S? 41 UNITED STATES ENVIRONMENTAL PROTECTION AGENCY WASHINGTON, D. C. 20460 ~ PRO~

FEB 13 2001 OFFICE OF PREVENTION, PESTICIDES AND TOXIC SUBSTANCES Dr. Peter Voytek HAP Task Force, Manager Regulatory Sciences International King Street Station 1800 Diagonal Road, Suite 500 Alexandria, VA 223 14 2808 RE: ECA Development ofEthylene Dichioride ( EDC) ( OPPTS  42197C)

Dear Dr. Voytek:

EPA has completed a detailed review of the HAP Task Force March 19, 1999, outline of testing protocols for ethylene dichloride ( EDC). As was the case for 1,1 ,2 trichloroethane ( TCE), the HAP Task Force did an excellent job in preparing this initial testing outline. The purpose of this letter is to confirm points ofagreement on the overall testing program, identify areas where the PKIMECH proposed testing needs further embellishment or clarification, and to map out next steps for developing the enforceable consent agreement ( ECA) for EDC. I hope we will be able to build on prior experience from working with the HAP Task Force on the TCE ECA so as to expedite the completion of the remaining work on this ECA.

The following points ofagreement are confirmed by our review of the March 19, 1999 submission:

The HAP Task Force would develop inhalation toxicity data for 1) acute toxicity with brochoalveolar lavage ( BAL) and histopathology and 2) acute neurotoxicity. This testing would be accomplished using a combined protocol following TSCA guidelines § 799.9135, and § 799.9620 modified as appropriate. EPA has determined that the macrophage function assay reported by Sherwood et. al., ( 1987) is adequate to partially fulfill the HAP rulemaking testing requirements for this element of the acute toxicity endpoint. The HAP Task Force should supply this reference as an integral part ofthe ECA for EDC, including hard copy as an appendix.

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° EPA agrees that the Payan et al., 1995 study in rats along with the study by Rao, 1980 in rabbits are adequate to fulfill the developmental toxicity testing requirement proposed in the HAPs rulemaking. The HAP Task Force would supply these references as an integral part ofthe ECA for EDC, including hard copy as an appendix.

° The PK/ MECH data to be developed must support the oral to inhalation extrapolation model by Gargas et al., 1989; 1990. The HAP Task Force would supply these references as an integral part ofthe ECA for EDC, including hard copy as an appendix.

° The PK/ MECH data to be developed must support oral to inhalation extrapolation of: 1) oral ( via corn oil gavage) subchronic toxicity data in rats ( Daniel et al., 1994; 2) oral ( via drinking water) subchronic neurotoxicity data in rats; 3) oral ( via drinking water) reproductive toxicity data in rats; and 4) each dosing paradigm for the reproductive toxicity studies by Alumot et al., 1976, Rao et al., 1980, and Lane et al., 1982. ( These oral studies would be developed or ( in the case oforal subchronic toxicity and reproductive toxicity) expanded by the HAP Task Force under Tier II Testing of this ECA.) The HAP Task Force would supply these references as an integral part ofthe ECA for EDC, including hard copy as an appendix.

° Toxicity data to be developed under Tier II Testing would be conducted by the oral route ( via drinking water) and would be governed by protocols following TSCA test guidelines ( with modifications as appropriate) for subchronic neurotoxicity ( TSCA Test Guideline § 799.9620) and for reproductive toxicity ( TSCA Test Guideline § 799.9380).

° Tier II route to route extrapolation reporting would be conducted for subchronic toxicity using data from Daniel et al., 1994, and data obtained from the Tier II subchronic neurotoxicity and reproductive toxicity testing.

EPA's review of the pharmacokinetics proposal identified several elements that need further consideration before final agreement can be reached on this aspect ofthe revised proposal. Specifically, revisions are needed in the approach to develop PKIMECH data forthe central nervous system ( brain) which is identified as a potential target organ of concern for EDC. The HAP Task Force PK proposal makes certain assumptions regarding selection ofthe parent compound in circulating blood and/ or the use of urine glutathione ( GSH) metabolites as the dose metric. EPA believes that this hypothesis, although plausible, has not been tested and would not fully inform EPA on the actions ofEDC under the HAP Task Force proposal. For example, the lipid content of the brain will most likely make EDC brain concentrations closer to those in adipose tissues than to blood. In addition, equilibration of EDC in the brain is not likely to be instantaneous due to the action of the blood brain barrier, resulting in brain concentrations that  3

will differ from the blood concentrations. There is a need to develop data to support a comprehensive understanding of the central nervous system ( CNS) component in the proposed model. A preferable approach would include the following:

1. Develop PK/ MECH data on parent compound in blood, parent compound in brain, and total GSH metabolites for use as potential dose metrics in order to compare for relevance to the tissue response.

2. Develop a comprehensive time course to rule out potential blood brain diffusion limitation. A potential design might include blood and brain time points such as 0.25, 0.5, 1, 2, 4, 8, 16, and 24 hours with a minimum of3 animals per time point.

We consider the addition of this information to be an essential component in the development of a scientifically sound approach to route to route extrapolation for EDC. In anticipation that the HAP Task Force will concur with EPA's view, we have incorporated this approach into the enclosed draft ECA.

The Panel is requested to review and comment, as appropriate, on the enclosed draft ECA between EPA and the member companies ofthe HAP Task Force on EDC. Incorporating PBPK as a component of the TSCA Section 4 Chemical Testing Program is a new approach for EPA's Office of Prevention, Pesticides, and Toxic Substances. As was noted for l, l, 2 TCE, it is essential to the success of this ECA that we include a measure to ensure that the data set used to inform modeling extrapolations is of the highest quality. For this reason, as I indicated during our previous discussions, EPA has included a Program Review step in this ECA. The purpose of the Program Review will be to confirm that all necessary dataelements have been adequately developed to inform the extrapolations specified in this ECA and to ensure that the proposed modeling extrapolations are both feasible and based on sound science.

As you read through this draft ECA, please pay particular attention to the information provided in Table 1. It is our intent that the HAP Task Force will develop the necessary appendices that will be attached to the ECA. This can be accomplished either by enhancing the outline to provide specific reference to EPA guidelines or by submitting photocopies ofexisting guidelines that include annotations as needed. Incorporating PBPK into the ECA adds a level of complexity that can be difficult to follow within the overall testing program. For this reason, we suggest that the first appendix be a flowchart of the overall testing program. The flowchart should indicate where the various elements ofthe PBPK data will be obtained within the overall testing program ( i. e., component ofendpoint testing, or stand alone study).

Please submit comments on the draft ECA along with a copy of the various attachment appendices ( without existing study reprints) by March 9, 2001. Once EPA and the member Companies of the HAP Task Force have reached agreement on the details ofthe ECA, we can move toward finalizing the ECA document and obtain signature approval by all parties.  4

As you are aware, EDC has been included as one ofthe chemicals available for sponsorship under the Voluntary Children's Chemical Evaluation Program ( VCCEP) pilot ( FR 65 FR 81699, December 26, 2000). As described in the VCCEP notice, Tier 1 information includes hazard assessment, exposure assessment, risk assessment, and a data needs assessment. The opportunity to voluntarily sponsor EDC in the VCCEP Pilot runs until June 25, 2001. While the testing included in the draft ECA under the HAPs rulemaking would meet many of the hazard data needs for EDC under the VCCEP Pilot, it would not address exposure information needs and there would also be deficiencies with regard to certain toxicity end points ( e. g., developmental neurotoxicity) described in the third tier of the VCCEP Pilot. In the event that this ECA can be concluded in the near future, EPA believes that a workable course ofaction would be for the HAP Task Force to separately volunteer to sponsor EDC for Tier 1 hazard information under the VCCEP Pilot. The HAP Task Force could use the results from the HAPs ECA when developing the VCCEP Tier 1 submission. If the HAP Task Force chooses this route, I could foresee that, for EDC, the delivery date for Tier 1 VCCEP information and assessment could be adjusted to take account ofthe timing elements in the HAPs ECA. In the event that the HAPs ECA on EDC cannot be concluded in the near future, EPA will consider EDC open for sponsorship under the YCCEP Pilot.

I look forward to successfully concluding an ECA for EDC. Ifyou have any questions please contact John Schaeffer at ( 202) 260 1266 or Richard Leukroth at ( 202) 260 0321.

