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Polymeric Betaine Registration Review Team

Human Health & Environmental Effects

Nathan Mottl

William Hazel

Jonathan Leshin

Siroos Mostaghimi

Srinivas Gowda

James Breithaupt

David Bays

Risk Management

SanYvette Williams

Stacey Grigsby

Rose Kyprianou

Office of General Counsel

Philip Ross
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Table of Contents

1 Introduction............................................................................................................................. 5

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

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

1.3 Chemical Identification and Properties............................................................................ 7

1.4 Use/Usage Description................................................................................................... 10

1.4.1 Registrations ........................................................................................................... 10

1.4.2 Summary of Registered Uses to be Assessed ......................................................... 10

1.4.3 Usage Information .................................................................................................. 11

1.5 Regulatory History ......................................................................................................... 11

1.5.1 Recent/Pending Regulatory Actions....................................................................... 11

1.5.2 Tolerance Information ............................................................................................ 11

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

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

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

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

3 Human Health Risk Assessment........................................................................................... 13

3.1 Existing Toxicological Endpoints.................................................................................. 13

3.2 Dietary Exposure............................................................................................................ 16

3.2.1 Food ........................................................................................................................ 16

3.2.2 Drinking Water ....................................................................................................... 16

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

3.3.1 Occupational Handler Exposures............................................................................ 17

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

3.3.3 Occupational Post-Application Exposures ............................................................. 19

3.3.4 Residential Post-Application Exposures................................................................. 19

3.4 Aggregate and Cumulative Exposure............................................................................. 19

3.4.1 Aggregate Exposures.............................................................................................. 19

3.4.2 Cumulative Exposures............................................................................................ 19

4 Environmental Risk Assessment........................................................................................... 19

4.1. Environmental Fate Assessment Summary ..................................................................... 20

4.1.1 Environmental Fate of Polymeric Betaine.............................................................. 20

4.1.2 Environmental Fate of DDAC ................................................................................ 21

4.1.3 Environmental Fate of Boric Acid.......................................................................... 22

4.2 Conceptual Models for Environmental Exposure Pathways.......................................... 22

4.3 Ecological Effects Assessment....................................................................................... 24

4.3.1 Measures of Effect (Ecotoxicology Endpoints)...................................................... 24

4.4 Exposure Analysis Plan.................................................................................................. 26

4.4.1 Aquatic and Terrestrial Wildlife Exposure Estimates ............................................ 26

4.5 Effects Analysis Plan ..................................................................................................... 26

5 Endocrine Disruptor Screening Program (EDSP)................................................................. 26

6 Optional Label Changes........................................................................................................ 27

7 Guidance for Commenters.................................................................................................... 28

7.1 Preliminary Work Plan................................................................................................... 28

7.1.1 Trade Irritants.......................................................................................................... 28

7.1.2 Water Quality.......................................................................................................... 28
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7.1.3 Environmental Justice............................................................................................. 29

7.1.4 Structure Activity Relationships............................................................................. 29

7.1.5 Additional Information ........................................................................................... 30

8 Next Steps............................................................................................................................. 30

9 References............................................................................................................................. 31

Appendix A Toxicology Profile............................................................................................... 40

Appendix B Environmental Fate ............................................................................................. 51

Appendix C Ecotoxicology Profile.......................................................................................... 56

Appendix D Product Chemistry............................................................................................... 65

List of Tables

Table 1 – Summary of Anticipated Risk Assessments and Data Needs: Polymeric Betaine ......... 6

Table 2 – Anticipated Registration Review Schedule .................................................................... 6

Table 3 – Chemical Identification of Polymeric Betaine................................................................ 7

Table 4 – Physical-Chemical and Environmental Fate Properties for Polymeric Betaine ........... 10

Table 5 – Summary of Polymeric Betaine Registered Uses to be Assessed ................................ 10

Table 6 – Studies Anticipated as Needed for the Registration Review of Polymeric Betaine ..... 12

Table 7 – Existing Toxicological Endpoints for Polymeric Betaine ............................................ 14

Table 8 – Occupational Handler Pressure Treatment Exposure Scenario for Workers Using 

Polymeric Betaine......................................................................................................................... 18

Table 9 – Existing Effects Endpoints for Risk Assessment of DDAC and Boric Acid................ 25

List of Figures

Figure 1 – Conceptual Model for Ecological Exposure and Effects of Polymeric Betaine to 

Aquatic and Terrestrial Organisms............................................................................................... 24
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1 Introduction 

This document is the United States Environmental Protection Agency’s (USEPA, EPA or “the 

Agency”) Preliminary Work Plan (PWP) for Polymeric betaine (boric acid (H3BO3), polymer 

with N-decyl-1-decanamine, oxirane and 1,2- propanediol). Polymeric betaine is a borate ester 

which when applied to wood breaks down to DDAC (didecyl dimethyl ammonium chloride) and 

boric acid. It is registered for use as a wood preservative. For human health occupational 

exposure, the Agency is concerned with the Technical Grade Active Ingredient (TGAI) which is 

the borate ester. For ecological assessments, the Agency is concerned with the compounds that 

leach from wood which are DDAC and boric acid.

The PWP document explains what EPA's Office of Pesticide Programs (OPP) knows about 

Polymeric betaine, 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 Polymeric betaine’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 Polymeric betaine and what types of new data or other 

information would be helpful for the Agency to receive as it moves toward a decision on 

Polymeric betaine. 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 EPA 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://www.epa.gov/oppsrrd1/registration_review/.

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

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

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

anticipated schedule for the Polymeric betaine case. 

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

in docket EPA-HQ-OPP-2013-0374. Below is a summary of the issues relevant to this 

registration review case. 

Table 1 – Summary of Anticipated Risk Assessments and Data Needs: Polymeric Betaine

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 6 for details)

Dietary (food) No N/A None None 

Dietary (drinking water) No N/A None None 

Occupational Handler Yes 9/2/2009 Updated 

Dermal Exposure

Inhalation Exposure

Product Use Information

Residential Handler No N/A None None

Occupational Post 

Application No 9/2/2009 None

Post-application job functions at 

pressure treatment facilities have been 

re-classified as “handlers”

Residental Post 

Application - Incidental 

Oral and Dermal 

No 9/2/2009 None None

Residental Post 

Application - Inhalation No 9/2/2009 None None

Aggregate No N/A None None 

Cumulative No N/A None None 

Tolerance Review No N/A None None 

Ecological Yes 9/20/2006 Updated Aquatic invertebrate life-cycle

Fish early-life stage

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 2013-12 2013-12-20
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Close Public Comment Period 2014-02

Phase 2: Case Development 

Issue Final Work Plan 2014-06

Issue Data Call-In (DCI) 2015-06

Receive Data to be Considered in Risk Assessment 2017-06 

Open 30-Day Public Comment Period for Preliminary Risk 

Assessment(s) 2018-12

Close Public Comment Period 2019-01

Phase 3: Registration Review Decision and Implementation 

Open 60-Day Public Comment Period for Proposed Decision 2019-06

Close Public Comment Period 2019-08

Issue Final Decision 2019-12

Begin Post-Decision Followup 2019

Total (years) 6

*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).

1.2 Case Overview

The docket for Polymeric betaine (Case 5116) has been established at 

http://www.regulations.gov in docket number EPA-HQ-OPP-2013-0374.

1.3 Chemical Identification and Properties

Table 3 presents the active ingredient to be assessed in Case 5116: Polymeric betaine (PC Code 

103679). 

Table 3 – Chemical Identification of Polymeric Betaine

Common 

Name

Polymeric Betaine

Chemical 

Name

Boric acid (H3BO3), polymer with N-decyl-1-decanamine, oxirane and 1,2- propanediol (CAS Name)

Didecyl-bis(2-hydroxyethyl)ammonium borate (AI statement declared on the label)

Classification Quaternary ammonium borate ester

Borate ester

PC Code 103679
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Common 

Name

Polymeric Betaine

CAS No. 214710-34-6

Molecular 

Formula

C48H102N2O5B1(Dimer polymeric betaine)

Molecular 

Weight 

798.14 g/mol (Dimer polymeric betaine)

Purity 59.6 % borate ester form (Dimer polymeric betaine)
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Common 

Name

Polymeric Betaine

Molecular 

Structure

 Dimer Polymeric betaine

 

 Principle Component: Borate ester Equilibrium Component (Free quat): Didecyldihydroxyethyl ammonium hydroxide

The principle component in the mixture is borate ester. It exists in equilibrium in aqueous solution 

with the free didecyldihydroxyethyl ammonium hydroxide and free boric acid.
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The Polymeric betaine product chemistry information relevant to risk assessment (MRIDs:

45808205, 45808206, 45808207) is summarized in Table 4 and details of the product chemistry 

and environmental fate information are discussed in Appendix D and B, respectively.

Table 4 – Physical-Chemical and Environmental Fate Properties for Polymeric Betaine

Guideline 

No.

Physical and Chemical 

Properties Polymeric Betaine

830.7000 pH 9.61 (1% w/v solution)

830.7050 UV/Visible Absorption <200 nm. Does not absorb UV light.

Does not absorb light at testing wavelengths

830.7200 Melting point Pour point: -13°C

830.7220 Boiling point 110.2 °C

830.7300 Density 1g/ml at 20°C

Rel. Density: 1.024

830.7370 Dissociation Constant Decomposes in water.

830.7550 Partition coefficient (noctanol/water) 

Not applicable. Polymeric betaine’s behavior is that of a surfactant. A 

partition coefficient of a surfactant is not determinable.

830.7840 Solubility in water Completely miscible with water.

830.7860 Solubility in organic 

solvents Soluble in organic solvents.

830.7950 Vapor pressure 1.12 ± 0.08 mm Hg at 25°C

1.4 Use/Usage Description

1.4.1 Registrations

There are three EPA-registered products that contain Polymeric betaine as an active ingredient 

(a.i.). The products include one technical use product and two end-use wood preservative 

products. 

1.4.2 Summary of Registered Uses to be Assessed

Table 5 presents a summary of the registered uses of Polymeric betaine that will be assessed in 

this registration review. Polymeric betaine is applied by pressure treatment.

Table 5 – Summary of Polymeric Betaine Registered Uses to be Assessed

Use Application Method Application Rate

Wood or Wood Structure Protection Treatments 

Pressure Treatment to Forest Products Pressure Treatment 0.1-0.6 pcf 1

1

The target rate of retention is 0.1-0.6 pcf of wood treated (1.6-9.6 kg/m3) for sapwood of softwood species such as 

pine and spruce. The 9.6 kg/m3 retention is for critical infrastructure use only. Do not exceed 6.0

kg/m3 retention for above ground applications (AWPA UC1—UC3).
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1.4.3 Usage Information

No data were identified.

1.5 Regulatory History 

The first product containing Polymeric betaine as an active ingredient was registered in the 

United States in 2006. The Agency did not complete a Reregistration Eligibility Decision (RED) 

for Polymeric betaine since it was first registered after November 1, 1984.

1.5.1 Recent/Pending Regulatory Actions 

There are no recent regulatory actions for Polymeric betaine.

1.5.2 Tolerance Information 

No tolerances, tolerance exemptions, or food additive regulations have been established for 

Polymeric betaine by either EPA or FDA.

1.6 Incidents

1.6.1 Human Health 

No Polymeric betaine human poisoning incidents have been reported in OPP’s Incident Data 

System (IDS) for the time period spanning 2005 to 2013.

1.6.2 Ecological

No ecological incidents have been reported to the Agency between 2001 and 2013.

2 Anticipated Data Needs 

Table 6 presents a summary of the data anticipated as being needed to support this registration 

review.
Docket Number EPA-HQ-OPP-2013-0374

www.regulations.gov

Page 12 of 66

Table 6 – Studies Anticipated as Needed for the Registration Review of Polymeric Betaine

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

875.12001

Indoor 

Dermal 

Exposure

TGAI 24 Occupational Handler Wood Preservative Wood Pressure 

Treatment 

875.14001

Indoor 

Inhalation 

Exposure

TGAI 24 Occupational Handler Wood Preservative Wood Pressure 

Treatment 

875.1700 Product Use TGAI 12 Occupational Handler Wood Preservative Wood Pressure 

Treatment 

875.27002 Product Use TGAI 12 Occupational PostApplication Wood Preservative Wood Pressure 

Treatment 

850.1300

Aquatic 

invertebrate

life-cycle

DDAC 24 Aquatic ecological 

assessment Wood preservative Wood pressure 

treatment

850.1400 Fish early-life 

stage DDAC 24 Aquatic ecological assessment Wood preservative Wood pressure treatment

1

It may be possible to use proprietary surrogate exposure data if data compensation issues are appropriately and adequately addressed. 2 This is a write-up on how the product is used. It is part of the other Product Use Guideline 875.1700.
Docket Number EPA-HQ-OPP-2013-0374

www.regulations.gov

Page 13 of 66

3 Human Health Risk Assessment

The Agency anticipates the need to conduct a human health risk assessment for Polymeric 

betaine. The Agency expects to use a combination of existing and new data to conduct 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 7 represents endpoints used in EPA’s most recent human health risk assessment in

support of the 2006 hazard assessment. The data gap identified initially in 2006 (lack of a cancer 

study in a second species) was re-considered in a joint meeting on April 1, 2009, of the 

Antimicrobials Division’s (AD) Toxicity Endpoint Selection Committee (ADTC) and the Health 

Effects Division’s (HED) Cancer Assessment Review Committee (CARC). This joint committee

determined that a cancer study in a second species was not needed on the following grounds:

In general, exposure associated with wood preservatives used in post-application residential 

settings (e.g., wood used for playground equipment) is considered as a high (long-term) human 

exposure use and to register this kind of use triggers both mouse and rat carcinogenicity studies 

to confirm the carcinogenicity potential of the chemical. However, the committee agreed the 

leaching information indicates that the parent Polymeric betaine does not leach out from the 

treated wood, but rather a monomeric derivative of the parent compound (Didecyl 

bis(hydroxyethyl) ammonium cation) or borate/boric acid (MRID 47484101). Therefore 

additional cancer studies on the parent compound would not provide additional information 

useful for making a carcinogenicity determination.

