### 2 H alohydantoins R egistration Review Team

Human Health William H azel Timothy Dole Jenny Tao

Environmental Fate and Effects Pat Jennings Srinivas Gowda Najm Shamim William Erickson

Risk Management Sandra O’Neill Rose Kypriano u

Office of General Counsel Philip Ross

### 3 

## Table of Contents
1 Introduction

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

................................ ................................ ................. 5 1.2 Updates to the Workplan

................................ ................................ ................................ .. 6 1.3 Ca se Overview

................................ ................................ ................................ ................. 8 1.4 Chemical Identification and Properties

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

................................ ................................ ................................ ... 10 1.5.1 Summary of Registered Uses

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

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

................................ ................................ ................................ ......... 12 1.6.1 Recent/Pending Regulatory Actions

................................ ................................ ....... 12 1.6.2 Tolerance Information

................................ ................................ ............................ 13 1.7 Incidents

................................ ................................ ................................ ......................... 13 1.7.1 Human Health

................................ ................................ ................................ ......... 13 1.7.2 Ecological

................................ ................................ ................................ ............... 14 2 Anticipated Da ta Needs

................................ ................................ ................................ ........ 14 3 Human Health Risk Assessment

................................ ................................ ........................... 18 3.1 Existing Toxicological Endpoints

................................ ................................ .................. 18 3.2 Dietary Exposure

................................ ................................ ................................ ............ 20 3.2.1 Food

................................ ................................ ................................ ........................ 20 3.2.2 Drinking Water

................................ ................................ ................................ ....... 20 3.3 Occupational and Residential Exposures

................................ ................................ ....... 20 3.3.1 Occupational Exposure

................................ ................................ ........................... 2 0 3.3.2 Residential Exposures

................................ ................................ ............................. 21 3.4 Aggregate and Cumulative Exposure

................................ ................................ ............. 22 3.4.1 Aggregate Exposures

................................ ................................ .............................. 22 3.4.2 Cumulative Exposures

................................ ................................ ............................ 22 4 Envi ronmental Risk Assessment

................................ ................................ ........................... 23 4.1 Environmental Fate Assessment

................................ ................................ .................... 23 4.2 Conceptual Models for Environmental Exposure Pathways

................................ .......... 25 4.3 Ecological Effects Assessment

................................ ................................ ....................... 34 4.3.1 Mechanism of Action

................................ ................................ .............................. 34 4.3.2 Measures of Effect (Ecotoxicology Endpoints)

................................ ...................... 34 4.4 Exposure Analysis Plan

................................ ................................ ................................ .. 37 4.4.1 Aquatic and Terrestrial Wildlife Exposure Estimates

................................ ............ 37 4.4.2 Screening Level Down

- the

- Drain Analysis

................................ ............................ 37 4.5 Effects Analysis Plan

................................ ................................ ................................ ..... 40 5 Endocrine Disruptor Screening Program (EDSP)

................................ ................................ . 40 6 Next Steps

................................ ................................ ................................ ............................. 41 7 References

................................ ................................ ................................ ............................. 42

Appendix A T oxicology Profile

................................ ................................ ............................... 43 Appendix B Environmental Fate

................................ ................................ ............................. 59 Appendix C Ecotoxicology Profile

................................ ................................ .......................... 63 Appendix D Ecotoxicity Profile for DMH and EMH

................................ .............................. 73 Appendix E Screening Level Down

- the

- Drain Analysis

................................ ........................ 80

### 4 Appendix F Product Chemistry

................................ ................................ ............................... 81 Appendix G Comments Received Concerning the Prelim inary Work Plan

............................ 83

List of Tables Table 1

– Summary of Anticipated Risk Assessments and Data Needs

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

– Anticipated Registration Review Schedule

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

- Chemical Identification of Halohydantoins

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

- Physical

- Chemical and Fate Properties for Halohydantoins

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

- Distribution of Products by Specific Halohydantoin

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

- Summary of Halohydantoin s Registered Uses

................................ .............................. 10 Table 7

- Incidents Reported for the Halohydantoins (2007 to 2013)

................................ .......... 14 Table 8

– Studies Anticipated as Needed for the Registration Review of Halohydantoins.

........ 14 Table 9

– Existing Human Health Toxicological Endpoints for DMH †



### ................................ ....... 19 Table 10

- Occupational Exposure Scenarios for the Halohydantoins

................................ ......... 21 Table 11

– Residential Exposure Scenarios for the Halohydantoins

................................ ............ 22 Table 12

– Selected Existing Effects Endpoints for Risk Assessment of Monohalohydantoins

.. 34 Table 13

– Selected Existing Effects Endpoints for Risk Assessment of DMH and EMH

.......... 35 Table 14

– Summary of Screening Level Down

- the

- Drain Analysis Results for Freshwater Fish and Invertebrates Exposed to DMH Assuming No Removal During Wastewater Treatment

..... 38 Table 15

– Summary of Screening Level Down

- the

- Drain Results for Freshwater Fish and Invertebrates Exposed to Monohalohydantoins Based on Extrapolation to BCDMH and Assuming No Removal During Wastewater Treatment

................................ ............................... 39

List of Figures Figure 1

– Conceptual Model for Ecological Exposure and Effects of Halohydantoin Degradates to Aquatic and Terrestrial Organisms from Cooling Water System Uses

................................ .... 27 Figure 2

– Conceptual Model for Ecological Exposure and Effects of Halohydantoin Degradates to Aquatic and Terrestrial Organisms from Pulp and Paper Mill Water Systems and Processing Water Systems

................................ ................................ ................................ .............................. 28 Figure 3

– Conceptual Model for Ecological Exposure and Effects of Halohydantoin Degradates to Aquatic and Terrestrial Organisms from Disinfectant/Sanitizers used on Hard Non

- porous Surfac es; Toilet Bowls and Urinals; Bathroom Premises; Hard Surfaces in Food Handling Establishments; Hard Surfaces in Commercial, Industrial, and Institutional Premises

................ 29 Figure 4

– Conceptual Model for Ecological Exposure and Effects of Halohydantoin Degradates from Oil Recovery Drilling Muds/Packer Fluids and Secondary Oil Recovery Injection Water to (A) Aquatic Organisms and to (B) Terrestrial Organisms

................................ ............................ 30 Figure 5

– Conceptual Model Diagram for Ecological Exposure and Effects of Halohydantoin Degradates from U se in Swimming Pools, Spas, Ornamental Ponds/Aquaria and HVAC and Humidifier Drip Pans to (A) Aquatic Organisms and (B) Terrestrial Organisms

........................ 31 Figure 6

– Conceptual Model Diagram for Ecological Exposure and Effects of Halohydantoin Degradates to Aquatic and Terrestrial Organisms from Use in Water Systems: Hydrostatic Sterilizer; Pasteurizer/Warmer/Canner/Retort; Transportation Clean ing

................................ ..... 32 Figure 7

– Conceptual Model Diagram for Ecological Exposure and Effects of Halohydantoin Degradates to Aquatic and Terrestri al Organisms from Use in Irrigation Systems and Influent Cooling Water Ponds, Lagoons, and Canals

................................ ................................ ................. 33

### 5 

# 1 Introduction

This document is the Environmental Protection Agency ’s (EPA or “the Agency ”) Final Work Plan ( F WP ) for halohydantoins . The PWP document explains what EPA's Office of Pesticide Programs knows about halohydantoins , highlighting anticipated data and assessmen t 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 the Halohydantoins registration review. This case includes the four dihalodialkylhy dantoins (PC Codes 006315, 006317, 028501, and 128826) which were evaluated in the 2007 Registration Eligibility Decision (RED) for Dihalodialkylhydantoins and also includes two dihalodialkylhydantoins (PC Codes 0 06322 and 128989) and a monohalodialkylhyda ntoin (PC Code 0 28500 ) that were registered after the November 1, 1984 cut

- off date involved in requiring REDs. Because this case contains both monohalo

- and dihalohydantoins

, this case is referred to herein as halohydantoins.

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

.



# 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 rev iew program is intended to make sure that, as the ability to assess risk evolves and as policies and practices change, all registered pesticides continue to meet the statutory standard of no unreasonable adverse effects to human health or the environment. Changes in science, public policy, and pesticide use practices will occur over time. Through the re gistration 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/r egistration_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 con tinues 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 i nitial docket is opened for each case. The docket is the Agency ’s opportunity to state what it knows about the pesticide and what additional risk analyses and data or information it believes are needed to make a registration review decision. The Halohydant oins Preliminary Work Plan (PWP) was published on June 26, 2013 and the 60

- day comment period ended on August 26, 2013. P ublic comments received concerning the PWP and documents associated with this registration review can be viewed at http://www.regulati ons.gov in docket EPA

- HQ

- OPP

- 2013

- 0220 . Below is a summary of the issues relevant to this registration review case.

### 6 

# 1.2 Updates to the Workplan

Since the publication of the PWP, the A gency has made the following updates:

• Corrected formatting and typographical errors.

• Consolidated data needs anticipated for the r egistration r eview and post

- RED DCIs

. A Tier I set of phototoxicty tests for DMH was listed as anticipated to be required for the post

- RED DCI

, t he registration review DCI list the same studies for Tier II ; as a result, the phytoxicity requirements listed for the post

- RED DCI are no longer anticipated to be required (comment 20) under the post

- RED DCI but are expected to be required by the registration review DCI

.

• Updated use site s triggering anticipated data requirements column for registration review GLN studies 875.1200, 875.1400, and removed footnote “ 1 ” from non surface residue studies in Table 8.

• Corrected the timeline in Table 2, the anticipated registration review table

.

• Revised Table 6, the summa ry of halohydantoin uses t able to include corrections to application rates

.

• Removed references of halohyda n toins as being used for preservation of products

.

• Corrected the title of a header in Appendix D to identify ECOSAR Version 1.10 Results for DMH

• Cor rected chemical information for monohalohydantoin throughout the FWP

.

• Updated the FWP to indicate that the halohydantoin granule and powder formulations are water soluble.

The Agency received 29 comments during the public comment period on the initial docket. See Appendix G for the Agency’s response s to these comments.

Comments received resulted in a modification to the anticipated data needs detailed in the Halohydantoins PWP

. T his document makes final the work plan for the Halohydantoins registration review process.

Table 1

– Summary of Anticipated Risk Assessments and Data Needs

Risk Assessment Assessment Necessary to Support Registration Review Date of Most Recent Assessment Type of Assessment Required (New/Updated) Data Anticipated as Needed (See Table 8 for more detail about anticipated d ata needs)

Dietary (food) Yes 12/3/12 Updated Residue data on processed fruits, vegetables, and meat product s Dietary (drinking water) Yes 12/3/12 Updated None

Occupational Handler Yes 09/10/04 Updated Inhalation Toxicity Dermal Exposure

– Indoor Inhalation Exposure

- Indoor

### 7 Risk Assessment Assessment Necessary to Support Registration Review Date of Most Recent Assessment Type of Assessment Required (New/Updated) Data Anticipated as Needed (See Table 8 for more detail about anticipated d ata needs)

Residential Handler Yes 09/10/04 Updated Inhalation Toxicity Dermal Exposure

– Indoor Inhalation Exposure

- Indoor

Residental Post Application

- Incidental Oral and Dermal Yes 09/10/04 Updated Indoor Surface Residues Bromate water concentration data for outdoor swimming pools 1
Aggregate Yes 12/3/12 Updated None

Cumulative No (see 3.4.2 ) N/A None None

Tolerance Review Yes N/A Updated None

Ecological Yes 09/10/04 Updated 2 Aquatic plants , fish, aquatic invertebrates

, seedling emergence in rice, vegetative vigor in rice, algal toxicity, activated sludge respiration inhibition , biodegradation in wastewater treatment plant N/A = Not applicable

1 Th ese data are needed to determine if bromate can be formed from the bromine that is released when bromohydantoin products are used in outdoor pools.

2 T he RED assessment was limited to freshwater fish and invertebrates exposed to the degradate DMH 

### ( 5,5

- dimethylhydantoin) in discharge waters from once

- through cooling systems; exposure to mono h alohydantoin needs to be assessed for freshwater and estuarine/marine organisms

. The updated assessment will also include

r ecirculating cooling systems, pulp and paper process waters, commercial and residential swimming pools, wastewater treatment systems, irrigation and automatic water distribution systems, recovery injection waters and drilling muds.



### 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

- 06 2013

- 06

- 26 Close Public Comment Period 2013

- 08 2013

- 08

- 26 Phase 2: Case Development Issue Final Work Plan 201 3

- 1 2 2013

- 12

- 3 0 Issue Data Call

- In (DCI) 201 4

- 12 Receive Data to be Considered in Risk Assessment 201 6

- 12 Open 30

- Day Public Comment Period for Preliminary Risk Assessment(s) 20 1 8

- 06 Close Public Comment Period 20 1 8

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

- Day Public Comment Period for Pro posed Decision 20 18

- 12 Close Public Comment Period 20 19

- 02 Issue Final Decision 20 19

- 06 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).

### 8 

# 1.3 Case Overview

The docket for the H alohydantoins Case (Case 3055 ) has been established at http://www.regulations.gov in docket number EPA

- HQ

- OPP

- 2013

- 0220

.
As discussed in the environmental fate section (see Section 4.1 ), halohydantoins are converted to degradate s, monohalohydantoin, 5,5

- dimethylhydantoin (DMH) or 5

- ethyl

- 5

- methylhydantoin (EMH). The Agency anticipates evaluating potential risk for halohydantoins based o n exposure to DMH and EMH for human health and on exposure to monohalohydantions, DMH, and EMH for ecological risks.



# 1.4 Chemical Identification and Properties

Table 3 presents the active ingredient s to be assessed in C ase 3055: Halohydantoins (PC Codes 006315, 006317, 006322, 028500, 028501, 128826 and 128989).

Table 3

- Chemical Identification of H alo h ydantoins

PC Code CAS No. Chemical Name ( Classification : Halogenated Alkylh ydantoin) Molecular Formula Mol. Wt. ( g/mol) Molecular Structure

006315 16079

- 88

- 2

, 32718

- 18

- 6 1

- Bromo

- 3

- chloro

- 5,5

- dimethylhydantoin 1

- Bromo

- 3

- chloro

- 5,5

- dimethyl

- 2,4

- imidazolidinedione Bromochloro

- 5,5dimethylimidazolidine

- 2,4

- dione ( BCDMH ) C 5 H 6 BrClN 2 O 2 241.47

006322 126

- 06

- 7 3

- Bromo

- 1

- chloro

- 5,5

- dimethylhydantoin 3

- Bromo

- 1

- chloro

- 5,5

- dimethyl

- 2,4

- imidazolidinedione ( BCDMH ) C 5 H 6 BrClN 2 O 2 241.47

006317 77

- 48

- 5 1,3

- Dibromo

- 5,5

- dimethylhydantoin 1,3

- Dibromo

- 5,5

- dimethyl

- 2,4

- imidazolidinedione (DBDMH) C 5 H 6 Br 2 N 2 O 2 285.92

028500 6921

- 17

- 1 1

- Chloro

- 5,5

- dimethylhydantoin 1

- Chloro

- 5,5

- dimethyl

- 2,4

- imidazolidinedione (CDMH) C 5 H 7 ClN 2 O 2 162.57

028501 118

- 52

- 5 1,3

- Dichloro

- 5,5

- dimethylhydantoin 1,3

- Dichloro

- 5,5

- dimethyl

- 2,4

- imidazolidinedione (DCDMH) C 5 H 6 Cl 2 N 2 O 2 197.02

### 9 PC Code CAS No. Chemical Name ( Classification : Halogenated Alkylh ydantoin) Molecular Formula Mol. Wt. ( g/mol) Molecular Structure

128826 89415

- 87

- 2 1,3

- Dichloro

- 5

- ethyl

- 5

- methylhydantoin 1,3

- Dichloro

- 5

- ethyl

- 5

- methyl

- 2,4

- imidazolidinedione ( DCEMH ) C 6 H 8 Cl 2 N 2 O 2 211.045

128989 91112

- 66

- 2 1

- Bromo

- 3

- chloro

- 5

- ethyl

- 5

- methylhydantoin 1

- Bromo

- 3

- chloro

- 5

- ethyl

- 5

- methyl

- 2,4

- imidazolidinedione ( BCEMH ) C 6 H 8 BrClN 2 O 2 255.49



### The halohydantoins product chemistry information relevant to risk assessment is summarized in Table 4 and details of the environmental fate properties are discussed in Appendix B and product chemistry information in Appendix F

.

Table 4

- Physical

- Chemical and Fate Properties for Halohydantoins

Guideline Numbers PC Code/AI
006315 BCDMH 006322 BCDMH 006317 DBDMH 028500 CDMH 028501 DCDMH 128826 DCEMH 128989 BCEMH
830.7000 pH at 25°C 6.5 (l% slurry at 25°C)

830.7050 UV/Visible Absorption UV max=260nm. Photolytically stable. Does not p hotolyze as it does not absorb UV light at wavelength s >260 nm

830.7200 Melting point (°C) 159

– 163 163

- 164 197

- 203 157.97 130

- 133 131.08 184.58

830.7370 Dissociation Constant pKa(s) pKa(s) ranged from 7.48 to 7.56 .

830.7550 Log Kow − 0.94

− 0.94

− 0.94

− 0.61

− 0.94

− 0.45 0.74

830.7840 Solubility in
water 0.22 g/100 g at 25°C 0.22 g/100 g at 25°C 0.1 g/100 g at 20 °C 0.20 g/ 100 g at 25 oC 0.21 g/100 g at 25 oC 0.1 g/100 g at 20 °C 0.1 g/100 g at 20 °C

830.7950 Vapor pressure mm Hg at 25 °C 6.61x10 - 6 3.54x10 - 6 1.2x10 - 6 9.31x10 - 7 2.4x10 - 5 1.29x10 - 5 1.87x10 - 8

Source: MRIDs 147318

, 35011701, 41952701, 41952801, 42478501, 43315902 a nd EPI Suite v4.1

### 10 

# 1.5 Use/Usage Description

1.5.1 Summary of Registered Uses
There are 119 products that contain one or more of the halohydantoins

. The distribution of products by specific halohydantoin is presented in Table 5 . Many of the products contain two or three halohydantoins

. The percent a.i , which is expressed as the total amount by weight of halohydantoins

, ranges from 6 .5 to 99.4 with many products containing more than 90 percent a.i. Most of the products are formulated as pellets/table t s or water soluble granules and a few products are formulated as water soluble powders

.

Table 5

- Distribution of Products by Specific H alohydan t oin

Chemical Name PC C ode Number of Products Percent

a. i

. Formulations

1

- Bromo

- 3

- chloro

5,5

- dimethylhydantoin 0 06315 99 4 to 99 Pellet/Tablet, Water Soluble Granul e , Solid Flowable Concentrate, Solid Soluble Concentrate, Water Soluble Powder 1,3

- Dibromo

- 5,5

- dimethylhydantoin 006317 14 8 to 99 Pellet/Tablet, Crystalline, Solid Soluble Concentrate 3

- Bromo

- 1

- chloro

5,5

- dimethylhydantoin 0 06322 1 96 Technical Only

– No end use products

1

- Chloro

5,5

- dimethylhydantoin 028500 1 90 Solid Soluble Concentrate
1,3

- Dichloro

5,5

- dimethylhydantoin 028501 44 1.8 to 97 Pellet/Tablet, Water Soluble Granul e , Solid Soluble Concentrate/Solid 1,3

- Dichloro

5

- ethyl

- 5

- methylhydantoin 128826 43 0.7 to 16.1 Pellet/Tablet, Water Soluble Granul e , Solid Soluble Concentrate 1

- Bromo

- 3

- chloro

5

- ethyl

- 5

- methylhydantoin 128989 1 98 Pellet/Tablet



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

. The halohydantoins can be applied by the following application methods: spra y, wipe, mop, placement or attachment of a solid and open pour of a solid.

Table 6

- Summary of Halohydantoins Registered Uses

Use Application Rate (Halohydantoin) Notes Regarding Specific Products

(EPA Reg. No.) Aquatic Areas

L akes/ponds/reservoirs (without human or wildlife use) O rnamental ponds/aquaria Spa water systems S wimming pool water systems 20 to 70 ppm 3.6 to 120 ppm 50 to 150 ppm 2.8 to 16 ppm N/A N/A N/A N/A 

### Commercial/Institutional/Industrial (CII) Premises and Equipment
Transportation Cleaning (Car Wash Water Systems) 3 to 24 ppm ( 6836

- 115 ) A



### Food Handling Premises and Equipment

### 11 Use Application Rate (Halohydantoin) Notes Regarding Specific Products

(EPA Reg. No.)
Beverage Can Rinsing F ood processing water systems Pasteurizer/ warmer/cannery cooling water systems 12 to 100 ppm 3.6 to 108 ppm 3.6 to 120 ppm (6836

- 115) A
N/A N/A



### Industrial Processes and Water Systems

A ir conditioner/refrigeration condensate water systems A ir washer /scrubber water systems W ater cooling systems

- Recirculating W ater cooling systems

- once thru E vaporative condenser water systems

– recirculating H eat exchanger water systems

– recirculating A uxiliary water systems P rocessing water

– recirculating Photographic processing wash water Pulp and paper processing water Oil Drilling Muds and Packer Fluids Oil Recovery Injection Water, Secondary S ewage and Waster Water Treatment systems Not Calculated C
3.6 to 120 ppm 3.6 to 120 ppm 3. 5 to 71 ppm 3.6 to 120 ppm 3.6 to 120 ppm 3.6 to 3.7 ppm 2.4 to 120 ppm 2.3 ppm 89 to 120 ppm Not Specified Not Specified 3.6 to 120 ppm N/A N/A N/A N/A N/A N/A N/A N/A N/A N/A ( 6836

- 114) B (6836

- 117) B
N/A



### Residential and Public Access Premises

A nimal kennels/sleeping quarters (commercial) Hard surfaces ( floors, tables , sinks, bathtubs) D omestic/commercial nonpotable water (waterbed water) R efuse/solid waste containers ( garbage cans ) T oilet bowls (interior surfaces) 30.4 ppm 30.4 ppm 22 to 40 ppm 30.4 ppm 25 to 46 ppm N/A ( 6836

- 324 ) A
N/A N/A N/A A. This is the only end use product label that has this use. B. These labels are formulation intermediates. The application rates are not specified on these labels. C. Products are tablets that are placed in condensate drain pans.



## 1.5.2 Usage Information
According to the Kline Biocides R eport for 2004/2005 (Kline, 200 6 ), the estimated volume consumption for the halohydantoins in 2004 was 31.7 million pounds with 22.5 million pounds used for recreational water and 9.2 million pounds used for cooling water systems . There was no usage reported f or the other registered use s of halohydantoins

. In the recreational water market segment, which includes swimming pools and spas, the halohydantoins make up 17 percent of the estimated U.S. consumption of specialty biocides by volume and 9 percent by val ue. They are generally sold in tablet form and the application rate is 3 to 5 ppm chlorine. The halohydantoins dominate the spa sanitizer market segment because they dissolve more slowly at the higher temperatures maintained in spas. The halohydantoins are reportedly not used in outdoor pools because bromine is not stable in sunlight (Kline, 200 6 )

. Because product labels do not specify that products must be used in indoor pools, for the purpose of the risk assessment, EPA will assume that products could potentially be used outdoors.

In the cooling water market segment, the halohydantoins make up 26 percent of the estimated U.S. consumption of specialty biocides by volume and 27 percent by value.

### 12 

# 1.6 Regulatory History

The first pesticide product containing a halohydantoin w as registered in October 1961

. 

### This case includes the four dihalodialkylhydantoins (PC Codes 006315, 006317, 028501, and 128826) which were evaluated in the 2007 RED for halodydantoins but also includes two dihalodialkylhydantoins (PC Codes 006322 and 128989) and a monohalodialkylhydantoin (PC Code 0 28500 ) that were registered after November 1, 1984.

The Agency has determined that cases 5101(Bromochloro

- 5

- ethyl

- 5

- methyl

- 2,4

- imidazolidinedione) and 5005 (2,4

- Imidazolidinedione, 3 bromo chloro

- 5,5

- dimethyl ) will be incorporated into the dihalohydantoins case (3055). The justification is supported by 40 CFR 155.42(b)(4) which indicates that the Agency may merge two or more registration review cases into a single registration review case. Thus, under registration review, cases 5105, 5005, and 3055 are being merged into one case. This case will be referred to as the halohydantoins case (3055). Therefore, the halohydantoins case (3055) now includes:

1) 1

- Bromo

- 3

- chloro

- 5,5

- dimethylhydantoin 1

- Bromo

- 3

- chloro

- 5,5

- dimethyl

- 2,4

- imidazolidinedione Bromochloro

- 5,5dimethylimidazolidine

- 2,4

- dione (BCDMH) (PC code 006315) ;

2) 1,3

- Dibromo

- 5,5

- dimethylhydantoin 1,3

- D ibromo

- 5,5

- dimethyl

- 2,4

- imidazolidinedione (DBDMH) (PC code 006317);

3) 1,3

- Dichloro

- 5,5

- dimethylhydantoin 1,3

- Dichloro

- 5,5

- dimethyl

- 2,4

- imidazolidinedione (DCDMH) (PC code 028501);

4) 1,3

- Dichloro

- 5

- ethyl

- 5

- methylhydantoin 1,3

- Dichloro

- 5

- ethyl

- 5

- methyl

- 2, 4

- imidazolidinedione (DCEMH) (PC code 128826);

5) 1

- Chloro

- 5,5

- dimethylhydantoin 1

- Chloro

- 5,5

- dimethyl

- 2,4

- imidazolidinedione (CDMH) (PC code 028500) ;

6) 1

- Bromo

- 3

- chloro

- 5

- ethyl

- 5

- methylhydantoin 1

- Bromo

- 3

- chloro

- 5

- ethyl

- 5

- methyl

- 2,4

- imidazolidinedione (B CEMH); (PC Code 128989);

7) 3

- Bromo

- 1

- chloro

- 5,5

- dimethylhydantoin 3

- Bromo

- 1

- chloro

- 5,5

- dimethyl

- 2,4

- imidazolidinedione (BCDMH) (PC code 006322).



## 1.6.1 Recent/Pending Regulatory Actions

In August 2011 EPA received a pesticide petition (1F7914 and 1F7914.02) from Albemarle Corporation requesting, pursuant to section 408(d) of the Federal Food, Drug, and Cosmetic Act (FFDCA), 21 U.S.C. 346a(d), to amend 40 CFR part 180. The petitions seek to establish exemptions from the requirements of tolerances for DBDMH . T he notice of filing of the petitions can be found on regulations.gov in docket EPA

- HQ

- OPP

- 2011

- 1033

. This action is pending before the Agency

. Additionally, i n July 201 2

, the Agency received a request for a new

-

### 13 use amendment for a halohydantoin label for EPA registration number 6836

- GLE ; the proposed new use is for treatment of drinking water (docket ID # EPA

- HQ

- OPP

- 2012

- 0625)

.