Sincerely,

Charles M. Auer, Director Chemical Control Division Enclosure cc: Greg Blumenthal Jane Caldwell Richard W. Leukroth, Jr. W. Caffey Norman, III John Schaeffer Docket OPPTS 42197C ENFORCEABLE CONSENT AGREEMENT FOR ETHYLENE DICHLORIDE ( EDC)

CAS No. 107 06 2 Docket No. OPPTS  42197C DRAFT February, 2001 ENFORCEABLE CONSENT AGREEMENT FOR ETHYLENE DICHLORIDE ( EDC)

Docket No. OPPTS 42 197C TABLE OF CONTENTS I. INTRODUCTION 1 II. CHEMICAL SUBJECT TO THE ECA 1 III. OBLIGATION OF SIGNATORY COMPANIES AND ROLE OF THE HAP TASK FORCE 1 IV. PURPOSE OF THE TESTING PROGRAM 2 V. SCOPE OF THE TESTING PROGRAM 3 VI. DESCRIPTION OF THE TESTING PROGRAM s VII. EPA PROGRAM REVIEW OUTCOMES 7 VIII. STANDARDS FOR CONDUCTING TESTING 9 IX. SUBMISSION OF STUDY PLANS 10 X. MODIFICATIONS TO ENFORCEABLE CONSENT AGREEMENT 10 XI. FAILURE TO COMPLY WITH THE ENFORCEABLE CONSENT AGREEMENT ... 10 XII. EPA MONITORING OF ENFORCEABLE CONSENT AGREEMENT TESTING .... 11 XIII. SUBMISSION OF DATA 11 XIV. PUBLICATION AND DISCLOSURE OF TEST RESULTS 11 XV. CONFIDENTIALITY OF INFORMATION 11 XVI. RESPONSIBILITIES OF THE COMPANIES 11 XVII. SEVERABILITY OF ENFORCEABLE CONSENT AGREEMENT PROVISIONS.. 12 DRAFT ECA for EDC 2/ 01 XVIII. FINAL AGENCYACTION . 12 XIX. PUBLIC RECORD 12 XX. EFFECTIVENESS 12 XXI. RIGHTS OF THE COMPANIES 13 XXII. IDENTITY OF THE COMPANIES 13 XXIII. SIGNATURE 14 Table 1 REQUIRED TESTING, TEST STANDARDS, REPORTING AND OTHER REQUIREMENTS FOR ETHYLENE DICHLORJDE 25 APPENDICES A. Flow Chart ofTesting Program B. TSCA Guidelines with Annotations as Appropriate: B. 1 Acute Inhalation Toxicity with BAL and Histopathology B .2 Acute Inhalation Neurotoxicity B. 3 Subchronic Neurotoxicity B. 4 Reproductive Toxicity C. PKIMECH Procedures and Route to Route Extrapolation Reporting: C. 1 Pharmacokinetic Studies for F344 Rats C. 2 Subchronic Toxicity C. 3 Subchronic Neurotoxicity C. 4 Reproductive Toxicity C. 5 PBPK Model Description and Coding C. 6 General Outline for Route to Route Extrapolation Reports D. Study Protocols: D. 1 Combined Acute Toxicity with BAL and Histopathology and Acute Neurotoxicity ( Inhalation) D. 2 Subchronic Neurotoxicity ( Oral) D. 3 Reproductive Toxicity ( Oral)

  11   DRAFT ECA for EDC 2/ 01 APPENDICES   continued E. Existing Toxicity Studies: E. 1 Existing Acute Toxicity Study a) Sherwood et al. ( 1987) E. 2 Existing Subchronic Toxicity Study a) Daniel et al. ( 1994) E. 3 Existing Developmental Toxicity Studies a) Raoetal. ( 1980) b) Payan et al. ( 1995) E. 4 Existing Reproductive Toxicity Studies a) Alumot et al. ( 1976) b) Raoetal. ( 1980) c) Lane et al. ( 1982)

  111   DRAFT ECA for EDC 2/ 01 I. INTRODUCTION Under the authority of section 4 of the Toxic Substances Control Act ( TSCA), 15 U. S. C. 2603, the United States Environmental Protection Agency ( EPA) and The Dow Chemical Company, Vulcan Materials Company, Occidental Chemical Corporation, Oxy Vinyls, LP, Georgia GulfCorporation, Westlake Chemical Corporation, PPG Industries, Inc., Borden Chemicals & Plastics Operating Limited Partnership, and Formosa Plastics Corporation, U. S. A. ( hereinafter collectively " the Companies") enter into this enforceable consent agreement ( ECA). This ECA takes effect on the date of publication ofthe notice in the Federal Register announcing the issuance ofthe testing consent order ( Order) that incorporates this ECA.

In EPA's proposed test rule for hazardous air pollutants ( HAP5) published on June 26, 1996 ( 61 FR 33178), amended on December 24, 1997 ( 62 FR 67466) and on April 21, 1998 ( 63 FR 19694), EPA invited the submission of alternative testing proposals for HAPs that would apply pharmacokinetics studies and mechanistic data ( PKIMECH) to inform route to route extrapolation of data from studies acceptable to EPA that were performed by a route of exposure other than inhalation. Such proposals would be used to develop a tailored testing program to provide the data needs identified by EPA in the proposed HAPs rulemaking via an ECA process. This ECA resulted from negotiations conducted as a part ofan ECA process for the HAP ethylene dichloride ( 62 FR 66626; December 19, 1997). The official record for this ECA, including the public version, is established under EPA docket control number OPPTS 42l97C. The procedures for ECA negotiations are described at 40 CFR 790.22( b).

II. CHEMICAL SUBJECT TO THE ECA The subject of this ECA is the chemical substance ethylene dichloride ( EDC), CAS No. 107 06 2. The ethylene dichloride to be tested must be as pure as can be reasonably attained, but must be at least 99.5? percent pure.

III. OBLIGATION OF SIGNATORY COMPANIES AND ROLE OF THE HAP TASK FORCE A. Testing will be sponsored by the Companies, which are responsible for complying with this ECA.

B. The Companies recognize that to implement this ECA, EPA will issue an Order under section 4 ofTSCA that incorporates the terms of this ECA. The Companies agree that all terms ofthis ECA will take effect on the date of publication of the notice in the Federal Register announcing the issuance ofthe Order that incorporates this ECA, and all applicable time periods will be treated as beginning on that publication date.

DRAFT ECA for EDC 2/ 01 1 C. The Companies are members ofthe HAP TASK FORCE, which is an association of manufacturers of ethylene dichioride. The HAP TASK FORCE will be responsible for coordinating and administering testing under this ECA and communicating with EPA about study plans, protocols, test standards, and other aspects ofthe testing program. In performing these functions, the HAP TASK FORCE will be acting as the agent of the Companies for purposes of compliance and communication with EPA. EPA and the Companies recognize that, except for its role as agent as specified in this ECA, the HAP TASK FORCE has no legal responsibility for complying with this ECA. Responsibility for complying with the ECA rests at all times with the individual Companies.

IV. PURPOSE OF THE TESTING PROGRAM The purpose ofthe testing program specified in this ECA is to supplement available information in order to further characterize the potential for acute toxicity, subchronic toxicity, neurotoxicity, developmental toxicity and reproductive toxicity effects ofethylene dichloride from inhalation exposures. One component of this testing program will develop PKJMECH data directed at characterizing the mode of action of ethylene dichloride. Such information, along with data from health effects studies acceptable to EPA and/ or from health effects studies to be conducted as part of this ECA testing program for ethylene dichloride, will be used to inform the route to route extrapolations that are specified in Table 1. EPA will also use the PK/ MECH data to provide the basis for determining the feasibility and appropriateness of using a tailored approach to testing and whether route to route extrapolations can be used to meet inhalation testing requirements for ethylene dichloride that are identified in the proposed HAPs test rule, as amended.

EPA believes that the PK/ MECH studies designed to construct quantitative dosimetric characterization ofthe disposition and relevant response mechanisms with regard to ethylene dichloride, in conjunction with the studies and route to route extrapolation reporting that are specified in Table 1 and described in Appendices B through E to this ECA, will generate data needed by EPA to determine whether ethylene dichloride presents an unreasonable risk ofinjury to human health from inhalation exposures. The data will also be used to implement several provisions of section 112 ofthe Clean Air Act, including determination of residual risk, estimation of the risks associated with accidental releases of ethylene dichloride, and determinations regarding whether substances should be removed from the Clean Air Act section 1 12( b)( 1) list of hazardous air pollutants. In addition, the data will also be used by other Federal agencies ( e. g., the Agency for Toxic Substances and Disease Registry ( ATSDR), the National Institute for Occupational Safety and Health ( NIOSH), the Occupational Safety and Health Administration ( OSHA), and the Consumer Product Safety Commission ( CPSC)) in assessing chemical risks and in taking appropriate actions within their programs. It is intended that the data generated under this ECA will satisfy the toxicological data needs for acute toxicity, subchronic toxicity, neurotoxicity, developmental toxicity and reproductive toxicity effects of ethylene dichloride as identified in the amended proposed HAPs rulemaking.

