2

Halohydantoins Registration Review Team

Human Health

William Hazel

Timothy Dole

Jenny Tao

Environmental Fate and Effects

Pat Jennings

Srinivas Gowda

Najm Shamim

William Erickson

Risk Management

Sandra O’Neill

Rose Kyprianou

Office of General Counsel

Philip Ross
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Table of Contents

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

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

1.2 Updates to the Workplan.................................................................................................. 6

1.3 Case 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 Data 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 ........................................................................................... 20

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 Environmental 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 Toxicology 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
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Appendix F Product Chemistry............................................................................................... 81

Appendix G Comments Received Concerning the Preliminary 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 Halohydantoins 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 

Surfaces; 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 Use 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 Cleaning..................................... 32

Figure 7 – Conceptual Model Diagram for Ecological Exposure and Effects of Halohydantoin 

Degradates to Aquatic and Terrestrial Organisms from Use in Irrigation Systems and Influent 

Cooling Water Ponds, Lagoons, and Canals................................................................................. 33
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1 Introduction 

This document is the Environmental Protection Agency’s (EPA or “the Agency”) Final Work 

Plan (FWP) for halohydantoins. The PWP document explains what EPA's Office of Pesticide 

Programs knows about halohydantoins, highlighting anticipated data and assessment needs, 

identifying the types of information that would be especially useful to the Agency in conducting 

the review, and providing an anticipated timeline for completing the Halohydantoins registration 

review. This case includes the four dihalodialkylhydantoins (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 006322

and 128989) and a monohalodialkylhydantoin (PC Code 028500) 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 review program is 

intended to make sure that, as the ability to assess risk evolves and as policies and practices 

change, all registered pesticides continue to meet the statutory standard of no unreasonable 

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

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

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

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

http://www.epa.gov/oppsrrd1/registration_review/.

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

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

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

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

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

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

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

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

Halohydantoins Preliminary Work Plan (PWP) was published on June 26, 2013 and the 60-

day comment period ended on August 26, 2013. Public comments received concerning the PWP

and documents associated with this registration review can be viewed at 

http://www.regulations.gov in docket EPA-HQ-OPP-2013-0220. Below is a summary of the 

issues relevant to this registration review case.
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1.2 Updates to the Workplan

Since the publication of the PWP, the Agency has made the following updates: 

• Corrected formatting and typographical errors.

• Consolidated data needs anticipated for the registration review 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, the 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 sites 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 summary of halohydantoin uses table to include corrections to 

application rates.

• Removed references of halohydantoins 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

• Corrected 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 responses to these comments.

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

Halohydantoins PWP. This 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 data needs)

Dietary (food) Yes 12/3/12 Updated Residue data on processed fruits, 

vegetables, and meat products

Dietary (drinking water) Yes 12/3/12 Updated None

Occupational Handler Yes 09/10/04 Updated 

Inhalation Toxicity

Dermal Exposure – Indoor

Inhalation Exposure - Indoor
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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 data 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 pools1

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 Updated2

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 These 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 The 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 monohalohydantoin needs 

to be assessed for freshwater and estuarine/marine organisms. The updated assessment will also include

recirculating 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 Preliminary Work Plan 2013-06 2013-06-26

Close Public Comment Period 2013-08 2013-08-26

Phase 2: Case Development 

Issue Final Work Plan 2013-12 2013-12-30

Issue Data Call-In (DCI) 2014-12

Receive Data to be Considered in Risk Assessment 2016-12

Open 30-Day Public Comment Period for Preliminary Risk Assessment(s) 2018-06

Close Public Comment Period 2018-07

Phase 3: Registration Review Decision and Implementation 

Open 60-Day Public Comment Period for Proposed Decision 2018-12

Close Public Comment Period 2019-02

Issue Final Decision 2019-06

Begin Post-Decision Followup 2019

Total (years) 6

*The anticipated schedule will be revised as necessary (e.g., need arising under the Endocrine Disruptor Screening Program with 

respect to the active ingredients in this case).
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1.3 Case Overview

The docket for the Halohydantoins 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 

degradates, monohalohydantoin, 5,5-dimethylhydantoin (DMH) or 5-ethyl-5-methylhydantoin 

(EMH). The Agency anticipates evaluating potential risk for halohydantoins based on 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 ingredients to be assessed in Case 3055: Halohydantoins (PC Codes 

006315, 006317, 006322, 028500, 028501, 128826 and 128989).

Table 3 - Chemical Identification of Halohydantoins

PC 

Code

CAS

No.

Chemical Name

(Classification: Halogenated 

Alkylhydantoin)

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)

C5H6BrClN2O2 241.47

006322 126-06-7

3-Bromo-1-chloro-5,5-dimethylhydantoin

3-Bromo-1-chloro-5,5-dimethyl-2,4-

imidazolidinedione

(BCDMH)

C5H6BrClN2O2 241.47

006317 77-48-5

1,3-Dibromo-5,5-dimethylhydantoin

1,3-Dibromo-5,5-dimethyl-2,4-

imidazolidinedione

(DBDMH)

C5H6Br2N2O2 285.92

028500 6921-17-1

1-Chloro-5,5-dimethylhydantoin

1-Chloro-5,5-dimethyl-2,4-

imidazolidinedione

(CDMH)

C5H7ClN2O2 162.57

028501 118-52-5

1,3-Dichloro-5,5-dimethylhydantoin

1,3-Dichloro-5,5-dimethyl-2,4-

imidazolidinedione

(DCDMH)

C5H6Cl2N2O2 197.02
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PC 

Code

CAS

No.

Chemical Name

(Classification: Halogenated 

Alkylhydantoin)

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)

C6H8Cl2N2O2 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)

C6H8BrClN2O2 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 photolyze as it does not absorb UV light at wavelengths >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 and EPI Suite v4.1
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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/tablets or water soluble granules and a few 

products are formulated as water soluble powders.