EPA anticipates issuing the post

- RED DCI in the near future.



## 1.6.2 Tolerance Information

As discussed in Section 1.6.1 , the pesticide petition from Albemarle Corporation seeking to establish exemptions from the requirements of tolerances is pending before the Agency

. EPA has not established a tolerance or tolerance exemption for residues of halohydantoins in food resulting from registered uses. Based on the current uses, the Agency has identified the need to establish a tolerance and/or exemption from the requi rement of a tolerance in 40 CFR Part 180. EPA intends to establish the appropriate tolerances and/or exemptions in response to the petitions expected to be received from registrants supporting the following uses: hard surfaces in food handling establishmen ts, beverage can rinsing, and pulp and paper mill water systems

. These tolerances and/or exemptions would be established for the halohydantoin chemicals with the following PC codes: 028501, 028500, 006315, 028501, and 128826

.

FDA has established a food add itive regulation for use of the 1,3

- dihalogenated hydantoins (bromine and/or chlorine) as slimicide s in paper and p aperboard mill water systems at ≤1.0 kg/1000 kg dry weight fiber (21 CFR 176.300). A Food Contact Substance Notification (FCN No. 1118) is co nsidered to be safe by FDA for the use of DBDMH (P.C. Code 006317) on shell eggs (500 ppm available bromine) and in water for process ing fruits and vegetables (900 ppm available bromine) followed by a potable water rinse. S even other FCNs (Nos. 334, 357, 453, 775, 792, 1 102 , and 1190 ) are in effect for use in water and ice for processing beef, goat, pork, poultry, and sheep carcasses, parts, and organs.



# 1.7 Incidents

1.7.1 Human Health

A total of 174 human health incidents are listed in the OPP Inci dent System for the halo hydantoins for the years 2007 ( when the RED was written ) to April 2013, when the most recent search was conducted

. There are 2 human major (HB) incidents, 14 human moderate (HC) incidents, 150 human minor (HD) incidents and 8 human unspecified (HE) incidents. A
summary of these incidents is given in Table 7

. The two HB incidents involved exposures at treated spas. One of these i ncidents resulted in dermal irritation, urinary system pain and numbness in extremities from being in a spa that was alleged to have high bromine levels (the bromine was released from the bromohydantoin that was used to treat the pool) . The other incident involved throat irritation and vocal cord damage from being in a therapy pool that was alleged to be improperly maintained

. Ten of the HC incidents involved dermal reactions ( i.e. hives) and irritation from being in treated hot tubes or pools, four HC incidents involved respiratory irritation while handling a spa product, one HC incident involved eye irritation when a toddler got a spa product in her eye

, and one incident involved alleged constipation from being in a treated hot tub. In one of the dermal incidents, 40 to 50 users of a health club therapy pool experienced rashes after the pool was

### 14 converted from a salt generator to bromina ting tablets. Bacterial testing indicated that bacteria were not li kely the cause of the rashes.

The HD and HE incidents were reported only in aggregate form and the details of each incident were not included.

Table 7

- Incidents Reported for the Halohydantoins (2007 to 201 3 )

Product Type Number of Incidents H uman Fatality

(HA) H uman Major (HB) H uman Moderate (HC) H uman Minor (HD) H uman Unspecified (H E ) Toilet Bowl Cleaner ( i.e. hockey puck) 0 0 1 65 3 Pools and Spas (Mainly spa uses) 0 2 13 84 5 Industrial 0 0 0 9 0 Total of Above 0 2 14 150 8



## 1.7.2 Ecological

No halohydantoins ecological incidents have been reported in either OPP’s Ecological Incident Information System (EIIS) or the Incident Data System (IDS , version 1.8 ).


# 2 Anticipated Data Needs

Table 8 presents a summary of the data anticipated as being needed to support this registration review. As discussed in the environmental fate section ( see Section 4.1 ), halohydantoins are converted to degradates, monohalohydantoin, 5,5

- dimethylhydantoin (DMH) or 5

- ethyl

- 5

- methylhydantoin (EMH).

Table 8

– Studies Anticipated as Needed for the Registration Review of Halohydantoins

.

GLN Study Name Test Substance * Time Frame ( M onths

from DCI Receipt) Risk Assessment(s)

Data Will Support Use Site(s) Triggering Anticipated Dat a

Requirement Applicable Exposure Scenario (s)

Studies Anticipated to be Required through the Registration Review DCI

860.1500 Crop Field Trials TEP 18 Dietary Food processing, indoor Rinsing of processed fruits, vegetables and meat products

No GLN Migration/residue transfer TEP 18 Dietary Food handling, indoor Beverage can rinse Food contact surface sanitizer

860.1340 Analytical method for data collection DMH 18 Dietary Food handling and processing facilities Processed fruits, vegetables, meat products; migration

### 15 GLN Study Name Test Substance * Time Frame ( M onths

from DCI Receipt) Risk Assessment(s)

Data Will Support Use Site(s) Triggering Anticipated Dat a

Requirement Applicable Exposure Scenario (s)

860.1380 Storage stability DMH 18 Dietary Food handling and processing facilities Processed fruits, vegetables, meat products; migration

875.2300 Indoor Surface Residues 1 TGAI 12 Residential Post Application Hard surface disinfection Toddlers playing on treated floors

No GLN Bromate in Swimming Pool Water 10 TGAI 12 Residential Post Application Outdoor Swimming Pools Swimming in treated pools.

870.3465 90

- Day Inhalation Study DMH 12 Occupational Handler Residential Handler Industrial water cooling systems, pulp and paper, oil drilling and
recovery, sewage and water treatment systems Pools and Spas Hard surface disinfection Open Pour Granules Open Pour Powders Mop Application Wipe Application Trigger spray application

875.1200 14 Dermal Exposure

- Indoor TGAI or Surrogate 2 12 Occupational Handler Residential Handler Industrial water cooling systems, pulp and paper, oil drilling and
recovery, sewage and water treatment systems Pools and Spas Hard surface disinfection Open Pour Granules Open Pour Powders Mop Application Wipe Application Trigger spray application

875.1400 14 Inhalation Exposure

- Indoor TGAI or Surrogate 2 12 Occupational Handler Residential Handler Industrial water cooling systems, pulp and paper, oil drilling and
recovery, sewage and water treatment systems Pools and Spas Hard surface disinfection Open Pour Granules Open Pour Powders Mop Application Wipe Application Trigger spray application

875.1700 Product Use Information NA 12 Occupational Handler Residential Handler Industrial water cooling systems, pulp and paper, oil drilling and
recovery, sewage and water treatment systems Pools and Spas Hard surface disinfection All scenarios

### 16 GLN Study Name Test Substance * Time Frame ( M onths

from DCI Receipt) Risk Assessment(s)

Data Will Support Use Site(s) Triggering Anticipated Dat a

Requirement Applicable Exposure Scenario (s)

850.1300 Aquatic invertebrate life

- cycle toxicity, freshwater sp. mono

halohydantoin, 12 Aquatic organisms All uses Transport to the aquatic environment

850.1350 Aquatic invertebrate life

- cycle toxicity, saltwater sp. mono

halohydantoin, 12 Aquatic organisms All uses Transport to the aquatic environment

850.1400 Freshwater Fish Early Life Stage 7 mono

halohydantoin 12 Aquatic organisms All uses Transport to the aquatic environment

850.1400 Saltwater Fish Early Life Stage 7 mono

halohydantoin, 12 Aquatic organisms All uses Transport to the aquatic environment

850.4100 11 Seedling emergence, rice mono

halohydantoin, DMH 12 Aquatic organisms Industrial process and water systems and pools and
spas; all others 3 Transport to the aquatic environment

850.4150 12 Vegetative vigor, rice mono

halohydantoin DMH 12 Aquatic organisms Industrial process and water systems; all others 3 Transport to the aquatic environment

850.4400 13 Aquatic Plant Testing using Lemna
sp., mono

halohydantoin, DMH 12 Aquatic organisms Industrial process and water systems; all others 5 Transport to the aquatic environment

850.4500 13 Algal Toxicity mono

halohydantoin, DMH 12 Aquatic organisms Industrial process and water systems 4 ; all others 5 Transport to the aquatic environment

850.4550 Algal Toxicity

- Cyanobacteria mono

halohydantoin, DMH 12 Aquatic organisms Industrial process and water systems; all others 6 Transport to the aquatic environment

OECD 209 or

850.6800 Activated Sludge Respiration Inhibition or Modified Activated Sludge Respiration Inhibition 8 mono

halohydantoin 12 Activated sludge microorganisms All uses Transport to
wastewater treatment plant and aquatic environment

835.3110 835.3220 835.3280 835.3240 Ready biodegradability test or one of three biodegradation in activated sludge simulation tests 9 mono

halohydantoin 12

- 24 Activated sludge microorganisms All uses Transport to
wastewater treatment plant and aquatic environment

Studies Expected to be Required through the Anticipated Post

- RED DCI

850.1400 Invertebrate life

cycle testing

- fresh
water DMH 12 Ecological Once through cooling tower systems Transport to the aquatic environment

### 17 GLN Study Name Test Substance * Time Frame ( M onths

from DCI Receipt) Risk Assessment(s)

Data Will Support Use Site(s) Triggering Anticipated Dat a

Requirement Applicable Exposure Scenario (s)

875.1200 14 Dermal Exposure

- Indoor TGAI or Surrogate 2 12 Occupational Handler Industrial water cooling systems, pulp and paper, oil drilling and
recovery, sewage and water
treatment systems Open Pour Granules Open Pour Powders

875.1400 14 Inhalation Exposure

- Indoor TGAI or Surrogate 2 12 Occupational Handler Industrial water cooling systems, oil drilling and recovery, pulp and paper, sewage and
water treatment systems Open Pour Granules Open Pour Powders

875.1200 14 Dermal Exposure

- Indoor TGAI or Surrogate 2 12 Occupational Handler Residential Handler Pools and Spas Open Pour Granules Open Pour Powders

875.1400 14 Inhalation Exposure

- Indoor TGAI or Surrogate 2 12 Occupational Handler Residential Handler Pools and Spas Open Pour Granules Open Pour Powders

875.2800 Description of human activity TGAI or Surrogate 2 12

- 24 Occupational Handler Residential Handler All uses Open Pour Granules Open Pour Powders

* The Agency recognizes EMH will be the main breakdown degradate for halohydantoins containing the EMH rather than the DMH structure. For those registrants with the EMH structure, the Agency expects to be able to accept either EMH or DMH data if the data are found to be acceptable (except as noted)

. 1 If surface residue data are not available, then the standard assumption of 100 percent transferable surface residue will be used which might overestimate the risk.
2 It may be possible to use proprietary surrogate exposure data if data compensation issues are appropriately and adequately addressed.

3 F or all uses other than industrial process and water systems, the study is expected to be required only if the risk quotient from any aquatic plant growth Tier II study exceeds a level of concern for aquatic plants

4 For monohalohydantoin, t esting is expected to be required for a marine diatom, a freshwater diatom, and a green algae species . For DMH, testing is expected to be required for a marine diatom, a freshwater d iatom (but not for a green algae species). Final 850 guidelines for the algal testing were posted in June 2012. The Public Draft OPPTS 850.5400 Algal Toxicity guideline was split into two separate guidelines and renumbered with the cyanobacteria species se parated into OCSPP 850.4550 and the other three species under OCSPP 850.4500.

5 F or all uses other than industrial process and water systems, testing with green algae is expected to be required; if the I C 50 from that test is less than 1.0 ppm (mg/L), then testing with marine and freshwater diatom s is expected to be required

. 6 F or all uses other than industrial process and water systems , t esting with a cyanobacteria sp. is expected to be required only if the I C 50 from the green algae test is less than 1.0 ppm (mg/L)

. 7 If a species other than the most acutely sensitive (rainbow trout) is used for testing, an acute value is also expected to be required for the test species to allow calculation of an acute

- to

- chroni c ratio.

### 18 8 OCSPP 850.6800 may be used in place of OECD 209 if the test substance is not sufficiently soluble to allow preparation of a concentrated stock solution in water.

9 EPA published draft guidance under guideline OPPTS 850.6800 and has since published final guidance for this study under guideline OCSPP 850.3300: http://www.regulations.gov/#!documentDetail;D=EPA

- HQ

- OPPT

- 2009

- 0154

- 0021 . The Agency has inc luded this study in 40 CFR 158(W). OECD Test Guideline 209 can also be used as guidance for this study, available online at http://www.oecd

- ilibrary.org/content/book/9789264070080

- en

. The results of this ASRI test will determine which of four biodegradation tests is/a re required. If the ASRI test EC 50 is less than or equal to 20 mg/L, then either the (i )Biodegradation in Activated Sludge Study or (ii) Simulation Test

– Aerobic Sewage Treatment: A. Activated Sludge Units or (iii) the Porous Pot Test is expected to be required. If the ASRI test EC 50 is greater than 20 mg/L, then the registrant would likely be required to conduct either: (i) Ready Biodegradability or (ii) a) Biodegradation in Activated Sludge or b) Simulation Test

– Aerobic Sewage Treatment: A. Activated Sludge Units or c) the Porous Pot Test. If the Ready Biodegradability study is conducte d and passes, then no further testing would be expected to be required. If, however, the antimicrobial fails the Ready Biodegradability study, then the a) Biodegradation in Activated Sludge or b) Simulation Test

– Aerobic Sewage Treatment: A. Activated Slu dge Units, or c) the Porous Pot study would likely be required.

10 The anticipated DCI will require that a protocol be submitted to the Agency for review and approval prior to conduct of the study.

1 1 Test guidelines 850.4100 and 850.4225 were merged and h armonized into OCSPP 850.4100 in a Federal Register Notice dated June 27, 2012 (FRL

- 9333

- 1).

1 2 Test guidelines 850.4 150 and 850.425 0 were merged and harmonized into OCSPP 850.41 5 0 in a Federal Register Notice dated June 27, 2012 (FRL

- 9333

- 1).

1 3 EPA changed t est guidelines 850.4400 “Aquatic Plant Toxicity Test Using Lemna Spp., Tiers I and II” and
850.4500 “Algal Toxicity, Tiers I and II” by removing “Tiers I and II” from the title in a Federal Register Notice dated June 27, 2012 (FRL

- 9333

- 1).

14 Dat a reporting and calculations are expected to be required when handler exposure data are submitted



# 3 Human Health Risk Assessment

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

. The Agency anticipates the need to require additional data for use in conducting the registration review.



# 3.1 Existing Toxicological Endpoints

T oxicological endpoints were selected for various exposure scenarios in a quantitative human health risk assessment for the hal ohydantoins RED in 2007. The degradate of all the halohydantoins in the presence of water is 5,5

- Dimethylhydantoin (5,5

- DMH or DMH) . It is formed rapidly and is the only degradate of toxicological concern for this class of antimicrobials. Thus, for the RE D as well as in registration review, the Agency supports use of DMH as the subject of the hazard (toxicity studies) component of risk. T hese t oxicologica l endpoints may be revised when conducting the risk assessment for the halohydantoins registration review. A summary of the existing human health t oxicological endpoints , which w as included in the 2007 RED, is provid ed in Table 9 below

.

### 19 Table 9

– Existing Human Health Toxicological Endpoints for DMH †

Exposure Scenario Dose Used in Risk Assessment, UF * Level of Concern for Risk Assessment Study and Toxicological Effects

Dietary Exposures (Includes FQPA SF of 1) Acute Dietary (f

emales 13

- 50 years of age ) NOAEL = 100 mg/kg/day UF = 100

Acute RfD = 1 mg/kg aPAD = acute RfD FQPA SF

= 1mg/kg/day Developmental Toxicity

– rabbit (MRID 42413101)

Developmental LOAEL = 500 mg/kg/day, based on skeletal variations. Chronic Dietary a (all populations) NOAEL = 300 mg/kg/day UF = 100

Chronic RfD = 3 mg/kg/day cPAD = chronic RfD FQPA SF

= 3mg/kg/day Chronic toxicity/carcinogenicity

– rat (MRID 43397702)

LOAEL = 1000 mg/kg/day, based on ↓ body wt/wt gain and lymph node hyperplasia.
Chronic Dietary a (f

emales 13

- 50 years of age ) NOAEL = 100 mg/kg/day UF = 100

Chronic RfD = 1 mg/kg/day cPAD = chronic RfD FQPA SF

= 1mg/kg/day Developmental Toxicity

– rabbit (MRID 42413101)

Developmental LOAEL = 500 mg/kg/day, based on skeletal variations.
Occupational and Residential Exposures (Includes FQPA SF of 1 for Residential Exposure) Incidental Oral

- Short

- Term (1 month ) O ral NOAEL = 500 mg/kg/day MOE = 100 ( Residential ) developmental toxicity

– r abbit

LOAEL = 1000 mg/kg/day

, based on decreased body weight gain in maternal rabbits. Incidental Oral

- Intermediate

- Term (1

- 6 months) O ral NOAEL = 300 mg/kg/day MOE = 100 ( Residential ) subchronic oral toxicity

– ra t

LOAEL = 1000 mg/kg/day based on decreased body weight and liver weight.

Dermal

- Short

, Intermediate , and Long

- Term D ermal NOAEL = 390 mg/kg/day (HDT) MOE = 100 (Occupational)

MOE = 100 ( Residental ) subchronic dermal toxicity

- rats

No systemic toxicity at the highest dose tested

Short

- Term Inhalation (1 month ) Oral NOAEL=100 b mg/kg/day MOE = 100 (Occupational)

MOE = 100 ( R esidential) developmental toxicity

– r abbit

LOAEL = 500 mg/kg/day

, based on skeletal effects in offspring.

† This endpoint summary table was includ ed in the 2007 RED (RED, 2007.)

* UF = uncertainty factor, FQPA SF = FQPA safety factor, NOAEL = no observed adverse effect level, LOAEL = lowest observed adverse effect level, PAD = population adjusted dose (a = acute , c = chronic) RfD = reference dose, MOE = margin of
exposure

.

a The Hazard Identification Assessment Review Committee ( HIARC ) selected separate chronic RfDs for females, ages 13

- 50, and the general population because this was an unusual case where the developmental NOAEL was lower than the lowest NOAEL available for chronic toxicity (RED, 2007) . The rabbit d evelopmental toxicity study (MRID 42413101 ) was the refore selected to provide adequate protection for the female (age 13

- 50) subpopulation.

b A 100% inhalation absorption value is used for route

- to

- route extrapolation

### 20 

# 3.2 Dietary Exposure

3.2.1 Food Human dietary exposure to halohydantoin residues could potentially occur as a result of the registered use as a beverage can rinse, as a food contact surface sanitizer, and as a slimicide in pulp and paper water systems used to make food

- contact paper and paperboard. The Agency conducted an assessment of dietary risk resu lting from th e food

- contact paper and paperboard in the 2007 RED ; a cute and chronic dietary risks were ≤ 1.6 % of the aPAD and cPAD for males, females and children. The Agency anticipates requiring a dditional data to estimate dietary exposure due to the consumption of washed, processed fruits, vegetables, and meat products associated with FDA’s FCNs for this registration review

. Also, both acute and chronic dietary risk assessments reflecting exposures to halohydantoin residues in food are expected to be conducted.



## 3.2.2 Drinking Water

As discussed in Section 1.6.1 , the Agency received a request for a new

- use amendment for treatment of drinking water in 2012 for a halohydantoin label. In addition, c ontamination of drinking water with halohydantoin resid ues may occur as a result of discharge of waste water from paper and paperboard mills, swimming pools , irrigation systems, ornamental ponds, cooling water systems (recirculating and once

- through), oil recovery water systems, sewage and
waste water treatmen t, etc . In the 2007 RED, t he once

- through cooling tower use was selected as being the worst

- case surface water scenario. Although risks were not of Agency concern, an antiquated model Probabilistic Dilution Model 4 (PDM4) was used to estimate water concentrations. B oth acute and chronic dietary risk assessments reflecting exposures to halohydantoin residues in drinking wat er are expected to be conducted using the most recently developed model

. R esidue chemistry data are not anticipated to be required to characterize drinking water exposure s.



# 3.3 Occupational and Residential Exposures

3.3.1 Occupational Exposure
Occupational handler dermal and inhalation exposures to halohydantoins were assessed in the 2007 RED for handlers pl acing tablets/pellets or pouring powder into cooling or process water systems, greenhouse and nursery irrigation systems and greenhouse footbaths and vehicle wash stations. With the exception of the dermal MOE of 76 for placing solids in cooling water
sys tems and the dermal MOE of 14 for placing solids in greenhouse and nursery irrigation systems, all of the dermal MOEs exceeded 100 if gloves were worn as required by the labels. The inhalation MOEs exceeded 1,000 which meant that a confirmatory inhalation toxicity study was not needed. To mitigate the MOE of 14 for the irrigation use, the RED specified that the pellet/tablet products could only be used in irrigation systems that use less than 35,000 gallo ns per day. Mitigation was not specified in the RED for the MOE of 76 for the cooling water use because the RED stated that this MOE represented a high

- end estimate of risk.

### 21 Occupational post application exposures were not assessed in the RED because the halohydantoins and their degradates have a low vapor pressure and because the release of aerosols was not anticipated following application.

O ccupational handler exposures will need to be assessed for the application of halohydantoin hard surface disinfectants which could be applied using a trigger sprayer, mop or wipe because these exposures were not assessed in the RED. A listing of the exposure scenarios that need to be assessed is included in Table 10

. The Agency anticipates the need to require additional occupational handler exposure data for registration review

.

Table 10

- Occupational Exposure Scenarios for the Halohydantoins

Scenario Exposure Route(s) Duration

Handler Exposures Open pour granules and powder for pool treatment

Dermal Inhalation Short and Intermediate Term Open pour granules and powders for cooling water
treatments Mop, wipe and trigger spray application for disinfection (Medical and CII premise and equipment) Post Application Exposures
None

- Post application exposures are not anticipated. N/A N/A



## 3.3.2 Residential Exposures

Residential handler dermal and inhalation ex posures were assessed in the RED for halohydantoins for handlers placing tablets/pellets into pools and spas.

Residential post application dermal, inhalation and incidental oral exposures were assessed in the RED for adult and children competitive and non

- competitive swimmers swimming in treated pools. The MOEs ranged from 1,400,000 to 7,100,000 for dermal exposures, 38,000 to 100,000 for inhalation exposures and 12,000 to 190,000 for incidental oral exposure. All of these MOEs exceeded the target MOE of 100.

It is important to note that the swimmer exposure assessment s included in the RED were based

on DMH , which is the primary degrad ate when the halohydantoins are used in indoor pools

. E xposures to bromates , which are potential degradate s when the bromo hyda ntoins are used in outdoor pools, were not evaluated because it was assumed in the RED that the halohydantoins were only used indoors. Although the Kline Report (Kline, 200 6 ) mentions that the halohydantoins are not used in outdoor pools because bromine is not stable in sunlight, the labels do no t preclude their use in outdoor pools. Therefore

, potential exposure from this route will be evaluated as part of the risk assessment for registration review.

Residential handler exposures will need to be assessed for the application of h alo h ydantoin hard surface disinfectants which could be applied using a trigger sprayer, mop or wipe. The Agency anticipates the need to require additional residential handler exposure data for registration review

. The post application exposure to toddlers playing on treat ed floors also needs to be assessed

. In addition, the post application bromate exposure to swimmer s in outdoor pools will

### 22 need to be assessed ; therefore, t he Agency anticipates the need to require additional residential post application data for registration review

. A listing of the residential exposure scenarios that need to be assessed is included in Table 11

.

Table 11

– Residential Exposure Scenarios for the Halohydantoins

Scenario Exposure Route(s) Duration

Handler Exposures Open pour granules and powder for pool treatment Dermal and Inhalation Short and Intermediate Term Mop, wipe and trigger spray application for hard surface disinfection 

### Post Application Exposures Swimming in Treated Outdoor Pools (Bromate) Incidental oral and Dermal Short and Intermediate Term Toddlers playing on disinfected floors



# 3.4 Aggregate and Cumulative Exposure

3.4.1 Aggregate Exposures

Human dietary (food) exposures to the persistent hydantoin degradate DMH are expected from the pulp and paper mill slimicide use . Human exposure to DMH residues in drinking water is expected as a result of dis charges of waste water from treated pulp and paper mills, swimming pools, and a wide variety of industrial water systems. Also, human exposure to DMH residues derived from the hydantoins in residential settings may occur in association with swimming pools, and products to disinfect surfaces such as floors. Thus, dietary (food and drinking water) and residential sources of exposure are associated with pesticidal use of the hydantoins and are likely to contribute to the aggregate risks. Therefore, aggregate r isks are anticipated to be assessed during the risk assessment period of this registration review.



## 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 the halohydantoins and any other subst ances and the halohydantoins do not appear to produce a toxic metabolite produced by other substances. For the purposes of this registration review, therefore, EPA has not assumed that the halohydantoins have a common mechanism of toxicity with other subst ances. 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 the policy statements released by EPA’s Office of Pesticide Programs at http://www.epa.gov/pesticides/cumulative/ http://www.epa.gov/pesticides/cumulative/ http://www
.epa.g ov/pesticides/cumulative/

.

### 23 

# 4 Environmental Risk Assessment

The ecological risk assessment planned during registration review will allow the Agency to determine potential acute and chronic risks to aquatic organisms exposed to halohydantoins that are transp orted from treatment sites into the aquatic environment. Such sites include recirculating and once

- through cooling systems, pulp and paper process waters, commercial and residential swimming pools, wastewater treatment systems, irrigation and automatic wa ter distribution systems, and oil recovery injection waters and drilling muds.

The Agency has not conducted a risk assessment that supports a complete endangered species determination for halohydantoins. The ecological risk assessment planned during reg istration review will allow the Agency to determine whether halohydantoins’ use has 'no effect' or 'may affect' federally listed threatened or endangered species (listed species) or their designated critical habitats. When an assessment concludes that a pe sticide’s use 'may affect' a listed species or its designated critical habitat, the Agency will consult with the U.S. Fish and Wildlife Service and/or National Marine Fisheries Services (the Services), as appropriate.



