„¦ v UNITED STATES ENVIRONMENTAL PROTECTION AGENCY
I ML t WASHINGTON, D.C. 20460
V&l
OFFICE OF
CHEMICAL SAFETY AND
POLLUTION PREVENTION
May 1,2020
Memorandum
SUBJECT: Transmittal of Meeting Minutes and Final Report for the TSCA Science Advisory
Committee on Chemicals Carbon Tetrachloride Meeting held February 25-26, 2020
TO:
FROM:
THRU:
Yvette Reyes Collazo, MS
Director
Office of Pollution, Prevention and Toxics
Tamue Gibson, MS
Designated Federal Official
TSCA Science Advisory Committee on Chemicals
Office of Science Coordination and Policy
Steven Knott, MS
Executive Secretary
TSCA Science Advisory Committee on Chemicals
Office of Science Coordination and Policy
STEVEN
KNOTT
Digitally signed by
STEVEN KNOTT
Date: 2020.05.01
15:13:15 -04'00'
Hayley Hughes, DrPH, MPH, CSP H AYLEY
Director
Office of Science Coordination and Policy HUGH ES
Digitally signed by HAYLEY
HUGHES
Date: 2020.05,01 15:53:25
-04'00'
Please find attached the meeting minutes and final report for the TSCA Science Advisory Committee on
Chemicals open public meeting held in Arlington, Virginia on February 25-26, 2020. This report
addresses a set of scientific issues being considered by the Environmental Protection Agency regarding the
Peer Review for the Draft Risk Evaluation for Carbon Tetrachloride.
Attachment
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cc:
Alexandra Dunn
David Fischer
Yvette Reyes Collazo
TalaHenry
Mark Hartman
Sheila Canavan
Stanley Bar one
Karen Eisenreich
Doritza Pagan-Rodriguez
OPPT Docket
TSCA Scientific Advisory Committee on Chemicals
Kenneth Portier, PhD
Henry Anderson, MD
Charles Barton, PhD
Steven Bennett, PhD
Sheri Blystone, PhD
James Bruckner, PhD
Deborah Cory-Slechta, PhD
Holly Davies, PhD
William Doucette, PhD
Kathleen Gilbert, PhD (Retired)
Conception Jimenez-Gonzalez, PhD
Mark Johnson, PhD
John Kissel, PhD (Retired)
Ruthann Rudel, MS
Daniel Schlenk, PhD
ISCAJSACC Ad Hoc Peer Remama
George P. Cobb III, PhD
Kenny Crump, PhD
David A. Eastmond, PhD
Laura Green, PhD
Maria Morandi, PhD
Emanuela Taioli, MD, PhD
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TSCA Science Advisory Committee on Chemicals
Meeting Minutes and Final Report
No. 2020-03
Peer Review for the United States
Environmental Protection Agency (EPA)
Draft Risk Evaluation for
Carbon Tetrachloride
February 25-26, 2020
TSCA Science Advisory Committee on Chemicals
Meeting
Held At
Holiday Inn Rosslyn, At Key Bridge
1900 Fort Myer Drive
Arlington, Virginia 22209
Page 1 of 96
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NOTICE
The Toxic Substances Control Act (TSCA) Science Advisory Committee on Chemicals (SACC)
is a Federal advisory committee operating in accordance with the Federal Advisory Committee
Act and established under the provisions of TSCA as amended by the Frank R. Lautenberg
Chemical Safety for the 21st Century Act of 2016. The TSCA SACC provides independent
advice and recommendations to the U.S. Environmental Protection Agency (EPA or Agency) on
the scientific basis for risk assessments, methodologies, and pollution prevention measures and
approaches for chemicals regulated under the Toxic Substances Control Act (TSCA). The SACC
serves as a primary scientific peer review mechanism of the EPA, Office of Pollution Prevention
and Toxics (OPPT), and is structured to provide balanced expert assessment of chemicals and
chemical-related matters facing the Agency. Additional peer reviewers are considered and from
time-to-time added on an ad hoc basis to assist in reviews conducted by the TSCA SACC. This
document constitutes the meeting minutes and final report and is provided as part of the activities
of the TSCA SACC.
The TSCA SACC carefully considered all information provided and presented by the Agency, as
well as information presented by the public. The minutes represent the views and
recommendations of the TSCA SACC and do not necessarily represent the views and policies of
the Agency, nor of other agencies in the Executive Branch of the Federal government. Mention
of trade names or commercial products does not constitute an endorsement or recommendation
for use.
The meeting minutes and final report do not create or confer legal rights or impose any legally
binding requirements on the Agency or any party. The meeting minutes and final report of the
February 25-26, 2020, TSCA SACC meeting represent the SACC's consideration and review of
scientific issues associated with "Peer Review for EPA Draft Risk Evaluation of
Carbon Tetrachloride." Steven Knott, MS, TSCA SACC Executive Secretary, reviewed the
minutes and final report. Kenneth Portier, PhD, TSCA SACC Chair, and Tamue Gibson, MS,
TSCA SACC Designated Federal Official, certified the minutes and final report. The report is
publicly available on the SACC website (https://vvvvvv.epa.gov/lsca-peer-revievv) under the
heading of "Meetings" and in the public e-docket, Docket No. EPA-HQ-OPPT-2019-0499,
accessible through the docket portal: https://www.regulations.gov. Further information about
TSCA SACC reports and activities can be obtained from its website at:
https://www.epa.gov/tsca-peer-review. Interested persons are invited to contact Tamue Gibson,
MS, SACC Designated Federal Official, via e-mail at eibson.tamue@epa.eov.
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TABLE OF CONTENTS
NOTICE 2
PARTICIPANTS 6
LIST OF ACRONYMS AND ABBREVIATIONS 9
INTRODUCTION 11
PUBLIC COMMENTERS 11
EXECUTIVE SUMMARY 13
Charge Question 1. - Environmental Fate and Exposure 18
Response Q 1.1- Characterization of exposure to aquatic receptors 18
Charge Question 2. - Environmental Hazard and Risk Characterization 26
Response Q 2.1 - Environmental Hazard and Risk Characterization 26
Charge Question 3. - Occupational Exposure and Releases 31
Response Q 3.1 - Exposure of Workers and ONU 31
Response Q 3.2 - Validity/Transparency of ONU Exposure 33
Response Q 3.3 - Alternatives approaches/data for workplace exposure assessment 34
Response Q 3.4- Dermal exposure assumptions 36
Response Q 3.5- Strengths/confidence in occupational exposure scenarios 37
Charge Question 4. - Human Health Effects 37
Response Q 4.1-Human health hazards 38
Response Q 4.2-Rationale for tumor used in cancer dose-response 44
Response Q 4.3-Low dose extrapolation approaches 50
Response Q 4.4- Dermal PODs and extrapolating CSF 52
Charge Question 5. - Risk Characterization 55
Response Q 5.1- Support for risk characterization 55
Response Q 5.2- Characterization of uncertainties and assumptions 59
Response Q 5.3- Specific confidence summaries in section 4.5 60
Response Q 5.4- Objectivity of data supporting risk characterization and sensitivity of
conclusions 61
Response Q 5.5- Other aspects of the human health risk characterization 62
Response Q 5.6- Has risk characterization adequately addressed PESS 63
Response Q 5.7- Has RA adequately described uncertainties and data limitations 64
Response Q 5.8- Reasoning, approach, assumptions and uncertainties for risk to working
using PPE 65
Charge Question 6. - Content and Organization 66
Response Q 6.1- Suggestions for improving clarity of the Evaluation 66
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Response Q 6.2- The Evaluation narrative objective, balanced and supportive 74
Response Q 6.3- Quality of data appropriate for purposes 77
Committee Response Q 6.4- Transparently documented uncertainties and assumptions .... 80
Response Q 6.5- Sensitivity of risk characterization conclusions to assumptions 81
EDITORIAL NOTES 82
REFERENCES 83
FIGURES
Figure 1: PRISMA 2009 Flow Diagram, from PRISMA web site 47
TABLES
Table 1: Dermal parameters recommended for inclusion in the current and future
TSCA RISK EVALUATIONS 22
Table 2: Example format for reporting epidemiologic studies 49
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TSCA Science Advisory Committee on Chemicals
Meeting Minutes and Final Report
No. 2020-03
Peer Review for the United States
Environmental Protection Agency (EPA)
Draft Risk Evaluation for
Carbon Tetrachloride
February 25-26, 2020
TSCA Science Advisory Committee on Chemicals
Meeting
Held At
Holiday Inn Rosslyn, At Key Bridge
1900 Fort Myer Drive
Arlington, Virginia 22209
Tamu&£ibson, MS '
Designated Federal Official
TSCA Science Advisory
Committee on Chemicals
Date
Page 5 of 96
[enneth Portier, PhD
TSCA SACC, Chair
TSCA Science Advisory
Committee on Chemicals
Date;
AW /, o
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Toxic Substances Control Act
Science Advisory Committee on Chemicals Meeting
February 25-26, 2020
Peer Review for EPA Draft Risk Evaluation of
Carbon Tetrachloride
PARTICIPANTS
TSCA SACC. Chair
Kenneth Portier, PhD
Consulting Biostatistician
Athens, Georgia
Designated Federal Official
Tamue Gibson, MS
TSCA Science Advisory Committee on Chemicals Staff
Office of Science Coordination and Policy, EPA
Washington, District of Columbia
TSCA Science Advisory Committee 011 Chemicals Members
Charles Barton, PhD
Independent Consultant
Alpharetta, Georgia
Steven Bennett, PhD
Household & Commercial Products Association
Washington, District of Columbia
Sheri Blystone, PhD
SNF Holding Company
Riceboro, Georgia
James Bruckner, PhD
University of Georgia
Athens, Georgia
Deborah Cory-Slechta, PhD
Department of Environmental Medicine
University of Rochester School of Medicine & Dentistry
Rochester, New York
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Holly Davies, PhD
Washington State Department of Health
Turn water, Washington
William Doucette, PhD
Utah State University
Logan, Utah
Kathleen Gilbert, PhD (Retired)
University of Arkansas for Medical Sciences
Little Rock, Arkansas and
Colorado State University
Fort Collins, Colorado
Concepcion (Conchita) Jimenez-Gonzalez, PhD
Environment, Health, Safety and Sustainability
GlaxoSmithKline
Research Triangle Park, North Carolina
Mark Johnson, PhD
US Army Public Health Center
Aberdeen Proving Ground, Maryland
John Kissel, PhD (Retired)
University of Washington
Seattle, Washington
Ruthann Rudel, MS
Silent Spring Institute
Newton, Massachusetts
Daniel Schlenk, PhD
University of California, Riverside
Riverside, California
TSCA SACC Ad Hoc Peer Reviewers
George P. Cobb III, PhD
Department of Environmental Science
Baylor University
Waco, Texas
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Kenny Crump, PhD
Independent Consultant
Ruston, Louisiana
David A. Eastmond, PhD
Department of Molecular, Cell and Systems Biology
University of California, Riverside
Riverside, California
Laura Green, PhD
Green Toxicology LLC
Brookline, Massachusetts
Maria Morandi, PhD
Independent Consultant
Houston, Texas
Emanuela Taioli, MD, PhD
Institute for Translational Epidemiology
Icahn Medical Institute
New York, New York
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LIST OF ACRONYMS AND ABBREVIATIONS
AEGL
Acute Exposure Guideline Level
AF
Adjustment Factor
BDL
Below Detection Limit
BMD
Benchmark Dose
BMDL
Benchmark Dose Level
BMR
Benchmark Risk
CAA
Clean Air Act
CARB
California Air Resources Board
CDC
Centers for Disease Control
CDR
Chemical Reporting Period
CI
Confidence Intervals
CNS
Central Nervous System
coc
Concentration of Concern
cou
Conditions of Use
CPSC
Consumer Product Safety Commission
CWA
Clean Water Act
DMR
Discharge Monitoring Reports
DNA
Deoxyribonucleic Acid
DPMA
Dipropylene Glycol Methyl Ether Acetate
DSF
Dermal Carcinogenic Slope Factor
EDTA
Ethylenediaminetetraacetic Acid
E-FAST
Exposure and Fate Assessment Screening Tool
EPI-Suite
Estimation Program Interface Suite
GI
Gastrointestinal
GPF
Glove Protection Factor
GSH
Hepatic Glutathione
GWAS
Genome-Wide Association Studies
H&E
Haematoxylin and Eosin
HEC
Human Equivalent Concentrations
HED
Human Equivalent Dose
HESI
Health and Environmental Sciences Institute
HFO
Hydrofluoroolefins
HSIA
Halogenated Solvent Industry Alliance
IP
Intraperitoneal
IRIS
Integrated Risk Information System
IUR
Inhalation Unit Risk
JBRC
Japan Bioassay Research Center
Koc
Organic Carbon Normalized Sorption Coefficient
LADD
Lifetime Average Daily Dose
LC10
Lethal Concentration Dose of 10% of the Exposed Population
LOAEL
Lowest Observed Adverse Effect Level
MCI
Molecular Connectivity Indices
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MO A Mode of Action
MOE Margin of Exposure
MRL Maximum Residue Limit
ND Non-Detections
NHANES National Health and Nutrition Examination Survey
NIOSH National Institute for Occupational Safety and Health
NOAA National Oceanic and Atmospheric Administration
NOAEL No Observed Adverse Effect Level
NPDES National Pollutant Discharge Elimination System
NTP National Toxicology Program
ONU Occupational Non-User
OSHA Occupational Safety and Health Administration
PCE Perchloroethylene
PDM Probabilistic Dilution Model
PEL Permissible Exposure Limit
PESS Potentially Exposed or Susceptible Subpopulations
POD Point of Departure
PPE Personal Protective Equipment
QPPR Quantitative Property-Property Relationship
QSAR Quantitative Structure Activity Relationship
QSPR Quantitative Structure Property Relationship
RCRA Resource Conservation and Recovery Act
RIVM Rijksinstituut voor Volksgezondheid en Milieu (National Institute for Public Health
and the Environment, Netherlands)
RQ Risk Quotients
SACC Science Advisory Committee on Chemicals
SDWA Safe Drinking Water Act
SNAP Significant New Alternatives Policy
TRI Toxic Release Inventory
TRV Toxicity Reference Value
TSCA Toxic Substances Control Act
TWA Time Weighted Average
UF Uncertainty Factor
UFa Interspecies Uncertainty Factor
UFh Intraspecies Uncertainty Factor
UFi LOAEL to NOAEL Uncertainty Factor
UFt Total Uncertainty Factor
VOC Volatile Organic Compounds
WOE Weight of Evidence
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INTRODUCTION
The Toxic Substances Control Act (TSCA) of 1976, as amended by The Frank R. Lautenberg
Chemical Safety for the 21st Century Act in 2016, Science Advisory Committee on Chemicals
(SACC) completed its review of the set of scientific issues being considered by the
Environmental Protection Agency (EPA) regarding the Draft Risk Evaluation for carbon
tetrachloride. The Draft Risk Evaluation (Evaluation), supplemental files, and related documents
in support of the SACC peer review meeting are posted in the public e-docket at
https://www.regulations.gov (ID: EPA-HQ-OPPT-2019-0499). The initial notice of availability
of the Draft Risk Evaluation, opening the docket for comments, and notice of meeting was
published in the Federal Register on January 27, 2020 (85 FR 4658). The review was conducted
in an open Committee meeting held in Arlington, Virginia, on February 25-26, 2020. Dr.
Kenneth Portier chaired the meeting. Tamue Gibson, MS, served as the Designated Federal
Official.
In preparing these meeting minutes and final report, the Committee carefully considered all
information provided and presented by the Agency presenters, as well as information presented
by public commenters. These meeting minutes and final report address the information provided
and presented at the meeting, especially the Committee response to the Agency charge.
The U.S. EPA presentation was provided during the TSCA SACC meeting by the following
(listed in order of presentation):
February 25-26, 2020:
Opening of Meeting - Tamue Gibson, MS, Designated Federal Official, EPA/Office of
Science Coordination and Policy (OSCP)
Introduction and Identification of SACC Members - Kenneth Portier, PhD, TSCA Science
Advisory Committee on Chemicals (SACC), Chair
Introduction and Welcome - Sheila Canavan, Acting Director, Risk Assessment Division
(RAD), Office of Pollution, Prevention and Toxics (OPPT), Office of Chemical Safety and
Pollution Prevention, EPA
OPPT Technical Presentation - Overview of Carbon Tetrachloride Risk Evaluation -
Doritza Pagan-Rodriguez, PhD, Toxicologist, RAD/OPPT/EPA
PUBLIC COMMENTERS
Oral statements were presented by:
Jennifer Sass, PhD, Natural Resources Defense Council
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Tracey Woodruff, PhD, University of California, San Francisco
Robert Sussman, Safer Chemicals Healthy Families
James Bus, PhD, Exponent
Jonathan Kalmuss-Katz, JD, EarthJustice
Kathrene Garcia, Environmental Investigation Agency
Suzanne Hartigan, PhD, American Chemistry Council
Written statements were provided by:
Jonathan Kalmuss-Katz, JD, EarthJustice
Richard Denison, PhD, Environmental Defense Fund
Kathrene Garcia, Christina Starr, and Avipsa Mahapatra, Environmental Investigation
Agency
Christopher Bevan, PhD, Halogenated Solvents Industry Alliance, Inc.
Michelle Roos, Environmental Protection Network
Robert Sussman, Safer Chemicals Healthy Families
Suzanne Hartigan, PhD, American Chemistry Council
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EXECUTIVE SUMMARY
The TSCA Science Advisory Committee on Chemicals (the Committee) responded to a
series of question on the Draft Risk Evaluation (the Evaluation) for Carbon Tetrachloride
as follows:
Charge Question 1 - Environmental Fate and Exposure
The Committee suggested that the Evaluation should provide additional rationale and procedural
detail for any decision to exclude non-aqueous media from the Evaluation. As in prior draft risk
evaluations for other chemicals, there are cases for which the justification for the exclusion of
one non-aqueous phase contradicts the exclusion of another. For example, the problem
formulation indicated that carbon tetrachloride was found in biosolids. This suggests that carbon
tetrachloride will likely sorb to sediments, contradicting statements in the Evaluation that any
carbon tetrachloride discharged into streams rapidly distributes into air. The Evaluation indicates
that carbon tetrachloride released into the atmosphere will rapidly degrade in the stratosphere.
However, carbon tetrachloride is very stable in the troposphere and the movement to the
stratosphere is an extremely slow process making it unlikely that tropospheric concentrations
will be reduced over the short term.
As discussed in reviews of other chemical risk evaluations, it is still not clear when a log Koc
(organic carbon normalized sorption coefficient) value is low enough to ignore sorption, and
when a Henry's Law constant is high enough to ignore all but volatilization. In addition, all
physical-chemical property values have some variability associated with them even if measured
using standard or high-quality measurement methods. The impacts of these uncertainties should
be considered in the conceptual model for environmental releases and in the environmental fate
models used to provide the estimated aquatic exposure concentrations. The Committee also
suggested adding several parameters to the physical-chemical properties table including more
that relate directly to dermal permeability.
Several Committee members indicated that complete biodegradation of carbon tetrachloride was
unlikely to occur under most environmental conditions and that the Agency should include some
discussion of the potential formation and the environmental fate of the transformation products.
Some Committee members were concerned about the lack of environmental monitoring data for
carbon tetrachloride especially given the apparent trend in increasing carbon tetrachloride
releases to the environment. A mass balance approach is recommended to estimate carbon
tetrachloride discharges to the environment that are not captured in the databases such as the
Toxics Release Inventory (TRI) to make sure important exposures are addressed. Mass balance
estimated discharges could be used along with environmental fate models to supplement the
limited monitoring data.
Charge Question 2. - Environmental Hazard and Risk Characterization
The Committee indicated that the Evaluation does not support the conclusions that expected
environmental concentrations are below hazard thresholds for aquatic species. Conservative
values are not used to assess either exposure or hazard threshold for aquatic species. Mean values
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for exposure were compared to rounded values of higher concentration threshold and do not
include adequate safety factors given the uncertainty of the estimates.
The Committee recommended evaluating degradation products of carbon tetrachloride and
conducting risk evaluations for terrestrial organisms and endangered species. The Evaluation
needs greater specificity in describing risks based on what is and is not assessed.
Charge Question 3. - Occupational Exposure and Releases
Many aspects of this evaluation are like prior chemical risk evaluations reviewed by the
Committee. The Committee viewed the expanded discussion of personal protective equipment
(PPE) practices as an improvement, although it did not lead to changes in risk calculations. The
Evaluation is generally transparent (due in part to its similarity to prior documents), but frequent
referrals to supplemental documents imposes a burden on readers. The Committee made some
specific recommendations to improve clarity and also made recommendations to aggregate
exposures and reconsider assumptions regarding the efficacy and efficiency of PPE. Reporting of
ambient air concentrations was of value in providing perspective on worker and Occupational
non-user (ONU) exposures. The tabulation of uncertainties in this Evaluation is supported, but
the Committee suggested that exposure route uncertainties be segregated.
Charge Question 4. - Human Health Effects
The Committee noted that the Evaluation fails to acknowledge the long study history of the
toxicity of carbon tetrachloride, which dates back at least 80 years. The Evaluation should note
that it has long been known that carbon tetrachloride is toxic to the liver and kidney, in both
laboratory rodent studies and in humans overexposed in occupational settings in decades past.
Carbon tetrachloride has been repeatedly shown to be carcinogenic to the liver of rodents and is
likely carcinogenic to the liver of humans as well, although epidemiologic studies of carbon
tetrachloride-exposed workers have not demonstrated this.
The Committee remarked that because of the widespread and long-standing knowledge of
toxicity from overexposures to carbon tetrachloride, current exposure-levels in the U.S. are a
small fraction of what they were prior to the middle of the 20th century. The Evaluation fails to
make this simple but important point. The remarkable persistence of carbon tetrachloride in
ambient air means that all of us are exposed to small, sub-part per billion concentration levels;
but the vastly larger exposures (measured in parts per million) that once occurred in some U.S.
workplaces no longer occur.
The Committee observed that information provided in the Evaluation is, at times, too limited to
assess the adequacy of animal and human health effects data. The description of carbon
tetrachloride toxicokinetics, metabolic activation, and factors influencing toxicity and
carcinogenicity potential should be expanded. This should include discussion on how exposure
routes influence systemic disposition and effects, and the immunotoxicity potential of carbon
tetrachloride.
The specific molecular and cellular mechanisms through which carbon tetrachloride exerts its
toxicity is known. There is little information that carbon tetrachloride directly causes
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deoxyribonucleic acid (DNA) damage or mutations but acts via a variety of indirect mechanisms
involving oxidation, lipid peroxidation, cytotoxicity, inflammation, cellular proliferation, and
inefficient DNA repair. Some Committee members recommended that the EPA address and
incorporate information on endocrine effects of carbon tetrachloride, as well as its
spermatotoxicity and immunotoxicity potential.
The derivations of the points of departure and inhalation unit risk estimate require more detail. A
simple but critical mathematical error resulted in a 100-fold underestimate of risks for the dermal
route of exposure. The inhalation unit risk estimate is adopted, without critical evaluation,
directly from the Integrated Risk Information System (IRIS) (2010) and the Committee felt that
this bears careful reappraisal. The Committee recommended that the EPA thoroughly consider
the extensive body of data supporting a threshold mode of action (MO A) in estimating cancer
risks. It was noted there was more limited evidence of a similar MOA for carbon tetrachloride.-
induced adrenal tumors. The Committee endorsed use of additional uncertainty factors due to
database uncertainties for adrenal and brain tumors.
Charge Question 5. - Risk Characterization
Some Committee members expressed concern that the rationale for ignoring pathways for
terrestrial organisms was cursory. Simply noting that this is under the purview of other agencies
or offices of EPA was insufficient in their opinion.
The Committee discussed linear low-dose extrapolation and non-linear or threshold dose-
response modeling, and the implications of these approaches for human health risk assessment.
Some Committee members questioned the scientific basis for the manner in which both the linear
approach and the non-linear approach were melded into a single risk model for quantifying low
dose risk. The argument made in the Evaluation in support of using a linear extrapolation to
assess the low dose risk from carbon tetrachloride is not that the dose-response was linear, but
that the dose-response was not sufficiently well understood to rule out a low-dose linear
component. Some Committee members agreed with this, while others suggested that the well-
established MOA for this chemical and its free radical metabolites argue for a non-linear
threshold-type dose-response model approach. Another Committee member stressed that carbon
tetrachloride is the most well-studied and well-understood of all chlorinated organic compounds
with regard to organ toxicity and carcinogenicity, such that the claim that its MOA has been
insufficiently characterized is unsupported.
There was robust discussion of uncertainty factors used in the human health risk characterization.
The Committee recommended that the basis for setting the interspecies uncertainty factor (UFa)
and the intraspecies uncertainty factor (UFh) be included in the document with appropriate
discussion. Other evidence-based assessments of the risks to human health (from both non-
cancer and cancer-effects alike) from plausible occupational exposures to carbon tetrachloride,
such as have been conducted by the German MAK working group (Maximale
Arbeitsplatzkonzentration: maximum workplace concentration), should be discussed and
considered as an improvement upon IRIS (2010), on which the Evaluation currently depends.
The Evaluation expresses low confidence in the risk estimates for dermal exposure, and the
Committee agreed with that assessment. The Evaluation concludes that the conservative
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assumptions used to derive points of departure (PODs) are likely to result in risk overestimates.
Several Committee members, considering the results observed in the Wahlberg and Boman
(1979) skin-painting study using guinea pigs, reiterated the importance of not underestimating
these risks. The underestimation of risk due to miss-calculating the PODs for acute occluded and
non-occluded dermal exposures need to be addressed before assessing whether the risks from
dermal exposure are over- or underestimated.