DRAFT ECA for EDC 2/ 01 2 V. SCOPE OF THE TESTING PROGRAM The Companies, through the HAP TASK FORCE, will jointly conduct or provide for the performance ofthe testing program specified in this ECA. This testing program will consist of: 1) conducting the testing listed in Table 1 in accordance with the test standards specified in Table 1 and described in Appendix B( l 4) as annotated in Appendix D( 1 3) to this ECA (" Test Standards"), and performing the PBPK studies and route to route extrapolations specified in Table 1 and described in Appendix C( 1  6) to this ECA; and 2) submitting the reports and documents specified in Table 1 in accordance with the deadlines set forth in Table 1.

The use ofPKIMECH data to support quantitative route to route extrapolation is a new approach for EPA's Office of Pollution Prevention and Toxics ( OPPT) in the TSCA section 4 Chemical Testing Program. It is essential to the success ofthis ECA testing program for EPA to ensure that the data used to inform the route to route extrapolations is ofthe highest quality. For this reason, a program review requirement has been incorporated into this ECA testing program ( see Part VI. C. and Part VII. A.  D. ofthis ECA).

EPA notes that the generation of PKIMECH data to support development ofdosimetry ( e. g.; physiologically based pharmacokinetics  PBPK) models should be chemical specific and based on an understanding, to the degree possible, ofthe mode ofaction for the various endpoint toxicities. Modeling is an iterative process. The nature ofchemical reactions between a xenobiotic agent and biological tissues, and the degree to which they are understood, have a profound influence on the scope of the modeling effort. A degree ofuncertainty regarding the model structure can be clarified by validation of the predications ofthe PBPK dosimetry model with appropriately designed experiments. New insights on important parameters and processes can then be additionally tested and used to further refine the model. Because these chemical and toxicity specific attributes can affect both the type of PKJMECH data necessary to characterize disposition ofa chemical and the type of model structure that would be adequate to describe it, EPA does not have guidelines available for the HAP TASK FORCE to utilize. General guidance is available in a number of references ( Woodruff et al., 19921; Ultman, 19942; Andersen et al.,

1 Woodruff, T. J., F. Y. Bois, D. Auslander and R. Spear. 1992. Structure andparameterization of pharmacokinetics models: Their impact on model predictions. Risk Anal. 12: 189 201.

2 Ultman, J. S. 1994. Dosimetry modeling: Approaches and issues. Inhal. Toxicol. 6: 59 71.

DRAFT ECA for EDC 2/ 01 3 1995~ Kohn, l997~ Buchanan et al., 1 9975)~ Key considerations for model structure include the degree ofparameterization and whether the model is to be used to extrapolate ( e. g., across species or across routes) versus interpolate data ( Woodruff et al., 1992).

The source ofeach model parameter value should be described, indicating whether it was: 1) obtained from prior literature ( copy ofreferences cited to be provided by the HAP TASK FORCE), 2) determined directly by a separate experiment described in the submitted report or peer reviewed paper, or 3) estimated by the fitting ofmodel output to experimental data. Parameter estimates derived independently oftissue time course or dose response data are preferred ( Andersen et al., 1995). Determination by separate experiment is preferred, particularly for critical target tissue parameters, such as partition coefficients. Model verification, the process ofevaluating the sufficiency ofthe model for its intended purpose, should be demonstrated by showing the ability ofthe model to predict the behavior ofexperimental data different from those on which it was based. Model validation should demonstrate the ability ofthe model to predict the behavior ofthe system under conditions which test the principal aspects ofthe underlying hypothetical structure. Objective measures of variance ( e. g., statistical goodness offit) that can be compared to residual variance are preferred, but accurate prediction ofthe general behavior of the data for the intended application ( e. g., a given range) may be a more important consideration. For this latter consideration, however, a factor of 2 fold ( on average) will be a general criterion applied to determine " reasonable" agreement of the model with the experimental data.

The choice ofwhich dose metric to use in the model to characterize a given endpoint toxicity should be based on some knowledge ofthe mode of action by which the toxic effects are induced. The mechanistic information does not necessarily have to be exhaustive but can rather be related to general aspects of the nature and causes of a particular toxic interaction. Certainly route specific toxicity needs to be characterized, both the effects in the portal of entry as well as modulation of systemic dose at remote sites. PKJMECH data must be developed that correspond to the species, dose level, exposure regimen and vehicle ( e. g., intermittent corn oil gavage versus drinking water ad lib versus diet) of the toxicity datathat are the object ofthe extrapolation. For the extrapolation ofthe chronic endpoint data, demonstration ofperiodicity during the experiments used to generate the PKIMECH data is required. Periodicity, as defined in U. S. EPA ( 1994) 6, is achieved when the internal concentration ofthe dose metric of interest ( e. g., parent ~ Andersen, M. E., H. J. Clewell, III and C. B. Frederick. 1995. Applying simulation modeling to problems in toxicology and risk assessment  A short perspective. Tox. Appl. Pharm. 133 187.

`~ Kohn, MC. 1997. The importance of anatomical realism for validation of physiological models of disposition of inhaled toxicants. Tox. Appl. Pharm. 147: 448 458.

~ Buchanan, JR., L. T. Burka, and R. L. Melnick. 1997. Purpose and guidelines for toxicokinetic studies within the National Toxicology Program. Environ. Hith. Perspecl. 105( 5): 468 471.

6 U. S. EPA. 1994. Methods for derivation of inhalation reference concentrations and application of inhalation ( continued...)

DRAFT ECA for EDC 2/ 01 4 venous concentration) versus time profile is the same for 90% of the exposure period. The rationale for the choice of various dose metrics should be provided.

Andersen et al. ( 1995) published a table ofcharacteristics ofa good modeling paper and documentation; EPA will utilize these same reporting requirements. These include: ( 1) clear presentation ofall equations; ( 2) clear definition of all variables and parameters; ( 3) clear definition ofunits to ensure proper dimensions; ( 4) definition of criteria to evaluate predictions or fits; ( 5) specification of the time, species, and exposure domain where the model is valid; and ( 6) discussion ofthe hypothesis testing and model discrimination as necessary. Graphical display of model fits to data are required; including both parent and metabolite( s) blood and target tissue time course data. EPA also requires a sensitivity analysis ofthe model. Documentation ofmodel code with comment fields must be provided. Computer hardware and software actually used in the application must be described. If specialized software functions must be referred to, they should be described sufficiently to enable someone unfamiliar with the software to understand their operation. Standard mathematical forms are preferred to software language functional forms.

VI. DESCRIPTION OF THE TESTING PROGRAM The testing program has four segments as follows: Tier I HAPs Testing; Tier I Program Review Testing; EPA Program Review; and Tier II Testing.

A. Tier I HAPs Testing: This testing will consist ofthe following endpoint testing, conducted by inhalation exposure, that EPA has deemed necessary to meet certain data needs identified in the proposed HAPs test rule, as amended: 1) acute toxicity testing with BAL and histopathology, and 2) acute neurotoxicity testing. EPA will not finalize the testing requirements for these Tier I HAPs Testing endpoints for ethylene dichloride as specified in the proposed HAPs test rule, as amended, because such testing will be conducted under this ECA. Furthermore, EPA considers the existing study by Sherwood et al. ( 1987), adequate to fulfill the macrophage function assay portion of the acute toxicity testing requirement ( see Appendix E. 1). In addition, EPA considers the existing studies by Rao et al. ( 1980) and Payan et al. ( 1995), adequate to characterize the developmental toxicity of ethylene dichloride under the proposed HAPs rulemaking, as amended ( see Appendix E. 3). Thus, EPA will not finalize the testing requirements for the developmental toxicity and macrophage function assay Tier I HAPs testing endpoints for EDC as specified in the HAPs proposed rule as amended, because available studies are acceptable for HAPs purposes. Tier 1 testing for acute toxicity and acute neurotoxicity and the extant data for macrophage function assay and developmental toxicity testing are specified in 6 (... continued)

dosimetry. Office of Research and Development. Environmental Criteria and Assessment Office, Research Triangle Park, NC. EPA/ 600/ 8 90/ 066F.

