UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C. 20460

     OFFICE OF

                                                                        
                                    PREVENTION, PESTICIDES  AND

               TOXIC SUBSTANCES

12/4/08

MEMORANDUM

SUBJECT:	2-((Hydroxymethyl)amino)ethanol (HHT/HMAE).  Human Health
Effects Scoping Document for the Registration Review Decision.  PC Code:
 099001.  Registration Review Case No.:  3070.  CAS No.:  34375-28-5. 
DP Barcode:  D358960.

FROM:		William J. Hazel, Ph.D., Chemist 

Risk Assessment and Science Support Branch (RASSB)

Antimicrobials Division (7510P)

TO:			Lance Wormell, Chemical Review Manager

Regulatory Management Branch II (RMB II)

Antimicrobials Division (7510P)

THRU:	Norman Cook, Chief

Risk Assessment and Science Support Branch (RASSB)

Antimicrobials Division (7510P)

Introduction

The Antimicrobials Division (AD) has generated this Human Health Effects
Scoping Document for the Registration Review Decision on a
broad-spectrum antimicrobial pesticide currently regulated under the
name of 2-((hydroxymethyl)- amino)ethanol (HMAE).  The active ingredient
in the EPA-registered products addressed herein has been considered to
be HMAE since 1975, the first year of registration.  Recently, however,
there has been evidence that linear HMAE is actually
hexahydro-1,3,5-tris(2-hydroxyethyl)-s-triazine (HHT).  HHT is a
cyclical antimicrobial preservative (PC Code 083301; CAS No. 4719-04-4)
containing a triazine ring.  The mechanism of antimicrobial activity for
both these compounds is due to the release of formaldehyde (HCHO). 
There are four EPA-registered end-use products (EPs) addressed herein
that have recently been claimed to contain HHT instead of HMAE:  three
EPs are registered to Troy Chemical Co. (Troy) and one to International
Specialty Products (ISP).  Evidence for the cyclical nature of the
active ingredient in these products follows.  

A Product Information bulletin was issued October, 2005 by BASF, an HHT
producer and registrant, stating that HMAE is not stable above 0°C and
that it spontaneously converts (cyclizes) to HHT above this temperature.
 Also, BASF states that products purporting to contain HMAE, in fact,
contain HHT.  Although the Agency is not aware of BASF data to support
these claims, ISP submitted nuclear magnetic resonance (NMR)
spectroscopy data supporting the identity of HMAE as actually being HHT.
 This submission was reviewed by the Agency (C. Jiang, 6/7/07, D338324)
and it was concluded that the active ingredient in ISP’s Nuosept 91
Preservative (EPA Reg. No. 1529-31) should be HHT rather than HMAE.  ISP
was asked to submit a revised CSF and label to reflect the proper name
of the active ingredient (HHT).

The four HMAE EPs are used as manufacturing in-process preservatives and
as in-can preservatives of caulks, sealants, grouts, lattices, resin
emulsions, adhesives, spackling, ready-mixed wallboard compounds,
pigment dispersions, joint cements, cutting oils, drilling additives,
and ready-mixed cements.  As described in the Reregistration Eligibility
Decision (RED) for HHT, just completed June, 2008, HHT is an
antimicrobial (PC Code 083301; CAS No. 4719-04-4) used as an in-can
preservative in many of these and several other similar industrial and
construction materials.  Note that the labels for both HMAE and HHT
limit use as a preservative to materials that contain water as a major
ingredient.  The HHT RED did not address the products thought to contain
HMAE.  Also, having been considered a separate active ingredient, the
Registration Review was scheduled for HMAE.  A RED was issued for HMAE
in December, 1993.

This Human Health Effects Scoping Document has examined the hazard and
human exposure databases and any available risk assessments conducted in
support of the registration of the subject four HMAE EPs (now considered
to contain HHT) because these are the products and use patterns the data
were intended to support.  Any data or assessments ISP or Troy (or their
predecessors) has submitted to this end have been considered initially
for their adequacy in determining data needs and whether any prior risk
assessments will remain protective of all American population groups. 
During the comment period, it is recommended that ISP and Troy are
requested to provide a complete list of citations (including MRIDs) they
consider fully satisfy all data requirements to support registration of
their products.  Also during the comment period, ISP and Troy are
requested to point out and provide an explanatory rationale for any and
all disparities between the results of all studies generated using HHT
as test substance (as per the HHT RED) vs. studies intended to satisfy
data requirements to support registration of the subject four products
heretofore considered to contain HMAE.  Upon receipt of this
information, the Agency will determine whether the available data (their
own or those requiring compensation) permit a decision that the subject
four EPs may fall under the June, 2008 HHT RED.  The Agency will also
determine whether current science policies, use patterns, or available
data materially affect the overall risk picture.  From this point
forward in this Human Health Scoping Document, unless necessary for
distinction, HMAE will be referred to as HHT/HMAE.  The Agency has
tentatively accepted the information submitted by BASF and ISP as
supporting the claim that HHT/HMAE is actually HHT.  However, additional
identification data (confirmatory NMR information) have been recommended
in the 12/4/08 Product Chemistry, Environmental Fate, and Ecotoxicity
Scoping Document for 2-((hydroxymethyl)amino)ethanol (S. Gowda; D358961)

≥7 and Troysan 174P only at pH ≥3) whereas the other two EP labels
(Mergal 364 and Nuosept 91 Preservative) do not specify a pH limit.

HHT/HMAE generally is of moderate to low acute toxicity although it is a
severe eye irritant.  It is in Toxicity Category I due to its severe eye
irritation effects.  It is of moderate toxicity (Toxicity Category III)
via the oral, inhalation, and dermal routes of exposure and is
nonirritating (Toxicity Category IV) to the skin.  HHT/HMAE is not a
dermal sensitizing agent; note that this is inconsistent with HHT being
recognized as a dermal sensitizer.

A subchronic dermal rat toxicity study resulted in skin reactions
(inflammation, dermal fibrosis, epithelial hyperplasia, and ulceration)
in males and females at all dose levels, with more severe reactions in
females.  As no systemic adverse effects were observed, the Low Observed
Adverse Effect Level (LOAEL) and the No Observed Adverse Effect Level
(NOAEL) for systemic effects were greater than 1000 mg/kg/day, the
highest dose tested.

In a rat developmental toxicity study, a developmental NOAEL was not
achieved, i.e., no developmental effects were observed at any dose.  The
maternal NOAEL was 250 mg/kg/day based upon reduced body weight gain,
reduced food consumption, and gastrointestinal abnormalities at the
LOAEL of 500 mg/kg/day.