A wide-ranging discussion on potentially exposed and susceptible subpopulations (PESS)
included the potential need to account for other effects, such as developmental neurotoxicity,
immune effects, sperm function/morphology, and testicular toxicology, particularly in male
workers of childbearing age. The committee recommended that the embryo and fetus (in
pregnant female workers) should be considered a PESS based on the neuroblastoma risk.
Individuals with hereditary hemochromatosis, an autosomal recessive disorder that affects about
one in 200 to 500 individuals should also be included in PESS because of their sensitivity to the
oxidative and peroxidative damage caused by exposure to carbon tetrachloride.
The Committee discussed whether the baseline environmental exposure of workers who live and
work in areas with higher background concentrations of carbon tetrachloride make them at
greater risk for carbon tetrachloride toxicity. Individuals evaluated for their risk to carbon
tetrachloride toxicity at work may already have a baseline environmental exposure that should be
factored into the risk evaluation.
Charge Question 6. - Content and Organization
The Committee is more familiar with the TSCA risk evaluation process and documentation and
as a result is better able to make recommendations to the EPA on ways to improve both the
content and organization of the current and future TSCA chemical risk evaluations. In addition,
the Committee continued to provide suggestions on how best to identify what information should
be in the body of the report, what should be in appendices and what should be in separate
supplemental documents. This issue is important in improving readability and transparency. The
Evaluation should provide more specific information about relevance of other legislation that
affects management of risks from carbon tetrachloride, and the specifics of environmental or
human health risks that are addressed by this other legislation and by other organizations. In
addition, the Committee made several recommendations to improve the systematic review
process.
While familiar with the current organization of the Evaluation, many Committee members
continued to advocate a report structure that has exposure, hazard and risk characterization
discussions under major sections for environment, human health and PESS. This restructuring is
argued to reduce repetition of discussion and to improve readability and flow.
The Committee identified several terms, such as "benchmark" and "surrogate COU" (conditions
of use) that should be carefully defined and/or used within restricted conditions. Several
situations occur where doses to rodents are not clearly distinguished from human equivalent
doses.
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The discussion on PPE and its effectiveness is much improved from previous draft chemical risk
evaluations and there is more emphasis on risk characterization estimates without assuming PPE
use. This Evaluation uses monitoring data from surrogate COUs to help assess exposures and
risk to other COUs. The Evaluation needs to ensure that the COU and its surrogate do not have
hugely different associated levels of uncertainty. It needs to also better describe the engineering
controls and worker activities associated with a COU and compare to their surrogate COU to
ensure they are not widely different.
The Committee has, in previous reviews, discussed the factors that need to be considered when
assessing the quality of data used for the risk evaluation. With respect to exposures, evaluations
continue to focus on the intrinsic quality of the data (i.e., whether exposure sampling and
analytical methods were appropriate and fully reported) as the single criteria for acceptability,
and this is important. The evaluations also need to focus on whether the amount of data available
is adequate to derive reliable estimates of exposures for occupational scenarios in a COU. Data
uncertainties and gaps that have implications on the quality of the Evaluation, primarily in the
exposure side of the risk evaluation, are also discussed, and recommendations were made for
improvement. The Committee recommended that the Agency consider scoring data and
assumption uncertainty and to utilize those scores to derive a final confidence score.
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PI T A 11 I I) COMMITTEE DISCUSSION AND RECOMMENDATIONS
As amended by the Frank R. Lautenberg Chemical Safety for the 21st Century Act on June 22,
2016, the Toxic Substances Control Act (TSCA) requires the U.S. Environmental Protection
Agency (EPA or Agency) to conduct risk evaluations on existing chemicals. In response to this
requirement, EPA has prepared and published a Draft Risk Evaluation for carbon tetrachloride.
The Risk Evaluation process is the second step, following Prioritization and before Risk
Management, in EPA's existing chemical process under TSCA. The purpose of risk evaluation is
to determine whether a chemical substance presents an unreasonable risk to health or the
environment, under the conditions of use, including an unreasonable risk to a relevant potentially
exposed or susceptible subpopulation. As part of this process, EPA must evaluate both hazard
and exposure, exclude consideration of costs or other non-risk factors, use scientific information
and approaches in a manner that is consistent with the requirements in TSCA for the best
available science, and ensure decisions are based on the weight-of-scientific-evidence. The draft
risk evaluation for carbon tetrachloride is the seventh to undergo a peer review by the TSCA
Science Advisory Committee on Chemicals (SACC).
Charge Question 1. - Environmental Fate and Exposure
Question 1. The environmental fate of carbon tetrachloride is characterized by partitioning to
the atmosphere, surface water and groundwater. Carbon tetrachloride in surface water is
expected to volatilize and diffuse upwardly in the troposphere, with a half-life greater than 330
years. Ultimate diffusion to the stratosphere leads to photodegradation. Carbon tetrachloride
has a low bioaccumulation potential and when in groundwater is expected to anaerobically
biodegrade. EPA did not further analyze the environmental fate of carbon tetrachloride as
indicated by the conceptual models in the problem formulation.
/'lease conmieiil on l/ie da/a. aj>/>roac/ies and or methods used lo characterize
exposure lo ai/iiaiic receptors.
Response Q 1.1- Characterization of exposure to aquatic receptors.
The Committee recognized the enormity of the task assigned to the Agency and commends those
that diligently worked to compile and analyze the environmental and human health data needed
to develop the TSCA draft risk evaluations. Relative to draft risk evaluations previously
reviewed, Committee members agreed that the environmental fate and exposure discussion
continues to be refined. However, the Committee continued to identify areas that need
improvement:
Recommendation 1: Improve the justifications/documentation for excluding non-aqueous
media from consideration.
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As with previous draft risk evaluations, the Committee agreed that releases to non-aqueous
phases should also be considered or, at a minimum, provide additional rationale and procedural
detail for any decision to exclude non-aqueous media from the Evaluation. The Committee
recommended that the Evaluation specifically reference the environmental discharges and
pathways that were addressed by other regulations by including hyperlinks, or a similar approach
that would direct the reader to the relevant regulations and documentation. This would allow the
Committee to make sure that their concerns are being adequately addressed by other regulatory
mechanisms.
For example, on page 21 of the Evaluation, it states:
"As explained in section 2.5.3.2 of the problem formulation (U.S. EPA, 759 2018d),
exposure to terrestrial organisms was removed from the scope of the evaluation. This
exposure pathway is considered to be covered under programs of other environmental
statutes, administered by EPA, which adequately assess and effectively manage
exposures and for which long-standing regulatory and analytical processes already exist."
Links to the specific environmental programs and statutes should be provided.
Similarly on Page 51, the Evaluation states:
"During problem formulation EPA determined that carbon tetrachloride present in
various media pathways (i.e., air, water, land) fall under the jurisdiction of existing
regulatory programs and associated analytical processes carried out under other EPA-
administered statutes and that these existing programs and processes adequately assess
and effectively manage the exposures (see section 2.5.3.2 of the problem formulation
document) (U.S. EPA, 2018d)."
Therefore, these exposure pathways were excluded from the scope of this risk evaluation, and
terrestrial environmental exposure data were not analyzed as part of this risk evaluation. Again,
links to the specific environmental programs and statutes and how those regulations will address
terrestrial risk should be provided.
Recommendation 2: Be consistent and better define how physical chemical properties and
terminology are used to justify the exclusion of various environmental fate processes and
distributions.
There continues to be cases where the justification for exclusion of one non-aqueous phase
contradicts the exclusion of another. For example, the problem formulation (U.S. EPA 2018b)
indicates that carbon tetrachloride was identified in the biosolids biennial reviews and that the
biosolids pathway for carbon tetrachloride is currently being addressed in the Clean Water Act
(CWA) regulatory analytical process. If carbon tetrachloride is found in biosolids, this indicates
that it will sorb to environmental solids. This also suggests that if water containing carbon
tetrachloride is discharged into streams, carbon tetrachloride is likely to be found in sediments.
Thus, stating that carbon tetrachloride discharged into streams rapidly distributes into air cannot
be supported without monitoring data or a dynamic stream contaminant model that can predict
the distribution to water, air and sediment.
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A related issue mentioned by several Committee members involves the definition of low
sorption. On page 47, the Evaluation states that"... the Koc could be approximately one order of
magnitude larger than predicted by EPI Suite™ before sorption would be expected to
significantly impact the mobility of carbon tetrachloride in groundwater." No reference is
provided to support this statement. As discussed in previous meetings, it is not clear what range
of log Koc values delineates low sorption. When is the log Koc of a compound low enough to
justify excluding sorption to sediment and assessing the impact to sediment dwelling organisms?
Similarly, when is a Henry's law constant high enough to ignore all other fate processes but
volatilization? If environmental monitoring data are limited or unavailable, several committee
members again suggested the need to consistently use an appropriate environmental fate model
(maybe something similar to fugacity level 3) with realistic inputs (emissions to water and air) to
determine when a log Koc value is low enough to ignore sorption to sediment and a Henry's law
constant is high enough to ignore all but volatilization.
Incorrect terminology continues to be used despite corrections provided by the Committee for
several previous draft risk evaluations. On page 25, line 299 of the Evaluation, carbon
tetrachloride is referred to as moderately miscible. Miscible is defined as completely soluble in a
solvent at all proportions (i.e., ethanol and water are miscible). A compound is either miscible in
water (or other solvent) or not. It can't be partially miscible. Another example is on page 25, line
297, where it is stated that carbon tetrachloride is expected to volatilize based on its high vapor
pressure (115 mm Hg at 25°C). Vapor pressure is related to intermolecular interactions (i.e.,
carbon tetrachloride to carbon tetrachloride interactions). Volatilization in the environment
depends on interactions between carbon tetrachloride molecules and the environmental phases it
is in contact with (i.e., carbon tetrachloride to water to soil interactions) along with
environmental conditions like temperature and wind speed. A more thorough review of the
document would catch these relatively simple but distracting mistakes.
Recommendation 3: Better define the quality and variability associated with physical-
chemical properties.
Most physical-chemical properties are obtained from compilations or secondary sources and it is
not clear how the individual properties within a compilation were evaluated for quality. There is
also no indication of variability associated with any of the physical-chemical properties listed in
Table 1-1 of the Evaluation. Any physical-chemical property measurement has some variability
associated with it even if standard or high-quality measurement methods were used. It is not
clear how these uncertainties in physical-chemical properties would impact the conceptual model
for environmental releases and the environmental fate models (i.e., Exposure and Fate
Assessment Screening Tool (E-FAST)) used to provide the aquatic exposure concentration
estimates.
As mentioned by the Committee in the previous review of the methylene chloride draft risk
evaluation, the experimental values obtained from the database contained within EPA's
Estimated Program Interface Suite (EPI-Suite) program and the estimated values derived from
routines within the program were considered to be high quality during the systematic review
process but several Committee members expressed concern that the values lack information
regarding variability or uncertainty that could impact the significance of some of the conceptual
pathways. The Committee suggested that the discussion on data quality assessment and
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variability for the properties obtained from EPI-Suite and other references should be expanded.
Committee members noted that the procedures used for assessing acceptability were much more
well defined for toxicology studies than fate studies and it would be helpful if there was a better
description of how the quality of the physical-chemical and fate properties are assessed. In
addition, several Committee members suggested estimating confidence intervals (CI) around
each property and conducting a sensitivity analysis to determine if potential variability would
significantly change the outcome of the qualitative pathway analysis.
Experimental values of physical-chemical or fate properties are generally considered more
reliable than estimated methods unless there are some obvious procedural or analytical problems.
The accuracy of an estimated property value varies depending on the estimation method used and
how well the compound fits within the method's domain of applicability. When more than one
estimation method is available within EPI-Suite, the rationale for selecting one estimation
method over another should be provided. Instead of assigning high quality to all values estimated
within EPI-Suite, members of the committee indicated that it would be more appropriate to rank
the values based on the reliability of the estimation method. For example, quantitative property-
property relationships (QPPRs) are generally more reliable than quantitative structure property
relationships (QSPRs). For properties estimated using EPI-Suite, the Committee recommended
specifically stating the estimation method that was used since several of the physical-chemical
and fate properties can be estimated by more than one approach. For example, the Koc can be
estimated from octanol-water partition coefficients or from structurally derived molecular
connectivity indices (MCIs).
The Committee also suggested several dermal parameters be included in the table of physical-
chemical properties or be included as a separate table in the Evaluation document. These dermal
parameters are presented in Table 1.
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Table 1: Dermal parameters recommended for inclusion in the current and future TSCA risk
evaluations.
Parameter
Symbol
Typical
Units
Description
Rationale
Reference
Aqueous permeability
coefficient
kp,sc/w
cm/h
Predictor of
permeability of stratum
corneum from aqueous
vehicle
Method previously
accepted by USEPA
USEPA RAGS Part E,
2004
Aqueous permeability
coefficient
kp,sc/w
cm/h
Predictor of
permeability of stratum
corneum from aqueous
vehicle
Alternative to RAGS
Part E method
NIOSH CIB61, 2009
Relative permeability
of the stratum
corneum to that of the
viable epidermis
B
H
Indicator of potential
error if resistance in
viable epidermis is
ignored
Cleek & Bunge,
1993
Theoretical maximum
steady-state flux
Jss,max
|jg/cm2-h
Product of aqueous
permeability coefficient
and aqueous solubility
Maximal sustainable
absorption rate
Ratio of evaporation
flux to absorption flux
C
H
Evaporation
competes with
absorption for
volatile compounds
Kasting & Miller,
2006
Octanol/air partition
coefficient
Ko/a
H
2-phase partition
coefficient at
thermodynamic
equilibrium
Analog to
octanol/water
partition coefficient
used to estimate Ksc/g
Stratum corneum/gas
partition coefficient
Ksc/g
[L/kg]
2-phase partition
coefficient at
thermodynamic
equilibrium
Key determinant of
vapor to skin
pathway
Weschler &
Nazaroff, 2014
Dermal vapor to
inhalation dose ratio,
modeled
D/lmodeled
H
Indicator of potential
error if dermal
uptake from vapor is
ignored
Weschler &
Nazaroff, 2014
Dermal vapor to
inhalation dose ratio,
measured
D/lmeasured
H
Check on D/Im0deied
Weschler &
Nazaroff, 2014
Observed absorption
flux
J
|jg/cm2-h
In vitro or in vivo
human, or in vivo
rodent data if available
Check on J ss, max;
especially important
if exposure is to pure
compound rather
than dilute aqueous
solution
Recommendation 4: Discuss the uncertainty associated with estimated exposures to aquatic
organisms by the lack of monitoring data.
As mentioned in the previous reviews, Committee members were concerned about the lack of
environmental monitoring data for carbon tetrachloride but could identify only one additional,
readily available source of data (U.S. EPA, 1977) other than state required monitoring data for
publicly owned wastewater treatment facilities.
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Monitoring has been performed by the Agency to determine chlorinated solvent concentrations
in water, air, soil, and sediment near industrial facilities (U.S. EPA, 1977). Data from those
studies show carbon tetrachloride concentrations in water downstream of five facilities. The 92nd
and 75th percentiles of those aqueous concentrations were 629 and 67 (J,g/L, respectively. These
concentrations are higher than any 20-day estimate from the E-FAST estimation and over 10
times higher than 95th percentile of the 20-day predictions reported in the Evaluation. Data from
this study are considered in other TSCA risk evaluations, and thus should be included in this
Evaluation, if for no other reason than to justify using higher centile E-FAST estimates, rather
than the currently used average.
Committee members were also concerned about the apparent trend in increasing carbon
tetrachloride releases to the environment as indicated by the following points.
Point 1: From the problem formulation document (U.S. EPA 2018b), 142,582,067 lbs produced
(Table 2-4, Production Volume of Carbon Tetrachloride in Chemical Data Reporting
(CDR) Reporting Period (2012 to 2015)) and 26,940,648 lbs. production related waste
(Table 2-6, Summary of Carbon Tetrachloride TRI Production-Related Waste Managed
in 2015 (lbs), 18.9% of production in waste stream) with 151,690 lbs (0.008%) in
releases with 68.6% to air, 0.03% to water, and 31.3% to land, "little under 500 pounds
were released to water" (EPA 2018b, page 33). By 2018, releases are estimated at
252,000 lbs (Evaluation, page 50) of which 69.8% to air, 0.08% to water and 30% to
land, with about 2,000 lbs to water. This indicates that water releases are increasing in
both quantity and fraction of total releases.
Point 2: Use and releases of carbon tetrachloride in the US are going up despite regulatory
pressure to reduce its use (Table 1-2). According to the 2015 National Air Toxics
Inventory, ambient air monitoring trends from 2003 to 2013 have shown that carbon
tetrachloride average concentrations have slightly increased in the atmosphere over the
10-year period.
Point 3: The number of major facilities with water releases is increasing: Of 21 facilities listed in
the Evaluation, Table E-l Releases to Water, 11 listed no discharges prior to 2017.
Table E-l does not list ALL facilities reporting carbon tetrachloride releases, only the
21 facilities with largest releases. A histogram (or estimated probability distribution
curve) of annual releases from all 49 facilities reporting releases would be very useful
in understanding the larger picture of releases.
Point 4: The pattern of water releases from known facilities is variable, but a number show
increasing trends. The largest discharger, AKZO Chemicals Inc. has gone from 56 lbs
to 700 lbs of water releases in five years. Some sites vary from zero lbs of releases one
year, to 79 lbs the following year. Two other facilities show gradual increases. A
number were stable. Only two facilities report decreasing releases.
Point 5: Accidental releases are not considered in TSCA evaluations. It is interesting to note that
Table E-l lists a 300+ lbs release from one of the 21 facilities in 2014 and another 14
lbs spill from another facility in 2015. It is difficult to know when spikes in releases
may be the result of an accidental spill. How many "spills" per year occur in the
population of 49 facilities? If one per year is the average, then the analysis of releases
should factor in one such release per year.
Point 6: It is possible for smaller companies to manufacture/import/use slightly less than 10,000
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lbs of carbon tetrachloride and dispose of all of this without having to report anything
to the TRI. Facilities are required to provide TRI reports if they manufacture (including
import) or process more than 25,000 lbs of carbon tetrachloride, or if they otherwise
use more than 10,000 lbs of carbon tetrachloride. Monitoring indicated carbon
tetrachloride was in national surface waters. As noted in the Evaluation, roughly 25%
or 163 of the 650 drinking water systems that had detects of carbon tetrachloride
greater than 0.5 [j,g/L (the maximum residue level (MRL)) came from surface water
sources.
Point 7: Removal mechanisms (i.e., biodegradation, photolysis in the troposphere) are likely too
slow to prevent environmental concentrations of carbon tetrachloride from increasing
based on the current trend of increasing inputs into the environment.
In summary, it seems that releases to water (wastewaters included) are increasing and the actual
amounts released to waters are uncertain. While use of carbon tetrachloride in consumer products
has decreased dramatically or has been eliminated, levels of use in commercial products is on the
increase. Future releases, while uncertain, and expected to increase from current levels unless
regulatory action is taken.
Recommendation 5: Include discussion of metabolic pathways and environmental breakdown
products.
Committee members acknowledged that complete biodegradation to carbon dioxide and chloride
might occur under specific environmental conditions (anaerobic conditions with appropriate
microbial community). However, not all groundwater and sediments are anaerobic. Soils above
groundwater are also likely to be aerobic. Carbon tetrachloride contamination of groundwater is
widespread suggesting rapid biodegradation is not occurring. Several Committee members
indicated that complete biodegradation (mineralization) was unlikely to occur under most
environmental conditions and that the Agency should include some discussion of the potential
formation and the environmental fate of the transformation products including chloroform,
methylene chloride, methyl chloride and phosgene. The flow map by EAWAG Tripp, et al.,
2020) entitled The Carbon Tetrachloride Graphical Pathway Map: Formation and the
Environmental Fate of the Transformation Products: Chloroform, Methylene Chloride, Methyl
Choride and Phosgene1 is an example of one such flow diagram.
Recommendation 6: Include a mass balance assessment of carbon tetrachloride released to
the environment.
Several Committee members recommended using a table of the amounts of carbon tetrachloride
manufactured/imported in the U.S., as well as amounts used in processes/products, released to
the environment or recycled (a mass balance table) in the U.S. This approach allows for better
estimation of those carbon tetrachloride discharges to the environment that are not captured in
the databases such as the TRI. It also ensures that these important exposures are addressed. The
table could be constructed for totals for any convenient timeframe, such as one year, five years or
a decade.
1 See http://eawag-bbci.efhz.cli/ctc/cto image map.html
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The COU discussion in the Evaluation notes that carbon tetrachloride is used as a feedstock in
the production of hydrochlorofluorocarbons (HCFCs), hydrofluorocarbons (HFCs),
hydrofluoroolefins (HFOs) and perchloroethylene (PCE: multiple locations). Additionally, the
Evaluation notes that the production of the hydrofluorocarbons HFC-245fa and HFC-365mfc
accounted for 71% and 23%, respectively, of total carbon tetrachloride consumption in 2016
(Evaluation, page 73). Separately, HFC-245fa and HFC-365mfc are being phased out as part of
the EPA's Significant New Alternatives Policy (SNAP) program and the feedstock usage for this
COU would be expected to decrease significantly. There is no discussion of how much feedstock
usage for manufacture of PCE or HFO is incorporated into the Evaluation. Given the timing of
the phasedowns, changes in production volume should be evident in the next CDR reporting
cycle or other reporting required of carbon tetrachloride under other authorities. Given these
observations, the Committee recommended that a mass-balance accounting of the COU should
be incorporated to better account for existing uses.
Mass balance estimated discharges could be used along with environmental fate models like the
Fugacity level 3 model to supplement limited monitoring data.
Moreover, given the relatively long aerobic half-life of carbon tetrachloride, if continual
discharge is occurring, then a "pseudo-persistent" scenario would occur negating the necessity of
high bioaccumulation rates, because exposure to aquatic life would be on-going and not require
trophic transfer or bioaccumulation.1
Recommendation 7: Add more discussion on the impact of more atmospheric input and long
tropospheric half-lives on ozone depletion.
The risk characterization indicates that carbon tetrachloride is released into the atmosphere and
rapidly degrades in the stratosphere (Evaluation, page 137: line 4437). However, more
importantly, as it was mentioned in EPA's verbal presentation to the Committee, carbon
tetrachloride is very stable in the troposphere and that the movement to the stratosphere is an
extremely slow process and is unlikely to significantly reduce tropospheric concentrations over
the short term. This was also supported by information provided in the problem formulation
document on page 34, which states:
"According to the 2015 National Air Toxics Inventory, ambient air monitoring trends
from 2003 to 2013 have shown that of the eight Hazardous Air Pollutants (HAPs)
monitored, only carbon tetrachloride average concentrations have slightly increased in
the atmosphere over the 10-year period. This is likely primarily due to its extremely long
half-life in the troposphere (U.S. EPA, 2015a)."
This contradicted other statements within the Evaluation that carbon tetrachloride diffusion into
the stratosphere is an important removal mechanism. The impact of carbon tetrachloride as an
ozone depleting substance in the stratosphere should also be further discussed. One Committee
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member cited the SPARC Report on carbon tetrachloride as a source for more information on
impacts.2
Recommendation 8: Add discussion, citations, or data to better support the assertion of de
minimis exposures.
The assertion of de minimis exposures is not adequately supported by citations or data
(Evaluation, page 30, lines 1062-1103). It's difficult to demonstrate the no use assertion. The
assertion of "no use" is weakened in the Evaluation by the admission that "carbon tetrachloride
may be present in a limited number of industrial products with chlorinated ingredients at a
concentration of less than 0.003% by weight," that is, 30 pounds per million pounds of product,
but there are millions of pounds of product created each year (Evaluation, line 1094).
Charge Question 2. - Environmental Hazard and Risk Characterization
Question 2. An analysis ofpotential risk to aquatic species indicates that expected
environmental concentrations are below hazard thresholds for aquatic species based on using
environmental hazard data, Probabilistic Dilution Model (PDM) within E-FAST, Discharge
Monitoring Reports (DMR) data, fate information, and physical/chemical properties. In addition,
a qualitative consideration ofphysical-chemical properties and the conditions of use in this
assessment indicate that risks to sediment-dwelling invertebrate species are not expected.
() 2.1
/'/ease comment on whether the mjormalion presented supports the hazard and
risk Inklings in the draft environmental hazard section I Section /) ami draft
risk characterization section (Section 4. h.
Response O 2.1 - Environmental Hazard and Risk Characterization
Overall, the Committee indicated that the information presented did not support the conclusions
that expected environmental concentrations were below hazard thresholds for aquatic species.
The Committee pointed out that the Agency did not use conservative values to assess either
exposure or hazard threshold for aquatic species. Mean values for exposures were compared to
rounded values of higher concentration threshold and did not include adequate safety factors
given the uncertainty of the estimates.
Recommendation 9: The Agency should evaluate degradation products of carbon
tetrachloride and conduct risk evaluations in terrestrial organisms as well as aquatic and
endangered species.
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Recommendation 10: The Agency should be very specific in language describing risks based
on what was and was not assessed.
The Committee recommended several changes to avoid underestimating risk to aquatic
organisms. Regarding the Concentrations of Concern (COC) values used as thresholds, the
Committee felt that inclusion of a developmental endpoint, particularly in amphibians was
appropriate.
A lethal concentration dose (LC 10) for 10% for chronic exposures (even when using an
assessment factor of 10) would be insufficient to be protective of amphibian populations
(Kienzler et al., 2017). The assumption that the larval life stage is particularly sensitive may not
be accurate (Evaluation, appendix G, page 272, line 7023). Studies have shown that
metamorphosis can be a more sensitive life stage for some compounds (e.g., thyroid disrupting
substances; Johnson et al., 2017).
