Page 2 of 66 Polymeric B etaine 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 RossPage 3 of 66 

### 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 Summar y 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 Ecologic al

................................ ................................ ................................ ............... 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 Pr eliminary Work Plan

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

................................ ................................ ................................ .......... 28
7.1.2 Water Quality

................................ ................................ ................................ .......... 28Page 4 of 66 7.1.3 Enviro nmental Justice

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

................................ ................................ ............. 29
7.1.5 Additional Information

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

................................ ................................ ................................ ............................. 30
9 References

................................ ................................ ................................ ............................. 31

Appendix A T oxicology Profile

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

................................ ................................ ............................. 51 Ap pendix 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 Prope rties 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

................................ ................................ ............................... 24Page 5 of 66 

## 1 Intr oduction

This document is the United States Environmental Protection Agency’s ( US EPA , EPA or “the
A gency”) Preliminary Work Plan (PWP) for P olymeric betaine (boric acid (H 3 BO 3 ), 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 t he Technical G rade A ctive I ngredient (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 Prog rams (OPP) knows about
P olymeric 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 P olymeric 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 in form 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 rev iew the PWP and to provide comments and additional information that will help the Agency’s decision

- making process for t his 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 t he 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 CF R 155.40. The Agency will consider benefits information and data as required by FIFRA. The public phase of registration review begins when the initial docket is opened for each case. The docket is the Agency’s opportunity to state what it knows abo ut 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 initialPage 6 of 66 comment period, the Age ncy will develop and commit to a F inal W ork P lan (FWP) and anticipated schedule for the Polymeric betaine c ase.

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 B etaine

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 detail s)

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 Preli minary Work
Plan 2013

- 12 2013

- 12

- 20Page 7 of 66 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 Pro posed Decision 2019

- 06

Close Public Comment Period 2019

- 08

Issue Final Decision 2019

- 12

Begin Post

- Decision Followup 20 19

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 B etaine

Common
Name Polymeric B etaine

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 103679Page 8 of 66 Common
Name Polymeric B etaine

CAS No. 214710

- 34

- 6

Molecular
Formula C 48 H 102 N 2 O 5 B 1 (Dimer p olymeric betaine )

Molecular Weight 798.14 g/mol (Dimer p olymeric betaine )

Purity 59.6 % borate ester form (Dimer p olymeric betaine )Page 9 of 66 Common
Name Polymeric B etaine

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

.Page 10 of 66 The P olymeric 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 B etaine

Guideline
No. Physical and Chemical Properties Polymeric B etaine

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 ( n

octanol/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 B etaine 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 pc f of wood treated (1.6

- 9.6 kg/m 3 ) for sapwood of softwood species such as pine and spruce. The 9.6 kg/m 3 retention is for critical infrastructure use only. Do not exceed 6.0 kg /m 3 retention for above ground applications ( AWPA UC1

— UC3).Page 11 of 66 

### 1.4.3 Usage Information

No data w ere 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 P olymeric betaine since it was first registered after November 1, 1984.



### 1.5.1 Recent/Pending Regulatory Actions

The re 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 201 3

.



### 1.6.2 Ecological

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



## 2 A nticipated 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 B etaine

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

875.1200 1 Indoor
Dermal Exposure TGAI 24 Occupational Handler Wood Preservative Wood Pressure
Treatment

875.1400 1 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. 2 700 2 Product Use TGAI 12 Occupational Post

Application 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 G uideline 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 A gency 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 r egistration 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 Committe e (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 preserva tives 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 carcin ogenicity 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(hydroxye thyl) 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 stu dies 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 potent ial 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 cont rol 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 decide d 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 retr ospective 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 preser vative 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 cu rr ently 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 B etaine

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)
LOAE L = 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

Intermediate

Term
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 accepta ble 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 ) . T herefore, 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)
LOAE L = 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

asso ciation pelvis

Intermediate

Term Dermal (1

- 6 months) NOAEL= 5.7 mg/kg/day R esidential/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.

L ong

- Term

Dermal ( > 6 months) NOAEL < 8.7 mg/kg/day Residential/Occupational MOE
= 3 00 (3 for using LOAEL, 10x for inter species variation, and 10X

for intra

- species variation) C hronic/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 R esidential/Occupational MOE

= 100 (10x for inter species variation,
and 10X for intra

- species variation) Rabbit Developmental Study (MRID 46315816)
LOAE L = 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 e of sin gle association pelvis

Intermediate

Term 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.

