BEFORE THE

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

COMMENTS OF THE ETHYLENE OXIDE/ETHYLENE GLYCOLS PANEL

OF THE AMERICAN CHEMISTRY COUNCIL

IN RESPONSE TO EPA'S NOTICE OF AVAILABILITY OF EPA'S HUMAN

HEALTH RISK ASSESSMENT AND RELATED DOCUMENTS FOR ETHYLENE OXIDE

\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_

Notice of Availability; )

Ethylene Oxide Risk Assessment ) OPP-2005-0203

[70 Fed. Reg. 44632 (Aug. 3, 2005)]{.underline} )

Courtney M. Price Karyn M. Schmidt, Esquire

Vice President Counsel, CHEMSTAR

CHEMSTAR

William P. Gulledge M. Jane Teta, Dr. P.H., M.P.H.

Manager, Ethylene Oxide/ Exponent, Inc.

Ethylene Glycols Panel

Of Counsel:

Christopher R. Kirman, M.S. Lynn L. Bergeson, Esquire

The Sapphire Group, Inc. Lisa M. Campbell, Esquire

> Bergeson & Campbell, P.C.

Dr. Richard Albertini 1203 Nineteenth Street, N.W.

University of Vermont Suite 300

Washington, D.C. 20036

Robert L. Sielken Jr., Ph.D.

Sielken & Associates Consulting, Inc.

October 3, 2005

[EXECUTIVE]{.underline} SUMMARY[]{#__RefHeading___Toc115771536 .anchor}

The Ethylene Oxide/Ethylene Glycols Panel (Panel) of the American
Chemistry Council submits these comments to the United States
Environmental Protection Agency's (EPA) Office of Pesticide Programs
(OPP) in response to the August 3, 2005, *Federal Register* notice
announcing the availability of the human health risk assessment and
related documents for the pesticide, ethylene oxide (EO) (together,
Preliminary Risk Assessment).

These comments incorporate by reference the July 5, 2005, comments
submitted by ARC Specialty Products, Balchem Corporation (ARC) and
Honeywell International, Inc. (Honeywell) \-- registrants under the
Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA) for
technical and end-use products that contain EO (together, the
Registrants) \-- on the preliminary versions of these documents. The
members of the Panel manufacture most of the EO produced in the United
States or use large amounts of EO. As manufacturers, users, and
registrants, the validity of the scientific basis for the Preliminary
Risk Assessment and its suitability for purposes of making
determinations for the reregistration eligibility decision (RED) are
highly important to the Panel.

The Panel's concerns regarding EPA's assessment of EO go to the core of
the Preliminary Risk Assessment's conclusions, and include:

-   **EPA Should Consider Additional Data and Information Not Referenced
    in the Preliminary Risk Assessment:** EPA should not move forward
    with a risk assessment that does not reflect a consideration of all
    relevant information.

-   **EPA Should Rely Upon More Recent and Comprehensive Neurotoxicity
    Studies to Determine Critical Endpoints:** It is scientifically
    indefensible to select the Snellings, *et al.* (1984a) screening
    level study to determine the no observed adverse effect level
    (NOAEL) for short-term inhalation exposure because more recent,
    comprehensive studies for this endpoint are available.

-   **EPA Should Not Rely Upon California EPA's (CalEPA) Unit Risk
    Factor (URF) to Determine Inhalation Cancer Risk and Instead Should
    Base Its Assessment on Epidemiology Data:** EPA should not rely upon
    CalEPA's URF to determine inhalation cancer risk when: (1) the
    mononuclear cell leukemia (MCL) rat data are of questionable
    relevance to human health; and (2) the scientific knowledge gained
    over the past 20 years permits use of human data and consideration
    of other approaches to modeling dose-response. EPA should rely on
    the significant amount of epidemiology data to complete its
    assessment.

-   **EPA Should Follow Its Guidelines for Carcinogen Risk Assessment
    (Cancer Risk Guidelines):** EPA ignores its Cancer Risk Guidelines,
    which state a general preference for human data over animal data,
    including a preference for epidemiology data "of high quality and
    adequate statistical power" for dose-response assessment,
    consideration of alternative dose-response models based on mode of
    action, and incorporation of points of departure in dose-response
    assessment.

-   **EPA Should Rely on Benchmark Dose (BMD) Modeling in Its Assessment
    of Non-Cancer Endpoints:** EPA considered only one of several
    studies available to assess the dose-response relationship for the
    reproductive/developmental effects of EO and should instead develop
    a more refined risk assessment by relying on BMD methods.

The Panel is also concerned with ethylene glycol's (EG) assessment, most
notably with regard to the following issues:

-   **EPA Determination of the NOAEL and Lowest Observed Adverse Effect
    Level (LOAEL) for EG Is Not Scientifically Defensible:** EPA should
    be consistent with its 1989 Integrated Risk Information System
    (IRIS) review of EG and determine that the kidney pathology from the
    DePass (1986a) study was the appropriate endpoint for the NOAEL and
    LOAEL. Observations of only oxalate crystals in the urine and mild
    fatty changes in female livers only after 24 months of treatment and
    with no other supporting evidence of liver effects are not
    observations of adverse effects and should not be used to determine
    a NOAEL.

-   **EPA Should Not Rely Upon the Gaunt, *et al.* (1974) Study for EG
    Effects:** The Gaunt *et al.* (1974) study is outdated and
    significantly flawed; EPA should instead rely upon Cruzan, *et al.*
    (2004), a modern peer-reviewed, published study using the same rat
    strain, same route of exposure, and the same length of treatment.

The issues specific to EG are discussed in more detail in Attachment 1.

EPA should revise the Preliminary Risk Assessment to address the
numerous technical concerns with the risk assessment that the Panel
outlines below. These technical concerns should be corrected to ensure
that the risk assessment is scientifically defensible and consistent
with EPA's stated commitment to transparency, and FIFRA, Administrative
Procedure Act (APA), and Information Quality Act (IQA) requirements.

[TABLE OF CONTENTS]{.underline}[]{#__RefHeading___Toc115771537 .anchor}

[EXECUTIVE SUMMARY i](#__RefHeading___Toc115771536)

[TABLE OF CONTENTS iii](#__RefHeading___Toc115771537)

[INTRODUCTION 1](#__RefHeading___Toc115771538)

[I. EPA SHOULD ENSURE CONSISTENCY AMONG THE ONGOING OR RECENTLY
COMPLETED ASSESSMENTS OF EO AND SHOULD NOT RUSH THE DEVELOPMENT OF THE
PRELIMINARY RISK ASSESSMENT WHEN PERTINENT ASSESSMENTS THAT COULD INFORM
AND MATERIALLY AFFECT OPP'S CONCLUSIONS ARE ONGOING
2](#__RefHeading___Toc115771539)

[A. EPA Should Coordinate Its RED Development with the Other EPA Offices
That Are Currently Conducting Assessments
6](#__RefHeading___Toc115771540)

[B. EPA, Stakeholders, and the Public Would Be Better Served If EPA
Harmonized Its Preliminary Risk Assessment with Other Ongoing or
Recently Completed Assessments 7](#__RefHeading___Toc115771541)

[II. THE CURRENT ASSESSMENT DOES NOT MEET LEGAL OR SCIENTIFIC STANDARDS
FOR RISK ASSESSMENT AND SHOULD NOT BE ISSUED
8](#__RefHeading___Toc115771542)

[A. EPA Is Obligated to Follow Certain Scientific and Legal Standards in
Issuing a Preliminary Risk Assessment under FIFRA
8](#__RefHeading___Toc115771543)

[B. The Current Assessment Fails to Meet These Standards
9](#__RefHeading___Toc115771544)

[1. EPA Has Not Considered At All or Adequately All Relevant Data and
Thus Violates EPA's Legal Obligations and Policies
9](#__RefHeading___Toc115771545)

[2. EPA Has Not Provided Access to All Pertinent Documents
12](#__RefHeading___Toc115771546)

[3. EPA Has Failed to Consider Previously Submitted Comments
14](#__RefHeading___Toc115771547)

[III. EPA'S CONCLUSIONS ON CRITICAL EXPOSURE AND TOXICITY ISSUES ARE NOT
DEFENSIBLE SCIENTIFICALLY OR LEGALLY AND EPA SHOULD REVISE ITS
PRELIMINARY RISK ASSESSMENT TO CORRECT CRITICAL SCIENTIFIC DEFICIENCIES
16](#__RefHeading___Toc115771548)

[A. EPA Should Revise Its Inhalation Cancer Risk Assessment for EO
16](#__RefHeading___Toc115771549)

[1. EPA Should Rely Upon the Body of Epidemiological Evidence to
Determine Inhalation Cancer Risk 17](#__RefHeading___Toc115771550)

[2. The Need to Consider Epidemiological Evidence Is Even More Important
Considering That EPA's Reliance Upon CalEPA's URF to Determine
Inhalation Cancer Risk Is Scientifically Indefensible Since MCL in
Female Rats, Which Is the Basis for CalEPA's URF, Is Not a Relevant
Endpoint for Humans 23](#__RefHeading___Toc115771551)

[3. EPA's Reliance on the Linearized Multi-stage Model When EPA's Cancer
Risk Guidelines Require Consideration of Other Plausible Nonlinearized
Models Based on Mode of Action Is Scientifically Indefensible
25](#__RefHeading___Toc115771552)

[a. There Is Toxicological Support for Nonlinearity
26](#__RefHeading___Toc115771553)

> [i. Dose-Response Relationship for Chromosomal Aberrations Is
> Nonlinear 27](#__RefHeading___Toc115771554)
>
> [ii. Dose-Response Relationship for Adduct Formation/Gene Mutation Is
> Nonlinear 30](#__RefHeading___Toc115771555)

[b. There Is Empirical Support for Nonlinearity
35](#__RefHeading___Toc115771556)

[B. EPA Should Consider More Recent and Comprehensive Guideline
Neurotoxicity Studies for EO 36](#__RefHeading___Toc115771557)

[C. EPA Should Use the BMD Approach to Assess Non-Cancer Risk for EO
38](#__RefHeading___Toc115771558)

[1. EPA's Decision Not to Use the Most Appropriate Studies for Assessing
Non-Cancer Risk Is Scientifically Indefensible When EPA Should Be
Considering a BMD Approach 38](#__RefHeading___Toc115771559)

[2. EPA's Method of Calculating a Human Equivalent Concentration for EO
in Air Is Indefensible Because the Dose Conversions from ppm to
mg/kg-day and mg/kg-day to µg/m^3^ Are Unnecessary
40](#__RefHeading___Toc115771560)

[3. EPA's Preliminary Risk Assessment for EO Should Not Be Based on
Findings at the 50 ppm Exposure Group in the Snellings *et al.* (1984a)
Study But Rather on the Definitive Rat Subchronic Neurotoxicity Study
41](#__RefHeading___Toc115771561)

[D. EPA Should Revise Statements Made about EO's Use in the European
Union (EU) 43](#__RefHeading___Toc115771562)

[E. EPA Should Revise Its Occupational Exposure Scenarios and Its
Non-Cancer and Cancer Occupational Exposure and Risk Estimates
Assumptions for EO 44](#__RefHeading___Toc115771563)

[F. EPA Should Revise Statements about Sterilization of Medical Devices
and Equipment for EO 45](#__RefHeading___Toc115771564)

[G. EPA Should Correct Typographical Errors
46](#__RefHeading___Toc115771565)

[V. EPA SHOULD CORRECT THE CRITICAL DEFICIENCIES IN THE PRELIMINARY RISK
ASSESSMENT BECAUSE THE ASSESSMENT IN ITS CURRENT FORM IS LEGALLY AND
SCIENTIFICALLY INDEFENSIBLE AND, MOREOVER, COULD HAVE A SIGNIFICANT AND
UNWARRANTED, UNNECESSARY NEGATIVE IMPACT ON USE OF THE PRODUCT, WHICH IS
ESSENTIAL FOR MANY CRITICAL PUBLIC HEALTH PURPOSES
47](#__RefHeading___Toc115771566)

[CONCLUSION 49](#__RefHeading___Toc115771567)

[REFERENCES 50](#__RefHeading___Toc115771568)

[ATTACHMENT 1 56](#__RefHeading___Toc115771569)

[ATTACHMENT 2 65](#__RefHeading___Toc115771570)

[INTRODUCTION]{.underline}[]{#__RefHeading___Toc115771538 .anchor}

The Ethylene Oxide/Ethylene Glycols Panel (Panel) of the American
Chemistry Council submits these comments to the United States
Environmental Protection Agency's (EPA) Office of Pesticide Programs
(OPP) in response to the August 3, 2005, *Federal Register* notice
announcing the availability of the human health risk assessment and
related documents for the pesticide, ethylene oxide (EO) (together,
Preliminary Risk Assessment).

These comments build upon and incorporate by reference the July 5, 2005,
comments submitted by ARC Specialty Products, Balchem Corporation (ARC)
and Honeywell International, Inc. (Honeywell) \-- registrants under the
Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA) for
technical and end-use products that contain EO (together, the
Registrants) \-- on the preliminary versions of these documents. The
members of the Panel manufacture most of the EO produced in the United
States or use large amounts of EO.[^1] As manufacturers, users, and
registrants, the validity of the scientific basis for the Preliminary
Risk Assessment and its suitability for purposes of making
determinations for the reregistration eligibility decision (RED) are
highly important to the Panel.

I. EPA SHOULD ENSURE CONSISTENCY AMONG THE ONGOING OR RECENTLY COMPLETED
ASSESSMENTS OF EO AND SHOULD NOT RUSH THE DEVELOPMENT OF THE PRELIMINARY
RISK ASSESSMENT WHEN PERTINENT ASSESSMENTS THAT COULD INFORM AND
MATERIALLY [AFFECT OPP'S CONCLUSIONS ARE
ONGOING]{.underline}[]{#__RefHeading___Toc115771539 .anchor}

The Preliminary Risk Assessment discusses several ongoing risk
assessments, including EPA's Office of Research and Development's (ORD)
assessment of EO's carcinogenicity for the Integrated Risk Information
System (IRIS), which EPA acknowledges has "not yet completed internal or
external peer review";[^2] and EPA's Office of Air and Radiation's (OAR)
assessment of risks from non-occupational ambient fugitive commercial
and industrial emissions.[^3] In addition, the National Advisory
Committee for Acute Exposure Guideline Levels (AEGL) is currently
preparing a technical support document and final AEGLs for EO, which is
scheduled to be available in 2005; this is not referenced in the
Preliminary Risk Assessment.[^4]

Important additional ongoing assessments are also not referenced or not
assessed or incorporated adequately. In particular, the International
Standards Organization (ISO) currently is preparing a revised
international standard, *Biological Evaluation of Medical Devices --
Part 7: Ethylene Oxide Sterilization Residuals* (ISO 10993-7: 1995
Standard). After more than five years of effort, with widespread input
from all major nations, which includes incorporating new human and
animal data and new assessment tools, this assessment has resulted in a
revised draft ISO 10993-7: 1995 Standard, which is now expected to be
circulated for ballot to 45 countries and 4 international liaison
organizations \-- including the World Health Organization (WHO) and the
Organization for Economic Cooperation and Development (OECD) \-- in the
fourth quarter of 2005. It will also be balloted by CEN in Europe as a
European Norm (Standard) under the Vienna Agreement.

The Food and Drug Administration (FDA) co-chairs the U.S. Committee and
Working Group that comments on the ISO 10993-7: 1995 Standard for the
United States. FDA has adopted the current version as the basis for
approval of new medical devices and compliance with those aspects of
current Good Manufacturing Practices that address EO sterilization
residuals. Because of the publication of the current version in 1995,
FDA withdrew its Notice of Intent for Proposed Rulemaking (NPRM) on this
subject.

The Panel urges EPA to review this standard when it is issued and revise
the Preliminary Risk Assessment. This standard, for example, does not
specify residues per gram of device, as stated in the Preliminary Risk
Assessment \-- it specifies delivered dose. The device manufacturer must
determine how the device is used (*e.g*., short-term vs. life-time, type
of procedure) and the size of the device. Some devices, such as
intraocular lenses and extracorporeal blood purifiers, have special
residue limits.

The Panel will supplement these comments and provide a copy of this
draft revised ISO 10993-7: 1995 Standard to EPA as soon as it is
available and approved for release. As discussed further below, the
ISO's comprehensive risk assessment, with global input, incorporates
final values significantly higher than those derived in the Preliminary
Risk Assessment, and EPA should review this important and nearly
completed assessment before moving forward with its own Preliminary Risk
Assessment. The Panel also urges EPA to review an additional ISO
standard, *Biological Evaluation of Medical Devices -- Part 17:
Establishment of Allowable Limits for Leachable Substances* (ISO
10993-17: 2002 Standard). This standard, which is not referenced in the
Preliminary Risk Assessment, should provide EPA with a better
understanding of the risk assessment methodologies used by ISO.

In addition, there are assessments of EO that have recently been
completed that EPA should review for potential discussion in the
Preliminary Risk Assessment. The Occupational Safety and Health
Administration (OSHA), for example, recently completed a review of the
EO OSHA standard in accordance with Section 610 of the Regulatory
Flexibility Act and the Regulatory Flexibility Act and Executive Order
12866.[^5] In this assessment, OSHA concluded that its EO standard,
which sets a 1 parts per million (ppm) 8-hour time-weighted average
(TWA) permissible exposure limit (PEL), and a 5 ppm 15-minute short-term
exposure limit (STEL) "should be continued without change."[^6] OSHA
further states:

> OSHA's original conclusions concerning the health risks of exposure to
> EtO have been supported by new epidemiological and health risk studies
> released since the promulgation of the standard in 1984. Based on
> exposure monitoring data from several sources indicating that
> occupational exposure to EtO has fallen markedly since the EtO
> standard went into effect, workers are being protected. . . . OSHA has
> therefore concluded that the EtO Standard continues to be needed to
> protect workers health and safety. Accordingly, OSHA finds that there
> is no need at this time to modify the rule through a rulemaking
> process to make it more effective or less burdensome.[^7]

The Panel urges EPA to ensure consistency among the Preliminary Risk
Assessment and these ongoing and recently completed studies and
evaluations. This is particularly important in the case of EO where EPA
is currently relying upon outdated assessments such as California EPA's
(CalEPA) Unit Risk Factor (URF). To do otherwise would gravely
compromise the scientific integrity of the document and EPA decisions
that will be based upon it, as well as the public participation process,
all to EPA's, the Panel's, and the public's detriment.

According to EPA's Schedule for Reregistration and Tolerance
Reassessment, the RED for EO is scheduled to be completed in June
2006.[^8] The Panel appreciates the variety of time and budget pressures
on EPA, but this cannot be a substitute for defensible science or an
adequate process. EPA should not rush to judgment under an arbitrary
deadline and sacrifice science in the process. Instead, EPA should
ensure that it has all available information, including pertinent
information from the various recently completed or ongoing assessments,
before moving forward with the assessment of EO.

