
[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
----------------------------------------------------------------------------------------------------------------
                                                                                            Deadline for final
           Testing segment                 Required testing          Test standard          report\1\ (months)
----------------------------------------------------------------------------------------------------------------

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))
----------------------------------------------------------------------------------------------------------------
\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]

BILLING CODE 6560-50-S
