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 

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Docket Number EPA-HQ-OPP-2014-0800

TERMS, ABBREVIATIONS AND SYMBOLS

A.I. or a.i. active ingredient

atm-m3

/mole atmospheric pressure-cubic meter per mole

°C degrees Celsius

CAS Chemical Abstracts Service 

CFR Code of Federal Regulations 

DCI data call-in

EC50 median (or 50 percent) effect concentration

EC05 5 percent effect concentration

ECOTOX ECOTOXicology

EDSP Endocrine Disruptor Screening Program 

EPA Environmental Protection Agency 

FDA Food and Drug Administration 

FFDCA Federal Food, Drug, and Cosmetic Act

FIFRA Federal Insecticide, Fungicide, and Rodenticide Act

FQPA Food Quality Protection Act 

FWP Final Work Plan

g/mol grams per mole

GLN guideline number

IDS Incident Data System 

Koc organic carbon normalized soil-water partition coefficient

Kow octanol-water partition coefficient

LC50 median (or 50 percent) lethal concentration

LD50 median (or 50 percent) lethal dose

LOAEC lowest-observed-adverse-effect-concentration 

LOAEL lowest-observed-adverse-effect-level

Log Kow logarithm of the octanol-water partition coefficient

μg microgram

mg/kg milligram per kilogram

mg/kg/day milligram per kilogram per day 

mg/L milligram per liter

mm Hg millimeter of mercury

MOE margin of exposure 

MRID Master Record Identification Number

MRL maximum residue limit 

N/A not applicable 

nm nanometers

NOAEC no-observed-adverse-effect-concentration

NOAEL no-observed-adverse-effect-level

OCSPP Office of Chemical Safety and Pollution Prevention

OECD Organization for Economic Co-operation and Development

OPP Office of Pesticide Programs

% percent

PC Code Pesticide Chemical Code

PCF pounds per cubic foot

pH power of hydrogen or power of the concentration of the hydrogen ion

ppm parts per million

PWP Preliminary Work Plan

QSAR quantitative structure-activity relationship

RED Reregistration Eligibility Decision

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SAR structure activity relationship

SF safety factor

TGAI technical grade active ingredient

TMDL total maximum daily loads

UF uncertainty factor

UV/VIS ultraviolet/visible light absorption

WWTPs wastewater treatment plants

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Docket 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 Human Health Risk Assessment........................................................................................... 14

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

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

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

3.2.1 Food ........................................................................................................................ 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 Environmental 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.................................................................................................... 22

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

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Docket Number EPA-HQ-OPP-2014-0800

8 Next Steps............................................................................................................................. 24

9 References............................................................................................................................. 25

Appendix A Toxicology 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 – Test Species Evaluated for Assessing Potential Ecological Effects of Copper and the 

Associated Acute Toxicity Classification..................................................................................... 19

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Docket 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, identifying 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 component 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 Regulatory 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 continue to meet the statutory standard of no unreasonable 

adverse effects to human health or the environment. Changes in science, public policy, and 

pesticide use practices will occur over time. Through the registration review program, the agency

periodically reevaluates pesticides to make sure that as change occurs, products in the 

marketplace can be used safely. Information on this program is provided at

http://www2.epa.gov/pesticide-reevaluation.

The agency is implementing the registration review program pursuant to Section 3(g) of the 

Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA) and will review each registered 

pesticide every 15 years to determine whether it continues to meet the FIFRA standard for 

registration. The regulations governing registration review begin at 40 CFR 155.40. The agency

will consider benefits information and data as required by FIFRA. The public phase of 

registration review begins when the initial docket is opened for each case. The docket is the 

agency’s opportunity to state what it knows about the pesticide and what additional risk analyses 

and data or information it believes are needed to make a registration review decision. After 

reviewing and responding to comments and data received in the docket during this initial 

comment period, the agency will develop and commit to a Final Work Plan (FWP) and 

anticipated schedule for the Cu HDO case. 