> A. EPA Should Coordinate Its RED Development with the Other EPA
> [Offices That Are Currently Conducting
> Assessments]{.underline}[]{#__RefHeading___Toc115771540 .anchor}

EPA should coordinate its RED development with the other EPA offices
that are conducting assessments at this time. If EPA bases its
Preliminary Risk Assessment on outdated and less reliable data, EPA runs
the risk of completing the entire six phases of the RED public
participation program \-- at considerable expenditure of time and
resources by EPA, stakeholders, and the public \-- with a scientifically
indefensible product, and may be compelled to revisit many critical
issues once related risk assessments are issued in final.

The Panel particularly urges EPA not to push forward with this
Preliminary Risk Assessment before ORD's new cancer risk assessment for
IRIS is complete. The ORD assessment could reach very different
conclusions from those stated in the Preliminary Risk Assessment, which
could force EPA to reassess and revise significantly the work it has
completed. The Panel strongly urges EPA to coordinate with ORD before
moving forward.

> B. EPA, Stakeholders, and the Public Would Be Better Served If EPA
> Harmonized Its Preliminary Risk Assessment with Other Ongoing or
> [Recently Completed
> Assessments]{.underline}[]{#__RefHeading___Toc115771541 .anchor}

EPA should ensure consistency among the various assessments now ongoing
by ensuring that all assessments rely upon essentially the same set of
relevant available data. The Panel is concerned that the several and
varied risk assessments the Health Effects Division (HED) and OAR are
undertaking may not be conducted in a manner that ensures consistency
with one another. In addition, the Panel believes it is important for
EPA to review other ongoing assessments, particularly the ISO 10993-7:
1995 Standard under current revision, that rely upon comprehensive
analyses and techniques that may better characterize EO than some of the
outdated assessment tools that were used for conclusions stated in the
current draft of the Preliminary Risk Assessment. If EPA does not
consider these standards, including the new ISO 10993-7: 1995 Standard
once available, in developing its Preliminary Risk Assessment, EPA could
reach conclusions that differ from ISO and could cause significant
issues with the global harmonization efforts of ISO and FDA. In
addition, EPA should also ensure that it reviews information from
recently issued assessments and incorporates that information,
including, but not limited to, OSHA's recently completed Section 610
Report, to the extent necessary into the Preliminary Risk Assessment.

In short, the ongoing and recently completed assessments discussed above
are directly relevant to EPA's efforts to assess exposure and risk
associated with handling and use of EO. EPA should not move forward with
its assessment without reviewing or otherwise addressing these
assessments, their utility, and their impact on EPA's efforts.

II\. THE CURRENT ASSESSMENT DOES NOT MEET LEGAL OR SCIENTIFIC [STANDARDS
FOR RISK ASSESSMENT AND SHOULD NOT BE
ISSUED]{.underline}[]{#__RefHeading___Toc115771542 .anchor}

> A. EPA Is Obligated to Follow Certain Scientific and Legal Standards
> in [Issuing a Preliminary Risk Assessment under
> FIFRA]{.underline}[]{#__RefHeading___Toc115771543 .anchor}

It is inconsistent with FIFRA, the Administrative Procedure Act (APA),
defensible science, EPA's stated commitment to transparency,[^9] and
common sense to place before the public information that may prove to be
erroneous and that could have been corrected.[^10] Moreover, it is
inconsistent with EPA's guidelines under the Information Quality Act
(IQA), which affirm that "EPA is dedicated to the collection,
generation, and dissemination of high quality information."[^11]

> B. [The Current Assessment Fails to Meet These
> Standards]{.underline}[]{#__RefHeading___Toc115771544 .anchor}
>
> 1\. EPA Has Not Considered At All or Adequately All Relevant Data and
> Thus Violates EPA's Legal Obligations [and
> Policies]{.underline}[]{#__RefHeading___Toc115771545 .anchor}

EPA's regulations implementing FIFRA require that EPA, when considering
a registration under FIFRA Section 3(c)(5), "review\[\] all relevant
data in the possession of the Agency."[^12] As EPA also has stated:

> Universally accepted scientific principles require that all relevant
> information, not an arbitrary selected subset of information, be
> considered in making risk/benefit decisions. The Agency has
> consistently adhered to this principle. The Agency rejects any
> interpretation of the statute that would limit the scope of the
> information reviewed or compromise the integrity of its scientific
> decisionmaking process.[^13]

In addition, EPA has emphasized on numerous occasions its policy of
ensuring that its decisions are scientifically based.[^14] In fact, EPA
is under a legal obligation to follow its own guidelines and policies
and ensure scientifically defensible decision-making absent a rational
explanation for departure from such precedent.[^15] An agency decision
is arbitrary and capricious if the agency has ignored information in its
possession or reached a decision that runs counter to the evidence
before the agency.[^16]

EPA is thus bound by law and its own policies to use the data that the
Registrants previously referenced and urged EPA to use. EPA is likewise
bound by law and its own policies to base the Preliminary Risk
Assessment on defensible science and to correct fundamental errors, as
the Registrants also have previously urged. The Preliminary Risk
Assessment, for example, continues to use and rely on the outdated
CalEPA URF, when more recent assessments and epidemiological data show
such use to be scientifically indefensible. Also notable, EPA did not
rely upon the most recent comprehensive neurotoxicity studies to
determine a critical endpoint. Moreover, EPA considered only one of
several studies available to assess the dose-response relationship for
the reproductive/developmental effects of EO and should instead develop
a more refined Preliminary Risk Assessment by relying on benchmark dose
(BMD) methods. These issues are all discussed in more detail in Section
III below.

> 2\. [EPA Has Not Provided Access to All Pertinent
> Documents]{.underline}[]{#__RefHeading___Toc115771546 .anchor}

The Panel has not had an adequate opportunity to comment on the
Preliminary Risk Assessment because EPA has not provided the required
opportunity for comment on key data that serve as the foundation of
EPA's assessment and underlie some of EPA's most significant
conclusions. As an initial matter, the Panel urges EPA to release
immediately its "Overview of the Ethylene Oxide Assessments" (Overview)
or suspend the comment period until this document is made available to
the Panel and the public. According to the e-docket, this document "is
under development and will be added later."[^17] This Overview is
intended to be a summary, in plain English, of EPA's determinations in
the Preliminary Risk Assessment. Without this document, the Panel and
other stakeholders are deprived of an adequate opportunity to comment on
the Preliminary Risk Assessment.

These data and EPA documents support critical EPA statements and
conclusions in the Preliminary Risk Assessment establishing human health
concerns and thresholds of concern for EO. The Panel is deprived of an
adequate opportunity to comment on the Preliminary Risk Assessment
without access to these critical documents. This is particularly
important in light of EPA's legal obligations and the goal of
transparency for the RED development process. Not to provide access to
these data, and an adequate opportunity to comment on them, and not to
consider adequately any of those comments in its assessment would
violate the Panel's due process rights and EPA's legal obligations.[^18]
While the cited cases address the requirement for notice and comment in
the context of rulemaking, the principles are equally applicable to the
issuance of a RED, which courts have concluded constitutes a final
agency action.[^19]

In addition, the Registrants received on September 26, 2005, a letter
from EPA responding to the Registrants' identification of documents and
data that EPA relied upon in the Preliminary Risk Assessment but to
which EPA has not provided access to the Registrants, the Panel. or the
public. In that letter, EPA notes that five of the references were
incorrect references to be corrected in the Preliminary Risk Assessment.
EPA also provided a copy of one study previously not available. The
Panel reserves the right to supplement these comments once it has had an
adequate opportunity to review the study at issue.

> 3\. EPA Has Failed to Consider Previously Submitted
> [Comments]{.underline}[]{#__RefHeading___Toc115771547 .anchor}

Requirements established by APA \-- including the need to provide
adequate opportunity to comment and the need to consider fully all
available data, as discussed above \-- are all intended to ensure that
agencies do not issue flawed documents.[^20] In addition, to issue a
risk assessment that contains substantive errors and misleading
information would be inconsistent with EPA's guidelines under the IQA,
which affirm that "EPA is dedicated to the collection, generation, and
dissemination of high quality information."[^21] IQA thus requires that
EPA disseminate information that it believes to be accurate, or at the
least avoid disseminating information that it knows to be
inaccurate.[^22] Agency actions that fail to address fundamental issues
raised by parties entitled to protection also have been found to violate
"basic concepts of fair play."[^23]

In this case, the Registrants have submitted comments to EPA on the
earlier version of the Preliminary Risk Assessment. Most of these
comments were not addressed by EPA, however. By not considering and
incorporating the Registrants' previous comments, yet releasing the risk
assessment publicly, EPA has failed to ensure that it does not issue a
flawed document. The Panel urges EPA to revise now the Preliminary Risk
Assessment to reflect its comments and the data brought to EPA's
attention previously and discussed again in these comments.

EPA should not rush forward arbitrarily now to complete a flawed
assessment. This is particularly the case in light of the many flaws in
the current version of the assessment and the failure of EPA to respond
adequately to comments submitted on the prior iteration of the risk
assessment and associated background documents. Completing such a flawed
assessment could have profound, irreversible, and unfounded product
deselection consequences, as well as state and local regulatory
consequences, that ultimately could deprive medical, laboratory, and
hospital settings with the use of a critical public health pesticide.

III\. EPA'S CONCLUSIONS ON CRITICAL EXPOSURE AND TOXICITY ISSUES ARE NOT
DEFENSIBLE SCIENTIFICALLY OR LEGALLY AND EPA SHOULD REVISE ITS
PRELIMINARY RISK ASSESSMENT TO CORRECT CRITICAL SCIENTIFIC
[DEFICIENCIES]{.underline}[]{#__RefHeading___Toc115771548 .anchor}

The Panel details below the critical scientific deficiencies with regard
to EPA's assessment of EO in the Preliminary Risk Assessment. The issues
specific to EPA's assessment of ethylene glycol (EG) are discussed in
Attachment 1.

> A. [EPA Should Revise Its Inhalation Cancer Risk Assessment for
> EO]{.underline}[]{#__RefHeading___Toc115771549 .anchor}

In its Preliminary Risk Assessment, EPA relies upon the outdated, 1984
CalEPA URF to determine inhalation cancer risk. Doing so is
scientifically indefensible given the existence of a complete
epidemiological database for EO.[^24] Those human data should be used
instead of the mononuclear cell leukemia (MCL) rat data used to
determine the URF if the Preliminary Risk Assessment is to be
scientifically defensible.

> 1\. EPA Should Rely Upon the Body of Epidemiological [Evidence to
> Determine Inhalation Cancer
> Risk]{.underline}[]{#__RefHeading___Toc115771550 .anchor}

The Panel urges EPA to consider the available epidemiological data to
determine EO's inhalation cancer risk. The epidemiological database for
EO that includes exposure estimates suitable for dose-response includes
more than 20,000 workers (Steenland *et al*., 1991; Teta *et al*.,
1993). These data were collected in two studies, one by the National
Institute for Occupational Safety and Health (NIOSH) (Steenland *et
al*., 1991) and the other by Union Carbide Corporation (Teta *et al.,*
1993). Considering their scientific significance, these important
studies should be used as the basis for the risk estimation for EO in
the Preliminary Risk Assessment if EPA is to produce a scientifically
defensible assessment.

The first epidemiology study of EO exposed workers, a cluster
investigation by Hogstedt *et al.*, was published in 1979 (Hogstedt *et
al.*, 1979a). This small investigation, including a follow-on
investigation by Hogstedt and his colleagues (Hogstedt *et al.*, 1979b)
and two other small cohort studies (Thiess *et al.*, 1981; Morgan *et
al.*, 1981) were the only epidemiological data available at the time of
the CalEPA 1984 EO risk assessment. These studies did not include
sufficient exposure data to incorporate in a dose-response assessment.
As a result, the CalEPA 1984 risk assessment was based on animal data.

Since the original cluster report, the number, quality, and size of the
published literature on EO exposed workers have expanded to include 21
published studies, 11 unique cohorts of nearly 33,000 workers with more
than 1,300 cancers from five countries. For purposes of dose-response
assessment using epidemiological data, the most critical information is
the quality and completeness of exposure information. The most accurate
and direct exposure data are from the Hagmar *et al.* (1991) study, that
included air concentrations and correlations with hemoglobin adducts
over the entire period of study observation. Unfortunately, the
population was too young and the follow up too short to be confident
that excess cancers with long latency would be detected. An update of
this study was published in 1995 that includes four more years'
observation but still only 12 years median follow up (Hagmar *et al.*,
1995).

Two studies investigated by NIOSH and Union Carbide (Steenland *et al*.,
1991, 2004; Teta *et al*., 1993), with very long follow up and EO
exposure estimates at the individual level, have the requisite
attributes to become the basis for dose-response modeling. These studies
meet acceptable standards of quality as evaluated by Shore *et al*. in
the 1993 meta-analysis. The NIOSH cohort included over 18,000 male and
female workers at 11 sterilant and three spice plants in the United
States. Workers were followed for an average of 16 years in the 1991
report and 27 years by the time of the update published in 2004. The
details of the NIOSH EO exposure estimation and validation have been
described by Greife *et al.* (1988) and Hornung *et al* (1994). The
Union Carbide cohort included almost 2,000 men exposed to EO in chemical
manufacturing, who were also followed an average of 27 years. Eight-hour
TWA concentrations were estimated over four time periods and three
exposure intensity categories. The details are provided in Teta *et al.*
(1999).

Dose-response modeling related to EO cumulative exposures and leukemia
have been conducted using these two epidemiological studies in two
peer-reviewed publications (Teta *et al.*, 1999; Kirman *et al.*, 2004).
These analyses conform to the state-of-the-art enhancements in the 2005
EPA Cancer Risk Guidelines in that they: (1) give preference to
available human data; (2) incorporate point of departure analyses; and
(3) provide ranges of risk estimates under various model assumptions.
These papers also address lack of consistency with the results derived
from animal-based dose-response, using MCL in the female rat.
Furthermore, there is no epidemiological evidence of an increased risk
for leukemia or non-Hodgkin's lymphoma among a large population of
EO-exposed females included in these studies. These risk assessments
were based on the then available NIOSH data with follow up through 1987.
The more recent publication by Steenland *et al*. with follow up through
1998 shows a weaker dose-response than the prior analyses, according to
the author \[Steenland - personal communication to Teta\].

The fact that EPA has not relied upon the epidemiological studies and
the Kirman *et al*. risk assessment to determine EO's inhalation cancer
risk is particularly concerning to the Panel considering that these
studies were comprehensively reviewed by Dr. Blondell for HED (DP
Barcode D319213). In HED's conclusions regarding Blondell's review, HED
concludes:

> Based on more recent studies the \[sic\] it may be appropriate to
> downgrade ethylene oxide to a probable carcinogen in humans based upon
> the relatively low strength of association, inconsistency between
> males and females, some lack of replication in other studies, and
> limited evidence of dose-response based on a lag-time that is not
> biologically justified.[^25]

The Preliminary Risk Assessment document states it relies on this review
which concludes that EO is not a potent leukemogen, based on the largest
epidemiological study with the longest follow up and exposure data that
permits dose-response assessment. This assertion is not consistent with
the Preliminary Risk Assessment's estimate of a 57 parts per trillion
(ppt) *de minimis* risk using MCL in the female rat. The details of this
inconsistency are described in greater detail below using the results
from Kirman *et al,* (2004).

Using state-of-the-art biology, mechanistic knowledge, biostatistics,
and the most extensive epidemiological data, Kirman *et al*. (2004) have
derived sound scientific estimates of the URF for EO. The estimates
reported by Kirman *et al*. have been peer-reviewed, published, and are
widely supported by the scientific community.[^26] In Table 1, the best
estimates of the *de minimis* occupational concentrations (associated
with a one in one million extra cancer risk) are calculated for the
linear model and quadratic model with several points of departure
assumptions. Kirman *et al.* concluded that the quadratic model is the
most biologically plausible model for the mechanism of action of EO. The
ratios of the *de minimis* occupational concentrations derived using
Kirman *et al.* estimates to the 57 ppt estimate derived by EPA are
listed in the last column. The results in Table 1 indicate that EPA's
estimate of 57 ppt is more than 6,000-fold smaller than the maximum
likelihood estimate of 358,714 ppt based on the most scientific
state-of-the-art estimate of the URF. The most conservative estimate in
Table 1 (the linear model fit to the epidemiological data) is
approximately 150-fold greater than EPA's estimate.

Even if 95 percent or 99 percent upper confidence limits on the URF were
used to estimate the *de minimis* occupational concentrations, which are
the most conservative estimates obtained using the epidemiological data,
the result would be much larger *de minimis* occupational concentrations
than those estimated by EPA.

Table 1. Maximum likelihood estimates of the *de minimis* occupational
concentration (extra risk of one in a million) based on the best
epidemiological model estimates with various points of departure (POD)
and the most scientifically complete epidemiological databases with more
than 20,000 workers in two studies: NIOSH (Steenland *et al.,* 1991) and
Union Carbide Corporation (Teta *et al.,* 1993)

+------------------------------+----------+-------------+-------------+
| Model Description            | Unit     | *De         | Ratio:      |
|                              | Risk     | Minimis*    |             |
|                              | Factor   |             | *De         |
|                              |          | (1 x        | Minimis*    |
|                              | (μg/m    | 10^-6^)     | O           |
|                              | ^3^)^-1^ | O           | ccupational |
|                              |          | ccupational | Co          |
|                              |          | Co          | ncentration |
|                              |          | ncentration |             |
|                              |          |             | To          |
|                              |          | (ppt)[^27]  |             |
|                              |          |             | July 19,    |
|                              |          |             | 2005 EPA's  |
|                              |          |             | Estimate    |
|                              |          |             | Based on    |
|                              |          |             | Female Rats |
|                              |          |             | MCL[^28]    |
+==============================+==========+=============+=============+
| Linear Extrapolation from a  | 1.       | 358,714     | 6,293       |
| POD of 0.000001 Using the    | 4×10^-8^ |             |             |
| Quadratic Model              |          |             |             |
+------------------------------+----------+-------------+-------------+
| Linear Extrapolation from a  | 4.       | 113,606     | 1,993       |
| POD of 0.00001 Using the     | 5×10^-8^ |             |             |
| Quadratic Model              |          |             |             |
+------------------------------+----------+-------------+-------------+
| Linear Extrapolation from a  | 1.       | 35,871      | 629         |
| POD of 0.0001 Using the      | 4×10^-7^ |             |             |
| Quadratic Model              |          |             |             |
+------------------------------+----------+-------------+-------------+
| Linear Extrapolation from a  | 4.       | 11,361      | 199         |
| POD of 0.001 Using the       | 5×10^-7^ |             |             |
| Quadratic Model              |          |             |             |
+------------------------------+----------+-------------+-------------+
| Linear Extrapolation from a  | 6.       | 8,400       | 147         |
| POD of 0.001 Using the       | 0×10^-7^ |             |             |
| Linear Model                 |          |             |             |
+------------------------------+----------+-------------+-------------+

In summary, the distribution of occupational concentrations for an extra
risk of one in a million workers derived using the most scientifically
valid risk assessment to date does not support EPA's estimate of 57 ppt,
which infers a potent carcinogen. In fact, EPA does not indicate that EO
is a potent carcinogen in its Preliminary Risk Assessment when it
states: "\[I\]t may be appropriate to downgrade ethylene oxide to a
probable carcinogen in humans based upon the relatively low strength of
association, inconsistency between males and females, some lack of
replication in other studies, and limited evidence of dose-response
based on a lag-time that is not biologically justified."[^29] The human
data rule out with high confidence the animal-based potency estimate.