# 4.1 Environmental Fate Assessment

Mode of activity of halohydantoins :
Dihalodialkyhydantoins contain two halide (chloride or bromide) ions

. Dih alo dialkyl

- hydantoins are designed such that in solution the loss of a halide (chloride or bromide) is the first step. The second step is the hydr olysis of the halide ion in solution as indicated by equation 1 for a chlorine ion :

Cl - 

### + H 2 

### O

---  HOCl + OH - 

### (1)

A similar reaction takes place with bromide ion s

. Therefore hypochlorous acid ( HOCl ) , an d hypobromous acid ( HOBr ) are the active moie ties and these in turn dissociate to form OCl - 

### and OBr - 

### which also act as active moieties ( It should be noted that hypobromous ions may convert to bromate ions which are known carcinogens )

. However extreme conditions are needed for a conversion ; f or example , the presence of a strong oxidizing agent like hypochlorite ions and or continuous exposure to sunlight. In the present system conversion to bromate is not likely to take place as the concentrations of hypochlorous and hypobromous ions are kept at lower level ( EPA 2005 )

. The Agency has n ot conducted an environmental fate risk assessment for these halohydantoins . But based on the in

- house fate data ( ACC 263903 and MRID# 42466201, see Appendix B for fate summaries ) , i t is assumed that halohydantoins reach the environmental media as mono halo dialkyl hydantoins.

D i halo dialkyl hydantoins hydrolyze, unde r abiotic conditions, los ing the first halide with a half life of less th an an hour . The loss of the second halide occurs with a half life of less than a day at pH 5, 7 and 9. Thus halohydantoins are stripped of the halide moieties and are converted to D MH or EMH within twenty four hours (ACC# 263983, and MRID# 42466201)

. Similar results are obtained for aquatic photolysis at pH 7 where the halohydantoins are photoly z ed to DMH within twenty four hours (MRID# 42466201)

.

### 24 Halohydantoins are highly water soluble (from one gram to 14 g /L, EPI Suite, version 4.1) , and have an estimated half lif e in air of less than two days or a maximum of two days (EPI Suite, version 4.1) , and therefore are not considered persistent in air. Halohydantoins have low vapor pressures under ambient conditions. Th ese pestici des appear to have borderline Henry Law C onstant s of 10 - 6



### – 10 - 8 

### atm

- m 3 

### /mole (EPI Suite, version 4.1) to slightly higher values which makes some of these substances slightly volatile from the surface water and some of these will volatilize mor e from surface water. The halohydantoins have lo w log Kow of

- 0.39 (EPI Suite, version 4.1) and hence are not likely to bioaccumulate in the aquatic organisms. The halohydantoins have low Koc values on the order of about 4.6 L/kg (EPI Suite, version 4.1) and will have a tendency to migrate into soils

, thus if applied to land would possibly contaminate surface water.

Exposure in the environmental media like water or soils is likely to be through monohalohydantoins and DMH moieties. As halohydantoins are s tripped of halides quickly, the common degradate s that would rea ch the environmental media are DMH or EMH

. The Agency has not conducted an environmental fate risk assessment for DMH but b ased on the fate data of DMH, the following paragraph explains the f ate profile: (see Appendix B for fate summaries) :

DMH is hydrolytically stable at pH 5, 7, and 9 under abiotic condition (MRID# 408046

- 01)

. The half life is extrapolated to be over a thousand days 1



### . A similar tendency of a long half life is observed for the DMH in an aquatic photolysis st udy. DMH is persistent in aerobic soil conditions (a long half life of over a year, M RID# 408046

- 03 ) as well as in aerobic and

an aerobic aquatic systems (half life over a month , MRID# 408046

- 04, and MRID# 408046

- 07 ). However, DMH does not bind strongly with soils as it has small K ads 

### which varies from 0.051 to 0.138 in different soils (MRID# 408046

- 06) and is lik ely to migrate into ground water. It has small log K ow 

### of

- 0.39 (MRID# 408652

- 01) and so it is not likely to bioaccumulate . Thus, due to its persistence in aquatic and soil systems, there is potential for aquatic organism exposure in surface water and to humans in drinking water. It is stable in soils, but is also highly water soluble. Thus it is not likely to be found in biosolids or sediments

. The fate risk assessment for halohydantoins, will include dialkylhydantoins ( DMH and EMH) as well as monohal ohydantoins. It should be no t ed that the Agency has assumed that the environmental fate of DMH and EMH would be similar in environmental media. Based on hydrolytic half

- life data for dihalodialkylhydantoins (ACC 2639 8 3; MRID 42466201)

, monohalohydantoins could be present in the environment for up to 24 hours at up to 50% of the initial concentration of dihalodialkylhydantoins released down

- the

- drain.

The Agency has not conducted a risk assessment on halohydantoins

, nor on the major degradate s DMH or EMH

. The Agency anticipate s the need to require wastewater studies (biodegradation and activated sludge respiration inhibition) for monohalohydantoins

. Although there may be high exposure potential for DMH and EMH

, the risk potential may be low . Although the re may be potential for drinking water exposure to monohalohydantoins and DMH, it appears that due to negligible toxicity the amounts of DMH that would trigger a potential risk for aquatic organisms would be much higher than the production volume (see Sect ion 4.4.2 )

. According to an initial screening level estima tes from DtD modeling for DMH, it would take over 300,000,000 kg/yr of

1 Extrapolation is done by estimating the percent degradation of the active on day 30, which is the duration of the study, and the time at which it will degrade. This is just an estimation, and not a rigorous value.

### 25 DMH to trigger one day of exceedance for endangered freshwater fish ( s ee Section 4.4.2 for a complete discussion of the screening level down

- the

- drain analysis)

.



# 4.2 Conceptual Model s for Environmental Exposure Pathways
Based on the summary of registered uses of halohydanto ins presented in Table 6 and physical/chemical properties and environmental fate data presented in Appendix B, the Agency has developed conceptual model diagrams for exposure of ecological organisms to halohydantoins and their degradates. Under abiotic co nditions and pH values of 5, 7, and 9, which are typical of pH values that occur under ambient environmental conditions, the experimentally

- determined hydrolytic half

- life is less than an hour for halohydantoins to form monohalohydantoins and less than a d ay for monohalohydantoins to form the hydantoins, DMH

or EMH (ACC 263903; MRID 42466201) . Chemicals that are released down

- the

- drain can typically take from a few to several hours to reach wastewater treatment plant intakes following their discharge and f rom several hours to roughly a day following their discharge down

- the

- drain to subsequently be discharged from wastewater treatment plants to surface water. Since the hydrolytic half

- life for removal of one halogen from halohydantoins is expected to be le ss than an hour and removal of both halogens is expected to be less than a day, monohalohydantoins, DMH , and EMH would be expected to enter wastewater treatment plants as a result of down

- the

drain discharges of halohydantoins. Unless biodegradation durin g wastewater treatment is determined to be a significant removal process for halohydantoin degradates entering wastewater treatment plants, based on a half

- life for removal of both halogen atoms from halohydantoins via hydrolysis at pH values of 5, 7, and 9 of less than one day, aquatic organisms in surface water downstream of both direct and indirect sources of halohydantoins would be expected to be exposed primarily to the degradates, DMH, EMH , and monohalohydantoins.

No laboratory studies were found on t he toxicity of monohalohydantoins to aquatic organisms and results from the ECOSAR class program provide conflicting information regarding toxicity of monohalohydantoins to aquatic organisms. Depending on where the halogen is attached to the hydantoin rin g, ECOSAR predicted very high toxicity by extrapolation to chemicals in the haloimide class, with toxicity similar to halohydantoins or practically no toxicity by extrapolation to chemicals in the neutral organics class, with toxicity similar to DMH. In t he absence of aquatic toxicity data for monohalohydantoins, it will be assumed that monohalohydantoins are as toxic as halohydantoins

. Under abiotic conditions, DMH is hydrolytically stable at pH values of 5, 7, and 9, with a half

life extrapolated to be a thousand days based on results of a hydrolysis test that examined degradation of the parent chemical over a 30

- day period. DMH also appears to be fairly stable in anaerobic aquatic systems with an experimentally

- determined half

- life of over a year determ ined in flooded sandy loam soil (MRID 408046

- 04). The low log K ow 

### and high solubility of DMH in water (EPI Suite, version 4.1) indicates that it is not likely to partition to suspended solids and aquatic sediments or to biosolids in wastewater treatment p lants. In aerobic soil environments, the half

- life of DMH has been determined to be over a year (MRID 408046

- 03). DMH does not bind strongly to soils (MRID 408046

- 06) and therefore, if present in soil, may have the potential to migrate to ground water.

### 26 Although monohalohydantoins, DMH, and EMH are expected to be discharged to wastewater treatment plants, no data were found regarding their biodegradability during wastewater treatment. If a chemical substance is present in a biotic environment and is susc eptible to biotic fate processes, half

- lives could be shorter than half

- lives determined solely on abiotic processes that occur in an abiotic environment.

The halohydantoins have numerous registered uses. Use sites and corresponding figures of conceptual model diagrams are as follows:

- Cooling water systems (Figure 1);

- Pulp and paper mill water systems and processing water systems (Figure 2);

- Disinfectant/Sanitizer: hard non

- porous surfaces; toilet bowls and urinals; bathroom premises; hard surfaces in food handling establishments; hard surfaces in commercial, industrial, and institutional premises (Figure 3);

- Oil recovery drilling muds/packer fluids and secondary oil recovery injection water (Figures 4a and 4b)

- Pools, spas, ornamental ponds/aquaria ; and HVAC and humidifier drip pans (Figure 5 a and 5b );

- Water systems: hydrostatic sterilizer; pasteurizer/warmer/canner/retort; transportation cleaning ; photo processing water; and sewage and wastewater treatment systems (Figure
6 ); and

- Irrigation systems and influent cooling water ponds, lagoons and canals (Figure 7 );

The screening

- level risk assessment that will be conducted as part of this registration review will evaluate potent ial risks to ecological organisms from exposure to the degradates of halohydantoins: DMH

, EMH , and monohalohydantoins.

### 27 Figure 1

– Conceptual Model for Ecological Exposure and Effects of Halohydantoin Degradates to Aquatic and Te rrestrial Organisms from Cooling Water System Uses



### 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 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 Cooling Tower (Once Through and/or Recirculating)

WWTP microorganisms Uptake or sorption

Population Respiration inhibition Direct Discharge

Surface Water

Sediment Volatilization

Terrestrial birds and mammals

Inhalation
exposure pathway

### 28 Figure 2

– Conceptual Model for Ecological Exposure and Effects of Halohydantoin Degradates to Aquatic and Terrestrial Organisms from Pulp and Paper Mill Water Systems and Processing Water Systems



### 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 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 On

- Site/Off

- Site Waste Water Treatment Plant (WWTP )

Key Most likely

exposure pathway contributing to risk Low likelihood of contributing to risk Pulp and Paper Mill Use

WWTP microorganisms Uptake or sorption

Population Respiration inhibition Disposal to On

- or Off

- Site WWTP

Terrestrial Soils (Biosolids Application) Air stripping

See Section X.X Treated water

reuse

Surface Water

Sediment Terrestrial birds and mammals

Inhalation
exposure pathway see

Figure (B) Volatilization

### 29 Figure 3

– Conceptual Model for Ecological Exposure and Effects of Halohydantoin Degradates to Aquatic and Ter restrial Organisms from Disinfectant/Sanitizers used on Hard Non

- porous Surfaces; Toilet Bowls and Urinals; Bathroom Premises; Hard Surfaces in Food Handling Establishments; Hard Surfaces in Commercial, Industrial, and Institutional Premises



### 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 Aquatic Animals Invertebrates Vertebrates 

### Exposure Media

Ingestion Ingestion Uptake/gills or integument

Aquatic Plants
Non

- vascular Vascular Uptake or sorption by

cells, 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 Waste Water Disposal Down

- the

- Drain

Surface Water

Sediment In

- Service Use of Disinfectants or Sanitizers on Indoor Surfaces,

Textile and Plastic/Rubber Material Preservative Use Sites

### 30 Figure 4

– Conceptual Model for Ecological Exposure and Effects of Halohydantoin Degradates from Oil Recovery Drilling Muds/Packer Fluids and Secondary Oil Recovery Injection Water to (A) Aquatic Organisms and to (B) Terrestrial Organisms

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 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 Deep Well Injection

Key Most likely

exposure pathway contributing to risk Low likelihood of contributing to risk Biocides in Oil and Gas Extraction Drilling Muds/Fluids, Hydraulic, Fracking Fluids, Primary, Secondary and Tertiary (Enhanced Oil) Recovery Fluids

WWTP microorganisms Uptake or sorption

Population Respiration inhibition Recovered Water/Fluids (Flowback

and Produced), Muds Disposal Migration into Groundwater (A)

Waste Water Treatment Plant (WWTP) Migration into Groundwater
Exposed Groundwater from Soil Applications see Figure (B) Surface Water

Sediment

Stressor

Source/ Exposure Media

Receptors and Exposure Routes

Attribute Change(s) Individual organisms Reduced survival (emergence*) Reduced growth Reduced reproduction** Food chain 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 Terrestrial Animals Birds (Reptiles, Amphibians) Mammals

Ingestion (B)

Key Most likely

exposure pathway contributing to risk Low likelihood of contributing to risk Recovered Water (Flowback and Produced) Open Pit Storage or Evaporation Pond Biocides in Oil Drilling Muds/Packer Fluids

, Hydraulic and Secondary Oil Recovery Injection Water

Irrigation Water Recovered Water (Flowback and Produced) Disposal

Terrestrial plants Grasses/forbs, fruit, seeds, trees, shrubs Contact/Uptake leaves, stems

Ingestion

*Refers to seedling emergence **Vegetative vigor and seedling emergence endpoints are assumed to be as sensitive or more sensitive than reproduction endpoint and plant reproduction s not explicitly evaluated. Soil

Root uptake Soil Leaching

Groundwater

See Figure (A) for aquatic exposure pathways

### 31 Figure 5

– Conceptual Model Diagram for Ecological Exposure an d Effects of Halohydantoin Degradates from Use in Swimming Pools, Spas, Ornamental Ponds/Aquaria and HVAC and Humidifier Drip Pans to (A) Aquatic Organisms and (B) Terrestrial Organisms

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 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 Use in Swimming Pools, Spas, Ornamental Ponds/Aquaria, HVAC and Humidifier Drip
Pans

WWTP microorganisms Uptake or sorption

Population Respiration inhibition Disposal of Water to sanitary drain system Disposal of w ater to stormwater drain (A)

Surface Water

Sediment Soil See Figure (B ) Disposal of water to

ground s urface

Stressor

Source/ Exposure Media

Receptors and Exposure Routes

Attribute Change(s) Terrestrial insects

Individual organisms Reduced survival (emergence*) Reduced growth Reduced reproduction** Food chain Reduction in plant biomass 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 Terrestrial plants Grasses/forbs, fruit, seeds, trees, shrubs

Terrestrial Animals Birds (Reptiles, Amphibians) Mammals Soil

Ingestion Ingestion Dermal uptake/

Ingestion Root uptake

Beneficial Insects Reduced survival

*Refers to seedling emergence **Vegetative vigor and seedling emergence endpoints are assumed to be as sensitive or more sensitive than reproduction endpoint and plant reproduction s not explicitly evaluated. (B)

Key Most likely

exposure pathway contributing to risk Low likelihood of contributing to risk Use in Swimming Pools, Spas, Ornamental Ponds/Aquaria, and HVAC and Humidifier Drip Pans
Disposal of water to

ground surface

### 32 Figure 6

– Conceptual Model Diagram for Ecological Exposure an d Eff ects of Halohydantoin Degradates to Aquatic and Terrestrial Organisms from Use in Water Systems: Hydrostatic Sterilizer; Pasteurizer/Warmer/Canner/Retort; Transportation Cleaning



### 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 Water Systems: Hydrostatic sterilizer; pasteurizer/warmer/canner/retort; transportation cleaning

WWTP microorganisms Uptake or sorption

Population Respiration inhibition Down

- the

- drain disposal

### 33 Figure 7

– Conceptual Model Diagram for Ecologic al Exposure an d Effects of Halohydantoin Degradates to Aquatic and Terrestrial Organisms from Use in Irrigation Systems and Influent Cooling Water Ponds, Lagoons, and Canals



### Stressor

Source

Receptors and Exposure Routes

Attribute Change(s) Irrigation Systems and Influent Cooling Water, Ponds, Lagoons, and Canals

Leaching

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 Aquatic Animals Invertebrates Vertebrates 

### Exposure Media

Ingestion Ingestion Uptake across gills or integument and/or sediment ingestion

Aquatic Plants
Non

- vascular Vascular Uptake or sorption by cell, roots, or 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 Key Most likely

exposure pathway contributing to risk Low likelihood of contributing to risk Surface Water Sediment

### 34 

# 4.3 Ecological Effects Assessment

4.3.1 Mechanism of Action
In the aquatic environment, toxic action of these active ingredients is largely due to the formation of hypochlorous acid or hypobromus acid when chlorine and bromine are released and react with
water (EPA 1985; Singleton 1989) . Adverse effects are due ma inly to corrosive action (EPA 1985; Singleton 1989) . Acute necrosis may occur (EPA 1985; Singleton 1989)

.


## 4.3.2 Measures of Effect (Ecotoxicology Endpoints)

Ecological effects data are used as measures of direct and indirect effects to aquatic and terrestrial organisms

. All available ecotoxicity endpoints from dihalohydantoin and DMH studies submitted by registrants are tabulated in Appendix C and Append ix D along with the data requirements and data gaps

. The most sensitive values for each receptor group are used for the risk assessment (Table 1 2 )

. Although DMH and EMH are acutely practically nontoxic to aquatic organisms ( Appendix D ), a screening level down

- the

- drain (DtD) risk assessment was performed for DMH (anticipated to have a higher loading than EMH) that is released to surface water via domestic WWTPs since there is potential for high amounts of DMH to be released to surface
wat er downstream of wastewater treatment plants to which halohydantoins may be discharged ( s ee 4.4.2 for specific details of this analysis)

.

No data a re available for monohalohydantoin s , and uncertainties exist as to its toxicity. Depending on where the single halogen is attached to the hydantoin ring, ECOSAR (v. 1.11) predicts that monohalohydantoin may be as highly toxic as dihalohydantoin or nontoxi c as is DMH. Because of this uncertainty, and in the absence of any actual toxicity data, the Agency assumes that monohalohydantoin is as highly toxic as dihalohydantoin. Additional toxicity data for aquatic and semi

- aquatic plants are needed for monohal ohydantoin as specified in Table 12

.

Table 12

– Selected Existing Effects Endpoints for Risk Assessment of Monoh alohydantoins

Receptor Group Surrogate Species Risk Scenario Toxicity Endpoint Reference (MRID)

Birds Mallard duck

-- Acute Oral LD 50 = 873 mg DCDMH eq /kg bw 00142071 Subacute Dietary LC 50 > 5620 mg DCDMH ppm

- diet Acc 253073 & 71

Chronic Not Required

--

Mammals Acute LD 50 524 mg DCDMH eq /kg

- bw 1 93076011; 00137105
Chronic Not Required

--

Freshwater fish Rainbow trout Acute 96

- h LC 50 = 0. 32 m g DCDMH
eq /L 00147323

Chronic Data Gap: Data anticipated to be required, need an early life stage for the most acutely sensitive species.

Freshwater invertebrates Waterflea Acute 48

- h EC 50 = 0.47 mg DCDMH
eq /L 00084524

Chronic Data Gap: Data required

--

### 35 Receptor Group Surrogate Species Risk Scenario Toxicity Endpoint Reference (MRID)

Freshwater benthic invertebrates -- Subchronic or Chronic Data not required: Not expected to be associated with sediment --

Estuarine/marine fish Sheepshead minnow Acute LC 50 = 1.2 mg ai/L 40993103

Chronic Data Gap: Data anticipated to be required --

Estuarine/marine invertebrates Eastern oyster Acute I C 50 = 0.86 mg Br 2 /L 40993101

Mysid Acute LC 50 = 0.92 mg Br 2 /L 40993102

Chronic Data gap: Data anticipated to be required --

Estuarine/marine benthic invertebrates -- Subchronic or Chronic Data not anticipated to be required: Not expected to be associated with sediment --

Aquatic Nonvascular plants Non

- listed Data gap: Data anticipated to be required (one green algae, one marine diatom, one freshwater diatom, one cyanobacteria sp.) -- Listed

Aquatic vascular Non

- listed Data gap: Data anticipated to be required -- Listed

Semi

- aquatic rooted plants/ Terrestrial plants Seedling emergence Non

listed Data gap: Data anticipated to be required -- Seedling Emergence Listed Vegetative Vigor Non

- listed Data gap: Data anticipated to be required -- Vegetative Vigor Listed

1 760 mg DBDMH/kg

- bw * 0.448 = 524 mg DCDMH equivalents/kg

- bw



### Table 13

– Selected Existing Effects Endpoints for Risk Assessment of DMH and EMH

Receptor Group Surrogate Species Risk Scenario Toxicity Endpoint Reference (MRID)

Birds Northern bobwhite

Acute Oral LD 50 : >2250 mg/kg

- bw Acc 253966 Subacute Dietary LC 50 >5000 mg/kg

- bw 43289904

Chronic Data not required

Mammals Rat Acute LD 50 >5000 mg/kg

- bw

Chronic Data not required

Freshwater fish Rainbow trout Acute 96

- h LC 50 = 12,700 mg/L 00046053

### 36 Receptor Group Surrogate Species Risk Scenario Toxicity Endpoint Reference (MRID)

Chronic DMH: NOAEC = 12.7 mg/L EMH: NOAEC = 1.2 mg/L Used ACR method 1 for DMH ECOSAR v 1.10 for EMH

Freshwater invertebrates Waterflea Acute 48

- hr LC 50 : 6051 mg/L 00046053

Chronic DMH: NOAEC = 6.0 mg/L EMH: NOAEC = 4.8 mg/L Used ACR method 2 for DMH Used ECOSAR v 1.10 for EMH

Freshwater benthic invertebrates -- Subchronic or Chronic Data not anticipated to be required: Not expected to be associated with sediment --

Estuarine/marine fish Sheepshead minnow Acute 96

- hr LC 50 : 8,100 mg/L 00046053, 93075035

Chronic DMH: NOAEC = 8.1 mg/L EMH: NOAEC = 3.8 mg/L Used ACR method 2 for DMH Used ECOSAR v1.10 for EMH

Estuarine/marine invertebrates Eastern oyster Acute 96

- hr IC 50 : >125 mg/L 43289902

Mysid Acute LC 50 >921 mg/L 42373602

Chronic Data not anticipated to be required: Will use results for fish as a conservative screen for risks to mysid. ECOSAR v1.10 indicated mysid are expected to be less sensitive than saltwater fish acutely.

Estuarine/marine benthic invertebrates -- Subchronic or Chronic Data not anticipated to be required: Not expected to be associated with sediment --

Aquatic Nonvascular plants -- Non

- listed Data gap: Data anticipated to be required (one marine diatom, one freshwater diatom, one cyanobacteria sp.) -- Listed

Aquatic vascular

-- Non

- listed Data gap: Data anticipated to be required Listed

Semi

- aquatic rooted plants/ Terrestrial plants -- Seedling emergence Non

listed Data gap: Data anticipated to be required -- Seedling Emergence Listed

-- Vegetative Vigor Non

- listed Data gap: Data anticipated to be required Vegetative Vigor Listed

1 Most sensitive acute species rainbow trout value was divided by an acute

- to

- chronic ratio (ACR) of 1000 (see Appendix D ) from freshwater fathead minnow data

. 2 Assumed the ACR f rom a freshwater fish (1000) is applicable (see Appendix D )

.

### 37 

# 4.4 Exposure Analysis Plan

4.4.1 Aquatic and Terrestrial Wildlife Exposure Estimates

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



## 4.4.2 Screening Level Down

- the

- Drain Analy sis

The Down

- the

- Drain (DtD ) module of E

- FAST (Exposure and Fate Assessment Screening Tool) was used to determine the potential for aquatic organisms downstream of domestic wastewater treatment plants that receive discharges from end

- use of halohydantoins to be exposed to the degrad ates of halohydantoins : monohalohydantoins

, DMH , and EMH . The results of the DtD module runs are expressed as number of days of exceedance of concentrations of concern (COC) for aquatic organisms. A detailed description of derivation of data for input pa rameters selected to run the DtD module and of the theoretical bas is for this model is pr esented in Appendix E . A conservative assumption of no removal during wastewater treatment was used in DtD model

runs.

Chemicals that are released down

- the

- drain can typically take from a few to several hours to reach wastewater treatment plant intakes following their discharge and from several hours to roughly a day following their discharge down

- the

- drain to subsequently be discharged from wastewater treatment plant s to surface water. Since the half

- life for removal of one halogen from halohydantoins to form monohalohydantoins is expected to be less than an hour and removal of both halogens to form DMH and EMH is expected to be less than a day (ACC 263903; MRID 42466201) , monohalohydantoins, DMH , and EMH would be expected to enter wastewater treatment plants and subsequently be discharged to surface water downstream as a result of DtD discha rges of dialkyldi halohydantoins

. Although halohydantoi ns are generally highly toxic to aquatic organisms, their degradates, DMH and EMH , are practically nontoxic ( s ee Section 4.3.2) . No laboratory data have been found on the aquatic toxicity of the intermediate degradates of halohydantoins , monohalohydantoin s. In the absence of such data, the Agency used the ECOSAR class program (version 1.11) to estimate toxicity to the monohalohydantoin, chlorohalohydantoin. Results from the ECOSAR program provide conflicting information regarding the toxicity of chloroha lohydantoins to aquatic organisms. Depending on where the chlorine is attached to the hydantoin ring, ECOSAR predicted high toxicity, similar to halohydantoins , by extrapolation to chemicals in the haloimide class or practically no toxicity, similar to DM H, by extrapolation to chemicals in the neutral organics class. There is lower confidence in ECOSAR results estimated by extrapolation to the generic class, neutral organics ( f or more information, see Section 4. 3.2 ).

Given that large quantities of both monohalohydantoins and DMH would be expected to be released to the aquatic environment downstream of wastewater treatment plants to which halohydant oins would be discharged (Kline

, 200 6 ) and the uncertainty regarding the toxicity of monohalohydantoins to aquatic organisms (ECOSAR, version 1.11) , the DtD module of E

- FAST was used to estimate potential exposures to aquatic organisms for both DMH and

### 38 mon ohalohydantoins. The DtD analysis for DMH is intended to serve two purposes: (1) to demonstrate the maximum WWTP influent volume of halohydantoins that would trigger potential concerns for aquatic organisms exposed to DMH downstream of domestic wastewater treatment plants and (2) to evaluate potential exposures based on the assumptions that the total production volume of halohydantoins enters domestic wastewater treatment plants and that toxicity of monohalohydantoins is similar to that of DMH. A key purp ose of the DtD analysis for monohalohydantoins is to determine the lowest maximum annual WWTP influent volumes of halohydantoins that would trigger potential concerns for aquatic organisms downstream of domestic WWTPs assuming that monohalohydantoins are a s toxic as halohydantoins

.