The leachates are either members the Group I cluster of the EPA cluster group for quats (DDAC 

and/or DDAC-like compounds) or compounds that would have no quaternary ammonium 

characteristics (e.g., boric acid) and are classified as "not likely to be carcinogenic to humans". 

Therefore, additional studies are not necessary to conduct a risk assessment for the exposure 

associated with wood preservative used in post-application residential settings.

The joint committee concluded that the currently selected long-term end-point is protective 

against potential carcinogenic concerns. For parent Polymeric betaine, the highest dose tested in 

the rat chronic toxicity/carcinogenicity (375 mg/kg/day) showed evidence of uterine adenoma 

and adenocarcinoma, but the incidence of these tumors was within historical control range. Thus, 

the CARC concluded that these tumors were not treatment-related (MRID 45808215). The dose 

selected as the end-point for long-term risk assessment was the NOAEL of ≤ 9 mg/kg/day. 

Therefore, the joint committee agreed that the endpoint for the non-carcinogenic effects of 

Polymeric betaine should be conservative enough to protect against any carcinogenic effects of 

Polymeric betaine. In addition, the committee did identify an immunotoxicity study as a data 

gap. However, the Agency has decided to waive the immunotoxicity study requirement on the 

following grounds:
14

1. Leaching data indicate that the parent compound does not leave the treated wood 

(MRID 47484101). The leachates are either chemicals that belong to the Group I 

cluster of the EPA cluster group for quats (DDAC and/or DDAC-like compounds) or 

compounds that would have no quaternary ammonium characteristics (e.g., boric 

acid).

2. Quaternary ammonium compounds are classified as "not likely to be immunotoxic to 

humans" based on an EPA retrospective completed in 2012 on immunotoxicity (2013. 

A Retrospective Analysis of the Immunotoxicity Study). Therefore, additional 

studies based on the group one quat component would not help the risk assessment 

for the exposure associated with wood preservative used in post-application 

residential setting.

3. In the 2012 immunotoxicity risk assessment, boric acid/borate was found to have 

immunotoxic concerns. However, the NOAEL set for boric acid/borate was 250 

mg/kg/day. The committee believes that the currently selected chronic end-point for 

Polymeric betaine is protective against potential immunotoxic concerns. The dosage 

that was used as the end-point in the risk assessment is ≤ 9 mg/kg/day. Therefore, the 

committee agreed that the end-point selected for non-immunotoxic effects should be 

conservative enough to protect against potential immunotoxicity concerns.

EPA anticipates that there will be no need to revise the existing toxicological endpoints as part of 

this registration review. Table 7 presents the endpoints used in EPA’s most recent human health 

risk assessment in support of the 2006 registration.

Table 7 – Existing Toxicological Endpoints for Polymeric Betaine

Exposure 

Scenario

Dose Used in 

Risk 

Assessment 

(mg/kg/day) 

Target Margin of Exposure 

(MOE), Uncertainty Factor 

(UF), FQPA Safety Factor 

(SF)

Study and Toxicological Effects

Short-Term

Incidental Oral 

(1-30 days)

NOAEL=9

mg/kg/day

Residential/Occupational MOE 

= 100

(10x for inter species variation, 

and 10X for intra-species 

variation)

Rabbit Developmental Study

(MRID 46315816)

LOAEL = 25 mg/kg/day

based on decreased total fetus index and live fetus index; 

increased embryonic/fetal death index and fetal resorption 

index; increased postimplantation loss; decreased 

ossification of the cranium and bones of the fore and hind 

feet; increased incidence of incomplete ossification of the 

public bone(s); and increased incidence of single 

association pelvis

IntermediateTerm

Incidental Oral 

(1- 6 months)

NOAEL= 5.7

mg/kg/day

Residential/Occupational MOE 

= 100

(10x for inter species variation, 

and 10X for intra-species 

variation)

40-day Rat oral Study

(MRID 45808213)

LOAEL = 28.5 mg/kg/day

based on squamous hyperplasia of the forestomach.
15

Exposure 

Scenario

Dose Used in 

Risk 

Assessment 

(mg/kg/day) 

Target Margin of Exposure 

(MOE), Uncertainty Factor 

(UF), FQPA Safety Factor 

(SF)

Study and Toxicological Effects

Relative dermal 

absorption rate

100%

There is no acceptable dermal absorption study. Although some evidence indicates the absolute dermal 

absorption factor may be low (MRID 45808301), the absorption of Polymeric betaine through oral route is 

also low (MRID 45808305). Therefore, for potential dermal risk assessments, dermal absorption factor of 

100% should be applied (oral equivalent) based on the comparable results in the oral and dermal toxic 

effects).

Short-Term

Dermal (1-30 

days)

NOAEL= 9

mg/kg/day

Residential/Occupational MOE 

= 100

(10x for inter species variation, 

and 10X for intra-species 

variation)

Rabbit Developmental Study

(MRID 46315816)

LOAEL = 25 mg/kg/day

based on decreased total fetus index and live fetus index; 

increased embryonic/fetal death index and fetal resorption 

index; increased postimplantation loss; decreased 

ossification of the cranium and bones of the fore and hind 

feet; increased incidence of incomplete ossification of the 

public bone(s); and increased incidence of single 

association pelvis

IntermediateTerm Dermal

(1- 6 months)

NOAEL= 5.7

mg/kg/day

Residential/Occupational MOE 

= 100

(10x for inter species variation, 

and 10X for intra-species 

variation)

40-day Rat oral Study

(MRID 45808213)

LOAEL = 28.5 mg/kg/day

based on squamous hyperplasia of the forestomach.

Long-Term

Dermal

( > 6 months)

NOAEL < 8.7

mg/kg/day

Residential/Occupational MOE 

= 300

(3 for using LOAEL, 10x for 

inter species variation, and 10X 

for intra-species variation)

Chronic/carcinogenicity – Rat

(MRID 45808215)

LOAEL = 8.7 mg/kg/day

Based on evidence of histiocytosis in the both the 

mandibular lymph nodes and mesenteric lymph nodes and 

atrophy of the salivary glands.

Short-Term

Inhalation

(1-30 days)

NOAEL= 9 

mg/kg/day

Residential/Occupational MOE 

= 100

(10x for inter species variation, 

and 10X for intra-species 

variation)

Rabbit Developmental Study

(MRID 46315816)

LOAEL = 25 mg/kg/day

based on decreased total fetus index and live fetus index; 

increased embryonic/fetal death index and fetal resorption 

index; increased postimplantation loss; decreased 

ossification of the cranium and bones of the fore and hind 

feet; increased incidence of incomplete ossification of the 

public bone(s); and increased incidence of single 

association pelvise of single association pelvis

IntermediateTerm Inhalation

(1- 6 months)

NOAEL= 5.7 

mg/kg/day

Residential/Occupational MOE 

= 100

(10x for inter species variation, 

and 10X for intra-species 

variation)

40-day Rat oral Study

(MRID 45808213)

LOAEL = 28.5 mg/kg/day

Based on squamous hyperplasia of the forestomach.

Long-Term

Inhalation

( > 6 months)

NOAEL < 8.7 

mg/kg/day

Residential/Occupational MOE 

= 300

(3 for using LOAEL, 10x for 

inter species variation, and 10X 

for intra-species variation)

Chronic/carcinogenicity – Rat

(MRID 45808215)

LOAEL = 8.7 mg/kg/day

Based on evidence of histiocytosis in the both the 

mandibular lymph nodes and mesenteric lymph nodes and 

atrophy of the salivary glands.
16

Exposure 

Scenario

Dose Used in 

Risk 

Assessment 

(mg/kg/day) 

Target Margin of Exposure 

(MOE), Uncertainty Factor 

(UF), FQPA Safety Factor 

(SF)

Study and Toxicological Effects

Cancer (oral, 

dermal, 

inhalation)

The determination of the potential of carcinogenic effects of Polymeric betaine technical was referred to the 

Cancer Assessment Review Committee. (CARC). The Committee decided that there is inadequate data to 

evaluate the potential carcinogenic concerns of this chemical. However, a leaching study indicates that the 

leachates are group I quaternary ammonium compounds and boric acid/borate. These are classified as "not 

likely to be carcinogenic to humans". Therefore, additional studies are not necessary for the risk assessment 

for the exposure associated with wood preservative used in post-application residential setting.

Immunotoxicity

The determination of the potential of immunotoxic effects of Polymeric betaine technical is referred to AD 

Toxicology issues committee. The Committee’s decision is there is inadequate data to evaluate the potential 

immunotoxic concerns of this chemical. However, a leaching study indicates that the leachates are group I 

quaternary ammonium compounds and boric acid/borate. Group I quaternary ammonium compounds are 

classified as "not likely to be immunotoxic to humans". Boric Acid/borate is considered immunotoxic but the 

NOAEL for immunotoxicity is 25 times greater than the chronic NOAEL. Therefore, additional studies 

would not help the risk assessment for the exposure associated with wood preservative used in postapplication residential setting.

3.2 Dietary Exposure

As part of the human health risk assessment for Polymeric betaine, the Agency has looked at the 

dietary route of exposure to determine whether or not food or drinking water assessments are 

needed.

3.2.1 Food 

Polymeric betaine is used solely for vacuum-pressure treatment of wood and wood products. The 

two EP labels prohibit use on wood that may come into contact with food or feed. Further, one 

label (EPA Reg. No. 75269-3) prohibits use on wood to be used to construct beehives. As a 

result, dietary exposure to Polymeric betaine via food is not expected. Therefore, neither a 

dietary risk assessment nor residue chemistry data are expected to be needed for Polymeric 

betaine based on the currently-approved use pattern.

3.2.2 Drinking Water

Although the Polymeric betaine labels prohibit use on wood to be used in or near fresh water or 

salt water, the Agency has determined that these restrictions are not practical or enforceable. 

Therefore, leaching and runoff to surface water is expected. Additionally, pressure treatment of 

wood products is likely to result in industrial discharges of waste water to surface water.

However, Polymeric betaine is cationic resulting in its sorption to soil and sediment in the 

presence of water.1 Further, it is expected to be removed in the process of drinking water 

treatment, especially in the flocculation step, where solid particles are chemically joined and then 

removed from the overlying water column by precipitation (see Section 5.1 and Appendix B, 

 1 Cornell University Cooperative Extension (2007). Cation Exchange Capacity Fact Sheet.

http://nmsp.cals.cornell.edu/publications/factsheets/factsheet22.pdf
17

Environmental Fate).

2 Therefore, Polymeric betaine is not likely to be present in drinking water. 

As a result, a drinking water assessment is not expected to be necessary for Polymeric betaine

and no residue chemistry data are needed to characterize drinking water exposures.

3.3 Occupational and Residential Exposures 

The Agency anticipates the need to revise the occupational assessments conducted in 2009 using 

new exposure data. The pressure treatment of wood with Polymeric betaine may result in 

occupational handler, occupational post-application and residential post-application exposures. 

Note: The previous occupational job functions at the pressure treatment facility were classified 

as “post-application” and have subsequently been re-classified under the heading of “handler” 

job functions. Therefore, the occupational post-application is no longer listed separately. 

The Agency has concerns that the surrogate data originally used for registration do not meet 

current Agency standards. EPA used wood treatment-related exposure from the Health and 

Safety Executive, United Kingdom (HSE) which is worker survey data (MRIDs 45808312/ 

45843707 based on the study by Garrod, et al.,1999, ”Exposure to Preservatives Used in the 

Industrial Pre-treatment of Timber, Ann. Occup. Hyg., 43(8), 543-555.) to address dermal and 

inhalation worker exposures. The HSE survey data are limited in scope and quality, and have 

QA/QC problems (lack of field fortification, laboratory recoveries, and/or storage stability 

information). The Agency believes that it may be possible to use proprietary surrogate exposure 

data if data compensation issues are appropriately and adequately addressed. EPA is aware that 

the Antimicrobial Exposure Assessment Task Force II (AEATF II) is currently developing 

proprietary surrogate wood treatment data for examining handler applications at wood-pressure

treatment facilities that may address the original deficiencies of the HSE survey. Or the 

registrants have the option to generate their own data.

As a result, EPA anticipates the need to conduct a human health risk assessment after receiving 

the appropriate dermal and inhalation worker exposure monitoring data for occupational handlers

at wood pressure treatment facilities. Since no residential handler uses are expected from the use 

of Polymeric betaine, a risk assessment is not required. In addition, EPA does not anticipate the 

need for wipe residue data for residential post-application exposures since EPA has already 

received adequate data. Since there are no new exposure updates and no new toxicological 

endpoints, the Agency does not plan to update the residential post-application risk assessment.

3.3.1 Occupational Handler Exposures

The Agency conducted occupational assessment for the registration of wood preservative uses of 

Polymeric betaine on September 2006 and later amended the ORE in February 2009 (D338434, 

D353174, and D355602). As part of the EPA 2009 review, the Agency used registrant submitted 

data, including surrogate data for wood treatment-related exposure (HSE worker survey data as 

cited in registrant submissions MRIDs 45808312/ 45843707). The HSE survey data are limited 

in scope and quality, and have quality assurance and quality control (QA/QC) problems which 

include the lack of field fortification, laboratory recoveries, and/or storage stability information

 2 http://www.sbwater.org/education.aspx?id=416
18

(U.S.EPA 2006 and SAP 2007). As a result, EPA anticipates the need to conduct a human health 

risk assessment after receiving the appropriate dermal and inhalation exposure monitoring data 

for wood pressure treatment exposures. Upon receipt and review of the needed exposure data, the 

Agency will conduct a new refined occupational risk assessment. 

