Document ID: EPA-HQ-OPP-2006-0244-0010
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2007-12-31T05:00Z

SEQ CHAPTER \h \r 1 United States 			Prevention, Pesticides		December
2007

  Environmental Protection                 and Toxic Substances

  Agency                                             (7510P)	

	

2,4 Imidazolidinedione (Hydroxymethyldimethyl Hydantoins)

Summary Document:  Final Work Plan

Registration Review



2,4 Imidazolidinedione (Hydroxymethyldimethyl Hydantoins)

Summary Document

Registration Review: Final Work Plan

December 2007

						

							Approved By:

							____________________

							Frank T. Sanders

							Director, Antimicrobials Division

____________________

Date

TABLE OF CONTENTS

I. Final Work
Plan….……………………………………………………….
.	5

II. Fact
Sheet…………………………………………………………
………………	

10

III. Status of Human Health and Ecological Risk Assessment for 

2,4 Imidazolidinedione (Hydroxymethyldimethyl Hydantoins) ….	

15

	A.
Introduction…………………….……………………………
…………...	15

	B. Use
Profile……………………….………………………………
………..	17

	C. Human Health Exposure and Risk
Assessment…...……………………	19

	D. Physical/Chemical Properties and Environmental
Fate……………….	24

	E. Ecological Exposure and Risk
Assessment...……………………………	26

IV. Glossary of Terms and
Abbreviations………………….……………...………	

28

V. Appendices

		A. Application and Specific Use
Information..……………...………….….	30

B. Toxicity Guideline Study Justification
………………..….....................	38

	C. Exposure Guideline Study
Justification………………..….....................	46

	D. Environmental Fate Guideline Study
Justification………...…………..	55

	E. Ecological Guideline Study
Justification...……………………………...	58

2,4 Imidazolidinedione (Hydroxymethyldimethyl Hydantoin) 

Registration Review Team

Human   SEQ CHAPTER \h \r 1 Health & Environmental Effects 

Nader Elkassabany

Srinivas Gowda

Timothy Leighton

Nathan Mottl

Rick Petrie

Najm Shamim

Jenny Tao

Risk Management

Diane Isbell

Office of General Counsel

Phil Ross

Final Work Plan - 2,4 Imidazolidinedione (Hydroxymethyldimethyl
Hydantoins)

Introduction:

The Food Quality Protection Act (FQPA) of 1996 amended the Federal
Fungicide Insecticide and Rodenticide Act (FIFRA) to mandate a new
program: registration review.  All pesticides distributed or sold in the
United States generally must be registered by EPA, based on scientific
data showing that they will not cause unreasonable risks to human
health, workers, or the environment when used as directed on product
labeling.  The new registration review program is intended to make sure
that, as the ability to assess and reduce risk evolves and as policies
and practices change, all registered pesticides continue to meet the
statutory standard of no unreasonable adverse effects.  Changes in
science, public policy, and pesticide use practices will occur over
time.  Through the new registration review program, the Agency
periodically reevaluates pesticides to make sure that as change occurs,
products in the marketplace can continue to be used safely.  Information
on this program is provided at:
http://www.epa.gov/oppsrrd1/registration_review/. 

The Agency has begun to implement the new registration review program
pursuant to FIFRA Section 3(g) and will review each registered pesticide
every 15 years to determine whether it continues to meet the FIFRA
standard for registration. 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.  2,4
Imidazolidinedione (hydroxymethyldimethyl hydantoin) is an antimicrobial
pesticide used in adhesives; air fresheners; caulking compounds;
cleansers; fabric softeners; hydraulic fluids; inks; liquid detergents;
metal working cutting fluids; paints, stains and coatings;
paper/paperboard coatings; polishes; synthetic polymers; powdered
detergents; sealants; carpet shampoos; soap; starch solutions; textiles;
and wax.

The initial Summary Document for 2,4 Imidazolidinedione 
(hydroxymethyldimethyl hydantoin)  Summary Document: Initial Docket, was
signed on June 21, 2007.  The initial Summary Document for the
hydroxymethyldimethyl hydantoins was updated per the comments received
during the public comment period. On December 19, 2007, this document,
the updated Hydroxymethyldimethyl Hydantoins Summary Document: Final
Work Plan, was signed. 

This is the Agency’s updated Summary Document: Final Work Plan for the
registration review of the Hydroxymethyldimethyl Hydantoins.  The
Summary Document: Final Work Plan for the Hydroxymethyldimethyl
Hydantoins addresses any errors found in the Initial Summary Document
and Preliminary Work Plan such as changes to the registration review
timeline and changes to the proposed data needs outlined in the Initial
Summary Document.  The Summary Document: Final Work Plan also addresses
public comments received during the public comment period, which are
posted and can be viewed in the Hydroxymethyldimethyl Hydantoins
registration review docket. 

2,4 Imidazolidinedione is comprised of two compounds: 
1,3-Bis(hydroxymethyl)-5,5-dimethyl hydantoin (also referred to as DMDM
Hydantoin) and Hydroxymethyl-5,5-dimethyl hydantoin (also referred to as
MDM Hydantoin).  Both of these active ingredients are formaldehyde
releasing compounds.  In this document these compounds may be referenced
as the hydroxymethyldimethyl hydantoins.

Risk Assessment Status &Anticipated Risk Assessment and Data Needs:

Human Health Risk:

The two active ingredients in this case are hydroxymethyldimethyl
hydantoins; these chemicals are formaldehyde releasers.  The
Reregistration Eligibility Decision (RED) for formaldehyde is scheduled
to be completed in 2008.  

The Agency believes the hydroxymethyldimethyl hydantoins may degrade to
5,5-dimethylhydantoin (DMH).  The halohydantoins are known to
hydrolyze/degrade to DMH.  A reregistration decision for the
halohydantoins was issued in 2004, based on the DMH data.  

Occupational and residential risk assessments will be needed to
determine potential risks from hydroxymethyldimethyl hydantoin uses,
including the potential inhalation exposure from the release of
formaldehyde.  

The Agency needs product chemistry data in order to assess the
hydroxymethyldimethyl hydantoins.  Some hydrolysis data were submitted
to the Agency during the public comment period.  A preliminary review of
these data was performed, indicating that the hydroxymethyldimethyl
hydantoins degrade rapidly via hydrolysis to dimethylhydroxymethyl (DMH)
and formaldehyde.  The Agency needs the complete study reports to fully
evaluate the hydrolysis of the hydroxymethyldimethyl hydantoins.  These
studies are considered supplemental, pending review of the complete
study.  Therefore, additional environmental fate data on the
hydroxymethyldimethyl hydantoins are still needed.  These data will
enable the Agency to determine how quickly and completely
hydroxymethyldimethyl hydantoins break down to DMH.  

Depending on how quickly hydroxymethyldimethyl hydantoins
hydrolyze/degrade to 5,5-dimethylhydantoin (DMH), we may need data on
the parent compounds, and/or other possible metabolites.  

If the degradation to DMH occurs rapidly and completely, data from DMH
will be used to conduct the human health risk assessment for
hydroxymethyldimethyl hydantoins.  In addition, the human health risk
assessment for formaldehyde will also be needed.

The Agency anticipates needing the following data in order to conduct a
complete human health risk assessment for all uses.  The toxicity data
base for formaldehyde will be evaluated during the reregistration
process, scheduled for completion in 2008.  Some studies listed below
may not be needed if the Agency determines that data from DMH may be
used for this risk assessment.  These studies are noted below.

DMDM Hydantoin & MDM Hydantoin  

For Human Health Effects/Toxicity

(GLN 870.2600) dermal sensitization 

(GLN 870.3150) 90-day oral toxicity – non-rodent  NOTEREF
_Ref170180504 \h  \* MERGEFORMAT  1 

(GLN 870.3250) 90-day dermal toxicity – rodent  NOTEREF _Ref170180504
\h  \* MERGEFORMAT  1 

(GLN 870.3465) 90-day inhalation toxicity – rat  NOTEREF _Ref170180504
\h  \* MERGEFORMAT  1 

(GLN 870.3700) prenatal developmental toxicity- rat  NOTEREF
_Ref170180504 \h  \* MERGEFORMAT  1 

(GLN 870.3800) reproduction and fertility effects – rodent  NOTEREF
_Ref170180504 \h  \* MERGEFORMAT  1 

(GLN 870.4100) chronic toxicity – rodent  NOTEREF _Ref170180504 \h  \*
MERGEFORMAT  1 

(GLN 870.4200) carcinogenicity – rat and mouse  NOTEREF _Ref170180504
\h  \* MERGEFORMAT  1 

5,5-DMH

(GLN 870.3465) 90-day inhalation toxicity – rat

(GLN 870.7600) dermal penetration – rat 

DMDM Hydantoin & MDM Hydantoin  

For Occupational and Residential Exposure

(GLN 875.1100) dermal outdoor exposure

(GLN 875.1200) dermal indoor exposure

(GLN 875.1300) inhalation outdoor exposure

(GLN 875.1400) inhalation indoor exposure

(GLN 875.1600 & 875.2900) data reporting and calculations 

(GLNs 875.1700 & 875.2700) product use information 

(GLN 875.2300) indoor surface residue dissipation

(GLN 875.2500) inhalation exposure2

(GLN 875.2700) product use information

(GLN 875.2900) data reporting2

(GLN 875.3000) non-dietary ingestion2

Environmental Fate and Ecological Risk:

An environmental fate and ecological effects risk assessment has not
been conducted for the hydroxymethyldimethyl hydantoins.  Please refer
to Section III, Ecological Effects Scoping Document for a detailed
discussion of the anticipated risk assessment needs.  

The Agency anticipates needing the following data in order to conduct a
complete environmental fate assessment:

(GLN 161.1)  hydrolysis;

(GLN 850.6800) modified activated sludge respiration inhibition;

(GLN 835.1110) activated sludge sorption isotherm; and

(GLN 835.3110) ready biodegradability.

The Agency anticipates needing the following data in order to conduct a
complete ecological risk assessment, including an endangered species
assessment for all uses:

(GLNs 850.4400 & 850.5400) algal toxicity (Tier II) using freshwater
green alga, Selenastrum capricornutum.

The planned ecological risk assessment will allow the Agency to
determine whether use of the hydroxymethyldimethyl hydantoins has "no
effect" or "may affect" federally listed threatened or endangered
species (listed species) or their designated critical habitat.  If the
assessment indicates that the hydroxymethyldimethyl hydantoins "may
affect" a listed species or its designated critical habitat, the
assessment will be refined.  The refined assessment will allow the
Agency to determine whether use of the hydroxymethyldimethyl hydantoins
is “likely to adversely affect” the species or critical habitat or
"not likely to adversely affect" the species or critical habitat.  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 National Marine Fisheries Service
(Services), as appropriate.

. 

Timeline:

	

EPA has created the following estimated timeline for the completion of
the 2,4 Imidazolidinedione (hydroxymethyldimethyl hydantoins)
registration review.  