Table 1 4 presents results of a screening

- level DtD analysis for the common non

- halogenated degradate of halohydantoins, DMH which, based on laboratory toxicity data for freshwater organisms, is practically nontoxic. Based on these aquatic toxicity data and the total annual production volume reported by Kline (200 6 ) for halohydantoins of 31.7 million pounds (14,300,000 kg) in 2004

, the DtD model predicted no exceedances of concentrations of concern for acute and endangered aqua tic organisms. In addition, a DtD analysis predicted that over 300,000,000 kg/yr of DMH would have to enter domestic wastewater treatment plants to result in an exceedance for one day of the concentration of concern (COC) for endangered freshwater fish

an d invertebrates. Furthermore, 70,000,000 kg/yr of DMH would have to enter domestic wastewater treatment plants to result in exceedance for one day of the chronic COC for freshwater fish.

Table 14

– Summary of Screening Level Down

- the

- Drain Analysis Results for Freshwater Fish and Invertebrates Exposed to DMH Assuming No Removal During Wastewater Treatment

WWTP Influent Volume Acute Freshwater Fish COC = 486,000 ug/L Endangered Freshwater Fish COC = 48,600 ug/L Freshwater Fish Chronic COC = 1 2

, 7 00 ug/L 14,300,000 kg/yr No exceedances No exceedances No exceedances 70,000,000 kg/yr No exceedances No exceedances 1.1 day per year 300,000,000 kg/yr No exceedances 1.4 days per year 20.5 days per year Acute Freshwater Invertebrates COC = 535,000 ug/L Endangered Freshwater Invertebrates COC = 53,500 ug/L Freshwater Invertebrates Chronic COC = no data available 14,300,300 kg/yr No exceedances No exceedances 300,000,000 kg/yr No exceedances 1.2 days per year

Table 1 5 presents inputs and results from screening level DtD model runs for monohalohydantoins based on total volume of halohydantoins reported to be consumed in 2004 (31.7 million pounds; 14,300,000 kg and volume halohydantoins repor ted to be used in recreational water in 2004 (22.5 million pounds; 10,200,000 kg) (Kline

, 200 6 ). Given that high amounts of halohydantoins are produced annually, that monohalohydantoins may persist long enough to be discharged at high levels downstream of domestic wastewater treatment plants, and that monohalohydantoins may be as toxic as halohydantoins , a screening level DtD analysis was performed for monohalohydantoins using concentrations of concern (COCs) for aquatic

### 39 organisms and the total volume cons umed in 2004 and the volume consumed in recreation water according to Kline (200 6 ) . The DtD model was also run to determine the lowest maximum annual production volume that would lead to exceedance of concentrations of concern for aquatic organisms.

Table 15

– Summary of Screening Level Down

- the

- Drain Results for Freshwater Fish and Invertebrates Exposed to Monohalohydantoins Based on Extrapolation to BCDMH and Assuming No Removal During Wastewater Treatment

WWTP Influent Volume Acu te Freshwater Fish COC = 200 ug/L Endangered Freshwater Fish COC = 20 ug/L Chronic Freshwater Fish COC = 14,000 ug/L for DCDMH (no data for BCDMH) 14,300,000 kg/yr 85 days per year 285 days per year 10,200,000 kg/yr 59 days per year 261 days per year 2,000,000 kg/yr 4 days per year 113 days per year 1,000,000 kg/yr < 1 day per year 56 days per year 200,000 kg/yr < 1 day per year 4 days per year 100,000 kg/yr < 1 day per year 1 day per year Acute Freshwater Invertebrates COC = 375 ug/L Endangered Freshwater Invertebrates COC = 37.5 ug/L Chronic Freshwater Invertebrates = no data

14,300,000 kg/yr 41 days per year 237 days per year 10,200,000 kg/yr 26 days per year 207 days per year 2,000,000 kg/yr 1 day per year 62 days per year 1,000,000 kg/yr <1 day per year 25 days per year 200,000 kg/yr < 1 day per year 1 day per year 100,000 kg/yr < 1 day per year < 1 day per year



### At the maximum annual volume of halohydantoins consumed, 14,300,000 kg/yr, assuming the wastewater treatment plant (WWTP) influent volume is equal to the maximum annual production volume, that there is no removal during wastewater treatment, and that monohalohydantoins are as toxic as BCDMH, the DtD model predicts the fol lowing exceedances of COCs for aquatic organisms: 85 days per year for non

- endangered freshwater fish; 41 days per year for non

endangered freshwater invertebrates; 285 days per year for endangered freshwater fish; and 237 days per year for endangered fres hwater invertebrates. At the volume consumed for recreational water, 10,200,000 kg/yr, the DtD model predicts the following exceedances of COCs for aquatic organisms : 59 days per year for nonendangered freshwater fish; 26 days per year for nonendangered freshwater invertebrates; 261 days per year for endangered freshwater fish; and 207 days per year for endangered freshwater invertebrates.

At a WWTP influent volume of 2,000,000 kg/yr, the DtD model predicts exceedances of COCs of more than 1 day for bot h non

- endangered and endangered freshwater fish and endangered freshwater invertebrates. At 1,000,000 kg/yr, the DtD model predicts no exceedances of COCs for non

- endangered aquatic organisms, but still predicts exceedances of the COC of 56 days for endan gered freshwater fish and exceedances of the COC of 25 days for endangered freshwater invertebrates. At 200,000 kg/yr, there are still exceedances of COCs for endangered freshwater fish (4 days per year) and for endangered freshwater invertebrates (1 day per year). Wastewater

### 40 treatment plant influent volumes would have to be less than 100,000 kg/yr to lead to no exceedances of COCs for endangered freshwater fish.

The substantially different DtD modeling results of number of days per year of exceedance of COCs for monohalohydantoins by extrapolation to COCs for DMH (See Table 1 4 ) versus results from extrapolation to COCs for BCDMH (Table 1 5 ) demonstrate the importance of determining the ecotoxicity of monohalohydantoins to determine whether they are more li ke DMH, which is practically nontoxic to aquatic organisms, or more like BCDMH, which is highly toxic to aquatic organisms.

This screening

- level analysis assumes that halohydantoins are released to domestic wastewater treatment plants. Based on registered uses of halohydantoins presented in Table 6 of this PWP, there are some uses, such as recirculating cooling water systems, for which discharges may enter surface directly without undergoing wastewater treatment. There are other uses, such as pulp and pap er processing water, for which discharges may enter industrial WWTPs rather than domestic WWTPs prior to entering surface water. Different methodologies for assessing potential exposures and associated ecological risks will be applied for these other type s of uses.



# 4.5 Effects Analysis Plan
Additional open literature studies will be identified through EPA’s ECOTOXicology (ECOTOX) database. The ECOTOX database will be searched when the risk assessment for the halohydantoins is prepared. Open literature studie s will be reviewed that potentially provide data for missing endpoint values or provide valu e s more sensitive than available from the registrant

submitted studies

. ECOTOX was created and is maintained by the US EPA ’s , Office of Research and Development, a nd the National Health and Environmental Effects Research Laboratory's Mid

- Continent Ecology Division.


# 5 Endocrine Disruptor Screening Program (EDSP)

As required by FIFRA and FFDCA, EPA reviews numerous studies to assess potential adverse outcomes from expos ure to chemicals. Collectively, these studies include acute, subchronic and chronic toxicity, including assessments of carcinogenicity, neurotoxicity, developmental, reproductive, and general or systemic toxicity. These studies include endpoints which may be susceptible to endocrine influence, including effects on endocrine target organ histopathology, organ weights, estrus cyclicity, sexual maturation, fertility, pregnancy rates, reproductive loss, and sex ratios in offspring. For ecological hazard assessm ents, EPA evaluates acute tests and chronic studies that assess growth, developmental and reproductive effects in different taxonomic groups. As part of the 2007 RED f or the h alohydantoins , 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), h alohydantoins are subject to the endocrine screening part of the En docrine Disruptor Screening Program (EDSP).

EPA has developed the EDSP to determine whether certain substances (including pesticide active and other ingredients) may have an effect in humans or wildlife similar to an effect produced by a “naturally occurr ing estrogen, or other such endocrine effects as the Administrator may designate.” The EDSP employs a two

- tiered approach to making the statutorily required

### 41 determinations. Tier 1 consists of a battery of 11 screening assays to identify the potential of a chemical substance to interact with the estrogen, androgen, or thyroid (E, A, or T) hormonal systems. Chemicals that go through Tier 1 screening and are found to have the potential to interact with E, A, or T hormonal systems will proceed to the next stage of the EDSP where EPA will determine which, if any, of the Tier 2 tests are necessary based on the available data. Tier 2 testing is designed to identify any adverse endocrine

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

- response relation ship 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 5 8 pesticide active ingredients and 9 inert ingredients. A second list of chemicals identified for EDSP screening was published on June 14, 2013 2 

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

. Neither of these l ists 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 list of chemicals, future lists, the test guidelines and the Tier 1 screening battery, please vi sit our website: http://www.epa.gov/endo/ http://www.epa.gov/endo/

. 

# 6 Next Steps

A DCI will be developed regarding the data needs listed under the “Risk Assessments and Anticipa ted Data Needs” section of this document. The Agency expects to issue the DCI in December of 201 4

.

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

- HQ

- OPPT

- 2009

- 0477

- 0074 for the final second list of

chemicals.

### 42 

# 7 References

Kline, 200 6 . Specialty Biocide s North America 2004 /2005 , Kline and Company, Inc.

Singleton, H.J. and R.P. Bio. 1989. Ambient Water Quality Criteria for Chlorine Technical Appendix. Resource Quality Section, Water Management Branch, Ministry of Environment, Province of British Columbia, Victoria, B.C.

U.S. EPA (1985). Ambient Water Quality Criteria for Chlorine

- 1984. Regulations and Standards, Criteria and Standards Division, Office of Water, Washington, DC.

U.S. EPA (2005). Agency Memorandum

- Leighton, T. to Hartman, M. Formation of Bromate Ion from Application of Dihalodialkylhydantoin Sanitizers (BCDMH a nd DBDMH) into Swimming Pools and Associated Cancer Risks for Swimmers. DP Barcode 324327

U.S. EPA (2007) Reregistration Eligibility Decision (RED) for Halohydantoins (Case 3055), September 2007. http://www.epa.gov/oppsrrd1/REDs/halohydantoins

red.pdf http://www.epa.gov/oppsrrd1/REDs/halohydantoins

- red.pdf

### 43 

# Appendix A T oxicology Profile Acute Toxicity for Product Labeling

The acute toxicity database is compl ete. No additional studies are anticipated to be required at this time.

The acute toxicity data on technical hydantoins are summarized in T able A 1 below.

Table A 1

– Acute Toxicity Studies for the Halo hy dantoins

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

5,5

- Dimethylhydantoin (DMH; CAS No. 77

- 71

- 4) 870.1100 Acute Oral Toxicity

– Rat 93074007; 93075010; 00046045 LD 50 (combined) > 5,000 mg/kg IV

870.1100 Acute Oral Toxicity

– Mouse 45738401 LD 50 (combined) > 5,000 mg/kg IV

870.2600 Skin Sensitization

– Guinea Pig 93074013; 93075016; 00165487 Mild skin sensitizer N/A

1

- Bromo

- 3

- chloro

- 5,5

- Dimethylhydantoin (BCDMH; CAS No. 16079

- 88

- 2) 870.1100 Acute Oral Toxicity

– Rat (91.3% purity) 93074006; 93075009 00128244 LD 50 (male) = 1,350 mg/kg LD 50 (female) = 1,520 mg/kg LD 50 (combined) = 1,390 mg/kg III

870.1100 Acute Oral Toxicity

– Rat 93077008; 00147325 LD 50 (male) = 1,037 mg/kg LD 50 (female) = 860 mg/kg LD 50 (combined) = 929 mg/kg III

870.1300 Acute Inhalation Toxicity

– Rat 43654101 LC 50 (male) = 0.157 mg/L LC 50 (female) = 0.213 mg/L LC 50 (combined) = 0.168 mg/L II

870.1300 Acute Inhalation Toxicity

– Rat (94.7% purity) 43125601 ; 43039001 LC 50 (male) = 0.41 mg/L LC 50 (female) = 0.68 mg/L LC 50 (combined) = 0.53 mg/L II

870.2500 Acute Dermal Irritation

– Rabbit 93074011; 93075014; 00128242 Severe skin irritant I

870.2500 Acute Dermal Irritation

– Rabbit 93077009; 00147326 Severe skin irritant I

870.2600 Skin Sensitization

– Guinea Pig 41670001 Skin sensitizer N/A

### 44 Guideline N o. /Study Type MRID No. Results Toxicity Category

1,3

- Dibromo

- 5,5

- Dimethylhydantoin (DBDMH; CAS No. 77

- 48

- 5) 870.1100 Acute Oral Toxicity

– Rat 93076011; 00137105 LD 50 = 760 mg/kg III

870.1100 Acute Oral Toxicity

– Rat (55.9% purity) 44988002 LD 50 (combined) = 448 mg/kg II

870.1200 Acute Dermal Toxicity

– Rat (55.9% purity) 44988001 LD 50 > 2,000 mg/kg III

870.1300 Acute Inhalation Toxicity

– Rabbit 44988003 LC 50 is between 0.51

- 2.02 mg/L II

870.2500 Acute Dermal Irritation

– Rabbit 93076017; 00137109 Severe skin irritant I

870.2500 Acute Dermal Irritation

– Rabbit 44988004 Corrosive to skin I

870.2600 Skin Sensitization

– Guinea Pig 44988005 Non

- sensitizer N/A

1

- Chloro

- 5,5

- D i methylhydantoin 1 Chloro

- 5,5

- Dimethyl

- 2,4

- Imidazolidinedione (CDMH; CAS No. 6921

- 17

- 1) 870.1100 Acute Oral Toxicity

– Rat 46586801 LD 50 > 2,000 mg/kg III

870.1300 Acute Inhalation Toxicity

– Rat 46693902 LC 50 > 0.053 mg/L II

870.1200 Acute Dermal Toxicity

– Rat 46693901 LD 50 > 200 mg/kg II

870.2600 Skin Sensitization

– Guinea Pig 46693903 Non

- sensitizer N/A

1,3

- Dichloro

- 5,5

- Dimethylhydantoin (DCDMH; CAS No. 118

- 52

- 5)
870.1100 Acute Oral Toxicity

– Mouse 00084174 LD 50 (male) = 769.3 mg/kg LD 50 (female) = 704.8 mg/kg LD 50 (combined) = 737.3 mg/kg III

870.1200 Acute Dermal Toxicity

– Rabbit 93076013; 00084176 LD 50 > 20,000 mg/kg IV

870.2400 Acute Eye Irritation

– Rabbit 00084173 Severe eye irritant I

870.2500 Acute Dermal Irritation

– Rabbit 00084172 Severe skin irritant I

870.2600 Skin Sensitization

– Guinea Pig 00084178 Sensitizer N/A

N/A=Not available

### 45 

# Subchronic Toxicity

The data base for subchronic toxicity of hydantoins includes 90

- day oral and dermal rat studies. No subchronic inhalation studies are located in the Agency ’s hazard database ; therefore, it is identified as a data gap and a 90

- day inhalation toxici t y study is anticipated to be required

.
870.3100 90

- Day Oral Toxicity

– Rat

(1) In a subchronic toxicity study (MRID 42009201), dimethylhydantoin (>99.5% a.i .) was administered orally by gavage to 15 Crl: CDBR (Sprague

- Dawley) rats/sex at dose levels of 0, 100, 300, or 1000 mg/kg/day, 5 days/week, for 13 weeks. There was no treatment

- related death or clinical signs of toxicity in any animal. No biologically significant effects were seen on body weight, body weight gain, or food consumption in either sex. Hematology and clinical chemistry analyses revealed no significant differences from controls; urinalysis was not performed. There
were no treatment

- related gross or microscopic lesions in any examined tissue. No treatment

related neoplastic findings were reported

. Under the conditions of this study, a LOAEL cannot be established for either male or female rats in the absence of treatment

- related findings. Th e NOAEL is greater than 1000 mg/kg/day (limit dose; highest dose tested [HDT]) for both sexes. This subchronic toxicity study is classified as Acceptable/guideline , and it satisfies the guideline requirement for a subchronic oral study (OPPTS 870.3100 [§8 2

- 1]) in rats.

(2) In a subchronic toxicity study (MRID 150238 ), dimethylhydantoin (>99% a.i.) was administered orally by gavage to 20 Crl: CDBR (Sprague

- Dawley) rats/sex at dose levels of 0, 250, 500, 1000, or 2000 mg/kg/day for 90 days. Under the condit ions of this study, a LOAEL cannot be established for either male or female rats in the absence of treatment

- related findings. The NOAEL is greater than 2 000 mg/kg/day (highest dose tested [HDT]) for both sexes. This subchronic toxicity study is classifi ed as Acceptable/guideline , and it satisfies the guideline requirement for a subchronic oral study (OPPTS 870.3100 [§82

- 1]) in rats.

870.3250 90

- Day Dermal Toxicity

– Rat

In a 90

- day subchronic toxicity study (MRID 43173901), male and female CD rats were t reated with 5,5

- dimethylhydantoin (DMH) by dermal occlusion at doses of 0, 39, 130, or 390 mg/kg/day for 6 hours/day, 5 days/week, for 13 weeks.

No statistically significant differences in group mean body weight or cumulative weight gain were observed at any dose level tested. There were no treatment

- related effects on mortality, skin irritation, or clinical signs of toxicity in males or females at any dose level tested. DMH caused no significant changes in hematology, clinical chemistry, or gross and m icroscopic pathology in male or female rats. Absolute weight of the adrenal gland was significantly decreased in male rats at the 39 and 390 mg/kg/day dose levels (12.5% and 13.6%, respectively). Adrenal to body weight ratio was also decreased by 11.1% i n female rats at 130 ppm. The differences in adrenal weight were considered unrelated to treatment as there was no definitive dose

- response and no evidence of microscopic lesions.

### 46 The NOAEL was determined to be 390 mg/kg/day (the highest dose tested [HD T]), and the LOAEL is not established at the HDT of 390 mg/kg/day. This study is classified as Acceptable

Guideline and satisfies the guideline requirements for a subchronic toxicity study [OPPTS 870.3250 (§82

- 1b)] in rats. Higher doses of DMH were not p ossible in this study; thus, although a limit dose was not tested, the study is considered A cceptable

. 

# Developmental Toxicity

The data base for prenatal developmental toxicity includes studies in both species of rats and rabbits, and it is considered complete. No additional studies are anticipated to be required at this time.

Developmental toxicity testing in the rat showed no i ncrease in susceptibility of the fetus to the toxic effects of DMH because maternal toxicity occurred at the highest dose tested in the absence of fetal effects. However, in the prenatal developmental study in rabbits, fetal and litter effects occurred at a lower dose level than that for maternal toxicity. Therefore, there is quantitative evidence of increased susceptibility for this species.

870.3700 Prenatal Developmental Toxicity Study

– Rat

In a developmental toxicity study (MRID 42432701), mated female CD rats were administered DMH (99.8% a.i.) by gavage (in filtered water) at dose levels of 0, 100, 300, or 1000 mg/kg/day on gestation days 6

- 15, inclusive.

There were no treatment

- related eff ects on mortality, clinical signs, food consumption, gross pathology or Caesarean section observations in dams at any dose level tested. Maternal toxicity was observed at 1000 mg/kg and consisted of a transient decrease in body weight gain (16%) on gestat ion days 12

- 15 for this dose group. The maternal toxicity NOAEL is 300 mg/kg/day and the maternal toxicity LOAEL is 1000 mg/kg/day based on the transient decrease in body weight gain during gestation days 9

- 12.

There was no evidence of developmental toxic ity in fetuses at any dose level tested; external, visceral and skeletal malformations occurred at similar incidences across dose groups or occurred as single, sporadic events. Based on the results of this study, the developmental toxicity NOAEL is greate r than or equal to1000 mg/kg/day ( HDT ), and the developmental toxicity LOAEL is not established.

This study is classified as Acceptable/guideline and satisfies the guideline requirements for a developmental toxicity study (OPPTS 870.3700 [§83

- 3]) in rats.

870.3700 Prenatal Developmental Toxicity Study

– Rabbit

(1) In a developmental toxicity study (MRID 42413101), groups of artificially inseminated New Zealand White Rabbits (20/dose) were administered 5,5

- DMH by gavage on gestation days 6 through 18 at dos es of 0, 100, 500, or 1000 mg/kg/day in a dose volume of 5 ml/kg.

Maternal toxicity was observed at the 1000 mg/kg/day dose level as decreased body weight gain and decreased food consumption during the dosing period. The maternal toxicity NOAEL is 500

### 47 m g/kg/day, and the maternal toxicity LOAEL is 1000 mg/kg/day, based on decreased body weight and food consumption during the dosing period

. Developmental toxicity was observed at the 500 mg/kg/day dose level as an increased incidence of skeletal variations of the 27 th 

### presacral vertebrae , which exceeded both the concurrent and historical control incidence. The developmental toxicity NOAEL is 100 mg/kg/day, and the developmental toxicity LOAEL is 500 mg/kg/day, based on the increased incidence of 27 th



### presa cral vertebrae

. This study is classified as Acceptable/guideline and satisfies the guideline [870.3700 ( § 83

- 3 )] for a developmental toxicity study in the rabbit.

(2) In a developmental toxicity study (MRID 42205401), 20 presumed pregnant New Zealand rabb its per group were administered 5

- Ethyl

- 5

- methylhydantoin (EMH) (99.5% a.i.; Batch No.: II) by gavage at doses of 0, 50, 125, or 375 mg/kg/day on gestation days (GD) 6

- 18, inclusive (phase I).

The only treatment

- related clinical sign of toxicity among su rviving animals was the observation of small amount or no stool in 16/20 does in the 1000 mg/kg/day group (6/20 in the concurrent controls). A high

- dose doe was killed on GD 22 and another was found dead on GD 21 following apparent abortions by both of th ese animals. In addition, three high

- dose does were sacrificed moribund, one each on GD 15, 16, and 18, after the observations of emaciation, hypoactivity, and/or prostration. All other does survived to terminal sacrifice. No treatment

related findings were observed in any animal at necropsy.

In the high dose group, lower body weight gains occurred (p ≤ 0.05 or 0.01) during the intervals of GD 9

- 12, 12

- 15, and 18

- 21 and an overall decrease in the rate of weight gain during the entire dosing interval (p ≤ 0.01) and during the entire study (p ≤ 0.05) was observed. Significant lower food consumption by the high

- dose group was reported during the entire dosing interval and overall for the study (51% and 24% vs. controls, respectively; p ≤ 0.01). The maternal tox icity LOAEL is 1000 mg/kg/day and the maternal toxicity NOAEL is 375 mg/kg/day, based on mortality and reduced body weights gains and food consumption.

No statistically significant differences were observed between the treated and control groups for numb er of corpora lutea/doe, implantations/doe, pre

- or postimplantation loss, resorptions/doe, or fetal sex ratios. The reproductive toxicity NOAEL is equal to or greater than 1000 mg/kg/day (highest dose tested [HDT]) and the r eproductive t oxicity LOAEL is greater than 1000 mg/kg/day (not established).

Body weights of the high

- dose female fetuses were significantly (12%; p ≤ 0.05) less than the concurrent controls. Body weights of the high

- dose male fetuses were not statistically different from the concurren t controls; however, the mean weight of the treated group was also 12% lower vs. the control level. No dose

- or treatment

- related external, visceral, or skeletal malformations/variations were observed in any fetus. The d evelopmental t oxicity NOAEL is 375 mg/kg/day and the d evelopmental t oxicity LOAEL is 1000 mg/kg/day

, based on decreased fe tal body weights

.

### 48 This study is classified as Acceptable/guideline and satisfies the guideline requirements for a developmental toxicity study (870.3700 [§83

- 3]) in rabbits. 

# Reproductive Toxicity

The data base for reproductive toxicity is considered complete. No additional studies are anticipated to be required at this time.

No increased susceptibility was observed in the reproduction studies.

870.3800 Reproduction and Fertility Effects

– Rat

(1) In a two

- generation reproduction study (MRID 42462502), male and female Sprague

- Dawley Crl:CD ® 

### rats (30/sex/dose/generation) were administered dimet h ylhydantoin (DMH; 96

- 98.7% purity; Lot No. 6) daily by gavage at dose levels of 0, 250, 500, or 1000 mg/kg/day for 10

- 11 weeks per generation for two successive generations.

No compound

- related effects, clinical signs, or mortalit y were observed in the parental animals at limit dose tested. Based on these results, the parental toxicity NOAEL w as 1000 mg/kg/day (limit dose )

, the LOAEL was not established

. No compound

- related reproductive toxicity was observed. Fertility, length of gestation

, pup body weight and viability were unaffected by the treated compound. Based on these results, the reproductive toxicity NOAEL wa s 1000 mg/kg/day

, the LOAEL for reproductive toxicity was not established

. This study is classified as Core minimu m and satisfies the minimum guideline requirements for
a two

- generation reproductive toxicity study (870.3800 [§83

- 4]) in rats.

(2) In a two

- generation reproduction study (MRID 43290601, 44243001), groups of 28 male and 28 female F0 and F1 CD rats were adm inistered 5,5

- DMH of 0, 2000, 6000 or 20,000 ppm in their diets for 10 weeks before mating and during mating, gestation, and lactation. Calculated doses were 136 and 127, 408 and 379, and 1396 and 1322 mg/kg/day, respectively, for F0 and F1 males (premati ng/postmating periods) and 176 and 158, 516 and 475, and 1775 and 1602 mg/kg/day, respectively, for F0 and F1 females (premating periods only).

There was no evidence that dietary administration of DMH resulted in treatment

- related effects on mortality, clinical signs of toxicity, gross lesions, or microscopic lesions in F0 or F1 adult rats of either sex. There were no treatment

- related effects on body weight or body weight gain in F0 and F1 females during the premating period. The parental/systemic toxicity NOAEL is equal to or greater than the highest dose tested (HDT) of 20,000 ppm (1322 and 1602 mg/kg/day, respectively) for male and female rat s. The parental/systemic toxicity LOAEL cannot be established (greater than 20,000 ppm)

. The indices (mating, fertility, and fecundity) of reproductive performance in F0 and F1 animals were similar to those of their corresponding controls; no treatment

- r elated effects were observed on the indices of reproductive performance as well as litter size, pup viability, pup survival or sex ratio. The NOAEL for reproductive toxicity is equal to or greater than 20,000 ppm

### 49 (1322 and 1602 mg/kg/day for males and fem ales, respectively) and the corresponding reproductive toxicity LOAEL is greater than 20,000 ppm (not established)

. Growth of F1 and F2 pups was reduced as indicated by lower body weights (7 to 8%; males and females combined) and body weight gain (7 to13 %) between day 7 of lactation and weaning in high

- dose (20,000 ppm) pups compared with the controls. Body weights were still significantly lower on day 28 in F1 and F2 females weanlings compared with controls. However, these effects may be explained as a transient rejection of the treated diets by the pups since the decreased body weight and body weight gain were seen only during a two week period that coincides with the period in time that the pups begin eating solid food. In the absence of any other re productive effect, the fact that the body weight effects were not observed at birth or during the first week after birth rules out any relationship to reproduction

. T he NOAEL for offspring toxicity is equal to or greater than 20,000 ppm (1322 and 1602 mg/kg/day for males and females, respectively) and the corresponding offspring toxicity LOAEL is greater than 20,000 ppm (not established)

. This study is classified as Acceptable/guideline and satisfies the guideline requirements for a
two

- generation repro ductive toxicity study (870.3800 [§83

- 4]) in rats. 

