1,1,2-Trichloroethane (TCE); EPA Program Review: Notice of Availability

Note: EPA no longer updates this information, but it may be useful as a reference or resource.

[Federal Register: July 9, 2003 (Volume 68, Number 131)]
[Notices]
[Page 40944-40947]
From the Federal Register Online via GPO Access [wais.access.gpo.gov]
[DOCID:fr09jy03-91]

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ENVIRONMENTAL PROTECTION AGENCY
[OPPT-2002-0056; FRL-7313-8]

1,1,2-Trichloroethane (TCE); EPA Program Review: Notice of
Availability

AGENCY: Environmental Protection Agency (EPA).
ACTION: Notice.

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SUMMARY: Under section 4 of the Toxic Substances Control Act (TSCA),
EPA issued a testing consent order (Order) that incorporates an
enforceable consent agreement (ECA) relating to 1,1,2-trichloroethane
(TCE) (CAS No. 79-00-5). The companies subject to this ECA, the Dow
Chemical company; Vulcan Materials Company; Occidental Chemical
Corporation; Oxy Vinyls, LP; Georgia Gulf Corporation; Westlake
Chemical Corporation; PPG Industries, Inc.; and Formosa Plastics
Corporation, U.S.A., have agreed to conduct toxicity testing, develop a
computational dosimetry model for route-to-route extrapolations of dose
response, and develop pharmacokinetics and mechanistic (PK/MECH) data
that are intended to satisfy the toxicological data needs for TCE
identified in a TSCA section 4 proposed test rule for a number of
hazardous air pollutant (HAP) chemicals. This notice announces the
availability of a report describing the findings and conclusions for
the program review component of the ECA for TCE, responds to comments
on the Tier I Program Review Testing, identifies modifications to Tier
II ECA activities, and establishes revised deadlines for completion of
Tier II testing and computational route dosimetry modeling for
extrapolations listed under Tier II of the ECA for TCE.

FOR FURTHER INFORMATION CONTACT: For general information contact:
Barbara Cunningham, Director, 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: Richard W. Leukroth, Jr., or
John E. Schaeffer, Jr., Chemical Control Division (7405M), Office of
Pollution Prevention and Toxics, Environmental Protection Agency, 1200
Pennsylvania Ave., NW., Washington, DC 20460-0001; telephone number:
(202) 564-8157; e-mail address: ccd.citb@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 the Toxic Substances
Control Act (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 person
listed under FOR FURTHER INFORMATION CONTACT.

B. How Can I Get Copies of this Document and Other Related Information?

1. EPA Docket. EPA has established an official public docket for
this action under docket (ID) number OPPT-2002-0056. The official
public docket consists of the documents specifically referenced in this
action, any public comments received, and other information related to
this action. Although, a part of the official docket, the public docket
does not include Confidential Business Information (CBI) or other
information for which disclosure is restricted by statute. The official
public docket is the collection of materials that is available for
public viewing at the EPA Docket Center, Rm. B102-Reading Room, EPA
West, 1301 Constitution Ave., NW., Washington, DC. The EPA docket
center is open from 8:30 a.m. to 4:30 p.m., Monday through Friday,
excluding legal holidays. The EPA Docket Center Reading Room telephone
number is (202) 566-1744 and telephone number for the OPPT Docket,
which is located in EPA docket center, is (202) 566-0280.
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/.
An electronic version of the public docket is available through
EPA's electronic public docket and comment system, EPA Dockets. You may
use EPA Dockets at http://www.epa.gov/edocket/ to submit or view public
comments, access the index listing of the contents of the official
public docket, and to access those documents in the public docket that
are available electronically. Although, not all docket materials may be
available electronically, you may still access any of the publicly
available docket materials through the docket facility identified in
Unit I.B.1. Once in the system, select ``search,'' then key in the
appropriate docket ID number.

II. Background

A. What is the EPA Program Review for TCE?

In the Federal Register of October 16, 2002 (67 FR 63913) (FRL-
7275-8) EPA announced that it was conducting the program review
component of the enforceable consent agreement (ECA) for the 1,1,2-
trichloroethane (TCE) alternative testing program, and solicited public
comment on data received under the Tier I Program Review testing
segment of the ECA for TCE (CAS No. 79-00-5). 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 can proceed for the Tier II
endpoints listed in the ECA for TCE.
Details of the testing program for TCE are available in the ECA
and in the Federal Register of June 15, 2000 (65 FR 37550)(FRL-6494-5),
in which EPA announced it had entered into an ECA and issued a testing
consent order for TCE. The ECA for TCE was developed in response to
EPA's request for ECA proposals for health effects testing of a number
of hazardous air pollutants (HAPs or HAP chemicals), including TCE (see
the proposed test rule in the Federal Register of June 26, 1996 (61 FR
33178) (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 route-to-route
dosimetry extrapolation to predict for inhalation exposures. The ECA
for TCE applies such an alternative approach to satisfy