S DRAFT ECA for EDC 2/ 01 the " Tier I HAPs Testing" segment of Table 1 and described in Appendix B( 1,2) as annotated in Appendix D( l)), and Appendix E( l, 3).

B. Tier I Program Review Testing: This testing, specified in the " Tier I Program Review Testing" segment of Table 1 and described in Appendix C. 1, will develop PK/ MECH data needed to inform about the acceptability of an alternate route to inhalation for Tier II testing. It will also develop and validate the dosimetry model ofGargas et al. ( 1989; 1990) in rats and verify the ability ofthe model to perform quantitative route to route extrapolations, as described in Appendix C( 2 5) and as will be reported following guidance provided in Appendix C. 6. Data from this testing will be the subject ofdiscussions at the EPA Program Review. While EPA believes that it is best to obtain this type of PKIMECH data in conjunction with the testing specified in the Tier I HAPs Testing ( see Part VI. A.), these PK! MECH data may also be obtained independently from stand alone studies. Specifically, the PKIMECH data will support: 1) oral toinhalation extrapolation of existing subchronic toxicity data in rats administered ethylene dichloride via corn oil gavage ( Daniel et al., 1 994)( see Appendix E. 2); 2) oral to inhalation extrapolation ofsubchronic neurotoxicity data in rats administered ethylene dichioride via drinking water ( see Tier II testing); and 3) oral to inhalation extrapolation ofreproductive toxicity data in rats administered ethylene dichloride via drinking water ( see Tier II testing) and each dosing paradigm of existing reproductive toxicity studies by Alumot et al. ( 1976), Rao et al. ( 1980), and Lane et al. ( l982)( see Appendix E. 4). The PKIMECH data will also support model simulations to demonstrate validation and verification of PBPK models for route to route extrapolation in order to evaluate acceptability of oral drinking water exposure in rats in the Tier II testing for subchronic neurotoxicity and reproductive toxicity.

C. EPA Program Review: A program review will be conducted by EPA to review the data collected from the Tier I Program Review Testing segment ( see Part VI. B. ofthis ECA) and other studies acceptable to EPA that would be applied to route to route extrapolations, as indicated in footnotes 4, 6, and 8 ofTable 1.

The purpose ofthe EPA Program Review will be 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 inform route to route extrapolations for endpoints listed in the Tier II Testing segment; ( 2) whether the data from the Tier I Program Review Testing segment ( see Part VI. B. ofthis ECA) provide a sufficient basis for conducting the endpoint testing and/ or the route to route extrapolations specified in the Tier II Testing segment; and/ or ( 3) the nature and scope ofany additional work that may be required prior to the commencement ofTier ii Testing and extrapolation reporting ( e. g., additional PK/ MECH data as described in Part VII. ofthis ECA).

Opportunity for public participation in the EPA Program Review will be provided either by a request for written comments or through an announcement of a public meeting. EPA will publish the request for public comments and/ or the announcement of a public meeting in the Federal Register. Following the EPA Program Review, EPA will place in the record for this DRAFT ECA for EDC 2/ 01 6 action a summary describing the EPA Program Review meeting, if such a meeting is held, a copy ofcomments received, and a copy ofthe letter sent to the HAP TASK FORCE informing the conclusions ofEPA's Program Review.

D. Tier II Testing: This segment will consist of additional endpoint testing not included in the Tier I HAPs Testing segment, as specified in Table 1 and described in Appendix B ( 3 4) as annotated in Appendix D( 2 3). Specifically this testing will consist of oral subchronic neurotoxicity testing and oral reproductive effects testing. Tier II will also consist ofroute toroute extrapolation reporting for existing subchronic toxicity data of Daniel et a!. ( 1994), the subchronic neurotoxicity and reproductive toxicity data obtained from Tier II testing, and extant data from reproductive toxicity studies by Alumot eta!. ( 1976), Rao eta!. ( 1980), and Lane eta!. ( 1982), as specified in Table 1 and Appendix C( 2 4) and reported following guidance provided in Appendix C. 6. Following a successful outcome of the EPA Program Review ( see Section VII. A. and B. l. a.), EPA will not finalize inhalation testing requirements for these Tier II testing endpoints for ethylene dichloride, as specified in the amended proposed HAPs test rule, because the data required under the HAPs rulemaking will be developed under this ECA.

VII. EPA PROGRAM REVIEW OUTCOMES The EPA Program Review segment can result in several possible outcomes, described below.

A. EPA Accepts Tier IProgram Review Testin.~ Data: EPA may determine that the Tier I Program Review Testing data can be used to inform and support Tier II testing for any or all ofthe endpoints and/ or associated route to route extrapolation reporting for ethylene dichloride that are specified in Table 1. In such an instance, EPA will notify the Companies in writing that Tier II endpoint testing and route to route extrapolation reporting must be conducted for: subchronic toxicity, subchronic neurotoxicity, and reproductive toxicity for ethylene dichloride. In addition, EPA will not finalize the testing requirements for these endpoints for ethylene dichloride as specified in the proposed HAPs test rule, as amended.

B. EPA IdentifIes Limitations in the Tier IPro~ ramReview Testin.~ Data: EPA may determine that additional Tier I Program Review Testing is needed before any or all ofthe Tier II endpoint testing and/ or associated route to route extrapolation reporting that are specified in Table 1 for ethylene dichloride can be conducted. In such an instance, EPA will inform the Companies by letter that additional Tier I Program Review Testing is needed and a copy ofthis letter will be placed in the record for this action. EPA may initiate technical discussions with the Companies on this matter.

( 1) Agreement on Additional Tier IProgram Review Testing: If EPA and the Companies agree to the additional testing, modifications to the relevant Test Standards specified in the Tier I Program Review Testing section ofTable 1 and described in the associated DRAFT ECA for EDC 2/ 01 7 appendices for the relevant Test Standards may be made according to the procedures contained in 40 CFR 790.68 ( see Part X of this ECA). The additional Tier I Program Review Testing will be conducted in accordance with these modifications. The data resulting from this additional testing will be reviewed to determine if such data meet EPA needs. This review may include one or more meeting( s) between the Companies and EPA. Opportunity for public participation will be provided either by a request for written comments and/ or through an announcement of a public meeting. Following such meeting( s), EPA will place in the record for this action a summary of each meeting along with a copy ofthe comments received.

( a) Additional Tier IProgram Review Testing Meets Data Needs: Ifand when the Tier I Program Review Testing data are determined to be acceptable to EPA, EPA will inform the Companies by letter that the data from the Tier I Program Review Testing can be used as a basis to inform and support Tier II Testing for any or all of the endpoints and associated route to route extrapolation reporting for ethylene dichloride that are specified in Table 1. In addition, the letter will indicate that EPA will not finalize the inhalation testing requirements for these Tier II Testing endpoints for ethylene dichloride as specified in the proposed HAPs test rule, as amended. A copy ofthe letter will be placed in the record for this action.

( b) Additional Tier IProgram Review Testing Does Not Meet Data Needs: If, at any point, EPA determines that the TierI Program Review Testing data, as supplemented by the additional Tier I Program Review Testing data, cannot be used to inform and support Tier II testing for any or all ofthe endpoints and/ or associated route to route extrapolations for ethylene dichloride that are specified in Table 1, thenthe outcome described in Part. VII . C. below will apply to these endpoints.

( 2) Failure to Agree on Additional Needed Tier I Program Review Testing: If the Companies and EPA do not agree to the additional Tier I Program Review Testing that EPA has determined to be needed the outcome described in Part VII. C. below will apply to these endpoints.

C. EPA Determines Tailored Approach to HAPs Testing is not Feasible: EPA may determine that the tailored approach to HAPs testing set forth in this ECA, for any or all Tier I Program Review Testing as applied to any or all Tier II endpoint testing and associated route toroute extrapolations, is not feasible. In such an instance, EPA will notify the Companies by certified letter or Federal Register notice. The notification will include the reason( s) for the determination and will be placed in the record for this action. IfEPA issues such a notification for any endpoint( s), the Companies' obligations to conduct testing or associated route to route extrapolations for that endpoint( s) as described under this ECA are terminated. EPA may pursue testing for such endpoint( s) under the HAPs rulemaking, a new rulemaking , or develop a separate ECA for the purpose ofobtaining the needed data, as appropriate.