The Agency anticipates the need to require new occupational handler studies for the wood 

preservative uses (exposure studies to monitor work exposure at pressure treatment plant) and to 

conduct a new occupational handler risk assessment to assess the dermal and inhalation routes of 

exposure from pressure treatment exposure during registration review. The Agency believes that 

it may be possible to use proprietary surrogate exposure data if data compensation issues are 

appropriately and adequately addressed. EPA is aware that the Antimicrobial Exposure 

Assessment Task Force II (AEATF II) is currently developing proprietary surrogate wood 

treatment data for examining handler and post-application of wood-pressure treatment scenario 

to address this data need. The scenarios outlined in Table 8 are the typical worker handler 

exposure scenarios that EPA currently believes exist for wood pressure treatment, but may 

change when EPA receives the final worker study from AEATF II.

Table 8 – Occupational Handler Pressure Treatment Exposure Scenario for Workers 

Using Polymeric Betaine

Scenario Exposure Route(s) Duration

Occupational Exposures

Pressure Treatment Workers Dermal and Inhalation Short, Intermediate, and Long- Term 

There are a variety of pressure treatment worker activities to address. For example workers

operate and monitor application system valves and controls, open and close cylinder doors, and 

supervise the insertion and removal of charges of timber from the treatment cylinders. Workers 

operate open-cab forklifts used to load untreated wood onto charge trams; move charges into and 

out of treatment cylinders; remove charge leads and bands from treated wood; distribute treated 

wood to load-out area, and load treated wood for shipment. Workers perform various labor and 

cleanup duties in treatment and drip pad area including: sweeping and pressure-washing drip pad 

and tracks; removing and shredding all bands from treated stacks of lumber; picking up and 

disposing treated wood waste; cleaning cylinders; and, handling hazardous waste (U.S. EPA 

2001). 

3.3.2 Residential Handler Exposures

EPA does not expect any residential handler exposures from the use of Polymeric betaine since 

no residential handler scenarios are expected.
19

3.3.3 Occupational Post-Application Exposures

For pressure treatment of wood, all of the job functions at the facility have been re-classified as 

“handler” exposures. Therefore, a separate post-application occupational assessment for workers 

at the pressure treatment facility is not warranted. 

3.3.4 Residential Post-Application Exposures

The Agency developed residential post-application risk assessments for Polymeric betaine from 

the wood preservative uses of Polymeric betaine on September 2006 and later amended the 

assessment in 2009. Chemical-specific data on dislodgeable residues from treated wood and 

leaching potential (MRIDs 47484102 and 47497001) were submitted to the Agency and used to 

develop residential post-application risk assessments for registration. Based on our current 

methods of assessment, the Agency believes these data will be adequate to support the residential 

post-application assessments and the Agency will not require any additional data or risk 

assessments for residential post-application exposures. 

3.4 Aggregate and Cumulative Exposure

3.4.1 Aggregate Exposures

As dietary exposure to Polymeric betaine via food and drinking water are not expected, 

aggregate risk is comprised of residential post application exposure only. As noted above, 

residential reassessment, and hence aggregate risk assessment, does not need to be updated.

3.4.2 Cumulative Exposures 

With respect to cumulative exposure, unlike other pesticides for which EPA has followed a 

cumulative risk approach based on a common mechanism of toxicity, EPA has not made a 

common mechanism of toxicity finding as to Polymeric betaine and any other substances, and 

Polymeric betaine does not appear to produce a toxic metabolite common to other substances. 

For the purposes of this registration review, therefore, EPA has not assumed that Polymeric 

betaine 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 has not conducted a risk assessment that supports a complete endangered species 

determination for Polymeric betaine. The ecological risk assessment planned during registration 

review will allow the Agency to determine whether Polymeric betaine’s use has 'no effect' or 

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

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

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

and/or National Marine Fisheries Services (the Services), as appropriate.
20

4.1. Environmental Fate Assessment Summary

The environmental fate risk assessment for Polymeric betaine will incorporate data on two 

additional ingredients. The Agency is concerned with the compounds that leach from wood 

which are DDAC and boric acid. 

4.1.1 Environmental Fate of Polymeric Betaine

Polymeric betaine is an equilibrium mixture of the free didecyl-bis(2-hydroxyl)ammonium 

cation, the free boric acid anion, and the combination of the cation and anion.3 At basic pH 

values, the TGAI is expected to be present in higher amounts as the free active cation and the 

inactive boric acid anion, while it would be present in the combined (non-ionized) form at pH 

values below 7.0.4 Because the active ingredient in Polymeric betaine is an equilibrium mixture 

of DDAC and boric acid, it has no relevant vapor pressure, flammability, or melting point.5

 It is 

completely miscible in water6 and therefore would not be likely to escape from water into air. 

Also, it is impossible to calculate a Henry’s Law constant because no relevant vapor pressure 

exists for the active cationic ingredient because it exists as a salt. Although the vapor pressure of 

the formulated product is 1.12 mm Hg, this vapor pressure reflects the water content of the 

formulation (Table 4). 

Abiotic (chemical) degradation of Polymeric betaine is not a significant route of dissipation in 

the environment. Polymeric betaine is stable to hydrolysis7 (no hydrolyzable functional groups) 

and does not absorb light between 290 and 800 nm in wavelength.8 As a result, it is not expected 

to undergo direct photodegradation in the environment. 

However, some biotic degradation of polymeric betaine can occur. Biotic degradation in the top 

layer of soil (aerobic soil metabolism)9

does contribute to the dissipation of Polymeric betaine in 

the environment. The parent compound half-lives ranged from 83-107 days10 for linear 

regression and 76-107 days for non-linear regression.11 The only non-volatile organic degradate 

formed in the studies was M-1, a dealkylated12 and hydroxylated quaternary ammonium 

compound. Using DDAC as a surrogate, the half-lives in surface water (aerobic aquatic 

metabolism) and sediment (anaerobic aquatic metabolism) were 180 and 261 days, respectively. 

No major non-volatile degradates were detected. 

For polymeric betaine, the non-ionized state of active ingredient (quaternary cation) is more 

likely to be removed from soil and sediment by leaching because the positive and negative 

charges of the non-ionized forms are partially negated when combined. As the pH of the soil and 

 3 MRIDs 45800203 (p. 18) and 47757601 (p. 17)

4 MRID 45808204, p. 13

5 MRID 45800202 (p. 18)

6 MRID 45800206, p. 8

7 MRID 47348101

8 MRIDs 46315828, 46404706

9 OCSPP 835.4100, MRIDs 45808209 and 47757601

10 Arithmetic mean of 97 days for 5 half-lives, linear first-order regression using all data points 11 Arithmetic mean of 90 days for 5 half-lives, non-linear first-order regression using all data points 12 Loss of one decyl (C10) chain
21

sediment increases, the soil and sediment becomes more negatively-charged and the cationic 

active ingredient becomes more tightly sorbed (opposite charges attract). The Freundlich Kads 

values were 190-4,300 ml/g for whole soil and the Koc values were 10,000-220,000 ml/g for 

organic carbon content.13 

The registrant conducted studies on retention and leaching rates for Polymeric betaine. For the 

treatment rates of 12-23 kg/m3, 97-99 % retention was observed.14 The maximum leaching rates 

in treated southern yellow pine were 1.8, 2.5, 3,3, and 4.6 ug/cm2

/day for the 3, 5, 7, and 9 kg/m3

treatments, respectively.15 The cumulative leaching rates were 18, 23, 31, and 38 ug/cm2 for 3, 5, 

7, and 9 kg/m3, respectively.16

4.1.2 Environmental Fate of DDAC 

DDAC is stable to chemical degradation, including hydrolysis and photodegradation in water. 

DDAC was hydrolytically stable under abiotic and buffered conditions over the pH 5-9 range17

and stable to photo-degradation in pH 7 buffered aqueous solutions (including the 

photosensitizer acetone)18 and on soil.19

DDAC is also essentially stable to metabolism in aerobic soil (non-flooded top layer of soil) and 

under aquatic conditions. DDAC only degraded slightly in an aerobic soil metabolism study.20

The half-lives under aerobic aquatic conditions21 (representing surface water) and anaerobic 

aquatic metabolism22 (representing bottom sediment) were 180 and 261 days, respectively. 

In a wastewater treatment plant (WWTP), DDAC was not readily biodegradable in an OECD 

301B CO2 evolution test. The 301B test guideline requires that 60 % of the theoretical carbon 

dioxide (ThCO2) be produced in 28 days, and only 52 % of ThCO2 was produced for DDAC. 

However, DDAC was shown to have inherent, primary biodegradability because the degradation 

in 28 days was between 20 and 60 %.23

DDAC is expected to be immobile in soil. DDAC has a strong tendency to bind to sediment and 

soil with Freundlich Kads values of 1,095, 8,179, 32,791, and 30,851 in sand, sandy loam, silty 

clay loam, and silt loam soils. The Koc values ranged from 437,805-1,599,564 ml/g. 24 Because 

of its strong adsorption to soils, DDAC is not expected to contaminate surface and ground 

waters.

 13 MRID 45808208 14 MRID 46735801 15 MRIDs 47497001 and 47484101 16 MRIDs 47497001 and 47484101 17 MRID 41175801 18 MRID 41175802

19 MRID 42480701 20 MRID 42253801 21 MRID 42253803 22 MRID 42253802 23 MRID 46865701 24 MRID 41385301
22

Bioaccumulation of DDAC in freshwater fish is not likely to occur. The mean steady state 

bioconcentration factors for DDAC were determined to be 38X, 140X, and 81X in the edible, 

non-edible, and whole body fish tissue, respectively. DDAC is not expected to pose a concern 

for bioconcentration in aquatic organisms.

25

Information on the aqueous availability of DDAC from treated wood (AWPA E11-97) indicates 

that the use of DDAC as a wood preservative may result in minimal releases to the 

environment.26

4.1.3 Environmental Fate of Boric Acid 

Boron is present in the environment as a result of natural and anthropogenic sources, and boric 

acid and boron-containing salts are ubiquitous in the environment. Boron occurs naturally in 

soils, water, fruits, vegetables, and forage crops. Boron is an essential nutrient for plants as well 

as an essential element for many organisms. The pKa value of boric acid is 9.15, indicating that 

at pH 9 approximately 50 percent of boric acid will be dissociated and 50 percent will remain in 

boric acid form. As the pH increases above 9, the percentage of boric acid that will dissociate 

will tend to increase and tetrahydroxyborate will tend to predominate rather than boric acid. 

Since the pH of many ambient waters is typically around 7, boric acid rather than 

tetrahydroxyborate is expected to be the predominant degradate in surface water under ambient 

environmental conditions. As the pH increases, the anionic boric acid component of polymeric 

betaine is expected to be less sorbed to soil and sediment (like charges repel).26 

4.2 Conceptual Models for Environmental Exposure Pathways

Polymeric betaine is an equilibrium mixture of the didecyl-bis(2-hydroxyl)ammonium cation and

the boric acid anion (dissociated form) and the combination of the cation and anion

(undissociated form).

27 At basic pH values, the TGAI is expected to be present in higher 

amounts as the separate active cation and the inactive boric acid anion, while it would be present 

in the combined (non-ionized) form at pH values below 7.0.28 No major degradates were 

observed in any of the environmental fate studies with the exception of M-1, a quaternary 

ammonium compound with a shortened alkyl chain in the aerobic soil metabolism studies.

29

Like all products used to protect wood outdoors, there will be some potential for leaching for the 

treated wood. The terrestrial uses are not unlikely to create significant aqueous residues of 

Polymeric betaine from the combined (non-ionic) form and cationic (positively-charged) form 

because these forms are tightly sorbed to soil and sediment30 and any residues that reach water 

are expected to be present in soil that is eroded. As the pH of the soil and sediment increases, the 

soil and sediment become more negatively-charged and the cationic active ingredient becomes 

 25 MRID 458341-01

26 Cornell University Cooperative Extension (2007). Cation Exchange Capacity Fact Sheet

http://nmsp.cals.cornell.edu/publications/factsheets/factsheet22.pdf

27 MRIDs 45800203 (p. 18) and 47757601 (p. 17) 28 MRID 45808204, p. 13

29 MRIDs 45808209 and 47757601 30 MRID 45808208, Freundlich Kads values of 190-4,300 ml/g and Koc values of 10,000-220,000 ml/g
23

more tightly sorbed (opposite charges attract). Conversely, the anionic boric acid component is 

expected to be less sorbed to soil and sediment as the pH increases (like charges repel).31 Boric 

acid is expected to exist at environmental pH values32 (pH 5-7) in the anionic (negativelycharged) state with all three oxygen molecules being deprotonated. This conclusion is based on 

the pKa values33 of 9.3, 12.7, and 13.9 which are higher than the range of environmental pH 

values.

The aquatic use is also expected to create minimal aqueous exposure because leached residues 

will be rapidly sorbed to sediment (bottom and suspended). However, the boric acid component 

is expected to be present in surface water because it is negatively-charged at environmental pHs. 

In addition to lack of environmental exposure, Polymeric betaine residues are not expected to 

bioconcentrate in aquatic organisms because of water solubility, positive and negative electrical 

charges, and rapid sorption to sediment. 

The Impralit KDS label34 for Polymeric betaine allows uses in a variety of domestic uses that can 

create environmental exposure such as fascia boards, pickets, guard rails, fencing, playground 

structures, outdoor furniture, and outdoor structures such as gazebos. It can also be used in 

“critical infrastructures” such as bridges, non-aquatic pilings, utility poles, foundation, and 

railway ties. The UC4 classification assumes ground contact and is subdivided into UC4A 

(general use)35, UC4B (heavy duty)36, and UC4C (extreme duty)37. The UC5 classification 

assumes marine use with salt- and brackish-water exposure and is subdivided into UC5A 

(northern waters)38, UC5B (central waters)39, and UC5C (southern waters)40. However, the 

Agency assumes that some aquatic exposure can occur because of the UC5 classification. An 

ecological conceptual model summarizing exposure pathways for Polymeric betaine and its 

reaction products/degradates is provided in Figure 1 with additional information in Appendix B.