Recommendation 11: Consider using benchmark dose methods to determine a POD for
amphibians and either provide more support for the application of an Adjustment Factor (AF)
of 10 or use an AF of 100 to the LD10.
Recommendation 12: A 9-day exposure value should be compared to the 2.5 |ig/L instead of
the rounded-up value of 3 |ig/L.
The use of 20 days of exceedance to determine risk was based on chronic invertebrate and fish
assays normally taking 21 or 28 days. However, if a developmental assay is used as a threshold
of effect, days of exceedance are not a relevant comparison as development can be altered by
exposure at even hourly (i.e., acute) exposure durations. At a minimum, a 9-day exposure value
should be compared to the 2.5 [j,g/L (not the rounded-up 3 (J,g/L) value.
One Committee member suggested that any time point can be used for risk quotient (RQ)
evaluations given the uncertainties of the data. If a developmental value is to be used, the
designation "Non-applicable" should be placed in columns for acute days of exceedance in
Tables E2 and E3 of the Evaluation.
The rationale to consider RQ exceedances for up to 20 days as acceptable for a lethal endpoint
was not provided. Ambystomidae (mole salamanders) a species of salamanders— not the species
used in this Evaluation, but the data are valid for similar salamanders — live for 30 years.
Therefore, by definition, a chronic exposure would exceed three years. However, only about a
month is typically spent in any one water body.
In the case of a developmental endpoint, an acute exposure could result in a developmental
effect. There was no consideration of effects in the aquatic prey base, which were not evaluated.
The risk characterization was not straightforward, and uncertainties should have been explicitly
stated and an attempt should have been made to account for them. This complexity also supports
an AF >10 or a range estimate for understanding risk from chronic effects (Kienzler et al.,
2017).
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Recommendation 13: The EPA should consider using an Adjustment Factor (AF) of 100 instead
of 10 which would incorporate additional uncertainly into risk characterization for
developmental effects.
The Committee suggested the use of LD10 for chronic exposures, even when using an
assessment factor of 10 would be insufficient to be protective of amphibian populations. The
assumption that the larval life stage is particularly sensitive may not be accurate (Evaluation, line
7023). Studies have shown that metamorphosis can be a more sensitive life stage for some
compounds (e.g., thyroid disrupting substances; Johnson et al., 2017). Several Committee
members recommended the EPA consider using benchmark dose methods to determine a POD
for amphibians, and either defend the application of the AF of 10, or use an AF of 100 from the
LC10, which is considered in many publications to be protective of lethal effects in aquatic
organisms (Kienzler et al., 2017). A similar argument for additional safety factors can be made
for the acute COC of 7 [j,g/L in fish. Table G-l in the Evaluation clearly shows the MOA
(hepatoxicity) of carbon tetrachloride was consistent between fish and mammals. The liver
serves an important role in fish reproduction. Consequently, since it appears to be a target organ
in fish as well as rodents, the weight of evidence (WOE) indicates reproduction may also be
impaired and indicates additional uncertainty for the risk characterization statement of "no
unreasonable risk."
Recommendation 14: If RQ > 1 in multiple sites, a more refined risk characterization with
better uncertainty estimates is needed.
Overall, the Committee felt that if Table 4.2 is evaluated in the light of any exceedance of the
predicted E-FAST value, occurrence of RQ > 1 for five out of 21 sites for the 20-day exposure
estimates and four out of 21 for the 250-day exposure estimates would indicate a more refined
risk characterization is needed; perhaps with measured values in surface water. The Committee
suggested these values could also be obtained from the National Pollutant Discharge Elimination
System (NPDES) monitoring reports from the same dischargers used to estimate surface water
values.
Recommendation 15: Clarify which criteria were used to determine acceptability (quality) and
relevance for studies on environmental hazards and consider using other studies to support
the evidence from the higher quality studies. Please also describe why more robust methods
(e.g., species sensitivity distributions) could not be used.
The Committee commented on both how the Agency identified and evaluated environmental
studies and how that was presented in the Evaluation. The methodology presented in Section
3.1.1 is not clear with how the ECOTOX database was used. In addition, there is a lot of
information presented in Appendix G that would have been clearer if included in the body of the
Evaluation. In Table G-l, many studies conducted in fish evaluated enzyme induction (which is
not in itself an adverse effect) and some are intraperitoneal (IP) exposures that were judged to be
high in data quality. The Evaluation states on page 96 (lines 3072-3073) that 61 of the 73 studies
were of unacceptable data quality (suggesting that they were excluded); however, this seems to
contradict the table in Appendix G. Table G-l has more than 12 studies that are rated high in
quality. Therefore, it seems that the EPA used other criteria to determine acceptability in addition
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to data quality. This was also inferred in lines 6992-7003 in Table G-l. The Committee
recommended that EPA specifically note what criteria were used to consider data relevance for
risk evaluation in addition to determining data quality. This could be added to the table as an
additional column and consider highlighting what studies were selected and used. Also consider
possibly using other data including those not considered high in quality or particularly relevant
for Toxicity Reference Value (TRV) derivation, in a corroborative sense to support high quality
studies used to develop a COC. A simple flow chart on this process may help clarify this in the
risk assessment.
Recommendation 16: Justify the change in COC for environmental risk from 7 to 3 |ig/L.
Several Committee members were also unclear why the COC was changed from seven to three
micrograms per liter (|~ig/L). The calculations based on amphibians and algae are included in
Table G.6 of the Evaluation. A justification for why the Agency decided to use the new COC is
needed, especially since it was not based on new studies.
Recommendation 17: Risk quotients should be made on conservative data from exposures as
well as effects.
The Committee also thought the aqueous exposure estimates in Tables E-2 and E-3 of the
Evaluation are not conservative because mean and median values were used. A more
conservative value would have been the maximum value or at least a 90th percentile value, if
available from the model. Several Committee members wondered if the later data from NPDES
permits agreed or disagreed with the TRI data.
The acute and chronic stream concentrations reported in Table E-2 were computed in E-FAST
using 5-year mean releases from Table E-l. The mean average reported in this analysis should
include a value other than zeros for early years when the facility was not manufacturing or using
carbon tetrachloride — that the facility was up and running and using/producing carbon
tetrachloride for each of these years should be clearly indicated. At least 11 sites show no
releases prior to 2016 and seven of these show releases for only 2018; the last year of data. For
these last seven sites, the best estimate of average release is five times the value presented in
Table E-l. One site (AL0001961) demonstrated steep increases in releases in the last five years
and two other sites (LA0038345 and TX0007072) demonstrated moderate increases. A more
reasonable estimate of mean releases for these increasing sites might be to extrapolate releases
for the next six years (timeframe for Safe Drinking Water Act (SDWA) review) and use the
average of these values in E-FAST. The existence of an upward trend in releases should be
examined for all 49 sites reporting releases.
The other (default) input values to the E-FAST model for each of the top release sites are not
reported. The problem formulation document mentions assuming "low hydrological flow" and "7
consecutive days of 10th percentile low flow" (U.S. EPA, 2018b, page 90) but the value used is
not specified.
The analysis in Appendix E tends to focus on the top 21 release sites, but there are only 49 TRI
reporting facilities. The committee indicated conducting the analysis on all 49 sites is not much
greater than the effort for the 21 sites, and hence all 49 sites should be reported and evaluated.
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On a minor point, Table E-l releases were in pounds per year and Table E-2 releases were in
kilograms per day (kg/day). The Committee indicated one or the other unit of measurement
should be used.
Recommendation 18: Include carbon tetrachloride transformation products in the Evaluation.
In addition to the carbon tetrachloride assessment, the committee recommended the toxicity for
major carbon tetrachloride transformation products, such as CHCb, should also be considered in
the Evaluation. This is essential given the Agency reliance on degradation to remove carbon
tetrachloride from water and sediment (Evaluation, page 45: lines 1413-1415).
Recommendation 19: Include an evaluation of risk for terrestrial receptors or provide
convincing logic why risk to terrestrial receptors would be negligible.
Terrestrial receptors should have been assessed (Evaluation, page 164-166) given the large
amount of waste disposed in this manner. Terrestrial organisms are mentioned in this section
(Evaluation, lines 3671-3673), but not further, suggesting that qualitative decisions were made
during problem formulation to discount the value of taking the assessment further. If the Agency
does not plan to evaluate risk to terrestrial receptors, the committee indicated more rationale was
needed in this section to justify not evaluating exposures to terrestrial organisms. During
problem formulation, terrestrial species exposure pathways were excluded since they were
"considered to be covered under programs of other environmental statutes administered by EPA,
which adequately assess and effectively manage such exposures (e.g., RCRA and CAA)."
(Evaluation, page 98) Is it the existence of the other environmental regulatory statutes or the
stated adequacy of those programs in addressing these pathways that justify the exclusion? If it
were demonstrated that the other environmental statutes administered by EPA do not adequately
assess or effectively manage these specific exposures, would terrestrial species exposure
pathways then be covered under TSCA? Several committee members indicated the EPA could
provide more information on how other EPA statutes are relevant to those hazards perhaps in a
flowchart.
The Agency should also cite the specific documents that have examined terrestrial exposures and
associated risks from carbon tetrachloride.
Recommendation 20: Discuss the possible impact on endangered species.
There is also no assessment of threatened or endangered species in the Evaluation, although the
Committee recognized that there is no a priori assumption that threatened or endangered species
would have any inherent sensitivity to toxicant exposure. The E-FAST model demonstrated that
there is a feature that allows "searching for endangered species in the vicinity of specific
facilities," which may be useful to production and use decisions where they are present.
Recommendation 21: Be very specific in language describing risks based on what was and was
not assessed. Broad statements of "no risk" are misleading given that all risks are relative and
no condition where exposure is present is without some level of risk.
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The Committee suggested that the Agency should be very specific in language describing what
risks were evaluated and what risks were not. Only risks posed through surface waters were
considered for environmental receptors in this Evaluation. Statements regarding "no
environmental risks" are misleading and must be modified. The assessment of no anticipated
concern for risk to environmental receptors is overly broad (Evaluation, page 18, line 641 and
many occurrences later in the document). Only aquatic receptors were evaluated and there is a
reasonable probability that their exposures are underestimated. Thus, the committee concluded
that the Agency cannot state that there is no unreasonable risk to environmental organisms
exposed via surface water. The limitation to only the aquatic species and confinement to releases
directly to water must be explicitly stated. The COU language obfuscates the severe limitation of
this assessment.
Charge Question 3. - Occupational Exposure and Releases
Question 3. Workers and occupational non-users may be exposed to carbon tetrachloride when
performing activities associated with conditions of use including, but not limited to:
• Connecting/disconnecting transfer lines used to unload carbon tetrachloride containers
into storage or reaction vessels,
• Cleaning and maintaining equipment,
• Sampling chemical formulations containing carbon tetrachloride for quality control,
• Repackaging products containing carbon tetrachloride,
• Handling, transporting and disposing wastes containing carbon tetrachloride, and
• Performing other work activities in or near areas where carbon tetrachloride is used.
() 3.1
/'lease comment on the characterization oj occupational exposure/or workers
and occupational non-nsers. Is the occupational exposure characlerizalion
supported by ihe in/oriiialion presented in Section 2.-1 oj the / h ajl Risk
I.valuation' What oilier additional informal/oil. or approaches if any. should
be considered'*
Response 0 3.1 - Exposure of Workers and ONU
The approach used by EPA to characterize worker's and ONU's exposures, as summarized
under the section entitled "Components of the Occupational Exposure Assessment" starting on
page 53, is conceptually similar to exposure characterizations in the Evaluations already
reviewed by the Committee. As in past Evaluations, EPA estimates central tendency and high-
end inhalation exposures using exposure monitoring data or modeling when monitoring data are
not available, and modeling for deriving dermal exposure estimates. The dermal and inhalation
approaches used in this Evaluation have, for the most part, been used in prior Evaluations. As
in past evaluations, in the absence of monitoring data, exposures to ONUs are assumed to be
the central tendency value for the worker in the same scenario (without use of PPE), with the
qualification that ONU's actual exposures are likely lower.
In this Evaluation, EPA presents a good summary of Occupational Safety and Health
Administration (OSHA) guidelines for exposure control and respiratory protection standards
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(Evaluation, pages 53-54). Section 2.4.2.5 describes good practices in exposure control and
cites evidence for the limitations and effectiveness of PPE. This material provides an
appropriate framework for discussion of EPA's assumptions about PPE in the context of risk
characterization. However, no change in EPA's application of PPE-related protection factors is
evident and multiple Committee members expressed some concern over EPA's approach. This
was discussed in greater detail under Charge Question 3.3.
One member mentioned that the availability of workplace measurements is low and that
dependence upon modeling is therefore high in this Evaluation. The Agency's hesitance to use
its authority to request industry data was again noted by the Committee. Discussion of
alternative data sources was broached but was also deferred to Questions 3.2 and 3.3.
Recommendation 22: Workplace exposure estimates should be aggregated.
Another recurrent issue was aggregate exposure. As indicated previously, multiple members
favor aggregating contemporaneous exposures.
Recommendations on other aspects of section 2.4 include the following:
Recommendation 23: Exclusions of COUs during problem formulation should be made more
explicit in the Evaluation rather than referencing the Scope of Work. For example, present
them in a summary table with the reasons for exclusion.
Recommendation 24: The EPA should develop a decision tree for using monitoring data or
modeling not just on the basis of the quality of monitoring data, but also on the quantity of
data available.
Recommendation 25: The justification for regrouping COUs should be described in more
detail wherever it was conducted. Surrogate groups should be named more specifically to
distinguish different types. For example, a chemical surrogate is different from a worker
activity surrogate, although the Evaluation seems to conflate the two.
Recommendation 26: Expand Appendix F to include pertinent material from Risk Evaluation
for carbon tetrachloride, Supplemental Information on Occupational Exposure Assessment
(U.S.EPA, 2020).
Appendix F of the Evaluation should include the specific information it is cited as having rather
than referring the reader to U.S. EPA (2020) — which appears to be incorrectly titled and dated.
Appendix F is often inadequate when referencing important aspects of the exposure estimation.
Charge Question 3.2. EPA distinguishes between workers (users) and occupational non-users
(ONUs) to acknowledge that different tasks and activities are associated with different levels of
exposures and thus risk in the same workplace. EPA assumes that area air monitoring is an
appropriate surrogate for ONUs' exposure. In the absence of ambient air monitoring data, EPA
assumes that the central tendency of personal breathing zone (PBZ) monitoring data is a good
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surrogate for ONU exposures because the Agency rarely has PBZ monitoring data for ONUs.
/'lease comment on the scientific validity and transparency oj /./' I \
approach and the assumptions /./'. I used to characterize exposure Jor ()\l s.
/'/ease a/so comment on the uncertainties related to the assumptions used to
characterize exposures Jor ().Xl s.
Response 0 3.2 - Va/idity/Transyarencv of ONU Exposure
Recommendation 27: Attempt estimation of ONU exposures where data permits as a check
on default assumption of mean worker exposure.
Recommendation 28: Consider a hierarchy of ONU exposures to distinguish extremes within
that classification.
Recommendation 29: Explain why it was decided not to use the Halogenated Solvent Industry
Alliance (HSIA) administrative/supervisory personnel data, even if only to compare it to their
exposure estimates for ONUs.
The EPA's description of the approach and assumptions for deriving ONU's exposure
estimates are adequately transparent. Scientific validity is questionable because the
uncertainties, while well described, are considerable (due in part to data scarcity). There are
some indications of positive movement toward recognition that the ONU category represents
a diverse group of workers, some with high potential for frequently being present in areas
where carbon tetrachloride is used, and some with fewer opportunities. The Agency could use
the job categories classified as ONUs and additional considerations to derive ONU exposure
estimates. In addition, it should be possible to use exposure or area modeling for at least some
of the COUs (for which EPA has data or can request it), as a comparison check for exposure
estimates. One Committee member suggested that the number of sites actively using carbon
tetrachloride was not so large that EPA could not request or attempt data collection in a
meaningful sample. Another member requested clarification as to whether HSIA data that
would appear to be pertinent to ONU exposures had been received by EPA and used in the
Evaluation. Those data involve seven full shift samples collected from
administrative/supervisory personnel, so it is likely that these are ONUs samples.
Concentrations were less than 0.063-0.066 ppm (under the limit of detection of the method).
Charge Question 3.3. Workp/ace inha/ation exposure concentrations to carbon tetrach/oride
were estimatedfor adu/ts using a combination of monitoring data and mode/ed exposure air
concentrations. For derma/ exposures, EPA mode/ed exposures for workers using parameters
such as exposed skin surface areas, body weight, and glove protection factors, if app/icab/e.
EPA used literature sources for estimating many of these occupational exposure parameters
and generic assumptions when data were not available.
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I'h:ase comment on the approaches unit assumptions used and provide any
specific suggestions or recommendations for allernalive approaches,
models or information l/ial should he considered hy ihe . Igcncy for
improving the workplace exposure assessment. More specifically, if oilier
sources of monitoring data are available to estimate air concentrations for
worker exposures, please provide specific citations.
Response 0 3.3 - Alternatives approaches/data for workplace exposure assessment-
As a preface to this question, several members believed that a more robust attempt at a
mass balance on production and fate of carbon tetrachloride would be beneficial to
understanding potential exposure pathways (see Recommendation 6 and associated
discussion).
Regarding other sources of occupational inhalation or dermal exposure data, one member
found a potentially useful biomonitoring study conducted in Italy (Ghittori et al., 1994) that
is not cited in the Evaluation. That study collected both environmental and biomarker data
for 55 workers exposed to carbon tetrachloride and potentially could provide a check on
exposure estimates in the Evaluation.
Recommendation 30: Use measured OSHA data in the Evaluation to inform "high end"
exposures.
A Committee member noted that measured air concentrations are available on an OSHA
website ,3 Values up to 39.5 ppm are reported there, although most values are below levels
of detection. The Committee member requested that the Evaluation summarize and discuss
the levels in this dataset in its discussion of "high end" exposure concentrations.
Recommendation 31: Estimate dermal exposure to vapor routinely.
In discussion of dermal exposure modeling, a Committee member reported that EPA was again
using a percent absorbed approach based on the Frasch (2012) interpretation of the work by
Kasting and Miller (2006). The Agency had previously switched to the Frasch and Bunge (2015)
paper which deals with absorption of the "skin depot" (post exposure) rather than the initial load.
The Committee did not verify that the numerical results are correctly computed, but the change
in approach is appropriate.
There was brief discussion of dermal exposure to the vapor phase of trichloroethylene (TCE).
One member pointed out that for volatile organic compounds (VOCs), in the absence of PPE,
inhalation would be expected to dominate dermal vapor exposure. However, if respiratory
protection, but not whole-body vapor protection is provided, dermal vapor exposure can exceed
(reduced) inhalation exposure. For instance, if the ratio of inhalation dose to dermal vapor dose
is 10 and an assigned protection factor (APF) of 25 is assumed, the dermal vapor dose becomes
the dominant exposure pathway.
3 https://www.osha.gov/opengov/heaIthsamples.html
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Recommendation 32: The EPA should replace the assumed APFs in Table 4-13 with data-
based estimates. If no reliable estimates can be developed, only risk estimates assuming no
PPE use should be presented, with appropriate caveats in the discussion.
The Committee spent a relatively large amount of time discussing use of PPE. Members noted
that ONU exposures were deemed unreasonable, but worker exposures were deemed
reasonable. Workers are assumed to be exposed both via inhalation (in higher concentration
environments than ONUs) and by dermal contact to liquids (while ONUs are not). The
counterintuitive finding that ONUs are at higher risk highlights the assumption made, in the
current and in prior Evaluations, that workers routinely have access to appropriate PPE and use it
effectively. Several Committee members expressed doubts regarding this assumption. In the case
of carbon tetrachloride, the finding of no unreasonable risk to workers via dermal contact with
liquid ultimately proved to be an artifact of an error in calculating the carcinogenic slope factor
for dermal exposures — see responses to charge question 4.4.
Multiple levels of dissatisfaction were revealed by the Committee during their discussion.
1) The EPA is not adequately considering the hierarchy of controls in occupational hygiene
and is emphasizing the last step, which is PPE.
2) The EPA is not adequately considering issues of training, availability of appropriate
materials, and human factors in compiling tables of PPE efficacy. Discussion on pp. 62-
63 of the Evaluation describes results of a National Institute for Occupational Safety and
Health (NIOSH) survey of U.S. employers regarding the use of respiratory protective
devices between August 2001 and January 2002 that suggested that full adherence to best
PPE practice is likely a minority occurrence. Estimation of central tendency and high-end
exposures with assumption that high degrees of protection are routinely achieved is
problematic.
3) Hard empirical evidence for assumed levels of PPE efficacy linked to the COUs being
described is not provided. The Agency relies upon generic tabulated values. This
approach entails substantial uncertainty.
4) The EPA does not discuss glove life/replacement when faced with chemical and
physical challenges.
Recommendation 33: EPA should provide sufficient detail on use of the conceptual model in
Cherrie et al. (2004) so that a reader could reproduce the values reported in Table 2.3.
If glove protection factors (PF) depend upon flux and time, explanation is needed why the values
reported in Table 2.3 depend on neither.
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/'/case comment on assumptions used in the absence oj specific exposure
information (e.if.. dermal surface area assumptions: luifh-enil values.
which represents two lull hands in coniaci i villi a In/iinl: X'Jd cur (mean
for females). 10 U air (mean for males): central tendency values,
w hich is half <>/ two full hands (a/niva/eni to one lull hand) in contact ivilli
a liquid and rcj>rcsenis only the palm-side oj both hands exposed to a
In/uid: 445cur (females). 535 cur (males)).
Response 0 3.4- Dermal exposure assumptions
The dermal surface estimates are a reasonable first estimate as point estimates. Experience
in the occupational agriculture sector does suggest that hands are disproportionately
exposed. The hand area data were obtained from the Exposures Factors Handbook, which
in turn derived the estimates from CDC's National Health and Nutrition Examination
Survey (NHANES) data.4 The Agency could use distributed values for hand surface area as
those are available. Section 2.4.1.8 presents a good discussion. However, EPA does not
have comparable data for many other assumptions.
Members had varied responses to use of the open burning/open detonation (OB/OD) data,
which are below limit of detection (LOD), for all scenarios under the COU for specialty
uses. Those data also raise the issue of whether large data sets with low results are
necessarily superior to smaller data sets with values of the LOD. The EPA should clarify
how it assesses the relative merits of data set size and quality.
One member found the discussion of whether carbon tetrachloride wastes are in the form of
mixed liquids, or as residues mixed into solid wastes to be inadequate as physical form affects
emissions and exposure estimates.
Recommendation 34: Fix the quote regarding the Consumer Product Safety Commission
(CPSC) ban for carbon tetrachloride on page 22 of the Evaluation.
On page 22, line 828, the quote regarding the CPSC ban for carbon tetrachloride is stated as:
"excluding unavoidable residues not exceeding 10 ppm atmospheric concentration." This is not
correct. The proper quote is provided on lines 1073-1076, page 30 of the Evaluation.
Recommendation 35: Tabulate ambient air levels for perspective in assessing consumer
background exposures.
Members also briefly discussed consumer and background exposures. The CPSC has
banned carbon tetrachloride in consumer products, but with an allowance for resultant local
air concentrations (10 ppm) that is fairly high compared to occupational exposures
estimated here. However, one Committee member reported that carbon tetrachloride does
4 https ://www.cdc. gov/ncfas/nfaa nes/i ndex.ht m
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not appear in the California Air Resources Board (CARB) consumer product database.5
Other members suggested that it would be valuable to have ambient air measurements
included for perspective on occupational exposures and to assess total daily exposures.
/'/case comment on 1.1'. I 's approach lo characterizing the strengths.
Iiiiiilalioiis and overall confnlcncc for each occii/Hilional exposure scenarios
presented in Section 2.-I. I. /'/ease coiiiiiiciii oil llie appropriateness oj these
con/ii/cncc ratings /or each scenario, /'/ease a/so coiiiiiiciii on I \
approach to characterizing lhe uncertainties summarized in Section 4.4.1.
Response 0 3.5- Strengths/confidence in occupational exposure scenarios
Recommendation 36: Levels of confidence should be provided for each route, in addition to
the overall result.
The Committee generally agreed that Table 2-19 of the Evaluation represents a positive step
toward provision of a clearer summary of EPA's confidence in its occupational exposure
estimates. However, one member suggested that levels of confidence should be provided for
each route of exposure, in addition to the overall confidence. In addition, that member thought
that the text should include a more extensive summary discussion of confidence.
The Committee was of mixed opinion on the merits of the graphical depiction of the confidence
ratings in Table 2-19. One committee member commented that the scale and use of color
implies a quantification that the Agency does not have. One member noted that Section 4.4.1
does not describe uncertainties of exposure estimates derived with the Tank Truck and Railcar
Loading and Unloading Release and Inhalation Exposure Model.
Charge Question 4. - Human Health Effects
Question 4. EPA evaluated human health hazards as follows:
• Reviewed reasonably available human health hazard data and determined whether
specific subgroups may have greater susceptibility to carbon tetrachloride hazard(s) than
the general population.
• Conducted hazard identification (the qualitative process of identifying non-cancer and
cancer endpoints) and dose-response assessment (the quantitative relationship between
hazard and exposure) for all identified human health hazard endpoints.
• Derived points of departure (PODs) where appropriate.
5 Details of the CARB Consumer Products Surveys can be found at
Imps ://ww3. arb. ca. gov//consprod/survev/survev .htm
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• Adjusted the PODs as appropriate to conform to the specific exposure scenarios
evaluated (e.g., adjust for duration of exposure).