D. Other Possible Outcomes: If the EPA Program Review or Tier II endpoint testing and associated route to route extrapolations do not result in any ofthe outcomes DRAFT ECA for EDC 2/ 01 8 described above, EPA and the Companies may modify this ECA according to the procedures contained in 40 CFR 790.68 ( see Part X. ofthis ECA).

VIII. STANDARDS FOR CONDUCTING TESTING A. Testing for specific toxicity endpoints ( acute toxicity, neurotoxicity, and reproductive toxicity) must be conducted in accordance with the Test Standards listed in Table 1 and described in Appendix B( l 4) as annotated in Appendix D( 1 3) to this ECA. Certain provisions ofthese Test Standards are considered to be mandatory and are referred to as " requirements". These requirements are identified by the use ofthe word " shall" in the text ofthe Test Standard.

Provisions that are not mandatory, and are therefore only recommended, are identified by the use of " should" statements. In the event such " should" provisions are not followed, the Companies will not be deemed by EPA to be in violation ofthis ECA and will not be subject to penalties or other enforcement actions, as described in Part XI. ofthis ECA. However, in such cases, EPA will use its professional judgement to determine the scientific adequacy and validity of the test results and any repeat testing that is determined by EPA to be necessary will be required either under a separate ECA or pursuant to a rule promulgated under section 4( a) of TSCA, 15 U. S. C. 2603( a).

For the purpose ofthis ECA, the words " will" and " must," if they appear in the Test Standards, are considered equivalent to the word " shall" and therefore delineate a test requirement to be followed or met.

B. The development ofPK/ MECH data to be used in this ECA testing program must be conducted in accordance with the guidance outlined in Appendix C( l 4) ofthis ECA. The development and application ofPKIMECH data is expected to be an iterative process and, as such, the final details ofthe testing may not be included in the presently available Test Standard( s). For the purposes of this ECA, Appendix C( 1 4) will be the " Test Standard( s)" for testing specified in Table 1 under Tier I Program Review Testing and Tier II Route to Route Extrapolation Reporting. The PKIMECH data development under this ECA will be the subject of discussions at the EPA Program Review, described in Part VI. C. and Part VII. A.  D. ofthis ECA.

C. The Companies, through the HAP TASK FORCE, and EPA will consult in a good faith effort to consider the need for Test Standard modifications if either EPA or the Companies desire such modifications. Modifications to this ECA will be governed by 40 CFR 790.68 ( see Part X. of this ECA).

D. All testing required by this ECA must be conducted in accordance with the EPA Good Laboratory Practice ( GLP) Standards contained in 40 CFR part 792.

DRAFT ECA for EDC 2/ 01 9 E. All final reports must be submitted by the Companies to EPA by the dates specified in Table 1 unless otherwise authorized by EPA pursuant to 40 CFR 790.68. Interim status reports describing the status of all studies to be performed under this ECA testing program must be submitted by the Companies to EPA every six months beginning six months from the effective date ofthis ECA and until the end ofthe ECA testing program. These interim reports should contain information such as a summary of the interim status ofeach study being performed under this ECA testing program, a description of significant activities and/ or difficulties experienced during the interim, and an explanation of the actions taken in response to difficulties. See Part XIII. ofthis ECA regarding submissions to EPA.

IX. SUBMISSION OF STUDY PLANS The Companies, through the HAP TASK FORCE, will submit a study plan to EPA for each test conducted pursuant to this ECA prior to the initiation oftesting in accordance with 40 CFR 790.62. ( For this ECA, EPA will not require the study plans to be submitted " no later than 45 days prior to the initiation oftesting," as specified at 40 CFR 790.62( a)). The content ofthe study plans submitted to EPA will comply with 40 CFR 790.62( b). Modifications to the study plans will be governed by the procedures of40 CFR 790.62( c). All study plans will become part of the official record ( Docket Control Number OPPTS 42l97C).

X. MODIFICATIONS TO ENFORCEABLE CONSENT AGREEMENT EPA and the Companies recognize that in some instances modifications to the schedule in Table 1 may be needed in view of uncertainties in developing PKIMECH data. Modifications to this ECA, if any, will be made according to the procedures contained in 40 CFR 790.68.

XI. FAILURE TO COMPLY WITH THE ENFORCEABLE CONSENT AGREEMENT The Companies acknowledge that a violation ofthe requirements ofthis ECA will constitute a " prohibited act" under section 15( 1) of TSCA, 15 U. S. C. 2614( 1), and will trigger all provisions applicable to a section 15 violation. In addition, noncompliance with any term ofthis ECA by any Company will constitute conduct " in violation of this Act" under section 20( a)( 1) of TSCA, 15 U. S. C. 26l9( a)( l), and could result in a citizen's civil action.

Under the penalty provisions of section 16 ofTSCA, 15 U. S. C. 2615, and the Federal Civil Penalties Inflation Adjustment Act of 1990, 28 U. S. C. 2461 note, as amended by the Debt Collection Improvement Act of 1996, 31 U. S. C. 3701 note, as implemented by 61 FR 69360 ( December 31, 1996), a non complying Company could be subject to a civil penalty ofup to $ 27,500 per violation, with each day in violation potentially constituting a separate violation under section 15. Knowing or willful violations may lead to the imposition ofcriminal penalties,

DRAFT ECA for EDC 2/ 01 10 or a fine ofnot more than $ 27,500 for each day of violation, or imprisonment for not more than one year, or both. In addition, EPA could enforce this ECA pursuant to section 17 of TSCA, 15 U. S. C. 2616, by seeking an injunction to compel adherence to the requirements ofthis ECA.

XII. EPA MONITORING OF ENFORCEABLE CONSENT AGREEMENT TESTING EPA may conduct monitoring activities of the testing conducted under this ECA such as laboratory inspections and study audits, as permitted under section 11 ofTSCA, 15 U. S. C. 2610.

XIII. SUBMISSION OF DATA All data submitted to EPA under this ECA will be identified by the Docket Number: OPPTS 42197C and the name: ethylene dichloride. Six ( 6) copies ofall submissions under this ECA will be provided to EPA at the address specified in 40 CFR 790.5( b).

XIV. PUBLICATION AND DISCLOSURE OF TEST RESULTS All results oftesting conducted pursuant to this ECA will be announced to the public by EPA in accordance with the procedures specified in section 4( d) ofTSCA, 15 U. S. C. 2603( d). Disclosure by EPA of data generated by such testing will be governed by section 14( b) of TSCA, 15 U. S. C. 2613( b), and 40 CFRpart2.

XV. CONFIDENTIALITY OF INFORMATION Any claims ofconfidentiality for information submitted under this ECA will be made under the terms of40 CFR 790.7. If no claim of confidentiality is made by the submitter ofthe information at the time ofsubmission, the information will be deemed by EPA, in accordance with 40 CFR 790.7, to be public, and may be made available to the public without further notice to the submitter. Information claimed as confidential will be treated in accordance with the procedures in 40 CFR part 2 established pursuant to section 14 of TSCA, 15 U. S. C. 2613.

XVI. RESPONSIBILITIES OF THE COMPANIES A. The Companies are bound by the terms ofthis ECA and the provisions of40 CFR 790.62 and 790.65.

B. The Companies will comply with the notification requirements of section 12( b)( 1) of TSCA, 15 U. S. C. 2611( b)( 1), and 40 CFR part 707, subpart D, if they export or intend to DRAFT ECA for EDC 2/ 01 11 export ethylene dichloride. Any other person who exports or intends tO export ethylene dichloride will be subject to these export notification requirements upon promulgation ofan export notification rule for ethylene dichioride under section l2( b)( l) ofTSCA.

C. Ifethylene dichloride becomes subject to a rule promulgated under TSCA section 5( a)( 2), 15 U. S. C. 2604( a)( 2), governing significant new uses ofethylene dichloride, then the Companies will be subject to the data submission requirements imposed by section 5( b)( l)( A) of TSCA, 15 U. S. C. 2604( b)( l)( A), as if the testing under this ECA had been required by a TSCA section 4 test rule.

XVII. SEVERABILITY OF ENFORCEABLE CONSENT AGREEMENT PROVISIONS In the event that one or more provisions ofthis ECA are determined by a court decision to be unenforceable, the remaining provisions of this ECA will not be presumed to be valid, and EPA will either initiate a rulemaking proceeding to require testing or publish in the Federal Register the reasons for not initiating such a proceeding.