This chemical shows some evidence of mutagenicity as it:  was mutagenic
in an E. coli strain and one out of five S. typhimurium strains; induced
a dose-related increase in mammalian cell gene mutations; but showed no
clear trend in bone marrow micronucleus chromosome aberration tests.

HHT/HMAE has no registered direct food uses although several of the
materials preserved with this antimicrobial may be used in food
preparation, processing, or serving areas potentially resulting in
inadvertent or indirect residues in food.  Such materials may include
caulks, sealants, and adhesives.  However, to determine whether dietary
exposure to the parent compound or HCHO is likely to occur from its use
as a preservative, a tiered set of data are recommended beginning with
detailed information on physical and chemical properties and use
information to elucidate the conditions, rates, and magnitude of HCHO
release from HHT/HMAE under various conditions and in the various
preserved materials that may contact food.  If the parent compound is
likely to remain and/or HCHO to be released into food, a conservative,
screening-level dietary assessment will be conducted by the Agency using
the traditional FDA calculations.  If this dietary risk assessment
results in an apparent risk of Agency concern, studies to determine the
rate and extent of migration from the preserved material to food may be
necessary.

Certain of the materials preserved with HHT/HMAE may result in exposure
of the general public and homeowners to the parent compound and HCHO. 
Such materials include latex paints, adhesives, joint cements, caulks,
sealants, grout, spackling, and ready-mixed wallboard compounds. 
However, to determine whether residential exposure to the parent
compound or HCHO is likely to occur from its use as a preservative, a
tiered set of data are recommended beginning with detailed information
on physical and chemical properties and use information to elucidate the
conditions, rates, and magnitude of HCHO release from HHT/HMAE under
various conditions and in various materials.  If the parent compound is
likely to remain and/or HCHO to be released into the air from preserved
materials, small chamber studies may be needed to better estimate
potential residential exposure.

HHT/HMAE products are added to industrial materials during the
manufacturing process using liquid pour or liquid pump application
methods.  During these processes, exposure to workers is expected. 
Further, HHT/HMAE hydrolyzes to form ethanolamine and HCHO, the latter
of which poses worker exposure concerns. However, since the conditions
under which HHT/HMAE hydrolyzes to HCHO and the rate of release are
unknown, the Agency cannot reliably estimate exposure to either the
parent compound or HCHO.  The major potential for occupational exposure
is likely to be to HCHO via the inhalation route provided that
protective eyewear and chemical-resistant gloves are used, as required
on product labels.  Note that one registered Troy product (Mergal® 364;
EPA Reg. No. 5383-47; 21% HHT/HMAE) requires handler use of a
pesticide-approved respirator but this product also contains 29%
tributyltin oxide.  To determine which preserved materials are likely to
result in occupational exposure to HCHO, a tiered set of data are
recommended beginning with detailed information on physical and chemical
properties and use information to elucidate the conditions (pH,
temperature, etc.), rates, and magnitude of HCHO release from HHT/HMAE
under various conditions and in various materials.  If HCHO is likely to
be released into the air from preserved materials, small chamber studies
are recommended for each such material to better estimate potential
occupational (mixer/loader and factory bystander) exposure.

The following additional toxicity studies are recommended at this time: 
90-day oral toxicity in nonrodents, 90-day inhalation toxicity in rats,
developmental toxicity in nonrodents, and a 2-generation reproductive
toxicity study.  In addition, because of the long-term/chronic exposures
expected from dietary exposure and the preservation of cutting oils: 
chronic toxicity and carcinogenicity studies are recommended.  Since
mixers/loaders and industrial facility bystanders could be exposed to
HCHO during handling and use of HHT/HMAE as a preservative,
data/information are recommended concerning the properties of the
antimicrobial, reactions and partitioning during use, and small chamber
studies to determine the rate and magnitude of HCHO-release from
preserved materials.  Such information/studies would also be of use to
estimate potential inhalation exposure of individuals (both residential
and commercial) to HCHO via release from materials preserved with
HHT/HMAE during manufacture.

The primary source of information for this assessment was the 12/93 RED
for HHT/HMAE.  Several new toxicity studies have been submitted to, and
reviewed by, the Agency since issuance of the 12/93 RED and the
associated data call-in.  The purpose of this scoping document is to
determine whether sufficient data are available to support registration
review, whether new human health assessments are needed to support
registration review, and to report why the Agency feels it may be
appropriate to require additional data and/or conduct new risk
assessments under the registration review process.

Section 1.  Chemical Identity

Table 1.1  Chemical Identity for HHT/HMAE (for HHT)

Common Name	HHT/HMAE  (HHT)

Chemical Name	2-((Hydroxymethyl)amino)ethanol

[Hexahydro-1,3,5-tris(2-hydroxyethyl)-s-triazine) for HHT]

Molecular Formula	C3H9O2N  (C9 H21N3O3 for HHT)

Molecular Weight	91  (219.29 for HHT)

PC Code	099001  (083301 for HHT)

CAS Registry Number	34375-28-5  (4719-04-4 for HHT)

Registration Review Case No.	3070  (3074 for HHT)

Chemical Structure

 

              HHT/HMAE                           HHT





HHT/HMAE has been reported in the 12/93 HHT/HMAE RED as having the
following physical/chemical properties:  a liquid at 20 °C with a sharp
amine odor that boils at 110 °C.  It has a density of 1.1545 g/ml at 25
°C, a vapor pressure of 16.4 mmHg, and a dissociation constant of 8.5
at 25 °C.  HHT/HMAE is completely miscible in water and isopropanol and
dissolves in octanol at 25 °C to the extent of 23.6 g/100 ml.  Note
that there are a number of differences between these properties and
those provided in the 6/08 HHT RED.  It is recommended that these
discrepancies be resolved and that applicable references be cited or new
studies submitted.