Table 5 - Distribution of Products by Specific Halohydantoin

Chemical Name PC Code Number of 

Products

Percent 

a.i. Formulations

1-Bromo-3-chloro5,5-dimethylhydantoin 006315 99 4 to 99

Pellet/Tablet, Water Soluble Granule, 

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-chloro5,5-dimethylhydantoin 006322 1 96 Technical Only – No end use products

1-Chloro5,5-dimethylhydantoin 028500 1 90 Solid Soluble Concentrate

1,3-Dichloro5,5-dimethylhydantoin 028501 44 1.8 to 97 Pellet/Tablet, Water Soluble Granule, 

Solid Soluble Concentrate/Solid

1,3-Dichloro5-ethyl-5-methylhydantoin 128826 43 0.7 to 16.1 Pellet/Tablet, Water Soluble Granule, 

Solid Soluble Concentrate

1-Bromo-3-chloro5-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: spray, 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

Lakes/ponds/reservoirs (without human or wildlife use)

Ornamental ponds/aquaria

Spa water systems 

Swimming 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
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Use Application Rate

(Halohydantoin)

Notes Regarding 

Specific Products

(EPA Reg. No.)

Beverage Can Rinsing

Food 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

Air conditioner/refrigeration condensate water systems

Air washer/scrubber water systems

Water cooling systems - Recirculating

Water cooling systems - once thru

Evaporative condenser water systems – recirculating

Heat exchanger water systems – recirculating

Auxiliary water systems

Processing water – recirculating

Photographic processing wash water

Pulp and paper processing water

Oil Drilling Muds and Packer Fluids

Oil Recovery Injection Water, Secondary

Sewage and Waster Water Treatment systems

Not CalculatedC

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

Animal kennels/sleeping quarters (commercial)

Hard surfaces (floors, tables, sinks, bathtubs)

Domestic/commercial nonpotable water (waterbed water)

Refuse/solid waste containers (garbage cans)

Toilet 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 Report for 2004/2005 (Kline, 2006), 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 for the other registered uses 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 value. 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, 2006). 

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 was 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 028500) 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, 3bromo 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-Dibromo-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 (BCEMH); (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. The 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, in July 2012, 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 requirement 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 establishments, 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 additive regulation for use of the 1,3-dihalogenated hydantoins 

(bromine and/or chlorine) as slimicides in paper and paperboard 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 considered 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 processing fruits and vegetables (900 ppm 

available bromine) followed by a potable water rinse. Seven other FCNs (Nos. 334, 357, 453, 

775, 792, 1102, 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 Incident System for the 

halohydantoins 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 incidents 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 brominating tablets. Bacterial testing indicated that bacteria 

were not likely 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 2013)

Product Type

Number of Incidents

Human 

Fatality 

(HA)

Human 

Major 

(HB)

Human 

Moderate 

(HC)

Human 

Minor 

(HD)

Human 

Unspecified 

(HE)

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 

(Months 

from 

DCI 

Receipt)

Risk 

Assessment(s) 

Data Will 

Support

Use Site(s) 

Triggering 

Anticipated Data 

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 

(Months 

from 

DCI 

Receipt)

Risk 

Assessment(s) 

Data Will 

Support

Use Site(s) 

Triggering 

Anticipated Data 

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 

Residues1 TGAI 12 Residential Post Application

Hard surface 

disinfection

Toddlers playing on 

treated floors

No GLN

Bromate in 

Swimming Pool 

Water10

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

875.120014 Dermal Exposure -

Indoor

TGAI or

Surrogate2 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 

875.140014 Inhalation Exposure 

- Indoor

TGAI or

Surrogate2 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 

(Months 

from 

DCI 

Receipt)

Risk 

Assessment(s) 

Data Will 

Support

Use Site(s) 

Triggering 

Anticipated Data 

Requirement

Applicable 

Exposure Scenario

(s)

850.1300

Aquatic invertebrate 

life-cycle toxicity, 

freshwater sp.

monohalohydantoin, 12 Aquatic 

organisms All uses Transport to the aquatic environment

850.1350

Aquatic invertebrate 

life-cycle toxicity, 

saltwater sp.

monohalohydantoin, 12 Aquatic 

organisms All uses Transport to the aquatic environment

850.1400 Freshwater Fish 

Early Life Stage7

monohalohydantoin 12 Aquatic 

organisms All uses Transport to the aquatic environment

850.1400 Saltwater Fish Early 

Life Stage7

monohalohydantoin, 12 Aquatic 

organisms All uses Transport to the aquatic environment

850.410011 Seedling emergence, 

rice

monohalohydantoin, 

DMH

12 Aquatic 

organisms

Industrial process 

and water systems 

and pools and 

spas;

all others3

Transport to the 

aquatic environment

850.415012 Vegetative vigor, 

rice

monohalohydantoin

DMH

12 Aquatic

organisms

Industrial process 

and water systems;

all others3

Transport to the 

aquatic environment

850.440013

Aquatic Plant 

Testing using Lemna

sp., 

monohalohydantoin, 

DMH

12 Aquatic 

organisms

Industrial process 

and water systems;

all others5

Transport to the 

aquatic environment

850.450013 Algal Toxicity 

monohalohydantoin, 

DMH

12 Aquatic 

organisms

Industrial process 

and water 

systems4;

all others5

Transport to the 

aquatic environment

850.4550 Algal Toxicity -

Cyanobacteria

monohalohydantoin, 

DMH

12 Aquatic 

organisms

Industrial process 

and water systems;

all others6

Transport to the 

aquatic environment

OECD 209 or 

850.6800

Activated Sludge 

Respiration 

Inhibition or 

Modified Activated 

Sludge Respiration 

Inhibition8

monohalohydantoin 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 tests9

monohalohydantoin 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 lifecycle testing-fresh 

water

DMH 12 Ecological

Once through 

cooling tower 

systems

Transport to the 

aquatic environment
17

GLN Study Name Test 

Substance*

Time 

Frame 

(Months 

from 

DCI 

Receipt)