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Docket 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 viewed 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 details)

Dietary (food) No N/A None None

Dietary (drinking water) No N/A None None

Occupational Handler Yes 9/10/2004 Updated

Dermal and inhalation exposure data

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

Residential Post 

Application - Incidental 

Oral and Dermal 

Yes 9/10/2004 Updated

Surface residue data

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 Preliminary 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) 2016-03

Receive Data to be Considered in Risk Assessment 2020-03

Open 30-Day Public Comment Period for Preliminary Risk Assessment(s) 2021-09

Close Public Comment Period 2021-10

Phase 3: Registration Review Decision and Implementation 

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Docket Number EPA-HQ-OPP-2014-0800

Open 60-Day Public Comment Period for Proposed 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 presents 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 Number 312600-89-8

Molecular Formula C12H22N4O4Cu

Molecular Weight 

(grams/mole) 349.9

Molecular Structure

Table 4 – Physical-Chemical Properties for 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 Kow)

2.6 @ pH 6.1 and 20 oC

1.6 @ pH 4 and 20 oC

45687201

830.7840 Solubility in water 

34 mg/L @ pH 4.0 and 23 oC

6.1 mg/L @ pH 7 and 23 oC

8.6 mg/L @ pH 9 and 23 oC

45687202

830.7950 Vapor pressure 7.5 x 10-7 mm Hg @ 20 oC 45687201

None 

(calculated) Henry’s Law Constant 5.7 x 10-8 atm-m3

/mol1

@ pH 7 and 25 oC (VP * MW)/(760 * water solubility)

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Docket Number EPA-HQ-OPP-2014-0800

1

atm-m3/mol = atmosphere cubic meter per mole

Table 5 – Chemical and Physical Properties of Cu HDO Degradates1

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 C6H13N2O2 C6H10O C6H11NO

Molecular weight 145.18 98.15 g/mol 113.16 g/mol

Octanol-water partition 

coefficient/Log Kow (830.7550)

-1.64 at 25 oC 0.81 @ 25 o

C 0.84 @ 25 oC

Solubility in water (830.7840) 733,900 mg/L 25,000 mg/L 18,000 mg/L

Vapor pressure (830.7950) 2.4 x 10-11 @ 25 oC 4.3 mm Hg @25 oC 1.09 x 10-2 mm Hg @ 25 oC

Henry's law constant 

No OCSPP number 

6.1 x 10-18 (atm-m3/mol) @ 

25 oC

9 x 10-6 (atm-m3/mol)

@ 25 oC 2.3 x 10-7 (atm-m3

/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 treatment 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 ingredients4 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 CXTM Type A 4 The other ingredients include copper carbonate (16.3 %) and boric acid (5 %)

NH

HO

N

OH

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Docket 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 UC2, Above Ground, Interior, Damp Pressure treatment 

using 0.2 to 3% 

a.i. in treatment 

solution 

0.206 PCF* 

Sawn Products UC3A, Above Ground, Exterior, Coated and rapid run off

Sawn Products UC3B, Above Ground, Exterior, Exposed and poor runoff 0.206 PCF*

Plywood UC1 and UC2 0.206 PCF*

*Retention 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 History

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

The EPA has not 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 any food use clearances in FFDCA Section 409 for Cu HDO. 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 pesticides 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 only reported for copper sulfate. Of the 24 reported incidents, 7 were associated with 

terrestrial plants and the rest were associated with kills of aquatic organisms, primarily fish. 

These remaining incidents were generally fish kills of carp, bass, trout, sunfish, perch, catfish, 

shiner and mosquitofish. Other aquatic organisms reported included frogs, clams and turtles. 

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Docket Number EPA-HQ-OPP-2014-0800

2 Anticipated Data Needs

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

review.

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Docket 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 

Exposure 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

870.38001 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

1Results 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.oecdilibrary.org/environment/test-no-443-extended-one-generation-reproductive-toxicity-study_9789264185371-en) will satisfy this anticipated requirement. 

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Docket 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 registration. 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 Endpoints

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 = 0.06

mg/kg/day

Carcinogenicity Study/Rats

LOAEL = 33 mg/kg/day based on increases 

in the incidence and/or severity of the nonneoplastic 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.

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Docket Number EPA-HQ-OPP-2014-0800

3.2 Dietary Exposure

The agency does not anticipate the need to conduct a dietary exposure assessment to support this 

registration review because dietary exposure is not expected based on the currently registered 

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 agency does not anticipate the need to conduct a dietary 

exposure (food only) assessment to support registration review.

3.2.2 Drinking 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 and 

anaerobic aquatic metabolism data to confirm microbial 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 

playground equipment and decks. These exposures were assessed in a human exposure review 

(EPA, 2004) that was written in support of Cu HDO as a new active ingredient. 