 31 Cornell University Cooperative Extension (2007). Cation Exchange Capacity Fact Sheet

http://nmsp.cals.cornell.edu/publications/factsheets/factsheet22.pdf

32 Environmental pH ranges from 5-9. 33 http://chemistry.about.com/od/chartstables/a/pkatable.htm

34 Reg. No. 75269-2, 8/10/2009 label, http://www.epa.gov/pesticides/chem_search/ppls/075269-00002-

20090810.pdf

35 UC4A general use includes use in regions of low natural potential for wood decay and insect attack 36 UC4B heavy duty use includes horticultural sites and moist temperate zones 37 UC4C extreme duty includes semi-tropical and tropical environments 38 UC5A runs from Long Island and northward on the east coast and San Francisco northward on the west coast

39 UC5B from from Long Island to southern border of Georgia on the east coast and San Francisco southward on the 

west coast

40 UC5C runs from south of Georgia and Gulf coasts in Eastern U.S. and includes Hawaii and Puerto Rico. 
24

Figure 1 – Conceptual Model for Ecological Exposure and Effects of Polymeric Betaine to Aquatic and 

Terrestrial Organisms

4.3 Ecological Effects Assessment

Polymeric betaine is intended for use as a wood preservative for terrestrial applications. 

The active ingredient of concern is a borate ester, which exists only in an aqueous solution, in 

equilibrium with the boric acid and quaternary ammonium compound that are the borate ester 

precursors. The component released into the environment after the chemical is applied to the 

wood is predominantly the quaternary ammonium compound, similar to didecyl dimethyl 

ammonium chloride (DDAC) and other quaternary compounds grouped together by the Agency 

as “Cluster I [alkyl or hydroalkyl (straight chain) substituted] quats and boric acid.” Therefore, 

in order to determine the exposure and risk to wildlife, plants, and aquatic organisms, toxicity 

endpoints and environmental fate characteristics of DDAC and boric acid are used in this 

assessment. 

Polymeric betaine demonstrates moderate acute toxicity to birds, and high acute toxicity to fish 

and freshwater invertebrates. DDAC demonstrates moderate to low acute toxicity to birds, high 

to moderate acute toxicity to fish, and very high acute toxicity to aquatic invertebrates. Boric 

acid is practically non-toxic to fish and aquatic invertebrates (Table 10).

4.3.1 Measures of Effect (Ecotoxicology Endpoints)

Ecotoxicity endpoint data are used as measures of effects to aquatic and terrestrial organisms. 

All available ecotoxicity endpoints in the Agency’s files from Polymeric betaine studies 

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

Stressor

Source

Receptors 

and Exposure 

Routes

Attribute

Change(s)

Individual organisms

Reduced survival

Reduced growth

Reduced reproduction

Food chain

Reduction in algae

Reduction in prey

Modification of PCEs related 

to prey availability

Habitat integrity

Reduction in primary productivity

Reduced cover

Community change

Modification of PCEs related to 

habitat

Surface Water/Sediment

Aquatic Animals

Invertebrates

Vertebrates

Exposure

Media

Ingestion Ingestion

Uptake/gills 

or integument

Aquatic Plants

Non-vascular

Vascular

Uptake or sorption/cell, roots, 

leaves, 

Piscivorous*

Invertebrates

Vertebrates

Phytoplanktivore/ 

Herbivore

Invertebrates

Vertebrates

*As used here this term refers to animals (terrestrial or aquatic) that eat not just fish but any aquatic animal (e.g., amphibians, mollusks, crustaceans, etc.)

Ingestion

Waste Water Treatment Plant (WWTP)

Key

Most likely

exposure pathway 

contributing to risk

Low likelihood of 

contributing to risk

WWTP 

microorganisms

Uptake or 

sorption

Population

Respiration 

inhibition

Dip, Pad or Pressure 

Treated Wood Process 

Facility Drain

Post-Treated Wood 

Product Storage

Leaching and Run-off

In-Use Service of Wood 

Treated Wood Products

Leaching and Run-off
25

literature are tabulated in Appendix C along with the data requirements and data gaps. The most 

sensitive values for each receptor group are used for the risk assessment (Table 9). These 

selected endpoints will be updated during the risk assessment phase based on any additional 

submitted data or data found in the public literature.

Table 9 – Existing Effects Endpoints for Risk Assessment of DDAC and Boric Acid

Receptor 

Group

Surrogate 

Species

Risk 

Scenario Toxicity Endpoint Reference

DDAC Endpoints

Freshwater fish Bluegill Sunfish Acute 96-h LC50 = 0.27 ppm MRID# 00007958

Chronic Data gap

Freshwater invertebrates Waterflea Acute 48-h EC50 = 0.018 ppm Onyx (1982c)

21 day Daphnid Chronic Data gap

Freshwater benthic 

invertebrates

Subchronic/

Chronic Not required _

Estuarine/marine fish Sheepshead

minnow Acute 96h LC50 = 0.96 ppm MRID# 43260001

Chronic None --

Estuarine/marine invertebrates Mollusk Acute EC50 = 0.094 ppm MRID# 

43260003

Shrimp Acute LC50 = 0.069 ppm MRID# 41578004

Chronic None --

Estuarine/marine benthic 

invertebrates

Subchronic/

Chronic None --

Algae Nonlisted EC50 = 0.0142 MRID# 48596402

Listed None NR

Aquatic vascular plants Duckweed Nonlisted None NR

Listed None NR

Seedling Emergence Nonlisted None NR

Listed None NR

Vegetative vigor Nonlisted None NR

Listed None NR

Birds Northern 

Bobwhite Acute LD50 > 664 mg/kg-bw MRID# 46768502

Mallard duck Subacute 

dietary

LC50 > 5620 ppm

(30% mortality at 

highest dose)

MRID# 41785802

Chronic None

Mammals Acute LD50 = 262 mg/kg MRID# 41394401

Chronic NOAEL = 10 mg/kg

 LOAEL = 20 mg/kg MRID# 41970401

Nontarget insects Honey bee Acute None NR

Boric Acid Endpoints

Freshwater fish Bluegill Sunfish Acute 96-h LC50 = 1021 ppm MRID# 40594602

Chronic Data gap* 

Freshwater invertebrates Waterflea Acute 48-h EC50 = 133 ppm MRID 40594601

21 day Daphnid Chronic NOAEC 6.4 ppm Data cited in Boric 

Acid RED 
26

NR = Not Required

*Will use acute to chronic ratio to fulfill data gap.

4.4 Exposure Analysis Plan

4.4.1 Aquatic and Terrestrial Wildlife Exposure Estimates

Available OPP models that estimate exposures from both direct and indirect discharges to

surface water (including potential discharges via a wastewater treatment plant, and leaching from 

stored pressure treated wood) will be used to determine the estimated environmental 

concentration (EECs) in the aquatic environment. These exposure estimates will be compared to 

the toxicity endpoints to determine whether or not the Agency’s levels of concern for acute and 

chronic risks to aquatic organisms, including listed species, are expected to be exceeded for each 

receptor group. This approach is consistent with other Registration Review cases for DDAC. 

According to Agency databases, at this time, production volume data indicates that the amount of 

Polymeric betaine produced is less than 1000 kg per year.

4.5 Effects Analysis Plan

Toxicity data presented in this work plan will be used to calculate risk quotients and/or calculate 

COCs. Any additional information submitted by the registrant(s), other interested parties or 

found in the open literature prior to conduct of the risk assessment will also be considered. The

open literature studies will be identified using EPA’s ECOTOXicology (ECOTOX)41 database,

which employs a literature search engine for locating chemical toxicity data for aquatic life, 

terrestrial plants, and wildlife. The ECOTOX database will be searched when the risk assessment 

for Polymeric betaine is prepared. The evaluation of these sources of data can also provide 

insight into the direct and indirect effects of pesticides on biotic communities from loss of 

species that are sensitive to the chemicals and from changes in structure and functional 

characteristics of the affected communities.

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 its most recent registration decision for Polymeric betaine, 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), 

 41 http://cfpub.epa.gov/ecotox
27

Polymeric betaine 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, 201342 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.43

6 Optional Label Changes

As described in this work plan, studies show that Polymeric betaine does not leach from treated 

wood material but DDAC and boric acid may leach. However, the Agency believes that the label

restriction against use of treated wood in or near fresh water or salt water is not enforceable. 

Therefore, it should be deleted. 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.

 42 See http://www.regulations.gov/#!documentDetail;D=EPA-HQ-OPPT-2009-0477-0074 for the final second list of 

chemicals. 43 http://www.epa.gov/endo/
28

7 Guidance for Commenters 

7.1 Preliminary Work Plan 

The public is invited to comment on EPA’s Preliminary Work Plan and rationale. 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 Polymeric betaine 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 

Polymeric betaine is not identified as a cause of impairment for any water bodies listed as 

impaired under section 303(d) of the Clean Water Act[1]. In addition, no Total Maximum Daily 

Loads (TMDL) has been developed for Polymeric betaine[2]. Use of Polymeric betaine for wood 

treatment is unlikely to result in impairment.

The use of Polymeric betaine results in the release of boric acid. Although boron is identified as a 

cause of impairment, as defined under section 303(d) of the Clean Water Act, for several water 

bodies, this impairment is not linked to the pesticidal uses of boron. Impairment due to boron is 

identified for three water bodies in California, eight water bodies in Colorado, six water bodies in 

Kansas, four water bodies in New Mexico, one water body in Nevada and one water body in Utah, 

based on information provided at: http://iaspub.epa.gov/tmdl waters lO/attains impaired 

waters.tmdls?p pollutant id=230.

More information on impaired water bodies and TMDLs can be found at EPA’s website[3]. 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 Process[4] in order to ensure they can be 

used quantitatively or qualitatively in pesticide risk assessments.

 [1] http://iaspub.epa.gov/tmdl_waters10/attains_nation_cy.cause_detail_303d?p_cause_group_id=885

[2]http://iaspub.epa.gov/tmdl_waters10/attains_nation.tmdl_pollutant_detail?p_pollutant_group_id=885&p_pollutant

_group_name=PESTICIDES

[3] http://www.epa.gov/owow/tmdl/

[4] http://www.epa.gov/oppsrrd1/registration_review/water_quality_sop.htm
29

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 Polymeric betaine compared to the general population.

Please 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 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. 
30

If stakeholders believe that submission of predicted data can fulfill one of the data needs for the 

Polymeric betaine 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. 

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 February 2014, the Agency will review and respond 

to any comments received in a timely manner, and then issue a Final Work Plan for the 

Polymeric betaine case.
31

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33

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34

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37

432600-03 1994. Collins, M.K. Didecyldimethylammoniumchloride (DDAC): Evaluation 

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toxicty/carcinogenicity study with didecylpolyoxethylammoniumborate by dietary 

administration in the rat. NOTOX B.V., The Netherlands. Laboratory Report No. 263611. 

September 13, 2002. Unpublished.

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NOTOX B.V. (The Netherlands). NOTOX Project 291847, October 2002. Unpublished.
38

458083-09 Frieling, W.J.A.M. (2002) Two-Generation Reproduction Toxicity Study with 

Didecylpolyoxethylammoniumborate by Dietary Administration in Wistar Rats. NOTOX 

B.V. (The Netherlands). NOTOX Projects 291869, 292106, 292117, 2921871, 292128, 

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458341-01 1990. Fackler, P.H., E. Dionne, D.A. Hartley, and S.P. Shepherd. 

Bioconcentration and Elimination of 14C- Residues by Bluegill (Lepomis macrochirus) 

Exposed to Didecyldimethylammonium Chloride (DDAC). Final Report. Study No. 

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463158-16 Beekhuijzen, M. (2004) Embryotoxicity and teratogenicity study with 

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fathead minnow (Pimephales promelas). Wildlife International, Ltd. Report ID: 289A155. 

465047-17 Jovanovich, A.P., Obenshain, K. R., Kroger, K., and V. Barth. 2005. Application 

for pesticide registration. Polymeric betaine Technical Grade Active Ingredient Wood 

Preservative. Submitted by Rutgers Organics GmbH. Keller and Heckman LLp., 

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465224-04 2004. Bogers, M. Acute toxicity Study in Daphnia magna with 

Didecylpolyoxethylammonium borate. Study No. NOTOX product 405664. 

Unpublished study prepared by NOTOX B.V. 

467685-01 2006. Sayres, L.E. Acute Toxicity to Bluegill Sunfish (Lepomis macrochirus) 

Under static conditions. Study No. 13856.6101. Unpublished study prepared by 

Springborn Smithers Laboratories. 
39

467685-02 2006. Stafford, J.M. Polymeric betaine Technical-Acute Oral Toxicity Test 

(LD50) with Northern Bobwhite Quail (Colinus virginianus). Study No. 13856.4100. 

Unpublished study prepared by Springborn Smithers Laboratories.

485964-02 Krueger, H.O., Desjardins, D., Kendall, T., and Vanhoven, R. (2003) Bardac 

 2280: A 96-hour toxicity test with the freshwater alga (Selenastrum 

 capricortutum) using natural surface water.
40

Appendix A Toxicology Profile

Acute Toxicity for Product Labeling 

Table A1 lists the acute toxicity for Polymeric betaine. Polymeric betaine is corrosive and is of 

moderate acute toxicity by the oral route. There are no acute dermal, acute inhalation, acute eye 

irritation, acute eye irritation studies. There is no acceptable dermal sensitization study. 

Although both DDAC and borate are not dermal sensitizers, OPP still has concerns for the 

potential dermal sensitization effects of Polymeric betaine. However, due to the corrosivity of 

the agent, further dermal testing is not recommended.

Table A1 – Acute Toxicity Studies for Polymeric Betaine

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

870.1100/ 

Acute oral toxicity 

No Study 

available

LD50 male rats = 2,800

LD50Female rats 700 – 2,800 III (1)

870.1200/ 

Acute dermal toxicity 2

No Study 

available I

870.1300/ 

Acute inhalation toxicity2

No Study 

available I

870.2400/ 

Acute eye irritation2

No Study 

available I

870.2500/ 

Acute dermal irritation2

No Study 

available I

870.2600/ 

Skin sensitization3

No Study 

available Potential Dermal Sensitizer

1 Calculated from results of more concentrated material (PMRA Submission No. 2003-0351, Page 118).

2 Acute dermal, inhalation, acute eye irritation, and acute skin irritation studies were not conducted due 

to the corrosive properties of Polymeric betaine. For these endpoints, Polymeric betaine was classified 

as toxicity category I on the basis of its known corrosivity.