Risk 

Assessment(s) 

Data Will 

Support

Use Site(s) 

Triggering 

Anticipated Data 

Requirement

Applicable 

Exposure Scenario

(s)

875.120014 Dermal Exposure -

Indoor

TGAI or

Surrogate2 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

875.140014 Inhalation Exposure 

- Indoor

TGAI or

Surrogate2 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 

875.120014 Dermal Exposure -

Indoor

TGAI or

Surrogate2 12

Occupational 

Handler

Residential 

Handler

Pools and Spas Open Pour Granules

Open Pour Powders

875.140014 Inhalation Exposure 

- Indoor

TGAI or

Surrogate2 12

Occupational 

Handler

Residential 

Handler

Pools and Spas Open Pour Granules

Open Pour Powders 

875.2800 Description of 

human activity

TGAI or

Surrogate2 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 For 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, testing 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 diatom (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 separated into OCSPP 850.4550 and the other three species under OCSPP 850.4500. 5 For all uses other than industrial process and water systems, testing with green algae is expected to be required; if 

the IC50 from that test is less than 1.0 ppm (mg/L), then testing with marine and freshwater diatoms is expected to be 

required. 6 For all uses other than industrial process and water systems, testing with a cyanobacteria sp. is expected to be 

required only if the IC50 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-chronic 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 included 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/are required. If the ASRI test EC50 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 EC50 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 conducted 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 Sludge 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.

11

Test guidelines 850.4100 and 850.4225 were merged and harmonized into OCSPP 850.4100 in a Federal Register 

Notice dated June 27, 2012 (FRL-9333-1). 12

Test guidelines 850.4150 and 850.4250 were merged and harmonized into OCSPP 850.4150 in a Federal Register 

Notice dated June 27, 2012 (FRL-9333-1).

13 EPA changed test 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 Data 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

Toxicological endpoints were selected for various exposure scenarios in a quantitative human 

health risk assessment for the halohydantoins 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 RED as well as in registration review, the Agency supports use of DMH as the 

subject of the hazard (toxicity studies) component of risk. These toxicological endpoints may be 

revised when conducting the risk assessment for the halohydantoins registration review. A 

summary of the existing human health toxicological endpoints, which was included in the 2007 

RED, is provided 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 

(females 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 Dietarya

(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 Dietarya

(females 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)

Oral NOAEL = 500 

mg/kg/day

MOE = 100 

(Residential)

developmental toxicity – rabbit

LOAEL = 1000 mg/kg/day, based on 

decreased body weight gain in maternal 

rabbits.

Incidental Oral - 

Intermediate-Term 

(1 - 6 months)

Oral NOAEL = 300 

mg/kg/day

MOE = 100 

(Residential)

subchronic oral toxicity – rat

LOAEL = 1000 mg/kg/day based on 

decreased body weight and liver weight.

Dermal - Short, 

Intermediate, and 

Long-Term 

Dermal 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=100b

mg/kg/day

MOE = 100 

(Occupational)

MOE = 100 

(Residential)

developmental toxicity – rabbit

LOAEL = 500 mg/kg/day, based on 

skeletal effects in offspring.

† This endpoint summary table was included 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 developmental toxicity study (MRID 42413101) was therefore 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 resulting from the food-contact paper and paperboard in 

the 2007 RED; acute and chronic dietary risks were ≤1.6% of the aPAD and cPAD for males, 

females and children. The Agency anticipates requiring additional 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, contamination of 

drinking water with halohydantoin residues 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 treatment, etc. In the 2007 RED, the 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. Both acute and chronic dietary risk assessments reflecting exposures to 

halohydantoin residues in drinking water are expected to be conducted using the most recently 

developed model. Residue chemistry data are not anticipated to be required to characterize 

drinking water exposures.

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 placing 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 

systems 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 gallons 

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.

Occupational 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 exposures 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 assessments included in the RED were based 

on DMH, which is the primary degradate when the halohydantoins are used in indoor pools. 

Exposures to bromates, which are potential degradates when the bromohydantoins 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, 2006) mentions that the 

halohydantoins are not used in outdoor pools because bromine is not stable in sunlight, 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.

Residential 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. The Agency

anticipates the need to require additional residential handler exposure data for registration 

review. The post application exposure to toddlers playing on treated floors also needs to be 

assessed. In addition, the post application bromate exposure to swimmers in outdoor pools will 
22

need to be assessed; therefore, the 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 Mop, wipe and trigger spray application for hard surface Short and Intermediate Term

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 discharges 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 risks 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 substances 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 substances. For information 

regarding EPA’s efforts to determine which chemicals have a common mechanism of toxicity 

and to evaluate the cumulative effects of such chemicals, see 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.gov/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 transported 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 water 

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 registration 

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 pesticide’s use 'may affect' a listed species 

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

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

4.1 Environmental Fate Assessment

Mode of activity of halohydantoins:

Dihalodialkyhydantoins contain two halide (chloride or bromide) ions. Dihalodialkyl-hydantoins 

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

second step is the hydrolysis of the halide ion in solution as indicated by equation 1 for a 

chlorine ion:

Cl-

 + H2O --- HOCl + OH- (1)

A similar reaction takes place with bromide ions. Therefore hypochlorous acid (HOCl), and 

hypobromous acid (HOBr) are the active moieties 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; for 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 not 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), it is assumed that halohydantoins reach the environmental 

media as monohalodialkylhydantoins. 

