[Federal Register: July 22, 2009 (Volume 74, Number 139)]
[Notices]
[Page 36196-36198]
From the Federal Register Online via GPO Access [wais.access.gpo.gov]
[DOCID:fr22jy09-62]
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ENVIRONMENTAL PROTECTION AGENCY
[EPA-HQ-OPPT-2003-0010; FRL-8426-6]
1,2-Ethylene Dichloride; Completion of EPA Program Review
AGENCY: Environmental Protection Agency (EPA).
ACTION: Notice.
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SUMMARY: EPA issued a testing consent order that incorporated an
enforceable consent agreement (ECA) for 1,2-Ethylene Dichloride (EDC)
in June 2003, using authorities under section 4 of the Toxic Substances
Control Act (TSCA). The companies subject to the ECA agreed to conduct
toxicity testing in a tiered testing program that included development
of pharmacokinetics and mechanistic data and a computational dosimetry
model for route-to-route extrapolations. The testing program was
designed to satisfy the toxicological data needs for EDC identified in
a TSCA section 4 proposed test rule for a number of hazardous air
pollutant chemicals. The modeling is intended to allow toxicological
studies conducted using oral exposures to be interpreted so that they
could also be used to predict the effects of inhalation exposures. This
notice announces the completion of the program review component of the
ECA for EDC. This notice also states EPA's findings and conclusion
regarding the adequacy of the derived models to perform satisfactory
route-to-route extrapolations, responds to comments on the Tier I
Program Review Testing, and establishes revised deadlines for
completion of Tier II testing and computational route-to-route
dosimetry modeling for extrapolations listed under Tier II of the ECA
for EDC.
FOR FURTHER INFORMATION CONTACT: For general information contact: Colby
Lintner, Regulatory Coordinator, Environmental Assistance Division
(7408M), Office of Pollution Prevention and Toxics, Environmental
Protection Agency, 1200 Pennsylvania Ave., NW., Washington, DC 20460-
0001; telephone number: (202) 554-1404; e-mail address: TSCA-
Hotline@epa.gov.
For technical information contact: John Schaeffer, Chemical Control
Division (7405M), Office Pollution Prevention and Toxics, Environmental
Protection Agency, 1200 Pennsylvania Ave., NW., Washington, DC 20460-
0001; telephone number: (202) 564-8173; e-mail address:
schaeffer.john@epa.gov.
SUPPLEMENTARY INFORMATION:
I. General Information
A. Does this Action Apply to Me?
This action is directed to the public in general, and may be of
particular interest to those persons who are or may be required to
conduct testing of chemical substances under TSCA. Since other entities
may also be interested, the Agency has not attempted to describe all
the specific entities that may be affected by this action. If you have
any questions regarding the applicability of this action to a
particular entity, consult the technical person listed under FOR
FURTHER INFORMATION CONTACT.
B. How Can I Get Copies of this Document and Other Related Information?
1. Docket. EPA has established a docket for this action under
docket identification (ID) number EPA-HQ-OPPT-2003-0010. All documents
in the docket are listed in the docket index available at http://
www.regulations.gov. Although listed in the index, some information is
not publicly available, e.g., Confidential Business Information (CBI)
or other information whose disclosure is restricted by statute. Certain
other material, such as copyrighted material, will be publicly
available only in hard copy. Publicly available docket materials are
available electronically at http://www.regulations.gov, or, if only
available in hard copy, at the OPPT Docket. The OPPT Docket is located
in the EPA Docket Center (EPA/DC) at Rm. 3334, EPA West Bldg., 1301
Constitution Ave., NW., Washington, DC. The EPA/DC Public Reading Room
hours of operation are 8:30 a.m. to 4:30 p.m., Monday through Friday,
excluding Federal holidays. The telephone number of the EPA/DC Public
Reading Room is (202) 566-1744, and the telephone number for the OPPT
Docket is (202) 566-0280. Docket visitors are required to show
photographic identification, pass through a metal detector, and sign
the EPA visitor log. All visitor bags are processed through an X-ray
machine and subject to search. Visitors will be provided an EPA/DC
badge that must be visible at all times in the building and returned
upon departure.
2. Electronic access. You may access this Federal Register document
electronically through the EPA Internet under the ``Federal Register''
listings at http://www.epa.gov/fedrgstr.