 

Section 2.  Toxicology

a. Acute Toxicity

The LC50 found in an acute inhalation test in rats was 0.62 mglL (MRID
41925401).  In an eye irritation study in rabbits, severe irritation and
corneal opacity was induced, some lasting for 21 days (MRID 40327501). 
These two studies were conducted with 100% HHT/HMAE.  In a series of
studies conducted with 50% HHT/HMAE in an innocuous substrate, an acute
oral toxicity test in rats found an LD50 of 1422 mg/kg for females and
1626 mg/kg for males (MRID 41850601).  The dermal LD50 was greater than
2000 mg/kg in rats (MRID 41850602).  A primary dermal irritation study
with rabbits showed no irritation (MRID 41850604); note that this
conflicts with the 12/93 HHT RED in which HHT is recognized as a dermal
sensitizer (as are many HCHO-releasers).

b. Subchronic Toxicity

2-((Hydroxymethyl)amino)ethanoI was used in a 90-day dermal study with
Sprague-Dawley rats. Test compound of 98.5% purity was diluted with
water to give doses of 0, 50, 250, or 1000 mg/kg/day.  There were skin
reactions including inflammation, dermal fibrosis, epithelial
hyperplasia, and ulceration in males and females at all dose levels,
with more severe reactions in females.  There were no other effects
related to test article administration.  The NOAEL and LOAEL for
systemic effects were both greater than 1000 mg/kg/day, which was the
highest dose tested (MRID 41586901).

c. Developmental Toxicity

In a developmental toxicity study, Sprague-Dawley rats were given 0,
100, 250, or 500 mg/kg/day of this chemical by gavage on days 6-16 of
gestation.  The developmental NOAEL was greater than 500 mg/kg/day, the
highest dose tested. The maternal NOAEL was 250 mg/kg/day and the LOAEL
was 500 mg/kg/day, due to reduced body weight gain, reduced food
consumption, and gastrointestinal abnormalities (MRID 41604601).

d. Chronic Toxicity

The chronic toxicity of HHT/HMAE has not been studied.  A chronic rodent
study is recommended because of the expected chronic dietary exposure
and long-term exposure to machinists working with preserved cutting
oils.

e. Carcinogenicity

The potential carcinogenicity of HHT/HMAE has not been elucidated. 
There are some indications of mutagenicity of HHT/HMAE in the
mutagenicity studies described below.  As noted above for chronic
toxicity, since there is the potential for chronic dietary exposure and
long-term occupational exposure to HHT/HMAE residues from use in cutting
oils, carcinogenicity studies in two rodent species are recommended.

 

f. Mutagenicity

An Ames test in Salmonella typhimurium with HHT/HMAE at 57.58% in an
innocuous substrate demonstrated weak mutagenic activity in the TA100
strain.  However, there was no mutagenic activity in four other strains
of S. typhimurium (TA98, TA1535, TA1537, and TA1538), with or without
metabolic activation (MRID 41850101).  In another Ames study, 98% pure
HHT/HMAE was mutagenic in the TA100 strain of S. tvphimurium and one
strain [WP2uvrA-(pKM101)] of Escherichia coli, with or without metabolic
activation (MRID 42001501). This compound was found to be mutagenic when
tested in L5178Y mouse lymphoma cells, with or without metabolic
activation (MRID 42293801).  HHT/HMAE showed no clear trend in bone
marrow micronucleus chromosome aberration tests (MRID 43585401).

g. Toxicology Data Needs

The following additional toxicity studies are recommended to be
conducted on HHT/HMAE at this time to be consistent with the HHT RED
requirements:

90-day oral toxicity in nonrodents

90-day inhalation toxicity in rats

Developmental toxicity in nonrodents

2-generation reproductive toxicity study

Chronic studies in rodents

Carcinogenicity studies (rat and mouse)

The chronic and cancer studies are recommended because of the chronic
dietary exposure and the long-term worker exposure from use of preserved
cutting oils.  

Toxicology of Formaldehyde (HCHO)

The characterization of HCHO toxicity and the selection of endpoints for
risk assessment has been described in the HCHO RED and has not been
addressed here.  The following statement addresses the status, as of
12/3/08, of the HCHO noncancer inhalation toxicity endpoint selection. 

OPP developed the formaldehyde inhalation noncancer toxicological
endpoint used in this RED through the established reregistration
process, which includes stakeholder consultation and public comment. 
However, the result has not been subjected to an interagency review or
external peer review.  Because of time constraints imposed by statutory
deadline, OPP could not consider all available peer-reviewed science
(for example, the intentional human dosing toxicity studies).  Thus,
this value should be considered an interim value, developed solely for
the purposes of this determination and subject to future revision and
subsequent peer review and should not be used in other contexts as EPA's
opinion of the best available science on the non-cancer effects of
formaldehyde. 

Section 3.  Dietary Exposure

a. Food Exposure

Dietary (food) exposure could potentially occur because HHT/HMAE is used
as a process preservative and an in-can preservative for materials
containing water as a major ingredient such as caulks, adhesives,
sealants that may be used in food contact situations such as food
preparation, food processing, and food serving areas.  A dietary
exposure and risk assessment has not been conducted in the past. 
However, migration of HHT/HMAE from these preserved materials to food
may occur to some extent.  Therefore, a dietary (food source) risk
assessment is recommended during the risk assessment stage of
Registration Review.  However, certain chemistry, use pattern, and
chronic/cancer studies are being recommended to permit more appropriate
exposure estimates and the selection of an endpoint for use in a chronic
dietary risk assessment.  Note that FDA does not currently regulate
HHT/HMAE as a direct or indirect food additive.

b. Drinking Water Exposure

The only registered uses (process and in-can preservative uses) of
HHT/HMAE take place in indoor manufacturing plants.  A drinking water
assessment has not been conducted for HHT/HMAE in the past.  However, as
per the HHT RED, HHT biodegrades with a short half-life (1 week) in
activated sludge medium and in water containing mineral salts.  The only
metabolite identified has been HCHO which is not stable in soils or
water.  HHT is not likely to contaminate surface or ground water
(drinking water) as a result of antimicrobial use patterns.  Based on
the present use scenarios on the four “HHT/HMAE” labels and those of
HHT, a drinking water assessment is not warranted at this time. 
However, the potential for contamination of drinking water will be
revisited pending the outcome of the “down-the-drain” studies
proposed to be required in the 11/28/08 Scoping Document for Product
Chemistry, Environmental Fate, and Ecotoxicity (D358961).

Section 4.  Residential Exposure

Although no pesticide products containing HHT/HMAE (or HHT) are labeled
for residential use, certain of the materials preserved with HHT/HMAE
may result in exposure of the general public and homeowners to the
parent compound and HCHO.  Such materials include latex paints,
adhesives, joint cements, caulks, sealants, grout, spackling, and
ready-mixed wallboard compounds.  However, to determine whether
residential exposure to the parent compound or HCHO is likely to occur
from its use as a preservative, a tiered set of data are recommended
beginning with detailed information on physical and chemical properties
and use information to elucidate the conditions, rates, and magnitude of
HCHO release from HHT/HMAE under various conditions and in various
materials.  If the parent compound is likely to remain and/or HCHO to be
released into the air from preserved materials, small chamber studies
may be needed to better estimate potential residential exposure.