Dihalodialkylhydantoins hydrolyze, under abiotic conditions, losing the first halide with a half 

life of less than 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 

DMH 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 photolyzed 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 life 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. These pesticides appear to have borderline Henry Law 

Constants of 10-6 – 10-8 atm-m3/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 more from surface water. The halohydantoins have low 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 stripped of halides quickly, the 

common degradates that would reach the environmental media are DMH or EMH. The Agency

has not conducted an environmental fate risk assessment for DMH but based on the fate data of 

DMH, the following paragraph explains the fate 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 days1

. A similar tendency of a long half life is 

observed for the DMH in an aquatic photolysis study. DMH is persistent in aerobic soil 

conditions (a long half life of over a year, MRID# 408046-03) as well as in aerobic and 

anaerobic 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 Kads which varies from 0.051 to 

0.138 in different soils (MRID# 408046-06) and is likely to migrate into ground water. It has 

small log Kow 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 

monohalohydantoins. It should be noted 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 263983; 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 degradates

DMH or EMH. The Agency anticipates 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 there 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 Section 4.4.2). According to an initial 

screening level estimates 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 (see Section 4.4.2 for a 

complete discussion of the screening level down-the-drain analysis).

4.2 Conceptual Models for Environmental Exposure Pathways

Based on the summary of registered uses of halohydantoins 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 conditions 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 day 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 from 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 less 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-thedrain discharges of halohydantoins. 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 the degradates, DMH, EMH, and monohalohydantoins.

No laboratory studies were found on the 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 ring, 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 the 

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 halflife 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 determined 

in flooded sandy loam soil (MRID 408046-04). The low log Kow 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 plants. 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 susceptible 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 5a 

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 potential 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 Terrestrial 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 Terrestrial 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 and 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 water to 

stormwater drain

(A)

Surface Water

Sediment

Soil

See Figure (B)

Disposal of water to 

ground surface

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 and Effects 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 Ecological Exposure and 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 mainly 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 Appendix D along with the data 

requirements and data gaps. The most sensitive values for each receptor group are used for the 

risk assessment (Table 12). 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 

water downstream of wastewater treatment plants to which halohydantoins may be discharged

(see 4.4.2 for specific details of this analysis).

No data are available for monohalohydantoins, 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 nontoxic 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 monohalohydantoin as specified in Table 12.

Table 12 – Selected Existing Effects Endpoints for Risk Assessment of 

Monohalohydantoins

Receptor 

Group

Surrogate

Species

Risk

Scenario

Toxicity

Endpoint

Reference

(MRID)

Birds Mallard duck--

Acute Oral LD50 = 873 mg DCDMH eq/kg bw 00142071

Subacute Dietary LC50 > 5620 mg DCDMH ppm-diet Acc 253073 & 71

Chronic Not Required --

Mammals

Acute LD50 524 mg DCDMH eq/kg-bw1 93076011; 

00137105

Chronic Not Required --

Freshwater fish Rainbow trout

Acute 96-h LC50 = 0.32 mg 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 EC50 = 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 LC50 = 1.2 mg ai/L 40993103

Chronic Data Gap: Data anticipated to be 

required --

Estuarine/marine 

invertebrates

Eastern

oyster

Acute IC50 = 0.86 mg Br2/L 40993101

Mysid

Acute LC50 = 0.92 mg Br2/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 Nonlisted 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 bobwhiteAcute Oral LD50: >2250 mg/kg-bw Acc 253966Subacute Dietary LC50 >5000 mg/kg-bw 43289904

Chronic Data not required

Mammals Rat

Acute LD50 >5000 mg/kg-bw

Chronic Data not required

Freshwater fish Rainbow trout Acute 96-h LC50 = 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 

method1 for DMH

ECOSAR v 1.10 

for EMH

Freshwater 

invertebrates Waterflea

Acute 48-hr LC50: 6051 mg/L 00046053

Chronic DMH: NOAEC = 6.0 mg/L

EMH: NOAEC = 4.8 mg/L

Used ACR 

method2 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 LC50: 8,100 mg/L 00046053, 

93075035

Chronic DMH: NOAEC = 8.1 mg/L

EMH: NOAEC = 3.8 mg/L

Used ACR 

method2 for DMH

Used ECOSAR 

v1.10 for EMH

Estuarine/marine 

invertebrates

Eastern

oyster

Acute 96-hr IC50: >125 mg/L 43289902

Mysid

Acute LC50 >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 

Listed required

Semi-aquatic 

rooted plants/ 

Terrestrial plants

--

Seedling 

emergence Nonlisted Data gap: Data anticipated to be 

required -- Seedling 

Emergence 

Listed

--

Vegetative Vigor

Non-listed Data gap: Data anticipated to be 

Vegetative Vigor required

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 from 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 Analysis

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 

degradates 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 parameters selected 

to run the DtD module and of the theoretical basis for this model is presented 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 plants 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 discharges of dialkyldihalohydantoins.

Although halohydantoins are generally highly toxic to aquatic organisms, their degradates, DMH 

and EMH, are practically nontoxic (see Section 4.3.2). No laboratory data have been found on 

the aquatic toxicity of the intermediate degradates of halohydantoins, monohalohydantoins. 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 chlorohalohydantoins 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 DMH, 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 (for 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 

halohydantoins would be discharged (Kline, 2006) 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

monohalohydantoins. 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 purpose 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 as toxic as halohydantoins. 

Table 14 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 (2006) 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 aquatic 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 

and 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 = 12,700 

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 15 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 reported to be used in 

recreational water in 2004 (22.5 million pounds; 10,200,000 kg) (Kline, 2006). 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 consumed in 2004 and the volume consumed in recreation water 

according to Kline (2006). 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 Acute 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 following exceedances of COCs for aquatic 

organisms: 85 days per year for non-endangered freshwater fish; 41 days per year for nonendangered freshwater invertebrates; 285 days per year for endangered freshwater fish; and 237 

days per year for endangered freshwater 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 both 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 

endangered 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 14) versus results 

from extrapolation to COCs for BCDMH (Table 15) demonstrate the importance of determining 

the ecotoxicity of monohalohydantoins to determine whether they are more like 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 paper 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 types 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 studies will be reviewed that potentially provide data 

for missing endpoint values or provide values more sensitive than available from the registrantsubmitted studies. ECOTOX was created and is maintained by the US EPA’s, Office of 

Research and Development, and the National Health and Environmental Effects Research 

Laboratory's Mid-Continent Ecology Division.

