Docket Number EPA

- HQ

- OPP

- 2014

- 0800

Copper HDO Registration Review Team

Human Health & Environmental Effects David Bays
Jim Breithaupt Siroos Mostaghimi
Jonathan Leshin Tim Dole Jaclyn Pyne

Risk Management Donna Kamarei Lorena Rivas Rose Kyprianou

Office of General Counsel Philip Ross

Page 2 of 47Docket Number EPA

- HQ

- OPP

- 2014

- 0800

TERMS, ABBREVIATIONS AND SYMBOLS

A.I. or a.i. active ingredient
atm

- m 3 /mole a tmospheric pressure

- cubic meter per mole °C d egrees Celsius CAS Chemical Abstracts Service CFR Code of Federal Regulations DCI data call

- in EC 50 m edian (or 50 percent) e ffect c oncentration EC 05 5 p ercent e ffect c oncentration ECOTOX ECOTOXicology EDSP E ndocrine Disruptor Screening Program EPA Environmental Protection Agency FDA Food and Drug Administration FFDCA Feder al Food, Drug, and Cosmetic Ac t FIFRA Federal Insecticide, Fungicide, and Rodenticide Act FQPA Food Quality Protection Act FWP Final Work Plan g/mol g rams per mole GLN guideline number IDS Incident Data System Koc o rganic carbon normalized soil

- water partition coefficient Kow o ctanol

- water partition coefficient LC 50 m edian (or 50 percent) l ethal c oncentration LD 50 m edian (or 50 percent) l ethal d ose LOAEC l owest

- o bserved

- a dverse

- e ffect

- c oncentration LOAEL lowest

- observed

- adverse

- e ffect

- l evel Log K ow l ogarithm of the octanol

- water partition coefficient
μg m icrogram mg/kg m illigram p er k ilogram mg/kg/day m illigram p er k ilogram p er d ay mg/L m illigram p er l iter mm Hg m illimeter of mercury MOE m argin of e xposure MRID Master Record Identification Number MRL m aximum r esidue l imit N/A n ot a pplicable

nm n anometers NOAEC no

- observed

- adverse

- effect

- c oncentration NOAEL n o

- o bserved

- a dverse

- e ffect

- l evel OCSPP Office of Chemical Safety and Pollution Prevention OECD Organization for Economic Co

- operation and Development OPP Office of Pesticide Programs % p ercent PC Code Pesticide Chemical Code PCF p ounds p er c ubic foot pH power of h ydrogen or power of the con centration of the hydrogen ion
ppm p arts p er m illion PWP Preliminary Work Plan QSAR q uantitative s tructure

- a ctivity r elationship RED Rere gistration Eligibility Decision

Page 3 of 47Docket Number EPA

- HQ

- OPP

- 2014

- 0800

SAR s tructure a ctivity r elationship SF s afety f actor TGAI t echnical grade active i ngredient TMDL total maximum daily l oads UF uncertainty factor UV/VIS ultraviolet/v isible light a bsorptio n WWTPs w astewater treatment plants

Page 4 of 47Docket Number EPA

- HQ

- OPP

- 2014

- 0800



### Table of Contents
1 Introduction

................................ ................................ ................................ ............................. 7 1.1 Statutory and Regulatory Authority

................................ ................................ ................. 7 1.2 Case Overview

................................ ................................ ................................ ................. 8 1.3 Chemical Identification and Properties

................................ ................................ ............ 9 1.4 Use/Usage Description

................................ ................................ ................................ ... 10 1. 4.1 Registrations

................................ ................................ ................................ ........... 10 1.4.2 Summary of Registered Uses

................................ ................................ .................. 10 1.5 Regulatory History

................................ ................................ ................................ ......... 11 1.5.1 Tolerance Information

................................ ................................ ............................ 11 1.6 Incidents

................................ ................................ ................................ ......................... 11 1.6.1 Human Health

................................ ................................ ................................ ......... 11 1.6.2 Ecological

................................ ................................ ................................ ............... 11 2 Anticipated Data Needs

................................ ................................ ................................ ........ 12 3 Hu man Health Risk Assessment

................................ ................................ ........................... 14 3.1 Existing Toxicological Endpoints

................................ ................................ .................. 14 Carcinogenicity Study/Rats

................................ ................................ ................................ .......... 14 3.2 Dietary Exposure

................................ ................................ ................................ ............ 15 3.2.1 Fo od

................................ ................................ ................................ ........................ 15 3.2.2 Drinking Water

................................ ................................ ................................ ....... 15 3.3 Occupational and Residential Exposures

................................ ................................ ....... 15 3.3.1 Occupational Exposures

................................ ................................ .......................... 15 3.3.2 Residential Exposures

................................ ................................ ............................. 15 3.4 Aggregate and Cumulative Exposure

................................ ................................ ............. 16 3.4.1 Aggregate Exposures

................................ ................................ .............................. 16 3.4.2 Cumulative Exposures

................................ ................................ ............................ 16 4 Environmental Risk Assessment

................................ ................................ ........................... 16 4.1 Environmental Fate Assessment

................................ ................................ .................... 17 4.1.1 Waste Water Treatment Plants (WWTPs)

................................ .............................. 17 4.1.2 Water Quality

................................ ................................ ................................ .......... 17 4.2 Envi ronmental Exposure Pathways

................................ ................................ ................ 18 4.2.1 Mechanism of Action

................................ ................................ .............................. 18 4.2.2 Measures of Effect (Ecotoxicology Endpoints)

................................ ...................... 18 4.3 Exposure Analysis Plan

................................ ................................ ................................ .. 20 4.3.1 Aquatic and Terrestrial Wildlife Exposure Estimates

................................ ............ 20 4.3.2 Screening Level Down

- the

- Drain Analysis

................................ ............................ 20 4.4 Effects Analysis Plan

................................ ................................ ................................ ..... 20 5 Endocrine Disruptor Screening Program (EDSP)

................................ ................................ . 21 6 Optional Label Changes

................................ ................................ ................................ ........ 22 7 Guidance for Commenters

................................ ................................ ................................ .... 2 2 7.1 Preliminary Work Plan

................................ ................................ ................................ ... 22 7.1.1 Trade Irritants

................................ ................................ ................................ .......... 22 7.1.2 Water Quality

................................ ................................ ................................ .......... 22 7.1.3 Environmental Justice

................................ ................................ ............................. 22 7.1.4 Structure Activity Relationships

................................ ................................ ............. 23 7.1.5 Additional Information

................................ ................................ ........................... 24

Page 5 of 47Docket Number EPA

- HQ

- OPP

- 2014

- 0800

8 Next Steps

................................ ................................ ................................ ............................. 24 9 References

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

Appendix A T oxicology Profile

................................ ................................ ............................... 28 Appendix B Environmental Fate

................................ ................................ ............................. 34 Appendix C Ecotoxicology Profile

................................ ................................ .......................... 40 Appendix D Chemical and Physical Properties

................................ ................................ ....... 47

List of Tables Table 1

– Anticipated Risk Assessments for Registration Review: Cu HDO

................................ . 8 Table 2

– Anticipated Registration Review Schedule

................................ ................................ .... 8 Table 3

– Chemical Identification of Cu HDO

................................ ................................ .............. 9 Table 4

– Physical

- Chemical Properties for Cu HDO

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

– Chemical and Physical Properties of Cu HDO Degradates

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

– Summary of Cu HDO Registered Uses

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

– Studies Anticipated as Needed for the Registration Review of Cu HDO

.................... 13 Table 8

– Existing Toxicological Endpoints

................................ ................................ ................. 14 Table 9

– Occupational Exposure Scenario for Cu HDO

................................ ............................. 15 Table 10

– Residential Exposure Scenario for Cu HDO

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

– T e st S p ec ies Eva lu a te d f or Ass e ss in g P o t e n tial E c olog i c al E f fec ts of Cop p e r a n d the A ssocia te d A c ut e Toxici t y Class if ica t i on

................................ ................................ ..................... 19

Page 6 of 47Docket Number EPA

- HQ

- OPP

- 2014

- 0800



## 1 Introduction

This document is the United States Environmental Protection Agency ’s ( USEPA, EPA or “the
agency ”) Preliminary Work Plan (PWP) for Copper, bis[1

- cyclohexyl

- 1,2

- di(hydroxy

- .kappa.O)diazeniumato(2

- )]

- , herein referred to as copper HDO or Cu HDO . The PWP document explains what EPA's Office of Pesticide Programs (OPP) knows about Cu HDO , highlighting anticipated data and assessment needs, identif ying the types of information that would be especially useful to the agency in conducting the review, and providing an anticipated timeline for completing Cu HDO ’s review.

The registration review process was designed to include a public participation compo nent to solicit input from interested stakeholders. The agency intends, by sharing this information in the docket, to inform the public of what it knows about Cu HDO and what types of new data or other information would be helpful for the agency to receive as it moves toward a decision on Cu HDO

. The agency encourages all interested stakeholders to review the PWP and to provide comments and additional information that will help the agency ’s decision

- making process for this chemical.



## 1.1 Statutory and Regulator y Authority
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 USEPA 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 policies and practices change, all registered pesticides continu e to meet the statutory standard of no unreasonable adverse effects to human health or the environment. Changes in science, public policy, and pesticide use practices will occur over time. Through the registration review program, the agency periodically re evaluates pesticides to make sure that as change occurs, products in the marketplace can be used safely. Information on this program is provided at http://www2.epa.gov/pesticide

- reevaluation

.

The a gency is implementing the registration review program pursuant to Section 3(g) of the Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA) and will review each registered pesticide every 15 years to determine whether it continues to meet the FIFRA s tandard for registration. The regulations governing registration review begin at 40 CF R 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 fo r 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. After reviewing and responding to commen ts and data received in the docket during this initial comment period, the agency will develop and commit to a F inal W ork P lan (FWP) and anticipated schedule for the Cu HDO case

.

Page 7 of 47Docket Number EPA

- HQ

- OPP

- 2014

- 0800



## 1.2 Case Overview

The docket for Cu HDO (case 5106) has been established at http://www.regulations.gov in docket number EPA

- HQ

- OPP

- 2014

- 0800. Documents associated with this registration review can be view ed at this docket

. Tables 1 and 2 below summarize the issues relevant to this registration review case and the anticipated registration review schedule.

Table 1

– Anticipated Risk Assessments for Registration Review : Cu HDO

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 7 for detail s)

Dietary (food) No N/A None None Dietary (drinking water) No N/A None None

Occupational Handler Yes 9/10/2004 Updated Dermal and i nhalation e xposure d ata Subchronic inhalation toxicity Reproduction and fertility effects study Carcinogenicity

– mouse Neurotox screening battery

, acute Neurotox screening battery

, subchronic Immunotoxicity

Residential Handler No N/A None None

Resident i al Post Application

- Incidental Oral and Dermal Yes 9/10/2004 Updated Surface r esidue d ata Neurotox screening battery

, acute Neurotox screening battery

, subchronic Immunotoxicity Aggregate No N/A None None

Cumulative No N/A None None

Tolerance Review No N/A None None

Ecological Yes 10/24/2005 Updated Aerobic soil metabolism Anaerobic aquatic metabolism
N/A = Not applicable

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 2015

- 03 2015

- 03

- 25
Close Public Comment Period 2015

- 05 Phase 2: Case Development
Issue Final Work Plan 2015

- 09
Issue Data Call

- In (DCI) 2016

- 0 3
Receive Data to be Considered in Risk Assessment 2020

- 03 Open 30

- Day Public Comment Period for Preliminary Risk Assessment(s) 202 1

- 09
Close Public Comment Period 202 1

- 10 Phase 3: Registration Review Decision and Implementation

Page 8 of 47Docket Number EPA

- HQ

- OPP

- 2014

- 0800

Open 60

- Day Public Comment Period for Pro posed Decision 2022

- 03
Close Public Comment Period 2022

- 05
Issue Final Decision 2022

- 09 Begin Post

- Decision Follow

- up 2022
Total (years) 7

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



## 1.3 Chemical Identification and Properties

Table 3 prese nts the active ingredient to be assessed in case 5106 : parent Cu HDO (PC Code 235500). Table 4 includes chemical and physical property data for parent Cu HDO and Table 5 includes chemical and physical property data for the degradates HDO, cyclohexanone oxime, and cyclohexanone

. The full citations for the product chemistry information can be found in Appendix D

.

