and P

- 100 prefilters are required for spray applications.

The occupational handler exposures listed in Table 11 will need to be reassessed during registration review to accou nt for the following factors that have changed:

The product assessed at the time of registration (11350

- GL: Sigma Nexxium 20 Antifouling) had 3.4 percent tralopyril 7 

### . Since that time other products have been registered that have as much as 7.28 percent tr alopyril.

The assessment was done using PHED unit exposure data for airless spraying. These data were based on studies where airless spraying of houses was conducted. In 2007, EPA received a worker exposure study of shipyard painting operations. The uni t exposures from this study range from 2.7 to 113 ug/m 3 

### per lb ai handled when expressed as an 8 hour time weighted average (TWA) and some are above the PHED unit exposure of 48 ug/m 3 

### /lb ai expressed as an 8 hour TWA.

The amount of paint handled was assume d in the occupational exposure assessment 7 

### to be either 14 gallons based on an observational study submitted by the registrant (MRID 468466

- 02) or 50 gallons based on a standard AD assumption that had been derived from an industry estimate provided by the American Chemistry Council in 2005. In comparison, the amount handled in the ZPT shipyard study ranged from 12 to 83 gallons with an average of 35 gallons.

Table 11

– Occupational Handler Exposure Scenarios for T ralopyril

Scenario Exposure Route(s) Duration Airless Sprayer Application of Antifoulant Paint Inhalation Short, Intermediate, and Long Term

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Page 20 of 69 

### 3.3.2 Residential Handler Exposures

Residential handler dermal and inhalation ex posures to tralopyril were assessed for the applica tion of tralopyril antifoulant paint products onto pleasure craft 8 

### . This assessment was based a product (2693

- 220, Trilux White Antifouling Paint) that contains 3.9 percent tralopyril. The dermal exposures were assessed using PHED unit exposure data for the brush/ roller scenario and the inhalation exposures were assessed using data from a literature study 9 

### . The amount of paint handled was based on the hull sizes of 14, 20 and 30 feet, coverage of 400 ft 2 

### per gallon and one to three coats painted within a 24 hour period. The dermal MOEs ranged from 360 to 4,300 without gloves and the inhalation MOEs ranged from 2,400 to 21,000 without respiratory protection.

The residential handler dermal exposures listed in Table 10 will need to be reassessed during

r egistration review to account for the following factors that have changed:

The product assessed at the time of registration had 3.9 percent tralopyril. Since that time other products have been registered that have as much as 7.28 percent tralopyril.

The dermal exposure assessment will need to be done with a more representative exposure study, MRID 465118

- 01 which was done on residential yacht painters. The mean dermal unit exposures from this study are 312 mg/lb ai with long sleeved shirt, long pants an d no gloves and 41 mg/lb ai with long sleeved shirt, long pants and gloves. These values are greater than the corresponding PHED unit exposures for brush/roller applications of 180 mg/lb ai and 24 mg/lb ai.

Dermal exposures were assessed using an endpoint of 1000 mg/kg/day for systemic effects from a dermal toxicity study. This assessment may need to be repeated to account for the dermal irritation NOAEL of 100 mg/kg/day which is from the same study where sores were observed at a LOAEL of 300 mg/kg/day.

Table 12

– Residential Handler Exposure Scenarios for tralopyril

Scenario Exposure Route(s) Duration Applying Paint Using Brushes and Rollers Dermal Short Term



### 3. 3 .3 Residential Post

- Application Exposures

Because tralopyri l is used only as an antifoulant paint, residential post application exposures are not anticipated.

8 Residential Exposure and Risk Assessment of the End Use Product, Trilux 44

– White Antifoulant Paint, (EPA Reg. No. 2693

- 220) Containing 3.9% of the Active Ingredient, 1 H

- Pyyrole

- 3

- carbonitrile, 4

- bromo

- 2

- (4

- chlorophenyl)

- 5

- (trifluoremethyl), as an Antifoulant in Paint for Pleasure Craft and Do

- it

- Yourself Applications, D384689, 4/10/ 2008. 9 Potential Exposure of Amateurs (Consumers) through Painting Wood Preservative and Antifoulant Preparations

. Garrod ANI, Guiver R, Rimmer DA. Annals Occupational Hygiene, Vol. 44, No. 6, pp.421

- 426. (MRIDs 462444

- 21 and 473073

- 08)

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Page 21 of 69 

## 3.4 Aggregate and Cumulative Exposure

3.4.1 Aggregate Exposures

Prior to the registration of tralopyril, assessments were conducted for dietary exposures from drinkin g water and for dermal and inhalation exposures from residential handler application of paints to pleasure craft; however, an aggregate assessment was not conducted. Upon a reevaluation and selection of toxicological endpoints, combined with the updated h uman health exposure assessments expected as a part of this registration review case, aggregate exposures

may need to be assessed. This assessment may include dietary ( drinking water ) exposures and residential exposures.



### 3.4.2 Cumulative Exposures

With respect to cumulative exposure, unlike other pesticides for which EPA has followed a cumulative risk approach based on a common mechanism of toxicity, EPA has not made a common mechanism of toxicity finding as to tralopyril and any other substances

, and tralopyri l does not appear to produce a toxic metabolite produced by other substances. For the purposes of this registration review, therefore, EPA has not assumed that tralopyril has a common mechanism of toxicity with other substances. For information regarding E PA’s efforts to determine which chemicals have a common mechanism of toxicity and to evaluate the cumulative effects of such chemicals, see http://www.epa.gov/pesticides/cumulative/

. 

# 4 Environmental Ri sk Assessment

The Agency conducted an ecological hazard assessment and environme ntal risk characterization for tralopyril and its degradates in April of 2007 10 

### as part of the new use registration as an antifoulant

. The 2007 risk assessment was not refined and therefore an endangered species effect determination was not made at the time of registration. The Agency will conduct a comprehensive updated ecological risk assessment for the antifoulant use of tralopyril.

The Agency anticipates needing the foll owing data in order to conduct a complete ecological risk assessment for tralopyril, including an endangered species assessment:

(OPPTS GLN 850.2300) Avian Reproduction

(OPPTS GLN 850.1075 or 850.1400) Acute Freshwater Fish Toxicity with Zebra fish or Fis h Early

- Life Stage with Rainbow Trout

(Special Study) Whole Sediment; Chronic Invertebrates Freshwater and Marine

Leaching from antifoulant paint in fresh water (EP with monitoring of tralopyril and its major degradates)

10 U.S. EPA (2007). An AD Memo from Richard Petrie to Marshall Swindell entitled EconeaTM (tralopyril) Antifoulant New Chemical Registration, Ecological Hazard Assessment and Environmental Risk Characterization (PC Code: 119093).

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Page 22 of 69 Log Kow (Log P) data for CL 322,250 , CL 322,248, and CL 325,195

To fill toxicity data gaps remaining for tralopyril’s major degradates CL322,250 and CL322,248, they will be assumed to be as toxic as the parent compound.

The Agency has not conducted a risk assessment that supports a compl ete endangered species determination. The planned update to the ecological risk assessment conducted during registration review will allow the Agency to determine whether tralopyril’s use has 'no effect' or 'may affect' federally listed threatened or enda ngered species (listed species) or their designated critical habitats. If the assessment indicates that tralopyril (parent and degradates/metabolies) “may affect” a listed species or its designated critical habitat, the assessment will be refined. A

mor e refined assessment involve s clear delineation of the action area associated with proposed use of tralopyril antifoulant and use of best available information on the temporal and spatial co

location of listed species with respect to the action area. 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 and/or National Marine Fisheries Services (the Services), as appropriate.



## 4.1 Env ironmental Fate and Exposure Pathways

A previous environmental risk assessment for ecological exposure to freshwater aquatic organisms (MRID 47301601) was submitted and reviewed. The 2007 risk assessment (MRID 47301601) assessed use in fresh water and sea water settings. Three different aquatic models were used to predict expected environmental concentrations (EEC’s) in harbors, marinas, bays, and channels in U.S. waters ; the assessment included application to naval vessels, commercial ships, cruise ships , and pleasure craft . Model runs submitted were reviewed for co mpleteness and accuracy by the Agency. Marine Antifouling Model to Predi ct Environmental Concentrations (MAM PEC) Model results , which had the highest EECs (Barbours Point
M arina, Houston) wer e used in the 2007 risk assessment.

Since the 2007 risk assessment, a further review indicates that additional information on environmental fate and ecological toxicity for parent tralopyril is needed to assess the risk to endangered and threatened feder ally listed ( i.e ., listed) species. Further review of the environmental fate studies indicates that the freshwater leaching rate used in the assessment was found not to be supported by any data in the Agency’s records. All submitted studies on the
leachi ng rate of parent tralopyril and its degradates were for salt water and not fresh water. In addition, an erroneous log Kow (log P) value of 3 for parent tralopyril was reported in place of the correct log Kow value of 3.5 and the log Kow of the CL 322,250 , CL 322,248, and CL 325,195 degradates needs to be submitted. These log Kow values will be used in modeling. Also, the stability of the degradates in sediment raises concerns over reproductive effects for aquatic benthic invertebrates but only subchroni c (10

- day) study results are available. The Agency plans to conduct an endangered species risk assessment that addresses the lack of leaching data for fresh water, the erroneous and missing log Kow values, and the lack of reproductive data.

Once parent tralopyril is released from the paint matrix into water, it is expected to form the primary and major degradate CL 322,250 (defluorinated parent compound)

. Aquatic exposure

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Page 23 of 69 will be primarily from the CL 322,250 degradate, which is more persistent than pa rent tralopyril 11 

### . Another major degradate, debrominated CL 322,250 (CL 322,248), is formed under anaerobic conditions (representing bottom sediment) and in saltwater conditions and did not degrade 12 

### . The study results may be seen in Table 17

.
Degradation of parent tralopyril produces compounds of different chemical and physical properties. The degradates have lower molecular weight, higher water solubility, and lower log Kow (Log P) values. Therefore, they would be expected to be present in water with a higher water:sediment ratio than parent tralopyril. Based on the molecular weights, vapor pressures, Henry’s Law constants, and study results (MRIDs 45673910, 45673911, 45673912, EPI

- Suite 4.1), neither parent tralopyril nor its degradates are expected to volatilize from water ( Table 19 ).

Parent tralopyril and its degradates are expected to be present in both the water and sediment compartments in water bodies. Parent tralopyril will continually leach and any organisms present will be exposed to the parent compound and its degradates. The exposure in the water column is expected to be higher in marinas with boat storage than in open water because of boat density, the constant presence of sitting boats, and the lack of water exchange because of a low flushing rate in some cases. However, the sorption based on suspended sediment in marinas is likely to reduce these water concentrations 13 

### . The limited depth in a marina relative to the op en water will mean that boat propellers will stir up sediment which will sorb aqueous residues of tralopyril and its degradates.

The registrant has submitted a bioconcentration in fish study (MRID 48680501) for parent tralopyril which has not been formall y reviewed but will be reviewed in Registration Review. The study reports bioconcentration factors (BCFs) of 3.2

- 32X (unitless) in carp at acid conditions, which are below the pKa of 7.08. As a result, the tralopyril was not ionized and would have had ma ximum bioconcentration. The pKa is not likely to change significantly for the major degradates because they retain the nitrile group which carries the pKa. The CL 322,250 degradate was not found based on persistence of parent tralopyril under acid condit ions.

A large number of ecotoxicity studies for tralopryil and it s degradates were submitted. The deterministic risk assessment us ed the maximum expected environmental concentration ( EEC ) and toxicity endpoints for avian species, fish, invertebrates, estuarine/marine species, sediment dwelling species, and plants to generate risk quotients for the degradates CL 322,250 and CL 322,248 (debrominated CL 322,250). Some limited ecotoxicity studies were submitted for the minor degradate 325,195 (debrominat ed parent tralopyril), however the 325,195 degradate is not a concern due to its relatively low rate of formation ( < 7.1 % of applied) 14 

### and low toxicity to test species (see Appendix C ). Terrestrial bird, mammal, or plant expo sure is not expected to occur to any great extent for antifoulants because the treated paint stays at or below the water line. However, the risk to waterfowl exposed to tralopryil and degradates through feeding were

11 MRIDs 45673908, 45673909, 45673910, 45673911, 45673912

12 MRID 45673910

13 MRIDs 45673913, 45673914

14 MRID 45673910 contained the maximum formation (7.1 % of applied tralopyril) of all environmental fate studies. Degradates formed at <10 % of applied parent compound are considered to be “minor” (5/10/11 memorandum from Don Brady, Environmental Fate and Effect s Division, Guidance for Determining Pesticide Residues of Concern in Drinking Water in Coordination with the HED ROCKS )

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Page 24 of 69 assessed based on avian concerns when c ompounds similar to tralopryil are used in agricultural fields.

As an antifoulant, parent tralopyril can leach from treated boat paints and degrades primarily to CL 322,250, defluorinated parent compound, in the environment. Cl 322,250 is more persistent and more mobile than parent tralopyril and will be the primary compound to which aquatic organisms are exposed Because pesticide residues have the potential to reach the habitat of aquatic organisms, it is necessary to determine the risk to aquatic fish, invertebrates, and plants that may occur from parent tralopyril and its degradates. An ecological conceptual model summarizing exposure pathways for tralopyril and its reaction products/degradates is provided in Figure 1.

In Figure 1 all lines for leaching of parent tralopyril and its metabolites are solid, indicating that environmental exposure is expected to occur primarily from parent tralopyril and the degradate/metabolite CL 322,250. The lines representing exposure from dow n

- the

- drain exposure leading into wastewater treatment plants (WWTPs) are dashed because all paints containing tralopryil are solvent based (not water based) and cannot be released into a wastewater treatment plant 15 

### . Exposure to total tralopyril residues (parent and degradates) will occur in both water and sediment 16 

### . In addition, the degradate debrominated CL 322,250 (CL 322,248) is expected to be present in anaerobic (representing sediment) and in saltwater conditions 17



### .
The registrant has submitted le aching data from antifoulant paints for parent tralopyril and degradates in salt water, but not from freshwater, and freshwater leaching data are required to assess the potential for effects on Federally

- listed species. The Agency assumes that tralopyril can be used to treat freshwater and marine ships and boats, and that treated boats can be used in both freshwater and saltwater. Leaching of tralopyril (parent and CL 322,250) from 19 antifoulant paints in salt water ( Table 20 ) w as observed at maximum rates of 2.2

- 48 ug/cm 2 

### /day 18 

### . However, the registrant assumed a leaching rate of 4 ug/cm 2 

### /day for the parent compound in freshwater in the risk assessments contained in MRIDs 47250101 and 47301601. Based on this assumed parent leach ing rate (4 ug/cm 2 

### /day), the registrant

- calculated leaching rates for the CL 322,250 and CL 322,248 degradates of 3.84 and 3.456 ug/cm 2 

### /day. These degradate leaching rates were based on the maximum percent formation of 96 and 86 % in the environmental fat e studies 19 

### . When compared to the actual maximum leaching rates (19 total), the assumed fresh water leaching rate of 4 ug/cm 2 

### /day for parent tralopyril was lower than 18 of the 19 observed maximum rates and lower than 17 of the 19 observed average and mini mum rates. Therefore, any predictions of the extent of leaching and ecological and drinking water exposure using the 4 ug/cm 2 

### /day value are likely to be underestimates.

15 http://des.nh.gov/organization/commis sioner/pip/factsheets/hw/documents/hw

- 29.pdf

16 MRIDs 45673910, 45673911, 45673912, 45673913, 45673914

17 MRID 45673910

18 MRIDs 48734904 , 48734905, 48734906, 48734907, 47500201, 45673201, 46934508, 47238912, 47550801, 47554203, 48297806, and 49046003

19 MRI Ds 45673908, 45673909, 47128801

, 45673910 , 45673911, 45673912, 45673913, 45673914.

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Page 25 of 69 Figure 1

– Conceptual Model for Ecological Exposure and Ef fects of Tralopyril to Aquatic Organisms from the Antifoulant Use



## 4.2 Ecological Effects Assessment

The ecological effects assessment evaluates the potential for adverse effects as a result of tralopyril’s use as an antifoulant. As described in the Agency’s O verview Document (U.S. EPA, 2004), the most sensitive endpoint for each taxa is evaluated. Assessment endpoints include direct toxic effects on the survival, reproduction, and growth of terrestrial and aquatic life, as well as indirect effects, such as re duction in prey base and/or modification of habitat. The evaluated taxa include birds, freshwater and marine/estuarine fish, freshwater and marine/estuarine aquatic invertebrates, small mammals, benthic freshwater and marine/estuarine invertebrates, algae , and terrestrial plants.