> 2\. The Need to Consider Epidemiological Evidence Is Even More
> Important Considering That EPA's Reliance Upon CalEPA's URF to
> Determine Inhalation Cancer Risk Is Scientifically Indefensible Since
> MCL in Female Rats, Which Is the Basis for CalEPA's URF, Is Not a
> Relevant [Endpoint for
> Humans]{.underline}[]{#__RefHeading___Toc115771551 .anchor}

There are several reasons why the MCL rat data upon which the URF was
derived are of questionable relevance to human health:

-   Compared to human cancers of the lymphohematopoietic system that are
    generally myeloid in origin, rodent tumors of the
    lymphohematopoietic system tend to be lymphoid in origin (USEPA,
    1997b);

-   MCL in rats is splenic in origin, and since splenic hematopoiesis
    occurs in rats but does not normally occur in humans, there is no
    corresponding tumor type for MCL in humans (Caldwell, 1999; Walker
    *et al*., 2000); and

-   MCL represents the most common life-threatening neoplasm in
    untreated F344 rats.

In fact, the background incidence for MCL in F344 rats is considerably
higher and more variable than the incidence reported for
lymphohematopoietic cancers in other rodent strains and species
(Stefanski *et al*., 1990). More importantly, the background incidence
of MCL in rats is much higher (as high as 50 percent) than that observed
for leukemia in the general human population (Furmanski and Rich, 1987;
Ward *et al*., 1990; Caldwell, 1999). Because of these important species
differences, the International Agency for Research in Cancer (IARC) has
categorized the MCL as an unclassified leukemia with no known human
counterpart (Swaen and Van Heerde, 1987).

In addition, there is no indication from these epidemiological data that
females are more sensitive for hematopoietic cancer endpoints (Steenland
*et al*., 2004; Coggon *et al*., 2004; Hogstedt, 1988; Norman *et al*.,
1995; Hagmar *et al.*, 1995). The body of epidemiological evidence
suggests just the opposite (Steenland *et al.*, 2004). The Panel,
therefore, urges EPA to correct this error of using the sensitive female
rat as a surrogate for potency estimation for humans.

> 3\. EPA's Reliance on the Linearized Multi-stage Model When EPA's
> Cancer Risk Guidelines Require Consideration of Other Plausible
> Nonlinearized Models Based on Mode of [Action Is Scientifically
> Indefensible]{.underline}[]{#__RefHeading___Toc115771552 .anchor}

In the absence of adequate epidemiology and sufficient mode of action
information available in the 1980s, the 1986 CalEPA assessment, which
EPA relies upon in the Preliminary Risk Assessment to determine the URF,
used the most sensitive animal species and the default linearized
multi-stage model. EPA, in its Cancer Risk Guidelines, issued in March
2005, as well as in the draft guidelines issued in 1996, urges
consideration of other plausible models based on mode of action, and
states its preference for using epidemiology data for dose-response
assessment.[^30] The scientific knowledge gained over the past 20 years,
therefore, requires consideration of other approaches to modeling
dose-response for EO.

##  {#section .unnumbered}

## Application of EPA's Cancer Risk Guidelines to a genotoxic carcinogen exhibiting a nonlinear dose-response relationship is complicated, and is likely to be controversial primarily because, in the past, a genotoxic mode of action has required an assumption of linearity at low doses by an EPA policy decision. Despite the fact that EO is a genotoxic carcinogen, there is a growing body of evidence to support that the relationship between exposure and leukemia is nonlinear (The Sapphire Group, 2001; Kirman et al., 2004), which has profound implications on the potential risks to human populations exposed to low doses. In fact, in 2005, the Society of Toxicology's Risk Assessment Specialty Division awarded the Kirman, et al. (2004) paper "Outstanding Published Paper Demonstrating an Application of Risk Assessment." Toxicological support (mode of action) and empirical support for a nonlinear dose-response relationship for EO and leukemia are summarized below and are presented more fully in Attachment 2. {#application-of-epas-cancer-risk-guidelines-to-a-genotoxic-carcinogen-exhibiting-a-nonlinear-dose-response-relationship-is-complicated-and-is-likely-to-be-controversial-primarily-because-in-the-past-a-genotoxic-mode-of-action-has-required-an-assumption-of-linearity-at-low-doses-by-an-epa-policy-decision.-despite-the-fact-that-eo-is-a-genotoxic-carcinogen-there-is-a-growing-body-of-evidence-to-support-that-the-relationship-between-exposure-and-leukemia-is-nonlinear-the-sapphire-group-2001-kirman-et-al.-2004-which-has-profound-implications-on-the-potential-risks-to-human-populations-exposed-to-low-doses.-in-fact-in-2005-the-society-of-toxicologys-risk-assessment-specialty-division-awarded-the-kirman-et-al.-2004-paper-outstanding-published-paper-demonstrating-an-application-of-risk-assessment.-toxicological-support-mode-of-action-and-empirical-support-for-a-nonlinear-dose-response-relationship-for-eo-and-leukemia-are-summarized-below-and-are-presented-more-fully-in-attachment-2. .unnumbered}

> a\. There Is Toxicological Support for
> [Nonlinearity]{.underline}[]{#__RefHeading___Toc115771553 .anchor}

Chromosomal aberrations and gene mutations have been shown to be
important in the pathogenesis of human leukemia with full progression to
disease requiring both the characteristic chromosome aberrations and the
gene mutations. The proposed mode of action for EO outlined below has
profound implications with respect to the shape of the dose-response
curve, such that significant departures from linearity are expected.
Chromosomal aberrations, which require more than one hit from a
monofunctional alkylating agent such as EO, are expected to be
proportionate to the square of the dose (*i.e.,* a quadratic
dose-response relationship). Efficient repair of EO DNA lesions protects
against fixed genotoxic effects (mutations and chromosome aberrations),
such that a threshold is expected for carcinogenic response.
Consideration of these factors and their relation to carcinogenic
potency is important for estimating risk to human health, as discussed
below.

> i\. Dose-Response Relationship for Chromosomal [Aberrations Is
> Nonlinear]{.underline}[]{#__RefHeading___Toc115771554 .anchor}

Number range CHAPTERA plausible mode of action for EO and leukemia was
developed based upon a consideration of significant information.
Alkylating agents, such as EO, produce chromosomal aberrations almost
exclusively by errors in DNA replication on an adducted template
(Preston, 1999a). It has been established by a large number of studies
that exposure to EO produces chromosomal aberrations in peripheral
lymphocytes in humans (Abrahams, 1980; Pero *et al.*, 1981; Thiess *et
al.*, 1981; Sarto *et al.*, 1984; Stolley *et al.*, 1984; Richmond *et
al.*, 1985; Karelova *et al.*, 1987; Tates *et al.*, 1991; Lerda and
Rizzi, 1992; Ribeiro *et al.*, 1994; Major *et al.*, 1996, 1999).
Chromosomal aberrations in peripheral lymphocytes are not, however, key
events in the production of leukemia for three important reasons:

-   Peripheral blood lymphocytes are not the target cells for leukemia.

-   Strictly speaking, the aberrations observed in human lymphocytes are
    produced *in vitro* rather than *in vivo* as manifestation of DNA
    adducts carried over into culture (Preston, 1999). In culture, the
    lymphocytes are stimulated to proliferate, not allowing time for DNA
    repair, resulting in the observed aberrations, most of which are
    cell lethals. As discussed in detail below, DNA repair is a critical
    factor in EO's genotoxicity (and therefore, its carcinogenicity).

-   As cell lethals, the kinds of *in vitro* events scored in these
    human studies are mostly those without leukemogenic potential.
    Nonetheless, the occurrence of such lesions in lymphocytes indicates
    that EO may produce chromosome level effects of the right kinds in
    target tissues *in vivo* where they may serve as initiating events
    in malignancies, thus serving as useful but indirect triple (cell
    type, *in vitro* occurrence and kind of event) surrogates for the
    true key event in leukemogenesis. The findings for chromosomal
    aberrations in exposed humans are supported by the results of animal
    studies, some of which are scored in bone marrow stem cells
    (considered below) (Embree and Hine, 1975; Lynch *et al.,* 1984b;
    Kligerman *et al.,* 1983; Ribeiro *et al.*, 1987; van Sittert *et
    al.*, 1985).

Specific chromosomal aberrations in target cells are associated strongly
with myeloid leukemia in humans, the kind associated with alkylating
agent exposures. These aberrations can be characterized as either
interstitial (internal) deletions or reciprocal translocations, both of
which require two independent "genotoxic hits" for their production. EO
also produces point mutations and small deletions as shown by *in vitro*
and *in vivo* studies (also considered in detail below) (Sisk *et al.*,
1997; van Sittert *et al.*, 2000). Gene mutations have also been shown
to be important in the pathogenesis of human leukemia with full
progression to disease requiring both the characteristic chromosome
aberrations and the gene mutations (Gilliland and Griffin, 2002).
Specific chromosome aberrations are, therefore, characteristic and
necessary changes found in the chemically-induced leukemias (USEPA,
1997b; Levine and Bloomfield, 1992; Yunis *et al.;* 1989, Rowley, 1998
and references therein; Gilliland and Griffin, 2002) with specific
oncogene mutations, *e.g.*, N-*ras,* K-*ras*, FLT3 serving as co-events
in full disease progression (Neubauer *et al.*, 1994; Gilliland and
Griffin, 2002).

Based on considerations that: (1) EO causes specific chromosomal
aberrations; (2) chromosomal aberrations are the characteristic events
in chemically-induced acute leukemia; and (3) additional gene mutations
are also important for full expression of disease, the following
sequence of events is proposed as the most plausible mode of action for
EO as a leukemogen:

Event 1: Exposure to EO (external dose, *e.g.,* ppm in air)

Event 2: Distribution of EO to hematopoietic/lymphopoietic cells

Event 3a: Reaction 1 with DNA (adduct formation), representing one end
of the translocation or interstitial deletion

Event 3b: Reaction 2 with DNA (adduct formation) representing the other
end of the translocation or interstitial deletion. Reaction 2 occurs
close in time to Reaction 1 (*e.g.,* before repair of Reaction 1 and
before cell division), so that adducts produced by both reactions are
simultaneously present during a single wave of DNA replication

Event 4: Error in DNA replication, resulting in translocation or
interstitial deletion that affects a critical gene for
hematopoiesis/lymphopoiesis

Event 5: Viable hematopoietic/lymphopoietic cell containing a
translocation or interstitial deletion that is transmissible to daughter
cells

> Event 6: Progression of disease with the occurrence of gene mutations
> in the same clone that suffered the chromosome aberration, some of
> which may be deletions, for full expression of leukemia.

The proposed mode of action for EO outlined above has profound
implications with respect to the shape of the dose-response curve. Based
on physiologically-based pharmacokinetic (PBPK) modeling simulations,
Event 2 is believed to be linearly proportional to dose (Event 1).
Events 3a and 3b, when considered separately, may conservatively be
assumed to be linearly proportional to Event 2 (and therefore to dose),
since saturation of DNA repair becomes an issue in rodents at
concentrations above the point of departure (33 to 100 ppm) (Walker *et
al.*, 1992). Because of the time restriction associated with two
independent events occurring during the same wave of replication,
translocations or deletions (Events 3a and 3b occurring together) are
predicted to be induced at a frequency proportional to the square of the
dose (Preston *et al*., 1995; Preston, 1999a). Without any specific
information regarding the dynamics of leukemia, Events 4 through 6 are
conservatively assumed to be linearly proportional to Event 3b.
Progression (Event 6) involves other genotoxic events (*e.g.*,
mutations) and can vary considerably in duration for human leukemia.
Some of these mutations (*e.g.,* the true point mutations), may occur as
single-hit events while others (*e.g.,* the deletion mutations), will be
similar to the specific chromosomal events requiring two-hits. In any
event, these mutations must arise in the same clone of cells
(descendents of the originally affected cell) in which the specific
chromosomal event occurred. Overall, the events leading from EO exposure
to the development of leukemia (and therefore risk) may conservatively
be considered to be proportional to the square of the dose, and
therefore, use of a nonlinear dose-response model (*e.g.,* quadratic) is
appropriate.

As the mode of action for EO's carcinogenic potential is genotoxicity,
considerations of the nature of this genotoxicity and its relation to
carcinogenic potency are important for estimating risk.

> ii\. Dose-Response Relationship for Adduct Formation/Gene [Mutation Is
> Nonlinear]{.underline}[]{#__RefHeading___Toc115771555 .anchor}

EO is a category 1 monofunctional alkylating agent that reacts directly
with DNA to produce primarily adducts at the N7 and N3 positions of
purines (Vogel *et al.*, 1998). Because such adducts are efficiently
repaired, relatively high exposure concentrations are necessary to
produce measurable genotoxic effects in repair proficient organisms
leading to a high acute toxicity to genotoxicity ratio (Vogel *et al.*,
1998). EO's category 1 status with its dependence for mutagenicity
resting on repair capacity is reflected in its genotoxicity profile.

As an alkylating agent, EO has been shown to be mutagenic in a broad
range of test systems including bacteria, fungi, higher plants,
[Drosophila]{.underline}, mammalian cells both *in vitro* and *in vivo*
and in humans. In high concentrations, EO is used as a positive control
in several mutagenicity studies for other industrial chemicals. EO
induces point mutations in bacteria (*e.g*., [Salmonella]{.underline}
TA100, TA1535, [Bacillus subtilis]{.underline} HA101 and TKJ 5211)
without addition of exogeneous mammalian metabolic activation system. In
fungi, EO has been shown to increase ad+ revertants ([Neurospora
crassa)]{.underline} and induce forward mutations ([Schizosaccharomyces
pombe]{.underline}). EO also is an effective mutagen in higher plants
(*e.g.,* induction of chlorophyll gene mutations in rice and barley).
Qualitatively, therefore, EO is a direct acting genotoxic agent as has
been well demonstrated by the *in vitro* studies. Quantitative effects
of relevance to humans, which speak to its genotoxic and carcinogenic
potencies, are reflected by the *in vivo* studies considered below.

The importance of DNA repair in protecting quantitatively against EO's
fixed genotoxic effects is shown at the germ cell level by studies of
sex-linked recessive lethal mutations in Drosophila. Although measurable
at exposure concentrations below the LD~50~, such mutations arise
primarily in the post-meiotic germ cells that lack repair capacity, with
protection seen in the repair proficient pre-meiotic cells (Vogel *et
al.*, 1998). A more definitive demonstration that mutation induction by
EO is sensitive to DNA repair in Drosophila was shown by mating treated
males with either repair deficient or repair proficient females.
Mutation induction was low to non-significant at low EO exposure
concentrations when repair proficient compared to repair deficient
females were tested (Nivard *et al.,* 2003).

Germ cell mutagenicity studies in rodents have also been informative.
Dominant lethal effects, heritable translocations, and specific locus
gene mutations have all been observed in EO-exposed male mice. Again,
these effects are seen in the post-meiotic germ cells that lack
effective repair (Generoso *et al*., 1986, 1990). In fact, all attempts
to induce specific locus mutations in pre-meiotic germ cells of mice
with any category 1 alkylating agent have failed (reviewed in Vogel *et
al.*, 1998). (Repair does occur in pre-meiotic germ cells as shown by
the dose dependent increase in unscheduled DNA synthesis (UDS) reported
in germinal cells of male mice exposed to EO). This has implications for
heritable risks in humans as it is the fixed genetic effects in the
pre-meiotic cells in the testes that would have the potential for
transmission to the next generation during the entire lifetime of the
exposed individual. These are the cells protected by efficient DNA
repair.

The EO-induced dominant lethal mutations and heritable translocations in
rodents are chromosome level effects. Given the importance of certain
kinds of chromosome aberrations (*e.g.,* balanced translocations and
interstitial deletions), as noted above, the dose-response
characteristics for these events is relevant. Both dominant lethal and
heritable translocation induction have shown nonlinear increases with
exposure concentration in the post-meiotic cells (Generoso *et al*.,
1986, 1990). In the first of these studies, the lowest concentration
tested was 300 ppm; in the second it was 165 ppm. In addition to
nonlinearity of the dose response-curve, therefore, no dominant lethals
were observed at this lowest concentration suggesting a threshold for
this genotoxic endpoint.

EO-induced somatic gene mutations have also been observed *in vivo* in
the splenic lymphocytes of mice. In male Big Blue (lacI transgenic)
B6C3F1 mice exposed to 0, 50, 100 or 200 ppm for 6h/day, 5d/week, for 4
weeks, the observed mean frequencies of mutations at the Hprt locus in
splenic T-lymphocytes were 2.2x10^-6^, 3.8x10^-6^, 6.8x10^-6^, and
14.1x10^-6^, respectively (Walker *et al*., 1997a, as cited in IPCS,
2003). EO's status as a category 1 alkylating agent was clearly
demonstrated in the results of a subsequent study by these same
investigators. A range of EO and ethylene exposure concentrations in
mice was related to N7 guanine (the relevant adduct for both agents as
ethylene is metabolized to EO *in vivo*) adduct levels and the adduct
levels then correlated with the frequencies of Hprt mutations. No
mutations over background in splenic lymphocytes were observed at adduct
levels corresponding to 12.7 ppm EO exposure (Walker *et al*., 2000).
These repair proficient animals showed, therefore, a clear threshold for
a mutagenic effect without showing a similar threshold for adduct
formation, revealing the importance of repair in protecting against the
irreversible genotoxic consequences of the adducts.

