[Federal Register Volume 71, Number 171 (Tuesday, September 5, 2006)]
[Notices]
[Pages 52329-52333]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: E6-14639]


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ENVIRONMENTAL PROTECTION AGENCY

[EPA-HQ-OPPT-2003-0010; FRL-8088-3]


1,2-Ethylene Dichloride Tier I Program Review Testing; Notice of 
Availability and Solicitation of Comment

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 that incorporated an enforceable 
consent agreement (ECA) for 1,2-ethylene dichloride (EDC). The 
companies subject to the ECA agreed to conduct toxicity testing, 
develop a computational dosimetry model for route-to-route 
extrapolations, and develop pharmacokinetics and mechanistic testing 
data that are intended 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. This notice announces that EPA is 
starting the program review component of the EDC ECA alternative 
testing program, and solicits comment on data received under the Tier I 
Program Review Testing segment of the EDC ECA. Comments are expected to 
inform EPA's decision on whether data and computational dosimetry model 
development completed by the test sponsors are sufficient to proceed 
with the Tier II Testing and computational dosimetry modeling for 
route-to-route extrapolations listed in the EDC ECA.

DATES: Comments must be received on or before October 5, 2006.

ADDRESSES: Submit your comments, identified by docket identification 
(ID) number EPA-HQ-OPPT-2003-0010, by one of the following methods:
     Federal eRulemaking Portal: http://www.regulations.gov. 
Follow the on-line instructions for submitting comments.
     Mail: Document Control Office (7407M), Office of Pollution 
Prevention and Toxics (OPPT), Environmental Protection Agency, 1200 
Pennsylvania Ave., NW., Washington, DC 20460-0001.
     Hand Delivery: OPPT Document Control Office (DCO), EPA 
East, Rm. 6428, 1201 Constitution Ave., NW., Washington, DC. Attention: 
Docket ID Number EPA-HQ-OPPT-2003-0010. The DCO is open from 8 a.m. to 
4 p.m., Monday through Friday, excluding legal holidays. The telephone 
number for the DCO is (202) 564-8930. Such deliveries are only accepted 
during the DCO's normal hours of operation, and special arrangements 
should be made for deliveries of boxed information.
    Instructions: Direct your comments to docket ID number EPA-HQ-OPPT-
2003-0010. EPA's policy is that all comments received will be included 
in the public docket without change and may be made available on-line 
at http://www.regulations.gov, including any personal information 
provided, unless the comment includes information claimed to be 
Confidential Business Information (CBI) or other information for which 
disclosure is restricted by statute. Do not submit information that you 
consider to be CBI or otherwise protected through regulations.gov or e-
mail. The regulations.gov website is an ``anonymous access'' system, 
which means EPA will not know your identity or contact information 
unless you provide it in the body of your comment. If you send an e-
mail comment directly to EPA without going through regulations.gov, 
your e-mail address will be automatically captured and included as part 
of the comment that is placed in the public docket and made available 
on the Internet. If you submit an electronic comment, EPA recommends 
that you include your

[[Page 52330]]

name and other contact information in the body of your comment and with 
any disk or CD ROM you submit. If EPA cannot read your comment due to 
technical difficulties and cannot contact you for clarification, EPA 
may not be able to consider your comment. Electronic files should avoid 
the use of special characters, any form of encryption, and be free of 
any defects or viruses.
    Docket: All documents in the docket are listed in the 
regulations.gov index. Although listed in the index, some information 
is not publicly available, e.g., CBI or other information for which 
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 either electronically 
at http://www.regulations.gov, or in hard copy at the OPPT Docket, EPA 
Docket Center (EPA/DC), EPA West, Rm. B102, 1301 Constitution Ave., 
NW., Washington, DC. The Public Reading Room is open from 8:30 a.m. to 
4:30 p.m., Monday through Friday, excluding legal holidays. The 
telephone number of the Public Reading Room is (202) 566-1744, and the 
telephone number for the OPPT Docket is (202) 566-0280.

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: [email protected].
    For technical information contact: Richard Leukroth or John 
Schaeffer, 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 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 either technical person listed under FOR 
FURTHER INFORMATION CONTACT.