Acute (short

- term) and chronic (long

- term) toxicity information was characterized based on registrant

- submitted studies. A summary of the available ecotoxicity information are provided in this preliminary work plan. Table 13

, Table 14 , and Table 15 summarize the most sensitive ecological toxicity endpoints based on an evaluation of the submitted studies.



### 4.2.1 Mode of Action

The mode of action is being reviewed to determine if a total toxic residue approach will be taken.



### 4.2.2 Measures of Effect (Ecotoxicology Assessment Endpoints)

Current selected ecotoxicological endpoints are summarized in Table 13

, Table 14 , and Table 15

. A more detailed description of the ecotoxicity studies are provided in Appendix C

.

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Page 26 of 69 Table 13

– Selected Effects Endpoints for the Ecological Risk Assessment of Tralopyril

Receptor Group Surrogate Species Risk Scenario Study Duration Toxicity

Endpoint Classification Reference

Terrestrial Animals : Birds Northern Bobwhite

( Colinus virginianus ) Acute Oral 14

- Day LD 50 = 24.7;

NOEL = 6 (mg ai/kg

- bw ) Acceptable M RID 43492809

Mallard Duck (

Anas platyrhynchos ) Subacute (Dietary) 10

- Day LC 50 = 10.76;

NOEL = 5.62 (mg/kg

- diet ) Acceptable MRID 46596005

Data Gap: Avian Reproduction

Aquatic Animals: Freshwater Fish Rainbow Trout

( Oncorhynchus mykiss ) Acute 96

- Hou r LC 50 = 1.3;

NOEC = 0.68 (μg a.i. /L) Acceptable MRID 46596002

Chronic 1 Data Gap: Early life stage with Rainbow Trout

( Oncorhynchus mykiss ) or Acute Zebra Fish 1 ( Danio rerio )

Aquatic Animals : Freshwater Invertebrates Water Flea ( Daphnia

magna ) Acute 48

- Hour EC 50 = 1.5

μg a.i. /L Acceptable MRID 46596001

Chronic 21

- Day N OEC = 0.20

μg a.i. /L Acceptable MRID 46596004

Aquatic Animals : Marine/Estuarine Fish Sheepshead Minnow

( Cyprinodon variegatus ) Acute 96

- Hour LC 50 = 23.71

μg a.i. /L Acceptable MRID 45674003

Chronic 34

- Day NOEC = 4.3

μg a.i. /L Acceptable MRID 45674007

Aquatic Animals : Marine/Estuarine Invertebrates Mysid

( Americamysis bahia ) Acute 96

- Hours LC 50 = 0.98

μg a.i. /L Acceptable MRID 45674006

Chronic 28

- Day NOEC = 2.28

μg/L Accepta ble MRID 44911101 Eastern Oyster ( Crassostrea virginica ) Acute (Shell

Deposition) 96

- Hour EC 50 = 0.64

μg a.i. /L Acceptable MRID 46751305

Aquatic Animals: Freshwater Benthic Invertebrates Two species

( Hyalella azteca and Chironomous sp.) Chronic Data G ap: Freshwater benthic invertebrate

Aquatic Animals: Estuarine /Marine Benthic Invertebrates Amphipod

( Leptocheirus plumulosus ) Chronic Not Anticipated to be Needed for Parent: In Estuarine/Marine environment the parent is highly unstable, data with stable degradate are anticipated to be needed

Aquatic Plants:
Non

- Vascular Marine Diatom

( Skeletonema

costatum ) Non

- listed 96

- hour I C 50 = 2.7 ; Acceptable MRID 46619901 Listed 96

- hour NOAEC = 1.5

μg/L

Aquatic Plant s : Vascular Duckweed ( Lemna

gibba) Non

- listed 7

- day I C 50 = 87.2 μg a.i. /L Acceptable MRID 45674116 Listed 7

- day NOAEC = 22

μg a.i. /L

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Page 27 of 69 Receptor Group Surrogate Species Risk Scenario Study Duration Toxicity

Endpoint Classification Reference

Aquatic Rooted Plant Rice ( Oryza sativa ) Seedling Emergence
Non

- listed 14

- day I C 25 = 170 μg

a.i. /L Acceptable MRID 45674115
Listed 14

- day NOAEC >

170 μg a.i. /L

Terrestrial Mammal Rat Acute (Oral) N/A L D 50 = 27.0 mg/kg 2 Acceptable MRID 43492824

Chronic N/A Not Required

1 Rainbow trout was the most acutely sensitive species tested. Because there can be wide differences in species sensitivity a chronic value is needed for this species so that chronic risk is not underestimated. This anticipated data requirement may be met by either a fish early stage chronic value for rainbow trout or a fathead minnow acute value which can be used along with the existing fathead minnow early life stage test to derive an acute

- to

- chronic ratio (ACR) which can be applied to the rainbow trout acute value to estimate a rainbow trout chronic value.

2 To asses risk to terrestrial animals ingesting water or food cont aminated with econea a value from available data will be used as a surrogate.



### Table 14

– Selected Effects Endpoints for the Ecological Risk Assessment of Tralopyril's Major Degradate CL322,250

Receptor Group Surrogate Species Risk Scenario Study

Duration Toxicity

Endpoint Classification/

Comments Reference

Terrestrial Animals : Birds Mallard Duck

( Anas platyrhynchos ) Subacute

(Dietary) 11

- Day LC 50 = 962;

NO A EL = 250 (mg /kg diet ) Acceptable MRID 46596013

Aquatic Animals : Freshw ater Fish Rainbow Trout

( Oncorhynchus mykiss ) Acute 96

- Hour LC 50 = 520;

NOAEC = 320 (ppb) Acceptable/

updated from 2007 risk assessment MRID

46596010

Chronic 1 ELS Data Gap: Early life stage with Rainbow Trout ( Oncorhynchus mykiss ) 1

Aquatic Animals : Freshwater Invertebrates Water Flea

( Daphnia magna ) Acute 48

- Hour EC 50 = 510;

NOAEC = 250 (ppb) Acceptable MRID 46596008

Chronic 21

- Day NOAEC = 300 ppb Acceptable MRID 46596011

Aquatic Animals : Marine/Estuarine Fish Sheepshead

Minnow ( Cyprinodon

v ariegatus ) Acute 96

- Hour LC 50 > 950 ; NOEC ≥ 950 ( ppb ) Supplemental/

For purposes of the risk assessment, the

non

- definitive LC 50 value will be used as the LC 50 value 2

. MRID

45674101

Chronic 34

- Day NOAEC = 240 ppb Acceptable MRID 45674106

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Page 28 of 69 Receptor Group Surrogate Species Risk Scenario Study

Duration Toxicity

Endpoint Classification/

Comments Reference

Aquatic Animals : Marine/Estuarine Invertebrates Mysid

( Americamysis bahia ) Acute 96

- Hour LC 50 = 550 ;

NOAEC = 330 (ppb ) Acceptable MRID 45674104

Chronic 28

- Day NOAEC = 82 ppb Acceptable MRID 46596012
Eastern Oyster ( Crassostrea virginica ) Acute (Shell

Deposition) 96

- Hour E C 50 = 310 ; NOEC = 46 (ppb ) Acc eptable MRID 45674103

Aquatic Animals: Freshwater Benthic Invertebrates -- Chronic Not anticipated to be needed. Data from tests with the parent will be used to assess risk to degradate in this case.

Aquatic Animals: Estuarine/Marine Benthic Invertebrat es Amphipod

( Leptocheirus plumulosus ) Chronic Data anticipated to be required. In seawater parent is not expected to be stable. CL322,250 is expected to be the compound present in sediments in seawater given its stability and Kd, Kow. No chronic reprod uction data are available.

Aquatic Plants:
Non

- Vascular Marine Diatom

( Skeletonema

costatum ) Non

- listed 96

- hour I C 50 = 660 ppb Acceptable MRID 46596014 Listed 96

- hour NOAEC = 500 ppb

Aquatic Plant: Vascular Duckweed ( Lemna

gibba) Non

- listed 7

- day I C 50 > 990 ppb Supplemental

— parent value will be used to conduct risk

assessment MRID

45674122 Listed 7

- day NOAEC = 530 ppb

Aquatic Rooted Plants Rice ( Oryza

sativa ) Seedling

emergence

non

- listed -- Not anticipated to be needed. Data from tests with

t he parent will be used to assess risk to degradate in this case. Listed

--

Terrestrial Mammals Rat Acute Oral N/A LD 50 = 2500 mg/kg Acceptable MRID 43492826

Chronic N/A Not anticipated to be required . Exposure not anticipated to be of chronic conce rn because neither parent n or degradate are expected to bioaccumulate. 3

1 No fish early life stage (ELS) test with the most acutely sensitive tested species , rainbow trout, is available . A chronic value for the rainbow trout is anticipated to be require d. The anticipated data requirement may be met in a number of ways such as submittal of a rainbow trout ELS test, or submittal of a zebra fish acute study to use in calculating a rainbow trout chronic NOAEC using an existing and acceptable zebra fish ELS test and an acute

- to

chronic ration (ACR) from the zebra fish data, or if no data are submitted, data from the parent will be used as a surrogate.

2 Without a definitive acute LC 50 or an acceptable limit test, risks may over estimated.

3 Based on Bioconcen tration factors (BCFs) of <32X (Level of concern is 1000X) [MRID 48680501].

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Page 29 of 69 Table 15

– Selected Effects Endpoints for the Ecological Risk Assessment of Tralopyril's Major Degradate CL322,248

Receptor Group Surrogate

Species Risk

Sc enario Study

Duration Toxicity Endpoint Classification Reference

Terrestrial Animals : Birds Mallard Duck

( Anas platyrhynchos ) Subacute

(Dietary) 8

- day L C 50 > 5620 ;

NOEC = 3160 ( ppm ) Acceptable MRID 46751310

Aquatic Animals : Freshwater Fish Rainbow Trou t

( Oncorhynchus mykiss ) Acute 96

- hour Data anticipated to be required. Based on available data from other species this degradate appears less toxic than the parent and CL322,250. For the risk assessment for a total toxic residue approach this degradate w ill be assumed to be as toxic as CL322,250.

Chronic 1 ELS Data anticipated to be required. Based on available

data from other species this degradate appears less toxic than the parent and CL322,250. For the risk assessment for a total toxic residue app roach this degradate will be assumed to be as toxic as CL322,250.

Aquatic Animals : Freshwater Invertebrates Water Flea

( Daphnia

magna ) Acute 48

- hour A supplemental study is available but because of study issues it is not suitable for use in the risk asses sment.

— Based on available data from other species this degradate appears less toxic than the parent and CL322,250. The CL322,250 value will be used to conduct risk assessment for this degradate.

Chronic 21

- day A supplemental study is available but bec ause of study

issues it is not suitable for use in the risk assessment.

— Based on available data from other species this degradate appears less toxic than the parent and CL322,250. The CL322,250 value will be used to conduct risk assessment for this degr adate.

Aquatic Animals : Marine/Estuarine Fish Sheepshead

Minnow ( Cyprinodon variegatus ) Acute 96

- hour LC 50 > 89,000 ppb Acceptable MRID 46751309

Chronic ELS Data anticipated to be required. Based on available

data from other species this degradate ap pears less toxic than the parent and CL322,250. For the risk assessment for a total toxic residue approach this degradate will be assumed to be as toxic as CL322,250.

Aquatic Animals : Marine/Estuarine Invertebrates Mysid

( Americamysis bahia ) Acute 96

- Hou r LC 50 = 4300 ppb Acceptable MRID 46751308

Chronic Data anticipated to be required. Based on available

data from other species this degradate appears less toxic than the parent and CL322,250. For the risk assessment for a total toxic residue approac h this degradate will be assumed to be as toxic as CL322,250.

Aquatic Animals: Freshwater Benthic Invertebrates -- Chronic Data anticipated to be required. Based on available data from other species this degradate appears less toxic than the parent and CL322,250. For the risk assessment for a total toxic residue approach this degradate will be assumed to be as toxic as CL322,250.

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Page 30 of 69 Receptor Group Surrogate

Species Risk

Sc enario Study

Duration Toxicity Endpoint Classification Reference

Aquatic Animals: Estuarine/Marine Benthic Invertebrates -- Chronic Data anticipated to be required. Based on available da ta from other species this degradate appears less toxic than the parent and CL322,250. For the risk assessment for a total toxic residue approach this degradate will be assumed to be as toxic as CL322,250.

Aquatic Plants: Algae Bluegreen Algae

( Anabaena flos

aquae ) Non

- listed IC 50 > 1000 ppb Supplemental

— CL 322,250 values will be used to conduct risk assessment MRID

45893904 Listed NOEC = 1000 ppb

Marine Diatom ( Skeletonema

costatum ) Non

- listed IC 50 > 1,200; NOEC = 160 (ppb) Supplemental

becaus e did not obtain definitive values

— will use this data if EEC values are lower otherwise will use CL322,250 data as surrogate MRID

45674127
Listed NOEC = 160 ppb

Aquatic Plant: Vascular Duckweed

( Lemna gibba) Non

- listed IC 50 > 930 ppb Supplemental b ecause did not obtain definitive values

— will use this data if EEC values are lower otherwise will use CL322,250 data as surrogate MRID

45674125

Listed NOEC > 930 ppb

Aquatic Rooted Plants Rice ( Oryza

sativa ) Seedling

emergence

non

- listed -- Not anti cipated to be needed. Data from tests with the

parent will be used to assess risk to degradate in this

case. Listed

--

Terrestrial Mammals Rat Acute Oral Data not anticipated to be required

Chronic Data not anticipated to be required



## 4.3 Exposure A nalysis Plan

4.3.1 Aquatic and Terrestrial Wildlife Exposure Estimates

The Agency in 2007 performed an ecological hazard and risk characterization for the use of tralopyril as an antifoulant. For assessment, the Agency used data based on two models which included MAMPEC (Marine Antifoulant Model to Predict Environmental Concentrations) and, EFDC ( Environmental Fluid Dynamic Code ). The environmental conditions for Barbours Cut (Houston), Baltimore Harbor (Maryland), and Norfolk Harbor/James River (Virgin ia) were used as inputs for running these models. The model simulations were used to estimate the concentrations of CL322,250 and CL 322,248 in the above harbor systems. The outputs from the

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Page 31 of 69 MAMPEC runs from the Barbours Point (Houston) were used for eco logical risk assessment of tralopyril. This assessment was focused on large ships only. The Agency has since developed a fresh water lake scenario for use of antifoulants. The Agency will reassess the fresh

- and saltwater exposure and risk to non

- liste d and listed species. The potential risk to endangered species was not addressed in previous assessment. To properly address the potential freshwater risk, leaching data in fresh water will be required for parent tralopyril as well as its two primary deg radates (CL 322,250, and CL 322,248).



# 5 Endocrine Disruptor Screening Program (EDSP)

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 e ndocrine 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 asse ss growth, developmental and reprod uctive effects in different taxonomic groups. As part of its 2008 reregistration decision for tralopyril , EPA reviewed these data and selected the most sensitive endpoints for relevant risk assessment scenarios from the

e xisting hazard database. However, as required by FFDCA section 408(p ), tralopyril 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 th rough 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 chemica ls. Between October 2009 and February 2010, EPA issued test orders/data call

- ins for the first group of 67 chemicals, which contains 58 pesticide active ingredients and 9 inert ingredients. A second list of chemicals identified for EDSP screening was pub lished on June 14, 2013 20 

### and includes some pesticides scheduled for registration review and chemicals found in water

. Neither of these lists should be construed as a list of known or likely endocrine disruptors.

20 See http://www.regulations.gov/#!documentDetail;D=EPA

- HQ

- OPPT

- 2009

- 0477

- 0074 for the final second list of chemicals.

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Page 32 of 69 For further information on the status of t he EDSP, the policies and procedures, the lists of chemicals, future lists, the test guidelines and the Tier 1 screening battery, please visit our
website. 21



# 6 Optional Label Changes

As discussed in Section 3.1.1., the Agency recommend s that labels be revise d to indicate that full face respirators with organic vapor removing cartridges and P

- 100 prefilters be required for spray applications.



# 7 Next Steps

A DCI will be developed regarding the data needs listed under Table 8 “Studies Anticipated as
Needed for th e Registration Review of Tralopyril ” of this document. The agency expects to issue the DCI in December 2014.



# 8 References

Best, S.; McGuire, G. (1999) Identification of Unknown Component Present in a Day 30 Surface Water Following Application of (Carbon

- 14)

- R107894 to Loamy Sand Sediment: Lab Project Number: 17802: 16787: 367605. Unpublished study prepared by Inveresk Research. 34 p. 45673912

Cafarella, M. (2005) R107894

- Acute Toxicity to Water Fleas, (Daphnia magna) Under Flow

Through Conditions. Projec t Number: 13751/6144, AGR/921. Unpublished study prepared by Springborn Smithers Laboratories. 66 p. 46596001.