3

There is one unacceptable dermal sensitization study. It does not contain initiation scores and positive 

control data. Due to the corrosiveness of this chemical, further dermal sensitization studies are waived 

(April 1, 2009 AD Toxicity Endpoint Selection Committee)
41

Subchronic Toxicity 

There are three subchronic oral studies (one 40-day rat gavage study, one 28-day rat feeding 

study, and one 90-day rat feeding study) available in the toxicology database.

40-day gavage study (MRID 45808213)

In a 40-day oral toxicity study (MRID 45808213) Polymeric betaine (57 % a.i.) was 

administered by gavage to 120 Sprague Dawley rats, 10 or 20/sex/dose at doses of 0, 5.7, 28.5, 

or 142.5 mg/kg body weight/day (dosage adjusted for 100% active ingredient). The study was 

originally designed as a 90-day study but was terminated early due to severe signs of toxicity in 

the high-dose groups. Treatment-related deaths occurred in the high-dose (142.5 mg/kg/day) 

group, with 4/20 males dying between days 22 and 28 and 7/20 females dying between days 3 

and 34. Of these deaths, one male and three females were euthanized for humane reasons. 

Additionally, one control female was found dead on day 33 of treatment and one low-dose (5.7 

mg/kg/day) female was found dead on day 14 of treatment. No other premature mortality was 

seen.

Treatment-related clinical signs were noted in all dosed animals. In males and females given 

142.5 mg/kg/day, clinical signs included excessive salivation, hunched posture, red/orange or 

brown appearance of body parts (head, snout, genital region, abdomen, and chest), pallor, and 

altered defecation. Additional effects noted in females at this dose level included piloerection, 

lethargy, uncoordinated movements, and emaciated appearance. In animals given 28.5

mg/kg/day, hunched posture and excessive salivation were noted in females while only excessive 

salivation was noted in males. In animals given 5.7 mg/kg/day, excessive salivation was noted in 

males and females. There were no significant treatment-related effects on body weight, and food 

consumption. A number of significant changes in hematological parameters were observed but 

discounted by the study authors because the values fell within normal ranges (not provided) and 

the changes did not show dose-related trends.

Males and females receiving 142.5 mg/kg/day showed a significant (p<0.01) increase in plasma 

alanine aminotransferase (ALAT). At 142.5 mg/kg/day, macroscopically-observed lesions 

consisted of irregular surface of the forestomach, gray-white appearance of the forestomach, 

thickened limiting ridge of the forestomach, hemorrhage in the glandular stomach and 

forestomach, a small spleen, a small thymus, small mesenteric lymph nodes, thickened or dilated 

(with yellow contents) esophagus, dilated cecum or gastrointestinal tract, and enlarged adrenals. 

No treatment-related effects on gross pathology were seen at lower doses.

At 142.5 mg/kg/day, there were marked increases in the severity and incidence of squamous 

hyperplasia of the gastric forestomach with associated inflammation and ulceration, with a low 

incidence of esophageal inflammation observed in females. In addition, splenic lymphoid 

atrophy was observed in 142.5 mg/kg/day female rats and was associated in some rats with 

lymphoid atrophy in the thymus and mesenteric lymph nodes. Vacuolization of the adrenal 

cortex was observed in 142.5 mg/kg/day female rats. At 28.5mg/kg/day, squamous hyperplasia 

of the forestomach was also observed at slightly higher incidence and severity than in the control 

rats, but with greatly reduced incidence and severity than at 142.5 mg/kg/day. At 5.7 mg/kg/day, 
42

the squamous hyperplasia of the forestomach was still present, but it was not significantly 

different from control incidence.

According to the methods discussed in the report (pg 18), tissues were apparently fixed in two 

large segments. One contained the upper part of the gastrointestinal tract together with the 

thoracic contents and the second contained the rest of the carcass. The remaining part of the 

animal was fixed as a whole and no further histological examination was performed. Therefore, 

this 40-day oral toxicity study in the rat is unacceptable (not upgradable)/Non-guideline.

The major deficiencies of this study are 1) it lacks the functional testing (sensory activity, grip 

strength or motor activity assessments) required by the 28-day guidelines, and 2) full 

histopathology on most of the organs and tissues listed in the guideline was not performed for all 

rodents. However, because, the gastrointestinal tract together with the thoracic contents 

were properly fixed, the pathological effects in the related organs in these area were 

considered real and can be considered for end-point selection for risk assessment.

28-day oral study (MRID 45808212)

In a 28-day oral toxicity study (MRID 45808212), Polymeric betaine (lot #106310439) was 

administered to five SPF-bred Sprague Dawley rats/sex/dose in diet at dose levels of 0, 28.5, 

85.5, or 256.5 mg/kg body weight/day (dosage adjusted for 100% active ingredient) 

At 256.5 mg/kg/day, toxicologically significant effects observed with dietary administration of 

the test compound were decreased body weight gain, hunched posture, piloerection, and 

decreased levels of blood calcium, total protein, globulin, and white blood cells in males and 

possibly females. There were no compound-related effects observed for mortality, food 

consumption, other hematological parameters, food consumption, other clinical chemistry 

parameters, organ weights, or gross and histologic pathology. The only hematological endpoint 

that was biological significantly different in treated groups was a 35% and 42% decrease in 

white blood cell count in mid- and high-dose males, respectively, which followed a dose-related 

trend. 

A meaningful NOAEL cannot be established due to lacking of histopathology data for the 

majority of organs and tissues recommended by the study guidelines.

This repeated dose 28-day oral toxicity study in the rat is Unacceptable (not upgradable)/ NonGuideline and does not satisfy the guideline requirement for a repeated dose 28-day oral toxicity 

study (OPPTS 870.3050) in the rat. 

90-day oral study (MRID 45808214)

In a 90-day oral toxicity study (MRID 45808214) Polymeric betaine (57% purity, batch 

106310439) was administered to 10 Sprague Dawley rats/sex/dose via diet mixtures at targeted 

dose levels of 0, 28.5, 85.5 or 256.5 mg/kg/day (dosage adjusted for 100% active ingredient). In 

addition, 10/sex/dose was assigned to 2 recovery groups at doses of 0 and 256.5 mg/kg/day. The 

mean test article intake for treated animals was 30, 84 and 251 mg/kg/day for males and 29, 84 
43

and 263 mg/kg/day for females in the 28.5, 85.5 and 256.5-mg/kg/day treatment groups, 

respectively.

Treatment-related clinical signs included hunched posture and piloerection in 85.5-mg/kg/day 

females and hunched posture, piloerection and emaciation in 256.5-mg/kg/day males and 

females. By Week 2 of recovery, these clinical signs were no longer present. Additional 

observations in 256.5-mg/kg/day rats included swollen abdomen and red/brown spots on paper 

under the flooring of the cage. Two 85.5-mg/kg/day females and two 256.5-mg/kg/day females 

died before study termination. The causes of death were not determined.

Treatment-related decreases in mean body weight, mean body weight gain and decreased food 

consumption were observed in 256.5-mg/kg/day rats. Decreased food efficiency in these treated 

rats correlated with the decrease in food consumption, contributing to the lower body weights of 

treated animals. In addition, food scatter, due to poor palatability of the diet preparations, was 

high which contributed to the reduced food intake in these treated rats. Food scatter was only 

evaluated qualitatively.

Fluctuations in hematology and clinical chemistry parameters were observed in 256.5-mg/kg/day 

treated rats. Changes in hematology parameters included significant decreases in total leukocyte 

count and partial thromboplastin time in 256.5-mg/kg/day males during treatment. Total 

leukocyte count was also significantly decreased in 256.5 -mg/kg/day females at 13 Weeks. 

These changes were not observed after recovery at 17 Weeks. At 13 Weeks, mean corpuscular 

volume and relative numbers of monocytes were significantly increased in 256.5-mg/kg/day 

females; these findings were absent after recovery. Changes in clinical chemistry parameters 

included increased alanine aminotransferase, decreased cholesterol, globulin, total protein and 

glucose during treatment; most of these changes were also reversed after recovery. 

Treatment-related changes in organ weights included decreased absolute and relative liver organ 

weights in 256.5-mg/kg/day males and females after treatment. Other statistically significant 

decreases in organ weights observed in 256.5-mg/kg/day rats at Week 13 included the following: 

absolute brain (males and females), absolute heart (males and females), relative heart (males), 

absolute kidney (males and females) and absolute adrenals and spleen (males). Only absolute 

heart organ weight in males remained significantly decreased after recovery at Week 17. In 

females, both absolute and relative ovarian weights were significantly increased at Week 17. 

These organ weight differences did not correlate with any histopathological findings.

Treatment-related macroscopic observations included enlarged cecum in 256.5-mg/kg/day males 

and females, and enlarged stomach in 256.5 -mg/kg/day females. Microscopic evaluations 

revealed stunted villus in the ileum of the small intestine in 256.5-mg/kg/day treated rats. These 

effects observed in the organs of the digestive system may be a reflection of the prolonged 

reduction of food consumption observed in the high-dose animals. The mucosal changes 

observed in the ileum may also reflect a potential target of the test compound. 

A LOAEL of 85.5 mg/kg/day was identified based on based on hunched posture, 

piloerection and death in females, with a NOAEL of 28.5 mg/kg/day.

This 90-day oral toxicity study in the rats is Acceptable (Guideline), and satisfies the guideline 

requirement for a 90-day oral toxicity (OPPTS 870.3100) in rats.
44

Developmental Toxicity 

There are two developmental toxicity studies in the toxicity database: One rat and one rabbit. 

Rat Developmental Toxicity Study (MRID 45808308)

In a rat developmental toxicity study (MRID 45808308) Polymeric betaine (58.4% a.i.) was 

administered to 24 Wistar Crl: (WI) BR (outbred, SPF-Quality) rats/dose in the diet at dose 

levels of 0, 10, 52, or 208 mg/kg bw/day (dosage adjusted for 100% active ingredient) from days 

6 through 21 of gestation. High-dose dams exhibited clear clinical signs of toxicity (hunched 

posture and piloerection; statistically-significant decreased food consumption [p≤0.01], body 

weight [p≤0.01], and body weight gain [p≤0.01]). Additionally 208 mg/kg bw/day dams 

exhibited a nontreatment-related, statistically-significant decrease in implantation index and a 

nontreatment-related, statistically-significant increase in pre-implantation loss. Therefore, the 

maternal LOAEL is 208 mg/kg/day based on clinical signs of toxicity and statistically 

significant decreased body weight, body weight gain, and food consumption. The maternal 

NOAEL is 52 mg/kg/day. 

At the high dose, treatment-related decreases in fetal weight and size were observed. There were 

no other treatment-related external malformations, and no treatment-related skeletal or visceral 

alterations were observed. Therefore, the developmental LOAEL is 208 mg/kg/day based on 

fetal weight and size. The developmental NOAEL is 52 mg/kg/.

This developmental toxicity study in the rat is classified Acceptable/ Guideline and satisfies the 

guideline requirement for a developmental toxicity study (OPPTS 870.3700) in the rat.

Rabbit Developmental Toxicity Study (MRID 46315816)

In a developmental toxicity study (MRID 46315816) Polymeric betaine (58.7%, Batch DEGE 

004110) was administered to 32 – 34 NZW rabbits/dose by dietary administrations at dose levels 

of 0, 9, 25 or 36 mg/kg/day (dosage adjusted for 100% active ingredient) from days 6 through 28 

of gestation. 

Signs of maternal toxicity were observed at 36 mg/kg/day and included the following: increased 

incidence of pale feces and reduced feces production; decreased body weights, body weight gain, 

and corrected body weight gain; and decreased food consumption and relative food consumption. 

The maternal lowest-observable-adverse-effect level (LOAEL) is 36 mg/kg/day 100% a.i. 

based on increased incidence of pale feces and reduced feces production; decreased body 

weights, body weight gain, and corrected body weight gain; and decreased food 

consumption and relative food consumption. The maternal NOAEL is 25 mg/kg/day.

Treatment-related developmental toxic effects were observed at 36 mg/kg/day included: 

decreased mean fetal weight for male and female fetuses on both an individual and litter basis; 

decreased mean total fetal weight on a litter and individual basis; increased incidence of small 
45

fetuses; decreased incidence of upper and lower incisors being erupted and teeth still present in 

the gums; decreased ossification of the cranium and bones of the fore and hind feet; and 

increased incidence of single association pelvis. There was an increased incidence of incomplete 

ossification of the pubic bone(s), sacral vertebral arches, and caudal vertebral arches in fetuses

from dams administered the high dose. With regard to morphological changes observed during 

the skeletal examination, the decreased incidence in double association pelvis (type I) and 

increased incidence of no association point(s) present on the 1st/2nd sacral vertebral arches of 

double associated pelvis may be treatment-related at the high dose. 

At a dose of 25 mg/kg bw/day treatment related developmental effects included: decreased total 

fetus index and live fetus index; increased embryonic/fetal death index and fetal resorption 

index; and increased postimplantation loss. Skeletal effects noted included: decreased 

ossification of the cranium and bones of the fore and hind feet; and increased incidence of single 

association pelvis. 

Therefore, the fetal LOAEL is 25 mg/kg/day (100% a.i.)based on decreased total fetus 

index and live fetus index; increased embryonic/fetal death index and fetal resorption 

index; increased postimplantation loss; decreased ossification of the cranium and bones of 

the fore and hind feet; increased incidence of incomplete ossification of the public bone(s); 

and increased incidence of single association pelvis. The fetal NOAEL is 9 mg/kg bw/day 

100% a.i. 

The developmental toxicity study in the rabbit is classified Acceptable-Guideline and satisfies 

the guideline requirement for a developmental toxicity study (OPPTS 870.3700) in rabbits.