Activities	Estimated Month/Year

Phase 1: Opening the docket

Open Public Comment Period for 2,4 Imidazolidinedione
(Hydroxymethyldimethyl Hydantoins)Docket  	July 2007

Close Public Comment Period 	October 2007

Phase 2:  Case Development

Develop Final Work Plan (FWP)	December 2007 

Issue DCI 	October - December 2008 

Data Submission	October - December 20123

Open Public Comment Period for Preliminary Risk Assessments 	December
2013

Close Public Comment Period	February 2014

Phase 3: Registration Review Decision

Open Public Comment Period for Proposed Reg. Review Decision 	April -
June 2014

Close Public Comment Period 	July - September 2014

Final Decision and Begin Post-Decision Follow-up	October – December
2014

Total (years)	7.53

3Time-frames may change depending on the studies needed.

Water Bodies

The 2,4 Imidazolidinedione (hydroxymethyldimethyl hydantoins) are not
identified as a cause of impairment for any water-bodies listed as
impaired under section 303(d) of the Clean Water Act, based on
information provided at:   HYPERLINK
"http://oaspub.epa.gov/tmdl/waters_list.impairments?p_impid=3" 
http://oaspub.epa.gov/tmdl/waters_list.impairments?p_impid=3 .  During
the public comment period for the Initial Summary Document, the Agency
invited submission of water quality data for this chemical.  It was
requested that, to the extent possible, data conform to the quality
standards in Appendix A of the “OPP Standard Operating Procedure:
Inclusion of Impaired Water Body and Other Water Quality Data in OPP’s
Registration Review Risk Assessment and Management Process,” ( 
HYPERLINK
"http://www.epa.gov/oppsrrd1/registration_review/water_quality_sop.htm" 
http://www.epa.gov/oppsrrd1/registration_review/water_quality_sop.htm ),
in order to ensure they can be used quantitatively or qualitatively in
pesticide risk assessments. No water quality data were submitted during
the public comment period for the initial 2,4 Imidazolidinedione
(hydroxymethyldimethyl hydantoins) Summary Document.

Trade Barriers

Through the registration review process, the Agency generally solicits
information on trade irritants and, to the extent feasible, take steps
toward facilitating irritant resolution.  Growers and other stakeholders
are asked to comment on any trade irritant issues resulting from lack of
Maximum Residue Limits (MRLs) or disparities between U.S. tolerances and
MRLs in key export markets, providing as much specificity as possible
regarding the nature of the concern.  No trade barrier information or
data were submitted during the public comment period for the initial 2,4
Imidazolidinedione (hydroxymethyldimethyl hydantoins)Summary Document.

Environmental Justice

The EPA seeks to achieve environmental justice, the fair treatment and
meaningful involvement of all people, regardless of race, color,
national origin, or income, in the development, implementation, and
enforcement of environmental laws, regulations, and policies.  To help
address potential environmental justice issues, the Agency seeks
information on any groups or segments of the population who, as a result
of their location, cultural practices, or other factors, may have
atypical, unusually high exposure to the 2,4 Imidazolidinedione
(hydroxymethyldimethyl hydantoins), compared to the general population. 
During the public comment period for the initial 2,4 Imidazolidinedione
(hydroxymethyldimethyl hydantoins)Summary Document, no environmental
justice information or data were submitted regarding any sub-populations
that may have atypical or unusually high exposure to 2,4
Imidazolidinedione (hydroxymethyldimethyl hydantoins) compared to the
general population.

Structure Activity Relationships

The EPA must rely upon information of appropriate quality and
reliability for each decision made by the Agency.  In the Office of
Pesticide Programs (OPP), the evaluation process for a pesticide
chemical traditionally begins with the applicant’s submission of a set
of studies conducted with the specific pesticide chemical of interest. 
The use of the results of such testing (measured data) is a logical,
scientifically rigorous process that identifies the physical, chemical,
and environmental fate properties of the pesticide, as well as the dose
and endpoints at which an adverse effect can occur in various animal
species. 

Today, there is significant interest in alternative techniques, i.e.,
techniques other than data generation that could significantly inform
the Agency’s decision-making process.  Recently, the OPP has made
increasing use of structure activity relationship (SAR) as part of its
regulatory decision-making process.  In the SAR process, a chemical's
molecular structure is compared to that of other chemicals for which
data are available.  These structural similarities are then used to make
predictive judgments about a chemical’s physical, chemical, and
biological properties.  Thus, the chemical’s physical, chemical, and
biological properties are a function of (or directly related to) the
chemical’s molecular structure.  Quantitative SAR is referred to as
QSAR.  To develop a QSAR, a selected set of measured data on a single
physical, chemical, or biological property is used to derive a model (an
equation) to predict the value of that property.  

	Since SAR assessments and QSAR modeling are another set of tools that
are available to Agency scientists, the OPP has begun a process shift
that envisions shifting from the current study-by-study approach to an
approach in which the use of predicted data, generated using validated
models, is considered along with information from open literature and
studies specifically generated under Part 158 requirements.  All
relevant information would be considered as part of a
weight-of-the-evidence evaluation.  

At this time, the EPA believes that for certain endpoints, especially
physical/chemical and fate properties, that SAR and QSAR might be
effectively utilized to fulfill these data requirements for many
antimicrobial pesticide chemicals.  When considering biological
properties, at this time, the EPA believes that SAR and QSAR can be most
effectively utilized in the evaluation of chemicals that exhibit lower
toxicity for human health and/or ecotoxicity parameters.  This is
appropriate because the risk assessment for lower toxicity chemicals can
be stream-lined (e.g., a screening-level assessment procedure rather
than multiple tiers of assessments with progressively more data
requirements). 

During the public comment period for the initial 2,4 Imidazolidinedione
(hydroxymethyldimethyl hydantoins) Summary Document, stakeholders were
asked to submit any information that they believe could fulfill one of
the data needs for the 2,4 Imidazolidinedione (hydroxymethyldimethyl
hydantoins). The Agency did not receive any comments regarding such
information during the public comment period. 

Summary of Comments Received During Docket Opening

The 2,4 Imidazolidinedione (hydroxymethyldimethyl hydantoins)
registration review docket was open for a 90-day comment period
beginning on July 6, 2007.  During that time two comments were received.
 These comments are summarized below. The comments, which are addressed
in this document, did not change the work plan or timeline set out in
the preliminary work plan. Further this document provides the final work
plan for the 2,4 Imidazolidinedione (hydroxymethyldimethyl hydantoins)
registration review processes. 

Summary of Comments Regarding Anticipated Risk Assessment and Data
Needs:

Comment:  Lonza, Inc. submitted comments on the preliminary work plan
and submitted preliminary hydrolysis data to the Agency, and asked the
Agency to consider using the avian and aquatic data that was previously
submitted.  In addition, some errors were noted.  

Response: The Agency thanks Lonza for its comments.  The Agency has
prepared a response to comment document that can be found in the
Agency’s docket for 2,4 Imidazolidinedione (hydroxymethyldimethyl
hydantoins).  

Comment: The FIFRA Endangered Species Task Force (FESTF) submitted a
comment requesting that any technical registrant for 2,4
Imidazolidinedione (hydroxymethyldimethyl hydantoins) 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.  In their comment, FESTF also noted that Lonza,
Inc. is the only technical registrant for 2,4 Imidazolidinedione
(hydroxymethyldimethyl hydantoins), and that Lonza, Inc. is not an FESTF
member. Therefore, the technical registrant must offer to pay FESTF to
rely on FESTF submitted data or develop substantial similar data on
their own. 

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. 

Next Steps

As detailed in the Risk Assessment Status & Anticipated Risk Assessment
and Data Needs section above, the Agency will prepare and issue a Data
Call In (DCI), which will identify the data needed to conduct both human
health and ecological risk assessments for 2,4 Imidazolidinedione
(hydroxymethyldimethyl hydantoins).  Complete human health and
ecological risk assessments, including an endangered species assessment,
for all uses will be conducted by the Agency. 

II. FACT SHEET

 

Background Information

2,4 Imidazolidinedione (hydroxymethyldimethyl hydantoin) registration
review case number: 5020

2,4 Imidazolidinedione; 1,3-bis (hydroxymethyl)-5,5-Dimethyl Hydantoin; 
DMDM Hydantoin is PC Code 115501 (CAS # 6440-58-0)

2,4 Imidazolidinedione; 1-(Hydroxymethyl)-5,5-Dimethyl Hydantoin; MDM
Hydantoin is PC Code 115502 (CAS # 116-25-6 )   

5,5-Dimehtyhydantoin (DMH) (CAS No. 77-71-4)

2,4 Imidazolidinedione; inert PC Code: 815502 (CAS # 27636-82-4) &
715501 (CAS#: 6440-58-0)	

Technical registrant: Lonza, Inc.

First approved for use in a registered product: 1985

Not subject to reregistration (no Reregistration Eligibility Decision
[RED]) 

Synonyms for 2,4-Imidazolidinedione,
1,3-bis(hydroxymethyl)-5,5-dimethyl- include:
1,3-Bis(hydroxymethyl)-5,5-dimethyl-2,4-imidazolidinedione,
1,3-Bis(hydroxymethyl)-5,5-dimethylhydantoin,
1,3-Di(hydroxymethyl)-5,5-dimethylhydantoin,
1,3-Dimethylol-5,5-dimethylhydantoin, 2,4-Imidazolidinedione,
1,3-bis(hydroxymethyl)-5,5-dimethyl-, 2,4-Imidazolidinedione,
1,3-bis(hydroxymethyl)-5,5-dimethyl-, DMDM Hydantoin, DMDMH, Hydantoin,
1,3-bis(hydroxymethyl)-5,5-dimethyl-, Hydantoin,
1,3-bis(hydroxymethyl)-5,5-dimethyl-, Hydantoin,
1,3-bis(hydroxymethyl)-5,5-dimethyl-,
N,N'-Dimethylol-5,5-dimethylhydantoin

Synonyms for 2,4 Imidazolidinedione, 1-(Hydroxymethyl)-5,5-Dimethyl
include:  1-(Hydroxymethyl)-5,5-dimethyl-2,4-imidazolinedione,
1-(Hydroxymethyl)-5,5-dimethylhydantoin, 2,4-Imidazolidinedione,
1-(hydroxymethyl)-5,5-dimethyl-, 2,4-Imidazolidinedione,
1-(hydroxymethyl)-5,5-dimethyl-, Hydantoin,
1-(hydroxymethyl)-5,5-dimethyl-, Hydantoin,
1-(hydroxymethyl)-5,5-dimethyl-, Hydantoin,
1-(hydroxymethyl)-5,5-dimethyl-, MDM Hydantoin, Monomethylol dimethyl
hydantoin, Monomethylol-5,5-dimethylhydantoin

PM: Adam Heyward:  heyward.adam@epa.gov  

Antimicrobials Division Chemical Review Manager (CRM):  Diane Isbell,
isbell.diane@epa.gov

Antimicrobials Division Product Manager (PM): Adam Heyward,    HYPERLINK
"mailto:heyward.adam@epa.gov"  heyward.adam@epa.gov 

Use & Usage Information 

For additional usage information and details, please refer to the
Appendix A.

The hydroxymethyldimethyl hydantoins are an antimicrobial used in
adhesives, air fresheners, caulking compounds, clay slurries, cleansers,
coatings, dispersed colors, resin emulsions, fabric softeners, hydraulic
fluids, inks, latex, liquid detergents, metal working cutting fluids,
paints (emulsion, latex, water-based), paper/paperboard coatings,
polishes, polymers (synthetic), powdered detergents, sealants, carpet
shampoos, soap, stains (preservative incorporation), starch solutions,
textiles, and wax.  