L ong

- Term
Inhalation ( > 6 months) NOAEL < 8.7 mg/kg/day Residential/Occupational MOE
= 3 00

(3 for using LOAEL, 10x for inter species variation, and 10X

for intra

- species variation) C hronic/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 refer r ed to the Cancer Assessment Review Committee. (CARC). The Committee decided that there is inadequate data to evaluate the potential carcinogenic concerns o f 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 fo r 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 iss ues 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. G roup I quaternary ammonium compounds are clas sified 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 no t help the risk assessment for the exposure associated with wood preservative used in post

application residential setting.



## 3.2 Dietary Exposure

As part of the human health risk assessment for Polymeric betain e, 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 t he 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

. A dditionally, 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 e xpected 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.pdf17 Environmen tal 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 n o residue chemistry data are needed to characterize drinking water e xposures.



## 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 exposure s

. 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

- relate d exposure from the Health and Safety Executive, United Kingdom ( HSE ) which is worker survey data ( MRIDs 45808312/
45843707 based on the study b y Garrod, et al .,1999, ”Exposure to Preservatives Used in the
Industrial Pre

- treatment of Timber, Ann. Occup. Hy g ., 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 bel ieves that i t 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 propri etary surrogate wood treatment data for examining handler a pplication s 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 handler s
at wood pressure treatment facilities

. Since no residential hand ler 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 a nd 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=41618 (U.S.EPA 2006 and SAP 2007)

. As a result, EPA anticipates the need to conduct a human health
risk assessment afte r 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 anticipat es 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 rou tes 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 th e 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 B etaine

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 charg e 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 Polymer ic betaine since
no residential handler scenarios are expected.19 

### 3 .3.3 Occupational Post

- Application Exposures

For pressure treatment of wood, all o f 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 Exposur es
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 fro m 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 t o 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 P o lymeric 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 mecha nism 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 r egistration 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 tha t 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. Th e Agency is concerned with the compounds that leach from wood
which are DDAC and boric acid.



### 4.1.1 Environmental Fate of Polymeric B etaine

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 DD AC and boric acid, it has no relevant vapor pressure, flammability, or melting point. 5 It is completely miscible in water 6 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 a s 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 hydrolysis 7 (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 days 10 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 dealkylated 12 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 dete cted.

For polymeric betaine, t he non

- io nized state of active ingredient (quaternary cation) i s 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 combi ned. 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 usin g all data points

12 Loss of one decyl (C 10 ) chain21 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 s oil 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/m 3 , 97

- 99 % retention was observed. 14 The maximum le aching rates in treated southern yellow pine were 1.8, 2.5, 3,3, and 4.6 ug/cm 2 /day for the 3, 5, 7, and 9 kg/m 3 treatments, respectively. 15 The cumulative leaching rates were 18, 23, 31, and 38 ug/cm 2 for 3, 5, 7, and 9 kg/m 3 , 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 range 17 and stable to photo

- degradation in pH 7 buffered aque ous 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 stu dy. 20

The half

- lives under aerobic aquatic conditions 21 (representing surface water) and anaerobic aquatic metabolism 22 (representing bottom sediment) were 180 and 261 days, respectively.

In a wastewater treatment plant (WWTP), DDAC was not readily biodeg radable in an OECD
301B CO 2 evolution test. The 301B test guideline requires that 60 % of the theoretical carbon dioxide (ThCO 2 ) be produced in 28 days, and only 52 % of ThCO2 was produced for DDAC. However, DDAC was shown to have inherent, primary biode gradability 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 K ads 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 4138530122 Bioaccumulation of DDAC in freshwater fish is not likely to occur. The m ean 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 organi sms

. 25

I nformation 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 envi ronment as a result of natural and anthropogenic sources , and b oric
acid and boron

- containing salts are ubiquitous in the environment. B oron 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 pe rcentage 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 b e 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 Model s 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 en vironmental 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, t here will be some potential for leaching for the

tre ated wood . The terrestrial uses are not un likely 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 sediment 30 and any res idues 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). Cati on 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/g23 more tightly sorbed (opposite charges a ttract). 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 values 32 (pH 5

