US Environmental Protection Agency
Office of Pesticide Programs
Reregistration Eligibility Decision (RED)
for Grotan (HHT)
June 27, 2008
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v>EPA
United States Office of Prevention, Pesticides EPA 739-R-08-003
Environmental Protection And Toxic Substances June 2008
Agency (751 OP)
Re registration Eligibility
Decision for HHT
ListC
Case No. 3074
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Reregistration Eligibility Decision (RED) Document
for
HHT
Approved by:
FranR Sanders
Director
Antimicrobials Division
Date:
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TABLE OF CONTENTS
ABSTRACT 7
I. Introduction 8
II. Chemical Overview 8
A. Case Overview 8
B. Use and Usage 10
III. Summary of HHT Risk Assessments 10
A. Human Health Risk Assessment 11
1. Background on Assessing Human Health Risks to Formaldehyde 11
2. Toxicity Profile 15
3. Dietary Exposure and Risk from Food and Drinking Water 19
4. Residential Exposure and Risk 20
5. Aggregate Exposure and Risk 22
6. Occupational Exposure and Risk 23
7. Incident Reports 25
B. Environmental Fate and Ecological Hazard Assessment 26
1. Environmental Fate 26
2. Ecological Hazard 27
3. Risk to Listed Species 28
IV. Reregistration and Risk Management Decisions 29
A. Determination of Reregistration Eligibility 29
1. Reregistration Eligibility Decision 29
2. Regulatory Rationale 31
B. Risk Management Decision 32
1. Risk Mitigation Measures 32
2. Product Label Amendments 33
V. What Registrants Need to Do 33
A. Manufacturing Use Products 33
1. Generic Data Requirements 33
B. End-Use Products 35
1. Product Specific Data Requirements 35
2. Labeling for End-Use Products 36
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HHT Reregistration Team
Office of Pesticide Programs:
Environmental Fate and Effects Risk Assessment
William Erickson
James Breithaupt
Health Effects Risk Assessment
William J. Hazel
Cassi Walls
Jenny Tao
Jonathan Chen
A. Najm Shamim
Tim Dole
Timothy Leighton
Nader Elkassabany
Risk Management
Lance Wormell
Diane Isbell
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Glossary of Terms and Abbreviations
AGDCI
ai
aPAD
AR
BCF
CFR
cPAD
CSF
CSFII
DCI
DEEM
DFR
EC
EDWC
EEC
EPA
EXAMS
EUP
FCID
FDA
FIFRA
FFDCA
FQPA
FOB
G
GENEEC
GLN
HAFT
IR
LD
50
LOC
LOD
LOAEL
mg/kg/day
mg/L
Agricultural Data Call-In
Active Ingredient
Acute Population Adjusted Dose
Anticipated Residue
Bioconcentration Factor
Code of Federal Regulations
Chronic Population Adjusted Dose
Confidential Statement of Formula
USDA Continuing Surveys for Food Intake by Individuals
Data Call-In
Dietary Exposure Evaluation Model
Dislodgeable Foliar Residue
Emulsifiable Concentrate Formulation
Estimated Drinking Water Concentration
Estimated Environmental Concentration
Environmental Protection Agency
Exposure Analysis Modeling System
End-Use Product
Food Commodity Intake Database
Food and Drug Administration
Federal Insecticide, Fungicide, and Rodenticide Act
Federal Food, Drug, and Cosmetic Act
Food Quality Protection Act
Functional Observation Battery
Granular Formulation
Tier I Surface Water Computer Model
Guideline Number
Highest Average Field Trial
Index Reservoir
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/1, mg/kg or ppm.
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.
Level of Concern
Limit of Detection
Lowest Observed Adverse Effect Level
Micrograms Per Gram
Micrograms Per Liter
Milligram Per Kilogram Per Day
Milligrams Per Liter
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MOE
MRID
MUP
NA
NAWQA
NPDES
NR
NOAEL
OP
OPP
OPPTS
PAD
PCA
PDF
PHED
PHI
ppb
PPE
ppm
PRZM/EXAMS
Qi*
RAC
RED
REI
RfD
RQ
SCI-GROW
SAP
SF
SLC
SLN
TGAI
TRR
USDA
USGS
UF
UV
WPS
Margin of Exposure
Master Record Identification (number). EPA's system of recording
and tracking studies submitted.
Manufacturing-Use Product
Not Applicable
USGS National Water Quality Assessment
National Pollutant Discharge Elimination System
Not Required
No Observed Adverse Effect Level
Organophosphate
EPA Office of Pesticide Programs
EPA Office of Prevention, Pesticides and Toxic Substances
Population Adjusted Dose
Percent Crop Area
USDA Pesticide Data Program
Pesticide Handler's Exposure Data
Preharvest Interval
Parts Per Billion
Personal Protective Equipment
Parts Per Million
Tier II Surface Water Computer Model
The Carcinogenic Potential of a Compound, Quantified by EPA's
Cancer Risk Model
Raw Agriculture Commodity
Reregi strati on Eligibility Decision
Restricted Entry Interval
Reference Dose
Risk Quotient
Tier I Ground Water Computer Model
Science Advisory Panel
Safety Factor
Single Layer Clothing
Special Local Need (Registrations Under Section 24(c) of FIFRA)
Technical Grade Active Ingredient
Total Radioactive Residue
United States Department of Agriculture
United States Geological Survey
Uncertainty Factor
Ultraviolet
Worker Protection Standard
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ABSTRACT
The Environmental Protection Agency (EPA or the Agency) has completed the
human health and environmental risk assessments for hexahydro-l,3,5-tris(2-hydroxyethyl)-
s-triazine (HHT) and is issuing its reregi strati on eligibility and risk management decisions.
The risk assessments, which are summarized in this document, are based on review of
registrant-submitted data supporting the use patterns of currently registered products,
citations from the open literature, and additional information received through the public
docket. The risk assessments have been revised, as needed, according to information
received since they were first made available to the public in April 2008. After considering
the risk assessments, available information about alternatives to HHT for specific uses,
public comments, and risk mitigation options, the Agency developed its reregi strati on
eligibility and risk management decisions for uses of HHT. As a result of this review, EPA
has determined that some uses of HHT are eligible for reregistration, provided that the
prescribed risk mitigation measures are adopted and labels are amended accordingly, and
required data are submitted. Other uses are not eligible for reregistration, based on a
combination of critical data gaps and unacceptable risks. The reregistration eligibility
decision and the associated risk mitigation measures are discussed fully in this document.
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I. Introduction
This document is the Environmental Protection Agency's (EPA or "the Agency")
reregi strati on eligibility determination (RED) for all currently registered uses of hexahydro-
l,3,5-tris(2-hydroxyethyl)-s-triazine (HHT). This document also summarizes the human
health and environmental risks used to make the reregi strati on eligibility decision.
The Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA) was amended in
1988 to accelerate the reregi strati on of products with active ingredients registered prior to
November 1, 1984, and amended again by the Food Quality Protection Act of 1996 (FQPA)
and the Pesticide Registration Improvement Act of 2003 (PRIA) to set time frames for the
issuance of Reregi strati on Eligibility Decisions. FIFRA calls for the development and
submission of data to support the reregi strati on of an active ingredient, as well as a review of
all data submitted to the U.S. Environmental Protection Agency (EPA or "the Agency").
Reregi strati on involves a thorough review of the scientific database underlying a pesticide's
registration. The purpose of the Agency's review is to reassess the potential hazards arising
from the currently registered uses of a pesticide, to determine the need for additional data on
health and environmental effects, and to determine whether or not the pesticide meets the "no
unreasonable adverse effects" criteria of FIFRA.
The Agency made its reregi strati on eligibility determination for HHT based on the
required data, the current guidelines for conducting acceptable studies to generate such data,
and published scientific literature. The Agency has found that currently registered uses of
HHT, with the exception of paints, stains, coatings, and industrial and household cleaning
products, are eligible for reregi strati on provided the requirements for reregi strati on identified
in this reregi strati on eligibility decision (RED) are implemented.
This document consists of six sections: Section I contains the regulatory framework
for reregi strati on reassessment; Section II provides an overview of the chemical, including a
profile of its use and usage; Section III gives an overview of the human health and ecological
risk assessments; Section IV presents the Agency's reregi strati on eligibility and risk
management decisions; Section V summarizes label changes necessary to implement the risk
mitigation measures outlined in Section IV; and Section VI includes the appendices, related
supporting documents, and Data Call-In (DCI) information. The revised risk assessment
documents and related addenda are not included in this document, but are available in the
Public Docket at http://www.regulations.gov in docket number EPA-HQ-OPP-2008-0193.
II. Chemical Overview
A. Case Overview
Case 3074, HHT, includes products containing Hexahydro-l,3,5-tris(2-hydroxyethyl)-s-
triazine, an antimicrobial chemical that displays some fungicidal activity. HHT products are
formulated as liquid concentrates and are registered for in-can preservation of adhesives and
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to preserve a variety of metal working cutting fluids, indoor construction compounds (e.g.,
caulk), lubricants, slurries, paints, stains, coatings, solutions, and emulsions.
The actual antimicrobial agent in HHT is formaldehyde (HCHO); therefore, this RED
also addresses potential risks associated with formaldehyde exposure from HHT uses only.