B. What Should I Consider as I Prepare My Comments for EPA?

    1. Technical and scientific considerations. EPA invites interested 
parties to provide views on the test sponsors' Tier I Program Review 
Testing reports entitled: 1,2-Dichloroethane (EDC): Limited 
Pharmacokinetics and Metabolism Study in Fischer 344 Rats and 
Physiologically Based Pharmacokinetic Model Development and Simulations 
for Ethylene Dichloride (1,2-Dichloroethane) in Rats (Refs. 1 and 2). 
These reports describe a computational dosimetry model for route-to-
route extrapolation and development of pharmacokinetics and mechanistic 
data (PK/MECH data) that will support the use of this model for 
quantitative route-to-route extrapolations specific to endpoints listed 
under Tier II of the EDC ECA. The computational dosimetry model and PK/
MECH data described in these reports, if deemed acceptable to EPA, will 
be applied to support the EDC ECA Tier II Testing and computational 
dosimetry model extrapolation reporting called for under Tier II of the 
EDC ECA. EPA is interested in comments on the PK/MECH data, the EDC 
computational dosimetry model for route-to-route extrapolation, and the 
utility of resulting derived computational data from the EDC 
computational dosimetry model that will be developed under Tier II of 
the EDC ECA.
    2. Submitting CBI. Do not submit CBI to EPA through regulations.gov 
or e-mail. Clearly mark the part or all of the information that you 
claim to be CBI. For CBI information contained in a disk or CD ROM that 
you mail to EPA, mark the outside of the disk or CD ROM as CBI and then 
identify electronically within the disk or CD ROM the specific 
information that is claimed CBI. In addition to one complete version of 
the comment that includes information claimed as CBI, a copy of the 
comment that does not contain the information claimed as CBI must be 
submitted for inclusion in the public docket. Information so marked 
will not be disclosed except in accordance with procedures set forth in 
40 CFR part 2.
    3. Tips for preparing your comments. When submitting comments, 
remember to:
    i. Identify the document by docket ID number and other identifying 
information (subject heading, Federal Register date and page number).
    ii. Follow directions. As discussed in Unit I.B.1., the Agency asks 
you to respond to specific questions regarding the EDC ECA program 
review.
    iii. Explain why you agree or disagree with the materials under 
consideration for the EDC ECA program review; provide a convincing 
argument for your views or offer alternative ways to improve the 
science.
    iv. Describe any assumptions and provide any technical information 
and/or data that you used.
    v. If you estimate potential costs or burdens, explain how you 
arrived at your estimate in sufficient detail to allow for it to be 
reproduced.
    vi. Provide specific examples to illustrate your concerns and 
suggested alternatives.
    vii. Explain your views as clearly as possible, avoiding the use of 
profanity or personal threats.
    viii. Make sure to submit your comments by the comment period 
deadline identified.

II. Background

A. What Testing is EPA Requiring for EDC?

    EPA proposed health effects testing under TSCA section 4(a) for a 
number of hazardous air pollutants (HAPs or HAP chemicals), including 
EDC, in the Federal Register of June 26, 1996 (Ref. 3), as amended 
(Refs. 4 and 5). The testing needs for EDC identified in the HAPs 
proposed rule, as amended, are acute toxicity, subchronic toxicity, 
developmental toxicity, reproductive toxicity, and neurotoxicity (acute 
and subchronic), to be conducted by the inhalation route of exposure.
    In that proposed TSCA section 4(a) rule, EPA also invited the 
submission of proposals that could use the performance of PK studies 
and computional dosimetry modeling to permit extrapolation from oral 
data to predict risk from inhalation exposure. Such proposals could 
provide the scientific basis for alternative testing to the testing 
proposed under the rule and form the basis for developing needed HAPs 
data via ECAs (Refs. 3, 4, and 5).
    On November 22, 1996, 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. (the Companies), under the 
auspices of the HAP Task Force (the principal testing sponsor), 
submitted a proposal for alternative testing of EDC that included 
physiologically based pharmacokinetics (PBPK) studies and computational 
dosimetry model development to support route-to-route

[[Page 52331]]

extrapolation of testing to be conducted under the ECA by the oral 
route (Ref. 6). EPA considered this proposal sufficient (Ref. 7) to 
enter into ECA negotiations with the Companies and other interested 
parties (Ref. 8). The ECA for EDC was announced in the Federal Register 
of June 3, 2003 (Ref. 9). Under the EDC ECA (Ref. 10), the HAPs data 
needs for EDC are being addressed via an alternative testing program 
that utilizes testing by inhalation and the oral route, computational 
dosimetry model development, and development of PK/MECH data to support 
route-to-route extrapolation modeling for health effects endpoints 
identified in the ECA. EPA anticipates fulfilling all of the health 
effects testing requirements identified in the HAPs proposed rule, as 
amended, by implementation of the testing to be performed under the EDC 
ECA and Order.