Table 3

– Chemical Identification of Cu HDO

Chemical Name Cu HDO
Chemical Classification Copper

- Diazenium

- Compound
Chemical name Bis

- (N

- cyclohexyldiazeniumdioxy)

- copper Smiles code C1(N2N=O{

- }[Cu]{2+}3(O2)O=NN(C2CCCCC2)O{

- }3)CCCCC1
PC Code 235500
CAS N umber 312600

- 89

- 8
Molecular Formula C 12 H 22 N 4 O 4 Cu Molecular Weight (grams/mole) 349.9

Molecular Structure

Table 4

– Physical

- Chemical Properties fo r Cu HDO

Guideline No. Parameter Cu HDO Reference (MRID unless specified) and comments

830.7050 UV/Visible Absorption Maximum sorption at 350 nm with sorption through 800 nm 45687201

830.7370 Dissociation constant Not applicable 45687203 No ionizable functional groups

830.7550 Octanol

- water partition coefficient (Log K ow ) 2.6 @ pH 6.1 and 20 o C 1.6 @ pH 4 and 20 o C 45687201

830.7840 Solubility in water 34 mg/L @ pH 4.0 and 23 o C 6.1 mg/L @ pH 7 and 23 o C 8.6 mg/L @ pH 9 and 23 o C 45687202

830.7950 Vapor pressure 7.5 x 10

- 7 mm Hg @ 20 o C 45687201
None (calculated) Henry’s Law Constant 5.7 x 10

- 8 atm

- m 3 /mol 1 @ pH 7 and 25 o C (VP * MW)/(760 * water solubility)

Page 9 of 47Docket Number EPA

- HQ

- OPP

- 2014

- 0800

1 atm

- m 3 /mol = atmosphere cubic meter per mole

Table 5

– Chemical and Physical Properties of Cu HDO Degradates 1

Test Guideline (OCSPP No.) HDO (half

- of molecule) Cyclohexanone Cyclohexanone oxime

Structure

Smiles code C1CCCCC1(N(O)=NO) O=C(CCCC1)C1 C(CCCC1)C1=NO Molecular formula C 6 H 13 N 2 O 2 C 6 H 10 O C 6 H 11 NO Molecular weight 145.18 98.15 g/mol 113.16 g/mol Octanol

- water partition coefficient /Log Kow ( 830.7550 ) - 1.64 at 25 o C 0.81 @ 25 o C 0.84 @ 25 o C
Solubility in water ( 830.7840 ) 7 33

, 90 0 mg/L 25,000 mg/L 18,000 mg/L Vapor pressure ( 830.7950 ) 2.4 x 10

- 11 @ 25 o C 4.3 mm Hg @ 25 o C 1.09 x 10

- 2 mm Hg @ 25 o C Henry's law constant No OCSPP number 6.1 x 10

- 18 ( atm

- m 3 /mol ) @ 25 o C 9 x 10

- 6 ( atm

- m 3 /mol ) @ 25 o C 2.3 x 10

- 7 ( atm

- m 3 /mol ) @ 25

o C



## 1.4 Use/Usage Description

1.4.1 Registrations

There are two EPA registered pressure

- treatment products that contain Cu HDO as an active ingredient (a.i.). One product is registered as a manufacturing use product (MUP, 97.75 % active ingredient, 17.75 % metallic copper) 2 and the other product is registered as an end

- use product (EUP, 3.5 % active ingredient, 10 % metallic copper). 3 Both products are liquid formulations (emulsifiable concentrates).



### 1.4.2 Summary of Registered Uses

Table 6 presents a summary of the registered uses of Cu HDO that will be assessed in this registration review

. Cu HDO can be applied using pressure treat ment to wood to be used in decking, rails, spindles, framing, sill plates , gazebos, fencing, and posts. The treatment solution should contain 0.2

- 3 % active ingredients 4 by weight, and the retention should adhere to the current specification of the American Wood Preservers Association (AWPA).

1 All values from EPI

- WEB 4.11.

2 EPA Reg. No. 241

- 420, approved 7/16/2010

3 EPA Reg. No. 71406

- 2, approved 5/21/2010, Protectol CX TM Type A

4 The other ingredients include copper carbonate (16.3 %) and boric acid (5 %) N

H H

O
N O

H

Page 10 of 47Docket Number EPA

- HQ

- OPP

- 2014

- 0800

Table 6

– Summary of Cu HDO Registered Uses

Use Application Method and Rate Retention per AWPA Lumber and plywood used as decking, rails, spindles, framing, sill plates, gazebos, fencing and posts

. Sawn Products UCI, Above Ground, Interior, Dry Sawn Products UC 2 , Above Ground, Interior, D amp Pressure treatment using 0.2 to 3% a.i. in treatment solution 0.206 PCF*

Sawn Products UC 3A , Above Ground, Exterior

, Coated and rapid run off Sawn Products UC 3B , Above Ground, Exterior

, Exposed and poor runoff 0.206 PCF*

Plywood UC1 and UC2 0.206 PCF *

* R etention for Cu HDO , Type A (CX

- A) which includes copper, boric acid and HDO

. The retention for the HDO portion is 0.023 pounds per cubic foot ( PCF )

. 

## 1.5 Regulatory Histor y

The first product containing Cu HDO was registered on November 22, 2005 for the use of wood

treatment

. A Reregistration Eligibility Decision (RED) was not completed for Cu HDO because it was registered after November 1, 1984.



### 1.5.1 Tolerance Information

T he EPA has no t established tolerances or exemptions from tolerances in raw agricultural commodities or processed food and feed products under the Federal Food, Drug and Cosmetic Act (FFDCA) Section 408 for Cu HDO

. The Food and Drug Administration (FDA) has not established an y food use clearances in FFDCA S ection 409 for Cu H DO. There are no currently registered uses for this active ingredient associated with food or feed.



## 1.6 Incidents

1.6.1 Human Health

No Cu HDO human poisoning incidents have been reported in OPP’s Incident Data System (IDS) for the time period spanning 11/22/2005 ( when Cu HDO was first registered) to the present (search conducted on 1/8/2015).



### 1.6.2 Ecological
No Cu HDO ecological incidents have been reported in EIIS since 2005 to the present (search conducted on 1/13/2015). Although copper compounds have been used as pes ticides for over 100 years, relatively few incidents have been associated with copper compounds and have been reported in the Ecological Incident Information System ( EIIS ) (before 10/24/2005). Incidents were onl y reported for copper sulfate. Of the 24 repo rted incidents, 7 were associated with terrestrial plants and the rest were associated with kills of aqua tic organisms, primarily fish. These remaining incidents were generally fish kills of carp, bass, trout, sunfish, perch, cat fish, shiner and mosquitofi sh. Other aquatic organisms reported incl uded frogs, clams and turtles.

Page 11 of 47Docket Number EPA

- HQ

- OPP

- 2014

- 0800



## 2 A nticipated Data Needs

Table 7 presents a summary of the data anticipated as being needed to support this registration review.

Page 12 of 47Docket Number EPA

- HQ

- OPP

- 2014

- 0800 www.regulations.gov Table 7

– Studies Anticipated as Needed for the Registration Review of Cu HDO

GLN Study Name Test Substance Time Frame (Measured in months from DCI Receipt) Risk Assessment(s) Data Will Support Use Site(s) Triggering Anticipated Data

Requirement Applicable Expos ure Scenario

Studies Anticipated to be Required through the Registration Review DCI

835.4100 Aerobic soil metabolism HDO 24 Environmental fate and ecological effects Pressure treatment of wood Environmental
exposure

835.4400 Anaerobic aquatic metabolism HDO 24 Environmental fate and ecological effects Pressure treatment of wood Environmental
exposure

870.3465 Subchronic inhalation toxicity TGAI Cu HDO 24 Human Health Pressure Treatment of wood Occupational

870.3800 1 Reproduction and fertility effects study TGAI Cu HDO 48 Human Health Pressure Treatment of wood All

870.4200 Carcinogenicity

– mouse TGAI Cu HDO 48 Human Health Pressure Treatment of wood All

870.6200 Neurotoxicity screening battery
acute TGAI Cu HDO 48 Human Health Pressure Treatment of wood All

870.6200 Neurotoxicity screening battery subchronic TGAI Cu HDO 48 Human Health Pressure Treatment of wood All

870.7800 Immunotoxicity TGAI Cu HDO 24 Human Health Pressure Treatment of wood All

875.2300 Surface Residues TGAI Cu HDO 12 Human Health Decking and Gazebos Residential

875.1200 Dermal Exposure TGAI or segregate 24 Human Health Pressure Treatment of wood Occupational

875.1400 Inhalation Exposure TGAI or segregate 24 Human Health Pressure Treatment of wood Occupational

1 Results from a multi

- generation (EPA guideline 870.3800) or an extended one

- generation reproductive and fertility effects study using OECD Test Guideline 443 ( http://www.oecd

ilibrary.org/environment/test

- no

- 443

- extended

- one

- generation

- reproductive

- toxicity

- study_9789264185371

- e n ) will satisfy this anticipated requirement.

Page 13 of 47Docket Number EPA

- HQ

- OPP

- 2014

- 0800 www.regulations.gov



## 3 Human Health Risk Assessment

The agency anticipates the need to conduct a human health risk assessment for Cu HDO . The
agency expects to require additional data for use in conducting the registration review

.


## 3.1 Existing Toxicological Endpoints

EPA anticipates the need to revise the existing toxicological endpoints as part of this registration review. Table 8 presents the endpoints used in EPA’s most recent human health risk assessment in support of the 2005 regis tration

. 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 establishing the endpoints to be used in the registration review risk assessment. A detailed description of the toxicity studies is provided in Appendix A

.

Table 8

– Existing Toxicological Endpoin ts

Exposure Scenario Dose Used in Risk Assessment Target Margin of Exposure (MOE), Uncertainty Factor (UF ) Study and Toxicological Effects

Acute Dietary (General population, including infants and children) NOAEL = 30 mg/kg/day UF = 10X intraspecies, 10X intraspecies, Acute RfD = 0.3 mg/kg/day Developmental Toxicity Study/Rabbit LOAEL = 60 mg/kg/day based on

embryotoxicity and fetotoxicity

Chronic Dietary (all populations) NOAEL = 6 mg/kg/day UF = 10X intraspecies, 10X intraspecies

Chronic RfD = 0.0 6 mg/kg/day Carcinogenicity Study/Rats LOAEL = 33 mg/kg/day based on increases in the incidence and/or severity of the non

neop lastic lesions of the forestomach (i.e. sub

- mucosal edema, ulceration, parakeratosis

and hyperplasia). The test material is not considered carcinogenic.

Incidental Oral, Short

- and Intermediate

- Term NOAEL= 26 mg/kg/day MOE = 300 (residential) [10x interspecies, 10x intraspecies, 3x database uncertainty]

MOE = 100 ( occupational ) Subchronic oral toxicity in Dogs LOAEL =69 mg/kg/day, Based on clinical toxicity, increased liver weight, and changes in clinical chemistry.

Dermal, Short

- , Intermediate

- , and Long

- Term Oral NOAEL = 26 mg/kg/day MOE = 300 (residential) [10x interspecies, 10x intraspecies, 3x database uncertainty]

MOE = 100 ( occupational ) Subchronic Oral Toxicity in Dogs (Same as above for incidental oral)

Inhalation, Short

- , Intermediate

- , and Long

- Term Oral NOAEL = 6 mg/kg/day MOE = 1000 [10x interspecies, 10x intraspecies, 10x route extrapolation] Carcinogenicity study in rats (Same as above for chronic dietary)

Carcinogenicity This compound is not currently considered carcinogenic based on a single rat study.

Page 14 of 47Docket Number EPA

- HQ

- OPP

- 2014

- 0800



## 3.2 Dietary Exposure

The a gency does not anticipate the need to conduct a dietary exposure assessment t o support this registration review because dietary exposure is not expected based on the currently regi stered

uses

.


### 3.2.1 Food

There are no registered uses for Cu HDO associated with food or feed (e.g.