Cafarella, M. (2005) R107894

- Full Life Cycle Toxicity Test with Water Fleas, Daphnia Magna, Under Flow

- Through Conditions. Project Number: 13 751/6145, AGR/922. Unpublished study prepared by Springborn Smithers Laboratories. 81 p. 46596004

Cafarella, M. (2005) CL322,250

- Acute Toxicity to Water Fleas, (Daphnia Magna) Under Flow Through Conditions. Project Number: 13751/6151, AGR/925. Unpublis hed study prepared by Springborn Smithers Laboratories. 68 p. 46596008.

Cafarella, M. (2005) CL322,250

- Full Life

- Cycle Toxicity Test with Water Fleas, Daphnia magna, Under Flow

- Through Conditions. Project Number: 13751/6152, AGR/926. Unpublished study prepared by Springborn Smithers Laboratories. 81 p. 46596011

Cafarella, M. (2005) CL322,250

- Life Cycle Toxicity Test with Mysids (Americamysis bahia). Project Number: 13751/6153, AGR/927. Unpublished study prepared by Springborn Smithers Laboratories. 87 p. 46596012

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

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Page 33 of 69 Cafarella, M. (2006) R107894

- Acute Toxicity to Eastern Oyster (Crassostrea virginica) Under Flow

- Through Conditions. Project Number: 13751/6157, AGR/1176, TS/FT/OYSTER/R107894. Unpublished study prepared by Springborn Laboratories Inc.
7 0 p. 46751305

Cox, P.; Ristorcelli, D. (2001) R107894: Determination of the Physico

- Chemical Properties (pH, pKa, and EC Tests A4, A6 and A8): Final Report: Lab Project Number: 1073/41

- D2141: AGR 00301. Unpublished study prepared by Covance Laboratories, Ltd. 59 p. MRID 45673906

.

Deltares Software. 2012. MAMPEC 3.0 model. http://www.deltares.nl/en/software/1039844/mampec/1232321

Dionne, E. (2001) CL322.250

-- Acute Toxicity to Eastern Oysters (Crassostrea virginica) Under Flow

- Through Conditions: Lab Project Number: 13751.6123: AGR 364: 031301/FIFRA/OPPTS/FT

- OYSTER. Unpublished study prepared by Springborn Laboratories, Inc. 71 p. {OPPTS 850.1025} 45674103

Durando, J. (2005) Primary Eye Irritation Study in Rabbits: R107894. Project Number: P324, 1734 2. Unpublished study prepared by Product Safety Laboratories. 17 p. 46539401

Gallagher, S.; Martin, K.; Beavers, J. (2005) R107894: A Dietary LC50 Study with the Mallard. Project Number: AGR/916, 168/101B. Unpublished study prepared by Wildlife Internati onal, Ltd. 75 p. 46596005

Gallagher, S.; Martin, K.; Beavers, J. (2005) CL322250: A Dietary LC50 Study with the Mallard. Project Number: AGR/1116, 168/102. Unpublished study prepared by Wildlife International, Ltd. 75 p. 46596013

Gallagher, S.; Martin, K.; Beavers, J. (2006) CL322248: A Dietary LC50 Study with the Mallard. Project Number: AGR/1174, 168/103. Unpublished study prepared by Wildlife International, Ltd. 62 p. 46751310

Garrod, Ani, R. Guiver, and D.A. Rimmer. Year??? Potential Exposure of Amateurs (Consumers) through Painting Wood Preservative and Antifoulant Preparations. Annals Occupation Hygiene, 44(6), pp. 421

- 426. MRIDs 46244421 and 47307308)

Hall, T.; Donald, E. (2001) R107894 Technical: Acute Oral Toxicity (Fixed Dose Procedure) Test in Rats: Lab Project Number: 19839: 577486. Unpublished study prepared by Inveresk Research. 39 p. {OPPTS 870.1100} 45673915

Hall, T.; Donald, E. (2001) R107894 Technical: Acute Dermal Toxicity (LD50) Test in Rats: Lab Project Number: 19836: 577470. Unpublished study prepared by Inveresk Research. 37 p. {OPPTS 870.1200} 45673916

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Page 34 of 69 Hawkins, W.; Donald, E. (2002) R107894 Technical: Buehler Test in Guinea Pigs for Delayed Skin Sensitisation Potential: Lab Project Number: 20973: AGR304: 577512. Unpublis hed study prepared by Inveresk Research Group. 61 p. 45673919

Hoberg, J. (2001) R107894

-- Toxicity to Duckweed, Lemna gibba: Lab Project Number: 13751.6104. Unpublished study prepared by Springborn Laboratories, Inc. 74 p. {OPPTS 850.4400} 45674116

Hobe rg, J. (2001) CL322,250

-- Toxicity to Duckweed, Lemna gibba: Lab Project Number: 13751.6108: AGR 338. Unpublished study prepared by LISEC. 70 p. {OPPTS 850.4400} 45674122

Hoberg, J. (2001) CL 322,248

-- Toxicity to Duckweed, Lemna gibba: Lab Project Number: 13751.6111: AGR 339. Unpublished study prepared by Springborn Laboratories, Inc. 70 p. {OPPTS 850.4400} 45674125

Hoberg, J. (2003) CL322, 248

-- Toxicity to the Freshwater Diatom, Naviculla pelliculosa: Lab Project Number: 13751.6135: AGR 479: EC/OPPTS/SA

- NAVICULA. Unpublished study prepared by Springborn Smithers Laboratories. 70 p. {OPPTS 850.5400} 45893904

Hoberg, J. (2005) R107894

- Acute Toxicity to the Marine Diatom, Skeletonema costatum, Under Static Conditions. Project Number: 13751/6147, AGR/1026 . Unpublished study prepared by Springborn Smithers Laboratories. 69 p. 46619901

Hoberg, J. (2005) CL322,250

- Acute Toxicity to the Marine Diatom, Skeletonema costatum, Under Static Conditions. Project Number: 13751/6154, AGR/1027. Unpublished study

pre pared by Springborn Smithers Laboratories. 70 p. 46596014

Hutchinson, A.; Donald, E. (2002) R107894 Technical: Acute Dermal Irritation Test in Rabbits: Lab Project Number: 20682: AGR 306: 577491. Unpublished study prepared by Inveresk Research. 38 p. {OP PTS 870.2500} 45673918

Knox III, D. (2011) Econea Technical: Preliminary Analysis. Project Number: 32442, AGR/4539, P809. Unpublished study prepared by Eurofins/Product Safety Laboratories. 84p. 48596802

Koga, Y. (2011) Bioconcentration Study of R10789 4 in Carp: Final Report. Project Number: 642/10/S/5626, 45626, AGR/4535. Unpublished study prepared by Chemicals Evaluation and Research Institute. 81p. 48680501

Lentz, N. (2007) Non

- GPL Photolysis of R107894 and CL332,250 in Sterile pH 5 Buffer and
Non

- GLP Indirect Photolysis of R107894 in Sterile Synthetic Humic Water (SHW). Project Number: 13751/6162. Unpublished study prepared by Springborn Smithers Laboratories. 45 p. 47128801

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Page 35 of 69 Lima, W. (2001) R107894

-- Acute Toxicity to Sheepshead Minnow (Cyprinodon variegatus) Under Flow

- Through Conditions: Lab Project Number: 13751.6119: AGR 368. Unpublished study prepared by Springborn Laboratories, Inc. 65 p. {OPPTS 850.1075} 45674003

Lima, W. (2001) R107894

-- Acute Toxicity to Mysids (Americamysis bahia) Under Flow

Through Conditions: Lab Project Number: 13751.6118: AGR 371. Unpublished study prepared by Springborn Laboratories, Inc. 64 p. {OPPTS 850.1035} 45674006

Lima, W. (2001) CL 322.250

-- Acute Toxicity to Sheepshead Minnow (Cyprinodon variegatus) Under Fl ow

- Through Conditions: Lab Project Number: 13751.6122: AGR 367: 020499/FIFRA/OPPTS/FT

- SHM. Unpublished study prepared by Springborn Laboratories, Inc. 62 p. {OPPTS 850.1075} 45674101

Mackie, J. (1997) Determination of the Hydrolytic Stability of (Carbon

- 14)

- RC107894: Lab Project Number: 390042: 15348. Unpublished study prepared by Inveresk Research. 105 p. 45673908

Mackie, J. (1998) Adsorption/Desorption of (Carbon

- 14)

- R107894 in Sediments: Lab Project Number: 390723: 15715. Unpublished study prepared by Inveresk Research. 122 p. 45673913

Mackie, J. (1999) Adsorption/Desorption of the Hydrolysis Products of (Carbon

- 14)

- R107894 in Sediments: Lab Project Number: 16693: 390770. Unpublished study prepared by Inveresk Research. 123 p. 45673914

Mackie, J . (1999) The Aerobic Degradation of (Carbon

- 14)

- R107894 in Two Water/Sediment Systems: Lab Project Number: 393001: 16787. Unpublished study prepared by Inveresk Research. 97 p. 45673911

Mackie, J. (2000) The Anaerobic Degradation of (Carbon

- 14)

- R107894 i n Two Water/Sediment Systems: Lab Project Number: 17832: 393017. Unpublished study prepared by Inveresk Research. 102 p. 45673910

Millen, W. (2001) Validation of HRGC Method M

- 3467.01 to Assay for CL 312264 and CL 322

, 697 in the Technical Grade of AC 303 268: Lab Project Number: APBR 1153: 00

- APBR

- 1125

- 9. Unpublished study prepared by BASF. 53 p. {OPPTS 830.1700}. MRID 45673903

Milligan, F.; Williams, S.; McGuire, G. (1997) Supplement to Hydrolytic Stability Report NO 15348: Identification of Hydrolytic D egradation Products of (Carbon

- 14)

- R107894: Lab Project Number: 15365: 364871: 15348. Unpublished study prepared by Inveresk Research. 37 p. 45673909

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Page 36 of 69 Moore, G. (2006) Acute Inhalation Toxicity Study in Rats

- Limit Test: R107894. Project Number: 19437, A GR/1269, P330. Unpublished study prepared by Product Safety Laboratories. 22 p. 46846601

Putt, A. (2001) CL 322,250

-- Acute Toxicity to Mysids (Americamysis bahia) Under Flow

Through Conditions: Lab Project Number: 13751.6121: AGR 370. Unpublished study

p repared by Springborn Laboratories, Inc. 62 p. {OPPTS 850.1035} 45674104

Putt, A. (2005) R107894

- Acute Toxicity to Rainbow Trout (Oncorhynchus mykiss) Under
Flow

- Through Conditions. Project Number: 13751/6143, AGR/920. Unpublished study prepared by Sp ringborn Smithers Laboratories. 67 p. 46596002

Putt, A. (2005) CL322,250

- Acute Toxicity to Rainbow Trout (Onchorynchus mykiss) Under
Flow

- Through Conditions. Project Number: 13751/6150, AGR/924. Unpublished study prepared by Springborn Smithers Laborat ories. 69 p. 46596010

Ristorcelli, D. (2001) R107894: Determination of the Physico

- Chemical Properties: Final Report: Lab Project Number: 1073/48

- D2149: AGR 00351. Unpublished study prepared by Covance Laboratories, Ltd. 65 p. MRID 45673907

Sayers, L. (2006) CL322,248

- Acute Toxicity to Sheepshead Minnow (Cyprinodon variegatus) under Static Conditions. Project Number: 13751/6159, AGR/1178, PPTS/SHM/STA/JANSSEN. Unpublished study prepared by Springborn Laboratories Inc. 60 p. 46751309

Sayers, L. (200 6) CL322,248

- Acute Toxicity to Mysids (Americamysis bahia) under Static Conditions. Project Number: 13751/6160, AGR/1179, PTS/MYSID/ST/JANSSEN. Unpublished study prepared by Springborn Laboratories Inc. 62 p. 46751308

Serak, K.; Hanh, J. (2006) Determi nation of the Leach Rate of Econea from Paint (International Copper Free) in Synthetic Seawater. Project Number: 49702, 49702/7. Unpublished study prepared by Analytical Bio

- Chemistry Labs., Inc. 62 p. 46934508

Serak, K. (2007) Determination of the Leach Rate of Organic Biocides from Two Paints in Substitute Ocean Water: Seaguard HMF 1 and Seaguard HMF 2: HMC Antifouling Paint. Project Number: 49912, 49912/1. Unpublished study prepared by ABC Laboratories, Inc. 125 p. 47238912

Sinning, D. (2002) Leach R ate Determination of Sigma Nexxium 20 Paint Containing Sea Nine 211 and AFO28 Antifoulings: Lab Project Number: 630

- 16. Unpublished study prepared by Case Consulting Laboratories, Inc. 34 p. 45673201

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Page 37 of 69 Sinning, D. (2008) Release Rate Determination of Tral opyril from Smart Solution. Project Number: 3990/01. Unpublished study prepared by Case Consulting Laboratories, Inc. 27

p. 47500201

Sinning, D. (2011) Leach Rate Determination of Pettit Hydrocoat ECO Antifouling Pain 1104 White: Final Report. Project Nu mber: 390/100. Unpublished study prepared by Case Consulting Laboratories, Inc. 34p. 48734904

Sinning, D. (2011) Leach Rate Determination of Pettit Hydrocoat ECO Antifouling Paint 1204 Blue: Final Report. Project Number: 390/101. Unpublished study prepa red by Case Consulting Laboratories, Inc. 34p. 48734905

Sinning, D. (2011) Leach Rate Determination of Pettit Hydrocoat ECO Antifouling Paint 1604 Red: Final Report. Project Number: 390/102. Unpublished study prepared by Case Consulting Laboratories, Inc . 34p. 48734906

Sinning, D. (2011) Leach Rate Determination of Pettit Hydrocoat ECO Antifouling Pain 1804 Black: Final Report. Project Number: 390/103. Unpublished study prepared by Case Consulting Laboratories, Inc. 34p. 48734907

Sinning, D. (2012) Le ach Rate and VOC Determination of Armor Solventbase Antifouling Paint: Final Report. Project Number: 260/10. Unpublished study prepared by Case Consulting Laboratories, Inc. 37p. 49046003

Sousa, J. (2001) R107894

-- Early Life

- Stage Toxicity Test with Shee pshead Minnow (Cyprinodon variegatus): Lab Project Number: 13751.6128: AGR 383. Unpublished study prepared by Springborn Laboratories, Inc. 84 p. 45674007

Sousa, J. (2001) CL 322,250

-- Early Life

- Stage Toxicity Test with Sheepshead Minnow (Cyprinodon vari egatus): Lab Project Number: 13751.6129: AGR 385. Unpublished study prepared by Springborn Laboratories, Inc. 83 p. 45674106

Teixeira, D. (2001) R107894

-- Determination of Effects on Seedling Emergence of Rice (Oryza sativa): Lab Project Number: 13751.612 7: AGR 362. Unpublished study prepared by Springborn Laboratories, Inc. 75 p. {OPPTS 850.4100, 850.4225} 45674115

Tunink, A. (2008) Determination of the Leach Rate of Organic Biocides from Four Paint Colors, Code No. LAg 2007 025

- Black, Red, Blue, and Green in Substitute Ocean Water. Project Number: 63315, AGR/3766, ASTM/D/6903/07. Unpublished study prepared by ABC Laboratories, Inc. 98 p. 47550801

Tunink, A. (2008) Determination of the Leach Rate of Organic Biocides from Three Paint Colors, Code No. LAg 2007 023

- Black, White, and Red, in Substitute Ocean Water. Project Number: 63311, AGR/3764, ASTM/D/6903/07. Unpublished study prepared by ABC Laboratories, Inc. 90 p. 47554203

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Page 38 of 69 Tunink, A. (2010) Determination of the Leach Rate of Organic Biocide at Three Different Temperatures from the Antifouling Paint Code No. Lag 2008 036

- Blue, in Substitute Ocean Water. Project Number: 65299, AGR/4345. Unpublished study prepared by ABC Laboratories, Inc. 86 p. 48297806

Tutorvista.com. 2013. Van der Waals Eq uation. http://chemistry.tutorvista.com/physical

chemistry/van

- der

- waals

- equation.html

U.S. Center for Disease Control. 2013. National Health and Nutrition Examination Survey (NHANES). http://www.cdc.gov/nchs/nhanes.htm

U.S. Environmental Protection Agency. 1996. OPPTS 850.1730 Fish BCF. EPA 712

– C

– 96

– 129

. http://www.epa.gov/ocspp/pubs/frs/publications/OPPTS_Harmonized/850_Ecological_Ef fects_Test_Guidelines/Drafts/850

- 1730.pdf

U.S. Environmental Protection Agency (EPA). 2002. ECOTOX User Guide: EC OTOXicology Database System. Version 3.0. Available: http://www.epa.gov/ecotox/

U.S. Environmental Protection Agency. 2007. An AD Memo from Richard Petrie to Marshall Swindell entitled Econea TM 

### (tralopyril) Ant ifoulant New Chemical Registration, Ecological Hazard Assessment and Environmental Risk Characterization (PC Code 119093)

U.S. Environmental Protection Agency (EPA). February 15, 2007. T ralopyril Occupational Exposure Re

- Assessment Using a Revised Dermal Toxicity Endpoint: Update of November 15, 2006 Review for a New Active Ingredient, 1H

- Pyrrole

- 3

- carbonitrile, 4

- bromo

- 2

- (4

- chlorophenyl)

- 5

- (trifluoromethyl)

, (a.k.a., tralopyril ), Proposed as an Antifoulant D295928, D327535, D327536 & D330452.