• Considered the route (s) of exposure (inhalation, dermal), available route-to-route
extrapolation approaches, and the available approaches to correlate internal and
external exposures to integrate the exposure and hazard assessments, and
• Evaluated the weight of the scientific evidence based on the available human health
hazard data for carbon tetrachloride.
/'lease comment on the reasonableness <>/ the evaluation oj human health
O 4.1 hazards. . Ire there any additional carbon tetrachloride specific data and or
other in/ormalion llial should be considered''
Response 0 4.1-Human hea/th hazards
The Committee remarked that because of the widespread and long-standing knowledge of
toxicity from overexposures to carbon tetrachloride, current exposure levels in the U.S. are a
small fraction of what they were prior to the middle of the 20th century. The Evaluation fails to
make this simple but important point. The remarkable persistence of carbon tet in ambient air
means that all of us are exposed to small, sub-part per billion concentration levels; but the vastly
larger exposures (more than parts per million) that once occurred in some U.S. workplaces no
longer occur.
Recommendation 37: The discussion of the modes of cytotoxic and carcinogenic effects of
carbon tetrachloride, in both the liver and adrenal gland, should be substantially expanded,
in light of the key roles that these mechanisms of action should play in estimating risks of
cancer.
The Committee noted that the Evaluation fails to acknowledge the deep knowledge that the
toxicology community has developed, over many decades, regarding this most "classical" of all
hepatotoxicants. The Evaluation would benefit from a discussion of at least some of these
seminal findings.
For example, it has long been established that carbon tetrachloride, at sufficiently large levels of
exposure, can poison the liver and the kidneys in both rodents and humans (Smetana, 1939;
McGee, 1949; Farrier and Smith, 1950; Adams et al., 1952; Partenheimer and Citron, 1952;
Slater, 1987; Williams & Burk, 1990; IARC, 1999; Plaa, 2000; Weber et al., 2003). Almost as
long-standing is the knowledge that carbon tetrachloride is also carcinogenic to the liver of
rodents, and likely carcinogenic to the liver of humans as well (Edwards, 1941; Edwards et al.„
1942; Eschenbrenner and Miller, 1946; Andervont, 1958; Delia Porta et al., 1961; IARC, 1972,
1979, & 1999; Bogen, 1990; Nagano et al., 2007b).
It is also well-known that carbon tetrachloride is toxic (and sometimes tumorigenic, although not
carcinogenic) to chromaffin cells in the adrenal gland — in rodents and likely in humans.
(Chatterjee and Bardhan, 1967; Brogan et al., 1983; Staats et al., 1990; Colby et al., 1994; Khan
& Younus, 2011; Sanz-Lazaro et al., 2019).
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The Committee was also struck by the Evaluation's failure to acknowledge that the specific,
molecular and cellular mechanisms through which carbon tetrachloride exerts its toxicity have
been thoroughly investigated (Kappus et al., 1985; WHO, 1999; Seifert et al., 1994; Weber et al.,
2003; Manibusan et al., 2007; Malaguarnera et al., 2012). This deep knowledge of the
mechanisms of action of carbon tetrachloride should be carried through to the human health risk
assessment, but unfortunately, in the Evaluation, they are not.
The Committee noted that the toxicity/tumorigenicity/carcinogenicity of carbon tetrachloride is
well known to depend upon:
• metabolism (in several organs) to the highly reactive, trichloromethyl free radical;
• essentially immediate, nonenzymatic oxidation of this metabolite to the highly reactive
trichloromethyl-peroxyl free radical;
• subsequent peroxidation of lipids and oxidation of/damage to other macromolecules; and
• destruction of cell membranes, cell necrosis and/or apoptosis.
Finally, although the Evaluation claims to have "Evaluated the weight of the scientific evidence
based on the available human health hazard data for carbon tetrachloride," the Committee noted
that convincing support for this claim is lacking. In particular, the Evaluation refers repeatedly to
a concern that low-level exposures to carbon tetrachloride may somehow act through genotoxic
mechanisms (evidence for this notwithstanding); indeed, this concern is its underlying
justification for using the "default" approach of applying a linearized model to the tumor mouse-
bioassay data in order to predict low-dose cancer-risk. But the weight of evidence clearly
indicates that any genotoxicity caused by carbon tetrachloride can occur only at exceedingly high
levels of exposure, and is caused not by carbon tetrachloride directly, but only indirectly after
high levels of lipid peroxide by-products (such as reactive aldehydes) have accumulated
intracellularly (See, for example, Slater, 1987; MAK, 2000; Weber et al., 2003; Eastmond, 2008;
Hernandez et al., 2009; Borgert et al., 2015).
Recommendation 38: The toxicokinetics discussion should be updated and expanded.
Particularly on the influence of exposure route on systemic disposition and effects, as well as
inter and intraspecies differences in metabolic activation and susceptibility.
It was noted on lines 4085-4091 of the Evaluation, for example, that the utility of the oral
developmental study of Narotsky et al. (1997) was limited due to first-pass metabolism of carbon
tetrachloride in the liver. The reason given was not clear, namely that first-pass hepatic
metabolism following ingestion reduced the amount of carbon tetrachloride reaching the
systemic (arterial) circulation and extra hepatic organs. With low dose oral exposures, the liver
and lungs, acting in concert, eliminated/removed virtually all carbon tetrachloride and other
VOCs before they enter the systemic circulation. High oral doses, however, can exceed the
uptake and metabolic capacity of the liver systemic circulation. The findings of Sanzgiri et al.
(1997) are applicable here. They characterized the influence of route and rate of administration
of carbon tetrachloride on blood and tissue levels of carbon tetrachloride in rats. Presystemic
elimination of carbon tetrachloride can be protective of extrahepatic organs, but the liver often
"bears the brunt" of adverse effects (Sanzgiri et al., 1995).
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There are no descriptions in Section 3.2.2 on Toxicokinetics of the time-course of carbon
tetrachloride or its key metabolites, for use in understanding the chronicity of adverse effects of
single and multiple exposures. Kim et al. (1990) delineated the kinetics of carbon tetrachloride in
rats. Carbon tetrachloride was found to be rapidly and extensively absorbed from the
gastrointestinal (GI) tract. Rao and Recknagel (1968, 1969) observed hepatic uptake, lipid
peroxidation and covalent binding of carbon tetrachloride (14 C-CCU ) within as little as five
minutes of oral dosing of rats.
The Committee agreed that it would be worthwhile to expand the description of carbon
tetrachloride metabolism, and to link the chemical's bioactivation to its MOA. The Committee
noted that there was an excellent publication by Slater (1987) describing biochemical reactions
and effects of the chloromethyl peroxyl radical and subsequent products of lipid peroxidation.
Section 3.2.5.4 in the Evaluation provides some useful information on the metabolic basis for
altered susceptibility to carbon tetrachloride hepatotoxicity, although the timing of exposures is
important. Concurrent exposure can be protective, since alcohol and carbon tetrachloride are
competitive metabolic inhibitors. Diabetics are a susceptible subpopulation due to elevated levels
of ketone bodies. Ketones stabilize the relevant metabolizing enzyme. Ketones are also markedly
elevated by food deprivation. Diurnal variance in carbon tetrachloride hepatotoxicity in rats has
been linked to patterns of food intake (Bruckner et al., 2002). Overnight fasting resulted in
increased acetone formation and carbon tetrachloride bioactivation. This, coupled with decreased
availability of hepatic glutathione (GSH), plays an important role in countering peroxidative
actions of free radicals.
The experimental protocol of an unpublished study by Benson and Springer (1999) is described
on pages 107 and 108 of the Evaluation, but relatively few of their findings or conclusions are
mentioned. It was surprising that liver microsomal protein levels were said to be increased and
enzyme induction was said to occur, since carbon tetrachloride metabolites target microsomes
and are "suicide inhibitors". Derivation of human metabolic rate constants was mentioned, but
no results were provided. Was any information obtained to assess the existence of genotoxic
versus non-genotoxic mechanisms of liver tumors? Thrall et al. (2000) did report the following
rank order of carbon tetrachloride metabolism: Hamster>mouse>rat>human.
Recommendation 39: Major points about genotoxicity of carbon tetrachloride should be
brought forward from Appendix I, and overall conclusions reached about strengths,
weaknesses, and limitations of existing studies, weight of evidence and data needs.
The account of Genotoxicity and Cancer Hazards in Section 3.2.3.3 of the Evaluation is
inadequate. There have been a large number of investigations of the chemical's genotoxic and
carcinogenic actions. The primary MOA involves bioactivation by cytochrome P450 isoforms,
notably CYP2E1, to the trichloromethyl radical. This moiety interacts with oxygen to yield the
trichloromethyl peroxyl radical, which initiates lipoperoxidative reactions, producing in turn a
complex mixture of unstable products (Slater, 1987). The free radicals have a very limited radius
of diffusion in the aqueous environment of cells. These moieties are essentially trapped within
their microenvironment due to their reactivity with a variety of macromolecules including
polyunsaturated fatty acids in membranes, phospholipids, enzymes, and structural proteins
(Manibusan et al., 2007). Proximate microsomes and microsomal enzymes are selectively
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damaged, Thus, DNA is largely spared, as reflected by the lack of evidence of point mutations.
Lipid peroxidation does generate a variety of DNA reactive intermediates including unstable
oxygen species, lipid peroxy radicals, aldehydes and carbonyls (Eastmond, 2008). High levels of
reduced GSH and other antioxidants protect against such agents, but their stores are finite. These
products of oxidation and peroxidation have a longer half-life and can diffuse further than
trichloromethyl/peroxyl radicals. Membrane damage releases calcium and activates proteases
and endonucleases. These diffusible moieties can reach the nucleus, producing manifestations of
genotoxicity including DNA adducts, single and double strand breaks, crosslinks, and apoptosis.
Binding to microtubules and enzymes involved in calcium homeostasis can disrupt normal
chromosome segregation. Most lesions will be efficiently repaired or result in cell death or
immune response. Leukocytes infiltrate damaged tissue and generate DNA reactive oxygen and
nitrogen species. Extensive cytotoxicity and rapid cellular proliferation can result in both
spontaneous and induced mutations, as cells may not have adequate time to repair DNA lesions.
Errors in DNA replication trigger mismatch repair processes involving endonucleases that cleave
newly replicated DNA before it can be converted into mutations by the next round of DNA
synthesis. This process is not always successful, so mutated cells may emerge. The transformed
cells are recognized as foreign/dangerous by cells of the immune system and destroyed (Corthay,
2014). Many studies have demonstrated that carbon tetrachloride impairs the immune system,
and that immune suppression promotes tumor growth. Some cancer treatments involve boosting
the immune system (Candeias and Gaipl, 2016). There is considerable evidence that primary
tumor cells can interfere with immune cell cross-talk, both locally and systemically, promoting a
chronic inflammatory yet immunosuppressive state that facilitates immune evasion and tumor
growth (Garner and Visser, 2020).
One Committee member recommended that EPA better explain why genomics, proteomics,
genotoxicity, indirect genotoxicity, changes in gene expression or mRNA levels were excluded
while evaluating carbon tetrachloride MOA studies of in vitro models.
Recommendation 40: The reproductive toxicity of carbon tetrachloride should be addressed
and incorporated into the document. The contribution of inhibition of immune function to an
indirect carcinogenic MOA should be discussed.
Adverse effects of carbon tetrachloride on sperm function and morphology have not been
addressed in the Human Health Hazards section. Some reproductive effects have been induced in
rodent-studies (Smyth et al., 1936; Adams et al., 1952), although only at dose-rates that are
higher than those needed to cause frank liver toxicity, and so much higher than those that occur
in U.S. workplaces. El-Faras et al. (2016) reported, that vitamin E enhanced the activities of
catalase and superoxide dismutase and reduced lipid peroxidation in carbon tetrachloride-treated
rats. Pomegranate juice ameliorated adverse testicular effects of high doses of carbon
tetrachloride given to rats (Turk et al., 2016). No increase in sperm head abnormalities were seen
in mice exposed to very high doses (more than three grams/kg) of carbon tetrachloride,
intraperitoneally. There do not appear to be similar investigations of oocytes.
Recommendation 41: The EPA should apply a non-linear model in estimating cancer risks, in
light of the preponderance of evidence that lipid peroxidation- and endonuclease-derived
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mutations, and other cytotoxic effects, are the origins of tumors of the liver and adrenal
gland.
The Committee noted that pheochromocytomas are tumors of chromaffin cells in the adrenal
gland. They are rare; occur in rodents and humans alike; and pheochromocytomas in mice, but
not in rats, are similar (histologically and functionally) to those that occur in humans (Hill et al.,
2003).
Carbon tetrachloride is among the small number of chemicals that can cause adrenal tumors in
mice; and, like carbon tetrachloride, these other chemicals (furan, pentachlorophenol, and 4,4'-
methylenedianiline) also cause liver tumors (Hill et al., 2003; based on results of National
Toxicology Program (NTP) bioassays of these chemicals).
Like the liver, the adrenal gland metabolizes carbon tetrachloride, generating proximately toxic
free radicals and, at sufficiently high dose-rates, adrenal necrosis in laboratory rodents (Castro et
al., 1972; Colby et al., 1981 & 1994). Necrosis is limited to the zona reticularis, the site of
metabolic activation of carbon tetrachloride in the adrenal cortex (Colby, 1988; Colby et al.,
1994). Khan and Younus (2011) reported that administration of one milliliter (ml) carbon
tetrachloride/kg once weekly for 16 weeks caused DNA fragmentation, diminished GSH levels,
produced lipid peroxidation and increased activities of antioxidant enzymes in the adrenal gland
of rats. Genotoxic events in the adrenal thus appear to be attributable to the indirect action of free
radicals.
Recommendation 42: Effects of carbon tetrachloride on the central nervous system (CNS), in
rodent studies, should be addressed.
There was considerable discussion about carbon tetrachloride and its potential role in causing
CNS effects. With respect to the likelihood of metabolic activation, several P450s are found in a
highly regionalized and cell-specific fashion in the brain (Navarro-Mabarak et al., 2018).
Furthermore, trans-sulfuration pathways exist there (Vitvitsky et al., 2006). There are several
studies documenting effects of high-level carbon tetrachloride exposure on oxidative stress/lipid
peroxidation markers in the brain of rodents (Ritesh et al., 2015; Naseem et al., 2014; Al-Olayan
et al., 2016).
Recommendation 43: Improve the discussion and include more details of the derivation of
the points of departure.
One Committee member suggested inclusion of a more comprehensive discussion of possible
endocrine effects in the carbon tetrachloride risk evaluation. Support for an endocrine-related
MOA comes from: (1) non-significant increases in tumors in female rats at low- and mid-doses
in the endometrium, ovary, thyroid, adrenal, pancreas, as well as spleen and subcutis (JBRC,
1998); (2) adrenal gland effect of carbon tetrachloride on steroidogenesis; (3) evidence from
Narotsky (1997) of effects on maternal progesterone and luteinizing hormone ( LH levels; and
(4) possible effects on steroid hormone synthesis or metabolism via cytochrome P450 induction
(CYP) or adrenal effects. Some specific observations from carbon tetrachloride studies include:
• In female rats, endometrial stromal polyps increased at all doses (page78 of JBRC, 1998).
Page 42 of 96
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• Female rat 2-year study (JBRC, 1998) tumors at low and mid doses in the adrenal,
endometrium, ovary, thyroid, as well as pancreas, spleen, and subcutis. Although these
are non-significant, the increases are consistent (typically elevated in low- and mid-dose
groups: high-dose group had excessive mortality, and many are 2X control incidence).
• The IRIS summary of Nagano et al. (2007) reports decrease in ovary weight.
• The JBRC (1998) 2-year study in mice reports ovary deposit of ceroid.
• Colby (1981) study of carbon tetrachloride effects on steroidogenesis in adrenal show
that carbon tetrachloride can stimulate lipid peroxidation in adrenal microsomes, but that
the peroxidation is not obligatory for the toxic effects of carbon tetrachloride on adrenal
microsomal enzymes (steroid hydroxylases).
More information (including calculations where possible) are needed about the selection and
derivation of the exposures/doses used for the points of departure. For example, in section
3.2.5.1.2 on page 128 of the Evaluation, why was the 25 parts per million (ppm) from the rat data
in the Nagano study selected to derive the POD rather than the mouse data from the same study,
or why weren't the eosinophilic granules seen in the rats at five ppm used? More information is
needed on the calculation of the Human Equivalent Concentrations (HEC) and the adjustments to
convert from continuous exposure to the 8- and 12-hr occupational exposures. Which benchmark
dose level (BMDLio) calculation was used and how was it used to derive the 14.3 mg/m3 value?
Most of the BMDLio outcomes from the modeling in the Appendix appear in |imol/L units,
which is very different from most EPA assessments. Similarly, it would help the reader if the
actual calculations were provided in the footnote of Table 3-14 to illustrate how the occupational
exposure levels were calculated. The basis for all of the critical PODs, especially those in Table
3-17, should be shown.
Recommendation 44: Key details on the derivation of the Inhalation Unit Risk (IUR), similar to
that provided in the IRIS summary, should also be provided in this Evaluation.
The document uses the IUR that was derived in the IRIS assessment. However, key details on the
derivation of the IUR (species, cancer type, extrapolation model, risk levels, etc.) should also be
provided in this document, similar to the IRIS summary information.
Recommendation 45: Include discussion on carbon tetrachloride effects on inflammatory and
immune effects.
One Committee member expressed concern that inflammatory and immune effects are not
adequately discussed in the Evaluation. This represents a large gap in the literature review on
carbon tetrachloride. There are many studies that use carbon tetrachloride as a positive control in
animal models of acute liver disease/fibrosis. While some of these studies use IP administration,
which may not have particular human relevance, many studies administer it orally or via
inhalation and cumulatively, these studies demonstrate that carbon tetrachloride has very
dramatic pro-inflammatory effects in the liver while simultaneously impairing the function of
certain immune cells. Numerous reports testing the anti-inflammatory activities of various
compounds have shown that inflammation drives much of carbon tetrachloride induced liver
injury. It is unclear why this aspect of carbon tetrachloride induced immunotoxicity was not
included in the draft risk evaluation.
Page 43 of 96
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Note that in the supplemental document entitled, Inclusion/Exclusion Criteria for Human Health
Hazard Literature, it states that these types of studies are to be included in the draft risk
evaluation. This does not seem to have happened for this evaluation.
Charge Question 4.2. EPA used a linear low-dose extrapolation for evaluating potential cancer
risks from chronic exposures to carbon tetrachloride.
O 4.2
I'lease comment 011 the rationale for selection of tumor type lor dose response
for cancer.
Response 0 4.2-Rationale for tumor used in cancer dose-response
Recommendation 46: Expand the discussion of carbon tetrachloride's MOAfor
carcinogenicity in both the liver and the adrenal gland.
The Committee noted that exposure to carbon tetrachloride has been associated with tumors,
both benign and malignant, in the liver and the adrenal gland, in laboratory rodents. In rodent
cancer bioassays, two types of tumor have been repeatedly seen. Liver tumors have been seen in
studies of male and female mice, rats, and hamsters administered carbon tetrachloride either
orally or by inhalation, and several studies have been performed to investigate the mechanisms
underlying its genotoxic and carcinogenic effects. The primary mechanism identified involves
reductive transformation to the trichloromethyl free radical, followed by spontaneous formation
of the trichloromethylperoxyl free radical, which initiates lipid peroxidation leading to
membrane damage and other signs of hepatotoxicity, genetic damage and DNA adducts.
Hepatoxicity was followed by regenerative proliferation, and the subsequent formation of liver
tumors. There was little evidence of carbon tetrachloride directly inducing mutations; mutations
if they do occur would appear to originate from indirect mechanisms and at high intracellular
concentrations.
Carbon tetrachloride has also been shown to induce pheochromocytomas of the adrenal gland in
male and female mice. However, in contrast to the liver, fewer studies have been conducted on
the adrenal gland with regard to this chemical.
Key steps occurring in both organs should be compared. A diligent effort should be made to
update the literature review in this area as there are likely to be relevant studies that have been
published in the 10-15 years since the IRIS document was written. For example, a study by Khan
and Younis (2011) describes oxidative damage occurring in the adrenal gland following carbon
tetrachloride administration. Also, the U.S. EPA (2010) evaluation missed key studies, such as
Slater (1987).
Recommendation 47: A critical and more comprehensive evaluation of the reported
associations between carbon tetrachloride and brain cancer is needed.
Page 44 of 96
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The brain may be a potential target for carbon tetrachloride tumorigenicity. Three epidemiologic
studies have reported associations between carbon tetrachloride exposure and risk of gliomas or
glioblastomas in workers, although other studies have been negative in this regard. In several of
the comparisons, the observed relative risk-estimates were large, although the confidence
intervals surrounding the estimates were also quite wide, indicating imprecision. The observation
of significant increases in brain tumors in multiple studies suggests that additional examination
of this as a potential target organ is warranted. However, members of the committee noted that
brain tumors have not been reported in laboratory animal bioassays of carbon tetrachloride; that a
reported association between ambient air concentrations and prevalence of neuroblastomas in
one study is not pertinent to this issue (since neuroblastomas are not tumors of the brain, contrary
to what is stated in the draft risk evaluation); and that the epidemiological studies overall are too
few and weak to be conclusive.
In addition to the more recent studies listed in the Evaluation document, the Evaluation should
include the Heineman et al. (1994) study as well as other epidemiological studies on carbon
tetrachloride that may have investigated the occurrence of gliomas, brain tumors, and other types
of cancer. Standard epidemiological approaches for extracting the data should be employed as
described earlier with the full range of risk estimates presented (see also Recommendation 9).
Recommendation 48: Modify epidemiologic study identification and selection methodology
to comply with established PRISMA guidelines.
The article selection for a systematic review should follow established guidelines, such as
PRISMA6 for observational studies. All epidemiologic journals currently require a PRISMA
figure (see Figure 1) that shows the data identification, screening, and eligibility of final included
articles. In addition, the exclusion and inclusion criteria should be defined a priori and applied to
the article selection and identification. This approach has been in place for over 10 years and
should be adopted for TSCA evaluations for assessing epidemiologic studies. This is one
solution to the issue with understanding the process for selecting and excluding articles and
related justifications that the Committee has discussed in previous reviews.
Recommendation 49: Add and discuss older epidemiologic studies to Tables 3-1 and 3-8. One
Committee member recommended that citation and discussion of the older epidemiologic studies
be added to Tables 3-7 and 3-8 of the Evaluation. Though the Committee member understands
the studies were part of the previous evaluation, they appear to add weight of evidence for the
overall evaluation of the chemical.
Recommendation 50: Use current best practice methods for quality review of literature
including use of two independent reviewers.
The quality evaluation of each study is of critical importance, as it allows grading the value of
each scientific contribution to the weight of evidence. However, the process for quality
evaluation used by EPA is completely obscure, and seems to be very qualitative in nature, and as
6 http://www.prisma-stafement.org/
Page 45 of 96
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such can be very subjective. The Committee suggests using one of the many published, validated
systems for evaluation of the quality of the literature, such as the NIH assessment tool (NIH.
Study Quality Assessment Tools7), or others available in the literature. This approach would
allow for a non-biased, standardized, accepted evaluation, comparable to other evaluations. In
addition, evaluation is usually performed by two independent reviewers, and any discrepancy in
findings are discussed and consensus is reached.
7 https://www.nhlbi.nih.gov/health-topics/study-quality-assessment-tools
Page 46 of 96
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Figure 1: PRISMA 2009 Flow Diagram, from PRISMA web site.
PRISMA 2009 Flow Diagram
Records identified through
database searching
(n = )
Additional records identified
through other sources
(n = )
Records after duplicates removed
(n = )
Records
(n
>creened
)
Full-text articles assessed
for eligibility
(n= )
Records excluded
Full-text articles excluded,
with reasons
(n = )
Studies included in
qualitative synthesis
(n = )
Studies included in
quantitative synthesis
(meta-analysis)
(n = )
Recommendation 51: Revise the table listing epidemiologic studies and apply Bradford-
Hill criteria in assessing study strengths.
A table listing cancer epidemiologic studies is presented in the Evaluation in an atypical fashion
and should be restructured per the example given in Table 2. Endpoints to consider should be
chosen a priori, and then reported uniformly across studies. In addition, the Bradford-Hill
criteria8 (Hill, 1965; Susser, 1986) for evaluating an epidemiologic finding should be considered
and applied to the available data.
8 www.epa.gov/caddis-vol 1/about-causal-assessment
Page 47 of 96
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Recommendation 52: Include a discussion of non-cancer health endpoints from epidemiologic
studies.
No justification is provided for why non-cancer endpoints, such as liver fibrosis, are not
considered. The Evaluation should clearly state why the non-cancer endpoints, identified and
discussed in epidemiological studies, may be less relevant at the low exposures being considered.
Recommendation 53: The discussion on PESS should include sub-groups and conditions
identified in epidemiologic studies and in more recent GWAS research.
The data on cancer endpoints suggest that there may be differences with age (adults versus
children for brain cancer, for example), race (Japanese Americans vs White Americans) and with
metabolic germline polymorphisms. None of this is discussed and analyzed in depth in this
document.
There are novel GWAS9 studies that suggest genetic differences that may modulate acute
exposure effects. These should be identified and discussed.
9 https://www.nebi.nlm.nih.gov/pubmed/?term=GWAS+and+earbon+tetraehloridefactors
Page 48 of 96
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AUTHOR
DESIGN
N CASES N CONTROLS SOURCE OF CASES PERIOD PLACE
Heineman 199^ case/control
Nelson 2012 cohort
137
123 death certificate 1878-81 luisiana, NJ, P/kin
matched 99 incidence and
9 controls mortality
1965-1988 Hawaii
EXPOSURE RESULTS
low: 1.2(0.8-1.7);
M: 3.6 (1.1-13.7);
questionnair H: 0.8 (0.4-1.9);
e to next of overall: 1.2 (0.9-
1.7)
medium: 0.62
(0.07-5.44); High
26.59
questionnaire (2.90-243.50)
COMMENTS
white men,
no dose-
CANCERTYI
response.