, bee hives and food packaging )

, thus the registered uses of Cu HDO are not anticipated to result in food exposures. However, the labels do not clearly state that uses are for non

- food contact; the labels should be revised to clearly state this. The a gency does not anticipate the need to conduct a dietary
exposure (food only) assessment to support registration review.



### 3.2.2 Dr inking Water

The agency does not expect Cu HDO or degradates to be present in drinking water , and runoff to surface water used for drinking water sources is expected to be limited

. Copper will sorb strongly to soil and sediment

, and the HDO portion is not expected to persist in the environment because of expected microbial degradation. The agency anticipates requiring aerobic soil metabolism a nd anaerobic aquatic metabolism data to confirm m icrobial degradation

.


## 3.3 Occupational and Residential Exposures
Occupational exposures to Cu HDO are anticipated to occur during pressure treatment

, and residential exposures are anticipated to occur during contact with treated wood that is used in
p layground equipment and decks. These exposures were assessed in a huma n exposure review (EPA, 2004) that was written in support of Cu HDO as a new active ingredient.



### 3.3.1 Occupational Exposure s EPA anticipates the need to revise the occupational handler assessment included in the 200 4 human exposure review to account for exposure data and toxicological data that are anticipated to be r equired in registration review. The o ccupational handler scenario to be assessed is included in Table 9

.

Table 9

– Occupational Exposure Scenario for Cu HDO

Scenario E xposure Route(s) Duration
Pressure Treatment Dermal and Inhalation Short, Intermediate, and Long Term


### 3.3.2 Residential Exposures

EPA anticipates the need to revise the 2004 human exposure review to account for new surface residue data that are anticipated to be required

. Dermal and incidental oral exposures could result when children come in contact with Cu HDO treated wood that is used in decks and playground equipment

. These exposures were assessed using a surface residue of 0.14 ug/cm 2 from a surface

res idue s tudy conducted in 2002 (MRID 456788

- 04 ) and t he oral NOAEL of 26 mg/kg/day. The

Page 15 of 47Docket Number EPA

- HQ

- OPP

- 2014

- 0800

MOEs were 1,700 for dermal exposures and 5,100 for incidental oral exposures which were greater than the target MOE of 300, meaning that the risks were not of concern. Th ere were limitations with the 2002 surface residue study; and therefore , a new wood wipe study is anticipated to be required during registration review to confirm the finding s of the 2002 study. Th e exposure scenario that will be assessed is included in Ta ble 10

.

Table 10

– Residential Exposure Scenario for Cu HDO

Scenario Exposure Route(s) Duration
Toddler Contact with Decks and Playground Equipment Dermal and Incidental Oral Short and Intermediate Term



## 3.4 Aggregate and Cumulative Exposure

3.4.1 Aggregate Exposures

EPA anticipates that an aggregate assessment will not be needed for Cu HDO because the dietary and drinking water exposures that would normally be aggregated with residential exposures are not anticipated as discussed in Section 3.2 above

.


### 3.4.2 Cumulative Exposures

W ith respect to cumulative exposure to the copper or HDO that dissociates from Cu HDO , unlike other pesticides for which EPA has followed a cumulative risk approach based on a common mechanism of t oxicity, EPA has not made a common mechanism of toxicity finding as to copper or HDO and any other substances and copper and HDO does not appear to produce a toxic metabolite produced by other substances. For the purposes of this registration review, there fore, EPA has not assumed that the copper and HDO that dissociate from Cu HDO has a common mechanism of toxicity with other substances. For information regarding EPA’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 Risk Assessment

The agency anticipates the need to conduct a n environmental risk assessment f or Cu HDO . The
agency expects to require additional data for use in conducting the registration review. I t has been determined from a leaching study that both copper an d HDO leach from treated wood. The risk assessment will include Cu HDO, but will focus p rimarily on copper and will be based on registrant generated Cu HDO data, c opper data available from the Office of Water, and any pertinent open literature.

The agency has not previously conducted a risk assessment that supports a complete endangered spe cies determination for Cu HDO. The ecological risk assessment planned during registration review will allow the agency to determine potential acute and chronic risks to aquatic organisms exposed to Cu HDO that are transported from treatme nt sites into the aquatic environment. Such sites include leaching from treated wood products. The risk assessment also will allow the agency to determine whether each use of the Cu HDO has 'no effect' or 'may

Page 16 of 47Docket Number EPA

- HQ

- OPP

- 2014

- 0800

affect' federally listed threatened or endange red species (listed species) or thei r designated critical habitats. When an assessment concludes that a pesticide’s use 'may affect' a listed species or its designated critical habitat, the agency will consult with the U.S. Fish and Wildlife Service and/or National Marine Fisheries Services (the Services), as appropriate.



## 4.1 Environmental Fate Assessment

Cu HDO forms four detectable residues in the environment after it leaches from treated wood as Cu ion and HDO separately

. The copper molecule will sorb to soil and undergo reduction

oxidation reactions, in addition to complexing with other chemical species and sorption to soil. 5 Two molecules of HDO are formed from each Cu HDO molecule , each of which can degrade sequentially to cyclohexanone oxime and then to cyclohexanone

. Cyclohexanone oxime and cyclohexanone we re significant degradates that did not degrade in a photodegradation in water study, indicating that they are stable to abiotic degradation (MRID 47512903). Cu HDO degraded in an aerobic aquatic metabolism study that represents surface water without forming significant quantities of degradates , indicating that both cyclohexanone oxime and cyclohexanone were not persistent because of microbia l metabolism (MRID 47468801)

. Based on wood leaching stud ies using rainfall (MRID s 45687218, 45678219 ), the copper portion of the Cu HDO molecule was shown to leach to soil for at least 280 days (length of study) and HDO leaching was detectable up to 57 d ays. Copper and HDO leach as separate molecules and not as the parent compound complex. In a submerged wood study, copper and HDO were also shown to leach separately for up to 60 days (MRID 47210205)

. The agency anticipated requiring aerobic soil metaboli sm and anaerobic aquatic metabolism data for HDO which will address the cyclohexanone and cyclohexanone oxime degradates. Additional information on the environmental fate of copper and HDO are available in Appendix B.



### 4.1.1 W aste W ater T reatment P lants (WWTPs)

Data for routes of dissipation and toxicity in WWTPs were not submitted , but are not anticipated to be required because Cu HDO is not expected to be transported to WWTPs. The sole end

- use product label states that wastes must be treated as hazardous waste and disposal must be conducted according to label instructions, a state pesticide or environmental control agency, or by guidance from a hazardous waste representative.



### 4.1.2 Water Quality

Cu HDO is not identified as a cause of impairment for any water b odies listed as impaired under S ection 303(d) of the Clean Water Act

. 6 In addition, no Total Maximum Daily Loads (TMDL) have been developed for Cu HDO

. 7 More information on impaired water bodies and TMDLs can be found at EPA’s website

. 8

5 Cavinder, May 2, 2014

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

7 http://iaspub.epa.gov/tmdl_waters10/attains_nation.tmdl_pollutant_detail?p_pollutant_group_id=885&p_pollutant_ group_name=PESTICIDES

8 http://www.epa.gov/owow/tmdl/
Page 17 of 47Docket Number EPA

- HQ

- OPP

- 2014

- 0800



## 4.2 Environmental Exposure Pathways

The screening

- level risk assessment that will be conducted as part of this registration review will evaluate potential risks to ecological organisms from exposure to parent Cu HDO and its Cu, HDO, cyclohexanone oxime, and cyclohexanone degradates. Based on antimicrobial use patterns, the agency developed conceptual models (CMDs) depicting potential routes of environmental exposure to terrestrial and aquatic recep tor groups. The “ Conceptual Models for Environmental Exposure Pathways of Antimicrobial Pesticides ” are located in the docket at www.regulations.gov (EPA

- HQ

- OPP

- 2014

- 0638

- 0002). For “ In

‐ Use Service of Wood Treated Wood Products ” see page 29 in that document.



### 4.2.1 Mechanism of Action
Exposure to copper causes disruption of the cellular membrane, with the thiol groups as the primary target (Eisler 2000). In fish, copper causes gill damage and can interfere with osmoregulatory processes. It has been associated with effects on ATP

- synthe sizing pathways and can int erfere with energy metabolism. In algae, it causes increased permeability of the cell membrane and leakage of the cell contents.



### 4.2.2 Measures of Effect (Ecotoxicology Endpoints)

Ecotoxicity endpoint data are used as measures of effects to aquatic and terrestrial organisms. Based on the submitted wood leaching data discussed above, copper leaches longer than HDO and is expected to be much more persistent and toxic to aquatic or ganisms than the HDO molecule. Therefore, the aquati c risk assessment will focus on the effects from copper residues. The registrants have submitted adequate Cu HDO data for labeling purposes

, and these data ar e listed in Appendix C. All available ecotoxicity endpoints in the agency ’s files from copper stu dies submitted by registrants or other interested parties, federal laboratory data, or from the public literature are tabulated in Appendix C along with the anticipated da ta requirements and data gaps. The most sensitive values for each receptor group will be used for the risk assessment

.

A c ute a nd c h r onic to x icity d a t a f rom stud i e s sub m i t ted b y p e st i c ide re g is t rants along with t he

a v a i l a ble op e n l i te r a ture will be used to ev a luate t he potential dir ec t a nd i n dir ec t e f f

e c ts of

c opp e r in Cu HDO to aq u a t i c re c e ptors. These data were taken from the Preliminary Problem Formulation for Ecological Risk, Environmental Fate, and Endangered Species Assessments for Coppers completed in 2010 (EPA, 2010)

. The registration review document presents all
copper compounds that have been used in a pesticide. The da ta have been correlated to present one set of ecological toxicity endpoints for all of the copper containing compounds. Due to a lack of exposure, potential direct and indirect effects of copper on terrestrial

r eceptors will not be assessed. Acute and chro nic toxicity data for Cu HDO will be used to evaluate the potential risk of Cu HDO to nontarget aquatic organisms

, and no additional Cu HDO or degradate data are anticipated to be required during registration review.

Ta b le 11 p r ovides a summa r y o f the information which will be used to assess the effects of copper on aquatic species

.

Page 18 of 47Docket Number EPA

- HQ

- OPP

- 2014

- 0800

Table 11

– T e st S p ec ies Eva lu a te d f or Ass e ss in g P o t e n tial E c olog i c al E f fec ts of Cop p e r a n d the A ssocia te d A c ut e Toxici t y Class if ica t i on

Taxa S u r rogat e S p e c ies Acu t e a nd Chr o nic T o x ici t y E n d p o ints Ci tat i o n M RID/Source Acute Toxicity Classification

Insects Honeybee LD 50 = >100 ug/bee 40764702 Practically nontoxic

Freshwater Fish 1 Sa l m o n i d s ( O n c o r h y n c u s

s p e c ies ) T h e Ge nu s M e a n A c u te Va l u e o f S a l m o n i d s 3

, 5 = 31

. 4 μg ai/L O W 2 Ve r y h i g h l y t o x ic

N A An a c u te to c h ro n ic r atio o f 3

. 2 2 will be applied 6 OW 2

Fr e s h w a ter i nv e r te br ates W ater f lea ( D aphn i a m a g n a ) T h e Ge nu s M e a n A c u te Va l u e o f

D a p hn i d s = 4

. 1 4 μg a i /L 7 OW 2 Ve r y h i g h l y t o x ic

NA An a c u te to c h ro n ic r atio o f 3

. 2 2

w i l l b e a pp lied 6 OW 2

E s t u a r i n e / m a r i n e f i s h S um m er f l ou n d er ( P a r a lic h th ys d e n t a t u s ) T h e Ge nu s M e a n A c u te Va l u e o f
est u a r i n e / m a r i n e f i s h = 12 .7 μg ai/L 7 OW 2 Ve r y h i g h l y t o x ic

NA An a c u te to c h ro n ic r atio o f 3

. 2 2

w i l l b e a pp lied 6 OW 2 N A

E s t u a r i n e / m a r i n e

i nv e r te br ates M u s s el ( Mytilus s p e c ies) Ge n u s M e a n A c u te V a l u e o f
est u a r i n e / m a r i n e i n v e r te br ates = 11 .5 μg ai/L 7 OW 2 Ve r y h i g h l y t o x ic