These studies of Hprt mutations in mice allow interpretation of similar
studies in humans where Hprt mutations as biomarkers of in vivo point
mutations in EO exposed workers have also been studied (Tates *et al*.,
1992, 1995). Chronic exposure levels (TWA) of 0.025 ppm with bursts in
air from 22 to 72 ppm were not associated with elevations above
background while higher TWA exposure concentrations of 5.0 ppm with
bursts in air from 14 to 400 ppm were (Tates *et al*., 1992). This
indicates a threshold similar to that seen in the controlled studies in
mice. Consistent with this was a subsequent observation of no Hprt
mutation induction over background in workers exposed acutely to even
higher EO concentrations ranging from 24 to 440 ppm (Tates *et al*.,
1995)

As for gene mutations, EO also induces chromosome level changes in
mammalian somatic cells *in vivo* (*e.g*., peripheral lymphocytes and
bone marrow cells) as manifest by increased frequencies of
sister-chromatid exchanges (SCE) and micronuclei in polychromatic
erythrocytes in rats and mice. EO was compared to other alkylating
agents as regards potency for inducing chromosome level changes in
rodents (both somatic and germinal) and was clearly shown to be among
the weakest of those studied on the basis of the lowest effective dose
(Vogel *et al*., 1998 \[Fig. 13\]). In humans, EO has consistently shown
chromosomal aberrations in peripheral blood lymphocytes obtained from
workers exposed to EO at ≥ 5 ppm, as indicated above. Two points are
relevant in assessing these human studies. First, the changes measured
in lymphocytes are neither in the target cells for leukemia (bone marrow
stem cells), true *in vivo* events, nor usually of the kinds
(translocations and interstitial deletions) important in leukemia as
discussed above. The second is that, even in the lymphocytes, it is
equivocal if effects have ever been observed at exposure concentrations
below 5 ppm again indicating a threshold. The SCEs observed in humans
are also seen at exposure concentrations ≥5 ppm (IPCS, 2003) but this
endpoint is more properly interpreted as an indicator of exposure and
not effect.

The low genotoxic potency of category 1 alkylating agents such as EO
translates directly to the low carcinogenic potency of agents in this
class. When the carcinogenic potency (expressed as 1/TD~50~ of lifetime
dose in rodents) of an alkylating agent was plotted against the acute
toxicity of the agent (expressed as 1/LD~50~), EO was found among the
weakest (Vogel *et al.,* 1998).

In summary:

-   Although EO is a direct acting mutagenic chemical, it is classified
    as a category 1 alkylating agent characterized by the production of
    N7 guanine and N3 adenine adducts that are efficiently repaired;

-   Efficient repair protects against fixed genotoxic effects (mutations
    and chromosome aberrations) at low EO exposure concentrations;

-   EO's category 1 status is reflected in germ cell studies in
    Drosophila and mice;

-   EO's category 1 status is reflected in studies of somatic cell
    mutations and chromosome level changes in mice;

-   Human studies reflect the weak mutagenicity and clastogenicity of EO
    at low exposure concentrations by showing apparent no observed
    adverse effect levels (NOAEL) in workers for both endpoints; and

-   EO's weak mutagenicity is reflected by its weak carcinogenicity in
    rodent studies (Vogel, 1998 \[Fig. 12\]).

> b\. [There Is Empirical Support for
> Nonlinearity]{.underline}[]{#__RefHeading___Toc115771556 .anchor}

Three sources of empirical evidence of nonlinearity in the
exposure-response relationship for EO and leukemia are summarized below.

-   **Epidemiology Exposure-Response Data:** Empirical evidence of
    nonlinearity is obtained from inspection of the plot of the fitted
    rate ratio model and exposure-response data from epidemiology
    studies (Teta *et al.,* 1999; Kirman *et al*., 2004), which
    demonstrate a substantial change in the slope of the response with
    increasing exposure.

-   **Data for Precursor Lesion/Key Event:** Empirical evidence suggests
    a nonlinear relationship between EO exposure and the production of
    chromosome translocations (identified as a key event in human
    leukemogenesis). Evidence can be found in the dose-response curve
    for EO and heritable translocations in mice (Generoso *et al.*,
    1990), also in which a notable increase in the slope of the response
    curve is evident with increasing exposure level. Additional support
    comes from the results of an unpublished study, in which a nonlinear
    relationship was observed for the formation of chromosomal
    aberrations in splenic lymphocytes from mice exposed to EO *in
    vivo*. (Preston, 2003, personal communication). Splenic lymphocytes
    are also continuously replicating, and are more directly related to
    the target tissue for EO cancers in rodents.

-   **Interspecies Concordance:** Empirical evidence suggests improved
    concordance between rodents and humans dose-response data when using
    a quadratic model as compared to using a linear model, which
    significantly overestimated the risk to human populations (Kirman
    *et al.*, 2004).

> B. EPA Should Consider More Recent and Comprehensive Guideline
> [Neurotoxicity Studies for
> EO]{.underline}[]{#__RefHeading___Toc115771557 .anchor}

In the Preliminary Risk Assessment, EPA selected Snellings, *et al*.
(1984a) to determine the NOAEL for short-term inhalation exposure.[^31]
It is scientifically indefensible for EPA to select this study when more
recent, comprehensive studies are available that better and more fully
address this endpoint. Snellings, *et al*. (1984a) was conducted over 20
years ago and is only a screening study. Snellings, *et al*. used a
typical general toxicology protocol to understand better the toxicity of
repeated exposures to EO in mice. As an add-on to this general
toxicology evaluation, a neurological screening study was conducted with
a small sub-set of animals. In the publication of this study, there are
a few statements indicating clearly that this is not a definitive
neurological study. The Methods Section, for example, states, "\[a\]
neuromuscular screening test was performed to determine the feasibility
of conducting larger scale neurologic examinations in subsequent
studies." There were four exposure groups, at 250, 100, 50, and 10 ppm.
The only significant findings, from the 50 ppm exposure groups, were
subjective observations of abnormal posture and reduced locomotor
activity. For less subjective findings, observations of abnormal
reflexes of righting, toe pinch, and tail pinch were seen mostly in the
250 ppm exposure group. In addition, the authors conclude that "with the
small sample size it was difficult to establish what level could be
regarded as a threshold." More concern for the use of these
screening-types of observations was noted when the authors concluded,
"\[t\]here were no abnormal microscopic findings in the brain, spinal
cord, peripheral nerve, or muscle which would explain the apparent
treatment-related effects observed in the Irwin screen test."

Reliance on the Snellings, *et al*. (1984a) study is even more
inappropriate considering more recent, definitive neurotoxicity studies
that EPA requested that the Registrants conduct are available and have
been classified as Acceptable/Guideline: (1) Subchronic Range-Finding
Study (MRID 44256401); and (2) Subchronic Inhalation Neurotoxicity Study
(MRID 44359401). EPA should review these studies and comments carefully
for purposes of this Preliminary Risk Assessment. In the Subchronic
Inhalation Neurotoxicity Study, rats were exposed to 0, 25, 50, 100, or
200 ppm EO for at least 65 exposures, followed by a 13 week recovery
period. The mean body weight in males and females in the highest
exposure group was reduced over the exposure period by approximately 16
percent in males and 9 percent in females. By the end of the recovery
period, body weights were within 3 percent of control values. A 25
percent reduction in hindlimb grip strength in high concentration
females was noted in the functional observation battery (FOB) at the end
of the exposure period, with no other treatment-related effects on motor
activity. EPA reviewers concluded for this Acceptable/Guideline
Subchronic Inhalation Neurotoxicity Study that "\[b\]ased on the results
of this study, the NOAEL for ethylene oxide administered to
Sprague-Dawley rats via whole body inhalation for 13-weeks (at least 65
exposures) is 100 ppm. The lowest observed adverse effect level (LOAEL)
is 200 ppm based on decreased body weight and body weight gain in males
and females and decreased hindlimb grip strength in females."[^32]

> C. [EPA Should Use the BMD Approach to Assess Non-Cancer Risk for
> EO]{.underline}[]{#__RefHeading___Toc115771558 .anchor}
>
> 1\. EPA's Decision Not to Use the Most Appropriate Studies for
> Assessing Non-Cancer Risk Is Scientifically Indefensible When EPA
> Should Be Considering a BMD
> [Approach]{.underline}[]{#__RefHeading___Toc115771559 .anchor}

In conducting its non-cancer risk assessment for long-term exposures to
EO, EPA established a NOAEL value of 7.5 ppm (13.5 mg/m^3^) based upon
the reproductive/developmental effects of EO in rats (Chun and
Neeper-Bradley, 1993; MRID 42788101). This, however, is only one of
several studies available to assess the dose-response relationship for
the reproductive/development effects of EO. A BMD method would allow EPA
to consider other relevant studies and remove the need to rely upon
NOAEL values as the basis for the non-cancer dose-response assessment.
EPA should, therefore, use benchmark concentrations (BMC) for all
relevant studies to establish a more appropriate basis for non-cancer
risk assessment.

In a paper entitled *Toxicological Review of Ethylene Oxide* (The
Sapphire Group, 2001), which was submitted to EPA's IRIS Submission Desk
on April 9, 2001, several studies were used to derive BMCs based upon
fetal mortality and changes in fetal body weight (Chun and
Neeper-Bradley, 1993; Snellings *et al*., 1982a,b). Specifically, BMD
methods were used to determine the concentration corresponding to a ten
percent increase in extra risk for mortality (BMC~10~) and its 95
percent lower confidence limit (BMCL~10~) for fetal mortality, as well
as the concentration corresponding to a five percent decrease in fetal
body weight (BMC~05~) and its 95 percent lower confidence limit
(BMCL~05~). Benchmark response rates of ten percent and five percent
were selected as default points of departure for quantal and continuous
data sets, respectively. Details of this non-cancer dose-response
assessment are located in Section 5.1 and Appendix A of the
Toxicological Review document (The Sapphire Group, 2001).

The resulting BMCs are presented in Table 2 below**,** expressed in
terms of both continuous exposure and occupational exposure. Based upon
the mean BMCL values for each endpoint, the non-cancer risk assessment
for occupational exposures should be based upon EO concentrations of
29-59 ppm (51-106 mg/m^3^) rather than a concentration of 7.5 ppm (13.5
mg/m^3^). Based upon a margin of exposure (MOE) of 30 (three for
interspecies variation, ten for intraspecies variation), the
concentration of EO in air at which non-cancer risk is not of concern to
human health for occupational exposures is approximately 1-2 ppm
(1.8-3.6 mg/m^3^).

Table 2. Summary of BMCs Derived for the Reproductive/Developmental
Effects of EO in Rats (Chun and Neeper-Bradley, 1993; Snellings *et
al*., 1982a,b; The Sapphire Group, 2001)

+--------+---------+----------------+---------------+----------------+
|        |         |                | **BMCL**      |                |
+========+=========+================+===============+================+
| **Endp | **Be    | # Data         | **Continuous  | **Occupational |
| oint** | nchmark |  Set {#data-se | Exposure^1^** | Exposure^2^**  |
|        | R       | t .unnumbered} |               |                |
|        | esponse |                |               |                |
|        | Rate**  |                |               |                |
+--------+---------+----------------+---------------+----------------+
| Fetal  | 10%     | Chun and       | 6.3 ppm       | 27 ppm         |
| Mor    |         | Neeper-Bradley |               |                |
| tality |         | (1993)-F~0~    | (11 mg/m^3^)  | (48 mg/m^3^)   |
+--------+---------+----------------+---------------+----------------+
|        |         | Chun and       | 6.2 ppm       | 26 ppm         |
|        |         | Neeper-Bradley |               |                |
|        |         | (1993)-F~1~    | (11 mg/m^3^)  | (47 mg/m^3^)   |
+--------+---------+----------------+---------------+----------------+
|        |         | Snellings *et  | 8.0 ppm       | 34 ppm         |
|        |         | al.* (1982a)-  |               |                |
|        |         | F~0~           | (14 mg/m^3^)  | (61 mg/m^3^)   |
+--------+---------+----------------+---------------+----------------+
|        |         | **Mean**       | **6.8 ppm**   | **29 ppm**     |
|        |         |                |               |                |
|        |         |                | **(12         | **(50          |
|        |         |                | m             | mg/m**^3^**)** |
|        |         |                | g/m**^3^**)** |                |
+--------+---------+----------------+---------------+----------------+
| Fet    | 5%      | Neeper-Bradley | 26 ppm        | 109 ppm        |
| al/Pup |         | and Kubena     |               |                |
| Body   |         | (1993)         | (47 mg/m^3^)  | (197 mg/m^3^)  |
| Weight |         |                |               |                |
+--------+---------+----------------+---------------+----------------+
|        |         | Snellings *et  | 16 ppm        | 67 ppm         |
|        |         | al.* (1982b)   |               |                |
|        |         |                | (29 mg/m^3^)  | (121 mg/m^3^)  |
+--------+---------+----------------+---------------+----------------+
|        |         | Chun and       | 9.7 ppm       | 41 ppm         |
|        |         | Neeper-Bradley |               |                |
|        |         | (1993)-F~0~    | (17 mg/m^3^)  | (73 mg/m^3^)   |
+--------+---------+----------------+---------------+----------------+
|        |         | Chun and       | 12 ppm        | 50 ppm         |
|        |         | Neeper-Bradley |               |                |
|        |         | (1993)-F~1~    | (22 mg/m^3^)  | (91 mg/m^3^)   |
+--------+---------+----------------+---------------+----------------+
|        |         | Snellings *et  | 4.7 ppm       | 20 ppm         |
|        |         | al.* (1982a)-  |               |                |
|        |         | F~0~           | (8.5 mg/m^3^) | (36 mg/m^3^)   |
+--------+---------+----------------+---------------+----------------+
|        |         | **Mean**       | **14 ppm**    | **59 ppm**     |
|        |         |                |               |                |
|        |         |                | **(25         | **(105         |
|        |         |                | m             | mg/m**^3^**)** |
|        |         |                | g/m**^3^**)** |                |
+--------+---------+----------------+---------------+----------------+

^1^BMCL corresponding to exposures for 24 hours/day, 7 days/week

^2^BMCL corresponding to exposures for 8 hours/day, 5 days/week

> 2\. EPA's Method of Calculating a Human Equivalent Concentration for
> EO in Air Is Indefensible Because the Dose Conversions from ppm to
> mg/kg-day and mg/kg-day [to µg/m^3^ Are
> Unnecessary]{.underline}[]{#__RefHeading___Toc115771560 .anchor}

The dosimetry approach used to calculate a human equivalent
concentration (HEC) for EO in air is incorrect.[^33] In USEPA (1985),
HECs were calculated by converting the air concentrations associated
with MCL to an equivalent dose (expressed in terms of mg/kg-day) based
upon the results of Tyler and McKelvey (1980), which was converted to a
human equivalent using allometric scaling (body weight raised to the 2/3
power), which was then converted back to an air concentration using
default values for human body weight and inhalation rate. The dose
conversions used here (ppm to mg/kg-day and mg/kg-day to µg/m^3^) are
unnecessary since the dose-response data are already expressed in the
units needed to derive the unit risk value (*i.e.,* ppm or µg/m^3^ in
air). In addition, the use of an allometric scaling factor of 2/3 for
inhalation exposures is not supported by the literature. Based upon
pharmacokinetic principles, a scaling factor of 1.0 (unscaled) has been
proposed for inhalation exposures when the mode of action involves the
parent chemical (Clewell *et al.,* 2002). Use of an allometric scaling
factor of 1.0 has been validated specifically for inhalation exposures
to EO using PBPK modeling (Kirman *et al*., 2003). For this reason,
these dosimetry practices to calculate HECs should be removed from EPA's
assessment for EO.

> 3\. EPA's Preliminary Risk Assessment for EO Should Not Be Based on
> Findings at the 50 ppm Exposure Group in the Snellings *et al.*
> (1984a) Study But Rather on the Definitive [Rat Subchronic
> Neurotoxicity Study]{.underline}[]{#__RefHeading___Toc115771561
> .anchor}

In the Preliminary Risk Assessment, EPA incorrectly concludes, for
short-term EO exposure in the Snellings, *et al*. (1984a) study, that
there were significant effects noted for absolute and relative organ
weight changes for the 50 ppm exposure group.[^34] Based on the findings
reported, the only organ noted with absolute and relative weight
differences was in the 100 ppm exposure group and not in the 250 or 50
ppm groups. The Preliminary Risk Assessment should be clarified
accordingly.

The author of this study has confirmed to the Panel that there could be
confusion if one were to rely only on the Table 4 values in the
publication for an interpretation. Specifically, because of space
limitations for publication, only the absolute testes weights of only
the right testes were printed in Table 4. In the actual study, the
absolute left testes weight of the 50 ppm group was not statistically
different from the controls. Moreover, if the relative organ weights for
the testes had been added correctly to the publication, there were no
significant depressions for any exposure group. In this study, there
were four exposure groups, 250, 100, 50, and 10 ppm. Nowhere in the text
of the published study does it state that there were significant
absolute and relative organ weight changes for the 50 ppm exposure
group. Instead, the published study states, "\[t\]here were
statistically significant differences between the means of treated and
control animals for the following organs in the 250-ppm exposure group:
the liver weights (relative) of the female mice were elevated; the
testicular weights (absolute) were depressed; and the spleen weights
(absolute and relative) of both sexes were depressed. For the rest of
the exposure groups, the mean spleen weight (absolute and relative) of
the 100-ppm-exposed females was the only other value that was
significantly different (depressed) from the control. Histologic
sections of liver, testes, spleen, and brain were normal."[^35]

Based on this information, the short-term risk evaluation from Snellings
*et al*. (1984a) should be based on effects seen at 250 ppm for both
sexes and on only minimal findings for spleen organ weights at 100 ppm
for only one sex with no accompanying histopathologic alterations. The
100 ppm value approximates a LOAEL for several endpoints in several rat
studies and is better supported than 50 ppm LOAEL derived from the mouse
study.

> D. EPA Should Revise Statements Made about EO's Use in the European
> [Union (EU)]{.underline}[]{#__RefHeading___Toc115771562 .anchor}

In its comments submitted on July 5, 2005, the Registrants noted that
Table 3 in the Preliminary Occupational Exposure Assessment of the
Antimicrobial Uses incorrectly states that the EU banned the use of EO
in 1991.[^36] The Registrants stated that the EU banned the use of EO
only as a plant pesticide, and implying that the EU banned the use of EO
for other critical uses at issue here would be erroneous and misleading.
While the Panel appreciates that EPA corrected this error in the current
draft of the Preliminary Occupational Exposure Assessment of the
Antimicrobial Uses, the same error still appears in the Preliminary Risk
Assessment and should similarly be removed.[^37]

Additionally, the United Kingdom has established a Workplace Exposure
Level (long-term exposure limit (8-hour TWA reference period) of 5 ppm
and this level should be included in Table 3 as an additional EO
regulatory level.[^38] A recent publication found that "the findings of
this study do not suggest any need to modify the current UK Occupational
exposure limit for EO of 5ppm" (Coggon *et al*., 2004).