EPA is preparing a separate formaldehyde RED to address potential risks associated with
non-HHT uses of formaldehyde. This document will be available in the formaldehyde public
docket at http://www.regulations.gov in docket number EPA-HQ-OPP-2008-0121.
The chemicals assessed in Case 3074 are presented in Table 1.
Table 1. Chemicals Assessed in the HHT RED1
Case
Number
3074
0556
CAS
Number
4719-04-4
50-00-0
PC
Code
083301
043001
Empirical
Formula
C9H21N3O3
CH2O (Gas or
anhydrous form)
H2C(OH)2 or
dH402
(Formaldehyde
monohydrate)
Chemical Name
Hexahydro- 1,3,5 -
tris(2-
hydroxyethyl)-s-
triazine
Formaldehyde (gas)
Formaldehyde
monohydrate
(aqueous solution)
Names Used in
RED
Documents
HHT
Formaldehyde,
HCHO, HCOH
Common Names
Grotan, Triadine,
Proxel, Onyxide,
Myacide, Nipacide, and
Surcide-P
Formaldehyde,
Formalin
1 This RED addresses potential risks associated with formaldehyde exposure from HHT uses only. EPA is
preparing a separate formaldehyde RED to address potential risks associated with non-HHT uses of
formaldehyde.
No direct food use is associated with HHT; therefore, no tolerance or tolerance
exemption has been established.
Prior to the reregi strati on program, EPA began reviewing chemicals under the
registration standard program. Chemicals for which Registration Standard documents were
written were referred to as "List A" chemicals in reregi strati on. HHT is a "List C"
reregi strati on chemical; therefore, no Registration Standard was completed. Data Call-Ins
(DCI) requiring chemical identity, toxicology, field trial, ecological, and other data were
issued for HHT in December 1992 (GDCI-083301-17025) and September 1993 (GDCI-
083301-17370). Data from submitted studies along with published scientific literature were
used to characterize the risks associated with the uses described in this document. Additional
data required as a result of reregi strati on are presented in Section V of this document.
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B. Use and Usage
Since the early 1980s, HHT products have been used to control microbial agents and
fungi. A detailed table of the uses of HHT eligible for reregi strati on can be found in
Appendix A.
Type of Pesticide:
Use Sites:
Target Pests:
Formulations:
Fungicide, Bacteriostat
Metal working cutting fluids; in-can preservation of adhesives;
chain lubricants; aqueous mineral slurries; paints; stains;
coatings; surfactant/detergent solutions and emulsions; chemical
and clinical reagents; inks and dyes; fuel and oil in storage;
indoor construction compounds such as caulks, spackling, grout,
adhesives, foams; and in industrial processes such as oil field
drilling muds, workover fluids, and completion fluids.
Microbial agents, bacteria
HHT products are formulated as liquid concentrates.
Application Methods: Products containing HHT can be applied in residential settings
by brush/roller and airless sprayer (paints); mop, wipe, trigger
pump/aerosol (cleaners); and in laundry detergents.
Commercial/occupational applications include liquid pour/pump,
brush/roller and airless sprayer (paints); and mop, wipe, trigger
pump/aerosol (cleaners).
III. Summary of HHT Risk Assessments
The purpose of this section is to summarize EPA's human health and ecological risk
conclusions for HHT to help the reader better understand EPA's risk management decisions.
The human health and ecological risk assessment documents and supporting information
listed in Appendix C were used to formulate the safety finding and regulatory decision for
HHT. The full risk assessments and related supporting documents are available at
http://www.regulations.gov in docket number EPA-HQ-OPP-2008-0193.
EPA developed this RED for HHT through a modified, 4-Phase public participation
process. The Agency uses public participation processes to involve the public in developing
pesticide reregi strati on decisions. EPA released its preliminary risk assessments for 60-day
public comment in March 2008. Substantive comments were incorporated into the final risk
assessments which were used to make this reregi strati on eligibility decision.
HHT is a formaldehyde releaser, meaning that the actual antimicrobial agent in HHT
is formaldehyde. As mentioned previously, this RED also addresses potential risks
associated with formaldehyde exposure from HHT uses only. EPA is preparing a separate
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formaldehyde RED to address potential risks associated with non-HHT uses of
formaldehyde.
The Agency's use of human studies in the HHT risk assessment is in accordance with
the Agency's Final Rule promulgated on January 26, 2006, related to Protections for Subjects
in Human Research, which is codified in 40 CFR Part 26.
A. Human Health Risk Assessment
EPA has conducted a human health risk assessment for HHT to support the
reregi strati on eligibility decision. EPA evaluated the submitted toxicology, product and
residue chemistry, and occupational/residential exposure studies as well as available open
literature and determined that the data are adequate to support a reregi strati on eligibility
decision. However, additional data for HHT are needed (see Section V). A summary of the
human health risk assessment findings and conclusions is provided below.
1. Background on Assessing Human Health Risks to Formaldehyde
a. Formaldehyde Non-Cancer Assessment
On June 12, 2008, members of the Antimicrobials Division's Toxicity endpoint
Selection Committee (ADTC) met to discuss the non-cancer inhalation toxicity endpoint for
formaldehyde that had been previously selected by the committee for use in conducting
inhalation toxicity risk assessments for the formaldehyde reregi strati on eligibility decision
(RED) document.
The original endpoint of 100 ppb was selected from the published report of Horvath
et al. [JAMA 259, no. 5: 701-707, 1988], who reported nasal and respiratory effects in 109
workers occupationally exposed to formaldehyde. The value of 100 ppb was selected as a
NOAEL for use in occupational risk assessments, while for the general population, a value of
10 ppb was selected. This value was derived by application of a 10-fold uncertainty factor to
the NOAEL value of 100 ppb to account for intraspecies variation in response in accordance
with Agency policy.
During the public comment phase of the formaldehyde risk assessment, the
Formaldehyde Council responded to the selection of the 100 ppb endpoint. They stated that
the Agency should consider the results of a 2007 publication by Noisel et al. [Regulatory
Toxicology and Pharmacology 48: 118-127), which reviewed some of the available scientific
literature. This study, in the Council's opinion, "is based on human exposure rather than
controlled human chamber studies and can be used for deriving a No-Observed-Adverse-
Effect-Level (NOAEL) for the non-cancer endpoint for formaldehyde."
The ADTC noted both observational human exposure data as well as data compiled
from exposure of human subjects under controlled conditions in the Noisel et al. publication.
Notwithstanding the need for intentional exposure data to be presented to the Agency's
Human Studies Review Board, the ADTC noted that irritant effects of formaldehyde have
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been reported in other studies below the 0.75 ppm concentration recommended by Noisel et
al. as a safe level. Further, this recommendation is for worker populations only.
The irritant effects of formaldehyde, including both eye and nasal irritation as well as
respiratory symptoms (irritation, changes in pulmonary function), can be considered from a
toxicological perspective to be composed of both physiological and adverse responses. Based
on the available data, the ADTC was not compelled to select a value higher than that already
proposed. With respect to the 10-fold uncertainty factor used for risk assessment to the
general population, the ADTC concluded that a reduction in this factor is not warranted at
this time. Contrary to the Formaldehyde Council's statement that "the nature of the health
effect does not suggest that there are particularly susceptible subpopulations which would
warrant application of the lOx intraspecies UF," the 1999 ATSDR Toxicological Review of
formaldehyde (ATSDR, 1999) noted two studies "...providing suggestive evidence that
children may be more sensitive to the irritant effects of formaldehyde." These studies were
not intentional exposure studies. It is also noted in the ATSDR review that "additional
research is necessary to confirm or discard the hypothesis that children may be more
susceptible than adults to the irritant effects of formaldehyde..."
The ADTC concluded that, based on the available data, it is appropriate to remain
with the NOAEL value selected from the 1988 Horvath et al. publication and with the 10-
fold uncertainty factor for risk assessments to the general population. The ADTC is also
aware, however, of ongoing efforts by ORD/NCEA to develop an inhalation reference
concentration, or RfC for formaldehyde. OPP will continue to coordinate its efforts with
ORD and other program offices to refine the non-cancer inhalation assessment as necessary.
b. Formaldehyde Cancer Assessment
The Agency is currently reevaluating the carcinogenic potential of formaldehyde. The
historical and ongoing development of an inhalation unit risk value to assess the carcinogenic
potential of formaldehyde is briefly summarized below. Contributors to this summary
included scientists from several EPA program offices (Office of Pesticide Programs [OPP],
Office of Pollution, Prevention, and Toxics [OPPT], Office of Research and
Development/National Center for Environmental Assessment [ORD/NCEA], Office of
Research and Development/National Health Effects Exposure Research Laboratory
[ORD/NHEERL], and Office of Air and Radiation [OAR] ).
• In 1991 IRIS published a weight-of-evidence characterization for carcinogenicity of
formaldehyde, classifying formaldehyde as a Bl probable human carcinogen with a
potency factor of 1.3 E-5 per (ug/m3) ) on the basis of squamous cell nasal tumors
observed in a two-year study in rats (Kerns et al., 1983).
• In 1999 the Chemical Industry Institute of Toxicology (CUT) developed a health risk
assessment for formaldehyde based upon the animal toxicology data (CUT, 1999).