Section 5.  Aggregate Risk

Based on the registered uses as a preservative during the manufacture of
various materials that may contact food, dietary exposure may occur from
use of HHT/HMAE.  However, HHT/HMAE residues are not expected to reach
drinking water because all uses are indoor industrial and due to the
rapid hydrolysis of HHT/HMAE and instability of HCHO in the environment
upon formation.  If the proposed information concerning use and biocide
chemistry lead the Agency to determine that nonoccupational/residential
postapplication inhalation exposure of adults and children to HHT/HMAE
and/or HCHO is likely to occur, then these exposures will be estimated. 
Thus, potential contributors to aggregate risk are exposures via food
and residential postapplication of HHT/HMAE and HCHO from preserved
materials.

Section 6.  Occupational Exposure

a. Occupational Handler Exposure (materials preservative use)

As a result of the corrosive properties of HHT/HMAE, the label currently
requires that handlers wear certain personal protective equipment (PPE)
including goggles or face shield, rubber gloves, and protective
clothing.  However, as HHT/HMAE has been classified as Toxicity Category
I for eye irritation and has a vapor pressure >10-3, a closed system
(e.g., vented through an exhaust stack) for loading/mixing is
recommended.

b. Occupational Handler Exposure (Use of preserved materials)

Occupational handler exposure may also refer to that occurring during
and after professional use or application of products made of materials
that had been preserved with HHT/HMAE when manufactured.  It is
recommended that a tiered set of data be required beginning with
detailed information on physical and chemical properties and use
information to elucidate the conditions, rates, and magnitude of HCHO
release from HHT/HMAE under various conditions and in various materials.
 If HCHO is likely to be released into the air from preserved materials,
small chamber studies may be needed to better estimate potential
occupational exposure.

It is also a proposed requirement that relevant Industrial Hygiene air
sampling data in commercial facilities manufacturing, storing, or using
large quantities of bulk or end-products made from preserved materials
be submitted.  It is recommended that assessment of occupational handler
exposure to HCHO from use of preserved materials be conducted during the
assessment stage of Registration Review as refined by the
chemical-specific data noted above.

Section 7.  Cumulative Risk

EPA does not have, at this time, available data to determine whether
HHT/HMAE has a common mechanism of toxicity with other substances or how
to include this pesticide in a cumulative risk assessment.  For the
purposes of this Registration Review, EPA has assumed that HHT/HMAE does
not have a common mechanism of toxicity with other substances.

Section 8.  Endocrine Disruption

EPA is required under the FFDCA, as amended by FQPA, to develop a
screening program to determine whether certain substances (including all
pesticide active and other ingredients) “may have an effect in humans
that is similar to an effect produced by a naturally-occurring estrogen,
or other such endocrine effects as the Administrator may designate.” 
Following the recommendations of its Endocrine Disruptor Screening and
Testing Advisory Committee (EDSTAC), EPA determined that there was
scientific basis for including, as part of the program, the androgen and
thyroid hormone systems, in addition to the estrogen hormone system. 
EPA also adopted EDSTAC’s recommendation that the Program include
evaluations of potential effects in wildlife.  For pesticide chemicals,
EPA will use FIFRA and, to the extent that effects in wildlife may help
determine whether a substance may have an effect in humans, FFDCA
authority to require the wildlife evaluations.  As the science develops
and resources allow, screening of additional hormone systems may be
added to the Endocrine Disruptor Screening Program [EDSP].

The Agency has no direct information regarding potential effects of
HHT/HMAE on the androgen, thyroid, or estrogen endocrine systems in
mammals. There is no information from the available scientific
literature to suggest that it would have adverse effects on these
endocrine systems.  Based on the weight of the evidence of available
data, no effects related to those endocrine systems currently included
in the EDSP have been identified or suggested for HHT/HMAE.  For the
purposes of this Registration Review, EPA has assumed that HHT/HMAE does
not disrupt endocrine systems.

Section 9.  Overall Conclusions

There is the potential for residues of HHT/HMAE to migrate into food due
to the use of this antimicrobial as a preservative of materials that may
have food contact.  At this time, there is no reason to expect that
HHT/HMAE will contaminate drinking water although environmental fate
data concerning passage through wastewater treatment plants will be used
to confirm this assumption in the event of a factory discharge.

Residential postapplication exposure could potentially occur following
the application/use of products made from preserved materials,
particularly in the event any of these materials contain HHT/HMAE and/or
continue to release HCHO.  To determine if residues of HHT/HMAE are
likely to survive the material manufacturing processes and whether HCHO
is released, the Agency proposes to require specific use pattern and
physicochemical behavior information as a first tier.  Since HHT/HMAE is
quite volatile (VP = 16.4 mmHg at 25 °C) and if HCHO continues to be
released, air monitoring studies (e.g., chamber studies) will be needed
to permit estimation of residential inhalation risk.  Aggregate (dietary
and residential) risk assessments will then need to be conducted.

As HHT/HMAE is volatile, corrosive, and a severe eye irritant, all
HHT/HMAE labels currently require that handlers in manufacturing
facilities who open valves and connect/disconnect lines must wear
goggles or face shield, rubber gloves, and protective clothing. 
However, due to concern for possible inhalation exposure of occupational
handlers and bystanders, the EP labels should be amended to state that a
closed system, e.g., vented to an exhaust stack) for loading/mixing must
be used to load/mix HHT/HMAE into materials requiring preservation.

Due to the high vapor pressure of HHT/HMAE and potential continued
release of HCHO, occupational handler inhalation exposure may also occur
as a result of professional use or application of products made from
preserved materials.  Examples of such products/activities could
include:  caulking, painting, applying drywall mud, etc.  To determine
if residues of HHT/HMAE and/or HCHO are likely to survive the materials
preservation processes, the Agency proposes to require specific use
pattern and physicochemical behavior information as first tier data.  If
volatile residues of HHT/HMAE and/or HCHO are concluded to be likely to
continue to be released upon use/application of preserved products, air
monitoring studies (e.g., chamber studies) are proposed to be required
to permit estimation of occupational handler inhalation risk.