- 7) in the anionic (negatively

charged) state with all three oxygen molecules being deprotonated. This conclusion is based on the pKa values 33 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 be cause 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 ex posure, 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 label 34 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 piling s , utility poles, foundation, and railway ties. The UC4 classification assumes ground contact and is s ubdivided into UC4A (general use) 35 , UC4B (heavy duty) 36 , and UC4C (extreme duty) 37 . The UC5 classification
assumes mari ne 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
ecol ogical 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). Cati on Exchange Capacity Fact Sheet http://nmsp.cals.cornell.edu/publications/factsheets/factsheet22.pdf

32 Environmental p H 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 att ack

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 B etaine 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 borat e 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 togeth er by the Agency as “Cluster I [alkyl or hydroalkyl (straight chain) substituted] q uats and boric acid .” Therefore, in order to determine the exposure and risk to wildlife, plants, and aquatic organisms, toxicity endpoints and environmental fate character istics 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 inver tebrates. Boric
aci d 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 ecotox icity 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

- off25 literature are tabulated in Appendix C along with the data requirements and data gaps. T he 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 LC 50 = 0. 27 ppm MRID# 00007958

Chronic Data gap

Freshwater invertebrates Waterflea Acute 48

- h EC 50 = 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 LC 50 = 0.96 ppm MRID# 432 6 0001

Chronic No ne

--

Estuarine/marine invertebrates Mollusk Acute EC 50 = 0.094 ppm MRID#
43260003 Shrimp Acute LC 50 = 0.069 ppm MRID# 41578004

Chronic None

-- Estuarine/marine benthic
invertebrates Subchronic/
Chronic No ne

--
Algae Nonlisted EC 50 = 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 N one NR

Listed No ne NR

Birds Northern
Bobwhite Acute LD 50 > 664 mg/kg

- bw MRID# 46768502

Mallard duck Subacute dietary LC 50 > 5620 ppm (30% mortality at

highest dose) MRID# 41785802

Chronic None

Mammals Acute LD 50 = 262 mg/kg MRID# 4139440 1

Chronic NOAEL = 10 mg/kg LOAEL = 20 mg/kg MRID# 41970401

Nontarget insects Honey bee Acute No ne NR Boric Acid Endpoints

Freshwater fish Bluegill Sunfish Acute 96

- h LC 50 = 1021 ppm MRID# 40594602

Chronic Data gap*

Freshwater invertebrates Waterflea Acute 48

- h EC 50 = 133 ppm MRID 40594601

21 day Daphnid Chronic NOAEC 6.4 ppm Data cited in Boric
Acid RED26 NR = Not Required

*Will use a cute to chronic r atio 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 DD AC. 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 q uotients 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 identif ied using EPA’s ECOTOXicology (ECOTOX) 41 database

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

te rrestrial plants, and wildlife. The ECOTOX database will be searched when the risk assessment
for Polymeric b etaine 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 functio nal
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, neurotoxici ty, 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 maturati on, 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/ecotox27 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 h umans 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 consi sts 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, 2013 42 and includes some pesticides schedul ed 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 P reliminary 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 pla n 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. T he 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 b etween 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 b etaine 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 quali ty 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 Assessme nt 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.htm29 

### 7.1.3 Environmental Justice

EPA seeks to achieve environmental justice, the fair treatment and meaningful involvement of all people, r egardless 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 o r 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

- population s 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 proce ss 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

pr ocess 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 techniq ues, 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.
Th us, 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 req uirements. All relevant information would be considered as part of a weight

- of

- the

evidence evaluation.

At this time, EPA believes that for certain endpoints, especially physical/chemical and fate properties, that SAR and QSAR might be effectively utilize d 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 toxicit y 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

mo re 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 pr edicted 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 ap plication
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) no t 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 betain e c ase.31 

## 9 References

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– Bobwhite quail: 10

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Onyx Chemical Co. (1982c) The acute toxicity of 10

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Shepler, K. 2009

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U.S. Environmental Protection Agency. High Production Volume Information System (HPVIS). http://www.epa.gov/hpvis/

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. Office of Pesticide Programs. Memorandum from N. Mottl to R. Whitiker. Sept. 2, 2009. D357957.

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. Office of Pesticide Programs. Memorandum from D. Aviado to M. Hartman. February 13, 2009. D338434, D353174, D355602

.

U.S. EPA. 2008. Risk Assessment and Science Support Branch’s (RASSB’s) Scoping Review of Impralit KDS. Memorandum from N. Coo k to A. Heyword. May 30, 2008. D352480

U.S. EPA. 2006. Environmental Fate Assessment of Didecyl dimethyl ammonium chloride (DDAC) for the Reregistration Eligibility Decision (RED) Document . Office of Pesticide Programs, Washington, DC.