3.3.1 Occupational Exposures

EPA anticipates the need to revise the occupational handler assessment included in the 2004

human exposure review to account for exposure data and toxicological data that are anticipated 

to be required in registration review. The occupational handler scenario to be assessed is

included in Table 9.

Table 9 – Occupational Exposure Scenario for Cu HDO

Scenario Exposure 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/cm2 from a surface 

residue study conducted in 2002 (MRID 456788-04) and the oral NOAEL of 26 mg/kg/day. The 

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Docket 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. There 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 findings of the 2002 study. 

The exposure scenario that will be assessed is included in Table 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 

With 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 toxicity, 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, therefore, 

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 an environmental risk assessment for Cu HDO. The 

agency expects to require additional data for use in conducting the registration review. It has 

been determined from a leaching study that both copper and HDO leach from treated wood. The 

risk assessment will include Cu HDO, but will focus primarily on copper and will be based on 

registrant generated Cu HDO data, copper 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 species 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 treatment 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 

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Docket Number EPA-HQ-OPP-2014-0800

affect' federally listed threatened or endangered species (listed species) or their designated 

critical habitats. When an assessment concludes that a pesticide’s use 'may affect' a listed species 

or its designated critical habitat, the agency will consult with the U.S. Fish and Wildlife Service 

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 reductionoxidation 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 were 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 microbial metabolism (MRID 47468801).

Based on wood leaching studies using rainfall (MRIDs 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 days. 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 metabolism 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 Waste Water Treatment Plants (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 bodies listed as impaired under 

Section 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 47

 
Docket 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 receptor 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-synthesizing pathways and 

can interfere 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 organisms than the HDO 

molecule. Therefore, the aquatic risk assessment will focus on the effects from copper residues. 

The registrants have submitted adequate Cu HDO data for labeling purposes, and these data are 

listed in Appendix C. All available ecotoxicity endpoints in the agency’s files from copper 

studies submitted by registrants or other interested parties, federal laboratory data, or from the 

public literature are tabulated in Appendix C along with the anticipated data requirements and 

data gaps. The most sensitive values for each receptor group will be used for the risk assessment.

Acute and chronic toxicity data from studies submitted by pesticide registrants along with the 

available open literature will be used to evaluate the potential direct and indirect effects of 

copper in Cu HDO to aquatic receptors. 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 data 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 

receptors will not be assessed. Acute and chronic 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. 

Table 11 provides a summary of the information which will be used to assess the effects of 

copper on aquatic species.

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Docket Number EPA-HQ-OPP-2014-0800

Table 11 – Test Species Evaluated for Assessing Potential Ecological Effects of Copper and 

the Associated Acute Toxicity Classification

Taxa Surrogate Species Acute and Chronic Toxicity

Endpoints

Citation

MRID/Source

Acute Toxicity 

Classification

Insects Honeybee LD50 = >100 ug/bee 40764702 Practically 

nontoxic

Freshwater Fish1

Salmonids 

(Oncorhyncus 

species)

The Genus Mean Acute Value of

Salmonids3,5 = 31.4μg ai/L OW2 Very highly toxic

NA An acute to chronic ratio of 3.22 will 

be applied6 OW2

Freshwater 

invertebrates

Water flea

(Daphnia magna)

The Genus Mean Acute Value of

Daphnids = 4.14μg ai/L7 OW2 Very highly toxic

NA An acute to chronic ratio of 3.22

will be applied 6 OW2

Estuarine/marine 

fish

Summer flounder 

(Paralichthys 

dentatus)

The Genus Mean Acute Value of

estuarine/marine fish = 12.7 μg 

ai/L7 OW2 Very highly toxic

NA An acute to chronic ratio of 3.22

will be applied6 OW2 NA

Estuarine/marine 

invertebrates

Mussel

(Mytilus species)

Genus Mean Acute Value of 

estuarine/marine invertebrates =

11.5 μg ai/L7

OW2 Very highly toxic

NA An acute to chronic ratio of 3.22

will be applied6

OW2 NA

Aquatic nonvascular plants

Green alga 

(Pseudokirchneriella 

subcapitata)

Acute 48-hr EC50/NOAEC =

3.1/2.0 μg ai/L 43363603 -

Aquatic vascular 

plants

Duckweed

(Lemna gibba)