Pests controlled include algae, animal pathogenic bacteria,
deterioration/spoilage bacteria, fungi, mold/mildew, slime-forming
bacteria, slime-forming fungi, and yeasts.

There are 16 registered products containing the hydroxymethyldimethyl
hydantoins as an active ingredient; these formulations are also
formaldehyde releasers.

Application rates for the active ingredient range from 0.5 – 20
lbs/1000lbs of material being preserved.    Application rates in liquid
soaps range from 2.5 – 10 lbs per 1000 lbs of soap being treated.  For
preservation of paper and paperboard, apply at levels of 1 – 6 lbs per
ton of aqueous mineral slurry. 

Recent Actions

No recent registration actions have occurred for the
hydroxymethyldimethyl hydantoins.

Human Health Risk Assessment Status

Please refer to Section IV of this document for a detailed discussion of
the anticipated risk assessment needs for human health.  A summary is
provided below.

Dietary (Food and Water):

Several dietary assessments were conducted in 2001- 2003 for various
indirect food contact uses on paper and other materials.

As a result of the hydroxymethyldimethyl hydantoins indirect food uses,
including paper and papermaking, adhesives, and liquid detergents, a
dietary risk assessment will be needed for these chemicals. 

Residential: 

Residential uses of the hydroxymethyldimethyl hydantoins include: liquid
detergents, fabric softeners, household cleaning products, soft soaps,
water-based paints, room deodorizers, air fresheners, water-based gels 
and polymer emulsions for household products, textiles, water-based
adhesives, sealants and caulks, latex for paper coatings, food and
non-food contact paper and paperboard, carpet shampoos, polishes, waxes.
 The Agency will conduct a residential risk assessment as part of
registration review.

Occupational:

No comprehensive occupational exposure assessment was performed for
these hydroxymethyldimethyl hydantoin products being considered for
registration review.  The Agency will complete an occupational risk
assessment for registration review of the hydroxymethyldimethyl
hydantoins.  

An occupational assessment was conducted in 2001 for the primary uses of
1,3-dichloro-5,5-dimethylhydantoin, as the active ingredient in
Dantochlor RW (81.1% a.i.), during batch mixing for introduction into
industrial cooling water systems and pulp and paper process water.  

Ecological Risk Assessment Status

Ecological exposure and risk assessments have not been conducted for the
hydroxymethyldimethyl hydantoins. Very limited ecological data on the
hydroxymethyldimethyl hydantoins have been submitted to the Agency;
however, the hydroxymethyldimethyl hydantoins degrade rapidly via
hydrolysis to dimethylhydroxymethyl (DMH) and formaldehyde (see Lonza
Inc. comments to the Agency in response to registration review summary
document, 10/03/07).  The ecotoxicity of DMH and formaldehyde can be
determined based on risk assessments associated with the DMH and
formaldehyde Reregistration Eligibility Decision documents, scheduled
for completion in 2008.  The Agency will rely on the DMH and
formaldehyde RED documents to assess the impacts of any releases of
hydroxymethyldimethyl hydantoins into the environment.  Please refer to
Section III of this document, Status of Human Health and Ecological Risk
Assessment for the Hydroxymethyldimethyl Hydantoins, for a detailed
discussion of the anticipated ecological risk assessment and data needs.

The planned ecological risk assessment will allow the Agency to
determine whether use of the hydroxymethyldimethyl hydantoins has "no
effect" or "may affect" federally listed threatened or endangered
species (listed species) or their designated critical habitat.  If the
assessment indicates that the hydroxymethyldimethyl hydantoins "may
affect" a listed species or its designated critical habitat, the
assessment will be refined.  The refined assessment will allow the
Agency to determine whether use of the hydroxymethyldimethyl hydantoins
is “likely to adversely affect” the species or critical habitat or
"not likely to adversely affect" the species or critical habitat.  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 National Marine Fisheries Service
(Services), as appropriate.

Tolerances 

The hydroxymethyldimethyl hydantoins are registered as an indirect
food-contact use as a slimicide in the manufacture of paper and
paperboard.  In addition the hydroxymethyldimethyl hydantoins are
registered as a preservative/coating preservative in food contact paper
and paperboard.  The hydroxymethyldimethyl hydantoin uses on paper and
paperboard are considered indirect food contact.  There are no uses
where hydroxymethyldimethyl hydantoins are applied directly to food. 
Currently there are no tolerances for this chemical. 

Data Call-In Status

A data call-in has not been issued for the hydroxymethyldimethyl
hydantoins since it was not subject to reregistration.

Labels 

There are 16 registered products for the hydroxymethyldimethyl
hydantoins.  A list of registration numbers is included below.  Product
registration labels may be obtained from the Pesticide Product Label
System (PPLS) website at:   HYPERLINK
"http://oaspub.epa.gov/pestlabl/ppls.home" 
http://oaspub.epa.gov/pestlabl/ppls.home .

2,4 Imidazolidinedione (Hydroxymethyldimethyl Hydantoin) Registration
Numbers

Registration 

Number	Product

Name	Company

Name

5383-111	Troysan 680	Troy Chemical Company

5383-123	Troysan 2063	Troy Chemical Company

6836-111	GlycoserveLAD	Lonza Inc.

6836-112	Glycoserve	Lonza Inc.

6836-119	Dantogard	Lonza Inc.

6836-199	Dantogard XL-1000	Lonza Inc.

6836-200	Dantogard Plus Industrial Preservative	Lonza Inc.

6836-207	Dantogard II Preservative	Lonza Inc.

6836-208	Glycoserve II Preservative	Lonza Inc.

6836-271	Dantogard Plus Liquid	Lonza Inc.

6836-306	Dantoserve SG	Lonza Inc.

6836-307	Dantoserve MS	Lonza Inc.

6836-322	Dantogard 2000 Preservative	Lonza Inc.

47371-188	Dantocil IG	H & S Chemicals Division

47371-189	Dantocil HG	H & S Chemicals Division

47371-190	Dantocil SG	H & S Chemicals Division

Incidents

No incidents related to the hydroxymethyldimethyl hydantoins use were
found during a search of the following databases:  the OPP Incident Data
System (IDS); Poison Control Center data; California Department of
Pesticide Regulation data; and National Pesticide Information Center
data.  

III. STATUS OF HUMAN HEALTH AND ECOLOGICAL RISK ASSESSMENT FOR 2,4
IMIDAZOLIDINEDIONE [DMDM HYDANTOIN (PC CODE 115501; CAS# 6440-58-0) AND
MDM HYDANTOIN (PC CODE 115502; CAS# 116-25-6)] –

 REGISTRATION REVIEW CASE NUMBER 5020

A. Introduction

	The 2,4-Imidazolindinedione registration review contains
1,3-Bis(hydroxymethyl)-5,5-dimethyl hydantoin (DMDM Hydantoin or DMDH)
and Hydroxymethyl-5,5-dimethyl hydantoin (MDM Hydantoin or MDMH), which
are often referred to as hydroxymethyldimethyl hydantoins. 
Hydroxymethyldimethyl hydantoins are antimicrobial pesticides that are
used in numerous materials preservatives applications. The Antimicrobial
Division Hydroxymethyldimethyl Hydantoins Registration Review Team has
evaluated the human health and ecological assessments to determine the
scope of work necessary to support the registration review. During
registration review the AD team will examine potential human and
ecological toxicity, physical/chemical properties, environmental fate,
exposures, and risks as a result of registered uses. The team considered
the uses of the hydroxymethyldimethyl hydantoins, which is presented in
Section B of this report.  The status of human exposure and risk
assessment of these hydroxymethyldimethyl hydantoins is presented in
Section C along with the corresponding chemical structures (see Table
1). The status of data on the physical/chemical properties and
environmental fate of these hydroxymethyldimethyl hydantoins is
presented in Section D of this report.  Ecological exposure and risk
assessment status for these two active ingredients is presented in
Section E of this report.  The purpose of reviewing the status of this
registration review case is to determine whether sufficient data are
available, whether new human health and ecological risk assessments are
needed to support registration review, and to report why new data may be
needed to support the registration review process.

	Although on September 30, 2004, the Agency issued a decision regarding
reregistration of halohydantoins, the Agency has not issued a decision
regarding reregistration of hydroxymethyldimethyl hydantoins.  In the
late 1980s, the Agency determined that halohydantoins are rapidly
metabolized by mammals to 5,5-dimethyl hydantoin (DMH).  Although
preliminary data showed that hydroxymethyldimethyl hydantoins hydrolyzed
rapidly to release formaldehyde and leave the carrier DMH as the stable
moiety at 60 0C and 37 0C, there are no guideline studies available to
demonstrate that hydroxymethyldimethyl hydantoins behave similarly to
halohydantoins to hydrolyze/degrade quickly to DMH at 25 0C.  As the
preliminary data showed unlike halohydantoins, hydroxymethyldimethyl
hydantoins break down to also form formaldehyde and therefore, are
referred to as formaldehyde-releasing hydantoins.  Consequently, the
assessment of risks for hydroxymethyldimethyl hydantoins must also
include an assessment of risks from exposure to formaldehyde.

Data Requirements and Data Waivers

The Agency employs a step-wise process to assist the registrant in
determining the data needed to support its particular product.  The
actual data and studies needed may be modified on an individual basis to
fully characterize the use and properties of specific pesticide products
under review.  While EPA will assist the registrant in outlining data
needs, it is important to emphasize that it is the registrant's
obligation under FIFRA to demonstrate that an individual product meets
the standard under FIFRA and/or FFDCA.  Accordingly, registrants are
encouraged to consult with the Agency on the appropriate data needs, as
outlined here, as related to their specific product during this
registration review process.

	Since each pesticide is unique and there is much variety in pesticide
chemistry, exposure, and hazard, the Agency tries to be flexible with
regard to data needs.  The Agency also recognizes, however, that due to
the particular nature and risk of some pesticides, registrants may seek
to obtain data waivers or may suggest alternative approaches to
satisfying data needs.  Some products may have unusual physical,
chemical, or biological properties or atypical use patterns which would
make particular data requirements inappropriate, either because it would
not be possible to generate the data or because the data would not be
useful in the Agency’s evaluation of the risks or benefits of the
product.  The Agency will waive data that it finds are inappropriate,
but will ensure that sufficient data are available to make the
determinations required by the applicable statutory standards.

  Considering the above, registrants may request to use surrogate data
or alternative methods to meet data needs or request a waiver of data
based upon chemistry, exposure, or hazard rationales that support their
position.  Registrants are encouraged to discuss the request with the
Agency before developing and submitting supporting data, information, or
other materials.  All waiver requests must be submitted to the Agency in
writing.  The request must clearly identify the data need(s) for which a
waiver is sought along with an explanation and supporting rationale why
the registrant believes the data need should be waived. In addition, the
registrant must describe any unsuccessful attempts to generate the
needed data, furnish any other information that the registrant(s)
believes would support the request, and when appropriate, suggest
alternative means of obtaining data to address the concern which
underlies the data need.  The Agency will review each waiver request and
subsequently inform the registrant in writing of its decision.