Data Needs

The Agency is proposing that the following toxicology studies be
required to be consistent with the 2008 HHT RED:  

Toxicology Data Needs

90-day oral toxicity in nonrodents (GLN 870.3150)

90-day inhalation toxicity in rats (GLN 870.3465)

Developmental toxicity in nonrodents (GLN 870.3700)

2-generation reproductive toxicity study (GLN 870.3800)

Chronic studies in rodents (GLN 870.4100)

Carcinogenicity studies (rat and mouse) (GLN 870.4200)

Note that an acute inhalation study (GLN 870.1300) has been required in
association with the 6/08 HHT RED.  However, it has not been proposed to
be required for HHT/HMAE in this Human Health Scoping Document because
what appears to be an acceptable study has already been conducted (MRID
41925401).

In addition, the nondietary exposure studies listed below (utility and
rationale provided in Appendix A) are proposed to be required to permit
assessment of several residential and occupational handler and
postapplication/bystander scenarios.  These requirements are consistent
with the 2008 HHT RED.

Residential/Occupational Exposure Data Needs 

Outdoor Dermal Exposure (GLN 875.1100)

Indoor Dermal Exposure (GLN 875.1200)

Outdoor Inhalation Exposure (GLN 875.1300)

Indoor Inhalation Exposure (GLN 875.1400)

Applicator Exposure Monitoring Data Reporting for Dermal and Inhalation
Data (GLN 875.1600)

Product Use Information – Outdoor (GLN 875.1700)

Product Use Information – Indoor (GLN 875.2700)

Descriptions of Human Activity (GLN 875.2800)

Data Reporting and Calculations (GLN 875.2900)

Risk Assessments Needed

A dietary (food) exposure assessment will be needed to estimate any risk
associated with residue transfer/migration from food-contact materials
preserved with HHT/HMAE.

If the environmental fate wastewater treatment studies provide evidence
that drinking water exposure to HHT/HMAE is likely, a dietary risk
(water) assessment will be conducted.

Residential postapplication dermal and inhalation risks to adults and
children from exposure to HHT/HMAE and/or HCHO following use/application
of products made from preserved materials will be assessed.

Food and water exposure sources will be aggregated with residential
exposure to estimate aggregate risks.

Occupational handler dermal and inhalation exposure and risk to HHT/HMAE
and/or HCHO resulting from professional use/application of EPs in
manufacturing facilities to preserve materials, use of preserved
metalworking fluids, and use/application of materials preserved with
HHT/HMAE should be assessed.

Exposure and risk to occupational bystanders working in materials
manufacturing facilities using HHT/HMAE as a preservative should be
assessed.

Appendix A

2-((Hydroxymethyl)-amino)ethanol (HHT/HMAE) is a broad-spectrum
antimicrobial.  It has been tentatively demonstrated to actually be HHT
which is a triazine antimicrobial that is also an HCHO-releaser. 
HHT/HMAE products are formulated as liquid or solid soluble concentrates
and are registered for in-can and in-process preservation of caulks,
sealants, grouts, lattices, resin emulsions, adhesives, spackling,
ready-mixed wallboard compounds, pigment dispersions, joint cements,
cutting oils, drilling additives, and ready-mixed cements.

The antimicrobial activity of HHT/HMAE is due to the release of
formaldehyde (HCHO); therefore, this Registration Review also addresses
potential risks associated with HCHO exposure from HHT/HMAE uses only. 
EPA prepared a separate formaldehyde RED to address potential risks
associated with non-HHT/HMAE uses of formaldehyde.  This document is
available in the formaldehyde public docket at   HYPERLINK
"http://www.regulations.gov"  http://www.regulations.gov  in docket
number EPA-HQ-OPP-2008-0121.  

At this time, there are four pesticide products that contain HHTHMAE as
an active ingredient.  Two companies manufacture these products.  Note
that an acute inhalation study (GLN 870.1300) has been required in
association with the 6/08 HHT RED.  However, it has not been proposed to
be required for HHT/HMAE in this Human Health Scoping Document because
what appears to be an acceptable study has already been conducted (MRID
41925401).

Need for, and Uses of, the Data

Guideline Number:  870.3150 

Study Title: 90-Day Oral Toxicity (Nonrodent)

Rationale for Requiring the Data



The use of HHT/HMAE in cutting oils, lattices, drilling additives, etc.
may result in high exposure to humans.  This study is required for an
active ingredient that is labeled in uses that may result in high
exposure to humans.  The use of HHT/HMAE to preserve these materials may
result in high exposure to persons using/applying these preserved
materials.  In addition, this study is needed to assess species
sensitivities to the toxicity of HHT/HMAE.  There are no subchronic oral
toxicity in non-rodent species data submitted to the Agency.  In order
to adequately assess the hazards and risks from several high-exposure
uses of HHT/HMAE, a subchronic oral toxicity study in a nonrodent
species is required.



Practical Utility of the Data

1.  How did the Agency make earlier regulatory decisions without these
data?

Only qualitative residential and occupational risk assessments were
conducted in the 12/93 RED for HHT/HMAE.  Only a dermal subchronic
toxicity study is available and the observed adverse effects were due to
irritation and not to systemic toxicity.  In the HHT RED, the absence of
subchronic oral toxicity in non-rodent data, an extra 10x database
uncertainty factor was applied to assess potential species sensitivities
to HHT.

2.   How will the data be used?  

The Agency will use the data to assess the hazard and risk to HHT/HMAE
in occupational and residential settings and the potential species
sensitivities to HHT.

3.  How could the data impact the Agency’s future decision-making?

In the absence of subchronic oral toxicity in non-rodent data, the
Agency would have to retain the additional 10x database uncertainty
factor to estimate the hazard and risk to HHT/HMAE in occupational and
residential settings.  The data generated would allow the Agency to
refine its risk assessment and to ensure that the MOEs derived using the
Agency’s best professional judgment were not an over- or
underestimation of risk from HHT/HMAE.  



Guideline Number:  870.3465 

Study Title: 90-Day Inhalation Toxicity (Rat)

Rationale for Requiring the Data



This study is required under the updated data requirements at 40 CFR
158.500 because HHT/HMAE is quite volatile and because there is a
likelihood of significant repeated exposure to workers who use/apply
materials preserved with HHT/HMAE.  In addition, there is a concern for
worker exposure to HCHO released from HHT/HMAE.  A 90-day inhalation
toxicity study has not been conducted and is required.  The inhalation
route is the major route of human exposure to HHT/HMAE as well as its
degradate HCHO.

