E6-14639. 1,2-Ethylene Dichloride Tier I Program Review Testing; Notice of Availability and Solicitation of Comment

AGENCY:

Environmental Protection Agency (EPA).

ACTION:

Notice.

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 [phone]. 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 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 [phone], and the telephone number for the OPPT Docket is [phone].

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: [phone]; e-mail address: [e-mail].

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: [phone]; e-mail address: [e-mail].

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 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 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

Dated: August 24, 2006.

Wardner G. Penberthy,

Acting Director, Chemical Control Division, Office of Pollution Prevention and Toxics.