XVIII. FINAL AGENCY ACTION Issuance ofthis ECA by EPA constitutes final EPA action forpurposes of 5 U. S. C. 704.

XIX. PUBLIC RECORD EPA has established a public record which will contain this ECA, the Order that incorporates this ECA, the Federal Register notice announcing issuance ofthe Order incorporating this ECA, and any and all relevant information, subject to the confidentiality provisions of section 14( b) ofTSCA and 40 CFR part 2. The official record for this ECA, including the public version, which does not include any information claimed as CBI, has been established under docket control number OPPTS 42197C.

XX. EFFECTIVENESS This ECA may be signed in separate counterparts. This ECA will not be effective unless signed by each ofthe Companies and by EPA. This ECA will take effect on the date of publication ofthe Federal Register notice announcing the issuance of the Order that incorporates this ECA.

DRAFT ECA for EDC2/ 01 12 XXI. RIGHTS OF THE COMPANIES By signing this ECA, the Companies waive their right to challenge EPA's authority to assess penalties for violations of the terms ofthis ECA. This waiver does not affect any other rights that the Companies may have under TSCA, including the right to dispute the amount ofany penalty or to dispute factually whether a violation of the terms of this ECA has occurred, or to seek judicial review ofany rule that may be adopted by EPA that imposes requirements to test ethylene dichloride.

XXII. IDENTITY OF THE COMPANIES The Companies subject to this ECA are:

The Dow Chemical Co. Louisiana Hwy 1 P. O. Box 150 Plaquemine, LA 70765 Vulcan Materials Company 1200 Urban Center Drive Birmingham, AL35242 Occidental Chemical Corporation 5005 LBJ Freeway Dallas, TX 75244 Oxy Vinyls, LP Suite 500, LB3O 5005 LBJ Freeway Dallas, TX 75244 CONDEA Vista Company P. O. Box 19029 900 Threadneedle Houston, TX 77079 Georgia Gulf Corporation 26100 LA 45 Plaquemine, LA 70764 Westlake Chemical Corporation 2801 Post Oak Blvd. Suite 600 Houston, TX 77056 PPG Industries, Inc. One PPG Place Pittsburgh, PA 15272 Borden Chemicals & Plastics Operating Limited Partnership 180 E. Broad Street Columbus, OH 43215 Formosa Plastics Corporation, U. S. A. 9 Peach Tree Hill Road Livingston, NJ 07039 DRAFT ECA for EDC 2/ 01 Ii XXIII. SIGNATURE Date: TEST SPONSOR The Dow Chemical Company Roger L. Bowlin R& D Director for Chlorinated Organics The Dow Chemical Company Louisiana Hwy I P. O. Box 150 Plaquemine, LA70765 0150 DRAFT ECA for EDC 2/ 01 XXIII. SIGNATURE TEST SPONSOR Vulcan Materials Company Date: George L. Fish Vice President, Technical Vulcan Chemicals Division Vulcan Materials Company 1200 Urban Center Drive Birmingham, AL 35242 DRAFT ECA for EDC 2/ 01 XXIII. SIGNATURE Date: TEST SPONSOR Occidental Chemical Corporation Charles L. Mears Vice President & General Manager Electrochemicals Occidental Chemical Corporation 5005 LBJ Freeway Dallas, TX 75244 DRAFT ECA for EDC 2/ 01 XXIII. SIGNATURE Date: TEST SPONSOR CONDEA Vista Company P. L. Jernigan Vice President ofOperations CONDEA Vista Company P. O. Box 19029 900 Threadneedle Houston, TX 77079 DRAFT ECA for EDC 2/ 01 XXIII. SIGNATURE Date: TEST SPONSOR Georgia Gulf Corporation Edward A. Schmitt President and CEO Georgia Gulf Corporation 26100 LA 45 Plaquemine, LA 70764 DRAFT ECA for EDC 2/ 01 XXIII. SIGNATURE TEST SPONSOR Westlake Chemical Corporation Date: Wayne Morse Senior Vice President, Vinyls Westlake Chemical Corporation 2801 Post Oak Blvd., Suite 600 Houston, TX 77056 DRAFT ECA for EDC 2/ 01 XXIII. SIGNATURE Date: TEST SPONSOR PPG Industries, Inc.

James A. Barter, Ph. D. Director, Environmental Health Sciences PPG Industries, Inc. One PPG Place Pittsburgh, PA 15272 DRAFT ECA for EDC 2/ 01 XXIII. SIGNATURE Date: TEST SPONSOR Borden Chemicals & Plastics Operating Limited Partnership Wayne P. Leonard Executive Vice President & Chief Operating Officer Borden Chemicals & Plastics Operating Limited Partnership 180 E. Broad Street, Columbus, OH 43215 DRAFT ECA for EDC 2/ 01 XXIII. SIGNATURE Date: TEST SPONSOR Formosa Plastics Corporation, U. S. A.

Robert F. Kelly Vice President for Environment, Health, Safety and Communication Formosa Plastics Corporation, U. S. A. 9 Peach Tree Hill Road Livingston, NJ 07039 DRAFT ECA for EDC 2/ 01 XXIII. SIGNATURE Date: TEST SPONSOR Oxy Vinyls, LP Duane Stamp Vice President/ General Counsel Oxy Vinyls, LP Suite 500, LB3O 5005 LBJ Freeway Dallas, TX 752 44 DRAFT ECA for EDC 2/ 01 XXIV. SIGNATURE UNITED STATES ENVIRONMENTAL PROTECTION AGENCY Assistant Administrator Office ofPrevention, Pesticides, and Toxic Substances U. S. Environmental Protection Agency Office ofPollution Prevention And Toxic Substances Ariel Rios Building 1200 Pennsylvania Avenue, N. W. Washington, DC 20460 Date:

Address:

DRAFT ECA for EDC 2/ 01 Table 1 REQUIRED TESTING, TEST STANDARDS, REPORTING AND OTHER REQUIREMENTS FOR ETHYLENE DICHLORIDE i~ estSiantlard I) t~ atIline I( I ( citatiotis are t ° 40 ( °~ tot mat I ~ Testing f~. I~ I~( ~ alT attached to this ~ I (~ Jonths~

Acute Toxicity with BAL and histopathology ( inhalation) 2 Developmental Toxicity Number of months after the effective date of the Order that incorporates this ECA when final report is due.

Interim status reports, describing the status of all testing to be performed under this ECA, must be submitted by the Companies to EPA every 6 months beginning six months from the effective date of this ECA until the end of the ECA testing program ( see Part VIII. E. and Part XIII. of this ECA).

2 Acute toxicity and acute neurotoxicity testing to be conducted under a combined protocol following § 799.9 135 and § 799.9620 as annotated in appendixDl. As specified in Part VI. A. of this ECA, EPA has determined that the macrophage function assay reported by Sherwood et al. ( 1987) adequately fulfills the rnacrophage function assay portion of the acute toxicity testing requirement. A copy of this report is included as Appendix El.

~ As specified in Part VI. A. of this ECA, EPA has determined that the developmental toxicity studies reported by Payan etal. ( 1995), in rats, and Rao eta 1 . ( 1980), in rabbits, adequately fulfill the HAPs rulemaking testing requirement for developmental toxicity testing for ethylene dichloride. A copy of these reports is included as Appendix E. 3. § 799.9135 ( as annotated in appendix D. 1) 18?

AcuteNeurotoxicity ( inhalation) 2 § 799.9620 ( as annotated in appendix D. l) 18?

Appendix E. 33 DRAFT ECA for EDC 2/ 01 TIER I Test Standard Deadline Program Review Testing ( citations are to 40 CFR; for Final for EDC4 appendices are attached to this ECA) Report ( Months)

PK/ MECH data to support model validation and verification oforalto inhalation extrapolation for the following data needs in the F344 rat~: a. Subchronic toxicity6 Appendix C ( 1 4) 15? a.. Subchronic Neurotoxicity7 b. Reproductive toxicity8 PBPK model simulations9 Appendix C ( 1 5) 24?

As described in Part VI. C. of this ECA, before work under the Tier II testing segment is conducted, EPA will conduct a Program Review of the Tier I Program Review Testing data and data from other studies acceptable to EPA that could be used in performing quantitative route to route extrapolations.

~ Previously published inhalation PBPK model ( Gargas et al., 1989; 1990) to be extended and validated to ( 1) periodic inhalation exposures based on PKJ'MECH data to be acquired as part ofthe Tier I Inhalation Toxicity' and ( 2) oral administration via corn oil gavage and drinking water.