[[Page 40945]]

data needs identified in the proposed HAPs rulemaking.
Under the TCE ECA testing program, the data needs for TCE are
being addressed via an informed testing program that utilizes, wherever
possible, extant data from acceptable studies performed by routes other
than inhalation, testing by inhalation and the oral route, and
development of pharmacokinetics and mechanistic (PK/MECH) data to
support a computational dosimetry model to perform route-to-route
extrapolations. Since this is 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 and subchronic toxicity. The Tier I
Program Review Testing included: (1) Development of a computational
dosimetry model specific for TCE in rats and mice; (2) simulation
testing of the predictive capability of the model against an inhalation
test data set; and (3) demonstration of the model's utility in
supporting quantitative route-to-route dosimetry extrapolations. The
test sponsors also developed PK/MECH data to support the application of
the model to oral-to-inhalation extrapolations of dose-response for
extant and Tier II Testing endpoint studies. Tier I HAPs Testing and
Tier I Program Review Testing results are available in the legacy
docket (OPPTS-42198C) and electronically in the e-Docket (OPPT-2002-
0056).
The purpose of the program review was to determine:
1. Whether it is feasible and appropriate to apply Tier I Program
Review testing data and data from other studies acceptable to EPA to
support computational route-to-route extrapolations for endpoints
listed in the Tier II testing segment of the ECA.
2. Whether the data from the Tier I Program Review testing segment
provide a sufficient basis for conducting the endpoint testing and/or
the computational route-to-route extrapolations specified in the Tier
II testing segment.
3. The nature and scope of any additional work that may be required
before Tier II testing and the application of the TCE model for route-
to-route extrapolation reporting (e.g., development of additional PK/
MECH data, modification to the TCE model).

B. What were the Public Comments on the Tier I Program Review Testing?

EPA received one public comment from the People for the Ethical
Treatment of Animals (PETA). The comment was submitted by PETA and on
behalf of themselves, the Physicians Committee for Responsible
Medicine, the Humane Society of the United States, the Doris Day Animal
League, and Earth Island Institute. PETA's comments were favorable on
the use of the alternative approach to address data needs utilizing
PBPK modeling which could result in a reduction in the number of
animals used in toxicity testing to meet EPA's data needs. Although,
PETA also stated their belief that the presently available data base
for TCE is sufficiently extensive to characterize the toxicity of TCE,
and that no additional testing is necessary, PETA did not include
comments regarding the scientific merit of the PK/MECH data or PBPK
model development for TCE.
EPA appreciates the expressed support for the application of
alternative approaches that incorporate PBPK modeling as a means to
address data needs for HAP chemicals. Although, computational
approaches are an increasingly important tool for EPA to use in
addressing data needs, they must be scientifically defensible and rely
on the development of PK/MECH data relevant to the modeling approach.
Computational dosimetry modeling approaches need critical empirical
data from toxicity studies conducted in a scientifically adequate
manner. EPA has concluded that the Tier II testing is necessary in this
case. EPA's basis for this decision is presented in previous Federal
Register notices, cited in Unit II.A.

C. What are the Conclusions of the EPA Program Review?

EPA has determined that the Tier I Program Review testing and data
from other studies acceptable to EPA can support computational route-
to-route dosimetry extrapolations for the endpoints listed in the Tier
II testing segment of the ECA. More specifically, EPA has concluded
that:
1. The PK/MECH data report and Tier I toxicity studies appear to
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 TCE PBPK model is appropriately chemical-specific, and
suitably based on the current understanding of the kinetics of TCE.
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 demonstrated that
periodicity was achieved in the studies that support the model.
EPA has also concluded, that the choice of dose metrics for Tier II
computational route dosimetry extrapolations should be revised to
correlate with Tier I study findings, and that selection of the dosing
regimens for Tier II testing could benefit from predictions derived
from the PBPK model for TCE. These changes to the original testing and
extrapolation reporting are described in the revised Table 1 (Table 1.
(amended)) of this Federal Register notice, and will be incorporated
into protocol development under Tier II activities. EPA's program
review activity, including the findings and conclusions, are described
in a report titled: ``Program Review Report on the Enforceable Consent
Agreement for 1,1,2-Trichloroethane'' (U.S. EPA, April 21, 2003). This
report is available electronically from the e-Docket OPPT-2002-0056.
It is EPA's decision that the HAP Task Force can proceed with Tier
II Testing under the schedule set forth in Table 1. of this Federal
Register notice. The testing schedule corresponds to that originally
set forth in the Federal Register notice announcing the ECA and Order
for TCE, but is modified to include the additional time needed to
complete the Program Review segment of the ECA for TCE, which was
longer than originally anticipated, plus additional time for Tier II
protocol development. Table 1. also identifies additional modifications
to Tier II activities to correlate with Tier I study findings. EPA does
not consider these modifications of the test schedules or Tier II
activities to be significant.