5 Endocrine Disruptor Screening Program (EDSP)

As required by FIFRA and FFDCA, EPA reviews numerous studies to assess potential adverse 

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

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

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

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

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

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

chronic studies that assess growth, developmental and reproductive effects in different 

taxonomic groups. As part of the 2007 RED for the halohydantoins, 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), halohydantoins are subject to 

the endocrine screening part of the Endocrine Disruptor Screening Program (EDSP). 

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

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

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

may designate.” The EDSP employs a two-tiered approach to making the statutorily required 
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 relationship between the dose and the E, A, or T effect. 

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

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

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

identified for EDSP screening was published on June 14, 20132 and includes some pesticides 

scheduled for registration review and chemicals found in water. Neither of these lists should be 

construed as a list of known or likely endocrine disruptors.

For further information on the status of the EDSP, the policies and procedures, the list of 

chemicals, future lists, the test guidelines and the Tier 1 screening battery, please visit 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

Anticipated Data Needs” section of this document. The Agency expects to issue the DCI in

December of 2014.

 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, 2006. Specialty Biocides 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 and 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/halohydantoinsred.pdfhttp://www.epa.gov/oppsrrd1/REDs/halohydantoins-red.pdf
43

Appendix A Toxicology Profile

Acute Toxicity for Product Labeling 

The acute toxicity database is complete. No additional studies are anticipated to be required at 

this time.

The acute toxicity data on technical hydantoins are summarized in Table A1 below.

Table A1 – Acute Toxicity Studies for the Halohydantoins 

Guideline No. /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

LD50 (combined) > 5,000 mg/kg IV

870.1100 Acute Oral Toxicity – Mouse 45738401 LD50 (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

LD50 (male) = 1,350 mg/kg

LD50 (female) = 1,520 mg/kg

LD50 (combined) = 1,390 mg/kg

III

870.1100 Acute Oral Toxicity – Rat 93077008; 

00147325 

LD50 (male) = 1,037 mg/kg

LD50 (female) = 860 mg/kg

LD50 (combined) = 929 mg/kg

III

870.1300 Acute Inhalation Toxicity – Rat 43654101 LC50 (male) = 0.157 mg/L

LC50 (female) = 0.213 mg/L

LC50 (combined) = 0.168 mg/L

II

870.1300 Acute Inhalation Toxicity – Rat 

(94.7% purity)

43125601;

43039001

LC50 (male) = 0.41 mg/L

LC50 (female) = 0.68 mg/L

LC50 (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 No. /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 

LD50 = 760 mg/kg III

870.1100 Acute Oral Toxicity – Rat 

(55.9% purity)

44988002 LD50 (combined) = 448 mg/kg II

870.1200 Acute Dermal Toxicity – Rat 

(55.9% purity)

44988001 LD50 > 2,000 mg/kg III

870.1300 Acute Inhalation Toxicity –

Rabbit

44988003 LC50 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-Dimethylhydantoin 1 Chloro-5,5-Dimethyl-2,4-Imidazolidinedione (CDMH; CAS No. 6921-

17-1)

870.1100 Acute Oral Toxicity – Rat 46586801 LD50 > 2,000 mg/kg III

870.1300 Acute Inhalation Toxicity – Rat 46693902 LC50 > 0.053 mg/L II

870.1200 Acute Dermal Toxicity – Rat 46693901 LD50 > 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 LD50 (male) = 769.3 mg/kg

LD50 (female) = 704.8 mg/kg

LD50 (combined) = 737.3 mg/kg

III

870.1200 Acute Dermal Toxicity – Rabbit 93076013;

00084176

LD50 > 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 toxicity 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 treatmentrelated 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. The 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 [§82-1]) 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 conditions 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 2000 mg/kg/day (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 [§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 treated 

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 microscopic 

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% in 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 [HDT]), and the 

LOAEL is not established at the HDT of 390 mg/kg/day. This study is classified as AcceptableGuideline and satisfies the guideline requirements for a subchronic toxicity study [OPPTS 

870.3250 (§82-1b)] in rats. Higher doses of DMH were not possible in this study; thus, although 

a limit dose was not tested, the study is considered Acceptable.

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 increase 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 effects 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 

gestation 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 toxicity 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 greater 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 doses 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

mg/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 27th 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 27th

presacral 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 

rabbits 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 surviving 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 these 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 treatmentrelated 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 toxicity 

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 

number 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 reproductive toxicity 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 concurrent 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 developmental toxicity NOAEL is 

375 mg/kg/day and the developmental toxicity LOAEL is 1000 mg/kg/day, based on decreased 

fetal 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 dimethylhydantoin (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 mortality were observed in the parental animals 

at limit dose tested. Based on these results, the parental toxicity NOAEL was 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 was 1000 mg/kg/day, the LOAEL for reproductive toxicity 

was not established.

This study is classified as Core minimum 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 administered 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 (premating/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 rats. 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-related 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 females, 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 reproductive 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. The 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 reproductive 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.

The combined chronic/carcinogenicity studies in rats 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 testicular 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 concentrations 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 consumption and organ weights, or on clinical pathology. At the 

highest dose level, statistically significant treatment-related decreases in 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 systemic 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 treated 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 same 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 animals. 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 

incidence 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 dose 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 females; and testicular fibrinoid vascular 

degeneration in early decedent males. The NOAEL for both sexes is 320 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 mg/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 hematology, 

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 diffuse 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-guideline and satisfies the guideline requirements for a chronic 

toxicity study (OPPTS 870.4100 [§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 weights 

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.

There is some evidence of target organ toxicity, but no evidence of positive tumorigenicity for 

the test material 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 were 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 were

statistically significant decreases in the mean absolute body weight and in mean body weight 

gain, compared to both control groups, which persisted from week 16 of the study. 