U.S. Enviro nmental Protection Agency. 2008. An AD Memo from Talia Lindheimer to Marshall Swindell on “Acute and Chronic Drinking Water Exposure and Risk Assessment for the Registration Action of tralopyril (EPA Reg. #2693

- 200)”, April 16, 2008.

U.S. Environmental Pr otection Agency. April 10, 2008. Residential Exposure and Risk Assessment of the End Use Product, Trilux 44

– White Antifoulant Paint, (EPA Reg. No. 2693

- 220) Containing 3.9% of the Active Ingredient, 1 H

- Pyyrole

- 3

- carbonitrile, 4

- bromo

- 2

- (4

- chlorophenyl )

- 5

- (trifluoremethyl), as an Antifoulant in Paint for Pleasure Craft and Do

- it

- Yourself Applications, D384689.

U.S. Environmental Protection Agency. May 10, 2011. Environmental Fate and Effects Division Guidance, Author, Don Brady. Guidance for Determi ning Pesticide Residues of Concern in Drinking Water in Coordination with the HED ROCKS.

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Page 39 of 69 U.S. Environmental Protection Agency. 2012. DEEM

- FCID/Calendex Version 3.18/9.14 Release

. http://www.epa.gov/pesticides/science/deem/

U.S. Environmental Protection Agency. 2012. EPI

- Suite 4.1. http://www.epa.gov/opptintr/exposure/pubs/episuitedl.htm

U.S. Environmental Protection Agency. December 2012. Registration Review Process. http:// www.epa.gov/oppsrrd1/registration_review/reg_review_process.htm

U.S. Environmental Protection Agency. 2013. Endocrine Disruptor Screening Program. http://www.epa.gov/endo/

U.S. Environmental Protection Agency (EPA)

. 2013. High Production Volume Informa tion System (HPVIS). http://www.epa.gov/hpvis/

U.S. Environmental Protection Agency. 2013. Impaired Waters 303(d) Listings. http://water.epa.gov/lawsregs/lawsguidance/cwa/tmdl/listing.cfm

Van der Kerken, K. (2002) Alga, Growth Inhibition Test Effect of CL 322,248 on the Growth of Skeletonema costatum: Final Report: Lab Project Number: AGR 00309: WE

- 06

- 272:
KV

- 2001

- 10532

- R

- MJ

- WE06272. Unpublished study prepared by LISEC. 78 p. {OPPTS 850.5400} 45674127

Williams, W. ; Northcott, W.; Marincic, K. (2007) Environmental and Ecological Risk Assessment of ECONEA Anti

- Foulant Agent in Freshwater Environments: Final Report. Project Number: WEI/567/01/F, JANSSEN/AGR/3762. Unpublished study prepared by Waterborne Environmental, Inc. (WEI). 28 p. 47301601

Yang, H. (2000) Validation of the Ion Chromatographic Method M

- 3417.01 to Assay for Triethylamine (TEA) in the CL 303268 Technical Grade Active Ingredient (TGAI): Lab Project Number: APBR 1130: 00

- APBR

- 1125

- 3. Unpublished study prepared by BASF. 49 p. {OPPTS 830.1700}. MRID 45673902.

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Page 40 of 69 

# Appendix A T oxicology Profile

Acute Toxicity for Product Labeling

As summarized in Table 1 6 , i n acute toxicity studies, tralopyril has been shown to have severe toxicity by the oral route (Toxicity Categor y I) , moderate toxicity by inhalation route (Toxicity Category II) and weak toxicity through dermal route (Toxicity category III). Tralopyril is a mild skin irritant (Toxicity Category IV) and a mild eye irritant (Toxicity Category I II ). Tral opyril is

no t a dermal sensitizer.

Table 16

– Acute Toxicity Data for T ralopyril

Guideline No. Data Requirement/ Species Conclusions/Acceptable/

Comments Tox Cat MRID

870.1100 Acute Oral/Rat LD 50 = Not established [Acceptable/

- Guideline] I 45673915

870.1200 Acute Dermal/Rabbit LD 50 >2000 mg/kg for both males and females [Acceptable/Guideline] III 45673916

870.1300 Acute Inhalation/Rat* LC50 = <510 mg/m 3 (males) LC50 = <510 mg/m 3 (females) LC50 = <510 mg/m 3 (males and females) [Accep table/Guideline] II 46846601

870.2500 Dermal Irritation/

Rabbit Mildly irritating based on very slight erythematic, but no edema at 72 hours [Acceptable/Guideline] IV 45673918

870.2400 Primary Eye

Irritation./Rabbit Mildly irritating [Acceptable/Guidel ine] III 46539401

870.2600 Dermal Sensitization/

Guinea Pig Not a dermal sensitizer [Acceptable/Guideline] N/A 45673919



## Subchronic Toxicity

The subchronic toxicology database includes a 90

- day oral study in rats, a 28

- day dermal range

finding study in rats, a 90

- day rat dermal study in rats, and a 90

- day rat inhalation study (with neurotoxicity battery measured) in rats. A summary of these studies is included below and more detailed information can be found in the data evaluation records:

90

- Day O ral T oxicity S tudy (MRID 46442201 and MRID 46659701)

This study was evaluated in D323129 of 06/29/06 under TXR #1,003,062 and it was found to be acceptable under the relevant guideline ( OPPTS 870.3100 )

. During this study tralopyril (94.6% a.i) was administere d to 10 Sprague

- Dawley rats/sex/dose via food at dose levels of 0, 80, 250, or 750 ppm active ingredient. These concentrations were equivalent to 5.2, 16.2, or 51.9

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Page 41 of 69 mg/kg/day, respectively, in males and 6.3, 20.9, or 62.0 mg/kg/day, respectively, in femal es. An additional study was performed with 10 Sprague

- Dawley rats/sex/dose at the same concentration as above with 5 rats/sex/dose were undergoing terminal sacrifice by in situ perfusion after anesthesia after 3 months of exposure and 5 rats/sex/dose under going a 4

- week recovery period. The intake of test article in these rats was similar to that observed in the main study animals (i.e., 5.1, 16.2, or 51.6 mg/kg/day, respectively, in males and 6.8, 20.7, or 61.4 mg/kg/day, respectively, in females).

No uns cheduled deaths occurred during the course of the study. There were no treatment

- related clinical signs of toxicity, ophthalmological findings, urinalysis, or macroscopic findings. Food consumption decreased in the first week of treatment in both males and females administered 750 ppm. The body weight gains were low throughout the study, likely due to low food consumption.

Hematology data indicated only minor (<10% difference from controls) effects in high

- dose animals, except for a 15% increase in pl atelets in the males with a corresponding increase in females that was not significant (9%). All hematological values were comparable to controls after the 4

- week recovery period. Alanine aminotransferase (ALT) and alkaline phosphatase (ALP) were statist ically

- significantly increased in the mid

- and high

- dose males, which correlate to increased relative liver weights in the main group. Females displayed a lesser increase in ALP with only the high

- dose group demonstrating a statistically significant chang e. Low

- dose males also displayed a statistically significant increase in ALP. Signs of dehydration and undernourishment were evident with statistically significant increases in phosphorus, urea, magnesium, and cholesterol; and a statistically significant decrease in glucose in high

- dose males and females.

Clinical chemistry findings in the recovery group indicate reversibility of the effects. Differences in creatinine and triglycerides were generally <10% different from the main control group and were thus considered due to biological variation.

Terminal body weight was reduced a statistically significant amount in mid

- and high

- dose males and high

- dose females, which affected the absolute and/or relative weights of several organs.

treatment

- related changes include increases in relative brain weights (mid

- and high

- dose males; high

- dose females) and liver weights (mid

- and high

- dose males; all treated females). However, the changes in ALP and ALT enzyme were reversible after 4 weeks and the increases in the liver were likely due to increased metabolism of the test article. The relative brain weights in the high

- dose animals remained elevated after the recovery period, though the males were the only statistically significant value. However, frank effe cts were noted in the brain at necropsy in these recovery group animals.

Microscopic findings of the brain and spinal cord observed in the main group were as follows: minimal to moderate multifocal vacuolation of the brain in the mid

- and high

- dose males and females as well as the low

- dose females; moderate to marked multifocal vacuolation of the thoracic cord in the high

- dose females; minimal to marked multifocal vacuolation of the lumbar cord in the mid

- and high

- dose males and females as well as the lo w

- dose females.

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Page 42 of 69 Microscopic finding of the brain and spinal cord of the animals that were in the perfusion fixation satellite group displayed treatment

- related finding which included slight to moderate vacuolization. The lumbar region (cauda equina) was most profoundly affected and the females appeared to be more sensitive.

Other treatment

- related microscopic findings in the main group were minimal to slight mucosal hyperplasia of the duodenum in the mid

- and high

- dose males and females that were revers ible after 4 weeks. These were spongiform myelinopathy in the central and the proximal peripheral nervous system. The most severe lesions were multifocal vacuolation of the white matter and intramyelinic vacuolation of the peripheral nerves in the cauda e quina (lumbar cord and root fibers). Peer review of the pathology confirmed the general findings, although there were some minor differences on severity and in some instances the involvement of vacuolation in several tissues.

There were no changes in be havior or parasympathetic movements (e.g. tremors, convulsions, impaired gait, posture, response to handling, activity, or arousal).

After 4 weeks of no treatment, microscopic lesions were still observed in the brain and lumbar region. Minimal multifocal vacuolization of the brain in high

- dose males and minimal to slight multifocal vacuolization of the brain in mid

- and high

- dose females were observed; minimal to slight multifocal vacuolization of the lumbar in mid

- and high

- dose males and minimal to moder ate multifocal vacuolization of the lumbar in all treated females. The lesion severity increased with dose.

The LOAEL is 16.2 mg/kg/day in males based on reduced body weight and body weight gain, reduced food consumption, hematology, clinical chemistry, organ weights, and microscopic findings of the brain and spinal cord. The LOAEL is 6.3 mg/kg/day in females based on microscopic findings of the brain and spinal cord. The NOAEL is 5.2 mg/kg/day in males and could not be determined in females.

28

- day R at R ange - F inding D ermal T oxicity S tudy (MRID 466597

- 02)

This study was evaluated in D323129 of 01/31/06 under TXR #1,003,056 and it was found to be acceptable under the relevant guideline ( OPPTS 870. 3200)

. During this study, tralopyril (94.6% a.i.) was administered to 5 rats/dose /sex at dose levels of 0, 30, 100, 300, or 1000 mg/kg/day for 29 days ( 6 hours/day, 5 days/week ). Results from this study were used to determine the dose range of a proposed 90

- day dermal subchronic study. Treatment

- related ef fects at 1000 mg/kg/day included ano

- genital staining but this was not considered to be toxicologically significant. There were no mortalities during this study. Additionally, there were no significant changes to body weight, food consumption, food effici ency, organ weight, or pathology (gross or microscopic). T he LOAEL is >1000 mg/kg/day (HDT). The NOAEL is < 1000 mg/kg/day. Based on these results, rats were be expected to tolerate an exposure of >1000 mg/kg/day in the subsequent 90

- day dermal study.

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Page 43 of 69 90

- day R at D ermal T oxicity S tudy (MRID 46802201, MRID 47006601)

This study was evaluated in D328778 of 06/29/06 under TXR #1,003,062 and it was found to be acceptable under the relevant guideline ( OPPTS 870. 3250, OECD 411)

. During this study, tralopyril (94.6%) was applied to the shaved skin of 10 rats per sex and dose at doses of 0, 100, 300, or 1000 mg/kg/day, 6 hours/day for 5 days/week during a 90

- day period. One 100

- mg/kg/day female died prior to study termination. A treatment

- related dose

- depende nt increase in small dermal sores was noted in both the mid

- and high

- dose group

. Consequently, the dermal NOAEL is 100 mg/kg/day; a dermal LOAEL is 300 mg/kg/day based on the appearance of sores. There were no other adverse findings with this substance.

The systemic NOAEL is > 1000 mg/kg/day (HDT). The systemic LOAEL is >1000 mg/kg/day.

90

- day R at I nhalation S tudy with N eurotoxicity B attery (MRID 46802202)

This study was evaluated in D328778 of 06/29/06 under TXR #1,003,062 and it was found to be accepta ble under the relevant guideline s ( OPPTS 870. 3465, 870.6200). During this study tralopyril (92.4% a.i.) was administered via nose

- only exposure to 10 Sprague Dawley rats per sex and air concentration in Phase I and 12 rats per sex and air concentration in Phase II. The air concentrations (both nominal and analytical) were 0, 20, 40, and 80 mg/m 3



### . The exposure period was 6 hours per day, 7 days per week for a minimum of 90 consecutive days. The particle size was within the accepted range.

The No Observabl e Adverse Effect Level (NOAEL) was 20 mg/m 3 

### for survival, hematology, clinical chemistry, or gross pathology. Nasal lesions were observed in the 20 mg/m 3 

### animals and were considered a local effect.

One female rat in the Phase I inhalation toxicity was foun d dead on study Day 9. This animal was in the control group, therefore the death was not considered test article

- related. Three males in the 80

- mg/m 3 

### Phase II neurotoxicity study group were found dead on study Days 0, 20, and 85, respectively. Additiona lly, an 80 mg/m 3 

### female in the Phase II neurotoxicity study group was found dead on Day 0 after the first exposure. Since there were numerous deaths in the 80 mg/m 3 

### group these deaths were considered test article

- related.

Clinical signs of toxicity relat ed to treatment included brown staining on multiple body surfaces in males and females of all three test article

- treated groups. Staining, which began on Day 11 and persisted through the end of the study, was observed on the neck, forelimb, abdominal area

, thoracic area, inguinal area, hindlimb, rump, anogenital area, urogenital area, and tail. Reduced mean body weights for the male and female animals of the 20

- (males), 40

- , and 80

- mg/m 3 

### test groups were statistically significantly lower than the control group.

Microscopic treatment related effects were limited to the nose of all of the treated animals. The effects were observed to be localized in the dorsal region of the nose, and included inflammation, ulceration or erosion, squamous or respiratory me taplasia, and olfactory or respiratory epithelial degeneration. These changes displayed a dose

- related increase in incidence and severity.

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Page 44 of 69 In the Phase I of the study, the LOAEL was 20 mg/m 3 

### for male and female is 20 mg/m 3 

### based on the findings observed in the N1 (Nasal section 1) for both sexes and N3 section in the females of the 20

- mg/m 3 

### animals. The 20

- mg/m 3 

### males exhibited chronic and subacute inflammation, ulcerations (N1), and exudate (N1), and the females had subacute inflammation (N1), epithelia l hyperplasia (N1), hyperkeratosis (N1), and degeneration of olfactory epithelium (N3) and decrease body weight gain in male. The NOAEL could not be determined (<20 mg/m3)(LDT).

In the phase II of the study, n eurobehavioral assessment (functional observ ational battery [FOB] and motor activity testing) was performed on all Phase II animals ( 12 rats /sex /group) prior to dose administration ( pretest), and at Weeks 3, 7, and 12 . Cholinesterase activity was not determined. At study termination, 6 animals/sex /dose in the controls and 80

- mg/m 3 

### group s were perfused in situ for neuropathological examination of the central and peripheral nervous system tissues

. For the Phase II neurotoxicity study, a fter the first day of exposure, 1 male and 1 female were found d ead in the 80 mg/m 3 

### group and were replaced. Two 80 mg/m 3 

### males died prior to study termination

, one on Day 20 and the other on Day 85.