N A An a c u te to c h ro n ic r atio o f 3

. 22

w i l l b e a pp lied 6 OW 2 NA

A q u atic n o n

v as c u lar p la n t s G r e e n al g a ( P s e udo kirc hn eriella

s ub c ap it a t a ) A c u te 4 8

- h r EC 50 /N O A E C = 3

. 1 / 2 .0 μg ai/L 433 6 36 0 3

-

A q u atic v a s c u lar
p la n ts D u c k w e e d ( Lem n a g i b b a ) A c u te 4 8

- h r EC 50 /N O A E C 4 = 2300 / 1 0 0 μg ai/L 433 6 36 0 4

Endpoints for Cu HDO

Freshwater Fish Zebra fish LC 50 = 0.9 mg/L NOAEC = 0.56 mg/L 47069401 (Cu HDO) Highly toxic

Freshwater

Invertebrates Water flea ( Daphnia magna) EC 50 = 1.1 mg/L 45687205 (Cu HDO) Moderately toxic

Estuarine Fish Sheepshead minnow EC 50 = 0.42 mg/L NOAEC = 0.32 mg/L 47320502 Highly toxic

Page 19 of 47Docket Number EPA

- HQ

- OPP

- 2014

- 0800

Estuarine Invertebrates Eastern oyster ( Crassostrea

virginica ) EC 50 = 0.103 mg/L NOAEC = 0.32 mg/L 47320503 Highly toxic

1 Fr e s h w a ter f i s h s e r v e as s u rro g a t es f o r a q u ati c

- p h ase a m p h i b ia n s

. 2 Of f ice o f W ate r’ s A m b ie n t W ater Q u ali t y C r ite r ia D o c u m e n t f o r C opp er

. 3 T h e s a l m o n id G M AV w a s r e v i s ed b y OW

. A s o f t h i s t i m e, t h e B L M i s p a r a m ete r ized f o r o n l y f r e s h w ater f a t h e a d mi nn o w a n d d a p hn i d s

. I f t h e B LM is n o t p a r a m ete r ized f o r s a l m o n i d s at t h e t i m e o f t h e

as s e ss m e n t, a c u te L C 5 0 s o f f a t h e a d m i nn o w w i ll b e a d j us ted b y t h e r atio o f t h e s a l m o n i d s GMAV to t h e f at h e a d m i nn o w G M AV s i m ilar to t h e a ppro a c h us ed in t h e 200 6 R ED.
4 T h e n o nv a s c u lar p la n t e n dpo i n t o f 3 .1 μg ai / L w as us ed in t h e c opp er R ED to d ete r m i n e r i s k to

v a s c u lar p la n ts als o

. 5 A s d e r i v ed in t h e 2 0 0 7 R e v i s ed A q u atic L i f e C opp er C r ite r ia b y O W f o r us e i n B LM m od el to d ete r m i n e

s i t e

- s p e c ific c opp er t o x ici t y v a l u es

. 6 An a c u te to c h ro n ic r atio o f 3

. 2 2 w i l l b e a pp lied to t h e B L M

- d e r i v ed s it e

- s p e c i f ic a c u te t o x i ci t y v al u e s as

w as do n e i n 200 6 R ED as t h e m i n i m u m d ata r e q u ir e m e n ts f o r c h ro n ic t o x i c i t y w e r e n o t m et to d e r i v e O W ’ s

c h ro n ic c r ite r ia

. 7 A s u s ed in t h e 200 6 R ED f o r us e i n B L M m od el t o d ete r mi n e s it e

- s p e c i f ic c opp er t o x ici t y v a l u es

. NA = N o t app lica b l e

. 

## 4.3 Exposure Analysis Plan

4.3.1 Aquatic and Terrestrial Wildlife Exposure Estimates

Available OPP models will be used to determine the estimated environmental concentration (EEC s) in the aquatic environment. Resulting exposure estimates will be compared to the toxicity endpoints to determine if levels of concern are exceeded for each receptor group.



### 4.3.2 Screening Level Down

- the

- Drain Analysis

The a gency does not anticipate the need for a Down

- the

- Drain (DtD) assessment be cause the Cu HDO treated wood at the site of the treatment is dried with a drain pad underneath and any leaked chemical is recycled for us e. Remainin g chemical in the pad (if any) must be treated as a hazardous waste and disposal (if any) must be conducted according to a state pesticide or environmental control agency, or by guidance from a hazardous waste representative.



## 4.4 Effects Analysis Plan

Additional open literature studies will be identified through EPA’s EC OTOXicology (ECOTOX) database. The ECOTOX d atabase will be searched during the risk assessment phase of Cu HDO and the data reviewed following the agency ’s policy for reviewing public literature for use in assessing risks from pesticide s

. 9 Those ecotoxicity values found in the public literature to be more sensitive than those currently available or which satisfy an existing data gap(s) will be used during the risk assessment phase of Cu HDO

. ECOTOX was created and is maintained by the

9 http://www.epa.gov/pesticides/science/efed/polic y_guidance/team_authors/endangered_species_reregistration_work group/esa_evaluation_open_literature.htm
Page 20 of 47Docket Number EPA

- HQ

- OPP

- 2014

- 0800

USEPA, Office of Research and D evelopment, and the National Health and Environmental Effects Research Laboratory's Mid

- Continent Ecology Division.


## 5 Endocrine Disruptor Screening Program (EDSP)

As required by FIFRA and FFDCA, EPA reviews numerous studies to assess potential adverse
outcom es 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 endpoin ts which may be susceptible to endocrine influence, including effects on endocrine target organ histopathology, organ weights, estrus cyclicity, sexual maturation, fertility, pregnancy rates, reproductive loss, and sex ratios in offspring. For ecological h azard assessments, EPA evaluates acute tests and chronic studies that assess growth, developmental and reproductive effects in different taxonomic groups. As part of the assessment for the 2005 registration , for Cu HDO , EPA reviewed these data and selected the most sensitive endpoints for relevant risk assessment scenarios from the existing hazard database. However, as required by FFDCA S ection 408(p), Cu HDO is subject to the endocrine screening part of the Endocrine Disruptor Screening Program (EDSP).

EP A 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 a s 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 estroge n, androgen, or thyroid (E, A, or T) hormonal systems. Chemicals that go through Tier 1 screening and are found to have the potential to interact with E, A, or T hormonal systems will proceed to the next stage of the EDSP where EPA will determine which, if any, of the Tier 2 tests are necessary based on the available data. Tier 2 testing is designed to identify any adverse endocrine

- related effects caused by the substance, and establish a dose

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

.

Under FFDCA S ection 408(p), the agency must screen all pesticide chemicals. Between October 2009 and February 2010, EPA issued test orders/data call

- ins for the first group of 67 chemicals, which contains 58 pesticide active ingredients and 9 inert ingredients. A second list of chemicals ident ified for EDSP screening was published on June 14, 2013 10 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.

For further information on the status of the EDSP, the policies and procedures, the lists of chemicals, future lists, the test guidelines and the Tier 1 screening battery, please visit our website. 11

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

- HQ

- OPPT

- 2009

- 0477

- 0074 for the final second list of

chemicals.

11 http://www.epa.gov/endo/
Page 21 of 47Docket Number EPA

- HQ

- OPP

- 2014

- 0800



## 6 Optional Label Changes

As discussed in Section 3.2 of this work plan , i t is reco mmended that all labels and use patterns be clarified to be intended for non

- food contact only

.

The agency invites comment on any label amendments that could be considered to eliminate the anticipated need for EPA to require certain data, reduc e the possibility that EPA’s planned risk assessments overestimate risk due to reliance on conservative assumptions, and/or improve label clarity.



## 7 Guidance for Commenters

7.1 Preliminary Work Plan
The public is invited to comment on EPA’s Preliminary Work Plan . The agency will carefully consider all comments as well as any additional information or data provided in a timely manner prior to issuing a final work plan for the Cu HDO registration review case.



### 7.1.1 Trade Irritants
Through the registration review process, the agency intends to solicit information on trade irritants and, to the extent feasible, take steps toward facilitating irritant resolution. The agency will work to harmonize tolerances and international maximum re sidue limits (MRLs) and may modify tolerance levels to do so, when possible. Stakeholders are asked to comment on any trade irritant issues resulting from lack of MRLs or disparities between U.S. tolerances and MRLs in key export markets, providing as much specificity as possible regarding the nature of the concern.



### 7.1.2 Water Quality

The agency invites submission of water quality data for this pesticide. To the extent possible, data should conform to the quality standards in Appendix A of the OPP Standard Opera ting Procedure: Inclusion of Impaired Water Body and Other Water Quality Data in OPP’s Registration Review Risk Assessment and Management Process 12 in order to ensure they can be used quantitatively or qualitatively in pesticide risk assessments.



### 7.1.3 Environmen tal Justice
EPA seeks to achieve environmental justice, the fair treatment and meaningful involvement of all people, regardless of race, color, national origin, or income, in the development, implementation, and enforcement of environmental laws, regulati ons, and policies. To help address potential environmental justice issues, the agency seeks information on any groups or segments of the population who, as a result of their location, cultural practices, or other factors, may have atypical, unusually high exposure to Cu HDO compared to the general population. Please

12 http://www.epa.gov/oppsrrd1/registration_review/water_quality_sop.htm
Page 22 of 47Docket Number EPA

- HQ

- OPP

- 2014

- 0800

comment if you are aware of any sub

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



### 7.1.4 Structure Activity Relationships
EPA must rely upon informati on of appropriate quality and reliability for each decision made by the agency . In the OPP, the evaluation process for a pesticide chemical traditionally begins with the applicant’s submission of a set of studies conducted with the specific pesticide chemi cal of interest. The use of the results of such testing (measured data) is a logical, scientifically rigorous process that identifies the physical, chemical, and environmental fate properties of the pesticide, as well as the dose and endpoints at which an adverse effect can occur in various animal species.

Today, there is significant interest in alternative techniques, i.e., techniques other than data generation that could significantly inform the agency ’s decision

- making process. Recently, OPP has made in creasing use of structure activity relationship (SAR) as part of its regulatory decision

- making process. In the SAR process, a chemical's molecular structure is compared to that of other chemicals for which data are available. These structural similarities are then used to make predictive judgments about a chemical’s physical, chemical, and biological properties. Thus, the chemical’s physical, chemical, and biological properties are a function of (or directly related to) the chemical’s molecular structure. Quantitative SAR is referred to as QSAR. To develop a QSAR, a selected set of measured data on a single physical, chemical, or biological property is used to derive a model (an equation) to predict the value of that property.

Since SAR assessments and QSA R modeling are another set of tools that are available to agency scientists, OPP has begun a process shift that envisions shifting from the current study

- by

- study approach to an approach in which the use of predicted data, generated using validated models, is considered along with information from open literature and s tudies specifically generated under Part 161 requirements. All relevant information would be considered as part of a weight

- of

- the

evidence evaluation.

At this time, EPA believes that for certain endpoints, especially physical/chemical and fate properties , that SAR and QSAR might be effectively utilized to fulfill these data requirements for many antimicrobial pesticide chemicals. When considering biological properties, at this time, EPA believes that SAR and QSAR can be most effectively utilized in the ev aluation of chemicals that exhibit lower toxicity for human health and/or ecotoxicity parameters. This is appropriate because the risk assessment for lower toxicity chemicals can be stream

- lined, i.e., a screening

- level assessment procedure rather than mul tiple tiers of assessments with progressively more data requirements.

If stakeholders believe that submission of predicted data can fulfill one of the data needs for the Cu HDO ca se, then the agency invites submission of this information. The submitter wo uld be expected to supply a rationale describing the utility of the information and provide documentation on the scientific validity of the information. The determination that the predicted data fulfills the data requirement would be at the sole discretion of the agency . Pre

- submission consultation with the agency is encouraged.