Reproductive Toxicity

In a 2-generation reproduction study (MRID 45808309), Polymeric betaine (58.4% a.i.) was 

administered to 24 rats (Wistar Crl:[WI]BR [outbred, SPF,-Quality])/sex/dose at dietary 

concentrations of 0, 240, 1200, or 6000 ppm (equivalent to 0, 13, 65, or 420 mg/kg bw/day of 

100% a.i. for males and 0, 14, 71, or 470 mg/kg bw/day of 100% a.i. for females). P animals 

(male and females) were exposed to the test material for 10 weeks prior to mating; females were 

exposed throughout gestation and lactation. Selection of parents (4 males and 4 females per 

litter) for the F1 generation was made when the pups were 4 days of age. F1 parents were 

exposed in the same manner as P parents.

Toxicity observed at 6000 ppm consisted of clinical signs (hunched posture, piloerection, 

diarrhea, and emaciation in P dams; red discoloration in cage bedding of P males and females; 

piloerection in F1 males; hunched posture in F1 females), significantly decreased body weights 

and body weight gains (P and F1 animals), significantly decreased body weights during gestation 

and lactation (P and F1 dams), significantly increased relative food consumption during pretreatment, gestation (except the last week), and the first week of lactation (F1 animals), 

significantly decreased food consumption during the last week of gestation and lactation (F1

dams), macroscopic changes including emaciation (P dams only) and enlarged cecum (P and F1

dams), and microscopic changes (ovarian interstitial cell atrophy, as well as cervical, uterine, and 
46

vaginal atrophy in P and F1 dams). Although food spillage was noted in P animals, males and 

females in previous studies with this test compound showed decreased food consumption 

(probably due to unpalatability of the diet) when exposed to 6000 ppm of the test material. Other 

alterations were observed, including additional microscopic changes and alterations in organ 

weights; however, these effects are considered secondary to body weight reduction. The 

parental systemic LOAEL is 6000 ppm (420 mg/kg bw/day of 100% a.i. in males, 470 

mg/kg bw/day of 100% a.i. in females), based on clinical signs of toxicity and decreased 

body weight, body weight gain, and food consumption, as well as macroscopic and 

microscopic changes. The parental systemic NOAEL is 1200 ppm (65 mg/kg bw/day 100% 

a.i. in males, 71 mg/kg bw/day 100% a.i. in females). 

At doses of 6000 ppm, pups exhibited clinical signs of toxicity (diarrhea, piloerection, and 

lethargy in F1 pups; piloerection, emaciation, lethargy, and hunched posture in F2 pups), lower 

litter and pup body weights during lactation, and clinical signs of toxicity at necropsy (enlarged 

cecum and/or distended cecum with gas in F1 pups; empty stomach or gastrointestinal tract in F2

pups). Additionally, a decrease (nonsignificant) in the weaning index was observed in F2 pups. 

Lower organ weights at weaning (brain, spleen, and thymus) were observed; however, this effect 

was considered secondary to decreased maternal body weight gain. High-dose F1 pups also 

exhibited significantly decreased vaginal opening and preputial separation, which probably was 

the result of poor health in the dams. The offspring LOAEL is 6000 ppm (420 mg/kg bw/day 

100% a.i. in males, 470 mg/kg bw/day 100% a.i. in females), based on clinical signs of 

toxicity and decreased litter and pup weights. The offspring NOAEL is 1200 ppm (65 

mg/kg bw/day 100% a.i. in males, 71 mg/kg bw/day 100% a.i. in females). 

The reproductive LOAEL is 6000 ppm (420 mg/kg bw/day 100% a.i. in males, 470 mg/kg 

bw/day 100% a.i. in females), based on microscopic changes (ovarian interstitial cell 

atrophy, as well as cervical, uterine, and vaginal atrophy) and decrease in weaning index. 

The reproductive NOAEL is 1200 ppm (65 mg/kg bw/day in males, 71 mg/kg bw/day in 

females). 

This study is classified as Acceptable-Guideline and satisfies the guideline requirement for a 2-

generation reproductive study (OPPTS 870.3800) in rats.

Chronic Toxicity 

There is one combined chronic / carcinogenicity study (MRID [45808215]). Polymeric betaine 

(58.7% a.i.; Batch # DEGE 004110) was administered to 50 Wistar rats/sex/dose in the diet at 

targeted dose levels of 0, 15, 75, or 375 mg/kg-day for 104 weeks. Satellite groups of 

10/sex/dose at the control, low and mid dose and 20/sex/dose at the high dose were exposed via 

diet to the test compound, and sacrificed at 52 weeks. No correction was made for the purity of 

the test substance in calculations for diet preparation.

Mortality was reduced in the high-dose groups relative to controls. However, a life table analysis 

indicated that the differences were not statistically significant. Hunched posture and piloerection 

were more frequently observed in high-dose males than in male controls, particularly in the 

second year of the study. Body weight gains and body weights were statistically decreased 
47

throughout the test period, beginning at weeks 5 and 7 for males and females, respectively. At 

study termination, the high-dose animals exhibited total weight gain deficits of 26% and 33% for 

males and females, respectively, relative to controls. This finding demonstrated that the testing 

concentration is adequate. Significant weight gain deficits were also seen over the last six

months of the study in mid-dose females, with a final deficit of 8% relative to concurrent 

controls. Food consumption, uncorrected for spillage, was reported to be significantly less than 

controls in high-dose males. Food efficiency was also decreased 22% and 16% for males and 

females, respectively, at the high dose relative to controls. 

There were no treatment-related neurological effects, as measured by a functional observation 

battery (FOB) administered at approximately week 52, and no opthalmologic effects. 

Statistically-significant differences in clinical chemistry at 375 mg/kg/day included: (1) 

increased alanine aminotransferase (ALAT) in males at 13, 26, 52, 78, and 104 weeks and in 

females at 13, 52, 78, and 104 weeks; (2) increased aspartate aminotransferase (ASAT) in males 

at 13 and 26 weeks; (3) decreased cholesterol in males and females at 52, 78, and 104 weeks; (4) 

decreased triglycerides in females at 104 weeks; (5) decreased glucose in females at 26, 52, and 

78 weeks; (6) increased urea in females at 78 and 104 weeks; (7) increased albumin/globulin 

ratios at 52, 78 and 104 weeks in males (associated with lower total globulin levels because 

albumin levels were within the control range at all three time intervals). Administration of 375 

mg/kg/day of the test material also resulted in significantly higher platelet counts in males at 13 

and 26 weeks and in females at all time points. Other significant hematological and clinical 

chemistry deviations were considered to be incidental if they were transient (i.e., occurred at 

some time intervals but not others) or within the range of normal biologic variation. There were 

no toxicologically significant treatment effects on urinary parameters.

At 375 mg/kg/day, the thymus gland in both males and females had lower absolute weights at 52 

and 104 weeks, and lower relative weights at 52 and 104 weeks in males; these findings were 

judged to be consistent with histopathological findings of atrophy in males and females at 52 

weeks. The absolute weights of the ovaries and uterus were increased in the two highest dose 

groups but were not reported to be statistically significant. However, at 375 mg/kg/day, the 

relative weights of these reproductive organs were significantly increased as compared with 

controls. Gross pathology demonstrated the occurrence of an increased incidence of high dose 

animals with red discoloration of the mesenteric lymph node, which was correlated with 

histopathological findings of hemorrhage. 

Reported treatment-related findings at terminal sacrifice included (1) a decrease in the number of 

germinal centers in Peyer’s patches at 75 and 375 mg/kg/day in both males and females; (2) an 

increased incidence and severity of sinus histiocytosis in the mandibular lymph nodes at 15 and 

75 mg/kg/day in females and at 75 and 375 mg/kg/day in males; (3) an increased incidence and 

severity of sinus histiocytosis in the mesenteric lymph nodes at 15 and 375 mg/kg/day in males 

and at 75 and 375 mg/kg/day in females; (4) hemorrhage (considered secondary to sinus 

histiocytosis) in the mesenteric lymph nodes at 75 and 375 mg/kg/day in males and at 375 

mg/kg/day in females; and (5) atrophy of the salivary glands in high-dose males. 

At a significance level of p < 0.05 and the following additional findings were noted (compared 
48

to controls): (1) hemorrhage in the mesenteric lymph nodes of males at 75 mg/kg/day; (2) 

increased incidence and severity of sinus histiocytosis of the mandibular lymph nodes in females 

at 375 mg/kg/day and in the mesenteric lymph nodes of males at 75 mg/kg/day; (3) atrophy of 

the salivary glands at 15, 75, and 375 mg/kg/day in females; (4) atrophy of the ovaries at 75 and 

375 mg/kg/day; and (5) a marginally significant increase in the incidence of stromal polyps of 

the uterus at 375 mg/kg/day.

The NOAEL is less than 15 mg/kg/day (8.7 mg/kg/day 100% a.i.) and the LOAEL is 15 

mg/kg/day (8.7 mg/kg/day 100% a.i) based on evidence of histiocytosis in the both the 

mandibular lymph nodes and mesenteric lymph nodes and atrophy of the salivary glands.

This chronic/carcinogenicity study in the Wistar rat is Acceptable / Guideline and satisfy the 

guideline requirement for a chronic/carcinogenicity study (OPPTS 870.4300). 

Carcinogenicity 

On April 1, 2009, a special AD Toxicity Endpoint Selection Committee (ADTC) meeting was 

held to discuss the March 29, 2009 presentation by RUTGERS Organics GmbH on the waiver 

request of the mouse cancer study for Polymeric betaine wood preservative. This special 

meeting included the members of AD’s Toxicity Endpoint Selection Committee as well as 

representative members of the Health Effects Division’s Carcinogenicity Assessment Review 

Committee (CARC). The conclusion of this meeting was to waive the need for a second species 

(mouse) carcinogenicity study. The reason for this was that 1) leaching data indicates that parent 

Polymeric betaine does not leach from the treated wood material, 2) the observed leachates are 

considered part of either the Group I cluster of the EPA cluster group for quats (DDAC and/or 

DDAC-like compounds) or boric acid/borate, both of which are considered “not likely to be 

carcinogenic in humans,” and 3) the endpoints already selected are protective of a carcinogenic 

effect (375 mg/kg/day was carcinogenic vs <9 mg/kg/day selected as endpoint with a 300 UF 

applied bringing exposure to 0.09 mg/kg/day).

In a combined chronic toxicity/carcinogenicity study (MRID 45808215) didecylpolyoxethylammonium borate (58.7% a.i.; Batch # DEGE 004110) was administered to 50 Wistar 

rats/sex/dose in the diet at targeted dose levels of 0, 15, 75, or 375 mg/kg/day for 104 weeks. 

Satellite groups of 10/sex/dose at the control, low and mid dose and 20/sex/dose at the high dose 

were exposed via diet to the test compound, and sacrificed at 52 weeks. No correction was made 

for the purity of the test substance in calculations for diet preparation. There were no statistically 

significant incremental changes in mortality with increasing doses of Polymeric betaine in 

female rats (Memo, L. Brunsman, 07/31/2006, TXR No. 0054289). At the doses tested, there 

was a treatment related increase in tumor incidence of uterine adenocarcinoma, when compared 

to controls. At terminal sacrifice, 4 females (out of 50 tested females, 8%) had uterine 

adenocarcinoma in the high dose group versus 0 females in the controls. A uterine adenoma was 

also detected in 1 satellite female administered 375 mg/kg/day at 52 weeks (out of 20 tested 

female, 5%). The incidences of adenocarcinoma, adenoma and combined (adenocarcinoma + 

adenoma) reported in the four historical control studies in female Wister rats carcinogenicity 

studies were (0%,0% , 7% and 4%), (0%,0%, 1%,and 4%), and (0,0,8%, and 8% ). Both the 
49

incidences of adenocarcinoma and adenoma were still within the findings in the historical 

control. Therefore, the Cancer Assessment Review Committee (CARC) did not consider the 

increase in uterine tumors to be treatment-related.

In acidic conditions, the equilibrium mixture of Polymeric betaine would rapidly shift from the 

complex borate ester form to the free Quats and borate. Boric acid/borate and Quats (using 

DDAC as surrogate) are classified as “not likely to be carcinogenic to humans” and are not a 

mutagenic concern. 

In accordance with the EPA's Final Guidelines for Carcinogen Risk Assessment (March, 2005), 

the CARC classified Polymeric betaine as “Inadequate Information to Assess Carcinogenic 

Potential” based on the lack of a mouse carcinogenicity study. The uterine tumors seen in 

female Wistar rats were not considered to be treatment-related. There is no concern for 

mutagenicity. SAR data indicate that the equilibrium products of Polymeric betaine are not 

carcinogenic. Quantification of carcinogenic potential is not required. 

Mutagenicity/Genotoxicity

The data base for mutagenicity is considered adequate based on EPA's 1991 mutagenicity 

guidelines and indicates that Polymeric betaine is not mutagenic or genotoxic. In a submitted 

bacterial study (MRID 45808302), Polymeric betaine was not mutagenic to the bacteria in the 

presence or absence of mammalian metabolic activation. An assay using cultured mouse 

lymphoma cells also proved negative (MRID 45808303). Finally, an in vivo unscheduled DNA 

synthesis in primary rat hepatocytes for genotoxicity using male Wistar also was negative 

(MRID 45808304).

Immunotoxicity

At a 2013 meeting of the AD Toxicology issues meeting, a decision was made to waive the 

immunotoxicity study requirement for the following reasons: Leaching data indicates that the 

parent compound does not leave the treated wood. The leachates are either chemicals that belong 

to the Group I cluster of the EPA cluster group for quats (DDAC and/or DDAC-like 

compounds) or compounds that would have no quaternary ammonium characteristics (e.g., boric 

acid). More recent leaching studies indicate the primary quat leached out is the quat monomer 

portion of the parent compound. Quaternary ammonium compounds are classified as "not likely 

to be immunotoxic to humans" based on an EPA retrospective completed in 2012 on 

immunotoxicity. Therefore, additional studies based on the group one quat component would 

not help the risk assessment for the exposure associated with wood preservative used in postapplication residential setting. In the 2012 immunotoxicity risk assessment, boric acid/borate was 

found to have immunotoxic concerns. However, the NOAEL set for boric acid/borate was 250 

mg/kg/day. The committee believes that the currently selected chronic end-point for Polymeric 

betaine is protective against potential immunotoxic concerns. The dosage that was used as the 

end-point in the risk assessment is ≤ 9 mg/kg/day. Therefore, the committee agreed that the endpoint selected for non-immunotoxic effects should be conservative enough to protect against 
50

potential immunotoxicity concerns, as it is over 25 fold less than the NOAEL for boric 

acid/borate immumotoxicity.