6 Relevant to existing data in rats administered EDC via corn oil gavage ( Daniel, et al. ( 1994)

Relevant to drinking water administration in rats 8 Relevant to drinking water administration and capable to inform route to route extrapolation from each dosing paradigm of extant data by Alumot, et a!. ( 1976), Rao, et al. ( 1980), and Lane, et a!. ( 1982)

~ The model simulations are to provide 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 dependent metabolism) in rats and humans to allow quantitative route to route extrapolations. These simulations will be used to evaluate the acceptability of: ( 1) subchronic neurotoxicity testing of oral exposure via drinking water in rats; ( 2) extant oral subchronic toxicity data of Daniel et a!. ( 1994) in rats via corn oil gavage, and ( 3) reproductive toxicity testing of oral exposure via drinking water in rats.

DRAFT ECA for EDC 2/ 01 Tier II Testing and/ or Extrapolation Reporting for EDC Test Standard ( citations are to 40 CFR; appendices are attached to this ECA) Deadline for Final Report ( Months)

Subchronic toxicity ( route toroute extrapolation ofextant data)' ° Appendix C. 2 and C. 6 39?

Subchronic neurotoxicity: a) testing by the oral route § 799.9620 ( as annotated in Appendix D. 2) 42?

b) route to route extrapolation1' Appendix C. 3 and C. 6 45?

Reproductive toxicity:' 2 a) testing by the oral route § 799.9380 ( as annotated in Appendix D. 3) 54?

b) route to route extrapolation' 3 Appendix C. 4 and C. 6 57?

10 Quantitative route to route extrapolation of extant data of Daniel et al. ( 1994) documented graphically and with tabular data using point estimates and uncertainty measures for parent compound ( peak and AUC) and total amount metabolized by glutathione dependent pathways to develop the dose metric.

~ Quantitative route to route extrapolation of subchronic toxicity testing developed under Tier II Testing,

documented graphically and with tabular data using point estimates and uncertainty measures for parent compound ( peak and AUC) in blood and brain and total amount metabolized by glutathione dependent pathways to develop the dose metric. Ability to characterize blood and CNStime course data, if possible, for both oral and inhalation routes must be demonstrated.

12 Control and high dose groups will be evaluated for fertility index, gestation index, gross necropsy, organ weight and histopathology to confirm lack of effect reported in extant studies by Alumot eta!., 1976; Rao et a!., 1980; and Lane et a!., 1982. Observation of an effect in the high dose will trigger detailed evaluation of low dose and mid dose groups for the above mentioned effects. Estrous cycle, sperm evaluation ( vaginal opening, preputial separation) will be evaluated for all dose groups.

~ Quantitative route to route extrapolation of reproductive toxicity testing developed under Tier II Testing and extant data from Alumot, et a!. ( 1976), Rao, eta!. ( 1980), and Lane, et ci!. ( 1982) documented graphically and with tabular data using point estimates and uncertainty measures for parent compound ( peak and AUC) and total amount metabolized by glutathione dependent pathways to develop the dose metric.

DRAFT ECA for EDC 2/ 01 APPENDIX A FLOW CHART OF TESTING PROGRAM *

* To be provided by the HAP Task Force DRAFT ECA for EDC 2/ 01 APPENDIX B ( 1 4)

TSCA Guidelines with Annotations as Appropriate *

* To be provided by the HAP Task Force DRAFT ECA for EDC 2/ 01 APPENDIX C ( 1 5)

PKIMECH Procedures and Route to Route Extrapolation Reporting *

* To be provided by the HAP Task Force DRAFT ECA for EDC 2/ 01 APPENDIX C. 6 General Outline for Route to Route Extrapolation Reporting for EDC A total of three route to route extrapolation reports will be generated for EDC, one for each of the following endpoints: subchronic toxicity, subchronic neurotoxicity, and reproductive toxicity. At a minimum, each of these reports will follow the general outline presented below.

1.0. Introduction Statement of objectives for specific endpoint route to route extrapolation relevant to the HAPs testing for EDC Application ofthe PBPK Model for EDC relevant to specific endpoint 2.0. Summary of Key Study( ies) For subchronic toxicity, the design and results of Daniel et al. ( 1994) will be summarized relevant to the route to route extrapolation and results from Tier I Program Review Testing.

For subchronic neurotoxicity, the design and results of the Tier II testing will be summarized relevant to the route to route extrapolation and results from Tier I Program Review Testing.

For reproductive toxicity, the design and results ofthe Tier II testing will be summarized and the design and results ofAlumot et al. ( 1976), Rao et al. ( 1980), and Lane et al. ( 1982) will be summarized relevant to the route to route extrapolation and results from Tier I Program Review Testing.

3.0. Selection of Critical Endpoint( s) and Dose Measure( s)

For subchronic toxicity, subchronic neurotoxicity, and reproductive toxicity, the endpoints and dose measures will be determined from the Tier II testing.

4.0 Route to Route Extrapolation Results Quantitative calculation ofinhalation NOAEL / LOAEL values for corresponding oral values 5.0. Sensitivity Analysis Assessment ofthe contribution of variability/ uncertainty in each parameter to PK modeling results 6.0 Conclusions 7.0 References DRAFT ECA for EDC 2/ 01 APPENDIX D ( 1 3)

STUDY PROTOCOLS *

* To be provided by the HAP Task Force DRAFT ECA for EDC 2/ 01 APPENDIX E ( 1 4)

EXISTING TOXICITY STUDIES *

* To be provided by the HAP Task Foi ce DRAFT ECA for EDC 2/ 01


[Federal Register Volume 77, Number 12 (Thursday, January 19, 2012)]
[Proposed Rules]
[Pages 2658-2659]
[FR Doc No: 2012-854]

========================================================================
Proposed Rules
                                                Federal Register
________________________________________________________________________

This section of the FEDERAL REGISTER contains notices to the public of
the proposed issuance of rules and regulations. The purpose of these
notices is to give interested persons an opportunity to participate in
the rule making prior to the adoption of the final rules.

========================================================================

Federal Register / Vol. 77, No. 12 / Thursday, January 19, 2012 /
Proposed Rules

DEPARTMENT OF TRANSPORTATION

Federal Aviation Administration

14 CFR Part 39

[Docket No. FAA-2011-1418; Directorate Identifier 2011-NM-187-AD]
RIN 2120-AA64

Airworthiness Directives; Bombardier, Inc. Airplanes

AGENCY: Federal Aviation Administration (FAA), DOT.

ACTION: Notice of proposed rulemaking (NPRM).

-----------------------------------------------------------------------

SUMMARY: We propose to adopt a new airworthiness directive (AD) for
certain Bombardier, Inc. Model DHC-8-400 series airplanes. This
proposed AD was prompted by chafing on high pressure fuel lines due to
improper installation of an expandable pin on the lower cowl assembly.
This proposed AD would require installing spring clips and
repositioning the lanyard attachment points at the forward end and the
forward firefloor of the lower cowl. We are proposing this AD to
prevent chafing of the high pressure fuel lines, which if not
corrected, could cause fuel leakage in a fire zone.

DATES: We must receive comments on this proposed AD by March 5, 2012.

ADDRESSES: You may send comments by any of the following methods:
     Federal eRulemaking Portal: Go to http://www.regulations.gov. Follow the instructions for submitting comments.
     Fax:<PHONE_NUMBER>.
     Mail: U.S. Department of Transportation, Docket
Operations, M-30, West Building Ground Floor, Room W12-140, 1200 New
Jersey Avenue SE., Washington, DC 20590.
     Hand Delivery: U.S. Department of Transportation, Docket
Operations, M-30, West Building Ground Floor, Room W12-140, 1200 New
Jersey Avenue SE., Washington, DC, between 9 a.m. and 5 p.m., Monday
through Friday, except Federal holidays.
    For service information identified in this proposed AD, contact
Bombardier, Inc., Q-Series Technical Help Desk, 123 Garratt Boulevard,
Toronto, Ontario M3K 1Y5, Canada; telephone<PHONE_NUMBER>; fax (416)
375-4539; email<EMAIL_ADDRESS>Internet http://www.bombardier.com. You may review copies of the referenced service
information at the FAA, Transport Airplane Directorate, 1601 Lind
Avenue SW., Renton, Washington. For information on the availability of
this material at the FAA, call<PHONE_NUMBER>.