The 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 oncogenicity study (OPPTS 870.4200b [§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 1000 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 mutagenicity assays and found they are acceptable. While 

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 Hamster Ovary (CHO) cells for 1,3-dichloro-5,5-

ethylmethylhydantoin (DEMH) and EMH technicals. 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 studies 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 14C radiolabeled 

5,5-dimethylhydantoin (14C-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 low-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 14C-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 administered 14C-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 14C radiolabeled 5-

ethyl-5-methylhydantoin (

14C-EMH; 97.8% purity; Lot No. 2675-095) and/or non-radiolabeled 

EMH (>99.5% purity; Batch No. B9430305) in the following dosing regimen: a single oral lowdose 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 repeated 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 14C-EMH. Under the conditions of this study, 

EMH 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 14C-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 

14C-DMH (91.31-96.88%) and 14C-EMH (96.38-97.61%), respectively, and the recovered 

unmetabolized 14C-DMH and 14C-EMH in the urine represented 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 14C-DMH and 100 mg/kg 

14C-EMH, respectively. 

Together, the metabolism studies on DMH and EMH are classified as Acceptable/guideline and 

satisfy the guideline requirement for a metabolism study in rats (OPPTS 870.7485 [§85-1]). 

Toxicity Profile

The toxicity profile for the halohydantoins is included in Table A2.

Table A2 - 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 27th 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 body 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 toxicity – 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

870.5100 -Ames Assay

DMH purity 97%

164036 

(265457

#1) (1986)

Negative

870.5100 -Ames Assay

DMH purity not stated

137100

(1982)

Negative

870.5100 -Ames Assay

MEH purity not stated

137095

(1982)

Negative
57

Guideline No./ 

Study Type/

Substance Purity

MRID No. 

(year) Results

870.5100 -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 TA1535 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)

DMH purity 97%

164037 

(265457

#2) (1986) 

Negative

870.5375 -In vitro Mammalian 

Chromosomal Aberration Assay

(CHO)

DMH 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. No ↑ in polyploid cells was observed in 

treated or in positive control cultures.

870.5550 -In vitro Unscheduled 

DNA Synthesis (UDS) in 

Mammalian Cells

DMH purity 97%

164038

(265457

#3) (1986)

Negative

870.5550 - In vitro Unscheduled 

DNA Synthesis (UDS) in 

Mammalian Cells

DMH purity not stated

132166

(1982) Negative

870.5550 - In vitro Unscheduled 

DNA Synthesis (UDS) in 

Mammalian Cells

MEH purity not stated

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 14CDMH). 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%

42173902, 

42123802

(1991)

MEH 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 14

CEMH). 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 Activity of Halohydantoins:

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- + H2O 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, and HOBr are the active 

moieties and these in turn dissociate to form OCl-

 and OBr- as hypobromous 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 study, under abiotic condition, was conducted at pH 5, 7, and 9 on 1-bromo3-chloro-5,5-dimethylhydantoin, 1,3-dichloro-5,5-dimethylhydantoin and 1,3-dichloro-5-

ethyl,5-methylhydantoin. These halohydantoins first degrade by losing one halide ion 

within an hour, while the second halide ion dissociates in less than a day. In both cases, 

hypohalides (hypochlorous or hypobromous acids) are formed which are the actual 

actives. If these actives are used in the swimming pools, and a high chlorine 

concentration is present, a degradate known as N-chloro-iso-propylimine is formed, 

which is known for its high toxicity. In the presence of excessive bromide, N-bromo-isopropylimine is formed. (ACC# 263983). A second hydrolysis study was conducted on 

radiolabeled halohydantoins, and its conclusions were similar to the one obtained with 

the first study. The second study also showed 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 actives. 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. Biodegradation 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 resulting 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 required.

Abiotic and Biotic Environmental fate of dialkylhydantoins (DMH and EMH)

Hydrolysis

DMH radiolabeled on the hydantoin ring was subjected to hydrolysis at pH 5, 7 and 9 in 

dark for 30 days. The active was 98.3% radiolabeled. At 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 resided with the sample. Material 

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 conducted 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 showed 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 to the flooded sandy loam soil immediately after the 

flooding process (while the aerobic condition was still present). Samples collected after 

one month showed that little change in the percent purity of the radiolabeled DMH. The 

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

Batch equilibrium study showed that DMH was mobile in: sandy loam, silt loam, loam, 

and clay loam soils. Kads 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).

Octanol/Water partition Coefficent

The Kow was measured using 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 occur (MRID# 408652-01).

Table B1 Estimated Physical/Chemical and Environmental Fate Characteristics of 

Halohydantoins (EPI Suite, version 4.1)

Property Cas# 118-52-5

DCDMH

Cas# 16079-88-2

1BCDMH

Cas# 89415-87-2

DCEMH

Cas# 77-48-5

DBDMH

Cas# 32718-18-6

1BCDMH

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-m3

/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

BCDMH

VP (mm Hg) 1.87 x10-8 7.9 x10-6

MP (C) 184 139

Henry Law constant (atm-m3/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 ecotoxicity effects data for the halohydantoins contained within the Agency’s files is 

provided in this appendix. Additional ecotoxicity 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 literature 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 freshwater 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 

Quality 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 (Br2) and 

some as equivalents of the test substance. A normalization is needed to allow comparison of 

toxicity across the dihalodialkylhydantoins. For example, if the LD50 for DCDMH is reported as 

197 mg ai/L and the LD50 for DBDMH is reported 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 LD50

sensitivity as it takes the same number of molecules 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 

(LD50’s range from 1070 to >2510 mg ai/kg-bw; Table C1). Several dietary studies are 

available. The data categorize the halohydantoins (TGAI) as being practically nontoxic to birds 

on a dietary basis (LC50’s >5620 ppm ai). The halohydantoins are not expected to 

bioaccumulate in the food chain and therefore no chronic data are required for halohydantoins. 