Acute 48-hr EC50/NOAEC 4

=

2300/100 μg ai/L

43363604

Endpoints for Cu HDO

Freshwater Fish Zebra fish LC50 = 0.9 mg/L

NOAEC = 0.56 mg/L

47069401

(Cu HDO)

Highly toxic

Freshwater 

Invertebrates

Water flea (Daphnia magna) EC50 = 1.1 mg/L

45687205

(Cu HDO) Moderately toxic

Estuarine Fish Sheepshead 

minnow

EC50 = 0.42 mg/L

NOAEC = 0.32 mg/L 47320502 Highly toxic

Page 19 of 47
Docket Number EPA-HQ-OPP-2014-0800

Estuarine 

Invertebrates

Eastern oyster

(Crassostrea 

virginica)

EC50 = 0.103 mg/L

NOAEC = 0.32 mg/L 47320503

Highly toxic

1 Freshwater fish serve as surrogates for aquatic-phase amphibians. 2 Office of Water’s Ambient Water Quality Criteria Document for Copper. 3 The salmonid GMAV was revised by OW. As of this time, the BLM is parameterized for only freshwater

fathead minnow and daphnids. If the BLM is not parameterized for salmonids at the time of the

assessment, acute LC50s of fathead minnow will be adjusted by the ratio of the salmonids GMAV to the

fathead minnow GMAV similar to the approach used in the 2006 RED. 4 The nonvascular plant endpoint of 3.1 μg ai/L was used in the copper RED to determine risk to

vascular plants also. 5 As derived in the 2007 Revised Aquatic Life Copper Criteria by OW for use in BLM model to determine

site-specific copper toxicity values. 6 An acute to chronic ratio of 3.22 will be applied to the BLM- derived site-specific acute toxicity values as 

was done in 2006 RED as the minimum data requirements for chronic toxicity were not met to derive OW’s 

chronic criteria.

 7 As used in the 2006 RED for use in BLM model to determine site-specific copper toxicity values.

NA = Not applicable.

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 

(EECs) 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 agency does not anticipate the need for a Down-the-Drain (DtD) assessment because 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 use. Remaining 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 ECOTOXicology (ECOTOX) 

database. The ECOTOX database 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 pesticides.

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/policy_guidance/team_authors/endangered_species_reregistration_work

group/esa_evaluation_open_literature.htm

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Docket Number EPA-HQ-OPP-2014-0800

USEPA, Office of Research and Development, 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 

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

chronic toxicity, including assessments of carcinogenicity, neurotoxicity, developmental, 

reproductive, and general or systemic toxicity. These studies include endpoints which may be 

susceptible to endocrine influence, including effects on endocrine target organ histopathology, 

organ weights, estrus cyclicity, sexual maturation, fertility, pregnancy rates, reproductive loss, 

and sex ratios in offspring. For ecological hazard assessments, EPA evaluates acute tests and 

chronic studies that assess growth, 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 Section 408(p), 

Cu HDO is subject to the endocrine screening part of the Endocrine Disruptor Screening 

Program (EDSP). 

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

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

produced by a “naturally occurring estrogen, or other such endocrine effects as the Administrator 

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

determinations. Tier 1 consists of a battery of 11 screening assays to identify the potential of a 

chemical substance to interact with the estrogen, androgen, or thyroid (E, A, or T) hormonal 

systems. Chemicals that go through Tier 1 screening and are found to have the potential to 

interact with E, A, or T hormonal systems will proceed to the next stage of the EDSP where EPA 

will determine which, if any, of the Tier 2 tests are necessary based on the available data. Tier 2 

testing is designed to identify any adverse endocrine-related effects caused by the substance, and 

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

Under FFDCA Section 408(p), the agency must screen all pesticide chemicals. Between October 

2009 and February 2010, EPA issued test orders/data call-ins for the first group of 67 chemicals, 

which contains 58 pesticide active ingredients and 9 inert ingredients. A second list of chemicals 

identified for EDSP screening was published on June 14, 201310 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/

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Docket Number EPA-HQ-OPP-2014-0800

6 Optional Label Changes

As discussed in Section 3.2 of this work plan, it is recommended 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, reduce 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 residue 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 Operating 

Procedure: Inclusion of Impaired Water Body and Other Water Quality Data in OPP’s 

Registration Review Risk Assessment and Management Process12 in order to ensure they can be 

used quantitatively or qualitatively in pesticide risk assessments.