> E. EPA Should Revise Its Occupational Exposure Scenarios and Its
> Non-Cancer and Cancer Occupational Exposure and Risk Estimates
> [Assumptions for EO]{.underline}[]{#__RefHeading___Toc115771563
> .anchor}

EPA should not state that the major activities associated with worker
exposure include both loading and unloading chambers.[^39] After
chambers have been unloaded with any materials that might have retained
EO, these steel chambers, when ready for subsequent loading of new
materials, are unlikely to have trapped any residual EO. In addition,
EPA should clarify that "process area potential emissions" would include
non-normal conditions, such as process upsets, equipment failures,
operator errors, or maintenance work.

EPA's statement in the second bullet on page 7 of the Preliminary
Occupational Exposure Assessment of the Antimicrobial Uses is also
incorrect because it does not recognize that properly aerated medical
devices meeting industry standards would not allow for this potential
exposure.

EPA also errs by assuming that hospital workers are by default exposed
to the OSHA PEL simply because they do not have current EO
concentrations.[^40] The LaMontagne study EPA cites within this same
document studied over 130,000 badges over a 16-year period, ending in
2001, and found that less than one percent of the hospitals exceeded the
PEL (1 ppm) and less than five percent exceeded the action level (AL)
(0.5 ppm). Hospitals monitor EO to comply with OSHA rules. EPA should
revise the Preliminary Risk Assessment to include this critical
information, which is included in a study EPA itself cites.

> F. EPA Should Revise Statements about Sterilization of Medical Devices
> and [Equipment for EO]{.underline}[]{#__RefHeading___Toc115771564
> .anchor}

EPA should revise and clarify statements in the discussion regarding
sterilization of medical devices and equipment in the Preliminary
Occupational Exposure Assessment of the Antimicrobial Uses. For example,
the second paragraph in Section 2.0 provides an incomplete description
by not including a sentence indicating that "\[h\]ospitals use about 5%
of the EO sterilizing gas sold each year in the United States." [^41]
Similarly:

-   EPA should provide clarification regarding the "typical
    sterilization chambers" to which it refers, by inserting after the
    word "chambers" in the first sentence "used by medical device
    manufacturers or contract sterilizers." This insertion is necessary
    because hospitals use much smaller chambers.

-   EPA should modify its language to ensure that it refers only to
    medical device manufacturers and contract sterilizers, and not
    hospitals. Manufacturers of hospital sterilizers set the controls
    such that only two FDA-validated cycles may be selected. Typically,
    the hospital may choose from one of two cycles \-- a "High
    Temperature Cycle" (55°C) and a "Low Temperature Cycle" (37°C) \--
    by pushing a button. Each cycle has been pre-validated by the
    manufacturer for temperatures, EO concentrations, times, pressures,
    and RH. Other than choosing the cycle, the hospital worker cannot
    make any parameter modifications.

-   EPA should modify its statement, "Afterwards, the medical devices
    are aerated for up to 12 hours to reduce or eliminate EtO residues."
    to note further that industrial sterilizers frequently utilize hot
    cells and altered chamber cycles to reduce EO residuals more
    effectively. Industrial medical devices are typically packaged in
    boxes, packed within corrugated cardboard containers. Some hospitals
    aerate in the sterilizer chamber, others in a separate aerator. In
    either technique, elevated temperatures are used to reduce EO
    residuals to levels compliant with the AAMI/ISO Standard 10993,
    Part 7. Hospital medical devices are typically sterilized in a
    barrier pack, made of a material like Tyvek® resin, sometimes placed
    in rigid metal or plastic containers. These materials retain less EO
    residues than does corrugated.

> G. [EPA Should Correct Typographical
> Errors]{.underline}[]{#__RefHeading___Toc115771565 .anchor}

In the Registrants' July 5, 2005, comments, the Registrants provided a
list of typographical errors to be corrected. Some of these errors
appear in the most recent drafts of the Preliminary Risk Assessment
documents, however. EPA should make the following changes:

-   Preliminary Occupational Exposure Assessment, Section 3.0,
    Toxicological Endpoints of Concern, Page 3, Para. 3, Line 2: To
    clarify the sentence, EPA should delete "toxicity for" and "that
    it."

-   Preliminary Occupational Exposure Assessment, Section 3.0,
    Toxicological Endpoints of Concern, Page 4, Para. 1, Line 4: EPA
    should correct the term "mononuclear leukemia," to insert the word
    "cell" after "mononuclear."

-   Preliminary Occupational Exposure Assessment, Section 5.0,
    Non-Cancer and Cancer Occupational Exposure and Risk Estimates, Page
    9, Para. 1, Line 2: EPA should correct the sentence to replace "and"
    with "an."

-   HED Risk Assessment, Table 6b, Page 20: In the rat metabolism
    section, EPA should change "is" to "are" in the last sentence.

-   HED Risk Assessment, Page 42, Para. 2, Lines 1-2: EPA should include
    an "a" in the following sentence: ". . . was selected from *a*
    chronic . . . in which Fischer . . ."

-   HED Risk Assessment, Page 50, Para. 4, Lines 1-2: EPA should include
    an "a" in the following sentence: ". . . was selected from *a*
    chronic . . . in which Fischer . . ."

V. EPA SHOULD CORRECT THE CRITICAL DEFICIENCIES IN THE PRELIMINARY RISK
ASSESSMENT BECAUSE THE ASSESSMENT IN ITS CURRENT FORM IS LEGALLY AND
SCIENTIFICALLY INDEFENSIBLE AND, MOREOVER, COULD HAVE A SIGNIFICANT AND
UNWARRANTED, UNNECESSARY NEGATIVE IMPACT ON USE OF THE PRODUCT, WHICH IS
ESSENTIAL FOR MANY [CRITICAL PUBLIC HEALTH
PURPOSES]{.underline}[]{#__RefHeading___Toc115771566 .anchor}

The Panel urges EPA to correct the critical deficiencies in this
Preliminary Risk Assessment. Without correcting these deficiencies
discussed above, the availability of a critical public health product
could be limited, or lead consumers to use less effective, unsuitable
products, resulting in human health risks that could have been avoided
through the proper use of EO. Medical, laboratory, and hospital settings
count on EO to sterilize equipment and protect patients from the risks
of infectious disease. Without this use, the medical community would be
left with less effective, impractical alternatives that could produce
devastating consequences.

Not only does the Preliminary Risk Assessment inappropriately magnify
the risks associated with use of EO, which could result in unfair
consequences for EO users, but they accord insufficient weight to the
many and substantial societal benefits EO provides. The benefits of EO's
critical public health uses include:

-   **EO Is Best Suited to Sterilize Equipment and Effectively Control
    Difficult Disease Strains, Including Those of Recent Concern Such As
    SARs, Ebola, and Tuberculosis (TB):** EO is a critically important
    public health pesticide that is essential for sterilization of
    medical and laboratory equipment against various bacteria, bacterial
    spores, yeast, mold, and viruses. Panel members have been informed
    verbally from many sources about the need for EO, for example, to
    prevent the transmission of antibiotic-resistant strains of TB. EPA
    itself has acknowledged that EO is used as a sterilant "because it
    possesses comprehensive antimicrobial activity" and is "effective
    against bacteria, bacterial spores, fungi, and viruses."[^42] EO is
    an important tool needed to help control infections from spreading
    in hospitals, whether from difficult disease strains or more typical
    sources of infection.

-   **There Are No Reasonable Substitutes for EO to Sterilize Complex
    and Fragile Medical Equipment:** While other low temperature
    sterilization processes are available, those processes use strong
    oxidizers which can react with other materials in medical devices
    and packaging, potentially damaging sensitive equipment. Chemicals
    other than EO, by reacting with the device material, cannot
    penetrate deep enough to kill the germs contained in complexly
    shaped equipment. EO provides the only effective and penetrating
    sterilization treatment for complex and fragile equipment that does
    not damage such equipment. OSHA notes in its 610 Report that
    hospitals "use EtO as a sterilant for reusable and single use items
    that would be damaged by steam sterilization or other sterilization
    processes."[^43] EPA has also recognized the indispensable need for
    EO:

> In the medical community, EtO is considered essential for
> sterilization of thermolabile, moisture sensitive critical care items
> such as surgical instruments and implants. . . . As the use of EtO on
> these critical care items is essential, the benefit of this use of EtO
> is considered very high.[^44]
>
> A recent Japanese study, for example, concludes that hydrogen peroxide
> plasma is a much less effective sterilant than EO.[^45] Although the
> article claims that Low Temperature Steam Formaldehyde (LTSF) could
> substitute for EO, LTSF is not a practical alternative. LTSF is run at
> a temperature of 80 degrees Celsius (°C), while EO is run between 45
> and 55°C. LTSF can be run at lower temperatures, however,
> sterilization efficacy decreases and it sterilizes more poorly than in
> the Japanese study. Even when EO is run at a higher temperature (55°C)
> where it is much more effective, it is still at a lower temperature
> than LTSF. Since many devices are not designed to tolerate an 80°C
> temperature, EO provides the only effective, practical sterilization
> process.

The critical public health need for EO makes it even more imperative for
EPA to ensure that any risk assessment it issues is accurate and
scientifically sound, based on the best available data.[^46]

[CONCLUSION]{.underline}[]{#__RefHeading___Toc115771567 .anchor}

The Panel appreciates this opportunity to offer its comments, and urges
EPA to make each of the corrections noted.

[REFERENCES]{.underline}[]{#__RefHeading___Toc115771568 .anchor}

Abrahams, R.H. (1980). Recent studies with workers exposed to ethylene
oxide. In: Safe use of ethylene oxide. Proceedings of the Educational
Seminar (ed J. F. Jorkasky) Health Industries Manufacturers Association,
Washington, DC.

Caldwell, D.J. (1999). Review of mononuclear cell leukemia in F-344 rat
bioassays and its significance to human cancer risk: A case study using
alkyl phthalates. *Reg Toxicol Pharmacol* 30:45-53.

Chun, J.S. and T.L. Neeper-Bradley (1993). Two-Generation Reproduction
Study of Inhaled Ethylene Oxide Vapor in CD Rats. Laboratory Project No.
91N0058. Export, PA, Bushy Run Research Center, Union Carbide Chemicals
and Plastics Company, Inc.

Clewell III, H.J., M.E., Andersen, H.A. Barton (2002). A consistent
approach for the application of pharmacokinetic modeling in cancer and
noncancer risk assessment. *Environ Health Perspect* 110:85-93.

Coggon, D., E.C. Harris, J. Poole, K.T. Palmer (2004). Mortality of
workers exposed to ethylene oxide: extended follow up of a British
cohort. *Occup. Environ. Med.* 61:358-362.

Cruzan, G., *et al.* (2004). Subchronic toxicity of ethylene glycol in
Wistar and F-344 Rats related to metabolism and clearance of
metabolites. *Toxicological Sciences* 81:502-511.

DePass, L.R., *et al.* (1986). Chronic toxicity and oncogenicity studies
of ethylene glycol in rats and mice. *Fund. Appl. Toxicol.* 7:566-572.

Embree, J.W. and C.H. Hine (1975). Mutagenicity of ethylene oxide.
*Toxicol. Appl. Pharmacol.* 33: 172-173.

Furmanski, P. and M.A. Rich (1987). Neoplasms of the hematopoietic
system. In: The mouse in biomedical research (Ed. Foster J.D., et al).
New York, NY: Academic Press, 351-371.

Gaunt, I.F., J. Hardey, S.D. Gangolli, *et al*. (1974). Short-term
toxicity of monoethylene glycol in the rat. Carshalton, Surrey (UK):
BIBRA International.

Generoso, W.M., K.T. Cain, C.V. Cornett, N.L. Cacheiro, L.A. Hughes
(1990). Concentration-response curves for ethylene-oxide-induced
heritable translocations and dominant lethal mutations. *Environ Mol
Mutagen.* 16(2):126-31.

Generoso, W.M., K.T. Cain, L.A. Hughes, G.A. Sega, P.W. Braden, D.G.
Gosslee, M.D. Shelby (1986). Ethylene oxide dose and dose-rate effects
in the mouse dominant-lethal test *Environ Mutagen* 8(1):1-7.

Gilliland, D.G. and J.D. Griffin (2002). The roles of FLT3 in
hematopoiesis and leukemia. *Blood* 100:1532-1542.

Greife, A.L., R.W. Hornung, L.G. Stayner, K.N. Steenland (1988).
Development of a model for use in estimating exposure to ethylene oxide
in a retrospective cohort mortality study. *Scand. J. Work Environ.
Health* 14:29-30.

Hagmar, L., Z. Mikoczy, H. Welinder (1995). Cancer incidence in Swedish
sterilant workers exposed to ethylene oxide. *Occup. Environ. Med.*
52:154-156.

Hagmar, L., H. Welinder, K. Linden, R. Attewall, S. Osterman-Golkar, M.
Tornqvist (1991). An epidemiological study of cancer risk among workers
exposed to ethylene oxide using hemoglobin adducts to validate
environmental exposure assessments. *Int. Arch. Occup. Environ. Health*
63: 271-277.

Hogstedt, L.C. (1988). Epidemiological studies on ethylene oxide and
cancer: an updating. *IARC Sci. Publ*. 89:1575-8.

Hogstedt, C., L. Aringer, A. Gustavsson (1979a). A cohort study of
mortality and cancer incidence in ethylene oxide production workers.
*Br. J. Ind. Med*. 36:276-280.

Hogstedt, C., N. Malmqvist, B. Wadman (1979b). Leukemia in workers
exposed to ethylene oxide*. J. Am. Med. Assoc*. 241:1132-1133.

Hornung, R.W., A.L. Greife, L.G. Stayner, K.N. Steenland, R.F. Herrick,
L.J. Elliot, V.L. Ringenburg, J. Morawetz (1994). Statistical model for
prediction of retrospective exposure to ethylene oxide in an
occupational mortality study. *Am. J. Ind. Med*. 25: 825-836.

IPCS (2003). Ethylene Oxide. Geneva, World Health Organization.
International Program on Chemical Safety, Concise International Chemical
Assessment Document 54, available at
http://www.inchem.org/documents/cicads/cicads/cicad54.htm.

Kanemitsu *et al.* (2005). A Comparative Study of Ethylene Oxide Gas,
Hydrogen Peroxide Gas Plasma, and Low-Temperature Steam Formaldehyde
Sterilization. *Infection Control Hospital Epidemiol.* 26:486-489.

Karelova, J., A. Jablonicka, M. Vargova (1987). Results of cytogenetic
testing of workers exposed to ethylene oxide. *J. Hyg. Epidemiol.
Microbiol. Immunol.* 31:119-126.

Kirman, C.R., L.M. Sweeney, M.E. Meek, M.L. Gargas (2003). Assessing the
dose-dependency of allometric scaling performance using physiologically
based pharmacokinetic modeling. *Reg. Tox. Pharmacol.* 38:345-367.

Kirman, C.R., L.M. Sweeney, M.J. Teta, R.L. Sielken, C. Valdez-Flores,
R.J. Albertini, M.L. Gargas (2004). Addressing nonlinearity in the
exposure-response relationship for a genotoxic carcinogen: cancer
potency estimates for ethylene oxide. *Risk Anal.* 24(5):1165-83.

Kligerman, A.D., G.L. Erexson, M.E., Phelps, J.L. Wilmer (1983).
Sister-chromatid exchange induction in peripheral blood lymphocytes of
rats exposed to ethylene oxide by inhalation. *Mutat.Res.* 120: 37-44.

Koul, *et al.* (1999). Oxalate: From crystal formation to crystal
retention. *J. Am. Soc. Nephrol.* 10, S417-S421.

Lerda D. and R. Rizzi (1992). Cytogenetic study of persons
occupationally exposed to ethylene oxide. *Mutat.Res.* 281: 31-37.

Levine, E.G. and C.D. Bloomfield (1992). Leukemias and myelodysplastic
syndromes secondary to drug, radiation, and environmental exposure.
*Seminars in Oncology* 19:47-84.

Lynch, D.W., T.R. Lewis, W.J. Moorman, J.R. Burg, D.K. Gulati, P. Kaur,
P.S. Sabharwal (1984b). Sister-chromatid exchanges and chromosome
aberrations in lymphocytes from monkeys exposed to ethylene oxide and
propylene oxide by inhalation. *Toxicol. Appl. Pharmacol.* 76: 85-95.

Major, J., M.G. Jakab, A. Tompa (1996). Genotoxicological investigation
of hospital nurses occupationally exposed to ethylene-oxide: I.
Chromosome aberrations, sister-chromatid exchanges, cell cycle kinetics,
and UV-induced DNA synthesis in peripheral blood lymphocytes. *Environ.
Mol. Mutagen.* 27: 84-92.

Major, J., M.G. Jakab, A. Tompa (1999). The frequency of induced
premature centromere division in human populations occupationally
exposed to genotoxic chemicals. *Mutat. Res.* 445: 241-249.

Morgan, R.W., K. Claxton, B. Divine, S. Kaplan, V. Harris (1981).
Mortality among ethylene oxide workers. *J. Occup. Med*. 23:767-770.

Neubauer, A., R.K. Dodge, S.L. George, F.R. Davey, R.T. Silver, C.A.
Schiffer, R.J. Mayer, E.D. Ball, D. Wurster-Hill, C.D. Bloomfield, *et
al*. (1994). Prognostic importance of mutations in the ras
proto-oncogenes in de novo acute myeloid leukemia. *Blood* 83:1603-11.

Nivard, M.J.M., K. Czene, D. Segerback, E.W. Vogel (2003). Mutagenic
activity of ethylene oxide and propylene oxide under XPG proficient and
deficient conditions in relation to N-7-(2-hydroxyalkyl)guanine levels
in Drosophila. *Mutation Res.* 529(1-2):95-107.

Norman, S.A., J.A. Berlin, K.A. Soper, B.F. Middendorf, P.D. Stolley
(1995). Cancer incidence in a group of workers potentially exposed to
ethylene oxide. *Intl. J. Epidemiol.* 24(2):276-284.

Pero, R.W., B. Widegren, B. Hogstedt, and F. Mitelman (1981). In vivo
and in vitro ethylene oxide exposure of human lymphocytes assessed by
chemical stimulation of unscheduled DNA synthesis. *Mutat. Res.* 83:
271-289.

Preston, R.J.. (2003). Personal communication.

Preston, R.J. (1999a). Chromosomal changes. IARC Scientific Publication
No. 146.

Preston, R.J., Fennell T.R., Leber A.P., Sielken R.L., Swenberg J.A.
(1995). Reconsideration of the genetic risk assessment for ethylene
oxide. Environ Mol Mutagen 26:189-202.

Preston, R.J. (1999). Cytogenetic effects of ethylene oxide with an
emphasis on population monitoring. *Crit. Rev in Toxicology* 29(3):
263-282.