During FOB handling measurement, the 40 and 80 mg/m 3 

### animals were observed to have soiled fur, unclean fur, and incre ased grooming (80 mg/m 3 

### males) during Weeks 7 and 12. These changes correlate with the clinical toxicity findings of soiled fur and were not considered adverse neurotoxicological findings. During Week 3 FOB measurements, an overall decrease in total loco motor activity was noted in the 40 and 80 mg/m 3 

### males and in ambulatory activities for 80 mg/m 3 

### males as a result of reduced activity in sub

- session measurements. During Week 12, the 80 mg/m 3 

### males were observed with total activity decrease compared to co ntrols.

At neuropathology

, an increase in minimal axonal degeneration was observed in the peroneal nerve in the 80 mg/m 3 

### animals (3/6 for both males and females) over controls (0/0 for both males and females).

The neurotoxicity LOAEL was 40 mg/m 3 

### in mal es based on decreased motor activity and 8 0 mg/m 3 

### in females based on axonal degeneration observed in the peroneal nerve. The neurotoxicity NOAEL was 20 mg/m 3 

### for males and 40 mg/m 3 

### for females.


## Developmental Toxicity

There is one rat developmental study in the tralopyril toxicology database. Since drinking water exposure can occur if tralopyril antifoulant paints are used on fresh water boats or ships, an additional developmental toxicity study on a second species ( i.e . non

- rodent) is anticipated to be needed for registration review

.
Rat Developmental Toxicity (MRID 46426902)

This study was evaluated in D312232 (not yet finalized) and it was found to be acceptable under the relevant guideline for a developmental toxicity study in rats (OPPTS 870.3700; OE CD 414). During this study, tralopyril (94.6% a.i.) was administered to 25 time

- mated Sprague

- Dawley female rats /dose by gavage at dose levels of 0, 5, 10 or 20 mg/kg/day from day 6 through 19 of gestation ( i.e . gd 6

- 19).

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Page 45 of 69 Treatment related maternal effe cts at 20 mg/kg/day included increased mortality, frequent salivation, reduced body weight gain, decreased uterine weight, decreased corrected body weight gain, increased resorptions (total, early and late) and decreased placental weight. At 10 mg/kg/day, dams exhibited frequented salivation . The maternal LOAEL is 10 mg/kg/day, based on frequent salivation. The NOAEL is 5 mg/kg/day.

Developmental findings also occurred at 10 and 20 mg/kg/day. Trea tm ent

- related effects at 20 mg/kg/day included decreased m ean fetal weight and an increased incidence of fetuses exhibiting disturbances and delays of ossification (non/incomplete/dumbbell/biparte) of various skeletal structures (skull, sternebrae), as well as supernumerary (14th) and wavy ribs. The ossification delays were considered to be secondary to maternal toxicity and correlated with decreased fetal weight. At 10 mg/kg/day, there was a decrease in mean fetal weight. The developmental LOAEL is 10 mg/kg/day, based on decreased fetal weight, the developmental NOAEL is 5 mg/kg/day.


## Reproductive Toxicity

There are no reproductive studies in the tralopyril toxicology database. Since drinking water exposure can occur if tralopyril antifoulant paints are used on fresh water boats or ships, a reproductive toxicity study is anticipated to be needed for registration review

. 

## Chronic Toxicity and Carcinogenicity

There are no chronic toxicity studies in the toxicology database. Since drinking water exposure can occur if tralopyril antifoulant paints are used on fresh wat er boats or ships, chronic toxicity and cancer studies are anticipated to be needed for registration review

. 

## Mutagenicity

There are two mutagenicity studies in the toxicology database:

1. In vitro Mammalian Cell Gene Mutation 2. In vivo Mammalian Cell Cytoge netics (Bone Marrow Micronucleus),

There is no in vitro Salmonella typhimurium Reverse Mutation Assay in the toxicology database and is considered as a data gap to evaluate the mutagenic potential of tralopyril.

In vitro Mammalian Cell Gene Mutation Ass ay (MRID 46426903),

Chinese hamster ovary (CHO) cells were exposed to tralopyril (94%) in dimethylsulfoxide up to cytotoxic and insolubility concentrations and was not mutagenic in the presence or absence of S9 activation. The positive controls did induc e the appropriate response. There was no evidence of a concentration

- related, positive response that induced mutant colonies over background. This study is classified as ACCEPTABLE

- GUIDELINE and satisfies the guideline requirement (OPPTS 870.5300, OECD 4 76) for in vitro mutagenicity (mammalian forward gene mutation) data.

In vivo Mammalian Cell Cytogenetics Assay (MRID 46426904)

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Page 46 of 69 Five 5 male mice per dose were exposed once by oral gavage to tralopyril (>94% pure) in olive oil at doses of 0, 3, 6, or 12 m g/kg bw. Bone marrow cells were harvested at 24 hours post

trea tm ent. There was no mortality among the animals tested in the main assay, however, clinical signs of toxicity (squatting posture) were observed in the 12 mg/kg bw animals at both 24

- and 48

- h our harvest times. No statistically

- significant increases in the number of small or large micronucleated PCEs or NCEs were reported at any dose or harvest time compared to the concurrent solvent control. Additionally, positive controls also showed a sign ificant increase in the percentage of micronucleated PCEs in males; therefore, the positive control elicited a clearly positive response. There was no significant increase in the frequency of micronucleated polychromatic erythrocytes in bone marrow after any trea tm ent time. This study is classified as ACCEPTABLE

- GUIDELINE and satisfies the guideline requirement (OPPTS 870.5395; OECD 474) for in vivo cytogenetic mutagenicity data.


## Other Toxicological Effects

There are neurotoxicity effects that have been o bserved in several submitted studies

1. In the 90

- day rat oral study ( MRID 46442201 and MRID 46659701 ), m icroscopic findings of the brain and spinal cord were observed in the main group as follows: minimal to moderate multifocal vacuolation of the brain in th e mid

- and high

- dose males and females as well as the low

- dose females

. These were spongiform myelinopathy in the central and the proximal peripheral nervous system. The most severe lesions were multifocal vacuolation of the white matter and intramyelini c vacuolation of the peripheral nerves in the cauda equina (lumbar cord and root fibers). After 4 weeks of no trea tm ent, microscopic lesions were still observed in the brain and lumbar region.

2. D ecreased motor activity and axonal degeneration in the per oneal nerve were o bserved in the 90

- day rat inhalation study ( MRID 46802202 ).

3. Frequent salivation was identified as a significant effect in the rat developmental study ( MRID 46426902 ).

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Page 4 7 of 69 

# Appendix B Environmental Fate

Parent tralopyril and its degradation products can create environmental exposure in water bodies where treated boats either reside or are in use. This is the only registered use of tralopyril, and therefore, exposure in terrestrial situations will not be assessed in this document. Aquatic

exposure w ill be highest in marinas and around docks where boats are stored, and lower outside marinas where boat density is lower. and therefore long

- term acute and chronic exposure to aquatic organisms inhabiting these areas will present. In other areas where bo ats are present and in use ( e.g . areas outside marinas), water exposure will be lower because of lower boat density.

Parent tralopyril degrades by both abiotic processes including hydrolysis 22 

### and photodegradation in water, 23 

### and by biotic processes 24 

### to form CL 322,250, which is defluorinated parent compound with a carboxylic acid group. Hydrolysis half

- lives for parent tralopyril ranged from
14

- 175 days at pH 5 to 0.1

- 0.6 days in pH 9 and seawater. CL 322,250 did not degrade in the hydrolysis study. T he photodegradation in water half

- lives were 1 day (distilled water and humic acid water) for parent tralopyril and 0.025 days (36 minutes) for CL 322,250. However, the photodegradation in water study has not been formally reviewed and will be in registrat ion review. Aquatic exposure in freshwater will occur from the parent compound and the more persistent CL 322,250 degradate under acid to neutral conditions. Under alkaline freshwater and in saltwater conditions, the primary exposure will be from the CL 3 22,250 degradate. The half

lives for parent tralopyril in anaerobic conditions were 29 and 0.7 days in freshwater and saltwater, and were 12 and 0.6 days under aerobic conditions. The half

- lives for CL 322,250 were 23

- 31 days in these conditions and we re longer than for parent tralopyril. Another major degradate, debrominated CL 322,250 (CL 322,248), is formed under anaerobic conditions (representing sediment) and in saltwater conditions and did not degrade ( Table 17 ).

Degrad ation of parent tralopyril produces compounds of different chemical and physical properties. The degradates have lower molecular weight, higher water solubility, and lower log Kow (Log P) values 25 

### . Therefore, the degradates would be expected to be present in water with a higher water:sediment ratio than parent tralopyril. Based on the molecular weights, vapor pressures, Henry’s Law constants, and study results 26 

### , neither parent tralopyril nor its degradates are expected to volatilize from water ( Table 19 ).

Sorption to sediment is a significant route of dissipation (disappearance) for tralopyril and its degradates/metabolites. For parent tralopyril and CL 322,250, the whole sediment sorption coefficients (Kf values ) ranged from 22

- 446 and 14

- 357 ml/g, respectively. The Koc values for parent tralopyril and CL 322,250 ranged from 3,143

- 20,273 and 4,571

- 23,150 ml/g, respectively. For parent tralopyril, the sorption for the freshwater and saltwater sediments was 96

- 98 and 82

-

22 MRIDs 45673908, 45673909

23 MRID 47128801

24 Aquatic metabolism, MRIDs 45673910, 45673911, 45673912

25 The Log P values in Table 18 for the degradates are questionable because the EPI

- Suite 4.1 model predicts higher water solubility than parent compound. The 830.7550 test (log P) involves shaking a pesticide in a mixture of octanol and water and more water soluble compounds will tend to partition to water, lowering the predicted log P.

26 MR IDs 45673910, 45673911, 45673912, EPI

- Suite 4.1

### Docket Number EPA

- HQ

- OPP

- 201 3

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Page 48 of 69 97 %, respectively. For CL 322,250, the sorption for the freshwater and saltwater sediments was
96

- 98 and 57

- 95 %, respectively 27 

### . However, the total sorption to sediment in the aquatic metabolism studies 28 

### did not exceed 70 %. In the anaerobic a quatic metabolism study 29 

### , the total sorption (extractable plus unextractable residues) was 70 and 37 % for the freshwater and salt water systems, respectively. In the aerobic aquatic metabolism study, 30 

### the total sorption (extractable plus unextractable re sidues) was 42 and 21 % for the freshwater and salt water systems, respectively.

The apparent difference in sorption can be explained by the water to sediment ratios in the studies, the use of shaking in the leaching

- adsorption

- desorption studies (standar d practice), and degradation to other compounds. In the leaching

- adsorption

- desorption studies 31 

### , the ratio of water to sediment was 5:1. The study design for leaching

- adsorption

- desorption does not allow for degradation of the tested compound. However, t he ratio of water to sediment in the aquatic metabolism studies 32 

### was 10:1. The main reasons for the apparent differences in study results lies in the fact that a lower water: sediment ratio forces higher sorption of a pesticide to the sediment 33 

### . Shaking of the water and sediment in the leaching

- adsorption

- desorption study (OCSPP 835.1230) to achieve sorption is also standard, while shaking is not used in metabolism studies because the shaking can enhance degradation over the long

- term 34 

### . Also, the degrada tion in the aquatic metabolism studies formed compounds that are more polar because of loss of halogen molecules (fluorine, bromine) 35 

### . As a result, further degradation of the parent compound and CL 322,250 results in more water solubility (based on EPI

- Su ite 4.1) and lower sorption ( Table 18 and Table 19 ). The Koc values (sorption to soil expressed as % organic carbon) estimated using EPI

- Suite 4.1 were 2,314 and 27

- 34 ml/g for the minor degradate CL 325,195 (debrominated parent) and major degradate CL 322,248 (debrominated 322,250), respectively ( Table 18 ). In the aquatic metabolism studies 36 

### , the applied parent tralopyril degraded to CL 322,250, CL 322,248, and CL 325,195 degradates which lose halogens and are sorbed to a lesser degree than parent compounds.

Leaching from antifoulant paints was also observed at up to 2.2

- 48 ug/cm 2 

### /day. Average and cumulative leaching rates ranged from 1.3

- 22 ug/cm 2 

### /day and 55.5

- 986 ug/cm 2 

### , respectively ( Table 20 ).

Bioconcentration in fish and aquatic invertebrates is also possible. There was a submitted bioconcentration in fish study 37 

### for parent tralopyril in carp that indicates limited bioconcentrati on factors (BCFs) of 3.2

- 32 depending on the treatment concentration. However, that study has not been formally reviewed and no conclusions can be drawn at this time. It will be reviewed in registration review.

27 MRIDs 45673913, 45673914, Table 16

28 MRIDs 45673910, 45673911, 45673912

29 MRID 45673910

30 MRIDs 45673911, 45673912

31 MRIDs 456734913, 45673914

32 MRIDs 45673910, 45673911, 45673912

33 835.1230 test guideline, http://www.regulations.gov/#!documentDetail;D=EPA

- HQ

- OPPT

- 2009

- 0152

- 0006

34 OCSPP 835.4300 and 835.4400

35 http://chemistry.tutorvista.com/physical

- chemistry/van

- de r

- waals

- equation.html

36 MRIDs 45673910, 45673911, 45673912

37 OCSPP 850.1730, MRID 48680501

### Docket Number EPA

- HQ

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- 201 3

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www.r egulations.gov

Page 49 of 69 Table 17

– Summ ary of parent tralopyril half

- lives and degradate amounts and half

- lives in environmental fate studies

Study Type MRID Parent Half

- lives (days) Maximum formation % based on applied parent compound 1 ,2 and half

- life CL 322,250 (%) 3 CL 325,195

- (%) 4 C L 3 22,248 (%) 5

Hydrolysis (835.2120) 45673908

(main study)

45673909 (degradate identification study) 10 o C

- Linear half

- lives of 175, 2.9, 0.6, and 0.6 days in pH 5, 7, and 9 water fresh and seawater (pH 8), respectively 25 o C

- Linear half

- lives of 14, 0.4, 0.1, and 0.1 days in pH 5, 7, and 9 water fresh and seawater (pH 8), respectively Distilled water

9.4

- 96.2 % (30 d) 1,2 (no half

- life calculated

-- stable) 6 1.4

- 4.6 % (30 d) 1

Minor degradate 7 Degradate not

formed in the study

Seawater
95. 7

- 96.3 % (1

- 4 d), 95.2

- 95.5 % (30 d) 1,2 (no half

- life calculated

-- stable) 6 2.7

- 2.8 % (0.5 d)

Minor degradate 7 Degradate not

formed in the study

Aqueous Photolysis (835.2240) 47128801 25 o C

- Non

- linear half

- lives of 1 and 0.9 days in distilled water and synthetic humic water (synthetic humic water represents natural water containing humic acid, a natural contaminant) Distilled water
75 % (0 d), <1 % by 5 d 1,2 (half

- life of 0.025 days, irradiated)
Dark control stable Degradate not

formed in the s tudy Degradate not

formed in the study (no half

- life calculated

-- stable) 6

Synthetic Humic Water No degradates analyzed No degradates

analyzed No degradates

analyzed
Anaerobic Aquatic Metabolism (835.4300) 45673910 Freshwater system (21 o C)

- Non

- l inear half

- life of 29 d 54 % (14 d),

7.2 % (364 d) 1,2 (half

- life of 31 days) 1.2 % (364 d) 1

Minor degradate 7 35.7 % (364 d) 1

Saltwater system (21 o C)

- Non

linear half

- life of 0.7 d 25 % (7 d) (half

- life of 22 days) 7.1 % (3 d),

0.8 % (364 d) 1

Minor degradate 7 19.9 % (273 d),

18.2 % (364 d) 1,2 (no half

- life calculated

-- stable) 6

Aerobic Aquatic Metabolism (835.4400) 45673911

45673912 Freshwater system (21 o C)

-

Non

- linear half

- life of 12 d 76 % (7 d),

38 % (30 d) 1,2 (half

- life of 25 days) 0.38 % (15 d),

<LOQ (30 d) 1 Minor degradate 7 Degradate not

formed in the study

Saltwater system (21 o C)

- Non

linear half

- life of 0.6 d 36

- 47 % (21

- 30 d) 1,2 (half

- life of 23 days) 1.9% (30 d) 1 30.3 % (30 d) 1,2

1 End of study period.

2 Numbers in red indicate significant percentages of applied compound.

3 CL 322,250 is parent tralopyril minus three fluorine molecules

4 CL 325,195 is deb ro minated parent tralopyril

### Docket Number EPA

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Page 50 of 69 5 CL 322,248 is debrominated CL 322,250

6 Half

- life not calculated because compound did not degrad e in the study and therefore the compound is assumed to be stable

7 Half

- life not calculated because compound formed at <10 % of applied parent in the study.