Practical Utility of the Data

1.  How did the Agency make its earlier regulatory decisions without
these data?

Only qualitative residential and occupational risk assessments were
conducted in the 12/93 RED for HHT/HMAE.  Only a dermal subchronic
toxicity study is available and the observed adverse effects were due to
irritation and not to systemic toxicity.  As the major exposure route is
inhalation, there is no subchronic oral toxicity study, and there were
only irritation effects in the subchronic dermal study, there is no
study to demonstrate the types of adverse effects that may be systemic
in nature or to most appropriately use in a quantitative risk
assessment.  The doses needed to induce systemic adverse effects may
need to be quite low to be just at and below the air concentrations of
HHT/HMAE inciting lung irritation.  In the 6/08 HHT RED, the Agency
applied an additional 10X route-to-route extrapolation uncertainty
factor to assess potential inhalation risks to persons handling
materials containing HHT as the active ingredient.

2.   How will the data be used?  

The data will be used to properly characterize and quantify the hazard
and risks to occupational workers as well as residential dwellers
exposed to materials that had been preserved with HHT/HMAE.

3.  How could the data impact the Agency’s future decision-making?

In the absence of inhalation toxicity data, the Agency would now have to
estimate inhalation risks using oral or dermal toxicity studies and rely
on the assumption that absorption and toxicity of HHT/HMAE are the same
via the dermal/oral and inhalation routes of exposure.  The 90-day
inhalation study would allow the Agency to refine its estimates of
inhalation risks and to ensure that the MOEs derived using the
Agency’s best professional judgment were not an over- or
underestimation of risks from HHT/HMAE. 



Guideline Number:  870.3700

Study Title:   Developmental Toxicity (rabbit)

Guideline Number:  870.3800

Study Title: Reproduction and Fertility Effects

Rationale for Requiring the Data



There is not a rabbit developmental toxicity study or a rat reproductive
toxicity study available for HHT/HMAE; therefore, the
developmental/reproductive toxicity database is incomplete.  Since the
response to developmental insult in one species is not necessarily the
same in another species, a second developmental study in another species
is needed as part of a complete developmental toxicity database.  The
FIFRA Science Advisory Panel (SAP) has acknowledged and supported the
need for two developmental toxicity studies. The two-generation rat
reproductive toxicity study can characterize potential hazard to the
human population during the entire human life span. Thus, these studies
provide critical scientific information needed to characterize potential
hazards to pregnant women, their fetuses, infants, and children, and are
some of the first studies that the Agency looks to for selecting doses
and endpoints for use in risk assessments.  Therefore, these data are
required to assess potential hazard and risks associated with the use of
products containing HHT/HMAE as the active ingredient.  



Practical Utility of the Data

1.  How did the Agency make its earlier regulatory decisions without
these data?

Qualitative residential and occupational risk assessments were conducted
in the 12/93 RED for HHT/HMAE.  Only a rat developmental study is
available and the observed adverse effects were limited to maternal and
were due to irritation, not systemic in nature.  The Agency was able to
make earlier decisions for HHT by adding a database uncertainty factor
of 10X, in lieu of having a complete developmental/reproductive toxicity
database to conduct the human health risk assessment.

2.  How will the data be used and how could the data impact the
Agency’s future decision-making?

After review and evaluation of the developmental and reproductive
toxicity studies, EPA will use the data to determine whether the 10X
database uncertainty factor continues to be appropriate, or if the data
show that the 10X uncertainty factor should be reduced or removed.  

3. How could the data impact the Agency’s future decision-making?

Given OPP’s experience in this regard, it is likely that the 10X
database uncertainty factor would be reduced or removed and so OPP would
most likely use the data to assess by how much the uncertainty factor
would be reduced and possibly removed.    If the Agency should select a
different dose and endpoint from one of the studies, then the risk could
increase, as the most likely reason to select a new dose and endpoint
would be greater sensitivity in one of the new studies.





Guideline Number:  870.4100 

Study Title: Chronic Toxicity

Rationale for Requiring the Data

Typically, chronic toxicity studies are required when the labeled uses
for an active ingredient may result in long-term or chronic exposure to
humans.  The use of HHT/HMAE in cutting oils (metalworking fluids) may
result in long-term exposure to persons, mixing, loading or applying
this antimicrobial chemical.  Also, any indirect food uses (migration
from preserved food contact materials to food) could result in chronic
dietary exposure.  There are no chronic toxicity data submitted to the
Agency.  Risks from chronic dietary exposure and the metalworking fluid
use of HHT/HMAE cannot be adequately characterized without these data. 
Therefore, a chronic toxicity in rodent (preferably in the rat) is
required to determine the chronic toxicity of HHT/HMAE.



Practical Utility of the Data

1.  How did the Agency make its earlier regulatory decisions without
these data?

There are only acute and subchronic toxicity data available for
HHT/HMAE.  In the absence of a chronic study, the Agency was not able to
establish a chronic toxicological endpoint for the Agency’s risk
assessment.  

2.  How will the data be used?  

The data will be used to determine the No Observed Adverse Effect Level
(NOAEL) endpoint.  The Agency will use the toxicological endpoint to
assess the potential chronic dietary hazard and evaluate risks in
occupational and residential settings.

3.  How could the data impact the Agency’s future decision-making?

The chronic toxicity data will allow the Agency to refine its risk
assessment and determine if additional mitigation measures are
necessary.  





Guideline Number:  870.4200 

Study Title: Carcinogenicity in two species (rat and mouse)

Rationale for Requiring the Data

Typically, carcinogenicity studies are required when the labeled uses
for an active ingredient may result in high exposure to humans and/or
over exposure over a lifetime.  Any indirect food uses (migration from
preserved food contact materials to food) could result in chronic
dietary exposure.  The use of HHT/HMAE in metalworking fluids may result
in long-term and high exposure to metalworkers using fluids preserved
with this antimicrobial chemical.  There are no carcinogenicity data
submitted to the Agency.  Risks from the cutting oil/metalworking fluid
use of HHT/HMAE cannot be adequately characterized without these data. 
In addition, there are some positive mutagenicity study findings and
HHT/HMAE is a known formaldehyde producer; therefore, carcinogenicity
studies in two species (rat and mouse) are required to determine the
carcinogenicity of HHT/HMAE.

Practical Utility of the Data

1.  How did the Agency make its earlier regulatory decisions without
these data?

There are only acute and subchronic toxicity data available for
HHT/HMAE.  In the absence of a carcinogenicity study, the Agency was not
able to establish a cancer classification for the Agency’s risk
assessment.  