D. What are the Modifications to the ECA for TCE?

This Federal Register notice incorporates modifications to the ECA
for the TCE test schedule for Tier II ECA activities, clarifies
protocol development for Tier II testing, expands consideration for
dose metrics to be applied in the Tier II route dosimetry
extrapolations and reporting, and identifies a change in signatory
companies to the ECA. The testing schedule corresponds to that
originally set forth in the Federal Register notice announcing the ECA
and Order for TCE, but is modified to allow for the time needed to
perform the EPA Program Review, which was longer than

[[Page 40946]]

anticipated. Additional time was also included in the schedule for Tier
II testing protocol development. Footnotes in Table 1. have been
revised to address refinements in Tier II protocol development and
extrapolation reporting changes identified as modification to Appendix
C.5 (General Outline for Route-to-Route Extrapolation Reporting) to
correlate with Tier I study findings. Finally, one of the signatory
companies to the ECA, Borden Chemicals and Plastics Operating Limited
Partnership, is no longer a participant in the ECA, due to bankruptcy.
The remaining companies that are signatories of the ECA for TCE have
agreed to assume the responsibilities for this change in membership to
the HAP Task Force. EPA does not consider these modifications to be
significant.

Table 1. (amended)--Required Testing, Test Standards, Reporting and Other Requirements for 1,1,2-Trichloroethane
----------------------------------------------------------------------------------------------------------------
Deadline
for Final
Testing Segment Required Testing Test Standard Report\1\
(Months)
----------------------------------------------------------------------------------------------------------------
Tier II Testing and/or Extrapolation Acute neurotoxicity Sec. 799.9620 (as 12
Reporting (drinking water). annotated in ECA Appendix
D.3)
----------------------------------------------------------============

-----------------------------------------------------------
Subchronic neurotoxicity Sec. 799.9620 (as 18
(drinking water). annotated in ECA Appendix
D.3)
-----------------------------------------------------------
Subchronic neurotoxicity ECA Appendix C 21
route-to-route
extrapolation of Tier II
drinking water subchronic
neurotoxicity data to
inhalation\2\.
-----------------------------------------------------------
Developmental toxicity Sec. 799.9370 (as 24
(drinking water) annotated in ECA Appendix
D.4)
-----------------------------------------------------------
Developmental toxicity ECA Appendix C 27
route-to-route
extrapolation of Tier II
drinking water
developmental toxicity
data to inhalation\3\.
-----------------------------------------------------------
Reproductive toxicity Sec. 799.9380 (as 30
(drinking water). annotated in ECA Appendix
D.5)
-----------------------------------------------------------
Reproductive toxicity route- ECA Appendix C 33
to-route extrapolation of
Tier II drinking water
reproductive toxicity data
to inhalation\4\
-----------------------------------------------------------
Immunotoxicity (route-to- ECA Appendix C 9
route extrapolation of
extant oral data in ECA
Appendix E.2 to
inhalation)\5\
-----------------------------------------------------------
Carcinogenicity (route-to- ECA Appendix C 6
route extrapolation of
extant oral data in ECA
Appendix E.3 to
inhalation\6\
----------------------------------------------------------------------------------------------------------------
\1\Number of months after the effective date of thisFederal Register Notice, 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 the ECA for TCE must be submitted by the companies to EPA.
\2\Quantitative route-to-route extrapolations based on the Tier II acute and subchronic drinking water
neurotoxicity study data, and developed for each of the following dose metrics: Parent compound in venous
blood and brain, as maximum concentration (Cmax) and as the area under the time-concentration curve (AUC), and
metabolite, as amount metabolized in the liver or brain per day normalized to organ weight.
\3\Quantitative route-to-route extrapolation based on the Tier II drinking water developmental toxicity study
data, and developed for each of the following dose metrics: Parent compound in venous blood, as maximum
concentration (Cmax) and as the area under the time-concentration curve (AUC), and metabolite, as amount
metabolized in the liver per day normalized to liver weight.
\4\Quantitative route-to-route extrapolation based on the Tier II drinking water reproductive effects toxicity
study data, and developed for each of the following dose metrics: Parent compound in venous blood, as maximum
concentration (Cmax) and as the area under the time-concentration curve (AUC), and metabolite, as amount
metabolized in the liver per day normalized to liver weight.
\5\Quantitative route-to-route extrapolation based on the PK/MECH data developed under this ECA and the data of
Sanders et al. (1985), and developed for each of the following dose metrics: parent compound in venous blood
and spleen, as maximum concentration (Cmax) and as the area under the time-concentration curve (AUC), and
metabolite, as amount metabolized in the liver or spleen per day normalized to organ weight.
\6\Quantitative route-to-route extrapolation based on the PK/MECH data developed under this ECA and the data of
NCI (1978), and developed for each of the following dose metrics: parent compound in venous blood and liver,
as maximum concentration (Cmax) and as the area under the time-concentration curve (AUC), and metabolite, as
amount metabolized in the liver per day normalized to liver weight.

[[Page 40947]]

List of Subjects

Environmental protection, Hazardous chemicals.

Dated: June 26, 2003.
Philip S. Oshida,
Acting Director, Chemical Control Division, Office of Pollution
Prevention and Toxics.
[FR Doc. 03-16927 Filed 7-8-03; 8:45 am]
BILLING CODE 6560-50-S

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