# Chronic Toxicity

The data base for chronic toxicity contains studies in the rat as well as in the dog, and it is considered complete. No additional studies are anticipated to be required at this time.

Th e combined chronic/carcinogenicity studies in rat s showed a decrement in body weight and body weight gain in females and increased mortality, particularly in females. Males showed increased incidences of hyperplasia of submandibular lymph nodes, and testi cular fibrinoid vascular degeneration in early decedents. Both sexes showed increased mammary galactoceles in early decedents and enlarged pituitary glands.

870.4100a (870.4300) Chronic Toxicity

– Rat

(1) In a chronic toxicity/carcinogenicity study (MRID 43397702), 5,5

- DMH (99.8% purity) was administered in the diet to groups of 60 CD rats/sex/dose for 104 weeks at dietary levels of 0 (first control), 100, 300, 1000, or 0 (second control) mg/kg/day. These dosage levels correspond to dietary concentration s of 5,5

- DMH over the course of the study that ranged from 1080

- 26,794 ppm (males) and from 945

- 20,890 ppm (females).

In both sexes at the highest dose tested, there was no evidence of compound related effects on clinical signs, mortality, food consumptio n and organ weights, or on clinical pathology. At the highest dose level, statistically significant treatment

- related decreases i n body weight and body weight gain were observed in females only at weeks 90, 92, and 96 (p<0.01 and p<0.05 for the controls I and II, respectively), and statistically significant treatment

- related increased incidences of hyperplasia of submandibular lymph nodes were reported in males only at week 104 (p<0.05 and p<0.01 for the controls I and II, respectively). The NOAEL for sys temic toxicity was 300 mg/kg/day and the LOAEL was 1000 mg/kg/day, based on the decreases in body weight and body weight gain in females and hyperplasia of submandibular lymph nodes in males.

### 50 There were no increases in tumor incidences for the 5,5

- DMH trea ted groups when compared to the control group. This study is classified as core guideline and satisfies the guideline requirement for a chronic toxicity/carcinogenicity study ( 870.4300 [ § 83

- 5] ) in rats.

(2) In a chronic/oncogenicity toxicity study (MRID 44095901), DMH (97.3%, 97.1% and 93.5% a.i. for lot #6, #2412

- 67

- D1, and #2412

- 67

- D2, respectively) was administered to 80 Crl:CDBR rats/sex/dose in the diet at dose levels of 0, 100, 320, or 1000 mg/kg/day for 104

- 105 weeks. The sam e doses of DMH were given to 20 rats/sex/dose in a 52

- week interim study.

No treatment

- related statistically significant increases in the incidences of any lesion were seen at the termination of this 105

- week study. However, the animals that died during the study tended to die earlier at the high dose, which contributed to the increased mortality seen during weeks 52

- 79 at the high dose (15% vs 11% in controls for males and 27% vs 7% in controls for females; p ≤ 0.001). Significantly increased incidences of enlarged pituitary glands were found in high dose early decedent males (38% vs 20% in controls; p ≤ 0.05) and females (61% vs 33% in controls; p ≤ 0.05), and pituitary pars distalis adenomas were the most common cause of early deaths in this group of animal s. Increased incidences of mammary galactoceles occurred in high dose early decedent females (59% vs 31% in controls; p ≤ 0.01). The incidence of testicular fibrinoid vascular degenerations was increased in high dose males (8% vs 13%; p ≤ 0.01). The inciden ce of iliac lymph node lymphangiectasia was increased in high dose males (26% vs 13%) and females (9% vs 1%). The number of times of dried yellow matting in the urogenital area observed over the 24

- month treatment period increased about 3

- fold in high dos e males and females compared to controls. Urine volume roughly doubled in high dose males and females, and specific gravity decreased during week 77. Kidney tubule dilation was increased (100% vs 65%; p ≤ 0.01), and so was lung mineralization (68% vs 30%; p ≤ 0.05) in high dose males at 52 weeks; while the mean absolute brain weight was decreased (4%; p ≤ 0.05), compared to the controls, in high dose males at 52 weeks.

The LOAEL is 1000 mg/kg/day for the males and females , based on enlarged pituitary glands in early decedents of both sexes; increased mortality earlier in the study, especially in females; increased mammary galactoceles in early decedent female s; and testicular fibrinoid vascular degeneration in early decedent males. The NOAEL for both sexes is 3 20 mg/kg/day

. At the doses tested, there was not a treatment

- related increase in tumor incidence after 105 weeks of treatment with DMH. The increase in the incidences of pituitary adenomas in the pars distalis in high dose females (50% vs 10%; p ≤ 0.01) and males (32% vs 10%; N.S.) at 52 weeks was not dose

- related. There were no differences in pituitary adenoma incidences between control and high dose groups by the end of the 105

- week study. The high dose of 1000 mg/kg/day meets the limit dose requirement for non

- toxic agents.

This study is classified as Acceptable/guideline and satisfies the guideline requirements for a chronic/carcinogenicity study ( OPPTS 870.4300 [§83

- 5]) in rats.

870.4100b Chronic Toxicity

– Dog

There are two chronic toxicity studies in dogs in the Agency ’s hazard database.

### 51 (1) In a chronic toxicity study in dogs (MRID 43553101), DMH (98.9% purity; Lot No. K2432887) was administered to 32 beagle dogs (4/sex/dose) in the diet at dose levels of 0, 4000, 12000, or 40000 ppm (corresponding to measured doses of 0, 120, 342, or 1506 m g/kg/day for males and 0, 121, 414, and 1352 mg/kg/day for females, respectively).

All animals survived to scheduled sacrifice. At all doses tested DMH had no effect on mean body weight in males and females. There were no treatment

- related changed in h ematology, clinical chemistry, and urinalysis.

Statistically significant increases in the absolute weight of the adrenals and adrenal/body weight and adrenal/brain weight ratios were reported in the high

- dose males. Microscopic examination revealed diff use and bilateral hypertrophy of the adrenal cortex in all high

- dose males, which was considered to be treatment

- related. There were no other statistically significant effects on organ weight or organ/body or brain weight ratios. The NOAEL is considered to be 12,000 ppm ( 342 mg/kg/day), and the LOAEL is 40,000 ppm (1506 mg/kg/day), based on enlarged adrenal glands in male dogs with hypertrophy of the adrenal cortex shown by microscopic examination.

This study is classified as Core

- guid e line and satisfies the guideline requirements for a chronic toxicity study ( OPPTS 870.4 1 00 [§83

- 1 ]) in dogs

. (2) In a chronic toxicity study in dogs (MRID 43813301), DMH (99.9% purity) was administered to 32 beagle dogs (4/sex/dose) by capsule at dose levels of 0, 250, 500, or 1000 mg/kg/day for 52 weeks (capsules given 7 days/week).

There were no treatment

- related effects on mortality, clinical signs, body weight and body weight changes, food consumption, hematology, clinical chemistry, urinalysis, organ weig hts and organ/body weight or organ/brain weight ratios, ophthalmological parameter, or grass or microscopic results from histological examination of selected tissues. The NOAEL is greater than 1000 mg/kg/day (HDT ) , and the LOAEL is not established at the HDT

. 

# Carcinogenicity

The data base for carcinogenicity is considered complete. No additional studies are anticipated to be required at this time.

T here is some evidence of target organ toxicity, but no evidence of positive tumorigenicity for the test mate rial in carcinogenicity testing of rats and mice

. 870.4200a Carcinogenicity Study

- rat

See chronic toxicity/carcinogenicity studies above (MRIDs 43397702 and 44095901).

870.4200b Carcinogenicity (feeding)

– Mouse

(1) In a carcinogenicity study (MRID 43397701), DMH (99.8% purity) was administered in the diet of CD

- 1 mice at dietary concentrations of 0, 400, 1850, or 8500 ppm (target doses of 0, 100, 300, or 1000 mg/kg/day) for 78 weeks. Two concurrent control groups we re used and

### 52 administered the same basal diet that was used to prepare the treatment diets. At the highest dose tested, there was no evidence of carcinogenicity, nor were there compound related clinical signs, effects on mortality, or on clinical pathology . In males at the highest dose level, there w ere statistically significant decrease s in the mean absolute body wei ght and in mean body weight gain, compared to both control groups, which persisted from week 16 of the study.

T he NOAEL was 300 mg/kg/day and the LOAEL was 1000 mg/kg/day , based on the decreases in body weight and body weight gain in males. No signs of toxicity were reported in females.

This study is classified as Acceptable/guideline and satisfies the guideline requirements for a

mouse on cogenicity study ( OPPTS 870.4200 b [ § 83

- 2b] )

. (2) In a mouse oncogenicity study (MRID 44063901), DMH (97.1

- 97.3% a.i.) was administered to CD

- 1 mice (80/sex/group) for 18 months at 0, 100, 320, or 1000 mg/kg/day.

No significant differences were observed in survival rates in male or female mice in any of the treated groups throughout the study when compared to the respective control groups. Overall body weight gains, leukocyte differential counts, absolute and relative organ weights, gross necropsy, as well as microscopic findings for both sexes at all doses were unaffected by treatment with DMH.

Negligible systemic toxicity was characterized by statistically significant decreases in mean body weights in males receiving the 1,000 or 320 mg/kg/day diet ( ↓ 3

- 5%; p<0.05 or 0.01) and increases in mean feed consumption by the high

- dose animals ( ↑ 3.8

- 9.8%; p<0.05 or 0.01); however, the biological significance the changes is unknown.

The systemic toxicity NOAEL is equal to or greater than 1000 mg/kg/day (HDT) , and the systemic toxicity LOAEL is not established at the HDT.

Under the conditions of this study, there was no evidence of carcinogenic potential in mice following treatment with DMH and the dosing was considered adequate because the highest dose of 100 0 mg/kg/day represents a “limit dose.”

This study is classified as Acceptable/guideline and satisfies the guideline requirements for a carcinogenicity study ( OPPTS 870.4200 [ § 83

- 2b] ) in mice. 

# Mutagenicity

The Agency reviewed the submitted m utagenicity ass ays and found they are acceptable. W hile no mutagenicity was observed in most of the assays, positive results were reported for Ames assay for 1

- Bromo

- 3

- chloro

- 5,5

- Dimethylhydantoin ( BCDMH ) technical and in vitro mammalian cytogenetics assay in Chinese Ha mster Ovary (CHO) cells for 1,3

- dichloro

- 5,5

- ethylmethylhydantoin ( DEMH ) and EMH technical s

. However, there is no evidence of positive tumorigenicity in carcinogenicity testing of rats and mice. The database for mutagenicity is considered to be complete. No additional studies are anticipated to be required at this time.

### 53 The detail of mutagenicity database is summarized in Table 2 Toxicology Profile for Halohydantoins

. 

# Metabolism

The database for metabolism is considered to be complete. No additional st udies are anticipated to be required at this time.

870.7485 Metabolism

- Rat

(1) In an absorption, distribution, metabolism and excretion (ADME) study (MRID 42173901), 20 male and 20 female Crl:CDBR rats (5/sex/group) were administered with 14 

### C radiolabele d 5,5

- dimethylhydantoin ( 14 

### C

- DMH; 98.8% purity) and/or non

- radiolabeled DMH (99.5% purity) in the following dosing regimen: a single oral low

- dose of 100 mg/kg; a single oral high

- dose of 1000 mg/kg; a repeated oral low

- dose of 100 mg/kg; and a single IV l ow

- dose of 100 mg/kg. In the repeated oral doses group, animals received non

- radiolabeled DMH at a dose level of 100 mg/kg for days 1 thru 7 and 80 mg/kg for days 8 thru 14 by gavage followed by a single oral dose of 14 

### C

- DMH. Under the conditions of this study, DMH was rapidly absorbed and was excreted primarily in the urine (90

- 96% vs <1.37% in feces). Most of the radioactivity was recovered in the first 12 hours in both sexes and there was very little accumulation in the tissue (<0.2% of the administer ed 14 

### C

- DMH). No differences were observed in the absorption, distribution, or excretion patterns in male and female rats in any of the dose groups.

This study is acceptable. This study alone does not satisfy the guideline requirements for a metabolism study; however, an additional study was conducted to identify the metabolites of DMH in the urine.

(2) In an absorption, distribution, metabolism and excretion (ADME) study (MRID 42173902 ), 20 male and 20 female Crl:CD Br rats (5/sex/group) were administered with 14 

### C radiolabeled 5

- ethyl

- 5

- methylhydantoin ( 14 

### C

- EMH; 97.8% purity; Lot No. 2675

- 095) and/or no n

- radiolabeled EMH (>99.5% purity; Batch No. B9430305) in the following dosing regimen: a single oral low

dose of 100 mg/kg; a single oral high

- dose of 1000 mg/kg; a repeated oral low

- dose of 100 mg/kg; and a single IV low

- dose of 100 mg/kg. In the repeat ed oral doses group, males and females received non

- radiolabeled EMH at a dose level of 100 mg/kg for 14 and 15 days, respectively, followed by a single oral dose of 14 

### C

- EMH. Under the conditions of this study, EMH was rapidly absorbed and was excreted pr imarily in the urine (91.7

- 101.82% vs <2.33% in feces). Most of the radioactivity was recovered in the first 12 hours in both sexes and there was very little accumulation in the tissue (<0.5% of the administered 14 

### C

- EMH). No differences were observed in the absorption, distribution, or excretion patterns in male and female rats in any of the dose groups.

(3) In an addendum (MRID 42123801/02 for DMH and EMH, respectively) and additional information submitted on analytical data (MRID 43020401/02 for DMH and EMH, respectively) to the above metabolism studies, confirmed that the major radioactive peak in the urine samples

was 14 

### C

- DMH (91.31

- 96.88%) and 14 

### C

- EMH (96.38

- 97.61%), respectively, and the recovered unmetabolized 14 

### C

- DMH and 14 

### C

- EMH in the urine repres ented more than 90% and more than 89% of the administered dose of DMH and EMH, respectively, when 5 male and 5 femal

### 54 Crl:CDBR rats were administered a single oral dose of 1000 mg/kg 14 

### C

- DMH and 100 mg/kg
14 

### C

- EMH, respectively.

Together, the metabolism st udies on DMH and EMH are classified as Acceptable / guideline and satisfy the guideline requirement for a metabolism study in rats ( OPPTS 870.7485 [ § 8 5

- 1 ] ).



# Toxicity Profile The toxicity profile for the halohydantoins is included in Table A2

.

Table A 2

- Toxicology Profile for Halohydantoins

Guideline No./

Study Type/ Substance Purity MRID No. (year) Results

Subchronic Toxicity
870.3100 90

- Day oral toxicity rodents

- Rat DMH purity > 99.5% 42009201 (1991) NOAEL ≥ 1000 mg/kg/day (highest dose tested [HDT] )

LOAEL > 1000 mg/kg/day (not established)

870.3100 90

- Day oral toxicity rodents

- Rat DMH purity > 99% 150238 NOAEL ≥ 2000 mg/kg/day (HDT)

870.3250 90

- Day dermal toxicity

– Rat DMH purity not stated 43173901 (1994) NOAEL ≥ 390 mg/kg/day (HDT)

LOAEL > 390 mg/kg/day (not established) 870.3465 90

- Day inhalation toxicity No study available.

Developmental/Reproductive Toxicity
870.3700 Prenatal developmental

– Rat DMH purity 99.8% 42432701 (1992) Maternal Toxicity NOAEL = 300 mg/kg/day

Maternal Toxicity LOAEL = 1000 mg/kg/day based on the transient decrease in body weight gain during gestation days 9

- 12.

Reproductive Toxicity NOAEL ≥ 1000 mg/kg/day ( HDT )

Reproductive Toxicity LOAEL > 1000 mg/kg/day (not established)

Developmental Toxicity NOAEL ≥ 1000 mg/kg/day ( HDT )

Developmental Toxicity LOAEL > 1000 mg/kg/day (not established)

### 55 Guideline No./

Study Type/ Substance Purity MRID No. (year) Results

870.3700 Prenatal developmental in nonrodents

– Rabbit DMH purity not stated 42413101 (1992) Maternal Toxicity NOAEL = 500 mg/kg/day Maternal Toxicity LOAEL = 1000 mg/kg/day, based on decreased body weight gain and food consumption during the dosing period.

Reproductive Toxicity NOAEL ≥ 1000 mg/kg/day (HDT) Reproductive Toxicity LOAEL > 1000 mg/kg/day (not established)

Developmental Toxicity NOAEL = 100 mg/kg/day Developmental Toxicity LOAEL = 500 mg/kg/day, based on the increased incidence of the 27 th presacral vertebrae.

870.3700 Prenatal developmental in nonrodents

– Rabbit MEH purity 99.5% 42205401 (1992) Maternal Toxicity NOAEL = 375 mg/kg/day Maternal Toxicity LOAEL = 1000 mg/kg/day, based on mortality, reduced body weights gains and reduced food consumption.

Developmental Toxicity NOAEL = 375 mg/kg/day Developmental Toxicity LOAEL = 1000 mg/kg/day, based on decreased fetal b ody weights.

870.3800 Reproduction and fertility effects DMH purity 96

- 98.7% 42462502 (1992) Parental/Systemic Toxicity NOAEL ≥ 1000 mg/kg/day (HDT) Parental/Systemic Toxicity LOAEL > 1000 mg/kg/day (not established)

Reproductive Toxicity NOAEL ≥ 1000 mg/kg/day (HDT) Reproductive Toxicity LOAEL > 1000 mg/kg/day (not established)

Offspring Toxicity NOAEL ≥ 1000 mg/kg/day (HDT) Offspring Toxicity LOAEL > 1000 mg/kg/day (not established)

870.3800 Reproduction and fertility effects DMH purity not stated 43290601, 44243001 (1994) Parental/Systemic Toxicity NOAEL ≥ 20,000 ppm (1322 and 1602 mg/kg/day, respectively [HDT]) Parental/Systemic Toxicity LOAEL > 20,000 ppm (not established)

Reproductive Toxicity NOAEL ≥ 20,000 ppm (1322 and 1602 mg/kg/day, respectively [HDT]) Reproductive Toxicity LOAEL > 20,000 ppm (not established)

Offspring Toxicity NOAEL ≥ 20,000 ppm (1322 and 1602 mg/kg/day, respectively [HDT]) Offspring Toxicity LOAEL > 20,000 ppm (not established) Chronic Toxicity/Carcinogenicity 870.4100 Chronic toxicity

– Rat DMH purity 99.8% 43397702 (1994) Systemic Toxicity NOAEL = 300 mg/kg/day Systemic Toxicity LOAEL = 1000 mg/kg/day, based on ↓ in body weight and body weight gain in females and hyperplasia of submandibular lymph nodes in males.

No evidence of carcinogenicity

.

### 56 Guideline No./

Study Type/ Substance Purity MRID No. (year) Results

870.4100 Chronic toxicity

– Rat DMH purity 97.3%, 97.1%, and 93.5% 44095901 (1996) Systemic Toxicity NOAEL = 320 mg/kg/day Systemic Toxicity LOAEL = 1000 mg/kg/day, based on enlarged pituitary glands in decedents of both sexes, increased mortality occurring early in (especially) females, increased mammary galactoceles in early decedents of both sexes and testicular fibroid vascular degeneration in early decedent males.

At the doses tested, there was not a treatment related ↑ in tumor incidence after 105 weeks of treatment with DMH.

No evidence of carcinogenicity

. 870.4100 Chronic tox icity

– Dog DMH purity 99.9% 43813301 (1996) NOAEL ≥ 1000 mg/kg/day (HDT)

LOAEL > 1000 mg/kg/day (not established)

870.4100 Chronic toxicity

– Dog DMH purity 98.9% 43553101 (1995) NOAEL = 12,000 ppm (342 mg/kg/day)

LOAEL = 40,000 ppm (1506 mg/kg/day), based on enlarged adrenal glands in male dogs, shown by microscopic examination to exhibit hypertrophy in the adrenal cortex.
870.4200 Carcinogenicity

– Rat DMH purity 99.8% 43397702 (1994) See Chronic Toxicity in Rodents

– Rat

No evidence of carcinogenicity

. 870.4200 Carcinogenicity

– Rat DMH purity 97.3%, 97.1%, and 93.5% 44095901 (1996) See Chronic Toxicity in Rodents

– Rat

No evidence of carcinogenicity

.

870.4300 Carcinogenicity

– Mouse DMH purity 99.8% 43397701 (1994) Systemic Toxicity NOAEL = 300 mg/kg/day

Systemic Toxicity LOAEL = 1000 mg/kg/day, based on ↓ in body weight and body weight gain in males.

No evidence of carcinogenicity

. 870.4300 Carcinogenicity

– Mouse DMH purity 97.1

- 97.3% 44063901 (1996) Systemic Toxicity NOAEL ≥ 1000 mg/kg/day (HDT) Systemic Toxicity LOAEL > 1000 mg/kg/day (not established)

No evidence of carcinogenicity

.

Mutagenicity 870.5 1 00

- Ames Assay D M H purity 9 7 % 1 64036 (265457 #1 ) (1986) Negative

870.5 1 00

- Ames Assay D M H purity not stated 137100 (198 2 ) Negative

870.5 1 00

- Ames Assay M EH purity not stated 137095 (1982) Negative

### 57 Guideline No./

Study Type/ Substance Purity MRID No. (year) Results

870.5 1 00

- Ames Assay BCDMH purity 98.4% 43125602 (42387201 ) (1993) Mutagenic
Dose

- related ↑ in the reversion to histidine prototrophy of S. tyhimurium strain TA1535 were obtained in both trials. In the confirmatory trial, fold ↑ in mutant colonies of S. tyhimurium strains TA 1535 ranged from 2.3 at 625 μg/plate +S9 to 5.2 at 2500 μg/plate +S9.
870.5300

- In vitro Mammalian Cell Gene Mutation Test DMH purity not stated 132165 (1983) Negative

870.5375

- In vitro Mammalian Chromosomal Aberration Assay (CHO) D M H purity 97% 164037 (265457 #2 ) (1986) Negative

870.5375

- In vitro Mammalian Chromosomal Aberration Assay (CHO) D M H purity not stated 137101 (1982) Negative

870.5375

- In vitro Chromosome Aberration Assay (CHO) DEMH purity not stated 40348201 (1987) Positive Significant ↑ in the % of cells with structural chromosomal aberrations (mainly chromatid and chromosome breaks and dicentrics) was seen at the highest dose tested without S9

- mix; the % of cells with structural chromosomal aberrations, excluding gaps, reached 9.5% at 60 μg/ml. The frequency of cells with structural chromosome aberrations was significantly ↑ in cultures treated with 120 and 60 μg/ml for 16 hours with S9

- mix, and at all dose levels in cultures treated for 22 hours with S9

- mix.
870.5375

- In vitro Chromosome Aberration Assay MEH purity not stated 137096 (1982) Positive
A two

- fold or greater ↑ in the % of cells with structural chromosomal aberrations, excluding gaps, was seen at two nonconsecutive doses in cultures treated with S9

- mix. No dose response was evident. Results from the treatment without S9

- mix were negative at all doses. N o ↑ in polyploid cells was observed in treated or in positive control cultures.
870.5550

- In vitro Unscheduled DNA Synthesis (UDS) in Mammalian Cells D M H purity 97% 164038 ( 265457 #3) (1986) Negative

870.5550

- In vitro Unscheduled DNA Synthesis (UDS) in Mammalian Cells D M H purity not stat ed 132166 (1982) Negative

870.5550

- In vitro Unscheduled DNA Synthesis (UDS) in Mammalian Cells M EH purity not stat ed 137097 (1982) Negative

### 58 Guideline No./

Study Type/ Substance Purity MRID No. (year) Results

870.7485

Metabolism and Pharmacokinetics

DMH purity 98.8% 42173901

, 42123801 (1991) DMH was rapidly absorbed and excreted primarily in the urine (90

- 96% vs <1.37% in feces). Most of the radioactivity was recovered in the first 12 hours in both sexes and there was very little accumulation in the tissue (<0.2% of the administered 14 C

DMH). No differences were observed in the absorption, distribution, or excretion patterns in male and female rats in any of the dose groups.
870.7485 Metabolism and Pharmacokinetics

MEH purity 97.8% 4217390 2, 42123802 (1991) M E H was rapidly absorbed and was excreted primarily in the urine (91.7

- 101.82% vs <2.33% in feces). Most of the radioactivity was recovered in the first 12 hours in both sexes and there was very little accumulation in the tissue (<0.5% of the administered 1 4 C

EMH). No differences were observed in the absorption, distribution, or excretion patterns in male and female rats in any of the dose groups.

DMH= 5,5

- dimethylhydantoin ; DEMH = 1,3

- dichloro

- 5,5

- ethylmethylhydantoin ; MEH= 5

- Ethyl

- 5

- methylhydantoin ; BCDMH=1

- Bromo

- 3

- chloro

- 5,5

- Dimethylhydantoin

### 59 

# Appendix B Environmental Fate

Mode of A ctivity of H alohydantoins:

In order to understand the antimicrobial activity of halohydantoins, it is instructive to understand some basic chemical reactions that together constitute the antimicrobial activity of these chemicals, which is provided below:

Halohydantoins are designed such that the loss of a halide (chloride or bromide) is the first step. Halohydantoins

--------  monohalohydantoins

---------------- (a) The second step is the hydrolysis of the halide ion as indicated by equation 1: Cl - 

### + H 2 

### O HOCl + OH -



### ------------------------- (1) Reaction 1 actually represents an equilibrium reaction, and it is more toward the reactants. As the halohalide is consumed (as an antimicrobial) additional hydrolytic reaction takes place between halide ions and water, till the entire halide ions are totally consumed. A similar reaction takes place with bromide ions. Therefore HOCl, an d HOBr are the active moieties and these in turn dissociate to form OCl - 

### and OBr - 

### as hypobro mo us or hypochlorous are not stable entities and hypochlorite and hypobromite ions also act as active moieties (2005 EPA)

.