U.S. EPA. 200 6. Ecological Hazard and Environmental Risk Assessment: Polymeric betaine

. Office of Pesticide Programs, Washington, DC.

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. Memorandum from D. Aviado to M. Hartman. September 22, 2006. D290031, D297992
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, Submitted September 24, 2001 by the American Chemistry Council’s Arsenical Wood Preservatives Task Force. D278302 (S604391). October 31, 2002. Versar, 200 6

. DDAC Modeling (TAF 1

- 4

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Submitted Studies by MRID : 411758

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422538

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432000

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432600

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458082

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458083

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458341

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Bioconcentration and Elimination of 14 C

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11696.0887.6104.140 . Unpublished study prepared by Springborn Laboratories, Inc.

458964

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A 96

- hr toxicity test with the freshwater alga ( Selenastrum capricornutum ).
Wil dlife International, Ltd.

46395605 Palmer, S.J. 2004. A flow

- through life

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463158

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rabbits . NOTOX B.V., The Netherlands. NOTOX Project 354994 , January 26, 2004. Unpublished.

46362301 Palmer, S.J. 2004. An early life

- stage toxicity test of Bardac 22C50 with the fathead minnow ( Pimephales promelas ). Wildlife International, Ltd. Report ID: 289A

155.

465047

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465224

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467685

- 01 2006. Sayres, L.E. Acute Toxicity to Bluegill Sunfish ( Lepo mis 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 T oxicology 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, acu te 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 . H owever, due to the corrosivity of the agent

, further dermal testing is not recommend ed

.

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 LD 50 male rats = 2,800

LD 50Female rats 700

– 2,800 III (1)

870.1200/ Acute dermal toxicity 2 No Study
available I

870.1300/ Acute inhalation toxicity 2 No Study
available I

870.2400/ Acute eye irritation 2 No Study
available I

870.2500/
Acute dermal irritation 2 No Study
available I

870.2600/
Skin sensitization 3 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 kn own 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 458 08213)
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 day s 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 f ound 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/oran ge 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 appearan ce. 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 sig nificant 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 chang es 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 f orestomach, 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 o f 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 wi th 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 seve rity 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. How ever, 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 4580821 2 )

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 ad justed 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, to tal 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 weigh ts, 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

- relat ed
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)/ Non

Guideline 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 g roups 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, 8443 and 263 mg/kg/day for females in the 28.5, 85.5 and 256.5

- mg/kg/day treatment groups, respectively.
Treatment

- relate d 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
obser vations 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.

Treatm ent

- 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 low er 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 o bserved 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 histopatholo gical 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 i n 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 45 808308)

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 LOAE L 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 siz e 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 / Gui deline and satisfies the guideline requirement for a developmental toxicity study (OPPTS 870.3700) in the rat.

Rabbit Developmental Toxicity Study ( MRID 4631581 6)

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 ingredien t) 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 an d 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 small45 fetuses; decreased incidence of upper and lower incisors being erupted and teeth still present in the gums; decreased ossifica tion 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 sa cral 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 h ind 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 A cceptable

- G uid eline 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 femal es) 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 F 1 generation was made when the pups were 4 days of age. F 1 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 F 1 males ; hunched posture in F 1 females), significantly decreased body weights and body weight gains (P and F 1 animals), significantly decreased body weights during gestation and lactation (P and F 1 dams), significantly increased relative food consumption during p re

treatment, gestation (except the last week), and the first week of lactation (F 1 animals), significantly decreased food consumption during the last week of gestation and lactation (F 1 dams), macroscopic changes including emaciation (P dams only) and enl arged cecum (P and F 1 dams), and microscopic changes (ovarian interstitial cell atrophy, as well as cervical, uterine, and46 vaginal atrophy in P and F 1 dams). Although food spillage was noted in P animals, males and females in previous studies with this tes t 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, th ese 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 w eight 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 t oxicity (diarrhea, piloerection, and lethargy in F 1 pups; piloerection, emaciation, lethargy, and hunched posture in F 2 pups), lower litter and pup body weights during lactation, and clinical signs of toxicity at necropsy (enlarged
cecum and/or distended c ecum with gas in F 1 pups; empty stomach or gastrointestinal tract in F 2 pups). Additionally, a decrease (nonsignificant) in the weaning index was observed in F 2 pups. Lower organ weights at weaning (brain, spleen, and thymus) were observed; however, this e ffect was considered secondary to decreased maternal body weight gain. High

- dose F 1 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 fe males). 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 we aning 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 rat s.