B. Use Profile

	The uses of antimicrobial pesticide chemicals regulated under FIFRA are
highly variable and complex and have been organized into twelve
categories of use patterns based on similarity of use, pesticide
function, method of incorporation into end-use products, method of
application of end-use products, types of establishments in which
products are used, environmental media to which antimicrobials are
expected to be released, and types of receptors expected to come into
contact with antimicrobial pesticides.  The twelve general use patterns
for antimicrobial pesticides include:

     Agricultural premises and equipment; 

     Food handling/storage establishments, premises, and equipment;

     Commercial, institutional and industrial premises and equipment; 

      Residential and public access premises;

      Medical premises and equipment;

      Human drinking water systems;

      Materials preservatives;

      Industrial processes and water systems;

      Antifoulants and ballast water;

Wood preservatives;

Swimming pools; and

Aquatic areas. 

Although halohydantoins and hydroxymethyldimethyl hydantoins have some
similar uses, some uses for these two groups of hydantoins are
different.  Halohydantoins are used as disinfectants in commercial and
residential swimming pools, spas, and hot tubs and as sanitizers for
treatment of toilet bowl water in homes whereas the
hydroxymethyldimethyl hydantoins are not.  The only potential
food-contact use for the halohydantoins is an indirect food-contact use
as a slimicide in the manufacture of food contact paper and paperboard. 
In addition to use as a slimicide in the manufacture of food contact
paper and paperboard, two additional indirect food-contact uses for
hydroxymethyldimethyl hydantoins include filler preservative in food
contact paper and paperboard and coating preservative for food contact
paper and paperboard.  There are no tolerances established for the
hydroxymethyldimethyl hydantoins.  Information on the use profile for
the hydroxymethyldimethyl hydantoins follows. 

	DMDM hydantoin and MDM hydantoin are both present as active ingredients
in 16 products.  Of the 12 general use patterns for antimicrobial
pesticides, two are applicable to the hydroxymethyldimethyl hydantoins: 
materials preservatives and residential and public access premises. 
Appendix A presents specific uses for general antimicrobial use patterns
applicable to the hydroxymethyldimethyl hydantoins.  Specific uses,
general use patterns, and potential for long-term exposure determine
data needs for terrestrial and aquatic non-target organisms,
environmental fate, human toxicity, and occupational and residential
exposure for the hydroxymethyldimethyl hydantoins.  Appendix A presents
information on each of the specific use sites for the general use
patterns that are applicable to the hydroxymethyldimethyl hydantoins,
including the method of application, application rate, and range of
percent by weight of active ingredient to be added to each use site.

C. Human Health Exposure and Risk Assessment 

No human health, occupational, or residential risk assessments have been
performed by the Agency for these hydroxymethyldimethyl hydantoins. 
When used as a material preservative in adhesives, liquid detergents,
papermaking chemicals and coatings, hydroxymethyldimethyl hydantoins
have potential indirect food contact uses.  As a result, dietary
exposure and risk assessments are needed.

Toxicity

In the late 1980s, the Agency determined 5,5-dimethylhydantoin (DMH) to
be the moiety of mammalian toxicological concern for halohydantoins and
selected this chemical to represent human health effects for this class
of chemicals.  Although preliminary data showed that
hydroxymethyldimethyl hydantoins hydrolyzed quickly to release
formaldehyde and leave the carrier DMH as the stable moiety at 60 0C and
37 0C, there are no guideline studies available to support the
conclusion that hydroxymethyldimethyl hydantoins behave similarly to
halohydantoins with regard to metabolic half-life and moieties of
concern under natural environmental conditions (such as at 25 0C of
temperature).  As the preliminary data showed unlike halohydantoins,
hydroxymethyldimethyl hydantoins break down to also form formaldehyde
and therefore, are referred to as formaldehyde-releasing hydantoins. 
The chemical structures of the hydroxymethyldimethyl hydantoins are
provided in table 1 and the metabolite DMH is in table 2. 

In general, the Agency needs a basic toxicity dataset to characterize
the hazard and risks through all exposure routes (oral, inhalation, and
dermal).  Based on a limited database that includes toxicity data gaps
for a number of data needs, the Agency was not able to select an oral,
dermal and/or inhalation toxicological endpoint for the
hydroxymethyldimethyl hydantoins, and the determination of cancer
potency was inconclusive.  A more complete toxicity database will be
needed to quantify risk for the dietary, incidental ingestion, dermal
and inhalation exposure scenarios and toxicity endpoints will need to be
established

For the hydroxymethyldimethyl hydantoins, the registrant has submitted a
90-day oral toxicity study in rats (MRID 250311/132103) and 21/28-day
toxicity study (MRID 138830/29025).  The 90-day oral study has been
reviewed by the Agency as core-minimum, but the 21/28-day study was
determined to be a supplementary study.  Only two doses tested (8 and
800 mg/kg/day); the LOAEL was determined to be 800 mg/kg/day based on
the well defined erythema, moderate edema, subdermal hemorrhages and
pustules with histopathological findings.  

	The registrant has also submitted a prenatal developmental toxicity
study in rabbits (MRID 258269/149559) for the hydroxymethyldimethyl
hydantoins that is core-minimum.  No fetal toxicity and/or developmental
toxicity were found at the highest dose tested (750 mg/kg/day).  It
should be noted that the Agency needs both rodent and non-rodent studies
to examine species sensitivity for both developmental and 90-day oral
toxicity studies.

Without the physical chemistry and fate data especially hydrolysis data
(OPP guideline number 161-1) (see also Section D) for the
hydroxymethyldimethyl hydantoins, it is difficult to confirm how fast or
slow the breakdown process is and whether the process is a relatively
complete or partial breakdown.  In addition, information on the
metabolic half-life in mammals (guideline 870.7485) is also needed to
determine whether humans are likely to be exposed primarily to the
parent chemicals or to their metabolites.  If the hydroxymethyldimethyl
hydantoins are not rapidly metabolized in humans and humans are likely
to be exposed to the parent chemicals for an extended period, the Agency
will need extensive mammalian toxicity tests on both DMDM and MDM
Hydantoins. The needed guideline (GLN) studies include:

(GLN 870.2600) dermal sensitization *

(GLN 870.3150) 90-day oral toxicity – non-rodent *

(GLN 870.3250) 90-day dermal toxicity – rodent *

(GLN 870.3465) 90-day inhalation toxicity – rodent *

(GLN 870.4100) chronic toxicity – rodent *

(GLN 870.4200) carcinogenicity – rat and mouse *

(GLN 870.3700) prenatal developmental toxicity- rat *

(GLN 870.3800) reproduction and fertility effects – rodent *

* These studies may not be needed based on the outcome of the
environmental fate studies conducted using hydroxymethyldimethyl
hydantoins.

In the event that the hydroxymethyldimethyl hydantoins degrade
relatively quickly to the metabolite DMH, the Agency would not need as
much data since the metabolite (DMH) has a relatively complete toxicity
database.  In addition, the Agency already has evaluated most of the
mammalian toxicity data for DMH in the course of assessing dietary
exposure and risk to the halohydantoins, reevaluated in 2004.  If DMH is
the metabolite of concern for the hydroxymethyldimethyl hydantoins,
fewer toxicity studies would be needed.  These needed studies are listed
below.

(GLN 870.3465) 90-day inhalation toxicity – rat

(GLN 870.7600) dermal penetration – rat

The Agency anticipates needing this data in order to conduct a complete
human health risk assessment for all uses.  The toxicity database for
formaldehyde will be evaluated during the reregistration process,
scheduled for completion in 2008.  

Refer to Appendix B for specific justifications on toxicity guideline
studies. This appendix identifies, for example, why certain
hydroxymethyldimethyl hydantoin use patterns may trigger the need for
specific toxicity studies, based on the length of exposure.  In
addition, Appendix B provides a rationale for examining species
sensitivity.  If the Agency identifies metabolites other than DMH and
formaldehyde, the Agency would also need mammalian toxicity data for
these metabolites.

It should be noted that although hydroxymethyldimethyl hydantoins have
adequate acute data, the Agency cannot use LD50 (lethal dose – a
single dose that kills half [50%] of the animals tested) from acute oral
studies for hazard characterization and toxicity endpoints selection for
risk assessment as toxicity observed in a repeated exposure setting is
much different and higher than toxicity observed in an one-time acute
exposure setting.

Dietary Risk Assessment

As a result of the hydroxymethyldimethyl hydantoins indirect food uses,
including paper and papermaking, adhesives, and liquid detergents, a
dietary risk assessment will be needed for these chemicals. 

Residue Chemistry

	Modeling can be used to estimate dietary intake that results from the
use of hydroxylmethyldimethyl hydantoins as a material preservative in
adhesives, detergents, paper making and coatings.  Often, a screening
level (Tier I) assessment is sufficient to determine dietary risk for
antimicrobial pesticides.  For a Tier I assessment, FDA methodologies
are employed for determining Estimated Daily Intakes (EDIs).  Estimation
of EDIs are based on the premise that some pesticide is likely to
migrate from treated surfaces into food from surfaces like counter tops,
cutting boards, paper and paper boards, kitchen utensils, etc.  EDIs
(mg/person/day) represent the migration of a pesticide into food from a
treated surface.  

EDIs are then converted into Daily Dietary Doses (DDD) (mg/kg/day). %
aPAD and % cPAD are estimated based on the acute and chronic dietary end
points.  If the Tier I assessments do not indicate risk concerns, then
no additional residue chemistry guideline studies would be needed. 
However, if risks of concern are identified in the Tier I assessments,
the Agency would need additional residue chemistry guideline studies.  

Drinking Water

In addition, if analysis of initial Tier I screening tests for
environmental fate and microbial effects indicate that the magnitude of
exposure to potential drinking water sources could be high rather than
negligible or low, it is possible that the Agency may need a human
drinking water risk assessments.

Occupational and Residential Risk Assessment

The hydroxymethyldimethyl hydantoins break down to form formaldehyde.  
Therefore the hydroxymethyldimethyl hydantoins, are referred to as
formaldehyde-releasing hydantoins.  As mentioned previously, no data
have been submitted indicating the half-life of environmental fate
processes and/or identifying resulting degradates of these
hydroxymethyldimethyl hydantoins. Consequently, it is not clear whether
humans will be exposed primarily to hydroxymethyldimethyl hydantoins or
to the metabolite via inhalation or dermal exposure in occupational and
residential settings in which products containing these
hydroxymethyldimethyl hydantoins as active ingredients are used.  The
chemicals for which the Agency needs data for the occupational and
residential risk assessments, depends upon the how quickly the parent
hydroxymethyldimethyl hydantoins, degrades and what degradates result. 
If studies indicate that the hydroxymethyldimethyl hydantoins degrade to
DMH, the common moiety with the halohydantoins, then it may be possible
to use existing data from the halohydantoins rather than new studies
conducted using the hydroxymethyldimethyl hydantoins.  In summary, a
risk assessment for these hydroxymethyldimethyl hydantoins must consider
potential risks associated with the active ingredients and the
metabolites of concern, including formaldehyde.