7.1.3 Environmental 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, regulations, 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

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Docket 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 information 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 chemical 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 increasing 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 QSAR 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 studies specifically generated under 

Part 161 requirements. All relevant information would be considered as part of a weight-of-theevidence 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 evaluation 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 multiple 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 case, then the agency invites submission of this information. The submitter would 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. 

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Docket 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 any 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 preservation) 

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

After 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 47
Docket 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 Cu-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 BASF 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-(Ncyclohexyldiazeniumdioxy)-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-(NCyclohexyldiazeniumdioxy)-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 Toxicity Study with Bis-(NCyclohexyldiazeniumdioxy)-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-Cyclohexyldiazeniumdioxy)-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 47
Docket Number EPA-HQ-OPP-2014-0800

45687212 Hellwig, J. (1991) Study of the Prenatal Toxicity of Bis-(N-Cyclohexyldiazeniumdioxy)-Copper in Rats After Oral Administration (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-Cyclohexyldiazeniumdioxy)-Copper in Rabbits After Oral Administration (Gavage): Lab Project Number: 

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 Number: 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 

Aktiengesellschaft. 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, D361768, D361769

Tisdale, S.L., Nelson, W.L., and J.D. Beaton. 1985. Soil Fertility and Fertilizers (4thed.)

Macmillan Publishing Company, 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 CuHDO 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 47
Docket 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 Assessments for 

Coppers. http://www.regulations.gov/#!documentDetail;D=EPA-HQ-OPP-2010-0212-0009

U.S. Environmental Protection Agency (EPA). Pesticide Fact Sheet, Cu HDO. 

http://www.epa.gov/oppad001/reregistration/cca/copper_hdo_fs.pdf

USEPA. 2009c. Revised Reregistration Eligibility Decision Coppers. 

http://www.epa.gov/oppsrrd1/REDs/copper_red_amend.pdf

Page 27 of 47
Appendix A Toxicology Profile

Acute Toxicity for Product Labeling 

As listed in Table 1, Cu HDO is a not a primary dermal irritant (Category 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

Guideline No./ Study Type MRID No. Results Toxicity Category

870.1100/ Acute oral toxicity 45671304 LD50 = 380 mg/kg II

870.1200/ Acute dermal toxicity 45671305 LD50 >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 an 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 oral toxicity study (MRID 45687208), 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 included 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 target organ of Cu HDO appears to be the liver, as 

incidences of chronic hepatitis, liver cirrhosis, 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 47
The 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 oral toxicity study (MRID 45687209), 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 4000 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 CuSO4 (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 the copper sulfate group was to 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 consumption, 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. In 

the CuSO4 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 been caused by the Cu+2 ion.

The NOAEL is 500 ppm (35 mg/kg/day for males and 41 mg/kg/day for females). The 

LOAEL for this study is 2000 ppm (140 mg/kg/day for males and 167 mg/kg/day for 

females), 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 lack 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 

carboxymethyl 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, including 

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 

reduced 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 loss, and reduced mean placental and fetal 

body weights. Treatment-related increases in the occurrence of skeletal variations (irregular 

shaped sternebra[e] and accessory 13th ribs) were observed at 30 and 60 mg/kg/day. An increased 

incidence of skeletal retardations (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 LOAEL 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 and 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 reproduction 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 dietary toxicity study (MRID 45687210), 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 CuSO4 (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 liver, 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 reflected 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 were 

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 was 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 

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

Carcinogenicity 

There is one carcinogenicity 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 levels 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 47
was used as a reference standard at the same molar concentration of copper (1350 ppm) as in the 

high dose concentration. 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 was 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 CuSO4. The forestomach was determined to be 

a target organ in male and female rats with increases observed in both gross pathology and nonneoplastic 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 - centrilobular 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 males 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 severity of the non-neoplastic lesions of the forestomach (i.e., sub-mucosal 

edema, ulceration, parakeratosis, hyperkeratosis, and hyperplasia). The NOAEL (noncarcinogenic) 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 tested for 

mutagenicity (MRID 45687215). 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 CuHDO 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 marrow of the mouse (MRID 45687216). The test substance 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 47
Ten 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 and 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 treatment with the test 

article cytotoxic effects 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 mutagenic in this micronucleus assay. This 

study is ACCEPTABLE/GUIDELINE.