Other Toxicological Effects 

There were no additional studies found in the literature investigating additional toxicological 

effects of Polymeric betaine.
51

Appendix B Environmental Fate

Environmental Fate Properties

Parent substance: Polymeric Betaine

Polymeric betaine is an equilibrium mixture of the didecyl-bis(2-hydroxyl)ammonium cation, the 

boric acid anion, and the combination of the cation and anion.44 At basic pH values, the TGAI is 

expected to be present in higher amounts as the separate active cation and the inactive boric acid 

anion, while it would be present in the combined (non-ionized) form at pH values below 7.0.45

Because the active ingredient in Polymeric betaine is an equilibrium mixture of DDAC and boric 

acid, it has no relevant vapor pressure, flammability, or melting point.46 It is completely 

miscible in water47 and therefore would not be likely to escape from water into air. Also, it is 

impossible to calculate a Henry’s Law constant because no relevant vapor pressure exists. 

Abiotic (chemical) degradation of Polymeric betaine is not a significant route of dissipation in 

the environment. Polymeric betaine is stable to hydrolysis48 (no hydrolyzable functional groups) 

and does not absorb light between 290 and 800 nm in wavelength.49 As a result, it is not 

expected to undergo direct photodegradation in the environment. 

However, biotic degradation in the top layer of soil (aerobic soil metabolism)50does contribute to 

the dissipation of Polymeric betaine in the environment. The parent compound half-lives ranged 

from 83-107 days51 for linear regression and 76-107 days.52 The only non-volatile organic 

degradate formed in the studies was M-1, a dealkylated53 and hydroxylated quaternary 

ammonium compound. 

The non-ionized state of active ingredient (quaternary cation) is more likely to be removed from 

soil and sediment by leaching because the positive and negative charges of the non-ionized forms 

are partially negated when combined. As the pH of the soil and sediment increases, the soil and 

sediment becomes more negatively-charged and the cationic active ingredient becomes more 

tightly sorbed (opposite charges attract). Table B1 shows the environmental fate and transport 

properties of polymeric betaine.

Environmental Fate of Boric Acid

Boron is present in the environment as a result of natural and anthropogenic sources, and boric 

acid and boron-containing salts are ubiquitous in the environment. Boron occur naturally in 

 44 MRIDs 45800203 (p. 18) and 47757601 (p. 17) 45 MRID 45808204, p. 13 46 MRID 45800202 (p. 18) 47 MRID 45800206, p. 8 48 MRID 47348101

49 MRIDs 46315828, 46404706 50 OCSPP 835.4100, MRIDs 45808209 and 47757601 51 Arithmetic mean of 97 days for 5 half-lives, linear first-order regression using all data points 52 Arithmetic mean of 90 days for 5 half-lives, non-linear first-order regression using all data points 53 Loss of one decyl (C10) chain
52

soils, water, fruits, vegetables, and forage crops. Boron is an essential nutrient for plants as well 

as an essential element for many organisms. The pKa value of boric acid is 9.15, indicating that 

at pH=9 approximately 50 percent of boric acid will be dissociated and 50 percent will remain in 

boric acid form. As the pH increases above 9, the percentage of boric acid that will dissociate 

will tend to increase and tetrahydroxyborate will tend to predominate rather than boric acid. 

Since the pH of many ambient waters is typically around 7, boric acid rather than 

tetrahydroxyborate is expected to be the predominant degradate in surface water under ambient 

environmental conditions. As the pH increases, the anionic boric acid component of polymeric 

betaine is expected to be less sorbed to soil and sediment (like charges repel).54 

Table B1. Environmental Fate and Transport Properties of Polymeric Betaine

Property Value Comments/Reference

Hydrolysis (835.2120) Stable at pH 4, 7, and 9 4734810155

Photodegradation in water 

(835.2240)

No data but expected to be 

stable

46315828

Does not absorb light at 

testing wavelengths (290-

800 nm)56,

57

Photodegradation on soil 

(835.2410)

Stable 46315828

46504706

Does not absorb light at 

testing wavelengths (290-

800 nm)58

Photodegradation in air 

(835.2370)

Stable 46315828

Does not absorb light at 

testing wavelengths (290-

 54 Cornell University Cooperative Extension (2007). Cation Exchange Capacity Fact Sheet.

http://nmsp.cals.cornell.edu/publications/factsheets/factsheet22.pdf

55 Required on 9/26/2006 and accepted on 2/23/09. 56 OECD GUIDELINES FOR THE TESTING OF CHEMICALS: Phototransformation of Chemicals in Water –

Direct Photolysis. OECD 316. Adopted October 3, 2008. http://www.oecdilibrary.org/docserver/download/9731601e.pdf?expires=1370613694&id=id&accname=guest&checksum=13B8A1

B779D2A1112C61756FA423A21E

57 Photodegradation in Water. 835.2240. Adopted October, 2008. 

http://www.regulations.gov/#!documentDetail;D=EPA-HQ-OPPT-2009-0152-0012 58 See same footnotes as for “Photodegredation in water.” 
53

800 nm)59

Aerobic Soil Metabolism 

(835.4100)

Parent Half-lives

101 days (linear)/107 days 

(non-linear)60

83 days (linear)/80 days 

(non-linear)

93 days (linear)/92 days 

(non-linear)

101 days (linear)/76 days 

(non-linear)

107 days (linear)/94 days 

(non-linear)

M-1 Half-lives

Estimated M-1 half-life in 

CA sandy loam soil was 

596 days (one decline 

interval)

45808209

Required on 9/26/2006, 

rejected on 2/23/0961, and 

later accepted on 8/25/09

Loam (UK)

Sandy loam (UK)

Silty clay loam (UK)

47757601 

Sandy loam soil (CA)

Ostlie sandy clay loam soil 

(ND)

Reviewed and accepted on 

8/25/2009 with combination 

of 45808209 and 47757601

Only non-volatile degradate 

was M-1, a quaternary 

ammonium compound with 

shortened carbon chain.

 59 See same footnotes as for “Photodegredation in water.” 60 Linear regression of natural log (ln) values of parent polymeric betaine (all intervals) using EXCEL. Non-linear 

regression using Solver add-in of EXCEL and all intervals. 61 Rejected on 2/23/09 because no degradation pathway was identified, no degradates were identified, and no 

monitoring study was conducted for aerobic conditions and moisture. Only 10 % of parent polymeric betaine 

degraded. Study was later accepted and used to satisfy the 835.4100 data requirement with the combination of 

45808209 and 47757601 on 8/25/2009.
54

M-1 half-life not calculated 

for ND sandy clay loam soil 

because it did not reach 10 

% of applied Polymeric 

betaine (minor degradate)

In CA, M-1 increased to 

23.7 % by 122 days and 

decreased to 15.7 % by end 

of study (366 days). In ND, 

M-1 was minor degradate 

(<10 %) of applied 

Polymeric betaine).

Leaching and AdsorptionDesorption (835.1230)Adsorption Kads (Koc) 

values [ml/g]62

Loam –1,700 (10,000) 

Silty clay—4,300 (220,000)

Silty clay loam—2,600 

(120,000)

Clay loam—3,200 (82,000)

Sand—190 (66,000)

45808208

Reviewed and accepted on 

2/23/09

D352480, 355602, 

D358401

Sorption related to clay 

content (r2=0.99)63

Field soil dissipation study Impralit KDS

Overall absorption was 16-

17 kg/m3. 

Boron absorption ~5.5 mg, 

while betaine and copper 

absorption were ~20 mg 

and ~30 mg. 

Impralit TSK 16® solution 

Overall absorption was ~21 

kg/m3, while the boron and 

betaine absorptions were 

~11 mg and ~410 mg. 

46313016

46313017

46522302

Reviewed on 1/26/09 and 

found to be acceptable.

D352480, D355602

Retention rate study (EN 

113) 

Retention of 97-99 % by 2 

days for treatment rates of 

12-23 kg/m3 for Cu and 

46735801

Required on 9/26/2006 and 

 62 Kads is an expression of the sorption of a pesticide to the entire soil (mineral + organic carbon), whereas Koc is an 

expression of the sorption to the organic portion (Kd*100)/% OC. 63 Linear regression of clay content (%) in soils (x) versus Kads values from study (y) using Excel.
55

Impralit Kds. accepted on 2/23/09

D353074

Also includes information 

from AWPA E19-04,64

May 2, 2008 information,65 

October 31, 2006 

information66

Special Leaching Study 

(E11-97)

Maximum leaching rates of 

1.8, 2.5, 3.3, and 4.6 

ug/cm2/day for 3, 5, 7, and 

9 kg/m3 in pine.

Minimum leaching rates of 

0.28, 0.33, 0.41, and 0.59 

ug/cm2/day for 3, 5, 7, and 

9 kg/m3 in pine.

Average leaching rates of 

0.6, 0.8, 1.0, and 1.4 

ug/cm2/day for 3, 5, 7, and 

9 kg/m3 in pine.

Cumulative leaching rates 

of 18, 23, 31, and 38 ug/cm2

for 3, 5, 7, and 9 kg/m3 in 

pine.

47497001 (leaching rate)

47484101 (chemical 

identity)

Required on 9/26/2006 and 

accepted on 4/21/2009

D355430

Soil biodegradation / 

column leaching 

(835.4100/835.1240)

None 46318530

Reviewed on 2/23/09

AI (Polymeric betaine) is an 

ionic salt and has no vapor 

pressure 

 64 American Wood-Preservers’ Association Standard Method for Determining Preservative Fixation of Inorganic 

Waterborne Wood Preservatives, http://www.awpa.com/standards/06tableofcontents.pdf .

65 Proposed Labeling for 75269-2-EP, Background Information Submission letter for 75269-2-EP.

66 Background Information Labeling for 75269-2-EP and Background Information Labeling for 75269-1-MUP, 

Label at http://www.epa.gov/pesticides/chem_search/ppls/075269-00002-20061031.pdf . 
56

Appendix C Ecotoxicology Profile 

Ecological Toxicity Data:

 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 Polymeric betaine

TGAI and DDAC. 

A. Toxicity to Terrestrial Animals

(1) Birds, Acute and Subacute

In order to establish the toxicity of a pesticide to avian species, the Agency requires an 

acute oral toxicity study using the TGAI. The preferred test species is either mallard duck (a 

waterfowl) or bobwhite quail (an upland game bird). The results of one study on Polymeric 

betaine TGAI and two toxicity studies on DDAC are provided in the following table (Table C1).

The results indicate that Polymeric betaine and DDAC are moderately toxic to birds on 

an acute oral basis. The studies are acceptable and fulfill guideline requirements (OPPTS 

850.2100).

A subacute dietary study using the TGAI may be required on a case-by-case basis 

depending on the results of lower-tier ecological studies and pertinent environmental fate 

characteristics in order to establish the toxicity of a chemical to avian species. This testing was 

not required for the wood preservation use of Polymeric betaine, but studies were available for 

DDAC. Results of these studies are provided in Table C2.

The results indicate that DDAC is practically non-toxic to avian species on a subacute 

dietary basis. The studies are acceptable and fulfill guideline requirements (OPPTS 850.2200).

(2) Mammals, Acute and Chronic Toxicity

Wild mammal testing was not required by the Agency. In most cases, mammalian 

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

risk assessments substitute for wild mammal testing. These toxicity values are reported below 

(Table C3). Further information on the mammalian toxicology of Polymeric betaine and DDAC 

may be found in the toxicology disciplinary document supporting this registration.

Acute Toxicity: DDAC shows moderate toxicity to small mammals when ingested, inhaled, or 

absorbed through the skin. It is corrosive to eyes and skin, but is not a dermal sensitizer.

Reproductive Toxicity: For reproductive toxicity, the toxicity database for DDAC includes a 2-

generational reproductive toxicity study in rats (MRID 41804501). The effects in offspring 

(decreased pup body weight/weight gain) occurred at the same dose level as maternal effects 
57

(decreased maternal body weight/weight gain and food consumption), 1500 ppm. The NOAEL 

for this study is 750 ppm (56 mg/kg/day) and the LOAEL for this study is 1500 ppm (113 

mg/kg/day). This study is classified as acceptable.

Chronic Toxicity: In a chronic, 1-year toxicity study in dogs (MRID 41970401), no 

treatment-related deaths occurred, but there were treatment-related clinical signs (soft/mucoid 

feces, emesis) observed frequently in high-dose animals. Hematology or urinalysis results were 

normal. Total cholesterol levels were significantly decreased in high-dose females. Gross and 

histopathological findings did not reveal any treatment-related effects. The NOAEL for both 

male and females was 10 mg/kg/day, and the LOAEL was 20 mg/kg/day. This study is classified 

as Acceptable – Guideline.

 (3) Toxicity to Non-Target Insects 

 Polymeric betaine labels specifically prohibit wood pressure treated with this chemical to 

be used for constructing beehives. Therefore, no data are anticipated to be required for toxicity 

to honeybees. 

B. Toxicity to Aquatic Animals

(1) Freshwater Fish, Acute

In order to establish the acute toxicity of pesticides to freshwater fish, the Agency 

requires freshwater fish toxicity studies using the TGAI. The preferred test species are rainbow 

trout (a coldwater fish) and bluegill sunfish (a warm-water fish). Results of submitted studies are 

presented in Table C4.

These data indicate that Polymeric betaine is highly toxic to freshwater fish, and DDAC 

is highly to moderately toxic to freshwater fish on an acute basis. The Guideline requirement 

(805.1075) is fulfilled.