Abiotic and Biotic Fate of Halohydantoins

Hydroloysis

A hydrolysis s tudy, under abiotic condition, was conducted a t pH 5, 7, and 9 on 1

- bromo

3

- chloro

- 5,5

- dimethylhydantoin, 1,3

- dichloro

- 5,5

- dimethylhydantoin and 1,3

- di chloro

- 5

- ethyl,5

- methylhydantoin. These halohyda ntoins first degrade by losing one halide ion within an hour, while the second halide ion dissociates in l ess than a day. In both cases, hypohalides (hypochlorous or hypob romous acids) are formed which are the actual actives. If these actives are used in the swi mming pools, and a high chlorine concentration is present
, a degradate known as N

- chloro

- i so

- propylimine is formed, which is known for its high toxicity. In the presence of excessive bromide, N

- bromo

- iso

propylimine is formed. (ACC# 263983). A second hydrolysis study was c onducted on radiolabeled halohy da ntoins, and its conclusions were similar to the one obtained with the first study. The second study also sh o w ed that DMH is stable at all three pHs (5,7, and 9) (MRID#424662

- 01)

Aqueous photolysis

The same study (ACC# 263983) also showed that sunlight did not change the rate of degradation of these activ es. Thus hydrolysis appears to be the degradation pathway for the halohydantoins.

### 60 Biodegradation in Wastewater Treatment Plants

Data for dihalohydantoins is not needed because of the rapid loss of the initial halogen. However, discharge of resulting monohalohydantoins residuals to wastewater treatment facilities may occur. There is no data on the ultimate biodegradation of monohalohydantoins in activated sludge. Biodegradati on data for monohaloalkylhydantoins in activated sludge is anticipated to be required.

Activated Sludge Respiration Inhibition

Toxicity data for dihalohydantoins is not needed because of the rapid loss of the initial halogen. However, discharge of resulti ng monohalohydantoins residuals to wastewater treatment facilities may occur. There is no data on the toxicity of monohalohydantoins to activated sludge. An activated sludge respiration inhibition study for monohaloalkylhydantoins is anticipated to be re quired.

Abiotic and Biotic Environmental fate of dialkylhydantoin s ( DMH and EMH )

Hydrolysis

DMH ra diolabeled on the hydantoin ring w as su bjected to hydrolysis at pH 5, 7 and 9 in dark for 30 days. The ac tive was 98.3% radiolabeled

. A t the end of 30 day period, the recovered radioactive material at pH 5 was: 99 .6 %, 94.2

- 96.4% at pH 7, and at pH 9, the percent was 90.0. The percent recovery ranged from 93.6 to 107.1. Thus DMH is hydrolytically stable under abiotic conditions at all three pHs (MRID#408046

- 01)

. Aqueous photolysis

A Radiolabeled DMS was subjected to aqueous photolysis study (radiolabeled purity 98.0%) at 10 ppm concentration at pH 7 for 30 days. The samples were irradiated for 30 days with a xenon light source. 90

- 92.8% radioactivity reside d with the sample . M a terial balance in the dark and irradiated sensitized and non

- sensitized samples ranged from 95.5% to 103%. DMH is stable photolytically under abiotic conditions (MRID# 408046

- 02)

.
Aerobic Soil Metabolism

A soil metabolism study conduc ted on the radiolabeled DMH in sandy loam soil showed that DMH degraded with a half life of over a year. Thus DMH is stable under aerobic soil conditions (MRID# 408046

- 03)

. Anaerobic Aquatic Metabolism

Radiolabeled DMH placed in flooded sandy loam soil s howed a half life of over a year. The material balance ranged from 95.7 to 105.8 %, after one year study. The amount of

### 61 radiolabeled carbon dioxide produced was 0.37%. Thus mineralization process is negligible (MRID# 408046

- 04)

. Aerobic Aquatic Metabolism

Radiolabeled DMH was added t o the flooded sandy loam soil imme diately after the flooding proce ss (while the aerobic condition was still present). Samples collected after one month showed that little change in the percent purity of the radiolabeled DMH. Th e sample analysis showed that after one month, the 108% of the applied radioactivity was present. Radioactivity ratio between soil/water was 5.4

- 8.4: 1. The material balance ranged from 82.4 to 113.7% of the applied (MRID#: 40804607)

. Leaching/ Adsorption /Desorption

B atch equilibrium study showed that DMH was mobile in: sandy loam, silt loam, loam, and clay loam soils. K ads 

### for sandy loam: 0.051; for silt loam: 0.077; for loam: 0.092; for clay loam: 0.138. The adsorptions constants are small meaning that DMH does not bind strongly with various soils. The study also showed that adsorption increased with increased organic matter content. (MRID# 408046

- 07) Soil leaching study showed high mobility in these soils (MRID#408046

- 06)

.

Octan o l/Water partition Coefficent

The K ow 

### was measured u sing 208 ppm or 416 ppm of DMH dissolved in phosphate buffer (100:20 ratio). The value ranged between 0.32 to 0.40. The low value indicates that bioaccumulation in aquatic organisms is not likely to occu r (MRID# 408652

- 01).

Table B1 Estimated Physical/C hemical and E nvironmental Fate C haracteristics of H alohydantoins (EPI Suite, version 4.1)

Property Cas# 118

- 52

- 5 DC DMH Cas# 16079

- 88

- 2 1BC DMH Cas# 89415

- 87

- 2 DCEMH Cas# 77

- 48

- 5 DB DMH Cas# 32718

- 18

- 6 1BC DMH VP (mm Hg) 2.4 x10

- 5 6.6 x10 - 6 1.3 x10 - 5 5.9 x10 - 7 2.5 x10 - 8 Mp (C) 184 95 131 154 182 Henry law constant (atm

- m 3 /mole) 1.02 x10 - 6 8 x10 - 7 1.36 x10 - 6 6.4 x10 - 7 1.2 x10 - 10

Log Kow

- 0.9441

- 0.94

- 0.45

- 0.94 0.33 Solubility (mg/L) 14000 5862 1488 6942 681 Koc 10 L/kg 10 L/kg 4.4 L/kg 10 L/kg 11.8 L/kg Half life in air 42 hours 42 hours 20 hours 42 hours 38 hours

### 62 Table B1

- 2

Property CAS# 91112

- 66

- 2 BCEMH CAS# 126

- 06

- 7 BC D MH VP (mm Hg) 1.87 x10 - 8 7.9 x10 - 6 MP (C) 184 139 Henry Law constant (atm

- m 3 /mole) 1.22 x10 - 12 8.1 x10 - 7 Log Kow 0.74

- 0.94 Solubility (mg/L) 5115 8264 Half life in air (hours) 52 42 Koc (L/kg) 10 2.34

### 63 

# Appendix C Ecotoxicology Profile

A review of eco toxicity effects data for the halohydantoins contained within the Agency ’s files is provided in this appendix. Additional eco toxicity information on the toxicity of hypochlorous acid, HOCl, formed from halohydantoins is obtained from the EPA Office of Water’s Ambient Water Quality Criteria for Chlorine

- 1984 (EPA 1985). The document contains a review of public li terature on effects of chlorine, which includes hypochlorous acid, and based on the data derives freshwater and saltwater organism acute and chronic water quality criteria as total chlorine residual (TRC) for freshwa ter and total residual oxidant (TRO) for seawater. Current ambient water quality criteria for chlorine or total chlorine residual are based on the data in the 1984 document and the method for deriving water quality standards discussed in a 1986 Water Qual ity Document (USEPA, 1986).

• Freshwater Criterion Maximum Concentration = 19 μg/L TRC ;

• Freshwater Criterion Continuous Concentration = 11 μg/L TRC ;

• Saltwater Criterion Maximum Concentration = 13 μg/L CPO ; and

• Saltwater Criterion Continuous Concentration = 7 .5 μg/L CPO

Toxicity data expressed in terms of a specific haloalkylhydantoin active ingredient concentration or dose or a mixture of dihaloalkylhydantoins will be normalized

. Some data has been normalized as DCDMH. Some data were measured and reported as total bromine (Br 2 

### ) and some as equivalents of the test substance. A normalization is needed to allow comparison of toxicity across the dihalodialkylhydantoins. For example, if the LD 50 

### for DCDMH is reported as 197 mg ai/L and the LD 50 

### for DBDMH is re ported as 286 mg ai/L this appears to mean that DCDMH is more toxic than DBDMH. However, since one mmole of DCDMH weighs 197 mg and one mmole of DBDMH weighs 286 mg there is actually no difference in their LD 50 

### sensitivity as it takes the same number of m olecules of each (one mmole/L) to elicit the same
response.
Toxicity of Halohydantoins to Terrestrial Receptors

Birds

The available data submitted for BCDMH, DCDMH, and DBDMH categorize the halohydantoins (TGAI) as being slightly to practically nontoxic to birds on an acute

- oral basis (LD 50 

### ’s range from 10 70 to >2 5 1 0 mg ai/kg

- bw ; Table C1 ). S everal dietary studies a re available. The data categorize the halohydantoins (TGAI) as being practically nontoxic to birds on a dietary basis (LC 50 

### ’s >5 62 0 ppm ai ). The halohydantoins are not expected to bioaccumulate in the food chain and therefore no c hronic data are required for halohydantoins

. No additional data are anticipa ted to be required for the risk assessment

.

### 64 Table C1

. Available Acute Avian Ecotoxicity Studies for the TGAI (BCDMH, DCDMH, DBDMH )

Study Type/ Species Test material (% ai) Toxicity * as active ingredient (expressed as equivalent DCDMH) MRID / Status / Toxicity Classification

Acute Avian Oral

Northern Bobwhite ( Colinus virginianus ) 1BCDMH (99) LD 50 : 1070 mg/kg

- bw (873 mg/kg

- bw) 95% CLs 781

– 1542 mg ai/kg

- bw

NOAEL = 250 mg ai/kg

- bw

Probit slope = 4.51 00142071 / Acceptable / Slightly toxic

1BCDMH (96) LD 50 : 1839 mg/kg

- bw (1500 mg/kg

- bw) 95% CLs 1350

– 2250 mg ai/kg

- bw

NOAEL = 1350 mg ai/kg

- bw (survival)

Probit slope = NA 00147319 / Acceptable / Slightly toxic

BCDMH (90) LD 50 : >2510 mg/kg

- bw (>1729 mg/kg

- bw)

NOAEL = 631 mg ai/kg

- bw (lethargy, 30% mortality at 2510 mg/kg

bw) 00 128162, 00149702 / Supplemental / Practically nontoxic

DCDMH (97) LD 50 : 1715 mg/kg

- bw 95% CLs 1253

– 2581 mg ai/kg

- bw (1182 mg/kg

- bw)

NOAEL = 398 mg/kg

- bw 0084179 / Acceptable / Slightly toxic

DBDMH (96) MBDMH ( 4 ) ** LD 50 : >2510 mg/kg

- bw (>1729 mg/kg

- bw)

NOAEL = 251 mg ai/kg

- bw (lethargy) 00137088, 433401110 / Acceptable / Practically nontoxic

DCEMH

(99.4) LD 50 : >2250 mg ai/kg

- bw ( mg ai/kg

- bw)

NOAEL = 1350 mg ai/kg

- bw 00145353 / Acceptable / Practically nontoxic

### 65 Study Type/ Species Test material (% ai) Toxicity * as active ingredient (expressed as equivalent DCDMH) MRID / Status / Toxicity Classification

Subacute Dietary

Northern Bobwhite ( Colinus virginianus ) 1BCDMH (99) LC 50 : >5620 ppm (>4586 ppm)

NOAEC = 1000 ppm ai (decreased body wt gain; no dose related mortality) 00143729 and 00144146 / Acceptable / Practically nontoxic

1BCDMH (96) LC 50 : >5620 ppm (>4586 ppm)

NOAEC =3160 ppm ai NR / Acceptable / Practically nontoxic

1BCDMH (96) LC 50 : >5620 ppm (>4586 ppm)

NOAEC > 5620 ppm ai 00147321 / Acceptable / Practically nontoxic

BCDMH (90) LC 50 : >5620 ppm (>4586 ppm)

NOAEC 3160 ppm ai 0014 9704 / Acceptable / Practically nontoxic

DBDMH (96) MBDMH (4)** LC 50 : >5620 ppm (>4586 ppm)

NOAEC < 5620 ppm ai 00137087 , 433401109 / Supplemental / Practically nontoxic

DCDMH (97) LC 50 : >5620 ppm

NOAEC = 1780 ppm ai (body weight) 00084525 / Acceptable / Practically nontoxic

Subacute Dietary

Mallard ( Anas platyrhynchos ) 1BCDMH (96) LC 50 : >5620 ppm ai (>4586 ppm)

NOAEC > 5620 ppm ai 00147320 / Acceptable / Practically nontoxic

1BCDMH (96) LC 50 : >5620 ppm (>4586 ppm)

NOAEC = 3160 ppm (reduction in body

weight gain and feed consumption, no mortality) NR / Acceptable / Practically nontoxic

BCDMH (90) LC 50 : >5620 ppm ai (>4586 ppm)

NOAEC > 5620 ppm ai 00128 457 / Acceptable / Practically nontoxic

DCDMH (97) LC 50 : > 5620 ppm (>4586 ppm) Acc 253073 & 71 / Acceptable / Practically nontoxic
DBDMH (96) MBDMH (4)** LC 50 : >5620 ppm (ppm) 00137089, 433401111 / Acceptable / Practically nontoxic

DCEMH

(99.4) LC 50 : >5620 ppm

NOAEC = 1780 ppm (reduction in body weight) 0014535 4 / Acceptable/ Practically nontoxic
NR = not reported *Corrected for purity unless otherwise noted. **Monobromodimethylhydantoin byproduct impurity.

### 66 Toxicity of Halohydantoins to Aquatic Organisms

Freshwater Fish

The re are e ight acute

- toxicity studies for BCDMH, DCDMH, and DBDMH which categorize the TGAI as being highly to moderately toxic to freshw ater fish (LC 50 

### ’s range from 0.4 0 to 2.33 m g ai/L ; Table C3 ). No additional acute data are anticipated to be required

.

There are no chronic data ava ilable for the monohaloalkylhydantoin a.i.s or the monohaloalkylhydantoin degradates. In the absence of such data, the Agency used the ECOSAR class program (version 1.11) to estimate toxicity to the monohalohydantoin, chlorohalohydantoin. Results from th e ECOSAR program provided conflicting information regarding the toxicity of chlorohalohydantoins to aquatic organisms. Depending on where the chlorine is attached to the hydantoin ring, ECOSAR predicted high toxicity, similar to halohydantoins, by extrapo lation to chemicals in the haloimide class or practically no toxicity, similar to DMH, by extrapolation to chemicals in the neutral organics class. There is no confidence in ECOSAR results estimated by extrapolation to the generic class, neutral organics, for this chemical. Chronic d ata on the monohaloalkylhydantoins are anticipated to be required

.

Table C 2

. Available Acute and Chronic Endpoints from Freshwater Fish Ecotoxicity Studies for the TGAI (BCDMH, DCDMH, DBDMH ) Study Type Test species, size, age/ Exposure, pH, temperature Test material (% ai) Toxicity MRID / Status / Toxicity Classification Acute toxicity

Rainbow trout, 0.32 g ( Oncorhynchus mykiss ) Static 1BCDMH (96) 96

- hr LC 50 : 0.14 mg ai/L 95% CLs 0.13

– 0.20 mg ai/L

Probit slope =8.7

NOAEC = 0.04 mg ai/L nr / Acceptable / Highly toxic

Rainbow trout, 0.9 g ( Oncorhynchus mykiss ) Static 1BCDMH (99) 96

- hr LC 50 : 0.75 mg ai/L 95% CLs NR

Probit slope =NR

NOAEC = 0.56 mg ai/L 00142070 / Acceptable / Highly toxic

Rainbow trout, 1.0 g ( Oncorhynchus mykiss ) Static 1BCDMH (96) 96

- hr LC 50 : 0.40 mg ai/L (0.33 mg/L) 95% CLs 0.30

– 0.56 mg ai/L

Probit slope =N/A

NOAEC = 0.18 mg ai/L 00147323 / Acceptable / Highly toxic

### 67 Study Type Test species, size, age/ Exposure, pH, temperature Test material (% ai) Toxicity MRID / Status / Toxicity Classification

Rainbow trout ( Oncorhynchus mykiss ) Static BCDMH (90) 96

- hr LC 50 : 0.67 mg ai/L (0.55 mg/L) 95% CLs 0.57

– 0.77 mg ai/L

Probit slope = 13.2

NOAEC = 0.18 mg ai/L 00142069 / Acceptable / Highly toxic

Rainbow trout, NR ( Oncorhynchus mykiss ) Static DCDMH (97) 96

- hr LC 50 : 0.91 mg ai/L 95% CLs 0.82

– 1.0 mg ai/L

Probit slope = NA

NOAEC < 0.56 00084523 / Acceptable / Highly toxic

Rainbow trout, NR ( Oncorhynchus mykiss ) Static DBDMH (nr) 96

- hr LC 50 : 0.58 mg ai/L (0.40 mg/L) 95% CLs 0.50

– 0.65 mg ai/L

Probit slope = NR

NOAEC <0.38 mg ai/L 00139551 / Supplemental/ Highly toxic

Rainbow trout, NR ( Oncorhynchus mykiss ) Static BCDMH (60%), DBDMH (10.6%), and DCDMH (27.4%) 96

- hr LC 50 : 0.50 mg ai/L ( mg/L) 95% CLs 0.30

– 0.90 mg ai/L

Probit slope = NR

NOAEC = 0.30 mg ai/L 00142069 / Supplemental/

Bluegill , 0.31 g ( Lepomis macrochirus )/ Static, 1BCDMH (99) 96

- hr LC 50 : 0.36 mg ai/L 95% CLs 0.18

– 0.561 mg ai/L

Probit slope = N/A

NOAEC = 0.18 mg ai/L n.r. / Acceptable/ Highly toxic

Bluegill, 0.24 ( Lepomis macrochirus )/ Static, 1BCDMH (96) 96

- hr LC 50 : 0.46 mg ai/L (0.37 mg/L) 95% CLs 0.37

– 0.59 mg ai/L

Probit slope = N/A

NOAEC = 0.18 mg ai/L 00147322 / Acceptable/ Highly toxic

Bluegill, NR ( Lepomis macrochirus )/ Static, DBDMH (nr) 96

- hr LC 50 : 0.75 mg ai/L (0.52 mg/L) 95% CLs 0.53

– 0.94 mg ai/L

Probit slope = 5.4

NOAEC = 0.18 mg ai/L 00137090 / Supplemental/ Highly toxic

### 68 Study Type Test species, size, age/ Exposure, pH, temperature Test material (% ai) Toxicity MRID / Status / Toxicity Classification

Bluegill, NR ( Lepomis macrochirus )/ Static, 1BCDMH (90) 96

- hr LC 50 : 1.17 mg ai/L (0.95 mg/L) 95% CLs 1.05

– 1.30 mg ai/L

Probit slope = N/A

NOAEC = 0.75 mg ai/L 00142070 / Acceptable/ Moderately toxic

Bluegill, NR ( Lepomis macrochirus )/ Static, DCDMH (97) 96

- hr LC 50 : 2.33 mg ai/L 95% CLs 1.78

– 2.98 mg ai/L

Probit slope = 6.6

NOAEC = 0.87 mg ai/L 00146039 / Acceptable/ Moderately toxic

Bluntnose minnow, 0.3 g ( Pimephales notatus )/ Static 1BCDMH (formulation) 96

- hr LC 50 : 2.25 mg ai/L ( mg/L) 95% CLs 2.0

– 2.5 mg ai/L

Probit slope = 14.9

NOAEC = 1.7 mg ai/L 00046053 / Acceptable/ Moderately toxic

N/A: not applicable



### Freshwater Invertebrates

T he six acute

- toxicity studies submitted for BCDMH, DCDMH, and DBDMH categorize the TGAI as being highly toxic to freshwater inve rtebrates (LC 50 

### ’s = 0.47 to 0.87 m g ai/L ; Table C 3 ). No additional acute data are anticipated to be required.

No acceptable chronic data for dihalo

- or monohalohydant oins are available (one unacceptable study was previously submitted). In the absence of such data, the Agency used the ECOSAR class program (version 1.11) to estimate toxicity to the monohalohydantoin, chlorohalohydantoin. Results from the ECOSAR program provided conflicting information regarding the toxicity of chlorohalohydantoins to aquatic organisms and therefore chronic d ata on the monohaloalkylhydantoins are anticipated to be required

— see the discussion under freshwater fish

.

### 69 Table C3

. Available En dpoints from Freshwater Invertebrate Ecotoxicity Studies for the TGAI (BCDMH, DCDMH, DBDMH , DCEMH ) Study Type Test species, size, age/ Exposure, pH, temperature Test material (% ai) Toxicity MRID / Status / Toxicity Classification Acute toxicity

Waterflea , <24 h ( Daphnia magna ) Static DCDMH (97) 48

- hr EC 50 : 0.47 mg ai/L 95% CLs 0.43

– 0.57 mg ai/L

Probit slope = NA

NOAEC = 0.10 mg ai/L 00084524 / Acceptable/ Highly toxic

Waterflea , <24 h ( Daphnia magna ) Static DCDMH (97) 48

- hr EC 50 : 0.50 mg ai/L 95% CLs 0.43

– 0.57 mg ai/L Nominal concentration

Probit slope = 5.7

NOAEC = 0.10 mg ai/L 00084524 / Acceptable/ Highly toxic

Waterflea , <24 h ( Daphnia magna ) Static 1BCDMH (99) 48

- hr EC 50 : 2.3 mg ai/L 95% CLs NR Nominal concentration

NOAEC = 1.0 mg ai/L 00142073 / Acceptable/ Moderately toxic

Waterflea , <24 h ( Daphnia magna ) Flow through 1BCDMH (96) 96

- hr EC 50 : 0.10 mg ai/L Nominal concentration

NOAEC = 0.022 mg ai/L NR / Acceptable/ Very highly toxic

Waterflea , <24 h ( Daphnia magna ) Static 1BCDMH (96) 48

- hr EC 50 : 0.75 mg ai/L 95% CLs 0.56

– 1.0 mg ai/L Nominal concentration

NOAEC = 0.32 mg ai/L 00147324 / Acceptable/ Highly toxic

Waterflea , <24 h ( Daphnia magna ) Static BCDMH (90) 48

- hr EC 50 : 0.87 mg ai/L 95% CLs 0.81

– 0.93 mg ai/L Nominal concentration

Probit slope = 3.7

NOAEC = 0.18 mg ai/L 00128166 / Acceptable/ Highly toxic

Waterflea , <24 h ( Daphnia magna ) Static DBDMH (nr)

- Glybrom 48

- hr EC 50 : 0.84 mg ts/L 95% CLs 0.77

– 0.91 mg ts/L Nominal concentration

Probit slope = 12.9

NOAEC = 0.30 mg ts/L 00137091 / Supplemental/ Highly toxic

Waterflea , <24 h ( Daphnia magna ) Static DCDMH (nr) 48

- hr EC 50 : 0.84 mg ai/L 95% CLs 0.77

– 0.91 mg ai/L

Probit slope = 12.9

NOAEC = 0.32 mg ai/L ACC252094 / Supplemental/ Highly toxic

### 70 Study Type Test species, size, age/ Exposure, pH, temperature Test material (% ai) Toxicity MRID / Status / Toxicity Classification

Waterflea, <24 h ( Daphnia magna ) flowthrough Dantobron BTB 93.9 total halogens (DBDMH, BCEMH) 48

- hr EC 50 : 0.63 mg ts/L 95% CLs 0.42

– 0.94 mg ts/L Measured concentration

NOAEC = 0.42 mg ts/L (mortality) 43179707 / Acceptable/ Highly toxic

Waterflea, <24 h ( Daphnia magna ) static DCEMH (99.4) 48

- hr EC 50 : 0.95 mg/L 95% CLs 0.75

– 1.2 mg/L Nominal concentration

NOAEC = 0.75 mg/L (mortality) 00145357 / Acceptable/ Highly toxic

Waterflea, <24 h ( Daphnia magna ) static DBDMH (27.3) DCDMH (18.8) 1BCDMN (23.1) 3BCDMN (23.1) 48

- hr EC 50 : 0.48 mg ts/L 95% CLs 0.53

– 0.42 mg ts/L Nominal concentration

Probit slope = 7.382

NOAEC = 0.3 mg ts/L (mortality) 0046053, 93075005/ Acceptable/ Highly toxic

Waterflea, <24 h static 1BCDMH (60) DCDMH (27.4) DCEMH (10.6) 48

- hr EC 50 : 0.4 mg ts/L 95% CLs 0.3

– 0.5 mg ts/L Nominal concentration

NOAEC = 0.3 mg ts/L (mortality) 0014968/ Acceptable/ Highly toxic

Chronic toxicity

Waterflea , <24 h ( Daphnia magna ) Flow through 1BCDMH (99.9) 21

- day NOAEC = 70.9 mg ai/L 21

- day LOAEC = 116 mg ai/L 42721701 / Acceptable/ NA



### Estuarine/Marine Fish and Invertebrates

A cute toxicit y studies are available (Table C 4 ) for BCDMH for three saltwater species (sheepshead minnow, mysid shrimp, and the eastern oyster) and with various mixtures of dihalohydantoins for these same three species . Th e se data categorize the halohydantoins as being moderately toxic to estuarine/marine fish and highly toxic to e stuarine/marine invertebrates. No additional acute data are anticipated to be required.

No acceptable chronic data for dihalo

- or monohalohydantoins are available. In the absence of such data, the Agency used the ECOSAR class program (version 1.11) to estimate toxicity to the monohalohydantoin, chlorohalohydantoin. Results from the ECOSAR program provided conflicting information regarding the toxicity of chlorohalohydantoins to aquatic organisms and ther efore estuarine/marine fish and mysid shrimp chronic d ata on the monohaloalkylhydantoins are anticipated to be required

— see the discussion under freshwater fish

.