[[Page 36197]]
II. Background
A. What is the EPA Program Review for EDC?
In the Federal Register of September 5, 2006 (71 FR 52329) (FRL-
8088-3), EPA announced that it was conducting the program review
component of the ECA for the EDC alternative testing program, and
solicited public comment on data received under the Tier I Program
Review testing segment of the ECA for EDC (CAS No. 107-06-2). Comments
were to inform EPA's decision on whether or not additional data and/or
model development are needed before Tier II testing and computational
route-to-route dosimetry modeling extrapolations could proceed for the
Tier II endpoints listed in the ECA for EDC. Details of the testing
program for EDC are available in the ECA and in the Federal Register of
June 3, 2003 (68 FR 33125) (FRL-7300-6), in which EPA announced it had
entered into an ECA and issued a testing consent order for EDC. The ECA
for EDC was developed in response to EPA's request for ECA proposal for
health effects testing of a number of hazardous air pollutants (HAPs or
HAP chemicals), including EDC (see the proposed test rule in the
Federal Register of June 26, 1996 (61 FR 33177) (FRL-4869-1), and the
proposed test rule, as amended, in the Federal Register of December 24,
1997 (62 FR 67466) (FRL-5742-2); February 5, 1998 (63 FR 5915) (FRL-
5769-3); and April 21, 1998 (63 FR 19694) (FRL-5780-6)). The HAPs
rulemaking proposed testing for health effects by the inhalation route
of exposure. In the proposed rule, EPA also invited the submission of
proposals that included pharmacokinetics studies and model development
that would permit the extrapolation of testing administered by other
exposure routes, such as the oral route, to predict for inhalation
exposures. On November 22, 1996, Dow Chemical Company, Vulcan Materials
Company (no longer in existence), Occidental Chemical Corporation, Oxy
Vinyls, LP, Georgia Gulf Corporation, Westlake Chemical Corporation,
PPG Industries, Inc., and Formosa Plastics Corporation, U.S.A. (the
``Companies''), under the auspices of the HAP Task Force, submitted a
proposal for alternative testing of EDC that included physiologically
based pharmacokinetics (PBPK) and model development to support route-
to-route extrapolation of testing to be conducted under the ECA by the
oral route. EPA considered this proposal sufficient to enter into ECA
negotiations with the Companies and other interested parties (62 FR
66626; December 19, 1997) (FRL-5763-1). The ECA for EDC that resulted
was announced in the Federal Register of June 3, 2003 (68 FR 33125).
Since the route-to-route extrapolation of test results was a new
approach, EPA and the Companies included a program review step within
the testing program. The testing program consists of Tier I HAPs
Testing; Tier I Program Review Testing; EPA Program Review; and Tier II
Testing.
Tier I HAPs Testing consisted of endpoint testing conducted by
inhalation exposure for acute toxicity, with bronchoalveolar lavage
(BAL) and histopathology, and acute neurotoxicity. The Tier I Program
Review Testing consisted of studies to develop PK/MECH data, analyze
glutathione metabolism, and perform model simulation. These studies
were conducted to extend the computational dosimetry model of D'Souza
et al. (1987, 1988; Refs. 1 and 2) to improve the model's application
to the specific health effects endpoints for EDC listed in the ECA. The
studies also enabled EPA to validate the model and verify the model's
ability to adequately perform quantitative route-to-route
extrapolations of dose response. Further description of the Tier I HAPs
Testing and the Tier I Program Review Testing is provided in the
Federal Register of September 5, 2006 (71 FR 52329). That notice, as
well as the final study reports, can be accessed in the docket (EPA-HQ-
OPPT-2003-0010) as explained in Unit I.B.
As specified in the ECA, the EPA program review is required before
the Tier II Testing segment is undertaken. In the Federal Register of
September 5, 2006 (71 FR 52329), EPA announced that it was conducting
the program review component of the ECA for EDC, and solicited public
comment on data received under the Tier I Program Review Testing
segment of the ECA. Comments were to inform EPA's decision on whether
or not additional data and/or model development were needed before Tier
II Testing and computational route-to-route dosimetry modeling
extrapolations can proceed for the Tier II endpoints listed in the ECA
for EDC.
B. What were the Public Comments on the Tier I Program Review Testing
for EDC?
EPA received two public comments in response to its solicitation
for comments on the Tier I Program Review Testing. Comments from People
for the Ethical Treatment of Animals (PETA) were on behalf of
themselves and the following organizations: The Physicians' Committee
for Responsible Medicine, the Humane Society of the United States, the
Doris Day Animal League, and Earth Island Institute. PETA expressed
support for the use of PBPK modeling to limit additional animal testing
through the use of route-to-route extrapolation to existing studies.
However, PETA also stated that they disagreed that additional Tier II
tests (i.e., for reproductive effect or subchronic neurotoxicity) are
needed; contending that existing studies for these effects are
adequate. EPA disagrees, and its basis for requiring this additional
testing is discussed in previous Federal Register documents, cited in
Unit II.A. A second comment, from a private citizen, was focused on
opposition to the manufacture of chlorine compounds in general,
including EDC, and not the testing program.
C. What are the Conclusions of the EPA Tier I Program Review Testing
for EDC?
The companies have completed the Tier I and Tier I Program Review
testing segments of the ECA for EDC. The companies have also examined
additional PBPK models and other available information in order to more
fully update the model developed by D'Souza et al., 1987, 1988; as
specified in the ECA agreement. The results of this work, the updated
model, and model simulations have been discussed with EPA (Refs. 3
through 6) and have also been recently published as a peer-reviewed
article in the scientific literature (Ref. 7). It is EPA's conclusion
that the PBPK model developed by the test sponsors under the EDC ECA is
acceptable for route-to-route extrapolations and that Tier II testing
and extrapolation reporting can proceed as per the schedule set forth
below (Ref. 8). Specifically, EPA concludes that:
1. The PK/MECH data report and Tier I toxicity studies have been
conducted in accordance with the protocols and specifications as
described in Appendix C of the ECA.