## 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

- d ay 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 calcu lations 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 decreased47 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 2 2% 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 opthalmologi c 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 wer e 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 organ s 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 hist iocytosis 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 significa nce level of p < 0.05 and the following additional findings were noted (compared48 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 increas e 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).



## Carcinogenici ty

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 Selec ti on 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 th e 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 Grou p 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 (37 5 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) didecylpolyoxethyl

ammonium 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 f or 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 in crease 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 car cinogenicity studies were (0%,0% , 7% and 4%), (0%,0%, 1%,and 4%), and (0,0,8%, and 8% ). Both the49 incidences of adenocarcinoma and adenoma were still within the findings in the historical control. Therefore, the Cancer Assessment Review Committee (CAR C) 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 Quat s (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 in dicate 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

gu idelines 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 cu ltured mouse lymphoma cells also proved negative (MRID 45808303 ). Finally, a n i n vivo u nscheduled DNA

s ynthesis in p rimary r at h epatocytes 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 mon omer 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 comp onent would not help the risk assessment for the exposure associated with wood preservative used in post

application residential setting. In the 2012 immunotoxicity risk assessment, boric acid/borate was found to have immunotoxic concerns. However, the NOA EL set for boric acid/borate was 250 mg/kg/day. The committee believes that the cu rrently 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 assessmen t is ≤ 9 mg/kg/day. Therefore, the committee agreed that the end

point selected for non

- immunotoxic effects should be conservative enough to protect against50 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

P arent substance : Polymeric B etai ne

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 P olymeric betaine is an equilibrium mixture of DDAC and boric
acid , it has no relevant v apor pressure, flammability, or melting point. 46 It is completely
miscible in water 47 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.

A biotic (chemical) degradation of Polymeric betaine is not a significant route of dissipation in
the environment. Polymeric betaine is stable to hydrolysis 48 (no hydrolyzable functional groups) and does not absorb light between 290 and 800 nm in wave length. 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) 50 does contribute to the dissipation of Polymeric betaine in the environment. The pare nt compound half

- lives ranged
from 83

- 107 days 51 for linear regression and 76

- 107 days. 52 The only non

- volatile organic degradate formed in the studies was M

- 1, a dealkylated 53 and hydroxylated quaternary ammonium compound.

The non

- io nized state of active ingredient (quaternary cation) i s 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 b oric
acid and boron

- containing salts are ubiquitous in the environment. B oron 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 (C 10 ) chain52 soils, water, fruits, vegetables, and forage crops. Boron is an es sential 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 p H 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 tetrahyd roxyborate 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 rep el). 54

Table B1 . Environmental Fate and Transport Properties of Polymeric B etaine

Property Value Comments/Reference

Hydrolysis (835.2120) Stable at pH 4, 7, and 9 47348101 55

Photodegradation in water (835.2240) No data but expected to be
stable 463158 28

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 Co operative Extension (2007). Cation Exchange Capacity Fact Sheet. http://nmsp.cals.cornell.edu/publications/factsheets/factsheet22.pdf

55 Required on 9/26/2006 and accepted o n 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.oecd

ilibrary.org/docserver/download/9731601e.pdf?expires=1370613694&id=id&accname=guest&checksum=13B8A1
B779D2A1112C61756FA423A21E

57 Photodegradation in Water. 835.2240. Adopted Octob er, 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

1 01 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 2/23/09 61 , 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 accept ed 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 be cause 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 835.41 00 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 (min or 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 Adsorption

Desorption (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

D 352480, 35560 2

, D358401

Sorption related to clay content (r 2 =0.99) 63

Field soil dissipation study Impralit KDS

Overall absorption was 16

- 17 kg/m 3

.
Boron absorption ~5.5 mg,
while betai ne 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.

D 352480, D 355602

Retention rate study (EN 113) Retention of 97

- 99 % by 2 days for treatment rates of
12

- 23 kg/m 3 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*10 0)/% 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, 2 008 information, 65
October 31, 2006
information 66

Special Leaching Study (E11

- 97) Maximum leaching rates of 1.8, 2.5, 3.3, and 4.6 ug/cm 2 /day for 3, 5, 7, and 9 kg/m 3 in pine.