Age and place astrocytic
adj brain ca
adjusted
glioblasto
ma
Neta 2012
case/control 489 G, 197 799 H
hospital
Glioma: possible
Boston, 0.7 (0.5, 0.9);
Pittsburgh, probable 0.6 (0.3,
Phoenix questionnaire 1.2)
adjusted, no
differences w
sex, years of
exposure,
weekly exp
etc
glioma and
meningio
ma
meningioma: 0.5
(0.2, 1.1); 0.6
(0.1, 2.9)
Ruder 2012 case/controls 798 1175 pop based
Table 2: Example format for reporting epidemiologic studies.
1995-97
Iowa,
Michigan,
Minnesota
and Wisconsi
questionnair
e, some
proxi 0.79 (0.65-0.97);
questionnair without proxi:
es 0.82(0.64-1.06)
adjusted, no
differences w
sex; no
effectc of GST
variants glioma
Page 49 of 96
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Recommendation 54: Include a summary table of tumors observed in endocrine-associated
tissues in the Japan Bioassay Research Center (1998) inhalation study, particularly for female
rats, and include a discussion of their significance.
As discussed in response to charge question 4.1, carbon tetrachloride has effects on endocrine-
responsive tissues. In the Japan Bioassay Research Center (1998) inhalation cancer bioassay,
there were increased tumors reported at low and mid doses for adrenal, endometrium, ovary, and
thyroid in female rats (as well as pancreas, spleen and subcutis). While many of these did not
reach statistical significance, taken together they are notable, and it would be a more complete
presentation to include a summary of these findings in the risk evaluation. In some cases, the
incidence in low- or mid-dose animals is twice what it is in controls. At high-dose, toxicity may
obscure these effects. These endocrine tumors are consistent with evidence of an endocrine
MOA for some non-cancer and cancer endpoints observed with carbon tetrachloride and further
discussion on this point would contribute to discussion of cancer MOA. For example, the tumors
may be a result of carbon tetrachloride action on the adrenal gland and subsequent effects on
hormone synthesis. Note, for example, that carbon tetrachloride is a known testicular toxicant,
affecting both cytochrome-P450 (initially) and lipid peroxidation (later) (de Toranzo et al.,
1978). And, based on in vitro studies, carbon tetrachloride affects steroid hydroxylases in the
adrenal even when lipid peroxidation is inhibited by ethylenediaminetetraacetic Acid (EDTA),
indicating that potential endocrine effects could be independent of lipid peroxidation (Colby,
1981).
/'/case comment on the appropriateness of using a linear lou -ilose extrapolation
O 4.3 versus a non-1 incur or threshold approach for assessing low exposures based on
I he cancer mode of action information presented in Section 3.2 and. \ppendixK.
Response Q 4.3-Low dose extrapolation approaches
The Committee concluded that the weight of a considerable body of scientific evidence indicates
that the relationship between carbon tetrachloride dose/exposure and its genotoxic response is
nonlinear with a steep dose-response. Less is known about mechanisms underlying adrenal gland
tumors in rodents or apparent glioblostomas in workers. Most of the Committee members
recommended that the EPA consider adoption and implementation of a threshold MOA when
estimating cancer risks. Use of uncertainty factors should be considered for adrenal and brain
tumors, due to limited information on the MO As and potential for these cancers in humans.
No support is provided for the EPA's designation of an "alternate MOA" that combines
cytotoxic mechanisms at relatively high carbon tetrachloride doses with "alternate, non-cytotoxic
mechanisms" at lower doses. What is meant by an "alternate non-cytotoxic mechanism"
(Evaluation Page 124, line 4005)? This appears to be speculation that something must be
occurring to produce an increased incidence in liver adenomas in the female mice dosed at five
ppm. Consideration should be given to the possibility that this was a chance occurrence in a
single study. The historical incidence of this benign tumor in control Cij:BDFl mice is as high as
10%. Had three of 50 control females exhibited liver adenoma in this particular experiment, the
difference between them and the five ppm dose group would not have been statistically
Page 50 of 96
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significant. There was no increase in liver carcinoma incidence in the females dosed at five ppm
and no significant increase over controls in combined benign and malignant liver tumors. It
should also be noted there was no increase in hepatocellular adenoma or carcinoma in the male
mice dosed at five ppm. Male mice metabolically activate more carbon tetrachloride and
experience a higher incidence of liver cancer then do females.
Much less is known about the mechanisms underlying the adrenal gland tumor induced by
carbon tetrachloride in mice. The adrenal gland tumor response has been strong and
reproducible. Of the limited number of studies that have investigated the mechanisms underlying
the adrenal cancers, most are quite old and of less-than-desired quality. However, they indicate
that the key events described in the liver (bioactivation by P450, induction of lipid peroxidation,
increase in oxidative stress, necrosis, DNA fragmentation, etc.) occur in the adrenal gland
following treatment with carbon tetrachloride. If one assumes that the key steps are the same in
both organs, extrapolation using a non-linear, threshold model would seem appropriate. This
would also be supported by the in vitro and the systemic in vivo genotoxicity data for carbon
tetrachloride, which are generally negative. One committee member suggested that carbon
tetrachloride, like other carcinogens, with multiple interacting modes of action will operate as
additive to background. As a result, the does-response relationship may look quite linear,
especially in a heterogenous population of humans (Crump, 2018).
Recommendation 55: Consider adoption of a threshold-type MOA in estimating the
carcinogenic risks of carbon tetrachloride.
Recommendation 56: Application of uncertainty factors should be considered for database
deficiencies, due to more limited mechanistic information about adrenal gland tumors in
mice and reported associations of occupational carbon tetrachloride exposure and increased
incidence of gliomas in workers.
Mechanisms underlying the carcinogenicity of carbon tetrachloride in the rodent liver have been
studied extensively. Using a WOE approach, it is likely that the relationship between carbon
tetrachloride dose per exposure and its genotoxic response is nonlinear with a steep dose-
response. This conclusion is primarily based upon the MOA identified from numerous
genotoxicity investigations, as well as several important factors that support/indicate a nonlinear
dose-response. These include recognition that:
1. The primary site of carbon tetrachloride bioactivation and adverse effects is the smooth
endoplasmic reticulum, a site removed from the nucleus and DNA;
2. The moieties which are formed are highly reactive and unlikely to travel far in the
aqueous cytoplasm from their site of formation;
3. The observed genotoxic effects appear to result from indirect mechanisms related to
oxidative and lipid peroxidation-mediated DNA damage, or damage occurring due to
necrosis and apoptosis;
4. Carbon tetrachloride metabolite-induced lipid peroxidation is an exponential chain
reaction, such that a single initiation event can lead to formation of many reactive
species. Thus, the extent of damage can have a distinct nonlinear component;
5. High levels of hepatoprotective agents and antioxidants are present in hepatocytes;
6. A close relationship is manifest between cytotoxicity and genotoxicity;
Page 51 of 96
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7. Oxidative and lipoperoxidation-related DNA damage occurs spontaneously in untreated
cells, and has been shown to be efficiently repaired; and
8. Apoptosis and recognition and destruction of transformed cells by the immune system are
additional protective mechanisms that argue against use of a linear dose-response model.
Charge Question 4.4. There are a limited number of quantitative studies on the absorption and
systemic toxicity of carbon tetrachloride by the dermal route. Therefore, PODs for dermal
exposures are based on (1) use of one unacceptable study and one acceptable study with similar
dosing regimens in a weight of evidence approach, (2) estimation of dermal absorption over time
of exposure; (3) estimation of evaporation losses for non-occluded exposures and (4)
extrapolation of dermal POD from inhalation POD (for chronic exposures).
/'lease comment on the appropriateness <>/ the approaches used for generating
/'()/ >s for dermal exposures, including the process et/iialion for extrapolating
the ('ancer slope factor (('SI ) and/'()/\/<>r chrome dermal exposures fdermal
///./».
Response 0 4.4- Derma/ PODs and extrapo/atins CSF
Recommendation 57: Explain why a poor-quality study (Kronevi, 1979) was used to establish
the acute dermal POD when so many other better quality studies were dismissed.
Recommendation 58: Acknowledge that there is insufficient data to devise an acute dermal
No Observed Adverse Effect Level (NOAEL) and POD using the Kronevi (1979) study.
As noted in the Evaluation, the acute dermal exposure evaluation was based on very limited data
generated in only three papers; one of which looked at liver pathology, one looked at mortality,
and one looked at absorption. Two of the three papers had data quality described as unacceptable
or not reliable by the EPA. In the Kronevi (1979) study (data quality unacceptable) guinea pigs
were exposed to carbon tetrachloride administered neat in one ml amounts inside a small (3.1
mc2) capped glass ring superglued (i.e., via a-cyanoacrylate) to the skin. The animals were
sacrificed at 0.25, 1, 4, or 16 hours (one animal/time point). Liver and kidney Hematoxylin and
Eosin (H&E) pathology was evaluated. There were no negative controls. Liver morphology
(marked hydropic changes and tendency to necrotic lesions) was altered only in the one guinea
pig evaluated at the 16-hour time point.
Recommendation 59: Use the Lowest Observed Adverse Effect Level (LOAEL) from the
Wahlberg and Boman (1979) study to determine the POD for acute occluded dermal exposure
to carbon tetrachloride.
Recommendation 60: Use the POD for occluded dermal exposure derived from the Wahlberg
and Boman (1979) LOAEL to calculate a POD for acute non-occluded dermal exposure.
Page 52 of 96
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A second paper by Wahlberg and Boman (1979) (data quality medium) also used guinea pigs to
study percutaneous toxicity of ten different industrial solvents, including carbon tetrachloride.
Toxicants were administered in 0.5 or 2 ml amounts to a glass-covered skin depot to 20
animals/chemical. Mortality was measured for up to 35 days. Carbon tetrachloride was one of
two compounds that caused the highest mortality rates. No mortality was observed in the group
of 20 control guinea pigs. Application of 0.5 ml carbon tetrachloride resulted in one mortality by
day three, and five deaths by day 14. Application of 2 mis of carbon tetrachloride resulted in one
mortality by as early as day one, and 13 deaths by day 35. Tissue pathology was not examined.
In terms of the dermal absorption rate for carbon tetrachloride, an attempt to estimate this was
made using the results from Morgan et al. (1991) (data quality not reliable). A 2-ml glass
exposure cell was attached using cyanoacrylate adhesive to the shaved skin of rats. Blood
samples were obtained before exposure, and 0.5, 1, 2, 4, 8, 12 and 24 hours after exposure. The
rats were sacrificed after 24 hours, and the volume of test solution remaining was used to
estimate absorption rate. Based on volume measurements, about 25% of the neat carbon
tetrachloride was absorbed after 24 hours. It is difficult to estimate how accurate the absorption
rate estimates were given the possibility that the solvents tested interfered with the cyanoacrylate
bond, and the rather crude method of determination. However, this study at least provides a
better-than-nothing estimate of absorption, and it is not unreasonable that it would be used to
calculate the POD.
These three disparate studies were used to devise an acute dermal exposure POD. Although the
wish to calculate a NOAEL from the limited data on occluded exposures is understandable, there
seem to be several problems with the approach which call into question the result.
Problems with calculating the dermal acute non-occluded POD:
• It is not clear why the Kronevi (1979) study that included very limited liver and kidney
tissue pathology was selected to determine acute dermal POD rather than the higher
quality study that evaluated mortality.
• On page 132, the Evaluation states: "Based on the assumption that induction of liver
toxicity is unlikely for animals dermally exposed for 4 hours to 0.5 ml carbon
tetrachloride from a skin depot of 3.1 cm2 (see section 3.2.5.1), an acute dose for
occluded conditions, which is associated with non-adverse liver effects was estimated.
Dose for occluded exposures = [(260 mg/cm2 x 3.1 cm2) / 0.440 kg] - 4 hours or 1,832
mg/kg - 4 hours." First, using liver toxicity data from a single animal in an unacceptable
study to determine the NOAEL seems questionable. Second, one cannot assume that
induction of liver toxicity is unlikely for animals dermally exposed for 4 hours to 0.5 ml
carbon tetrachloride just because that toxicity was not observed at that time point in one
animal. A 4-hour exposure could induce liver toxicity that did not manifest until a later
time point. Thus, this cannot be used to obtain a NOAEL. Third, the NOAEL seems to be
calculated under the assumption that the animals in the Kronevi (1979) study were
exposed to 0.5 ml of carbon tetrachloride, when they were in fact exposed to 1.0 ml of
carbon tetrachloride. The NOAEL in the draft risk evaluation would basically say that a
4-hour dermal exposure (presumably followed by exposure cessation) resulting in 110
mg/kg/day (the estimated NOAEL) was not expected to be harmful. Once the calculation
Page 53 of 96
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was corrected for the correct volume the information conveyed would be that 216
mg/kg/day of dermal exposure was not expected to be harmful. This was not justified.
• The NOAEL of 110 mg/kg/day for occluded exposure was used to devise the NOAEL for
the non-occluded exposure by dividing by the default absorbed factor of 4% to yield a
POD of 2,750 mg/kg/day. If the occluded exposure NOAEL was faulty it could not be
used to describe a non-occluded dermal exposure NOAEL. The EPA noted that the POD
of 2,750 mg/kg/day is similar to a POD of 2,450 mg/kg/day derived by using the chronic
inhalation values to extrapolate a chronic dermal value, and then further extrapolating an
acute dermal POD by inexplicably multiplying by a factor of ten. Just because two
questionable methods end up with similar values did not seem to be sufficient
justification for their use.
• On page 60 of the Evaluation it was noted that the only gloves recommended for use with
carbon tetrachloride were Viton, as most nitrile gloves offer limited protection. It was
also noted that there were very little data concerning glove use for carbon tetrachloride.
Considering the lethality of occluded dermal exposure, which was not impossible with
the wrong gloves, it would be even more important to describe an accurate POD.
Recommendation 61: Correct the calculation of the cancer slope factor for dermal exposure,
and, adjust the risk calculations accordingly.
There is a major problem associated with the calculation of the dermal cancer slope factor. The
IRIS Cancer Inhalation Unit Risk of 6 x 10"6 per [j,g/m3 for continuous lifetime exposure was
modified to estimate the cancer slope factor for dermal exposure. However, the calculation of the
dermal slope factor on pages 134 and 135 of the Evaluation is incorrect. To estimate a slope
factor based on absorbed rather than gross dose, correction for an assumed pulmonary
bioavailability of 63% is attempted. However, division by 63, rather than 0.63 results in a 100-
fold underestimation of the dermal slope factor. Since carcinogenic risk is linearly related to
carcinogenic potency, this means that all worker dermal pathway cancer risk evaluations are also
underestimated by a factor of 100. More explicitly, the equation string on lines 4334-4342 (page
134-135) currently reads as follows:
6 ¦ 1(T6 1 day 1000 |ig 1 8 ¦ 10~4
DSF = —lTr T7T1' 80 k§ -'Z5= mg
rJiM/i 10m3 mg 63 r m& i
Lm3J Lkg ¦ dayJ
Whereas it should be:
6 ¦ 10-6 1 day 1000 |ig 1 8 ¦ 10-2
°SF ~ "ST' 10^3 " 80 k§" —— oi63 ~ m§
Lin3 J kg ¦ day
Recommendation 62: Provide justification for the use of the Jongeneel equation to
extrapolate chronic inhalation HEC to chronic dermal Human Equivalent Dose (HED).
The Nagano et al. (2007) study seemed appropriate to examine a POD for chronic inhalation
exposure. The route-to-route extrapolation equation developed by Jongeneel (2012) for NMP
was used to convert a chronic inhalation HEC to a dermal HED for non-occluded retained doses
of carbon tetrachloride. The Jongeneel study was presented as a Rijksinstituut voor
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Volksgezondheid en Milieu (RIVM) letter report to the National Institute for Public Health,
which may mean that it is considered gray literature rather than peer reviewed. It was not
referenced in PubMed, making it difficult to determine if it is routinely referenced as an
appropriate approach. Its use should be justified.
Recommendation 63: Consider assessing combined dermal and inhalation exposure for
workers.
One Committee member recommended that the EPA consider assessing combined dermal and
inhalation exposure for workers since it is very unlikely that dermal exposure to carbon
tetrachloride would occur in the absence of inhalation exposure.
Charge Question 5. - Risk Characterization
Question 5. EPA calculated human health risks for acute and chronic exposures. For non-
cancer effects EPA used a margin of exposure (MOE'), which is the ratio of the hazard value to
the exposure to calculate human health risks. Using an acute non-cancer POD, EPA evaluated
potential acute risks for workers for certain scenarios. A benchmark MOE of 10 was used with
the acute POD based on central nervous system (CNS) effects. For chronic occupational risks,
EPA used a POD for liver effects as the basis of the chronic non-cancer MOE calculations. A
benchmark MOE of 30 was used to interpret chronic risks for workers. An Inhalation unit risk
(IUR) for adrenal gland tumors was used to evaluate potential chronic risks to cancer endpoints
for worker exposure scenarios. The risk characterization also provides a discussion of the
uncertainties surrounding the risk calculations.
/'lease coiiwieiil on w hether the injornialion presented supports the Jiiiding
oin/ined in the drajt risk characterization section. // not. please suggest
alternative approaches or injornialion llnil could be used lo jurilier develop risk
estimates i\ iilim l/ie context oj l/ie ret/nil enienis stated in 1.1'. 1 \ luial Rule.
Procedures Jor ('lieiuical Risk I .valuation I inler the . Intended loxtc Substances
('otitrol. let (X2 I R
Response 0 5.1- Support for risk characterization.
Some Committee members expressed concern that the rationale for ignoring pathways for
terrestrial organisms was cursory. Simply noting that this is under the purview of other agencies
or offices of EPA was insufficient to provide a complete assessment of carbon tetrachloride
risks. See the discussion following Recommendation 19.
Recommendation 64: State clearly and justify whether a low-dose linear risk assessment
approach or a non-linear risk assessment approach is preferred.
For risks to human health, the Committee discussed what is meant by a linear low-dose
extrapolation or a non-linear or threshold approach and the implications for health risk
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evaluation. Before deciding on whether a linear low-dose extrapolation or a non-linear or
threshold approach provides a more appropriate model for assessing the carcinogenicity of low
exposures to carbon tetrachloride, the Agency needs to be clear about what these terms mean.
According to Crump (2011), a "threshold" dose-response is one in which there is a dose (the
threshold dose) below which exposures to carbon tetrachloride are incapable of having any effect
on the likelihood that a cancer occurs — the dose-response is constant (at the background
response) for doses less than the threshold dose. A "low-dose linear dose-response" is one which
is approximately linear at the lowest doses (i.e., one in which the slope of the dose-response is
positive and finite at dose of zero). A low-dose sub-linear response is one in which the dose-
response has no threshold dose, but the slope of the dose-response is zero at a dose of zero (e.g.,
~ dose2). A "low-dose supra-linear dose-response" is one that has an infinite slope at zero dose
(e.g., ~ dose"2).
The EPA Cancer guidelines (U.S. EPA 2005) defines low-dose linearity in the same way as
above: as a dose-response "whose slope is greater than zero at a dose of zero." Rather than
separately defining low-dose sub-linear and threshold, EPA (2005) defines "low-dose non-
linear" as a dose-response "whose slope is zero at a dose of zero." Note that this includes both
low-dose sub-linear and threshold dose-responses as defined above but does not include supra-
linear dose-responses as defined above. The EPA guidelines do not discuss or define supra-
linearity.
In order to conclude that the low dose-response is non-linear or threshold, it is not sufficient to
conclude that carcinogenicity is not produced via a mutagenic MOA. There are mechanisms
other than mutagenicity that can produce a low-dose linear response. For example, there is the
additivity to background argument — that is, if background tumors and tumors caused by
exposure are produced by a common mechanism, and if exposure acts by augmenting the
mechanism whereby background tumors are formed, then the low dose-response is expected to
be linear (Crump et al. 1976, See also Bogen 2016, Crump 2017). The discussion following
Recommendation 55 and Recommendation 56 are also pertinent to this discussion.
The Committee further discussed that while the Evaluation appears to present two approaches to
calculating low-dose risk (a low dose linear approach and a non-linear approach), these two
approaches appeared to be melded into a single risk assessment model (lines 621 and 4325). The
low dose linear approach was used for "low dose exposures of carbon tetrachloride." The non-
linear approach was used only for doses "exceeding the POD" of 18 mg/m3. It was not clear to
the Committee how the non-linear approach is to be implemented. Both the linear and non-linear
approaches are alternative approaches for quantifying low dose risk. The Committee does not
understand what it meant for the non-linear approach to be implemented for high doses only.
Some members noted that this confusion was due to the Evaluation's reliance on IRIS (U.S.
EPA, 2010) for its human health risk evaluations. Given this, the Committee wondered whether
any discussion of cancer induction mechanism was needed in the Evaluation, since, again, none
of it seems to be used for purposes of either qualitative or quantitative human health risk
evaluation.
The argument made by EPA in support of a linear extrapolation to assess the low dose risk from
carbon tetrachloride was not that the dose-response is linear but that the dose-response was not
sufficiently well understood to rule out a low-dose linear component. Some members of the
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Committee agreed with EPA's determination while other disagreed based on the MOA for this
chemical and its free radical metabolites. Some Committee members would like to see a non-
linear threshold-type of approach also presented for the cancer risks based on long-standing,
published, peer-reviewed evidence regarding the peroxyl radical-based mechanisms by which
carbon tetrachloride induces tumors.
The Committee concluded that the Evaluation should clearly state whether a low-dose linear risk
assessment approach or a non-linear risk assessment approach is preferred. The Agency should
not attempt to meld them into a single approach but consider presenting both methods (linear low
dose vs. threshold) in a side by side comparison to see the potential impact, if any, to the risk
characterization. Alternatively, the Agency should just rely on IRIS. If the latter, the Evaluation
should explain why it believed that IRIS, despite being more than 10 years old, was still
"correct" regarding its assessment of carbon tetrachloride.
Recommendation 65: Explain the basis and the calculations used in determining the points of
departure.
There appeared to be no description of the calculation of the POD of 18 mg/m3 in the document.
Recommendation 66: Describe what the two uncertainty factors, UFa and UFh, represent and
give some basis for their values.
The NOAEL was generally based on observing no statistically significant increase in response
from a few dozen rodents. This provides very slim evidence that it represents a true no-effect
level even in the rodent population from which it was derived. Likewise, when a BMDL is used
instead of a NOAEL, the BMDL does not represent a no-effect level but rather a statistical lower
bound on the dose corresponding to a positive response level (i.e., 10 percent). Two uncertainty
factors were generally applied in either calculation (UFa = 3 and UFh = 10). These two
uncertainty factors do not account for the 10 percent risk at the BMDL or the uncertainty as to
whether the NOAEL was actually a no-effect level. (Frequently, if both can be calculated, the
BMDL for an extra risk of 0.1 will be smaller than the NOAEL). Therefore, another factor is
needed to reduce the risk to an acceptable threshold, if a threshold was being assumed. It could
also be argued that a factor is needed to account for the seriousness of the health effect. Given
that there is uncertainty in the assumption that the NOAEL, or BMDL safety factor approach for
non-cancer effects actually reduces the risk to non-significance, life-threatening effects should be
regulated more stringently than less serious effects. This could be accomplished by assigning a
factor to account for the seriousness of the health effect.
Recommendation 67: Review and discuss uncertainty factors (UFs) used by other expert
bodies for carbon tetrachloride and consider any changes needed for this Evaluation. Explain
how assessments from other jurisdictions were, or were not, considered for this Evaluation.
The Evaluation does not contain any basis for uncertainty factors UFa and UFh or state precisely
what they represent. The Committee recommended that the basis for these uncertainty factors be
included in the document with appropriate discussion. Committee members also suggested that
EPA review the UF's used by other expert bodies, such as those used for setting the maximum
workplace concentration or Occupation Exposure Limits for carbon tetrachloride in Germany,
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the MAK (2000), that is based on its potential to cause toxicity, including tumors, in humans.
Another Committee member noted that Table 1-3 (Evaluation pages 27-28) includes assessments
done by other countries, including the Health Canada guidelines for drinking water. The German
MAK assessment should be added to Table 1-3. In addition, the Evaluation should include more
details on how the completed assessments were used in this risk evaluation.
Another Committee member commented that there appears to be an important data gap and
uncertainty about what exposure level will protect a developing fetus for a pregnant woman
exposed in the workplace. This chemical is an acute neurotoxicant and the Evaluation assumes
that the acute no observed adverse effect level for dizziness will protect for developmental
neurotoxicity, with an MOE of 10. There does not appear to be any developmental neurotoxicity
or multigenerational studies that inform this issue. The developmental toxicity study was only
conducted at high doses.
Recommendation 68: Consider whether additional uncertainty factors are needed.
A Committee member commented that the National Academy of Sciences in their
recommendations for operating procedures in the setting of acute exposure guideline levels
(AEGLs) (NRC, 2001) provided more leeway in the choice of uncertainty factors than may be
indicated by the Agency's own guidance. In particular, Sections 2.5 and 2.6 in NRC (2001)
described decision roadmaps on how to establish chemical-specific uncertainty and modifying
factors that consider the broad range of uncertainties in deriving risk-based health protection
values. This Committee member commented that EPA should consider adapting this type of
decision roadmap in order to increase clarity and transparency when adopting uncertainty
factors.