2. The available study records are sufficient to allow an
evaluation of the quality of the studies performed.
3. The EDC PBPK model is appropriately chemical-specific, and
suitably based on the current understanding of the kinetics of EDC.
4. The species, dose level, exposure regimens, and vehicles used
are relevant for the toxicity data that are the object of the Tier II
extrapolations.
5. The Tier I Program Review PK/MECH data, along with additional
data, show that periodicity was demonstrated and that the various data
sets bearing on the issue of periodicity can be properly
[[Page 36198]]
interpreted and managed in the studies that support the model.
6. Refinements of the model related to absorption, tissue
distribution, and metabolism were accomplished, or suitably explained,
including the role of extrahepatic metabolism as it impacts the model
dose metrics and route-to-route extrapolation; appreciably improving
prior PBPK models of EDC.
It is EPA's decision that the HAP Task Force can proceed with the
Tier II Testing under the schedule set forth in Table 1. of this
Federal Register document.
Table 1.--Required Testing, Test Standards, and Reporting Requirements for EDC
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Deadline for final
Testing segment Required testing Test standard report\1\ (months)
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Tier II testing and/or extrapolation Subchronic toxicity ECA appendix C.2 and 12
reporting route-to-route C.6
extrapolation of dose-
response (oral Tier II
testing to inhalation)
of a study reported by
Daniel, et al., (1994)
Subchronic 40 CFR 799.9620 (as 18
neurotoxicity (oral) annotated in ECA
appendix D.2)
Subchronic ECA appendix C.3 and 21
neurotoxicity route-to- C.6
route extrapolation of
dose-response (oral
Tier II testing to
inhalation)
Reproductive toxicity 40 CFR 799.9380 (as 25
(oral) annotated in ECA
appendix D.3)
Reproductive toxicity ECA appendix C.4 and 28
route-to-route C.6
extrapolation of dose-
response (oral data to
inhalation, including
Tier II testing and
extant studies
reported by Alumot, et
al., (1976), Rao, et
al., (1980), and Lane,
et al., (1982))
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\1\Number of months after the date of publication of this Federal Register document, which announces that EPA
has concluded the EPA Program Review, when the final report is due. In addition, every 6 months from the
effective date of the Order until the end of the ECA testing program, interim reports describing the status of
all testing to be performed under this ECA must be submitted by the Companies to EPA.
III. References
1. D'Souza, R.W., Francis, W.R., Bruce R.D., and Andersen, M.E.
Physiologically based pharmacokinetic model for ethylene dichloride and
its application in risk assessment. P. 286-301, In: Pharmacokinetics in
Risk Assessment. National Academy Press. Washington, D.C. (1987).
2. D'Souza, R.W., Francis, W.R., and Andersen, M.E. Physiological
model for tissue glutathione depletion and increased resynthesis after
ethylene dichloride exposure. Journal of Pharmacology and Experimental
Therapeutics. 245(2):563-568. (1988).
3. EPA, Office of Prevention, Pesticides and Toxic Substances,
Chemical Control Division. Letter from Jim Willis, Director, CCD to Dr.
Peter Voytek, HAP Task Force. RE: EPA Tier I Program Review for EDC.
January 10, 2007.
4. EPA and HAP Task Force. Technical Consultation Meeting on 1, 2-
Ethylene Dichloride Program Review. February 12, 2007.
5. HAP Task Force. Letter from Peter E. Voytek, Manager, HAP Task
Force to Jim Willis, Director, Chemical Control Division, Office of
Pollution Prevention and Toxics, with Enclosure: Response to Issues
Raised in EPA's Tier 1 Data Evaluation Meeting. May 23, 2007.
6. Sweeny, L. M. and Gargas, M.I. Physiologically based
pharmacokinetic model development and simulations for ethylene
dichloride (1,2-dichlorethane) in rats. Prepared by the Sapphire Group,
Dayton Ohio for the HAP Task Force, Millwood, Virginia. Revised Draft
Report. March 11, 2009.
7. Sweeny, L. M., Saghir, S. A., and Gargas, M.I. Physiologically
based pharmacokinetic model development and simulations for ethylene
dichloride (1,2-dichlorethane) in rats. Regulatory Toxicology and
Pharmacology. 51:311-323. (2008).
8. EPA. Email from Rob Dewoskin, PhD, DABT, US EPA/NCEA (National
Center for Environmental Assessment) to John Schaeffer. Review of Final
report - EDC ECA Program Review Completion. April 22, 2009.
List of Subjects
Environmental protection, 1,2-Ethylene Dichloride, EDC, Hazardous
chemicals.
Dated: July 10, 2009.
Jim Willis,
Director, Chemical Control Division, Office of Pollution Prevention and
Toxics.
[FR Doc. E9-17170 Filed 7-21-09; 8:45 am]
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