This document presented the dose-response modeling of these data in two distinct
parts: 1) based upon a biologically-based dose response (BBDR) model, and 2)
benchmark dose models that were based upon point of departures at various response
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levels of the tumor and precursor data. Both these approaches made extensive use of
the available time-to-tumor and mechanistic information. The 1999 assessment was
subsequently published in various articles in peer-reviewed journals (2001, 2002,
2003, 2004).
• In 1999, the U.S. EPA's Office of Air and Radiation and Office of Research and
Development, in conjunction with Health Canada, conducted an external peer review
workshop for the CUT BDDR model as well as an external written peer review and
public comment period for their assessments. While the review was largely positive
on the overall approach in the assessment, reviewers also pointed to the potential for
significant uncertainty due to model mis-specification and uncertainties in key
parameters involved in the BBDR model.
• Based on the peer review of the CUT model, OAR determined in 2004 that the CUT
model was the most appropriate tool for risk assessment for formaldehyde. OAR has
subsequently used the formaldehyde cancer potency derived using the CUT model for
a number of risk assessments involving formaldehyde emissions to the atmosphere
such as the Plywood and Composite Wood Products National Emission Standard for
Hazardous Air Pollutants (final rule 2004, reconsidered final rule 2006, remanded to
EPA by court 2007); Control of Hazardous Air Pollutants from Mobile Sources (Final
Rule 2007); and Proposed Rule for National Emission Standard for Combustion
Turbines (2004). Health Canada, Australia, the World Health Organization, and the
German Maximale Arbeitsplatzkonzentrationen (MAK) Commission have also used
the CUT model. Model strengths include consideration of the mode of action data for
formaldehyde and a conservative approach to account for potential direct DNA
interaction and mutation induction. Model uncertainties include variability for some
of the parameters of the model (e.g., cell proliferation) which can affect predictions of
risk (Subramanian et. al., 2007; 2008 [in press]).
• In 2004, NCEA convened a panel of experts, including scientists from CUT, to
provide advice on these and other critical biological and statistical uncertainties. The
strength of the CUT model is its consideration of mode of action and extensive
mechanistic information.
• Although current OAR assessments still use the CUT model, these assessments now
acknowledge previously unknown uncertainties with the CUT model when
characterizing the risk results.
• In 2004, the International Agency for Research on Cancer (IARC) characterized
formaldehyde as a human carcinogen based on their review of the current literature
(IARC, 2004), including data in humans on nasopharyngeal cancer, cancer of the
nasal cavity and paranasal sinuses, and leukemia. It should be noted that some
epidemiology studies did not find a reported association between formaldehyde
exposure and carcinogenicity. For example, Coggon et. al., 2003 studied over 14,000
workers exposed to formaldehyde in industrial workplaces and reported no excesses
of either leukemia or nasal and nasopharyngeal cancer.
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• In 2005, the Scientific Review Panel (SRP) of the California Office of Environmental
Health Hazard Assessment responded to the CA Air Resources Board request to
reevaluate the carcinogenic potential of formaldehyde. The Panel noted in this 2005
review that California's Office of Environmental Health (OEHH A) 's November 2002
evaluation of a petition had included the 1999 report on the CUT model and other
information, and that OEHHA had concluded that "the evidence... (1) did not change
the determination that formaldehyde is a carcinogen; (2) presented information that
considered the possibility of non-linear dose response relationships, but presented no
clear grounds to review the original "no threshold" determination; and (3) did not
provide any new epidemiology or bioassays supporting a change in potency. In
addition, there was insufficient information to fully evaluate the CUT model, issues
such as model uncertainty were not adequately addressed...." The Scientific Review
Panel's overall conclusion in 2005 was, "The Panel concluded that there was not
sufficient new data to support the petition to review the [OEHHA 's earlier 1992]
formaldehyde risk assessment. In addition, the newly published studies represented
relevant new information, but they did not allow determination of a causal
relationship between formaldehyde exposure and leukemia. These studies deserve
further evaluation over time given their potential importance. " (Froines, 2005).
• EPA is currently completing a new IRIS assessment and unit risk value for
formaldehyde; the reassessment is scheduled to start internal peer review in May
2008 and begin independent external peer review in January 2009
(http://cfpub.epa.gov/ncea/iri strac/index.cfm?fuseaction=viewChemical.showChemic
al&sw_id=1031). EPA anticipates that the peer review of the formaldehyde
assessment will be a longer process then that of EPA's reregi strati on process
scheduled to conclude in September 2008.
Based of the on going development of the science to predict carcinogenic potential of
formaldehyde, OPP has decided to present the formaldehyde cancer risks for the pesticidal
uses using both the existing 1991 IRIS cancer unit risk of 1.3 E-5 per (|ig/m3) and the CUT
BBDR model until any new cancer estimates are fully peer reviewed. OPP also
acknowledges the wide range in cancer risks using these approaches and will coordinate with
other offices in EPA on the outcome of the upcoming peer review process on the
carcinogenicity of formaldehyde. Because formaldehyde air concentrations approach those
associated with ocular and respiratory tract irritation, the risk mitigation measures to be
implemented in the meantime for the pesticidal uses will be based on mitigating the non-
cancer effects at a limit of 0.01 ppm. It is believed that this level will reduce exposures
sufficiently such that the cancer risks would not be of concern. The EPA process of
regulating pesticides allows for reevaluation at any time if new information from the peer
review process of the carcinogenic potential of formaldehyde warrants.
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2. Toxicity Profile
The toxicological databases for HHT and formaldehyde are adequate to support a
reregi strati on eligibility decision. As discussed above, HHT and formaldehyde are
considered lexicologically unique and were evaluated separately.
a. Acute Toxicity Profile
HHT has moderate to low acute toxicity via the oral, dermal, and inhalation routes
(Category III and IV). It is an eye irritant (Category I), a moderate dermal irritant (Category
III), and not a skin sensitizer. Table 2 presents the acute toxicity profile for HHT. The acute
toxicity profile for formaldehyde is presented in the June 2008 Formaldehyde RED available
at http://www.regulations.gov in docket number EPA-HQ-OPP-2008-0121.
Table 2. Acute Toxicity Profile for HHT
Guideline
Number
870.1100
(§81-1)
870.1100
(§81-1)
870.1200
(§81-2)
870.1300
(§81-3)
870.2400
(§81-4)
870.2500
(§81-5)
870.2500
(§81-5)
870.2600
(§81-6)
Study Type/Test substance
(% a.i.)
Acute Oral - Rat
Purity 79.4%
Acute Oral - Mouse
(Supplemental)
Purity 78.5%
Acute Dermal - Rabbit
Purity 79.96%
Acute Inhalation - Rat
Primary Eye Irritation -
Rabbit
Purity 79.96%
Primary Dermal Irritation -
Rabbit
Purity 79.96%
Primary Dermal Irritation -
Guinea pigs
Purity 79.96%
Dermal Sensitization -
Guinea pigs
MRID
Number
41675206
00155959
00155984
N/A
00155985
00155986
00155987
00155987
Results
LD50=1250mg/kg
(males)
LD50 =763 mg/kg
(females)
LD50= 1.30mL/kg
LD50 > 2000 mg/kg
N/A
Corrosive
Mild irritant
Mild irritant
Not a Sensitizer
Toxicity
Category
III
III
III
N/A
I
IV
IV
N/A
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Guideline
Number
Study Type/Test substance
(% a.i.)
Purity 79.96%
MRID
Number
Results
Toxicity
Category
b. Toxic Effects and Carcinogenicity
The target organ following oral and inhalation exposure to HHT is believed to be the
gastrointestinal tract. The target organs following inhalation exposure to formaldehyde is
believed to be the eye, nose, and throat.
HHT is not classified as a carcinogen (no data available); therefore, quantification of
cancer risk is not required for HHT and a cancer analysis was not performed. Formaldehyde
is classified as a Bl substance (probable human carcinogen - based on limited evidence of
carcinogenicity in humans); therefore, quantification of cancer risk is needed and a cancer
analysis was performed for formaldehyde.
c. Toxicological Endpoints
i. HHT Toxicological Endpoints
The toxicological endpoints used in the human health risk assessment for HHT are
presented in Table 3. The uncertainty and safety factors used to account for interspecies
extrapolation, intraspecies variability, and for completeness of the database are also
presented.
Table 3. Summary of HHT Toxicological Endpoints
Exposure Scenario
Dose Used
in Risk Assessment, UF
Special FQPA SF and Level of
Concern (LOC)
for Risk Assessment
Study and
Toxicological Effects
Dietary Risk Assessment
Acute Dietary
(All populations)
Oral NOAEL =
500 mg/kg/day
UF= 1,000 (lOx-Inter;
lOx - Intra; and lOx -
database UF)
N/A
Rat Developmental Toxicity
(MRID 41161801), based on
ulcerations and scarring of the
stomach mucosa
Chronic Dietary
(All populations)
Oral NOAEL =
50 mg/kg/day
UF = 100 (lOx-Intra;
lOx - Inter)
N/A
Rat 90-day Oral Study (MRID
41483001), based on lymphocytic
infiltration in females and erosion of
gastric mucosa and prominence of
the limiting ridge of the stomach in
males
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Exposure Scenario
Dose Used
in Risk Assessment, UF
Special FQPA SF and Level of
Concern (LOC)
for Risk Assessment
Study and
lexicological Effects
Non-Dietary Risk Assessments
Short-Term
Incidental Oral
(1-30 days)
Oral NOAEL =
500 mg/kg/day
UF= 1,000 (lOx-Inter;
lOx - Intra; and lOx -
database UF)
N/A
Rat Developmental Toxicity (MRID
41161801), based on ulcerations and
scarring of the stomach mucosa
Intermediate-Term
Incidental Oral
(30 days- 6 months)
Oral NOAEL =
50 mg/kg/day
UF = 100 (lOx-Intra;
lOx - Inter)
N/A
Rat 90-day Oral Study (MRID
41483001), based on lymphocytic
infiltration in females and erosion of
gastric mucosa and prominence of
the limiting ridge of the stomach in
males
Dermal Absorption
Factor
Not required as a dermal toxicity study has been used for the dermal endpoint.