Rao, G.N., J. Edmondson, M.R. Elwell (1993). Influence of Dietary
Protein Concentration on Severity of Nephropathy in Fischer-344
(F-344/N) rats. *Toxicol. Pathol*. 21(4): 353-361.

Ribeiro, L.R., M.N. Rabello-Gay, D.M. Salvadori, C.A. Pereira, W. Becak
(1987). Cytogenetic effects of inhaled ethylene oxide in somatic and
germ cells of mice. *Arch. Toxicol.* 59: 332-335.

Ribeiro, L.R., D.M. Salvadori, A.C. Rios, S.L. Costa, A.D. Tates, M.
Tornqvist, A.T. Natarajan (1994). Biological monitoring of workers
occupationally exposed to ethylene oxide. *Mutat. Res.* 313: 81-87.

Richmond, G.W., R.H. Abrahams, J.H. Nemenzo, C.H. Hine (1985). An
evaluation of possible effects on health following exposure to ethylene
oxide. *Arch. Environ. Health* 40:20-25.

Rowley, J.D. (1998). The critical role of chromosome translocations in
human leukemia. *Ann Rev of Genetics* 32: 495-519.

The Sapphire Group (2001). Toxicological Review of Ethylene Oxide.
Prepared on April 6, 2001. Submitted to USEPA IRIS Submission Desk on
April 9, 2001.

Sarto, F., I. Cominato, A.M. Pinton, P.G. Brovedani, C.M. Faccioli, V.
Bianchi, A.G. Levis (1984). Cytogenetic damage in workers exposed to
ethylene oxide. *Mutat. Res.* 138:185-195.

Shore R.E., M.J. Gardner, B. Pannett (1993). Ethylene Oxide: An
Assessment of the Epidemiological Evidence on Carcinogenicity. *Br. J.
Ind. Med.* 50:971-997.

Sisk, S.C., L.J. Pluta, K.G. Meyer, B.C. Wong, L. Recio (1997).
Assessment of the in vivo mutagenicity of ethylene oxide in the tissues
of B6C3F1 lacI transgenic mice following inhalation exposure. *Mutat
Res.* 391:153-164.

Snellings, W.M., *et al.* (1984a). A subchronic inhalation study on the
toxicologic potential of ethylene oxide in B6C3F1 mice. *Toxicol. Appl.
Pharmacol.*, 76:510-518.

Snellings, W.M., R.R. Maronpot, J.P. Zelenak, *et al*. (1982a).
Teratology study in Fischer 344 rats exposed to ethylene oxide by
inhalation. *Toxicol. Appl. Pharmacol.* 64:476-481.

Snellings, W.M., J.P. Zelenak, C.S. Weil (1982b). Effects on
reproduction in Fischer 344 rats exposed to ethylene oxide by inhalation
for one generation. *Toxicol. Appl. Pharmacol.* 63:382-388.

Steenland, K., L. Stayner, J. Deddens (2004). Mortality analysis in a
cohort of 18 235 ethylene oxide exposed workers: follow up extended from
1987 to 1998. *Occup. Environ. Med.* 61:2-7.

Steenland, K., L. Stayner, E. Greife, W. Halperin, R. Hayes, R. Hornung,
S. Nowlin (1991). Mortality among workers exposed to ethylene oxide.
*New England Journal of Medicine* 324(20):1402-1407.

Stefanski, S.A., M.R. Elwell, P.C. Stronmberg (1990). Spleen, lymph
nodes, and thymus. In: Pathology of the Fischer rat. (Ed: Boorman G.A.,
et al.). San Diego, CA: Academic Press.

Stolley, P.D., K.A. Soper, S.M. Galloway, W.W. Nichols, S.A. Norman,
S.R. Wolman (1984). Sister-chromatid exchanges in association with
occupational exposure to ethylene oxide. *Mutat. Res.* 129: 89-102.

Swaen, G.J.W. and P. Van Heerde (1987). Tumors of the hematopoeitic
system. In Pathology of tumors in laboratory animals. Vol 1. Tumors of
the Rats (Ed., Turusov VS). Lyon, France: International Agency for
Research on Cancer.

Tates A.D., P.J. Boogaard, F. Darroudi, A.T. Natarajan, M.E. Caubo, N.J.
van Sittert (1995). Biological effect monitoring in industrial workers
following incidental exposure to high concentrations of ethylene oxide.
*Mutation Res.* 329(1): 63-77.

Tates, A.D., T. Grummt, M. Tornqvist, P.B. Farmer, F.J. van Dam, H. van
Mossel, H.M. Schoemaker, S. Osterman-Golkar, C. Uebel, Y.S. Tang, *et
al*. (1991). Biological and chemical monitoring of occupational exposure
to ethylene oxide. *Mutat. Res.* 250:483-497.

Teta, M.J., R.L. Sielken Jr., C. Valdez-Flores (1999). Ethylene oxide
cancer risk assessment based on epidemiological data: application of
revised regulatory guidelines. *Risk Analysis* 19: 1135-1155.

Teta, M.J., L.O. Benson, J.N. Vitale (1993). Mortality study of ethylene
oxide workers in chemical manufacturing: A 10-year update. *British
Journal Industrial Medicine* 50:704-709.

Thiess, A.M., H. Schwegler, I. Fleig, *et al*. (1981). Mutagenicity
study on workers exposed to alkene oxides (ethylene oxide/propylene
oxide) and derivatives. *J. Occup. Med.* 23: 343-347.

Tyler, T. and J. McKelvey (1980). Dose-dependent disposition of C14
labeled ethylene oxide in rats. Carnegie Mellon Institute of Research,
Pittsburgh, PA.

USEPA (2005). Guidelines for Carcinogen Risk Assessment. Washington, DC:
U.S. Environmental Protection Agency. EPA/630/P-03/001B, available at
http://www.epa.gov/cancerguidelines.

USEPA (1997b). Chemical and radiation leukemogenesis in humans and
rodents and the value of rodent models for assessment risks of
lymphohematopoietic cancers. EPA/600/R-97/090. 1997. Washington, DC,
United States Environmental Protection Agency.

USEPA (1985). Health assessment document for ethylene oxide. Research
Triangle Park, NC: U.S. Environmental Protection Agency. EPA
600/8-84-009F.

van Sittert, N.J., G. de Jong, M.G. Clare, R. Davies, B.J. Dean, L.J.
Wren, A.S. Wright (1985). Cytogenetic, immunological, and haematological
effects in workers in an ethylene oxide manufacturing plant. *British
Journal of Industrial Medicine* 42:19-26.

van Sittert, N.J., P.J. Boogaard, A.T. Natarajan, A.D. Tates, L.G.
Ehrenberg, M.A. Tornqvist (2000). Formation of DNA adducts and induction
of mutagenic effects in rats following 4 weeks inhalation exposure to
ethylene oxide as a basis for cancer risk assessment. *Mutat Res.*
447(1):27-48.

Vogel, E.W., A. Barbin, M.J. Nivard, H.F. Stack, M.D. Waters, P.H.
Lohman (1998). Heritable and cancer risks of exposures to anticancer
drugs: inter-species comparisons of covalent deoxyribonucleic
acid-binding agents. *Mutation Res.* 400(1-2):509-540.

Walker, V.E., T.R. Fennell, P.B. Upton, T.R. Skopek, V. Prevost, D.E.
Shuker, J.A. Swenberg (1992). Molecular dosimetry of ethylene oxide:
formation and persistence of 7-(2-hydroxyethyl) guanine in DNA following
repeated exposures of rats and mice. *Cancer Res.* 52: 4328-4334.

Walker, V.E., S.C. Sisk, P.B. Upton, *et al.* (1997a). *In vivo*
mutagenicity of ethylene oxide at the *hprt* locus in T-lymphocytes of
B6C3F1 *lacI* transgenic mice following inhalation exposure. *Mutation
Res.* 392:211-222.

Walker, V.E., K.Y. Wu, P.B. Upton, A. Ranasinghe, N. Scheller, M.H. Cho,
J.S. Vergnes, T.R. Skopek, J.A. Swenberg (2000). Biomarkers of exposure
and effect as indicators of potential carcinogenic risk arising from in
vivo metabolism of ethylene to ethylene oxide. *Carcinogenesis*
21(9):1661-1669.

Ward, J.M., S. Rehm, C.W. Reynolds (1990). Pathology of tumors in
laboratory animals. Tumors of the rat. Tumors of the haematopoietic
system. *IARC Sci Pub.* 125-57.

Yunis, J.J., A.J. Boot, M.G. Mayer, J.L. Bos (1989). Mechanisms of ras
mutation in myelodysplastic syndrome. *Oncogene* 4:609-14.

**ATTACHMENT 1**[]{#__RefHeading___Toc115771569 .anchor}

## ATTACHMENT 1 {#attachment-1 .unnumbered}

In addition to its concerns with EPA's assessment of ethylene oxide
(EO), the Panel also provides the following comments with regard to
EPA's assessment of ethylene glycol (EG).

## EPA's Reliance upon the Gaunt, et al. (1974) Study, an Old and Flawed Study, Is Scientifically Indefensible When Another Current, Sound [Study, Cruzan, et al. (2004), Is Available]{.underline} 

Put simply, EPA relied upon the wrong EG study, Gaunt *et al.* (1974),
to estimate a subchronic endpoint for EG.[^47] EPA should not perform a
risk assessment on EG based on the Gaunt *et al.* (1974) study, which is
unpublished, old, and significantly flawed. Faults with the Gaunt *et
al.* (1974) study include:

-   Rats were fed a diet with high protein content that is now known to
    adversely affect the kidneys (Rao *et al*., 1993);

-   The report describes clinical signs associated with two different
    infectious diseases for all animals on the study (pneumonia and
    sialodacryoadenitis);

-   Questionable diagnosis was attributed to treatment-related renal
    effects, but findings of chronic progressive nephrosis that normally
    occur in this strain of rat were not separated from the
    treatment-related effects; and

-   Statistical significance for the kidney effects were not obtained
    until the different kidney lesions were combined.

EPA's reliance on the Gaunt *et al.* (1974) study is also of concern
considering that there is a modern peer-reviewed, published study using
the same rat strain, same route of exposure, for the same length of
treatment (Cruzan *et al.,* 2004). The renal pathology of this recent
study was conducted by Dr. Gordon Hard, an internationally known and
leading renal pathologist who has more than 100 publications on renal
pathology. EPA should review and rely upon this study in place of the
outdated and flawed Gaunt *et al*. (1974) study. In addition, a 12-month
chronic study has just been completed.[^48] The NOAEL for both the
subchronic and chronic study is 150 mg/kg. In the chronic study, the
calculated BMDL~05~ is also 150 mg/kg for compound-induced nephropathy.
The Preliminary Risk Assessment section for EG should be based on these
recent studies.

## EPA's Use of the DePass, et al. (1986) Study for EG's Renal Risk Assessment Based Only on the Finding of Calcium Oxalate Crystals in [the Urine Is Scientifically Indefensible]{.underline} 

In the HED Preliminary Risk Assessment section on EG, the DePass *et
al*. (1986) rat study was used incorrectly to determine the NOAEL and
LOAEL doses for combined chronic toxicity.[^49] In this study at the 200
mg/kg dose, calcium oxalate urinary crystals were observed in male rats.
At this dosage, however, there were no treatment-related effects on
water consumption, urine volumes, kidney weights, or kidney
histopathology. The oxalate crystals found in the urine are a normal
consequence of the metabolism of EG and should not be used to determine
the NOAEL and LOAEL. Moreover, since the finding of oxalate crystals in
urine of non-treated rats is normally seen, this finding alone in the
DePass study should not be considered an adverse effect.

The 1989 IRIS Document uses the correct endpoint in the DePass study for
determining the NOAEL and LOAEL.[^50] EPA should not change the
conclusions from the IRIS database for determining the NOAEL and LOAEL
for this strain of rat.

#### 1. EPA Should Not Base the Preliminary Risk Assessment on a Finding of a Metabolite at a Level Below a Threshold for [any Adverse Effects]{.underline}  {#epa-should-not-base-the-preliminary-risk-assessment-on-a-finding-of-a-metabolite-at-a-level-below-a-threshold-for-any-adverse-effects .unnumbered}

It has been noted for EG, and any other chemical that is metabolized,
that at some level and at some interval the metabolites can be detected.
With EG, as with many alcohols, the alcohol (EG) is metabolized to
aldehyde, which is quickly metabolized to acids and then handled by
different pathways. It is also known that at certain levels the alcohol
and acids can normally be found in the urine with no adverse effects.
This is considered a normal physiological event of elimination of the
parent compounds and metabolites. It is also known that calcium, a
normal element found in the body, can combine with oxalic acid, one of
the acid metabolites of EG, at levels below a threshold where no adverse
effects occur. These responses should not be used, nor the findings of
any other metabolites, for establishing a risk assessment when these
metabolites are below a threshold for adverse effect.

These metabolites are considered a part of a normal mechanism for
detoxification. When the level of calcium oxalate is increased and is
found in the kidney tissues above a certain concentration, then adverse
renal effects can occur. This event occurs at a dosage of EG in rats
that is greater than 150 mg/kg, not 40 mg/kg as stated by EPA in the
Preliminary Risk Assessment.

> 2\. EPA Should Not Use the Presence of Crystals in the Urine with No
> Additional Renal Findings, Since Urinary Crystals [Can Be Found in
> Non-Treated Animals]{.underline}

EPA should not use the presence of crystals in the urine with no
additional renal findings. The following observations provide strong
support for recognizing that observations of only crystals in the urine
should not be used to determine the adverse treatment effect level:

-   Urinary calcium oxalate crystals can normally be found in
    non-treated animals with no effects on kidney function or
    histopathology as seen in the DePass *et al*. (1986) control animals
    (one control male at the 12-month sacrifice and four control males
    at the 24-month sacrifice with urinary calcium oxalate crystals).

-   Urinary calcium oxalate crystals were found in one female rat at
    doses 25 times lower than the highest tested dose and in six female
    rats at doses five times lower than the highest dose, but there were
    no treatment-related kidney effects seen for any of the treated
    female rats in the DePass study.

-   Urinary calcium oxalate crystals have been found in more controls
    than just the DePass study. One control rat in the 16-week study by
    Cruzan *et al.* (2004) also had crystals, even though it was a
    healthy, non-treated rat.

Oxalates are normally found in certain foods as shown in Table 1. Oxalic
acid is also a normal metabolite of ascorbic acid and glycine in humans.
In addition, Koul *et al*. (1999) discuss that urinary crystal formation
in humans is normal and that crystal formation is by no means equivalent
to kidney disease, since most of the solid particles crystallizing
within the urinary tract will be excreted freely. They conclude that
uncomplicated crystalluria does not indicate adverse effects on the
kidney.

Table 1. Oxalates Found in Nature

+-----------------------+-----------------------+-----------------------+
| **Food**              | **Level**             | **Reference**         |
+-----------------------+-----------------------+-----------------------+
| Wild edible plants    | 0.4 to 2 g per 100 g  | Guil *et al.* (1996)  |
|                       | of fresh weight       |                       |
+-----------------------+-----------------------+-----------------------+
| Celery (CE), Carrots  | 0.02 g per 100 g      | Trevaskis and Craige  |
| (HPLC)                |                       | (1996)                |
+-----------------------+-----------------------+-----------------------+
| Beetroot              | 0.14 g per 100 g      | Wills *et al.* (1983) |
|                       |                       |                       |
| Rhubarb               | 0.43 g per 100 g      |                       |
|                       |                       |                       |
| Broccoli              | 0.05 g per 100 g      |                       |
|                       |                       |                       |
| Silverbeet            | 0.46 g per 100 g      |                       |
+-----------------------+-----------------------+-----------------------+

> 3\. EPA Should Not Base the Preliminary Risk Assessment on a Finding
> of Only Mild Fatty Changes in the Liver with No [Other Supporting
> Evidence]{.underline}

The Preliminary Risk Assessment states incorrectly that the NOAEL is
also based on mild fatty changes in the female livers. The Preliminary
Risk Assessment should not be based on the observation of only mild
fatty metamorphosis in the liver of one sex at only the 24-month
sacrifice of the DePass study with no other supporting evidence of
adverse effects. Fatty metamorphosis is a common and non-specific
finding in the liver characterized by small- to medium-sized spherical
vacuoles within hepatocyte. While fatty metamorphosis may be indicative
of compromised hepatocellular function, it sometimes results merely from
increased metabolism of fat seen in aging rats.

The following reasons demonstrate why this particular observation should
not be considered an adverse treatment-related effect in this study:

-   There was no supportive evidence of adverse effects based on liver
    organ weight changes or abnormal serum clinical chemistry findings.

-   Increased incidence of fatty metamorphosis was not observed for the
    males at any sacrifice interval.

-   Increased incidence of fatty metamorphosis in the female rats was
    not observed at 6-, 12-, or 18-month sacrifice periods. (Note, at
    the 18-month sacrifice interval there were 20 rats per sex per
    treatment group submitted for histopathology evaluation to better
    address the chronic non-cancer effects from exposure. For fatty
    metamorphosis, the incidence was 1, 0, 1, 1, and 0 rats for the
    1,000 mg/kg, 200 mg/kg, 40 mg/kg, 0 mg/kg (control A), and 0 mg/kg
    (control B), respectively. At the 24-month sacrifice, increases in
    this finding were noted. It is expected at the 24-month sacrifice,
    however, that the background incidence for tumors and age-related
    diseases normally increase, which can affect the general health and
    make the interpretation of non-supportive and non-specific effects
    not meaningful.)

-   Increased incidence of fatty metamorphosis was not observed in the
    2-year NTP mouse study.

There were, therefore, no adverse effect when the calcium oxalate
crystals were reported in the urine of control and 200 mg/kg treated
rats of the DePass study. It is considered a normal metabolic
consequence of EG exposure (below a threshold for adverse effects) or a
consequence of ingestion of a healthy normal diet and should not be used
for risk assessment determination. Likewise, the finding of liver mild
fatty changes alone should not be used for a risk assessment
determination. EPA's 1989 IRIS Document for EG correctly states the
endpoint for determining the NOAEL/LOAEL in a chronic toxicity study. At
a level above 200 mg/kg/day, EG treatment resulted in significant renal
adverse effects. EPA states:

> Confidence in the DePass et al. (1986a) study is rated high because it
> was a well-conducted lifetime study in two species by a relevant route
> and defined a NOAEL and LOAEL. Confidence in the database is also high
> because it contains another chronic rat study and a monkey study that
> support the NOEL and LOAEL from the DePass et al. (1986a) study. It
> also contains data which indicate that the RfD is protective of
> teratogenic and reproductive effects. Confidence in the RfD is
> therefore high.[^51]

Thus, if the DePass *et al*. (1986) study is used for purposes of this
Preliminary Risk Assessment, EPA should use a NOAEL of 200 mg/kg and a
LOAEL of 1,000 mg/kg.