### 71 Table C4

. Available Endpoints from Saltwater Fish and Invertebrate Ecotoxicity Studies for th e TGAI ( BCDMH , DCDMH, DCDMH ) Study Type Test species, size, age/ Exposure, pH, temperature, salinity Test material (% ai) Toxicity MRID / Status / Toxicity Classification

Sheepshead minnow, 0.27 g, 22

mm ( Cyprinodon variegatus ) Flowthrough, NR, 1BCDMH (60) DCDMH (27.4) DCEMH (10.6) LC 50 = 1.2 mg Br 2 /L 95% CLs 1.0

– 1.6 Br 2 /L Measured concentration

Probit slope = 1.37

NOAEC < 0.2 mg Br 2 /L (30% mortality at lowest treatment concentration) 40993103 / Acceptable/ Moderately toxic

Sheepshead minnow, 0.27 g, 22

mm ( Cyprinodon variegatus ) Flowthrough, NR, BCDMH (90) LC 50 = 1.5 mg eq/L 95% CLs 1.0

– 2.4 eq/L Measured concentration

NOAEC = 0.32 mg eq/L (lethargy) 42076102, 43687301/ Acceptable/ Moderately toxic

Sheepshead minnow, 29 + 2 days old, 0.05 g, 8

– 22 mm ( Cyprinodon variegatus ) Static, NR. 22

- 25 o C, 21 ppt DBDMH (27.3) DCDMH (18.8) 1BCDMN (23.1) 3BCDMN (23.1) LC 50 = 20 mg ts/L 95% CLs 17

– 23 mg ts/L Nominal concentration

NOAEC = 11.2 mg ts/L 0046053 / Supplemental (low D.O.)/ Slightly toxic

Eastern oyster, spat (shell deposition) ( Crassostrea virginica ) Flowthrough, ,11 o C, 32 ppt BCDMH (60) DCDMH (27.4) DCEMH (10.6), 96

- h LC 50 = 0.86 mg Br 2 /L 95% CLs NR Measured concentration

NOAEC = 0.37 mg Br 2 /L 40993101/ Acceptable/ Highly toxic

Eastern oyster, spat (shell deposition) ( Crassostrea virginica ) Flowthrough, 7.7

- 8.0, 20

- 22 o C, 30

- 31 ppt 1BCDMH (90) 96

- hr EC 50 : 1.1 mg eq/L 95% CLs 1.01

– 1.15 mg eq/L Measured concentrations

NOAEC = 0.73 mg eq/L 42076101, 43687302 / Acceptable/ Moderately toxic

Eastern oyster, avg 0.18 g ww tissue (acute mortality test) ( Crassostrea virginica ) Static, NR, 22

- 24 o C, 20

- 22 ppt DBDMH (27.3) DCDMH (18.8) 1BCDMN (23.1) 3BCDMN (23.1) 96

- h LC 50 > 640 mg ts/L Nominal concentration

NOAEC <20 mg ts/L (mortality in all exposure concentrations except control) 0046053 / Supplemental (low D.O., not sensitive life stage mortality study)/ Slightly toxic

Mysid shrimp, <24 h old ( Americamysis bahia ) Flowthrough, , 25 + 1 o C, 31 ppt BCDMH (60) DCDMH (27.4) DCEMH (10.6), 96

- h LC 50 = 0.92 mg Br 2 /L 95% CLs 0.7

– 1.4 mg Br 2 /L Measured concentrations

Probit slope = 5.0

NOAEC = 0.1 mg Br 2 /L (mortality) 40993102 / Acceptable/ Highly toxic

### 72 Study Type Test species, size, age/ Exposure, pH, temperature, salinity Test material (% ai) Toxicity MRID / Status / Toxicity Classification

Mysid shrimp, <24 h old ( Americamysis bahia ) Flowthrough , , 7.8

- 7.9, 26 + 1 o C, 31

- 32 ppt 1BCDMH (90) 96

- h LC 50 = 1.8 mg eq/L 95% CLs 1.5

– 2.0 mg eq/L Measured concentrations

NOAEC = 0.36 mg eq/L (mortality and erratic swimming behavior) 42076103, 43687303 / Acceptable/ Moderately toxic

Grass shrimp, avg 0.18 g, 17

- 38

mm ( Palaemonetes pugio ) Static, NR, 19

- 20 o C, 20 ppt DBDMH (27.3) DCDMH (18.8) 1BCDMN (23.1) 3BCDMN (23.1) 96

- h LC 50 = 13.8 mg ts/L 95% CLs 11.6

– 16.4 mg ts/L Nominal concentration

Probit slope = 5.276

NOAEC = 0.64 mg ts/L (mortality) 0046053 / Supplemental (low D.O.)/ Slightly toxic

NA: not applicable
ts: test substance eq: equivalents of


### Aquatic plants

No data for the dihalo or monohalohydantoins have been submitted. Data using the monohalohydantoins are anticipated to be required for one vascular aquatic species ( Lemna sp., OCSPP 850.4400) and for four species of nonvascular plants ( OCSPP 850.4500 : green algae, freshwater and marine diatom; and OCSPP 850.4550: cyanobacteria ).

Semi

- aquatic and Terrestrial P lants

No seedling emergence or vegetative vigor data for the dihalo or monohalohydantoins have been submitted. Seedling emergence and vegetative vigor d ata for rice using the monohalohydantoins

are anticipated to be required

.

### 73 

# Appendix D Ecotoxicity Profile for DMH and EMH

A review of toxicity effects data for the major dialkyl degradates

, DMH and EMH

, contained within the Agency ’s files is provided in this appendix. Additionally, for data gaps the results of modeled values from ECOSAR that will be used in the risk assessme nt are identified and discussed.

Toxicity of DMH and EMH to Terrestrial Organisms

Birds

There is an avian acute oral study and a subacute dietary study for DMH but not for EMH (Table D1) . Based on the acute data

, DMH is practically nontoxic to birds. There are no toxicity data for EMH but because of the similarity in the two compounds, EMH would also be expected to be practically nontoxic to birds. No additional data are anticipated to be required.

Table D1

. Av ailable Acute Avian Ecotoxicity Studies for the degradate DMH

Study Type Species Test material

(% ai) Toxicity * MRID / Status / Toxicity Classification

Acute

– Avian Oral 850.2100 Northern Bobwhite ( Colinus virginianus ) DMH (97.2) LD 50 : >2250 mg ai /kg

- bw ( mg ai/kg

- bw)

NOAEL = 1350 mg ai/kg

- bw Acc # 253966

- 72 / Acceptable / Practically nontoxic

Acute

– Avian Dietary 850.2200 Northern Bobwhite ( Colinus virginianus ) DMH (97.2) LC 50 : >5000 ppm

NOAEC > 5000 ppm 43289904 / Acceptable / Practically nontoxic

Mallard

( Anas platyrhynchos ) DMH (97.2) LC 50 : >5000 ppm

NOAEC > 5000 ppm 43289903 / Acceptable / Practically nontoxic *Corrected for purity unless otherwise noted.



### Mammals

See Appendix A for toxicity data available on mammals. No additional data are anticipated to be required.

Toxicity of DMH and EMH to Aquatic Organisms

Freshwater Fish

There are five acute tests with three species for the major degradate, DMH. The major degradate, DMH, is classified as practically nontoxic. There are no toxicity data on EMH.

### 74 There is one fish chronic (early

- life stage) study available for the degradate DMH. The study was conducted using the fathead minnow ( Pimephales promelas ). The lowest observed adverse effects were on growth at 29 mg ai/L (Tabl e D2 ). The NOAEC is 14 mg ai/L. An acute

- to

chronic ratio for freshwater fish is 1000 for DMH based on the definitive fathead minnow value divided by the chronic value (14,100 mg/L ÷ 14 mg/L= 1000). Application of this ACR to the most acutely sensitive species, rainbow trout, results in a chronic NOAEC for this species of 12.7 mg/L. No additional DMH data are expected to be required.

Data for EMH w ere modeled using ECOSAR v. 1.10 (see results at end of this appendix). EMH falls into the carbonyl urea g roup, as does DMH. To check if the model would provide reasonable results ECOSAR v.1.10 for DMH was also run and the model results compared to measured values. The acute DMH toxicity value for fish (290 mg/L) was lower than measured values for fish (>972 to 14,100 mg/L) but the chronic NOAEC was on the same order (2.1 mg/L versus 12.7)

. The model predicts that EMH would be slightly more toxic than DMH. The chronic EMH value of 1.2 mg/L for fish from ECOSAR v1.10 will be used for EMH. No additional EMH data are expected to be required.

Table D2

. Available Acute and Chronic Endpoints from Freshwater Fish Ecotoxicity Studies for the Degradate (DMH)
Study Type Test species, size, age/ Exposure, pH, temperature Test material (% purity) Toxicity MRID / Status / Toxicity Classification
Acute toxicity

Rainbow trout , 0.24 g Static DMH (97.1) 96

- hr LC 50 : >972 mg/L 42373601 / Acceptable/ Practically nontoxic

Rainbow trout, NR Static DMH (97) 96

- hr LC 50 : 12,700 mg/L 95% CLs 11,300

– 14,200 mg/L

Probit slope = 13.2

NOAEC = 5,000 mg/L 00046053 / Acceptable/ Practically nontoxic

Bluegill, 0.45 g Static DMH (97.1) 96

- hr LC 50 : >1017 mg//L 42368501 / Acceptable/ Practically nontoxic
Fathead minnow, 0.3 g Static DMH (97.1) 96

- hr LC 50 : >1085 mg/L 42374702 / Acceptable/ Practically nontoxic

Fathead minnow, NR Static DMH (97) 96

- hr LC 50 : 14,100 mg/L 95% CLs 13,386

– 14,990 mg/L

NOAEC = 10,000 mg/L 00046053 / Supplemental/ Practically nontoxic

Chronic toxicity

Fathead minnow ( P. promelas ) DMH (99.9, 98.34

labeled) NOAEC = 14 mg/L LOAEC = 29 mg/L Measured concentrations 42721702 / Acceptable/ N/A

### 75 Freshwater Invertebrates

There are two acceptable acute DMH studies with the waterflea, Daphnia magna (Table D3). The results classify DMH as practically nontoxic. There are no chronic data for DMH . There

are no acute or chronic data for EMH.

Chronic daphnid data for DMH was modeled using ECOSAR v. 1.10 (see results at end of appendix), EMH falls into the carbonyl urea group, as does DMH. A comparison of the modeled acute DMH value (820 mg/L) was lower than actual study values (>1070

– 6,051 mg/L). Data for EMH was also modeled using ECOSAR v. 1.10 (see results at end of this appendix). The model predicts that EMH would be slightly more t oxic than DMH. The chronic EMH value of 4.8 mg/L for fish from ECOSAR v1.10 will be used for EMH. No additional DMH or EMH data

are anticipated to be required.

Table D3 . Available Endpoints from Freshwater Invertebrate Ecotoxicity Studies for the Degrad ate (DMH) Study Type Test species, size, age/ Exposure, pH, temperature Test material (% purity) Toxicity MRID / Status / Toxicity Classification Waterflea, <24 h ( Daphnia magna ) Static, DMH (97.1) 48

- hr LC 50 : >1070 mg/L Measured concentration 42373603 / Acceptable/ Practically nontoxic

Waterflea DMH (>99.9, labeled 98.34) -- 42721701/ Unacceptable (mercury contamination ) Waterflea, <24 h ( Daphnia magna ) Static DMH (97) 48

- hr LC 50 : 6051 mg/L 95% CLs 5,300

– 6,765 mg/L Nominal concentration 00046053 / Supplemental/ Practically nontoxic



### Estuarine/Marine Fish and Invertebrates

Acute toxicity studies are available for the sheepshead minnow, mysid shrimp, and the eastern oyster with the major degradate, DMH (Table D4) . These studies indicate that DMH is practically nontoxic. Modeled data for an estuarine/marine fish and the mysid are available. This data indicate that EMH would also be practically nontoxic. No additional acute toxicity data are anticipated for estuarine/marine fish and invertebrates.

C hronic estuarine/marine fish data for DMH and EMH w ere modeled using ECOSAR v. 1.10 ( see results at end of appendix). EMH and DMH fall into the carbonyl urea group. The chronic saltwater fish NOAEC value of 3.8 mg/L for EMH from ECOSAR v. 1.10 will be us ed to screen risks for the exposure to the se degradates. No additional fish chronic data for EMH or DMH are anticipated.

The model does not provide EMH or DMH chronic value s for the mysid shrimp. However, the model does indicate that the mysid shrimp (96

- hr LC 50 

### = 1,449 and 5,987 for EMH and DMH, respectively) is expected to be less sensitive than the estuarine/marine fish (96

- hr LC 50 

### = 150 and 254 for EMH and DMH, respectively) on an acute basis ; therefore chronic risks calculated

### 76 for estuarine/marine fish should be conservative for the mysid shrimp. No additional invertebrate chronic data for EMH or DMH are anticipated.

Table D4

. Available Endpoints from Saltwater Fish and Invertebrate Ecotoxicity Studies for the Degradate (DMH) Study Type Test species, size, age/ Exposure, pH, temperature, salinity Test material (% Purity) Toxicity MRID / Status / Toxicity Classification
Sheepshead minnow, 0.27 g, 18

mm ( Cyprinodon variegatus ) Static, 7.6

- 8.2, 20.4

- 21.7 o C, 25 ppt DMH (97.1) 96

- hr LC 50 : >1006 mg/L Measured concentration

NOAEC > 1006 mg/L 42374701/ Acceptable/ Practically nontoxic

Sheepshead minnow, ( Cyprinodon variegatus ) Static DMH (97) 96

- hr LC 50 : 8,100 mg/L

Probit slope = NA

NOAEC = 6,500 mg/L 00046053, 93075035 / Supplemental (low D.O.)/ Practically nontoxic

Sheepshead minnow, 45 + 2 days old, 0.13 g, 10

- 26 mm ( Cyprinodon variegatus ) Static, NR, DMH (97) 96

- hr LC 50 : 8100 mg/L 95% CLs 6,500

– 10,000 mg/L Nominal concentration

Probit slope = NA

NOAEC = 6,500 mg/L 00046053 / Supplemental/ Practically nontoxic

Eastern oyster, 0.18 g ww tissue, adult mortality ( Crassostrea virginica ) Static DMH (97) 96

- hr LC 50 : 12,800 mg/L 95% CLs 11,173

– 14,300 mg/L Nominal concentration

NOAEC < 10,400 mg/L 00046054 / Supplemental (low D.O., not mortality with a sensitive life stage)/ Practically nontoxic Eastern oyster, 32

- 63 mm valve length, shell deposition study ( Crassostrea virginica ) Flowthrough, 7.7

- 8.0, 21.8 + 1 o C, 29

- 32 ppt DMH (97.2) 96

- hr IC 50 : >125 mg/L Measured concentration

NOAEC > 125 mg/L 43289902 / Supplemental (Variable concentrations, high variability in growth)/ Practically nontoxic

Mysid, <24 h old ( Americamysis bahia ) Static, 7.6

- 8.2, 25

- 26 o C, 25 ppt DMH (97) LC 50 >921 mg/L Measured concentration

NOAEC < 921 mg/L 30% mortality 42373602 / Supplemental / Practically nontoxic

Grass shrimp, juvenile ( Palaemonetes pugio ) Static, NR, 20

– 26 o C, 20

- 31 ppt DMH (97) 96

- hr EC 50 : 1,255 mg/L 95% CLs 1,077

– 1,445 mg/L Nominal concentration

Probit slope = 5.8

NOAEC < 760 mg/L 00046053, 93075036 Acc 243015 / Supplemental (low D.O.)/ Practically nontoxic

### 77 Aquatic Plants

No data for EMH or DMH ha ve been submitted. Green algae data for DMH and EMH w ere modeled using ECOSAR v. 1.10 (see results at end of appendix) , EMH and DMH fall into the carbonyl urea group. The green algae 96

- h IC 50 

### value of 0.011 mg/L and MATC (geometric mean of the NOAEC and LOAEC) of 0.003 mg/L of for EMH from ECOSAR v. 1.10 will be used to screen risks for the exposure to green algae from thes e degradates. The model does not provide toxicity data for duckweed, freshwater diatoms, marine diatoms, or cyanobacteria; d ata for EMH and DMH are anticipated to be required for these species.

Semi

- aquatic and Terrestrial P lants

No seedling emergence or vegetative vigor data for DMH or EMH have been submitted. Seedling emergence and vegetative vigor d ata for rice using DMH and EMH are anticipated to be required

. 

## ECOSAR Version 1.10 Results Page for E MH

SMILES : O=C(NC(C1(=O))(CC)C)N1 CHEM : 2,4

- Imidazolidinedione, 5

- ethyl

- 5

- methyl

CAS Num: 005394

- 36

- 5 ChemID1: MOL FOR: C6 H10 N2 O2 MOL WT : 142.16 Log Kow: 0.219 (EPISuite Kowwin v1.68 Estimate) Log Kow: (User Entered) Log Kow: (PhysProp DB exp value

- for comparison only) Melt Pt: (User Entered for Wat Sol estimate) Melt Pt: (deg C, PhysProp DB exp value for Wat Sol estimate) Wat Sol: 2611 (mg/L, EPISuite WSKowwin v1.43 Estimate) Wat Sol: (User Entered) Wat Sol: (Phys Prop DB exp value)

-------------------------------------- Values used to Generate ECOSAR Profile

-------------------------------------- Log Kow: 0.219 (EPISuite Kowwin v1.68 Estimate) Wat Sol: 2611 (mg/L, EPISuite WSKowwin v1.43 Estimate)

------------------------------------------------ Available Measured Data from ECOSAR Training Set

------------------------------------------------

No Data Available

-------------------------------------- ECOSAR v1.1 Class

- specific Estimations

-------------------------------------- Carbonyl Ureas Predicted ECOSAR Class Organism Duration End Pt mg/L (ppm)

=========================== =============== === ======== ====== ========== Carbonyl Ureas : Fish 96

- hr LC50 171.450 Carbonyl Ureas : Daphnid 48

- hr LC50 293.644

### 78 Carbonyl Ureas : Green Algae 96

- hr EC50 0.011 Carbonyl Ureas : Fish ChV 1.235 Carbonyl Ureas : Daphnid ChV 4.783 Carbonyl Ureas : Green Algae ChV 0.003 Carbonyl Ureas : Fish (SW) 96

- hr LC50 149.782 Carbonyl Ureas : Mysid (SW) 96

- hr LC50 1449.146 Carbonyl Ureas : Fish (SW) ChV 3.839

=========================== ========== ======== ======== ====== ========== Neutral Organic SAR : Fish 96

- hr LC50 4643.975 * (Baseline Toxicity) : Daphnid 48

- hr LC50 1752.409 : Green Algae 96

- hr E C50 1608.729 : Fish ChV 373.894 : Daphnid ChV 138.042 : Green Algae ChV 153.299

Note: * = asterisk designates: Chemical may not be soluble enough to measure this predicted effect. If the effect level exceeds the water solubility by 10X, typically no effects at saturation (NES) are reported.

-------------- ---------------- Class Specific LogKow Cut

- Offs

------------------------------ If the log Kow of the chemical is greater than the endpoint specific cut

- offs presented below, then no effects at saturation are expected for those endpoints.

Carbonyl Ureas :

--------------- Maximum LogKow: 5.0 (LC50) Maximum LogKow: 6.4 (EC50) Maximum LogKow: 8.0 (ChV)

Baseline Toxicity SAR Limitations:

--------------------------------- Maximum LogKow: 5.0 (Fish 96

- hr LC50; Daphnid LC50) Maximum LogKow: 6.4 (Green Algae EC5 0) Maximum LogKow: 8.0 (ChV)

------------------------------------------------------------------------------ 

## ECOSAR Version 1.10 Results Page for DMH

SMILES : O=C(NC(C1(=O))(C)C)N1 CHEM : 2,4

- Imidazolidinedione, 5,5

- dimethyl

CAS Num: 000077

- 71

- 4 ChemID1: MOL FOR: C5 H8 N2 O2 MOL WT : 128.13 Log Kow:

- 0.272 (EPISuite Kowwin v1.68 Estimate) Log Kow: (User Entered) Log Kow:

- 0.48 (PhysProp DB exp value

- for comparison only) Melt Pt: (User Entered for Wat Sol estimate ) Melt Pt: 178.00 (deg C, PhysProp DB exp value for Wat Sol est) Wat Sol: 2.828E+004 (mg/L, EPISuite WSKowwin v1.43 Estimate) Wat Sol: (User Entered) Wat Sol: 1E+005 (mg/L, PhysProp DB exp value)

-------------------------------------- Values used to Generate ECOSAR Profile

### 79 -------------------------------------- Log Kow:

- 0.272 (EPISuite Kowwin v1.68 Estimate) Wat Sol: 1E+005 (mg/L, PhysProp DB exp value)

------------------------------------------------ Available Measured Dat a from ECOSAR Training Set

------------------------------------------------

No Data Available

-------------------------------------- ECOSAR v1.1 Class

- specific Estimations

-------------------------------------- Carbonyl Ureas Predicted ECOSAR Class Organism Duration End Pt mg/L (ppm)

=========================== ================== ======== ====== ========== Carbonyl Ureas : Fish 96

- hr LC50 290.340 Carbonyl Ureas : Daphnid 48

- hr LC50 820.629 Carbonyl Ureas : Green Algae 96

- hr EC50 0.010 Carbonyl Ureas : Fish ChV 2.095 Carbonyl Ureas : Daphnid ChV 9.007 Carbonyl Ureas : Green Algae ChV 0.003 Carbonyl Ureas : Fish (SW) 96

- hr LC50 2 53.618 Carbonyl Ureas : Mysid (SW) 96

- hr LC50 5987.038 Carbonyl Ureas : Fish (SW) ChV 5.478

=========================== ================== ======== ====== ========== Neutral Organic SAR : Fish 96

- hr LC50 11556.589 (Baseline Toxicity) : Daphnid 48

- hr LC50 3972.908 : Green Algae 96

- hr EC50 3636.874 : Fish ChV 881.981 : Daphnid ChV 289.369 : Green Algae ChV 273.216

Note: * = asterisk designates: Chemical may not be soluble enough to measure this predicted effect. If the effect level exceeds the water solubility by 10X, typically no effects at saturation (NES) are reported.

---------------- -------------- Class Specific LogKow Cut

- Offs

------------------------------ If the log Kow of the chemical is greater than the endpoint specific cut

- offs presented below, then no effects at saturation are expected for those endpoints.

Carbonyl Ureas :

- -------------- Maximum LogKow: 5.0 (LC50) Maximum LogKow: 6.4 (EC50) Maximum LogKow: 8.0 (ChV)

Baseline Toxicity SAR Limitations:

--------------------------------- Maximum LogKow: 5.0 (Fish 96

- hr LC50; Daphnid LC50) Maximum LogKow: 6.4 (Green Algae EC50) Maximum LogKow: 8.0 (ChV)

### 80 

# Appendix E Screening Level Down

- the

Drain Analysis

The Down

- the

- Drain (DtD) module of E

- FAST (Exposure and Fate Assessment Screening Tool), version 2 was used to screen for the potential for aquatic organisms downstream of domestic wastewater treatment plants to be exposed to halohydantoins and their degradates. The Down

- the

- Drain module uses daily per capita release of household wastewaters, stream di lution factors, and wastewater treatment plant removal efficiency to provide both high

end and median (average) time

- averaged surface water concentrations of chemicals discharged from domestic wastewater treatment plants. The high

- end scenario uses surfac e water concentrations downstream of domestic wastewater treatment plants based on the 10 th 

### percentile stream dilution factor (SDF); the average scenario uses surface water concentrations based on the 50 th 

### percentile SDF. SDF is defined as the ratio of th e stream flow downstream of a wastewater treatment plant to the wastewater treatment plant flow. Inputs used to run the DtD module included concentrations of concern (COCs) for aquatic organisms, percent removal during wastewater treatment , and wastewate r treatment plant influent volumes (generally derived from information on maximum annual production volume of the chemical being assessed).

The results of the DtD module are expressed as number of days of exceedance of COCs for aquatic organisms. COCs for acute effects were determined by dividing LC 50 

### values from acute toxicity tests on aquatic vertebrates and invertebrates by 2. COCs for chronic effects for

non

- listed species were based on No Observed Adverse Effects Concentration (NOAEC) values from tests on aquatic vertebrates and invertebrates . COCs for listed endangered and threatened aquatic organisms were determined by dividing LC 50 

### values from acute toxicity tests on aquatic vertebrates and invertebrates by 20. The Down

- the

- Drain module was r un using a high

- end scenario to determine whether the model predicted exceedances of concentrations of concern.

### 81 

# Appendix F Product Chemistry

The Halohydantoins product chemistry information is summarized in Table E1 (source: MRIDs 147318

, 

### 35011701, 41952701, 41952801, 42478501

, 43315902

, and EPI Suite v4.1)

.
Table E1

– Product Chemistry of Halohydantoins

Guideline Numbers PC Code/AI
006315 BCDMH 006322 BCDMH 006317 DBDMH 028500 CDMH 028501 DCDMH 128826 DCEMH 128989 BCEMH
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 Potentiometric titration with silver nitrate HPLC

830.1900 Submittal of samples CBI

830.6302 Color White

830.6303 Physical State Solid

830.6304 Odor Faint halogen odor

830.6313 Stability Stable under normal conditions. Starts to decompose at160 °C

830.6314 Oxidation/Reduction Oxidizer. Incompatible with oxidizers and bases.

830.6315 Flammability Non

- flammable. Does not contain a combustible liquid.

### 82 Guideline Numbers PC Code/AI
006315 BCDMH 006322 BCDMH 006317 DBDMH 028500 CDMH 028501 DCDMH 128826 DCEMH 128989 BCEMH
830.6316 Explodability The ingredients are non

- combustible.

830.7000 pH at25°C 6.5 (l% slurry at 25°C)

830.7050 UV/Visible Absorption UV max=260nm. Photolytically stable. Does not p hotolyze as it does not absorb UV light at wavelength s >260 nm
830.7200 Melting point (°C) 159

– 163 163

- 164 197

- 203 157.97 130

- 133 131.08 184.58

830.7220 Boiling point Not applicable (solid)

830.7300 Density g/cm 3 1.9 1.918 1.36 1.432 1.888 1.502 1.794

830.7370 Dissociation Constant pKa(s) pKa(s) ranged from 7.48 to 7.56 and 8.64 to 8.79 in 5% acetonitrile solution.

830.7550 Log Kow − 0.94

− 0.94

− 0.94

− 0.61

− 0.94

− 0.45 0.74

830.7840 Solubility in water 0.22 g/100 g at 25°C 0.22 g/100 g at 25°C 0.1 g/100 g at 20 °C 0.20 g/ 100
g at 25 oC 0.21 g/100 g at 25 oC 0.1 g/100 g at 20 °C 0.1 g/100 g at 20 °C
830.7860 Solubility in organic solvents Soluble in many organic solvents

830.7950 Vapor pressure mm Hg at 25 °C 6.61x10 - 6 3.54x10 - 6 1.2x10 - 6 9.31x10 - 7 2.4x10 - 5 1.29x10 - 5 1.87x10 - 8

### 83 

# Appendix G Comments Received Concerning the Preliminary Work Plan

On June 26, 2013 EPA opened a 60

- day public comment period on the preliminary work plan (PWP) for the registration review of halohydantoins. The comment period ended on August 26, 2013. During the public comment period the Agency received 29 comments. Comments received resulted in a modification to the anticipated data needs detailed in the Halohydantoins PWP.

Most of the comments were received fro m the American Chemistry Council (ACC) Biocides Panel Halohydantoins Work Group (Work Group), whose members include EPA registrants Albemarle Corporation; BioLab, Inc., a Chemtura Company; BWA Water Additives, US; ICL

- IP America, Inc.; and Lonza Inc. The W ork Group comments sought to c onfirm current registered product uses and labeled application rates, address assumptions EPA used for estimating environmental exposure potentials from halohydantoin use categories, and present technical corrections

. The Ag ency received additional comments from The Bay Area Clean Water Agencies (BACWA), the California Stormwater Quality Association (CASQA), the FIFRA Endangered Species Task Force (FESTF), and the Physicians Committee for Responsible Medicine (PCRM).