Dermal Short-Term
(1-30 days)
No risk assessment necessary. No adverse systemic effects observed in a 21-day dermal toxicity
study up to 1,000 mg/kg/day.
Dermal
Intermediate- and
long-term (30 days-
6 months and >6
months)
Oral NOAEL =
250 mg/kg/day
UF= 1,000 (lOx-Intra;
lOx - Inter; and lOx -
database UF)
N/A
Rat 90-day dermal Study (MRID
41483002), based on systemic
NOAEL was found to be greater than
250 mg/kg/day (the HOT)
Inhalation (all
durations)
Oral NOAEL =
50 mg/kg/day
UF = 100 (lOx-Inter;
lOx - Intra); extra lOx -
database UF to require
inhalation toxicity study)
N/A
Rat 90-day Oral Study (MRID
41483001), based on lymphocytic
infiltration in females and erosion of
gastric mucosa and prominence of
the limiting ridge of the stomach in
males
Cancer (oral,
dermal, inhalation)
No cancer data are available.
ii. Formaldehyde Toxicological Endpoints
Although HHT is known to release formaldehyde, the exact rate of release and
transformation cannot be meaningfully estimated based on currently available data. For
example, because actual air monitoring data for laundry detergents and cleaners were not
available, EPA made the conservative assumption that 100% formaldehyde formation
Page 17 of 38
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occurred from HHT. Confirmatory data are needed to refine estimates based on the actual
amount of formaldehyde formation to better estimate exposure and risk.
The toxicological endpoints used in the human health risk assessment for
formaldehyde are presented in Table 4. The uncertainty and safety factors used to account
for interspecies extrapolation, intraspecies variability, and for completeness of the database
are also presented. Formaldehyde is classified as a Bl substance (probable human
carcinogen - based on limited evidence of carcinogenicity in humans); therefore,
quantification of cancer risk is required and a cancer analysis was performed. EPA estimates
lifetime cancer risk using the estimated exposure and the carcinogenic potential of the
compound (Qi* or "cancer slope factor"). The risk is expressed as a probability of
developing cancer (e.g., one-in-a-million or 1 x 10"6).
Table 4. Summary of Formaldehyde Toxicological Endpoints
Exposure
Scenario
Dose Used in Risk
Assessment
(mg/kg/day)
Target MOE, UF,
Special FQPA SF* for
Risk Assessment
Study and Toxicological
Effects
Dietary Risk Assessments
Acute Dietary
(general population including
infants and children)
An acute dietary assessment is not needed for the registered antimicrobial uses of
formaldehyde; however, an indirect food use assessment was conducted.
Chronic Dietary
(all populations)
A chronic dietary assessment is not needed for the registered antimicrobial uses of
formaldehyde; however, an indirect food use assessment was conducted.
Non-Dietary Risk Assessments
Incidental Oral
An incidental oral risk assessment is not required for the registered antimicrobial uses of
formaldehyde.
Dermal (all durations)
A dermal risk assessment is not required for the registered antimicrobial uses of
formaldehyde.
Inhalation
(all durations)
NOAEL (human) = 0.1
ppm
UF = 1 (occupational)
UF = 10 (residential)
ACGIH 2001 publication on
formaldehyde
Horvath, E.P. etal. (1986):
JAMA 259(5): 701-707.
Based on complaints of eye,
nose, and throat irritation in
particle board workers at
concentrations of
formaldehyde from 0.4 - 1.0
ppm.
Redden, J. (2005): Section 18
Emergency Exemption for the
use of Paraformaldehyde: U.S.
Army Medical Research
Institute of Infectious Diseases.
Page 18 of 38
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Exposure
Scenario
Dose Used in Risk
Assessment
(mg/kg/day)
Target MOE, UF,
Special FQPA SF* for
Risk Assessment
Study and lexicological
Effects
Cancer
Lifetime extra cancer unit risk estimate of 1.3 x 10~5 per (ig/m3 (US EPA IRIS
http://www.epa.gov/ncea/iris/subst/0419.htm)
And
CUT modeling: Tables 8A (for residential) andB (for professional). Hockey stick-shaped
CRCP (nonsmoking) (Conolly, 2004)
3. Dietary Exposure and Risk from Food and Drinking Water
No direct food use is associated with HHT. However, because HHT products may be
used in ways that could result in indirect food contact (e.g., use of cleaners on countertops or
cutting boards), EPA estimated acute and chronic non-cancer dietary risk from exposure to
HHT. The Agency did not identify a dietary endpoint for formaldehyde and therefore did not
estimate dietary risk from exposure to formaldehyde.
HHT is largely used indoors as a materials preservative; therefore, effluents
containing this chemical are not expected to contact fresh water environments. In addition
HHT biodegrades with a short half-life in activated sludge (one week) and water that
contains salts. Formaldehyde is the only metabolite identified for HHT. Formaldehyde has
been determined not to be stable in soils or water. Therefore, based on the use patterns, and
the short half-life, the potential for HHT to impact drinking water sources is negligible and,
therefore, a quantitative drinking water assessment was not conducted. For additional
information please see the Drinking Water Risk Assessment for HHT (Grotan), dated
January 30, 2008.
Non-cancer dietary risk is expressed as a percentage of a level of concern. The level
of concern is the dose at or below which no unreasonable adverse health effects to any
human population subgroup are expected to occur. This dietary level of concern is termed
the population adjusted dose (PAD), which reflects the reference dose (RfD), either acute or
chronic, adjusted for (divided by) the FQPA safety factor. Estimated risks that are less than
100% of the PAD are below EPA's level of concern. The acute PAD (aPAD) is the highest
predicted dose to which a person could be exposed on a single day with no expected adverse
health effect. The chronic PAD (cPAD) is the highest predicted dose to which a person
could be exposed over the course of a lifetime with no expected adverse health effect.
Using conservative assumptions, EPA estimated dietary exposure to HHT to be <1%
of the aPAD and cPAD for adhesives and approximately 80% of the aPAD and cPAD for
countertop and cutting boards. Therefore, because the aPAD and cPAD are well below
100%, dietary exposure does not exceed the Agency's level of concern. For additional
information please see the Dietary Risk Assessment for HHT (Grotan), dated February 12,
2008.
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4. Residential Exposure and Risk
Because HHT is currently registered for use in residential settings, residential users
(handlers) have the potential to be exposed to HHT and formaldehyde by using products
containing HHT. Therefore, EPA estimated risk to residential handlers as a result of
exposure to HHT and formaldehyde from products containing HHT.
Residential non-cancer risk estimates are typically expressed as a margin of exposure
(MOE) which is a ratio of the dose from a toxicological study selected for risk assessment,
typically a NOAEL, to the predicted exposure (MOE = dose + exposure). Estimated MOEs
are then compared to the "target MOE" which represents the dose selected for risk
assessment and uncertainty factors (UF) applied to that dose (target MOE = dose *
uncertainty factors). The standard UF is lOOx, which includes lOx for interspecies
extrapolation (to account for differences between laboratory animals and humans) and lOx
for intraspecies variation (to account for differences within the same species). Additional
uncertainty or safety factors may also be applied.
Residential cancer risk estimates are typically expressed as a probability of
developing cancer (e.g., one-in-a-million or 1 x 10"6) which is calculated based on exposure
estimates and the carcinogenic potential of the compound (Qi* or "cancer slope factor").
There is the potential for individuals in residential settings to be exposed to HHT and
formaldehyde during and following application of products containing HHT. Table 5
presents the representative scenarios used to estimate residential risk from products
containing HHT.
Table 5. Representative HHT and Formaldehyde Residential Exposure Scenarios
Chemical
HHT
Representative Use
Using treated paints
Using treated household cleaners
Using treated laundry detergents
Exposure Scenario
Handler:
ST inhalation (aerosol)
Handler:
ST inhalation (aerosol)
Post-app child:
ST and IT incidental
ingestion and IT dermal
Post-app child:
ST and IT incidental
ingestion and IT dermal
Application Method
• brush/ roller
• airless sprayer
• mop
• wipe
• trigger pump/ aerosol
NA
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Chemical
Representative Use
Exposure Scenario
Application Method
Formaldehyde
Using treated paints
Handler:
ST inhalation (vapor) and
cancer
NA
Using treated household cleaners
Handler:
ST inhalation (vapor) and
cancer
NA
Using treated laundry detergents
Handler:
ST inhalation (vapor) and
cancer
NA
The duration of exposure for most homeowner applications of cleaning and paint
products is believed to be best represented by the short-term duration (1 to 30 days). Only
short-term (ST) exposure durations were estimated for the painter based on the assumption
that a homeowner or do-it-yourself painter would typically paint on an intermittent basis (i.e.,
a few times per year). Furthermore, household cleaning exposure scenarios are assumed to
be episodic, not daily. In addition, homeowners are also assumed to use different cleaning
products with varying active ingredients, not exclusively HHT treated products. For
additional information, please see the Occupational and Residential Exposure and Risk
Assessment, dated June 30, 2008.
a. HHT Residential Risk
Even using conservative assumptions, estimated risk from exposure to HHT in
residential settings does not exceed the Agency's level of concern during application (lowest
MOE = 12,000; target MOE = 100) or post-application (lowest MOE = 3,500; target MOE =
1,000). For additional information, please see the Occupational and Residential Exposure
and Risk Assessment, dated June 30, 2008.
b. Formaldehyde Residential Risk
Because FIHT is a formaldehyde releaser (i.e., formaldehyde is released from
products containing FIHT), EPA estimated residential risk from formaldehyde.