[REFERENCES]{.underline}

Cruzan, G., *et al.* (2004). Subchronic toxicity of ethylene glycol in
Wistar and F-344 Rats related to metabolism and clearance of
metabolites. *Toxicological Sciences* 81:502-511.

DePass, L.R., *et al.* (1986). Chronic toxicity and oncogenicity studies
of ethylene glycol in rats and mice. *Fund. Appl. Toxicol.* 7:566-572.

Gaunt, I.F., J. Hardey, S.D. Gangolli, *et al*. (1974). Short-term
toxicity of monoethylene glycol in the rat. Carshalton, Surrey (UK):
BIBRA International.

Guil, J.L., M. Espernza Torija, J.J. Gimenez, I. Rodriguez-Garcia, A.
Gimenez (1996). Oxalic acid and calcium determination in wild edible
plants. *J Agri Food Chem* 44(7):1821-1823.

Koul, *et al.* (1999). Oxalate: From crystal formation to crystal
retention. *J. Am. Soc. Nephrol.* 10, S417-S421.

Rao, G.N., J. Edmondson, M.R. Elwell (1993). Influence of Dietary
Protein Concentration on Severity of Nephropathy in Fischer-344
(F-344/N) rats. *Toxicol. Pathol*. 21(4): 353-361.

Trevaskis, M. and V. Craige (1996). An investigation into the
determination of oxalic acid in vegetables by capillary electrophoresis.
*Food Chem* 57(2):323-330.

Wills, R.B., J.S. Lim, H. Greenfield, T. Bayliss-Smith (1983). Nutrient
composition of taro (*Colocasia esculenta*) cultivars from the Papua New
Guinea Highlands. *J Sci Food Agric*. 34(10):1137-42.

**ATTACHMENT 2**[]{#__RefHeading___Toc115771570 .anchor}

## ATTACHMENT 2 {#attachment-2 .unnumbered}

##  {#section-1 .unnumbered}

## [Nonlinearity in EO Leukemogenesis]{.underline} {#nonlinearity-in-eo-leukemogenesis .unnumbered}

##  {#section-2 .unnumbered}

## Application of USEPA's Guidelines for Carcinogen Risk Assessment (USEPA, 2005) to a genotoxic carcinogen exhibiting a nonlinear dose-response relationship is complicated, and is likely to be controversial primarily because, in the past, a genotoxic mode of action has required an assumption of linearity at low doses. Despite the fact that ethylene oxide (EO) is a genotoxic carcinogen, there is a growing body of evidence to support that the relationship between exposure and leukemia is nonlinear (The Sapphire Group, 2001; Kirman et al., 2004), which has profound implications on the potential risks to human populations exposed to low doses. Toxicological support (mode of action) and empirical support for a nonlinear dose-response relationship for EO and leukemia are summarized below. {#application-of-usepas-guidelines-for-carcinogen-risk-assessment-usepa-2005-to-a-genotoxic-carcinogen-exhibiting-a-nonlinear-dose-response-relationship-is-complicated-and-is-likely-to-be-controversial-primarily-because-in-the-past-a-genotoxic-mode-of-action-has-required-an-assumption-of-linearity-at-low-doses.-despite-the-fact-that-ethylene-oxide-eo-is-a-genotoxic-carcinogen-there-is-a-growing-body-of-evidence-to-support-that-the-relationship-between-exposure-and-leukemia-is-nonlinear-the-sapphire-group-2001-kirman-et-al.-2004-which-has-profound-implications-on-the-potential-risks-to-human-populations-exposed-to-low-doses.-toxicological-support-mode-of-action-and-empirical-support-for-a-nonlinear-dose-response-relationship-for-eo-and-leukemia-are-summarized-below. .unnumbered}

##  {#section-3 .unnumbered}

## [Toxicological Support for Nonlinearity]{.underline} {#toxicological-support-for-nonlinearity .unnumbered}

Number range CHAPTERA plausible mode of action for EO and leukemia was
developed based upon a consideration of significant information.
Alkylating agents, such as EO, produce chromosomal aberrations almost
exclusively by errors in DNA replication on an adducted template
(Preston, 1999a). It has been established by a large number of studies
that exposure to EO produces chromosomal aberrations in peripheral
lymphocytes in humans (Abrahams, 1980; Pero *et al.*, 1981; Thiess *et
al.*, 1981; Sarto *et al.*, 1984; Stolley *et al.*, 1984; Richmond *et
al.*, 1985; Karelova *et al.*, 1987; Tates *et al.*, 1991; Lerda and
Rizzi, 1992; Ribeiro *et al.*, 1994; Major *et al.*, 1996, 1999).
Chromosomal aberrations in peripheral lymphocytes are not, however, key
events in the production of leukemia for three important reasons:

-   Peripheral blood lymphocytes are not the target cells for leukemia.

-   Strictly speaking, the aberrations observed in human lymphocytes are
    produced *in vitro* rather than *in vivo* as manifestation of DNA
    adducts carried over into culture (Preston, 1999). In culture, the
    lymphocytes are stimulated to proliferate, not allowing time for DNA
    repair, resulting in the observed aberrations, most of which are
    cell lethals. As discussed in detail below, DNA repair is a critical
    factor in EO's genotoxicity (and therefore, its carcinogenicity).

-   As cell lethals, the kinds of *in vitro* events scored in these
    human studies are mostly those without leukemogenic potential.
    Nonetheless, the occurrence of such lesions in lymphocytes indicates
    that EO may produce chromosome level effects of the right kinds in
    target tissues *in vivo* where they may serve as initiating events
    in malignancies, thus serving as useful but indirect triple (cell
    type, *in vitro* occurrence and kind of event) surrogates for the
    true key event in leukemogenesis. The findings for chromosomal
    aberrations in exposed humans are supported by the results of animal
    studies, some of which are scored in bone marrow stem cells
    (considered below) (Embree and Hine, 1975; Lynch *et al.,* 1984b;
    Kligerman *et al.,* 1983; Ribeiro *et al.*, 1987; van Sittert *et
    al.*, 1985).

Specific chromosomal aberrations in target cells are strongly associated
with leukemia in humans, the kind associated with alkylating agent
exposures. These aberrations can be characterized as either interstitial
(internal) deletions or reciprocal translocations, both of which require
two independent "genotoxic hits" for their production. EO also produces
point mutations and small deletions as shown by *in vitro* and *in vivo*
studies (also considered in detail below) (Sisk *et al.*, 1997; van
Sittert *et al.*, 2000). Gene mutations have also been shown to be
important in the pathogenesis of human leukemia with full progression to
disease requiring both the characteristic chromosome aberrations and the
gene mutations (Gilliland and Griffin, 2002). Specific chromosome
aberrations are, therefore, characteristic and necessary changes found
in the chemically-induced leukemias (USEPA, 1997b; Levine and
Bloomfield, 1992; Yunis *et al.,* 1989, Rowley, 1998 and references
therein; Gilliland and Griffin, 2002) with specific oncogene mutations,
*e.g.*, N-*ras,* K-*ras*, FLT3 serving as co-events in full disease
progression (Neubauer *et al.*, 1994; Gilliland and Griffin, 2002).

Based on considerations that: (1) EO causes chromosomal aberrations; (2)
chromosomal aberrations are the characteristic events in chemically
induced acute leukemia, and (3) additional gene mutations are also
important for full expression of disease, the following sequence of
events is proposed as the most plausible mode of action for EO as a
leukemogen:

Event 1: Exposure to EO (external dose, *e.g.,* ppm in air)

Event 2: Distribution of EO to hematopoietic/lymphopoeitic cells

Event 3a: Reaction 1 with DNA (adduct formation), representing one end
of the translocation or deletion

Event 3b: Reaction 2 with DNA (adduct formation) representing the other
end of the translocation or deletion. Reaction 2 occurs close in time to
reaction 1 (*e.g.,* before repair of Reaction 1 and before cell
division), so that adducts produced by both reactions are simultaneously
present during a single wave of DNA replication

Event 4: Error in DNA replication, resulting in translocation or
interstitial deletion that affects a critical gene for
hematopoiesis/lymphopoiesis

Event 5: Viable hematopoietic/lymphopoietic cell containing a
translocation or interstitial deletion that is transmissible to daughter
cells

> Event 6: Progression of disease with the occurrence of gene mutations
> in the same clone that suffered the chromosome aberration, some of
> which may be deletions, for full expression of leukemia

The proposed mode of action for EO outlined above has profound
implications with respect to the shape of the dose-response curve. Based
on physiologically-based pharmacokinetic (PBPK) modeling simulations,
Event 2 is believed to be linearly proportional to dose (Event 1).
Events 3a and 3b, when considered separately, may conservatively be
assumed to be linearly proportional to Event 2 (and therefore to dose),
since saturation of DNA repair becomes an issue in rodents at
concentrations above the point of departure (33 to 100 ppm) (Walker *et
al.*, 1992). Because of the time restriction associated with two
independent events occurring during the same wave of replication,
translocations or deletions (Events 3a and 3b occurring together) are
predicted to be induced at a frequency proportional to the square of the
dose (Preston *et al.*, 1995; Preston, 1999a). Without any specific
information regarding the dynamics of leukemia, Events 4 through 6 are
conservatively assumed to be linearly proportional to Event 3b.
Progression (Event 6) involves other genotoxic events (*e.g.*,
mutations), and can vary considerably in duration for human leukemia.
Some of these mutations, (*e.g.,* the true point mutations), may occur
as single-hit events while others (*e.g.,* the deletion mutations), will
be similar to the specific chromosomal events requiring two-hits. In any
event, these mutations must arise in the same clone of cells
(descendents of the originally affected cell) in which the specific
chromosomal event occurred. Overall, the events leading from EO exposure
to the development of leukemia (and therefore risk) may conservatively
be considered to be proportional to the square of the dose, and,
therefore, use of a nonlinear dose-response model (*e.g.,* quadratic) is
appropriate.

#  {#section-4 .unnumbered}

# [Empirical Support for Nonlinearity]{.underline} {#empirical-support-for-nonlinearity .unnumbered}

Three sources of empirical evidence of nonlinearity in the
exposure-response relationship for EO and leukemia are summarized below.

-   *Epidemiology Exposure-Response Data* - Empirical evidence of
    nonlinearity is obtained from inspection of the plot of the fitted
    rate ratio model and exposure-response data from epidemiology
    studies (Teta *et al.*, 1999; Kirman *et al.*, 2004), which
    demonstrate a substantial change in the slope of the response with
    increasing exposure (**Figure 1**).

-   *Data for Precursor Lesion/Key Event* - Empirical evidence suggests
    a nonlinear relationship between EO exposure and the production of
    chromosome translocations (identified as a key event in human
    leukemogenesis). Evidence can be found in the dose-response curve
    for EO and heritable translocations in mice (**Figure 2**, Generoso
    *et al.*, 1990), also in which a notable increase in the slope of
    the response curve is evident with increasing exposure level.
    Additional support comes from the results of an unpublished study,
    in which a nonlinear relationship was observed for the formation of
    chromosomal aberrations in splenic lymphocytes from mice exposed to
    EO *in vivo*. (Preston, 2003, personal communication). Splenic
    lymphocytes are also continuously replicating, and are more directly
    related to the target tissue for EO cancers in rodents.

-   *Interspecies Concordance* - Empirical evidence suggests improved
    concordance between rodents and humans dose-response data when using
    a quadratic model as compared to using a linear model (**Figure
    3**), which significantly overestimated the risk to human
    populations (Kirman *et al.*, 2004).

    ![](media/image1.wmf){width="9.824305555555556in" height="6.25in"}

    ![](media/image3.wmf){width="9.572916666666666in"
    height="5.749305555555556in"}

    ![](media/image5.wmf){width="9.0in" height="0.8333333333333334in"}

[REFERENCES]{.underline}

Abrahams, R.H. (1980). Recent studies with workers exposed to ethylene
oxide. In: Safe use of ethylene oxide. Proceedings of the Educational
Seminar (ed J. F. Jorkasky) Health Industries Manufacturers Association,
Washington, DC.

Embree, J.W. and C.H. Hine (1975). Mutagenicity of ethylene oxide.
*Toxicol. Appl. Pharmacol.* 33: 172-173.

Generoso, W.M., K.T. Cain, C.V. Cornett, N.L. Cacheiro, L.A. Hughes
(1990). Concentration-response curves for ethylene-oxide-induced
heritable translocations and dominant lethal mutations. *Environ Mol
Mutagen.* 16(2):126-31.

Gilliland, D.G. and J.D. Griffin (2002). The roles of FLT3 in
hematopoiesis and leukemia. *Blood* 100:1532-1542.

Karelova, J., A. Jablonicka, M. Vargova (1987). Results of cytogenetic
testing of workers exposed to ethylene oxide. *J. Hyg. Epidemiol.
Microbiol. Immunol.* 31:119-126.

Kirman, C.R., L.M. Sweeney, M.J. Teta, R.L. Sielken, C. Valdez-Flores,
R.J. Albertini, M.L. Gargas (2004). Addressing nonlinearity in the
exposure-response relationship for a genotoxic carcinogen: cancer
potency estimates for ethylene oxide. *Risk Anal.* 24(5):1165-83.

Kligerman, A.D., G.L. Erexson, M.E., Phelps, J.L. Wilmer (1983).
Sister-chromatid exchange induction in peripheral blood lymphocytes of
rats exposed to ethylene oxide by inhalation. *Mutat.Res.* 120: 37-44.

Lerda D. and R. Rizzi (1992). Cytogenetic study of persons
occupationally exposed to ethylene oxide. *Mutat.Res.* 281: 31-37.

Levine, E.G. and C.D. Bloomfield (1992). Leukemias and myelodysplastic
syndromes secondary to drug, radiation, and environmental exposure.
*Seminars in Oncology* 19:47-84.

Lynch, D.W., T.R. Lewis, W.J. Moorman, J.R. Burg, D.K. Gulati, P. Kaur,
P.S. Sabharwal (1984b). Sister-chromatid exchanges and chromosome
aberrations in lymphocytes from monkeys exposed to ethylene oxide and
propylene oxide by inhalation. *Toxicol. Appl. Pharmacol.* 76: 85-95.

Major, J., M.G. Jakab, A. Tompa (1996). Genotoxicological investigation
of hospital nurses occupationally exposed to ethylene-oxide: I.
Chromosome aberrations, sister-chromatid exchanges, cell cycle kinetics,
and UV-induced DNA synthesis in peripheral blood lymphocytes. *Environ.
Mol. Mutagen.* 27: 84-92.

Major, J., M.G. Jakab, A. Tompa (1999). The frequency of induced
premature centromere division in human populations occupationally
exposed to genotoxic chemicals. *Mutat. Res.* 445: 241-249.

Neubauer, A., R.K. Dodge, S.L. George, F.R. Davey, R.T. Silver, C.A.
Schiffer, R.J. Mayer, E.D. Ball, D. Wurster-Hill, C.D. Bloomfield, *et
al*. (1994). Prognostic importance of mutations in the ras
proto-oncogenes in de novo acute myeloid leukemia. *Blood* 83:1603-11.

Pero, R.W., B. Widegren, B. Hogstedt, and F. Mitelman (1981). In vivo
and in vitro ethylene oxide exposure of human lymphocytes assessed by
chemical stimulation of unscheduled DNA synthesis. *Mutat. Res.* 83:
271-289.

Preston, R.J.. (2003). Personal communication.

Preston, R.J. (1999a). Chromosomal changes. IARC Scientific Publication
No. 146.

Preston, R.J., Fennell T.R., Leber A.P., Sielken R.L., Swenberg J.A.
(1995). Reconsideration of the genetic risk assessment for ethylene
oxide. Environ Mol Mutagen 26:189-202.

Preston, R.J. (1999). Cytogenetic effects of ethylene oxide with an
emphasis on population monitoring. *Crit. Rev in Toxicology* 29(3):
263-282.

Ribeiro, L.R., M.N. Rabello-Gay, D.M. Salvadori, C.A. Pereira, W. Becak
(1987). Cytogenetic effects of inhaled ethylene oxide in somatic and
germ cells of mice. *Arch. Toxicol.* 59: 332-335.

Ribeiro, L.R., D.M. Salvadori, A.C. Rios, S.L. Costa, A.D. Tates, M.
Tornqvist, A.T. Natarajan (1994). Biological monitoring of workers
occupationally exposed to ethylene oxide. *Mutat. Res.* 313: 81-87.

Richmond, G.W., R.H. Abrahams, J.H. Nemenzo, C.H. Hine (1985). An
evaluation of possible effects on health following exposure to ethylene
oxide. *Arch. Environ. Health* 40:20-25.

Rowley, J.D. (1998). The critical role of chromosome translocations in
human leukemia. *Ann Rev of Genetics* 32: 495-519.

The Sapphire Group (2001). Toxicological Review of Ethylene Oxide.
Prepared on April 6, 2001. Submitted to USEPA IRIS Submission Desk on
April 9, 2001.

Sarto, F., I. Cominato, A.M. Pinton, P.G. Brovedani, C.M. Faccioli, V.
Bianchi, A.G. Levis (1984). Cytogenetic damage in workers exposed to
ethylene oxide. *Mutat. Res.* 138:185-195.

Sisk, S.C., L.J. Pluta, K.G. Meyer, B.C. Wong, L. Recio (1997).
Assessment of the in vivo mutagenicity of ethylene oxide in the tissues
of B6C3F1 lacI transgenic mice following inhalation exposure. *Mutat
Res.* 391:153-164.

Stolley, P.D., K.A. Soper, S.M. Galloway, W.W. Nichols, S.A. Norman,
S.R. Wolman (1984). Sister-chromatid exchanges in association with
occupational exposure to ethylene oxide. *Mutat. Res.* 129: 89-102.

Tates, A.D., T. Grummt, M. Tornqvist, P.B. Farmer, F.J. van Dam, H. van
Mossel, H.M. Schoemaker, S. Osterman-Golkar, C. Uebel, Y.S. Tang, *et
al*. (1991). Biological and chemical monitoring of occupational exposure
to ethylene oxide. *Mutat. Res.* 250:483-497.

Teta, M.J., R.L. Sielken Jr., C. Valdez-Flores (1999). Ethylene oxide
cancer risk assessment based on epidemiological data: application of
revised regulatory guidelines. *Risk Analysis* 19: 1135-1155.

Thiess, A.M., H. Schwegler, I. Fleig, *et al*. (1981). Mutagenicity
study on workers exposed to alkene oxides (ethylene oxide/propylene
oxide) and derivatives. *J. Occup. Med.* 23: 343-347.

USEPA (2005). Guidelines for Carcinogen Risk Assessment. Washington, DC:
U.S. Environmental Protection Agency. EPA/630/P-03/001B, available at
http://www.epa.gov/cancerguidelines.

