[Federal Register Volume 68, Number 131 (Wednesday, July 9, 2003)]
[Notices]
[Pages 40944-40947]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 03-16927]


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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: [email protected].
    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: [email protected].

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