### Table 18

– Sorption (Kf/Koc) of parent tralopyril and its main degradates

Compound

Parent tralopyril CL 322,250 CL 325,195 Debrominated CL 322,250 (CL 322,248)
Kf (Koc) 1 Freshwater

349

- 446 ml/g (Kf) 17,450

- 20,273 ml/g (Koc)

Seawater

22

- 183 ml/g (Kf) 3,143

- 5,229 ml/g (Koc)

MRID 45673913 Freshwater

189

- 357 ml/g (Kf) 21,8 18

- 23,150 ml/g (Koc)

Seawater

14

- 119 ml/g (Kf) 4,571

- 6,743 ml/g (Koc)

MRID 45673914 2,314 ml/g

Epi

- Suite 4.1 No Kf data available 27

- 34 ml/g (Koc)

Epi

- Suite 4.1 No Kf data available

1 Kf is the Freundlich adsorption coefficient for whole sediment. Ko c is the Kf/% organic carbon.



### Table 19

– Physical

- Chemical Properties for Tralopyril and its Primary Metabolites

Compound Molecular

weight (g/mol) Water

Solubility (mg/l) Log P

(Log Kow) Disassociation

constant (pKa) Vapor

Pressure (mm Hg) Henry’s

Law (a m 3

mol - 1 ) Reference

tralopyril 349.54 0.17 1 (fresh water, pH 4.9)

0.16 (seawater, pH 8.1) 3.5 7.08 at 26 o C 1.42 x 10 - 10 at 20 C 1

3.45 x 10 - 10 at 25 C 3.8 x 10 - 10 Table 4 above

CL 322,250 281.54 5.63 3.72 2 None 7.62 x 10 - 7 5 x 10 - 8 EPI

- Suite 4.1
CL 325,195 302.64 17.95 4.17 2 None 3.45 x 10 - 9 7.65 x 10 - 11 EPI

- Suite 4.1 CL 322,248 (Debrominated
CL 322,250) 248.67 476 1.68 2 None 7.0 x 10 - 11 4.8 x 10 - 14 EPI

- Suite 4.1

1 Values used in Henry’s Law Calculations.

2 The EPI

- Suite 4.1 values are questionable because the experimental log P value for parent traloyril with 3 fluorines and 1 bromine was 3.5 (MRID 45673906). The loss of halogens to form the degradates results in compounds that are likely to have a lower log P value because they are more water soluble. The EPI

- Suite 4.1 program predicts higher water solubilities for the dehalogenated degradates, and the log P study design in 830.7550 requires the shaking of a flask containing n

- octanol, distilled water, and the pesticide of interest. Water

- soluble pesticides will preferentially partition to water instead of octanol because of increased hydrogen bonding.

### Docket Number EPA

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- OPP

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Page 51 of 69 Table 20

– Reviewed and Accepted Paint Leaching Studies for Tralopyril in Seawater

MRID Paint

Ingr edients (% w/w) Temp

( o C) CL 322,250 1

measured? Review

Date Results

Maximum, Minimum, and Average Units are ug/cm 2 /day and Cumulative Units are ug/cm 2 )
48734904 Petit Hydrocoat

ECO Antifouling Paint 1104 White Tralopyril , 6% Zn pyrithione

, 4.8 % 25 Yes 4/25/12 Rate Maximum Minimum Average Average Cumulative Cumulative Value

48
14 30
21 381 881 Time Interval

1 day 42 days
1

- 14 days
1

- 45 days
1

- 14 days
1

- 45 days

48734905 Petit Hydrocoat

ECO Antifouling Paint 1204 Blue Tralopyril, 6 % Zn pyrithione

, 4.8 % 25 Yes 4/25/12 Rate Maximum Minimum Average Average Cumulative Cumulative Value

48 10 36 20 351 842 Time Interval

1 day 45 days
1

- 10 days
1

- 45 days
1

- 10 days
1

- 45 days

48734906 Petit Hydrocoat

ECO Antifouling Paint 1604 RED Tralopyril, 6 %
Z n pyrithione

, 4.8 % 25 Yes 4/25/12 Rate Maximum Minimum Average Average Cumulative Cumulative Value

45 8 34 18 325 782 Time Interval

1 day 45 days
1

- 10 days
1

- 45 days
1

- 10 days
1

- 45 days

48734907 Petit Hydrocoat

ECO Antifouling Paint 1804 Black
Tr alopyril , 6 % Zn pyrithione

, 4.8 25 Yes 4/25/12

Rate Maximum Minimum Average Average Cumulative Cumulative Value

31
12
24
17 232 706 Time Interval

1 day 45 days
1

- 10 days
1

- 45 days
1

- 10 days
1

- 45 days

47500201 Smart Solution

Tralopyril, 2. 9% 25 Yes 11/13/08

Rate Maximum Minimum Average Average Cumulative Cumulative Value

44 10.3 34.4 20.9 452 850 Time Interval

1 day 45 days
1

- 14 days
1

- 45 days
1

- 14 days
1

- 45 days
45673201 Sigma Nexxium 20

Paint (Red

- Brown) Tralopyril, 3.68 %
RH

- 5287

, 3.43 % 25 Yes 1/6/05 Rate Value Time Interval
Maximum 20.8 3 days
Minimum 6.0 14 days Average 13.3 1

- 14 days Average 10.6 14

- 45 days
Cumulative 188 1

- 14 days

### Docket Number EPA

- HQ

- OPP

- 201 3

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www.r egulations.gov

Page 52 of 69 MRID Paint

Ingr edients (% w/w) Temp

( o C) CL 322,250 1

measured? Review

Date Results

Maximum, Minimum, and Average Units are ug/cm 2 /day and Cumulative Units are ug/cm 2 )
Cumulative 454 14

- 45 days

46934508 International

Copper

- Free Paint Tralo pyril, 3.9 %
RH

- 5287

, 4.12 % 25 Yes 1/11/07 Rate Value Time Interval
Maximum 7.0 31 days
Minimum 4.15 77 days Average 5.9 1

- 14 days Average 5.8 1

- 91 days
Cumulative 82.2 1

- 14 days
Cumulative 512 1

- 91 days
47238912 HMF Antifouling

Paint I
T ralopyril, 7.28 % Zn pyrithione

, 6.38 % Yes 1/10/08 Rate Value Time Interval
Maximum 13.5 31 days
Minimum 6.8 77 days Average 9.2 1

- 14 days Average 10.3 1

- 91 days
Cumulative 127 1

- 14 days
Cumulative 912 1

- 91 days
47550801 Lag 2007 025, Black

Paint Tralopyril, 3.9 % Zn pyrithione

, 4.12 % 25 Yes 1/8/09 Rate Value Time Interval
Maximum 17.9 14 days
Minimum 6.7 1 day Average 13.7 1

- 14 days Average 14.6 1

- 45 days
Cumulative 194 1

- 14 days
Cumulative 678 1

- 45 days
47550801 Lag 2007 02 5, Red

Paint Tralopyril, 3.9 % Zn pyrithione

, 4.12 % 25 Yes 1/8/09 Rate Value Time Interval
Maximum 19 7 days
Minimum 5.4 1 day Average 14.2 1

- 14 days Average 15.9 1

- 45 days
Cumulative 206 1

- 14 days
Cumulative 751 1

- 45 days
47550801 Lag 200 7 025, Blue

Paint Tralopyril, 3.9% Zn pyrithione

, 4.12
% 25 Yes 1/8/09 Rate Value Time Interval
Maximum 18.4 14 days
Minimum 5.7 1 day Average 13.3 1

- 14 days Average 14.4 1

- 45 days
Cumulative 186 1

- 14 days
Cumulative 670 14

- 45 days

### Docket Number EPA

- HQ

- OPP

- 201 3

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www.r egulations.gov

Page 53 of 69 MRID Paint

Ingr edients (% w/w) Temp

( o C) CL 322,250 1

measured? Review

Date Results

Maximum, Minimum, and Average Units are ug/cm 2 /day and Cumulative Units are ug/cm 2 )
475508 01 Lag 2007 025,

Green Paint Tralopyril, 3.9 % Zn pyrithione

, 4.12 % 25 Yes 1/8/09 Rate Value Time Interval
Maximum 21.2 21 days
Minimum 5.1 1 day Average 13.9 1

- 14 days Average 16.7 1

- 45 days
Cumulative 206 1

- 14 days
Cumulative 801 14

- 45 days
47554203 Lag 2007 023, Black

Paint Percent active ingredients not stated 25 Yes 1/8/09 Rate Value Time Interval
Maximum 13 45 days
Minimum 8.1 3 days Average 9.9 1

- 10 days Average 9.9 1

- 71 days
Cumulative 136 1

- 10 days
Cumulative 713 1

- 71 days
47554203 Lag 2007 023,

Red Paint Percent active ingredients not stated 25 Yes 1/8/09 Rate Value Time Interval
Maximum 10.8 21 days
Minimum 8.6 1 day Average 9.5 1

- 10 days Average 9.7 1

- 71 days
Cumulative 89 1

- 10 days
Cumulative 695 1

- 71 days
47554203 Lag 2007 023,

White Paint Percent active ingredients not stated 25 Yes 1/8/09 Rate Value Time Interval
Maximum 8.5 10 days
Minimum 5.0 71 days Average 7.5 1

- 10 days Average 6.5 10

- 71 days
Cumulative 159 1

- 10 days
Cumulat ive 474 10

- 71 days
48297806 Shelter Island Plus

Deep Blue Paint (Lag 2008 036 Blue Paint)

Tralopyril, 5.92 % Zn pyrithione

, 4.15 % 5 Yes 3/1/11

Rate Maximum Minimum Average Average Cumulative Cumulative Value

2.2 0.4 1.0 1.3 12.8 55.5 Time In terval

45 days 7 days
1

- 14 days
1

- 45 days
1

- 14 days
1

- 45 days
48297806 Shelter Island Plus

Deep Blue Paint (Lag 2008 036 Blue Paint ) Tralopyril, 5.92% Zn pyrithione

, 4.15 % 15 Yes 3/1/11 Rate Value Time Interval
Maximum 5.3 45 days
Minimum 1.7 1 d ay

Average 2.6 1

- 14 days

Average 3.3 1

- 45 days

### Docket Number EPA

- HQ

- OPP

- 201 3

- 0217

www.r egulations.gov

Page 54 of 69 MRID Paint

Ingr edients (% w/w) Temp

( o C) CL 322,250 1

measured? Review

Date Results

Maximum, Minimum, and Average Units are ug/cm 2 /day and Cumulative Units are ug/cm 2 )
Cumulative 35.4 1

- 14 days

Cumulative 149 1

- 45 days

48297806 Shelter Island Plus

Deep Blue Paint (Lag 2008 036 Blue Paint Tralopyril, 5.92 % Zn pyrithione

, 4.15 % 25 Yes 3/1/11 Rate Value Time Inte rval
Maximum 17.7 45 days

Minimum 4.7 1 day Average 7.8 1

- 14 days Average 11.0 1

- 45 days

Cumulative 108 1

- 14 days

Cumulative 492 1

- 45 days

49046003 2 Armor Solvent

Based Antifouling Paint Tralopyril, 5.6 % Zn pyrithione

, 4 % 25 Yes N/A Rate Value Time Interval
Maximum 34.5 3 days
Minimum 12.9 45 day Average 28.6 1

- 14 days Average 22.0 1

- 45 days
Cumulative 390 1

- 14 days
Cumulative 986 1

- 45 days

1 All parent tralopyril residues were chemically converted to the degradate CL 322, 250 in the studies for chemical analysis.

2 MRID 49046003 was has not been formally reviewed but will be reviewed in Registration Review

### Docket Number EPA

- HQ

- OPP

- 201 3

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Page 55 of 69 

# Appendix C Ecotoxicology Profile

Toxicity to Terrestrial Receptors

Birds, Acute and Subacute

— Parent and Degradates

For antifo ulant coatings and paints , a n acute oral toxicity study with a waterfowl and an upland game bird using the technical grade of the active ingredient (TGAI) is anticipated to be required to establish the toxicity of a pesticide to birds. This information is used to determine label hazard statements, as well as to estimate risk for pesticides which could be directly ingested by birds. Acute oral data for both a waterfowl and an upland game bird have been submitted to the

agency. Results of this test are tab ulated in Table 21

. These results indicate that tralopryil technical is moderately to highly toxic to avian sp ecies on an acute oral basis. All avian acute oral data requirements are fulfilled for the parent.

Avian acute oral te sting was also conducted on the CL325,195 metabolite of tralopryil . The results of testing are provided in Table 21

. These results indicate that the CL325,195 degradate is slightly toxic to practically non

- toxic to birds on an a cute oral basis.

Two subacute dietary studies using the technical grade of the active ingredient are anticipated to be required to establish the toxicity of a pesticide to birds, if the use of the pesticide is expected to result in exposure to birds via fo od items. The preferred test species are mallard duck (a waterfowl) and bobwhit e quail (an upland gamebird). Avian dietary testing with waterfowl was required for tralopyril technical and the two major aquatic degradates in order to address the toxicity of the compounds to waterfowl, which may be exposed through feeding or ingestion of

water in waters containing tralopyril or its degradates. Results of the submitted avian subacute dietary tests are provided in Table 21

. These r esults indicate that CL322,250 is highly toxic to waterfowl when ingested via food items. All avian subacute data requirements are fulfilled for the parent and its two major degradates (CL322,250 and CL322,248).

Birds, Chronic

Avian reproduction studies u sing the technical grade of the active ingredient are anticipated to be required for tralopyril because the following conditions are met: (1) birds may be subject to repeated or continuous exposure to the pesticide, especially preceding or during the breed ing season, (2) the pesticide is stable in the environment to the extent that potentially toxic am ounts may persist in animal feed which also includes ingestion of water

, and (3) the pesticide is stored or accumulated in plant or animal tissues (indicated by a K ow 

### value of greater than 1000) . Avian reproduction testing is required for the currently proposed uses of tralopyril

.

### Docket Number EPA

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Page 56 of 69 Table 21

– Toxicity Profile of Tralopyril Parent and Degradates to Birds

Chemical MRID Test Species Study
D uration Toxicity Endpoint Classification

Econea technical 46596005 Mallard Duck ( Anas platyrhynchos ) 11 D L C 50 = 10.76 ppm NOAEL = 5.62 ppm Acceptable

Econea technical 43492809 Northern Bobwhite ( Colinus virginianu s) 14 D LD 50 = 24.7 ; NOAEL = 6 ( mg ai/kg

- bw) Acceptable

Econea technical 43492808 Mallard Duck ( Anas platyrhynchos ) 14 D LD 50 = 77 NOAEL = 20 ( mg ai/kg

- bw) Acceptable

CL 322,250 46596013 Mallard Duck ( Anas platyrhynchos ) 11 D L C 50 = 962 ppm NOAEL = 250 ppm Acceptable

CL 322,248 467 51310 Mallard Duck ( Anas platyrhynchos ) 8 D L C 50 > 5620 ppm NOAEL = 3160 ppm Acceptable

CL 325,195 44452612 Mallard Duck ( Anas platyrhynchos ) 14 D LD 50 > 2250 NOAEL > 2250 ( mg ai/kg

- bw) Acceptable

CL 325,195 44452611 Northern Bobwhite ( Colinus virgini anu s) 14 D LD 50 > 741 NOAEL = 192 ( mg ai/kg

- bw) Acceptable



### Mammals

Wild mammal testing is required on a case

- by

- case basis, depending on the results of lower tier laboratory mammalian studies, intended use pattern and pertinent environmental fate char acteristics. In most cases, rat or mouse toxicity values obtained from studies conducted to support data requirements for human health risk assessment substitute for wild mammal testing. The Agency uses LC 50 

### values from acute oral mammalian studies and N OEC values from 2

- generation reproduction studies along with other mammalian data which may be used for risk characterization (e.g. dermal studies). These toxicity values are reported in Table 16

. 

## Toxicity to Freshwater Aquatic R eceptors

Freshwater Fish, Acute

— Parent and Degradates

Two freshwater fish , one warm water species and one cold water species, toxicity studies using the technical grade of the active ingredient (TGAI) are anticipated to be required to establish the toxicit y of tralopyril to fish. This information is used to determine label hazard statements, as well as to estimate risk to freshwater fish from the proposed use. The preferred test species are rainbow trout (a coldwater fish) and bluegill sunfish (a warmwate r fish). Results for the parent, tralopyril, are tabulated in Table 22

. These results indicate that tralopryil is very highly toxic to freshwater fish on an acute basis. All acute freshwater fish data requirements have been ful filled for the parent.

### Docket Number EPA

- HQ

- OPP

- 201 3

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Page 57 of 69 Based on the patterns of toxicity seen in marine/estuarine fish acute tests, and in freshwater fish chronic tests, the degradates of concern are less toxic than parent tralopryil. Freshwater fish acute toxicity test s with several tr alopryil degradates w ere submitted, however, those studies were determined to be invalid and are therefore are not included. Freshwater fish acute toxicity testing with a coldwater species (Rainbow Trout) using degradate CL322,250 was listed as a data

gap in the 2007 risk assessment. This data gap was fulfilled by MRID 46596010 and additionally a Bluegill Sunfish acute test was submitted (MRID 46596009). All acute freshwater fish data requirements for the major degradates have been fulfilled. The result s of the study confirm that degradate CL322,250 is believed to be less toxic than parent, tralopyril.