No additional data are anticipated 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)

LD50: 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)

LD50: 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)

LD50: >2510 mg/kg-bw

(>1729 mg/kg-bw)

NOAEL = 631 mg ai/kg-bw

(lethargy, 30% mortality at 2510 mg/kgbw)

00128162, 00149702/

Supplemental /

Practically nontoxic

DCDMH

(97)

LD50: 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)**

LD50: >2510 mg/kg-bw

(>1729 mg/kg-bw)

NOAEL = 251 mg ai/kg-bw

(lethargy)

00137088, 433401110 /

Acceptable /

Practically nontoxic

DCEMH

(99.4)

LD50: >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)

LC50: >5620 ppm

(>4586 ppm)

NOAEC = 1000 ppm ai (decreased body 

wt gain; no dose related mortality)

00143729 and 00144146 /

Acceptable /

Practically nontoxic

1BCDMH

(96)

LC50: >5620 ppm

(>4586 ppm)

NOAEC =3160 ppm ai

NR /

Acceptable /

Practically nontoxic

1BCDMH

(96)

LC50: >5620 ppm

(>4586 ppm)

NOAEC > 5620 ppm ai

00147321 /

Acceptable /

Practically nontoxic

BCDMH

(90)

LC50: >5620 ppm

(>4586 ppm)

NOAEC 3160 ppm ai

00149704 /

Acceptable /

Practically nontoxic

DBDMH (96)

MBDMH (4)**

LC50: >5620 ppm

(>4586 ppm)

NOAEC < 5620 ppm ai

00137087, 433401109 /

Supplemental /

Practically nontoxic

DCDMH

(97)

LC50: >5620 ppm

NOAEC = 1780 ppm ai

(body weight)

00084525 /

Acceptable /

Practically nontoxic

Subacute Dietary

Mallard

(Anas platyrhynchos)

1BCDMH

(96)

LC50: >5620 ppm ai

(>4586 ppm)

NOAEC > 5620 ppm ai

00147320 /

Acceptable /

Practically nontoxic

1BCDMH

(96)

LC50: >5620 ppm

(>4586 ppm)

NOAEC = 3160 ppm (reduction in body 

weight gain and feed consumption, no 

mortality)

NR /

Acceptable /

Practically nontoxic 

BCDMH

(90)

LC50: >5620 ppm ai

(>4586 ppm)

NOAEC > 5620 ppm ai

00128457 /

Acceptable /

Practically nontoxic

DCDMH

(97)

LC50: >5620 ppm

(>4586 ppm)

Acc 253073 & 71 /

Acceptable/

Practically nontoxic

DBDMH (96)

MBDMH (4)**

LC50: >5620 ppm

(ppm)

00137089, 433401111 /

Acceptable /

Practically nontoxic

DCEMH

(99.4)

LC50: >5620 ppm

NOAEC = 1780 ppm

(reduction in body weight)

00145354 /

Acceptable/

Practically nontoxic

NR = not reported

*Corrected for purity unless otherwise noted.

**Monobromodimethylhydantoin byproduct impurity.
66

Toxicity of Halohydantoins to Aquatic Organisms

Freshwater Fish

There are eight acute-toxicity studies for BCDMH, DCDMH, and DBDMH which categorize the 

TGAI as being highly to moderately toxic to freshwater fish (LC50’s range from 0.40 to 2.33 mg 

ai/L; Table C3). No additional acute data are anticipated to be required.

There are no chronic data available 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 the 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 extrapolation 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 data on the monohaloalkylhydantoins are anticipated to be required.

Table C2. 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 LC50: 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 LC50: 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 LC50: 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 LC50: 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 LC50: 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 LC50: 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 LC50: 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 LC50: 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 LC50: 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 LC50: 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 LC50: 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 LC50: 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 LC50: 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

The six acute-toxicity studies submitted for BCDMH, DCDMH, and DBDMH categorize the 

TGAI as being highly toxic to freshwater invertebrates (LC50’s = 0.47 to 0.87 mg ai/L; Table 

C3). No additional acute data are anticipated to be required.

No acceptable chronic data for dihalo- or monohalohydantoins 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 data 

on the monohaloalkylhydantoins are anticipated to be required—see the discussion under 

freshwater fish.
69

Table C3. Available Endpoints 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 EC50: 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 EC50: 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 EC50: 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 EC50: 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 EC50: 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 EC50: 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 EC50: 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 EC50: 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 EC50: 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 EC50: 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 EC50: 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 EC50: 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

Acute toxicity studies are available (Table C4) 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. These data categorize the halohydantoins as 

being moderately toxic to estuarine/marine fish and highly toxic to estuarine/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 

therefore estuarine/marine fish and mysid shrimp chronic data 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 the 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)

LC50 = 1.2 mg Br2/L

95% CLs 1.0 – 1.6 Br2/L

Measured concentration

Probit slope = 1.37

NOAEC < 0.2 mg Br2/L (30% 

mortality at lowest treatment 

concentration)

40993103 /

Acceptable/

Moderately toxic

Sheepshead minnow, 0.27 g, 22 

mm

(Cyprinodon variegatus)

Flowthrough, NR,

BCDMH

(90)

LC50 = 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)

LC50 = 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 LC50 = 0.86 mg Br2/L

95% CLs NR

Measured concentration

NOAEC = 0.37 mg Br2/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 EC50: 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 LC50 > 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 oC, 31 ppt

BCDMH (60)

DCDMH (27.4)

DCEMH (10.6),

96-h LC50 = 0.92 mg Br2/L

95% CLs 0.7 – 1.4 mg Br2/L

Measured concentrations

Probit slope = 5.0

NOAEC = 0.1 mg Br2/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 oC, 

31-32 ppt

1BCDMH (90)

96-h LC50 = 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 LC50 = 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 Plants