Page 23 of 47Docket Number EPA

- HQ

- OPP

- 2014

- 0800



### 7.1.5 Additional Information

Stakeholders are also specifically asked to provide available information and data that will assist the agency in refining its risk assessments, including a ny species

- specific ecological effects determinations. The agency is interested in receiving the following information:

1. Confirmation on the following label information: A. Sites of application B. Formulations C. Application methods and equipment D. Maximum application rates E. Frequency of application, application intervals and maximum number of applications F. Geographic limitations on use 2. Use or potential use distribution 3. Use history 4. Usage/use information for non

- agricultural uses (e.g., materials p reservation) 5. Typical application interval 6. State or local use restrictions 7. Ecological incidents (non

- target plant damage and avian, fish, reptilian, amphibian and mammalian mortalities) not already reported to the agency 8. Monitoring data



## 8 Next Steps

Afte r the 60

- day comment period closes in May 2015

, the agency will review and respond to any comments received in a timely manner, and then issue a Final Work Plan for the Cu HDO case.

Page 24 of 47Docket Number EPA

- HQ

- OPP

- 2014

- 0800



## 9 References

45671304 Gelbke, H. (1977) Report on the Study of the Acute Oral Toxicity of Cu

- NCH in the Rat: Lab Project Number: CK 180681. Unpublished study prepared by BASF Aktiengesellschaft. 12 p.

45671305 Zeller, H. (1975) Study of the Acute Dermal Toxicity of C u

- NCH in the Rat: Lab Project Number: CK 180682. Unpublished study prepared by BASF Corp. 9 p

45671306 Kuhlem, C. (1998) Report on the Study of the Acute Eye Irritation of Cu

- NCH in the Rabbit: Lab Project Number: CK220681. Unpublished study prepared by BA SF Corp. 9 p.

45671307 Kuhlem, C. (1975) Study of the Acute Dermal Irritation/Corrosion of Cu

- NCH in the Rabbit: Lab Project Number: CK220682. Unpublished study prepared by BASF Corp. 9 p.

45687201. Buldt, D. (2001) Physico

- Chemical Properties of Bis

- (N

cyclohexyldiazeniumdioxy)

- copper: Lab Project Number: 01L00056: 01L00055. Unpublished study prepared by BASF AG. 31 p.

45687202. Brunner, E. (1992) Solubility of Bis

- (N

- cyclohexyldiazeniumdioxy)

- copper in Water at pH 4,7 and 9 at 23 degrees C: Lab Project Number: 92.15.1. Unpublished study prepared by BASF AG. 12 p.

45687203. Woll, (1992) Dissociation Constant of Bis

- (N

- cyclohexyldiazeniumdioxy) copper: Lab Project Number: 92.15.2. Unpublished study prepared by BASF. 14 p.

45687207 Rossbacher, R. ( 1992) Maximization Test for the Sensitizating Potential of Bis

- (N

Cyclohexyldiazeniumdioxy)

- Kupfer (Cu

- HDO) in Guinea Pigs: Lab Project Number: 30H0679/892377. Unpublished study prepared by BASF Corp. 31 p.

45687208 Hellwig, J. (1995) Subchronic Oral Tox icity Study with Bis

- (N

Cyclohexyldiazeniumdioxy)

- copper in Beagle Dogs: Administration in the Diet for 3 Months: Lab Project Number: 31D0141/92060. Unpublished study prepared by BASF. 456 p.

45687209 Mellert, W. (1991) Study of the Oral Toxicity of Bis

- (N

- Cyclohexyldiazeniumdioxy)

- copper in Rats: Administration via the Diet for 3 Months: Lab Project Number: 30C0679/89041. Unpublished study prepared by BASF. 543 p.

45687210 Mellert, W. (1993) Study of the Chronic Toxicity of Bis

- (N

- Cyclohexyl

diazeniumd ioxy)

- copper in Rats: Administration in the Diet for 12 Months: Lab Project Number: 50C0679/89080. Unpublished study prepared by BASF. 953 p.

45687211 Mellert, W. (1996) Carcinogenicity Study with Bis

- (N

- Cyclohexyl

- diazeniumdioxy)

- Copper in Wistar Rats: Administration in the Diet for 24 Months: Lab Project Number: 70C679/89113. Unpublished study prepared by BASF. 1501 p.

Page 25 of 47Docket Number EPA

- HQ

- OPP

- 2014

- 0800

45687212 Hellwig, J. (1991) Study of the Prenatal Toxicity of Bis

- (N

- Cyclohexyl

diazeniumdioxy)

- Copper in Rats After Oral Administrati on (Gavage): Lab Project Number: 30R0679/89059. Unpublished study prepared by BASF. 325 p.

45687213 Hellwig, J. (1994) Study of the Prenatal Toxicity of Bis

- (N

- Cyclohexyl

diazeniumdioxy)

- Copper in Rabbits After Oral Administration (Gavage): Lab Project N umber: 40R0141/92031. Unpublished study prepared by BASF. 320 p.

45687214 Gelbke, H. (1992) Rat Hepatocyte DNA

- Repair Assay (UDS) in Vitro: Lab Project Number: 81M0679/894495. Unpublished study prepared by BASF Corp. 27 p.

45687215 Engelhardt, G. (1987 ) Study of Cu

- HDO in the Ames

- Test: Lab Project Number: 40M0254/874050. Unpublished study prepared by BASF. 40 p.

45687216 Volkner, W. (1990) Micronucleus Assay in Bone Marrow Cells of the Mouse with Bis

- (N

- Cyclohexyldiazeniumdioxy)

- Kupfer: Lab Project N umber: 26M0679/899010: 183306. Unpublished study prepared by Cytotest Cell Research GmbH & Co. KG. 27 p.

47210201. Winkler, J. (2006) Adsorption/Desorption Study with Cu

- HDO According to OECD Guideline No. 106. Project Number: 05/10/35/2028. Unpublished study prepared by Biochem Agrar, Lab fuer Biologische und Chemische. 141 p.

47512903. Hassink, J. (2006) Aqueous Photolysis of Cu

- HDO [

- U

- (Carbon 14)]: Final Report. Project Number: 242482, 2006/1019626. Unpublished study prepared by BASF Aktiengesellsch aft. 45 p.

EPI

- WEB 4.11. 2012. U.S. EPA. http://www.epa.gov/oppt/exposure/pubs/episuitedl.htm

Petrie, R., Breithaupt, J., and S. Mostaghimi. March 25, 2009. Registrant Response To: Reassessment Of Environmental Risk Assessment And Ecotoxicity Data Reviews for Copper HDO (Protectol CX Type A); To Allow Use In Aquatic Habitats

. D361109, D 361768, D 361769

T i s d ale, S. L

., Nels o n , W

. L

., a n d J .D. B e a t o n

. 1 985

. S o il Fe r til i t y a n d Fe r til i z er s ( 4 th e d

. ) M a c m ill a n P u b li s h i n g C o m p a n y , NY.

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

U.S. Environmental Protection Agency (EPA). 2004. Human Exposure Review in Support of Registration of Protectol CX Type A(a.k.a. Wolmanit CX

- 10) Wood Preservative Containing Cu

HDO as a New Active Ingredient, D293628/D297719, Memorandum from Doreen Aviado to Connie Welch, September 10, 2004.

U.S. Environmental Protection Agency (EPA). 2010. Coppers: Human Health Assessment Scoping Document in Support of Registration Review. http://www.regulations.gov/#!documentDetail;D=EPA

- HQ

- OPP

- 2010

- 0212

- 0008

Page 26 of 47Docket Number EPA

- HQ

- OPP

- 2014

- 0800

U.S. Environmental Protection Agency (EPA). 2010. Registration Review: Preliminary Problem Formulation for Ecological Risk, Environmental Fate, and Endangered Species Assess ments for Coppers. http://www.regulations.gov/#!documentDetail;D=EPA

- HQ

- OPP

- 2010

- 0212

- 0009

U.S. Environmental Protection Agency (EPA). Pesticide Fact Sheet, Cu HD O. http://www.epa.gov/oppad001/reregistration/cca/copper_hdo_fs.pdf

USE P A

. 20 0 9 c. R e v i s ed R e r e g i s trati o n El i g i b ili t y De c i s i o n Co pp e r s

. h tt p :/ / ww w .e p a

. g o v / opp s rrd1 / R EDs / c opp e r_r e d_ a m e n d

. pdf

Page 27 of 47

# Appendix A T oxicology Profile

Acute Toxicity for Product Labeling

As listed in Table 1

, Cu HDO is a not a primary dermal irritant (Ca tegory IV) and is in Category II for acute oral toxicity based on guideline studies. It is a corrosive eye irritant (Category I), and is a Category III for acute dermal toxicity. It is not a dermal sensitizer.

Table 1

– Acute Toxicity Studies for Cu HDO

G uideline No./ Study Type MRID No. Results Toxicity Category 870.1100/ Acute oral toxicity 45671304 LD 50 = 380 mg/kg II 870.1200/ Acute dermal toxicity 45671305 LD 50 >2500 mg/kg III 870.1300/ Acute inhalation toxicity N/A No acceptable studies available Unknown 870.2400/ Acute eye irritation 45671306 Corrosive I 870.2500/ Acute dermal irritation 45671307 Not a skin irritant IV
870.2600/ Skin sensitization 45687207 Not a dermal sensitizer N/A N/A=Not available 

## Subchronic Toxicity

There are two subchronic oral studies, one in dogs and one in rats. The lack of a n inhalation study has been identified as a data gap

, and an inhalation study is anticipated to be required due to inhalation as a route of exposure during pressure treatment

. Subchronic Oral Toxicity Study/Dogs :
In a 90 day subchronic o ral toxicity study (MRID 456872 08), Cu HDO (99% a.i.) was administered to 40 Beagle dogs (5/sex/dose) in the diet at dose levels of 0, 300, 900, and 2,700 parts per million (ppm) (equivalent to approximately 0, 9, 26, and 69 mg/kg/day in all animals, respectively). No compound related changes in mortality, hematology (except prothrombin time) or ophthalmology occurred.

At 2700 ppm, compound related effects in both male and female animals include d vomiting, decreases in body weight gain (weight loss) in both sexes , decreased food consumption, and reduced food efficiency occurred. Clinicochemical compound related effects in males and/or females included increased alanine aminotransferase, aspartate aminotransferase, potassium levels, prolonged prothrombin time, and decreased calcium, total protein, albumin, globulins, cholesterol, and glucose levels

. The targ et organ of Cu HDO appears to be the liver, as incidences of chronic hepatitis, liver cirrho sis, and copper pigment storage in hepatocytes and Kupffer cells were noted, as well as gross lesions on the liver and significantly decreases in mean absolute/relative liver weights in males and relative liver weight in females.

Page 28 of 47The NOAEL for this study is 900 ppm (26 mg/kg/day) for male and female animals. The LOAEL is 2,700 ppm (69 mg/kg/day, both sexes) based, in both sexes, on clinical observations, decreases in body weight gain, decreased food consumption, clinical chemistry changes , decreased liver weight, and pathological changes in the liver. This study is ACCEPTABLE/GUIDELINE.

Subchronic Oral Toxicity Study/Rat

In a 90

- day subchronic o ral toxicity study (MRID 456872 09), Cu HDO (99.7% a.i.) was administered to 80 Wistar rats (10/sex/dose level) by incorporation into feed at dose levels of 0 ppm. 500 (35 mg/kg/day for males and 41 mg/kg/day for females ) , 2,000 ppm (140 mg/kg/day for males and 167 mg/kg/day for females ) and 400 0 ppm ( 275 mg/kg/day for males and 322 mg/kg/day for females). Twenty additional rats (10/sex/dose) were administered feed treated with CuSO 4 (99.7% a.i. ) at a dose level of 1800 ppm (125 mg/kg/day for males and 144 mg/kg/day for females ) . The purpose of t he copper sulfate group was t o differentiate toxicity of Cu +2 from the toxicity of the test substance.

No treatment

- related effects were observed in clinical signs (other than black or brown feces), mortality, body weight, body weight gain, food consumptio n, ophthalmology, hematology or absolute, and relative organ weights.

In the high dose, Cu HDO males, an increase in ALT and AST at days 29 and 87 occurred. In the high dose Cu HDO females, a decrease in globulin and cholesterol were seen on day 29 only. I n the CuSO 4 animals, globulin was decreased on day 29 only.