Another Committee member commented that while the EPA used the uncertainty factor of 10 for
acute CNS depression, the AEGL committee determined that the value of three was sufficient.
Therefore, EPA should clarify that the uncertainly factor would protect against liver toxicity for
all purposes.
Another Committee member commented that sensitivity to carbon tetrachloride toxicity is
directly correlated to the levels of CYP2E1 present in the individual. Ethanol is an inducer of
CYP2E1. According to the Centers for Disease Control and Prevention (CDC), over 50% of the
U.S. population aged 12 years and over consume ethanol (CDC, 2018). A 12-fold intra-human
variability was found in the quantities of hepatic microsomal CYP2E1 (Snawder and Lipscomb,
2000). For this reason, the Committee member questioned if the uncertainty factor for intra-
human variability should be greater than 10 and suggested a factor of 12 be used.
Another Committee member discussed the terms of selecting PODs, and the effects observed at
the lowest dose levels (from JBRC, 1998). This Committee member suggested this process of
selecting the POD from the JBRC studies should be considered for the selection of the POD. The
same Committee member explained that the JBRC study did not appear to establish a NOAEL,
which is the basis for Nagano (2007) and the Evaluation hazard and dose-response assessments.
For example, there were changes in the mouse liver histology at 10 ppm at 13 weeks (JBRC,
1998, page 118), and changes in blood parameters in the male mouse at five ppm for two years
(JBRC, 1998, p 132), with effects on the spleen in male rats at five ppm, as well as non-
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significant increases in many types of endocrine tumors at low- and mid-dose in female rats (see
comment to Question 4.1). Despite the many changes observed in the JBRC studies at the lowest
doses, the Evaluation reports lowest and mid-doses as NOAELs for key endpoints in Appendix
H, and line 4175 of the Evaluation that are higher.
A Committee member noted that Tables 4.3 to 4.6 of the Evaluation are very helpful, though
some Committee members preferred other formats versus stacked bars (e.g., parallel bars). The
previous Committee member commented that Figures 4-1 to 4-4 were very good and that the
EPA should do the same type of graphical representation for dermal exposure.
Recommendation 69: Use a 45-year working lifetime instead of a 40-year lifetime to align
with the NIOSH policy. It would also be useful to calculate risk using ranges of work lifetimes.
The Committee requested additional information on the use of a lxlO"4 cancer risk in previous
reviews and was pleased to note the Agency provided this information here with a reference to
the NIOSH Chemical Carcinogen Policy. This policy explains the NIOSH approach to reducing
risk including quantification using a risk management limit of lxlO"4 over a working lifetime of
45 years. It also discusses the use of a hierarchy of controls, which starts with elimination or
substitution and ends with PPE as the last option. A Committee member noted that EPA has
taken a different perspective than that of NIOSH, which seeks out practical ways to protect
workers who are using the target chemical. Under TSCA, EPA is actively evaluating risk to
human health and the environment for the defined conditions of use.
As with other reviews, the Committee noted that workers were exposed both dermally and via
inhalation concurrently, and that the Agency should aggregate exposures See also the
discussion following Recommendation 22.
/'lease comment on the characterization oj uncertainties and assumptions
including whether I has presented a dear explanation oj underlying
assumptions, and accurate coniexiiializalion oj uncertainties. /'lease provide
information oil additional uncertainties ami assumptions that 1 has not
adequately presented.
Response Q 5.2- Characterization of uncertainties and assumptions
Recommendation 70: EPA should clearly describe which COUs pose unacceptable risks in the
absence of PPE. This should be clarified in the Executive Summary and in Tables 4-13 and
Table 5-1 of the Evaluation.
A Committee member commented that they would like to see more discussions as to why a
NOAEL of five ppm is used when there were effects seen in JBRC (1998) (e.g., spleen, urine
analysis, white blood cell count) at five ppm that do not seem to be reported in Nagano et al.
(2007a). This Committee member suggested that these observed effects could inform levels
impacting developmental neurotoxicity and immune effects.
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Another Committee member commented that the characterization for estimates of exposure
based on monitoring data are appropriate, however the modeling estimates requires additional
analysis and discussion in terms of uncertainty.
It was mentioned that monitoring data from OSHA and/or NIOSH inspections could be useful
for informing exposure levels. One Committee member commented that the OSHA inspection
data available online reports measured workplace levels at 39.5 ppm and possibly higher, values
much higher than the "high end" exposure level reported in the Evaluation.
The Committee suggested that the EPA make it clearer which COUs pose unacceptable risks in
the absence of PPE. Risk determinations can be found on pages 22-23 of the Evaluation. These
COU risk determinations should list COUs that pose unreasonable risk assuming no PPE use,
and further identify those COUs where assumed PPE use reduces risk to a level that the COU is
assessed as having reasonable risks. This step is needed to support safety professionals and the
public in identifying those COUs where use of carbon tetrachloride poses potential risk when
workers do not use PPE. This will also assist in targeting risk management. Similarly, it was
noted that the Agency should clarify PPE assumptions and risks with and without PPE in Table
4-13 and Table 5-1 of the Evaluation.
I'h:ase comment on the validity <>j specific conh deuce summaries presented in
section 4.5.
Response 0 5.3- Specific confidence summaries in section 4.5
A Committee member commented that the confidence summaries are appropriate as written,
while also expressing the sentiment that it would be more useful to have confidence expressed in
a more quantified manner. The Committee member recognized the difficulty of accomplishing
this in practice.
Recommendation 71: present a more detailed discussion of the links between uncertainties
and the overall level of confidence assigned to each risk estimate.
Another Committee member commented that, in general, there appears to be discrepancies
between the types and levels of uncertainties described by the Agency, and the resulting levels of
confidence. For example, high confidence relating to environmental risk appears overstated
given the uncertainties described as related to environmental risks. Similarly, the high level of
confidence for surrogate scenarios is not well justified. Section 4.5 of the Evaluation should
present a more detailed discussion of the links between uncertainties in exposure as well as
hazard assessment, and the overall level of confidence assigned to each risk estimate. Little was
stated about uncertainties in the hazard assessment as compared to the exposure estimation in
this section of the Evaluation.
Recommendation 72: Re-evaluate the description of uncertainties in dermal risk after
addressing the faulty calculations used in estimating the dermal POD.
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The Evaluation states that the EPA has low confidence in the risk estimates for dermal exposure.
The Committee agreed with that assessment. However, the EPA stated the conservative
assumptions used to derive PODs were likely to result in overestimation of risk. However, some
Committee members disagreed with this statement. It was the opinion of some members,
regarding mortality observed in the Wahlberg and Boman (1979) study (the only dermal study
with an acceptable rating), the importance to refrain from underestimating risk. The Committee
also noted that PODs could be erroneously calculated for acute occluded and non-occluded
dermal exposure. The Agency should address over or underestimating risks prior to its
determination. See also the discussion following Recommendation 59, Recommendation 62, and
Recommendation 61.
/'/case comment on the objectivity oj the selection oj the data used to support
() 5.4 the risk characterization and the sensitivity oj the agency's conclusions to
analytic assumptions made.
Response Q 5.4- Objectivity of data supporting risk characterization and sensitivity of
conclusions
During the meeting, Committee members made comments for this question that have
subsequently been integrated into the discussion and recommendations made for previous
questions. This includes use of the HSIA exposure measurement data as discussed for
Recommendation 29, and the consideration of sperm function/morphology and testicular
toxicology as discussed for Recommendation 38.
Some Committee members noted that the HSIA exposure measurement data provided to EPA
had several personal samples (all less than 0.066 ppm) collected for a non-user (i.e., a worker in
a supervisory role). The Evaluation does not mention these data or why they are not used in
estimating ONUs' exposures or to compare with the default exposure estimate of central
tendency for the worker. As discussed for Recommendation 29, the Agency should clarify this
issue as it may be construed as a data selection bias.
As discussed previously for Recommendation 45, the EPA needs to explain the exclusion of the
many studies that evaluated the immune responses induced when carbon tetrachloride was used
as a positive control for inducing liver inflammation/fibrosis in animals.
Recommendation 65: Explain why studies that evaluated the immune responses induced
when carbon tetrachloride was used as a positive control for inducing liver
inflammation/fibrosis in animals were excluded from data integration during systematic
review.
The issue of changes of sperm function and testicular toxicology discussed for Recommendation
39 were also discussed.
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Recommendation 73: Consider incorporating the additional studies identified by the
Committee as important into the Evaluation.
Additional studies considered important by the Committee are in the discussions following:
1. Recommendation 14 - additional environmental studies,
2. Recommendation 38 - additional genotoxicity studies,
3. Recommendation 39 - additional spermatotoxicity studies, and,
4. Recommendation 41 - additional epidemiology studies.
Recent studies on oxidative stress in the brains of rodents administered high doses of carbon
tetrachloride (Okora, et.al 2019, Altinoz, et. al. 2018, and Ritesh, et. al. 2015) were identified as
important but not included in the Evaluation. The Ritesh et al. (2015) paper was identified in the
initial literature search but determined to be "off topic" for environmental hazard (U.S. EPA
2017a) and thus not carried forward for evaluation. The initial literature search classified some
animal studies as potentially relevant for environmental hazard, even those studies on model
organisms whose findings should be considered for informing human health hazards. The
Committee noted this is another example of how the current TSCA systematic review process is
not working as expected.
Regarding MOA for both the toxicity and tumorigenicity of carbon tetrachloride, one Committee
member recommended the Evaluation rely upon Slater (1987) and studies cited therein.
Recommendation 74: Consider performing a more robust sensitivity analysis such as the one
proposed in Thabane et al. (2013) study.
Another Committee member noted that it was not possible to address the issue of how sensitive
the Evaluation's conclusions are to the analytic assumptions made when there is no formal
sensitivity analysis. After discussion it was proposed that EPA should look at how small changes
in grouping COUs affect the conclusions. Consider parametrizing some of the qualitative
assumptions or input different assumptions and assess how the risk conclusions vary. Refer to
the study from Thabane et al. (2013) for insights on how to conduct a more robust sensitivity
analysis.
() 5.5
I'lease comment on any oilier aspects oj the human health risk characterization
thai has no! been meniionci/above.
Response O 5.5- Other aspects of the human health risk characterization
Recommendation 75: Improve the discussion and summarize the data supporting the decision
to exclude consumer exposures from this evaluation.
Consumer exposures were not evaluated. This is justified by the fact that there are several
indoor, outdoor and personal monitoring studies demonstrating low-level concentrations of
carbon tetrachloride. The Evaluation should include a table and a brief discussion of these data
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(as was done for the methylene chloride evaluation) to provide a more objective context for its
decision not to evaluate risk for consumers, and for contrasting with occupational exposures.
Recommendation 76: Include background exposures in the assessment for workers and ONUs
or alternatively provide a more detailed justification why background exposures are not
considered.
The National Oceanic and Atmospheric Administration (NOAA) reports that atmospheric levels
of carbon tetrachloride have remained relatively constant for the last 30 years. This is supported
by data from Clean Air Act (CAA) that show that for those sites where carbon tetrachloride is
detected, many show no change, but some show an increase over the last 10 years. Several
Committee members noted that the estimated worker and ONU risks from carbon tetrachloride
exposure does not include in the exposure estimate these ambient (background) levels. The
Committee understood that monitoring and regulation of ambient air levels of carbon
tetrachloride (and other similar volatile chemicals) fall under the purview of the CAA. For many
on the Committee, this fact should not excuse not including ambient carbon tetrachloride
concentration in exposure calculations for workers, ONUs and consumers. There are concerns
that ambient carbon tetrachloride concentration values, in some locations, exposes workers,
ONUs and consumers living in these areas to greater risk for carbon tetrachloride and subsequent
health effects.
Other issues relating to ONU exposure estimation that were discussed as part of this question
have been incorporated into the discussions following Recommendation 28 Recommendation
29, and Recommendation 30.
Charge Question 5.6. The Frank R Lautenberg Chemical Safety for the 21st Century Act
(2016; amended TSCA (TSCA § 6(b)(4)(A)) requires that "potentially exposed or susceptible
subpopulations " (PESS) be considered in the risk evaluation process.
/'lease conmieiil on whether /he risk eva/nalioii has adei/na/ely addressed
poleniia/ly exposed or susceptible siibpopn/aiioiis.
Response 0 5.6- Has risk characterization adequately addressed PESS
Recommendation 77: Consolidate explanation of PESS into one section and develop more
protective guidelines for PESS.
One Committee member noted that the discussion in Section 4.3 of the Evaluation was
reasonable and that it was clear as to why the Agency considered PESS in the context of
workers. It was not clear as to why Section 2.5.1 appears to be abbreviated versus later
discussions in Section 4.3, which describes potential PESS within workers and ONUs.
Discussions located near the end of the last paragraph in Section 4.3 address UFs for non-cancer
effects (which refers readers to Section 3.2.5.2). The PESS section does not mention if
intraspecies UFs of 10 were applied. As previously discussed by the Committee, UFs of lOx are
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generally used to account for variation among people and not for known PESS. There are
variations in the intraspecies UF guidelines, including at times workers being assigned
intraspecies UFs of five, because workers are assumed to be a more homogeneous population.
Another Committee member noted that the Evaluation lists the variables that define PESS in
both sections 3.2.5.4 and 4.3, and that the general PESS categories are appropriate (refer to the
Evaluation, lines 4384-4392, and 4932-4935). However, each category is described to different
extents, in some places extensively, in other places briefly, and occasionally not at all. For
example, there are no descriptive discussions regarding subpopulations with pre-existing disease,
beyond identifying the subpopulations as a category. The paragraph in lines 4964-4966 does not
offer additional explanations in Section 4.3 due to workers and ONUs as being identified as
PESS earlier in previous paragraphs.
Recommendation 78: Consider including and discussing individuals who are sensitive to
oxidative damage and the embryo/fetus of pregnant female workers as PESS.
Hereditary hemochromatosis is an autosomal recessive disorder that affects about one in 200 to
500 individuals. Individuals with this condition have high levels of iron in their body and are
likely to be sensitive to oxidative and peroxidative damage caused by carbon tetrachloride. This
is supported by animal studies (Arezzini et al., 2003; Sebastiani et al., 2011). In addition, about
10% of the U.S. population are heterozygous for this condition, and there is evidence that they
may also be at increased risk for oxidative damage (Houglum et al., 1997). Those who are either
homozygous or heterozygous for this condition should be included among the groups that would
be more sensitive to carbon tetrachloride-induced oxidative and peroxidative damage.
Another Committee member commented that the embryo and fetus (pregnant female workers)
should be considered a PESS based on the neuroblastoma risk.
Later in the meeting, a Committee member noted that the discussion of PESS appears disjointed
and not very compelling without a risk evaluation for susceptible populations.
/'/case comment on whether the risk evaluation iloeiinieni has adei/nately
described the uncertainties am/data /imitations associated ivilli the
methodologies used lo assess the human health risks with respect to
potentially exposed or susceptible subpopulations. I'lease comment
on whether this information is presented in a clear and transparent manner.
Response O 5.7- Has RA adequately described uncertainties and data limitations
Recommendation 79: Expand and clarify the uncertainty factor discussions, especially
regarding PESS.
Uncertainty factors were discussed by the Committee as part of this question. Some of this
discussion is a repeat or expansion of the points discussed following Recommendation 56,
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Recommendation 66, Recommendation 67, and Recommendation 68. These previous discussions
are not repeated here.
Collectively, these discussions point to a need to expand and clarify the uncertainty factor
discussions in the Evaluation. The Evaluation lacks a separate section that discusses how UFs
should be applied under TSCA. It is difficult to determine from reading the many sections that
discuss uncertainty factors in the Evaluation the extent to which all pertinent factors are used to
inform UFs, and whether the UFs applied adequately account for the uncertainties in the data and
the methods used to derive risk estimates.
One Committee member noted that the Evaluation is inconsistent in discussing uncertainties and
data limitations associated with methodology limitations, and in particular how this impacts the
assessment of health risks for PESS. Transparency is increased by having separate paragraphs for
each of the PESS categories. The Committee has recommended this be done for some cases,
such as alcohol consumption or variability in CYP2E1 status. This Committee member
suggested summarizing the pertinent information in terms of what is known about each specific
susceptibility category and indicating how this information has been included in the risk
characterization.
Charge Question 5.8. EPA characterization of human health risk from inhalation exposure to
workers includes estimates of risk for respirator use. These estimates are calculated by
multiplying the high end and central tendency MOE or extra cancer risk estimates without
respirator use by the respirator assigned protection factors (APFs) of 10, 25 and 50 (air-
supplied respirators). EPA did not assume occupational non-users (ONUs) or consumers used
personal protective equipment in the risk estimation process.
/'lease eoiiinieiil oil whether 1.1'. I has ai/ec/naie/v. e/ear/v. ami appropriately
0 5.8 presented l/ie reasoning, approach, assumptions, am! iinceriainiies for
characterizing risk lo workers iisini: I'I'E.
Response 0 5.8- Reasoning, approach, assumptions and uncertainties for risk to w orkins usins
PPE
A Committee member stated as part of its Risk21® effort, the Health and Environmental
Sciences Institute (HESI) developed a graphic that may prove useful in demonstrating risks with
and without the use of PPE. The graphic can be generated using a web-based tool10 available
from the risk21.org web site.
Another Committee member commented that EPA continues to improve in the description of
exposure controls, PPE, and the effectiveness of PPE with each new evaluation. The same
Committee member noted, the Agency was responsive to the prior comments from the
10 https://risk21.org/webtool/
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Committee regarding the lack of robust discussions in previous chemical Evaluations. However,
the Risk Characterization section should briefly summarize this information even if it is
discussed in detail elsewhere in the document.
Another Committee member commented that any use of glove protection factors listed in various
tables or in discussion should clearly reference OSHA guidelines.
One Committee member recommended that the COU risk determination tables within the
Executive Summary (Line 837) should include all of the COUs that pose an unreasonable risk
without PPE and identify COUs where using PPE is estimated to bring it into the acceptable
range. It is important that all COUs where carbon tetrachloride poses a potential risk without
PPE are identified.
Charge Question 6. - Content and Organization
Question 6. EPA's Final Rule, Procedures for Chemical Risk Evaluation Under the
Amended Toxic Substances Control Act (82 FR 33 726) stipulates the process by which EPA
is to complete risk evaluations under the Frank R. Lautenberg Chemical Safety for the 21st
Century Act. To that end, EPA has completed a draft risk evaluation for carbon
tetrachloride.
The evaluation of potential environmental and occupational exposures was considered by the
Committee as reasonably available information, including manufacture, use, and release
information, and physical-chemical characteristics. It is important that the information
presented in the risk evaluation and accompanying documents are clear and concise and
describes the process in a scientifically credible manner.
To increase the quality and credibility of scientific information disseminated by the Agency, it is
recommended the EPA should utilize the peer review process specifically as a tool for
determining fitness of scientific information for the intended purpose. The metrics below are
intended to guide the peer reviewers toward determining if EPA collected, used and
disseminated information that is fit for purpose' based on utility (the data's utility for its
intended users andfor its intended purpose), integrity (the data's security), and objectivity
(whether the disseminated information is accurate, reliable, and unbiased as a matter of
presentation and substance). The peer reviewers' critical focus should pertain to
recommendations of the technical information's usefulness for intended users and the public.
Tlease provide suggestions for improving i/ie clarity oj l/ie injornialion
presented in l/ie drafl risk evaluation.
Response 0 6.1- Sussestions for improvins clarity of the Evaluation
In general, the Committee found the Evaluation for carbon tetrachloride is an improvement in
terms of clarity from the past draft chemical evaluations. However, several areas require
additional explanation and/or revisions.
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Recommendation 80: Consider reordering the presentation of materials in the Evaluation to
discuss environmental exposures, hazard and risk characterization before human health
exposures, hazard and risk characterization and followed by PESS exposures, hazard and risk
characterization.
Members of the Committee had divergent opinions regarding the clarity of the information
presented in the Evaluation, both in terms of general organization and its content. Some
Committee members were satisfied or stated they did not have any issues with the current
organization of the Evaluation. The Committee discussed the extent to which clarity and
readability would be improved if rather than having Environment, Human Health, and PESS in
rotating order under major headings of Exposure (Section 2), Hazard (Section 3) and Risk
Characterization (Section 4), EPA organize the Evaluation document to cluster the Exposure,
Hazard, and Risk under the major headings of Environment (new Section 2), Human Health
(new Section 3), and PESS (new Section 4). The alternative format follows the organization used
in the Agency's technical slide presentation made to the Committee by EPA. A majority of the
Committee supported this recommendation as one way to reduce the repetition that occurs
throughout the document.
The remaining Committee members, while recognizing that this was a long-standing
organizational format, proposed that clarity and readability would be improved by
presenting the environmental and occupational exposure, hazard, and risk characterizations
as two distinct sections instead of rotating through these topics in Section 2 (Exposures),
Section 3 (Hazards), and Section 4 (Risk Characterization).
Recommendation 81: For cancer risk, the term benchmark dose (BMD) should be reserved for
PODs that are estimated by BMDs corresponding to risks (BMRs) at the lower end of the
observable range (e.g., 0.1%), estimated using the methods discussed in U.S. EPA (2012).
Recommendation 82: For non-cancer risk, the "benchmark MOE" should be appropriately
termed instead of the "total uncertainty factor (UFt)."
One Committee member indicated that the word "benchmark" was used to represent two
fundamentally different concepts in the Evaluation, which both differ from how benchmark is
typically used by the EPA (U.S. EPA 2012; Davis et al., 2011) and other organizations such as
the European Food Safety Authority (EFSA 2017; Haber et al., 2018).
For cancer effects, the Evaluation defines benchmark risk as the target risk (10"4) and BMD as
the dose estimated to correspond to that target 10"4 risk. For non-cancer effects, the benchmark
MOE is a unitless factor that is divided into the POD (generally the NOAEL exposure) to
determine a sufficiently safe exposure. Both uses differ from how EPA has used the BMD term
previously, and also differ from the original purpose of the BMD.
The BMD was introduced as a method for defining the dose corresponding to a BMR, which
represented a risk near the lower limit of the range of observable data, i.e., a risk (e.g., a risk of 1
in 10) for which the corresponding dose could be accurately estimated with little model
dependency (Crump, 1984). It was proposed as a replacement for the NOAEL in situations in
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which the data are sufficient to permit its calculation. This is also how BMD has been used by
EPA (Davis et al., 2011; U.S. EPA, 2012) in the past.
In the carbon tetrachloride Evaluation, BMD is used to represent the dose corresponding to a
specified small risk (e.g., lxlO"4 for occupational workers). For describing the risk for cancer
effects, the Evaluation defines BMD as the dose corresponding to a risk of lxlO"4, a dose that is
often far smaller than one that can be estimated with little model dependency and/or near the
lower limit of observable data.
This non-standard use of the word "benchmark" is apt to cause confusion among readers of the
Evaluation. Likewise, the term "benchmark MOE" used with non-cancer risk assessment can
also be confusing because it does not agree with the traditional use of the word "benchmark."
The word "benchmark" also incorporates estimates that include the total uncertainty factor
(UFx).
The Committee agreed that this defining term for "benchmark" would be more descriptive than
"benchmark MOE." The Committee also agreed that assigning the term "benchmark dose" to the
estimated dose corresponding to a risk of lxlO"4 can lead to confusion. Even if this dose was
calculated using benchmark software (U.S. EPA, 2012), the risk of lxlO"4 was clearly too small
to be free of significant model dependence. However, the Committee noted that since this dose
was estimated using a linear model, it is probably very close to the dose that would have been
obtained using standard benchmark methodology, i.e., by defining a POD as the BMD
corresponding to a risk of 0.1 and extrapolating down linearly from that POD to a risk of lxlO"4.
Recommendation 83: Adopt a method for distinguishing exposures to rodents from human
equivalent doses and apply this distinction consistently.
Some Committee members found that the explanation in the Evaluation of the approach used to
calculate human equivalent doses using a pharmacokinetic model difficult to follow. It is not
always clear if the dose being discussed represents the dose applied to a rodent, or the human
equivalent dose. For example, it was not clear on first reading by one Committee member that
the BMDLio of 14.3 mg/m3 (line 4103 in the Evaluation) refers to the human equivalent dose.
EPA should develop and use consistently a way of distinguishing rodent from human doses in
these situations.
The Committee found the discussion on PPE and its effectiveness much improved in this
Evaluation compared to previous Evaluations. There is more emphasis on risk characterization
estimates without PPE. There is recognition that effectiveness is not just a function of the
physical properties of PPE as a barrier, but also on the extent to which the PPE is used and
used appropriately in practice. There are some areas that require improvement (which were
presented to some extent in previous Evaluations).
Recommendation 84: Consider carefully which information needs to be provided explicitly in
the body of the Evaluation from the more detailed information available in the Appendices.
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In previous reviews of TSCA Evaluations, the Committee commented on how often key
information is not found in the body of the Evaluation but found in one or more Appendices or
supplemental documents.
The Agency is getting better at reducing this issue. The Committee recognized that the carbon
tetrachloride Evaluation was a challenge due to the volume of information available to inform
exposures and risks and the difficulties of sorting and integrating this often-disparate
information into a coherent risk evaluation. Some key information is not located in the body of
the Evaluation, but the reader is referred to an Appendix for detail. Once in the Appendix, the
reader is referred to a supplemental document for the information. This daisy chain of referrals
complicates reading and comprehension. An example of this is the text on page 53, line 1662
of the Evaluation that references Appendix F — Occupational Exposures. Appendix F has a
total of 4 lines that essentially points the reader to the supplemental document U.S. EPA (2020)
for details on occupational exposures.
The Committee continued to encourage placing that information/discussion that is crucial to
establishing the exposure, hazard, and risk findings into the body of the Evaluation, and
placing the detailed arguments and computations into Appendices or Supplemental Documents.