Freshwater Fish, Chronic

A freshwater fish early life

- stage test using the technical grade of the active ingredient (TGAI) is anticipated to be required for tralopyril because the end

- use product is expected to be transported to water from the intended use site, and (1) tralopyril is intended for a use such that both the parent and it’s degradates will have a presence in water that is likel y to be continu ous or recurrent, and (2) aquatic acute LC 50 

### values are less than 1 mg/l for the parent and major degradate CL 322,250 . The preferred test species is rainbow trout in this case because it is the most acutely sensitive species tested

, but other species may be used. However, if other species are used an acute test for the chronic tested species is also needed to allow calculation of an

acute

- to

- chronic ratio (ACR). The ACR is then used to estimate the chronic value for the most acutely sensitive species. The results of chronic testing are summarized in Table 22 ; while there are fish early life stage tests with zebra fish there are no corresponding acute 96

- hr LC 50 

### values which would allow calculation of ACR. Therefore, chronic da ta for the most acutely sensitive species is anticipated to be required but may be addressed by either an acceptable zebra fish acute study or a rainbow trout ELS study.

Table 22

– Toxicity Profile of Tralopyril Parent and De gradate s to Freshwater Fish, Acute and Chronic

Chemical MRID Test Species Study Duration Toxicity Endpoint Classification

Econea technical 45893901 Zebrafish ( Danio rerio ) 33 days (ELS) NOAEC =0.17 ppb

LOEC = 0.37 ppb Acceptable

Econea technical 46596002 Rain bow trout ( Oncorhynchus mykiss ) 96 hr LC 50 = 1.300 ppb
NOAEC = 0.68 ppb Acceptable

Econea technical 46596003 Bluegill sunfish ( Lepomis macrochirus ) 96 hr LC 50 = 3.2 ppb
NOAEC = 1.3 ppb Acceptable

CL 322,250 46596009 Bluegill sunfish ( Lepomis macrochirus ) 96 hr LC 50 = 1200 ppb
NOAEC = 550 ppb Acceptable

CL 322,250 46596010 Rainbow trout ( Oncorhynchus mykiss ) 96 hr LC 50 = 520 ppb
NOAEC = 320 ppb Acceptable

CL 322,250 46751307 Zebrafish ( Danio rerio ) 35 d (ELS) LOEC = 140 ppb
NOAEC = 69 ppb Acceptable

EL S: early life stage test

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Page 58 of 69 Freshwater Invertebrates, Acute

— Parent and Degradates

A freshwater aquatic invertebrate toxicity test using the technical grade of the active ingredient is anticipated to be required to establish the toxicity of tralopyril to inv ertebrates. The preferred test species is Daphnia magna . Results of this test using the parent, tralopyril, are listed in Table 23

. The daphnid acute study (MRID #465960

- 01)

, was classified as supplemental due to unexplained lo w percent recoveries in the measured chemical analysis. The guideline deviations were corrected by the registrants (MRID 469179

- 01) and the study was reclassified as acceptable. The results indicate that parent tralopryil is very highly toxic to aquatic i nvertebrates on an acute basis.

A freshwater aquatic invertebrate toxicity test using major degradates CL322,250 and CL322,248, as well as minor degradate CL325,195 were also performed. Results of these tests are listed in Table 23

. The results indicate that C L 322,250 is moderately to highly toxic to aquatic invertebrates on an acute basis and that CL322,248 is slightly toxic to aquatic invertebrates on an acute basis. R esults indicate that minor degradate CL325,195 is moderat ely toxic to aquatic invertebrates on an acute basis.

Freshwater Invertebrates, Chronic

A freshwater aquatic invertebrate life

- cycle test using the technical grade of the active ingredient (TGAI) was required for tralopyril because the end

- use product is expected to be transported to water from the intended use site, and (1) tralopyril is intended for a use such that both the parent and it’s degradates will have a presence in water that is likel y to be continuous or recurrent, and (2) aquatic acute EC 5 0 

### values are less than 1 mg/l for the parent and major degradate CL 322,250. P referred test species is Daphnia magna . Freshwater aquatic invertebrate life

- cycle testing was required for tralopyril due to the likelihood of repeated or continuous exposure from boat hulls, as well as the high acute toxicity to freshwater invertebrates. Results of this test are listed in Table 23

.
These studies show that the parent compound and degradates can cause growth and reproductive effects in aquatic invertebrates, but the degradates are substantially less toxic than the parent compound.

Table 23

– Toxicity Profile of Tralopyril Parent and Degradates to Freshwater
Invertebrates , Acute and Chronic

Chemical MRID Test Spec ies Study Duration Toxicity Endpoint Classification

Econea technical 46596001 Water flea ( Daphnia

magna ) 48 hr EC 50 = 1.5 ppb
NOAEC = 0.32 ppb Acceptable

Econea technical 46596004 Water flea ( Daphnia

magna ) 21 days (LC) N O A EC = 0. 20 ppb a

LOAEC = 0. 57 p pb Acceptable

CL 325,195 45706902 Water flea ( Daphnia

magna ) 48 hr EC 50 = 3, 51 0 ppb NOAEC = 2, 7 00 ppb Supplemental

CL 322,250 46596008 Water flea ( Daphnia

magna ) 48 hr EC 50 = 510 ppb
NOAEC = 250 ppb Acceptable

CL 322,250 45706903 Water flea ( Daphnia

mag na ) 48 hr EC 50 = 1, 63 0 ppb NOAEC = 1, 0 00 ppb Supplemental

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Page 59 of 69 Chemical MRID Test Spec ies Study Duration Toxicity Endpoint Classification

CL 322, 250 45674102 Water flea ( Daphnia

magna ) 48 hr EC 50 = 70 0 ppb
NOAEC = 43 0 ppb Supplemental

CL 322,250 46596011 Water flea ( Daphnia

magna ) 21 days (LC) N O AEC = 30 0 ppb a

LOAEC = 540 ppb Acce ptable

CL 322,248 45674112 Water flea ( Daphnia

magna ) 48 hr EC 50 > 16, 8 00 ppb
NOAEC = 11

, 8 00 ppb Supplemental

CL 322,248 45674113 Water flea ( Daphnia

magna ) 21 days (LC) NOAEC > 1, 37 0 ppb b Supplemental

LC : life cycle test

a ACR for econea and CL 322,2 50 (using only acceptable data) in D. magna is 7.5 and 1.7, respectively. ACR =
acute value chronic NOAEC. The acute NOAEC for CL 322,250 of 250 ppb is lower than the chronic NOAEC of 300 ppb, so the ACR based on this pairing is not sound and is an und erestimate of the ACR.

b An ACR for CL 322,248 cannot be calculated because the acute value and chronic NOAEC are both non

- definitive values.


## Toxicity to Estuarine and Marine Animals

Estuarine and Marine Fish, Acute

— Parent and Degradates

Acute toxicity tes ting with estuarine/marine fish using the technical grade of the active ingredient (TGAI) is anticipated to be required for tralopyril because it is intended for direct application to the marine/estuarine environment. The preferred test species is sheepsh ead minnow. This testing is anticipated to be required for antifoulants. Summaries of the results of studies submitted with tralopyril and degradates are provided in Table 24

. The results indicate that tralopryil parent is highl y toxic to estuarine/marine fish on an acute basis. All acute estuarine/marine fish data requirements have been fulfilled for the parent. The results indicate that CL322,250 is highly toxic to marine/estuarine fish on an acute basis

, that CL322,248 is sl ightly toxic to estuarine/marine fish on an acute basis and that CL325,195 is slightly toxic to marine/estuarine fish on an acute basis.

Estuarine and Marine Fish, Chronic

— Parent and Degradates

Fish early life

- stage toxicity testing was conducted using par ent tralopyril, major degradate CL322,250, and minor degradate CL325,195. These data in Table 24 demonstrate that the parent compound and degradates are capable of impacting fish larval survival and growth. The degradates are su bstantially less toxic than the parent compound.

Table 24

– Toxicity Profile of Tralopyril Par ent and Degradates to Estuarine and Marine Fish , Acute and Chronic

Chemical MRID Test Species Study Duration Toxicity Endpoint Classificat ion

Econea technical 45674003 Sheepshead minnow ( Cyprinodon variegatus ) 96 hr LC 50 = 23.71 ppb NOAEC = 10.0 ppb Acceptable

Econea technical 45674007 Sheepshead minnow ( Cyprinodon variegatus ) 34 d (ELS) N O A EC = 4.3 ppb a
LOAEC = 8.7 ppb Acceptable

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Page 60 of 69 Chemical MRID Test Species Study Duration Toxicity Endpoint Classificat ion

CL 325 ,195 45674013 Sheepshead minnow ( Cyprinodon variegatus ) 96 hr LC 50 > 16 ,000 pp b NOAEC > 16 ,000 pp b Supplemental

CL 325,195 45674017 Sheepshead minnow ( Cyprinodon variegatus ) 34 d (ELS) N O A EC = 1,300 pp b a LOAEC = 2,700 pp b Acceptable

CL 322,248 46751309 Sheepshead minnow ( Cyprinodon variegatus ) 96 hr LC 50 > 89

, 000 ppb
NOAEC > 89

, 000 ppb Acceptable

CL 322,250 45674101 Sheepshead minnow ( Cyprinodon variegatus ) 96 hr LC 50 > 95 0 pp b
NOAEC > 95 0 pp b Supplemental

CL 322,250 45674106 Sheepshead minnow ( Cypri nodon variegatus ) 34 d (ELS) N O A EC = 240 pp b a
LOAEC = 510 pp b Acceptable

ELS: early life stage test

a ACR for tralopyril, CL325,195, and CL 322,250 in sheepshead minnow is 5.51, >12.3, and >3.96, respectively.
ACR = acute value chronic NOAEC.



### Estuarine and Marine Invertebrates, Acute

— Parent and Degradates

Acute toxicity testing with estuarine/marine invertebrates using the technical grade of the active ingredient (TGAI) was required for tralopyril because the end

- use product is intended for direct appli cation to the marine/estuarine environment and testing is required for its major degradate

. The preferred test species are mysid shrimp and eastern oyster. Results of these tests are listed in Table 25

. The results indicate that parent tralopryil is very highly toxic to estuarine/marine invertebrates on an acute basis. E stuarine/marine invertebrate acute toxicity studies using the degradates were also submitted. The results indicate that CL322,250 is highly toxic to estuarine/m arine invertebrates on an acute basis

, CL322,248 is moderately toxic to estuarine/marine invertebrates on an acute basis , and CL325,195 is slightly toxic to marine/estuarine invertebrates on an acute basis.

Estuarine and Marine Invertebrates, Chronic

— Par ent and Degradates

An estuarine/marine invertebrate life

- cycle toxicity test was required for tralopyril because the end

- use product is expected to be transported to water from the intended use site, and (1) tralopyril is intended for a use such that both the parent and it’s degradates will have a presence in water that is likel y to be continuous or recurrent, and (2) aquatic acute EC 50 

### values are less than 1 mg/l for the parent and major degradate CL 322,250. Results of these test s are listed in Table 25

.

Table 25

– Toxicity Profile of Tralopyril Par ent and Degradates to Estuarine and Marine Invertebrates, Acute and Chronic

Chemical MRID Test Species Study Duration Toxicity Endpoint Classification

Econea

t echnical 45674005 Eastern oyster ( Crassostrea virginica ) 96 hr (shell deposition) EC 50 = 0.56 ppb

NOAEC = 0.19 ppb Supplemental

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Page 61 of 69 Chemical MRID Test Species Study Duration Toxicity Endpoint Classification

Econea technical 46751305 Eastern oyster ( Crassostrea virginica ) 96 hr (shell deposition) EC 50 = 0.64 ppb

NOAEC = 0.29 ppb Acceptable

Econea technical 45674006 Mysid ( Americamysis bahia ) 96 hr LC 50 = 0.98 ppb
NOAEC = 0.36 ppb Acceptable

Econea technical 45674009 Mysid ( Americamysis bahia ) 28 d (LC) N O A EC = 0. 25 ppb a
LOAEC = 0. 51 ppb Supplemental

Econea technical 4491110 1 Mysid ( Americamysis bahia ) 28 d (LC) NOAEC = 2.28 ppb LOAEC = 4.2 ppb Acceptable (Study has a higher NOAEC than acute test)

CL 325,195 45674014 Eastern oyster ( Crassostrea virginica ) 96 hr (shell deposition) EC 50 = 14 ,000 pp b

NOAEC = 6,900 ppb Accepta ble

CL 325,195 45674015 Mysid ( Americamysis bahia ) 96 hr LC 50 = 12,250 ppb NOAEC = 5, 3 00 pp b Acceptable

CL 322, 250 45674103 Eastern oyster ( Crassostrea virginica ) 96 hr EC 50 = 310 ppb
NOAEC = 46 ppb Acceptable

CL 322, 250 45674104 Mysid ( Americamy sis bahia ) 96 hr LC 50 = 550 ppb
NOAEC = 33 0 pp b Acceptable

CL 322,250 46596012 Mysid ( Americamysis bahia ) 28 d (LC) N O A EC = 82 ppb
LOAEC = 160 ppb Acceptable

CL 322,248 46751308 Mysid ( Americamysis bahia ) 96 hr LC 50 = 4300 ppb NOAEC = 2500 ppb Acceptab le

LC : life cycle test

a ACR for tralopyril and CL 322,250 in Americamysis bahia is 3.92 and 6.7, respectively. ACR = acute value chronic NOAEC.



### Benthic Invertebrates, Freshwater and Estuarine/Marine

— Parent and Degradates

Sediment toxicity testing is a nticipated to be required for tralopyril and its major degradate CL 322,250 because based on environmental fate characteristics which indicate the se chemical s are expected to partition to sediment, and ecological effects information which indicate high tox icity to aquatic invertebrate species. Parent tralopyril and its degradates are expected to be present in both the water and sediment compartments in water bodies. Parent tralopyril will continually leach and any organisms present will be exposed to the parent compound and its degradates. Subchronic s ediment testing was submitted for tralopryil and its major metabolites, and is summarized in Table 26 . However, these are not chronic reproduction tests. Tralopyril under acidic t o neutral conditions is expected to predominate and be stable for greater than 10 days in freshwater environments and the major degradate CL 322,250 is expected to be stable in seawater conditions. Therefore chronic reproduction tests are anticipated to b e required for the parent in freshwater and for the major degradate CL 322,250 in seawater.

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Page 62 of 69 Table 26

– Toxicity Profile of Tralopyril Parent and Degradat es to Benthic Invertebrates, Freshwater and Estuarine/Marine

Chemical MRID Te st Species Study Duration Toxicity Endpoint Classification

Econea technical 45674010 Amphipod ( Hyalella

azteca ) 10D (subchronic) LC 50 = 2.2 mg/kg

- sed

NOAEC = 1.0 mg/kg

- sed Acceptable

Econea technical 45674011 Amphipod ( Leptocheirus plumulosus ) 10 D (su b chronic) LC 50 = 1.1 mg/kg

- sed

NOAEC = 0.50 mg/kg

sed Acceptable

CL 325,195 45674019 Amphipod ( Hyalella

azteca ) 10 D (subchronic) LC 50 = 49 mg/kg

- sed

NOAEC = 49 mg/kg

- sed Supplemental

CL 325,195 45674020 Amphipod ( Leptocheirus plumulosus ) 10 D (subchron ic) LC 50 = 27 mg/kg

- sed

NOAEC = 27 mg/kg

- sed Acceptable

CL 322,248 45674114 Amphipod ( Leptocheirus plumulosus ) 10 D (subchronic) LC 50 = 75 mg/kg

- sed

NOAEC = 75 mg/kg

- sed Acceptable

CL 322,248 45695804 Amphipod ( Hyalella

azteca ) 10 D (subchronic) LC 50 = 37 mg/kg

- sed

37 mg/kg

- sed Acceptable

CL 322, 250 45674108 Amphipod ( Hyalella

azteca ) 10 D (subchronic) LC 50 = 35 mg/kg

- sed

NOAEC = 35 mg/kg

- sed Acceptable

CL 322, 250 45674109 Amphipod ( Leptocheirus plumulosus ) 10 D (subchronic) LC 50 = 70 mg/kg

- sed

N OAEC = 70 mg/kg

- sed Acceptable



## Toxicity to Plants

Terrestrial/Semi

- Aquatic Plants

— Parent and Minor Degradate

Currently, semi

- aquatic plant testing is anticipated to be required for antifoulant pesticides on one species, rice ( Oryza sativa ). Studies were conducted using parent tralopyril and minor degradate CL325,195. Results of the studies are listed in Table 27

.