Formaldehyde has a high vapor pressure (1mm Hg); therefore, vapor inhalation is the
primary route of residential exposure.
Several scenarios exceeded the Agency's cancer and non-cancer levels of concern
both during application and after application (post-application). Table 6 and Table 7 present
the cancer and non-cancer risks of concern identified for residential handlers exposed to
formaldehyde as a result of HHT use during application. Specific information related to
Page 21 of 38
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formaldehyde toxicity and calculation of risk estimates is presented in the Occupational and
Residential Exposure and Risk Assessment, dated June 30, 2008. See Section IV of this
document for EPA's HHT risk management strategy.
Table 6. HHT Residential Handler Cancer Risks of Concern: Inhalation of Formaldehyde
Representative
Use
Paint
Household
cleaners
Laundry
detergent
Percent
Conversion
30%
100%
100%
100%
Cancer Risk Estimate
IRIS
6.8 xlO'6
2.2 xlO'5
2.5 x 10'5
1.5 xlO'5
CUT Modeling
<2.94 x 10'9
<2.94 x 10'9
<2.94 x 10'9
<2.94 x 10'9
Cancer Risk Target
l.OxlO'6
Table 7. HHT Residential Handler Non-Cancer Risks of Concern: Inhalation of
Formaldehyde
Representative Use
Paint
Household cleaners
Laundry detergent
Non-Cancer Risk
Estimate (MOE)
0.22
0.41
0.22
Non-Cancer Target
MOE
10
10
10
The post-application residential scenarios assessed (dermal/incidental oral exposure
for children contacting treated floors, exposure to laundered clothing) did not exceed the
Agency's level of concern. The Agency did not estimate risks associated with post-
application residential exposure to formaldehyde from paint because exposure during
application exceeded EPA's level of concern by such a large degree; therefore, although
post-application exposure to paint likely exceeds EPA's level of concern, the risks are likely
lower than the residential handler scenario the Agency used to make its risk management
decisions. See Section IV of this document for EPA's HHT risk management strategy.
5. Aggregate Exposure and Risk
The Food Quality Protection Act amendments to the Federal Food, Drug, and
Cosmetic Act (FFDCA, Section 408(b)(2)(A)(ii)) require "that there is reasonable certainty
that no harm will result from aggregate exposure to pesticide chemical residue, including all
anticipated dietary exposures and other exposures for which there are reliable information."
Aggregate exposure is the total exposure to a single chemical (or its residues) that may occur
from dietary (i.e., food and drinking water), residential, and other non-occupational sources.
Table 8 summarizes the scenarios included in the short- and intermediate-term
aggregate assessments. The Agency notes that based on the use patterns and probability of
co-occurrence, an aggregate assessment was not necessary to conduct for
FORMALDEHYDE residues resulting from the use of HHT treated products.
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Table 8. Representative HHT Aggregate Exposure Scenarios
Adults
Children
Short-term Aggregate
Inhalation:
• Mopping applicator
• Wiping applicator
• Trigger pump applicator
Oral:
• Post-app exposure to floor
cleaner residues
• Post-app exposure to laundry
detergent residues
Intermediate-Term Aggregate
Dermal or Oral or Inhalation:
• No applicable exposures
Oral:
• Post-app exposure to floor cleaner
residues
• Post-app exposure to laundry
detergent residues
Dermal:
• Post-app exposure to floor cleaner
residues
• Post-app exposure to laundry
detergent residues
Aggregate exposure did not exceed EPA's level of concern for adult residential
handlers of HHT products (lowest MOE = 23,000; target = 100) or children exposed to
residues of HHT products (lowest MOE = 2,100; target = 1,000).
6. Occupational Exposure and Risk
Because HHT is currently registered for use in occupational settings, occupational
handlers have the potential to be exposed to HHT and formaldehyde through mixing,
loading, applying a pesticide or re-entering treated sites. Therefore, EPA estimated risk to
occupational handlers as a result of exposure to HHT and formaldehyde from products
containing HHT. Occupational non-cancer risks are presented as margins of exposure
(MOE) and occupational cancer risks are presented as a probability of developing cancer
(e.g., one-in-a-million or 1 x 10"6).
There is the potential for individuals in occupational settings to be exposed to HHT and
formaldehyde during and following application of products containing HHT. Table 9
presents the representative occupational uses assessed for HHT.
Table 9. Representative HHT and Formaldehyde Occupational Exposure Scenarios
Chemical
HHT
Representative Use
Paints1
Exposure Scenario
Handler:
ST inhalation (aerosol);
IT dermal and
inhalation (aerosol)
Painter:
ST inhalation (aerosol)
Application Method
Preservation of paint
• Liquid pour
• Liquid pump
Professional painter
• Brush/Roller
• Airless sprayer
Page 23 of 3 8
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Chemical
Formaldehyde
Representative Use
Commercial/
household cleaners
Metal working
fluids
Oil field
Using treated paints
Using treated metal
working fluids
Exposure Scenario
Handler:
ST inhalation (aerosol);
IT dermal and
inhalation (aerosol)
Handler:
ST inhalation (aerosol);
IT dermal and
inhalation (aerosol)
Machinist:
IT/LT dermal and
ST/IT/LT inhalation
(aerosol)
Handler:
ST inhalation (aerosol);
IT dermal and
inhalation (aerosol)
Handler and Bystander1 :
ST inhalation (vapor)
and cancer
Handler:
ST inhalation (vapor)
and cancer
Application Method
• mop
• wipe
• trigger pump/ aerosol
Preservation of fluid
• Liquid pour
• Liquid pump
Professional machinist
• Liquid pour
• Liquid pump
NA
NA
1 The bystander scenario in a paint manufacturing facility also represents all occupational bystander scenarios in
a general industrial facility.
To assess handler risk, the Agency used surrogate unit exposure data primarily from the
proprietary Chemical Manufacturers Association (CMA) Antimicrobial Exposure Study
(USEPA 1999) and the Pesticide Handlers Exposure Database (PHED) (USEPA 1998). For
the occupational scenarios in which CMA data were insufficient, other data and methods
were applied. For additional information, please see the Occupational and Residential
Exposure and Risk Assessment, dated June 30, 2008.
a. HHT Occupational Risk
Even using conservative assumptions, most estimated risks from exposure to HHT in
occupational settings did not exceed the Agency's level of concern during application or
post-application. However, Table 10 presents the application occupational risks for HHT
that exceeded EPA's level of concern.
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Table 10. HHT Occupational Handler Non-Cancer Risks of Concern: Dermal Exposure to
HHT
Representative Use
Paint
Professional cleaners
Oil field secondary
recovery
Non-Cancer Risk
Estimate (MOE)
Non-Cancer Target
MOE
N/A1
400
690
1000
1000
1 Although assessed, intermediate-term dermal handler exposure to paint in occupational settings did not exceed
EPA's level of concern
See Section IV of this document for EPA's HHT risk management strategy.
b. Formaldehyde Occupational Risk
Even using conservative assumptions, most estimated risks from exposure to
formaldehyde in occupational settings did not exceed the Agency's level of concern during
application or post-application. However, Table 11 and Table 12 present the cancer and non-
cancer occupational handler risks for formaldehyde that exceeded EPA's level of concern.
Table 11. HHT Occupational Handler Cancer Risks of Concern: Inhalation of Formaldehyde
Representative
Use
Metal working
fluid
Paint
Percent
Conversion
N/A1
30%
100%
Cancer Risk Estimate
IRIS
2.2xlO-4to
3.7 xlO'4
8.7 xlO'4
2.9 xlO'3
CUT Modeling
1.46X10'8 to
1.86xlO-8
3.13xlQ-8
l.llxlO'7
Cancer Risk Target
1.0xlO-4to l.OxlO'6
1 Not applicable; risk estimates for this scenario were based on exposure information from a study in metal
working facilities that use HHT-preserved fluids
Table 12. HHT Occupational Handler Non-Cancer Risks of Concern: Inhalation of
Formaldehyde
Representative Use
Paint
Metal working fluid
Non-Cancer Risk
Estimate (MOE)
0.22
0.21
Non-Cancer Target
MOE
1
1
See Section IV of this document for EPA's HHT risk management strategy.
7. Incident Reports
Only limited incident reports are associated with exposure to end-use products
containing HHT. Dermal irritation and dermal sensitization are the primary concerns
associated with HHT exposure; conjunctivitis and bronchial asthma have also been reported.