Changes occurred in the livers, kidneys, forestomach and small intestine of the animals. Findings of note include hepatic single cell necrosis, pigmentated Kupffer’s cells, hyaline droplets in the proximal tubular epithelial cells of the kidneys and diffuse hyperkeratosis in sections of the small intestine and fore

- stomach. Because similar changes were noted in animals treated with CuSO4, the effects in these animals treated with Cu

- HDO may have be en caused by the Cu+2 ion.

The NOAEL is 500 ppm (35 mg/kg/day for male s and 41 mg/kg/day for female s) . The LOAEL for this study is 2000 ppm (140 mg/kg/day for male s and 167 mg/kg/day for female s ) , based on histo

- pathology changes of the liver, kidney and forestomach. This study is ACCEPTABLE/GUIDELINE.

Page 29 of 47

## Developmental Toxicity

There are two developmental studies for Cu HDO , one in rabbit and one in rat, and the database is considered complete. One study is considered unacceptable, however, this is due to l ack of a LOAEL and therefore a second study is not required, as any endpoint would be well above the current POD.

Prenatal Developmental Toxicity Study

- Rabbit

In a developmental toxicity study (MRID 45687213), Cu HDO (99% a .i.) in 0.5% aqueous carboxymet hyl cellulose was administered to mated female Himalayan rabbits (15/dose) orally by gavage at dose levels of 0 (Control), 10, 30, or 60 mg/kg/day from days 7 through 19 of gestation (gd 7

- 19). Maternal effects was observed at 30 and 60 mg/kg/day, includin g significantly decreased food consumption and body weight gain throughout the treatment period. Also, high

- dose dams exhibited clinical signs of toxicity (constipation and blood in bedding) and redu ced mean gravid uterine weight. The maternal LOAEL is 30 mg/kg/day, based on decreased food consumption and body weight gain. The maternal NOAEL is 10 mg/kg/day.

Evidence of embryotoxicity and fetotoxicity occurred at 60 mg/kg/day, consisting of slightly increased resorption rate, increased postimplantation lo ss, and reduced mean pla cental and fetal body weights. Treatment

- related increases in the occurrence of skeletal variations (irregular shaped sternebra[e] and accessory 13 th ribs) were ob served at 30 and 60 mg/kg/day. An increased incidence of skeletal ret ardations (incomplete ossification of the sacral vertebral arch[es] and/or talus) at the high

- dose level also was observed. The developmental LOAEL is 30 mg/kg/day, based on increased incidence of skeletal variations. The developmental NOAEL is 10 mg/kg/ day. This study is ACCEPTABLE/GUIDELINE.

Prenatal Developmental Toxicity Study/Rat

In a developmental toxicity study (MRID 45687212), Cu HDO (93% a.i.) in 0.5% aqueous carboxymethyl cellulose was administered to mated female Wistar rats (30/dose) orally by gavage at dose levels of 0 (Control), 10, 30, or 100 mg/kg/day from days 6 through 15 of gestation (gd 6

- 15).

There were no treatment

- related clinical signs of toxicity on maternal parameters. The maternal NOAEL is 100 mg/kg/day (HDT). The maternal LOA EL is >100 mg/kg/day.

There were no treatment

- related external, visceral, or skeletal malformations observed in any of the treatment groups. The developmental NOAEL is 100 mg/kg /day (HDT). The developmental LOAEL is >100 mg/kg/day

. This developmental toxicity study in the rat is classified as Unacceptable a nd does not satisfy the guideline requirement for a developmental toxicity study in rats (OPPTS 870.3700/§83

- 3/OECD 414). The highest dose used was not high enough to elicit any toxicological effect

, therefore, the statistical and biological significance of the effects remains unclear.

Page 30 of 47

## Reproductive Toxicity

There is no reproductive toxicity study available and such a study is required to support pressure treatment of wood

. A two generation reproductio n study is therefore anticipated to be needed for registration review. 

## Chronic Toxicity

The data base for chronic toxicity is adequate for the wood pressure treatment use of Cu HDO

.

In a 12

- month chronic diet ary toxicity study (MRID 456872 10), Cu

- HDO (95% a.i.) was administered to 20 male and 20 female Wistar rats each in the diet at dose levels of 0, 100, 300, 1,000, and 3,000 ppm (equivalent in both sexes to 0, 6.1, 18.3, 61, and 183 mg/kg/day). The 3000 ppm Cu

- HDO group was compared to an equimolar concentration of copper as contained in Cu SO 4 (1350 ppm) (see text). At the end of the administration period (1 year) all animals were subjected to a gross pathology followed by histopathology examination of selected organs.

The target organs were the liv er, kidney, stomach and duodenum. No changes were seen in the clinical findings, ophthalmology, food consumption, or absolute body weight. No test substance related findings were noted at 100 ppm and 300 ppm. Body weight gain in males showed a decrease of ≈ 30% at 1000 and 3000 ppm by the end of the study. Clinical chemistry parameters, showed a statistically significant increase in alanine aminotransferase ( ↑ 159%) and aspartate aminotransferase ( ↑ 66%) at 3000 ppm males at termination.

Gross pathology reflec ted the microscopic pathology noted below. In the liver of both sexes at 1000 and 3000 ppm, swollen and pigmented Kupffer cells were found. In the kidneys of both sexes at 1000 and 3000 ppm, hyaline droplets (males only), hyaline casts and hyperplasia wer e observed in the renal proximal tubules. The forestomach of both sexes showed hyperkeratosis, hyperplasia and edema. Diffuse minimal thickening of the glandular mucosa in the glandular stomach was observed at 3000 ppm. Additionally, the duodenal mucosa wa s minimally thickened in females at 3000 ppm. The 1000 ppm animals of both sexes showed a decreased incidence or lack of lesions.

The LOAEL is 1,000 ppm (67 mg/kg /day for females and 54 mg/kg /day for males) and the NOAEL is 300 ppm (20 mg/kg/ day for females ) and 16 mg/kg /day for males) based on treatment related pathology in the liver, kidneys, and digestive tract and increases in

c linical chemistry parameters (ALT and AST). This study is ACCEPTABLE/GUIDELINE. 

## Carcinogenicity

There is one carcinogen icity study available in the rat. For wood pressure treatment uses, a second study in the mouse is anticipated to be required.

In a carcinogenicity study (MRID 45687211 ) Cu

- HDO ( 88

- 93% a.i. ) was administered to 50 Wistar rats/sex/dose in the diet at dose l evels of 0 (C), 100 (LDT), 600 (MDT), or 3000 ppm (HDT) (equivalent to 0, 6, 33, and 169 mg/kg / day) for 24 months in both sexes. Copper sulfate

Page 31 of 47was used as a reference standard at the same molar concentration of copper (1350 ppm) as in the high dose concen tration. Information on the toxicity of copper sulfate can be found in the text.

No substance related mortality was seen in either males or females. Body weight and body weight gain were reduced by 10 and 12%, respectively, in high

- dose (3000 ppm) males. Body weight and body weight gain was unaffected in other male treatment groups and all treated females. Food consumption was unaffected. There was also no apparent treatment

- related effect on food efficiency. Hematology was not remarkable.

Black feces w as common in rats treated with the HDT and was likely due to the copper in the compound as it also occurred in rats treated with CuSO 4 . The forestomach was determined to be a target organ in male and female rats with increases observed in both gross pathol ogy and non

neoplastic lesions (submucosal edema, ulceration, parakeratosis, hyperkeratosis, and hyperplasia) with dose

- related increases in the incidence and/or severity in both males and females. Male and female rats treated with 3000 ppm (HDT) also had an increase in lesions in the liver

- centri

lobular hepatocyte vacuolation in males and single cell necrosis and cysts in females.

There was a statistically significant [p<0.05] dose

- related increase in hemangioma of the mesenteric lymph nodes of both m ales and females, but pair

- wise comparisons were not statistically significant. The tumor incidence was similar to the historical control incidences.

The LOAEL (non

- carcinogenic) is 29 mg/kg/day (600 ppm), based on increases in the incidence and/or sever ity of the non

- neoplastic lesions of the forestomach (i.e., sub

- mucosal edema, ulceration, parakeratosis, hyperkeratosis, and hyperplasia). The NOAEL (non

carcinogenic) is 5 mg/kg/day (100 ppm). The test material is not considered carcinogenic. This study is ACCEPTABLE/GUIDELINE. 

## Mutagenicity

There is no evidence that Cu HDO is mutagenic. The database for mutagenicity is considered complete.

Using the Salmonella typhimurium reverse mutation assay (Ames test), Cu HDO was teste d for mutagenicity (MRID 456872 15). Standard plate tests were conducted for test concentrations ranging from 1.25 μg/plate to 5000 μg/plate, both in the presence and absence of S

- 9 mix. Preincubation tests were performed at test concentrations ranging from 0.6 μg/plate to 25 μg/ plate, both in the presence and absence of S

- 9 mix. The number of revertants on each plate was counted. In both protocols, the positive controls gave the appropriate response. All testing was performed up to and greater than the toxic concentration. There was no evidence that Cu

HDO is mutagenic in the Ames test. This study is ACCEPTABLE/GUIDELINE.

In a study ( in vivo ), Cu HDO was used to induce micronuclei in polychromatic erythrocytes (PCE) in the bone m arrow of the mouse (MRID 456872 16). The test substa nce was suspended in polyethylene glycol 400 (PEG 400). PEG 400 was also used as the negative control. The volume administered orally was 10 ml/kg/bw . The bone marrow cells were collected for micronuclei analysis at 24 hours, 48 hours and 72 hours after a single dose of the test article.

Page 32 of 47Ten animals (5 males, 5 females) per test group were evaluated for the occurrence of micronuclei in PCEs. 1000 PCEs/animal were scored for micronuclei. To describe a cytotoxic effect due to the treatment with the test article, the ratio between polychromatic and normochromatic erythrocytes (NCE) was determined in the same sample and reported as number of NCEs per 1000 PCEs. The following dose levels of the test article were tested: 24 h preparation interval: 50, 170 a nd 500 mg/kg b.w.; 48 h preparation interval: 500 mg/kg b.w.; and 72 h preparation interval: 500 mg/kg b.w. In a series of pre

- experiments 500 mg/kg b.w. was estimated to be the maximum tolerated dose. The animals expressed toxic reactions. After treatm ent with the test article cytotoxic e ffects were observed at the 48 hours interval. Under the experimental conditions reported, the test article did not induce micronuclei in the test system. Based on the test results Cu

- HDO is not considered to be mutagen ic in this micronucleus assay. This study is ACCEPTABLE/GUIDELINE.

In an unschedule d DNA repair assay (MRID 456872 14), the genotoxic activity of the test substance Cu

- HDO (89% a.i.) was investigated in vitro in hepatocytes obtained from male rats. Unschedu led DNA

- synthesis caused by the test substance can be detected via the incorporation of 3 H

- thymidine into DNA. The exposure time of the test chemical (6 concentration levels) was for 18 hours during which time 3 H

- thymidine was added. The cells were washe d and fixed and subsequently examined for unscheduled DNA synthesis by autoradiography. The control and positive controls showed the appropriate responses. The test material did not show genotoxic activity under the test conditions employed at doses up to the toxic level. This study is ACCEPTABLE/GUIDELINE. 

## Other Toxicological Effects

There are no acute neurotoxicity, subchronic neurotoxicity, and immunotoxicity studies in the database

, these have been identified as data gap s and are anticipated to be req uired

.

Page 33 of 47

# Appendix B Environmental Fate

Environmental Fate and Transport Properties of Cu HDO and its Degradates Copper, Cyclohexanone oxime , and Cyclohexanone

T his environmental fate assessment addresses the persistence and mobility of parent Cu HDO ( Bis

- (N

- cyclohexyldiazeniumdioxy)

– copper ), and the degradates copper metal, HDO, cyclohexanone oxime , and cyclohe x anone.

Cu HDO forms four detectable residues in the environment after it leaches from treated wood as Cu ion and HDO separately. The copper m olecule will sorb to soil and undergo reduction

oxidation reactions, in addition to complexing with other chemical species and sorption to soil. 13 Two molecules of HDO are formed from each Cu HDO molecule, each of which can degrade sequentially to cyclohex anone ox ime and then to cyclohexanone. Cyclohexanone oxime and cyclohexanone were significant degradates that did not degrade in a photodegradation in water study, indicating that they are stable to abioti c degradation (MRID 47512903). Cu HDO degraded in a n aerobic aquatic metabolism study that represents surface water without forming significant quantities of degradates, indicating that both cyclohexanone oxime and cyclohexanone were not persistent because of microbial degradation (MRID 47468801). Data on aerobic soil metabolism and anaerobic aquatic metabolism for HDO are anticipated to be required based on the fact that HDO sequentially degrades to cyclohexanone oxime and cyclohexanone.