In an unscheduled DNA repair assay (MRID 45687214), the genotoxic activity of the test 

substance Cu-HDO (89% a.i.) was investigated in vitro in hepatocytes obtained from male rats. 

Unscheduled 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 3H-thymidine was added. The cells were washed 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 gaps and are anticipated to be required.

Page 33 of 47
Appendix B Environmental Fate

Environmental Fate and Transport Properties of Cu HDO and its 

Degradates Copper, Cyclohexanone oxime, and Cyclohexanone 

This 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 cyclohexanone. 

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 reductionoxidation 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 cyclohexanone oxime 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 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 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 studies using rainfall (MRIDs 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 days. Copper and HDO leach as separate molecules and 

not as the parent compound complex. Once leached, copper will sorb strongly to soil and 

sediment, but the amount of biologically-available copper will depend on the soil texture, pH, 

and cation 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 insoluble (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 soil 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 physical 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 physical properties 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 47

 
Cu HDO is stable to hydrolysis (MRIDs 45687218, 46621001, and 46336501) but degraded 

rapidly in irradiated water with 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 

persistent 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 required, 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 oC (MRIDs 45687218, 46621001, 

46336501).

UV Visible Light and Aqueous Photolysis

Cu HDO absorbs UV light with maximum 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 cyclohexanone were major degradates that reached maximum values 

of 45 and 51 % of parent compound by the end of the study (MRID 47512903).

Octanol-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, 

bioconcentration 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. Aqueous 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). 

Anaerobic 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 47

 
Data 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/Desorption Batch Equilibrium

Parent Cu HDO was slightly mobile to immobile in five soils with Freundlich Kads 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 Metabolism

Data 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 into soil (MRID 

45687219). HDO is the predominant portion of parent compound other than Cu.

Anaerobic 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 the 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.

Leaching from Treated Wood

Based on a rainfall leaching study (EN-84, AWPA E20-08, MRID 45687219), 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/cm2

/day and the cumulative leaching 

rate over 280 days was 2,001 ug/cm2. 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 47

 
were 25.1, 7.5, and 14 ug/cm2

/day and the cumulative leaching rate over 57 days was 920 

ug/cm2

.

In addition, Cu HDO has been demonstrated to leach from submerged wood (CEN-TR 15119, 

similar to AWPA E11-06, MRID 47210205) as its separate Cu and HDO components. The 

leaching rates were 1.94 (maximum), 0.30 (minimum) 0.67 (average), and 0.42 (median)

ug/cm2

/day. The cumulative leaching rate was 38.4 ug/cm2.

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 

by 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

Normal 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 required

HDO leaches from treated wood to soil 

and water where it can degrade 

metabolically to cyclohexanone 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 required

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 total 

Acceptable

Page 37 of 47
system, 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 soil16

Durability of wood and woodbased 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/cm2

/day (max, min, average)

Ug/cm2 (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 boards

3.9 % Cu leached by 280 days

Unspecified % of HDO leached in 57 

days

Ug/cm2

/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 Project Number: 92/15/3. Unpublished study prepared by BASF 

Aktiengesellschaft. 15 p.

16 Based on FAO classification system

Page 38 of 47

 
MRID 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-(NCyclohexyldiazeniumdioxy)copper at pH 4, 7 and 9. Project Number: 92/15/3. Unpublished 

study prepared 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 46621001. 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/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.

MRID 47210205. 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.

MRID 47210206. Hettler, W. (2007) Waiver Request: Behavior of Bis-(NCyclohexyldiazeniumdioxy)-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-(NCyclohexyldiazeniumdioxy)-Copper, Cu-HDO, in Water. Project Number: WOL/ET/070703. 

Unpublished 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 Agvise 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 Office of Pesticide Programs (OPP) completed a preliminary problem formulation for the

ecological risk, environmental fate, and endangered species assessments to be conducted as part 

of the Registration Review of copper compounds which included copper sulfate pentahydrate

(EPA, 2010). The purpose of the problem formulation was to provide an understanding of what 

is known about the environmental fate and ecological effects of the registered uses of coppercontaining compounds. Unlike most pesticides evaluated by the OPP, the active ingredient 

proposed for registration review is elemental copper rather than an organic moiety. 