B. How is EPA Implementing Testing for EDC Under the ECA?

    The EDC ECA alternative testing program has four segments, as 
follows: Tier I HAPs Testing, Tier I Program Review Testing, EPA 
Program Review, and Tier II Testing and/or Extrapolation Reporting.
    1. Tier I HAPs Testing. The ECA testing and reporting requirements 
for Tier I HAPs Testing have been completed. Under this segment of the 
EDC ECA, the Companies performed endpoint testing for acute toxicity, 
with bronchoalveolar lavage (BAL) and histopathology, and acute 
neurotoxicity (Ref. 11). These studies were conducted under a combined 
protocol by inhalation exposure. The ECA acknowledged that macrophage 
function testing (a component of EPA's acute toxicity test guideline 40 
CFR 799.9135) is adequately fulfilled by existing data published by 
Sherwood et al. (1987; Ref. 12) and also acknowledged that the 
developmental studies reported by Rao et al. (1980; Ref. 13), in 
rabbits, and Payan et al. (1995; Ref. 14) in rats, adequately fulfill 
the HAPs rulemaking testing requirements for developmental toxicity 
testing for EDC.
    2. Tier I Program Review Testing. The ECA testing and reporting 
requirements for Tier I Program Review Testing have been completed. 
Under this segment of the EDC ECA the Companies conducted studies to 
extend the computational dosimetry model of D'Souza et al. (1987, 1988; 
Refs. 15 and 16) in order to apply the model to the specific health 
effects endpoints for EDC listed in the ECA, validate the model, and 
verify the model's ability to perform quantitative route-to-route 
extrapolations of dose response. The ECA provided for the development 
of PK/MECH data to support the application of the computational 
dosimetry model for the endpoints listed under Tier II of the EDC ECA. 
The Companies also provided model simulations with point and 
uncertainty estimates of internal dose metrics (parent chemical peak 
and area under the curve (AUC) concentrations in blood and brain, and 
24-hour total glutathione (GSH)-dependent metabolism in lung and liver) 
in rats and humans to inform quantitative route-to-route extrapolations 
of the EDC dose response. Furthermore, based on an additional analysis 
of the D'Souza et al. model, the ECA was modified to include the kidney 
in the examination of GSH-dependent metabolism (Refs. 17, 18, and 19). 
Information derived from the GSH-metabolism, PK/MECH data, and model 
simulations will be used to evaluate the acceptability of performing:
    i. Oral-to-inhalation extrapolation of subchronic toxicity data 
reported by Daniel, et al. (1994; Ref. 20) relevant to corn oil gavage.
    ii. Oral-to-inhalation extrapolation of subchronic neurotoxicity 
data relevant to drinking water exposure of a study to be conducted 
under Tier II Testing.
    iii. Oral-to-inhalation extrapolation of reproductive effects 
testing conducted under Tier II Testing and each dosing paradigm of 
studies reported by Alumot et al. (1976; Ref. 21), Rao et al. (1980, 
Ref. 13), and Lane et al. (1982; Ref. 22).
    3. EPA Program Review. As indicated in Unit VI.C. of the EDC ECA 
and Unit II.B.3. of this notice, computational dosimetry model 
development and data from Tier I Program Review Testing are subject to 
an EPA Program Review. The EPA Program Review will determine whether 
the computational dosimetry model and the PK/MECH data used to support 
the route-to-route extrapolations of dose response are scientifically 
sound and provide the highest quality data. Specifically, as described 
in Unit VII. of the EDC ECA, the EPA Program Review will determine:
    i. 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 of dose response 
for any or all of the endpoints listed in the Tier II Testing segment 
of the ECA, including endpoint data from extant studies cited in the 
EDC ECA;
    ii. 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 for the dose responses 
specified in the Tier II Testing segment; and/or
    iii. The nature and scope of any additional work (e.g., development 
of additional PK/MECH data, modification to the EDC computational 
dosimetry model) that may be required to support Tier II Testing and 
application of the EDC computational dosimetry model for route-to-route 
extrapolation of dose-response reporting for the testing endpoints 
listed under Tier II of the EDC ECA.
    4. Tier II Testing and/or Extrapolation Reporting. This segment of 
the EDC ECA alternative testing program will consist of endpoint 
testing by drinking water exposure for subchronic neurotoxicity and 
reproductive toxicity. The reproductive effects toxicity testing is 
intended to confirm studies reported by Alumot et al. (1976; Ref. 21), 
Rao et al. (1980; Ref. 13), and Lane et al. (1982; Ref. 22), and 
provide data needed on fertility index, gestation index, gross 
necropsy, organ weight, histopathology, estrous cycle, sperm 
evaluation, vaginal opening, and preputial separation as described in 
the ECA. This segment will also include application of the EDC 
computational dosimetry model for quantitative route-to-route 
extrapolation reporting (oral to inhalation) for Tier II endpoint 
testing (subchronic neurotoxicity and reproductive toxicity) and 
similar computational extrapolation reporting for extant subchronic 
toxicity reported by Daniel et al. (1994; Ref. 20).