USEPA (1997b). Chemical and radiation leukemogenesis in humans and
rodents and the value of rodent models for assessment risks of
lymphohematopoietic cancers. EPA/600/R-97/090. 1997. Washington, DC,
United States Environmental Protection Agency.

van Sittert, N.J., G. de Jong, M.G. Clare, R. Davies, B.J. Dean, L.J.
Wren, A.S. Wright (1985). Cytogenetic, immunological, and haematological
effects in workers in an ethylene oxide manufacturing plant. *British
Journal of Industrial Medicine* 42:19-26.

van Sittert, N.J., P.J. Boogaard, A.T. Natarajan, A.D. Tates, L.G.
Ehrenberg, M.A. Tornqvist (2000). Formation of DNA adducts and induction
of mutagenic effects in rats following 4 weeks inhalation exposure to
ethylene oxide as a basis for cancer risk assessment. *Mutat Res.*
447(1):27-48.

Walker, V.E., T.R. Fennell, P.B. Upton, T.R. Skopek, V. Prevost, D.E.
Shuker, J.A. Swenberg (1992). Molecular dosimetry of ethylene oxide:
formation and persistence of 7-(2-hydroxyethyl) guanine in DNA following
repeated exposures of rats and mice. *Cancer Res.* 52: 4328-4334.

Yunis, J.J., A.J. Boot, M.G. Mayer, J.L. Bos (1989). Mechanisms of ras
mutation in myelodysplastic syndrome. *Oncogene* 4:609-14.

[^1]: The EO -producing members of the Panel are: Abbott Laboratories;
    ARC; BASF Corporation; Bayer Corporation; Celanese Chemicals, on
    behalf of itself and Old World Industries; The Dow Chemical Company;
    Eastman Chemical Company; Equistar Chemicals LP; Huntsman
    Corporation; Honeywell; Sasol North America, Inc.; Shell Chemical
    LP; and Sunoco, Inc. The Panel is the successor organization to the
    Ethylene Oxide Industry Council (EOIC) of the American Chemistry
    Council.

[^2]: Ethylene Oxide HED Risk Assessment for Reregistration Eligibility
    Document (RED) PC Code No 042301 (July 20, 2005), DP Barcode No.
    D319212 at 6 (HED Preliminary Risk Assessment).

[^3]: Preliminary Occupational Exposure Assessment of the Antimicrobial
    Uses of Ethylene Oxide for the Reregistration Eligibility Decision
    (RED) (July 14, 2005), DP Barcode No. 319378 at 2 (Preliminary
    Occupational Exposure Assessment of Antimicrobial Uses).

[^4]: 69 Fed. Reg. 53916 (Sept. 3, 2004) (announcing meeting to discuss
    AEGLs for EO); AEGL Program, Ethylene Oxide Results, available at
    [http://www.epa.gov/oppt/aegl/
    results15.htm](http://www.epa.gov/oppt/aegl/ results15.htm) (noting
    "Technical Support Document in preparation. Please check back
    later").

[^5]: 70 Fed. Reg. 20807 (Apr. 22, 2005) (noting release of EO Section
    610 Report); *see, e.g.,* Phase 1 Revised Occupational and
    Residential Exposure Assessment and Recommendations for the
    Reregistration Eligibility Decision (RED) for Ethylene Oxide (July
    19, 2005), DP Barcode Nos. 316649, 237240 at 5 (Revised ORE
    Assessment) (noting that the OSHA review "is scheduled to be
    available to the public in 2005").

[^6]: Office of Evaluations and Audit Analysis, OSHA, *Regulatory Review
    of the Occupational Safety and Health Administration's Ethylene
    Oxide Standard \[29 CFR 1910.1047\]* (Section 610 Report) (Mar.
    2005) at ES-3.

[^7]: *Id*.

[^8]: EPA, *Schedule for Reregistration and Tolerance Reassessment*,
    available at http://cfpub.epa.gov/oppref/rereg/status.cfm?show=sched
    (last visited Aug. 2, 2005).

[^9]: *See, e.g.,* Environmental Protection Agency 2005 Annual
    Performance Plan and Congressional Justification at IV-13, IV-32
    through IV-33 ("Additional program requirements and priorities
    within FQPA include: . . . Transparency of our regulatory decisions
    . . . . The Agency has worked extensively with stakeholders through
    the Pesticide Program Dialogue Committee (PPDC) and the Committee to
    Advise on Reassessment and Transition (CARAT) to ensure transparency
    in decision-making and a fuller understanding of the implications
    for growers, producers and the public."), available at
    http://www.epa.gov/ocfo/budget/2005/g04final.pdf; *see also* EPA's
    Office of Science Policy Update (Feb. 2004) at 1 ("'The public
    launch of the Science Inventory is another example of open,
    transparent government,' said Steve Johnson"), available at
    http://www.epa.gov/osp/recent/0402qrt.pdf; Office of Environmental
    Information FY2003 Program and Highlights (Oct. 2003) at 7 ("Quality
    and transparent information is critical to EPA's ability to make
    sound decisions."), available at
    http://www.epa.gov/oei/pdf/OEI_FY03_Accomplishments_Report.pdf.

[^10]: Ensuring that the data relied on in the risk assessments are
    available quickly also would be consistent with the EPA Directive,
    which specifically sets aggressive timelines for making toxicity
    studies relied on in the risk assessments available to the public.
    *See* Memorandum to Stephen L. Johnson, Acting Assistant
    Administrator, OPPTS, from Christine Todd Whitman, Administrator
    (Mar. 19, 2001) at 3-4 (EPA Directive), available at
    http://www.epa.gov/oppfead1/cb/csb_page/updates/directive3-20.pdf.

[^11]: EPA, *Guidelines for Ensuring and Maximizing the Quality,
    Objectivity, Utility, and Integrity, of Information Disseminated by
    the Environmental Protection Agency* (Oct. 2002) at 10, available at
    http://www.epa.gov/quality/informationguidelines/documents/
    EPA_InfoQualityGuidelines.pdf.

[^12]: 40 C.F.R. § 152.112(b). *See also* 21 U.S.C. § 346a(b)(2)(D)
    (Section 408(b)(2)(D) of the Federal Food, Drug, and Cosmetic Act
    (FFDCA), as amended by the Food Quality Protection Act (FQPA), the
    controlling authority for the EO Risk Assessment regarding dietary
    exposure, requires that EPA consider, among other relevant factors,
    "(i) the validity, completeness, and reliability of the available
    data from studies of the pesticide chemical and pesticide chemical
    residue; (ii) the nature of any toxic effect shown to be caused by
    the pesticide chemical . . . in such studies; \[and\] (iii)
    available information concerning the relationship of the results of
    such studies to human risk").

[^13]: 49 Fed. Reg. 30884, 30902 (Aug. 1, 1984).

[^14]: *See, e.g.,* EPA, *General Principles for Performing Aggregate
    Exposure and Risk Assessments* (Nov. 28, 2001) at 58, available at
    [http://www.epa.gov/pesticides/trac/
    science/aggregate/pdf](http://www.epa.gov/pesticides/trac/ science/aggregate/pdf).
    ("Transparency in environmental decision-making, clarity in
    communication, consistency in core assumptions and science policies
    from case to case, and reasonableness are important elements of risk
    characterization"); EPA, U.S. Environmental Protection Agency Fiscal
    Year 2000 Annual Report (Mar. 2001) at cover letter and Report at
    II-32 (EPA will use "the best available science in the review of new
    and existing pesticides" and base its "policies and decisions on
    sound science and meaningful peer review").

[^15]: *Western States Petroleum Ass'n v. EPA* , 87 F.3d 280, 284 (9th
    Cir. 1996) ("EPA 'may not depart, sub silento, from its usual rules
    of decision to reach a different, unexplained result in a single
    case.'") (citation omitted); *Northwest Airlines, Inc. v. U.S. Dep't
    of Transp.*, 15 F.3d 1112, 1121 (D.C. Cir. 1994) ("An agency should
    not gloss over or swerve away from prior precedent without
    discussion."); *Japan Air Lines Co., et al. v. Dole*, 801 F.2d 483,
    486 (D.C. Cir. 1986), *cert. denied*, 480 U.S. 917 (1987)
    ("\[T\]here exists a presumption against unexplained changes in
    agency interpretations"); *Lucas v. Hodges*, 730 F.2d 1493, 1504
    n.20 (D.C. Cir. 1984) ("it is a familiar principle of federal
    administrative law that agencies may be bound by their own
    substantive and procedural rules and policies, whether or not
    published in the Federal Register, if they are intended as
    mandatory"), *vacated as moot*, 738 F.2d 1392 (D.C. Cir. 1984);
    *National Conservative* *Political Action Comm. v. FEC*, 626 F.2d
    953, 959 (D.C. Cir. 1980) ("Agencies are under an obligation to
    follow their own regulations, procedures, and precedents, or provide
    a rational explanation for their departures."); *Greater Boston
    Television Corp. v. FCC,* 444 F.2d 841, 852 (D.C. Cir. 1970), *cert.
    denied*, 403 U.S. 923 (1971) (footnote omitted) ("\[A\]n agency
    changing its course must supply a reasoned analysis indicating that
    prior policies and standards are being deliberately changed, not
    casually ignored, and if an agency glosses over or swerves from
    prior precedents without discussion it may cross the line from the
    tolerably terse to the intolerably mute").

[^16]: *See Retail Store Employees Union, Local 880, R.C.I.A. v. FCC*,
    436 F.2d 248, 254 (D.C. Cir. 1970) (citations omitted); *see also
    Sierra Club v. Interstate Commerce Comm'n*, 1978 U.S. App. LEXIS
    12538 (D.C. Cir. 1978).

[^17]: *See*,
    [http://docket.epa.gov/edkpub/do/EDKStaffItemDetailView?objectId=090007d48090
    f74e](http://docket.epa.gov/edkpub/do/EDKStaffItemDetailView?objectId=090007d48090f74e).

[^18]: *See, e.g., Grossman v. Axelrod*, 466 F. Supp. 770, 775 (S.D.N.Y.
    1979), *aff'd,* 646 F.2d 768 (2d Cir. 1981); *Synthetic Organic
    Chem. Mfrs. Ass'n v. Brennan*, 506 F.2d 385, 388-89 (3d Cir. 1974),
    *cert. denied sub nom., Oil, Chem. & Atomic Workers Int\'l Union v.
    Dunlop*, 423 U.S. 830 (1975) (Court remanded standards to the
    Department of Labor where the Department did not give interested
    parties adequate time to comment because it published a proposed
    rule before the advisory committee submitted its final report on the
    rule); *see also Chemical Waste Management, Inc. v. EPA*, 976 F.2d
    2, 28 (D.C. Cir. 1992), *cert. denied sub nom., Chemical Mfrs.
    Ass\'n v. EPA*, 507 U.S. 1057 (1993); *Florida Power & Light Co. v.
    United States*, 846 F.2d 765, 771 (D.C. Cir. 1988), *cert. denied,*
    490 U.S. 1045 (1989) (agency must "provide sufficient factual detail
    and rationale for the rule to permit interested parties to comment
    meaningfully"); *Horsehead Resource Dev. Co. v. Browner*, 16 F.3d
    1246, 1267-68 (D.C. Cir. 1994), *cert. denied sub nom., Cement Kiln
    Recycling Coalition v. Browner*, 513 U.S. 816 (1994).

[^19]: A RED, like a final rule, constitutes final agency action under
    the APA and clearly impacts a registrant's legal rights and
    obligations. *See* Order Denying Motion to Dismiss at 10-11, *United
    Farmworkers of America v. U.S. EPA*, (W.D. Wa. 2005) (No.
    C04-099RSM); *New York v. U.S. EPA,* 350 F. Supp. 2d 429, 435
    (S.D.N.Y. 2004) (EPA determination announced in a RED constitutes
    final agency action regardless of whether it results in a change in
    regulation).

[^20]: 5 U.S.C. §§ 551, 553 (setting forth notice and comment framework
    and procedural conditions).

[^21]: *Guidelines for Ensuring and Maximizing the Quality, Objectivity,
    Utility, and Integrity, of Information Disseminated by the
    Environmental Protection Agency* at 10.

[^22]: Moreover, Congress enacted the IQA to ensure the consistency and
    quality of information disseminated by federal agencies. IQA
    requires the Office of Management and Budget (OMB) to develop
    government-wide guidelines, to "provide policy and procedural
    guidance to Federal agencies for ensuring and maximizing the
    quality, objectivity, utility, and integrity of information
    (including statistical information) disseminated by Federal
    agencies." 67 Fed. Reg. 369 (Jan. 3, 2002). Another integral part of
    OMB's information quality assurance initiative is its "Final
    Information Quality Bulletin for Peer Review," which establishes
    peer review principles for federal agencies government-wide. OMB,
    "Issuance of OMB's Final Information Quality Bulletin for Peer
    Review" (Dec. 16, 2004), available at
    [http://www.whitehouse.gov/omb/memoranda/
    fy2005/m05-03.pdf](http://www.whitehouse.gov/omb/memoranda/ fy2005/m05-03.pdf).

[^23]: *Wellford v. Ruckelshaus*, 439 F.2d 598, 602 (D.C. Cir. 1971)
    ("We are troubled by the possibility that the Secretary failed to
    give petitioner's allegations \[made in a petition to suspend use of
    a pesticide\] the careful consideration to which they were entitled
    . . ."); *EDF v. Hardin*, 428 F.2d 1093, 1100 (D.C. Cir. 1970)
    (court directed EPA to provide detailed explanation for failure to
    take action to suspend DDT in face of "impressive evidence presented
    by petitioners"); *Public Citizen Health Research Group v. Tyson*,
    796 F.2d 1479, 1497, 1507 (D.C. Cir. 1986) (court remanded case to
    the Occupational Safety and Health Administration (OSHA) for failure
    to set short-term exposure limits (STEL) on grounds that OSHA's
    deliberations on this issue were incomplete and OSHA had "entirely
    failed to consider an important aspect of the problem . . ."); *see
    also Olenhouse v. Commodity Credit Corp*., 42 F.3d 1560, 1583 (10th
    Cir. 1994), *citing Garvey v. Freeman*, 397 F.2d 600, 612 (10th Cir.
    1968)*; Gulf S. Insulation v. CPSC*, 701 F.2d 1137, 1146 (5th Cir.
    1983) (Consumer Product Safety Commission\'s (CPSC) exclusive
    reliance on a rat study was inadequate to support its rule where the
    Commission failed to consider a body of available epidemiology
    studies)*; Love v. Thomas*, 858 F.2d 1347, 1358-1363 (9th Cir. 1988)
    (EPA's decision to suspend the use of the pesticide dinoseb was
    arbitrary and capricious, an abuse of discretion, and not in
    accordance with FIFRA because EPA failed to evaluate information in
    its possession about potentially disastrous and unique impacts of
    the suspension on agriculture in the Pacific Northwest), *cert.
    denied sub nom., AFL-CIO v. Love*, 490 U.S. 1035 (1989).

[^24]: HED Preliminary Risk Assessment at 6, 52, 67.

[^25]: HED Preliminary Risk Assessment at 54.

[^26]: In fact, this paper was awarded *Outstanding Published Paper
    Demonstrating an Application of Risk Assessment* by the Risk
    Assessment Specialty Section of the Society of Toxicology at their
    annual meeting in New Orleans, LA, March, 2005.

[^27]: Concentrations corresponding to an acceptable risk range
    (1x10^-6^ to 1x10^-4^) may be up to 100 times higher than those
    presented in Table 1.

[^28]: Ratios corresponding to an acceptable risk range (1x10^-6^ to
    1x10^-4^) may be up to 100 times higher than those presented in
    Table 1.

[^29]: HED Preliminary Risk Assessment at 54.

[^30]: USEPA (2005) at 2-3, available at
    <http://www.epa.gov/cancerguidelines> ("When human data of high
    quality and adequate statistical power are available, they are
    generally preferable over animal data and should be given greater
    weight in hazard characterization and dose-response assessment,
    although both can be used").

[^31]: HED Preliminary Risk Assessment at 44; Revised ORE Assessment at
    4 (Table 1).

[^32]: Subchronic Inhalation Neurotoxicity Study DER (Apr. 7, 2005) at
    5.

[^33]: HED Preliminary Risk Assessment at 53.

[^34]: Revised ORE Assessment at 4 (Table 1).

[^35]: *Id*.

[^36]: Preliminary Occupational Exposure Assessment of the Antimicrobial
    Uses at 6.

[^37]: HED Preliminary Risk Assessment at 66.

[^38]: United Kingdom, Health and Safety Executive, Table 1: List of
    approved workplace exposure limits, available at
    <http://www.hse.gov.uk/coshh/table1.pdf>.

[^39]: Preliminary Occupational Exposure Assessment of the Antimicrobial
    Uses at 7.

[^40]: *Id*. at 8.

[^41]: Preliminary Occupational Exposure Assessment of the Antimicrobial
    Uses at 3.

[^42]: EPA Memorandum, *Summary of Benefits of Ethylene Oxide Uses and
    Evaluation of Alternatives* (Jan. 17, 1996) at 1.

[^43]: OSHA 610 Report at II-5.

[^44]: *Summary of Benefits of Ethylene Oxide Uses and Evaluation of
    Alternatives* at 1-2.

[^45]: Kanemitsu, *et al.* (2005) at 489 ("Our results suggest that
    PLASMA methods may be inadequate for sterilizing complex
    instruments, especially those with long, narrow lumens that cannot
    be properly washed prior to sterilization").

[^46]: In addition to the grave potential consequences to public health
    with the release of an erroneous risk assessment, substantial
    business losses could occur due to the unfounded fears that could
    arise among customers, applicators, and consumers who rely on EPA's
    statements \-- albeit couched in terms of a "draft" or "revised"
    risk assessment about EO. As EPA knows well, any suggestion by EPA
    that a product poses a health problem has far-reaching consequences,
    all of them adverse to the product. These misapprehensions could
    result in product deselection, *i.e*., the choice of potentially
    less effective alternative products by current and prospective EO
    customers.

[^47]: HED Preliminary Risk Assessment at 26 (Table 8b); Revised
    Occupational and Residential Exposure Assessment at 3 (Table 1).

[^48]: American Chemistry Council Report, ETHYLENE GLYCOL: 12-Month
    Dietary Toxicity Study In Wistar Han Rats, Study ID 031079 (June 8,
    2005).

[^49]: HED Preliminary Risk Assessment at 26 (Table 8b).

[^50]: EPA, IRIS Entry for Ethylene Glycol (last revised Sept. 1, 1989),
    available at <http://www.epa.gov/iris/subst/0238.htm>.

[^51]: 1989 IRIS Document at Section I.A.5.