Copper is a metallic element that lies between the Group IIA and the Group IIB elements in the 

periodic table. Being an element, it will not break down further and continues to cycle in the 

environment after it is released.

Copper is an essential element for living systems, and is a key atom in the oxygen carrying 

protein, hemocyanin, for some invertebrates. Various forms of copper occur naturally in the 

environment. It is used in a wide variety of industrial and consumer applications, in addition to 

being used as a pesticide for over 100 years, thus in most areas where a copper containing 

pesticide is applied, it must be assumed that there is an existing background concentration that 

must be considered. The average concentration of copper in the earth crust typically ranges 

from 55 mg/Kg to 70 mg/Kg. Total copper content of soils of the United States commonly

ranges from 1 mg/Kg to 40 mg/Kg and averages about 9 mg/Kg (Tisdale et al, 1985). 

Toxicity to Terrestrial Receptors

The toxicity endpoints presented below are based on the results of ecotoxicity studies submitted 

to EPA to meet the agency’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 C1).

Page 40 of 47
Table C1: 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%

LD50 = 189

NOAEL = 63

Highly 

toxic

Yes (Acceptable)

- 14-day test 

duration

457709-01

Bobwhite quail

(Colinus 

virginianus)

Copper HBO 

31.4%

LD50 = 1389

NOAEL = 250

Slightly 

toxic

Yes (Acceptable)

- 14-day test 

duration

457709-02

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

Rat toxicity values obtained from studies conducted to support data requirements for human 

health risk assessments substitute for wild mammal testing. Refer to the human toxicology 

chapter of this review 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 47
Freshwater Fish

The results of freshwater fish acute studies submitted for Cu HDO are presented in Table C2.

Table C2: 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%

LC50 = 0.9 

NOAEC = 

0.56

Highly 

toxic

Yes (Acceptable)

- 96-hr test duration

- flow-through test 

system

470694-01

Rainbow Trout 

(Oncorhynchus 

mykiss)

Cu HDO

99% 

(18.2% 

Cu)

LC50 = 0.29

NOEAC = 0.1

Highly 

toxic

Yes (Acceptable)

- 96-hr test duration

- flow-through test 

system

456872-04

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 47
Freshwater Invertebrates

The results of one Daphnia magna study was submitted for Cu HDO and is provided in the 

following table (Table C3).

Table C3: 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)

EC50 = 1.1 Moderately toxicYes (Acceptable)

- 48-hr test 

duration

- flow-through test 

system

456872-05

The results of the daphnid study indicate that Cu HDO is moderately toxic 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 expected to reach this environment. The results of toxicity 

studies submitted for Cu HDO are presented in Table C4.

Page 43 of 47
Table C4: 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%

EC50 = 0.103

NOAEC = 

0.320

Highly 

toxic

Yes (Acceptable)

- 48-hr test duration 

- static test system

473205-03

Mysid shrimp Cu HDO

100%

EC50 = 0.490

NOAEC =

0.320

Highly 

toxic

Yes (Acceptable) 473205-04

Sheepshead 

minnow

Cu HDO

98% 

(18.16%)

EC50 = 0.420

NOAEC = 

0.320

Highly 

toxic

Yes (Acceptable) 473205-02

The results of the studies indicate that Cu HDO is highly toxic to estuarine/marine invertebrates 

on an acute basis. The Eastern oyster, Mysid shrimp and Sheepshead minnow studies fulfill the 

guideline requirements OPPTS 850.1055 for acute estuarine/marine toxicity studies.

Aquatic Organisms, Chronic

Chronic toxicity testing (aquatic invertebrate life cycle) was submitted for Cu HDO and is 

presented in Table C5.

Page 44 of 47
Table C5: Chronic Aquatic Toxicity Testing.

Species Chemical 

(% a.i.)

Endpoint

(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)

475129-01

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 gibba) 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 this study is presented in Table C6.

Table C6: 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%

EC50 = 0.1203

EC05 = 0.0146

Yes (Acceptable) 472102-02

Page 45 of 47
The study above is classified as acceptable and fulfills the guideline requirements for vascular 

plant toxicity testing (850.4550). 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-(Ncyclohexyldiazeniumdioxy)-copper: Lab Project Number: 01L00056: 01L00055. Unpublished 

study prepared by BASF AG. 31 p.

MRID 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.

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/

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