(2) Freshwater Invertebrates, Acute

The Agency requires a freshwater aquatic invertebrate toxicity study using the TGAI to 

establish the acute toxicity of a pesticide to freshwater invertebrates. The preferred test species 

is Daphnia magna. Results of studies for Polymeric betaine and DDAC are provided in the 

following table (Table C5).

The results of this study indicate that Polymeric betaine is highly toxic and DDAC is very 

highly toxic to freshwater invertebrates on an acute basis. The guideline requirement has been 

fulfilled (850.1010).
58

(3) Estuarine and Marine Organisms, Acute

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 currently 

proposed uses of Polymeric betaine are for treating wood intended for terrestrial applications. 

Therefore, this testing is not expected to be required for the currently proposed uses of Polymeric 

betaine. 

Although significant runoff from terrestrial treated wood structures into estuarine/marine 

habitats is unlikely, marine/estuarine ecotoxicity data are available for DDAC, and, therefore, 

this information is included in this risk assessment. The results of submitted studies are 

summarized in the table below (Table C6).

 These data indicate that DDAC is highly toxic to marine/estuarine fish, moderately to 

very highly toxic to oysters, and very highly toxic to marine/estuarine invertebrates on an acute 

basis.

(4) Aquatic Organisms, Chronic

Chronic toxicity testing (Fish early life stage, 850.1300 and aquatic invertebrate life 

cycle, 850.1400) using the technical grade of the active ingredient are required for a pesticide 

when it is used as a wood preservative. Testing must be conducted with the most acutely 

sensitive species. No data on this topic have been submitted for DDAC.

 (5) Whole Sediment Acute Toxicity

 Although significant impact to freshwater sediments from the terrestrial uses of 

Polymeric betaine are unlikely, data on this topic are available for DDAC, and are therefore 

included in this assessment (Table C7).

C. Toxicity to Plants

 To support registration of a wood preservative which can be used in aquatic areas, Tier II 

(dose-response) toxicity testing with terrestrial and aquatic plants is required. For terrestrial 

plants, seedling emergence and vegetative vigor tests are required on rice (Oryza sativa) 

(Guidelines 850.4225 and 850.4250). For aquatic plants, testing on one vascular plant species 

(preferably the duckweed, Lemna gibba), and four alga species (freshwater green alga, bluegreen alga, freshwater diatom, and marine diatom) is required (Guidelines 850.4400 and 

850.5400). Terrestrial plant testing has not been submitted for Polymeric betaine or DDAC. The 

currently proposed terrestrial uses of Polymeric betaine do not require this testing.

 One alga test on DDAC has been submitted and reviewed by the Agency. The results of 

this test are provided in Table C8, below. This study indicates that DDAC is toxic to algae at 

very low levels.
59

Toxicity to Terrestrial Receptors

Table C1. Acute Oral Toxicity of Polymeric Betaine and DDAC to Birds (Guideline 

850.2100/71-1a)

Species Active 

ingredient, %

Endpoint 

(mg/kg)

Toxicity 

Category

Satisfies Guideline 

Requirements/Comments

Reference

Polymeric 

betaine

14-day LD50 

= 664 (528-

835) mg/kg

NOEC = 253 

mg/kg

Moderately 

toxic

Yes 467685-02

Northern 

bobwhite

(Colinus 

virginianus)

DDAC, 80.9% 14-day LD50 = 

217 (167-298 

mg/kg)

NOEL < 31 

mg/kg)

Moderately 

toxic

Yes 417858-03

Northern 

bobwhite

(Colinus 

virginianus)

DDAC, 50% 14-day LD50 = 

54.4 (42.9-

67.1 mg/kg)

NOEL < 39 

mg/kg)

Moderately 

toxic

Yes ACC258798

Table C2. Subacute Dietary Toxicity of DDAC to Birds (850.2200/71-2a)

Species Active 

ingredient, %

Endpoint, ppm Toxicity 

Category

Satisfies Guideline 

Requirements/Comments

Reference

Mallard, Anas 

platyrhynchos

80.8 8 day dietary 

LC50 > 5620 

ppm

NOEC = 562 

ppm

Yes 417858-02

Mallard, Anas 

platyrhynchos

50 14 day dietary 

LC50 > 5620 

ppm

NOEC = 1780 

Yes ACC258798
60

ppm

Bobwhite quail, 

Colinus virginianus

80.8 8 day dietary 

LC50 >5620 

ppm

NOEC = 1780 

ppm

Yes 417858-01

Bobwhite quail, 

Colinus virginianus

50 8 day dietary 

LC50 > 5620 

ppm

NOEC = 3180 

ppm

Yes ACC258798

Table C3. Acute Toxicity Profile for DDAC

Guideline 

Number

Study Type/ Test 

substance (% a.i.)

MRID Number/ 

Citation

Results Toxicity 

Category

870.1100

(§81-1)

Acute oral, rat

(Purity 65%)

MRID 41394404 LD50 =262 mg/kg 

(combined)

LD50 =331 mg/kg 

(males)

LD50 =238 mg/kg 

(females)

II

870.1100

(§81-1)

Acute oral, rat

(Purity 80%)

MRID 42296101 LD50 =238 mg/kg 

(combined)

II

870.1200

(§81-2)

Acute dermal, rabbit

(Purity 65%)

MRID 42053801 LD50 =2930 mg/kg 

(combined)

LD50 =3140 mg/kg 

III
61

Table C3. Acute Toxicity Profile for DDAC

Guideline 

Number

Study Type/ Test 

substance (% a.i.)

MRID Number/ 

Citation

Results Toxicity 

Category

(males)

LD50 =2730 mg/kg 

(females)

870.1300

(§81-3)

Acute inhalation, rat

(Purity not reported)

MRID 00145074

TRID 455201010

LC50 (combined) = 

0.07 mg/L

II

870.2400

(§81-4)

Primary eye irritation, 

rabbit

(Purity 65% a.i.)

MRID 41394404 Corrosive. I

870.2400

(§81-4)

Primary eye irritation, 

rabbit

(Purity 80% a.i.)

MRID 42161602 Corrosive. I

870.2500

(§81-5)

Primary dermal 

irritation, rabbit

(Purity 80%)

MRID 42161601 Corrosive. I

870.2600

(§81-6)

Dermal sensitization, 

guinea pigs

(Purity 80%)

MRID 46367601 Not a sensitizer. NA
62

Toxicity to Aquatic Receptors

Table C4. Acute Toxicity of Polymeric betaine and DDAC to Freshwater Fish 

(850.1075/72-1)

Species % Active 

Ingredient 

(ai)

Endpoints

(ppm)

Toxicity 

Category

Satisfies Guidelines/

Comments

Reference

Bluegill sunfish

(Lepomis macrochirus)

Polymeric 

betaine, 

TGAI

96h static 

LC50 = 0.89 

(0.54 - 1.3) 

mg/L; NOEC 

= 0.54 mg/L

Highly Toxic No – supplemental 

study, however, no 

further testing is 

expected to be 

required as the study 

is used for labeling 

purposes only and a 

repeat study would not 

likely change the label 

statement.

MRID #467685-01

Coho salmon 

(Oncorhynchus kisutch)

DDAC, 

41.2%

96h static 

LC50 = 1.0 

(0.59 – 1.2) 

mg/L; 

NOEC<0.59 

mg/L

Highly Toxic Yes MRID #415780-03

Bluegill sunfish

(Lepomis macrochirus)

DDAC, 

100%

96h static 

LC50 = 0.6 

(0.5 – 0.7) 

mg/L; NOEC 

not reported

Highly Toxic Yes Occidental Labs (no 

identification #)

Bluegill sunfish

(Lepomis macrochirus)

DDAC, 

41.2%

96-hr static 

LC50 = 

0.320 (0.242 

– 0.419) 

mg/L; NOEC 

<0.100 mg/L

Highly Toxic Yes MRID #415780-01

Rainbow Trout 

(Oncorhynchus mykiss)

DDAC, 

100%

96h static

LC50 = 2.8 

(2.5 – 3.2) 

mg/L; NOEC 

= 1.8 mg/L

Moderately 

Toxic

Yes Occidental Labs (no 

ID #)
63

Table C5. Acute Toxicity of Polymeric Betaine and DDAC to Freshwater Invertebrates

Species Active 

Ingredient

Endpoints 

(ppm)

Toxicity 

Category

Satisfies 

Guidelines/Comments

Reference

Waterflea

(Daphnia 

magna)

Polymeric 

betaine, TGAI

48h static EC50 

= 0.39 (0.34 –

0.46) mg/L

NOEC = 0.06 

mg/L

Highly Toxic Yes MRID 

#456224-04

Waterflea

(Daphnia 

magna)

DDAC, 100% 48h static EC50 

= 0.018 (0.014-

0.022) mg/L; 

NOEC < 0.0056 

mg/L

Very Highly 

Toxic

Yes Occidental 

Labs (no ID 

#)

Waterflea

(Daphnia 

magna)

DDAC, 41.2% 48h static EC50 

= 0.094(0.074-

0.120) mg/L; 

NOEC = 0.074 

mg/L

Very Highly 

Toxic

Yes MRID 

#415780-02

Table C6. Acute Toxicity of DDAC to Marine/Estuarine Organisms

Species Active 

Ingredient

Endpoints 

(ppm)

Toxicity 

Category

Satisfies 

Guidelines/Comments

Reference

Sheepshead 

minnow, 

(Cyprinodon 

variegatus)

DDAC, 80.5% 96h LC50 = 

0.960 mg/L

NOEC = 0.390 

mg/L

Highly Toxic Yes MRID 

#436200-01

Eastern oyster, 

(Crassostrea 

virginica)

DDAC, 84.6 96h static shell 

deposition 

EC50 = 0.094 

mg/L; NOEC 

= 0.063 mg/L

Very Highly 

Toxic

Yes MRID 

#436200-03

Eastern oyster, 

(Crassostrea 

virginica)

DDAC, 50% 96h static 

embryo-larvae 

LC50 = 6.4 

mg/L; NOEC 

= 0.090 mg/L

Moderately 

Toxic

Yes ACC#249002

Mysid 

(Americamysis 

bahia)

DDAC 41.2% 96h static 

LC50 = 0.069 

(0.052-0.084) 

mg/L;

NOEC = 0.052 

Very Highly 

Toxic

Yes MRID#415780-

04
64

mg/L

Table C7. Whole Sediment Acute Toxicity to DDAC

Species Active 

Ingredient, %

Endpoints (mg/kg) Satisfies 

Guidelines/Comments

Reference

Midge 

(Chironomus 

tentans)

DDAC, 92.9% 

(radiolabled)

14d LC50>2200 mg/kg

14d emergence EC50 = 

1438 mg/kg

14d growth NOEC = 

530 mg/kg

28d LC50= 1000 mg/kg

28d emergence EC50 = 

1981 mg/kg

28d emergence 

NOEC=260 mg/kg

No – supplemental study

This study was submitted as 

additional information and 

not required for regulatory 

decision making.

MRID#458217-01

Table C8. Acute Toxicity of DDAC to Aquatic Plants

Species Active Ingredient, 

% ai

Endpoints

(ppm)

Satisfies 

Guidelines/comm

ents

Reference

Freshwater green alga, 

Selenastrum 

capricornutum

DDAC 96-h EC50 = 0.0142 

mg/L

NOEC 0.008 mg/L

Yes MRID 485964-

02
65

Appendix D Product Chemistry

Polymeric betaine product chemistry information is summarized in Table D1 (source: MRIDs 

45808205, 45808206, and 45808207).

Table D1 – Product Chemistry of Polymeric Betaine

Guideline 

No. Physical and Chemical Properties Polymeric Betaine

830.1550 Product identity and composition Refer to Table 3

830.1600 Description of materials used to 

produce the product

Confidential Business Information (CBI)

830.1620 Description of production process CBI

830.1650 Description of Formulation Process CBI

830.1670 Description of Formulation Process CBI

830.1700 Preliminary analysis CBI

830.1750 Certified limits CBI

830.1800 Enforcement analytical method 

NMR MS

Titrimetric Determination of Cationic Amines in Polymeric 

betaine.

Infusion electrospray ionization mass spectrometry in the 

positive ion mode.

830.1900 Submittal of samples CBI

830.6302 Color Slightly yellowish

Colorless

830.6303 Physical State Viscous liquid.

830.6304 Odor Mildly pungent, sweet 

830.6313 Stability to normal and elevated 

temperature, metals/metal ions 

No hazardous reaction when stored and handled according to

prescribed instruction 

Polymeric betaine demonstrated moderate stability at elevated 

temperature over a period of 28 days with no significant signs of 

degradation.

Polymeric betaine under the normal (room temperature) storage 

conditions of ambient temperature proved to be stable.

Stable at 50°C for 28 days.

830.6314 Oxidation/Reduction Does not contain any oxidizer

830.6315 Flammability Flash point: 235°F (112.8°C)

830.6316 Explodability Not explodable.

830.6320 Corrosion Characteristic Corrosive liquid, Basic

830.7000 pH 9.61 - 1% w/v 

830.7050 UV/Visible Absorption 

<200 nm

Does not absorb UV light.

Does not absorb light at testing wavelengths
66

Guideline 

No. Physical and Chemical Properties Polymeric Betaine

830.7200 Melting point Pour point - 13°C MSDS

830.7220 Boiling point 110.2° C 

830.7300 Density 1g/ml @ 20°C

Rel. Density: 1.024

830.7100 Viscosity 130 to 180 mPa @50°C MSDS

Viscous liquid 

830.7370 Dissociation Constant 

Decomposes in water 

Exists in equilibrium forms in solution depending on 

concentration.

830.7550 Partition coefficient (n-octanol/water) Polymeric betaine’s behavior is that of a surfactant. A partition 

coefficient of a surfactant is not determinable. It is an emulsifier.

830.7840 Solubility in water Completely miscible with water.

830.7860 Solubility in organic solvents Soluble in organic solvents.

830.7950 Vapor pressure 1.12 ± 0.08mm Hg at 25°C