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B. Environmental Fate and Ecological Hazard Assessment
EPA has conducted an environmental fate assessment and an ecological hazard
assessment for HHT to support the reregi strati on eligibility decision. Based on the currently
registered use patterns, release and exposure levels are expected to be minimal when
products are applied according to label directions and use precautions. EPA evaluated the
submitted environmental fate and ecological studies as well as available open literature and
determined that the data are adequate to support a reregi strati on eligibility decision. A
summary of the ecological hazard and environmental fate findings and conclusions is
provided below; the full risk assessments are available at http://www.regulations.gov in
docket number EPA-HQ-OPP-2008-0193.
1. Environmental Fate
a. Hydrolysis
HHT is a symmetric triazine compound with three ethanol side chains attached to the
meta nitrogens (see Figure 1). Triazine ethanol was hydrolyzed with an estimated half-life of
3.1 days at pH 5. The hydrolysis half-lives of HHT were 50 and 302 days for pH 7 and 9,
respectively.
Figure 1. Chemical Structure of HHT
The only radiolabeled triazine hydrolytic degradate observed in the study was
identified as formaldehyde. At pH 5, formaldehyde formation reached 50 % by 2 days, 85 %
by 7 days, and 97-100 % by 14-30 days. At pH 7, formaldehyde reached 19 % by 1 day, 25
% by 14 days, and 31 % by 30 days. At pH 9, formaldehyde reached 17-21 % by 1-30 days.
HHT hydrolyzed more quickly at pH 8 than pHs 9.5 and 10.9. At 22 °C, the half-
lives were 3.4 hours, 16 minutes, and 32 seconds at pH 10.9, 9.5, and 8.0, respectively. At
60 °C, the half-lives were 3.1 minutes and 6.3 seconds for pH 10.9 and 9.5, respectively. The
degradation product was not identified, although it was likely to be formaldehyde from
breakdown of the triazine ring.
b. Biodegradability
Based on Voets et al. (1975), HHT at 70 mg/L was tested in activated sewage sludge
at 1/10th of its intended use concentration. Flasks were incubated at 28 °C for 24 hours on a
Page 26 of 3 8
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rotary shaker. Under both aerobic and anaerobic conditions, 100 % of HHT was degraded
by direct metabolism. Formaldehyde was identified as the metabolism product of HHT.
2. Ecological Hazard
The potential for HHT to be released into the environment at exposure levels of
concern to terrestrial and aquatic organisms is low for the registered indoor use patterns.
Therefore, EECs have not been modeled and risk has not been assessed for any current HHT
uses. The hazard assessment will be used to meet current labeling needs and to determine
hazard endpoints for ecological organisms potentially exposed in the event of a spill or other
potential environmental releases.
The toxicity endpoints used in the ecological hazard assessment were obtained from
guideline toxicity studies conducted for wildlife, aquatic organisms, and plants (40 CFR
§158.2060).
One available acute oral study on the bobwhite quail indicates that HHT is only
slightly toxic to birds (LDso of 1520 mg/kg). Although not required for the current uses of
HHT, the three available dietary studies on the northern bobwhite quail and the mallard duck
categorize HHT as being practically nontoxic when ingested (LCso of >5000 ppm). An avian
precautionary statement is not required on product labels.
Refer to the human toxicology chapter for details on the available acute mammalian
toxicity studies submitted for human health assessment. Based on acute studies in mice and
rats, HHT is slightly to moderately toxic via oral dosing (LDso from 750-1300 mg/kg) and
dermally in rabbit (>2000 mg/kg).
Honeybee toxicity data are not needed based on the current uses of HHT.
One acute toxicity study is required to establish the toxicity of HHT to freshwater
fish. The preferred test species is either the rainbow trout (Oncorhynchus mykiss), a
coldwater fish, or the bluegill (Lepomis macrochirus), a sunfish. For HHT, acute studies are
available for both the rainbow trout and the bluegill and for the channel catfish (Ictalurus
punctatus). The acute toxicity values from these studies categorize HHT as being slightly
toxic to freshwater fish (96-hr LCso of 36-77 mg/L). A precautionary label statement is not
required.
One study is required to establish the acute toxicity (ECso) of HHT to freshwater
invertebrates. The preferred test species is Daphnia magnet, a water flea. Based solely on
mortality (LCso), two studies categorize HHT as being moderately toxic to freshwater
invertebrates (48-hr LCso of 5.4-26 mg/L). However, an ECso (based on immobility of
exposed daphnids) was not determined in either study. The guideline requirement (OPPTS
850.1010) is satisfied for current uses. However, a study establishing an ECso (based on
mortality and immobility) would be needed to support any new uses in which HHT is
expected to reach the aquatic environment at exposure levels of concern for aquatic
organisms.
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Acute toxicity testing with estuarine and marine organisms is required when an end-
use product is intended for direct application to the marine/estuarine environment or the
active ingredient is toxic to aquatic organisms and is expected to reach this environment via
other transport pathways. Studies are required for HHT to support drilling uses in the
estuarine/marine environment. The preferred test species are the sheepshead minnow
(Cyprinodon variegatus), mysid shrimp (Mysidopsis bahia), and Eastern oyster (Crassostrea
virginica). The available data are presented in Table 13. Test results indicate that HHT is
practically nontoxic to moderately toxic to estuarine/marine organisms.
Table 13. Acute Toxicity of HHT to Estuarine/Marine Invertebrates
Test
Species
Sheepshead
minnow
Eastern oyster
Mysid shrimp
%ai
tested
83.8
83.8
83.8
96-h LC50 or
EC50
(mg ai/L)
>118
2.3
(shell deposition)
12
Toxicity
Category
practically
nontoxic
moderately
toxic
slightly toxic
Study Status
supplemental
core
supplemental
MRID No.
43143102
43175402
43143103
3. Risk to Listed Species
Section 7 of the Endangered Species Act, 16 U.S.C. Section 1536(a)(2), requires all
federal agencies to consult with the National Marine Fisheries Service (NMFS) for marine
and anadromous listed species, or the United States Fish and Wildlife Services (FWS) for
listed wildlife and freshwater organisms, if they are proposing an "action" that may affect
listed species or their designated habitat. Each federal agency is required under the Act to
insure that any action they authorize, fund, or carry out is not likely to jeopardize the
continued existence of a listed species or result in the destruction or adverse modification of
designated critical habitat. To jeopardize the continued existence of a listed species means
"to engage in an action that reasonably would be expected, directly or indirectly, to reduce
appreciably the likelihood of both the survival and recovery of a listed species in the wild by
reducing the reproduction, numbers, or distribution of the species" (50 CFR §402.02).
To facilitate compliance with the requirements of the Endangered Species Act
subsection (a)(2) the Environmental Protection Agency, Office of Pesticide Programs has
established procedures to evaluate whether a proposed registration action may directly or
indirectly reduce appreciably the likelihood of both the survival and recovery of a listed
species in the wild by reducing the reproduction, numbers, or distribution of any listed
species (U.S. EPA 2004). After the Agency's screening-level risk assessment is performed,
if any of the Agency's Listed Species LOG Criteria are exceeded for either direct or indirect
effects, a determination is made to identify if any listed or candidate species may co-occur in
the area of the proposed pesticide use. If determined that listed or candidate species may be
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present in the proposed use areas, further biological assessment is undertaken. The extent to
which listed species may be at risk then determines the need for the development of a more
comprehensive consultation package as required by the Endangered Species Act.
For certain use categories, the Agency assumes there will be minimal environmental
exposure, and only a minimal toxicity data set is required (Overview of the Ecological Risk
Assessment Process in the Office of Pesticide Programs U.S. Environmental Protection
Agency - Endangered and Threatened Species Effects Determinations, 1/23/04, Appendix A,
Section IIB, pg.81). Chemicals in these categories therefore do not undergo a full screening-
level risk assessment, and are considered to fall under a no effect determination. The
material preservative uses for HHT fall into this category.
IV. Reregistration and Risk Management Decisions
A. Determination of Reregistration Eligibility
1. Reregistration Eligibility Decision
Section 4(g)(2)(A) of FIFRA calls for EPA to determine, after submission of relevant
data concerning an active ingredient, whether or not products containing the active ingredient
are eligible for reregi strati on. EPA has previously identified and required the submission of
the generic (i.e., active ingredient-specific) data required to support reregi strati on of products
containing HHT as an active ingredient. The Agency has reviewed these generic data, and
has determined that the data are sufficient to support a reregi strati on eligibility decision for
all products containing HHT.
The Agency has completed its assessment of the residential, occupational and
ecological risks associated with the use of pesticide products containing the active ingredient
HHT. The Agency has determined that all HHT containing products are eligible for
reregi strati on provided that: 1) all risk mitigation measures are implemented; 2) current data
gaps and confirmatory data needs are addressed; and 3) label amendments are made as
described in Section V. Appendix A summarizes the uses of HHT that are eligible for
reregi strati on. Appendix B identifies the generic data requirements that the Agency reviewed
as part of its determination of reregi strati on eligibility of HHT and lists the submitted studies
that the Agency found acceptable. Data gaps are identified as generic data requirements that
have not been satisfied with acceptable data.