	Based on the registered uses of hydroxymethyldimethyl hydantoins for
use as material preservatives and in residential and public access
premises, there is potential for occupational and residential exposure. 
Although an occupational exposure assessment was performed for DMH, no
occupational exposure assessment was performed for the
hydroxymethyldimethyl hydantoins.  Consequently, the Agency will likely
perform an occupational exposure and risk assessment for registration
review of the parent compound, the metabolite, and also examine the
release of formaldehyde hydroxymethyldimethyl hydantoins depending
largely on the fate and persistence of the parent compound.  In
addition, the Agency will need to conduct a residential exposure and
risk assessment.  For occupational exposures, mixer/loader and
applicator exposure scenarios include open and closed loading in
industrial settings, such as the manufacturing process for paints,
textiles, paper, and metal working fluids for hydroxymethyldimethyl
hydantoins.  In addition, there is the potential for applicator exposure
during painting (residential and professional painters) and for metal
working fluid machinists.  Occupational postapplication exposure is
expected to be minimal. However, potential residential post-applicator
exposures are likely to include exposures to treated products such as
textiles.

 

	To assess both the occupational and residential assessments, additional
toxicity data are needed.  For example, a 90-day inhalation toxicity
endpoint is needed in order to conduct an inhalation assessment and a
90-day dermal toxicity endpoint is also needed to perform a dermal
assessment. For screening purposes, an oral endpoint with a default
assumption of 100% absorption could potentially be used in lieu of
inhalation data. However, this all depends on the toxicological
database.  For dermal exposure, it is also possible that oral toxicity
data could also be used.  However, the Agency may also need a dermal
penetration study.  The need for this study would likely be conditional,
depending on the completion of the toxicity database.  For a residential
incidental ingestion exposure assessment, oral toxicity data are also
needed.  

	Dermal and inhalation occupational assessments are needed during
registration review for use in manufacturing settings (e.g. paper
making), commercial painters, and metal working fluid machinists.  Based
on most of the currently supported uses, short-and intermediate-term
dermal and inhalation scenarios are needed for registration review.
Long-term exposure estimates are only needed for estimating risks to
machinists using metal working fluid.  Residential assessments are
needed for short- and intermediate-term inhalation (e.g. painting) and
children’s postapplication incidental oral exposures for textiles and
carpets. The Agency will likely use task force submitted data for
applicator to conduct these occupational or residential assessments.
Refer to Appendix C for more details on the exposure data needed and a
rationale for why this information is necessary.

D. Physical/Chemical Properties and Environmental Fate

	Submission of physical/chemical property data is needed for
registration of hydroxymethyldimethyl hydantoins.  No product chemistry
data have been submitted for either of the hydroxymethyldimethyl
hydantoins.  As a result, the Agency anticipates needing these data. 
Physical/chemistry data help the Agency in evaluating hazard and
exposure including acute toxicity (inhalation), workers’ exposure
(vapor pressure), and bioaccumulation (environmental fate).  Storage
stability data helps the Agency in determining if the product would
remain stable in a formulation.  Hydrolysis data (GLN 161-1) are needed
in order to predict how fast or slow the breakdown process of
hydroxymethyldimethyl hydantoins is to DMH and formaldehyde, and whether
the degradation process is relatively complete or a partial breakdown.  

The Agency has limited data on the physical form of the
hydroxymethyldimethyl hydantoin products. However, a product chemistry
review of Dantogard XL-1000, a manufacturing use product containing the
highest percentage of a single hydantoin as the active ingredient was
completed in the early 1990s.  The label indicates that the physical
form of this manufacturing use product is a solid.  Because melting
points of the active ingredients and the manufacturing use product
exceed 30 degrees centigrade, no vapor pressure data were provided. 
Labels for several other products containing the hydroxymethyldimethyl
hydantoins, indicate that they are liquids.  Although the percentage of
the two active ingredients is always indicated on the product labels,
the physical form of the registered products is not.  The physical form
of the manufacturing use products and end use products can influence the
potential for exposure to the two active ingredients.  Given the absence
of product chemistry data for either of the hydroxymethyldimethyl
hydantoins, the Agency needs product chemistry data for both.  In
addition, the Agency needs information on the physical form of each
registered product. 

	Additionally, the Agency is planning to determine (1) the potential of
antimicrobial pesticides and/or their major degradates to directly
adversely affect biological treatment processes present in a wastewater
treatment plant (WWTP); (2) the amount of an antimicrobial pesticide
and/or its major degradates present in influents to a WWTP and in
effluents (water or bio-solids) that a WWTP releases to the environment;
and (3) whether antimicrobial pesticides found in WWTP effluents, such
as surface water, exceed the Agency’s Levels of Concern (LOCs) for
non-target organisms.  One source of antimicrobials in surface water is
disposal of consumer products such as soaps and detergents, into
household wastewater.  Also, if EPA determines that other use categories
result in discharges to WWTPs, the Agency will conduct any other
assessments normally performed for these other use categories.

The anticipated environmental fate data needs for the
hydroxymethyldimethyl hydantoins or any of its major degradates that are
identified to be of potential concern are listed below. 

(GLN 161-1) hydrolysis study

(GLN 850.6800) modified activated sludge respiration inhibition test

(GLN 835.1110) activated sludge sorption isotherm test

(GLN 835.3110) ready biodegradability study 

Data from the hydrolysis study will enable the Agency to determine if
the antimicrobial pesticide hydrolyzes in water discharged to WWTPs, in
aquatic effluents WWTPs discharge to surface waters, or in surface
waters.  The modified activated sludge respiration inhibition test will
allow the Agency to identify antimicrobial pesticides which could harm
microorganisms found in biological wastewater treatment systems and
would also indicate suitable concentrations for use in the ready
biodegradability study.  The activated sludge adsorption isotherm test
will allow EPA to assess the distribution of antimicrobials among the
aqueous, solid, and vapor phases of WWTPs.  In addition, this study will
identify those chemicals that are likely to adsorb to sludge. 
Examination of the sludge compartment is necessary since humans and
non-target organisms may potentially be exposed to antimicrobials that
adsorb strongly to sludge that are applied to land as a soil amendment. 
Finally, the activated sludge adsorption isotherm test results will help
determine which ready biodegradability test method is most appropriate. 
 The ready biodegradability study will enable the Agency to determine
the likelihood that an antimicrobial will biodegrade during the
wastewater treatment process.  It is possible that under specific
conditions the Agency may need additional environmental fate studies. 
Further description of the environmental fate guideline studies needed
by the EPA is presented in Appendix D.  

E. Ecological Exposure and Risk Assessment

				

Based on the hydroxymethyldimethyl hydantoins uses as material
preservatives and in residential and public access premises, the
potential for exposure to ecological organisms is expected to be low. 
Although the Agency has not conducted an ecological exposure and risk
assessment, the Agency expects to conduct a risk assessment for the
active ingredient and/or any of its metabolic and/or hydrolytic
degradate products identified as DMH and formaldehyde to be of potential
concern.  The potential exists for environmental exposure to ecological
organisms in the event of a spill or other environmental release of
hydroxymethyldimethyl hydantoins or hydroxymethydimethyl
hydantoin-containing products.  Although ecological toxicity studies
conducted by Industrial Biotest Laboratories, Inc. were previously
submitted, the Agency classified these studies as invalid.  Due to rapid
hydrolysis of the parent to DMH and formaldehyde, the Agency will rely
on ecotoxicity studies submitted to support the DMH and formaldehyde
REDs for this ecological risk assessment.  Potential for environmental
exposure exists for material preservative uses of hydroxymethyldimethyl
hydantoins in down the drain exposures, such as disposal of consumer
products such as soaps and detergents into household wastewater.  An
endangered species risk assessment will also be performed.  Studies that
the Agency needs to conduct a risk assessment include the following:

(GLN 850.5400).algal toxicity (Tier II) using freshwater green alga,
Selenastrum capricornutum.

		

The Agency has no ecological risk assessment for hydroxymethyldimethyl
hydantoins to date.  All uses were previously considered “indoor”
having little potential for environmental exposure.  In response to
concerns over persistent compounds in surface waters and disruptions to
sewage treatment processes, the Agency has reevaluated the definition of
“indoor uses” with regard to environmental exposure.  

In order to perform wastewater treatment plant (WWTP) and ecological
risk assessments, the Agency must evaluate the toxicity of
hydroxymethyldimethyl hydantoins to non-target and endangered or
threatened terrestrial and aquatic animals and plants. 
Hydroxymethyldimethyl hydantoins uses having potential for environmental
exposure are industrial or consumer materials preservative discharges on
land and in marine areas.  

The justification for a nontarget plant guideline study is presented in
Appendix E.  As mentioned in Appendix E, these guideline studies will
provide the Agency with endpoints to be used in wastewater treatment
plant surface water exposures. It is possible that after further review
and under specific conditions the Agency may need additional ecological
toxicity tests.  

The planned ecological risk assessment will allow the Agency to
determine whether use of the hydroxymethyldimethyl hydantoins has "no
effect" or "may affect" federally listed threatened or endangered
species (listed species) or their designated critical habitat.  If the
assessment indicates that the hydroxymethyldimethyl hydantoins "may
affect" a listed species or its designated critical habitat, the
assessment will be refined.  The refined assessment will allow the
Agency to determine whether use of the hydroxymethyldimethyl hydantoins
is “likely to adversely affect” the species or critical habitat or
"not likely to adversely affect" the species or critical habitat.  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 National Marine Fisheries Service
(Services), as appropriate.

	

	

GLOSSARY of TERMS & ABBREVIATIONS

ai		Active Ingredient

AR		Anticipated Residue

ASTM		American Society for Testing and Materials

AWPA		American Wood Preserver’s Association

CFR		Code of Federal Regulations

cPAD		Chronic Population Adjusted Dose

CSF		Confidential Statement of Formula

CSFII		USDA Continuing Surveys for Food Intake by Individuals

DCI		Data Call-In

DEEM		Dietary Exposure Evaluation Model

DFR		Dislodgeable Foliar Residue

DNT		Developmental Neurotoxicity

DWLOC		Drinking Water Level of Comparison

EC		Emulsifiable Concentrate Formulation

EDWC		Estimated Drinking Water Concentration

EEC		Estimated Environmental Concentration

EPA			Environmental Protection Agency

EUP		End-Use Product

FDA		Food and Drug Administration

FIFRA		Federal Insecticide, Fungicide, and Rodenticide Act

FFDCA		Federal Food, Drug, and Cosmetic Act

FQPA		Food Quality Protection Act

FOB		Functional Observation Battery

GENEEC		Tier I Surface Water Computer Model

IR		Index Reservoir

LC50	Median Lethal Concentration.  A statistically derived concentration
of a substance that can be expected to cause death in 50% of test
animals.  It is usually expressed as the weight of substance per weight
or volume of water, air or feed, e.g., mg/l, mg/kg or ppm.

LD50	Median Lethal Dose.  A statistically derived single dose that can
be expected to cause death in 50% of the test animals when administered
by the route indicated (oral, dermal, inhalation).  It is expressed as a
weight of substance per unit weight of animal, e.g., mg/kg.

LOC		Level of Concern

LOAEL		Lowest Observed Adverse Effect Level

µg/g		Micrograms Per Gram

µg/L		Micrograms Per Liter

mg/kg/day		Milligram Per Kilogram Per Day

mg/L		Milligrams Per Liter

MOE		Margin of Exposure 

MRID	Master Record Identification (number).  EPA's system of recording
and tracking submitted studies.