Creating a concise and comprehensive discussion in the body of the Evaluation is difficult but
important to constituent understanding.
Recommendation 85: Optimize the use of active links within the Evaluation and provide
external access to increase readability and transparency.
The Committee provided several recommendations in previous TSCA risk evaluation reviews
on optimizing use of active links within the Evaluation and on how links to external documents
enhances readability and transparency. These recommendations also apply to this Evaluation,
maybe more so due to the large amount of information provided in large supplemental
documents. It would be very helpful to improving reading comprehension if links could be
provided that tie directly to the sub-section of the document (an appendix or supplemental
document) where the specific information (i.e., to the specific table, section, page, etc.) is
located. Currently, links are to a whole document that require readers to search the document
for the specific information referenced. Specifically, key values in summary tables (e.g., tables
of exposure estimates, PODs, risk estimates, etc.) should be linked either internally to where
they are discussed in the Evaluation document or externally to documents where the value is
derived and/or discussed.
Recommendation 86: Highlight for readers those COUs where the determination of no
unreasonable risk is directly related to the assumption of PPE use.
The Committee noted the expansion in this Evaluation of background information on the use of
occupational exposure controls and PPE effectiveness. This was considered an improvement
over that provided in previously reviewed chemical evaluations. The Committee expects that
many readers will likely focus on risk determination values under conditions with and without
PPE use, and not also carefully consider the background information about PPE presented in
this Evaluation. The Evaluation should alert readers to pay attention to this information, and in
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particular, alert readers to COUs where the decision of no unreasonable risk is directly tied to
assumptions of PPE use.
Whenever EPA derives or cites a risk that is not unreasonable because of the assumption of PPE
use, a modifying phrase should be added to enhance attention to the limitations in this
assumption (e.g., EPA has determined that COUx (Scenario x) does not present an unreasonable
risk contingent upon adherence to OSHA standards on exposure controls and PPE requirements
and recommendations).
Recommendation 87: Provide more specific information about relevance of other legislation
and the specifics of environmental or human health risk addressed by other organizations.
In Section 1.3 — Regulatory and Assessment History (Evaluation, pages 26-28) the Evaluation
mentions national and international laws to which carbon tetrachloride is subject (Evaluation
subsection 1.3.1, page 21 and Appendix A) and prior assessments by other national and
international agencies with regulatory mandates on carbon tetrachloride, (Evaluation, Table 1-
3, page 27). However, the section is not very informative. It needs to provide a brief and
specific description of the relevance to the current Evaluation, or whether the prior assessments
have indeed addressed exposures and risks that EPA decided not to address in this Evaluation
(for example, risks to populations in close vicinity to major point sources). Having a statutory
mandate for evaluating environmental or human health risk from a compound was not
sufficient to demonstrate that indeed such evaluation has been done for all relevant situations.
Recommendation 88: Develop and display a "key" for the reference section that facilities
identifying and tracing sources throughout the process of systematic peer review and data
source evaluation/validation.
The EPA relies heavily on prior carbon tetrachloride assessments done by other Agencies, as it
has done with some varying extent in prior Evaluations. There is a potential for missing key or
supporting studies if prior assessments had not adhered to systematic review. The Evaluation
should include clear statements as to whether principles of systematic review were applied in the
prior assessments and, if so, to what extents. A member of the Committee acknowledged that
EPA initiated the systematic review process, but there was still an issue of insufficient
transparency in the application of systematic review for selecting data sources and references
used in support of the risk evaluation and risk characterization. In the Evaluation, EPA
recognizes that some sources were not subject to the systematic review process (see, for
example, Evaluation page 45, lines 1408-1411). This member of the Committee proposed to
develop a "key" to the reference section of the Evaluation to make it easy to identify key and
supporting sources, identify the section of the evaluation where they are pertinent, know whether
the citations were subject to data quality evaluation (including, if applicable, the specific prior
review in which it was included), and identify sources that were not subject to data quality
evaluation and the reason why. The Committee agreed that the clarity and transparency in the
application of systematic review, the selection of key and supporting sources, as well as data
evaluation needs improvement.
Recommendation 89: Specifically note the criteria used to assess data relevance for risk
assessment in addition to determining data quality.
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Recommendation 90: Consider using other data in a corroborative sense to support high
quality studies used to develop a concentration of concern (COC).
Another Committee member noted an additional area of needed clarity in the data source
information provided in Section G.l — Systematic Review (Evaluation, Appendix G, pages 247-
269). The Agency lists many studies conducted in fish that evaluated enzyme induction (which is
not in itself an adverse effect) and some are IP exposures that were judged to be high in data
quality. However, EPA stated (refer to the Evaluation, page 96, lines 3072-3073) that 61 of 73
studies were of unacceptable data quality (suggesting that they were excluded), which seems to
contradict the information presented in Table Apx G-l table in Appendix G. Table G-l lists
more than 12 studies that are rated high in quality. Therefore, it appears the EPA used other
criteria to determine acceptability in addition to data quality. This was also inferred from the
statements in lines 6992-7003 of Section G.3 (Evaluation, page 272).
EPA should specifically note what criteria are being used to assess data relevance for risk
assessment in addition to determining data quality. In addition, EPA should consider using other
data in a corroborative sense to support high quality studies used to develop a COC. A simple
flow chart on this process may help clarify these issues in the risk evaluation.
Recommendation 91: Provide a brief description of the rationale for linking the information
on occupational exposure control to the decision to apply respirator and glove protection
factors.
A Committee member noted there are gaps between the description of the exposure control
hierarchy and the application of the PPE protection factors that reduces clarity. This Committee
member observed that the Evaluation should provide one or two paragraphs describing the
decision process between acknowledgement of guidelines for exposure control and the
application of protection factors for PPE. The remaining Committee members agreed with this
recommendation.
Recommendation 92: Add explanatory information in Tables 1-2 and D-l describing the
differences between the reporting periods for production and release.
Another Committee member indicated that the production and releases of carbon tetrachloride
are difficult to reconcile in terms of mass balance when comparing the releases reported in
Table Apx D-l (Evaluation, Appendix D, page 237; 2018 TRI Data), and the production volume
listed in Table 1-2 (Evaluation, page 26) for the CDR 2012 to 2015. In particular, the footer in
Table 1-2 [i.e., "The CDR data for the 2016 reporting period is available via ChemView
(https://java.epa.gov/chemview) (U.S. EPA, 2016d)"] raises the question why it was not added to
the release volumes. The Committee discussed potential explanations for the apparent
discrepancies but agreed that the Evaluation is not clear in this respect.
Recommendation 93: Correct formatting issue with Table 4-13 and improve clarity of Figures
4-1 to 4-4.
A Committee member emphasized that there are formatting issues with Table 4-13 (Evaluation,
page 160-163) that makes it difficult to read, and there is a lack of correspondence between some
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of the row across columns. Figures 4-1 to 4-4 (Evaluation, pages 156-157) could be made clearer
by using stacked bars rather than parallel bars.
Comments that relate to previous discussions:
Relates to Recommendation 75: Another member of the Committee indicated that the EPA
stated (Evaluation, lines 504 and 941), in 1970, the CPSC banned most consumer products
excluding those with unavoidable residues that would result in atmospheric concentrations not
exceeding 10 ppm. The EPA used this ban to support a decision to not evaluate risks from
consumer uses. This decision should be further supported.
A Committee member commented on the statement on page 20, lines 737-739:
"In each risk evaluation under TSCA section 6(b), EPA determines whether a chemical
substance presents an unreasonable risk of injury to health or the environment, under the
conditions of use. The determination does not consider costs or other non-risk factors."
Since decisions, such as to set the target cancer risk for exposed workers at 10"4, set MOE levels
at 10 or 100, set BMR levels at 5% or 10%, set expected working life length (see
Recommendation 61) or apply uncertainty factors, are all policy decisions that can involve costs
or other non-risk factors, the Committee member considers the statement above not exactly true
and that EPA should modify this statement.
Relates to Recommendation 85: The tables presented under the Summary of Risk
Determinations (Evaluation, Executive Summary, pages 22-23), starting in line 837 should list
all COUs that posed unreasonable risk with no PPE, and identify those where PPE is estimated to
bring that risk into reasonable range. Similarly, Table 4-13 (Evaluation, page 160) should clarify
PPE assumptions and Table 5-1 (Evaluation, page 177) should present the risks with and without
PPE.
Relates to Recommendation 80 and Recommendation 81: A Committee member found the
discussion in Section 5.1.2.2 — Determining Cancer Risks (Evaluation, page 173), also to be
unclear. Specifically, this section attempts to justify the choice of 10"4 as an acceptable risk and
disagreed with the unit risk also. This Committee member felt the Evaluation disregarded long
standing EPA policy, as also suggested by some of the public commenters. After some
clarifying explanations from EPA, another Committee member indicated that part of the
problem was that in a complicated document such as this Evaluation, it was easy for the
authors to believe that other people are familiar with the terminology as applied in the
document. He provided several examples, such as the use of the term "slope" in the paragraph
starting on line 4202 (Evaluation, page 131) or the term "MS-combo model" (Evaluation, page
134, line 4318), which was not referred to or referenced. There are also alternatives to the
approach taken by EPA in this regard. The EPA should also consider the approach described in
Chiu and Crump (2012) in the derivation of unit risk.
Recommendation 94: Quantify what is entailed in the phrase "Public outreach and literature
searches."
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On page 28, line 1012 the Evaluation indicates that "EPA conducted public outreach and
literature searches to collect information about carbon tetrachloride conditions of use and has
reviewed reasonably available information obtained or possessed by EPA concerning activities
associated with carbon tetrachloride." It would increase confidence if the "public outreach and
literature searches" could be quantified. As currently written, the text provides no specifics at all.
For example, have enforcement activities identified no violations of the 1998 Montreal Protocol,
1990 Clean Air Act Title VI or 1970 Consumer Product Safety Commission rulings? Just
because there are laws, it does not necessarily follow that there are no violators. In fact, this
assertion is weakened in the Evaluation by the admission that "carbon tetrachloride may be
present in a limited number of industrial products with chlorinated ingredients at a concentration
of less than 0.003% by weight" (Evaluation, page 30, line 1094). This could translate to 30
pounds per million pounds of product but there are millions of pounds of product created each
year.
Recommendation 95: The assertion of no significant use in consumer products should be
supported by a more specific description of the documentation used by EPA to arrive at its
conclusion.
One member of the Committee made comments regarding the presence of carbon tetrachloride in
consumer products. On page 30, lines 1062-1103, the Evaluation asserts that based on
information identified by the EPA, there are no approved consumer uses for carbon tetrachloride.
Further, carbon tetrachloride is not a direct reactant or additive in the formulation of
commercially available aerosol and non-aerosol adhesives/sealants, paints/coatings, and
cleaning/degreasing solvent products, and hence any exposures would be de minimis and
produce insignificant risks (Evaluation, page 30, line 1063). The problem formulation document
suggests the source of this information was "public outreach and literature searches" which were
directed at identifying activities currently associated with carbon tetrachloride and identifying
cou.
To demonstrate the "no use" assertion, one Committee member noted it was an exercise in
attempting to prove a negative condition — that is to demonstrate that the condition does not
exist. This was much harder than demonstrating a positive condition. One counterexample can
essentially disprove the negative conjecture. In science, the Committee believes a negative only
after extensive research fails to demonstrate the positive result, i.e. establishing the
overwhelming impossibility of the positive condition. It is the amount of searching, the
unbiasedness of the experiments that are the key to being convinced of the negative condition.
The Agency should provide better documentation for supporting the assertion of no significant
use in consumer products. An example of better documentation of uses can be found in Table A2
Sources Searched for Uses of Dipropylene Glycol Methyl Ether Acetate (DPMA)and Table A3
Uses of DPMA in the Draft Dossier for (TSCA) Candidate Low-Priority Substance Propanol,
l(or 2)-(2-methoxymethylethoxy)-, acetate (CASRN 88917-22-0) (DPMA) (U.S. EPA, 2019).
One Committee member thanked EPA for making very clear statements (Evaluation, pages 20-
22, lines 764, 782, 792, 825, 835) about excluding certain exposure and use scenarios from this
risk evaluation, for example terrestrial organisms or consumer products. These statements are
helpful because they provide guidance about which conditions of use would be preempted from
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state action because EPA included them in its Evaluation, versus uses that have been excluded
from EPA's Evaluation and, therefore, could be addressed by states without preempting EPA
authority. The Executive Summary should identify the COUs where carbon tetrachloride poses
potential risk without PPE so users can be made aware of the importance of PPE, and to help
target risk management.
Other comments:
The Committee noted that, in contrast to other EPA documents such as the IRIS toxicological
reviews, the names of EPA staff who were involved in writing the current document are not
listed. The Committee hopes that that these staff members will be recognized in the immediate
future for their work.
/.v the draft risk evaluation narrative presented in an ob/eclive and balanced
Manner and supportive of the risk characterization'* 1J nol. /'/ease provide
some specific recommendations to improve the draft risk evaluation in this
area.
Response 0 6.2- The Evaluation narrative objective, balanced and supportive
In its response to previous questions, the Committee addressed several areas that needed
additional clarification in order to present the information provided in the Evaluation in a
clearly objective and balance manner. These areas included the description of the engineering
assessment of worker activities, more specific and careful designations when using the term
"surrogate," clarification in the discussion about MOA, and the recommendation to fit both
linear and non-linear dose-response models, selecting the most conservative for the evaluation
of risk.
Relates to Recommendation 55: With respect to MOA, some public commenters suggested,
and the Committee agreed, that when there was conflicting information on the cancer MOA,
the EPA should at a minimum include a risk characterization for both to allow for comparison
of the results.
Relates to Recommendation 33: A member of the Committee re-emphasized the concern
about the use of respirator protection factors, discussed previously by the Committee. This
concern was particularly germane to exposures for manufacturing and processing as
reactant/intermediate (8-hr and 12-hr Time Weighted Average [TWA]).]). Even though EPA
estimated high-end chronic inhalation exposures with non-cancer MOEs below the benchmark
and cancer risks greater than the benchmark, EPA drew a conclusion that there was no
unreasonable risk in any of the manufacturing scenarios because of the exposure reductions
expected as a result of use of respirators which lead to MOEs greater than the benchmark
MOE (Evaluation, Section 4.2.8, page 158, and Table 4-13). In a similar manner, there were
cancer risks above the cancer risk benchmark for the high-end exposures for the additive,
processing agent/aid, import and repackaging, specialty uses-DoD and disposal/recycling
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conditions of use, but the EPA also accounted for the use of respirator protection factors to
conclude the cancer risk was below the benchmark.
Recommendation 96: Consider performing a wider assessment accounting for these
excluded pathways, which will provide a more reliable measure of the risk.
The EPA did not include in this Evaluation exposure pathways under programs of other
environmental regulations. The current exclusion of exposure pathways to general population
through releases to ambient air, drinking water, ambient water, biosolids, and disposal
pathways could lead to underrepresentation of the risks.
Relates to Recommendation 77: There was an additional discussion on PESS, and the factors
that make those populations susceptible (e.g., age, nutrition, alcohol consumption, nutritional
status, pre-existing medical conditions, and genetic variations). The Agency describes how an
uncertainty factor was used to account for variations of sensitivity, but it is not clear whether
the EPA did a separate assessment for these more susceptible individuals. It would seem that
the EPA is considering them as part of the workers and ONU groups, but this explanation is
not clear in the document.
Recommendation 97: Be specific when using the term "surrogate" when applying data from
one COU to another.
Recommendation 98: Ensure that the COU and its surrogate do not have hugely different
associated levels of uncertainty.
Recommendation 99: Describe better the engineering and worker activities associated with
a COU and compare to their surrogate COU to ensure they are not significantly different.
This was the first of the Evaluations reviewed by the Committee where EPA applies
monitoring data from one COU to another. The term "surrogate data" can mean different
things, with different levels of uncertainty. One example was applying monitoring data for the
target chemical to a different COU, like in the case of the manufacturing and processing COU.
The assumptions in this case are multiple (similar source types, similar processes, similar
worker activities, etc.). Another use of surrogate data consists of using monitoring data for a
chemical other than the target (which was not measured) on the basis that the surrogate
chemical has similar physicochemical properties (or differences in exposure concentrations
could be estimated from the properties). This type of surrogate requires less assumptions and is
likely to introduce lower uncertainty in exposure estimates than in the prior example. The
EPA's hierarchy of exposure estimation approaches does not distinguish between the two,
although they would be expected to have different levels of uncertainty, and both seem to
comingle in the Evaluation. It can be argued also that EPA uses workers' exposures as the
surrogate for estimating ONUs' exposures, which is yet another application of the term
surrogate.
Recommendation 100: The environmental risk characterization should be qualified to the
organisms actually evaluated.
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A Committee member noted that there may be risks to environmental receptors that are not
assessed in this Evaluation. There were multiple instances where the text points out uncertainties
that may overestimate risk, but it is also possible that these uncertainties could lead to
underestimation. Only aquatic receptors are quantitatively assessed in this Evaluation. Thus, the
risk characterization should make it clear that the EPA's findings in the Evaluation and
discussion are limited to those organisms. The language used to describe the scope of this
assessment (see Evaluation, lines 558, 581, 588, 1129, 1298, 3062-3070, 3076, 3084-3090, 3104,
4436, 4474, 5099, 5333, 6899-6872, 6964, and 7099) is insufficient. Several of these passages
are overly broad in describing the data that were assessed or in describing conclusions that are
drawn. The environmental concentrations are above the hazard thresholds and the conclusion of
no unreasonable risk is not fully justified (Evaluation, pages 175-176, lines 5430-5450). In
particular, the description of risk to environmental receptors should be appropriately constrained
to the organisms and species that were included in the evaluation, and the conclusion of no
unreasonable risk based on environmental concentrations above hazard thresholds be
reconsidered.
Recommendation 101: Expand the discussion of the Heineman et al., 1994, study.
The Committee discussed the results of the occupational epidemiology study by Heineman et al.,
(1994) that examined length of occupational exposures to four chlorinated aliphatic solvents and
the risk of astrocytic brain cancer. The authors reported; "Associations of astrocytic brain
cancer were observed with likely exposure to carbon tetrachloride, methylene chloride,
tetrachloroethylene, and trichloroethylene, but were strongest for methylene chloride."
The study reports a positive odds ratio for trend in risk of brain cancer by average intensity and
duration of exposure to carbon tetrachloride controlling for age and study area (Table III, page
162 Heineman et al., 1994). However, after adjusting for co-exposure to the other three
chlorinated aliphatic hydrocarbons, the association of carbon tetrachloride to brain cancer was no
longer statistically significant and the odds ratio at the highest level of exposure actually
decreased from the medium exposure level (Table IV, page 163, Heineman et al., 1994). One
Committee member was concerned about the importance of this finding due to the large number
of statistical analyses performed with no experiment-wide adjustment of significance.
Regardless, the Committee concluded that this study should be better described in the
Evaluation.11
It was noted with some concern by one Committee member that the risk assessment and
document did not appear to use in vitro studies on carbon tetrachloride. Another member noted
that caution should be used when evaluating in vitro carbon tetrachloride data given its volatility
and that common diluents used for in vitro studies [methanol, ethanol, dimethyl sulfoxide
(DMSO)] were competitive inhibitors of CYP2E1 and may interfere with carbon tetrachloride
bioactivation in those systems.
Recommendation 102: Continue to improve the systematic review process.
11 The IRIS review of carbon tetrachloride (U.S. EPA, 2010) concluded that there is some evidence for an
association between carbon tetrachloride and astrocytic brain cancer based on the Heineman et al., (1994) study but
felt that studies of this type suffer from poor characterization of exposures and confounding by other chemicals.
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One Committee member submitted a relatively simple, standard template for data extraction
from epidemiology studies (refer to charge question 4.2). When using this template, the specifics
of data extraction must be decided before evaluating the study. The template also included
objective criteria for quality evaluation of studies, so both the criteria for quality scoring and data
extraction are decided before looking at the findings.
Another Committee member noted that the quality of several studies in the Evaluation was
described as unacceptable but were used in the risk evaluation, nonetheless. This appears to
undermine the goal of using the best quality studies. This Committee member suggested an
alternative descriptor such as "poor" could be used to differentiate these studies from those
completely unacceptable. Another Committee member noted that this issue has been discussed in
prior reviews. The term "unacceptable" should be restricted to a study deemed of unacceptable
quality for a reason (i.e., unacceptable for...).
The quality versus acceptability issue also applies to human health studies. For example, a
publication could be of high quality but may not mention some important aspect of a protocol
making it unacceptable. Or, the study could be a high-quality single dose study, which makes it
unacceptable for deriving dose-response or a POD, but could be useful for a different purpose. A
different Committee member indicated that the systematic review needs to provide the context
for which a publication may be acceptable or not. This context is not always clear because the
names assigned to criteria for selection in the systematic review process do not always reflect
clearly the criteria.
(> 6.3
Is the (/iici/ily oj the data usee/in the risk characterization appropriate Jor the
purposes oj the evaluation ' 1] not. please provide specific cxanij'/cs ami
recommendations that may include additional data that IT. I could consider
in their assessment.
Response 0 6.3- Quality of data appropriate for purposes.
Recommendation 103: Address directly the issue of how many and what kinds of samples are
adequate to quantify exposures for COU scenarios.
The Committee has, in previous reviews, discussed the factors that need to be considered
when assessing the quality of data used for the risk evaluation. With respect to exposures,
evaluations continue to focus on the intrinsic quality of the data (i.e., whether exposure
sampling and analytical methods were appropriate and fully reported) as the single criteria for
acceptability. The Evaluations have not focused on whether the amount of data available is
adequate to derive reliable estimates of exposures for occupational scenarios in a COU. For
example, two personal monitoring samples collected with the appropriate methods can still be
insufficient to derive a reliable estimate of expected exposures for any COU scenario. This
Evaluation is clearer than others in this respect, but the issue of deciding whether there are
adequate samples for supporting exposure estimates remains essentially unaddressed.
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Recommendation 104: Confidence statements on risk estimates should synthesize
uncertainties in data and assumptions.
One Committee member expressed appreciation with the fact that EPA performed a
comprehensive data search and evaluation of available data, as documented in the Strategy for
Conducting Literature Searches for Carbon Tetrachloride: Supplemental Document to the
TSCA Scope Document (U.S. EPA, 2017). The member noted that EPA identified relevant
data from the initial search and incorporated "backward reference searching" into the data
search, technique that will be incorporated in future searches. In general, this was a widely
studied chemical and the hazard data was well understood by the risk community. Conversely,
the EPA did not consider the environmental risk of carbon tetrachloride as an ozone depleting
substance.
The Committee has, in previous reviews, discussed the issue that confidence statements on
risk estimates do not seem to be linked strongly to statements of uncertainty in data or
assumptions. This concern remains with the current Evaluation in that specific data
inadequacies/uncertainty and assumption uncertainties are not carried through to confidence
assessment of risk estimates.
For example, when comparing the uncertainties in risk estimates with or without PPE, it
would seem logical to have less confidence in risk estimates assuming PPE use when there is
no information as to whether the correct type of PPE is used in practice, or when used, is used
appropriately. The PPE risk estimates have additional sources of uncertainty than the no PPE
risk estimates, so the level of confidence in the two cannot not be the same unless we have
good knowledge of PPE use practices. Similarly, if one exposure estimate is based on 2
measurements and another is based on 10 measurements, one would expect the one based on
10 measurements to have less uncertainty. Given similar quality data, the two exposure
estimates cannot be assigned the same level of confidence. If we have risk results from two
alternative data sources, or two models, the associated data and assumption uncertainties are
unlikely to be same. Similar logic can be also applied to the biological aspects of the
evaluation. The Evaluation does not provide a clear and concise description of how all the
various data and assumption uncertainties carry through in assigning confidence to risk
estimates. A formal process needs to be established, described, and consistently followed.
The Committee also discussed data uncertainties and gaps that have implications on the
quality of the evaluation, primarily in the exposure side of the risk evaluation. Some
Committee members mentioned the lack of exposure data for several use scenarios and
subpopulations (e.g.. Table 2-19, Evaluation page 89), including:
• lack of inhalation exposure data for ON Us;
• very limited (three) data sets for specialty use of carbon tetrachloride;
• lack of exposure data during reactive ion etching;
• lack of exposure data in the processing agent/aid scenario;
• lack of exposure data for the additive use scenario;
• lack of exposure data for the laboratory use scenario;
• lack of exposure data for waste handling activities.
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Another insufficient data source is the lack of dermal exposure data, for which EPA has relied
on model-based estimation.
To increase confidence in risk conclusions, EPA will need to use its statutory authority to
request limited studies to obtain the quality data to better support these parts of the
assessment. This is particularly important for the draft determination of unreasonable risk for
ON Us. In addition, the Evaluations should include more sensitivity analysis results. This
relates to the discussion of charge question 6.5.
Recommendation 105: Include a summary of residential indoor and outdoor air
concentrations of carbon tetrachloride as well as personal air concentrations of the residents.
One Committee noted that EPA should provide a summary of the indoor, outdoor and
personal concentration measurements for the general population to provide more context for
its decision to not evaluate consumers exposures, as it did in the evaluation for methylene
chloride. The sources for these data are the same as those cited in that evaluation.
Recommendation 106: Discuss limitations and inadequacies of occupational monitoring data
collected to meet PEL standards rather than assess relevant health effects.