EPA considered the available information and has determined that the uses of HHT
summarized in Table 14 will not pose unreasonable risks to humans or the environment if the
requirements for reregi strati on outlined in this document are implemented; see Appendix A
for a detailed list. Unless labeled and used as specified in this document, HHT would present
risks inconsistent with FIFRA. Accordingly, should a registrant fail to implement any of the
requirements for reregi strati on identified in this document, the Agency may take regulatory
action to address the potential risk concerns from the use of HHT.
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Table 14. Summary of HHT Uses Eligible for Reregi strati on
Use Site1
Metal working fluids
Adhesives
Aqueous mineral slurries
Construction compounds (caulks, joint cements, spackling, grout,
tapes, mortar
Aqueous analytical and diagnostic reagents
Synthetic fiber lubricants (spin finishes)
Fuel systems (diesel oil, fuel oil, gasoline or kerosene systems)
Oil field applications (drilling muds, workover/completion fluids, oil
recovery injection systems)
Mitigation Required
Yes2
No
No
No
No
No
No
Yes2
1 Detailed information is presented in Appendix A
2 This use is eligible for reregistration provided the mitigation measures and accompanying label changes
identified in Table 15 and Table 17 are implemented.
a. Endocrine Disrupter Effects
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 endocrine effects as the Administrator may designate."
Following recommendations of its Endocrine Disrupter Screening and Testing Advisory
Committee (EDSTAC), EPA determined that there was a 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 EPA include
evaluations of potential effects in wildlife. For pesticides, EPA will use its authorities under
FIFRA and/or the FFDCA to require any necessary data on endocrine-related effects. As the
science develops and resources allow, screening for additional hormone systems may be
added to the Endocrine Disrupter Screening Program (EDSP).
b. Cumulative Risks
Risks summarized in this document are those that result only from the use of FIHT.
The Food Quality Protection Act (FQPA) requires that, when considering whether to establish,
modify, or revoke a tolerance, the Agency consider "available information" concerning the
cumulative effects of a particular pesticide's residues and "other substances that have a
common mechanism of toxicity." Unlike other pesticides for which EPA has followed a
cumulative risk approach based on a common mechanism of toxicity, EPA has not made a
common mechanism of toxicity finding as to FIHT. EPA has not assumed that the FIHT share
a common mechanism of toxicity with other compounds.
c. Public Comments and Response
Through EPA's public participation process, EPA worked with stakeholders and the
public to reach the regulatory decisions for HHT. During the public comment period on the
risk assessments, which closed on June 23, 2008, the Agency received one comment from the
Troy Corporation including the submission of an additional inhalation exposure study for
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paint. The results of this study, along with other information provided, are reflected in the
final risk assessments and this document. All comments and EPA's official responses are
available at http://www.regulations.gov in docket number EPA-HQ-OPP-2008-0193.
2. Regulatory Rationale
The Agency has determined that HHT is eligible for reregi strati on provided that the
registrants implement the mitigation measures in this RED through amended labeling. With
amended labeling, EPA believes that HHT will not present risks inconsistent with FIFRA and
that the benefits of HHT to society - including antimicrobial use in metal working fluids and
industrial materials - outweigh the remaining risks. A summary of EPA's rationale for
reregistering and managing risks associated with HHT is presented below.
a. Performing Residential Activities
There is the potential for homeowners to be exposed to HHT and formaldehyde either
during or after the application of HHT products. To estimate the potential risks associated
with these exposures, the Agency assessed representative application and/or post-application
exposure scenarios including treated paints, cleaning products, and laundry detergents.
Because the estimated risks associated with treated paints, cleaning products, and
laundry detergents exceeded EPA's level of concern by such a large degree - in some cases
by more than several orders of magnitude - the Agency believes that these and similar uses
do not meet the "no unreasonable adverse effects" criteria of FIFRA. Therefore, HHT
products for use in paints, stains, coatings, and institutional and household cleaning products
in residential settings are not eligible for reregi strati on.
However, the Agency believes that certain other residential uses of HHT (see
Appendix A) result in significantly lower exposure and risk and present a benefit to society.
Therefore, residential uses other than paints, stains, coatings, and institutional and household
cleaning products meet the "no unreasonable adverse effects" criteria of FIFRA and are
eligible for reregi strati on.
b. Performing Occupational Activities
There is the potential for workers to be exposed to HHT and formaldehyde either
during or after the application of HHT products in an occupational setting. To estimate the
potential risks associated with these exposures, the Agency assessed representative
application and/or post-application exposure scenarios including treated paints, metal
working fluids, and oil fields.
Because the estimated risks associated with treated paints exceeded EPA's level of
concern by such a large degree, the Agency believes that this use and similar uses (e.g., stains
and coatings) do not meet the "no unreasonable adverse effects" criteria of FIFRA.
Therefore, HHT products for use in paints, stains, and coatings in occupational settings are
not eligible for reregi strati on.
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However, the Agency believes that certain other occupational uses of HHT (see
Appendix A) result in significantly lower exposure and risk and present a benefit to society.
Therefore, occupational uses other than paints, stains, and coatings meet the "no
unreasonable adverse effects" criteria of FIFRA and are eligible for reregi strati on provided
the mitigation measures and associated label changes presented in Table 15 and Table 17 are
implemented.
EPA notes that its level of concern for formaldehyde is below the Occupational
Safety and Health Administration (OSHA) permissible exposure limit (PEL). EPA's
mitigation measures to reduce exposure for non-cancer effects (e.g., irritation) also account
for protecting exposures in the lower range of the cancer assessment.
B. Risk Management Decision
HHT uses presented in Appendix A are eligible for reregistration provided that
registrants comply with the requirements outlined in this document including implementing
risk mitigation measures, amending product labels, and submitting required confirmatory
data.
1. Risk Mitigation Measures
Products containing HHT are eligible for reregi strati on provided that the registrants
implement the risk mitigation measures presented in Table 15. Specific labeling
requirements to implement these measures are presented in Table 17. In the future,
registrants may request that EPA remove or reduce certain restrictions or mitigation measures
upon submission of acceptable toxicity and exposure studies that demonstrate risk exposure
to HHT is below OPP's level of concern.
Table 15. Risk Mitigation Measures for HHT
Use Site
Paints, Stains, and
Coatings
Metal Working
Fluids
Institutional and
Household Cleaning
Products
Oil Field Secondary
Recovery
Risk(s) of Concern
Residential handler inhalation exposure
to HHT in paint
Occupational handler inhalation
exposure to formaldehyde in paint
Occupational handler inhalation
exposure to formaldehyde in metal
working fluids
Residential handler inhalation exposure
to formaldehyde in cleaners
Residential handler inhalation exposure
to HHT in laundry detergent
Occupational handler dermal exposure
to HHT in oil field secondary recovery
uses
Mitigation Measures1
• Delete use
• Reduce maximum application
rate from 1600 ppb to 500 ppb
• Delete use
• Reduce maximum application
rate from 0.16% active
ingredient (ai) to 0.12% ai
1 In the future, registrants may request that EPA remove or reduce certain restrictions or mitigation measures
upon submission of acceptable toxicity and exposure studies that demonstrate risk to HHT is below OPP's level
of concern.
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2. Product Label Amendments
Manufacturing-Use Products and End-Use Products must be amended to reflect the
mitigation measures presented in Table 15 and the label amendments presented in Table 17
(see Section V).
V. What Registrants Need to Do
The Agency has determined that HHT is eligible for reregi strati on provided that the
requirements for reregi strati on identified in this RED are implemented (see Section IV). The
registrant will also need to amend product labeling for each product.
The database supporting the reregi strati on of HHT has been reviewed and determined
to be adequate to support a reregi strati on eligibility decision. However, additional
confirmatory data are required to support continued registration.
A. Manufacturing Use Products
1. Generic Data Requirements
The generic database supporting the reregi strati on of HHT for currently registered
uses has been reviewed and determined to be adequate to support a reregi strati on eligibility
decision. However, the confirmatory data presented in Table 16 are required. Generally,
registrants will have 90 days from receipt of a generic data call-in (GDCI) to complete and
submit response forms or request time extensions and/or waivers with a full written
justification. Timeframes for submitting generic data will be presented in the GDCI.
Table 16. Generic Data Required to Support HHT Registrations
EPA Guideline Number
870.1300
870.3150
870.3465
870.3700
870.3800
870.4100
870.4200
875.1100
875.1200
875.1300
875.1400
875.1600
875.1700
875.2700
875.2800
875.2900
Requirement Name
Acute Inhalation Study
90-day Oral Toxicity in (Non- Rodents)
90-Day Inhalation Toxicity in Rats
Developmental Toxicity (Non-Rodents)
2-Generation Reproductive Toxicity Study
Chronic Toxicity
Carcinogenicity (Rat and Mouse)
Dermal Outdoor Exposure
Dermal Indoor Exposure
Inhalation Outdoor Exposure
Inhalation Indoor Exposure
Applicator Exposure Monitoring Data Reporting
Product Use Information
Product Use Information
Description of Human Activity
Data Reporting and Calculations
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The Agency determined that there are data gaps in the hazard database for HHT based
on the current use patterns. Due to the potential inhalation exposure in occupational and
residential settings, and based on the lack of inhalation toxicity data, an acute inhalation
toxicity study (870.1300) and 90-day inhalation toxicity study (870.3465) must be performed
for HHT. In addition, a 90-day oral toxicity in non-rodents (870.3150) is required to assess
species sensitivities to the toxicity of HHT.