MUP		Manufacturing-Use Product

NA		Not Applicable

NAWQA		USGS National Ambient Water Quality Assessment

NPDES		National Pollutant Discharge Elimination System

NR		Not Required

NOAEL		No Observed Adverse Effect Level

OPP		EPA Office of Pesticide Programs

OPPTS		EPA Office of Prevention, Pesticides and Toxic Substances

PAD		Population Adjusted Dose

PAIRA		Pure Active Ingredient Radiolabelled

PCA		Percent Crop Area

PDP		USDA Pesticide Data Program

PHED		Pesticide Handler's Exposure Data 

PHI		Preharvest Interval

ppb		Parts Per Billion

PPE		Personal Protective Equipment

ppm		Parts Per Million

PRZM/EXAMS		Tier II Surface Water Computer Model  

Q1*	The Carcinogenic Potential of a Compound, Quantified by the EPA's
Cancer Risk Model

RAC		Raw Agriculture Commodity

RED		Reregistration Eligibility Decision

REI		Restricted Entry Interval

RfD		Reference Dose

RQ		Risk Quotient

SCI-GROW		Tier I Ground Water Computer Model

SAP		Science Advisory Panel

SF		Safety Factor

SLN		Special Local Need (Registrations Under Section 24©) of FIFRA)

TGAI		Technical Grade Active Ingredient

TEP		Typical End-Use Product

USDA		United States Department of Agriculture

UF		Uncertainty Factor

WPS			Worker Protection Standard



Appendix A.  Application and Specific Use Information for DMDM Hydantoin
(PC Code 115501) and MDM Hydantoin (PC Code 115502)

Use Site	Formulation Type and Reg. No.	Method of Application	Application
Rate/ No. of applications	Use Limitations

Materials preservatives

Water based stains, sealants, adhesives, caulks, joint cements, resin
emulsions, inks, textile processing chemicals, liquid detergents, fabric
softeners, soft soaps, household cleaners, room deodorizers, air
fresheners, and water based surfactants, polymer emulsions, protective
or decorative coatings, water based gels for household and industrial
products, textiles, water-based adhesives, sealants, caulks, latex for
paper coatings, water based paints for industrial and household use.	

Soluble concentrate

6836-199

6836-200

5383-111

5383-123

6836-207

__________

Soluble concentrate

6836-111

Soluble 

concentrate

6836-271

__________

Soluble concentrate

6836-322

__________

Formulation intermediate

6836-208	

Incorporation	Product should be added to the formulation to be preserved
at a rate of 0.1% to 1.0% or 1,000 to 10,000ppm, based upon the total
weight of the product to be protected

To ensure uniform distribution, slowly disperse product into product
with agitation. Mix thoroughly until

evenly dispersed throughout product.

______________________

Product should be added to the liquid detergent or soft soap formulation
at the rate of 2.5 to 10 pounds per 1000 lbs. or to 2,500 to 10,000 ppm
based upon the total weight of the formulation

__________

Product should be added to the formulation to be preserved at a rate of
2.0 to 20.0 lbs. per 1000 lbs or 0.2% to 2.0% or 2,000 to 20,000 ppm
based upon the total weight of the product to be protected

__________

Add to formulation to be preserved at the rate of 2.3 to 9.4 lbs per
1000 lbs or 2300 to 9400 ppm based upon the total weight of the
formulation to be protected

__________

	

This product is not to be used for food-contact packaging (6836-199),
(6836-200), (6836-207), (6836-271)

Liquid detergents, soft soaps, room deodorizers/air fresheners,
water-based surfactants, polymer emulsions, water-based gels for
household/industrial products and textiles

	47371-189

	Incorporation	Should be added to the formulation to be preserved at a
rate of 0.2% (2,000 ppm) based upon the total weight of the product to
be protected

	Non-food contact water-based adhesives, latex products, titanium
dioxide and calcium carbonate dispersions typically used for paper
coatings	47371-190	Incorporation	Use at levels of 4.0 lbs per ton of
material being treated (2000 ppm)

	Aqueous mineral slurry

used in the manufacture of paper and paperboard

	Soluble concentrate

47371-190

6836-119

4.0 pounds per ton of material being treated (2000ppm)

To ensure uniform distribution, slowly disperse product into product
with agitation. Mix thoroughly until evenly dispersed throughout product

	 This product is not to be used for food-contact packaging (6836-119)

Aqueous dispersions of inorganic mineral slurries such as clay, kaolin
clay, calcium carbonate and titanium dioxide used in the manufacture of
food contact and non-food contact paper and paperboard for both filler
and paper coatings applications	6836-307

	Incorporation	Should be added to the mineral slurry to be preserved at
a rate of 0.05% to 0.30% (500 to 3,000 ppm) based on the total weight of
the product to be protected; to ensure uniform distribution, slowly
disperse product into product with agitation. Mix thoroughly until
evenly dispersed throughout product

	

Metalworking fluids:

Electroplating, electro deposition, phosphatizing, galvanizing, and
general metal cleaning operations

	Soluble concentrate

6836-199

6836-200

6836-271

6836-306

6836-119

__________

47371-188	

Incorporation	To control bacterial and fungal growth in metalworking
fluids add at a concentration of 0.05% to 1.00% ( 500 to 10,000ppm) 

Re-dose as necessary depending upon the rate of preservation, dilution
with makeup fluid, the nature and severity of contamination, level of
microbial control required, filtration effectiveness, system design,
etc.

__________

Should be added to the cleaning fluid to be preserved at a rate of 0.2%
(2,000 ppm) based upon the total weight of the solution	           None
stated

__________

Not to be used to preserve fluids that will be used for food-contact
packaging

High water-based hydraulic fluids and invert emulsion hydraulic fluids

	47371-188	Incorporation	Should be added to the hydraulic fluid to be
preserved at a rate of 0.2% (2,000 ppm) based upon the total weight of
the solution

	Polymer emulsions and natural latex, surfactant solutions, tackifiers
derived from rosin and hydrocarbon resins, water-based paints, paint
components, stains and coatings for household and industrial use,
protective and decorative coatings, water-based adhesives, sealants,
joint cements and caulks, latex for paper coatings, water-based gels for
industrial products and textiles; and water-based inks	6836-306

47371-188	Incorporation	Product should be added at a rate of 0.05% to
1.00% (500 to 10,000 ppm) based on the total weight of the product to be
protected.  

Should be added to formulation to be preserved at a rate of 0.2% (2,000
ppm) based upon the total weight of the product to be protected	This
product is not to be used for food-contact packaging.

Residential and public access premises

(Materials preservative)

Liquid detergent, fabric softener, soft soap	Soluble concentrate

47371-189

6836-199

6836-200

5383-111

5383-123

6836-207

__________

Soluble concentrate

6836-111

6836-322

	Incorporation	Product should be added to the formulation to be
preserved at a rate of 0.1% to 1.0% or 1,000 to 10,000ppm, based upon
the total weight of the product to be protected

To ensure uniform distribution, slowly disperse product into product
with agitation. Mix thoroughly until

Evenly dispersed

______________________

Product should be added to the liquid detergent or soft soap formulation
at the rate of 2.5 to 10 pounds per 1000 lbs. or to 2,500 to 10,000ppm
based upon the total weight of the formulation

	          None stated

	Formulation intermediate

6836-112

6836-208

	



Appendix B. Toxicity Guideline Study Justifications 

Guideline	Study Title	Practical Utility of the Data

870.3150	90-Day Oral Toxicity Study (Non-rodent) 	1)  What is the value
of the study?

The Agency does not have a full picture of the potential effects which
could occur as a result of exposure via the oral route.  The needed
study will provide insight into concerns regarding toxicity via the oral
route.  It may also provide a toxicity endpoint applicable to risk
assessment.

2)  How will the data be used?

The study will form the foundation for hazard characterization and
toxicity endpoints selection for risk assessment through all exposure
routes (oral, inhalation, and dermal).  These data will allow the Agency
to conclude more definitively whether or not there would be any concerns
for oral toxicity in a non-rodent species.  This will provide a more
complete hazard characterization of 2,4 Imidazolidinedione with regard
to the potential risks to the U.S. general population including infants
and children as required by the FQPA.

3)  How could the data affect the risk assessment?

The study will form the foundation for hazard characterization and
toxicity endpoints selection for risk assessment through all exposure
routes (oral, inhalation, and dermal).  It is possible that the database
uncertainty factor be reduced or removed, resulting in different
magnitude of the value of the endpoint used for regulation.

4)  What is triggering the need for this data?

The difficulty of predicting real world human oral exposure (as well as
inhalation and/or dermal) with limited data and no repeated-dose
toxicity data or other alternative information, such as SAR
(structure-activity-relationship), surrogate data, and/or
weight-of-evidence to the Agency triggered the need for a 90-day
(guideline) oral toxicity study, in order to adequately evaluate real
world human exposure to 2,4 Imidazolidinedione based on how it is used.

870.2500	90-Day Dermal Toxicity Study (Rat)	1)  What is the value of the
study?

The Agency does not have a full picture of the potential effects which
could occur as a result of exposure via the dermal route.  The needed
study will help provide insight into concerns regarding toxicity via the
dermal route.  It may also provide a toxicity endpoint applicable to
risk assessment.

2)  How will the data be used?

The data should help the Agency to conclude more definitively whether or
not there would be any concerns for dermal toxicity.  This will provide
a more complete hazard characterization of 2,4 Imidazolidinedione in
regards to the potential risks to the U.S. general population.

3)  How could the data affect the risk assessment?

It is possible that the database uncertainty factor be reduced or
removed, resulting in different magnitude of the value of the endpoint
used for regulation.

4)  What is triggering the need for this data?

The difficulty of predicting real world human dermal exposure with
limited data or other alternative information, such as SAR
(structure-activity-relationship), surrogate data, and/or
weight-of-evidence to the Agency triggered the need for a 90-day
(guideline) dermal toxicity study, in order to adequately evaluate real
world human exposure to 2,4 Imidazolidinedione based on how it is used.

870.3465	90-Day Inhalation Toxicity Study

(Rat)	1)  What is the value of the study?

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
needed study will provide insight into concerns regarding toxicity via
the inhalation route.  It may also provide a toxicity endpoint
applicable to risk assessment.

2)  How will the data be used?

The study may result in a change in how risks are quantified.  The data
will allow the Agency to conclude more definitively whether or not there
would be any concerns for inhalation toxicity in the rat.  This will
provide a more complete hazard characterization of 2,4
Imidazolidinedione in regards to the potential risks to the U.S. general
population.

3)  How could the data affect the risk assessment?

The study may result in a change in how risks are quantified.  It is
possible that the database uncertainty factor be reduced or removed,
resulting in different magnitude of the value of the endpoint used for
regulation.

4)  What is triggering the need for this data?

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 to the Agency triggered the need for a 90-day
(guideline) Inhalation toxicity study, in order to adequately evaluate
real world human exposure to 2,4 Imidazolidinedione particles based on
how it is used. (The OPPTS Guidelines specify an MMAD of 1-3 (m in
inhalation toxicity studies of aerosols so that a portion of the test
article will reach the lungs).