Examining the AD Docket

    You may examine the AD docket on the Internet at http://www.regulations.gov; or in person at the Docket Operations office
between 9 a.m. and 5 p.m., Monday through Friday, except Federal
holidays. The AD docket contains this proposed AD, the regulatory
evaluation, any comments received, and other information. The street
address for the Docket Operations office (telephone<PHONE_NUMBER>) is
in the ADDRESSES section. Comments will be available in the AD docket
shortly after receipt.

FOR FURTHER INFORMATION CONTACT: Mazdak Hobbi, Aerospace Engineer,
Propulsion and Services Branch, ANE-173, FAA, New York Aircraft
Certification Office, 1600 Stewart Avenue, Suite 410, Westbury, NY
11590; telephone<PHONE_NUMBER>; fax<PHONE_NUMBER>.

SUPPLEMENTARY INFORMATION:

Comments Invited

    We invite you to send any written relevant data, views, or
arguments about this proposed AD. Send your comments to an address
listed under the ADDRESSES section. Include ``Docket No. FAA-2011-1418;
Directorate Identifier 2011-NM-187-AD'' at the beginning of your
comments. We specifically invite comments on the overall regulatory,
economic, environmental, and energy aspects of this proposed AD. We
will consider all comments received by the closing date and may amend
this proposed AD based on those comments.
    We will post all comments we receive, without change, to http://www.regulations.gov, including any personal information you provide. We
will also post a report summarizing each substantive verbal contact we
receive about this proposed AD.

Discussion

    Transport Canada Civil Aviation (TCCA), which is the aviation
authority for Canada, has issued Canadian Airworthiness Directive CF-
2011-21, dated July 12, 2011 (referred to after this as ``the MCAI''),
to correct an unsafe condition for the specified products. The MCAI
states:

    During routine maintenance, an operator discovered evidence of
chafing on a high pressure (HP) fuel line. The source of chafing was
related to the improper installation of an expandable pin on the
lower cowl assembly, which caused the lanyard to foul against the HP
fuel line. This condition, if not corrected, may cause fuel leakage
in a fire zone.
    Bombardier has issued Service Bulletin (SB) 84-71-13 to
introduce spring clips to positively retain and control the
lanyards, regardless of the installation orientation of the
expandable pin to rectify this problem.

    You may obtain further information by examining the MCAI in the AD
docket.

Relevant Service Information

    Bombardier has issued Service Bulletin 84-71-13, dated May 19,
2011. The actions described in this service information are intended to
correct the unsafe condition identified in the MCAI.

FAA's Determination and Requirements of This Proposed AD

    This product has been approved by the aviation authority of another
country, and is approved for operation in the United States. Pursuant
to our bilateral agreement with the State of Design Authority, we have
been notified of the unsafe condition described in the MCAI and service
information referenced above. We are proposing this AD because we
evaluated all pertinent information and determined an unsafe condition
exists and is likely to exist or develop on other products of the same
type design.

Costs of Compliance

    Based on the service information, we estimate that this proposed AD
would affect about 83 products of U.S. registry. We also estimate that
it would take about 3 work-hours per product to comply with the basic
requirements of this proposed AD. The average labor rate is $85 per
work-hour. Required

parts would cost about $19 per product. Where the service information
lists required parts costs that are covered under warranty, we have
assumed that there will be no charge for these parts. As we do not
control warranty coverage for affected parties, some parties may incur
costs higher than estimated here. Based on these figures, we estimate
the cost of the proposed AD on U.S. operators to be $22,742, or $274
per product.

Authority for This Rulemaking

    Title 49 of the United States Code specifies the FAA's authority to
issue rules on aviation safety. Subtitle I, section 106, describes the
authority of the FAA Administrator. ``Subtitle VII: Aviation
Programs,'' describes in more detail the scope of the Agency's
authority.
    We are issuing this rulemaking under the authority described in
``Subtitle VII, Part A, Subpart III, Section 44701: General
requirements.'' Under that section, Congress charges the FAA with
promoting safe flight of civil aircraft in air commerce by prescribing
regulations for practices, methods, and procedures the Administrator
finds necessary for safety in air commerce. This regulation is within
the scope of that authority because it addresses an unsafe condition
that is likely to exist or develop on products identified in this
rulemaking action.

Regulatory Findings

    We determined that this proposed AD would not have federalism
implications under Executive Order 13132. This proposed AD would not
have a substantial direct effect on the States, on the relationship
between the national Government and the States, or on the distribution
of power and responsibilities among the various levels of government.
    For the reasons discussed above, I certify this proposed
regulation:
    1. Is not a ``significant regulatory action'' under Executive Order
12866;
    2. Is not a ``significant rule'' under the DOT Regulatory Policies
and Procedures (44 FR 11034, February 26, 1979);
    3. Will not affect intrastate aviation in Alaska; and
    4. Will not have a significant economic impact, positive or
negative, on a substantial number of small entities under the criteria
of the Regulatory Flexibility Act.
    We prepared a regulatory evaluation of the estimated costs to
comply with this proposed AD and placed it in the AD docket.

List of Subjects in 14 CFR Part 39

    Air transportation, Aircraft, Aviation safety, Incorporation by
reference, Safety.

The Proposed Amendment

    Accordingly, under the authority delegated to me by the
Administrator, the FAA proposes to amend 14 CFR part 39 as follows:

PART 39--AIRWORTHINESS DIRECTIVES

    1. The authority citation for part 39 continues to read as follows:

    Authority:  49 U.S.C. 106(g), 40113, 44701.

Sec.  39.13  [Amended]

    2. The FAA amends Sec.  39.13 by adding the following new AD:

Bombardier, Inc.: Docket No. FAA-2011-1418; Directorate Identifier
2011-NM-187-AD.

(a) Comments Due Date

    We must receive comments by March 5, 2012.

(b) Affected ADs

    None.

(c) Applicability

    This AD applies to Bombardier, Inc. Model DHC-8-400, -401, and -
402 airplanes; certificated in any category; serial numbers 4001,
4003 through 4354 inclusive; and 4356 through 4363 inclusive.

(d) Subject

    Air Transport Association (ATA) of America Code 71: Power Plant.

(e) Reason

    This AD was prompted by chafing on high pressure fuel lines due
to improper installation of an expandable pin on the lower cowl
assembly. We are issuing this AD to prevent chafing of the high
pressure fuel lines, which if not corrected, could cause fuel
leakage in a fire zone.

(f) Compliance

    You are responsible for having the actions required by this AD
performed within the compliance times specified, unless the actions
have already been done.

(g) Actions

    Within 6,000 flight hours or 36 months after the effective date
of this AD, whichever occurs first, install new or serviceable
spring clips and re-position the lanyard attachment points, in
accordance with the Accomplishment Instructions of Bombardier
Service Bulletin 84-71-13, dated May 19, 2011.

(h) Other FAA AD Provisions

    The following provisions also apply to this AD:
    (1) Alternative Methods of Compliance (AMOCs): The Manager, New
York Aircraft Certification Office (ACO), ANE-170, FAA, has the
authority to approve AMOCs for this AD, if requested using the
procedures found in 14 CFR 39.19. In accordance with 14 CFR 39.19,
send your request to your principal inspector or local Flight
Standards District Office, as appropriate. If sending information
directly to the ACO, send it to ATTN: Program Manager, Continuing
Operational Safety, FAA, New York ACO, 1600 Stewart Avenue, Suite
410, Westbury, New York 11590; telephone<PHONE_NUMBER>; fax (516)
794-5531. Before using any approved AMOC, notify your appropriate
principal inspector, or lacking a principal inspector, the manager
of the local flight standards district office/certificate holding
district office. The AMOC approval letter must specifically
reference this AD.
    (2) Airworthy Product: For any requirement in this AD to obtain
corrective actions from a manufacturer or other source, use these
actions if they are FAA-approved. Corrective actions are considered
FAA-approved if they are approved by the State of Design Authority
(or their delegated agent). You are required to assure the product
is airworthy before it is returned to service.

(i) Related Information

    Refer to MCAI Canadian Airworthiness Directive CF-2011-21, dated
July 12, 2011; and Bombardier Service Bulletin 84-71-13, dated May
19, 2011; for related information.

    Issued in Renton, Washington, on January 6, 2012.
Ali Bahrami,
Manager, Transport Airplane Directorate, Aircraft Certification
Service.
[FR Doc. 2012-854 Filed 1-18-12; 8:45 am]
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