The An timicrobials Division (AD) generally used an outline format to address the comments (with name of submitter, comment and AD response, in that order).

### Page 84 of 95 Comments Received on the Registration Review Preliminary Work Plan for Halohydantoins

Submitter: American Chemistry Council (ACC) Biocides Panel Halohydantoins Work Group (Work Group)

1. Comment: The Work Group members are reviewing tables to delete any obs olete registered product uses listed in Table 6, and to confirm and standardize the application rates from product labels for accuracy as presented in Table 7. This information is fundamental to determine data needs for assessing human and environmental ex posure potentials and for risk assessment calculations.

1. Page 11, Table 6: Corrections to listed dose rates to be taken into account.

a) A pplication rates are in ppm of halohydantoin. However, normal practice is to state dose rates in terms of available Cl2 or Br2 as the type of halohydantoin can affect the dose needed. The listed doses seem to be a mixture of halohydantoin application rates and the available Cl2 or Br2 residual levels.

b) It appears that some of the dose rates presented may be incorre ct, for example a higher dose level is generally quoted for spas than pools. Also residential premises and hard surfaces are quoted as requiring very high dose levels of 588 ppm in comparison to hard surfaces in food handling establishments (34 ppm). These dose levels have then been used for exposure assessment which would lead to gross over

- estimations of risk.

c) The following corrections to certain of the listed doses were submitted in May 2010 in response to the publication of the Halohydantoin RED: M ore correctly, this should read “add 0.5 to 2.5 pounds per 10,000 gallons of water to yield 6

- 30 ppm halohydantoin with 1

- 4 ppm halogen” for pools (1

- 3 ppm halogen in residential pools and 3

- 5 ppm halogen in commercial pools). Likewise for spas, “add 0.1 t o 0.5 pounds per 1,000 gallons of water to yield 12 to 60 ppm of halohydantoins with 2

- 6 ppm halogen” (2

- 4 ppm halogen in residential spas, and 4

- 6 ppm halogen in commercial spas). For decorative waters without fish, the halogen use level should be 0.5 to 5.0 ppm halogen to reflect approved end

- use product registration use level.

d) Consider revising the table to include the application rate in amount of product per volume of water for applying the product into a water system. For hard surface disinfectio n consider giving a typical area that the typical rate amount would cover. Furthermore, indicate if dosing is shock, intermittent or continuous applications. In addition to providing a typical range, give an actual typical single dose value that should be used for more representative risk assessment, rather than working with the top end of the range, dosed continuously as a worse case.

### Page 85 of 95 AD Response: EPA concurs with the comments included in paragraphs a, b and c, and has revised Table 6 accordingly. With respect to paragraph d, EPA prefers to list the applications rates by the amount of active ingredient applied rather than by the amount of product applied. This enables the EPA to compare application rates between products that have different a.i. concentrations so that a representative application rate for a particular use can be used for risk assessment. The EPA is also aware that rates can var y depending upon the type of treatment and considers this information in selecting the rates for risk assessment and in characterizing the calculated risks.

2. Comment: Page 12, Sec 1.4.2, para 2: Halohydantoins are currently not restricted from use in outdo or pools, as incorrectly indicated in the PWP based on statement cited from Kline, 2006. Also for page 22, starting last para, through page 23.

AD Response: The PWP does not state that halohydantoins are restricted from use in outdoor pools. Rather, it s tates that “...the halohydantoins are not used in outdoor pools because bromine is not stable in sunlight...” On p. 22, the PWP goes on to state that “... the labels do not preclude their use in outdoor pools. Therefore, potential exposure from this route will be evaluated as part of the risk assessment for registration review.” The Agency realizes that this is an issue only for the bromohydantoins and not for the chlorohydantoins.

3. Comment: Page 22, Sec 3.3.2: References to “household cleaning products preserved with hydromethylhydantoins

. ” Halohydantoins are not used for preservation of products whereas the similar substance dimethylol dimethylhydantoin (DMDMH) is. While aggregate exposures to the common DMH chemical moiety may be of interest, DMDMH is outside sc ope of halohydantoins case (see page 9 and page 13). The following references to DMDMH should be deleted: a) para 1 (except first sentence) and para 2 b) Page 23 para 2 second sentence. c) Page 23, Sec 3.4.1: Delete “...and preservative of paper

- making chemicals.” , and “...treatment of fabrics and diapers” as these uses also pertain to the preservative DMDMH, not covered in this PWP.

AD Response: EPA concurs with these comments and has revised the FWP accordingly.

4. Comment: Page 24 and page 25: Release of monohalogenated species is assumed based on EPI Suite assumptions. Is EPI Suite valid for this type of substance that hydrolyzes in water? It should also be mentioned that the hydrolysis rates summarized in Annex B are those for distilled water. Hydrolysis rates due to the antimicrobial action are higher.

AD Response: The Agency would like to clarify that the hydrolysis data discussed for the dihalohydantoins is not EPI Suite based but it is based on the data submitted by the registrants and was reviewed and accepted by the Agency ( ACC 263903 and MRID# 42466201)

### Page 86 of 95 5. Comment: Page 26+, Sec 4.2: If the models use the dose rates from Table 6 then the assumptions on dosing are probably over

- estimated. If the dose rate is the amount of residual halogen then the actual amount of halohydantoin initially dosed will be unknown and potentially underestimated.

AD Response: EPA has worked to clarify the use rates and calculations in the risk assessment and will consider any changes to the use or dose rates. However, with regard to input data the models use, the Down

- the

- Drain module of E

FAST uses wastewater treatment plant influent volume in kilograms per year rather than dose rates presented in Table 6 of this Preliminary Work Plan.

6. Comment: Page 26 Sec 4.2 , end of first paragraph: The sentence on biodegradation infers that if di

- halo species do not inhibit sewage sludge micro

- organisms and DMH/EMH are readily biodegradable, then the downstream exposure could be ruled out.

AD Response: The last sentence a t the end of the first paragraph of Section 4.2 states, “Unless biodegradation during wastewater treatment is determined to be a significant removal process for halohydantoin degradates entering wastewater treatment plants, based on a half

- life for removal of both halogen atoms from halohydantoins via hydrolysis at pH values of 5, 7, and 9 of less than one day, aquatic organisms in surface water downstream of both direct and indirect sources of halohydantoins would be expected to be exposed primarily to deg radates, DMH, EMH, and monohalohydantoins” (ACC 263903; MRID 42466201).

With a hydrolytic half

- life of one hour for dihalohydantoins to form

m onohalohydantoins, dihalohydantoins are expected to form monohalohydantoins quite rapidly. Unlike the unhalogena ted hydantoins, DMH and EMH, which have been found to be relatively nontoxic to aquatic organisms, the Agency has found no evidence to indicate that monohalohydantoins are not as toxic to aquatic organisms as dihalohydantoins, which studies on aquatic orga nisms indicate are highly toxic. Consequently, because of uncertainty about toxicity of monohalohydantoins and about their potential to biodegrade or be removed by fate and transport processes other than hydrolysis, there is a potential concern for waste water treatment plant microorganisms and aquatic organisms that may be exposed to monohalohydantoins. Data are anticipated to be needed to reduce uncertainties about toxicity to wastewater treatment plant and aquatic organisms and rate of disappearance of monohalohydantoins in the environment.

7. Comment: Page 26 Sec 4.2, last para: Is ECOSAR valid for monohalohydantoins? Toxicity of the dihalohydantoins is related to release of HOBr/HOCl not the DMH moiety as can be seen from consideration of HOBr/HOCl aquat ic toxicity.

AD Response: As the workplan stated on page s 26 and 69 , ECOSAR modeling provided conflicting estimates for the ecotoxicity of the monohalohydantoins. The ECOSAR values and the Acute to Chronic ratio values were presented to show that the Agency cannot rule out the possibility of toxicity to aquatic organisms

. Therefore, Table 8 provides a list of studies which would definitively address whether the monohalohydantoins are toxic to aquatic organisms. EPA will consider any information

### Page 87 of 95 the workgroup can provide to show that monohalohydantoins are not toxic and that DMH is not chronically toxic. 8. Comment: Page 27, 1st para: MRID 408046

- 03: This study has been identified as invalid under EU evaluation due to lack of evidence of microbial viab ility.

AD Response: The Agency will re

- evaluate this study during the risk assessment phase. Additional data are not anticipated to be required for aerobic metabolism of DMH, but the Agency will consider pertinent information on the aerobic degradation of DMH if the ACC Biocides Panel would like to submit the information. If the study MRID 408046

- 03 is found to be invalid, the Agency will assume that DMH does not degrade by aerobic metabolism.

9. Comment: Page 27, last para: Are the data needs identified in Table 8 intended for “screening level risk assessment” as indicated in the text, or more extensive?

AD Response: The Agency will first do a “screening level risk assessment” to determine where to focus the more in

- depth a risk assessment that supports a complete endangered species determination for the dihalohydantoins

.

10. Comment: Page 35+, Sec 4.3.1: Review with EPA the fate of di

- and monohalogenated hydantoins for environmental exposure estimates with these uses. Need to investigate if monohalohydant oin(s) actually will be released to environment with these uses, or if it/they will be consumed before significant environmental exposure.

AD Response: The purpose of the ready biodegradability test which is anticipated to be required on monohalohydantoins, is to determine if the monohalohydantoin will be degraded prior to release to the environment. The hydrolysis data show degradation of the monohalohydantoin within 24 hours, but depending on the use, water containing monohalohydantoin could be released prior to degradation.

The Agency encourages the submission of environmental fate data on the monohalohydantoin, DMH and EMH to clarify the behavior of these compounds in the environment.

11. Comment: Page 35+, 4.3.2: There are several references to ECOSAR predictive modeling used when data are not available. However, since different ECOSAR versions are cited, how will this impact the estimates derived from each? Also, there may be limitations based on chemical structure to the use of ECOSAR that need to be investigated for application with these substances. (See comment on page 26 Sec 4.2 above).

AD Response: At the time of the risk assessment, the Agency will consult the most recent version of ECOSAR which is available to the Agency for any endpoint which is not available from registrant submitted information or public literature. As noted before, ECOSAR provided conflicting estimates and the Agency would prefer to have as much data as is feasible.

### Page 88 of 95 12. Comment: Page 38+, Sec 4.4: There are various models used and a number of assumptions to take into account and understand to derive the aquatic and terrestrial wildlife exposure estimates and the screening level down the drain analysis. Since the esti mates derived from these models and screens may trigger substantial testing, that may or may not be necessary, we need to review with EPA to better understand their approach for their Exposure Analysis Plan for these use scenarios; e. g., no removal during wastewater treatment used as a worse case assumption. The Work Group has study data that shows a high percent removal prior to and during WWTP for both the dihalohydantoins and degradants.

AD Response: The Agency will be glad to review study data collec ted by the ACC Biocides Panel Workgroup on the environmental fate of dihalohydantoins and degradates. The conservative nature of the workplan is based on the lack of useful environmental fate information at this time.

13. Comment: Page 39, Table 15: Assumes 50% of dihalogens used are released to surface water as the mono species. The Work Group would like to understand what the basis for this assumption is as data may be available to elucidate this point.

AD Response: The Agency considered information on th e range of possible transit times from source to receptor and on rate of formation of monohalohydantoins, DMH, and EMH from dihalohydantoins in its conceptual models for environmental exposure pathways. As mentioned in the Agency response to comment 6, be cause of uncertainties regarding environmental fate and toxicity of monohalohydantoins formed via hydrolysis of dihalohydantoins, there is particularly a potential concern for wastewater treatment plant microorganisms and aquatic organisms that may be expo sed to monohalohydantoins. Hydrolysis studies on dihalohydantoins that were reviewed by the Agency indicate that the time period for monohalohydantoin levels to be reduced by one

half via hydrolysis can be as much as one day and that one day or less is a short enough time period for monohalohydantoins to reach surface water from the time they are discharged from a source. (The hydrolytic half

- life for formation of DMH and EMH, which are practically non

- toxic to aquatic organisms, has been experimentally determined to be up to one day.) In addition, the Agency has found no information to indicate that the overall half

- life of monohalohydantoins may be less than the hydrolytic half

- life as a result of biodegradation or other potential fate and transport pr ocesses that could remove monohalohydantoins once they are released from a source. Consequently, the Agency used assumptions that conservatively estimated exposure. The Agency welcomes additional scientific evidence that can be use to refine estimates of exposure and risk to degradates of dihalohydantoins.

14. Comment: Page 41, 1st para: Assumption that monohalogens are persistent; on what basis?

AD Response: The Agency does not assume that monohalogens are persistent. On page 38, the workplan discusses t hat chemicals released down the drain reached wastewater treatment plants within a few hours and water is discharged from treatment plants within

### Page 89 of 95 a day. The hydrolysis half life of the monohalohydantoins is expected to be no more than one day and therefo re, unless degraded more rapidly by biotic processes, some monohalohydantoin will be available for release to surface water.

The discussion on page 41 is contrasting the down the drain modeling results of assuming that monohalohydantoins are toxic versu s not toxic since ECOSAR provided conflicting estimates of toxicity.

15. Comment: Page 69 Table C2 and preamble: EPA has stated in several places that during hydrolysis, removal of first halogen takes place in less than 1 hour. However, this fact does not seem to have been considered when reviewing ecotoxicity studies where the organism s must have been exposed to the mono halogen species for the majority of the exposure period (24

– 96 hours for acute studies). Due to the hydrolysis rates of the halogenated species it is unclear how chronic studies would be performed and interpreted

as v ery low levels of HOBr/HOCl are acutely toxic to fish and invertebrates. There are also ethical considerations of performing chronic tests on fish when the toxicity of the substance is linked to the oxidizing effect of the released HOCl/HOBr.

AD Response : For a chronic test with a test material that is not stable, a flow

- through test must be used to ensure exposure. A static test is not appropriate. The anticipated need for ecotoxicity chronic testing with monohalohydantoin will be reevaluated if the

re gistrant provides adequate information that exposure to monohalohydantoin is not likely to occur (see responses to Comments 10 and 12). Regarding ethical considerations of chronic testing, the Agency agrees this is an important issue and will consider thi s information as it conducts the registration review.

16. Comment: Page 81, ECOSAR Version 1.10 Results: Need to identify these results are for DMH, include “DMH” in this header, as for “EMH” on page 80.

AD Response: The Agency agrees that the table on page 81 reflects the result s of the DMH ECOSAR modeling and the final workplan now reflects this addition.

17. Comment: The correct PC Code for the only monohalohydantoin listed is 028500 1

- Chloro

- 5,5

- dimethylhydantoin 1

- Chloro

- 5,5

- dimethyl

- 2,4

- imidazolidinedion e (CDMH; CAS No. 6921

- 17

- 1), see page 6, page 9 Table 3 and page 13 for corrections. Also, on page 47 Appendix A table of toxicology data

– referred to as mono

- chloro

- 5,5

- dimethylhydantoin (MCDMH), which is inconsistent with CDMH used elsewhere.

AD Respo nse: EPA concurs with these comments and has revised the FWP accordingly.

18. Comment: Page 10, Table 5: Formulation terminology for solid forms is from conventional pesticides, and may not be appropriate to antimicrobials (e. g., granules). AEATF

- II Pour Solid Work Group raised this previously with EPA

- AD, in pointing out that “formulation categories and terminologies for conventional pesticides differ from antimicrobial pour solid formulations where the two primary categories are powders and granules. An antimicrobial ready

- to

- use dust similar to an agricultural dust does not exist.

### Page 90 of 95 Althoug h the same term (“granule”) is used in the antimicrobial industry, it does not have the same meaning as an agricultural granule, both from a physical standpoint and its use pattern. Antimicrobial powders and granules, with very few exceptions, are added to water or some other liquid carrier. As such antimicrobial powders and granules are typically fully water soluble.” This distinction in terms used for solid forms of antimicrobial vs. agricultural pesticide formulations should be reflected in the work plan terminology.

AD Response: EPA concurs with this comment and has the changed the FWP to indicate that the halohydantoin granule and powder formulations are water soluble

.

19. Comment: Page 13, Sec. 1.5.1: “EPA anticipates issuing the post

- RED DCI in the nea r future.” Does this PWP cover the data needs identified in the RED, and if not, what are the other data needs? Also, for those data needs that overlap, there should be a consideration to consolidate testing; i.e., from Halohydantoins RED:

AD Response: Table 8 in the PWP lists both the new data needs that are anticipated to be required for the r egistration r eview DCI and confirms the data needs still anticipated to be required for the post

- RED DCI. Since issuance of the 2007 RED, the Ag ency has made efforts to eliminate unneeded studies, such as the Data and Reporting Calculations study (GLN 875.1600) referenced in the RED table above, since the information to be addressed can be received in the submission of the remaining anticipated da ta requirements. Table 8 reflects these updates and identifies what data is anticipated to be required for both the post

- RED and r egistration r eview DCIs.

20. Comment: Pages 15

- 18, Table 8, Data Needs: Combines data needs anticipated for

r egistration r eview a nd for post

- RED DCIs (RED phytotox requirements have been amended from limit to definitive tests and expanded to cover monohalohydantoin as well

### Page 91 of 95 as DMH). Will these be issued together and consolidated?

AD Response : The Agency recognizes the DMH phytotoxi city requirements are listed for both the post

- RED and registration review DCIs. Since the registration review DCI cover Tier II studies, the phytoxicity requirements listed for the post

- RED DCI are no longer anticipated to be required under the post

- RED D CI but are expected to be required by the registration review DCI. The limit test DMH studies in the post

- RED DCI that are no longer anticipated to be required are GLN studies 850.4100, 850.4150, 850.4400, and 850.4500. Table 8 in the final work plan has been adjusted to reflect this update.

21. Comment: Page 37, Table 13: Data available on DMH and EMH for aquatic toxicity endpoints have mixed results, which is difficult to assess. In addition, some ecotox studies used ACR (acute

- to

- chronic ratio) method for DMH and ECOSAR for EMH, with substantial difference for chronic freshwater fish NOAEC value. This triggers two issues:

1. Does the EPA consider data for DMH and EMH to be interchangeable for these ecotoxicity endpoints?

If ACR is acute

- to

- chronic ratio, i.e., application of a factor of 1000 to the acute data on DMH to get chronic NOEC but ECOSAR predicts acute and chronic to xicity directly, comparison of the two methods should be possible to determine the accuracy of the ECOSAR prediction method by checking of DMH experimental acute values against ECOSAR predictions. This method could also be used to check the predicted value s of dihalogenated halohydantoins against the experimental values to determine if the monohalohydantoin results are valid.

AD Response: 1. It isn’t clear what is meant by the word “interchangeable”. The Agency believes that the ECOSAR predicted values are comparable with predictions that EMH is more toxic than DMH. 2. The Agency agrees that, in theory, it should be possible to check an ECOSAR prediction of a chemical if one compared experimental values with ECOSAR predictions for a related chemical.

For t he monohalohydantoins, the issue was not if the ECOSAR predictions were valid, but rather, which predictions were valid. Depending on the configuration of the molecule, ECOSAR predicted the compound to be very toxic similar to the dihalohydantoins or les s toxic similar to DMH. The Agency does not believe that a comparison of ECOSAR predictions versus measured acute toxicity values for the dihalohydantoins will resolve this issue.

22. Comment: Page 41, Sec 4.5: Regarding the use of open literature to “...pote ntially provide data for a missing endpoint or provide values more sensitive than available from the registrant submitted studies” is disturbing. We would expect EPA takes into account WoE of literature studies and the reliability of all data available to assess a data endpoint,

### Page 92 of 95 as recent EPA guidance on literature data indicate, and that acceptable studies submitted by the registrant would have priority over lesser non

- targeted, published reports.

AD Response: In addition to the OCSPP 850 series guidelin e studies submitted by the registrants, ecological effects data contained within the open literature are considered in ecological risk assessments conducted by OPP. Based on an agreement with the U.S. Fish and Wildlife Service and National Marine Fishe ries Service, OPP uses the EPA Ecotoxicity Database (ECOTOX) as its search engine to obtain relevant data on the ecotoxicological effects of pesticides. ECOTOX is a publicly available database summarizing the ecological effects of single chemicals to a quatic and terrestrial plants and animals ( http://www.epa.gov/ecotox ). ECOTOX was developed by EPA's Office of Research and Development's Mid

- Continental Ecology Division, which routinely conducts literature searches for pesticides undergoing Registration Review. The extent to which open literature data classified as either "quantitative" or "qualitative" should be used in the risk assessment is discussed in detail on EPA’s website ( http://www.epa.gov/pesticides/science/literature

- studies.html )

.

23. Comment: Page 44, Sec 6.1.5: The list of additional information the agency is interested in receiving appears to be a template for convent ional pesticides, and not specific to antimicrobials. Perhaps AD can edit this section more specifically to antimicrobials for future work plans.

AD Response: AD thanks ACC for its comment . This list was developed to reflect information needs for both antimicrobial and conventional pesticides

. The Agency would welcome specific suggestions on additional information specific to antimicrobials that we should solicit.

24. Comment: Page 46, Appendix A: DMH is classified as a “mild skin sensitizer”. This is inco rrect and needs to be corrected in the work plan. DMH is not sensitizing. However, some of the dihalogenated halohydantoins are classified as skin sensitizers.

AD Response: The conclusion of a “mild skin sensitizer” was based on the following submitted study:

MRID 00165487 (MRIDs 93074013 and 93075016) Thompson, G (1983) Guinea Pig Maximization Study with Dimethyl

- hydantoin: Study No. WIL

- 12028. Unpublished study prepared by WIL Research Laboratories, Inc. 17 p.

25. Comment: Page 48, Appendix A: Subchronic toxicity indicates the need for 90

- Day inhalation test with DMH. What is the exposure potential to DMH that justifies this study? No repeated exposure studies could be found for DMH or EMH for inhalation other than acute toxicity, with the LC50s ranging f rom 5.4 to 15.0 mg/L. However, 28

- day and 90

- day oral and dermal studies show no systemic toxicity at doses that are as high as 1,000 mg/kg/day. In addition, no differences between the results from the repeated exposure toxicity studies were apparent for D MH and EMH. Based on the lack

### Page 93 of 95 of systemic toxicity and/or organ toxicity from repeated exposures following oral and dermal routes of exposures, and ethical consideration of performing a sub

- chronic animal study in absence of indications that a specific tox ic effect will occur via this route of exposure, the need for further testing via the inhalation route of exposure is not warranted.

AD Response: Occupational and residential exposures via inhalation route do exist in the open pour granules and/or powders, mop and/or wipe application, and trigger spray application. There is no route

- specific repeated dose inhalation toxicity study for DMH, the chemical used for risk assessments for halohydantoins. The Agency does not have a full picture of the potential effects which could occur as a result of exposure via the inhalation route. The difficulty of predicting real world human inhalation exposure with limited data and no inhalation data or other alternative information

- such as SAR (structure

- activity

- relationship), surrogate data, and/or weight

- of

- evidence (WOE)

- triggered the need for a 90

- day (guideline) inhalation toxicity study, in order to adequately evaluate real world human exposure to halohydantoins based on how the y are used (the OPPTS Guidelines specify an MMAD of 1

- 3 μ m in inhalation toxicity studies of aerosols so that a portion of the test article will reach the lungs). The study would provide insight into concerns regarding toxicity via the inhalation route, a s extrapolation from an oral study may underestimate inhalation risk. The study may result in a change in how risks are quantified. The data would likely help the Agency conclude more definitively whether or not there would be any concerns for inhalation toxicity in the rat. This likely would provide a more complete hazard characterization of halohydantoins in regards to the potential risks to the U.S. general population. It is possible that the database uncertainty factor could be reduced or removed, r esulting in different magnitude of the value of the endpoint used for regulation.

26. Comment: Page 25 last para; Reference to “ACC 263903” is a typo. Please correct to “ACC#263983”.

AD Response: The Agency thanks ACC for this correction; the final work pla n has been updated.

Submitter: Bay Area Clean Water Agencies (BACWA) and the California Stormwater Quality Association (CASQA)

27. Comment: Both BACWA and CASQA submitted comments commending the Agency for improving examination of surface water quality risk s in the Antimicrobials Division registration review work plans and acknowledged the Halohydantoin PWP includes conceptual models that appropriately identify pathways for transport of antimicrobial pesticides through urban storm drainage systems to surface waters.

AD Response: AD appreciates submission of these comments and continues to review ways to improve ecological risk assessments.

### Page 94 of 95 Submitter: FIFRA Endangered Species Task Force (FESTF)

28. Comment: FESTF submitted a comment noting that it has data that will assist the Agency in conducting an endangered species risk assessment for halohydantoins, and requesting that any technical registrant for halohydantoins who is not a member of the FESTF (or a com pany having met its data compensation obligations) be asked to provide a formal offer

- to

- pay to FESTF for reliance on their data.

AD Response: The Agency thanks FESTF for its comment and will consider this information as it conducts the registration review and makes its registration review decisions.

Submitter: Physicians Committee for Responsible Medicine (PCRM)

29. Comment: PCRM submitted a comment regarding the 90

- day inhalation toxicity study. PCRM asserts that halohydantoins “are corrosive materials an d constitute risk of pervasive corrosive injury to animals’ respiratory tissues during the 90

- day inhalation study.” Furthermore, FESTF states it’s possible to predict respiratory tissue effects based on experience with other similar chemicals and structur e

- activity analysis. FESTF asserts diluting materials for longer

- term studies might make the compounds more corrosive and encourages the Agency to waive the 90

- day inhalation study and require protective labeling for its known hazards.

AD Response: The Age ncy does not require the undiluted TGAI be used to conduct the 90

- day inhalation toxicity study. According to EPA’s published OPPTS Health Effects Test Guidelines 870.3465, “it is desirable to have a concentration

- response relationship as well as a NOEL. T herefore, at least three concentration levels plus a control and, where appropriate, a vehicle...shall be used. Concentrations should be spaced appropriately to produce test groups with a range of toxic effects.” The Agency anticipates requiring the submissi on of subchronic inhalation toxicity studies conducted with dilute concentrations of PCMC or Na PCMC that demonstrate toxic effects at noncorrosive/ non

- caustic levels. In the absence of these data, the Agency may assume 100% respiratory absorption and, if risks of concern are identified, utilize mitigation measures through future risk assessment and decision

- making. For future decisions, the 90

- day inhalation study should help the Agency conduct human

- health risk assessments using real

- world, chemical

- speci fic inputs and minimize the potential for underestimating or overestimating risk. In regard to QSAR, the Agency has and will continue to consider

### Page 95 of 95 accepting SAR/QSAR to fulfill data requirements on a case

- by

- case basis, based on the quality and completeness of information and supporting rationale provided. Registrants are encouraged to submit available information to support SAR/QSAR analyses and then work with EPA to provide any additional information needed.