870.4100	Chronic Toxicity Study (Rodent)	1)  What is the value of the
study?

The Agency does not have a full picture of the potential effects which
could occur as a result of long-term exposure.  The study will provide
insight into concerns regarding toxicity through long-term exposure.  It
may also provide a toxicity endpoint applicable to risk assessment.

2)  How will the data be used?

The study may result in a change in how risks are quantified.  The data
will allow the Agency to conclude more definitively whether or not there
would be any concerns for chronic toxicity in the rat.  This will
provide a more complete hazard characterization of 2,4
Imidazolidinedione in regards to the potential risks to the U.S. general
population including infants and children as required by the FQPA.

3)  How could the data affect the risk assessment?

The study may result in a change in how risks are quantified.  It is
possible that the database uncertainty factor be reduced or removed,
resulting in different magnitude of the value of the endpoint used for
regulation.

4)  What is triggering the need for this data?

The difficulty of predicting real world human exposure via all routes
(oral, inhalation or dermal) with limited data and no chronic data or
other alternative information, such as SAR
(structure-activity-relationship), surrogate data, and/or
weight-of-evidence to the Agency triggered the need for a chronic
(guideline) toxicity study, in order to adequately evaluate real world
human exposure to 2,4 Imidazolidinedione based on how it is used,
particularly used as material preservative in Metal Working Fluids
(MWF). 



870.4200	Carcinogenicity Study (Rat)	1)  What is the value of the study?

The Agency does not have a full picture of the potential effects which
could occur as a result of long-term exposure.  The study will provide
insight into concerns regarding carcinogenicity through long-term
exposure.  It may also provide a toxicity endpoint applicable to risk
assessment.

2)  How will the data be used?

The study may result in a change in how risks are quantified.  The data
will allow the Agency to conclude more definitively whether or not there
would be any concerns for carcinogenicity in the rat.  This will provide
a more complete hazard characterization of 2,4 Imidazolidinedione in
regards to the potential risks to the U.S. general population including
infants and children as required by the FQPA.

3)  How could the data affect the risk assessment?

The study may result in a change in how risks are quantified.  It is
possible that the database uncertainty factor be reduced or removed,
resulting in different magnitude of the value of the endpoint used for
regulation.

4)  What is triggering the need for this data?

The inconclusive results of the mutagenicity data, difficulty of
predicting real world human exposure via oral routes with limited data
and no carcinogenicity data or other alternative information, such as
SAR (structure-activity-relationship), surrogate data, and/or
weight-of-evidence to the Agency triggered the need for a
carcinogenicity (guideline) study, in order to adequately evaluate real
world human exposure to 2,4 Imidazolidinedione based on how it is used,
particularly used as material preservatives in Metal Working Fluids
(MWF) and the fact of releasing formaldehyde, a known carcinogen.



870.4200	Carcinogenicity Study (Mouse)	1)  What is the value of the
study?

The Agency does not have a full picture of the potential effects which
could occur as a result of long-term exposure.  The study will provide
insight into concerns regarding carcinogenicity through long-term
exposure.  It may also provide a toxicity endpoint applicable to risk
assessment.

2)  How will the data be used?

The study may result in a change in how risks are quantified.  The data
will allow the Agency to conclude more definitively whether or not there
would be any concerns for carcinogenicity in the mouse.  This will
provide a more complete hazard characterization of 2,4
Imidazolidinedione in regards to the potential risks to the U.S. general
population including infants and children as required by the FQPA.

3)  How could the data affect the risk assessment?

The study may result in a change in how risks are quantified.  It is
possible that the database uncertainty factor be reduced or removed,
resulting in different magnitude of the value of the endpoint used for
regulation.

4)  What is triggering the need for this data?

The inconclusive results of the mutagenicity data, difficulty of
predicting real world human exposure via oral routes with limited data
and no carcinogenicity data or other alternative information, such as
SAR (structure-activity-relationship), surrogate data, and/or
weight-of-evidence to the Agency triggered the need for a
carcinogenicity (guideline) study, in order to adequately evaluate real
world human exposure to 2,4 Imidazolidinedione based on how it is used,
particularly used as material preservatives in Metal Working Fluids
(MWF) and the fact of releasing formaldehyde, a known carcinogen.



870.3700	Developmental Toxicity Study (Rat)	1)  What is the value of the
study?

The study will provide insight into concerns regarding pre- and/or
postnatal toxicity as required by FQPA.  It may also provide a toxicity
endpoint applicable to risk assessment.

2)  How will the data be used?

The study may result in a change in how risks are quantified.  The data
will allow the Agency to conclude more definitively whether or not there
are any concerns for pre- and/or postnatal toxicity in the rat.  This
will provide a more complete hazard characterization of 2,4
Imidazolidinedione in regards to the potential risks of developmental
toxicity.

3)  How could the data affect the risk assessment?

The study may result in a change in how risks are quantified.  It is
possible that the database uncertainty factor be reduced or removed,
resulting in different magnitude of the value of the endpoint used for
regulation.

4)  What is triggering the need for this data?

The difficulty of predicting real world human exposure via oral route
with limited data and no developmental toxicity data in rabbit or other
alternative information, such as SAR (structure-activity-relationship),
surrogate data, and/or weight-of-evidence to the Agency triggered the
need for a developmental (guideline) toxicity study in rabbit, in order
to adequately evaluate real world human exposure to 2,4
Imidazolidinedione, particularly women in the 15-49 years of age and
infants and children, based on how it is used. 



870.3800

 

	Reproduction and Fertility Effects (Rodent)

	1)  What is the value of the study?

The study will provide insight into concerns regarding the potential
risks of reproductive toxicity in the rat as well as potential
neurotoxicity in developing offspring.  It may also provide a toxicity
endpoint applicable to risk assessment.

2)  How will the data be used?

The data will allow the Agency to conclude more definitively whether or
not there are any concerns for potential reproductive toxicity in the
rat.  Since the reproductive toxicity study will also include
neurotoxicity evaluations, it will also provide some information
regarding potential neurotoxicity in developing offspring exposed to 2,4
Imidazolidinedione.

3)  How could the data affect the risk assessment?

 

The study may result in a change in how risks are quantified.  The study
may provide a toxicity endpoint applicable to risk assessment.  It is
possible that the database uncertainty factor be reduced or removed,
resulting in a different magnitude of the value of the endpoint used for
regulation.  

4)  What is triggering the need for this data?

The difficulty of predicting real world human exposure via oral route
with limited data and no reproductive toxicity data in rat or other
alternative information, such as SAR (structure-activity-relationship),
surrogate data, and/or weight-of-evidence to the Agency triggered the
need for a reproducitve (guideline) toxicity study in rat, in order to
adequately evaluate real world human exposure to 2,4 Imidazolidinedione,
particularly women in the 15-49 years of age and infants and children,
based on how it is used. 



Appendix C: Occupational and Residential Exposure Guideline Study
Justifications 

Guideline	Study Title	Practical Utility of the Data

875.1300 and

875.1400

(Applicator)	Inhalation Outdoor Exposure and Inhalation Indoor Exposure
Note:  Inhalation exposure data are needed for both residential and
occupational uses.  The selection of an outdoor versus an indoor site is
based on the high end exposure scenario (for inhalation the selection is
typically indoors).  In almost all cases, repeating an exposure study
for the same scenario outdoors and indoors is not necessary.

1)  What is the value of the study?

The inhalation exposure route is very important for exposure scenarios
such as paint rollers and airless sprayers where aerosols will be
generated.  In addition, inhalation exposures from liquid pouring are
evident in exposure studies in the Pesticide Handlers Exposure Database
(PHED).  Finally, there is also the potential for inhalation exposure
for machinist using treated metal working fluids (MWF).  The potential
for the release of and exposure to formaldehyde during the product use
also needs to be determined. The existing CMA data base and PHED for
these scenarios are limited in scope for QA/QC and number of monitoring
units.  EPA presented the need for additional handler exposure data to
the January 2007 Science Advisory Panel (SAP) as well as to the April
2007 Human Studies Review Board (HSRB) and both groups agreed that
additional data are warranted. 

2)  How will the data be used?

The inhalation exposure data will be used to assess the residential
short-term duration of painting with a paint brush/roller and an airless
sprayer.  For occupational uses, the inhalation exposure data will be
used to assess the short- and intermediate-term commercial painters
(brush/roller and airless sprayer), up to a long-term duration for
machinists using metal working fluids (MWFs), as well as open pouring of
the product (e.g., poured into paint as a preservative in manufacturing
settings, paper making, etc).  The data will also be used to determine
if the release of formaldehyde occurs and to what extent.

3)  How could the data affect the risk assessment?

The inhalation exposure data will be used to determine the accuracy of
the inhalation risks to both residence and occupational workers.  If
risks warrant mitigation, the inhalation exposure data will provide the
types of mitigation necessary such as respiratory protection from
respirators or closed systems for commercial uses to potential removal
of uses from the label.

What is triggering the need for this data?

The criteria for the inhalation exposure data are based on the potential
for respiratory exposure from the labeled uses (e.g., airless sprayers,
machinists, etc.) and evidence of toxicity.  If the toxicological
endpoints from 5,5-dimethylhydantoin are used to assess the risks, there
is an endpoint of concern for the oral route.  Note:  No inhalation
route specific toxicology data are available.

875.1100 and 875.1200

(Applicator)

	Dermal Outdoor Exposure and Dermal Indoor Exposure	Note:  Dermal
exposure data are needed for both residential and occupational uses. 
The selection of an outdoor versus an indoor site is based on the high
end exposure scenario.  In almost all cases, repeating an exposure study
for the same scenario outdoors and indoors is not necessary.

1)  What is the value of the study?

The potential for dermal exposure is very likely for exposure scenarios
such as paint rollers, airless sprayers, liquid pouring, and for
machinist using treated metal working fluids (MWF).  The existing CMA
data base and PHED for these scenarios are limited in scope for QA/QC
and number of monitoring units.  EPA presented the need for additional
handler exposure data to the January 2007 Science Advisory Panel (SAP)
as well as to the April 2007 Human Studies Review Board (HSRB) and both
groups agreed that additional data are warranted. 

2)  How will the data be used?

The dermal exposure data will be used to assess the residential
short-term duration of painting with a paint brush/roller and an airless
sprayer.  For occupational uses, the dermal exposure data will be used
to assess the short- and intermediate-term commercial painters
(brush/roller and airless sprayer), up to a long-term duration for
machinists using metal working fluids (MWFs), as well as open pouring of
the product (e.g., poured into paint as a preservative in manufacturing
settings, paper making, etc).  

3)  How could the data affect the risk assessment?

The dermal exposure data will be used to determine the accuracy of the
dermal risks to both residence and occupational workers.  If risks
warrant mitigation, the dermal exposure data will provide the types of
mitigation necessary such as chemical resistant gloves or closed systems
for commercial uses to potential removal of uses from the label.

4)  What is triggering the need for this data?

The criteria for the dermal exposure data are based on the potential for
dermal exposure from the labeled uses (e.g., airless sprayers,
machinists, etc.) and evidence of toxicity.  If the toxicological
endpoints from 5,5-dimethylhydantoin are used to assess the risks, there
is an endpoint selected for the dermal route.  