Based on wood leaching stud ies using rainfall (MRID s 45687218, 45678219 ), the copper portion of the Cu HDO molecule was shown to leach to soil for at least 280 days (length of study) and HDO leaching was d etectable up to 57 days. Copper and HDO leach as separate molecules and
not a s the parent compound complex. Once l eached, copper will sorb strongly to soil and sediment, but the amount of biologically

- available copper will depend on the soil texture, pH, and c ation exchange capacity (CEC). Copper sorption will increase with increasing clay content and higher pH values

. In a submerged wood study, copper and HDO were also shown to leach separately for up to 4 days (MRID 47210205).

In the environment, Cu HDO is relatively insol uble ( 8.6 mg/l, Table 4), and will largely partition
to sediment in the presence of water based on leaching

- adsorption

- desorption data (MRID 47210201). Based on its low vapor pressure and Henry’s law constant (Table 4) , it is unlikely to move from soi l or water into air. However, the HDO degradate is miscible in water but is not likely to volatilize from either soil or water based on the chemical and p hysical properties in Table 5. The cyclohexanone oxime and cyclohexanone degradates are miscible in water, and are likely to volatilize from soil but not from water based on the chemical and ph ysical pro perties in Table 5. Once in soil or water, HDO, cyclohexanone oxime, and cyclohexanone are expected to rapidly degrade by microorganisms.

13 Cavinder, May 2, 2014

Page 34 of 47Cu HDO is stable to hydrolysis (MRIDs 45687218, 46621001, and 46336501) but degraded rapidly in irradiated water wit h a half

- life of 7.6 hours (MRID 47512903). However, this route of dissipation is expected to be limited because of sorption to sediment (bottom and suspended) and lack of light penetration caused by suspended sediment and shading. Cu HDO was relatively
pe rsistent in an aerobic aquatic metabolism study (MRID 47468801) with a half

- life of 17 days. Residues in water were higher for water than sediment for only three days. Data on aerobic soil metabolism have not been submitted and are anticipated to be requir ed, but Cu HDO was slightly mobile to immobile in five soils (MRID 47210201). 14 As a result, transport of parent Cu HDO by runoff to surface water and by leaching to ground water from treated wood is expected to be limited. For anaerobic aquatic metabolism

, data are anticipated to be required for the degradate HDO because the HDO component of the parent compound has the potential to leach from treated wood separately from copper and move across the soil surface to surface water (MRID 45687219)

.

Water and Sediment

Hydrolysis

Cu HDO is stable to hydrolysis at pH 7, 9, and 11 at 25

- 40 o C (MRID s 45687218, 46621001, 46336501 ).

UV Visible Light and Aqueous Photolysis

Cu HDO absorbs UV light with m aximum sorption at 350 nm and continuous sorption through 800 nm ( Table 4). As a result, the half

- life in a photodegradation in water study was 7.6 hours. Cyclohexanone oxime and c yclohexanone were major degradates that reached maximum values of 45 and 51 % of parent compound by the end of the study (MRID 47512903 ).

O ctanol

- Water Partition Coefficient and Bioconcentration in Fish

The log Kow values of Cu HDO are 1.6

- 2.6 and these values are <3 (Table 4), which indicates that bioconcentration in fish and other aquatic animals is expected to be limited. As a result, bio concentration in fish data are not anticipated to be required for Cu HDO.

Aerobic Aquatic Metabolism

The half

- life of parent Cu HDO in an aquatic system containing silt loam soil and pond water was 17 days with no significant degradates being detected. Aq ueous residues of parent Cu HDO were higher for water than sediment for 0

- 3 days and sediment residues were higher for the remainder of the study (up to 30 days) (MRID 47468801).

A na erobic Aquatic Metabolism

14 Log Koc values of 0

- 2 are mobile to highly mobile and Log Koc values of 3

- 4 are considered to be slightly mobile ( http://www.fao.org/docrep/003/x2570e/x2570e06.htm )

Page 35 of 47Data are anticipated to be required for HDO because the HDO component of the parent compound has the potential to leach from treated wood separately from copper and move across the soil surface to surface water (MRID 45687219)

. HDO is the predominant portion of parent compound other than copper. While this runoff is expected to be limited near drinking water intakes, it is possible near areas where lumber may be stored. These data will confirm that HDO is not persistent in surface water and sediments.

Soil

Soil Leaching/Adsorption/D esorption Batch Equilibrium

Parent Cu HDO was slightly mobile to immobile in five soils with Freundlich K ads values of 55

- 2,103 L/kg and Koc values of 8,739

- 114,910 L/kg in soil textures ranging from sandy to clay loam (MRID 47210201). 15

Aerobic Soil Metab olism

Data are anticipated to be required for HDO because the HDO component of the parent compound has the potential to leach from treated wood sep arately from copper into soil (MRID 45687219)

. HDO is the predominant portion of parent compound other than Cu.

A na erobic Soil Metabolism

Data were not submitted for anaerobic soil metabolism, but this data requirement can be satisfied with submission of anaerobic aquatic metabolism data

. Photodegradation on Soil

Even though parent Cu HDO absorbs UV light in th e range of 290

- 350 nm (see Table 4), data for photodegradation on soil are not anticipated to be required because the compound leaches from treated wood as its degradate components and not the parent compound ( MRID 45687219)

. The copper component is not expected to photodegrade because it’s a metallic element. Also, the HDO and its degradates are highly water soluble (see Table 5) and are expected to leach into shallow soil depths where photodegradation would not occur

.

Leachi ng from Treated Wood

Based on a rainfall leaching study ( EN

- 84, AWPA E20

- 08, MRID 4 5687219 ), the Cu and HDO components of Cu HDO can leach from treated wood onto soil as separate compounds. Pine wood boards were treated and leached using simulated rainfall

. The maximum, minimum, and average copper leaching rates were 21.1, 1.5, and 6.8 ug/cm 2 /day and the cumulative leaching rate over 280 days was 2,001 ug/cm 2

. The maximum, minimum, and average HDO leaching rates

15 Log Koc values of 3

- 4 are slightly mobile and Log Koc values of >5 are considered to be immobile ( http://www.fao.org/docrep/003/x2570e/x2570e06.htm )

Page 36 of 47were 25.1, 7.5, and 14 ug/cm 2 /day and the cum ulative leaching rate over 57 days was 920 ug/cm 2

. In addition, Cu HDO has been demonstrated to leach from submerged wood ( CEN

- TR 15119

, similar to AWPA E11

- 06, MRID 47210205 ) as its s eparate Cu and HDO components. The leaching rates were 1.94 (max imum )

, 0.30 (min imum ) 0 .67 (average) , and 0.42 (median) ug/cm 2 /day

. Th e cumulative leaching rate was 38.4 ug/cm 2

. Fate and Transport in WWTP

Data for routes of dissipation and toxicity in WWTPs were not submitted but are not anticipated to be required because Cu HDO is not expected to be transported to WWTPs. The sole end

- use product label states that wastes must be treated as hazardous waste and disposal must be conducted according to label instructions, a state pesticide or environmental control agency, or b y guidance from a hazardous waste representative.

Table 2. Environmental Fate Data Requirements for Cu HDO

Guideline Guideline No. Results Status and Reference (MRID unless specified)

Hydrolysis

835.2120 Stable to hydrolysis at pH 7, 9 and 11 Acceptable 45687218, 46621001, 46336501
N ormal environmental temperatures (25

– 40 o C) Photodegradation in water

835.2240 Half

- life of 7. 6 hours in irradiated water, stable in dark controls Acceptable
47512903 Cyclohexanone oxime and Cyclohexanone were major degradates that reached 45 and 51 % by end of study
Aerobic soil metabolism

835.4100 Data anticipated to be required for HDO Anticipated to be r equired
HDO leaches from treated wood to soil and water where it can degrade metabolically to cyclohexano ne oxime and cyclohexanone
Anaerobic soil metabolism 835.4200 No data submitted Not anticipated to be required because data on anaerobic aquatic metabolism will satisfy the data requirement Anaerobic aquatic metabolism

835.4400 Data anticipated to be required for HDO Anticipated to be r equired Required for wood preservatives when they are used in the aquatic environment. The hydrolysis half

- life is >4 days for the parent compound also. Aerobic aquatic metabolism 835.4300 Half

- life of 17 days in to tal Acceptable

Page 3 7 of 47system, no major degradates formed 47468801

Leaching and adsorption/desorption

835.1230 Freundlich Kads values of 55

- 2,103 L/kg
Koc values of 8,739

- 114,910 L/kg Acceptable
47210201
5 soils Cu HDO was slightly mobile to immobile in soil 16

Durability of wood and wood

based products

- Estimation of emissions from preservative treated wood to the environment

. Preservatives Class 4 or 5 (in contact with the ground, fresh water or seawater)

- Laboratory method CEN

- TR 15119 (draft OECD

protocol ) 1.94 (max) 0.30 (min) 0.67 (average) 0.42 (median) 38.4 (cumulative) 47210205 Supplemental data useful
60

- day leaching study using submerged boards and fresh water Ug/cm 2 /day (max, min, average) Ug/cm 2 (cumulative)

Standard Method for Determining the Leachability of Wood Preservatives in Soil Contact

AWPA E20

- 08/EN

- 84 Copper 21.1 (max) 1.5 (min) 6.8 (average) 2,001 (cumulative)

HDO 25.1 (max) 7.5 (min) 14 (average) 920 (cumulative) 45687219 Acceptable
280

- day study using simulated rainfall and board s 3.9 % Cu leached by 280 days Unspecified % of HDO leached in 57 days Ug/cm 2 /day (max, min, average) Ug/cm2 (cumulative)

References

Cavinder, Zoe. May 2, 2014. Risk Assessment for the Proposed Registration of the New Use of Cuprous Oxide , Zinc and Silver as a Thermostatic Antifouling Powered Coating for Use on Boat and Ship Hulls and Marine Structures . DP Barcode 412011

. Food and Agriculture Organization of the United Nations. APPENDIX 2 : Parameters of pesticides that influence processes in the soil

. http://www.fao.org/docrep/003/x2570e/x2570e06.htm

MRID 45687218. Brunner, E. (1993) Hydrolysis of Bis

- (N

- Cyclohexyldiazeniumdioxy) Copper at pH 4, 7 and 9: Lab Proje ct Number: 92/15/3. Unpublished study prepared by BASF Aktiengesellschaft. 15 p.

16 Based on FAO classification sys tem
Page 38 of 47MRID 45687219. Hettler, W. (2002) Cu

- HDO Mobility Studies Leaching and Adsorption/Desorption: Lab Project Number: 02/1103: 314: 312. Unpublished study prepared by Dr. Wolman GmbH. 53 p.

MRID 46336501. Jung, M. (2004) Response to the EPA Letter Dated July 01, 2004 Regarding
MRID # 45687218 Cu HDO : Supplement to Hydrolysis of Bis

- (N

Cyclohexyldiazeniumdioxy)copper at pH 4, 7 and 9. Project Number: 92/15/3. Unpublished study pre pared by Dr. Wolman Gmbh. 13 p.

MRID 46336601. Jung, M. (2004) Response to the EPA Letter Dated June 16, 2004 Regarding MRID # 45687219: Cu HDO . Project Number: BASF/02/1103, EN/84, E/11/97. Unpublished study prepared by Dr. Wolman GMBH. 23 p.

MRID 466210 01. Hettler, W. (2005) Hydrolysis as a Function of pH and Temperature of "Bis

- (N

- Cyclohexyl

- diazeniumdioxy)

- Copper". Project Number: BASF/05L00057. Unpublished study prepared by BASF Corporation. 60 p.

MRID 47210201. Winkler, J. (2006) Adsorption/Desorpt ion Study with Cu

- HDO According to OECD Guideline No. 106. Project Number: 05/10/35/2028. Unpublished study prepared by Biochem Agrar, Lab fuer Biologische und Chemische. 141 p.