Table 27

– Toxicity Profile of Tralopyril Parent and Degradates to Terristrial/Semi Aquati c Plants

Chemical MRID Test Species Study Duration Toxicity Endpoint Classification

Econea technical 45674115 Rice ( Oryza sativa ) 14 D EC 25 > 0.17 ppm NOAEC ≥ 0.17 ppm Acceptable

CL 325,195 45674115 Rice ( Oryza sativa ) 14 D EC 25 > 0.17 ppm NOAEC > 0.17 ppm Acceptable

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Page 63 of 69 Aquatic Plants

— Parent and Degradates

Aquatic plant testing is required for antifoulant pesticides such as tralopyril . Testing is required on one vascular plant ( Lemna sp.), and four species of algae. Results of submitted studies for tral opryil and major d egradates are summarized in Table 28

.

Table 28

– Toxicity Profile of Tralopyril Parent and Degradates to Aquatic Plants

Chemical MRID Test Species Study Duration Toxicity Endpoint Classifi cation

Econea technical 45674117 Freshwater g reen algae ( Raphidocelis subcapitata ) 96 Hr I C 50 = 4.49 ppb
NOAEC = 3.1 ppb Supplemental

Econea technical 45674118 Marine diatom ( Skeletonema

costatum ) 96 Hr I C 50 = 2.88 ppb NOAEC = 0.54 ppb Supplemental

Ec onea technical 45893902 Bluegreen algae ( Anabaena flos

- aquae ) 96 hr I C 50 = 350 ppb
NOAEC = 9.2 ppb Acceptable

Econea technical 45893903 Freshwater diatom ( Navicula

pelliculosa ) 96 hr I C 50 = 5.5 ppb
NOAEC = 0.99 ppb Acceptable

Econea technical 46596006 Freshwater g reen algae ( Pseudokirchneriella subcapitata ) 96 hr I C 50 = 11 ppb
NOAEC = 6.8 ppb Acceptable

Econea technical 46619901 Marine diatom ( Skeletonema

costatum ) 96 hr I C 50 = 2.7 ppb
NOAEC = 1.5 ppb Acceptable

CL 325,195 45674116 Duckweed ( Lemna g ibba ) 7 D I C 50 = 87 .2 ppb
NOAEC = 22 pp b Acceptable

CL 325,195 45674119 Duckweed ( Lemna gibba ) 7 D I C 50 = 13 ,000 ppb NOAEC = 5, 9 00 pp b Acceptable

CL 325,195 45674120 Green algae ( Raphidocelis

subcapitata ) 96 Hr I C 50 = 44 0 ppb
NOAEC = 23 0 pp b Supplemental

CL 325,195 45674121 Marine diatom ( Skeletonema

costatum ) 96 Hr I C 50 = 47 0 ppb
NOAEC = 28 0 pp b Supplemental

CL 325,195 45893906 Freshwater diatom ( Navicula

pelliculosa ) 96 hr I C 50 = 1

, 510 ppb NOAEC = 850 ppb Acceptable

CL 325,195 45945201 Bluegreen alga e ( Anabaena flos

- aquae ) 96 hr I C 50 = 6, 5 00 ppb NOAEC = 1, 4 00 pp b Acceptable

CL 322,250 45674122 Duckweed ( Lemna gibba ) 7 D I C 50 = 99 0 ppb
NOAEC = 53 0 ppb Supplemental

CL 322,250 45674123 Green algae ( Raphidocelis

subcapitata ) 96 Hr I C 50 = 4, 62 0 ppb
NOAEC = 1, 15 0 ppb Supplemental

CL 322,250 45674124 Marine diatom ( Skeletonema

costatum ) 96 Hr I C 50 = 1, 14 0 ppb NOAEC = 180 ppb Supplemental

CL 322,250 45893907 Bluegreen algae ( Anabaena flos

- aquae ) 96 hr I C 50 > 830 ppb
NOAEC > 830 ppb Supplemental

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Page 64 of 69 Chemical MRID Test Species Study Duration Toxicity Endpoint Classifi cation

CL 322,250 45893908 Freshwater diatom ( Navicula

pelliculosa ) 96 hr I C 50 > 930 ppb NOAEC > 930 ppb Supplemental

CL 322,250 46596014 Marine diatom ( Skeletonema

costatum ) 96 hr I C 50 = 660 ppb
NOAEC = 500 ppb Acceptable

CL 322,248 45674125 Duckweed ( Lemna gibba ) 7 d I C 50 > 93 0 ppb
NOAEC > 930 ppb Supplemental

CL 322,248 45674126 Green algae ( Raphidocelis

subcapitata ) 96 h r I C 50 > 1.99 ppm NOAEC > 1.99 ppm Supplemental

CL 322,248 45674127 Marine diatom ( Skeletonema

costatum ) 96 h r I C 50 = 1, 20 0 ppb
NOAEC = 16 0 pp b S upplemental

CL 322,248 45893904 Bluegreen algae ( Anabaena flos

- aquae ) 96 hr I C 50 > 1000 ppb
NOAEC = 1000 ppb Supplemental

CL 322,248 45893905 Freshwater diatom ( Navicula

pelliculosa ) 96 hr I C 50 > 980 ppb NOAEC > 980 ppb Supplemental

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Page 65 of 69 

# Appendix D C omments Received Concerning the Preliminary Work Plan

The Agency received fourteen comment s on the initial docket, described below.

In the PWP, the Agency solicited comments on specific topics: environmental justice, water body impairment, trade irritant s, and structure activity relationships. No comments or information were received during the public comment period concerning these issues.

The Office of Pesticide Programs' Antimicrobial Division (AD) has reviewed the public comments received on the Prel iminary Work Plan (PWP) for the Tralopyril Registration Review Case #5114 ( Docket ID Number EPA

- HQ

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- 201 3

- 0217 ). Twelve c omments were received from an anonymous submitter and two comments were received from the Physicians Committee for Responsible M edicine.

I

- Anonymous Submitter Comments

The following are the comments submitted by an anonymous submitter and EPA ’s response s

.

C omment 1

- Section 1.5 Regulatory History 

### The regulatory history is not correct. An application for registration of the tec hnical product was received by the Antimicrobial Division of USEPA in May 2002. The first registration for both the technical and end

- use product was issued on April 23, 2007. This appears to be out of cycle with the Registration Review timeline of 15 year s. Please comment.

EPA Response to Comment 1 : The Agency thanks the submitter for the information and has made appropriate changes to this document to reflect it.



### Comment 2

- 

### Section 2 Anticipat ed Data Needs 

### An in vitro Salmonella typhimurium reverse mut ation assay (Ames test) has already been reviewed by the Agency. The MRID is 43492840.

EPA Response to Comment 2: EPA concurs. This study has been reviewed and the data are acceptable. The FWP will be updated to remove the Ames test requirement from the Anticipated Data Needs in the final workplan.



### Comment 3

- 

### All of the chronic studies on mammals, anticipated to be required for Registration Review, which are triggered because of the freshwater uses and the need to update the drinking

water assessmen t, (870.3700, .3800, .4100, 4200), are available for the precursor molecule of tralopyril. In the new 40 CFR 158 Data Requirements for Antimicrobial Pesticides, USEPA mentions its intention to use integrated approaches to testing and risk assessment, to ma ximize the use of existing data from similar compounds, including in silico predictive models. EPA should utilize these studies to satisfy these specific data gaps, especially considering the low anticipated exposure from incidental ingestion and drinking water because of the rapid

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Page 66 of 69 degradation half

- lives by biotic and abiotic processes, hydrolysis, and photolysis. This is an excellent case to employ QSAR modeling and TTC analysis for tralopyril and degradates.

EPA Response to Comment 3: The Agency encour ages the use integrated approaches to testing and risk assessment, to maximize the use of existing data from similar compounds, including in silico predictive models . However, based on the list of the anticipated study requirements, once the data are requi red, the registrant will need to submit information (including any waiver requests) to fulfill the data requirements. The a gency will review the package to decide whether the information provided is good enough to waive any of the required studies. The A gency and Health Canada’s Pest Management Regulatory Agency (PMRA) have cooperated on the development of a guidance document on the use of Quantitative Structure Activity Relationships [(Q)SAR] for pesticide risk

assessors. The guidance document will be us ed as a base to evalu ate the submitted information. The guidance document is located at: http://www.epa.gov/oppfead1/cb/csb_page/updates/2012/qsar

guidance.html

.



### Comment 4

- 

### Table 7

– Leaching from antifoulant paint in freshwater. Tralopyril hydrolyses rapidly, with a half

- life of 0.4 days in freshwater (pH 7). Because of this property, the analytical method recommended by ISO 15181

- 6: 20121, for determining the release r ate of tralopyril, specifies for accelerating the conversion of released tralopyril into the primary hydrolysis degradate CL322,250 by heat treatment and quantifying the concentration of the CL 322,250 degradation produc, and back calculating to determine the tralopyril concentration. EPA should provide guidance whether ISO 15181

- 6: 2012 with the additional analysis of degradate CL 322,248 would provide the Agency the information needed for risk assessment, or whether new sample handling procedures need to be developed and validated which stop or significantly slow the hydrolytic and photolytic degradation of tralopyri,l so that tralopyril and two degradates can all be measured.

EPA Response to Comment 4 : The commenter is correct in the observation that tr alopyril hydrolyses rapidly, with a half

- life of 0.4 days in freshwater (pH 7) to form CL 322,250. The commenter also suggests using the analytical method recommended by ISO 15181

- 6 for determining the release rate of tralopyril. Although the commenter provides a reasonable approach for calculating the leaching rate and potential exposure from parent tralopyril, the ISO 15181

- 6 test guideline is based on simulated seawater, and not fresh water. As a result, the use of this methodology is not acceptable at this time. If it is possible to demonstrate that leaching rates are similar in fresh and sea water, then this methodology could possibly be used to determine the leach rates of tralopyril and its degradates.
There is a need for leaching data from trea ted paints in freshwater environments. Freshwater leaching would provide information for use in the assessment of tralopyril, and the CL 322,250 degradate in the environment

.



### Comment 5

- Section 3.1.2 Drinking Water 

### Fourth bullet

– EPA anticipates reque sting freshwater leaching data, which are generally conducted according to ASTM test metho ds . However it is clearly stated in the standard that “The results of this test method do not reflect environmental biocide release rates for antifouling products, an d are not suitable for direct use in the process of generating environmental risk assessments, environmental loading estimates, or for establishing release rate limits for regulatory purposes.” It further states that “results obtained using this test metho d do not reflect

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Page 67 of 69 actual biocide release rates that will occur in service, but provide comparisons of the release rate characteristics of different antifouling formulations...” and that “ the results of this generic rotating

- cylinder test method significantly overestimate the release rate of biocide compared to release rates under in

- service conditions.” Rather, the ISO calculation method is a much better predictor of leach rate under in

- service use conditions. Please comment on how AD sees the utility of thes e two methods, if it is the intention to use the results from the ISO method in the MAMPEC modeling for risk assessments and how either release rate methods will be used to refine drinking water residue values.

EPA Response to Comment 5 : The ASTM methods generally do not provide realistic estimates of the leaching that occurs from antifoulant paints in fresh and salt water. However, it is uncertain at this time whether or not the ISO method will be useful as an alternative to the ASTM methods because it i s based on numerical estimations without confirmatory laboratory data. As a result, the EPA intends to use the ASTM leaching study results as a MAMPEC input and to address drinking

water.



### Comment 6

- Section 4.1 Environmental Fate and Exposure Pathways


### F inal paragraph page 23

– EPA is critical of the leach rates used for the freshwater risk assessments in MRIDs 47250101 and 47301601. The leach rate for this particular AF paint was 1.9 μg/cm2/day based on the mass balance calculation, as prescribed by ISO 10890:2010; the release rate used in the assessment was more than double the calculated in service release rate. Please also see comments under 3.1.2 for using the ISO method as a refinement to the leach rate determined by ASTM.

EPA Response to Comment 6 : At this time, EPA relies on ASTM methodology because of the availability of confirmatory laboratory data. The EPA has not received data that would validate the ISO calculation method, and therefore the EPA intends to use ASTM leaching rates in its risk

assessments.



### Comment 7

- Section 4.2.2 Measures of Effect (Ecotoxicology Assessment Endpoints)



### Table 12

– For terrestrial mammal/rat/acute oral, there is an acceptable study under MRID 43492826 in which definitive LD50 values were obtained. These wer e reported as:

o Males = 27.0 mg/kg

o Females = 29.4 mg/kg

o Combined = 28.7 (16.8

– 30.7) mg/kg (95% CI)

EPA Response to Comment 7 : EPA concurs that we can use 

### MRID 43492824 to provide information for tralopyril on the LD50 for rats. T able 1 3 will b e revised to reflect this change

. These data were not listed in the anticipated data requirements table. Note that the comment refers to MRID 43492826. According to EPA’s records, MRID 43492824 was conducted with the parent compound and MRID 43492826 wa s conducted with CL 322.250

.

Comment 8

- Table 13

- For terrestrial mammal/rat/acute oral, there is an acceptable study under MRID 43492824 in which definitive LD50 values were obtained

. These were reported as:

o Males > 5,000 mg/kg o Females = 2,500 (1 ,581

– 3,954) mg/kg (95% CI)

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Page 68 of 69 EPA Response to Comment 8 : EPA concurs that we can use 

### MRID 4349282 6 to provide information for CL 322.250 (the defluorinated tralopyril) on the LD50 for rats. T able 13 will be revised to reflect this change . These data w ere not listed in the anticipated data requirements table. Note that the comment refers to MRID 43492824. According to EPA’s records, MRID 43492824 was conducted with the parent compound and MRID 43492826 was conducted with CL 322.250

.

Comment 9

- 

### Tab le 1 3

- For terrestrial mammal/rat/chronic

– the reference should be to Table 7 (not table 1) for anticipated data needs

. Table 7 references chronic studies for tralopyril only. There is no anticipated requirement for chronic studies for degradate CL 322,2 50. Please see second bullet under 2 Anticipated Data Needs suggesting the proposed use of QSAR modeling where appropriate. Please note that both 14

- day (dose

- range finding) and 28

- day oral toxicity studies were performed with degradate CL 322,250 in Septe mber 2012 and assigned MRIDs 48937101 and 48937102, respectively.

EPA Response to Comment 9 : Please see Response to Comment 3. EPA will consider QSAR modeling where appropriate. The registrant should provide either the data or the QSAR rationale.



### Com ment 10

- Section 4.3 Exposure Analysis Plan 

### See comment under 2 Anticipated Data Needs under the third bullet, with regard to the request for fresh water leaching data.

EPA Response to Comment 1 0: See response under Comment 4.



### Comment 11

- Appendix A Toxicology Profile



### Table 15, acute oral, rat

– same comment as above under 4.2.2, Table 12.

EPA Response to Comment 1 1: Please see response Comment 7.



### Comment 12

- Mutagenicity

– see comment under 2. Anticipated Data Needs under the first bullet with regard to the availability of an acceptable Ames test already reviewed by the Agency.

EPA Response to Comment 12 : Please see response Comment 2. The mutagenicity test will be removed from the anticipated data needs.



### II

– Physicians Committee for Resp onsible Medicine Comments

Comments 13 and 14 were received from the Physicians Committee for Responsible Medicine

.

Comment 13

- Because the technical registrant, Janssen Pharmaceutica, Inc., is a pharmaceutical company we believe that data may be availab le, especially for the chronic and

### Docket Number EPA

- HQ

- OPP

- 201 3

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Page 69 of 69 reproductive toxicity endpoints. We encourage the registrant to attempt to rely on existing data as much as possible. Under EU regulatory authority, Tralopyril is classified as a biocide and was recently discussed by the Joint Research Centre, based on a publicly available agenda. Therefore, some data may be available at the European Chemicals Agency (ECHA). We encourage the EPA to contact ECHA and attempt to accept any data it may receive. We also encourage the registran t to look into data that ECHA may hold.

EPA Response to Comment 13 : Due to the persistent degradate of the chemical tralopyril we believe that chronic data are necessary and anticipate requiring them . Along with Physicians Committee for Responsible Medi cine

, we encourage the registrant to submit any chronic data already developed, as long it satisfies the Agency’s needs to allow for a complete risk assessment
of the chemical.

Comment 14

- If it is determined that the reproductive study is required then w e suggest the registrant use the OECD TG 443 Extended One

- Generation Reproductive Toxicity Study (EOGRTS) instead of the EPA guideline 870.3800 Two

- Generation Reproduction. This will allow the registrant to conduct one extended study saving many animals li ves while addressing endpoints of interest. The TG is currently available on the OCED web site

.
EPA Response to Comment 14: EPA 

### considers the OECD E xtended O ne

- G eneration
R eproductive T oxicity Study to be an acceptable substitute for GLN 870.3800 Two

- Gen eration Reproduction

.