2.  How will the data be used?  

Metalworking fluid use of antimicrobials has always been considered a
high exposure, long-term scenario for which carcinogenicity data have
been required (1987 Antimicrobial Data Call In Notice). Recently, the
Agency has been working with a revised data requirement policy for
metalworking fluid use in ‘enclosed metalworking systems.’  Under
this proposal, certain toxicology data requirements (i.e.
chronic/carcinogenicity, second developmental toxicity, and reproductive
toxicity) would be held in reserve pending submission and Agency review
of worker exposure data reflecting antimicrobial use in these enclosed
systems.  Although the Agency has proposed that closed systems be
required when HHT/HMAE is mixed/loaded for preservation of materials,
there is no indication that HHT/HMAE use is intended to be limited to
enclosed metalworking systems.  If the registrant submits the
description of human activity data (Guideline Number 875.2800)
demonstrating that use of treated metalworking fluid is only done in a
closed system and that venting is to the outside, then the cancer study
is not needed.  If the systems are not closed, then these data will be
used to determine the carcinogenic potential to workers using products
containing HHT/HMAE to treat metalworking fluid.

3.  How could the data impact the Agency’s future decision-making?

The carcinogenicity data will allow the Agency to refine its risk
assessment and determine if additional mitigation measures are
necessary.  The carcinogenicity study will not be required for the
metalworking fluid use if the use is limited to “enclosed metalworking
systems” vented to the outside.  If open systems are used, then the
Agency needs these data to conduct cancer risk assessment.



Guideline Number:  875.1100

Study Title:  Outdoor Dermal Exposure

Guideline Number:  875.1200

Study Title:  Indoor Dermal Exposure

Rationale for Requiring the Data

The dermal exposure route is very important for exposure scenarios such
as metal working fluids, oil field activities, paint rollers and airless
sprayers where aerosols will be generated.  However, very limited worker
exposure monitoring data are available for antimicrobial pesticides,
including material preservatives used in paint and other consumer
products.  EPA used these limited data to perform screening level risk
assessments for the HHT RED.  

The existing data in the Chemical Manufacturers Association (CMA)
database and Pesticide Handlers Exposure Database (PHED) for worker
exposure scenarios are limited in scope and quality.  The CMA data also
has QA/QC problems, including the lack of field fortification,
laboratory recoveries, and/or storage stability information.  In
addition the CMA data have an insufficient amount of replicates.  

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. 

To protect workers from dermal exposures to pesticides, EPA requires
dermal exposure monitoring data.  The RED identified the lack of
chemical-specific dermal exposure data, which this study will provide,
as a data need.  The data are needed to support handler exposures for
the industrial and residential uses.

Practical Utility of the Data

1.  How did the Agency make its earlier regulatory decisions without
these data?

EPA used surrogate data from the PHED and CMA databases to estimate
exposure and risks to handlers using the formulated products containing
HHT.  Without chemical-specific data, the Agency’s risk assessment is
a high-end screening level risk assessment.  For metalworking fluid
handlers, a screening-level long-term dermal exposure estimate was
derived from a model.  The dermal risk is based on a number of
conservative assumptions and may be an overestimation of the risk. 

2.  How will the data be used?

The dermal exposure data will be used to assess the occupational and
residential exposure of handlers mixing/loading the preservative EPs
into materials during the manufacturing process.  These data will also
be used to assess workers using materials preserved in-can, particularly
metalworking fluids, paints, and emulsions such as painting with a paint
brush/roller and an airless sprayer.  

3.  How could the data impact the Agency’s future decision-making?

The dermal exposure data will be used to determine the accuracy of the
dermal risks to occupational workers using the formulated products and
materials preserved with HHT/HMAE.  These data will be used to refine
the risk assessment to more accurately reflect the actual exposure. 

By refining the assessment, the Agency would be able to determine
whether the MOEs derived from the surrogate data, the Agency’s best
professional assumptions, and the screening level tools used as part of
the HHT RED process are applicable to HHT/HMAE.   If future risk
assessments are performed in the absence of these data, the Agency will
have to assume a significant degree of uncertainty in its regulatory
decision-making process and that the current mitigation measures (i.e.,
personal protective equipment) may not provide adequate protection for
workers using HHT in industrial settings.  The lack of these data will
limit the flexibility of the Agency and registrants with respect to
decisions made from high-end screening level assessments that may
overestimate exposures. 





	

Guideline Number:  875.1300

Study Title:  Outdoor Inhalation Exposure

Guideline Number:  875.1400

Study Title:  Indoor Inhalation Exposure

Rationale for Requiring the Data



The inhalation exposure route is very important for exposure scenarios
such as metal working fluids, oil field activities, paint rollers and
airless sprayers where aerosols will be generated.    In addition, HCHO
is likely to be released from these preserved materials during and after
use.  However, very limited worker exposure monitoring data are
available for antimicrobial pesticides, including material preservatives
used in paint and other consumer products.  EPA used these limited data
to perform screening level risk assessments for the HHT/HMAE and HHT
REDs.

The existing data in the Chemical Manufacturers Association (CMA)
database and Pesticide Handlers Exposure Database (PHED) for worker
exposure scenarios are limited in scope and quality.  For the CMA data,
inhalation concentrations were typically below the detection limits, so
the unit exposures for the inhalation exposure could not be accurately
calculated.  The CMA data also has QA/QC problems, including the lack of
either/or field fortification, laboratory recoveries, and storage
stability information.  In addition the CMA data have an insufficient
amount of replicates.

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.

To protect workers from inhalation exposure to pesticides, EPA requires
inhalation exposure monitoring data. The RED identified the lack of
chemical specific exposure data, which this study will provide, as a
data need.  The data are required to support handler exposures for the
industrial and residential uses.



Practical Utility of the Data

1.  How did the Agency make its earlier regulatory decisions without
these data?

Only qualitative residential and occupational risk assessments were
conducted in the 12/93 RED for HHT/HMAE.  In the 6/08 HHT RED, EPA used
surrogate data from the PHED and CMA databases to estimate exposure and
risks to metalworking fluid handlers, painters and other handlers using
the formulated and in-can preservative products.  Without chemical
specific data, the Agency is able to conduct only a high-end
screening-level risk assessment.  

2.  How will the data be used?

The inhalation exposure data will be used to assess the occupational
exposure of workers mixing and loading formulated products containing
HHT/HMAE into materials as a preservative.   It will also be used to
evaluate residential and occupational exposures that may result from
use, application, or storage of preserved materials that may release
HCHO.