III. What Action is the Agency Taking?

A. What Opportunity is There for Public Involvement in EPA's Program 
Review?

    Tier I HAPs Testing for EDC is completed and reports for Tier I 
Program Review Testing have been submitted by the Companies. Copies of 
these submissions are available in the public docket (EPA-HQ-OPPT-2003-
0010). As described in Unit II.B.3. and stated in Part VI. of the EDC 
ECA, the next step is for EPA to conduct a Program Review on the data 
collected from the Tier I Program Review Testing segment of the EDC ECA 
alternative testing program. As noted in Unit I.B., this notice of 
availability and request for written comments provides an opportunity 
for public comment on reports subject to this EPA Program Review.

B. What Happens at the Conclusion of EPA's Program Review?

    A description of the possible outcomes of the EPA Program Review is 
provided in Part VII. of the EDC ECA. Following the EPA Program Review, 
EPA will place in the public docket for

[[Page 52332]]

this action (under docket ID number EPA-HQ-OPPT-2003-0010) a copy of 
each comment received, and a copy of the letter informing the HAP Task 
Force of the outcome from EPA's Program Review. EPA will publish a 
Federal Register notice which announces the availability of a report 
describing the findings and conclusions of the Program Review, responds 
to comments on the Tier I Program Review Testing, identifies any 
modifications to Tier II ECA activities, and establishes revised 
deadlines as needed for completion of Tier II Testing and route-to-
route computational dosimetry modeling for extrapolations listed under 
Tier II of the ECA for EDC.