There are no chronic toxicity and carcinogenicity data for HHT. Risks from the
metalworking fluid use of HHT cannot be adequately characterized without these data.
Because there are potential endocrine disruption concerns, some positive mutagenicity study
findings, and because HHT is a known formaldehyde producer, a chronic toxicity study
(870.4100) and carcinogenicity studies (870.4200) in two species are needed. In addition,
metalworking fluid use is considered a long-term exposure antimicrobial use pattern and
triggers the requirement for carcinogenicity studies and chronic toxicity studies as described
on the 1987 Antimicrobial Data Call-In Notice.
There are no data for the reproductive toxicity of HHT. The data for characterizing
the developmental and reproductive toxicity of HHT are limited to only developmental
toxicity study in rats. Specifically, a non-rodent species should be tested to assess species
sensitivity to the toxicity of HHT. A reproductive toxicity study is also necessary to assess
any effects on fertility and reproduction, and is required to support the current uses of HHT.
Surrogate dermal and inhalation unit exposure values were taken from the proprietary
CMA antimicrobial exposure study (USE EPA 1999: DP Barcode D247642). Most of the
CMA data are of poor quality and, therefore, the Agency requests that confirmatory
monitoring data be generated to support the values used in the occupational and residential
risk assessments and to further refine these assessments. The following confirmatory
monitoring data are needed: dermal exposure-indoor & outdoor data (875.1200 and
875.1100, respectively), and inhalation exposure-indoor & outdoor data (875.1400 and
875.1300, respectively). Product use information (875.1700 and 875.2700), description of
human activity data (875.2800), and data reporting and calculations (875.2900) are also
needed to further define the exposure scenarios being supported and to further refine the
assessments.
For HHT technical grade active ingredient products, the registrant needs to submit the
following items:
Within 90 days from receipt of the generic data call-in (DCI):
1. Completed response forms to the generic DCI (i.e., DCI response form and
requirements status and registrant's response form); and
2. Submit any time extension and/or waiver requests with a full written justification.
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Within the time limit specified in the generic DCI:
1. Cite any existing generic data which address data requirements or submit new
generic data responding to the DCI.
Please contact Lance Wormell at (703) 603-0523 with questions regarding generic
reregi strati on.
By US mail: By express or courier service:
Document Processing Desk Document Processing Desk
Lance Wormell Lance Wormell
Office of Pesticide Programs (751 OP) Office of Pesticide Programs (751 OP)
U.S. Environmental Protection Agency U.S. Environmental Protection Agency
1200 Pennsylvania Ave., NW One Potomac Yard, Room S-4900
Washington, DC 20460-0001 2777 South Crystal Drive
Arlington, VA 22202
B. End-Use Products
1. Product Specific Data Requirements
Section 4(g)(2)(B) of FIFRA calls for the Agency to obtain any needed product-
specific data regarding the pesticide after a determination of eligibility has been made. The
registrant must review previous data submissions to ensure that they meet current EPA
acceptance criteria and if not, commit to conduct new studies. If a registrant believes that
previously submitted data meet current testing standards, then the study MRID numbers
should be cited according to the instructions in the Requirement Status and Registrants
Response Form provided for each product. The Agency intends to issue a separate product-
specific data call-in (PDCI) outlining specific data requirements.
Generally, registrants will have 90 days from receipt of a PDCI to complete and
submit response forms or request time extensions and/or waivers with a full written
justification. Registrants will have eight months to submit product-specific data.
For end-use products containing the active ingredient HHT, the registrant needs to submit the
following items for each product.
Within 90 days from the receipt of the product-specific data call-in (PDCI):
1. Completed response forms to the PDCI (i.e., PDCI response form and
requirements status and registrant's response form); and
2. Submit any time extension or waiver requests with a full written justification.
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Within eight months from the receipt of the PDCI:
1. Two copies of the confidential statement of formula (EPA Form 8570-4);
2. A completed original application for reregi strati on (EPA Form 8570-1). Indicate
on the form that it is an "application for reregi strati on";
3. Five copies of the draft label incorporating all label amendments outlined in Table
17 of this document;
4. A completed form certifying compliance with data compensation requirements
(EPA Form 8570-34);
5. If applicable, a completed form certifying compliance with cost share offer
requirements (EPA Form 8570-32); and
6. The product-specific data responding to the PDCI.
Please contact Marshal Swindell at (703) 308-6341 with questions regarding product
reregi strati on and/or the PDCI. All materials submitted in response to the PDCI should be
addressed as follows:
By US mail: By express or courier service:
Document Processing Desk Document Processing Desk
Marshal Swindell Marshal Swindell
Office of Pesticide Programs (751 OP) Office of Pesticide Programs (751 OP)
U.S. Environmental Protection Agency U.S. Environmental Protection Agency
1200 Pennsylvania Ave., NW Room S-4900, One Potomac Yard
Washington, DC 20460-0001 2777 South Crystal Drive
Arlington, VA 22202
2. Labeling for End-Use Products
To be eligible for reregi strati on, labeling changes are necessary to implement
measures outlined in Section IV. Specific language to incorporate these changes is presented
in Table 17. Generally, conditions for the distribution and sale of products bearing old
labels/labeling will be established when the label changes are approved. However, specific
existing stocks time frames will be established case-by-case, depending on the number of
products involved, the number of label changes, and other factors.
Registrants may generally distribute and sell products bearing old labels/labeling for
26 months from the date of the issuance of this Reregi strati on Eligibility Decision document.
Persons other than the registrant may generally distribute or sell such products for 52 months
from the approval of labels reflecting the mitigation described in this RED. However,
existing stocks time frames will be established case-by-case, depending on the number of
products involved, the number of label changes, and other factors. Refer to "Existing Stocks
of Pesticide Products; Statement of Policy," Federal Register, Volume 56, No. 123, June 26,
1991.
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Table 17. Required Label Changes for Manufacturing and End-Use Products Containing HHT
Description
HHT: Required Labeling Language
Placement on Label
Manufacturing-Use Products
For all Manufacturing
Use Products
"Only for formulation as a preservative for the following use(s) [fill blank
only with those uses that are being supported by MP registrant]."
"Only for formulation into end-use products with directions for use that
prohibit use in paints, stains, coatings, and institutional and household
cleaning products."
Directions for Use
One of these statements
may be added to a label
to allow reformulation of
the product for a specific
use or all additional uses
supported by a formulator
or user group.
"This product may be used to formulate products for specific use(s) not listed
on the MP label if the formulator, user group, or grower has complied with
U.S. EPA submission requirements regarding support of such use(s)."
"This product may be used to formulate products for any additional use(s) not
listed on the MP label if the formulator, user group, or grower has complied
with U.S. EPA submission requirements regarding support of such use(s)."
Directions for Use
Environmental Hazards
Statements Required by
the RED and Agency
Label Policies
"Do not discharge effluent containing this product into lakes, streams, ponds,
estuaries, oceans, or other waters unless in accordance with the requirements
of a National Pollution Discharge Elimination System (NPDES) permit and
the permitting authority has been notified in writing prior to discharge. Do
not discharge effluent containing this product to sewer systems without
previously notifying the local sewage treatment plant authority. For guidance
contact your State Water Board or Regional Office of the EPA."
Precautionary Statements
End- Use Products
PPE Requirements
Established by the RED
"Personal Protective Equipment (PPE)"
All mixers and other handlers must wear the following PPE:
- long-sleeved shirt and long pants,
- shoes plus socks,
- chemical-resistant gloves, and
- goggles, face shield, or safety glasses."
Immediately following/below
Precautionary Statements: Hazards
to Humans and Domestic Animals
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User Safety Requirement
"Follow manufacturer's instructions for cleaning/maintaining PPE. jf no
such instructions for washables exist, use detergent and hot water. Keep and
wash PPE separately from other laundry."
"Discard clothing and other absorbent material that have been drenched or
heavily contaminated with the product's concentrate. Do not reuse them."
Precautionary Statements: Hazards
to Humans and Domestic Animals
Immediately following the PPE
requirements
User Safety
Recommendations
"USER SAFETY RECOMMENDATIONS"
"Users should wash hands before eating, drinking, chewing gum, using
tobacco, or using the toilet."
"Users should remove clothing/PPE immediately if pesticide gets inside.
Then wash thoroughly and put on clean clothing."
"Users should remove PPE immediately after handling this product. Wash
the outside of gloves before removing. As soon as possible, wash thoroughly
and change into clean clothing."
Precautionary Statements: Hazards
to Humans and Domestic Animals
immediately following Engineering
Controls
(Must be placed in a box.)
Other Application
Restrictions
(Risk Mitigation)
For products intended for use in metal working fluids, include the following:
"For metal working fluids, the maximum use concentration is 500 parts per
billion (ppb) of active ingredient."
For products intended for use in oil field secondary recovery, include the
following:
"For oil field secondary recovery use, the maximum use concentration is
0.12% active ingredient."
Directions for Use Associated with
the Specific Use Pattern
Other Application
Restrictions
(Risk Mitigation)
"Use of this product in paints, stains, coatings, and institutional and
household cleaning products is prohibited."
Directions for Use under Other Use
Precautions
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