3.  How could the data impact the Agency’s future decision-making?

The inhalation exposure data will be used to determine the accuracy of
the inhalation risks to occupational workers using the formulated
products and in-can-preserved materials in residential and industrial
settings.  By refining the assessment, the Agency would be able to
determine whether the MOEs derived from the surrogate data, the
Agency’s best professional assumptions, and the screening level tools
used as part of the HHT reregistration process are applicable to
HHT/HMAE.   If future risk assessments are performed without these data,
the Agency will have to assume a significant degree of uncertainty in
its regulatory decision-making process and that the current mitigation
measures (i.e., personal protective equipment) may not provide adequate
protection for workers using HHT/HMAE in industrial and residential
settings.  The lack of these data will limit the flexibility of the
Agency and registrants with respect to decisions made from high-end
screening level assessments that may overestimate exposures. If risks
warrant mitigation, the inhalation exposure data will provide the types
of mitigation necessary, such as closed systems for commercial uses
and/or potential removal of uses from the label.



Guideline Number:  875.1600 

Study Title:  Applicator Exposure Monitoring Data Reporting for Dermal
and Inhalation Data

Rationale for Requiring the Data



This data requirement is linked to the dermal and inhalation exposure
data also being required. The submission of these exposure monitoring
data serves as quality assurance and control (QA/QC) for the dermal and
inhalation data.  These data are intended to ensure that the product
manufacturer and registrant conducting the study adhere to a defined set
of quality criteria and meet the study requirements of the Agency. 
These data allow the Agency to determine if the quality of data provided
will serve the risk assessment needs of the Agency and support the
registrant’s goal for product re-registration. Submission of exposure
monitoring data reporting increases the Agency’s confidence in the
data submitted.   



Practical Utility of the Data



1.  How did the Agency make its earlier regulatory decisions without
these data?  

There were no chemical-specific data available to assess worker dermal
and inhalation exposures to HHT/HMAE or HHT.   Therefore, there was no
reporting data.  

2.  How will the data be used? 

These studies will be used to validate the data provided from the indoor
and outdoor dermal and inhalation applicator exposure studies.  These
data are important because it allows EPA to assess the quality of the
exposure study and thus the accuracy of the exposure calculations
derived from that study.   Information that must be submitted includes a
description of the purpose of the study and what requirement(s) it is
intended to satisfy, a summary of the study, a comprehensive section on
materials, methods, and calculations, a section interpreting the
scientific results of the study, a discussion of quality assurance,
identification of the location of the raw data, and any references,
communications, and protocols relevant to the conduct of the study.   

3.  How could the data impact the Agency’s future decision-making?

If the exposure monitoring data reporting is not submitted in
conjunction with the indoor and outdoor dermal and inhalation applicator
exposure studies, the Agency may not be able to utilize the studies to
the fullest extent to conduct its human health exposure and risk
assessments.  The lack of such data could cause the Agency to use
inadequate surrogate data, resulting in a high-end screening level risk
assessment and a potential overestimation of exposures.





Guideline Number:  875.1700 and 875.2700

Study Title:  Product Use Information (Outdoor and Indoor)

Rationale for Requiring the Data



Product use information is a narrative description of how the product is
actually applied; it is not a field study.  A description of how
products containing HHT/HMAE are used will provide a comprehensive,
realistic assessment of its potential applications and resulting handler
and postharvest exposure .  Product use information is a description of
which, when, and how materials are preserved; it is not a field study. 
Descriptions are needed of:  (i) what specific types of materials are
treated; (ii) what stage in the manufacturing process each material is
treated; (iii) the conditions to which the HHT/HMAE will be exposed
(temperatures, pH’s, etc.); (iv) the rate of release of HCHO; etc. 
Any detail that can permit a decision as to the likelihood and rate of
HCHO formation from HHT/HMAE in each preserved material will permit the
selection of worst-case scenarios for which the chemical-specific
exposure studies would be necessary.  These will provide a
comprehensive, realistic assessment of potential residential and
occupational exposures. Therefore, these data are required.

Product use information permits EPA to more accurately assess pesticide
exposure to applicators by describing how the pesticide is actually used
and applied.  EPA requires this information because differences in use
can translate to significant differences in exposure, and thus in risk. 

The guideline for postapplication product use information was presented
to the FIFRA Science Advisory Panel (SAP) in March 1998. (The draft
guideline is available at   HYPERLINK
"http://www.epa.gov/scipoly/sap/meetings/1998/march/contents.htm" 
http://www.epa.gov/scipoly/sap/meetings/1998/march/contents.htm .).  The
guideline for applicator product use information should be substantially
similar to the one for post-application.

Practical Utility of the Data

1.  How did the Agency make its earlier regulatory decisions without
these data?

The Agency used its best professional judgment based on its years of
experience and general use information from the registered product
labels, and product chemistry data.  

2.  How will the data be used?  

The description of the materials preserved, application techniques, and
physicochemical disposition will be used to determine the exposure
scenarios for which exposure studies will be required for use in risk
assessment.

3.  How could the data impact the Agency’s future decision-making?

These data will enable the Agency to understand how the EPs are applied
and ensure that the risk assessment is inclusive of the types of
exposures occurring during pesticide use and from any potential
postapplication contact.  This information will permit a determination
of which use patterns are expected to result in exposures less than the
Agency’s level of concern, which ones must be supported by additional
data, and which ones are likely to have risks of concern and, therefore,
must be mitigated.



Guideline Number:  875.2800

Study Title:  Descriptions of Human Activity

Guideline Number:  875.2900

Study Title:  Data Reporting and Calculations

Rationale for Requiring the Data



Very limited worker activity data are available for antimicrobial
pesticides, including material preservatives used in paint and other
consumer products.  Worker application parameters are generally defined
by the physical nature of the formulation (e.g., formula and packaging),
by the equipment required to deliver the chemical to the use site, and
by the application rate required to achieve an efficacious dose. The
risk assessment noted that many of the use parameters used (e.g., amount
handled and duration of use) were based on professional judgments. These
data are needed to fill this data gap and provide information needed to
refine the risk assessment.



Practical Utility of the Data

How did the Agency make its earlier regulatory decisions without these
data?

The Agency used its best professional judgment and general use
information from the registered product labels, and product chemistry
data.  

2.  How will the data be used?  

These data will clearly identify the specific equipment used to deliver
HHT to the use site, which, in high exposure scenarios such as
metalworking fluid use and paint applications, will allow the Agency to
refine its risk assessment. 

3.  How could the data impact the Agency’s future decision-making?

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