Minimum leaching rates of 0.28, 0.33, 0.41, and 0.59 ug/cm 2 /day for 3, 5, 7, an d 9 kg/m 3 in pine.

Average leaching rates of 0.6, 0.8, 1.0, and 1.4 ug/cm 2 /day for 3, 5, 7, and 9 kg/m 3 in pine.

Cumulative leaching rates of 18, 23, 31, and 38 ug/cm 2 for 3, 5, 7, and 9 kg/m 3 in pine. 47497001 (leaching rate)

47 4 84101 (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 C 1).

The results indicate that Polymeric betaine and DDAC are moderately toxic to birds on
an acute oral basis. The studies a re 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 C 2.

The results indicat e 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 C 3). Further information on the mam malian 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 c orrosive 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 effects57 (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 f requently 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 b oth 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 r equired 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 su bmitted studies are presented in Table C 4.

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) F reshwater 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 C 5).

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 betain e 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 estuari ne/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 C 6)

.

The se 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 ear ly 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 t opic are available for DDAC, and are therefore included in this assessment (Table C 7).

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, blue

green alga, freshwater diatom, an d 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 C 8 , below. This study indicates that DDAC is toxic to algae at very low levels.59 

## Toxicity to Terrestrial Receptors

Table C 1. Acute Oral Toxic ity of Polymeric B etaine 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 LD 50 = 217 (167

- 298 mg/kg)

NOEL < 31 mg/kg) Moderately
toxic Yes 417858

- 03

Northern
bobwhite

(Colinus virginianus) DDAC, 50% 14

- day LD 50 = 54.4 (42.9

- 67.1 mg/kg)

NOEL < 39 mg/kg) Moderately
toxic Yes ACC258798

Table C 2. 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

LC 50 > 5620

ppm

NOEC = 562

ppm Yes 417858

- 02

Mallard, Anas platyrhynchos 50 14 day dietary

LC 50 > 5620

ppm

NOEC = 1780 Yes ACC25879860 ppm

Bobwhite quail, Colinus virginianus 80.8 8 day dietary

LC 50 >5620

ppm

NOEC = 1780

ppm Yes 417858

- 01

Bobwhite quail, Colinus virginianus 50 8 day dietary

LC 50 > 5620

ppm

NOEC = 3180

ppm Yes ACC258798

Table C 3. 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 LD 50 =262 mg/kg (combined)

LD 50 =331 mg/kg (males)

LD 50 =238 mg/kg (females) II

870.1100

(§81

- 1) Acute oral, rat

(Purity 80%) MRID 42296101 LD 50 =238 mg/kg (combined) II

870.1200

(§81

- 2) Acute dermal, rabbit

(Purity 65%) MRID 42053801 LD 50 =2930 mg/kg (combined)

LD 50 =3140 mg/kg III61 Table C 3. Acute Toxicity Profile for DDAC

Guideline
Number Study Type/ Test substance (% a.i.) MRID Number/
Citation Results Toxicity Category

(males)

LD 50 =2730 mg/kg (females)

870.1300

(§81

- 3) Acute inhalation, rat

(Purity not reported) MRID 00145074

TRID 455201010 LC 50 (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. NA62 

## Toxicity to Aquatic Receptors

Table C 4. 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 C 5. Acute Toxicity of Polymeric B etaine 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 C 6. 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
#436 2 00

- 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

- 0464 mg/L

Table C 7. 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 =
1 981 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 C 8. 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

- 0265 

# Appendix D Product Chemistry

Polymeric betaine product chemistry information is summarized in Table D 1 (source: MRIDs 45808205, 45808206, and 45808207 ).

Table D 1

– P roduct Chemistry of Polymeric B etaine

Guideline
No. Physical and Chemical Properties Polymeric B etaine

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

. I nfusion electros pray ionization mass spectrometr y 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 M ildly 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 t emperature proved to be stable

. Stable at 50 ° C for 28 days.

830.6314 Oxidation/Reduction D oes not contain any oxidizer

830.6315 Flammability Flash point: 235 ° F (112.8 ° C )

830.6316 Explodability Not explo dable

.

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 wavelengths66 Guideline
No. Physical and Chemical Properties Polymeric B etaine

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
E xists 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 emuls ifier.

830.7840 Solubility in water Completely miscible with water

. 830.7860 Solubility in organic solvents Soluble in o rganic solvents.

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