IV. Materials in the Docket

    The docket for this document has been established under docket ID 
number EPA-HQ-OPPT-2003-0010. The public docket is available for review 
as specified in ADDRESSES. The following is a listing of the documents 
referenced in this preamble that have been placed in the public docket 
for this document:
    1. HAP Task Force. Letter from Peter E. Voytek to the Document 
Control Office with attachment entitled: 1,2-Dichloroethane (EDC): 
Limited Pharmacokinetics and Metabolism Study in Fischer 344 Rats. 
March 2, 2006. (See Document ID No. EPA-HQ-OPPT-2003-0010-0081 (for 
letter) and Document ID No. EPA-HQ-OPPT-2003-0010-0082 (for 
attachment)).
    2. HAP Task Force. Letter from Peter E. Voytek to the Document 
Control Office with attachment entitled: Physiologically Based 
Pharmacokinetic Model Development and Simulations for Ethylene 
Dichloride (1,2-Dichloroethane) in Rats. July 7, 2006. (See Document ID 
No. EPA-HQ-OPPT-2003-0010-0086).
    3. EPA. Proposed Test Rule for Hazardous Air Pollutants. Proposed 
Rule. Federal Register (61 FR 33178, June 26, 1996) (FRL-4869-1). 
Available on-line at http://www.epa.gov/fedrgstr/.
    4. EPA. Amended Proposed Test Rule for Hazardous Air Pollutants; 
Extension of Comment Period. Proposed Rule. Federal Register (62 FR 
67466, December 24, 1997) (FRL-5742-2). Available on-line at http://www.epa.gov/fedrgstr/.
    5. EPA. Amended Proposed Test Rule for Hazardous Air Pollutants; 
Extension of Comment Period. Proposed Rule. Federal Register (63 FR 
19694, April 21, 1998) (FRL-5780-6). Available on-line at http://www.epa.gov/fedrgstr/.
    6. HAP Task Force. Letter from Peter E. Voytek to the Document 
Control Office with attachment entitled: Proposal for Pharmacokinetics 
Study of Ethylene Dichloride, November 22, 1996. November 22, 1996. 
(See Document ID No. EPA-HQ-OPPT-2003-0010-0034).
    7. EPA. Letter from Charles M. Auer to Peter E. Voytek with 
attachment entitled: Preliminary EPA Technical Analysis of Proposed 
Industry Pharmacokinetics (PK) Strategy for Ethylene Dichloride, June, 
1997. June 26, 1997. (See Document ID No. EPA-HQ-OPPT-2003-0010-0035).
    8. EPA. Enforceable Consent Agreement Development for Ethylene 
Dichloride; Solicitation of Interested Parties and Notice of Public 
Meeting. Notice. Federal Register (62 FR 6626, December 19, 1997) (FRL-
5763-1). Available on-line at http://www.epa.gov/fedrgstr/.
    9. EPA. 1,2-Ethylene Dichloride; Final Enforceable Consent 
Agreement and Testing Consent Order. Notice. Federal Register (68 FR 
33125, June 3, 2003) (FRL-7300-6). Available on-line at http://www.epa.gov/fedrgstr/.
    10. EPA. Enforceable Consent Agreement for 1,2-Ethylene Dichloride. 
May 15, 2003. (CAS No. 107-06-2) (See Document ID No. EPA-HQ-OPPT-2003-
0010-0002).
    11. HAP Task Force. Letter from Peter E. Voytek to the Document 
Control Office with attachment entitled: 1,2-Dichloroethane (EDC): 
Acute Inhalation Toxicity with Bronchoalveolar Lavage and 
Histopathology/Acute Inhalation Neurotoxicity Study in F344/DUCRL Rats. 
June 21, 2006. (See Document ID Nos. EPA-HQ-OPPT-2003-0010-0087 through 
EPA-HQ-OPPT-2003-0010-0087.6).
    12. Sherwood, R.L.; O'Shea, W.; Thomas, P.T.; Ratajczak, H.V.; and 
Aranyi, C. Effects of inhalation of ethylene dichloride on pulmonary 
defenses of mice and rats. Toxicology and Applied Pharmacology 91: 491-
496 (1987).
    13. Rao, K.S.; Murray, J.S.; Deacon, M.M.; John, J.A.; Calhoun, 
L.L.; and Young, J.T. Teratogenicity and reproduction studies in 
animals inhaling ethylene dichloride. Banbury Report 5: 149-166 (1980).
    14. Payan, J.P.; Saillenfait, A.M.; Bonnet, P.; Fabry, J.P.; 
Langonne, I.; and Sabate J.P. Assessment of the developmental toxicity 
and placental transfer of the 1,2-dichloroethane in rats. Fundamental 
and Applied Toxicology 28: 187-198 (1995).
    15. 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, pp 286-301. Pharmacokinetics in 
Risk Assessment. National Academy Press. Washington, DC (1987).
    16. 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).
    17. EPA. Letter dated March 24, 2004 from Wardner G. Penberthy to 
Peter E. Voytek with two attachments entitled:
    i. Addendum Modification to Enforceable Consent Agreement for 
1,2,Ethylene Dichloride (EDC).
    ii. Application of a PBPK model for cancer and non-cancer risk 
assessment of 1,2-dicholoroethane. Phase I: Evaluation of issues 
related to the use of a PBPK model for DCE. Requisition Reference No. 
2WE59, QT-DC-030387.
(See Document ID Nos. EPA-HQ-OPPT-2003-0010-0059 (for letter) and EPA-
HQ-OPPT-2003-0010-0060 (for attachments)).
    18. HAP Task Force. Letter from Peter E. Voytek to the Document 
Control Office Re: Testing Consent Order for Ethylene Dichloride; 
Request for Modification of Enforceable Consent Agreement. June 21, 
2004. (See Document ID No. EPA-HQ-OPPT-2003-0010-0063).
    19. EPA. Letter dated July 14, 2004 from Wardner G. Penberthy to 
Peter E. Voytek RE: 1,2-Ethylene Dichloride (EDC), Request for 
Modification of PBPK Testing in Tier I Testing of the EDC ECA. (See 
Document ID No. EPA-HQ-OPPT-2003-0010-0065).
    20. Daniel, F.B.; Robinson, M.; Olson, G.R.; York, R.G.; and 
Condie, L.W. Ten and ninety-day toxicity studies of 1,2-dichloroethane 
in Sprague-Dawley rats. Drug and Chemical Toxicology 17: 463-477 
(1994).
    21. Alumot, E.; Nachtomi, E.; Mandel, E.; Holstein, P.; Bondi, A.; 
and Herzberg, M. Tolerance and acceptable daily intake of chlorinated 
fumigants in the rat diet. Food, Cosmetics and Toxicology 14: 105-110 
(1976).
    22. Lane, R.W.; Riddle, B.L.; and Borzelleca, J.F. Effects of 1,2-
dichloroethane and 1,1,1-trichloroethane in drinking water on 
reproduction and development in mice. Toxicology and Applied 
Pharmacology 63: 409-421 (1982).

List of Subjects

    Environmental protection, 1,2-Ethylene Dichloride, Hazardous 
chemicals.



[[Page 52333]]


    Dated: August 24, 2006.
Wardner G. Penberthy,
Acting Director, Chemical Control Division, Office of Pollution 
Prevention and Toxics.
[FR Doc. E6-14639 Filed 9-1-06; 8:45 am]
BILLING CODE 6560-50-S