No seedling emergence or vegetative vigor data for the dihalo or monohalohydantoins have been 

submitted. Seedling emergence and vegetative vigor data 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 assessment 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. Available 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)

LD50: >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)

LC50: >5000 ppm

NOAEC > 5000 ppm

43289904 /

Acceptable /

Practically nontoxic

Mallard

(Anas 

platyrhynchos)

DMH

(97.2)

LC50: >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 (Table D2). The NOAEC is 14 mg ai/L. An acute-tochronic 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 were modeled using ECOSAR v. 1.10 (see results at end of this appendix). EMH 

falls into the carbonyl urea group, 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 LC50: >972 mg/L

42373601 /

Acceptable/

Practically nontoxic

Rainbow trout, NR

Static

DMH

(97)

96-hr LC50: 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 LC50: >1017 mg//L

42368501 /

Acceptable/

Practically nontoxic

Fathead minnow, 0.3 g

Static

DMH

(97.1) 96-hr LC50: >1085 mg/L

42374702 /

Acceptable/

Practically nontoxic

Fathead minnow, NR

Static

DMH

(97)

96-hr LC50: 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 toxic 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 

Degradate (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 LC50: >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 LC50: 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.

Chronic estuarine/marine fish data for DMH and EMH were 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 used to screen 

risks for the exposure to these degradates. No additional fish chronic data for EMH or DMH are 

anticipated.

The model does not provide EMH or DMH chronic values for the mysid shrimp. However, the 

model does indicate that the mysid shrimp (96-hr LC50 = 1,449 and 5,987 for EMH and DMH, 

respectively) is expected to be less sensitive than the estuarine/marine fish (96-hr LC50 = 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 LC50: >1006 mg/L

Measured concentration

NOAEC > 1006 mg/L

42374701/ 

Acceptable/

Practically nontoxic

Sheepshead minnow,

(Cyprinodon variegatus)

Static

DMH

(97)

96-hr LC50: 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 LC50: 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 LC50: 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 oC, 

29-32 ppt

DMH

(97.2)

96-hr IC50: >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)

LC50 >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 EC50: 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 have been submitted. Green algae data for DMH and EMH were

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 IC50 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 these degradates. The model does not 

provide toxicity data for duckweed, freshwater diatoms, marine diatoms, or cyanobacteria; data 

for EMH and DMH are anticipated to be required for these species.

Semi-aquatic and Terrestrial Plants

No seedling emergence or vegetative vigor data for DMH or EMH have been submitted. 

Seedling emergence and vegetative vigor data for rice using DMH and EMH are anticipated to 

be required.

ECOSAR Version 1.10 Results Page for EMH

SMILES : O=C(NC(C1(=O))(CC)C)N1

CHEM : 2,4-Imidazolidinedione, 5-ethyl-5-methylCAS 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: (PhysProp 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 EC50 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 EC50)

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-dimethylCAS 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 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 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 253.618

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-theDrain 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 dilution factors, and wastewater treatment plant removal efficiency to provide both highend and median (average) time-averaged surface water concentrations of chemicals discharged 

from domestic wastewater treatment plants. The high-end scenario uses surface water 

concentrations downstream of domestic wastewater treatment plants based on the 10th percentile 

stream dilution factor (SDF); the average scenario uses surface water concentrations based on the 

50th percentile SDF. SDF is defined as the ratio of the 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 wastewater 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 LC50 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 LC50 values from acute toxicity tests on aquatic 

vertebrates and invertebrates by 20. The Down-the-Drain module was run 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 photolyze as it does not absorb UV light at wavelengths >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/cm3 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 from 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 Work Group comments sought to confirm 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 Agency 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 Antimicrobials 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 obsolete 

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 exposure 

potentials and for risk assessment calculations. 

1. Page 11, Table 6: Corrections to listed dose rates to be taken into account. 

a) Application 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 incorrect, 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: More 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 to 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 disinfection 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 vary 

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 outdoor 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 states 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 scope 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 EFAST 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 at 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 degradates, DMH, EMH, and monohalohydantoins”

(ACC 263903; MRID 42466201).

With a hydrolytic half-life of one hour for dihalohydantoins to form 

monohalohydantoins, dihalohydantoins are expected to form monohalohydantoins quite 

rapidly. Unlike the unhalogenated 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 organisms 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 wastewater 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 aquatic toxicity. 

AD Response: As the workplan stated on pages 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 viability. 

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 

monohalohydantoin(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 

estimates 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 collected 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 the 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, because 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 exposed to 

monohalohydantoins. Hydrolysis studies on dihalohydantoins that were reviewed by the 

Agency indicate that the time period for monohalohydantoin levels to be reduced by onehalf 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 processes 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 that 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 therefore, 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 versus 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 

organisms 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 very 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 

registrant 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 this 

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 results 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- imidazolidinedione (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 Response: 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

Although 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 near 

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 registration review DCI and confirms the data needs still anticipated to be 

required for the post-RED DCI. Since issuance of the 2007 RED, the Agency 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 data 

requirements. Table 8 reflects these updates and identifies what data is anticipated to be 

required for both the post-RED and registration review DCIs.

20. Comment: Pages 15-18, Table 8, Data Needs: Combines data needs anticipated for 

registration review and 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 phytotoxicity 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 DCI 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 toxicity 

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 

values 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 the 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 less 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 “...potentially 

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 guideline 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 Fisheries 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 aquatic 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 conventional 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 

incorrect 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 from 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 DMH 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 toxic 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 they are 

used (the OPPTS Guidelines specify an MMAD of 1-3 μm 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, as 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, resulting 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 plan 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 risks 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.
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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 company 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 and 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 structure-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 Agency 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. Therefore, 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 submission 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, utilizemitigation 

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-specific inputs and minimize the potential for underestimating 

or overestimating risk. In regard to QSAR, the Agency has and will continue to consider 
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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.