The Committee discussed the issue of occupational exposure data often not being of adequate
quality to support the Evaluation. Actual measurements are usually reported as non-detectable
because the methods used for occupational exposure monitoring are typically keyed to the
permissible exposure limit (PEL). Most of the occupational exposure measurements used in
the Evaluation occurred in scenarios that are considered well-controlled and for which more
data are available. While NIOSH and OSHA measurement methods may lag in analytical
precision, the data have been useful for evaluating effects on worker health. The data
identified for ONUs are predominately non-detections (NDs) as well.
One Committee member suggested that non-detectable values (also referred to as BDLs -
below detection limit values) are not so much inadequate as insufficiently informative for the
task of estimating exposures. There is a whole body of literature of how to treat ND values in
order to derive useful information, but these methods typically require some measurements to
be above the ND value. In the statistical literature this is referred to as estimation using left-
censored data.
Some Committee members noted that the HEC computed in the Evaluation is below doses
observed in the original animal study and similarly below the current PEL. The basis for the
chronic inhalation POD was set using the NOAEC for liver cancer of five ppm based on the
Nagano et al., (2007b) rodent study (Page 130, lines 4176-78). Using the PBPK model, the
associated POD for chronic inhalation for workers is computed (Table 3-14) as 31.1 mg/m3
(4.94 ppm) for eight hrs/d and five days per week of exposure and 26.4 mg/m3 (4.1 ppm) for
12 hrs/d and five days per week.
The Committee discussed the extent to which the five ppm was an appropriate basis for
setting the HEC. The Committee felt that more data is needed to validate use of such a low
HEC value. It was suggested that such data might be obtained by the NTP via a 13-week
Page 79 of 96
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inhalation study using four or five concentrations between 50 ppb to five ppm. Barring this
study, the risk characterization in the Evaluation should be labeled as preliminary, primarily
due to this low-dose extrapolation.
The Committee noted that the current PEL for carbon tetrachloride was not set based on the
health outcomes considered in the Evaluation, they were established many years ago. Lacking
an adequate biological basis for past exposure measures, it is important that the Evaluation
emphasize the dependency of the final risk determination on exposure estimates derived from
air concentrations measured as below detection limits. Since exposures to ONUs are predicted
using worker exposure levels, the same qualifier applies to ONU risk determinations. Because
of this, the Committee suggested that the Evaluation should indicate that all exposure
estimates for ONUs are preliminary.
One Committee member suggested that EPA partner with OSHA, or NIOSH, to get more
sensitive sampling and analytical methods in use in order to allow estimation of exposure
concentrations closer to 40 ppb or lower, (to allow for actual detected levels). Another
Committee member suggested that the amended TSCA law is a mechanism for starting a new
discussion on occupational exposure measurement and the PEL framework is no longer
appropriate. Another Committee member noted that public commenters indicated that there
are monitoring data relevant for ONUs in the manufacturing and processing sectors which
may be useful to the Agency to consider.
. Ire the uncertainties and assumptions miderlyin^ the risk assessment
transparently documented'' IJ not. w hich uncertainties and assumptions could
henefit from additional coniexiiiahialion and or clarification''
Committee Response 0 6.4- Transparently documented uncertainties and assumptions
Issues of uncertainties, assumptions, and their propagation through the evaluation of risk have
been largely addressed in the response to Question 6.3. In general, uncertainties and
assumptions are clearly described, particularly in terms of data gaps for inhalation exposure
for ONUs, inhalation-to-dermal route-to-route extrapolations, use of limited dermal data, and
gaps in the evidence to support a MO A for carcinogenesis at low dose levels. Appropriate
uncertainty and assumption characterization were presented in Section 4 - Risk
Characterization. Exposure assessments have been done following a statistical approach that
was appropriate and fit for use. Uncertainty factors used in non-cancer margin of exposure
were clearly documented (e.g., in Tables 4-3 through 4-6). Additional clarity is needed on
how the uncertainties propagate and are translated into the levels of confidence about risk the
estimates, or in decisions about adjustment factors.
Recommendation 107: Consider scoring data and assumption uncertainty to derive a final
confidence score.
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This Evaluation demonstrates progress but more needs to be done. One approach would be to
(numerically) score each data uncertainty and assumption uncertainty and subsequently derive
a final confidence score. The decision may be binary in many cases. For example, as indicated
earlier, given a risk estimate with no glove use for a scenario, the corresponding risk estimate
with glove use should have a higher level of uncertainty because of the addition assumptions
about glove used and effectiveness.
A Committee member indicated that the confidence rate of "high" presented in Section 3.1.2
(Evaluation, page 97, lines 3108-3 I 12) for risk to environmental receptors is not well supported
when compared to statements on page 160, lines 5173-5179, with respect to confidence in human
health risk, and considering the complexity that includes environmental breakdown products and
potential for indirect effects (e.g., lack of invertebrate prey base), neither of which were
evaluated. As a result, the confidence rating of "high" is not well supported. Raising uncertainty
factors and/or adjustment factors should correspond to raising confidence scores.
Relates to Recommendation 61: A member of the Committee warned that the primary
conclusions of the Evaluation were very sensitive to the error made in calculation of the dermal
carcinogenic slope factor (DSF) (see response to Question 4.4). In its current form, the
Evaluation found unreasonable risk only for inhalation exposure to ONUs. All worker COUs
exposures were found to not present unreasonable risk (if PPE was used effectively). Barring
changes other than correction of the DSF, worker exposures would exceed the 10"4 cancer risk
level for all dermal scenarios. The lowest cancer Lifetime Average Daily Dose (LADD) in the
right-hand column of Table 2-20 (Evaluation, page 94) is 5 -10"3 mg/kgd (a value that requires
assumption of a maximal GPF of 20). The product of that absorbed dose and the corrected DSF
[8 -10"2 (mg/kg d)"1] is 4-10"4. The error in the DSF (100X) was so large that no plausible
adjustment to the assumed glove protection factors could compensate for it. The final Evaluation
for carbon tetrachloride should find unreasonable risk for all worker COUs.
ll'hal additional analyses uiiifhl provide useful insight into the sensitivity of
() 6.5 ihe risk characterization conclusions, inch/din^ hm noi hmiicil lo the
assumptions iiicntionci/ in Sections 2. 4. ami 5. oj the draft risk evaluation?
Response 0 6.5- Sensitivity of risk characterization conclusions to assumptions
The Evaluation does not present an assessment of the sensitivity or risk characterizations to
assumptions. Concerns were expressed by some Committee members about the level of
experience within EPA with occupational exposure assessment and how this limited
experience impacts the Evaluation. One Committee member suggested that the risk evaluation
approaches used by Health Canada, the Netherlands, and the German MAK could be good
models to follow in this regard. Another Committee member noted that there are barriers to
adopting these approaches, and that the TSCA risk evaluations that have come to the
Committee for review go significantly beyond a literature or a regulatory review, which was
not to say that they cannot be improved.
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EDITORIAL NOTES
On p. 24 there's a "Section 0"
The title of U.S. EPA, 2019b (i.e., "Risk Evaluation for Carbon Tetrachloride, Supplemental
Information on Releases and Occupational Exposure Assessment") should be changed "Draft
Risk Evaluation for Carbon Tetrachloride Supplemental File: Occupational Exposure
Assessment." as shown in HERO.
Table 3-10: According to Nagano et al., (2007a) 31 male mice in the 125-ppm group had a
pheochromocytoma, not 32.
Line 4177: It seems that the Nagana et al. (2007b) reference should be Nagana et al. (2007a).
Paragraph beginning on line 4202: How is "slope" defined in this paragraph?
Line 4321 The "MS-combo model" is not defined. Perhaps the approach in Chiu and Crump
(2012) could prove useful in combining the risk from liver and adrenal tumors.
It is recommended that the entire document be reviewed to ensure that all notation has been
clearly defined and is used properly.
Line 800 the same sentence is repeated in this spot.
Table 2.3 needs a reference to Cherrie et al. (2004) (if that is what was used in developing the
Table).
On line 2143 "Cherrie" is misspelled, and a complete citation is needed.
Page 53, lines 1687-1695: The calculations for dermal occupational exposure without personal
protective equipment (PPE) are not explained, but it is said that "Dermal exposure assessment as
described in more detail in Appendix E of the document Risk Evaluation for Carbon
Tetrachloride Supplemental Information on Releases and Occupational Exposure Assessment'
(US EPA 2019b). When a reviewer tried to access this information, Appendix E was not found in
that supplemental document. The reference for the dermal assessment needs to be corrected.
Table 4-13, page 161 of the Evaluation consists of several formatting issues.
Page 82 of 96
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Table of Recommendations
Recommendation 1: Improve the justifications/documentation for excluding non-aqueous media from consideration. 18
Recommendation 2: Be consistent and better define how physical chemical properties and terminology are used to justify
THE EXCLUSION OF VARIOUS ENVIRONMENTAL FATE PROCESSES AND DISTRIBUTIONS 19
Recommendation 3: Better define the quality and variability associated with physical-chemical properties 20
Recommendation 4: Discuss the uncertainty associated with estimated exposures to aquatic organisms by the lack of
MONITORING DATA 22
Recommendation 5: Include discussion of metabolic pathways and environmental breakdown products 24
Recommendation 6: Include a mass balance assessment of carbon tetrachloride released to the environment 24
Recommendation 7: Add more discussion on the impact of more atmospheric input and long tropospheric half-lives on
OZONE DEPLETION 25
Recommendation 8: Add discussion, citations, or data to better support the assertion of de minimis exposures 25
Recommendation 9: The Agency should evaluate degradation products of carbon tetrachloride and conduct risk
EVALUATIONS IN TERRESTRIAL ORGANISMS AS WELL AS ENDANGERED SPECIES 26
Recommendation 10: The Agency should be very specific in language describing risks based on what was and was not
ASSESSED 27
Recommendation 11: Consider using benchmark dose methods to determine a POD for amphibians and either provide
MORE SUPPORT FOR THE APPLICATION OF AN AF OF 10 OR USE AN AF = 100 TO THE LD10 27
Recommendation 12: A 9-day exposure value should be compared to the 2.5 mg/L instead of the rounded-up value of 3
mg/L 27
Recommendation 13: The EPA should consider using an Adjustment Factor (AF) of 100 instead of 10 which would
INCORPORATE ADDITIONAL UNCERTAINLY INTO RISK CHARACTERIZATION FOR DEVELOPMENTAL EFFECTS 28
Recommendation 14: If RQ > 1 in multiple sites, a more refined risk characterization with better uncertainty estimates is
NEEDED 28
Recommendation 15: Clarify which criteria were used to determine acceptability (quality) and relevance for studies on
ENVIRONMENTAL HAZARDS AND CONSIDER USING OTHER STUDIES TO SUPPORT THE EVIDENCE FROM THE HIGHER QUALITY STUDIES.
Please also describe why more robust methods (e.g. species sensitivity distributions) could not be used 28
Recommendation 16: Justify the change in COC for environmental risk from 7to3 ug/l 29
Recommendation 17: Risk quotients should be made on conservative data from exposures as well as effects 29
Recommendation 18: Include carbon tetrachloride transformation products in the Evaluation 30
Recommendation 19: Include an evaluation of risk for terrestrial receptors or provide convincing logic why risk to
TERRESTRIAL RECEPTORS WOULD BE NEGLIGIBLE 30
Recommendation 20: Discuss the possible impact on endangered species 30
Recommendation 21: Be very specific in language describing risks based on what was and was not assessed. Broad
STATEMENTS OF "NO RISK" ARE MISLEADING GIVEN THAT ALL RISKS ARE RELATIVE AND NO CONDITION WHERE EXPOSURE IS PRESENT
IS WITHOUT SOME LEVEL OF RISK 30
Recommendation 22: Workplace exposure estimates should be aggregated 32
Recommendation 23: Exclusions of COUs during problem formulation should be made more explicit in the Evaluation
RATHER THAN REFERENCING THE SCOPE OF WORK. FOR EXAMPLE, PRESENT THEM IN A SUMMARY TABLE WITH THE REASONS FOR
EXCLUSION 32
Recommendation 24: EPA should develop a decision tree for using monitoring data or modeling notjustonthe basis of
THE QUALITY OF MONITORING DATA, BUTALSOONTHE QUANTITY OF DATA AVAILABLE 32
Recommendation 25: The justification for regrouping COUs should be described in more detail wherever it was
CONDUCTED. SURROGATE GROUPS SHOULD BE NAMED MORE SPECIFICALLY TO DISTINGUISH DIFFERENT TYPES. FOR EXAMPLE, A
CHEMICAL SURROGATE IS DIFFERENT FROM A WORKER ACTIVITY SURROGATE, ALTHOUGH THE EVALUATION SEEMS TO CONFLATE THE
two 32
Recommendation 26: Expand Appendix F to include pertinent material from Risk Evaluation for carbon tetrachloride,
Supplemental Information on Occupational Exposure Assessment (U.S.EPA, 2020) 32
Recommendation 27: Attempt estimation of ONU exposures where data permits as a check on default assumption of
MEAN WORKER EXPOSURE 33
Recommendation 28: Consider a hierarchy of ONU exposures to distinguish extremes within that classification 33
Recommendation 29: Explain why itwas decided notto use the HSIA administrative/supervisory personnel data, even if
ONLY TO COMPARE ITTO THEIR EXPOSURE ESTIMATES FOR ONUS 33
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Recommendation 30: Use measured OSHA data in the Evaluation to inform "high end" exposures 34
Recommendation 31: Estimate dermal exposure to vapor routinely 34
Recommendation 32: EPA should replace the assumed APFs in Table 4-13 with data-based estimates. If no reliable
ESTIMATES CAN BE DEVELOPED, ONLY RISK ESTIMATES ASSUMING NO PPE USE SHOULD BE PRESENTED, WITH APPROPRIATE CAVEATS
IN THE DISCUSSION 35
Recommendation 33: EPA should provide sufficient detail on use of the conceptual model in Cherrie etal. (2004) that a
READER COULD REPRODUCE THE VALUES REPORTED IN TABLE 2.3 35
Recommendation 34: Fix the quote regarding the CPSC ban for carbon tetrachloride on page 22 36
Recommendation 35: Tabulate ambient air levels for perspective in assessing consumer background exposures 36
Recommendation 36: Levels of confidence should be provided for each route, in addition to the overall result 37
Recommendation 37: The discussion of the modes of cytotoxic and carcinogenic effects of carbon tet, in both the liver
AND ADRENAL GLAND, SHOULD BE SUBSTANTIALLY EXPANDED, IN LIGHT OF THE KEY ROLES THAT THESE MECHANISMS OF ACTION
SHOULD PLAY IN ESTIMATING RISKS OF CANCER 38
Recommendation 38: The toxicokinetics discussion should be updated and expanded. Particularly on the influence of
EXPOSURE ROUTE ON SYSTEMIC DISPOSITION AND EFFECTS, AS WELL AS INTER AND INTRASPECIES DIFFERENCES IN METABOLIC
ACTIVATION AND SUSCEPTIBILITY 39
Recommendation 39: Major points about genotoxicity of carbon tetrachloride should be brought forward from
Appendix I, and overall conclusions reached about strengths, weaknesses, and limitations of existing studies,
WEIGHT OF EVIDENCE AND DATA NEEDS 40
Recommendation 40: The reproductive toxicity of carbon tetrachloride should be addressed and incorporated into the
document. The contribution of inhibition of immune function to an indirect carcinogenic MOA should be
DISCUSSED 41
Recommendation 41: The EPA should apply a non-linear model in estimating cancer risks, in light of the preponderance
OF EVIDENCE OF THAT LIPID PEROXIDATION- AND ENDONUCLEASE-DERIVED MUTATIONS, AND OTHER CYTOTOXIC EFFECTS, ARE THE
ORIGINS OF TUMORS OF THE LIVER AND ADRENAL GLAND 41
Recommendation 42: Effects of carbon tetrachloride on the central nervous system (CNS), in rodent studies, should be
ADDRESSED 42
Recommendation 43: Improve the discussion and include more details of the derivation of the points of departure 42
Recommendation 44: Key details on the derivation of the IUR similar to that provided in the IRIS summary should also be
PROVIDED IN THIS EVALUATION 43
Recommendation 45: Include discussion on carbon tetrachloride effects on inflammatory and immune effects 43
Recommendation 46: Expand the discussion of carbon tetrachloride's MOA for carcinogenicity in both the liver andthe
ADRENAL GLAND 44
Recommendation 47: A critical and more comprehensive evaluation of the reported associations between carbon
TETRACHLORIDE AND BRAIN CANCER IS NEEDED 44
Recommendation 48: Modify epidemiologic study identification and selection methodology to comply with established
PRISMA GUIDELINES 45
Recommendation 49: Add and discuss older epidemiologic studies to Tables 3-1 and 3-8 45
Recommendation 50: Use current best practice methods for quality review of literature including use of two
INDEPENDENT REVIEWERS 45
Recommendation 51: Revise the table listing epidemiologic studies and apply Bradford-Hill criteria in assessing study
STRENGTHS 47
Recommendation 52: Include a discussion of non-cancer health endpoints from epidemiologic studies 48
Recommendation 53: The discussion on PESS should include sub groups and conditions identified in epidemiologic
STUDIES AND IN MORE RECENT GWAS RESEARCH 48
Recommendation 54: Include a summary table of tumors observed in endocrine-associated tissues in the Japan Bioassay
Research Center (1998) inhalation study, particularly for female rats, and include a discussion of their
SIGNIFICANCE 50
Recommendation 55: Consider adoption of a threshold-type MOA in estimating the carcinogenic risks of carbon
TETRACHLORIDE 51
Recommendation 56: Application of uncertainty factors should be considered for database deficiencies, due to more
LIMITED MECHANISTIC INFORMATION ABOUT ADRENAL GLAND TUMORS IN MICE AND REPORTED ASSOCIATIONS OF OCCUPATIONAL
CARBON TETRACHLORIDE EXPOSURE AND INCREASED INCIDENCE OF GLIOMAS IN WORKERS 51
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Recommendation 57: Explain why a poor-quality study ( Kronevi, 1979) was used to establish the acute dermal POD
WHEN SO MANY OTHER BETTER QUALITY STUDIES WERE DISMISSED 52
Recommendation 58: Acknowledged that there is insufficient data to devise an acute dermal NOAELand POD using the
Kronevi (1979) study 52
Recommendation 59: Use the LOAEL from the Wahlberg and Boman (1979) studyto determine the POD for acute
OCCLUDED DERMAL EXPOSURE TO CARBON TETRACHLORIDE 52
Recommendation 60: Use the POD for occluded dermal exposure derived from the Wahlberg and Boman (1979) LOAEL
TO CALCULATE A POD FOR ACUTE NON-OCCLUDED DERMAL EXPOSURE 52
Recommendation 61: Correct the calculation of the cancer slope factor for dermal exposure, and, adjust the risk
CALCULATIONS ACCORDINGLY 54
Recommendation 62: Provide justification for the use of the Jongeneel equation to extrapolate chronic inhalation HEC
TO CHRONIC DERMAL HED 54
Recommendation 63: Consider assessing combined dermal and inhalation exposure for workers 55
Recommendation 64: State clearly and justify whether a low-dose linear risk assessment approach or a non-linear risk
ASSESSMENT APPROACH IS PREFERRED 55
Recommendation 65: Explain the basis andthe calculations used in determining the points of departure 57
Recommendation 66: Describe whatthe two uncertainty factors, U Fa and UFh, represent and give some basis for their
VALUES 57
Recommendation 67: Review and discuss UF's used by other expert bodies for carbon tetrachloride and consider any
CHANGES NEEDED FOR THIS EVALUATION. EXPLAIN HOW ASSESSMENTS FROM OTHER JURISDICTIONS WERE, OR WERE NOT,
CONSIDERED FOR THIS EVALUATION 57
Recommendation 68: Consider whether additional uncertainty factors are needed 58
Recommendation 69: Use a 45-year working lifetime instead of a 40-year lifetime to align with the NIOSH policy. It
WOULD ALSO BE USEFULTO CALCULATE RISK USING RANGES OF WORK LIFETIMES 59
Recommendation 70: EPA should clearly describe which COUs pose unacceptable risks in the absence of PPE. This should
BE CLARIFIED IN THE EXECUTIVE SUMMARY AND IN TABLES 4-13 AND TABLE 5-1 OF THE EVALUATION 59
Recommendation 71: present a more detailed discussion of the links between uncertainties andthe overall level of
CONFIDENCE ASSIGNED TO EACH RISK ESTIMATE 60
Recommendation 72: Re-evaluate the description of uncertainties in dermal risk after addressing the faulty
CALCULATIONS USED IN ESTIMATING THE DERMAL POD 60
Recommendation 73: Consider incorporating the additional studies identified by the Committee as important into the
Evaluation 62
Recommendation 74: Consider performing a more robust sensitivity analysis such as the one proposed inThabane etal.
(2013) study 62
Recommendation 75: Improve the discussion and summarize the data supporting the decision to exclude consumer
EXPOSURES FROM THIS EVALUATION 62
Recommendation 76: Include background exposures in the assessment for workers and ONUs or alternatively provide a
MORE DETAILED JUSTIFICATION WHY BACKGROUND EXPOSURES ARE NOT CONSIDERED 63
Recommendation 77: Consolidate explanation of PESS into one section and develop more protective guidelines for
PESS 63
Recommendation 78: Consider including and discussion individuals who are sensitive to oxidative damage andthe
embryo/fetus of pregnant female workers as PESS 64
Recommendation 79: Expand and clarify the uncertainty factor discussions, especially regarding PESS 64
Recommendation 80: Consider reordering the presentation of materials in the Evaluation to discuss environmental
EXPOSURES, HAZARD AND RISK CHARACTERIZATION BEFORE HUMAN HEALTH EXPOSURES, HAZARD AND RISK CHARACTERIZATION AND
FOLLOWED BY PESS EXPOSURES, HAZARD AND RISK CHARACTERIZATION 67
Recommendation 81: For cancer risk, the term BMD should be reserved for PODs that are estimated by BMDs
CORRESPONDING TO RISKS (BMRs) ATTHE LOWER END OF THE OBSERVABLE RANGE (E.G., 0.1%), ESTIMATED USING THE METHODS
discussed in EPA (2012) 67
Recommendation 82: For non-cancer risk, the "benchmark MOE" should be appropriately termed instead of the "total
UNCERTAINTY FACTOR (UFt)." 67
Recommendation 83: Adopt a method for distinguishing exposures to rodents from human equivalent doses and apply
THIS DISTINCTION CONSISTENTLY 68
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Recommendation 84: Consider carefully which information needs to be provided explicitly in the body of the Evaluation
FROM THE MORE DETAILED INFORMATION AVAILABLE IN THE APPENDICES 68
Recommendation 85: Optimize the use of active links within the Evaluation and provide external access to increase
READABILITY AND TRANSPARENCY 69
Recommendation 86: Highlight for readers those COUs where the determination of no unreasonable risk is directly
RELATED TO THE ASSUMPTION OF PPE USE 69
Recommendation 87: Provide more specific information about relevance of other legislation and the specifics of
ENVIRONMENTAL OR HUMAN HEALTH RISK ADDRESSED BY OTHER ORGANIZATIONS 70
Recommendation 88: Develop and display a "key" for the reference section that facilities identifying and tracing sources
THOUGHT THE PROCESS OF SYSTEMATIC PEER REVIEW AND DATA SOURCE EVALUATION/VALIDATION 70
Recommendation 89: Specifically note the criteria used to assess data relevance for risk assessment in addition to
DETERMINING DATA QUALITY 70
Recommendation 90: Consider using other data in a corroborative sense to support high quality studies used to develop
A CONCENTRATION OF CONCERN (COC) 71
Recommendation 91: Provide a brief description of the rationale for unking the information on occupational exposure
CONTROL TO THE DECISION TO APPLY RESPIRATOR AND GLOVE PROTECTION FACTORS. FACTORS 71
Recommendation 92: Add explanatory information in Tables 1-2 and D-l describing the differences between the
REPORTING PERIODS FOR PRODUCTION AND RELEASE 71
Recommendation 93: Correct formatting issue with Table 4-13 and improve clarity of Figures 4-1 to 4-4 71
Recommendation 94 Quantify what is entailed in the phrase "Public outreach and literature searches" 72
Recommendation 95: The assertion of no significant use in consumer products should be supported by a more specific
DESCRIPTION OF THE DOCUMENTATION USED BY EPA TO ARRIVE AT ITS CONCLUSION 73
Recommendation 96: Consider performing a wider assessment accounting for these excluded pathways, which will
PROVIDE A MORE RELIABLE MEASURE OF THE RISK 75
Recommendation 97: Be specific when using the term "surrogate" when applying data from one COU to another 75
Recommendation 98: Ensure thatthe COU and itssurrogate do not have hugely different associated levels of
UNCERTAINTY 75
Recommendation 99: Describe better the engineering and worker activities associated with a COU, and compare to their
SURROGATE COU TO ENSURE THEY ARE NOT SIGNIFICANTLY DIFFERENT 75
Recommendation 100: The environmental risk characterization should be qualified to the organisms actually
EVALUATED 75
Recommendation 101: Expandthe discussion of the Heineman etal., 1994, study 76
Recommendation 102: Continue to improve the systematic review process 76
Recommendation 103: Address directly the issue of how many and what kinds of samples are adequate to quantify
EXPOSURES FOR COU SCENARIOS 77
Recommendation 104: Confidence statements on risk estimates should synthesize uncertainties in data and assumptions.
78
Recommendation 105: Include a summary of residential indoor and outdoor air concentrations of carbon
TETRACHLORIDE AS WELL AS PERSONAL AIR CONCENTRATIONS OF THE RESIDENTS 79
Recommendation 106: Discuss limitations and inadequacies of occupational monitoring data collected to meet PEL
STANDARDS RATHER THAN ASSESS RELEVANT HEALTH EFFECTS 79
Recommendation 107: Consider scoring data and assumption uncertainty to derive a final confidence score 80
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