MRID 47210205. Winkler, J. (2006) Adsorption/Desorption Study with Cu

- HDO Acc ording to OECD Guideline No. 106. Project Number: 05/10/35/2028. Unpublished study prepared by Biochem Agrar, Lab fuer Biologische und Chemische. 141 p.

MRID 47210206. Hettler, W. (2007) Waiver Request: Behavior of Bis

- (N

Cyclohexyldiazeniumdioxy)

- Copper, Cu

- HDO, in Soil. Project Number: WOL/ET/070104. Unpublished study prepared by Dr. Wolman GmbH. 24 p.

MRID 47210207. Hettler, W. (2007) Waiver Request: Behavior of Bis

- (N

Cyclohexyldiazeniumdioxy)

- Copper, Cu

- HDO, in Water. Project Number: WOL/ET/070703.
U npublished study prepared by Dr. Wolman GmbH. 9 p.

MRID 47468801. Singh, M. (2008) Aerobic Aquatic Metabolism of [Carbon 14] Cu

- HDO: Final Report. Project Number: 325744, 2008/7007202. Unpublished study prepared by BASF Agricultural Research Center and Ag vise Laboratories. 116 p.

MRID 47512903. Hassink, J. (2006) Aqueous Photolysis of Cu

- HDO [

- U

- (Carbon 14)]: Final Report. Project Number: 242482, 2006/1019626. Unpublished study prepared by BASF Aktiengesellschaft. 45 p.

Page 39 of 47

# Appendix C Ecotoxicology Profile

The O f fi c e of P e st i c ide P rog ra ms (OP P ) c om p let e d a p re l i m i n a r y p robl e m fo r mu l a t i on f or t h e

ec ol o g i ca l risk, envi r on m e ntal fate, a nd e nd a n g e r e d s p ec i e s a ssessments to be c ondu c ted a s p a rt of the R e g is t r a t i on R e view o f c opp e r c ompounds whi c h included c opp e r sulfate pentahydrate (EPA, 2010). The purp ose o f the prob l e m fo r mu l a t i on was to provide a n und e rst a ndi n g of wh a t i s known a bout the e nvironme n tal f a te a n d ec ol o g ic a l e f f

e c ts of t h e r e g is t e r e d us e s of c op p e r

c on t a in i ng c ompound s . Unlike most p e st i c ides e v a lua t e d b y the OP P , the ac t i ve i n g r e dient
p ropos e d for r e g is t r a t i on r e view i s el e ment a l copp e r ra t h e r than a n o r g a nic mo i e t y

. Copp e r is a m e tall i c e le m e nt t h a t l ies b e tw ee n t he G r oup I I A a nd the G roup I I B e lem e nts i n the
p e riodic tabl e

. B e i n g a n e lem e nt, i t will not br ea k down f u r ther a nd c ont i n u e s to c y c le in the

e nvironme n t a f t e r it is r e le a s e d. Copp e r is a n e ssential e l e ment f or l i ving s y stems, a nd is a k e y a tom in t he o x y g e n ca r r y i n g p r otein, h e mo c y a nin, f o r some inv e rt e b ra t e s. V a r i ous fo r ms of c opp e r o c c u r n a tur a l l y in t he

e nvironme n t. I t i s used in a wide v a r i e t y o f indust r ial a nd c onsum e r a p p l i c a t i ons, in a ddi t ion t o b e ing us e d a s a p e st i c i d e for ov e r 100 y e a rs, thus i n most a rea s w h e re a c o p p e r c ontaini n g p e st i c ide is a ppl i e d, it must be a ssu m e d that the r e is an e x is t ing b ac k g rou n d c on ce nt r a t i on that
must be c onsid e r e d. T h e a v e rage c o n ce nt r a t ion of c opp e r in the e a rth c rust t y p i c a l l y r a n g e s f rom 55 m g / K g to 70 m g / K g

. Tot a l copp e r c ontent of s oi l s of the U ni t e d S tat e s c om m on l y

ra n g e s f r om 1 m g / K g to 40 m g / Kg a nd a v e ra g e s a bout 9 m g / K g ( Tisdale e t al, 1 9 85). 

## Toxicity to Terrestrial Receptors

The toxicity endpoints presented below are based on the results of ecotoxicity studie s submitted to EPA to meet the a gency’s data requirements for the uses of Cu HDO

.

Birds

The results of two acute oral toxicity studies, submitted for Cu HDO , are provided in the following table (Table C 1).

Page 40 of 47Table C 1: Acute Avian oral toxicity testing.

Species Chemical,

% Active Ingredient Endpoint

(mg/kg) Toxicity Category Satisfies Guidelines/

Comments Reference

(MRID No.)

Bobwhite quail

( Colinus virginianus ) Copper HBO
98% LD 50 = 189
NOAEL = 63 Highly toxic Yes (Acceptable)

- 14

- day test duration 457709

- 01

Bobwhite quail

( Colinus virginianus ) Copper HBO
31.4% LD 50 = 1389
NOAEL = 250 Slight ly toxic Yes ( Acceptable )

- 14

- day test duration 4 57 7 09

- 02

These acceptable acute oral toxicity studies indicate that Cu HDO is highly to slightly toxic to birds on an acute oral basis. The guideline requirement OPPTS 850.2100 is satisfied.

Mammals

R at toxicity values obtained from studies conducted to support data requirements for human health risk assessments subst itute for wild mammal testing. Refer to the human toxicology chapter of this r eview for mammalian toxicity data. 

## Toxicity to Aquatic Receptors

The following aquatic toxicity studies were conducted with Cu HDO

, since under typical use conditions, it can be introduced into the aquatic environment.

Page 41 of 47Freshwater Fish

The results of freshwater fish acute stu dies submitted for Cu HDO are presented in Table C 2

.

Table C 2 : Toxicity of Cu HDO to freshwater fish.

Species Chemical,

% Active Ingredient

(a.i.)
Tested Endpoint

(mg/L) Toxicity Category Satisfies Guidelines/

Comments Reference

(MRID

No.)

Zebra fish Cu HDO
100% LC 50 = 0. 9
NOAEC = 0. 56 H ighly toxic Yes ( Acceptable )

- 96

- hr test duration

- flow

- through test

system 4 70694

- 0 1

Rainbow Trout (O ncorhynchus mykiss ) Cu HDO
99% (18.2% Cu) LC 50 = 0. 2 9
NOE A C = 0. 1 H ighly toxic Yes ( Acceptable )

- 96

- hr test duration

- flow

- through test

system 4 56872

- 0 4

Freshwater acute toxicity tests indicate that Cu HDO is highly toxic to the coldwater rainbow trout and zebra fish on an acute basis. Guideline requirement OPPTS 850.1075 is fulfilled.

Page 42 of 47Freshwater Invertebrates

The results of one Daphnia magna study was s ubmitted for Cu HDO and is provided in the following table (Table C 3 ).

Table C 3 : Acute Toxicity of Cu HDO to Freshwater Invertebrates

Species Chemical,

% Active Ingredient

(a.i.)
Tested Endpoint

(mg/L) Toxicity Category Satisfies Guidelines/

Comments Reference

(MRID

No.)

Waterflea ( Daphnia
magna ) Cu HDO 99% (18.2% Cu) EC 50 = 1 .1 Moderate

ly toxic Yes ( Acceptable )

- 48

- hr test

duration

- flow

- through test

system 4 56872

- 0 5

The results of the daphnid study indicate that Cu HDO is moderate ly toxi c to freshwater invertebrates. This study fulfills guideline requirement OPPTS 850.1010

.

Estuarine/Marine Fish and Invertebrates

Acute toxicity testing with estuarine and marine organisms using the TGAI is required when the end

- use product is intended for direct application to the marine/estuarine environment or effluent containing the active ingredient is expec ted to reach this environment. T he results of toxicity studies submitt ed for Cu HDO are presented in Table C 4

.

Page 43 of 47Table C 4 : Estuarine and marine toxicity testing

.

Species Chemical,

% Active Ingredient

(a.i.)
Tested Endpoint

(mg/L) Toxicity Category Satisfies Guidelines/

Comments Reference

(MRID

No.)

Eastern oyster ( Crassostrea virginica ) Cu HDO
100% EC 50 = 0.1 03
NOAEC = 0.320 H ighly toxic Yes ( Acceptable )

- 48

- hr test duration

- static test system 4 73205

- 03

Mysid shrimp Cu HDO
100% EC 50 = 0.490
NOAEC = 0.320 Highly toxic Yes (Acceptable) 473205

- 04

Sheepshead minnow Cu HDO
98% (18.16%) EC 50 = 0.420
NOAEC = 0.320 Highly toxic Yes (Acceptable) 473205

- 02

The results of the stud ies indicate that Cu HDO is highly toxic to estuarine/marine in vertebrates on an acute basis. The Eastern oyster , Mysid shrimp and Sheepshead minnow stud ies fulfill the guideline requirement s OPPTS 850.10 5 5 for acute estuarine/marine toxicity stud ies

. Aquatic Organisms, Chronic

Chronic toxicity testing (aquatic invert ebrate life cycle) w as submitted for Cu HDO and is presented in Table C 5

.

Page 44 of 47Table C 5 : Chronic Aquatic Toxicity Testing

.

Species Chemica l (% a.i.) E ndpoint

(mg/L) Toxicity Category Satisfies Guidelines

Comments Reference

( MRID No.)

Daphnia ( Daphnia
magna ) Cu HDO 99% (18.2% Cu) NOAEC = 0.38

LOAEC = 0.75 Highly toxic Yes (Supplemental) 4 75129

- 0 1

The results of the chronic daphnia study indicate that Cu HDO is chronically highly toxic to daphnia.

Aquatic Plants

The use of Cu HDO as a wood treatment may result in chemical leachate from treated wood into the aquatic environment. Aquatic plant toxicity data are necessary for a non

- target plant risk
assessment. Testing is conducted with one species of aquatic vascular plant ( Lemna gi bba ) and four species of algae: (1) freshwater green alga, Selenastrum capricornutum, (2) marine diatom, Skeletonema costatum, (3) freshwater diatom, Navicula pelliculosa, and (4) bluegreen cyanobacteria, Anabaena flos

- aquae. The rooted aquatic macrophyte rice ( Oryza sativa ) is also tested in seedling emergence and vegetative vigor tests.

One aquatic plant study was reviewed. Results of th is stud y is presented in Table C 6

.

Table C 6 : Toxicity of Cu HDO to Aquatic Plants

Species Chemical,

% Active Ingredient

(a.i.)
Tested Endpoint

(mg/L) Satisfies Guidelines/

Comments Reference

(MRID No.)

Lemna gibba Cu HDO
100% EC 50 = 0.1203
EC 05 = 0.0146 Yes (Acceptable) 472102

- 02

Page 45 of 47The stu dy above is classified as acceptable and fulfill s the guideline requirements for vascular plant t oxicity test ing (850.4 55 0). Cu HDO is highly toxic to Lemna gibba

. It is only slightly toxic to the marine diatom.

Page 46 of 47

# Appendix D Chemical and Physical Properties

All available, pertinent Cu HDO chemical and physical property information is provided in Section 1 of the Preliminary Workplan.

References

EPI

- WEB 4.11. 2012. U.S. EPA. http://www.epa.gov/oppt/exposure/pubs/episuitedl.htm

MRID 45687201. Buldt, D. (2001) Physico

- Chemical Properties of Bis

- (N

cyclohexyldiazeniumdioxy)

- copper: Lab Project Number: 01L00056: 01L00055. Unpublished study prepared by BASF AG. 31 p.

MRID 45687202. Brunner, E. (1992) Solubility of Bis

- (N

- cyclohexyldiaze niumdioxy)

- copper in Water at pH 4,7 and 9 at 23 degrees C: Lab Project Number: 92.15.1. Unpublished study prepared by BASF AG. 12 p.

MRID 45687203. Woll, (1992) Dissociation Constant of Bis

- (N

- cyclohexyldiazeniumdioxy) copper: Lab Project Number: 92.15.2 . Unpublished study prepared by BASF. 14 p.

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

Page 47 of 47