875.1600

(Applicator)	Data Reporting and Calculations 	1)  What is the value of
the study?

For all exposure studies these data are needed to facilitate the review
of the data.

2)  How will the data be used?

The study report and all raw data/calculations will be reviewed for the
adequacy of the data.

3)  How could the data affect the risk assessment?

The data are needed to interpret the dermal exposure data collected.

4)  What is triggering the need for this data?

This data need is triggered if an exposure study is conducted.

875.1700

(Applicator)	Product Use Information	1)  What is the value of the study?

Product use information is a description of how the product is actually
applied; it is not a field study.  A description of how this product is
used will provide for a comprehensive realistic assessment of its
potential applications.

2)  How will the data be used?

The description of the application techniques will be used to define the
exposure scenarios to be assessed in the risk assessment.

3)  How could the data affect the risk assessment?

A complete description of product use will ensure that the risk
assessment is inclusive of the types of exposures occurring during
residential and occupational use.

What is triggering the need for this data?

The need for a risk assessment as required under Registration Review,
will require that the risk assessor understands how the products are
applied.  These data will provide information on how these products are
actually applied.

875.2500

(Post Application)

	Inhalation Exposure

	1)  What is the value of the study?

The post application inhalation exposure may be needed if it is
determined that the use of these products have the potential to release
formaldehyde during the product use conditions (e.g., open systems).

2)  How will the data be used?

The post application inhalation exposure data will be used to assess the
residential and/or occupational inhalation risks to formaldehyde if
released based on product use.   

3)  How could the data affect the risk assessment?

The inhalation exposure data will be used to determine the accuracy of
the post application inhalation risks to formaldehyde to both residence
and occupational bystanders.  If risks warrant mitigation, the
inhalation exposure data will provide the types of mitigation necessary
such as respiratory protection from respirators or closed systems for
commercial uses to potential removal of uses from the label.

4)  What is triggering the need for this data?

The potential for these products to release formaldehyde is triggering
the need for post application exposure data specifically to monitor for
formaldehyde.  

875.2300

(Post Application)	Indoor Surface Residue Dissipation	1)  What is the
value of the study?

No data are currently available to determine the residues available for
dermal and incidental oral exposure from treated textiles and carpets. 
Specific data needs for post application dermal exposure can be
fulfilled using these residue data.  As a first tier to the risk
assessment 100% residue transfer is assumed.  If no risk concerns are
evident, this study will not be needed.  If risks of concern are
indicated at 100% residue transfer, then this study is needed to refine
the assessment.

2)  How will the data be used?

This product is used as a material preservative in textiles and as a
carpet shampoo.  The available residues from clothing and carpets will
be used to determine the magnitude of children’s dermal and incidental
exposure from treated clothing and from treated carpets.

3)  How could the data affect the risk assessment?

The data are needed to refine the risk estimates if risks of concern are
identified assuming 100% residue transfer from treated clothing apparel
and carpets. 

What is triggering the need for this data?

The specific 2,4 imidazolidinedione uses triggering the criteria for the
surface residue data are the potential for dermal incidental oral
exposure from the material preservative use in textiles along with the
carpet shampoo and evidence of toxicity.  If risks of concern are not
identified when 100% residue transfer is assumed, the data are not
needed.

875.2700

(Post Application)	Product Use Information	1)  What is the value of the
study?

Product use information for the post application data need is a
description of what types of consumer products are treated; it is not a
field study.  A description of what types of consumer products are
treated, specifically what types of textiles, will provide for a
comprehensive realistic assessment of potential post application
exposures.

2)  How will the data be used?

The listing of the end use consumer products will be used to define the
exposure scenarios to be assessed in the risk assessment.  For example,
if treated textiles include clothing, bedding, etc then a children’s
exposure scenario needs to be assessed.  However, if the treated
textiles are limited to awnings, doormats, etc., a post application
assessment for textiles may not be needed. 

3)  How could the data affect the risk assessment?

A complete description of consumer products treated will ensure that the
risk assessment is inclusive of the types of exposures occurring during
residential use.

What is triggering the need for this data?

The need for a risk assessment as required under Registration Review
will require that the risk assessor understands how the product is
applied.  These data will enable the risk assessor to understand how the
products are applied.

875.2900

(Post Application)	Data Reporting and Calculations	1)  What is the value
of the study?

For all exposure studies these data are needed to facilitate the review
of the data.

2)  How will the data be used?

The study report and all raw data/calculations will be reviewed for the
adequacy of the data.

3)  How could the data affect the risk assessment?

The data are needed to interpret the residue data collected.

4)  What is triggering the need for this data?

The data reporting need is triggered if a residue study is conducted.

875.3000

(Post Application)

 

	Non-dietary Ingestion Exposure

	1)  What is the value of the study?

The design of the non dietary ingestion exposure study can be combined
with the Indoor Surface Residue Dissipation study (875.2300) to
determine the available residue leaching from a child mouthing treated
clothing articles as well as hand-to-mouth behavior on treated carpets.

2)  How will the data be used?

This product is used as a material preservative in textiles and as a
carpet shampoo.  The available residues from clothing and carpets will
be used to determine the magnitude of children’s incidental exposure
from treated clothing and carpets.

3)  How could the data affect the risk assessment?

The data are needed to refine the risk estimates if risks of concern are
identified assuming 100% residue transfer from treated clothing apparel
and carpets. 

4)What is triggering the need for this data?

The criteria for the surface residue data is the potential for
incidental oral exposure from the material preservative use in
textiles/carpets and evidence of toxicity.  If risks of concern are not
identified when 100% residue transfer is assumed, the data are not
needed.



Appendix D: Environmental Fate Guideline Study Justifications

Guideline	Study Title	Practical Utility of the Data

OPP 161-1	Hydrolysis	1)  What is the value of the study?

Results from the hydrolysis study will indicate the stability and
persistence of 2,4 Imidazolidinedione, indicating the potential for this
chemical to contaminate water discharged to WWTPs.   In aquatic
effluents, WWTPs may discharge directly to surface waters.  The Agency
will address the risks of concern.

2)  How will the data be used?

Data will show/help in establishing chemical hydrolysis as a route for
degradation of a pesticide and to identify, if possible, the hydrolytic
products formed which may adversely affect non-target organisms and may
contaminate water and food source of aquatic organisms.

3)  How could the data affect the risk assessment?

The results of hydrolysis data would indicate if 2,4 Imidazolidinedione
is persistent or it degrades into degradation products which may
adversely affect nontarget organisms and may contaminate their food and
water and possibly soil.

4)  What is triggering the need for this data?                          
                                                                       
Hydrolysis data are needed to conduct the fate assessment to support
indoor uses for 2,4 Imidazolidinedione.

850.6800	Modified Activated Sludge, Respiration Inhibition	1)  What is
the value of the study?

The modified activated sludge respiration inhibition test will allow EPA
to identify antimicrobial pesticides which could harm microorganisms
found in biological wastewater treatment systems and would also help
establish correct concentrations for use in the ready biodegradability
test.

2)  How will the data be used?

These data will be used to determine the potential of 2,4
Imidazolidinedione to directly harm the nontarget organisms and/or to
microbial treatment processes present in a WWTP and to determine
suitable noninhibitory concentrations of 2,4 Imidazolidinedione to be
used in biodegradability tests.

3)  How could the data affect the risk assessment?

If the data shows that 2,4 Imidazolidinedione is toxic to nontarget
organisms and/or to microbial process found in WWTPs, then the Agency
may need Tier II environmental fate data to evaluate potential adverse
effects on WWTPs.

4)  What is triggering the need for this data?

Studies are needed to conduct environmental fate assessment and to
determine the potential exposure of 2,4 Imidazolidinedione to waste
water treatment plants (WWTPs) (via effects on WWTP microbes).

835.1110	Activated Sludge Sorption Isotherm	1)  What is the value of the
study?

The results from activated sludge sorption study will allow EPA to
assess the distribution of the antimicrobial among the solid, aqueous,
and vapor phases of WWTPs.  Specifically, this study identifies those
chemicals which sorb to sludge biomass. 

2)  How will the data be used?

These data will be used to determine the sorption potential of 2,4
Imidazolidinedione to activated sludge biomass and in biological
wastewater treatment systems.

3)  How could the data affect the risk assessment?

If 2,4 Imidazolidinedione is not sorbed or biodegraded then, it will
pass through a biological treatment system unaffected and it will
contaminate surface and drinking waters and also have potential adverse
effects to nontarget organisms.

4)  What is triggering the need for this data?

Studies are needed to conduct environmental fate assessment and to
determine the sorption potential of activated sludge for the removal of
specific chemical compounds in biological wastewater treatment systems.



835.3110

	Ready Biodegradability	1)  What is the value of the study?

The ready biodegradability study will enable the Agency to determine the
likelihood that the antimicrobial pesticide of biodegrading in aquatic
environments under aerobic conditions.

2)  How will the data be used?

The results from the data will be used to determine the rate and extent
of aerobic biodegradation of 2,4 Imidazolidinedione when it is released
into aquatic environments and will help establish if 2,4
Imidazolidinedione is stable or not stable under real environmental
conditions.   

3)  How could the data affect the risk assessment?

If the study results shows low biodegradability then, 2,4
Imidazolidinedione will occur in significant quantities in WWTP
effluents (water and biosolids) and in environmental compartments (e.g.,
surface waters) such that potential adverse effects to nontarget
organisms, found in such environmental compartments, may occur.

4)  What is triggering the need for this data?

Data are needed to conduct environmental fate assessment and to
determine the ready biodegradability of 2,4 Imidazolidinedione.



Appendix E: Ecological Guideline Study Justifications            

Guideline	Study Title	Practical Utility of the Data:  

850.5400*	Tier II green algae using

Selenastrum capricornutum

	1)  What is the value of the study?  As part of a Tier I risk
assessment, one indicator plant species is tested for phytotoxicity. 
This study will allow the Agency to categorize formaldehyde releasing
hydantoins as toxic or non-toxic to plants.  If toxic, additional higher
tier plant tests will be needed.  An endangered species assessment for
endangered or threatened plants is not possible without this study.

2)  How will the data be used?  This study will be used to generate a
plant toxicity endpoint so the Agency can evaluate the toxicity of
formaldehyde releasing hydantoins to non-target plants in terrestrial
and aquatic ecosystems.  

3)  How could the data affect the risk assessment?  Adverse effects to
non-target plants in terrestrial and aquatic ecosystems may result in
mitigation to protect species at risk.  A plant toxicity endpoint will
allow the Agency to determine if endangered or threatened species are at
risk or if aquatic non-target plants are impacted before and after
passing through WWTP into surface waters.  

4)  What is triggering the need for this data?  Increased concern from
state regulators and the public to evaluate impacts on WWTP operations,
endangered species, and persistence in the environment, since initial
registration, have triggered the need for this study.  Green algae are
critical to ecosystem health and productivity.  Data are needed to
conduct ecological and endangered species assessments for down the drain
uses as described above.   

 These studies may not be needed based on the outcome of the
environmental fate studies conducted with hydroxymethyldimethyl
hydantoins.

 These studies may not be needed based on the outcome of other studies
or 100% residue transfer assumptions in the risk assessment.

Docket Number: EPA-HQ-OPP-2006-0244

www.regulations.gov

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